US20070010669A1 - Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof - Google Patents
Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof Download PDFInfo
- Publication number
- US20070010669A1 US20070010669A1 US11/474,042 US47404206A US2007010669A1 US 20070010669 A1 US20070010669 A1 US 20070010669A1 US 47404206 A US47404206 A US 47404206A US 2007010669 A1 US2007010669 A1 US 2007010669A1
- Authority
- US
- United States
- Prior art keywords
- compound
- mmol
- acid
- etoac
- compounds
- 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 [1*]NC(=O)C(*[2*])CC(=O)NO Chemical compound [1*]NC(=O)C(*[2*])CC(=O)NO 0.000 description 23
- VQOMRPVLCGWPHT-SFHVURJKSA-N O=C(CCCCC[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCC[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO VQOMRPVLCGWPHT-SFHVURJKSA-N 0.000 description 4
- XPVBVOAGPWTRHU-QFIPXVFZSA-N CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1 XPVBVOAGPWTRHU-QFIPXVFZSA-N 0.000 description 3
- ZROZVGQJRARHQY-UHFFFAOYSA-N COP(C)(=O)NCCCCCC(=O)NC1=CC=CC=C1 Chemical compound COP(C)(=O)NCCCCCC(=O)NC1=CC=CC=C1 ZROZVGQJRARHQY-UHFFFAOYSA-N 0.000 description 3
- DOJFCDQNFGWIDH-UHFFFAOYSA-N CS(=O)(=O)NCCCCCC(=O)NC1=CC=CC=C1 Chemical compound CS(=O)(=O)NCCCCCC(=O)NC1=CC=CC=C1 DOJFCDQNFGWIDH-UHFFFAOYSA-N 0.000 description 3
- SQGNVWSNUGLNRK-CCEZHUSRSA-N O=C(/C=C/C1=CC=CC(C(C(=O)NC2=CC=CC=C2)C(=O)NC2=CC=CC=C2)=C1)NO Chemical compound O=C(/C=C/C1=CC=CC(C(C(=O)NC2=CC=CC=C2)C(=O)NC2=CC=CC=C2)=C1)NO SQGNVWSNUGLNRK-CCEZHUSRSA-N 0.000 description 3
- UEGKDJGASMFKBQ-NRFANRHFSA-N O=C(CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO Chemical compound O=C(CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO UEGKDJGASMFKBQ-NRFANRHFSA-N 0.000 description 3
- WXEGFZIFQSDJQY-UHFFFAOYSA-N C=CCCC(=O)NC1=CC=CC=C1 Chemical compound C=CCCC(=O)NC1=CC=CC=C1 WXEGFZIFQSDJQY-UHFFFAOYSA-N 0.000 description 2
- XOVOQQFWGNOQHJ-UHFFFAOYSA-N CC(=O)SCCCCCC(=O)NC1=CC=CC=C1 Chemical compound CC(=O)SCCCCCC(=O)NC1=CC=CC=C1 XOVOQQFWGNOQHJ-UHFFFAOYSA-N 0.000 description 2
- LMKBRMCDBIEZSX-UHFFFAOYSA-N CC(=O)SCCCCCCCC(=O)NC1=CC=CC=C1 Chemical compound CC(=O)SCCCCCCCC(=O)NC1=CC=CC=C1 LMKBRMCDBIEZSX-UHFFFAOYSA-N 0.000 description 2
- JUDCKORCMYXODX-INIZCTEOSA-N CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC(=O)O Chemical compound CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC(=O)O JUDCKORCMYXODX-INIZCTEOSA-N 0.000 description 2
- NNGUEDMYISAVCC-SFHVURJKSA-N CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1 NNGUEDMYISAVCC-SFHVURJKSA-N 0.000 description 2
- MCUBNMOHCODAHP-UHFFFAOYSA-N CCOC(=O)CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=CC=CC2=C1N=CC=C2 Chemical compound CCOC(=O)CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=CC=CC2=C1N=CC=C2 MCUBNMOHCODAHP-UHFFFAOYSA-N 0.000 description 2
- LPURTZZOXZBSBN-LFWRRJNUSA-N CN(C(=O)CC/C=C/C=C/C(=O)NO)C1=CC=CC=C1 Chemical compound CN(C(=O)CC/C=C/C=C/C(=O)NO)C1=CC=CC=C1 LPURTZZOXZBSBN-LFWRRJNUSA-N 0.000 description 2
- CXRQIODADRYUDL-HNNXBMFYSA-N COC(=O)C[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound COC(=O)C[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 CXRQIODADRYUDL-HNNXBMFYSA-N 0.000 description 2
- JFTKFDYZAOJDGU-LBPRGKRZSA-N COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1=CC=CC=C1 Chemical compound COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1=CC=CC=C1 JFTKFDYZAOJDGU-LBPRGKRZSA-N 0.000 description 2
- NEGSHUGYEIDSGT-UHFFFAOYSA-N COP(=O)(NCCCCCC(=O)NC1=CC=CC=C1)OC Chemical compound COP(=O)(NCCCCCC(=O)NC1=CC=CC=C1)OC NEGSHUGYEIDSGT-UHFFFAOYSA-N 0.000 description 2
- NJHPTRCDNRQRLW-UHFFFAOYSA-N NCCCCCC(=O)NC1=CC=CC=C1 Chemical compound NCCCCCC(=O)NC1=CC=CC=C1 NJHPTRCDNRQRLW-UHFFFAOYSA-N 0.000 description 2
- JLHCFJVDVVLLCA-UHFFFAOYSA-N NS(=O)(=O)CCCCCCC(=O)NC1=CC=CC=C1 Chemical compound NS(=O)(=O)CCCCCCC(=O)NC1=CC=CC=C1 JLHCFJVDVVLLCA-UHFFFAOYSA-N 0.000 description 2
- BYLQVNZTCGIJPH-UHFFFAOYSA-N O=C(CCCCCBr)NC1=CC=CC=C1 Chemical compound O=C(CCCCCBr)NC1=CC=CC=C1 BYLQVNZTCGIJPH-UHFFFAOYSA-N 0.000 description 2
- LWVBYBDGJGWNFB-UHFFFAOYSA-N O=C(CCCCCC(C(=O)NC1=CC=CC2=C1C=CC=N2)C(=O)NC1=CC=CC2=C1C=CC=N2)NO Chemical compound O=C(CCCCCC(C(=O)NC1=CC=CC2=C1C=CC=N2)C(=O)NC1=CC=CC2=C1C=CC=N2)NO LWVBYBDGJGWNFB-UHFFFAOYSA-N 0.000 description 2
- YFVLSFYVMSLZSA-UHFFFAOYSA-N O=C(CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=CC=CC2=C1N=CC=C2)NO Chemical compound O=C(CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=CC=CC2=C1N=CC=C2)NO YFVLSFYVMSLZSA-UHFFFAOYSA-N 0.000 description 2
- UNEQHJFBFOEIKJ-UHFFFAOYSA-N O=C(CCCCCC(C(=O)NC1=CC=CC=C1)(C(=O)NC1=CC=CC=C1)C1=CC=CC=C1)NO Chemical compound O=C(CCCCCC(C(=O)NC1=CC=CC=C1)(C(=O)NC1=CC=CC=C1)C1=CC=CC=C1)NO UNEQHJFBFOEIKJ-UHFFFAOYSA-N 0.000 description 2
- PTBRFGUFULUYRY-UHFFFAOYSA-N O=C(CCCCCC(C(=O)NC1=CN=C2C=CC=CC2=C1)C(=O)NC1=CN=C2C=CC=CC2=C1)NO Chemical compound O=C(CCCCCC(C(=O)NC1=CN=C2C=CC=CC2=C1)C(=O)NC1=CN=C2C=CC=CC2=C1)NO PTBRFGUFULUYRY-UHFFFAOYSA-N 0.000 description 2
- KRCXZGYVOZSCSF-UHFFFAOYSA-N O=C(CCCCCCC(=O)C(F)(F)F)NC1=CC=CC=C1 Chemical compound O=C(CCCCCCC(=O)C(F)(F)F)NC1=CC=CC=C1 KRCXZGYVOZSCSF-UHFFFAOYSA-N 0.000 description 2
- HONYVUNWWNBOJD-UHFFFAOYSA-N O=C(CCCCCCC(=O)NC1=CC=CC2=CC=CN=C21)NO Chemical compound O=C(CCCCCCC(=O)NC1=CC=CC2=CC=CN=C21)NO HONYVUNWWNBOJD-UHFFFAOYSA-N 0.000 description 2
- MUIPEDPJLVDJHO-IBGZPJMESA-N O=C(O)CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound O=C(O)CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1 MUIPEDPJLVDJHO-IBGZPJMESA-N 0.000 description 2
- CQXJUNISCLRVII-UHFFFAOYSA-N C.C[PH](I)(I)(I)(I)I.NS(=O)(=O)CCCCCC(=O)NC1=CC=CC=C1.O=C(CCCCCS)NC1=CC=CC=C1.O=C(Cl)CCCCCS(=O)(=O)Cl.O=C(O)CCCCCS.O=C(O)CCCCCS(=O)(=O)O Chemical compound C.C[PH](I)(I)(I)(I)I.NS(=O)(=O)CCCCCC(=O)NC1=CC=CC=C1.O=C(CCCCCS)NC1=CC=CC=C1.O=C(Cl)CCCCCS(=O)(=O)Cl.O=C(O)CCCCCS.O=C(O)CCCCCS(=O)(=O)O CQXJUNISCLRVII-UHFFFAOYSA-N 0.000 description 1
- HVZNGNYAFRQGON-UHFFFAOYSA-N C1=CC=C(NC2=CC=CC=C2)C=C1.C1=CC=C2SC3=CC=CC=C3NC2=C1.C1CCC(NC2CCCCC2)CC1.CC1=C2N=CC=CC2=CC=C1.CC1=C2NC=N(C)C2=NC=N1.CC1=CC=C2C=CC=NC2=C1.CC1=CC=CC2=CC=CC=C12.NC1=C2N=CC=NC2=NC=N1 Chemical compound C1=CC=C(NC2=CC=CC=C2)C=C1.C1=CC=C2SC3=CC=CC=C3NC2=C1.C1CCC(NC2CCCCC2)CC1.CC1=C2N=CC=CC2=CC=C1.CC1=C2NC=N(C)C2=NC=N1.CC1=CC=C2C=CC=NC2=C1.CC1=CC=CC2=CC=CC=C12.NC1=C2N=CC=NC2=NC=N1 HVZNGNYAFRQGON-UHFFFAOYSA-N 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N C=CC1=CC=CC=C1 Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- WJOIEGFUOHFXQT-UHFFFAOYSA-N CC(=O)C(F)(F)F.CC(=O)CC(CC1=CC=CC=C1)C(=O)O.CC1(C(F)(F)F)O[Zn](C)(C)(C)O1.CNC1(C)O[Zn](C)(C)(C)O1.C[Zn](C)C Chemical compound CC(=O)C(F)(F)F.CC(=O)CC(CC1=CC=CC=C1)C(=O)O.CC1(C(F)(F)F)O[Zn](C)(C)(C)O1.CNC1(C)O[Zn](C)(C)(C)O1.C[Zn](C)C WJOIEGFUOHFXQT-UHFFFAOYSA-N 0.000 description 1
- UJJXRAAYAYCKDI-UHFFFAOYSA-N CC(=O)CCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C Chemical compound CC(=O)CCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C UJJXRAAYAYCKDI-UHFFFAOYSA-N 0.000 description 1
- QTLTWXOFXLSDOC-UHFFFAOYSA-N CC(C)(C)OC(=O)CC(=O)OC(C)(C)C.CC(C)(C)[O-]C(=O)C(CCCCCCO[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)C(C)(C)C.CC(C)(C)[Si](OCCCCCCBr)(C1=CC=CC=C1)C1=CC=CC=C1.CONCC(CCCCCC(=O)C(F)(F)F)C(=O)NC1=CC=CC=C1.NC1=CC=CC=C1.O=[C-]O.O=[C-]O.O=[C-]O.[H]C(=O)CCCCCC(C(=O)[O-]C(C)(C)C)C(C)(C)C.[H]C(O)(CCCCCC(C(=O)[O-]C(C)(C)C)C(C)(C)C)C(F)(F)F.[H]C(O)(CCCCCC(CNOC)C(=O)NC1=CC=CC=C1)C(F)(F)F Chemical compound CC(C)(C)OC(=O)CC(=O)OC(C)(C)C.CC(C)(C)[O-]C(=O)C(CCCCCCO[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)C(C)(C)C.CC(C)(C)[Si](OCCCCCCBr)(C1=CC=CC=C1)C1=CC=CC=C1.CONCC(CCCCCC(=O)C(F)(F)F)C(=O)NC1=CC=CC=C1.NC1=CC=CC=C1.O=[C-]O.O=[C-]O.O=[C-]O.[H]C(=O)CCCCCC(C(=O)[O-]C(C)(C)C)C(C)(C)C.[H]C(O)(CCCCCC(C(=O)[O-]C(C)(C)C)C(C)(C)C)C(F)(F)F.[H]C(O)(CCCCCC(CNOC)C(=O)NC1=CC=CC=C1)C(F)(F)F QTLTWXOFXLSDOC-UHFFFAOYSA-N 0.000 description 1
- HLSLRFBLVZUVIE-LBPRGKRZSA-N CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)O Chemical compound CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)O HLSLRFBLVZUVIE-LBPRGKRZSA-N 0.000 description 1
- JWMAGPRSYRSMMX-UHFFFAOYSA-N CC(C)(C)OC(=O)NCCCCCC(=O)NC1=CC=CC=C1 Chemical compound CC(C)(C)OC(=O)NCCCCCC(=O)NC1=CC=CC=C1 JWMAGPRSYRSMMX-UHFFFAOYSA-N 0.000 description 1
- GESVXPBSHSMVBH-UHFFFAOYSA-N CC1=C2N=CC=CC2=CC=C1.CC1=C2N=CC=NC2=NC=N1.CC1=C2NC=N(C)C2=NC=N1.CC1=CC=C2C=CC=NC2=C1.CC1=CC=CC2=CC=CC=C12.CC1=CC=CC=C1.CC1=CC=CC=C1.CC1=CC=CC=C1SC1=CC=CC=C1C.CC1CCCCC1.CC1CCCCC1 Chemical compound CC1=C2N=CC=CC2=CC=C1.CC1=C2N=CC=NC2=NC=N1.CC1=C2NC=N(C)C2=NC=N1.CC1=CC=C2C=CC=NC2=C1.CC1=CC=CC2=CC=CC=C12.CC1=CC=CC=C1.CC1=CC=CC=C1.CC1=CC=CC=C1SC1=CC=CC=C1C.CC1CCCCC1.CC1CCCCC1 GESVXPBSHSMVBH-UHFFFAOYSA-N 0.000 description 1
- AKGLPKRCCPWJDP-UHFFFAOYSA-N CC1=CC2=CC=CC=C2C=C1.CC1=CC2=CC=CC=C2C=C1.CC1=CC2=CC=CN=C2C=C1.CC1=CC2=CC=CN=C2C=C1.CC1=CC=CC2=CC=CC=C12.CC1=CC=CC2=CN=CC=C12.CC1=CC=CC2=NC=CC=C12.CC1=CC=NC2=CC=CC=C12.CC1=CC=NC2=CC=CC=C12.CC1=CN=CC2=CC=CC=C12 Chemical compound CC1=CC2=CC=CC=C2C=C1.CC1=CC2=CC=CC=C2C=C1.CC1=CC2=CC=CN=C2C=C1.CC1=CC2=CC=CN=C2C=C1.CC1=CC=CC2=CC=CC=C12.CC1=CC=CC2=CN=CC=C12.CC1=CC=CC2=NC=CC=C12.CC1=CC=NC2=CC=CC=C12.CC1=CC=NC2=CC=CC=C12.CC1=CN=CC2=CC=CC=C12 AKGLPKRCCPWJDP-UHFFFAOYSA-N 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N CCCC(C)=O Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- WAYYTQKCDWLHMA-UHFFFAOYSA-N CCOC(=O)C(C(=O)OCC)C1=CC(Br)=CC=C1 Chemical compound CCOC(=O)C(C(=O)OCC)C1=CC(Br)=CC=C1 WAYYTQKCDWLHMA-UHFFFAOYSA-N 0.000 description 1
- KBTOZUHMPOHMLQ-UHFFFAOYSA-N CCOC(=O)CCCCCC(C(=O)O)C(=O)O Chemical compound CCOC(=O)CCCCCC(C(=O)O)C(=O)O KBTOZUHMPOHMLQ-UHFFFAOYSA-N 0.000 description 1
- KZPSCVNISXICTB-NQPRBDNZSA-N CN(C(=O)CC/C=C/C=C/C(=O)O)C1=CC=CC=C1 Chemical compound CN(C(=O)CC/C=C/C=C/C(=O)O)C1=CC=CC=C1 KZPSCVNISXICTB-NQPRBDNZSA-N 0.000 description 1
- MCUFFAPLDKFWCI-UHFFFAOYSA-N CN(C(=O)CCCCCCC(=O)NO)C1=CC=CC=C1 Chemical compound CN(C(=O)CCCCCCC(=O)NO)C1=CC=CC=C1 MCUFFAPLDKFWCI-UHFFFAOYSA-N 0.000 description 1
- JRZDTHAEGDGWMH-UHFFFAOYSA-N CN(C)C1=CC=CC2=C1C=CC(S(=O)(=O)NCCCCCC(=O)NO)=C2 Chemical compound CN(C)C1=CC=CC2=C1C=CC(S(=O)(=O)NCCCCCC(=O)NO)=C2 JRZDTHAEGDGWMH-UHFFFAOYSA-N 0.000 description 1
- ZAGZJMXJVXVXOY-WJPDYIDTSA-N COC(=O)/C=C/C=C/CC(C(=O)O)C(=O)O Chemical compound COC(=O)/C=C/C=C/CC(C(=O)O)C(=O)O ZAGZJMXJVXVXOY-WJPDYIDTSA-N 0.000 description 1
- WMQPEIUFHXFSDC-CDKJVOIVSA-N COC(=O)/C=C/C=C/CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C Chemical compound COC(=O)/C=C/C=C/CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C WMQPEIUFHXFSDC-CDKJVOIVSA-N 0.000 description 1
- JKWDDMJQGWOMEJ-GUNLQBCDSA-N COC(=O)/C=C/C=C/CCC(=O)N(C)C1=CC=CC=C1 Chemical compound COC(=O)/C=C/C=C/CCC(=O)N(C)C1=CC=CC=C1 JKWDDMJQGWOMEJ-GUNLQBCDSA-N 0.000 description 1
- CQUFERZLCMQRAI-NQPRBDNZSA-N COC(=O)/C=C/C=C/CCC(=O)NC1=CC=CC=C1 Chemical compound COC(=O)/C=C/C=C/CCC(=O)NC1=CC=CC=C1 CQUFERZLCMQRAI-NQPRBDNZSA-N 0.000 description 1
- ZWZWOSJNTXGLHG-SBIWHPGTSA-N COC(=O)/C=C/C=C/CCC(=O)OC(C)(C)C Chemical compound COC(=O)/C=C/C=C/CCC(=O)OC(C)(C)C ZWZWOSJNTXGLHG-SBIWHPGTSA-N 0.000 description 1
- LPSSYWMXTQDQGV-UHFFFAOYSA-N COC(=O)CCCCCCC(=O)C(F)(F)F Chemical compound COC(=O)CCCCCCC(=O)C(F)(F)F LPSSYWMXTQDQGV-UHFFFAOYSA-N 0.000 description 1
- YOMMZDLCHHFTSF-IBGZPJMESA-N COC(=O)CCCCC[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound COC(=O)CCCCC[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 YOMMZDLCHHFTSF-IBGZPJMESA-N 0.000 description 1
- INBABWAMCLVGNU-IBGZPJMESA-N COC(=O)CCCCC[C@H](NC(=O)C1CCCCC1)C(=O)NC1=CC=CC=C1 Chemical compound COC(=O)CCCCC[C@H](NC(=O)C1CCCCC1)C(=O)NC1=CC=CC=C1 INBABWAMCLVGNU-IBGZPJMESA-N 0.000 description 1
- RKTDOZTUWTWCDD-INIZCTEOSA-N COC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1=CC=CC=C1 Chemical compound COC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1=CC=CC=C1 RKTDOZTUWTWCDD-INIZCTEOSA-N 0.000 description 1
- SYHFXJDLWMBSKW-UHFFFAOYSA-N COP(C)(=O)NCCCCBr.[H]C(C)(O)CCCCCBr Chemical compound COP(C)(=O)NCCCCBr.[H]C(C)(O)CCCCCBr SYHFXJDLWMBSKW-UHFFFAOYSA-N 0.000 description 1
- RHOYQYXRAGCBLG-UHFFFAOYSA-N CS(=O)(=O)NCCCCCC(=O)O Chemical compound CS(=O)(=O)NCCCCCC(=O)O RHOYQYXRAGCBLG-UHFFFAOYSA-N 0.000 description 1
- IPGHHSXWWSAFFZ-UHFFFAOYSA-N NS(=O)(=O)CCCCCC(=O)NC1=CC=CC=C1 Chemical compound NS(=O)(=O)CCCCCC(=O)NC1=CC=CC=C1 IPGHHSXWWSAFFZ-UHFFFAOYSA-N 0.000 description 1
- MZVIGMRALAUAEN-KEUGWDEGSA-N NS(=O)(=O)CSC1=CC(C(=O)NC2=CC=CC=C2)=CC=C1.O=C(NC1=CC=CC=C1)C1=CC=CC(/C=C/C(=O)C(F)(F)F)=C1.O=C(NC1=CC=CC=C1)C1=CC=CC(Br)=C1.O=C(NC1=CN=CC=C1)C1=CC=CC(/C=C/C(=O)C(F)(F)F)=C1.[H]C(=O)/C=C/C1=CC(C(=O)NC2=CC=CC=C2)=CC=C1.[H]C(=O)/C=C/C1=CC(C(=O)NC2=CN=CC=C2)=CC=C1 Chemical compound NS(=O)(=O)CSC1=CC(C(=O)NC2=CC=CC=C2)=CC=C1.O=C(NC1=CC=CC=C1)C1=CC=CC(/C=C/C(=O)C(F)(F)F)=C1.O=C(NC1=CC=CC=C1)C1=CC=CC(Br)=C1.O=C(NC1=CN=CC=C1)C1=CC=CC(/C=C/C(=O)C(F)(F)F)=C1.[H]C(=O)/C=C/C1=CC(C(=O)NC2=CC=CC=C2)=CC=C1.[H]C(=O)/C=C/C1=CC(C(=O)NC2=CN=CC=C2)=CC=C1 MZVIGMRALAUAEN-KEUGWDEGSA-N 0.000 description 1
- IXFMCCZPFNWHJY-UHFFFAOYSA-N NS(=O)(=O)CSC1=CC(C(=O)NC2=CN=CC=C2)=CC=C1.O=C(NC1=CN=CC=C1)C1=CC=CC(Br)=C1 Chemical compound NS(=O)(=O)CSC1=CC(C(=O)NC2=CN=CC=C2)=CC=C1.O=C(NC1=CN=CC=C1)C1=CC=CC(Br)=C1 IXFMCCZPFNWHJY-UHFFFAOYSA-N 0.000 description 1
- JWEJHZRCHWXZMQ-MDZDMXLPSA-N O=C(/C=C/C1=CC(C(=O)NC2=CC=CC=C2)=CC=C1)NO Chemical compound O=C(/C=C/C1=CC(C(=O)NC2=CC=CC=C2)=CC=C1)NO JWEJHZRCHWXZMQ-MDZDMXLPSA-N 0.000 description 1
- BNYSWHSUCZNXLF-CCEZHUSRSA-N O=C(/C=C/C1=CC(C(C(=O)NC2=CC=CC3=C2N=CC=C3)C(=O)NC2=C3/N=C\C=C/C3=CC=C2)=CC=C1)NO Chemical compound O=C(/C=C/C1=CC(C(C(=O)NC2=CC=CC3=C2N=CC=C3)C(=O)NC2=C3/N=C\C=C/C3=CC=C2)=CC=C1)NO BNYSWHSUCZNXLF-CCEZHUSRSA-N 0.000 description 1
- XSXKKTCULYLPKR-MDZDMXLPSA-N O=C(/C=C/C1=CC(CC(=O)NC2=CC=CC=C2)=CC=C1)NO Chemical compound O=C(/C=C/C1=CC(CC(=O)NC2=CC=CC=C2)=CC=C1)NO XSXKKTCULYLPKR-MDZDMXLPSA-N 0.000 description 1
- SKMVPDQELBRKSN-VGILEQFFSA-N O=C(/C=C/C1=CC=CC(C(=O)NC2=CC=CC=C2)=C1)NO.O=C(/C=C/C1=CC=CC(C(=O)NC2=CC=CN=C2)=C1)NO Chemical compound O=C(/C=C/C1=CC=CC(C(=O)NC2=CC=CC=C2)=C1)NO.O=C(/C=C/C1=CC=CC(C(=O)NC2=CC=CN=C2)=C1)NO SKMVPDQELBRKSN-VGILEQFFSA-N 0.000 description 1
- RMLTYADWPTYXJV-UHFFFAOYSA-N O=C(CCCCCC(C(=O)NC1=CC=C2N=CC=CC2=C1)C(=O)NC1=CC2=C(C=C1)/N=C\C=C/2)NO Chemical compound O=C(CCCCCC(C(=O)NC1=CC=C2N=CC=CC2=C1)C(=O)NC1=CC2=C(C=C1)/N=C\C=C/2)NO RMLTYADWPTYXJV-UHFFFAOYSA-N 0.000 description 1
- KVSZYVALGYAPOO-UHFFFAOYSA-N O=C(CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)(C(=O)NC1=CC=CC2=C1N=CC=C2)C1=CC=CC=C1)NO Chemical compound O=C(CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)(C(=O)NC1=CC=CC2=C1N=CC=C2)C1=CC=CC=C1)NO KVSZYVALGYAPOO-UHFFFAOYSA-N 0.000 description 1
- DKABPJRYPLLBPQ-UHFFFAOYSA-N O=C(CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=C2N=CC=CC2=CC=C1)NO.[H]C(CCCCCC(=O)NO)(NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC2=C1N=CC=C2 Chemical compound O=C(CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=C2N=CC=CC2=CC=C1)NO.[H]C(CCCCCC(=O)NO)(NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC2=C1N=CC=C2 DKABPJRYPLLBPQ-UHFFFAOYSA-N 0.000 description 1
- UBIIPQSXXYMEMK-UHFFFAOYSA-N O=C(CCCCCC(C(=O)NC1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCCC(C(=O)NC1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO UBIIPQSXXYMEMK-UHFFFAOYSA-N 0.000 description 1
- KLCLONRITQTFOB-UHFFFAOYSA-N O=C(CCCCCC(CCCCCC(=O)NO)(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=C2N=CC=CC2=CC=C1)NO Chemical compound O=C(CCCCCC(CCCCCC(=O)NO)(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=C2N=CC=CC2=CC=C1)NO KLCLONRITQTFOB-UHFFFAOYSA-N 0.000 description 1
- ALFREMIRVGCWKP-UHFFFAOYSA-N O=C(CCCCCC(NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCCC(NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO ALFREMIRVGCWKP-UHFFFAOYSA-N 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N O=C(CCCCCCC(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCCCC(=O)NC1=CC=CC=C1)NO WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- RFEFMPTWMIKCRC-UHFFFAOYSA-N O=C(CCCCCCC(=O)NC1=NC=CS1)NC1=CC=CC=C1 Chemical compound O=C(CCCCCCC(=O)NC1=NC=CS1)NC1=CC=CC=C1 RFEFMPTWMIKCRC-UHFFFAOYSA-N 0.000 description 1
- RZCHBVYEFGOGPI-UHFFFAOYSA-N O=C(CCCCCCC(=O)NC1=NNC=C1)NC1=CC=CC=C1 Chemical compound O=C(CCCCCCC(=O)NC1=NNC=C1)NC1=CC=CC=C1 RZCHBVYEFGOGPI-UHFFFAOYSA-N 0.000 description 1
- OWDYDLVCUCFVDV-UHFFFAOYSA-N O=C(CCCCCCC(=O)NCC1=CC=CC=C1)NO Chemical compound O=C(CCCCCCC(=O)NCC1=CC=CC=C1)NO OWDYDLVCUCFVDV-UHFFFAOYSA-N 0.000 description 1
- JFZDNUDRFOOGRK-UHFFFAOYSA-N O=C(CCCCCCN1C=CN=C1)NC1=CC=CC=C1 Chemical compound O=C(CCCCCCN1C=CN=C1)NC1=CC=CC=C1 JFZDNUDRFOOGRK-UHFFFAOYSA-N 0.000 description 1
- JBCIUMAIKKEMCI-UHFFFAOYSA-N O=C(CCCCCN1C=CN=C1)NC1=CC=CC=C1 Chemical compound O=C(CCCCCN1C=CN=C1)NC1=CC=CC=C1 JBCIUMAIKKEMCI-UHFFFAOYSA-N 0.000 description 1
- SSUQSWVDYYVPHT-HXUWFJFHSA-N O=C(CCCCC[C@@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO Chemical compound O=C(CCCCC[C@@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO SSUQSWVDYYVPHT-HXUWFJFHSA-N 0.000 description 1
- KGSHCBPYJKPYNF-SFHVURJKSA-N O=C(CCCCC[C@@H](NC(=O)C1=CC=CC=C1)NC(=O)C1CCCCC1)NO Chemical compound O=C(CCCCC[C@@H](NC(=O)C1=CC=CC=C1)NC(=O)C1CCCCC1)NO KGSHCBPYJKPYNF-SFHVURJKSA-N 0.000 description 1
- AJLUGKOMGXJADD-QGZVFWFLSA-N O=C(CCCCC[C@@H](NC(=O)C1=CC=CN=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCC[C@@H](NC(=O)C1=CC=CN=C1)C(=O)NC1=CC=CC=C1)NO AJLUGKOMGXJADD-QGZVFWFLSA-N 0.000 description 1
- QPYMPYVHDZQBPO-NRFANRHFSA-N O=C(CCCCC[C@H](NC(=O)C1=CC2=C(C=CC=C2)N=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCC[C@H](NC(=O)C1=CC2=C(C=CC=C2)N=C1)C(=O)NC1=CC=CC=C1)NO QPYMPYVHDZQBPO-NRFANRHFSA-N 0.000 description 1
- SSUQSWVDYYVPHT-FQEVSTJZSA-N O=C(CCCCC[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO Chemical compound O=C(CCCCC[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO SSUQSWVDYYVPHT-FQEVSTJZSA-N 0.000 description 1
- AJLUGKOMGXJADD-KRWDZBQOSA-N O=C(CCCCC[C@H](NC(=O)C1=CC=CN=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCC[C@H](NC(=O)C1=CC=CN=C1)C(=O)NC1=CC=CC=C1)NO AJLUGKOMGXJADD-KRWDZBQOSA-N 0.000 description 1
- LMVPKTRCGGXYDS-HNNXBMFYSA-N O=C(CCCCC[C@H](NC(=O)C1=CC=CS1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCC[C@H](NC(=O)C1=CC=CS1)C(=O)NC1=CC=CC=C1)NO LMVPKTRCGGXYDS-HNNXBMFYSA-N 0.000 description 1
- SOHCAGOJUINGTO-SFHVURJKSA-N O=C(CCCCC[C@H](NC(=O)C1CCCCC1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCC[C@H](NC(=O)C1CCCCC1)C(=O)NC1=CC=CC=C1)NO SOHCAGOJUINGTO-SFHVURJKSA-N 0.000 description 1
- ALFREMIRVGCWKP-IBGZPJMESA-N O=C(CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO ALFREMIRVGCWKP-IBGZPJMESA-N 0.000 description 1
- HRSYWLWCWPPQTC-INIZCTEOSA-N O=C(C[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO Chemical compound O=C(C[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO HRSYWLWCWPPQTC-INIZCTEOSA-N 0.000 description 1
- GITUQMXYVXMMQE-AWEZNQCLSA-N O=C(C[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(C[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO GITUQMXYVXMMQE-AWEZNQCLSA-N 0.000 description 1
- YUTZZCNZNKBNQQ-ZDUSSCGKSA-N O=C(C[C@H](NC(=O)C1=CC=CN=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(C[C@H](NC(=O)C1=CC=CN=C1)C(=O)NC1=CC=CC=C1)NO YUTZZCNZNKBNQQ-ZDUSSCGKSA-N 0.000 description 1
- RJSIDTDCYVJVIE-KRWDZBQOSA-N O=C(C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO Chemical compound O=C(C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=C2N=CC=CC2=CC=C1)NO RJSIDTDCYVJVIE-KRWDZBQOSA-N 0.000 description 1
- UOQJIRZUUPHGMQ-HNNXBMFYSA-N O=C(C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO Chemical compound O=C(C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1)NO UOQJIRZUUPHGMQ-HNNXBMFYSA-N 0.000 description 1
- MJNYWUOIQBNKPH-UHFFFAOYSA-N O=C(NC1=CC=CC=C1)C(C(=O)NC1=CC=CC=C1)C1=CC(Br)=CC=C1 Chemical compound O=C(NC1=CC=CC=C1)C(C(=O)NC1=CC=CC=C1)C1=CC(Br)=CC=C1 MJNYWUOIQBNKPH-UHFFFAOYSA-N 0.000 description 1
- MKCVMTGUUGBSLJ-UHFFFAOYSA-N O=C(NC1=CC=CC=C1)C(CCCCCC(=O)C(F)(F)F)C(=O)NC1=CC=CC=C1 Chemical compound O=C(NC1=CC=CC=C1)C(CCCCCC(=O)C(F)(F)F)C(=O)NC1=CC=CC=C1 MKCVMTGUUGBSLJ-UHFFFAOYSA-N 0.000 description 1
- AJXNAJQRTYNZCN-CCEZHUSRSA-N O=C(O)/C=C/C1=CC=CC(C(C(=O)NC2=CC=CC=C2)C(=O)NC2=CC=CC=C2)=C1 Chemical compound O=C(O)/C=C/C1=CC=CC(C(C(=O)NC2=CC=CC=C2)C(=O)NC2=CC=CC=C2)=C1 AJXNAJQRTYNZCN-CCEZHUSRSA-N 0.000 description 1
- XZJHCUNIKYBKEN-UHFFFAOYSA-N O=C(O)CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=CC=CC2=C1N=CC=C2 Chemical compound O=C(O)CCCCCC(C(=O)NC1=CC=CC2=C1N=CC=C2)C(=O)NC1=CC=CC2=C1N=CC=C2 XZJHCUNIKYBKEN-UHFFFAOYSA-N 0.000 description 1
- MBPQVYCQHGBIGO-UHFFFAOYSA-N O=C(O)CCCCCC(NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC2=C1N=CC=C2 Chemical compound O=C(O)CCCCCC(NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC2=C1N=CC=C2 MBPQVYCQHGBIGO-UHFFFAOYSA-N 0.000 description 1
- GDKZARKDCVGQQL-UHFFFAOYSA-N O=C(O)CCCCCCC(=O)NCC1=CC=CC=C1 Chemical compound O=C(O)CCCCCCC(=O)NCC1=CC=CC=C1 GDKZARKDCVGQQL-UHFFFAOYSA-N 0.000 description 1
- XNZTZYVCXCXUBW-GOSISDBHSA-N O=C(O)CCCCC[C@@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound O=C(O)CCCCC[C@@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 XNZTZYVCXCXUBW-GOSISDBHSA-N 0.000 description 1
- WNJPHIGQCDNDRB-QGZVFWFLSA-N O=C(O)CCCCC[C@@H](NC(=O)C1=CC=CN=C1)C(=O)NC1=CC=CC=C1 Chemical compound O=C(O)CCCCC[C@@H](NC(=O)C1=CC=CN=C1)C(=O)NC1=CC=CC=C1 WNJPHIGQCDNDRB-QGZVFWFLSA-N 0.000 description 1
- XNZTZYVCXCXUBW-SFHVURJKSA-N O=C(O)CCCCC[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound O=C(O)CCCCC[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 XNZTZYVCXCXUBW-SFHVURJKSA-N 0.000 description 1
- NTUILUDNUYAJLW-SFHVURJKSA-N O=C(O)CCCCC[C@H](NC(=O)C1CCCCC1)C(=O)NC1=CC=CC=C1 Chemical compound O=C(O)CCCCC[C@H](NC(=O)C1CCCCC1)C(=O)NC1=CC=CC=C1 NTUILUDNUYAJLW-SFHVURJKSA-N 0.000 description 1
- MBPQVYCQHGBIGO-NRFANRHFSA-N O=C(O)CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC2=C1N=CC=C2 Chemical compound O=C(O)CCCCC[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC2=C1N=CC=C2 MBPQVYCQHGBIGO-NRFANRHFSA-N 0.000 description 1
- VOWQCYXJZWJEFU-AWEZNQCLSA-N O=C(O)C[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound O=C(O)C[C@H](NC(=O)C1=CC=CC=C1)C(=O)NC1=CC=CC=C1 VOWQCYXJZWJEFU-AWEZNQCLSA-N 0.000 description 1
- DDVUCYOIBAMPSY-HNNXBMFYSA-N O=C(O)C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1 Chemical compound O=C(O)C[C@H](NC(=O)OCC1=CC=CC=C1)C(=O)NC1=CC=CC=C1 DDVUCYOIBAMPSY-HNNXBMFYSA-N 0.000 description 1
- IZBHSYKCCSZEGD-UHFFFAOYSA-N O=CC1=CC2=CC=CC=C2C=C1.O=CC1=CC2=CC=CN=C2C=C1.O=CC1=CC=CC2=CC=CC=C12.O=CC1=CC=CC2=CN=CC=C12.O=CC1=CC=CC2=NC=CC=C12.O=CC1=CC=NC2=CC=CC=C12.O=CC1=CC=NC2=CC=CC=C12.O=CC1=CN=CC2=CC=CC=C21.O=[SH](=O)C1=CC2=CC=CC=C2C=C1.O=[SH](=O)C1=CC2=CC=CN=C2C=C1 Chemical compound O=CC1=CC2=CC=CC=C2C=C1.O=CC1=CC2=CC=CN=C2C=C1.O=CC1=CC=CC2=CC=CC=C12.O=CC1=CC=CC2=CN=CC=C12.O=CC1=CC=CC2=NC=CC=C12.O=CC1=CC=NC2=CC=CC=C12.O=CC1=CC=NC2=CC=CC=C12.O=CC1=CN=CC2=CC=CC=C21.O=[SH](=O)C1=CC2=CC=CC=C2C=C1.O=[SH](=O)C1=CC2=CC=CN=C2C=C1 IZBHSYKCCSZEGD-UHFFFAOYSA-N 0.000 description 1
- UDFMZNREPUSKKD-UHFFFAOYSA-N OC(C1=NC=CN1)(C1=NC=CN1)C1=NC(CCCCCC2=CN=C(C(O)(C3=NC=CN3)C3=NC=CN3)N2)=CN1 Chemical compound OC(C1=NC=CN1)(C1=NC=CN1)C1=NC(CCCCCC2=CN=C(C(O)(C3=NC=CN3)C3=NC=CN3)N2)=CN1 UDFMZNREPUSKKD-UHFFFAOYSA-N 0.000 description 1
- PFIDDDJZHVOSSC-RHUFWMAKSA-N [H][C@@](CCCCCC(=O)NO)(NC(=O)OCC1=CC=CC=C1)C(=O)NC.[H][C@@](CCCCCC(=O)NO)(NC(=O)[Y])C(=O)NC.[H][C@@](CCCCCC(=O)NO)(NS(=O)(=O)[Y])C(=O)NC Chemical compound [H][C@@](CCCCCC(=O)NO)(NC(=O)OCC1=CC=CC=C1)C(=O)NC.[H][C@@](CCCCCC(=O)NO)(NC(=O)[Y])C(=O)NC.[H][C@@](CCCCCC(=O)NO)(NS(=O)(=O)[Y])C(=O)NC PFIDDDJZHVOSSC-RHUFWMAKSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
-
- 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
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/42—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/44—Amides thereof
- C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4465—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms which normally govern proliferation and differentiation.
- a recent approach to cancer therapy has been to attempt induction of terminal differentiation of the neoplastic cells (1).
- differentiation has been reported by exposure of cells to a variety of stimuli, including: cyclic AMP and retinoic acid (2, 3), aclarubicin and other anthracylcines (4).
- neoplastic transfonnation does not necessarily destroy the potential of cancer cells to differentiate (1, 5, 6).
- tumor cells which do not respond to the normal regulators of proliferation and appear to be blocked in the expression of their differentiation program, and yet can be induced to differentiate and cease replicating.
- agents including some relatively simple polar compounds (5, 7-9), derivatives of vitamin D and retinoic acid (10-12), steroid hormones (13); growth factors (6, 14), proteases (15, 16), tumor promoters (17,18), and inhibitors of DNA or RNA synthesis (4, 19-24), can induce various transformed cell lines and primary human tumor explants to express more differentiated characteristics.
- HMBA hybrid polar/apolar compound N,N′-hexamethylene bisacetamide
- SAHA suberoylanilide hydroxamic acid
- HMBA-induced MEL cell terminal erythroid differentiation is a multistep process.
- HMBA Upon addition of HMBA to MEL cells (745A-DS19) in culture, there is a latent period of 10 to 12 hours before commitment to terminal differentiation is detected. Commitment is defined as the capacity of cells to express terminal differentiation despite removal of inducer (25).
- HMBA Upon continued exposure to HMBA there is progressive recruitment of cells to differentiate.
- the present inventors have reported that MEL cell lines made resistant to relatively low levels of vincristine become markedly more sensitive to the inducing action of HMBA and can be induced to differentiate with little or no latent period (26).
- HMBA is capable of inducing phenotypic changes consistent with differentiation in a broad variety of cells lines (5).
- the characteristics of the drug induced effect have been most extensively studied in the murine erythroleukemia cell system (5, 25, 27, 28).
- MEL cell induction of differentiation is both time and concentration dependent.
- the minimum concentration required to demonstrate an effect in vitro in most strains is 2 to 3 mM; the minimum duration of continuous exposure generally required to induce differentiation in a substantial portion (>20%) of the population without continuing drug exposure is about 36 hours.
- HMBA protein kinase C is involved in the pathway of inducer-mediated differentiation.
- the in vitro studies provided a basis for evaluating the potential of HMBA as a cytodifferentiation agent in the treatment of human cancers (30).
- phase I clinical trials with HMBA have been completed (31-36). Clinical trials have shown that this compound can induce a therapeutic response in patients with cancer (35, 36).
- phase I clinical trials also have demonstrated that the potential efficacy of HMBA is limited, in part, by dose-related toxicity which prevents achieving optimal blood levels and by the need for intravenous administration of large quantities of the agent, over prolonged periods.
- some of the present inventors have turned to synthesizing compounds that are more potent and possibly less toxic than HMBA (37).
- TSA trichostatin A
- SAHA suberoylanilide hydroxamic acid
- phenylbutyrate Several experimental antitumor compounds, such as trichostatin A (TSA), trapoxin, suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have been shown to act, at least in part, by inhibiting histone deacetylases (38, 39, 42).
- diallyl sulfide and related molecules (43), oxamflatin, (44), MS-27-275, a synthetic benzamide derivative, (45) butyrate derivatives (46), FR901228 (47), depudecin (48), and m-carboxycinnamic acid bishydroxamide (39) have been shown to inhibit histone deacetylases.
- these compounds can inhibit the growth of fibroblast cells by causing cell cycle arrest in the G1 and G2 phases (49-52), and can lead to the terminal differentiation and loss of transforming potential of a variety of transformed cell lines (49-51).
- phenylbutyrate is effective in the treatment of acute promyelocytic leukemia in conjunction with retinoic acid (53).
- SAHA is effective in-preventing the formation of mammary tumors in rats, and lung tumors in mice (54, 55).
- U.S. Pat. No.5,369,108 (41) issued to some of the present inventors discloses compounds useful for selectively inducing terminal differentiation of neoplastic cells, which compounds have two polar end groups separated by a flexible chain of methylene groups, wherein one or both of the polar end groups is a large hydrophobic group. Such compounds are stated to be more active than HMBA and HMBA related compounds.
- U.S. Pat. No. 5,369,108 does not disclose that an additional large hydrophobic group at the same end of the molecule as the first hydrophobic group would further increase differentiation activity about 100 fold in an enzymatic assay and about 50 fold in a cell differentiation assay.
- This new class of compounds of the present invention may be useful for selectively inducing terminal differentiation of neoplastic cells and therefore aid in treatment of tumors in patients.
- the subject invention provides a compound having the formula:
- R 1 and R 2 are the same or different and are each a hydrophobic moiety; wherein R 3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from 3 to 10, or a pharmaceutically acceptable salt thereof.
- the subject invention also provides A compound having the formula:
- each of R 1 and R 2 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purino-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group; wherein R 3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; wherein R 4 is hydrogen, a halogen, a phenyl, or a cycloalkyl moiety; wherein A may be the same or different and represents an amide moiety, —O—, —S—, —NR 5 —, or —CH 2 —, where R 5 is a substituted or unsubstituted C 1 -C 5 alkyl;
- the subject invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of the aforementioned compound.
- FIG. 1 The effect of Compound 1 according to the subject invention on MEL cell differentiation.
- FIG. 2 The effect of Compound 1 according to the subject invention on Histone Deacetylase 1 activity.
- FIG. 3 The effect of Compound 2 according to the subject invention on MEL cell differentiation.
- FIG. 4 The effect of Compound 3 according to the subject invention on MEL cell differentiation.
- FIG. 5 The effect of Compound 3 according to the subject invention on Histone Deacetylase 1 activity.
- FIG. 6 The effect of Compound 4 according to the subject invention on MEL cell differentiation.
- FIG. 7 The effect of Compound 4 according to the subject invention on Histone Deacetylase 1 activity.
- FIG. 8 A photoaffinity label (3H-498) binds directly to HDAC 1.
- FIG. 9 SAHA causes accumulation of acetylated histones H3 and H4 in the CWR22 tumor xenograft in mice.
- FIG. 10 SAHA causes accumulation of acetylation histones H3 and H4 in peripheral blood nonnuclear cells in patients.
- SAHA was administered by IV infusion daily ⁇ 3. Samples were isolated before (Pre), following infusion (Post) and 2 hours after infusion.
- FIGS. 11 a - 11 f Show the effect of selected compounds on affinity purified human epitope-tagged (Flag) HDAC1.
- the subject invention provides a compound having the formula:
- R 1 and R 2 are the same or different and are each a hydrophobic moiety; wherein R 3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from 3 to 10; or a pharmaceutically acceptable salt of the compound.
- each of R 1 and R 2 is directly attached or through a linker, and is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- the linker may be an amide moiety, —O—, —NH—, or —CH 2 —.
- n may be 3-10, preferably 3-8, more preferably 3-7, yet more preferably 4, 5 or 6, and most preferably 5.
- the compound has the formula:
- each of R 1 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- R 2 may be -amide-R 5 , wherein R 5 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naptha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- each of R 1 and R 2 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group; wherein R 3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; wherein R 4 is hydrogen, a halogen, a phenyl, or a cycloalkyl moiety; wherein A may be the same or different and represents an amide moiety, —O—, —S—, —NR 5 —, or —CH 2 —, where R 5 is a substituted or unsubstituted C 1 -C 5 alkyl; and
- the compound has the formula:
- the compound has the formula:
- each of R 1 and R 2 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, t-butyl, aryloxy, arylalkyloxy, or pyridine group; and wherein n is an integer from 3 to 8.
- the aryl or cycloalkyl group may be substituted with a methyl, cyano, nitro, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodo, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 3,5-difluoro, 2,6-difluoro, 1,2,3-trifluoro, 2,3,6-trifluoro, 2,4,6-trifluoro, 3,4,5-trifluoro, 2,3,5,6-tetrafluoro, 2,3,4,5,6-pentafluoro, azido, hexyl, t-butyl, phenyl, carboxyl, hydroxyl, methoxy, phenyloxy, benzyloxy, phenylaminooxy, phenylaminocarbonyl, methyoxycarbonyl, methylamino
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- the compound has the formula:
- This invention is also intended to encompass enantiomers and salts of the compounds listed above.
- the compound has the formula:
- R 1 and R 2 are the same or different and are each a hydrophobic moiety:
- R 5 ′ is —C(O)—NHOH (hydroxamic acid), —C(O)—CF 3 (trifluoroacetyl), —NH—P(O))H—CH 3 , —SO 2 NH 2 (sulfonamide), —SH (thiol), —C(O)—R 6 , wherein R 6 is hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from 3 to 10, or a pharmaceutically acceptable salt thereof.
- each of R 1 and R 2 may be directly attached or through a linker, and is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- the linker may be an amide moiety, —O—, —S—, —NH—, or —CH 2 —.
- the compound has the formula:
- each of R 7 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- R 2 may be -sulfonamide-R 6 , or -amide-R 8 wherein R 8 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- the R 2 may be —NH—C—(O)—Y, —NH—SO 2 —Y, wherein Y is selected from the group consisting of:
- the R 7 may be selected from the group consisting of the following and designated R 7 :
- the compound has the formula:
- R 1 and R 2 are the same or different and are each a hydrophobic moiety:
- L may also be a linker consisting of —(CH 2 ) n —, —C(O)—, —S—, —O—, —(CH ⁇ CH) m —, -phenyl-, or -cycloalkyl-, or any combination thereof, wherein n is an integer from 3 to 10, and m is an integer from 0 to 10,
- n may be from 4-7, and m is from 0-7.
- n is 5 or 6, most preferably n is 6.
- m is from 1-6, more preferably m is 2-5, most preferably m is 3 or 4,
- each of R 1 and R 2 may be directly attached or through a linker, and is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridine group.
- the linker may be an amide moiety, —O—, —S—, —NH—, or —CH 2 —.
- This invention is also intended to encompass enantiomers, salts and pro-drugs of the compounds disclosed herein.
- L is a linker selected from the group consisting of —(CH 2 )—, —(CH ⁇ CH)—, -phenyl-, -cycloalkyl-, or any combination thereof, and wherein each of R 1 and R 2 are independently substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- the linker L comprises the moiety
- the compound has the formula:
- Any of the disclosed compounds can be formed into a pharmaceutical composition together with a pharmaceutically acceptable carrier.
- Any of the compounds can also be formed into a pharmaceutically acceptable salt of the compound using well known pharmacological techniques.
- a prodrug of any of the compounds can also be made using well known pharmacological techniques.
- Any of the compounds can be used in a method of inducing differentiation of tumor cells in a tumor comprising contacting the cells with an effective amount of the compound so as to thereby differentiate the tumor cells.
- Any of the compounds can also be used in a method of inhibiting the activity of histone deacetylase comprising contacting the histone deacetylase with an effective amount of the compound so as to thereby inhibit the activity of histone deacetylase.
- homologs are molecules having substantial structural similarities to the above-described compounds and analogs are molecules having substantial biological similarities regardless of structural similarities.
- the subject invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of any one of the aforementioned compounds and a pharmaceutically acceptable carrier.
- the subject invention provides a method of selectively inducing growth arrest, terminal differentiation and/or apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of any one of the aforementioned compounds.
- the contacting should be performed continuously for a prolonged period of time, i.e. for at least 48 hours, preferably for about 4-5 days or longer.
- the method may be practiced in vivo or in vitro. If the method is practiced in vitro, contacting may be effected by incubating the cells with the compound.
- the concentration of the compound in contact with the cells should be from about 1 nM to about 25 mM, preferably from about 20 nM to about 25 mM, more preferably from about 40 nM to 100 ⁇ M, yet more preferably from about 40 nM to about 200 nM. The concentration depends upon the individual compound and the state of the neoplastic cells.
- the method may also comprise initially treating the cells with an antitumor agent so as to render them resistant to an antitumor agent and subsequently contacting the resulting resistant cells under suitable conditions with an effective amount of any of the compounds above, effective to selectively induce terminal differentiation of such cells.
- the present invention also provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient an effective amount of any of the compounds above, effective to selectively induce growth arrest, terminal differentiation and/or apoptosis of such neoplastic cells and thereby inhibit their proliferation.
- the method of the present invention is intended for the treatment of human patients with tumors. However, it is also likely that the method would be effective in the treatment of tumors in other mammals.
- the term tumor is intended to include any cancer caused by the proliferation of neoplastic cells, such as prostate cancer, lung cancer, acute leukemia, multiple myeloma, bladder carcinoma, renal carcinoma, breast carcinoma, colorectal carcinoma, neuroblastoma or melanoma.
- Routes of administration for the compound of the present invention include any conventional and physiologically acceptable route, such as, for example, oral, pulmonary, parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), inhalation (via .a fine powder formulation or a fine mist), transdermal, nasal, vaginal, rectal, or sublingual routes of administration and can be formulated in dosage forms appropriate for each route of administration.
- routes of administration for the compound of the present invention include any conventional and physiologically acceptable route, such as, for example, oral, pulmonary, parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), inhalation (via .a fine powder formulation or a fine mist), transdermal, nasal, vaginal, rectal, or sublingual routes of administration and can be formulated in dosage forms appropriate for each route of administration.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier, such as sterile pyrogen-free water, and a therapeutically acceptable amount of any of the compounds above.
- the effective amount is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount which causes toxicity in a patient.
- the present invention provides the pharmaceutical composition above in combination with an antitumor agent, a hormone, a steroid, or a retinoid.
- the antitumor agent may be one of numerous chemotherapy agents such as an alkylating agent, an antimetabolite, a hormonal agent, an antibiotic, colchicine, a vinca alkaloid, L-asparaginase, procarbazine, hydroxyurea, mitotane, nitrosoureas or an imidazole carboxamide. Suitable agents are those agents which promote depolarization of tubulin.
- the antitumor agent is colchicine or a vinca alkaloid; especially preferred are vinblastine and vincristine.
- an amount is administered to render the cells are resistant to vincristine at a concentration of about 5 mg/ml.
- the administration of the agent is performed essentially as described above for the administration of any of the compounds.
- the administration of the agent is for a period of at least 3-5 days.
- the administration of any of the compounds above is performed as described previously.
- the pharmaceutical composition may be administered daily in 2-6 hour infusions for a period of 3-21 days, for example, daily in a 4 hour infusion for a period of 5 days.
- Examples 1-5 show the synthesis of substituted L- ⁇ -aminosuberic hydroxamic acids according to the subject invention, and Examples 6 and 7 show the effects of compounds 1-5 on MEL cell differentiation and Histone Deacetylase activity.
- N-Cbz- ⁇ -t-butyl-(L)- ⁇ -aminosuberate, dicyclohexylamine salt was purchased from Research Plus, Bayonne, N.J.
- N-Boc- ⁇ -methyl-(L)- ⁇ -aminosuberate (493 mg, 1.63 mmoles) was dissolved under Ar in 7mL of dry CH 2 Cl 2 .
- EDC 470 mg, 2.45 mmoles
- aniline 230 ⁇ L, 2.52 mmoles
- the solution was stirred at room temperature for 2 h 30 min, then washed with dilute HCl (pH 2.4, 2 ⁇ 5 mL), sat. NaHCO 3 (10 mL), and H 2 O (2 ⁇ 10 mL).
- the product was purified by column chromatography (Silica gel, Hexanes: AcOEt 3.5:1).
- N-Cbz-(L)-Asu (OtBu)-OH, dicyclohexylamine salt (100 mg, 0.178 mmol) was partitioned between 1 M HCl (5 mL) and EtOAc (10 mL). The organic layer was removed, and the aqueous portion washed with EtOAc (3 ⁇ 3 mL). The organic fractions were combined, washed with brine (1 ⁇ 2 mL), and dried (MgSO 4 ). The mixture was filtered and concentrated to a colorless film (67 mg, 0.176 mmol, 99%). This compound was used immediately in the next step.
- N-Cbz-(L)-Asu (OtBu)-OH (67 mg, 0.176 mmol) was dissolved in dry CH 2 Cl 2 (2.5 mL).
- Aniline (17 ⁇ L, 0.187 mmol), PyBOP (97 mg, 0.187 mmol), and iPr 2 NEt (46 ⁇ L, 0.266 mmol) were added and the mixture stirred for 2 h.
- the reaction was complete as indicated by TLC.
- the mixture was diluted with EtOAc (5 mL) and water (5 mL), and the layers separated. The aqueous portion was washed with EtOAc (3 ⁇ 3 mL) and the organic fractions combined.
- N-Cbz-(L)-ASU (OtBu)-anilide (76 mg, 0.167 mmol) was dissolved in dry CH 2 Cl 2 (5 mL) and TFA (0.5 mL) added dropwise. The reaction was complete by TLC after 3 h. The mixture was concentrated in vacuo to give the title compound (80 mg, crude). This compound was taken on without purification to the next step.
- N-Cbz-(L)-Asu (OH)-anilide 80 mg, crude
- O-t-butyldiphenylsilyl-hydroxylamine 60 mg, 0.221 mmol
- PyBOP 125 mg, 0.241 mmol
- iPr 2 NEt 52 ⁇ L, 0.302 mmol
- Murine erythroleukemia (MEL) cell differentiation Murine erythroleukemia (MEL) cell differentiation.
- the MEL cell differentiation assay was used to assess the ability of Compound 1 to induce terminal differentiation.
- MEL cells (logarithmically dividing) were cultured with the indicated concentrations of Compound 1. Following a 5-day culture period, cell growth was determined using a Coulter Counter and differentiation was determined microscopically using the benzidine assay to determine hemoglobin protein accumulation on a per cell basis.
- Histone Deacetylase HDAC
- Murine exythroleukemia (MEL) cell differentiation :
- the MEL cell differentiation assay was used to assess the ability of Compound 2 to induce terminal differentiation.
- MEL cells (logarithmically dividing) were cultured with the indicated concentrations of Compound 2. Following a 5-day culture period differentiation was determined microscopically using the benzidine assay to determine hemoglobin protein accumulation on a per cell basis.
- Murine erythroleukemia (MEL) cell differentiation :
- the MEL cell differentiation assay was used to assess the ability of Compound 3 to induce terminal differentiation.
- MEL cells (logarithmically dividing) were cultured with the indicated concentrations of Compound 3. Following a 5-day culture period differentiation was determined microsdopically using the benzidine assay to determine hemoglobin protein accumulation on a per cell basis.
- Histone deacetylase (HDAC) enzymatic activity HDAC
- Compound 3 is a potent inhibitor of HDAC1 enzymatic activity (ID50-100 nM).
- Murine erythroleukemia (MEL) cell differentiation :
- the MEL cell differentiation assay was used to assess the ability of Compound 4 to induce terminal differentiation.
- MEL cells (logarithmically dividing) were cultured with the indicated concentrations of Compound 4. Following a 5-day culture period differentiation was determined microscopically using the benzidine assay to determine hemoglobin protein accumulation on a per cell basis.
- Histone deacetylase HDAC
- Compound 4 is a potent inhibitor of HDAC1 enzymatic activity (ID50 ⁇ 10 nM).
- SAHA inhibits the activity of affinity purified HDAC1 and HDAC3 (39).
- SAHA causes the accumulation of acetylated histones H3 and H4 in vivo.
- the in vivo effect of SAHA has been studied using the CWR22 human prostate xenograft in mice (68).
- SAHA 50 mg/kg/day
- SAHA administration at this dose caused an increase in acetylated histones H3 and H4 in the tumor xenograft ( FIG. 9 ).
- SAHA is currently in Phase I Clinical Trials in patients with solid tumors.
- SAHA causes an accumulation of acetylated histones H3 and H4 in the peripheral blood mononuclear cells isolated from patients undergoing treatment ( FIG. 10 ).
- Table 1 shows a summary of the results of the Examples 7-10, testing compounds 1-4, and also compares the results to the results obtained from using SAHA. TABLE 1 Summary of Test results of compounds 1-4, and comparison to SAHA results. Com- MEL Differentiation HDAC Inhibition pound Range Opt.
- % B+ Range ID 50 1 0.1 to 50 ⁇ M 200 nM 44% 0.0001 to 100 1 nM ⁇ M 2 0.2 to 12.5 ⁇ M 800 nM 27% TBT 3 0.1 to 50 ⁇ M 400 nM 16% 0.01 to 100 ⁇ M 100 nM 4 0.01 to 50 ⁇ M 40 nM 8% 0.01 to 100 ⁇ M ⁇ 10 nM SAHA 2500 nM 68% 0.01 to 100 ⁇ M 200 nM
- TSA Trichostatin A
- Oxamflatin there is a chain of four carbons containing a double bond and an ethinyl link between the hydroxamic acid and the first phenyl ring, and Oxamflatin has been claimed to be an effective inhibitor of HDAC. We incorporate some of these features in our compounds, including those compounds that are not hydroxamic acids.
- the aldehyde is prepared and then converted to the trifluoromethylcarbinol with Rupperts reagent [57, 58].
- the malonic bis-anilides are prepared, and the carbinol oxidized to the ketone 12 with the Dess-Martin reagent [59].
- Other approaches were tried unsuccessfully. In particular, attempts to convert a carboxylic acid derivative directly to a trifluoromethyl ketone did not work.
- Compound 12 has been tested with HDAC and found to be an inhibitor of the enzyme. Thus, we also adapt this synthesis to the preparation of analogs of 12 with unsaturation, etc., in the chain, and other groups at the left end of the molecule.
- a classic inhibitor of the Zn(II) enzyme carbonic anhydrase is a sulfonamide, whose anion binds to the Zn(II) [61].
- compound 14 an analog of SAHA with a sulfonamide group, is synthesized as shown below.
- a carboxylic sulfonic bis-chloride with aniline and ammonia. Since the carboxylic acid chloride reacts faster, we use the sequence of aniline, then ammonia, but the sequence may be reversed, or the mixture may be separated if the two are of similar reactivity.
- thiol 15 easily made from the corresponding haloacid.
- Thiols are also inhibitors of Zn(II) enzymes such as carboxypeptidase A and related peptidases such as Angiotensin Converting Enzyme (ACE), so we convert 15 to 16 as an inhibitor of HDAC.
- ACE Angiotensin Converting Enzyme
- a similar synthesis can be used to attach the NH—P(O)OH—CH 3 group to other compounds, in particular compounds 6 and 7.
- Additional compounds may be synthesized, such as 19 and 20 to incorporate the trifluoromethyl ketone group of 12 that we know is effective as a Zn (II) binder in HDAC.
- the syntheses involve preparing compounds 21 and 22 and then adding CF 3 to form the carbinol, followed by oxidation as in the synthesis of 12.
- a simple synthesis involves Heck coupling of compounds 23 and 24 with ethyl acrylate, and conversion of the ester to aldehydes 21 and 22 by reduction to the carbinol and then reoxidation. All the chains shown so far contain only carbon atoms, but thioether links may be acceptable and even useful, and they add synthetic ease.
- sulfonamides such as 25 and 26, related to 19 and 20, from the corresponding thiophenol and bromomethylsulfonamide.
- a related synthesis may be used to make the corresponding phosphonamidates 27 and 28, if this class proves to be useful HDAC inhibitors and cytodifferentiators.
- (N-protected) m-aminobenzoic acid is used to acylate the arylamines, then phosphorylate the anilino group.
- the 0-protected hydroxylamine is acylated with bromohexanoic acid, and the compound then alkylates the bis-pentafluoro ester of malonic acid.
- the resulting 29 then reacts with various amines, and the protecting group is removed with acid.
- Reagents and starting materials were obtained from commercial suppliers and used without further purification unless otherwise indicated.
- solvents were freshly distilled prior to use: tetrahydrofuran was distilled under argon from sodium metal utilizing benzophenone as an indicator; dichloromethane and acetonitrile were distilled from powdered calcium hydride.
- Anhydrous benzene, anhydrous DIEA, and anhydrous pyridine were drawn by syringe from a sealed bottle purchased from Aldrich. Tert-Butanol was dried over 4A molecular sieves before use.
- Sodium hydride was purchased as a 60% dispersion in mineral oil.
- TLC thin-layer chromatography
- silica gel 60 F-254, 0.25 mm thickness manufactured by EM Science, Germany. Eluted compounds were visualized by one or more of. the following: short-wave ultraviolet light, 12 vapor, KMnO 4 stain, or FeCl 3 stain.
- Preparative TLC was carried out on Whatman precoated plates of either 500 ⁇ m or 1000 ⁇ m silica gel thickness. Flash column chromatography was performed on Merck Kieselgel 60, 230-400 mesh.
- NMR spectra were measured on Bruker DPX300 and DRX400 spectrometers; 1 H was observed at 300 and 400 MHz, and 19 F at 376 MHz. Chemical shifts are reported as ⁇ values in ppm relative to the solvent residual peak.
- Mass spectra were obtained on a Nermag R-10-1 instrument for chemical ionization (CI) or, electron impact ionization (EI) spectra, and on a Jeol JMS LCmate for electrospray ionization (ESI+) spectra.
- CI spectra were run with either ammonia (NH 3 ) or methane (CH 4 ) as the ionization gas.
- Ester 45 (260 mg, 0.95 mmol) was dissolved in MeOH (7.5 mL). A solution of LiOH.H 2 O (200 mg, 4.76 mmol) in H 2 O (2.5 mL) was then added and the mixture stirred for 6 h. The reaction was acidified with HCl (1 N) until pH 2 and then extracted with EtOAc (3 ⁇ 10 mL). The organic fractions were combined and washed with H 2 O and brine, dried over MgSO 4 , and filtered. Evaporation under reduced pressure left the product pure 46 as a brown solid (200 mg, 0.77 mmol, 81%).
- N-Cbz-L-2-aminosuberic acid 8-t-butyl ester, dicyclohexylamine salt (100 mg, 0.18 mmol) was dissolved in HCl (5 mL; 1 N) and extracted with EtOAc (3 ⁇ 10 mL). The extracts were combined, washed with brine, and dried over MgSO 4 . Evaporation left the free acid as a white solid (68 mg, 0.179 mmol). This was dissolved in CH 2 Cl 2 (2.5 mL), to which were added aniline (17 ⁇ L, 0.19 mmol), DIEA (46 ⁇ L, 0.27 mmol), and finally Py.BOP (97 mg, 0.19 mmol).
- This compound was prepared from suberic acid monomethyl ester in similar fashion to 48, with the use of 8-aminoquinoline.
- the crude residue obtained after TFA deprotection of the protected hydroxamate was taken up in a small volume of EtOAc and precipitated with hexanes to give 60 as a white solid (18 mg, 0.057 mmol, 21% from the carboxylic acid).
- Diacid 62 150 mg, 0.609 mmol
- 8-aminoquinoline 211 mg, 1.462 mmol
- DMAP 5 mg
- THF 6 mL
- EDC 350 mg, 1.827 mmol
- the mixture was concentrated under reduced pressure and the product purified by flash chromatography (40% EtOAc/hexanes). Evaporation of the combined product fractions left 63 as a light brown solid (100 mg, 0.201 mmol, 14%).
- 6-aminohexanoic acid (904 mg, 6.89 mmol) and NaOH (415 mg, 10.34 mmol) were dissolved in H 2 O (30 mL) and cooled to 0-5 ° C.
- Methanesulfonyl chloride (0.586 mL, 7.58 mmol) was added dropwise and the reaction mixture stirred for 2 h, then warmed to ambient temperature and stirred for an additional 2 h.
- the mixture was acidified with HCl (1 N) and extracted with EtOAc (3 ⁇ 15 mL). The extracts were combined, washed with H 2 O, then brine, dried over MgSO 4 , and filtered.
- ester 71 To solution of ester 71 (300 mg, 1.25 mmol) in THF (18 mL) was added a solution of LiOH.H 2 O (262 mg, 6.24 mmol) in H 2 O (6 mL) and the suspension was stirred overnight. The mixture was then acidified with HCl (1 N) to pH 2 and then extracted with EtOAc (3 ⁇ 15 mL). The extracts were combined, washed with brine, dried over MgSO 4 , and filtered. Concentration under reduced pressure left a white solid (211 mg, 0.93 mmol, 75%).
- Diethyl 3-bromophenyl malonate was prepared according to the procedures of Cehnevert, R. and Desjardins, M. Can. J. Chem. 1994. 72, 3212-2317.
- compound 77 The effect of compound 77 on MEL cell differentiation and Histone Deacetylase activity is shown in Table 2. Compound 77 corresponds to structure 683 in Table 2. As evident from Table 2, compound 77 is expected to be a highly effective cytodifferentiating agent.
- Table 2 shows the results of testing of only a subgroup of compounds. Table 2 is compiled from experiments similar to the experiments described in Examples 7-10 above. The tested compounds were assigned structure numbers as shown in Table 2. The structure numbers were randomly assigned and do not correlate to the compound numbers used elsewhere in this disclosure.
- Table 2 verify the generat accuracy of the predictive principals for the design of compounds having cell differentiation and HDAC inhibition activity discuss.ed above in this disclosure. Based on the principals and synthesis schemes disclosed, a number of additional compounds can readily be designed, prepared and tested for cell differentiation and HDAC inhibition activity.
- FIGS. 11 a - f show the effect of selected compounds on affinity purified human epitope-tagged (Flag) HDAC1.
- the effect was assayed by incubating the enzyme preparation in the absence of substrate on ice for 20 minutes with the indicated amounts of compound.
- Substrate([ 3 H]acetyl-labeled murine erythroleukemia cell-derived histones) was added and the samples were incubated for 20 minutes at 37° C. in a total volume of 30 ⁇ l. The reactions were then stopped and released acetate was extracted and the amount of radioactivity released determined by scintillation counting. This is a modification of the HDAC Assay described in Richon et al. 1998 (39). TABLE 2 Inhibition data of selected compounds.
Abstract
Description
- This application is a continuation of U.S. application Ser. No. 09/645,430, filed Aug. 24, 2000 which claims the benefit of U.S. Provisional Application 60/208,688 filed Jun. 1, 2000 and U.S. Provisional Application 60/152,755; filed Sep. 8, 1999.
- Throughout this application various publications are referenced by Arabic numerals within parentheses. Full citation for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
- Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms which normally govern proliferation and differentiation. A recent approach to cancer therapy has been to attempt induction of terminal differentiation of the neoplastic cells (1). In cell culture models differentiation has been reported by exposure of cells to a variety of stimuli, including: cyclic AMP and retinoic acid (2, 3), aclarubicin and other anthracylcines (4).
- There is abundant evidence that neoplastic transfonnation does not necessarily destroy the potential of cancer cells to differentiate (1, 5, 6). There are many examples of tumor cells which do not respond to the normal regulators of proliferation and appear to be blocked in the expression of their differentiation program, and yet can be induced to differentiate and cease replicating. A variety of agents, including some relatively simple polar compounds (5, 7-9), derivatives of vitamin D and retinoic acid (10-12), steroid hormones (13); growth factors (6, 14), proteases (15, 16), tumor promoters (17,18), and inhibitors of DNA or RNA synthesis (4, 19-24), can induce various transformed cell lines and primary human tumor explants to express more differentiated characteristics.
- Early studies by the some of present inventors identified a series of polar compounds that were effective inducers of differentiation in a number of transformed cell lines (8,9). One such effective inducer was the hybrid polar/apolar compound N,N′-hexamethylene bisacetamide (HMBA) (9), another was suberoylanilide hydroxamic acid (SAHA) (39, 50). The use of these compounds to induce murine erythroleukemia (MEL) cells to undergo erythroid differentiation with suppression of oncogenicity has proved a useful model to study inducer-mediated differentiation of transformed cells (5, 7-9).
- HMBA-induced MEL cell terminal erythroid differentiation is a multistep process. Upon addition of HMBA to MEL cells (745A-DS19) in culture, there is a latent period of 10 to 12 hours before commitment to terminal differentiation is detected. Commitment is defined as the capacity of cells to express terminal differentiation despite removal of inducer (25). Upon continued exposure to HMBA there is progressive recruitment of cells to differentiate. The present inventors have reported that MEL cell lines made resistant to relatively low levels of vincristine become markedly more sensitive to the inducing action of HMBA and can be induced to differentiate with little or no latent period (26).
- HMBA is capable of inducing phenotypic changes consistent with differentiation in a broad variety of cells lines (5). The characteristics of the drug induced effect have been most extensively studied in the murine erythroleukemia cell system (5, 25, 27, 28). MEL cell induction of differentiation is both time and concentration dependent. The minimum concentration required to demonstrate an effect in vitro in most strains is 2 to 3 mM; the minimum duration of continuous exposure generally required to induce differentiation in a substantial portion (>20%) of the population without continuing drug exposure is about 36 hours.
- There is evidence that protein kinase C is involved in the pathway of inducer-mediated differentiation (29). The in vitro studies provided a basis for evaluating the potential of HMBA as a cytodifferentiation agent in the treatment of human cancers (30). Several phase I clinical trials with HMBA have been completed (31-36). Clinical trials have shown that this compound can induce a therapeutic response in patients with cancer (35, 36). However, these phase I clinical trials also have demonstrated that the potential efficacy of HMBA is limited, in part, by dose-related toxicity which prevents achieving optimal blood levels and by the need for intravenous administration of large quantities of the agent, over prolonged periods. Thus, some of the present inventors have turned to synthesizing compounds that are more potent and possibly less toxic than HMBA (37).
- Recently, a class of compounds that induce differentiation, have been shown to inhibit histone deacetylases. Several experimental antitumor compounds, such as trichostatin A (TSA), trapoxin, suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have been shown to act, at least in part, by inhibiting histone deacetylases (38, 39, 42). Additionally, diallyl sulfide and related molecules (43), oxamflatin, (44), MS-27-275, a synthetic benzamide derivative, (45) butyrate derivatives (46), FR901228 (47), depudecin (48), and m-carboxycinnamic acid bishydroxamide (39) have been shown to inhibit histone deacetylases. In vitro, these compounds can inhibit the growth of fibroblast cells by causing cell cycle arrest in the G1 and G2 phases (49-52), and can lead to the terminal differentiation and loss of transforming potential of a variety of transformed cell lines (49-51). In vivo, phenylbutyrate is effective in the treatment of acute promyelocytic leukemia in conjunction with retinoic acid (53). SAHA is effective in-preventing the formation of mammary tumors in rats, and lung tumors in mice (54, 55).
- U.S. Pat. No.5,369,108 (41) issued to some of the present inventors discloses compounds useful for selectively inducing terminal differentiation of neoplastic cells, which compounds have two polar end groups separated by a flexible chain of methylene groups, wherein one or both of the polar end groups is a large hydrophobic group. Such compounds are stated to be more active than HMBA and HMBA related compounds.
- However, U.S. Pat. No. 5,369,108 does not disclose that an additional large hydrophobic group at the same end of the molecule as the first hydrophobic group would further increase differentiation activity about 100 fold in an enzymatic assay and about 50 fold in a cell differentiation assay.
- This new class of compounds of the present invention may be useful for selectively inducing terminal differentiation of neoplastic cells and therefore aid in treatment of tumors in patients.
-
- wherein R1 and R2 are the same or different and are each a hydrophobic moiety; wherein R3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from 3 to 10, or a pharmaceutically acceptable salt thereof.
-
- wherein each of R1 and R2 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purino-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group; wherein R3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; wherein R4 is hydrogen, a halogen, a phenyl, or a cycloalkyl moiety; wherein A may be the same or different and represents an amide moiety, —O—, —S—, —NR5—, or —CH2—, where R5 is a substituted or unsubstituted C1-C5 alkyl; and wherein n is an integer from 3 to 10, or a pharmaceutically acceptable salt thereof.
- The subject invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of the aforementioned compound.
-
FIG. 1 . The effect ofCompound 1 according to the subject invention on MEL cell differentiation. -
FIG. 2 . The effect ofCompound 1 according to the subject invention on Histone Deacetylase 1 activity. -
FIG. 3 . The effect ofCompound 2 according to the subject invention on MEL cell differentiation. -
FIG. 4 . The effect ofCompound 3 according to the subject invention on MEL cell differentiation. -
FIG. 5 . The effect ofCompound 3 according to the subject invention on Histone Deacetylase 1 activity. -
FIG. 6 . The effect ofCompound 4 according to the subject invention on MEL cell differentiation. -
FIG. 7 . The effect ofCompound 4 according to the subject invention onHistone Deacetylase 1 activity. -
FIG. 8 . A photoaffinity label (3H-498) binds directly toHDAC 1. -
FIG. 9 . SAHA causes accumulation of acetylated histones H3 and H4 in the CWR22 tumor xenograft in mice. -
FIG. 10 . SAHA causes accumulation of acetylation histones H3 and H4 in peripheral blood nonnuclear cells in patients. SAHA was administered by IV infusion daily ×3. Samples were isolated before (Pre), following infusion (Post) and 2 hours after infusion. -
FIGS. 11 a-11 f. Show the effect of selected compounds on affinity purified human epitope-tagged (Flag) HDAC1. -
- wherein R1 and R2 are the same or different and are each a hydrophobic moiety; wherein R3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from 3 to 10; or a pharmaceutically acceptable salt of the compound.
- In the foregoing compound each of R1 and R2 is directly attached or through a linker, and is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- Where a linker is used, the linker may be an amide moiety, —O—, —NH—, or —CH2—.
- According to this invention, n may be 3-10, preferably 3-8, more preferably 3-7, yet more preferably 4, 5 or 6, and most preferably 5.
-
- wherein each of R1 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group. R2 may be -amide-R5, wherein R5 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naptha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
-
- wherein each of R1 and R2 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group; wherein R3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; wherein R4 is hydrogen, a halogen, a phenyl, or a cycloalkyl moiety; wherein A may be the same or different and represents an amide moiety, —O—, —S—, —NR5—, or —CH2—, where R5 is a substituted or unsubstituted C1-C5 alkyl; and wherein n is an integer from 3 to 10, or a pharmaceutically acceptable salt thereof.
-
-
-
- wherein each of R1 and R2 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, t-butyl, aryloxy, arylalkyloxy, or pyridine group; and wherein n is an integer from 3 to 8.
- The aryl or cycloalkyl group may be substituted with a methyl, cyano, nitro, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodo, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 3,5-difluoro, 2,6-difluoro, 1,2,3-trifluoro, 2,3,6-trifluoro, 2,4,6-trifluoro, 3,4,5-trifluoro, 2,3,5,6-tetrafluoro, 2,3,4,5,6-pentafluoro, azido, hexyl, t-butyl, phenyl, carboxyl, hydroxyl, methoxy, phenyloxy, benzyloxy, phenylaminooxy, phenylaminocarbonyl, methyoxycarbonyl, methylaminocarbonyl, dimethylamino, dimethylaminocarbonyl, or hydroxylaminocarbonyl group.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
-
- or an enantiomer thereof.
- This invention is also intended to encompass enantiomers and salts of the compounds listed above.
-
- wherein R1 and R2 are the same or different and are each a hydrophobic moiety:
- wherein R5′ is —C(O)—NHOH (hydroxamic acid), —C(O)—CF3 (trifluoroacetyl), —NH—P(O))H—CH3, —SO2NH2 (sulfonamide), —SH (thiol), —C(O)—R6, wherein R6 is hydroxyl, amino, alkylamino, or alkyloxy group; and n is an integer from 3 to 10, or a pharmaceutically acceptable salt thereof.
- In the foregoing compound, each of R1 and R2 may be directly attached or through a linker, and is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- The linker may be an amide moiety, —O—, —S—, —NH—, or —CH2—.
-
- wherein each of R7 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
- In the foregoing compound, R2 may be -sulfonamide-R6, or -amide-R8 wherein R8 is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
-
-
-
- wherein R1 and R2 are the same or different and are each a hydrophobic moiety:
- wherein R5′ is —C(O)—NHOH (hydroxamic acid), —C(O)—CF3 (trifluoroacetyl), —NH—P(O))H—CH3, —SO2NH2 (sulfonamide), —SH (thiol), —C(O)—R6, wherein R6 is hydroxyl, amino, alkylamino, or alkyloxy group; and wherein L is a linker consisting of —(CH2)—, —C(O)—, —S—, —O—, —(CH=CH)—, -phenyl-, or -cycloalkyl-, or any combination thereof, or a pharmaceutically acceptable salt thereof.
- L may also be a linker consisting of —(CH2)n—, —C(O)—, —S—, —O—, —(CH═CH)m—, -phenyl-, or -cycloalkyl-, or any combination thereof, wherein n is an integer from 3 to 10, and m is an integer from 0 to 10,
- In the foregoing compound, n may be from 4-7, and m is from 0-7. Preferably n is 5 or 6, most preferably n is 6. Preferably m is from 1-6, more preferably m is 2-5, most preferably m is 3 or 4,
- In the compound, each of R1 and R2 may be directly attached or through a linker, and is, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridine group.
- The linker may be an amide moiety, —O—, —S—, —NH—, or —CH2—.
- This invention is also intended to encompass enantiomers, salts and pro-drugs of the compounds disclosed herein.
-
- wherein L is a linker selected from the group consisting of —(CH2)—, —(CH═CH)—, -phenyl-, -cycloalkyl-, or any combination thereof, and wherein each of R1 and R2 are independently substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, 9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group.
-
-
- Any of the disclosed compounds can be formed into a pharmaceutical composition together with a pharmaceutically acceptable carrier.
- Any of the compounds can also be formed into a pharmaceutically acceptable salt of the compound using well known pharmacological techniques.
- A prodrug of any of the compounds can also be made using well known pharmacological techniques.
- Any of the compounds can be used in a method of inducing differentiation of tumor cells in a tumor comprising contacting the cells with an effective amount of the compound so as to thereby differentiate the tumor cells.
- Any of the compounds can also be used in a method of inhibiting the activity of histone deacetylase comprising contacting the histone deacetylase with an effective amount of the compound so as to thereby inhibit the activity of histone deacetylase.
- This invention, in addition to the above listed compounds, is further intended to encompass the use of homologs and analogs of such compounds. In this context, homologs are molecules having substantial structural similarities to the above-described compounds and analogs are molecules having substantial biological similarities regardless of structural similarities.
- In a further embodiment, the subject invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of any one of the aforementioned compounds and a pharmaceutically acceptable carrier.
- In a yet further embodiment, the subject invention provides a method of selectively inducing growth arrest, terminal differentiation and/or apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an effective amount of any one of the aforementioned compounds.
- The contacting should be performed continuously for a prolonged period of time, i.e. for at least 48 hours, preferably for about 4-5 days or longer.
- The method may be practiced in vivo or in vitro. If the method is practiced in vitro, contacting may be effected by incubating the cells with the compound. The concentration of the compound in contact with the cells should be from about 1 nM to about 25 mM, preferably from about 20 nM to about 25 mM, more preferably from about 40 nM to 100 μM, yet more preferably from about 40 nM to about 200 nM. The concentration depends upon the individual compound and the state of the neoplastic cells.
- The method may also comprise initially treating the cells with an antitumor agent so as to render them resistant to an antitumor agent and subsequently contacting the resulting resistant cells under suitable conditions with an effective amount of any of the compounds above, effective to selectively induce terminal differentiation of such cells.
- The present invention also provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient an effective amount of any of the compounds above, effective to selectively induce growth arrest, terminal differentiation and/or apoptosis of such neoplastic cells and thereby inhibit their proliferation.
- The method of the present invention is intended for the treatment of human patients with tumors. However, it is also likely that the method would be effective in the treatment of tumors in other mammals. The term tumor is intended to include any cancer caused by the proliferation of neoplastic cells, such as prostate cancer, lung cancer, acute leukemia, multiple myeloma, bladder carcinoma, renal carcinoma, breast carcinoma, colorectal carcinoma, neuroblastoma or melanoma.
- Routes of administration for the compound of the present invention include any conventional and physiologically acceptable route, such as, for example, oral, pulmonary, parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), inhalation (via .a fine powder formulation or a fine mist), transdermal, nasal, vaginal, rectal, or sublingual routes of administration and can be formulated in dosage forms appropriate for each route of administration.
- The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, such as sterile pyrogen-free water, and a therapeutically acceptable amount of any of the compounds above. Preferably, the effective amount is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount which causes toxicity in a patient.
- The present invention provides the pharmaceutical composition above in combination with an antitumor agent, a hormone, a steroid, or a retinoid.
- The antitumor agent may be one of numerous chemotherapy agents such as an alkylating agent, an antimetabolite, a hormonal agent, an antibiotic, colchicine, a vinca alkaloid, L-asparaginase, procarbazine, hydroxyurea, mitotane, nitrosoureas or an imidazole carboxamide. Suitable agents are those agents which promote depolarization of tubulin. Preferably the antitumor agent is colchicine or a vinca alkaloid; especially preferred are vinblastine and vincristine.
- In embodiments where the antitumor agent is vincristine, an amount is administered to render the cells are resistant to vincristine at a concentration of about 5 mg/ml. The administration of the agent is performed essentially as described above for the administration of any of the compounds. Preferably, the administration of the agent is for a period of at least 3-5 days. The administration of any of the compounds above is performed as described previously.
- The pharmaceutical composition may be administered daily in 2-6 hour infusions for a period of 3-21 days, for example, daily in a 4 hour infusion for a period of 5 days.
- This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
- Experimental Details
- Examples 1-5 show the synthesis of substituted L-α-aminosuberic hydroxamic acids according to the subject invention, and Examples 6 and 7 show the effects of compounds 1-5 on MEL cell differentiation and Histone Deacetylase activity.
- N-Boc-ω-methyl-(L)-α-aminosuberate, Boc-Asu (OMe) was prepared according to a published procedure (40). (“Boc“=t-butoxycarbonyl; “Asu”=α-aminosuberate (or α-aminosuberic acid))
- N-Cbz-ω-t-butyl-(L)-α-aminosuberate, dicyclohexylamine salt was purchased from Research Plus, Bayonne, N.J.
-
- N-Boc-ω-methyl-(L)-α-aminosuberate (493 mg, 1.63 mmoles) was dissolved under Ar in 7mL of dry CH2Cl2. EDC (470 mg, 2.45 mmoles) was added, followed by aniline (230 μL, 2.52 mmoles). The solution was stirred at room temperature for 2
h 30 min, then washed with dilute HCl (pH 2.4, 2×5 mL), sat. NaHCO3 (10 mL), and H2O (2×10 mL). - The product was purified by column chromatography (Silica gel, Hexanes: AcOEt 3.5:1).
- The isolated yield was 366 mg (60%).
- 1H-NMR and Mass Spectroscopy were consistent with the product.
-
- 90 mg of N-Bloc-ω-methyl-(L)-α-aminosuberateanilide (0.238 mmoles) were treated with 3.2 mL of 25% trifluoroacetic acid (TFA) CH2Cl2 for 30 min. The solvent was removed and the residue left under high vacuum for 12 h. It was dissolved under Ar in 3 mL of dry CH2Cl2 and benzotriazole-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (149 mg, 0.286 mmoles), benzoic acid (44 mg, 0.357 mmoles) and diisopropylethylamine (114 μL, 0.655 mmoles). The solution was stirred at room temperature for 1 h. The product was purified by column chromatography (Silica gel, Hexanes: AcOEt 3:1-2:1) as a white solid: 75 mg, 82%.
- 1H-NMR and Mass Spectroscopy were consistent with the product.
- The foregoing coupling reaction was also successfully accomplished using 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) as a reagent.
-
- 75 mg (0.196 mmoles) of N-benzoyl—aminosuberateanilide were stirred for 6 h at 0° C. in 1M NaOH:THF:MeOH 1:1:1. After complete disappearance of the starting material, the solution was neutralized (1M HCl) and extracted with AcOEt. The organic phase was collected and dried. Solvent removal yielded the product as a white solid: 67 mg, 93%.
- 1H-NMR and Mass Spectroscopy were consistent with the product.
-
- To a suspension of 26 mg of N-benzoyl-ω-methyl-(L)-α-aminosuberateanilide (I2) in 1 mL of dry CH2Cl2 was added 58 mg of H2NOTBDPS (H2NO-t-butyldiphenylsilyl) followed by 22 mg of EDC. The reaction was stirred at room temperature for 4 h. The intermediate protected hydroxamic acid was purified by column chromatography (silica gel, CH2Cl2: MeOH 100:0-98-2). It was deprotected by treatment with 5% TFA in CH2Cl2 for 1 h30 min. The product was precipitated from acetone-pentane.
- 1H-NMR (d6-DMSO, 500 MHz) δ=10.29 (s, 1H), 8.53 (d, 1H), 7.90 (d, 2H), 7.60 (d, 2H), 7.53 (m, 1H), 7.46 (t, 2H), 7.28 (t, 2H), 7.03 (t, 2H), 4.53 (q, 1H), 1.92 (t, 2H), 1.78 (m, 2H), 1.50-1.25 (m, 6H).
- ESI-MS: 384 (M+1),406 (M+Na), 422 (M+K)
-
- It was prepared from N-Boc-ω-methyl-L-α-aminosuberate following the same procedure used for the benzoyl analog. Yields and chromatographic behaviour were comparable.
- 1H-NMR (d6-DMSO, 500 MHz) δ=10.30 (s, 1H), 10.10 (s, 1H), 9.05 (m, 1H), 8.80 (m, 1H), 8.71 (m, 1H), 8.24 (m, 1H), 7.60 (m, 2H), 7.30 (m, 2H), 7.04 (m, 1H), 4.56 (m, 1H), 1.93 (t, 2H), 1.79 (m, 2H), 1.55-1.30 (m, 6H). ESI-MS: 385 (M+1), 407 (M+Na)
-
- N-Cbz-(L)-Asu (OtBu)-OH, dicyclohexylamine salt (100 mg, 0.178 mmol) was partitioned between 1 M HCl (5 mL) and EtOAc (10 mL). The organic layer was removed, and the aqueous portion washed with EtOAc (3×3 mL). The organic fractions were combined, washed with brine (1×2 mL), and dried (MgSO4). The mixture was filtered and concentrated to a colorless film (67 mg, 0.176 mmol, 99%). This compound was used immediately in the next step.
-
- N-Cbz-(L)-Asu (OtBu)-OH (67 mg, 0.176 mmol) was dissolved in dry CH2Cl2 (2.5 mL). Aniline (17 μL, 0.187 mmol), PyBOP (97 mg, 0.187 mmol), and iPr2NEt (46 μL, 0.266 mmol) were added and the mixture stirred for 2 h. The reaction was complete as indicated by TLC. The mixture was diluted with EtOAc (5 mL) and water (5 mL), and the layers separated. The aqueous portion was washed with EtOAc (3×3 mL) and the organic fractions combined. This solution was washed with 1 M HCl (1×, 2 mL) and brine (1×2 mL), dried (MgSO4), filtered, and concentrated to a crude oil. This was passed through a plug of silica gel (30% EtOAc/hexanes) to remove baseline impurities, affording the compound (76 mg, 0.167 mmol, 94%).
- 1H NMR (CDCl3, 400 MHz, no TMS) δ 8.20 (br s, 1H), 7.47 (d, 2H), 7.32 (m, 5H), 7.28 (t, 2H), 7.08 (t, 1H), 5.39 (d, 1H), 5.10 (m, 2H), 4.26 (m, 1H), 2.18 (t, 2H), 1.93 (m, 1H), 1.67 (m, 1H), 1.55 (m, 3H), 1.42 (s, 9H), 1.36 (m, 3H).
-
- N-Cbz-(L)-ASU (OtBu)-anilide (76 mg, 0.167 mmol) was dissolved in dry CH2Cl2 (5 mL) and TFA (0.5 mL) added dropwise. The reaction was complete by TLC after 3 h. The mixture was concentrated in vacuo to give the title compound (80 mg, crude). This compound was taken on without purification to the next step.
- 1H NMR (DMSO-d6, 400 MHz) δ 11.93 (br s, 1H), 9.99 (br s, 1H), 7.57 (m, 3H), 7.34 (m, 5H), 7.29 (t, 2H), 7.03 (t, 1H), 5.02 (m, 2H), 4.11 (m, 1H), 2.17 (t, 2H), 1.46 (m, 2H).
-
- N-Cbz-(L)-Asu (OH)-anilide (80 mg, crude) and O-t-butyldiphenylsilyl-hydroxylamine (60 mg, 0.221 mmol) were dissolved in CH2Cl2 (4 mL). To this was added PyBOP (125 mg, 0.241 mmol) and iPr2NEt (52 μL, 0.302 mmol) and stirred overnight. TLC indicated reaction completion. The mixture was concentrated in vacuo and then passed through a plug of silica gel (50% EtOAc/hexanes) to remove baseline impurities. Evaporation of volatiles afforded 107 mg of material which was then dissolved in dry CH2Cl2 (5 mL) and TFA (0.25 mL) was added. Monitoring by TLC indicated completion after 1.5h. Concentrated in vacuo to remove all volatiles. The residue was taken up in EtOAC (3 mL), and then hexanes was added slowly to result in the precipitation of a white gel. The supernatant was removed, and the precipitate washed with hexanes (3×2 mL). This material was taken to dryness under reduced pressure, to afford the title compound (40 mg, 0.097 mmol, 59%).
- 1H NMR (DMSO-d6, 400 MHz) δ 10.32 (s, 1H), 10.00 (s, 1H), 8.64 (br s, 1H), 7.57 (m, 3H), 7.37 (m, 5H), 7.30 (t, 2H), 7.04 (t, 1H), 5.02 (m, 2H), 4.12 (m, 1H), 1.93 (t, 2H), 1.62 (m, 2H), 1.45 (m, 2H), 1.29 (m, 4H); ESI-MS 414 (M+1).
-
- Prepared in similar manner to compound 3.
- 1H NMR (DMSO-d6, 400 MHz) δ 10.45 (s, 1H), 10.31 (s, 1H), 8.85 (dd, 1H), 8.63 (dd, 1H), 8.42 (dd, 1H), 8.13 (dd, 1H), 8.68 (m, 2H), 7.60 (t, 1H), 7.37 (m, 2H), 7.28 (m, 2H), 5.10 (m, 2H), 4.24 (m, 1H), 1.93 (t, 2H), 1.85 (m, 1H), 1.70 (m, 1H ), 1.50 (m, 2H), 1.42 (m, 2H), 1.30 (m, 2H); ESI-MS 465 (M+1).
-
- A sample of the N-Cbz-ω-t-butyl L-α-aminosuberoyl-8-quinolinamide (90 mg, 0.178 mmoles) was obtained from the previous synthesis. The Cbz group was removed by hydrogenation in MeOH on 5% Pd on C. The resulting free amine was coupled with benzoic acid using EDC in dry CH2Cl2 (69% over the two steps). After TFA deprotection of the t-butyl ester, the usual coupling with H2NOTBDPS followed by deprotection afforded the desired hydroxamic acid.
- 1H-NMR (d6-DMSO, 500 MHz) δ=10.55 (s, 1H), 10.30 (s, 1H), 9.03 (m, 1H), 8.78 (m, 1H), 8.62 (m, 1H), 8.40 (m, 1H0, 7.97 (m, 2H), 7.67-7.46 (m, 6H), 4.66 (m, 1H), 1.94 (t, 2H), 1.87 (m, 1H), 1.80-1.20 (m, 7H). ESI-MS: 435 (M+1).
-
-
-
-
-
- from which R′ is removed and converted to hydroxamic acid (NHOH) as in the previous examples.
- In the foregoing scheme, R may be t-butyl, removed with trifluoroacetic acid; R′ may be methyl, removed with a base or LiI; and each R″ may be the same or different, depending on the reagent used.
- Murine erythroleukemia (MEL) cell differentiation.
- The MEL cell differentiation assay was used to assess the ability of
Compound 1 to induce terminal differentiation. MEL cells (logarithmically dividing) were cultured with the indicated concentrations ofCompound 1. Following a 5-day culture period, cell growth was determined using a Coulter Counter and differentiation was determined microscopically using the benzidine assay to determine hemoglobin protein accumulation on a per cell basis. - It was observed, as shown in
FIG. 1 , that Compound 1 (200 nM) is able to induce MEL cell differentiation. - Histone Deacetylase (HDAC) enzymatic activity.
- The effect of
Compound 1 on affinity purified human epitope-tagged (Flag) HDAC1 was assayed by incubating the enzyme preparation in the absence of substrate on ice for 20 min with the indicated amounts ofCompound 1. Substrate ([3H]acetyl-labeled murine erythroleukemia cell-derived histone) was added and the samples were incubated for 20 min at 37° C. in a total volume of 30 μl. The reaction were then stopped and released acetate was extracted and the amount of radioactivity released determined by scintillation counting. - It was observed, as shown in
FIG. 2 , thatCompound 1 is a potent inhibitor of HDAC1 enzymatic activity (ID50=1 nM). - Murine exythroleukemia (MEL) cell differentiation:
- The MEL cell differentiation assay was used to assess the ability of
Compound 2 to induce terminal differentiation. MEL cells (logarithmically dividing) were cultured with the indicated concentrations ofCompound 2. Following a 5-day culture period differentiation was determined microscopically using the benzidine assay to determine hemoglobin protein accumulation on a per cell basis. - It was observed, as shown in
FIG. 3 , that Compound 2 (800 nM) is able to induce MEL cell differentiation. - Murine erythroleukemia (MEL) cell differentiation:
- The MEL cell differentiation assay was used to assess the ability of
Compound 3 to induce terminal differentiation. MEL cells (logarithmically dividing) were cultured with the indicated concentrations ofCompound 3. Following a 5-day culture period differentiation was determined microsdopically using the benzidine assay to determine hemoglobin protein accumulation on a per cell basis. - It was observed, as shown in
FIG. 4 , that Compound 3 (400 nM) is able to induce MEL cell differentiation. - Histone deacetylase (HDAC) enzymatic activity:
- The effect of
Compound 3 on affinity purified human epitope tagged (Flag) HDAC1 was assayed by incubating the enzyme preparation in the absence of substrate on ice for 20 min with the indicated amounts of HPC. Substrate ([3H]acetyl-labelled murine erythroleukemia cell-derived histone) was added and the samples were incubated for 20 min at 37° C. in a total volume of 30 μl. The reactions were then stopped and relaesed acetate was extracted and the amount of radioactivity released determined by scintillation counting. - It was observed, as shown in
FIG. 5 , thatCompound 3 is a potent inhibitor of HDAC1 enzymatic activity (ID50-100 nM). - Murine erythroleukemia (MEL) cell differentiation:
- The MEL cell differentiation assay was used to assess the ability of
Compound 4 to induce terminal differentiation. MEL cells (logarithmically dividing) were cultured with the indicated concentrations ofCompound 4. Following a 5-day culture period differentiation was determined microscopically using the benzidine assay to determine hemoglobin protein accumulation on a per cell basis. - It was observed, as shown in
FIG. 6 , that Compound 4 (40 nM) is able to induce MEL cell differentiation. - Histone deacetylase (HDAC) enzymatic activity:.
- The effect of
Compound 4 on affinity purified human epitopetagged (Flag) HDAC1 was assayed by incubating the enzyme preparation in the absence of substrate on ice for 20 min with indicated amounts of HPC. Substrate ([3H]acetyl-labelled murine erythroleukemia cell-derived histone) was added and the samples were incubated for 20 min at 37° C. in a total volume of 30 μl. The reactions were then stopped and released acetate was extracted and the amount of radioactivity released determined by scintillation counting. - It was observed, as shown in
FIG. 7 , thatCompound 4 is a potent inhibitor of HDAC1 enzymatic activity (ID50<10 nM). - SAHA inhibits the activity of affinity purified HDAC1 and HDAC3 (39).
- Crystallographic studies with SAHA and a HDAC related protein reveal that SAHA inhibits HDAC by a direct interaction with the catalytic site (66). Additional studies demonstrate that a tritium labeled photoaffinity SAHA analog (3H-498) that contains an azide moiety (67) binds directly to HDAC1 (
FIG. 8 ). These results indicate that this class of hydroxamic acid based compound inhibits HDAC activity through a direct interaction with the HDAC protein. - SAHA causes the accumulation of acetylated histones H3 and H4 in vivo. The in vivo effect of SAHA has been studied using the CWR22 human prostate xenograft in mice (68). SAHA (50 mg/kg/day) caused a 97% reduction in mean final tumor volume compared to controls with no .apparent toxicity. SAHA administration at this dose caused an increase in acetylated histones H3 and H4 in the tumor xenograft (
FIG. 9 ). SAHA is currently in Phase I Clinical Trials in patients with solid tumors. SAHA causes an accumulation of acetylated histones H3 and H4 in the peripheral blood mononuclear cells isolated from patients undergoing treatment (FIG. 10 ). - Table 1 shows a summary of the results of the Examples 7-10, testing compounds 1-4, and also compares the results to the results obtained from using SAHA.
TABLE 1 Summary of Test results of compounds 1-4, and comparison to SAHA results. Com- MEL Differentiation HDAC Inhibition pound Range Opt. % B+ Range ID 50 1 0.1 to 50 μM 200 nM 44% 0.0001 to 100 1 nM μM 2 0.2 to 12.5 μM 800 nM 27 % TBT 3 0.1 to 50 μM 400 nM 16% 0.01 to 100 μM 100 nM 4 0.01 to 50 μM 40 nM 8% 0.01 to 100 μM <10 nM SAHA 2500 nM 68% 0.01 to 100 μM 200 nM - In additional studies we found that
compounds Compound 6 had ID50 of 2.5 nM, andcompound 7 had ID50 of 50 nM. This contrasts with an ID50 for SAHA of 1 μM, much higher. Note that the 1 μM ID50 for SAHA as an inhibitor of HDAC is of the same general magnitude as its 2.5 μM optimal dose for the cytodifferentiation of MEL cells, but this close similarity is not true for all the compounds examined. In some cases very effective HDAC inhibitors are less effective as cytodifferentiaters, probably because the drugs are metabolized in the cell assays. Also, all cell types are not the same, and some compounds are much better against human tumor cells such as HT-29 than they are against MEL cells. Thus, inhibition of HDAC cells is a preliminary indicator. - Of the above compounds which are hydroxamic acids, we have found that they undergo enzymatic hydrolysis rather rapidly to the carboxylic acids, so their biological lifetimes are short. We were interested in evolving compounds which might be more stable in vivo. Thus we have developed inhibitors of HDAC that are not hydroxamic acids, and that can be used as cytodifferentiating agents with longer biological lifetimes. Furthermore, we found that the newly evolved compounds have better ‘selectivity to HDAC than, e.g. SAHA.
- We have evolved compounds that have double bonds, similarly to Trichostatin A (TSA) to see if the resulting compounds have even greater efficacy. Also, the chain in TSA is only five carbons, not the six of SAHA. In Oxamflatin there is a chain of four carbons containing a double bond and an ethinyl link between the hydroxamic acid and the first phenyl ring, and Oxamflatin has been claimed to be an effective inhibitor of HDAC. We incorporate some of these features in our compounds, including those compounds that are not hydroxamic acids.
- Also disclosed are simple combinatorial methods for screening a variety of such compounds for efficacy and selectivity with respect to HDAC inhibition.
-
- Since the target for HDAC is an acetyllysine sidechain of histone, we make compounds in which transition state analogs of the substrate are present. For example, we synthesize compounds like SAHA in which the hydroxamic acid group —CO—NHOH, is replaced by a trifluoroacetyl group, —CO—CF3. The resulting 8 will easily form a hydrate, and thus bind to the Zn(II) of HDAC in a mimic 9 of the transition state 10 for deacetylation. This is related to the work published by Lipscomb [56] on the binding to carboxypeptidase A of a substrate analog 11 containing a CF3—CO—CH2 group in place of the normal amide. The hydrate of the ketone coordinated to the Zn(II) as a mimic of the transition state for catalyzed hydrolysis of an amide substrate. Our synthesis of a particular example 12 in the fluoroketone series is shown in Scheme below:
- After the malonic ester alkylation, the aldehyde is prepared and then converted to the trifluoromethylcarbinol with Rupperts reagent [57, 58]. The malonic bis-anilides are prepared, and the carbinol oxidized to the
ketone 12 with the Dess-Martin reagent [59]. Other approaches were tried unsuccessfully. In particular, attempts to convert a carboxylic acid derivative directly to a trifluoromethyl ketone did not work. -
Compound 12 has been tested with HDAC and found to be an inhibitor of the enzyme. Thus, we also adapt this synthesis to the preparation of analogs of 12 with unsaturation, etc., in the chain, and other groups at the left end of the molecule. - An analog of SAHA in which the CH2—CO—NHOH group is replaced by NH—P—(O)OH—CH3 may be synthesized by the general scheme shown below. The resulting compound, 13, binds to the Zn(II) of HDAC the way a related group binds to the Zn(II) of carboxypeptidase in analogs such as that prepared by Bartlett [60].
- A classic inhibitor of the Zn(II) enzyme carbonic anhydrase is a sulfonamide, whose anion binds to the Zn(II) [61]. Thus compound 14, an analog of SAHA with a sulfonamide group, is synthesized as shown below. In the last step we react a carboxylic sulfonic bis-chloride with aniline and ammonia. Since the carboxylic acid chloride reacts faster, we use the sequence of aniline, then ammonia, but the sequence may be reversed, or the mixture may be separated if the two are of similar reactivity.
- In the course of the synthesis of 14, we use a thiol 15 easily made from the corresponding haloacid. Thiols are also inhibitors of Zn(II) enzymes such as carboxypeptidase A and related peptidases such as Angiotensin Converting Enzyme (ACE), so we convert 15 to 16 as an inhibitor of HDAC. A similar synthesis can be used to attach the NH—P(O)OH—CH3 group to other compounds, in
particular compounds - Based on the results with Oxamflatin, it seems that a phenyl ring can be of the chain between the Zn(II) binding group and the left hand section of the molecule as drawn, particularly when the phenyl ring is meta substituted. Thus, we provide a synthesis t o incorporate such meta substituted chains into other of our compounds. We construct compounds 17 and 18. The simple syntheses, not shown in detail, only require that instead of the hydroxamic acid attached to the phenyl ring we make the aryl amides of 17 and 18.
- Additional compounds may be synthesized, such as 19 and 20 to incorporate the trifluoromethyl ketone group of 12 that we know is effective as a Zn (II) binder in HDAC. The syntheses involve preparing compounds 21 and 22 and then adding CF3 to form the carbinol, followed by oxidation as in the synthesis of 12. A simple synthesis involves Heck coupling of compounds 23 and 24 with ethyl acrylate, and conversion of the ester to aldehydes 21 and 22 by reduction to the carbinol and then reoxidation. All the chains shown so far contain only carbon atoms, but thioether links may be acceptable and even useful, and they add synthetic ease. Thus, sulfonamides such as 25 and 26, related to 19 and 20, from the corresponding thiophenol and bromomethylsulfonamide. A related synthesis may be used to make the corresponding phosphonamidates 27 and 28, if this class proves to be useful HDAC inhibitors and cytodifferentiators. In this case, (N-protected) m-aminobenzoic acid is used to acylate the arylamines, then phosphorylate the anilino group.
-
- In the synthesis the 0-protected hydroxylamine is acylated with bromohexanoic acid, and the compound then alkylates the bis-pentafluoro ester of malonic acid. The resulting 29 then reacts with various amines, and the protecting group is removed with acid.
- With this compound as the starting material, we synthesize related libraries carrying the other Zn(II) binding groups. For example, alkylation of the malonate with compound 32 lets us make a phosphonamidate library, and compound 33 will let us make a CF3—CO library. In a similar way, a sulfonamide library can be made if the work described earlier indicates that this is a promising Zn(II) binding group for HDAC. Of course after malonate alkylation and aminolysis the compound from 32 will be demethylated, while that from 33 will be oxidized.
- This also allows to expand on the structure of
compound 6, the derivative of aminosuberic acid. As described, this was one of the most effective HDAC inhibitor we have examined. We prepared this compound using an enzymatic hydrolysis to achieve optical resolution and selectivity among the two carbomethoxy groups of i4 so that we could convert one of them to the aminoquinoline amide of 6 while protecting the nitrogen as a carbobenzoxy group. At the end of the synthesis we converted the remote carbomethoxy group to a hydroxamate. However, 6 is an intermediate that can be used to prepare other derivatives. The carbobenzoxy group from 6 can be removed and the amine 35 can be acetylated with a variety of carboxylic acids to prepare library 36, or sulfonic acid chlorides to prepare the corresponding sulfonamides. - Also, we synthesize a different library of amides 37 related to 6, and then expand it with a library of other amides 38 by acylating the amino group after deprotection. We also synthesize a group of compounds 39 in which after the carbobenzoxy group of 37 is removed we make a library of sulfonamides using various sulfonyl chlorides. In all this, it the hydroxamic acid group may be protected.
- The foregoing synthesis schemes can be used to generate compounds having a large number of variation. Some substituent groups that are likely to result in compounds having potential good affinity to HDAC or having got differentiating activity are as follows:
-
-
- Reagents and starting materials were obtained from commercial suppliers and used without further purification unless otherwise indicated. For moisture-sensitive reactions, solvents were freshly distilled prior to use: tetrahydrofuran was distilled under argon from sodium metal utilizing benzophenone as an indicator; dichloromethane and acetonitrile were distilled from powdered calcium hydride. Anhydrous benzene, anhydrous DIEA, and anhydrous pyridine were drawn by syringe from a sealed bottle purchased from Aldrich. Tert-Butanol was dried over 4A molecular sieves before use. Sodium hydride was purchased as a 60% dispersion in mineral oil. Aniline, diisopropylamine, N-methylaniline, and benzyl alcohol were freshly distilled before use. Deuterated solvents were obtained from Cambridge Isotope Laboratories. Air- and/or moisture-sensitive reactions were carried out under an atmosphere of dry argon in oven- or flame-dried glassware equipped with a tightly-fitting rubber septum. Syringes and needles were oven-dried before use. Reactions at 0° C. were carried out in an ice/water bath. Reactions at -78° C. were carried out in a dry ice/acetone bath.
- Chromatography
- Analytical thin-layer chromatography (TLC) was conducted on glass plates precoated with silica gel 60 F-254, 0.25 mm thickness, manufactured by EM Science, Germany. Eluted compounds were visualized by one or more of. the following: short-wave ultraviolet light, 12 vapor, KMnO4 stain, or FeCl3 stain. Preparative TLC was carried out on Whatman precoated plates of either 500 μm or 1000 μm silica gel thickness. Flash column chromatography was performed on Merck Kieselgel 60, 230-400 mesh.
- Instrumentation
- NMR spectra were measured on Bruker DPX300 and DRX400 spectrometers; 1H was observed at 300 and 400 MHz, and 19F at 376 MHz. Chemical shifts are reported as δ values in ppm relative to the solvent residual peak. Mass spectra were obtained on a Nermag R-10-1 instrument for chemical ionization (CI) or, electron impact ionization (EI) spectra, and on a Jeol JMS LCmate for electrospray ionization (ESI+) spectra. CI spectra were run with either ammonia (NH3) or methane (CH4) as the ionization gas.
-
- To a stirred solution of NaH (60% disp., 234 mg, 5.85 mmol) in THF (35 mL) at 0° C. was added di-t-butyl malonate (1.20 mL, 5.37 mmol) dropwise. Gas evolution was observed, and the solution was allowed to warm to ambient temperature and stirred for 6 h. A solution of methyl 6-bromo-2,4-hexadienoate (62) (1.00 g, 4.88 mmol) in THF (20 mL) was prepared in a separate flask and stirred in a water bath. To this was cannulated dropwise the malonate mixture, and the reaction allowed to proceed overnight. The reaction was quenched with sat. NH4Cl (5 mL), then H2O (10 mL) was added and the mixture extracted with Et2O (3×15 mL). The organic fractions were combined and washed with H2O (1×10 mL ), then with brine, dried over MgSO4, and filtered. Evaporation under reduced pressure followed by flash chromatography (0-20% EtOAc/hexanes) gave 40 as a clear colorless oil (850 mg, 2.49 mmol, 51%). TLC Rf 0.66 (20% EtOAc/hexanes); 1H-NMR (CDCl3, 400 MHz) δ 7.26 (dd, 1H), 6.26 (dd, 1H), 6.10 (m, 1H), 5.82 (d, 1H), 3.78 (s, 3H), 3.12 (t, 1H), 2.64 (t, 2H), 1.41 (s, 18H).
-
- To a stirred solution of 40 (200 mg, 0.59 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL). The reaction was allowed to proceed overnight. Volatiles were removed under reduced pressure to leave 41 as a white solid (112 mg, 0.49 mmol, 83%). 1H-NMR (CD3OD, 400 MHz) δ 7.11 (dd, 1H), 6.33 (dd, 1H), 6.16 (m, 1H), 5.81 (d, 1H), 3.76 (s, 3H), 3.15 (t, 1H), 2.70 (t, 2H).
-
- To a stirred solution of oxalyl chloride (2.0 M in CH2Cl2, 11.5 mL, 23.1 mmol) in CH2Cl2 (100 mL) and DMF (1 drop) at 0° C. was added 4-pentenoic acid (2.25 mL, 22.0 mmol). This was allowed to warm to ambient temperature. Upon cessation of gas evolution, the mixture was returned to 0° C. and a solution of aniline (2.00 mL, 22.0 mmol) and TEA (6.72 mL, 26.3 mmol) in CH2Cl2 (5 mL) was added dropwise. After warming to ambient temperature, the reaction was allowed to proceed for 3 h. The mixture was concentrated under reduced pressure, and then partitioned between HCl (1 N, 10 mL) and EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×15 mL) and the organic layers combined, washed with brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave a yellowish solid, which was recrystallized with toluene to obtain 42 as white crystals (1.97 g, 11.24 mmol, 51%). TLC Rf0.68 (50% EtOAc/hexanes); 1H-NMR (300 MHz, CDCl3) δ 7.49 (d, 2H), 7.29 (t, 2H), 7.08 (t, 1H), 5.88 (m, 1H), 5.10 (dd, 2 H), 4.42 (br s, 4 H).
-
- To a stirred solution of diisopropylamine (2.06 mL, 14.7 mmol) in THF (25 mL) at −78° C. was added n-BuLi (2.0 M in hexanes, 6.2 mL, 12.4 mmol) and allowed to stir 20 min at this temperature. A solution of phosphonate 43a (63) (2.66 g, 11.3 mmol) in THF (4 mL) was then added dropwise, giving a deep yellow color upon addition. After 20 min at −78° C., the mixture was warmed to 0° C. and a solution of aldehyde 43b (64) (1.78 g, 11.3 mmol) in THF (4 mL) was added dropwise. After addition the solution was allowed to warm to ambient temperature and stirred overnight. It was diluted with Et2O (30 mL) and washed with H2O (3×10 mL). The aqueous washings were combined and extracted with Et2O (2×10 mL), and the organic portions combined, washed with brine, dried over MgSO4, and filtered. Evaporation under reduced pressure followed by flash chromatography (10-20% EtOAc/hexanes) gave 43 as a clear oil (1.54 g, 57%). TLC Rf 0.56 (20% EtOAc/hexanes); 1H-NMR (400 MHz, CDCl3) 6 7.22 (dd, 1H), 6.19 (dd, 1H), 6.08 (m, 1H), 5.77 (d, 1H), 2.42 (m, 2H), 2.32 (t, 2H), 1.42 (s, 9H).
-
- To a stirred solution of diester 43 (1.00 g, 4.61 mmol) in CH2Cl2 (40 mL) was added TFA (4.0 mL) and let react for 6 h. The mixture was concentrated under reduced pressure to remove volatiles. A white solid consisting of the crude acid (710 mg, 3.85 mmol) remained. This acid (400 mg, 2.17 mmol) was dissolved in CH2Cl2 (20 mL) and to this stirred solution were added DMAP (13 mg), aniline (218 μL, 2.39 mmol), and EDC (500 mg, 2.61 mmol). After 1.5 h, the mixture was diluted with EtOAc and washed with H2O. The layers were separated, and the aqueous extracted with EtOAc (3×15 mL).
- The organic portions were combined and washed with HCl (1 N, 1×5 mL) and brine, dried over MgSO4, and filtered. Concentration under reduced pressure left a brown solid. This was dissolved in a minimum of CH2Cl2, then passed through a plug of silica gel (20-30% EtOAc/hexanes, 200 mL) to remove baseline impurities. The eluent was concentrated to a light brown oil which was taken up in a small amount of CH2Cl2 and from which crystals were precipitated upon the addition of hexanes/diethyl ether. The mother liquor was drawn off, the crystals rinsed with ether, and the liquid fraction concentrated and this procedure repeated several times to ultimately give 44 as off-white crystals (324 mg, 1.25 mmol, 58%). TLC Rf 0.44 (50% EtOAc/hexanes); 1H-NMR (400 MHz, CDCl3) δ 7.47 (d, 1H), 7.30 (t, 2H), 7.24 (m, 1H), 7.09 (t, 1H), 6.24 (dd, 1H), 6.14 (m, 1H), 5.81 (d, 1H), 3.72 (s, 3H), 2.60 (m, 2H), 2.47 (t, 2H).
-
- The crude acid intermediate from the first step of the preparation of 44 (200 mg, 1.09 mrnol) and N-methylaniline (130 μL, 1.19 mmol) were dissolved in CH2Cl2 (10 mL) and stirred. EDC (271 mg, 1.41 mmol) and DMAP (5 mg) were then added and the reaction run overnight. The mixture was partitioned between H2O and EtOAc and the layers separated. The aqueous layer was extracted with EtOAc (3×10 mL), the, organic portions combined and washed with HCl (1 N, 1×5 mL), then brine, dried over MgSO4, and filtered. Evaporation under reduced pressure left pure 45 as a brown oil (286 mg, 1.05 mmol, 96%). TLC Rf 0.81 (5% MeOH/CH2Cl2); 1H-NMR (300 MHz, CDCl3) δ 7.40 (t, 2H), 7.35 (t, 1H), 7.20 (d, 2H), 7.15 (dd, 1H), 6.20 (m, 2H), 5.76 (d, 1H), 3.70 (s, 3H), 3.24 (s, 3H), 2.42 (m, 2H), 2.18 (t, 2H).
-
- Ester 45 (260 mg, 0.95 mmol) was dissolved in MeOH (7.5 mL). A solution of LiOH.H2O (200 mg, 4.76 mmol) in H2O (2.5 mL) was then added and the mixture stirred for 6 h. The reaction was acidified with HCl (1 N) until
pH 2 and then extracted with EtOAc (3×10 mL). The organic fractions were combined and washed with H2O and brine, dried over MgSO4, and filtered. Evaporation under reduced pressure left the product pure 46 as a brown solid (200 mg, 0.77 mmol, 81%). TLC Rf 0.13 (40% EtOAc/hexanes); 1H-NMR (300 MHz, CD3OD) δ 7.47 (t, 2H), 7.41 (d, 1H), 7.28 (d, 2H), 7.19 (dd, 1H), 6.18 (dd, 1H), 6.05 (m, 1H), 3.27 (s, 3H), 3.40 (m, 2H), 2.22 (t, 2H). -
- Acid 46 (200 mg, 0.77 mmol) and TBDPSO—NH, (220 mg, 0.81 mmol) were dissolved in CH2Cl2 (8 mL). To this stirred solution were added EDC (178 mg, 0.93 mmol) and DMAP (5 mg) and the reaction allowed to proceed overnight. The mixture was concentrated and then passed through a plug of silica gel (EtOAc). Evaporation under reduced pressure left a light brown oil (383 mg, 0.75 mmol, 97%). The protected hydroxamate (270 mg, 0.53 mmol) was dissolved in CH2Cl2 (10 mL) and TFA was added (0.5 mL). The solution was stirred for 2 h, and a new spot on TLC was observed which stained with FeCl3. The solution was concentrated under reduced pressure and diethyl ether added, giving a residue which adhered to the flask. The liquid phase was drawn off, the residue was triturated with EtOAc, the liquid removed, and evaporation of all volatiles from the residue gave 47 as a brown gum (23 mg, 0.084 mmol, 16%). TLC Rf 0.22 (5% MeOH/CH2Cl2); 1H-NMR (400 MHz, CD3OD) 6 7.50 (t, 2H), 7.40 (t, 1H), 2.27 (d, 2H), 7.08 (m, 1H), 6.11 (m, 1H), 5.97 (m, 1H), 5.80 (m, 1H), 3.23 (s, 3H), 3.39 (m, 2H), 2.21 (t, 2H).
-
- The title compound 48 was obtained as a brown gum (9 mg) by a series of steps analogous to the preparation of 47. TLC Rf 0.20 (5% MeOH/CH2Cl2); 1H-NMR (400 MHz, CD3OD) δ 7.51 (t, 2H), 7.41 (t, 1H), 7.30 (d, 2H), 3.29 (s, 3H), 2.11 (m, 4H), 1.58 (m, 4H), 1.22 (m, 4H).
-
- To a stirred solution of suberoyl chloride (1.00 mL, 5.55 mmol) in THF (40 mL) at 0° C. was added a solution of benzylamine, (0.61 mL, 5.55 mmol) and DIEA (1.45 mL, 8.33 mmol) in THF (10 mL) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 1 h. Then, HCl (10 mL, 1 N) was added and the mixture stirred for 0.5 h. The contents were diluted with EtOAc (30 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL), the organics combined, washed with brine (5 mL), and dried over MgSO4. Filtration and concentration under reduced pressure left 49 as an off-white solid. 1H-NMR (300 MHz, DMSO-d6) δ 11. 98 (br s, 1H), 9.80 (t, 1H), 7.32 (m, 2H), 7.23 (m, 3H), 4.25 (d, 2H), 2.19 (t, 2H), 2.12 (t, 2h), 1.50 (m, 4H), 1.25 (m, 4H).
-
- This compound was prepared from 49 through its protected hydroxamate as-described for earlier compounds. Obtained 50 as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.27 (t, 1H), 7.28 (m, 2H), 7.23 (m, 3H), 5.65 (d, 2H), 2.11 (t, 2H), 1.91 (t, 2H), 1.46 (m, 4H), 1.23 (m, 4H).
-
- N-Cbz-L-2-aminosuberic acid 8-t-butyl ester, dicyclohexylamine salt (100 mg, 0.18 mmol) was dissolved in HCl (5 mL; 1 N) and extracted with EtOAc (3×10 mL). The extracts were combined, washed with brine, and dried over MgSO4. Evaporation left the free acid as a white solid (68 mg, 0.179 mmol). This was dissolved in CH2Cl2 (2.5 mL), to which were added aniline (17 μL, 0.19 mmol), DIEA (46 μL, 0.27 mmol), and finally Py.BOP (97 mg, 0.19 mmol). The solution was stirred for 1 h, then concentrated, and the residue partitioned between H2O (5 mL) and EtOAC (10 mL). The layers were separated, and the aqueous portion extracted with EtOAc (3×10 mL). The extracts were pooled and washed with HCl (1 N), then brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave a solid residue which was passed through a plug of silica gel (30% EtOAc/hexanes). The collected eluent was evaporated to give 51 as a white solid (76 mg, 0.167 mmol, 94%). TLC Rf 0.38 (30% EtOAc/hexanes) 1H-NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.48 (d, 2H), 7.32 (m, 5H), 7.28 (t, 2H), 7.08 (t, 1 H ), 5.39 (br d, 1 H), 5.10 (m, 2H), 4.26 (br dd, 1H), 2.07 (t, 2H), 1.92 (m, 1H), 1.66 (m, 1H), 1.55 (m, 2H), 1.42 (s, 9H), 1.38 (m, 4H).
-
- To a solution of ester 51 (76 mg, 0.167 mmol) i n CH2Cl2 (5 mL) was added TFA (0.5 mL) and the reaction solution stirred for 5h. The s o I u t i o n was concentrated under-reduced pressure to give crude 52 as a white solid (80 mg), which was used in the next step without purification. TLC Rf 0.32 (5% MeOH/CH2Cl2); 1H-NMR (400 MHz, DMSO-d6), 7.55 (d, 1H), 7.35 (m, 4H), 7.29 (t, 2H) 7.03 (t, 1H) 5.02 (m, 2H), 4.11 (br dd, 1H), 2.17 (t, 2H), 1.59 (m, 2H), 1.48 (m, 2H), 1.22, (m, 4H).
-
- To a solution of crude acid 52 (80 mg) and TBDPSO—NH2 (60 mg, 0.221 mmol) in CH2Cl2 were added DIEA (52 μL, 0.302 mmol) followed by Py.BOP (125 mg, 0.241 mmol). The solution was stirred for 3 h, then concentrated under reduced pressure. The residue was passed through a plug of silica gel (50% EtOAc/hexanes and the collected eluent evaporated. A white foam (107 mg, 0.164 mmol, 82%) was obtained, this was dissolved in CH2Cl2 (5 mL) and TFA (0.25 mL) was added and the solution stirred for 2 h. A new spot that stained with FeCl3 was indicated by TLC analysis. The mixture was concentrated under reduced pressure, and the residue was solvated in a minimum of EtOAc and the product precipitated with hexanes. The resulting white gel was rinsed with hexanes and dried under vacuum, to give 53 as a white solid (40 mg, 0.097 mmol, 58% over three steps). 1H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.99 (s, 1H), 7.59 (d, 2H), 7.56 (d, 1H), 7.37 (m, 4H), 7.29 (t, 2H), 7.02 (t, 1H), 5.02 (m, 2H), 4.11 (dt, 1H), 1.90 (t, 2H), 1.61 (m, 2H), 1.47 (m, 2H), 1.30 (m, 4H). MS (ESI+) calcd for C22H27N3O5 413, found 414 [M+H]+.
-
- The title compound was made from N-Cbz-L-2-aminosuberic acid 8-t-butyl ester, dicyclohexylamine salt in a manner similar to that for 51. Flash chromatography (0-1% MeOH/CH2Cl2) gave 54 as a light brown solid (70 mg, 0.138 mmol, 82%). TLC Rf 0.42 (2% MeOH/CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 8.77 (dd, 1H), 8.71 (dd, 1H), 8.15 (dd, 1H), 7.52 (m, 2H), 7.45 (m,1H), 7.33 (m, 4H); 5.50 (br d, 1H), 5.15 (m, 2H), 4.51 (br dd, 1 H), 2.17 (t, 2H), 2.00 (m, 1H), 1.79 (m, 1H), 1.56 (m, 2H), 1.45 (m, 2H), 1.40 (s, 9H), 1.38 (m, 2H).
-
- Prepared from 54 in a manner similar to that for 52. Obtained 55 as a brown solid (72 mg, 0.129 mmol). TLC Rf 0.16 (50% EtOAc/hexanes); 1H-NMR (400 MHz, DMSO-d6) δ 11.92 (br s, 1H), 10.46 (s, 1H), 8.49 (dd, 1H), 8.63 (dd, 1H), 8.42 (dd, 1H), 8.10 (d, 1H), 7.68 (dd, 1H), 7.58 (t, 1H), 7.36 (m, 2H), 7.28 (m, 2H), 5.09 (m, 2H), 4.22 (m, 1H), 2.19 (t, 2H), 1.83 (m, 1H), 1.67 (m, 1H), 1.48 (m, 2H), 1.39 (m, 2H), 1.28 (m, 2H).
-
- Prepared from 55 in a manner similar to that for 53. Obtained 56 as a white solid (15 mg, 0.032 mmol, 44%). 1H-NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 10.31 (s, 1H), 8.85 (dd, 1H), 8.63 (dd, 1H), 8.42 (dd, 1H), 8.12 (d, 1H), 8.66 (m, 2H), 7.58 (t, 1H), 7.37 (m, 2H), 7.28 (m, 2H), 7.20-6.90 (1H), 5.10 (m, 2H), 4.10 (m, 1H), 1.92 (t, 2H), 1.82 (m, 1H), 1.68 (m, 1H), 1.49 (m, 2H), 1.40 (m, 2H), 1.26 (m, 2H). MS (ESI+) calcd for C25H28N4O5 464, found 465 [M+H]+.
-
- To a solution of 5 (81 mg, 0.214 mmol) in CH2Cl2 (10 mL) was added TFA (0.5 mL) and the solution stirred for 2 h. The mixture was concentrated under reduced pressure. To a solution of this amine (62 mg, 0.223 mmol) and cyclohexane carboxylic acid ( 3∴μL, 0.245 mmol) in CH2Cl2 (4 mL) were added Py.BOP (140 mg, 0.268 mmol) and DIEA (58 μL, 0.335 mmol). The solution was stirred for 2 h, concentrated under reduced pressure, and the product purified by flash chromatography (40% EtOAc/hexanes). Evaporation left crude 57 as a white solid (95 mg) containing a small amount of unreacted cyclohexane acid impurity. This material was used in the next step without further purification. TLC Rf 0.58 (50% EtOAc/hexanes); 1H-NMR (400 MHz, CDCl3) δ 8.58 (s, 1 H ), 7.50 (d, 2H), 7.28 (t, 2H), 7.07 (t, 1H), 6.14 (d, 1H), 4.56 (dt, 1H), 3.64 (s, 3 H), 2.28 (t, 2H), 2.13 (tt, 1 H), 1.94 (m, 1H), 1.85 (m, 2H), 1.76 (m, 2H), 1.64 (m, 4H), 1.41 (m, 5H), 1.22 (m, 4H).
-
- To a solution of ester 57 (95 mg) in MeOH (2.5 mL) at 0° C. was added a solution of NaOH (1 M, 2.5 mL). A white precipitate formed upon addition, which was re-dissolved by the addition of THF (2.5 mL). Additional NaOH (1 M, 1.0 mL) was added after 3 h and the temperature maintained at 0° C. Upon complete disappearance of starting material by TLC analysis, the reaction contents were acidified with HC1 (1 N) to obtain a white precipitate. The supernatant was drawn off, and the solid filtered under aspiration. The combined liquors were extracted with EtOAc (3×5 mL), and the extracts combined, washed with brine, dried over MgSO4, and filtered. Concentration under reduced pressuxe left a white solid which was combined with the filter cake and dried under vacuum to obtain the carboxylic acid 58 (75 mg, 0.200 mmol, 90%). 1H-NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.98 (s, 1H), 7.90 (d, 1H), 7.58 (d, 1H), 7.28 (t, 2H), 7.02 (t, 1H), 4.33 (dt, 1H), 2.22 (tt, 1H), 2.17 (t, 2H), 1.67 (m, 6H), 1.60 (m, 2H), 1.46 (m, 2H), 1.22 (m, 9H).
-
- Acid 58 (70 mg, 0. 187 mmol), TBDPSO—NH2 (61 mg, 0.224 mmol), and DMAP (5 mg) were dissolved in CH2Cl2 (4 mL) and EDC (47 mg, 0.243 mmol) was added. The solution was stirred overnight. After concentration under reduced pressure, the material was purified by flash chromatography (50% EtOAc/hexanes). Evaporation of the combined product fractions gave a white foam (80 mg, 0. 131 mmol, 70%). To a solution of this protected hydroxamate in CH2Cl2 (2 mL) and THF (3 mL) was added TFA (0.25 mL) and stirred for 1.5 h. A new spot which stained immediately with FeCl3 was observed on TLC. The solution was concentrated and all volatiles removed under vacuum. The residue was triturated with EtOAc and obtain a white gel precipitate which was. transferred to a plastic tube with EtOAc (5 mL). The tube was centrifuged to form a pellet, the supernatant drained, and EtOAc (10 mL) added. The pellet was resuspended with sonication, then centrifuged again, the supernatant discarded, and the residue dried under vacuum. A white solid 59 (18 mg, 0.046 mmol, 35%) was obtained. 1H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H) 9.97 (s, 1H), 7.89 (d, 1H), 7.57 (d, 2H), 7.28 (t, 2H), 7.02 (t, 1H), 4.33 (dt, 1H), 2.22 (t, 2H), 1.91 (t, 2H), 1.61 (m, 6H), 1.68 (m, 2H), 1.45 (m, 2H), 1.21 (9H).
-
- This compound was prepared from suberic acid monomethyl ester in similar fashion to 48, with the use of 8-aminoquinoline. The crude residue obtained after TFA deprotection of the protected hydroxamate was taken up in a small volume of EtOAc and precipitated with hexanes to give 60 as a white solid (18 mg, 0.057 mmol, 21% from the carboxylic acid). 1H-NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 10.02 (s, 1H), 8.92 (dd, 1H), 8.61 (dd, 1H), 8.40 (dd, 1H), 7.65 (dd, 1H), 7.63 (dd, 1H), 7.56 (t, 1H), 2.56 (t, 1H), 1.93 (t, 1H), 1.63 (m, 2H), 1.49 (m, 2H), 1.28 (m, 4H). MS (ESI+) calcd for C17H21N3O3 315, found 316 [M+H]+.
-
- To a stirred suspension of NaH (60% disp., 197 mg, 4.913 mmol) in THF (25 mL) at 0° C. was added di-t-butyl malonate (1.00 mL, 4.466 mmol) and the mixture allowed to warm to ambient temperature. After 1 h, gas had ceased evolving and ethyl 6-bromohexanoate (0.88 mL, 4.913 mmol) was added dropwise. The reaction was brought to reflux overnight. The reaction was carefully quenched with H2O (10 mL) and diluted with EtOAc. After separation of the layers, the aqueous portion was extracted with EtOAc (3×10 mL). The extracts were pooled and washed with H,O, then brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave a yellow oil which was passed through a plug of silica gel (10% EtOAc/hexanes). Evaporation left a light yellow syrup 61 (1.52 g, 4.24 mol, 95%). TLC Rf 0.44 (10% EtOAc/hexanes); 1H-NMR (400 MHz, CDCl3) δ 4.10 (q, 2H), 3.08 (t, 1H), 2.26 (t, 2H), 1.76 (m, 2H), 1.60 (m, 2H), 1.43 (s, 18H), 1.32 (m, 4H), 1.23 (m, 3H).
-
- To a solution of triester 61 (500 mg, 1.395 mmol) in CH2Cl2 (20 mL) was added TFA (2.0 mL) and the reaction mixture stirred overnight. Volatile components were evaporated under vacuum, and the residue repeatedly dissolved in CH2Cl2 and evaporated to remove all traces of TFA. A solid 62 (327 mg, 1.33 mmol) was obtained and used directly in the next step without further purification. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 2H), 4.03 (q, 2H), 3.16 (t, 1H), 2.25 (t, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 1.25 (m, 4H), 1.16 (t, 3H).
-
- Diacid 62 (150 mg, 0.609 mmol), 8-aminoquinoline (211 mg, 1.462 mmol), and DMAP (5 mg) were dissolved in THF (6 mL). To this solution was added EDC (350 mg, 1.827 mmol) and the reaction allowed to proceed overnight. The mixture was concentrated under reduced pressure and the product purified by flash chromatography (40% EtOAc/hexanes). Evaporation of the combined product fractions left 63 as a light brown solid (100 mg, 0.201 mmol, 14%). 1H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 2H), 8.92 (dd, 2H), 8.64 (dd, 2H), 8.40 (dd, 2H), 7.68 (dd, 2H), 7.62 (dd, 2H), 7.57 (t, 2H), 4.35 (t, 1H), 3.98 (q, 2H), 2.24 (t, 2H), 2.00 (m, 2H), 1.51 (m, 2H), 1.37 (m, 4H), 1.12 (t, 3H).
-
- To a solution of ester 63 (94 mg, 0.212 mol) in MeOH (3 mL) and THF (1 mL) was added a solution of LiOH.H2O (44 mg, 1.062 mmol) in H2O (1 mL) and the mixture was stirred for 5 h. After acidification with HCl (1 N) to
pH 7, EtOAc (10 mL) was added and the layers separated. The aqueous portion was extracted with EtOAc (3×5 mL), and the extracts combined, washed with sat. NH4Cl (3 mL), H2O (3 mL), then brine, dried over MgSO4, and filtered. Concentration under reduced pressure left 64 as a white solid (94 mg, 0.200 mmol, 94%). TLC Rf 0.21 (50% EtOAc/hexanes); 1H-NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.85 (s, 2H), 8.93 (dd, 2H), 8.65 (dd, 2H), 8.40 (dd, 2H), 7.69 (dd, 2H), 7.63 (dd, 2H), 7.58 (t, 2H), 4.35 (t, 1H), 2.16 (t, 2H), 2.00 (m, 2H), 1.49 (m, 2H), 1.38 (m, 4H). -
- Acid 64 (94 mg, 0.200 mmol), TBDPSO—NH2 (74 mg, 0.272 mmol), and DMAP (5 mg) were dissolved in CH2Cl2 (4 mL) and EDC (57 mg, 0.295 mmol) was added. The solution was stirred overnight, then concentrated under reduced pressure. Purification by flash chromatography (30-50% EtOAc/hexanes) and evaporation of the combined product fractions gave a white foam. To a solution of this protected hydroxamate in CH2Cl2 (4 mL) was added TFA (0.2 mL) and the solution stirred for 4 h. TLC indicated complete consumption of starting material and a new spot that stained with FeCl3. The solution was concentrated under reduced pressure, and the residue dissolved in a minumum of EtOAc. Addition of hexanes gave a white precipitate, from which the mother liquor was removed. After rinsing with hexanes, the residue was dried under vacuum to leave 65 as a white solid (30 mg, 0.061 mmol, 22% from the carboxylic acid). 1H-NMR (400 MHz, CDCl3) δ 10.85 (s, 2H), 10.30 (s, 1H), 8.93 (dd, 2H), 8.65 (dd, 2H), 8.40 (dd, 2H), 7.69 (dd, 2H), 7.63 (dd, 2H), 7.58 (t, 2H), 4.35 (t, 1H), 1.99 (m, 2H), 1.92 (t. 2H), 1.48 (m, 2H), 1.35 (m, 4H). MS (ESI+) calcd for C27H27N5O4 485, found 486 [M+H]+.
-
- The title compound was made from diacid 62 as analogous to 65. 1H-NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 10.34 (s, 1H), 8.95 (dd, 2H), 8.74 (s, 2H), 7.93 (dd, 2H), 7.64 (dd, 2H), 7.56 (dd, 2H), 3.71 (t, 1H), 1.96 (m, 4H), 1.51 (m, 2H), 1.34 (m, 4H).
-
- To a solution of 6-bromohexanoyl chloride (1.00 mL, 6.53 mmol) in THF (35 mL) at 0° C. was added dropwise a solution of aniline (0.60 mL, 6.53 mmol) and TEA (1.09 mL, 7.84 mmol) in THF (5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was filtered, the solids rinsed with EtOAc, and the filtrate reduced under vacuum. The residue was partitioned between H2O (15 mL) and EtOAc (20 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL) and the organic layers combined, washed with HCl (1 N), brine, dried over MgSO4, and filtered. Concentration under reduced pressure left a brown oil which was passed through a plug of silica gel (30% EtOAc/hexanes) under aspiration. Concentration under reduced pressure left 67 as a solid (1.55 g, 5.74 mmol, 88%). TLC Rf 0.36 (25% EtOAc/hexanes); 1H-NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.57 (d, 2H), 7.27 (t, 2H), 7.01 (t, 1H), 3.53 (t, 2H), 2.30 (t, 2H), 1.81 (t, 2H), 1.63 (m, 2H), 1.42 (m, 2H); MS (ESI+) calcd for C12H16BrNO 268+270, found 269+271 [M+H]+.
-
- Bromide 67 (200 mg, 0.74 mmol), potassium thioacetate (110 mg, 0.96 mmol), and sodium iodide (10 mg) were combined in THF (625 mL) and the vigorously stirred mixture brought to reflux overnight. The reaction mixture was concentrated, the passed through a plug of silica gel (20% EtOAc/hexanes, 200 mL) under aspiration. Evaporation under reduced pressure left 68 as an orange crystalline solid (190 mg, 0.72 mmol, 97%). TLC Rf 0.22 (25% EtOAc/hexanes); 1H-NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.56 (d, 2H), 7.27 (t, 2H), 7.00 (t, 1H) 2.82 (t, 2H), 2.30 (s, 3H), 2.28 (t, 2H), 1.57 (m, 2H), 1.52 (m, 2H), 1.35 (m, 2H).
-
- 6-aminohexanoic acid (904 mg, 6.89 mmol) and NaOH (415 mg, 10.34 mmol) were dissolved in H2O (30 mL) and cooled to 0-5 ° C. Methanesulfonyl chloride (0.586 mL, 7.58 mmol) was added dropwise and the reaction mixture stirred for 2 h, then warmed to ambient temperature and stirred for an additional 2 h. The mixture was acidified with HCl (1 N) and extracted with EtOAc (3×15 mL). The extracts were combined, washed with H2O, then brine, dried over MgSO4, and filtered. Evaporation under reduced pressure gave 69 as a white crystalline solid (207 mg, 0.99 mmol, 14%). 1H-NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 6.91 (t, 1H), 2.90 (dt, 2H), 2.87 (s, 3H), 2.20 (t, 2H), 2.48 (m, 2H), 2.43 (m, 2H), 1.27 (m, 2H).
-
- To a solution of acid 69 (100 mg, 0.48 mmol), aniline (60 μL, 0.66 mmol), and DMAP (5 mg) in THF (5 mL) was added EDC (119 mg, 0.57 mmol). The reaction mixture was stirred overnight, then partitioned between H2O (10 mL) and EtOAc (15 mL). The layers were separated, and the aqueous portion extracted with EtOAc (3×10 mL). The organic fractions were combined, washed with sat. NH4Cl (5 mL), then brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave 70 as a white crystalline solid (130 mg, 0.46 mmol, 95%). 1H-NMR (4.0.0M Hz, DMSO-d6) δ 9.84 (s, 1H), 7.57 (d, 2H), 7.26 (t, 2H), 7.00 (t, 1H), 6.92 (t, 1H), 2.91 (dt, 2H) 2.85 (s, 3H), 1.58 (m, 2H), 1.47 (m, 2H), 1.31 (m, 2H).
-
- To a solution of suberic acid monomethyl ester (1.00 g, 5.31 mmol) in THF (15 mL) was added oxalyl chloride (2 mL) followed by DMF (1 drop). The solution was stirred for 2 h, then concentrated under reduced pressure. Volatiles were removed under high vacuum overnight, leaving a yellow oil (1.08 g, 5.22 mmol, 98%). This crude acid chloride was then transformed into the trifluoromethyl ketone by a literature method as follows (65). To a solution of the acid chloride (1.08 g, 5.22 mmol) in CH2Cl2 (45 mL) at 0° C. were added trifluoroacetic anhydride (4.64 mL, 32.81 mmol) and pyridine (3.54 mL, 43.74 mmol). The mixture was allowed to warm to ambient temperature and stirred for 2 h. After returning to 0° C., ice-cold H2O (20 mL) was added carefully. Additional H2O (100 mL) was added and the layers separated. The aqueous phase was extracted with CH2Cl2 (2×30 mL) and the organic layers combined, washed with brine, dried over MgSO4, and filtered. Evaporation under reduced pressure left a brown oil, which was purified by flash chromatography (2-4% MeOH/CH2Cl2) to give 71 as a clear oil (641 mg, 2.67 mmol, 49%). TLC Rf 0.24 (2% MeOH/CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 2.71 (t, 2H), 2.31 (t, 2H), 1.65 (m, 4H), 1.35 (m, 4H).
-
- To solution of ester 71 (300 mg, 1.25 mmol) in THF (18 mL) was added a solution of LiOH.H2O (262 mg, 6.24 mmol) in H2O (6 mL) and the suspension was stirred overnight. The mixture was then acidified with HCl (1 N) to
pH 2 and then extracted with EtOAc (3×15 mL). The extracts were combined, washed with brine, dried over MgSO4, and filtered. Concentration under reduced pressure left a white solid (211 mg, 0.93 mmol, 75%). To a solution of this acid (109 mg, 0.48 mmol), EDC (111 mg, 0.58 mmol), and DMAP (5 mg) in CH2Cl2 (5 mL) was added aniline (49 μL, 0.53 mmol) and the reaction allowed to proceed overnight. The solution was partitioned between H2O (5 mL) and EtOAc (10 mL). The layers were separated, and the aqueous phase extracted with EtOAc (3×5 mL). The organic portions were combined, washed with brine, dried over MgSO4, and filtered. Evaporation under reduced pressure left a solid which was purified by preparative TLC (30% EtOAC/hexanes) with isolation of the least polar band by EtOAc extraction. The extract was concentrated to give 72 as a yellowish solid (92 mg, 0.31 mmol, 65%). TLC Rf 0.48 (50% EtOAc/hexanes); 1H-NMR (400 MHz, CDCl3) δ 7.51 (d, 2H), 7.32 (t, 2H), 7.10 (t, 1H), 2.72 (t, 2H), 2.36 (t, 2H), 1.72 (m, 4H), 1.40 (m, 4H); 19F-NMR (? MHz, CDCl3) −78.40 (s, 3F); MS (APCI+) calcd for C15H19F3NO2 301, found 325 [M+Na]+. -
- To a solution of N-Boc-6-aminohexanoic acid (2.50 g, 10.81 mmol), EDC (2.69 g, 14.05 nimol), and DMAP (20 mg) in CH2Cl2 (100 mL) was added aniline (1.04 mL, 11.35 mmol) and the mixture stirred overnight. The solution was evaporated under reduced pressure to a small volume, then partitioned between H2O (20 mL) and EtOAc (30 mL). The layers were separated, and the aqueous phase extracted with EtOAc (3×15 mL). The organic portions were combined, washed with sat. NH4Cl (5 mL), then brine, dried over MgSO4, and filtered. Concentration under reduced pressure left pure 73 as a white solid (3.14 g, 10.25 mmol, 95%). TLC Rf 0.40 (50% EtOAc/hexanes); 1H-NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.56 (d, 2H), 7.26 (t, 2H), 7.00 (t, 1H), 6.74 (t, 1H), 2.89 (dt, 2H), 2.27 (t, 2H), 1.56 (m, 2H), 1.38 (m, 2H), 1.35 (s, 9H), 1.25 (m, 2H).
-
- To a solution of carbamate 73 (300 rng, 0.98 mmol) in CH2Cl2 (15 mL) was added TFA (0.75 mL) and the solution stirred overnight. Complete consumption of starting material was confirmed by TLC. The mixture was evaporated under reduced pressure to remove all volatiles, leaving an off-white solid (295 mg, 0.92 mmol, 94%). Crude 74 was used without further purification.
-
- To a stirred suspension of ammonium salt 74 (197 mg, 0.62 mmol) and DIEA (148 μL, 0.85 mmol) in CH2Cl2 (7 mL) at 0C was added dropwise dimethyl chlorophosphate (77 μL, 0.72 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The solution was diluted with H2O (10 mL) and the layers separated. The aqueous phase was extracted with CH2Cl2 (3×10 mL), the organic portions combined, washed with sat. NH4Cl (5a), then brine, dried over MgSO4, and filtered. After concentration, the residue was purified by flash chromatography (2-5% MeOH/CH2Cl2), and the fractions containing the more polar of the two UV-active bands on TLC were combined and concentrated, giving 75 as a clear oil (40 mg, 0.13 mmol, 20%). TLC Rf 0.23 (5% MeOH/CH2Cl2); 1H-NMR (400 MHz, DMSO-d) δ 9.84 (s, 1H), 7.57 (d,2H), 7.26 (t, 2H), 7.00 (t, 1H), 4.90 (dt, 1H), 3.51 (d, 6H), 2.71 (m, 2H), 2.28 (t, 2H), 1.56 (m, 2H), 1.40 (m, 2H), 1.29 (m, 2H).
-
- To a suspension of ammonium salt 74 (155 mg, 0.48 mmol) in CH3CN (8 mL) were added DIEA (0.21 mL) and methyl methylphosphonochloridate (77 mg, 0.600 mmol). The reaction mixture was stirred overnight, during which time it clarified. The solution was partitioned between H2O (10 mL) and EtOAc (15 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL) and the organics combined, washed with sat. NH4Cl (1×5 mL), then brine, dried over MgSO4, and filtered. The product was purified by flash chromatography (3-10% MeOH/CH2Cl2), and the fractions containing the more polar spot were combined and concentrated to give 76 as a clear oil (102 mg, 0.34 mmol, 71%). TLC Rf 0.16 (58 MeOH/CH2Cl2); 1H-NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.57 (d, 2H), 7.26 (t, 2H), 7.00 (t, 1H), 4.52 (dt, 1H), 3.43 (d, 3H), 2.73 (m, 2H), 2.28 (t, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 1.28 (m, 2H), 1.26 (d, 3H).
-
- Diethyl 3-bromophenyl malonate was prepared according to the procedures of Cehnevert, R. and Desjardins, M. Can. J. Chem. 1994. 72, 3212-2317. 1H NMR (CDCl3, 300 MHz) δ 7.6 (s, 1H), 7.50 (d, 1H, J =7.9 Hz), 7.37 (d, 1H, J =7.9 Hz), 7.26 (t, 1H, J =7.9 Hz), 4.58 (s, 1H), 4.22 (m, 4H), 1.29 (t, J=10 Hz).
-
- Diethyl 3-bromophenyl malonate (I g, 3.2 mmol) was added to aniline (5 mL). The reaction mixture was purged with Ar (g) and brought to reflux for 2h. After cooling, the reaction mixture was diluted with 10% HCl (20 mL) and ethyl acetate (50 mL). The organic layer was separated and concentrated to afford 3-bromophenyl malonyl di(phenylamide) as a white powder. (540 mg, 1.3 mmol, 42%). 1H NMR (d6-DMSO, 300 MHz) δ 10.3 (bs, 2H), 7.65 ) s, 1H), 7.60 (d, 4H, J=7.9 Hz), 7.54 (d, 1H, J=7.9 Hz), 7.46 (d, 1H, J=7.8 Hz), 7.35 (t, 1H, J=7.8Hz), 7.31 (t, 4H, J=7.8 Hz), 7.06 (t, 2H, J=7.6 Hz), 4.91 (9s, 1H).
-
- 3-bromophenyl malonyl di(phenylamide) (500 mg, 1.22 mmol), acrylic acid (115 mg, 1.6 mmol, 1.3 equiv.), Pd (OAc)2 (2 mg), tri-o-tolyl phosphone (20 mg), tributyl amine (0.6 mL) and xylenes (5 mL) were heated to 120° C. for 6 h in a sealed vessel. After cooling, the reaction was diluted with 5% HCl (10 mL) and ethyl acetate (50 mL). The organic layer was separated, filtered and on standing 3-(malonyl di(phenyl amide)) cinnamic acid precipitated as a white powder (450 mg, 1.12 mmol, 92%). 1H-NMR (d6-DMSO, 300 MHz, 6 12.4 (bs, 1H), 10.3 (bs, 2H), 7.73 (s, 1H), 7.7-7.5 (m, 6H), 7.52 (d, 1H, J=7.7 Hz), 7.43 (t, 1H, J=7.6 Hz), 7.31 (t, 4H, J=7.5Hz), 7.06 (t, 2H, J=7.4 Hz), 6.52 (d, 1H, J=16 Hz), 4.95 (s, 1H). APCI-MS 401 (M+1).
-
- 3-(malonyl di(phenylamide))cinnamic acid (200 mg, 0.5 mmol) was dissolved in dry CH2Cl2 (10 mL). Isobutylchloroformate (0.10 mL, 0.77 mmol) and triethylamine (0.20 mL) were added at 0° C. with stirring. After 2 h at 25° C., O-(t-butyldiphenyl silyl)hydroxylamine was added and the mixture was stirred an additional 4h. The crude reaction mixture was applied directly to a pad a silica gel (15 g) and elution with 20% ethyl acetate/hexanes afforded the corresponding silyl protected hydroxamic acid (Rf=0.58, 50% ethyl acteate/hexanes) as a foam. This was treated directly with 10% trifluoracetic acid in dichloromethane (10 mL) for 4 h. The solvents were concentrated at 50° C. by rotavap and the residue was suspended in ethyl ether (10 mL). Filtration of the resultant precipitate afforded compound 77 as a white powder (150 mg, 0.365 mmol, 73%). 1H NMR (d6-DMSO, 300 MHz, δ 10.8 (bs, 0.5H), 10.2 (bs, 2H), 9.06 (bs, 0.5H), 7.7-7.55 (m, 5H), 7.53-7.38 (m, 4H), 7.31 (t, 4H, J=7.7 Hz), 7.06 (t, 2H, J=7.3 Hz), 6.50 (d, 1H, J=16Hz), 4.92 (s, 1H). APCI-MS 416 (M+1).
- The effect of compound 77 on MEL cell differentiation and Histone Deacetylase activity is shown in Table 2. Compound 77 corresponds to structure 683 in Table 2. As evident from Table 2, compound 77 is expected to be a highly effective cytodifferentiating agent.
- Results
- All the compounds which were prepared were tested. Table 2 below shows the results of testing of only a subgroup of compounds. Table 2 is compiled from experiments similar to the experiments described in Examples 7-10 above. The tested compounds were assigned structure numbers as shown in Table 2. The structure numbers were randomly assigned and do not correlate to the compound numbers used elsewhere in this disclosure.
- The results shown in Table 2 verify the generat accuracy of the predictive principals for the design of compounds having cell differentiation and HDAC inhibition activity discuss.ed above in this disclosure. Based on the principals and synthesis schemes disclosed, a number of additional compounds can readily be designed, prepared and tested for cell differentiation and HDAC inhibition activity.
-
FIGS. 11 a-f show the effect of selected compounds on affinity purified human epitope-tagged (Flag) HDAC1. The effect was assayed by incubating the enzyme preparation in the absence of substrate on ice for 20 minutes with the indicated amounts of compound. Substrate([3H]acetyl-labeled murine erythroleukemia cell-derived histones) was added and the samples were incubated for 20 minutes at 37° C. in a total volume of 30 μl. The reactions were then stopped and released acetate was extracted and the amount of radioactivity released determined by scintillation counting. This is a modification of the HDAC Assay described in Richon et al. 1998 (39).TABLE 2 Inhibition data of selected compounds. MEL Diff Cells/ HDAC inh NO: Structure Range Opt. % B+ ml × 10−5 Range ID50 SAHA (390) 0.5 to 50 μM 2.5 μM 68 3.6 0.001 to 100 μM 200 nM 654 0.1 to 50 μM 200 nM 44 9 0.0001 to 100 μM 1 nM 655 0.1 to 50 μM 400 nM 16 3.3 0.01 to 100 μM 100 nM 656 0.4 to 50 μM 0 0.01 to 100 μM >100 μm 657 0.4 to 50 μM 0 0.01 to 100 μM >100 μm 658 0.1 to 50 μM 40 nM 8 13 0.0001 to 100 μM 2.5 nM 659 0.4 to 50 μM 0 0.01 to 100 μM 10 μM 660 0.2 to 12.5 μM 800 nM 27 0.01 to 100 μM 50 nM 661 0.1 to 50 μM 500 nM 7 0.01 to 100 μM 20 nM 662 0.2 to 50 μM 0 0.0001 to 100 μM >100 μM 663 0.2 to 50 μM 200 nM 43 7 0.001 to 100 μM 100 nM 664 0.2 to 50 μM 400 nM 33 22 0.001 to 100 μM 50 nM 665 0.1-50 μM 150 nM 24 30 0.001 to 100 μM 50 nM 666 0.1-50 μM 150 nM 31 28 0.001 to 100 μM 100 nM 667 0.02-10 μM 80 nM 27 2 0.001 to 100 μM 50 nM 668 0.02-10 μM 10 μM 11 4.7 0.001 to 100 μM 100 nM 669 0.8 to 50 μM 4 μM 11 16.0 0.001 to 100 μM 10 μM 670 0.4 to 50 μM No effect up to 25 μM — 13.0 0.001 to 100 μM >100 μM 671 0.4 to 50 μM 3.1 μM 35 12.5 0.001 to 100 μM 200 nM 672 0.8 to 50 μM 0 No inh 0.01 to 100 μM 100 μM 673 0.8 to 50 μM 0 No inh 0.01 to 100 μM 100 μM 674 0.8 to 50 μM 0 Dead at 25 μM 0.01 to 100 μM 50 μM 675 0.8 to 50 μM 0 No inh 0.001 to 100 μM >100 μM 676 0.8 to 50 μM 0 No inh 0.01 to 100 μM 100 μM 677 0.5 to 25 μM 1.6 μM 23 4.5 0.001 to 100 μM 5 nM 678 0.8 to 50 μM 0 No inh 0.001 to 100 μM >100 μM 679 0.8 to 50 μM 0 No inh 0.001 to 100 μM >100 μM 680 0.01 to 100 μM >100 μM 681 0.8 to 50 μM 3 μM 3 2.5 0.01 to 100 μM 200 nM 682 0.8 to 50 μM 50 μM 8 1.1 0.01 to 100 μM 150 nM 683 0.01 to 0.1 μM 20 nM 9 9.0 0.001 to 100 μM 1 nM 684 0.4 to 50 μM 0 No inh 0.01 to 100 μM 100 μM 685 0.125 to 5 μM 1.0 μM 20 1.0 0.01 to 100 μM 150 nM 686 0.4 to 50 μM 0 No inh 0.01 to 100 μM 100 μM 687 0.125 to 5 μM 0 No inh 0.01 to 100 μM 200 μM 688 0.4 to 50 μM 0 No inh 0.01 to 100 μM >100 μM 689 5.0 to 40 μM 35 μM 48 0.01 to 100 μM 200 nM 690 5.0 to 40 μM 10 μM 38 0.01 to 100 μM 150 nM 691 1.0 to 25 μM 0 No inh 0.01 to 100 μM 100 nM 692 0.03 to 5 μM 1 μM 27 0.01 to 100 μM 1 nM 693 0.4 to 50 μM 0 No inh 0.01 to 100 μM >100 μM -
- 1. Sporn, M. B., Roberts, A. B., and Driscoll, J. S. (1985) in Cancer: Principles and Practice of Oncology, eds. Hellman, S., Rosenberg, S. A., and DeVita, V. T., Jr., Ed. 2, (J. B. Lippincott, Pa.) P. 49.
- 2. Breitman, T. R., Selonick, S. E., and Collins, S. J. (1980) Proc. Natl. Acad. Sci. USA 77: 2936-2940.
- 3. Olsson, I. L. and Breitman, T. R. (1982) Cancer Res. 42: 3924-3927.
- 4. Schwartz, E. L. and Sartorelli, A. C. (1982) Cancer Res. 42:2651-2655.
- 5. Marks, P. A., Sheffery, M., and Rifkind, R. A. (1987) Cancer Res. 47: 659.
- 6. Sachs, L. (1978) Nature (Lond.) 274: 535.
- 7. Friend, C., Scher, W., Holland, J. W., and Sato, T. (1971) Proc. Natl. Acad. Sci . (USA) 68: 378-382.
- 8. Tanaka, M., Levy, J., Terada, M., Breslow, R., Rifkind, R. A., and Marks, P. A. (1975) Proc. Natl. Acad. Sci. (USA) 72: 1003-1006.
- 9. Reuben, R. C., Wife, R. L., Breslow, R., Rifkind, R. A., and Marks, P. A. (1976) Proc. Natl. Acad. Sci. (USA) 73: 862-866.
- 10. Abe, E., Miyaura, C., Sakagami, H., Takeda, M., Konno, K., Yamazaki, T., Yoshika, S., and Suda, T. (1981) Proc. Natl Acad Sci. (USA) 78: 4990-4994.
- 11. Schwartz, E. L., Snoddy, J. R., Kreutter, D., Rasmussen, H., and Sartorelli, A. C. (1983) Proc. Am. Assoc. Cancer Res. 24: 18.
- 12. Tanenaga, K., Hozumi, M., and Sakagami, Y. (1980) Cancer Res. 40: 914-919.
- 13. Lotem, J. and Sachs, L. (1975) Int . J. Cancer 15: 731-740.
- 14. Metcalf, D. (1985) Science, 229: 16-22.
- 15. Scher, W., Scher, B. M., and Waxman, S. (1983) Exp. Hematol. 11: 490-498.
- 16. Scher, W., Scher, B. M., and Waxman, S. (1982) Biochem. & Biophys. Res. Comm. 109: 348-354.
- 17. Huberman, E. and Callaham, M. F. (1979) Proc. Natl. Acad. Sci. (USA) 76: 1293-1297.
- 18. Lottem, J. and Sachs, L. (1979) Proc. Natl. Acad. Sci. (USA) 76: 5158-5162.
- 19. Terada, M., Epner, E., Nudel, U., Salmon, J., Fibach, E., Rifkind, R. A., and Marks, P. A. (1978) Proc. Natl. Acad. Sci. (USA) 75: 2795-2799.
- 20. Morin, M. J. and Sartorelli, A. C. (1984) Cancer Res. 44: 2807-2812.
- 21. Schwartz, E. L., Brown, B. J., Nierenberg, M., Marsh, J. C., and Sartorelli, A. C. (1983) Cancer Res. 43: 2725-2730.
- 22. Sugano, H., Furusawa, M., Kawaguchi, T., and Ikawa, Y. (1973) Bibl. Hematol. 39: 943-954.
- 23. Ebert, P. S., Wars, I., and Buell, D. N. (1976) Cancer Res. 36: 1809-1813.
- 24. Hayashi, M., Okabe, J., and Hozumi, M. (1979) Gann 70: 235-238.
- 25. Fibach, E., Reuben, R. C., Rifkind, R. A., and Marks, P. A. (1977) Cancer Res. 37: 440-444.
- 26. Melloni, E., Pontremoli, S., Damiani, G., Viotti, P., Weich, N., Rifkind, R. A., and Marks, P. A. (1988) Proc. Natl. Acad. Sci. (USA) 85: 3835-3839.
- 27. Reuben, R., Khanna, P. L., Gazitt, Y., Breslow, R., Rifkind, R. A., and Marks, P. A. (1978) J. Biol. Chem. 253: 4214-4218.
- 28. Marks, P. A. and Rifkind, R. A. (1988) International Journal of Cell Cloning 6: 230-240.
- 29. Melloni, E., Pontremoli, S., Michetti, M., Sacco, O., Cakiroglu, A. G., Jackson, J. F., Rifkind, R. A., and Marks, P. A. (1987) Proc. Natl. Acad. Sciences (USA) 84: 5282-5286.
- 30. Marks, P. A. and Rifkind, R. A. (1984) Cancer 54: 2766-2769.
- 31. Egorin, M. J., Sigman, L. M., VanEcho, D. A., Forrest, A., Whitacre, M. Y., and Aisner, J. (1987) Cancer Res. 47: 617-623.
- 32. Rowinsky, E. W., Ettinger, D. S., Grochow, L. B., Brundrett, R. B., Cates, A. E., and Donehower, R. C. (1986) J. Clin. Oncol. 4: 1835-1844.
- 33. Rowinsky, E. L., Ettinger, D. S., McGuire, W. P., Noe, D. A., Grochow, L. B., and Donehower, R. C. (1987) Cancer Res. 47: 5788-5795.
- 34. Callery, P. S., Egorin, M. J., Geelhaar, L. A., and Nayer, M. S. B. (1986) Cancer Res. 46: 4900-4903.
- 35. Young, C. W., Fanucchi, M. P., Walsh, T. B., Blatzer, L., Yaldaie, S., Stevens, Y. W., Gordon, C., Tong, W., Rifkind, R. A., and Marks, P. A. (1988) Cancer Res. 48: 7304-7309.
- 36. Andreeff, M., Young, C., Clarkson, B., Fetten, J., Rifkind, R. A., and Marks, P. A. (1988) Blood 72: 186a.
- 37. Marks, P. A., Richon, V. M., Breslow, R., Rifkind, R. A., Life Sciences 1999, 322: 161-165.
- 38. Yoshida et a 1., 1990, J. Biol. Chem. 265: 17174-17179.
- 39. Richon, V. M., Emiliani, S., Verdin, E., Webb, Y., Breslow, R., Rifkind, R. A., and Marks, P. A., Proc. Natl. Acad. Sci.(USA) 95: 3003-3007 (1998).
- 40. Nishino, N. et. al. Chem. Pharm. Bull. 1996, 44, 212-214.
- 41. U.S. Pat. No. 5,369,108, issued Nov. 29, 1994.
- 42. Kijima et a 1., 1993, J. Biol. Chem. 268: 22429-22435.
- 43. Lea et al., 1999, Int. J. Oncol. 2: 347-352.
- 44. Kim et al., 1999, Oncogene 15: 2461-2470.
- 45. Saito et al., 1999, Proc. Natl. Acad. Sci. USA 96: 4592-4597.
- 46. Lea and Tulsyan, 1995, Anticancer Res. 15: 879-883.
- 47. Nokajima et al., 1998, Exp. Cell Res. 241:126-133.
- 48. Kwon et al., 1998, Proc. Natl. Acad. Sci. USA 233356-3361.
- 49. Richon et al, 1996, Proc. Natl. Acad. Sci. USA 93: 5705-5708.
- 50. Kim et al., 1999, Oncogene 18:2461-2470.
- 51. Yoshida et al., 1995, Bioessays 17: 423-430.
- 52. Yoshida & Beppu, 1988, Exp. Cell. Res. 177: 122-131.
- 53. Warrell et al., 1998, J. Natl. Cancer Inst. 90:1621-1625.
- 54. Desai et al., 1999, Proc. ACCR 40: abstract #2396.
- 55. Cohen et al., Antitumor Res., submitted.
- 56. D. W. Christianson and W. N. Lipscomb, “The Complex Between Carboxypeptidase A and a Possible Transition-state Analogue: Mechanistic Inferences from High-Resolution X-ray Structures of Enzyme-inhibitor Complexes,” J. Am. Chem. Soc. 1986, 108, 4998-5003.
- 57. G. H. S. Prakash and A. K. Yudin, “Perfluoroalkylation with Organosilicon Reagents” Chem. Rev. 1997, 97, 757-786.
- 58. J.-C. Blazejewski, E. Anselmi, and M. P. Wilmshurst, “Extending the Scope of Ruppert's Reagent: Trifluoromethylation of Imines,” Tet.
Letters 1999, 40, 5475-5478. - 59. R. J. Lindehan and D. M. Graves, “Oxidation of Fluoroalkyl-Substituted Carbinols by the Dess-Martin Reagent,” J. Org. Chem. 1989, 54, 661-668.
- 60. N. E. Jacobsen and P. A. Bartlett, “A Phosphonamidate Dipeptide Analogue as an Inhibitor of Carboxypeptidase A,” J. Am. Chem. Soc. 1981, 303, 654-657.
- 61. S. Lindskog, L. E. Henderson, K. K. Kannan, A. Liljas, P. O. Nyman, and B. Strandberg, “Carbonic Anhydrase”, in The Enzymes, 3rd edition, P. D. Boyer, ed., 1971, vol. V, pp.587-665, see p. 657.
- 62. Durrant, G.; Greene, R. H.; Lambeth, P. F.; Lester, M. G.; Taylor, N. R., J. Chem. Soc., Perkin Trans. 1 1983, 2211-2214.
- 63. Burden, R. S.; Crombie, L., J. Chem. Soc. (C) 1969, 2477.
- 64. Farquhar, D.; Cherif, A.; Bakina, E.; Nelson, J. A., J. Med. Chem., 1998, 41, 965-972.
- 65. Boivin, J.; El Kaim, L.; Zard, S. Z., Tet. Lett. 1992, 33, 1285-1288.
- 66. Finnin, M. S. et al., Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188-93 (1999).
- 67. Webb, Y. et al., Photoaffinity labeling and mass spectrometry identify ribosomal protein 53 as a potential target for hybrid polar cytodifferentiation agents. J. Biol. Chem. 274, 14280-14287 (1997).
- 68. Butler, L. M. et al., Suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylase, suppresses the growth of the CWR22 human prostate cancer xenograft submitted (2000).
Claims (13)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/474,042 US20070010669A1 (en) | 1999-09-08 | 2006-06-22 | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15275599P | 1999-09-08 | 1999-09-08 | |
US20868800P | 2000-06-01 | 2000-06-01 | |
US09/645,430 US6511990B1 (en) | 1999-09-08 | 2000-08-24 | Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US10/281,875 US7126001B2 (en) | 1999-09-08 | 2002-10-25 | Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US11/474,042 US20070010669A1 (en) | 1999-09-08 | 2006-06-22 | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/281,875 Continuation US7126001B2 (en) | 1999-09-08 | 2002-10-25 | Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20070010669A1 true US20070010669A1 (en) | 2007-01-11 |
Family
ID=26849835
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/645,430 Expired - Lifetime US6511990B1 (en) | 1999-09-08 | 2000-08-24 | Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US10/281,875 Expired - Fee Related US7126001B2 (en) | 1999-09-08 | 2002-10-25 | Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US11/473,839 Abandoned US20070010536A1 (en) | 1999-09-08 | 2006-06-22 | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US11/474,042 Abandoned US20070010669A1 (en) | 1999-09-08 | 2006-06-22 | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US11/474,043 Expired - Fee Related US7345174B2 (en) | 1999-09-08 | 2006-06-22 | Cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/645,430 Expired - Lifetime US6511990B1 (en) | 1999-09-08 | 2000-08-24 | Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US10/281,875 Expired - Fee Related US7126001B2 (en) | 1999-09-08 | 2002-10-25 | Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US11/473,839 Abandoned US20070010536A1 (en) | 1999-09-08 | 2006-06-22 | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/474,043 Expired - Fee Related US7345174B2 (en) | 1999-09-08 | 2006-06-22 | Cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
Country Status (19)
Country | Link |
---|---|
US (5) | US6511990B1 (en) |
EP (1) | EP1231919B1 (en) |
JP (1) | JP2003509343A (en) |
KR (1) | KR20020059393A (en) |
CN (1) | CN1378450A (en) |
AU (1) | AU6932700A (en) |
BR (1) | BR0014254A (en) |
CA (1) | CA2383999A1 (en) |
EA (2) | EA007649B1 (en) |
HU (1) | HUP0202707A3 (en) |
IL (1) | IL148497A0 (en) |
MX (1) | MXPA02002505A (en) |
NZ (1) | NZ517613A (en) |
PL (1) | PL200861B1 (en) |
SK (1) | SK3302002A3 (en) |
TR (1) | TR200201052T2 (en) |
UA (1) | UA74345C2 (en) |
WO (1) | WO2001018171A2 (en) |
YU (1) | YU22402A (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060241129A1 (en) * | 1999-09-08 | 2006-10-26 | Ronald Breslow | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
WO2009045440A1 (en) | 2007-10-01 | 2009-04-09 | Lixte Biotechnology Holdings, Inc. | Hdac inhibitors |
US20100030858A1 (en) * | 2008-08-04 | 2010-02-04 | Chasin C Scott | Method and system for centralized contact management |
CN101894348A (en) * | 2010-07-20 | 2010-11-24 | 中兴通讯股份有限公司 | Self-expanded online transaction system and implementing method thereof |
US20100317739A1 (en) * | 2007-12-14 | 2010-12-16 | Brown Milton L | Histone deacetylase inhibitors |
US7998957B2 (en) | 2007-02-06 | 2011-08-16 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicylcoheptenes, their preparation and use |
US8058268B2 (en) | 2008-08-01 | 2011-11-15 | Lixte Biotechnology, Inc. | Neuroprotective agents for the prevention and treatment of neurodegenerative diseases |
US8227473B2 (en) | 2008-08-01 | 2012-07-24 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
WO2013052110A1 (en) * | 2011-10-03 | 2013-04-11 | The Trustees Of Columbia University In The City Of New York | Novel molecules that selectively inhibit histone deacetylase 6 relative to histone deacetylase 1 |
US20150231049A1 (en) * | 2011-10-31 | 2015-08-20 | Avon Products, Inc. | Cosmetic Use of N-Heteroarylbisamide Analogs and Related Compounds |
US9890136B2 (en) | 2013-12-23 | 2018-02-13 | The Trustees Of Columbia University In The City Of New York Memorial Sloan-Kettering Cancer Center | Selective HDAC6 inhibitors |
US11931354B2 (en) | 2013-04-09 | 2024-03-19 | Lixte Biotechnology, Inc. | Formulations of oxabicycloheptanes and oxabicycloheptenes |
Families Citing this family (145)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6822267B1 (en) * | 1997-08-20 | 2004-11-23 | Advantest Corporation | Signal transmission circuit, CMOS semiconductor device, and circuit board |
AU3979200A (en) * | 1999-04-09 | 2000-11-14 | British Biotech Pharmaceuticals Limited | Antimicrobial agents |
KR20020070285A (en) * | 1999-11-23 | 2002-09-05 | 메틸진, 인크. | Inhibitors of histone deacetylase |
PE20020354A1 (en) | 2000-09-01 | 2002-06-12 | Novartis Ag | HYDROXAMATE COMPOUNDS AS HISTONE-DESACETILASE (HDA) INHIBITORS |
AU9013101A (en) | 2000-09-29 | 2002-04-22 | Prolifix Ltd | Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors |
EP2083005A1 (en) | 2000-09-29 | 2009-07-29 | TopoTarget UK Limited | Carbamic acid compounds comprising an amide linkage as HDAC inhibitors |
GB0023983D0 (en) | 2000-09-29 | 2000-11-15 | Prolifix Ltd | Therapeutic compounds |
US7312247B2 (en) | 2001-03-27 | 2007-12-25 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
US7842727B2 (en) * | 2001-03-27 | 2010-11-30 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
US8026280B2 (en) * | 2001-03-27 | 2011-09-27 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
US7314953B2 (en) * | 2001-03-27 | 2008-01-01 | Errant Gene Therapeutics, Llc | Treatment of lung cells with histone deacetylase inhibitors |
CA2465075A1 (en) | 2001-06-14 | 2002-12-27 | Sloan-Kettering Institute For Cancer Research | Hdac9 polypeptides and polynucleotides and uses thereof |
PT1426054E (en) | 2001-08-21 | 2011-12-06 | Astellas Pharma Inc | Medicinal use of histone deacetylase inhibitor and method of evaluating antitumor effect thereof |
AU2002340253C1 (en) * | 2001-10-16 | 2011-03-31 | Sloan-Kettering Institute For Cancer Research | Treatment of neurodegenerative diseases and cancer of the brain |
AU2002348474A1 (en) | 2001-10-18 | 2003-04-28 | The Salk Institute For Biological Studies | Methods of using deacetylase inhibitors to promote cell differentiation and regeneration |
EP1482962A4 (en) * | 2002-02-15 | 2009-12-23 | Sloan Kettering Inst Cancer | Method of treating trx mediated diseases |
US20050288227A1 (en) * | 2002-02-15 | 2005-12-29 | Marks Paul A | Use of thioredoxin measurements for diagnostics and treatments |
US20070060614A1 (en) * | 2002-03-04 | 2007-03-15 | Bacopoulos Nicholas G | Methods of treating cancer with hdac inhibitors |
US7148257B2 (en) | 2002-03-04 | 2006-12-12 | Merck Hdac Research, Llc | Methods of treating mesothelioma with suberoylanilide hydroxamic acid |
US20060276547A1 (en) * | 2002-03-04 | 2006-12-07 | Bacopoulos Nicholas G | Methods of treating cancer with HDAC inhibitors |
US20040132825A1 (en) * | 2002-03-04 | 2004-07-08 | Bacopoulos Nicholas G. | Methods of treating cancer with HDAC inhibitors |
US7456219B2 (en) | 2002-03-04 | 2008-11-25 | Merck Hdac Research, Llc | Polymorphs of suberoylanilide hydroxamic acid |
EP2082737B1 (en) * | 2002-03-04 | 2014-12-31 | Merck HDAC Research, LLC | Methods of inducing terminal differentiation |
AU2003220119A1 (en) | 2002-03-07 | 2003-09-22 | University Of Delaware | Methods, compositions, and kits for enhancing oligonucleotide-mediated nucleic acid sequence alteration using compositions comprising a histone deacetylase inhibitor, lambda phage beta protein, or hydroxyurea |
WO2003088954A1 (en) * | 2002-04-15 | 2003-10-30 | Sloan-Kettering Institute For Cancer Research | Combination therapy for the treatment of cancer |
CA2486303C (en) * | 2002-05-22 | 2013-04-30 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors based on alpha-ketoepoxide compounds |
TW559390U (en) * | 2002-08-27 | 2003-10-21 | Molex Inc | Electrical connector |
US7154002B1 (en) | 2002-10-08 | 2006-12-26 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
US7250514B1 (en) | 2002-10-21 | 2007-07-31 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
US20040092558A1 (en) * | 2002-11-12 | 2004-05-13 | Alcon, Inc. | Histone deacetylase inhibitors for the treatment of ocular neovascular or edematous disorders and diseases |
US7244751B2 (en) | 2003-02-14 | 2007-07-17 | Shenzhen Chipscreen Biosciences Ltd. | Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity |
KR20050122210A (en) | 2003-03-17 | 2005-12-28 | 다케다 샌디에고, 인코포레이티드 | Histone deacetylase inhibitors |
CN1839121A (en) * | 2003-04-01 | 2006-09-27 | 斯隆-凯特林癌症研究所 | Hydroxamic acid compounds and methods of use thereof |
AU2004241729A1 (en) * | 2003-05-21 | 2004-12-02 | Novartis Ag | Combination of histone deacetylase inhibitors with chemotherapeutic agents |
EP1644323B1 (en) * | 2003-07-07 | 2015-03-18 | Georgetown University | Histone deacetylase inhibitors and methods of use thereof |
US7842835B2 (en) * | 2003-07-07 | 2010-11-30 | Georgetown University | Histone deacetylase inhibitors and methods of use thereof |
ATE462426T1 (en) | 2003-08-26 | 2010-04-15 | Merck Hdac Res Llc | USING SAHA TO TREAT MESOTHELIOMA |
CN102349927A (en) * | 2003-08-29 | 2012-02-15 | Hdac默克研究有限责任公司 | Combination methods of treating cancer |
WO2005034880A2 (en) * | 2003-10-09 | 2005-04-21 | Aton Pharma, Inc. | Thiophene and benzothiophene hydroxamic acid derivatives |
WO2005053609A2 (en) * | 2003-11-26 | 2005-06-16 | Guilford Pharmaceuticals Inc. | Methods of nad+-dependent deacetylase inhibitors |
US20090023718A1 (en) * | 2003-11-26 | 2009-01-22 | Aton Pharma, Inc. | Diamine and Iminodiacetic Acid Hydroxamic Acid Derivatives |
EP1694640A4 (en) * | 2003-11-28 | 2007-01-10 | Univ Queensland | Anti-cancer agents |
EP1697538A1 (en) * | 2003-12-18 | 2006-09-06 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Method for identifying histone deacetylase inhibitors |
WO2005065681A1 (en) * | 2003-12-19 | 2005-07-21 | Takeda San Diego, Inc. | N- hydroxy-3-(3-(1h-imidazol-2-yl)-phenyl)-acrylamide derivatives and related compounds as histone deacetylase (hdac) inhibitors for the treatment of cancer |
US20050137234A1 (en) * | 2003-12-19 | 2005-06-23 | Syrrx, Inc. | Histone deacetylase inhibitors |
US20080113874A1 (en) * | 2004-01-23 | 2008-05-15 | The Regents Of The University Of Colorado | Gefitinib sensitivity-related gene expression and products and methods related thereto |
US8017321B2 (en) * | 2004-01-23 | 2011-09-13 | The Regents Of The University Of Colorado, A Body Corporate | Gefitinib sensitivity-related gene expression and products and methods related thereto |
EP1745022B1 (en) * | 2004-04-05 | 2014-08-13 | Aton Pharma, Inc. | Histone deacetylase inhibitor prodrugs |
AU2005249492B2 (en) | 2004-05-27 | 2011-09-22 | The Regents Of The University Of Colorado | Methods for prediction of clinical outcome to epidermal growth factor receptor inhibitors by cancer patients |
EP1768955A1 (en) * | 2004-07-12 | 2007-04-04 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Amide derivatives as inhibitors of histone deacetylase |
JP2008505971A (en) * | 2004-07-12 | 2008-02-28 | メルク エンド カムパニー インコーポレーテッド | Histone deacetylase inhibitor |
JP2008505964A (en) * | 2004-07-12 | 2008-02-28 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | Amide derivatives as inhibitors of histone deacetylase |
CN1997625A (en) * | 2004-07-12 | 2007-07-11 | 默克公司 | Histone deacetylase inhibitors |
US7507858B2 (en) * | 2004-07-19 | 2009-03-24 | Merck & Co., Inc. | Histone deacetylase inhibitors |
MX2007001550A (en) * | 2004-08-09 | 2007-04-10 | Astellas Pharma Inc | Hydroxyamide compounds having activity as inhibitors of histone deacetylase (hdac). |
CN101035542A (en) * | 2004-08-25 | 2007-09-12 | 默克公司 | Histone deacetylase inhibitors |
KR100584811B1 (en) | 2004-10-21 | 2006-05-30 | 한국화학연구원 | N,n-dimethylaminophenyl octanoic acid hydroxyamide derivatives with inhibitory activity against histone deacetylase and method for the preparation thereof |
US20070021612A1 (en) * | 2004-11-04 | 2007-01-25 | University Of Notre Dame Du Lac | Processes and compounds for preparing histone deacetylase inhibitors and intermediates thereof |
US7235688B1 (en) | 2004-11-04 | 2007-06-26 | University Of Notre Dame Du Lac | Process for preparing histone deacetylase inhibitors and intermediates thereof |
WO2006052916A2 (en) * | 2004-11-08 | 2006-05-18 | Errant Gene Therapeutics, Inc. | Histone deacetylase inhibitors |
US7642275B2 (en) * | 2004-12-16 | 2010-01-05 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
WO2006094068A2 (en) | 2005-03-01 | 2006-09-08 | The Regents Of The University Of Michigan | Hdac inhibitors that promote brm expression and brm related diagnostics |
BRPI0608039A2 (en) * | 2005-03-11 | 2009-06-16 | Univ Colorado | cancer cells sensitive to histone deacetylase inhibitors |
WO2006113606A2 (en) * | 2005-04-18 | 2006-10-26 | Johns Hopkins University | Histone deacetylase inhibitors |
AU2006240258A1 (en) * | 2005-04-20 | 2006-11-02 | Merck Sharp & Dohme Corp. | Benzothiophene derivatives |
CA2603986A1 (en) * | 2005-04-20 | 2006-11-02 | Merck & Co., Inc. | Benzothiophene hydroxamic acid derivatives |
WO2006115833A1 (en) | 2005-04-20 | 2006-11-02 | Merck & Co., Inc. | Benzothiophene hydroxamic acid derivatives with carbamate, urea, amide and sulfonamide substitutions |
GB0509226D0 (en) * | 2005-05-05 | 2005-06-15 | Chroma Therapeutics Ltd | Enzyme and receptor modulation |
GB0509223D0 (en) | 2005-05-05 | 2005-06-15 | Chroma Therapeutics Ltd | Enzyme inhibitors |
GB0509225D0 (en) | 2005-05-05 | 2005-06-15 | Chroma Therapeutics Ltd | Inhibitors of enzymatic activity |
US20090215800A1 (en) * | 2005-05-05 | 2009-08-27 | Chroma Therapeutics Ltd | Enzyme and Receptor Modulation |
US7642253B2 (en) * | 2005-05-11 | 2010-01-05 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
TWI415603B (en) | 2005-05-20 | 2013-11-21 | Merck Sharp & Dohme | Formulations of suberoylanilide hydroxamic acid and methods for producing same |
CA2612420A1 (en) * | 2005-06-24 | 2007-01-04 | Merck & Co., Inc. | Modified malonate derivatives |
JP2009501236A (en) * | 2005-07-14 | 2009-01-15 | タケダ サン ディエゴ インコーポレイテッド | Histone deacetylase inhibitor |
GB0518237D0 (en) * | 2005-09-07 | 2005-10-19 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
KR100696139B1 (en) * | 2005-11-01 | 2007-03-20 | 한국화학연구원 | Alkylcarbamoyl naphthalenyloxyoctenoylhydroxyamide derivatives having inhibitory activity against histone deacetylase and preparation thereof |
AU2006312083A1 (en) | 2005-11-03 | 2007-05-18 | Merck Sharp & Dohme Corp. | Histone deacetylase inhibitors with aryl-pyrazolyl motifs |
WO2007055942A2 (en) * | 2005-11-03 | 2007-05-18 | Merck & Co., Inc. | Substituted nicotinamide compounds |
EP1947936A4 (en) * | 2005-11-04 | 2010-02-10 | Merck & Co Inc | Methods of using saha and bortezomib for treating cancer |
WO2007056244A2 (en) * | 2005-11-04 | 2007-05-18 | Merck & Co., Inc. | Methods of using saha and erlotinib for treating cancer |
JP2009515887A (en) | 2005-11-11 | 2009-04-16 | ザ スクリプス リサーチ インスティテュート | Histone deacetylase inhibitors as therapeutic agents for nervous system diseases |
AR057579A1 (en) | 2005-11-23 | 2007-12-05 | Merck & Co Inc | SPIROCICLICAL COMPOUNDS AS INHIBITORS OF ACETYLASE HISTONE (HDAC) |
SI1975158T1 (en) * | 2005-12-27 | 2011-10-28 | Univ Pais Vasco | Novel pyrrole derivatives with histone deacetylase inhibitor activity |
WO2007087130A2 (en) * | 2006-01-12 | 2007-08-02 | Merck & Co., Inc. | Hydroxyalkylarylamide derivatives |
WO2007087129A2 (en) * | 2006-01-12 | 2007-08-02 | Merck & Co., Inc. | Fluorinated arylamide derivatives |
JP2009525955A (en) * | 2006-01-13 | 2009-07-16 | タケダ サン ディエゴ インコーポレイテッド | Histone deacetylase inhibitor |
PT1981877E (en) * | 2006-02-07 | 2012-05-24 | Astellas Pharma Inc | N-hydroxyacrylamide compounds |
MX2008010462A (en) | 2006-02-14 | 2009-04-17 | Harvard College | Histone Deacetylase Inhibitors. |
GB0603041D0 (en) * | 2006-02-15 | 2006-03-29 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
AU2007221207A1 (en) * | 2006-02-28 | 2007-09-07 | Merck Sharp & Dohme Corp. | Inhibitors of histone deacetylase |
WO2007113644A2 (en) * | 2006-04-05 | 2007-10-11 | Orchid Research Laboratories Limited | New hdac inhibitors |
US20100137239A1 (en) | 2006-04-24 | 2010-06-03 | Gloucester Pharmaceuticals | Gemcitabine combination therapy |
JP2009535333A (en) | 2006-04-26 | 2009-10-01 | メルク エンド カムパニー インコーポレーテッド | Disubstituted aniline compounds |
WO2007136605A2 (en) * | 2006-05-18 | 2007-11-29 | Merck & Co., Inc. | Aryl-fused spirocyclic compounds |
US8957027B2 (en) * | 2006-06-08 | 2015-02-17 | Celgene Corporation | Deacetylase inhibitor therapy |
US7981874B2 (en) * | 2006-07-20 | 2011-07-19 | Merck Sharp & Dohme Corp. | Phosphorus derivatives as histone deacetylase inhibitors |
CA2661024A1 (en) * | 2006-08-28 | 2008-03-06 | The Regents Of The University Of California | Small molecule potentiator of hormonal therapy for breast cancer |
WO2008033466A2 (en) * | 2006-09-14 | 2008-03-20 | Combinatorx (Singapore) Pre. Ltd. | Compositions and methods for treatment of viral diseases |
CA2663569A1 (en) | 2006-09-28 | 2008-04-03 | Merck & Co., Inc. | Pharmaceutical compositions of hdac inhibitors and chelatable metal compounds, and metal-hdac inhibitor chelate complexes |
GB0619753D0 (en) | 2006-10-06 | 2006-11-15 | Chroma Therapeutics Ltd | Enzyme inhibitors |
GB0620823D0 (en) | 2006-10-19 | 2006-11-29 | Univ London | Histone deacetylase inhibitors |
CA2668070A1 (en) | 2006-10-30 | 2008-05-08 | Chroma Therapeutics Ltd. | Hydroxamates as inhibitors of histone deacetylase |
EP2086323A4 (en) * | 2006-11-03 | 2010-01-06 | Univ Maryland | Methods of using saha and bortezomib for treating multiple myeloma |
WO2008083288A2 (en) | 2006-12-29 | 2008-07-10 | Gloucester Pharmaceuticals | Purifiction of romidepsin |
US20100324034A1 (en) * | 2007-02-08 | 2010-12-23 | Hazuda Daria J | Methods of Using SAHA for Treating HIV Infection |
GB2445630B (en) * | 2007-03-12 | 2008-11-12 | Cvon Innovations Ltd | Dynamic message allocation system and method |
WO2008110583A1 (en) * | 2007-03-13 | 2008-09-18 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Amide compounds and their use as antitumor agents |
US20080288310A1 (en) * | 2007-05-16 | 2008-11-20 | Cvon Innovation Services Oy | Methodologies and systems for mobile marketing and advertising |
EP2359828A1 (en) | 2007-06-06 | 2011-08-24 | University of Maryland, Baltimore | HDAC inhibitors and hormone targeted drugs for the treatment of cancer |
US8389553B2 (en) * | 2007-06-27 | 2013-03-05 | Merck Sharp & Dohme Corp. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
CA2692153A1 (en) * | 2007-06-27 | 2009-01-08 | Richard W. Heidebrecht, Jr. | Pyridyl and pyrimidinyl derivatives as histone deacetylase inhibitors |
US20110053991A1 (en) * | 2007-11-19 | 2011-03-03 | Gore Lia | Treatment of Histone Deacetylase Mediated Disorders |
CA2706750A1 (en) * | 2007-11-27 | 2009-06-04 | Ottawa Health Research Institute | Amplification of cancer-specific oncolytic viral infection by histone deacetylase inhibitors |
US7863315B2 (en) | 2008-01-15 | 2011-01-04 | Shenzhen Chipscreen Biosciences, Ltd. | 2-indolinone derivatives as selective histone deacetylase inhibitors |
US8158656B2 (en) | 2008-05-16 | 2012-04-17 | Shenzhen Chipscreen Biosciences Ltd. | 2-indolinone derivatives as multi-target protein kinase inhibitors and histone deacetylase inhibitors |
US8178577B2 (en) | 2008-05-21 | 2012-05-15 | Shenzhen Chipscreen Biosciences Ltd. | Tricyclic derivatives as potent and selective histone deacetylase inhibitors |
WO2010028193A1 (en) * | 2008-09-03 | 2010-03-11 | Repligen Corporation | Compounds including pimelic acid derivatives as hdac inhibitors |
GB0903480D0 (en) | 2009-02-27 | 2009-04-08 | Chroma Therapeutics Ltd | Enzyme Inhibitors |
US8211901B2 (en) | 2009-05-22 | 2012-07-03 | Shenzhen Chipscreen Biosciences Ltd. | Naphthamide derivatives as multi-target protein kinase inhibitors and histone deacetylase inhibitors |
CN101906076B (en) | 2009-06-04 | 2013-03-13 | 深圳微芯生物科技有限责任公司 | Naphthaline amide derivative serving as protein kinase inhibitor and histone deacetylase inhibitor and preparation method and application thereof |
CN102020588B (en) * | 2009-09-16 | 2014-01-29 | 深圳微芯生物科技有限责任公司 | Tricyclic compound with histone deacetylases inhibition activity and preparation method and application thereof |
HUE044575T2 (en) | 2010-04-20 | 2019-11-28 | Fujifilm Toyama Chemical Co Ltd | Hydroxamic acid derivative |
AU2011255281A1 (en) * | 2010-05-21 | 2013-01-10 | Sloan-Kettering Institute For Cancer Research | Selective HDAC inhibitors |
ES2755909T3 (en) | 2010-07-12 | 2020-04-24 | Celgene Corp | Solid forms of romidepsin and its uses |
US8859502B2 (en) | 2010-09-13 | 2014-10-14 | Celgene Corporation | Therapy for MLL-rearranged leukemia |
CN102775368B (en) * | 2011-05-10 | 2016-08-17 | 上海驺虞医药科技有限公司 | One class thiazole compound and its production and use |
US8921533B2 (en) | 2011-07-25 | 2014-12-30 | Chromatin Technologies | Glycosylated valproic acid analogs and uses thereof |
CN103732577B (en) * | 2011-09-19 | 2017-04-05 | 希格马托制药工业公司 | As effective hdac inhibitor carrying lactams thio derivative and they as medicine purposes |
EP2837681B1 (en) | 2012-04-06 | 2018-02-21 | Kyoto University | Method for inducing erythropoietin-producing cell |
AU2013202506B2 (en) | 2012-09-07 | 2015-06-18 | Celgene Corporation | Resistance biomarkers for hdac inhibitors |
AU2013202507B9 (en) | 2012-11-14 | 2015-08-13 | Celgene Corporation | Inhibition of drug resistant cancer cells |
NZ630311A (en) | 2013-12-27 | 2016-03-31 | Celgene Corp | Romidepsin formulations and uses thereof |
WO2015184260A2 (en) | 2014-05-30 | 2015-12-03 | The Johns Hopkins University | Methods for treating mendelian disorders of the epigenetic machinery |
WO2017017108A1 (en) | 2015-07-28 | 2017-02-02 | Vilmorin & Cie | Method for producing haploid, dihaploid and doubled haploid plants by isolated microspore culture |
TWI794171B (en) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-l1 inhibitors |
WO2019036607A1 (en) * | 2017-08-17 | 2019-02-21 | The University Of Toledo | Imidazole-based anticancer agents and derivatives thereof, and methods of making and using same |
EP3461480A1 (en) | 2017-09-27 | 2019-04-03 | Onxeo | Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer |
EP3461488A1 (en) | 2017-09-27 | 2019-04-03 | Onxeo | Combination of a dbait molecule and a hdac inhibitor for treating cancer |
CN107698464A (en) * | 2017-10-12 | 2018-02-16 | 江苏师范大学 | His analogue of Baily department with histon deacetylase (HDAC) inhibitory action and its application |
CN107822916A (en) * | 2017-11-14 | 2018-03-23 | 江苏师范大学 | A kind of whitening active ingredients |
CN112469697A (en) | 2018-07-11 | 2021-03-09 | 鲁贝多生命科学公司 | Anti-aging composition and application thereof |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
WO2023041805A1 (en) | 2021-09-20 | 2023-03-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for improving the efficacy of hdac inhibitor therapy and predicting the response to treatment with hdac inhibitor |
WO2023194441A1 (en) | 2022-04-05 | 2023-10-12 | Istituto Nazionale Tumori Irccs - Fondazione G. Pascale | Combination of hdac inhibitors and statins for use in the treatment of pancreatic cancer |
Family Cites Families (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2895991A (en) | 1959-07-21 | New chloromethylated amlides | ||
US2346665A (en) | 1940-05-08 | 1944-04-18 | Du Pont | Acid |
US2279560A (en) | 1940-05-08 | 1942-04-14 | Du Pont | Viscous hydrocarbon oil |
US3450673A (en) | 1965-09-07 | 1969-06-17 | Ashland Oil Inc | Polyurethane compositions from diaminimides |
DE1272540B (en) | 1965-11-11 | 1968-07-11 | Bayer Ag | Process for the polymerization of diisocyanates with aliphatic NCO groups |
US3632783A (en) | 1969-05-27 | 1972-01-04 | Hall Co C P | Treatment of mosquito bites employing certain tetraalkyl diamides |
CH567388A5 (en) * | 1972-04-18 | 1975-10-15 | Lundqvist Harald | |
US4056524A (en) | 1974-04-09 | 1977-11-01 | Stauffer Chemical Company | Bis-substituted succinamides and their utility as herbicides |
US3875301A (en) | 1974-04-30 | 1975-04-01 | Interx Research Corp | Useful tetraalkyl diamides in the treatment of poison ivy |
NL7607987A (en) | 1975-08-08 | 1977-02-10 | Merck & Co Inc | METHOD FOR PREPARING PEPTIDES. |
JPS52108027A (en) | 1976-03-09 | 1977-09-10 | Rikagaku Kenkyusho | Anticarcinogen |
JPS5819669B2 (en) * | 1978-10-28 | 1983-04-19 | 白井松新薬株式会社 | Novel bioactive peptide compounds and their production methods |
IT1123574B (en) | 1979-09-10 | 1986-04-30 | Anic Spa | PROCESS FOR THE PRODUCTION OF DIESTEREDIAMIDES |
US4442305A (en) | 1981-08-24 | 1984-04-10 | The United States Of America As Represented By The United States Department Of Energy | Polycatecholamide chelating agents |
US4480125A (en) | 1981-11-16 | 1984-10-30 | Polaroid Corporation | Itaconamide compounds and method of preparation |
US4935450A (en) | 1982-09-17 | 1990-06-19 | Therapeutical Systems Corporation | Cancer therapy system for effecting oncolysis of malignant neoplasms |
EP0137640A1 (en) * | 1983-08-15 | 1985-04-17 | Dana-Farber Cancer Institute, Inc. | Chain extended analogues of methotrexate and aminopterin |
US4537781A (en) | 1983-09-16 | 1985-08-27 | Research Corporation | Pharmaceutically useful malonamides |
US5900237A (en) * | 1983-11-29 | 1999-05-04 | Igen International, Inc. | Catalytic antibodies which hydrolyze primary amides and methods for eliciting such antibodies |
EP0169645A1 (en) * | 1984-06-27 | 1986-01-29 | Johnson Matthey Public Limited Company | Platinum co-ordination compounds |
US4611053A (en) | 1985-02-15 | 1986-09-09 | Sasa Michiyuki Mitch | Polyhydroxamide polymer |
JPS61205221A (en) | 1985-03-08 | 1986-09-11 | Univ Osaka | New process for preparation of amide from nitrile and amine |
PH24782A (en) * | 1985-10-24 | 1990-10-30 | Sankyo Co | Composition containing a penem or carbapenem antibiotic and the use of the same |
US4863967A (en) | 1986-06-16 | 1989-09-05 | Research Corporation | N,N-diaminophthalamides |
US4882346A (en) | 1987-06-16 | 1989-11-21 | The United States Of America As Reprsented By The Department Of Health And Human Services | Chemical differentiating agents |
JP2777193B2 (en) * | 1988-10-24 | 1998-07-16 | 生化学工業株式会社 | Method for producing peptide |
US5055608A (en) | 1988-11-14 | 1991-10-08 | Sloan-Kettering Institute For Cancer Research | Novel potent inducers of thermal differentiation and method of use thereof |
US5330744A (en) | 1988-11-14 | 1994-07-19 | Sloan-Kettering Institute For Cancer Research | Method for increasing sensitivity to chemically induced terminal differentiation |
US5175191A (en) | 1988-11-14 | 1992-12-29 | Sloan-Kettering Institute For Cancer Research | Potent inducers of terminal differentiation and methods of use thereof |
EP0594577B1 (en) * | 1989-11-14 | 1998-12-30 | Sloan-Kettering Institute For Cancer Research | Novel potent inducers of terminal differentiation and method of use thereof |
FR2665159B1 (en) | 1990-07-24 | 1992-11-13 | Rhone Poulenc Sante | NEW PYRIDINE AND QUINOLEIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
ZA924811B (en) | 1991-06-28 | 1993-12-29 | Endorecherche Inc | Controlled release systems and low dose androgens |
US5700811A (en) | 1991-10-04 | 1997-12-23 | Sloan-Kettering Institute For Cancer Research | Potent inducers of terminal differentiation and method of use thereof |
US5369108A (en) * | 1991-10-04 | 1994-11-29 | Sloan-Kettering Institute For Cancer Research | Potent inducers of terminal differentiation and methods of use thereof |
US6399568B1 (en) * | 1997-09-02 | 2002-06-04 | Japan Energy Corporation | Cyclic tetrapeptide derivatives and medicinal use thereof |
PL200861B1 (en) * | 1999-09-08 | 2009-02-27 | Sloan Kettering Inst Cancer | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
AU2002340253C1 (en) * | 2001-10-16 | 2011-03-31 | Sloan-Kettering Institute For Cancer Research | Treatment of neurodegenerative diseases and cancer of the brain |
EP1482962A4 (en) * | 2002-02-15 | 2009-12-23 | Sloan Kettering Inst Cancer | Method of treating trx mediated diseases |
US7148257B2 (en) * | 2002-03-04 | 2006-12-12 | Merck Hdac Research, Llc | Methods of treating mesothelioma with suberoylanilide hydroxamic acid |
WO2003088954A1 (en) * | 2002-04-15 | 2003-10-30 | Sloan-Kettering Institute For Cancer Research | Combination therapy for the treatment of cancer |
US20040008968A1 (en) * | 2002-07-09 | 2004-01-15 | L3 Optics, Inc. | Photosensitive optical glass |
-
2000
- 2000-08-24 PL PL364175A patent/PL200861B1/en not_active IP Right Cessation
- 2000-08-24 WO PCT/US2000/023232 patent/WO2001018171A2/en active IP Right Grant
- 2000-08-24 EA EA200200333A patent/EA007649B1/en not_active IP Right Cessation
- 2000-08-24 EA EA200601252A patent/EA200601252A1/en unknown
- 2000-08-24 US US09/645,430 patent/US6511990B1/en not_active Expired - Lifetime
- 2000-08-24 JP JP2001522383A patent/JP2003509343A/en active Pending
- 2000-08-24 KR KR1020027003114A patent/KR20020059393A/en not_active Application Discontinuation
- 2000-08-24 HU HU0202707A patent/HUP0202707A3/en unknown
- 2000-08-24 BR BR0014254-9A patent/BR0014254A/en not_active Application Discontinuation
- 2000-08-24 IL IL14849700A patent/IL148497A0/en unknown
- 2000-08-24 UA UA2002042818A patent/UA74345C2/en unknown
- 2000-08-24 TR TR2002/01052T patent/TR200201052T2/en unknown
- 2000-08-24 AU AU69327/00A patent/AU6932700A/en not_active Abandoned
- 2000-08-24 YU YU22402A patent/YU22402A/en unknown
- 2000-08-24 SK SK330-2002A patent/SK3302002A3/en not_active Application Discontinuation
- 2000-08-24 MX MXPA02002505A patent/MXPA02002505A/en not_active Application Discontinuation
- 2000-08-24 CA CA002383999A patent/CA2383999A1/en not_active Abandoned
- 2000-08-24 CN CN00814006A patent/CN1378450A/en active Pending
- 2000-08-24 EP EP00957757.8A patent/EP1231919B1/en not_active Expired - Lifetime
- 2000-08-24 NZ NZ517613A patent/NZ517613A/en unknown
-
2002
- 2002-10-25 US US10/281,875 patent/US7126001B2/en not_active Expired - Fee Related
-
2006
- 2006-06-22 US US11/473,839 patent/US20070010536A1/en not_active Abandoned
- 2006-06-22 US US11/474,042 patent/US20070010669A1/en not_active Abandoned
- 2006-06-22 US US11/474,043 patent/US7345174B2/en not_active Expired - Fee Related
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060241129A1 (en) * | 1999-09-08 | 2006-10-26 | Ronald Breslow | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US20070010536A1 (en) * | 1999-09-08 | 2007-01-11 | Ronald Breslow | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US7345174B2 (en) | 1999-09-08 | 2008-03-18 | Sloan-Kettering Institute For Cancer Research | Cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof |
US10399993B2 (en) | 2007-02-06 | 2019-09-03 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
US9079917B2 (en) | 2007-02-06 | 2015-07-14 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
US10023587B2 (en) | 2007-02-06 | 2018-07-17 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
US8822461B2 (en) | 2007-02-06 | 2014-09-02 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
US8426444B2 (en) | 2007-02-06 | 2013-04-23 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
US7998957B2 (en) | 2007-02-06 | 2011-08-16 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicylcoheptenes, their preparation and use |
CN101854804A (en) * | 2007-10-01 | 2010-10-06 | 利克斯特生物技术公司 | HDAC inhibitor |
US8143445B2 (en) | 2007-10-01 | 2012-03-27 | Lixte Biotechnology, Inc. | HDAC inhibitors |
US8455688B2 (en) | 2007-10-01 | 2013-06-04 | Lixte Biotechnology, Inc. | HDAC inhibitors |
EA018618B1 (en) * | 2007-10-01 | 2013-09-30 | Ликсте Байотекнолоджи, Инк. | Hdac inhibitors |
WO2009045440A1 (en) | 2007-10-01 | 2009-04-09 | Lixte Biotechnology Holdings, Inc. | Hdac inhibitors |
US8293513B2 (en) | 2007-12-14 | 2012-10-23 | Georgetown University | Histone deacetylase inhibitors |
US20100317739A1 (en) * | 2007-12-14 | 2010-12-16 | Brown Milton L | Histone deacetylase inhibitors |
US8227473B2 (en) | 2008-08-01 | 2012-07-24 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
US8329719B2 (en) | 2008-08-01 | 2012-12-11 | Lixte Biotechnology, Inc. | Neuroprotective agents for the prevention and treatment of neurodegenerative diseases |
US8058268B2 (en) | 2008-08-01 | 2011-11-15 | Lixte Biotechnology, Inc. | Neuroprotective agents for the prevention and treatment of neurodegenerative diseases |
US8541458B2 (en) | 2008-08-01 | 2013-09-24 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
US20100030858A1 (en) * | 2008-08-04 | 2010-02-04 | Chasin C Scott | Method and system for centralized contact management |
CN101894348A (en) * | 2010-07-20 | 2010-11-24 | 中兴通讯股份有限公司 | Self-expanded online transaction system and implementing method thereof |
WO2013052110A1 (en) * | 2011-10-03 | 2013-04-11 | The Trustees Of Columbia University In The City Of New York | Novel molecules that selectively inhibit histone deacetylase 6 relative to histone deacetylase 1 |
US9499479B2 (en) | 2011-10-03 | 2016-11-22 | The Trustees Of Columbia University In The City Of New York | Molecules that selectively inhibit histone deacetylase 6 relative to histone deacetylase 1 |
US9545367B2 (en) * | 2011-10-31 | 2017-01-17 | Avon Products, Inc. | Cosmetic use of N-heteroarylbisamide analogs and related compounds |
US20150231049A1 (en) * | 2011-10-31 | 2015-08-20 | Avon Products, Inc. | Cosmetic Use of N-Heteroarylbisamide Analogs and Related Compounds |
US11931354B2 (en) | 2013-04-09 | 2024-03-19 | Lixte Biotechnology, Inc. | Formulations of oxabicycloheptanes and oxabicycloheptenes |
US9890136B2 (en) | 2013-12-23 | 2018-02-13 | The Trustees Of Columbia University In The City Of New York Memorial Sloan-Kettering Cancer Center | Selective HDAC6 inhibitors |
US10626100B2 (en) | 2013-12-23 | 2020-04-21 | The Trustees Of Columbia University In The City Of New York | Selective HDAC6 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
AU6932700A (en) | 2001-04-10 |
WO2001018171A2 (en) | 2001-03-15 |
NZ517613A (en) | 2004-01-30 |
IL148497A0 (en) | 2002-09-12 |
US20060241129A1 (en) | 2006-10-26 |
CN1378450A (en) | 2002-11-06 |
CA2383999A1 (en) | 2001-03-15 |
JP2003509343A (en) | 2003-03-11 |
EA007649B1 (en) | 2006-12-29 |
MXPA02002505A (en) | 2004-09-10 |
YU22402A (en) | 2006-01-16 |
EA200200333A1 (en) | 2002-10-31 |
EA200601252A1 (en) | 2006-10-27 |
US7345174B2 (en) | 2008-03-18 |
KR20020059393A (en) | 2002-07-12 |
TR200201052T2 (en) | 2003-01-21 |
SK3302002A3 (en) | 2002-07-02 |
HUP0202707A2 (en) | 2002-12-28 |
US20070010536A1 (en) | 2007-01-11 |
HUP0202707A3 (en) | 2003-11-28 |
WO2001018171A3 (en) | 2002-06-27 |
EP1231919A2 (en) | 2002-08-21 |
PL364175A1 (en) | 2004-12-13 |
US6511990B1 (en) | 2003-01-28 |
EP1231919A4 (en) | 2005-02-23 |
UA74345C2 (en) | 2005-12-15 |
US20040002506A1 (en) | 2004-01-01 |
EP1231919B1 (en) | 2015-09-30 |
BR0014254A (en) | 2002-08-27 |
PL200861B1 (en) | 2009-02-27 |
US7126001B2 (en) | 2006-10-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7345174B2 (en) | Cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof | |
CA2190765C (en) | Novel potent inducers of terminal differentiation and methods of use thereof | |
RU2128643C1 (en) | New compounds as potential inducers of terminal differentiation of tumor cells, a pharmaceutical composition based on said | |
JP4976354B2 (en) | Hydroxamic acid compounds containing sulfonamide linkages as histone deacetylase (HDAC) inhibitors | |
US6924392B2 (en) | Ortho, meta-substituted bisaryl compounds, processes for their preparation, their use as medicaments, and pharmaceutical preparations comprising them | |
US5015644A (en) | Antihyperlipidemic and antiatherosclerotic urea and carbamate compounds | |
US7923579B2 (en) | Tricyclic hydroxamate and benzamide derivatives, compositions and methods | |
US20110212943A1 (en) | Novel bridged cyclic compounds as histone deacetylase inhibitors | |
JP2010065041A (en) | Inhibiting raf kinase using substituted heterocyclic urea | |
TW200530166A (en) | Acylurea connected and sulfonylurea connected hydroxamates | |
Marks et al. | Polar/apolar chemical inducers of differentiation of transformed cells: strategies to improve therapeutic potential. | |
MXPA02000822A (en) | Carboxylic acid amides, medicaments containing these compounds and the use and production thereof. | |
US20030166693A1 (en) | Benzene derivatives and pharmaceutical use thereof | |
EP1402887A1 (en) | New compounds for the inhibition of undesired cell proliferation and use thereof | |
US20090318454A1 (en) | Novel antioxidants and methods of treatment | |
AU2005205805B2 (en) | Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof | |
US9216954B2 (en) | Serine racemase inhibitor | |
US20100160392A1 (en) | Histone deacetylase inhibitors | |
CA2574103A1 (en) | Novel potent inducers of terminal differentiation and methods of use thereof | |
EP1068176A1 (en) | Cysteine amides as farnesyl transferase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH, NEW Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MARKS PAUL A.;RICHON, VICTORIA M.;RIFKIND, RICHARD A.;REEL/FRAME:018138/0906;SIGNING DATES FROM 20001003 TO 20001004 |
|
AS | Assignment |
Owner name: TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW Free format text: DOCUMENT PREVIOUSLY RECORDED AT REEL 018138 FRAME 0906 CONTAINED ERRORS IN PATENT APPLICATION NUMBER 11/474,043. DOCUMENT RERECORDED TO CORRECT ERRORS ON STATED REEL.;ASSIGNORS:BRESLOW, RONALD;BELVEDERE, SANDRO;GERSHELL, LELAND;AND OTHERS;REEL/FRAME:018525/0261;SIGNING DATES FROM 20001101 TO 20001103 Owner name: SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH, NEW Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MARKS, PAUL A.;RICHON, VICTORIA M.;RIFKIND, RICHARD A.;REEL/FRAME:018522/0262;SIGNING DATES FROM 20001003 TO 20001004 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |