US20040157851A1 - CRF receptor antagonists and methods relating thereto - Google Patents
CRF receptor antagonists and methods relating thereto Download PDFInfo
- Publication number
- US20040157851A1 US20040157851A1 US10/701,394 US70139403A US2004157851A1 US 20040157851 A1 US20040157851 A1 US 20040157851A1 US 70139403 A US70139403 A US 70139403A US 2004157851 A1 US2004157851 A1 US 2004157851A1
- Authority
- US
- United States
- Prior art keywords
- compound
- substituted
- alkyl
- phenyl
- methoxy
- Prior art date
- 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.)
- Abandoned
Links
- 0 CC.[1*]N1cc*2BC([Ar])C3=C2C1=CC([2*])=N3 Chemical compound CC.[1*]N1cc*2BC([Ar])C3=C2C1=CC([2*])=N3 0.000 description 59
- AZLAWGCUDHUQDB-UHFFFAOYSA-N CCCC(CCC)C(C)C Chemical compound CCCC(CCC)C(C)C AZLAWGCUDHUQDB-UHFFFAOYSA-N 0.000 description 31
- XIMCWSMVGVJQQN-UHFFFAOYSA-N CC(C)CC1CC1 Chemical compound CC(C)CC1CC1 XIMCWSMVGVJQQN-UHFFFAOYSA-N 0.000 description 26
- BZHMBWZPUJHVEE-UHFFFAOYSA-N CC(C)CC(C)C Chemical compound CC(C)CC(C)C BZHMBWZPUJHVEE-UHFFFAOYSA-N 0.000 description 11
- AFABGHUZZDYHJO-UHFFFAOYSA-N CCCC(C)C Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
- CKABARUORCUAGG-UHFFFAOYSA-N CC(C)C(=O)C1CC1 Chemical compound CC(C)C(=O)C1CC1 CKABARUORCUAGG-UHFFFAOYSA-N 0.000 description 5
- GXDHCNNESPLIKD-UHFFFAOYSA-N CCCCC(C)C Chemical compound CCCCC(C)C GXDHCNNESPLIKD-UHFFFAOYSA-N 0.000 description 5
- YPMNDMUOGQJCLW-UHFFFAOYSA-N CCCCCC(C)C(C)C Chemical compound CCCCCC(C)C(C)C YPMNDMUOGQJCLW-UHFFFAOYSA-N 0.000 description 5
- ZQAYBCWERYRAMF-UHFFFAOYSA-N COCCC(C)C Chemical compound COCCC(C)C ZQAYBCWERYRAMF-UHFFFAOYSA-N 0.000 description 5
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N CC(C)CC1=CC=CC=C1 Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 4
- QWTDNUCVQCZILF-UHFFFAOYSA-N CCC(C)C Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 4
- CHDRTUMRSLJXOC-UHFFFAOYSA-N CCCC(CCC)C(=O)C(C)C Chemical compound CCCC(CCC)C(=O)C(C)C CHDRTUMRSLJXOC-UHFFFAOYSA-N 0.000 description 4
- WSSSPWUEQFSQQG-UHFFFAOYSA-N C=CCC(C)C Chemical compound C=CCC(C)C WSSSPWUEQFSQQG-UHFFFAOYSA-N 0.000 description 3
- YGPBAWXZRCBYMD-UHFFFAOYSA-N CC(C)C(=O)C1=CC=NO1 Chemical compound CC(C)C(=O)C1=CC=NO1 YGPBAWXZRCBYMD-UHFFFAOYSA-N 0.000 description 3
- HPBROFGYTXOJIO-UHFFFAOYSA-N CC(C)C1CC1 Chemical compound CC(C)C1CC1 HPBROFGYTXOJIO-UHFFFAOYSA-N 0.000 description 3
- RFHQRRJFJJCQDJ-UHFFFAOYSA-N CC(C)C1CCC1 Chemical compound CC(C)C1CCC1 RFHQRRJFJJCQDJ-UHFFFAOYSA-N 0.000 description 3
- TUIWMHDSXJWXOH-UHFFFAOYSA-N CC(C)CC(=O)C(C)C Chemical compound CC(C)CC(=O)C(C)C TUIWMHDSXJWXOH-UHFFFAOYSA-N 0.000 description 3
- HRHZVFKTPFMCPP-UHFFFAOYSA-N CC(C)CC1=CC=C(S(C)(=O)=O)C=C1 Chemical compound CC(C)CC1=CC=C(S(C)(=O)=O)C=C1 HRHZVFKTPFMCPP-UHFFFAOYSA-N 0.000 description 3
- HYTRYEXINDDXJK-UHFFFAOYSA-N CCC(=O)C(C)C Chemical compound CCC(=O)C(C)C HYTRYEXINDDXJK-UHFFFAOYSA-N 0.000 description 3
- SPLBTWOVRQPGQN-UHFFFAOYSA-N CCC(CC)C(=O)C(C)C Chemical compound CCC(CC)C(=O)C(C)C SPLBTWOVRQPGQN-UHFFFAOYSA-N 0.000 description 3
- HIGGFWFRAWSMBR-UHFFFAOYSA-N CCCC(=O)C(C)C Chemical compound CCCC(=O)C(C)C HIGGFWFRAWSMBR-UHFFFAOYSA-N 0.000 description 3
- NKMJCVVUYDKHAV-UHFFFAOYSA-N CCCCC(CC)C(C)C Chemical compound CCCCC(CC)C(C)C NKMJCVVUYDKHAV-UHFFFAOYSA-N 0.000 description 3
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N CC(=O)C(C)C Chemical compound CC(=O)C(C)C SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- OVCHQRXVZXVQNQ-UHFFFAOYSA-N CC(C)C(=O)C(C)(C)C Chemical compound CC(C)C(=O)C(C)(C)C OVCHQRXVZXVQNQ-UHFFFAOYSA-N 0.000 description 2
- PKENGBIQADQPPL-UHFFFAOYSA-N CC(C)C(=O)C1=C(F)C=CC=C1F Chemical compound CC(C)C(=O)C1=C(F)C=CC=C1F PKENGBIQADQPPL-UHFFFAOYSA-N 0.000 description 2
- CPMFTFZWDCIXLE-UHFFFAOYSA-N CC(C)C(=O)C1CCCC1 Chemical compound CC(C)C(=O)C1CCCC1 CPMFTFZWDCIXLE-UHFFFAOYSA-N 0.000 description 2
- XOYXUTUANRHAEM-UHFFFAOYSA-N CC(C)C(=O)CC1=CC=CS1 Chemical compound CC(C)C(=O)CC1=CC=CS1 XOYXUTUANRHAEM-UHFFFAOYSA-N 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N CC(C)C(C)C Chemical compound CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- TVSBRLGQVHJIKT-UHFFFAOYSA-N CC(C)C1CCCC1 Chemical compound CC(C)C1CCCC1 TVSBRLGQVHJIKT-UHFFFAOYSA-N 0.000 description 2
- SANOUVWGPVYVAV-UHFFFAOYSA-N CC(C)CC(N)=O Chemical compound CC(C)CC(N)=O SANOUVWGPVYVAV-UHFFFAOYSA-N 0.000 description 2
- QEOOUOLWAGVCIH-UHFFFAOYSA-N CC(C)CC1=CC=CC=C1OC(F)(F)F Chemical compound CC(C)CC1=CC=CC=C1OC(F)(F)F QEOOUOLWAGVCIH-UHFFFAOYSA-N 0.000 description 2
- MTQUKYRLCVNXJC-UHFFFAOYSA-N CC(C)CC1CCC1 Chemical compound CC(C)CC1CCC1 MTQUKYRLCVNXJC-UHFFFAOYSA-N 0.000 description 2
- FFROMNOQCNVNIH-UHFFFAOYSA-N CC(C)CC1CCCCC1 Chemical compound CC(C)CC1CCCCC1 FFROMNOQCNVNIH-UHFFFAOYSA-N 0.000 description 2
- YCRIFATXXXUQRB-UHFFFAOYSA-N CC(C)CC1CCCO1 Chemical compound CC(C)CC1CCCO1 YCRIFATXXXUQRB-UHFFFAOYSA-N 0.000 description 2
- UWNADWZGEHDQAB-UHFFFAOYSA-N CC(C)CCC(C)C Chemical compound CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 description 2
- RIQHEIKMKGOIQN-UHFFFAOYSA-N CC(C)CCC1=CNC2=CC=CC=C12 Chemical compound CC(C)CCC1=CNC2=CC=CC=C12 RIQHEIKMKGOIQN-UHFFFAOYSA-N 0.000 description 2
- KEVMYFLMMDUPJE-UHFFFAOYSA-N CC(C)CCCCC(C)C Chemical compound CC(C)CCCCC(C)C KEVMYFLMMDUPJE-UHFFFAOYSA-N 0.000 description 2
- JTKHUJNVHQWSAY-UHFFFAOYSA-N CC(C)CCCCCCCCO Chemical compound CC(C)CCCCCCCCO JTKHUJNVHQWSAY-UHFFFAOYSA-N 0.000 description 2
- QNFYLUDPMZVIOW-UHFFFAOYSA-N CC(C)CCN1C=CC=C1 Chemical compound CC(C)CCN1C=CC=C1 QNFYLUDPMZVIOW-UHFFFAOYSA-N 0.000 description 2
- RLCGGBORWFVIJF-UHFFFAOYSA-N CC(C)N(C)CC(O)C1=CC=CC=C1 Chemical compound CC(C)N(C)CC(O)C1=CC=CC=C1 RLCGGBORWFVIJF-UHFFFAOYSA-N 0.000 description 2
- XCNAPBRWCDLTKB-UHFFFAOYSA-N CC(C)N1CC=CCC1 Chemical compound CC(C)N1CC=CCC1 XCNAPBRWCDLTKB-UHFFFAOYSA-N 0.000 description 2
- ZTBMYEYBMRNGEU-UHFFFAOYSA-N CC(C)N1CCC(O)(C2=CC=CC=C2)CC1 Chemical compound CC(C)N1CCC(O)(C2=CC=CC=C2)CC1 ZTBMYEYBMRNGEU-UHFFFAOYSA-N 0.000 description 2
- CKPAOPWAVKSUPQ-UHFFFAOYSA-N CC(C)N1CCCC1C(=O)O Chemical compound CC(C)N1CCCC1C(=O)O CKPAOPWAVKSUPQ-UHFFFAOYSA-N 0.000 description 2
- XJCUYISZYNEDKN-UHFFFAOYSA-N CC(C)N1CCCC1CO Chemical compound CC(C)N1CCCC1CO XJCUYISZYNEDKN-UHFFFAOYSA-N 0.000 description 2
- NSGBJARPGNPRKD-UHFFFAOYSA-N CC(C)N1CCCCC1C Chemical compound CC(C)N1CCCCC1C NSGBJARPGNPRKD-UHFFFAOYSA-N 0.000 description 2
- VTWYQAQIXXAXOR-UHFFFAOYSA-N CC(C)S(C)(=O)=O Chemical compound CC(C)S(C)(=O)=O VTWYQAQIXXAXOR-UHFFFAOYSA-N 0.000 description 2
- ATJMSNSOVYWOQZ-UHFFFAOYSA-N CC(C)SO(O)C(C)C Chemical compound CC(C)SO(O)C(C)C ATJMSNSOVYWOQZ-UHFFFAOYSA-N 0.000 description 2
- ITALGWAPQUXCDK-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(C(C)C)C=C1 Chemical compound CC(C)SO(O)C1=CC=C(C(C)C)C=C1 ITALGWAPQUXCDK-UHFFFAOYSA-N 0.000 description 2
- ZQCWKOWLVLJUCK-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(C(F)(F)F)C=C1 Chemical compound CC(C)SO(O)C1=CC=C(C(F)(F)F)C=C1 ZQCWKOWLVLJUCK-UHFFFAOYSA-N 0.000 description 2
- KJVJYOPTGSQYSB-UHFFFAOYSA-N CC(C)SO(O)CC1=CC=CC=C1 Chemical compound CC(C)SO(O)CC1=CC=CC=C1 KJVJYOPTGSQYSB-UHFFFAOYSA-N 0.000 description 2
- XZLYZLJOUJEYNI-UHFFFAOYSA-N CC1=CC=C(O(O)SC(C)C)C=C1 Chemical compound CC1=CC=C(O(O)SC(C)C)C=C1 XZLYZLJOUJEYNI-UHFFFAOYSA-N 0.000 description 2
- DUPUVYJQZSLSJB-UHFFFAOYSA-N CCC(CC)C(C)C Chemical compound CCC(CC)C(C)C DUPUVYJQZSLSJB-UHFFFAOYSA-N 0.000 description 2
- KYCZJIBOPKRSOV-UHFFFAOYSA-N CCC(CC)CC(C)C Chemical compound CCC(CC)CC(C)C KYCZJIBOPKRSOV-UHFFFAOYSA-N 0.000 description 2
- IQMKGKDMBSUSIF-UHFFFAOYSA-N CCC(COC)C(C)C Chemical compound CCC(COC)C(C)C IQMKGKDMBSUSIF-UHFFFAOYSA-N 0.000 description 2
- XYYMFUCZDNNGFS-UHFFFAOYSA-N CCCCC(=O)C(C)C Chemical compound CCCCC(=O)C(C)C XYYMFUCZDNNGFS-UHFFFAOYSA-N 0.000 description 2
- ALZCRHWYCQKCQK-UHFFFAOYSA-N CCCCC(CCCC)C(C)C Chemical compound CCCCC(CCCC)C(C)C ALZCRHWYCQKCQK-UHFFFAOYSA-N 0.000 description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N CCCCCC(C)C Chemical compound CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 2
- NRAPDZRPWHOPKB-UHFFFAOYSA-N CCCN(CCC)C(C)C Chemical compound CCCN(CCC)C(C)C NRAPDZRPWHOPKB-UHFFFAOYSA-N 0.000 description 2
- CCUOSFRXUCGGNA-UHFFFAOYSA-N CCCO(O)SC(C)C Chemical compound CCCO(O)SC(C)C CCUOSFRXUCGGNA-UHFFFAOYSA-N 0.000 description 2
- UTLDDSNRFHWERZ-UHFFFAOYSA-N CCN(C)C(C)C Chemical compound CCN(C)C(C)C UTLDDSNRFHWERZ-UHFFFAOYSA-N 0.000 description 2
- DGVATXSTBKCAGL-UHFFFAOYSA-N CCO(O)SC(C)C Chemical compound CCO(O)SC(C)C DGVATXSTBKCAGL-UHFFFAOYSA-N 0.000 description 2
- WCPUFSIDCWSGEW-UHFFFAOYSA-N COC(C)(CC(C)C)OC Chemical compound COC(C)(CC(C)C)OC WCPUFSIDCWSGEW-UHFFFAOYSA-N 0.000 description 2
- QPKMJKGNHMQLPA-UHFFFAOYSA-N COC1=C(C(=O)C(C)C)C=CC=C1 Chemical compound COC1=C(C(=O)C(C)C)C=CC=C1 QPKMJKGNHMQLPA-UHFFFAOYSA-N 0.000 description 2
- WIMPRGWRRFUZDD-UHFFFAOYSA-N COC1=CC=C(O(O)SC(C)C)C=C1 Chemical compound COC1=CC=C(O(O)SC(C)C)C=C1 WIMPRGWRRFUZDD-UHFFFAOYSA-N 0.000 description 2
- MJDDENYNARWBHQ-UHFFFAOYSA-N COCC(=O)C(C)C Chemical compound COCC(=O)C(C)C MJDDENYNARWBHQ-UHFFFAOYSA-N 0.000 description 2
- OEVLGZMQOSOPMO-UHFFFAOYSA-N BrBr.BrCCBr.CC1=NC2=C(NC=C2)C(Cl)=N1.CC1=NC2=C(NC=C2Br)C(Cl)=N1.CCCC(CCC)N1CCN2/C=C(/C3=CC=C(Cl)C=C3Cl)C3=C2C1=NC(C)=N3.CCCC(CCC)NC1=NC(C)=NC2=C1NC=C2Br.CCCC(CCC)NC1=NC(C)=NC2=C1NC=C2C1=C(Cl)C=C(Cl)C=C1.CCCC(N)CCC Chemical compound BrBr.BrCCBr.CC1=NC2=C(NC=C2)C(Cl)=N1.CC1=NC2=C(NC=C2Br)C(Cl)=N1.CCCC(CCC)N1CCN2/C=C(/C3=CC=C(Cl)C=C3Cl)C3=C2C1=NC(C)=N3.CCCC(CCC)NC1=NC(C)=NC2=C1NC=C2Br.CCCC(CCC)NC1=NC(C)=NC2=C1NC=C2C1=C(Cl)C=C(Cl)C=C1.CCCC(N)CCC OEVLGZMQOSOPMO-UHFFFAOYSA-N 0.000 description 1
- BOUXKDUEPHBXPJ-UHFFFAOYSA-N BrBr.BrCCBr.CC1=NC2=C(NN=C2)C(Cl)=N1.CC1=NC2=C(NN=C2)C(O)=N1.CC1=NC2=C(NN=C2Br)C(Cl)=N1.CCCC(CCC)N1CCN2/N=C(/C3=CC=C(Cl)C=C3Cl)C3=C2C1=NC(C)=N3.CCCC(CCC)NC1=NC(C)=NC2=C1NN=C2Br.CCCC(CCC)NC1=NC(C)=NC2=C1NN=C2C1=CC=C(Cl)C=C1Cl.CCCC(N)CCC.O=P(Cl)(Cl)Cl Chemical compound BrBr.BrCCBr.CC1=NC2=C(NN=C2)C(Cl)=N1.CC1=NC2=C(NN=C2)C(O)=N1.CC1=NC2=C(NN=C2Br)C(Cl)=N1.CCCC(CCC)N1CCN2/N=C(/C3=CC=C(Cl)C=C3Cl)C3=C2C1=NC(C)=N3.CCCC(CCC)NC1=NC(C)=NC2=C1NN=C2Br.CCCC(CCC)NC1=NC(C)=NC2=C1NN=C2C1=CC=C(Cl)C=C1Cl.CCCC(N)CCC.O=P(Cl)(Cl)Cl BOUXKDUEPHBXPJ-UHFFFAOYSA-N 0.000 description 1
- QBLJXCPPINSHCK-UHFFFAOYSA-N BrBr.C.C.C.CC(=O)Cl.CC(=O)NC1=C(C)N=C(C)C=C1.CC1=CC2=C(C=CC(C)=N2)N1.CC1=CC2=C(C=CC(C)=N2=O)N1.CC1=CC2=C(N1)C(Cl)=CC(C)=N2.CC1=CC=CC(C)=N1.CC1=NC(C)=C(N)C=C1.CC1=NC2=C(NC(C)=C2Br)C(Cl)=C1.CCCC(CCC)NC1=CC(C)=NC2=C1NC(C)=C2Br.CCO[Na].O=P(Cl)(Cl)Cl Chemical compound BrBr.C.C.C.CC(=O)Cl.CC(=O)NC1=C(C)N=C(C)C=C1.CC1=CC2=C(C=CC(C)=N2)N1.CC1=CC2=C(C=CC(C)=N2=O)N1.CC1=CC2=C(N1)C(Cl)=CC(C)=N2.CC1=CC=CC(C)=N1.CC1=NC(C)=C(N)C=C1.CC1=NC2=C(NC(C)=C2Br)C(Cl)=C1.CCCC(CCC)NC1=CC(C)=NC2=C1NC(C)=C2Br.CCO[Na].O=P(Cl)(Cl)Cl QBLJXCPPINSHCK-UHFFFAOYSA-N 0.000 description 1
- VAKXZXAVJNCFGH-UJGXPDPASA-N BrBr.C.C1=CNN=C1.CC1=NC2=C(NN=C2)C(Cl)=C1.CC1=NC2=C(NN=C2)C(O)=C1.CC1=NC2=C(NN=C2Br)C(Cl)=C1.CCCCC(CCCC)NC1=CC(C)=NC2=C1NN=C2Br.CCCCC(N)CCCC.CCOC(=O)/C=C(\C)NC1=CNN=C1.NC1=CNN=C1.O=P(Cl)(Cl)Cl.O=[N+]([O-])C1=CNN=C1.O=[N+]([O-])O.OB(O)C1=C(Cl)C=C(Cl)C=C1.[HH] Chemical compound BrBr.C.C1=CNN=C1.CC1=NC2=C(NN=C2)C(Cl)=C1.CC1=NC2=C(NN=C2)C(O)=C1.CC1=NC2=C(NN=C2Br)C(Cl)=C1.CCCCC(CCCC)NC1=CC(C)=NC2=C1NN=C2Br.CCCCC(N)CCCC.CCOC(=O)/C=C(\C)NC1=CNN=C1.NC1=CNN=C1.O=P(Cl)(Cl)Cl.O=[N+]([O-])C1=CNN=C1.O=[N+]([O-])O.OB(O)C1=C(Cl)C=C(Cl)C=C1.[HH] VAKXZXAVJNCFGH-UJGXPDPASA-N 0.000 description 1
- QPFBHTHINHJORZ-BNGKJXOCSA-M BrCCBr.CC1=NC2=C(NN=C2C2=C(Cl)C=C(Cl)C=C2)C(Cl)=C1.CC1=NC2=C(NN=C2C2=C(Cl)C=C(Cl)C=C2)C(O)=C1.CCCC(CCC)N1/C=C\N2N=C(C3=C(Cl)C=C(Cl)C=C3)C3=C2C1=CC(C)=N3.CCCC(CCC)N1CCN2N=C(C3=C(Cl)C=C(Cl)C=C3)C3=C2C1=CC(C)=N3.CCCC(CCC)NC1=CC(C)=NC2=C1NN=C2C1=C(Cl)C=C(Cl)C=C1.CCOC(=O)CC(C)=O.CN(C)/C=C(\C(=O)C1=C(Cl)C=C(Cl)C=C1)N1C(=O)C2=C(C=CC=C2)C1=O.NC1=CNN=C1C1=C(Cl)C=C(Cl)C=C1.O=C(CCl)C1=C(Cl)C=C(Cl)C=C1.O=C(CN1C(=O)C2=C(C=CC=C2)C1=O)C1=C(Cl)C=C(Cl)C=C1.O=C1C2=CC=CC=C2C(=O)N1[K].O=P(Cl)(Cl)Cl.O=[Mn]=O Chemical compound BrCCBr.CC1=NC2=C(NN=C2C2=C(Cl)C=C(Cl)C=C2)C(Cl)=C1.CC1=NC2=C(NN=C2C2=C(Cl)C=C(Cl)C=C2)C(O)=C1.CCCC(CCC)N1/C=C\N2N=C(C3=C(Cl)C=C(Cl)C=C3)C3=C2C1=CC(C)=N3.CCCC(CCC)N1CCN2N=C(C3=C(Cl)C=C(Cl)C=C3)C3=C2C1=CC(C)=N3.CCCC(CCC)NC1=CC(C)=NC2=C1NN=C2C1=C(Cl)C=C(Cl)C=C1.CCOC(=O)CC(C)=O.CN(C)/C=C(\C(=O)C1=C(Cl)C=C(Cl)C=C1)N1C(=O)C2=C(C=CC=C2)C1=O.NC1=CNN=C1C1=C(Cl)C=C(Cl)C=C1.O=C(CCl)C1=C(Cl)C=C(Cl)C=C1.O=C(CN1C(=O)C2=C(C=CC=C2)C1=O)C1=C(Cl)C=C(Cl)C=C1.O=C1C2=CC=CC=C2C(=O)N1[K].O=P(Cl)(Cl)Cl.O=[Mn]=O QPFBHTHINHJORZ-BNGKJXOCSA-M 0.000 description 1
- QKETWUNXRTVTDE-UHFFFAOYSA-N BrCCBr.CCCC(CCC)N1CCN2C3=C(N=C(C)C=C31)/C(C1=C(Cl)C=C(Cl)C=C1)=C\2C.CCCC(CCC)NC1=CC(C)=NC2=C1NC(C)=C2C1=C(Cl)C=C(Cl)C=C1 Chemical compound BrCCBr.CCCC(CCC)N1CCN2C3=C(N=C(C)C=C31)/C(C1=C(Cl)C=C(Cl)C=C1)=C\2C.CCCC(CCC)NC1=CC(C)=NC2=C1NC(C)=C2C1=C(Cl)C=C(Cl)C=C1 QKETWUNXRTVTDE-UHFFFAOYSA-N 0.000 description 1
- OXRWICUICBZVAE-UHFFFAOYSA-N C#CCC(C)C Chemical compound C#CCC(C)C OXRWICUICBZVAE-UHFFFAOYSA-N 0.000 description 1
- LCKNOLZWXCBQGK-UHFFFAOYSA-K C.CC(=O)CO.CC1=CC(C)=C(N)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC3=C(Cl)C=C(C)N=C32)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC3=C(O)C=C(C)N=C32)C(C)=C1.CCOC(=O)C1=C(C)N=C2C(=C1O)C=C(C)N2C1=C(C)C=C(C)C=C1C.CCOC(=O)C1=C(N)N(C2=C(C)C=C(C)C=C2C)C(C)=C1.CCOC(=O)C=C(C)OCC.Cl[Al](Cl)Cl.O=C(Cl)CCl.O=P(Cl)(Cl)Cl Chemical compound C.CC(=O)CO.CC1=CC(C)=C(N)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC3=C(Cl)C=C(C)N=C32)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC3=C(O)C=C(C)N=C32)C(C)=C1.CCOC(=O)C1=C(C)N=C2C(=C1O)C=C(C)N2C1=C(C)C=C(C)C=C1C.CCOC(=O)C1=C(N)N(C2=C(C)C=C(C)C=C2C)C(C)=C1.CCOC(=O)C=C(C)OCC.Cl[Al](Cl)Cl.O=C(Cl)CCl.O=P(Cl)(Cl)Cl LCKNOLZWXCBQGK-UHFFFAOYSA-K 0.000 description 1
- QSACGCAUVMLJNS-SNAWJCMRSA-N C/C=C/C(=O)C(C)C Chemical compound C/C=C/C(=O)C(C)C QSACGCAUVMLJNS-SNAWJCMRSA-N 0.000 description 1
- GHBKCPRDHLITSE-SNAWJCMRSA-N C/C=C/CC(C)C Chemical compound C/C=C/CC(C)C GHBKCPRDHLITSE-SNAWJCMRSA-N 0.000 description 1
- JGKPUHXTYYLNTF-UHFFFAOYSA-N C=C(C)CN(CC)C(C)C Chemical compound C=C(C)CN(CC)C(C)C JGKPUHXTYYLNTF-UHFFFAOYSA-N 0.000 description 1
- AKJZOCZADYKWTQ-UHFFFAOYSA-N C=C(OCC)[Sn](CCCC)(CCCC)CCCC.CC.CCCC(CCC)N1CC/C2=N/N(C3=CC=C(Cl)C=C3Cl)C3=NC(C)=NC1=C32.CCCC(CCC)NC1=C(C(=O)OCC)C(Cl)=NC(C)=N1.CCCC(CCC)NC1=C2C(C(=O)CBr)=NN(C3=CC=C(Cl)C=C3Cl)C2=NC(C)=N1.CCCC(CCC)NC1=C2C(Cl)=NN(C3=CC=C(Cl)C=C3Cl)C2=NC(C)=N1.CCCC(CCC)NC1=C2C(O)=NN(C3=CC=C(Cl)C=C3Cl)C2=NC(C)=N1.CCCC(CCC)NC1=NC(C)=NC(Cl)=C1C(=O)OCC.CCO.CCOC(=O)C1=C(Cl)N=C(C)N=C1Cl.O=P(Cl)(Cl)Cl Chemical compound C=C(OCC)[Sn](CCCC)(CCCC)CCCC.CC.CCCC(CCC)N1CC/C2=N/N(C3=CC=C(Cl)C=C3Cl)C3=NC(C)=NC1=C32.CCCC(CCC)NC1=C(C(=O)OCC)C(Cl)=NC(C)=N1.CCCC(CCC)NC1=C2C(C(=O)CBr)=NN(C3=CC=C(Cl)C=C3Cl)C2=NC(C)=N1.CCCC(CCC)NC1=C2C(Cl)=NN(C3=CC=C(Cl)C=C3Cl)C2=NC(C)=N1.CCCC(CCC)NC1=C2C(O)=NN(C3=CC=C(Cl)C=C3Cl)C2=NC(C)=N1.CCCC(CCC)NC1=NC(C)=NC(Cl)=C1C(=O)OCC.CCO.CCOC(=O)C1=C(Cl)N=C(C)N=C1Cl.O=P(Cl)(Cl)Cl AKJZOCZADYKWTQ-UHFFFAOYSA-N 0.000 description 1
- UBOKOMAUUUTAHC-UHFFFAOYSA-M C=CC(=O)C1=C(Cl)C=C(C)N=C1Cl.C=CC(O)C1=C(Cl)C=C(C)N=C1Cl.C=C[Mg]Br.CC1=CC(Cl)=C(C=O)C(Cl)=N1.CC1=CC(Cl)=C(CO)C(Cl)=N1.CC1=CC=C(S(=O)(=O)O)C=C1.CCCC(CCC)C1CCC(=O)C2=C(Cl)C=C(C)N=C21.CCCC(CCC)N1CCC(=O)C2=C1/C=C(C)\N=C/2Cl.CCOC(=O)C1=C(Cl)C=C(C)N=C1Cl.ClC1=CC(Cl)=C2(=N(=CC3=CC=CC=C3)N2)C=C1 Chemical compound C=CC(=O)C1=C(Cl)C=C(C)N=C1Cl.C=CC(O)C1=C(Cl)C=C(C)N=C1Cl.C=C[Mg]Br.CC1=CC(Cl)=C(C=O)C(Cl)=N1.CC1=CC(Cl)=C(CO)C(Cl)=N1.CC1=CC=C(S(=O)(=O)O)C=C1.CCCC(CCC)C1CCC(=O)C2=C(Cl)C=C(C)N=C21.CCCC(CCC)N1CCC(=O)C2=C1/C=C(C)\N=C/2Cl.CCOC(=O)C1=C(Cl)C=C(C)N=C1Cl.ClC1=CC(Cl)=C2(=N(=CC3=CC=CC=C3)N2)C=C1 UBOKOMAUUUTAHC-UHFFFAOYSA-M 0.000 description 1
- XZHPAJFRLSMBDQ-UHFFFAOYSA-M C=CC(=O)C1=C(Cl)C=C(C)N=C1Cl.C=CC(O)C1=C(Cl)C=C(C)N=C1Cl.C=C[Mg]Br.CC1=CC(Cl)=C(C=O)C(Cl)=N1.CC1=CC(Cl)=C(CO)C(Cl)=N1.CCCC(CCC)C1CCC(=O)C2=C(Cl)C=C(C)N=C21.CCCC(CCC)N1CCC(=O)C2=C1/C=C(C)\N=C/2Cl.CCOC(=O)C1=C(Cl)C=C(C)N=C1Cl Chemical compound C=CC(=O)C1=C(Cl)C=C(C)N=C1Cl.C=CC(O)C1=C(Cl)C=C(C)N=C1Cl.C=C[Mg]Br.CC1=CC(Cl)=C(C=O)C(Cl)=N1.CC1=CC(Cl)=C(CO)C(Cl)=N1.CCCC(CCC)C1CCC(=O)C2=C(Cl)C=C(C)N=C21.CCCC(CCC)N1CCC(=O)C2=C1/C=C(C)\N=C/2Cl.CCOC(=O)C1=C(Cl)C=C(C)N=C1Cl XZHPAJFRLSMBDQ-UHFFFAOYSA-M 0.000 description 1
- DFVOXRAAHOJJBN-UHFFFAOYSA-N C=CCCCC(C)C Chemical compound C=CCCCC(C)C DFVOXRAAHOJJBN-UHFFFAOYSA-N 0.000 description 1
- FNTKCFXJXGIBPO-UHFFFAOYSA-N C=CCN(C)C(C)C Chemical compound C=CCN(C)C(C)C FNTKCFXJXGIBPO-UHFFFAOYSA-N 0.000 description 1
- FUUFQLJQGPHRIP-UHFFFAOYSA-N C=CCN(CC)C(C)C Chemical compound C=CCN(CC)C(C)C FUUFQLJQGPHRIP-UHFFFAOYSA-N 0.000 description 1
- QDWXFCUKTJVMOZ-UHFFFAOYSA-N CC(=O)C1=CC=C(O(O)SC(C)C)C=C1 Chemical compound CC(=O)C1=CC=C(O(O)SC(C)C)C=C1 QDWXFCUKTJVMOZ-UHFFFAOYSA-N 0.000 description 1
- NYRICVIEYBWQOG-UHFFFAOYSA-K CC(=O)CO.CC(=O)NC1=C(C#N)C=C(C)N1C1=C(C)C=C(C)C=C1C.CC(=O)OC(C)=O.CC1=CC(C)=C(N)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC(C#N)=C2N)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC3=C(Cl)N=C(C)N=C32)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC3=C(O)N=C(C)N=C32)C(C)=C1.Cl[Al](Cl)Cl.O=C(Cl)CCl.O=P(=O)OO.O=P(Cl)(Cl)Cl.[HH] Chemical compound CC(=O)CO.CC(=O)NC1=C(C#N)C=C(C)N1C1=C(C)C=C(C)C=C1C.CC(=O)OC(C)=O.CC1=CC(C)=C(N)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC(C#N)=C2N)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC3=C(Cl)N=C(C)N=C32)C(C)=C1.CC1=CC(C)=C(N2C(C)=CC3=C(O)N=C(C)N=C32)C(C)=C1.Cl[Al](Cl)Cl.O=C(Cl)CCl.O=P(=O)OO.O=P(Cl)(Cl)Cl.[HH] NYRICVIEYBWQOG-UHFFFAOYSA-K 0.000 description 1
- IDXQYOPUVDGIBR-UHFFFAOYSA-N CC(=O)NC1=CC=C(O(O)SC(C)(C)C)C=C1 Chemical compound CC(=O)NC1=CC=C(O(O)SC(C)(C)C)C=C1 IDXQYOPUVDGIBR-UHFFFAOYSA-N 0.000 description 1
- ZLNGWLBIEPKAPX-UHFFFAOYSA-N CC(=O)NC1=CC=C(O(O)SC(C)C)C=C1 Chemical compound CC(=O)NC1=CC=C(O(O)SC(C)C)C=C1 ZLNGWLBIEPKAPX-UHFFFAOYSA-N 0.000 description 1
- XALJDSYTMGPRFJ-UHFFFAOYSA-N CC(=O)NC1=NC=C(O(O)SC(C)C)S1 Chemical compound CC(=O)NC1=NC=C(O(O)SC(C)C)S1 XALJDSYTMGPRFJ-UHFFFAOYSA-N 0.000 description 1
- SVCYVJUTDRKFSK-UHFFFAOYSA-N CC(=O)NC1=NC=C(S(=O)(=O)C(C)C)S1 Chemical compound CC(=O)NC1=NC=C(S(=O)(=O)C(C)C)S1 SVCYVJUTDRKFSK-UHFFFAOYSA-N 0.000 description 1
- LNTLGVXCZRDJFJ-UHFFFAOYSA-N CC(=O)NC1CCN(C(C)(C)C)C1 Chemical compound CC(=O)NC1CCN(C(C)(C)C)C1 LNTLGVXCZRDJFJ-UHFFFAOYSA-N 0.000 description 1
- OOYBITFWBADNKC-UHFFFAOYSA-N CC(=O)OCCCCC(C)C Chemical compound CC(=O)OCCCCC(C)C OOYBITFWBADNKC-UHFFFAOYSA-N 0.000 description 1
- DICUPLXUNISGAQ-UHFFFAOYSA-N CC(=O)OCCCCCC(C)C Chemical compound CC(=O)OCCCCCC(C)C DICUPLXUNISGAQ-UHFFFAOYSA-N 0.000 description 1
- CRSOQBOWXPBRES-UHFFFAOYSA-N CC(C)(C)C Chemical compound CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 description 1
- WVLYELMSOVNEFD-UHFFFAOYSA-N CC(C)(C)N1CCC2=C(CC3=CC=CC=C32)C1.CC(C)N1CC=CC1.CC(C)N1CCCC1.CC(C)N1CCCCC1 Chemical compound CC(C)(C)N1CCC2=C(CC3=CC=CC=C32)C1.CC(C)N1CC=CC1.CC(C)N1CCCC1.CC(C)N1CCCCC1 WVLYELMSOVNEFD-UHFFFAOYSA-N 0.000 description 1
- AYAWKOHZQYLQQL-HYXAFXHYSA-N CC(C)/C(F)=C/I Chemical compound CC(C)/C(F)=C/I AYAWKOHZQYLQQL-HYXAFXHYSA-N 0.000 description 1
- VFZIUYUUQFYZBR-UHFFFAOYSA-N CC(C)=CCC(C)C Chemical compound CC(C)=CCC(C)C VFZIUYUUQFYZBR-UHFFFAOYSA-N 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N CC(C)C Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- NLCCAFQWEKMQLM-UHFFFAOYSA-N CC(C)C(=O)C(F)(F)F Chemical compound CC(C)C(=O)C(F)(F)F NLCCAFQWEKMQLM-UHFFFAOYSA-N 0.000 description 1
- FWOHZDJXBIUNAK-UHFFFAOYSA-N CC(C)C(=O)C1=C(C(F)(F)F)C=CC=C1 Chemical compound CC(C)C(=O)C1=C(C(F)(F)F)C=CC=C1 FWOHZDJXBIUNAK-UHFFFAOYSA-N 0.000 description 1
- DIANJNDWLUCSDF-UHFFFAOYSA-N CC(C)C(=O)C1=C2C=CC=CC2=CC=C1 Chemical compound CC(C)C(=O)C1=C2C=CC=CC2=CC=C1 DIANJNDWLUCSDF-UHFFFAOYSA-N 0.000 description 1
- OCZYIFMCWNRVOW-UHFFFAOYSA-N CC(C)C(=O)C1=CC2=C(C=CC=C2)C=C1 Chemical compound CC(C)C(=O)C1=CC2=C(C=CC=C2)C=C1 OCZYIFMCWNRVOW-UHFFFAOYSA-N 0.000 description 1
- UZHSMJBRPOTYRQ-UHFFFAOYSA-N CC(C)C(=O)C1=CC=C(F)C(F)=C1 Chemical compound CC(C)C(=O)C1=CC=C(F)C(F)=C1 UZHSMJBRPOTYRQ-UHFFFAOYSA-N 0.000 description 1
- BSMGLVDZZMBWQB-UHFFFAOYSA-N CC(C)C(=O)C1=CC=CC=C1 Chemical compound CC(C)C(=O)C1=CC=CC=C1 BSMGLVDZZMBWQB-UHFFFAOYSA-N 0.000 description 1
- IQSLUERCHTWGDH-UHFFFAOYSA-N CC(C)C(=O)C1=CC=CO1 Chemical compound CC(C)C(=O)C1=CC=CO1 IQSLUERCHTWGDH-UHFFFAOYSA-N 0.000 description 1
- PJSIVCTXKFMCHK-UHFFFAOYSA-N CC(C)C(=O)C1CCC1 Chemical compound CC(C)C(=O)C1CCC1 PJSIVCTXKFMCHK-UHFFFAOYSA-N 0.000 description 1
- XRLQPWQYUOVNTR-UHFFFAOYSA-N CC(C)C(=O)C1CCCCC1 Chemical compound CC(C)C(=O)C1CCCCC1 XRLQPWQYUOVNTR-UHFFFAOYSA-N 0.000 description 1
- KJWBHOKFRSFCBZ-UHFFFAOYSA-N CC(C)C(=O)CC(C)(C)C Chemical compound CC(C)C(=O)CC(C)(C)C KJWBHOKFRSFCBZ-UHFFFAOYSA-N 0.000 description 1
- QHQKYJAIOSKSFL-UHFFFAOYSA-N CC(C)C(=O)NCC1=CC=CC=C1 Chemical compound CC(C)C(=O)NCC1=CC=CC=C1 QHQKYJAIOSKSFL-UHFFFAOYSA-N 0.000 description 1
- ZISSAWUMDACLOM-UHFFFAOYSA-N CC(C)C(C)(C)C Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 description 1
- GQEFPXSNRRKUHO-UXBLZVDNSA-N CC(C)C/C=C/C1=CC=CC=C1 Chemical compound CC(C)C/C=C/C1=CC=CC=C1 GQEFPXSNRRKUHO-UXBLZVDNSA-N 0.000 description 1
- JROWVHVMSLMBJC-UHFFFAOYSA-N CC(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 Chemical compound CC(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 JROWVHVMSLMBJC-UHFFFAOYSA-N 0.000 description 1
- RWGFKTVRMDUZSP-UHFFFAOYSA-N CC(C)C1=CC=CC=C1 Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 1
- HKTCLPBBJDIBGF-UHFFFAOYSA-N CC(C)C1=CC=CC=C1C1=CC=CC=C1 Chemical compound CC(C)C1=CC=CC=C1C1=CC=CC=C1 HKTCLPBBJDIBGF-UHFFFAOYSA-N 0.000 description 1
- GNUWNVNXXOHZNM-UHFFFAOYSA-N CC(C)C1=CC=CC=C1OC(F)(F)F Chemical compound CC(C)C1=CC=CC=C1OC(F)(F)F GNUWNVNXXOHZNM-UHFFFAOYSA-N 0.000 description 1
- VOWPKRCDLUZWOQ-UHFFFAOYSA-N CC(C)C1CCC2=CC=CC=C2C1.CC(C)C1CCCC2=CC=CC=C21 Chemical compound CC(C)C1CCC2=CC=CC=C2C1.CC(C)C1CCCC2=CC=CC=C21 VOWPKRCDLUZWOQ-UHFFFAOYSA-N 0.000 description 1
- GVOWGGCGIKWFNI-UHFFFAOYSA-N CC(C)C1CCC2=CC=CN=C2C1.CC(C)C1CCC2CCCCC2C1.CC(C)C1CCCC2=CC=CN=C21.CC(C)C1CCCC2CCCCC21 Chemical compound CC(C)C1CCC2=CC=CN=C2C1.CC(C)C1CCC2CCCCC2C1.CC(C)C1CCCC2=CC=CN=C21.CC(C)C1CCCC2CCCCC21 GVOWGGCGIKWFNI-UHFFFAOYSA-N 0.000 description 1
- LRCMZPVVFRECQR-UHFFFAOYSA-N CC(C)C1CCCC2=CC=CC=C21 Chemical compound CC(C)C1CCCC2=CC=CC=C21 LRCMZPVVFRECQR-UHFFFAOYSA-N 0.000 description 1
- GWESVXSMPKAFAS-UHFFFAOYSA-N CC(C)C1CCCCC1 Chemical compound CC(C)C1CCCCC1 GWESVXSMPKAFAS-UHFFFAOYSA-N 0.000 description 1
- UMWPTXOKSJXVDS-UHFFFAOYSA-N CC(C)C1CCCCC1C Chemical compound CC(C)C1CCCCC1C UMWPTXOKSJXVDS-UHFFFAOYSA-N 0.000 description 1
- FFBHNPXMPLIAAR-MCIGGMRASA-N CC(C)C1C[C@H]1C1C=CC=CC1 Chemical compound CC(C)C1C[C@H]1C1C=CC=CC1 FFBHNPXMPLIAAR-MCIGGMRASA-N 0.000 description 1
- PFVGUSSOKDLRMI-UHFFFAOYSA-N CC(C)CBr.CCC1CN2/C=C(/C3=C(Cl)C=C(Cl)C=C3)C3=C2C(=CC(C)=N3)N1.CCC1CN2/C=C(/C3=C(Cl)C=C(Cl)C=C3)C3=C2C(=CC(C)=N3)N1CC(C)C Chemical compound CC(C)CBr.CCC1CN2/C=C(/C3=C(Cl)C=C(Cl)C=C3)C3=C2C(=CC(C)=N3)N1.CCC1CN2/C=C(/C3=C(Cl)C=C(Cl)C=C3)C3=C2C(=CC(C)=N3)N1CC(C)C PFVGUSSOKDLRMI-UHFFFAOYSA-N 0.000 description 1
- HSGZPXMLNNPXIW-UHFFFAOYSA-N CC(C)CBr.CCC1CN2/C=C(/C3=C(Cl)C=C(Cl)C=C3)C3=C2C(=NC(C)=N3)N1.CCC1CN2/C=C(/C3=C(Cl)C=C(Cl)C=C3)C3=C2C(=NC(C)=N3)N1CC(C)C Chemical compound CC(C)CBr.CCC1CN2/C=C(/C3=C(Cl)C=C(Cl)C=C3)C3=C2C(=NC(C)=N3)N1.CCC1CN2/C=C(/C3=C(Cl)C=C(Cl)C=C3)C3=C2C(=NC(C)=N3)N1CC(C)C HSGZPXMLNNPXIW-UHFFFAOYSA-N 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N CC(C)CC(C)(C)C Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- WVYWICLMDOOCFB-UHFFFAOYSA-N CC(C)CC(C)O Chemical compound CC(C)CC(C)O WVYWICLMDOOCFB-UHFFFAOYSA-N 0.000 description 1
- QSTJOHVLWZPHGL-UHFFFAOYSA-N CC(C)CC(O)C(F)(F)F Chemical compound CC(C)CC(O)C(F)(F)F QSTJOHVLWZPHGL-UHFFFAOYSA-N 0.000 description 1
- KWXSTAUVUZAMGW-UHFFFAOYSA-N CC(C)CC(O)C1=CC=CC=C1 Chemical compound CC(C)CC(O)C1=CC=CC=C1 KWXSTAUVUZAMGW-UHFFFAOYSA-N 0.000 description 1
- IUADYGVMSDKSMB-UHFFFAOYSA-N CC(C)CC(O)CC1=CC=CC=C1 Chemical compound CC(C)CC(O)CC1=CC=CC=C1 IUADYGVMSDKSMB-UHFFFAOYSA-N 0.000 description 1
- RONQQBGOAJWPHT-UHFFFAOYSA-N CC(C)CC(O)CF Chemical compound CC(C)CC(O)CF RONQQBGOAJWPHT-UHFFFAOYSA-N 0.000 description 1
- SOXCUYKWCXNSJN-UHFFFAOYSA-N CC(C)CC1=C(Cl)C=CC=C1 Chemical compound CC(C)CC1=C(Cl)C=CC=C1 SOXCUYKWCXNSJN-UHFFFAOYSA-N 0.000 description 1
- LTICOUAGNDJDTE-UHFFFAOYSA-N CC(C)CC1=CC=C(F)C=C1 Chemical compound CC(C)CC1=CC=C(F)C=C1 LTICOUAGNDJDTE-UHFFFAOYSA-N 0.000 description 1
- DEGXTCKEZCCZOP-UHFFFAOYSA-N CC(C)CC1=CN=CC=C1 Chemical compound CC(C)CC1=CN=CC=C1 DEGXTCKEZCCZOP-UHFFFAOYSA-N 0.000 description 1
- XNXIYYFOYIUJIW-UHFFFAOYSA-N CC(C)CCC1=CC=CC=C1 Chemical compound CC(C)CCC1=CC=CC=C1 XNXIYYFOYIUJIW-UHFFFAOYSA-N 0.000 description 1
- BBCIDAVDQLJDMP-UHFFFAOYSA-N CC(C)CCC1CCCCC1 Chemical compound CC(C)CCC1CCCCC1 BBCIDAVDQLJDMP-UHFFFAOYSA-N 0.000 description 1
- XJKKSYAVEVAGFX-UHFFFAOYSA-N CC(C)CCCC(C)C(C)C Chemical compound CC(C)CCCC(C)C(C)C XJKKSYAVEVAGFX-UHFFFAOYSA-N 0.000 description 1
- SUMOGCZUNXXYRP-UHFFFAOYSA-N CC(C)CCCC1=CC=CC=C1 Chemical compound CC(C)CCCC1=CC=CC=C1 SUMOGCZUNXXYRP-UHFFFAOYSA-N 0.000 description 1
- FFXHZESBJFDNKX-UHFFFAOYSA-N CC(C)CCN(C)C(C)C Chemical compound CC(C)CCN(C)C(C)C FFXHZESBJFDNKX-UHFFFAOYSA-N 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N CC(C)CCO Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- DTADFKNTXRGGOR-UHFFFAOYSA-N CC(C)CCSC1=CC=CC=C1 Chemical compound CC(C)CCSC1=CC=CC=C1 DTADFKNTXRGGOR-UHFFFAOYSA-N 0.000 description 1
- MVACCSDGGZEFBJ-UHFFFAOYSA-N CC(C)CN(CC(C)C)C(C)C Chemical compound CC(C)CN(CC(C)C)C(C)C MVACCSDGGZEFBJ-UHFFFAOYSA-N 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N CC(C)CO Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- HIIBZFKVMXEQMR-UHFFFAOYSA-N CC(C)COC(C)C Chemical compound CC(C)COC(C)C HIIBZFKVMXEQMR-UHFFFAOYSA-N 0.000 description 1
- ONNUYWHIJSKABC-UHFFFAOYSA-N CC(C)COC1=CC=CC=C1 Chemical compound CC(C)COC1=CC=CC=C1 ONNUYWHIJSKABC-UHFFFAOYSA-N 0.000 description 1
- SWQCTKRPBDMCKM-UHFFFAOYSA-N CC(C)COCC1=CC=CO1 Chemical compound CC(C)COCC1=CC=CO1 SWQCTKRPBDMCKM-UHFFFAOYSA-N 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N CC(C)N(C(C)C)C(C)C Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- VMOWKUTXPNPTEN-UHFFFAOYSA-N CC(C)N(C)C Chemical compound CC(C)N(C)C VMOWKUTXPNPTEN-UHFFFAOYSA-N 0.000 description 1
- FVKBGFOJTMNLMC-UHFFFAOYSA-N CC(C)N(C)C(C)OC1=CC=C(Cl)C=C1 Chemical compound CC(C)N(C)C(C)OC1=CC=C(Cl)C=C1 FVKBGFOJTMNLMC-UHFFFAOYSA-N 0.000 description 1
- PZOWGIAHGMYOCO-UHFFFAOYSA-N CC(C)N(C)C1CCN(C)C1 Chemical compound CC(C)N(C)C1CCN(C)C1 PZOWGIAHGMYOCO-UHFFFAOYSA-N 0.000 description 1
- NFOIDBSVEXPOOU-UHFFFAOYSA-N CC(C)N(C)C1CCN(C)CC1 Chemical compound CC(C)N(C)C1CCN(C)CC1 NFOIDBSVEXPOOU-UHFFFAOYSA-N 0.000 description 1
- RMLIHPQMHVOHNZ-UHFFFAOYSA-N CC(C)N(C)CC(=O)O Chemical compound CC(C)N(C)CC(=O)O RMLIHPQMHVOHNZ-UHFFFAOYSA-N 0.000 description 1
- DUPFCUUEFMUGNL-UHFFFAOYSA-N CC(C)N(C)CC1=CC=CC2=C1C=CC=C2 Chemical compound CC(C)N(C)CC1=CC=CC2=C1C=CC=C2 DUPFCUUEFMUGNL-UHFFFAOYSA-N 0.000 description 1
- WFMUJLWWGDJDBF-UHFFFAOYSA-N CC(C)N(C)CC1=CC=CC=C1 Chemical compound CC(C)N(C)CC1=CC=CC=C1 WFMUJLWWGDJDBF-UHFFFAOYSA-N 0.000 description 1
- BCGGAOYAPDJKCL-UHFFFAOYSA-N CC(C)N(C)CC1=CC=CC=C1Cl Chemical compound CC(C)N(C)CC1=CC=CC=C1Cl BCGGAOYAPDJKCL-UHFFFAOYSA-N 0.000 description 1
- ATKTVSXPUMMVRZ-UHFFFAOYSA-N CC(C)N(C)CC1OCCO1 Chemical compound CC(C)N(C)CC1OCCO1 ATKTVSXPUMMVRZ-UHFFFAOYSA-N 0.000 description 1
- KLRXOQGSWRYLJJ-UHFFFAOYSA-N CC(C)N(C)CCC#N Chemical compound CC(C)N(C)CCC#N KLRXOQGSWRYLJJ-UHFFFAOYSA-N 0.000 description 1
- YSUMPKHHJFFDOI-UHFFFAOYSA-N CC(C)N(C)CCC(O)C1=CC=CC=C1 Chemical compound CC(C)N(C)CCC(O)C1=CC=CC=C1 YSUMPKHHJFFDOI-UHFFFAOYSA-N 0.000 description 1
- HJLQPXCLODDOHV-UHFFFAOYSA-N CC(C)N(C)CCC1=CC=CC=C1 Chemical compound CC(C)N(C)CCC1=CC=CC=C1 HJLQPXCLODDOHV-UHFFFAOYSA-N 0.000 description 1
- KHLCRWAOMYUAAB-UHFFFAOYSA-N CC(C)N(C)CCC1=CC=NC=C1 Chemical compound CC(C)N(C)CCC1=CC=NC=C1 KHLCRWAOMYUAAB-UHFFFAOYSA-N 0.000 description 1
- NWRCXTYMMZCWFO-UHFFFAOYSA-N CC(C)N(C)CCC1=NC=CC=C1 Chemical compound CC(C)N(C)CCC1=NC=CC=C1 NWRCXTYMMZCWFO-UHFFFAOYSA-N 0.000 description 1
- ICRWAMCPMFNZSW-UHFFFAOYSA-N CC(C)N(C)CCN(C)C Chemical compound CC(C)N(C)CCN(C)C ICRWAMCPMFNZSW-UHFFFAOYSA-N 0.000 description 1
- SKLIDVHPPBHWKC-UHFFFAOYSA-N CC(C)N(C)CN1CCC(C2=CC=CC=C2)C1 Chemical compound CC(C)N(C)CN1CCC(C2=CC=CC=C2)C1 SKLIDVHPPBHWKC-UHFFFAOYSA-N 0.000 description 1
- GOTQULLXGZGQMK-UHFFFAOYSA-N CC(C)N(CC1=CC=CC=C1)C(C)C Chemical compound CC(C)N(CC1=CC=CC=C1)C(C)C GOTQULLXGZGQMK-UHFFFAOYSA-N 0.000 description 1
- HLJOCCQVHGRQPB-UHFFFAOYSA-N CC(C)N(CC1=CC=CC=C1)CC1=CC=CC=C1 Chemical compound CC(C)N(CC1=CC=CC=C1)CC1=CC=CC=C1 HLJOCCQVHGRQPB-UHFFFAOYSA-N 0.000 description 1
- QEBGYWLSCQHLIF-UHFFFAOYSA-N CC(C)N(CC1=CC=CC=N1)CC1=CC=CC=N1 Chemical compound CC(C)N(CC1=CC=CC=N1)CC1=CC=CC=N1 QEBGYWLSCQHLIF-UHFFFAOYSA-N 0.000 description 1
- MRVPBCSKUAFEIL-UHFFFAOYSA-N CC(C)N(CCC#N)C1CCCCCCC1 Chemical compound CC(C)N(CCC#N)C1CCCCCCC1 MRVPBCSKUAFEIL-UHFFFAOYSA-N 0.000 description 1
- RXDZKRMEMWSZMQ-UHFFFAOYSA-N CC(C)N(CCC#N)CC1=CC=CC=C1 Chemical compound CC(C)N(CCC#N)CC1=CC=CC=C1 RXDZKRMEMWSZMQ-UHFFFAOYSA-N 0.000 description 1
- IFZIZFMTAJRKIU-UHFFFAOYSA-N CC(C)N(CCN(C)C)CC1=CC=CC=C1 Chemical compound CC(C)N(CCN(C)C)CC1=CC=CC=C1 IFZIZFMTAJRKIU-UHFFFAOYSA-N 0.000 description 1
- VDEMCLUFYJGNTM-UHFFFAOYSA-N CC(C)N(CCO)C1CCCCC1 Chemical compound CC(C)N(CCO)C1CCCCC1 VDEMCLUFYJGNTM-UHFFFAOYSA-N 0.000 description 1
- XUGHYFDCUUPWTJ-UHFFFAOYSA-N CC(C)N(CCO)CC1=CC=CC=C1 Chemical compound CC(C)N(CCO)CC1=CC=CC=C1 XUGHYFDCUUPWTJ-UHFFFAOYSA-N 0.000 description 1
- HHRGNKUNRVABBN-UHFFFAOYSA-N CC(C)N(CCO)CCO Chemical compound CC(C)N(CCO)CCO HHRGNKUNRVABBN-UHFFFAOYSA-N 0.000 description 1
- JLUVYNNUSJOSKB-UHFFFAOYSA-N CC(C)N1CC1C Chemical compound CC(C)N1CC1C JLUVYNNUSJOSKB-UHFFFAOYSA-N 0.000 description 1
- MXJXGVAHWNWPHD-UHFFFAOYSA-N CC(C)N1CC=CC1 Chemical compound CC(C)N1CC=CC1 MXJXGVAHWNWPHD-UHFFFAOYSA-N 0.000 description 1
- QDOQCOOUTPQMKW-UHFFFAOYSA-N CC(C)N1CCC(C(=O)O)CC1 Chemical compound CC(C)N1CCC(C(=O)O)CC1 QDOQCOOUTPQMKW-UHFFFAOYSA-N 0.000 description 1
- NWMHTCNZTAJELX-UHFFFAOYSA-N CC(C)N1CCC(C)(CC2=CC=CC=C2)CC1 Chemical compound CC(C)N1CCC(C)(CC2=CC=CC=C2)CC1 NWMHTCNZTAJELX-UHFFFAOYSA-N 0.000 description 1
- FKVLUASRCRCCJQ-UHFFFAOYSA-N CC(C)N1CCC(C2=CC=CC=C2F)CC1 Chemical compound CC(C)N1CCC(C2=CC=CC=C2F)CC1 FKVLUASRCRCCJQ-UHFFFAOYSA-N 0.000 description 1
- QAAXBCPKKJHDSF-UHFFFAOYSA-N CC(C)N1CCC(CC2=CC=CC=C2)CC1 Chemical compound CC(C)N1CCC(CC2=CC=CC=C2)CC1 QAAXBCPKKJHDSF-UHFFFAOYSA-N 0.000 description 1
- CQESJDGMFKMMRE-UHFFFAOYSA-N CC(C)N1CCC(N(C)C)C1 Chemical compound CC(C)N1CCC(N(C)C)C1 CQESJDGMFKMMRE-UHFFFAOYSA-N 0.000 description 1
- HFVBKRVIQWTVQM-UHFFFAOYSA-N CC(C)N1CCC(N2CCCC2)CC1 Chemical compound CC(C)N1CCC(N2CCCC2)CC1 HFVBKRVIQWTVQM-UHFFFAOYSA-N 0.000 description 1
- FKGQPSYLXOHMJZ-UHFFFAOYSA-N CC(C)N1CCC(N2CCCCC2)CC1 Chemical compound CC(C)N1CCC(N2CCCCC2)CC1 FKGQPSYLXOHMJZ-UHFFFAOYSA-N 0.000 description 1
- ZAKSXYZRRWKMGM-UHFFFAOYSA-N CC(C)N1CCC(NC(=O)OC(C)(C)C)C1 Chemical compound CC(C)N1CCC(NC(=O)OC(C)(C)C)C1 ZAKSXYZRRWKMGM-UHFFFAOYSA-N 0.000 description 1
- GCHZHYGFCGNTBT-UHFFFAOYSA-N CC(C)N1CCC(O)(C2=CC=C(F)C=C2)CC1 Chemical compound CC(C)N1CCC(O)(C2=CC=C(F)C=C2)CC1 GCHZHYGFCGNTBT-UHFFFAOYSA-N 0.000 description 1
- MYFPIRLHESHOGR-UHFFFAOYSA-N CC(C)N1CCC(O)C1 Chemical compound CC(C)N1CCC(O)C1 MYFPIRLHESHOGR-UHFFFAOYSA-N 0.000 description 1
- UZRXHHMTKCJKTQ-UHFFFAOYSA-N CC(C)N1CCC(O)CC1 Chemical compound CC(C)N1CCC(O)CC1 UZRXHHMTKCJKTQ-UHFFFAOYSA-N 0.000 description 1
- YVWYOWRHHFYZPH-UHFFFAOYSA-N CC(C)N1CCC2(CC1)OCCO2 Chemical compound CC(C)N1CCC2(CC1)OCCO2 YVWYOWRHHFYZPH-UHFFFAOYSA-N 0.000 description 1
- KLQCVTZZJGVRGZ-UHFFFAOYSA-N CC(C)N1CCC2=C(CC3=CC=CC=C32)C1 Chemical compound CC(C)N1CCC2=C(CC3=CC=CC=C32)C1 KLQCVTZZJGVRGZ-UHFFFAOYSA-N 0.000 description 1
- UKXXZHBWKKSUGE-UHFFFAOYSA-N CC(C)N1CCC2=CC=CC=C2C1 Chemical compound CC(C)N1CCC2=CC=CC=C2C1 UKXXZHBWKKSUGE-UHFFFAOYSA-N 0.000 description 1
- LXAFXTLVXQLAPC-UHFFFAOYSA-N CC(C)N1CCCC(C(N)=O)C1 Chemical compound CC(C)N1CCCC(C(N)=O)C1 LXAFXTLVXQLAPC-UHFFFAOYSA-N 0.000 description 1
- LZXLHLSTUPFULX-UHFFFAOYSA-N CC(C)N1CCCC(CO)C1 Chemical compound CC(C)N1CCCC(CO)C1 LZXLHLSTUPFULX-UHFFFAOYSA-N 0.000 description 1
- YQOPNAOQGQSUHF-UHFFFAOYSA-N CC(C)N1CCCC1 Chemical compound CC(C)N1CCCC1 YQOPNAOQGQSUHF-UHFFFAOYSA-N 0.000 description 1
- HTUUNUBTALKZIP-UHFFFAOYSA-N CC(C)N1CCCC1C Chemical compound CC(C)N1CCCC1C HTUUNUBTALKZIP-UHFFFAOYSA-N 0.000 description 1
- ILVCLKGYLJSJNM-UHFFFAOYSA-N CC(C)N1CCCC1C(=O)O.CC(C)N1CCCC1CO.CC1CCN(C(C)C)C1 Chemical compound CC(C)N1CCCC1C(=O)O.CC(C)N1CCCC1CO.CC1CCN(C(C)C)C1 ILVCLKGYLJSJNM-UHFFFAOYSA-N 0.000 description 1
- HVMJFSYMJXIBJK-UHFFFAOYSA-N CC(C)N1CCCC1C(=O)OC(C)(C)C Chemical compound CC(C)N1CCCC1C(=O)OC(C)(C)C HVMJFSYMJXIBJK-UHFFFAOYSA-N 0.000 description 1
- NHNYSSNFWPFZRG-UHFFFAOYSA-N CC(C)N1CCCC2CCCCC21 Chemical compound CC(C)N1CCCC2CCCCC21 NHNYSSNFWPFZRG-UHFFFAOYSA-N 0.000 description 1
- QFLCTAXQTJMMJD-UHFFFAOYSA-N CC(C)N1CCCCC1C(=O)O Chemical compound CC(C)N1CCCCC1C(=O)O QFLCTAXQTJMMJD-UHFFFAOYSA-N 0.000 description 1
- KGWQFWBXMGBYGM-UHFFFAOYSA-N CC(C)N1CCCCC1CC1CCCN1C Chemical compound CC(C)N1CCCCC1CC1CCCN1C KGWQFWBXMGBYGM-UHFFFAOYSA-N 0.000 description 1
- LAMSVRIEWYFPIV-UHFFFAOYSA-N CC(C)N1CCCCC1CCN1CCCCC1 Chemical compound CC(C)N1CCCCC1CCN1CCCCC1 LAMSVRIEWYFPIV-UHFFFAOYSA-N 0.000 description 1
- APOPEAINGUMRKM-UHFFFAOYSA-N CC(C)N1CCCCC1CCO Chemical compound CC(C)N1CCCCC1CCO APOPEAINGUMRKM-UHFFFAOYSA-N 0.000 description 1
- MGHBKVAZXQNHPK-UHFFFAOYSA-N CC(C)N1CCCCC1CO Chemical compound CC(C)N1CCCCC1CO MGHBKVAZXQNHPK-UHFFFAOYSA-N 0.000 description 1
- BXVAVXHPXVAUBU-UHFFFAOYSA-N CC(C)N1CCCCCC1 Chemical compound CC(C)N1CCCCCC1 BXVAVXHPXVAUBU-UHFFFAOYSA-N 0.000 description 1
- BVNRPYGWXZDYKO-UHFFFAOYSA-N CC(C)N1CCCN(C)CC1 Chemical compound CC(C)N1CCCN(C)CC1 BVNRPYGWXZDYKO-UHFFFAOYSA-N 0.000 description 1
- YKMBNBXUPNOYHE-UHFFFAOYSA-N CC(C)N1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CC(C)N1CCN(C(=O)OC(C)(C)C)CC1 YKMBNBXUPNOYHE-UHFFFAOYSA-N 0.000 description 1
- ODIQTOYGORNLPE-UHFFFAOYSA-N CC(C)N1CCN(C)CC1 Chemical compound CC(C)N1CCN(C)CC1 ODIQTOYGORNLPE-UHFFFAOYSA-N 0.000 description 1
- ABEPPYHDHSOORR-UHFFFAOYSA-N CC(C)N1CCN(C2=CC=C(F)C=C2)CC1 Chemical compound CC(C)N1CCN(C2=CC=C(F)C=C2)CC1 ABEPPYHDHSOORR-UHFFFAOYSA-N 0.000 description 1
- BMBPGRMBBHKAEP-UHFFFAOYSA-N CC(C)N1CCN(C2=CC=C(O)C=C2)CC1 Chemical compound CC(C)N1CCN(C2=CC=C(O)C=C2)CC1 BMBPGRMBBHKAEP-UHFFFAOYSA-N 0.000 description 1
- KRNQNTPUHRIZIE-UHFFFAOYSA-N CC(C)N1CCN(C2=CC=CC=C2)CC1 Chemical compound CC(C)N1CCN(C2=CC=CC=C2)CC1 KRNQNTPUHRIZIE-UHFFFAOYSA-N 0.000 description 1
- JMSBGUKOMZSBMF-UHFFFAOYSA-N CC(C)N1CCN(C2=NC=CC=N2)CC1 Chemical compound CC(C)N1CCN(C2=NC=CC=N2)CC1 JMSBGUKOMZSBMF-UHFFFAOYSA-N 0.000 description 1
- UGRNAAOSAUZBIT-UHFFFAOYSA-N CC(C)N1CCN(C=O)CC1 Chemical compound CC(C)N1CCN(C=O)CC1 UGRNAAOSAUZBIT-UHFFFAOYSA-N 0.000 description 1
- LYXXHMOCQTVBIM-UHFFFAOYSA-N CC(C)N1CCN(CC2=CC=CC=C2)CC1 Chemical compound CC(C)N1CCN(CC2=CC=CC=C2)CC1 LYXXHMOCQTVBIM-UHFFFAOYSA-N 0.000 description 1
- KDYNMWFSJAIPSW-UHFFFAOYSA-N CC(C)N1CCN(CCO)CC1 Chemical compound CC(C)N1CCN(CCO)CC1 KDYNMWFSJAIPSW-UHFFFAOYSA-N 0.000 description 1
- GKKMPVKAIMRHMO-UHFFFAOYSA-N CC(C)N1CCNC(=O)C1C Chemical compound CC(C)N1CCNC(=O)C1C GKKMPVKAIMRHMO-UHFFFAOYSA-N 0.000 description 1
- XLZMWNWNBXSZKF-UHFFFAOYSA-N CC(C)N1CCOCC1 Chemical compound CC(C)N1CCOCC1 XLZMWNWNBXSZKF-UHFFFAOYSA-N 0.000 description 1
- IJFOEELDPVHEGL-UHFFFAOYSA-N CC(C)N1CCSCC1 Chemical compound CC(C)N1CCSCC1 IJFOEELDPVHEGL-UHFFFAOYSA-N 0.000 description 1
- ZFEPTZZXRJDQEL-UHFFFAOYSA-N CC(C)N1CSCC1C(=O)O Chemical compound CC(C)N1CSCC1C(=O)O ZFEPTZZXRJDQEL-UHFFFAOYSA-N 0.000 description 1
- MKQGTJLOHXQRMF-UHFFFAOYSA-N CC(C)S(Cc1ccccc1)(=O)=O Chemical compound CC(C)S(Cc1ccccc1)(=O)=O MKQGTJLOHXQRMF-UHFFFAOYSA-N 0.000 description 1
- FNTLJLQFCBDGSG-UHFFFAOYSA-N CC(C)S(c(cc1)ccc1NC(C)=O)(=O)=O Chemical compound CC(C)S(c(cc1)ccc1NC(C)=O)(=O)=O FNTLJLQFCBDGSG-UHFFFAOYSA-N 0.000 description 1
- DLQWIFLZNNJWOK-CMDGGOBGSA-N CC(C)SO(O)/C=C/C1=CC=CC=C1 Chemical compound CC(C)SO(O)/C=C/C1=CC=CC=C1 DLQWIFLZNNJWOK-CMDGGOBGSA-N 0.000 description 1
- CMWHNFUPYYMDMV-UHFFFAOYSA-N CC(C)SO(O)C1=C(Cl)C=C(Cl)C=C1 Chemical compound CC(C)SO(O)C1=C(Cl)C=C(Cl)C=C1 CMWHNFUPYYMDMV-UHFFFAOYSA-N 0.000 description 1
- BGTXUEIYPAKQIC-UHFFFAOYSA-N CC(C)SO(O)C1=C(Cl)SC(Cl)=C1 Chemical compound CC(C)SO(O)C1=C(Cl)SC(Cl)=C1 BGTXUEIYPAKQIC-UHFFFAOYSA-N 0.000 description 1
- KJQIQMKFDVZZMW-UHFFFAOYSA-N CC(C)SO(O)C1=C(F)C=C(F)C=C1 Chemical compound CC(C)SO(O)C1=C(F)C=C(F)C=C1 KJQIQMKFDVZZMW-UHFFFAOYSA-N 0.000 description 1
- JICFXQUJDKXQIX-UHFFFAOYSA-N CC(C)SO(O)C1=CC(Cl)=C(Cl)S1 Chemical compound CC(C)SO(O)C1=CC(Cl)=C(Cl)S1 JICFXQUJDKXQIX-UHFFFAOYSA-N 0.000 description 1
- QEKYMLCMRYAUHB-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(Br)C=C1 Chemical compound CC(C)SO(O)C1=CC=C(Br)C=C1 QEKYMLCMRYAUHB-UHFFFAOYSA-N 0.000 description 1
- MGBDAIXDISJFDX-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(C(=O)O)C=C1 Chemical compound CC(C)SO(O)C1=CC=C(C(=O)O)C=C1 MGBDAIXDISJFDX-UHFFFAOYSA-N 0.000 description 1
- VQDHMVBAEQTKKE-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(C(C)(C)C)C=C1 Chemical compound CC(C)SO(O)C1=CC=C(C(C)(C)C)C=C1 VQDHMVBAEQTKKE-UHFFFAOYSA-N 0.000 description 1
- GTCFNPPGXWOXOF-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(Cl)C=C1 Chemical compound CC(C)SO(O)C1=CC=C(Cl)C=C1 GTCFNPPGXWOXOF-UHFFFAOYSA-N 0.000 description 1
- WUDGLUDGOPJQQG-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(Cl)S1 Chemical compound CC(C)SO(O)C1=CC=C(Cl)S1 WUDGLUDGOPJQQG-UHFFFAOYSA-N 0.000 description 1
- RVMVDISEYGWPBC-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(F)C=C1 Chemical compound CC(C)SO(O)C1=CC=C(F)C=C1 RVMVDISEYGWPBC-UHFFFAOYSA-N 0.000 description 1
- FGEIEWVYFIIFRG-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C(S(C)(=O)=O)C=C1 Chemical compound CC(C)SO(O)C1=CC=C(S(C)(=O)=O)C=C1 FGEIEWVYFIIFRG-UHFFFAOYSA-N 0.000 description 1
- HYUMODHODZUBLM-UHFFFAOYSA-N CC(C)SO(O)C1=CC=C2C=CC=CC2=C1 Chemical compound CC(C)SO(O)C1=CC=C2C=CC=CC2=C1 HYUMODHODZUBLM-UHFFFAOYSA-N 0.000 description 1
- BFSXJYNNKGZAPQ-UHFFFAOYSA-N CC(C)SO(O)C1=CC=CC2=C1C=CC=C2 Chemical compound CC(C)SO(O)C1=CC=CC2=C1C=CC=C2 BFSXJYNNKGZAPQ-UHFFFAOYSA-N 0.000 description 1
- IHYDEHFRWAPOEH-UHFFFAOYSA-N CC(C)SO(O)C1=CC=CC2=C1N=CC=C2 Chemical compound CC(C)SO(O)C1=CC=CC2=C1N=CC=C2 IHYDEHFRWAPOEH-UHFFFAOYSA-N 0.000 description 1
- KPIBYOREWYUATC-UHFFFAOYSA-N CC(C)SO(O)C1=CC=CC=C1 Chemical compound CC(C)SO(O)C1=CC=CC=C1 KPIBYOREWYUATC-UHFFFAOYSA-N 0.000 description 1
- PUHWFLFHTCXJAE-UHFFFAOYSA-N CC(C)SO(O)C1=CC=CS1 Chemical compound CC(C)SO(O)C1=CC=CS1 PUHWFLFHTCXJAE-UHFFFAOYSA-N 0.000 description 1
- QULSZAQTJYSWMU-UHFFFAOYSA-N CC(C)SO(O)CC(F)(F)F Chemical compound CC(C)SO(O)CC(F)(F)F QULSZAQTJYSWMU-UHFFFAOYSA-N 0.000 description 1
- ZEMPHPIZMNHXNN-UHFFFAOYSA-N CC(C)c(cc1)ccc1S(C(C)C)(=O)=O Chemical compound CC(C)c(cc1)ccc1S(C(C)C)(=O)=O ZEMPHPIZMNHXNN-UHFFFAOYSA-N 0.000 description 1
- FOWXQMONAFWJAD-UHFFFAOYSA-N CC(Cc1ccc[s]1)=O Chemical compound CC(Cc1ccc[s]1)=O FOWXQMONAFWJAD-UHFFFAOYSA-N 0.000 description 1
- PUGSCJUFSYWJPL-JYRVWZFOSA-N CC/C=C(\C1=CC=CC=C1)C(C)C Chemical compound CC/C=C(\C1=CC=CC=C1)C(C)C PUGSCJUFSYWJPL-JYRVWZFOSA-N 0.000 description 1
- APQKOKVXMIUSCR-UHFFFAOYSA-N CC1=C(C(=O)C(C)C)SN=N1 Chemical compound CC1=C(C(=O)C(C)C)SN=N1 APQKOKVXMIUSCR-UHFFFAOYSA-N 0.000 description 1
- KFXOVQCRLACLSJ-UHFFFAOYSA-N CC1=C(C)C(C)=C(O(O)SC(C)C)C(C)=C1C Chemical compound CC1=C(C)C(C)=C(O(O)SC(C)C)C(C)=C1C KFXOVQCRLACLSJ-UHFFFAOYSA-N 0.000 description 1
- WFOPYVSELPBWBS-UHFFFAOYSA-N CC1=C(C)C(N2CCN(C(C)C)CC2)=CC=C1 Chemical compound CC1=C(C)C(N2CCN(C(C)C)CC2)=CC=C1 WFOPYVSELPBWBS-UHFFFAOYSA-N 0.000 description 1
- SAEXDBIYAUHTAA-UHFFFAOYSA-N CC1=CC(C)=C(C(=O)C(C)C)C(C)=C1 Chemical compound CC1=CC(C)=C(C(=O)C(C)C)C(C)=C1 SAEXDBIYAUHTAA-UHFFFAOYSA-N 0.000 description 1
- XCKWGGYDYWLKAN-UHFFFAOYSA-N CC1=CC(C)=C(N2C3=NC(C)=CC(Cl)=C3C(C(=O)CCl)=C2C)C(C)=C1.CCCC(CCC)N1CC/C2=C(\C)N(C3=C(C)C=C(C)C=C3C)C3=NC(C)=CC1=C32.CCCC(CCC)NC1=C2C(=NC(C)=C1)N(C1=C(C)C=C(C)C=C1C)C(C)=C2C(=O)CCl.CCCC(N)CCC Chemical compound CC1=CC(C)=C(N2C3=NC(C)=CC(Cl)=C3C(C(=O)CCl)=C2C)C(C)=C1.CCCC(CCC)N1CC/C2=C(\C)N(C3=C(C)C=C(C)C=C3C)C3=NC(C)=CC1=C32.CCCC(CCC)NC1=C2C(=NC(C)=C1)N(C1=C(C)C=C(C)C=C1C)C(C)=C2C(=O)CCl.CCCC(N)CCC XCKWGGYDYWLKAN-UHFFFAOYSA-N 0.000 description 1
- FWDCNOJIQGIUIN-UHFFFAOYSA-N CC1=CC(C)=C(N2C3=NC(C)=NC(Cl)=C3C(C(=O)CCl)=C2C)C(C)=C1.CCCC(CCC)N1CC/C2=C(\C)N(C3=C(C)C=C(C)C=C3C)C3=NC(C)=NC1=C32.CCCC(CCC)NC1=C2C(=NC(C)=N1)N(C1=C(C)C=C(C)C=C1C)C(C)=C2C(=O)CCl.CCCC(N)CCC Chemical compound CC1=CC(C)=C(N2C3=NC(C)=NC(Cl)=C3C(C(=O)CCl)=C2C)C(C)=C1.CCCC(CCC)N1CC/C2=C(\C)N(C3=C(C)C=C(C)C=C3C)C3=NC(C)=NC1=C32.CCCC(CCC)NC1=C2C(=NC(C)=N1)N(C1=C(C)C=C(C)C=C1C)C(C)=C2C(=O)CCl.CCCC(N)CCC FWDCNOJIQGIUIN-UHFFFAOYSA-N 0.000 description 1
- PLLUFSIOMDZORX-UHFFFAOYSA-N CC1=CC(Cl)=C(N)C=C1.CC1=CC=C(S(=O)(=O)O)C=C1.CCCC(CCC)N1CCC(=COC)C2=C1/C=C(C)\N=C/2Cl.CCCC(CCC)N1CCC2=CN(C3=CC=C(C)C=C3Cl)/C3=N/C(C)=C\C1=C23 Chemical compound CC1=CC(Cl)=C(N)C=C1.CC1=CC=C(S(=O)(=O)O)C=C1.CCCC(CCC)N1CCC(=COC)C2=C1/C=C(C)\N=C/2Cl.CCCC(CCC)N1CCC2=CN(C3=CC=C(C)C=C3Cl)/C3=N/C(C)=C\C1=C23 PLLUFSIOMDZORX-UHFFFAOYSA-N 0.000 description 1
- RZWVFFHOBKANGS-UHFFFAOYSA-N CC1=CC(N2CCN(C(C)C)CC2)=C(C)C=C1 Chemical compound CC1=CC(N2CCN(C(C)C)CC2)=C(C)C=C1 RZWVFFHOBKANGS-UHFFFAOYSA-N 0.000 description 1
- GPAOVJRYCVFFQA-UHFFFAOYSA-N CC1=CC=C(N2CCN(C(C)C)CC2)C=C1 Chemical compound CC1=CC=C(N2CCN(C(C)C)CC2)C=C1 GPAOVJRYCVFFQA-UHFFFAOYSA-N 0.000 description 1
- CWIRCHCLTVSLHU-UHFFFAOYSA-N CC1=CC=C(N2CCN(C(C)C)CC2)C=C1C Chemical compound CC1=CC=C(N2CCN(C(C)C)CC2)C=C1C CWIRCHCLTVSLHU-UHFFFAOYSA-N 0.000 description 1
- QMNVXKMUGSDTEZ-KYHHQAMNSA-N CC1=NC2=C(NC=C2C2=C(Cl)C=C(Cl)C=C2)C(Cl)=C1.CCC(CO)NC1=CC(C)=NC2=C1NC=C2C1=C(Cl)C=C(Cl)C=C1.CCC(N)CO.CCOC(=O)C1=C(N)C(C2=C(Cl)C=C(Cl)C=C2)=CN1.CCOC(=O)Cl.COC(=O)CN.COC(=O)CN/C=C(\C#N)C1=CC=C(Cl)C=C1Cl.N#CC(C=O)C1=C(Cl)C=C(Cl)C=C1.N#CCC1=C(Cl)C=C(Cl)C=C1.[2H]B=N.[H]C(=O)OCC Chemical compound CC1=NC2=C(NC=C2C2=C(Cl)C=C(Cl)C=C2)C(Cl)=C1.CCC(CO)NC1=CC(C)=NC2=C1NC=C2C1=C(Cl)C=C(Cl)C=C1.CCC(N)CO.CCOC(=O)C1=C(N)C(C2=C(Cl)C=C(Cl)C=C2)=CN1.CCOC(=O)Cl.COC(=O)CN.COC(=O)CN/C=C(\C#N)C1=CC=C(Cl)C=C1Cl.N#CC(C=O)C1=C(Cl)C=C(Cl)C=C1.N#CCC1=C(Cl)C=C(Cl)C=C1.[2H]B=N.[H]C(=O)OCC QMNVXKMUGSDTEZ-KYHHQAMNSA-N 0.000 description 1
- LCGRQHZGLADHKA-KYHHQAMNSA-N CC1=NC2=C(NC=C2C2=C(Cl)C=C(Cl)C=C2)C(Cl)=N1.CCC(CO)NC1=NC(C)=NC2=C1NC=C2C1=C(Cl)C=C(Cl)C=C1.CCC(N)CO.CCOC(=O)C1=C(N)C(C2=C(Cl)C=C(Cl)C=C2)=CN1.CCOC(=O)Cl.COC(=O)CN.COC(=O)CN/C=C(\C#N)C1=CC=C(Cl)C=C1Cl.N#CC(C=O)C1=C(Cl)C=C(Cl)C=C1.N#CCC1=C(Cl)C=C(Cl)C=C1.[2H]B=N.[H]C(=O)OCC Chemical compound CC1=NC2=C(NC=C2C2=C(Cl)C=C(Cl)C=C2)C(Cl)=N1.CCC(CO)NC1=NC(C)=NC2=C1NC=C2C1=C(Cl)C=C(Cl)C=C1.CCC(N)CO.CCOC(=O)C1=C(N)C(C2=C(Cl)C=C(Cl)C=C2)=CN1.CCOC(=O)Cl.COC(=O)CN.COC(=O)CN/C=C(\C#N)C1=CC=C(Cl)C=C1Cl.N#CC(C=O)C1=C(Cl)C=C(Cl)C=C1.N#CCC1=C(Cl)C=C(Cl)C=C1.[2H]B=N.[H]C(=O)OCC LCGRQHZGLADHKA-KYHHQAMNSA-N 0.000 description 1
- FMYRUJWCAHRGDG-UHFFFAOYSA-N CC1=NC2=C(NN=C2C2=C(Cl)C=C(Cl)C=C2)C(Cl)=C1.CC1=NC2=C(NN=C2C2=C(Cl)C=C(Cl)C=C2)C(NCC(O)C2=CC=CC=C2)=C1.CCCC(CCC)N1CC(C2=CC=CC=C2)N2N=C(C3=C(Cl)C=C(Cl)C=C3)C3=C2C1=CC=N3.ClC1=CC(Cl)=C(C2=NN3C4=C2N=CC=C4NCC3C2=CC=CC=C2)C=C1.NCC(O)C1=CC=CC=C1.[NaH] Chemical compound CC1=NC2=C(NN=C2C2=C(Cl)C=C(Cl)C=C2)C(Cl)=C1.CC1=NC2=C(NN=C2C2=C(Cl)C=C(Cl)C=C2)C(NCC(O)C2=CC=CC=C2)=C1.CCCC(CCC)N1CC(C2=CC=CC=C2)N2N=C(C3=C(Cl)C=C(Cl)C=C3)C3=C2C1=CC=N3.ClC1=CC(Cl)=C(C2=NN3C4=C2N=CC=C4NCC3C2=CC=CC=C2)C=C1.NCC(O)C1=CC=CC=C1.[NaH] FMYRUJWCAHRGDG-UHFFFAOYSA-N 0.000 description 1
- YGVBOLZJGVSPLT-UHFFFAOYSA-N CC1CC(C)CN(C(C)C)C1 Chemical compound CC1CC(C)CN(C(C)C)C1 YGVBOLZJGVSPLT-UHFFFAOYSA-N 0.000 description 1
- QRDCBPPMQOPHOU-UHFFFAOYSA-N CC1CCCC(C(C)C)C1 Chemical compound CC1CCCC(C(C)C)C1 QRDCBPPMQOPHOU-UHFFFAOYSA-N 0.000 description 1
- ORTAXXZJVCPZJF-UHFFFAOYSA-N CC1CCCN(C(C)C)C1 Chemical compound CC1CCCN(C(C)C)C1 ORTAXXZJVCPZJF-UHFFFAOYSA-N 0.000 description 1
- IGCABXIFWGCNDH-UHFFFAOYSA-N CC1CCN(C(C)C)CC1 Chemical compound CC1CCN(C(C)C)CC1 IGCABXIFWGCNDH-UHFFFAOYSA-N 0.000 description 1
- ZZMDOTWZZOLFDG-UHFFFAOYSA-N CC1CN(C(C)C)C(C)CN1 Chemical compound CC1CN(C(C)C)C(C)CN1 ZZMDOTWZZOLFDG-UHFFFAOYSA-N 0.000 description 1
- IJUOMCMYAFYRGH-UHFFFAOYSA-N CC1CN(C(C)C)CC(C)O1 Chemical compound CC1CN(C(C)C)CC(C)O1 IJUOMCMYAFYRGH-UHFFFAOYSA-N 0.000 description 1
- DXVYLFHTJZWTRF-UHFFFAOYSA-N CCC(=O)CC(C)C Chemical compound CCC(=O)CC(C)C DXVYLFHTJZWTRF-UHFFFAOYSA-N 0.000 description 1
- CHHSZYZSMJFJTR-UHFFFAOYSA-N CCC(C)(C)C1=CC=C(O(O)SC(C)C)C=C1 Chemical compound CCC(C)(C)C1=CC=C(O(O)SC(C)C)C=C1 CHHSZYZSMJFJTR-UHFFFAOYSA-N 0.000 description 1
- DOXHHIAPXSNNNN-UHFFFAOYSA-N CCC(C1)Nc(cc(C)nc23)c2[n]1nc3-c1ccc(C(F)(F)F)cc1OC Chemical compound CCC(C1)Nc(cc(C)nc23)c2[n]1nc3-c1ccc(C(F)(F)F)cc1OC DOXHHIAPXSNNNN-UHFFFAOYSA-N 0.000 description 1
- ZHUGTTYMERKMFA-UHFFFAOYSA-N CCC1=CC=C(O(O)SC(C)C)C=C1 Chemical compound CCC1=CC=C(O(O)SC(C)C)C=C1 ZHUGTTYMERKMFA-UHFFFAOYSA-N 0.000 description 1
- QAOZIIFHISKHPV-UHFFFAOYSA-N CCC1CCC(C)N(C(C)C)C1 Chemical compound CCC1CCC(C)N(C(C)C)C1 QAOZIIFHISKHPV-UHFFFAOYSA-N 0.000 description 1
- MXRGNGUGUOFVCK-UHFFFAOYSA-N CCC1CCCCN1C(C)C Chemical compound CCC1CCCCN1C(C)C MXRGNGUGUOFVCK-UHFFFAOYSA-N 0.000 description 1
- XQNQGXFLQLWFTH-UHFFFAOYSA-N CCC1CN2N=C(C3=CC=C(C(F)(F)F)C=C3OC)/C3=N/C(C)=C\C(=C32)N1C(=O)NC Chemical compound CCC1CN2N=C(C3=CC=C(C(F)(F)F)C=C3OC)/C3=N/C(C)=C\C(=C32)N1C(=O)NC XQNQGXFLQLWFTH-UHFFFAOYSA-N 0.000 description 1
- UZFGNRPLAWDDMY-UHFFFAOYSA-N CCC1CN2N=C(C3=CC=C(C(F)(F)F)C=C3OC)/C3=N/C(C)=C\C(=C32)N1CC(C)O Chemical compound CCC1CN2N=C(C3=CC=C(C(F)(F)F)C=C3OC)/C3=N/C(C)=C\C(=C32)N1CC(C)O UZFGNRPLAWDDMY-UHFFFAOYSA-N 0.000 description 1
- QZPXMRHTZZJOCX-UHFFFAOYSA-N CCC1CN2N=C(C3=CC=C(C(F)(F)F)C=C3OC)/C3=N/C(C)=C\C(=C32)N1CCNC Chemical compound CCC1CN2N=C(C3=CC=C(C(F)(F)F)C=C3OC)/C3=N/C(C)=C\C(=C32)N1CCNC QZPXMRHTZZJOCX-UHFFFAOYSA-N 0.000 description 1
- MVLOWDRGPHBNNF-UHFFFAOYSA-N CCCC(CC)C(C)C Chemical compound CCCC(CC)C(C)C MVLOWDRGPHBNNF-UHFFFAOYSA-N 0.000 description 1
- HJLNASIDHYJLFM-UHFFFAOYSA-N CCCC(CCC)N1CC/C2=N/N(C3=CC=C(Cl)C=C3Cl)C3=NC(C)=CC1=C32 Chemical compound CCCC(CCC)N1CC/C2=N/N(C3=CC=C(Cl)C=C3Cl)C3=NC(C)=CC1=C32 HJLNASIDHYJLFM-UHFFFAOYSA-N 0.000 description 1
- LOXTUWSLGKIBPI-UHFFFAOYSA-N CCCC(CCC)N1CC/C2=N/N(C3=NC=C(Cl)C=C3C(F)(F)F)C3=NC(C)=CC1=C32.CCCC(CCC)N1CC/C2=N/NC3=NC(C)=CC1=C32.CCCC(CCC)NC1=C2C(=NC(C)=C1)NN=C2C(=O)CBr.FC(F)(F)C1=CC(Cl)=CN=C1Cl Chemical compound CCCC(CCC)N1CC/C2=N/N(C3=NC=C(Cl)C=C3C(F)(F)F)C3=NC(C)=CC1=C32.CCCC(CCC)N1CC/C2=N/NC3=NC(C)=CC1=C32.CCCC(CCC)NC1=C2C(=NC(C)=C1)NN=C2C(=O)CBr.FC(F)(F)C1=CC(Cl)=CN=C1Cl LOXTUWSLGKIBPI-UHFFFAOYSA-N 0.000 description 1
- UTYVXGANZUPTOR-UHFFFAOYSA-N CCCC(COC)C(C)C Chemical compound CCCC(COC)C(C)C UTYVXGANZUPTOR-UHFFFAOYSA-N 0.000 description 1
- MILIWJJOZDIMLH-UHFFFAOYSA-N CCCC1=CC=C(O(O)SC(C)C)C=C1 Chemical compound CCCC1=CC=C(O(O)SC(C)C)C=C1 MILIWJJOZDIMLH-UHFFFAOYSA-N 0.000 description 1
- ZYEQSLLHBOITAM-UHFFFAOYSA-N CCCCC(CC)CC(C)C Chemical compound CCCCC(CC)CC(C)C ZYEQSLLHBOITAM-UHFFFAOYSA-N 0.000 description 1
- NMPFOISAAOKLBS-UHFFFAOYSA-N CCCCC(CCCC)N1CCN2N=C(C3=CC=C(Cl)C=C3Cl)C3=C2C1=CC(C)=N3.CCCCC(CCCC)NC1=CC(C)=NC2=C1NN=C2C1=CC=C(Cl)C=C1Cl Chemical compound CCCCC(CCCC)N1CCN2N=C(C3=CC=C(Cl)C=C3Cl)C3=C2C1=CC(C)=N3.CCCCC(CCCC)NC1=CC(C)=NC2=C1NN=C2C1=CC=C(Cl)C=C1Cl NMPFOISAAOKLBS-UHFFFAOYSA-N 0.000 description 1
- PQAKTGQWKGOOGN-UHFFFAOYSA-N CCCCCCCCO(O)SC(C)C Chemical compound CCCCCCCCO(O)SC(C)C PQAKTGQWKGOOGN-UHFFFAOYSA-N 0.000 description 1
- CFXYWRKVXRYKBE-UHFFFAOYSA-N CCCCCCN(CCCCCC)C(C)C Chemical compound CCCCCCN(CCCCCC)C(C)C CFXYWRKVXRYKBE-UHFFFAOYSA-N 0.000 description 1
- CYJSLDKIWHQQFF-UHFFFAOYSA-N CCCCCN(CCCCC)C(C)C Chemical compound CCCCCN(CCCCC)C(C)C CYJSLDKIWHQQFF-UHFFFAOYSA-N 0.000 description 1
- WWDWSIMVIBPDNW-UHFFFAOYSA-N CCCCN(CC)C(C)C Chemical compound CCCCN(CC)C(C)C WWDWSIMVIBPDNW-UHFFFAOYSA-N 0.000 description 1
- NGZCULQWMVRPKE-UHFFFAOYSA-N CCCCN(CCCC)C(C)C Chemical compound CCCCN(CCCC)C(C)C NGZCULQWMVRPKE-UHFFFAOYSA-N 0.000 description 1
- TZHBKRQKWCRMGA-UHFFFAOYSA-N CCCCO(O)SC(C)C Chemical compound CCCCO(O)SC(C)C TZHBKRQKWCRMGA-UHFFFAOYSA-N 0.000 description 1
- NMLLTHLOSVNFMY-UHFFFAOYSA-N CCCCOCCC(C)C Chemical compound CCCCOCCC(C)C NMLLTHLOSVNFMY-UHFFFAOYSA-N 0.000 description 1
- OYQDUCLFZSKBCZ-UHFFFAOYSA-N CCCN(C)C(C)C Chemical compound CCCN(C)C(C)C OYQDUCLFZSKBCZ-UHFFFAOYSA-N 0.000 description 1
- YYDHPKGSIYLSSC-UHFFFAOYSA-N CCCN(CC)C(C)C Chemical compound CCCN(CC)C(C)C YYDHPKGSIYLSSC-UHFFFAOYSA-N 0.000 description 1
- JFSXJKOOFLYHPY-UHFFFAOYSA-N CCCN(CC1=CC=CC=C1)C(C)C Chemical compound CCCN(CC1=CC=CC=C1)C(C)C JFSXJKOOFLYHPY-UHFFFAOYSA-N 0.000 description 1
- VTVMQXSYOIPNJH-UHFFFAOYSA-N CCCN(CC1CC1)C(C)C Chemical compound CCCN(CC1CC1)C(C)C VTVMQXSYOIPNJH-UHFFFAOYSA-N 0.000 description 1
- VXEXNSLAVSWNKX-UHFFFAOYSA-N CCCN(CCC1=NC=CC=C1)C(C)C Chemical compound CCCN(CCC1=NC=CC=C1)C(C)C VXEXNSLAVSWNKX-UHFFFAOYSA-N 0.000 description 1
- GYWWIDNDJPVOSH-UHFFFAOYSA-N CCCN(CCO)C(C)C Chemical compound CCCN(CCO)C(C)C GYWWIDNDJPVOSH-UHFFFAOYSA-N 0.000 description 1
- ZZCCSJGBKSBOII-UHFFFAOYSA-N CCCN(CCOC)C(C)C Chemical compound CCCN(CCOC)C(C)C ZZCCSJGBKSBOII-UHFFFAOYSA-N 0.000 description 1
- GBCPISLFHGGRGP-UHFFFAOYSA-N CCCN1C2=C3/C(=N\C(C)=C/2)C(C2=CC=C(C(F)(F)F)C=C2OC)=NN3CC1CC Chemical compound CCCN1C2=C3/C(=N\C(C)=C/2)C(C2=CC=C(C(F)(F)F)C=C2OC)=NN3CC1CC GBCPISLFHGGRGP-UHFFFAOYSA-N 0.000 description 1
- SZQWKMOABGHVHY-UHFFFAOYSA-N CCN(C(C)C)C1CCCCC1 Chemical compound CCN(C(C)C)C1CCCCC1 SZQWKMOABGHVHY-UHFFFAOYSA-N 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N CCN(CC)C(C)C Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- XNUQCLVKJRDREQ-UHFFFAOYSA-N CCN(CC)CCN(C)C(C)C Chemical compound CCN(CC)CCN(C)C(C)C XNUQCLVKJRDREQ-UHFFFAOYSA-N 0.000 description 1
- FPPBRZSEFNORFB-UHFFFAOYSA-N CCN(CC1=CC=C(C)C=C1)C(C)C Chemical compound CCN(CC1=CC=C(C)C=C1)C(C)C FPPBRZSEFNORFB-UHFFFAOYSA-N 0.000 description 1
- PCIHHFVXFCFJKC-UHFFFAOYSA-N CCN(CC1=CC=C(Cl)C=C1)C(C)C Chemical compound CCN(CC1=CC=C(Cl)C=C1)C(C)C PCIHHFVXFCFJKC-UHFFFAOYSA-N 0.000 description 1
- KPIYYTYWEKVDLD-UHFFFAOYSA-N CCN(CC1=CC=CC(C)=C1)C(C)C Chemical compound CCN(CC1=CC=CC(C)=C1)C(C)C KPIYYTYWEKVDLD-UHFFFAOYSA-N 0.000 description 1
- LDISDPDZZUDKHE-UHFFFAOYSA-N CCN(CC1=CC=CC=C1)C(C)C Chemical compound CCN(CC1=CC=CC=C1)C(C)C LDISDPDZZUDKHE-UHFFFAOYSA-N 0.000 description 1
- RITWYTYNWBIAIU-UHFFFAOYSA-N CCN(CC1=CC=CC=C1C)C(C)C Chemical compound CCN(CC1=CC=CC=C1C)C(C)C RITWYTYNWBIAIU-UHFFFAOYSA-N 0.000 description 1
- BWJHGRPKYBDOBU-UHFFFAOYSA-N CCN(CC1=CC=CC=C1F)C(C)C Chemical compound CCN(CC1=CC=CC=C1F)C(C)C BWJHGRPKYBDOBU-UHFFFAOYSA-N 0.000 description 1
- CPRLNEYCSRYXLG-UHFFFAOYSA-N CCN(CC1=CC=NC=C1)C(C)C Chemical compound CCN(CC1=CC=NC=C1)C(C)C CPRLNEYCSRYXLG-UHFFFAOYSA-N 0.000 description 1
- MIVFXYWOERKXFM-UHFFFAOYSA-N CCN(CCC1=NC=CC=C1)C(C)C Chemical compound CCN(CCC1=NC=CC=C1)C(C)C MIVFXYWOERKXFM-UHFFFAOYSA-N 0.000 description 1
- VYTWUHNMPKVLKM-UHFFFAOYSA-N CCN(CCN(C)C)C(C)C Chemical compound CCN(CCN(C)C)C(C)C VYTWUHNMPKVLKM-UHFFFAOYSA-N 0.000 description 1
- DTJOCIYKEFIORQ-UHFFFAOYSA-N CCN(CCOC)C(C)C Chemical compound CCN(CCOC)C(C)C DTJOCIYKEFIORQ-UHFFFAOYSA-N 0.000 description 1
- AZFYRRIOKRSPQV-UHFFFAOYSA-N CCOC(=O)C1CCCCN1C(C)C Chemical compound CCOC(=O)C1CCCCN1C(C)C AZFYRRIOKRSPQV-UHFFFAOYSA-N 0.000 description 1
- LUVKHTGJKFFLMR-UHFFFAOYSA-N CCOC(=O)C1CCN(C(C)C)CC1 Chemical compound CCOC(=O)C1CCN(C(C)C)CC1 LUVKHTGJKFFLMR-UHFFFAOYSA-N 0.000 description 1
- CDORXIUVSNTOKU-UHFFFAOYSA-N CCOC(=O)N(CC1=CC=CC=C1)C(C)C Chemical compound CCOC(=O)N(CC1=CC=CC=C1)C(C)C CDORXIUVSNTOKU-UHFFFAOYSA-N 0.000 description 1
- HQUVLOKKTRUQNI-UHFFFAOYSA-N CCOCCC(C)C Chemical compound CCOCCC(C)C HQUVLOKKTRUQNI-UHFFFAOYSA-N 0.000 description 1
- HDGQICNBXPAKLR-QMMMGPOBSA-N CC[C@H](C)CC(C)C Chemical compound CC[C@H](C)CC(C)C HDGQICNBXPAKLR-QMMMGPOBSA-N 0.000 description 1
- VELGOYBSKBKQFF-UHFFFAOYSA-N CN(C)CCC(c1ccccc1)O Chemical compound CN(C)CCC(c1ccccc1)O VELGOYBSKBKQFF-UHFFFAOYSA-N 0.000 description 1
- NKWVBPZZQFOVCE-UHFFFAOYSA-N COC(=O)C(=O)C(C)C Chemical compound COC(=O)C(=O)C(C)C NKWVBPZZQFOVCE-UHFFFAOYSA-N 0.000 description 1
- XKBVKKADZHQMDE-UHFFFAOYSA-N COC(=O)C1CC(C)CN1C(C)C Chemical compound COC(=O)C1CC(C)CN1C(C)C XKBVKKADZHQMDE-UHFFFAOYSA-N 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N COC(=O)CC(C)C Chemical compound COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- QIYDQYBDGDYJKD-UHFFFAOYSA-N COC(=O)CCCCC(C)C Chemical compound COC(=O)CCCCC(C)C QIYDQYBDGDYJKD-UHFFFAOYSA-N 0.000 description 1
- ZNEANJQKYVAVSU-UHFFFAOYSA-N COC(CN(C)C(C)C)OC Chemical compound COC(CN(C)C(C)C)OC ZNEANJQKYVAVSU-UHFFFAOYSA-N 0.000 description 1
- DCPJUOIXRYQOFL-UHFFFAOYSA-N COC1=C(OC)C=C(CCN(C)C(C)C)C=C1 Chemical compound COC1=C(OC)C=C(CCN(C)C(C)C)C=C1 DCPJUOIXRYQOFL-UHFFFAOYSA-N 0.000 description 1
- HWINBBUYLKWIBO-UHFFFAOYSA-N COC1=CC(C(C)C)=CC=C1 Chemical compound COC1=CC(C(C)C)=CC=C1 HWINBBUYLKWIBO-UHFFFAOYSA-N 0.000 description 1
- BFSBRRDYIMUSBW-UHFFFAOYSA-N COC1=CC=C(OCC(C)C)C=C1 Chemical compound COC1=CC=C(OCC(C)C)C=C1 BFSBRRDYIMUSBW-UHFFFAOYSA-N 0.000 description 1
- PMKBFFXMBMLPDT-UHFFFAOYSA-N COC1=CC=CC=C1C1CCN(C(C)C)CC1 Chemical compound COC1=CC=CC=C1C1CCN(C(C)C)CC1 PMKBFFXMBMLPDT-UHFFFAOYSA-N 0.000 description 1
- WAFKWLVWZORWPS-UHFFFAOYSA-N COCCN(C(C)C)C(C)C Chemical compound COCCN(C(C)C)C(C)C WAFKWLVWZORWPS-UHFFFAOYSA-N 0.000 description 1
- ZFLBJYJRXLWTJI-UHFFFAOYSA-N COCCN(C)C(C)C Chemical compound COCCN(C)C(C)C ZFLBJYJRXLWTJI-UHFFFAOYSA-N 0.000 description 1
- VTLAOFNWLFSDLF-UHFFFAOYSA-N COCCN(CCOC)C(C)C Chemical compound COCCN(CCOC)C(C)C VTLAOFNWLFSDLF-UHFFFAOYSA-N 0.000 description 1
- LIIFEDVAAQVLIY-ZNJVAXHLSA-N [H][C@]12CC3(C(=O)C(C)C)C[C@@]([H])(C1)C[C@@]([H])(C3)C2 Chemical compound [H][C@]12CC3(C(=O)C(C)C)C[C@@]([H])(C1)C[C@@]([H])(C3)C2 LIIFEDVAAQVLIY-ZNJVAXHLSA-N 0.000 description 1
- KWCVRTQTFBBOME-QHGLUPRGSA-N [H][C@]12CCC(O(O)SC(C)C)(C(=O)C1)C2(C)C Chemical compound [H][C@]12CCC(O(O)SC(C)C)(C(=O)C1)C2(C)C KWCVRTQTFBBOME-QHGLUPRGSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/16—Peri-condensed systems
Definitions
- This invention relates generally to CRF receptor antagonists, and to methods of treating disorders by administration of such antagonists to a warm-blooded animal in need thereof.
- the first corticotropin-releasing factor (CRF) was isolated from ovine hypothalmi and identified as a 41-amino acid peptide (Vale et al., Science 213:1394-1397, 1981). Subsequently, sequences of human and rat CRF were isolated and determined to be identical, but different from ovine CRF in 7 of the 41 amino acid residues (Rivier et al., Proc. Natl. Acad. Sci. USA 80:4851, 1983; Shibahara et al., EMBO J. 2:775, 1983).
- CRF has been found to produce profound alterations in endocrine, nervous and immune system function.
- CRF is believed to be the major physiological regulator of the basal and stress-release of adrenocorticotropic hormone (“ACTH”), ⁇ -endorphin, and other pro-opiomelanocortin (“POMC”)-derived peptides from the anterior pituitary (Vale et al., Science 213:1394-1397, 1981).
- ACTH adrenocorticotropic hormone
- POMC pro-opiomelanocortin
- the CRF receptor is coupled to a GTP-binding protein (Perrin et al., Endocrinology 118:1171-1179, 1986) which mediates CRF-stimulated increase in intracellular production of cAMP (Bilezikjian, L. M., and W. W.
- the receptor for CRF has now been cloned from rat (Perrin et al., Endo 133(6):3058-3061, 1993), and human brain (Chen et al., PNAS 90(19):8967-8971, 1993; Vita et al., FEBS 335(1):1-5, 1993).
- This receptor is a 415 amino acid protein comprising seven membrane spanning domains. A comparison of identity between rat and human sequences shows a high degree of homology (97%) at the amino acid level.
- CRF In addition to its role in stimulating the production of ACTH and POMC, CRF is also believed to coordinate many of the endocrine, autonomic, and behavioral responses to stress, and may be involved in the pathophysiology of affective disorders. Moreover, CRF is believed to be a key intermediary in communication between the immune, central nervous, endocrine and cardiovascular systems (Crofford et al., J. Clin. Invest. 90:2555-2564, 1992; Sapolsky et al., Science 238:522-524, 1987; Tilders et al., Regul. Peptides 5:77-84, 1982). Overall, CRF appears to be one of the pivotal central nervous system neurotransmitters and plays a crucial role in integrating the body's overall response to stress.
- CRF may be hypersecreted in the brain in depression, anxiety-related disorders, and anorexia nervosa.
- CRF receptor antagonists may represent novel antidepressant and/or anxiolytic drugs that may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF.
- the first CRF receptor antagonists were peptides (see, e.g., Rivier et al., U.S. Pat. No. 4,605,642; Rivier et al., Science 224:889, 1984). While these peptides established that CRF receptor antagonists can attenuate the pharmacological responses to CRF, peptide CRF receptor antagonists suffer from the usual drawbacks of peptide therapeutics including lack of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been reported. For example, substituted 4-thio-5-oxo-3-pyyrazoline derivatives (Abreu et al., U.S. Pat. No.
- CRF receptor antagonists would be useful in the treatment of endocrine, psychiatric and neurologic conditions or illnesses, including stress-related disorders in general.
- this invention is generally directed to CRF receptor antagonists, and more specifically to CRF receptor antagonists having the following general structure (I):
- n, m, A, B, C, X, R, R 1 , R 2 , and Ar are as defined below.
- the CRF receptor antagonists of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders or illnesses, including stress-related disorders. Such methods include administering an effective amount of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition, to an animal in need thereof. Accordingly, in another embodiment, pharmaceutical compositions are disclosed containing one or more CRF receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.
- the present invention is directed generally to compounds useful as corticotropin-releasing factor (CRF) receptor antagonists.
- CCF corticotropin-releasing factor
- the CRF receptor antagonists of this invention have the following structure (I):
- n 1 or 2;
- a and C are each independently nitrogen, carbon or CH;
- B is nitrogen or CR 3 ;
- A, B and C are nitrogen; A, B and C are not all nitrogen; and either A-B or B-C is a double bond;
- X is nitrogen or Cr q ;
- R q is hydrogen, alkyl or halo
- Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl
- R is an optional substituent which, at each occurrence, is independently alkyl, alkylidenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein m is 0, 1, 2 or 3 and represents the number of R substituents;
- R 1 is —C(H) 0,1 (R 4 )(R 5 ) or —SO 2 R 5 ;
- R 2 is hydrogen, alkyl, haloalkyl or cyano
- R 3 is hydrogen, alkyl or haloalkyl
- R 4 is hydrogen, oxo, alkyl, substituted alkyl, alkylidenyl or halo
- R 5 is a radical of the formula —Y-Z-R 6 , wherein
- Y is an alkanediyl, substituted alkanediyl, or a direct bond
- Z is NH, —N(R 7 ), O, S, SO 2 , C( ⁇ O), C( ⁇ O)O, OC( ⁇ O), NHC( ⁇ O), C( ⁇ O)NH, NH(SO 2 ), (SO 2 )NH, NR 8 C( ⁇ O)O, or a direct bond;
- R 6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocyclealkyl;
- R 7 and R 8 are alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
- R 6 and R 7 taken together with the nitrogen atom to which they are attached form a heterocyle ring or substituted heterocyle ring;
- R 4 and R 5 taken together with the carbon atom to which they are attached form cycloalkyl, substituted cycloalkyl, cycloalkylcycloalkyl, substituted cycloalkylcycloalkyl, cycloalkylaryl, substituted cycloalkyaryl, cycloalkylheterocycle, or substituted cycloalkylheterocycle.
- Alkyl means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term “lower alkyl” has the same meaning as alkyl but contains from 1 to 6 carbon atoms.
- Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
- saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH 2 cyclopropyl, —CH 2 cyclobutyl, —CH 2 cyclopentyl, —CH 2 cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
- Cyclic alkyls also referred to as “homocyclic rings,” and include di- and poly-homocyclic rings such as decalin and adamantyl.
- Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”, respectively).
- Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like.
- Alkylidenyl represents a divalent alkyl from which two hydrogen atoms are taken from the same carbon atom, such as ⁇ CH 2 , ⁇ CHCH 3 , ⁇ CHCH 2 CH 3 , ⁇ C(CH 3 )CH 2 CH 3 , and the like.
- Alkanediyl means a divalent alkyl from which two hydrogen atoms are taken from the same carbon atom or from different carbon atoms, such as —CH 2 — —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 —, and the like.
- Aryl means an aromatic carbocyclic moiety such as phenyl or naphthyl.
- Arylalkyl means an alkyl having at least one alkyl hydrogen atoms replaced with an aryl moiety, such as benzyl, —CH 2 —(1 or 2-naphthyl), —(CH 2 ) 2 phenyl, —(CH 2 ) 3 phenyl, —CH(phenyl) 2 , and the like.
- Heteroaryl means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
- Representative heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quin
- Heteroarylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as —CH 2 pyridinyl, —CH 2 pyrimidinyl, and the like.
- Heterocycle (also referred to herein as a “heterocycle ring”) means a 5- to 7-membered monocyclic, or 7- to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings.
- the heterocycle may be attached via any heteroatom or carbon atom.
- Heterocycles include heteroaryls as defined above.
- heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
- Heterocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as —CH 2 morpholinyl, and the like.
- Cycloalkyl means a saturated or unsaturated (but not aromatic) carbocyclic ring containing from 3-8 carbon atoms, such as cyclopentane, cyclohexane, cycloheptane, cyclohexene, and the like.
- Cycloalkylcycloalkyl means a cycloalkyl ring fused to a cycloalkyl ring, such as decalin.
- Cycloalkylaryl means a cycloalkyl ring fused to aryl, such as tetralin.
- Cycloalkylheterocycle means a cycloalkyl ring fused to a heterocycle ring.
- substituted means any of the above groups (e.g., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, etc.) wherein at least one hydrogen atom is replaced with a substituent.
- a keto substituent (“—C( ⁇ O)—”) two hydrogen atoms are replaced.
- substituted within the context of this invention include halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —NR a R b , —NR a C( ⁇ O)R b , —NR a C( ⁇ O)NR a NR b , —NR a C( ⁇ O)OR b —NR a SO 2 R b , —OR a , —C( ⁇ O)R a —C( ⁇ O)OR a , —C( ⁇ O)NR a R b ,
- Halogen means fluoro, chloro, bromo and iodo.
- Haloalkyl means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.
- Alkoxy means an alkyl moiety attached through an oxygen bridge (i.e., —O-alkyl) such as methoxy, ethoxy, and the like.
- Alkylthio means an alkyl moiety attached through a sulfur bridge (i.e., —S—alkyl) such as methylthio, ethylthio, and the like.
- Alkylsulfonyl means an alkyl moiety attached through a sulfonyl bridge (i.e., —SO 2 -alkyl) such as methylsulfonyl, ethylsulfonyl, and the like.
- Alkylamino and dialkylamino mean one or two alkyl moiety attached through a nitrogen bridge (i.e., —N-alkyl) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.
- Haldroxyalkyl means an alkyl substituted with at least one hydroxyl group.
- “Mono- or di(cycloalkyl)methyl” represents a methyl group substituted with one or two cycloalkyl groups, such as cyclopropylmethyl, dicyclopropylmethyl, and the like.
- Alkylcarbonylalkyl represents an alkyl substituted with a —C( ⁇ O)alkyl group.
- Alkylcarbonyloxyalkyl represents an alkyl substituted with a —C( ⁇ O)Oalkyl group or a —OC( ⁇ O)alkyl group.
- Alkyloxyalkyl represents an alkyl substituted with a —O-alkyl group.
- Alkylthioalkyl represents a alkyl substituted with a —S-alkyl group.
- “Mono- or di(alkyl)amino represents an amino substituted with one alkyl or with two alkyls, respectively.
- “Mono- or di(alkyl)aminoalkyl” represents a alkyl substituted with a mono- or di(alkyl)amino.
- Moieties in this regard are —CH 2 CH(R)—, —CH(R)CH 2 —, —CH(R)CH(R)—, —CH ⁇ C(R)—, —C(R) ⁇ CH—, —C(R) ⁇ C(R)—, —CH 2 CH 2 CH(R)—, —CH 2 CH(R)CH 2 —, —CH(R)CH 2 CH 2 —, —CH(R)CH 2 CH(R), —CH(R)CH(R)CH 2 and —CH 2 CH(R)CH(R)—, wherein each occurrence of R is the same or different and independently selected from the R groups as set forth above.
- representative compounds of this invention include the following structures (Ia) through (In):
- n is 1 and m is 0 and the CRF receptor antagonists of this invention have structure (Ia). In another embodiment, n is 1 and m is 1 and the CRF receptor antagonists of this invention have structure (Ib) or (Ic).
- the CRF receptor antagonists of this invention include compounds having the following structures (I-1), (I-2), (I-3) and (I-4):
- representative compounds of this invention include the following compounds (I-1a), (I-2a), (I-3a), and (I-4a); and when X of compounds (I-1), (I-2), (I-3) and (I-4) is nitrogen, representative compounds of this invention include the following compounds (I-1b), (I-2b), (I-3b) and (I-4b):
- R 1 is —SO 2 R 5 , as represented by the following structure:
- R 1 is —C(H) 0,1 (R 4 )(R 5 ) which represents both —CH(R 4 )(R 5 ) and —C(R 4 )(R 5 ).
- Representative embodiments in this regard include the following R 1 moieties (i), (ii) and (iii):
- R 4 moieties of this invention include, but are not limited to, hydrogen, oxo (i.e., ⁇ O), halogen (fluoro, chloro, bromo and iodo), methyl, ethyl, n-propyl, n-butyl, n-penty, ⁇ CH 2 , ⁇ CHCH 3 , and ⁇ CHCH 2 CH 3 .
- representative R 1 moieties include (but are not limited to) the following:
- Cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, and the like.
- substituted cycloalkyls are cycloalkyls having one or more substituents as defined above.
- the cycloalkyl is substituted with one or more alkyl groups, and representative R 1 moieties include the following:
- R′ and R′′ are the same or different and independently selected from, for example, alkyl such as methyl or ethyl.
- R 4 and R 5 groups of R 1 taken together form a cycloalkylaryl and the resulting R 1 group include compounds having the structure:
- R 4 and R 5 are taken together to form a cycloalkylcycloalky or cycloalkylheterocycle, and the resulting R 1 group include, for example, compounds having the structure:
- R 5 is a radical of the formula —Y-Z-R 6 , wherein
- Y is an alkanediyl, substituted alkanediyl, or a direct bond
- Z is NH, —N(R 7 ), O, S, SO 2 , C( ⁇ O), C( ⁇ O)O, OC( ⁇ O), NHC( ⁇ O), C( ⁇ O)NH, NH(SO 2 ), (SO 2 )NH, NR 8 C( ⁇ O)O, or a direct bond;
- R 6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
- R 7 and R 8 are the same or different and independently alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
- R 6 and R 7 taken together with the nitrogen atom to which they are attached form a heterocyle ring or substituted heterocyle ring.
- the R 5 moiety has Y as an alkanediyl, Z as a direct bond, and R 6 as hydrogen.
- R 5 moieties include alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl.
- Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., —CH(Et) 2 ) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
- the R 5 moiety has Y and Z being direct bonds while R 6 includes an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl.
- R 6 includes an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, and chlorophenyl.
- R 5 moiety has Y being a direct bond, Z being NH and R 6 being as defined above.
- R 6 may be hydrogen such that R 5 is amino.
- R 6 may be alkyl, such that R 5 is an alkyl-substituted amino group, e.g., isopropylamino, and ethylamino.
- R 6 may be an aryl or substituted aryl, such that R 5 is an arylamino or substituted arylamino group, e.g., (methoxyphenyl)amino, ((trifluoromethoxy)phenyl)amino, (phenyl substituted phenyl)amino (also known as (biphenyl)amino), and (di(trifluoromethyl)phenyl)amino.
- arylamino or substituted arylamino group e.g., (methoxyphenyl)amino, ((trifluoromethoxy)phenyl)amino, (phenyl substituted phenyl)amino (also known as (biphenyl)amino), and (di(trifluoromethyl)phenyl)amino.
- R 6 may be arylalkyl or substituted arylalkyl, such that R 5 is an (arylalkyl)amino or (substituted arylalkyl)amino, e.g., (benzyl)amino (also known as (phenylmethyl)amino), (cyclopropylphenyl)amino, and (phenylethyl)amino.
- R 5 is an (arylalkyl)amino or (substituted arylalkyl)amino, e.g., (benzyl)amino (also known as (phenylmethyl)amino), (cyclopropylphenyl)amino, and (phenylethyl)amino.
- R 4 is carbonyl.
- the R 5 moiety has Y being alkanediyl, Z being N(R 7 ) and R 6 being as defined above, where R 7 is also as defined above. Accordingly, R 5 is —Y—N(R 7 )(R 6 ), i.e., includes a disubstituted amino moiety.
- Y is methylene, i.e., —CH 2 —, so that R 5 is —CH 2 —N(R 7 )(R 6 ).
- R 6 and R 7 are each selected from alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, or substituted heterocyclealkyl, where R 6 may additionally be hydrogen. In one embodiment, R 6 is hydrogen.
- R 6 and R 7 groups of —N(R 6 )(R 7 ) group may be alkyl or substituted alkyl, including saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl.
- Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., —CH(Et) 2 ) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
- R 6 and R 7 groups of —N(R 6 )(R 7 ) group may include an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, and chlorophenyl.
- —N(R 6 )(R 7 ) may be, for example, (propyl)(cyclopropylmethyl) amino, (2-cyanoethyl)(methyl) amino, (2-cyanoethyl)(benzyl) amino, (ethyl)((2-(dimethylamino)ethyl)) amino, (2-hydroxyethyl)(benzyl) amino, di(2-hydroxyethyl) amino, (propyl)(2-hydoxyethyl) amino, (cyclohexyl)(ethyl) amino, (carboxymethyl)(methyl) amino, di(benzyl) amino, and ((2-hydroxy)(2-phenyl)ethyl))(methyl) amino.
- R 6 and R 7 taken together with the nitrogen atom to which they are both attached may form a heterocycle ring or substituted heterocycle ring.
- —N(R 6 )(R 7 ) may represent a heterocycle ring, such as aziridinyl, methyl-substituted aziridinyl,
- a heterocycle may include more heteroatoms (i.e., non-carbon atoms) than the nitrogen of —N(R 6 )(R 7 ).
- the heterocycle may additionally include a second nitrogen, or an oxygen, or a sulfur.
- the heterocycle will have two nitrogens, as in, e.g., piperazinyl.
- the heterocycle will have both an oxygen and a nitrogen, as in, e.g., morpholinyl.
- a sulfur is present, the heterocycle will have both a sulfur and a nitrogen, as in, e.g., thiomorpholinyl.
- heterocycles having two or more heteroatoms may be substituted or non-substituted.
- the morpholinyl group may be substituted with two alkyl group, e.g., one methyl group on either side of the morpholinyl oxygen atom.
- the heterocycle is a piperazinyl group
- the nitrogen atom not explicitly shown in the formula —N(R 6 )(R 7 ) may be substituted, where exemplary substituents are, for example, alkyl (e.g., methyl), substituted alkyl (e.g., 2-hydroxyethyl), or arylalkyl (e.g., benzyl).
- Y is substituted alkanediyl
- Z is a heteroatom or a direct bond
- R 6 is as defined above.
- R 4 is hydrogen.
- Y is an alkanediyl having a substituent, where the substituent may be, for example, hydroxy.
- the alkanediyl may be, for example, ethylene (i.e., —CH 2 —CH 2 —), or n-propylene (i.e., —CH 2 CH 2 CH 2 —), such that a substituted alkanediyl may be, e.g., —CH(OH)—CH 2 —, or —CH 2 —CH(OH)—CH 2 —
- Y is alkanediyl, e.g., methylene (—CH 2 —), Z is amido, i.e., —NHC( ⁇ O)— or —C( ⁇ O)NH—, and R 6 is as defined above.
- R 4 is hydrogen.
- R 5 is —CH 2 —NHC( ⁇ O)—R 6 .
- Y is alkanediyl, e.g., methylene (—CH 2 —), Z is sulfonylamido, i.e., —NHSO 2 — or —SO 2 NH—, and R 6 is as defined above.
- R 4 is hydrogen.
- R 5 is —CH 2 —NHSO 2 —R 6 .
- Y and Z are direct bonds and R 6 is as defined above.
- R 5 is —R 6 .
- R 4 is alkyl when R 5 is —R 6 .
- R 4 is carbonyl when R 5 is —R 6 .
- the R 6 moiety may be alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl.
- Representative examples are methyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., —CH(Et) 2 ) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
- the R 6 may be substituted alkyl, where a substituted alkyl may have one, two, or more substituents.
- Y and Z are direct bonds and R 6 is as defined above.
- R 5 is —R 6 .
- R 4 is hydrogen when R 5 is —R 6 .
- R 4 is alkyl when R 5 is —R 6 .
- Y is a direct bond
- Z is an ester group, i.e., —C( ⁇ O)O— or —OC( ⁇ O)—
- R 6 is as defined above.
- R 5 is -ester-R 6 , and preferably R 5 is —C( ⁇ O)—O—R 6 .
- R 4 is hydrogen.
- the R 6 moiety may be alkyl, preferably lower saturated alkyl, e.g., methyl, ethyl, propyl, etc.
- Y is substituted alkanediyl
- Z is a direct bond or oxygen
- R 6 is as defined above.
- R 4 is preferably H.
- R 4 is preferably alkyl.
- the alkanediyl may be a C 1 -C 6 alkanediyl, e.g., methylene, ethylene, propylene, etc.
- the substituent on the alkanediyl may be, e.g., hydroxy, halogen, amino, alkyl, etc.
- Y may be —CH(OH)— or —CH(OH)—CH 2 —, etc.
- R 6 is aryl or substituted aryl, e.g., phenyl or chlorophenyl. In another embodiment, R 6 is alky or substituted alkyl, e.g., methyl or fluoromethyl.
- R 1 is SO 2 R 5 , where Y is a direct bond, Z is a direct bond, and R 6 is as defined above. Accordingly, in this embodiment, R 1 is —SO 2 —R 6 .
- Y is alkanediyl
- Z is O or S
- R 6 is as defined above.
- R 5 may be —CH 2 —O—CH 3 where Y is methylene, Z is O, and R 6 is an alkyl, and specifically methyl.
- R 4 is carbonyl.
- R 4 is hydrogen.
- R 4 is alkyl.
- Y is a direct bond
- Z is a direct bond
- R 6 is alkyl or substituted alkyl of the formula ⁇ CH 2 , ⁇ CH—CH 3 , ⁇ CH—CH 2 —CH 3 , ⁇ CH—CH(CH 3 )—CH 3 , and homologs thereof.
- the substituent on the substituted alkyl may be, for example, hydroxyl or halogen (e.g., fluoro).
- the R 6 moiety may be alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl.
- Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., —CH(Et) 2 ) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
- R 6 moiety may be substituted alkyl, where substituted alkyls may have one or may substituents. Suitable substituents include trifluoromethyl, hydroxy, and halogen (i.e., fluoro, chloro, bromo, iodo).
- the R 6 moiety may include an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, methoxyphenyl, and chlorophenyl.
- the R 6 moiety may be heterocycle, heterocyclealkyl, substituted heterocycle, substituted heterocyclealkyl, e.g., furanyl, furanylmethyl, and thienyl, thienymethyl.
- R 4 is hydrogen when R 5 is —R 6 and R 6 is alkyl as set forth above. In another embodiment, R 4 is alkyl when R 5 is —R 6 and R 6 is alkyl as set forth above. In a preferred embodiment, R 4 is hydrogen when R 5 is —R 6 and R 6 includes an aromatic ring as set forth above. In another embodiment, R 4 is alkyl when R 5 is —R 6 and R 6 includes an aromatic ring as set forth above.
- R 1 groups of this invention specifically include each of the R 1 groups disclosed in the Examples, as well as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, —CH(ethyl) 2 , —CH(n-propyl) 2 , —CH(n-butyl) 2 , —CH 2 CH 2 OCH 3 , —CH(methyl)(CH 2 OCH 3 ), —CH(ethyl)(CH 2 OCH 3 ), —CH(n-propyl)(CH 2 OCH 3 ), —CH(n-butyl)(CH 2 OCH 3 ), —CHC ⁇ —CH, —CH(methyl)(ethyl), —CH(methyl)(n-propyl), —CH(methyl)(n-propyl
- R groups of this invention include, when present, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, ⁇ CH 2 , ⁇ CHCH 3 and phenyl.
- representative Ar groups of this invention include (but are not limited to) the Ar groups identified in the Examples, as well as 2,4-dichlorophenyl, 2,4-dimethyl-phenyl, 2-chloro-4-methylphenyl, 2-methyl-4-chlorophenyl, 2,4,6-trimethylphenyl, 2-chloro-4-methoxyphenyl, 2-methyl-4-methoxyphenyl, 2,4-dimethoxyphenyl, 2-trifluoromethyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-trichloromethylphenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl 2-methoxy-4-methylphenyl, 4-methyl-6-dimethylaminopyridin-3
- compounds of this invention have structure (I) above, wherein R 4 is hydrogen, keto, C 1-6 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, C 3-6 cycloalkyl, C 3-6 alkenyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyloxyC 1-6 alkyl, or C 1-6 alkyloxyC 1-6 alkyl; R 5 is hydrogen, Ar, C 1-6 alkylAr, OAr, C 1-8 alkyl, C 3-6 cycloalkyl, O(C 1-8 alkyl), mono- or di(C 3-6 cycloalkyl)methyl, C 3-6 alkenyl, C 3-6 alkynyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxyAr, hydroxyC 1-6 alkyl, thienylC 1-6 alkyl, furanylC 1-6 alkyl, C 1-6 alkylthioC
- the compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples, and may generally be utilized as the free base. Alternatively, the compounds of this invention may be used in the form of acid addition salts. Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids.
- Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
- Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
- the compounds of structure (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth in the Examples.
- the synthesis of structure (I) will generally proceed by synthesis of the desired sub-structure (I-1), (I-2), (I-3) or (I-4), as represented below.
- synthesis of each of these sub-structures is exemplified in the Examples.
- compounds of structure (I-1) and (I-4) may be made by the following Reaction Scheme A by synthesis of intermediate 4, which is then converted to the corresponding structure (I-1) (structure “10”) or (I-4) (structure “8”):
- Suitable CRF antagonists of this invention are capable of inhibiting the specific binding of CRF to its receptor and antagonizing activities associated with CRF.
- a compound of structure (I) may be assessed for activity as a CRF antagonist by one or more generally accepted assays for this purpose, including (but not limited to) the assays disclosed by DeSouza et al. ( J. Neuroscience 7:88, 1987) and Battaglia et al. ( Synapse 1:572, 1987).
- suitable CRF antagonists include compounds which demonstrate CRF receptor affinity.
- CRF receptor affinity may be determined by binding studies that measure the ability of a compound to inhibit the binding of a radiolabeled CRF (e.g., [ 125 I]tyrosine-CFR) to its receptor (e.g., receptors prepared from rat cerebral cortex membranes).
- a radiolabeled CRF e.g., [ 125 I]tyrosine-CFR
- receptor e.g., receptors prepared from rat cerebral cortex membranes.
- the radioligand binding assay described by DeSouza et al. (supra, 1987) provides an assay for determining a compound's affinity for the CRF receptor.
- a compound's CRF receptor antagonist activity may be established by the ability of the compound to antagonize an activity associated with CRF.
- CRF is known to stimulate various biochemical processes, including adenylate cyclase activity. Therefore, compounds may be evaluated as CRF antagonists by their ability to antagonize CRF-stimulated adenylate cyclase activity by, for example, measuring cAMP levels.
- the CRF-stimulated adenylate cyclase activity assay described by Battaglia et al. (supra, 1987) provides an assay for determining a compound's ability to antagonize CRF activity.
- CRF receptor antagonist activity may be determined by assay techniques which generally include an initial binding assay (such as disclosed by DeSouza (supra, 1987)) followed by a cAMP screening protocol (such as disclosed by Battaglia (supra, 1987)).
- assay techniques which generally include an initial binding assay (such as disclosed by DeSouza (supra, 1987)) followed by a cAMP screening protocol (such as disclosed by Battaglia (supra, 1987)).
- CRF receptor antagonists of this invention have a K i of less than 10 ⁇ M.
- a CRF receptor antagonist has a K i of less than 1 ⁇ M, and more preferably less than 0.25 ⁇ M (i.e., 250 nM).
- K i values of representative compounds of this invention were assayed by the methods set forth in Example 9.
- Preferred compounds having a K i of less than 1 ⁇ M are compound numbers I-2a-1 to I-2a-6, I-2a-8, I-2a-9, I-2a-12 to I-2a-25, I-2a-27 to I-2a-44, I-2a-46 to I-2a-76, I-2a-92, I-2a-173, I-4b-1 and I-4b-2.
- More preferred compounds having a K i of less than 250 nM are compound numbers I-2a-1 to I-2a-4, I-2a-6, I-2a-8, I-2a-9, I-2a-12 to I-2a-18, I-2a-20 to I-2a-25, I-2a-28 to I-2a-36, I-2a-38 to I-2a-43, I-2a-46 to I-2a-73, I-2a-76, I-4b-1 and I-4b-2.
- the CRF receptor antagonists of the present invention demonstrate activity at the CRF receptor site, and may be used as therapeutic agents for the treatment of a wide range of disorders or illnesses including endocrine, psychiatric, and neurologic disorders or illnesses. More specifically, the CRF receptor antagonists of the present invention may be useful in treating physiological conditions or disorders arising from the hypersecretion of CRF. Because CRF is believed to be a pivotal neurotransmitter that activates and coordinates the endocrine, behavioral and automatic responses to stress, the CRF receptor antagonists of the present invention can be used to treat neuropsychiatric disorders.
- Neuropsychiatric disorders which may be treatable by the CRF receptor antagonists of this invention include affective disorders such as depression; anxiety-related disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, cardiovascular abnormalities such as unstable angina and reactive hypertension; and feeding disorders such as anorexia nervosa, bulimia, and irritable bowel syndrome.
- CRF antagonists may also be useful in treating stress-induced immune suppression associated with various diseases states, as well as stroke.
- Other uses of the CRF antagonists of this invention include treatment of inflammatory conditions (such as rheumatoid arthritis, uveitis, asthma, inflammatory bowel disease and G.I. motility), Cushing's disease, infantile spasms, epilepsy and other seizures in both infants and adults, and various substance abuse and withdrawal (including alcoholism).
- compositions containing one or more CRF receptor antagonists are disclosed.
- the compounds of the present invention may be formulated as pharmaceutical compositions.
- Pharmaceutical compositions of the present invention comprise a CRF receptor antagonist of the present invention (i.e., a compound of structure (I)) and a pharmaceutically acceptable carrier and/or diluent.
- the CRF receptor antagonist is present in the composition in an amount which is effective to treat a particular disorder—that is, in an amount sufficient to achieve CRF receptor antagonist activity, and preferably with acceptable toxicity to the patient.
- the pharmaceutical compositions of the present invention may include a CRF receptor antagonist in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more preferably from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
- compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
- the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a CRF receptor antagonist, diluents, dispersing and surface active agents, binders, and lubricants.
- One skilled in this art may further formulate the CRF receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences , Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990.
- prodrugs are also included within the context of this invention.
- Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient.
- Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
- Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
- prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I).
- esters may be employed, such as methyl esters, ethyl esters, and the like.
- the compounds of structure (I) may have chiral centers and may occur as recemates, reacemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
- the present invention provides a method for treating a variety of disorders or illnesses, including endocrine, psychiatric and neurologic disorders or illnesses.
- Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the disorder or illness.
- Such methods include systemic administration of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition.
- systemic administration includes oral and parenteral methods of administration.
- suitable pharmaceutical compositions of CRF receptor antagonists include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions.
- compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
- the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the CRF receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
- administering can be used to treat a wide variety of disorders or illnesses.
- the compounds of the present invention may be administered to a warm-blooded animal for the treatment of depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome, stress-induced immune suppression, stroke, inflammation, Cushing's disease, infantile spasms, epilepsy, and substance abuse or withdrawal.
- the CRF receptor antagonists of this invention may be prepared by the methods disclosed in Examples 1-12.
- Example 13 presents a method for determining the receptor binding activity (K i )
- Example 14 discloses an assay for screening compounds of this invention for CRF-stimulated adenylate cyclase activity.
- Ethyl 2,4-dichloro-6-methylnicotinate (9) (8.04 g, 34.3 mmol) was dissolved in THF (40 mL) and added to a stirred suspension of LAH (6.52 g, 0.170 mmol) in THF (80 mL) at ⁇ 78° C. The mixture was stirred for 6 hours at this temperature and for 1 hour at ⁇ 30° C. followed by cautious treatment with water (5.5 mL), 15% aqueous NaOH (5.5 mL) and water (16.5 mL) with vigorous stirring. The mixture was warmed to room temperature and filtered. The white precipitate was washed liberally with ethyl acetate. The combined organic portions were dried (MgSO 4 ) and concentrated under vacuum to afford 6.40 g (97%) of (10) as a colorless oil which solidified on standing: LCMS (MH + , 192).
- Enone (13) (920 mg, 4.26 mmol) was dissolved in ethanol (20 mL) and treated with 4-heptylamine (0.64 mL, 4.3 mmol). The mixture was heated at 60° C. for 16 hours and then was concentrated under vacuum. The residue was taken up in ethyl acetate (50 mL), washed with aqueous sodium bicarbonate (20 mL), dried (MgSO 4 ), and again concentrated.
- the temperature was raised to room temperature to a suspension of pyridinium perbromide (75.0 mmoles) in CCl4. The temperature was raised to room temperature and stirred for 4 hours. The mixture was diluted with chloroform and washed successively with brine, hydrochloric acid solution (10%), saturated solution of bicarbonate, dried over sodium carbonate and concentrated in vacuum. The compound (6′) was purified by silica gel column.
- compounds of structure (I-2a) may be prepared by the following procedure.
- compounds of structure (I-2a) may be made by the following procedure:
- the residue was triturated with ether and used in the next step without further purification.
- the solid obtained was treated with an aqueous solution of LiOH (18 mL, 1M) in methanol and the mixture was heated at reflux for 18 hr.
- the solution was poured into a solution of 1M HCl (18 mL).
- the solution was extracted with ethyl acetate, washed with brine, dried with sodium sulfate and concentrated in vacuo to give a solid which was heated in diphenyl ether at 230° C. for 1.5 hr.
- the solid obtained after diluting with ether was dried in vacuo.
- compounds of structure (T-4b) may also be prepared according to the following reaction.
- Acetamidine hydrochloride (11.2 g, 119 mmol) was added to a stirred solution of sodium methoxide (6.41 g, 119 mmol) in methanol (180 mL). After 5 min, diethyl allylmalonate (18 mL, 91 mmol) was added and the mixture was heated to reflux for 15 h, cooled to rt, and concentrated under vacuum to afford 20 g of the crude pyridinone as a white solid. This material was heated to reflux in phosphorus oxychloride (100 mL) for 5 h.
- Tetrakis(triphenylphosphine)palladium(0) 22 mg, 0.019 mmol was added to a stirred solution of (14) (83 mg, 0.16 mmol) and potassium acetate (85 mg, 0.87 mmol) in DMF (3 ml), and the resulting mixture was heated at 83° C. for 45 min. The mixture was cooled to room temperature, poured into aqueous NaCl, and extracted with ethyl acetate. The combined extracts were concentrated under vacuum, and the residue was purified by preparative TLC (elution with 15% ethyl acetate in hexanes) to afford 59 mg (86%) of (15) as a colorless oil.
- Ethyl 2,4-dichloro-6-methylnicotinate (10′) (8.04 g, 34.3 mmol) was dissolved in THF (40 mL) and added to a stirred suspension of LAH (6.52 g, 170 mmol) in THF (80 mL) at ⁇ 78° C. The mixture was stirred for 6 h at this temperature and 1 h at ⁇ 30° C. and treated cautiously with water (5.5 mL), 15% aqueous NaOH (5.5 mL) and water (16.5 mL) with vigorous stirring. The mixture was warmed to room temperature and filtered. The white precipitate was washed liberally with ethyl acetate. The combined organic portions were dried (MgSO 4 ) and concentrated under vacuum to afford 6.40 g (97%) of (11′) as a colorless oil which solidified on standing: LCMS (MH + , 192).
- NMO N-methylmorpholine N-oxide
- TPAP tetrapropylammonium perruthenate
- Enone (14′) (920 mg, 4.26 mmol) was dissolved in ethanol (20 mL) and treated with 4-heptylamine (0.64 mL, 4.3 mmol). The mixture was heated at 60° C. for 16 h and concentrated under vacuum. The residue was taken up in ethyl acetate (50 mL), washed with aqueous sodium bicarbonate (20 mL), dried (MgSO 4 ), and again concentrated.
- 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyridin-4-one (15′): NMR, LCMS (MH + , 295), R f 0.70 (30% ethyl acetate in hexanes); 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin-4-one (16′): mp 82-85° C., LCMS (MH + , 295), R f 0.14 (30% ethyl acetate in hexanes).
- the compounds of this invention may be evaluated for binding activity to the CRF receptor by a standard radioligand binding assay as generally described by DeSouza et al. ( J. Neurosci. 7:88-100, 1987).
- the assay may be used to evaluate the binding activity of the compounds of the present invention with any CRF receptor subtype. Briefly, the binding assay involves the displacement of a radiolabeled CRF ligand from the CRF receptor.
- the binding assay is performed in 1.5 ml Eppendorf tubes using approximately 1 ⁇ 10 6 cells per tube stably transfected with human CRF receptors.
- Each tube receives about 0.1 ml of assay buffer (e.g., Dulbecco's phosphate buffered saline, 10 mM magnesium chloride, 20 ⁇ M bacitracin) with or without unlabeled sauvagine, urotensin I or CRF (final concentration, 1 ⁇ M) to determine nonspecific binding, 0.1 ml of [ 125 I] tyrosine-ovine CRF (final concentration ⁇ 200 ⁇ M or approximately the K D as determined by Scatchard analysis) and 0.1 ml of a membrane suspension of cells containing the CRF receptor.
- assay buffer e.g., Dulbecco's phosphate buffered saline, 10 mM magnesium chloride, 20 ⁇ M bacitracin
- urotensin I or CRF final
- the mixture is incubated for 2 hours at 22° C. followed by the separation of the bound and free radioligand by centrifugation. Following two washes of the pellets, the tubes are cut just above the pellet and monitored in a gamma counter for radioactivity at approximately 80% efficiency. All radioligand binding data may be analyzed using the non-linear least-square curve-fitting program LIGAND of Munson and Rodbard ( Anal. Biochem. 107:220, 1990).
- the compounds of the present invention may also be evaluated by various functional testing.
- the compounds of the present invention may be screened for CRF-stimulated adenylate cyclase activity.
- An assay for the determination of CRF-stimulated adenylate cyclase activity may be performed as generally described by Battaglia et al. ( Synapse 1:572, 1987), with modifications to adapt the assay to whole cell preparations.
- the standard assay mixture may contain the following in a final volume of 0.5 ml: 2 mM L-glutamine, 20 mM HEPES, and 1 mM IMBX in DMEM buffer.
- whole cells with the transfected CRF receptors are plated in 24-well plates and incubated for 1 h at 37° C. with various concentrations of CRF-related and unrelated peptides in order to establish the pharmacological rank-order profile of the particular receptor subtype. Following the incubation, the media is aspirated, the wells rinsed once gently with fresh media, and the media aspirated.
- cAMP intracellular cAMP
- 300 ⁇ l of a solution of 95% ethanol and 20 mM aqueous hydrochloric acid is added to each well and the resulting suspensions are incubated at ⁇ 20° C. for 16 to 18 hours.
- the solution is removed into 1.5 ml Eppendorf tubes and the wells washed with an additional 200 ⁇ l of ethanol/aqueous hydrochloric acid and pooled with the first fraction.
- the samples are lyophilized and then resuspended with 500 ⁇ l sodium acetate buffer.
- the measurement of cAMP in the samples is performed using a single antibody kit from Biomedical Technologies Inc. (Stoughton, Mass.).
- a single concentration of CRF or related peptides causing 80% stimulation of cAMP production is incubated along with various concentrations of competing compounds (10 ⁇ 12 to 10 ⁇ 6 M).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure:
including stereoisomers and pharmaceutically acceptable salts thereof, wherein n, m, A, B, C, R, R1, R2 and Ar are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same
Description
- This application is a continuation of U.S. application Ser. No. 10/339,780, filed Jan. 8, 2003; which is a continuation of U.S. application Ser. No. 09/574,751, filed May 18, 2000; which is a continuation-in-part of U.S. application Ser. No. 09/439,840, filed Nov. 12, 1999; which is a continuation-in-part of U.S. application Ser. No. 09/401,364, filed Sep. 21, 1999; which is a continuation-in-part of U.S. application Ser. No. 09/370,837, filed Aug. 9, 1999; which is a continuation-in-part of U.S. application Ser. No. 09/191,073, filed Nov. 12, 1998; which applications are hereby incorporated by reference in their entirety.
- 1. Field of the Invention
- This invention relates generally to CRF receptor antagonists, and to methods of treating disorders by administration of such antagonists to a warm-blooded animal in need thereof.
- 2. Description of the Related Art
- The first corticotropin-releasing factor (CRF) was isolated from ovine hypothalmi and identified as a 41-amino acid peptide (Vale et al.,Science 213:1394-1397, 1981). Subsequently, sequences of human and rat CRF were isolated and determined to be identical, but different from ovine CRF in 7 of the 41 amino acid residues (Rivier et al., Proc. Natl. Acad. Sci. USA 80:4851, 1983; Shibahara et al., EMBO J. 2:775, 1983).
- CRF has been found to produce profound alterations in endocrine, nervous and immune system function. CRF is believed to be the major physiological regulator of the basal and stress-release of adrenocorticotropic hormone (“ACTH”), β-endorphin, and other pro-opiomelanocortin (“POMC”)-derived peptides from the anterior pituitary (Vale et al.,Science 213:1394-1397, 1981). Briefly, CRF is believed to initiate its biological effects by binding to a plasma membrane receptor which has been found to be distributed throughout the brain (DeSouza et al., Science 224:1449-1451, 1984), pituitary (DeSouza et al., Methods Enzymol. 124:560, 1986; Wynn et al., Biochem. Biophys. Res. Comm. 110:602-608, 1983), adrenals (Udelsman et al., Nature 319:147-150, 1986) and spleen (Webster, E. L., and E. B. DeSouza, Endocrinology 122:609-617, 1988). The CRF receptor is coupled to a GTP-binding protein (Perrin et al., Endocrinology 118:1171-1179, 1986) which mediates CRF-stimulated increase in intracellular production of cAMP (Bilezikjian, L. M., and W. W. Vale, Endocrinology 113:657-662, 1983). The receptor for CRF has now been cloned from rat (Perrin et al., Endo 133(6):3058-3061, 1993), and human brain (Chen et al., PNAS 90(19):8967-8971, 1993; Vita et al., FEBS 335(1):1-5, 1993). This receptor is a 415 amino acid protein comprising seven membrane spanning domains. A comparison of identity between rat and human sequences shows a high degree of homology (97%) at the amino acid level.
- In addition to its role in stimulating the production of ACTH and POMC, CRF is also believed to coordinate many of the endocrine, autonomic, and behavioral responses to stress, and may be involved in the pathophysiology of affective disorders. Moreover, CRF is believed to be a key intermediary in communication between the immune, central nervous, endocrine and cardiovascular systems (Crofford et al.,J. Clin. Invest. 90:2555-2564, 1992; Sapolsky et al., Science 238:522-524, 1987; Tilders et al., Regul. Peptides 5:77-84, 1982). Overall, CRF appears to be one of the pivotal central nervous system neurotransmitters and plays a crucial role in integrating the body's overall response to stress.
- Administration of CRF directly to the brain elicits behavioral, physiological, and endocrine responses identical to those observed for an animal exposed to a stressful environment. For example, intracerebroventricular injection of CRF results in behavioral activation (Sutton et al.,Nature 297:331, 1982), persistent activation of the electroencephalogram (Ehlers et al., Brain Res. 278:332, 1983), stimulation of the sympathoadrenomedullary pathway (Brown et al., Endocrinology 110:928, 1982), an increase of heart rate and blood pressure (Fisher et al., Endocrinology 110:2222, 1982), an increase in oxygen consumption (Brown et al., Life Sciences 30:207, 1982), alteration of gastrointestinal activity (Williams et al., Am. J. Physiol. 253:G582, 1987), suppression of food consumption (Levine et al., Neuropharmacology 22:337, 1983), modification of sexual behavior (Sirinathsinghji et al., Nature 305:232, 1983), and immune function compromise (Irwin et al., Am. J. Physiol. 255:R744, 1988). Furthermore, clinical data suggests that CRF may be hypersecreted in the brain in depression, anxiety-related disorders, and anorexia nervosa. (DeSouza, Ann. Reports in Med. Chem. 25:215-223, 1990). Accordingly, clinical data suggests that CRF receptor antagonists may represent novel antidepressant and/or anxiolytic drugs that may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF.
- The first CRF receptor antagonists were peptides (see, e.g., Rivier et al., U.S. Pat. No. 4,605,642; Rivier et al.,Science 224:889, 1984). While these peptides established that CRF receptor antagonists can attenuate the pharmacological responses to CRF, peptide CRF receptor antagonists suffer from the usual drawbacks of peptide therapeutics including lack of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been reported. For example, substituted 4-thio-5-oxo-3-pyyrazoline derivatives (Abreu et al., U.S. Pat. No. 5,063,245) and substituted 2-aminothiazole derivatives (Courtemanche et al., Australian Patent No. AU-A-41399/93) have been reported as CRF receptor antagonists. These particular derivatives were found to be effective in inhibiting the binding of CRF to its receptor in the 1-10 μM range and 0.1-10 μM range, respectively.
- More recently, numerous small molecule CRR receptor antagonists have been proposed, including the compounds disclosed in the following patent documents: WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676, WO 94/13677, WO 95/10506, WO 95/33750, WO 96/35689, WO 97/00868, WO 97,35539, WO 97/35580, WO 97,35846, WO 97/44038, WO 98/03510, WO 98/05661, WO 98/08846, WO 98/08847, WO 98/11075, WO 98/15543, WO 98/21200 and WO 98/29413.
- Due to the physiological significance of CRF, the development of biologically-active small molecules having significant CRF receptor binding activity and which are capable of antagonizing the CRF receptor remains a desirable goal. Such CRF receptor antagonists would be useful in the treatment of endocrine, psychiatric and neurologic conditions or illnesses, including stress-related disorders in general.
- While significant strides have been made toward achieving CRF regulation through administration of CRF receptor antagonists, there remains a need in the art for effective small molecule CRF receptor antagonists. There is also a need for pharmaceutical compositions containing such CRF receptor antagonists, as well as methods relating to the use thereof to treat, for example, stress-related disorders. The present invention fulfills these needs, and provides other related advantages.
-
- including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein n, m, A, B, C, X, R, R1, R2, and Ar are as defined below.
- The CRF receptor antagonists of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders or illnesses, including stress-related disorders. Such methods include administering an effective amount of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition, to an animal in need thereof. Accordingly, in another embodiment, pharmaceutical compositions are disclosed containing one or more CRF receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.
- These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain procedures, compounds and/or compositions, and are hereby incorporated by reference in their entirety.
- The present invention is directed generally to compounds useful as corticotropin-releasing factor (CRF) receptor antagonists.
-
- including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof,
- wherein:
- n is 1 or 2;
- A and C are each independently nitrogen, carbon or CH;
- B is nitrogen or CR3;
- with the provisos that at least one of A, B and C is nitrogen; A, B and C are not all nitrogen; and either A-B or B-C is a double bond;
- X is nitrogen or Crq;
- Rq is hydrogen, alkyl or halo;
- Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- R is an optional substituent which, at each occurrence, is independently alkyl, alkylidenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein m is 0, 1, 2 or 3 and represents the number of R substituents;
- R1 is —C(H)0,1(R4)(R5) or —SO2R5;
- R2 is hydrogen, alkyl, haloalkyl or cyano;
- R3 is hydrogen, alkyl or haloalkyl;
- R4 is hydrogen, oxo, alkyl, substituted alkyl, alkylidenyl or halo; and
- R5 is a radical of the formula —Y-Z-R6, wherein
- Y is an alkanediyl, substituted alkanediyl, or a direct bond,
- Z is NH, —N(R7), O, S, SO2, C(═O), C(═O)O, OC(═O), NHC(═O), C(═O)NH, NH(SO2), (SO2)NH, NR8C(═O)O, or a direct bond;
- R6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocyclealkyl;
- R7 and R8 are alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
- R6 and R7 taken together with the nitrogen atom to which they are attached form a heterocyle ring or substituted heterocyle ring;
- or R4 and R5 taken together with the carbon atom to which they are attached form cycloalkyl, substituted cycloalkyl, cycloalkylcycloalkyl, substituted cycloalkylcycloalkyl, cycloalkylaryl, substituted cycloalkyaryl, cycloalkylheterocycle, or substituted cycloalkylheterocycle.
- As used herein, the above terms have the following meaning:
- “Alkyl” means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term “lower alkyl” has the same meaning as alkyl but contains from 1 to 6 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH2cyclopropyl, —CH2cyclobutyl, —CH2cyclopentyl, —CH2cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls, also referred to as “homocyclic rings,” and include di- and poly-homocyclic rings such as decalin and adamantyl. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”, respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like.
- “Alkylidenyl” represents a divalent alkyl from which two hydrogen atoms are taken from the same carbon atom, such as ═CH2, ═CHCH3, ═CHCH2CH3, ═C(CH3)CH2CH3, and the like.
- “Alkanediyl” means a divalent alkyl from which two hydrogen atoms are taken from the same carbon atom or from different carbon atoms, such as —CH2— —CH2CH2—, —CH2CH2CH2—, —CH(CH3)CH2—, and the like.
- “Aryl” means an aromatic carbocyclic moiety such as phenyl or naphthyl.
- “Arylalkyl” means an alkyl having at least one alkyl hydrogen atoms replaced with an aryl moiety, such as benzyl, —CH2—(1 or 2-naphthyl), —(CH2)2phenyl, —(CH2)3phenyl, —CH(phenyl)2, and the like.
- “Heteroaryl” means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
- “Heteroarylalkyl” means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as —CH2pyridinyl, —CH2pyrimidinyl, and the like.
- “Heterocycle” (also referred to herein as a “heterocycle ring”) means a 5- to 7-membered monocyclic, or 7- to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Thus, in addition to the aromatic heteroaryls listed above, heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
- “Heterocyclealkyl” means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as —CH2morpholinyl, and the like.
- “Cycloalkyl” means a saturated or unsaturated (but not aromatic) carbocyclic ring containing from 3-8 carbon atoms, such as cyclopentane, cyclohexane, cycloheptane, cyclohexene, and the like.
- “Cycloalkylcycloalkyl” means a cycloalkyl ring fused to a cycloalkyl ring, such as decalin.
- “Cycloalkylaryl” means a cycloalkyl ring fused to aryl, such as tetralin.
- “Cycloalkylheterocycle” means a cycloalkyl ring fused to a heterocycle ring.
- The term “substituted” as used herein means any of the above groups (e.g., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, etc.) wherein at least one hydrogen atom is replaced with a substituent. In the case of a keto substituent (“—C(═O)—”) two hydrogen atoms are replaced. When substituted, “substituents” within the context of this invention include halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —NRaRb, —NRaC(═O)Rb, —NRaC(═O)NRaNRb, —NRaC(═O)ORb—NRaSO2Rb, —ORa, —C(═O)Ra—C(═O)ORa, —C(═O)NRaRb, —OC(═O)NRaRb, —SH, —SRa, —SORa, —S(═O)2Ra, —OS(═O)2Ra, —S(═O)2ORa, wherein Ra and Rb are the same or different and independently hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocylealkyl or substituted heterocyclealkyl.
- “Halogen” means fluoro, chloro, bromo and iodo.
- “Haloalkyl” means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.
- “Alkoxy” means an alkyl moiety attached through an oxygen bridge (i.e., —O-alkyl) such as methoxy, ethoxy, and the like.
- “Alkylthio” means an alkyl moiety attached through a sulfur bridge (i.e., —S—alkyl) such as methylthio, ethylthio, and the like.
- “Alkylsulfonyl” means an alkyl moiety attached through a sulfonyl bridge (i.e., —SO2-alkyl) such as methylsulfonyl, ethylsulfonyl, and the like.
- “Alkylamino” and “dialkylamino” mean one or two alkyl moiety attached through a nitrogen bridge (i.e., —N-alkyl) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.
- “Hydroxyalkyl” means an alkyl substituted with at least one hydroxyl group.
- “Mono- or di(cycloalkyl)methyl” represents a methyl group substituted with one or two cycloalkyl groups, such as cyclopropylmethyl, dicyclopropylmethyl, and the like.
- “Alkylcarbonylalkyl” represents an alkyl substituted with a —C(═O)alkyl group.
- “Alkylcarbonyloxyalkyl” represents an alkyl substituted with a —C(═O)Oalkyl group or a —OC(═O)alkyl group.
- “Alkyloxyalkyl” represents an alkyl substituted with a —O-alkyl group.
- “Alkylthioalkyl” represents a alkyl substituted with a —S-alkyl group.
- “Mono- or di(alkyl)amino represents an amino substituted with one alkyl or with two alkyls, respectively.
- “Mono- or di(alkyl)aminoalkyl” represents a alkyl substituted with a mono- or di(alkyl)amino.
-
- of structure (I) represents —CH2CH2— or —CH═CH— optionally substituted with 1 or 2 R substituents (i.e., when n=1 and m=1 or 2), or —CH2CH2CH2— optionally substituted with 1, 2 or 3 R substituents (i.e., when n=2 and m=1, 2 or 3). Moieties in this regard are —CH2CH(R)—, —CH(R)CH2—, —CH(R)CH(R)—, —CH═C(R)—, —C(R)═CH—, —C(R)═C(R)—, —CH2CH2CH(R)—, —CH2CH(R)CH2—, —CH(R)CH2CH2—, —CH(R)CH2CH(R), —CH(R)CH(R)CH2 and —CH2CH(R)CH(R)—, wherein each occurrence of R is the same or different and independently selected from the R groups as set forth above.
-
- In one embodiment, n is 1 and m is 0 and the CRF receptor antagonists of this invention have structure (Ia). In another embodiment, n is 1 and m is 1 and the CRF receptor antagonists of this invention have structure (Ib) or (Ic).
-
-
-
-
-
-
-
- wherein R′ and R″ are the same or different and independently selected from, for example, alkyl such as methyl or ethyl.
-
- including optionally substituted analogs thereof as defined above.
-
- including optionally substituted analogs as defined above.
- As noted above, in one embodiment, R5 is a radical of the formula —Y-Z-R6, wherein
- Y is an alkanediyl, substituted alkanediyl, or a direct bond,
- Z is NH, —N(R7), O, S, SO2, C(═O), C(═O)O, OC(═O), NHC(═O), C(═O)NH, NH(SO2), (SO2)NH, NR8C(═O)O, or a direct bond;
- R6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
- R7 and R8 are the same or different and independently alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
- R6 and R7 taken together with the nitrogen atom to which they are attached form a heterocyle ring or substituted heterocyle ring.
- In one embodiment, the R5 moiety has Y as an alkanediyl, Z as a direct bond, and R6 as hydrogen. Such R5 moieties include alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., —CH(Et)2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
- In another embodiment, the R5 moiety has Y and Z being direct bonds while R6 includes an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, and chlorophenyl.
- In another embodiment, the R5 moiety has Y being a direct bond, Z being NH and R6 being as defined above. Thus, R6 may be hydrogen such that R5 is amino. Alternatively, R6 may be alkyl, such that R5 is an alkyl-substituted amino group, e.g., isopropylamino, and ethylamino. Alternatively, R6 may be an aryl or substituted aryl, such that R5 is an arylamino or substituted arylamino group, e.g., (methoxyphenyl)amino, ((trifluoromethoxy)phenyl)amino, (phenyl substituted phenyl)amino (also known as (biphenyl)amino), and (di(trifluoromethyl)phenyl)amino. Alternatively, R6 may be arylalkyl or substituted arylalkyl, such that R5 is an (arylalkyl)amino or (substituted arylalkyl)amino, e.g., (benzyl)amino (also known as (phenylmethyl)amino), (cyclopropylphenyl)amino, and (phenylethyl)amino. Accordingly to this embodiment, a preferred R4 is carbonyl.
- In another embodiment, the R5 moiety has Y being alkanediyl, Z being N(R7) and R6 being as defined above, where R7 is also as defined above. Accordingly, R5 is —Y—N(R7)(R6), i.e., includes a disubstituted amino moiety. In one embodiment, Y is methylene, i.e., —CH2—, so that R5 is —CH2—N(R7)(R6). As defined above, R6 and R7 are each selected from alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, or substituted heterocyclealkyl, where R6 may additionally be hydrogen. In one embodiment, R6 is hydrogen.
- Either one or both of the R6 and R7 groups of —N(R6)(R7) group may be alkyl or substituted alkyl, including saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., —CH(Et)2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
- Either one or both of the R6 and R7 groups of —N(R6)(R7) group may include an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, and chlorophenyl.
- Thus, —N(R6)(R7) may be, for example, (propyl)(cyclopropylmethyl) amino, (2-cyanoethyl)(methyl) amino, (2-cyanoethyl)(benzyl) amino, (ethyl)((2-(dimethylamino)ethyl)) amino, (2-hydroxyethyl)(benzyl) amino, di(2-hydroxyethyl) amino, (propyl)(2-hydoxyethyl) amino, (cyclohexyl)(ethyl) amino, (carboxymethyl)(methyl) amino, di(benzyl) amino, and ((2-hydroxy)(2-phenyl)ethyl))(methyl) amino.
-
-
- A heterocycle, as defined above, may include more heteroatoms (i.e., non-carbon atoms) than the nitrogen of —N(R6)(R7). For instance, the heterocycle may additionally include a second nitrogen, or an oxygen, or a sulfur. When a second nitrogen is present, the heterocycle will have two nitrogens, as in, e.g., piperazinyl. When an oxygen is present, the heterocycle will have both an oxygen and a nitrogen, as in, e.g., morpholinyl. When a sulfur is present, the heterocycle will have both a sulfur and a nitrogen, as in, e.g., thiomorpholinyl. These heterocycles having two or more heteroatoms may be substituted or non-substituted. For instance, the morpholinyl group may be substituted with two alkyl group, e.g., one methyl group on either side of the morpholinyl oxygen atom. When the heterocycle is a piperazinyl group, the nitrogen atom not explicitly shown in the formula —N(R6)(R7) may be substituted, where exemplary substituents are, for example, alkyl (e.g., methyl), substituted alkyl (e.g., 2-hydroxyethyl), or arylalkyl (e.g., benzyl).
- In another embodiment, Y is substituted alkanediyl, Z is a heteroatom or a direct bond, and R6 is as defined above. In a preferred embodiment, R4 is hydrogen. Thus, Y is an alkanediyl having a substituent, where the substituent may be, for example, hydroxy. The alkanediyl may be, for example, ethylene (i.e., —CH2—CH2—), or n-propylene (i.e., —CH2CH2CH2—), such that a substituted alkanediyl may be, e.g., —CH(OH)—CH2—, or —CH2—CH(OH)—CH2—
- In another embodiment, Y is alkanediyl, e.g., methylene (—CH2—), Z is amido, i.e., —NHC(═O)— or —C(═O)NH—, and R6 is as defined above. In a preferred embodiment, R4 is hydrogen. Thus, in one embodiment, R5 is —CH2—NHC(═O)—R6.
- In another embodiment, Y is alkanediyl, e.g., methylene (—CH2—), Z is sulfonylamido, i.e., —NHSO2— or —SO2NH—, and R6 is as defined above. In a preferred embodiment, R4 is hydrogen. Thus, in this embodiment, R5 is —CH2—NHSO2—R6.
- In another embodiment, Y and Z are direct bonds and R6 is as defined above. Thus, in this embodiment, R5 is —R6. In one embodiment, R4 is alkyl when R5 is —R6. In another embodiment, R4 is carbonyl when R5 is —R6. The R6 moiety may be alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl. Representative examples are methyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., —CH(Et)2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl. The R6 may be substituted alkyl, where a substituted alkyl may have one, two, or more substituents.
- In another embodiment, Y and Z are direct bonds and R6 is as defined above. Thus, in this embodiment, R5 is —R6. In one embodiment, R4 is hydrogen when R5 is —R6. In another embodiment, R4 is alkyl when R5 is —R6.
- In another embodiment, Y is a direct bond, Z is an ester group, i.e., —C(═O)O— or —OC(═O)—, and R6 is as defined above. In this embodiment, R5 is -ester-R6, and preferably R5 is —C(═O)—O—R6. In a one embodiment, R4 is hydrogen. The R6 moiety may be alkyl, preferably lower saturated alkyl, e.g., methyl, ethyl, propyl, etc.
- In another embodiment, Y is substituted alkanediyl, Z is a direct bond or oxygen, and R6 is as defined above. In this embodiment, R4 is preferably H. In an alternative embodiment, R4 is preferably alkyl. The alkanediyl may be a C1-C6 alkanediyl, e.g., methylene, ethylene, propylene, etc., and the substituent on the alkanediyl may be, e.g., hydroxy, halogen, amino, alkyl, etc. Accordingly, Y may be —CH(OH)— or —CH(OH)—CH2—, etc. In one embodiment, R6 is aryl or substituted aryl, e.g., phenyl or chlorophenyl. In another embodiment, R6 is alky or substituted alkyl, e.g., methyl or fluoromethyl.
- In another embodiment, R1 is SO2R5, where Y is a direct bond, Z is a direct bond, and R6 is as defined above. Accordingly, in this embodiment, R1 is —SO2—R6.
- In another embodiment, Y is alkanediyl, Z is O or S, and R6 is as defined above. For example, R5 may be —CH2—O—CH3 where Y is methylene, Z is O, and R6 is an alkyl, and specifically methyl. In a preferred embodiment, R4 is carbonyl. In another preferred embodiment, R4 is hydrogen. In yet another preferred embodiment, R4 is alkyl.
- In another embodiment, Y is a direct bond, Z is a direct bond, and R6 is alkyl or substituted alkyl of the formula ═CH2, ═CH—CH3, ═CH—CH2—CH3, ═CH—CH(CH3)—CH3, and homologs thereof. The substituent on the substituted alkyl may be, for example, hydroxyl or halogen (e.g., fluoro).
- The R6 moiety may be alkyl, saturated alkyl, unsaturated alkyl, lower alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated straight chain alkyls, saturated branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl, and branched chain alkynyl. Representative examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e., —CH(Et)2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
- The R6 moiety may be substituted alkyl, where substituted alkyls may have one or may substituents. Suitable substituents include trifluoromethyl, hydroxy, and halogen (i.e., fluoro, chloro, bromo, iodo).
- The R6 moiety may include an aromatic ring, such as aryl, substituted aryl, arylalkyl, substituted arylalkyl. Representative examples are phenyl, methoxyphenyl, and chlorophenyl.
- The R6 moiety may be heterocycle, heterocyclealkyl, substituted heterocycle, substituted heterocyclealkyl, e.g., furanyl, furanylmethyl, and thienyl, thienymethyl.
- In a preferred embodiment, R4 is hydrogen when R5 is —R6 and R6 is alkyl as set forth above. In another embodiment, R4 is alkyl when R5 is —R6 and R6 is alkyl as set forth above. In a preferred embodiment, R4 is hydrogen when R5 is —R6 and R6 includes an aromatic ring as set forth above. In another embodiment, R4 is alkyl when R5 is —R6 and R6 includes an aromatic ring as set forth above.
- Representative R1 groups of this invention specifically include each of the R1 groups disclosed in the Examples, as well as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, —CH(ethyl)2, —CH(n-propyl)2, —CH(n-butyl)2, —CH2CH2OCH3, —CH(methyl)(CH2OCH3), —CH(ethyl)(CH2OCH3), —CH(n-propyl)(CH2OCH3), —CH(n-butyl)(CH2OCH3), —CHC═—CH, —CH(methyl)(ethyl), —CH(methyl)(n-propyl), —CH(methyl)(n-butyl), —CH(methyl)(n-pentyl), —CH(methyl)(CH2CH2CH2CH(CH3)2), —CH(ethyl)(n-propyl), —CH(ethyl)(n-butyl), —CH(ethyl)(n-pentyl), ), —CH(n-propyl)(n-butyl), —CH(n-propyl)(n-pentyl), cyclopropyl, cyclobutyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 1,2,3,4-tetrahydronaphthyl (1 and 2), benzyl, 2-chlorobenzyl, —CH(methyl)(benzyl), —CH(ethyl)(benzyl), —CH(n-propyl)(benzyl), —CH(n-butyl)(benzyl), —CH2(cyclopropyl), —CH2(cyclobutyl), —CH2CH(methyl)CH2CH3, —CH2CH(ethyl)CH2CH3, —CH2C(CH3)3, —CH2C═—CH, —CH2C(═O)CH2CH3, —C(═O)cyclopropyl, —C(═O)NHbenzyl.
- Representative optional R groups of this invention include, when present, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, ═CH2, ═CHCH3 and phenyl.
- In more specific embodiments of this invention, representative Ar groups of this invention include (but are not limited to) the Ar groups identified in the Examples, as well as 2,4-dichlorophenyl, 2,4-dimethyl-phenyl, 2-chloro-4-methylphenyl, 2-methyl-4-chlorophenyl, 2,4,6-trimethylphenyl, 2-chloro-4-methoxyphenyl, 2-methyl-4-methoxyphenyl, 2,4-dimethoxyphenyl, 2-trifluoromethyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-trichloromethylphenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl 2-methoxy-4-methylphenyl, 4-methyl-6-dimethylaminopyridin-3-yl, 4-dimethylamino-6-methyl-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl and 4-dimethylamino-pyridin-3-yl.
- In another embodiment, compounds of this invention have structure (I) above, wherein R4 is hydrogen, keto, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, or C1-6alkyloxyC1-6alkyl; R5 is hydrogen, Ar, C1-6alkylAr, OAr, C1-8alkyl, C3-6cycloalkyl, O(C1-8alkyl), mono- or di(C3-6cycloalkyl)methyl, C3-6alkenyl, C3-6alkynyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxyAr, hydroxyC1-6alkyl, thienylC1-6alkyl, furanylC1-6alkyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, (C1-6alkylAr)amino, (C1-6alkyl)(Ar)amino, C1-6alkylcarbonylC1-6alkyl, sulfonyl(C1-8alky), —C(═O)C1-6alkyl, C1-6alkyl substituted with imidazolyl, or a radical of the formula —(C1-6alkanediyl)-O—(CO)0,1—Ar; or R4 and R5 taken together form a C3-8cycloalkyl or a C5-8cycloalkyl fused to Ar optionally substituted with one or more substituents independently selected from C1-6alkyl; and Ar is, at each occurrence, independently phenyl or naphthyl, optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, triflouromethyl, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino, and mono- or di(C1-6alkyl)amino; or an aromatic C3-12heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, triflouromethyl, hydroxy, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino, mono- or di(C1-6alkyl)amino, and piperidinyl.
- The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples, and may generally be utilized as the free base. Alternatively, the compounds of this invention may be used in the form of acid addition salts. Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Thus, the term “pharmaceutically acceptable salt” of structure (I) is intended to encompass any and all acceptable salt forms.
- In general, the compounds of structure (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth in the Examples. For example, the synthesis of structure (I) will generally proceed by synthesis of the desired sub-structure (I-1), (I-2), (I-3) or (I-4), as represented below. In turn, synthesis of each of these sub-structures is exemplified in the Examples.
-
-
-
-
-
-
-
-
- The effectiveness of a compound as a CRF receptor antagonist may be determined by various assay methods. Suitable CRF antagonists of this invention are capable of inhibiting the specific binding of CRF to its receptor and antagonizing activities associated with CRF. A compound of structure (I) may be assessed for activity as a CRF antagonist by one or more generally accepted assays for this purpose, including (but not limited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7:88, 1987) and Battaglia et al. (Synapse 1:572, 1987). As mentioned above, suitable CRF antagonists include compounds which demonstrate CRF receptor affinity. CRF receptor affinity may be determined by binding studies that measure the ability of a compound to inhibit the binding of a radiolabeled CRF (e.g., [125I]tyrosine-CFR) to its receptor (e.g., receptors prepared from rat cerebral cortex membranes). The radioligand binding assay described by DeSouza et al. (supra, 1987) provides an assay for determining a compound's affinity for the CRF receptor. Such activity is typically calculated from the IC50 as the concentration of a compound necessary to displace 50% of the radiolabeled ligand from the receptor, and is reported as a “Ki” value calculated by the following equation:
- where L=radioligand and KD=affinity of radioligand for receptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).
- In addition to inhibiting CRF receptor binding, a compound's CRF receptor antagonist activity may be established by the ability of the compound to antagonize an activity associated with CRF. For example, CRF is known to stimulate various biochemical processes, including adenylate cyclase activity. Therefore, compounds may be evaluated as CRF antagonists by their ability to antagonize CRF-stimulated adenylate cyclase activity by, for example, measuring cAMP levels. The CRF-stimulated adenylate cyclase activity assay described by Battaglia et al. (supra, 1987) provides an assay for determining a compound's ability to antagonize CRF activity. Accordingly, CRF receptor antagonist activity may be determined by assay techniques which generally include an initial binding assay (such as disclosed by DeSouza (supra, 1987)) followed by a cAMP screening protocol (such as disclosed by Battaglia (supra, 1987)).
- With reference to CRF receptor binding affinities, CRF receptor antagonists of this invention have a Ki of less than 10 μM. In a preferred embodiment of this invention, a CRF receptor antagonist has a Ki of less than 1 μM, and more preferably less than 0.25 μM (i.e., 250 nM). As set forth in greater detail below, the Ki values of representative compounds of this invention were assayed by the methods set forth in Example 9. Preferred compounds having a Ki of less than 1 μM are compound numbers I-2a-1 to I-2a-6, I-2a-8, I-2a-9, I-2a-12 to I-2a-25, I-2a-27 to I-2a-44, I-2a-46 to I-2a-76, I-2a-92, I-2a-173, I-4b-1 and I-4b-2. More preferred compounds having a Ki of less than 250 nM are compound numbers I-2a-1 to I-2a-4, I-2a-6, I-2a-8, I-2a-9, I-2a-12 to I-2a-18, I-2a-20 to I-2a-25, I-2a-28 to I-2a-36, I-2a-38 to I-2a-43, I-2a-46 to I-2a-73, I-2a-76, I-4b-1 and I-4b-2.
- The CRF receptor antagonists of the present invention demonstrate activity at the CRF receptor site, and may be used as therapeutic agents for the treatment of a wide range of disorders or illnesses including endocrine, psychiatric, and neurologic disorders or illnesses. More specifically, the CRF receptor antagonists of the present invention may be useful in treating physiological conditions or disorders arising from the hypersecretion of CRF. Because CRF is believed to be a pivotal neurotransmitter that activates and coordinates the endocrine, behavioral and automatic responses to stress, the CRF receptor antagonists of the present invention can be used to treat neuropsychiatric disorders. Neuropsychiatric disorders which may be treatable by the CRF receptor antagonists of this invention include affective disorders such as depression; anxiety-related disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, cardiovascular abnormalities such as unstable angina and reactive hypertension; and feeding disorders such as anorexia nervosa, bulimia, and irritable bowel syndrome. CRF antagonists may also be useful in treating stress-induced immune suppression associated with various diseases states, as well as stroke. Other uses of the CRF antagonists of this invention include treatment of inflammatory conditions (such as rheumatoid arthritis, uveitis, asthma, inflammatory bowel disease and G.I. motility), Cushing's disease, infantile spasms, epilepsy and other seizures in both infants and adults, and various substance abuse and withdrawal (including alcoholism).
- In another embodiment of the invention, pharmaceutical compositions containing one or more CRF receptor antagonists are disclosed. For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a CRF receptor antagonist of the present invention (i.e., a compound of structure (I)) and a pharmaceutically acceptable carrier and/or diluent. The CRF receptor antagonist is present in the composition in an amount which is effective to treat a particular disorder—that is, in an amount sufficient to achieve CRF receptor antagonist activity, and preferably with acceptable toxicity to the patient. Preferably, the pharmaceutical compositions of the present invention may include a CRF receptor antagonist in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more preferably from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
- Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a CRF receptor antagonist, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the CRF receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those disclosed inRemington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990.
- In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I). Further, in the case of an carboxylic acid (—COOH), esters may be employed, such as methyl esters, ethyl esters, and the like.
- With regard to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as recemates, reacemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
- In another embodiment, the present invention provides a method for treating a variety of disorders or illnesses, including endocrine, psychiatric and neurologic disorders or illnesses. Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the disorder or illness. Such methods include systemic administration of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions of CRF receptor antagonists include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the CRF receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
- As mentioned above, administration of a compound of the present invention can be used to treat a wide variety of disorders or illnesses. In particular, the compounds of the present invention may be administered to a warm-blooded animal for the treatment of depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome, stress-induced immune suppression, stroke, inflammation, Cushing's disease, infantile spasms, epilepsy, and substance abuse or withdrawal.
- The following examples are provided for purposes of illustration, not limitation.
- The CRF receptor antagonists of this invention may be prepared by the methods disclosed in Examples 1-12. Example 13 presents a method for determining the receptor binding activity (Ki), and Example 14 discloses an assay for screening compounds of this invention for CRF-stimulated adenylate cyclase activity.
-
- Compound (2)
- 2,4-dichloro-6-methyl-3-ethylester pyridine (1) (5.0 g, 21.36 mmoles), 4-heptylamine (21.36 mmoles) and triethyl amine (2.97 ml, 21.36 mmole) in ethanol were heated at reflux over night. Ethanol was evaporated and the residue was dissolved in ethyl acetate, washed with saturated solution of bicarbonate and brine. The organic layer was dried over sodium carbonate and concentrated in vacuum. Compound (2) was separated from (1) and (3) by silica gel column eluting with ethyl acetate-hexane.
- Compound (4)
- Compound (2) (20.0 mmoles) and hydrazine (25.0 mmoles) in ethanol was refluxed over night. Ethanol was evaporated and the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuum to give compound (4) which was used in the next step without further purification.
- Compound (5)
- A mixture of compound (4) (15.0 mmoles) and phosphorus oxychloride (15 ml) was refluxed for 3 hours, cooled, poured onto ice and neutralized by 1N NaOH. The aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried under sodium sulfate, and concentrated to yield the desired compound (5).
- Compound (6)
- To a solution of compound (5) (15.0 mmoles) in THF were added tri-n-butyl (1-ethoxy) vinyl tin (10.0 mmoles) and bis(triphenylphosphine) palladium (II) chloride (10% mole). The mixture was refluxed for 24 hours. The solution was partitioned between ethyl acetate and water. The organic phase washed with brine dried over sodium sulfate and concentrated in vacuum. The residue was dissolved in CCl4 and added at ice bath temperature to a suspension of pyridinium perbromide (75.0 mmoles) in CCl4. The temperature was raised to room temperature and stirred for 4 hours. The mixture was diluted with chloroform and washed successively with brine, hydrochloric acid solution (10%), saturated solution of bicarbonate, dried over sodium carbonate and concentrated in vacuum. Compound (6) was purified by silica gel column.
- Compound (7)
- To a solution of compound (6) (10.0 mmoles) in THF was added 1 M lithium hexamethyldisilizane in THF (11.0 mmoles) and the mixture was stirred at room temperature over night. The mixture was neutralized by 1N HCl diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was dissolved in THF and BH3-THF (1M) was added and the reaction was refluxed for 8 hours. The mixture was hydrolyzed with 1N HCl and diluted with ethyl acetate, the organic layer was washed with saturated solution of sodium bicarbonate and brine then concentrated in vacuum to give compound (7).
- Compound (8) (I-1a-1)
- To a solution of compound (7) (0.5 mmoles) in DMF was added NaH (0.6 mmoles) followed by 2,3-chloro-5-trifluomethyl-pyridine (0.6 mmoles). The mixture was heated at 90° C. over night. The reaction mixture was neutralized with 1N HCl and partitioned between water and ethyl acetate. The organic layer was washed with saturated solution of sodium bicarbonate and brine and concentrated in vacuum. Compound (8) was purified by silica gel column eluting with ethyl acetate-hexane.
-
- 2,4-Dichloro-3-hydroxymethyl-6-methylpyridine (10)
- Ethyl 2,4-dichloro-6-methylnicotinate (9) (8.04 g, 34.3 mmol) was dissolved in THF (40 mL) and added to a stirred suspension of LAH (6.52 g, 0.170 mmol) in THF (80 mL) at −78° C. The mixture was stirred for 6 hours at this temperature and for 1 hour at −30° C. followed by cautious treatment with water (5.5 mL), 15% aqueous NaOH (5.5 mL) and water (16.5 mL) with vigorous stirring. The mixture was warmed to room temperature and filtered. The white precipitate was washed liberally with ethyl acetate. The combined organic portions were dried (MgSO4) and concentrated under vacuum to afford 6.40 g (97%) of (10) as a colorless oil which solidified on standing: LCMS (MH+, 192).
- 2,4-Dichloro-6-methylpyridine-3-carboxaldehyde (11)
- DMSO (14.2 mL, 200 mmol) was added to a stirred solution of oxalyl chloride (8.7 mmol, 99 mmol) in dichloromethane (100 mL) at −70° C. After 15 min, alcohol (10) (6.40 g, 33.3 mmol) in dichloromethane (25 mL) was added, followed by triethylamine (56 mL). The mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was washed with aqueous sodium bicarbonate (75 mL), dried (MgSO4), and concentrated under vacuum. The residue was purified by column chromatography (elution with 10% ethyl acetate in hexanes) to afford 5.00 g (78%) of (11) as a pale yellow oil which solidified on standing: LCMS (MH+, 190), Rf 0.48 (20% ethyl acetate in hexanes).
- 2,4-Dichloro-6-methyl-3-[1-(1-hydroxyallyl)]pyridine (12)
- Vinylmagnesium bromide in THF (1.0 M, 6.7 mL, 6.7 mmol) was added to a stirred solution of aldehyde (11) (1.15 g, 6.05 mmol) in THF (20 mL) at −78° C. The mixture was stirred at this temperature for 30 min, warmed to room temperature and quenched with aqueous sodium bicarbonate (40 mL). The mixture was extracted with ethyl acetate (2×50 mL) and the combined extracts were dried (MgSO4) and concentrated under vacuum to afford 1.37 g of crude (12) a yellow oil: LCMS (MH+, 218), Rf 0.28 (20% ethyl acetate in hexanes).
- 2,4-Dichloro-6-methyl-3-(vinylcarbonyl)pyridine (13)
- The above material (12) and N-methylmorpholine N-oxide (NMO, 1.06 g, 9.05 mmol) were dissolved in dichloromethane (27 mL) and treated with 4 angstrom molecular sieves (1.3 g). The mixture was stirred for 20 min, and tetrapropylammonium perruthenate (TPAP, 65 mg) was added. The mixture was stirred for 1 hour. Some starting material persisted so additional NMO (1.06 g) and TPAP (65 mg) were added, and stirring was continued for 1 hour. The mixture was filtered (Celite), concentrated under vacuum, and the residue was purified on a silica gel column (elution with 10% ethyl acetate in hexanes) to afford 0.50 g (38%) of (13) as a pale yellow oil: LCMS (MH+, 216), Rf 0.52 (20% ethyl acetate in hexanes).
- 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyridin-4-one (14) and 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin-4-one (15)
- Enone (13) (920 mg, 4.26 mmol) was dissolved in ethanol (20 mL) and treated with 4-heptylamine (0.64 mL, 4.3 mmol). The mixture was heated at 60° C. for 16 hours and then was concentrated under vacuum. The residue was taken up in ethyl acetate (50 mL), washed with aqueous sodium bicarbonate (20 mL), dried (MgSO4), and again concentrated. The residue was purified on a silica gel column (elution with 5% ethyl acetate in hexanes for (14) and 25% ethyl acetate in hexanes for (15)) to afford 314 mg (25%) of (14) as a yellow oil followed by 214 mg (17%) of (15) as white solid. 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyridin-4-one (14): NMR, LCMS (MH+, 295), Rf 0.70 (30% ethyl acetate in hexanes); 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin-4-one (15): mp 82-85° C., NMR, LCMS (MH+, 295), Rf 0.14 (30% ethyl acetate in hexanes).
- Compound (16) (I-1 a-2)
- Compound (15) (68 mg, 0.23 mmol), TsOH.H2O (50 mg, 0.26 mmol) and hydrazone (93 mg, 0.35 mmol) were heated at 140° C. for 5 hours The mix was cooled to room temperature, diluted with aqueous NaHCO3 (2 mL) and extracted with EtOAc (4×2 mL). The combined extracts were dried (MgSO4), concentrated in vacuo the residue was purified by prep. TLC (elution with 30% EtOAc/hexane) to afford compound (16) (21 mg, 22%), LCMS (MH+, 417).
- Further representative compounds were prepared by the above procedure, the structure and analytical data for which are set forth in the following Table 1.
TABLE 1 Analytical Data for Representative Compounds Cpd. No. Ar R1 LCMS (I-1a-3) 2-chloro-4-trifluorophenyl 451 (MH+) (I-1a-4) 4-chloro-2-methylphenyl 397 (MH+) (I-1a-5) 2,4-dimethylphenyl 377 (MH+) (I-1a-6) 2,4-dichlorophenyl 417 (MH+) (I-1a-7) 2-chloro-4-trifluorophenyl 451 (MH+) (I-1a-8) 4-chloro-2-methylphenyl 397 (MH+) (I-1a-9) 2,4-dichlorophenyl 377 (MH+) (I-1a-10) 2,4-difluorophenyl 385 (MH+) -
- Compound (4′)
- Compound (2′) (20.0 mmoles) and 2,4-dichlorophenlyhydrazine (25.0 mmoles) in ethanol was refluxed overnight. Ethanol was evaporated and the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuum to give compound (4′) which was used in the next step without further purification.
- Compound (5′)
- A mixture of (4′) (15.0 mmoles) and phosphorus oxychloride (15 ml) was refluxed for 3 hours, cooled, poured onto ice and neutralized by 1N NaOH. The aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried under sodium sulfate, concentrated to yield the desired product (5′).
- Compound (6′)
- To a solution of compound (5′) (15.0 mmoles) in THF were added tri-n-butyl (1-ethoxy) vinyl tin (10.0 mmoles) and bis(triphenylphosphine) palladium (II) chloride (10.0% mole). The mixture was refluxed for 24 hours. The solution was partitioned between ethyl acetate and water. The organic phase washed with brine dried over sodium sulfate and concentrated in vacuum. The residue was dissolved in CCl4 and added at ice bath temperature to a suspension of pyridinium perbromide (75.0 mmoles) in CCl4. The temperature was raised to room temperature to a suspension of pyridinium perbromide (75.0 mmoles) in CCl4. The temperature was raised to room temperature and stirred for 4 hours. The mixture was diluted with chloroform and washed successively with brine, hydrochloric acid solution (10%), saturated solution of bicarbonate, dried over sodium carbonate and concentrated in vacuum. The compound (6′) was purified by silica gel column.
- Compound (7′)
- To a solution of (6′) (10.0 mmoles) in THF was added sodium hydride (11.0 mmoles) and the mixture was stirred at room temperature overnight. The mixture was neutralized by 1N HCl diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was dissolved in THF and BH3-THF (1M) was added and the reaction was refluxed for 8 hours. The mixture was hydrolyzed with 1N HCl and diluted with ethyl acetate, the organic layer was washed with saturated solution of sodium bicarbonate and brine then concentrated in vacuum to give compound (7′).
-
- α-phthalimide-2,4-trichloroacetophenone (1)
- α-2,4-trichloroacetophenone (15 gms, 67 mmol) was added with stirring to a suspension of potassium phtalimide (16 gms, 86 mmol) in N,N-dimethylformamide (70 ml) at 5° C. After 5 min., the resulting solution was allowed to warm to room temperature, followed by heating for 0.5 hr at 50° C. After heating the solution was concentrated on pump and the resulting solid was partitioned between ethyl acetate/sodium bicarbonate solution and the resulting organic layers were combined. These were dried and all solvent removed to yield solid. This solid was recrystallized from methylene chloride and ether to yield compound (1), 9.6 gms.
- Compound (2)
- A solution of α-phthalimide-2,4-trichloroacetophenone (1) (9.6 gms) in dimethylformamide dimethyl acetal (30 ml) and refluxed for 1 hour. After reflux, t.l.c. indicate the completion of the reaction and all solvent was removed on high vacuum to yield tan solid (2).
- 2-(2′,4′-Dichlorophenyl)-3-aminopyrazole (3)
- To a suspension of compound (2) (14 g, 36 mmol) in dry ethanol (300 mL) was added anhydrous hydrazine (1.2 g, 36 mmol). The tan suspension slowly turned into a clear dark brown solution. The solution was stirred at room temperature for 1 hr and more anhydrous hydrazine (1.2 g, 36 mmol) was added. The solution was heated to reflux for 2 hrs and a white solid formed. The reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate was concentrated and partitioned between aqueous saturated sodium bicarbonate solution and ethyl acetate. The ethyl acetate layer was washed with Brine, dried by sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to provide the desired product (3) as a brown sticky solid (7.7 g, 33.8 mmol, 94%), which was confirmed by GC/MS.
- 2-Methyl-4-Hydroxy-7-(2′,4′-Dichlorophenyl)-pyrrozolepyridine (4)
- A solution of compound (3) (7.7 g, 33.8 mmol), ethyl acetoacetate (8.4 g, 65 mmol) and 120 mg of p-tolunesulfonic acid monohydrate in 200 mL of benzene was refluxed for 2 hrs. The reaction mixture was concentrated and dissolved in 20 mL of diphenylether. The diphenylether was heated to 240° C. for 10 minutes, cooled and the solid was collected by filtration, and rinsed with diethyl ether. The product (4) was obtained as a brown solid (2.5 g, 8.4 mmol, 25%), which was confirmed by1H NMR.
- 2-Methyl-4-Chloro-7-(2′,4′-Dichlorophenyl)-pyrrozolepyridine (5)
- A mixture of compound (4) (2.0 g, 6.8 mmol) and phosphorous oxychloride (10 mL) as refluxed for 2 hr, cooled, poured onto a crack ice, neutralized by 1N NaOH. The aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried under sodium sulfate, concentrated to yield a yellow solid which was triturated in ether. The desired product (5) was obtained as a pale yellow solid (1.1 g, 3.2 mmol, 47%), which was identified by GC/MS, Elemental Analysis and1H NMR.
- 2-Methyl-4-(N-4-heptyl)-7-(2′,4′-Dichlorophenyl)-pyrrozolepyridine (6)
- A mixture of (5) (0.3 g, 0.96 mmol) and p-toluenesulfonic acid monohydrate (250 mg) in 0.8 mL of 4-heptylamine in a 5 mL Reacti-Vials was refluxed at 180° C. for 6 hours. The reaction mixture was cooled, partitioned between ethyl acetate and water. The organic layer was washed with Brine, dried under sodium sulfate, concentrated, purified by flash chromatography on silica gel (Hexane/EtOAc, 1:1) to provide the desired product (6) as a yellow oil (140 mg, 0.36 mmol, 37%), which was identified by GC/MS and1H NMR.
- Compound (7) (I-2a-1)
- A mixture of 2-methyl-4-(N-4-heptyl)-7-(2′,4′-Dichlorophenyl)-pyrrozolepyridine (6) (43.9 mgs, 0.11 mmoles), potassium carbonate (31.0 mgs, 0.22 mmoles) and 1,2-dibromoethane in butanone (2 ml) was heated to 85° C. overnight. The solvent was removed in vacuum and the residue was partitioned between ethyl acetate and water, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. Compound (7) was purified by silica gel column eluting with dichloromethane-methanol (10-1), and identified by LC/MS.1H NMR (CDCl3, TMS):0.93 (t, 6H); 1.37 (m, 4H); 1.61 (m, 4H); 2.58 (5, 3H); 3.67 (t, 24); 3.82 (m, 1H); 4.45 (t, 2H); 6.22 (s, 1H); 7.35 (d, 1H); 7.53 (s, 1H); 7.86 (d, 1H).
- Compound (8)
- A solution of compound (7) (43 mg, 0.1 mmol) in toluene (2 ml) was treated with activated manganese dioxide catalyst (100 mg) at reflux for 16 hrs. The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness and purified by Prepative TLC (silica gel) with ethyl acetate:hexane (1:1) to provide compound (8).
-
- 4-nitropyrazole (9).
- Pyrazole (Lancaster) (30.0 g, 441 mmol) was portionwise added to 220 ml of sulfuric acid 97% in an ice-bath. The mixture was heated at 55° C. and 30 ml of nitric acid 70% (0.5 mol, 1.1 eq.) were added slowly. The reaction mixture was then stirred at 55° C. for 3 hours (reaction checked by TLC Ethylacetate/Hexane 1/1 pyrazole Rf=0.4, 12 active, nitropyrazole Rf=0.6, UV active), cooled down, poured into 600 ml of ice-water and neutralized with 6N NaOH solution (pH=7). The product was then extracted with ethyl acetate (5×150 ml). The organic phases were combined, washed with water (100 ml), a brine solution (100 ml) and dried with sodium sulfate, filtered and concentrated by vacuum to yield the desired product (9) as a white solid (37.0 g, 326 mmol, 74%). GC/MS: m/z=113 (100%).
- 4-aminopyrazole (10).
- The 4-nitropyrazole (9) (15.0 g, 133 mmol) was added to a suspension of palladium on carbon 10% (7.0 g, 6.65 mmol, 5% mmol) in ethanol (100 ml). The mixture was shaken for 3 hours under hydrogen pressure (40 psi) at room temperature. The end of reaction checked by TLC (Ethylacetate/Hexane 1/1, 4-nitropyrazole Rf=0.6, UV active, 4-aminopyrazole Rf 0.1, UV active). The catalyst was removed by filtration through a pad of Celite and the solvent was evaporated. The product (10) was obtained as a burgundy oil (10.5 g, 126 mmol, 95%), which was used in the following step without purification. GC/MS: m/z=83 (100%).
- Imine (11).
- A solution of 4-aminopyrazole (10) (10.5 g, 126 mmol), ethylacetoacetate (18.0 g, 140 mmol, 1.05 eq.) and a catalytic amount of para-toluenesulfonic acid monohydrate (1.3 g, 6.65 mmol, 5%) in 100 mL of benzene was refluxed with a Dean-Stark trap for about 1 hour. The end of reaction checked by TLC (Ethylacetate/Hexane 1/1, 4-aminopyrazole Rf=0.1, imine Rf=0.5, UV active, brown after overnight). Solvents were removed under vacuum and the imine was purified by running through a short silica chromatography column to give the desired product (11) as a tan solid (22.4 g, 125 mmol, 91%). GC/MS: m/z=195 (100%).
- 5-Methyl-7-hydroxy-pyrazolo[4,3-b]pyridine (12).
- The imine (11) (7.03 g, 35.9 mmol) was added to a boiling solution of dioxane (30 mL) and diphenyl ether (30 mL). The mixture was heated until solid formed (5 min). The reaction mixture was continued heating for 2 more minutes. Heating was stopped. The end of the cylcization was checked by LC/MS (disappearance of 196). After cooling down at room temperature, 300 ml of diethyl ether were added the reaction mixture was stirred for 15 minutes. The solid was rinsed with diethyl ether. The desire product (12) was obtained as a tan crystalline solid (5.09 g, 34.1 mmol, 95%). LC/MS: [M+H]′=150.
- 5-Methyl-7-chloro-pyrazolo[4,3-b]pyridine (13).
- The cyclized compound (12) (4.58 g, 30.7 mmol) in phosphorus oxychloride (30 mL) was heated at 110° C. for 30 minutes. The end of the reaction was checked by LC/MS (disappearance of 150, appearance of 168). After cooling down at room temperature, the reaction mixture was poured on ice and pH was adjusted with a 6N NaOH solution to pH=5. The solid was collected with filtration and the mother aqueous layer was extracted with ethyl acetate (3×250 ml). The above solid was dissolved in the combined organic phases, washed with a brine solution (1×250 ml) and dried with sodium sulfate, filtered and concentrated. The crude product was purified by running through a short silica gel chromatography column to give the desired product (13) as a pale yellow solid (4.50 g, 26.8 mmol, 87%). GC/MS: m/z=167 (100%); LC/MS: [M+H]′=168.
- 3-Bromo-5-methyl-7-chloro-pyrazolo[4,3-b]pyridine (14).
- The chloro compound (13) (600 mg, 3.58 mmol) was dissolved in a mixture of water/methanol (12 mL/12 mL) in an ice-bath. A solution of bromine (629 mg, 3.94 mmol, 1.1 eq.) in a solution of H2O/MeOH 1 mL/1 mL) was added dropwise to the cooled mixture. After 10 minutes, the solution was clearer and the LC/Ms showed no more chloro compound. The reaction mixture was concentrated to remove the MeOH. The crude reaction mixture was extracted with ethyl acetate (3×50 ml). The organic phases were combined, washed with a brine solution (1×100 ml) and dried with sodium sulfate, filtered and concentrated by vacuum. The desired product (14) was obtained as a pale yellow solid. GC/MS: m/z=245, 247 (100%); LC/MS: [M+H]′=246, 248.
- 3-Bromo-5-methyl-7-(5-aminononane)-pyrazolo[4,3b]pyridine (15).
- Compound (14) (1.0 g, 0.4 mmol) and 5-aminononane (1.7 g, 12 mmol) and p-toluenesulfonic acid (1.5 g, 8 mmol) were heated in reaction vial at 160° C. over night. The residue was dissolved in ethyl acetate, washed with saturated solution of sodium bicarbonate, brine, dried with MgSO4 and concentrated in vacuum. The residue was triturated with toluene and the solid formed was isolated and dried in vacuum to give 912 mg of product (15) as a white solid. LCMS: (M+H)=353, 354.
- 3-(2,4-dichlorophenyl)-5-methyl-7-(5-aminononane)-pyrazolo[4,3b]pyridine (16).
- A mixture of compound (15) (100 mg, 0.27 mmol), 2,4-dichlorophenylboronic acid (63.7 mg), ethanol (0.6 ml), 2M solution of sodium carbonate (0.6 ml), Pd(PPh3)4 (10 mg) and toluene (1.6 ml) was heated at 160° C. over night. The solution was partitioned between EtOAc and water. The organic layer was dried with MgSO4 and concentrated in vacuum. The residue was purified by chromatography on silica gel to give 34 mg of product (16). LCMS (M+H)=419, 420.
- Compound (17) (I-2a-2)
- To compound (16) (34 mg, 0.08 mmol) in 2-butanone (3 ml) was added potassium carbonate (67.18 mg, 0.48 mmol) and dibromoethane (30.48 mg, 0.16 mmol) and the mixture was heated at reflux over night. The mixture was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate and concentrated in vacuum. The crude product was purified by chromatography on silica gel eluting with ethyl acetate-hexane (1-1) to give 10 mg of product (17) (referred in Table 2 below as “Cpd. No. (I-2a-2)”. LC/MS (M+H)=445, 446
- Further representative compounds of this invention were prepared by the procedures set forth in the above examples, the analytical data for which are set forth in the following Table 2.
TABLE 2 Analytical Data for Representative Compounds Cpd. No. Ar R1 Analytical Data (I-2a-1) 2,4-dichloro- phenyl 0.93 (t, 6H); 1.37 (m, 4H); 1.61 (m, 4H); 2.58 (5, 3H); 3.67 (t, 24); 3.82 (m, 1H); 4.45 (t, 2H); 6.22 (s, 1H); 7.35 (d, 1H); 7.53 (s, 1H); 7.86 (d, 1H). (I-2a-2) 2,4-dichloro- phenyl LC/MS (M + H) = 445, 446 (I-2a-3) 2,4-dichloro- phenyl LC/MS (MH+) = 376 (I-2a-4) 2,4-dichloro- phenyl LC/MS (M + H) = 387 (I-2a-5) 2,4-dichloro- phenyl LC/MS (M + H) = 401 (I-2a-6) 2,4-dichloro- phenyl LC/MS (M + H) = 415 (I-2a-7) 2,4-dichloro- phenyl LC/MS (M + H) = 415 (I-2a-8) 2,4-dichloro- phenyl LC/MS (M + H) = 449 (I-2a-9) 2,4-dichloro- phenyl LC/MS (M + H) = 431 (I-2a-10) 2,4-dichloro- phenyl LC/MS (M+ + 1) = 409 (I-2a-11) 2,4-dichloro- phenyl 7.87 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 2.1 Hz, 1 H), 7.42-7.29 (m, 6 H), 6.29 (s, 1 H), 5.83 (t, J = 7.7 Hz, 1 H), 4.51 (dd, J = 5.7, 5.1 Hz, 2 H), 3.86 (dd, J = 5.4, 4.8 Hz, 2 H), 2.51 (s, 3 H), 2.41-2.31 (m, 2 H), 1.14 (t, J = 7.7 Hz, 3 H); LCMS (M+ + 1) = 449. (I-2a-12) 2,4-dichloro- phenyl LC/MS 405 (MH+) (I-2a-13) 2,4-dichloro- phenyl LC/MS (MH+) = 390 (I-2a-14) 2,4-dichloro- phenyl LC/MS (MH+) = 418 (I-2a-15) 2,4-dichloro- phenyl LC/MS (MH+ = 419 (I-2a-16) 2,4-dichloro- phenyl LC/MS 417 (MH+) (I-2a-17) 2-chloro-4- methylphenyl LC/MS (MH+) = 397 (I-2a-18) 2-chloro-4- methylphenyl LC/MS (MH+) = 397 (I-2a-19) 2-chloro-4- methylphenyl LC/MS (MH+) = 413 (I-2a-20) 2-chloro-4- methylphenyl LC/MS (MH+) = 385 -
- Compound (19)
- Combined substituted chloropyrazolopyridine (18) (100 mg, 0.33 mmol), aminophenylethanol (133 mg, 0.97 mmol) and p-toluenesulfonic acid (124 mg, 0.65 mmol) in a sealed vial and heated at 120° C. for 3 hours. LCMS showed product peak (19) (MH+=413) and no starting material. The reaction mixture was used, as is, in the following step.
- Compound (20)
- A 48% aqueous solution of HBr (0.5 mL) was added to the reaction mixture containing (19) and the resulting mixture was heated overnight at 80° C. LCMS shows the product peak at MH+=395. The reaction mixture was poured onto ice, made basic with sodium hydroxide, and extracted with ethyl acetate. The organic layer was evaporated and dried to give (20) (134 mg, quantitative yield).
- Compound (21) (I-2a-21)
- A solution of (20) (105 mg, 0.268 mmol) in DMF (3 mL) was cooled in an ice bath. NaH (95%, 8 mg, 0.321 mmol) was added and the reaction mixture was stirred for 30 minutes. Added 4-bromoheptane (58 mg, 0.321 mmol) and stirred overnight. The reaction was quenched with aqueous NH4Cl and was concentrated. Brine and ethyl acetate were added followed by concentration of the organic layer. Prep TLC gave product compound (21) (6 mg, MS ion=493).
-
- Compound (2′)
- A mixture of (1′) (4.50 g, 30 mmol) (T. Huynh-Dinh et al.,J. Org. Chem. 40: 2825-2830, 1975) and phosphorous oxychloride (15 mL) was refluxed for 3 hrs, cooled, poured onto a crack ice, neutralized by 1N NaOH. The aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried under sodium sulfate, concentrated to yield the desired product (2′).
- Compound (3′)
- To a mixture of (2′) (3.37 g, 20 mmol) in methanol (20 mL) and water (20 mL) was added bromine (3.84 g, 24 mmol) in methanol (10 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was washed with sodium thiosulfate aqueous solution, extracted with ethyl acetate. The residue was purified by flash chromatography on silica gel to provide the desired product (3′).
- Compound (4′)
- A mixture of (3′) (2.50 g, 10 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in 3 mL of 4-heptylamine was refluxed by 120° C. for 5 hours. The reaction mixture was cooled, partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried under sodium sulfate, concentrated, purified by flash chromatography on silica gel to provide the desired product (4′).
- Compound (5′)
- To a stirring solution of (4′) (1.63 g, 5 mmol) in 10 mL of toluene was added tetrakis(triphenylphosphine)-(palladium(0) (578 mg, 0.5 mmol, 10% mol) and 2.0M aqueous sodium carbonate solution (8 mL) followed by addition of 2,4-dichloro-benzeneboronic acid (1.14 g, 6 mmol) in ethyl alcohol (8 mL). The resulting mixture was refluxed under nitrogen overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated ammonium chloride solution once. The organic layer was dried by sodium sulfate, filtered, concentrated. The residue was purified by flash chromatography on silica gel to provide the desired product (5′).
- Compound (6′)
- A mixture of (5′) (390 mg, 1 mmol), 1,2-dibromoethane (1 mL) and potassium carbonate (276 mg, 2 mmol) in 10 ML 2-butanol was refluxed for 4 hours. The reaction mixture was cooled, partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried under sodium sulfate, concentrated, purified by flash chromatography on silica gel to provide the desired product (6′).
-
- N-Oxide (4)
- A mixture of compound (3) (7.31 g, 50 mmol) prepared by the technique disclosed by Clayton and Kenyon (J. Chem. Soc., 2952-57, 1950), mCPBA (9.49 g, 55 mmol) in dichloromethane (200 mL) was stirred at room temperature for 2 hours. The reaction mixture was partitioned between dichloromethane and water. The dichloromethane was dried under sodium sulfate, filtered and concentrated to yield N-oxide (4) as the desired product.
- Compound (5)
- A mixture of N-oxide (4) (4.87 g, 30 mmol) and phosphorous oxychloride (15 mL) was refluxed for 3 hours, cooled, poured onto a crack ice, and neutralized by 1N NaOH. The aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried under sodium sulfate, and concentrated to yield compound (5).
- Compound (6)
- To a mixture of compound (5) (3.61 g, 20 mmol) in methanol (20 mL) and water (20 mL) was added bromine (3.84 g, 24 mmol) in methanol (10 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with sodium thiosulfate aqueous solution, and extracted with ethyl acetate. The ethyl acetate layers were combined, dried by sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to provide compound (6).
- Compound (7)
- A mixture of (6) (2.60 g, 10 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in 3 mL of 4-amino-heptane was refluxed at 120° C. for 5 hours. The reaction mixture was cooled, partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic layer was washed with Brine, dried under sodium sulfate, concentrated, purified by flash chromatography on silica gel to provide compound (7).
- Compound (8)
- To a stirring solution of compound (7) (1.69 g, 5 mmol) in 10 mL of toluene was added tetrakis(triphenylphosphine)-palladium(0) (Lancaster) (578 mg, 0.5 mmol, 10% mol) and 2.0M aqueous sodium carbonate solution (8 mL) followed by addition of 2,4-dichloro-benzeneboronic acid (1.14 g, 6 mmol) in ethyl alcohol (8 mL). The resulting tan mixture was refluxed overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated ammonium chloride solution once. The organic layer was dried by sodium sulfate, filtered, concentrated. The residue was purified by flash chromatography on silica gel to provide compound (8).
- Compound (9)
- A mixture of compound (8) (404 mg, 1 mmol), 1,2-dibromoethane (1 ml) and potassium carbonate (276 mg, 2 mmol) in 10 mL 2-butanol was refluxed for 4 hours. The reaction mixture was cooled, partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic layer was washed with Brine, dried under sodium sulfate, concentrated, purified by flash chromatography on silica gel to provide compound (9).
-
- Compound (11)
- Under nitrogen atmosphere, ethyl formate (7.38 g, 99.6 mmol) in anhydrous THF (100 mL) was added dropwise to a stirred mixture of NaH (1.75 g, 72.9 mmol) and compound (10) (6.93 g, 37.5 mmol) in THF (100 mL). The mixture was stirred over night. Additional portions of NaH and HCO2Et (2 equiv each) were added, and the mixture was refluxed for 30 min and then stirred at room temperature overnight. After solvent evaporation, the residue in ice cold water (100 mL) was adjusted to pH 6 with cold 6 N HCl and was extracted with CHCl3 (3×100 mL). The extract was washed with water (100 mL), dried (Na2SO4), and evaporated. The residue was triturated with hexane, which was decanted. Column chromatography of the residue on silica gel (using CHCl3 as eluant) led to compound (11).
- Compound (12)
- A solution of compound (11) (1.13 g, 5.31 mmol), methyl glycinate hydrochloride (1.00 g, 7.97 mmol), and sodium acetate (0.654 g, 7.97 mmol) in MeOH (40 mL) and H2O (10 mL) was stirred at room temperature for 48 hr. The mixture was extracted with CHCl3 (2×25 mL), and the organic extract was washed with water (20 mL), dried (Na2SO4), and evaporated to give compound (12).
- Compound (13)
- A solution of compound (12) (1.27 g, 4.5 mmol) in dry CH2Cl2 (25 mL) was cooled to 0° C. and treated with 1,5-diazabicyclo(4.3.0)non-5-ene (DBN, 1.12 g, 9.04 mmol) followed by ethyl chloroformate (0.735 g, 6.78 mmol). After refrigeration for 24 h, 0.2 mL of DBN and 0.1 mL of ClCO2Et were added to consume the small quantity of remaining starting material, then an additional equivalent of DBN (0.6 g) was added, and the mixture was refrigerated for 20 h. Solvent was evaporated and the gummy residue was chromatographed on a silica gel column (CHCl3 eluant) to give compound (13).
- Compound (14)
- A solution of compound (13) (2.9 g, 9.9 mmol), ethyl acetoacetate (9.9 mmol) and p-toluenesulfonic acid monohydrate (0.01 mmol) in 10 mL of xylene was refluxed for 2 hrs. Half of solvent was removed by slow distillation over 1 hr. The solution was allowed to cool to room temperature and a solution of potassium t-butoxide (9.8 mmol) in 24 mL of ethanol was added. This mixture was heated to 80° C. for 2 hrs. The mixture was diluted with ethyl acetate and washed with saturated NaCl solution. The organic layer was dried with sodium sulfate and concentrated in vacuo. The residue was triturated with ether and used in the next step without further purification. The solid obtained was treated with an aqueous solution of LiOH (18 mL, 1M) in methanol and the mixture was heated at reflux for 18 hr. The solution was poured into a solution of 1M HCl (18 mL). The solution was extracted with ethyl acetate, washed with brine, dried with sodium sulfate and concentrated in vacuo to give a solid which was heated in diphenyl ether at 230° C. for 1.5 hr. The solid obtained after diluting with ether was dried in vacuo. The solid was heated at 100 C in POCl3 for 2 hrs then allowed to cool to room temperature and poured into ice and neutralized with NaHCO3. The solution was extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate and concentrated in vacuo. Compound (14) was purified by flash chromatography on silica gel silica gel eluting with ethyl acetate-hexane (1:3).
- Compound (15)
- A mixture of (14) (0.15 g, 0.5 mmol), p-toluenesulfonic acid monohydrate (1 mmol) and 2-amino butanol was heated at 160° C. over night. The reaction mixture was cooled and purified by flash chromatography on silica gel (Hexane/EtOAc, 5:1) to give compound (15).
- Compound (16)
- Compound (15) (0.1 g, 0.28 mmol) was dissolved in 48% HBr and heated at 130° C. for 3 days. The mixture was cooled to room temperature, cautiously basified with solid NaOH, and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated in vacuo to afford compound (16).
- Compound (17)
- Sodium hydride mineral oil dispersion (60%, 0.1 mmol) was added to stirred solution of compound (16) (30 mg, 0.09 mmol) in DMF. After 15 min, 1-bromopropane was added and stirring was continued for 10 minutes. The mixture was diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The combined extracts were concentrated in vacuo, and the residue was purified by preparative TLC (elution with 10% methanol in dichloromethane) to afford compound (17).
-
- Compound (2′)
- To a mixture of (1′) (Imai,Chem Pharm. Bull. 12:1030-1039, 1964) (3.34 g, 20 mmol) in methanol (20 mL) and water (20 mL) was added bromine (3.84 g, 24 mmol) in methanol (10 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was washed with sodium thiosulfate aqueous solution, extracted with ethyl acetate. The ethyl acetate layers were combined, dried by sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to provide the desired product (2′).
- Compound (3′)
- A mixture of (2′) (2.48 g, 10 mmol) and p-toulenesulfonic acid monohydrate (100 mg) in 3 mL of 4-heptylamine was refluxed at 120° C. for 5 hours. The reaction mixture was cooled, partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried under sodium sulfate, concentrated, purified by flash chromatography on silica gel to provide the desired product (3′).
- Compound (4′)
- To a stirring solution of (3′) (1.63 g, 5 mmol) in 10 mL of toluene was added tetrakis(triphenylphosphine)-(palladium(0) (578 mg, 0.5 mmol, 10% mol) and 2.0M aqueous sodium carbonate solution (8 mL) followed by addition of 2,4-dichloro-benzeneboronic acid (1.14 g, 6 mmol) in ethyl alcohol (8 mL). The resulting mixture was refluxed under nitrogen overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated ammonium chloride solution once. The organic layer was dried by sodium sulfate, filtered, concentrated. The residue was purified by flash chromatography on silica gel to provide the desired product (4′).
- Compound (5′)
- A mixture of (4′) (390 mg, 1 mmol), 1,2-dibromoethane (1 mL) and potassium carbonate (276 mg, 2 mmol) in 10 ML 2-butanol was refluxed for 4 hours. The reaction mixture was cooled, partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried under sodium sulfate, concentrated, purified by flash chromatography on silica gel to provide the desired product (5′).
-
- Compound (7′)
- Under nitrogen atmosphere, ethyl formate (7.38 g, 99.6 mmol) in anhydrous THF (100 mL) was added dropwise to a stirred mixture of NaH (1.75 g, 72.9 mmol) and compound (6′) (6.93 g, 37.5 mmol) in THF (100 mL). The mixture was stirred over night. Additional portions of NaH and HCO2Et (2 equiv each) were added, and the mixture was refluxed for 30 min and then stirred at room temperature overnight. After solvent evaporation, the residue in ice cold water (100 mL) was adjusted to pH 6 with cold 6 N HCl and was extracted with CHCl3 (3×100 mL). The extract was washed with water (100 mL), dried (Na2SO4), and evaporated. The residue was triturated with hexane, which was decanted. Column chromatography of the residue on silica gel (using CHCl3 as eluant) led to compound (7′).
- Compound (8′)
- A solution of compound (7′) (1.13 g, 5.31 mmol), methyl glycinate hydrochloride (1.00 g, 7.97 mmol), and sodium acetate (0.654 g, 7.97 mmol) in MeOH (40 mL) and H2O (10 mL) was stirred at room temperature for 48 hr. The mixture was extracted with CHCl3 (2×25 mL), and the organic extract was washed with water (20 mL), dried (Na2SO4), and evaporated to give compound (8′).
- Compound (9′)
- A solution of compound (8′) (1.27 g, 4.5 mmol) in dry CH2Cl2 (25 mL) was cooled to 0° C. and treated with 1,5-diazabicyclo(4.3.0)non-5-ene (DBN, 1.12 g, 9.04 mmol) followed by ethyl chloroformate (0.735 g, 6.78 mmol). After refrigeration for 24 h, 0.2 mL of DBN and 0.1 mL of ClCO2Et were added to consume the small quantity of remaining starting material, then an additional equivalent of DBN (0.6 g) was added, and the mixture was refrigerated for 20 h. Solvent was evaporated and the gummy residue was chromatographed on a silica gel column (CHCl3 eluant) to give compound (9′).
- Compound (10′)
- HCl gas was bubbled into a solution of compound (9′) and acetonitrile in dioxane at room temperature. The reaction was monitored by TLC until all starting material was consumed. The mixture was basified with 10% aqueous ammonium hydroxide and then was extracted with ethyl acetate. The solid obtained was washed with water and dried to give brown solid. The solid was then treated with POCl3 and heated at 100° C. for 2 hrs. POCl3 was evaporated in vacuo and the residue obtained was neutralized with 2N NaOH, and extracted with ethyl acetate. The organic layer was dried with MgSO4 and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Hexane/EtOAc, 4:1) to give compound (10′).
- Compound (11′)
- A mixture of (10′) (0.15 g, 0.5 mmol), p-toluenesulfonic acid monohydrate (1 mmol) and 2-amino butanol was heated at 160° C. over night. The reaction mixture was cooled and purified by flash chromatography on silica gel (Hexane/EtOAc, 5:1) to give compound (11′).
- Compound (12′)
- Compound (11′) (0.1 g, 0.28 mmol) was dissolved in 48% HBr and heated at 130° C. for 3 days. The mixture was cooled to room temperature, cautiously basified with solid NaOH, and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated in vacuo to afford compound (12′).
- Compound (13′)
- Sodium hydride mineral oil dispersion (60%, 0.1 mmol) was added to stirred solution of compound (12′) (30 mg, 0.09 mmol) in DMF. After 15 min, 1-bromopropane was added and stirring was continued for 10 minutes. The mixture was diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The combined extracts were concentrated in vacuo, and the residue was purified by preparative TLC (elution with 10% methanol in dichloromethane) to afford compound (13′).
-
- 2-Amino-5-methyl-1-(2,4,6-trimethylphenyl)-1H-pyrrole-3-carbonitrile (3)
- A solution of acetol (1) (20.0 mL, 0.260 mol), 2,4,6-trimethylaniline (2) (36.5 mL, 0.260 mol), and 4-toluenesulfonic acid monohydrate (0.20 g) were refluxed in benzene (115 mL) using a Dean-Stark trap to remove water. After 2 hours, malonitrile (16.4 mL, 0.260 mol) was added and heating was continued for 14 hours. The mixture was cooled to room temperature, concentrated, and the residue chromatographed (elution with 15% ethyl acetate in hexanes) to afford 27.0 g (43%) of compound (3) as a brown oil.
- N-[3-Cyano-5-methyl-1-(2,4,6-trimethylphenyl)-1H-pyrrol-2-yl]acetamide (4)
- A mixture of compound (3) (25.3 g, 0.106 mol) and acetic anhydride (11.0 mL, 0.117 mol) were refluxed in acetic acid (25 mL) for 45 minutes, cooled to room temperature, poured onto crushed ice and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate, dried, and concentrated to give 33.6 g (100%) of compound (4) as a yellow foam.
- 2,6-Dimethyl-7-(2,4,6-trimethylphenyl)-3,7-dihydro-pyrrol[2,3-d]pyrimidin-4-one (5)
- A mixture of compound (4) (32.1 g, 0.144 mol) and 85% phosphoric acid (30 mL) was heated at 130° C. for 30 minutes. The resulting mixture was cooled to room temperature, poured into ice water with vigorous stirring, and the resulting precipitate was filtered and dried under vacuum to afford 21.6 g (67%) of compound (5) as a pink solid.
- 4-Chloro-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-3,7-dihydro-pyrrol[2,3-d]pyrimidine (6)
- A mixture of compound (5) (18.3 g, 65.0 mmol) in POCl3 (30 mL) was refluxed for 3 hours, cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The combined organic extracts were washed with aqueous sodium bicarbonate, dried, and concentrated under vacuum. The residue was chromatographed (elution with 10% ethyl acetate in hexanes) to afford 16.3 g (84%) of compound (6) as a tan powder.
- 4-Chloro-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-5-(2-chloroacetyl)-3,7-dihydropyrrolo[2,3-d]pyrimidine (7)
- Compound (6) (11.2 g, 37.4 mmol) was added to a chloroform solution (150 ml) or 20 equivalents of aluminum chloride and 25 equivalents of chloracetyl chloride. The solution was heated at reflux for 16 hrs. The organic layer was departed and the water layer extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to yield compound (7).
- 4-(4-heptylamino)-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-5-(2-chloroacetyl)-3,7-dihydropyrrolo[2,3-d]pyrimidine (8)
- A mixture of compound (7) (730 mg, 2 mmol), 4-aminoheptane (250 mg, 2.2 mmol) and triethylamine (250 mg, 2.5 mmol) were stirred at ambient temperature for 16 hours. The solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and evaporated to dryness to provide compound (8).
- Compound (9)
- A solution of (8) (440 mg, 1 mmol) in THF (10 ml) was cooled to 0° C. and a 1M solution of lithium hexamethyldisilizane in THF (1 ml) was slowly added. The reaction was heated at reflux for 16 hrs, evaporated to dryness, and purified by flash chromatography with ethyl acetate and hexane to provide compound (9).
-
- 5-Allyl-4,6-dichloro-2-methylpyrimidine (10)
- Acetamidine hydrochloride (11.2 g, 119 mmol) was added to a stirred solution of sodium methoxide (6.41 g, 119 mmol) in methanol (180 mL). After 5 min, diethyl allylmalonate (18 mL, 91 mmol) was added and the mixture was heated to reflux for 15 h, cooled to rt, and concentrated under vacuum to afford 20 g of the crude pyridinone as a white solid. This material was heated to reflux in phosphorus oxychloride (100 mL) for 5 h. The mixture was cooled to rt, poured over crushed ice (200 mL), neutralized with powdered NaHCO3, and extracted with ethyl acetate. The combined extracts were dried (MgSO4), concentrated in vacuo, and the residue was chromatographed (elution with 10% ethyl acetate in hexanes) to afford 7.32 g (30%) of pyrimidine (10) as a pale yellow oil.
- 5-Allyl-4-chloro-6-(2,4-dichloroanilino)-2-methylpyrimidine (11)
- Sodium hydride mineral oil dispersion (60%, 1.38 g, 34.5 mmol) was added to a stirred solution of pyrimidine (10) (3.50 g, 17.2 mmol) and 2,4-dichloroaniline (3.07 g, 18.9 mmol) in DMF (40 mL). After 25 min, the mixture was poured into water (100 mL) and extracted with dichloromethane. The combined extracts were dried (MgSO4), concentrated under vacuum, and the residue was chromatographed (elution with dichloromethane) to afford 2.09 g (37%) of pyrimidine (11) as a white powder.
- 4-Chloro-1-(2,4-dichlorophenyl)-6-methyl-5,7-diazaindole (12)
- Sodium periodate (3.83 g, 17.9 mmol) was added to a stirred solution of (11) (1.94 g, 5.90 mmol) in 3:1 acetone-water (55 mL). The mixture was heated briefly to obtain homogeneity, and a 2.5% solution of osmium tetroxide in t-butanol (0.4 mL) was added. After 20 h, the mixture was diluted with water (50 mL) and saturated sodium thiosulfate (50 mL), and extracted with ethyl acetate. The combined extracts were concentrated under vacuum, and the residue was stirred in dichloromethane (40 mL) and 4 N HCl (5 mL) for 4 h. The mixture was poured into saturated NaHCO3, extracted with dichloromethane, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed (elution with dichloromethane) to afford 0.929 g (50%) of diazaindole (12) as a white solid.
- 3-Bromo-1-(2,4-dichlorophenyl)-4-(4-heptylamino)-6-methyl-5,7-diazaindole (13)
- Bromine (0.077 mL, 1.5 mmol) was added to a stirred solution of (12) (214 mg, 0.685 mmol) in dioxane (21 mL). After 4 hours, the mixture was diluted with aqueous NaCl, and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated under vacuum to afford the crude bromide. This material was taken up 4-heptylamine (3 mL) and heated at 90° C. for 45 min. The resulting mixture was cooled to room temperature, concentrated under vacuum, and the residue was purified by preparative TLC (elution with 15% ethyl acetate in hexanes) to afford 227 mg (70%) of (13) as a yellow oil which solidified on standing.
- N-Allyl-3-bromo-1-(2,4-dichlorophenyl)-4-(4-heptyl)amino-6-methyl-5,7-diazaindole (14)
- Sodium hydride mineral oil dispersion (60%, 80 mg, 2.0 mmol) was added to a stirred solution of (13) (186 mg, 0.396 mmol) in DMF (5 mL). After 10 min, allyl iodide (0.15 mL, 1.6 mmol) was added, and stirring was continued for 90 min. The mixture was diluted with water and aqueous NaCl, and extracted with ethyl acetate. The combined extracts were dried (MgSO4), concentrated under vacuum, and the residue was purified by preparative TLC (elution with 5% ethyl acetate in hexanes) to afford 117 mg (58%) of (14) as a white solid.
- Compound (15) (I-4b-1)
- Tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) was added to a stirred solution of (14) (83 mg, 0.16 mmol) and potassium acetate (85 mg, 0.87 mmol) in DMF (3 ml), and the resulting mixture was heated at 83° C. for 45 min. The mixture was cooled to room temperature, poured into aqueous NaCl, and extracted with ethyl acetate. The combined extracts were concentrated under vacuum, and the residue was purified by preparative TLC (elution with 15% ethyl acetate in hexanes) to afford 59 mg (86%) of (15) as a colorless oil.1H-NMR (300 MHz, CDCl3) δ 7.57 (d, J=2.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.6, 2.3 Hz, 1H), 6.98 (s, 1H), 5.38 (br s, 1H), 5.12 (br s, 1H), 4.93 (h, J=5.0 Hz, 1H), 4.03 (br s, 2H), 2.54 (s, 3H), 1.71-1.48 (m, 4H), 1.38-1.26 (m, 4H), 0.92 (t, J=7.4 Hz, 6H); LCMS (MH+, 429).
- Compound (16) (I-4b-2)
- Olefin (15) (9.4 mg, 0.022 mmol) and 10% palladium on activated charcoal (3 mg) were stirred in ethyl acetate (2 mL) under a balloon of hydrogen for 5 h. The mixture was filtered through a plug of Celite, concentrated under vacuum, and the residue was purified by preparative TLC (elution with 15% ethyl acetate in hexanes) to afford 4.9 mg (52%) of (16) as a colorless oil:1H-NMR (300 MHz, CDCl3) δ 7.55 (d, J=2.7 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.7, 2.7 Hz, 1H), 6.63 (br s, 1H), 4.85 (h, J=4.9 Hz, 1H), 3.43 (dd, J=12.3, 4.8 Hz, 1H), 3.23-3.19 (m, 1H), 3.22 (dd, J=12.0, 9.6 Hz, 1H), 2.54 (s, 3H), 1.68-1.43 (m, 4H), 1.39-1.25 (m, 7H), 0.95-0.89 (m, 6H); LCMS (MH+, 431).
-
- Ethyl 2-Amino-5-methyl-1-(2,4,6-trimethylphenyl)-1H-pyrrole-3-carboxylate (3′)
- A solution of acetol (1′) (20 mL, 0.26 mol), 2,4,6-trimethylaniline (2′) (36.5 mL, 0.260 mol), and 4-toluenesulfonic acid monohydrate (0.21 g) were refluxed in benzene (115 mL) using a Dean-Stark trap to remove water. After 2 hours, ethyl cyanoacetate (27.7 mL, 0.26 mol) was added and heating was continued for 14 hours. The mixture was cooled to room temperature, concentrated, and the residue chromatographed (elution with 15% ethyl acetate in hexanes) to afford 21.4 g (29%) of compound (3′) as a yellow oil.
- 3-Carboethoxy-4-hydroxy-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-1H-pyrrolo[2,3-b]pyridine (4′)
- A solution of compound (3′) (12.3 g, 43.0 mmol), ethyl 3-ethoxycrotonate (6.79 g, 43.0 mmol) and 4-toluenesulfonic acid monohydrate (0.50 g) in xylene (100 mL) were refluxed for 30 minutes. The solvent was distilled off over an additional 30 minutes, and the mixture was cooled to room temperature. Potassium t-butoxide (4.82 g, 43.0 mmol) in absolute ethanol (50 mL) was added and the mixture was heated at 80° C. for 3 hours, cooled to room temperature, treated with acetic acid (2.50 mL) and concentrated under vacuum. The residue was taken up in ethyl acetate, and treated with diethyl ether to precipitate 6.91 g (46%) of compound (4′) as a white powder.
- 4-Hydroxy-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-1H-pmrrolo[2,3-b]pyridine (5′)
- Compound (4′) (4.11 g, 11.7 mmol) in 1.0 M lithium hydroxide (25 mL) and ethanol (15 mL) was heated at reflux for 17 hours. The mixture was cooled to room temperature, neutralized with dilute aqueous hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed with aqueous sodium chloride, dried, and concentrated under vacuum. This material was heated at 200° C. for 2 hours in diphenyl ether (2.5 mL), cooled to room temperature, and crystallized from methanol-ethyl acetate to afford 1.41 g (43%) of compound (5′) as a white powder.
- 4-Chloro-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-1H-pyrrolo[2,3-b]pyridine (6′)
- Compound (6′) was prepared from compound (5′) according to the same procedure as above used in the preparation of compound (6).
- 4-Chloro-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-5-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridine (7′)
- Compound (7′) was prepared from compound (6′) according to the same procedure as disclosed above in the preparation of compound (7).
- 4-(4-Heptylamino)-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-5-(2-chloroacetly)-1H-pyrrolo[2,3-b]pyridine (8′)
- Compound (8′) was prepared from compound (7′) according to the same procedure as disclosed above in the preparation of compound (8).
- Compound (9′)
- Compound (9′) was prepared from compound (8′) according to the same procedure as used above in the preparation of compound (9). Similar compounds wherein the 2,4,6-trimethylphenyl group is replaced with 4-methoxyphenyl (MS/MH+=392), or with 2-trifluoromethyl-4-isopropylphenyl (MS/MH+=458), may be made by the same procedure, but employing the appropriately-substituted starting material 2′ in place of 2,4,6-trimethylaniline.
-
- 2,4-Dichloro-3-hydroxymethyl-6-methylpyridine (11′)
- Ethyl 2,4-dichloro-6-methylnicotinate (10′) (8.04 g, 34.3 mmol) was dissolved in THF (40 mL) and added to a stirred suspension of LAH (6.52 g, 170 mmol) in THF (80 mL) at −78° C. The mixture was stirred for 6 h at this temperature and 1 h at −30° C. and treated cautiously with water (5.5 mL), 15% aqueous NaOH (5.5 mL) and water (16.5 mL) with vigorous stirring. The mixture was warmed to room temperature and filtered. The white precipitate was washed liberally with ethyl acetate. The combined organic portions were dried (MgSO4) and concentrated under vacuum to afford 6.40 g (97%) of (11′) as a colorless oil which solidified on standing: LCMS (MH+, 192).
- 2,4-Dichloro-6-methylpyridine-3-carboxaldehyde (12′)
- DMSO (14.2 mL, 200 mmol) was added to a stirred solution of oxalyl chloride (8.7 mmol, 99 mmol) in dichloromethane (100 mL) at −70° C. After 15 min, alcohol (11′) (6.40 g, 33.3 mmol) in dichloromethane (25 mL) was added, followed by triethylamine (56 mL), and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was washed with aqueous sodium bicarbonate (75 mL), dried (MgSO4), and concentrated under vacuum. The residue was purified by column chromatography (elution with 10% ethyl acetate in hexanes) to afford 5.00 g (78%) of (12′) as a pale yellow oil which solidified on standing: LCMS (MH+, 190), Rf 0.48 (20% ethyl acetate in hexanes).
- 2,4-Dichloro-6-methyl-3-(vinylcarbonyl)pyridine (14′)
- Vinylmagnesium bromide in THF (1.0 M, 6.7 mL, 6.7 mmol) was added to a stirred solution of aldehyde (12′) (1.15 g, 6.05 mmol) in THF (20 mL) at −78° C. The mixture was stirred at this temperature for 30 min, warmed to room temperature and quenched with aqueous sodium bicarbonate (40 mL). The mixture was extracted with ethyl acetate (2×50 mL) and the combined extracts were dried (MgSO4) and concentrated under vacuum to afford 1.37 g of crude (13′) a yellow oil: LCMS (MH+, 218), Rf 0.28 (20% ethyl acetate in hexanes).
- The above material and N-methylmorpholine N-oxide (NMO, 1.06 g, 9.05 mmol) were dissolved in dichloromethane (27 mL) and treated with 4 angstrom molecular sieves (1.3 g). The mixture was stirred for 20 min, and tetrapropylammonium perruthenate (TPAP, 65 mg) was added. The mixture was stirred for 1 h. Some starting material persisted so additional NMO (1.06 g) and TPAP (65 mg) were added, and stirring was continued for 1 h. The mixture was filtered (Celite), concentrated under vacuum, and the residue was purified on a silica gel column (elution with 10% ethyl acetate in hexanes) to afford 0.50 g (38%) of (14′) as a pale yellow oil: LCMS (MH+, 216), Rf 0.52 (20% ethyl acetate in hexanes).
- 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyridin-4-one (15′) and 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin-4-one (16′)
- Enone (14′) (920 mg, 4.26 mmol) was dissolved in ethanol (20 mL) and treated with 4-heptylamine (0.64 mL, 4.3 mmol). The mixture was heated at 60° C. for 16 h and concentrated under vacuum. The residue was taken up in ethyl acetate (50 mL), washed with aqueous sodium bicarbonate (20 mL), dried (MgSO4), and again concentrated. The residue was purified on a silica gel column (elution with 5% ethyl acetate in hexanes for (15′) and 25% ethyl acetate in hexanes for (16′) to afford 314 mg (25%) of (15′) as a yellow oil followed by 214 mg (17%) of (16′) as white solid. 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyridin-4-one (15′): NMR, LCMS (MH+, 295), Rf 0.70 (30% ethyl acetate in hexanes); 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin-4-one (16′): mp 82-85° C., LCMS (MH+, 295), Rf 0.14 (30% ethyl acetate in hexanes).
- Compound (17′)
- LDA in THF (0.325M, 0.83 ml, 0.27 mmol) was added to a stirred solution of the phosphine oxide (66 mg, 0.27 mmol) in THF (2 mL) at −25° C. After 15 min, compound (16′) (11 mg, 0.034 mmol) in THF (1 mL) was added and the mixture was stirred for 15 min. NaH (30 mg) was added, the mixture was warmed to room temperature and stirred for 16 hrs. The mixture was diluted with water (15 mL) and extracted with EtOAc (4×10 mL). The combined extracts were dried (MgSO4), concentrated in vacuo and the residue was purified by preparative TLC (elution with 30% EtOAc/Hex.) to afford compound (17′) as a colorless oil. (4.6 mg, 42%), LCMS (MH+, 323).
- Compound (18′)
- Compound (17′) (4.6 mg, 0.014 mmol), TsOH.H2O (4.2 mg, 0.022 mmol) and the aniline (12 mg, 0.085 mmol) was heated at 130° C. for 16 hrs. The mixture was cooled to room temperature, diluted with aqueous NaHCO3 (2 mL) and extracted with EtOAc (4×2 mL). The combined extracts were dried (MgSO4), concentrated in vacuo and the residue was purified by preparative TLC to afford compound (18′) as a yellow oil. (1.0 mg, 18%), LCMS (MH+, 396).
-
- Compound (2)
- Compound (1) (270 mg, 0.86 mmol), p-toluenesulfonic acid monohydrate (225 mg, 1.18 mmol) and DL-2-amino-1-pentanol (1 mL) were heated at 160° C. for 3 hours. The mixture was cooled to room temperature, diluted with dichloromethane, and purified on a silica gel column (elution with 10% methanol in dichloromethane) to afford 408 mg (100%) of compound (2) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=4.8 Hz. 1H), 7.53 (br s, 1H), 7.24-7.12 (m, 2H), 7.20 (d, J=7.8 Hz, 1H), 6.12 (s, 1H), 3.76-3.67 (m, 3H), 2.49 (s, 3H), 1.63-1.56 (m, 2H), 1.45-1.32 (m, 3H), 0.89 (t, J=7.1 Hz, 3H); LC/MS (MH+, 379).
- Compound (3)
- Compound (2) (478 mg, 0.86 mmol) was dissolved in 48% HBr (5 mL) and heated at 110° C. for 4 days. The mix was cooled to room temperature, cautiously basified with solid NaOH, and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated under vacuum to afford 159 mg (51%) of compound (3) as a yellow foam: 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J=8.4 Hz. 1H), 7.52 (d, J=2.1 Hz, 1H), 7.34 (dd, J=8.1, 2.1 Hz, 1H), 6.30 (s, 1H), 4.69 (br s, 1H), 4.60 (dd, J=12.0, 3.6 Hz, 1H), 4.10 (dd, J=12.2, 8.6 Hz, 1H), 3.88-3.85 (m, 1H), 2.58 (s, 3H), 1.78-1.55 (m, 4H), 1.05 (t, J=7.4 Hz, 3H); LC/MS (MH+, 361).
- Compound (4)
- Sodium hydride mineral oil dispersion (60%, 10 mg, 0.25 mmol) was added to a stirred solution of compound (3) (16 mg, 0.044 mmol) in DMF (0.5 mL). After 5 min, 1-bromopropane (0.050 mL, 0.55 mmol) was added and stirring was continued for 10 minutes. The mixture was cautiously diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The combined extracts were concentrated under vacuum, and the residue was purified by preparative TLC (elution with 10% methanol in dichloromethane) to afford 7 mg (40%) of compound (4) where R1 is n-propyl as a yellow oil.
- This technique is representative of the synthesis of the compounds presented in Table 3.
TABLE 3 Analytical Data for Representative Compounds Cpd. No. R R1 Analytical Data (I-2a-21) n-propyl 7.91 (d, J = 8.4 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.35 (dd, J = 8.4, 2.1 Hz, 1 H), 6.14 (s, 1 H), 4.52 (dd, J = 12.2, 1.2 Hz, 1 H), 4.34 (dd, J = 12.3, 3.9 Hz, 1 H), 3.80-3.74 (m, 1 H), 3.63-3.54 (m, 1 H), 3.21-3.11 (m, 1 H), 2.59 (s, 3 H), 1.86-1.60 (m, 4 H), 1.56-1.34 (m, 2 H), 1.01 (t, J = 7.4 Hz, 3 H), 0.94 (t, J = 7.2 Hz, 3 H); LCMS (MH+, 403) (I-2a-22) n-propyl 7.91 (d, J = 8.4 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.36 (dd, J = 8.4, 2.1 Hz, 1 H), 6.13 (s, 1 H), 4.52 (dd, J = 12.2, 2.0 Hz, 1 H), 4.33 (dd, J = 12.3, 4.2 Hz, 1 H), 3.80-3.74 (m, 1 H), 3.65-3.56 (m, 1 H), 3.23-3.14 (m, 1 H), 2.59 (s, 3 H), 1.80-1.60 (m, 5 H), 1.55-1.34 (m, 5 H), 0.97-0.91 (m, 6 H); LCMS (MH+, 431). (I-2a-23) n-propyl 7.91 (d, J = 8.4 Hz, 1 H), 7.54 (d, J =2.4 Hz, 1 H), 7.36 (dd, J = 8.4, 2.1 Hz, 1 H), 6.11 (s, 1 H), 4.54 (dd, J = 12.5, 1.4 Hz, 1 H), 4.37 (dd, J = 12.5, 4.1 Hz, 1 H), 3.76-3.70 (m, 1 H), 3.48 (dd, J =14.4, 6.3 Hz, 1 H), 2.90 (dd, J = 14.1, 8.7 Hz, 1 H), 2.59 (s, 3 H), 2.13-2.04 (m, 1 H), 2.0-1.25 (m, 4 H), 1.01 (d, J =6.3 Hz, 3 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.93 (t, # J = 7.2 Hz, 3 H); LCMS (MH+, 417) (I-2a-24) n-propyl 7.91 (d, J = 8.4 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.35 (dd, J = 8.3, 2.0 Hz, 1 H), 6.18 (s, 1 H), 4.56 (dd, J = 12.6, 1.8 Hz, 1 H), 4.36 (dd, J = 12.5, 4.1 Hz, 1 H), 4.02-3.96 (m, 1 H), 3.57 (dd, J =14.4, 6.0 Hz, 1 H), 3.05 (dd, J = 14.6, 7.4 Hz, 1 H), 2.59 (s, 3 H), 1.86-1.34 (m, 4 H), 1.13-1.09 (m, 1 H), 0.94 (t, J =7.2 Hz, 3 H), # 0.70-.61 (m, 2 H), 0.37-0.27 (m, 2 H); LCMS (MH+, 415) (I-2a-25) n-propyl 7.90 (d, J = 8.1 Hz, 1 H), 7.54 (d, J =2.4 Hz, 1 H), 7.36 (dd, J = 8.4, 2.1 Hz, 1 H), 6.15 (s, 1 H), 4.50 (dd, J = 12.2, 1.7 Hz, 1 H), 4.34 (dd, J = 12.2, 4.1 Hz, 1 H), 3.92-3.88 (m, 1 H), 3.78-3.72 (m, 1 H), 3.64-3.60 (m, 2 H), 3.51-3.42 (m, 1 H), 3.37 (s, 3 H), 2.59 (s, 3 H), 1.69-1.25 (m, 4 H), 0.94 (t, J = 7.4 Hz, 3 H); LCMS (MH+, 419). 7.90 (d, J = 8.1 Hz, 1 H), # 7.54 (d, J = 2.4 Hz, 1 H), 7.36 (dd, J = 8.4, 2.1 Hz, 1 H), 6.15 (s, 1 H), 4.50 (dd, J = 12.2, 1.7 Hz, 1 H), 4.34 (dd, J = 12.2, 4.1 Hz, 1 H), 3.92-3.88 (m, 1 H), 3.78-3.72 (m, 1 H), 3.64-3.60 (m, 2 H), 3.51-3.42 (m, 1 H), 3.37 (s, 3 H), 2.59 (s, 3 H), 1.69-1.25 (m, 4 H), 0.94 (t, J = 7.4 Hz, 3 H); LCMS (MH+, 419) (I-2a-26) n-propyl 7.93 (d, J = 8.4 Hz, 1 H), 7.54 (d, J =2.1 Hz, 1 H), 7.41-7.30 (m, 6 H), 6.23 (m, 1 H), 4.86 (d, J = 15.6 Hz, 1 H), 4.51 (dd, J = 12.6, 2.1 Hz, 1 H), 4.37 (d, J = 16.2 Hz, 1 H), 4.33 (dd, J =12.0, 4.2 Hz, 1 H), 3.75-3.71 (m, 1 H), 2.57 (s, 3 H), 1.71-1.32 (m, 4 H), 0.91 (t, J = 7.2 Hz, 3 H); LCMS (MH+, 451) (I-2a-27) n-propyl 7.55 (d, J = 2.4 Hz, 1 H), 7.48-7.20 (m, 5 H), 6.16 (s, 1 H), 4.85 (d, J = 16.5 Hz, 1 H), 4.58-4.51 (m, 2 H), 4.40 (dd, J = 12.6, 3.9 Hz, 1 H), 3.82-3.74 (m, 1 H), 2.56 (s, 3 H), 1.76-1.25 (m, 4 H), 0.94 (t, J = 7.4 Hz, 3 H); LCMS (MH+, 485) (I-2a-28) n-propyl 7.92 (dd, J = 8.1 Hz, 1 H), 7.53 (d, J =1.8 Hz, 1 H), 7.35 (dd, J = 8.6, 2.3 Hz, 1 H), 6.18 (s, 1 H), 4.59 (dd, J = 12.2, 1.4 Hz, 1 H), 4.10 (dd, J = 12.5, 3.5 Hz, 1 H), 3.83 (d, J = 10.8 Hz, 1 H), 3.70 (pent, J = 7.0 Hz, 1 H), 2.59 (s, 3 H), 1.81-1.18 (m, 12 H), 1.01 (t, J = 7.2 Hz, 3 H), 0.93 (t, J = 7.1 Hz, 3 H), 0.89 (t, J = 7.2 Hz, 3 H); LCMS (MH+, 459) (I-2a-29) n-propyl 7.90 (d, J = 8.4 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.36 (dd, J = 8.3, 2.2 Hz, 1 H), 6.15 (s, 1 H), 4.53 (dd, J = 12.5, 1.7 Hz, 1 H), 4.32 (dd, J = 12.5, 4.1 Hz, 1 H), 3.80-3.72 (m, 1 H), 3.63 (dd, J =14.6, 6.6 Hz, 1 H), 3.23 (dd, J = 14.3, 8.0 Hz, 1 H), 2.77-2.70 (m, 1 H), 2.61 (s, 3 H), 2.16-1.26 (m, 6 H), 0.94 (t, J =7.2 Hz, 3 H), 1.01-0.83 (m, 4 H); LCMS (MH+, 429). (I-2a-30) ethyl(S) 7.90 (d, J = 8.1 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.36 (dd, J = 8.3, 2.3 Hz, 1 H), 6.12 (s, 1 H), 4.58 (dd, J = 12.5, 1.4 Hz, 1 H), 4.36 (dd, J = 12.8, 3.5 Hz, 1 H), 3.68-3.65 (m, 1 H), 3.50 (dd, J =14.0, 6.2 Hz, 1 H), 2.92 (dd, J = 14.0, 8.6 Hz, 1 H), 2.59 (s, 3 H), 2.11-2.06 (m, 1 H), 1.80-1.57 (m, 2 H), 1.04-0.98 (m, 9 H), LCMS (MH+, 403). (I-2a-31) ethyl(S) 7.91 (d, J = 8.4 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.34 (dd, J = 8.3, 2.3 Hz, 1 H), 6.19 (s, 1 H), 4.59 (dd, J = 12.5, 2.0 Hz, 1 H), 4.36 (dd, J = 12.3, 3.6 Hz, 1 H), 3.94-3.90 (m, 1 H), 3.59 (dd, J =14.3, 5.9 Hz, 1 H), 3.06 (dd, J = 14.4, 7.2 Hz, 1 H), 2.59 (s, 3 H), 1.78-1.74 (m, 1 H), 1.67-1.59 (m, 1 H), 1.13-1.11 (m, 1 H), 1.02 (t, J = 7.5 Hz, 3 H), 0.70-0.61 (m, 2 H), # 0.34-0.30 (m, 2 H); LCMS (MH+, 401). (I-2a-32) ethyl(R) 7.90 (d, J = 8.1 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.36 (dd, J = 8.3, 2.3 Hz, 1 H), 6.12 (s, 1 H), 4.58 (dd, J = 12.5, 1.4 Hz, 1 H), 4.36 (dd, J = 12.8, 3.5 Hz, 1 H), 3.68-3.65 (m, 1 H), 3.50 (dd, J =14.0, 6.2 Hz, 1 H), 2.92 (dd, J = 14.0, 8.6 Hz, 1 H), 2.59 (s, 3 H), 2.11-2.06 (m, 1 H), 1.80-1.57 (m, 2 H), 1.04-0.98 (m, 9 H), LCMS (MH+, 403). (I-2a-33) ethyl(R) 7.91 (d, J = 8.4 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.34 (dd, J = 8.3, 2.3 Hz, 1 H), 6.19 (s, 1 H), 4.59 (dd, J = 12.5, 2.0 Hz, 1 H), 4.36 (dd, J = 12.3, 3.6 Hz, 1 H), 3.94-3.90 (m, 1 H), 3.59 (dd, J =14.3, 5.9 Hz, 1 H), 3.06 (dd, J = 14.4, 7.2 Hz, 1 H), 2.59 (s, 3 H), 1.78-1.74 (m, 1 H), 1.67-1.59 (m, 1 H), 1.13-1.11 (m, 1 H), 1.02 (t, J = 7.5 Hz, 3 H), 0.70-0.61 (m, 2 H), # 0.34-0.30 (m, 2 H); LCMS (MH+, 401). (I-2a-34) iso-propyl 7.90 (d, J = 8.4 Hz, 1 H), 7.53 (d, J =2.1 Hz, 1 H), 7.36 (dd, J = 8.4, 2.1 Hz, 1 H), 6.22 (s, 1 H), 4.67 (dd, J = 12.3, 2.0 Hz, 1 H), 4.31 (dd, J = 12.5, 4.4 Hz, 1 H), 3.82-3.73 (m, 2 H), 3.00 (dd, J =14.6, 7.7 Hz, 1 H), 2.60 (s, 3 H), 2.14 (m, 1 H), 1.14-1.07 (m, 1 H), 1.02 (d, J =6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.64-0.55 (m, 2 H), 0.37-0.23 (m, 2 H); LCMS (MH+, 415). (I-2a-35) iso-propyl 7.90 (d, J = 8.1 Hz, 1 H), 7.53 (d, J =1.8 Hz, 1 H), 7.36 (dd, J = 8.4, 2.1 Hz, 1 H), 6.15 (s, 1 H), 4.64 (dd, J = 12.6, 1.8 Hz, 1 H), 4.28 (dd, J = 12.6, 4.5 Hz, 1 H), 3.77-3.68 (m, 1 H), 3.57-3.52 (m, 1 H), 3.24-3.14 (m, 1 H), 2.59 (s, 3 H), 2.17-2.10 (m, 1 H), 1.76-1.64 (m, 2 H), 1.03 (d, J = 6.9 Hz, 3 H), 0.98 (t, J =7.4 Hz, 3 H), 0.88 (d, J = 6.9 Hz, # 3 H); LCMS (MH+, 403). (I-2a-36) iso-propyl LC/MS 417 (MH+) (I-2a-37) ethyl LC/MS 432 (MH+) (I-2a-38) ethyl(S) LC/MS 445 (MH+) - The representative compounds of Table 4 were made by the procedures set forth above in Example 5.
TABLE 4 Analytical Data for Representative Compounds Cpd. No. R R1 Analytical Data (I-2a-39) ethyl(S) 7.82 (d, J = 8.1 Hz, 1 H), 7.29-7.25 (m, 2 H), 6.18 (s, 1 H), 4.55 (dd, J = 12.3, 2.0 Hz, 1 H), 4.32 (dd, J = 12.3, 3.6 Hz, 1 H), 3.94-3.89 (m, 1 H), 3.59 (dd, J =14.4, 5.7 Hz, 1 H), 3.06 (dd, J = 14.4, 7.2 Hz, 1 H), 2.59 (s, 3 H), 2.53 (s, 3 H), 1.83-1.71 (m, 1 H), 1.67-1.57 (m, 1 H), 1.15-1.10 (m, 1 H), 1.02 (t, J = 7.5 Hz, 3 H), 0.71-0.61 (m, 2 H), 0.39-0.28 (m, 2 H); # LCMS (MH+, 381). (I-2a-40) ethyl(S) 7.83 (d, J = 8.1 Hz, 1 H), 7.30-7.25 (m, 2 H), 6.11 (s, 1 H), 4.53 (dd, J = 12.3, 1.2 Hz, 1 H), 4.33 (dd, J = 12.5, 4.1 Hz, 1 H), 3.68-3.63 (m, 1 H), 3.49 (dd, J =14.1, 6.3 Hz, 1 H), 2.91 (dd, J = 14.1, 8.7 Hz, 1 H), 2.59 (s, 3 H), 2.54 (s, 3 H), 2.16-2.05 (m, 1 H), 1.77-1.57 (m, 2 H), 1.04-0.98 (m, 9 H); LCMS (MH+, 383). (I-2a-41) ethyl(S) 7.82 (d, J = 8.7 Hz, 1 H), 7.30-7.25 (m, 2 H), 6.17 (s, 1 H), 4.56 (dd, J = 12.3, 0.9 Hz, 1 H), 4.42 (dd, J = 12.3, 3.3 Hz, 1 H), 3.64-3.60 (m, 1 H), 3.47 (d, J = 14.4 Hz, 1 H), 2.91 (d, J = 15.0 Hz, 1 H), 2.58 (s, 3 H), 2.54 (s, 3 H), 1.77-1.63 (m, 1 H), 1.61-1.53 (m, 1 H), 1.02 (s, 9 H), 1.07-0.98 (m, 3 H); LCMS (MH+, 397). (I-2a-42) ethyl(S) 7.82 (d, J = 8.4 Hz, 1 H), 7.29-7.25 (m, 2 H), 6.17 (s, 1 H), 4.60 (dd, J = 12.3, 1.2 Hz, 1 H), 4.06 (dd, J = 11.9, 3.5 Hz, 1 H), 3.75-3.68 (m, 2 H), 2.59 (s, 3 H), 2.54 (s, 3 H), 1.78-1.44 (m, 7 H), 1.36-1.21 (m, 3 H), 1.05-0.96 (m, 6 H), 0.90 (t, J = 7.2 Hz, 3 H); LCMS (MH+, 425). (I-2a-43) ethyl(S) LC/MS 365 (MH+) (I-2a-44) iso-butyl(S) LC/MS 397 (MH+) (I-2a-45) iso-butyl(S) LC/MS 409 (MH+) (I-2a-46) ethyl(S) LC/MS 397 (MH+) (I-2a-47) ethyl(S) 7.90 (d, J = 8.4 Hz, 1 H), 7.33-7.28 (m, 3 H), 5.30-5.20 (m, 1 H), 4.59 (dd, J =13.2, 1.2 Hz, 1 H), 4.50 (dd, J = 12.6, 3.6 Hz, 1 H), 2.71 (s, 3 H), 2.54 (s, 3 H), 2.30-2.21 (m, 1 H), 1.74-1.41 (m, 4 H), 1.25-0.97 (m, 2 H), 0.97 (t, J = 7.5 Hz, 3 H); LCMS (MH+, 395). (I-2a-48) ethyl(S) 7.82 (d, J = 7.8 Hz, 1 H), 7.29-7.24 (m, 2 H), 6.46 (s, 1 H), 4.54 (dd, J = 12.2, 0.8 Hz, 1 H), 4.27 (dd, J = 12.3, 4.2 Hz, 1 H), 3.80-3.74 (m, 1 H), 2.73-2.68 (m, 1 H), 2.62 (s, 3 H), 2.52 (s, 3 H), 1.93-1.82 (m, 2 H), 1.64-1.54 (m, 1 H), 1.05 (t, J =7.5 Hz, 3 H), 0.90-0.67 (m, 3 H); LCMS (MH+, 367). - The representative compounds of Table 5 were made by the following procedure (R=ethyl or hydrogen):
TABLE 5 Analytical Data for Representative Compounds Cpd. No. Ar R R1 Analytical Data (I-2a-49) 2-trifluoromethyl- 4-chlorophenyl ethyl(S) LC/MS 439 (MH+) (I-2a-50) 2-trifluoromethyl- 4-chlorophenyl ethyl(S) LC/MS 435 (MH+) (I-2a-51) 2-trifluoromethyl- 4-chlorophenyl ethyl(S) LC/MS 514 (MH+) (I-2a-52) 2-methoxy-4- trifluromethyl- phenyl ethyl(S) 7.77 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 2.7 Hz, 1 H), 7.15 (dd, J = 8.4, 2.7 Hz, 1 H), 6.18 (s, 1 H), 4.54 (dd, J =12.3, 1.8 Hz, 1 H); 4.33 (dd, J = 11.9, 4.1 Hz, 1 H), 3.95-3.90 (m, 1 H); 3.89 (s, 3 H), 3.58 (dd, J = 14.4, 6.0 Hz, 1 H), 3.05 (dd, J = 14.4, 7.2 Hz, 1 H); 2.57 (s, 3 H); 1.86-1.73 (m, 1 H), 1.67-1.57 (m, 1 H), 1.57-1.06 (m, 1 H), 1.01 # (t, J = 7.4 Hz, 3 H), 0.70-0.61 (m, 2 H); 0.37-0.28 (m, 2 H); LCMS (MH+, 431). (I-2a-53) 2-trifluoromethyl- 4-chlorophenyl H LC/MS 451 (MH+) (I-2a-54) 2,5-dimethoxy-4- chlorophenyl H 7.60 (s, 1 H); 7.07 (s, 1 H); 6.27 (s, 1 H); 4.49 (t, 2 H); 3.93 (s, 3 H); 3.91 (s, 3 H); 3.86 (m, 1 H); 3.73 (t, 2 H); 2.73 (s, 3 H); 1.60-1.75 (m, 4 H); 1.20-1.40 (m, 4 H); 0.95 (t, 6 H). LC/MS m + 1 (443, 445). (I-2a-55) 2-methoxy-4- trifluoromethyl- phenyl H 7.75 (d, J = 8.4 Hz, 1 H); 7.32 (d, J = 2.7 Hz, 1 H); 7.15 (dd, J = 8.7, 2.7 Hz, 1 H); 6.21 (s, 1 H); 4.42 (t, J =5.3 Hz, 2 H); 3.89 (s, 3 H); 3.86-3.80 (m, 1 H); 3.65 (t, J =5.3 Hz, 2 H); 2.56 (s, 3 H); 1.76-1.58 (m, 4 H); 1.41-1.24 (m, 4 H); 0.94 (t, J = 7.2 Hz, 6 H); LCMS (MH+, 447). (I-2a-56) 2-methoxy-4- methylphenyl H 7.79 (d, J = 7.5 Hz, 1 H); 6.89 (d, J = 7.5 Hz, 1 H); 6.86 (br s, 1 H); 6.21 (s, 1 H); 4.46 (t, J = 5.3 Hz, 2 H); 3.92 (s, 3 H); 3.88-3.83 (m, 1 H); 3.66 (t, J = 5.3 Hz, 2 H); 2.66 (s, 3 H); 2.41 (s, 3 H); 1.71-1.53 (m, 4 H); 1.41-1.25 (m, 4 H); 0.93 (t, J = 7.4 Hz, 6 H); LCMS (MH+, 393). (I-2a-57) 4-methyl-6- dimethylamino- pyridin-3-yl H 8.58 (s, 1 H); 6.46 (s, 1 H); 6.20 (s, 1 H); 4.41 (t, 2 H); 3.86 (m, 1 H); 3.66 (t, 2 H); 3.12 (s, 6 H); 2.58 (s, 3 H); 2.48 (s, 3 H); 1.50-1.72 (m, 4 H); 1.28-1.44 (m, 4 H); 0.96 (t, 6 H). LC/MS m + 1 (407). (I-2a-58) 2-methoxy-4- isopropylphenyl H LC/MS 421 (MH+) (I-2a-59) 2-methoxy-4- methylphenyl H LC/MS 393 (MH+) (I-2a-59-1) 2-4- di(trifluoromethyl)- phenyl H — (I-2a-60) 2,4-dimethyl- phenyl ethyl(S) LC/MS 361 (MH+) (I-2a-61) 2-methoxy-4- isopropylphenyl ethyl(S) LC/MS 405 (MH+) (I-2a-62) 2-formyl-4- methoxyphenyl ethyl(S) LC/MS 391 (MH+) (I-2a-63) 2,4,6-trimethyl- phenyl ethyl(S) LC/MS 375 (MH+) (I-2a-64) 2,4,6-trimethyl- phenyl H LC/MS 391 (MH+) (I-2a-65) 2-chloro-4- (C(═O)OCH3)- phenyl ethyl(S) LC/MS 425 (MH+) (I-2a-66) 2-chloro-4- C(OH)(CH3)2- phenyl ethyl(S) LC/MS 425 (MH+) (I-2a-67) 2-trifluoromethyl- 4-isopropyl- phenyl ethyl(S) LC/MS 443 (MH+) (I-2a-68) 2-chloro-4,6- dimethylphenyl ethyl(S) LC/MS 395 (MH+) (I-2a-69) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 1.00 (9 H, t), 1.66 (2 H, m), 2.10 (1 H, m), 2.55 (3 H, s), 2.90 (1 H, q), 3.48 (1 H, q), 3.65 (1 H, m), 3.89 (3 H, s), 4.33 (1 H, m), 4.53 (1 H, d), 6.12 (1 H, s), 7.15 (1 H, m), 7.32 (1 H, d), 7.78 (1 H, d). (I-2a-70) 2,4,6-trimethyl- phenyl ethyl(S) 1.01 (9 H, t) 1.65 (2 H, m), 2.12 (7 H, m), 2.30 (3 H, s), 2.52 (3 H, s), 2.90 (1 H, m), 3.47 (1 H, m), 3.64 (1 H, m), 4.32 (1 H, d), 4.50 (1 H, d), 6.07 (1 H, s), 6.91 (2 H, s). (I-2a-71) 2,4-dimethyl- phenyl ethyl(S) 1.00 (9 H, m), 1.65 (2 H, m), 2.09 (1 H, m), 2.35 (3 H, s), 2.51 (3 H, s), 2.57 (3 H, s), 2.90 (1 H, m), 3.48 (1 H, m), 3.63 (1 H, m), 4.31 (1 H, m), 5.51 (1 H, d), 6.09 (1 H, s), 7.09 (2 H, m), 7.72 (1 H, d). (I-2a-72) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 468 (MH+) (I-2a-73) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 417 (MH+) (I-2a-74) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 449 (MH+) (I-2a-75) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 489 (MH+) (I-2a-76) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 485 (MH+) (I-2a-77) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 445 (MH+) (I-2a-78) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 435 (MH+) (I-2a-79) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 470 (MH+) (I-2a-80) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-81) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-82) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-83) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 417 (I-2a-84) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-85) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 421 (I-2a-86) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 461 (I-2a-87) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 531 (I-2a-88) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-89) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-90) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 453 (I-2a-91) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 403 (I-2a-92) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 433 (I-2a-93) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 481 (I-2a-94) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-95) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-96) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 473 (I-2a-97) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-98) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-99) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) — (I-2a-100) 2-methoxy-4- trifluoromethyl- phenyl ethyl — (I-2a-101) 2-methoxy-4- trifluoromethyl- phenyl ethyl — (I-2a-102) 2-methoxy-4- trifluoromethyl- phenyl ethyl — (I-2a-103) 2-methoxy-4- trifluoromethyl- phenyl ethyl — (I-2a-104) 2-methoxy-4- trifluoromethyl- phenyl ethyl — (I-2a-105) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 405 (MH+) (I-2a-106) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 419 (MH+) (I-2a-107) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 491 (MH+) (I-2a-108) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 547 (MH+) (I-2a-109) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 449 (MH+) (I-2a-110) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 459 (MH+) (I-2a-111) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 473 (MH+) (I-2a-112) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 487 (MH+) (I-2a-113) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 417 (MH+) (I-2a-114) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 430 (MH+) (I-2a-115) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 447 (MH+) (I-2a-116) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 513 (MH+) (I-2a-117) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 493 (MH+) (I-2a-118) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 551 (MH+) (I-2a-119) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 545 (MH+) (I-2a-120) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 431 (MH+) (I-2a-121) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 459 (MH+) (I-2a-122) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 419 (MH+) (I-2a-123) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 433 (MH+) (I-2a-124) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 447 (MH+) (I-2a-125) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 431 (MH+) (I-2a-126) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 447 (MH+) (I-2a-127) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 461 (MH+) (I-2a-128) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 489 (MH+) (I-2a-129) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 435 (MH+) (I-2a-130) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 458 (MH+) (I-2a-131) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 391 (MH+) (I-2a-132) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 403 (MH+) (I-2a-133) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 419 (MH+) (I-2a-134) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 447 (MH+) (I-2a-135) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 417 (MH+) (I-2a-136) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 431 (MH+) (I-2a-137) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 447 (MH+) (I-2a-138) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 491 (MH+) (I-2a-139) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 405 (MH+) (I-2a-140) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) LC/MS 506 (MH+) (I-2a-141) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 421 (MH+) (I-2a-142) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 433 (MH+) (I-2a-143) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 461 (MH+) (I-2a-144) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 503 (MH+) (I-2a-145) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 472 (MH+) (I-2a-146) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 445 (MH+) (I-2a-147) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 461 (MH+) (I-2a-148) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) LC/MS 447 (MH+) (I-2a-149) 2-trifluoromethyl- 4-methoxy-phenyl H — (I-2a-150) 2-trifluoromethyl- 4-methoxy-phenyl ethyl(S) — (I-2a-151) 2-trifluoromethyl- 4-methoxy-phenyl ethyl(S) — (I-2a-152) 2-trifluoromethyl- 4-methoxy-phenyl ethyl(S) — (I-2a-153) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 419 (MH+) (I-2a-154) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 461 (MH+) (I-2a-155) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 475 (MH+) (I-2a-156) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 539 (MH+) (I-2a-157) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 463 (MH+) (I-2a-158) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 523 (MH+) (I-2a-159) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 511 (MH+) (I-2a-160) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 517 (MH+) (I-2a-161) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 549 (MH+) (I-2a-162) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 531 (MH+) (I-2a-163) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 531 (MH+) (I-2a-164) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 503 (MH+) (I-2a-165) 2-methoxy-4- trifluoromethyl- phenyl ethyl LC/MS 503 (MH+) (I-2a-166) 2-chloro-4- methoxyphenyl ethyl(S) 7.81 (d, J = 8.7 Hz, 1 H), 7.07 (d, J = 3.0 Hz, 1 H), 6.93 (dd, J = 8.7, 3.0 Hz, 1 H), 6.17 (s, 1 H), 4.57 (12.3, 1.8 Hz, 1 H), 4.34 (dd, J =12.3, 4.2 Hz, 1 H), 3.93-3.88 (m, 1 H), 3.84 (s, 3 H), 3.58 (dd, J = 14.1, 6.0 Hz, 1 H), 3.05 (dd, J = 14.6, 7.1 Hz, H); LC/MS 397 (MH+) (I-2a-167) 2-methyl-4- chlorophenyl ethyl(S) 7.79 (d, J = 8.4 Hz, 1 H), 7.29-7.27 (m, 2 H), 6.19 (s, 1 H), 4.56 (dd, J = 12.3, 1.8 Hz, 1 H), 4.33 (dd, J = 12.3, 4.2 Hz, 1 H), 3.97-3.91 (m, 1 H), 3.63 (dd, J = 14.1, 5.7 Hz, 1 H), 3.08 (dd, J = 14.4, 7.5 Hz, 1 H), 2.62 (s, 3 H), 2.52 (s, 3 H), 1.88-1; LC/MS 381 (MH+) (I-2a-168) 2-methyl-4- chlorophenyl H 7.75 (d, J = 8.4 Hz, 1 H), 7.28-7.21 (m, 2 H), 6.21 (s, 1 H), 4.42 (dd, J = 5.4, 5.1 Hz, 2 H), 3.89-3.81 (m, 1 H), 3.65 (dd, J = 5.4, 5.1 Hz, 2 H), 2.57 (s, 3 H), 2.51 (s, 3 H), 1.74-1.53 (m, 4 H), 1.43-1.24 (m, 4 H), 0.94 (t, J = 7.4 Hz, 6 H); LC/MS 397 (MH+) (I-2a-169) 2,4-dimethyl- phenyl H 7.66 (d, J = 7.5 Hz, 1 H), 7.11-7.08 (m, 2 H), 6.20 (s, 1 H), 4.42 (dd, J = 5.5, 4.8 Hz, 2 H), 3.89-3.81 (m, 1 H), 3.65 (dd, J = 5.4, 5.1 Hz, 2 H), 2.58 (s, 3 H), 2.48 (s, 3 H), 2.35 (s, 3 H), 1.72-1.53 (m, 4 H), 1.43-1.30 (m, 4 H), 0.94 (t, J = 7.2 Hz, 6 H); LC/MS 377 (MH+) (I-2a-170) 2,4-dimethyl-6- chlorophenyl H 7.15 (s, 1 H), 7.01 (s, 1 H), 6.20 (s, 1 H), 4.50-4.39 (m, 2 H), 3.89-3.8 1 (m, 1 H), 3.67 (dd, t, J = 5.3 Hz, 2 H), 2.56 (s, 3 H), 2.33 (s, 3 H), 2.17 (s, 3 H), 1.72-1.54 (m, 4 H), 1.44-1.32 (m, 4 H), 0.95 (t, J =7.5 Hz,6 H); LC/MS 411 (MH+) (I-2a-171) 2-chloro-4- trifluoromethyl- phenyl ethyl(S) 8.13 (d, J = 8.4 Hz, 1 H), 7.79 (s, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 6.21 (s, 1 H), 4.61 (dd, J = 12.6, 1.8 Hz, 1 H), 4.39 (dd, J = 12.5, 3.8 Hz, 1 H), 3.95-3.93 (m, 1 H), 3.60 (dd, J = 14.4, 5.7 Hz, 1 H), 3.06 (dd, J = 14.1, 7.2 Hz, 1 H), 2.60 (s, 3 H); LC/MS 435 (MH+) (I-2a-172) 2-chloro-4- trifluoromethyl- phenyl H 8.10 (d, J = 8.4 Hz, 1 H), 7.78 (s, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 6.24 (s, 1 H), 4.48 (dd, J = 6.0, 4.8 Hz, 2 H), 3.91-3.82 (m, 1 H), 3.67 (dd, J = 5.4, 5.1 Hz, 2 H), 2.59 (s, 3 H), 1.74-1.54 (m, 4 H), 1.43-1.31 (m, 4 H), 0.94 (t, J =7.2 Hz, 6 H); LC/MS 451 (MH+) (I-2a-173) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 1.01 (9 H, t), 1.28 (6 H, d), 1.63 (2 H, m), 2.15 (1 H, m), 2.56 (3 H, s), 2.95 (2 H, m), 3.49 (1 H, m), 3.65 (1 H, m), 4.36 (1 H, m), 4.53 (1 H, m), 6.51 (1 H, s), 7.48 (1 H, d), 7.63 (1 H, s), 7.76 (1 H, d) (I-2a-174) 2-methyl-4- methoxyphenyl ethyl(S) 0.31 (2 H, m), 0.64 (2 H, m), 1.02 (3 H, t), 1.10 (1 H, m), 1.63 (1 H, m), 1.75 (1 H, m), 2.06 (1 H, s), 2.53 (3 H, s), 2.58 (3 H, s), 3.04 (1 H, q), 3.57 (1 H, q), 3.83 (3 H, s), 4.29 (1 H, m), 4.53 (1 H, d), 6.16 (1 H, s), 6.84 (2 H, m), 7.78 (1 H, d) (I-2a-175) 2-chloro-4- fluorophenyl ethyl(S) 0.32 (2 H, m), 0.65 (2 H, m), 1.02 (3 H, t), 1.10 (1 H, m), 1.67 (2 H, m), 2.58 (3 H, s), 3.05 (1 H, q), 3.59 (1 H, q), 3.92 (1 H, m), 4.35 (1 H, m), 4.57 (1 H, d), 6.19 (1 H, s), 7.10 (1 H, m), 7.27 (1 H, m), 7.90 (1 H, m) (I-2a-176) 2-(2-chloro-4- fluorophenyl)-4- fluorophenyl ethyl(S) LC/MS 379 (MH+) (I-2a-177) 4-fluorophenyl ethyl(S) 0.31 (2 H, m), 0.64 (2 H, m), 1.01 (3 H, t), 1.10 (1 H, m), 1.65 (2 H, m), 2.62 (3 H, s), 3.04 (1 H, q), 3.57 (1 H, q), 3.89 (1 H, m), 4.28 (1 H, m), 4.53 (1 H, d), 6.18 (1 H, s), 7.16 (2 H, t), 8.45 (2 H, m) (I-2a-178) 2-methoxy-4- chlorophenyl ethyl(S) 0.31 (2 H, m), 0.63 (2 H, m), 1.01 (3 H, t), 1.10 (1 H, m), 1.70 (2 H, m), 2.58 (3 H, s), 3.04 (1 H, q), 3.57 (1 H, q), 3.87 (1 H, m), 3.90 (3 H, s), 4.32 (1 H, m), 4.58 (1 H, d), 6.16 (1 H, s), 7.02 (1 H, d), 7.08 (1 H, d), 8.06 (1 H, d) (I-2a-179) 2-methyl-4- methoxyphenyl ethyl(S) 1.00 (9 H, q), 1.68 (2 H, m), 2.09 (1 H, m), 2.53 (3 H, s), 2.57 (3 H, s), 2.90 (1 H, q), 3.48 (1 H, q), 3.63 (1 H, m), 3.83 (3 H, s), 4.30 (1 H, m), 4.51 (1 H, d), 6.08 (1 H, s), 6.84 (2 H, m), 7.77 (1 H, d) (I-2a-180) 2,4-dimethoxy- phenyl ethyl(S) 0.30 (2 H, m), 0.63 (2 H, m), 1.01 (3 H, t). 1.09 (1 H, m), 1.70 (2 H, m), 2.09 (1 H, s), 2.58 (3 H, s), 3.03 (1 H, q), 3.57 (1 H, q), 3.86 (3 H, s), 3.88 (3 H, s), 4.30 (1 H, m), 4.57 (1 H, d), 6.15 (1 H, s), 6.62 (2 H, m), 8.03 (1 H, d) (I-2a-181) 2-methoxy-4- chlorophenyl H 0.93 (6 H, t), 1.34 (4 H, m), 1.63 (4 H, m), 2.58 (3 H, s), 3.62 (2 H, d), 3.84 (1 H, m), 3.90 (3 H, s), 4.45 (2 H, t), 6.20 (1 H, s), 7.04 (2 H. m), 8.00 (1 H, d) (I-2a-182) 2-chloro-4- methoxyphenyl H 0.94 (6 H, t), 1.36 (4 H, m), 1.63 (4 H, m), 2.58 (3 H, s), 3.65 (2 H, t), 3.84 (4 H, m), 4.44 (2 H, t), 6.21 (1 H, s), 6.32 (1 H, d), 7.07 (1 H, d), 7.79 (1 H, d) (I-2a-183) 2-chloro-4- carboxyphenyl H 0.78 (6 H, t), 1.20 (5 H, m), 1.43 (3 H, m), 2.33 (3 H, s), 3.43 (2 H, m), 3.67 (1 H, m), 4.25 (2 H, m), 6.01 (1 H, s), 7.45 (1 H, d), 7.86 (1 H, d), 7.97 (1 H, s) (I-2a-184) 2,6-dimethyl-4- methoxyphenyl H 0.95 (6 H, t), 1.40 (4 H, m), 1.64 (4 H, m), 2.16 (6 H, s), 2.54 (3 H, s), 3.66 (2 H, t), 2.81 (4 H, m), 4.41 (2 H, t), 6.18 (1 H, s), 6.67 (2 H, s) (I-2a-185) 2,6-dimethyl-4- methoxyphenyl ethyl(S) 0.34 (2 H, m), 0.66 (2 H, m), 1.02 (3 H, t), 1.13 (1 H, m), 1.74 (4 H, m), 2.15 (5 H, s), 2.54 (3 H, s), 3.05 (1 H, q), 3.58 (1 H, m), 3.81 (3 H, s), 3.92 (1 H, m), 4.32 (1 H, m), 4.52 (1 H d), 6.16 (1 H, s), 6.67 (2 H, s) (I-2a-186) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-187) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-188) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-189) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-190) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-191) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-192) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-193) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-194) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-195) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-196) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-197) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-198) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-199) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-200) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-201) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-202) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-203) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-204) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-205) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-206) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-207) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-208) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-209) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-210) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-211) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-212) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-213) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-214) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-215) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-216) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-217) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-218) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-219) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-220) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-221) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-222) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-223) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-224) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-225) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-226) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-227) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-228) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-229) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-230) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-231) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) — (I-2a-232) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) — (I-2a-233) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) — (I-2a-234) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) — (I-2a-235) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) — (I-2a-236) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) — (I-2a-237) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) — (I-2a-238) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) — - The representative compounds of Table 6 were made by the following procedure:
TABLE 6 Analytical Data for Representative Compounds Cpd. No. Ar R1 Analytical Data (I-2a-239) 2-methyl-4- methoxyphenyl LC/MS 421 (MH+) (I-2a-240) 2-methyl-4- methoxyphenyl LC/MS 365 (MH+) (I-2a-241) 2-methyl-4- methoxyphenyl LC/MS 393 (MH+) (I-2a-242) 2,4-dimethoxy- phenyl LC/MS 409 (MH+) (I-2a-243) 2-methyl-4- methoxyphenyl LC/MS 393 (MH+) - The representative compounds of Table 7 were made by the following procedure:
TABLE 7 Analytical Data for Representative Compounds Cpd. No. COR'/SO2R' (I-2a-244) (I-2a-245) (I-2a-246) (I-2a-247) (I-2a-248) (I-2a-249) (I-2a-250) (I-2a-251) (I-2a-252) (I-2a-253) (I-2a-254) (I-2a-255) (I-2a-256) (I-2a-257) (I-2a-258) (I-2a-259) (I-2a-260) (I-2a-261) (I-2a-262) (I-2a-263) (I-2a-264) (I-2a-265) (I-2a-266) (I-2a-267) (I-2a-268) (1-2a-269) -
- The representative compounds of Table 9 were made by the following procedure:
TABLE 9 +UZ,/6/27 Analytical Data for Representative Compounds Cpd. No. R' LC/MS (MH+) (I-2a-283) — (I-2a-284) 486 (I-2a-285) 562 (I-2a-286) — (I-2a-287) 508 (I-2a-288) — (I-2a-289) 530 (I-2a-290) — (I-2a-291) 554 (I-2a-292) 600 (I-2a-293) — (I-2a-294) — (I-2a-295) 536 (I-2a-296) 472 (I-2a-297) 474 (I-2a-298) 518 (I-2a-299) — (I-2a-300) 490 (I-2a-301) 486 (I-2a-302) 565 (I-2a-303) 583 (I-2a-304) 517 (I-2a-305) 503 (I-2a-306) 579 (I-2a-307) 533 (I-2a-308) 490 (I-2a-309) 518 (I-2a-310) — (I-2a-311) 546 (I-2a-312) 488 (I-2a-313) — (I-2a-314) — (I-2a-315) 518 (I-2a-316) 516 (I-2a-317) — (I-2a-318) — (I-2a-319) — (I-2a-320) 516 (I-2a-321) 518 (I-2a-322) 504 (I-2a-323) 580 (I-2a-324) 560 (I-2a-325) — (I-2a-326) — (I-2a-327) 578 (I-2a-328) — (I-2a-329) 571 (I-2a-330) 531 (I-2a-331) 542 (I-2a-332) 536 (I-2a-333) 502 (I-2a-334) 448 (I-2a-335) — (I-2a-336) 538 (I-2a-337) 581 (I-2a-338) — (I-2a-339) — (I-2a-340) — (I-2a-341) 552 (I-2a-342) 532 (I-2a-343) 462 (I-2a-344) 538 (I-2a-345) 476 (I-2a-346) 519 (I-2a-347) — (1-2a-348) — (I-2a-349) 476 (I-2a-350) 504 (I-2a-351) — (I-2a-352) — (I-2a-353) 560 (I-2a-354) 588 (I-2a-355) — (I-2a-356) 502 (I-2a-357) — (I-2a-358) 488 (I-2a-359) — (I-2a-360) 552 (I-2a-361) 490 (I-2a-362) 602 (I-2a-363) — (I-2a-364) — (I-2a-365) — (I-2a-366) — (I-2a-367) — (I-2a-368) 553 (I-2a-369) 567 (I-2a-370) 539 (I-2a-371) — (I-2a-372) — (I-2a-373) 557 (I-2a-374) — (I-2a-375) 583 (I-2a-376) — (I-2a-377) 567 (I-2a-378) 572 (I-2a-379) — (I-2a-380) 504 (I-2a-381) — (I-2a-382) 552 (I-2a-383) 552 (I-2a-384) 488 (I-2a-385) — (I-2a-386) — (I-2a-387) — (I-2a-388) 517 (I-2a-389) 583 (I-2a-390) — (I-2a-391) 504 (I-2a-392) — (I-2a-393) 581 (I-2a-394) — (I-2a-395) 598 (I-2a-396) — (I-2a-397) — (I-2a-398) — (I-2a-399) — (I-2a-400) 531 (I-2a-401) 599 (I-2a-402) 602 (I-2a-403) — (I-2a-404) — (I-2a-405) 478 (I-2a-406) — (I-2a-407) 492 (I-2a-408) 574 (I-2a-409) 517 (I-2a-410) — (I-2a-411) 517 (I-2a-412) — (I-2a-413) — - The representative compounds of Table 10 were made by the following procedure:
TABLE 10 Analytical Data for Representative Compounds Cpd. No. R' LC/MS (MH+) (I-2a-414) 462 (I-2a-415) 448 (I-2a-416) 526 (I-2a-417) 632 (I-2a-418) 510 (I-2a-419) 524 (I-2a-420) 572 (I-2a-421) 476 (I-2a-422) 580 (I-2a-423) 536 - The compounds of this invention may be evaluated for binding activity to the CRF receptor by a standard radioligand binding assay as generally described by DeSouza et al. (J. Neurosci. 7:88-100, 1987). By utilizing various radiolabeled CRF ligands, the assay may be used to evaluate the binding activity of the compounds of the present invention with any CRF receptor subtype. Briefly, the binding assay involves the displacement of a radiolabeled CRF ligand from the CRF receptor.
- More specifically, the binding assay is performed in 1.5 ml Eppendorf tubes using approximately 1×106 cells per tube stably transfected with human CRF receptors. Each tube receives about 0.1 ml of assay buffer (e.g., Dulbecco's phosphate buffered saline, 10 mM magnesium chloride, 20 μM bacitracin) with or without unlabeled sauvagine, urotensin I or CRF (final concentration, 1 μM) to determine nonspecific binding, 0.1 ml of [125I] tyrosine-ovine CRF (final concentration ˜200 μM or approximately the KD as determined by Scatchard analysis) and 0.1 ml of a membrane suspension of cells containing the CRF receptor. The mixture is incubated for 2 hours at 22° C. followed by the separation of the bound and free radioligand by centrifugation. Following two washes of the pellets, the tubes are cut just above the pellet and monitored in a gamma counter for radioactivity at approximately 80% efficiency. All radioligand binding data may be analyzed using the non-linear least-square curve-fitting program LIGAND of Munson and Rodbard (Anal. Biochem. 107:220, 1990).
- The compounds of the present invention may also be evaluated by various functional testing. For example, the compounds of the present invention may be screened for CRF-stimulated adenylate cyclase activity. An assay for the determination of CRF-stimulated adenylate cyclase activity may be performed as generally described by Battaglia et al. (Synapse 1:572, 1987), with modifications to adapt the assay to whole cell preparations.
- More specifically, the standard assay mixture may contain the following in a final volume of 0.5 ml: 2 mM L-glutamine, 20 mM HEPES, and 1 mM IMBX in DMEM buffer. In stimulation studies, whole cells with the transfected CRF receptors are plated in 24-well plates and incubated for 1 h at 37° C. with various concentrations of CRF-related and unrelated peptides in order to establish the pharmacological rank-order profile of the particular receptor subtype. Following the incubation, the media is aspirated, the wells rinsed once gently with fresh media, and the media aspirated. To determine the amount of intracellular cAMP, 300 μl of a solution of 95% ethanol and 20 mM aqueous hydrochloric acid is added to each well and the resulting suspensions are incubated at −20° C. for 16 to 18 hours. The solution is removed into 1.5 ml Eppendorf tubes and the wells washed with an additional 200 μl of ethanol/aqueous hydrochloric acid and pooled with the first fraction. The samples are lyophilized and then resuspended with 500 μl sodium acetate buffer. The measurement of cAMP in the samples is performed using a single antibody kit from Biomedical Technologies Inc. (Stoughton, Mass.). For the functional assessment of the compounds, a single concentration of CRF or related peptides causing 80% stimulation of cAMP production is incubated along with various concentrations of competing compounds (10−12 to 10−6 M).
- It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.
Claims (49)
1. A compound having the following structure:
including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof,
wherein:
n is 1 or 2;
A and C are each independently nitrogen, carbon or CH;
B is nitrogen or CR3;
with the provisos that at least one of A, B and C is nitrogen; A, B and C are not all nitrogen; and either A-B or B-C is a double bond;
X is nitrogen or CRq;
Rq is hydrogen, alkyl or halo;
Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R is an optional substituent which, at each occurrence, is independently alkyl, alkylidenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein m is 0, 1, 2 or 3 and represents the number of R substituents;
R1 is —C(H)0,1(R4)(R5) or —SO2R5;
R2 is hydrogen, alkyl, haloalkyl or cyano
R3 is hydrogen, alkyl or haloalkyl;
R4 is hydrogen, oxo, alkyl, substituted alkyl, alkylidenyl or halo; and
R5 is a radical of the formula —Y-Z-R6, wherein
Y is an alkanediyl, substituted alkanediyl, or a direct bond,
Z is NH, —N(R7), O, S, SO2, C(═O), C(═O)O, OC(═O), NHC(═O), C(═O)NH, NH(SO2), (SO2)NH, NR8C(═O)O, or a direct bond;
R6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; w
R7 and R8 are alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
R6 and R7 taken together with the nitrogen atom to which they are attached form a heterocyle ring or substituted heterocyle ring;
or R4 and R5 taken together with the carbon atom to which they are attached form cycloalkyl, substituted cycloalkyl, cycloalkylcycloalkyl, substituted cycloalkylcycloalkyl, cycloalkylaryl, substituted cycloalkyaryl, cycloalkylheterocycle, or substituted cycloalkylheterocycle.
3. The compound of claim 1 wherein n is 2 and having one of the following structures:
7. The compound of claim 1 wherein Ar is phenyl or substituted phenyl.
8. The compound of claim 7 wherein substituted phenyl is 2,4-dichlorophenyl, 2-chloro-4-methyl-phenyl, 2-methyl-4-chloro-phenyl, 2,4,6-trimethyl-phenyl, 2-chloro-4-methoxy-phenyl, 2-methyl-4-methoxy-phenyl, or 2,4-dimethoxy-phenyl.
9. The compound of claim 1 wherein Ar is heteroaryl or substituted heteroaryl.
10. The compound of claim 9 wherein heteroaryl is pyridinyl.
11. The compound of claim 9 wherein substituted heteroaryl is 4-methyl-6-dimethylamino-pyridin-3-yl, 4-dimethylamino-6-methyl-pyridin-3-yl or 6-dimethylamino-pyridin-3-yl.
12. The compound of claim 1 wherein m is zero.
13. The compound of claim 1 wherein R is alkyl.
14. The compound of claim 1 wherein R is arylalkyl.
15. The compound of claim 1 wherein R1 is —CH(n-propyl)2, —CH(n-propyl)(CH2OCH3), —CH(phenyl)(CH2OCH3), —CH(CH2OR′)2, —CH(CH2OR′)(ethyl), —CH(CH2OR′)(n-butyl), —CH(CH2OR′)(tert-butyl), —CH(CH2OR′)(4-chloro-phenyl), —CH(CH2OR)(CH2CH2SCH3), —CH(CH2CH3)(CH2O phenyl), where each occurrence of R′ is independently selected from C1-6alkyl.
16. The compound of claim 1 wherein R1 is —SO2R5.
17. The compound of claim 1 wherein R1 is —C(H)0,1(R4)(R5).
18. The compound of claim 17 wherein R1 is —CH2R5.
19. The compound of claim 17 wherein R1 is —C(═O)R5.
20. The compound of claim 17 wherein R1 is —CH(R4)(R5).
21. The compound of claim 1 wherein R4 is hydrogen.
22. The compound of claim 1 wherein R4 is alkyl.
23. The compound of claim 1 wherein R4 is keto.
24. The compound of claim 1 wherein Y is alkanediyl or substituted alkanediyl.
25. The compound of claim 1 wherein Y is a direct bond.
26. The compound of claim 1 wherein Z is NH, —N(R7), O, S, SO2, C(═O), C(═O)O, OC(═O), NHC(═O), C(═O)NH, NH(SO2), (SO2)NH or NR8C(═O)O.
27. The compound of claim 1 wherein Z is a direct bond.
28. The compound of claim 1 wherein R6 is hydrogen, alkyl or substituted alkyl.
29. The compound of claim 1 wherein R6 is aryl, substituted aryl, arylalkyl or substituted arylalkyl.
30. The compound of claim 1 wherein R6 is heterocyle, substituted heterocycle, heterocyclealkyl or substituted heterocylcealkyl.
31. The compound of claim 1 wherein R2 is methyl.
32. The compound of claim 1 wherein R2 is ethyl.
34. The compound of claim 33 wherein Ar is 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2-trifluorometyl-4-chlorophenyl, or 2-methoxy-4-trifluoromethyl.
35. The compound of claim 33 wherein m is 0.
36. The compound of claim 33 wherein R1 is CH(alkyl)(alkyl).
37. The compound of claim 36 wherein R1 is CH(n-propyl)2.
38. The compound of claim 36 wherein R1 is CH(n-butyl)2.
39. The compound of claim 33 wherein m is 1 and R is alkyl.
40. The compound of claim 39 wherein R is methyl, ethyl or n-propyl.
41. The compound of claim 40 wherein R1 is —CH2(cycloalkyl).
42. The compound of claim 41 wherein R1 is —CH2(cyclopropyl).
43. The compound of claim 40 wherein R1 is CH(alkyl)(alkyl).
44. The compound of claim 43 wherein R1 is CH(n-propyl)2 or CH(n-butyl)2.
45. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier or diluent.
46. A method for treating a disorder manifesting hypersecretion of CRF in a warm-blooded animal, comprising administering to the animal an effective amount of the pharmaceutical composition of claim 45 .
47. The method of claim 46 wherein the disorder is stroke.
48. The method of claim 46 wherein the disorder is depression.
49. The method of claim 46 wherein the disorder is anxiety.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/701,394 US20040157851A1 (en) | 1998-11-12 | 2003-11-04 | CRF receptor antagonists and methods relating thereto |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19107398A | 1998-11-12 | 1998-11-12 | |
US37083799A | 1999-08-09 | 1999-08-09 | |
US40136499A | 1999-09-21 | 1999-09-21 | |
US09/439,840 US6514982B1 (en) | 1998-11-12 | 1999-11-12 | CRF receptor antagonists and methods relating thereto |
US09/574,751 US6531475B1 (en) | 1998-11-12 | 2000-05-18 | CRF receptor antagonists and methods relating thereto |
US10/339,780 US20040087589A1 (en) | 1998-11-12 | 2003-01-08 | CRF receptor antagonists and methods relating thereto |
US10/701,394 US20040157851A1 (en) | 1998-11-12 | 2003-11-04 | CRF receptor antagonists and methods relating thereto |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/339,780 Continuation US20040087589A1 (en) | 1998-11-12 | 2003-01-08 | CRF receptor antagonists and methods relating thereto |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040157851A1 true US20040157851A1 (en) | 2004-08-12 |
Family
ID=24297480
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/574,751 Expired - Lifetime US6531475B1 (en) | 1998-11-12 | 2000-05-18 | CRF receptor antagonists and methods relating thereto |
US10/339,780 Abandoned US20040087589A1 (en) | 1998-11-12 | 2003-01-08 | CRF receptor antagonists and methods relating thereto |
US10/701,394 Abandoned US20040157851A1 (en) | 1998-11-12 | 2003-11-04 | CRF receptor antagonists and methods relating thereto |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/574,751 Expired - Lifetime US6531475B1 (en) | 1998-11-12 | 2000-05-18 | CRF receptor antagonists and methods relating thereto |
US10/339,780 Abandoned US20040087589A1 (en) | 1998-11-12 | 2003-01-08 | CRF receptor antagonists and methods relating thereto |
Country Status (3)
Country | Link |
---|---|
US (3) | US6531475B1 (en) |
AU (1) | AU2001264657A1 (en) |
WO (1) | WO2001087885A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070027166A1 (en) * | 2005-07-22 | 2007-02-01 | Sunesis Pharmaceuticals, Inc. | Pyrazolo pyrimidines useful as aurora kinase inhibitors |
US20110136780A1 (en) * | 2009-06-08 | 2011-06-09 | Takeda Pharmaceutical Company Limited | Dihydropyrrolonaphtyridinone compounds as inhibitors of jak |
US10023535B2 (en) * | 2014-11-03 | 2018-07-17 | Olon S.P.A. | Method for the preparation of 1-(2-halogen-ethyl)-4 piperidine-carboxylic acid ethyl esters |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6531475B1 (en) * | 1998-11-12 | 2003-03-11 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods relating thereto |
US7273871B2 (en) * | 2001-07-17 | 2007-09-25 | Sb Pharmco Puerto Rico Inc. | Phenyl-5,6,6A,7,8,9-hexahydro-4H-1,4,9-triaza-phenalene derivatives as CRF antagonists |
EP2335700A1 (en) | 2001-07-25 | 2011-06-22 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C virus polymerase inhibitors with a heterobicylic structure |
RU2345995C2 (en) | 2003-06-25 | 2009-02-10 | Оно Фармасьютикал Ко., Лтд. | Methanesulfonic acid salt of pyrazolpyrimidine compound, its crystal and method of obtaining it |
US20060024661A1 (en) * | 2003-07-30 | 2006-02-02 | The Regents Of The University Of California | Modulation of CRF potentiation of NMDA receptor currents via CRF receptor 2 |
JP2008503444A (en) * | 2004-02-13 | 2008-02-07 | エスビー・ファルムコ・プエルト・リコ・インコーポレイテッド | CRF receptor antagonist, its preparation, its pharmaceutical composition and its use |
NZ549079A (en) | 2004-02-20 | 2010-08-27 | Boehringer Ingelheim Int | Viral polymerase inhibitors |
US7869958B2 (en) * | 2004-08-09 | 2011-01-11 | Research Development Foundation | Structure-based modulators of B1 G-protein coupled receptors |
EP1802621B1 (en) * | 2004-10-19 | 2009-05-06 | SmithKline Beecham (Cork) Limited | Crf receptor antagonists and methods relating thereto |
WO2008093075A2 (en) * | 2007-02-01 | 2008-08-07 | Astrazeneca Ab | 5,6,7,8-tetrahydropteridine derivatives as hsp90 inhibitors |
WO2010114905A1 (en) * | 2009-03-31 | 2010-10-07 | Arqule, Inc. | Peri-fused pyrazolo-pyrimidine compounds |
CN102892768A (en) * | 2009-12-30 | 2013-01-23 | 艾科尔公司 | Substituted pyrrolo-aminopyrimidine compounds |
WO2012143143A1 (en) | 2011-04-21 | 2012-10-26 | Origenis Gmbh | Heterocyclic compounds as kinase inhibitors |
TWI606049B (en) * | 2011-04-21 | 2017-11-21 | 原真股份有限公司 | Novel kinase inhibitors |
WO2014060112A1 (en) * | 2012-10-19 | 2014-04-24 | Origenis Gmbh | Pyrazolo[4,3-d]pyrimidines as kinase inhibitors |
US10000482B2 (en) | 2012-10-19 | 2018-06-19 | Origenis Gmbh | Kinase inhibitors |
CA2936974A1 (en) | 2014-01-21 | 2015-07-30 | Neurocrine Biosciences, Inc. | Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia |
WO2022221182A1 (en) * | 2021-04-12 | 2022-10-20 | Jnana Therapeutics Inc. | Small molecule inhibitors of mammalian slc34a1 function |
CN115594634A (en) * | 2022-10-26 | 2023-01-13 | 浙江工业大学(Cn) | Novel process for continuously preparing 4-nitropyrazole |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4605642A (en) * | 1984-02-23 | 1986-08-12 | The Salk Institute For Biological Studies | CRF antagonists |
US4904658A (en) * | 1988-04-15 | 1990-02-27 | American Cyanamid Company | Substituted-6H,8H-pyrimido-[1,2,3-cd]purine-8,10-(9H)-diones and substituted-6H,10H-pyrimido[1,2-cd]purin-10-ones |
US5063245A (en) * | 1990-03-28 | 1991-11-05 | Nova Pharmaceutical Corporation | Corticotropin-releasing factor antagonism compounds |
US5464847A (en) * | 1992-06-24 | 1995-11-07 | Elf Sanofi | Branched alkylamino derivatives of thiazole, processes for preparing them and pharmaceutical compositions containing them |
US5880135A (en) * | 1995-06-21 | 1999-03-09 | Sanofi | Substituted 4-phenylaminothiazoles, their process of preparation and the pharmaceutical compositions containing them |
US6514982B1 (en) * | 1998-11-12 | 2003-02-04 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods relating thereto |
US6531475B1 (en) * | 1998-11-12 | 2003-03-11 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods relating thereto |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL176526B1 (en) | 1992-12-17 | 1999-06-30 | Pfizer | Pyrolopyrimidines as compounds acting as antagonists of corticotrophin releasing factor |
JP2781661B2 (en) | 1992-12-17 | 1998-07-30 | フアイザー・インコーポレイテツド | Substituted pyrazoles as CRF antagonists |
TW336932B (en) | 1992-12-17 | 1998-07-21 | Pfizer | Amino-substituted pyrazoles |
US5712303A (en) | 1992-12-17 | 1998-01-27 | Pfizer Inc. | Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity |
TW444018B (en) | 1992-12-17 | 2001-07-01 | Pfizer | Pyrazolopyrimidines |
WO1995010506A1 (en) | 1993-10-12 | 1995-04-20 | The Du Pont Merck Pharmaceutical Company | 1n-alkyl-n-arylpyrimidinamines and derivatives thereof |
TW530047B (en) | 1994-06-08 | 2003-05-01 | Pfizer | Corticotropin releasing factor antagonists |
DK0765327T3 (en) | 1994-06-16 | 1999-11-29 | Pfizer | Pyrazolo and pyrrolopyridines |
EP0770080B1 (en) | 1995-05-12 | 1999-07-14 | Neurogen Corporation | Novel deazapurine derivatives; a new class of crf1 specific ligands |
US6107300A (en) | 1996-03-27 | 2000-08-22 | Dupont Pharmaceuticals | Arylamino fused pyrimidines |
ZA973884B (en) * | 1996-05-23 | 1998-11-06 | Du Pont Merck Pharma | Tetrahydropteridines and pyridylpiperazines for treatment of neurological disorders |
DE69736711T2 (en) * | 1996-08-28 | 2007-09-20 | Pfizer Inc. | SUBSTITUTED 6,5-HETEROBICYCLIC DERIVATIVES |
US6187777B1 (en) | 1998-02-06 | 2001-02-13 | Amgen Inc. | Compounds and methods which modulate feeding behavior and related diseases |
-
2000
- 2000-05-18 US US09/574,751 patent/US6531475B1/en not_active Expired - Lifetime
-
2001
- 2001-05-17 WO PCT/US2001/016048 patent/WO2001087885A1/en active Application Filing
- 2001-05-17 AU AU2001264657A patent/AU2001264657A1/en not_active Abandoned
-
2003
- 2003-01-08 US US10/339,780 patent/US20040087589A1/en not_active Abandoned
- 2003-11-04 US US10/701,394 patent/US20040157851A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4605642A (en) * | 1984-02-23 | 1986-08-12 | The Salk Institute For Biological Studies | CRF antagonists |
US4904658A (en) * | 1988-04-15 | 1990-02-27 | American Cyanamid Company | Substituted-6H,8H-pyrimido-[1,2,3-cd]purine-8,10-(9H)-diones and substituted-6H,10H-pyrimido[1,2-cd]purin-10-ones |
US5063245A (en) * | 1990-03-28 | 1991-11-05 | Nova Pharmaceutical Corporation | Corticotropin-releasing factor antagonism compounds |
US5464847A (en) * | 1992-06-24 | 1995-11-07 | Elf Sanofi | Branched alkylamino derivatives of thiazole, processes for preparing them and pharmaceutical compositions containing them |
US5880135A (en) * | 1995-06-21 | 1999-03-09 | Sanofi | Substituted 4-phenylaminothiazoles, their process of preparation and the pharmaceutical compositions containing them |
US6514982B1 (en) * | 1998-11-12 | 2003-02-04 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods relating thereto |
US6531475B1 (en) * | 1998-11-12 | 2003-03-11 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods relating thereto |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070027166A1 (en) * | 2005-07-22 | 2007-02-01 | Sunesis Pharmaceuticals, Inc. | Pyrazolo pyrimidines useful as aurora kinase inhibitors |
WO2007013964A1 (en) * | 2005-07-22 | 2007-02-01 | Sunesis Pharmaceuticals, Inc. | Pyrazolo pyrimidines useful as aurora kinase inhibitors |
JP2009502801A (en) * | 2005-07-22 | 2009-01-29 | サネシス ファーマシューティカルズ, インコーポレイテッド | Pyrazolopyrimidines useful as Aurora kinase inhibitors |
US7932257B2 (en) | 2005-07-22 | 2011-04-26 | Sunesis Pharmaceuticals, Inc. | Substituted pyrazolo[4,3-d]pyrimidines as aurora kinase inhibitors |
US20110136780A1 (en) * | 2009-06-08 | 2011-06-09 | Takeda Pharmaceutical Company Limited | Dihydropyrrolonaphtyridinone compounds as inhibitors of jak |
US8420816B2 (en) | 2009-06-08 | 2013-04-16 | Takeda Pharmaceutical Company Limited | Dihydropyrrolonaphthyridinone compounds as inhibitors of JAK |
US8785429B2 (en) | 2009-06-08 | 2014-07-22 | Takeda Pharmaceutical Company Limited | Dihydropyrrolonaphthyridinone compounds as inhibitors of JAK |
US10023535B2 (en) * | 2014-11-03 | 2018-07-17 | Olon S.P.A. | Method for the preparation of 1-(2-halogen-ethyl)-4 piperidine-carboxylic acid ethyl esters |
Also Published As
Publication number | Publication date |
---|---|
US20040087589A1 (en) | 2004-05-06 |
US6531475B1 (en) | 2003-03-11 |
AU2001264657A1 (en) | 2001-11-26 |
WO2001087885A1 (en) | 2001-11-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6514982B1 (en) | CRF receptor antagonists and methods relating thereto | |
US6531475B1 (en) | CRF receptor antagonists and methods relating thereto | |
US6352990B1 (en) | CRF receptor antagonists and methods relating thereto | |
EP1129096B1 (en) | Crf receptor antagonists and methods relating thereto | |
US6583143B2 (en) | CRF receptor antagonists and methods relating thereto | |
WO2005063756A1 (en) | Crf receptor antagonists and methods relating thereto | |
EP1341793B1 (en) | Crf receptor antagonists and methods relating thereto | |
ZA200308810B (en) | Tri-and tetraaza-acenaphthylen derivatives as CFR receptor antagonists. | |
US6440960B1 (en) | CRF receptor antagonists and methods relating thereto | |
EP1282624B1 (en) | Crf receptor antagonists and methods relating thereto | |
MXPA01004799A (en) | Crf receptor antagonists and methods relating thereto | |
ZA200104441B (en) | CRF receptor antagonists and methods relating thereto. | |
AU2004201701A1 (en) | Biazacyclic CRF antagonists | |
ZA200104442B (en) | CRF receptor antagonists and methods relating thereto. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |