AU2010319581C1 - Spiropiperidine compounds as ORL-1 receptor antagonists - Google Patents

Info

Publication number

AU2010319581C1

AU2010319581C1 AU2010319581A AU2010319581A AU2010319581C1 AU 2010319581 C1 AU2010319581 C1 AU 2010319581C1 AU 2010319581 A AU2010319581 A AU 2010319581A AU 2010319581 A AU2010319581 A AU 2010319581A AU 2010319581 C1 AU2010319581 C1 AU 2010319581C1

Authority

AU

Australia

Prior art keywords

methyl

piperidine

pyran

pyrazol

pyridyl

Prior art date

2009-11-16

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

• Espacenet
• Global Dossier
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• 108010020615 nociceptin receptor Proteins 0.000 title abstract description 29
• 229940044551 receptor antagonist Drugs 0.000 title abstract description 4
• 239000002464 receptor antagonist Substances 0.000 title abstract description 4
• JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical class C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 225
• 238000011282 treatment Methods 0.000 claims abstract description 40
• 238000000034 method Methods 0.000 claims abstract description 23
• 208000008589 Obesity Diseases 0.000 claims abstract description 15
• 235000020824 obesity Nutrition 0.000 claims abstract description 15
• 206010033307 Overweight Diseases 0.000 claims abstract description 13
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 10
• 206010027599 migraine Diseases 0.000 claims abstract description 10
• 208000020401 Depressive disease Diseases 0.000 claims abstract description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 184
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 170
• -1 chloro, cyano, cyanomethyl Chemical group 0.000 claims description 80
• 125000003003 spiro group Chemical group 0.000 claims description 62
• 150000003839 salts Chemical class 0.000 claims description 51
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 20
• 125000001153 fluoro group Chemical group F* 0.000 claims description 19
• YYNOJCBVROUTEB-UHFFFAOYSA-N 2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=2SC(Cl)=CC=2C(F)(F)COC21CCNCC2 YYNOJCBVROUTEB-UHFFFAOYSA-N 0.000 claims description 16
• 241000124008 Mammalia Species 0.000 claims description 15
• 239000001257 hydrogen Substances 0.000 claims description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims description 13
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 9
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 8
• DWYGLHSLUMTSPC-UHFFFAOYSA-N spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1CNCCC21C(SC=C1)=C1CCO2 DWYGLHSLUMTSPC-UHFFFAOYSA-N 0.000 claims description 8
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• NKQHBJNRBKHUQR-UHFFFAOYSA-N [2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridin-3-yl]methanol Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1CO NKQHBJNRBKHUQR-UHFFFAOYSA-N 0.000 claims description 6
• 150000002431 hydrogen Chemical class 0.000 claims description 6
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
• 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 6
• 239000011570 nicotinamide Substances 0.000 claims description 5
• 235000005152 nicotinamide Nutrition 0.000 claims description 5
• 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 5
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
• 125000004849 alkoxymethyl group Chemical group 0.000 claims description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 4
• XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 4
• 230000001225 therapeutic effect Effects 0.000 claims description 4
• 239000004615 ingredient Substances 0.000 claims description 3
• IGQNOFOHZUSKIL-UHFFFAOYSA-N methyl n-methylcarbamate Chemical compound [CH2]NC(=O)OC IGQNOFOHZUSKIL-UHFFFAOYSA-N 0.000 claims description 3
• 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 claims description 2
• 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 2
• TVSCFMXJYNZEER-UHFFFAOYSA-N 7-methoxy-11a-methyl-1,9b,10,11-tetrahydronaphtho[1,2-g]indole Chemical compound C1CC2(C)CC=NC2=C2C=CC3=CC(OC)=CC=C3C21 TVSCFMXJYNZEER-UHFFFAOYSA-N 0.000 claims description 2
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
• 125000004859 cyclopropyloxymethyl group Chemical group C1(CC1)OC* 0.000 claims description 2
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 2
• VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 2
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 2
• BQXKTCTYBNIVRH-UHFFFAOYSA-N 1'-[[1-[3-(cyclopropylmethoxymethyl)pyridin-2-yl]-3-methylpyrazol-4-yl]methyl]-2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)C(C)=NN1C1=NC=CC=C1COCC1CC1 BQXKTCTYBNIVRH-UHFFFAOYSA-N 0.000 claims 1
• RGMXESVFZCOUOR-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridin-3-yl]-n-methylmethanamine Chemical compound CNCC1=CC=CN=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 RGMXESVFZCOUOR-UHFFFAOYSA-N 0.000 claims 1
• CFOXHLURCUNTKL-UHFFFAOYSA-N 1-[[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridin-3-yl]methyl]pyrrolidin-2-one Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1CN1CCCC1=O CFOXHLURCUNTKL-UHFFFAOYSA-N 0.000 claims 1
• FMNCOQWPZMTZCV-UHFFFAOYSA-N 2-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridin-3-yl]oxyacetamide Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1OCC(N)=O FMNCOQWPZMTZCV-UHFFFAOYSA-N 0.000 claims 1
• JLMBGCBVKOUZSZ-UHFFFAOYSA-N 2-[[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridin-3-yl]methylamino]acetonitrile Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1CNCC#N JLMBGCBVKOUZSZ-UHFFFAOYSA-N 0.000 claims 1
• XCNZVBKTSMGMJH-UHFFFAOYSA-N 2-chloro-1'-[[1-(3-cyclopropylpyridin-2-yl)-3-methylpyrazol-4-yl]methyl]-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1C1CC1 XCNZVBKTSMGMJH-UHFFFAOYSA-N 0.000 claims 1
• IMAVADOOMXAIRY-UHFFFAOYSA-N 2-chloro-1'-[[1-[3-(cyclopropylmethoxy)pyridin-2-yl]-3-methylpyrazol-4-yl]methyl]-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1OCC1CC1 IMAVADOOMXAIRY-UHFFFAOYSA-N 0.000 claims 1
• HRNMBMNBYUCZJD-UHFFFAOYSA-N 2-chloro-1'-[[1-[3-(cyclopropyloxymethyl)pyridin-2-yl]-3-methylpyrazol-4-yl]methyl]-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1COC1CC1 HRNMBMNBYUCZJD-UHFFFAOYSA-N 0.000 claims 1
• VDMVSMLZRXDEPQ-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-(3-fluoropyridin-2-yl)-3-(propan-2-yloxymethyl)pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(COC(C)C)=NN1C1=NC=CC=C1F VDMVSMLZRXDEPQ-UHFFFAOYSA-N 0.000 claims 1
• AOVBNGOCCRPLFB-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-(3-fluoropyridin-2-yl)-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1F AOVBNGOCCRPLFB-UHFFFAOYSA-N 0.000 claims 1
• LPFDKJMWNDVQFM-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-(3-methoxypyridin-2-yl)-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound COC1=CC=CN=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 LPFDKJMWNDVQFM-UHFFFAOYSA-N 0.000 claims 1
• JZMFAUAYWJPFEI-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[3-(methoxymethyl)pyridin-2-yl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound COCC1=CC=CN=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 JZMFAUAYWJPFEI-UHFFFAOYSA-N 0.000 claims 1
• HJXAIXDACWTMGX-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-[3-(1,2,4-triazol-1-ylmethyl)pyridin-2-yl]pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1CN1C=NC=N1 HJXAIXDACWTMGX-UHFFFAOYSA-N 0.000 claims 1
• XPCIAJNSDCJNMF-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-[3-(1,2-oxazol-3-yl)pyridin-2-yl]pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1C=1C=CON=1 XPCIAJNSDCJNMF-UHFFFAOYSA-N 0.000 claims 1
• ZJXUCKXYNWULFU-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl]pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound CC1=NOC(C=2C(=NC=CC=2)N2N=C(C)C(CN3CCC4(CC3)C=3SC(Cl)=CC=3C(F)(F)CO4)=C2)=N1 ZJXUCKXYNWULFU-UHFFFAOYSA-N 0.000 claims 1
• PZEYMCUWJVWSPG-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-[3-(triazol-2-ylmethyl)pyridin-2-yl]pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1CN1N=CC=N1 PZEYMCUWJVWSPG-UHFFFAOYSA-N 0.000 claims 1
• KCZNIYARWQILNB-UHFFFAOYSA-N 2-fluoro-1'-[[1-(3-fluoropyridin-2-yl)-3-methylpyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)C(C)=NN1C1=NC=CC=C1F KCZNIYARWQILNB-UHFFFAOYSA-N 0.000 claims 1
• OGHRJWWYAIJCEL-UHFFFAOYSA-N 2-fluoro-1'-[[1-[3-(methoxymethyl)pyridin-2-yl]-3-methylpyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] Chemical compound COCC1=CC=CN=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)=C1 OGHRJWWYAIJCEL-UHFFFAOYSA-N 0.000 claims 1
• REYOBJPPVHJNAQ-UHFFFAOYSA-N 2-fluoro-1'-[[3-methyl-1-[3-[(2-methylimidazol-1-yl)methyl]pyridin-2-yl]pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(F)=CC=2CCO3)C(C)=NN1C1=NC=CC=C1CN1C=CN=C1C REYOBJPPVHJNAQ-UHFFFAOYSA-N 0.000 claims 1
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 1
• OXMFGBCNHJLRBL-UHFFFAOYSA-N [4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-1-(3-methylpyridin-2-yl)pyrazol-3-yl]methanol Chemical compound CC1=CC=CN=C1N1N=C(CO)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 OXMFGBCNHJLRBL-UHFFFAOYSA-N 0.000 claims 1
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims 1
• OWLJCHWQDDNUGR-UHFFFAOYSA-N n-[[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridin-3-yl]methylidene]hydroxylamine Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1C=NO OWLJCHWQDDNUGR-UHFFFAOYSA-N 0.000 claims 1
• 238000002360 preparation method Methods 0.000 abstract description 62
• 239000005557 antagonist Substances 0.000 abstract description 18
• 238000012423 maintenance Methods 0.000 abstract description 8
• 238000010171 animal model Methods 0.000 abstract description 5
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 227
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 210
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 153
• 239000000203 mixture Substances 0.000 description 140
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 110
• 239000000243 solution Substances 0.000 description 107
• 239000002904 solvent Substances 0.000 description 84
• 235000019439 ethyl acetate Nutrition 0.000 description 76
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 74
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 62
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
• 239000011541 reaction mixture Substances 0.000 description 51
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 49
• 239000012071 phase Substances 0.000 description 48
• 239000012044 organic layer Substances 0.000 description 44
• 239000007787 solid Substances 0.000 description 44
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 42
• 238000004587 chromatography analysis Methods 0.000 description 40
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 39
• 230000002829 reductive effect Effects 0.000 description 39
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 33
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
• 238000006243 chemical reaction Methods 0.000 description 33
• 229910052938 sodium sulfate Inorganic materials 0.000 description 33
• 235000011152 sodium sulphate Nutrition 0.000 description 33
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
• 102000005962 receptors Human genes 0.000 description 32
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
• 235000019341 magnesium sulphate Nutrition 0.000 description 31
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
• 108020003175 receptors Proteins 0.000 description 30
• 239000000725 suspension Substances 0.000 description 29
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 28
• 102400001111 Nociceptin Human genes 0.000 description 28
• 239000007864 aqueous solution Substances 0.000 description 28
• PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 description 28
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• 230000000694 effects Effects 0.000 description 26
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