WO2001009149A1 - Bisplatinum complexes active through the oral route - Google Patents
Bisplatinum complexes active through the oral route Download PDFInfo
- Publication number
- WO2001009149A1 WO2001009149A1 PCT/EP2000/007276 EP0007276W WO0109149A1 WO 2001009149 A1 WO2001009149 A1 WO 2001009149A1 EP 0007276 W EP0007276 W EP 0007276W WO 0109149 A1 WO0109149 A1 WO 0109149A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bis
- alkyl
- aza
- group
- hydrogen
- Prior art date
Links
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical group 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 5
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims abstract description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001450 anions Chemical class 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims abstract description 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- 239000011630 iodine Substances 0.000 claims abstract description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims abstract description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000004962 physiological condition Effects 0.000 claims abstract description 3
- ROHAEUVBFQHNSG-UHFFFAOYSA-N I.[O-][N+]([O-])=O Chemical compound I.[O-][N+]([O-])=O ROHAEUVBFQHNSG-UHFFFAOYSA-N 0.000 claims abstract 2
- -1 preferably C5-Cg Chemical group 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- 230000000259 anti-tumor effect Effects 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 150000002402 hexoses Chemical class 0.000 claims description 5
- 150000002972 pentoses Chemical class 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 150000004671 saturated fatty acids Chemical class 0.000 claims description 4
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 4
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 2
- 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 2
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 229910052702 rhenium Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 230000002195 synergetic effect Effects 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- DCAYPVUWAIABOU-UHFFFAOYSA-N alpha-n-hexadecene Natural products CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 description 53
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 29
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 20
- RSJKGSCJYJTIGS-UHFFFAOYSA-N N-undecane Natural products CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 16
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 15
- 239000000284 extract Substances 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- IIYFAKIEWZDVMP-UHFFFAOYSA-N linear paraffin C13 Natural products CCCCCCCCCCCCC IIYFAKIEWZDVMP-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 10
- 150000003057 platinum Chemical class 0.000 description 10
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 9
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 description 7
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 5
- PJFHRRVCKBIDSR-UHFFFAOYSA-N 2,2,2-trifluoro-n-[4-[3-[(2,2,2-trifluoroacetyl)amino]propylamino]butyl]acetamide Chemical compound FC(F)(F)C(=O)NCCCCNCCCNC(=O)C(F)(F)F PJFHRRVCKBIDSR-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 229910021607 Silver chloride Inorganic materials 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- HUEBIMLTDXKIPR-UHFFFAOYSA-N methyl heptadecanoate Chemical compound CCCCCCCCCCCCCCCCC(=O)OC HUEBIMLTDXKIPR-UHFFFAOYSA-N 0.000 description 4
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VZXVGMJSTIUCQS-UHFFFAOYSA-N 1-hexadecylsulfonyl-4-nitrobenzene Chemical compound CCCCCCCCCCCCCCCCS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 VZXVGMJSTIUCQS-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- QHMGJGNTMQDRQA-UHFFFAOYSA-N dotriacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC QHMGJGNTMQDRQA-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- JQIUFPPAGDWAEH-UHFFFAOYSA-N hexyl heptadecanoate Chemical compound CCCCCCCCCCCCCCCCC(=O)OCCCCCC JQIUFPPAGDWAEH-UHFFFAOYSA-N 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 3
- GWVDBZWVFGFBCN-UHFFFAOYSA-N tetratriacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC GWVDBZWVFGFBCN-UHFFFAOYSA-N 0.000 description 3
- JZTIKKOVQPBYLX-UHFFFAOYSA-N (4-nitrophenyl)methyl heptadecanoate Chemical compound CCCCCCCCCCCCCCCCC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JZTIKKOVQPBYLX-UHFFFAOYSA-N 0.000 description 2
- 0 *NCCCNCCCCNI Chemical compound *NCCCNCCCCNI 0.000 description 2
- QJILSKRRMFTLOH-UHFFFAOYSA-N 1-dodecylsulfonyl-4-nitrobenzene Chemical compound CCCCCCCCCCCCS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 QJILSKRRMFTLOH-UHFFFAOYSA-N 0.000 description 2
- RYJYHDWBXOJJKP-UHFFFAOYSA-N 2,2,2-trifluoro-n-[3-[4-[3-[(2,2,2-trifluoroacetyl)amino]propylamino]butylamino]propyl]acetamide Chemical compound FC(F)(F)C(=O)NCCCNCCCCNCCCNC(=O)C(F)(F)F RYJYHDWBXOJJKP-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
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- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- HKXBPYQGPDKLHV-UHFFFAOYSA-N butyl tridecanoate Chemical compound CCCCCCCCCCCCC(=O)OCCCC HKXBPYQGPDKLHV-UHFFFAOYSA-N 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
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- 125000005843 halogen group Chemical group 0.000 description 2
- KBZBPAKPLBKEMD-UHFFFAOYSA-N hexyl n-(3-aminopropyl)-n-[4-[3-aminopropyl(hexoxycarbonyl)amino]butyl]carbamate Chemical compound CCCCCCOC(=O)N(CCCN)CCCCN(CCCN)C(=O)OCCCCCC KBZBPAKPLBKEMD-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- IJXHLVMUNBOGRR-UHFFFAOYSA-N methyl nonanoate Chemical compound CCCCCCCCC(=O)OC IJXHLVMUNBOGRR-UHFFFAOYSA-N 0.000 description 2
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- 125000006850 spacer group Chemical group 0.000 description 2
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- MHSGOABISYIYKP-UHFFFAOYSA-N (4-nitrophenyl)methyl carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(COC(Cl)=O)C=C1 MHSGOABISYIYKP-UHFFFAOYSA-N 0.000 description 1
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- IFABLCIRROMTAN-MDZDMXLPSA-N (e)-1-chlorooctadec-9-ene Chemical compound CCCCCCCC\C=C\CCCCCCCCCl IFABLCIRROMTAN-MDZDMXLPSA-N 0.000 description 1
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- ZLCPPDYRKWCRDS-UHFFFAOYSA-N 2,2,2-trifluoro-N-[2-[(4-nitrophenyl)sulfonyl-[2-[(2,2,2-trifluoroacetyl)amino]ethyl]amino]ethyl]acetamide Chemical compound FC(C(=O)NCCN(CCNC(C(F)(F)F)=O)S(=O)(=O)C1=CC=C(C=C1)[N+](=O)[O-])(F)F ZLCPPDYRKWCRDS-UHFFFAOYSA-N 0.000 description 1
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- APPPBNTTWQCEIM-UHFFFAOYSA-N 2,2,2-trifluoro-N-[3-[[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]acetyl]-[4-[[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]acetyl]-[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino]butyl]amino]propyl]acetamide Chemical compound FC(C(=O)NCCCN(CCCCN(CCCNC(C(F)(F)F)=O)C(COCCOCCOCCOC)=O)C(COCCOCCOCCOC)=O)(F)F APPPBNTTWQCEIM-UHFFFAOYSA-N 0.000 description 1
- UAYZYUOQUHKICV-UHFFFAOYSA-N 2,2,2-trifluoro-N-[3-[hexadecyl-[4-[hexadecyl-[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino]butyl]amino]propyl]acetamide Chemical compound CCCCCCCCCCCCCCCCN(CCCCN(CCCCCCCCCCCCCCCC)CCCNC(=O)C(F)(F)F)CCCNC(=O)C(F)(F)F UAYZYUOQUHKICV-UHFFFAOYSA-N 0.000 description 1
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- AHQVVELBEDFWAD-UHFFFAOYSA-N butyl N-[4-[butoxycarbonyl-[5-[(2,2,2-trifluoroacetyl)amino]pentyl]amino]butyl]-N-[5-[(2,2,2-trifluoroacetyl)amino]pentyl]carbamate Chemical compound CCCCOC(=O)N(CCCCCNC(=O)C(F)(F)F)CCCCN(CCCCCNC(=O)C(F)(F)F)C(=O)OCCCC AHQVVELBEDFWAD-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JXVPAYIPRLGMCX-UHFFFAOYSA-N butyl heptadecanoate Chemical compound CCCCCCCCCCCCCCCCC(=O)OCCCC JXVPAYIPRLGMCX-UHFFFAOYSA-N 0.000 description 1
- DOLFPCDDMUMIMR-UHFFFAOYSA-N butyl nonanoate Chemical compound CCCCCCCCC(=O)OCCCC DOLFPCDDMUMIMR-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 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 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 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
- HMSWAIKSFDFLKN-UHFFFAOYSA-N hexacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC HMSWAIKSFDFLKN-UHFFFAOYSA-N 0.000 description 1
- OYGNULIUPPIYOK-UHFFFAOYSA-N hexyl N-[4-[hexoxycarbonyl-[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino]butyl]-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]carbamate Chemical compound CCCCCCOC(=O)N(CCCCN(CCCNC(=O)C(F)(F)F)C(=O)OCCCCCC)CCCNC(=O)C(F)(F)F OYGNULIUPPIYOK-UHFFFAOYSA-N 0.000 description 1
- KIWBRXCOTCXSSZ-UHFFFAOYSA-N hexyl carbonochloridate Chemical compound CCCCCCOC(Cl)=O KIWBRXCOTCXSSZ-UHFFFAOYSA-N 0.000 description 1
- CYOONLPPEGKHED-UHFFFAOYSA-N hexyl tridecanoate Chemical compound CCCCCCCCCCCCC(=O)OCCCCCC CYOONLPPEGKHED-UHFFFAOYSA-N 0.000 description 1
- 208000029080 human African trypanosomiasis Diseases 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VTWISDFYMSRDON-UHFFFAOYSA-N methyl N-[4-[methoxycarbonyl-[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino]butyl]-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]carbamate Chemical compound COC(=O)N(CCCCN(CCCNC(=O)C(F)(F)F)C(=O)OC)CCCNC(=O)C(F)(F)F VTWISDFYMSRDON-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- MDLNUDQNFCTUEQ-UHFFFAOYSA-N methyl n-(3-aminopropyl)-n-[4-[3-aminopropyl(methoxycarbonyl)amino]butyl]carbamate Chemical compound NCCCN(C(=O)OC)CCCCN(CCCN)C(=O)OC MDLNUDQNFCTUEQ-UHFFFAOYSA-N 0.000 description 1
- JNDDPBOKWCBQSM-UHFFFAOYSA-N methyl tridecanoate Chemical compound CCCCCCCCCCCCC(=O)OC JNDDPBOKWCBQSM-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- CTRVEWVMNDAEOZ-KTKRTIGZSA-N n'-(2-aminoethyl)-n'-[(z)-octadec-9-enyl]ethane-1,2-diamine Chemical compound CCCCCCCC\C=C/CCCCCCCCN(CCN)CCN CTRVEWVMNDAEOZ-KTKRTIGZSA-N 0.000 description 1
- BYYVCNLRLYIGIE-KTKRTIGZSA-N n'-(6-aminohexyl)-n'-[(z)-octadec-9-enyl]hexane-1,6-diamine Chemical compound CCCCCCCC\C=C/CCCCCCCCN(CCCCCCN)CCCCCCN BYYVCNLRLYIGIE-KTKRTIGZSA-N 0.000 description 1
- RGYICGNDXWYTTG-KTKRTIGZSA-N n'-(7-aminoheptyl)-n'-[(z)-octadec-9-enyl]octane-1,8-diamine Chemical compound CCCCCCCC\C=C/CCCCCCCCN(CCCCCCCN)CCCCCCCCN RGYICGNDXWYTTG-KTKRTIGZSA-N 0.000 description 1
- KCPZNUAIWIPFHF-CLFAGFIQSA-N n,n'-bis(3-aminopropyl)-n,n'-bis[(z)-octadec-9-enyl]butane-1,4-diamine Chemical compound CCCCCCCC\C=C/CCCCCCCCN(CCCN)CCCCN(CCCN)CCCCCCCC\C=C/CCCCCCCC KCPZNUAIWIPFHF-CLFAGFIQSA-N 0.000 description 1
- DNIRVFWTFBJVRE-UHFFFAOYSA-N n,n-bis(6-aminohexyl)-4-nitrobenzenesulfonamide Chemical compound NCCCCCCN(CCCCCCN)S(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 DNIRVFWTFBJVRE-UHFFFAOYSA-N 0.000 description 1
- GWEPYVASYJGQCQ-UHFFFAOYSA-N n-(2-aminoethyl)-n-(5-aminopentyl)-4-nitrobenzenesulfonamide Chemical compound NCCCCCN(CCN)S(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 GWEPYVASYJGQCQ-UHFFFAOYSA-N 0.000 description 1
- JNABXGRHDBDWCL-UHFFFAOYSA-N n-(7-aminoheptyl)-n-(8-aminooctyl)-4-nitrobenzenesulfonamide Chemical compound NCCCCCCCCN(CCCCCCCN)S(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 JNABXGRHDBDWCL-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- ZYURHZPYMFLWSH-UHFFFAOYSA-N octacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCC ZYURHZPYMFLWSH-UHFFFAOYSA-N 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000005543 phthalimide group Chemical class 0.000 description 1
- IIMIOEBMYPRQGU-UHFFFAOYSA-L picoplatin Chemical compound N.[Cl-].[Cl-].[Pt+2].CC1=CC=CC=N1 IIMIOEBMYPRQGU-UHFFFAOYSA-L 0.000 description 1
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000007391 self-medication Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- POOSGDOYLQNASK-UHFFFAOYSA-N tetracosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC POOSGDOYLQNASK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N triacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 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
Definitions
- the present invention relates to novel platinum complexes having antitumor activity when administered orally.
- the oral administration of a medicament involves a number of advantages compared with the other administration routes commonly used, such as the intravenous or subcutaneous administrations.
- a better compliance by the patient who does not often willingly agree with the treatment with m ⁇ ectable formulations, as their administration is intrinsically inconvenient.
- Another remarkable advantage with the oral administration is the possibility of self -medication cy the patient himself, who conversely, has to depend on skilled personnel m the case of mjectable preparations.
- the multmuclear platinum complexes disclosed m US 5,744,497 have an interesting antitumor activity profile, due to their activity against tumors with cisplatin intrinsic or acquired resistance (G. Pratesi et al , Br. J. Cancer, 1999, Aug 80:12, 1912-9; P. Perego et al . , Mol . Pharmacol., 55, 528-534, 1999). Said complexes are however poorly effective when administered through tne oral route. This may, m some cases, restrict the use thereof.
- platinum (II) dmuclear complexes m which natural polyammes such as spermme and spermidme and their synthetic analogues are bridging two monofunctional platinum spheres.
- the in vitro most potent complexes are characterized by the presence of one or two secondary amino groups in the spacer bridging the two platinum atoms.
- the introduction of tert-butoxycarbonyl groups on said amino groups induces a marked decrease in both the in vitro cytotoxic activity and the in vivo antitumor activity.
- B is a group of formula —NR- wherein R is a group convertible into a hydrogen atom under physiological conditions, with the proviso that R is different from C-,-C 4 alkyl or acyl and from ter-butoxycarbonyl .
- Q " P is an anion selected from the group of chloride, bromide, iodide, nitrate, sulfate, hydrogen sulfate and perchlorate .
- groups R comprise groups of formulae:
- R 1# R 2 and R 3 which can be the same or different, are hydrogen, C- ] _-C 4 alkyl, C 5 -Cg cycloalkyl, phenyl optionally substituted with one or more C 1 -C 4 alkyl, C- j _-C 4 alkoxy, halogen, hydroxy, or are C 7 -C 10 aralkyl ; or R ⁇ , R 2 and R 3 are the residue of an ⁇ -amino acid in the D or L configuration; and
- R a is - j _-Cg alkyl, preferably t -butyl
- R 4 is hydrogen, C ⁇ -Cg cycloalkyl, preferably Cc-Cg, phenyl optionally substituted with C ⁇ ⁇ C 4 alkyl, c ⁇ _ C 4 alkoxy, hydroxy, nitro, cyano, halogen; alkyl C 1 -C 2 -phenyl ; ethyloxy or C 3 -C 8 alkyl interrupted by 1 to 4 oxygen atoms with the exception of —O-CI ⁇ -O- acetal groups; or R4 is a residue of a saturated or unsaturated fatty acid or a residue of a hexose or pentose sugar;
- R 5 is C 1 -C- L8 alkyl (with the exception of t- butyl) , C " 3 -C 18 alkenyl, benzyl or benzyl substituted at the phenyl position with one or more hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, cyano, acetoxy, c ⁇ " c 3 alkylaminocarbonyloxy, c ⁇ " C 3 alkoxycarbonyloxy groups; a residue of a hexose or pentose sugar, a group of formula:
- Rg is methyl or phenyl; or a group of formula
- Rg is hydrogen or C- ] _-C 4 alkyl and w is an integer 1 to 6; 5) wherein Rg is as above defined; 6) wherein Rg and R 7 , which can be the same or different, are hydrogen or C- ⁇ - ⁇ alkyl;
- Rg is hydrogen or C- L -C 4 alkyl
- R 9 is hydrogen or C- j _-C 4 alkyl and RIO is C-,-C 4 alkyl; 9)
- R 1;L and R 12 which can be the same or different, are hydrogen, - j _-C 4 alkyl, phenyl;
- Rb is C- ⁇ -Cg alkyl, preferably methyl 11)
- R ⁇ is as defined above and R c , R ⁇ , R e and R j , which can be the same or different, are H, CH 3 or OCH 3 ;
- Z is C 2" C 4 alkylene, cycloalkylene, optionally substituted phenylene, T is an oxygen atom or a —NH- or —N-R 14 group, wherein
- R 14 is C 1" C 4 alkyl ;
- Y is a bond, an oxygen atom, a NH or —N-R 14 group as defined above;
- R 13 is C 1 -C 4 alkyl, c s ⁇ C 6 cycloalkyl, phenyl; phenyl optionally substituted with C- j _-C 3 alkyl, C- j _-C 3 alkoxy, nitro, cyano, hydroxy groups.
- Examples of 1 -C 4 alkyl groups comprise methyl, ethyl, propyl , isopropyl, butyl, isobutyl, tert -butyl.
- Examples of C 5" C 6 cycloalkyl groups comprise cyclopentyl and cyclohexyl .
- phenyl groups comprise phenyl, 4-methylphenyl , 2 , 4 -dimethoxyphenyl , 4- methoxyphenyl , 4-n ⁇ trophenyl , 3-chlorophenyl , 4- hydroxyphenyl , 3 , 5-d ⁇ methoxy-4 -hydroxyphenyl , 3- cyanopheny1 , 2 -hydroxyphenyl , 2 -carboxypheny1.
- Examples of aralkyl groups comprise benzyl and phenethyl .
- Q is preferably nitrate.
- the groups ⁇ R are preferably hydrogen or alkyl.
- R 4 is preferably an alkyl group interrupted by oxygen atoms, such as polyoxyethylene, or a residue of a saturated or unsaturated fatty acid.
- R 5 is preferably methyl, i -butyl, n-hexyl, benzyl, p- nitro-benzyl , 4 -acetyloxy-benzyl , 4-methylammocarbonyl- oxybenzyl , 4 -methoxycarbonyloxy-benzyl .
- Rg and R 7 are preferably hydrogen, methyl, ter -butyl, isopropyl .
- R c , R ⁇ , R e and Rf in the group of formula D are preferably hydrogen or methyl, most preferably at least one of R c and R f being methyl.
- Z is preferably ethylene, 1, 2-cyclohexenyl, 3,4- butenyl .
- T and Y are preferably oxygen atoms and R 13 is preferably -
- the compounds of formula (III) can be prepared "in situ" by reaction of a complex of formula trans-Pt (NH 3 ) 2 X 2 wherein X is as defined above, in dimethylformamide in the presence of equimolar amounts of silver nitrate. Usually the resulting complexes of formula (III) are not recovered but they are directly reacted with a compound of formula (ID .
- the compounds of formula (II) may be prepared from the corresponding polyamines in which R is hydrogen, by selective protection of the primary amino groups, followed by functionalization of the secondary amino groups with suitable R-G groups wherein R is as defined above and G is a suitable reactive group such as a halogen atom, a leaving group such as 4-nitrophenyl , mesyl, tosyl or an activated carbonyl .
- the protective groups for the primary amino groups will of course be stable under the reaction conditions used for the functionalization of the secondary amino groups, and they will be selected so as to be cleaved under selective conditions without removing at the same time the groups R.
- suitable protective groups can be tert- butoxycarbonyl groups or benzylydene derivatives which can be removed by treatment under mildly acidic conditions.
- suitable protective groups may be phthalimides or bromocarbobutyloxycarbonyl or other groups which can be removed under neutral conditions.
- suitable protective groups when the groups R are acid-sensitive, suitable protective groups can be t ⁇ fluoroacetyls or similar acyl derivatives, which can be removed by basic hydrolysis.
- the compounds of formula (I) prepared as described above may optionally be subjected to further salification, separation of the enantiomers when at least one asymmetry center is present, conversion of an R group into another R group according to conventional procedures.
- the intermediates of formula (II) are novel and therefore are a further otject of the invention.
- the compounds of the invention when administered to humans or animals bearing tumors which can be treated with cis-platmum or which are resistant to cis-plat um, at doses ranging from 0.1 mg to 1.2 g / m 2 of body area, are capable of inducing the regression of said tumors.
- the compounds of the invention can be used for the treatment of the same patnological conditions for which cis-platmum is used. This includes the treatment of tumors, the sensitization or enhancement of radiations
- another ob ect of the present invention are pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I) in mixture with conventional carriers and excipients.
- the effective dosage of the compounds of the invention may be determined by the expert clinicians according to conventional methods.
- the relationship between the dosages used for animals of various species and sizes and those for humans (on the basis of mg/ body area) is described by Freirech et al . , Quantitative Comparison of Toxicity of Anticancer Agents m Mouse, Rat, Hamster, Dog, Monkey and Man, Cancer Chemother. Rep., 50. N.4, 219-244 (1986).
- the patient will however receive doses of the complex ranging from 0.1 to 200 mg/kg body weight, with a dosage regimen which will depend on a number of factors which are well known to the expert clinicians.
- the treatment regimen may be suitably varied, as it is well known to the expert clinicians, depending on the type of tumor to be treated and the conditions of the patient.
- the compounds of the invention may be administered through the parenteral or oral routes .
- compositions for the parenteral administration include sterile saline solutions, as defined below, or sterile powders for the extemporary preparation of solutions, as well as oily preparations for the intramuscular dm) or traperitoneal dp) administrations.
- the compounds of the invention may be preferaoly administered as sterile aqueous solution, optionally containing sodium chloride in suitable concentration (0.1 - 0.9 %) .
- the solutions are administered preferably through the intravenous ( ⁇ v) or mtra-arterial da) routes, although m particular cases other administration forms could be envisaged.
- compositions useful for the oral administration comprise, for example, syrups or similar liquid forms, as well as solid forms such as tablets, capsules and the like.
- the pharmaceutical compositions according to the present invention are prepared following conventional methods, such as those reported m Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
- the platinum complexes of the present invention can be administered together with reduced glutathione, as disclosed m GB 2,174,905 and in U.S. 4,871,528.
- a further OD ect of the present invention are pharmaceutical compositions containing at least one compound of formula (I) m combination with a platinum complex having antitumor activity.
- a further obi ect of the invention is the use of the compounds of formula (I) for the preparation of pharmaceutical compositions for the treatment of mammals bearing tumors which can be treated with cis-platmum or which are resistant to cis-platmum.
- the mixture is concentrated to small volume under vacuum, taken up with 20 mL of water and extracted with AcOEt (2 x 50 mL) .
- the combined extracts are washed first with water then with saturated NaCl, dried over Na 2 S0 4 and concentrated under vacuum thereby obtaining a transparent oil, 0.74 g (96%) .
- the product is purified by column chromatography (Si0 2 230 mesh, eluent CHCl 3 /MeOH 9:1) to yield 0.58 g of a transparent oil pure by TLC.
- 1, 12 -bis (trifluoroacetylammo) -4,9-d ⁇ aza-4,9-b ⁇ s( ⁇ - butyloxycarbonyl) dodecane A solution of 1 , 12-b ⁇ s (trifluoroacetamido) -4 , 9- diazadodecane [N ,N -bis-tnfluoroacetylspermine] (1 g, 2.5 mmol) m dry THF (35 mL) at 25°C is added with triethylam e (TEA: 0.35 mL, 5 mmol), then with l-butyl chloroformate (0.76 g, 5.6 mmol) dissolved 5 mL of THF.
- THF triethylam e
- 1, 16-b " is (trif luoroacetylammo) -7, 10-d ⁇ aza-7,10-b ⁇ s (n-hexyl - oxycarbonyl) hexadecane;
- aqueous phase is extracted with CHCl 3 /MeOH 20:1 (3 x 30 mL) , the combined extracts are dried over Na 2 S0 4 and concentrated to dryness under vacuum, thereby yielding 0.403 g (96%) of a transparent oil.
- 1, 12-d ⁇ ammo-4, 9-d ⁇ aza-4 , 9-bis (i-butyloxycarbonyl) dodecane 0.2N NaOH (27 mL, 5.35 mmol) is dropped in 30' into a methanolic solution (45 mL) of 1,12-b ⁇ s- (trifluoroacetylammo) -4, 9-d ⁇ aza-4, 9 -bis d -butyloxycarbonyl) dodecane (1.45 g, 2.43 mmol) cooled to 10°C. After stirring overnight at 25°C, the mixture is concentrated under vacuum to remove MeOH.
- EXAMPLE 1 bis [ trans-diammmechloroplatmum (II) ] - ⁇ - [1, 12-d ⁇ ammo- 4 , 9-d ⁇ aza-4 , 9-bis (methoxycarbonyl) dodecane] dmitrate trans-d ⁇ ammmed ⁇ chloroplatmum(II) (0.705 g, 2.35 mmol) is dissolved m dry DMF (70 mL) then a solution of AgN0 3 - (0.399 g, 2.35 mmol) m DMF (5 mL) is added and the resulting mixture is stirred for 20h at 20°C, shielded from light.
- EXAMPLE 2 bis [ trans-diamminechloroplatinum(II) ] - ⁇ - [1, 12-diamino- 4 , 9-diaza-4 , 9-bis (n-hexyloxycarbonyl) dodecane] dinitrate trarts-diamminedichloroplatinum(II) (0.524 g, 1.747 mmol) is dissolved in dry DMF (52 mL) then a solution of AgN0 3 (0.296 g, 1.747 mmol) in DMF (3 mL) is added and the resulting mixture is stirred for 20h at 20°C, shielded from the light.
- EXAMPLE 3 bis [ trans-diammmechloroplatmum (II) ] - ⁇ - [1, 8 -diammo- 4-aza-4- (benzyloxycarbonyl) octane] dmitrate trans-diammmedichloroplatmum (II) (0.725 g, 2.416 mmol) is dissolved m dry DMF (75 mL) , then a solution of AgN0 3 (0.410 g, 2.416 mmol) m DMF (10 mL) is added and the resulting mixture is stirred for 20h at 20°C, shielded from the light.
- EXAMPLE 4 bis [ trans-diammmechloroplatmum (II) ] - ⁇ - [1, 12 -diammo- 4 , 9-d ⁇ aza-4 , 9-bis ( i -butyloxycarbonyl ) dodecane] dmitrate trans-diammedichloroplatmum (II ) (0.750 g, 2.5 mmol) is dissolved dry DMF (78 mL) , then a solution of AgN0 3 (0.424 g, 2.5 mmol) m DMF (10 mL) is added and the resulting mixture is stirred for 20h at 20°C, shielded from the light.
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00958309A EP1200454A1 (en) | 1999-08-03 | 2000-07-28 | Bisplatinum complexes active through the oral route |
CA002393917A CA2393917A1 (en) | 1999-08-03 | 2000-07-28 | Bisplatinum complexes active through the oral route |
JP2001513956A JP2003506332A (en) | 1999-08-03 | 2000-07-28 | Bisplatinum complex active for oral administration |
AU69878/00A AU6987800A (en) | 1999-08-03 | 2000-07-28 | Bisplatinum complexes active through the oral route |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT1999MI001742A IT1313594B1 (en) | 1999-08-03 | 1999-08-03 | BISPLATIN ORAL ACTIVITIES. |
ITMI99A001742 | 1999-08-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001009149A1 true WO2001009149A1 (en) | 2001-02-08 |
Family
ID=11383492
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/007276 WO2001009149A1 (en) | 1999-08-03 | 2000-07-28 | Bisplatinum complexes active through the oral route |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1200454A1 (en) |
JP (1) | JP2003506332A (en) |
AU (1) | AU6987800A (en) |
CA (1) | CA2393917A1 (en) |
IT (1) | IT1313594B1 (en) |
WO (1) | WO2001009149A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1427739A1 (en) * | 2001-08-22 | 2004-06-16 | Virginia Commonwealth University | Targeted bisplatinum polyamines as pro-drugs: selective release of platinum |
AU2014262764B2 (en) * | 2013-05-07 | 2018-11-15 | The Regents Of The University Of California | Radiomitigating pharmaceutical formulations |
EP3955903A4 (en) * | 2019-04-15 | 2023-01-25 | Jawaharlal Nehru Centre For Advanced Scientific Research | Small-molecular adjuvants and implementations thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20052449A1 (en) * | 2005-12-22 | 2007-06-23 | Cell Therapeutics Europe Srl | NEW BIS-PLATINUM COMPLEX WITH ANTITUMOR ACTIVITY |
JP6061321B2 (en) * | 2011-02-24 | 2017-01-18 | 国立大学法人 東京大学 | Plant activator |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998003519A2 (en) * | 1996-07-22 | 1998-01-29 | F. Hoffmann-La Roche Ag | New bis-platinum complexes with polyamine ligands as antitumor agents |
-
1999
- 1999-08-03 IT IT1999MI001742A patent/IT1313594B1/en active
-
2000
- 2000-07-28 CA CA002393917A patent/CA2393917A1/en not_active Abandoned
- 2000-07-28 JP JP2001513956A patent/JP2003506332A/en active Pending
- 2000-07-28 EP EP00958309A patent/EP1200454A1/en not_active Withdrawn
- 2000-07-28 WO PCT/EP2000/007276 patent/WO2001009149A1/en not_active Application Discontinuation
- 2000-07-28 AU AU69878/00A patent/AU6987800A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998003519A2 (en) * | 1996-07-22 | 1998-01-29 | F. Hoffmann-La Roche Ag | New bis-platinum complexes with polyamine ligands as antitumor agents |
Non-Patent Citations (1)
Title |
---|
RAUTER, HOLGER ET AL: "Selective Platination of Biologically Relevant Polyamines. Linear Coordinating Spermidine and Spermine as Amplifying Linkers in Dinuclear Platinum Complexes", INORG. CHEM., vol. 36, no. 18, 1997, pages 3919 - 3927, XP002150713 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1427739A1 (en) * | 2001-08-22 | 2004-06-16 | Virginia Commonwealth University | Targeted bisplatinum polyamines as pro-drugs: selective release of platinum |
EP1427739A4 (en) * | 2001-08-22 | 2008-02-13 | Univ Virginia Commonwealth | Targeted bisplatinum polyamines as pro-drugs: selective release of platinum |
US7579373B2 (en) * | 2001-08-22 | 2009-08-25 | Virginia Commonwealth University | Targeted bisplatinum polyamines as pro-drugs: selective release of platinum |
AU2014262764B2 (en) * | 2013-05-07 | 2018-11-15 | The Regents Of The University Of California | Radiomitigating pharmaceutical formulations |
EP3955903A4 (en) * | 2019-04-15 | 2023-01-25 | Jawaharlal Nehru Centre For Advanced Scientific Research | Small-molecular adjuvants and implementations thereof |
Also Published As
Publication number | Publication date |
---|---|
JP2003506332A (en) | 2003-02-18 |
CA2393917A1 (en) | 2001-02-08 |
EP1200454A1 (en) | 2002-05-02 |
IT1313594B1 (en) | 2002-09-09 |
ITMI991742A1 (en) | 2001-02-03 |
AU6987800A (en) | 2001-02-19 |
ITMI991742A0 (en) | 1999-08-03 |
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