WO2010121575A1 - Oxalato complexes of platinum - Google Patents
Oxalato complexes of platinum Download PDFInfo
- Publication number
- WO2010121575A1 WO2010121575A1 PCT/CZ2009/000135 CZ2009000135W WO2010121575A1 WO 2010121575 A1 WO2010121575 A1 WO 2010121575A1 CZ 2009000135 W CZ2009000135 W CZ 2009000135W WO 2010121575 A1 WO2010121575 A1 WO 2010121575A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- cycloheteroalkyl
- platinum
- cycloalkyl
- cycloheteroalkenyl
- Prior art date
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 129
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 36
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- NWBJYWHLCVSVIJ-UHFFFAOYSA-N N-benzyladenine Chemical class N=1C=NC=2NC=NC=2C=1NCC1=CC=CC=C1 NWBJYWHLCVSVIJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 12
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 125000000524 functional group Chemical group 0.000 claims abstract description 8
- 125000005017 substituted alkenyl group Chemical group 0.000 claims abstract description 8
- 125000004426 substituted alkynyl group Chemical group 0.000 claims abstract description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 8
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 6
- 125000004429 atom Chemical group 0.000 claims abstract description 5
- 230000003647 oxidation Effects 0.000 claims abstract description 5
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 229930024421 Adenine Natural products 0.000 claims abstract description 3
- NPDLYUOYAGBHFB-WDSKDSINSA-N Asn-Arg Chemical group NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NPDLYUOYAGBHFB-WDSKDSINSA-N 0.000 claims abstract description 3
- 229960000643 adenine Drugs 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- -1 cycloheteroalkyl Chemical group 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000000144 pharmacologic effect Effects 0.000 claims description 4
- 150000003138 primary alcohols Chemical class 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 150000003333 secondary alcohols Chemical class 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000006323 alkenyl amino group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 2
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000005026 carboxyaryl group Chemical group 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 159000000011 group IA salts Chemical class 0.000 claims description 2
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- 238000004566 IR spectroscopy Methods 0.000 description 16
- 239000012153 distilled water Substances 0.000 description 14
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 13
- 101100498160 Mus musculus Dach1 gene Proteins 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000003013 cytotoxicity Effects 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 238000004455 differential thermal analysis Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 5
- 229960001756 oxaliplatin Drugs 0.000 description 5
- 150000003057 platinum Chemical class 0.000 description 5
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-YYWVXINBSA-N N,N-dimethylformamide-d7 Chemical compound [2H]C(=O)N(C([2H])([2H])[2H])C([2H])([2H])[2H] ZMXDDKWLCZADIW-YYWVXINBSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- MLCJWRIUYXIWNU-OWOJBTEDSA-N (e)-ethene-1,2-diamine Chemical compound N\C=C\N MLCJWRIUYXIWNU-OWOJBTEDSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- WRKDNJQBWFMBHS-UHFFFAOYSA-N 2-chloro-n-[(2,4-dimethoxyphenyl)methyl]-9-propan-2-ylpurin-6-amine Chemical compound COC1=CC(OC)=CC=C1CNC1=NC(Cl)=NC2=C1N=CN2C(C)C WRKDNJQBWFMBHS-UHFFFAOYSA-N 0.000 description 3
- XEFUFVXONNYENZ-UHFFFAOYSA-N 2-chloro-n-[(2-methoxyphenyl)methyl]-9-propan-2-ylpurin-6-amine Chemical compound COC1=CC=CC=C1CNC1=NC(Cl)=NC2=C1N=CN2C(C)C XEFUFVXONNYENZ-UHFFFAOYSA-N 0.000 description 3
- HUPWWOTYHSMCEW-UHFFFAOYSA-N 2-chloro-n-[(3,4-dimethoxyphenyl)methyl]-9-propan-2-ylpurin-6-amine Chemical compound C1=C(OC)C(OC)=CC=C1CNC1=NC(Cl)=NC2=C1N=CN2C(C)C HUPWWOTYHSMCEW-UHFFFAOYSA-N 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- NSQQTIIWZCVMRW-UHFFFAOYSA-N n-benzyl-2-chloro-9-propan-2-ylpurin-6-amine Chemical compound N1=C(Cl)N=C2N(C(C)C)C=NC2=C1NCC1=CC=CC=C1 NSQQTIIWZCVMRW-UHFFFAOYSA-N 0.000 description 3
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 3
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 3
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 3
- 238000004834 15N NMR spectroscopy Methods 0.000 description 2
- 238000004294 195Pt NMR spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FRGZCWSUTYKXPB-UHFFFAOYSA-N 2-chloro-n-[(3,5-dimethoxyphenyl)methyl]-9-propan-2-ylpurin-6-amine Chemical compound COC1=CC(OC)=CC(CNC=2C=3N=CN(C=3N=C(Cl)N=2)C(C)C)=C1 FRGZCWSUTYKXPB-UHFFFAOYSA-N 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 2
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 2
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 2
- 208000036566 Erythroleukaemia Diseases 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 208000021841 acute erythroid leukemia Diseases 0.000 description 2
- OPQGFIAVPSXOBO-UHFFFAOYSA-N bohemine Chemical compound N1=C(NCCCO)N=C2N(C(C)C)C=NC2=C1NCC1=CC=CC=C1 OPQGFIAVPSXOBO-UHFFFAOYSA-N 0.000 description 2
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 2
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical class NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- GTVPOLSIJWJJNY-UHFFFAOYSA-N olomoucine Chemical compound N1=C(NCCO)N=C2N(C)C=NC2=C1NCC1=CC=CC=C1 GTVPOLSIJWJJNY-UHFFFAOYSA-N 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
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- 238000002076 thermal analysis method Methods 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 1
- 0 *OC(C(Oc1ccccc1)=O)=O Chemical compound *OC(C(Oc1ccccc1)=O)=O 0.000 description 1
- WHDJEAZLMYPLGL-UHFFFAOYSA-N 2-[[6-[(phenylmethyl)amino]-9-propan-2-yl-2-purinyl]amino]ethanol Chemical compound N1=C(NCCO)N=C2N(C(C)C)C=NC2=C1NCC1=CC=CC=C1 WHDJEAZLMYPLGL-UHFFFAOYSA-N 0.000 description 1
- PDMSQJKBAMAEQE-UHFFFAOYSA-N 2-chloro-n-[(4-methoxyphenyl)methyl]-9-propan-2-ylpurin-6-amine Chemical compound C1=CC(OC)=CC=C1CNC1=NC(Cl)=NC2=C1N=CN2C(C)C PDMSQJKBAMAEQE-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
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- 238000002965 ELISA Methods 0.000 description 1
- 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 1
- 229910020427 K2PtCl4 Inorganic materials 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L Oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- DPKHZNPWBDQZCN-UHFFFAOYSA-N acridine orange free base Chemical class C1=CC(N(C)C)=CC2=NC3=CC(N(C)C)=CC=C3C=C21 DPKHZNPWBDQZCN-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
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- 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 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 1
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- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- VKIRRGRTJUUZHS-UHFFFAOYSA-N cyclohexane-1,4-diamine Chemical compound NC1CCC(N)CC1 VKIRRGRTJUUZHS-UHFFFAOYSA-N 0.000 description 1
- MKYNHKOAYQRSBD-UHFFFAOYSA-N dioxouranium;nitric acid Chemical compound O=[U]=O.O[N+]([O-])=O.O[N+]([O-])=O MKYNHKOAYQRSBD-UHFFFAOYSA-N 0.000 description 1
- QCPTVXCMROGZOL-UHFFFAOYSA-L dipotassium;oxalate;hydrate Chemical compound O.[K+].[K+].[O-]C(=O)C([O-])=O QCPTVXCMROGZOL-UHFFFAOYSA-L 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
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- 230000002045 lasting effect Effects 0.000 description 1
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- 238000005497 microtitration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- XRYGCVVVDCEPRL-UHFFFAOYSA-N n,1-dimethylpiperidin-4-amine Chemical compound CNC1CCN(C)CC1 XRYGCVVVDCEPRL-UHFFFAOYSA-N 0.000 description 1
- IQUFIVQRGAZYMZ-UHFFFAOYSA-N n-benzyl-7h-purin-6-amine Chemical compound N=1C=NC=2N=CNC=2C=1NCC1=CC=CC=C1.N=1C=NC=2N=CNC=2C=1NCC1=CC=CC=C1 IQUFIVQRGAZYMZ-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 229960002378 oftasceine Drugs 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- MUTQTHUBSRXFQO-UHFFFAOYSA-L oxalate;platinum(2+) Chemical class [Pt+2].[O-]C(=O)C([O-])=O MUTQTHUBSRXFQO-UHFFFAOYSA-L 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000003375 plant hormone Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000004436 sodium atom Chemical group 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the invention that belongs to the area of the platinum-based drugs of tumor diseases, relates to the platinum oxalate complexes involving the N6-benzyladenine derivatives, their preparation using M 2 [Pt(Ox) 2 ] • xhbO, where M is H, K, or Na atom, and their use in the medical practice as drugs and pharmaceutical compositions, which contain these complexes as the active substance.
- Platinum oxalato complexes are an important group of compounds, which is used in practice thanks to [(1 R,2R)-1 ,2-diaminocyclohexane-N,N ' ]-(oxalato-O,O ' )- platinum(ll) complex (oxaliplatin) having the general formula (A).
- Oxaliplatin synthesis is described in e.g. ⁇ Kidani, Y.; Inagaki, K. J. Med. Chem., 1978, 21, 1315-1318), US 4 169 846 patent or CZ 294668 patent and it consists of three steps depicted in the Scheme 1 , K 2 PtCl 4 + dach > [Pt(dach)Cl 2 ] (1)
- (1 ) is the preparation of c/s-[Pt(dach)Cl2] by the reaction of potassium tetrachloroplatinate, K 2 PtCU, with (1 R,2R)-1 ,2-diaminocyclohexane (dach) in water,
- (2) is the reaction of the prepared c/s-[Pt(dach)CI 2 ] with a silver(l) salt of an inorganic acid (e.g. AgNO 3 ) in water giving a diaqua-complex of the c/s-[Pt(dach)(H 2 O) 2 ] 2+ type,
- a silver(l) salt of an inorganic acid e.g. AgNO 3
- N6- benzyladenine derivatives were used: 2-chloro-N6-benzyl-9-isopropyladenine (L 1 ), 2- chloro-N6-(2-methoxybenzyl)-9-isopropyladenine (L 2 ), 2-chloro-N6-(4-methoxybenzyl)- 9-isopropyladenine (L 3 ), 2-(R)-(1 -ethyl-2-hydroxyethylamino)-N6-benzyl-9- isopropyladenine ⁇ roscovitine; L 4 ), 2-(3-hydroxypropylamino)-N6-benzyl-9- isopropyladenine (bohemine; L 5 ), 2-(2-hydroxyethylamino)-N6-benzyl-9- methyladenine (olomoucine; L 6 ), 2-(2-hydroxyethylamino)-N6-benzyl-9- isopropyladenine (isopropyl-
- the above-mentioned organic compounds are derived from a plant hormone 6-benzylaminopurine (N6-benzyladenine) described in CZ 294535 patent.
- Derivatives with various amino alcohols at the C2 position of the purine ring and with alkyl substituent at the N9 position of the purine skeleton belong to the group of the cyclin dependent kinase (CDK) inhibitors, which were proven significantly in vitro and in vivo cytotoxic active, as described in (Meijer, L; Borgne, A.; Mulner, 0.; Chong, J.P.J.; Blow, J. J.; Inagaki, N.; Inagaki, M.; Delcros, J.G.; Moulinoux, J.
- CDK cyclin dependent kinase
- platinum(ll) complexes of the general formula CZs-[Pt(L) 2 Cb] involving N6-benzyladenine-based CDK-inhibitors coordinated to the Pt(II) ion show high in vitro cytotoxic activity.
- formerly prepared platinum(ll) complexes with cytotoxic inactive N6-benzyladenin-based N-donor ligand substituted at the C2 position by a chlorine atom were determined to be non-cytotoxic as well.
- the IC50 values obtained on the mentioned cancer cells are 19, 20 and 50 ⁇ M, respectively, for roscovitine, 3, 3 and 5 ⁇ M, respectively, for cisplatin and 7, 7 and 8 ⁇ M, respectively, for oxaliplatin, described in publication (Malo ⁇ , M.; Travnicek, Z; Marek, R. Strnad, M. J. Inorg. Biochem. 2005, 99, 2127-2138).
- platinum(ll) oxalato complexes with various N-donor ligands have been prepared, e.g. with substituted 1 ,2-diaminocyclohexane, as described in WO 03/106469 file or in (Habala, L; Galanski, M.; Yasemi, A.; Nazarov, AA; von Keyse ⁇ ingk, N.G.; Keppler, B.K. Eur. J. Med. Chem. 2005, 40, 1149-1155), with ammonia, ⁇ Rochon, F.D.; Melanson, R.; Macquet, J. P.; Belanger-Gariepy, F.; Beauchamp, A.L. Inorg.
- the invention provides oxalato complexes of platinum in the oxidation state +Il and their crystal-solvates including a structural motif (I) or having the general formula (II) expressed by the structural formula [Pt(L) 2 (Ox)] or the general formula (III) expressed by the structural formula [Pt(L)(L ' )(ox)], where the symbols L and L ' stand for N6-benzyladenine derivative of the general formula (IV) bonded to the platinum atom of the basic motif (V)
- substituents R1, R2 a R3 are independently chosen from the group of: hydrogen atom, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, functional group and N-R ' R " group, where R ' and R " independently symbolize hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, alkenyl, substituted alkenyl, alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
- - functional group as employed herein by itself or as a part of another group represents amino, alkylamino, dialkylamino, alkenylamino, cycloalkylamino, cycloheteroalkylamino, cycloalkenylamino, cycloheteroalkenylamino, arylamino, heteroarylamino, acylamino, hydroxy, alkylhydroxy, alkoxy, aryloxy, cyano, carboxy, alkylcarboxy, carboxyalkyl, arylcarboxy, carboxyaryl, hydroxyamino, acyl, nitro, amido, nitroso, sulfonyl, sulfinyl, sulfamido, thio, alkylthio, arylthio, merkapto, carbamoyl,
- substituted alkyl substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloheteroalkyl, substituted cycloalkenyl, substituted cycloheteroalkenyl, substituted aryl and substituted heteroaryl as employed herein by themselves or as parts of other groups represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl and heteroaryl substituted by the substituents from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl, heteroaryl and a functional group.
- ⁇ x represents the number of the solvate molecules, preferably 1 to 6
- (SoIv) represents a concrete molecule of the used solvent and/or some of the reaction components, usually chosen from the group consisting of water, primary alcohol, secondary alcohol, acetone, ⁇ /, ⁇ / ' -dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, acetonitrile or diethyl ether, either individually or in combinations of the mentioned solvate molecules.
- the invention also provides the method of preparation of the platinum(ll) oxalato complexes of the general formulas (II) or (III), which uses reaction of the bis(oxalato)platinate alkaline salt or corresponding acid of the general formula M 2 [Pt(Ox) 2 ] • XH 2 O, where M comprises mainly H, K and Na, with an N6-benzyladenine derivative.
- the compound of the general formula (II) or (III) can be profitably prepared by the reaction of two molar equivalents of the N6-benzyladenine derivative dissolved at the temperature of 40 to 80 0 C in the minimum volume of the solvent from the group consisting of primary alcohol, secondary alcohol, or acetone, with one molar equivalent of the M 2 [Pt(Ox) 2 ] • xH 2 0 compound, where M represents H, K or Na, dissolved in the minimum volume of 50 to 80 0 C hot water, followed by the stirring of the reaction mixture for 2 to 4 days at the temperature of 50 to 80 0 C, then the obtained product is filtered off, washed with the hot solvent used for the reaction and dried.
- Another invention objective is the use of the platinum(ll) oxalate complexes as starting compounds for the preparation of analogically substituted platinum complexes in the oxidation state +IV.
- the invention also provides a pharmaceutical and pharmacological substance containing a therapeutically effective amount of the platinum(ll) oxalato complexes or a pharmaceutical composition of the platinum(ll) oxalato complexes with one or more acceptable carriers and additional substances for medicinal use as a drug for tumor diseases.
- Fig. 1 is the IR spectrum (the measurement in the 400-4000 cm 1 region was performed by the KBr pellet technique) of the potassium bis(oxalato)platinate dihydrate, K 2 [Pt(Ox) 2 ] • 2H 2 O (Fig. 1A) and bis[2-(R)-(1-ethyl-2-hydroxyethyl)amino-N6- benzyl-9-isopropyladenine]- (oxalato-O,O ' )-platinum(ll) complex, [Pt(L 4 ) 2 (ox)] (Fig. 1 B),
- - Fig. 2 is the molecular structure of the complex [Pt(U) 2 (Ox)] determined by a single crystal X-ray structural analysis and - Fig. 3 represents the thermal decomposition of the complex [Pt(Li 2 MoX)] ⁇ 2H 2 O determined by methods of thermogravimetry (TG) and differential thermal analysis (DTA)
- the invention uses potassium bis(oxalato)platinate(ll) dihydrate, K 2 [Pt(Ox) 2 ] ⁇ 2H 2 O, as the starting platinum(ll) compound.
- the mentioned salt is commercially available (Aldrich), or it can be easily prepared by the modified procedure (Krogmann, K; Dodel, P., Chem. Ber. Reel., 1966, 99, 3402) using the reaction of potassium tetrachloroplatinate(ll) with five molar equivalents of potassium oxalate monohydrate according to Scheme 2.
- IR VKB ⁇ /C ⁇ T ⁇ 1 ): 3345, 3109, 3057, 2980, 2939, 2885, 2832, 1723, 1670, 1621 , 1583, 1540, 1492, 1463, 1439, 1407, 1348, 1320, 1243, 1165, 1118, 1074, 1027, 977, 940, 891 , 811 , 785, 755, 666, 636, 613, 575, 532, 494, 463.
- 1 H NMR (DMF-Cf 7 , SiMe 4 , ppm): ⁇ .
- 13 C NMR DF-Cf 7 , SiMe 4 , ppm): ⁇ .
- IR VKB ⁇ /C ⁇ T ⁇ 1 : 3434, 3127, 3064, 2978, 2933, 2852, 2838, 1720, 1670, 1619, 1587, 1539, 1508, 1486, 1463, 1439, 1417, 1408, 1347, 1319, 1290, 1233, 1209, 1158, 1129, 1115, 1072, 1036, 978, 937, 891 , 812, 785, 667, 636, 573, 521 , 466.
- thermogram 3 showing the thermal analysis (thermogravimetry, TG, and differential thermal analysis, DTA) course of the complex [Pt(L ⁇ ) 2 (Ox)] • 4H 2 O is given in Figure 3.
- Example 7 In vitro cytotoxic activity of the new compounds against human cancer cell lines
- the cytotoxic activities of the prepared complexes were tested by micro-titration analysis using Calcein acetoxymethyl (AM).
- the test detected living cells, whose number corresponds to reduced the Calcein AM quantity.
- In vitro cytotoxicity was tested against the following human cancer cells: breast adenocarcinoma (MCF-7) and chronic myelogenous erythroleukemia (K562).
- MCF-7 breast adenocarcinoma
- K562 chronic myelogenous erythroleukemia
- the cells were maintained in plastic tissue culture flasks in the DMEM medium (5 g/L of glucose, 2 mM of glutamine, 100 U/mL of penicillin, 100 ⁇ g/mL of streptomycine, 10% fetal calf serum and sodium hydrogen carbonate) for cell cultures.
- the cell suspensions (ca 1.25 x 10 5 cells ml_ "1 ) were pipetted (80 ⁇ l_) into 96-well microplates. They were incubated at 37 0 C in the CO2 atmosphere for 24 hrs.
- the tested platinum(ll) oxalato complexes were dissolved in ⁇ /, ⁇ / ' -dimethylformamide, diluted to the 0.2-25.0 ⁇ M concentration and added to the incubated cancer cell suspension. Then the mixtures were incubated for 72 hrs at 37 0 C, 100% humidity and in the CO2 atmosphere.
- the Calcein AM solution was added followed by the incubation lasting 1 hr.
- the living cancer cell fluorescence (F) was measured at 485/538 nm (excitation/emission) on the Labsystem FIA Fluoroscan Ascent device (Microsystems).
- the living cancer cell percentage (A) was counted according to the formula:
- the concentrations of the tested complexes ( ⁇ M) lethal for 50% of the cancer cells (inhibition constant IC50) were counted from the appropriate dose curves and the values are given in Table 1.
- the in vitro cytotoxicity of the prepared complexes against human osteosarcoma (HOS) cell line was also determined by an MTT assay. The method is based on the ability of metabolic-active cells to reduce (by mitochondrial dehydrogenases) the yellow salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) leading to the blue formazane dye formation. Because the reduction proceeds only in the living cells, the cytotoxicity of various compounds can be determined using this process.
- the insoluble formazane is quantified after dissolving in dimethyl sulfoxide (DMSO) with ammonium on the spectrophotometer (ELISA reader).
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Abstract
Oxalato complexes of platinum in the oxidation state +II and their crystal-solvates including the structural motif (I) or having the general formula (II) expressed by the structural formula [Pt(L)2(ox)] (II) or the general formula (III) expressed by the structural formula [Pt(L)(L')(ox)] (III), where the symbols L and L' stand for N6- benzyladenine derivatives of the general formula (IV) bound to the platinum atom of the basic motif (V) through any adenine nitrogen atom independently chosen from the N1, N3, N6, N7 or N9 atoms, depending on the substitution rate of the molecules (IV), where the substituents R1, R2 a R3 are independently chosen from the group of: hydrogen atom, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, functional group and N-R'R" group, where R' and R" independently symbolize hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and functional group.
Description
OXALATO COMPLEXES OF PLATINUM
Field of the Invention
The invention, that belongs to the area of the platinum-based drugs of tumor diseases, relates to the platinum oxalate complexes involving the N6-benzyladenine derivatives, their preparation using M2[Pt(Ox)2] • xhbO, where M is H, K, or Na atom, and their use in the medical practice as drugs and pharmaceutical compositions, which contain these complexes as the active substance.
Background of the Invention
Platinum oxalato complexes are an important group of compounds, which is used in practice thanks to [(1 R,2R)-1 ,2-diaminocyclohexane-N,N']-(oxalato-O,O')- platinum(ll) complex (oxaliplatin) having the general formula (A). It belongs, together with c/s-diamminedichlorido-platinum(ll) complex (cisplatin) of the general formula (B) and diammine-1 ,1 '-cyclobutanedicarboxylato-platinum(ll) complex (carboplatin) of the general formula (C), to the platinum-based drugs applied as the active substances of the pharmaceutical compositions in the anticancer therapy.
B
Oxaliplatin synthesis is described in e.g. {Kidani, Y.; Inagaki, K. J. Med. Chem., 1978, 21, 1315-1318), US 4 169 846 patent or CZ 294668 patent and it consists of three steps depicted in the Scheme 1 ,
K2PtCl4 + dach > [Pt(dach)Cl2] (1)
[Pt(dach)CI2] + Ag+ -^r> [Pt(dach)(H2O)2]2+ + AgCl (2)
[Pt(dach)(H2O)2]i+ + M2Ox • nH2O -^r> [Pt(dach)(ox)] (3)
Scheme 1 where the equation
(1 ) is the preparation of c/s-[Pt(dach)Cl2] by the reaction of potassium tetrachloroplatinate, K2PtCU, with (1 R,2R)-1 ,2-diaminocyclohexane (dach) in water,
(2) is the reaction of the prepared c/s-[Pt(dach)CI2] with a silver(l) salt of an inorganic acid (e.g. AgNO3) in water giving a diaqua-complex of the c/s-[Pt(dach)(H2O)2]2+ type,
(3) is the reaction of c/s-[Pt(dach)(H2O)2]2+ with oxalic acid or alkaline oxalate in water, thereby the final product of the composition [Pt(dach)ox] is obtained.
Referred platinum(ll) oxalato complexes involving N6-benzyladenine derivatives (L) follow formerly published platinum complexes of the general formula c/s-[Pt(L)2CI2], in which the chloride ions act as leaving ligands coordinated to the central atom, as reported in publications (Travnicek, Z; Maloή, M.; Zatloukal, M.; Dolezal, K.; Strnad, M.; Marek, J. J. Inorg. Biochem. 2003, 94, 307-316, Maloή, M.; Travnicek, Z; Marek, R. Strnad, M. J. Inorg. Biochem. 2005, 99, 2127-2138; Szϋcova, L; Travnicek, Z; Zatloukal, M.; Popa, I. Bioorg. Med. Chem. 2006, 14, 479-491; Szϋcova, L; Travnicek, Z; Popa, I.; Marek, J. Polyhedron 2008, 27, 2710-2720). The following N6- benzyladenine derivatives were used: 2-chloro-N6-benzyl-9-isopropyladenine (L1), 2- chloro-N6-(2-methoxybenzyl)-9-isopropyladenine (L2), 2-chloro-N6-(4-methoxybenzyl)- 9-isopropyladenine (L3), 2-(R)-(1 -ethyl-2-hydroxyethylamino)-N6-benzyl-9- isopropyladenine {roscovitine; L4), 2-(3-hydroxypropylamino)-N6-benzyl-9- isopropyladenine (bohemine; L5), 2-(2-hydroxyethylamino)-N6-benzyl-9- methyladenine (olomoucine; L6), 2-(2-hydroxyethylamino)-N6-benzyl-9- isopropyladenine (isopropyl-olomoucine; L7), 2-(R)-(1-ethyl-2-hydroxyethylamino)-N6- (3-hydroxybenzyl)-9-isopropyladenine (L8), 2-(R)-(1 -isopropyl-2-hydroxyethylamino)- N6-(3-hydroxybenzyl)-9-isopropyladenine (L9).
The above-mentioned organic compounds are derived from a plant hormone 6-benzylaminopurine (N6-benzyladenine) described in CZ 294535 patent. Derivatives with various amino alcohols at the C2 position of the purine ring and with alkyl substituent at the N9 position of the purine skeleton belong to the group of the cyclin dependent kinase (CDK) inhibitors, which were proven significantly in vitro and in vivo cytotoxic active, as described in (Meijer, L; Borgne, A.; Mulner, 0.; Chong, J.P.J.; Blow, J. J.; Inagaki, N.; Inagaki, M.; Delcros, J.G.; Moulinoux, J. P. Eur. J. Biochem. 1997, 243, 527-536) or US 6 703 395 patent. A representative of these organic compounds - roscovitine - is currently in the 2b phase of the clinical trials on patients suffering from non-small cell lung cancer (NSCLC), as published in (Benson, C; Kaye, S.; Workman, P.; Garret, M.; Walton, M.; de Bono, J. Br. J. Cancer 2005, 92, 7-12). On the other hand, most of the N6-benzyladenine derivatives with a chlorine atom at the C2 position do not belong among the CDK-inhibitors, their in vitro cytotoxicity is considerably lower. Analogically, platinum(ll) complexes of the general formula CZs-[Pt(L)2Cb] involving N6-benzyladenine-based CDK-inhibitors coordinated to the Pt(II) ion, show high in vitro cytotoxic activity. However, formerly prepared platinum(ll) complexes with cytotoxic inactive N6-benzyladenin-based N-donor ligand substituted at the C2 position by a chlorine atom were determined to be non-cytotoxic as well. The best results, obtained for the platinum(ll) complex involving N6-benzyladenine derivatives, were those of the CZs-[Pt(L-I)2Ch] complex, L4 = roscovitine, whose IC50 values equaled to 1 μM on malignant melanoma (G-361 ), osteogenic sarcoma (HOS) and chronic myelogenous erythroleukemia (K562) human cancer cell lines. The IC50 values obtained on the mentioned cancer cells are 19, 20 and 50 μM, respectively, for roscovitine, 3, 3 and 5 μM, respectively, for cisplatin and 7, 7 and 8 μM, respectively, for oxaliplatin, described in publication (Maloή, M.; Travnicek, Z; Marek, R. Strnad, M. J. Inorg. Biochem. 2005, 99, 2127-2138).
To date, platinum(ll) oxalato complexes with various N-donor ligands have been prepared, e.g. with substituted 1 ,2-diaminocyclohexane, as described in WO 03/106469 file or in (Habala, L; Galanski, M.; Yasemi, A.; Nazarov, AA; von Keyseήingk, N.G.; Keppler, B.K. Eur. J. Med. Chem. 2005, 40, 1149-1155), with ammonia, {Rochon, F.D.; Melanson, R.; Macquet, J. P.; Belanger-Gariepy, F.; Beauchamp, A.L. Inorg. Chim. Acta, 1985, 108, 1-6), with substituted acridine orange, (Bowler, B.E.; Ahmed, K. J.; Sυndquist, W.I.; HoIHs, LS.; Whang, E.E.; Lippard, S.J. J.Am. Chem. Soc, 1989, 111, 1299-1306), with ethylene-1 ,2-diamine (Battle, A.R.;
Deacon, G.B.; Dolman, R.C.; Hambley, T W. Aust. J. Chem., 2002, 55, 699), with bis(hydroxyethyl)ethylene-1 ,2-diamine (Xu, Q.; Khokhar A.R.; Bear, J. L. Inorg. Chim. Acta, 1990, 178, 107-111), with 1 ,4-diaminocyclohexane (Shamsuddin, S.; Takahashi, I.; Siddik, Z.H.; Khokhar, K.H. J. Inorg. Biochem. 1996, 61, 291-301), with substituted 2-methylthioalkylimidazole and 2-methylthioalkylpyridine (WO 2007/085957 A1 patent), with hexamethyleneimine (AIi, M.S.; Thurston, J. H.; Whitmire, K.H.; Khokhar, K.H. Polyhedron 2002, 21 , 2659-2666), with piperidine and its derivatives (Mukhopadhyay, U.; Thurston, J. H.; Whitmire, K.H.; Siddik, Z.H.; Khokhar, K.H. J. Inorg. Biochem. 2003, 94, 179-185, AIi Khan, S.R.; Guzman-Jimenez, I.; Whitmire, K.H.; Khokhar, K.H. Polyhedron 2000, 19, 975-981 , AIi Khan, S.R.; Guzman-Jimenez, I.; Whitmire, K.H.; Khokhar, K.H. Polyhedron 2000, 19, 983-989, Sen, V. D.; Golubev, V.A.; Volkova, L. M.; Konovalova, NP. J. Inorg. Biochem. 1996, 64, 69-77), with morpholinoethylamine (Chen, X.; Xie, M.; Liu, W.; Ye, Q.; Yu, Y.; Hou, S.; Gao, W.; Liu, G. Inorg. Chim. Acta 2007, 360, 2851-2856), with histamine (Chen, X.Z.; Ye, O.S.; Lou, LG.; Xie, M.J.; Liu, W.P.; Yu, Y.; Hou, S.Q. Arch. Pharm., 2008, 341 , 132-136), with homopiperazine (AIi, M.S.; Powers, C.A.; Whitmire, K.H.; Guzman-Jimenez, I.; Khokhar, A.R. J. Coord. Chem., 2001 , 52, 273-287), or with 2-amino alcohols (Meelich, M.; Galanski, M.; Arion, V.B.; Keppler, B. K. Eur. J. Inorg. Chem. 2006, 2476-2483). All of the above-mentioned platinum(ll) oxalato complexes were synthesized by the procedure coming out of that of oxaliplatin, as described above (Scheme 1). Some of these complexes were tested for in vitro cytotoxicity against various cancer cell lines and for example cytotoxicity of some complexes with substituted 1 ,2-diaminocyclohexane exceeded oxaliplatin. The in vitro antitumor activities of the oxalato complexes with ethylene-1 ,2-diamine, fraA7S-3,4-diamino-2,2,6,6-tetramethylpiperidine-l-oxyl, or 1 -methyl-4-(methylamino) piperidine were found to be higher, in comparison with the platinum(ll) analogues involving a different leaving group than oxalate dianion.
Summary of the Invention
The invention provides oxalato complexes of platinum in the oxidation state +Il and their crystal-solvates including a structural motif (I) or having the general formula (II) expressed by the structural formula [Pt(L)2(Ox)] or the general formula (III) expressed by the structural formula [Pt(L)(L')(ox)], where the symbols L and L' stand
for N6-benzyladenine derivative of the general formula (IV) bonded to the platinum atom of the basic motif (V)
(I) (II) (III)
through any adenine nitrogen atom independently chosen from the N1 , N3, N6, N7 or N9 atoms, depending on the substitution rate of the molecules (IV), where the substituents R1, R2 a R3 are independently chosen from the group of: hydrogen atom, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, functional group and N-R'R" group, where R' and R" independently symbolize hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and functional group, where term: - halogen represents the fluorine, chlorine, bromine, or iodine atom,
alkyl as employed herein by itself or as a part of another group represents a straight or branched hydrocarbon chain from up to 18, preferably from 1 to 8 carbon atoms, alkenyl as employed herein by itself or as a part of another group represents a straight or branched hydrocarbon chain from up to 18, preferably from 2 to 8 carbon atoms, including at least one carbon-carbon double bond, alkynyl as employed herein by itself or as a part of another group represents a straight or branched hydrocarbon chain from up to 18, preferably from 2 to 8 carbon atoms, including at least one carbon-carbon triple bond, cycloalkyl as employed herein by itself or as a part of another group represents a cyclic hydrocarbon chain from 3 to 12, preferably from 3 to 8 carbon atoms, which may be fused with 1 or 2 cycles which are independently selected from the group consisting of cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl a heteroaryl, cycloheteroalkyl as employed herein by itself or as a part of another group represents cykloalkyl where at least one carbon atom is exchanged for a heteroatom from the group consisting of nitrogen, oxygen, sulphur, cycloalkenyl as employed herein by itself or as a part of another group represents cycloalkyl including at least one carbon-carbon double bond, cycloheteroalkenyl as employed herein by itself or as a part of another group represents cycloheteroalkyl including at least one carbon-carbon, carbon-heteroatom, or heteroatom-heteroatom double bond, aryl as employed herein by itself or as a part of another group represents a group including at least one aromatic ring,
- heteroaryl 7 as employed herein by itself or as a part of another group represents a 5 to 12 membered, preferably 5 to 6 membered aromatic ring, which includes one or more heteroatoms from the group consisting of nitrogen, oxygen, sulphur and which may be optionally fused with 1 or 2 cycles independently chosen from the group consisting of cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl and heteroaryl,
- functional group as employed herein by itself or as a part of another group represents amino, alkylamino, dialkylamino, alkenylamino, cycloalkylamino, cycloheteroalkylamino, cycloalkenylamino, cycloheteroalkenylamino, arylamino, heteroarylamino, acylamino, hydroxy, alkylhydroxy, alkoxy, aryloxy, cyano, carboxy, alkylcarboxy, carboxyalkyl, arylcarboxy, carboxyaryl, hydroxyamino, acyl, nitro, amido, nitroso, sulfonyl, sulfinyl, sulfamido, thio, alkylthio, arylthio, merkapto, carbamoyl,
- substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloheteroalkyl, substituted cycloalkenyl, substituted cycloheteroalkenyl, substituted aryl and substituted heteroaryl as employed herein by themselves or as parts of other groups represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl and heteroaryl substituted by the substituents from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl, heteroaryl and a functional group.
The platinum(ll) oxalato complex crystal-solvates of the general formula [Pt(L)2(ox)] ■ xSolv or [Pt(L)(L ')(ox)] • xSolv are the next objective of the invention; {x) represents the number of the solvate molecules, preferably 1 to 6, and (SoIv) represents a concrete molecule of the used solvent and/or some of the reaction components, usually chosen from the group consisting of water, primary alcohol, secondary alcohol, acetone, Λ/,Λ/'-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, acetonitrile or diethyl ether, either individually or in combinations of the mentioned solvate molecules.
The invention also provides the method of preparation of the platinum(ll) oxalato complexes of the general formulas (II) or (III), which uses reaction of the bis(oxalato)platinate alkaline salt or corresponding acid of the general formula
M2[Pt(Ox)2] • XH2O, where M comprises mainly H, K and Na, with an N6-benzyladenine derivative.
The compound of the general formula (II) or (III) can be profitably prepared by the reaction of two molar equivalents of the N6-benzyladenine derivative dissolved at the temperature of 40 to 80 0C in the minimum volume of the solvent from the group consisting of primary alcohol, secondary alcohol, or acetone, with one molar equivalent of the M2[Pt(Ox)2] • xH20 compound, where M represents H, K or Na, dissolved in the minimum volume of 50 to 80 0C hot water, followed by the stirring of the reaction mixture for 2 to 4 days at the temperature of 50 to 80 0C, then the obtained product is filtered off, washed with the hot solvent used for the reaction and dried.
Another invention objective is the use of the platinum(ll) oxalate complexes as starting compounds for the preparation of analogically substituted platinum complexes in the oxidation state +IV.
The invention also provides a pharmaceutical and pharmacological substance containing a therapeutically effective amount of the platinum(ll) oxalato complexes or a pharmaceutical composition of the platinum(ll) oxalato complexes with one or more acceptable carriers and additional substances for medicinal use as a drug for tumor diseases.
Description of the figures
The concrete examples of the invention are documented by the attached drawings, where
- Fig. 1 is the IR spectrum (the measurement in the 400-4000 cm 1 region was performed by the KBr pellet technique) of the potassium bis(oxalato)platinate dihydrate, K2[Pt(Ox)2] • 2H2O (Fig. 1A) and bis[2-(R)-(1-ethyl-2-hydroxyethyl)amino-N6- benzyl-9-isopropyladenine]- (oxalato-O,O')-platinum(ll) complex, [Pt(L4)2(ox)] (Fig. 1 B),
- Fig. 2 is the molecular structure of the complex [Pt(U)2(Ox)] determined by a single crystal X-ray structural analysis and
- Fig. 3 represents the thermal decomposition of the complex [Pt(Li2MoX)] ■ 2H2O determined by methods of thermogravimetry (TG) and differential thermal analysis (DTA)
Examples
In the following section, the invention is documented but not limited, by the concrete examples of its realization. The invention range is unambiguously limited by the invention claims.
The prepared compounds, mentioned below in the examples 1-6, were characterized by the following physical methods:
- elemental analysis (C, H and N)
- molar conductivity measurements of the DMF solution of the prepared complexes,
- infrared spectroscopy (IR), by the KBr pellet technique in the 400 to 4000 cm'1 region and by the Nujol technique in the 150 to 600 cm"1 region,
- nuclear magnetic resonance (NMR) - 1H, 13C, 195Pt, 1H-1H gs-COSY, 1H-13C gs-HMQC, 1H-13C gs-HMBC and 1H-15N gs-HMBC experiments,
- thermal analysis with methods of thermogravimetry (TG) and differential thermal analysis (DTA) and
- single crystal X-ray structural analysis.
The invention uses potassium bis(oxalato)platinate(ll) dihydrate, K2[Pt(Ox)2] ■ 2H2O, as the starting platinum(ll) compound. The mentioned salt is commercially available (Aldrich), or it can be easily prepared by the modified procedure (Krogmann, K; Dodel, P., Chem. Ber. Reel., 1966, 99, 3402) using the reaction of potassium tetrachloroplatinate(ll) with five molar equivalents of potassium oxalate monohydrate according to Scheme 2.
K2RCI4 + K2Ox • H2O ^- K2[R(Ox)2] ■ 2H2O z 4 z z distlled water z *
7O 0C 3 days
Scheme 2
The reaction proceeded in the distilled water at the temperature of 70 0C. A pale green product formed in 3 days, which is filtered off, washed by hot (70 0C) distilled water and recrystallized. Recrystallization provided pale green needle-like crystals of K2[Pt(Ox)2] • 2H2O.
Percentual content of the C, H, N elements given as: calculated value (found value in parenthesis) for C4O8K2Pt ■ 2H2O: C1 9.9 (10.1 ); H, 0.8 (0.9)%. IR (vNφl/cm- 1):568, 457, 375, 330, 166. IR (Wcnrr1): 3563, 3479, 3338, 3236, 2774, 2477, 1709, 1673, 1386, 1235, 901 , 826, 570, 465. 13C NMR (D2O, SiMe4, ppm): δ 167.87 (C19, C20).
Example 1 : Synthesis of bis(2-chloro-N6-benzyl-9-isopropyladenine)-(oxalato-0,0')- platinum(ll) complex, [Pt(Li)2(Ox)]
Two molar equivalents (2 mmol) of 2-chloro-N6-benzyl-9-isopropyladenine (U) dissolved in the minimum volume of hot isopropanol were mixed with one molar equivalent (1 mmol) of K2[Pt(Ox)2] • 2H2O dissolved in the minimum volume of hot distilled water (70 0C) according to Scheme 3.
Scheme 3
The reaction mixture was refluxed for 3 days at 70 0C. The obtained pale grey product, [Pt(Li)2(Ox)] depicted with atom numbering within the particular molecules according to Scheme 4, was filtered off, repeatedly washed with isopropanol and hot distilled water and dried at 40 0C.
Scheme 4
Percentual content of the C, H, N elements given as: calculated value (found value in parenthesis) for C32H32N10O4CI2Pt: C, 43.4 (42.9); H, 3.6 (3.5); N1 15.8 (15.3)%. ΛM (DMF solution, S cm2 moh1): 0.4. IR (iWcnfr1): 570, 541 , 524, 499, 467, 453, 432, 398, 362, 335, 309, 280, 270, 227, 213. IR (Wcm-1): 3330, 3102, 3063, 3030, 2981 , 2937, 2881 , 1713, 1672, 1618, 1582, 1540, 1488, 1456, 1409, 1377, 1347, 1321 , 1227, 1164, 1136, 1107, 1071 , 1029, 977, 936, 889, 811 , 784, 752, 721 , 700, 668, 638, 600, 572, 542, 523, 490, 467, 405. 1H NMR (DMF-Cf7, SiMe4, ppm): δ 9.14 (t, 6.2, N6H, 1 H), 9.00 (s, C8H, 1 H), 7.48 (dd, 8.1 , 1.6, C11 H, C15H, 2H), 7.29 (m, C12H, C13H, C14H, 3H), 4.89 (d, 6.4, C9H, 2H), 4.84 (sep, 6.8, C16H, 1 H), 1.57 (d, 6.8, C17H, C18H, 6H). 13C NMR (DMF-oV, SiMe4, ppm): δ 165.94 (C19, C20), 155.23 (C6), 153.96 (C2), 149.94 (C4), 144.31 (C8), 139.27 (C10), 129.00 (C12, C14), 128.16 (C11 , C15), 127.62 (C13), 116.87 (C5), 49.84 (C16), 45.07 (C9), 21.99 (C17, C18). 15N NMR (DMF-oV, ppm): δ 232.2 (N1 ), 224.3 (N3), 185.5 (N9), 128.2 (N7), 99.1 (N6). 195Pt NMR (DMF-d7, K2PtCI4, ppm): δ -1685.
Example 2: Synthesis of bis[2-chloro-N6-(2-methoxybenzyl)-9-isopropyladenine]- (oxalato-O,O')-platinum(ll) complex, [Pt(L2)2(ox)]
Two molar equivalents (2 mmol) of 2-chloro-N6-(2-methoxybenzyl)-9- isopropyladenine (L2) dissolved in the minimum volume of hot isopropanol were mixed with one molar equivalent (1 mmol) of K2[Pt(Ox)2] • 2H2O dissolved in the minimum volume of hot distilled water (70 0C) according to Scheme 3.
The reaction mixture was refluxed for 3 days at 70 0C. The obtained pale grey product, [Pt(L2)2(ox)] depicted in the Scheme 5,
Scheme 5
was filtered off, repeatedly washed with isopropanol and hot distilled water and dried at 40 0C. The single crystals suitable for a single crystal X-ray analysis were obtained by the recrystallization of the complex [Pt(L2J2(Ox)] in the N, N '-dimethylformamide. The molecular structure of the complex [Pt(L2J2(Ox)] is depicted in figure 2.
Percentual content of the C, H, N elements given as: calculated value (found value in parenthesis) for C34H36Ni0O6CI2Pt: C, 43.1 (42.8); H1 3.8 (3.9); N, 14.8 (14.4)%. ΛM (DMF solution, S cm2 moM): 0.0. IR (VNUJOI/CITΓ1): 565, 542, 531, 491 , 465, 440, 410, 368, 354, 342, 295, 286, 220. IR (VKBΓ/CΓTΓ1): 3345, 3109, 3057, 2980, 2939, 2885, 2832, 1723, 1670, 1621 , 1583, 1540, 1492, 1463, 1439, 1407, 1348, 1320, 1243, 1165, 1118, 1074, 1027, 977, 940, 891 , 811 , 785, 755, 666, 636, 613, 575, 532, 494, 463. 1H NMR (DMF-Cf7, SiMe4, ppm): δ . 13C NMR (DMF-Cf7, SiMe4, ppm): δ . 15N NMR (DMF-d7, ppm): δ . 195Pt NMR (DMF-Cf7, K2PtCI4, ppm): δ -1686.
Example 3: Synthesis of bis[2-chloro-N6-(2,4-dimethoxybenzyl)-9-isopropyladenine] (oxalato-O,O')-platinum(ll) complex, [Pt(Li0MOx)],
Two molar equivalents (2 mmol) of 2-chloro-N6-(2,4-dimethoxybenzyl)-9- isopropyladenine (Li0) dissolved in the minimum volume of hot isopropanol were mixed with one molar equivalent (1 mmol) of K2[Pt(Ox)2] ■ 2H2O dissolved in the minimum volume of hot distilled water (70 0C) according to Scheme 3. The reaction mixture was refluxed for 3 days at 70 0C. The pale grey product, [Pt(Li0MoX)] depicted in the Scheme 6, was obtained after partial evaporation of the water/isopropanol mixture.
Scheme 6
It was filtered off, repeatedly washed with isopropanol and hot distilled water and dried at 40 0C.
Percentual content of the C, H, N elements given as: calculated value (found value in parenthesis) for C36H40N10O8CI2Pt: C, 43.0 (42.9); H, 4.0 (3.8); N, 13.9 (13.8)%. ΛM (DMF solution, S cm2 mol"1): 2.1. IR (VNUJO/CΓTΓ1): 571 , 540, 461 , 429, 395, 360, 306, 285, 262, 224. IR (VKBΓ/CΓTΓ1): 3434, 3127, 3064, 2978, 2933, 2852, 2838, 1720, 1670, 1619, 1587, 1539, 1508, 1486, 1463, 1439, 1417, 1408, 1347, 1319, 1290, 1233, 1209, 1158, 1129, 1115, 1072, 1036, 978, 937, 891 , 812, 785, 667, 636, 573, 521 , 466.
Example 4: Synthesis of bis[2-chloro-N6-(3,4-dimethoxybenzyl)-9-isopropyladenine]- (oxalato-O,O')-platinum(ll) complex, [Pt(Ln)2(Ox)]
Two molar equivalents (2 mmol) of 2-chloro-N6-(3,4-dimethoxybenzyl)-9- isopropyladenine (Ln) dissolved in the minimum volume of hot isopropanol were mixed with one molar equivalent (1 mmol) of K2[Pt(Ox)2] • 2H2O dissolved in the minimum volume of hot distilled water (70 0C) according to Scheme 3. The reaction mixture was refluxed for 3 days at 70 0C. The pale grey product, [Pt(Ln)2(Ox)] depicted in the Scheme 7, was obtained after partial evaporation of the water/isopropanol mixture.
Scheme 7
It was filtered off, repeatedly washed with isopropanol and hot distilled water and dried at 40 0C.
Percentual content of the C, H, N elements given as: calculated value (found value in parenthesis) for C36H40Ni0O8CI2Pt: C, 43.0 (43.0); H, 4.0 (4.3); N, 13.9 (13.9)%. ΛM (DMF solution, S cm2 moM): 1.6. IR (ι/Nujo/cm-1): 584, 568, 543, 525, 452, 430, 398, 357, 302, 273, 215. IR
3433, 3123, 3062, 2979, 2937, 2836, 1724, 1669, 1620, 1583, 1538, 1516, 1485, 1464, 1419, 1347, 1320, 1267, 1236, 1158, 1140, 1072, 1027, 941 , 891 , 811 , 785, 766, 669, 639, 572, 552, 522, 467.
Example 5: Synthesis of bis[2-chloro-N6-(3,5-dimethoxybenzyl)-9-isopropyladenine]- (oxalato-O,O')-platinum(ll) complex tetrahydrate, [Pt(Li2)2(ox)] ■ 4H2O
Two molar equivalents (2 mmol) of 2-chloro-N6-(3,5-dimethoxybenzyl)-9- isopropyladenine (L12) dissolved in the minimum volume of hot isopropanol were mixed with one molar equivalents (1 mmol) of K2[Pt(Ox)2] ■ 2H2O dissolved in the minimum volume of hot distilled water (70 0C) according to Scheme 3. The reaction mixture was refluxed for 3 days at 70 0C. The pale grey product, [Pt(Li2J2(Ox)] depicted in the Scheme 8, was obtained after partial evaporation of the water/isopropanol mixture.
Scheme 8
It was filtered off, repeatedly washed with isopropanol and hot distilled water and dried at 40 0C. The thermogram showing the thermal analysis (thermogravimetry, TG, and differential thermal analysis, DTA) course of the complex [Pt(L^)2(Ox)] • 4H2O is given in Figure 3.
Percentual content of the C, H, N elements given as: calculated value (found value in parenthesis) for C36H40Ni0O8CI2Pt ■ 4H2O: C, 40.1 (40.0); H, 4.5 (4.4); N, 13.0 (13.5)%. ΛM (DMF solution, S cm2 mol"1): 1.9. IR {vmojcπ\-'): 595, 568, 540, 523, 501 , 469, 438, 409, 397, 351 , 321 , 310, 293, 272, 241. IR (\Wcrτr1): 3334, 3272, 3144,
3097, 2978, 2937, 2839, 1712, 1677, 1620, 1539, 1461 , 1426, 1411 , 1385, 1368, 1341 , 1322, 1284, 1229, 1199, 1156, 1095, 1060, 1022, 988, 939, 893, 868, 839; 812, 785, 681 , 668, 635, 615, 568, 540, 523, 469, 436.
Example 6: Synthesis of bis[2 -(R)-(I -ethyl-2-hydroxyethyl)amino]-N6-benzyl-9-iso- propyladenine]-(oxalato-0,0')-platinum(ll) complex, [Pt(L4MoX)]
Two molar equivalents (2 mmol) of 2-(R)-(1-ethyl-2-hydroxyethyl)amino]-N6- benzyl-9-isopropyladenine (L4) dissolved in the minimum volume of hot isopropanol were mixed with one molar equivalents (1 mmol) of K2[Pt(Ox)2] • 2H2O dissolved in the minimum volume of hot distilled water (70 0C) according to Scheme 3. The reaction mixture was refluxed for 3 days at 70 0C. The pale grey product, [Pt(L4)2(ox)] depicted in the Scheme 9, was obtained after the partial evaporation of the water/isopropanol mixture.
Scheme 9
It was filtered off, repeatedly washed with isopropanol and hot distilled water and dried at 40 0C.
Percentual content of the C, H, N elements given as: calculated value (found value in parenthesis) for C40H52N12O6Pt: C, 48.4 (48.3); H, 5.3 (5.7); N, 16.9 (16.9)%. IR (vNφ/cm-1): 570, 544, 526, 507, 491 , 484, 465, 403, 355, 332, 306, 263. IR (vκBr/crτr1): 3365, 3120, 3064, 3030, 2965, 2932, 2875, 1718, 1681 , 1611 , 1544, 1519, 1494, 1419, 1356, 1268, 1212, 1134, 1084, 1059, 810, 785, 754, 737, 700, 668, 635, 600, 571 , 526, 471 , 417, 404.
Example 7: In vitro cytotoxic activity of the new compounds against human cancer cell lines
The cytotoxic activities of the prepared complexes were tested by micro-titration analysis using Calcein acetoxymethyl (AM). The test detected living cells, whose number corresponds to reduced the Calcein AM quantity. In vitro cytotoxicity was tested against the following human cancer cells: breast adenocarcinoma (MCF-7) and chronic myelogenous erythroleukemia (K562). The cells were maintained in plastic tissue culture flasks in the DMEM medium (5 g/L of glucose, 2 mM of glutamine, 100 U/mL of penicillin, 100 μg/mL of streptomycine, 10% fetal calf serum and sodium hydrogen carbonate) for cell cultures.
The cell suspensions (ca 1.25 x 105 cells ml_"1) were pipetted (80 μl_) into 96-well microplates. They were incubated at 37 0C in the CO2 atmosphere for 24 hrs. The tested platinum(ll) oxalato complexes were dissolved in Λ/,Λ/'-dimethylformamide, diluted to the 0.2-25.0 μM concentration and added to the incubated cancer cell suspension. Then the mixtures were incubated for 72 hrs at 37 0C, 100% humidity and in the CO2 atmosphere. The Calcein AM solution was added followed by the incubation lasting 1 hr. The living cancer cell fluorescence (F) was measured at 485/538 nm (excitation/emission) on the Labsystem FIA Fluoroscan Ascent device (Microsystems). The living cancer cell percentage (A) was counted according to the formula:
The concentrations of the tested complexes (μM) lethal for 50% of the cancer cells (inhibition constant IC50) were counted from the appropriate dose curves and the values are given in Table 1.
The in vitro cytotoxicity of the prepared complexes against human osteosarcoma (HOS) cell line was also determined by an MTT assay. The method is based on the ability of metabolic-active cells to reduce (by mitochondrial dehydrogenases) the yellow salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) leading to the blue formazane dye formation. Because the reduction proceeds only in the living cells, the cytotoxicity of various compounds can be determined using this process. The insoluble formazane is quantified after dissolving in dimethyl sulfoxide (DMSO) with ammonium on the spectrophotometer (ELISA reader).
Table 1. Concentration of tested complexes (IC5O, μM) lethal for 50% cancer cells
nt) not tested to date
Li) 2-chloro-N6-benzyl-9-isopropyladenine
L2) 2-chloro-N6-(2-methoxybenzyl)-9-isopropyladenine
Lio) 2-chloro-N6-(2,4-dimethoxybenzyl)-9-isopropyladenine
Lii) 2-chloro-N6-(3,4-dimethoxybenzyl)-9-isopropyladenine
U) 2-(R)-(1-ethyl-2-hydroxyethyl)amino-N6-(4-methoxybenzyl)-9-isopropyladenine a) AM assay
") MTT assay
°) Travnicek, Z.; Szϋcova, L.; Popa, I. J. Inorg. Biochem. 2007, 101 , 477-492
") Travnicek, Z.; Maloή, M.; Zatloukal, M.; Dolezal, K.; Strnad, M.; Marek, J. J. Inorg. Biochem. 2003, 94, 307-316
Claims
1. Oxalato complexes of platinum in the oxidation state +Il and their crystal-solvates including the structural motif (I) or having the general formula (II) expressed , by the structural formula [Pt(L)2(Ox)] (II) or the general formula (III) expressed by the structural formula [Pt(L)(L')(ox)] (III), where the symbols L and • L' stand for N6-benzyladenine derivatives of the general formula (IV) bound to the platinum atom of the basic motif (V)
through any adenine nitrogen atom independently chosen from the N1 , N3, N6, N7 or N9 atoms, depending on the substitution rate of the molecules (IV), where the substituents R1, R2 a R3 are independently chosen from the group of: hydrogen atom, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, functional group and N-R'R" group, where R' and R" independently symbolize hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and functional group, where the term: halogen represents the fluorine, chlorine, bromine, or iodine atom, alkyl as employed herein by itself or as a part of another group represents a straight or branched hydrocarbon chain from up to 18, preferably from 1 to 8 carbon atoms, alkenyl as employed herein by itself or as a part of another group represents a straight or branched hydrocarbon chain from up to 18, preferably from 2 to 8 carbon atoms, including at least one carbon-carbon double bond, alkynyl as employed herein by itself or as a part of another group represents a straight or branched hydrocarbon chain from up to 18, preferably from 2 to 8 carbon atoms, including at least one carbon-carbon triple bond, cycloalkyl as employed herein by itself or as a part of another group represents a cyclic hydrocarbon chain from 3 to 12, preferably from 3 to 8 carbon atoms, which may be fused with 1 or 2 cycles which are independently selected from the group consisting of cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl a heteroaryl, cycloheteroalkyl as employed herein by itself or as a part of another group represents cykloalkyl where at least one carbon atom is exchanged for a heteroatom from the group consisting of nitrogen, oxygen, sulphur,
• cycloalkenyl as employed herein by itself or as a part of another group represents cycloalkyl including at least one carbon-carbon double bond,
■ cycloheteroalkenyl as employed herein by itself or as a part of another group represents cycloheteroalkyl including at least one carbon-carbon, carbon-heteroatom, or heteroatom-heteroatom double bond, - aryl as employed herein by itself or as a part of another group represents a, group including at least one aromatic ring,
- heteroaryl as employed herein by itself or as a part of another group represents a 5 to 12 membered, preferably 5 to 6 membered aromatic ring with at least one carbon atom exchanged for a heteroatom from the group consisting of nitrogen, oxygen, sulphur and which may be optionally fused with 1 or 2 cycles independently chosen from the group consisting of cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl and heteroaryl,
- functional group as employed herein by itself or as a part of another group represents amino, alkylamino, dialkylamino, alkenylamino, cycloalkylamino, cycloheteroalkylamino, cycloalkenylamino, cycloheteroalkenylamino, arylamino, heteroarylamino, acylamino, hydroxy, alkylhydroxy, alkoxy, aryloxy, cyano, carboxy, alkylcarboxy, carboxyalkyl, arylcarboxy, carboxyaryl, hydroxyamino, acyl, nitro, amido, nitroso, sulfonyl, sulfinyl, sulfamido, thio, alkylthio, arylthio, merkapto, carbamoyl,
- substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloheteroalkyl, substituted cycloalkenyl, substituted cycloheteroalkenyl, substituted aryl and substituted heteroaryl as employed herein by themselves or as parts of other groups represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl and heteroaryl substituted by the substituents from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl, heteroaryl and functional group.
2. The crystal-solvates of the platinum(ll) oxalato complexes according to claim 1 , wherein within the general formula [Pt(L)2(Ox)] • xSolv or [Pt(L)(L')(ox)] ■ xSolv, the symbol (x) represents a number of the solvate molecules, preferably 1 to 6, and (SoIv) represents a concrete molecule of the used solvent and/or some of the reaction components, usually chosen from the group consisting of water, primary alcohol, secondary alcohol, acetone, Λ/,Λ/'-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, acetonitrile or diethyl ether, either individually or in combinations of the mentioned solvate molecules.
3. The method of preparation of the platinum(ll) oxalato complexes according to claim 1 , wherein the compound of the general formula (II) or (III) is prepared using the reaction of the bis(oxalato)platinate alkaline salt or corresponding acid of the general formula M2[Pt(Ox)2] ■ xH20, where M comprises mainly H, K and Na, with an N6-benzyladenine derivative.
4. The method of preparation of the platinum(ll) oxalato complexes according to claim 3, wherein the compound of the general formula (II) or (III) is prepared by the reaction of two molar equivalents of the N6-benzyladenine derivative dissolved at the temperature of 40 to 80 0C in the minimum volume of the solvent from the group consisting of primary alcohol, secondary alcohol, or acetone, with one molar equivalent of the M2[Pt(Ox)2] xH20 compound, where M represents H, K or Na, dissolved in the minimum volume of 50 to 80 0C hot water, followed by stirring of the reaction mixture for 2 to 4 days at the temperature of 50 to 80 0C, than the obtained product is filtered off, washed with the hot solvent used for the reaction and dried.
5. The use of the platinum(ll) oxalato complexes according to claim 1 as starting compounds for the preparation of analogically substituted complexes of platinum in the oxidation state +IV.
6. A pharmaceutical or pharmacological substance distinguished by the fact that it contains a therapeutically effective amount of the platinum(ll) oxalato complexes according to claim 1 and a pharmaceutical composition of the platinum(ll) oxalato complexes with one or more acceptable carriers and additional substances.
7. A pharmaceutical or pharmacological substance according to claim 6 for medicinal use.
8. The use of the pharmaceutical or pharmacological substance according to claim 7, as a drug for tumor diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ20090257A CZ302623B6 (en) | 2009-04-22 | 2009-04-22 | Platinum oxalate-complexes with N6-benzyladenine derivatives, process of their preparation and use of such complexes as medicaments in antitumor therapy |
| CZPV2009-257 | 2009-04-22 |
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| PCT/CZ2009/000135 WO2010121575A1 (en) | 2009-04-22 | 2009-11-10 | Oxalato complexes of platinum |
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| CZ (1) | CZ302623B6 (en) |
| WO (1) | WO2010121575A1 (en) |
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| WO2006024897A1 (en) * | 2004-09-01 | 2006-03-09 | Platco Technologies (Proprietary) Limited | Preparation of platinum(ii) complexes |
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| CZ2009257A3 (en) | 2010-11-03 |
| CZ302623B6 (en) | 2011-08-03 |
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