WO1995018092A1

WO1995018092A1 - Amino ketone derivative

Info

Publication number: WO1995018092A1
Application number: PCT/JP1994/002177
Authority: WO
Inventors: Takeaki Matsui; Hirofumi Yamazaki; Masako Hashinaga; Yuichiro Tanaka; Kazuo Kimura; Tetsuo Toga; Tomohiro Naruse; Hirokazu Hiraoka
Original assignee: Maruho Co., Ltd.
Priority date: 1993-12-28
Filing date: 1994-12-22
Publication date: 1995-07-06

Abstract

An amino ketone derivative represented by general formula (I), a physiologically acceptable salt thereof, a process for producing the same, and a central muscle relaxant and a remedy for frequent urination each containing the derivative as the active ingredient, wherein A represents optionally substituted phenyl, naphthyl or heteroaryl; B represents lower cycloalkyl, etc.; one off R?1 and R2¿ represents hydrogen and the other of them represents lower alkyl, lower alkoxy, phenyl, lower alkylthio, etc.; R3 represents hydrogen, etc.; R4 represents hydrogen, lower alkyl, etc.; R5 represents hydrogen, etc.; Y represents carbonyl, -CH(OH)-, etc.; j represents 0 or 1; 1 represents 0 or 1; and k represents an integer of 0, 1, etc.

Description

Specification

Aminoketone derivative

Technical field

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.

Conventional technology

Hitherto, as a drug having a central muscle relaxing action, 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). .

These compounds have a sufficient muscle relaxing action, but are short-acting actions and have a small safety-factor, so they are difficult drugs to use.

BRIEF DESCRIPTION OF THE FIGURES

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, and 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.

According to Newman-Keuls test.

**: p <0.01

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.

**: p <0.01

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.

Disclosure of the invention

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. In addition, it has been found that the derivative has a strong pollakiuria treatment effect.

That is, 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. General formula (I)

[In the formula, 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

-(CH ₂ ) _m -E

(In the formula, m represents an integer of 0 to 4, E represents a lower cycloanolealkyl group or a group represented by the above A), and a group represented by the following formula:

R ⁵ represents a hydrogen atom or a lower alkyl group,

Y is

One CH (OH) —, One CH (OR) —, C = 〇

(Wherein, R represents a lower alkyl group) or a linear or cyclic ketone group-(provided that the substituent of RR ² or A is a cyclic group) Represents a 0 or 1, j represents 0 or 1, and k represents an integer of 0 to 4 (provided that R is an integer from 0 to 4). ⁵ , when one of R ² and R ^{3 is} a substituent having an aryl group or a methylthio group, j = j = 0 is excluded). ]

An aminoketone derivative represented by the formula: and its physiologically acceptable o

Wherein, A, B, R \ R 2 RRRY, j, k and I are the same above. ]

A central muscle relaxant comprising, as an active ingredient, an aminoketone derivative represented by the following formula or a physiologically acceptable salt thereof.

3. — General formula (I)

(I)

^{Wherein, A, B, RR 2 RRRY} , j, k and 1 are the same above. ]

A therapeutic agent for pollakiuria comprising, as an active ingredient, an aminoketone derivative represented by the formula (I) or a physiologically acceptable salt thereof.

4. — General formula (a)

R

A— C-CH (a

II L

〇 R ²

[Wherein, A, R ¹ and R ² are the same as above. A ketone represented by the formula (b):

[Wherein, B, R ⁴ and k are as defined above. ].

A general formula (la) characterized by reacting with an amine represented by:

(la)

[Wherein, A, B, R ′, R ² , R ⁴ and k are as defined above. ] A method for producing an aminoketone derivative represented by the formula:

5. General formula (a ')

R ¹

I

A— C-CH ₂ (a *)

II

〇

[Wherein, A and R ¹ are the same as above. ]

Is reacted with N, Ν, Ν 'Ν'-ίtramethyl' vaminomethane and anhydrous lower fatty acid to obtain the general formula (c)

R 1

Α— C-1 C2 CH 2 (C)

〇

[Wherein, A and R ¹ are the same as above. ] And the β-unsaturated ketone (c) is represented by the general formulas (b) and (b).

[Wherein, B, R ⁴ and k are as defined above. ]

A general formula characterized by reacting with an amine represented by the formula (lb): (lb)

Wherein, A, B, RR ⁴ and k are the same above. ] A method for producing an aminoketone derivative represented by the formula:

6. — General formula (la)

( ^Ia)

Wherein, A, B, R \ RR 4 and k are the same above. A general formula (Ic) characterized in that the compound represented by the formula is reduced in the presence of a reducing agent.

Wherein, A, B, RRR ⁴ and k is the preparation of A Mi Roh Ke tons derivative represented the the in same.

7. —General formula ()

A— (ia)

[Wherein 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. )

Wherein, 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. A group forming a cyclic ketal. ] A method for producing an aminoketone derivative represented by the formula: 8 General formula (Ic):

( I c)

[Wherein, A, B, R ′, R ² , R ⁴ and k are as defined above. Wherein 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).

[Wherein, A, B, R, R], R ² , R ⁴ and k are the same as those described above for the process for producing an aminoketone derivative.

-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. As such a salt, 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.

Examples of the formaldehyde compound include paraformaldehyde and an aqueous solution of formaldehyde, and paraformaldehyde is particularly preferred. And 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.

^{R, R \ RR 3, R} \ R 5 or is lower alkyl group and to the methylation group represented by R ^6, Echiru group, n - pro pin group, Lee Seo propyl group, n _ Examples thereof include an alkyl group having 1 to 4 carbon atoms such as a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.

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. For 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. 5-membered ring group having one 5-membered ring group with 2 heteroatoms, 6-membered ring group with 1 heteroatom such as pyridyl group, pyrimidinyl group, pyridazinyl group, virazinyl 6-membered ring group having two heteroatoms such as a group, and other groups such as an indril group, an isoindril group, an indazolinole group, a quinolyl group, and an isoquinolyl group. Nore, naphthyridyl, benzoxazolyl,-benzoisoxazolyl, benzothiazolyl, Zinzothiazolyl group, Frazanil group, Benzofuraninole group, Benzoisofuranyl group, Benzimidinazolyl group, 1H-indazolyl group, quinoxari And a quinazolinyl, cinolinyl, and phthalazinyl group.

A phenyl, naphthyl or heteroaryl group represented by A and E; and a naphthyl group represented by B Or a heteroaryl group, the phenyl group has 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents. 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. One or two, preferably one, for a five-membered ring having two heteroatoms, and one to four, preferably for a six-membered ring having one heteroatom. 1 to 2; 1 to 3 for a 6-membered ring having 2 heteroatoms; preferably 1 to 2; and 1 to 4 for other groups. , Preferably one to three, more preferably one to two.

A phenyl, naphthinole or heteroaryl group represented by A and E; and a naphthyl or heteroaryl group represented by B Examples of the 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 Examples of such groups include a methyl group, a cyclopropyl group, and a cyclopropylmethyl group.

Among the above substituents, the lower alkyl group and the lower alkoxy group are the same as described above. 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. Methynorea mino group, Jetinorea mino group, di-n-propylamino group, diisopropinorea mino group, di-n-butinorea mino group, diisobutylamino group, di Examples thereof include a C1-C4 dialkylamino group such as one sec-butinorea amino group and di-tert-butylamino group. 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.く基基基, イプピ基、、 n — — — 基モモ基基基基基基基基基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. Group, iso-pro pinores-no-remo group, n-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.

Among the aminoketone derivatives of the present invention, preferred substituents include the following:

A: A phenyl group substituted with a phenyl group or a lower alkyl group which may have a substituent, an isothiazolyl group, an isoxozolyl group, a benzisoxazolyl group, a naphthyl group, Chenyl, furyl and thiazolyl groups;

Y: C = 0 or C H (OH);

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;

B: lower cycloalkyl group; j: 0 or 1;

k: 0 or 1;

1: 0 or 1.

Among the 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);

Y: C = 0;

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;

B: lower cycloalkyl group;

j: 1;-k: 0 or 1

1: 0.

Among the groups represented by A and E, 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).

(In the formula, 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

(Provided, however, the compounds of general formula (II), NR ^{2 ^a} R ³ ^a is a case of Kishirua Mi amino group to consequent b except rather) a group represented by.

Ί

Commercially available compounds were purchased for the reagents and synthesis-intermediates used in the present invention, and compounds known in the literature were synthesized based on the descriptions in the literature.

The compounds of the present invention and synthetic intermediates not known in the literature were synthesized according to the following Reaction Schemes A to H and Alternatives 1 to 4.

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.

And the phenyl, naphthyl, or heteroaryl group represented by A and E, or the naphthyl group represented by B. 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. When the compound has a rubamyl group or the like, a protecting group generally used for such a substituent (eg, a benzyl group, a benzyloxycarbonyl group, a tert-butene group) is used. Xyl carbonyl group etc.) can be used as needed.

f,, /,-

B- (CH ₂ ) _k OH + TsCl> B- (CH ₂ ) _k OTs (i)

(one two Three)

B- (C (ϋ)

[Wherein, B, R ⁴ and k are the same as above. ]

Process (i) By reacting the alcohol of the above general formula (1) with P-norrenoresinolenorinochloride (2) in a solvent, a compound of the general formula (3) is obtained. The reaction is carried out at 0 to 40 ° C for 30 minutes to 2 days using 1 to 3 moles of p-toluene norefoninolechloride with respect to 1 mole of the general formula (1). Let Examples of the solvent include pyridin, methylene chloride, tetrahydrofuran, and the like, and examples of the base include pyridin, triethylamine, and the like. Are mentioned.

Process (ii)

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. Reaction process formula B>

, (Grignard Ji _{_{anti-J ',) Α ^ ττ ^}} ττ

A-CHO + R ^l CH ₂ MgX —- ^ ^ A-CHCH ₂ R ^]

(6) (7)

A-CHCH2R ¹ (oxidized) A-CCHnR ¹ (iv)

II

OH o

(8) (a ')

(Alkylation)

A-CCH2R ¹ + R ² X A-CCHRiR ² (v)

II

O (10) o

(a ') a

A-X A-MgX

(12) (13) ό

(a)

[Wherein, A, R ¹ and R ² are as defined above. X represents a chlorine atom, a bromine atom or an iodine atom. Step (iii)

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.

Process (iv)

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. In the case of DMS 0 oxidation, phenolic tri-oxide (pyridin complex, oxalinolene complex DMSO, N-chlorosiloxane) Use 1 to 6 equivalents of 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. Examples of 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.

Process (V)

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. When 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). Examples of the solvent include ethers, ethers such as tetrahydrofuran, and the like.

Process— (vi i) The Grignard reagent (13) obtained in the above step (vi) is reacted with nitrile of the general formula (14) in a solvent, followed by adding an excess amount of water and treating with an acid. The reaction for obtaining the compound of the general formula (a) is carried out by using about 1 to 4 mol of the general formula (13) with respect to 1 mol of the general formula (14) at 0 to 40 ° C for 10 minutes to 4 hours. Let react. Ethers such as ether and tetrahydrofuran can be used as the solvent. After adding an excessive amount of water to the above product, 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.

<Reaction scheme C> r (VII

(16)

A-

(ix)

[In the formula, 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. Examples of 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.

Process (ix)

An amination reaction is carried out using the same reaction conditions as in step (ii) to obtain a compound of the general formula (If).

<Reaction process formula D> 1 H

_{A -C-CHR ^ R ^ +} R3 C HO ( aldol reaction), ACCC-OH (x)

II I

° (a) (17) 0 R ² (18)

R ¹ HR ¹ H

(Toshiroi dani)

A-C-C-C-OH + TsCl A-C-C-C-OTs (xi)

0 11

2 R ³ (18) (2) 〇 R ² R ³ (19)

A

R ¹ R ³ R 丄 1 R r, 3

(Oxidation)

A-CH-C = CH A-C— C = CH (xiv)

II-OH (21) 0 (22)

A-C- (xv) II

O ₂ ) _k B

J ^k

Wherein, A, B, R \ R 2, R 3, R 4 and k are the same above. ] Process (x)

An aldol reaction is carried out under the same reaction conditions as in step (v) to obtain a compound of the general formula (18).

Process (xi)

The tosylation reaction is performed under the same reaction conditions as in step (i) to obtain a compound of the general formula (19).

Process (xii)

An amination reaction is carried out under the same reaction conditions as in step (ii) to obtain a compound of the general formula Ug).

Process (xiii)

A Grignard reaction is performed using the same reaction conditions as in step (iii) to obtain a compound of the general formula (21).

Process (xiv)

An oxidation reaction is performed using the same reaction conditions as in step (iv) to obtain a compound of the general formula (22). -Process (XV)

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. Reaction process formula E〉

A- OH (xvi)

(a) (24)

R ¹ HHR ¹ HH

(Tosylation)

A-C-C-C-C-OH + TsCl A— C-C-C-C-OTs (xvii)

Base II L L

OR ² R ³ R ^J O ² R ³ R-

Ten

(24) (25)

^{Wherein, A, B, RRR 3,} RR 5 and k is same above. Step 20 (xyi) An alkylation reaction is performed under the same reaction conditions as in step (V) to obtain a compound of the general formula (24). Process (xyii)

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).

Process (xyiii)

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).

Reaction scheme F>

di)

(Where A, B,

1 is the same as above.

(Xix)

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.

(Ik)

+

Wherein, A, B, R, R ', RR 3, R \ R 5, j, k 1 and X are the same above. ]-Process (XX)

An alkylation reaction is carried out using the same reaction conditions as in step (V) to obtain a compound of the general formula (II). Reaction process formula H〉

^{Wherein, A, B, RR 2,} R 3, RR 5, j, k and 1 are the same above. n represents 2 or 3. ]

Process (xxi)

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. Examples of the solvent include halogenated hydrocarbons such as chloroform and methylene chloride, ethers such as ether and tetrahydrofuran, benzene and toluene. Examples of such hydrocarbons include p-toluenesulfonate, methansnorephonate, sulfuric acid, hydrochloric acid, and p-toluenesulfonate pyridini.ゥ is used. In addition, 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>

(Dehydration reaction)

B- (CH ₂ ) _k NH ₂ + PhCHO B- (CH ₂ )>, N = CHPh

(la) (2a) (3a) a

B- (CH ₂ ) _k N = CHPh + R ⁴ I ------ → B-CCH ₂ ) _k N = CHPh b}

(3a) (lb) (2b) R ⁴ {c}

(Hydrolysis)

B- (CH ₂ ) _k N = CHPh HN

ヽ

(2b) I (CH ₂ ) _k B

(b)

[Wherein B, R ⁴ and k are the same as above. 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.

Step {b}

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.

Step {c}

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.

Alternative 2>

A- {d

^{Wherein, A, B, R:,} RR 4 and k are the same above. Process U)

By reacting the ketone of the above general formula (a) with a formaldehyde compound and an amine of the general formula (b) in a solvent, 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. Examples of 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

3 5

Examples thereof include aromatic hydrocarbons such as alcohols and mixed solvents thereof. 0 Ku Alternative 3>

Then rt ₂

R 4

N,

ヽ (CH ₂ ) _k -B only)

(b) 0 [where A, B, RR ⁴ and k are the same as above. ] Step {e}

Ketone compound of general formula (a ') and チル, Ν,, Ν'-tetramethyl By reacting diaminomethane (le) and an anhydrous lower fatty acid in the presence or absence of a solvent, a β-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. Examples of the lower fatty acid anhydride 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.

Process

By reacting the α.; 8-unsaturated ketone of the general formula (c) obtained above with the amine of the general formula (b) in a solvent, 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. You. Examples of 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. <Alternative 4>

R ¹ 4

/

ACC-CH ₂ -N + alcohol!

II shi \ (CH ₂ ) _k -B

O

(Id)

Wherein, A, B, R \ RR 4, R 5, R 6 and k are the same above. ]

Process (g)

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). Let react. Examples of the solvent include halogenated hydrocarbons such as methylformaldehyde and methylene chloride, ethers such as ether and tetrahydrofuran, benzene and toluene. Examples of 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.

1.Oral preparation

Excipients: lactose, mannitol, corn starch, crystalline cellulose, low-substituted hydroxypropyl propylcellulose Binder: starch, α- 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 In addition, a glossing agent, a flavoring agent, a stabilizing agent, a coloring agent, and the like can be used according to the purpose.

2.Injection

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.

3.Suppository

Base: cocoa butter, hardened oil, saturated fatty acid glycerol ester, branched saturated alcohol, macrogol, etc. Emulsifier Ionic surfactant, non-ionic surfactant, etc.

4. Patch

Thickeners: sodium alginate, gelatin, methyl cellulose, carboxyl vinyl polymer, sodium polyacrylate, etc.

Moisturizer: Glycerin, macro-gore

Filler: kaolin, titanium dioxide, zinc white

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.

5 ointment

Base: White ヮ 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.

6. Aerosol Solvents Base: ethanol, 2-propanol, propylene glycol, etc.

Emulsifier: various surfactants

Gas: chlorofluorocarbon, liquefied petroleum gas, compressed gas, etc.

Further, the present invention provides the following composition.

* General formula (I)

A— γ (I)

Wherein, A, B, R \ R 2, R 3, R 4, R s, Y, j, k and 1 are the same above. ]

A central muscle relaxant composition comprising an aminoketone derivative represented by the formula: or a physiologically acceptable salt thereof, and a pharmaceutical additive.

* General formula (I)

^{Wherein, A, B, RR 2,} R 3, R> RR 55 ,, YY ,, ji, k and 1 are the same above. ]

Or a physiologically acceptable derivative thereof. 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

Hereinafter, the present invention will be described in detail with reference to examples. Example 1

3 — Cyclopentylamino 4'-ethyl-1 2 — Methylpropionone nonon hydrochloride

(1) 3 — Cyclopentinorea Minor 4 ′ -Echinole 1 2 — Methinolepropiophenone

4'-Echinore 1 2 — Methinorea Crylophenone 5.23 g (30.0 mimol) was dissolved in 5 ml of ethanol and cyclopentylamine 2.1. 3 g (25.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 6 hours. The reaction mixture is poured into hydrochloric acid aqueous solution, washed with ether, and the aqueous layer is made alkaline with potassium carbonate. Tell was extracted. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to remove the yellow oily substance 3 — cyclopentinorea. This yielded 5.53 g of thiopropionene.

The analysis results (NMR (5 ppm, CDCI)) of the obtained oil are shown in Table 1.

(2) 3 — cyclopentylamino 1 ''-ethinole ^ "2-methylpropiovanone hydrochloride

5.53 g of the ketone compound produced in the above (1) was dissolved in 60 ml of ether and converted into a hydrochloride with hydrochloric acid gas. This is purified by recrystallization (solvent: ethanol-ether), and 3-cycloventinolemino 4'-ethylethyl 12-methylpropiophenone hydrochloride To obtain colorless crystals.

The analysis results of the obtained hydrochloride are shown below.

Yield 3.83g (51.8% yield)

Insect point 152-153 ° C

Elemental analysis values (shown in Table 1) Examples 2 to 3

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. )) 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. Example 4

5-(2-Cyclopentinorea Minoruminori Butyorinor) 1 3-Purinuisokisazoru monohydrochloride

(1) 5-(2-cyclopentinorea,,,,,,,,,,,,,,,,,,,,,,,) 3-monophenylisoxazole hydrochloride

5 — (2 — Echinorea Kuriro Inore) 1 3 — Dissolve 6.70 g (29.5 milliliter) in 50 ml of Etanole 2.76 g (32.5 milliliters) of lopentylamine was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into a hydrochloric acid aqueous solution, and the precipitated crystals were collected by filtration and washed with ether. This was purified by recrystallization (solvent: 2-propanol), and 5-(2-cyclopentinole) was purified. Colorless crystals of soxazole hydrochloride were obtained. The analysis results of the obtained hydrochloride are shown below.

Yield 4.56g (Yield 44.4¾)

Melting point 172 ~ 174 ° C

Elemental analysis value (shown in Table 2) (2) 5-(2-cyclopentinole))-3-dinolei soxazole

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.

The resulting analysis of oil was (NMR ((5 ρρπ !, CDC1 3)) shown in Table 2. Examples 5-6

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. Each of the compounds shown in Table 3 was obtained in the same manner as in Example 4 except that zole, 3-((2-ethylethyl chloroyl))-5-phenylisoxazole was used.

Table 3 shows the analysis results of each compound obtained. Example 1 1

5-(2-cyclopentinoleminomethylenol 1-hydroxybutyl)-3-phenylisosoxazole-hydrochloride (1) 5-(2-cyclohexane Pentinolea minomethinole 1 1-Hydroxybutyl) 13-Phenylamine Soxazolone resinoma-Mixture-Example 4-Ketone body prepared in (2) 26.5 g (84.2 mimol) was dissolved in 250 inl of ethanol, sodium borohydride was added under water cooling, and the mixture was stirred for 5 minutes. The reaction solution was poured into an aqueous solution of hydrochloric acid and washed with ether, and the aqueous layer was made alkaline with potassium carbonate and extracted with ether. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure to obtain a colorless oily 5- (2-cyclopentyla). 1-Hydroxy-butynol) 1- 3-Fenilisoxazole 22. Og was obtained.

The analysis results of the obtained oil are shown below.

_{NMR (δ ppm, CDC1 3)} : 0.95 - 1.02 (3H, m), 1.22 - 1.89 (11 H, m), 2.04-2.10C1H, m), 2.77 - 2.99 (2H, m), 3.03-3.10C1H, m),

4.92 (0.27H, d, J = 5.4Hz), 5.14 (0.73H, d, J = 2.7Hz), 6.57 (0

.73H, s), 6.61 (0.27H, s), 7.42-7.50 (3H, in), 7.79-7.84 (2H

, m)

Based on the above analysis results, it is considered that the obtained oil was a mixture of diastereomers (mixing ratio: 8: 3).

(2) 5 — (2 — cyclopentylaminomethyltin-1-hydroxybutyl) 13 — phenylisosoxazole hydrochloride The alcohol prepared by the above (1) 22. Og was converted into hydrochloride in the same manner as in Example 11 (2). This was recrystallized (solvent: ethanol) to separate and purify the diastereomer, and 5-(2-cyclopentylaminomethyl-1-) Colorless crystals of (hydroxybutyl) -1-3-phenylisoxazole hydrochloride were obtained.

The analysis results of the obtained hydrochloride are shown below.

Yield 14.5g (Yield 49.1%) ! Insect point 192 ~ 194 ° C

Elemental analysis value (shown in Table 4)

(3) 5-(2-cyclopentinole) 1-hydroxybutinole 1-3-vinylinone (1) Manufactured in (2) above. The hydrochloride was treated in the same manner as in Example 4 (1) (2) to obtain a colorless oily substance of 5— (2—cyclopentylaminomethyl thiosole 1—1—hydroxybutynole) 1—3—F Anything is so.

Analysis results of the obtained oil _{(NMR (5 ppm, CDC1 3} )) shown in Table 4. Example 1 2

5 — (2 — Cyclopentylaminomethyl 1 — methoxybutyl) 1 3 — Phenoninole Soso-kisazoline Noremaleic acid

(1) 5-{2-[tert-(tert-butoxycinolenorrium) cyclopentinole minare] 1-1-hydroxylose} 1 3 — PS

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) 口口 — — メ — 3 3 — — 3 3 3 一 3 一一.

The analysis results of the obtained crystals are shown below.

Yield 15. Og (Yield 100%)

_{NMR (δ ppm, CDC1 3)} : 0.84 (3H, t, J = 7.8Hz), 1.20-1.3K2H, m), 1.49C9H, s), 1.60 - 1.96 C9H, m), 3.06 (1H, dd, J = 14.9, 4.6Hz), 3.65 (1H, dd, J = 14.9, 12.2Hz), 4.87 (1H, m), 5.10C1H, br.s), 6.66C1H, s ), 7.42 -7.47 (3H, m), 7.80-7.84 (2H, m)

(2) 5 — {2-[N-(tert-butoxycinolenorrium) cyclopentinorea minomethinole]-1-methoxybutyr} 1-3-venirui Soxa sole

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. After that, the organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure to remove colorless crystals of 5- (2- [N- (tert-butoxyquinolone)]. [Clopentylaminomethyl] -1-methoxybutyl} — '3—phenylisoxazole. The analysis results of the obtained crystals are shown below.

Yield 4.53 g (Yield 87.6%)

_{. NMRC 5 ppm CDC1 3):} 0.90C3H, †, J = 7.6Hz), 1.33 - 1.88 (11 H, m), 1.47C9H, s), 3.19 (1H, dd, J = 14.0, 6.5Hz), 3.30 -3.50 (3H, in), 3.70-4.00C1H, m), 4.69C1H, d, J = 3. OHz), 6.5K1H, s), 7.45 -7.49 (3H, m), 7.81-7.84C2H, m)

(3) 5 — (2 — cyclopentinorea minomethyltin butyl) 1 3 — Phenylioxoxazone

Dissolve 4.53 g (10.8 mimol) of the methoxy body prepared in (2) above in 20,0 ml of dichloromethan, and add 3.45 ml (31,7 mi) of anisol. Then, 20.0 ml of trifluoroacetic acid was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow oily substance, 5-5. (2—cyclopentinorea minomethyltin-1-butyl methoxy) 1-3—vinylinoxone monosodium (3.00 g) was obtained. Table 4 shows the analysis results of the obtained oil.

(4) 5 — (2 — cyclopentinole acetonitrile 11-methoxybutylinolate) 1-3-pheninolei soxazozole monomaleate

3. The methoxide prepared in (3) above 3. Dissolve OOg in 50. Oml of ethanol, add maleic acid 1.23g (10.6 millimono) and stir at room temperature for 1 hour did. The solvent was distilled off to obtain colorless crystals. This was purified by recrystallization (solvent: ethanol / ether), and 5— (2—cyclopentylaminomethyl) was removed. Yellow crystals of eninorei soxazonolemalate were obtained.

The analysis results of the obtained maleate are shown below.

Yield 3.50g (74.5% yield)

142-143 ° C

Elemental analysis values (shown in Table 4)-Example 13

5 — (2 — Cyclopentinorea minomethyl-1-isobutylyloxybutyl) 1-3-Funinolay Soxazonole maleate

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.

(1) 5 — {2 — [N-(tert-butoxycinolenorcinol) cyclopentylaminomethyl]-1 1-isobutylyloxybutyl} 1 3 — Beniyi Soxasol

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. The reaction solution was poured into water, extracted with methanol, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure And red-orange oily substance 5 — {2-[N-(tert-butoxysica norebonizole) cyclopentylamino-methylinole] — 1 — 3.84 g of Pheninolei Soxazole was obtained.

The analysis results of the obtained oil are shown below.

_{NMR ((ppm, CDC1 3)} : 0.95 (3H, t, J = 7.6Hz), 1.22 - 1.82 (25 H, m)) 2.20-2.40 (lH, Di), 2.60-2.80 (2H) m), 3.20 -3.40 (2H ₁ m) _I 3.70-3.90 (lH, m), 5.95 (lH, d, J = 3.7Hz) _I 6.39 (lH, s), 7 • 40- 7.50 (3H, m), 7.70- 7.84 (2H, m) Example 14

5 — (2 — cyclopentinorea minomethinol 1 1 — ethylenoxy butyl) 1 3 — phenylinole soxazono monolemanate

(1) 5 — (2 — cyclopentinorea minometyl 1 — ethylene dibutyl butyl) 1 3 — phenylene soxazole

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. The filtrate was extracted with ether, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Clopentinolea methyl methisolate 11-Ethylenedioxybutyl) 13-phenylenoxazole 5.80 g was obtained.

The analysis results of the obtained oil are shown below.

_{NMR (ά ppm, CDC1 3)} :.. 0. 96C3H, t, J = 7. 3Hz), 1. 19-1 90 (10 H, m), 2. 13-2 24 (lH, m), 2 . 56 (lH, dd, J = 10. 7 (3. 8Hz), 2. 76 (1H, dd, J = 12.5, 7.3Hz), 3.0K1H, m), 3.88-4.17 (4H, m), 656 (lH, s), 7.44-7.48 (3H ₍ m), 7.79-7.93 (2H , m)

(2) 5 — (2 — cyclopentinorea minomethinolate 1 — ethylenoxybutyl) 1 3 — phenyl soxazolumalate

From 5.80 g of the ethylenedioxy derivative produced in the above (1) and 1.8 Og (15.5 mmol) of maleic acid, a fine powder was obtained in the same manner as in Example 12-2 (4). Orange crystals were obtained. This was purified by recrystallization (solvent: ethanol), and 5— (2—cycloventinoleminomethylinole 1—ethylenoxybutinole) was purified. Colorless crystals of soxazole maleate were obtained.

The analysis results of the obtained maleate are shown below.

Yield 2.46g (Yield 29.5¾)

Insect point 157-158 ° C

Elemental analysis: C ₂₁ H ₂₈ N ₂ 0 ₃ * C ₄ H ₄ 0 ₄

C H N

Cal. (¾) 63.54 6.83 5.93

Found (%) 63.46 6.80 6.00 Example 15

5-(3 — cyclopentinorea Propionyl) 1-3 — phenylisoxazolone olemareate

(1) 5 — (3 — cyclopentinorea mino _ 2, 2 — dimethylpropionyl) — 3 — phenyloysoxazoline

5 Dissolve 10.8 g (50.0 mi monole) in 50.0 ml of ethanol, and dissolve 10.0 g of pentylamine in the mouth of the bottle. and (5150 millimeter mol), 75% Roh, ⁰ La ho

Five

2.60 g (65.0 milliliter) of Lum aldehyde were added, and the mixture was refluxed for 30 minutes. The reaction solution was poured into a hydrochloric acid aqueous solution, washed with ether, the aqueous layer was made alkaline with potassium carbonate, and extracted with ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove yellow oily 5- (3-cyclopentylamino 2,2-diene). There was obtained 6.63 g of methinolepionyl) -13-phenylisoxazole. The analysis results of the obtained oil are shown below.

_{MR (5 ppm, CDC1 3)} : 1.11-1.83 (2H, m), 1.37 (6H, s), 1.39 -1.70 (6H, m), 2.88 - 2.98 C1H, m), 3.06 (2H, s), 7.2 K1H, s), 7.46-7.5K3H, m), 7.82-7.86 (2H, m)

(2) 5 — (3 — cyclopentylamino _ 2, 2 — dimethylpropionyl) 1 3 — Phenylioxooxazuma Lainate

From 4.50 g of the ketone body and 1.67 g of maleic acid (14.4 S rimole) produced in (1) above, colorless crystals were obtained in the same manner as in Example 12-2 (4). Obtained. This was purified by recrystallization (solvent: ethanol), and colorless crystals of 5— (3—cycloventinolemino 2,2,2—dimethinolepropionyl) 13—phenylenyliso Oxazolmaleinate was obtained.

The analysis results of the obtained maleate are shown below.

Yield 4.29 g (29.0% yield)

Melting point 166 ~ 167 ° C

Elemental _{_{_{analysis: C 1 S H 24 N 2}}} 0 2, C 4 H 4 0 4

C H N

Cal. (%) 64.47 6.59 6.54

Found (%) 64.39 6.73 6.59 Example 16

5-(3-cyclopentinorea mino 1-hydroxy 2, 2-dimethyl propyl) 13-phenylisoxoxazol maleate

(1) 5-(3-cyclopentinole 1)-hydroxy 2, 2-dimethinole propinole 1-3-feninole Nore 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 analysis results of the obtained oil are shown below.

_{NMRC 5 ppm, CDC1 3):} 0.94C3H, s), 1.06 (3H, s), 1.30-2.00 (9H, m), 2.66 (1H, d, J = 12.2Hz), 2.80C1H, d, J = 12.4 Hz), 3.0 0-3.20C1H, m), 4.80C1H, s), 6.56 (1H, s), 7.30-7.50 C3H, m), 7.70-7.90 C2H, m)

(2) 5 — (3 — Cyclopentinole 1) — Hydroxy 1, 2, 2 — Dimethyl phenol 1, 2 — 3 — Funininole Sol-maleinate-A method similar to that of Example 12-(4) from 2.30 g of the alcohol form and 0.85 g (7.32 mimol) of maleic acid produced in (1) above. As a result, colorless crystals were obtained. This is purified by recrystallization (solvent: ether-ether) to give colorless crystals of 5— (3—cyclopentinorea mino 1-hydroquinone 1,2, 2—Dimethyl propylene) 1-3—Pininoleic soxazole maleate was obtained. The analysis results of the obtained maleate are shown below.

Yield 2.29 g (Yield from Example 15— (1) 23.1¾) Melting point 123-124 ° C

Elemental analysis: C ₁₃ H ₂₆ N ₂ 0 ₂ 'C ₄ H ₄ 0 ₄

C H N

Cal. (%) 64.17 7.02 6.51

Found (%) 63.76 6.98 6.47

_

9Γ 8ΓΖ.ΕΕ,-..,

-

OS o (Dimension βo-

Example of pharmacological test〉

It was confirmed by animal experiments that 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.

In addition, it was confirmed that 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).

In addition, acute toxicity tests were conducted, and safety factors were examined.

(Test compound)

Compound A (Example 1) 3 — Cyclopentylamino — 4 — Echinole 1 2 — Methinolepropiophenone hydrochloride

Compound B (Example 3) 4'-Ethyl_2-Methynole-1- (N-methylhexylhexinoleamino) propio'phenone hydrochloride-Compound C (Example 4) ) 5-(2-cyclopentyl amino methinolebutyryl) 1-3-benzoninole soxazol hydrochloride

Compound D (Example 5) 5-[2 — (N-methylcyclohexylaminoaminotinol) butyrinole] 1 3 — phenylisosoxazolmylmaleic acid salt 1. Anti-nicotine action

The effects of Compound C and Compound D on convulsive death after nicotine-induced convulsions were examined and compared with eperisone hydrochloride.

〔Method〕

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).

These compounds were dissolved or suspended in distilled water for injection or 0.5% CMC-Na solution.

Table 5 shows the results.

Table 5 (anti-nicotine action)

2. Anti-shock convulsion

The effects of compound C and compound D on maximal electroconvulsive seizures were examined and compared with eperisone hydrochloride. 〔Method〕

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).

These compounds were dissolved or suspended in distilled water for injection, 0.5% CMC-Na solution or 0.1% Tween80 solution.

Table 6 shows the results.

Table 6 (Anti-convulsive action)

3. Muscle relaxing action

Compound A, Compound B, Compound C and Compound! ) Was evaluated by the rotating bar method and compared with eperisone hydrochloride. 〔Method〕

Six male ddY mice (5 weeks old) fasted overnight were used per group. 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.

These compounds were dissolved or suspended in distilled water for injection or 0.5% CMC-Na solution. The administered dose was shown as a free body.

Table 7 shows the results.

Table 7 (muscle relaxing action)

4. Relief action of decerebrate rigidity

Effect of Wistar male rat (body weight 322-395 g) on Sherrington-type decerebrate rigidity 4 — 1.

〔Method〕 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. 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.

Result ¾r ¾έ 8 Table 8 (Sherrington-type decerebrate rigidity remission)

Maximum suppression effect (n = 3)

4-2 Effects on ischemic decerebrate rigidity

〔Method

The decerebrate rigidity was prepared according to the method of Fukuda et al. (Japn. J. Pharmacol. 24: 810 (1974 :)). In other words, 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. Exposing the skull at the base of the brain and using an electric drill (Minimo 7, Minuyuichi Co., Ltd.) to a diameter of approximately 3 m

After making a hole in D1 and incising the dura, the basilar artery was ligated. In addition, 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.

Table 9 shows the results.

Table 9 (Release effect of ischemic decerebrate rigidity)

* Maximum inhibitory effect (n = 3) This compound increases the frequency of myoelectric discharge, both in Sherrington-type decerebrate rigidity, where the motor system is dominant, and in ischemic decerebrate rigidity, where the motor system is dominant. Restrained. Eperisone hydrochloride used as a control drug inhibited both myocardial discharge frequency in Sherrington-type decerebrate rigidity and in ischemic decerebrate rigidity, in any rigidity model. Also had a weaker action than the compound of the present invention.

From the above results, 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.

5. Urinary reflex suppression (under anesthesia)

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.

〔Method〕

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. Next, 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.

The 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 (%).

Statistical processing was performed by the Newman-Keuls test on the latency length of the micturition reflex in the group to which the solvent distilled water for injection was intravenously administered.o

The results are shown in Table 10 and FIG.

Table 10 (urinary reflex suppression effect)

Test compound Dose Number of subjects Extension rate

Cmg / kg, i.v.) (% ± standard error) Distilled water for injection 6 101 7 ± 10.3 Compound c 0.4. 4 1 16.8 ± 12.0

0.8 4 16 20.0 ± 34.4

2 4 262.3 ± 42.9 Flavoxate hydrochloride 1 4 95.5 ± 15.7

2 4 135.5 ± 13.6

4 4 248. 3 ± 43.3 **

： There is a significant difference of P <0.01 compared with the injection water administration group ₍

6. Urinary output control (under anesthesia)

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.

〔Method〕

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.

Statistical processing is for the group receiving distilled water for injection

Student's t_test.

The results are shown in Table 11, Table 12, Figure 2 and Figure 3.

Table 11 (Urine output suppression effect)

**: Administration of distilled water for injection-p <0.01 significantly different from the group. Table 12 (Urine output suppression effect)

7. Acute toxicity

The acute toxicity of compound C and compound D was examined and compared with eperisone hydrochloride.

〔Method〕

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.

These compounds were dissolved or suspended in distilled water for injection, 0.5% CMC-Na solution or O. Tween80.

Table 13 shows the results. Table 13 (Acute toxicity)

7

8. Safety factor 5

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)

From the results of Tables 5 to 14 and FIGS. 1 to 3, the utility of the compound of the present invention as a central muscle relaxant and a therapeutic agent for pollakiuria was confirmed.

Claims

The scope of the claims

① General formula (I) A-

B represents 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 is a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower phenol quinolethio group; a phenyl group; a benzyl group; A aryl group; a lower alkyl group substituted with a trifluoromethyl group, a lower alkoxy group or a lower alkylthio group; or a cyclopropylmethyl group. And

R ³ represents a hydrogen atom or a lower alkyl group, respectively, or a group linked to R ¹ or R ² to form an alicyclic five-membered or six-membered ring; Show

R is a hydrogen atom, a lower alkyl group or

— (CH ₂ ) _M — E

(In the formula, m represents an integer of 0 to 4, and E represents a lower cycloalkyl group or a group represented by the above A.) Denote the group,

R ⁵ represents a hydrogen atom or a lower alkyl group

Y is

— CH (OH) —, CH (OR) —, ^ C = 0

(Wherein, R represents a lower alkyl group) or a linear or cyclic ketone group (provided that the substituent of RR ² or A is a cyclopropyl group) J indicates 0 or 1, 1 indicates 0 or 1, and k indicates an integer from 0 to 4 (however, any one of RR ² ) Is a substituent having an aryl group or a methylthio group, except for j = 1 = 0). ]

And a physiologically acceptable aminoketone derivative represented by

(I) B

[Wherein A, B, R ¹ , RRRRY, J k and 1 are the same as above. J

A central muscle relaxant comprising, as an active ingredient, an aminoketone derivative represented by the following formula and a physiologically acceptable salt thereof.

③ General formula (I)

^{Wherein, A, B, RR 2 RRRY} , j, k and I are the same above. ] A therapeutic agent for pollakiuria comprising, as an active ingredient, the aminoketone derivative represented by the formula: and a physiologically acceptable salt thereof. ④ General formula (a)

R 1 i o A— C-CH (a)

II LOR ²

[In the formula, A represents a phenyl group, a naphthyl group or a heteroaryl group which may have a substituent, and R ¹ and R ² are the same or different. They may be different, each being a hydrogen atom; a lower alkyl group; a lower alkoxy group; a lower alkylthio group; a phenylinole group; a benzoinole group; an arinole group; Represents a lower alkyl group substituted by a tyl group, a lower alkoxy group or a lower alkylthio group; or a cycloalkyl group. A ketone represented by the formula (b):

[In the formula, B represents a lower cycloalkyl group; a naphthyl group or a heteroaryl group which may have a substituent; R ⁴ represents a hydrogen atom or a lower alkyl group; Or

— (CH ₂ ) _m -E

(Wherein, m represents an integer of 0 to 4, E represents a lower cycloalkyl group or a group represented by A), and k represents 0 to 4. Indicates an integer of 4. ]

A general formula characterized by reacting with an amine represented by

(la): da)

Wherein, A, B, R \ RR 4 and k are the same above. ] A method for producing an aminoketone derivative represented by the formula:

⑤ General formula (

〇

In the formula, A and R ¹ are the same as described above. ] Is reacted with N, N, N'N'-tetramethyl'aminomethane and anhydrous lower fatty acid to give a general formula (c)

R

A— ς— C2 CH ₂

II (c)

0

[Wherein, A and R ¹ are the same as above. And β-unsaturated ketone, and then the α, β

—Unsaturated ketone (c) is replaced by general formula (b)

[Wherein, B, R ⁴ and k are as defined above. A general formula (lb) characterized by reacting with an amine represented by the formula:

A— C— ( ^Ib)

¾

Wherein, A, B, R \ R 4 and k are the same above. A method for producing an aminoketone derivative represented by the formula: ⑥ General formula (la)

[Wherein A, B, R ^: , R ² , R ⁴ and k are the same as above. A general formula (Ic) characterized in that the compound represented by the formula (Ic) is reduced in the presence of a reducing agent.

Wherein, A, B, R \ RR 4 and k is the preparation of § Mi Roh Ke tons derivative represented by the same above.

⑦ General formula (la) Ha)

[Wherein A, B, RRR ⁴ and k are the same as above. General formula a compound represented by wherein that you make the reaction with alcohol Ichiru acids in the presence of a catalyst] (Id) ^{(1 d)}

[Wherein A, B, R ¹ , R ² , R ⁴ and k are the same as above (provided that When using the compound (lb) obtained by the method in Item 2, R ² is a hydrogen atom.)

R ⁵ and R ⁶ are the same or different and represent a lower alkyl group, or R ⁵ and R ⁶ are linked to form a 5-membered methyl group. It represents a group that forms a ring or a 6-membered cyclic ketal. ]

A method for producing an aminoketone derivative represented by the formula:

⑧ General formula (Ic): (W

Wherein, A, B, R \ R 2, R 4 and k are the same above. Wherein R represents a lower alkyl group and X represents a halogen atom. The compound represented by the general formula (Ie ) ( ^{1 e} )

[In the formula, A, B, R, R \ R ² , R ⁴ and k are the same as those described above:] A method for producing an aminoketone derivative represented by the formula: