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WO1996038422A1 - Derives condenses de benzodiazepinone et composition pharmaceutique les ayant pour base - Google Patents

Derives condenses de benzodiazepinone et composition pharmaceutique les ayant pour base Download PDF

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Publication number
WO1996038422A1
WO1996038422A1 PCT/JP1996/001462 JP9601462W WO9638422A1 WO 1996038422 A1 WO1996038422 A1 WO 1996038422A1 JP 9601462 W JP9601462 W JP 9601462W WO 9638422 A1 WO9638422 A1 WO 9638422A1
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Prior art keywords
group
substituted
substituent
lower alkyl
atom
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PCT/JP1996/001462
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English (en)
Japanese (ja)
Inventor
Toshihiro Watanabe
Akio Kakefuda
Akihiro Tanaka
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU58447/96A priority Critical patent/AU5844796A/en
Publication of WO1996038422A1 publication Critical patent/WO1996038422A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a medicament, in particular, a condensed benzodiazepinone derivative or a salt thereof, and a pharmaceutical composition containing the compound. These materials are useful in the prevention or treatment of cardiac diseases involving muscarinic M 2 receptor.
  • Brain arrhythmia is a condition in which the pulse rate decreases due to a functional or organic disorder of the heart's conduction system.
  • the main types of bradyarrhythmias are sinus insufficiency syndrome and atrioventricular block, of which about 50% of all bradycardia patients are caused by impairment of the sinus node, which acts as a cardiac pacemaker.
  • the atrioventricular block is due to a failure of the atrioventricular node that connects the atrium and ventricle.
  • artificial pacemakers are mainly used to treat bradyarrhythmias.
  • nervous syncope vagal syncope, etc.
  • the disease is a condition in which the vagus nerve is hyperexcited due to hyperconstriction of the heart and mental anxiety, resulting in syncope as a result of cerebral ischemia via transient cardiac arrest.
  • Drugs useful in these diseases include heart blockers, S-blockers, theophylline and disopyramide, which inhibit hyperconstriction of the heart, and atotopin (muscarinic receptors), which suppress vagal hyperexcitability, which causes functional disorders.
  • a musculin receptor antagonist with particularly improved side effects is expected to replace an artificial pacemaker as a chemical pacemaker.
  • compounds having a muscular phosphoric acid receptor antagonistic activity have been used in various forms such as tachycardia, anti-bradycardia, bronchial expansion, gastrointestinal motility suppression, acid secretion suppression, blood loss, mydriasis, bladder contraction suppression, sweat reduction It is known to cause physiological effects. It is known that there are at least three subtypes of this muscarinic receptor. Mainly receptors in the brain or the like, M 2 receptors in the heart or the like, and M 3 receptors are present in smooth muscle and glandular tissue.
  • Atotopin has a strong affinity for muscarinic receptors and is used as an anti- bradycardic agent to block its action.
  • Atto port pin, M is a subtype of muscarinic receptors, 2, has substantially the same affinity to all the M 3, the non-selective because it antagonizes the (biological chemistry, 4 2 (5 ), 38 1 (1991)).
  • side effects such as bile, nausea, urinary retention, constipation, and mydriasis, which are thought to be caused by musculin receptor antagonism other than the intended anti-bradycardia effect.
  • atotopin is known to have central side effects such as mental dysfunction due to its central migration, and its improvement has been demanded.
  • a compound having a low central nervous system is expected to act as a drug acting only on the heart without having any side effects of the central system, particularly, psychiatric disorders caused by receptors.
  • the condensed benzodiazepinone derivative of the present invention differs from these compounds in having a substituted phenylacetyl group, and is far superior in M 2 selectivity and M 2 receptor antagonism.
  • n 2 to 5
  • R and R 2 represent a lower alkyl group or the like.
  • the compound of the present invention is a compound having a substituted funinyl acetyl group.
  • An object of the present invention have a potent and selective Mus force phosphoric M 2 receptor antagonism different in chemical structure from the conventional compounds, and less central migratory, compounds which have a cardiac-specific effects Is to provide. Disclosure of the invention
  • the present inventors have, per compound having a Mus force phosphoric M 2 receptor antagonism, sharpness meaning studied a result, a substituted Fueniruasechiru group, i.e., bind to Fuweniru group via an oxygen atom, a sulfur atom or a nitrogen atom substituted have preventive and therapeutic effects of the novel condensation base Nzojiazepinon derivative excellent Mus force phosphoric M 2 receptor involved heart disease with Fuweniruasechiru group substituted with a group at the 5-position, and Mii that low side effect The present invention has been completed.
  • the present invention relates to a fused benzodiazepinone derivative represented by the following general formula (I) or a salt thereof.
  • Y an oxygen atom or a group represented by the formula NR 4 , S (0) ⁇ ⁇ ⁇ ⁇ or NR 5 CO
  • R 4 , R 5 same or different, hydrogen atom or lower alkyl group
  • n integer from 0 to 2
  • R 1 and R 2 are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may have a substituent, an aralkyl group which may have a substituent, or R 1 is integrated with the nitrogen atom to be bonded, and may further contain any one of an oxygen atom, a sulfur atom and a nitrogen atom, and may form a 4- to 9-membered nitrogen-containing saturated heterocyclic group.
  • the 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent R 3 : a hydrogen atom, a lower alkyl group which may have a substituent, a hydroxyl group, a lower alkyl group. Coxy group, nitro group, halogen atom, lower acyl group or amino group with substituents
  • Preferred compounds in the compound of the present invention include, in the above general formula (I), R 1 and R 2 are the same or different and are substituted with a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a substituent of the following group B.
  • a 4- to 9-membered nitrogen-containing saturated heterocyclic group may be formed, and the 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent represented by the following group C.
  • R 3 may be a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, a nitro group, a halogen atom, a lower acyl group or a group of the following group E which may be substituted with a substituent of the following group D.
  • Group B substituted with a halogen atom, a hydroxyl group, a lower alkylthio group, a lower alkoxycarbonyl group, a nitro group, an amino group, a mono- or di-lower alkylamino group, a methylenedioxy group, or a lower alkyl group; Good 5 to 7 members A 5- to 7-membered nitrogen-containing saturated heterocyclic group which may be substituted with a lower saturated heterocyclic group or a lower alkoxycarbonyl group, or a lower alkyl group which may be substituted with a halogen atom,
  • Group C a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an aryl group which may be substituted with a substituent of Group B, an aryl group which may be substituted with a substituent of Group B
  • B A aralkylthio group, an amino group, a mono or di-lower alkylamino group, an arylamino group, or an aralkylamino group, which may be substituted with a group of substituents;
  • Group D halogen atom, hydroxyl group or amino group
  • Group E a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, or a lower alkylsulfonyl group.
  • More preferred compounds are a 5- to 7-membered nitrogen-containing saturated heterocyclic group in which R 1 and R 2 are the same or different and may be substituted with a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a lower alkyl group.
  • An aryl group which may be substituted, an aryl group which may be substituted with a 5- to 7-membered nitrogen-containing saturated heterocyclic group which may be substituted with a lower alkyl group, or R 1 and R 2 May be integrated with the nitrogen atom to be bonded, and may further contain any one of an oxygen atom, a sulfur atom and a nitrogen atom, and may form a 4- to 9-membered nitrogen-containing saturated heterocyclic group.
  • the 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent represented by the following group C1, wherein R 3 is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, A halogen atom, a lower acyl group or a group E group below A mono-amino group which may be substituted,
  • a fused benzodiazepinone derivative or a salt thereof A fused benzodiazepinone derivative or a salt thereof.
  • Group C lower alkyl group, lower alkoxy group, lower alkylthio group, aryl group, aralkyl group, aryloxy group, aralkyloxy group, arylthio group, aralkylthio group, amino group, mono or di-lower alkylamino group, arylamino group, Or an aralkylamino group
  • Group E a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, or a lower alkylsulfonyl group.
  • a condensed benzodiazepinone derivative or a salt thereof, Y is an oxygen atom, a condensed benzodiazepinone derivative or a salt thereof, or Y is a group represented by the formula NH CO. Its salts are particularly preferred.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a condensed benzodiazepinone derivative represented by the above general formula (I) or a salt thereof and a pharmaceutically acceptable carrier, particularly a heart disease involving a muscarinic M 2 receptor. It also relates to prophylactic or therapeutic agents.
  • sinus insufficiency syndrome including sinus bradycardia, sinus arrest or bradycardia tachycardia syndrome or bradyarrhythmias including vagal excitability-induced bradycardia including atrioventricular blockade, neural syncope (carotid sinus hypersensitivity) And the like.
  • lower alkyl group specifically refers to, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3 — Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-Ethylbutyl group, 2-Ethylbutyl group,
  • an alkylene group having 1 to 6 carbon atoms is preferable, and specifically, a methylene group, an ethylene group, a methylmethylene group, a trimethylene Group, propylene group, 2-propylene group, dimethylmethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, 1-ethylethylene group, 2-ethylethyl group, 2,2-dimethylethylene group, 1,1-dimethylethylene group, ethylmethylmethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group Methylene group, 1,1-dimethyltrimethylene group, 2,2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, 1,3-dimethyltrimethylene group, 2,3-dimethyltrimethylene group, 1, 2-dimethyltrimethylene group
  • the "cycloalkyl group” preferably has 3 to 8 carbon atoms, and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and the like. Preferably it is a cyclohexyl group.
  • aryl group_ means a carbocyclic aryl group unless otherwise specified, and specifically includes, for example, a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group and the like, preferably a phenyl group.
  • the “aralkyl group” means a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted with the above “aryl group”.
  • an aryl group is exemplified by a phenyl group, specifically, Benzyl group, phenyl group, 1-phenylethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 1-phenylpropyl group, 1-methyl1-2-phenylethyl group, diphenylmethyl group (benzhydryl group), trityl group And the like.
  • Preferred are a benzyl group and a phenethyl group.
  • halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and the like.
  • lower acetyl group means a lower alkyl group such as a formyl group and an acetyl group, a propionyl group, a butylyl group, an isobutyryl group, a valeryl group, an isovaleryl group, a bivaloyl group, and a hexanoyl group.
  • the substituent in the “aryl group optionally having substituent (s)” or the “aralkyl group optionally having substituent (s)” may be any as long as it is generally used as a substituent of an aryl group. It is preferably a substituent shown in the above group B, and more preferably a 5- to 7-membered nitrogen-containing saturated heterocyclic group which may be substituted with a lower alkyl group. One or more of these substituents may be substituted.
  • the “5- to 7-membered nitrogen-containing saturated ring group” is a 5- to 7-membered ring of the above “nitrogen-containing saturated heterocyclic group”, preferably a pyrrolidyl group, a piperidyl group, or a morphonyl group And a piperazinyl group.
  • the 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent, and the substituent may be a carbon atom or a nitrogen atom of a nitrogen-containing saturated heterocyclic ring.
  • Any substituent may be used as long as it is used as a substituent of It is a substituent shown in the above-mentioned group C, and is more preferably a substituent shown in the above-mentioned group C1.
  • Particularly preferred are a lower alkyl group, an aryl group, an aralkyl group, an aryloxy group, an arylamino group and an aralkyloxy group.
  • any group may be used as long as it is generally used as a substituent for a lower alkyl group. Group.
  • the substituent in the amino group J which may have a substituent in R 3 may be any of those usually used as a substituent of a nitrogen atom of an amino group, but is preferably a group of the group E
  • the amino group may be mono- or di-substituted by any of these groups, and is preferably mono-substituted.
  • lower alkylthio group and “lower alkoxy group” are each a group in which a hydrogen atom of a mercapto group or a hydroxyl group is substituted by the above-mentioned "lower alkyl group J", and is preferably a methylthio group, an ethylthio group, or Examples include a methoxy group and an ethoxyquin group.
  • the “mono- or di-lower alkylamino group” is a group in which one or two of the hydrogen atoms of the amino group are substituted with the above “lower alkyl group”, and is preferably a methylamino group, an ethylamino group, or a dimethylamino group. Clogged, getylamino group.
  • “Lower alkoxycarbonyl groups j include methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyl A straight-chain or branched alcohol having 1 to 6 carbon atoms, such as a oxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a tert-pentyloxycarbonyl group, a hexyloxycarbonyl group,
  • the term "lower alkylsulfonyl group” means a group in which a sulfur atom of a sulfonyl group is substituted by any of the above-mentioned "lower alkyl groups”.
  • aryloxy and arylthio include phenoxy And ether or thioether residues derived from aromatic monocyclic or polycyclic hydrocarbon hydroxy or mercapto compounds such as (or phenylthio) and naphthyloxy (or thio) groups.
  • Alkyloxy group or “aralkylthio group” means a group in which any hydrogen atom of the above “lower alkoxy group” or “lower alkylthio group” has been substituted with the above “aryl group”. Benzyloxy (or thio) group, phenethyloxy (or thio) group, 1-phenylethoxy (or ethylthio) group, 3-phenylloopoxy (or propylthio) group, 2-phenyloxypropyl (or propylthio) ) Group, 1-phenylloopoxy (or propylthio) group and the like.
  • Arylamino group” or “aralkylamino group” refers to a group in which any hydrogen atom of an amino group is substituted with the above “aryl group” or “aralkyl group”. Specifically, a phenylamino group, Examples include a naphthylamino group, a benzylamino group, a phenethylamino group and the like.
  • the compound (I) of the present invention may have tautomers, geometric isomers, and optical isomers based on asymmetric carbon atoms, depending on the type of the substituent.
  • the present invention includes all of these isomers, isolated or mixtures thereof.
  • 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 acids, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid and the like can be mentioned.
  • the present invention also includes hydrates of compound (I), solvates such as ethanol, and polymorphic substances.
  • the compound (I) of the present invention can be produced by applying various production methods.
  • the typical manufacturing method is described below. (Method 1)
  • R 1 , R 2 , R 3 , A, X and Y have the above-mentioned meanings, and R 1 ′ and R 2 ′ are the same as R 1 and R 2 , or an amino-protecting group. And ⁇ mean a halogen atom.
  • the compound of the present invention represented by the general formula (I) is produced by reacting an alkyl halide (I) with an amino ( ⁇ ).
  • compound ( ⁇ ) is equimolar to compound (H) in the absence of a solvent or in an organic solvent that does not participate in the reaction such as benzene, toluene, xylene, dimethylformamide, dichloromethane, dichloroethane, methanol, or ethanol. It is advantageous to carry out the reaction at room temperature or under heating or by heating to reflux using a slight excess of mol. You.
  • secondary or tertiary bases such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine and dimethylamine, sodium iodide, sodium carbonate, sodium carbonate, hydrogencarbonate
  • an inorganic base such as sodium is advantageous for smoothly proceeding the reaction.
  • ⁇ 0 is potassium imidophthalate, or a toluenesulfonyl group, an acetyl group, a phenacylsulfonyl group, a trifluoromethanesulfonyl group, a bisbenzenesulfonyl group, etc.
  • protecting group J for the amino group defined by R 1 ′ and R 2 ′ which are the groups of the compound of formula ( ⁇ ) It means a protecting group usually used by a trader, and is typically a lower alkanoyl group such as a formyl group, an acetyl group, a propionyl group, or the like as a protecting group for an acetyl group.
  • Lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxyquincarbonyl group and BOC, lower alkanesulfonyl groups such as methanesulfonyl group and ethanesulfonyl group, methoxyacetyl group, methoxypropionyl group, benzoyl group, and benzyloquincarbonyl group
  • An aliphatic acetyl group such as p-nitrobenzoyloxycarbonyl group, or a heterocyclic lower alkanoyl group such as a chenylacetyl group, a thiazolylacetyl group, a tetrazolylacetyl group, an azolylglycoxyloyl group, And a heterocyclic acyl group such as a chenylglyoxyloyl group.
  • aralkyl-based amino-protecting group examples include a benzyl group, a p-nitrobenzyl group, a benzhydryl group, and a trityl group. Further, a tri-lower alkylsilyl group such as a trimethylsilyl group is exemplified.
  • the removal of the protecting group of the amino group may be carried out according to a conventional method.
  • the protecting group is a tri-loweralkylsilyl group or the like
  • the removal can be easily performed by treating with water.
  • it is a protecting group such as t-butyl group or formyl group
  • it can be easily removed by treating it with an acid such as formic acid, trifluoroacetic acid, a mixture of trifluoroacetic acid and anisol, a mixture of hydrobromic acid and acetic acid, or a mixture of hydrochloric acid and dioxane. Is done.
  • the compound (I) of the present invention can be obtained by performing an N-alkyl reaction by a conventional method such as reductive amination or substitution with a halogen compound on the amino compound after removing the protecting group for the amino group. it can.
  • the compound wherein Y is an oxygen atom or a sulfur atom is hydroquine or It can also be obtained by reacting a thio compound (H ') with an alkyl halide (Iff').
  • This reaction is carried out in a solvent such as dimethylformamide, hexamethylphosphoramide, acetonitrile or dimethyl ether, in the presence of an inorganic base such as potassium carbonate or sodium hydrogen carbonate, usually at room temperature or under heating.
  • a solvent such as dimethylformamide, hexamethylphosphoramide, acetonitrile or dimethyl ether
  • the compound (I) of the present invention thus produced is isolated or purified as it is or after subjecting it to a salt-forming treatment by a conventional method. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the starting compound (I) of the present invention can be produced by the following method I or IT.
  • R 3 , A, X and Z have the above-mentioned meanings, R ′ is an ester residue, Y 2 is ⁇ or S, Y 3 is SO or S ⁇ 2 and Z ′ is halogen
  • the starting compound (la) or (lb) of the compound in which Y is ⁇ or S (0) survive(n: 0 to 2) is represented by the above formula.
  • This step is a step of reacting a hydroxy or thio compound (W) with an alkyl halide (V) to obtain a compound (VI).
  • This reaction is carried out in a solvent such as dimethylformamide, hexamethylphosphoramide, acetonitrile, or dimethyl ether, in the presence of an inorganic salt group such as potassium carbonate or sodium hydrogen carbonate, usually at room temperature or under heating.
  • a solvent such as dimethylformamide, hexamethylphosphoramide, acetonitrile, or dimethyl ether
  • This step is a method for obtaining a compound (W) which is a carboxylic acid by hydrolyzing an ester compound (YD.)-This reaction is carried out by using a base such as sodium carbonate, sodium hydroxide, or trifluoroacetic acid; A conventional method of hydrolyzing in the presence of hydrochloric acid or the like can be applied.
  • a base such as sodium carbonate, sodium hydroxide, or trifluoroacetic acid
  • This step is a step of obtaining an amide compound (Ia) by condensing amine 01) or a salt thereof with a carboxylic acid represented by the general formula (1) or a reactive derivative thereof according to a conventional method.
  • Reactive derivatives of compound (W) include acid halides such as acid chloride and acid promide; acid azide; N-hydroxybenzotriazol (HOBT); P-dinitrophenyl N-hydroxysuccinimi; And symmetrical acid anhydrides; mixed acid anhydrides with alkyl carbonic acid, p-toluenesulfonic acid, and the like.
  • reaction conditions vary slightly depending on the starting compound, especially the type of reactive derivative of compound (W), but pyridine, tetrahydrofuran, dioxane, ether, N, N-dimethylformamide, benzene, toluene, xylene, methylene chloride,
  • organic solvent inert to the reaction such as chloroethane, chloroform, ethyl acetate, or acetonitrile, it is advantageous to react the starting compounds (II) and (VII) in equimolar amounts or the starting compound (W) in excess moles. is there.
  • an organic base such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, N-methylmorpholine, or carbonic acid is used in the reaction. It may be advantageous to carry out the reaction in the presence of a base such as potassium, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, an inorganic base such as 7j potassium oxide. Note that pyridin can also serve as a solvent.
  • the reaction temperature differs depending on the type of the reactive derivative and is set as appropriate.
  • the raw material compounds (IT a) By mid Y 2 is oxidizing a compound which is S, the present invention compound (I) Medium Y is sulfoxide (SO) or sulfone (S 0 2) at a reduction compound This is a step of obtaining a compound (lb).
  • sulfide (S) can be obtained by oxidizing sulfide (S) with hydrogen peroxide or a peracid (such as metabenzo-perbenzoic acid or peracetic acid) under mild conditions.
  • Sulfone (S 0 2 ) can be obtained under strong conditions in the presence of excess oxidizing agent.
  • the starting compound (1 ′) of the compound in which ⁇ is 0 or S is obtained by condensing a compound (Cor) with a carboxylic acid derivative (vr) by an ordinary method. ') Can be obtained.
  • the reaction can be carried out in the same manner as in the above (Step c).
  • This step is a step of reacting compound (H) with compound (VIV) by an amidation reaction to obtain compound (X).
  • This reaction can be carried out in substantially the same manner as in the method described in the above I (step c).
  • This step is a step of obtaining a compound (XI) having an amino group by reducing the compound (X) having a nitro group.
  • the reduction can be carried out according to the usual methods of metal / metal salts (zinc, iron, stannous chloride, etc.) or catalytic reduction (catalyst: palladium Z-carbon, platinum oxide, Raney nickel, etc.).
  • the compound (XI) and the compound (II) are reacted by an amidation reaction, and the compound (He) (the starting compound of the compound in which Y is NR 5 CO in the compound (I) of the present invention) ) Can be obtained.
  • the compound (XI) is reacted with the alkyl halide (V) to obtain a compound (Id) (a starting compound of the compound of the present invention, wherein Y is NR 4 ).
  • the compounds of the present invention Mel useful for the prevention or treatment of cardiac diseases M 2 receptors are involved.
  • Sinus dysfunction syndromes such as sinus bradycardia, sinus arrest, bradycardia tachycardia syndrome; atrioventricular block It may be useful as a prophylactic and / or therapeutic agent for other bradyarrhythmias such as vagus nerve excitation-induced bradycardia, and neuronal syncope (such as carotid sinus hypersensitivity).
  • the present invention compounds compared to the M 3 receptor, high selectivity for M 2 receptor, Furthermore, since the central migratory low reduced side effects bradyarrhythmia such effects on B thirst Ya central Useful as a preventive and therapeutic agent.
  • pericardium specimen with 3 H—qu i nu clidi ny lb en zi 1 ate (QNB) (M 2 ass ay).
  • Submandibular gland membrane specimen is 3 H—N-one methy lsc op ol (M 3 assa) with amine (NMS) 45 minutes each after incubation, filtered using Watma nGF / B fi 1 ter, and measured the radiation dose with a liquid scintillation counter .
  • Non specificbindi ng was determined by inc ub ati on by simultaneously adding 2X 1 0 _5 M atro P ine respectively.
  • the preparation of the membrane, the preparation of the compound, and the incubation were all performed in HEP ES buffer [4- (2-hyroxy—et hyl) -1 -piperzainet hanesulfon icacid 20 mM, Na C 110 mM, gC 121 OmM, pH 7.5] was used.
  • Table 1 shows the results of the above-mentioned affinity test for musculin receptor.
  • the present invention compounds exhibit higher affinity to M 2 receptor, confirmed that yet other muscarinic receptors, a high M 2 receptor selectivity, especially compared to the M 3 receptor was done.
  • Pentobarbital 6 Omg / kg i.p. was used in male Wistar rats (300 to 350 g), anesthesia was performed, tracheal force neuration, carotid artery force neuration, left-right vagus nerve transection, and spinal cord destruction were performed. After 15 minutes of stabilization under artificial respiration, the test compound or physiological saline was administered 15 minutes after the administration of athenolol 1 OmgZkg i.v., and 15 minutes later, oxotremorine was cumulatively administered. The evaluation compound was administered i.v. through the femoral vein.
  • the heart rate immediately before oxotremorine administration was set at 100, and the rate of decrease in heart rate due to cumulative oxotremorine administration in the presence and absence of the test compound was determined to obtain a dose-response curve.
  • Evaluation absence of compound and ED 50 values in the (control) (50% heart rate reducing effect dose by Okisotoremori down), ED 5 in the presence.
  • the dose After calculating the rightward movement width (Dos e- ratio) of the action curve, expand to Schi 1 dpiot, and DR ,. And expressed as a negative logarithmic value (pDR,., Mo 1 / kg).
  • the salivary secretion rate of the control compound was determined assuming the salivary secretion of the control as 100%, and the 50% inhibitory dose (ID 5. value) was calculated. The negative logarithmic value was expressed as (p I Dso, molZkg). did.
  • Table 2 shows the results of the above-mentioned musculin phosphoreceptor antagonism test (invivo).
  • an evaluation compound or a solvent physiological saline, etc.
  • a solvent physiological saline, etc.
  • loxotremorine lmg / kg was administered subcutaneously on the back (s.c.), and behavior was observed 5, 10, and 15 minutes later.
  • the compound of the present invention may be a prophylactic / therapeutic agent for heart diseases having low central side effects.
  • a preparation containing one or more of the compound of the present invention or a salt thereof as an active ingredient is prepared using carriers, excipients and other additives commonly used in the preparation of pharmaceuticals.
  • carriers and excipients for pharmaceutical preparations include solid or liquid emergency pharmaceutical substances. Examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. .
  • Administration is oral, such as tablets, pills, capsules, granules, powders, and liquids, or non-injection, such as intravenous or intramuscular injections, suppositories, transdermals, inhalants, or intravesical injections. Any form of oral administration may be used.
  • the dose is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject, gender, etc., but in the case of oral administration, for adults, 0.0 mg / kg to 10 mg / kg / day.
  • the dose is about g, and is administered once or in 2 to 4 divided doses. When given intravenously due to symptoms, it is usually administered once or more than once a day in the range of 0.001 mg zkg to 1 Omg / kg per adult.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicone. It is mixed with magnesium acid aluminate.
  • the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizing agents such as lactose.
  • tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.
  • a solubilizing agent such as glutamic acid or aspartic acid Good.
  • tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, for example, purified Contains 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 solution and drowning agent examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like.
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). ,.
  • adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid).
  • stabilizing agents eg, lactose
  • solubilizing agents eg, glutamic acid, aspartic acid
  • the compound of the present invention is not limited to the compounds described in the following Examples, and furthermore, the compound represented by the general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, its geometrical and optical isomers
  • the crystal includes all polymorphs.
  • the starting compounds of the compound of the present invention include novel compounds. Production examples of these compounds will be described as reference examples.
  • the reaction solution was evaporated under reduced pressure, and the obtained residue was dissolved in chloroform.
  • the residue obtained by distilling off the solvent was purified by silica gel column chromatography using a solvent system, chloroform-form-methanol-28% aqueous ammonia (15: 1: 0.1), and the 5- [4- [N — (3-Piveridino propylamino) 1-phenyl] acetyl] 1,5,10-dihydro-11H-dibenzo [b, el [1, 4] diazepine 11 1-one 1 15 Omg as foam Obtained.
  • the following table shows the nuclear magnetic resonance spectra of the compounds obtained as amorphous among the example compounds in the above table.

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Abstract

La présente invention concerne des dérivés condensés de benzodiazépinone représentés par la formule générale (I), ou des sels de ces dérivés, qui ont des effets médicaux, en particulier des effets préventifs ou thérapeutiques sur les affections cardiaques, auxquels participent des récepteurs de muscarine M2. Dans cette formule (I), X représente CH ou N; Y représente l'oxygène, NR4, S(O)¿n? ou NR?5CO, R4 et R5¿ étant identiques ou non et représentant chacun l'hydrogène ou un alkyle inférieur, et n est un nombre entier de 0 à 2; A représente un alkylène inférieur; R1 et R2 sont identiques ou non et représentent chacun l'hydrogène, un alkyle inférieur, un cycloalkyle, un aryle ou un aralkyle éventuellement substitués, ou bien R1 et R2 peuvent former, avec l'atome d'azote auquel ils sont liés, un composé hétérocyclique saturé ayant de 4 à 9 chaînons, comportant de l'azote et pouvant comporter de plus, en variante, un atome pris parmi l'oxygène, le soufre et l'azote et pouvant, en variante, avoir un ou plusieurs substituants, et R3 représente l'hydrogène, un alkyle inférieur éventuellement substitué, un hydroxy, alcoxy inférieur, nitro, halogéno, acyle inférieur ou un amino éventuellement substitué.
PCT/JP1996/001462 1995-05-31 1996-05-30 Derives condenses de benzodiazepinone et composition pharmaceutique les ayant pour base WO1996038422A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58447/96A AU5844796A (en) 1995-05-31 1996-05-30 Fused benzodiazepinone derivatives and medicinal composition of the same

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JP13360995 1995-05-31
JP7/133609 1995-05-31

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WO2001005763A3 (fr) * 1999-07-16 2002-01-17 Acadia Pharm Inc Composes possedant une activite sur les recepteurs muscariniques
US20140213813A9 (en) * 2009-03-11 2014-07-31 Bayer Intellectual Property Gmbh Haloalkylmethyleneoxyphenyl-Substituted Ketoenols
US10399970B2 (en) 2015-06-09 2019-09-03 Femtogenix Limited Pyrridinobenzodiazepine and benzopyrridodiazecine compounds
US10975072B2 (en) 2015-08-21 2021-04-13 Femtogenix Limited Substituted 6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepines as anti-proliferative agents
US10975074B2 (en) 2015-08-21 2021-04-13 Femtogenix Limited Anti-liferative agents comprising substituted benzo[e]pyrido[1,2-a][1,4]diazepines

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6528529B1 (en) 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
US7485651B2 (en) 1998-03-31 2009-02-03 Acadia Pharmaceuticals, Inc. Compounds with activity on muscarinic receptors
WO2001005763A3 (fr) * 1999-07-16 2002-01-17 Acadia Pharm Inc Composes possedant une activite sur les recepteurs muscariniques
US20140213813A9 (en) * 2009-03-11 2014-07-31 Bayer Intellectual Property Gmbh Haloalkylmethyleneoxyphenyl-Substituted Ketoenols
US9045390B2 (en) * 2009-03-11 2015-06-02 Bayer Cropscience Ag Haloalkylmethyleneoxyphenyl-substituted ketoenols
US10399970B2 (en) 2015-06-09 2019-09-03 Femtogenix Limited Pyrridinobenzodiazepine and benzopyrridodiazecine compounds
US10975072B2 (en) 2015-08-21 2021-04-13 Femtogenix Limited Substituted 6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepines as anti-proliferative agents
US10975074B2 (en) 2015-08-21 2021-04-13 Femtogenix Limited Anti-liferative agents comprising substituted benzo[e]pyrido[1,2-a][1,4]diazepines
US11912700B2 (en) 2015-08-21 2024-02-27 Pheon Therapeutics Ltd Anti-proliferative agents comprising substituted benzo[e]pyrido[1,2-a][1,4]diazepines

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AU5844796A (en) 1996-12-18

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