TWI465453B - 作為ｏｒｌ－１受體拮抗劑之螺哌啶化合物 - Google Patents

Info

Publication number

TWI465453B

TWI465453B TW099138241A TW99138241A TWI465453B TW I465453 B TWI465453 B TW I465453B TW 099138241 A TW099138241 A TW 099138241A TW 99138241 A TW99138241 A TW 99138241A TW I465453 B TWI465453 B TW I465453B

Authority

TW

Taiwan

Prior art keywords

methyl

mmol

compound

pharmaceutically acceptable

pyran

Prior art date

2009-11-16

Links

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• -1 Spiropiperidine compound Chemical class 0.000 title claims description 89
• 108010020615 nociceptin receptor Proteins 0.000 title description 32
• 239000002464 receptor antagonist Substances 0.000 title description 2
• 229940044551 receptor antagonist Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 198
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 161
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 77
• 150000003839 salts Chemical class 0.000 claims description 51
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
• 229910052731 fluorine Inorganic materials 0.000 claims description 17
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
• 208000008589 Obesity Diseases 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 16
• 239000011737 fluorine Substances 0.000 claims description 16
• 235000020824 obesity Nutrition 0.000 claims description 16
• 206010033307 Overweight Diseases 0.000 claims description 14
• 239000001257 hydrogen Substances 0.000 claims description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims description 13
• 208000019695 Migraine disease Diseases 0.000 claims description 12
• 239000000460 chlorine Substances 0.000 claims description 12
• 238000004519 manufacturing process Methods 0.000 claims description 12
• 206010027599 migraine Diseases 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 208000020401 Depressive disease Diseases 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
• 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 7
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
• 125000004849 alkoxymethyl group Chemical group 0.000 claims description 4
• 150000002431 hydrogen Chemical class 0.000 claims description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
• 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
• XTVMMUUMUBGOPK-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-[3-(pyrazol-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=CC=N1 XTVMMUUMUBGOPK-UHFFFAOYSA-N 0.000 claims description 2
• GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims description 2
• ZAOZBWZTMUTPSX-UHFFFAOYSA-N [4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-1-(3-fluoropyridin-2-yl)pyrazol-3-yl]methanol Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(CO)=NN1C1=NC=CC=C1F ZAOZBWZTMUTPSX-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
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 2
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 2
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 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
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 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
• DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 claims 4
• 125000001153 fluoro group Chemical group F* 0.000 claims 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 361
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
• 235000019439 ethyl acetate Nutrition 0.000 description 157
• 239000000203 mixture Substances 0.000 description 137
• 239000000243 solution Substances 0.000 description 99
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 91
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
• 238000002360 preparation method Methods 0.000 description 64
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
• 239000012044 organic layer Substances 0.000 description 52
• 239000011541 reaction mixture Substances 0.000 description 52
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 46
• 239000002904 solvent Substances 0.000 description 45
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 39
• 239000007787 solid Substances 0.000 description 37
• 239000012071 phase Substances 0.000 description 36
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 33
• 238000006243 chemical reaction Methods 0.000 description 33
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
• 239000000725 suspension Substances 0.000 description 29
• 230000000694 effects Effects 0.000 description 28
• 239000013058 crude material Substances 0.000 description 27
• 238000012360 testing method Methods 0.000 description 25
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• 238000004587 chromatography analysis Methods 0.000 description 24
• 102000005962 receptors Human genes 0.000 description 24
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 23
• 235000019341 magnesium sulphate Nutrition 0.000 description 23
• 238000003756 stirring Methods 0.000 description 23
• 102400001111 Nociceptin Human genes 0.000 description 22
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 22
• 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 22
• 108020003175 receptors Proteins 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
• 229910000027 potassium carbonate Inorganic materials 0.000 description 20
• 229910052938 sodium sulfate Inorganic materials 0.000 description 20
• 235000011152 sodium sulphate Nutrition 0.000 description 20
• 238000000034 method Methods 0.000 description 19
• 239000000700 radioactive tracer Substances 0.000 description 19
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
• 241000699670 Mus sp. Species 0.000 description 18
• 239000005557 antagonist Substances 0.000 description 18
• 239000003480 eluent Substances 0.000 description 18
• 230000002829 reductive effect Effects 0.000 description 18
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
• 108090000622 Nociceptin Proteins 0.000 description 16
• 229910052757 nitrogen Inorganic materials 0.000 description 16
• 229920006395 saturated elastomer Polymers 0.000 description 16
• 239000013078 crystal Substances 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
• 239000007864 aqueous solution Substances 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 14
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
• 235000017557 sodium bicarbonate Nutrition 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
• 239000012074 organic phase Substances 0.000 description 13
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• 239000010410 layer Substances 0.000 description 12
• 150000003892 tartrate salts Chemical class 0.000 description 12
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 11
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
• 238000002441 X-ray diffraction Methods 0.000 description 10
• 239000000935 antidepressant agent Substances 0.000 description 10
• RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 10
• 238000001727 in vivo Methods 0.000 description 10
• 238000011813 knockout mouse model Methods 0.000 description 10
• 239000003921 oil Substances 0.000 description 10
• 125000003003 spiro group Chemical group 0.000 description 10
• 238000012799 strong cation exchange Methods 0.000 description 10
• 108091006146 Channels Proteins 0.000 description 9
• 241000124008 Mammalia Species 0.000 description 9
• 102100028646 Nociceptin receptor Human genes 0.000 description 9
• 229910021529 ammonia Inorganic materials 0.000 description 9
• 230000001430 anti-depressive effect Effects 0.000 description 9
• 229940005513 antidepressants Drugs 0.000 description 9
• 230000015572 biosynthetic process Effects 0.000 description 9
• 238000001816 cooling Methods 0.000 description 9
• 238000000746 purification Methods 0.000 description 9
• 239000003981 vehicle Substances 0.000 description 9
• 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 description 8
• 101001122499 Homo sapiens Nociceptin receptor Proteins 0.000 description 8
• 101001010792 Homo sapiens Transcriptional regulator ERG Proteins 0.000 description 8
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 8
• 208000002193 Pain Diseases 0.000 description 8
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
• 238000004458 analytical method Methods 0.000 description 8
• 230000027455 binding Effects 0.000 description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
• 239000012458 free base Substances 0.000 description 8
• IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
• QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 8
• 239000007858 starting material Substances 0.000 description 8
• JRHPOFJADXHYBR-HTQZYQBOSA-N (1r,2r)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@@H]1CCCC[C@H]1NC JRHPOFJADXHYBR-HTQZYQBOSA-N 0.000 description 7
• RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 7
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 7
• 206010015866 Extravasation Diseases 0.000 description 7
• 241000699666 Mus <mouse, genus> Species 0.000 description 7
• 241000700159 Rattus Species 0.000 description 7
• 239000002585 base Substances 0.000 description 7
• 230000037396 body weight Effects 0.000 description 7
• 229940098773 bovine serum albumin Drugs 0.000 description 7
• 239000003153 chemical reaction reagent Substances 0.000 description 7
• 230000036251 extravasation Effects 0.000 description 7
• 229960002464 fluoxetine Drugs 0.000 description 7
• 239000000047 product Substances 0.000 description 7
• 239000011734 sodium Substances 0.000 description 7
• NWDMGTFNIOCVDU-UHFFFAOYSA-N 5-methyl-1h-pyrazole-4-carbaldehyde Chemical compound CC=1NN=CC=1C=O NWDMGTFNIOCVDU-UHFFFAOYSA-N 0.000 description 6
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
• XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 6
• 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 6
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
• 102100037469 Protein DEPP1 Human genes 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
• 239000000908 ammonium hydroxide Substances 0.000 description 6
• 239000008346 aqueous phase Substances 0.000 description 6
• 150000002148 esters Chemical class 0.000 description 6
• 239000000706 filtrate Substances 0.000 description 6
• 238000004128 high performance liquid chromatography Methods 0.000 description 6
• FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 6
• 239000012280 lithium aluminium hydride Substances 0.000 description 6
• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
• 239000000463 material Substances 0.000 description 6
• 230000001404 mediated effect Effects 0.000 description 6
• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
• 108090000765 processed proteins & peptides Proteins 0.000 description 6
• PNNRZXFUPQQZSO-UHFFFAOYSA-N pyran Chemical compound [CH]1OC=CC=C1 PNNRZXFUPQQZSO-UHFFFAOYSA-N 0.000 description 6
• 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 description 6
• 230000005855 radiation Effects 0.000 description 6
• 229910052708 sodium Inorganic materials 0.000 description 6
• 239000012312 sodium hydride Substances 0.000 description 6
• 229910000104 sodium hydride Inorganic materials 0.000 description 6
• 229940095064 tartrate Drugs 0.000 description 6
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
• GNFWMEFWZWXLIN-UHFFFAOYSA-N 2-bromopyridine-3-carbaldehyde Chemical compound BrC1=NC=CC=C1C=O GNFWMEFWZWXLIN-UHFFFAOYSA-N 0.000 description 5
• JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 5
• 229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
• 241000237858 Gastropoda Species 0.000 description 5
• 108010024636 Glutathione Proteins 0.000 description 5
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
• 241001465754 Metazoa Species 0.000 description 5
• 150000001299 aldehydes Chemical class 0.000 description 5
• 150000001412 amines Chemical class 0.000 description 5
• 235000019270 ammonium chloride Nutrition 0.000 description 5
• 210000003169 central nervous system Anatomy 0.000 description 5
• 210000001951 dura mater Anatomy 0.000 description 5
• 235000013305 food Nutrition 0.000 description 5
• WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
• 229960003180 glutathione Drugs 0.000 description 5
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
• 238000012423 maintenance Methods 0.000 description 5
• 239000012528 membrane Substances 0.000 description 5
• 239000012299 nitrogen atmosphere Substances 0.000 description 5
• 239000013641 positive control Substances 0.000 description 5
• 239000000843 powder Substances 0.000 description 5
• 239000002244 precipitate Substances 0.000 description 5
• 102000004169 proteins and genes Human genes 0.000 description 5
• 108090000623 proteins and genes Proteins 0.000 description 5
• 239000011780 sodium chloride Substances 0.000 description 5
• DWYGLHSLUMTSPC-UHFFFAOYSA-N spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] Chemical class C1CNCCC21C(SC=C1)=C1CCO2 DWYGLHSLUMTSPC-UHFFFAOYSA-N 0.000 description 5
• 230000000638 stimulation Effects 0.000 description 5
• 230000009182 swimming Effects 0.000 description 5
• 238000003786 synthesis reaction Methods 0.000 description 5
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
• NEWLOSCWMVKPGI-UHFFFAOYSA-N 2-bromo-3-(bromomethyl)pyridine Chemical compound BrCC1=CC=CN=C1Br NEWLOSCWMVKPGI-UHFFFAOYSA-N 0.000 description 4
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