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WO1995018092A1 - Derive de l'aminocetone - Google Patents

Derive de l'aminocetone Download PDF

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Publication number
WO1995018092A1
WO1995018092A1 PCT/JP1994/002177 JP9402177W WO9518092A1 WO 1995018092 A1 WO1995018092 A1 WO 1995018092A1 JP 9402177 W JP9402177 W JP 9402177W WO 9518092 A1 WO9518092 A1 WO 9518092A1
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WIPO (PCT)
Prior art keywords
group
general formula
formula
same
compound
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PCT/JP1994/002177
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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 WO1995018092A1 publication Critical patent/WO1995018092A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • the present invention relates to a novel aminoketone derivative, a method for producing the same, and a central muscle relaxant and a therapeutic agent for pollakiuria containing the derivative as an active ingredient.
  • an aminoketon derivative such as troperizone hydrochloride or eperisone hydrochloride has been clinically used, and its derivatives have also been used.
  • Many reports have been made (for example, see JP-A-60-255767, JP-A-61-207379, JP-A-63-39816, JP-A-63-119444 and JP-A-3-157375). .
  • FIG. 1 shows the results of a prolongation test of micturition reflex latency by intravenous administration of compound C of the present invention and a control drug, flavoxalate hydrochloride.
  • the vertical axis shows the rate of change of the urinary reflex latency
  • the horizontal axis shows the drug administered, the dose administered, and the number of experimental cases.
  • vehicle is the drug
  • the vehicle for injection, distilled water for injection, and the lightly shaded column indicate the group to which the compound (:, the darkly shaded column indicates the group to which flavoxalt hydrochloride was administered.
  • the length of the column on the graph was The vertical line on the column shows the standard error of the mean value of each administration group.
  • FIG. 2 shows the results of suppression of urine output by oral administration of Compound C of the present invention.
  • the vertical axis shows the amount of urination, and the horizontal axis shows the administered dose.
  • vehi cle indicates the solvent of the drug.
  • the length of the column on the graph indicates the mean value of urine output in each administration group, and the vertical line on the column indicates the standard error. The test for significance was based on the student's t-test.
  • Figure 3 shows the results of suppression of urination by oral administration of the control drug flavoxate hydrochloride.
  • the vertical axis shows the amount of urination, and the horizontal axis shows the administered dose.
  • vehi cle indicates the solvent of the drug.
  • the length of the column on the graph indicates the mean value of urine output in each administration group, and the vertical line on the column indicates the standard error. The test was performed with a significant difference at student's st-1 e st, and no significant difference was found.
  • Aminoketone derivatives having a known muscle relaxing action are All have cyclic amines such as piperidine, pyrrolidine, and piperazine as the amino groups of the above.
  • the present inventor has determined that the amine moiety has a non-cyclic structure, and further, as a substituent, a cycloalkyl group, a cycloalkyl group, or the like is bonded.
  • a new aminoketone derivative has been discovered that has a greater safety factor while maintaining muscle relaxant action and has a longer duration of action.
  • the derivative has a strong pollakiuria treatment effect.
  • the present invention provides an aminoketone derivative represented by the following 1. to 8., a method for producing the same, and a pharmaceutical use: c 1.
  • A represents a phenyl group, a naphthyl group or a heteroaryl group which may have a substituent
  • B is a lower cycloalkyl group; a naphthyl group or a heteroaryl group which may have a substituent;
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkoxy group; a phenyl group; a benzyl group; Ryl group; trifluoromethyl group, lower alkoxy group or lower alkyl group A lower alkyl group substituted with a quinthio group; or a cyclopropyl propyl methylene group;
  • R 3 represents a hydrogen atom or a lower alkyl group, or is linked to R 1 or R 2 to form an alicyclic five-membered ring or a six-membered ring. Denote the group,
  • R 4 is a hydrogen atom, a lower alkyl group or
  • m represents an integer of 0 to 4
  • E represents a lower cycloanolealkyl group or a group represented by the above A
  • R 5 represents a hydrogen atom or a lower alkyl group
  • a central muscle relaxant comprising, as an active ingredient, an aminoketone derivative represented by the following formula or a physiologically acceptable salt thereof.
  • a therapeutic agent for pollakiuria comprising, as an active ingredient, an aminoketone derivative represented by the formula (I) or a physiologically acceptable salt thereof.
  • A, B, R ⁇ RR 4 and k are the same above.
  • A, B, RRR 4 and k is the preparation of A Mi Roh Ke tons derivative represented the the in same.
  • A, B, RR 2 , R 4 and k represent a compound represented by the general formula (Id) Ud, wherein the compound represented by the above is reacted with an alcohol in the presence of a catalyst.
  • A, B, RRR 4 and k are the same in the (then However, when using the compound obtained in section 2 method (lb), R 2 is Ru Oh a hydrogen atom).
  • R 5 and R 6 represent the same lower alkyl group, or a 5- or 6-membered ring in which R 5 and R 5 may be linked to have 1 to 4 methyl groups.
  • R represents a lower alkyl group and X represents a halogen atom.
  • the compound represented by the general formula (Ie) is characterized by reacting a halogenated alkyl represented by RX (wherein R represents a lower alkyl group and X represents a halogen atom).
  • the present invention represented by the general formula (I).
  • the compound may have an asymmetric carbon atom, and may have various optical isomers.
  • the present invention relates to an optical compound having an absolute configuration of R or S. It includes both the active form and these racemic forms. When two or more asymmetric carbons are present, each diastereomer is also within the scope of the present invention.
  • the compound produced by the present invention can be obtained in a physiologically acceptable form.
  • a salt such as salt Inorganic salts such as acid, hydrobromide, sulfate, nitrate, phosphate, etc. and formate, acetate, citrate, succinate, maleate, Organic salts such as malate, tartrate, methansnorfonate, toluenesulfonate and lactate are listed. These salts can be easily produced from a free salt group by a conventionally known method.
  • the ketone group represented by Y in the compound of the general formula (I) refers to a ketone form of the general formula (I), an ethylene glycol, or a trimethylene. 5 or 6 which may have 1 to 4 methyl groups formed by reacting with glycols such as glycols A cyclic ketal of a membered ring, and a compound having 1 to 4 carbon atoms such as a compound in which Y is a carbonyl group and a compound such as methanol, ethanol, propanol, or butanol.
  • Acyclic ketal formed by the reaction with Norekole. Therefore, the phenols used in the reaction include ethylene glycol or trimethylene, which may have 1 to 4 methyl groups. Glycols such as coconut and alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol and butanol.
  • formaldehyde compound examples include paraformaldehyde and an aqueous solution of formaldehyde, and paraformaldehyde is particularly preferred.
  • anhydrous lower primary fatty acid, anhydrous formic acid, acetic anhydride, propionitrile phosphate include any anhydrous fatty acid having a carbon number of 2-8 anhydrous acid.
  • the lower cycloalkyl group represented by B or E includes cyclopropinole, cyclobutyl, cyclopentinole, cyclohexyl, and cyclohexyl groups. And a cycloalkyl group having 3 to 8 carbon atoms such as a heptinole group and a cyclooctyl group.
  • the lower alkoxy group represented by R 1 or R 2 includes a methoxy group, an ethoxy group, n-propoxy group, an isopropoxy group, and n-butyl Examples thereof include alkoxy groups having 1 to 4 carbon atoms, such as a toxin group, an iso-butoxy group, a sec-butoxy group, and a tert-butoxy group.
  • Lower alkylthio groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc. And 1-4 alkylthio groups.
  • a lower alkyl group substituted with a trifluorenemethyl group a lower alkoxy group or a lower alkylthio group, a lower alkoxy group, a lower alkyl group, and a lower alkynolethio group
  • Examples of the group include the same groups as described above.
  • the heteroaryl group which may have the substituents represented by A and B includes a heteroatom such as a phenyl group, a phenyl group, and a furyl group.
  • the number of the substituents of the naphthyl group is 1 to 7, preferably 1 to 5, more preferably 1 to 3, and most preferably 1 to 2.
  • the number of substituents on the heteroaryl group is 1-3 for a 5-membered ring having one heteroatom atom, preferably 1-2, and more preferably 1.
  • substituents include a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a mono-lower alkylamino group, and a di-lower amino group.
  • Lucylamino group monolinolemino group, diarynomino group, anilino group, diphenylamino group, halogen atom, lower alkyl carboxylic acid amino group Group, acryloylamino group, propioloylamino group, metacryloylamino group Group, crotonoi enorea mino group or isocrotono inorea mino group, lower alkyls phenolic amino group, carbamoyl ole group, N—mono monoalkyl alkanol Group, N—di-lower alkyl group, N—diene group, N—diene group, N—diphenyl group, Sulfamoyl group, di-lower alkinoles norfamoyl group, phenyl group, benzyl group, trifluorene methylene group, 2 — trifnoreo mouth
  • such groups include a methyl group, a cyclopropyl group, and a cyclo
  • Mono lower alkylamino groups include methinoleamino, ethinoreamino, n-propylamino, isopropinoreamino, and n-butinoreamino, a Monoalkylamino groups having 1 to -4 carbon atoms, such as a so-butinorea mino group, sec-butinorea mino group, and tert-butylamino group, include di-lower alkylamino groups.
  • Halogen atoms include fluorine, chlorine, bromine and iodine. Yes.
  • Lower alkyl amides include acetonamide, propionamide, butynoleamide, isobutylamine, and tert-butylamide. And a mid group.
  • Lower alkylsulfonylamino groups such as methylsulfonylamino groups, ethylsulfonylamino groups, n-propinoles-lesinolinoleamino groups, isopropinoles-norrehonylamino groups, n— Alkylsulfonylamino groups having 1 to 4 carbon atoms, such as butylsnorhonylamino group, isobutylinolenorhonylamino group, sec-butylinolenorhonolinrea amino group, tert-butylsulfonylamino group, and the like. It is.
  • N mono lower alkyl group
  • Lubamoyl group includes methylcarboyl group, ethinole group Lubamoyl group, n — pro-pinoreca noreva group, isopro pizoleca norebamoyl group, n — Alkyl power with 1 to 4 carbon atoms, such as butyl butyl group, isobutyl butyl group, sec-butyl butyl group, and tert-butyl butyl group Ill groups are listed.
  • the lower phenolic group is a dimer group, such as a di-methyl group, a di-group, a di-group, a di-n-propyl group.
  • Examples thereof include a dialkyl alkyl group having 1 to 4 carbon atoms, such as a lucanolebamoyl group.
  • Low grade Examples of the methyl group include methyl group, methyl group, ethyl group, and n-propyl pyrene group.
  • iso-pro pinores-no-remo group iso-butyls-no-re-mo-mo-no-re group, iso-butyl-no-re-no-mo-mo-no-re group, sec-buty-no-re-no-mo Examples thereof include an alkylsulfamoyl group having 1 to 4 carbon atoms, such as an inole group and a tert-butyl alcohol group.
  • aminoketone derivatives of the present invention preferred substituents include the following:
  • R 1 and R 2 are hydrogen atoms and the other is a lower alkyl group, a phenyl group, a lower alkoxy group or a lower alkylthio group, or both are lower alkyl groups which may be the same or different;
  • R 3 a hydrogen atom
  • R 4 hydrogen atom, lower alkyl group
  • R 5 hydrogen atom
  • aminoketone derivatives of the present invention particularly preferred substituents include the following:
  • A substituted with a phenyl group which may have a substituent (a phenyl group, an isothiazolyl group, an isooxazolinol group, a benzodioxoxazolyl group) Group);
  • R 1 and R 2 — is a hydrogen atom and the other is a lower alkyl group, a phenyl group, a lower alkoxy group, a lower alkylthio group;
  • R 3 a hydrogen atom
  • R 4 hydrogen atom, lower alkyl group
  • preferred substituents of a phenyl group, a naphthyl group and a heteroaryl group include a hydrogen atom, a lower alkyl group, Examples thereof include a lower alkoxy group, a trifluoromethyl group, a nitrogen atom, a phenyl group, and a cyclopropyl group.
  • a particularly preferred substituent is water. Examples include an atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, and a halogen atom.
  • Particularly preferred compounds of the present invention include compounds represented by the following general formulas (II) to (VI).
  • 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 18 represents a methyl group, an ethyl group, an isopropyl group, a phenyl group, a methoxy group or a methylthio group.
  • NR 2a R 3a is the following formula
  • NR 2 a R 3 a is a case of Kishirua Mi amino group to consequent b except rather) a group represented by.
  • the aldehyde form (6) represented by the following general formula is a compound synthesized by a method known in the literature or a method known in the literature.
  • the compound was synthesized from the corresponding carboxylic acid, estenole or alcohol obtained in the above, by a method well known in synthetic chemistry.
  • the heteroaryl group is a hydroxyl group, an amino group, a mono-lower alkylamino group, a carbamoyl group, or an N-mono lower alkyl group as a substituent.
  • a protecting group generally used for such a substituent eg, a benzyl group, a benzyloxycarbonyl group, a tert-butene group
  • Xyl carbonyl group etc. can be used as needed.
  • the compound of the general formula (b) is obtained by reacting the compound of the general formula (3) obtained in the above step (i) with an amine of the general formula (4) in a solvent.
  • the reaction is carried out at 0 to 140 ° C for 1 hour to 4 days using 1 mol to excess of compound (4) per 1 mol of compound (3).
  • Solvents include halogenated hydrocarbons such as methanol, ethanol, and other alcohols, black-mouthed form, methylene chloride, and the like, ethers, tetramers, and the like. Examples include ethers such as hydrofuran, and aromatic hydrocarbons such as benzene and toluene.
  • the aldehyde of the general formula (6) is reacted with the Grignard reagent of the general formula (7) in a solvent at ⁇ 20 to 40 ° C. for 10 minutes to 4 hours to obtain an alcohol of the general formula (8).
  • the reaction is carried out using 1 to 4 moles of Grignard reagent of general formula (7) for one aldehyde of general formula (6).
  • Solvents include dry ether and dry tet Ethers such as lahydrofuran can be used.
  • the alcohol (8) obtained in the above step (iii) is oxidized or DMS 0-oxidized with an oxidizing agent in a solvent to convert the ketone of the general formula (a '). Obtainable.
  • the reaction using an oxidizing agent is carried out at 0 to 60 ° C for 30 minutes to 24 hours, using 1 equivalent to excess amount of oxidizing agent per mole of phenol (8). Let it go.
  • Solvents include pyridin, methylene chloride, carbon tetrachloride, and the like.Oxidizing agents include chromic acid, pyridinium dichromate, and activated carbon dioxide. Ngan, etc.
  • phenolic tri-oxide pyridin complex, oxalinolene complex DMSO, N-chlorosiloxane
  • reagents used for DMS 0 oxidation such as imidodimethyl phenol or non-reflector, and react at -80 to 40 ° C for 30 minutes to 6 hours. After reacting, react with triamine or 4-amine.
  • solvents include halogenated hydrocarbons such as formaldehyde and methylene chloride, ethers, ethers such as tetrahydrofuran, and benzene. And aromatic hydrocarbons such as tonoleene, and DMS 0.
  • the ketone of the general formula (a ') obtained in the above step (iv) is By reacting with an alkyl halide of the general formula (10) in the presence of an intermediate base, a compound of the general formula (a) is obtained.
  • the reaction uses about 1 to 4 moles of the alkyl halide of the formula (10) and about 1 to 2. moles of the base per mole of the ketone of the formula (a '). Incubate at ⁇ 80 ° C for 10 minutes to 24 hours.
  • Solvents include halogenated hydrocarbons such as methylene chloride, ethers such as ether, tetrahydrofuran, and aromatic hydrocarbons such as benzene and benzene. And so on.
  • Trietinoreamin lithium diisopropinoleamide, n-phenyllithium and the like are used as bases. Lithium is used as a base.
  • diisopropinoleamide or n-butynolium was used, the enolate was formed by pretreating the ketone of the general formula (a ') with a base in a solvent. Then, it is reacted with an alkyl halide of the general formula (10).
  • Step (vi)-The Grignard reagent represented by the general formula (13) is obtained by reacting the compound (12) with magnesium in a solvent.
  • the reaction is carried out at 0 to 60 ° C. for 10 minutes to 8 hours using about 0.6 to 4 moles of magnesium with respect to 1 mole of the compound (i 2).
  • the solvent include ethers, ethers such as tetrahydrofuran, and the like.
  • hydrochloric acid, sulfuric acid, or the like is added as an acid in an amount of 1 mol to an excess with respect to 1 mol of the general formula (14), and 0 to 40. React for 10 minutes to 6 hours at ° C to hydrolyze.
  • A, B, RR 2 , R 4 and k are the same as those described above in Step 1 (viii) by reacting the ketone of the above general formula (a) with bromine (15) in a solvent.
  • a compound of the general formula (16) is obtained.
  • the reaction is a compound About 1 to 2 mol of bromine is used for 1 mol of (a), 0 to 40. Incubate with C for 30 minutes to 6 hours.
  • the solvent include halogenated hydrocarbons such as carbon tetrachloride, chloroform, and methylene chloride, ethers such as ether and tetrahydrofuran. Is received.
  • An acid such as hydrochloric acid or sulfuric acid is used as a catalyst if necessary.
  • step (ii) An amination reaction is carried out using the same reaction conditions as in step (ii) to obtain a compound of the general formula (If).
  • step (v) An aldol reaction is carried out under the same reaction conditions as in step (v) to obtain a compound of the general formula (18).
  • the tosylation reaction is performed under the same reaction conditions as in step (i) to obtain a compound of the general formula (19).
  • step (ii) An amination reaction is carried out under the same reaction conditions as in step (ii) to obtain a compound of the general formula Ug).
  • a Grignard reaction is performed using the same reaction conditions as in step (iii) to obtain a compound of the general formula (21).
  • the compound of the general formula (Ih) is obtained by reacting the ketone of the general formula (22) obtained in the above step (xiv) with an amine of the general formula (b) in a solvent.
  • the reaction is carried out at 0 to 100 ° C for 30 minutes to 10 days using 0.5 to 4 mol of the amide of the general formula (b) per 1 mol of the ketone of the general formula (22).
  • Solvents include methanol, ethanol, and other phenols, chlorophenols, and salts. Examples include halogenated hydrocarbons such as methylene chloride, ethers such as ether, and tetrahydrofuran.
  • Step 20 An alkylation reaction is performed under the same reaction conditions as in step (V) to obtain a compound of the general formula (24).
  • the tosylation reaction is performed under the same reaction conditions as in the above step (i) to obtain a compound of the general formula (25).
  • the amination reaction is carried out using the same reaction conditions as in the above step (ii) to obtain the desired compound of the general formula (Ii).
  • the carboxy group of the above general formula (I] ′) is reduced in a solvent in the presence of a reducing agent to obtain an alcohol of the general formula (Ik).
  • the reaction is carried out by adding 1 equivalent to an excess amount of a reducing agent to 1 mole of the compound of the general formula (I] '), and reacting at 40 to 60 ° C for 10 minutes to 6 hours.
  • Solvents include methanol, ethanol, and other phenols, and alcohols.
  • Examples include ethers such as telluride, tetrahydrofuran, etc., and reducing agents such as hydrogenated lithium hydride and borohydride Examples include tritium, lithium borohydride, and diborane.
  • A, B, RR 2, R 3, RR 5, j, k and 1 are the same above.
  • n represents 2 or 3.
  • the compound of the general formula (Im) is obtained by reacting the compound of the general formula (Ij) with the glycol of the general formula (27) in a solvent in the presence of a catalyst.
  • the reaction is carried out using about 1 mol to an excess amount of the glycol of the general formula (27) and about 0.1 to 2 mol of the catalyst with respect to i mol of the compound of the general formula (1 '), 0 to 140 °. Incubate with C for 10 minutes to 3 days.
  • the solvent include halogenated hydrocarbons such as chloroform and methylene chloride, ethers such as ether and tetrahydrofuran, benzene and toluene.
  • hydrocarbons examples include p-toluenesulfonate, methansnorephonate, sulfuric acid, hydrochloric acid, and p-toluenesulfonate pyridini. ⁇ is used.
  • the above reaction scheme H shows the synthesis method of ketones using polyethylene glycol and trimethyl alcohol. However, the same conditions can be applied by using other glycols or alcohols instead of these ethylene glycols and trimethylene glycols. By reacting below, other kettles can be easily synthesized.
  • the compound of the present invention can also be synthesized according to the following alternative methods 1 to 4. ⁇ Alternative 1>
  • Step a) A compound of the general formula (3a) is obtained by reacting the amine of the above general formula (la) with a benzaldehyde (2a). In the reaction, about 1 mol of benzylaldehyde (2a) is used for 1 mol of the general formula (la), and the reaction is carried out at 0 to 60 ° C for 30 minutes to 1 day.
  • the compound of the general formula (2b) is obtained by reacting the compound of the general formula (3a) with the iodide of the general formula (lb) in a sealed tube. In the reaction, about 1 to 3 mol of the iodide of the general formula (lb) is used per 1 mol of the general formula (3a), and the reaction is performed at 50 to 50 ° C for 1 hour to 2 days.
  • the compound of the general formula (b) is obtained by dissolving the compound of the general formula (2b) in water and heating. The reaction is carried out at a temperature of 60 ° C to the boiling point of the solvent for 10 minutes to 6 hours.
  • the compound of formula (la) is obtained.
  • the reaction uses about 1 to 4 moles of the formaldehyde compound and 1 to 4 moles of the amide of the formula (b) per 1 mole of the ketone of the formula (a).
  • Room temperature to 150 ° C Incubate for 10 minutes to 24 hours.
  • the solvent include alcohols such as ethanol and methanol, halogenated hydrocarbons such as carbon tetrafluoride, carbon form, chlorinated methylene, and the like.
  • Ethers such as mono-tel, tetrahydrofuran, benzene, tonoleet
  • Ketone compound of general formula (a ') and ⁇ ⁇ , ⁇ ,, ⁇ '-tetramethyl By reacting diaminomethane (le) and an anhydrous lower fatty acid in the presence or absence of a solvent, a ⁇ -unsaturated ketone of the general formula (c) is obtained. The reaction is carried out for 1 mol of ketone in the general formula (a '), and N, N, N', N'-tetramethyldiamine in the general formula (le) 1 to 5 About 1 mole to about 7.5 moles of anhydrous lower fatty acid, and react at room temperature to 120 for 10 minutes to 3 hours.
  • lower fatty acid anhydride examples include 2 to 8 carbonic anhydride fatty acids such as formic anhydride, acetic anhydride, propionic anhydride, and butyric anhydride.
  • Solvents are exemplified by aromatic hydrocarbons such as benzene, toluene and acetonitril, which are not necessarily required.
  • the compound of the general formula (lb) is obtained. Obtain the compound.
  • the reaction is performed using-about 0.5 to 4 moles of the amine of the general formula (b) with respect to 1 mole of the ketone of the general formula (c)-and reacting at 0 to 100 ° C for 30 minutes to 10 days.
  • the solvent include alcohols such as ethanol, methanol, and the like, nitrogen-containing hydrocarbons such as carbon tetrachloride, carbon form, methylene chloride, and ethers. And other solvents such as tetrahydrofuran and the like, or a mixed solvent thereof.
  • the compound of the general formula (Id) is obtained by reacting the compound of the general formula (la) with phenols in a solvent in the presence of a catalyst.
  • the reaction is carried out at 0 to 140 ° C for 10 minutes to 3 days, using 1 mol to excess of alcohols and 0.1 to 2 mol of catalyst per 1 mol of the compound of the general formula (Ia).
  • the solvent include halogenated hydrocarbons such as methylformaldehyde and methylene chloride, ethers such as ether and tetrahydrofuran, benzene and toluene.
  • the aromatic hydrocarbons include, for example, p-tonolene sulphonic acid, methansulphonic acid, sulfuric acid, hydrochloric acid, and p-toluenesulphonic acid pyridini. Something is used.
  • the therapeutic dose of the compound of the present invention depends on the age and sex of the patient, the condition to be treated and the method of administration, and is used as a central muscle relaxant and a therapeutic agent for pollakiuria. In general, the dose can be generally 1 to 100 mg / day, preferably 10 to 100 mg / day for an adult.
  • the dosage form is oral, such as capsules, tablets, fine granules, syrups, and powders, or injections, suppositories, patches, ointments, aerosols, etc. It can be administered orally or parenterally.
  • Examples of the pharmaceutical additives to be added to the compound of the present invention include the following, and the pharmaceutical additives can be appropriately used according to the dosage form.
  • Excipients lactose, mannitol, corn starch, crystalline cellulose, low-substituted hydroxypropyl propylcellulose Binder: starch, ⁇ - Starch, gelatin, methyl senorelose, polyvininole pyrrolidone, hydroxypropinolemethinolose, hydroxylase, hydroxypropylenolose , Crystal cellulose, etc.
  • Disintegrators starch, carboxymethyl tylenolate cellulose, low-substituted hydroxypropynolecellulose, cellulose Boiled rice
  • Lubricants magnesium stearate, evening glue, gay anhydride, etc.
  • Coating agents sucrose, tanolek, sedimentation; calcium carbonate, gelatin, arabia gum, punorerane, canorena uno, mouth, hydroxypropinoleme
  • a glossing agent, a flavoring agent, a stabilizing agent, a coloring agent, and the like can be used according to the purpose.
  • Solvents distilled water for injections, 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, acetic acid, sodium acetate Etc.-Local anesthetics: benzyl alcohol, pro-hydrochloric acid, etc.
  • Preservatives parabens, such as methyl parabenzoate, etc.
  • Base cocoa butter, hardened oil, saturated fatty acid glycerol ester, branched saturated alcohol, macrogol, etc.
  • Emulsifier Ionic surfactant, non-ionic surfactant, etc.
  • Thickeners sodium alginate, gelatin, methyl cellulose, carboxyl vinyl polymer, sodium polyacrylate, etc.
  • Moisturizer Glycerin, macro-gore
  • Cross-linking agent acetate aldehyde, dimethyl ketone, aluminum sulfate, etc.
  • Solubilizers ethanol, 2-propanol, etc., alcohols, macromolecules, etc.
  • Emulsifiers anionic surfactants, non-ionic surfactants, etc.
  • Base White ⁇ Hydrocarbons such as selenium and liquid paraffin. Oils and fats such as soybeans, rows such as miro, lanolin, stearic acid, olay Fatty acids such as fatty acids, higher alcohols and their esters, macrogol, etc.
  • Emulsifiers anionic surfactants, nonionic surfactants, etc.
  • Aerosol Solvents Base ethanol, 2-propanol, propylene glycol, etc.
  • Emulsifier various surfactants
  • Gas chlorofluorocarbon, liquefied petroleum gas, compressed gas, etc.
  • the present invention provides the following composition.
  • a central muscle relaxant composition comprising an aminoketone derivative represented by the formula: or a physiologically acceptable salt thereof, and a pharmaceutical additive.
  • A, B, RR 2, R 3, R> RR 55 ,, YY ,, ji, k and 1 are the same above.
  • a therapeutic agent for pollakiuria comprising a salt to be used and a pharmaceutical additive as active ingredients.
  • the compound of the present invention and a physiologically acceptable salt thereof have excellent muscle relaxation, anticonvulsant action, and the like, and are caused by diseases such as lumbar back pain, herniated disc, and neck-shoulder-arm syndrome. It is extremely useful as an active ingredient of a therapeutic agent for spastic palsy caused by diseases such as muscle tone and cerebrovascular disorder, spastic spinal palsy, and cerebral palsy. Further, the compound of the present invention has an excellent urinary reflex-suppressing action and urinary output-suppressing action, and is useful as a therapeutic agent for pollakiuria.
  • Example 1 illustrates one sheet click b Bae Nchinorea Mi down your only that the (1) in Table 1 - NR 2 a R 3 HNR 2 a for a introduction R 3 a (- NR 2 a R 3 a Table 1 To Indicates what is shown. ))
  • Example 4 Were obtained in the same manner as in Example 1 except that each of the compounds was replaced with an amine capable of forming Table 1 shows the analysis results of the obtained compounds.
  • the hydrochloride prepared in the above (1) was treated with potassium carbonate to give a colorless oily 5- (2-cyclopentylamino. Methylbutyrinole) 1-3-fuyininolei It was decided.
  • Example 11 In Example 1 (1), the 4′-ethyl 2-enethyl acrylophenone was replaced with 5 — (2-ethyl acryloyl ino) 13 — phenylisoxazole, and shows the sheet click Ropenchirua Mi down in 1) in Table 2 - NR 2 a R 3 a guide needful of HNR 2 a R 3 a (- . NR 2 a R 3 a is representative of those shown in Table 2) was formed Each compound shown in Table 2 was obtained in the same manner as in Example 1 except that each of the possible amines was replaced with maleic acid instead of the hydrochloric acid gas in Example 11 (2).
  • Table 2 shows the analysis results of the obtained compounds. Examples 7 to 10
  • Example 4 5 in (1) — (2 — echinorea cryloinole) 1 — 3— 5 — (2—Iso propylacriloinore) 1 3 _ baninoreisosozozoru, 5 — (2 — Echinore acriloinore) 1 3 — P — Methoxy dinosaur sonozone, 3 — p — Chloroquinone 1 5 — (2 — echinorea cri.
  • Table 3 was obtained in the same manner as in Example 4 except that zole, 3-((2-ethylethyl chloroyl))-5-phenylisoxazole was used.
  • Example 11 After dissolving 11.2 g (35.6 milliliters) of the alcohol compound produced in 1- (3) in 100 ml of dichloromethane, di-tert-butyrolite was obtained. 8.55 g (39.2 millimeters) was added and stirred at room temperature for 18 hours. The reaction solution was poured into water, and dichloromethane was extracted. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove colorless crystals. — [N — (tert — butoxynoleboninole) ⁇ ⁇ — — ⁇ — 3 3 — — 3 3 3 ⁇ 3 ⁇ ⁇ .
  • 0.53 g (13.3 mimol) of 60% sodium hydrogen is suspended in 5.00 ml of tetrahydrofuran, and the alcohol prepared in the above (1) is suspended.
  • a 27.0 ml solution of 5.00 g (12.1 milimonole) of tetrahydrofuran was added dropwise, and the mixture was stirred at 50 ° C for 1 hour.
  • the reaction solution was cooled to 0 ° C., and 0.91 ml (14.5 milliliters) of Yo-I-Dai-Meinore was added dropwise. The mixture was stirred for 30 minutes as it was, and then for 30 minutes at room temperature did.
  • the reaction solution was poured into water and extracted with ether.
  • Example 12 2 shown in Table 4 in the same manner as in Example 12 except that the experimental item (1) shown below was used instead of item (2). Compound was obtained.
  • Table 4 shows the analysis results of the obtained compounds.
  • Example 12 2.86 g (6.90 mmol) of the alcohol produced in (1) was dissolved in 15 ml of dichloromethane, and 1.05 ml of triethylamine (1.05 ml) was dissolved in 15 ml of dichloromethane. (7.59 mmol) and 0.76 ml (7.25 mmol) of isobutylinole chloride were added dropwise, and the mixture was stirred at room temperature overnight.
  • Example 4 6.00 g (17.2 milliliters) of the hydrochloride prepared in (1) was dissolved in 100 ml of gaseous hydrochloric acid-saturated toluene, and 5.89 g (31.0 g) of p-tonolenosorephonic acid was dissolved. The mixture was refluxed for 34 hours while adding ethyl alcohol 21.Oml in several portions. The reaction solution was cooled to room temperature, and a saturated aqueous solution of potassium carbonate was added to the solution after the filtration, and the precipitated insoluble material was separated by filtration.
  • Example 15 3.01 g (9.70 millimoles) of the ketone body produced in 5-(1) and 0.37 g (9.70 millimoles) of hydrogenated boron sodium were used in Example 11 1) In the same manner as in (1), 5— (3—Cyclopentylamino 1—Hydroquinone 2,2—Dimethyl propylene) as a colorless oil One 3.30 g of phenol-isosolazole was obtained.
  • the compound of the present invention and a physiologically acceptable salt have a central muscle relaxing action, which has an anticonvulsant action, a muscle relaxing action and a decerebrate rigidity-releasing action.
  • the compound of the present invention has a therapeutic effect on pollakiuria by animal experiments on the urinary reflex suppressing effect (under anesthesia) and the urinary output suppressing effect (under anesthesia).
  • mice One group of 10 ddY male mice (5 weeks old) fasted overnight was used. Oral administration of test compound, 30 minutes later, administration of 3 mg / kg nicotine tartrate via tail vein to prevent seizures caused by nicotine by clonic seizures and tonic extension convulsions Antagonism was studied. The measured value was expressed as a 50% effective dose of free body (ED50, mg / kg).
  • mice One group of 10 ddY male mice (5 weeks old) fasted overnight was used.
  • the test compound was orally administered, and 30 minutes later, a current of 20 mA was applied from the electrodes applied to both eyes for 0.2 seconds to examine the antagonism to the tonic convulsions caused by electrical stimulation.
  • the measured value was expressed as a 50% effective dose of the free form (ED50, mg / kg).
  • Test compound is administered orally, and 15, 30, and 60 minutes later The sample was placed on a rotating rod (diameter: 3 cm, llr. Pm), and the residence time was measured up to 120 seconds. In addition, animals with a residence time of 60 seconds or less were judged to have a positive muscle relaxant effect.Based on the number of positive animals 30 minutes after administration, a 50% effective amount of Compound C, Compound D and eperisone hydrochloride in a single unit (ED50, mg / kg) was calculated.
  • ED50 50% effective amount of Compound C, Compound D and eperisone hydrochloride in a single unit
  • the decerebrate rigidity was prepared according to the method of Ono et al. (Gen Pharmacol. 18:57 (1987)). That is, a tracheal force neurite and a femoral vein were implanted with force neurite under anesofolane anesthesia, and the rat was fixed to a stereotaxic apparatus. Drill a hole in the skull with an electric drill (Minimo 7, Minyu Yuichi Co., Ltd.) and place it at the midbrain (AP: 0, V: -3, L: ⁇ 1.5). The electrode of the generator (REG-4.
  • Radionics Inc. was inserted, and the coagulation of the brain was raised to 75 ° C in 10 seconds, and then performed at 75-85 ° C for 180 seconds. Then, the depth of anesthesia was reduced. The other side was also incinerated in the same procedure. After surgery, anesthesia was stopped, and after 1 to 2 hours, a rat with typical decerebrate rigidity was lightly fixed in a dorsal position, and a needle-shaped concentric electrode (NM-320T) was placed on the gastrocnemius muscle. , Nihon Kohden Co., Ltd.), then induces myoelectric discharge into a brown tube oscilloscope (VC-11A, Nihon Kohden Corporation), and adds a reaction and a histogram analysis device.
  • NM-320T needle-shaped concentric electrode
  • the discharge frequency per unit time was measured by (QC-111J, Nihon Kohden Co., Ltd.) and recorded on the heat book recorder (T-645G, Nihon Kohden Co., Ltd.). The measurement time was up to 60 minutes after the administration.
  • the test compound was administered under the conditions that the test volume was 1 ml / kg and the administration rate was 2 ml / min. Test compounds were dissolved in distilled water for injection.
  • the decerebrate rigidity was prepared according to the method of Fukuda et al. (Japn. J. Pharmacol. 24: 810 (1974 :)).
  • the rat is fixed in the dorsal position under isoflurane anesthesia, the tracheal force and the femoral vein are inserted into the rat, and then the esophagus and trachea are cut off and the ventral side is cut off.
  • the basilar artery was ligated.
  • both common carotid arteries were ligated. Ligation of the basilar artery and bilateral common carotid artery was performed at a reduced depth of anesthesia. With the anesthesia awakening, myoelectric discharge from the triceps forelimb in the same manner as in the previous section was measured. The measurement time was up to 60 minutes after the administration. The test compound dissolved in distilled water for injection was administered under the same conditions as in the previous section.
  • the compound of the present invention has two experimental rigidities.
  • the model showed a muscle relaxant effect and was clearly useful as a new muscle relaxant.
  • Urinary reflex was induced by injecting saline into rat bladder, and it was examined whether the test compound had a prolonged action (increased bladder capacity) until urination.
  • a male Sprague-Dawley ft-rat with a body weight of 250 to 410 g was anesthetized with 500 mg / kg i-p, 50 mg / kg ip-chloralose, ip, and fixed in a dorsal position.
  • the bladder was exposed through a median incision in the lower abdomen, and a polyethylene tube was inserted through a small incision at the top.
  • the other end of the polyethylene tubing is connected to a continuous infusion device to inject physiological saline into the bladder at a rate of 5 to 10 ml / hr, and to urinate the bladder with urine (saline) drainage Contraction was induced artificially.
  • the time from the start of infusion of physiological saline until contraction of micturition occurred was measured as the latency of the micturition reflex.
  • Urinary contraction was detected by recording changes in the tension of the thread tied to the bladder on a pen recorder via a displacement meter.
  • test compound was administered by a catheter inserted into the right external jugular vein one minute before the start of the physiological saline infusion into the bladder. Flavoxate hydrochloride was used as a control drug. Testing The effect of the compound was determined by averaging the latencies of the two micturition reflexes before administration as 100 for the control, and the latency of the micturition reflex for the test compound was determined as this control. Expressed as a percentage (%).
  • test compound After administration of the test compound to the rat, water is forcibly applied to promote urination, and the test compound has an effect of reducing urinary output. We examined whether we had it.
  • a Sprague-Dawley male rat weighing 180 to 270 g was divided into a control group and a drug-administered group.Distilled water for injection was used for the control group, and test compound was administered for the drug-administered group at a dose volume of 2 ml / kg. Was orally administered. One hour after administration, distilled water for injection was • administered orally at 20 ml / kg, water was removed, and the amount of rat naturally excreted within 1 hour after water loading was measured. Flavoxant hydrochloride was used as a control drug.
  • mice Four to six ddY male mice (5 weeks old) fasted overnight were used per group.
  • the test compound was administered orally, and the general condition and death status were observed up to 72 hours after the administration.
  • the 50% lethal dose (LD50, mg / kg) was calculated from the cumulative number of deaths 72 hours after administration.
  • Table 13 shows the results. Table 13 (Acute toxicity)
  • Table 14 shows the safety factors (LD50 value ZED50 value) of compound C, compound D and eperisone hydrochloride calculated from the above experimental results.
  • the LD50 value was calculated as a free body.
  • Table 14 (Safety factor)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un dérivé de l'aminocétone représenté par la formule générale (I), un sel physiologiquement acceptable de ce dernier, un procédé de production de ce dérivé, un relaxant musculaire central et un médicament contre la miction, contenant chacun le dérivé sous forme de principe actif, où A correspond à phényle, naphtyle ou hétéroaryle éventuellement substitutés; B correspond à cycloalkyle inférieur, etc.; R1 ou R2 correspond à hydrogène, et l'autre représente alkyle inférieur, alcoxy inférieur, phényle, alkylthio inférieur, etc., R3 correspond à hydrogène, etc.; R4 correspond à hydrogène, alkyle inférieur, etc.; R5 correspond à hydrogène, etc.; Y correspond à carbonyle, -CH(OH)-, j correspond à 0 ou 1; 1 correspond à 0 ou 1; et k correspond à un nombre entier 0, 1, etc.
PCT/JP1994/002177 1993-12-28 1994-12-22 Derive de l'aminocetone WO1995018092A1 (fr)

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Application Number Priority Date Filing Date Title
JP33857693 1993-12-28
JP5/338576 1993-12-28
JP6/158799 1994-07-11
JP15879994 1994-07-11

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010567A1 (fr) * 1994-09-30 1996-04-11 Maruho Co., Ltd. Derive d'aminocetone et sel physiologiquement acceptable de celle-ci et leur utilisation
WO1999045914A1 (fr) * 1998-03-13 1999-09-16 Maruho Kabushikikaisha Derive alkylamine et agent anesthesique utilisant ce derive
WO2003030636A1 (fr) * 2001-10-02 2003-04-17 Eisai Co., Ltd. Rongeur atteint de troubles urinaires, technique permettant de provoquer ces troubles et techniques de selection de medicament destine a traiter ces troubles, utilisant ledit rongeur
EP1405633A1 (fr) * 2002-10-03 2004-04-07 L'oreal Composition, notamment cosmétique, comprenant une aminecétone aromatique
EP1506767A1 (fr) * 2003-08-11 2005-02-16 L'oreal Utilisation d'une amine carbonylée pour stimuler la pousse des fibres kératiniques et/ou freiner leur chute

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3940400A (en) * 1974-11-14 1976-02-24 Morton-Norwich Products, Inc. 3-Methyl-4-phenyl-1,2,3,4-tetrahydrobenz[g]isoquinoline hydrobromide
JPS52125195A (en) * 1976-02-26 1977-10-20 Hoechst Ag Aminoalkylpyrorobenzoxaaza alkane and process for preparing same
JPS6270374A (ja) * 1985-09-16 1987-03-31 アメリカン・ホ−ム・プロダクツ・コ−ポレイシヨン 抗精神病γ−カルボリン
JPH01216994A (ja) * 1988-01-15 1989-08-30 Lilly Ind Ltd 医薬化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3940400A (en) * 1974-11-14 1976-02-24 Morton-Norwich Products, Inc. 3-Methyl-4-phenyl-1,2,3,4-tetrahydrobenz[g]isoquinoline hydrobromide
JPS52125195A (en) * 1976-02-26 1977-10-20 Hoechst Ag Aminoalkylpyrorobenzoxaaza alkane and process for preparing same
JPS6270374A (ja) * 1985-09-16 1987-03-31 アメリカン・ホ−ム・プロダクツ・コ−ポレイシヨン 抗精神病γ−カルボリン
JPH01216994A (ja) * 1988-01-15 1989-08-30 Lilly Ind Ltd 医薬化合物

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010567A1 (fr) * 1994-09-30 1996-04-11 Maruho Co., Ltd. Derive d'aminocetone et sel physiologiquement acceptable de celle-ci et leur utilisation
WO1999045914A1 (fr) * 1998-03-13 1999-09-16 Maruho Kabushikikaisha Derive alkylamine et agent anesthesique utilisant ce derive
WO2003030636A1 (fr) * 2001-10-02 2003-04-17 Eisai Co., Ltd. Rongeur atteint de troubles urinaires, technique permettant de provoquer ces troubles et techniques de selection de medicament destine a traiter ces troubles, utilisant ledit rongeur
EP1405633A1 (fr) * 2002-10-03 2004-04-07 L'oreal Composition, notamment cosmétique, comprenant une aminecétone aromatique
FR2845288A1 (fr) * 2002-10-03 2004-04-09 Oreal Composition, notamment cosmetique, comprenant une amine secondaire ou tertiaire carbonylee
EP1506767A1 (fr) * 2003-08-11 2005-02-16 L'oreal Utilisation d'une amine carbonylée pour stimuler la pousse des fibres kératiniques et/ou freiner leur chute
FR2858770A1 (fr) * 2003-08-11 2005-02-18 Oreal Utilisation d'une amine carbonylee pour stimuler la pousse des fibres keratiniques et/ou freiner leur chute

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