AU2004247721C1 - Fused compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor - Google Patents

Info

Publication number

AU2004247721C1

AU2004247721C1 AU2004247721A AU2004247721A AU2004247721C1 AU 2004247721 C1 AU2004247721 C1 AU 2004247721C1 AU 2004247721 A AU2004247721 A AU 2004247721A AU 2004247721 A AU2004247721 A AU 2004247721A AU 2004247721 C1 AU2004247721 C1 AU 2004247721C1

Authority

AU

Australia

Prior art keywords

compound

formula

dihydro

inden

indazol

Prior art date

2003-06-12

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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• 150000001875 compounds Chemical class 0.000 title claims abstract description 697
• 108010025083 TRPV1 receptor Proteins 0.000 title claims abstract description 37
• 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 title claims description 24
• 102000005962 receptors Human genes 0.000 title claims description 7
• 238000000034 method Methods 0.000 claims abstract description 141
• 150000003839 salts Chemical class 0.000 claims abstract description 68
• 230000008569 process Effects 0.000 claims abstract description 42
• 241000124008 Mammalia Species 0.000 claims abstract description 27
• 239000000651 prodrug Substances 0.000 claims abstract description 23
• 229940002612 prodrug Drugs 0.000 claims abstract description 23
• 230000036407 pain Effects 0.000 claims abstract description 18
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 17
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 378
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 237
• -1 hexahydro-1 H-azepinyl Chemical group 0.000 claims description 178
• 125000000217 alkyl group Chemical group 0.000 claims description 145
• 239000000203 mixture Substances 0.000 claims description 116
• 229910052739 hydrogen Inorganic materials 0.000 claims description 115
• 239000001257 hydrogen Substances 0.000 claims description 115
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 107
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 100
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 96
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 89
• 239000002904 solvent Substances 0.000 claims description 80
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 76
• 239000004202 carbamide Substances 0.000 claims description 74
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 68
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 66
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 65
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
• 229910052736 halogen Inorganic materials 0.000 claims description 40
• 150000002367 halogens Chemical class 0.000 claims description 40
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 36
• 239000002253 acid Substances 0.000 claims description 35
• 125000003545 alkoxy group Chemical group 0.000 claims description 35
• 125000003118 aryl group Chemical group 0.000 claims description 33
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 33
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
• 125000001188 haloalkyl group Chemical group 0.000 claims description 30
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 27
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 26
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 26
• 239000012298 atmosphere Substances 0.000 claims description 24
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 24
• 238000004519 manufacturing process Methods 0.000 claims description 24
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 23
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 22
• 229910052757 nitrogen Inorganic materials 0.000 claims description 21
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims description 20
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 20
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 19
• 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 19
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 19
• 238000011282 treatment Methods 0.000 claims description 19
• 125000003342 alkenyl group Chemical group 0.000 claims description 18
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 18
• 125000004414 alkyl thio group Chemical group 0.000 claims description 18
• 125000000304 alkynyl group Chemical group 0.000 claims description 18
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 238000003756 stirring Methods 0.000 claims description 18
• 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 17
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• 125000004995 haloalkylthio group Chemical group 0.000 claims description 17
• 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 17
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
• 208000035475 disorder Diseases 0.000 claims description 15
• 125000004967 formylalkyl group Chemical group 0.000 claims description 15
• QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 13
• YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 11
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 11
• 235000010288 sodium nitrite Nutrition 0.000 claims description 10
• INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims description 9
• 208000004454 Hyperalgesia Diseases 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 9
• 239000012279 sodium borohydride Substances 0.000 claims description 9
• 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
• 238000000605 extraction Methods 0.000 claims description 8
• 125000001072 heteroaryl group Chemical group 0.000 claims description 8
• 206010046543 Urinary incontinence Diseases 0.000 claims description 7
• 108010062740 TRPV Cation Channels Proteins 0.000 claims description 6
• 102000011040 TRPV Cation Channels Human genes 0.000 claims description 6
• 230000002757 inflammatory effect Effects 0.000 claims description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 125000004193 piperazinyl group Chemical group 0.000 claims description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
• UJHPWLQNPUIFJU-UHFFFAOYSA-N 1-(5-tert-butyl-2,3-dihydro-1h-inden-1-yl)-3-(3-methylisoquinolin-5-yl)urea Chemical compound C1CC2=CC(C(C)(C)C)=CC=C2C1NC(=O)NC1=C2C=C(C)N=CC2=CC=C1 UJHPWLQNPUIFJU-UHFFFAOYSA-N 0.000 claims description 4
• VPSCJCQPUGKRNC-UHFFFAOYSA-N 1-(5-tert-butyl-2,3-dihydro-1h-inden-1-yl)-3-isoquinolin-5-ylurea Chemical compound N1=CC=C2C(NC(=O)NC3C4=CC=C(C=C4CC3)C(C)(C)C)=CC=CC2=C1 VPSCJCQPUGKRNC-UHFFFAOYSA-N 0.000 claims description 4
• XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical class NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 claims description 4
• 125000004429 atom Chemical group 0.000 claims description 4
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 125000005961 oxazepanyl group Chemical group 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 4
• IKMATCBNKRNPBM-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(4-methyl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C1CC=2C(C)=CC=CC=2C1NC(=O)NC1=CC=CC2=C1C=NN2 IKMATCBNKRNPBM-UHFFFAOYSA-N 0.000 claims description 3
• ASHXOMOCDINDTE-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(4-morpholin-4-yl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC1CCC2=C1C=CC=C2N1CCOCC1 ASHXOMOCDINDTE-UHFFFAOYSA-N 0.000 claims description 3
• PKVCREBZFWTVRQ-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(4-pyridin-2-yl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC1CCC2=C1C=CC=C2C1=CC=CC=N1 PKVCREBZFWTVRQ-UHFFFAOYSA-N 0.000 claims description 3
• UIIWXLYPGXOGTO-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(4-pyridin-3-yl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC1CCC2=C1C=CC=C2C1=CC=CN=C1 UIIWXLYPGXOGTO-UHFFFAOYSA-N 0.000 claims description 3
• OUIHQJINQZAAFC-UHFFFAOYSA-N 1-(4-bromo-2,3-dihydro-1h-inden-1-yl)-3-(1h-indazol-4-yl)urea Chemical compound C1CC=2C(Br)=CC=CC=2C1NC(=O)NC1=CC=CC2=C1C=NN2 OUIHQJINQZAAFC-UHFFFAOYSA-N 0.000 claims description 3
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
• 150000001555 benzenes Chemical class 0.000 claims description 3
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
• HFCFJYRLBAANKN-UHFFFAOYSA-N 2-methyl-3-nitroaniline Chemical compound CC1=C(N)C=CC=C1[N+]([O-])=O HFCFJYRLBAANKN-UHFFFAOYSA-N 0.000 claims description 2
• 229940077388 benzenesulfonate Drugs 0.000 claims description 2
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 14
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
• TYOYXJNGINZFET-SFHVURJKSA-N 1-[(1s)-5-tert-butyl-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound N([C@@H]1C2=CC=C(C=C2CC1)C(C)(C)C)C(=O)NC1=CC=CC2=C1C=NN2 TYOYXJNGINZFET-SFHVURJKSA-N 0.000 claims 1
• XFMUCOATRRXTLZ-UHFFFAOYSA-N 1-[4-(2,6-dimethylmorpholin-4-yl)-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound C1C(C)OC(C)CN1C1=CC=CC2=C1CCC2NC(=O)NC1=CC=CC2=C1C=NN2 XFMUCOATRRXTLZ-UHFFFAOYSA-N 0.000 claims 1
• VTVZETXZBPJECM-UHFFFAOYSA-N 1-[4-(3,3-difluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound C1C(F)(F)CCCN1C1=CC=CC2=C1CCC2NC(=O)NC1=CC=CC2=C1C=NN2 VTVZETXZBPJECM-UHFFFAOYSA-N 0.000 claims 1
• YCVQWQOSFHWGAV-UHFFFAOYSA-N 1-[4-(4,4-difluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound C1CC(F)(F)CCN1C1=CC=CC2=C1CCC2NC(=O)NC1=CC=CC2=C1C=NN2 YCVQWQOSFHWGAV-UHFFFAOYSA-N 0.000 claims 1
• UAQDBQBNVDZUEF-UHFFFAOYSA-N 1-[5-(1,1-dioxo-1,4-thiazinan-4-yl)-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC(C1=CC=2)CCC1=CC=2N1CCS(=O)(=O)CC1 UAQDBQBNVDZUEF-UHFFFAOYSA-N 0.000 claims 1
• 125000003114 inden-1-yl group Chemical group [H]C1=C([H])C([H])(*)C2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 7
• 238000005481 NMR spectroscopy Methods 0.000 description 124
• 239000000243 solution Substances 0.000 description 90
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 77
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 76
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 62
• 239000007787 solid Substances 0.000 description 62
• 238000010511 deprotection reaction Methods 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
• RCPFHUXEZIREGX-UHFFFAOYSA-N 5-(1-methoxy-2-methylpropan-2-yl)-2,3-dihydro-1h-inden-1-amine Chemical compound COCC(C)(C)C1=CC=C2C(N)CCC2=C1 RCPFHUXEZIREGX-UHFFFAOYSA-N 0.000 description 40
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• 235000019439 ethyl acetate Nutrition 0.000 description 36
• 239000000047 product Substances 0.000 description 35
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 34
• 238000006243 chemical reaction Methods 0.000 description 34
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 34
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
• 235000019441 ethanol Nutrition 0.000 description 28
• 235000013877 carbamide Nutrition 0.000 description 26
• 230000002829 reductive effect Effects 0.000 description 26
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
• 239000003921 oil Substances 0.000 description 24
• 235000019198 oils Nutrition 0.000 description 24
• 229960000583 acetic acid Drugs 0.000 description 22
• 150000001412 amines Chemical class 0.000 description 21
• 239000000706 filtrate Substances 0.000 description 21
• 239000012044 organic layer Substances 0.000 description 21
• 238000000746 purification Methods 0.000 description 21
• 239000011541 reaction mixture Substances 0.000 description 21
• IIJPVOVAVTZFRH-UHFFFAOYSA-N 5-tert-butyl-2,3-dihydroinden-1-one Chemical compound CC(C)(C)C1=CC=C2C(=O)CCC2=C1 IIJPVOVAVTZFRH-UHFFFAOYSA-N 0.000 description 20
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 19
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 18
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
• 235000019341 magnesium sulphate Nutrition 0.000 description 17
• NSKGQURZWSPSBC-VVPCINPTSA-N ribostamycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](N)C[C@@H]1N NSKGQURZWSPSBC-VVPCINPTSA-N 0.000 description 17
• 239000002585 base Substances 0.000 description 16
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• 229960002504 capsaicin Drugs 0.000 description 16
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
• 238000010992 reflux Methods 0.000 description 15
• 238000000926 separation method Methods 0.000 description 15
• 238000005160 1H NMR spectroscopy Methods 0.000 description 14
• 125000003396 thiol group Chemical class [H]S* 0.000 description 13
• JYRVCRJPCWMDQT-UHFFFAOYSA-N 5-tert-butyl-2,3-dihydro-1h-inden-1-amine Chemical compound CC(C)(C)C1=CC=C2C(N)CCC2=C1 JYRVCRJPCWMDQT-UHFFFAOYSA-N 0.000 description 12
• 241001465754 Metazoa Species 0.000 description 12
• 238000001914 filtration Methods 0.000 description 12
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
• 150000003672 ureas Chemical class 0.000 description 12
• 238000003556 assay Methods 0.000 description 11
• 150000002148 esters Chemical class 0.000 description 11
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
• DIDJZJDDXQPTLN-UHFFFAOYSA-N indazole-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)N=CC2=C1 DIDJZJDDXQPTLN-UHFFFAOYSA-N 0.000 description 11
• 239000002244 precipitate Substances 0.000 description 11
• 239000000725 suspension Substances 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• KBHCTNGQJOEDDC-UHFFFAOYSA-N 5-methyl-2,3-dihydroinden-1-one Chemical compound CC1=CC=C2C(=O)CCC2=C1 KBHCTNGQJOEDDC-UHFFFAOYSA-N 0.000 description 10
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
• 239000003054 catalyst Substances 0.000 description 10
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• 229940079593 drug Drugs 0.000 description 10
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• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
• QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical class C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 9
• 150000002473 indoazoles Chemical class 0.000 description 9
• 239000000741 silica gel Substances 0.000 description 9
• 229910002027 silica gel Inorganic materials 0.000 description 9
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
• 108091006146 Channels Proteins 0.000 description 8
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
• 238000002441 X-ray diffraction Methods 0.000 description 8
• 238000000113 differential scanning calorimetry Methods 0.000 description 8
• 238000004128 high performance liquid chromatography Methods 0.000 description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
• 150000004657 carbamic acid derivatives Chemical class 0.000 description 7
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