US20010039270A1 - Tin polyoxaalkanecarboxylates and compositions containing them - Google Patents
Tin polyoxaalkanecarboxylates and compositions containing them Download PDFInfo
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- US20010039270A1 US20010039270A1 US09/770,299 US77029901A US2001039270A1 US 20010039270 A1 US20010039270 A1 US 20010039270A1 US 77029901 A US77029901 A US 77029901A US 2001039270 A1 US2001039270 A1 US 2001039270A1
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- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 239000000203 mixture Substances 0.000 title claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 18
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- 238000000921 elemental analysis Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 229910001868 water Inorganic materials 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- WCRDXYSYPCEIAK-UHFFFAOYSA-N dibutylstannane Chemical compound CCCC[SnH2]CCCC WCRDXYSYPCEIAK-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 3
- 150000003606 tin compounds Chemical class 0.000 description 3
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 3
- SBXWFLISHPUINY-UHFFFAOYSA-N triphenyltin Chemical compound C1=CC=CC=C1[Sn](C=1C=CC=CC=1)C1=CC=CC=C1 SBXWFLISHPUINY-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- SVMPYNHSWHDELJ-UHFFFAOYSA-N COC(=O)C1=CC2=C(C=C1)OCCOCCOCCOCCO2.COC(=O)C1=CC2=C(C=C1)OCCOCCOCCOCCOCCO2.COCCOCC(=O)OC.COCCOCCOCC(=O)OC Chemical compound COC(=O)C1=CC2=C(C=C1)OCCOCCOCCOCCO2.COC(=O)C1=CC2=C(C=C1)OCCOCCOCCOCCOCCO2.COCCOCC(=O)OC.COCCOCCOCC(=O)OC SVMPYNHSWHDELJ-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- VRZKUMDKMJKIJO-UHFFFAOYSA-N tributyl-[butyl(dipropoxy)stannyl]oxystannane Chemical compound CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(OCCC)OCCC VRZKUMDKMJKIJO-UHFFFAOYSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- 0 *[Sn](*)(OC(=O)COCCOC)OC(=O)COCCOC.*[Sn](*)(OC(=O)COCCOC)O[Sn](*)(*)OC(=O)COCCOC.*[Sn](*)(OC(=O)COCCOCCOC)OC(=O)COCCOCCOC.*[Sn](*)(OC(=O)COCCOCCOC)O[Sn](*)(*)OC(=O)COCCOCCOC.*[Sn](*)(OC(=O)c1ccc2c(c1)OCCOCCOCCOCCO2)OC(=O)c1ccc2c(c1)OCCOCCOCCOCCO2.*[Sn](*)(OC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2)OC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2.*[Sn](*)(OC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2)O[Sn](*)(*)OC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2.C.C.C.C.COC(=O)c1ccc2c(c1)OCCOCCOCCOCCO2.COC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2.COCCOCC(=O)OC.COCCOCCOCC(=O)OC Chemical compound *[Sn](*)(OC(=O)COCCOC)OC(=O)COCCOC.*[Sn](*)(OC(=O)COCCOC)O[Sn](*)(*)OC(=O)COCCOC.*[Sn](*)(OC(=O)COCCOCCOC)OC(=O)COCCOCCOC.*[Sn](*)(OC(=O)COCCOCCOC)O[Sn](*)(*)OC(=O)COCCOCCOC.*[Sn](*)(OC(=O)c1ccc2c(c1)OCCOCCOCCOCCO2)OC(=O)c1ccc2c(c1)OCCOCCOCCOCCO2.*[Sn](*)(OC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2)OC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2.*[Sn](*)(OC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2)O[Sn](*)(*)OC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2.C.C.C.C.COC(=O)c1ccc2c(c1)OCCOCCOCCOCCO2.COC(=O)c1ccc2c(c1)OCCOCCOCCOCCOCCO2.COCCOCC(=O)OC.COCCOCCOCC(=O)OC 0.000 description 1
- ZZBRYLQABGKPTC-UHFFFAOYSA-M 2-[2-(2-methoxyethoxy)ethoxy]acetate;tributylstannanylium Chemical compound COCCOCCOCC([O-])=O.CCCC[Sn+](CCCC)CCCC ZZBRYLQABGKPTC-UHFFFAOYSA-M 0.000 description 1
- NQEZDDPEJMKMOS-UHFFFAOYSA-N 4-trimethylsilylbut-3-yn-2-one Chemical compound CC(=O)C#C[Si](C)(C)C NQEZDDPEJMKMOS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
- JMPBCSMCRFCZFI-UHFFFAOYSA-L CCCC[Sn+2]CCCC.COCCOCCOCC([O-])=O.COCCOCCOCC([O-])=O Chemical compound CCCC[Sn+2]CCCC.COCCOCCOCC([O-])=O.COCCOCCOCC([O-])=O JMPBCSMCRFCZFI-UHFFFAOYSA-L 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 238000004813 Moessbauer spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- RIMNFOSWUGWTHD-UHFFFAOYSA-N [H]OC(=O)C1=CC2=C(C=C1)OCCOCCOCCOCCO2.[H]OC(=O)C1=CC2=C(C=C1)OCCOCCOCCOCCOCCO2.[H]OC(=O)COCCOC.[H]OC(=O)COCCOCCOC Chemical compound [H]OC(=O)C1=CC2=C(C=C1)OCCOCCOCCOCCO2.[H]OC(=O)C1=CC2=C(C=C1)OCCOCCOCCOCCOCCO2.[H]OC(=O)COCCOC.[H]OC(=O)COCCOCCOC RIMNFOSWUGWTHD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- BFWMWWXRWVJXSE-UHFFFAOYSA-M fentin hydroxide Chemical compound C=1C=CC=CC=1[Sn](C=1C=CC=CC=1)(O)C1=CC=CC=C1 BFWMWWXRWVJXSE-UHFFFAOYSA-M 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WBERKXQQZQURFA-UHFFFAOYSA-M triphenylstannyl 2-[2-(2-methoxyethoxy)ethoxy]acetate Chemical compound COCCOCCOCC([O-])=O.C1=CC=CC=C1[Sn+](C=1C=CC=CC=1)C1=CC=CC=C1 WBERKXQQZQURFA-UHFFFAOYSA-M 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2224—Compounds having one or more tin-oxygen linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to novel tin polyoxaalkanecarboxylates and to anti-tumour compositions containing such compounds.
- the anti-tumour activity of tin compounds is known; it is also known that the anti-tumour activity of tin compounds could be enhanced by increasing their solubility in water.
- the invention now provides water-soluble tin compounds which show strong in vitro anti-tumour activities against a broad spectrum of tumours, as appears from the experimental part, disclosed hereinafter.
- the invention relates to tin polyoxaalkanecarboxylates having the formula
- R 1 represents C 1 -C 6 alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms,
- R 2 is a carboxylic residue selected from:
- R 1 a phenyl group or a n-butyl group in a compound having formula (1), (2) or (3).
- the compounds according to the invention can be synthesized by effecting a condensation reaction between a carboxylic acid having formula
- triaryltin hydroxide trialkyltin acetate or dialkyltin oxide, preferably triphenyltin hydroxide, tri-n-butyltin acetate or di-n-butyltin oxide, according to the following reaction schemes:
- the condensation can be performed in toluene/ethanol.
- the water formed during the condensation is eliminated by azeotropic distillation (Dean-Stark funnel)
- these compounds can also be prepared by a two-step procedure, dibutyltin oxide being first condensed with n-propanol to yield tetrabutyldipropoxydistannoxane:
- NMR spectra CDCl 3 solutions; 1 H and 13 C chemical shifts ⁇ in ppm vs. TMS, homonuclear coupling constants in Hz, in parentheses; Mössbauer parameters (quadrupole splitting QS, isomers shift IS, and band widths ⁇ 1 and ⁇ 2 ) in mm/s; s: singlet; d: doublet; dd: doublet of doublets; m: complex pattern; t: triplet; tq: triplet of quartets; ⁇ s, pseudo-singlet.
- Electrospray mass spectra positive monoisotopic ions ( 12 C, 1 H, 16 O, 23 Na, 39 K, 120 Sn). Na and/or K are already present in the electrospray mass spectra of the starting carboxylic acids.
- Compound 2 tri-n-butyltin 4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20) ,21-triene-1-carboxylate prepared according to method 1,
- Compound 3 di-n-butyltin bis[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylate, prepared according to method 1,
- Compound 4 bis ⁇ di-n-butyl-[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylato]tin ⁇ oxide, prepared according to method 3
- Compound 7 di-n-butyltin bis[4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3(17),18-triene-1-carboxylate], prepared according to methode 2,
- Compound 11 bis[di-n-butyl(3,6-dioxaheptanoato)tin]oxide, prepared according to method 3,
- Compound 13 tri-n-butyltin 3,6,9-trioxadecanoate, prepared according to method 2,
- Compound 14 di-n-butyltin bis (3,6,9-trioxadecanoate), prepared according to method 3,
- MS: M+K + (m/z 627), 12%; M+Na + , 22%; Mössbauer: QS: 3.77; IS: 1.42; ⁇ 1 : 1.36; ⁇ 2 : 1.18.
- Compound 15 bis[di-n-butyl(3,6,9-trioxadecanoato)tin]oxide, prepared according to method 3,
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Catalysts (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
Tin polyaalkanecarboxylates having the formula [(R1 pR2 qSn)rOs]t wherein R1 represents C1-C6 alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms, R2 is carboxylic residue selected from (I), (II), (III) or (IV); and p, q, r, s and t have the following meanings: P=3, q=1, r=1, s=) and t=1, p=2, q=2, r=1, s=0, and t=1, p=2, q=1, r=2, s=1 and t=2, have anti-tumor activity.
Description
- The invention relates to novel tin polyoxaalkanecarboxylates and to anti-tumour compositions containing such compounds.
- The anti-tumour activity of tin compounds is known; it is also known that the anti-tumour activity of tin compounds could be enhanced by increasing their solubility in water.
- The invention now provides water-soluble tin compounds which show strong in vitro anti-tumour activities against a broad spectrum of tumours, as appears from the experimental part, disclosed hereinafter.
- More specifically the invention relates to tin polyoxaalkanecarboxylates having the formula
- [(R 1 p R 2 q S n)r O s]t
- wherein
- R 1 represents C1-C6 alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms,
- R 2 is a carboxylic residue selected from:
- and p, q, r, s and t have the following meanings:
- p=3, q=1, r=1, s=0 and t=1;
- p=2, q=2, r=1, s=0 and t=1;
- p=2, q=1, r=2, s=1 and t=2.
- According to a preferred embodiment of the invention, represents R 1 a phenyl group or a n-butyl group in a compound having formula (1), (2) or (3).
- The compounds according to the invention can be synthesized by effecting a condensation reaction between a carboxylic acid having formula
- with triaryltin hydroxide, trialkyltin acetate or dialkyltin oxide, preferably triphenyltin hydroxide, tri-n-butyltin acetate or di-n-butyltin oxide, according to the following reaction schemes:
- a) RCOOH+(C 6H5)3SnOH→(C6H5)3SnOCOR+H2O
- b) RCOOH+Bu 3SnOCOCH3→Bu2SnOCOR+CH3COOH
- c) 2RCOOH+Bu 2SnO→Bu2Sn(OCOR)2+H2O
- d) 2RCOOH+2Bu 2SnO→½{[Bu2(RCOO)Sn]2O}2+H2O
- Different media and methods can be used to synthesize such derivatives
- 1) the condensation can be performed in toluene/ethanol. The water formed during the condensation is eliminated by azeotropic distillation (Dean-Stark funnel)
- 2) benzene can be used instead of toluene/ethanol
- 3) these compounds can also be prepared by a two-step procedure, dibutyltin oxide being first condensed with n-propanol to yield tetrabutyldipropoxydistannoxane:
- 2Bu2SnO+2PrOH→(PrOSnBu2)2O+H2O
- An a second step, the carboxylic acid is added at room temperature to this tetrabutyldipropoxydistannoxane in the desired molar ratio.
- The compounds synthesized by one of these methods were characterized by elemental analysis, 1H, 13C and 117Sn NMR, electrospray mass spectrometry and 119mSn Mössbauer spectroscopy. Chromatography on Sephadex LH-20 proved to be a very efficient method to separate 3 (or 7) from 4 (or 8), or 11, 12, 15 and 16 from the starting carboxylic acid.
- The structures of the compounds synthesized are depicted below
- NMR spectra: CDCl 3 solutions; 1H and 13C chemical shifts δ in ppm vs. TMS, homonuclear coupling constants in Hz, in parentheses; Mössbauer parameters (quadrupole splitting QS, isomers shift IS, and band widths Γ1 and Γ2) in mm/s; s: singlet; d: doublet; dd: doublet of doublets; m: complex pattern; t: triplet; tq: triplet of quartets; ψs, pseudo-singlet.
- Electrospray mass spectra: positive monoisotopic ions ( 12C, 1H, 16O, 23Na, 39K, 120Sn). Na and/or K are already present in the electrospray mass spectra of the starting carboxylic acids.
- Charaterization of Compounds 1 to 15
- Compound 1: triphenyltin 4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3 (20 ,21-triene-1-carboxylate prepared according to method 1,
- 10 h of reflux, recrystallized from diethyl ether/hexane, m.p. 110-1 12° C., yield 98%, elemental analysis: exp. (calc. for C 35H38SnO8): C: 60.2 (59.60); H: 5.5 (5.43); 1H NMR: 7.7-7.8, m, H(o) & H(5); 7.62, d (4J(1H-1H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.91, d (3J(1H-1H)=9), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.67, ψs, H(12) & H(13); 13C NMR: 172.7, C(7); 152.9, C(1); 148.0, C(2); 138.5, C(i); 137.0, C(o) 2J(117/119Sn—13C)=47/49; 130.2, C(p) 4J(117/119Sn—13C)=13; 129.0, C(m) 3J(117/119Sn—13C)=61/63; 125.1, C(5); 122.8, C(4); 114.9, C(3); 111.7, C(6); 70.80 & 70.77, C(10) & C(15); 70.71 & 70.66, C(12) & C(13); 70.53, 70.51, 69.4, 69.2, 68.8 & 68.6, C(8), C(9), C(11), C(14), C(16) & C(17); 117Sn NMR: −115.7; electrospray MS: M+K++(m/z=745), 14%; M+Na+, 100%; Mössbauer: QS: 2.26; IS: 0.55; Γ1: 1.34; Γ2: 1.32.
- Compound 2: tri-n-butyltin 4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20) ,21-triene-1-carboxylate prepared according to method 1,
- 4 h of reflux, recryst. hexane/chloroform, m.p. 45-47° C., yield 80%, elemental analysis: exp. (calc. for C 29H50SnO8.H2O): C: 52.5 (52.50); H: 8.3 (7.90); 1H NMR: 7.63, dd (3J(1H-1H)=8; 4J(1H-1H)=2), H(5); 7.54, d (4J(1H-1H)=2), H(3); 6.82, d (3J(1-1H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.65, ψs, H(12) & H(13);=2, HOH; 1.6-1.7, m H(β); 1.2-1.3, m, H(α) & H(γ); 0.89, t (3J(1-1H)=7), H(δ); 13C NMR: 171.4, C(7); 152.2, C(1); 148.1, C(2); 125.0, C(4); 124.2, C(5); 115.0, C(3); 112.1, C(6); 70.96 & 70.84, C(10) & C(15); 70.77 & 70.73, C(12) & C(13); 70.66, 70.61, 69.5, 69.4, 68.9 & 68.8, C(8), C(9), C(11), C(14), C(16) & C(17); 27.9, C(β) 2J(117/119Sn—13C)=20; 27.0, C(γ) 3J(117/119Sn—13C)=62/65; 16.6, C(α) 1J(117/119Sn—13C)=341/358; 13.7, C(δ); 117Sn NMR: 108.2; electrospray MS: M+Na+ (m/z=669), 6%; M+H2O+H+, 9%; M+H+, 11%; Mössbauer: QS: 3.40; IS: 1.39; Γ1: 0.72; Γ2: 0.85.
- Compound 3: di-n-butyltin bis[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylate, prepared according to method 1,
- 6 h of reflux, recryst. hexane/chloroform, m.p. 125-127° C., yield 96%, elemental analysis: exp. (calc. for C 42H64SnO16): C: 53.5 (53.46); H: 7.1 (6.84); 1H NMR: 7.73, d (3J(1-1H)=8) , H(5); 7.58, s, H(3); 6.86, d (3J(1-1H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(l0), H(11), H(14) & H(15); 3.65, ψs, H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.37, tq, (3J(1-1H)=7, 3J(1-1H)=7), H(γ); 0.86, t (3J(1-1H)=7), H(δ); 13C NMR: 175.7, C(7); 153.3, C(1); 148.3, C(2); 124.9, C(5); 122.7, C(4); 115.3, C(3); 112.3, C(6); 70.9, C(10) & C(15); 70.81 & 70.76, C(12) & C(13); 70.73 & 70.67, 69.5, 69.4, 69.2 & 69.0, C(8), C(9), C(11), C(14), C(16) & C(17); 26.7, C(β) 2J(117/119Sn-13C)=33; 26.3, C(γ) 3J(117/119Sn-13C)=95; 25.4, C(α) 1J(117/119Sn—13C)=569/596; 13.5, C(δ); 117Sn NMR: −156.2; electrospray MS: M+Na+ (m/z 967), 100%; Mössbauer: QS: 3.41; IS: 1.44; ψ1: 10.94; ψ2: 0.94.
- Compound 4: bis{di-n-butyl-[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylato]tin}oxide, prepared according to method 3
- 12 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride; recryst. hexane/chloroform, m.p. 96-98° C., yield 90%, elemental analysis: exp. (calc. for C 100H[64Sn4O34): C: 50.0 (50.35); H: 7.1 (6.94); 1H NMR: 7.54, d (3J(1H-1H)=8), H(5); 7.49, s, H(3); 6.84, d (3J(1-1H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.62, ψs, H(12) & H(13); 1.6-1.8, m, H(β); 1.4-1.6, m, H(α); 1.1-1.4, m, H(γ); 0.7-0.9, m, H(8); 13C NMR: 172.6, C(7); 152.5, C(1); 148.3, C(2); 126.3, C(4); 124.0, C(5); 115.3, C(3); 112.4, C(6); 70.8, C(10) & C(15); 70.7 & 70.6, C(12) & C(13); 70.6, 70.5, 69.42, 69.35, 69.1 & 68.9, C(8), C(9), C(11), C(14), C(16) & C(17); 26.7 & 26.6, C(β); 27.6 & 27.4, C(γ); 29.5 & 28.3, C(α); 13.5 & 13.4, C(δ); 117Sn NMR: −213.0 & −217.3; electrospray MS: M/2+K+ (m/z=1233), 11%:; Mössbauer: QS: 3.36; IS: 1.27; Γ1: 0.96; Γ2: 0.99.
- Compound 5: triphenyltin 4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3 (17),18-triene-1-carboxylate, prepared according to method 2,
- 48 h of reflux, recryst. hexane, m.p.: 130-131° C., yield 95%, elemental analysis: exp. (calc. for C 33H34SnO7.1 H2O): C: 58.4 (58.34); H: 5.7 (5.35); 1H NMR: 7.7-7.8, m, H(o) & H(5); 7.60, d (4J(1H-1H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.82, d (3J(1H-1H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-3.9, m, H(9) & H(14); 3.73, ψs, H(10), H(11), H(12) & H(13);=2, HOH; 13C NMR: 172.8, C(7); 153.1, C(1); 148.3, C(2); 138.7, C(i); 136.9, C(o) 2J(117/119Sn—13C)=47/49; 130.1, C(p) 4J(117/119Sn—13C)=13; 128.9, C(m) 3J(117/119Sn—13C)=62/65; 125.2, C(5); 123.3, C(4); 115.7, C(3); 112.1, C(6); 70.95 & 70.92, C(8) & C(15); 70.31 & 70.23, C(9) & C(14); 69.3, 69.2, 69.9 & 68.5, C(10), C(11), C(12) & C(13); 117Sn NMR: −116.3; electrospray MS: M+K+ (m/z=701, 67%); M+Na+, 73%; Mössbauer: QS: 2.77; IS: 1.23; Γ1: 0.94; Γ2: 0.88.
- Compound 6: tri-n-butyltin 4,7,10,13,16-pentaoxadicyclo 13.4.0]cosa-1,3 (17),18-triene-1-carboxylate, 20 prepared according to method 2,
- 25 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride, liquid; yield 90%; elemental analysis: exp. (calc. for C 27H46SnO7.½ H2O): C: 53.1 (53.14); H: 7.8 (7.77); 1H NMR: 7.63, dd (3J(1-1H)=8; 4J(1-1H)=2), H(5); 7.54, d (4J(1H-1H)=2), H(3); 6.82, d (3J(1-1H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-3.9, m, H(9) & H(14); 3.73, ψs, H(10), H(11), H(12) & H(13); 1.6-1.7, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.89, t (3J(1H-1H)=7), H(δ); 13C NMR: 171.4, C(7); 152.5, C(1); 148.4, C(2); 125.1, C(4); 124.4, C(5); 115.5, C(3); 112.3, C(6); 71.2, C(8) & C(15); 70.57 & 70.52, C(9) &° C(14); 69.6, 69.5, 69.1 & 68.9, C(10), C(11), C(12) & C(13); 27.9, C(β) 2J(117/119Sn—13C)=20; 27.0, C(γ) 3J(117/119Sn—13C)=62/65; 16.6, C(α) 1J(117/119Sn—13C)=350/362; 13.6, C(δ); 117Sn NMR: 107.4; electrospray MS: M+Na+(m/z=625), 5%; M+NH4 +, 9%; Mössbauer: QS: 3.29; IS: 1.45; Γ1: 0.94; Γ2: 0.88.
- Compound 7: di-n-butyltin bis[4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3(17),18-triene-1-carboxylate], prepared according to methode 2,
- 48 h of reflux, recrystallized from petroleum ether/methylene chloride, m.p.: 130-1329C; yield 98%; elemental analysis: exp. (calc. for C 38H56SnO14): C: 53.9 (53.35); H: 6.7 (6.60); 1H NMR: 7.74, dd (3J(1-1H)=8, 4J(1-1H)=2), H(5); 7.59, d (4J(1H -1H)=2) , H(3); 6.86, d (3J(1H- 1H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-4.0, m, H(9) & H(14); 3.75, ψs, H(10), H(11), H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.38, tq (3J(1H-1H)=7, 3J(1H-1H)=7), H(γ); 0.86, t (3J(1H-1H)=7), H(8); 13C NMR: 175.8, C(7); 153.5, C(l); 148.5, C(2); 125.0, C(5); 122.9, C(4); 115.4, C(3); 112.2, C(6); 71.11 & 71.09, C(8) & C(15); 70.39 & 70.31, C(9) & C(14); 69.4, 69.2, 69.0 & 68.6, C(10), C(11), C(12) & C(13); 26.7, C(β), 2J(117/119Sn—13C)=34; 26.4, C(γ), 3J(117/119Sn—13C)=103; 25.5, C(α), 1J(117/119Sn—13C)=561/588; 13.6, C(δ); 117Sn NMR: −156.8; electrospray MS: M+Na+ (m/z=879), 27%, M+K+, 27%; Mössbauer: QS: 3.28; IS: 1.41; Γ1: 0.92; Γ2: 0.93.
- Compound 8: triphenyltin 3,6-diheptanoate, prepared according to method 2,
- 8 h of reflux, recrystallized from hexane/chloroform, m.p.: 100-102° C., yield 95%, elemental analysis: exp. (calc. for C 13H24SnO4): C: 57.4 (57.18); H: 4.7 (5.01); 1H NMR: 7.7-7.8, m. H(o); 7.4-7.5, m, H(m) & H(p); 4.25, s, H(2); 3.7-3.8, m, H(4); 3.5-3.6, m, H(5); 3.35, s, H(7); 13C NMR: 176.5, C(1); 137.7, C(i); 136.8, C(o) 2J(117/119Sn—13C)=49; 130.2, C(p) 4J(117/119Sn—13C)=13; 128.9, C(m) 3J(117/119Sn—13C)=62/65; 72.0, C(5); 70.6, C(4); 69.0, C(2); 59.0, C(7); 117Sn NMR: −100.0; electrospray MS: M+Na+ (m/z=507), 5%, M+H+, 2%; Mössbauer: QS: 3.60; IS: 1.24; Γ1: 0.85; Γ2: 0.79.
- Compound 9: tri-n-butyltin 3,6-diheptanoate, prepared according to methode 2,
- 8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 95% elemental analysis: exp. (calc. for C 17H36SnO4.½ H2O): C: 47.4 (47.27); H: 8.6 (8.63);; 1H NMR: 4.09, S, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(S); 3.36, S. H(7);=2, HOH; 1.5-1.6, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.88, t (3J(1-1H)=7), H(δ); 3C NMR: 175.2, C(l); 71.9, C(S); 70.4, C(4); 69.0, C(2); 59.0, C(7); 27.8, C(β) 2J(117/119Sn—13C)=20; 27.1, C(γ) 3J(117/119Sn—13C)=64/67; 16.6, C(α) 1J(117/119Sn—13C)=338/355; 13.7, C(8); 117Sn NMR: 120.7; electrospray MS: M+Na+ (m/z=447), 7%; Mössbauer: QS: 3.81; IS: 1.47; Γ1: 1.15; Γ2: 1.14.
- Compound 10: di-n-butyltin bis(3,6-diheptanoate), prepared according to method 3,
- 12 h of reflux, liquid, yield 98%; elemental analysis: exp. (calc. for C 18H36SnO8): C: 43.4 (43.31); H: 7.5 (7.27); 1H NMR: 4.16, s, H(2); 3.6-3.8, m, H(4); 3.5-3.6, m, H(5); 3.36, s, H(7); 1.6-1.7, m, H(β) & H(α); 1.34, tq (3J(1-1H)=7, 3J(1-1H)=7), H(γ); 0.87, t (3J(1H-1H)=7), H(δ); 13C NMR: 178.3, C(1); 71.8, C(5); 70.7, C(4); 68.6, C(2); 59.0, C(7); 26.5, C(β) 2J(117/119Sn—13C) 34; 26.3, C(γ) 3J(117/119Sn—13C)=98/102; 25.7, C(α) 1J(117/119Sn—13C)=538/567; 13.4, C(δ); 117Sn NMR: −124.7; electrospray MS: M+Na+ (m/z=523), 77%; M+K+, 13%; Mössbauer: QS: 3.90; IS: 1.44; Γ1: 1.28; Γ2: 1.02.
- Compound 11: bis[di-n-butyl(3,6-dioxaheptanoato)tin]oxide, prepared according to method 3,
- 12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 80%; elemental analysis: exp. (calc. for C 52H108Sn4O18.2H2O): C: 40.7 (40.76); H: 7.2 (7.37); 1H NMR: 3.95, s, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(5); 3.34, s, H(7);˜2, HOH; 1.5-1.7, m, H(β); 1.3-1.5, m, H(α); 1.30, tq, (3J(1H-1H)=7, 3J(1H-1H)=7), H(γ); 0.86, m, H(δ); 13C NMR: 174.9, C(1); 71.8, C(5); 70.2, C(4); 69.8, C(2); 58.9, C(7); 27.5 & 27.2, C(β); 26.8 & 26.7, C(γ); 29.0 & 26.3, C(α); 13.57 & 13.55, C(δ); 117Sn NMR: −204.8 & −215.8; electrospray MS: M/2+Bu2SnOH+(m/z=1001), 40%; Mössbauer: QS: 3.42; IS: 1.34; Γ1: 1.22; Γ2: 1.18.
- Compound 12: triphenyltin 3,6,9-trioxadecanoate, prepared according to method 2,
- 8 h of reflux, recryst. diethyl ether/methylene chloride, m.p.: 109-111° C., yield 92%, elemental analysis: exp. (calc. for C 25H28SnO5 ): C: 57.1 (56.96); H: 5.4 (5.36);; 1H NMR: 7.7-7.8, m, H(o); 7.4-7.5, m, H(m) & H(p); 4.22, s, H(2); 3.7-3.8, m, H(4); 3.6-3.7, m, H(5); 3.5-3.6, m, H(7); 3.4-3.5, m, H(8); 3.34, s, H(10); 13C NMR: 176.4, C(1); 137.8 C(i); 136.9, C(o) 2J(117/119Sn—13C)=47-50; 130.2, C(p) 4J(117/119Sn—13C)=13; 128.9, C(m) 3J(117/119Sn—13C)=63/66; 72.0, C(8); 70.7, 70.7 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 59.0 C(10);117Sn NMR: −103.2; electrospray MS: M+K+(m/z=567), 2%; M+Na+, 11%; M+H+, 6%; Mössbauer: QS: 3.44; IS: 1.29; Γ1: 0.91; Γ2: 0.87.
- Compound 13: tri-n-butyltin 3,6,9-trioxadecanoate, prepared according to method 2,
- 8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 92%;elemental analysis: exp. (calc. for C 19H40SnO5.½H20): C: 47.7 (47.94); H: 8.8 (8.68); 1H NMR: 4.09, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.36, s, H(10);˜2, HOH, 1.5-1.7, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.89, t (3J(1H-1H)=7), H(δ); 13C NMR: 175.1, C(I); 72.0, C(8); 70.6, 70.5 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 58.9, C(10); 27.8, C(β) 2J(117/119Sn—13C)=20; 27.0, C(γ) 3J(117/119Sn—13C)=63/66; 16.6, C(α) 1J(117/119Sn—13C)=349/355; 13.6, C(δ); 117Sn NMR: 120.7; electrospray MS: M+K+(m/z=507), 18%; M+Na+, 51%; Mössbauer: QS: 3.84; IS: 1.47; γ1: 1.07; Γ2: 1.02.
- Compound 14: di-n-butyltin bis (3,6,9-trioxadecanoate), prepared according to method 3,
- 12 h of reflux, liquid, yield 95%; elemental analysis: exp. (calc. for C 22H44SnO10 ): C: 44.8 (44.99); H: 7.8 (7.56); 1H NMR: 4.15, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.35, s, H(10); 0.6-0.8, m, H(β) & H(α); 1.35, tq (3J(1H-1H)=7, 3J(1H-1H)=7), H(γ); 0.88, t (3J(1H-1H)=7), H(δ); 13C NMR: 175.8, C(1); 71.8, C(8); 71.1, 70.6 & 70.4, C(4), C(5) & C(7); 68.7, C(2); 59.0, C(10); 26.6, C(β), 2J(117/119Sn—13C)=38; 26.3, C(γ), 3J(117/119Sn—13C)=99; 25.6, C(α), 1J(117/119Sn—13C)=540/567; 13.5, C(δ); 117Sn NMR: −124.1; electrospray
- MS: M+K +(m/z=627), 12%; M+Na+, 22%; Mössbauer: QS: 3.77; IS: 1.42; Γ1: 1.36; Γ2: 1.18.
- Compound 15: bis[di-n-butyl(3,6,9-trioxadecanoato)tin]oxide, prepared according to method 3,
- 12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, elemental analysis: exp. (calc. for C 60H124Sn4O22.2 H20): C: 42.2 (42.18); H: 7.4 (7.56); yield 80%; 1H NMR: 3.96, s, H(2); 3.6-3.7, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.34, s, H(10);=2, HOH; 1.57, tt (3J(1H-1H)=7, 3J(1H-1H)=7), H(β); 1.4-1.5, m, H(α); 1.27, tq (3J(1-1H)=7, 3J(1H-1H)=7), H(γ); 0.8-0.9, m, H(δ); 13C NMR: 175.1, C(1); 72.0, C(8); 70.60, 70.55 & 70.4, C(4), C(5) & C(7); 69.9, C(2); 59.0, C(10); 27.6 & 27.3, C(β); 26.9 & 26.7, C(γ); 29.1 & 25.8, C(α); 13.6, C(δ); 117Sn NMR: −204.9 & −217.6; electrospray MS: M/2+Na+ (m/z=861), 10%; M/2+Bu2SnOH+, 33%; Mössbauer: QS: 3.49; IS: 1.32; Γ1: 0.90; Γ2: 0.90.
- Stability in Water of Organotin Polyoxaalkanenecarboxylates
- The stability in the presence of water of four compounds, 6, 8, 9 and 12, was determined. Solutions in CD 3CD2OD exhibit a single resonance in 117Sn NMR (at 36.5, −210.7, 27.9 and −212.0 ppm, respectively) that is regularly slightly shifted after the addition of increasing amounts of D2O.
- Antitumour activity of compounds 1 to 15
- The ID 50 inhibition doses in ng/ml of the tested compounds are given in the table as well as those for some known reference compounds.
IG- MCF-7 EVSA-T WiDr ROV M19 A498 H226 1 15 12 13 30 16 43 37 2 35 6 11 30 70 97 100 3 155 128 781 260 219 282 281 4 36 46 239 82 68 126 73 5 <3 <3 <3 <3 <3 <3 <3 6 <3 <3 <3 <3 <3 <3 <3 7 273 237 332 321 286 49 854 8 13 12 34 37 31 32 33 9 32 40 82 84 90 153 61 10 60 62 379 128 115 134 161 11 <3 <3 6 <3 <3 <3 5 12 9 9 19 33 24 21 25 13 36 25 40 89 78 93 56 14 86 66 495 178 167 145 280 15 <3 <3 3 <3 <3 <3 <3 cisplatin 699 422 967 169 558 2253 3269 doxorubicin 10 8 11 60 16 90 199 etoposide 2594 317 150 580 505 1314 3934 5-fluoro-uracil 750 475 225 297 442 143 340 methotrexate 18 5 <3 7 23 37 2287 - Inhibition doses ID 50 in vitro (in ng/ml) against some tumoural cell lines of human origin, two mammary cancers, (MCF-7, EVSA-T), a colon carcinoma (WiDr), an ovarian cancer (IGROV), a melanoma (M19 MEL), a renal cancer (A 498) and a non small cell lung cancer (H226) of organotin derivatives of carboxybenzocrown and di- or trioxaalkanecarboxylic acids, and of some known reference compounds.
Claims (3)
1. Tin polyoxaalkanecarboxylates having the formula
[(R1 pR2 qSn)rOs]t
wherein
R1 represents C1-C6 alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms,
R2 is a carboxylic residue selected from:
and p, q, r, s and t have the following meanings:
p=3, q=1, r=1, s'0 and t=1;
p=2, q=2, r=1, s'0 and t=1;
p=2, q=1, r=2, s'1 and t=2.
2. Anti-tumour compositions, containing as an active ingredient one or more tin polyoxaalkanecarboxylates of the formula
R1 3SnR2 (1);R1 2SnR2 2 (2); or{[R1 2R2Sn]2O}2 (3),
wherein R1 and R2 have the meanings as defined in ,
claim 1
and a pharmaceutically acceptable carrier.
3. A composition according to , containing a compound having the formula (1), (2) or (3) as defined in the claims 1 and 2, wherein R1 represents a phenylgroup or a n-butylgroup.
claim 2
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/NL1998/000429 WO2000006583A1 (en) | 1998-07-29 | 1998-07-29 | Tin polyoxaalkanecarboxylates and compositions containing them |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/NL1998/000429 Continuation WO2000006583A1 (en) | 1998-07-29 | 1998-07-29 | Tin polyoxaalkanecarboxylates and compositions containing them |
Publications (2)
| Publication Number | Publication Date |
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| US20010039270A1 true US20010039270A1 (en) | 2001-11-08 |
| US6407265B2 US6407265B2 (en) | 2002-06-18 |
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| US09/770,299 Expired - Fee Related US6407265B2 (en) | 1998-07-29 | 2001-01-29 | Tin polyoxaalkanecarboxylates and compositions containing them |
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| Country | Link |
|---|---|
| US (1) | US6407265B2 (en) |
| EP (1) | EP1100804B1 (en) |
| JP (1) | JP2002521486A (en) |
| AT (1) | ATE225796T1 (en) |
| AU (1) | AU8650398A (en) |
| CA (1) | CA2338801C (en) |
| DE (1) | DE69808673T2 (en) |
| DK (1) | DK1100804T3 (en) |
| ES (1) | ES2184311T3 (en) |
| PT (1) | PT1100804E (en) |
| WO (1) | WO2000006583A1 (en) |
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| CN103044482B (en) * | 2013-01-22 | 2015-08-19 | 聊城大学 | A kind of dibutyl tin coordination compound and preparation method thereof and application |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0484596A1 (en) | 1990-11-06 | 1992-05-13 | Pharmachemie B.V. | Organotin compounds and anti-tumor compositions containing them |
| ES2070417T3 (en) * | 1991-10-22 | 1995-06-01 | Pharmachemie Bv | NEW ORGANIC TIN COMPOUND WITH AN ANTI-TUMOR ACTIVITY AND ANTI-TUMOR COMPOSITIONS OR THE PROCESS TO PREPARE THESE COMPOSITIONS. |
| JP3282047B2 (en) * | 1993-02-18 | 2002-05-13 | コニカ株式会社 | Purification method of crown compound |
| EP0700921A1 (en) | 1994-09-09 | 1996-03-13 | Pharmachemie B.V. | Aromatic fluorine-containing organotin compounds and anti-tumour compositions |
-
1998
- 1998-07-29 AT AT98937860T patent/ATE225796T1/en not_active IP Right Cessation
- 1998-07-29 AU AU86503/98A patent/AU8650398A/en not_active Withdrawn
- 1998-07-29 PT PT98937860T patent/PT1100804E/en unknown
- 1998-07-29 CA CA002338801A patent/CA2338801C/en not_active Expired - Fee Related
- 1998-07-29 DK DK98937860T patent/DK1100804T3/en active
- 1998-07-29 DE DE69808673T patent/DE69808673T2/en not_active Expired - Fee Related
- 1998-07-29 ES ES98937860T patent/ES2184311T3/en not_active Expired - Lifetime
- 1998-07-29 EP EP98937860A patent/EP1100804B1/en not_active Expired - Lifetime
- 1998-07-29 WO PCT/NL1998/000429 patent/WO2000006583A1/en active IP Right Grant
- 1998-07-29 JP JP2000562381A patent/JP2002521486A/en active Pending
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2338801C (en) | 2008-10-14 |
| JP2002521486A (en) | 2002-07-16 |
| AU8650398A (en) | 2000-02-21 |
| EP1100804B1 (en) | 2002-10-09 |
| WO2000006583A1 (en) | 2000-02-10 |
| ES2184311T3 (en) | 2003-04-01 |
| DE69808673D1 (en) | 2002-11-14 |
| DK1100804T3 (en) | 2003-02-03 |
| EP1100804A1 (en) | 2001-05-23 |
| PT1100804E (en) | 2003-02-28 |
| DE69808673T2 (en) | 2003-08-07 |
| ATE225796T1 (en) | 2002-10-15 |
| CA2338801A1 (en) | 2000-02-10 |
| US6407265B2 (en) | 2002-06-18 |
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