JPH0569107B2 - - Google Patents
Info
- Publication number
- JPH0569107B2 JPH0569107B2 JP60127210A JP12721085A JPH0569107B2 JP H0569107 B2 JPH0569107 B2 JP H0569107B2 JP 60127210 A JP60127210 A JP 60127210A JP 12721085 A JP12721085 A JP 12721085A JP H0569107 B2 JPH0569107 B2 JP H0569107B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- oxazolidin
- diphenyl
- group
- Prior art date
- 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.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 64
- 239000000126 substance Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 125000005905 mesyloxy group Chemical group 0.000 claims description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 2
- -1 (4RS,5RS)-4,5-diphenyl-3-(3- piperidinopropyl)-1,3-oxazolidin-2-one Chemical compound 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 5
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 208000007502 anemia Diseases 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 230000002040 relaxant effect Effects 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000009881 Decerebrate State Diseases 0.000 description 3
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- GIZSHQYTTBQKOQ-UHFFFAOYSA-N threo-Syringoylglycerol Chemical compound COC1=CC(C(O)C(O)CO)=CC(OC)=C1O GIZSHQYTTBQKOQ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OBOBUDMMFXRNDO-UHFFFAOYSA-N 1-(3-chloropropyl)piperidine;hydron;chloride Chemical compound Cl.ClCCCN1CCCCC1 OBOBUDMMFXRNDO-UHFFFAOYSA-N 0.000 description 2
- VDQIPIMKSTXOFE-UHFFFAOYSA-N 4-methyl-5-phenyl-3-(2-piperidin-1-ylethyl)-1,3-oxazolidin-2-one;hydrochloride Chemical compound Cl.CC1C(C=2C=CC=CC=2)OC(=O)N1CCN1CCCCC1 VDQIPIMKSTXOFE-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- GQEZLLGQUIRVHL-UHFFFAOYSA-N 1-(3-chloropropyl)azepane;hydrochloride Chemical compound Cl.ClCCCN1CCCCCC1 GQEZLLGQUIRVHL-UHFFFAOYSA-N 0.000 description 1
- UUPCYQIIQHSPKR-UHFFFAOYSA-N 1-(3-chloropropyl)pyrrolidine;hydrochloride Chemical compound Cl.ClCCCN1CCCC1 UUPCYQIIQHSPKR-UHFFFAOYSA-N 0.000 description 1
- FSKFPVLPFLJRQB-UHFFFAOYSA-N 2-methyl-1-(4-methylphenyl)-3-(1-piperidinyl)-1-propanone Chemical compound C=1C=C(C)C=CC=1C(=O)C(C)CN1CCCCC1 FSKFPVLPFLJRQB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LTENIVFVXMCOQI-UHFFFAOYSA-N 4,5-diphenyl-1,3-oxazolidin-2-one Chemical compound O1C(=O)NC(C=2C=CC=CC=2)C1C1=CC=CC=C1 LTENIVFVXMCOQI-UHFFFAOYSA-N 0.000 description 1
- IVQWDVWFSJCQGK-UHFFFAOYSA-N 4-methyl-5-phenyl-3-(2-pyrrolidin-1-ylethyl)-1,3-oxazolidin-2-one Chemical compound CC1C(C=2C=CC=CC=2)OC(=O)N1CCN1CCCC1 IVQWDVWFSJCQGK-UHFFFAOYSA-N 0.000 description 1
- HGGKFQZBFBTUAE-UHFFFAOYSA-N 4-methyl-5-phenyl-3-(2-pyrrolidin-1-ylethyl)-1,3-oxazolidin-2-one;hydrochloride Chemical compound Cl.CC1C(C=2C=CC=CC=2)OC(=O)N1CCN1CCCC1 HGGKFQZBFBTUAE-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 210000000103 occipital bone Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960005334 tolperisone Drugs 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 231100000691 up-and-down procedure Toxicity 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- 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)
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は次の一般式（）
【化】
（式中、R1、R2およびR3は水素原子を示し、ｎ
は４、５または６を示す）
で表わされる１，３−オキサゾリジン−２−オン
誘導体およびその酸付加塩の製造法に関する。
〔従来の技術及び発明が解決しようとする問題
点〕
本発明者らは新規な医薬品を提供せんと種々の
オキサゾリジン−２−オン誘導体を合成し、その
医薬効果を検討していたところ（）式で表わさ
れるオキサゾリジン−２−オン誘導体が優れた中
枢性筋弛緩作用すなわち貧血性除脳固縮に対する
固縮緩解作用を有していることを見い出した。
本発明化合物と構造的に類似する化合物として
は、すでに４−メチル−５−フエニル−３−（２
−ピベリジノエチル）−１，３−オキサゾリジン
−２−オン〔Zikolovaら：Farmatsiya（Sofia）、
14、16−21（1964）及びNikolova：Izv.Inst.
Fiziol.Bulg.Akad.Nank.、12、217−226
（1969）〕、及び４−メチル−５−フエニル−３−
（２−ピロリジノエチル）−１，３−オキサゾリジ
ン−２−オン〔Zikolovaら：Farmatsiya
（Sofia）、14、16−21（1964）〕が知られている。
しかしながら、Zikolovaらはこれらの化合物
の薬理作用については全く報告しておらず、また
Nikolovaは、４−メチル−５−フエニル−３−
２−ピベリジノエチル）−１，３−オキサゾリジ
ン−２−オンは鎮痛作用を有するが、抗痙攣作用
及び中枢性筋弛緩作用はないと報告している。そ
して、後述するように、本発明者の実験において
も、上記公知化合物の中枢性筋弛緩作用は極めて
弱いものである。
〔問題点を解決するための手段〕
従つて、本発明は、優れた固縮緩解作用を有
し、医薬品として有用な、上記一般式（）で表
わされる新規な１，３−オキサゾリジン−２−オ
ン誘導体を提供するものである。
更にまた、本発明は、１，３−オキサゾリジン
−２−オン誘導体を製造するための新規な製造法
を提供するものである。
また、（）式の化合物には、シス体（4RS，
5SR）、トランス体（4RS，5RS）の立体異性体
及び（4R，5S）、（4S，5R）、（4R，5R）、（4S，
5S）の光学異性体があるが、これらの異性体は
何れも本発明に含まれるものである。
本発明化合物は、例えば次に示す何れかの方法
によつて製造される。
方法１：
化合物（）に化合物（）を反応せしめて本
発明化合物（）を製造する。
【化】
【化】
（式中、R1、R2およびR3は水素原子を示し、ｎ
は４、５または６を示し、Ｘはハロゲン原子、ト
シルオキシ基、メシルオキシ基またはアセトキシ
基のような脱離基を示す）
化合物（）と化合物（）との反応は、炭酸
カリウムまたは炭酸ナトリウム等の弱塩基の存在
下、アセトン、メチルエチルケトン、メチルイソ
ブチルケトン等の有機溶媒中、50℃〜還流温度で
行われる。
反応に際して化合物（）は、化合物（）に
対して１〜２倍モル、炭酸カリウム、炭酸ナトリ
ウム等の弱塩基は２倍モル以上使用するのが好ま
しく、反応温度は２〜50時間が好ましい。また化
合物（）は安定な塩酸塩の形で使用するのが好
ましい。
方法２：
化合物（）に化合物（）または化合物
（）を反応せしめて本発明化合物（）を製造
する。
【化】
【化】
（式中Ｙはハロゲン原子、またはトリクロロメチ
ルオキシ基を示し、R4は低級アルキル基を示し、
R1、R2、R3およびｎは前記と同じ）
反応は水酸化ナトリウム等のアルカリの存在
下、エーテル、クロロホルム等の有機溶媒と水と
の不均一溶媒中で−10〜10℃の温度で行われる。
反応に際して、化合物（）または化合物（）
は化合物（）に対して２〜４倍モル用いるのが
好ましく、反応時間は0.5〜２時間が好ましい。
方法３：
化合物（）に化合物（）を反応せしめて化
合物（）となし、次いでこれを塩基の存在下加
熱して環化せしめて本発明化合物（）を製造す
る。
【化】
【化】
【化】
（式中、R5は低級アルキル基を示し、R1、R2、
R3、およびｎは前記と同じ）
化合物（）と化合物（）の反応は、水酸化
ナトリウム等の存在下、エーテル、クロロホルム
等の有機溶媒と水との不均一溶媒中で−５〜15℃
の温度で行われる。化合物（）の環化はナトリ
ウムメトキシド、ナトリウムエトキシド、アルミ
ニウムイソプロポキシド等の塩基の存在下、トル
エン、キシレン等の溶媒中で100〜140℃で加熱す
ることにより行われる。
反応に際して化合物（）は化合物（）に対
して１〜２モル使用するのが好ましく、反応時間
は0.5〜２時間が好ましい。
原料の式および式の化合物は例えば次の反
応式によつて示される方法によつて製造される。
【化】
【化】
【化】
【化】
（式中、R1、R2、R3、Ｙおよびｎは前記と同じ）
化合物（）は、化合物（）にフタルイミド
カリウム等を反応させることにより製造される。
化合物（XI）は、化合物（）を水素化シアノ
ホウ素ナトリウムあるいはアルミニウムイソプロ
ポキサイド等の還元剤を用いて還元することによ
り製造される。
化合物（）は、化合物（XI）に抱水ヒドラジ
ン等を用いて脱フタリル化することにより製造さ
れる。
化合物（）は、化合物（）に化合物（）
を反応せしめることにより製造される。
化合物（）は、化合物（）に化合物（）
を反応せしめることにより製造される。
なお、化合物（）のエリスロ体又はスレオ体
を得るには、化合物（）のエリスロ体又はスレ
オ体が優先的に得られる方法を採用するか、又は
化合物（XI）のエリスロ体とスレオ体の混合物を
分離する方法を採用する。
斯くして得られる１，３−オキサゾリジン−２
−オン誘導体は、常法により酸との付加塩とする
ことができる。酸付加塩としては、塩酸、臭化水
素酸、硫酸、Ｐ−トリエンスルホン酸、フマル
酸、クエン酸、マレイン酸、シユウ酸などの塩が
挙げられる。
本発明化合物（）の代表的な化合物を挙げれ
ば次のとおりである。
化合物 （4RS，5SR）−４，５−ジフエニル
−３−（３−ピペリジンプロピル）−１，３−オ
キサゾリジン−２−オン
化合物１ （4RS，5RS）−４，５−ジフエニル
−３−（３−ピペリジノプロピル）−１，３−オ
キサゾリジン−２−オン
化合物３ （4S，5R）−４，５−ジフエニル−３
−（３−ピペリジノプロピル）−１，３−オキサ
ゾリジン−２−オン
化合物４ （4S，5S）−４，５−ジフエニル−３
−（３−ピペリジノプロピル）−１，３−オキサ
ゾリジン−２−オン
化合物５ （4R，5S）−４，５−ジフエニル−３
−（３−ピペリジノプロピル）−１，３−オキサ
ゾリジン−２−オン
化合物６ （4R，5R）−４，５−ジフエニル−
３−（３−ピペリジノプロピル）−１，３−オキ
サゾリジン−２−オン
化合物７ （4RS，5SR）−４，５−ジフエニル
−３−（３−ピロリジノプロピル）−１，３−オ
キサゾリジン−２−オン
化合物８ （4RS，5RS）−４，５−ジフエニル
−３−（３−ピロリジノプロピル）−１，３−オ
キサゾリジン−２−オン
化合物９ （4RS，5SR）−４，５−ジフエニル
−３−〔３−（ペルヒドロアゼピン−１−イル）
プロピル〕−１，３−オキサゾリジン−２−オ
ン
化合物10 （4RS，5RS）−４，５−ジフエニル
−３−〔３−（ペルヒドロアゼピン−１−イル）
プロピル〕−１，３−オキサゾリジン−２−オ
ン
〔作用〕
本発明化合物（）の中枢性筋弛緩作用（貧血
性除脳固縮標本に対する固縮緩解作用）及び毒性
試験の結果は次のとおりである。尚比較化合物と
しては、次の化合物を用いた。
比較化合物１ 塩酸トルペリゾン
比較化合物２ （4RS，5SR）−４−メチル−５
−フエニル−３−（２−ピペリジノエチル）−
１，３−オキサゾリジン−２−オン塩酸塩
比較化合物３ （4RS，5RS）−４−メチル−５
−フエニル−３−（２−ピペリジノエチル）−
１，３−オキサゾリジン−２−オン塩酸塩
比較化合物４ （4RS，5SR）−４−メチル−５
−フエニル−３−（２−ピロリジノエチル）−
１，３−オキサゾリジン−２−オン塩酸塩
比較化合物５ （4RS，5RS）−４−エチル−５
−フエニル−３−（２−ピロリジノエチル−１，
３−オキサゾリジン−２−オン塩酸塩
実験１ 貧血性除脳固縮に対する作用
貧血性除脳固縮標本は福田ら（Japan.J.
Pharmacol24、810（1974））の手法を原法として
作成した。すなわち、Wistar系雄性ラツト（体
重270〜350ｇ）をエーテル麻酔下背位に固定し頚
部切開後、気管カニユーレを挿入し気管、食道お
よび両側総頚動脈を二重結紮し切断した。次に後
頭骨を露出し、円孔をあけて中央に走る基底動脈
を二重結紮した。ラツトが麻酔から回復するに従
い前肢に固縮状態を呈した。測定は、固縮状態に
あるラツトの前肢上腕、三頭筋より筋パルスを導
出し、これを10秒毎の積算値に変換しヒストグラ
ムとしてレコーダーに記録した。被験物質の作用
は、被験物質の生理食塩水溶液を大腿静脈より投
与（本発明化合物：２mg／Kg、比較化合物：３
mg／Kg）後10分間の抑制率（第１図で示す面積
比）として求めた。
抑制率（％）＝ａ／Ａ×100
ａ：被験物質投与によるヒストグラム減少部分の
面積
Ａ：被験物質未投与時のヒストグラム部の面積
その結果を表１に示す。
【表】
実験２ 急性毒性
ddN雄性マウスを用いて、up and down法によ
り求めた。
被験物質は生理食塩水に溶解し尾静脈より投与
した。
結果を表２に示す。
【表】
〔実施例〕
次に実施例を挙げて説明する。
実施例 １
(1) （4RS，5SR）−４，５−ジフエニル−３−
（３−ピペリジノプロピル）−１，３−オキサゾ
リジン−２−オン：
（4RS，5SR）−４，５−ジフエニル−１，
３−オキサゾリジン−２−オン359mg（1.5ｍ
mol）、塩酸１−（３−クロロプロピル）ピペリ
ジン357mg（1.8ｍmol）、粉末無水炭酸カリウ
ム518mg（3.75ｍmol）およびメチルイソブチ
ルケトン17mlの混合物を攪拌下６時間加熱還流
した。冷後、酢酸エチルを加え、水で３回、飽
和食塩水で１回洗浄し、芒硝で乾燥した。減圧
下溶媒を留去し、残留物をヘキサンから再結晶
して、標題の化合物を淡赤色結晶として440mg
得た（収率80％）。
mp 106.5〜107.5℃
IRνKBr nax（cm-1） 3430、2940、1735、1450、
1420、1235、1020、760、695
NMR（CDCl2）
δ：1.28〜1.92（8H、ｍ、
【式】）
2.12〜2.52（6H、ｍ、
【式】）
2.58〜2.98（1H、ｍ、【式】）
3.44〜3.86（1H、ｍ、【式】）
5.09（1H、ｄ、Ｊ＝８Hz、【式】）
5.82（1H、ｄ、Ｊ＝８Hz、【式】）
6.64〜7.28（10H、ｍ、芳香族水素）
(2) （4RS，5SR）−４，５−ジフエニル−３−
（３−ピペリジノプロピル）−１，３−オキサゾ
リジン−２−オン塩酸塩
上記化合物300mg（0.82ｍmol）をエタノー
ルに溶解し、1.2NHClエタノール溶液（１ml）
を加え、減圧下溶媒を留去した。残留物をエタ
ノール−ヘキサンから再結晶して標題の化合物
を白色結晶として220mg得た（収率67％）。
mp 161〜164℃
IRνKBr nax（cm-1） 2960、1745、1640、1450、
1410、1235、1020、760、710、695
実施例 ２
(1) （4RS，5RS）−４，５−ジフエニル−３−
（３−ピペリジノプロピル）−１，３−オキサゾ
リジン−２−オン
（4RS，5RS）−４，５−ジフエニル−１，
３−オキサゾリジン−２−オン359mg（1.5ｍ
mol）、塩酸１−（３−クロロプロピル）ピペリ
ジン357mg（1.8ｍmol）、粉末無水炭酸カリウ
ム518mg（3.7ｍmol）およびメチルイソブチル
ケトン７mlを用い、実施例１−(1)と同様にして
黄色油状物として465mg得た（収率85％）。
IRνneat nax（cm-1） 2930、2850、2800、2760、
1755、1445、1405、1320、1215、1120、
1035、750、690
NMR（CDCl3）
δ：1.20〜1.96（8H、ｍ、
【式】）
1.96〜2.40（6H、ｍ、
【式】）
2.60〜3.00（1H、ｍ、【式】）
3.28〜3.68（1H、ｍ、【式】）
4.57（1H、ｄ、Ｊ＝７Hz、【式】）
5.23（1H、ｄ、Ｊ＝７Hz、【式】）
7.04〜7.52（10H、ｍ、芳香族水素）
(2) （4RS，5RS）−４，５−ジフエニル−３−
（３−ピペリジノプロピル）−１，３−オキサゾ
リジン−２−オンフマル酸塩
上記化合物465mg（1.28ｍmol）及びフマル
酸149mg（1.28ｍmol）をエタノール（６ml）
に加熱溶解し、減圧下溶媒留去した。残渣をエ
タノール（２ml）−エーテル（４ml）から再結
晶して標題の化合物を淡褐色結晶として400mg
得た（収率65％）。
mp 142〜143℃（分解）
IRνKBr nax（cm-1）：3420、2940、2620、2530、
1750、1680、1610、1455、1410、1330、
1280、1220、980、750、700、640
実施例 ３
(1) （4RS，5SR）−４，５−ジフエニル−３−
（３−ピロリジノプロピル）−１，３−オキサゾ
リジン−２−オン
（4RS，5SR）−４，５−ジフエニル−１，
３−オキサゾリジン−２−オン240mg（1.0ｍ
mol）、塩酸１−（３−クロロプロピル）ピロリ
ジン239mg（1.3ｍmol）、粉末無水炭酸カリウ
ム346mg（2.5ｍmol）およびメチルイソブチル
ケトン３mlを用い、実施例１−(1)と同様にして
淡褐色結晶として253mg得た（収率72.2％）。
mp 104〜106℃
IRνKBr nax（cm-1） 2940、2750、1730、1440、
1410、1225、1200、1140、1010、750、710、
690
NMR（CDCl3）
δ：1.44〜1.96（6H、ｍ、
【式】）
2.08〜2.64（6H、ｍ、【式】）
2.64〜3.00（1H、ｍ、【式】）
3.48〜3.88（1H、ｍ、【式】）
5.06（1H、ｄ、Ｊ＝８Hz、【式】）
5.82（1H、ｄ、Ｊ＝８Hz、【式】）
6.60〜7.28（10H、ｍ、芳香族水素）
(2) （4RS，5SR）−４，５−ジフエニル−３−
（３−ピロリジノプロピル）−１，３−オキサゾ
リジン−２−オン塩酸塩
上記化合物を用い、実施例１−(2)と同様にし
て淡褐色結晶として123mg得た（収率66.6％）。
mp 156〜160℃（分解）
IRνKBr nax（cm-1） 2960、2680、2600、1740、
1630、1450、1410、1230、1025、755、700、
695
実施例 ４
(1) （4RS，5SR）−４，５−ジフエニル−３−
〔３−（ペルヒドロアゼピン−１−イル）プロピ
ル〕−１，３−オキサゾリジン−２−オン
（4RS，5SR）−４，５−ジフエニル−１，
３−オキサゾリジン−２−オン240mg（1.0ｍ
mol）、塩酸１−（３−クロロブロピル）ペルヒ
ドロアゼピン255mg（1.2ｍmol）、粉末無水炭
酸カリウム518mg（3.7ｍmol）およびメチルイ
ソブチルケトン３mlを用い、実施例１−(1)と同
様にして淡褐色結晶として267mg得た（70.5
％）。
mp 98〜99℃
IRνKBr nax（cm-1） 2920、1740、1450、1420、
1235、1030、750、690
NMR（CDCl3）
δ：1.24〜1.84（10H、ｍ、
【式】）
2.12〜2.94（7H、ｍ、
【式】【式】）
3.38〜3.80（1H、ｍ、【式】
5.09（1H、ｄ、Ｊ＝８Hz、【式】
5.82（1H、ｄ、Ｊ＝８Hz、【式】
6.60〜7.24（10H、ｍ、芳香族水素）
(2) （4SR，5SR）−４，５−ジフエニル−３−
〔３−（ペルヒドロアゼピン−１−イル）プロピ
ル〕−１，３−オキサゾリジン−２−オン塩酸
塩
上記化合物を用い、実施例１−(2)と同様にし
て淡褐色結晶として120mg得た（収率41％）。
mp 158〜160℃（分解）
IRνKBr nax（cm-1） 2940、1740、1630、1445、
1405、1230、1030、755、710、695 [Detailed Description of the Invention] [Industrial Application Field] The present invention relates to the following general formula () [Chemical formula] (In the formula, R 1 , R 2 and R 3 represent a hydrogen atom, and n
represents 4, 5 or 6) and a method for producing a 1,3-oxazolidin-2-one derivative and an acid addition salt thereof. [Prior art and problems to be solved by the invention] The present inventors synthesized various oxazolidin-2-one derivatives and investigated their medicinal effects in order to provide novel pharmaceuticals. It has been found that the oxazolidin-2-one derivative represented by has an excellent central muscle relaxing effect, that is, a rigidity-releasing effect on anemic decerebrate rigidity. As a compound structurally similar to the compound of the present invention, 4-methyl-5-phenyl-3-(2
-piveridinoethyl)-1,3-oxazolidin-2-one [Zikolova et al.: Farmatsiya (Sofia),
14, 16-21 (1964) and Nikolova: Izv.Inst.
Fiziol.Bulg.Akad.Nank., 12 , 217−226
(1969)], and 4-methyl-5-phenyl-3-
(2-pyrrolidinoethyl)-1,3-oxazolidin-2-one [Zikolova et al.: Farmatsiya
(Sofia), 14 , 16-21 (1964)]. However, Zikolova et al. have not reported any pharmacological effects of these compounds, and
Nikolova is 4-methyl-5-phenyl-3-
It has been reported that 2-piveridinoethyl)-1,3-oxazolidin-2-one has analgesic effect, but no anticonvulsant or central muscle relaxant effect. As will be described later, in experiments conducted by the present inventors, the central muscle relaxing effect of the above-mentioned known compounds is extremely weak. [Means for Solving the Problems] Therefore, the present invention provides a novel 1,3-oxazolidine-2- represented by the above general formula (), which has an excellent rigidity-reducing effect and is useful as a pharmaceutical. ion derivatives. Furthermore, the present invention provides a novel method for producing 1,3-oxazolidin-2-one derivatives. In addition, the compound of formula () has a cis form (4RS,
5SR), trans stereoisomers (4RS, 5RS) and (4R, 5S), (4S, 5R), (4R, 5R), (4S,
5S), and all of these isomers are included in the present invention. The compound of the present invention can be produced, for example, by any of the following methods. Method 1: The compound () of the present invention is produced by reacting the compound () with the compound (). [C] [C] (In the formula, R 1 , R 2 and R 3 represent hydrogen atoms, and n
(represents 4, 5 or 6, and X represents a leaving group such as a halogen atom, tosyloxy group, mesyloxy group or acetoxy group) It is carried out in the presence of a weak base in an organic solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc. at 50° C. to reflux temperature. In the reaction, it is preferable to use compound () in an amount of 1 to 2 times the mole of compound (), and use a weak base such as potassium carbonate or sodium carbonate in an amount of 2 times or more in mole, and the reaction temperature is preferably 2 to 50 hours. Moreover, it is preferable to use the compound () in the form of a stable hydrochloride. Method 2: Compound () is reacted with compound () or compound () to produce the compound () of the present invention. [C] [C] (In the formula, Y represents a halogen atom or a trichloromethyloxy group, R 4 represents a lower alkyl group,
(R 1 , R 2 , R 3 and n are the same as above) The reaction is carried out in a heterogeneous solvent of water and an organic solvent such as ether or chloroform at a temperature of -10 to 10°C in the presence of an alkali such as sodium hydroxide. It will be held in
During the reaction, the compound () or the compound ()
It is preferable to use 2 to 4 times the mole of compound (2), and the reaction time is preferably 0.5 to 2 hours. Method 3: The compound () is reacted with the compound () to form the compound (), which is then heated in the presence of a base to cyclize it to produce the compound () of the present invention. [C] [C] [C] (In the formula, R 5 represents a lower alkyl group, R 1 , R 2 ,
R 3 and n are the same as above) The reaction between compound () and compound () is carried out at -5 to 15°C in a heterogeneous solvent of water and an organic solvent such as ether or chloroform in the presence of sodium hydroxide, etc.
carried out at a temperature of Cyclization of compound () is carried out by heating at 100 to 140°C in a solvent such as toluene or xylene in the presence of a base such as sodium methoxide, sodium ethoxide, or aluminum isopropoxide. In the reaction, compound () is preferably used in an amount of 1 to 2 moles relative to compound (), and the reaction time is preferably 0.5 to 2 hours. The raw material formula and the compound of the formula are produced, for example, by the method shown by the following reaction formula. [C] [C] [C] [C] [C] (In the formula, R 1 , R 2 , R 3 , Y and n are the same as above) Compound () can be obtained by reacting compound () with potassium phthalimide etc. Manufactured. Compound (XI) is produced by reducing compound () using a reducing agent such as sodium cyanoborohydride or aluminum isopropoxide. Compound () is produced by defthalylating Compound (XI) using hydrazine hydrate or the like. compound() is compound() to compound()
It is produced by reacting. compound() is compound() to compound()
It is produced by reacting. In addition, in order to obtain the erythro form or the threo form of the compound (), a method that preferentially obtains the erythro form or the threo form of the compound (), or a mixture of the erythro form and the threo form of the compound (XI) is used. Adopt a method that separates the 1,3-oxazolidine-2 thus obtained
The -one derivative can be converted into an addition salt with an acid by a conventional method. Examples of acid addition salts include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, P-trienesulfonic acid, fumaric acid, citric acid, maleic acid, oxalic acid, and the like. Representative compounds of the compound () of the present invention are as follows. Compound (4RS,5SR)-4,5-diphenyl-3-(3-piperidinepropyl)-1,3-oxazolidin-2-one Compound 1 (4RS,5RS)-4,5-diphenyl-3-(3- piperidinopropyl)-1,3-oxazolidin-2-one compound 3 (4S,5R)-4,5-diphenyl-3
-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 4 (4S,5S)-4,5-diphenyl-3
-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 5 (4R,5S)-4,5-diphenyl-3
-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 6 (4R,5R)-4,5-diphenyl-
3-(3-Piperidinopropyl)-1,3-oxazolidin-2-one Compound 7 (4RS,5SR)-4,5-diphenyl-3-(3-pyrrolidinopropyl)-1,3-oxazolidine- 2-one compound 8 (4RS,5RS)-4,5-diphenyl-3-(3-pyrrolidinopropyl)-1,3-oxazolidin-2-one compound 9 (4RS,5SR)-4,5-diphenyl- 3-[3-(perhydroazepin-1-yl)
propyl]-1,3-oxazolidin-2-one compound 10 (4RS,5RS)-4,5-diphenyl-3-[3-(perhydroazepin-1-yl)
Propyl]-1,3-oxazolidin-2-one [Action] The central muscle relaxant effect (rigidity-relaxing effect on anemic decerebrate rigidity specimens) and toxicity test results of the compound of the present invention () are as follows. be. The following compounds were used as comparative compounds. Comparative compound 1 Tolperisone hydrochloride Comparative compound 2 (4RS,5SR)-4-methyl-5
-Phenyl-3-(2-piperidinoethyl)-
1,3-oxazolidin-2-one hydrochloride comparison compound 3 (4RS,5RS)-4-methyl-5
-Phenyl-3-(2-piperidinoethyl)-
1,3-oxazolidin-2-one hydrochloride comparison compound 4 (4RS,5SR)-4-methyl-5
-Phenyl-3-(2-pyrrolidinoethyl)-
1,3-oxazolidin-2-one hydrochloride comparison compound 5 (4RS,5RS)-4-ethyl-5
-phenyl-3-(2-pyrrolidinoethyl-1,
3-Oxazolidin-2-one hydrochloride experiment 1 Effect on anemic decerebrate rigidity Anemic decerebrate rigid specimens were prepared by Fukuda et al. (Japan.J.
Pharmacol 24 , 810 (1974)) was used as the original method. That is, a male Wistar rat (weighing 270 to 350 g) was fixed in the dorsal position under ether anesthesia, and after neck incision, a tracheal cannula was inserted, and the trachea, esophagus, and bilateral common carotid arteries were double ligated and cut. Next, the occipital bone was exposed, a circular hole was made, and the basal artery running through the center was double ligated. As the rat recovered from anesthesia, its forelimbs became rigid. For measurements, muscle pulses were derived from the forelimb upper arm and triceps muscles of a rat in a rigid state, converted to integrated values every 10 seconds, and recorded on a recorder as a histogram. The effect of the test substance was determined by administering a physiological saline solution of the test substance through the femoral vein (inventive compound: 2 mg/Kg, comparative compound: 3
mg/Kg) for 10 minutes (area ratio shown in Figure 1). Suppression rate (%) = a / A × 100 a: Area of the histogram portion decreased by administration of the test substance A: Area of the histogram portion when the test substance was not administered The results are shown in Table 1. [Table] Experiment 2 Acute toxicity dd N was determined by the up and down method using male mice. The test substance was dissolved in physiological saline and administered through the tail vein. The results are shown in Table 2. [Table] [Example] Next, examples will be given and explained. Example 1 (1) (4RS,5SR)-4,5-diphenyl-3-
(3-Piperidinopropyl)-1,3-oxazolidin-2-one: (4RS,5SR)-4,5-diphenyl-1,
3-oxazolidin-2-one 359mg (1.5m
A mixture of 357 mg (1.8 mmol) of 1-(3-chloropropyl)piperidine hydrochloride, 518 mg (3.75 mmol) of powdered anhydrous potassium carbonate, and 17 ml of methyl isobutyl ketone was heated under reflux for 6 hours with stirring. After cooling, ethyl acetate was added, washed three times with water and once with saturated brine, and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane to give 440 mg of the title compound as pale red crystals.
(yield 80%). mp 106.5~107.5℃ IRν KBr nax (cm -1 ) 3430, 2940, 1735, 1450,
1420, 1235, 1020, 760, 695 NMR ( CDCl2 ) δ: 1.28-1.92 (8H, m,
[Formula]) 2.12~2.52 (6H, m,
[Formula]) 2.58 to 2.98 (1H, m, [Formula]) 3.44 to 3.86 (1H, m, [Formula]) 5.09 (1H, d, J=8Hz, [Formula]) 5.82 (1H, d, J= 8Hz, [Formula]) 6.64-7.28 (10H, m, aromatic hydrogen) (2) (4RS, 5SR)-4,5-diphenyl-3-
(3-piperidinopropyl)-1,3-oxazolidin-2-one hydrochloride 300 mg (0.82 mmol) of the above compound was dissolved in ethanol, and a 1.2NHCl ethanol solution (1 ml) was added.
was added, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol-hexane to obtain 220 mg of the title compound as white crystals (yield 67%). mp 161-164℃ IRν KBr nax (cm -1 ) 2960, 1745, 1640, 1450,
1410, 1235, 1020, 760, 710, 695 Example 2 (1) (4RS, 5RS)-4,5-diphenyl-3-
(3-piperidinopropyl)-1,3-oxazolidin-2-one (4RS,5RS)-4,5-diphenyl-1,
3-oxazolidin-2-one 359mg (1.5m
A yellow oil was prepared in the same manner as in Example 1-(1) using 357 mg (1.8 mmol) of 1-(3-chloropropyl)piperidine hydrochloride, 518 mg (3.7 mmol) of powdered anhydrous potassium carbonate, and 7 ml of methyl isobutyl ketone. 465 mg was obtained (yield 85%). IRν neat nax (cm -1 ) 2930, 2850, 2800, 2760,
1755, 1445, 1405, 1320, 1215, 1120,
1035, 750, 690 NMR (CDCl 3 ) δ: 1.20 to 1.96 (8H, m, [Formula]) 1.96 to 2.40 (6H, m,
[Formula]) 2.60 to 3.00 (1H, m, [Formula]) 3.28 to 3.68 (1H, m, [Formula]) 4.57 (1H, d, J=7Hz, [Formula]) 5.23 (1H, d, J= 7Hz, [Formula]) 7.04-7.52 (10H, m, aromatic hydrogen) (2) (4RS, 5RS)-4,5-diphenyl-3-
(3-piperidinopropyl)-1,3-oxazolidin-2-one fumarate 465 mg (1.28 mmol) of the above compound and 149 mg (1.28 mmol) of fumaric acid were added to ethanol (6 ml).
The mixture was heated and dissolved, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol (2 ml) and ether (4 ml) to give 400 mg of the title compound as pale brown crystals.
(yield 65%). mp 142-143℃ (decomposition) IRν KBr nax (cm -1 ): 3420, 2940, 2620, 2530,
1750, 1680, 1610, 1455, 1410, 1330,
1280, 1220, 980, 750, 700, 640 Example 3 (1) (4RS, 5SR)-4,5-diphenyl-3-
(3-pyrrolidinopropyl)-1,3-oxazolidin-2-one (4RS,5SR)-4,5-diphenyl-1,
3-oxazolidin-2-one 240mg (1.0m
Light brown crystals were prepared in the same manner as in Example 1-(1) using 239 mg (1.3 mmol) of 1-(3-chloropropyl)pyrrolidine hydrochloride, 346 mg (2.5 mmol) of powdered anhydrous potassium carbonate, and 3 ml of methyl isobutyl ketone. 253 mg was obtained (yield 72.2%). mp 104～106℃ IRν KBr nax (cm -1 ) 2940, 2750, 1730, 1440,
1410, 1225, 1200, 1140, 1010, 750, 710,
690 NMR (CDCl 3 ) δ: 1.44-1.96 (6H, m, [Formula]) 2.08-2.64 (6H, m, [Formula]) 2.64-3.00 (1H, m, [Formula]) 3.48-3.88 (1H, m, [formula]) 5.06 (1H, d, J = 8Hz, [formula]) 5.82 (1H, d, J = 8Hz, [formula]) 6.60-7.28 (10H, m, aromatic hydrogen) (2) ( 4RS, 5SR)-4,5-diphenyl-3-
(3-pyrrolidinopropyl)-1,3-oxazolidin-2-one hydrochloride Using the above compound, 123 mg of pale brown crystals were obtained in the same manner as in Example 1-(2) (yield 66.6%). mp 156-160℃ (decomposition) IRν KBr nax (cm -1 ) 2960, 2680, 2600, 1740,
1630, 1450, 1410, 1230, 1025, 755, 700,
695 Example 4 (1) (4RS,5SR)-4,5-diphenyl-3-
[3-(perhydroazepin-1-yl)propyl]-1,3-oxazolidin-2-one (4RS,5SR)-4,5-diphenyl-1,
3-oxazolidin-2-one 240mg (1.0m
mol), 255 mg (1.2 mmol) of 1-(3-chloropropyl)perhydroazepine hydrochloride, 518 mg (3.7 mmol) of powdered anhydrous potassium carbonate, and 3 ml of methyl isobutyl ketone to produce a light brown color in the same manner as in Example 1-(1). Obtained 267 mg as crystals (70.5
%). mp 98~99℃ IRν KBr nax (cm -1 ) 2920, 1740, 1450, 1420,
1235, 1030, 750, 690 NMR (CDCl 3 ) δ: 1.24 to 1.84 (10H, m, [Formula]) 2.12 to 2.94 (7H, m, [Formula] [Formula]) 3.38 to 3.80 (1H, m, [Formula]) Formula] 5.09 (1H, d, J = 8Hz, [Formula] 5.82 (1H, d, J = 8Hz, [Formula]] 6.60-7.24 (10H, m, aromatic hydrogen) (2) (4SR, 5SR) -4 ,5-diphenyl-3-
[3-(Perhydroazepin-1-yl)propyl]-1,3-oxazolidin-2-one hydrochloride 120 mg of light brown crystals were obtained in the same manner as in Example 1-(2) using the above compound ( yield 41%). mp 158-160℃ (decomposition) IRν KBr nax (cm -1 ) 2940, 1740, 1630, 1445,
1405, 1230, 1030, 755, 710, 695
第１図は、本発明化合物及び比較化合物の固縮
緩解作用を算出する方法を示す図である。
FIG. 1 is a diagram showing a method for calculating the rigidity-reducing effects of the compounds of the present invention and comparative compounds.
Claims (1)
は４、５または６を示す） で表わされる１，３−オキサゾリジン−２−オン
誘導体およびその酸付加塩。 ２ 次の一般式 【式】 （式中、R1、R2およびR3は水素原子を示す） で表わされる化合物を炭酸カリウムまたは炭酸ナ
トリウムの存在下、一般式 【式】 （式中、Ｘはハロゲン原子、トシルオキシ基、メ
シルオキシ基またはアセトキシ基のような脱離基
を示し、ｎは４、５または６を示す） で表わされる化合物と反応せしめ、所望により生
成物を酸付加塩とすることを特徴とする 一般式（） 【化】 （式中、R1、R2、R3およびｎは前記と同じ） で表わされる１，３−オキサゾリジン−２−オン
誘導体およびその酸付加塩の製造法。[Claims] 1 The following general formula () [Chemical formula] (In the formula, R 1 , R 2 and R 3 represent a hydrogen atom, and n
represents 4, 5 or 6) 1,3-oxazolidin-2-one derivatives and acid addition salts thereof. 2. A compound represented by the following general formula [Formula] (wherein, R 1 , R 2 and R 3 represent hydrogen atoms) was added to a compound represented by the general formula [Formula] (wherein, X represents a leaving group such as a halogen atom, tosyloxy group, mesyloxy group or acetoxy group, and n represents 4, 5 or 6), and optionally convert the product into an acid addition salt. Production of 1,3-oxazolidin-2-one derivatives and acid addition salts thereof, characterized by the general formula () [Chemical formula] (wherein R 1 , R 2 , R 3 and n are the same as above) Law.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60127210A JPS61286375A (en) | 1985-06-13 | 1985-06-13 | Novel 1,3-dioxazolidin-2-one derivative and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60127210A JPS61286375A (en) | 1985-06-13 | 1985-06-13 | Novel 1,3-dioxazolidin-2-one derivative and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61286375A JPS61286375A (en) | 1986-12-16 |
| JPH0569107B2 true JPH0569107B2 (en) | 1993-09-30 |
Family
ID=14954447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60127210A Granted JPS61286375A (en) | 1985-06-13 | 1985-06-13 | Novel 1,3-dioxazolidin-2-one derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61286375A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3003550U (en) * | 1994-04-26 | 1994-10-25 | 葉子 西前 | Airy perforated stockings |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR950704278A (en) * | 1992-10-15 | 1995-11-17 | 시오노 요시히꼬 | OXAZOLINONE DERIVATIVE HAVING INTRACELLULAR PHOSPHOLIPASE A₂INHIBITOR ACTIVITY With Intracellular Phospholipase A 2 Inhibitory Activity |
| JP2005239602A (en) * | 2004-02-25 | 2005-09-08 | Sumitomo Chemical Co Ltd | Method for producing 2-oxazolidinones |
-
1985
- 1985-06-13 JP JP60127210A patent/JPS61286375A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3003550U (en) * | 1994-04-26 | 1994-10-25 | 葉子 西前 | Airy perforated stockings |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61286375A (en) | 1986-12-16 |
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