HRP920778A2 - Novel 1-oxa-2-oxo-8-azaspiro74,5/ decane derivatives, pharmaceutical preparations containing them and process for the preparation thereof - Google Patents
Novel 1-oxa-2-oxo-8-azaspiro74,5/ decane derivatives, pharmaceutical preparations containing them and process for the preparation thereof Download PDFInfo
- Publication number
- HRP920778A2 HRP920778A2 HRP-1538/90A HRP920778A HRP920778A2 HR P920778 A2 HRP920778 A2 HR P920778A2 HR P920778 A HRP920778 A HR P920778A HR P920778 A2 HRP920778 A2 HR P920778A2
- Authority
- HR
- Croatia
- Prior art keywords
- formula
- group
- defined above
- oxo
- decane
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 43
- 239000000825 pharmaceutical preparation Substances 0.000 title claims 2
- 238000002360 preparation method Methods 0.000 title abstract description 31
- DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical class CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000000203 mixture Substances 0.000 claims abstract description 36
- 239000002253 acid Substances 0.000 claims abstract description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 18
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 239000011575 calcium Substances 0.000 claims abstract description 7
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 6
- 230000000141 anti-hypoxic effect Effects 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims abstract description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 230000000496 anti-anoxic effect Effects 0.000 claims abstract description 4
- 125000004953 trihalomethyl group Chemical group 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 4
- 238000006243 chemical reaction Methods 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000007363 ring formation reaction Methods 0.000 claims description 21
- -1 p-toluene-sulfonyloxy group Chemical group 0.000 claims description 18
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 239000004480 active ingredient Substances 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000012948 isocyanate Substances 0.000 claims description 11
- 150000002513 isocyanates Chemical class 0.000 claims description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 10
- DTNXRKYDRUCILN-UHFFFAOYSA-N (4-acetylpiperidin-4-yl) carbamate Chemical class NC(=O)OC1(C(=O)C)CCNCC1 DTNXRKYDRUCILN-UHFFFAOYSA-N 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- CYCSGNGCLXFNFZ-UHFFFAOYSA-N (4-ethynylpiperidin-4-yl) carbamate Chemical class NC(=O)OC1(C#C)CCNCC1 CYCSGNGCLXFNFZ-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 7
- 239000008096 xylene Substances 0.000 claims description 7
- VWADBHVASFOEHX-UHFFFAOYSA-N 1-(4-hydroxypiperidin-4-yl)ethanone Chemical class CC(=O)C1(O)CCNCC1 VWADBHVASFOEHX-UHFFFAOYSA-N 0.000 claims description 6
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 6
- GVZFMFFUAZKMOB-UHFFFAOYSA-N 4-ethynylpiperidin-4-ol Chemical class C#CC1(O)CCNCC1 GVZFMFFUAZKMOB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- SEUNTAIZLCAWDW-UHFFFAOYSA-N 1-oxa-8-azaspiro[4.5]decan-2-one Chemical class O1C(=O)CCC11CCNCC1 SEUNTAIZLCAWDW-UHFFFAOYSA-N 0.000 claims description 5
- ASPBBYVNTMIKLA-UHFFFAOYSA-N 2,8-diazaspiro[4.5]decan-3-one Chemical class C1NC(=O)CC21CCNCC2 ASPBBYVNTMIKLA-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
- SKGCHBGIBOPGHV-UHFFFAOYSA-N 1,3-dioxolan-2-imine Chemical class N=C1OCCO1 SKGCHBGIBOPGHV-UHFFFAOYSA-N 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 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 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- JKRDGUNXJABQFX-UHFFFAOYSA-N 3-cyclohexyl-8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound O=C1OC2(CCN(CCC=3C=CC(F)=CC=3)CC2)C(C)(O)N1C1CCCCC1 JKRDGUNXJABQFX-UHFFFAOYSA-N 0.000 claims description 3
- VRQDXCMKHWFAFO-UHFFFAOYSA-N 3-ethyl-8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound CC1(O)N(CC)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 VRQDXCMKHWFAFO-UHFFFAOYSA-N 0.000 claims description 3
- LCZRHNUWROXOTJ-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-4-methyl-3-propyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound CC1(O)N(CCC)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 LCZRHNUWROXOTJ-UHFFFAOYSA-N 0.000 claims description 3
- WMZXBIYCKCIDTB-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-cyclohexyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC2(C(N(C3CCCCC3)C(=O)O2)=C)CC1 WMZXBIYCKCIDTB-UHFFFAOYSA-N 0.000 claims description 3
- RINGGRQYDNFYMI-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-methylidene-1,3-dioxa-8-azaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC2(C(OC(=O)O2)=C)CC1 RINGGRQYDNFYMI-UHFFFAOYSA-N 0.000 claims description 3
- DXZFOANBRHMEGN-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-methylidene-3-phenyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC2(C(N(C(=O)O2)C=2C=CC=CC=2)=C)CC1 DXZFOANBRHMEGN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- KWYZAOLBJXZIQM-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-butyl-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound CC1(O)N(CCCC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 KWYZAOLBJXZIQM-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims 1
- 208000029028 brain injury Diseases 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 3
- 230000006931 brain damage Effects 0.000 abstract 1
- 231100000874 brain damage Toxicity 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 72
- 238000002844 melting Methods 0.000 description 54
- 230000008018 melting Effects 0.000 description 54
- 239000000243 solution Substances 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 230000002829 reductive effect Effects 0.000 description 28
- 239000002585 base Substances 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000000354 decomposition reaction Methods 0.000 description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012300 argon atmosphere Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 206010021143 Hypoxia Diseases 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-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
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 239000008298 dragée Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 230000007954 hypoxia Effects 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 150000007530 organic bases Chemical group 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010039966 Senile dementia Diseases 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000003920 cognitive function Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 description 3
- 239000012433 hydrogen halide Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- QDINHDOFPCBCDX-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)butyl]-4-ethynylpiperidin-4-ol Chemical compound C1CC(O)(C#C)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 QDINHDOFPCBCDX-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- VAYWNGUOZUVHQZ-UHFFFAOYSA-N 3-methyl-4-methylidene-8-(3-phenylpropyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(C)C(=O)OC11CCN(CCCC=2C=CC=CC=2)CC1 VAYWNGUOZUVHQZ-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- UGXBRFVWHZKUSR-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-3,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound CC1(O)N(C)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 UGXBRFVWHZKUSR-UHFFFAOYSA-N 0.000 description 2
- UGGIBROMPUIOKO-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-butyl-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(CCCC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 UGGIBROMPUIOKO-UHFFFAOYSA-N 0.000 description 2
- GOCCZEHUQUMBMB-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-butyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CCCC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 GOCCZEHUQUMBMB-UHFFFAOYSA-N 0.000 description 2
- MCAALVOMMYVHDQ-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-methyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(C)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 MCAALVOMMYVHDQ-UHFFFAOYSA-N 0.000 description 2
- WATNIUPZNBYOCC-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-hydroxy-4-methyl-3-propyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(CCC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 WATNIUPZNBYOCC-UHFFFAOYSA-N 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 208000002381 Brain Hypoxia Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 240000007651 Rubus glaucus Species 0.000 description 2
- 235000011034 Rubus glaucus Nutrition 0.000 description 2
- 235000009122 Rubus idaeus Nutrition 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000000181 anti-adherent effect Effects 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 238000003350 crude synaptosomal preparation Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229960002900 methylcellulose Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- YAFMYKFAUNCQPU-UHFFFAOYSA-N 1-(2-bromoethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CCBr)C=C1 YAFMYKFAUNCQPU-UHFFFAOYSA-N 0.000 description 1
- FLRUNCJXOVYWDH-UHFFFAOYSA-N 1-(2-bromoethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCBr)C=C1 FLRUNCJXOVYWDH-UHFFFAOYSA-N 0.000 description 1
- DZRCOQCVJZJNHG-UHFFFAOYSA-N 1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-hydroxypiperidin-4-yl]ethanone;hydrochloride Chemical compound Cl.C1CC(C(=O)C)(O)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 DZRCOQCVJZJNHG-UHFFFAOYSA-N 0.000 description 1
- VRWGWLXAOCAQHO-UHFFFAOYSA-N 1-[2-(4-chlorophenyl)ethyl]-4-ethynylpiperidin-4-ol Chemical compound C1CC(O)(C#C)CCN1CCC1=CC=C(Cl)C=C1 VRWGWLXAOCAQHO-UHFFFAOYSA-N 0.000 description 1
- NHROLWJBOUFSRG-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)butyl]-4-ethynylpiperidin-4-ol;hydrochloride Chemical compound Cl.C1CC(O)(C#C)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 NHROLWJBOUFSRG-UHFFFAOYSA-N 0.000 description 1
- UXXLTPGCINZEFM-UHFFFAOYSA-N 1-[4-chloro-1-(4-fluorophenyl)butyl]-4-fluorobenzene Chemical compound C1=CC(F)=CC=C1C(CCCCl)C1=CC=C(F)C=C1 UXXLTPGCINZEFM-UHFFFAOYSA-N 0.000 description 1
- GZQMPBBUYIHCDV-UHFFFAOYSA-N 1-[4-hydroxy-1-(2-phenylethyl)piperidin-4-yl]ethanone Chemical compound C1CC(C(=O)C)(O)CCN1CCC1=CC=CC=C1 GZQMPBBUYIHCDV-UHFFFAOYSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- BDQNKCYCTYYMAA-UHFFFAOYSA-N 1-isocyanatonaphthalene Chemical compound C1=CC=C2C(N=C=O)=CC=CC2=C1 BDQNKCYCTYYMAA-UHFFFAOYSA-N 0.000 description 1
- LQGLKWIXYWZNGB-UHFFFAOYSA-N 1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical class O1C(=O)NCC11CCNCC1 LQGLKWIXYWZNGB-UHFFFAOYSA-N 0.000 description 1
- OZDAOHVKBFBBMZ-UHFFFAOYSA-N 2-aminopentanedioic acid;hydrate Chemical compound O.OC(=O)C(N)CCC(O)=O OZDAOHVKBFBBMZ-UHFFFAOYSA-N 0.000 description 1
- NENUCJVGUPDXPC-UHFFFAOYSA-N 3,3-diphenylpropyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC(C=1C=CC=CC=1)C1=CC=CC=C1 NENUCJVGUPDXPC-UHFFFAOYSA-N 0.000 description 1
- MLVLWJVPBQEFMC-UHFFFAOYSA-N 3-[2-(3,4-dimethoxyphenyl)ethyl]-4-methylidene-8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=C(OC)C(OC)=CC=C1CCN1C(=C)C2(CCN(CCC=3C=CC=CC=3)CC2)OC1=O MLVLWJVPBQEFMC-UHFFFAOYSA-N 0.000 description 1
- DIUDMTSQBBWVPD-UHFFFAOYSA-N 3-benzyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound O=C1OC2(CCNCC2)C(=C)N1CC1=CC=CC=C1 DIUDMTSQBBWVPD-UHFFFAOYSA-N 0.000 description 1
- OFKJXESQNRAOAX-UHFFFAOYSA-N 3-benzyl-8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound O=C1OC2(CCN(CCC=3C=CC(F)=CC=3)CC2)C(C)(O)N1CC1=CC=CC=C1 OFKJXESQNRAOAX-UHFFFAOYSA-N 0.000 description 1
- IVWUSTQDHLGJNY-UHFFFAOYSA-N 3-benzyl-8-[2-(4-fluorophenyl)ethyl]-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1CCN1CCC2(C(N(CC=3C=CC=CC=3)C(=O)O2)=C)CC1 IVWUSTQDHLGJNY-UHFFFAOYSA-N 0.000 description 1
- UQNVCGXELDWMMF-UHFFFAOYSA-N 3-benzyl-8-[4,4-bis(4-fluorophenyl)butyl]-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.O=C1OC2(CCN(CCCC(C=3C=CC(F)=CC=3)C=3C=CC(F)=CC=3)CC2)C(C)(O)N1CC1=CC=CC=C1 UQNVCGXELDWMMF-UHFFFAOYSA-N 0.000 description 1
- ATJISRBMSWCLFL-UHFFFAOYSA-N 3-benzyl-8-[4,4-bis(4-fluorophenyl)butyl]-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC2(C(N(CC=3C=CC=CC=3)C(=O)O2)=C)CC1 ATJISRBMSWCLFL-UHFFFAOYSA-N 0.000 description 1
- VHOUNXRLQDWTKR-UHFFFAOYSA-N 3-butyl-8-[2-(4-chlorophenyl)ethyl]-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CCCC)C(=O)OC11CCN(CCC=2C=CC(Cl)=CC=2)CC1 VHOUNXRLQDWTKR-UHFFFAOYSA-N 0.000 description 1
- VWNUQUVAAXKTQC-UHFFFAOYSA-N 3-butyl-8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound CC1(O)N(CCCC)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 VWNUQUVAAXKTQC-UHFFFAOYSA-N 0.000 description 1
- XVOFFZASFRNJGG-UHFFFAOYSA-N 3-cyclohexyl-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound O=C1OC2(CCNCC2)C(C)(O)N1C1CCCCC1 XVOFFZASFRNJGG-UHFFFAOYSA-N 0.000 description 1
- RMIAOQVGIXLKAW-UHFFFAOYSA-N 3-cyclohexyl-4-methylidene-8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound O=C1OC2(CCN(CCC=3C=CC=CC=3)CC2)C(=C)N1C1CCCCC1 RMIAOQVGIXLKAW-UHFFFAOYSA-N 0.000 description 1
- IEXYYBDEFFUBMZ-UHFFFAOYSA-N 3-cyclohexyl-8-[2-(4-fluorophenyl)ethyl]-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1CCN1CCC2(C(N(C3CCCCC3)C(=O)O2)=C)CC1 IEXYYBDEFFUBMZ-UHFFFAOYSA-N 0.000 description 1
- JVKXGEYSRQHGTJ-UHFFFAOYSA-N 3-ethyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CC)C(=O)OC11CCNCC1 JVKXGEYSRQHGTJ-UHFFFAOYSA-N 0.000 description 1
- QKDLQERUSQMYLY-UHFFFAOYSA-N 3-ethyl-4-methylidene-8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CC)C(=O)OC11CCN(CCC=2C=CC=CC=2)CC1 QKDLQERUSQMYLY-UHFFFAOYSA-N 0.000 description 1
- OEYBKFPEOWXKRJ-UHFFFAOYSA-N 3-ethyl-4-methylidene-8-[2-(4-methylphenyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.C=C1N(CC)C(=O)OC11CCN(CCC=2C=CC(C)=CC=2)CC1 OEYBKFPEOWXKRJ-UHFFFAOYSA-N 0.000 description 1
- DJIDDCHCRPAINZ-UHFFFAOYSA-N 3-ethyl-8-[2-(4-fluorophenyl)ethyl]-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CC)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 DJIDDCHCRPAINZ-UHFFFAOYSA-N 0.000 description 1
- RGCKJSPKMTWLLX-UHFFFAOYSA-N 3-iodopropylbenzene Chemical compound ICCCC1=CC=CC=C1 RGCKJSPKMTWLLX-UHFFFAOYSA-N 0.000 description 1
- CXCWJIXRYUBKKM-UHFFFAOYSA-N 3-methyl-4-methylidene-8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(C)C(=O)OC11CCN(CCC=2C=CC=CC=2)CC1 CXCWJIXRYUBKKM-UHFFFAOYSA-N 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HHPWVBUPMWKKPS-UHFFFAOYSA-N 4-ethynyl-1-[2-(4-fluorophenyl)ethyl]piperidin-4-ol Chemical compound C1CC(O)(C#C)CCN1CCC1=CC=C(F)C=C1 HHPWVBUPMWKKPS-UHFFFAOYSA-N 0.000 description 1
- CSVUXAAJXDKDJH-UHFFFAOYSA-N 4-hydroxy-3,4-dimethyl-8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound CC1(O)N(C)C(=O)OC11CCN(CCC=2C=CC=CC=2)CC1 CSVUXAAJXDKDJH-UHFFFAOYSA-N 0.000 description 1
- WLCCCNSINMDGSH-UHFFFAOYSA-N 4-methylidene-1,3-dioxa-8-azaspiro[4.5]decan-2-one Chemical class C=C1OC(=O)OC11CCNCC1 WLCCCNSINMDGSH-UHFFFAOYSA-N 0.000 description 1
- UKEFJOZZELHXDK-UHFFFAOYSA-N 4-methylidene-3-propyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CCC)C(=O)OC11CCNCC1 UKEFJOZZELHXDK-UHFFFAOYSA-N 0.000 description 1
- UQBVBNUWFUOGQL-UHFFFAOYSA-N 4-methylidene-8-(2-phenylethyl)-3-propyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CCC)C(=O)OC11CCN(CCC=2C=CC=CC=2)CC1 UQBVBNUWFUOGQL-UHFFFAOYSA-N 0.000 description 1
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical class O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 1
- VWDMUWQNWPRKJV-UHFFFAOYSA-N 8-[2-(3,4-dimethoxyphenyl)ethyl]-3-methyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CCN1CCC2(C(N(C)C(=O)O2)=C)CC1 VWDMUWQNWPRKJV-UHFFFAOYSA-N 0.000 description 1
- XVFPHMGHSWAJHJ-UHFFFAOYSA-N 8-[2-(4-chlorophenyl)ethyl]-3-(3,4-dichlorophenyl)-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1CCN1CCC2(C(N(C(=O)O2)C=2C=C(Cl)C(Cl)=CC=2)=C)CC1 XVFPHMGHSWAJHJ-UHFFFAOYSA-N 0.000 description 1
- GLPDNYFQAPURLX-UHFFFAOYSA-N 8-[2-(4-chlorophenyl)ethyl]-3-[(3,4-dichlorophenyl)methyl]-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.O=C1OC2(CCN(CCC=3C=CC(Cl)=CC=3)CC2)C(C)(O)N1CC1=CC=C(Cl)C(Cl)=C1 GLPDNYFQAPURLX-UHFFFAOYSA-N 0.000 description 1
- XJAYQGDMCAFIRD-UHFFFAOYSA-N 8-[2-(4-chlorophenyl)ethyl]-3-cyclohexyl-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound O=C1OC2(CCN(CCC=3C=CC(Cl)=CC=3)CC2)C(C)(O)N1C1CCCCC1 XJAYQGDMCAFIRD-UHFFFAOYSA-N 0.000 description 1
- YFXGZOCQXUSXJU-UHFFFAOYSA-N 8-[2-(4-chlorophenyl)ethyl]-3-ethyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CC)C(=O)OC11CCN(CCC=2C=CC(Cl)=CC=2)CC1 YFXGZOCQXUSXJU-UHFFFAOYSA-N 0.000 description 1
- YTMMBSMORBBZOY-UHFFFAOYSA-N 8-[2-(4-chlorophenyl)ethyl]-3-methyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(C)C(=O)OC11CCN(CCC=2C=CC(Cl)=CC=2)CC1 YTMMBSMORBBZOY-UHFFFAOYSA-N 0.000 description 1
- YURMCNKYZHOCKP-UHFFFAOYSA-N 8-[2-(4-chlorophenyl)ethyl]-4-methylidene-3-propan-2-yl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(C(C)C)C(=O)OC11CCN(CCC=2C=CC(Cl)=CC=2)CC1 YURMCNKYZHOCKP-UHFFFAOYSA-N 0.000 description 1
- TXEQTWHQBFSHBT-UHFFFAOYSA-N 8-[2-(4-chlorophenyl)ethyl]-4-methylidene-3-propyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CCC)C(=O)OC11CCN(CCC=2C=CC(Cl)=CC=2)CC1 TXEQTWHQBFSHBT-UHFFFAOYSA-N 0.000 description 1
- WNXFWNVHRUTQLB-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-3-methyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(C)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 WNXFWNVHRUTQLB-UHFFFAOYSA-N 0.000 description 1
- SERHZXKLFFYVEG-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-4-methyl-3-naphthalen-1-yl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(C=2C3=CC=CC=C3C=CC=2)C(=O)OC1(CC1)CCN1CCC1=CC=C(F)C=C1 SERHZXKLFFYVEG-UHFFFAOYSA-N 0.000 description 1
- XVUCOUBOVFCQCQ-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-4-methyl-3-phenyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(C=2C=CC=CC=2)C(=O)OC1(CC1)CCN1CCC1=CC=C(F)C=C1 XVUCOUBOVFCQCQ-UHFFFAOYSA-N 0.000 description 1
- XHOKMAGQRBTZLE-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-hydroxy-4-methyl-3-propan-2-yl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound CC1(O)N(C(C)C)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 XHOKMAGQRBTZLE-UHFFFAOYSA-N 0.000 description 1
- UNRFSKMSKBUNJJ-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-methylidene-3-naphthalen-1-yl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1CCN1CCC2(C(N(C(=O)O2)C=2C3=CC=CC=C3C=CC=2)=C)CC1 UNRFSKMSKBUNJJ-UHFFFAOYSA-N 0.000 description 1
- QXUZAQAGGCNXBW-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-methylidene-3-phenyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1CCN1CCC2(C(N(C(=O)O2)C=2C=CC=CC=2)=C)CC1 QXUZAQAGGCNXBW-UHFFFAOYSA-N 0.000 description 1
- VUXPHDLYHYMKJL-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-methylidene-3-propan-2-yl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(C(C)C)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 VUXPHDLYHYMKJL-UHFFFAOYSA-N 0.000 description 1
- STHKZMXODQXZGN-UHFFFAOYSA-N 8-[2-(4-fluorophenyl)ethyl]-4-methylidene-3-propyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CCC)C(=O)OC11CCN(CCC=2C=CC(F)=CC=2)CC1 STHKZMXODQXZGN-UHFFFAOYSA-N 0.000 description 1
- TWQPKDMEBNXCQI-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-cyclohexyl-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.O=C1OC2(CCN(CCCC(C=3C=CC(F)=CC=3)C=3C=CC(F)=CC=3)CC2)C(C)(O)N1C1CCCCC1 TWQPKDMEBNXCQI-UHFFFAOYSA-N 0.000 description 1
- JGRBDGLCAYAYCD-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-decyl-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound CC1(O)N(CCCCCCCCCC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JGRBDGLCAYAYCD-UHFFFAOYSA-N 0.000 description 1
- MKFJMTAZLCLCSE-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-decyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CCCCCCCCCC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 MKFJMTAZLCLCSE-UHFFFAOYSA-N 0.000 description 1
- JFYSPSUWLIMRFJ-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-ethyl-4-hydroxy-4-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(CC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JFYSPSUWLIMRFJ-UHFFFAOYSA-N 0.000 description 1
- RQCQFYAOSOZJQQ-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-3-ethyl-4-methylidene-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 RQCQFYAOSOZJQQ-UHFFFAOYSA-N 0.000 description 1
- ZCJFYCIXRHEPHS-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-hydroxy-3,4-dimethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(C)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ZCJFYCIXRHEPHS-UHFFFAOYSA-N 0.000 description 1
- ODYPKIMMGYZZBW-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-hydroxy-4-methyl-3-naphthalen-1-yl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(C=2C3=CC=CC=C3C=CC=2)C(=O)OC1(CC1)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 ODYPKIMMGYZZBW-UHFFFAOYSA-N 0.000 description 1
- ZMPRUADVLMJBKQ-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-hydroxy-4-methyl-3-phenyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(C=2C=CC=CC=2)C(=O)OC1(CC1)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 ZMPRUADVLMJBKQ-UHFFFAOYSA-N 0.000 description 1
- VJDOORVWJXDXJE-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-hydroxy-4-methyl-3-propan-2-yl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;hydrochloride Chemical compound Cl.CC1(O)N(C(C)C)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 VJDOORVWJXDXJE-UHFFFAOYSA-N 0.000 description 1
- GEVQGWNIMSGWSR-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-methylidene-3-naphthalen-1-yl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC2(C(N(C(=O)O2)C=2C3=CC=CC=C3C=CC=2)=C)CC1 GEVQGWNIMSGWSR-UHFFFAOYSA-N 0.000 description 1
- LQBGJLVMYJGVSS-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-4-methylidene-3-propyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound C=C1N(CCC)C(=O)OC11CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 LQBGJLVMYJGVSS-UHFFFAOYSA-N 0.000 description 1
- DBANIFBSDHBPBL-UHFFFAOYSA-N 8-azaspiro[4.5]decane-3,4-dione Chemical class O=C1C(=O)CCC11CCNCC1 DBANIFBSDHBPBL-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N Aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 206010053398 Clonic convulsion Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 231100000642 Histotoxic hypoxia Toxicity 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 1
- RFMMMVDNIPUKGG-YFKPBYRVSA-N N-acetyl-L-glutamic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- UHPGWIUJTRACRS-UHFFFAOYSA-N [1-[4,4-bis(4-fluorophenyl)butyl]-4-butyl-4-ethynylpiperidin-2-yl] carbamate Chemical compound NC(=O)OC1CC(CCCC)(C#C)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 UHPGWIUJTRACRS-UHFFFAOYSA-N 0.000 description 1
- GSHOLEJLKIOBLP-UHFFFAOYSA-N [1-[4,4-bis(4-fluorophenyl)butyl]-4-ethynylpiperidin-4-yl] n-butylcarbamate;hydrochloride Chemical compound Cl.C1CC(OC(=O)NCCCC)(C#C)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 GSHOLEJLKIOBLP-UHFFFAOYSA-N 0.000 description 1
- DYYWYSKAMNJCHW-UHFFFAOYSA-N [4-acetyl-4-methyl-1-(2-phenylethyl)piperidin-2-yl] carbamate Chemical compound NC(=O)OC1CC(C(=O)C)(C)CCN1CCC1=CC=CC=C1 DYYWYSKAMNJCHW-UHFFFAOYSA-N 0.000 description 1
- PPAUYDBWBYEXQJ-UHFFFAOYSA-N [4-ethynyl-1-(3-phenylpropyl)piperidin-4-yl] n-methylcarbamate Chemical compound C1CC(OC(=O)NC)(C#C)CCN1CCCC1=CC=CC=C1 PPAUYDBWBYEXQJ-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 230000007654 ischemic lesion Effects 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- WSGCRAOTEDLMFQ-UHFFFAOYSA-N nonan-5-one Chemical compound CCCCC(=O)CCCC WSGCRAOTEDLMFQ-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229940114930 potassium stearate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- XOVSRHHCHKUFKM-UHFFFAOYSA-N s-methylthiohydroxylamine Chemical compound CSN XOVSRHHCHKUFKM-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical group C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU894095A HU204530B (en) | 1989-08-10 | 1989-08-10 | Process for producing new 1-oxa-2-oxo-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them |
| YU153890A YU47748B (sh) | 1989-08-10 | 1990-08-09 | 1-oksa-2-okso-8-azaspiro(4,5)dekan derivati i postupak za njihovo dobijanje |
| SG96294A SG96294G (en) | 1989-08-10 | 1994-07-16 | 1-oxa-2-oxo-8-azaspiro[4,5] decane derivatives, processes for their preparation and pharmaceutical compositions thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP920778A2 true HRP920778A2 (en) | 1998-02-28 |
Family
ID=26317733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP-1538/90A HRP920778A2 (en) | 1989-08-10 | 1992-10-01 | Novel 1-oxa-2-oxo-8-azaspiro74,5/ decane derivatives, pharmaceutical preparations containing them and process for the preparation thereof |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US5118687A (de) |
| EP (1) | EP0414421B1 (de) |
| JP (1) | JPH0749431B2 (de) |
| KR (1) | KR940006635B1 (de) |
| AT (1) | ATE103920T1 (de) |
| AU (1) | AU622039B2 (de) |
| BG (1) | BG60436B2 (de) |
| DD (1) | DD299429A5 (de) |
| DE (1) | DE69007904T2 (de) |
| DK (1) | DK0414421T3 (de) |
| ES (1) | ES2052180T3 (de) |
| FI (1) | FI93455C (de) |
| HK (1) | HK145994A (de) |
| HR (1) | HRP920778A2 (de) |
| HU (2) | HU204530B (de) |
| IE (1) | IE64911B1 (de) |
| IL (1) | IL95320A (de) |
| NO (1) | NO177962C (de) |
| NZ (1) | NZ234848A (de) |
| PL (3) | PL163431B1 (de) |
| SG (1) | SG96294G (de) |
| SI (1) | SI9011538A (de) |
| ZA (1) | ZA906302B (de) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| YU150489A (sh) * | 1989-08-10 | 1992-12-21 | W.L. Gore & Co. Gmbh. | Uređaj za ispitivanje odevnih predmeta na nepromočivost |
| JP4703926B2 (ja) * | 1999-10-15 | 2011-06-15 | ジェネティクス インスティテュート，エルエルシー | 骨形成蛋白をデリバリーするためのヒアルロン酸の処方 |
| KR20020091462A (ko) * | 2001-05-30 | 2002-12-06 | 삼성광주전자 주식회사 | 원료 굳음 방지기능을 갖는 자동판매기 및 그 제어방법 |
| GB201416346D0 (en) * | 2014-09-16 | 2014-10-29 | Shire Internat Gmbh | Spirocyclic derivatives |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR96352E (fr) * | 1967-12-29 | 1972-06-16 | Science Union & Cie | Nouveaux dérives du spiro (4,5) decane et leur procédé de préparation. |
| BE790675A (fr) * | 1971-10-29 | 1973-04-27 | Science Union & Cie | Nouveaux derives de l'oxa-1 diaza-3,8 spiro (4,5) decane |
| EP0189370A3 (de) * | 1985-01-16 | 1988-01-27 | Sandoz Ag | Spiro-dioxolane, -dithiolane und -oxothiolane |
| HU204529B (en) * | 1989-08-10 | 1992-01-28 | Richter Gedeon Vegyeszet | Process for producing new 1-oxa-2-oxo-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them |
| KR940003491B1 (ko) * | 1989-08-10 | 1994-04-23 | 리히터 게데온 베기에스제티 기아르 알.티 | 4,4-이중 치환된 피페리딘 유도체와 그 제조방법 및 상기 화합물을 함유하는 약제학적 조성물 |
-
1989
- 1989-08-10 HU HU894095A patent/HU204530B/hu not_active IP Right Cessation
-
1990
- 1990-08-09 NO NO903512A patent/NO177962C/no unknown
- 1990-08-09 EP EP90308784A patent/EP0414421B1/de not_active Expired - Lifetime
- 1990-08-09 DK DK90308784.9T patent/DK0414421T3/da active
- 1990-08-09 AU AU60807/90A patent/AU622039B2/en not_active Ceased
- 1990-08-09 IE IE288490A patent/IE64911B1/en not_active IP Right Cessation
- 1990-08-09 DE DE69007904T patent/DE69007904T2/de not_active Expired - Fee Related
- 1990-08-09 ES ES90308784T patent/ES2052180T3/es not_active Expired - Lifetime
- 1990-08-09 NZ NZ234848A patent/NZ234848A/en unknown
- 1990-08-09 IL IL9532090A patent/IL95320A/en not_active IP Right Cessation
- 1990-08-09 KR KR1019900012256A patent/KR940006635B1/ko not_active IP Right Cessation
- 1990-08-09 ZA ZA906302A patent/ZA906302B/xx unknown
- 1990-08-09 AT AT90308784T patent/ATE103920T1/de not_active IP Right Cessation
- 1990-08-09 DD DD90343361A patent/DD299429A5/de not_active IP Right Cessation
- 1990-08-09 SI SI9011538A patent/SI9011538A/sl unknown
- 1990-08-09 JP JP2209358A patent/JPH0749431B2/ja not_active Expired - Lifetime
- 1990-08-10 PL PL90291701A patent/PL163431B1/pl unknown
- 1990-08-10 PL PL90291702A patent/PL163593B1/pl unknown
- 1990-08-10 PL PL90286440A patent/PL163370B1/pl unknown
- 1990-08-10 FI FI903972A patent/FI93455C/fi not_active IP Right Cessation
- 1990-08-10 US US07/566,275 patent/US5118687A/en not_active Expired - Fee Related
-
1992
- 1992-10-01 HR HRP-1538/90A patent/HRP920778A2/hr not_active Application Discontinuation
-
1993
- 1993-12-02 BG BG98261A patent/BG60436B2/bg unknown
-
1994
- 1994-07-16 SG SG96294A patent/SG96294G/en unknown
- 1994-10-12 HU HU94P/P00036P patent/HU210072A9/hu unknown
- 1994-12-22 HK HK145994A patent/HK145994A/xx not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6180647B1 (en) | Substituted benzolactam compounds as substance P antagonists | |
| EP0258755B1 (de) | Alpha-alkyl-4-amino-3-chinolin-methanole und 1-(4-Aralkylamino-3-chinolyl)alkanone, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel | |
| AU633858B2 (en) | Arylpiperidine derivatives | |
| KR940002826B1 (ko) | 4-메틸렌-2-옥소-8-아자스피로[4,5]데칸 유도체, 그것의 이성질체, 산부가염, 제4급 암모늄염과 그것의 제조방법 및 그것을 함유하는 약제학적 조성물 | |
| KR950001022B1 (ko) | 신규한 2-옥소-1-옥사-8-아자스피로[4, 5]데칸 유도체와 이들을 포함하는 약제학적 조성물 및 그 제조방법 | |
| JP2665422B2 (ja) | 置換された１，２，３，４−テトラヒドロシクロペント〔ｂ〕インドール、１，２，３，３ａ，４，８ａ−ヘキサヒドロシクロペント〔ｂ〕インドールおよび関連化合物 | |
| US4243666A (en) | 4-Amino-2-piperidino-quinazolines | |
| US5118693A (en) | 4,4-disubstituted piperidine derivatives, pharmaceutical compositions containing them and process for preparing same | |
| CZ199992A3 (en) | 2-(piperidin-1-yl)ethanol derivatives, process of their preparation and pharmaceutical compositions containing said derivatives | |
| HRP920778A2 (en) | Novel 1-oxa-2-oxo-8-azaspiro74,5/ decane derivatives, pharmaceutical preparations containing them and process for the preparation thereof | |
| KR930006777B1 (ko) | 피리도[1,2-a]인돌 화합물 및 그 제조방법 | |
| US4277470A (en) | Heterocyclic spiro-linked amidines, compositions and use thereof | |
| FR2605008A1 (fr) | Derives d'imidazo (4,5-b)pyridinone-2, leur preparation et leur application en therapeutique | |
| DD147668A5 (de) | Verfahren zur herstellung von 7,8,9,10-tetrahydrothieno-eckige klammer auf 3,2-e eckige klammer zu pyrido eckige klammer auf 4,3-b eckige klammer zu indolen | |
| JPH085885B2 (ja) | 置換ピリミドインド−ル | |
| GB2115811A (en) | Ergot alkaloids | |
| EP0318166A2 (de) | Isoxazol[4,5-C]azepinderivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen | |
| CA2023019A1 (en) | 1-oxa-2-oxo-8-azaspiro/4,5/decane derivatives, pharmaceutical compositions containing them and process for preparing the same | |
| HU186810B (en) | Process for producing 2h-azeto/2,1-a/ isoquinoline-derivatives | |
| HU205119B (en) | Process for producing new 2-oxo-3,8-diaza-1-oxaspiro/4,5/decane derivatives and pharmaceutical compositions comprising same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A1OB | Publication of a patent application | ||
| AIPI | Request for the grant of a patent on the basis of a substantive examination of a patent application | ||
| ODBC | Application rejected |