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WO1996010567A1 - Derive d'aminocetone et sel physiologiquement acceptable de celle-ci et leur utilisation - Google Patents

Derive d'aminocetone et sel physiologiquement acceptable de celle-ci et leur utilisation Download PDF

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Publication number
WO1996010567A1
WO1996010567A1 PCT/JP1995/001965 JP9501965W WO9610567A1 WO 1996010567 A1 WO1996010567 A1 WO 1996010567A1 JP 9501965 W JP9501965 W JP 9501965W WO 9610567 A1 WO9610567 A1 WO 9610567A1
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Prior art keywords
group
compound
general formula
methyl
lower alkyl
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PCT/JP1995/001965
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English (en)
Japanese (ja)
Inventor
Takeaki Matsui
Hirofumi Yamazaki
Masako Hashinaga
Yuichiro Tanaka
Kazuo Kimura
Tetsuo Toga
Tomohiro Naruse
Hirokazu Hiraoka
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Maruho Co., Ltd.
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Publication of WO1996010567A1 publication Critical patent/WO1996010567A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a novel aminoketone derivative having a central muscle relaxing action, or a physiologically acceptable salt thereof, and a therapeutic agent containing the same as an active ingredient.
  • the compound of the present invention and a physiologically acceptable salt thereof are used for the treatment of diseases having spastic paralysis as a main symptom, painful muscle spasticity associated with musculoskeletal diseases, etc. It is useful as an active ingredient of the drug.
  • aminoketone derivatives such as tonoleperizone hydrochloride and eperizone hydrochloride have been clinically used.
  • Many reports have also been made (for example, Japanese Patent Application Laid-Open No. Sho 60-255 767, Japanese Patent Application Laid-open No. 61-2077379.
  • JP-A-63-114944, JP-A-3-157375 and JP-A-5151380 All of these aminoketon derivatives are
  • R ′ represents a hydrogen atom
  • Rb represents a lower alkyl group
  • C ′ represents an asymmetric carbon atom
  • An object of the present invention is to provide a muscle relaxant which is excellent in muscle relaxing action, has a large safety factor, and has a long action holding time.
  • the present invention aims to provide a novel therapeutic agent for pollakiuria.
  • FIG. 1 shows the results regarding the frequency-reducing effect.
  • the present inventor has proposed that aromatic 3 ⁇ 4 in the above structure is heterogeneous.
  • Aminoketone derivative obtained by substituting R 'with a lower alkyl group in a compound that is a thiol group has a muscle relaxing action and a therapeutic action for pollakiuria, and its action duration And found that the safety factor was long, and completed the present invention.
  • A represents a Holl tertiary group to y which may have a substituent, and R 1 and R 2 may be the same or different and each is a lower alkyl group.
  • R 3 represents a hydrogen atom or a lower alkyl group;
  • R 4 and R 5 may be the same or different and each represents a lower alkyl group;
  • R 4 and R 5 are linked to each other to form an alicyclic 5-, 6- or 7-membered ring, and Y is
  • the present invention provides a central muscle relaxant comprising, as an active ingredient, the aminoketone derivative represented by the general formula (I) or a physiologically acceptable salt thereof. It is provided.
  • the present invention provides a therapeutic agent for pollakiuria comprising, as an active ingredient, the aminoketone derivative represented by the general formula (I) or a physiologically acceptable salt thereof. That is what we do.
  • lower with respect to “alkyl”, “alkyl group” or “alkoxy group” has 1 to 5 carbon atoms unless otherwise defined. It preferably means 1 to 4 pieces, more preferably 1 to 3 pieces.
  • the compound of the present invention represented by the general formula (I) may have an asymmetric carbon atom, and has various optical isomers.
  • the present invention includes both the optically active isomers having the absolute configuration of R or S and these racemic isomers. It is.
  • each of the diastereomers is also within the scope of the present invention, and the physiologically acceptable salts of the compound of the present invention include: Inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and formate, acetate, citrate, succinate, maleate, Malate, tartrate.
  • Organic salts such as methansulfonate, p-tonolensulfonate, and lactate. These salts can be easily produced from a free base by a conventionally known method.
  • the heteroaryl group which may have a substituent represented by A in the compound of the general formula (I) may be a ceynole group, a phenol group or a fluorine group.
  • 5-membered ring group having one heteroatom such as benzoyl group, virazolyl group, thiazolyl group isothiazolyl group, oxazolyl group, isosoyl group 5-membered ring group having 2 hetero atoms such as oxazolyl group and imidazolyl group, and 6-membered ring having one hetero atom such as pyridyl group Group having two hetero atoms such as pyridinyl group, pyrimidinyl group, pyridinyl group, and pyracinyl group, and other isoindolinol groups , Indazolyl group, quinolyl group, isoquinolinol group, naphthyridyl group, benzoxazolyl group, benzoiso
  • the number of substituents is preferably 1 to 3 in the case of a 5-membered ring having one heteroatom atom, and is preferably Is one or two, more preferably one, and in the case of a five-membered ring having two heteroatoms, one or two, preferably one, and One to four, preferably one to two, for a six-membered ring with one child, and one to three, preferably for a six-membered ring with two heteroatoms.
  • the number is 1 to 4, preferably 1 to 3, and more preferably 1 to 2.
  • Examples of the substituent of the heteroaryl group represented by A include-a lower alkyl group, a lower alkoxy group, a hydroxy group-a nitro group, a cyano group, Amino group, mono-lower alkylamino group, di-lower alkylamino group, monoarylamino group, diarynoamino group, anilino group, diphenylamine Group, halogen atom, lower alkyl carbonyl Acid amide groups, acryloinorea ino groups, propioloinorea ino groups, metacryloinorea ino groups, and crotoinoinorea ino groups Is isocrotonoinoamino group, lower alkylsulfonylamino group, rubamoyl group, N-mono lower alkyl group, rubamoyl group, N—di-lower phenol ⁇ , ⁇ , —, —, —, —, —, —, —, —,
  • the lower alkyl group includes a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butynole group, isobutynole group, se c-Alkyl groups having 1 to 4 carbon atoms, such as butynole group and tert-butyl group.
  • Lower alkoxy groups include methoxy, ethoxy, n-propoxy, iso-prooxy, n-butoxy, iso Examples thereof include an alkoxy group having 1 to 4 carbon atoms, such as a butoxy group, a sec-hydroxy group, and a tert-butoxy group.
  • Mono lower alkylamino groups include methylamino group, ethylamino group, n-propylamino group, and Monoalkylamines having 1 to 4 carbon atoms, such as isopropylamino, n-butylamino, isobutylamino, sec-butynoleamino, tert-butylamino, etc.
  • di-lower alkylamino group examples include a dimethinoleamino group, a getylamino group, a di-n-phenylamino group, a diisopropinoleamino group, Dialkylamino groups having 2 to 8 carbon atoms, such as di-n-butinorea mino group, diisobutinorea mino group, disec-butinorea mino group, di-tert-butylamino group, etc.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and a iodine atom.
  • the lower alkyl carboxylic acid amide group includes an acetate amide group, a propion amide group, a butyl amide group, an isobutynoleamide group, and a sec-butyl amide group. And a tert-butyl amide group.
  • the lower alkylsulfonylamino groups include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, and n-butylsulfonylamino.
  • alkylsulfonylamino group having 1 to 4 carbon atoms such as an isobutylsulfonylamino group, a sec-butylsulfonylamino group, and a tert-butylsulfonylamino group.
  • Rubamoyl groups include methylone group, methyl group, ethylethyl group, methyl group, n-propisoleca group, isopropyl group, 'Moinole group, n-butynole cane' Moinole group, isobutynol force Norevamoinole group, sec-Butylcanoleno, 'Moinole group, tert-butyl carbamoyl group, etc. 2 to 5 alkynolecal /, 'moyl groups.
  • N Di-lower alkyl caneno, 'Mo-no-re group, di-methyl-no-ha' mo-no-re, Jetirka-no-reno, 'Mo-no-re, G-n-propynole Noreno, Mo'nore, diisopropinole, Noreno, Mo'nore, di-n-butynocanoleno, Mo'nole, diisopropinole And a dialkyl-alkenyl group having 3 to 9 carbon atoms, such as a z-sec-butynole group.
  • Examples of the lower alkyls group include a methyl group, a methyl group, a methyl group, and an n-propynole group. Nore group, Isopropinoresorenomoinore group, n-butylinoresorenomoreoinore group, Isobutinoresorinorewamoinore group, sec—Buchi
  • Examples of the phenol group include a phenol group having 1 to 4 carbon atoms, such as a tert-butyl famoyl group, such as a tert-butyl famoyl group.
  • the ketone group represented by Y in the compound of the general formula (I) Means that a compound in which Y is a carbonyl group is reacted with glycols such as ethyl glycol, trimethyl glycol and the like.
  • glycols such as ethyl glycol, trimethyl glycol and the like.
  • the 5- or 6-membered cyclic ketal which may have 1 to 4 methyl groups formed thereby, and the ⁇ is a carbonyl group Formed by the reaction of the compound with phenolic compounds having 1 to 4 carbon atoms such as methanol, ethanol, propanol, butanol, etc. Means a non-annular ketal.
  • the hetero atom include a nitrogen atom, an oxygen atom, and a sulfur atom.
  • the number of lower alkyl groups is determined by the size of the ring, the type of hetero atom and Depending on the number, usually one to three, preferably Is one or two.
  • the alicyclic five-membered, six-membered and seven-membered rings which may be formed by linking R 4 and R 5 include a lipocyclic ring and a piperidine. Ring, morpholine ring, pyrazine ring, homopyridine ring, thiomorpholine ring, homomorpholine ring, and homopyrazine ring.
  • A substituted with a heteroaryl group substituted with a phenyl group which may have a substituent, particularly a phenyl group which may have a lower alkyl group.
  • R 1 and R 2 are the same lower alkyl group
  • R 3 a hydrogen atom or n is 0;
  • R 5 methyl or ethyl or N (R 4 )
  • R 5 is N-pyrrolidinyl, N—piperidinyl, N—morpholinyl , Which may have a lower alkyl group at the 4-position, N — piperazinyl group,
  • a preferred phenyl group having a phenyl group substituted with a phenyl group which may have the above substituent group is as follows.
  • a hydrogen atom (when there is no substituent), a lower alkyl group, a lower alkoxy group, a trifluoromethizole group, a halogen atom, a vinylinole group, and a cyclopro group Pill groups are exemplified, and particularly preferable substituents include a hydrogen atom (when no substituent is present), a lower alkyl group, a lower alkoxy group, and a trifluorene methacrylate. And a halogen atom.
  • Particularly preferred compounds of the present invention include compounds of the following general formulas (11), (111), (IV) and (V):
  • R represents a hydrogen atom, a methyl group, an ethyl group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a methoxy group or an ethoxy group.
  • R 1 ′ and R 2 ′ are the same and represent a methyl group or an ethyl group.
  • R 41 and R 6 ′ may be the same or different and each represents a force representing a methyl group or an ethyl group, respectively, or NR 4 ′ R S * Represents a group represented by ].
  • the compound of the present invention can be synthesized according to the following reaction schemes D to I.
  • the reaction process formulas D to ⁇ The ketone represented by the following general formula (6), which is used as a starting material, can be synthesized according to the reaction schemes A to (:
  • the aldehyde derivative represented by the following general formula (1), which is used as a starting material in the above, can be synthesized by a method known in the literature, and can also be obtained by a method known in the literature. It can be synthesized from the corresponding carboxylic acid, ester or alcohol by a method well known in synthetic chemistry.
  • Other reagents and intermediates used in formulas A-I are commercially available compounds that can be purchased or are known in the literature, It can be synthesized based on the description in the literature.
  • the heteroaryl group represented by A is a hydroxyl group, an amino group, a mono-lower alkylamino group as a substituent, or a canolebamo-inole group or N— Mono If the compound has a lower alkynolecal bamoyl group or the like, a protecting group generally used for such a substituent (for example, a benzyl group, a benzyloxy carbonyl group) , Tert-butoxycarbonyl) etc. can be used as needed.
  • a protecting group generally used for such a substituent for example, a benzyl group, a benzyloxy carbonyl group
  • Tert-butoxycarbonyl Tert-butoxycarbonyl
  • R 1 and R 2 are the same as above.
  • X represents a chlorine atom, a bromine atom or an iodine atom.
  • the aldehyde of the above general formula (1) is reacted with the Grignard reagent of the general formula (2) in a solvent at -20 to 40 for 10 minutes to 4 hours. Obtain the alcohol of (3).
  • the reaction is carried out by reacting one mole of the aldehyde of the general formula (1) with the Grignard reagent of the general formula (2). Use 1 to 4 moles. Ethers such as dry ether and dry tetrahydrofuran can be used as the solvent.
  • the alcohol (3) obtained in the above step (i) is oxidized or DMS 0-oxidized in a solvent using an oxidizing agent, so that the alcohol represented by the general formula (4) is obtained.
  • Get a ton In the reaction using an oxidizing agent, use 1 equivalent to an excess amount of the oxidizing agent with respect to 1 mole of the alcohol (3), and react at 0 to 60 for 30 minutes to 24 hours.
  • the solvent include pyridin, methylene chloride, carbon tetrachloride and the like.
  • the oxidizing agent include chromic acid, pyridinium chromium mouth chromate, and activated manganese dioxide.
  • Solvents include halogenated hydrocarbons such as methylene chloride, ethers such as ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene. And so on.
  • base triethylamine, sodium hydride, lithium diisopropinoleamide, n-butyllithium and the like are used.
  • sodium hydride, lithium diisopropylamine, or n-butyllithium is used as the base, the ketone of the general formula (4) is used in a solvent. After forming an enolate by pretreatment with a base, it is reacted with an alkyl halide of the general formula (5).
  • the compound of the general formula (8) is reacted by reacting the compound of the general formula (7) with magnesium in a solvent.
  • the reaction is a compound of the general formula (7)
  • solvent examples include ethers such as ether and tetrahydrofuran.
  • the compound of the present invention of the general formula (12) is obtained.
  • about 1 to 4 moles of dialkylamine of general formula (11) and about 1 to 4 moles of formaldehyde are used for 1 mole of ketone of general formula (6).
  • Solvents include aliphatic alcohols such as ethanol, halogenated hydrocarbons such as methylene chloride, ethers such as ether and tetrahydrofuran. And aromatic zero-group hydrocarbons such as benzene.
  • Y in the general formula (I) is a carbonyl group and n is 1>
  • the compound of the general formula (16) is obtained by reacting the alcohol of the general formula (14) with p-toluenes-norefonyl chloride (15) in a solvent.
  • a solvent In the reaction, about 1 to 3 moles of p-toluenesulfonyl chloride is used per 1 mole of the phenolic alcohol of the general formula (14) at 0 to 40 ° C for 30 minutes. Let react for ⁇ 2 days.
  • the solvent include pyridin, methylene chloride, and tetrahydrofuran.
  • the base include pyridin and triethylamine.
  • the compound of the present invention of the general formula (17) is obtained.
  • 1 mol of the amide of the general formula (11) is used per 1 mol of the compound of the general formula (16) to an excess amount.
  • the reaction is performed at 0 to 140 ° C for 1 hour to 4 hours. Let it react for days.
  • the solvent include phenolic alcohols such as methanol and ethanol, halogenated hydrocarbons such as chlorophonolem, and methylene chloride, ethers and tetrahydro.
  • ethereals such as droflan, aromatic hydrocarbons such as benzene and toluene.
  • the carbonyl group of the aminoketone compound of the above general formula (18) is reduced in a solvent in the presence of a reducing agent, and the amino group of the general formula (19) is reduced.
  • a reducing agent 1 equivalent to an excess amount of a reducing agent is added to 1 mol of the aminoketone compound of the general formula (18), and the reaction is performed in a range of 40 to 60. Perform at C for 10 minutes to 6 hours.
  • the solvent include phenolic compounds such as methanol and ethanol, ethers such as ether and tetrahydrofuran, and the like. It is.
  • the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride, diborane, and the like.
  • the amide of the general formula (23) is obtained.
  • the intended compound of the present invention is obtained.
  • the reaction is carried out in such a manner that 1 mol of the amino group of the general formula (22) is added to 1 mol to an excess amount, and 0.1 to 2 mol of the catalyst is used per 1 mol of the aminoketone compound of the general formula (18).
  • the solvent include halogenated hydrocarbons such as chloroporous dimethyl chloride, ethers, ethers such as tetrahydrofuran, and benzene.
  • hydrocarbons such as toluene and the like.
  • P-tonorensorephonic acid methansnorrephonic acid
  • sulfuric acid hydrochloric acid
  • p-toluenesulfonate pyridinium hydrocarbons such as toluene and the like.
  • reaction scheme H shows a method for synthesizing a kettle in the case of using ethylene glycol and trimethyl alcohol. Under similar conditions, use other glycols or alcohols instead of ethylene glycol and trimethylene glycol. By reacting, other keta can be easily synthesized.
  • R ' ⁇ R ⁇ R 2, R 3, R ⁇ R 5 and n are the same above.
  • X represents a chlorine atom or a bromine atom.
  • the amino alcohol of the above general formula (19) is esterified with a carboxylic anhydride or a carboxylic acid halide of the general formula (24) in the presence of a base in a solvent.
  • a compound of the general formula (25) The reaction is carried out with respect to 1 mol of the amino phenol of the general formula (19) and one mono- to excess of the anhydrous carboxylic acid or halogenated carboxylic acid of the general formula (24) 1 to 10 mol of base and 0 to 60 mol Run for 5 minutes to 2 days.
  • the solvent include pyridin, methylene chloride, tetrahydrofuran, and the like.
  • the base include pyridin and triethylamine. If necessary, 4-dimethylaminopyrrolidine is used as a catalyst.
  • the compound of the present invention has a central muscle relaxing action and a therapeutic action for pollakiuria, and can be used as an active ingredient of a central muscle relaxant and a therapeutic agent for pollakiuria.
  • the therapeutic dose of a therapeutic agent for a central muscle relaxant or pollakiuria containing the compound of the present invention as an active ingredient depends on the patient's age, sex, the condition to be treated, and the method of administration. Depending on the strength, it can usually be 1 to 200 mg per day for an adult, preferably 10 to 200 mg per day.
  • Dosage forms include oral preparations such as capsules, tablets, fine granules, syrups and powders, or injections, suppositories, patches, ointments and aerosols. It can be administered orally or parenterally.
  • the following excipients can be used as appropriate according to the dosage form.
  • Binders starch, na-starch, gelatin, methylcellulose, polyvinylidene-lipidone, hydroxypropinolemethylcellulose, Hydroxypropyl phenolic cellulose, crystalline cellulose, etc .;
  • Disintegrants starch, carboxymethylcellulose canolesum, low-substituted hydroxypropinolylcellulose, canolepoximetyl starch, etc. ;
  • Lubricants magnesium stearate, evening water, anhydrous genoic acid, etc .;
  • Coating agents sucrose, talc, precipitated calcium carbonate, gelatin, arabic gum, punoreran, canola naenuro, hydroxip Lopinoretorenoroseororofufu rate, etc .;
  • a brightening agent a flavoring agent, a stabilizer, a coloring agent, and the like can be appropriately used.
  • Solvents water for injection, vegetable oils such as sesame oil, macrogol, etc .;
  • Tonicity agent sodium chloride, etc .
  • Buffering agents sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, vinegar Acid, sodium acetate, etc .;
  • Soothing agent benzyl alcohol, procaine hydrochloride, etc .;
  • Preservative Parabens such as methyl parabenzoate, benzyl alcohol, etc. can be used according to the purpose.
  • Base cocoa butter, hardened oil, saturated fatty acid glycerin ester, branched saturated alcohol, macrogol, etc.
  • Emulsifier anionic surfactant, non-ionic An active surface active agent can be used according to the purpose.
  • Thickeners sodium alginate, gelatin, methylcellulose, canoleboxininole repolymer, sodium polyacrylate, etc .;
  • Moisturizers glycerin, macrogol, etc .
  • Fillers kaolin, titanium dioxide, zinc oxide, etc .
  • Crosslinkers acetoaldehyde, dimethylketone, Aluminum sulfate, etc .
  • Solubilizers alcohols such as ethanol, 2-propanol, macrogol, etc .; Emulsifier: Anionic surfactants and nonionic surfactants can be used according to the purpose.
  • Base White petrolatum, hydrocarbons such as liquid paraffin, fats and oils such as soybeans, rowes such as beeswax and lanolin, stearic acid, oleic acid, etc. Fatty acids, higher alcohols and their esters, macrogol, etc .; emulsifiers: use anionic surfactants, nonionic surfactants, etc. according to the purpose. It can be.
  • Solvents' base ethanol, 2-propanol, propylene glycol, etc .;
  • Emulsifier various surfactants
  • Fluorinated hydrocarbons Fluorinated hydrocarbons, liquefied petroleum gas, compressed gas, etc. can be used according to the purpose.
  • the compound of the present invention and a physiologically acceptable salt thereof have excellent muscle relaxation, anti-crazing activity, etc., and muscles caused by diseases such as lumbar back pain, herniated disc, and shoulder-like arm syndrome. It is extremely useful as an active ingredient of a therapeutic agent for spastic paralysis caused by diseases such as tension and cerebrovascular disorder, spastic spinal palsy, and cerebral palsy. It is also useful as a therapeutic agent for pollakiuria.
  • reaction solution was washed with a 1N hydrochloric acid aqueous solution, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove 5- (1 95.2 g of ⁇ -xy-2-methyl 7 ° ⁇ -yl) -3-phenyiI-no-kis-a-kia-factor (alcohol compound) was obtained as crude yellow crystals.
  • reaction solution After stirring at room temperature for 1 hour, the reaction solution is poured into water, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off to remove the yellowish yellow ⁇ 5- ( 37.2-g of crude product of 3-human, lipo-2,2-cyclomethylthyryl) -3-phenylisophenol was obtained as a crude product.
  • the hydroxy compound obtained above was dissolved in 200 ml of pyridin, and 21.0 g (110 mi) of tosinole chloride was added under ice cooling. Stirred for hours. The reaction solution was poured into ice water-concentrated hydrochloric acid, and methylene chloride was extracted. Methyl chloride The ren layer was washed successively with water, saturated aqueous sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove 5- (2,2-cis-methyl) methyl alcohol. 1-3-Tosyl-sulfur xyph * tyryl) -3-Fu-nirui 36.8 g as crude product was obtained.
  • the compound of the present invention has a central muscle relaxing action by an animal experiment of an anti-crazing action and a muscle relaxing action. In addition, an acute toxicity test was conducted, and the safety factor was also examined. In addition, it was confirmed by an animal experiment of the effect of suppressing pollakiuria that it had the effect of treating pollakiuria. Eperizon hydrochloride, inaperizon hydrochloride, and flavoxate hydrochloride were used as control drugs.
  • mice Six to ten ddY male mice (5-week-old) fasted overnight were used per group. The test compound is orally administered, and 30 minutes later, 3 mg / kg of nicotine tartrate is administered via the tail vein to produce clonic and tonic eccentric spasms caused by nicotine. The effect of antagonism on pancreatic death after birth was examined. The measured value was expressed as a 50% effective dose of the free form (ED 50 , mg / kg).
  • mice Six male ddY mice (5 weeks old) fasted overnight were used per group.
  • the test compound was orally administered, and 30 minutes later, a current of 20 mA was applied for 0.2 seconds from the electrodes applied to both eyes, and the antagonism to the tonic convulsions caused by electrical stimulation was examined.
  • Measurements 503 ⁇ 4 effective amount of off rie body (ED S., Mg / kg ) and to the table.
  • mice Six dd Y male mice (5-week-old) fasted at night were used per group. The test compound was orally administered, and after 15, 30, 60 and 120 minutes, a rotating rod (diameter 3 cm, llr pm) and the residence time was measured up to a maximum of 120 seconds. In addition, animals with a residence time of 60 seconds or less were judged to have a positive muscle relaxant action.Based on the number of positive animals 30 minutes after administration, Compound A, Compound B, Compound C, Compound D, Compound E, Compound F and Fri 50% effective amount of control drug
  • the muscle-relaxing effect of compound G was investigated using the rotating bar method and compared with that of eperizon hydrochloride.
  • the test compound was orally administered, placed on a rotating rod after 15, 30, and 60 minutes, and the residence time was measured up to a maximum of 120 seconds.
  • the residence time of 30 minutes after administration is determined 60 seconds following animal with muscle relaxant positive, 50% effective amount of positive animals Number or al of compound G and the control drug full rie body (ED 5 0 mg / kg) was calculated.
  • Rats Injected saline into the bladder induced a micturition reflex and examined whether compound B had a prolonged action (increased bladder volume) until urination.
  • a male Sprague-Dawley rat weighing 250 to 400 g was anesthetized with 500 mg / kg of perethane, ip, a-chlorose 50 mg / kg, ip, and fixed in the dorsal position.
  • the bladder was exposed through a midline incision in the lower abdomen, and a small incision was added to the top of the bladder, and a silicone tube was inserted.
  • the other end of the silicon tubing was connected to a low-pressure transducer and a continuous infusion device, and physiological saline was injected into the bladder at a rate of 5 to 20 ml / hr.
  • Urine (saline) drainage Urinary contraction of the urinary bladder was artificially induced.
  • the compound was administered by a catheter inserted into the right external jugular vein one minute before the start of saline infusion into the bladder.
  • Inaperizon hydrochloride and flavoxate hydrochloride were used as control drugs.
  • the dose of Compound B and the control drug was 2 mg / kg, calculated as the free form, and these were dissolved in distilled water for injection before use.
  • the effect of the test compound was determined by averaging the latencies of the two micturition reflexes before administration as 100, and the latency of the micturition reflex after administration of the test compound was determined as this. Expressed as a ratio (%) to the control.
  • mice Four to six ddY male mice (5 weeks old) fasted overnight were used per group.
  • the test compound was orally administered, and the general condition and mortality were observed up to 72 hours after administration.
  • a 50% lethal dose (LD so, mg Z kg) was calculated from the cumulative number of deaths 72 hours after administration. did.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un dérivé d'aminocétone représenté par la formule générale (I), un sel physiologiquement acceptable de celui-ci, et un relaxant des muscles centraux ainsi qu'un remède contre la miction fréquente contenant chacun ce dérivé comme principe actif. Dans la formule (I), A représente hétéroaryle éventuellement substitué; R1 et R2 peuvent être identiques ou différents et représentent chacun alkyle inférieur; R3 représente hydrogène ou alkyle inférieur; R4 et R5 peuvent être identiques ou différents et représentent chacun alkyle inférieur, ou R4 et R5 peuvent être liés l'un à l'autre pour former un noyau alicyclique à cinq, six ou sept éléments; Y représente (II, III, IV, V), (R' et R' représentant chacun alkyle inférieur) ou cétal linéaire ou cyclique; et n vaut 0 ou 1.
PCT/JP1995/001965 1994-09-30 1995-09-28 Derive d'aminocetone et sel physiologiquement acceptable de celle-ci et leur utilisation WO1996010567A1 (fr)

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JP6/236412 1994-09-30
JP23641294 1994-09-30
JP175495 1995-01-10
JP7/1754 1995-01-10

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WO1996010567A1 true WO1996010567A1 (fr) 1996-04-11

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0942566A3 (fr) * 1998-03-10 2000-05-03 Lucent Technologies Inc. Réduction du rapport entre la puissance de crête et la puissance moyenne dans des système multiporteurs
JP2006503111A (ja) * 2002-10-15 2006-01-26 田辺製薬株式会社 高コンダクタンス型カルシウム感受性ｋチャネル開口薬
JP2011141287A (ja) * 2004-08-25 2011-07-21 Takeda Chem Ind Ltd 腹圧性尿失禁の予防・治療剤及びそのスクリーニング方法

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JPS61148172A (ja) * 1984-12-21 1986-07-05 Tokyo Tanabe Co Ltd １−（２，３−ジヒドロ−５−ベンゾフラニル）−１−プロパノン誘導体及びそれを有効成分とする中枢性筋弛緩剤
JPS6339816A (ja) * 1987-04-13 1988-02-20 Hokuriku Seiyaku Co Ltd ３−ピロリジノ置換プロピオフエノン誘導体を有効成分とする筋弛緩剤
JPS63119444A (ja) * 1985-04-11 1988-05-24 Nippon Kayaku Co Ltd 新規アミノケトン誘導体
JPH03157375A (ja) * 1989-08-04 1991-07-05 Mitsui Toatsu Chem Inc アミノケトン誘導体及びその用途
WO1995018092A1 (fr) * 1993-12-28 1995-07-06 Maruho Co., Ltd. Derive de l'aminocetone

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JPS61148172A (ja) * 1984-12-21 1986-07-05 Tokyo Tanabe Co Ltd １−（２，３−ジヒドロ−５−ベンゾフラニル）−１−プロパノン誘導体及びそれを有効成分とする中枢性筋弛緩剤
JPS63119444A (ja) * 1985-04-11 1988-05-24 Nippon Kayaku Co Ltd 新規アミノケトン誘導体
JPS6339816A (ja) * 1987-04-13 1988-02-20 Hokuriku Seiyaku Co Ltd ３−ピロリジノ置換プロピオフエノン誘導体を有効成分とする筋弛緩剤
JPH03157375A (ja) * 1989-08-04 1991-07-05 Mitsui Toatsu Chem Inc アミノケトン誘導体及びその用途
WO1995018092A1 (fr) * 1993-12-28 1995-07-06 Maruho Co., Ltd. Derive de l'aminocetone

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0942566A3 (fr) * 1998-03-10 2000-05-03 Lucent Technologies Inc. Réduction du rapport entre la puissance de crête et la puissance moyenne dans des système multiporteurs
US6301268B1 (en) 1998-03-10 2001-10-09 Lucent Technologies Inc. Communication method for frequency division multiplexing signalling systems with reduced average power requirements
JP2006503111A (ja) * 2002-10-15 2006-01-26 田辺製薬株式会社 高コンダクタンス型カルシウム感受性ｋチャネル開口薬
JP2011141287A (ja) * 2004-08-25 2011-07-21 Takeda Chem Ind Ltd 腹圧性尿失禁の予防・治療剤及びそのスクリーニング方法
US8685924B2 (en) 2004-08-25 2014-04-01 Takeda Pharmaceutical Company Limited Preventives/remedies for stress urinary incontinence and method of screening the same

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