JPH0710851A - Aminoalcohol derivative and its use - Google Patents
Aminoalcohol derivative and its useInfo
- Publication number
- JPH0710851A JPH0710851A JP15704193A JP15704193A JPH0710851A JP H0710851 A JPH0710851 A JP H0710851A JP 15704193 A JP15704193 A JP 15704193A JP 15704193 A JP15704193 A JP 15704193A JP H0710851 A JPH0710851 A JP H0710851A
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- Japan
- Prior art keywords
- compound
- added
- solution
- physiologically acceptable
- phenyl
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、けい性麻ひを主症状と
する疾患、運動器疾患に伴う有痛性筋けい縮等の疾患の
治療や、神経因性膀胱や不安定膀胱等による頻尿症状の
改善にも有効であるアミノアルコール誘導体及びその生
理学的に許容される塩に関する。また、本発明はこれら
の化合物の少なくとも１種を有効成分とする上記の疾患
のための治療剤に関する。FIELD OF THE INVENTION The present invention is intended to treat diseases such as spastic paralysis as a main symptom and painful muscle spasms associated with motor organ diseases, and to prevent frequent occurrence of neurogenic bladder or unstable bladder. The present invention relates to amino alcohol derivatives and physiologically acceptable salts thereof which are also effective in improving urinary symptoms. The present invention also relates to a therapeutic agent for the above-mentioned diseases, which comprises at least one of these compounds as an active ingredient.
【０００２】[0002]
【従来の技術】従来、筋弛緩作用を有する薬物としては
塩酸トルペリゾン、塩酸エペリゾン、チザニジン等が知
られている。しかしながら、本発明の一般式（Ｉ）で表
わされるアミノアルコール誘導体自体について、更に該
誘導体が筋弛緩作用を有することについては知られてい
ない。2. Description of the Related Art Tolperisone hydrochloride, eperisone hydrochloride, tizanidine and the like have been conventionally known as drugs having a muscle relaxant action. However, it is not known about the aminoalcohol derivative itself represented by the general formula (I) of the present invention, and further that the derivative has a muscle relaxing action.
【０００３】[0003]
【発明が解決しようとする課題】現在、塩酸トルペリゾ
ン、塩酸エペリゾンやチザニジンが、けい性麻ひを主症
状とする疾患の治療に広く用いられている。しかしこれ
らは作用の強さが十分でなく、また持続性も短く、中枢
抑制作用がある等の問題点がある。本発明の目的は一般
式（Ｉ）で表わされるアミノアルコール誘導体又はその
生理学的に許容される塩を用いることで、筋弛緩作用が
強く、持続性が永く、副作用の低い有用な筋弛緩剤を提
供することにある。本発明の他の目的は、一般式（Ｉ）
で表わされるアミノアルコール誘導体又はその生理学的
に許容される塩を用いた頻尿治療剤を提供することにあ
る。At present, tolperisone hydrochloride, eperisone hydrochloride and tizanidine are widely used for the treatment of diseases whose main symptoms are spastic paralysis. However, these have the problems that the strength of action is not sufficient, the duration is short, and they have a central depressant action. The object of the present invention is to provide a useful muscle relaxant having a strong muscle relaxant action, long duration, and low side effects by using the aminoalcohol derivative represented by the general formula (I) or a physiologically acceptable salt thereof. To provide. Another object of the invention is the general formula (I)
Another object of the present invention is to provide a therapeutic agent for frequent urination using an amino alcohol derivative represented by or a physiologically acceptable salt thereof.
【０００４】[0004]
【課題を解決するための手段】本発明のアミノアルコー
ル誘導体は、下記一般式（Ｉ）で表わされる化合物であ
る。The amino alcohol derivative of the present invention is a compound represented by the following general formula (I).
【０００５】[0005]
【化２】 （式中、Ｒ1は水素原子又は炭素数が１〜４のアルキル
基を、Ｒ2及びＲ3はそれぞれ独立して炭素数が１〜４の
アルキル基を示すか又は窒素原子と共に脂環式５員環ま
たは６員環を形成する。） 上記一般式（Ｉ）で表わされる本発明のアミノアルコー
ル誘導体及びその生理学的に許容される塩は、優れた筋
弛緩作用と排尿抑制作用を示しまた副作用も低く、筋弛
緩剤及び頻尿治療薬の有効成分として極めて有用であ
る。[Chemical 2] (In the formula, R 1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 and R 3 each independently represent an alkyl group having 1 to 4 carbon atoms, or an alicyclic group together with a nitrogen atom. A 5-membered ring or a 6-membered ring is formed.) The aminoalcohol derivative of the present invention represented by the above general formula (I) and a physiologically acceptable salt thereof exhibit excellent muscle relaxing action and urination suppressing action, and It has few side effects and is extremely useful as an active ingredient of muscle relaxants and therapeutic agents for frequent urination.
【０００６】前記一般式（Ｉ）で表されるアミノアルコ
ール誘導体は分子中に２個の不整炭素を有するので４種
の光学異性体が存在するが、これらの異性体は何れも本
発明に含まれるものである。Since the aminoalcohol derivative represented by the general formula (I) has two asymmetric carbons in the molecule, there are four kinds of optical isomers, and all of these isomers are included in the present invention. It is what is done.
【０００７】本発明のアミノアルコール誘導体の生理学
的に許容される塩（酸付加塩）を構成できる酸として
は、生理学的に許容されるものであれば特に制限はな
く、例えば、塩酸、硫酸、リン酸等から無機酸塩、又は
酢酸、クエン酸、コハク酸、マレイン酸、フマール酸、
酒石酸、メタンスルホン酸、乳酸等から形成される有機
酸塩類などを挙げることができる。該酸付加塩の形成
は、アミノアルコール誘導体と所望の酸とを、水、アル
コール等の有機溶媒またはこれらの混合物の中で反応さ
せることにより行うことができる。There are no particular restrictions on the acid that can form the physiologically acceptable salt (acid addition salt) of the aminoalcohol derivative of the present invention, provided it is physiologically acceptable, and examples thereof include hydrochloric acid, sulfuric acid, and Inorganic acid salts from phosphoric acid, etc., or acetic acid, citric acid, succinic acid, maleic acid, fumaric acid,
Examples thereof include organic acid salts formed from tartaric acid, methanesulfonic acid, lactic acid and the like. The formation of the acid addition salt can be carried out by reacting the amino alcohol derivative with a desired acid in water, an organic solvent such as alcohol, or a mixture thereof.
【０００８】本発明のアミノアルコール誘導体は一般的
には以下に示す反応工程（ａ）及び（ｂ）を有する方法
により製造することができる。The amino alcohol derivative of the present invention can be generally produced by a method having the following reaction steps (a) and (b).
【０００９】[0009]
【化３】 [Chemical 3]
【００１０】[0010]
【化４】 なお、（ａ）の反応工程は、例えば特開平３−１５７３
７５公報及び特開平４−２１０９７４５公報に記載の方
法を利用して行うことができる。また、（ｂ）の反応
は、アルコールを溶媒として反応温度０〜１００℃で実
施することができる。望ましいアルコールとしてはメタ
ノールまたはエタノールを挙げることができ、望ましい
反応温度は１０〜４０℃の範囲の温度である。[Chemical 4] The reaction step (a) is carried out, for example, in JP-A-3-1573.
75 and Japanese Patent Application Laid-Open No. 4-2109745. The reaction (b) can be carried out at a reaction temperature of 0 to 100 ° C using alcohol as a solvent. The preferred alcohol may include methanol or ethanol, and the preferred reaction temperature is in the range of 10 to 40 ° C.
【００１１】本発明のアミノアルコール誘導体及びその
生理学的に許容される塩の少なくとも１種を有効成分と
して、筋弛緩剤及び頻尿治療薬を形成することができ、
患者への投与量は、治療すべき症状及び投与方法により
異なるが、通常成人に１日５〜１０００ｍｇ、好ましく
は５０〜３００ｍｇである。A muscle relaxant and a treatment agent for frequent urination can be formed by using at least one of the amino alcohol derivative of the present invention and a physiologically acceptable salt thereof as an active ingredient,
The dose to a patient varies depending on the condition to be treated and the administration method, but is usually 5 to 1000 mg, preferably 50 to 300 mg per day for an adult.
【００１２】投与形態は、カプセル剤、錠剤、細顆粒
剤、シロップ剤、散剤等の経口投与剤にするか、あるい
は注射剤、座剤、塗薬等にして非経口的に投与すること
ができる。The dosage form can be an oral administration agent such as capsules, tablets, fine granules, syrups, and powders, or can be parenterally administered as injections, suppositories, coatings and the like. .
【００１３】製剤用添加剤としては、賦形剤（ラクトー
ス、コーンスターチ、シュガー、ソルビット、リン酸カ
ルシウム等）、結合剤（シロップ、アラビアゴム、ゼラ
チン、ソルビット、ポリビニルピロリドン、ヒドロキシ
プロピルセルロース等）、滑沢剤（ステアリン酸マグネ
シウム、タルク、ポリエチレングリコール、シリカ
等）、崩壊剤（ポテトスターチ、カルボキシルメチルセ
ルロース等）、湿潤剤（ラウリル酸ナトリウム）等を剤
形に従って適宜使用することができる。As additives for pharmaceuticals, excipients (lactose, corn starch, sugar, sorbit, calcium phosphate, etc.), binders (syrup, gum arabic, gelatin, sorbit, polyvinylpyrrolidone, hydroxypropylcellulose, etc.), lubricants (Magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agent (potato starch, carboxymethyl cellulose, etc.), wetting agent (sodium laurate), etc. can be appropriately used according to the dosage form.
【００１４】[0014]
【発明の効果】本発明のアミノアルコール誘導体及びそ
の生理学的に許容される塩は、優れた筋弛緩作用、脊髄
反射抑制作用、抗ケイレン作用等を有しており、腰背痛
症、椎間板ヘルニア、頸肩腕症候群等の疾患による筋緊
張状態及び脳血管障害、ケイ性脊髄麻ヒ、脳性麻ヒ等の
疾患によるケイ性麻ヒの治療剤の有効成分としてきわめ
て有用である。The amino alcohol derivative of the present invention and the physiologically acceptable salt thereof have excellent muscle relaxant action, spinal cord reflex inhibitory action, anti-kaylene action, etc., and lumbago back pain, disc herniation. , And is extremely useful as an active ingredient of a therapeutic agent for muscular tone and cerebrovascular disorder due to diseases such as cervical-shoulder-arm syndrome, cerebral palsy and cerebral palsy.
【００１５】更に、本発明のアミノアルコール誘導体及
びその生理学的に許容される塩は排尿反射抑制作用を有
しており、頻尿治療剤の有効成分として有用である。Furthermore, the aminoalcohol derivative of the present invention and its physiologically acceptable salt have an action of suppressing micturition reflex and are useful as an active ingredient of a therapeutic agent for frequent urination.
【００１６】[0016]
【実施例】以下に、参考例及び実施例を挙げて本発明化
合物を具体的に説明する。EXAMPLES The compounds of the present invention will be specifically described below with reference to Reference Examples and Examples.
【００１７】参考例１ ［３−フェニル−５−プロピオニルイソオキサゾールの
製造］ベンズアルドキシム２．５ｇ（２０．７ｍｍｏ
ｌ）、１−ペンチン−３−オール２．１ｇ（２５ｍｍｏ
ｌ）をジクロロメタン１２．５ｍｌに溶解した。反応液
を氷冷し、１２％次亜塩素酸ナトリウム水溶液を、該化
合物の添加量が１４．５ｇ（２５ｍｏｌ）となるよう
に、内温を１５〜２５℃に保ちながら滴下した。滴下終
了後、内温を１５〜２５℃に保ちながら３時間攪拌し
た。Reference Example 1 [Production of 3-phenyl-5-propionylisoxazole] Benzaldoxime 2.5 g (20.7 mmo)
l), 2.1 g of 1-pentyn-3-ol (25 mmo
1) was dissolved in 12.5 ml of dichloromethane. The reaction solution was ice-cooled, and a 12% aqueous sodium hypochlorite solution was added dropwise while keeping the internal temperature at 15 to 25 ° C so that the amount of the compound added was 14.5 g (25 mol). After the completion of dropping, the mixture was stirred for 3 hours while keeping the internal temperature at 15 to 25 ° C.
【００１８】この反応液に１２％次亜塩素酸ナトリウム
水溶液を該化合物の添加量が３９．０ｇ（６３ｍｍｏ
ｌ）となるように滴下した。反応液の内温を１０℃に冷
却し、攪拌しながらピリジン塩酸塩０．７ｇ（６．１ｍ
ｍｏｌ）を水３ｍｌに溶かした溶液の全量を２０分間か
けて滴下した。滴下終了後反応液を７０分間攪拌した。
反応溶液を分液し、下相のジクロロメタン溶液とり、５
％亜硫酸ナトリウム水溶液２５ｍｌを加えて３０分間攪
拌した。混合液を分液し、ジクロロメタン相を水２５ｍ
ｌ、１Ｎ塩酸水溶液２５ｍｌで洗浄した。次に、洗浄さ
れたジクロロメタン相を分液して、減圧濃縮し、得られ
た残渣をメタノール１０ｍｌから再結晶して３−フェニ
ル−５−プロピオニルイソオキサゾール３．０ｇ（１
４．９ｍｍｏｌ、収率７２．０％）を得た。A 12% aqueous solution of sodium hypochlorite was added to this reaction solution in an amount of 39.0 g (63 mmo).
l) was added dropwise. The internal temperature of the reaction solution was cooled to 10 ° C., and while stirring, pyridine hydrochloride 0.7 g (6.1 m
(mol) in 3 ml of water was added dropwise over 20 minutes. After completion of dropping, the reaction solution was stirred for 70 minutes.
The reaction solution is separated and the lower phase dichloromethane solution is taken.
% Aqueous sodium sulfite solution (25 ml) was added and the mixture was stirred for 30 minutes. The mixture is separated and the dichloromethane phase is washed with 25 m of water.
1, washed with 25 ml of 1N hydrochloric acid aqueous solution. Next, the washed dichloromethane phase was separated, concentrated under reduced pressure, and the obtained residue was recrystallized from 10 ml of methanol to give 3.0 g of 3-phenyl-5-propionylisoxazole (1
4.9 mmol, yield 72.0%) was obtained.
【００１９】参考例２ ［３−フェニル−５−｛２−（１−ピペリジニルメチ
ル）プロピオニル｝イソオキサゾールの製造］３−フェ
ニル−５−プロピオニルイソオキサゾール２．０ｇ（１
０ｍｍｏｌ）及びピペリジン１．７ｇ（２０ｍｍｏｌ）
をエチルアルコール１０ｍｌに加えた。得られた溶液
に、氷冷下で３７％ホルムアルデヒド水溶液１．６３ｍ
ｌ（２０ｍｍｏｌ）を滴下し、室温で２時間攪拌した。
反応液を減圧濃縮し、得られた残渣をエチルエーテル３
０ｍｌに溶解した。得られたエーテル溶液を水で洗浄
し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧留去
して、２．３ｇの３−フェニル−５−｛２−（１−ピペ
リジニルメチル）プロピオニル｝イソオキサゾールの白
色結晶を得た。（収率７８％） 実施例１ ［５−｛１−ヒドロキシ−２−（１−ピペリジニルメチ
ル）プロピル｝−３−フェニルイソオキサゾールの製
造］３−フェニル−５−｛２−（１−ピペリジニルメチ
ル）プロピオニル｝イソオキサゾール１．５ｇをメタノ
ール１５ｍｌに溶解した。得られた溶液に、水素化ホウ
素ナトリウム５４ｍｇを加え、６０℃で１時間攪拌した
後、反応溶液を冷却し酢酸で中和した。中和後、反応溶
液を減圧濃縮し、水１５ｍｌを加えた後、酢酸エチル３
０ｍｌで抽出した。酢酸エチル相を硫酸ナトリウムで乾
燥後、溶媒を減圧留去した。得られた残渣をシリカゲル
カラムにかけ、クロロホルム／メタノール混合溶液（容
量比８０：２０）で精製した。溶出したフラクションを
集め、溶媒を減圧留去して、５−｛１−ヒドロキシ−２
−（１−ピペリジニルメチル）プロピル｝−３−フェニ
ルイソオキサゾールの油状物１．３ｇ（収率７８．０
％）を得た。 得られた化合物の分析結果： ＮＭＲ（ｄppm、ＣＤＣｌ3）：０．８〜１．３（３Ｈ、
ｍ）；１．４〜２．０（６Ｈ，ｍ）；２．２〜３．０
（７Ｈ，ｍ）；４．６〜５．１（１Ｈ，ｓ）；６．７
（１Ｈ，ｍ）；７．３（１Ｈ，ｓ）；７．３〜７．７
（３Ｈ，ｍ）；７．８〜８．０（２Ｈ，ｍ）実施例２ ［５−｛１−ヒドロキシ−２−（１−ピペリジニルメチ
ル）プロピル｝−３−フェニルイソオキサゾール塩酸塩
（化合物１）の製造］５−｛１−ヒドロキシ−２−（１
−ピペリジニルメチル）プロピル｝−３−フェニルイソ
オキサゾールの１．０ｇをエチルエーテル１０ｍｌに溶
解し、これに８Ｎ塩酸エタノール溶液１ｍｌを加えた。
得られた溶液を減圧濃縮し、残渣を減圧乾燥して５−
｛１−ヒドロキシ−２−（１−ピペリジニルメチル）プ
ロピル｝−３−フェニルイソオキサゾール塩酸塩（化合
物１）１．１ｇを得た。 得られた化合物の分析結果： 融点：１７４〜１７６℃ 参考例３ ［３−フェニル−５−ブチリルイソオキサゾールの製
造］ベンズアルドキシム１０ｇ（０．０８２ｍｏｌ）及
び１−ヘキシン−３−オール９ｇ（０．０９２ｍｏｌ）
をジクロロメタン５０ｍｌに溶解した。反応液を氷冷
し、１２％次亜塩素酸ナトリウム水溶液を該化合物の添
加量が５８ｇ（０．１０ｍｏｌ）となるように内温１５
〜２５℃に保ちながら滴下した。滴下終了後、内温を１
５〜２５℃に保ちながら３時間攪拌した。Reference Example 2 [Production of 3-phenyl-5- {2- (1-piperidinylmethyl) propionyl} isoxazole] 2.0 g of 3-phenyl-5-propionylisoxazole
0 mmol) and 1.7 g (20 mmol) of piperidine
Was added to 10 ml of ethyl alcohol. The resulting solution was cooled with ice to form a 37% aqueous formaldehyde solution (1.63 m).
1 (20 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours.
The reaction mixture was concentrated under reduced pressure, and the resulting residue was mixed with ethyl ether 3
It was dissolved in 0 ml. The obtained ether solution was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.3 g of 3-phenyl-5- {2- (1-piperidinylmethyl) propionyl}. White crystals of isoxazole were obtained. (Yield 78%) Example 1 [Production of 5- {1-hydroxy-2- (1-piperidinylmethyl) propyl} -3-phenylisoxazole] 3-phenyl-5- {2- (1- 1.5 g of piperidinylmethyl) propionyl} isoxazole was dissolved in 15 ml of methanol. Sodium borohydride (54 mg) was added to the obtained solution, and the mixture was stirred at 60 ° C for 1 hr, then the reaction solution was cooled and neutralized with acetic acid. After neutralization, the reaction solution was concentrated under reduced pressure, 15 ml of water was added, and then ethyl acetate 3
Extracted with 0 ml. The ethyl acetate phase was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was applied to a silica gel column and purified with a chloroform / methanol mixed solution (volume ratio 80:20). The eluted fractions were collected and the solvent was evaporated under reduced pressure to give 5- {1-hydroxy-2
1.3 g of an oily product of-(1-piperidinylmethyl) propyl} -3-phenylisoxazole (yield 78.0).
%) Was obtained. Analysis results of the obtained compound: NMR (d ppm , CDCl 3 ): 0.8 to 1.3 (3H,
m); 1.4 to 2.0 (6H, m); 2.2 to 3.0
(7H, m); 4.6-5.1 (1H, s); 6.7
(1H, m); 7.3 (1H, s); 7.3 to 7.7
(3H, m); 7.8-8.0 (2H, m) Example 2 [5- {1-hydroxy-2- (1-piperidinylmethyl) propyl} -3-phenylisoxazole hydrochloride ( Production of Compound 1)] 5- {1-hydroxy-2- (1
1.0 g of -piperidinylmethyl) propyl} -3-phenylisoxazole was dissolved in 10 ml of ethyl ether, and 1 ml of 8N hydrochloric acid ethanol solution was added thereto.
The resulting solution was concentrated under reduced pressure, the residue was dried under reduced pressure, and
1.1 g of {1-hydroxy-2- (1-piperidinylmethyl) propyl} -3-phenylisoxazole hydrochloride (Compound 1) was obtained. Analysis results of the obtained compound: Melting point: 174 to 176 ° C. Reference Example 3 [Production of 3-phenyl-5-butyrylisoxazole] Benzaldoxime 10 g (0.082 mol) and 1-hexyne-3-ol 9 g ( 0.092 mol)
Was dissolved in 50 ml of dichloromethane. The reaction solution was ice-cooled, and a 12% sodium hypochlorite aqueous solution was added at an internal temperature of 15 so that the amount of the compound added was 58 g (0.10 mol).
The solution was added dropwise while maintaining at -25 ° C. After dropping, the internal temperature is 1
The mixture was stirred for 3 hours while maintaining the temperature at 5 to 25 ° C.
【００２０】この反応液に１２％次亜塩素酸ナトリウム
水溶液を該化合物の添加量が１５６ｇとなるように滴下
した。反応液の内温を１０℃に冷却し、攪拌しながらピ
リジン塩酸塩２．８ｇを水１２ｍｌに溶かした溶液の全
量を反応温度を１５〜２０℃に保ちながら滴下した。滴
下終了後反応液を７０分間攪拌した。反応溶液を分液
し、下相のジクロロメタン溶液とり、５％亜硫酸水素ナ
トリウム水溶液１００ｍｌを加えて３０分間攪拌した。
混合液を分液し、ジクロロメタン相を水１００ｍｌ、１
Ｎ塩酸水溶液１００ｍｌで洗浄した。洗浄されたジクロ
ロメタン相を分液して、減圧濃縮した。得られた残渣を
メタノール４０ｍｌから再結晶して３−フェニル−５−
ブチリルイソオキサゾール１０．６ｇ（収率５９．６
％）を得た。 得られた化合物の分析結果： 融点：８９〜９０℃ 参考例４ ［３−フェニル−５−｛２−（１−ピロリジニルメチ
ル）ブチリル｝イソオキサゾールの製造］３−フェニル
−５−ブチリルイソオキサゾール２０ｇ（９３ｍｍｏ
ｌ）及びピロリジン７．９３ｇ（１１１ｍｏｌ）をメタ
ノール６２ｇに加えた。得られた反応液を攪拌し、内温
を２０〜３０℃に保ちながら、これに３７％ホルマリン
水溶液を該化合物の添加量が９．０４ｇ（１１１ｍｍｏ
ｌ）となるように滴下した。滴下終了後、内温を２０〜
３０℃に保ちながら１時間攪拌した。反応液を分液ロー
トに取り、酢酸ブチル１７８ｇを加え攪拌した。分液し
て有機相を取り、水５０ｍｌを加えて３回洗浄した後、
硫酸ナトリウムで乾燥した。有機相から溶媒を減圧留去
して、３−フェニル−５−｛２−（１−ピロリジニルメ
チル）ブチリル｝イソオキサゾールの白色結晶２０．３
ｇを得た。（収率７３％） 得られた化合物の分析結果： 融点：６８〜６９℃ 実施例３ ［５−｛１−ヒドロキシ−２−（１−ピロリジニルメチ
ル）ブチル｝−３−フェニルイソオキサゾール塩酸塩
（化合物２）の製造］３−フェニル−５−｛２−（１−
ピロリジニルメチル）ブチリル｝イソオキサゾール６．
９ｇ（２３ｍｍｏｌ）をエタノール１００ｍｌに溶解し
た。得られた溶液に、水素化ホウ素ナトリウム０．９７
ｇを室温下に徐々に加えてから、室温下で２時間攪拌し
た。得られた反応混合物にアセトン２０ｍｌを加えた
後、溶媒を減圧留去し、残渣に水１５０ｍｌを加え、攪
拌した。攪拌後、ジエチルエーテル２０ｍｌを加えて抽
出を行った。有機相をとり、水１００ｍｌで２回、飽和
食塩水１００ｍｌで１回洗浄した。洗浄された有機相
に、無水硫酸ナトリウムで乾燥した。次に、有機相から
硫酸ナトリウムを濾別し、濾液を減圧留去して、５−
｛１−ヒドロキシ−２−（１−ピロリジニルメチル）ブ
チリル｝−３−フェニルイソオキサゾールを油状物とし
て得た。この油状物をシリカゲルカラムにかけ、クロロ
ホルム／メタノール／酢酸エチル（容量比：１０：１：
１）混合溶媒で溶出した。最初のフラクションを集め減
圧下に溶媒を留去した。濃縮残渣に水１５０ｍｌを加
え、炭酸ナトリウム水溶液で中性にした。得られた溶液
にエチルエーテルを加えて抽出した。分液して有機相を
取り、水、炭酸ソーダ水溶液で洗浄した。洗浄した有機
相を分液し、無水硫酸アルミニウムで乾燥した後、溶媒
を減圧留去して油状の残渣を得た。この油状物をメタノ
ール１５ｍｌに溶かし、攪拌しながら１０％塩酸メタノ
ール溶液を過剰に加えた。反応溶液を減圧濃縮した。残
渣を室温下で減圧乾燥すると、５−｛１−ヒドロキシ−
２−（１−ピロリジニルメチル）ブチル｝イソオキサゾ
ール塩酸塩１．３ｇが得られた。 得られた化合物の分析結果： 融点：１０２〜１０４℃ 参考例５ ［（Ｒ）−３−フェニル−５−｛２−（１−ピロリジニ
ルメチル）ブチリル｝イソオキサゾール Ｌ−カンファ
スルホン酸塩の製造］３−フェニル−５−｛２−（１−
ピロリジニルメチル）ブチリル｝イソオキサゾール２０
ｇを酢酸エチル１５０ｍｌに溶かし、Ｌ−カンファスル
ホン酸４３．７ｇを加え５０〜６０℃に加熱して溶解さ
せた。反応液を攪拌しながら１０℃まで冷却した。冷却
によって析出した結晶を濾取し、酢酸エチルで洗浄し
た。結晶を減圧乾燥して（Ｒ）−３−フェニル−５−
｛２−（１−ピロリジニルメチル）ブチリル｝イソオキ
サゾールのＬ−カンファスルホン酸塩２１．３ｇを得
た。 得られた化合物の分析結果： 光学純度：９８．７％ｅｅ 融点：１１５．８〜１１６．３℃ ［α］20 D ＝−１４．４゜（Ｃ＝０．５、エタノール） 参考例６ ［（Ｒ）−３−フェニル−５−｛２−（１−ピロリジニ
ルメチル）ブチリル｝イソオキサゾール塩酸塩の製造］
（Ｒ）−３−フェニル−５−｛２−（１−ピロリジニル
メチル）ブチリル｝イソオキサゾールのＬ−カンファス
ルホン酸塩２０ｇを水１５０ｍｌ、クロロホルム１５０
ｍｌの混合液に加え、攪拌した。この混合液に１０％炭
酸ナトリウム水溶液９７ｍｌを滴下した。反応液を１０
分間攪拌した後、分液して有機相を得た。得られた有機
相を１０％炭酸ナトリウム水溶液、水の順に洗浄した。
内温を１０℃以下に保ちながら有機相に２Ｎ塩酸水溶液
９０ｍｌを滴下した。分液して得られた有機相を硫酸ナ
トリウムで乾燥した。有機相から硫酸ナトリウムを濾過
して除き、濾液を５℃に冷却しながら攪拌下に酢酸エチ
ル３００ｍｌを徐々に加えた。析出した結晶を濾取し、
少量の酢酸エチルで洗浄した。結晶を減圧乾燥し、目的
とする（Ｒ）−３−フェニル−５−｛２−（１−ピロリ
ジニルメチル）ブチリル｝イソオキサゾール塩酸塩７．
５ｇを得た。 得られた化合物の分析結果： 融点：１５８〜１５９．５℃ ［α］20 D ＝＋２９゜（Ｃ＝０．５、水） 実施例４ ［（１Ｒ，２Ｒ）−５−｛１−ヒドロキシ−２−（１−
ピロリジニルメチル）ブチル｝−３−フェニルイソオキ
サゾール塩酸塩（化合物）の製造］（Ｒ）−３−フェニ
ル−５−｛２−（１−ピロリジニルメチル）ブチリル｝
イソオキサゾール７ｇをエタノール１００ｍｌに溶解し
た。得られた溶液に、水素化ホウ素ナトリウム１．０ｇ
を室温下に徐々に加えた後、室温下で２時間攪拌した。
反応混合物にアセトン２０ｍｌを更に加えてから、溶媒
を減圧留去し、残渣に水１５０ｍｌを加え、攪拌した。
得られた反応液にジエチルエーテル２０ｍｌでの抽出を
行った。有機相をとり、水１００ｍｌで２回、飽和食塩
水１００ｍｌで１回洗浄した。洗浄された有機相を更に
無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムを
濾別し、濾液を減圧留去して５−｛１−ヒドロキシ−２
−（１−ピロリジニルメチル）ブチル｝−３−フェニル
イソオキサゾールの光学異性体ＲＲとＳＲの混合物が油
状物として得られた。A 12% aqueous solution of sodium hypochlorite was added dropwise to the reaction solution so that the amount of the compound added was 156 g. The internal temperature of the reaction solution was cooled to 10 ° C, and the whole amount of a solution prepared by dissolving 2.8 g of pyridine hydrochloride in 12 ml of water was added dropwise while maintaining the reaction temperature at 15 to 20 ° C. After completion of dropping, the reaction solution was stirred for 70 minutes. The reaction solution was separated, the dichloromethane solution in the lower phase was taken, 100 ml of a 5% aqueous sodium hydrogen sulfite solution was added, and the mixture was stirred for 30 minutes.
The mixture was separated, and the dichloromethane phase was mixed with 100 ml of water, 1
It was washed with 100 ml of N hydrochloric acid aqueous solution. The washed dichloromethane phase was separated and concentrated under reduced pressure. The obtained residue was recrystallized from 40 ml of methanol to give 3-phenyl-5-
Butyryl isoxazole 10.6 g (yield 59.6
%) Was obtained. Analysis result of the obtained compound: Melting point: 89 to 90 ° C. Reference Example 4 [Production of 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole] 3-phenyl-5-butyryl 20 g of isoxazole (93 mmo
l) and 7.93 g (111 mol) of pyrrolidine were added to 62 g of methanol. The resulting reaction solution was stirred, and while maintaining the internal temperature at 20 to 30 ° C., a 37% formalin aqueous solution was added thereto at an amount of 9.04 g (111 mmo).
l) was added dropwise. After dropping, the internal temperature is 20 ~
The mixture was stirred for 1 hour while maintaining the temperature at 30 ° C. The reaction solution was placed in a separating funnel, 178 g of butyl acetate was added, and the mixture was stirred. After liquid separation and removal of the organic phase, adding 50 ml of water and washing three times,
It was dried over sodium sulfate. The solvent was distilled off from the organic phase under reduced pressure, and white crystals of 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole 20.3
g was obtained. (Yield 73%) Analysis result of the obtained compound: Melting point: 68 to 69 ° C. Example 3 [5- {1-hydroxy-2- (1-pyrrolidinylmethyl) butyl} -3-phenylisoxazole hydrochloride Production of Salt (Compound 2)] 3-Phenyl-5- {2- (1-
Pyrrolidinylmethyl) butyryl} isoxazole 6.
9 g (23 mmol) was dissolved in 100 ml of ethanol. Sodium borohydride 0.97 was added to the obtained solution.
g was gradually added at room temperature and then stirred at room temperature for 2 hours. After adding 20 ml of acetone to the obtained reaction mixture, the solvent was distilled off under reduced pressure, 150 ml of water was added to the residue, and the mixture was stirred. After stirring, 20 ml of diethyl ether was added for extraction. The organic phase was collected and washed twice with 100 ml of water and once with 100 ml of saturated saline. The washed organic phase was dried over anhydrous sodium sulfate. Next, sodium sulfate was filtered off from the organic phase, the filtrate was distilled off under reduced pressure, and 5-
{1-Hydroxy-2- (1-pyrrolidinylmethyl) butyryl} -3-phenylisoxazole was obtained as an oil. This oily substance was applied to a silica gel column, and chloroform / methanol / ethyl acetate (volume ratio: 10: 1:
1) Elution with a mixed solvent. The first fraction was collected and the solvent was distilled off under reduced pressure. 150 ml of water was added to the concentrated residue and the mixture was made neutral with an aqueous sodium carbonate solution. Ethyl ether was added to the resulting solution for extraction. The layers were separated, the organic phase was taken, and washed with water and an aqueous solution of sodium carbonate. The washed organic phase was separated, dried over anhydrous aluminum sulfate, and then the solvent was distilled off under reduced pressure to obtain an oily residue. This oily substance was dissolved in 15 ml of methanol, and 10% hydrochloric acid-methanol solution was added in excess while stirring. The reaction solution was concentrated under reduced pressure. The residue was dried under reduced pressure at room temperature to give 5- {1-hydroxy-
1.3 g of 2- (1-pyrrolidinylmethyl) butyl} isoxazole hydrochloride was obtained. Analysis result of the obtained compound: Melting point: 102 to 104 ° C. Reference Example 5 [(R) -3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole L-camphorsulfonate Production] 3-phenyl-5- {2- (1-
Pyrrolidinylmethyl) butyryl} isoxazole 20
g was dissolved in 150 ml of ethyl acetate, 43.7 g of L-camphorsulfonic acid was added, and the mixture was heated to 50 to 60 ° C. to be dissolved. The reaction solution was cooled to 10 ° C with stirring. The crystals precipitated by cooling were collected by filtration and washed with ethyl acetate. The crystals are dried under reduced pressure and then (R) -3-phenyl-5-
21.3 g of L-camphorsulfonate of {2- (1-pyrrolidinylmethyl) butyryl} isoxazole was obtained. Analysis results of the obtained compound: Optical purity: 98.7% ee Melting point: 115.8-116.3 ° C [α] 20 D = -14.4 ° (C = 0.5, ethanol) Reference Example 6 [ Production of (R) -3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole hydrochloride]
20 g of L-camphorsulfonate of (R) -3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole was added to 150 ml of water and 150 ml of chloroform.
It was added to the mixed solution of ml and stirred. 97 ml of a 10% sodium carbonate aqueous solution was added dropwise to this mixed solution. 10 reaction liquids
After stirring for 1 minute, the layers were separated to obtain an organic phase. The obtained organic phase was washed with a 10% aqueous sodium carbonate solution and water in this order.
While maintaining the internal temperature at 10 ° C. or lower, 90 ml of 2N hydrochloric acid aqueous solution was added dropwise to the organic phase. The organic phase obtained by liquid separation was dried over sodium sulfate. Sodium sulfate was removed from the organic phase by filtration, and 300 ml of ethyl acetate was gradually added with stirring while cooling the filtrate to 5 ° C. The precipitated crystals are collected by filtration,
It was washed with a small amount of ethyl acetate. The crystals are dried under reduced pressure, and the desired (R) -3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole hydrochloride 7.
5 g was obtained. Analysis result of the obtained compound: Melting point: 158 to 159.5 ° C. [α] 20 D = + 29 ° (C = 0.5, water) Example 4 [(1R, 2R) -5- {1-hydroxy- 2- (1-
Production of pyrrolidinylmethyl) butyl} -3-phenylisoxazole hydrochloride (compound)] (R) -3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl}
7 g of isoxazole was dissolved in 100 ml of ethanol. 1.0 g of sodium borohydride was added to the obtained solution.
Was gradually added at room temperature and then stirred at room temperature for 2 hours.
After 20 ml of acetone was further added to the reaction mixture, the solvent was distilled off under reduced pressure, 150 ml of water was added to the residue, and the mixture was stirred.
The obtained reaction liquid was extracted with 20 ml of diethyl ether. The organic phase was collected and washed twice with 100 ml of water and once with 100 ml of saturated saline. The washed organic phase was further dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off and the filtrate was evaporated under reduced pressure to give 5- {1-hydroxy-2.
A mixture of optical isomers RR and SR of-(1-pyrrolidinylmethyl) butyl} -3-phenylisoxazole was obtained as an oil.
【００２１】この油状物をシリカゲルカラムにかけ、ク
ロロホルム／メタノール／酢酸エチル（容量比；１０：
１：１）混合溶媒で溶出した。有機物を含む三つのフラ
クションのうちの３番目のフラクションを取り、減圧下
に溶媒を留去した。この３番目のフラクションの濃縮残
渣に水１５０ｍｌを加え、炭酸ナトリウム水溶液で中性
にした。得られた溶液にエチルエーテル１５０ｍｌを加
え抽出した。分液して有機相を取り、水、炭酸ソーダ水
溶液で洗浄した。洗浄された有機相を分液し、無水硫酸
アルミニウムで乾燥した。乾燥後の有機相から溶媒を減
圧留去して、０．９９ｇの油状の残渣を得た。この油状
物をシリカゲルカラムにかけクロロホルムで溶出させて
精製した。 得られた化合物の分析結果： ＮＭＲ（ｄppm、ＣＤＣｌ3）：０．８〜０．９（３Ｈ，
ｍ）；１．１〜１．２（１Ｈ，ｍ）；１．３〜１．４
（１Ｈ，ｍ）；１．７〜１．９（３Ｈ，ｍ）；２．０〜
２．１（１Ｈ，ｍ）；２．５〜３．０（６Ｈ，ｍ）；
４．８〜４．９（１Ｈ，ｄ）；６．６（１Ｈ，ｓ）；
７．３（１Ｈ，ｓ）；７．４〜７．５（２Ｈ，ｍ）；
７．８〜７．９（２Ｈ，ｍ） 更に実施例３の方法に従い白色無定形の塩酸塩１．０５
ｇを得た。This oily substance was applied to a silica gel column and chloroform / methanol / ethyl acetate (volume ratio: 10:
Elution with 1: 1) mixed solvent. The third fraction of the three fractions containing organic matter was taken and the solvent was distilled off under reduced pressure. To the concentrated residue of this third fraction, 150 ml of water was added and neutralized with an aqueous sodium carbonate solution. 150 ml of ethyl ether was added to the resulting solution for extraction. The layers were separated, the organic phase was taken, and washed with water and an aqueous solution of sodium carbonate. The washed organic phase was separated and dried over anhydrous aluminum sulfate. The solvent was distilled off from the dried organic phase under reduced pressure to obtain 0.99 g of an oily residue. The oil was purified by applying it to a silica gel column and eluting with chloroform. Analysis results of the obtained compound: NMR (d ppm , CDCl 3 ): 0.8 to 0.9 (3H,
m); 1.1 to 1.2 (1H, m); 1.3 to 1.4
(1H, m); 1.7 to 1.9 (3H, m); 2.0 to
2.1 (1H, m); 2.5-3.0 (6H, m);
4.8-4.9 (1H, d); 6.6 (1H, s);
7.3 (1H, s); 7.4-7.5 (2H, m);
7.8 to 7.9 (2H, m) Further according to the method of Example 3, white amorphous hydrochloride 1.05
g was obtained.
【００２２】実施例５ ［（１Ｓ，２Ｒ）−５−｛１−ヒドロキシ−２−（１−
ピロリジニルメチル）ブチル｝−３−フェニルイソオキ
サゾール塩酸塩（化合物４）の製造］実施例４のシリカ
ゲルカラムから得られた１番目のフラクションから減圧
下に溶媒を留去し、得られた濃縮残渣に水１５０ｍｌを
加え、更に炭酸ナトリウム水溶液を加えて中性にした。
得られた溶液に、エチルエーテル１５０ｍｌを加え抽出
した。分液し有機相を取り、水、炭酸ナトリウム水溶液
で洗浄した。洗浄した有機相を、無水硫酸アルミニウム
で乾燥した後、溶媒を減圧留去して（１Ｓ，２Ｒ）−５
−｛１−ヒドロキシ−２−（１−ピロリジニルメチル）
ブチル｝−３−フェニルイソオキサゾールの白色結晶
１．７ｇを得た。 得られた化合物の分析結果： 融点：７０〜７１℃ ＮＭＲ（ｄppm、ＣＤＣｌ3）：０．９〜１．１（３Ｈ，
ｍ）；１．１〜１．２（１Ｈ，ｍ）；１．２〜１．４
（１Ｈ，ｍ）；１．７〜１．９（４Ｈ，ｍ）；２．２〜
２．９（６Ｈ，ｍ）；５．０〜５．１（１Ｈ，ｄ）；
６．５（１Ｈ，ｓ）；７．２（１Ｈ，ｓ）；７．４〜
７．５（２Ｈ，ｍ）；７．８〜７．９（２Ｈ，ｍ） この化合物から実施例３の方法に従って塩酸塩を合成し
た。Example 5 [(1S, 2R) -5- {1-hydroxy-2- (1-
Production of Pyrrolidinylmethyl) butyl} -3-phenylisoxazole Hydrochloride (Compound 4)] The solvent was distilled off from the first fraction obtained from the silica gel column of Example 4 under reduced pressure, and the obtained concentration was obtained. 150 ml of water was added to the residue, and an aqueous sodium carbonate solution was further added to neutralize the residue.
150 ml of ethyl ether was added to the resulting solution for extraction. The layers were separated, the organic phase was taken, and washed with water and an aqueous sodium carbonate solution. The washed organic phase was dried over anhydrous aluminum sulfate, and the solvent was distilled off under reduced pressure (1S, 2R) -5.
-{1-hydroxy-2- (1-pyrrolidinylmethyl)
1.7 g of white crystals of butyl} -3-phenylisoxazole were obtained. Analysis result of the obtained compound: Melting point: 70 to 71 ° C. NMR (d ppm , CDCl 3 ): 0.9 to 1.1 (3H,
m); 1.1 to 1.2 (1H, m); 1.2 to 1.4
(1H, m); 1.7-1.9 (4H, m); 2.2
2.9 (6H, m); 5.0-5.1 (1H, d);
6.5 (1H, s); 7.2 (1H, s); 7.4-
7.5 (2H, m); 7.8-7.9 (2H, m) From this compound, the hydrochloride salt was synthesized according to the method of Example 3.
【００２３】参考例７ ［（Ｓ）−３−フェニル−５−｛（２−ピロリジニルメ
チル）ブチリル｝イソオキサゾール塩酸塩の製造］参考
例５、６と同様にしてＤ−カンファスルホン酸を用いて
１０ｇの３−フェニル−５−｛２−（１−ピロリジニル
メチル）ブチリル｝イソオキサゾールを光学分割し、そ
の（Ｓ）体３．７ｇを得た。（収率３７％） 得られた化合物の分析結果： 光学純度 ９９．８％ｅｅ 実施例６ ［（１Ｓ，２Ｓ）−３−フェニル−５−｛１−ヒドロキ
シ−２−（１−ピロリジニル）ブチル｝イソオキサゾー
ル塩酸塩の製造］実施例４と同様にして、（Ｓ）−３−
フェニル−５−｛２−（１−ピロリジニルメチル）ブチ
リル｝イソオキサゾールを水素化ホウ素ナトリウムで還
元し、カラムを用いて（１Ｓ，２Ｓ）体を分離した。 得られた化合物の分析結果： 融点：４１．７〜４２．４℃ ＮＭＲ（ｄppm、ＣＤＣｌ3）：０．８〜０．９（３Ｈ，
ｍ）；１．１〜１．２（１Ｈ，ｍ）；１．３〜１．４
（１Ｈ，ｍ）；１．７〜１．９（３Ｈ，ｍ）；２．０〜
２．１（１Ｈ，ｍ）；２．５〜３．０（６Ｈ，ｍ）；
４．８〜４．９（１Ｈ，ｄ）；６．６（１Ｈ，ｓ）；
７．３（１Ｈ，ｓ）；７．４〜７．５（２Ｈ，ｍ）；
７．８〜７．９（２Ｈ，ｍ） 更に、実施例３に従ってこの化合物の塩酸塩を合成し
た。Reference Example 7 [Production of (S) -3-phenyl-5-{(2-pyrrolidinylmethyl) butyryl} isoxazole hydrochloride] D-camphorsulfonic acid was prepared in the same manner as in Reference Examples 5 and 6. Using 10 g of 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole, the compound was optically resolved to obtain 3.7 g of its (S) form. (Yield 37%) Analysis result of the obtained compound: Optical purity 99.8% ee Example 6 [(1S, 2S) -3-phenyl-5- {1-hydroxy-2- (1-pyrrolidinyl) butyl] } Production of isoxazole hydrochloride] In the same manner as in Example 4, (S) -3-
Phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole was reduced with sodium borohydride, and the (1S, 2S) form was separated using a column. Analysis results of the obtained compound: Melting point: 41.7 to 42.4 ° C NMR (d ppm , CDCl 3 ): 0.8 to 0.9 (3H,
m); 1.1 to 1.2 (1H, m); 1.3 to 1.4
(1H, m); 1.7 to 1.9 (3H, m); 2.0 to
2.1 (1H, m); 2.5-3.0 (6H, m);
4.8-4.9 (1H, d); 6.6 (1H, s);
7.3 (1H, s); 7.4-7.5 (2H, m);
7.8-7.9 (2H, m) Further, the hydrochloride salt of this compound was synthesized according to Example 3.
【００２４】実施例７ ［（１Ｒ，２Ｓ）−３−フェニル−５−｛１−ヒドロキ
シ−２−（１−ピロリジニル）ブチル｝イソオキサゾー
ル塩酸塩の製造］実施例４と同様にして（Ｓ）−３−フ
ェニル−５−｛２−（１−ピロリジニルメチル）ブチリ
ル｝イソオキサゾールを水素化ホウ素ナトリウムで還元
し、実施例５と同様にしてカラムを用いてその（１Ｒ，
２Ｓ）体を分離した。 得られた化合物の分析結果： 融点：６９．４〜７０．２℃ ＮＭＲ（ｄppm、ＣＤＣｌ3）：０．９〜１．１（３Ｈ，
ｍ）；１．１〜１．２（１Ｈ，ｍ）；１．２〜１．４
（１Ｈ，ｍ）；１．７〜１．９（４Ｈ，ｍ）；２．２〜
２．９（６Ｈ，ｍ）；５．０〜５．１（１Ｈ，ｄ）；
６．５（１Ｈ，ｓ）；７．２（１Ｈ，ｓ）；７．４〜
７．５（２Ｈ，ｍ）；７．８〜７．９（２Ｈ，ｍ） 更に、実施例３に従って塩酸塩を合成した。Example 7 [Production of (1R, 2S) -3-phenyl-5- {1-hydroxy-2- (1-pyrrolidinyl) butyl} isoxazole hydrochloride] In the same manner as in Example 4 (S) -3-Phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole was reduced with sodium borohydride and the column (1R,
2S) bodies were separated. Analysis result of the obtained compound: Melting point: 69.4 to 70.2 ° C NMR (d ppm , CDCl 3 ): 0.9 to 1.1 (3H,
m); 1.1 to 1.2 (1H, m); 1.2 to 1.4
(1H, m); 1.7-1.9 (4H, m); 2.2
2.9 (6H, m); 5.0-5.1 (1H, d);
6.5 (1H, s); 7.2 (1H, s); 7.4-
7.5 (2H, m); 7.8 to 7.9 (2H, m) Further, the hydrochloride was synthesized according to Example 3.
【００２５】実施例８ ［中枢性筋弛緩作用試験］本発明のイソキサゾ−ル誘導
体の中枢性筋弛緩作用をラットの除脳固縮モデルを用い
て評価した。ウィスター系雄性ラット（体重３００〜３
５０ｇ）を、一群３〜５匹で使用した。エーテル麻酔下
に、ラット脳の上丘下丘間に相当する部位を、電気的に
破壊して、固縮モデルを作製した（Ｈ．Ｏｎｏ ｅｔａ
ｌ．，Ｇｅｎｅｒａｌ Ｐｈａｒｍａｃｏｌ．１８，５
７（１９８７）参照）。固縮出現後に、試験化合物を静
脈内投与し、固縮の強さの変化を観察した。 試験化合物は、３ mg/kgを静脈内投与した。結果を表１
に示した。Example 8 [Central muscle relaxant action test] The central muscle relaxant action of the isoxazol derivative of the present invention was evaluated using a rat decerebral rigidity model. Wistar male rats (weight 300 to 3
50 g) was used in groups of 3-5. Under ether anesthesia, the region corresponding to the superior colliculus of the rat brain was electrically destroyed to prepare a rigid model (H. Ono eta.
l. , General Pharmacol. 18 , 5
7 (1987)). After the appearance of rigidity, the test compound was intravenously administered, and changes in the strength of rigidity were observed. The test compound was intravenously administered at 3 mg / kg. The results are shown in Table 1.
It was shown to.
【００２６】実施例７ ［排尿反射抑制作用試験］ウィスター系雄性ラット（体
重３００〜３５０ｇ）を、一群３匹で使用した。ウレタ
ン１．５ｇ／ｋｇを皮下投与し、膀胱にバルーンカテー
テルを挿入した。バルーン内に０．２５〜０．５ｍｌの
蒸留水を注入し、この時発現する膀胱の自動運動による
膀胱内圧の変化を記録した。試験化合物３ｍｇ／ｋｇを
総頸静脈より投与し、試験化合物の効果を、排尿反射に
よって生じる膀胱反射の消失時間で表した。結果を表１
に示した。Example 7 [Test for action of suppressing micturition reflex] Male Wistar rats (body weight: 300 to 350 g) were used in groups of 3 animals. Urethane 1.5 g / kg was subcutaneously administered, and a balloon catheter was inserted into the bladder. 0.25 to 0.5 ml of distilled water was injected into the balloon, and changes in the intravesical pressure due to the automatic movement of the bladder that occurred at this time were recorded. The test compound (3 mg / kg) was administered through the common jugular vein, and the effect of the test compound was expressed by the disappearance time of the bladder reflex caused by the micturition reflex. The results are shown in Table 1.
It was shown to.
【００２７】実施例９ ［急性毒性試験］ｄｄｙ系雄性マウス（体重２５〜３０
ｇ）を、一群１０匹で使用した。試験化合物を静脈内投
与し、７日以内に死亡したマウスの数を数えた。５０％
致死量ＬＤ50（ｍｇ／ｋｇ）を算出した。結果を表１に
示した。なお、対照として、試験化合物の投与用溶液を
調製するための溶媒のみを投与した。Example 9 [Acute toxicity test] Male ddy mice (body weight: 25-30)
g) was used in groups of 10 animals. The test compound was administered intravenously, and the number of mice that died within 7 days was counted. 50%
The lethal dose LD 50 (mg / kg) was calculated. The results are shown in Table 1. As a control, only the solvent for preparing a solution for administration of the test compound was administered.
【００２８】[0028]
【表１】 [Table 1]
Claims (5)
基を、Ｒ2及びＲ3はそれぞれ独立して炭素数が１〜４の
アルキル基を示すか又は窒素原子と共に脂環式５員環ま
たは６員環を形成する）で表されるアミノアルコール誘
導体及びその生理学的に許容される塩。1. The following general formula (I): (In the formula, R 1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 2 and R 3 each independently represent an alkyl group having 1 to 4 carbon atoms, or an alicyclic group together with a nitrogen atom. Forming a 5-membered ring or a 6-membered ring) and a physiologically acceptable salt thereof.
素原子と共にピロリジン環を形成する特許請求項１に記
載のアミノアルコール誘導体及びその生理学的に許容さ
れる塩。2. The amino alcohol derivative according to claim 1, wherein R 1 is an ethyl group, and R 2 and R 3 form a pyrrolidine ring together with a nitrogen atom, and a physiologically acceptable salt thereof.
素原子と共にピペリジン環を形成する特許請求項１に記
載のアミノアルコール誘導体及びその生理学的に許容さ
れる塩。3. The aminoalcohol derivative according to claim 1, wherein R 1 is a methyl group, and R 2 and R 3 form a piperidine ring together with a nitrogen atom, and a physiologically acceptable salt thereof.
誘導体又はその生理学的に許容される塩を有効成分とす
る筋弛緩剤。4. A muscle relaxant comprising the aminoalcohol derivative according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.
誘導体又はその生理学的に許容される塩を有効成分とす
る頻尿治療剤。5. A therapeutic agent for frequent urination comprising the amine alcohol derivative according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5157041A JP2986652B2 (en) | 1993-06-28 | 1993-06-28 | Amino alcohol derivatives and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5157041A JP2986652B2 (en) | 1993-06-28 | 1993-06-28 | Amino alcohol derivatives and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0710851A true JPH0710851A (en) | 1995-01-13 |
| JP2986652B2 JP2986652B2 (en) | 1999-12-06 |
Family
ID=15640905
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| Country | Link |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6473267B2 (en) | 1999-12-01 | 2002-10-29 | Matsushita Electric Industrial Co., Ltd. | Floppy disk drive unit with mounting plate between carriage and lower magnetic head |
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1993
- 1993-06-28 JP JP5157041A patent/JP2986652B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6473267B2 (en) | 1999-12-01 | 2002-10-29 | Matsushita Electric Industrial Co., Ltd. | Floppy disk drive unit with mounting plate between carriage and lower magnetic head |
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