WO1999043656A1 - Propylamine derivatives and use thereof - Google Patents

Abstract

Propylamine derivatives represented by formula (I) and salts thereof: wherein A is aryl substituted by halogeno, etc. or optionally substituted heteroaryl; R?1 and R2¿ are the same or different lower alkyls, or one of R?1 and R2¿ is hydrogen and the other is lower alkyl, lower alkoxy, aryl, etc.; one of R?3 and R4¿ is hydrogen or lower alkyl and the other is lower cycloalkyl, or R3 or R4 are the same or different lower alkyls or are bonded to each other to form a ring which contains one or more nitrogen or oxygen atoms and is optionally substituted by lower alkyl, etc.; and R5 is hydrogen, lower alkyl, or aryl.

Description

 Description Proviramine derivatives and uses thereof

 The present invention relates to a novel propylamine derivative and a physiologically acceptable salt thereof, and a central muscle relaxant and a therapeutic agent for dysuria containing these as an active ingredient. Conventional technology

 Heretofore, ^ -aminoketone derivatives such as tolperisone hydrochloride and eperisone hydrochloride have been known as drugs having a central muscle relaxing action. In addition, in addition to these, Japanese Patent Application Laid-Open Nos. Sho 60-255 7677, Sho 61-207 779, and Sho 63-398 8 16 In Japanese Patent Application Laid-open Nos. Sho 633-119444, Hei 3-157375 and Hei 7-10851, amino-ketones and their carbonyls are disclosed. Compounds in which the group has been converted to a hydroxy group are described as compounds having a central muscle relaxing action. In addition, U.S. Pat. No. 3,432,036 describes proviramine derivatives having a carbamoyloxy group.

 Tolperisone hydrochloride and eperisone hydrochloride are widely used in diseases with spastic paralysis as the main symptom, but these compounds are notable for their potency, side effects, persistence and bioavailability. It is not always satisfactory as a central muscle relaxant.

 Therefore, development of a more effective and safe central muscle relaxant is desired.

 On the other hand, as a probiamine derivative having a carbamoyloxy group,

(Continued on the next page with margins) NR ¹ — N e ₂

The compounds represented by are each known. However, these compounds are known as compounds having an anti-reserpine action or an antihypertensive action, and none of them are known to have a central muscle relaxing action. Disclosure of the invention

 According to the present invention, the general formula [I]

R ¹

A-CH— C-CH ₇ — NR ³ R ⁴ [I]

OCONHR ⁵

(Wherein, A is an aryl group substituted with a substituent selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, lower alkyl, lower alkoxy, halo-lower alkyl and aryl, or substituted A heteroaryl group which may be 1 ^ Oyobi 1 ² may be identical or different lower alkyl groups, also a yes deviation or the other is a hydrogen atom and the other is a lower alkyl group, a lower alkoxy group, a lower alkylthio group, Ariru group, Ararukiru Or a lower alkyl group substituted with a lower alkoxy or lower alkylthio group;

R ³ and R ⁴ are either a hydrogen atom or a lower alkyl group and the other is a lower cycloalkyl group, or the same or different and a lower alkyl group, or both of these lower alkyl groups; The groups may be linked to each other with or without a nitrogen or oxygen atom to form a ring, wherein said ring may be substituted with lower alkyl, lower alkanol or aralkyl;

R ⁵ is a hydrogen atom, a lower alkyl group or an aryl group)

And a physiologically acceptable salt thereof.

 The present invention also provides a central muscle relaxant and a therapeutic agent for dysuria, comprising as an active ingredient a proviramine derivative represented by the above general formula [I] or a physiologically acceptable salt thereof. BEST MODE FOR CARRYING OUT THE INVENTION

 The object compound of the present invention is a propylamine derivative having a carbamoyloxy group at the 1-position, that is, a novel compound represented by the above general formula [I] and a physiologically acceptable salt thereof. Further, the optical isomer of the compound [I] having an asymmetric center at the 1-position and the 2-position is also included in the target compound of the present invention. In this specification, the carbon atom adjacent to the substituent A of the propylamine derivative is conveniently named as 1-position. The object compound of the present invention has an excellent central muscle relaxing action and an urinary reflex suppressing action.

 In the following description, “lower” refers to those having 1 to 6 carbon atoms unless otherwise specified.

Examples of the “aryl group” of A in the general formula [I] include a phenyl group, a naphthyl group and an anthranyl group. These aryl groups include halogen atoms (fluorine, chlorine, bromine, iodine), hydroxy groups, nitro groups, cyano groups, and aryl groups. Mino group, lower alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.), lower alkoxy group (methoxy, ethoxy, propoxy, etc.), halo-lower It shall be substituted with a substituent selected from the group consisting of an alkyl group (trifluoromethyl, trifluoroethyl, etc.) and an aryl group (phenyl, naphthyl, etc.). The number of these substituents on the aryl group is preferably 1 to 3.

 Specific examples of the "substituted aryl group" include, for example, chlorophenyl, hydroxyphenyl, nitrophenyl, cyanophenyl, aminophenyl, methylphenyl, ethylphenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethyl Loethylphenyl, biphenylil, chloronaphthyl, hydroxynaphthyl, nitronaphthyl, cyanonaphthyl, aminonaphthyl, methylnaphthyl, methoxynaphthyl, trifluoromethylnaphthyl, dimethylphenyl, getylphenyl, di (trifluoromethyl) phenyl, Trimethylphenyl, triethylphenyl, tri (trifluoromethyl) phenyl and the like. Examples of the "heteroaryl group" of A in the general formula [I] include a 5-membered ring group having one hetero atom such as a carboxy group, a furyl group and a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, and an isothiazolyl group. Group, oxazolyl group, isooxazolyl group, etc., a 5-membered ring group having two identical or different hetero atoms, pyridyl group, etc., 6-membered ring group having one heteroatom, pyrimidinyl group, pyridazinyl group, virazinyl Examples include a 6-membered ring group having two identical or different heteroatoms such as a group, and a heteroatom-containing fused ring group such as a benzophenyl group and a benzofuryl group. These heteroaryl groups may be substituted, and in such a case, the same substituents as those described above on the aryl group are exemplified. The number of substituents on the heteroaryl group is preferably 1 to 3 in the case of a 5- or 6-membered ring having 1 or 2 heteroatoms. The above-mentioned hetero atom means a nitrogen atom, a sulfur atom and an oxygen atom as understood from the specific examples.

"Preferred examples of the optionally substituted heteroaryl group I include a compound represented by the formula

And the like.

The “lower alkyl group” of R ¹ and R ² in the general formula [I] means a linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl and the like. The lower alkyl groups of R ¹ and R ² may be the same or different.

1 ^ Oyobi 1 ² "lower alkoxy group" is a lower alkyl group and an alkoxy group having an oxygen atom attached thereto, such as the above. Specific examples include methoxy, ethoxy, propoxy, and isopropoxy.

1 ^ Oyobi 1 ² as the "lower alkylthio group" is preferably an alkyl Chio group having 1 to 6 carbon atoms, specifically, methylthio, Echiruchio, n- propylthio, Isopurobiruchio and the like.

1 ^ Oyobi 1 ² as a "Ariru group", phenyl group, a naphthyl group or § And anthranyl group. These aryl groups include halogen atoms (fluorine, chlorine, bromine, and iodine), hydroxy groups, nitro groups, cyano groups, amino groups, and lower alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl). , Sec-butyl, tert-butyl, etc.), lower alkoxy groups (methoxy, ethoxy, propoxy, etc.), halo-lower alkyl groups (trifluoromethyl, trifluoroethyl, etc.) and aryl groups (phenyl, naphthyl, etc.) Etc.) may be substituted with a substituent selected from the group consisting of When substituted, the number of these substituents on the aryl group is preferably 1 to 3.

 Specific examples of the "optionally substituted aryl group" include, for example, phenyl, chlorophenyl, hydroxyphenyl, nitrophenyl, cyanophenyl, aminophenyl, methylphenyl, ethylphenyl, methoxyphenyl, trifluorophenyl, trifluoromethylphenyl , Trifluoroethylphenyl, biphenylyl, naphthyl, chloronaphthyl, hydroxynaphthyl, nitronaphthyl, cyanonaphthyl, aminonaphthyl, methylnaphthyl, methoxynaphthyl, trifluoromethylnaphthyl, dimethylphenyl, getylphenyl, di (trifluryl) Phenyl, trimethylphenyl, triethylphenyl, tri (trifluoromethyl) phenyl and the like.

The term `` aralkyl group '' in 1 to ¹² means a group in which the above aryl group and a lower alkyl group are bonded, and specific examples include benzyl, phenethyl, phenylpropyl, and naphthylmethyl. Among them, benzyl is preferred.

The “lower alkoxy”, “lower alkylthio” and “lower alkyl” in the “lower alkyl group substituted with lower alkoxy or lower alkylthio” for R ¹ and R ² are the same as those described above, and the lower alkyl group The number of the above substituents is preferably one. Examples of the “lower alkyl group substituted by lower alkoxy or lower alkylthio” specifically include methoxymethyl, ethoxymethyl, methylthiomethyl, and ethylthiomethyl.

As the “lower alkyl group” for R ³ and R ⁴ in the general formula [I], those similar to the above can be mentioned. Examples of the “lower cycloalkyl group” include cyclopentyl, cyclohexyl and cycloheptyl. Combination of R ³ and R ⁴ A methyl group and a methyl group, an ethyl group and an ethyl group, a methyl group and an ethyl group, a hydrogen atom and a cyclopentyl group, a hydrogen atom and a cyclohexyl group, a hydrogen atom and a cycloheptyl group, a methyl group and a cyclopentyl group, Preferred are a methyl group and a cyclohexyl group, a methyl group and a cycloheptyl group, an ethyl group and a cyclopentyl group, an ethyl group and a cyclohexyl group, and an ethyl group and a cycloheptyl group.

The “ring formed by the lower alkyl group bonded to each other via a nitrogen atom or an oxygen atom or not” as R ³ and R ⁴ includes pyrrolidine, piberidine, hexamethyleneimine, morpholine, Pyrazine and the like, and among them, pyrrolidine and bipyridine are preferable. These rings may be substituted with a lower alkyl group, a lower alkanol group or an aralkyl group. Here, the “lower alkyl group” and “aralkyl group” include the same as those described above. The term "lower alkanoyl group" means an alkanoyl group having 1 to 5 carbon atoms. Specific examples include formyl, acetyl, propionyl, petyryl, valeryl and the like.

As the “lower alkyl group” for R ⁵ in the general formula [I], those similar to the above can be mentioned. Of these, methyl and ethyl are preferred as the lower alkyl group. As the “aryl group”, the same as the “aryl group” in R ¹ and R ² can be mentioned, and among them, phenyl and the like are preferable.

 Specific examples of preferred compounds belonging to compound [I] in the present invention are shown in the following table.

R ¹

 I

A-CH-C-CB NR ³ R ⁴ [I]

R ²

OCONHR ^f

In the present invention, a physiologically acceptable salt of the compound [I] is also included in the target compound. Examples of such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and formic acid, acetic acid, oxalic acid, cunic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, and methanesulfone. And salts with organic acids such as acid and lactic acid. The compound [I] of the present invention has at least one asymmetric carbon atom and thus has two or more optical isomers, and those isomers and mixtures thereof are also included in the target compound of the present invention. Is done. Further, when the compound has two asymmetric carbon atoms, each diastereomer is also included in the target compound of the present invention. Compound [I] can be synthesized, for example, by the following production method A to production method C. The reaction reagent and the synthetic intermediate may be a commercially available compound, a compound described in the literature (for example, JP-A-7-10851, International Patents WO 95/18092 and WO 96/10567) or described in the literature. Or a compound produced according to the method. The optically active compound may be prepared by asymmetric synthesis of the compound [V] in the production method C according to the production method (a), using the compound produced, or described in the literature (for example, see JP-A-7-1085). No. 1) or the production method described in the literature or a compound produced according to the method.

 <Production method A>

1 R ¹

 I, PhOCOQ base

_{A-CH-C-CH 2} -NR 3 R 4) ^ A - CH - C - CH 2 - NR 3 R 4

i _HR 2 2) R ⁵ NH ₂ [III] R ²

 OCONHI ^

(Wherein, ARR ² R ³ R ⁴ and R ⁵ are as defined above)

 This production method is carried out by reacting the corresponding propyl alcohol (JP-A-7-10851, WO 96/10567, etc.) with phenyl chlorocarbonate and then with amine.

 Specifically, reaction with propyl alcohol [II] is carried out in an organic solvent in the presence of a base using chlorophenyl carbonate slightly in excess of a chemical equivalent at room temperature for about 30 minutes to 2 hours. Examples of the organic solvent at this time include pyridine, methylene chloride, tetrahydrofuran, and toluene. As the base, pyridine, triethylamine and the like can be used.

Subsequently, the above reaction product and the amine [III] are mixed at room temperature for about 30 minutes in an organic solvent. Allow to react for minutes to 12 hours. Examples of the organic solvent at this time include alcohols such as methanol, ethanol, and 2-propanol. Examples of the amine [III] include ammonia, methylamine, ethylamine, benzylamine and the like.

 Manufacturing method B>

R ¹

R ⁵ NCO [IV]

A-CH-C-CH ₂ -NR ⁴ A-CH-C-CH ₂ -NR ³ R ⁴

OH

OCONHR ⁵

[Π] [I]

(Wherein, A, RR ² , R ³ , R ⁴ and R ⁵ are as defined above)

 This process is carried out by reacting the corresponding propyl alcohol with isocyanate [IV] in an organic solvent.

 This reaction is carried out at room temperature for about 30 minutes to 15 hours using a stoichiometric equivalent or a slight excess of isocyanate [IV] with respect to propyl alcohol [II] in an organic solvent. Examples of isocyanates include ethyl isocyanate and phenyl isocyanate. At this time, an acid catalyst such as trifluoroacetic acid may be added as needed. Examples of the organic solvent at this time include methylene chloride and benzene.

This method is particularly preferable when R ⁵ is an aryl group in the target compound [I] of the present invention.

Manufacturing method C>

R ¹ R ¹

A-CH— CH— -CH ₂ OX _R ¾ _NH A-CH— C-CH ₂ — NR ³ R ⁴

OCONHR ⁵ R ²

OCONHR ⁵

 [I]

(Where A, R ³ , R ⁴ and R ⁵ are as defined above, X is a substituted sulfonyl group, and R ² is a hydrogen atom) In this method, compound [I] is obtained by reacting compound [V] with amine [VI] in an organic solvent.

 This reaction is carried out by reacting the compound [V] with a chemical equivalent or excess of the amine [VI] at about 0 140 ° C for about 1 hour to 4 days. Examples of the organic solvent include alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and methyl chloride, and ethers such as ether and tetrahydrofuran.

 One

And aromatic hydrocarbons such as benzene, tol R Nene and the like, and amine [VI] may be used as the organic solvent.

 Compound [V] can be produced by the following two methods.

Method for producing compound [V] (a)

(R

 [VII] [IX]

Y

R ¹

 MOR / HOR

 A-CH— CH- A-CH— CH— C-OR

 OH OH O

[X]

^R 1) PhOCOCl, base R ¹

 I

A-CH— CH— C-OR 2, R ⁵ NH ₂ [III] A-CH— CH- C-OR

 (i)

OH O OCONHR ⁵ O

Or R ⁵ NCO [IV]

 pq

R ¹

 I I

A— CH— CH- ■ C-OR Μ7Ώ A-CH— CH—— CH ₂ OH

OCONHR ⁵ O OCONHR ⁵

 (iv) pa] net

R ¹ R ¹

 I I

A-CH— CH— • CH ₂ OH sulfonylated A-CH— CH—— CH ₂ OX

(v) OCONHR ⁵ ^ OCONHR ⁵

Net [V] Wherein A, RR ⁵ and X are as defined above, R ⁶ is phenyl, benzyl, t-butyl or isopropyl, R is hydrogen, lower alkyl, M is an alkali metal And Y is an oxygen atom or a sulfur atom.) This method is particularly advantageous when the stereoisomer at the 1- and 2-positions of the target compound [I] of the present invention is asymmetrically synthesized.

 , Process (i)

 In this step, the compound [VII] is reacted with a Lewis acid and an amine in an organic solvent, and the aldehyde [VIII] is subjected to an alditol condensation with the reaction product to obtain a compound [IX].

 In this reaction, compound [VII] is first reacted with a chemical equivalent or an excess of Lewis acid, followed by a chemical equivalent or an excess of amine at about 180 to 0 ° C for about 10 minutes to 2 hours. It is performed by Subsequently, the compound [IX] is obtained by reacting the aldehyde [VIII], which is slightly in excess of the chemical equivalent, at about 180 ° C. to room temperature for about 10 minutes to 12 hours.

 Examples of the Lewis acid include dibutyl boron triflate, titanium tetrachloride and the like. Examples of the amine include triethylamine, N, N-diisopropylethylamine, N, N, N ,, N'-tetramethylethylenediamine and the like. Examples of the organic solvent include methylene chloride, ether, toluene, and tetrahydrofuran, and among them, methylene chloride is preferable.

 In this step, the compound [IX] can be asymmetrically synthesized by appropriately selecting reaction conditions such as the type and amount of Lewis acid, the type and amount of amine, the type of organic solvent, and the reaction temperature. . The compound [IX] synthesized in a stereoselective manner is used to carry out the following steps (ii) to (V) and the above-mentioned production method C, whereby the compound [I] finally synthesized in a stereoselective manner is obtained. ] Can be obtained. · Process (ii)

 Compound [X] is obtained by reacting compound [IX] obtained in step (i) with a base in a solvent.

This reaction is carried out by reacting compound [IX] with a chemical equivalent of a base at about 120 to 40 ° C for about 10 minutes to 12 hours. As the solvent, water or Examples include alcohols such as methanol and ethanol. Examples of the base include lithium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate and the like, and alcoholate as a solvent is preferable. Among them, sodium methylate is more desirable.

 'Process (i i i)

 In this step, compound [XI] is obtained by treating compound [X] obtained in step (ii) in the same manner as in production method A or production method B.

 • Process (i V)

 Compound [XII] is obtained by reacting compound [XI] obtained in step (iii) with a reducing agent in an organic solvent.

 This reaction is carried out by reacting compound [XI] with a chemical equivalent or an excess amount of a reducing agent in an organic solvent at about 120 ° C. to reflux for about 1 to 24 hours. Examples of the reducing agent include lithium borohydride, sodium borohydride-lithium chloride, and the like. As the organic solvent, ethers such as dry ether and dry tetrahydrofuran are used.

 • Process (V)

 In this step, compound [V] is obtained by reacting compound [XII] obtained in the above step (iv) with P-toluenesulfonyl chloride or methanesulfonyl chloride in an organic solvent in the presence of a base.

 In this reaction, the compound [XII] is reacted with p-toluenesulfonyl chloride or methanesulfonyl chloride in a stoichiometric amount to 4 times the amount at about -20 to 40 ° C for about 30 minutes to 2 days. It is performed by Examples of the organic solvent include pyridine, methylene chloride, tetrahydrofuran and the like, and examples of the base include pyridine, triethylamine, N, Ν, Ν ′, Ν′-tetramethylethylenediamine, potassium carbonate and the like.

Production method of compound [V] (b):

(Hereafter, on the next page) R ¹

 BrMg [ΧΙΠ] I

A-CHO [νπη A-CH— C— CH ₂

(H ₂ 0 0)

 OH

 Net

 1) PhOCOCl, base J

2) R ⁵ NH ₂ [m

A-CH— C— CH ₂ 〗

A-CH— C— CH ₂

OH or R ⁵ NCO [IV]

 OCONHR ^

[XV] R ¹ R ¹

 1) Hydroboration I

A-CH— C = CH ₂ A-CH— CH—— CH ₂ OH (Si)

 2) oxidation and

OCONHR ⁵ Hydrolysis OCONHR ⁵

Net

A-CH— CH— CH ₂ OH A-CH— CH—— CH ₂ OX (iv) OCONHR ⁵ OCONHR ⁵

 Net [V]

(Wherein, A, RR ⁵ and X are as defined above)

 • Process (i)

 The compound [XIV] is obtained by reacting the aldehyde [VIII] with the corresponding Grignard reagent [XIII] in an organic solvent.

 This reaction is carried out by using a Grignard reagent [XIII], which is slightly in excess of the stoichiometric equivalent with respect to the aldehyde [VIII], and stirring at room temperature for about 5 minutes to 1 hour. Aldehyde [VIII] may be synthesized by a method known in the literature, or can be synthesized from the corresponding carboxylic acid, ester or alcohol obtained by a method known in the literature by a conventional method. Ethers such as dry ether and dry tetrahydrofuran can be used as the organic solvent.

 'Process (ii)

Compound [XV] is obtained by treating compound [XIV] obtained in step (i) in the same manner as in Production method A or Production method B described above. 'Process (iii)

 The compound [XV] obtained in the step (ii) is hydroborated, then oxidized and hydrolyzed in an organic solvent to obtain a compound [XII].

 Hydroboration is carried out by reacting compound [XV] with a stoichiometric or excess borane compound in an organic solvent at room temperature for about 10 to 20 hours. Oxidation and hydrolysis of the obtained reaction product are carried out by reacting sodium hydroxide and hydrogen peroxide solution. Examples of the borane compound include diborane, 9-borabicyclo [3.3.1] nonane, and the like. Ethers such as dry ether and dry tetrahydrofuran are used as the organic solvent. 'Process (iv)

 Compound [V] is obtained by treating compound [XII] obtained in step (ii) in the same manner as in step (V) of production method (a) of compound [V] in production method C. The compound [I] and a salt thereof of the present invention have a central muscular relaxation action, and are used as a therapeutic agent for diseases having spastic paralysis as a main symptom. Useful.

 The compound [I] of the present invention and a salt thereof have an activity of relieving destruction of the superior colliculus and inferior colliculus in rats. Rat superior and inferior dissection decerebrate rigidity (a rigidity) Remission is a method used to evaluate the main efficacy of muscle relaxants (Fukuda H., Yakugaku Zasshi, 1991, 111, 147 or Ono et al., Gen. Pharmacol., 1987, 18, 57), tolperisone hydrochloride (Fukuda et al., Chem. Pharm. Bull., 1974, 22, 2883) and eperisone hydrochloride (Tanaka et al "Nippon Yakurigaku Zasshi, 1981). It has been shown that existing central muscle relaxants such as, 77,511) also have a remission effect on the cerebellar decerebrate rigidity (a rigidity) between the superior and inferior colliculi.

Therefore, the compound [I] of the present invention and a salt thereof are useful as central muscle relaxants, and include, for example, painful spasms associated with musculoskeletal disorders; scapulohumeral syndrome, shoulder peri-arthritis, lumbago or Improvement of muscle tone due to spondyloarthropathy; cerebrovascular disorder, spinal cord palsy, cervical spondylosis, cerebral (child) palsy, post-operative sequelae (including brain and spinal cord tumors), sequelae of trauma (spinal cord injury, Head trauma), spinocerebellar degeneration, multiple sclerosis Syndrome, amyotrophic lateral sclerosis, spinal vascular disorders, SMON, ossification of the posterior longitudinal ligament, sequelae of stroke, other cerebral spinal cord diseases or other paralysis due to myelobees; rigidity in Parkinson's syndrome It can be used as a muscle relaxant for improving the condition.

 Further, the compound [I] of the present invention and a salt thereof have a urinary reflex-suppressing action in rats. Rhythmic bladder contraction in rats reflects human urinary reflex

(Subissi et al., Jpn. J. Pharmacol., 1986, 42, 153). Drugs with an anti-micturition reflex show an effect of improving pollakiuria and urinary incontinence (Yamada T, Yakkyoku, 1996, 47, 353). , Flavoxanit hydrochloride (Kimura et al., Int. J. Urol., 1996, 3, 218) and oxyptinin hydrochloride (Mayuzumi et al., Nippon Yakurigaku Zasshi, 1986, 87, 557). The therapeutic agent for urinary incontinence also has a urinary reflex suppressing effect on rhythmic bladder contraction.

 Therefore, the compound [I] of the present invention and a salt thereof are also useful as a therapeutic agent for pollakiuria and urinary incontinence, for example, neuropathic bladder, unstable bladder, bladder irritation

(Cystitis, bladder cancer, bladder stones, prostatitis, prostatic hypertrophy, urethritis, etc.), it can be used as a therapeutic agent for dysuria for urinary frequency and urinary incontinence. The central muscle relaxant and the therapeutic agent for dysuria of the present invention are used in the form of a preparation for oral administration or a preparation for parenteral administration containing Compound [I] or a physiologically acceptable salt thereof as an active ingredient. .

 Formulations for oral administration include, for example, tablets, pills, powders, granules, fine granules, capsules, solutions, suspensions, emulsions, etc.Formulations for parenteral administration include injections , Drops, suppositories, ointments, plasters, patches, aerosols and the like. These formulations can be manufactured by conventional methods commonly known in the art.

For example, tablets can be prepared using conventional excipients such as lactose, starch, microcrystalline cellulose, binders such as starch solution, carboxymethyl cellulose, disintegrants such as dried starch, calcium carbonate, sucrose, stearic acid, cocoa butter, Disintegration inhibitors such as hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, Using humectants such as Lyserine and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal keic acid, lubricants such as purified talc, stearates, boric acid powder, polyethylene glycol, etc. It is manufactured by a conventional method.

 For pills, use excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and silk, binders such as gum arabic, tragacanth, gelatin, and disintegrants such as laminaran and agar. And is manufactured by an ordinary method.

 Tablets, pills, granules, and the like can be made into a usual coated form as needed, such as a sugar-coated tablet, a gelatin encapsulating agent, an enteric encapsulating agent, a film coating agent, and the like. The tablet may be a multilayer tablet such as a double-layer tablet.

 Capsules are produced by mixing the active ingredient of the present invention with the above-mentioned various carriers and filling the mixture into hard capsules or soft capsules according to a conventional method. Liquid oral preparations can be prepared by adding carriers such as flavoring agents, buffers and stabilizing agents to the active ingredient of the present invention, if necessary, to give oral liquids, syrups, elixirs and the like in the usual manner. it can. As a flavoring agent, sucrose, orange peel, citric acid, tartaric acid and the like can be used. As a buffering agent, sodium citrate and the like can be used, and as a stabilizer, tragacanth, gum arabic, gelatin and the like can be used.

 Injections or drops are prepared by adding a carrier or diluent such as a pH adjuster, buffer, stabilizer, local anesthetic or isotonic agent to the active ingredient of the present invention, if necessary. Can be used as an injection or drip for intravenous, intramuscular, subcutaneous, intradermal or intraperitoneal use.

 Examples of pH adjusters and buffers include sodium citrate, sodium acetate, and sodium phosphate.Examples of stabilizers include sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, and thiolactic acid. Examples include procaine hydrochloride and lidocaine hydrochloride, examples of the tonicity agent include salt, glucose or glycerin, and examples of the diluent include water, ethyl alcohol, macrogol, and propylene glycol.

Suppositories can be prepared according to a conventional method after adding a base and, if necessary, a surfactant to the active ingredient of the present invention. Suppository bases include, for example, macrogol, lanolin, cocoa oil, fatty acid triglycerides, witepsol (dai An oily base such as (Namaite Novels) can be used.

 The ointment is formulated by mixing a base ordinarily used for the active ingredient of the present invention and, if necessary, a carrier such as a stabilizing agent, a wetting agent and a preservative, and mixing them by a conventional method. Ointment bases include liquid paraffin, white petrolatum, beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl parahydroxybenzoate, propyl paraoxybenzoate, and the like.

 A patch can be prepared by applying an ointment, paste, cream, gel, or the like containing the active ingredient of the present invention to a support in a conventional manner. Examples of the support include woven or non-woven fabrics made of cotton, swoof, and chemical fibers, films of soft vinyl chloride, polyethylene, polyurethane, and the like, and foam sheets. The pharmaceutical composition of the present invention may be administered orally, intravenously, subcutaneously or intradermally, intramuscularly, intraarticularly, rectally, transmucosally, etc., depending on the type and degree of the disease. Oral administration and intravenous administration are preferred, although they can be used by administration.

 Furthermore, the pharmaceutical composition of the present invention may contain, if desired, ordinary additives such as coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals, as long as the effects of the present invention are not impaired. You can also.

 The dosage of the active ingredient of the present invention may be appropriately increased or decreased according to the type of disease, the symptoms and severity of the patient, body weight, age, sex, drug tolerance, drug administration form, other conditions, and the like. However, it can be usually 1 to 100 mg / day, preferably 10 to 50 mg / day for an adult. Hereinafter, a method for producing the proviramine derivative of the present invention will be described with reference to Production Examples and Examples, and pharmacological effects will be described with Test Examples. Production Example 1

 (S) -4 4-benzyl 3-ptyryloxazolidine-1 2-thione

(S) —4-Benzyloxazolidine-12-thione (J. Org. Chem., 1995, 60, 6604-6607) 15.7 g (81.2 mmol) of methylene chloride (15 0 ml) The liquid was cooled with dry ice / acetone under a nitrogen atmosphere, and 7.2 ml of pyridine was added thereto, followed by stirring for 5 minutes. A solution of 10.6 g (97 mmol) of n-butyryl chloride in methylene chloride (10 ml) was added dropwise to the reaction mixture while cooling with dry ice / acetone. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 3.5 hours. After 100 ml of methylene chloride was added to the reaction solution, the obtained mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution in that order, and then dried over anhydrous magnesium sulfate. The obtained mixture was concentrated under reduced pressure to obtain a yellow oil. The oily substance was cooled to crystallize, and washed with ethanol to obtain 10.4 g of white crystals. The mother liquor was further concentrated under reduced pressure, and the residue was purified by recrystallization (solvent: 2-propanol / n-hexane) to obtain 4.43 g of white crystals. The crystals were combined to give 14.8 g (69.4%) of (S) -14-benzyl-13-butyryloxazolidine-12-thione.

Thigh _{(d ppm, CDC1 3):} 1.03 (3H, t, J = 7.3Hz), 1.69- 1.81 (2H, m), 2.72- 2.81 (lH, m), 3.16-3.44 (3H, m), 4.25- 4.35 (2H, m), 4.89-4.98 (lH, m), 7.21-7.37 (5H, m) Melting point 58〜58.5 ° C

[H] ² . _D = — 1 16. l. (C = l.0, black mouth form) Production Example 2

 (R) 1-3-butyryl-14-isopropylisopropylazolidin-1-2-one

(R) 14-Isopropyloxazolidin-12-one (J. Org. Chem., 1985, 50, 1830-1835) A solution of 30.0 g (232 mmol) in toluene (300 ml) was cooled on ice. 9.30 g (233 mmol) of sodium hydride (60% oily) were added, and the mixture was stirred for 30 minutes. To this solution, a solution of 25.9 g (243 mmol) of n-butyryl chloride in toluene (200 ml) was slowly added dropwise under ice-cooling, and the mixture was stirred at room temperature for 17 hours. To this reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of carbonated water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a colorless oil. The oil was purified by distillation under reduced pressure to give (R) -3-butyryl-4-iso- 44.9 g (colorless oil, 97.1%) of propyloxazolidine-1-one was obtained.

_{NMR (0- ppm, CDCl 3)} : 0.86-0.93 (6H, m), 0.99 (3H, t, J = 7.3Hz), 1.66-1.74 (2H, m), 2.35- 2.44 (lH, m), 2.78 -3.04 (2H, m), 4.18-4.30 (2H, m), 4.41-4.47 (lH, m) Boiling point 1 15 ° C (4mmHg)

[a] ²⁰ _D = -90. 7 ° (c = 2.1, ethanol) Production Example 3

 (S) — 3-butyryl-1-4-isopropyloxazolidin-1 2-one

 (S) —4-Isoproviroxazolidine-1-one (J. Org. Chem., 1985, 50, 1830-1835) 20. Same as Production Example 2 using O g (155 mmol) According to the method described above, 22.0 g (colorless oily substance, 71.3%) of (S) -3-butyryl-1-isopropyloxazolidine-12-one was obtained.

NMR (d ppm, CDCl ₃ ): 0.86-0.93 (6H, m), 0.99 (3H, t, 7.3 Hz), 1.66-1.74 (2H, m), 2.35-2.44 (lH, m), 2.78-3.04 ( 2H, m), 4.18-4.30 (2H, m), 4.41-4.47 (lH, m) Boiling point 105 ° C (4mmHg)

 [a] = + 90.4 ° (c = 2.0, first time) Example 1

 5— [1-Lubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] -3-Phenylisoxazolyl hydrochloride

(1) 5- [1-carbamoyloxy 2- (1 -pyrrolidinylmethyl) butyl] —3-phenylisoxazolyl

5- [1-Hydroxy-2- (1-pyrrolidinylmethyl) butyl] synthesized by a known method (JP-A-7-10851) in 50 ml of methylene chloride. Dissolve 8.30 g (27.6 mmol) of 3-phenylisoxazolyl and 2.62 g (33.2 mmol) of pyridin and add 4.54 g (29.0 mmol) of phenyl chlorocarbonate under ice-cooling. ) Was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain an oil (12.4 g).

 To this oil, 10 Oml of 2-propanol blown with ammonia gas under ice cooling was added. After the mixture was stirred at room temperature for 4 hours, the solvent was distilled off from the reaction solution, hydrochloric acid was added, and the mixture was washed with ether. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. After the ether layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: ethyl acetate) to give an oily 5- [1-butyrobyloxy-2- (1-pyrrolidinidine). 8.49 g of 1-phenylisoxazole.

 (2) 5- [1-Ferubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] -1-phenylisoxazolyl p-Toluenesulfonate

 Dissolve 8.49 g (24.7 mmol) of 5- [1- (1-pyrrolidinylmethyl) butyl] —3-phenylisoxazole obtained above in 30 ml of methanol and p — 4.70 g (24.7 mmol) of toluenesulfonic acid was added. After distilling off the solvent, the diastereomer was separated by recrystallization (solvent: methanol / ether), and the crystallized 5- [1-forcebamoyloxy 2- (1-pyrrolidinylmethyl) butyl] 13 —Diastereomer A of phenylisosoxazole p-toluenesulfonate (yield: 6.16 g) and non-crystalline 5- [1- (1-pyrrolimoyloxy-2- (1-pyrrolidinylmethyl) butyl)] There was obtained ditereomer B (yield: 5.68 g) of p-toluenesulfonyl p-toluenesulfonate.

 (3-1) 5— [1-Lubemoyloxy 1- 2- (1-pyrrolidinylmethyl) butyl] 1-Diphenylisoxazolyl diastereomer A

A diastereomer of 5 -— [1-hydroxy-l-bamoyloxy-1- (1-pyrrolidinylmethyl) butyl] -13-phenylisoxazolyl p-toluenesulfonate prepared in the above (2) A4.12 g (12.0 Mmol) in water The mixture was made alkaline with potassium acid and extracted with ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 5- [1-1-rubbamoyloxy 2- (1-pyrrolidinylmethyl) butyl] -3-diphenylisoxazole. A colorless crystal of stereomer A (4.12 g) was obtained.

_{NMR (6ppm, CDC1 3):} 0.93 (3H, t, J = 7.5Hz), 1.34-1.60 (2H, m), 1.62- 1.82 (4H, m), 2.10- 2.24 (lH, m), 2.34-2.60 (6H, m), 4.68-4.96 (2H, brs), 6.13 (lH, d, J = 4.4Hz), 6.49 (lH, s), 7.40-7.50 (3H, m), 7.76-7.84 (2H, m) (3-2) 5— [1—Rubamoyloxy 2— (1—Pyrrolidinylmethyl) butyl] Diastereomers of 1-3-phenylisoxazolyl B

 The diastereomer of the 5- [1- [1-pyrrolidoxyl-2- (1-pyrrolidinylmethyl) butyl] —3-phenylisoxazolyl p-toluenesulfonate B 5.68 g (12. Was dissolved in water, made alkaline with potassium carbonate, and extracted with ether. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel cam chromatography (solvent: ethyl acetate) to give 5- [1-forcerubamoyloxy-1- (1-pyrrolidinyl). Methyl) butyl] — 3-phenylisoxazole diastereo: oil of B-2 B 2.13 g was obtained.

_{NMR ((5ppm, CDC1 3)} : 0.98 (3H, t, J = 7.6Hz), 1.28-1.40 (lH, m), 1,50- 1.60 (lH, m), 1: 62- l: '84 ( 4H, m), 2.10-2.22 (lH, m), 2,30- 2.58 (6H, m), 4.60-4.92 (2H, brs), 6.16 (lH, d, J = 4.4Hz), 6.48 (lH , s), 7.38-7.50 (3H, m), 7.74- 7.84 (2H, m)

(4- 1) 5— [1-yl rubamoyloxy 2 -— (1-pyrrolidinylmethyl) butyl] —Diastereomer of 3-phenylisoxazolyl hydrochloride A prepared according to (3-1) above 5— [1—Rubamoyloxy-1- (1-pyrrolidinylmethyl) butyl]-3.25 g (12.4 mmol) of the diastereomer of 3-phenylisoxazolyl A was dissolved in the ether. Hydrogen chloride gas was blown into the hydrochloride. After distilling off the solvent, the residue is purified by recrystallization (solvent: ethanol / ether) to give 5- [1-l-rubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] -3-phenylisoxazolyl hydrochloride The diastereomer — Colorless crystals of A were obtained.

Yield: 4.00 g (total yield from Example 1 (1) 36.8%) Melting point: 152-155 ° C

Elemental analysis: C ₁₉ H ₂₅ N ₃ 0 ₃ · HC 1

 C H N

 Calculated value (%): 60.07 6.90 11.06

 Found (%): 59.81 6.77 10.99

 (4-2) 5- [1-Ferubamoyloxy 2- (1-pyrrolidinipyl) -13-phenylisoxazolyl hydrochloride diastereomer B The 5- [1] produced in the above (3-2) —2— (1-pyrrolidinylmethyl) butyl] —3-Diphenylisoxazole diastereomer B 2.13 g is dissolved in ether, hydrogen chloride gas is blown into the hydrochloride, and the solvent is dissolved. After distilling off, the diastereomer of 5— [1—Power-l-bamoyloxy-1- (1-pyrrolidinylmethyl) butyl) —3-phenylisoxazolyl hydrochloride (4-1 diastereomer) oil B B 2 18 g (20.8% of the total yield of Example 1 (1) or ¾) was obtained.

 (1 S, 2R) 1 5— [1-L-bummoyloxy 2- 2- (1-pyrrolidinylmethyl) butyl] —3-phenylisoxazolyl oxalate

(COOH)

(1) (I S, 2 R) 1-5— [1-Rubamoyloxy-1 2 -— (1-pyrrolidinylmethyl) butyl] 1-3-phenylisoxazolyl

(1S, 2R) -5- [1-Hydroxy-2- (1-pyrrolidinylmethyl) butyl] synthesized by a known method (JP-A-7-10851) 13.8 g (46.1 mmol) of phenylisosoxazole was rubamoylated in the same manner as in Example 1 (1) to give (1 S, 2 R) —5— [1 lbamoyloxy-2— (1-pyrrolidinylmethyl) butyl] 1-1.3-phenylisoxazolyl 11.1 g was obtained.

_{NMR (ippm, CDC1 3):} 0.93 (3H, t, J = 7.6Hz), 1.3-1.5 (2H, m), 1.6-1.8 (4H, m), 2.1- 2.3 (lH, m), 2.3- 2.6 (6H, m), 4.6-4.9 (2H, brs), 6.13 (lH, d, J = 4.3Hz), 6.49 (lH, s), 7.43-7.46 (3H, m), 7.78-7.82 (2H, m)

Optical purity 100% e e

Melting point 1 1 1 to 1 12 ° C

[H] " _D = -27. 8 ° (c = l. 0, methanol)

 (2) (I S, 2 R) 15- [1 rubamoyloxy 2- (1-pyrrolidinylmethyl) butyl] -3-phenylisoxazolyl oxalate

 10.7 g (31.2 mmol) of the carbamoyloxy derivative prepared in the above (1) was dissolved in methanol, and oxalic acid was obtained using oxalic acid. This was purified by recrystallization (solvent: 2-butanone) to give (1 S, 2R) -5- [1-Rubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] -13-phenyl Colorless crystals of ruisoxazolusyl oxalate were obtained.

Yield 11.9 g (Total yield from Example 2 (1) 63.4%)

Melting point 78-81 ° C

Elemental analysis: C ₁₉ H ₂₆ N ₃ 〇 ₃ · C ₂ H ₂ 0 ₄

 C H N

 Calculated value (%): 58.19 6.28 9.69

 Actual value (%): 57.87 6.43 9.41 Example 3

(1R, 2 R) 1—5— [1—Rubamoyloxy 2 -— (1—Pyrrolidinylmethyl) butyl Ί1—3-phenylisoxazole oxalate — Cl-b '-—Ό NI · ( (COOH) ₂

OCONH ₂ (1) (1 R, 2R) 1-5-[1-rubamoyloxy 1-2-(1 -pyrrolidinylmethyl) butyl] 1-3-phenylisoxazole

 (1R, 2R) —5 -— [1-hydroxy-12- (1-pyrrolidinylmethyl) butyl] synthesized by a known method (Japanese Patent Laid-Open No. 7-10851) —3-phenylisoxazole 5. 16 g (17.2 mmol) was rubamoylated in the same manner as in Example 1 (1) to give (1 R, 2 R) —5— [1-—rubuamoyloxy—2 -— (1-pyrrolidinyl) Methyl) butyl] — 3-phenylisoxazole 4.30 g.

_{NMR (5ppm, CDC1 3):} 0.98 (3H, t, J = 7.6Hz), 1.2-1.4 (lH, m), 1.4-1.8 (5H, m), 2.1- 2.3 (lH, m), 2.3- 2.6 (6H, m), 4.6-4.9 (2H, m), 6.16 (lH, d, J = 4.9Hz), 6.49 (lH, s), 7.4-7.5 (3H, m), 7.7-7.9 (2H, m )

Optical purity 100% e e

Melting point 13-1 15 ° C

[a] ²⁰ _D = + 5.0 ° (c = l. 0, methanol)

 (2) (1R, 2R) —5— [1-Rubamoyloxy-1- (1-pyrrolidinylmethyl) butyl] —3-phenylisoxazolyl oxalate

 4.24 g (12.3 mmol) of the carbamoyloxy derivative prepared in the above (1) was treated in the same manner as in Example 2 (2) to give an oxalate, and (1 R, 2R) — 5— [1— Colorless crystals of potassium rubamoyloxy 2- (1-pyrrolidinylmethyl) butyl] -3-phenylisoxazolyl oxalate were obtained.

Yield 4.74 g (Total yield 64.6% from Example 3 (1))

Melting point 128-129 ° C

Elemental _{analysis: C 19 H 26 N 3 0} 3 · C 2 H 2 〇 ₄

 C H N

 Calculated value (%): 58.19 6.28 9.69

Measured value (%): 58.01 6.32 9.55 Example 4

 (1 R, 2 S) — 5— [1—Rubamoyloxy 2— (1-Pyrrolidinylmethyl) butyl] 1-3-Fenylisoxazolyl oxalate

(1) (1 R, 2 S) — 5— [1—Rubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] — 3-Phenylisoxazole

 (1R, 2S) -5- [1-Hydroxy-12- (1-pyrrolidinylmethyl) butyl] 13-phenyl synthesized by a known method (Japanese Patent Application Laid-Open No. 7-10851). The phenylisosoxazole 31.1 (103 mmol) was converted to rubamoyl in the same manner as in Example 1 (1) to give (1R, 2S) -5- [1- rubamoyloxy 2- ( 1-Pyrrolidinylmethyl) butyl] —3-phenylisoxazolyl 27.2 g was obtained.

_{NMR ((5ppm, CDC1 3)} : 0.93 (3H, t, J = 7.6Hz), 1.3- 1.6 (2H, m), 1.6- 1.8 (4H, m), 2.1- 2.3 (lH, m), 2.3- 2.6 (6H, m), 4.6-4.9 (2H, m), 6.13 (lH, d, J = 4.6Hz), 6.49 (lH, s), 7.4-7.5 (3H, m), 7.7-7.9 (2H, m m)

Optical purity 100% e e

Melting point 109-1 1 1 ° C

[a] ²⁰ _D = + 27.7 ° (c = l.0, methanol)

 (2) (1 R, 2 S) — 5— [1—Rubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] 1-3-phenylisoxazolyl oxalate

 17.8 g (51.7 mmol) of the carbamoyloxy derivative prepared in the above (1) was treated in the same manner as in Example 2 (2) to give oxalate, and (1R, 2S) -5- Colorless crystals of [1-carbamoyloxy-2- (1-pyrrolidinylmethyl) butyl] -1,3-phenylisoxazolyl oxalate were obtained.

Yield 16.2 g (Total yield from Example 4 (1) 57.8%)

83-85 ° C Elemental _{analysis: C 19 H 26 N 3 0} 3 · C 2 H 2 〇 ₄

 C H N

 Calculated value (%): 58.19 6.28 9.69

 Actual value (%): 57.97 6.52 9.46 Example 5

(IS, 2 S) —5— [1-Rubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] — 3-phenylisoxazole oxalate

OCONH ₂

(1) (I S, 2 S)-5-[1-Rubamoyloxy 2- (1-pyrrolidinylmethyl) butyl] — 3-phenylisoxazole

 (1S-t 2S) -5- [1-hydroxy-12- (1-pyrrolidinylmethyl) butyl] 13-phenylisoxoxa synthesized by a known method (Japanese Patent Application Laid-Open No. 7-10851). Zol 7.51 (25.0 mmol) was converted to rubamoyl in the same manner as in Example 1 (1) to give (1S, 2S) -15- [1 rubamoyloxy-2- (1-pyrrolidinyl) Butyl) —3-phenylisoxazol 6.57 g was obtained.

_{NMR (<5ppm, CDC1 3)} : 0.98 (3H, t, J = 7.3Hz), 1.2-1.45 (lH, m), 1.45_1.9 (5H, m), 2.1- 2.3 (lH, m), 2.3 -2.6 (6H, m), 4.6-4.9 (2H, brs), 6.16 (lH, d, J = 4.3Hz), 6.49 (lH, s), 7.4-7.5 (3H, m), 7.7-7.9 ( 2H, m)

Optical purity 100% e e

Melting point 112 ~ 113C

[ _a ] ²⁰ _D = -4.7 ° (C = 1.0, methanol)

 (2) (1 S, 2 S) — 5— [1-Rubamoyloxy-1- 2- (1-pyrrolidinylmethyl) butyl] — 3-phenylisoxazole oxalate

6.47 g (18.8 mmol) of the carbamoyloxy derivative prepared in (1) above Was treated in the same manner as in Example 2 (2) to form an oxalate, and (1 S, 2 S) -5- [1—pothambyloxy-2- (1-virolidinylmethyl) butyl] 1-3 —Colorless crystals of phenylisoxazole oxalate were obtained.

Yield 6.10 g (59.3% yield from Example 5 (1))

Melting point 128-131 ° C

Elemental _{analysis: C 19 H 26 N 3 0} 3 · C 2 H 2 0 4

 C H N

 Calculated value (%): 58.19 6.28 9.69

 Actual value (%): 58.15 6.31 9.64 Example 6

 (1 R, 2 S) —5— [1-Rubamoyloxy 2 (1-pyrrolidinylmethyl) butyl] —3-phenylisoxazolyl

(1) (4 S) —3— [(2R) 1 2— [(1R) 1-1-hydroxy-1- (3—phenylisoxazolyl 5-yl)] methyl] butyryl-1 4-benzyloxoxazolidine 1 2 —Thion

(S) A solution of 7.90 g (30.0 mmol) of 1,4-benzyl-3-butyryloxazolidine-12-thione in methylene chloride (180 ml) under ice-cooling was treated with 6.58 ml of titanium tetrachloride (60 ml). 0.0 mmol) was added dropwise. After stirring for 5 minutes, 5.64 ml (32.4 mmol) of N, N-diisopropylethylamine was added dropwise. After stirring for 20 minutes under ice-cooling, the mixture was cooled to 140 ° C., and a solution of 5.71 (33.0 mmol) of 3-phenylisoxazolu-5-carbaldehyde (33.0 mmol) in methylene chloride (33 ml) was added dropwise. After the dropwise addition, the mixture was stirred at the same temperature for 1.5 hours, and then returned to 0 ° C. To the reaction solution, 180 ml of an aqueous solution obtained by diluting a saturated aqueous solution of ammonium chloride two-fold was added, and the organic layer was separated. After drying the organic layer over anhydrous magnesium sulfate, Concentration under reduced pressure gave 14.6 g of a brown oil. This was purified by silica gel column chromatography (solvent: ethyl acetate / n-hexane = 1/3 → 1/2) to obtain 10.6 g of yellow crystals. This was purified again by silica gel column chromatography (solvent: chromatoform / methanol = 100/1), and the desired product (4S) -3-[(2R) 1-2 — [(1R) —1-hydroxy 9.10 g of white crystals of 1- (3-phenylisoxazolyl 5-yl)] methyl] butyryl-1-4-benzyloxazolidin-2-thione were obtained. The fraction containing impurities was again subjected to silica gel column chromatography again to obtain 0.63 g of the target compound as a slightly yellow oil. The total yield was 9.73 g (74.3%).

Thigh (5 ppm, CDCl ₃ ): 0.93 (3H, t, J = 7.7Hz), 1.70-1.99 (2H, m),

2.79 (lH, dd, J = 9.9 and 13.2Hz), 3.2-3.4 (2H, m), 4.27-4.39 (2H, m), 4.93-5.02 (lH, m), 5.42-5.53 (2H, m), 6.68 (lH, d, J = 0.7Hz), 7.20-7.37 (5H, m), 7.42- 7.48 (3H, m), 7.78-7.83 (2H, m)

Melting point 107.5-109 ° C

[a] ²⁰ _D = +1 18.3 ° (c = l.0, ethanol)

 (2) (1R, 2R) -5- (1-Hydroxy-2-methoxycarbonyl) butyl-3-phenylisoxazole

(4S) -1-[(2R) -2-[(1R) -1-1-hydroxy-11- (3-phenylisoxazoyl-1-yl)] methyl] butyryl-4 To a solution of 4.37 g (10.0 mmol) of benzyloxysazolidine-1-thione in methanol (20 ml), under ice-cooling, 2.12 g (11.0 mmol) of a 28% sodium methylate methanol solution was added dropwise. After stirring for 15 minutes, 7 ml of a saturated aqueous ammonium chloride solution and 30 ml of ether were added. Water was further added thereto to dissolve insolubles, and then extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4.44 g of a yellow oil. This is purified by silica gel column chromatography (solvent: ethyl acetate / n-hexane = 1/2 1/1) to give (1R, 2R) — 5— (1-hydroxy-2-methoxycarbonyl) butyl — 3.29 g of 3-phenylisoxazole (colorless oil, 83.1%) (100% ee, 99.58% de).

_{NMR (c5 ppm, CDC1 3)} : 0.95 (3H, t, J = 7.3Hz), 1.5-2.0 (2H, m), 2.90-2.97 (lH, m), 3.76 (3H, s), 5.22 (lH, d, J = 4.4Hz), 6.62 (lH, d, J = 0.7Hz), 7.44-7.47 (3H, m), 7.79-7.82 (2H, i)

[a] ²⁰ _D = — 12.5 ° (c = l. 0, ethanol)

 (3) (1R, 2R) —5— (1-force rubamoyloxy-2-methoxycarbonyl) butyl-1-phenylisoxazole

 (1R, 2R) -5- (1-Hydroxy-1-methoxycarbonyl) butyl-3-phenylisoxazole 1.93g (7.01mmol) of methylene chloride (14ml) solution under ice cooling Then, 0.67 g (8.4 mmol) of pyridine and 1.21 g (7.73 mmol) of phenyl carbonate were added dropwise. After stirring at the same temperature for 1 hour, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3.03 g of a yellow oil. 50 ml of isopropanol was added to the oil, the mixture was cooled with ice, and ammonia gas was blown into the solution for 30 minutes. The solution was returned to room temperature, concentrated under reduced pressure, and the precipitated crystals were washed with hexane and collected by filtration to obtain 2.29 g of white crystals. This was purified by recrystallization (solvent: ethyl acetate / n-hexane) to give (1R, 2R) -15- (1-forcerubamoyloxy-2-methoxycarbonyl) butyl-3-phenylisoxazole 2.00 g (white crystals, 89.6%) were obtained.

NMR (d ppm, CDCl ₃ ): 0.96 (3H, t, J = 7.7 Hz), 1.77-1.84 (2H, m), 3.07-3.15 (lH, m), 3.67 (3H, s), 4.77 (2H, br s), 6.17 (lH, d, J = 8.1Hz), 6.59 (lH, s), 7.43-7.46 (3H, m), 7.77-7.81 (2H, m)

129-130 ° C

[H] ²⁰ _D = + 32.6 ° (c = 1.0, ethanol)

 (4) (1R, 2 S) —5— (1-force rubamoyloxy-1-hydroxymethyl) butyl—3-phenylisoxazole

(1 R, 2 R) — 5— (1 rubumyloxy-2-methoxycarbonyl) butyl 3-phenylisoxazol 1.36 g (4.27 mmol) of nothing To a solution of water in tetrahydrofuran (28 ml) was added 0.19 g (8.7 mmol) of lithium borohydride under ice-cooling. After stirring for 6 hours under ice cooling, the mixture was further stirred at room temperature. Water was added to the mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.20 g of a colorless oil. This was purified by silica gel column chromatography (solvent: ethyl acetate / η-^^ xane = 2/1 3/1) to give (1R, 2S) -5- (1-force rubamoyloxy-1-hydroxymethyl) butyl 0.79 g (white crystals, 64%) of 3-phenylisoxazole was obtained.

_{· NMR (0- ppm, CDC1 3} ): 0.94 (3H, t, J = 7.3Hz), 1.26-1.57 (2H, m), 2.16-2.22 (lH, m), 3.57 (lH, dd, J = 8.1 And 11.7Hz), 3.72 (lH, dd, J = 4.8 and 11.7Hz), 4.83 (2H, brs), 6.20 (lH, d, J = 4.4Hz), 6.55 (lH, d, J = 0.7Hz) , 7.44-7.47 (3H, m), 7.79-7.82 (2H, m)

 Melting point 107 ~; 109.5 ° C

[H] ²⁰ _D = +3 1.9 ° (c = 1.0, ethanol)

 (5) (1R, 2 S) — 5— (1—Rubamoyloxy-1-tosyloxymethyl) Butyl-3-phenylisoxazozol

(1R, 2 S) —5— (1-force rubamoyloxy-1-hydroxymethyl) butyl-3-3-phenylisoxazole 0.63 g (2.2 mmol) of a methylene chloride (20 ml) solution in ice-cooled solution Below, add 0.50 g (4.3 mmol) of N, N, Ν ', Ν, -tetramethylethylenediamine and 0.50 g (2.6 mmol) of p-toluenesulfonyl chloride, and add 2 at the same temperature. Stirred for hours. Further, 0.10 g (0.52 mmol) of p-toluenesulfonyl chloride was added thereto, followed by stirring at the same temperature for 30 minutes. Ice water and then 10 ml of 1N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with methylene chloride. After washing sequentially with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.92 g of white crystals. This was purified by recrystallization (solvent: ethyl acetate / n-hexane) to give (1R, 2S) -15- (1-1-rubumoyloxy-1-2-tosyloxymethyl) butyl-3-phenylisoxazole 0.77 g (white Color crystals, 80%).

NMR ((5 pm, CDCl ₃ ): 0.93 (3H, t, J = 7.4 Hz), 1.48-1.58 (2H, m), 2.34 (4H, m), 3.91 (lH, dd, J = 4.3 and 10.3 Hz ), 4.18 (lH, dd, J = 5.6 and 10.3Hz), 4.70 (2H, brs), 5.93 (lH, d, J = 6.2Hz,), 6.48 (lH, d, J = 0.8Hz), 7.25 -7.28 (2H, m), 7.44-7.47 (3H, m), 7.73-7.77 (4H, m)

137-138 ° C

[H] ² % = + 34.8 ° (c = 0.26, ethanol)

 (6) (1R, 2 S) — 5— [1-Rubamoyloxy-1- (1-pyrrolidinylmethyl) butyl] — 3-phenylisoxazole

 (1 R, 2 S) — 5- (1-potassium rubamoyloxy-2-tosyloxymethyl) butyl-1,3-phenylisoxazolyl 0.58 g (1.3 mmol) to 5.6 g of pyrrolidine (79 Mmol) and 0.22 g (1.6 mmol) of lithium carbonate were added, and the mixture was stirred at room temperature for 4 hours. Ice was added to the reaction solution, and extracted with ether. The organic layer was extracted with 1N hydrochloric acid, and the aqueous layer was washed with ether. The aqueous layer was made basic by adding a saturated aqueous solution of potassium carbonate, extracted with ether, and the extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure to obtain 0.41 g of white crystals. This is purified by recrystallization (solvent: ethyl acetate / n-hexane) to give (1R, 2S) —5— [1-Rubamoyloxy —2— (1-pyrrolidinylmethyl) butyl] — 3— 0.38 g (white crystals, 85%) of phenylisoxazole was obtained.

_{NMR ((5 ppm, CDC1 3} ): 0.96 (3H, t, J = 7.3Hz), 1.3 - 1.6 (2H, m), 1.6- 2.0 (4H, m), 2.1- 2.3 (lH, m), 2.3 -3.0 (6H, m), 4.6-5.2 (2H, brs), 6.12 (lH, d, J2 4.4Hz), 6.5-6.7 (lH, brs), 7.4-7.5 (3H, m), 7.7 -7.9 (2H, m)

Melting point 110 ~ 1 12 ° C

[H] ² % = + 28.0 ° (c = 1,0, methanol) Example 7

(IS, 2 R) -5- [1 rubamoyloxy 2- (1-pyrrolidinylmethyl) butyl] 1-3-phenylisoxazolyl

(1) (4 S) 1 3— [(2 S) 1 2— [(IS) — 1-hydroxy-11- (3—phenylisoxazolyl-1-5-yl)] methyl] butylyl-41-isopropyl Oxazolidine 1-one

 1M dibutylboron in a solution of 0.6 g (3.0 mmol) of methylene chloride (12 ml) in (S) -3-butyryl-1--4-isopropyloxazolidin-2-one in a nitrogen atmosphere at -5 ° C or less 3.3 ml (3.3 mmol) of a solution of triflate in methylene chloride was added. Further, 0.47 g (3.6 mmol) of N, N-diisopropylethylamine was slowly added dropwise thereto, and the mixture was stirred at 15 ° C or lower for 50 minutes. After cooling the reaction mixture to 1-78 ° C, a solution of 0.57 g of 3-phenylisoxazolyl 5-carbaldehyde in 6 ml of methylene chloride was maintained at a temperature of -60 ° C or lower. While stirring, the mixture was stirred for 1 hour. The reaction solution was returned to room temperature and stirred for 30 minutes. After cooling the reaction solution to 5 ° C or lower, 3 ml of a phosphate buffer (pH 7) and then 0.9 ml of a 30% hydrogen peroxide solution were added, and the reaction solution was stirred at the same temperature for 1 hour. . The reaction solution was poured into 6 ml of water, and this was extracted with methylene chloride. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain 2.27 g of a yellow oil. This oily product was purified by silica gel column chromatography (solvent: chloroform / ethyl acetate = 9/1) to give (4S) — 3— [(2 S) 1 2 — [(1 S) — 1-hydroxy 1 1 There was obtained 0.83 g (yellow oily substance, 74%) of 1- (3-phenylisoxazolyl-5-yl)] methyl] butyryl-4-isopropyloxazolidin-12-one.

_{NMR (c5 ppm, CDC1 3)} : 0.82-0.98 (9H, m), 1.84-1.94 (2H, m), 2.33- 2.40 (lH, m), 3.21 (lH, d, J = 4.1Hz), 4.16- 4.31 (2H, m), 4.42-4.51 (2H, m), 5.24 (lH, dd, J = 4.9 and 4.3Hz), 6.63 (lH, s), 7.42-7.48 (3H, m), 7.79-7.82 ( 2H, m)

[H] ² = + 78.9 ° (c = 1.0, ethanol)

(2) (IS, 2 S) — 5— (1-hydroxy-12-methoxycarbonyl) Chill 3-phenylisoxazole

 (4 S) -3- [(2 S) -2- [(1 S) — 1-hydroxy-1- 1- (3-phenylisoxazolyl 5-yl)] methyl] butyryl 4-isopropyl oxazolidine 3.1 g (8.3 mmol) of 1-2-one was treated in the same manner as in Example 6 (2) to give (1S, 2S) -5- (1-hydroxy-12-methoxycarbonyl). 1.5 g (yellow oil, 66%) of butyl 3-phenylisoxazole was obtained.

NMR (d ppm, CDCl ₃ ): 0.95 (3H, t, J = 7.6 Hz), 1.60-1.88 (2H, m), 2.91-2.98 (lH, m), 3.37 (lH, d, J = 4.3 Hz) , 3.76 (3H, s), 5.20-5.24 (lH, m), 6.62 (lH, s), 7.43- 7.48 (3H, m), 7.78-7.83 (2H, m)

[a] ² = + 12.0 ° (C = 1.0, ethanol)

 (3) (I S, 2 S) — 5— (1 rubumoyloxy-2-methoxycarbonyl) Butyl-3-phenylisoxazole

 1.4 g (5.1 mmol) of (1S, 2S) -5- (1-hydroxy-l-methoxycarbonyl) butyl-3-phenylisoxazolyl was treated in the same manner as in Example 6 (3). As a result, 1.4 g (white crystal, 88%) of (1 S, 2 S) -5- (1-force rubamoyloxy-l-methoxycarbonyl) butyl-l-phenylisoxazolyl was obtained.

NMR (d ppm, CDCl ₃ ): 0.97 (3H, t, J = 7.6 Hz), 1.74-1.84 (2H, m), 3.07-3.15 (lH, m), 3.67 (3H, s), 4.73 (2H, br s), 6.17 (lH, d, J = 7.6Hz), 6.59 (lH, s), 7.43- 7.47 (3H, m), 7.77-7.81 (2H, m)

130-132 ° C

[H] ²⁰ _D = —31.0 ° (c = 1.0, ethanol)

 (4) (I S, 2 R) -1-5- (1-Rubamoyloxy-1-hydroxymethyl) butyl-3-phenylisoxazole

1.2 g (3.8 mmol) of (1 S, 2 S) -5- (1 rubamoyloxy-2-methoxycarbonyl) butyl 3-phenylisoxazolyl was treated in the same manner as in Example 6 (4). And (1 S, 2 R) —5— (1 rubamoyloxy 1-2-hydroxymethyl) butyl-1-phenylisoxazole 0.69 g (White crystals, 63%) was obtained.

_{NMR (6 ppm, CDC1 3)} : 0.94 (3H, t, J = 7.6Hz), 1.32-1.55 (2H, m), 2.16-2.30 (2H, m), 3.50-3.80 (2H, m), 4.83 ( 2H, brs), 6.20 (lH, d, J = 5.1Hz), 6.55 (lH, s), 7.44- 7.47 (3H, m), 7.79-7.82 (2H, m)

Melting point 112 ~ 113C

[a] ²⁰ _D = -31.5 ° (c = 0.9, ethanol)

 (5) (I S, 2 R) — 5— (1 rubamoyloxy-2-tosyloxymethyl) butyl-3-phenylisoxazolyl

 0.60 g (2.1 mmol) of (1S, 2R) -5- (1-hydroxyrubumoxy-1-hydroxymethyl) butyl 3-phenylisoxazolyl was treated in the same manner as in Example 6 (5). Thus, 0.68 g (white crystals, 74%) of (IS, 2R) -15- (1-carbamoyloxy-2-tosyloxymethyl) butyl-3-phenylisoxazolyl was obtained.

_{NMR ((5 ppm, CDC1 3} ): 0.88- 0.95 (3H, m), 1.42- 1.60 (2H, m), 2.25-2.40 (4H, m), 3.88-3.93 (lH, m), 4.15- 4.21 ( lH, m), 4.71 (2H, brs), 5.93 (lH, d, J = 6. ". iz), 7.25-7.28 (2H, m), 7.44-7.48 (2H, m), 7.72-7.79 (4H , m)

136-137 ° C

[H] ² = —36.3 ° (c = 1.0, ethanol)

 (6) (I S, 2R) — 5— [1-Ferubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] -1-phenylisoxazole

 Example 6 (6) and 0.52 g (1.2 mmol) of (1 S, 2R) -15- (1-force rubamoyloxy-12-tosyloxymethyl) butyl-3-phenylisoxazol In the same manner, 0.35 g of (IS, 2R) —5 -— [1-hydroxyl-bamoyloxy 2 -— (1-pyrrolidinylmethyl) butyl) -13-phenylisoxazozol (light yellow crystals, 90%).

_{NMR ((5 ppm, CDC1 3} ): 0.93 (3H, t, J = 7.4Hz), 1.3- 1.5 (2H, m), 1.6- 1.8 (4H, m), 2.1-2.3 (lH, m), 2.3 -2.6 (6H, m), 4.6- 4.9 (2H, brs), 6.13 (lH, d, J = 4.3Hz), 6.49 (lH, s), 7.42-7.47 (3H, m), 7.77-7.82 ( 2H, m)

Melting point 11 1 ~ 1 12 ° C [H] ² = — 27.7 ° (c = 1.0, methanol) Example 8

 (1R, 2 R) —5— [1—Rubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] — 3-Phenylisoxazole

(1) (4R) -3-[(2S) -2-[(1R) -1-Hydroxy-1- (3—phenylisoxazolyl-5-yl)] methyl] butyryl-1-41-isoproviroxa Zolidine 1-one

 (R) -3-Ptyryl-1--4-isopropyloxazolidin-1-one A solution of 5.98 g (30.0 mmol) of methylene chloride (150 ml) in a stream of nitrogen at 0 ° C under a nitrogen atmosphere was treated with titanium tetrachloride 6 .7 ml (60 mmol) and 5.6 ml (33 mmol) of N, N-diisopropylethylamine were added dropwise. After the addition, the mixture was stirred at the same temperature for 30 minutes. After cooling to 78 ° C, 3-phenylisoxazole-5-carbaldehyde 5.71 (33.0 mmol) of methylene chloride was added to the reaction mixture.

(30 ml) The solution was added dropwise, followed by stirring at the same temperature for 1 hour. The temperature of the reaction solution was raised to 0 ° C, a saturated aqueous solution of ammonium chloride was added thereto, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (solvent: ethyl acetate / _n- hexane = 1/2) to separate diastereomers. This was further purified by silica gel column chromatography (solvent: ethyl acetate / chloroform = 1/2) to give (4R) -3-[[2S) -2-[(1R) 1-1-hydroxy One 1- (3-phenylisoxazolyl-5-yl)] methyl] butyryl-41-isoproviroxazolidine-2-one 2.31 (pale yellow crystal, 71.5%) was obtained.

NMR (5 ppm, CDCl ₃ ): 0.72 (3H, d, J = 7.0 Hz), 0.83 (3H, d, J-7.0 Hz), 1.05 (3H, t, J = 7.3Hz), 1.75-1.90 (2H, m), 2.17-2.26 (lH, m),

4.07 (lH, d, J = 10.3Hz), 4.ll-4.30 (2H, m), 4.40-4.49 (2H, m), 5.04 (lH, dd, J = 5.5 and 10.3Hz), 6.60 (lH, s), 7.42-7.47 (3H, m), 7.75-7.81 (2H, m)

Melting point 98 ~; L 00 ° C

[a] ²⁰ _D = + 5.9 ° (c = 1.0, ethanol)

 (2) (1R, 2S) -5- (1-Hydroxy-12-methoxycarbonyl) butyl-3-phenylisoxazole

 (4R) —3— [(2 S) 1 2— [(1 R) — 1-hydroxy-11- (3-phenylisoxazolyl-5-yl)] methyl] butyryl— 4— 7.82 g (21.0 mmol) of isopropyloxazolidin-2-one were treated in the same manner as in Example 6 (2) to give (1R, 2S) -5- (1-hydroxy-12-methoxycarbonyl) butyl 3.57 g (white crystals, 61.2%) of 1-3-phenylisoxazole was obtained.

Thigh _{(5 ppm, CDC1 3):} 1.01 (3H, t, J two 7.8Hz), l, 73_l, 84 (2H, m), 2.92-2.99 (lH, m), 3.71 (3H, s), 3.73 ( lH, d, J = 8.8Hz), 5.01 (lH, dd, J = 5.5 and 8.8Hz),

6.58 (lH, d, J = 0.7Hz), 7.42-7.48 (3H, m), 7.78-7.82 (2H, m)

Melting point 89-90 ° C

[H] ²⁰ _D = +30.3. (C = 1.0, ethanol)

 (3) (1R, 2 S) —5 -— (1-potassium 2-methoxycarbonyl) butyl-3-phenylisoxazolyl

 3.36 g (12.2 mmol) of (1R, 2S) -15- (1-hydroxy-12-methoxycarbonyl) butyl-3-phenylisoxazol were treated in the same manner as in Example 6 (3). As a result, (1R, 2S) -5- (1-hydroxyrubbamoyloxy-2-methoxycarbonyl) butyl-3-phenylisoxazolyl 3.26 (white crystal, 83.9%) was obtained.

Thigh (<5 pm, CDCl ₃ ): 0.92 (3H, t, J = 7.5Hz), l, 41-l, 64 (2H, m),

3.15 (lH, ddd, J = 4.4,5.1 and 9.9Hz), 3.76 (3H, s), 4.67 (2H, br s),

6.06 (lH, d, J = 9,9Hz), 6.66 (lH, s), 7.43-7.48 (3H, m), 7.77-7.82 (2H, m) Melting point 145 ~ 147 ° C [H] ²⁰ _D = + 27.5 ° (c = 1.0, ethanol)

 (4) (1 R, 2 R) —5— (1-force rubamoyloxy-2-hydroxymethyl) butyl-3-phenylisoxazolyl

 (1R, 2S) -5- (1-potassium 2-methoxycarbonyl) butyl-3-phenylisoxazol 3.00 g (9.42 mmol) as in Example 6 (4) To give (1R, 2R) -5- (1-potassium 2-hydroxymethyl) butyl-1-phenylisoxazolyl 1.01 g (white crystals, 37.0%). Was.

Thigh _{((5 ppm, CDC1 3)} : 0.96 (3H, t, J = 7.5Hz), 1,20- l, 61 (2H, m), 2.04-2.17 (2H, m), 3.76 (2H, br s ), 4.88 (2H, brs), 5.97 (lH, d, J = 8.4Hz), 6.58 (lH, s), 7.43-7.50 (3H, m), 7.77-7.84 (2H, m)

133-134 ° C

[H] ²⁰ _D = + 29.8 ° (c = 1.0, ethanol)

 (5) (1R, 2R) 1-5-(1-rubamoyloxy 1-2-tosyloxymethyl) butyl-3-phenylisoxazolyl

 0.75 g (2.6 mmol) of (1R, 2R) -5- (1-forcerbamoyloxy-2-hydroxymethyl) butyl-3-phenylisoxazole was treated in the same manner as in Example 6 (5). Then, 1.03 g (white crystal, 89.8%) of (1R, 2R) -15- (1-l-rubamoyloxy-2-tosiloxymethyl) butyl-3-phenylisoxazolyl was obtained. .

_{NMR ((5 ppm, CDC1 3} ): 0.90 (3H, t 3 J = 7.3Hz), 1.36- 1.57 (2H, m), 2.30- 2.40 (lH, m), 2.40 (3H, s), 4.10- 4.22 (2H, m), 4.70 (2H, br s), 5.88 (lH, d, J = 7.3Hz),

6.53. (LH, s), 7.31 (2H, d, J = 8.4Hz), 7.43-7.47 (3H, m), 7.74-7.79 (4H, m) Melting point 129 ~ 130 ° C

[H] ²⁰ _D = + 7.1 ° (c = 0.25, ethanol)

 (6) (1R, 2R) — 5 -— [1-Rubamoyloxy-2-((1-pyrrolidinylmethyl) butyl)] 1-3-phenylisoxazolyl

0.51 g (1.2 mmol) of (1R, 2R) —5— (1-force rubamoyloxy-2-tosyloxymethyl) butyl 3-phenylisoxazole 3. S 'ZOT ~ S' OOT nZ) 0 'L-9L'L'(n'HS) WL-WL ⁽ (s'm) 09'9 '(ΖΗ6

·0 ： (^εΐ3(Ι。 ' ρ)画 Ζ '(m) 0S-ΟΓΖ' ΙΕ) 06Ι- 0 ΐ '(ΐ ^' HS O'I

· 0: ( ^ε Ι3 (Ι. 'Ρ)

. ^ ¾ (% ■ £ L ^B ^ ^) S 6-9 ^-Z · ^-^ Α ^^-τ _ _ε )-I-^ α.1 Ά- Ϊ-(ST)]-Z-(HZ )]

— Ε— (st) ^^ ^ m ^ (τ) s mm ^ n ^ o o T) s o

• oz ^-z-a, -f-((^--(s) oz

 c) ΐ— く, ^ ad tt— (si)]-z-(Ή. ΖΏ— ε— (s (T)

ί- η a„ - τ ) - ζ - ^^ ( ^^ic - 1 ] - g - (s ζ ^£s τ ) ² HNOOO

ί- η a „-τ)-ζ-^^ (^^ ic-1]-g-(s ζ ^£ s τ)

 6 mm οι

{Λ (-~ ί, ο · τ = ο). 2's + two ^α _οζ [»]

 ο. t τ τ〜 ε τ τ

(^ Z) Q'L-L'L '(M ⁽ HS) 9'-'(s'HI) 6 9' (ΖΗ8 '^ Γ'Ρ'Ηΐ) 9Γ9 ⁽ (s Jq'HZ) 6- -S '(^ Ε9) 9'Ζ-ζ'Ζ'(n'HI)S'Z- Γ2 S ^< (ω'Η9) 6ΐ-5 ^ ΐ ΐ '(n'HOS'ΐ-Ζ'ΐ' (ZH "= f ^ ^£ H £) 86" 0: ( ^ε ΐ.α. (ρ)

 . Meeting (% ο 6 w ^ m) s 9 ε 'ο

—, 4 ^ Λ two cho ε— (Λ (-^^ Λ (-Γι a „-I) one S—

 ] -g- (z τ τ), 教 ¾¾ ^ ^ (9) 9

6SZ.00 / 66df / IDd 9S9C 66 O [H] ²⁰ _D = —7. O ° (c = 1.0, ethanol)

 (2) (I S, 2 R) 15- (1-hydroxy-12-methoxycarbonyl) butyl-1-phenylisoxazolyl

 (4 S)-3-[(2R) 1-2-[(1 S)-1-hydroxy-1-(3-fluoroisoxazol-5-yl)] methyl] butyryl-1-isopropyl 67.2 g (180 mmol) of oxazolidin-1-one was treated in the same manner as in Example 6 (2) to give (IS, 2R) -5- (1-hydroxy-12-methoxycarbonyl) butyl. 38.8 g (yellow oil, 78.1%) of 3-phenylisoxazol were obtained.

_{NMR (6 ppm, CDC1 3)} : 1.02 (3H, t, J = 7.3Hz), 1.73-1.84 (2H, m), 2.92- 2.99 (lH, m), 3.71 (3H, s), 5.00 (lH, br s), 6.58 (lH, s), 7.43-7.48 (3H, m), 7.77-7.82 (2H, m) Melting point 89.5 ~ 90.5 ° C

[H] ²⁰ _D = — 30.6 ° (c = 1.0, ethanol)

 (3) (I S, 2 R) — 5— (1-force rubamoyloxy 2-methoxycarbonyl) butyl-1-phenylisoxazolyl

 (1S, 2R) -5- (1-Hydroxy-2-methoxycarbonyl) butyl-3-3-phenylisoxazol 69.0 g (251 mmol) was treated in the same manner as in Example 6 (3). There were obtained 69.3 g (white crystals, 87.0%) of (1S, 2R) -15- (1-force rubamoyloxy-2-methoxycarbonyl) butyl-1-phenylisoxazolyl.

_{NMR ((5 ppm, CDC1 3} ): 0.92 (3H, t, J two 7.6Hz), 1.40-1.70 (2H, m ),

3.14 (lH, dt, J = 9.8 and 4.7Hz), 3.76 (3H, s), 4.70 (2H, brs),

6.06 (lH, d, J = 9.7Hz), 6.66 (lH, s), 7.43-7.48 (3H, m), 7.78-7.82 (2H, m) Melting point 146 ~ 149 ° C

[H] ²⁰ _D = -27.7 ° (c = 1.0, ethanol)

 (4) (I S, 2 S) 1-5-(1-forcerubamoyloxy 1-2-hydroxymethyl) butyl-3-phenylisoxazolyl

(IS, 2R) 5.00 g (25.1 mmol) of 15- (1-potassium rubamoyloxy-2-methoxycarbonyl) butyl-3-phenylisoxazolyl was obtained. Example 6 Processed in the same manner as (4), to give (1 S, 2 S) -5- (1-carbamoyloxy-2-hydroxymethyl) butyl 3-phenylisoxazol 4.30 g (white Crystals, 58.9%).

_{NMR ((5 ppm, CDCl 3} ): 0.96 (3H, t, J = 7.3Hz), 1.22- 1.32 (lH, m), 1.43- 1.54 (lH, m), 2.07-2.15 (2H, m), 3.70 -3.82 (2H, m), 4.93 (2H, brs), 5.97 (lH, d, J = 8.1Hz), 6.58 (lH, s), 7.43-7.48 (3H, m), 7.79-7.83 (2H, m)

133-135 ° C

[H] ²⁰ _D = — 31.3 ° (c = 1.1, ethanol)

 (5) (I S, 2 S) — 5— (1—Rubamoyloxy 2-tosyloxymethyl) Butyl-3-phenylisoxazolyl

 10.8 g (37.2 mmol) of (1 S, 2 S) -15- (1-force rubamoyloxy-2-hydroxymethyl) butyl-13-phenylisoxazole was added to 80 ml of pyridine and cooled with ice water. . To this was added 8.80 g (46.2 mmol) of p-toluenesulfonyl chloride, and the mixture was stirred at room temperature for 5 hours. Under ice cooling, 180 ml of concentrated hydrochloric acid and then water were added to the mixture, and the mixture was extracted with methylene chloride. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 17.7 g of white crystals. This was purified by recrystallization to obtain 12.6 g of (1 S, 2 S) -5- (1 -caproluvyloxy-2-tosiloxymethyl) butyl-3-phenylisoxoxazole (white crystals, 76 2%).

NMR ((5 ppm, CDCl ₃ ): 0.90 (3H, t, J 二 7.4Ηζ), 1.3-1.5 (2H, m), 2.2-2.4 (lH, m), 2.40 (3H, s), 4.10- 4.23 (2H, m), 4.71 (2H, br s), 5.88 (lH, d, J = 7.0Hz),

6.53 (lH, s), 7.31 (2H, d, J = 8.1Hz), 7.44-7.47 (3H, m), 7.75-7.79 (4H, m) Melting point 129.5-130.5 ° C

[a] ²⁰ _D = —6.9 ° (c = 1.0, ethanol)

 (6) (I S, 2 S) -5- [1-Felbamoyloxy-1- (1-pyrrolidinylmethyl) butyl] — 3-phenylisoxazolyl

(1 S, 2 S) —5— (1—force rubamoyloxy-1-tosyloxymethyl) butyl-3—phenylisoxazolyl 12.4 g (27.9 mmol) Example 6 (1), treated in the same manner as in (6) to give (1 S, 2 S) —5 -— [1-carbamoyloxy-2- (1-pyrrolidinylmethyl) butyl] —3-phenylisoxazole 8.50 g (light yellow crystals, 88.7%) were obtained.

_{NMR (5 ppm, CDC1 3)} : 0.98 (3H, t, J two 7.3Hz), 1.25-1.45 (lH, m ), 1.45- 1.8 (5H, m), 2.1-2.3 (lH, m), 2.3- 2.6 (6H, m), 4.6-4.9 (2H, brs), 6.16 (lH, d, J = 4.6Hz), 6.49 (lH, s), 7.42-7.47 (3H, m), 7.7-7.9 (2H , M)

Melting point 11;! ~ 1 12.5 ° C

[] ²⁰ _D twenty-one 4. 4 ° (c = 1. 0 , methanol) Example 10

 5-(1-carbamoyloxy 3-dimethylamino-2, 2-dimethylpropido) 1-phenylisoxazole maleate

^Ph , _ CH ₃

¹ , then CH— C-CH ₂ — NMe ₂ · (CHCOOH) ₂

CH ₃

OCONH ₂

(1) 5- (1-Felbamoyloxy-3-dimethylamino-1,2,2-dimethylpropyl) -1-phenylisoxazolyl

 5.0 g of 5- (3-dimethylamino-1-hydroxy-2,2-dimethylpropyl) -13-phenylisoxazole synthesized in 25 ml of methylene chloride according to a known method (WO 96/10567). (18.2 mmol) and 1.73 g (21.9 mmol) of pyridine were dissolved, and under ice-cooling, 2.85 g (18.2 mmol) of phenyl carbonate was added dropwise. After the dropwise addition, the mixture was stirred for 2 hours, an aqueous saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain 7.36 g of colorless crystals.

1.18 g (3.0 mmol) of this was dissolved in 1 ml of tetrahydrofuran, and 10 ml of 2-propanol into which ammonia gas had been blown under ice cooling was added. The reaction was allowed to proceed at room temperature for 4 hours, the solvent was distilled off from the reaction solution, hydrochloric acid was added to the residue, and the mixture was washed with ether. The aqueous layer is made alkaline with potassium carbonate and extracted with ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by recrystallization (solvent: ether) to give colorless crystals of 5- (1-carbamoyloxy-3-dimethylamino-1,2,2-dimethylpropyl) -1,3-phenylisoxazolyl 0.92 g was obtained.

_{NMR (dppm, CDC1 3):} 0.96 (3H, s), 1.04 (3H, s), 2.16 (lH, d, J two 14 · 0Ηζ),

2.31 (6H, s), 2.38 (lH, d, J = 14.0Hz), 4.76 (2H, brs), 5.91 (lH, s), 6.52 (lH, s), 7.4-7.5 (3H, m), 7.7-7.9 (2H, m)

 (2) 5- (1-carbamoyloxy-3-dimethylamino-2,2-dimethylpropyl) -3-phenylisoxazole maleate

 42.0 g (132 mmol) of the carbamoyloxy derivative prepared in the above (1) was suspended in 800 ml of ethanol, and a maleate was formed using maleic acid. This was purified by recrystallization (solvent: ethanol / ether) to give 5- (1-force rubamoyloxy-13-dimethylamino-1,2,2-dimethylpropyl) -13-phenylisoxazole maleate as colorless crystals. I got

Yield 46.0 g (total yield from Example 10 (1) 77.9%) Melting point 107-109 ° C

Elemental _{analysis: C 17 H 23 N 3 0} 3 · C 4 H 4 0 4

 C H N

 Calculated value (%): 58.19 6.29 9.69

 Obtained value (%): 57.96 6.29 9.62 Example 11

 5— [3—Dimethylamino 1— (N—e

 2-Dimethylpropyl] 1-3-phenylisoxazol-maleate

NMe ゥ (CHCOOH);

 OCONHEt

(1) 5 [3-Dimethylamino 1- (N- 2,2-Dimethylpropyl] 1-3-phenylisoxazole

 Example 10 The same treatment as in Example 10 (1) was carried out except that ethylamine was used instead of ammonia in (1), to give 5- (3-dimethylamino-1-hydroxy-2,2-dimethylpropyl) 13. —Phenylisoxazolyl 4.12 g (10.0 mmol) from 5— [3-Dimethylamino-11- (N-ethylcarbamoyloxy) -1,2,2-dimethylmethylpropyl] —3-Phenylisozo 3.24 g of colorless crystals of oxazole were obtained.

_{NMR ((5ppm, CDC1 3)} : 0.95 (3H, s), 1.03 (3H, s), 1.13 (3H, t, J = 7.0Hz), 2.15 (2H, d, J two 13.8Hz), 2.30 (6H , s), 2.37 (2H, d, J = 13.8 Hz), 3.15- 3.28 (2H, m), 4.79 (lH, br), 5.89 (lH, s), 6.50 (lH, s), 7.41-7.47 ( 3H, m), 7.78-7.82 (2H, m) (2) 5- [3-Dimethylamino-11- (N-ethylcarbamoyloxy) -1,2,2-dimethylpropyl] -1-3-phenylisoxazolylmalein 3.24 g (9.4 mmol) of the catalyzed rubamoyloxy compound obtained in the above (1) was dissolved in 20 ml of ethanol to obtain maleate with maleic acid, which was recrystallized (solvent: ethanol / Ether) to give colorless crystals of 5- [1-dimethylamino-1 (N-ethylcarbamoyloxy) -1,2,2-dimethylpropyl] -13-phenylisoxazol-maleate. Obtained.

Yield 3.72 g (Total yield from Example 11 (1) 53.7%) Melting point 147-148 ° C

Elemental _{analysis: C 19 H 27 N 3 0} 3 · C 4 H 4 0 4

 C H N

 Calculated value (%): 59.86 6.77 9.10

 Obtained value (%): 59.87 6.82 9.03 Example 12

5- [3-Dimethylamino-1,2-dimethyl-11- (N-phenylcarbamoyloxy) propyl] 1-3-phenylisoxazolyl hydrochloride

 OCONHPh

 (1) 5-[3-Dimethylamino-2,2-dimethyl-1- (N-phenyl carbamoyloxy) propyl] — 3-phenylisoxazolyl

 5- (3-Dimethylamino-1-hydroxy-1,2,2-dimethylpropyl) -13-phenylisoxazole 2.74 g (10.0 mmol) of 20 ml of methylene chloride in phenyl isocyanate at room temperature. 25 g (10,5 mmol) were added dropwise. The solvent was distilled off 30 minutes after the dropwise addition, and colorless crystals of 5- [3-dimethylamino-1,2,2-dimethyl-1- (N-phenylcarbamoyloxy) propyl] -13-phenylisoxazolyl 3.92 g was obtained.

NMR (5 ppm, CDCl ₃ ): 0.99 (3H, s), 1.09 (3H, s), 2.19 (lH, d, J = 14.0 Hz), 2.32 (6H, s), 2.41 (lH, d, J = 14.0 Hz), 6.03 (lH, s), 6.55 (lH, s), 6.72 (lH, br), 7.07 (lH, t, J = 7.6Hz), 7.27-7.45 (8H, m), 7.78-7.82 (2H , m)

 (2) 5- [3-Dimethylamino-1,2,2-dimethyl-1- (N-phenyl carbamoyloxy) propyl] — 3-phenylisoxazolyl hydrochloride The carbamoyloxy derivative obtained in (1) above 3.92 g (10.0 mmol) was treated in the same manner as in Example 1 (4-1) to give 5- [3-dimethylamino-2,2-dimethyl-1- (N-phenylcarbamoyloxy) propyl]. Colorless crystals of 1-3-phenylisoxazole hydrochloride were obtained.

Yield 3.88 g (Total yield 90.2% from Example 12 (1))

200-204 ° C

Elemental _{analysis: C 23 H 27 N 3 0} 3 - HC 1

 C H N

 Calculated value (%): 64.25 6.56 9.77

Found (%): 64.13 6.62 9.59 Example 13 1-carpamoyloxy 2-methyl-3 (3 1 (4 1-trifluoromethylphenyl) ^ acid salt

(1) 1-Hydroxy-1 2-methyl-1 3- (3-Methylbiperidino) 1-11 (4—Trifluoromethylphenyl) propane

 18.1 g (57.9 mmol) of 2-methyl-3- (3-methylbiperidino) -14,1-trifluoromethylpropiophenone synthesized according to a known method (Japanese Patent Publication No. Sho 60-7627) was obtained. According to a conventional method, reduction is carried out using sodium borohydride, and a mixture of diastereomers, 1-hydroxy-12-methyl-3- (3-methylbiperidino) -11- (4-trifluoromethylphenyl) propane 18 .2 g were obtained as an oil. This was subjected to silica gel column chromatography (solvent: n-hexane / ethyl acetate = 5/1) to separate diastereomers and eluted first 1-hydroxy-12-methyl-3- (3-methylbiperidino) One 1— (4-Trifluoromethylphenyl) propane was added to diastereomer A (yield: 3.10 g), then eluted 1-hydroxy-2-methyl-1-3- (3-methylbiperidino) 1 1— ( 4-Trifluoromethylphenyl) propane was used as diastereomer B (yield: 2.82 g).

 (2) 1-Rubamoyloxy 2-methyl-3- (3-methylbiperidino)-1- (4-trifluoromethylphenyl) propane

 Diastereomer B (1-hydroxy-12-methyl-3- (3-methylbiperidino) -1-1 (4-trifluoromethylphenyl)) obtained in (1) above 3.57 g (1 1 (3 mmol) was converted to rubamoyl in the same manner as in Example 10 (1) to give colorless crystals of 1-rubumyloxy-2-methyl-3- (3-methylbiperidino) -1- (4-trifluoromethylphenyl). ) 4.08 g of propane were obtained.

_{NMR (5ppm, CDC1 3):} 0.85 (6H, d, J = 5.9Hz), 0.72- 0.94 (lH, m), 1.42- 1.72 (5H, m), 1.74-1.90 (lH, m), 2.02-2.30 (3H, m), 2.60-2.76 (2H, m),

4.83 (2H, s), 5.81 (lH, d, J = 3.7Hz), 7.37 (2H, d, J = 8.4Hz), 7.58 (2H, d, J2 8.1Hz) (3) 1-force rubamoyloxy 2-Methyl-1- (3-methylbiperidino) -1- (4-trifluoromethylphenyl) propanemethanesulfonate 3.35 g (9.3 mmol) of the carbamoyloxy compound obtained in the above (2) Was dissolved in 1 Oml of ethanol to obtain a methanesulfonic acid salt using methanesulfonic acid. This was purified by recrystallization (solvent: ethanol / ether) to give 1-rubamoyloxy-1-methyl-3- (3-methylbiperidino) 1-1- (4-trifluoromethylphenyl) propane methanesulfonate Colorless crystals were obtained.

Yield 4.13 g (Total yield from Example 13 (1) 15.0%) Melting point 114 to 117 ° C

Elemental analysis: C ₁₈ H ₂₅ F ₃ N ₃ 〇 ₂ 'CH ₃ S0 ₃ H' 1 / 2H ₂ 〇

 C H N

 Calculated value (%): 49.23 6.52 6.04

 Measured value (%): 49.43 6.38 5.98 Example 14

 1-Rubamoyloxy 1- (4-Ethylphenyl) 1-Methyl-3- (1-Pyrrolidinyl) Propane hydrochloride

(1) 1- (4-Ethylphenyl) 1-1-hydroxy-12-methyl-3- (1-Vyloridinyl) propane

2,1.4 g (87.3 mmol) of 4,1-ethyl-2-methyl-3- (1-pyrrolidinyl) propiophenone synthesized according to a known method (Japanese Patent Publication No. 60-7627) was obtained by a conventional method. To reduce with sodium borohydride A mixture of stereoisomers 1- (4-ethylphenyl) 1-hydroxy-1

2-Methyl-1- (1-pyrrolidinyl) propane 21. Og was obtained as an oil. This was converted into a hydrochloride using hydrogen chloride gas, and the diastereomer was separated by recrystallization (solvent: ethanol / ether), and 1- (4-ethylfurenyl) 1-1-hydroxy-1 2 having a melting point of 163 to 166 ° C was used. —Methyl-3- (1-pyrrolidinyl) propane hydrochloride was converted to diastereomer A (yield: 11.9 g), mp 131-1.

1- (4-Ethylphenyl) -1-hydroxy-12-methyl-13- (1-pyrrolidinyl) propane hydrochloride at 33 ° C. was designated as diastereomer B (yield: 1. Olg).

 (2) 1-Rubamoyloxy 1- (4-ethylphenyl) -2-methyl-1 3- (1-pyrrolidinyl) propane

 Diastereomer A (1- (4-ethylphenyl) -11-hydroxy-12-methyl-3- (1-1-pyrrolidinyl) propane hydrochloride obtained in (1) above) (Melting point 163-166 ° 0 treated with base Example 21 (1) was obtained by adding 5.21 g (21.1 mmol) of the free product obtained by the reaction, 11- (4-ethylphenyl) -11-hydroxy-12-methyl-13- (1-pyrrolidinyl) propane, to Example 10 (1). Then, 3.06 g of colorless crystals of 1-force rubamoyloxy-11- (4-ethylphenyl) -12-methyl-13- (1-pyrrolidinyl) propane were obtained.

_{NM (dppm, CDC1 3):} 0.96 (3H, d, J = 7.0Hz), 1.68- 1.80 (4H, m), 2.00- 2.14 (lH, m), 2.28- 2.50 (6H, m), 4.69 (2H , br), 5.66 (lH, d, J = 5.1Hz), 7.13-7.21 (4H, m)

 (3) 1-Rubamoyloxy 1- (4-ethylphenyl) 1-2-methyl-3- (1-pyrrolidinyl) propane hydrochloride

 3.92 g (13.5 mmol) of the carbamoyloxy derivative obtained in the above (2) was dissolved in 30 ml of ether and converted into a hydrochloride using hydrogen chloride gas. This was purified by recrystallization (solvent: ethanol / ether) to obtain colorless crystals of 1-hydroxyl-rubamoyloxy-1- (4-ethylphenyl) -1-methyl-3- (1-pyrrolidinyl) propane hydrochloride. .

Yield 3 · 44 g (Total yield from Example 14 (1) 18.7%) Melting point 123-126 ° C

Elemental _{analysis: C 17 H 2e N 2 0} 2 'HCl' l / 2H 2 0

 C H N

 Calculated value (%): 60.79 8.40 8.34

 Observed value (%): 60.44 8.11 8.32 In order to confirm that the compound of the present invention has a central muscle relaxing action, an animal experiment was conducted on the decerebrate rigidity-releasing action. The bioavailability was also examined. Furthermore, in order to confirm that it has a micturition reflex inhibitory effect, the effect on rhythmic bladder contraction was examined. Animal experiments were also conducted for acute toxicity. (Test compound)

 Compound A (Example 1 (4-1)) 5- [1-Iruvamoyloxy 2- (1-pyrrolidinylmethyl) butyl] -3-phenylisoxazolyl hydrochloride (Compounds E and F described below) Racemic)

 Compound B (Example 1 (4-2)) 5- [1-Ferubamoyloxy-2- (1-pyrrolidinylmethyl) butyl] -13-phenylisoxazolyl hydrochloride (Compounds G and H described below) Racemic)

 Compound C (Example 10) 5- (1-D-rubamyloxy-3- (dimethylamino-1,2,2-dimethylpropyl) -13-phenylisoxazolylmaleic acidCompound D (Example 13) 1-D-rubamoyl Xie 2-methyl-3- (3-methylbiperidino) 1-1- (4-trifluoromethylphenyl) propane meta Compound E (Example 4) (1R, 2S) 1-5- [1-carbamoyloxy 2- (1-pyrrolidinylmethyl) butyl] 3-phenylisoxazolsulphate

Compound F (Example 2) (IS, 2R) 15- [1-Rubamoyloxy-21- (1-pyrrolidinylmethyl) butyl] 13-phenylisoxazole oxalate Compound G (Example 3) (1 R, 2 R) 1-5— [1-forcerubamoyloxy 2- 2- (1-pyrrolidinylmethyl) butyl] 13-phenylisoxazolyl sulphate

 Compound H (Example 5) (1 S, 2 S) 1-5— [1-carbamoyloxy 2- (1-pyrrolidinylmethyl) butyl] —3-phenylisoxazolyl sulphate The following compounds ad were used as test compounds for comparison.

 Compound a 3-Phenyl-1-5- [2- (1-pyrrolidinylmethyl) butyryl] isoxazolyl hydrochloride

 Compound b 5— (3-Dimethylamino-1-hydroxy-2,2-dimethylpropyl) -3-phenylisoxazolyl maleate

 Compound c eperisone hydrochloride

 Compound d Flavoxate hydrochloride Test Example 1-1: Decentrative action of decerebrate rigidity

 The effects of Compounds A and B on decerebrate rigidity and remission were examined using a model of decerebrate cerebral rigidity (A-rigidity) between the superior and inferior colliculus and compared with Compounds a and c.

 According to the method of Ono et al. (Gen. Pharmacol., 1987, 18, 57), the effect on superior colliculus-inferior colliculus dissection and brain rigidity was examined. Using Wistar male rats, the animals were fixed in a stereotaxic apparatus under isoflurane anesthesia. Drill holes in the corresponding parts of the bilateral midbrain and stimulate the electrodes of the region generator (AP: 0.0, V: -3.0, L: Sat 1.5, Pellegrino et al. (1979)) Was coagulated, and the inhalation anesthesia was terminated. One to three hours after the end of inhalation anesthesia, the animals exhibiting rigidity were lightly fixed in the dorsal position, and a concentric needle electrode was inserted into the gastrocnemius muscle of the hind limb to measure the frequency of myoelectric discharge. The test compound was dissolved in distilled water for injection and orally administered under the conditions of a dose of 100 mg / 5.0 ml / kg (equivalent to the free form).

The results are shown in Table 11-11. table 1

 *: Free substance conversion value: Maximum suppression rate

 Test example 1-2

 The decerebrate rigidity-releasing effects of Compounds A and B, Compounds E and F, which are optically active compounds of Compound A, and Compound G and Compound H, which are optically active forms of Compound B, were evaluated in the above Test Examples 1-1. The study was conducted in the same manner as described above. However, the test compound was dissolved in physiological saline and administered intravenously under the conditions of a dose of 4.0 mg / 5.0 ml / kg (converted to free substance). The results are shown in Tables 1-2.

 Table 1-2

Equivalent value in free form Maximum inhibition rate As shown in Table 11, compound A and compound B of the present invention, which are provamine amines, have better rigidity and relaxation than compounds a and c, which are ketone bodies. The effect is shown. In addition, as shown in Tables 12 and 12, the compounds A, B and EH of the present invention, which are proviramines, show an excellent action of relieving rigidity. Test Example 2: Remission of decerebrate rigidity

 The decerebrate rigidity-releasing action of Compound C was evaluated in comparison with Compounds b and c in the same manner as in Test Examples 11-11. However, the dose was 50. Omg / 5.0 ml / kg (converted to free substance) and orally administered. Table 2 shows the results.

 Table 2

 *: Free substance conversion value: Maximum suppression rate

 As shown in Table 2, Compound C, which is a propylamine compound, has more excellent rigidity-releasing action than Compound b, which is a hydroxy compound, and Compound c, which is a ketone compound. Test Example 3: Bioavailability-

 The bioavailability of Compounds a and b and Compounds A to C, in which the oxo group and hydroxyl group in the basic structure were converted to carbamoyloxy groups, were compared.

 [Test method]

 Five male SD rats were fasted overnight. Test compounds were administered intravenously or orally, blood was collected from the jugular vein over time, and plasma concentrations were measured by LC-MS / MS. The test compound was dissolved in physiological saline or 0.5% aqueous methylcellulose solution. The area under the plasma concentration-time curve (AUC) was calculated from the obtained plasma concentration to determine the bioavailability. Table 3 shows the results.

(Hereafter, on the next page) Table 3

表 3に示す通り、 化合物 A、 Bおよび Cは化合物 aおよび bより生物学的利 用能が高い。 試験例 4 ：排尿反射抑制作用 （麻酔下）

As shown in Table 3, Compounds A, B and C are more bioavailable than Compounds a and b. Test Example 4: Urinary reflex suppression (under anesthesia)

 The effect of compound D on rhythmic bladder contractions was evaluated. Compound d was used as a control.

 [Test method]

 The male SD rats were anesthetized with urethane 50 O mg / kg, i.p. and sodium chloralose 5 O mg / kg, i.p., and fixed in a dorsal position. After securing a spontaneous respiration by inserting a tracheal force neura, a midline incision is made in the lower abdomen to expose the bladder, and a polyethylene tube is inserted through a small incision added to the top of the bladder. The change in pressure was measured. After ligating the urethra, rhythmic bladder contraction was induced by injecting saline into the bladder and increasing the intravesical pressure.

 The test compound was dissolved in distilled water for injection, and administered via a force transducer inserted into the duodenum or external vein. After administration of the test compound, the time required for bladder rhythmic contraction to disappear and rhythmic contraction to develop again was measured, and the urinary reflex inhibitory effect was evaluated using this time as an index.

Table 4-1 shows the results of intravenous administration, and Table 4-2 shows the results of intraduodenal administration. Table 4-1

 *: Free substance conversion value

 As shown in Tables 4-1 and 4-2, Compound D exhibits an inhibitory effect on micturition reflex by intravenous administration that is equal to or higher than that of Compound d as a control drug, and that by duodenal administration is higher than that of Compound d. Test Example 5: Acute toxicity

 The test compound A was administered once to rats, and the acute toxicity was examined.

 [Test method]

 Male SD rats (3 per group) fasted overnight.

 Compounds were dissolved in distilled water for injection and orally administered once to rats. Pathological anatomical examinations were performed continuously for up to 1 hour after administration, thereafter every hour for up to 6 hours, and for 7 days from the day after administration. Table 5 shows the results.

 Table 5

 Test compound Lethal dose * (mg / kg)

Compound A 75 0 Compound a 75 0 *: Free substance conversion value

 As shown in Table 5, compound A exhibits almost the same acute toxicity as compound a. Industrial applicability

 As is clear from Tables 1-1 to 5 above, the target compound of the present invention is useful as a central muscle relaxant and a therapeutic agent for dysuria.

Claims

"Kume, ^ E ^ SJ 1. General formula [I] R ¹  I A-CH— C-CH ₂ -NR ³ R ⁴ R ² OCONHR ⁵  [I] (Wherein A is an aryl group substituted with a substituent selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, lower alkyl, lower alkoxy, halo-lower alkyl and aryl, or substituted A heteroaryl group which may be 1 ^ Oyobi 11 ² may be identical or different lower alkyl groups, also Yes displacement or the other is a hydrogen atom and the other is a lower alkyl group, a lower alkoxy - alkoxy group, a lower alkylthio group, Ariru group An aralkyl group or a lower alkyl group substituted by a lower alkoxy or a lower alkylthio; R ³ and R ⁴ are either a hydrogen atom or a lower alkyl group and the other is a lower cycloalkyl group, or the same or different and a lower alkyl group, or both of these lower alkyl groups; The groups may be linked to each other with or without a nitrogen or oxygen atom to form a ring, wherein said ring may be substituted with lower alkyl, lower alkanol or aralkyl; R ⁵ is a hydrogen atom, a lower alkyl group or an aryl group) And a physiologically acceptable salt thereof. 2. In the general formula [I], A is an aryl group substituted with 1 to 3 lower alkyl or halo-lower alkyl, or

An optionally substituted heteroaryl group selected from the group consisting of: 1 ^ Oyobi 1 ² may be identical or different lower alkyl groups, or either one is a hydrogen atom and the other a lower alkyl group; R ³ and R ⁴ may be the same or different and are a lower alkyl group, or both lower alkyl groups may be bonded to each other via a nitrogen atom to form a ring, and the ring may be a lower alkyl group; May be replaced by 2. The compound according to claim 1, which is a proviramine derivative and a physiologically acceptable salt thereof. 3. The compound of general formula [I] is 5-[1-rubamoyloxy 2-(1-bilolidinylmethyl) butyl] 1-3-phenylisoxazolyl, 5-(1-force rubamoyloxy 1-3-dimethylamino-2,2-dimethylpropyl pill) 1-3-phenylisoxazolyl,  5- [3-dimethylamino-1- (diethylcarbamoyloxy) -1,2,2-dimethylpropyl] -3-phenylisoxazolyl,  5- [3-dimethylamino-1,2-dimethyl-11- (Ν-phenylcarbamoyloxy) propyl] — 3-phenylisoxazolyl,  1-force rubamoyloxy 2-methyl-3- (3-methylbiperidino) -1- (4-trifluoromethylphenyl) propane or  1-Rubamoyloxy 1- (4-Ethylphenyl) 1-2-Methyl-1- (1-pyrrolidinyl) propane And the physiologically acceptable salt thereof. 4. The compound of the general formula [I] is  (1 R, 2 S) 1-5-[1-Rubimoyloxy 1-2-(1-pyrrolidinylmethyl) butyl] — 3-phenylisoxazolyl,  (1 S, 2 R) 1 5— [1—Rubamoyloxy 1—2— (1—pyrrolidinylmethyl) butyl] 1—3-phenylisoxazolyl,  (1R, 2R) 1-5— [1 rubamoyloxy 1—2— (1 pyrrolidinylmethyl) butyl] 1—3-phenylisoxazolyl or  (1 S, 2 S)-5-[1—Power-l-bamoyloxy-1- (1-pyrrolidinylmethyl) butyl] 1-3-Fenylisoxazole And the physiologically acceptable salt thereof. 5. A central muscle relaxant comprising, as an active ingredient, a proviramine derivative represented by the general formula [I] according to claim 1 or a physiologically acceptable salt thereof. 6. A therapeutic agent for dysuria comprising, as an active ingredient, a proviramine derivative represented by the general formula [I] according to claim 1 or a physiologically acceptable salt thereof. 7. —General formula [V] R ¹ A-CH— CH—— CH ₂ OX [V] OCONHR ⁵ Wherein A, R ¹ and R ⁵ are the same as defined in formula [I], and X is a substituted sulfonyl group. The compound represented by the general formula [VI] R ³ R NH [VI] [Wherein R ³ and R ⁴ are the same as defined in formula [I]] General formula [I] consisting of reacting with an amine represented by R ¹  I A-CH— C-CH ₂ -NR ³ R ⁴ [I] R ²  OCONHR " [Wherein A, R ¹ , R ³ , R ⁴ and R ⁵ are the same as defined in claim 1, and R ² is a hydrogen atom] Or a physiologically acceptable salt thereof. 8. The compound of the general formula [V] according to claim 7, wherein  (i) General formula [VI I] R ¹ -net

[Wherein, R ¹ is the same as defined in formula [I], R ⁶ is a phenyl, benzyl, t-butyl or isopropyl group, and Y is an oxygen atom or a sulfur atom. Ru] To the compound of formula [VI I I]  A-CHO [VI I I]  [Where A is the same as defined in equation [I]] Aldol condensation of the compound represented by the general formula [IX]

Wherein A, RR ⁶ and Y are the same as above. To obtain a compound represented by the formula  (ii) reacting compound [IX] with a base to obtain a compound of general formula [X] R ¹  A— CH— CH—— C-one OR [X]  I II OH [Wherein A and R ¹ are as described above, and R is a hydrogen atom or lower alkyl] To obtain a compound represented by the formula  (i i i) Compound [X] is converted into a compound by the general formula [XI] R ¹  I  A-CH—— CH—— C-OR [XII  I II OCONHR ⁵ 0 [Where A, RR ⁵ and R are as described above] To obtain a compound represented by the formula  (iv) Compound [XI] is reduced to give a general formula [XII] R ¹  I A-CH— CH—— CH ₂ OH [Π] OCONHR ⁵ Wherein A, R ¹ and R ⁵ are as defined above,  (V) The method according to claim 7, which is produced by sulfonylating the compound [XI I].