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WO1998013364A1 - Derives de 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline ou compositions medicinales obtenues - Google Patents

Derives de 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline ou compositions medicinales obtenues Download PDF

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Publication number
WO1998013364A1
WO1998013364A1 PCT/JP1997/003378 JP9703378W WO9813364A1 WO 1998013364 A1 WO1998013364 A1 WO 1998013364A1 JP 9703378 W JP9703378 W JP 9703378W WO 9813364 A1 WO9813364 A1 WO 9813364A1
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Prior art keywords
lower alkyl
piperidyl
salt
group
compound
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PCT/JP1997/003378
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English (en)
Japanese (ja)
Inventor
Toshihiro Watanabe
Akio Kakefuda
Noriyuki Masuda
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU43197/97A priority Critical patent/AU4319797A/en
Publication of WO1998013364A1 publication Critical patent/WO1998013364A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a pharmaceutical, particularly a novel 2- (3-piperidyl) 1-1,2,3,4-tetrahydroisoquinoline derivative or a salt thereof having an If current-inhibiting action, and a pharmaceutically acceptable derivative thereof. It relates to a pharmaceutical composition containing an acceptable carrier.
  • adenosine receptor agonists in the former, M 2 muscarinic receptor agonists and ⁇ adrenergic A typical example is a receptor antagonist, and the latter is a calcium channel inhibitor.
  • Such heart rate-lowering drugs may be used for various clinical symptoms resulting from an imbalance between the supply and demand of oxygen in the heart muscle, for example, angina, ischemic heart disease such as myocardial infarction, or arrhythmia, heart failure. It has been confirmed that it is useful as a preventive and therapeutic agent for cardiovascular diseases such as cardiovascular diseases.
  • ischemic heart disease eg, angina pectoris, myocardial infarction, etc.
  • cardiovascular diseases arrhythmia, heart failure, etc.
  • it is also useful in controlling an excessively increased heart rate and maintaining a constant heart rate during an operation using anesthesia.
  • Zatebradine which is known as a compound having a heart rate lowering effect, is based on the action of inhibiting If current.
  • Zatebradme causes visual impairment with a heart rate lowering effect (William H. Frishman, J. Am. Coll. Cardiol, 26: 305-312, 1995; Stephen P. Glasser et al. al., The American Journal of Cardiology, 79: 1401-1405, 1997).
  • Ih current a current having properties similar to the If current exists in photoreceptors (Shaul Hestrin, J. Physiol. 39 319-333, 1987). At the same time, it is expected that such visual impairment will occur because it also inhibits the Ih current.
  • A is one CH2-CH2-, one CH-CH-, etc.
  • B is methylene, carbonyl or thiocarbonyl
  • E is a straight-chain alkylene having 1 to 3 carbon atoms and optionally substituted with alkyl having 1 to 3 carbon atoms,
  • n is a number of 0, 1 or 2, but n + m must be 3, 4 or 5.
  • B is one CH2-, one CH2-CH2-, one CO- or one CH2-C ⁇ ,
  • E is a straight-chain alkylene having 1 to 3 carbon atoms and optionally substituted with alkyl having 1 to 3 carbon atoms,
  • n represents the number 0, 1, 2 or 3, but n + m must represent 3, 4, 5 or 6.
  • the present inventors have conducted intensive studies on the above-mentioned agents that suppress the If current, and as a result, a series of compounds represented by the following general formula (I) suppresses the If current and has a heart rate lowering effect in the heart. The inventors have found that the present invention has been completed and completed the present invention.
  • the present invention relates to a 2- (3-piperidyl) -1,2,3,4-dihydrohydroquinoline derivative represented by the following general formula (I) or a salt thereof.
  • R ', R 2 the same or different and represent a hydrogen atom, a halogen atom, hydroxy, lower alkyl, halogeno-lower alkyl, lower alkyl - 0-, nitro, Shiano, Ami's O Kiso pyrrolidinylmethyl, lower alkyl -0- CO - NH -, lower alkyl - CO-NH- or lower alkyl - S02-NH - group, or R 'and became R 2 guard member - 0 - form 0-group, - lower alkylene
  • R 3 , R 4 each form a hydrogen atom or an oxo group in which R 3 and R 4 are
  • Ring B an optionally substituted hydrocarbon ring group or an optionally substituted heterocyclic group which may be condensed with benzene, and so on
  • Particularly preferred compounds of the compound (I) of the present invention include a 2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative in which R 3 and R 4 form an integrated oxo group or Its salt;
  • Ring B is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl, lower alkyl-O-, nitro, cyano, aminooxopyrrolidinyl, lower alkyl-O-CO-NH-, lower alkyl-CO-NH- Lower alkyl-S02-NH- and -0-lower alkylene-0-phenyl optionally substituted with 1 to 3 substituents, phenyl, naphthyl, indanyl, 1,2,3,4- ⁇ Trahydronaphthyl, furyl, phenyl, pyridyl, 2,3-dihydro-3-oxobenzofuranyl or 2,3-dihydrid 2- (3-piperidyl) -1,2,1-H-indolyl group 3,4-tetrahydroisoquinoline derivative or a salt thereof; 2- (3-piperidyl) -1,2,3,4-pentahydroisoquinoline derivative or salt thereof where
  • R ′ and R 2 are lower alkyl-0-groups, and ring B is phenyl optionally substituted with one or two substituents selected from lower alkyl-0-, methylenedioxy and ethylenedioxy groups.
  • substituents selected from lower alkyl-0-, methylenedioxy and ethylenedioxy groups.
  • R ', R 2 force ⁇ a methoxy group and phenyl which is optionally substituted on ring B with one or two substituents selected from methoxy, ethoxy, methylenedioxy and ethylenedioxy groups.
  • Particularly preferred compounds are 6,7-dimethoxy-2- ⁇ 1- [3- (3,4-methylenedioxyphenoxy) propyl] -3-piperidyl 1,2,3,4-tetrahydroisoquinoline or Its salt,
  • a pharmaceutical composition containing a 2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative of the compound (I) of the present invention or a salt thereof, and particularly a pharmaceutically acceptable carrier,
  • the present invention relates to a pharmaceutical composition which is a current inhibitor, and more particularly to a pharmaceutical composition which is a heart rate lowering agent.
  • the compound (I) of the present invention has a structural feature in that the nitrogen atom of the 1,2,3,4-tetrahydroisoquinoline ring and the carbon atom at the 3-position of the piperidine ring are directly bonded.
  • the structure differs from the patent application compound described in the background art particularly in the above point.
  • the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.
  • lower alkyl group in the present specification include, for example, a methyl group, an ethyl group, and a linear or branched propyl, butyl, pentyl and hexyl group. It is preferably an alkyl having 1 to 4 carbon atoms, and particularly preferably a methyl, ethyl, propyl and isopropyl group.
  • the “lower alkylene group” is a divalent group obtained by removing any hydrogen atom from the above “lower alkyl group”, preferably an alkylene group having 1 to 4 carbon atoms, and particularly preferably methylene and ethylene. , Propylene and butylene groups.
  • the lower alkylene represented by the group A in the general formula is preferably an ethylene or propylene group.
  • the hydrocarbon ring group of the “optionally substituted hydrocarbon ring group” is a saturated or unsaturated, monocyclic or condensed hydrocarbon ring group, preferably a aryl group or a cycloalkyl group. .
  • the “aryl group” is an aryl group having 6 to 14 carbon atoms, specifically, phenyl, dolyl, xylyl, biphenyl, naphthyl, indenyl, anthryl and phenanthryl groups. And dihydro, trihydro, and tetrahydro forms in which a hydrogen atom has been added to any carbon atom of the thiol group.
  • phenyl, naphthyl or 1,2,3,4-ditrahydronaphthyl group particularly preferred is phenyl or 1,2,3,4-tetrahydronaphthyl group.
  • cycloalkyl group a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl group having 3 to 8 carbon atoms are preferable.
  • the ⁇ heterocyclic group which may be substituted and which may be condensed with a benzene ring '' ⁇ the heterocyclic group which may be condensed with a benzene ring '' means that a benzene ring is condensed with the heterocyclic group described below. It is a cyclic group or an uncondensed heterocyclic group.
  • ring group J in which a benzene ring is condensed to a heterocyclic group include quinolyl, isoquinolyl, quinazolinyl, quinolizinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl and 1,2-benzoisoxyl.
  • Means condensed heteroaryl groups such as sazolyl, benzoyloxazolyl, benzothiazolyl, oxazolopyridyl, isothiazolopyridyl, and benzochenyl, and 2,3-dihydro-1H-indole and 3-oxo-benzofuranyl. And the like.
  • 2,3-dihydro - a base Nzofuraniru group - 1 H - indole, 3-year old Kiso.
  • heterocyclic group a heteroatom consisting of an oxygen atom, a sulfur atom or a nitrogen atom is It means a heteroaryl group or a saturated heterocyclic group containing up to four, and the heteroaryl group is preferably a 5- or 6-membered group, furyl, chenyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, Examples include monocyclic heteroaryl groups such as isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, virazyl, triazolyl and tetrazolyl groups, and bicyclic heteroaryl groups such as naphthyridinyl group. Preferred are furyl, phenyl and pyridyl groups.
  • the “saturated heterocyclic group” is preferably a 5- to 7-membered ring. Specific examples include a pyrrolidinyl, imidazolidinyl, virazolidinyl, piperidyl, piperazinyl, and morpholinyl group, and a piperidyl group is preferable.
  • the substituent of the ⁇ hydrocarbon ring group which may be substituted '' and the ⁇ heterocyclic group which may be S-substituted or optionally condensed '' is a group which can be usually substituted on these ring groups. Any may be used.
  • halogen atom lower alkyl, lower alkenyl, lower alkynyl, hydroxy, mercapto, halogeno lower alkyl, lower alkyl-0-, lower alkyl-S-, lower alkyl-0-CO-, carboxy, sulfonyl, sulfinyl, Lower alkyl-SO 2- , lower alkyl- S0-, lower alkyl-C0-, lower alkyl-GO-0-, levamoyl, lower alkyl-NH-CO-, di-lower alkyl-N-C0-, nitro, Lower alkyl-NH-, di-lower alkyl-N- and -0-lower alkylene-0- groups.
  • substituents may be substituted with one or more, preferably one to three.
  • the “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl, 1-probenyl, 2-propenyl (aryl), butyl Nyl, pentenyl and hexenyl groups.
  • the lower alkynyl group J is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, and specific examples include ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups.
  • Halogen atom means a fluorine atom, chlorine atom, bromine atom or iodine atom
  • halogeno lower alkyl group means a group in which any hydrogen atom of the above lower alkyl group is substituted by a halogen atom.
  • the compound (I) of the present invention has at least one asymmetric carbon atom, and there are optical isomers such as (R) -form and (S) -form, racemic forms, diastereomers and the like based on this. Further, depending on the type of the S-substituent, a geometric isomer or a tautomer exists.
  • the present invention includes all separated or mixtures of these isomers.
  • the compound (I) of the present invention may form a salt with an acid.
  • Such salts include mineral acids with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid can be mentioned. Further, the present invention also includes hydrates of compound (I), solvates such as ethanol, and yarns;
  • the compound (I) of the present invention can be produced by applying various production methods. Hereinafter, a typical manufacturing method will be described.
  • R 1, R 2, R 3, R 4, A, B ring and X are as defined above.
  • a ' represents a single bond or a carbon number C, and alkylene groups of ⁇ 5.
  • Z is This represents a leaving group or a halogen atom of hydroxy.
  • the production method of the compound of the present invention is based on the perhydroisoquinoline compound represented by the general formula (II) or any one of the methods A, B and C. This is a method for obtaining (I). The three cases, Method A, Method B, and Method C, are described below.
  • This reaction is a reaction using a base such as compound (III).
  • This reaction is carried out without solvent or in a solvent.
  • the compound (11) and the compound (III) are used in an equimolar amount to an excess molar amount of the compound (III), and the reaction temperature varies depending on the type of the reaction compound and is appropriately set. For some compounds, it may be advantageous to carry out the reaction in the presence of a base.
  • Solvents include solvents that are advantageous for the reaction and inert solvents.
  • the inert solvent include pyridin, tetrahydrofuran, dioxane, ether, N, N-dimethylformamide, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, ethyl acetate, and acetonitrile.
  • it is acetonitrile.
  • the base examples include organic bases such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, and N-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide. Is mentioned. Note that pyridin can also serve as a solvent.
  • Examples of the leaving group for hydroxy include mesyl, tosyl, and trifluoromethanesulfonyl group.
  • This reaction is a reaction using a reductive amination reaction.
  • This reaction is a method in which compound (IV) is appropriately dissolved in the above solvent, reacted with amine of compound (III), and the resulting Schiff base is isolated or not, and then the Schiff base is reduced. is there.
  • compound (IV) and compound (II) are used in an amount corresponding to the reaction or in a slightly excessive amount, preferably in the presence of an acid catalyst such as p-toluenesulfonic acid, adipic acid, oxalic acid, pyridine hydrochloride, and diacid.
  • an acid catalyst such as p-toluenesulfonic acid, adipic acid, oxalic acid, pyridine hydrochloride, and diacid.
  • the reaction may be performed by adding a hygroscopic agent such as potassium hydroxide or molecular sieves, or by using a Dean-Stark trap (azeotropic dehydrator) to remove the generated water.
  • a hygroscopic agent such as potassium hydroxide or molecular sieves
  • azeotropic dehydrator azeotropic dehydrator
  • the reduction of the resulting Schiff base is carried out by adding a metal hydride complex (sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) Or by adding a reducing agent such as borane.
  • a metal hydride complex sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.
  • a reducing agent such as borane.
  • This reaction is a reaction in which the compound (II) is reacted with a carboxylic acid represented by the general formula (V) or a derivative thereof, and further, a reduction reaction is used.
  • This reaction is carried out without a solvent or in the solvent described above, using an equimolar amount of the compound (11) or the compound (V) or an excess amount of the compound (V) to obtain a compound (VI).
  • the reaction temperature varies depending on the type of reaction compound. And it is set appropriately.
  • Examples of the reactive derivative of compound (V) include acid halides such as acid chloride and acid bromide; acid azides; active esters with N-hydroxybenzotriazole (HOB), P-ditrophenyl ⁇ N-hydroxysuccinimide and the like. Symmetric acid anhydrides; mixed acid anhydrides with alkyl carbonic acid, p-toluenesulfonic acid, and the like.
  • the above reduction reaction is carried out in the above inert solvent under cooling to room temperature, at room temperature to heating (reflux), using a reducing agent such as the metal hydride complex of the above-mentioned Method B or borane.
  • a reducing agent such as the metal hydride complex of the above-mentioned Method B or borane.
  • This production method is a method for obtaining a compound (la) of the present invention by a reductive amination reaction of a tetrahydroisoquinoline compound represented by the general formula (VII) with a oxopiperidine compound represented by the general formula (VIII).
  • the reductive amination reaction is the same as in the first method B, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the first method B.
  • R ′ represents an acyl-protecting group, specifically, a lower alkyl or benzyl group
  • Ra represents a hydroxy group. And specifically a lower alkyl group.
  • This production method comprises reacting compound (IX) with compound (X), further obtaining a compound of the present invention (lb) by a cyclization reaction, and optionally performing a reduction reaction to obtain a compound of the present invention (ia). It is.
  • the reaction is carried out in the above-mentioned inert solvent under cooling to room temperature, at room temperature to heating (reflux), using an equimolar amount of each of compound (IX) and compound (X) or an excess mole of compound (X). In some cases, it is advantageous to carry out the reaction in the presence of the base described in the first production method, if desired.
  • the cyclization reaction is performed in the above inert solvent in the presence of an acid. Acids used in this reaction include polyphosphoric acid (PPA), phosphorus oxychloride (POCI 3 ), anhydrous J-fluoroacetic acid-dimethylaminopyridine (J. Chem. Soc. Ghem. Commum. 2551-2553 (1995)). And the like.
  • the reduction reaction to be carried out as desired is the same as in the first production method C, and the conditions such as the reaction solvent and the reaction temperature are the same as in the above production method.
  • the compound (XII) is reacted with the compound (XIII), and the compound (lb) of the present invention is further obtained by 1) cyclization reaction and 2) reduction reaction. This is a method for obtaining compound (la).
  • the acylation reaction and the optional reduction reaction are performed in the same manner as in the third production method A, and the conditions such as the reaction solvent and the reaction temperature are also the same as those in the above production method.
  • the cyclization reaction is performed in the above-mentioned inert solvent in the presence of hydrochloric acid, a mixed solution of acetic acid-monohydrochloric acid, a mixed solution of acetic acid-monosulfuric acid, trifluoroacetic acid and the like.
  • R 1 , R 2 , R 3 R 4 , A, A ′, a ring and X have the above-mentioned meanings.
  • ⁇ represents a hydroxy or mercapto group.
  • the compound represented by the general formula (XVI) is obtained by a reductive amination reaction using the compound (II) and the aldehyde of the compound (XV), and further represented by the compound (XVI) and the general formula (XVII)
  • the reductive amination reaction is the same as in the first production method, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the above production method.
  • the reaction of the compound (XVI) with the compound (XVII) is carried out in the above-mentioned inert solvent under cooling to room temperature, at room temperature to heating (reflux), and the compound (XVI) and the compound (XVI I) are each equimolar to the compound. (XVII) using an excess molar amount, and if desired, i) the base described in the first production method, or ⁇ ) an interlayer transfer catalyst (for example, a quaternary ammonium salt crown such as tetrabutylammonium bromide). It may be advantageous to carry out the reaction in the presence of alcohols.
  • an interlayer transfer catalyst for example, a quaternary ammonium salt crown such as tetrabutylammonium bromide. It may be advantageous to carry out the reaction in the presence of alcohols.
  • R 1 and R 2 have the meanings given above.
  • R ′′ ′ represents an amino protecting group.
  • This production method is a method of condensing compound (VII) and compound (XVIII) with oxopiperidine according to a conventional method to obtain a raw material compound (lla).
  • the synthesis of the starting compound Ola) is the same as in the reductive amination reaction of the first production method B.
  • This reaction is carried out without solvent or in the above-mentioned solvents, using equimolar amounts of compound (Vll) and compound (XVIII) and an excess mole of compound (XVIII).
  • the conditions such as the reaction solvent and the reaction temperature are the same as those in the first production method B.
  • R ′ ′′ examples include a protecting group for an acyl-based amino group and a protecting group for an aralkyl-based amino group.
  • the protecting group for the acyl-based amino group include lower alkanol groups such as formyl, acetyl, and propionyl groups, methoxycarbonyl, and ethoxy.
  • Lower alkoxycarbonyl groups such as carbonyl and BOC groups, lower alkanesulfonyl groups such as methanesulfonyl and ethanesulfonyl groups, and aliphatic acyls such as methoxyacetyl, methoxypropionyl, benzoyl, benzyloxycarbonyl, and p-nitrobenzyloxycarbonyl groups.
  • Examples of the group include a heterocyclic lower alkanol group such as a ceryl acetyl, thiazolyl acetyl, and perazolyl acetyl group, and a heterocyclic acyl group such as an azolyl glyoxyloyl and a cyenyl glyoxyloyl group.
  • Aralkyl-based protecting groups for the amino group include benzyl, P -nitrobenzyl, benzhydryl, and trityl groups.
  • compound (XX) is obtained from 3 piberidinol of compound (XIX) by using any of the first production method A, method B or method C described above, and further subjected to an oxidation reaction to give the starting compound (VIII). There is a way to get
  • the reaction for synthesizing compound (XX) from compound (XIX) is the same as in the first method A, method B, and method C, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the above method. or.
  • Oxidation reaction Commonly used oxidizing agents (for example, organic peracids such as m-chloroperbenzoic acid, pyridinum dichromate (PCC), pyridinium dichromate (PDC), inorganic peracids such as sodium periodate, and peroxidation It can be carried out by using chromic acid oxidation using hydrogen, 03 pyridine, CuCrOs, or the like, or dimethyl sulfoxide (DMS ⁇ ) oxidation.
  • the reaction temperature varies depending on the type of the reaction compound and is set as appropriate.
  • This production method comprises: i) a method of reacting an amine represented by the compound (XXI) with an oxopiperazine compound of the compound (VIII) and performing reductive amination to obtain a starting compound (IX); ) Is reacted with an oxopiperazine compound of the compound (XVIII) to perform reductive amination to obtain the compound (XXII).
  • the reductive amination reaction is the same as in the first production method B, and the conditions such as the reaction solvent and the reaction temperature are the same as in the first production method B.
  • This production method comprises: i) a method of reacting an amamine represented by the compound (XXIII) with a oxopiperazine compound of the compound (VIII) to carry out reductive amination to obtain a starting compound (XII); and ⁇ ) a compound (XXIII) Indicated by
  • a compound (XXIV) is obtained by reacting a benzoamine with an oxopiperazine compound of the compound (XVIII) to perform reductive amination.
  • the reductive amination reaction is the same as in the first method B, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the first method B.
  • Method A an amine of compound (XXII) is reacted with a carboxylic acid derivative of compound (X) to carry out carbamoylation, followed by a compound represented by the general formula (XXV), 1) cyclization reaction, 2 )
  • This is a method in which the raw material compound (lib) is deprotected to obtain the raw material compound (Ha) by further performing a reduction reaction.
  • a series of reactions such as the acylation reaction, the subsequent cyclization reaction, and the deprotection are the same as in the third production method A, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the third production method A.
  • Method B In this production method, an amide of compound (XXIV) is reacted with a carboxylic acid derivative of compound (XXVI) to carry out acylation, and through a compound represented by the general formula (XXVII), 1) cyclization reaction, 2) reduction Reaction 3)
  • This is a method in which the starting compound (lib) is obtained by deprotection and the starting compound (lla) is obtained by further performing a reduction reaction.
  • a series of reactions such as the acylation reaction, the subsequent cyclization reaction, and the deprotection are the same as in the third production method B, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the third production method B.
  • the reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. Salt can be produced by subjecting it to the usual salt-forming treatment.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, shrinkage, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the various isomers can be isolated by a conventional method utilizing physical differences between the isomers, and the optical isomers can be separated by a general racemic resolution method, for example, fractional crystallization or chromatography.
  • the optical isomer can also be synthesized from an appropriate optically active starting compound.
  • fractional crystallization fractional crystallization using an optically active organic acid such as a tartaric acid derivative, a mandelic acid derivative, and a camphorsulfonic acid derivative is suitably performed.
  • an optically active organic acid such as a tartaric acid derivative, a mandelic acid derivative, and a camphorsulfonic acid derivative is suitably performed.
  • the solvent a solvent capable of performing optical resolution efficiently is appropriately selected. Industrial applicability
  • the compound of the present invention has an activity of inhibiting If current, selectively lowers the heart rate, and exhibits a strong and specific activity of reducing myocardial oxygen consumption, thereby inhibiting angina pectoris and myocardial infarction. It is useful as a therapeutic agent for the prevention and treatment of cardiovascular diseases such as ischemic heart disease, depressive heart failure and arrhythmia.
  • cardiovascular diseases such as ischemic heart disease, depressive heart failure and arrhythmia.
  • the compounds of the present invention are particularly useful for the prevention or treatment of various clinical conditions arising between the supply and consumption of myocardial oxygen, such as thoracic angina, myocardial infarction and associated arrhythmias, and for the treatment of arrhythmias, especially supraventricular arrhythmias. Highly useful for prevention or treatment.
  • the compound of the present invention is expected to have an effect of reducing vascular hemodynamic compression and thereby reducing complications of sclerosis, particularly coronary sclerosis. Further, the compound of the present invention is an agent which suppresses an excessively elevated heart rate and is useful also in controlling the heart rate to a constant state during general surgery.
  • the compound of the present invention directly acts on the If current in the above-mentioned heart rate lowering action, it has been confirmed that the selectivity of the heart rate lowering action for visual impairment which does not suppress the atrioventricular conduction or the cardiac contractile function is high. I have.
  • an ion current contributing to the formation of an action potential in the heart includes a current passing through a Na channel, a K channel, and a Ca channel. Inhibits the If current other than the If current present in the heart Since no significant inhibitory effect is shown at the dose, it is expected that there are few side effects due to current inhibition other than If current. Therefore, the compound of the present invention is useful as a heart rate-lowering agent having few side effects for the prevention and treatment of the above-mentioned various diseases.
  • the compound of the present invention is useful as an inhibitor of abnormal automatic hyperactivity caused by If current in certain disease states such as myocardial infarction or hypertension.
  • the heart was promptly removed while exsanguinating the carotid artery.
  • the heart was transferred into Tyrode's solution in which a gas mixture of 95% oxygen + 5% carbon dioxide was sufficiently ventilated, and the sinoatrial node (pacemaker) site (about 3 x 5 mm) was cut out.
  • the excised sinoatrial node was treated with a collagenase (manufactured by Yakult) (1.5 mg / ml) in a Ca 2+ -free Tyrode solution at 37 ° C. for 30 minutes. Then, it was left still at 4 ° C for 1 hour or more in K + rich solution ("KB recovery solution").
  • the treated sinoatrial node was minced with an injection needle and pipetting was performed to obtain isolated cardiomyocytes.
  • the isolated myocardium thus obtained was scattered in a dedicated chamber, and patch-clamping (whole cell mode) was applied to spindle-shaped cells undergoing spontaneous contraction.
  • the holding potential was set at ⁇ 40 mV, and an If current was induced by sequentially applying a hyperpolarizing pulse (1 second) from this potential to ⁇ 10, ⁇ 20, ⁇ 30, ⁇ , ⁇ 80 mV. Because the If current force was the largest due to the -80 mV hyperpolarizing pulse, the drug efficacy was evaluated by evaluating the effect of the test compound on the If® current induced by the -80 mV pulse.
  • the perfusion of the extracellular fluid (Tyrode solution) containing the test compound was started, an If current was induced by a hyperpolarizing pulse of -80 mV at 5-second intervals, and recording was performed until the 100th pulse (about 8 minutes). It was confirmed that the action of the drug reached saturation after 90 pulses or more.
  • the inhibitory effect of the test compound on If current was measured by measuring the If current obtained before perfusion of the drug solution and after 90 pulses, respectively, and comparing them with the concentration (IC 5 ) of 50% that inhibits the If current.
  • Atrial specimens were prepared in Krebs-Henseleit solution sufficiently ventilated with 95% oxygen + 5% carbon dioxide.
  • the sample is mounted on a stainless steel hook and suspended under a load tension of 0.5 g in a Magnus tube filled with Krebs-Henseleit solution sufficiently ventilated with 95% oxygen + 5% carbon dioxide gas, and the heart rate oscillates spontaneously.
  • the test compound is cumulatively added to the Magnus tube at 30-minute intervals, and the portability action curve is determined from the value 30 minutes after the substance administration to determine the effect.
  • Heart rate-lowering effect was compared by EC (concentration of substance) which reduced spontaneous heart rate by 30% before test substance administration.
  • the compound of the present invention did not show an inhibitory effect on cardiac contractility at a strain rate that shows a favorable heart rate lowering effect.
  • compositions containing one or more of the compounds of the present invention or salts thereof are prepared using ordinary pharmaceutically acceptable carriers.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally by injection, suppository, transdermal, inhalant or intravesical injection.
  • Dose symptoms, age of the administration subject, per day per adult human in the case 0.1 8 to 1 00 0 ⁇ Bruno about in ⁇ Li force normal oral administration in view of the sex and the like are appropriately determined depending on the individual case This should be given once or in 24 divided doses.
  • Pharmaceutical carriers include solid or liquid non-toxic pharmaceutical substances.
  • the one or more active substances comprise at least one inert diluent, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, agar. , Pectin, magnesium metasilicate, and magnesium aluminate.
  • the composition may contain, in a conventional manner, an additive other than an inert diluent, such as a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, A solubilizing agent such as glutamic acid or aspartic acid may be contained.
  • a lubricant such as magnesium stearate
  • a disintegrant such as calcium cellulose glycolate
  • a stabilizer such as lactose
  • a solubilizing agent such as glutamic acid or aspartic acid may be contained.
  • tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified Includes water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline.
  • non-aqueous solutions and suspensions include ethylene glycol, propylene glycol, polyethylene glycol, cocoa butter, vegetable oils such as olive oil and sesame oil, alcohols such as ethanol, gum arabic, polysorbate 80 (trade name). ).
  • compositions may also contain additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (e.g., lactose), and solubilizers (e.g., glutamic acid, asnolaginic acid). May be included. These are sterilized by, for example, passing through a bacteria storage filter, blending a bactericide or irradiation. They also produce sterile solid compositions which may be sterile in water or sterile before injection. It can also be used by dissolving it in a solvent for spraying.
  • additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (e.g., lactose), and solubilizers (e.g., glutamic acid, asnolaginic acid). May be included. These are sterilized by, for example, passing through a bacteria storage filter, blending a bactericide or ir
  • a conventional addition reaction was carried out using 13.8 g of sesamol and 60 g of 1,3-dibromopropane to obtain 17.7 g of 1- (3-bromopropoxy) -3,4-methylenedioxybenzene as white crystals. .
  • Reference Example 16 1 one (3-blanking opening Mopuropokishi) - 3 _ chlorobenzene
  • the reaction solution was washed with 5% sodium bicarbonate and saturated saline, and the organic layer was dried over magnesium sulfate.
  • the residue obtained by evaporating the solvent was dissolved in tetrahydrofuran (20 ml), and lithium aluminum hydride (220 mg) was slowly added under ice-cooling.
  • the reaction solution was heated under reflux for 1 hour and then cooled on ice. Water was added to the reaction solution until the foaming was completed, and the precipitated unnecessary substances were removed by filtration.
  • reaction solution was made alkaline (pH about 10) with a 1N aqueous sodium hydroxide solution, dissolved in chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Tables 1 and 2 show the physicochemical properties of the reference example, and Tables 3 to 9 show the structural formulas and physicochemical properties of the compounds of the examples.
  • Ph phenyl diOMe: dimethoxy

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Abstract

L'invention porte sur des dérivés de 2-(3-pipéridyl)-1,2,3,4-tétrahydroisoquinoline représentés par la formule générale (I) ou sur les sels et les compositions médicinales contenant ces dérivés ou les sels de ceux-ci, ainsi que des excipients pharmaceutiquement acceptables, formule dans laquelle R1 et R2 sont identiques ou différents et représentent chacun hydrogène, halogéno, hydroxy, alkyle inférieur, alkyle inférieur halogéné, (alkyle inférieur)-O-, nitro, cyano, amino, oxopyrrolidinyle, (alkyle inférieur)-O-CO-NH-, (alkyle inférieur)-CO-NH- ou (alkyle inférieur)-SO¿2?-NH-, ou bien R?1 et R2¿ peuvent former -O-(alkylène inférieur)-O-; R3 et R4 représentent chacun hydrogène ou bien peuvent former oxo; X représente une liaison simple, oxygène ou soufre; A représente alkylène inférieur; et le noyau B représente un noyau d'hydrocarbure substitué ou un hétérocycle éventuellement substitué pouvant être lié à un noyau de benzène. Ces composés ont un effet inhibiteur courant If et sont utilisés comme dépresseurs agissant sur le rythme cardiaque dans la prévention ou le traitement, notamment, de maladies cardiaques telles que l'angor (angine de poitrine) et l'infarctus du myocardiaque, et les maladies circulatoires telles que l'insuffisance cardiaque congestive et les arythmies (arythmie supraventriculaire, etc.).
PCT/JP1997/003378 1996-09-25 1997-09-24 Derives de 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline ou compositions medicinales obtenues WO1998013364A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43197/97A AU4319797A (en) 1996-09-25 1997-09-24 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives or medicinal compositions thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/253576 1996-09-25
JP25357696 1996-09-25

Publications (1)

Publication Number Publication Date
WO1998013364A1 true WO1998013364A1 (fr) 1998-04-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075133A1 (fr) * 1999-06-03 2000-12-14 Yamanouchi Pharmaceutical Co., Ltd. Derives d'isoquinoline ou leurs sels
WO2009036117A1 (fr) * 2007-09-12 2009-03-19 Wyeth Dérivés d'azacyclylisoquinolinone et d'isoindolinone convenant comme antagonistes de l'histamine-3

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283470A (en) * 1976-01-01 1977-07-12 Ciba Geigy Ag Piperidine derivatives
JPS6445831A (en) * 1987-08-12 1989-02-20 Kuraray Co Full-aromatic polyester spun yarn

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283470A (en) * 1976-01-01 1977-07-12 Ciba Geigy Ag Piperidine derivatives
JPS6445831A (en) * 1987-08-12 1989-02-20 Kuraray Co Full-aromatic polyester spun yarn

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075133A1 (fr) * 1999-06-03 2000-12-14 Yamanouchi Pharmaceutical Co., Ltd. Derives d'isoquinoline ou leurs sels
US6573279B1 (en) 1999-06-03 2003-06-03 Yamanouchi Pharma Co Ltd Isoquinoline derivatives or salts thereof
WO2009036117A1 (fr) * 2007-09-12 2009-03-19 Wyeth Dérivés d'azacyclylisoquinolinone et d'isoindolinone convenant comme antagonistes de l'histamine-3

Also Published As

Publication number Publication date
AU4319797A (en) 1998-04-17

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