TW201300361A - 抑制香草類化物受體（ｖａｎｉｌｌｏｉｄ ｒｅｃｅｐｔｏｒ）次型１（ｖｒ１）受體之稠合化合物 - Google Patents

Info

Publication number

TW201300361A

TW201300361A TW101107398A TW101107398A TW201300361A TW 201300361 A TW201300361 A TW 201300361A TW 101107398 A TW101107398 A TW 101107398A TW 101107398 A TW101107398 A TW 101107398A TW 201300361 A TW201300361 A TW 201300361A

Authority

TW

Taiwan

Prior art keywords

compound

formula

dihydro

indol

urea

Prior art date

2003-06-12

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 660
• 108010025083 TRPV1 receptor Proteins 0.000 title claims abstract description 22
• 102000005962 receptors Human genes 0.000 title claims description 12
• 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 title claims description 9
• 238000000034 method Methods 0.000 claims abstract description 142
• 150000003839 salts Chemical class 0.000 claims abstract description 54
• 239000000651 prodrug Substances 0.000 claims abstract description 30
• 229940002612 prodrug Drugs 0.000 claims abstract description 30
• 208000002193 Pain Diseases 0.000 claims abstract description 15
• 230000036407 pain Effects 0.000 claims abstract description 15
• 230000008569 process Effects 0.000 claims abstract description 13
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 363
• -1 decylalkyl Chemical group 0.000 claims description 210
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 198
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 161
• 125000000217 alkyl group Chemical group 0.000 claims description 126
• 239000000203 mixture Substances 0.000 claims description 114
• 239000001257 hydrogen Substances 0.000 claims description 109
• 229910052739 hydrogen Inorganic materials 0.000 claims description 109
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 106
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 90
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 83
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 81
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 70
• 239000002904 solvent Substances 0.000 claims description 70
• 239000004202 carbamide Substances 0.000 claims description 69
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 66
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 54
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 53
• 238000002360 preparation method Methods 0.000 claims description 49
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
• 229910052757 nitrogen Inorganic materials 0.000 claims description 46
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 41
• 150000002431 hydrogen Chemical class 0.000 claims description 40
• 229910052736 halogen Inorganic materials 0.000 claims description 39
• 150000002367 halogens Chemical class 0.000 claims description 39
• 239000002253 acid Substances 0.000 claims description 35
• 125000003545 alkoxy group Chemical group 0.000 claims description 33
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 31
• 125000003118 aryl group Chemical group 0.000 claims description 31
• 125000001188 haloalkyl group Chemical group 0.000 claims description 31
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 31
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 28
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 26
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 26
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 24
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 22
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 22
• 125000000623 heterocyclic group Chemical group 0.000 claims description 19
• 201000010099 disease Diseases 0.000 claims description 18
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 16
• 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
• 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 16
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 15
• 125000004414 alkyl thio group Chemical group 0.000 claims description 15
• 125000000304 alkynyl group Chemical group 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
• 125000003342 alkenyl group Chemical group 0.000 claims description 14
• 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 14
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 13
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 13
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
• QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 11
• 125000004995 haloalkylthio group Chemical group 0.000 claims description 11
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
• 238000000746 purification Methods 0.000 claims description 11
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 10
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 235000010288 sodium nitrite Nutrition 0.000 claims description 9
• INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims description 8
• OCKPCBLVNKHBMX-UHFFFAOYSA-N butylbenzene Chemical compound CCCCC1=CC=CC=C1 OCKPCBLVNKHBMX-UHFFFAOYSA-N 0.000 claims description 8
• 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 8
• DRRCSCZWHQJCDS-UHFFFAOYSA-N CC(C)(C)C1=CC2=C(C=C1)N(CC2)NC(=O)NC3=CC=CC4=C3C=CN=C4 Chemical compound CC(C)(C)C1=CC2=C(C=C1)N(CC2)NC(=O)NC3=CC=CC4=C3C=CN=C4 DRRCSCZWHQJCDS-UHFFFAOYSA-N 0.000 claims description 7
• BOBJECZWRXTBRH-UHFFFAOYSA-N CC1=CC2=C(C=CC=C2NC(=O)NN3CCC4=C3C=CC(=C4)C(C)(C)C)C=N1 Chemical compound CC1=CC2=C(C=CC=C2NC(=O)NN3CCC4=C3C=CC(=C4)C(C)(C)C)C=N1 BOBJECZWRXTBRH-UHFFFAOYSA-N 0.000 claims description 7
• 208000004454 Hyperalgesia Diseases 0.000 claims description 7
• 239000012279 sodium borohydride Substances 0.000 claims description 7
• 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• 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 5
• XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical class NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 claims description 5
• WCNAYRYRQAXMEY-UHFFFAOYSA-N COC1=C2CCN(C2=CC=C1OC)NC(=O)NC1=C2C=NNC2=CC=C1 Chemical compound COC1=C2CCN(C2=CC=C1OC)NC(=O)NC1=C2C=NNC2=CC=C1 WCNAYRYRQAXMEY-UHFFFAOYSA-N 0.000 claims description 5
• 206010020853 Hypertonic bladder Diseases 0.000 claims description 5
• 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 5
• 206010046543 Urinary incontinence Diseases 0.000 claims description 5
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 5
• 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 208000020629 overactive bladder Diseases 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
• 208000035154 Hyperesthesia Diseases 0.000 claims description 4
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
• 229910052717 sulfur Inorganic materials 0.000 claims description 4
• 235000012141 vanillin Nutrition 0.000 claims description 4
• FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims description 4
• 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 description 3
• SIKZBZHXHBSSEA-UHFFFAOYSA-N 1-[4-(3-fluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound C1C(F)CCCN1C1=CC=CC2=C1CCC2NC(=O)NC1=CC=CC2=C1C=NN2 SIKZBZHXHBSSEA-UHFFFAOYSA-N 0.000 claims description 3
• 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 description 3
• LDPUXYQORLSBQP-UHFFFAOYSA-N BrC=1C=C2CCN(C2=CC1)NC(=O)NC1=C2C=CN=CC2=CC=C1 Chemical compound BrC=1C=C2CCN(C2=CC1)NC(=O)NC1=C2C=CN=CC2=CC=C1 LDPUXYQORLSBQP-UHFFFAOYSA-N 0.000 claims description 3
• GJEHLSQOOZTIGK-UHFFFAOYSA-N C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=C(C=CC=C12)OC(F)(F)F Chemical compound C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=C(C=CC=C12)OC(F)(F)F GJEHLSQOOZTIGK-UHFFFAOYSA-N 0.000 claims description 3
• FDUSASRINVTKIT-UHFFFAOYSA-N C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=CC=C(C=C12)C Chemical compound C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=CC=C(C=C12)C FDUSASRINVTKIT-UHFFFAOYSA-N 0.000 claims description 3
• ODRNCDWPBLRBQT-UHFFFAOYSA-N C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=CC=C(C=C12)F Chemical compound C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=CC=C(C=C12)F ODRNCDWPBLRBQT-UHFFFAOYSA-N 0.000 claims description 3
• QAAXYDRVAKOQAD-UHFFFAOYSA-N C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=CC=CC(=C12)C Chemical compound C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=CC=CC(=C12)C QAAXYDRVAKOQAD-UHFFFAOYSA-N 0.000 claims description 3
• CIDIBYJIJFUPQR-UHFFFAOYSA-N COC=1C=C2CCN(C2=CC1OC)NC(=O)NC1=C2C=NNC2=CC=C1 Chemical compound COC=1C=C2CCN(C2=CC1OC)NC(=O)NC1=C2C=NNC2=CC=C1 CIDIBYJIJFUPQR-UHFFFAOYSA-N 0.000 claims description 3
• ROYPPXGJJBYESZ-UHFFFAOYSA-N ClC1=C2CCN(C2=CC=C1)NC(=O)NC1=C2C=NNC2=CC=C1 Chemical compound ClC1=C2CCN(C2=CC=C1)NC(=O)NC1=C2C=NNC2=CC=C1 ROYPPXGJJBYESZ-UHFFFAOYSA-N 0.000 claims description 3
• LUGHMUGEDZFKKY-UHFFFAOYSA-N ClC=1C=C2CCN(C2=CC1)NC(=O)NC1=C2C=NNC2=CC=C1 Chemical compound ClC=1C=C2CCN(C2=CC1)NC(=O)NC1=C2C=NNC2=CC=C1 LUGHMUGEDZFKKY-UHFFFAOYSA-N 0.000 claims description 3
• ZAMABONHWDIEAV-UHFFFAOYSA-N FC1=C(C=C2CCN(C2=C1)NC(=O)NC1=C2C=NNC2=CC=C1)N1CCCCC1 Chemical compound FC1=C(C=C2CCN(C2=C1)NC(=O)NC1=C2C=NNC2=CC=C1)N1CCCCC1 ZAMABONHWDIEAV-UHFFFAOYSA-N 0.000 claims description 3
• JPKRTXQWMWHCSI-UHFFFAOYSA-N N1(CCCCC1)C1CCN(CC1)C=1C=C2CCN(C2=CC1)NC(=O)NC1=C2C=NNC2=CC=C1 Chemical compound N1(CCCCC1)C1CCN(CC1)C=1C=C2CCN(C2=CC1)NC(=O)NC1=C2C=NNC2=CC=C1 JPKRTXQWMWHCSI-UHFFFAOYSA-N 0.000 claims description 3
• CDSFTOLCFNWVMB-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=C(C=CC=C12)C1=CC=NC=C1 Chemical compound N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=C(C=CC=C12)C1=CC=NC=C1 CDSFTOLCFNWVMB-UHFFFAOYSA-N 0.000 claims description 3
• YGEDZVIBQQMWTK-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=C(C=CC=C12)C=1C=NC=CC1 Chemical compound N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=C(C=CC=C12)C=1C=NC=CC1 YGEDZVIBQQMWTK-UHFFFAOYSA-N 0.000 claims description 3
• YMWLDVFKKCOYMY-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=CC(=CC=C12)N1C(CCCC1)=O Chemical compound N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=CC(=CC=C12)N1C(CCCC1)=O YMWLDVFKKCOYMY-UHFFFAOYSA-N 0.000 claims description 3
• HGBHQYSMMDDYKN-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=CC(=CC=C12)N1CC(CCC1)C Chemical compound N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=CC(=CC=C12)N1CC(CCC1)C HGBHQYSMMDDYKN-UHFFFAOYSA-N 0.000 claims description 3
• 125000004429 atom Chemical group 0.000 claims description 3
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 3
• 125000000392 cycloalkenyl 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
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 3
• MGALILGJTHFPJG-UHFFFAOYSA-N C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=C(C=CC=C12)N1CCCCC1 Chemical compound C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=C(C=CC=C12)N1CCCCC1 MGALILGJTHFPJG-UHFFFAOYSA-N 0.000 claims description 2
• 150000001555 benzenes Chemical class 0.000 claims description 2
• 238000012545 processing Methods 0.000 claims description 2
• 150000001335 aliphatic alkanes Chemical class 0.000 claims 2
• 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 1
• WIPBDFYJQOHJLH-UHFFFAOYSA-N C(C)(C)(C)C=1C=C2CCN(C2=CC1)NC(=O)NC=1C=CCC2=NC3=CC=CC=C3C12 Chemical compound C(C)(C)(C)C=1C=C2CCN(C2=CC1)NC(=O)NC=1C=CCC2=NC3=CC=CC=C3C12 WIPBDFYJQOHJLH-UHFFFAOYSA-N 0.000 claims 1
• DVIGGPSDTCGLRR-UHFFFAOYSA-N C(C)C1C(=CC2=CC=CC=C12)N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=CC(=C(C=C12)OC)OC Chemical compound C(C)C1C(=CC2=CC=CC=C12)N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=CC(=C(C=C12)OC)OC DVIGGPSDTCGLRR-UHFFFAOYSA-N 0.000 claims 1
• FENHHJQRBUCGLB-UHFFFAOYSA-N C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=CC(=CC=C12)C(F)(F)F Chemical compound C1C=CC(=C2C3=CC=CC=C3N=C12)NC(=O)NN1CCC2=CC(=CC=C12)C(F)(F)F FENHHJQRBUCGLB-UHFFFAOYSA-N 0.000 claims 1
• PICKCQMOSPNEAG-UHFFFAOYSA-N FC1CCN(CC1)C1=C2CCC(C2=CC=C1)NC(=O)NC=1C=CCC2=NC3=CC=CC=C3C12 Chemical compound FC1CCN(CC1)C1=C2CCC(C2=CC=C1)NC(=O)NC=1C=CCC2=NC3=CC=CC=C3C12 PICKCQMOSPNEAG-UHFFFAOYSA-N 0.000 claims 1
• AEKIYVBCIZLYQU-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=C(C=CC=C12)N1CC2CCCCC2CC1 Chemical compound N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=C(C=CC=C12)N1CC2CCCCC2CC1 AEKIYVBCIZLYQU-UHFFFAOYSA-N 0.000 claims 1
• GYSAZCVLSNOBBR-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=C(C=CC=C12)N1CCOCC1 Chemical compound N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=C(C=CC=C12)N1CCOCC1 GYSAZCVLSNOBBR-UHFFFAOYSA-N 0.000 claims 1
• YRSFOOLUIIQCMD-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=CC(=CC=C12)N1C(CCCC1)C Chemical compound N1N=CC2=C(C=CC=C12)NC(=O)NN1CCC2=CC(=CC=C12)N1C(CCCC1)C YRSFOOLUIIQCMD-UHFFFAOYSA-N 0.000 claims 1
• 241000009298 Trigla lyra Species 0.000 claims 1
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims 1
• 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 1
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 9
• 241000124008 Mammalia Species 0.000 abstract description 5
• 238000005481 NMR spectroscopy Methods 0.000 description 137
• 239000000243 solution Substances 0.000 description 76
• 235000019439 ethyl acetate Nutrition 0.000 description 72
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 66
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
• 239000007787 solid Substances 0.000 description 56
• 238000010511 deprotection reaction Methods 0.000 description 50
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
• YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 38
• 238000004458 analytical method Methods 0.000 description 36
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
• 239000011541 reaction mixture Substances 0.000 description 32
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
• 239000000047 product Substances 0.000 description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
• 238000000921 elemental analysis Methods 0.000 description 24
• 150000001412 amines Chemical class 0.000 description 23
• 239000002585 base Substances 0.000 description 22
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• JWWIHTSMTIHTGK-UHFFFAOYSA-N methyl 4-[[4-(2-methylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCCCC1C JWWIHTSMTIHTGK-UHFFFAOYSA-N 0.000 description 1
• IVYJPWRXQTXABB-UHFFFAOYSA-N methyl 4-[[4-(3,3-difluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCCC(F)(F)C1 IVYJPWRXQTXABB-UHFFFAOYSA-N 0.000 description 1
• JNKHNFFHNSIESN-UHFFFAOYSA-N methyl 4-[[4-(3-fluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCCC(F)C1 JNKHNFFHNSIESN-UHFFFAOYSA-N 0.000 description 1
• QISJFUZXGABDMI-UHFFFAOYSA-N methyl 4-[[4-(3-methylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCCC(C)C1 QISJFUZXGABDMI-UHFFFAOYSA-N 0.000 description 1
• ZQKDPUTZNPLTRC-UHFFFAOYSA-N methyl 4-[[4-(4,4-difluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCC(F)(F)CC1 ZQKDPUTZNPLTRC-UHFFFAOYSA-N 0.000 description 1
• SLLDSDHFZJGDFP-UHFFFAOYSA-N methyl 4-[[4-(4-fluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCC(F)CC1 SLLDSDHFZJGDFP-UHFFFAOYSA-N 0.000 description 1
• YYCDICITOPVCIX-UHFFFAOYSA-N methyl 4-[[4-(4-methylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCC(C)CC1 YYCDICITOPVCIX-UHFFFAOYSA-N 0.000 description 1
• SVYQNXVHHHMROM-UHFFFAOYSA-N methyl 4-[[4-(8-azabicyclo[3.2.1]octan-8-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CCC2CCC1N2C1=CC=CC2=C1CCC2NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 SVYQNXVHHHMROM-UHFFFAOYSA-N 0.000 description 1
• LBFLPGKLLOUUDH-UHFFFAOYSA-N methyl 4-[[4-(trifluoromethoxy)-2,3-dihydroindol-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound FC(OC1=C2CCN(C2=CC=C1)NC(NC1=C2C=NN(C2=CC=C1)C(=O)OC)=O)(F)F LBFLPGKLLOUUDH-UHFFFAOYSA-N 0.000 description 1
• XUNOUBBDMRUCKC-UHFFFAOYSA-N methyl 4-[[4-(trifluoromethyl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CC(C(=CC=C2)C(F)(F)F)=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 XUNOUBBDMRUCKC-UHFFFAOYSA-N 0.000 description 1
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