WO1995018104A1 - Nouveau derive du benzamide et composition medicinale le contenant - Google Patents

Nouveau derive du benzamide et composition medicinale le contenant Download PDF

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Publication number
WO1995018104A1
WO1995018104A1 PCT/JP1994/002261 JP9402261W WO9518104A1 WO 1995018104 A1 WO1995018104 A1 WO 1995018104A1 JP 9402261 W JP9402261 W JP 9402261W WO 9518104 A1 WO9518104 A1 WO 9518104A1
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Prior art keywords
group
ethyl
benzamide
compound
amino
Prior art date
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PCT/JP1994/002261
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English (en)
French (fr)
Japanese (ja)
Inventor
Takeshi Suzuki
Naoki Imanishi
Hirotsune Itahana
Takeshi Kamato
Keiji Miyata
Mitsuaki Ohta
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU12823/95A priority Critical patent/AU1282395A/en
Publication of WO1995018104A1 publication Critical patent/WO1995018104A1/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • 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
    • C07D243/08—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 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention 5-HT 4 useful novel Benzuami de derivatives as receptor agonists, pharmaceutically acceptable salts, and pharmaceutical compositions thereof.
  • Serotonin (5-HT) receptors has been recognized that multiple subtypes exist, 5-HT, are classified into 5 -HT 2, 5 -HT 3 and 5-HT 4 receptor such as ing.
  • the compounds of the invention acts as potent and selective agonists of the 5 _HT 4 receptors widely distributed in urinary system soil organism.
  • the compound of the present invention exerts its action directly or indirectly by releasing acetylcholine from efferent nerve endings.
  • 5-HT 4 receptors work Doyaku the central nervous system, digestive system, circulatory system, believed to be useful with respect to disorders such as urinary system.
  • a patent disclosing a compound in which the substituted benzamide and a nitrogen-containing heterocycle (particularly a nitrogen-containing saturated heterocycle such as piperidine, pyrrolidine, etc., refer to the same in the following) via an alkylene group U.S. Pat. No. 4,772,459.
  • a compound represented by the following general formula is disclosed as a general formula, but a compound in which a substituted benzamide and a 2-position of a nitrogen-containing hetero ring are bonded via an ethylene group as in the compound of the present invention. (That is, W is an ethylene group), there is no specific description.
  • the patent does not describe anything about the 5-HT 4 receptor agonist activity of the compound of the present invention.
  • British Patent No. 1,466,822 and Japanese Patent Application Laid-Open No. 2-104572 include compounds having an antiemetic, anti-ulcer, central nervous system improving effect or gastrointestinal function enhancing effect.
  • the compounds of the present invention in which the substituted benzamide and nitrogen-containing compound are bonded to the nitrogen-containing ring at the 2-position of the tetracyclic ring through an ethylene group, and the 5-HT 4 agonistic activity are described in the following. There is no specific description.
  • the present invention has been completed based on the finding that a compound that binds via an (ethylene group) has a surprisingly remarkable 5-HT 4 receptor activating activity. That is, the present invention provides the following general formula
  • the present invention relates to a benzamide derivative represented by (I), a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a pharmaceutical composition comprising a compound represented by the following general formula (I) as an active ingredient.
  • Z an oxygen atom, a sulfur atom, a group represented by the formula CHR 6 , or a group represented by the formula NR 7
  • R 1a R lb , R 2a , R 2b same or different, hydrogen atom, lower alkyl group, hydroxyl group, or lower alkoxy group
  • R "and R lb or R 2e and R 2b may be combined to form a 4- to 7-membered cycloalkyl group
  • RR 5 hydrogen atom or lower alkyl group
  • R 4 hydrogen atom, lower alkyl group, or oxo group
  • RR 7 together with hydrogen atom, lower alkyl group, aralkyl group or R 3 may form ethylene
  • the compound of the present invention has a chemical structural characteristic in that (4-amino-5-halogeno 2-lower alkoxy) benzamide and a nitrogen-containing heterocycle are bonded via an ethylene group, and 5-HT 4 receptor is present. It has pharmacological characteristics in that it has agonistic activity on the body. Therefore, the compounds of the present invention, the light of the features of the pharmacological activity, drugs physiologically active different 5-HT 4 receptor before Symbol mentioned for compounds with antagonistic activity PC T WO 9 3 0 3725 issue of the present invention (1993) As described above, pamphlets can be said to be new compounds that are not considered to have been disclosed.
  • a first object of the present invention is to provide a novel benzamide derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a benzamide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It is in.
  • the present invention aims at providing the physician pharmaceutical composition as 5-HT 4 receptor agonists.
  • a lower alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group Group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, 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 Butyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl group
  • the lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specifically, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1, 2-dimethylpropoxy, hexyloxy, isohexyloxy, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,
  • 4- to 7-membered cycloalkyl group examples include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group, and a cyclohexyl group is preferable.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is particularly preferred.
  • Examples of the aralkyl group include, for example, benzyl group, phenyl group, 11-phenyl group, phenylpropyl group, 1-phenylpropyl group, 2-phenylpropyl group, phenylpropane-12-yl group, phenylbutyl group, Examples include 1-phenylbutyl group, 2-phenylbutyl group, 3-phenylbutyl group, phenylbutane-12-yl group, phenylbutane-13-yl group, naphthylmethyl group, and naphthylethyl group, of which benzyl group is preferred. is there.
  • nitrogen-containing heterocyclic group represented by the formula examples include, for example, for example, there are a piperidyl group, a pyrrolidinyl group, a morpholinyl group, a 1,4-diazabicyclo mouth [2.2.2] octyl group, a thiomorpholinyl group, a piperazinyl group, and a hexahydroazepinyl group. It may be substituted with an alkyl group, an oxo group, an aralkyl group and the like.
  • the compound (I) of the present invention forms an acid addition salt.
  • salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, Organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, cunic acid, methanesulfonic acid and ethanesulfonic acid, and amino acids such as aspartic acid and glutamic acid And acid addition salts thereof.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • Organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, cunic acid, me
  • the present invention also includes hydrates, various solvates and polymorphic substances of the compound (I) of the present invention.
  • the compound represented by the general formula (I) has at least one asymmetric carbon atom, several kinds of optical isomers may exist. These optical isomers, mixtures thereof, and racemates are included in the compounds of the present invention.
  • the present compound has stereoisomers (exo-form and endo-form) based on a group constituted by a nitrogen-containing heterocyclic ring, and the present invention includes both a mixture thereof and an isolated form. .
  • the compound of the present invention can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the type of the substituent.
  • the typical production method is shown below.c
  • the benzamide derivative of the present invention represented by the general formula (I) is obtained by reacting a carboxylic acid represented by the general formula (E) or a reactive derivative thereof or a salt thereof with a compound represented by the general formula (II). It can be manufactured by doing.
  • examples of the reactive derivative of the carboxylic acid include a lower alkyl ester, an activated ester, an acid anhydride, an acid halide and the like.
  • Active esters include p-nitrophenyl ester, 2,4,5-trichloro Mouth phenyl ester, pentachlorophenyl ester, cyanomethyl ester,
  • N-Hydroxysuccinic acid imido ester N-Hydroxyphthalimid ester, N-Hydroxy-5-Norbornene 1,2,3-Dicarboximidide ester, N-Hydroxypiperidine ester, 8-Hydroxyquinoline ester, 2— Examples include hydroxy xyphenyl ester, 2-hydroxy-14,5-dichlorophenyl ester, 2-hydroxypyridine ester, 2-pyridylthiol ester, and 1-benzotriazolyl ester.
  • the acid anhydride a symmetrical acid anhydride or a mixed acid anhydride is used.
  • the mixed acid anhydride include a mixed acid anhydride with an alkyl carbonate such as ethyl ethyl carbonate and isobutyl carbonate.
  • Mixed acid anhydride with chloroalkyl carbonate such as benzyl carbonate, acid anhydride mixed with chlorocarbonate such as phenyl carbonate, isovaleric acid, vivalic acid And mixed acid anhydrides with alkanoic acid.
  • the reaction can be carried out in the presence of a condensing agent.
  • a condensing agent examples include dicyclohexylcarpoimide, 1-ethyl-3- (3-dimethyla). (Minopropyl) carbodiimid hydrochloride, N, N'-carbonyldiimidazole, 1-ethoxycarbonyl-2,2-ethoxyquin-1,2-dihydroquinoline and the like.
  • solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; ethyl acetate, acetonitrile, and dimethylform.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as getyl ether, tetrahydrofuran, and dioxane
  • halogenated hydrocarbons such as methylene chloride and chloroform
  • ethyl acetate, acetonitrile, and dimethylform ethyl acetate, acetonitrile, and dimethylform.
  • Amide, dimethyl sulfoxide, ethylene glycol, water, etc., and these solvents can be used alone or as a mixture of two or more. Can be.
  • the solvent should be appropriately selected according to the type of the starting compound and the like.
  • This reaction is carried out in the presence of a base, if necessary.
  • a base include an alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, an alkali carbonate such as sodium carbonate and potassium carbonate, or triethylamine, tributylamine, diisopropyle. Chilamine,
  • reaction temperature varies depending on the type of the starting compound used, but is usually from 130 ° C to 200 ° C, preferably from 10 ° C to 150 ° C.
  • the pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting the compound to a conventional salt formation reaction.
  • Isolation and purification are carried out in a conventional manner by applying ordinary chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography.
  • exo-endo isomers can be separated by subjecting them to fractional chromatography utilizing the difference in adsorption affinity between the isomers and various adsorbents.
  • the optical isomer is separated into diastereomeric compounds by selecting an appropriate starting compound, or by a racemic resolution method (for example, an inoculation method) of a racemic compound or by condensation with a general optically active compound.
  • a salt can be formed with an optically active acid, and can be converted into a stereochemically pure isomer by a method such as optical fractionation.
  • the present invention compound or a salt, solvate or hydrate, central and peripheral nervous system, digestive system, cardiovascular system, by acting specifically on 5-HT 4 receptors present on such urinary system
  • Central nervous system disorders such as schizophrenia, depression, anxiety, memory disorders, dementia, gastroesophageal reflux diseases such as reflux esophagitis and gastroesophageal reflux associated with cystic fibrosis, Barrett's syndrome, non-ulcer Dyspepsia, abdominal indeterminate complaints, stomach stasis, bloating, anorexia, nausea Post resection syndrome, or sudden, chronic gastritis, stomach "duodenum It is useful in the treatment and prevention of gastrointestinal motility disorders associated with diseases such as ulcers, gastric neurosis, gastric ptosis, and diabetes.
  • the compound of the present invention is useful for diseases associated with cardiac dysfunction such as heart failure and myocardial ischemia, urinary diseases such as urinary tract obstruction, difficulty urinating due to ureteral stones or anterior hypertrophy, spinal cord injury, and pelvis. It can be used to treat constipation and difficulty urinating due to floor insufficiency.
  • the compound of the present invention has an anti-nociceptive activity, and is therefore useful as an anti-nociceptive agent for analgesia for increasing the threshold of pain.
  • the pharmacological activity of the compound of the present invention was confirmed by the following experimental method. Things.
  • a longitudinal muscle sample was prepared from the ileum of a male Hartley guinea pig (300-450 g), suspended in a Magnus tube filled with a krebs solution at a static tension of 1 g, and suspended at 0.1 Hz for 3 msec. By applying square wave electrical stimulation, the effect of enhancing contraction during drug administration was observed. b) Desensitization with 5-Methoxytributane
  • the compounds of the present invention has a structure connecting the 2-position of the heterocycle base Nzuami head portion and the nitrogen-containing 2 carbon (ethylene group), 5-HT 4 rather clearly all the correlation between the structure of the working active, Benzuami de Comparison of a compound with a compound in which the 2-position of the nitrogen-containing heterocycle is linked via a 1-carbon (methylene group) or 3-carbon (propylene group) via a 1-carbon (methylene group) or 3-carbon (propylene group) (Piperidine) The test was performed on the compound. As a result, both Example 1 and Example 4, in which the benzamide moiety and the 2-position of the nitrogen-containing heterocycle are linked via a two-carbon (ethylene group) ', showed significant dose-dependent contraction-enhancing effects. Was.
  • the compound in which the benzamide moiety and the nitrogen-containing heterocycle are bonded via two carbon atoms is a compound which is bonded via one carbon (methylene group) or It was found to have a remarkable guinea-pig ileal contractility-enhancing effect as compared to a compound bonded through three carbons (propylene groups).
  • Benzuami head portion and contraction-enhancing effect of the guinea pig ileum according to Examples 1 and 4 are compounds binding to the nitrogen-containing hetero ring 2 through a carbon (ethylene group) is 5 -HT 4 receptor agonistic is medicine 5 the main Tokishitoripu evening Min 1 0 IV [by desensitization is 8 0-9 0% inhibition, that by the action of the powerful guinea pig most of ileum contraction potentiation is 5 HT 4 receptor Was confirmed.
  • Such effects on other receptors may cause side effects, specifically, extrapyramidal disorders, diarrhea, constipation, and effects on the circulatory system.
  • the compound of the present invention which is a selective 5HT 4 receptor agonist, can be said to be a safer drug with less risk of side effects.
  • compositions containing one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient are commonly used carriers for pharmaceuticals. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, etc., using the preparations and other additives, and administered orally or parenterally.
  • the dosage is appropriately determined depending on the individual case in consideration of the symptoms, age, gender, body weight, etc. of the administration subject, but is usually 0.1 to 20 mg / day, preferably 1 to 100 mg / day for an adult. It is administered once to several times a day in the range of 100 mg.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, It is mixed with magnesium metasilicate aluminate.
  • the composition may, in a conventional manner, be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, or glumin.
  • a solubilizing agent such as an acid or aspartic acid may be contained. Tablets or pills may be coated with a film of a gastric material such as sucrose, gelatin, hydroquinol propyl cellulose, or hydroxypropyl methylcellulose phthalate, if necessary.
  • a gastric material such as sucrose, gelatin, hydroquinol propyl cellulose, or hydroxypropyl methylcellulose phthalate, if necessary.
  • 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 injection and physiological saline.
  • non-aqueous solutions and suspensions examples include vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and ethanol. And polysorbate 80. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (eg, lactose), and dissolution aids (eg, glutamic acid, aspartic acid). Good. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use. BEST MODE FOR CARRYING OUT THE INVENTION
  • the starting compound of the present invention also contains a novel substance, and the production method is shown in Reference Examples.
  • the resulting oil was purified by alumina column chromatography (eluent: methanol) and purified as brown oily methyl (1,4 diazabicyclo [2.2.2] oct-12-yl) acetate. 58 g were obtained.
  • reaction solution was cooled to 0 ° C., 4.0 g of sodium sulfate 10 hydrate was added, and the mixture was stirred for 30 minutes at room temperature.
  • the solid matter was separated by filtration, and the filtrate was concentrated under reduced pressure. 770 mg of colorless oily 2- (1,4-diazabicyclo [2.2.2] oct-2-yl) ethylamine was obtained.
  • 2-N- (2-pyridyl) propionitrile 1.50 g of ethanol solution 20 m 1, 4 N hydrogen chloride dioxane solution 5 m 1 are added, and platinum oxide 20 Omg is added as a catalyst. The mixture was stirred at 50 ° C for 2 days. After removing the catalyst by filtration and concentrating the filtrate, a mixed solvent of methanol and Z ether was added, and the mixture was neutralized with powdered potassium hydroxide. The precipitated inorganic salt was removed by filtration, and the filtrate was concentrated to obtain 1.45 g of 2- (2-piberidyl) propylamine as a yellow oil.
  • Mass spectrometry value (mZz, GO: 150 (M + )
  • Mass spectrometry value (mZz, GO: 3 1 5, 3 1 7 (M + )
  • Mass spectrometry value (mZ z, EI): 402, 404 (M + )
  • Example 1 1.0 Lactose 1 0 9 6 Microcrystalline cellulose 2 7 4 Light gay anhydride 15 Magnesium stearate 15 Compound of Example 1 30 g, lactose 3 28.8 g And 82.2 g of the microcrystal cell opening were mixed using a DC mixer. The mixture was compression-molded using a roller compactor to obtain a flake-like compact. The flake-like compact was pulverized using a hammer mill, and the pulverized product was sieved using a 2 O Mesh sieve. To the sieved product were added 4.5 g of light anhydrous silicic acid and 4.5 g of magnesium stearate, and mixed with a DC mixer. The mixture was tableted using a 7.5 mm diameter mortar and punch to give 300 tablets, each weighing 15 Omg.

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PCT/JP1994/002261 1993-12-28 1994-12-27 Nouveau derive du benzamide et composition medicinale le contenant WO1995018104A1 (fr)

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AU12823/95A AU1282395A (en) 1993-12-28 1994-12-27 Novel benzamide derivative and medicinal composition containing the same

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JP5/334396 1993-12-28
JP33439693 1993-12-28

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WO1995018104A1 true WO1995018104A1 (fr) 1995-07-06

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0748807A1 (fr) * 1995-06-13 1996-12-18 Synthelabo Dérivés de N- (1,4-diazabicyclo 2.2.2 oct-2-yl)méthyl benzamide, leur préparation et leur application en thérapeutique
FR2756563A1 (fr) * 1996-12-04 1998-06-05 Synthelabo Derives de benzoate de 1,4-diazabicyclo[2.2.2]oct-2-yl- methyle, leur preparation et leur application en therapeutique
FR2756564A1 (fr) * 1996-12-04 1998-06-05 Synthelabo Derives d'acide quinoleine-8-carboxylique, leur preparation et leur application en therapeutique
WO2005016876A3 (en) * 2003-08-08 2005-09-22 Schering Corp Cyclic amine bace-1 inhibitors having a benzamide substituent
JP2008540371A (ja) * 2005-05-03 2008-11-20 バイエル・クロツプサイエンス・エス・アー 新規ヘテロシクリルエチルベンズアミド誘導体
US7598250B2 (en) 2003-08-08 2009-10-06 Schering Corporation Cyclic amine BACE-1 inhibitors having a heterocyclic substituent
WO2012086807A1 (ja) 2010-12-22 2012-06-28 東ソー株式会社 新規な環状アミン化合物及びそれを用いたポリウレタン樹脂の製造方法
US8299267B2 (en) 2007-09-24 2012-10-30 Comentis, Inc. (3-hydroxy-4-amino-butan-2-yl) -3- (2-thiazol-2-yl-pyrrolidine-1-carbonyl) benzamide derivatives and related compounds as beta-secretase inhibitors for treating
US8648080B2 (en) 2009-07-09 2014-02-11 Raqualia Pharma Inc. Acid pump antagonist for the treatment of diseases involved in abnormal gastrointestinal motility
US8829028B2 (en) 2002-05-16 2014-09-09 Serodus As 5-HT4 receptor antagonists for the treatment of heart failure
WO2022189636A1 (en) * 2021-03-12 2022-09-15 Biomedcode Hellas Sa Anti-inflammatory carboxamide derivatives

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JPH05507942A (ja) * 1991-03-07 1993-11-11 ジー．ディー．サール　アンド　カンパニー 新規セロトニン作動性剤としての新規なｍｅｓｏ―アザ環式芳香族酸アミド化合物およびエステル化合物
JPH06306075A (ja) * 1993-04-23 1994-11-01 Sanwa Kagaku Kenkyusho Co Ltd エトキシベンズアミド誘導体

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JPH05507942A (ja) * 1991-03-07 1993-11-11 ジー．ディー．サール　アンド　カンパニー 新規セロトニン作動性剤としての新規なｍｅｓｏ―アザ環式芳香族酸アミド化合物およびエステル化合物
JPH06306075A (ja) * 1993-04-23 1994-11-01 Sanwa Kagaku Kenkyusho Co Ltd エトキシベンズアミド誘導体

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0748807A1 (fr) * 1995-06-13 1996-12-18 Synthelabo Dérivés de N- (1,4-diazabicyclo 2.2.2 oct-2-yl)méthyl benzamide, leur préparation et leur application en thérapeutique
FR2735475A1 (fr) * 1995-06-13 1996-12-20 Synthelabo Derives de n-((1,4-diazabicyclo(2.2.2)oct-2-yl)methyl) benzamide, leur preparation et leur application en therapeutique
US5663173A (en) * 1995-06-13 1997-09-02 Synthelabo N-[(1,4-diazabicyclo[2.2.2] oct-2-yl)methyl] benzamide derivatives, their preparations and their application in therapeutics
FR2756563A1 (fr) * 1996-12-04 1998-06-05 Synthelabo Derives de benzoate de 1,4-diazabicyclo[2.2.2]oct-2-yl- methyle, leur preparation et leur application en therapeutique
FR2756564A1 (fr) * 1996-12-04 1998-06-05 Synthelabo Derives d'acide quinoleine-8-carboxylique, leur preparation et leur application en therapeutique
WO1998024790A1 (fr) * 1996-12-04 1998-06-11 Synthelabo Derives de benzoate de 1,4-diazabicyclo[2.2.2]oct-2-ylmethyle, leur preparation et leur application en therapeutique
US8829028B2 (en) 2002-05-16 2014-09-09 Serodus As 5-HT4 receptor antagonists for the treatment of heart failure
US7598250B2 (en) 2003-08-08 2009-10-06 Schering Corporation Cyclic amine BACE-1 inhibitors having a heterocyclic substituent
US7662816B2 (en) 2003-08-08 2010-02-16 Schering Corporation Cyclic amine BACE-1 inhibitors having a benzamide substituent
US7910590B2 (en) 2003-08-08 2011-03-22 Schering Corporation Cyclic amine bace-1 inhibitors having a heterocyclic substituent
US8278334B2 (en) 2003-08-08 2012-10-02 Merck, Sharp & Dohme Corp. Cyclic amine BACE-1 inhibitors having a benzamide substituent
WO2005016876A3 (en) * 2003-08-08 2005-09-22 Schering Corp Cyclic amine bace-1 inhibitors having a benzamide substituent
US9062007B2 (en) 2003-08-08 2015-06-23 Merck Sharp & Dohme Corp. Cyclic amide BACE-1 inhibitors having a benzamide substituent
JP2008540371A (ja) * 2005-05-03 2008-11-20 バイエル・クロツプサイエンス・エス・アー 新規ヘテロシクリルエチルベンズアミド誘導体
US8299267B2 (en) 2007-09-24 2012-10-30 Comentis, Inc. (3-hydroxy-4-amino-butan-2-yl) -3- (2-thiazol-2-yl-pyrrolidine-1-carbonyl) benzamide derivatives and related compounds as beta-secretase inhibitors for treating
US8648080B2 (en) 2009-07-09 2014-02-11 Raqualia Pharma Inc. Acid pump antagonist for the treatment of diseases involved in abnormal gastrointestinal motility
WO2012086807A1 (ja) 2010-12-22 2012-06-28 東ソー株式会社 新規な環状アミン化合物及びそれを用いたポリウレタン樹脂の製造方法
WO2022189636A1 (en) * 2021-03-12 2022-09-15 Biomedcode Hellas Sa Anti-inflammatory carboxamide derivatives

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