TWI431007B - 作為α７菸鹼乙醯膽鹼受體配位體之啶化合物 - Google Patents

Info

Publication number

TWI431007B

TWI431007B TW098113525A TW98113525A TWI431007B TW I431007 B TWI431007 B TW I431007B TW 098113525 A TW098113525 A TW 098113525A TW 98113525 A TW98113525 A TW 98113525A TW I431007 B TWI431007 B TW I431007B

Authority

TW

Taiwan

Prior art keywords

mmol

methyl

amine

pyrimidinyl

pyridyl

Prior art date

2008-04-23

Links

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• 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 title description 4
• 239000003446 ligand Substances 0.000 title description 4
• 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 title description 3
• 150000008584 quinuclidines Chemical class 0.000 title 1
• -1 isothiazolopyridinyl Chemical group 0.000 claims description 657
• 150000001875 compounds Chemical class 0.000 claims description 88
• 125000004076 pyridyl group Chemical group 0.000 claims description 38
• 150000003839 salts Chemical class 0.000 claims description 31
• 125000000217 alkyl group Chemical group 0.000 claims description 30
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 26
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 22
• 125000003545 alkoxy group Chemical group 0.000 claims description 19
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
• 125000005843 halogen group Chemical group 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 17
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 15
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 15
• 229910052799 carbon Inorganic materials 0.000 claims description 14
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
• 201000000980 schizophrenia Diseases 0.000 claims description 12
• 125000000335 thiazolyl group Chemical group 0.000 claims description 12
• 208000024827 Alzheimer disease Diseases 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 10
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 9
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 9
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 9
• 125000005956 isoquinolyl group Chemical group 0.000 claims description 9
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
• 125000001624 naphthyl group Chemical group 0.000 claims description 8
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
• 125000001425 triazolyl group Chemical group 0.000 claims description 8
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 7
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 239000001257 hydrogen Substances 0.000 claims description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• 125000002971 oxazolyl group Chemical group 0.000 claims description 7
• 125000001544 thienyl group Chemical group 0.000 claims description 7
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 6
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 6
• JUXTWKYSGNVPGS-UHFFFAOYSA-N 7,8-dihydro-6h-quinazolin-5-one Chemical compound C1=NC=C2C(=O)CCCC2=N1 JUXTWKYSGNVPGS-UHFFFAOYSA-N 0.000 claims description 5
• 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 5
• 125000006378 chloropyridyl group Chemical group 0.000 claims description 5
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
• 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 4
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
• 125000006396 chloropyrazinyl group Chemical group 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
• 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 3
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
• 125000001246 bromo group Chemical group Br* 0.000 claims description 3
• 125000006380 bromopyridyl group Chemical group 0.000 claims description 3
• 125000006402 chloropyridazinyl group Chemical group 0.000 claims description 3
• 125000006390 chloropyrimidinyl group Chemical group 0.000 claims description 3
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 3
• 125000006379 fluoropyridyl group Chemical group 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 125000006399 methylpyrazinyl group Chemical group 0.000 claims description 3
• 125000006405 methylpyridazinyl group Chemical group 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• 125000005493 quinolyl group Chemical group 0.000 claims description 3
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
• 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
• GBTRMNJQEKCYRN-UHFFFAOYSA-N fluoren-2-one Chemical compound C1=CC=CC2=CC3=CC(=O)C=CC3=C21 GBTRMNJQEKCYRN-UHFFFAOYSA-N 0.000 claims description 2
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 125000004306 triazinyl group Chemical group 0.000 claims description 2
• 150000003852 triazoles Chemical class 0.000 claims description 2
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 2
• GEJMMWFZMSFPRD-UHFFFAOYSA-N 2-methoxy-1,3-thiazolidine Chemical compound COC1NCCS1 GEJMMWFZMSFPRD-UHFFFAOYSA-N 0.000 claims 2
• UBKKNWJGYLSDSJ-UHFFFAOYSA-N 2-methylpyridine-3-carbonitrile Chemical compound CC1=NC=CC=C1C#N UBKKNWJGYLSDSJ-UHFFFAOYSA-N 0.000 claims 2
• HXTSOMZAFUTVCP-UHFFFAOYSA-N 2-propan-2-yloxypyrazine Chemical compound CC(C)OC1=CN=CC=N1 HXTSOMZAFUTVCP-UHFFFAOYSA-N 0.000 claims 2
• 229960003677 chloroquine Drugs 0.000 claims 2
• WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims 2
• HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims 2
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
• QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 claims 2
• FGFUBBNNYLNVLJ-UHFFFAOYSA-N indolone Natural products C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 claims 2
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 786
• 235000019439 ethyl acetate Nutrition 0.000 description 357
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 294
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 278
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 273
• 238000005481 NMR spectroscopy Methods 0.000 description 259
• 239000000203 mixture Substances 0.000 description 253
• 238000006243 chemical reaction Methods 0.000 description 219
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 153
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 124
• 239000000047 product Substances 0.000 description 114
• 239000000243 solution Substances 0.000 description 102
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 99
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 88
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 85
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 84
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 84
• 239000007787 solid Substances 0.000 description 84
• 238000000034 method Methods 0.000 description 79
• 239000000843 powder Substances 0.000 description 66
• 239000011541 reaction mixture Substances 0.000 description 63
• BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 47
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 46
• CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 40
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
• 239000002244 precipitate Substances 0.000 description 39
• 239000012043 crude product Substances 0.000 description 38
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 35
• BEPZJGUUEAAGDN-UHFFFAOYSA-N pyridin-3-ol dihydrochloride Chemical compound Cl.Cl.Oc1cccnc1 BEPZJGUUEAAGDN-UHFFFAOYSA-N 0.000 description 35
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
• 239000000725 suspension Substances 0.000 description 33
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 32
• 238000002360 preparation method Methods 0.000 description 32
• 238000010898 silica gel chromatography Methods 0.000 description 32
• 238000000746 purification Methods 0.000 description 31
• QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 30
• 239000013058 crude material Substances 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
• 238000004587 chromatography analysis Methods 0.000 description 28
• 238000003818 flash chromatography Methods 0.000 description 25
• 239000010410 layer Substances 0.000 description 25
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 24
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 23
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
• 239000012044 organic layer Substances 0.000 description 22
• 229910052938 sodium sulfate Inorganic materials 0.000 description 22
• 235000011152 sodium sulphate Nutrition 0.000 description 22
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
• 239000012267 brine Substances 0.000 description 20
• 239000003921 oil Substances 0.000 description 20
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
• 238000004440 column chromatography Methods 0.000 description 19
• 238000001914 filtration Methods 0.000 description 19
• 239000012071 phase Substances 0.000 description 19
• 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 18
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 18
• 229910002091 carbon monoxide Inorganic materials 0.000 description 17
• 239000002904 solvent Substances 0.000 description 16
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 16
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• 238000003556 assay Methods 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
• 210000004027 cell Anatomy 0.000 description 14
• 125000003003 spiro group Chemical group 0.000 description 14
• 239000011575 calcium Substances 0.000 description 13
• 230000003287 optical effect Effects 0.000 description 13
• DUKKRSPKJMHASP-UHFFFAOYSA-N 6-chloropyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC=N1 DUKKRSPKJMHASP-UHFFFAOYSA-N 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
• 239000002253 acid Substances 0.000 description 12
• 239000004202 carbamide Substances 0.000 description 12
• 235000013877 carbamide Nutrition 0.000 description 12
• RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 12
• 239000000706 filtrate Substances 0.000 description 12
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
• 235000019341 magnesium sulphate Nutrition 0.000 description 11
• 239000007858 starting material Substances 0.000 description 11
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
• 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 10
• 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 10
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 10
• 230000015572 biosynthetic process Effects 0.000 description 10
• 238000012512 characterization method Methods 0.000 description 10
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 10
• 239000000463 material Substances 0.000 description 10
• 102000005962 receptors Human genes 0.000 description 10
• 108020003175 receptors Proteins 0.000 description 10
• 238000000926 separation method Methods 0.000 description 10
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
• 239000000908 ammonium hydroxide Substances 0.000 description 9
• 125000005605 benzo group Chemical group 0.000 description 9
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 9
• 239000011734 sodium Substances 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
• 150000001412 amines Chemical class 0.000 description 8
• 239000003795 chemical substances by application Substances 0.000 description 8
• 239000000543 intermediate Substances 0.000 description 8
• 230000014759 maintenance of location Effects 0.000 description 8
• 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
• 238000010992 reflux Methods 0.000 description 8
• 238000003756 stirring Methods 0.000 description 8
• 238000012360 testing method Methods 0.000 description 8
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
• 241000237858 Gastropoda Species 0.000 description 7
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
• ZGGNERQUFKZVBA-UHFFFAOYSA-N azanium;chloroform;hydroxide Chemical compound [NH4+].[OH-].ClC(Cl)Cl ZGGNERQUFKZVBA-UHFFFAOYSA-N 0.000 description 7
• 239000012141 concentrate Substances 0.000 description 7
• 235000008504 concentrate Nutrition 0.000 description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
• OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 7
• 208000015122 neurodegenerative disease Diseases 0.000 description 7
• 230000002829 reductive effect Effects 0.000 description 7
• 238000010079 rubber tapping Methods 0.000 description 7
• 229920006395 saturated elastomer Polymers 0.000 description 7
• 239000000741 silica gel Substances 0.000 description 7
• 229910002027 silica gel Inorganic materials 0.000 description 7
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
• 235000017557 sodium bicarbonate Nutrition 0.000 description 7
• 229910000029 sodium carbonate Inorganic materials 0.000 description 7
• 208000024891 symptom Diseases 0.000 description 7
• SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 6
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
• 108091006146 Channels Proteins 0.000 description 6
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
• 208000019022 Mood disease Diseases 0.000 description 6
• 150000001408 amides Chemical class 0.000 description 6
• 239000008346 aqueous phase Substances 0.000 description 6
• UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
• 229910000024 caesium carbonate Inorganic materials 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• 239000013078 crystal Substances 0.000 description 6
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 6
• 230000000694 effects Effects 0.000 description 6
• 239000007788 liquid Substances 0.000 description 6
• 238000011068 loading method Methods 0.000 description 6
• 229960002715 nicotine Drugs 0.000 description 6
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