WO1996010567A1

WO1996010567A1 - Aminoketone derivative, physiologically acceptable salt thereof, and use of the same

Info

Publication number: WO1996010567A1
Application number: PCT/JP1995/001965
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: 1994-09-30
Filing date: 1995-09-28
Publication date: 1996-04-11

Abstract

An aminoketone derivative represented by general formula (I), a physiologically acceptable salt thereof, and a central muscle relaxant and a remedy for frequent urination each containing the same as the active ingredient, wherein A represents optionally substituted heteroaryl; R?1 and R2¿ may be the same or different and represent each lower alkyl; R3 represents hydrogen or lower alkyl; R?4 and R5¿ may be the same or different and represent each lower alkyl, or R?4 and R5¿ may be bound together to form a five-, six- or seven-membered alicyclic ring; Y represents (II), (III), (IV), (V) (R' and R'' being each lower alkyl) or linear or cyclic ketal; and n is 0 or 1.

Description

Specification

Amino ketone derivatives, their physiologically acceptable salts and their uses

Technical field

The present invention relates to a novel aminoketone derivative having a central muscle relaxing action, or a physiologically acceptable salt thereof, and a therapeutic agent containing the same as an active ingredient. The compound of the present invention and a physiologically acceptable salt thereof are used for the treatment of diseases having spastic paralysis as a main symptom, painful muscle spasticity associated with musculoskeletal diseases, etc. It is useful as an active ingredient of the drug.

Background technology

Conventionally, as a drug having a central muscle relaxing action, aminoketone derivatives such as tonoleperizone hydrochloride and eperizone hydrochloride have been clinically used. Many reports have also been made (for example, Japanese Patent Application Laid-Open No. Sho 60-255 767, Japanese Patent Application Laid-open No. 61-2077379. Japanese Patent Application Laid-Open No. 63-39816). And JP-A-63-114944, JP-A-3-157375 and JP-A-5151380). All of these aminoketon derivatives are

[In the formula, R ′ represents a hydrogen atom, ^Rb represents a lower alkyl group, and C ′ represents an asymmetric carbon atom. ]

It has a structure represented by In addition, it is also known that in a specific compound in which the aromatic group in the above structure is a phenyl group, a compound in which R ′ is substituted with a lower alkyl group has the same type of action.

Although these compounds had a sufficient muscle relaxing action, they were difficult to use because of their short duration of action and low safety factor.

An object of the present invention is to provide a muscle relaxant which is excellent in muscle relaxing action, has a large safety factor, and has a long action holding time.

Further, the present invention aims to provide a novel therapeutic agent for pollakiuria.

FIG. 1 shows the results regarding the frequency-reducing effect.

Disclosure of the invention

The present inventor has proposed that aromatic ¾ in the above structure is heterogeneous. Aminoketone derivative obtained by substituting R 'with a lower alkyl group in a compound that is a thiol group has a muscle relaxing action and a therapeutic action for pollakiuria, and its action duration And found that the safety factor was long, and completed the present invention.

That is, the present invention relates to the general formula (I): co = one (I)

[In the formula, A represents a Holl tertiary group to y which may have a substituent, and R ¹ and R ² may be the same or different and each is a lower alkyl group. R ³ represents a hydrogen atom or a lower alkyl group; R ⁴ and R ⁵ may be the same or different and each represents a lower alkyl group; Or R ⁴ and R ⁵ are linked to each other to form an alicyclic 5-, 6- or 7-membered ring, and Y is

H H

C— — C—

I

OH OR (Wherein, R ′ and R ′ each represent a lower alkyl group.) Or a linear or cyclic ketal group, and n represents 0 or 1. Show. ]

And a physiologically acceptable salt thereof.

In addition, the present invention provides a central muscle relaxant comprising, as an active ingredient, the aminoketone derivative represented by the general formula (I) or a physiologically acceptable salt thereof. It is provided.

Further, the present invention provides a therapeutic agent for pollakiuria comprising, as an active ingredient, the aminoketone derivative represented by the general formula (I) or a physiologically acceptable salt thereof. That is what we do.

In the present specification, "lower" with respect to "alkyl", "alkyl group" or "alkoxy group" has 1 to 5 carbon atoms unless otherwise defined. It preferably means 1 to 4 pieces, more preferably 1 to 3 pieces.

The compound of the present invention represented by the general formula (I) may have an asymmetric carbon atom, and has various optical isomers. The present invention includes both the optically active isomers having the absolute configuration of R or S and these racemic isomers. It is. When two or more asymmetric carbon atoms are present, each of the diastereomers is also within the scope of the present invention, and the physiologically acceptable salts of the compound of the present invention include: Inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and formate, acetate, citrate, succinate, maleate, Malate, tartrate. Organic salts such as methansulfonate, p-tonolensulfonate, and lactate. These salts can be easily produced from a free base by a conventionally known method.

The heteroaryl group which may have a substituent represented by A in the compound of the general formula (I) may be a ceynole group, a phenol group or a fluorine group. 5-membered ring group having one heteroatom such as benzoyl group, virazolyl group, thiazolyl group isothiazolyl group, oxazolyl group, isosoyl group 5-membered ring group having 2 hetero atoms such as oxazolyl group and imidazolyl group, and 6-membered ring having one hetero atom such as pyridyl group Group having two hetero atoms such as pyridinyl group, pyrimidinyl group, pyridinyl group, and pyracinyl group, and other isoindolinol groups , Indazolyl group, quinolyl group, isoquinolinol group, naphthyridyl group, benzoxazolyl group, benzoisoxazolyl group Linole group, Benzothiazolyl group, Benzoisothiazolyl group, Benzochenil group, Benzoisochinyl group, Frazanil group, Benzofuranorenol group , Benzisofuranyl group, benzimidazolinole group, 1H-indazolyl group, quinoxalinyl group, quinazolinyl group, cinolinyl group, And a phthalazinyl group.

When the heteroaryl group represented by A has a substituent, the number of substituents is preferably 1 to 3 in the case of a 5-membered ring having one heteroatom atom, and is preferably Is one or two, more preferably one, and in the case of a five-membered ring having two heteroatoms, one or two, preferably one, and One to four, preferably one to two, for a six-membered ring with one child, and one to three, preferably for a six-membered ring with two heteroatoms. In the case of other groups, the number is 1 to 4, preferably 1 to 3, and more preferably 1 to 2.

Examples of the substituent of the heteroaryl group represented by A include-a lower alkyl group, a lower alkoxy group, a hydroxy group-a nitro group, a cyano group, Amino group, mono-lower alkylamino group, di-lower alkylamino group, monoarylamino group, diarynoamino group, anilino group, diphenylamine Group, halogen atom, lower alkyl carbonyl Acid amide groups, acryloinorea ino groups, propioloinorea ino groups, metacryloinorea ino groups, and crotoinoinorea ino groups Is isocrotonoinoamino group, lower alkylsulfonylamino group, rubamoyl group, N-mono lower alkyl group, rubamoyl group, N—di-lower phenolカ, 、, —, —, —, —, —, —, —, —, —, —, ス, 、, 、, 、, —, —, —, —, —, —, — Di-lower quinole sole pho mo in ole group, phenyl group, benzyl group, trif ole ole meth ine ole group, 2,2,2—trif nore ole Ethynole group, cyclopropynole group, cycle mouth propylmethyl group, etc.

Of the above substituents, the lower alkyl group includes a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butynole group, isobutynole group, se c-Alkyl groups having 1 to 4 carbon atoms, such as butynole group and tert-butyl group. Lower alkoxy groups include methoxy, ethoxy, n-propoxy, iso-prooxy, n-butoxy, iso Examples thereof include an alkoxy group having 1 to 4 carbon atoms, such as a butoxy group, a sec-hydroxy group, and a tert-butoxy group.

Mono lower alkylamino groups include methylamino group, ethylamino group, n-propylamino group, and Monoalkylamines having 1 to 4 carbon atoms, such as isopropylamino, n-butylamino, isobutylamino, sec-butynoleamino, tert-butylamino, etc. Examples of the di-lower alkylamino group include a dimethinoleamino group, a getylamino group, a di-n-phenylamino group, a diisopropinoleamino group, Dialkylamino groups having 2 to 8 carbon atoms, such as di-n-butinorea mino group, diisobutinorea mino group, disec-butinorea mino group, di-tert-butylamino group, etc. No. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and a iodine atom.

The lower alkyl carboxylic acid amide group includes an acetate amide group, a propion amide group, a butyl amide group, an isobutynoleamide group, and a sec-butyl amide group. And a tert-butyl amide group. The lower alkylsulfonylamino groups include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, and n-butylsulfonylamino. And an alkylsulfonylamino group having 1 to 4 carbon atoms, such as an isobutylsulfonylamino group, a sec-butylsulfonylamino group, and a tert-butylsulfonylamino group. N — mono-lower alkyl group Rubamoyl groups include methylone group, methyl group, ethylethyl group, methyl group, n-propisoleca group, isopropyl group, 'Moinole group, n-butynole cane' Moinole group, isobutynol force Norevamoinole group, sec-Butylcanoleno, 'Moinole group, tert-butyl carbamoyl group, etc. 2 to 5 alkynolecal /, 'moyl groups. N — Di-lower alkyl caneno, 'Mo-no-re group, di-methyl-no-ha' mo-no-re, Jetirka-no-reno, 'Mo-no-re, G-n-propynole Noreno, Mo'nore, diisopropinole, Noreno, Mo'nore, di-n-butynocanoleno, Mo'nole, diisopropinole And a dialkyl-alkenyl group having 3 to 9 carbon atoms, such as a z-sec-butynole group.

Examples of the lower alkyls group include a methyl group, a methyl group, a methyl group, and an n-propynole group. Nore group, Isopropinoresorenomoinore group, n-butylinoresorenomoreoinore group, Isobutinoresorinorewamoinore group, sec—Buchi Examples of the phenol group include a phenol group having 1 to 4 carbon atoms, such as a tert-butyl famoyl group, such as a tert-butyl famoyl group.

The ketone group represented by Y in the compound of the general formula (I) Means that a compound in which Y is a carbonyl group is reacted with glycols such as ethyl glycol, trimethyl glycol and the like. The 5- or 6-membered cyclic ketal which may have 1 to 4 methyl groups formed thereby, and the Υ is a carbonyl group Formed by the reaction of the compound with phenolic compounds having 1 to 4 carbon atoms such as methanol, ethanol, propanol, butanol, etc. Means a non-annular ketal.

^{R \ R '\ RRR 3,} R 4 or is a lower alkyl group and to the methylation group that will be the table in R ^5, Echiru group, n - profile Pinore group, Lee Seo profile propyl group, n - Examples thereof include an alkyl group having 1 to 4 carbon atoms such as a butyl group, an isobutyl group and a sec-butyl group. R ⁴ and R ⁵ and the child and there you formed by linking Ru alicyclic five-membered ring, six-membered ring your good beauty seven-membered ring can and child that having a hetero atom and Russia on 2偭以Further, it may have a lower alkyl group as a substituent. Examples of the hetero atom include a nitrogen atom, an oxygen atom, and a sulfur atom.

When the ring formed by linking R ⁴ and R ⁵ has a lower alkyl group as a substituent, the number of lower alkyl groups is determined by the size of the ring, the type of hetero atom and Depending on the number, usually one to three, preferably Is one or two. The alicyclic five-membered, six-membered and seven-membered rings which may be formed by linking R ⁴ and R ⁵ include a lipocyclic ring and a piperidine. Ring, morpholine ring, pyrazine ring, homopyridine ring, thiomorpholine ring, homomorpholine ring, and homopyrazine ring.

— Among the compounds of the general formula (I), preferred substituents include the following:

A: substituted with a heteroaryl group substituted with a phenyl group which may have a substituent, particularly a phenyl group which may have a lower alkyl group. Isothiazolyl group, isoxazozolyl group, benzisoxazolyl group, thienyl group, benzoxenolinol group, fluorinol group and benzoyl group N-zofranyl group;

Y: C = 0 or C H (0H), especially C H (0H)

R ¹ and R ² are the same lower alkyl group;

R ³ : a hydrogen atom or n is 0;

And R ⁵ : methyl or ethyl or N (R ⁴ ) R ⁵ is N-pyrrolidinyl, N—piperidinyl, N—morpholinyl , Which may have a lower alkyl group at the 4-position, N — piperazinyl group, A preferred phenyl group having a phenyl group substituted with a phenyl group which may have the above substituent group is as follows. , A hydrogen atom (when there is no substituent), a lower alkyl group, a lower alkoxy group, a trifluoromethizole group, a halogen atom, a vinylinole group, and a cyclopro group Pill groups are exemplified, and particularly preferable substituents include a hydrogen atom (when no substituent is present), a lower alkyl group, a lower alkoxy group, and a trifluorene methacrylate. And a halogen atom.

Particularly preferred compounds of the present invention include compounds of the following general formulas (11), (111), (IV) and (V):

[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 ¹ ′ and R ² ′ are the same and represent a methyl group or an ethyl group. R ⁴¹ and R ⁶ ′ may be the same or different and each represents a force representing a methyl group or an ethyl group, respectively, or NR ⁴ ′ R ^S *

Represents a group represented by ].

The compound of the present invention can be synthesized according to the following reaction schemes D to I. The reaction process formulas D to 〖 The ketone represented by the following general formula (6), which is used as a starting material, can be synthesized according to the reaction schemes A to (: The aldehyde derivative represented by the following general formula (1), which is used as a starting material in the above, can be synthesized by a method known in the literature, and can also be obtained by a method known in the literature. It can be synthesized from the corresponding carboxylic acid, ester or alcohol by a method well known in synthetic chemistry. Other reagents and intermediates used in formulas A-I are commercially available compounds that can be purchased or are known in the literature, It can be synthesized based on the description in the literature.

The heteroaryl group represented by A is a hydroxyl group, an amino group, a mono-lower alkylamino group as a substituent, or a canolebamo-inole group or N— Mono If the compound has a lower alkynolecal bamoyl group or the like, a protecting group generally used for such a substituent (for example, a benzyl group, a benzyloxy carbonyl group) , Tert-butoxycarbonyl) etc. can be used as needed. Preparation of starting materials 1> Reaction process formula A

A-CHO -Ri _C H ₂ MgX ^Gri g ^nard A-¾ (i)

(1) (2) OH

(3) Oxidation

A-CHCH ₂ Ri A-CCHR ¹ (ii)

II

OH 0

(3) (4) Alkylation

A CCKy ¹ + R ² X A-CCHR ^ ²⁰ O

(4) (5) (6)

[Wherein A, R ¹ and R ² are the same as above. X represents a chlorine atom, a bromine atom or an iodine atom. ]

Process (i>

The aldehyde of the above general formula (1) is reacted with the Grignard reagent of the general formula (2) in a solvent at -20 to 40 for 10 minutes to 4 hours. Obtain the alcohol of (3). The reaction is carried out by reacting one mole of the aldehyde of the general formula (1) with the Grignard reagent of the general formula (2). Use 1 to 4 moles. Ethers such as dry ether and dry tetrahydrofuran can be used as the solvent.

Process ()

The alcohol (3) obtained in the above step (i) is oxidized or DMS 0-oxidized in a solvent using an oxidizing agent, so that the alcohol represented by the general formula (4) is obtained. Get a ton. In the reaction using an oxidizing agent, use 1 equivalent to an excess amount of the oxidizing agent with respect to 1 mole of the alcohol (3), and react at 0 to 60 for 30 minutes to 24 hours. You. Examples of the solvent include pyridin, methylene chloride, carbon tetrachloride and the like. Examples of the oxidizing agent include chromic acid, pyridinium chromium mouth chromate, and activated manganese dioxide.

In the case of DMS 0 oxidation, alcohol (3) per mole of sulfatrioxydopyridin complex, oxazolysyl chloride — DMSO, N—chloro Use 1 to 6 equivalents of the reagents used for DMSO oxidation, such as rosin imidazole methyl olenolide, at 180 ° (: up to 40 ° C. After reacting for 0 minutes to 6 hours, it is reacted with an amine such as triethylamine, 41-methylmorpholine, etc. The solvent is chlorophonolene or methyl chloride. Halogen hydrocarbons such as ren, ethers, tetrahydrofuran And aromatic hydrocarbons such as benzene and tonolene, and DMS0.

Step (iii)

By reacting the ketone of general formula (4) obtained in the above step (ii) with an alkyl halide of general formula (5) in a solvent in the presence of a base, The compound of the general formula (6) is obtained. The reaction is carried out using about 1 to 4 mol of the phenolic halide of the general formula (5) and about 1 to 2 mol of the base per mol of the ketone of the general formula (4). Incubate for 10 minutes to 24 hours.

Solvents include halogenated hydrocarbons such as methylene chloride, ethers such as ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene. And so on. As the base, triethylamine, sodium hydride, lithium diisopropinoleamide, n-butyllithium and the like are used. When sodium hydride, lithium diisopropylamine, or n-butyllithium is used as the base, the ketone of the general formula (4) is used in a solvent. After forming an enolate by pretreatment with a base, it is reacted with an alkyl halide of the general formula (5). <Production of starting materials 2>

Reaction equation B

A-X A-MgX (i V)

(7) (8)

R ^ CHCN + AMgX ^ ^gd reaction 'A- CCHRiR ² (v)

(9) (8) o

(6) [In the formula, A, R ¹ and R ² are as defined above. X represents a chlorine atom, a bromine atom or an iodine atom. ]

Process (iV)

The compound of the general formula (8) is reacted by reacting the compound of the general formula (7) with magnesium in a solvent.

Obtain Grignard reagent. The reaction is a compound of the general formula (7)

Use 0.6 to 4 moles of magnesium per 1 mole and react at 0 to 60 for 10 minutes to 8 hours.

Examples of the solvent include ethers such as ether and tetrahydrofuran.

XH (V)

After reacting the Grignard reagent (8) obtained in the above step (iV) with nitrile of the general formula (9) in a solvent. An excess amount of water is added and treated with an acid to obtain a ketone represented by the general formula (6). For the reaction, use 1 to 4 mol of the Grignard reagent of the general formula (8) with respect to 1 trinole of the general formula (9), at 0 to 40 ° C for 10 minutes to 4 min. Allow time to react. As the solvent, ethers such as ether and tetrahydrofuran can be used. After adding an excess amount of water to the product of the above Grignard reaction, hydrochloric acid, sulfuric acid, or the like is added as one acid to one mole of the nitrile of the general formula (9). Add an excess amount and react at 0 to 40 ° C for 10 minutes to 6 hours to hydrolyze. <Production of starting materials 3>

Reaction process formula C

-CHCffl ^ R ² > A-CCHR ^ ² (vi) I II OH O

(10) (6)

[Wherein A, R ¹ and R ² are the same as above. ]

Step (vi)

By oxidizing the alcohol of the above general formula (10) under the same reaction conditions as in step (ii),

Get the ketone of (6).

C-General formula (I) [In Y force, 'force Norebonil ^ and n force · <0 Production of the compound of the present invention>

Reaction process formula

[Wherein, A, RRR ⁴ and R ⁵ are the same as above. Step (vii)

0 By reacting the ketone of the above general formula (6) with an amine of the general formula (11) in a solvent in the presence of formaldehyde, the compound of the present invention of the general formula (12) is obtained. Get. In the reaction, about 1 to 4 moles of dialkylamine of general formula (11) and about 1 to 4 moles of formaldehyde are used for 1 mole of ketone of general formula (6). Incubate at 0 to 150 ° C for 10 minutes to 10 days. Solvents include aliphatic alcohols such as ethanol, halogenated hydrocarbons such as methylene chloride, ethers such as ether and tetrahydrofuran. And aromatic zero-group hydrocarbons such as benzene. Production of the compound of the present invention wherein Y in the general formula (I) is a carbonyl group and n is 1>

Reaction process formula E

(viii)

(6) (13) (14)

ϋ

(17)

[In the ^{^{formula, A, RR 2, R 3}} , R 4 your good beauty R $ is the same in the. T s represents a p-toluenesulfonyl group. V v (viii) The alkylation reaction is carried out under the same reaction conditions as in the above step (iii) to obtain a compound of the general formula (14). However, the ketone of general formula (6) is used in place of the ketone of general formula (4) used as a raw material in step (iii), and the ketone of general formula (6) is used instead of the alkyl halide of general formula (5). The compound of the general formula (13) is used.

Process (ix)

The compound of the general formula (16) is obtained by reacting the alcohol of the general formula (14) with p-toluenes-norefonyl chloride (15) in a solvent. In the reaction, about 1 to 3 moles of p-toluenesulfonyl chloride is used per 1 mole of the phenolic alcohol of the general formula (14) at 0 to 40 ° C for 30 minutes. Let react for ~ 2 days. Examples of the solvent include pyridin, methylene chloride, and tetrahydrofuran. Examples of the base include pyridin and triethylamine.

Process (X)

By reacting the compound of the general formula (16) obtained in the above step (ix) with an amine of the general formula (11) in a solvent, the compound of the present invention of the general formula (17) is obtained. . For the reaction, 1 mol of the amide of the general formula (11) is used per 1 mol of the compound of the general formula (16) to an excess amount. The reaction is performed at 0 to 140 ° C for 1 hour to 4 hours. Let it react for days. Examples of the solvent include phenolic alcohols such as methanol and ethanol, halogenated hydrocarbons such as chlorophonolem, and methylene chloride, ethers and tetrahydro. Examples include ethereals such as droflan, aromatic hydrocarbons such as benzene and toluene.

Reaction process formula F

^{Wherein, A, R \ RR 3,} R 4 and R ⁵ are the same above. n indicates 0 or 1. ]

Process (xi)

The carbonyl group of the aminoketone compound of the above general formula (18) is reduced in a solvent in the presence of a reducing agent, and the amino group of the general formula (19) is reduced. (The compound of the present invention) In the reaction, 1 equivalent to an excess amount of a reducing agent is added to 1 mol of the aminoketone compound of the general formula (18), and the reaction is performed in a range of 40 to 60. Perform at C for 10 minutes to 6 hours. Examples of the solvent include phenolic compounds such as methanol and ethanol, ethers such as ether and tetrahydrofuran, and the like. It is. Examples of the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride, diborane, and the like.

Reaction process formula G-alkylation

(19)

(twenty one)

^{Wherein, A, R, RRR 3,} R \ R s and n are the same above. ]

(Xii)

An alkylation reaction is carried out under the same reaction conditions as in the above step (iii) to obtain the compound of the present invention targeted by the general formula (21). However, in place of the ketone of the general formula (4) used as a raw material in the step (iii), the amino alcohol of the general formula (19) obtained in the above step (xi) is used, The alkyl halide of the general formula (20) is used instead of the alkyl halide of the general formula (5).

Reaction process formula H

(xiii)

^{^{Wherein, A, RR 2, R 3}} , R \ R 5 and n are same as before SL. m represents 2 or 3. ]

(Xiii)

By reacting the aminoketone compound of the above general formula (18) with the glycol of the general formula (22) in a solvent in the presence of a catalyst, the amide of the general formula (23) is obtained. The intended compound of the present invention is obtained. The reaction is carried out in such a manner that 1 mol of the amino group of the general formula (22) is added to 1 mol to an excess amount, and 0.1 to 2 mol of the catalyst is used per 1 mol of the aminoketone compound of the general formula (18). For about, O ~ 140 ° C Run for 10 minutes to 3 days. Examples of the solvent include halogenated hydrocarbons such as chloroporous dimethyl chloride, ethers, ethers such as tetrahydrofuran, and benzene. And hydrocarbons such as toluene and the like. As the catalyst, P-tonorensorephonic acid, methansnorrephonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonate pyridinium and the like are used.

The above reaction scheme H shows a method for synthesizing a kettle in the case of using ethylene glycol and trimethyl alcohol. Under similar conditions, use other glycols or alcohols instead of ethylene glycol and trimethylene glycol. By reacting, other keta can be easily synthesized.

Production of the compound of the present invention wherein Y in the general formula (I) is CH (0 (CO) R)>

Reaction process formula I

(19) (24)

Wherein, A, R '\ R \ R 2, R 3, R \ R 5 and n are the same above. X represents a chlorine atom or a bromine atom. :)

(Xiv)

The amino alcohol of the above general formula (19) is esterified with a carboxylic anhydride or a carboxylic acid halide of the general formula (24) in the presence of a base in a solvent. To obtain a compound of the general formula (25). The reaction is carried out with respect to 1 mol of the amino phenol of the general formula (19) and one mono- to excess of the anhydrous carboxylic acid or halogenated carboxylic acid of the general formula (24) 1 to 10 mol of base and 0 to 60 mol Run for 5 minutes to 2 days. Examples of the solvent include pyridin, methylene chloride, tetrahydrofuran, and the like. Examples of the base include pyridin and triethylamine. If necessary, 4-dimethylaminopyrrolidine is used as a catalyst.

The compound of the present invention has a central muscle relaxing action and a therapeutic action for pollakiuria, and can be used as an active ingredient of a central muscle relaxant and a therapeutic agent for pollakiuria. The therapeutic dose of a therapeutic agent for a central muscle relaxant or pollakiuria containing the compound of the present invention as an active ingredient depends on the patient's age, sex, the condition to be treated, and the method of administration. Depending on the strength, it can usually be 1 to 200 mg per day for an adult, preferably 10 to 200 mg per day.

Dosage forms include oral preparations such as capsules, tablets, fine granules, syrups and powders, or injections, suppositories, patches, ointments and aerosols. It can be administered orally or parenterally. The following excipients can be used as appropriate according to the dosage form.

1. Oral administration

Excipients: lactose, mannitol, corn starch, crystalline cellulose, low-substituted hydroxypropyl Etc .;

Binders: starch, na-starch, gelatin, methylcellulose, polyvinylidene-lipidone, hydroxypropinolemethylcellulose, Hydroxypropyl phenolic cellulose, crystalline cellulose, etc .;

Disintegrants: starch, carboxymethylcellulose canolesum, low-substituted hydroxypropinolylcellulose, canolepoximetyl starch, etc. ;

Lubricants: magnesium stearate, evening water, anhydrous genoic acid, etc .;

Coating agents: sucrose, talc, precipitated calcium carbonate, gelatin, arabic gum, punoreran, canola naenuro, hydroxip Lopinoretorenoroseororofufu rate, etc .;

In addition, a brightening agent, a flavoring agent, a stabilizer, a coloring agent, and the like can be appropriately used.

2-injection

Solvents: water for injection, vegetable oils such as sesame oil, macrogol, etc .;

Tonicity agent: sodium chloride, etc .;

Buffering agents: sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, vinegar Acid, sodium acetate, etc .;

Soothing agent: benzyl alcohol, procaine hydrochloride, etc .;

Preservative: Parabens such as methyl parabenzoate, benzyl alcohol, etc. can be used according to the purpose.

3-suppositories

Base: cocoa butter, hardened oil, saturated fatty acid glycerin ester, branched saturated alcohol, macrogol, etc. Emulsifier: anionic surfactant, non-ionic An active surface active agent can be used according to the purpose.

4-patch

Thickeners: sodium alginate, gelatin, methylcellulose, canoleboxininole repolymer, sodium polyacrylate, etc .;

Moisturizers: glycerin, macrogol, etc .; Fillers: kaolin, titanium dioxide, zinc oxide, etc .; Crosslinkers: acetoaldehyde, dimethylketone, Aluminum sulfate, etc .;

Solubilizers: alcohols such as ethanol, 2-propanol, macrogol, etc .; Emulsifier: Anionic surfactants and nonionic surfactants can be used according to the purpose.

5. Imperial sound agent

Base: White petrolatum, hydrocarbons such as liquid paraffin, fats and oils such as soybeans, rowes such as beeswax and lanolin, stearic acid, oleic acid, etc. Fatty acids, higher alcohols and their esters, macrogol, etc .; emulsifiers: use anionic surfactants, nonionic surfactants, etc. according to the purpose. It can be.

6. Aerosol

Solvents' base: ethanol, 2-propanol, propylene glycol, etc .;

Emulsifier: various surfactants;

Gas: Fluorinated hydrocarbons, liquefied petroleum gas, compressed gas, etc. can be used according to the purpose.

The compound of the present invention and a physiologically acceptable salt thereof have excellent muscle relaxation, anti-crazing activity, etc., and muscles caused by diseases such as lumbar back pain, herniated disc, and shoulder-like arm syndrome. It is extremely useful as an active ingredient of a therapeutic agent for spastic paralysis caused by diseases such as tension and cerebrovascular disorder, spastic spinal palsy, and cerebral palsy. It is also useful as a therapeutic agent for pollakiuria. BEST MODE FOR CARRYING OUT THE INVENTION

Reference Example 1 Production of starting materials

5-Isofu'tyryl-3-Fenirui '

(1) 5— (1-t-to-π-xy-2-methyl-methyl.)-3-3-phenylisoxyl benzylbenzene hydroxamic acid chloride 62.2 g (400 mmol) ) And 4-methyl-1-. 42-3 Og (430 mmol) is dissolved in 250 ml of octafluorophore, 43.5 g (430 mmol) of triethylamine is added dropwise under ice cooling, and then at room temperature for 2 hours. Stirred. The reaction solution was washed with a 1N hydrochloric acid aqueous solution, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove 5- (1 95.2 g of π-xy-2-methyl 7 ° π-yl) -3-phenyiI-no-kis-a-kia-factor (alcohol compound) was obtained as crude yellow crystals.

(2) 5-Isofu, 'Thi ¹ J -3-7 phenyl isocyanate T'

78.1 g (585 mmol :) of N-α-rosuccinimide was dissolved in 1.00 L of toluene, and 48.5 g (780 mmol) was added dropwise to 'Vantyl sulfy' under ice-cooling. Cooled to C. A solution prepared by dissolving 95.2 g of the alcohol compound produced in the above (1) in 400 ml of toluene was added dropwise thereto, and the mixture was stirred for 1.5 hours. At the same temperature, 59.5 g (585 ml) of triethylamine was added dropwise, stirred for 30 minutes, and then stirred at room temperature for 30 minutes.

Ether 1.0 L was added to the reaction solution, and the The crystals were filtered off. The filtrate was washed with a 1N aqueous solution of hydrochloric acid, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an orange oil. This was purified by silica gel chromatography (solvent: hexane ethyl acetate = 19/1) to obtain colorless crystals. Further, this was purified by recrystallization (solvent: ethanol) to obtain colorless crystals of 5-isobutyryl-3-7-enylisohexylpar. Yield 60.3 g (70.0% yield) The analysis results of the obtained crystals are shown below.

_{NMR (5ppm, CDC1 3):} 1.28 (. 6H d), 3. 0 - 3.60 (1 H, m), 7. 22 (lH, s) (7.40-7.50 (3H, m), 7.80-7.90 (2H , in)

Melting point 68.0-71.0 ° C

Example 1

5- (3-sheet '- methyl 7 minnow 2, 2 sheets * Mechirufu. Nt ^e old) -3- Fueniruiso old Kisa'厂_ le hydrochloride

(1) 5- (3-S "methylamino-2,2-S" ^ Methyl-F. Mouth t ° -Sil-Nil) 1-3-phenyl

Dissolve 39.3 g (182 mmol) of 5-yl and thyryl-3-phenylisobenzene in 250 ml of ethanol, and add a 50% aqueous solution of dimethylamine. 23. After adding Qg (255 mmol), 25.2 g (310 mmol) of a 37% aqueous solution of formaldehyde was added dropwise, and the mixture was stirred at room temperature for 4 days. After concentrating the reaction solution, it was poured into aqueous hydrochloric acid solution and washed with ether. After extracting the water layer with carbonic acid reamer to make it more alkaline, ether extraction was performed. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 5- (3-si, 'methylamino-2,2-si * methylphenyl) as pale yellow crystals. Nt 'ニルニル一 3 — — — — 一 — 3 3 3''.

The analysis results of the obtained crystals are shown below.

(2) 5-(3-dimethylamino 2.2-dimethylpropionyl) 1-3-phenolic soxazole

"3πιYoun" an

6.0 g of the ketone compound produced in the above (1) was dissolved in 10 mL of ether, and converted into a hydrochloride with hydrochloric acid gas. This is purified by recrystallization (solvent: methanolic ether), and 5 — (3-dimethylamino 2,2-dimethylpropionyl) 13-phenyl Colorless crystals of nitrile soxazole hydrochloride were obtained.

Yield 6.20 g (Yield 78.0%)

The analysis results of the obtained hydrochloride are shown in Table 1 below. Example 2

5— [2,2-Si "Methyl-3— (1-H- ^O- Rishi, 'Nil').

(1) 5— “2.2—methyl 3— (1-t ° π lysine). 5—Isophoric acid 3—Fenyl isocyanate, water, 10.8 g (50.0 mmol :), liposome 4.98 g (70.0 mmol), aqueous solution in 35-formaldehyde 29 g (85.0 mmol) and slightly yellow crystals were obtained in the same manner as in Example 1, (1). This was purified by recrystallization (solvent: hexane) to give slightly yellow crystals of 5- [2,2-cy'methyl-3- (1-1'pi'ricinyl) 7. t. Onyl] -3-phenylisoxazolyl was obtained. Yield S 10.7g (Yield 71.0¾)

The analysis results of the obtained crystals are shown in Table 1 below. (2) 5-[2, 2-Dimethylenol 3-(1-pyrrolidinyl) propionyl] 13-Phenylisoxazole-hydrochloride

The ketone body produced in (1) above. 3. A colorless oily 5- (2,2) -dimethynorate 3 was obtained from OO g by the same method as in (2) of Example 1. — (1—Pyrrolidinole) propionyl] -13—Pininoleic soxazonole hydrochloride 3.20 g was obtained.

Example 3

5— (3-Si, 'Methylamino 1-Human,' Mouth pheasant-2,2-Simethylf. i.

(1) 5-(3-S-methylamino-1-!: To π-xy-2,2-S, 'methyl 7 ° α)-

3—Phenyl isose

5.45 g (20.0 g) of the ketone body produced in (1) of Example 1 Was dissolved in 30. Oml of ethanol, 0.76 g (20.0 mmol) of sodium borohydride was added, and the mixture was stirred for 5 minutes. The reaction solution was poured into an aqueous solution of hydrochloric acid and washed with ether. The aqueous layer was made alkaline with carbon dioxide and extracted with ether. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a colorless oily 5- (3-methylamino-1-t * π-xy 2,2 —Sh * methylf. Mouth) 5.3-g of 3-phenylisoxazol.

() 5— (3-methylamino 1-human * π-diphenyl 2.2—methyl-methyl-butanol) 3-phenyl,

5.29 g of the alcohol compound produced in the above (1) was dissolved in 10.0 ml of ethanol, and 2.24 g (19.3 mmol) of maleic acid was added, followed by stirring at room temperature for 1 hour. The solvent was distilled off to obtain a colorless crystal. This was purified by recrystallization (solvent: ethanol / ether) to give colorless crystals of 5- (3-'Vanthylamizo-1-! ' nt.) -3-phenyl isocyanate T'-maleate was used. Yield 5.36 g (yield from (1) in Example 1 59.3S

The results of analysis of the obtained maleate are shown in Table 1 below.

Example 4

5- [1-hydroxy-1,2,2-methyl-1- (N-methylethylami /) Lohi. 1] 3-phenylisolate (1) 5- [2. 2-S-methyl-1- (N-methylethylamino) Lohi.ニル nil — -3—

5-Iso 7 "Chillyl 3-phenylisocyanate" 15. lg (70.0 mmol), N-methylethylamine 3.94 g (67.0 mmol), 35¾ formol 7 Solution 8. From 58 g (100 mmol) of the yellow oily 5- [2,2-dimethyl-3- (N to ethylmethyla) by the same method as (1) in Example 1. Mino) Huh. D t. Old sulfonyl] -3-Hue was a two Ruiso talent Kisaso ,, Lumpur 3 · 52 g ₀

(2) 5— [1 human, 'D pheasant 2,2-si, methyl-3- (N-methylethylamino). π ^{11 11}一一一一 3 3 — 3

Same as (1) in Example 3 from 3.42 g (ll. 9 mmol) of the ketone body produced in (1) above and 0.50 g (13.1 mmol) of sodium borohydride. By the above method, colorless crystals were obtained. This was purified by recrystallization (solvent: hexane) to give colorless crystals of 5- [1-D-di-butoxy-2,2-di- ', methyl-3-(Ν'-methyl). Thiamizo) f.c] -le] -3-phenyl isocyanate was obtained. Yield 2.04 g (Yield 10.6¾)

The analysis results of the obtained crystals are shown in Table 1 below.

(3) 5 — [1-Hydroxy 2.2-Dimethyltin 1-3-(N-methylethylamino) Propyl 13-3-Funinylisoxoxazole hydrochloride

From 2,04 g of the alcohol compound produced in (1) above, a colorless oil was obtained by the same method as in (2) of Example 1. Object 5 — [1-Hydroxy 2, 2 — Dimethylino 3 — (N—methylinoethylamino) Propinore1-3—Feni Rui Soo 2.25 g of oxazole hydrochloride was obtained. Example 5

5- (3-Si * -π-F.F.Amino 1-Heat) α-Xii 2,2-S-methylF.H.

-3—Fenilisiso Kisaso Ilmalein

(1) 5-(3-ン, π π-。. at. Leamino-2.2-シメチル "メチルヒ才才 3 — 3 3 一一一 3 3)

5-Izov,, Chilelu 3-Feniruzo Ikisazo ', 5.00 g (23.2 mmol :), Si,' -n-fu. πhi. Lumin 4.46 ml (32.5 mmol :), 37% formarte * Human, from aqueous solution 3.21 ml (39.5 mmol) by the same method as (1) in Example 1 to give 5- (3 -'Ba-n-fu. Nl: ° lumino-2,2-si "methyl-fu. Pi-hi.i-nil) 1-3-phenyliso-kixa'/" i-lu 5.18 g obtained ₀

(2) 5-(3-1-π-f. Mouth t. Luamizo 11-:, 'π-xy 2, 2--,' Methylo-Roh. Rule

From 1.84 g (5.60 mmol) of the ketone body produced in the above (1) and 0.2 lg (5.60 mmol) of sodium borohydride, the same as (1) of Example 3 According to the same method, 5_ (3-S-I-N-F.nt. Lamino_1-Human) π pheasant-2,2-S-, 'Methyl-F. 1.86g of Hue Sansui Kiseki 'Factory'-, Les.

The analysis results of the obtained oil are shown below.

(3) 5 — (_ 3—sh, '_π-f. D t :. Le:) -3-phenyliso-kisazo "lmaleate

From 1.86 g of the alcohol compound produced in (2) above and 0.65 g (5.63 mmol) of maleic acid, a colorless oil was obtained in the same manner as in (2) of Example 3. The 5- (3-si "-n-fu.m.luami /-1-human * mouth pheasant-2,2-shi * methylfu.mouth t.ru) one 3-phenylisocyanate Obtained.

Yield 2.48 g (Yield 67.6¾) Example 6

5-[1-t to ^ J xy -2, 2-shi, methyl-3-(1-!:. Lohi. Le; I-3—Fenilisiso Tadashi "Rumalein ^ ^

(1) 5— [1— I: G, π-xy 2,2-Si, -Methyl-1- 3— (1 t ° mouth Rishi, 'nil) Mouth f 1] 3—Fenriso

3.02 g (10.1 mmol) of the ketone compound produced in (1) of Example 2 and 0.38 g (10.1 mmol) of sodium borohydride were obtained from Example 3 and By the same method as in (1), colorless crystals were obtained. This was purified by recrystallization (solvent: hexane / ether) to give α-oxy-2,2-dimethyl-3- (1-l-cyclohexyl-5- [1-phenyl) as colorless crystals. Nil) Hu. Mouth t. 3--3-phenylisolate. Yield 2.15 g (50.2% yield from (1) in Example 2)

The analysis results of the obtained crystals are shown in Table 1 below.

(2) 5 -_ [1 -t to 'α-xy 2' 2-si, methyl-3-(1-1 ° mouth lysinyl) Le] 1-Phenyl-isolated kiss

From 2.13 g of the alcohol compound produced in the above (1) and 0.82 g (7.09 mmol) of maleic acid, a colorless oily substance was obtained in the same manner as in (2) of Example 3. 5-[Tohiroquin-2,2-dimethyl-3- (1-hydroxy π lysinyl) fu; Lohi. 2] 72 g of -1-maleine ® was obtained.

Example 7

5- (3-Shi 'Mechiruamizo - 1 Metokishi -. 2, 2-Shi / Chirufu ¹¹ [pi human Le) Single 3 - phenyl Isookisa' - le hydrochloride

(1) 5-(3-, methyl-1-1-methoxy2, 2-, 2,-, methyl, methyl) 1-3-phenylisoxazole

3.29 g (12.0 mmol) of the alcohol compound prepared in (1) of Example 3 was dissolved in 15 ral pi-furan, and 0.48 g (13.0 mm) of 60% hydrogenated sodium was dissolved. Mmol) and 50. The mixture was stirred at C for 40 minutes. The reaction solution was cooled to 0 ° C, 1.85 g (13.0 mmol) of methyl iodide was added dropwise, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into an aqueous solution of hydrochloric acid and washed with ether, and the aqueous layer was made alkaline by a carbon dioxide reamer, followed by ether extraction. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give a colorless oil O5- (3-methylamino-1,2-dioxin-2,2-) 3. "Methylphenyl ° π.:))))) 3)) 3))))). The results of analysis of the obtained oil are shown in Table 1 below.

(2) 5-(3-, methylamino-1-toxic-2.2-meth * methyl).

3.16 g of the methoxy compound produced in the above (1) was dissolved in 10. Oml of ethanol, and converted into a hydrochloride with hydrochloric acid gas to obtain colorless crystals. This was purified by recrystallization (solvent: ethanol / ether) to give colorless crystals of 5- (3-'bamethylamino_1 toxic-2,2-'vanityl 7.D) -3. Phenyli '/ said Kisaso'-HCl hydrochloride was obtained. Yield 2.78 g (Yield from (1) of Example 3 71.0¾)

The analysis results of the obtained hydrochloride are shown below.

Example 8

5- (3-Si * Methylamino-1 -Isofu * Tyryl pheasant 2,2-Si, Methyl pi.Hil :)-3 -Fenirui

(1) 5- (3-Si, 'Methylamizo-1') / 2- (Silyl-methyl) 2-methyl-.

5.49 g (20.0 mmol) of the alcohol compound produced in (1) of Example 3 was dissolved in 30.Oml of methylene chloride, and 2.34 g (22.0 mmol) of isobutylinole chloride was added to the solution. 2.23 g (22.0 mmol) of lichenoreamine was added, and the mixture was stirred at room temperature for 10 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 a carbon dioxide reamer and extracted with ether. The organic layer was washed with a saturated saline solution and anhydrous sulfuric acid was added. After drying with magnesium, the solvent was distilled off under reduced pressure to give a yellow oil.

05- (3-Si * methylami / -1 -isofur * tyril-2,2-shi, -methyl) .1-3-phenylisohexyl * 6.70 g was obtained.

(2) 5- (3-S * methylamino-1-y) / F * Tyryl 1,2-S * Methyl 7 * Hole)

6.70 g of the isobutyryloxy compound prepared in the above (1) was dissolved in 30.0 ml of ethanol, and the solution was converted into a hydrochloride with hydrochloric acid gas to obtain colorless crystals. This was purified by recrystallization (solvent: ethanol-ether) to give colorless crystals of 5- (3-si * (tylamino-1-isobutylyloxy-2,2-si-, methylph.). Yield of 1,3-phenylisosoxa'par hydrochloride was obtained, yield 6.35 g (of Example 3).

(Yield from (1) 83.0%)

The analysis results of the obtained hydrochloride are shown in Table 1 below. Example 9

5- (3-Si, 'Methylamino-2,2-Si'-methyl-1-fu. N t. Nil-year-old Kisif. Mouth Hi.

(1) 5- (3-methylamino-2,2-methyl-2-methyl. Lohi.

3.00 g (10.9 mmol) of the alcohol compound prepared in (1) of Example 3 was dissolved in 80.0 ml of methylene chloride, and 1.50 g (ll) of anhydrous pionic anhydride was added. .5 mmol) and 1.2 lg (12.0 mmol) of triethylamine were added and stirred at room temperature for 4 hours. reaction The solution was poured into an aqueous solution of hydrochloric acid and washed with ether, and the aqueous layer was made alkaline with carbon dioxide 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 5- (3-methylmethylazoline) as a yellow oily substance. 3.32 g of xy-2,2-si * methylfuro-3) -3-phenylisoxazole.

(2) 5-(3-dimethylamino 2.2-dimethyl 1-propionyloxycyclopropyl) 1-3-phenyl benzoyl hydrochloride

3.3 lg of the propionyloxy compound produced in the above (1) was dissolved in 15 · Oml of ethanol, and converted into a hydrochloride with gaseous hydrochloride to obtain colorless crystals. This was purified by recrystallization (solvent: ethanol-ether), and 5— (3—dimethylamino 2,2—dimethyl alcohol 1-colorless crystal was obtained. Oninoleoxypropinole) 1-3-Phenylyl soxazole hydrochloride was obtained. Yield 2.95 g ((1) force of Example 3, yield 73.8%) The analysis results of the obtained hydrochloride are shown in Table 1 below. Example 10

5-(1-acetoxy-1-3-methyl * mino 2,2—si, 'Methyl-fu. At. Le) 1-3-Feni-rui'

(1) 5- (1-Acetoki _ cis 1-cis, 'Methylamizo -2 ^ 2-cis, methyl ph. Nisoiso Kisoso *

2.74 g (10.0 mmol) of the alcohol compound produced in (1) of Example 3 was dissolved in pyridinium 10. Onil, and 1.53 g (15.0 mmol) of acetic anhydride was added to 4 ′ ′, Metchi, Reaminohi. 0.2 g of resin was added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into an aqueous solution of hydrochloric acid and washed with ether, and the aqueous layer was alkalified with potassium carbonate and then 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 5- (1-acetoxy-3-'bamethylamino-2,2-) as a yellow oil. Methyl phenyl.) 1 3 phenylisopropyl, 2 g 35-g ( _0- (2) 5- (1-acetoxy 3-methyl-amino 2,2) : ° ： :)-3-Fluisoxa'pal hydrochloride

2.35 g of the acetoxy compound prepared in the above (1) was dissolved in 10.0 ml of ethanol, and the solution was converted into a hydrochloride with hydrochloric acid gas to obtain colorless crystals. . This is recrystallized (solvent: D data Bruno Lumpur one error over ether) by Ri purified, colorless crystals of 5- (1 Asetokishi 3, Mechiruami / one 2, 2 'methyl 7 ° opening t ^e le ) -3-Feniruiso-kisazolo "-l-hydrochloride was obtained. Yield 2.35 g (Yield of (1) force of Example 3, 67.0%)

The analysis results of the obtained hydrochloride are shown in Table 1 below. table 1

Table 1 (continued)

Table 1 (continued)

m ι 1

5- (3-methylmethylamino-2,2-dimethylmethyl) -3-phenylisoxate

(1) 5- (3-methylamino-2.2-'^ methylbutyryl)) 3-phenyliso Hillool

11.7 g (102 mmol, 35-oil suspension) of hydrogenation power rim and 200 ml of tetrahydrofuran were added to the flask. Then add 21.5 g (100 milliliters) of 5 — isobutanol in a nitrogen stream at 0 ° C. A solution dissolved in 100 ml of franc was added dropwise over 1 hour. One hour later, the reaction solution was cooled to -78 ° C using dry methanol. Ethylene oxide gas was passed through this solution for 15 minutes. After 15 minutes, the refrigerant was removed and the reaction temperature was gradually raised to room temperature. After stirring at room temperature for 1 hour, the reaction solution is poured into water, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off to remove the yellowish yellow ø5- ( 37.2-g of crude product of 3-human, lipo-2,2-cyclomethylthyryl) -3-phenylisophenol was obtained as a crude product.

The hydroxy compound obtained above was dissolved in 200 ml of pyridin, and 21.0 g (110 mi) of tosinole chloride was added under ice cooling. Stirred for hours. The reaction solution was poured into ice water-concentrated hydrochloric acid, and methylene chloride was extracted. Methyl chloride The ren layer was washed successively with water, saturated aqueous sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove 5- (2,2-cis-methyl) methyl alcohol. 1-3-Tosyl-sulfur xyph * tyryl) -3-Fu-nirui 36.8 g as crude product was obtained.

The obtained tosyl form, 135 g (1.5 mol) of a 50% aqueous solution of dimethylamine, 20.7 g (150 mol) of potassium carbonate, and 150 ml of ethanol were added to the flask. After stirring at about 50 ° C for 15 hours, water was added and ethanol was distilled off under reduced pressure. This was extracted with ether, and the ether layer was washed with saturated saline and extracted with 3N-hydrochloric acid. The extracted aqueous layer was washed with ether, 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 to give a slightly yellow oil of 5- (3-si, 'methylamino-2,2-si "methylphthyl). ) One-third phenyl isosol

The analysis results of the obtained crystals are shown below.

_{NMR (δ ρρπι, CDC1 3)} : 1.36C6H, s), 1.98 (6H, s), 2.12 (2H, t, J = 6.6Hz), 2.25 (2H, t, J = 6.6Hz), 7.13 (1H, s), 7.47-7.49C3H, m), 7.83-7.86 (2H, m)

(2) 5- (3-S ', methylamino 2,2-S-methylf,' Tyryl) _3-phenylisoxanol 'N-"-HCl

7.01 g of the ketone body produced in (1) above was added to ether 1 It was dissolved in 00 ml and converted into a hydrochloride with hydrochloric acid gas. This was purified by recrystallization (solvent: ethanol), and 5- (3-methylamino-2,2-methylthityl) -13-phenylisothiazole was purified. ^ Colorless crystals of the acid salt were obtained.

The analysis results of the obtained hydrochloride are shown below.

Yield 6.71g (Yield 53.6¾)

170-171 ° C

Elemental analysis _{_{_{value: d 7 H 2 3 C1N 2}}} 0 2

C H N

Cal. (¾) 63.45 7.20 8.70

Found (¾) 63.20 7.21 8.57

Example 1 2

5— (3—S ”Methylamino 1-11!: T ^! Xy -2,2—S, 'Methylph'tyl) -3 Nil

(1) 5-(3-, 'methylamino-11!: "キシ 2, 2-,' methylphthyl ')-3-fenirui' zoshikiki 'Γ'-ル

Dissolve 10.0 g (35.0 milliliters) of the ketone body produced in (1) of Example 1 in 60 ml of ethanol, and add sodium hydrogenated boron to 0.66 ml. g (17.5 mi) was added and stirred for 5 minutes. The reaction solution was poured into aqueous hydrochloric acid solution, washed with ether, the aqueous layer was made alkaline with potassium carbonate, and then extracted with ether. The organic layer was washed with saturated saline, After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give colorless crystals of 5 — (3 — dimethylamino 1 — hydrazine xy 2,2 — dimethyl olebutinole). 3.69 g of phenolic sonosol was obtained.

The analysis results of the obtained oil are shown below.

_{NMR (5 ppm, CDC1 3)} :....... 0.99 (3H, s), 1.04 (3H, s), 1. AT- l SBClH n l GS-l TSClH n J. S GH s Z. AO- 2.4 4 (2H, m), 4.52 (1H, s), 6.53 (1H, s), 7.42-7.49 (3H, m), 7.80-7.84 (2H, m), 9.05 (1H, br.s)

(2) 5- (3-methyl * methyl-amino-1-human D pheasant-2 · 2'-methylmethyl)

3-Fruy '/ Oxa' Factory-Hydrochloride

9.69 g of the alcohol compound prepared in (1) above was dissolved in 150 ml of ether and converted to hydrochloride with hydrochloric acid gas. This was purified by recrystallization (solvent: ethanol / ether) to give 5- (3-cis, 'methylamizo-1-human', mouth xii 2, 2-si, 'methylph, chill' ) —3—Fenilisiso Kisaso ”

-Colorless crystals of hydrochloride were obtained.

The analysis results of the obtained hydrochloride are shown below.

Yield 9.93g (Yield 87.4¾)

145-147 ° C

Elemental _{_{_{analysis: C 1 7 H 25 C1N 2}}} 0 2

C H N

Cal. («) 62.86 76 8.62 Found (¾) 62. 79 7, 80 8.56

Pharmacology test example>

It was confirmed that the compound of the present invention has a central muscle relaxing action by an animal experiment of an anti-crazing action and a muscle relaxing action. In addition, an acute toxicity test was conducted, and the safety factor was also examined. In addition, it was confirmed by an animal experiment of the effect of suppressing pollakiuria that it had the effect of treating pollakiuria. Eperizon hydrochloride, inaperizon hydrochloride, and flavoxate hydrochloride were used as control drugs.

(Test compound)

Compound A (Example 1) 5- (3-'Methylamino-2,2-methylthiophene ^β- t.

Compound B (Example 3) 5- (3-S-methylamino) /-1-Hydroxy- 1,2,2-S-'methylph.

Compound C (Example 8) 5- (3-sheet.. 'Mechiruamino - 1 - iso 7' dust Rusaiki 'Hmm 2, 2-Shi "Mechirufu π human Le) _ 3-phenylene Louis, Nookisa ¹ gamma Rule

Compound D (Example 9) 5- (3-Methylamino-2,2-methylmethyl-1-olefin. Le ^

Compound E (Example 10) 5- (1-Rethoxyethoxy-3-'methylamino-2,2-cis, methyl-nt)

Compound F (Comparative Example) 5- (3-methylmethyl) /-! Compound G (Example 11) 5- (3-'methyl '/-2,2-cyclo "methyl * tyryl) -3-phenylisopropyl" ^^ ^ ^

Control drugs Eperizon hydrochloride, Inaperizon hydrochloride, Flaboxate hydrochloride

1. Anti-nicotine action

The effects of Compound A, Compound B and Compound F on nicotine-induced spastic death after spasticity were examined and compared with epelizone hydrochloride.

[Method ]

Six to ten ddY male mice (5-week-old) fasted overnight were used per group. The test compound is orally administered, and 30 minutes later, 3 mg / kg of nicotine tartrate is administered via the tail vein to produce clonic and tonic eccentric spasms caused by nicotine. The effect of antagonism on pancreatic death after birth was examined. The measured value was expressed as a 50% effective dose of the free form (ED ₅₀ , mg / kg).

These compounds were dissolved in 0.1% Tween80 solution or 0: 5XCMC-Na solution.

Table 2 shows the results. Table 2

2. Anti-lightning scoping action

The effects of Compound A, Compound B and Compound F on maximal lightning cramping were examined and compared with epelizone hydrochloride.

[Method ]

Six male ddY mice (5 weeks old) fasted overnight were used per group. The test compound was orally administered, and 30 minutes later, a current of 20 mA was applied for 0.2 seconds from the electrodes applied to both eyes, and the antagonism to the tonic convulsions caused by electrical stimulation was examined. Measurements, 50¾ effective amount of off rie body _{(ED S., Mg / kg} ) and to the table.

These compounds were dissolved in a 0.1% Tween80 solution. Table 3 shows the results. Table 3

3. Muscle relaxation (N'o. L)

The muscle-relaxing effects of compound A, lig compound B, compound (:, lig compound D, compound E, and compound F were examined by a rotating rod method and compared with that of eperizon hydrochloride.

[Method ]

— Six dd Y male mice (5-week-old) fasted at night were used per group. The test compound was orally administered, and after 15, 30, 60 and 120 minutes, a rotating rod (diameter 3 cm, llr pm) and the residence time was measured up to a maximum of 120 seconds. In addition, animals with a residence time of 60 seconds or less were judged to have a positive muscle relaxant action.Based on the number of positive animals 30 minutes after administration, Compound A, Compound B, Compound C, Compound D, Compound E, Compound F and Fri 50% effective amount of control drug

_{(ED S., Mg / kg} ) was calculated. These conjugates were dissolved in 0.1 Tween 80 solution or 0.5% CMC Na solution. Dosage should be displayed in free form.

-,

Table 4 shows the results.

Table 4 Dosage Average time (seconds) Muscle relaxation II action 9 IAK 1 j A Sweet M mi

(ng / kg) 1 5 minutes ¾ 30 minutes later 60 minutes later 120 minutes later E DSOft

6 0 9 1.1 1 0 0.4 1 0 2.3 9 8. 1

8 0 5 9.9 4 5.7 6 8.3 95.9 Compound A 78.6

1 2 0 7 3.8 4 5.05 5 3.7 1 0 2.9

1 6 0 1 0.1 5.7 2 2.4 8 1.4

5 0 1 0 8.6 1 0 2.7 9 7.7 1 2 0.0

6 0 7 3. 0 9 0.6 0.6 1 0 2.6 9 8.6 Compound 《Β Β 6 5.7

7 0 6 7. 8 6 3.9 1 1 6.1 1 2 0.0

β 0 1 0.3 3 1 5. 4 4 3. 7 1 0 2.4

8 0 7 4. 7 7 3.5 1 2 0.0 1 1 1.8

1 0 0 5 3.2 6 3.7 8 1.7 8.2 Compound c 1 25.2

1 2 0 4 5.8 5 7.2 7 9.6 1 0 3.1

1 6 0 3 5. 3 3 7. 6 4 1.2 6 6.8

8 0 9 6.3 1 0 6.3 1 1 0.3 1 2 0.0

1 0 0 4 4.5 5 4.4.6 6 .6 85.0 Compound D 1 1 0.3

1 2 0 3 6. 2 6 5.6 1 0 1 .5 1 1 5.6

1 6 0 1 3.6 8.1 29.5 1 0 8.7

4 0 9 9.2 9 3.6 9 7.5 1 0 0.4

6 0 6 6. 7 7 3. 1 8 9-1 9 6.0

Compound E 8 0 5 9. 3 4 6. 6 8 5. 1 1 0 3.3 6 4. 4

1 2 0 1 1.9 9. 3 5 3. 4 1 1 3.4

1 6 0 2 0.β 1 3.2 2 3. 9 8 3.3 β 0 9 9. 7 1 1.3 1 1 6.9 1 2 0.0

1 2 0 7 2.4 1 0 8.9 1 0 4.7 1 20.0 Compound F 1 6 0 4 8.78 8 0.9.1 11.6 1 1 5.1 2 48.2

2 1 0 5 0. 0 5 9.2 8 9. 7 1 2 0.0

2 8 0 2 4. 0 5 2.4 9 3. 2 1 2 0.0

8 5 1 2 0.0 1 1 5.3 1 1 5.2 1 1 5.2

1 2 0 8 7.7 1 1 6.6 1 1 6.0 1 1 6.0

1 9 0.2 Eperisone

1 7 ϋ 6 9.3 1 0 3.9 1 0 9.6 1 0 9.6

2 0 0 1 1 .7 4 7.11 1 1 1.6 1 1 1.6 59 Muscle relaxing action (No.2)

The muscle-relaxing effect of compound G was investigated using the rotating bar method and compared with that of eperizon hydrochloride.

〔Method〕

Six Sprague-Dawley male rats fasted overnight were used in each group. The rat was placed on a rotating rod with a rotation speed of lOr.pm in the opposite direction to the rotation, and a rat that did not fall for more than 5 minutes was selected for the experiment. The test compound was orally administered, placed on a rotating rod after 15, 30, and 60 minutes, and the residence time was measured up to a maximum of 120 seconds. The residence time of 30 minutes after administration is determined 60 seconds following animal with muscle relaxant positive, 50% effective amount of positive animals Number or al of compound G and the control drug full rie body (ED _{5 0} mg / kg) was calculated.

These compounds were dissolved in water for injection or 0.1% Tween80 solution.

Table 5 shows the results.

Table 5 4. Relief action of decerebrate rigidity

Decreases the ameliorating effect of compound G on decerebrate rigidity

(α-rigidity) model was examined and compared with eperizon hydrochloride.

〔Method〕

According to the method of Fukuda et al. (Japn. J. Pharmacol. 24: 810 (1974)), the effect on ischemic decerebrate rigidity was examined. — Using a Wistar male rat that had been fasted at night, under isoflurane anesthesia, the animal was fixed in the dorsal position, the skull at the base of the brain was exposed from the ventral side, and a hole was made. Was ligated, and both common carotid arteries were ligated. The frequency of myoelectric discharge was measured from the triceps brachii muscles, which exhibited rigidity with the waking of anesthesia. The compound was administered when the myoelectric discharge frequency became stable, and the inhibition rate when the discharge frequency before administration was set to 100% indicates that the compound G and the control drug had a 50% inhibition of the free form (ID). _{5 U} , mg / kg) was calculated.

These compounds were dissolved in water for injection and administered via a catheter inserted into the duodenum in advance. Table 6 shows the results. Table 6

5. Urinary reflex suppression (under anesthesia)

Rats Injected saline into the bladder induced a micturition reflex and examined whether compound B had a prolonged action (increased bladder volume) until urination.

[Method ]

A male Sprague-Dawley rat weighing 250 to 400 g was anesthetized with 500 mg / kg of perethane, ip, a-chlorose 50 mg / kg, ip, and fixed in the dorsal position. Next, the bladder was exposed through a midline incision in the lower abdomen, and a small incision was added to the top of the bladder, and a silicone tube was inserted. The other end of the silicon tubing was connected to a low-pressure transducer and a continuous infusion device, and physiological saline was injected into the bladder at a rate of 5 to 20 ml / hr. Urine (saline) drainage Urinary contraction of the urinary bladder was artificially induced. The time from the start of the saline infusion until the contraction of urination occurred was measured as the latency of the urination reflex. Urinary contractions were detected by a low-pressure transducer as a sudden transient increase in bladder pressure, and the change in the internal pressure was recorded on a heat injury recorder.

The compound was administered by a catheter inserted into the right external jugular vein one minute before the start of saline infusion into the bladder. Inaperizon hydrochloride and flavoxate hydrochloride were used as control drugs. The dose of Compound B and the control drug was 2 mg / kg, calculated as the free form, and these were dissolved in distilled water for injection before use. The effect of the test compound was determined by averaging the latencies of the two micturition reflexes before administration as 100, and the latency of the micturition reflex after administration of the test compound was determined as this. Expressed as a ratio (%) to the control.

Statistical processing was performed by Scheff Fe's multiple comparison of the latency of the micturition reflex in the groups to which each compound was administered, including the group to which distilled water for injection, which was the solvent for the compound, was administered.

The results are shown in Table 7 and Figure 1. 7

*: P <0.05 compared with distilled water injection group

There is a significant difference.

6. Acute toxicity

The acute toxicity of Compound A, Compound B, Compound C, Compound D and Compound F was examined and compared with epelizone hydrochloride.

[Method ]

Four to six ddY male mice (5 weeks old) fasted overnight were used per group. The test compound was orally administered, and the general condition and mortality were observed up to 72 hours after administration. A 50% lethal dose (LD so, mg Z kg) was calculated from the cumulative number of deaths 72 hours after administration. did.

Claims

These compounds were dissolved or disturbed in a 0.1% Tween 80 solution or a 0.5% CMC—Na solution.

Table 8 shows the results.

Table 8

7. Safety factor

Above experimental results or we calculated Compound A, indicating Compound B Compound C, Compound D, the safety factor of the compound F and hydrochloric Epe re zone down the (LD s. Value ZED _5. Value) in Table 9. In addition, LD _5. The value was calculated as a free form. Table 9

From the results in Tables 1 to 9, the usability of the compound of the present invention was confirmed.

The scope of the claims

① General formula (I)

[In the formula, A represents a heteroaryl group which may have a substituent, and R ¹ and R ² may be the same or different, and each may be lower. Represents an alkyl group; R ³ represents a hydrogen atom or a lower alkyl group; R ⁴ and R ⁵ may be the same or different and each represents a lower alkyl group; or And R ⁶ are linked to each other to form an alicyclic 5-, ^6- or 7-membered ring, and Y is

(Wherein, R and R ′ each represent a lower alkyl group.) Or a straight-chain or cyclic ketone And n represents 0 or 1. ]

And a physiologically acceptable salt thereof.

(2) A: Heteroaryl group substituted with a phenyl group which may have a substituent, particularly a phenyl group which may have a lower alkyl group. Sothizazolyl, isoxazolyl, benzoisoxazolyl, chenyl, benzochenyl, furyl and benzofuranyl;

Y: C = 0 or is CH (OH), in particular CH (OH); R ¹ and R ^2: both the same lower alkyl group;

R ³ : a hydrogen atom or n is 0;

R ⁴ and R ⁵ : methyl or ethyl or N (R ⁴ ) R ⁵ represents N-pyrrolidinyl, N-piperidinyl, N-morpholinyl 2. The aminoketone derivative or a physiologically acceptable salt thereof according to claim 1, which is an N-piperazinyl group optionally having a lower alkyl group at the 4-position.

③ In formula (I), Y is a force Noreboniru Motoa Ru have the Ri CH (0 H) der, R ¹ and R ² are Ri same der, is and, n is 0 der Rukama other R ^{3. The} aminoketone derivative according to claim 1, wherein ³ is a hydrogen atom, or a physiologically acceptable aminoketone derivative thereof. Salt to be contained.

④ General formula (Π), (111), (IV) or (V)

(II)

(III)

(V)

(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. Represents a group. R ¹ 'and R ² ' are the same and denote a methyl group or an ethyl group. You. R ⁴ 'and R ⁵ may be the same or different, and each represents a force representing a methyl group or an ethyl group, respectively, or NR ⁴ ' R ⁵ '. Where N 〇-NN—CH ₃

Represents a group represented by The aminoketone derivative according to claim 1, which is represented by the following formula: and a physiologically acceptable salt thereof.

中 A central muscle relaxant comprising the aminoketone derivative according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.

(4) A therapeutic agent for pollakiuria comprising the aminoketone derivative according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.