DE10114106C1 - New quaternary ammonio-substituted orthosilicate esters, useful as anticancer agents having strong activity against a broad spectrum of human tumor cell lines - Google Patents
New quaternary ammonio-substituted orthosilicate esters, useful as anticancer agents having strong activity against a broad spectrum of human tumor cell linesInfo
- Publication number
- DE10114106C1 DE10114106C1 DE10114106A DE10114106A DE10114106C1 DE 10114106 C1 DE10114106 C1 DE 10114106C1 DE 10114106 A DE10114106 A DE 10114106A DE 10114106 A DE10114106 A DE 10114106A DE 10114106 C1 DE10114106 C1 DE 10114106C1
- Authority
- DE
- Germany
- Prior art keywords
- compound
- substituted
- general formula
- cell lines
- compound according
- 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.)
- Expired - Fee Related
Links
- 239000002246 antineoplastic agent Substances 0.000 title description 2
- 230000000694 effects Effects 0.000 title description 2
- 210000004881 tumor cell Anatomy 0.000 title description 2
- 150000004762 orthosilicates Chemical class 0.000 title 1
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 238000011321 prophylaxis Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000732 arylene group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002577 pseudohalo group Chemical group 0.000 claims description 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052710 silicon Inorganic materials 0.000 abstract description 2
- 239000010703 silicon Substances 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 7
- 235000003599 food sweetener Nutrition 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- -1 Polyoxyethylene stearate Polymers 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 235000017060 Arachis glabrata Nutrition 0.000 description 3
- 244000105624 Arachis hypogaea Species 0.000 description 3
- 235000010777 Arachis hypogaea Nutrition 0.000 description 3
- 235000018262 Arachis monticola Nutrition 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 239000005662 Paraffin oil Substances 0.000 description 3
- 229910003902 SiCl 4 Inorganic materials 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 235000020232 peanut Nutrition 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 206010006417 Bronchial carcinoma Diseases 0.000 description 2
- 244000001582 Canarium odontophyllum Species 0.000 description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 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
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960001031 glucose Drugs 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960004903 invert sugar Drugs 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229960003540 oxyquinoline Drugs 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- LZFIOSVZIQOVFW-UHFFFAOYSA-N propyl 2-hydroxybenzoate Chemical class CCCOC(=O)C1=CC=CC=C1O LZFIOSVZIQOVFW-UHFFFAOYSA-N 0.000 description 2
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 2
- 235000020374 simple syrup Nutrition 0.000 description 2
- 229960001462 sodium cyclamate Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- VXEGSRKPIUDPQT-UHFFFAOYSA-N 4-[4-(4-methoxyphenyl)piperazin-1-yl]aniline Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=CC(N)=CC=2)CC1 VXEGSRKPIUDPQT-UHFFFAOYSA-N 0.000 description 1
- 244000301344 Acacia baileyana Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 244000046127 Sorghum vulgare var. technicum Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 231100000434 photosensitization Toxicity 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 150000003377 silicon compounds Chemical class 0.000 description 1
- 239000005049 silicon tetrachloride Substances 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000338 sulforhodamine B assay Toxicity 0.000 description 1
- 239000000829 suppository Substances 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07F7/02—Silicon compounds
- C07F7/04—Esters of silicic acids
- C07F7/06—Esters of silicic acids with hydroxyaryl compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die vorliegende Erfindung betrifft Siliciumverbindungen, Verfahren zur ihrer Herstellung und deren Verwendung als Arzneimittel zur Prophylaxe und/oder Behandlung von Krebserkrankungen.The present invention relates to silicon compounds, processes for their preparation and their use as Medicines for the prophylaxis and / or treatment of cancer.
In der US-A-4 278 666 werden (Trihydrocarbylsilylmethyloxyimino)alkane und deren Verwendung zur Behandlung von Tumorerkrankungen beschrieben.In US-A-4,278,666 (trihydrocarbylsilylmethyloxyimino) alkanes and their Use for the treatment of tumor diseases described.
Die US-A-5 484 778 beschreibt Silicium-Phthalocyanine mit Amin-Liganden am Metallatom sowie deren Verwendung zur Krebsbehandlung durch Photosensibilisierung.US-A-5 484 778 describes silicon phthalocyanines with amine ligands Metal atom and its use for cancer treatment by photosensitization.
In der US-A-5910485 werden Antitumormittel offenbart, die als Wirkstoff eine Mischung organischer Verbindungen mit Amino- und Silyl-Gruppen enthalten, in der Adriamycin enthalten ist.In US-A-5910485 antitumor agents are disclosed which are a mixture as an active ingredient contain organic compounds with amino and silyl groups, in the Adriamycin is included.
Aufgabe der vorliegenden Erfindung ist es, Verbindungen zur Behandlung von Krebserkrankungen zur Verfügung zu stellen, die eine hohe Wirksamkeit aufweisen.The object of the present invention is to provide compounds for the treatment of To provide cancers that are highly effective.
Diese Aufgabe wird gelöst durch eine Verbindung der allgemeinen Formel (I)
This object is achieved by a compound of the general formula (I)
worin R eine NH+-haltige Gruppe ist, gewählt aus einer Gruppe der allgemeinen
Formel (II) und (III):
wherein R is a group containing NH + , selected from a group of the general formulas (II) and (III):
worin
R1 C1-C6-Alkylen, C3-C6-Cycloalkylen, C2-C6-Alkenylen, C6-C14-
Arylen oder ein Heterocyclus, die jeweils substituiert oder unsubstituiert
sein können, ist;
R2 und R3 C1-C10-Alkyl, C3-C6-Cycloalkyl, C2-C10-Alkenyl, C6-C14-Aryl,
oder ein Heterocyclus, die jeweils substituiert oder unsubstituiert sein
können, oder Wasserstoff ist;
und R1 und R2, oder R1 und R3, oder R2 und R3 einen Heterocyclus bilden
können, der gegebenenfalls weitere Stickstoffatome enthalten kann;
und
wherein
R 1 is C 1 -C 6 alkylene, C 3 -C 6 cycloalkylene, C 2 -C 6 alkenylene, C 6 -C 14 arylene or a heterocycle, each of which may be substituted or unsubstituted;
R 2 and R 3 are C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 10 alkenyl, C 6 -C 14 aryl, or a heterocycle, each of which may be substituted or unsubstituted, or Is hydrogen;
and R 1 and R 2 , or R 1 and R 3 , or R 2 and R 3 can form a heterocycle which can optionally contain further nitrogen atoms;
and
worin
R4 die gleiche Bedeutung wie R1 besitzt, R5 die gleiche Bedeutung wie R2
besitzt, und
R4 und R5 zusammen mit NH einen gegebenenfalls aromatischen Ring
bilden können, der weitere Stickstoffatome enthalten kann;
und
Y ein Halogen, Pseudohalogen, HCO3 oder R'COO, worin R' C1-C6-Alkyl, C2-
C6-Alkenyl oder Aryl, die jeweils substituiert oder unsubstituiert sein können, ist.wherein
R 4 has the same meaning as R 1 , R 5 has the same meaning as R 2 , and
R 4 and R 5 together with NH can form an optionally aromatic ring which can contain further nitrogen atoms;
and
Y is a halogen, pseudohalogen, HCO 3 or R'COO, where R 'is C 1 -C 6 alkyl, C 2 - C 6 alkenyl or aryl, each of which may be substituted or unsubstituted.
In einer bevorzugten Ausführungsform ist R1 Ethylen.In a preferred embodiment, R 1 is ethylene.
In weiteren bevorzugten Ausführungsformen kann R in der allgemeinen Verbindung (I)
aus
In further preferred embodiments, R in the general compound (I) can consist of
gewählt werden.to get voted.
In einer weiteren bevorzugten Ausführungsform ist Y in der allgemeinen Formel (I) Chlor.In a further preferred embodiment, Y in the general formula (I) Chlorine.
Die Aufgabe wird weiterhin durch ein Verfahren zum Herstellen einer Verbindung der
allgemeinen Formel (I) gelöst. Dabei wird eine Verbindung der allgemeinen Formel (IV)
The object is further achieved by a process for the preparation of a compound of the general formula (I). A compound of the general formula (IV)
SiY4 (IV)
SiY 4 (IV)
worin
Y wie vorstehend definiert ist;
mit einer Verbindung der allgemeinen Formel (V) oder (VI)
wherein
Y is as defined above;
with a compound of the general formula (V) or (VI)
worin
R1, R2 und R3 wie vorstehend definiert sind,
wherein
R 1 , R 2 and R 3 are as defined above,
worin
R4 und R5 wie vorstehend definiert sind,
umgesetzt.wherein
R 4 and R 5 are as defined above,
implemented.
Ferner wird die Aufgabe der vorliegenden Erfindung durch ein Arzneimittel gelöst, das die erfindungsgemäße Verbindung enthält. Die erfindungsgemäße Verbindung kann zur Prophylaxe und/oder Behandlung von Krebserkrankungen eingesetzt werden.Furthermore, the object of the present invention is achieved by a medicament which contains the compound of the invention. The compound of the invention can Prophylaxis and / or treatment of cancer can be used.
Im folgenden wird das Arzneimittel, enthaltend eine erfindungsgemäße Verbindung, genauer beschrieben.In the following, the medicament containing a compound according to the invention is described in more detail.
Das erfindungsgemäße Arzneimittel wird vor allem intravenös, aber auch intramuskulär, intraperitoneal, subkutan oder peroral verabreicht. Auch eine äußerliche Applikation ist möglich. Bevorzugt ist die Verabreichung durch intravenöse Injektion oder intravenöse Infusion.The medicament according to the invention is primarily intravenous, but also intramuscular, administered intraperitoneally, subcutaneously or orally. An external application is also possible. Administration by intravenous injection or intravenous is preferred Infusion.
Das Arzneimittel wird nach an sich bekannten Verfahren hergestellt, wobei die erfindungsgemäße Verbindung als solche oder gegebenenfalls in Kombination mit geeigneten pharmazeutischen Trägerstoffen eingesetzt wird. Enthält das erfindungsgemäße Arzneimittel neben dem Wirkstoff pharmazeutische Trägerstoffe, beträgt der Wirkstoffgehalt dieser Mischung 0,1 bis 99,5, vorzugsweise 0,5 bis 95 Gew.- % der Gesamtmischung.The medicinal product is produced by methods known per se, the Compound according to the invention as such or optionally in combination with suitable pharmaceutical carriers is used. Contains that pharmaceuticals according to the invention in addition to the active ingredient pharmaceutical carriers, the active substance content of this mixture is 0.1 to 99.5, preferably 0.5 to 95% by weight % of the total mix.
Das erfindungsgemäße Arzneimittel kann in jeder geeigneten Formulierung angewandt werden unter der Voraussetzung, dass die Ausbildung bzw. Aufrechterhaltung von ausreichenden Wirkstoffpegeln gewährleistet ist. Das kann beispielsweise durch orale oder parenterale Gabe in geeigneten Dosen erreicht werden. Vorteilhafterweise liegt die pharmazeutische Zubereitung des Wirkstoffs in Form von Einheitsdosen vor, die auf die gewünschte Verabreichung abgestimmt sind. Eine Einheitsdosis kann zum Beispiel eine Tablette, ein Dragee, eine Kapsel, ein Suppositorium oder eine gemessene Volumenmenge eines Pulvers, eines Granulates, einer Lösung, einer Emulsion oder einer Suspension sein.The medicament according to the invention can be used in any suitable formulation are provided that the training or maintenance of sufficient drug levels are guaranteed. This can be done, for example, through oral or parenteral administration in suitable doses. Advantageously, the Pharmaceutical preparation of the active substance in the form of unit doses based on the desired administration are coordinated. For example, a unit dose may be one Tablet, dragee, capsule, suppository or measured Volume of a powder, granulate, solution, emulsion or a suspension.
Unter "Einheitsdosis" im Sinne der vorliegenden Erfindung wird eine physikalisch bestimmte Einheit verstanden, die eine individuelle Menge des aktiven Bestandteils in Kombination mit einem pharmazeutischen Trägerstoff enthält und deren Wirkstoffgehalt einem Bruchteil oder Vielfachen einer therapeutischen Einzeldosis entspricht. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben, einer drittel oder einer viertel Tagesdosis entspricht. Wenn für eine einzelne therapeutische Verabreichung nur ein Bruchteil, wie die Hälfte oder ein Viertel der Einheitsdosis benötigt wird, ist die Einheitsdosis vorteilhafterweise teilbar, z. B. in Form einer Tablette mit Bruchkerbe."Unit dose" in the sense of the present invention is a physical understood specific unit that contains an individual amount of the active ingredient Contains combination with a pharmaceutical carrier and their active ingredient content corresponds to a fraction or multiple of a single therapeutic dose. A Single dose preferably contains the amount of active ingredient in one application is administered and usually a whole, a half, a third or one corresponds to a quarter of the daily dose. If for a single therapeutic administration only a fraction, such as half or a quarter of the unit dose, is that Unit dose advantageously divisible, e.g. B. in the form of a tablet with a score line.
Die erfindungsgemäßen Arzneimittel können, wenn sie in Einheitsdosen vorliegen und für Applikationen z. B. am Menschen bestimmt sind, etwa 0,1 bis 500 mg, bevorzugt 10 bis 200 mg und insbesondere 50 bis 150 mg Wirkstoff enthalten.The pharmaceuticals according to the invention can, if they are in unit doses and for applications e.g. B. intended for humans, about 0.1 to 500 mg, preferably 10 contain up to 200 mg and in particular 50 to 150 mg of active ingredient.
Im allgemeinen werden in der Humanmedizin der oder die Wirkstoffe in einer Tagesdosis von 0,1 bis 5, vorzugsweise 1 bis 3 mg/kg Körpergewicht, gegebenenfalls in Form mehrerer, vorzugsweise 1 bis 3 Einzelgaben zur Erzielung der gewünschten Ergebnisse verabreicht. Eine Einzelgabe enthält den oder die Wirkstoffe in Mengen von 0,1 bis 5, vorzugsweise 1 bis 3 mg/kg Körpergewicht. Bei einer oralen Behandlung können ähnliche Dosierungen zur Anwendung kommen.In general, the active ingredient or ingredients in human medicine Daily dose of 0.1 to 5, preferably 1 to 3 mg / kg body weight, optionally in Form of several, preferably 1 to 3 individual doses to achieve the desired Results administered. A single dose contains the active ingredient (s) in quantities of 0.1 to 5, preferably 1 to 3 mg / kg body weight. With an oral treatment similar doses can be used.
Die therapeutische Verabreichung des erfindungsgemäßen Arzneimittels kann 1 bis 4 mal am Tage zu festgelegten oder variierenden Zeitpunkten erfolgen, z. B. jeweils vor den Mahlzeiten und/oder am Abend. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art, dem Körpergewicht und dem Alter der zu behandelnden Individuen, der Art und Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der oben genannten Menge Wirkstoff auszukommen, während in anderen Fällen die oben angeführte Wirkstoffmenge überschritten werden muss. Es kann sich auch als zweckmäßig erweisen, die Arzneimittel nur einmalig oder im Abstand von mehreren Tagen zu verabreichen.The therapeutic administration of the medicament according to the invention can be 1 to 4 times a day at fixed or varying times, e.g. B. each before with meals and / or in the evening. However, it may be necessary from the mentioned doses vary, depending on the type, the Body weight and the age of the individuals to be treated, the type and severity of the Disease, the type of preparation and application of the drug and the Period or interval within which the administration takes place. So it can be in in some cases, be sufficient with less than the above amount of active ingredient get along, while in other cases the amount of active ingredient mentioned above must be exceeded. It can also prove useful to Administer medication only once or at intervals of several days.
Die Festlegung der erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens erfolgen.Determining the required optimal dosage and type of application Active ingredients can be made by any specialist on the basis of their specialist knowledge.
Die erfindungsgemäßen Arzneimittel bestehen in der Regel aus den erfindungsgemäßen Verbindungen und nichttoxischen, pharmazeutisch verträglichen Arzneimittelträgern, die als Zumischung oder Verdünnungsmittel, beispielsweise in fester, halbfester oder flüssiger Form oder als Umhüllungsmittel, beispielsweise in Form einer Kapsel, eines Tablettenüberzugs, eines Beutels oder eines anderen Behältnisses für den therapeutisch aktiven Bestandteil in Anwendung kommen. Ein Trägerstoff kann z. B. als Vermittler für die Arzneimittelaufnahme durch den Körper, als Formulierungshilfsmittel, als Süßungsmittel, als Geschmackskorrigens, als Farbstoff oder als Konservierungsmittel dienen.The pharmaceuticals according to the invention generally consist of Compounds of the invention and non-toxic, pharmaceutically acceptable Medicament carriers that are used as an admixture or diluent, for example in solid, semi-solid or liquid form or as a coating agent, for example in the form a capsule, pill cover, sachet, or other container for the therapeutically active ingredient. A carrier can z. B. as a mediator for drug absorption by the body, as Formulation aid, as a sweetener, as a taste corrector, as a color or serve as a preservative.
Zur oralen Anwendung können z. B. Tabletten Dragees, harte und weiche Kapseln, z. B. aus Gelatine, dispergierbare Pulver, Granulate, wässrige und ölige Suspensionen, Emulsionen, Lösungen oder Sirupe kommen.For oral use, e.g. B. tablets coated tablets, hard and soft capsules, e.g. B. from gelatin, dispersible powders, granules, aqueous and oily suspensions, Emulsions, solutions or syrups are coming.
Tabletten können inerte Verdünnungsmittel, z. B. Calciumcarbonat, Calciumphosphat, Natriumphosphat oder Laktose; Granulierungs- und Verteilungsmittel, z. B. Maisstärke oder Alginate; Bindemitte, z. B. Stärke, Gelatine oder Akaziengummi; und Gleitmittel, z. B. Aluminium- oder Magnesiumstearat, Talkum oder Silikonöl, enthalten. Sie können zusätzlich mit einem Überzug versehen sein, der auch so beschaffen sein kann, dass er eine verzögerte Auflösung und Resorption der Arzneimittelzubereitung im Gastrointestinaltrakt bewirkt, so dass z. B. eine bessere Verträglichkeit, Protahierung oder Retardierung erreicht wird. Gelatinekapseln können den Arzneistoff vermischt mit einem festen, z. B. Calciumcarbonat oder Kaolin, oder einem öligen, z. B. Oliven-, Erdnuss-, oder Paraffinöl, Verdünnungsmittel enthalten.Tablets can contain inert diluents, e.g. B. calcium carbonate, calcium phosphate, Sodium phosphate or lactose; Granulating and distributing agents, e.g. B. corn starch or alginates; Binding agents, e.g. B. starch, gelatin or acacia; and lubricants, z. As aluminum or magnesium stearate, talc or silicone oil. You can additionally be provided with a coating, which can also be such that it delayed dissolution and absorption of the drug preparation in the Gastrointestinal tract causes, so that, for. B. better tolerability, protahtion or retardation is achieved. Gelatin capsules can be mixed with the drug a fixed, e.g. As calcium carbonate or kaolin, or an oily, e.g. B. olive, Contain peanut or paraffin oil, diluent.
Wässrige Suspensionen können Suspendiermittel, z. B. Natriumcarboxymethylcellulose, Methylcellulose, Hydroxypropylcellulose, Natriumalginat, Polyvinylpyrrolidon, Traganthgummi oder Akaziengummi; Dispergier- und Benetzungsmittel, z. B. Polyoxyethylenstearat, Heptadecaethylenoxycatanol, Polyoxyethylensorbitolmonooleat oder Lecithin; Konservierungsmittel, z. B. Methyl- oder Propylhydroxybenzoate; Geschmacksmittel; Süßungsmittel, z. B. Saccharose, Lactose, Natriumcyclamat, Dextrose, Invertzuckersirup, enthalten.Aqueous suspensions can include suspending agents, e.g. B. sodium carboxymethyl cellulose, Methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, Tragacanth or acacia; Dispersing and wetting agents, e.g. B. Polyoxyethylene stearate, heptadecaethyleneoxycatanol, polyoxyethylene sorbitol monooleate or lecithin; Preservatives, e.g. B. methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. B. sucrose, lactose, sodium cyclamate, Dextrose, invert sugar syrup, included.
Ölige Suspensionen können z. B. Erdnuss-, Oliven-, Sesam-, Kokos- oder Paraffinöl und Verdickungsmittel, wie z. B. Bienenwachs, Hartparaffin oder Cetylalkohol, enthalten; ferner Süßungsmittel, Geschmacksmittel und Antioxidantien.Oily suspensions can e.g. B. peanut, olive, sesame, coconut or paraffin oil and Thickeners such as B. beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
In Wasser dispergierbare Pulver und Granulate können die erfindungsgemäße Verbindung in Mischung mit Dispergier-, Benetzungs- und Suspendiermitteln, z. B. den oben genannten, sowie mit Süßungsmitteln, Geschmacksmitteln und Farbstoffen enthalten.Powders and granules dispersible in water can be the inventive Compound mixed with dispersing, wetting and suspending agents, e.g. B. the above, as well as with sweeteners, flavoring agents and colorings contain.
Emulsionen können z. B. Oliven-, Erdnuss-, oder Paraffinöl neben Emulgiermitteln, wie z. B. Akaziengummi, Traganthgummi, Phosphatiden, Sorbitanmonooleat, Polyoxyethylensorbitanmonooleat, und Süßungs- und Geschmacksmittel enthalten.Emulsions can e.g. B. olive, peanut, or paraffin oil in addition to emulsifiers, such as z. B. acacia, tragacanth, phosphatides, sorbitan monooleate, Polyoxyethylene sorbitan monooleate, and contain sweeteners and flavoring agents.
Wässrige Lösungen können Konservierungsmittel, z. B. Methyl- oder Propylhydroxybenzoate; Verdickungsmittel; Geschmacksmittel; Süßungsmittel, z. B. Saccharose, Laktose, Natriumcyclamat, Dextrose, Invertzuckersirup, sowie Geschmacksmittel und Farbstoffe enthalten.Aqueous solutions can preservatives, e.g. B. methyl or propyl hydroxybenzoates; Thickener; Flavoring agents; Sweeteners, e.g. B. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, and Contain flavoring and coloring.
Zur parenteralen Anwendung der Arzneistoffe dienen steril injizierbare, wässrige Lösungen, isotonische Salzlösungen oder sonstige Lösungen.Sterile injectable aqueous solutions are used for parenteral use of the medicinal substances Solutions, isotonic saline solutions or other solutions.
Die folgenden Beispiele erläutern die Erfindung. The following examples illustrate the invention.
Die Herstellung erfolgt durch Umsetzung von Siliciumtetrachlorid (SiCl4) mit 8- Hydroxychinolin in Dichlormethan (CH2Cl2). Hierzu werden pro ml eingesetztem SiCl4 5.068 g 8-Hydroxchinolin in 120 ml CH2Cl2 gelöst und anschließend das SiCl4 mittels Injektionskanüle zugegeben. Das ausfallende Produkt wird 2-3 h unter Rückfluss bei 35-40°C gerührt, abgesaugt, mit CHCl3 gewaschen und im Hochvakuum getrocknet.They are produced by reacting silicon tetrachloride (SiCl 4 ) with 8-hydroxyquinoline in dichloromethane (CH 2 Cl 2 ). For this purpose, 5,068 g of 8-hydroxyquinoline are dissolved in 120 ml of CH 2 Cl 2 per ml of SiCl 4 used and then the SiCl 4 is added by means of an injection cannula. The product which precipitates is stirred under reflux at 35-40 ° C, suction filtered, washed with CHCl 3 and dried in a high vacuum.
Berechnet: C: 57,61; H: 3,76;
Gefunden: C: 57,46; H: 4,20.Calculated: C: 57.61; H: 3.76;
Found: C: 57.46; H: 4.20.
Im 48 h-Sulforhodamin B-Assay an über 50 humanen Tumorzellinien wurde eine gute
Wirksamkeit von Tetrakis(8-chinolinolato)silicium(IV)-Tetrahydrochlorid mit folgenden
Kennwerten festgestellt:
In the 48-hour sulforhodamine B assay on over 50 human tumor cell lines, the effectiveness of tetrakis (8-quinolinolato) silicon (IV) tetrahydrochloride was determined with the following parameters:
Die stärkste Wirksamkeit wurde an einer kleinzelligen Bronchialkarzinomlinie (DMS 114) beobachtet. Überdurchschnittliche Aktivitäten wurden weiters an einer Reihe von nicht kleinzelligen Bronchialkarzinomlinien sowie an Kolonkarzinom-, Ovarialkarzinom- und einzelnen Melanom-Zellinien beobachtet.The greatest effectiveness was found on a small cell bronchial carcinoma line (DMS 114) observed. Above-average activities were also not carried out on a number of small cell lines of bronchial carcinoma as well as on colon carcinoma, ovarian carcinoma and single melanoma cell lines were observed.
An Nacktmäusen mit subkutan implantierten humanen Tumoren zeigte sich am Nierenzellkarzinom-Xenograft RXF-393 in Abhängigkeit vom Schedule eine tumorhemmende Wirkung mit einer Verringerung des Tumorwachstum auf bis zu 37% und einer Verzögerung des Tumorwachstums um bis zu 32% im Vergleich zu unbehandelten Kontrollgruppen.Nude mice with subcutaneously implanted human tumors showed: Renal cell carcinoma xenograft RXF-393 depending on the schedule anti-tumor effects with a reduction in tumor growth of up to 37% and a delay in tumor growth of up to 32% compared to untreated control groups.
Claims (12)
worin R eine NH+-haltige Gruppe ist, gewählt aus einer Gruppe der allgemeinen Formel (II) und (III):
worin
R1 C1-C6-Alkylen, C3-C6-Cycloalkylen, C2-C6-Alkenylen, C6-C14- Arylen oder ein Heterocyclus, die jeweils substituiert oder unsubstituiert sein können, ist;
R2 und R3 C1-C10-Alkyl, C3-C6-Cycloalkyl, C2-C10-Alkenyl, C6-C14-Aryl, oder ein Heterocyclus, die jeweils substituiert oder unsubstituiert sein können, oder Wasserstoff ist;
und R1 und R2, oder R1 und R3, oder R2 und R3 einen Heterocyclus bilden können, der gegebenenfalls weitere Stickstoffatome enthalten kann;
und
worin
R4 die gleiche Bedeutung wie R1 besitzt, R5 die gleiche Bedeutung wie R2 besitzt, und
R4 und R5 zusammen mit NH einen gegebenenfalls aromatischen Ring bilden können, der weitere Stickstoffatome enthalten kann;
und
Y ein Halogen, Pseudohalogen, HCO3 oder R'COO, worin R' C1-C6-Alkyl, C2- C6-Alkenyl oder Aryl, die jeweils substituiert oder unsubstituiert sein können, ist;1. Compound of the general formula (I)
wherein R is a group containing NH + , selected from a group of the general formulas (II) and (III):
wherein
R 1 is C 1 -C 6 alkylene, C 3 -C 6 cycloalkylene, C 2 -C 6 alkenylene, C 6 -C 14 arylene or a heterocycle, each of which may be substituted or unsubstituted;
R 2 and R 3 are C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 10 alkenyl, C 6 -C 14 aryl, or a heterocycle, each of which may be substituted or unsubstituted, or Is hydrogen;
and R 1 and R 2 , or R 1 and R 3 , or R 2 and R 3 can form a heterocycle which can optionally contain further nitrogen atoms;
and
wherein
R 4 has the same meaning as R 1 , R 5 has the same meaning as R 2 , and
R 4 and R 5 together with NH can form an optionally aromatic ring which can contain further nitrogen atoms;
and
Y is halogen, pseudohalogen, HCO 3 or R'COO, where R 'is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or aryl, each of which may be substituted or unsubstituted;
ist.3. A compound according to claim 1, wherein R
is.
ist.4. A compound according to claim 1, wherein R
is.
ist.5. A compound according to claim 1, wherein R
is.
ist. 6. A compound according to claim 1, wherein R
is.
ist.7. A compound according to claim 1, wherein R
is.
ist.8. A compound according to claim 1, wherein R
is.
SiY4 (IV)
worin
Y wie in Anspruch 1 definiert ist;
mit einer Verbindung der allgemeinen Formel (V) oder (VI)
worin
R1, R2 und R3 wie in Anspruch 1 definiert sind,
worin
R4 und R5 wie in Anspruch 1 definiert sind,
umgesetzt wird.10. A method for producing a compound of general formula (I) according to any one of claims 1 to 9, wherein a compound of general formula (IV)
SiY 4 (IV)
wherein
Y is as defined in claim 1;
with a compound of the general formula (V) or (VI)
wherein
R 1 , R 2 and R 3 are as defined in claim 1,
wherein
R 4 and R 5 are as defined in claim 1,
is implemented.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10114106A DE10114106C1 (en) | 2001-03-23 | 2001-03-23 | New quaternary ammonio-substituted orthosilicate esters, useful as anticancer agents having strong activity against a broad spectrum of human tumor cell lines |
PCT/EP2002/001654 WO2002076994A1 (en) | 2001-03-23 | 2002-02-15 | Tumor-inhibiting silicon compounds |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10114106A DE10114106C1 (en) | 2001-03-23 | 2001-03-23 | New quaternary ammonio-substituted orthosilicate esters, useful as anticancer agents having strong activity against a broad spectrum of human tumor cell lines |
Publications (1)
Publication Number | Publication Date |
---|---|
DE10114106C1 true DE10114106C1 (en) | 2002-02-21 |
Family
ID=7678608
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE10114106A Expired - Fee Related DE10114106C1 (en) | 2001-03-23 | 2001-03-23 | New quaternary ammonio-substituted orthosilicate esters, useful as anticancer agents having strong activity against a broad spectrum of human tumor cell lines |
Country Status (2)
Country | Link |
---|---|
DE (1) | DE10114106C1 (en) |
WO (1) | WO2002076994A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10218312C1 (en) * | 2002-04-24 | 2003-10-23 | Faustus Forschungs Cie | New bis-(amino-hydrocarbyloxy or N-containing heterocyclyloxy)-silicon compounds, useful as anticancer agents |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4278666A (en) * | 1979-03-12 | 1981-07-14 | Shin-Etsu Chemical Co., Ltd. | Novel organosilicon compounds and anti-transplanted tumor agents containing the same |
US5484778A (en) * | 1990-07-17 | 1996-01-16 | University Hospitals Of Cleveland | Phthalocyanine photosensitizers for photodynamic therapy and methods for their use |
US5910485A (en) * | 1996-01-31 | 1999-06-08 | Japan Science And Technology Corporation | Antitumor agents comprising as the principal compounds containing silicon and nitrogen |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL100405B1 (en) * | 1975-05-23 | 1978-10-31 | METHOD OF MAKING NEW TETRAKIS- / TROYALKILOAMINO / ALCOXY / SILANE AND TETRAKIS- / DUALKILOAMINO / ALCOXY / SILANO CHLORIDE | |
DE3047443A1 (en) * | 1980-12-17 | 1982-07-22 | Bayer Ag, 5090 Leverkusen | MOLDED STABILIZERS AGAINST THERMOLYSIS WITH LOW MONOMER CONTENT |
JPH08311078A (en) * | 1995-05-17 | 1996-11-26 | Yokohama Rubber Co Ltd:The | Production of oxazolidinesilyl ether compound |
JPH1053759A (en) * | 1996-08-12 | 1998-02-24 | Toyo Ink Mfg Co Ltd | Organic electroluminescent element material and organic electroluminescent element prepared therefrom |
-
2001
- 2001-03-23 DE DE10114106A patent/DE10114106C1/en not_active Expired - Fee Related
-
2002
- 2002-02-15 WO PCT/EP2002/001654 patent/WO2002076994A1/en not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4278666A (en) * | 1979-03-12 | 1981-07-14 | Shin-Etsu Chemical Co., Ltd. | Novel organosilicon compounds and anti-transplanted tumor agents containing the same |
US5484778A (en) * | 1990-07-17 | 1996-01-16 | University Hospitals Of Cleveland | Phthalocyanine photosensitizers for photodynamic therapy and methods for their use |
US5484778C1 (en) * | 1990-07-17 | 2001-05-08 | Univ Cleveland Hospitals | Phthalocynine photosensitizers for photodynamic therapy and methods for their use |
US5910485A (en) * | 1996-01-31 | 1999-06-08 | Japan Science And Technology Corporation | Antitumor agents comprising as the principal compounds containing silicon and nitrogen |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10218312C1 (en) * | 2002-04-24 | 2003-10-23 | Faustus Forschungs Cie | New bis-(amino-hydrocarbyloxy or N-containing heterocyclyloxy)-silicon compounds, useful as anticancer agents |
Also Published As
Publication number | Publication date |
---|---|
WO2002076994A1 (en) | 2002-10-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0240829A2 (en) | Carcinostatic agent | |
DE10103565B4 (en) | Compositions containing a ruthenium (III) complex and a heterocycle | |
EP0191096A1 (en) | Ruthenium compounds having a tumor inhibiting activity. | |
EP1984005B1 (en) | Use of gallium(iii) complexes for the treatment of melanomas | |
DE10141528A1 (en) | Platinum (II) and platinum (IV) complexes and their use | |
DE3518447A1 (en) | TITANOCEN COMPLEXES AND THEIR USE AS CYTOSTATICA IN CANCER FIGHTING | |
DE10114222C1 (en) | Tropolonato-silicon derivatives useful for the prevention and treatment of cancers | |
DE10114106C1 (en) | New quaternary ammonio-substituted orthosilicate esters, useful as anticancer agents having strong activity against a broad spectrum of human tumor cell lines | |
EP0073502B1 (en) | Metal complexes having an antineoplastic activity, and medicaments containing these complexes | |
DE10138561B4 (en) | Tumor-inhibiting cerium compounds and their use | |
DE10113185A1 (en) | Composition containing a gallium (III) complex and a therapeutically active platinum complex | |
DE10138538C2 (en) | Anti-tumor lanthanum compounds | |
DE10116527C2 (en) | Tumor-inhibiting gallium compounds, their use as a medicament and a medicament containing them | |
WO2006110931A1 (en) | Use of gallium (iii) complexes for treating tumours of the liver | |
AT505367A1 (en) | New ruthenium and osmium-thiosemicarbazonato complex, useful as a drug and for preparing a medicament to treat and prevent cancer, preferably ovarian cancer, breast cancer, lung cancer and colon cancer | |
WO1984003042A1 (en) | Process for producing therapeutical antineoplastic preparations | |
DE10218312C1 (en) | New bis-(amino-hydrocarbyloxy or N-containing heterocyclyloxy)-silicon compounds, useful as anticancer agents | |
DE10226592A1 (en) | Anti-tumor platinum (II) oxalato complexes | |
WO2004075887A1 (en) | Use of 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)-urea for the treatment of pancreatic cancer, soft-tissue sarcoma, testicular tumors, lymphoma, thymoma, wilm's tumors, renal carcinoma, melanoma, lung cancer, intracerebral metastasis, tumors in the head and neck region, and mammary carcinoma | |
DE3048109A1 (en) | Antitumour medicaments contg. metal complexes - comprising beta-di:ketone complexes of tin, titanium, zirconium or hafnium | |
DE3037665A1 (en) | Antitumour medicaments contg. metal complexes - comprising beta-di:ketone complexes of tin, titanium, zirconium or hafnium | |
DE2825322A1 (en) | 1-Alkyl-piperidine (N)-oxide derivs. - useful as CNS stimulants and tremorine antagonists | |
DE3115919A1 (en) | Antineoplastic transition metal complexes and medicaments containing them | |
DE3400435A1 (en) | ANTINEOPLASTIC PLATINUM-KRONENETHER COMPLEXES AND MEDICINAL PRODUCTS CONTAINING THEM | |
DE19701692A1 (en) | Anticancer pharmaceutical composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
8100 | Publication of the examined application without publication of unexamined application | ||
D1 | Grant (no unexamined application published) patent law 81 | ||
8364 | No opposition during term of opposition | ||
8339 | Ceased/non-payment of the annual fee |