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WO1996013488A1 - Nouveau derive de benzodiazepinone et composition medicinale constituee de celui-ci - Google Patents

Nouveau derive de benzodiazepinone et composition medicinale constituee de celui-ci Download PDF

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Publication number
WO1996013488A1
WO1996013488A1 PCT/JP1995/002217 JP9502217W WO9613488A1 WO 1996013488 A1 WO1996013488 A1 WO 1996013488A1 JP 9502217 W JP9502217 W JP 9502217W WO 9613488 A1 WO9613488 A1 WO 9613488A1
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WIPO (PCT)
Prior art keywords
group
ethyl
substituted
lower alkyl
salt
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PCT/JP1995/002217
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English (en)
Japanese (ja)
Inventor
Toshihiro Watanabe
Akio Kakefuda
Isao Kinoyama
Isao Yanagisawa
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU37544/95A priority Critical patent/AU3754495A/en
Publication of WO1996013488A1 publication Critical patent/WO1996013488A1/fr

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    • 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
    • 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

Definitions

  • the present invention relates to a novel benzodiazepinone derivative and a pharmaceutical composition thereof.
  • the present invention relates to a medicament, particularly a benzodiazepinone derivative or a salt thereof, and a pharmaceutical composition containing the compound.
  • a medicament particularly a benzodiazepinone derivative or a salt thereof
  • a pharmaceutical composition containing the compound are useful in the treatment.
  • Bradyarrhythmia is a condition in which the pulse rate decreases due to functional or organic impairment of the cardiac conduction system.
  • the main types of bradyarrhythmias are sinus insufficiency syndrome and atrioventricular block.
  • sinus insufficiency syndrome which accounts for about 50% of all bradycardia patients, is a disorder of the sinus node that plays the role of heart-knee pacemaker.
  • Atrioventricular block is caused by damage to the atrioventricular node that connects the atrium and ventricle.
  • artificial pacemakers are mainly used to treat bradyarrhythmias.
  • Indications for artificial pacemakers include neuronal syncope (such as carotid sinus hypersensitivity), and some of these disorders, especially cardiac depression, have vagus nerves due to hyperconstriction of the heart and mental anxiety. It is the result of cerebral ischemia through over-delivery and transient cardiac arrest.
  • Drugs for the treatment of bradyarrhythmias include the musculin antagonist, which suppresses vagal hyperexcitability, which is the cause of functional impairment, and the theophylline / S2 stimulant ⁇ theophylline.
  • the treatment of nervous syncope suppresses cardiac hyperconstriction.
  • Blockade drugs and disoviramide which has a non-selective anticholinergic effect, and vagus Atotopin (Merck Index, 11th edition, p. 138; muscarinic antagonist), which suppresses Shinkyo S, has been used.
  • vagus Atotopin Merck Index, 11th edition, p. 138; muscarinic antagonist
  • muscarinic antagonists are expected to replace artificial pacemakers as chemical pacemakers.
  • compounds with muscarinic receptor antagonistic activity may cause tachycardia, anti-bradycardia, bronchodilation, suppression of gastrointestinal motility, suppression of acid secretion, b. Mydriasis, suppression of bladder atrophy, reduction of sweating, etc.
  • Muslin receptors There are at least three subtypes of this Muslin receptor. Mainly, M and receptors are present in the brain, etc., M 2 receptors are present in the heart and the like, and M 3 receptors are present in smooth muscle and glandular tissues.
  • Atotopin has a strong affinity for muscarinic receptors and blocks its action, so it is used as an anti- bradycardic agent.
  • the atotocin has almost the same affinity for all of the muscarinic receptor subtypes, o and Mg, and non-selectively antagonizes it (biological chemistry, 42 ( 5), 381 (1991)), which have side effects other than the intended effects, such as muscarinic receptor antagonism, effects on the central nervous system, effects on the center, nausea, urinary closure, constipation, and mydriasis This is known, and improvement has been desired.
  • compounds having a selective antagonism to Micromax 2 receptor are expected effects such as KoJo pulse is and expected to other muscarinic Li emissions receptor-based side effects subtype antagonism is small You.
  • a compound having high central migration with Micromax 2 receptor antagonism diseases of the central nervous system, are expected to be particularly useful for the treatment of Alzheimer's disease and Parkinson's disease.
  • Alzheimer's disease by the blocking child choline agonizing presynaptic nerve Micromax 2 inhibitory receptors (O over preparative. Receptors) in the central, Asechiru from nerve endings Increases choline release (Life science. Vol. 52 pp497-565 (1993)).
  • Parkinson's disease is a useful therapeutic agent that has no atotopin-like side effects compared to conventional centrally acting anticholinergic drugs (non-selective musculin receptor antagonists). (NEW Pharmacology pp254-292 (1989)).
  • Is a compound having a selective M 2 receptor antagonism are known conventionally, 5 having a substituted alkynyl carbonylation Le group in Japanese Patent Kokoku 5 68474 11th, 11- dihydric draw 6H- pyrido [2,3-b] [1,4]
  • Benzodiazepin-16-one derivatives have been disclosed and included in this publication 11-[[2- (Jetylaminomethyl) 1-1-piperidinyl) [Acetyl] 1-5,11-dihydro 6H-pyrido [2,3-b] [1,4] benzodiazepin-16-one (AF-DX116) is a compound currently under development.
  • JP-A-3-291273 As a patent disclosing a dibenzodiazepinone derivative, JP-A-3-291273 is cited. This publication describes a compound having the following general formula.
  • the structure of the compound of the present invention is different from that of the compound of the present invention in that the compound has a rubamoylpropionyl group on the 5-position nitrogen atom of the dibenzodiazepinone skeleton.
  • An object of the present invention has excellent Mus force Li emissions M 9 receptor affinity having different chemical structure from the conventional compounds, and Mus force Li emissions M 2 receptor antagonism It is to provide a compound having: Disclosure of the invention
  • the present inventors have compounds diary with the Mus force Li emissions M 2 receptor antagonism, a result of intensive studies, the new force Rubamoirupuro Pio two Le based on Benzojiazepino down derivative excellent Mus force re having a 1-position and completed the present invention found to have a selective antagonism of emissions M 2 receptors. That is, the present invention relates to a benzodiazepinone derivative represented by the following general formula (I) or a salt thereof.
  • R 1 is a hydrogen atom, a lower alkyl group which may be substituted, or cycloanolequinole 3
  • R hydrogen atom, optionally substituted lower alkyl group, cycloalkyl group, aryl group or aralkyl group
  • Ring B optionally substituted hydrocarbon ring group or 5- or 6-membered monocyclic heteroaryl group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms
  • n an integer from 1 to 5
  • R 1 is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group which may be substituted by a lower alkylthio group or a cycloalkyl group: or a cycloalkyl group;
  • R 2 is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkyl group which may be substituted with a lower alkylthio group or a cycloalkyl group; a cycloalkyl group; an aryl group; Group,
  • Ring B is an aryl group, a cycloalkyl group, or a 5- to 6-membered monocyclic heterocyclic group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms, and these ring groups are Alkenyl group; lower alkynyl group; halogen atom; hydroxyl group; mercapto group; lower alkylthio group; lower alkoxycarbonyl group; carboxy group; sulfonyl group; sulfinyl group; lower alkylsulfonyl group; lower alkylsulfinyl group; Mono- or di-lower alkyl group rubamoyl group; lower alkenyl group; lower alkenyl group; nitro group; cyano group; amino group; mono- or di-lower alkylamino group; 1-3 alkylenedioxy group; cycloalkyl group; aryl group; optionally substituted nitrogen-containing saturated ring group Or, optionally substituted lower
  • R 1 is a hydrogen atom or a lower alkyl group
  • R 2 is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted by a lower alkoxy group or a lower alkylthio group; a cycloalkyl group; an aryl group; or an aralkyl group;
  • Ring B may be substituted with a phenyl, naphthyl, lower alkyl or aryl group, C5-7 cycloalkyl group, furyl group, phenyl group, pyrrolyl group, imidazolyl group, thiazolyl group, isothia A zolyl group, a pyridyl group, a pyrimidinyl group, or a birazinyl group, wherein the funyl group is a halogen atom; a hydroxyl group; a mercapto group; Alkylthio group; lower alkoxycarbonyl group; carboxy group; carbamoyl group; mono or di-lower alkyl group rubamoyl group; nitro group; cyano group; amino group; mono or di-lower alkylamino group; 1-3 alkylenedioxy group; cycloalkyl group; aryl group; lower alkyl group, lower alkoxy group or nitrogen-containing saturated ring group
  • Benzodiazepinone derivative or a benzodiazepinone derivative which may be substituted with a lower alkyl group or a lower alkoxy group which may be substituted with a group, an amino group, or a mono- or di-lower alkylamino group salt ;
  • R 1 is a lower alkyl group
  • R 2 is a hydrogen atom; a halogen atom or a lower alkyl group which may be substituted with a lower alkoxy group; a cycloalkyl group; or an aralkyl group;
  • Ring B is a C5-7 cycloalkyl group, a phenyl group, or a phenyl group, which may be substituted with a fuunyl group, a naphthyl group, or an aryl group; the fuunyl group is a halogen atom; a hydroxyl group; A lower alkoxycarbonyl group; a nitro group; a mono or di-lower alkylamino group; a methylenedioxy group; a 5- to 7-membered nitrogen atom which may be substituted by a lower alkyl group or a lower alkoxycarbonyl group.
  • a benzodiazepinone derivative which is a phenyl group substituted with a 5- to 7-membered nitrogen-containing saturated ring group, wherein ring B may be substituted with a lower alkyl group, or a salt thereof;
  • lower means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.
  • lower alkyl group in the present specification specifically includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isopropyl group, a sec-butyl group, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl Group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethyl group T-butyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl
  • an alkylene group having 1 to 6 carbon atoms is preferable, and specifically, a methylene group, an ethylene group, a methylethylene group, a trimethylene group, a propylene group and the like.
  • cycloalkyl group those having 3 to 8 carbon atoms are preferable, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloalkyl groups. And a heptyl group.
  • hydrocarbon ring group is a saturated or unsaturated, monocyclic or condensed hydrocarbon ring group, and is preferably an “aryl group” or a “cycloalkyl group”. Or "cycloalkynyl group”.
  • an aryl group having 6 to 14 carbon atoms is preferable. Specifically, a phenyl group, a tril group, a xylyl group, a biphenyl group Phenyl, naphthyl, indenyl, anthryl, and phenanthryl; more preferably phenyl or naphthyl; and most preferably phenyl.
  • Examples of the “cycloalkenyl group” include those having 3 to 8 carbon atoms, specifically, 1-cyclopropenyl group, 2-cyclopropenyl group, 1-cyclobutenyl group, 2-cyclopropyl group. Cyclobutenyl group, 1-cyclopentenyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, 1-cyclohexenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, 1-cycloheptenyl group, 2 —Cycloheptenyl group, 3 —cycloheptenyl group, 1-cyclooctenyl group, 2 —cyclooctenyl group, 3-cyclooctenyl group, 4-cyclooctenyl group, 2,4 —cyclopentenyl group, 2,5 —six Rohexagenenyl group, 2,4—cycloheptagenyl group and 2,6—cycloheptagenyl group.
  • the “aralkyl group” means a group in which any hydrogen of the above “lower alkyl group” is substituted with an aryl group.
  • aryl group examples thereof include phenylalkyl groups such as benzyl group, phenyl group, phenylpropyl group and phenylbutyl group, and naphthylalkyl groups such as naphthylmethyl group and naphthylethyl group.
  • a “5- to 6-membered monocyclic heteroaryl group containing 1 to 4 oxygen, sulfur or nitrogen atoms” is a group containing 1 to 4 heteroatoms consisting of oxygen, sulfur or nitrogen atoms.
  • a 6-membered monocyclic heteroaryl group Specifically, a furyl group, a phenyl group, a thienyl group, a pyridine group, an imidazolyl group, a thiazolyl group, a pyrazolyl group, an isotizazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidyl group, and a pyridazinyl group.
  • a furyl group a chenyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyrimidinyl group, a virazinyl group, and the like are preferable.
  • a jyl group a furyl group, a chenyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyrimidinyl group, a virazinyl group, and the like are preferable.
  • a jyl group a furyl group, a chenyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyrimidinyl
  • substituent of the “optionally substituted lower alkyl group” for R 1 and R 2 include a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, and a cycloalkyl group.
  • Preferred are a halogen atom, a hydroxyl group, a lower alkoxy group and a lower alkylthio group, and more preferred are a halogen atom and a lower alkoxy group.
  • substituent of the “optionally substituted hydrocarbon ring group or a 5- or 6-membered monocyclic heteroaryl group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms” on the B ring include a lower alkenyl group, a lower alkynyl group, a halogen atom, a hydroxyl group, a mercapto group, a lower alkylthio group, a lower alkoxycarbonyl group, a carboxy group, a sulfonyl group, a sulfinyl group, a lower alkylsulfonyl group, and a lower alkyl group.
  • Rusulfinyl group carbamoyl group, mono- or di-lower alkyl Kill force rubamoyl group, lower alkanoyl group, lower alkanoyloxy group, nitro group, cyano group, amino group, mono- or di-lower alkylamino group.
  • Examples include a xy group, a cycloalkyl group, an aryl group, a nitrogen-containing saturated ring group which may be substituted, a lower alkyl group or a lower alkoxy group which may be substituted.
  • Preferable are a halogen atom, a hydroxyl group, a mercapto group, a lower alkylthio group, a lower alkoxycarbonyl group.
  • a 5- or 7-membered nitrogen-containing saturated ring group which may be substituted with a lower or lower alkoxycarbonyl group, a lower alkyl group which may be substituted with a halogen atom, or a di-lower alkylamino group. Is a lower alkoxy group which may be substituted.
  • the “lower alkoxy group” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy) ) Group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 11-ethylpropoxy group, hexyloxy group, and the like. It is a toxic group.
  • lower alkylthio group means a group in which a hydrogen atom in a mercapto group is substituted with the above lower alkyl group, and is a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group. Group, pentylthio group, hexylthio group and the like.
  • Halogen atom means a fluorine, chlorine, bromine, or iodine atom.
  • the “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, a propyl group, a butenyl group, a methylpropyl group, a methylpropyl group. Group, dimethylvinyl group, pentenyl group, methylbutenyl group, dimethylpropyl group, ethylpropyl group, hexenyl group, dimethylbutenyl group, methylpentenyl group and the like.
  • the “lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, and specifically includes ethynyl, propynyl, petynyl, methylpropynyl, pentynyl, methylbutynyl. And a hexynyl group.
  • “Lower alkoxycarbonyl” includes methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl. Isobutoxycarbonyl, sec-butoxycarbonyl, tert-butyl Toxoxycarbonyl group, pentyloxy (amiroxy) carbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxycarbonyl group, 2-methylbutoxycarbonyl group, 1, 2- Examples include a dimethylpropoxycarbonyl group, an 11-ethylpropoxycarbonyl group, and a hexyloxycarbonyl group.
  • lower alkylsulfonyl group examples include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group, and a hexylsulfonyl group.
  • lower alkylsulfinyl group examples include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group, a pentylsulfinyl group, and a hexylsulfinyl group.
  • “Mono- or di-lower alkyl group” refers to a carbamoyl group in which one or two hydrogen atoms in the group are substituted with the above lower alkyl group, and a methylcarbamoyl group. , Ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl and the like.
  • lower alkanol group examples include a formyl group, an acetyl group, a propionyl group, a butylyl group, a valeryl group and a bivaloyl group.
  • lower alkenyl group means a group in which an oxygen atom is added to the carbonyl carbon of the above “lower alkenyl group”, specifically, a formyloxy group, an acetyloxy group, a propionyloxy group, These include petityloxy, valeryloxy, and vivaloyloxy.
  • the “mono- or di-lower alkylamino group” means an amino group in which one or two hydrogen atoms in the amino group have been substituted with the above “lower alkyl group”, Examples thereof include a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group, a getylamino group, and a dipropylamino group.
  • the “C 1-3 alkylenedioxy group” is one in which oxygen atoms are bonded to both sides of an alkylene chain having 1 to 3 carbon atoms, and examples thereof include a methylenedioxy group, an ethylenedioxy group and a propylenedioxy group. And is preferably a methylenedioxy group.
  • Examples of the “lower alkyl group optionally substituted by a halogen atom” include a fluoromethyl group, a chloromethyl group, a bromomethyl group, a chloroethyl group, a dichloromethyl group, a bromochloromethyl group, and a trimethyl group. And a fluoromethyl group. Preferred is a trifluoromethyl group.
  • nitrogen-containing saturated ring group means a saturated heterocyclic group containing one or two nitrogen atoms and optionally having an oxygen atom or a sulfur atom, and is preferably a 5-membered to 7-membered ring. It is a member ring. Specific examples include a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group and the like, preferably a piperidyl group, a piperazinyl group, a morpholinyl group. Group. More preferably, these groups are linked to group A via a nitrogen atom.
  • the “nitrogen-containing saturated ring group” may be substituted, and examples of the substituent include a lower alkyl group, a lower alkoxy group, and a lower alkoxycarbonyl group. Preferably, it is a lower alkyl group.
  • substituent in the “optionally substituted lower alkyl group or lower alkoxy group” include a halogen atom, a hydroxyl group, a phenyl group, an amino group, a mono- or di-lower alkyl group, and the like.
  • the compound (I) of the present invention may have one or more asymmetric carbon atoms, and based on this, optical isomers such as (R) -form and (S) -form, racemic forms, diastereomers, etc. Exists. Also, depending on the type of substituent, it has a double bond, and there are geometric isomers such as (Z) -form and (E) -form.
  • the present invention embraces all of the isomers 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, lactic acid, lingic acid, quinic acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid.
  • Acid addition salts with organic acids such as glutamic acid .
  • the present invention includes hydrates of compound (I), solvates such as ethanol, and polymorphic substances. (Manufacturing method)
  • the compound (I) of the present invention can be produced by applying various production methods. Hereinafter, a typical production method will be described. First manufacturing method;
  • the amide compound represented by the general formula (IV) is represented by the general formula (II) and amide (II) or a salt thereof. It can be produced by condensing the carboxylic acid shown or a reactive derivative thereof according to a conventional method.
  • Reactive derivatives of compound (III) include acid halides such as acid chloride and acid bromide; acid azide; N-hydroxybenzotriazole (HOBT); P-diphenyl and N-hydroxysk. Active esters with imides and the like; symmetrical acid anhydrides; mixed acid anhydrides with alkyl carbonates, P-toluenesulfonic acid and the like.
  • the reaction conditions vary slightly depending on the starting compound, especially the type of reactive derivative of the compound ( ⁇ ⁇ ), ', pyridine, tetrahydrofuran, dioxane, ether, N, N-dimethylformamide, benzene, toluene.
  • Raw materials (II) and (III) in equimolar to raw materials in an organic solvent inert to the reaction, such as benzene, xylene, methylene chloride, dichloroethane, chloroform, ethyl acetate, acetonitrile, etc. It is advantageous to carry out the reaction using an excess of compound (III).
  • trimethylamine, triethylamine, pyridine, picolin, lutidine, dimethylanilinine, N-methylmorpholine The method is carried out in the presence of a base such as an organic base such as phosphorus, or an inorganic base such as sodium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide or potassium hydroxide. May be advantageous. Pyridines can also serve as solvents.
  • the reaction temperature varies depending on the type of the reactive derivative. It is set as appropriate.
  • the carboxyl-protecting group include lower alkyl groups such as methyl, ethyl, butyl, isopropyl, and tert-butyl.
  • Removal of the carboxyl-protecting group may be carried out according to a conventional method, and can be easily carried out, for example, by hydrolysis. (Second step)
  • R la and R 2a are the same groups as the corresponding R 1 and R 2 or the amino groups, respectively. Means a protecting group.
  • the amide compound represented by the general formula (I), which is the compound of the present invention, is produced by condensing carboxylic acid (IV) or a reactive derivative thereof with the amine represented by the general formula (V) according to a conventional method. can do.
  • Reactive derivatives of compound (IV) include acid halides such as acid chlorides and acid bromides; acid azides; N-hydroxybenzotriazole (HOBT), p-ditrophenyl and N-hydroxysk. Active esters with synimide and the like can be mentioned.
  • This reaction can be carried out under the same conditions as in the method described in the first step.
  • “Amino group-protecting group” represented by R la and R 2a which are the groups possessed by the compound of the formula (V) means a protecting group commonly used by those skilled in the art, and is typically an acyl group.
  • a protecting group for the amino group a formyl group, Lower alkanoyl groups such as tyl group and propionyl group, lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, BOC, etc., lower alkane sulfonyl groups such as ethanesulfonyl group and ethanesulfonyl group, methoxyacetyl group, Aliphatic acetyl groups such as methoxypropionyl group, benzoyl group, benzyloxycarbonyl group and p-2-trobenzoyloxyl carbonyl group, or chenyl acetyl group, thiazolyl acetyl group, tetra
  • benzyl, p-nitrobenzoyl, benzhydryl, trityl and the like can be mentioned as protective groups for aralkyl amino groups.
  • a tri-lower alkylsilyl group such as a trimethylsilyl group may be mentioned.
  • Removal of the protecting group from the amino group may be carried out according to a conventional method.
  • the protecting group is a tri-lower alkylsilyl group, etc.
  • the removal can be easily performed by treating with water.
  • a protecting group such as a benzhydryl group, a p-methoxybenzyl group, a trityl group, a tert-butyl group, or a formyl group
  • the N-alkyl reaction of the amino compound from which the amino-protecting group has been removed is carried out by a conventional method such as reductive amination, substitution with a halogen compound, etc. to obtain the compound (I) of the present invention. ) Can be obtained.
  • the compound (I) of the present invention is obtained by condensing a carboxylic acid (IV) or a reactive derivative thereof with a hydroxy compound represented by the general formula (VI) according to a conventional method to give a compound represented by the general formula (VII). Then, it can be produced by oxidizing to an aldehyde compound represented by the general formula (VIII) and condensing it with an amine represented by the general formula (IX) according to a conventional method.
  • the reaction between the compound represented by the general formula (IV) or a reactive derivative thereof and the compound represented by the general formula (VI) can be performed under the same conditions as in the method described in the first step of the first production method. is there.
  • the reactive derivative of the compound (VI) the same derivative as described in the second step of the first production method can be used.
  • the amide compound of the present invention represented by the general formula (I) is According to a conventional method, boronic acid or its reactive derivative (III) and the compound represented by the general formula (V) are condensed first, and then the reaction product (X) is deprotected to produce the compound (XI). However, it can be produced by subjecting the compound (XI) and the amine represented by the compound ⁇ ) to a condensation reaction.
  • the method of synthesizing compound (X) from carboxylic acid or its reactive derivative and the compound represented by general formula (V) is the same as in the second step of the first production method, and the reaction conditions and the like are the same as those in the second step. It is as described in.
  • the reaction of deprotecting the compound (X) to give the compound (XI) may be carried out according to a conventional method for removing the protecting group of the carboxyl group, for example, it can be easily carried out by hydrolysis.
  • the reaction for producing the compound (I) of the present invention by subjecting the compound represented by the general formula (XI) to a condensation reaction with the amine represented by the general formula (II) is the same as in the first step of the first production method.
  • the reaction conditions and the like are the same as in the first step.
  • Musca Li emissions M 2 receptors have antagonism, preventing young properly for various diseases M 2 receptors are involved are useful in the treatment.
  • Sinus dysfunction group such as sinus bradycardia, sinus arrest, bradycardia tachycardia syndrome; bradyarrhythmia such as atrioventricular block and other vagus nerve-induced bradycardia, neural syncope (carotid sinus hypersensitivity) Sex)).
  • the compounds of the present invention also include compounds that can be preventive and therapeutic agents for central nervous diseases such as Alzheimer's disease and Parkinson's disease, or compounds that have antispasmodic activity on peripheral organs, particularly the colon and bladder.
  • the present invention compounds compared to the M 3 receptor is a smooth muscle Mus force Li down operation movement portion position
  • high selectivity for M 2 receptor is the heart Mus force Li down operation movement portion position
  • Micromax 3 receptor antagonists based on the action, b thirst is particularly useful for bradyarrhythmias as less Micromax 2 receptor antagonist of side effects, such as effects on the central.
  • Affinity (Micromax M 2 and M 3) and M 2 receptor antagonism against Musca Li down receptors of the compounds of the present invention was confirmed by the following tests.
  • Wistar male rats 300-350 g were asphyxiated and killed with carbon dioxide using dry ice, and then the cerebral cortex, heart, and submandibular gland were excised, and the membrane fraction was prepared by a conventional method.
  • a specimen was obtained.
  • Cerebral cortex membrane preparation is 3 H - pirenzepine with (Mjassay), il, ⁇ specimens with J H- quinuclidinyl benzilate (QNB) ( Moassay), submandibular gland membrane specimen 3 H- N-methyl with Scopolamine (NMS) (Mgassay) After incubation for 45 minutes each, the mixture was filtered using a WhatmanGF / B filter, and the radiation dose was measured using a liquid scintillation counter.
  • Nonspecific binding was determined by adding 2 x 10-5 Matropine simultaneously and incubating.
  • HEPES buffer [4- (2-hydroxy-ethyl)-1-piperazinethane sulfonic acid 20 mM, NaCl lOOmM, MgCl 9 lOmM, pH 7.5] was used for membrane preparation, compound preparation, and incubation. used.
  • anesthesia with pentobarbiter was performed at 60 mgZkg ip, tracheal power, carotid power, left and right vagus nerve transection, and spinal cord destruction was performed.
  • the test compound or physiological saline was administered 15 minutes after administration of atenolol 10 mgZkg iv, and 15 minutes later, oxotremorine was cumulatively administered.
  • the evaluation compound was administered iv from the femoral vein.
  • the heart rate immediately before oxotremorine administration was set to 100%, and the dose-response curve was obtained by determining the rate of decrease in heart rate due to cumulative oxotremorine administration in the presence and absence of the test compound.
  • Evaluation absence of compound and ED 5 in (Con trolls) () value (Okiso preparative Remori 50% heart rate reducing effect for the amount due down), from the ratio of the ED 5 () value in the presence, dose- after calculating the rightward movement width of the curve (Dose- ratio), and Schild PLOu this deployment, determine the DR 10, it was expressed with a negative logarithmic value (pDR 10, mol / kg) .
  • urethane 1.2 gZkg 10 minutes after iP anesthesia administer the test compound or physiological saline, and after 15 minutes, oxotremorin 0.8 mol / kg iv. was administered.
  • the saliva secreted for 5 minutes immediately after oxotremorine administration was collected, and the weight was used as the salivary secretion.
  • the evaluation compound was administered i.v. from the femoral vein.
  • the salivary secretion of the control was defined as 100%, and the salivary secretion inhibition rate of the test compound was determined.
  • the 50% inhibitory dose (ID 5Q value) was calculated and expressed as a negative logarithmic value (PIDKQ.mol / kg). .
  • Table 2 shows the results of the above muscarinic receptor antagonist test (in vivo).
  • M2 / M3 Relative ratio compound of each compound when was the 1 M2ZM3 ratio
  • Atorobin A Kokoku 5 - than 68474 JP
  • Example 32 Compound above Mus force Li down antagonistic test results, the compounds of the present invention M 2 receptor high have binding shown, it was confirmed that further high M 2 receptor selectivity as compared with the M 3 receptors.
  • Pharmaceutical preparations containing one or more of the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients and other additives commonly used in pharmaceutical preparations.
  • Examples of carriers and excipients for pharmaceuticals include solid or liquid emergency pharmaceutical substances. Examples of these include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylen glycol, and other commonly used ones. Is exemplified.
  • Administration is via tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intravenous or intramuscular injections, suppositories, transdermals, inhalants, or intravesical injection. Any form of parenteral administration may be used.
  • the dose is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject of administration, gender, etc. However, in the case of oral administration, the dose is usually about 0.1 to 0.1 mg / kg for adults per day. This may be administered once or in 2-4 divided doses. When given intravenously due to symptoms, it is usually administered once or more than once daily in the range of O.OO lmgZkg to lOmgZkg per adult.
  • the one or more active substances may contain at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, poly, and the like. It is mixed with vinylpyrrolidone and magnesium aluminate.
  • the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium glycerol glycolate, and lactose. It may contain stabilizing agents, solubilizing agents such as glutamate or aspartate.
  • Tablets or pills may be sugar-coated such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc. May be coated with a film of an enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents. , For example, purified water. Contains ethanol. This composition may contain, in addition to the inert diluent, auxiliaries such as wetting agents and suspending agents, sweeteners, flavoring agents, flavoring agents and preservatives.
  • auxiliaries such as wetting agents and suspending agents, sweeteners, flavoring agents, flavoring agents 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.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. is there.
  • Such compositions may also include preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), and solubilizing agents (eg, glutamate, aspartic acid).
  • Adjuvants may be included.
  • the compounds of the present invention are not limited to the compounds described in the following Examples, and may also be those represented by the above general formula (I), salts thereof, hydrates thereof, solvates thereof, geometrical and optical properties thereof. It includes all isomers and polymorphs.
  • the starting compounds of the compounds of the present invention include novel compounds, and the production examples of these compounds will be described as reference examples.
  • Reference example 1 4-Morpholinobenzaldehyde A solution of 610 mg of dichloromethane (20 ml) in ice-cooled N, N'-ethylethyldiamine 1.85 g, acetic acid 2.74 g, triacetoxytridium borohydride (NaBH (OAc) 3 ) 2.02 g was added in sequence, and the mixture was returned to room temperature and stirred overnight. To the reaction solution was added a 1N aqueous sodium hydroxide solution (20 ml) to make it alkaline, and the mixture was extracted twice with chloroform (20 ml).
  • N— (2-chloroethyl) 1 N—methyl 4—morpholine To a solution of 380 mg of ethanol in ethanol (10 ml) was added 460 mg of aqueous solution of ethylamine 709, and the reaction mixture was stirred with 60 drops. After distilling off the solvent under reduced pressure, the resulting residue is crystallized from ether to give 300 mg of N'-ethyl-1-N-methyl-N- (4-morpholino) benzylethylenediamine hydrochloride in white color. Obtained as crystals.
  • N- [4- (4-Isopropyl-1-1-piperazinyl) benzyl] -N-methylamine 5.75 g of a 40% aqueous solution of chloroformate in 7.20 g of a chloroform solution (50 ml) under ice cooling. 3.52 g of acetic acid and 9.80 g of sodium triacetoxyborohydride were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. 1N sodium hydroxide was added to the reaction mixture, and the mixture was extracted twice with black-mouthed form to make it more viscous. After adjusting the form of the port, the mixture was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • N- (2-Chloroethyl) N— [4- (4-Isopropyl-11-piperazinyl) benzyl] —N-methylamine 5.94 g of ethanol 6.25 g of a 70% aqueous solution of ethyl ethylamine was added to the solution (40 ml), and the mixture was stirred at 60 for 2 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform (50 ml), 1N sodium hydroxide was added, and the mixture was extracted twice with chloroform.
  • Raw material compound N-cyclohexylmethyl N, N'-Jetlhetylenediamine
  • Example 59 Quality i Analytical value (m / z): FAB 629 (MH + ) In the same manner as in Example 1, the following compounds of Example 59 and Example 60 were obtained.
  • Example 59
  • nPr normal propyl group, iPr isopropyl group

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Abstract

Dérivé de benzodiazépinone ou son sel, représenté par la formule générale (I). Ce dérivé présente un antagonisme sélectif pour les récepteurs M2 de la muscarine et est utile comme agent prophylactique ou curatif de diverses maladies impliquant l'action des récepteurs M2 de la muscarine, telles que le syndrome de dysfonctionnement sinusal, notamment la bradycardie sinusale, l'arrêt sinusal et le syndrome de bradycardie-tachycardie, la bradyarythmie, notamment la bradycardie du bloc atrioventriculaire et la bradycardie vagale, et la syncope nerveuse (anaphylaxie du sinus carotidien).
PCT/JP1995/002217 1994-10-31 1995-10-30 Nouveau derive de benzodiazepinone et composition medicinale constituee de celui-ci WO1996013488A1 (fr)

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AU37544/95A AU3754495A (en) 1994-10-31 1995-10-30 Novel benzodiazepinone derivative and medicinal composition thereof

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JP26660994 1994-10-31
JP6/266609 1994-10-31
JP7/71869 1995-03-29
JP7186995 1995-03-29

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0217124A (ja) * 1988-05-17 1990-01-22 Dr Karl Thomae Gmbh 微小循環障害治療剤
JPH0232074A (ja) * 1988-06-08 1990-02-01 Dr Karl Thomae Gmbh 新規縮合ジアゼピノン類、それらを製造する方法及びこれらの化合物を含有する医薬組成物
JPH0240381A (ja) * 1988-06-15 1990-02-09 Dr Karl Thomae Gmbh 新規縮合ジアゼピノン類、それらの製造方法及びこれらの化合物を含有する医薬組成物
JPH0363274A (ja) * 1989-04-20 1991-03-19 Boehringer Ingelheim Pharmaceut Inc ６，１１―ジヒドロ―５Ｈ―ピリド［２，３―ｂ］［１，５］ベンゾジアゼピン―５―オン及び―チオン並びに該化合物のＡＩＤＳの予防又は治療における使用法
WO1991010654A1 (fr) * 1990-01-06 1991-07-25 Pfizer Limited Antagosnistes de recepteurs muscariniques
JPH0597845A (ja) * 1991-04-12 1993-04-20 Dr Karl Thomae Gmbh 縮合ジアゼピノン及びこれらの化合物を含む薬剤

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0217124A (ja) * 1988-05-17 1990-01-22 Dr Karl Thomae Gmbh 微小循環障害治療剤
JPH0232074A (ja) * 1988-06-08 1990-02-01 Dr Karl Thomae Gmbh 新規縮合ジアゼピノン類、それらを製造する方法及びこれらの化合物を含有する医薬組成物
JPH0240381A (ja) * 1988-06-15 1990-02-09 Dr Karl Thomae Gmbh 新規縮合ジアゼピノン類、それらの製造方法及びこれらの化合物を含有する医薬組成物
JPH0363274A (ja) * 1989-04-20 1991-03-19 Boehringer Ingelheim Pharmaceut Inc ６，１１―ジヒドロ―５Ｈ―ピリド［２，３―ｂ］［１，５］ベンゾジアゼピン―５―オン及び―チオン並びに該化合物のＡＩＤＳの予防又は治療における使用法
WO1991010654A1 (fr) * 1990-01-06 1991-07-25 Pfizer Limited Antagosnistes de recepteurs muscariniques
JPH0597845A (ja) * 1991-04-12 1993-04-20 Dr Karl Thomae Gmbh 縮合ジアゼピノン及びこれらの化合物を含む薬剤

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