WO2005068469A1 - Multi-nuclear metal complexes partially encapsulated by cucurbit[7-12]urils - Google Patents
Multi-nuclear metal complexes partially encapsulated by cucurbit[7-12]urils Download PDFInfo
- Publication number
- WO2005068469A1 WO2005068469A1 PCT/AU2005/000045 AU2005000045W WO2005068469A1 WO 2005068469 A1 WO2005068469 A1 WO 2005068469A1 AU 2005000045 W AU2005000045 W AU 2005000045W WO 2005068469 A1 WO2005068469 A1 WO 2005068469A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- metal complex
- cucurbit
- independently selected
- ligand
- formula
- Prior art date
Links
- 229910052751 metal Inorganic materials 0.000 title abstract description 28
- 239000002184 metal Substances 0.000 title abstract description 28
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 143
- 238000000034 method Methods 0.000 claims abstract description 41
- 230000000694 effects Effects 0.000 claims abstract description 31
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 27
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 239000003446 ligand Substances 0.000 claims description 61
- 125000004429 atom Chemical group 0.000 claims description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
- MSBXTPRURXJCPF-DQWIULQBSA-N cucurbit[6]uril Chemical compound N1([C@@H]2[C@@H]3N(C1=O)CN1[C@@H]4[C@@H]5N(C1=O)CN1[C@@H]6[C@@H]7N(C1=O)CN1[C@@H]8[C@@H]9N(C1=O)CN([C@H]1N(C%10=O)CN9C(=O)N8CN7C(=O)N6CN5C(=O)N4CN3C(=O)N2C2)C3=O)CN4C(=O)N5[C@@H]6[C@H]4N2C(=O)N6CN%10[C@H]1N3C5 MSBXTPRURXJCPF-DQWIULQBSA-N 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 229910052697 platinum Inorganic materials 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 150000007942 carboxylates Chemical class 0.000 claims description 12
- 230000001988 toxicity Effects 0.000 claims description 11
- 231100000419 toxicity Toxicity 0.000 claims description 11
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 238000001727 in vivo Methods 0.000 claims description 8
- 229910002651 NO3 Inorganic materials 0.000 claims description 7
- 150000003141 primary amines Chemical class 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 150000003335 secondary amines Chemical class 0.000 claims description 7
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 125000005750 substituted cyclic group Chemical group 0.000 claims description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 2
- -1 H2P04 " or HP04 2") Chemical class 0.000 description 70
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 44
- ZDOBFUIMGBWEAB-XGFHMVPTSA-N cucurbit[7]uril Chemical class N1([C@H]2[C@H]3N(C1=O)CN1[C@H]4[C@H]5N(C1=O)CN1[C@H]6[C@H]7N(C1=O)CN1[C@H]8[C@H]9N(C1=O)CN1[C@H]%10[C@H]%11N(C1=O)CN([C@@H]1N(C%12=O)CN%11C(=O)N%10CN9C(=O)N8CN7C(=O)N6CN5C(=O)N4CN3C(=O)N2C2)C3=O)CN4C(=O)N5[C@H]6[C@@H]4N2C(=O)N6CN%12[C@@H]1N3C5 ZDOBFUIMGBWEAB-XGFHMVPTSA-N 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 13
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 13
- 229960004316 cisplatin Drugs 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 239000003814 drug Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 150000003057 platinum Chemical class 0.000 description 9
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical class [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- CONWISUOKHSUDR-LBCLZKRDSA-N cucurbit[8]uril Chemical class N1([C@@H]2[C@@H]3N(C1=O)CN1[C@@H]4[C@@H]5N(C1=O)CN1[C@@H]6[C@@H]7N(C1=O)CN1[C@@H]8[C@@H]9N(C1=O)CN1[C@@H]%10[C@@H]%11N(C1=O)CN1[C@@H]%12[C@@H]%13N(C1=O)CN([C@H]1N(C%14=O)CN%13C(=O)N%12CN%11C(=O)N%10CN9C(=O)N8CN7C(=O)N6CN5C(=O)N4CN3C(=O)N2C2)C3=O)CN4C(=O)N5[C@@H]6[C@H]4N2C(=O)N6CN%14[C@H]1N3C5 CONWISUOKHSUDR-LBCLZKRDSA-N 0.000 description 8
- 231100000682 maximum tolerated dose Toxicity 0.000 description 8
- 241000282412 Homo Species 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 125000002577 pseudohalo group Chemical group 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- AJJRSBHJPIUSSF-YUMGADRSSA-N cucurbit[10]uril Chemical class N1([C@@H]2[C@@H]3N(C1=O)CN1[C@@H]4[C@@H]5N(C1=O)CN1[C@@H]6[C@@H]7N(C1=O)CN1[C@@H]8[C@@H]9N(C1=O)CN1[C@@H]%10[C@@H]%11N(C1=O)CN1[C@@H]%12[C@@H]%13N(C1=O)CN1[C@@H]%14[C@@H]%15N(C1=O)CN1[C@@H]%16[C@@H]%17N(C1=O)CN([C@H]1N(C%18=O)CN%17C(=O)N%16CN%15C(=O)N%14CN%13C(=O)N%12CN%11C(=O)N%10CN9C(=O)N8CN7C(=O)N6CN5C(=O)N4CN3C(=O)N2C2)C3=O)CN4C(=O)N5[C@@H]6[C@H]4N2C(=O)N6CN%18[C@H]1N3C5 AJJRSBHJPIUSSF-YUMGADRSSA-N 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 4
- 0 CC(*)(C(C)(*)N(C1(*)C2(*)N3C(*)*(*)*(*)C(*)N22)C3=*)N1C2=* Chemical compound CC(*)(C(C)(*)N(C1(*)C2(*)N3C(*)*(*)*(*)C(*)N22)C3=*)N1C2=* 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000003973 alkyl amines Chemical class 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001805 chlorine compounds Chemical group 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 231100001231 less toxic Toxicity 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 229940063673 spermidine Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- CFOKZVVHHHGHEE-UHFFFAOYSA-N 5-(1h-pyrazol-5-ylmethyl)-1h-pyrazole Chemical compound C1=CNN=C1CC=1C=CNN=1 CFOKZVVHHHGHEE-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000012766 Growth delay Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 125000002877 alkyl aryl group Chemical group 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 229930195734 saturated hydrocarbon Natural products 0.000 description 3
- 125000005017 substituted alkenyl group Chemical group 0.000 description 3
- 125000004426 substituted alkynyl group Chemical group 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 150000001734 carboxylic acid salts Chemical class 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 229940074045 glyceryl distearate Drugs 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004336 3,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 244000303258 Annona diversifolia Species 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 125000000739 C2-C30 alkenyl group Chemical group 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241001466804 Carnivora Species 0.000 description 1
- 241000283153 Cetacea Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 244000276331 Citrus maxima Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108020005124 DNA Adducts Proteins 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241001331845 Equus asinus x caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000148687 Glycosmis pentaphylla Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000283089 Perissodactyla Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241001493546 Suina Species 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 241001416177 Vicugna pacos Species 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 150000003975 aryl alkyl amines Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- 229940092782 bentonite Drugs 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- BWOVZCWSJFYBRM-UHFFFAOYSA-N carbononitridic isocyanate Chemical compound O=C=NC#N BWOVZCWSJFYBRM-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 125000001046 glycoluril group Chemical group [H]C12N(*)C(=O)N(*)C1([H])N(*)C(=O)N2* 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- LJDZFAPLPVPTBD-UHFFFAOYSA-N nitroformic acid Chemical compound OC(=O)[N+]([O-])=O LJDZFAPLPVPTBD-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000003367 polycyclic group Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- 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
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to multi-nuclear metal complexes partially encapsulated by one or more cucurbit [7 to 12]urils or analogues thereof.
- the invention further relates to methods for treating cancer by administering a multi-nuclear metal complex having anti-tumour activity partially encapsulated by one or more cucurbit [7 to 12]urils or analogues thereof, and pharmaceutical compositions comprising a multi-nuclear metal complex having anti-tumour activity partially encapsulated by one or more cucurbit [7 to 12]urils or analogues thereof.
- Cucurbituril is the name ' given to a cyclic oligomer formed by linking six (6) glycoluril units via methylene bridges.
- cucurbituril has also been used, and is used in this specification, to refer to a family of compounds (the family including the compound cucurbituril) .
- the compound cucurbituril is referred to in this specification as "unsubstituted cucurbit [6]uril” .
- Cucurbiturils are a family of cyclic compounds. Cucurbiturils comprise a macrocyclic ring consisting of 4 to 12 units of the formula (C) :
- Cucurbiturils have a central cavity with two openings to the central cavity, the two openings being surrounded by the R 3 groups (and R 5 groups) , and the central cavity having a larger diameter than the two openings. Cucurbiturils can encapsulate various compounds, including gases and volatile compounds, within the cavity of the cucurbituril. Unsubstituted cucurbit [6] uril was first described in the literature in 1905 in a paper by R. Behrend, E. Meyer, F. Rusche, Leibigs Ann. Chem. , 399, 1, '1905.
- Unsubstituted cucurbit [6] uril has a chemical formula of C 3S H 3S N20 ⁇ 2 and is a macrocyclic compound having a central cavity.
- WO 00/68232 describes the synthesis of various unsubstituted and substituted cucurbit [n] rils .
- US patent no. 6,365,734 also describes the synthesis of various cucurbit [n] urils .
- cucurbit [n] urils and methods of preparing cucurbit [n] urils, are described in co-pending international patent application no. PCT/AU2004/001232.
- Various cucurbituril analogues have also recently been described. These analogues have the basic structure of a cucurbituril as described above, but wherein one or some of the units of the formula (C) referred to above are replaced with another group, such as an aromatic group (for example, as- described in Lagona J. et al, "Cucurbit [n] uril Analogues", Organic Letters, 2003, Vol 5, No. 20, 3745-3747) .
- Cisplatin is a mono-nuclear platinum complex having anti-tumour activity.
- Cisplatin has been used for the treatment of a variety of cancers in humans, including testicular, ovarian, bladder, head and neck, lung and cervical cancers.
- cisplatin has a number of drawbacks. Many human cancers have natural resistance to cisplatin, and of the cancers that initially respond to cisplatin treatment, many later acquire resistance to the drug. The use of cisplatin has been further limited by its toxicity. Other mono-nuclear platinum complexes having anti-tumour activity have been developed, such as carboplatin. • Some of these complexes have less toxicity than cisplatin.
- Two or more of the platinum centres in the multi-nuclear platinum complex can each bind to DNA, and the complex is thus capable of forming a completely different range of DNA adducts compared to cisplatin and other mono-nuclear platinum complexes.
- These multi-nuclear platinum complexes are recognised in the art to comprise a unique class of anti-tumour agent.
- These complexes have distinct chemical and biological properties compared to mono-nuclear platinum complexes such as cisplatin, carboplatin and those described in US patent no. 4,225,529. In contrast to mono-nuclear platinum complexes, most multi-nuclear platinum complexes are charged species. US patent ' no.
- 4,797,393 describes a bis-platinum(II) complex which is delivered to the active site as a bis- platinum (II) complex.
- This Jbis-platinum complex has a bridging diamine or polya ine ligand and has primary or secondary amines or pyridine type nitrogens coordinated to the platinum atoms, as well as two different or identical ligands which may be a halide, sulphate, phosphate, nitrate, carboxylate, substituted carboxylate or dicarboxylate .
- US patent no. 5,380,897 describes tri-platinum (II) complexes containing three platinum coordination spheres coupled via diamine or triam ine bridging agents.
- the present invention provides a multi-nuclear metal complex partially encapsulated by one or more cucurbit [7 to 12] urils or analogues thereof.
- the metal complex is typically a bi-nuclear or tri-nuclear metal complex.
- the metal complex is a metal complex of the formula (IIA) , (IIB) , (IIC) or (IID) :
- the metal complex is a metal complex of formula (IIIA) , (IIIB) , (IIIC) or (HID) :
- X is typically selected from the group consisting of halide, sulphate, phosphate (i.e. H 2 P0 4 " or HP0 4 2" ) , nitrate, carboxylate and substituted carboxylate.
- B is selected from the group consisting of ammine, primary amines, secondary amines, tertiary amines, and groups containing heterocyclic rings containing one or more N atoms .
- the metal complex is encapsulated by a cucurbit [7 to 12] uril.
- the cucurbit [7 to 12] uril is a cucurbituril of the formula (I)
- n is an integer from 7 to 12, and wherein for each unit of the formula (B) :
- R 1 and R 2 may be the same or different and are each a univalent radical, or
- R 1 , R 2 and the carbon atoms to which they are bound together form an optionally substituted cyclic group, or
- an electron withdrawing group such as -N0 2 , -C0 2 R, -COR or - CX 3 , X is halo and R is H, an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical, or an optionally substituted heterocyclyl radical
- each R 5 is independently selected from the group consisting of H, alkyl and aryl .
- the present invention provides a method for reducing the in vivo toxicity of a multi- nuclear metal complex, the method comprising forming an association of the metal complex with one or more cucurbit [7 to 12] urils or analogues thereof wherein the metal complex is partially encapsulated by the one or more cucurbit [7 to 12] urils or analogues thereof.
- the association of the metal complex with the one or more cucurbit [7 to 12] urils or analogues thereof is formed by contacting the metal complex with the one or more cucurbit [7 to 12] urils or analogues thereof.
- the present invention provides a method for treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a multi-nuclear metal complex having anti-tumour activity partially encapsulated by one or more cucurbit [7 to 12]urils or analogues thereof.
- the present invention further provides the use of a multi-nuclear metal complex having anti-tumour activity partially encapsulated by one or more cucurbit [7 to 12] urils or analogues thereof in the manufacture of a medicament for treating cancer in a subject.
- the cancer may, for example, be testicular cancer, ovarian cancer/ bladder cancer, cancer of the head and neck, lung cancer or cervical cancer.
- the cancer may be a cancer having resistance to cisplatin.
- the present invention provides a pharmaceutical composition comprising a multi-nuclear metal complex having anti-tumour activity partially encapsulated by one or more cucurbit [7 to 12] urils or analogues thereof, and a pharmaceutically acceptable carrier.
- cucurbit [n] uril refers to a cucurbituril comprising a ring consisting of n units of the formula (C) :
- R 1 , R 2 , R 3 and R 5 may be any group, and n is an integer from 4 to 12.
- R 1 , R 2 , R 3 and R 5 are as defined above for formula (I) .
- the term "unsubstituted cucurbit [n] uril” refers to a cucurbit [n] uril wherein R 3 is 0 and R 1 , R 2 and R 5 are all H in all of the units of the formula (C) in the cucurbit [n] uril
- substituted cucurbit [n] uril refers to a cucurbit [n] uril other than an unsubstituted cucurbit [n] uril .
- an "analogue" of a cucurbit [n] uril refers to a compound having a cyclic structure similar to a cucurbit [n] uril but in which one or some of the units of the formula
- a multi-nuclear metal complex being partially encapsulated by a cucurbit [7 to 12] uril or analogue thereof, it is meant that part of the metal complex is located within the cavity of the cucurbit [7 to 12] uril or analogue thereof.
- the metal complex is reversibly encapsulated by the cucurbit [n] uril or analogue thereof in the sense that under certain conditions the metal complex is released from the cucurbit [n] uril or analogue thereof.
- alkyl used either alone or in a compound word such as "alkylaryl” denotes a straight chain, branched or mono- or poly- cyclic alkyl, preferably C ⁇ -30 alkyl .
- straight chain and branched alkyl include methyl, ethyl, propyl , isopropyl, butyl, isbutyl, sec-butyl, tert-butyl, amyl , isoa yl, sec-amyl, 1,2- dimethylpropyl , 1, 1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl , 1,1- dimethylbutyl , 2 , 2 -dimethylbutyl , 3 , 3-dimethylbutyl, 1,2- dimethylbutyl , 1 , 3-dimethylbutyl , 1 , 2 , 2-trimethylpropyl , 1,
- cyclic alkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl and the like.
- alkenyl used either alone or in compound words denotes a straight chain, branched or cyclic alkene, preferably C 2 - 30 alkenyl .
- alkenyl examples include vinyl, allyl, 1-methylvinyl , butenyl , iso-butenyl, 3- methyl-'2-butenyl , 1-pentenyl, cyclopentenyl, 1-methyl- cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1- heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl , 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3- butadienyl, 1- , pentadienyl , 1, 3-cyclopentadienyl , 1,3- hexadienyl, 1, 4-hexadienyl, 1 , 3-cyclohexadienyl , 1,4- cyclohexadienyl , 1 , 3-cycloheptadie
- alkoxy used either alone or in compound words denotes straight chain or branched alkoxy, preferably C ⁇ _ 30 alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy isomers.
- aryl used either alone or in compound words denotes a single, polynuclear, conjugated or fused residue of an aromatic hydrocarbon or aromatic heterocyclic ring system. Examples of aryl include phenyl, naphtyl, pyridyl, furanyl , and the like.
- the aromatic heterocyclic ring system may contain 1 to 4 heteratoms independently selected from N, 0 and S.
- the present invention relates to multi-nuclear metal complexes partially encapsulated by one or more cucurbit [7 to 12] urils or analogues thereof.
- Such an association ofthe metal complex and one or more cucurbit [7 to 12] urils or analogues thereof may be referred to as an "association adduct" of the complex with the cucurbit [7 to 12] uril (s). or analogue (s) thereof.
- the metal complex is partially encapsulated by the cucurbit [7 to 12] uril or analogue ⁇ thereof and thus part of the metal complex protrudes from one or both of the openings of the cucurbit [7 to 12] uril or analogue thereof.
- the metal complex is partially encapsulated by two or more cucurbit [7 to 12] urils or analogues thereof.
- the metal complex may be any multi-nuclear metal complex. The metal centres in the complex may be the same or different.
- the metal complex is a metal complex of the formula (HA) , (IIB) , (IIC) , (IID) , (IIIA) , (IIIB) , (IIIC) or (HID) as defined above.
- Metal complexes of these formulas have anti-tumour activity.
- Metal complexes of these formulas are also resistant to chemical breakdown of the multi-nuclear complex in a human or animal body such that when the complex is administered to a human or animal body the complex is delivered to the active site in the body (eg a tumour) as a multi-nuclear metal complex.
- the present invention is not limited to metal complexes of formula (HA) , (IIB) , (IIC) , (IID) , (IIIA) , (IIIB) , (IIIC) or (HID) .
- the metal may for example be another multi -nuclear metal complex such as a complex of the formula: or
- the metal complex is a metal complex of the formula (HA) , (IIB) , (IIC), (IID) , (IIIA), (IIIB), (IIIC) or (HID), wherein M is Pt(II) .
- the metal complex is a metal complex of the formula (HA) or (IIIA) , wherein M is Pt(II) .
- R 6 groups may be the same or different and may be hydrogen, optionally substituted straight or branched alkyl (eg Cx-s alkyl) , optionally substituted aryl, optionally substituted alkylaryl, optionally substituted .
- arylalkyl optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl , halogen, pseudohalogen, hydroxy, carbonyl, formyl , nitro, amido, a ino, alkoxy, aryloxy and sulfonic acid salts, or the two R 6 groups in (R) 2 may be combined so that the (R ⁇ ) 2 represents a double bonded oxygen or sulfur.
- the optional substituents may be selected from aryl, cycloalkyl of 2 to 6 carbon atoms, cycloalkenyl, arylalkyl, halogen, pseudohalogen, hydroxyl, alkoxy, acycloamino or carboxylic acid salts or esters of 1 to 5 carbon atoms.
- the term "pseudohalogen” has the meaning found at page 560 of "Advanced Inorganic Chemistry" by Cotton and Wilkinson, Interscience Publishers, 1966. That text describes a pseudohalogen as being a molecule consisting of more than two electronegative atoms, which, in the free state, represents halogens .
- B is selected from the group consisting of ammine (NH 3 ) , primary amines, secondary amines, tertiary amines, and groups containing heterocyclic rings containing one or more N atoms.
- the heterocyclic ring containing one or more N atoms may be an aromatic group or an aliphatic group.
- B may for example be a branched or straight chain alkyl amine (typically C ⁇ _ 5 alkyl amine) , aryl amine, arylalkylamine or an alkenyl amine (typically C ⁇ _ 5 alkenyl amine) .
- B may also be a cycloakylamine, polycyclic hydrocarbon amine, nucleoside, nucleotide, pyridine-type nitrogen containing group or an amine with hydroxy, alkoxy (typically C ⁇ _ 5 alkoxy) , carboxylic acid or acid ester, nitro or halo substituents .
- Preferred primary amines are alkyl -amines of the formula NH 2 -R 10 where R 10 is a linear or branched C ⁇ _ 5 alkyl, a C 3 -C e cycloalkyl group (i.e. cyclopropyl , cyclobutyl, cyclopentyl or cyclohexyl) , or -CH 2 0H.
- Preferred secondary amines include alkyl -amines of the formula NH(R 10 ) 2 wherein each R 10 is independently selected and R 10 is as defined above.
- Two B ligands coordinated to a single M atom may be a bidentate ligand such as a diammine.
- E and one or two B ligands may be part of the same tridentate or tetradentate ligand.
- E may be any ligand containing two or more N atoms having a lone pair of electrons wherein one such N atom is coordinated with one M atom, and another such N atom is coordinated with another M atom.
- E may for example have the formula:
- R 7 and R 9 groups are each independently selected from the group consisting of hydrogen, alkyl (typically Ci- 5 alkyl), aryl, cycloalkyl, cycloalkenyl, arylalkyl, halogen, pseudohalogen, hydroxy, alkoxy, aryloxy, carboxylic acid ester and carboxylic acid salt, preferably all R 7 and R 9 groups are H;
- R 8 is selected from the group consisting of alkyl (eg.
- each D and G is independently selected from hydrogen, alkyl (typically C ⁇ _ 5 alkyl), aryl, alkylaryl, arylalkyl, alkenyl, cycloalkyl, cycloalkenyl, halogen, pseudohalogen, hydroxy, alkoxy, aryloxy or sulphonic acids or salts thereof.
- D and G are hydrogen.
- E may for example be spermidine, spermidine doubly methylated at the central N atom, spermine, dipyrazolylmethane or 1, 6-hexanediammine.
- B and E are neutral in charge, the overall charge of the metal complex of formula (HA) , (IIB) or (IIC) is typically 2 + and the metal complex of formula (IID) is typically neutral.
- B and E are neutral in charge, the overall charge of the metal complex of formula (IIIA) , (IIIB) or (IIIC) is typically 4 + and the metal complex of formula (HID) is typically 2 + .
- Various multi-nuclear platinum (II) complexes having anti-tumour activity are described in the prior art.
- multi-nuclear platinum(II) complexes having anti -tumour activity are described in the article Wheate NJ and Collins JG, "Multi-nuclear platinum complexes as anti-cancer drugs", Coordinated Chemistry Reviews, 241 (2003), 133-145, and in the chapter by Farrell, N in "Platinum-Based Drugs in Cancer Therapy", Humana Press Totowa, Kellard L.R. and Farrell N.P. (Eds) , 2000, pp 321-338, both of which are incorporated herein by reference.
- the multi-nuclear metal complex used in the present invention may be any of the multi-nuclear platinum(II) complexes described in ' either of those references . Examples of specific multi-nuclear platinum (II) complexes having anti-tumour activity described in the prior art include:
- the metal complex is a metal complex of formula (HA) wherein X is chloride, B is ammine and E is dipyrazolylmethane .
- This complex, with the counter ion chloride, is known as ⁇ trans-diamminechloro ( ⁇ -dipyrazolylmethane) platinum (II) ⁇ chloride.
- the complex is referred to below as "Di-Pt" .
- the metal complex is a metal complex of formula (HA) wherein X is chloride, B is ammine and E is spermidine.
- the metal complex is a metal complex of formula (IIIA) wherein X is chloride, B is ammine, E is dipyrazolylmethane.
- This complex with chloride counter ions is known as ⁇ trans- diamminebis ⁇ trans-diamminechloro ( ⁇ -dipyrazolyl methane) platinum (II) ⁇ platinum(H) jchloride .
- This complex is referred to below as "Tri-Pt" .
- the metal complex is a metal complex of formula (IIIA) wherein X is chloride, B is ammine and E is 1, 6-hexanediammine .
- This complex with nitrate counter ions, is known as ⁇ trans- diamminebis ⁇ trans-diamminechloro ( ⁇ -1 , 6- hexanediamine) platinum (II) ⁇ platinum(H) ⁇ nitrate.
- This complex is referred to below as "BBR3464" .
- the cucurbit [7 to 12] uril or analogue thereof may be any cucurbit [7 to 12] uril or analogue thereof capable of encapsulating part of the metal complex.
- the cucurbit [7 to 12] uril is a cucurbit [7 to 12] uril of the formula (I) .
- the metal complex is partially encapsulated by two or more cucurbit [7 to 12] urils or analogues thereof, the two or more cucurbit [7 to 12] urils or analogues thereof may be the same or different.
- R 1 and R 2 are univalent radicals, R 1 and R 2 are independently selected from the group consisting of -R, -OR, -SR, -NR 2 where each R is independently selected, -N0 2 , -CN, -X,
- each R is independently selected, -SR, o -SOR, -S-o-R , -S0 2 R, -S-S-R, -BR? where each R is independently selected, -PR 2 where each R is independently selected, o o II II
- R is independently selected, -P-NR.
- OR NR • .2 where each R is independently selected, -P + R 2 where each R is independently selected and a metal or metal complex, wherein R is H, an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical, or an optionally substituted heterocyclyl radical, and X is halo.
- R may for example be H or a straight chain or branched C ⁇ _ 5 alkyl, or C 2 -5 alkenyl.
- R 1 and R 2 may for example be selected from H, an optionally substituted alkyl (e.g.
- a C X - 5 alkyl such as methyl, ethyl, propyl , isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, etc), optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl (e.g. phenyl , naphthyl, pyridyl, furanyl or thiophenyl) , -OR, -SR or -NR 2 .
- R 1 and R 2 are univalent radicals
- R 1 and R 2 each include less than 30 carbon atoms.
- R 1 and R 2 may for example be independently selected from the group consisting of alkyl groups of 1 to 30 carbon atoms, alkenyl groups of 2 to 30 carbon atoms, cyclic hydrocarbon groups of 5 to 30 carbon atoms, cyclic groups of 4 to 30 carbon atoms with one or more heteroatoms such as 0, N or S, aryl groups of 6 to 30 carbon atoms, and aryl groups of 5 to 30 carbon atoms with one or more hetero atoms such as 0, N or S .
- R 1 and R 2 may for example be an alkoxy group such as methoxy, ethoxy, propyloxy etc.
- R 1 and R 2 may also be a hydroxy, halo, cyano, nitro, amino, alkylamino or alkylthio radical .
- optionally substituted cyclic groups formed by R 1 , R 2 and the carbon atoms to which they are bound include optionally substituted saturated or unsaturated cyclic hydrocarbon groups of 5 to 30 carbon atoms, and optionally substituted saturated or unsaturated cyclic groups of 3 to 30, typically 4 to 30, carbon atoms with one or more heteroatoms such as O, N or S .
- the divalent radical which may link R 1 and R 2 of adjacent units of the formula (B) in the compound of formula (1) may for example, be a divalent optionally substituted straight chain or branched, saturated or unsaturated hydrocarbon radical comprising 1 or more carbon atoms.
- the divalent radical may consist of or contain one or more heteroatoms such as 0, N or S .
- R is an optionally substituted hydrocarbon radical or an optionally substituted heterocyclyl radical
- the hydrocarbon radical or the heterocyclyl radical may be substituted by one or more substituents.
- R 1 , R 2 and the carbon atoms to which they are bound together form an optionally substituted cyclic group the cyclic group may be substituted by one or more substituents.
- the optional substituents can be any group and may for example be an optionally substituted alkyl (eg a Ci- 5 alkyl) , an optionally substituted alkenyl (eg. a C 2 -s alkyenyl) , an optionally substituted alkynyl (eg a C 2 _ 5 alkynyl) , an optionally substituted heterocyclyl, an optionally substituted aryl, halo (e.g.
- the optional substituent may also be a borane, a phosphorous containing group such as a phosphine, alkyl phosphine, phosphate or phosphoramide, a silicon containing group or a selenium containing group.
- Z is selected from the group consisting of
- X is halo (e.g. F, Cl , Br or I) and R is H, alkyl (eg C ⁇ . 5 alkyl) , alkenyl (eg C 2 _ 5 alkynyl, alkynyl (eg C 2 - 5 alkynyl), aryl, heteroaryl or saturated or unsaturated heterocyclyl .
- alkyl eg C ⁇ . 5 alkyl
- alkenyl eg C 2 _ 5 alkynyl, alkynyl (eg C 2 - 5 alkynyl)
- aryl aryl
- heteroaryl saturated or unsaturated heterocyclyl .
- the majority of cucurbit [4 to 12]urils prepared to date are cucurbit [4 to 12] urils wherein R 3 is O and R 5 is H in all units of the formula (B) making up the cucurbituril .
- the cucurbit [7 to 12] uril is a cucurbit [7 to 12]uril of formula (I), wherein R 3 is 0 and R 5 is H in all the units of formula (B) making up the formula (I) .
- Cucurbit [7 to 12]urils of formula (I) may be prepared as described in WO 00/68232, US patent no. 6,365,734 or as described in international patent application no. PCT/AU2004/001232.
- Analogues of cucurbit [7 to 12] urils may be prepared as described in Lagona J. et al , "Cucurbit [n] uril Analogue", Organic Letters, 2003, vol 5, no.
- An association adduct of a multi-nuclear metal complex and a cucurbit [7 to 12] uril or an analogue thereof may be prepared by contacting the metal complex with the cucurbit [7 to 12] uril or analogue thereof.
- the metal complex is contacted with the cucurbit [7 to 12] uril or analogue thereof by dissolving or suspending the metal complex and the cucurbit [7 to 12] uril or analogue thereof in a solvent, typically water.
- the association adduct may for example be formed by the following process: 1 or 2 mole equivalents of cucurbit [7 to 12] uril or analogue thereof (note 1) to the metal complex are either dissolved or suspended in water (note 2) , the metal complex is then added, and the mixture stirred at ambient temperature ( ⁇ 35°C) .
- the reverse order of addition can be used particularly when the cucurbit [7 to 12] uril or analogues thereof has a low solubility in an aqueous system (note 3) . After several hours, all insoluble material is collected or removed by filtration. The formation of the association adduct may be verified by NMR spectroscopy. The aqueous mixture is then freeze-dried (note 4) to give the association adduct as a fine powder.
- the stoichiometry is dependent upon the requirement for a 2:1, a 1:1 or any other required combination of cucurbit [7 to 12] uril or analogue thereof to the multi- nuclear metal complex in the association adduct.
- saline solution may be used. Heating to boiling can be used to dissolve cucurbit [7 to 12]uril or analogue thereof in an aqueous system which is then cooled to ambient temperature before the addition of the metal complex.
- the present inventors have found that multi-nuclear metal complexes partially encapsulated by one or more cucurbit [7 to 12] urils or analogues thereof, are less toxic to humans and animals than the unassociated metal complex.
- the present invention therefore provides a method for reducing the in vivo toxicity of a multi-nuclear metal complex, the method comprising forming an association of the metal complex with one or more cucurbit [7 to 12] urils or analogues thereof wherein part of the metal complex is encapsulated by the one or more cucurbit [7 to 12] urils or analogues thereof.
- the present inventors believe that the reduction in vivo toxicity of the multi-nuclear metal complex when partially encapsulated by one or more cucurbit [7 to 12] urils or analogues thereof is due to the encapsulation of the metal complex resulting in a decrease in undesirable reactions between the metal complex and compounds in the human or animal body. It is believed that the toxicity of multi- nuclear metal complexes is due, at least in part, to reactions between compounds in the human or animal body, such as thioproteins and/or plasma proteins, and the metal complex, the products of which are believed to induce a toxic ' reaction.
- the partial encapsulation of the metal complex by one or more cucurbit [7 to 12] urils or analogues thereof is believed to reduce these reactions, particularly in the blood stream.
- the reduction in undesirable bio reactions is believed to be due to the cucurbit [7 to 12] uril or analogue thereof hindering reactions between molecules in the body and the multi- nuclear metal complex either sterically by the bulk of the cucurbit [7 to 12] uril or analogue thereof or through a repulsive action by the electronegative portals of the cucurbit [7 to 12] ril or analogue thereof.
- Many multi-nuclear metal complexes have anti-tumour activity.
- the present invention provides a method for treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a multi-nuclear metal complex having anti-tumour activity partially encapsulated by one or more cucurbit [7 to 12] urils or analogues thereof.
- the anti-tumour activity of a multi-nuclear metal complex can readily be determined by a person skilled in the art by in vi tro screening of the activity of the complex against cancer cell lines.
- the multi-nuclear metal complex having anti- tumour activity is a metal complex of formula (HA) , (IIB), (IIC), (IID), (IIIA), (IIIB), (IIIC) or (HID) as defined above.
- the multi-nuclear metal complex is a metal complex of formula (HA) , (IIB) , (IIC) , (IID) , (IIIA) , (IIIB) , (IIIC) or (HID) in which M is Pt(II) .
- the multi-nuclear metal complex having anti-tumour activity is selected from
- the subject may be a mammal, preferably a human.
- the subject may be a non-human primate or non-primate such as used in animal model testing. While it is particularly contemplated that the method is suitable for use in medical treatment of humans, it is also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, ponies, donkeys, mules, llama, alpaca, pigs, cattle and sheep, or zoo animals such as primates, felids, canids, bovids, and ungulates.
- Suitable mammals include members of the Orders Primates, Rodentia, Lagomorpha, Cetacea, Carnivora, Perissodactyla and Artiodactyla.
- therapeutically effective amount refers to an amount effective to yield a desired therapeutic response, for example, to treat cancer by slowing the rate of growth or spread of the cancer cells.
- the specific "therapeutically effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the subject, the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulation employed.
- the association adduct may for example be administered at an effective dose relative to cisplatin taking into account the LD 50 value of the association adduct.
- the terms "treating", “treatment” and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect.
- the effect may be prophylactic in terms of completely or partially preventing a disease or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure of a disease.
- Treating covers any treatment of, or prevention of disease, and includes: (a) preventing the disease from occurring in a subject that may be predisposed to the disease, but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving or ameliorating the effects of the disease, i.e., cause regression of the effects of the disease.
- the association adduct of the metal complex and one or more cucurbit [7 to 12] urils or analogues thereof may additionally be combined with other therapeutic agents to provide an operative combination. It is intended to include any chemically compatible combination of therapeutic agents, as long as the combination does not eliminate the activity of the association adduct.
- association adduct and the other therapeutic agent may be administered separately, sequentially or simultaneously.
- the association adduct can be administered to the subject, orally or parenterally by injection. Administration may be intravenously, intraarterial , intraperitoneally, intramuscularly, subcutaneously, intracavity, transdermally or infusion by, for example, osmotic pump.
- the compositions of the present invention comprise at least one association adduct of a multi-nuclear metal complex having anti-tumour activity and one or more cucurbit [7 to 12] urils or analogues thereof, together with one or more pharmaceutically acceptable carriers.
- the composition may optionally also comprise other therapeutic agents.
- compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
- the compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the pharmaceutically acceptable carrier and any other components of the composition. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with the carrier and any other components of the composition, and then if necessary shaping the product.
- a "pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the active ingredient to the subject.
- the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
- the carrier is pharmaceutically "acceptable" in the sense of being not biologically or otherwise undesirable i.e. the carrier may be administered to a subject along with the active ingredient without causing any or a substantial adverse reaction.
- a pharmaceutical composition of the present invention for oral use may contain one or more agents selected from the group of sweetening agents, disintegrating agents, flavouring agents, colouring agents, preservatives, lubricants and time delay agents, in order to produce pharmaceutically elegant and palatable preparations.
- Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
- Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
- Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
- Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
- Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
- Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
- compositions of the present invention in the form of tablets may contain (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- non-aqueous carriers which may be used in such compositions are propylene glycol , polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, anti-microbials, anti-oxidants , chelating agents, growth factors and inert gases and the like.
- Veterinary compositions may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for: (a) oral administration, e.g.
- parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat;
- topical applications e.g. as a cream, ointment or spray applied to the skin; or
- intravaginally e.g. as a pessary, cream or foam.
- EXAMPLE 2 Preparation of a triplatinu complex encapsulated by cucurbit [n] uril, 1:2 association adduct Approximately 50 mg of either unsubstituted cucurbit [7] uril or unsubstituted cucurbit [8] uril dissolved in water (10 mL) was added to half a molar equivalent of BBR3464 dissolved in water (10 mL) . Samples were left to stir for 1 hr at room temperature, after which the solutions were freeze-dried. The samples were analysed by 1 H NMR spectroscopy showing that the metal complex was encapsulated by the cucurbituril. Similar methods could also be used to prepare an association adduct of the metal complex with other unsubstituted or substituted cucurbit [7 to 12]urils, or analogues of cucurbit [7 to 12] urils.
- BBR3464/unsubstituted cucurbit [8] uril adducts were prepared as in Example 2.
- the BBR3464/unsubstituted cucurbit [10] uril adduct was prepared as described in Example 5.
- EXAMPLE 5 Sparingly soluble cucurbit [n] uril BBR3464 (6 mg) dissolved in water (2 mL) was added to 5 mg of unsubstituted cucurbit [10] uril , another '4 mL of water added and the suspension stirred overnight. An additional 5 mg of cucurbit [10] uril and 5 mL of water was then added, and the suspension stirred for a further 48 hr. The suspension was then centrifuged and the supernatant freeze-dried. Samples were analysed by ⁇ NMR spectroscopy showing that the metal complex was encapsulated by the cucurbituril.
- association adducts As the association adducts gave similar values to the free complex, the association adducts are considered effective anti-cancer agents against these leukaemia cell lines.
- the general cytotoxic activity of BBR3571 and Di-Pt was' thus maintained in the association adducts of BBR3571 and Di-Pt with unsubstituted cucurbit [7] uril .
- the maximum tolerated dose of free platinum complex BBR3571 is 0.1 mg/kg compared to 0.45 mg/kg for the cucurbit [7] uril/BBR3571 association adduct.
- the cytotoxic activity of the association adduct of BBR3571 and unsubstituted cucurbit [7] uril at a drug equivalence of 1 (equimolar amount) was compared to the free metal complex.
- the experiment was limited to the MTD of the free metal complex.
- Female balb/c nude mice were inoculated subcutaneously on the flank with cells from the 2008 ovarian carcinoma cell line.
- mice were randomised into groups and administered either a saline solution of BBR3571 at MTD or a saline solution of the association adduct of unsubstituted cucurbit [7] uril and BBR3571 in an equimolar amount (0.27 mg/kg of the association adduct) .
- the controls were administered either as saline or a saline solution of unsubstituted cucurbit [7] uril .
- Doses were administered on days 0, 4 and 8. The results are shown in Table IV.
- TGI Tumour Growth Index
- GDI Growth Delay Index
- EXAMPLE 8 General X H NMR spectra of cucurbit [ ⁇ ] ril/metal complex association adducts
- the characteristic shielding effect of the cavity of cucurbit [n] uril shows that in most examples the proton resonances of the metal complex as an association adduct are shifted up field (indicated by a minus sign) when compared to samples of the free metal complex. This shows that the linking group E is bound within the cavity of cucurbit [n] uril, and thus confirming that the metal complex is partially encapsulated by the cucurbituril.
- the present inventors have found that cucurbit [7 to 12] urils and analogues thereof partially encapsulate multi-nuclear metal complexes, and that the resultant association adducts are less toxic to the human or animal body than the free metal complex. In view of the size of multi-nuclear metal complexes, they are not fully encapsulated within the cucurbit [7 to 12] uril or analogue thereof.
- association adducts of multi-nuclear metal complexes having anti-tumour activity and one or more cucurbit [7 to 12] urils or analogues thereof may be used for the treatment of conditions which can be treated using the metal complex.
- the partial encapsulation of the multi-nuclear metal complex by one or more cucurbit [7 to 12] rils or analogues thereof may also provide a number of other advantages.
- the cucurbit [7 to 12]uril or analogue thereof may provide for better delivery or targeting of the multi- nuclear metal complex to the desired site in the body. Targeting could be achieved through appropriate substituents on the cucurbit [7 to 12] uril or analogue thereof.
- a lipophilic group on the cucurbit [7 to 12] uril or analogue thereof may assist in the delivery of the multi-nuclear metal complex to lipophilic tumours and cancers such as those of the liver.
- cucurbit [7 to 12] urils or analogues thereof attached to or incorporated -into polymers could provide a means for delivery of the multi-nuclear metal complex overextended periods of time.
- different cucurbit [7 to 12] urils may have different binding capacities to the multi-nuclear metal complex, and thus could be used to provide a particular rate of release of the multi-nuclear metal complex over time.
- the multi -nuclear metal complexes partially encapsulated by one or more cucurbit [7 to 12] urils or analogues thereof of the present invention have a wide range of applications in the medical and veterinary fields.
- the method for reducing the in vivo toxicity of a multi-nuclear metal complex of the present invention can, for example, be used to reduce the toxicity of pharmaceutically active multi- nuclear metal complexes, including multi-nuclear metal complexes having anti-tumour activity.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05700077A EP1704151A4 (en) | 2004-01-15 | 2005-01-14 | Multi-nuclear metal complexes partially encapsulated by cucurbit[7-12] urils |
JP2006548042A JP2007517809A (en) | 2004-01-15 | 2005-01-14 | Polynuclear metal complex partially encapsulated in cucurbit [7-12] uril |
CA002552027A CA2552027A1 (en) | 2004-01-15 | 2005-01-14 | Multi-nuclear metal complexes partially encapsulated by cucurbit[7-12]urils |
AU2005204589A AU2005204589A1 (en) | 2004-01-15 | 2005-01-14 | Multi-nuclear metal complexes partially encapsulated by Cucurbit[7-12]urils |
US10/586,302 US20080182834A1 (en) | 2004-01-15 | 2005-01-14 | Multi-Nuclear Metal Complexes Partially Encapsulated by Cucurbit[7-12]Urils |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004900173A AU2004900173A0 (en) | 2004-01-15 | Association Adduct | |
AU2004900173 | 2004-01-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005068469A1 true WO2005068469A1 (en) | 2005-07-28 |
Family
ID=34754141
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AU2005/000045 WO2005068469A1 (en) | 2004-01-15 | 2005-01-14 | Multi-nuclear metal complexes partially encapsulated by cucurbit[7-12]urils |
Country Status (7)
Country | Link |
---|---|
US (1) | US20080182834A1 (en) |
EP (1) | EP1704151A4 (en) |
JP (1) | JP2007517809A (en) |
KR (1) | KR20060124696A (en) |
CN (1) | CN1922187A (en) |
CA (1) | CA2552027A1 (en) |
WO (1) | WO2005068469A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008123685A1 (en) * | 2007-04-04 | 2008-10-16 | Postech Academy-Industry Foundation | Liposome sensitive to ph or reductive condition and method of preparing the same |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014077640A1 (en) * | 2012-11-16 | 2014-05-22 | Postech Academy-Industry Foundation | Composition for slow emission of fragrance comprising complexes of cucurbituril and fragrance molecule |
CN103288882B (en) * | 2013-05-30 | 2016-08-10 | 贵州大学 | One class eight yuan melon ring macropore Supramolecular self assembly body and synthetic method thereof |
CN104086691B (en) * | 2014-07-18 | 2016-08-24 | 山东大学 | A kind of preparation method of the polymer containing Cucurbituril structure |
GB2556619B (en) * | 2016-08-24 | 2019-01-02 | Aqdot Ltd | Suspension compositions |
CN107737345A (en) * | 2017-10-26 | 2018-02-27 | 昆明理工大学 | A kind of inclusion compound of Nedaplatin and cucurbit [n] urea |
CN107737346A (en) * | 2017-10-26 | 2018-02-27 | 昆明理工大学 | A kind of inclusion compound of picoplatin and cucurbit [n] urea |
US20240262853A1 (en) * | 2021-05-24 | 2024-08-08 | Northwestern University | Selective separation of hexachloroplatinate(iv) dianions based on exo-binding with cucurbit[6]uril |
CN113563351B (en) * | 2021-07-13 | 2022-11-29 | 昆明理工大学 | Water-soluble ring-opening cucurbituril fluorescent probe and application thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003024978A1 (en) * | 2001-09-18 | 2003-03-27 | Postech Foundation | Inclusion compound comprising cucurbituril derivatives as host molecule and pharmaceutical composition comprising the same |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE447902B (en) * | 1977-10-19 | 1986-12-22 | Johnson Matthey Co Ltd | CIS COORDINATION ASSOCIATION OF PLATINUM AND COMPOSITION CONTAINING ASSOCIATION |
US4797393A (en) * | 1986-07-25 | 1989-01-10 | University Of Vermont And State Agricultural College | Bis-platinum complexes as chemotherapeutic agents |
US5380897A (en) * | 1993-05-25 | 1995-01-10 | Hoeschele; James D. | Tri(platinum) complexes |
EP1094065B1 (en) * | 1999-10-21 | 2003-12-17 | Pohang University of Science and Technology Foundation | Preparation methods of cucurbituril derivatives |
US6673370B2 (en) * | 2001-05-15 | 2004-01-06 | Biomedicines, Inc. | Oxidized collagen formulations for use with non-compatible pharmaceutical agents |
-
2005
- 2005-01-14 WO PCT/AU2005/000045 patent/WO2005068469A1/en active Application Filing
- 2005-01-14 CN CNA2005800056646A patent/CN1922187A/en active Pending
- 2005-01-14 KR KR1020067016213A patent/KR20060124696A/en not_active Application Discontinuation
- 2005-01-14 US US10/586,302 patent/US20080182834A1/en not_active Abandoned
- 2005-01-14 JP JP2006548042A patent/JP2007517809A/en active Pending
- 2005-01-14 CA CA002552027A patent/CA2552027A1/en not_active Abandoned
- 2005-01-14 EP EP05700077A patent/EP1704151A4/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003024978A1 (en) * | 2001-09-18 | 2003-03-27 | Postech Foundation | Inclusion compound comprising cucurbituril derivatives as host molecule and pharmaceutical composition comprising the same |
Non-Patent Citations (3)
Title |
---|
KIM S.Y. ET AL: "Macromolecules: Cyclen, Cyclam, and their Transition Metal Complexes Encapsulated in Cucurbit(8)uril.", ANGEW.CHEM.INT.ED. 20011, vol. 40, no. 11, 2001, pages 2119 - 2121, XP008096003 * |
See also references of EP1704151A4 * |
WHANG D. ET AL: "A Molecular Bowl with Metal Ion as Bottom: Reversible Inclusion of Organic Molecules in Cesium Ion Complexed Cucurbituril.", AGNEW.CHEM.INT ED.1998., vol. 37, no. 1/2, 1998, pages 78 - 80, XP008096004 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008123685A1 (en) * | 2007-04-04 | 2008-10-16 | Postech Academy-Industry Foundation | Liposome sensitive to ph or reductive condition and method of preparing the same |
Also Published As
Publication number | Publication date |
---|---|
EP1704151A1 (en) | 2006-09-27 |
KR20060124696A (en) | 2006-12-05 |
EP1704151A4 (en) | 2008-07-30 |
JP2007517809A (en) | 2007-07-05 |
US20080182834A1 (en) | 2008-07-31 |
CN1922187A (en) | 2007-02-28 |
CA2552027A1 (en) | 2005-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2005068469A1 (en) | Multi-nuclear metal complexes partially encapsulated by cucurbit[7-12]urils | |
EP1212323B1 (en) | Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity | |
DE69224839T2 (en) | Manganese complexes with nitrogen-containing macrocyclic ligands, effective as superoxide dismutase catalysts. | |
AU2016326392B2 (en) | Modified cytotoxins and their therapeutic use | |
AU2011314319B2 (en) | Metal complexes of N-heterocyclic carbenes | |
AU2004270730B2 (en) | Metal complexes of N-heterocyclic carbenes as radiopharmaceuticals and antibiotics | |
KR20090107039A (en) | Radioprotector compounds and related methods | |
US20190381179A1 (en) | Modified cytotoxins and their therapeutic use | |
AU2005204589A1 (en) | Multi-nuclear metal complexes partially encapsulated by Cucurbit[7-12]urils | |
AU2010306994B2 (en) | Metal complexes of N-heterocyclic carbenes | |
AU2019281584B2 (en) | Selective A2A receptor antagonist | |
JP5919202B2 (en) | Medical carbon monoxide releasing rhenium compounds | |
WO2007058630A1 (en) | Novel bis(amino)-ortho-dicarbaborane cluster compounds | |
FI83086C (en) | Process for the preparation of complexes with anti-tumor effect | |
EP1185540B1 (en) | Ruthenium dimeric complexes suitable as antimetastatic and antineoplastic agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 3638/DELNP/2006 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2552027 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005700077 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006548042 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005204589 Country of ref document: AU |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: DE |
|
ENP | Entry into the national phase |
Ref document number: 2005204589 Country of ref document: AU Date of ref document: 20050114 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2005204589 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020067016213 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200580005664.6 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 2005700077 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020067016213 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10586302 Country of ref document: US |