BG61186B1 - Цис-2,3,3а,4,5,9в-хексахидро-1н-бензо(е)- индолови производни - Google Patents
Цис-2,3,3а,4,5,9в-хексахидро-1н-бензо(е)- индолови производни Download PDFInfo
- Publication number
- BG61186B1 BG61186B1 BG97201A BG9720192A BG61186B1 BG 61186 B1 BG61186 B1 BG 61186B1 BG 97201 A BG97201 A BG 97201A BG 9720192 A BG9720192 A BG 9720192A BG 61186 B1 BG61186 B1 BG 61186B1
- Authority
- BG
- Bulgaria
- Prior art keywords
- cis
- benzo
- hexahydro
- indol
- racemic
- Prior art date
Links
- 229940054051 antipsychotic indole derivative Drugs 0.000 title description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title 1
- -1 1-oxoisoindolin-2-yl Chemical group 0.000 claims abstract description 284
- 239000000203 mixture Substances 0.000 claims abstract description 215
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 11
- 125000003435 aroyl group Chemical group 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 7
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 7
- 125000005239 aroylamino group Chemical group 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 29
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 18
- JEYXDYNMDRWXJC-UHFFFAOYSA-N CN(C)C(=O)OC1=CC=C2C=CNC2=C1 Chemical compound CN(C)C(=O)OC1=CC=C2C=CNC2=C1 JEYXDYNMDRWXJC-UHFFFAOYSA-N 0.000 claims description 17
- 208000024827 Alzheimer disease Diseases 0.000 claims description 16
- 125000003277 amino group Chemical group 0.000 claims description 16
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- DWLVWMUCHSLGSU-UHFFFAOYSA-M n,n-dimethylcarbamate Chemical compound CN(C)C([O-])=O DWLVWMUCHSLGSU-UHFFFAOYSA-M 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 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 12
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 8
- 208000028698 Cognitive impairment Diseases 0.000 claims description 8
- 206010039966 Senile dementia Diseases 0.000 claims description 8
- 208000010877 cognitive disease Diseases 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 230000006993 memory improvement Effects 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- GWYZNBPESTULJZ-UHFFFAOYSA-N 2,3,3a,4,5,9b-hexahydro-1h-benzo[e]indole Chemical class C1=CC=C2C3CCNC3CCC2=C1 GWYZNBPESTULJZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- YUJCWMGBRDBPDL-UHFFFAOYSA-N 4,4-dimethylpiperidine-2,6-dione Chemical compound CC1(C)CC(=O)NC(=O)C1 YUJCWMGBRDBPDL-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 claims 1
- ZFRRYMKUWNBSPT-MJGOQNOKSA-N [(3aS,9bR)-3-(2-morpholin-4-ylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl] N,N-dimethylcarbamate Chemical compound CN(C(OC1=CC=CC=2[C@H]3CCN([C@H]3CCC21)CCN2CCOCC2)=O)C ZFRRYMKUWNBSPT-MJGOQNOKSA-N 0.000 claims 1
- JBGYYUFGDQQMKX-QUCCMNQESA-N [(3aS,9bR)-3-(cyclohexylmethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl] N,N-dimethylcarbamate Chemical compound CN(C(OC1=CC=CC=2[C@H]3CCN([C@H]3CCC21)CC2CCCCC2)=O)C JBGYYUFGDQQMKX-QUCCMNQESA-N 0.000 claims 1
- KTYICEXUPNKGIA-XXBNENTESA-N [(3aS,9bR)-3-[4-(1,3-dioxoisoindol-2-yl)butyl]-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl] N,N-dimethylcarbamate Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCCN1CC[C@@H]2C(C=CC=C3OC(=O)N(C)C)=C3CC[C@@H]21 KTYICEXUPNKGIA-XXBNENTESA-N 0.000 claims 1
- GXMHAHSLRYIDHI-CTNGQTDRSA-N [(3as,9br)-3-(2-cyclohexylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl] n,n-dimethylcarbamate Chemical compound C([C@@H]1C=2C=CC=C(C=2CC[C@@H]11)OC(=O)N(C)C)CN1CCC1CCCCC1 GXMHAHSLRYIDHI-CTNGQTDRSA-N 0.000 claims 1
- GVUHTASBVQCMBI-CTNGQTDRSA-N [(3as,9br)-3-(2-cyclohexylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl] n-ethylcarbamate Chemical compound C([C@@H]1C=2C=CC=C(C=2CC[C@@H]11)OC(=O)NCC)CN1CCC1CCCCC1 GVUHTASBVQCMBI-CTNGQTDRSA-N 0.000 claims 1
- HUGQDDJXYKRDAL-QUCCMNQESA-N [(3as,9br)-3-(2-cyclohexylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl] n-methylcarbamate Chemical compound C([C@@H]1C=2C=CC=C(C=2CC[C@@H]11)OC(=O)NC)CN1CCC1CCCCC1 HUGQDDJXYKRDAL-QUCCMNQESA-N 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 431
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 425
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 299
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 243
- 239000000243 solution Substances 0.000 description 234
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 192
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 180
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 119
- 239000000741 silica gel Substances 0.000 description 119
- 229910002027 silica gel Inorganic materials 0.000 description 119
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 113
- 239000013078 crystal Substances 0.000 description 110
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 108
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 108
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 104
- 239000003921 oil Substances 0.000 description 100
- 235000019198 oils Nutrition 0.000 description 100
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 93
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 92
- 229910052938 sodium sulfate Inorganic materials 0.000 description 92
- 235000011152 sodium sulphate Nutrition 0.000 description 92
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 70
- 238000004949 mass spectrometry Methods 0.000 description 66
- 239000012074 organic phase Substances 0.000 description 65
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 63
- 238000004587 chromatography analysis Methods 0.000 description 61
- 238000004821 distillation Methods 0.000 description 59
- 239000002585 base Substances 0.000 description 58
- 238000010992 reflux Methods 0.000 description 54
- 239000002904 solvent Substances 0.000 description 54
- 235000017557 sodium bicarbonate Nutrition 0.000 description 53
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 53
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 48
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 46
- 229920006395 saturated elastomer Polymers 0.000 description 45
- 238000002844 melting Methods 0.000 description 41
- 230000008018 melting Effects 0.000 description 41
- 238000001914 filtration Methods 0.000 description 40
- 238000001035 drying Methods 0.000 description 36
- 238000000605 extraction Methods 0.000 description 32
- 239000000460 chlorine Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- 239000000047 product Substances 0.000 description 26
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 239000011780 sodium chloride Substances 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- 239000000284 extract Substances 0.000 description 23
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 23
- 235000019341 magnesium sulphate Nutrition 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000001816 cooling Methods 0.000 description 21
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 20
- 238000001704 evaporation Methods 0.000 description 19
- 230000008020 evaporation Effects 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000012280 lithium aluminium hydride Substances 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 17
- 238000001953 recrystallisation Methods 0.000 description 16
- 239000006260 foam Substances 0.000 description 15
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 15
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 13
- 239000007868 Raney catalyst Substances 0.000 description 13
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 13
- 229910000564 Raney nickel Inorganic materials 0.000 description 13
- 238000002425 crystallisation Methods 0.000 description 13
- 230000008025 crystallization Effects 0.000 description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 description 12
- 238000000354 decomposition reaction Methods 0.000 description 12
- ZGBUJKAZQOPWGZ-UHFFFAOYSA-N ethyl 2-(5-methoxy-2-oxo-3,4-dihydro-1h-naphthalen-1-yl)acetate Chemical compound C1=CC=C2C(CC(=O)OCC)C(=O)CCC2=C1OC ZGBUJKAZQOPWGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 11
- 239000012300 argon atmosphere Substances 0.000 description 11
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 11
- 239000013543 active substance Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 235000009518 sodium iodide Nutrition 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 230000008719 thickening Effects 0.000 description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000008108 microcrystalline cellulose Substances 0.000 description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229960004373 acetylcholine Drugs 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000010411 cooking Methods 0.000 description 4
- QXNCRJVBIMSYRT-UHFFFAOYSA-N isoindole-1,3-dione;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)NC(=O)C2=C1 QXNCRJVBIMSYRT-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- TXVLRUUCFLXUPI-UHFFFAOYSA-N 6-methoxy-1,3,4,5-tetrahydrobenzo[e]indol-2-one Chemical compound N1C(=O)CC2=C1CCC1=C2C=CC=C1OC TXVLRUUCFLXUPI-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 239000004368 Modified starch Substances 0.000 description 3
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 3
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 235000014121 butter Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 235000019426 modified starch Nutrition 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000011241 protective layer Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- OQURWGJAWSLGQG-UHFFFAOYSA-N 1-isocyanatopropane Chemical compound CCCN=C=O OQURWGJAWSLGQG-UHFFFAOYSA-N 0.000 description 2
- LJTNQTHDJSXZBM-UHFFFAOYSA-N 2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl N,N-dimethylcarbamate Chemical compound C1CNC2CCC3=C(C12)C=CC=C3OC(N(C)C)=O LJTNQTHDJSXZBM-UHFFFAOYSA-N 0.000 description 2
- NILLIUYSJFTTRH-UHFFFAOYSA-N 2-cyclopentylacetyl chloride Chemical compound ClC(=O)CC1CCCC1 NILLIUYSJFTTRH-UHFFFAOYSA-N 0.000 description 2
- ZUKTUEOOOXEFML-UHFFFAOYSA-N 2-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC=C2C(=O)C(OC)CCC2=C1 ZUKTUEOOOXEFML-UHFFFAOYSA-N 0.000 description 2
- LYUQWQRTDLVQGA-UHFFFAOYSA-N 3-phenylpropylamine Chemical compound NCCCC1=CC=CC=C1 LYUQWQRTDLVQGA-UHFFFAOYSA-N 0.000 description 2
- FTBWBGSIRBQWHC-UHFFFAOYSA-N 6-bromo-1-(3,4-dimethoxyphenyl)hexan-1-one Chemical compound COC1=CC=C(C(=O)CCCCCBr)C=C1OC FTBWBGSIRBQWHC-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- LPDFJIGNWBBNHV-UHFFFAOYSA-N C1C=NC=2C=CC3=C(C12)C=CC=C3O Chemical compound C1C=NC=2C=CC3=C(C12)C=CC=C3O LPDFJIGNWBBNHV-UHFFFAOYSA-N 0.000 description 2
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical class NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- GICPQDXTOXLAFH-CTNGQTDRSA-N [(3aS,9bR)-3-(2-cyclohexylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]-methylcarbamic acid Chemical compound CN(C1=CC=CC2=C1CC[C@H]3[C@@H]2CCN3CCC4CCCCC4)C(=O)O GICPQDXTOXLAFH-CTNGQTDRSA-N 0.000 description 2
- BNOSWDNBZTXLQH-RPWUZVMVSA-N [(3aS,9bR)-3-(4-cyclohexylbutyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCCCC4CCCCC4)C(=O)O BNOSWDNBZTXLQH-RPWUZVMVSA-N 0.000 description 2
- MUMTYKHVSRRDKY-PKTZIBPZSA-N [(3aS,9bR)-3-(4-oxo-4-phenylbutyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCCC(=O)C4=CC=CC=C4)C(=O)O MUMTYKHVSRRDKY-PKTZIBPZSA-N 0.000 description 2
- FTRUHFLMWGBDPL-RTWAWAEBSA-N [(3aS,9bR)-3-(cyclohexylmethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CC4CCCCC4)C(=O)O FTRUHFLMWGBDPL-RTWAWAEBSA-N 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 125000005543 phthalimide group Chemical group 0.000 description 2
- 125000005544 phthalimido group Chemical group 0.000 description 2
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 2
- 229960001697 physostigmine Drugs 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 108010085082 sigma receptors Proteins 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- OFBLAAHAENUFKV-ZFNKBKEPSA-N (3aS,9bR)-3-(2-cyclohexylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-ol hydrochloride Chemical compound Cl.C([C@@H]1C=2C=CC=C(C=2CC[C@@H]11)O)CN1CCC1CCCCC1 OFBLAAHAENUFKV-ZFNKBKEPSA-N 0.000 description 1
- BRPJAXPTSWGJPU-UHFFFAOYSA-N 1-(2-piperidin-1-ylethyl)benzo[e]indol-2-one Chemical compound N1(CCCCC1)CCC=1C(N=C2C=CC3=C(C=12)C=CC=C3)=O BRPJAXPTSWGJPU-UHFFFAOYSA-N 0.000 description 1
- QQCSGYBVHXFEFG-UHFFFAOYSA-N 1-(4-bromobutyl)-4,4-dimethylpiperidine-2,6-dione Chemical compound CC1(C)CC(=O)N(CCCCBr)C(=O)C1 QQCSGYBVHXFEFG-UHFFFAOYSA-N 0.000 description 1
- DOGQFDKGPZUREJ-UHFFFAOYSA-N 1-(5-bromopentyl)-4,4-dimethylpiperidine-2,6-dione Chemical compound CC1(C)CC(=O)N(CCCCCBr)C(=O)C1 DOGQFDKGPZUREJ-UHFFFAOYSA-N 0.000 description 1
- NXMSERABFMBJIC-UHFFFAOYSA-N 1H-indol-6-yl N-ethylcarbamate Chemical compound C(C)NC(OC1=CC=C2C=CNC2=C1)=O NXMSERABFMBJIC-UHFFFAOYSA-N 0.000 description 1
- PQLRKLNTODQYQC-UHFFFAOYSA-N 1h-benzo[e]indole Chemical compound C1=CC=CC2=C3CC=NC3=CC=C21 PQLRKLNTODQYQC-UHFFFAOYSA-N 0.000 description 1
- ARHLPAHITBIHRC-UHFFFAOYSA-N 2,3,3a,4,5,9b-hexahydro-1h-benzo[e]indol-6-ol Chemical compound C12CCNC2CCC2=C1C=CC=C2O ARHLPAHITBIHRC-UHFFFAOYSA-N 0.000 description 1
- UXFWTIGUWHJKDD-UHFFFAOYSA-N 2-(4-bromobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCBr)C(=O)C2=C1 UXFWTIGUWHJKDD-UHFFFAOYSA-N 0.000 description 1
- QKVHAKICMNABGB-UHFFFAOYSA-N 2-(5-bromopentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCCBr)C(=O)C2=C1 QKVHAKICMNABGB-UHFFFAOYSA-N 0.000 description 1
- XOQFMNXQYSTQPE-UHFFFAOYSA-N 2-bromo-1-phenylpentan-1-one Chemical compound CCCC(Br)C(=O)C1=CC=CC=C1 XOQFMNXQYSTQPE-UHFFFAOYSA-N 0.000 description 1
- YAQLSKVCTLCIIE-UHFFFAOYSA-N 2-bromobutyric acid Chemical compound CCC(Br)C(O)=O YAQLSKVCTLCIIE-UHFFFAOYSA-N 0.000 description 1
- JRQAAYVLPPGEHT-UHFFFAOYSA-N 2-bromoethylcyclohexane Chemical compound BrCCC1CCCCC1 JRQAAYVLPPGEHT-UHFFFAOYSA-N 0.000 description 1
- TUVZJIFNOYFYNS-UHFFFAOYSA-N 2-butyl-3h-isoindol-1-one Chemical compound C1=CC=C2C(=O)N(CCCC)CC2=C1 TUVZJIFNOYFYNS-UHFFFAOYSA-N 0.000 description 1
- RWAKBGVDMQRDNA-UHFFFAOYSA-N 2-chloro-1-phenylbutan-1-one Chemical compound CCC(Cl)C(=O)C1=CC=CC=C1 RWAKBGVDMQRDNA-UHFFFAOYSA-N 0.000 description 1
- PFSLCDNYNJTYDO-UHFFFAOYSA-N 2-cyclopentylpropanoyl chloride Chemical compound ClC(=O)C(C)C1CCCC1 PFSLCDNYNJTYDO-UHFFFAOYSA-N 0.000 description 1
- CJNRGSHEMCMUOE-UHFFFAOYSA-N 2-piperidin-1-ylethanamine Chemical compound NCCN1CCCCC1 CJNRGSHEMCMUOE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- UIKUBYKUYUSRSM-UHFFFAOYSA-N 3-morpholinopropylamine Chemical compound NCCCN1CCOCC1 UIKUBYKUYUSRSM-UHFFFAOYSA-N 0.000 description 1
- SHOJVFLWKSRVPH-UHFFFAOYSA-N 3-propyl-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-ol Chemical compound C1=CC=C2C3CCN(CCC)C3CCC2=C1O SHOJVFLWKSRVPH-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
- HXAOUYGZEOZTJO-UHFFFAOYSA-N 4-chloro-1-(4-fluorophenyl)butan-1-one Chemical compound FC1=CC=C(C(=O)CCCCl)C=C1 HXAOUYGZEOZTJO-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- AJBWNNKDUMXZLM-UHFFFAOYSA-N 4-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=C(C(O)=O)C=C1 AJBWNNKDUMXZLM-UHFFFAOYSA-N 0.000 description 1
- AGNFWIZBEATIAK-UHFFFAOYSA-N 4-phenylbutylamine Chemical compound NCCCCC1=CC=CC=C1 AGNFWIZBEATIAK-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- MDAIAXRTLTVEOU-UHFFFAOYSA-N 5-methoxy-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1C(=O)CCC2=C1C=CC=C2OC MDAIAXRTLTVEOU-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ATBGWANMMRTMLX-UHFFFAOYSA-N 6-methoxy-1,3,3a,4,5,9b-hexahydrobenzo[e]indol-2-one Chemical compound C12CC(=O)NC2CCC2=C1C=CC=C2OC ATBGWANMMRTMLX-UHFFFAOYSA-N 0.000 description 1
- MLYIUHOUXKYDNT-UHFFFAOYSA-N 6-methoxy-2,3,3a,4,5,9b-hexahydro-1h-benzo[e]indole Chemical compound C12CCNC2CCC2=C1C=CC=C2OC MLYIUHOUXKYDNT-UHFFFAOYSA-N 0.000 description 1
- INXBNRUOTLRZHH-UHFFFAOYSA-N 6-methoxy-3-(2-morpholin-4-ylethyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-one Chemical compound C12CCC=3C(OC)=CC=CC=3C2CC(=O)N1CCN1CCOCC1 INXBNRUOTLRZHH-UHFFFAOYSA-N 0.000 description 1
- VUKJBNUKLLGULS-UHFFFAOYSA-N 6-methoxy-3-propyl-1,2,3a,4,5,9b-hexahydrobenzo[e]indole Chemical compound C1=CC=C2C3CCN(CCC)C3CCC2=C1OC VUKJBNUKLLGULS-UHFFFAOYSA-N 0.000 description 1
- RFPQPZZKJLRNHU-UHFFFAOYSA-N 6-methoxy-3-propyl-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-one Chemical compound C1CC2=C(OC)C=CC=C2C2C1N(CCC)C(=O)C2 RFPQPZZKJLRNHU-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- BTYBORAHYUCUMH-UHFFFAOYSA-N 8-methoxy-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1CC(=O)CC2=C1C=CC=C2OC BTYBORAHYUCUMH-UHFFFAOYSA-N 0.000 description 1
- HPUKPOAWHHZLIX-UHFFFAOYSA-N 9-methoxy-3-propyl-1,2,3a,4,5,9b-hexahydrobenzo[e]indole Chemical compound C1=CC(OC)=C2C3CCN(CCC)C3CCC2=C1 HPUKPOAWHHZLIX-UHFFFAOYSA-N 0.000 description 1
- NPJUHLQEIGCEOI-UHFFFAOYSA-N Br.N1C=CC2=CC=C(C=C12)O Chemical compound Br.N1C=CC2=CC=C(C=C12)O NPJUHLQEIGCEOI-UHFFFAOYSA-N 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- DIFJERMTSUPXSB-YADHBBJMSA-N CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCCN4CCCCC4)C(=O)O Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCCN4CCCCC4)C(=O)O DIFJERMTSUPXSB-YADHBBJMSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HDPXRRBHNJGDJG-UHFFFAOYSA-N Cl.CN(C(=O)OC1=CC=C2C=CNC2=C1)C Chemical compound Cl.CN(C(=O)OC1=CC=C2C=CNC2=C1)C HDPXRRBHNJGDJG-UHFFFAOYSA-N 0.000 description 1
- BFJMNZVENWTQNI-UHFFFAOYSA-N Cl.CN(C(OC1=CC=CC=2C3CCNC3CCC21)=O)C Chemical compound Cl.CN(C(OC1=CC=CC=2C3CCNC3CCC21)=O)C BFJMNZVENWTQNI-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 101100114416 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) con-10 gene Proteins 0.000 description 1
- 101100432028 Rattus norvegicus Yes1 gene Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LWTIMMGSHYBSGP-RTWAWAEBSA-N [(3aS,9bR)-3-(2-cyclohexylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]-ethylcarbamic acid Chemical compound CCN(C1=CC=CC2=C1CC[C@H]3[C@@H]2CCN3CCC4CCCCC4)C(=O)O LWTIMMGSHYBSGP-RTWAWAEBSA-N 0.000 description 1
- UYNNADWEGNDTRN-RTWAWAEBSA-N [(3aS,9bR)-3-(2-cyclopentylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCC4CCCC4)C(=O)O UYNNADWEGNDTRN-RTWAWAEBSA-N 0.000 description 1
- NOGUVXJKMUBGDR-MOPGFXCFSA-N [(3aS,9bR)-3-(3-methylbutyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CC(C)CCN1CC[C@H]2[C@@H]1CCC3=C(C=CC=C23)CN(C)C(=O)O NOGUVXJKMUBGDR-MOPGFXCFSA-N 0.000 description 1
- PDJHWFQCWFWSCW-RDGATRHJSA-N [(3aS,9bR)-3-[5-(1,3-dioxoisoindol-2-yl)pentyl]-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCCCCN4C(=O)C5=CC=CC=C5C4=O)C(=O)O PDJHWFQCWFWSCW-RDGATRHJSA-N 0.000 description 1
- RBXUHGKZXQXKAJ-RPWUZVMVSA-N [(3aS,9bR)-3-[5-(3,4-dimethoxyphenyl)-5-oxopentyl]-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCCCC(=O)C4=CC(=C(C=C4)OC)OC)C(=O)O RBXUHGKZXQXKAJ-RPWUZVMVSA-N 0.000 description 1
- XPEJVRXHEKKHDG-FTJBHMTQSA-N [(3aS,9bR)-3-[5-(3-oxo-1H-isoindol-2-yl)pentyl]-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCCCCN4CC5=CC=CC=C5C4=O)C(=O)O XPEJVRXHEKKHDG-FTJBHMTQSA-N 0.000 description 1
- VUACLKOOGWOJCL-SXOMAYOGSA-N [(3aS,9bR)-3-[6-(3-oxo-1H-isoindol-2-yl)hexyl]-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl]methyl-methylcarbamic acid Chemical compound CN(CC1=C2CC[C@H]3[C@@H](C2=CC=C1)CCN3CCCCCCN4CC5=CC=CC=C5C4=O)C(=O)O VUACLKOOGWOJCL-SXOMAYOGSA-N 0.000 description 1
- GIJYWCFZRQURNP-LBPAWUGGSA-N [(3as,9br)-3-(2-cyclohexylethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-6-yl] n-ethyl-n-methylcarbamate;hydrochloride Chemical compound Cl.C([C@@H]1C=2C=CC=C(C=2CC[C@@H]11)OC(=O)N(C)CC)CN1CCC1CCCCC1 GIJYWCFZRQURNP-LBPAWUGGSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BFAKENXZKHGIGE-UHFFFAOYSA-N bis(2,3,5,6-tetrafluoro-4-iodophenyl)diazene Chemical compound FC1=C(C(=C(C(=C1F)I)F)F)N=NC1=C(C(=C(C(=C1F)F)I)F)F BFAKENXZKHGIGE-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- AQNQQHJNRPDOQV-UHFFFAOYSA-N bromocyclohexane Chemical compound BrC1CCCCC1 AQNQQHJNRPDOQV-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- UTZVRFPLSSHYGF-UHFFFAOYSA-N carboxy(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)C(O)=O UTZVRFPLSSHYGF-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 150000003950 cyclic amides Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- AVKNGPAMCBSNSO-UHFFFAOYSA-N cyclohexylmethanamine Chemical compound NCC1CCCCC1 AVKNGPAMCBSNSO-UHFFFAOYSA-N 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- UWRZJQUXJAOASA-UHFFFAOYSA-N ethyl 2-(8-methoxy-2-oxo-3,4-dihydro-1H-naphthalen-1-yl)acetate Chemical compound COC=1C=CC=C2CCC(C(C=12)CC(=O)OCC)=O UWRZJQUXJAOASA-UHFFFAOYSA-N 0.000 description 1
- XIMFCGSNSKXPBO-UHFFFAOYSA-N ethyl 2-bromobutanoate Chemical compound CCOC(=O)C(Br)CC XIMFCGSNSKXPBO-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- JPYAHQUNMYHNDY-MHECFPHRSA-N n-[(1r,2s)-2-(3,4-dimethoxyphenyl)-7-methoxy-6-propan-2-yloxy-1,2,3,4-tetrahydronaphthalen-1-yl]-n-methylformamide Chemical compound C1=C(OC)C(OC)=CC=C1[C@H]1[C@@H](N(C)C=O)C2=CC(OC)=C(OC(C)C)C=C2CC1 JPYAHQUNMYHNDY-MHECFPHRSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XZVYDRLPXWFRIS-UHFFFAOYSA-N n-ethyl-n-methylcarbamoyl chloride Chemical compound CCN(C)C(Cl)=O XZVYDRLPXWFRIS-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent 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
- 150000003892 tartrate salts Chemical class 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH380691 | 1991-12-20 | ||
| CH325492 | 1992-10-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| BG97201A BG97201A (bg) | 1993-12-24 |
| BG61186B1 true BG61186B1 (bg) | 1997-02-28 |
Family
ID=25692569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BG97201A BG61186B1 (bg) | 1991-12-20 | 1992-12-18 | Цис-2,3,3а,4,5,9в-хексахидро-1н-бензо(е)- индолови производни |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US5318966A (ja) |
| EP (1) | EP0548664B1 (ja) |
| JP (1) | JPH07119215B2 (ja) |
| CN (1) | CN1037510C (ja) |
| AT (1) | ATE123277T1 (ja) |
| AU (1) | AU661076B2 (ja) |
| BG (1) | BG61186B1 (ja) |
| CA (1) | CA2084442A1 (ja) |
| CZ (1) | CZ381092A3 (ja) |
| DE (1) | DE59202406D1 (ja) |
| DK (1) | DK0548664T3 (ja) |
| ES (1) | ES2073847T3 (ja) |
| FI (1) | FI925774A (ja) |
| GR (1) | GR3017256T3 (ja) |
| HU (2) | HUT68178A (ja) |
| IL (1) | IL104080A (ja) |
| IS (1) | IS3961A (ja) |
| MY (1) | MY108026A (ja) |
| NO (1) | NO179325C (ja) |
| NZ (1) | NZ245463A (ja) |
| TW (1) | TW239127B (ja) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5486611A (en) * | 1989-07-13 | 1996-01-23 | The Upjohn Company | Carboxamido-(1,2N)-carbocyclic-2-aminotetralin derivatives |
| AU648032B2 (en) * | 1989-07-13 | 1994-04-14 | Pharmacia & Upjohn Company | (1,2N) and (3,2N)-carbocyclic-2-amino tetralin derivatives |
| JP3049089B2 (ja) * | 1990-01-11 | 2000-06-05 | ファルマシア・アンド・アップジョン・カンパニー | 新規な中枢作用性の６，７，８，９―テトラヒドロ―３Ｈ―ベンズ［ｅ］インドールヘテロ環式化合物 |
| US5434170A (en) * | 1993-12-23 | 1995-07-18 | Andrulis Pharmaceuticals Corp. | Method for treating neurocognitive disorders |
| CN1166169A (zh) * | 1994-07-27 | 1997-11-26 | 三共株式会社 | 用作毒蕈碱性受体别构效应物的杂环化合物 |
| US5859295A (en) * | 1994-12-05 | 1999-01-12 | University Of Kentucky Research Foundation | Canavanine analogs and their use as chemotherapeutic agents |
| IL117149A0 (en) * | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
| US5889006A (en) * | 1995-02-23 | 1999-03-30 | Schering Corporation | Muscarinic antagonists |
| GB9612153D0 (en) * | 1996-06-11 | 1996-08-14 | Smithkline Beecham Plc | Compounds |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1277789A (en) * | 1969-09-08 | 1972-06-14 | Logeais Labor Jacques | Improvements in or relating to new polycyclic pyrrole derivatives |
| JPS4930836B1 (ja) * | 1971-07-22 | 1974-08-16 | ||
| JPS4916862A (ja) * | 1972-06-14 | 1974-02-14 | ||
| SE8004002L (sv) * | 1980-05-29 | 1981-11-30 | Arvidsson Folke Lars Erik | Terapeutiskt anvendbara tetralinderivat |
| SE8302361D0 (sv) * | 1983-04-27 | 1983-04-27 | Astra Laekemedel Ab | New tricyclic amines |
| ES2123500T3 (es) * | 1989-05-31 | 1999-01-16 | Upjohn Co | Derivados de 8-heterociclil-2-aminotetralina activos sobre el sistema nervioso central. |
| AU648032B2 (en) * | 1989-07-13 | 1994-04-14 | Pharmacia & Upjohn Company | (1,2N) and (3,2N)-carbocyclic-2-amino tetralin derivatives |
-
1992
- 1992-11-27 TW TW081109528A patent/TW239127B/zh active
- 1992-12-03 CA CA002084442A patent/CA2084442A1/en not_active Abandoned
- 1992-12-09 DK DK92120925.0T patent/DK0548664T3/da active
- 1992-12-09 ES ES92120925T patent/ES2073847T3/es not_active Expired - Lifetime
- 1992-12-09 AT AT92120925T patent/ATE123277T1/de active
- 1992-12-09 DE DE59202406T patent/DE59202406D1/de not_active Expired - Fee Related
- 1992-12-09 EP EP92120925A patent/EP0548664B1/de not_active Expired - Lifetime
- 1992-12-14 NO NO924829A patent/NO179325C/no unknown
- 1992-12-14 HU HU9203956A patent/HUT68178A/hu unknown
- 1992-12-14 NZ NZ245463A patent/NZ245463A/en unknown
- 1992-12-14 IL IL104080A patent/IL104080A/xx not_active IP Right Cessation
- 1992-12-14 HU HU9203956A patent/HU9203956D0/hu unknown
- 1992-12-15 AU AU30186/92A patent/AU661076B2/en not_active Ceased
- 1992-12-18 BG BG97201A patent/BG61186B1/bg unknown
- 1992-12-18 IS IS3961A patent/IS3961A/is unknown
- 1992-12-18 FI FI925774A patent/FI925774A/fi not_active Application Discontinuation
- 1992-12-18 MY MYPI92002338A patent/MY108026A/en unknown
- 1992-12-19 CN CN92114640A patent/CN1037510C/zh not_active Expired - Fee Related
- 1992-12-21 CZ CS923810A patent/CZ381092A3/cs unknown
- 1992-12-21 JP JP4355382A patent/JPH07119215B2/ja not_active Expired - Lifetime
-
1993
- 1993-07-16 US US08/093,412 patent/US5318966A/en not_active Expired - Fee Related
- 1993-09-03 US US08/118,831 patent/US5318967A/en not_active Expired - Fee Related
-
1995
- 1995-08-30 GR GR950402372T patent/GR3017256T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06128228A (ja) | 1994-05-10 |
| TW239127B (ja) | 1995-01-21 |
| NZ245463A (en) | 1995-05-26 |
| FI925774A0 (fi) | 1992-12-18 |
| GR3017256T3 (en) | 1995-11-30 |
| CN1088576A (zh) | 1994-06-29 |
| NO179325C (no) | 1996-09-18 |
| ES2073847T3 (es) | 1995-08-16 |
| EP0548664B1 (de) | 1995-05-31 |
| CZ381092A3 (en) | 1993-09-15 |
| IL104080A (en) | 1997-04-15 |
| NO924829D0 (no) | 1992-12-14 |
| AU3018692A (en) | 1993-06-24 |
| IL104080A0 (en) | 1993-05-13 |
| NO924829L (no) | 1993-06-21 |
| BG97201A (bg) | 1993-12-24 |
| FI925774A (fi) | 1993-06-21 |
| AU661076B2 (en) | 1995-07-13 |
| HUT68178A (en) | 1995-05-29 |
| EP0548664A1 (de) | 1993-06-30 |
| MY108026A (en) | 1996-07-30 |
| US5318967A (en) | 1994-06-07 |
| CN1037510C (zh) | 1998-02-25 |
| CA2084442A1 (en) | 1993-06-21 |
| ATE123277T1 (de) | 1995-06-15 |
| HU9203956D0 (en) | 1993-03-29 |
| DK0548664T3 (da) | 1995-09-04 |
| JPH07119215B2 (ja) | 1995-12-20 |
| DE59202406D1 (de) | 1995-07-06 |
| US5318966A (en) | 1994-06-07 |
| NO179325B (no) | 1996-06-10 |
| IS3961A (is) | 1993-06-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5585378A (en) | Composition containing an oxoindole compound | |
| AU662960B2 (en) | N-sulphonyl-2-oxoindole derivatives having affinity for vasopressin and/or ocytocin receptors | |
| JPH11512701A (ja) | 選択的なβ▲下３▼アドレナリン作動性アゴニスト | |
| JPH06199784A (ja) | 新規なアリールエチアミン化合物、その製法、及びこれを含有する医薬組成物。 | |
| FR2796644A1 (fr) | Nouveaux derives de beta-carboline, leur procede de preparation et les compositions pharmaceutiques qui les contiennent | |
| NO177007B (no) | Analogifremgangsmåte for fremstilling av terapeutisk aktive tetrahydrobenzimidazolderivater | |
| US4153789A (en) | Phenylindolines | |
| EP0677042B1 (fr) | Ligands selectifs des recepteurs 5ht1d-5ht1b derives d'indole-piperazine utiles comme medicaments | |
| EP0694536A1 (fr) | Dérivés de 1-benzyl-1,3-dihydro-2H-benzimidazol-2-one, leur préparation, et compositions pharmaceutiques les contenant | |
| EP0496314B1 (en) | Substituted 1,2,3,4-tetrahydrocyclopent[b]indoles, 1,2,3,3a,4,8a-hexahydrocyclopent[b]indoles and related compounds, intermediates and a process for the preparation thereof and their use as medicaments | |
| CA2065986C (en) | 1-(pyrido[3,4-b]-1,4-oxazinyl-4-yl)-1h-indoles, intermediates and a process for their preparation, and their use as medicaments | |
| BG61186B1 (bg) | Цис-2,3,3а,4,5,9в-хексахидро-1н-бензо(е)- индолови производни | |
| US5330986A (en) | Indole-7-carboxamide derivatives | |
| US4420485A (en) | 1'-[3-(1,2-Benzisoxazol-3-yl) proply]spiro[benzofuran-2(3H),3' or 4'-piperidines or 3'-pyrrolidines] | |
| WO1995001334A1 (fr) | Composes indoliques derives d'arylamines comme ligands selectifs des recepteurs 5ht1d et 5ht¿1b? | |
| SK281761B6 (sk) | Fenylindolová zlúčenina, farmaceutický prostriedok s jej obsahom a jej použitie | |
| EP0004342B1 (en) | Carbazoles, process for their preparation, pharmaceutical compositions containing them, and intermediates thereto | |
| JPH0377866A (ja) | 新規４，４‐二置換ピペリジン誘導体、それらを含む医薬組成物およびそれらの調製方法 | |
| US5344927A (en) | Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same | |
| US5298626A (en) | Select cyclopent[b]indoles | |
| JPH0733744A (ja) | インダゾール誘導体およびその塩 | |
| US5192789A (en) | Substituted 1,2,3,4-tetrahydrocyclopent[b]indoles, 1,2,3,3a,4,8a-hexahydrocyclopent[b]indoles and related compounds | |
| US4343812A (en) | Antidepressant 2-amino-and-2-(substituted amino)-cis-hexahydro-carbazoles, compositions and use | |
| CA2346506C (fr) | Derives d'aryl-{4-fluoro-4-[(2-pyridin-2-yl-ethylamino)-methyl]-piperidin-1-yl}-methanone comme agonistes du recepteur 5-ht1 | |
| CA2614000A1 (fr) | Nouveaux derives 1h-indole-pyridinecarboxamides et 1h-indole-piperidinecarboxamide, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |