EP0409894A1 - Platinum-amine-sulfoxides as anti-tumor agents - Google Patents
Platinum-amine-sulfoxides as anti-tumor agentsInfo
- Publication number
- EP0409894A1 EP0409894A1 EP89904974A EP89904974A EP0409894A1 EP 0409894 A1 EP0409894 A1 EP 0409894A1 EP 89904974 A EP89904974 A EP 89904974A EP 89904974 A EP89904974 A EP 89904974A EP 0409894 A1 EP0409894 A1 EP 0409894A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- platinum complex
- complex according
- alkyl
- platinum
- dach
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000002246 antineoplastic agent Substances 0.000 title description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 105
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 31
- 150000001412 amines Chemical class 0.000 claims abstract description 20
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 17
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 150000001450 anions Chemical class 0.000 claims abstract description 7
- 125000000962 organic group Chemical group 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 229910002651 NO3 Inorganic materials 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 238000002560 therapeutic procedure Methods 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000002993 cycloalkylene group Chemical group 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 claims 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 150000003057 platinum Chemical class 0.000 abstract description 18
- 238000001727 in vivo Methods 0.000 abstract description 5
- 230000002349 favourable effect Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 101100498160 Mus musculus Dach1 gene Proteins 0.000 description 31
- 150000003462 sulfoxides Chemical class 0.000 description 24
- 239000003446 ligand Substances 0.000 description 16
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 15
- 229960004316 cisplatin Drugs 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 229910019032 PtCl2 Inorganic materials 0.000 description 8
- 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 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 6
- 229960004562 carboplatin Drugs 0.000 description 6
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- 229910021607 Silver chloride Inorganic materials 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 4
- 241000894007 species Species 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- -1 Methyl Tolyl Sulfoxide Chemical class 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
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- 230000001225 therapeutic effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229910020427 K2PtCl4 Inorganic materials 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000007942 carboxylates Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000005917 in vivo anti-tumor Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JXTGICXCHWMCPM-UHFFFAOYSA-N (methylsulfinyl)benzene Chemical compound CS(=O)C1=CC=CC=C1 JXTGICXCHWMCPM-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- FMFAHVFEPAMZQL-UHFFFAOYSA-N 1-methyl-2-methylsulfinylbenzene Chemical compound CC1=CC=CC=C1S(C)=O FMFAHVFEPAMZQL-UHFFFAOYSA-N 0.000 description 1
- MJWNJEJCQHNDNM-UHFFFAOYSA-N 1-methyl-4-(4-methylphenyl)sulfinylbenzene Chemical compound C1=CC(C)=CC=C1S(=O)C1=CC=C(C)C=C1 MJWNJEJCQHNDNM-UHFFFAOYSA-N 0.000 description 1
- SDIOBNKHLKIWOP-UHFFFAOYSA-N 2,2-diethylpropane-1,3-diamine Chemical compound CCC(CC)(CN)CN SDIOBNKHLKIWOP-UHFFFAOYSA-N 0.000 description 1
- ZOMWZCRTJGAKAA-UHFFFAOYSA-N 2-(aminomethyl)-3,3,5-trimethylcyclohexan-1-amine Chemical compound CC1CC(N)C(CN)C(C)(C)C1 ZOMWZCRTJGAKAA-UHFFFAOYSA-N 0.000 description 1
- ZUYYQGFCSKJGDO-UHFFFAOYSA-N 2-(aminomethyl)cyclohexan-1-amine Chemical compound NCC1CCCCC1N ZUYYQGFCSKJGDO-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- JJHHIJFTHRNPIK-UHFFFAOYSA-N Diphenyl sulfoxide Chemical compound C=1C=CC=CC=1S(=O)C1=CC=CC=C1 JJHHIJFTHRNPIK-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- LISVNGUOWUKZQY-UHFFFAOYSA-N Methyl benzyl sulfoxide Chemical compound CS(=O)CC1=CC=CC=C1 LISVNGUOWUKZQY-UHFFFAOYSA-N 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010041848 Squamous cell carcinoma of the cervix Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- HTMQZWFSTJVJEQ-UHFFFAOYSA-N benzylsulfinylmethylbenzene Chemical compound C=1C=CC=CC=1CS(=O)CC1=CC=CC=C1 HTMQZWFSTJVJEQ-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 206010006007 bone sarcoma Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 238000001142 circular dichroism spectrum Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
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- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- DBBUVLSRTWYISN-UHFFFAOYSA-N cycloheptane-1,2-diamine Chemical compound NC1CCCCCC1N DBBUVLSRTWYISN-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical group NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
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- 238000007429 general method Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000012750 in vivo screening Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- GZAJJDUWYRDMPO-UHFFFAOYSA-N methylsulfinylmethane;platinum Chemical compound [Pt].CS(C)=O GZAJJDUWYRDMPO-UHFFFAOYSA-N 0.000 description 1
- YYROCZQCWNIJNV-UHFFFAOYSA-N n-methylpiperidin-2-amine Chemical compound CNC1CCCCN1 YYROCZQCWNIJNV-UHFFFAOYSA-N 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- JAKNYTQAGPEFJB-UHFFFAOYSA-N piperidin-2-amine Chemical compound NC1CCCCN1 JAKNYTQAGPEFJB-UHFFFAOYSA-N 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
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- 125000003375 sulfoxide group Chemical group 0.000 description 1
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- 125000004434 sulfur atom Chemical group 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- 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
Definitions
- Cisplatin cis-[PtCl 2 (NH3) 2 ]
- Curable testicular cancer
- sensitive ovarian
- responsive head and neck, small cell lung
- CBDCA 1,1'-cyclobutanedicarboxylate
- a number of amines give complexes which are non-crossresistant with cisplatin.
- the principal complexes studied by the prior art are those of 1,2-diaminocyclohexane (dach) and 1,1'-bis(aminomethyl) cyclohexane (damch).
- dach 1,2-diaminocyclohexane
- damch 1,1'-bis(aminomethyl) cyclohexane
- the present invention provides platinum complexes which exhibit good water-solubility and favorable antitumor activity, both in vitro and in vivo. Those complexes have the following structures:
- Z(NH 2 ) 2 and 2 Z'NH 2 will be designated as (amine) 2 or am 2 in one-line structural formulas.
- the present invention provides a general method for the solubilization of Pt(amine) 2 moieties which have been shown to have anti-tumor activity.
- the method of the present invention involving the use of unsymmetrical sulfoxides, produces more water-soluble species than the parent [Pt(am) 2 Cl 2 ] compounds.
- any platinum complexes utilizing bidentate amines or monodentate amines developed in the future can be solubilized by the unsymmetrical sulfoxide method of the present invention.
- the sulfoxide moieties which are present in the platinum complexes of the present invention are unsymmetrical sulfoxide moieties.
- one or both of R' and R" may be aliphatic, such as alkyl or the like, or one or both of R' and R" may be aromatic, such as aryl, alkaryl, aralkyl, or the like.
- R' is an aliphatic moiety
- R" is an aromatic moiety (that is, R" is aryl or is a group having an aryl substituent thereon).
- the aryl groups are preferably phenyl, and the alkyl groups are preferably lower alkyl.
- R' and R" are independently selected from the group consisting of C 1 -C 6 alkyl which is unsubstituted or substituted by phenyl, carboxy, C 1 -C 4 alkyl ester or C 2 -C 6 alkenyl; C 3 -C 7 cycloalkyl which is unsubstituted or substituted by phenyl, carboxy, C 1 -C 4 alkyl ester or C 2 -C 6 alkenyl; or phenyl; wherein each phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy (especially methoxy), halogen, hydroxy, C 2 -C 4 alkenyl, carboxy, C 1 -C 4 alkyl ester, amino, C 1 -C 4 alkyl amino and di(C 1 -C 4 alkyl) amino. It is essential that R' and R" be
- Complexes of the general formula [Pt(am) 2 (R'R"SO)Cl] are cationic (the sulfoxide group is neutral) and an anion X- is required to balance the charge on the complex.
- Any pharmaceutically acceptable anion is suitable for this purpose. Particularly suitable are Cl, Br, NO 3 , weak nucleophiles such as HSO 4 , H 2 PO 4 , BF 4 , PF 6 , carboxylates such as formate, acetate, benzoate, and the like. Most preferred is NO-.
- complexes of the general formula [Pt(am) 2 (R'R"SO)(SO 4 )] are neutral and are not associated with an external anion.
- Bidentate amines which can be utilized in the platinum complexes of the present invention include 1,2-diaminocyclohexane (dach), 1-amino-2-aminomethylcyclohexane (amch), 1,1'-bis(aminomethyl) cyclohexane (damch), 1-amino-2-aminomethyl-3, 3,5-trimethylcyclohexane, 2-aminopyridine, 2-aminomethylpyridine, 2-aminopiperidine, 2-methylaminopiperidine, 1,2-diaminobenzene (wherein the benzene ring is unsubstituted or substituted by C 1 -C 6 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, C 2 -C 4 alkenyl, carboxy, C 1 -C 4 alkyl ester, amino, C 1 -C 4 alkylamino, and di(C 1 -C 4 alkyl) amino, ethylene diamine, 1,3-prop
- Monodentate amines which can be utilized in the platinum complexes of the present invention include cyclopentylamine, cyclohexylamine, n-butylamine, iso-propylamine, and the like.
- monodentate amine moieties will preferably be of the general formula
- Z'-NH 2 wherein Z' is a moiety selected from the group comprising (a) cycloalkyl of 3 to 8 carbon atoms (b) alkyl of 3 to 10 carbon atoms, said cycloalkyl and alkyl moieties being unsubstituted or substituted by at least one substituent selected from the group comprising C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl and substituted phenyl, wherein the substituents on the phenyl ring are C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, C 2 -C 4 alkenyl, carboxy, amino, C 1 -C 4 alkyl amino, and di(C 1 -C 4 alkyl) amino.
- the sulfate complexes are prepared from the known aminesulfate complexes (See for instance H.A. Menema et al.: Inorcr. Chem. Acta 114,127 (1986).
- Reaction 1 is normally conducted at a temperature of 24 to 35°C, in water.
- Reaction 2 is generally conducted at a temperature of 24 to 35°C, in methanol.
- Reaction 3 is generally conducted at a temperature of 24 to 35°C, in methanol.
- Reaction 4 is generally conducted at a temperature of 24 to 35°C, in water.
- Reaction 5 is generally conducted at a temperature of 24 to 35°C, in methanol.
- Reaction 6 is generally conducted at a temperature of 24 to 35°C, in methanol.
- the compounds of the present invention are water-soluble, stable complexes which exhibit antitumor activity with some of the compounds, such as [Pt(damch) (MPSO)Cl]NO 3 , showing particularly high activity.
- the present results indicate that variation of the sulfoxide moiety results in potentiation of antitumor activity.
- platinum complexes of the present invention may be administered to patients, including humans or animals, having tumors susceptible to platinum therapy, especially cisplatin and carboplatin therapy. Furthermore, since the compounds of the present invention are non-crossresistant with cisplatin, the tumors which can be treated include tumors which are resistant to cisplatin (and carboplatin) therapy.
- the compounds may be administered in the form of sterile aqueous solutions, which are preferably administered intravaneously or interarterially, although other forms of administration may be indicated in given cases.
- Suitable dosage forms can also include oily or aqueous injectable preparations, for intramuscular or intraperitoneal injection, syrups or the like liquid preparations, and solid dosage forms such as capsules, tablets and the like.
- the effective amount of the complex of the present invention which should be administered to a patient can be determined by conventional methods which will be apparent to the skilled clinician. Normally, the activity of the platinum complex of the present invention will be evaluated in the screen along with the known complex such as cis-platin or carboplatin.
- the relative potency and the therapeutic index, i.e., the ratio of therapeutic effectiveness to toxicity, compared to that of the known analog will normally determine the relative dosage compared to the conventional doses of the analog for the type of malignancy being treated. Normally, however, from 1 to 500 mg/kg of the platinum complex will be administered to the patient in a given dose, with the dosage regime varying depending upon various factors which are well known to the skilled clinician.
- the platinum complex of the present invention may be administered together with reduced glutathione, as taught by U.S. patent application serial number 105,169, filed 7 October 1987, the disclosure of which is hereby incorporated by reference.
- platinum complexes having the formula shown above may have sufficiently high toxicity, or sufficiently low therapeutic indices, so as to be unsuitable for antitumor therapy in patients.
- these parameters can be readily determined by conventional screenin tests, such as, for instance, with L-1210 murine leukemia cell implanted in mice, and such complexes should naturally b avoided.
- the tumors in patients which are to be treated with th platinum complexes of the present invention are those tumor which are known to be susceptible to platinum therapy, such a tumors which are known to be treatable with cis-platin and carbo platin, as is well known to those in the art. It is known tha cisplatin and carboplatin have been clinically used at th present to treat testicular, ovarian, bladder and head and nec cencers. It is also known that these agents have shown at leas limited activity against non-small-cell lung cancer, osteogeni sarcoma, Hodgkins lymphoma, melanoma and breast cancer.
- Cisplati has been found to be active against squamous cell carcinoma o the head and neck, squamous cell carcinoma of the cervix, oa cell or small cell anaplastic lung cancer, non-small-cell lun cancer (in combination with VP-16 or vinca alkaloids), adenocarcinoma of the stomach, carcinoma of the esophagus, adenocarcinoma of the prostate, osteogenic sarcoma, soft tissu and bone sarcomas, non-Hodgkins lymphoma, adenocarcinoma of th breast, brain tumors, thyroid cancer and endometrial cancer . All of the proceeding tumors should respond to treatment with the platinum complexes of the present invention.
- the complexes of the present invention should also be active against certain tumors which are resistant to cisplatin, as is shown by animal studies conducted on the present complexes .
- the principal in vivo screen is also L-1210 murine leukemia.
- the cells are grown as an ascites by weekly intraperitoneal inoculation of 10 6 cells to BDF 1 mice (from NIH). Treatment is routinely by i.p. administration 24h after inoculation. Primary treatment schedules are day 1, days 1 , 5 , 9 or days 1 through 9. Usually the second scheme is employed but final doses may be adapted depending on toxicity response.
- the efficacy is determined as %T/C by calculation of MST (Mean S.urvival Time) of treated versus control x 100. Survivors to 30d are not included.
- Table IV illustrates the antitumoral activity of some optically active complexes (single enantiomers and single diasteroisomers) of the invention.
- the sign (+) or (-) refers to the optical rotation of the optically active chiral sulfoxide produced when the unsymmetrical sulfoxide is complexed with the platinum compound.
- the chiral sulfoxides of the present invention do not exhibit cross-resistance to cisplatin, which is a significant advantage.
- the chiral sulfoxides have a broad therapeutic range and high activity, and no disadvantages have been noted, compared to other platinum-containing chemotherapeutic agents.
- the Chloride salt was redissolved in MeOH. To this solution was added an equimolar weight of AgNO 3 dissolved in hot MeOH. The mixture was stirred in the dark overnight. After filtering insoluble AgCl the methanol was rotoevaporated giving the nitrate salt [Pt(dach) (DMSO)Cl]NO 3 . The product was recrystallized from MeOH/Ether by dissolving in MeOH, reducing the volume to 2 ml., diluting with ether and freezing overnight. The white crystals which formed were washed with ether and dried in a pistol over
- the Platinum (dach) -methylphenyl sulfoxide (MPSO) complexes were prepared by adding an equimolar amount of MPSO (0.0151 g., 0.0065 mol) to a slurry of Pt(dach)Cl 2 (2.4843 g., 0.0065 mol) in HPLC grade methanol. To this was added 1 equivalent of AgNO 3 dissolved in hot methanol. The reaction mixture was stirred overnight in. the dark. The insoluble AgCl precipitate was filtered and the filtrate rotoevaporated until the volume of methanol was approximately 2 ml. The concentrated solution was diluted with ether until a white solid just began forming. It was placed in the freezer overnight and the resultant white crystals were filtered and washed with ether. A second recrystallization was done in the same manner. The complex was dried in vacuum over
- R' CH 3
- R" Ph 1146 342 3020 - 3240
- R ' CH 3
- R CH 2 Ph 1132 355 3020 - 3280
- R' CH 3
- R" Ph 1144 334 3010 - 3250
- R' CH 3
- R" CH 2 Ph 1120 335 3010 - 3280 cha
- R' CH 3
- R'' CH 2 Ph 1128 340 3020 - 3280
- This example relates to the use of complexes containing optically pure sulfoxide liganda (+)- and (-) -mathyl (p-tolyl) sulfoxide
- optically pure complexes should have only one CH 3 resonance for the CH 3 group of the MTSO ligand, unlike diastereomers previously studied. This is confirmed in all cases.
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Abstract
Des complexes au platine ayant les formules [Pt(am)2ClR'R"SO]+X- et [Pt(am)2SO4R'R"SO], dans lesquelles (am)2 représente une amine bidentée, R' et R" sont des groupes organiques différents et X- représente un anion, présentent une acitivité anti-tumorale favorable in vivo contre des tumeurs susceptibles d'être traitées au platine.Platinum complexes having the formulas [Pt (am) 2ClR'R "SO] + X- and [Pt (am) 2SO4R'R" SO], in which (am) 2 represents a bidentate amine, R 'and R " are different organic groups and X- represents an anion, exhibit favorable anti-tumor activity in vivo against tumors capable of being treated with platinum.
Description
PLATINUM-AMINE-SULFOXIDES AS ANTI-TUMOR AGENTS
Background of the Invention
The clinical use of platinum complexes in cancer chemotherapy is now well established. The clinical utility of Cisplatin (cis-[PtCl2(NH3)2]) may be classified principally as curable (testicular cancer), sensitive (ovarian) and responsive (head and neck, small cell lung) and this spectrum of activity is matched by the "second-generation" analog Carboplatin ([Pt(NH3)2(CBDCA)], CBDCA = 1,1'-cyclobutanedicarboxylate). The principal advantage of the latter complex is considered to be the reduction in the severe nephrotoxicity of the parent complex, the spectrum of activity being very similar, although this may eventually change.
Current areas for further development of platinum complexes (and indeed metal complexes in general) have been described as disease-oriented and drug-oriented. In the former, combination with other drugs or radiation is necessary to expand the clinical role. In drug-oriented terms increase in allowable dosage by limitation of toxic side effects or changes in route of administration can be achieved. Besides bettering the clinical spectrum of cisplatin itself, some of these desired improvements could be incorporated into analogs and the selection of potentially useful drugs involves the search for complexes which satisfy one, or all, of three basic criteria:
1. Development of new selectivity, including a broader spectrum of activity than cisplatin, and especially activity in cisplatin-resistant lines.
2. Modification of the therapeutic index, either through greater clinical effectiveness or reduced toxicity, in the latter case with activity at least equal to cisplatin.
3. Modification of pharmacokinetic properties such as solubility which would allow other routes of administration. The structure-activity relationships developed for platinum complexes has led to the development of a large number of complexes with antitumor activity. The basic adaptation of the parent molecule involved use of other amines besides NH3 and modification of the leaving group by substitution of the chloride
with groups such as carboxylate, dicarboxylate or sulfate.
A number of amines give complexes which are non-crossresistant with cisplatin. The principal complexes studied by the prior art are those of 1,2-diaminocyclohexane (dach) and 1,1'-bis(aminomethyl) cyclohexane (damch). Despite considerable interest in a full clinical trial of a dach or damch complex, no one compound with suitable properties of aqueous solubility, stability and ease of formulation and synthesis has as yet been found, and early results on Phase 1 trials of such complexes have been disappointing. A clinical trial of a compound non-cross-resistant with cisplatin is a high priority of the art.
A limiting factor in development of dach and damch platinum complexes has been both aqueous solubility and chemical stability. Thus, whereas complexes of NH3 containing dicarboxylate ligands are stable for days in aqueous solution, the corresponding complexes of dach hydrolyse more readily.
The potential for use of sulfur-bound dimethylsulfoxide as leaving group in complexes of type cis-[Pt(am)2(DMSO)2]2+ has been recently, outlined; see N. Farrell "Platinum, Gold and Other Metal Chemotherapeutic Agents" ACS Symposium 209, 279 (1983) and N. Farrell: J. Chem. Soc. (Chem. Comm.) 1014 (1980). The rationale for these complexes is that despite the high trans influence of DMSO, which would be expected to labilize the group trans to it, the mutual labilization of the two DMSO ligands results in initial loss of DMSO to give aquo species, maintaining the cis-Pt(am)2 moiety intact. Kinetic studies confirmed these observations; see S. Lanza, D. Minnitti, R. Romeo, and M.L. Tobe: Inorg. Chem. 22, 2006 (1983). Further hydrolysis would give the active diaquo species:
[Pt(am)2(DMSO)2]2+ → [Pt(am)2.(DMSO) (H2O)]2+→ [Pt(am)2(H2O)2]2+
The series of bis (DMSO) complexes were not, however, active in vivo, due perhaps to the 2+ charge and lack of penetration into the cell. A further problem may be the rate at which the second sulfoxide ligand reacts, either to give the active diaquo species
or in a direct reaction with DNA, the purported intracellular target of Pt complexes; see A.L. Pinto and S.J. Lippard: Biochem. Biophvs. Acta 780, 167 (1985). The series [Pt(am)2(DMSO)Cl]+ has been studied for their kinetic parameters and it is stated that this series is not antitumor active; (see A.R. Khokhar and M.L. Tobe: J. Clin. Hematol. Oncol. 7(1), 114 (1977).
Summary of the Invention The present invention provides platinum complexes which exhibit good water-solubility and favorable antitumor activity, both in vitro and in vivo. Those complexes have the following structures:
wherein is a bidentate amine, Z'NH2 is a monodentate
amine, R' and R" are different organic groups and X- is a pharmaceutically acceptable anion. Since SO4 is divalent, there is no anion X~ in those complexes wherein the Cl attached to the central platinum atom is replaced by sulfate.
For convenience, Z(NH2)2 and 2 Z'NH2 will be designated as (amine)2 or am2 in one-line structural formulas.
In general the present invention provides a general method for the solubilization of Pt(amine)2 moieties which have been shown to have anti-tumor activity. In all instances, the method of the present invention, involving the use of unsymmetrical sulfoxides, produces more water-soluble species than the parent [Pt(am)2Cl2] compounds. Thus any platinum complexes utilizing bidentate amines or monodentate amines developed in the future can be solubilized by the unsymmetrical sulfoxide method of the present invention.
Detailed Description of the Invention
As indicated above, the sulfoxide moieties which are present in the platinum complexes of the present invention are unsymmetrical sulfoxide moieties. In these unsymmetrical sulfoxide moieties, one or both of R' and R" may be aliphatic, such as alkyl or the like, or one or both of R' and R" may be aromatic, such as aryl, alkaryl, aralkyl, or the like. Preferably, however, R' is an aliphatic moiety and R" is an aromatic moiety (that is, R" is aryl or is a group having an aryl substituent thereon). The aryl groups are preferably phenyl, and the alkyl groups are preferably lower alkyl.
More specifically, R' and R" are independently selected from the group consisting of C1-C6 alkyl which is unsubstituted or substituted by phenyl, carboxy, C1-C4 alkyl ester or C2-C6 alkenyl; C3-C7 cycloalkyl which is unsubstituted or substituted by phenyl, carboxy, C1-C4 alkyl ester or C2-C6 alkenyl; or phenyl; wherein each phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy (especially methoxy), halogen, hydroxy, C2-C4 alkenyl, carboxy, C1-C4 alkyl ester, amino, C1-C4 alkyl amino and di(C1-C4 alkyl) amino. It is essential that R' and R" be different so that the S atom in the sulfoxide, when complexed with the Pt(amine)2-containing compound, is chiral.
Complexes of the general formula [Pt(am)2(R'R"SO)Cl] are cationic (the sulfoxide group is neutral) and an anion X- is
required to balance the charge on the complex. Any pharmaceutically acceptable anion is suitable for this purpose. Particularly suitable are Cl, Br, NO3, weak nucleophiles such as HSO4, H2PO4, BF4, PF6, carboxylates such as formate, acetate, benzoate, and the like. Most preferred is NO-. As indicated above, complexes of the general formula [Pt(am)2(R'R"SO)(SO4)] are neutral and are not associated with an external anion.
Abbreviations are used in this specification for the sulfoxides R'R"SO as listed below:
Dimethyl Sulfoxide DMSO
Methyl Benzyl Sulfoxide MBSO
Dibenzyl Sulfoxide DBSO
Methyl Phenyl Sulfoxide MPSO
Diphenyl Sulfoxide DPSO
Methyl Tolyl Sulfoxide MTSO
Bidentate amines which can be utilized in the platinum complexes of the present invention include 1,2-diaminocyclohexane (dach), 1-amino-2-aminomethylcyclohexane (amch), 1,1'-bis(aminomethyl) cyclohexane (damch), 1-amino-2-aminomethyl-3, 3,5-trimethylcyclohexane, 2-aminopyridine, 2-aminomethylpyridine, 2-aminopiperidine, 2-methylaminopiperidine, 1,2-diaminobenzene (wherein the benzene ring is unsubstituted or substituted by C1-C6 alkyl, C1-C4 alkoxy, halogen, hydroxy, C2-C4 alkenyl, carboxy, C1-C4 alkyl ester, amino, C1-C4 alkylamino,
and di(C1-C4 alkyl) amino, ethylene diamine, 1,3-propane diamine, 2,2-diethyl-1,3-propanediamine and 1,2-diaminocycloheptane. Thus the bidentate amine moieties will preferably be of the general formula:
Z-[(CH2)n-NH2]2 wherein Z is a divalent moiety selected from the group comprising (a) cycloalkyl of 3 to 8 carbon atoms, (b) alkyl of 3 to 10 carbon atoms, (c) pyridine, (d) piperidine, and (e) phenyl; said moieties being further unsubstituted or substituted by at least one further substituent selected from the group comprising C1-C6 alkyl, C2-C6 alkenyl, phenyl and substituted phenyl, wherein the substituents on the phenyl ring are C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, C2-C4 alkenyl, carboxy, amino, C1-C4 alkyl amino, and di(C,-C4 alkyl) amino, and n is 0 or an integer of 1 to 6.
Monodentate amines which can be utilized in the platinum complexes of the present invention include cyclopentylamine, cyclohexylamine, n-butylamine, iso-propylamine, and the like.
Thus the monodentate amine moieties will preferably be of the general formula
Z '-NH2 wherein Z' is a moiety selected from the group comprising (a) cycloalkyl of 3 to 8 carbon atoms (b) alkyl of 3 to 10 carbon atoms, said cycloalkyl and alkyl moieties being unsubstituted or
substituted by at least one substituent selected from the group comprising C1-C6 alkyl, C2-C6 alkenyl, phenyl and substituted phenyl, wherein the substituents on the phenyl ring are C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, C2-C4 alkenyl, carboxy, amino, C1-C4 alkyl amino, and di(C1-C4 alkyl) amino.
There are two general synthetic schemes for preparing the complexes of the present invention. In one, displacement of sulfoxide from known [PtCl2(R'R"SO)2], prepared by standard methods, see J.H. Price, A.N. Williamson, R.F. Schramm, and B.B. Wayland: Inorcr. Chem. 11, 1280 (1972), by a chelating diamine results in the desired cation, as described for DMSO complexes; see R.Romeo, D. Minnitti, S. Lanza, and M.L. Tobe: Inorg. Chem. Acta 22, 87 (1977):
1) K2PtCl4 + R'R"SO → [PtCl2(R'R"SO)2] + 2KCl
2) [PtCl2(R'R"SO)2] + 2am → [PtCl(R'R"SO)(am)2]Cl + R'R"SO
3) [PtCl(R'R"Sb)(am)2]Cl + AgNO3 → [Pt(am)2(R'R"SO)Cl]NO3 +
AgCl
In the second scheme, displacement of chloride from the known [PtCl2(am)2] gives the desired complex:
4) K2PtCl4 + 2 am → [PtCl2(am)2]
5) [PtCl2(am)2] + R'R"RSO + AgNO3 → [Pt(am)2(R'R"SO)Cl]NO3 + AgCl
The sulfate complexes are prepared from the known aminesulfate complexes (See for instance H.A. Menema et al.: Inorcr. Chem. Acta 114,127 (1986).
6) [Pt(am)2SO4] + R'R"SO → [Pt(am)2(R'R''SO)SO4]
Reaction 1 is normally conducted at a temperature of 24 to 35°C, in water. Reaction 2 is generally conducted at a temperature of 24 to 35°C, in methanol. Reaction 3 is generally conducted at a temperature of 24 to 35°C, in methanol. Reaction
4 is generally conducted at a temperature of 24 to 35°C, in water. Reaction 5 is generally conducted at a temperature of 24 to 35°C, in methanol. Reaction 6 is generally conducted at a temperature of 24 to 35°C, in methanol.
In the case of 1,2-diaminocyclohexane (dach) the differential activity of the optical and geometric isomers has been recognized (see M. Noji, K. Oktamoto, Y. Kidani and T. Tashiro: J. Med. Chem. 24, 508 (1981). The present inventors have used both a racemic mixture (denoted dach) and the optically pure isomers (denoted R,R-dach and S,S-dach), and noted differences in activity but noted further that sulfoxides such as methylphenyl and methylbenzyl are also optically active. Their complexes with optically active amines therefore lead to diastereomers, as evidenced by two peaks for the -CH3 protons of MPSO in the 1HNMR spectrum of [Pt(dach) (MPSO)Cl]NO3. The 1HNMR spectrum of the -CH3 protons of [Pt(R,R-dach) (MPSO)Cl]NO3 also show splitting, indicating a pair of diastereomers. The chirality of the sulfoxide is a dictating factor in the activity. This is a novel feature of this invention, as the unsymmetrical sulfoxides represent the first examples of chiral ligands as leaving groups in platinum complexes which exhibit antitumor activity.
The compounds of the present invention are water-soluble, stable complexes which exhibit antitumor activity with some of the compounds, such as [Pt(damch) (MPSO)Cl]NO3, showing particularly high activity. The present results indicate that variation of the sulfoxide moiety results in potentiation of antitumor activity.
These platinum complexes of the present invention may be administered to patients, including humans or animals, having tumors susceptible to platinum therapy, especially cisplatin and carboplatin therapy. Furthermore, since the compounds of the present invention are non-crossresistant with cisplatin, the tumors which can be treated include tumors which are resistant to cisplatin (and carboplatin) therapy. The compounds may be administered in the form of sterile aqueous solutions, which are
preferably administered intravaneously or interarterially, although other forms of administration may be indicated in given cases.
Solutions for intravaneous injections will normally be sterile physiological solutions. Suitable dosage forms can also include oily or aqueous injectable preparations, for intramuscular or intraperitoneal injection, syrups or the like liquid preparations, and solid dosage forms such as capsules, tablets and the like.
The effective amount of the complex of the present invention which should be administered to a patient can be determined by conventional methods which will be apparent to the skilled clinician. Normally, the activity of the platinum complex of the present invention will be evaluated in the screen along with the known complex such as cis-platin or carboplatin. The relative potency and the therapeutic index, i.e., the ratio of therapeutic effectiveness to toxicity, compared to that of the known analog will normally determine the relative dosage compared to the conventional doses of the analog for the type of malignancy being treated. Normally, however, from 1 to 500 mg/kg of the platinum complex will be administered to the patient in a given dose, with the dosage regime varying depending upon various factors which are well known to the skilled clinician.
At times it may be advantageous to administer the platinum complex of the present invention in combination with one or more agents that potentiate the tumor activity or mitigate any undesired side-effects of the platinum complex. For instance, the platinum complexes of the present invention may be administered together with reduced glutathione, as taught by U.S. patent application serial number 105,169, filed 7 October 1987, the disclosure of which is hereby incorporated by reference.
It is recognized that certain of the platinum complexes having the formula shown above may have sufficiently high toxicity, or sufficiently low therapeutic indices, so as to be unsuitable for antitumor therapy in patients. However, these
parameters can be readily determined by conventional screenin tests, such as, for instance, with L-1210 murine leukemia cell implanted in mice, and such complexes should naturally b avoided.
The tumors in patients which are to be treated with th platinum complexes of the present invention are those tumor which are known to be susceptible to platinum therapy, such a tumors which are known to be treatable with cis-platin and carbo platin, as is well known to those in the art. It is known tha cisplatin and carboplatin have been clinically used at th present to treat testicular, ovarian, bladder and head and nec cencers. It is also known that these agents have shown at leas limited activity against non-small-cell lung cancer, osteogeni sarcoma, Hodgkins lymphoma, melanoma and breast cancer. Cisplati has been found to be active against squamous cell carcinoma o the head and neck, squamous cell carcinoma of the cervix, oa cell or small cell anaplastic lung cancer, non-small-cell lun cancer (in combination with VP-16 or vinca alkaloids), adenocarcinoma of the stomach, carcinoma of the esophagus, adenocarcinoma of the prostate, osteogenic sarcoma, soft tissu and bone sarcomas, non-Hodgkins lymphoma, adenocarcinoma of th breast, brain tumors, thyroid cancer and endometrial cancer . All of the proceding tumors should respond to treatment with the platinum complexes of the present invention. The complexes of the present invention should also be active against certain tumors which are resistant to cisplatin, as is shown by animal studies conducted on the present complexes .
The in vitro and in vivo" evaluation procedures utilized have been outlined, (see M.P. Hacker et al.: Cancer Res. 45, 4748 (1985). In tissue culture, L-1210 murine leukemia cells are grown using McCoy's 5A modified medium supplemented with glutamine, antibiotics, and 10% horse serum. The population doubling time is of the order of 12h. Cells are seeded at a concentration of 1-2 × 105 cells/ml and complex concentrations added and tested in triplicate. Percent inhibition is calculated in standard fashion
using a computer program based on the Litchfield and Wilcoxon procedure. An arbitrary concentration of 15 uM is considered a reasonable cut off point.
The principal in vivo screen is also L-1210 murine leukemia. The cells are grown as an ascites by weekly intraperitoneal inoculation of 106 cells to BDF1 mice (from NIH). Treatment is routinely by i.p. administration 24h after inoculation. Primary treatment schedules are day 1, days 1 , 5 , 9 or days 1 through 9. Usually the second scheme is employed but final doses may be adapted depending on toxicity response. The efficacy is determined as %T/C by calculation of MST (Mean S.urvival Time) of treated versus control x 100. Survivors to 30d are not included.
TABLE I
IN VITRO ACTIVTY OF [Pt(am)2(R'-R"-SO)Cl]NO3 in L1210 LEUKEMIA
AMINE R'R"SO ID50 (ug/ml) dach DMSO 4.3
(R,R)dach MBSO 0.52
(R,R)dach DBSO 3.5 dach MPSO 0.9 dach DTSO 2.7 damch DMSO 3.3 damch MBSO 2.9 damch MPSO 0.61 damch DPSO 0.39 cha* MBSO 3.5 cha* DBSO 2.7 cpa* MPSO 2.5 and for [Pt(am)2(R 'R"SO)(SO4)] : dach MBSO 5.0 dach DBSO 3.1
*cha = cyclohexylamine cpa = cyclopentylamine
It will be noted that all of the platinum complexes which produced low ID50 values in Table I were unsymmetrical complexes except for the ninth complex, wherein the sulfoxide moioty was DPSO. However, that complex was toxic, as reflected by Table II. While a comparison of the last two compounds of Table I indicate that the DBSO moiety produced better (or lower) values of ID50, Table III indicates that in vivo the MBSO moiety produced significantly higher antitumor results than the DBSO moiety.
TABLE II IN VIVO ANTITUMOR ACTIVITY [Pt(am)2(R'R"SO)Cl]NO3 L1210 am R'R"SO* Dose# . %T/C
(mg/kg)
R,R-dach DMSO 3 × 100 131
R,R-dach MPSO 3 × 50 211 (1/6)
3 × 25 176
R,R-dach MBSO 3 × 100 292 (3/6)
3. × 50 165
RfU-dach DBSO 3 × 100 142 dainαh. DMSO 3 × 100 152 dawoh MPSO 3 × 50 280 (2/6) 2 × 100 158 (1/6) dαtoσh DPSO 1 × 100 TOXIC
# Complexes dissolved in 0.1M Salino solution. 30day survivor parentheses.
*all sulfoxides as racemic mixtures
TABLE III
IN VIVO ANTITUMOR ACTIVITY [Pt(am)2(R'R"SO) (SO4)] L1210 am R'R"SO Dose# T/C (mg/kg)
dach MBSO 3 × 100 222(1/6) dach DBSO 3 × 50 120
TABLE IV
Biological data for Opticallv Pure Complexes. L1210 DATA FOR [Pf (amine) (R1R2SO)Cl]NO3 @ AMINE R1R2SO * DOSE %T/C# (mg/kg) damch (-)MTSO 50 × 3 205 (1/6)
2.5* 100 × 3 146 (2/6) damch (+)MTSO 50 × 3 229 (2/6)
50 × 1 176 (1/6)
100 × 1 208 (3/5) 321* (2/5)
R,R-dach (-)MTSO 50 × 3 244 (2/6) 100 × 3 281 (2/6)
R,R-dach (+)MTSO 50 × 3 129
100 × 1 103
S,S-dach (-)MTSO 50 × 3 190 (1/6) 251* 100 × 3 290 (3/6) 315* (2/6)
S,S-dach (+)MTSO 50 × 3 139
MTSO = methyltolylsulfoxide, dach - 1,2-diaminocyclohexane. damch - 1,1-diaminomethylcyclohexane. @ injections on a 1,5,9d schedule. All complexes dissolved in 0.9% saline. 30d. Survivors in parentheses.
# T/C values calcd. at 30d, exclusive of survivors.
* T/C values calcd. at 60d, exclusive of survivors.
Table IV illustrates the antitumoral activity of some optically active complexes (single enantiomers and single diasteroisomers) of the invention. For each of the compounds reported in table IV, the sign (+) or (-) refers to the optical rotation of the optically active chiral sulfoxide produced when the unsymmetrical sulfoxide is complexed with the platinum compound.
It will be noted from the results reported in Table IV that, independent of the chirality of the amine ligand (in compounds 1, 2 damch is an achiral ligand; in compounds 3, 4, 5 and 6 R,R-dach and S,S-dach are chiral ligands), significantly better results are observed with one of the two possible enantiomers of the chiral sulfoxide. Based on these results, it appears that using unsymmetrical sulfoxides as leaving groups in platinum complexes, the absolute configuration S and/or R of the chiral sulfoxide ligand affects the overall antitumor activity of the complexes.
In general, the chiral sulfoxides of the present invention do not exhibit cross-resistance to cisplatin, which is a significant advantage. The chiral sulfoxides have a broad therapeutic range and high activity, and no disadvantages have been noted, compared to other platinum-containing chemotherapeutic agents.
Examples of the Invention COMPARATIVE EXAMPLE A
PREPARATION OF [Pt(dach)(DMSO)Cl]NO3 FROM [PtCl2(DMSO)2] The neutral Platinum Dimethylsulfoxide complex, [Pt(DMSO)2Cl2], was prepared according to Price, supra. The complex (2.35 g., 0.0056 mol) was added to a solution of 1,2-Diaminocyclohexane (Dach) (0.69 ml. 0.0056 mol) in HPLC grade methanol. The slurry was stirred for 10 minutes, during which time the light yellow-Platinum complex dissolved. The mixture was stirred for an additional hour to ensure completion of the
reaction. The methanol was rotoevapora ted giving [Pt(Dach) (DMSO)Cl]Cl, a white solid, which was filtered and washed with acetone.
The Chloride salt was redissolved in MeOH. To this solution was added an equimolar weight of AgNO3 dissolved in hot MeOH. The mixture was stirred in the dark overnight. After filtering insoluble AgCl the methanol was rotoevaporated giving the nitrate salt [Pt(dach) (DMSO)Cl]NO3. The product was recrystallized from MeOH/Ether by dissolving in MeOH, reducing the volume to 2 ml., diluting with ether and freezing overnight. The white crystals which formed were washed with ether and dried in a pistol over
P2O5.
EXAMPLE 1
PREPARATION OF [Pt(dach) (MPSO)Cl]NOP FROM [Pt(Dach)Cl2] The [Pt(1,2-diaminocyclohexane)Cl2] was prepared by standard procedures.
The Platinum (dach) -methylphenyl sulfoxide (MPSO) complexes were prepared by adding an equimolar amount of MPSO (0.0151 g., 0.0065 mol) to a slurry of Pt(dach)Cl2 (2.4843 g., 0.0065 mol) in HPLC grade methanol. To this was added 1 equivalent of AgNO3 dissolved in hot methanol. The reaction mixture was stirred overnight in. the dark. The insoluble AgCl precipitate was filtered and the filtrate rotoevaporated until the volume of methanol was approximately 2 ml. The concentrated solution was diluted with ether until a white solid just began forming. It was placed in the freezer overnight and the resultant white crystals were filtered and washed with ether. A second recrystallization was done in the same manner. The complex was dried in vacuum over
P2O5.
ELEMENTAL ANALYSES (Calculated. (Found))
[Pt (am)2(R'R"SO)Cl]NO3
(am) 2 R'R"SO %C %H %N
(dach) R'=R"=CH3 19.82 (20.14) 4.13 (4.25) 8.67 ( 8.58)
R'=CH3, R"=Ph 28.55 (28.52) 4.03 (3.90) 7.69 ( 7.57)
R'=R"=Ph-CH3 37.71 (35.24) 4.40 (4.67) 6.60 ( 6.46)
(tolyl)
R'=CH3, R"=CH2Ph 29.71 (29.97) 4.09 (4.20) 7.08 (7.49) R'= R"=CH2Ph 38.95 (37.71) 4.15 (4.40) 6.68 (6.60)
(damch) *R'=R"=CH3 23.41 (22.34) 4.68 (4.20) 8.19 ( 7.50)
R'=CH3, R"=ph 31.32 (31.21) 4.52 (4.34) 7.31 ( 7.30)
R'=R"=Ph 37.69 (37.54) 4.40 (4.20) 6.60 ( 6.72)
R'=CH3, R"=CH2Ph 32.22 (32.62) 4.27(4.75) 7.81 (7.14)
cpa R'=CH3, R'=Ph 35.27(33.86) 5.09(4.98) 6.51(6.97)
Cha R,=CH3, R"=CH2Ph 36.87(37.23) 5.79(5.59) 6.52(6.28) and for [Pt(dach) (R'R"SO)SO4] :
R'=CH3, R"=CH2Ph 30.05(29.91) 4.27(4.29) 4.96(5.00)
R'= R"=CH2Ph 40.96(41.57) 5.64(5.35) 5.15(4.41)
MAJOR IR PEAkS [Pt (am)2(R,R"SO)Cl]NO3
(am)2 R'R"SO v(S=O) cm-1 v(Pt-Cl) cm-1 v(NH2) cm-1
(dach) R'=R"=CH3 1134 318 3020 - 3240
R'=CH3, R"=Ph 1146 342 3020 - 3240 R'=R"=Ph-CH3 1172 3020 - 3240 R '=CH3 , R=CH2Ph 1132 355 3020 - 3280 R'=R"=CH2Ph 1105 (1170,1155sh) 338 3020 - 3250
(damch) *R'=R"=CH3 1103 334 2910 - 3250
R'=CH3, R"=Ph 1144 334 3010 - 3250 R'=R"=Ph 1100 320 3010 - 3250 R'=CH3, R"=CH2Ph 1120 335 3010 - 3280 cha R'=CH3, R''=CH2Ph 1128 340 3020 - 3280 R'= R"=CH2Ph 1115 342 3020 - 3250
and for [Pt(R,R-dach) (R'R"SO)SO4]
R'=CH3, R"=CH2Ph v(SO) 1175 (sharp), 1120(br)
(MBSO)
R'=R"=CH2Ph (DBSO) v(SO) = 1140 (v. br.) sh = shoulder, br = broad, v. br. = very broad.
NMR PEAKS [Pt (am)2R'R"SO)Cl]NO3
(am)2 R'R"SO CH3-RSO Ph-RSO Diammine ligand
(Dach) R'=R"=CH3 3.49 (d)6H } 2.58 (m)2H R'=CH3, R"=Ph 3.52 (d)3H 7.75 (d)3H } 2.05 (m)2H 8.15 (d)2H } 1.60 (m)2H } 1.10-1.40 (m) 4H
(Damch) *R'=R"=CH3 3.49 (s)6H } 1.30-1.50 (m) 10H R'=CH3, R"=Ph 3.73 (s)3H 7.75 (d)3H } 2.50-2.65 (m) 4H 8.15 (d)2H } s = singlet d = doublet m = multiplet EXAMPLE 2
Preparation of [Pt(am)2(MTSO)Cl]NO3
This example relates to the use of complexes containing optically pure sulfoxide liganda (+)- and (-) -mathyl (p-tolyl) sulfoxide
(Ma(p-CH3C6H4)SO,MTSO). The ligand was prepared by the general procedure of Drabowicz et al. J. Org_. Chem. 47, 3325 (1982). The free ligands were characterised by their optical rotation as given in the above quoted paper:
(+) MTS0 [α]D = 144.3° (lit. value 150.1, optical purity 86%)
(-) MTSO [α]D = -145° (optical purity 86 %) Tha complexes were prepared in the standard manner by addition of one equivalent of the ligand to a suspension of the appropriate
[Pt(diamine)Cl2] in MeOH in the presence of one equivalent of
AgNO3. To obtain optically pure enantiomers of the 1,2-diaminocyclohexane (dach) ligand the pure forms (R,R and S,S) were used.
These were obtained commercially and used without furthe purification. Work up was as per previous examples. The complexe were characterised by IR, NMR, CD and elemental analyses. Th
sign of, the optically pure sulfoxide changes upon complexation to Platinum. The signs quoted and used hereinbelow refer to the sign of the complexed ligand, incorporated into the specific complex.
Elemsntal Analyses for [Pt (am)2(R1R2SO)Cl]NO3
(am)2 R1R2SO %C %H %N
(1) damch (-)MTSO 32.34(32.57) 4.59(4.52) 6.97(7.31)
(2) damch (+)MTSO 31.60(32.57) 4.47(4.52) 7.08(7.31)
(3) R,R-dach (-)MTSO 29.67(20.55) 4.06(4.03) 7.20(7.69)
(4) R,R-dach (+)MTSO 30.12(28.55) 4.04(4.03) 7.22(7.69)
(5) S,S-dach (-)MTSO 28.84(20.55) 3.94(4.03) 7.33(7.69)
(6) S,S-dach (+)MTSO 30.03(28.55) 3.97(4.03) 7.29(7.69)
Spectroscopic Data
The optically pure complexes should have only one CH3 resonance for the CH3 group of the MTSO ligand, unlike diastereomers previously studied. This is confirmed in all cases.
Major NMR data for [Pt(am)2 (R'R"SO)Cl]NO3
(am)2 R'R"SO Chemical Shift of S-CH3
(Pt-H coupling for Pt-S-C-H in Hz)
damch (-)MTSO 3.67 (17.93) damch (+)MTSO 3.65
R,R-dach (-)MTSO 3.69 (15.80)
R,R-dach (+)MTSO 3.67 (22.2)
S,S-dach (-)MTSO 3.68 (14.5)
S,S-dach (+)MTSO 3.67 (17.1)
All complexes run in D2O. The rest of the spectra show peaks typical of the amine and p-tolyl (CH3 and -C6H4-) residues. The Circular Dichroism Spectra of one set of complexes (those of the damch ligand) are shown in Fig.1. These confirm the optical purity of the complexes and also the sign inversion.
Claims
1. A platinum complex of the formula
wherein is a bidentate amine, Z'NH2 is a monodentate amine, R' and R" are different organic groups and X- is a pharmaceutically acceptable anion.
2. A platinum complex according to claim 1 of the formula
or
A platinum complex according to claim 1 of the formula
or
4. A platinum complex according to claim 1 wherein R' and R" are independently selected from the group consisting of C1-C6 alkyl optionally substituted by phenyl, carboxy, C1-C4 alkyl ester or C2-C6 alkenyl; C3-C7 cycloalkyl optionally substituted by phenyl, carboxy, C1-C4 alkyl ester or C2-C6 alkenyl; and phenyl optionally substituted by a substituent selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, C2-C4 alkenyl, carboxy C1-C4 alkyl ester, amino, C1-C4 alkyl amino, and di(C1-C4 alkyl) amino.
5. A platinum complex according to claim 4, wherein Z' is C3-C8 cycloalkyl or C3-C10 alkyl, each alkyl being optionally substituted with a substituent selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, phenyl and substituted phenyl.
6. A platinum complex according to claim 5, wherein Z' is cycloalkyl.
7. A platinum complex according to claim 6, wherein Z' is cyclopentyl or cyclohexyl.
8. A platinum complex according to claim 4, wherein Z is an alkylene group of 3 to 10 carbon atoms, a cycloalkylene group of 3 to 10 carbon atoms, phenylene or pyridyl.
9. A platinum complex according to claim 8, wherein Z is cyclohexylidene.
10. A platinum complex according to claim 4, wherein R' is methyl and R" is phenyl, tolyl or benzyl.
11. A platinum complex according to claim 1, wherein X is Cl, Br or NO3.
12. A platinum complex according to claim 11, wherein X is NO3.
13. A platinum complex according to claim 1 which is optically active.
14. An anti-tumor composition comprising an anti-tumor effective amount of a platinum complex according to claim 1 in combination with a pharmaceutically acceptable carrier.
15. An anti-tumor composition according to claim 14 containing 1-500 mg of the platinum complex.
16. A method of treating an animal having a tumor susceptible to therapy with platinum which comprises administering to said animal an anti-tumor effective amount of a platinum complex according to claim 1.
17. A pharmaceutical composition comprising a compound as claimed in claim 1 for use in a method of treating an animal having a tumor susceptible to therapy with platinum which comprises administering to said animal an anti-tumor effective amount of a platinum complex according to claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18095688A | 1988-04-13 | 1988-04-13 | |
| US180956 | 1994-01-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0409894A1 true EP0409894A1 (en) | 1991-01-30 |
| EP0409894A4 EP0409894A4 (en) | 1992-12-02 |
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ID=22662298
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19890904974 Withdrawn EP0409894A4 (en) | 1988-04-13 | 1989-04-12 | Platinum-amine-sulfoxides as anti-tumor agents |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0409894A4 (en) |
| KR (1) | KR900700097A (en) |
| AU (1) | AU3447289A (en) |
| ES (1) | ES2013433A6 (en) |
| GR (1) | GR890100246A (en) |
| WO (1) | WO1989009598A1 (en) |
| ZA (1) | ZA892706B (en) |
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| IT1238078B (en) * | 1990-01-31 | 1993-07-05 | Silvano Spinelli | CIS-PLATINUM COMPLEXES WITH AMINES AND CHELANTS SULFINYLCARBOSSILATES |
| NL9001639A (en) * | 1990-07-19 | 1992-02-17 | Amc Amsterdam | PT-CONTAINING COMPOUND, METHOD FOR PREPARING IT, AND USE OF SUCH COMPOUNDS. |
| DE60219621T2 (en) * | 2002-08-29 | 2007-12-20 | Jih-Ru Hwu | Organometallic complex |
| AU2016374759B2 (en) * | 2015-12-22 | 2021-04-01 | Nippon Kayaku Kabushiki Kaisha | Polymer conjugate of sulfoxide derivative-coordinated platinum(II) complex |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0296321A1 (en) * | 1987-06-23 | 1988-12-28 | American Cyanamid Company | Synthesis of cisplatinum analogs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55144422A (en) * | 1979-04-28 | 1980-11-11 | Nippon Kayaku Co Ltd | Purification of cis-dichlorodiammineplatinum(2) |
-
1989
- 1989-04-12 AU AU34472/89A patent/AU3447289A/en not_active Abandoned
- 1989-04-12 KR KR1019890702309A patent/KR900700097A/en not_active Application Discontinuation
- 1989-04-12 EP EP19890904974 patent/EP0409894A4/en not_active Withdrawn
- 1989-04-12 WO PCT/US1989/001520 patent/WO1989009598A1/en not_active Application Discontinuation
- 1989-04-13 ES ES8901289A patent/ES2013433A6/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0296321A1 (en) * | 1987-06-23 | 1988-12-28 | American Cyanamid Company | Synthesis of cisplatinum analogs |
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 86, 1977, page 19, abstract no. 182963x, Columbus, Ohio, US; M.L. TOBE et al.: "Structure, activity, reactivity and solubility relations of platinum diamine complexes", & J. CLIN. HEMATOL. ONCOL. 1977, 7(1), 114-37 * |
| See also references of WO8909598A1 * |
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| ES2013433A6 (en) | 1990-05-01 |
| AU3447289A (en) | 1989-11-03 |
| EP0409894A4 (en) | 1992-12-02 |
| KR900700097A (en) | 1990-08-11 |
| GR890100246A (en) | 1990-01-31 |
| WO1989009598A1 (en) | 1989-10-19 |
| ZA892706B (en) | 1989-11-29 |
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