US20130274263A1 - Tubulin inhibitors - Google Patents
Tubulin inhibitors Download PDFInfo
- Publication number
- US20130274263A1 US20130274263A1 US13/797,568 US201313797568A US2013274263A1 US 20130274263 A1 US20130274263 A1 US 20130274263A1 US 201313797568 A US201313797568 A US 201313797568A US 2013274263 A1 US2013274263 A1 US 2013274263A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- independently
- hetaryl
- aryl
- alkylnr
- 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 *C([W])N([1*])C1=CC=CC(C2=CC=CC=C2)=C1.*C([W])N([1*])C1=CC=CC(C2=CC=CC=C2)=C1.*C([W])N([1*])C1=CN=CC(C2=CC=CC=C2)=N1.*C([W])N([1*])C1=CN=CC(C2=CC=CC=C2)=N1.CC[Y].CC[Y].[2*]C.[2*]C.[2*]C.[2*]C.[3*]C.[3*]C.[4*]C.[4*]C Chemical compound *C([W])N([1*])C1=CC=CC(C2=CC=CC=C2)=C1.*C([W])N([1*])C1=CC=CC(C2=CC=CC=C2)=C1.*C([W])N([1*])C1=CN=CC(C2=CC=CC=C2)=N1.*C([W])N([1*])C1=CN=CC(C2=CC=CC=C2)=N1.CC[Y].CC[Y].[2*]C.[2*]C.[2*]C.[2*]C.[3*]C.[3*]C.[4*]C.[4*]C 0.000 description 15
- SZBZPAKISJWWOL-NJGKNCJVSA-N CC1=CN=CC=C1.CC1CCC(=O)C1.CC1CCCNC1.CC1CCNCC1.CC1NC(=O)NC1=O.CCCCN1CCOCC1.CN1C=CN=C1.CN1CCC(O)CC1.CN1CCCC1.CN1CCCCC1.CN1CCC[C@H]1CO.CN1CCN(C)CC1.CN1CCOCC1 Chemical compound CC1=CN=CC=C1.CC1CCC(=O)C1.CC1CCCNC1.CC1CCNCC1.CC1NC(=O)NC1=O.CCCCN1CCOCC1.CN1C=CN=C1.CN1CCC(O)CC1.CN1CCCC1.CN1CCCCC1.CN1CCC[C@H]1CO.CN1CCN(C)CC1.CN1CCOCC1 SZBZPAKISJWWOL-NJGKNCJVSA-N 0.000 description 3
- COYHINGWCPWBDM-LJQANCHMSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CC)C3=CC=CN=C3)=C(C)C=N2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CC)C3=CC=CN=C3)=C(C)C=N2)C=C1OC COYHINGWCPWBDM-LJQANCHMSA-N 0.000 description 2
- FHIJWYAHRBLTJW-HXUWFJFHSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CCC)C3=CC=CN=C3)=C(C)C=N2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CCC)C3=CC=CN=C3)=C(C)C=N2)C=C1OC FHIJWYAHRBLTJW-HXUWFJFHSA-N 0.000 description 2
- JGIWFZJRMCDKSQ-UHFFFAOYSA-N CCCC(CC1=NN=C(C)C(C2=CC(OC)=C(OC)C(OC)=C2)=N1)C1=CC=CC=C1 Chemical compound CCCC(CC1=NN=C(C)C(C2=CC(OC)=C(OC)C(OC)=C2)=N1)C1=CC=CC=C1 JGIWFZJRMCDKSQ-UHFFFAOYSA-N 0.000 description 2
- WVUOBKMZWLWSCK-MRXNPFEDSA-N CCC[C@H](CC1=C(C)C=NC(C2=CC=C(O)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCC[C@H](CC1=C(C)C=NC(C2=CC=C(O)C(OC)=C2)=N1)C1=CC=CN=C1 WVUOBKMZWLWSCK-MRXNPFEDSA-N 0.000 description 2
- LLFBCFIERDCSSJ-GOSISDBHSA-N CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CN=C1 LLFBCFIERDCSSJ-GOSISDBHSA-N 0.000 description 2
- HPTFQTCAGVVXRT-OAHLLOKOSA-N CC[C@H](CC1=C(C)C=NC(C2=CC=C(O)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CC[C@H](CC1=C(C)C=NC(C2=CC=C(O)C(OC)=C2)=N1)C1=CC=CN=C1 HPTFQTCAGVVXRT-OAHLLOKOSA-N 0.000 description 2
- FXRMANVELJRFEV-ZDUSSCGKSA-N COC1=C(O)C=CC(C2=NC(C[C@H](C)C3=CC=CC=C3)=NN=C2C)=C1 Chemical compound COC1=C(O)C=CC(C2=NC(C[C@H](C)C3=CC=CC=C3)=NN=C2C)=C1 FXRMANVELJRFEV-ZDUSSCGKSA-N 0.000 description 2
- MAJRDIHNXUCIJL-ZDUSSCGKSA-N [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)[C@@H](C)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)[C@@H](C)C1=CC=CC=C1 MAJRDIHNXUCIJL-ZDUSSCGKSA-N 0.000 description 2
- OEURSOCIEXBPQE-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(OCCN(CC)CC)C(OC)=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(OCCN(CC)CC)C(OC)=C2)=N1)C(CCC)C1=CC=CC=C1 OEURSOCIEXBPQE-UHFFFAOYSA-N 0.000 description 2
- GFYPMWSFVHTPCU-UHFFFAOYSA-N BrC1=CN=CC(Br)=C1.CCCC(CC1=CC(Br)=CN=C1)C1=CC=CC=C1 Chemical compound BrC1=CN=CC(Br)=C1.CCCC(CC1=CC(Br)=CN=C1)C1=CC=CC=C1 GFYPMWSFVHTPCU-UHFFFAOYSA-N 0.000 description 1
- DSJGCTCSJJKDLK-UHFFFAOYSA-N C(c1ccccc1)Nc1cncc(-c2ccc(CN3CCCC3)cc2)n1 Chemical compound C(c1ccccc1)Nc1cncc(-c2ccc(CN3CCCC3)cc2)n1 DSJGCTCSJJKDLK-UHFFFAOYSA-N 0.000 description 1
- WMRORYPITGNACG-UTONKHPSSA-N CC1=C(Cl)N=C(Cl)N=C1.CCC[C@H](CC1=C(C)C=NC(Cl)=N1)C1=CC=CN=C1 Chemical compound CC1=C(Cl)N=C(Cl)N=C1.CCC[C@H](CC1=C(C)C=NC(Cl)=N1)C1=CC=CN=C1 WMRORYPITGNACG-UTONKHPSSA-N 0.000 description 1
- STGILYMMMJKHBW-UHFFFAOYSA-N CC1=C(N)C=CC(Br)=C1.CCCC(=O)CC1=C(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C1 Chemical compound CC1=C(N)C=CC(Br)=C1.CCCC(=O)CC1=C(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C1 STGILYMMMJKHBW-UHFFFAOYSA-N 0.000 description 1
- HFRJWXXPQDVWHT-UHFFFAOYSA-N CC1=NN=C(Cl)N=C1Cl.COC1=CC(C2=NC(Cl)=NN=C2C)=CC=C1OCC1=CC=CC=C1 Chemical compound CC1=NN=C(Cl)N=C1Cl.COC1=CC(C2=NC(Cl)=NN=C2C)=CC=C1OCC1=CC=CC=C1 HFRJWXXPQDVWHT-UHFFFAOYSA-N 0.000 description 1
- AZOKTMKGWQFZIT-UHFFFAOYSA-N CCCC(=O)C1=CC(C)=CN=C1.CCCC(N)C1=CC(C)=CN=C1 Chemical compound CCCC(=O)C1=CC(C)=CN=C1.CCCC(N)C1=CC(C)=CN=C1 AZOKTMKGWQFZIT-UHFFFAOYSA-N 0.000 description 1
- CSLZZRKCFYZKJX-HNCPQSOCSA-N CCCC(=O)C1=CC=C(F)C=C1.CCC[C@@H](O)C1=CC=C(F)C=C1 Chemical compound CCCC(=O)C1=CC=C(F)C=C1.CCC[C@@H](O)C1=CC=C(F)C=C1 CSLZZRKCFYZKJX-HNCPQSOCSA-N 0.000 description 1
- OERMFCKKSHJMQF-UHFFFAOYSA-N CCCC(=O)C1=CC=CC(F)=C1.CON(C)C(=O)C1=CC=CC(F)=C1 Chemical compound CCCC(=O)C1=CC=CC(F)=C1.CON(C)C(=O)C1=CC=CC(F)=C1 OERMFCKKSHJMQF-UHFFFAOYSA-N 0.000 description 1
- PPKAKLPKYNIMRJ-SBSPUUFOSA-N CCCC(=O)C1=CC=CN=C1.CCC[C@@H](O)C1=CC=CN=C1 Chemical compound CCCC(=O)C1=CC=CN=C1.CCC[C@@H](O)C1=CC=CN=C1 PPKAKLPKYNIMRJ-SBSPUUFOSA-N 0.000 description 1
- GXXJRMVOGNKGRH-LJQANCHMSA-N CCCC(=O)CC1=CC=C(C2=CC(C[C@@H](CCC)C3=CC=CN=C3)=NC=N2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=CC(C[C@@H](CCC)C3=CC=CN=C3)=NC=N2)C=C1OC GXXJRMVOGNKGRH-LJQANCHMSA-N 0.000 description 1
- DLSSSLOPMJWVQN-HCUKNYMBSA-N CCCC(=O)CC1=CC=C(C2=CC(C[C@@H](CCC)C3=CC=CN=C3)=NC=N2)C=C1OC.CCCC(CC1=CN=CC(C2=CC=C(CN)C(OC)=C2)=N1)C1=CC=CN=C1.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)CN(C)C)C(OC)=C2)=N1)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC=C(CN)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound CCCC(=O)CC1=CC=C(C2=CC(C[C@@H](CCC)C3=CC=CN=C3)=NC=N2)C=C1OC.CCCC(CC1=CN=CC(C2=CC=C(CN)C(OC)=C2)=N1)C1=CC=CN=C1.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)CN(C)C)C(OC)=C2)=N1)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC=C(CN)C=C2)=N1)C(CCC)C1=CC=CC=C1 DLSSSLOPMJWVQN-HCUKNYMBSA-N 0.000 description 1
- GQQFUVBDDIENLW-UHFFFAOYSA-N CCCC(=O)CC1=CC=C(C2=NC(CC(CCC)C3=CC=CC=C3)=C(C)N=C2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(CC(CCC)C3=CC=CC=C3)=C(C)N=C2)C=C1OC GQQFUVBDDIENLW-UHFFFAOYSA-N 0.000 description 1
- XYJDLIAPIMBJDP-OXVLKALQSA-N CCCC(=O)CC1=CC=C(C2=NC(CC(CCC)C3=CC=CC=C3)=C(C)N=C2)C=C1OC.CCCC(=O)CC1=CC=C(C2=NC(CC(CCOC)C3=CC=CC=C3)=CN=C2)C=C1OC.CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](COC)C3=CC=CC=C3)=CN=C2)C=C1OC.CCCC(CC1=CN=CC(C2=CC=C(C(=O)NCCCCCN)C(C)=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CN=C1C.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NC)C(OC)=C2)=N1)C1=CC=CC=N1 Chemical compound CCCC(=O)CC1=CC=C(C2=NC(CC(CCC)C3=CC=CC=C3)=C(C)N=C2)C=C1OC.CCCC(=O)CC1=CC=C(C2=NC(CC(CCOC)C3=CC=CC=C3)=CN=C2)C=C1OC.CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](COC)C3=CC=CC=C3)=CN=C2)C=C1OC.CCCC(CC1=CN=CC(C2=CC=C(C(=O)NCCCCCN)C(C)=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CN=C1C.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NC)C(OC)=C2)=N1)C1=CC=CC=N1 XYJDLIAPIMBJDP-OXVLKALQSA-N 0.000 description 1
- ZJMRENMXRSXKKB-UHFFFAOYSA-N CCCC(=O)CC1=CC=C(C2=NC(CC(CCOC)C3=CC=CC=C3)=CN=C2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(CC(CCOC)C3=CC=CC=C3)=CN=C2)C=C1OC ZJMRENMXRSXKKB-UHFFFAOYSA-N 0.000 description 1
- QCHJNQDJPUNHHX-GOSISDBHSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](C)C3=CC=CC=C3)=CN=C2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](C)C3=CC=CC=C3)=CN=C2)C=C1OC QCHJNQDJPUNHHX-GOSISDBHSA-N 0.000 description 1
- GASOUYBUYLITDF-GOSISDBHSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CC)C3=CC=CN=C3)=CN=C2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CC)C3=CC=CN=C3)=CN=C2)C=C1OC GASOUYBUYLITDF-GOSISDBHSA-N 0.000 description 1
- NXXOLPSVTWFSNY-UQTKDWPTSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CC)C3=CC=CN=C3)=CN=C2)C=C1OC.CCCC(CC1=CN=CC(C2=CC=C(C(=O)N3CCN(C)CC3)C=C2)=N1)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)C3CCNCC3)C=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC=C(C(=O)NCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(C(=O)NCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(C(=O)NCCN(C)C)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CC)C3=CC=CN=C3)=CN=C2)C=C1OC.CCCC(CC1=CN=CC(C2=CC=C(C(=O)N3CCN(C)CC3)C=C2)=N1)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)C3CCNCC3)C=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC=C(C(=O)NCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(C(=O)NCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(C(=O)NCCN(C)C)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 NXXOLPSVTWFSNY-UQTKDWPTSA-N 0.000 description 1
- XLKLOTLLHWBUIQ-OAFLPQRXSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CCC)C3=CC=CN=C3)=C(C)C=N2)C=C1OC.CCC[C@H](CC1=C(C)C=NC(Cl)=N1)C1=CC=CN=C1 Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CCC)C3=CC=CN=C3)=C(C)C=N2)C=C1OC.CCC[C@H](CC1=C(C)C=NC(Cl)=N1)C1=CC=CN=C1 XLKLOTLLHWBUIQ-OAFLPQRXSA-N 0.000 description 1
- NZHWSZZALFVHHU-LJQANCHMSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CCC)C3=CC=CN=C3)=CC=N2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CCC)C3=CC=CN=C3)=CC=N2)C=C1OC NZHWSZZALFVHHU-LJQANCHMSA-N 0.000 description 1
- INBNKMOJNAXJPB-RDPZFBCOSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CCC)C3=CC=CN=C3)=CN=C2)C=C1OC.CCC[C@H](CC1=CN=CC(Cl)=N1)C1=CC=CN=C1 Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](CCC)C3=CC=CN=C3)=CN=C2)C=C1OC.CCC[C@H](CC1=CN=CC(Cl)=N1)C1=CC=CN=C1 INBNKMOJNAXJPB-RDPZFBCOSA-N 0.000 description 1
- KNWFURKOZKZLHG-QFIPXVFZSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](COC)C3=CC=CC=C3)=CN=C2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](COC)C3=CC=CC=C3)=CN=C2)C=C1OC KNWFURKOZKZLHG-QFIPXVFZSA-N 0.000 description 1
- FTLGLWKLPITSSU-QHCPKHFHSA-N CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](COCC)C3=CC=CC=C3)=CN=C2)C=C1OC Chemical compound CCCC(=O)CC1=CC=C(C2=NC(C[C@@H](COCC)C3=CC=CC=C3)=CN=C2)C=C1OC FTLGLWKLPITSSU-QHCPKHFHSA-N 0.000 description 1
- MGNLQQOPVYPTPX-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC(C)=C(O)C(C)=C2)=C1)C1=CC=CC=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC(C)=C(O)C(C)=C2)=C1)C1=CC=CC=C1 MGNLQQOPVYPTPX-UHFFFAOYSA-N 0.000 description 1
- XTCHHXOJGYVUJJ-BPLPWMOCSA-N CCCC(CC1=CN=CC(C2=CC(C)=C(O)C(C)=C2)=C1)C1=CC=CC=C1.CCCC(CC1=CN=CC(C2=CC(OC)=C(O)C=C2)=C1)C1=CC=CC=C1.CCCC(CC1=CN=CC(C2=CC(OC)=C(OC)C(OC)=C2)=C1)C1=CC=CC=C1.CCCC(CC1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)C1=CC=CN=C1.CCCC(CC1=NN=C(C)C(C2=CC(OC)=C(O)C=C2)=N1)C1=CC=CC=C1.CCCC(CC1=NN=C(C)C(C2=CC(OC)=C(OC)C(OC)=C2)=N1)C1=CC=CC=C1.COC1=C(O)C=CC(C2=CC(C[C@@H](C)C3=CC=CC=C3)=CN=C2)=C1.COC1=CC(C2=NC(C[C@H](C)C3=CC=CC=C3)=NN=C2C)=CC(OC)=C1OC Chemical compound CCCC(CC1=CN=CC(C2=CC(C)=C(O)C(C)=C2)=C1)C1=CC=CC=C1.CCCC(CC1=CN=CC(C2=CC(OC)=C(O)C=C2)=C1)C1=CC=CC=C1.CCCC(CC1=CN=CC(C2=CC(OC)=C(OC)C(OC)=C2)=C1)C1=CC=CC=C1.CCCC(CC1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)C1=CC=CN=C1.CCCC(CC1=NN=C(C)C(C2=CC(OC)=C(O)C=C2)=N1)C1=CC=CC=C1.CCCC(CC1=NN=C(C)C(C2=CC(OC)=C(OC)C(OC)=C2)=N1)C1=CC=CC=C1.COC1=C(O)C=CC(C2=CC(C[C@@H](C)C3=CC=CC=C3)=CN=C2)=C1.COC1=CC(C2=NC(C[C@H](C)C3=CC=CC=C3)=NN=C2C)=CC(OC)=C1OC XTCHHXOJGYVUJJ-BPLPWMOCSA-N 0.000 description 1
- QEXFJUGSQQBIBQ-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC(OC)=C(O)C=C2)=C1)C1=CC=CC=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC(OC)=C(O)C=C2)=C1)C1=CC=CC=C1 QEXFJUGSQQBIBQ-UHFFFAOYSA-N 0.000 description 1
- YHPASIQTQQGWLL-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC(OC)=C(OC)C(OC)=C2)=C1)C1=CC=CC=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC(OC)=C(OC)C(OC)=C2)=C1)C1=CC=CC=C1 YHPASIQTQQGWLL-UHFFFAOYSA-N 0.000 description 1
- WATRQHJYRHFVBS-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCCC3)C=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCCC3)C=C2)=N1)C1=CC=CN=C1 WATRQHJYRHFVBS-UHFFFAOYSA-N 0.000 description 1
- MZZIPOBTFUMQKK-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCCC3)C=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCN(C)CC3)C=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCOCC3)C=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(C(=O)N3CCOCC3)C=C2)=N1)C1=CC=CC=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCCN3CCOCC3)C(OC)=C2)=N1)C1=CC=CN=C1.CCNC(=O)CC1=CC=C(C2=NC(CC(C)C3=CC=CN=C3)=CN=C2)C=C1OC Chemical compound CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCCC3)C=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCN(C)CC3)C=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCOCC3)C=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(C(=O)N3CCOCC3)C=C2)=N1)C1=CC=CC=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCCN3CCOCC3)C(OC)=C2)=N1)C1=CC=CN=C1.CCNC(=O)CC1=CC=C(C2=NC(CC(C)C3=CC=CN=C3)=CN=C2)C=C1OC MZZIPOBTFUMQKK-UHFFFAOYSA-N 0.000 description 1
- KSSFJUSNINWWIK-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCN(C)CC3)C=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCN(C)CC3)C=C2)=N1)C1=CC=CN=C1 KSSFJUSNINWWIK-UHFFFAOYSA-N 0.000 description 1
- SHVYKCDATFNJJD-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCOCC3)C=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC(OC)=C(OCCCN3CCOCC3)C=C2)=N1)C1=CC=CN=C1 SHVYKCDATFNJJD-UHFFFAOYSA-N 0.000 description 1
- OAEXZRMOGQQUGR-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(C(=O)N3CCN(C)CC3)C=C2)=N1)C1=CC=CC=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(C(=O)N3CCN(C)CC3)C=C2)=N1)C1=CC=CC=C1 OAEXZRMOGQQUGR-UHFFFAOYSA-N 0.000 description 1
- ZMIUIJBONLIYIL-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(C(=O)N3CCOCC3)C=C2)=N1)C1=CC=CC=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(C(=O)N3CCOCC3)C=C2)=N1)C1=CC=CC=C1 ZMIUIJBONLIYIL-UHFFFAOYSA-N 0.000 description 1
- LHYYQGYYPCGTOS-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(C(=O)NCCCCCN)C(C)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(C(=O)NCCCCCN)C(C)=C2)=N1)C1=CC=CN=C1 LHYYQGYYPCGTOS-UHFFFAOYSA-N 0.000 description 1
- ZGSMFVUZXJQGPN-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=C(C)C=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=C(C)C=CN=C1 ZGSMFVUZXJQGPN-UHFFFAOYSA-N 0.000 description 1
- ZCAOEMWDSGXEOT-CIMPTMRPSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=C(C)C=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CC=N1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=C(C)C=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CC=N1.CCCC(CC1=CN=CC(C2=CC=C(CO)C(OC)=C2)=N1)C1=CC=CN=C1.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CC=N1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=C(C)C=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CC=N1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=C(C)C=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CC=N1.CCCC(CC1=CN=CC(C2=CC=C(CO)C(OC)=C2)=N1)C1=CC=CN=C1.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CC=N1 ZCAOEMWDSGXEOT-CIMPTMRPSA-N 0.000 description 1
- JZQSSCYWKYYNQT-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CC=N1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CC=N1 JZQSSCYWKYYNQT-UHFFFAOYSA-N 0.000 description 1
- RKEVCRJCZVCRNK-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CN=C1 RKEVCRJCZVCRNK-UHFFFAOYSA-N 0.000 description 1
- ZFGOJKDMVZWQAY-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(CC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(CC)=C2)=N1)C1=CC=CN=C1 ZFGOJKDMVZWQAY-UHFFFAOYSA-N 0.000 description 1
- WQOKNFQPFABTQE-JZMFQGMNSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(CC)=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC(C)=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCCN(CC)CC)C(OC)=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCN(C)C)C(OC)=C2)=N1)C1=CC=CN=C1.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CN=C1.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(CC)=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC(C)=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCCN(CC)CC)C(OC)=C2)=N1)C1=CC=CN=C1.CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCN(C)C)C(OC)=C2)=N1)C1=CC=CN=C1.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CN=C1.CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CN=C1 WQOKNFQPFABTQE-JZMFQGMNSA-N 0.000 description 1
- PJVLJOUUAJOXNW-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=C(C)C=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=C(C)C=CN=C1 PJVLJOUUAJOXNW-UHFFFAOYSA-N 0.000 description 1
- IHVABWISIMSGAF-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC(C)=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC(C)=CN=C1 IHVABWISIMSGAF-UHFFFAOYSA-N 0.000 description 1
- XAHDLBXYNDMLSS-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CC=N1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CC=N1 XAHDLBXYNDMLSS-UHFFFAOYSA-N 0.000 description 1
- IMFSZJXNQBALIM-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CN=C1C Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CN=C1C IMFSZJXNQBALIM-UHFFFAOYSA-N 0.000 description 1
- OLLYCSRRBNTIFI-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCCN(CC)CC)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCCN(CC)CC)C(OC)=C2)=N1)C1=CC=CN=C1 OLLYCSRRBNTIFI-UHFFFAOYSA-N 0.000 description 1
- PYMNRGHQGSQPLK-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCCN3CCOCC3)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCCN3CCOCC3)C(OC)=C2)=N1)C1=CC=CN=C1 PYMNRGHQGSQPLK-UHFFFAOYSA-N 0.000 description 1
- FYXGSEWZUHABRV-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCN(C)C)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CC(=O)NCCN(C)C)C(OC)=C2)=N1)C1=CC=CN=C1 FYXGSEWZUHABRV-UHFFFAOYSA-N 0.000 description 1
- DKMKYCNWBWFJRX-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CN)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CN)C(OC)=C2)=N1)C1=CC=CN=C1 DKMKYCNWBWFJRX-UHFFFAOYSA-N 0.000 description 1
- MGQZJXKZAHHPKB-UHFFFAOYSA-N CCCC(CC1=CN=CC(C2=CC=C(CO)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCCC(CC1=CN=CC(C2=CC=C(CO)C(OC)=C2)=N1)C1=CC=CN=C1 MGQZJXKZAHHPKB-UHFFFAOYSA-N 0.000 description 1
- FTTAIHNCBSHKQE-UHFFFAOYSA-N CCCC(CC1=CN=CC(Cl)=N1)C1=CC(N)=CC=C1.CCCC(CC1=CN=CC(Cl)=N1)C1=CC(NC(C)=O)=CC=C1 Chemical compound CCCC(CC1=CN=CC(Cl)=N1)C1=CC(N)=CC=C1.CCCC(CC1=CN=CC(Cl)=N1)C1=CC(NC(C)=O)=CC=C1 FTTAIHNCBSHKQE-UHFFFAOYSA-N 0.000 description 1
- SWFQGNBNUDLCDQ-UHFFFAOYSA-N CCCC(CC1=CN=CC(Cl)=N1)C1=CC=C(C(F)(F)F)C=C1.CCCC(N)C1=CC=C(C(F)(F)F)C=C1 Chemical compound CCCC(CC1=CN=CC(Cl)=N1)C1=CC=C(C(F)(F)F)C=C1.CCCC(N)C1=CC=C(C(F)(F)F)C=C1 SWFQGNBNUDLCDQ-UHFFFAOYSA-N 0.000 description 1
- KTCODDKWQLMARX-UHFFFAOYSA-N CCCC(CC1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)C1=CC=CN=C1 Chemical compound CCCC(CC1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)C1=CC=CN=C1 KTCODDKWQLMARX-UHFFFAOYSA-N 0.000 description 1
- SXFGIRIWHPJLRH-UHFFFAOYSA-N CCCC(CC1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)C1=CC=CN=C1.CCCC(CC1=NC=NC(Cl)=C1)C1=CC=CN=C1 Chemical compound CCCC(CC1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)C1=CC=CN=C1.CCCC(CC1=NC=NC(Cl)=C1)C1=CC=CN=C1 SXFGIRIWHPJLRH-UHFFFAOYSA-N 0.000 description 1
- LFVHRVZYGJRDPO-UHFFFAOYSA-N CCCC(CC1=NC=NC(Cl)=C1)C1=CC=CN=C1.ClC1=CC(Cl)=NC=N1 Chemical compound CCCC(CC1=NC=NC(Cl)=C1)C1=CC=CN=C1.ClC1=CC(Cl)=NC=N1 LFVHRVZYGJRDPO-UHFFFAOYSA-N 0.000 description 1
- LEGNRHVSLHBPBG-UHFFFAOYSA-N CCCC(CC1=NN=C(C)C(C2=CC(OC)=C(O)C=C2)=N1)C1=CC=CC=C1 Chemical compound CCCC(CC1=NN=C(C)C(C2=CC(OC)=C(O)C=C2)=N1)C1=CC=CC=C1 LEGNRHVSLHBPBG-UHFFFAOYSA-N 0.000 description 1
- FTJVADHXVORGOD-UHFFFAOYSA-N CCCC(CC1=NN=C(C)C(C2=CC=C(OCC3=CC=CC=C3)C(OC)=C2)=N1)C1=CC=CC=C1.COC1=CC(C2=NC(Cl)=NN=C2C)=CC=C1OCC1=CC=CC=C1 Chemical compound CCCC(CC1=NN=C(C)C(C2=CC=C(OCC3=CC=CC=C3)C(OC)=C2)=N1)C1=CC=CC=C1.COC1=CC(C2=NC(Cl)=NN=C2C)=CC=C1OCC1=CC=CC=C1 FTJVADHXVORGOD-UHFFFAOYSA-N 0.000 description 1
- RXDYFMDVQLPQGQ-UHFFFAOYSA-N CCCC(N)C1=CC=C(C(F)(F)F)C=C1.CCCC(N=[N+]=[N-])C1=CC=C(C(F)(F)F)C=C1 Chemical compound CCCC(N)C1=CC=C(C(F)(F)F)C=C1.CCCC(N=[N+]=[N-])C1=CC=C(C(F)(F)F)C=C1 RXDYFMDVQLPQGQ-UHFFFAOYSA-N 0.000 description 1
- UFAPGAZFFMGJHK-UHFFFAOYSA-N CCCC(N=[N+]=[N-])C1=CC=C(C(F)(F)F)C=C1.CCCC(O)C1=CC=C(C(F)(F)F)C=C1 Chemical compound CCCC(N=[N+]=[N-])C1=CC=C(C(F)(F)F)C=C1.CCCC(O)C1=CC=C(C(F)(F)F)C=C1 UFAPGAZFFMGJHK-UHFFFAOYSA-N 0.000 description 1
- HPTVMQGTRZLVDF-UHFFFAOYSA-M CCCC(O)C1=CC=C(C(F)(F)F)C=C1.CCC[Mg]Cl.[H]C(=O)C1=CC=C(C(F)(F)F)C=C1 Chemical compound CCCC(O)C1=CC=C(C(F)(F)F)C=C1.CCC[Mg]Cl.[H]C(=O)C1=CC=C(C(F)(F)F)C=C1 HPTVMQGTRZLVDF-UHFFFAOYSA-M 0.000 description 1
- BJCDMWISPSWROB-UHFFFAOYSA-N CCCC(c1ccc(C(F)(F)F)cc1)N Chemical compound CCCC(c1ccc(C(F)(F)F)cc1)N BJCDMWISPSWROB-UHFFFAOYSA-N 0.000 description 1
- PZCTXAXFFNZQQI-UHFFFAOYSA-N CCCC(c1ccccc1)Nc1cc(-c(cc2OC)ccc2O)cnc1 Chemical compound CCCC(c1ccccc1)Nc1cc(-c(cc2OC)ccc2O)cnc1 PZCTXAXFFNZQQI-UHFFFAOYSA-N 0.000 description 1
- MMJGXNHPZSDCSS-UHFFFAOYSA-N CCCC(c1cnccc1)Nc1nc(-c(cc2OC)ccc2OCCCN2CCCC2)cnc1 Chemical compound CCCC(c1cnccc1)Nc1nc(-c(cc2OC)ccc2OCCCN2CCCC2)cnc1 MMJGXNHPZSDCSS-UHFFFAOYSA-N 0.000 description 1
- ZBQXUMNPYYNKTB-UHFFFAOYSA-N CCCC(c1cnccc1C)Nc1nc(-c(cc2)cc(C)c2NC(NCC)=O)cnc1 Chemical compound CCCC(c1cnccc1C)Nc1nc(-c(cc2)cc(C)c2NC(NCC)=O)cnc1 ZBQXUMNPYYNKTB-UHFFFAOYSA-N 0.000 description 1
- GRWCIMWQRWLFCF-UHFFFAOYSA-N CCCC(c1ncccc1)Nc1nc(-c(cc2)cc(C)c2NC(NCC)=O)cnc1 Chemical compound CCCC(c1ncccc1)Nc1nc(-c(cc2)cc(C)c2NC(NCC)=O)cnc1 GRWCIMWQRWLFCF-UHFFFAOYSA-N 0.000 description 1
- WAXOKXVETHHTDG-LJQANCHMSA-N CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)CN(C)C)C(OC)=C2)=N1)C1=CC=CN=C1 Chemical compound CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)CN(C)C)C(OC)=C2)=N1)C1=CC=CN=C1 WAXOKXVETHHTDG-LJQANCHMSA-N 0.000 description 1
- OGKPDOVOVZOQFW-QGZVFWFLSA-N CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NC)C(OC)=C2)=N1)C1=CC=CC=N1 Chemical compound CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NC)C(OC)=C2)=N1)C1=CC=CC=N1 OGKPDOVOVZOQFW-QGZVFWFLSA-N 0.000 description 1
- RKEVCRJCZVCRNK-HXUWFJFHSA-N CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CN=C1 Chemical compound CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(C)=C2)=N1)C1=CC=CN=C1 RKEVCRJCZVCRNK-HXUWFJFHSA-N 0.000 description 1
- XAHDLBXYNDMLSS-GOSISDBHSA-N CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CC=N1 Chemical compound CCC[C@H](CC1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C1=CC=CC=N1 XAHDLBXYNDMLSS-GOSISDBHSA-N 0.000 description 1
- CHSYTSMHPLPKHF-UHFFFAOYSA-N CCNC(=O)CC1=CC=C(C2=NC(CC(C)C3=CC=CN=C3)=CN=C2)C=C1OC Chemical compound CCNC(=O)CC1=CC=C(C2=NC(CC(C)C3=CC=CN=C3)=CN=C2)C=C1OC CHSYTSMHPLPKHF-UHFFFAOYSA-N 0.000 description 1
- RQOXEMMAAVCMRU-UHFFFAOYSA-N CN(C(c1cc(F)ccc1)=O)OC Chemical compound CN(C(c1cc(F)ccc1)=O)OC RQOXEMMAAVCMRU-UHFFFAOYSA-N 0.000 description 1
- IDBDULWMYBAKBL-OAHLLOKOSA-N COC1=C(O)C=CC(C2=CC(C[C@@H](C)C3=CC=CC=C3)=CN=C2)=C1 Chemical compound COC1=C(O)C=CC(C2=CC(C[C@@H](C)C3=CC=CC=C3)=CN=C2)=C1 IDBDULWMYBAKBL-OAHLLOKOSA-N 0.000 description 1
- NWDMNRCBBDGINP-CHNGVTQJSA-N COC1=C(O)C=CC(C2=NC(C[C@H](C)C3=CC=CC=C3)=NN=C2C)=C1.[H]N(C1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)[C@@H](C)C1=CC=CC=C1 Chemical compound COC1=C(O)C=CC(C2=NC(C[C@H](C)C3=CC=CC=C3)=NN=C2C)=C1.[H]N(C1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)[C@@H](C)C1=CC=CC=C1 NWDMNRCBBDGINP-CHNGVTQJSA-N 0.000 description 1
- BNZCWDLQDYOAPV-UHFFFAOYSA-N COC1=CC(C2=NC(CC(CCO)C3=CC=CC=C3)=C(C)C=N2)=CC=C1O Chemical compound COC1=CC(C2=NC(CC(CCO)C3=CC=CC=C3)=C(C)C=N2)=CC=C1O BNZCWDLQDYOAPV-UHFFFAOYSA-N 0.000 description 1
- CEKPOUFNBQNEFT-AWEZNQCLSA-N COC1=CC(C2=NC(C[C@H](C)C3=CC=CC=C3)=NN=C2C)=CC(OC)=C1OC Chemical compound COC1=CC(C2=NC(C[C@H](C)C3=CC=CC=C3)=NN=C2C)=CC(OC)=C1OC CEKPOUFNBQNEFT-AWEZNQCLSA-N 0.000 description 1
- LVTISRZKXDCOFE-UHFFFAOYSA-N CON(C)C(=O)C1=CC=CC(F)=C1.O=C(O)C1=CC=CC(F)=C1 Chemical compound CON(C)C(=O)C1=CC=CC(F)=C1.O=C(O)C1=CC=CC(F)=C1 LVTISRZKXDCOFE-UHFFFAOYSA-N 0.000 description 1
- VHAWHYGKBBSGIW-AWEZNQCLSA-N C[C@@H](c1ccccc1)Nc1cncc(-c(cc2OC)ccc2O)c1 Chemical compound C[C@@H](c1ccccc1)Nc1cncc(-c(cc2OC)ccc2O)c1 VHAWHYGKBBSGIW-AWEZNQCLSA-N 0.000 description 1
- ORUHJUWZOHCZJR-UHFFFAOYSA-N NC(CC(=O)O)C1=CC=CC=C1.NC(CCO)C1=CC=CC=C1 Chemical compound NC(CC(=O)O)C1=CC=CC=C1.NC(CCO)C1=CC=CC=C1 ORUHJUWZOHCZJR-UHFFFAOYSA-N 0.000 description 1
- MXNBDFWNYRNIBH-UHFFFAOYSA-N OC(c1cc(F)ccc1)=O Chemical compound OC(c1cc(F)ccc1)=O MXNBDFWNYRNIBH-UHFFFAOYSA-N 0.000 description 1
- VSSRHFINAWKZTQ-ZDUSSCGKSA-N [H]N(C1=CC=NC(C2=CC=C(O)C(OC)=C2)=N1)[C@@H](C)C1=CC=CC=C1 Chemical compound [H]N(C1=CC=NC(C2=CC=C(O)C(OC)=C2)=N1)[C@@H](C)C1=CC=CC=C1 VSSRHFINAWKZTQ-ZDUSSCGKSA-N 0.000 description 1
- YXICCOJOZYDMJH-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)C3=CN=CC=C3)C=C2)=N1)C(CCC)C1=CC=CN=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)C3=CN=CC=C3)C=C2)=N1)C(CCC)C1=CC=CN=C1 YXICCOJOZYDMJH-UHFFFAOYSA-N 0.000 description 1
- OWVDAUIGPFUHSC-NXDCJUMTSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)C3=CN=CC=C3)C=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CC(=O)CCC)C=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC=C(CN(C)C)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCC(O)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCC[C@H]3CO)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCNCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)C3=CN=CC=C3)C=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CC(=O)CCC)C=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC=C(CN(C)C)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCC(O)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCC[C@H]3CO)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCNCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 OWVDAUIGPFUHSC-NXDCJUMTSA-N 0.000 description 1
- LIZOQLKZHPPETP-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)C3CCNCC3)C=C2)=N1)C(CCC)C1=CC=CN=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)C3CCNCC3)C=C2)=N1)C(CCC)C1=CC=CN=C1 LIZOQLKZHPPETP-UHFFFAOYSA-N 0.000 description 1
- LWHNXLSYTFLCPK-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)N3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CN=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)N3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CN=C1 LWHNXLSYTFLCPK-UHFFFAOYSA-N 0.000 description 1
- IPXJQYHEMCSYSF-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)N3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCO)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(CC(=O)N3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCO)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C(CCC)C1=CC=CN=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 IPXJQYHEMCSYSF-UHFFFAOYSA-N 0.000 description 1
- LGMMOLXIFRXGPJ-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1 LGMMOLXIFRXGPJ-UHFFFAOYSA-N 0.000 description 1
- JNGOZVLPIRFQOE-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3C=CN=C3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCC(=O)N3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCCNC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3C=CN=C3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCC(=O)N3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCCNC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 JNGOZVLPIRFQOE-UHFFFAOYSA-N 0.000 description 1
- SIBREVUTLLHBFC-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN)C=C2)=N1)C(CCC)C1=CC=CC=C1 SIBREVUTLLHBFC-UHFFFAOYSA-N 0.000 description 1
- WGIYPFKECILTQL-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 WGIYPFKECILTQL-UHFFFAOYSA-N 0.000 description 1
- ILYGSSHVRPRZCS-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 ILYGSSHVRPRZCS-UHFFFAOYSA-N 0.000 description 1
- NFGCNGBCPRMCPZ-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 NFGCNGBCPRMCPZ-UHFFFAOYSA-N 0.000 description 1
- PPGXYSPWCQYYEK-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 PPGXYSPWCQYYEK-UHFFFAOYSA-N 0.000 description 1
- XKRTZDFJTBFPED-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCO)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCCO)C=C2)=N1)C(CCC)C1=CC=CC=C1 XKRTZDFJTBFPED-UHFFFAOYSA-N 0.000 description 1
- DLCMNUCPCUVWGH-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN(CC)CC)C=C2)=N1)C(CCC)C1=CC=CC=C1 DLCMNUCPCUVWGH-UHFFFAOYSA-N 0.000 description 1
- FKFMSYCZAHOQHL-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3C=CN=C3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3C=CN=C3)C=C2)=N1)C(CCC)C1=CC=CC=C1 FKFMSYCZAHOQHL-UHFFFAOYSA-N 0.000 description 1
- UJDOFUHOEDOEHX-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 UJDOFUHOEDOEHX-UHFFFAOYSA-N 0.000 description 1
- CWQVDXJEZLAEMK-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 CWQVDXJEZLAEMK-UHFFFAOYSA-N 0.000 description 1
- WWKJRBHJBFGLIR-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 WWKJRBHJBFGLIR-UHFFFAOYSA-N 0.000 description 1
- AHTPVELUEWDAKM-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCO)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCO)C=C2)=N1)C(CCC)C1=CC=CC=C1 AHTPVELUEWDAKM-UHFFFAOYSA-N 0.000 description 1
- GDNOFYVHZMUEDX-YXMJSPGTSA-N [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCO)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C(CCC)C1=CC=CC(F)=C1.[H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)[C@@H](CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CO)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(OCCN(CC)CC)C(OC)=C2)=N1)C(CCC)C1=CC(C)=CN=C1.[H]N(C1=CN=CC(C2=CC=C(OCCN(CC)CC)C(OC)=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC(OC)=C(OCCCO)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C(CCC)C1=CC=CC(F)=C1.[H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)[C@@H](CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CN3CCCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(CO)C=C2)=N1)C(CCC)C1=CC=CC=C1.[H]N(C1=CN=CC(C2=CC=C(OCCN(CC)CC)C(OC)=C2)=N1)C(CCC)C1=CC(C)=CN=C1.[H]N(C1=CN=CC(C2=CC=C(OCCN(CC)CC)C(OC)=C2)=N1)C(CCC)C1=CC=CC=C1 GDNOFYVHZMUEDX-YXMJSPGTSA-N 0.000 description 1
- ABCUGQUZZDBPRM-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(C(=O)NCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(C(=O)NCCCN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 ABCUGQUZZDBPRM-UHFFFAOYSA-N 0.000 description 1
- IGVQRCQKLYRQIR-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(C(=O)NCCN(C)C)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(C(=O)NCCN(C)C)C=C2)=N1)C(CCC)C1=CC=CC=C1 IGVQRCQKLYRQIR-UHFFFAOYSA-N 0.000 description 1
- QFBVJCNAYWHDRA-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CC(=O)CCC)C=C2)=N1)C(CCC)C1=CC=CN=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CC(=O)CCC)C=C2)=N1)C(CCC)C1=CC=CN=C1 QFBVJCNAYWHDRA-UHFFFAOYSA-N 0.000 description 1
- XHMLQUZPWKJOPK-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C(CCC)C1=CC=CC(F)=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C(CCC)C1=CC=CC(F)=C1 XHMLQUZPWKJOPK-UHFFFAOYSA-N 0.000 description 1
- GSTYWQMJHJNBPF-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C(CCC)C1=CC=CN=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)C(CCC)C1=CC=CN=C1 GSTYWQMJHJNBPF-UHFFFAOYSA-N 0.000 description 1
- IQZCIRYBFKBOBS-NRFANRHFSA-N [H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)[C@@H](CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CC(=O)NCC)C(OC)=C2)=N1)[C@@H](CCC)C1=CC=CC=C1 IQZCIRYBFKBOBS-NRFANRHFSA-N 0.000 description 1
- DJUACURCMSSRHL-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CN(C)C)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CN(C)C)C=C2)=N1)C(CCC)C1=CC=CC=C1 DJUACURCMSSRHL-UHFFFAOYSA-N 0.000 description 1
- HTFJJPDLXDTEJV-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CN)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CN)C=C2)=N1)C(CCC)C1=CC=CC=C1 HTFJJPDLXDTEJV-UHFFFAOYSA-N 0.000 description 1
- TTZVEPTUSLPUJG-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CN3CCC(O)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CN3CCC(O)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 TTZVEPTUSLPUJG-UHFFFAOYSA-N 0.000 description 1
- WVNRAJPXZXSWNA-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CN3CCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 WVNRAJPXZXSWNA-UHFFFAOYSA-N 0.000 description 1
- MKHOOWPMOHSPHU-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CN3CCCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CN3CCCCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 MKHOOWPMOHSPHU-UHFFFAOYSA-N 0.000 description 1
- LZCXAPVDCCLTBD-UXMRNZNESA-N [H]N(C1=CN=CC(C2=CC=C(CN3CCC[C@H]3CO)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CN3CCC[C@H]3CO)C=C2)=N1)C(CCC)C1=CC=CC=C1 LZCXAPVDCCLTBD-UXMRNZNESA-N 0.000 description 1
- YFBGGFYQWFMGGW-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CN3CCN(C)CC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 YFBGGFYQWFMGGW-UHFFFAOYSA-N 0.000 description 1
- NKIQFKYVHQJQJY-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CN3CCOCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 NKIQFKYVHQJQJY-UHFFFAOYSA-N 0.000 description 1
- JTYUGBIHZUNMGW-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCC(=O)N3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCC(=O)N3)C=C2)=N1)C(CCC)C1=CC=CC=C1 JTYUGBIHZUNMGW-UHFFFAOYSA-N 0.000 description 1
- SAQCEPSGGCGGRA-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCCNC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCCNC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 SAQCEPSGGCGGRA-UHFFFAOYSA-N 0.000 description 1
- ZCRRIFVVUDJMMN-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCNCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CNC(=O)C3CCNCC3)C=C2)=N1)C(CCC)C1=CC=CC=C1 ZCRRIFVVUDJMMN-UHFFFAOYSA-N 0.000 description 1
- YCNCRZKLXIOMTQ-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(CO)C=C2)=N1)C(CCC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(CO)C=C2)=N1)C(CCC)C1=CC=CC=C1 YCNCRZKLXIOMTQ-UHFFFAOYSA-N 0.000 description 1
- XYELFVFIXOYHKD-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=C(C2=CC=CN=C2)C=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=C(C2=CC=CN=C2)C=C1 XYELFVFIXOYHKD-UHFFFAOYSA-N 0.000 description 1
- VXOZLWXHTOBNRY-NTXFRFEOSA-N [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=C(C2=CC=CN=C2)C=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CC=NC=C2)=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CC=NC=C2)=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CN=CC=C2)=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)[C@H]2CCCN2)=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)[C@@H](CC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=C(C2=CC=CN=C2)C=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CC=NC=C2)=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CC=NC=C2)=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CN=CC=C2)=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)[C@H]2CCCN2)=C1.[H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)[C@@H](CC)C1=CC=CC=C1 VXOZLWXHTOBNRY-NTXFRFEOSA-N 0.000 description 1
- SGSDAEPNWPSGLB-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CC=NC=C2)=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CC=NC=C2)=C1 SGSDAEPNWPSGLB-UHFFFAOYSA-N 0.000 description 1
- OGUXIIVNLOQWIC-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CN=CC=C2)=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)C2=CN=CC=C2)=C1 OGUXIIVNLOQWIC-UHFFFAOYSA-N 0.000 description 1
- QRVIKHJJJQBRES-XCWJXAQQSA-N [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)[C@H]2CCCN2)=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)C(C)C1=CC=CC(NC(=O)[C@H]2CCCN2)=C1 QRVIKHJJJQBRES-XCWJXAQQSA-N 0.000 description 1
- AITABWXKYWCQSY-INIZCTEOSA-N [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)[C@@H](CC)C1=CC=CC=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(O)C(OC)=C2)=N1)[C@@H](CC)C1=CC=CC=C1 AITABWXKYWCQSY-INIZCTEOSA-N 0.000 description 1
- LCHGCHNSOGDPFX-UHFFFAOYSA-N [H]N(C1=CN=CC(C2=CC=C(OCCN(CC)CC)C(OC)=C2)=N1)C(CCC)C1=CC(C)=CN=C1 Chemical compound [H]N(C1=CN=CC(C2=CC=C(OCCN(CC)CC)C(OC)=C2)=N1)C(CCC)C1=CC(C)=CN=C1 LCHGCHNSOGDPFX-UHFFFAOYSA-N 0.000 description 1
- UOECACLXFDFNQD-ZDUSSCGKSA-N [H]N(C1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)[C@@H](C)C1=CC=CC=C1 Chemical compound [H]N(C1=NC=NC(C2=CC=C(O)C(OC)=C2)=C1)[C@@H](C)C1=CC=CC=C1 UOECACLXFDFNQD-ZDUSSCGKSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to methods of suppressing the growth of cancers and other proliferative diseases by the administration of compounds that act by binding to tubulin and to novel heterocyclic compounds suitable for such administration.
- Psoriasis is another disease that is characterized by uncontrolled or abnormal cellular proliferation.
- Psoriasis is a common chronic skin disease characterized by the presence of dry scales and plaques. The disease results from hyperproliferation of the epidermis and incomplete differentiation of keratinocytes.
- Psoriasis often involves the scalp, elbows, knees, back, buttocks, nails, eyebrows, and genital regions, and may range in severity from mild to extremely debilitating, resulting in psoriatic arthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. There is, at present, no general therapeutic cure that exists for psoriasis. Whilst milder cases are often treated with topical cortico-steroids, more severe cases may be treated with antiproliferative agents, such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea, and the microtubule disrupter colchicine.
- antiproliferative agents such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea, and the microtubule disrupter colchicine.
- diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved; inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved; myocardial infarction, where heart muscle cells are involved; glomerular nephritis, where kidney cells are involved; transplant rejection, where endothelial cells are involved; and infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved.
- Inhibition of cellular proliferation can be brought about by several mechanisms, including; alkylating agents; topoisomerase inhibitors; nucleotide analogues; antibiotics; hormone antagonists; and nucleic acid damaging agents; inter alia.
- One pharmacologically important mechanism of inhibiting cellular proliferation is by means of binding tubulin.
- Tubulin is an asymmetric dimer composed of alpha and beta subunits, that polymerizes to form structural components of the cytoskeleton called microtubules.
- Microtubules must be highly dynamic in order to carry out many of their functions. At certain stages of the cell cycle, or in particular cell types or organelles, stable microtubules are required, such as for transport within axons or for ciliary-and flagellar movement.
- Micro-tubules assemble during the G2 phase of the cell cycle, and participate in the formation of the mitotic spindle which facilitates the segregation of sister chromatids during the process of cell division.
- the essential role of microtubules in cell division and the ability of drugs that interact with tubulin to interfere with the cell cycle have made tubulin a successful target for applications that include anti-cancer drugs, fungicides, and herbicides.
- tubulin ligands such as colchicine, paclitaxel, the Vinca alkaloids such as vinblastine, the epothilones, the halicondrins, benomyl and mebendazole directly inhibit cell division by binding to tubulin which leads to the arrest of the cell cycle at the G2/M boundary of mitosis.
- This mechanism is the basis of the therapeutic value of compounds of this type, such as treating gout with colchicine, restenosis with paclitaxel, cancer with paclitaxel, vinblastine, epothilones and halichondrins, and fungal infections with benomyl and malaria and helminths with mebendazole.
- Paclitaxel (TaxolTM) and related taxanes represent a class of drugs that stabilize microtubules, a process that ultimately leads to the “freezing” of the microtubule structures so that they cannot be restructured (Jordan M A. and Wilson L., 1998). Subsequent arrest at mitosis induces the apoptotic mechanism to cause cell death.
- a number of colchicine analogues, as well as several other compounds that bind to the same site on ⁇ -tubulin as colchicine disrupt tubulin polymerization and disrupt microtubular formation.
- Vinblastine and several other vinca-related drugs bind to a site that is distinct from the colchicine site.
- the present invention aims to provide compounds which are directly or indirectly toxic to actively dividing cells and are useful in the treatment of cancer, viral and bacterial infections, vascular restenosis, inflammatory diseases, autoimmune diseases, or psoriasis.
- the present invention is also directed to therapeutic compositions for treating said conditions.
- Further aspects of the invention are to provide methods for killing actively proliferating cells, such as cancerous, bacterial, or epithelial cells, and treating all types of cancers, infections, inflammatory, and generally proliferative conditions.
- a further aspect relates to provide methods for treating other medical conditions characterized by the presence of rapidly proliferating cells, such as psoriasis and other skin disorders.
- the method of the invention is used in the treatment of sarcomas, carcinomas and/or leukemias.
- exemplary disorders for which the subject method can be used alone or as part of a treatment regimen include: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medu
- the method of the invention is to be used to treat disorders such as carcinomas forming from tissue of the breast, prostate, kidney, bladder or colon.
- the method of the invention is used to treat hyperplastic or neoplastic disorders arising in adipose tissue, such as adipose cell tumors, e.g., lipomas, fibrolipomas, lipoblastomas, lipomatosis, hibemomas, hemangiomas and/or liposarcomas.
- adipose cell tumors e.g., lipomas, fibrolipomas, lipoblastomas, lipomatosis, hibemomas, hemangiomas and/or liposarcomas.
- infectious and parasitic agents e.g. bacteria, trypanosomes, fungi, etc
- subject compositions and compounds can also be controlled using the subject compositions and compounds.
- the present inventors have found that a group of compounds based upon a substituted heterocyclic scaffold inhibit the growth and proliferation of cancer cells.
- the present inventors have further shown that these compounds can bind to tubulin. Such compounds would also be useful in the treatment of other hyperproliferation related disorders.
- the present invention provides a method of modulating microtubule polymerisation in a subject, the method comprising administering a therapeutically effective amount of at least one compound of the general formula
- the present invention provides a compound of the general formula
- the present invention provides a composition comprising a carrier and at least one compound of the second aspect.
- the present invention provides a method of treating a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one compound of the second aspect or a composition of the third aspect.
- the present invention provides a compound of the general formula
- the present invention provides a composition comprising a carrier and one or more compounds of the fifth aspect.
- the present invention provides a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the fifth aspect or a composition according to the sixth aspect.
- the present invention consists in a method of treating a protein-kinase related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the fifth aspect or a composition according to the sixth aspect.
- the present invention provides a compound of the general formula
- the present invention provides a composition comprising a carrier and one or more compounds of the ninth aspect.
- the present invention provides a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the ninth aspect or a composition according to the tenth aspect.
- the present invention consists in a method of treating a protein-kinase related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the ninth aspect or a composition according to the tenth aspect.
- the present invention provides a method of modulating microtubule polymerisation in a subject, the method comprising administering a therapeutically effective amount of at least one compound of the general formula
- the method is used in the treatment of a hyperproliferation-related disorder.
- the compound is selected from the compounds set out in Table 2.
- the present invention provides a compound of the general formula
- the present invention comprises a composition comprising a carrier and at least one compound of the second aspect.
- the present invention comprises a method of treating a hyperproliferation-related disorder in a subject, the method Comprising administering a therapeutically effective amount of at least one compound of the second aspect or a composition of the third aspect.
- the hyperproliferation-related disorder is treatable by the modulation of microtubule polymerisation.
- the present invention provides a compound of the general formula
- the present invention provides a composition comprising a carrier and one or more compounds of the fifth aspect.
- the present invention provides a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the fifth aspect or a composition according to the sixth aspect.
- the hyperproliferation-related disorder is treatable by the modulation of microtubule polymerisation.
- the present invention consists in a method of treating a protein-kinase related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the fifth aspect or a composition according to the sixth aspect.
- the present invention provides a compound of the general formula
- the present invention provides a composition comprising a carrier and one or more compounds of the ninth aspect.
- the present invention provides a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the ninth aspect or a composition according to the tenth aspect.
- the hyperproliferation-related disorder is treatable by the modulation of microtubule polymerisation.
- the present invention consists in a method of treating a protein-kinase related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the ninth aspect or a composition according to the tenth aspect.
- the compounds of this invention include all conformational isomers (eg. cis and trans isomers).
- the compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
- This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
- the compounds of formula I, II, III, IV and V may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
- Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of formulae I, II, III, IV and V.
- the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methioine sulfone.
- Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formulae I, II, III, IV and V through the carbonyl carbon prodrug sidechairt.
- Prodrugs also include phosphate derivatives of compounds of formulae I, II, III, IV and V (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formulae I, II, Ill, IV and V.
- Prodrugs also include compounds wherein acyloxyalkyl or phosphonooxyalkyl moieties are covalently attached to compounds of formula I, II, III, IV and V possessing a free hydroxyl group.
- Acyloxyalkyl or phosphonooxyalkyl moieties may also be covalently attached to compounds of formulae I, II, III, IV and V possessing a pyridyl ring through formation of a N-(acyloxyalkyl)- or N-(phosphonooxyallcyl)-pyridinium salt.
- This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula I, II, III, IV and V.
- this invention encompasses methods of treating or preventing disorders that can be treated or prevented by the modulation of microtubule dynamics comprising administering prodrugs of compounds of the formula I, II, III, IV and V.
- This invention further encompasses methods of treating or preventing disorders that can be treated or prevented by the disruption of microtubules comprising administering prodrugs of compounds of the formula II, III, IV and V.
- the compound possesses Schirality at the chiral carbon bearing W, where W is C 1-4 alkyl or C 1-4 alkylamino.
- W is C 1-4 alkyl or C 1-4 alkylamino.
- the compound can be used as a purified isomer or as a mixture of any ratio of isomers. It is however preferred that the mixture comprises at least 70%, 80%, 90%, 95%, or 99% of the preferred isomer.
- the present invention provides a compound selected from the compounds of Table 1; compositions comprising a carrier and one or more compounds of Table 1; and, a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering at least one of the compounds of Table 1.
- the hyperproliferation related disorder is treatable by the modulation of microtubule polymerisation.
- the present invention further provides for a method of modulating microtubule polymerisation in a subject, the method comprising the administration of a therapeutically effective amount of a compound of any one of Formulas I, II, III, IV and V.
- a method of modulating microtubule polymerisation in a subject comprising the administration of a therapeutically effective amount of a compound selected from the compounds of Table 1.
- the present invention provides that the compounds of formula I, II, III, IV and V may be administered for the treatment of hyperproliferation-related disorders.
- the hyperproliferation-related disorder is treatable by the modulation of microtubule polymerisation.
- the hyperproliferation-related disorder or disease state is selected from the group consisting of Cancer, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland
- Cancer such as
- the compounds of formula II, II and IV may also be used in the treatment of a hyperproliferation-related disorder or disease state and/or a protein-kinase related disorder or disease state.
- the disease state is selected from the group consisting of Atopy, such as Allergic Asthma, Atopic Dermatitis (Eczema), and Allergic Rhinitis; Cell Mediated Hypersensitivity, such as Allergic Contact Dermatitis and Hypersensitivity Pneumonitis; Rheumatic Diseases, such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjogren's Syndrome, Scleroderma, Polymyositis, Ankylosing Spondylitis, Psoriatic Arthritis; Other autoimmune diseases such as Type I diabetes, autoimmune.thyroid disorders, and Alzheimer's disease; Viral Diseases, such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1,
- an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
- the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
- a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
- compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
- mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
- the method can also be practiced in other species, such as avian species (e.g., chickens).
- the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
- the subjects treated in the above methods, in whom which cell growth inhibition is desired are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.
- terapéuticaally effective amount means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
- administering should be understood to mean providing a compound of the invention to the individual in need of treatment.
- compositions comprising at least one of the compounds of the formula I, II, III, IV and V capable of treating a hyperproliferation-related disorder in an amount effective therefore, and a pharmaceutically acceptable vehicle or diluent.
- the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
- the compounds of the formula I, II, III, IV and V may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
- parenterally such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in
- the compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
- composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
- the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- sweetening agents such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these, Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
- topical application shall include mouthwashes and gargles.
- the compounds of the present invention can also be administered in the form of liposomes.
- liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
- the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like.
- the preferred lipids are the phospholipids and phosphatidyl cholines, both natural and synthetic. Methods to form liposomes are known in the art.
- the pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.
- the combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
- Examples of other therapeutic agents include the following:
- Tyrosine kinase inhibitors such as imatinib (GlivecTM), and gefitinib (IressaTM) inter alia; cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD401g and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as
- the pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are known inhibitors or substrates of drug efflux systems or drug detoxification and excretory systems.
- Such systems include P-glycoprotein, multidrug resistance-associated protein, lung resistance protein and glutathione S-transferase isoenzymes alpha, mu, pi, sigma, theta, zeta and kappa.
- Co-administration of drugs known to inhibit or reduce the activity of these systems may increase the efficacy of the compounds described in the present invention through increasing the amount of therapeutic agent in the cell. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages, thus reducing the potential for adverse side effects.
- inhibitors or substrates for these systems include; verapamil, probenecid, dipyridamole, ethacrynic acid, indomethacin, sulfasalazine, buthionine sulfoximine, cyclosporin A and tamoxifen.
- Compounds are generally prepared in a 2-step process starting from a dihaloheterocycle.
- the first step is a nucleophilic aromatic substitution to generate a monoamino-monohalo intermediate.
- the nucleophilic aromatic substitution is typically carried out by addition of a primary or secondary amine to the di-halogenated heterocycle in a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, ethoxyethanol, toluene or xylene.
- a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, ethoxyethanol, toluene or xylene.
- the reaction is typically performed at elevated temperature in the presence of excess amine or a non-nucleophilic base such as triethylamin.e or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.
- the amino substituent may be introduced through a transition metal catalysed. amination reaction.
- Typical catalysts for such transformations include Pd(OAc) 2 /P(t-Bu) 3 , Pd 2 (dba) 3 /BINAP and Pd(OAc) 2 /BINAP. These reactions are typically carried out in solvents such as toluene or dioxane, in the presence of bases such as caesium carbonate or sodium or potassium tert-butoxide at temperatures ranging from room temperature to reflux.
- amines employed in the first step of the synthesis of these compounds are obtained commercially or are prepared using methods well known to those skilled in the art.
- Typical reductants include lithium aluminium hydride, hydrogen gas in the presence of palladium on charcoal catalyst, Zn in the presence of hydrochloric acid, sodium borohydride in the presence of a Lewis acid such as TiCl 3 , ZraCl 4 , NiCl 2 and MoO 3 , or sodium borohydride in conjunction with Amberlyst H15 ion exchange resin and LiCl.
- ⁇ -Alkylbenzylamines may also be prepared by reductive amination of the corresponding ketones.
- a classical method for such a transformation is the Leuckart-Wallach reaction, though catalytic conditions (HCO 2 NH 4 , [(CH 3 ) 5 C 5 RhCl 2 ] 2 )or alternative procedures (e.g. NH 4 OAc, Na(CN)BH 3 ) can also be used.
- ⁇ -Alkylbenzylamin.es may also be prepared from the corresponding ⁇ -alkylbenzyl alcohols. Such methods include derivatisation of the hydroxyl as a mesylate or tosylate and displacement with a nitrogen nucleophile, such as phthalimide or azide which is converted to the primary amine using conventional synthetic methods; or, displacement of the hydroxyl with a suitable nitrogen nucleophile under Mitsunobu-like conditions.
- ⁇ -Alkylbenzyl alcohols can be prepared by reduction of the corresponding ketones with a reducing agent such as sodium borohydride in a solvent such as methanol.
- ⁇ -alkylbenzyl alcohols can be obtained through addition of an alkyl metal species (such as a Grignard reagent) to a benzaldehyde derivative, typically performed at room temperature or below in solvents such as tetrahydrofuran.
- an alkyl metal species such as a Grignard reagent
- ⁇ -Alkyl benzylamines of high optical purity may be prepared from chiral ⁇ -alkyl benzyl alcohols using the methods outlined above.
- the chiral ⁇ -alkyl benzyl alcohols may be obtained through chiral reduction of the corresponding ketones.
- Chiral reducing methods are now well known in organic chemistry and include enzymatic processes, asymmetric hydrogenation procedures and chiral oxazaborolidines.
- the second step of the synthesis typically involves a palladium mediated cross-coupling of the monoamino-monochloro intermediate with a suitably functionalised coupling partner.
- Typical coupling partners are boronic acids or esters (Suzuki coupling: see for example Miyaura, N. and Suzuki, Chem Rev. 1995, 952457), stannanes (Stine coupling: see for example Stifle, J. K., Angew, Chem., Int. Ed. Engl., 1986, 25, 508), Grignard reagents (Kumada coupling: Kumada, M.; Tamao, K.; Sumitani, K. Org. Synth. 1988, Coll. Vol.6, 407.) or organozinc species (Negishi. coupling: Negishi, E.; J. Organomet. Chem. 2002, 653, 34).
- the Suzuki coupling is the preferred coupling method and is typically performed in a solvent such as DME, THF, DMF, ethanol, propanol, toluene, or 1,4-dioxane in the presence of a base such as potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate.
- a base such as potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate.
- the reaction may be carried out at elevated temperatures and the palladium catalyst employed may be selected from Pd(PPh 3 ) 4 , Pd(OAc) 2 , [PdCl 2 (dppf)], Pd 2 (dba) 3 /P(t-Bu) 3 .
- the products formed from this reaction sequence may be further derivatised using techniques well-known to those skilled in the art.
- derivatisation of the mono-amino mono-halo inteunecliate may be undertaken prior to displacement of the halo substituent. This derivatisation typically involves functionality originally present on the amine species and employs methods well known to those skilled in the art.
- the preparation sequence can be reversed beginning with the palladium mediated cross-coupling reaction to furnish a mono-halo heterocyclic species. Amine displacement of the halo substituent can then be undertaken using procedures outlined above.
- the aqueous layers were combined and basified to pH-12 with 5M NaOH.
- the aqueous phase was extracted with ethyl acetate (3 ⁇ 50 mL) and the combined organic phases dried (Na 2 SO 4 ) and concentrated /71 vacuo to separate the product which was used without further purification (0.9 g, 49%).
- K562 Choronic Myeloid Leukemia
- PC3 Prostate Cancer
- DU145 Prostate Cancer
- ATCC American Type Culture Collection
- K562 was grown in RPMI, with 10% FBS with Glutamx added.
- DU145 cells were cultured in DMED, with 10% FBS and Glutamx and MEM non-essential amino acids added.
- PC3 cells were grown in F12K medium, with 10% FBS and Glutamx and MEM non-essential amino acids added. All cells were grown at 37° C. in 5% CO 2 .
- the coding region encompassing nucleotides 1-487 of TEL was amplified by PCR using the oligonucleotides STEL (5′-GGA GGA TCC TGA TCT CTC TCG CTG TGA GAC-3′) and 3TEL (5′-AGGC GTC GAC TEC ITC TIC ATG GTT CTG-3′) and U937 mRNA as template.
- STEL 5′-GGA GGA TCC TGA TCT CTC TCG CTG TGA GAC-3′
- 3TEL 5′-AGGC GTC GAC TEC ITC TIC ATG GTT CTG-3′
- JAK2 The regions encompassing the kinase domains of JAK2 (nucleotides 2994-3914; ; JAK2F 5′-ACGC GTC GAC GGT GCC GAA GAC CGG GAT-3′; JAK2R 5′-ATA GTT TAG CGG CCG CTC AGA ATG AAG GTC ATT T-3′) and JAK3 (nucleotides 2520-3469; JAK3F 5′-GAA GTC GAC TAT GCC TGC CAA GAC CCC ACG ATC TT-3′; JAK3R 5′-GGA TCT AGA CTA TGA AAA GGA CAG GGA GTG GTG 111 -3′) were generated by PCR using Taq DNA Polymerase (Gibco/BRL) and U937 mRNA as template.
- a Sall site was incorporated into the forward primer of JAK2 and JAK3, a Not I site was incorporated into the JAK2 reverse primer and a Xba I
- a TEL/Jak2 fusion was generated by digestion of the TELPCR product with BamHI/Sal I, digestion of the JAK2 PCR product with Sal I/ Not I followed by ligation and subcloning into the mammalian expression Vector pTRE 2 (Clontech) digested with BamH I-Not I (pTELJAK2).
- pTELJAK2 mammalian expression Vector pTRE 2 (Clontech) digested with BamH I-Not I
- the growth factor dependent myelomonocytic cell line BaF3 bearing the pTET-off plasmid (Clontech) was transfected with either pTELJAK2 or pTELJAK3 and the cells selected for factor independent growth.
- BaF 3 wild type cells were cultured in DMEM 10% FCS, 10% WEHI 3B conditioned medium.
- BaF3 IELJAK cells were cultured in DMEM 10% Tet-System Approved FBS (without WEHI 3B conditioned medium).
- Cell suspensions were prepared by harvesting cells from culture. (Cells used in this test should be in later log phase growth and high viability.) Cells were diluted in correct growth medium to 1.1 ⁇ final concentration (from 50000 cell/mL to 200,000 cell/mL, depending on cell line).
- Turbidometric assays of microtubule assembly were performed by incubating microtubule protein in cuvettes at 37° C. in a thermostatically controlled spectrophotometer measuring the change in absorbance at 340 nm over time.
- the microtubule protein was incubated with the each test compound at 0° C. and polymerisation was initiated by addition of 1 mM GTP, prior to heating to 37° C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Transplantation (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Toxicology (AREA)
- Physical Education & Sports Medicine (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Compounds of general formula (I), (II), (III) and (V) are described for use in modulating microtubule polymerisation and in the treatment of associated disease states. Use of compounds (I), (III) and (V) in the treatment of kinase-associated disease states is also described. Further described are novel compounds of formula (II), (III) and (V).
Description
- This application is a continuation of U.S. Ser. No. 13/183,348, filed 14 Jul. 2011, U.S. Pat. No. 8,394,806, which is a divisional of U.S. Ser. No. 10/581,534 with an international filing date of 3 Dec. 2004, U.S. Pat. No. 7,981,900, which claims benefit under 35 U.S.C. § 119(e) to
- International application No. PCT/AU2004/001689 filed 3 Dec. 2004, which claims benefit of Australian Application No. 2003906680 filed 3 Dec. 2003. The disclosures of these applications are incorporated herein by reference in their entirety.
- The present invention relates to methods of suppressing the growth of cancers and other proliferative diseases by the administration of compounds that act by binding to tubulin and to novel heterocyclic compounds suitable for such administration.
- There are many human and veterinary diseases that stem from processes of uncontrolled or abnormal cellular proliferation. Most important among these diseases is cancer, the generic name given to a broad range of cellular malignancies characterized by unregulated growth and lack of differentiation. Psoriasis is another disease that is characterized by uncontrolled or abnormal cellular proliferation. Psoriasis is a common chronic skin disease characterized by the presence of dry scales and plaques. The disease results from hyperproliferation of the epidermis and incomplete differentiation of keratinocytes. Psoriasis often involves the scalp, elbows, knees, back, buttocks, nails, eyebrows, and genital regions, and may range in severity from mild to extremely debilitating, resulting in psoriatic arthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. There is, at present, no general therapeutic cure that exists for psoriasis. Whilst milder cases are often treated with topical cortico-steroids, more severe cases may be treated with antiproliferative agents, such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea, and the microtubule disrupter colchicine.
- Other diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved; inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved; myocardial infarction, where heart muscle cells are involved; glomerular nephritis, where kidney cells are involved; transplant rejection, where endothelial cells are involved; and infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved.
- Inhibition of cellular proliferation can be brought about by several mechanisms, including; alkylating agents; topoisomerase inhibitors; nucleotide analogues; antibiotics; hormone antagonists; and nucleic acid damaging agents; inter alia. One pharmacologically important mechanism of inhibiting cellular proliferation is by means of binding tubulin. Tubulin is an asymmetric dimer composed of alpha and beta subunits, that polymerizes to form structural components of the cytoskeleton called microtubules. Microtubules must be highly dynamic in order to carry out many of their functions. At certain stages of the cell cycle, or in particular cell types or organelles, stable microtubules are required, such as for transport within axons or for ciliary-and flagellar movement. Micro-tubules assemble during the G2 phase of the cell cycle, and participate in the formation of the mitotic spindle which facilitates the segregation of sister chromatids during the process of cell division. The essential role of microtubules in cell division and the ability of drugs that interact with tubulin to interfere with the cell cycle have made tubulin a successful target for applications that include anti-cancer drugs, fungicides, and herbicides. Typical tubulin ligands such as colchicine, paclitaxel, the Vinca alkaloids such as vinblastine, the epothilones, the halicondrins, benomyl and mebendazole directly inhibit cell division by binding to tubulin which leads to the arrest of the cell cycle at the G2/M boundary of mitosis. This mechanism is the basis of the therapeutic value of compounds of this type, such as treating gout with colchicine, restenosis with paclitaxel, cancer with paclitaxel, vinblastine, epothilones and halichondrins, and fungal infections with benomyl and malaria and helminths with mebendazole.
- Interfering with microtubule dynamics or stability can inhibit cell division in several ways. Both stablili7ing microtubules or inhibiting their polymerization will prevent the cytoskeleton restructuring that is required at several points in the cell cycle and lead to an arrest of the cell's progression from one stage in the cell cycle to the next. Three main classes of tubulin-binding drugs, namely colchicine analogues, Vinca alkaloids, and the taxanes, have been identified, each of which possesses a specific binding site on the (3-tubulin molecule. Paclitaxel (Taxol™) and related taxanes represent a class of drugs that stabilize microtubules, a process that ultimately leads to the “freezing” of the microtubule structures so that they cannot be restructured (Jordan M A. and Wilson L., 1998). Subsequent arrest at mitosis induces the apoptotic mechanism to cause cell death. A number of colchicine analogues, as well as several other compounds that bind to the same site on β-tubulin as colchicine disrupt tubulin polymerization and disrupt microtubular formation. Vinblastine and several other vinca-related drugs bind to a site that is distinct from the colchicine site. Compounds that bind at the Vinca-site prevent microtubule formation and destabilize microtubules (Jordan et al, 1986; Rai and Wolff (1996). This invention is therefore directed to compounds that potentially modulate microtubule dynamics by binding to tubulin.
- Accordingly, the present invention aims to provide compounds which are directly or indirectly toxic to actively dividing cells and are useful in the treatment of cancer, viral and bacterial infections, vascular restenosis, inflammatory diseases, autoimmune diseases, or psoriasis. The present invention is also directed to therapeutic compositions for treating said conditions. Further aspects of the invention are to provide methods for killing actively proliferating cells, such as cancerous, bacterial, or epithelial cells, and treating all types of cancers, infections, inflammatory, and generally proliferative conditions. A further aspect relates to provide methods for treating other medical conditions characterized by the presence of rapidly proliferating cells, such as psoriasis and other skin disorders.
- In one embodiment, the method of the invention is used in the treatment of sarcomas, carcinomas and/or leukemias. Exemplary disorders for which the subject method can be used alone or as part of a treatment regimen include: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.
- In certain embodiments, the method of the invention is to be used to treat disorders such as carcinomas forming from tissue of the breast, prostate, kidney, bladder or colon.
- In other embodiments, the method of the invention is used to treat hyperplastic or neoplastic disorders arising in adipose tissue, such as adipose cell tumors, e.g., lipomas, fibrolipomas, lipoblastomas, lipomatosis, hibemomas, hemangiomas and/or liposarcomas.
- In still other embodiments, infectious and parasitic agents (e.g. bacteria, trypanosomes, fungi, etc) can also be controlled using the subject compositions and compounds.
- The present inventors have found that a group of compounds based upon a substituted heterocyclic scaffold inhibit the growth and proliferation of cancer cells. The present inventors have further shown that these compounds can bind to tubulin. Such compounds would also be useful in the treatment of other hyperproliferation related disorders.
- Accordingly, in a first aspect the present invention provides a method of modulating microtubule polymerisation in a subject, the method comprising administering a therapeutically effective amount of at least one compound of the general formula
- or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- R1 is H, C1-4 alkyl;
- Q is a bond, or C1-4 alkyl;
- A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4 alkyl, CH2F, CHF2, CF3, CN, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR4R5, Oaryl, Ohetaryl, CO2R4, CONR4R5, nitro, NR4R5, C1-4 allcylNR4R5, NR6C1-4alkylNR4R5, NR4COR5, NR6CONR4R5, NR4SO2R5;
- R4, R5 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R6 is selected from H, C1-4 alkyl;
- R7 is selected from H, C1-4 alkyl, aryl, hetaryl, C1-4 alkyl aryl, C1-4 alkyl hetaryl;
- R2 is 0-2 substituents independently selected from halogen, C1-4alkyl, OH, OC1-4alkyl, CH2F, CHF2, CF3, OCF3, CN, C1-4alkylNR8R9, OC1-4alkylNR8R9, CO2R8, CONR8R9, NR8R9, NR8COR9, NR10CONR8R9, NR8SO2R9;
- R8, R9 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4 alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR11;
- R10 is selected from H, C1-4 alkyl, aryl or hetaryl;
- R11 is selected from H, C1-4 alkyl, aryl, hetaryl, C1-4 alkyl aryl, C1-4 alkyl hetaryl;
- Y is halogen, OH, NR12R13, NR14COR12, NR14CONR12R13, N14SO2R13;
- R12 and R13 are each independently H, CH2F, CHF2, CF3, CN, C1-4 alkyl optionally substituted with OH, OC1-4alkyl or NR15R16, cycloalkyl; cyclohetalkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S, NR14
- R14, R15 and R16 are each independently selected from H, C1-4 alkyl;
- R12 and R13 are each independently H, CH2F, CHF2, CF3, CN, C1-4 alkyl optionally substituted with OH, OC1-4alkyl or NR15R16, cycloalkyl; cyclohetalkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S, NR14
- n=0-4;
- W is selected from H, C1-4alkyl, C2-6alkenyl; where C1-4allcyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl, —NR15R16;
- R15, and R16 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- R17 is selected from H, C1-4 alkyl.
- R15, and R16 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- In a second aspect the present invention provides a compound of the general formula
- or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- R1 is H, C1-4 alkyl;
- Q is a bond, or C1-4 alkyl;
- A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4 alkyl, CH2F, CHF2, CF3, CN, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR4R5, Oaryl, Ohetaryl, CO2R4, CONR4R5, nitro, NR4R5, C1-4 alkylNR4R5, NR6C1-4alkyINR4R5, NR4COR5, NR6CONR4R5, NR4SO2R5;
- R4, R5 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R6 is selected from H, C1-4 alkyl;
- R7 is selected from H, C1-4 alkyl, aryl, hetaryl, C1-4 alkyl aryl, C1-4 alkyl hetaryl;
- R2 is 0-2 substituents independently selected from C1-4alkyl and OC1-4alkyl;
- Y is CH2OH, OC1-4alkylOH, OC1-4alkylR12, OC1-4alkylNR12NR13, C(O)R12, CH2R12, COOR12, CONR12R13, OCONR12R13, CH2NR12R13, NHCOR12, NHCONR12R13,
- R12 and R13 are each independently H, C1-2 alkyl, (CH2)3NEt2, (CH2)2NMe2, (CH2)5NH2, (CH2)2OH,
-
- W is selected from H, C1-4alkyl, C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl, NR15R16;
- R15, and R16 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17
- R17 is selected from H, C1-4 alkyl;
- R15, and R16 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17
- wherein when Y is CH2R12 then R12 is not H,
- W is selected from H, C1-4alkyl, C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl, NR15R16;
- In a third aspect, the present invention provides a composition comprising a carrier and at least one compound of the second aspect.
- In a fourth aspect the present invention provides a method of treating a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one compound of the second aspect or a composition of the third aspect.
- In a fifth aspect the present invention provides a compound of the general formula
- or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- X1, X2, X3, X4 are selected from the following:
- (i) X1 and X2 are N and X3 and X4 are C independently substituted with Y;
- (ii) X1 and X4 are N and X2 and X3 are C independently substituted with Y;
- (iii) X1 and X3 are N and X2 and X4 are C independently substituted with I;
- (iv) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
- (v) X1 is N and X2, X3, and X4 are C independently substituted with Y;
- (vi) X3 is N and X1, X2, and X4 are C independently substituted with Y;
- (vii) X4 is N and X1, X2, and X3 are C independently substituted with Y;
- (viii) X2 is N and X1, X3, and X4 are C independently substituted with Y; and
- (ix) X1, X2 and X3 are N and X1 is C substituted with Y;
- R1 is H, C1-6alkyl, C1-6 allcylNR5R6, C1-6alkylNR5COR6, C1-6alkylNR5SO2R6, C1-6alkylCO2R5, C1-6alkylCONR5R6;
- R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-4alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R7 is selected from H, C1-4allcyl;
- R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-4alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R2 is selected from C1-6alkylOH, OC2-6alkylOH, C1-6alkylNR8R9, OC2-6alkylNR8R9, C1-6alkylNR8COR9, OC2-6alkylNR8COR9, C1-6allcylhetaryl, OC2-6alkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9, NR8COR12;
- R8, R9 are each independently H, C1-4alkyl, C1-4alkylNR11R13, hetaryl, cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R12 is C2-4alkyl, C1-4alkylNR11R13, hetaryl, cyclohetalkyl;
- R11, R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R14 is selected from H, C1-4alkyl;
- R10 is H, C1-4 alkyl;
- R3 and R4 are each independently H, halogen, C1-4alkyl, OH, OC1-4alkyl, CF3, OCF3;
- Q is a bond, or C1-4 alkyl;
- W is selected from H, C1-4alkyl, C2-6alkenyl; where C1-4all<yl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl, NR15R16;
- R15, and R16 are each independently H, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetallyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- R17 is selected from H, C1-4alkyl;
- R15, and R16 are each independently H, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetallyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4 alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-3alkylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19, C1-4 alkyINR18R19, NR20C1-4alkyINR18R19, NR18COR19, NR20CONR18R19, NR18SO2R19;
- R18, R19 are each independently H, C1-4 alkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R21 is selected from H,
- R20 is selected from H, C1-4alkyl;
- R18, R19 are each independently H, C1-4 alkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- Y is selected from H, C1-4alkyl, OH, NR22R23;
- R22, R23 are each independently H,
- In a sixth aspect, the present invention provides a composition comprising a carrier and one or more compounds of the fifth aspect.
- In a seventh aspect, the present invention provides a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the fifth aspect or a composition according to the sixth aspect.
- In an eighth aspect, the present invention consists in a method of treating a protein-kinase related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the fifth aspect or a composition according to the sixth aspect.
- In a ninth aspect, the present invention provides a compound of the general formula
- or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- X1, X2, X3, X4 are selected from the following:
- (i) X1 and X2 are N and X3 and X4 are C independently substituted with Y;
- (ii) X1 and X4 are N and X2 and X3 are C independently substituted with Y;
- (iii) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
- (iv) X1 is N and X2, X3, and X4 are C independently substituted with Y;
- (v) X3 is N and X1, X2, and X4 are C independently substituted with Y;
- (vi) X4 is N and X1, X2, and X3 are C independently substituted with Y;
- (vii) X2 is N and X1, X3, and X4 are C independently substituted with Y; and
- (viii) X1, X2 and X3 are N and X4 is C substituted with Y;
- R1 is H, C1-6alkyl, C1-6 alkylNR5R6, C1-6alkylNR5COR6, C1-6alkylNR5SO2R6, C1-6alkylCO2R5, C1-6alkylCONR5R6;
- R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-4alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R7 is selected from H, C1-4 alkyl;
- R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-4alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R2 is selected from OH, OC1-6alkyl,C1-6alkylOH, OC2-6alkylOH, C1-6alkyINR8R9, OC2-6alkylNR8R9, C1-6allcylNR8COR9, OC2-6alkyINR8COR9, C1-6alkylhetaryl, OC2-6alkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9, NR8COR12;
- R8, R9 are each independently H, C1-4alkyl, C1-4alkylNR11R13, hetaryl, cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R12 is C2-4alkyl, C1-4alkylNR11R13, hetaryl, cyclohetalkyl;
- R11, R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R14 is selected from H, C1-4alkyl;
- R11, R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R10 is H, C1-4 alkyl;
- R3 and R4 are each independently H, halogen, C1-4alkyl, OH, OC1-4alkyl, CF3, OCF3;
- Q is a bond, or C1-4alkyl;
- W is selected from H, C1-4alkyl, C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl, NR15R16;
- R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- R17 is selected from H, C1-4alkyl;
- R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4 alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5allcylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19, C1-4 allcyINR18R19, NR20C1-4alkylNR18R19, NR18COR19, NR2OCONR18R19, NR18SO2R19;
- R18, R19 are each independently H, C1-4 alkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R21 is selected from H, C1-4 alkyl;
- R20 is selected from H, C1-4 alkyl;
- R18, R19 are each independently H, C1-4 alkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- Y is selected from H, C1-4alkyl, OH, NR22R23;
- R22, R23 are each independently H, C1-4 alkyl.
- In a tenth aspect, the present invention provides a composition comprising a carrier and one or more compounds of the ninth aspect.
- In an eleventh aspect, the present invention provides a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the ninth aspect or a composition according to the tenth aspect.
- In a twelfth aspect, the present invention consists in a method of treating a protein-kinase related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the ninth aspect or a composition according to the tenth aspect.
- In a first aspect the present invention provides a method of modulating microtubule polymerisation in a subject, the method comprising administering a therapeutically effective amount of at least one compound of the general formula
- or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- R1 is H, C1-4 alkyl;
- Q is a bond, or C1-4 alkyl;
- A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4 alkyl, CH2F, CHF2, CF3, CN, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR4R5, Oaryl, Ohetaryl, CO2R4, CONR4R5, nitro, NR4R5, C1-4 alkylNR4R5, NR6C1-4alkylNR4R5, NR4COR5, NR6CONR4R5, NR4SO2R5; and R4, R5 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7; and R6 is selected from H, C1-4 alkyl; and R7 is selected from H, C1-4 alkyl, aryl, hetaryl, C1-4 alkyl aryl, C1-4 alkyl hetaryl;
- R2 is 0-2 substituents independently selected from halogen, C1-4alkyl, OH, OC1-4alkyl, CH2F, CHF2, CF3, OCF3, CN, C1-4alkylNR8R9, OC1-4alkylNR8R9, CO2R8, CONR8R9, NR8R9, NR8COR9, NR10CONR8R9, NR8SO2R9; and R8, R9 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4 alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR11; and R10 is selected from H, C1-4 alkyl, aryl or hetaryl; and R11 is selected from H, C1-4 alkyl, aryl, hetaryl, C1-4 alkyl aryl, C1-4 alkyl hetaryl;
- Y is halogen; OH; NR12R13; NR14COR12; NR14CONR12R13; N14SO2R13; and R12 and R13 are each independently H; CH2F; CHF2; CF3; CN; C1-4 alkyl optionally substituted with OH, OC1-4alkyl or NR15R16; cycloalkyl; cyclohetalkyl; C1-4 alkyl cycloalkyl; C1-4 alkyl cyclohetalkyl; or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S, NR14 and R14, R15 and R16 are each independently selected from H, C1-4 alkyl;
- n=0-4;
- W is selected from H, C1-4alkyl, C2-6all<enyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl, NR15R16; and R15, and R16 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17 and R17 is selected from H, C1-4 alkyl.
- Preferably, the method is used in the treatment of a hyperproliferation-related disorder.
- Preferably, the compound is selected from the compounds set out in Table 2.
- In a second aspect the present invention provides a compound of the general formula
- or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- R1 is H, C1-4 alkyl;
- Q is a bond, or C1-4 alkyl;
- A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4 alkyl, CH2F, CHF2, CF3, CN, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylINR4R5, Oaryl, Ohetaryl, CO2R4, CONR4R5, nitro, NR4R5, C1-4 alkylNR4R5, NR6C1-4aLkylNR4R5, NR4COR5, NR6CONR4R5, NR4SO2R5; and R4, R5 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7; and R6 is selected from H, C1-4 alkyl; and R7 is selected from H, C1-4 alkyl, aryl, hetaryl, C1-4 alkyl aryl, C1-4 alkyl hetaryl;
- R2 is 0-2 substituents independently selected from C1-4alkyl and OC1-4alkyl;
- Y is CH2OH, OC1-4alkylR12, OC1-4alkyINR12NR13, C(O)R12, CH2R12, COOR12, CONR12R13, OCONR12R13, CH2NR12R13, NHCOR12, NHCONR12R13, and R12 and R13 are each independently H, C1-2 alkyl, (CH2)3NEt2, (CH2)2NMe2, (CH2)5NH2, (CH2)2OH,
-
- W is selected from H, C1-4allcyl, C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4allcyl, NR15R16; and R15, and R16 are each independently H, C1-4 alkyl, C1-4 alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17 and R17 is selected from H, C1-4 alkyl;
- wherein when Y is CH2R12 then R12 is not H, C1-2alkyl.
- In a third aspect, the present invention comprises a composition comprising a carrier and at least one compound of the second aspect.
- In a fourth aspect the present invention comprises a method of treating a hyperproliferation-related disorder in a subject, the method Comprising administering a therapeutically effective amount of at least one compound of the second aspect or a composition of the third aspect.
- Preferably, the hyperproliferation-related disorder is treatable by the modulation of microtubule polymerisation.
- In a fifth aspect the present invention provides a compound of the general formula
- or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- X1, X2, X3, X4 are selected from the following:
- (i) X1 and X2 are N and X3 and X4 are C independently substituted with Y;
- (ii) X1 and X4 are N and X2 and X3 are C independently substituted with Y;
- (iii) X1 and X3 are N and X2 and X4 are C independently substituted with Y;
- (iv) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
- (v) X1 is N and X2, X3, and X4 are C independently substituted with Y;
- (vi) X3 is N and X1, X2 , and X4 are C independently substituted with Y;
- (vii) X4 is N and X1, X2, and X3 are C independently substituted with Y;
- (viii) X2 is N and X1, X3, and X4 are C independently substituted with Y; and
- (ix) X1, X2 and X3 are N and X1 is C substituted with Y;
- R1 is H, C1-6 alkylNR5R6, C1-6alkylNR5COR6, C1-6alkylNR5SO2R6, C1-6alkylCO2R5, C1-6alkylCONR5R6, where R5 and R6 are each independently H, C1-4allcyl, aryl, hetaryl, C1-4alkylaryl, C1-4alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R7 is selected from H, C1-4alkyl;
- R2 is selected from C1-6alkylOH, OC2-6alkylOH, C1-6allcylNR8R9, OC2-6alkyINR8R9, C1-6alkylNR8COR9, OC2-6alkylNR8COR9, C1-6alkylhetaryl, OC2-6aLkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9, NR8COR12;
- R8, R9 are each independently H, C1-4alkylNR11R13, hetaryl, cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R12 is C2-4alkyl, C1-4allcylNR11R13, hetaryl, cyclohetalkyl;
- R11, R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
-
-
- R14 is selected from H, C1-4alkyl;
-
- R10 is H, C1-4 alkyl;
-
- R3 and R4 are each independently H, halogen, C1-4alkyl, OH, OC1-4alkyl, CF3, OCP3;
- Q is a bond, or C1-4 alkyl;
- W is selected from H, C1-4alkyl, C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl, NR15R16;
- R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- R17 is selected from H, C1-4alkyl;
- R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4 alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19, C1-4 alkylNR18R19, NR20C1-4alkylNR18R19, NR18COR19, NR2OCONR18R19, NR18SO2R19;
- R18, R19 are each independently H, C1-4 alkyl, C1-4 alkyl cyclohetallcyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R21 is selected from H, C1-4alkyl;
- R20 is selected from H, C1-4alkyl;
- R18, R19 are each independently H, C1-4 alkyl, C1-4 alkyl cyclohetallcyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- Y is selected from H, C1-4alkyl, OH, NR22R23;
- R22, R23 are each independently H, C1-4alkyl.
- In the above description it will be appreciated that:
-
- C1-4 alkyl means an unsubstituted or optionally substituted straight or branched alkyl chain
- Aryl means unsubstituted or optionally substituted phenyl or naphthyl.
- Hetaryl means an unsubstituted or optionally substituted 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, S.
- Cycloalkyl means a 3-8 membered saturated ring
- Cyclohetalkyl means an optionally substituted 3-8 membered saturated ring containing 1-3 heteroatoms selected from O, S, NR24, where R24 is H, C1-4 alkyl, aryl, hetaryl.
- In a preferred embodiment the compound is selected from compounds of the general formula
- or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- X1, X2, X3, X4 are selected from the following:
- (i) X1 and X2 are N and X3 and X4 are C independently substituted with Y;
- (ii) X1 and X4 are N and X2 and X3 are C independently substituted with Y;
- (iii) X1 and X3 are N and X2 and X4 are C independently substituted with Y;
- (iv) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
- (v) X1 is N and X2, X3, and X4 are C independently substituted with Y;
- (vi) X3 is N and X1, X2, and X4 are C independently substituted with Y;
- (vii) X4 is N and X1, X2 , and X3 are C independently substituted with Y;
- (viii) X2 is N and X1, X3, and X4 are C independently substituted with Y; and
- (ix) X1, X2 and X3 are N and X4 is C substituted with Y;
- R1 is H, C1-6alkylNR5R6, where R5 and R6-are each independently H, C1-4alkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R7 is selected from H, C1-4 alkyl;
- R2 is selected from C1-6alkylOH, OC2-6alkylOH, C1-6alkylNR8R9, OC2-6alkylNR8R9, C1-6alkylNR8COR9, OC2-6alkylNR8COR9, C1-6alkylhetaryl, OC2-6alkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9, NR8COR12;
- R8, R9 are each independently H, C1-4alkyl, C1-4alkylNR11R13, hetaryl, cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R12 is C2-4alkyl, C1-4alkylNR11R13, hetaryl, cyclohetalkyl;
- R11, R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
-
- R14 is selected from H, C1-4alkyl;
-
- R10 is H, C1-4alkyl;
- R3 and R4 are each independently H, halogen, C1-4alkyl, OH, OC1-4alkyl, CF3, OCF3;
- Q is CH;
- W is selected from C1-4alkyl, C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl, NR15R16;
- R15, and R16 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- R17 is selected from H,
- R15, and R16 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- A is aryl, hetaryl optionally substituted with 0-2 substituents independently chosen from halogen, C1-4 alkyl, CF3, aryl, hetaryl, OCF3, OC2-3alkylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19, C1-4 alkylNR18R19, NR20C1-4alkylNR18R19, NR18COR19, NR2OCONR18R19, NR18SO2R19;
- R18, R19 are each independently H, C1-4alkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4alkyl hetaryl, or may be joined to faun an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R21 is selected from H, C1-4alkyl;
- R20 is selected from H, C1-4alkyl;
- R18, R19 are each independently H, C1-4alkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4alkyl hetaryl, or may be joined to faun an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- Y is selected from H, NR22R23;
- R22, R23 are each independently H, C1-4alkyl.
- In the above description it will be appreciated that:
-
- C1-4 alkyl means an unsubstituted or optionally substituted straight or branched alkyl chain
- Aryl means unsubstituted or optionally substituted phenyl or naphthyl.
- Hetaryl means an unsubstituted or optionally substituted 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, S.
- Cycloalkyl means a 3-8 membered saturated ring
- Cyclohetalkyl means an optionally substituted 3-8 membered saturated ring containing 1-3 heteroatoms selected from O, S, NR24, where R24 is H, C1-4 alkyl, aryl, hetaryl.
- In a sixth aspect, the present invention provides a composition comprising a carrier and one or more compounds of the fifth aspect.
- In a seventh aspect, the present invention provides a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the fifth aspect or a composition according to the sixth aspect.
- Preferably, the hyperproliferation-related disorder is treatable by the modulation of microtubule polymerisation.
- In an eighth aspect, the present invention consists in a method of treating a protein-kinase related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the fifth aspect or a composition according to the sixth aspect.
- In a ninth aspect, the present invention provides a compound of the general formula
- or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
-
- X1, X2, X3, X4 are selected from the following:
- (i) X1 and X2 are N and X3 and X4 are C independently substituted with Y;
- X1 and X4 are N and X2 and X3 are C independently substituted with Y;
- (iii) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
- (iv) X1 is N and X2, X3, and X4 are C independently substituted with Y;
- (v) X3 is N and X1, X2 and X4 are C independently substituted with Y;
- (vi) X4 is N and X1, X2, and X3 are C independently substituted with Y;
- (vii) X2 is N and X1, X3, and X4 are C independently-substituted with Y; and
- (viii) X1, X2 and X3 are N and X4 is C substituted with Y;
- R1 is H, alkylNR5R6, C1-6alkyINR5COR6, C1-6alkylNR5SO2R6, C1-6alkylCO2R5, C1-6alkylCONR5R6, where R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-4alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR7;
- R7 is selected from H, C1-4 alkyl;
- R2 is selected from OH, OC16alkyl, OC2-6alkylOH, C1-6alkyINR8R9, OC2-6alkylNR8R9, C1-6alkylNR8COR9, OC2-6alylNR8COR9, C1-6alkylhetaryl, OC2-6alkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9, NR8COR12;
- R8, R9 are each independently H, C1-4alkyl, C1-4alkylINR11R13, hetaryl, cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R12 is C24alkyl, C1-4alkylNR11R13, hetaryl, cyclohetalkyl;
- R11, R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R14 is selected from H, C1-4alkyl;
- R11, R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR14;
- R10 is H, C1-4 alkyl;
- R3 and R4 are each independently H, halogen, C1-4allcyl, OH, OC1-4alkyl, CF3, OCF3;
- Q is a bond, or C1-4alkyl;
- W is selected from H, C1-4alkyl, C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with OH, OC1-4allcyl, NR15R16;
- R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- R17 is selected from H, C1-4allcyl;
- R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- A is aryl, hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4 alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkyINR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19, C1-4 alkylNR18R19, NR2OC1-4alkylNR18R19, NR18COR19, NR2OCONR18R19, NR18SO2R19;
- R18, R19 are each independently H, C1-4 alkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R21 is selected from H, C1-4 alkyl;
- R20 is selected from H, C1-4 alkyl;
- R18, R19 are each independently H, C1-4 alkyl, C1-4 alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- Y is selected from H, OH, NR22R23;
- R22, R23 are each independently H, C1-4 alkyl.
- In the above description it will be appreciated that:
-
- C1-4 alkyl means an unsubstituted or optionally substituted straight or branched alkyl chain
- Aryl means unsubstituted or optionally substituted phenyl or naphthyl.
- Hetaryl means an unsubstituted or optionally substituted 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, S.
- Cycloalkyl means a 3-8 membered saturated ring
- Cyclohetalkyl means an optionally substituted 3-8 membered saturated ring containing 1-3 heteroatoms selected from O, S, NR24, where R24 is H, C1-4 alkyl, aryl, hetaryl.
- In a tenth aspect, the present invention provides a composition comprising a carrier and one or more compounds of the ninth aspect.
- In an eleventh aspect, the present invention provides a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the ninth aspect or a composition according to the tenth aspect.
- Preferably, the hyperproliferation-related disorder is treatable by the modulation of microtubule polymerisation.
- In a twelfth aspect, the present invention consists in a method of treating a protein-kinase related disorder in a subject, the method comprising administering a therapeutically effective amount of at least one of the compounds of the ninth aspect or a composition according to the tenth aspect.
- The compounds of this invention include all conformational isomers (eg. cis and trans isomers). The compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. The compounds of formula I, II, III, IV and V may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
- Compounds of formula I, II, HI, IV and V having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of formulae I, II, III, IV and V. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methioine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formulae I, II, III, IV and V through the carbonyl carbon prodrug sidechairt. Prodrugs also include phosphate derivatives of compounds of formulae I, II, III, IV and V (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formulae I, II, Ill, IV and V. Prodrugs also include compounds wherein acyloxyalkyl or phosphonooxyalkyl moieties are covalently attached to compounds of formula I, II, III, IV and V possessing a free hydroxyl group. Acyloxyalkyl or phosphonooxyalkyl moieties may also be covalently attached to compounds of formulae I, II, III, IV and V possessing a pyridyl ring through formation of a N-(acyloxyalkyl)- or N-(phosphonooxyallcyl)-pyridinium salt. This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula I, II, III, IV and V. In addition, this invention encompasses methods of treating or preventing disorders that can be treated or prevented by the modulation of microtubule dynamics comprising administering prodrugs of compounds of the formula I, II, III, IV and V. This invention further encompasses methods of treating or preventing disorders that can be treated or prevented by the disruption of microtubules comprising administering prodrugs of compounds of the formula II, III, IV and V.
- In a still further preferred embodiment the compound possesses Schirality at the chiral carbon bearing W, where W is C1-4 alkyl or C1-4alkylamino. The compound can be used as a purified isomer or as a mixture of any ratio of isomers. It is however preferred that the mixture comprises at least 70%, 80%, 90%, 95%, or 99% of the preferred isomer.
- In a yet further preferred embodiment, the present invention provides a compound selected from the compounds of Table 1; compositions comprising a carrier and one or more compounds of Table 1; and, a method of treatment of a hyperproliferation-related disorder in a subject, the method comprising administering at least one of the compounds of Table 1.
- More preferably, the hyperproliferation related disorder is treatable by the modulation of microtubule polymerisation.
- The present invention further provides for a method of modulating microtubule polymerisation in a subject, the method comprising the administration of a therapeutically effective amount of a compound of any one of Formulas I, II, III, IV and V.
- In a preferred embodiment, there is provided a method of modulating microtubule polymerisation in a subject, the method comprising the administration of a therapeutically effective amount of a compound selected from the compounds of Table 1.
- The present invention provides that the compounds of formula I, II, III, IV and V may be administered for the treatment of hyperproliferation-related disorders. Preferably, the hyperproliferation-related disorder is treatable by the modulation of microtubule polymerisation. In a preferred embodiment, the hyperproliferation-related disorder or disease state is selected from the group consisting of Cancer, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma, and carcinomas forming from tissue of the breast, prostate, kidney, bladder or colon, and neoplastic disorders arising in adipose tissue, such as adipose cell tumors, e.g., lipomas, fibrolipomas, lipoblastomas, lipomatosis, hibemomas, hemangiomas and/or liposarcomas; infectious diseases such as viral, malarial and bacterial infections; vascular restenosis; inflammatory diseases, such as autoimmune diseases, glomerular nephritis myocardial infarction and psoriasis.
- The compounds of formula II, II and IV may also be used in the treatment of a hyperproliferation-related disorder or disease state and/or a protein-kinase related disorder or disease state. Preferably, the disease state is selected from the group consisting of Atopy, such as Allergic Asthma, Atopic Dermatitis (Eczema), and Allergic Rhinitis; Cell Mediated Hypersensitivity, such as Allergic Contact Dermatitis and Hypersensitivity Pneumonitis; Rheumatic Diseases, such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjogren's Syndrome, Scleroderma, Polymyositis, Ankylosing Spondylitis, Psoriatic Arthritis; Other autoimmune diseases such as Type I diabetes, autoimmune.thyroid disorders, and Alzheimer's disease; Viral Diseases, such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV), Human Papilloma Virus (HPV).
- In the treatment or prevention of hyperproliferation-related disorders and/or protein kinase related disorders an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
- It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
- In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
- Diseases and conditions associated with inflammation and infection can be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
- The subjects treated in the above methods, in whom which cell growth inhibition is desired, are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.
- The term “therapeutically effective amount” means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
- The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
- The present invention provides pharmaceutical compositions comprising at least one of the compounds of the formula I, II, III, IV and V capable of treating a hyperproliferation-related disorder in an amount effective therefore, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
- The compounds of the formula I, II, III, IV and V may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
- The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
- The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these, Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
- The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
- For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)
- The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and phosphatidyl cholines, both natural and synthetic. Methods to form liposomes are known in the art.
- The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
- Examples of other therapeutic agents include the following:
- Tyrosine kinase inhibitors, such as imatinib (Glivec™), and gefitinib (Iressa™) inter alia; cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD401g and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, aspirin, acetaminophen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisolone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, antineoplastic agents such as azathioprine, VP-16, etoposide, fludarabine, cisplatin, doxorubicin, adriamycin, amsacrine, camptothecin, cytarabine, gemcitabine, fluorodeoxyuridine, melphalan and cyclophosphamide, TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.
- When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
- The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are known inhibitors or substrates of drug efflux systems or drug detoxification and excretory systems. Such systems include P-glycoprotein, multidrug resistance-associated protein, lung resistance protein and glutathione S-transferase isoenzymes alpha, mu, pi, sigma, theta, zeta and kappa. Co-administration of drugs known to inhibit or reduce the activity of these systems may increase the efficacy of the compounds described in the present invention through increasing the amount of therapeutic agent in the cell. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages, thus reducing the potential for adverse side effects. Examples of inhibitors or substrates for these systems include; verapamil, probenecid, dipyridamole, ethacrynic acid, indomethacin, sulfasalazine, buthionine sulfoximine, cyclosporin A and tamoxifen.
- Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
- All publications mentioned in this specification are herein incorporated by reference.
- Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.
- In order that the nature of the present invention may be more clearly understood preferred forms thereof will now be described by reference to the following non-limiting Examples.
- Materials and Methods:
- Compound Synthesis
- Compounds are generally prepared in a 2-step process starting from a dihaloheterocycle.
- The first step is a nucleophilic aromatic substitution to generate a monoamino-monohalo intermediate.
- The nucleophilic aromatic substitution is typically carried out by addition of a primary or secondary amine to the di-halogenated heterocycle in a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, ethoxyethanol, toluene or xylene. The reaction is typically performed at elevated temperature in the presence of excess amine or a non-nucleophilic base such as triethylamin.e or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.
- Alternatively, the amino substituent may be introduced through a transition metal catalysed. amination reaction. Typical catalysts for such transformations include Pd(OAc)2/P(t-Bu)3, Pd2(dba)3/BINAP and Pd(OAc)2/BINAP. These reactions are typically carried out in solvents such as toluene or dioxane, in the presence of bases such as caesium carbonate or sodium or potassium tert-butoxide at temperatures ranging from room temperature to reflux.
- The amines employed in the first step of the synthesis of these compounds are obtained commercially or are prepared using methods well known to those skilled in the art. Of particular interest are α-alkylbenzylamines which may be prepared through reduction of oximes. Typical reductants include lithium aluminium hydride, hydrogen gas in the presence of palladium on charcoal catalyst, Zn in the presence of hydrochloric acid, sodium borohydride in the presence of a Lewis acid such as TiCl3, ZraCl4, NiCl2 and MoO3, or sodium borohydride in conjunction with Amberlyst H15 ion exchange resin and LiCl.
- α-Alkylbenzylamines may also be prepared by reductive amination of the corresponding ketones. A classical method for such a transformation is the Leuckart-Wallach reaction, though catalytic conditions (HCO2NH4, [(CH3)5C5RhCl2]2)or alternative procedures (e.g. NH4OAc, Na(CN)BH3) can also be used.
- α-Alkylbenzylamin.es may also be prepared from the corresponding α-alkylbenzyl alcohols. Such methods include derivatisation of the hydroxyl as a mesylate or tosylate and displacement with a nitrogen nucleophile, such as phthalimide or azide which is converted to the primary amine using conventional synthetic methods; or, displacement of the hydroxyl with a suitable nitrogen nucleophile under Mitsunobu-like conditions. α-Alkylbenzyl alcohols can be prepared by reduction of the corresponding ketones with a reducing agent such as sodium borohydride in a solvent such as methanol. Alternatively, α-alkylbenzyl alcohols can be obtained through addition of an alkyl metal species (such as a Grignard reagent) to a benzaldehyde derivative, typically performed at room temperature or below in solvents such as tetrahydrofuran.
- α-Alkyl benzylamines of high optical purity may be prepared from chiral α-alkyl benzyl alcohols using the methods outlined above. The chiral α-alkyl benzyl alcohols may be obtained through chiral reduction of the corresponding ketones. Chiral reducing methods are now well known in organic chemistry and include enzymatic processes, asymmetric hydrogenation procedures and chiral oxazaborolidines.
- The second step of the synthesis typically involves a palladium mediated cross-coupling of the monoamino-monochloro intermediate with a suitably functionalised coupling partner. Typical coupling partners are boronic acids or esters (Suzuki coupling: see for example Miyaura, N. and Suzuki, Chem Rev. 1995, 952457), stannanes (Stine coupling: see for example Stifle, J. K., Angew, Chem., Int. Ed. Engl., 1986, 25, 508), Grignard reagents (Kumada coupling: Kumada, M.; Tamao, K.; Sumitani, K. Org. Synth. 1988, Coll. Vol.6, 407.) or organozinc species (Negishi. coupling: Negishi, E.; J. Organomet. Chem. 2002, 653, 34).
- The Suzuki coupling is the preferred coupling method and is typically performed in a solvent such as DME, THF, DMF, ethanol, propanol, toluene, or 1,4-dioxane in the presence of a base such as potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate. The reaction may be carried out at elevated temperatures and the palladium catalyst employed may be selected from Pd(PPh3)4, Pd(OAc)2, [PdCl2(dppf)], Pd2(dba)3/P(t-Bu)3.
- The products formed from this reaction sequence may be further derivatised using techniques well-known to those skilled in the art. Alternatively, derivatisation of the mono-amino mono-halo inteunecliate may be undertaken prior to displacement of the halo substituent. This derivatisation typically involves functionality originally present on the amine species and employs methods well known to those skilled in the art.
- Alternatively the preparation sequence can be reversed beginning with the palladium mediated cross-coupling reaction to furnish a mono-halo heterocyclic species. Amine displacement of the halo substituent can then be undertaken using procedures outlined above.
- In order that the nature of the present invention may be more clearly understood, preferred forms thereof will now be described with reference to the following non-limiting examples.
-
- A 2M solution of propylmagnesium chloride in ether (4 ml, 8 mmol) was added to a solution of the aldehyde (1.14 g, 6.6 mmol) in dry THF (10 ml) cooled to 0° C. under N2. The mixture was stirred for 16 h at room temperature, after which time saturated ammonium chloride solution was added. The product was extracted into ethyl acetate, and the ethyl acetate layer dried and concentrated to furnish pure product (1.4 g, 98%).
- 1H-n.m.r. (CDCl3) δ 0.94 (t, 3H, J=7.2 Hz, CH3), 1.41 (m, 2H, CH2), 1.75 (m, CH2, 2H), 4.77 (br s, 1H, CH), 7.44-7.62(m, 4H, ArH)
-
- A solution of 1-[4-(trifluoromethyl)phenyl]butan-1-ol (1.4 g, 6.4 mmol) and diphenylphosphoryl azide (2.8 ml, 12.8 mmol) in THF (6 mL) cooled to −10° C. under N2 was treated with DBU (1.9 mL, 12.8 mmol). The resulting solution was stirred at room temperature for 20 hours and then diluted with a mixture of ether and H2O. The organic phase was dried and concentrated and the residue purified by column chromatography using hexane:ethyl acetate (10:1) as eluent to furnish pure azide (0.85 g, 54%).
- 1H-n.m.r. (CDCl3) δ 0.94 (t, 3H, J=7.2 Hz, CH3), 1.37 (m, 2H, CH2), 1.75 (m, 2H, CH2), 4.50 (t, 1H, CH), 7.42 (d, J=7.8 Hz, 2H, ArH), 7.64 (d, 2H, J=7.8 Hz, ArH)
-
- A mixture of 1-(1-azidobutyl)-4-(trifluoromethyl)benzene (0.84 g, 3.5 mmol) and triphenylphosphine (1.8 g, 6.9 mmol) in ethyl acetate (6 mL) and 10% HCl (6 ml) was stirred at room temperature for 64 h. The aqueous phase was collected and the organic phase extracted with 10% HCl (3×5 mL). The aqueous layers were combined and basified with 5M NaOH, and then extracted with ethyl acetate (5×15 mL). The organic phase was dried and concentrated to give pure amine (0.4 g, 54%).
- 1H-n.m.r. (CDCl3) δ 0.91 (t, J=7.4 Hz, 3H CH3), 1.31 (m, 2H, CH2), 1.62 (m, 2H, CH2), 3.97 (m, 1H, CH), 7.43 (AA′XX′, 2H, ArH), 7.58 (AA′XX′, 2H, ArH)
-
- To a suspension of 3-fluorobenzoic acid (140 mg, 1 mmol) and N,O-dimethylhydroxylamine hydrochloride (107 mg, 1.1 mmol) in dichloromethane (2.5 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (211 mg, 1.1 mmol) and the mixture stirred at room temperature for 75 h. The solvents were removed under reduced pressure and the residue chromatographed using ethyl acetate-hexane (4:6) to separate the pure product (130 mg, 71%).
- 1H-n.m.r. (CDCl3) δ 3.36 (s, 3H, N-Me), 3.55 (s, 3H, N-OMe), 7.1.-7.2 (m, 1H, ArH), 7.3-7.5 (m, 3H, Ar)
-
- To a solution of 3-fluoro-N-methoxy-N-methylbenzamide (130 mg, 0.71 mmol) in dry THF (2 mL) cooled to −10° C. was added propyl magnesium chloride (532 μl, 2M solution in ether, 1.1 mmol) under nitrogen. The solution was stirred at −10° C. for 1 h and at room temperature for 75 min. The solution was the poured into saturated aqueous ammonium chloride and the product extracted into ethyl acetate (3×25 mL). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated to give a pale yellow oil, which was purified by chromatography using ethyl acetate-hexane (1:9) to separate the pure product (78 mg, 66%).
- 1H-n.m.r. (CDCl3) δ 1.01 (t, 3H, J=7.4 Hz, Me), 1.77 (m, 2H, CH 2CH3), 2.93 (t, J=7.2 Hz, 2H, COCH2), 7.15-7.30 (m, 1H, Ar), 7.35-7.50 (m, 1H, Ar), 7.60-7.70 (m, 1H, Ar), 7.70-7.80 (m, 1H, Ar).
-
- To a solution of 1-(5-methylpyridin-3-yl)butan-1-one (800 mg, 4.9 mmol) and ammonium formate (1.55 g, 24.5 mmol) in methanol (5 mL) under nitrogen was added dichloro(pentamethykyclopentadienyl)rhodium (LH) dimer (45 mg, 0.074 mmol). The solution was heated at reflux for 8 h. after which time the solution was cooled to room temperature and acidified to pH ˜2 with 2M HCl. The mixture was washed with dichloromethane (3×15 mL) and the aqueous phase then basified to pH ˜12 by addition of solid KOH. The aqueous phase was extracted with dichloromethane (3×15 mL) and the combined organic layers washed with brine, dried (Na2SO4) and concentrated to give a pure product (620 rag, 77%).
- 1H-n.m.r. (CDCl3) δ 0.91 (t, 3H, J=7.4 Hz, CH2 CH 2 CH3), 1.14-1.82 (m, 6H, 2×CH2, NH), 2.33 (s, 3H, CH3), 3.91 (t, 1H, J=6.8 Hz, CHNH2), 7.47 (s, 1H, ArH), 8.32 (br s, 2H, Ar).
-
- Diethylaniline-borane complex (2.4 mL, 13.4 mmol) was added dropwise over 5 min. to a solution of (1S,2R)-1-aminoindan-2-ol (201 mg, 1.4 mmol) in dry THF (20 mL) cooled to 0° C. under nitrogen. After 40 min. a solution of the ketone in THF (40 mL) was added dropwise over 90 min. The cooling bath was then removed and the solution then stirred at RT for 5 h. Acetone (6 mL) was added and the resulting solution stirred at RT for 60 min. before the solvents were removed under reduced pressure. The residue was dissolved in toluene (100 mL) and washed successively with 1M H2SO4 (4×50 mL), H2O (2×50 mL) and brine (50 mL) and then dried (Na2SO4).
- (CDCl3) δ 0.93 (t, 3H, J=7.2 Hz, CH2 CH 3), 1.17-1.51 (m, 2H, CH2 CH 2, CH3), 1.58-1.82 (m, 2H, CH 2CH2CH3), 4.66 (t, J=6.6 Hz, CHNH2), 6.98-7.07 (m, 2H, ArH), 7.26-7.34 (m, 2H, ArH).
-
- To a solution of S-(−)-α,α-diphenyl-2-pyrrolidinemethanol (500 mg, 2 mmol) and trimethylborate (0.27 ml, 2.4 mmol) in THF (20 mL) was added borane-dimethylsulfide complex (20 mL, 2M in THF, 40 mmol). The mixture was cooled to 0° C. and 1-pyridin-3-ylbutan-1-one was added dropwise over 4 h. The solution was stirred at RT overnight and then treated with 2M HCl (175 mL) and stirring continued for 4 h. The volatiles were removed under reduced pressure and the resulting cloudy solution basified to pH 11 with aqueous ammonia. The product was extracted into ethyl acetate (3×100 mL) and the combined organic layers washed with brine (100 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded ˜3 g of product.
- 1H-n.m.r. (CDCl3) δ 0.94 (t, 3H, J=7.4 Hz, CH2 CH2 CH 3), 1.20-1.54 (m, 2H, CH2 CH 2CH3), 1.60-1.91 (m, 2H, CH 2CH2CH3), 2.64 (br s, 1H, OH), 4.73 (t, 1H, J=6.6 Hz, CHOH), 7.24-7.30 (m, 1H, Ar), 7.68-7.74 (m, 1H, Ar), 8.47-8.52 (m, 2H, Ar).
-
- To a suspension of 3-amino-3-phenylpropanoic acid (2.0 g, 12.1 mmol) in dry THE (45 mL) cooled to 0° C. under N2 was added portionwise over 20 minutes solid LiAlH4 (920 mg, 24.2 mmol). Stirring was continued at room temperature for 24 h. after which time solid Na2SO4.10H2O was added with stirring until only a heavy white precipitate was present. The organic layer was diluted with ether and filtered through Celite® and the concentrated ia vacua. The residue was dissolved in ethyl acetate (50 mL) and extracted with 1N HCl (3×40 mL). The aqueous layers were combined and basified to pH-12 with 5M NaOH. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic phases dried (Na2SO4) and concentrated /71 vacuo to separate the product which was used without further purification (0.9 g, 49%).
- 1H-n.m.r. (CDCl3) δ 1.84-1.94 (m, 2H, CH 2CH2OH), 2.68 (br s, 1H, NH2), 3.79 (t, 2H, J=5.8 Hz, CH2CH 2OH), 4.08-4.15 (m, 1H, CHNH2), 4.77 (q, 1H, CH), 7.21-7.38 (m, 5H, ArH)
-
- To a solution of 1-[4-(trifluoromethyl)phenyl]butan-1-amine (0.40 g, 1.9 mmol) and 2,6-dichloropyrazine (0.55 g, 3.7 mmol) in 1,4-dioxane (6 mL) was added anhydrous potassium carbonate (0.39 g, 2.8 mmol). The resulting mixture was heated at reflux for 18 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and H2O. The organic phase was collected, dried and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give pure product (0.03 g, 5%).
- 1H-n.m.r (CDCl3) δ 0.95 (t, 3H, J=7.4 Hz, CH3), 1.39 (m, 2H, CH2), 1.81 (m, 2H, CH2), 4.77 (q, 1H, CH), 5.09 (br d, 1H, NH), 7.42-7.62 (m, 5H, ArH), 7.80 (s, 1H, pyraz.-H)
-
- To a stirred solution of N-[1-(3-aminophenyl)butyl]-6-chloropyrazin-2-amine (0.10 g, 0.36 mmol) and triethylamine (100 μl, 0.72 mmol) in dichloromethane (3 mL) cooled to 0° C. was added acetyl chloride (31 μL, 0.43 mmol). The resulting mixture was stirred at room temperature for 18 h. then diluted with dichloromethane (10 mL) and washed with H2O (10 mL) and brine (10 mL). The organic phase was collected, dried and concentrated and the residue purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give pure product (94 mg, 82%).
- 1H-n.m.r(CDCl3) δ 0.93 (t, 3H, J=7.4 Hz, Me), 1.28-1.43 (m, 2H, CH2), 1.76-1.85 (m, 2H, CH2), 2.16 (s, 3H, COCH3), 4.48-4.59 (m, 1H, CHCH2CH2CH3), 5.15 (br d, J=6.8 Hz, 1H, NH), 7.06 (d, 1H, J=7.4 Hz, Ar), 7.23-7.33 (m, 3H, Ar), 7.54 (s, 1H, CONH), 7.60 (s,1H, pyraz-H), 7.77 (s, 1H, pyraz-H).
-
- Under a nitrogen atmosphere a mixture of 6-chloro-N-[(1S)-1-pyridin-3-ylbutyl]pyrazin-2-amine (53 g, 0.2 mmol), 4-{[(ethylamino)carbonyl]amino}-3-methoxyphenylboronic acid pinacol diester (69 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) in toluene—n-propanol (2.6 mL, 3:1) was treated with 2M aqueous sodium carbonate solution (0.15 mL, 0.3 mmol). The resulting mixture was stirred vigorously whilst being heated at 100° C. for 22 hours. Once cool ethyl acetate (10 mL) was added and the mixture washed with H2O (6×10 mL) and brine (10 mL) and then dried (Na2SO4). Removal of solvent in vacuo then yielded crude product, which was purified by column chromatography using dichloromethane-methanol-aqueous ammonia (93:7:1) as eluent to furnish the product (60 mg).
- 1H-n.m.r. (CDCl3) δ 0.98 (t, 3H, J=7.4 Hz, CH3), 1.14 (t, 3H, J=7.2 Hz, CH3), 1.36-1.52 (m, 2H, CH2),1.78-1.98 (m, 2H, CH2), 2.27 (s, 3H, CH3), 3.23-3.37 (m, 2H, CH2), 4.84-4.94 (m, 2H, CH, NHCONH), 5.19 (d, 1H, J=6.2 Hz, CHNH), 6.31 (s, 1H, ArNH), 7.24-7.30 (m, 1H, ArH), 7.55-7.73 (m, 4H, ArH), 7.75 (s, 1H, pyraz.-H), 8.21 (s, 1H, pyraz.-H), 8.49-8.52 (m, 1H, ArH), 8.69 (d, 1H, J=2.0 Hz, ArH).
-
- The aniline (500 mg, 2.7 mmol) was dissolved in pyridine (5 mL) and to this was added ethyl isocyanate (424 μL, 5.4 mmol). The resulting solution was stirred overnight during which time a thick precipitate formed which was filtered and dried in vacua to give the ethyl urea (595 mg, 86%). 1H-n.m.r. (d6-DMSO) δ 1.05 (t, 3H, J=7.4 Hz, CH3), 2.15 (s, 3H, CH3), 3.09 (dq, 2H, J=7.4, 5.4 Hz, CH2), 6.55 (br t, 1H, J=5.4 Hz, NH), 7.24 (dd, J=8.8, 2.2 Hz, Ar-H), 7.30 (d, 1H, J=2.2 Hz, Ar-H), 7.66 (s, 1H, NH), 7.82 (d, 1H, J=8.8 Hz, ArH).
- To a degassed suspension of the ethyl urea bromide (514 mg, 2 mmol), potassium acetate (784 mg, 8 mmol) and bis(pinacolato)diboron (508 mg, 2 mmol) in a mixture of ethanol (10 mL) and dioxane (2 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (44 mg, 0.06 mmol). The solution was heated at reflux for 2 h. and then allowed to cool to RT. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane (60 mL). This was washed with H2O (2×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed using ethyl acetate-hexane (1:1) as eluant to separate the pure product as a solid (351 mg, 58%).
- H-n.m.r. (CDCl3) δ 1.12 (t, 3H, J=6.8 Hz, CH3), 1.34 (s, 12H, CH3), 2.26 (s, 3H, CH3), 3.09 (dq, 2H, J=6.8, 5.2 Hz, CH2), 4.69 (br t, 1H, NH), 6.06 (s, 1H, NH), 7.49 (d, 1H, J=7.8 Hz, Ar-H), 7.67 (m, 2H, ArH).
-
- To a degassed solution of 3,5-dibromopyridine (0.4 g, 1.7 mmol), sodium Cert-butoxide (227 mg, 3.6 mmol), tris(dibenzylideneacetone)dipalladium (145 mg, 0.09 mmol) and rac-BINAP (105 mg, 0.2 mmol) in dry toluene (10 mL) was added 1-phenylbutan-1-amine (0.2 mL). The mixture was heated at reflux for 24 h and upon cooling to room temperature was diluted with ether and washed with brine (3×30 mL). The solution was dried (Na2SO4) and concentrated and the residue chromatographed using ethyl acetate-hexane (40:60) as eluant. From the early fractions 97 mg of pure product was obtained.
- 1H-n.m.r. (CDCl3) δ 0.94 (t, 3H, J=7.2 Hz, CH3), 1.21-1.53 (m, 2H, CH2), 1.68-1.87 (m, 2H, CH2), 4.19-4.32 (m, 2H, CH and NH), 6.86 (t, 1H, J=2.0 Hz, ArH), 7.20-7.38 (m, 5H, ArH), 7.88 (d, 1H, J=2.0 Hz, ArH), 7.92 (d, 1H, J=2.0 Hz, ArH).
-
- A degassed solution of 3,5-dichloro-6-methyl-1,2,4-triazine (151 mg, 0.9 mmol), 4-(benzyloxy)-3-methoxybenzene boronic acid (236 g, 0.9 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.05 mmol) and tripotassium. phosphate (249 mg, 1.2 mmol) in dimethoxyethane (5 mL) was heated at reflux for 24 h. Upon cooling to room temperature the solution was diluted with CHCl3 and filtered through Celite®. The filtrate was concentrated in vacua and the product purified by column chromatography using ethyl acetate-hexane (25:75) as eluent to furnish (75 mg, 22%).
- 1H-n.m.r. (CDCl3) δ 0.88 (s, 3H, Ar-CH3), 3.98 (s, 3H, OCH3), 5.26 (s, 2H, CH2), 6.99 (d, 1H, J=8.5 Hz, ArH), 7.25-7.44 (m, 7H, ArH).
-
- A solution of the triazene (50 mg, 0.14 mmol) in ethoxyethanol (2.5 mL) was treated with cliisopropylamine (50 μL, 0.28 mmol) and 1-phenylbutan-1-amine (46 μL, 0.28 mmol) and the resulting solution heated at 110° C. for 3 days. The solvent was then removed in vacua to give an orange residue which was chromatographed using ethyl acetate-dichloromethane (20:80) as eluant to separate the product as a pale yellow solid (60 mg, 90%).
- 1H-n.m.r. (CDCl3) δ 0.94 (t, 3H, CH3), 1.21-1.53 (m, 2H, CH2), 1.78-1.97 (m, 2H, CH2), □0.62 (s, 3H, Ar-CH3), 3.89 (s, 3H, OCH3), 5.10 (br q, 1H, CH2), 5.22 (s, 2H, CH2), 5.65 (br s, 1H, NH), 6.87 (d, 1H, J=9.2 Hz, ArH), 7.12-7.44 (m, 12H, Ar-H).
-
- To a solution of (1S)-1-pyridin-3-ylbutan-1-amine (600 mg, 4.0 mmol) in ethanol (20 mL) was added 2,4-dichloro-5-methylpyrimidine (717 mg, 4.4 mmol) and diisopropylethylamine (1.4 mL, 8 mmol). The solution was heated at reflux for 24 h after which time the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with H2O (2×15 mL), brine (15 mL) and dried (Na2SO4). The residue remaining after concentration in vacuo was chromatographed using ethyl acetate-hexanes (9:1) as eluant to separate the desired product (370 mg).
- H-n.m.r. (CDCl3) δ 0.96 (t, 3H, J=7.2 Hz, CH3), 1.23-1.52 (m, 2H, CH2), 1.85-1.99 (m, 2H, CH2), 2.03 (d, 3H, J=0.8 Hz, Ar-Me), 5.03 (br d, 1H, J=7.2 Hz, NH), 5.22-5.33 (m, 1H, CH), 7.24-7.30 (m, 1H, ArH), 7.65-7.71 (m, 1H, ArH), 7.81 (d, 1H, J=0.8 Hz, ArH), 8.51 (dd, J=5.6, 1.4 Hz, 1H, ArH), 8.64 (d, 1H, J=1.8 Hz, ArH).
-
- Under a nitrogen atmosphere a mixture of 2-chloro-5-methyl-N-[(1S)-1-pyridin-3-ylbutyl]pyrimidin-4-amine (277 mg, 1.0 mmol), 4-{[(ethylamino)carbonyl]amino}-3-methoxyphenylboronic acid pinacol diester (416 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol) in toluene—n-propanol (12 mL, 3:1) was treated with 2M aqueous sodium carbonate solution (750 μL, 1.5 mmol). The resulting mixture was stirred vigorously whilst being heated at 100° C. for 17 hours. Once cool ethyl acetate (25 mL) was added and the mixture washed with H2O (6×15 mL), brine (20 mL) and dried (Na2SO4). Removal of solvent in vacua then yielded crude product, which was purified by column chromatography using dichloromethane-methanol-aqueous ammonia (93:7:1) as eluent to furnish the product (110 mg, 57%).
- 1H-n.m.r. (CDCl3) δ 0.99 (t, 3H, J=7.4 Hz, CH3), 1.18 (t, 3H, J=7.2 Hz, CH3), 1.33-1.60 (m, 2H, CH2), 1.82-2.02 (m, 2H, CH2), 2.11 (s, 3H, Ar-Me), 3.25-3.39 (m, 2H, CH2), 3.87 (s, 3H, OMe), 4.80-4.96 (m, 2H, 2×NH), 5.26-5.36 (m, 1H, CH), 6.98 (br s, 1H, Ar-NHCONH), 7.22-7.28 (m, 1H, ArH), 7.67-7.72 (m, 2H, ArH), 7.83-7.88 (m, 1H, ArH), 8.05 (d, 1H, J=0.8 Hz, ArH), 8.10 (d, 1H, J=8.2 Hz, ArH), 8.47 (dd, 1H, J=6.6, 1.8 Hz, ArH), 8.69 (d, 1H, J=2.0 Hz, ArH).
-
- To a solution of 1-pyridin-3-ylbutan-1-amine (100 mg, 0.67 mmol) in ethanol (4 mL) was added 4,6-dichloropyrimidine (109 mg, 0.73 mmol) and diisopropylethylamine (232 μL, 1.33 mmol). The solution was stirred for 3 days after which time the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and washed with H2O (3×15 mL), brine (15 mL) and dried (Na2SO4). The residue remaining after concentration in vacuo was chromatographed using ethyl acetate-hexanes (4:6-9:1) as eluant to separate the desired product (28 mg).
- 1H-n.m.r. (CDCl3) δ 0.96 (t, 3H, J=7.2 Hz, CH3), 1.22-1.51 (m, 2H, CH2), 1.76-1.96 (m, 2H, CH2), 4.76 (br s, 1H, CH), 5.63 (br s, 1H, NH), 6.23 (s, 1H, ArH), 7.26-7.32 (m, 1H, ArH), 7.59-7.65 (m, 1H, ArH), 8.33 (s, 1H, ArH), 8.53-8.56 (m, 1H, ArH), 8.60 (d, 1H, J=1.8 Hz, ArH).
-
- Using an analogous procedure to that described in Example 12, reaction of 6-chloro-N-(1-pyridin-3-ylbutyl)pyrimidin-4-amine (24 mg, 0.09 mmol) with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.11 mmol) afforded the desired product as a brown foam (12 mg).
- 1H-n.m.r. (CDCl3) δ 0.97 (t, 3H, J=7.2 Hz, CH3), 1.32-1.55 (m, 2H, CH2), 1.83-1.95 (m, 2H, CH2), 3.94 (s, 3H, OMe), 4.87 (br s, 1H, CH), 5.43 (br s, 1H, NH), 6.50 (s, 1H, ArH), 6.93 (d, 1H, J=8.4 Hz, ArH), 7.25-7.31 (m, 2H, ArH), 7.55 (d, 1H, J=2.0 Hz, ArH), 7.66-7.71 (m, 1H, ArH), 8.53 (dd, 1H, J=4.9, 1.6 Hz, ArH), 8.58 (d, 1H, J=1.6 Hz, ArH), 8.66 (d, 1H, J=2.0 Hz, ArH).
- Screening
- Compound Dilution
- For screening purposes, compounds were diluted in 96 well plates at a concentration of 20 μM. Plates were warmed at 37° C. for 30 minutes before assay.
- Growth and Maintenance of Cancer Cell Lines
- K562 (Chronic Myeloid Leukemia), PC3 (Prostate Cancer), and DU145 (Prostate Cancer) were obtained from the American Type Culture Collection (ATCC). K562 was grown in RPMI, with 10% FBS with Glutamx added. DU145 cells were cultured in DMED, with 10% FBS and Glutamx and MEM non-essential amino acids added. PC3 cells were grown in F12K medium, with 10% FBS and Glutamx and MEM non-essential amino acids added. All cells were grown at 37° C. in 5% CO2.
- Establishment of TEL:JAK Cell Lines
- The coding region encompassing nucleotides 1-487 of TEL was amplified by PCR using the oligonucleotides STEL (5′-GGA GGA TCC TGA TCT CTC TCG CTG TGA GAC-3′) and 3TEL (5′-AGGC GTC GAC TEC ITC TIC ATG GTT CTG-3′) and U937 mRNA as template. A BamH I site was present into the 5TEL Primer, a Sal I site was incorporated into the 3TEL primer. The regions encompassing the kinase domains of JAK2 (nucleotides 2994-3914; ; JAK2F 5′-ACGC GTC GAC GGT GCC GAA GAC CGG GAT-3′; JAK2R 5′-ATA GTT TAG CGG CCG CTC AGA ATG AAG GTC ATT T-3′) and JAK3 (nucleotides 2520-3469; JAK3F 5′-GAA GTC GAC TAT GCC TGC CAA GAC CCC ACG ATC TT-3′; JAK3R 5′-GGA TCT AGA CTA TGA AAA GGA CAG GGA GTG GTG 111 -3′) were generated by PCR using Taq DNA Polymerase (Gibco/BRL) and U937 mRNA as template. A Sall site was incorporated into the forward primer of JAK2 and JAK3, a Not I site was incorporated into the JAK2 reverse primer and a Xba I site was added to the reverse primer of JAK3.
- A TEL/Jak2 fusion was generated by digestion of the TELPCR product with BamHI/Sal I, digestion of the JAK2 PCR product with Sal I/ Not I followed by ligation and subcloning into the mammalian expression Vector pTRE 2 (Clontech) digested with BamH I-Not I (pTELJAK2). For JAK3 Sal I/ Not I cleaved kinase domain PCR product was ligated with BamHI/Sal I cleaved TELproduct followed by ligation into BamH I/Not I cleaved pTRE2 (pIELJAK3).
- The growth factor dependent myelomonocytic cell line BaF3 bearing the pTET-off plasmid (Clontech) was transfected with either pTELJAK2 or pTELJAK3 and the cells selected for factor independent growth. BaF 3 wild type cells were cultured in DMEM 10% FCS, 10% WEHI 3B conditioned medium. BaF3 IELJAK cells were cultured in DMEM 10% Tet-System Approved FBS (without WEHI 3B conditioned medium).
- Cellular assays were performed as follows:
- Cell suspensions were prepared by harvesting cells from culture. (Cells used in this test should be in later log phase growth and high viability.) Cells were diluted in correct growth medium to 1.1× final concentration (from 50000 cell/mL to 200,000 cell/mL, depending on cell line).
- Compounds to be tested were added (10 μL, 10× final concentration) to a flat bottom 96-well plate. The cellular suspension (90 μL per well) was added, and the plate incubated for 40 hr at 37° C., 5% CO2. MTT (20 μL per well, 5 mg/mL in PBS) was added and the plates were returned to the incubator for a further 6 hours. Lysis buffer (100 μL per well, 10% SDS, 0.01N HCl) was added and the plate stored in the incubator overnight. The plate was then read at 590 nm.
- Tubulin Assay
- Turbidometric assays of microtubule assembly were performed by incubating microtubule protein in cuvettes at 37° C. in a thermostatically controlled spectrophotometer measuring the change in absorbance at 340 nm over time. The microtubule protein was incubated with the each test compound at 0° C. and polymerisation was initiated by addition of 1 mM GTP, prior to heating to 37° C.
- Results
- The activity of a range of compounds is shown in Tables 1 and 2. Compounds that exhibited a capacity to inhibit greater than 50% of cellular growth at a concentration of 20 μM are designated as “+”; compounds which did not inhibit 50% of cellular growth at 20 μM are designated as “−”; compounds which were not tested are designated as “NT”. Likewise, compounds which inhibited tubulin polymerisation by greater than 50% at 50 μM are designated as “+”; compounds which did not inhibit tubulin polymerisation by 50% at 50 μM are designated as “−”; and compounds which were not tested are designated as “NT”.
-
TABLE 1 CHEMISTRY DU145 PC3 K562 TelJak2 TelJak3 Tubulin + + + + + + − − + + + NT + + + + + + − − − + + NT + + + + + + + + + + + + + + + + + + − − − + − NT − − − + + NT + + + + + + + + + + + + − + + + + NT + + + + + + − + − + + NT + + + + + + + + + + + + + + + + + + + + + + + + − − + + + NT + + + + + + − − + + + NT + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + − − + + + NT − − + + + NT − − + + + NT − − + + + NT − − + + + NT + + + + + + + + + + + + − − − + + NT + + + + + + + + + + + + + + + + + + + + + + + + − + + + + NT + + + + + + + + + + + + + + + + + + − − + + − NT − − − + + NT + − + + + NT − − − + + NT NT − − + + NT NT − − + + NT NT − NT + + NT + + + + + + − − − + + NT − − + + + NT − − − + + NT + + + + + + + + + + + + − − − + + NT + + + + + + + + + + + + + + + + + + + + + + + + − − + + + NT + + + + + + + + + + + + + + + + + + + + + + + + + + + + + NT + + + + + + + + + + + + − − + + + NT + + + + + + + + + + + + + + + + + + + + + + + + + − + + + NT + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + − − + + + NT − − + + + NT + + + + + + + + + + + + + + + + + + + + + + + + − − + + + NT − − + + + NT + + + + + + + + + + + + - Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
- All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed anywhere before the priority date of each claim of this application.
- It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
-
-
- 1. Jordan M A. and Wilson L. (1998) Microtubules and actin filaments: dynamic targets for cancer chemotherapy. Curr. Op. Cell Biol,10, 123-130.
- 2. Jordan M A, Margolis R L, Himes R H, Wilson L., (1986) Identification of a distinct class of vinblastine binding sites on microtubules. J. Mol. Biol. 187:61-73
- 3. Rai S S, and Wolff J., (1996) Localization of the vinblastine-binding site on β-tubulin. J. Biol. Chem. 271:14707-11
Claims (19)
1. A method of modulating microtubule polymerisation in a subject, said method comprising administering a therapeutically effective amount of at least one compound of formula (I)
or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof, wherein:
R1 is H or C1-4alkyl;
Q is a bond or C1-4alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently selected from halogen, C1-4alkyl, CH2F, CHF2, CF3, CN, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR4R5, Oaryl, Ohetaryl, CO2R4, CONR4R5, nitro, NR4R5, C1-4alkylNR4R5, NR6C1-4alkylNR4R5, NR4COR5, NR6CONR4R5 and NR4SO2R5;
R4 and R5 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR';
R6 is selected from H and C1-4alkyl;
R7 is selected from H, C1-4alkyl, aryl, hetaryl, C1-4alkyl aryl and C1-4alkyl hetaryl;
R2 is 0-2 substituents independently selected from halogen, C1-4alkyl, OH, OC1-4alkyl, CH2F, CHF2, CF3, OCF3, CN, C1-4alkylNR8R9, OC1-4alkylNR8R9, CO2R8, CONR8R9, NR8R9, NR8COR9, NR10CONR8R9 and NR8SO2R9;
R8 and R9 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR11;
R10 is selected from H, C1-4alkyl, aryl and hetaryl;
R11 is selected from H, C1-4alkyl, aryl, hetaryl, C1-4alkyl aryl and C1-4alkyl hetaryl;
Y is halogen, OH, NR12R13, NR14COR12, NR14CONR12R13 or NR14SO2R13;
R12 and R13 are each independently H, CH2F, CHF2, CF3, CN, C1-4alkyl optionally substituted with OH, OC1-4alkyl, NR15R16, cycloalkyl, cyclohetalkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S and NR14;
R14, R15 and R16 are each independently selected from H and C1-4alkyl;
n=0-4;
W is selected from H, C1-4alkyl and C2-6alkenyl; where C1-3alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR15R16;
R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR17;
R17 is selected from H and C1-4alkyl.
3. A method according to claim 1 , wherein said subject is treated for a hyperproliferation-related disorder or disease state.
4. A method according to claim 3 , wherein the hyperproliferation-related disorder or disease state is selected from the group consisting of cancer, infectious diseases, vascular restenosis and inflammatory diseases.
5. A compound of formula (II)
or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
R1 is H or C1-4alkyl;
Q is a bond, or C1-4alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4alkyl, CH2F, CHF2, CF3, CN, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR4R5, Oaryl, Ohetaryl, CO2R4, CONR4R5, nitro, NR4R5, C1-4alkylNR4R5, NR6C1-4alkylNR4R5, NR4COR5, NR6CONR4R5 and NR4SO2R5;
R4 and R5 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR7;
R6 is selected from H and C1-4alkyl;
R7 is selected from H, C1-4alkyl, aryl, hetaryl, C1-4alkyl aryl and C1-4alkyl hetaryl;
R2 is 0-2 substituents independently selected from C1-4alkyl and OC1-4alkyl;
Y is CH2OH, OC1-4alkylOH, OC1-4alkylR12, OC1-4alkylNR12NR13, C(O)R12, CH2R12, COOR12, CONR12R13, OCONR12R13, CH2NR12R13, NHCOR12 or NHCONR12R13;
R12 and R13 are each independently H, C1-2 alkyl, (CH2)3NEt2, (CH2)2NMe2 (CH2)5NH2, (CH2)2OH,
W is selected from H, C1-4alkyl and C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR15R16;
R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
R17 is selected from H and C1-4alkyl;
wherein when Y is CH2R12 then R12 is not H or C1-2alkyl.
7. A compound of formula (III)
or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
X1, X2, X3, X4 are selected from the following:
(i) X1 and X4 are N and X2 and X3 are C independently substituted with Y;
(ii) X1 and X3 are N and X2 and X4 are C independently substituted with Y;
(iii) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
(iv) X1 is N and X2, X3, and X4 are C independently substituted with Y;
(v) X3 is N and X1, X2 and X4 are C independently substituted with Y;
(vi) X4 is N and X1, X2, and X3 are C independently substituted with Y;
(vii) X2 is N and X1, X3, and X4 are C independently substituted with Y; and
(viii) X1, X2, and X3 are N and X4 is C substituted with Y;
R1 is H, C1-6alkyl, C1-6alkylNR5R6, C1-6alkylNR5COR6, C1-6alkylNR5SO2R6, C1-6alkylCO2R5 or C1-6alkylCONR5R6, where R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-2alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR7;
R7 is selected from H and C1-4alkyl;
R2 is selected from C1-6alkylOH, OC2-6alkylOH, C1-6alkylNR8R9, OC2-6alkylNR8R9, C1-6alkylNR8COR9, OC2-6alkylNR8COR9, C1-6alkylhetaryl, OC2-6alkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9 and NR8COR12;
R8 and R9 are each independently H, C1-4alkylNR11R13, hetaryl, cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR14;
R12 K is C2-4alkyl, C1-4alkylNR11R13, hetaryl or cyclohetalkyl;
R11 and R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR14;
R14 is selected from H and C1-4alkyl;
R10 is H or C1-4alkyl;
R3 and R4 are each independently H, halogen, C1-4alkyl, OH, OC1-4alkyl, CF3 or OCF3;
Q is a bond, or C1-4alkyl;
W is selected from H, C1-4alkyl and C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR
R15 and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR17;
R17 is selected from H and C1-4alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19,C1-4alkyl NR18R19, NR20C1-4l alkylNR18R19, NR18COR19, NR20CONR18R19 and NR18SO2R19;
R18 and R19 are each independently H, C1-4alkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR21;
R21 is selected from H and C1-4alkyl;
R20 is selected from H and C1-4alkyl;
Y is selected from H, OH and NR22R23;
R22, R23 are each independently H or C1-4alkyl.
8. A compound according to claim 7 , wherein
R1 is H, C1-6alkyl or C1-6alkylNR5R6, where R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR7;
Q is CH;
W is selected from C1-4alkyl and C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR15R16;
R15 and R16 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR17;
A is aryl or hetaryl optionally substituted with 0-2 substituents independently chosen from halogen, C1-4alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19, C1-4alkylNR18R19, NR20C1-4alkylNR18R19, NR18COR19, NR20CONR18R19 and NR18SO2R19;
Y is selected from H, C1-4alkyl and NR22R23.
10. A compound of formula (V)
or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
(i) X1 and X4 are N and X2 and X3 are C independently substituted with Y;
(ii) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
(iii) X1 is N and X2, X3, and X4 are C independently substituted with Y;
(iv) X3 is N and X1, X2, and X4 are C independently substituted with Y;
(v) X4 is N and X1, X2, and X3 are C independently substituted with Y;
(vi) X2 is N and X1, X3, and X4 are C independently substituted with Y; and
(vii) X1, X2 and X3 are N and X4 is C substituted with Y;
R1 is H, C1-6alkyl, C1-6alkylNR5R6, C1-6alkylNR5COR6, C1-6alkylNR5SO2R6, C1-6alkylCO2R5 or C1-6alkylCONR5R6, where R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-4alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR7;
R7 is selected from H and C1-4alkyl;
R2 is selected from OH, OC1-6alkyl, C1-6alkylOH, OC2-6alkylOH, C1-6alkylNR8R9, OC2-6alkylNR8R9, C1-6alkylNR8COR9, OC2-6alkylNR8COR9, C1-6alkylhetaryl, OC2-6alkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9 and NR8COR12;
R8 and R9 are each independently H, C1-4alkyl, C1-4alkylNR11R13, hetaryl or cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR14;
R12 is C2-4alkyl, C1-4alkylNR11R13, hetaryl or cyclohetalkyl;
R11 and R13 are each independently H or C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR14;
R14 is selected from H and C1-4alkyl;
R10 is H or C1-4alkyl;
R3 and R4 are each independently H, halogen, C1-4alkyl, OH, OC1-4alkyl, CF3 or OCF3;
Q is a bond or C1-4alkyl;
W is selected from H, C1-4alkyl and C2-6alkenyl; where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR15R16;
R15 and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl or hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR17;
R17 is selected from H and C1-4alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19, C1-4alkylNR18R19, NR20C1-4alkylNR18R19, NR18COR19, NR20CONR18R19 and NR18SO2R19;
R18 and R19 are each independently H, C1-4alkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl or C1-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR21;
R21 is selected from H and C1-4alkyl;
R2° is selected from H and C1-4alkyl;
Y is selected from H, C1-4alkyl, OH and NR22R23;
R22, R23 are each independently H or C1-4alkyl.
13. A composition comprising a carrier and at least one compound according to claim 7 .
14. A method to treat a hyperproliferation-related disorder or disease state in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7 .
15. A method according to claim 14 , wherein the hyperproliferation-related disorder or disease state is treatable by the modulation of microtubule polymerisation.
16. A method according to claim 14 , wherein the hyperproliferation-related disorder or disease state is selected from the group consisting of cancer, infectious diseases, vascular restenosis or inflammatory diseases.
17. A method to treat a protein-kinase related disorder or disease state in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7 .
18. A method according to claim 17 , wherein the protein-kinase related disorder to disease state is selected from the group consisting of atopy, cell mediated hypersensitivity, rheumatic diseases, other autoimmune diseases and viral diseases.
19. A method to treat diseases and conditions associated with inflammation and infection in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7 .
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/797,568 US20130274263A1 (en) | 2003-12-03 | 2013-03-12 | Tubulin inhibitors |
US14/194,543 US9139560B2 (en) | 2003-12-03 | 2014-02-28 | Substituted pyrazines as tubulin inhibitors |
US14/811,503 US9732046B2 (en) | 2003-12-03 | 2015-07-28 | Substituted 1,2,4-triazines as tubulin inhibitors |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003906680 | 2003-12-03 | ||
AU2003906680A AU2003906680A0 (en) | 2003-12-03 | Tubulin Inhibitors | |
PCT/AU2004/001689 WO2005054199A1 (en) | 2003-12-03 | 2004-12-03 | Tubulin inhibitors |
US10/581,534 US7981900B2 (en) | 2003-12-03 | 2004-12-03 | 2-phenyl pyrimidines which are tubulin inhibitors |
US13/183,348 US8394806B2 (en) | 2003-12-03 | 2011-07-14 | 2-phenyl pyrazines as tubulin inhibitors |
US13/797,568 US20130274263A1 (en) | 2003-12-03 | 2013-03-12 | Tubulin inhibitors |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/183,348 Continuation US8394806B2 (en) | 2003-12-03 | 2011-07-14 | 2-phenyl pyrazines as tubulin inhibitors |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/194,543 Continuation US9139560B2 (en) | 2003-12-03 | 2014-02-28 | Substituted pyrazines as tubulin inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
US20130274263A1 true US20130274263A1 (en) | 2013-10-17 |
Family
ID=34637692
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/581,534 Active 2027-12-25 US7981900B2 (en) | 2003-12-03 | 2004-12-03 | 2-phenyl pyrimidines which are tubulin inhibitors |
US13/183,348 Active US8394806B2 (en) | 2003-12-03 | 2011-07-14 | 2-phenyl pyrazines as tubulin inhibitors |
US13/797,568 Abandoned US20130274263A1 (en) | 2003-12-03 | 2013-03-12 | Tubulin inhibitors |
US14/194,543 Active US9139560B2 (en) | 2003-12-03 | 2014-02-28 | Substituted pyrazines as tubulin inhibitors |
US14/811,503 Active 2025-03-11 US9732046B2 (en) | 2003-12-03 | 2015-07-28 | Substituted 1,2,4-triazines as tubulin inhibitors |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/581,534 Active 2027-12-25 US7981900B2 (en) | 2003-12-03 | 2004-12-03 | 2-phenyl pyrimidines which are tubulin inhibitors |
US13/183,348 Active US8394806B2 (en) | 2003-12-03 | 2011-07-14 | 2-phenyl pyrazines as tubulin inhibitors |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/194,543 Active US9139560B2 (en) | 2003-12-03 | 2014-02-28 | Substituted pyrazines as tubulin inhibitors |
US14/811,503 Active 2025-03-11 US9732046B2 (en) | 2003-12-03 | 2015-07-28 | Substituted 1,2,4-triazines as tubulin inhibitors |
Country Status (20)
Country | Link |
---|---|
US (5) | US7981900B2 (en) |
EP (2) | EP1689715B1 (en) |
JP (2) | JP4772690B2 (en) |
KR (2) | KR101206843B1 (en) |
CN (2) | CN1890218B (en) |
AT (1) | ATE497949T1 (en) |
AU (1) | AU2004294354B2 (en) |
BR (1) | BRPI0417354A (en) |
CA (2) | CA2545422C (en) |
CY (1) | CY1111410T1 (en) |
DE (1) | DE602004031357D1 (en) |
DK (1) | DK1689715T3 (en) |
ES (2) | ES2528302T3 (en) |
IL (1) | IL175576A (en) |
NZ (1) | NZ546057A (en) |
PL (1) | PL1689715T3 (en) |
PT (2) | PT1689715E (en) |
SI (1) | SI1689715T1 (en) |
WO (1) | WO2005054199A1 (en) |
ZA (1) | ZA200602664B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9139560B2 (en) | 2003-12-03 | 2015-09-22 | Ym Biosciences Australia Pty Ltd. | Substituted pyrazines as tubulin inhibitors |
WO2016167795A1 (en) * | 2015-04-17 | 2016-10-20 | Southern Research Institute | Treatment of hepatitis b viral |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2002953255A0 (en) | 2002-12-11 | 2003-01-02 | Cytopia Research Pty Ltd | Protein kinase inhibitors |
SG150533A1 (en) | 2003-11-20 | 2009-03-30 | Janssen Pharmaceutica Nv | 6-alkenyl and 6-phenylalkyl substituted 2-quinolinones and 2- quinoxalinones as poly(adp-ribose) polymerase inhibitors |
NZ546990A (en) | 2003-11-20 | 2010-03-26 | Janssen Pharmaceutica Nv | 7-Phenylalkyl substituted 2-quinolinones and 2 quinoxalinones as poly(adp-ribose) polymerase inhibitors |
CA2568835C (en) | 2004-06-30 | 2014-05-27 | Janssen Pharmaceutica N.V. | Quinazolinone derivatives as parp inhibitors |
AU2005259189B2 (en) | 2004-06-30 | 2011-04-21 | Janssen Pharmaceutica N.V. | Phthalazine derivatives as PARP inhibitors |
MXPA06014541A (en) | 2004-06-30 | 2007-03-23 | Janssen Pharmaceutica Nv | Quinazolinedione derivatives as parp inhibitors. |
US20090196912A1 (en) * | 2004-07-30 | 2009-08-06 | Gpc Botech Ag | Pyridinylamines |
WO2006133498A1 (en) * | 2005-06-15 | 2006-12-21 | Cytopia Research Pty Ltd | Acid addition salts of n-ethyi-n'-[2-methoxy-4-(5-methyi-4-{[(1s)-1-pyridin-3-ylbutyi]amino}pyrimidin- 2-yl)phenyl]urea and uses thereof |
WO2008022164A2 (en) * | 2006-08-16 | 2008-02-21 | Boehringer Ingelheim International Gmbh | Pyrazine compounds, their use and methods of preparation |
DE102006049618A1 (en) * | 2006-10-20 | 2008-05-08 | Tschesche, Harald, Prof. Dr. | Triazines and their use as metalloproteinase inhibitors |
EP2099774A4 (en) | 2006-11-15 | 2010-11-24 | Ym Biosciences Australia Pty L | Inhibitors of kinase activity |
AU2013273769B2 (en) * | 2006-11-15 | 2016-05-12 | Ym Biosciences Australia Pty Ltd | Inhibitors of Kinase Activity |
CA2678248C (en) | 2007-03-08 | 2016-06-28 | Janssen Pharmaceutica Nv | Quinolinone derivatives as parp and tank inhibitors |
US8404713B2 (en) | 2007-10-26 | 2013-03-26 | Janssen Pharmaceutica Nv | Quinolinone derivatives as PARP inhibitors |
WO2009096198A1 (en) * | 2008-02-01 | 2009-08-06 | Pharma Ip Limited Liability Intermediary Corporations | Novel biaryl derivative |
SI2271626T1 (en) | 2008-03-27 | 2015-03-31 | Janssen Pharmaceutica, N.V. | Tetrahydrophenanthridinones and tetrahydrocyclopentaquinolinones as parp and tubulin polymerization inhibitors |
US8168644B2 (en) | 2008-03-27 | 2012-05-01 | Janssen Pharmaceutica Nv | Quinazolinone derivatives as tubulin polymerization inhibitors |
CA2723358A1 (en) * | 2008-05-05 | 2009-11-12 | Allison B. Reiss | Method for improving cardiovascular risk profile of cox inhibitors |
WO2009143389A1 (en) | 2008-05-21 | 2009-11-26 | Ariad Pharmaceuticals, Inc. | Phosphorous derivatives as kinase inhibitors |
KR101354763B1 (en) | 2008-08-25 | 2014-01-22 | 아이알엠 엘엘씨 | Hedgehog pathway modulators |
WO2010046780A2 (en) * | 2008-10-22 | 2010-04-29 | Institut Pasteur Korea | Anti viral compounds |
JP2012513409A (en) * | 2008-12-23 | 2012-06-14 | アボット・ラボラトリーズ | Antiviral compounds |
MX2011006333A (en) | 2008-12-23 | 2011-06-27 | Abbott Lab | Anti-viral compounds. |
EP2419404B1 (en) | 2009-04-15 | 2015-11-04 | AbbVie Inc. | Anti-viral compounds |
EP2322537A1 (en) | 2009-11-12 | 2011-05-18 | R & D Biopharmaceuticals Gmbh | Tubulin inhibitors |
ES2581207T3 (en) | 2009-11-12 | 2016-09-02 | Tube Pharmaceuticals Gmbh | Tubulin Inhibitors |
US9248198B2 (en) * | 2011-06-13 | 2016-02-02 | The Board Of Trustees Of The University Of Illinois | Peptide compositions and methods for treating lung injury, asthma, anaphylaxis, angioedema, systemic vascular permeability syndromes, and nasal congestion |
IN2014MN01622A (en) * | 2012-02-17 | 2015-05-15 | Univ Cape Town | |
CN102826985B (en) * | 2012-09-18 | 2015-08-19 | 厦门大学 | A kind of preparation method of 1-(3,4,5-trihydroxy-) phenyl-1-alkyl ketone |
JP2016506417A (en) * | 2013-01-10 | 2016-03-03 | プルモキネ、インコーポレイテッド | Treatment indicators for kinase inhibitors |
DK3007689T3 (en) | 2013-01-10 | 2018-06-14 | Pulmokine Inc | NON-SELECTIVE KINASE INHIBITORS |
CN111743901B (en) | 2013-10-11 | 2023-09-12 | 普尔莫凯恩股份有限公司 | Spray-dried formulations |
CN106167482A (en) * | 2015-05-19 | 2016-11-30 | 重庆大学 | A kind of compound suppressing prostate cancer growth and application thereof |
WO2017181974A1 (en) * | 2016-04-20 | 2017-10-26 | 苏州苏领生物医药有限公司 | Five-membered heterocyclic compound, preparation method therefor, pharmaceutical composition and use |
CN107304202A (en) * | 2016-04-20 | 2017-10-31 | 苏州苏领生物医药有限公司 | Five-membered heterocycles and preparation method thereof, pharmaceutical composition and purposes |
CN106565685B (en) * | 2016-10-11 | 2019-03-01 | 深圳海王医药科技研究院有限公司 | Antitubulin |
CN110087653A (en) | 2016-10-27 | 2019-08-02 | 普尔莫凯恩股份有限公司 | For treating the combination treatment of pulmonary hypertension |
EP3720436A4 (en) * | 2017-12-06 | 2021-06-02 | Lin Bioscience, Pty Ltd. | Tubulin inhibitors |
AU2019215799B2 (en) * | 2018-02-01 | 2022-04-14 | The University Of Sydney | Anti-cancer compounds |
CN108658963A (en) * | 2018-06-20 | 2018-10-16 | 桑文军 | A kind of antitumor drug acting on tubulin |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040235862A1 (en) * | 2002-05-23 | 2004-11-25 | Burns Christopher John | Protein kinase inhibitors |
Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE82928C (en) | 1893-06-18 | 1895-10-01 | ||
FR352807A (en) | 1905-03-28 | 1905-08-22 | Julius Schroeder | Improvements made to the smoke boxes of boilers with boiling tubes and cleaning brushes |
GB253816A (en) | 1925-12-29 | 1926-06-24 | Spencer Bonecourt Ltd | Improvements relating to the cleaning of the fire-tubes of a boiler |
US3354490A (en) | 1964-06-15 | 1967-11-28 | Power Tube Inc | Boiler tube cleaning apparatus |
CH593266A5 (en) * | 1973-09-20 | 1977-11-30 | Delalande Sa | |
US4367790A (en) | 1980-12-16 | 1983-01-11 | Draeger Walter A | Multiple tube cleaning apparatus |
JPS61228296A (en) | 1985-03-30 | 1986-10-11 | Takao Sakamoto | Cleaning of inner surface of heating tube in heat exchanger |
GB9523675D0 (en) * | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
US6147080A (en) | 1996-12-18 | 2000-11-14 | Vertex Pharmaceuticals Incorporated | Inhibitors of p38 |
AT405973B (en) | 1998-06-26 | 2000-01-25 | Hackl Hubert | CLEANING DEVICE FOR HEAT EXCHANGERS |
DE19853278A1 (en) * | 1998-11-19 | 2000-05-25 | Aventis Pharma Gmbh | New 4-amino-2-aryl-cyclopentapyrimidine derivatives are activators of soluble guanylate cyclase, useful for treating or preventing e.g. thrombosis and restenosis |
JP2000180093A (en) | 1998-12-15 | 2000-06-30 | Toshiba Plant Kensetsu Co Ltd | Method and apparatus for cleaning and detecting flaw in pipe of heat exchanger |
PL355639A1 (en) | 1999-09-10 | 2004-05-04 | Merck & Co, Inc. | Tyrosine kinase inhibitors |
JP2004510707A (en) * | 2000-08-08 | 2004-04-08 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | Neuroprotective 2-pyridinamine compositions and related methods |
WO2002020495A2 (en) * | 2000-09-06 | 2002-03-14 | Chiron Corporation | Inhibitors of glycogen synthase kinase 3 |
MXPA03002294A (en) * | 2000-09-15 | 2005-09-08 | Vertex Pharma | Pyrazole compounds useful as protein kinase inhibitors. |
US7129242B2 (en) * | 2000-12-06 | 2006-10-31 | Signal Pharmaceuticals, Llc | Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto |
WO2002047690A1 (en) * | 2000-12-12 | 2002-06-20 | Cytovia, Inc. | Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
EP1363702A4 (en) * | 2001-01-30 | 2007-08-22 | Cytopia Pty Ltd | Methods of inhibiting kinases |
US6949544B2 (en) * | 2001-03-29 | 2005-09-27 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases |
WO2003026661A1 (en) * | 2001-09-14 | 2003-04-03 | Yamanouchi Pharmaceutical Co., Ltd. | Insulin secretion accelerator and novel pyrimidine derivative |
AU2002342051B2 (en) * | 2001-10-12 | 2009-06-11 | Irm Llc | Kinase inhibitor scaffolds and methods for their preparation |
AUPS251502A0 (en) * | 2002-05-23 | 2002-06-13 | Cytopia Pty Ltd | Protein kinase inhibitors |
AU2003232919B2 (en) * | 2002-05-23 | 2009-03-05 | Ym Biosciences Australia Pty Ltd | Protein kinase inhibitors |
US7015227B2 (en) * | 2002-06-21 | 2006-03-21 | Cgi Pharmaceuticals, Inc. | Certain amino-substituted monocycles as kinase modulators |
EP1562911B1 (en) * | 2002-11-01 | 2010-01-06 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of jak and other protein kinases |
JP2006508107A (en) * | 2002-11-05 | 2006-03-09 | バーテックス ファーマシューティカルズ インコーポレイテッド | Compounds useful as inhibitors of JAK and other protein kinases |
KR20050074571A (en) * | 2002-11-11 | 2005-07-18 | 바이엘 헬스케어 아게 | Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist |
AU2002953255A0 (en) * | 2002-12-11 | 2003-01-02 | Cytopia Research Pty Ltd | Protein kinase inhibitors |
GB2400101A (en) | 2003-03-28 | 2004-10-06 | Biofocus Discovery Ltd | Compounds capable of binding to the active site of protein kinases |
US20050014753A1 (en) * | 2003-04-04 | 2005-01-20 | Irm Llc | Novel compounds and compositions as protein kinase inhibitors |
CA2530389A1 (en) * | 2003-07-02 | 2005-01-13 | Biofocus Discovery Limited | Pyrazine and pyridine derivatives as rho kinase inhibitors |
AU2004261484A1 (en) * | 2003-07-30 | 2005-02-10 | Cyclacel Limited | 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors |
EP1689715B1 (en) | 2003-12-03 | 2011-02-09 | YM BioSciences Australia Pty Ltd | Tubulin inhibitors |
WO2006133498A1 (en) | 2005-06-15 | 2006-12-21 | Cytopia Research Pty Ltd | Acid addition salts of n-ethyi-n'-[2-methoxy-4-(5-methyi-4-{[(1s)-1-pyridin-3-ylbutyi]amino}pyrimidin- 2-yl)phenyl]urea and uses thereof |
EP2114900B1 (en) | 2007-01-31 | 2018-10-10 | YM BioSciences Australia Pty Ltd | Thiopyrimidine-based compounds and uses thereof |
-
2004
- 2004-12-03 EP EP04801111A patent/EP1689715B1/en active Active
- 2004-12-03 ZA ZA200602664A patent/ZA200602664B/en unknown
- 2004-12-03 AT AT04801111T patent/ATE497949T1/en active
- 2004-12-03 KR KR20067010930A patent/KR101206843B1/en not_active IP Right Cessation
- 2004-12-03 US US10/581,534 patent/US7981900B2/en active Active
- 2004-12-03 DE DE200460031357 patent/DE602004031357D1/en active Active
- 2004-12-03 AU AU2004294354A patent/AU2004294354B2/en not_active Ceased
- 2004-12-03 KR KR1020117031131A patent/KR101260717B1/en not_active IP Right Cessation
- 2004-12-03 CN CN2004800361061A patent/CN1890218B/en not_active Expired - Fee Related
- 2004-12-03 EP EP20100010746 patent/EP2277865B1/en active Active
- 2004-12-03 NZ NZ546057A patent/NZ546057A/en not_active IP Right Cessation
- 2004-12-03 DK DK04801111T patent/DK1689715T3/en active
- 2004-12-03 JP JP2006541750A patent/JP4772690B2/en not_active Expired - Fee Related
- 2004-12-03 CA CA2545422A patent/CA2545422C/en not_active Expired - Fee Related
- 2004-12-03 ES ES10010746.5T patent/ES2528302T3/en active Active
- 2004-12-03 ES ES04801111T patent/ES2360703T3/en active Active
- 2004-12-03 PT PT04801111T patent/PT1689715E/en unknown
- 2004-12-03 PT PT100107465T patent/PT2277865E/en unknown
- 2004-12-03 CA CA2857067A patent/CA2857067C/en not_active Expired - Fee Related
- 2004-12-03 SI SI200431653T patent/SI1689715T1/en unknown
- 2004-12-03 BR BRPI0417354-6A patent/BRPI0417354A/en not_active Application Discontinuation
- 2004-12-03 WO PCT/AU2004/001689 patent/WO2005054199A1/en active Application Filing
- 2004-12-03 PL PL04801111T patent/PL1689715T3/en unknown
- 2004-12-03 CN CN2010106215795A patent/CN102127056B/en not_active Expired - Fee Related
-
2006
- 2006-05-11 IL IL175576A patent/IL175576A/en not_active IP Right Cessation
-
2011
- 2011-01-11 JP JP2011002891A patent/JP5318126B2/en not_active Expired - Fee Related
- 2011-05-05 CY CY20111100435T patent/CY1111410T1/en unknown
- 2011-07-14 US US13/183,348 patent/US8394806B2/en active Active
-
2013
- 2013-03-12 US US13/797,568 patent/US20130274263A1/en not_active Abandoned
-
2014
- 2014-02-28 US US14/194,543 patent/US9139560B2/en active Active
-
2015
- 2015-07-28 US US14/811,503 patent/US9732046B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040235862A1 (en) * | 2002-05-23 | 2004-11-25 | Burns Christopher John | Protein kinase inhibitors |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9139560B2 (en) | 2003-12-03 | 2015-09-22 | Ym Biosciences Australia Pty Ltd. | Substituted pyrazines as tubulin inhibitors |
US9732046B2 (en) | 2003-12-03 | 2017-08-15 | Ym Biosciences Australia Pty Ltd. | Substituted 1,2,4-triazines as tubulin inhibitors |
WO2016167795A1 (en) * | 2015-04-17 | 2016-10-20 | Southern Research Institute | Treatment of hepatitis b viral |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9732046B2 (en) | Substituted 1,2,4-triazines as tubulin inhibitors | |
US7122550B2 (en) | Protein kinase inhibitors | |
US8084456B2 (en) | Pyrazine-based tubulin inhibitors | |
MXPA06006111A (en) | Tubulin inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: YM BIOSCIENCES AUSTRALIA PTY LTD, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BURNS, CHRISTOPHER J.;WILKS, ANDREW F.;HARTE, MICHAEL;AND OTHERS;SIGNING DATES FROM 20131121 TO 20140317;REEL/FRAME:032529/0710 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |