JPH0481990B2 - - Google Patents
Info
- Publication number
- JPH0481990B2 JPH0481990B2 JP4628885A JP4628885A JPH0481990B2 JP H0481990 B2 JPH0481990 B2 JP H0481990B2 JP 4628885 A JP4628885 A JP 4628885A JP 4628885 A JP4628885 A JP 4628885A JP H0481990 B2 JPH0481990 B2 JP H0481990B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- phenyl
- oxazolidin
- group
- piperidinopropyl
- 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 26
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 claims description 2
- GUBNMFJOJGDCEL-UHFFFAOYSA-N dicyclomine hydrochloride Chemical group [Cl-].C1CCCCC1C1(C(=O)OCC[NH+](CC)CC)CCCCC1 GUBNMFJOJGDCEL-UHFFFAOYSA-N 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229940049906 glutamate Drugs 0.000 description 7
- 229930195712 glutamate Natural products 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- -1 (4RS, 5RS)-4-n-butyl-5-phenyl-3-(3-piperidinopropyl) -1,3-oxazolidin-2-one compound Chemical class 0.000 description 3
- 241000238017 Astacoidea Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class 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
- 206010044565 Tremor Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002964 excitative effect Effects 0.000 description 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 210000000715 neuromuscular junction Anatomy 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- PBMSFBDTUDFZDV-YADHBBJMSA-N (4r,5s)-4-hexyl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound O([C@H]([C@H]1CCCCCC)C=2C=CC=CC=2)C(=O)N1CCCN1CCCCC1 PBMSFBDTUDFZDV-YADHBBJMSA-N 0.000 description 2
- MHBJZUXIFIWPRT-UHFFFAOYSA-N 1-phenyl-2-(3-piperidin-1-ylpropylamino)octan-1-ol;dihydrochloride Chemical compound Cl.Cl.C=1C=CC=CC=1C(O)C(CCCCCC)NCCCN1CCCCC1 MHBJZUXIFIWPRT-UHFFFAOYSA-N 0.000 description 2
- CBHDABYZJQLLTK-UHFFFAOYSA-N 3-[3-(azepan-1-yl)propyl]-4-hexyl-5-phenyl-1,3-oxazolidin-2-one Chemical compound CCCCCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCCC1 CBHDABYZJQLLTK-UHFFFAOYSA-N 0.000 description 2
- ABZZCQSSDIPILA-UHFFFAOYSA-N 4-(2-methylbutan-2-yl)-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCC(C)(C)C1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 ABZZCQSSDIPILA-UHFFFAOYSA-N 0.000 description 2
- OOBBCXZWSAKESQ-UHFFFAOYSA-N 4-(4-methylpentyl)-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CC(C)CCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 OOBBCXZWSAKESQ-UHFFFAOYSA-N 0.000 description 2
- OGJFJARREZDRDX-UHFFFAOYSA-N 4-(5-methylhexyl)-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CC(C)CCCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 OGJFJARREZDRDX-UHFFFAOYSA-N 0.000 description 2
- OFBIBBBFSZWAGQ-UHFFFAOYSA-N 4-(6-methylheptyl)-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CC(C)CCCCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 OFBIBBBFSZWAGQ-UHFFFAOYSA-N 0.000 description 2
- JHTJDDYJMSHYRE-UHFFFAOYSA-N 4-heptan-2-yl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCCCC(C)C1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 JHTJDDYJMSHYRE-UHFFFAOYSA-N 0.000 description 2
- OGAUOMHFUPCPGP-UHFFFAOYSA-N 4-heptyl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCCCCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 OGAUOMHFUPCPGP-UHFFFAOYSA-N 0.000 description 2
- XPRAKDAUULBJFD-UHFFFAOYSA-N 4-hexan-2-yl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCCC(C)C1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 XPRAKDAUULBJFD-UHFFFAOYSA-N 0.000 description 2
- DCYRXBWGUBWFDZ-UHFFFAOYSA-N 4-hexan-3-yl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCC(CC)C1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 DCYRXBWGUBWFDZ-UHFFFAOYSA-N 0.000 description 2
- PBMSFBDTUDFZDV-UHFFFAOYSA-N 4-hexyl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCCCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 PBMSFBDTUDFZDV-UHFFFAOYSA-N 0.000 description 2
- OSRVBESJHNACJN-UHFFFAOYSA-N 4-hexyl-5-phenyl-3-(3-pyrrolidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCCCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCC1 OSRVBESJHNACJN-UHFFFAOYSA-N 0.000 description 2
- MFNKZRGUASOKIC-UHFFFAOYSA-N 4-octan-2-yl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCCCCC(C)C1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 MFNKZRGUASOKIC-UHFFFAOYSA-N 0.000 description 2
- MUFGJIZOGFJGKK-UHFFFAOYSA-N 4-octyl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCCCCCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 MUFGJIZOGFJGKK-UHFFFAOYSA-N 0.000 description 2
- OVTNNOPFEYZNOO-UHFFFAOYSA-N 4-pentan-2-yl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound CCCC(C)C1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 OVTNNOPFEYZNOO-UHFFFAOYSA-N 0.000 description 2
- INKOFLHPHGCTFZ-UHFFFAOYSA-N 5-phenyl-3-(3-piperidin-1-ylpropyl)-4-propyl-1,3-oxazolidin-2-one Chemical compound CCCC1C(C=2C=CC=CC=2)OC(=O)N1CCCN1CCCCC1 INKOFLHPHGCTFZ-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- ASNFTDCKZKHJSW-REOHCLBHSA-N Quisqualic acid Chemical compound OC(=O)[C@@H](N)CN1OC(=O)NC1=O ASNFTDCKZKHJSW-REOHCLBHSA-N 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
- 239000003513 alkali Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IRJCBFDCFXCWGO-SCSAIBSYSA-N (2r)-2-azaniumyl-2-(3-oxo-1,2-oxazol-5-yl)acetate Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC(=O)NO1 IRJCBFDCFXCWGO-SCSAIBSYSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- PBMSFBDTUDFZDV-FGZHOGPDSA-N (4r,5r)-4-hexyl-5-phenyl-3-(3-piperidin-1-ylpropyl)-1,3-oxazolidin-2-one Chemical compound O([C@@H]([C@H]1CCCCCC)C=2C=CC=CC=2)C(=O)N1CCCN1CCCCC1 PBMSFBDTUDFZDV-FGZHOGPDSA-N 0.000 description 1
- HDDNBUNZJIQDBQ-UHFFFAOYSA-N 1-(3-chloropropyl)piperidine Chemical compound ClCCCN1CCCCC1 HDDNBUNZJIQDBQ-UHFFFAOYSA-N 0.000 description 1
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Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は新規な１，３−オキサゾリジン−２−
オン誘導体、更に詳細には、次の一般式（）、
（式中、Ｒはノルマルプロピル基、ノルマルブチ
ル基、ペンチル基、ヘキシル基、ヘプチル基又は
オクチル基を示し、ｎは４、５、又は６を示す）
で表わされる１，３−オキサゾリジン−２−オン
誘導体及びその酸付加塩並びにその製造法に関す
る。
〔従来の技術及び発明が解決しようとする問題
点〕
グルタミン酸は、高等動物中枢神経系や下等動
物の神経筋接合部において、興奮性神経伝達物質
として働いていることが強く示唆されており
〔“Glutamata as ａ Neurotransmitter”、ed.
by G.D.D.Chiara ＆ G.L.Gessa、Raven
Press、New York、1981：H.M.Gerschenfeld、
Physiol.Rev.53、１−119（1973）〕、高等動物にグ
ルタミン酸の極めて強力なアゴニストであるカイ
ニン酸、ドーモイ酸、キスカル酸、イボテン酸等
を投与すると、異常行動、固縮、振戦、痙攣等が
誘発されることが報告されている〔Olnreyら：
Brain Res.、77、507−512（1974）〕。
一方、老化と共に中枢ならびに末梢神経系は機
能低下をおこし、パーキンソン氏病、運動ニユー
ロン疾患、痴呆、振戦、脊髄小脳変性症等が生ず
ることも知られており、これらはある特定部位の
神経細胞の欠落あるいは神経系全般の機能低下に
基づく興奮性および抑制性神経の平衡関係（たと
えばグルタミン酸とGABAの平衡関係）の破綻
に起因するものと考えられている（平井俊栄：神
経進歩」17、69、（1973）。
以上のことから、グルタミン酸を選択的に遮断
する薬物は、老人に多い神経疾患すなわち神経系
のバランスの崩れや筋パルスの異常亢進などによ
り起るめまい、肩こり、けいれんやふるえ等の疾
患の治療薬として有用である。
一方グルタミン酸は昆虫の神経筋接合部の興奮
性伝達物質として働いており、これを遮断する薬
物は昆虫の活動を滅弱させることから農薬として
も利用できる。〔江藤守総 化学と生物、21、725
（1983）〕。
斯かる実情において、本発明者は鋭意研究を行
つた結果、前記一般式（）で表わされる新規な
１，３−オキサゾリジン−２−オン誘導体が優れ
たグルタミン酸遮断作用を有することを見出し
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
−ピペリジノエチル）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.Nauk.、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。
〔問題点を解決するための手段〕
従つて、本発明は、優れたグルタミン酸遮断作
用を有し、医薬品及び農薬として有用な、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。
（式中、Ｙはハロゲン原子又はトリクロロメチル
オキシ基を示し、Ｒ、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。
又方法２からも本発明化合物は得られる。
方法２：
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。
（式中、R1は低級アルキル基を示し、Ｒ，ｎは
前記と同じ）
化合物（）の（）との反応は、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−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。
原料の（）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。
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
素塩、硫酸、Ｐ−トルエンスルホン酸、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１ （4RS、5RS）−５−フエニル−３−
（３−ピペリジノプロピル）−４−ノルマルプロ
ピル−１，３−オキサゾリジン−２−オン
化合物２ （4RS、5SR）−５−フエニル−３−
（３−ピペリジノプロピル）−４−ノルマルプロ
ピル−１，３−オキサゾリジン−２−オン
化合物３ （4RS、5RS）−４−ノルマルブチル
−５−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 （4RS、5SR）−４−ノルマルブチル
−５−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 （4RS、5RS）−４−ノルマルペンチ
ル−５−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 （4RS、5SR）−４−ノルマルペンチ
ル−５−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、5RS）−４−（３−メチルブチ
ル）−５−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８ （4RS、5SR）−４−（３−メチルブチ
ル）−５−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９ （4RS、5RS）−４−ヘキシル−５−
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10 （4RS、5SR）−４−ヘキシル−５−
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11 （4RS、5RS）−４−ヘキシル−５−
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12 （4RS、5SR）−４−ヘキシル−５−
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13 （4RS、5RS）−４−ヘキシル−３−
〔３−（ペルヒドロアゼピン−１−イル）プロピ
ル〕−５−フエニル−１，３−オキサゾリジン
−２−オン
化合物14 （4RS、5SR）−４−ヘキシル−３−
〔３−（ペルヒドロアゼピン−１−イル）プロピ
ル〕−５−フエニル−１，３−オキサゾリジン
−２−オン
化合物15 （4R、5R）−４−ヘキシル−５−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16 （4R、5S）−４−ヘキシル−５−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17 （4R、5S）−４−ヘキシル−５−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18 （4R、5R）−４−ヘキシル−５−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19 （4RS、5RS）−４−ヘプチル−５−
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20 （4RS、5SR）−４−ヘプチル−５−
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21 （4RS、5RS）−５−フエニル−３−
（３−ピペリジノプロピル）−４−オクチル−
１，３−オキサゾリジン−２−オン
化合物22 （4RS、5SR）−５−フエニル−３−
（３−ピペリジノプロピル）−４−オクチル−
１，３−オキサゾリジン−２−オン
化合物23 （4RS、5RS）−４−（１−メチルブチ
ル）−５−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24 （4RS、5SR）−４−（１−メチルブチ
ル）−５−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25 （4RS、5RS）−４−（４−メチルペン
チル）−５−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26 （4RS、5SR）−４−（４−メチルペン
チル）−５−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27 （4RS、5RS）−４−（１−メチルペン
チル）−５−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28 （4RS、5SR）−４−（１−メチルペン
チル）−５−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29 （4RS、5RS）−４−（５−メチルヘキ
シル）−５−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30 （4RS、5SR）−４−（５−メチルヘキ
シル）−５−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31 （4RS、5RS）−４−（１−メチルヘキ
シル）−５−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32 （4RS、5SR）−４−（１−メチルヘキ
シル）−５−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33 （4RS、5RS）−４−（６−メチルヘプ
チル）−５−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34 （4RS、5SR）−４−（６−メチルヘプ
チル）−５−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35 （4RS、5RS）−４−（１−メチルヘプ
チル）−５−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36 （4RS、5SR）−４−（１−メチルヘプ
チル）−５−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37 （4RS、5RS）−４−（１，１−ジメチ
ルプロピル）−５−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38 （4RS、5SR）−４−（１，１−ジメチ
ルプロピル）−５−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39 （4RS、5RS）−４−（１−エチルブチ
ル）−５−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40 （4RS、5SR）−４−（１−エチルブチ
ル）−５−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
〔作用〕
本発明化合物（）のグルタミン酸遮断作用及
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 （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２ （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
実験１ ザリガニ神経筋接合部におけるグルタミ
ン酸遮断作用：
Ishidaら〔J.Physiol.、298、301−319（1980）〕
及びShinozakiら〔Comp.Biochem.Phyaiol、
70c、49−58（1981）〕の方法に従つて行つた。
すなわち、ザリガニ第一歩脚の開鋏筋を実験材
料として用いた。神経筋標本を、液槽中に固定
し、一定流速のザリガニ用生理溶液（組成
（mM）：NaCl（195）CACl2（18）、KCl（5.4）、
Tris−maleate buffer（PH7.5）（10）、glucose
（11））で室温下に灌流し、3M−KCl溶液を満た
したガラス微小電極を筋線維中央に挿入し、筋細
胞膜電位の変化を細胞内記録した。被験物質のグ
ルタミン酸遮断作用はＬ−グルタミン酸
（10-4M）を灌流適用して誘発される脱分極に対
する被験物質薬液（本発明化合物：２×10-5M、
比較化合物：２×10-4M）の５分間前処理による
Ｌ−グルタミン酸誘発脱分極の抑制率として求め
た。その結果を表１に示す。
【表】
実験２ 急性毒性
ddN系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。
被験物質：比合物８
LD50：53.6mg／Kg・iv
実施例
（1RS、2RS）−１−フエニル−２−（３−ピペ
リジノプロピルアミノ）オクタン−１−オール二
塩酸塩（1.00ｇ、2.38ｍmol）を10％水酸化ナト
リウム水溶液（14ml）に懸濁させ、エーテル（33
ml）を加えて撹拌混合し、澄明になつたところで
氷冷し、20％トリクロロメチル クロロフオルメ
ート トルエン溶液（4.8ml）を１時間かけて滴
下した。滴下終了後、室温にて30分間撹拌した
後、有機層を分取し、飽和食塩水で１回洗浄し
た。芒硝で乾燥し、滅圧下溶媒留去して得た粗体
を、シリカゲルカラムクロマトグラフイー（溶
媒：クロロホルム／メタノール＝20：１）にて精
製し、（4RS、5RS）−４−ヘキシル−５−フエニ
ル−３−（３−ピペピジノプロピル）−１，３−オ
キサゾリジン−２−オンを淡黄色油状物として
0.88ｇ（収率100％）得た。
IRνNaCl nax（cm-1）：2920，2850，2770，1750，1600
，
1450，1410，1230，1120，1030，1010，755，
695.
NMR（CDCl3）δppm
0.76〜1.04（3H、ｍ）、1.16〜1.92（18H、ｍ）、
2.04〜2.52（6H、ｍ）、2.84〜3.24（1H、ｍ）、
3.32〜3.76（2H、ｍ）、5.06（1H、ｄ、Ｊ＝５
Hz）、7.34（5H、ｍ）．
mp フマル酸塩：92〜94℃（エタノール−エー
テル）
同様にして下記表２の化合物を得た。
【表】
【表】
参考例
（1RS、2RS）−１−フエニル−２−（３−ピペ
リジノプロピルアミノ）オクタン−１−オール
二塩酸塩：
（1RS、2RS）−２−アミノ−１−フエニルオ
クタン−１−オール（1.77ｇ、8.0ｍmol）及び１
−（３−クロロプロピル）ピペリジン（1.29ｇ、
8.0ｍmol）の混合物を窒素ガス雰囲気下70℃に
て混融し、つづいて110〜120℃の油浴上にて、３
時間加熱した。空冷後反応混合物にエタノール及
び濃塩酸（0.67ml）を加えて加熱溶解し、空冷後
酢酸エチルを加えて析出する結晶を取、酢酸エ
チルつづいてヘキサンで洗浄後乾燥して標題の化
合物を白色結晶として1.96ｇ得た。（収率59％）
mp231〜234℃（分解）
IRνKBr nax（cm-1）：3310，2925，2700，1585，1450，
1055，760，700
遊離塩基は水酸化ナトリウム水溶液と処理した
後、クロロホルムで押出して得た。
IRνneat nax（cm-1）：3280，2920，2850，2800，1600
，
1465，1450，1345，1150，1120，1035，755，
695
NMR（CDCl3）
δ0.68〜1.02（3H、ｍ、CH2CＨ 3）
1.02〜1.90（20H、ｍ、（ＣＨ 2）5CH3、
【式】ＮＨ、ＯＨ）
2.16〜2.90（9H、ｍ、
【式】）
4.24（1H、ｄ、Ｊ＝８Hz、ＣＨ−Ｏ）
7.30（5H、ｍ、芳香族水素）
以下同様にして下記表３の原料化合物を合成し
た。
【表】
【表】 [Detailed Description of the Invention] [Industrial Application Field] The present invention provides novel 1,3-oxazolidine-2-
on derivatives, more specifically, the following general formula (), (In the formula, R represents a normal propyl group, a normal butyl group, a pentyl group, a hexyl group, a heptyl group, or an octyl group, and n represents 4, 5, or 6) 1,3-oxazolidine-2- This invention relates to on derivatives, acid addition salts thereof, and methods for producing the same. [Prior art and problems to be solved by the invention] It has been strongly suggested that glutamate acts as an excitatory neurotransmitter in the central nervous system of higher animals and the neuromuscular junction of lower animals. “Glutamata as a Neurotransmitter”, ed.
by GDDChiara & GLGessa, Raven
Press, New York, 1981: HMGerschenfeld,
Physiol.Rev. 53 , 1-119 (1973)], when extremely strong glutamate agonists such as kainic acid, domoic acid, quisqualic acid, and ibotenic acid are administered to higher animals, abnormal behavior, rigidity, tremor, It has been reported that convulsions are induced [Olnrey et al.
Brain Res., 77 , 507-512 (1974)]. On the other hand, it is known that the functions of the central and peripheral nervous systems decline with aging, leading to Parkinson's disease, motor neuron disease, dementia, tremor, spinocerebellar degeneration, etc. This is thought to be caused by a breakdown in the equilibrium relationship between excitatory and inhibitory nerves (for example, the equilibrium relationship between glutamate and GABA) due to a lack of or a decline in the overall function of the nervous system (Toshiei Hirai: Neurological Advances 17 ). 69, (1973). Based on the above, drugs that selectively block glutamate can be used to treat neurological diseases that are common in the elderly, such as dizziness, stiff shoulders, convulsions, and tremors caused by imbalances in the nervous system and abnormal acceleration of muscle pulses. On the other hand, glutamic acid acts as an excitatory transmitter in the neuromuscular junction of insects, and drugs that block it can also be used as pesticides because they dampen insect activity. [Morisou Eto Chemistry and Biology, 21, 725
(1983)]. Under these circumstances, the inventors of the present invention conducted extensive research and found that the novel 1,3-oxazolidin-2-one derivative represented by the above general formula () has an excellent glutamate blocking effect. As a compound structurally similar to the compound of the present invention, 4-methyl-5-phenyl-3-(2
-piperidinoethyl)1,3-oxazolidine-
2-on [Zikolova et al.: Farmatsiya (Sofia),
14, 16-21 (1964) and Nikolova: Izv.Inst.
Fiziol.Bulg.Akad.Nauk., 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)]. [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 glutamic acid blocking effect and is useful as pharmaceuticals and agricultural chemicals. -one derivatives. Furthermore, the present invention provides a novel method for producing 1,3-oxazolidin-2-one derivatives. In addition, the compound of formula () has the 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 the method shown below. Method 1: The compound () of the present invention is produced by reacting the compound () with the compound (). (In the formula, Y represents a halogen atom or a trichloromethyloxy group, and R 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 in the presence of an alkali such as sodium hydroxide. It is carried out at a temperature of -10 to 10°C.
The compound of the present invention can also be obtained by method 2. Method 2: 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. (In the formula, R 1 represents a lower alkyl group, and R and n are the same as above.) The reaction of compound () with () is carried out using an organic solvent such as ether or chloroform in the presence of an alkali such as sodium hydroxide. −5 in a heterogeneous solvent with water
It is carried out at a temperature of ~15 °C. Cyclization of compound () is performed using sodium methoxide, sodium ethoxide,
100-140℃ in a solvent such as toluene or xylene in the presence of a base such as aluminum isopropoxide
This is done by heating. The compound of formula () as a raw material is produced, for example, by the method shown by the following reaction formula. 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, hydrobromide, sulfuric acid, P-toluenesulfonic 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 1 (4RS, 5RS)-5-phenyl-3-
(3-piperidinopropyl)-4-n-propyl-1,3-oxazolidin-2-one compound 2 (4RS, 5SR)-5-phenyl-3-
(3-piperidinopropyl)-4-n-propyl-1,3-oxazolidin-2-one compound 3 (4RS, 5RS)-4-n-butyl-5-phenyl-3-(3-piperidinopropyl) -1,3-oxazolidin-2-one compound 4 (4RS, 5SR) -4-n-n-butyl-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 5 ( 4RS, 5RS)-4-Normalpentyl-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one Compound 6 (4RS, 5SR)-4-Normalpentyl-5-phenyl -3-(3-Piperidinopropyl)-1,3-oxazolidin-2-one Compound 7 (4RS, 5RS)-4-(3-methylbutyl)-5-phenyl-3-(3-piperidinopropyl )-1,3-oxazolidin-2-one Compound 8 (4RS, 5SR)-4-(3-methylbutyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidine-2- Compound 9 (4RS, 5RS)-4-hexyl-5-
Phenyl-3-(3-piperidinopropyl)-
1,3-oxazolidin-2-one compound 10 (4RS, 5SR)-4-hexyl-5-
Phenyl-3-(3-piperidinopropyl)-
1,3-oxazolidin-2-one compound 11 (4RS, 5RS)-4-hexyl-5-
Phenyl-3-(3-pyrrolidinopropyl)-
1,3-oxazolidin-2-one compound 12 (4RS, 5SR)-4-hexyl-5-
Phenyl-3-(3-pyrrolidinopropyl)-
1,3-oxazolidin-2-one compound 13 (4RS, 5RS)-4-hexyl-3-
[3-(Perhydroazepin-1-yl)propyl]-5-phenyl-1,3-oxazolidin-2-one compound 14 (4RS, 5SR)-4-hexyl-3-
[3-(Perhydroazepin-1-yl)propyl]-5-phenyl-1,3-oxazolidin-2-one Compound 15 (4R,5R)-4-hexyl-5-phenyl-3-(3-phenyl) peridinopropyl)-1,
3-Oxazolidin-2-one compound 16 (4R,5S)-4-hexyl-5-phenyl-3-(3-piperidinopropyl)-1,3
-Oxazolidin-2-one compound 17 (4R,5S)-4-hexyl-5-phenyl-3-(3-piperidinopropyl)-1,3
-Oxazolidin-2-one compound 18 (4R, 5R)-4-hexyl-5-phenyl-3-(3-piperidinopropyl)-1,
3-oxazolidin-2-one compound 19 (4RS, 5RS)-4-heptyl-5-
Phenyl-3-(3-piperidinopropyl)-
1,3-oxazolidin-2-one compound 20 (4RS, 5SR)-4-heptyl-5-
Phenyl-3-(3-piperidinopropyl)-
1,3-oxazolidin-2-one compound 21 (4RS, 5RS)-5-phenyl-3-
(3-piperidinopropyl)-4-octyl-
1,3-oxazolidin-2-one compound 22 (4RS, 5SR)-5-phenyl-3-
(3-piperidinopropyl)-4-octyl-
1,3-oxazolidin-2-one compound 23 (4RS, 5RS)-4-(1-methylbutyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 24 (4RS, 5SR)-4-(1-methylbutyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 25 (4RS, 5RS)-4-( 4-Methylpentyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 26 (4RS, 5SR)-4-(4-methylpentyl)-5-phenyl -3-(3-Piperidinopropyl)-1,3-oxazolidin-2-one compound 27 (4RS, 5RS)-4-(1-methylpentyl)-5-phenyl-3-(3-piperidino propyl)-1,3-oxazolidin-2-one compound 28 (4RS, 5SR)-4-(1-methylpentyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidine- 2-one compound 29 (4RS, 5RS)-4-(5-methylhexyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 30 (4RS, 5SR )-4-(5-methylhexyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one Compound 31 (4RS, 5RS)-4-(1-methylhexyl )-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one Compound 32 (4RS, 5SR)-4-(1-methylhexyl)-5-phenyl-3-( 3-piperidinopropyl)-1,3-oxazolidin-2-one compound 33 (4RS, 5RS)-4-(6-methylheptyl)-5-phenyl-3-(3-piperidinopropyl)-1 ,3oxazolidin-2-one compound 34 (4RS, 5SR)-4-(6-methylheptyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 35 (4RS, 5RS)-4-(1-methylheptyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one Compound 36 (4RS, 5SR)-4-( 1-Methylheptyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one Compound 37 (4RS, 5RS)-4-(1,1-dimethylpropyl)-5 -Phenyl-3-(3-piperidinopropyl)-1,3-oxazolidine-2
-one compound 38 (4RS, 5SR)-4-(1,1-dimethylpropyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidine-2
-one compound 39 (4RS, 5RS) -4-(1-ethylbutyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one compound 40 (4RS, 5SR) - 4-(1-Ethylbutyl)-5-phenyl-3-(3-piperidinopropyl)-1,3-oxazolidin-2-one [Action] The results of the glutamate blocking action and toxicity test of the compound of the present invention () are as follows: It is as follows. The following compounds were used as comparative compounds. Comparative compound 1 (4RS, 5SR)-4-methyl-5
-Phenyl-3-(2-piperidinoethyl)-
1,3-oxazolidin-2-one hydrochloride comparison compound 2 (4RS, 5SR)-4-methyl-5
-Phenyl-3-(2-pyrrolidinoethyl)-
1,3-Oxazolidin-2-one hydrochloride experiment 1 Glutamate blocking effect in crayfish neuromuscular junction: Ishida et al. [J.Physiol., 298 , 301-319 (1980)]
and Shinozaki et al. [Comp.Biochem.Phyaiol,
70c, 49-58 (1981)]. That is, the scissor muscle of the first leg of a crayfish was used as an experimental material. The neuromuscular specimens were fixed in a liquid bath and treated with a constant flow rate of crayfish physiological solution (composition (mM): NaCl (195), CACl 2 (18), KCl (5.4),
Tris−maleate buffer (PH7.5) (10), glucose
(11)) at room temperature, a glass microelectrode filled with 3M-KCl solution was inserted into the center of the muscle fiber, and changes in muscle cell membrane potential were recorded intracellularly. The glutamate blocking effect of the test substance was demonstrated by the test substance drug solution (compound of the present invention: 2× 10 -5 M ,
It was determined as the inhibition rate of L-glutamic acid-induced depolarization by pretreatment with a comparative compound (2×10 −4 M) for 5 minutes. The results are shown in Table 1. [Table] Experiment 2 Acute toxicity Up and down using ddN male mice
Required by law. The test substance was dissolved in physiological saline and administered through the tail vein. Test substance: Compound 8 LD50: 53.6mg/Kg・iv Example (1RS, 2RS)-1-phenyl-2-(3-piperidinopropylamino)octan-1-ol dihydrochloride (1.00g, 2.38 mmol) was suspended in 10% aqueous sodium hydroxide solution (14 ml), and ether (33
ml) was added thereto, the mixture was stirred, and when the mixture became clear, it was cooled on ice, and a 20% trichloromethyl chloroformate toluene solution (4.8 ml) was added dropwise over 1 hour. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes, and then the organic layer was separated and washed once with saturated brine. The crude product obtained by drying with Glauber's salt and evaporating the solvent under reduced pressure was purified by silica gel column chromatography (solvent: chloroform/methanol = 20:1) to obtain (4RS, 5RS)-4-hexyl-5. -Phenyl-3-(3-pipepidinopropyl)-1,3-oxazolidin-2-one as pale yellow oil
0.88g (yield 100%) was obtained. IRν NaCl nax (cm -1 ): 2920, 2850, 2770, 1750, 1600
，
1450, 1410, 1230, 1120, 1030, 1010, 755,
695. NMR ( CDCl3 ) δppm 0.76-1.04 (3H, m), 1.16-1.92 (18H, m),
2.04~2.52 (6H, m), 2.84~3.24 (1H, m),
3.32-3.76 (2H, m), 5.06 (1H, d, J=5
Hz), 7.34 (5H, m). mp Fumarate: 92-94°C (ethanol-ether) Compounds shown in Table 2 below were obtained in the same manner. [Table] [Table] Reference example (1RS, 2RS)-1-phenyl-2-(3-piperidinopropylamino)octan-1-ol dihydrochloride: (1RS, 2RS)-2-amino-1- phenyl octan-1-ol (1.77 g, 8.0 mmol) and 1
-(3-chloropropyl)piperidine (1.29g,
A mixture of 8.0 mmol) was melted at 70°C under a nitrogen gas atmosphere, and then melted on an oil bath at 110 to 120°C for 3
heated for an hour. After cooling in air, add ethanol and concentrated hydrochloric acid (0.67 ml) to the reaction mixture and dissolve by heating. After cooling in air, add ethyl acetate to collect the precipitated crystals. Wash with ethyl acetate and then hexane and dry to obtain the title compound as white crystals. 1.96g was obtained. (Yield 59%) mp231-234℃ (decomposition) IRν KBr nax (cm -1 ): 3310, 2925, 2700, 1585, 1450,
1055,760,700 The free base was obtained by treatment with aqueous sodium hydroxide followed by extrusion with chloroform. IRν neat nax (cm -1 ): 3280, 2920, 2850, 2800, 1600
，
1465, 1450, 1345, 1150, 1120, 1035, 755,
695 NMR ( CDCl3 ) δ0.68 ~ 1.02 (3H, m , CH2CH3 ) 1.02~ 1.90 (20H, m, ( CH2 ) 5CH3 ,
[Formula] NH , O H) 2.16-2.90 (9H, m, [Formula]) 4.24 (1H, d, J=8Hz, C H - O) 7.30 (5H, m, aromatic hydrogen) Similarly, The raw material compounds shown in Table 3 below were synthesized. [Table] [Table]
Claims (1)
チル基、ペンチル基、ヘキシル基、ヘプチル基又
はオクチル基を示し、ｎは４、５、又は６を示
す） で表わされる１，３−オキサゾリジン−２−オン
誘導体及びその酸付加塩。 ２ 一般式 （式中、Ｒは、ノルマルプロピル基、ノルマルブ
チル基、ベンチル基、ヘキシル基、ヘプチル基又
はオクチル基を示し、ｎは４、５、又は６を示
す） で表わされる化合物に一般式 （式中、Ｙはハロゲン原子又はトリクロロメチル
オキシ基を示す） で表わされる化合物を反応せしめ、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
（） （式中、Ｒ及び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
誘導体及びその酸付加塩の製造法。[Claims] First-order general formula () (In the formula, R represents a normal propyl group, a normal butyl group, a pentyl group, a hexyl group, a heptyl group, or an octyl group, and n represents 4, 5, or 6) -one derivatives and acid addition salts thereof. 2 General formula (wherein, R represents a normal propyl group, a normal butyl group, a bentyl group, a hexyl group, a heptyl group, or an octyl group, and n represents 4, 5, or 6) (In the formula, Y represents a halogen atom or a trichloromethyloxy group) A general formula () characterized by reacting a compound represented by the following and optionally converting the product into an acid addition salt. (In the formula, R and n are the same as above.) A method for producing a 1,3-oxazolidin-2-one derivative and an acid addition salt thereof.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4628885A JPS61205268A (en) | 1985-03-08 | 1985-03-08 | Novel 1,3-oxazolidin-2-one derivative and production thereof |
| CN 85104606 CN1011507B (en) | 1985-03-08 | 1985-06-17 | Processes for preparing 1,3-oxazolidine-2-one derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4628885A JPS61205268A (en) | 1985-03-08 | 1985-03-08 | Novel 1,3-oxazolidin-2-one derivative and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61205268A JPS61205268A (en) | 1986-09-11 |
| JPH0481990B2 true JPH0481990B2 (en) | 1992-12-25 |
Family
ID=12743025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4628885A Granted JPS61205268A (en) | 1985-03-08 | 1985-03-08 | Novel 1,3-oxazolidin-2-one derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61205268A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0314562A (en) * | 1988-04-11 | 1991-01-23 | Nippon Chemiphar Co Ltd | Novel alkylenediamine derivative and glutamic acid-blocking agent |
-
1985
- 1985-03-08 JP JP4628885A patent/JPS61205268A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61205268A (en) | 1986-09-11 |
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