DE3400435A1 - ANTINEOPLASTIC PLATINUM-KRONENETHER COMPLEXES AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents
ANTINEOPLASTIC PLATINUM-KRONENETHER COMPLEXES AND MEDICINAL PRODUCTS CONTAINING THEMInfo
- Publication number
- DE3400435A1 DE3400435A1 DE19843400435 DE3400435A DE3400435A1 DE 3400435 A1 DE3400435 A1 DE 3400435A1 DE 19843400435 DE19843400435 DE 19843400435 DE 3400435 A DE3400435 A DE 3400435A DE 3400435 A1 DE3400435 A1 DE 3400435A1
- Authority
- DE
- Germany
- Prior art keywords
- crown ether
- platinum
- mono
- complexes
- crown
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229940126601 medicinal product Drugs 0.000 title description 4
- 230000000118 anti-neoplastic effect Effects 0.000 title description 3
- -1 bicyclic crown ether Chemical class 0.000 claims abstract description 31
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical class [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 22
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000003983 crown ethers Chemical class 0.000 claims abstract description 18
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 15
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 8
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- UOUDIVQOIUZSDB-UHFFFAOYSA-M chloroplatinum(1+) Chemical compound [Pt+]Cl UOUDIVQOIUZSDB-UHFFFAOYSA-M 0.000 claims 1
- 230000001085 cytostatic effect Effects 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- 150000001412 amines Chemical group 0.000 abstract 1
- 150000001450 anions Chemical class 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 10
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229960004316 cisplatin Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 239000000824 cytostatic agent Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- HMSWAIKSFDFLKN-UHFFFAOYSA-N hexacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC HMSWAIKSFDFLKN-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
- VHQQPFLOGSTQPC-UHFFFAOYSA-N pentatriacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC VHQQPFLOGSTQPC-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
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- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 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
- NLMDJJTUQPXZFG-UHFFFAOYSA-N 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane Chemical compound C1COCCOCCNCCOCCOCCN1 NLMDJJTUQPXZFG-UHFFFAOYSA-N 0.000 description 1
- LIQFCELSAWJXJN-UHFFFAOYSA-N 1,4,10,13-tetraoxa-7,16-dithiacyclooctadecane Chemical compound C1COCCSCCOCCOCCSCCO1 LIQFCELSAWJXJN-UHFFFAOYSA-N 0.000 description 1
- HELCSRZMDRYPIJ-UHFFFAOYSA-N 1,4,7,10,13,16-hexathiacyclooctadecane Chemical compound C1CSCCSCCSCCSCCSCCS1 HELCSRZMDRYPIJ-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
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- HDLXPNDSLDLJHF-UHFFFAOYSA-N 4,7,13,16,21-pentaoxa-1,10-diazabicyclo[8.8.5]tricosane Chemical compound C1COCCOCCN2CCOCCOCCN1CCOCC2 HDLXPNDSLDLJHF-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 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 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 241000819038 Chichester Species 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 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 1
- 240000007817 Olea europaea Species 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 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
- 239000000654 additive Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 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 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002739 cryptand Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- YSSSPARMOAYJTE-UHFFFAOYSA-N dibenzo-18-crown-6 Chemical compound O1CCOCCOC2=CC=CC=C2OCCOCCOC2=CC=CC=C21 YSSSPARMOAYJTE-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- RVRCFVVLDHTFFA-UHFFFAOYSA-N heptasodium;tungsten;nonatriacontahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W] RVRCFVVLDHTFFA-UHFFFAOYSA-N 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229920005568 monocyclic polymer Polymers 0.000 description 1
- QHMGJGNTMQDRQA-UHFFFAOYSA-N n-Dotriacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC QHMGJGNTMQDRQA-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000005292 ovarian small cell carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- LZFIOSVZIQOVFW-UHFFFAOYSA-N propyl 2-hydroxybenzoate Chemical class CCCOC(=O)C1=CC=CC=C1O LZFIOSVZIQOVFW-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Antineoplastisch wirkende Platin-KronenetherAntineoplastic platinum crown ethers
Komplexe und diese enthaltende Arzneimittel Antineopl asti sch wirkende Pl ati n-Kronenether-Kompl exe und diese enthaltende Arzneimittel Technisches Gebiet Die Erfindung bezieht sich auf antineol,lastisch wirkende Platin-Kronenether-Kompl exe und diese enth 1 tende Arzneimittel.Complex and medicinal products containing them Antineopl astic acting platinum crown ether compl exes and drugs containing them Technical Field The invention relates to antineol, resilient platinum crown ether compl exe and medicinal products containing them.
Stand der Technik Kürzlich wurde ein die Komplexverbindung cis-Diammindichloroplatin(II) enthaltendes Arzneimittel als Chemotherapeutikum gegen Krebs in den Handel gebracht. Diese unter dem International Nonproprietary Name (INN) Cisplatin bekannte Verbindung hat sich als äußerst potentes Antitumormittel, insbesondere bei der Behandlung von Hodentumoren, aber auch z.B. von Eierstocktumoren und kleinzelligen Bronchialkarzinomen erwiesen.Background Art Recently, the complex compound cis-diamminedichloroplatinum (II) drug containing as a chemotherapeutic agent for cancer brought on the market. This compound known by the International Nonproprietary Name (INN) cisplatin has proven to be an extremely potent anti-tumor agent, especially in the treatment of Testicular tumors, but also e.g. from ovarian tumors and small-cell bronchial carcinomas proven.
Nachteilig an Cisplatin ist seine relativ große Toxizität. Besonders gravierend sind seine Knochenmarkstoxizität.The disadvantage of cisplatin is its relatively high toxicity. Particularly its bone marrow toxicity is serious.
Es wurden in letzter Zeit zahlreiche andere Platinkomplexe (DE-OS 24 45 418, DE-OS 28 37 237, DE-OS 26 26 559, DE-OS 25 39 179) und Komplexverbindungen anderer Obergangsmetalle als cytostatisch wirkende Mittel vorgeschlagen.Numerous other platinum complexes (DE-OS 24 45 418, DE-OS 28 37 237, DE-OS 26 26 559, DE-OS 25 39 179) and complex compounds other transition metals proposed as cytostatic agents.
Es ist bekannt, daß bestimmte Kronenether eine bakteriostatische und virustatische Wirksamkeit zeigen, wofür ihre Fähigkeit zur Bildung von Komplexen mit Metallen verantwortlich gemacht wird. Ferner wurden Oberlegungen angestellt, die Spezifität einiger Kronenether für Alkali- und Erdalkaliionen für die Beeinflussung des Mi neral stoffwechsels des menschlichen und tierischen Körpers auszunutzen. It is known that certain crown ethers are bacteriostatic and virustatic efficacy show what their ability to form complexes is held responsible with metals. Furthermore, considerations were made, the specificity of some crown ethers for alkali and alkaline earth ions for influencing the mineral metabolism of the human and animal body.
Beschreibung der Erfindung Oberraschend wurde nun gefunden, daß Platin-Kronenether-Komplexe der allgemeinen Formel I, [A Pt x2]y2 (I), worin A einen mono- oder bicyclischen Kronenether, A Ammoniak oder ein Mono- oder Di-C1-C4-alkylamin und Y Halogen bedeuten, eine dem Cisplatin zumindest gleichwertige cytostatische Wirksamkeit bei geringerer Toxität aufweisen. Gleichzeitig ist ihre Wasserlöslichkeit bedeutend größer als die von Cisplatin, was ihre therapeutische Verwendung sehr erleichtert. Diese Platin-Kronenether-Komplexe sind daher für die Behandlung von Krebskrankheiten sehr geeignet.Description of the invention It has now surprisingly been found that platinum-crown ether complexes of the general formula I, [A Pt x2] y2 (I), in which A is mono- or bicyclic Crown ether, A is ammonia or a mono- or di-C1-C4-alkylamine and Y is halogen, a cytostatic effectiveness at least equivalent to that of cisplatin with a lower one Exhibit toxicity. At the same time, their solubility in water is significantly greater than that of cisplatin, which greatly facilitates its therapeutic use. These platinum crown ether complexes are therefore very suitable for the treatment of cancer diseases.
Gegenstand der Erfindung sind daher die neuen Platinkronenether-Komplexe der vorstehenden Formel I, worin A, X und Y die vorstehend angegebenen Bedeutungen haben und sie enthaltende Arzneimittel, insbesondere solche zur Behandlung von Krebskrankheiten.The invention therefore relates to the new platinum crown ether complexes of the above formula I, in which A, X and Y have the meanings given above and medicinal products containing them, in particular those for the treatment of cancer diseases.
Ein bevorzugter Gegenstand der Erfindung sind Platin-Kronenether-Komplexe der allgemeinen Formel I, worin A einen mono- oder bicyclischen Kronenether, X Ammoniak und Y Chlor bedeuten.A preferred subject of the invention are platinum-crown ether complexes of the general formula I, in which A is a mono- or bicyclic crown ether, X is ammonia and Y mean chlorine.
Besonders bevorzugt ist der Pl atin-Kronenether-Koiipl ex [183 Krone( 6 )ci sdiammindichloroplatin(II).Particularly preferred is the platinum-crown-ether-koiipl ex [183 crown ( 6) ci sdiammine dichloroplatinum (II).
Unter Cl-C4-Alkyl wird ein geradkettiger oder verzweigter Alkylrest mit 1 bis 4 Kohlenstoffatomen verstanden, wobei geradkettige Alkylreste bevorzugt sind. Besonders bevorzugt ist der Methylrest.Cl-C4-alkyl is a straight-chain or branched alkyl radical Understood having 1 to 4 carbon atoms, straight-chain alkyl radicals being preferred are. The methyl radical is particularly preferred.
Unter Halogen wird Fluor, Chlor, Brom und Iod verstanden, wobei Fluor, Chlor und Brom bevorzugt sind. Besonders bevorzugt ist Chlor.Halogen is understood to mean fluorine, chlorine, bromine and iodine, where fluorine, Chlorine and bromine are preferred. Chlorine is particularly preferred.
Unter Kronenether werden nicht nur die monocyclischen Polymeren von Ethylenglykol (-OCH2CH2)n, deren Benzo-substituierten Derivate und Thiaanaloge verstanden, sondern auch solche, in denen die Länge der Alkylenbrücken variiert und/oder solche in denen die Ethersauerstoffatome teilweise oder ganz durch Stickstoffatome ersetzt sind und/oder solche, die heteroaromatische Systeme, wie z.B. Pyridin-, Furan- oder Thiophen-Ringe, umfassen. Solche Kronenether werden im englischen Sprachgebrauch als "coronands" und die entsprechenden Komplexe als coronates" bezeichnet.Crown ethers not only refer to the monocyclic polymers of Ethylene glycol (-OCH2CH2) n, their benzo-substituted derivatives and thia analogs understood, but also those in which the length of the alkylene bridges varies and / or those in which the ether oxygen atoms are partially or wholly replaced by nitrogen atoms are and / or those that have heteroaromatic systems, such as pyridine, furan or Thiophene rings. Such crown ethers are used in English referred to as "coronands" and the corresponding complexes as coronates ".
Weiterhin werden im Zusammenhang mit dieser Erfindung unter Kronenether auch bicyclische Diammine, in denen die beiden Stickstoffatome durch Polyethylenoxybrücken verbunden sind, verstanden. Kronenether dieses Strukturtyps werden als "cryptands" und deren Komplexe als "cryptates" bezeichnet. Einen Oberblick über Kronenether und deren Darstellung ist beispielsweise zu finden bei D.A. Laidler und J.F.Furthermore, in connection with this invention, crown ethers also bicyclic diammines, in which the two nitrogen atoms are bound by polyethyleneoxy bridges connected, understood. Crown ethers of this structure type are called "cryptands" and their complexes called "cryptates". An overview of the crown ethers and their representation can be found, for example, at D.A. Laidler and J.F.
Stoddart, "Synthesis of crown ethers and analogues" in Supplement E., The chemistry of ethers, crown ethers, hydroxyl yroups and their sulphur analogues, Part 1, Herausgeber Saul Patai, John Wiley % Sons 1980, Chichester, New York, Brisbane, Toronto, Seite 1 bis 57.Stoddart, "Synthesis of crown ethers and analogues" in Supplement E., The chemistry of ethers, crown ethers, hydroxyl yroups and their sulfur analogues, Part 1, editors Saul Patai, John Wiley% Sons 1980, Chichester, New York, Brisbane, Toronto, pages 1 to 57.
Im Rahmen der vorliegenden Erfindung kommen als Kronenether beispielsweise in Betracht: [1BJKrone(6) (IUPAC-Nomenklatur: 1,4,7,10,13,16-Hexaoxacyclooctadecan); [152Krone(5); 2,3-Benzo-1 ,4,7,10,13-pentaoxacyclopentadecen-2; 2,3-Monocyclohexyl-1 ,4,7,10,13-pentaoxacyclopentadecan; [12]Krone(4); 2,3,11,12-Dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-dien; 2,3,11,12-Dicyclohexyl-1,4,7,10,13sl6-hexaoxacyclooctadecan; 2,3,14,15-Dibenzo-1 ,4,7,1O,13,16,19,22-octaoxacyclotetracosan-2,14-dien; 2,3,14,15-Dicyclohexyl-1 ,4,7,10,13,16,19,22-octacyclotetracosan; 1 ,4,10,13-Tetraoxa-7,16-dithiacyclooctadecan Ol,04 >04,010,013,57,516; 1,4,7,10,13,16-Hexathiacyclooctadecan; Hexaoxadiazabicyclo [8.8.8.]hexacosan( Kryptofi xC'222) ; 4,7,13,16-Tetraoxa-1,10-diazacyclooctadecan(Kryptofix 221); Heptaoxadiazabicycl o [8.8.11. loctacosan(Kryptofi x'322); Octaoxadiazabicyclo[8.11.11.]dotriacontan(Kryptofix 332); Nonaoxodiazabicyclo[11.11.11.]pentatriacontan(Krpytofix 333).In the context of the present invention, for example, crown ethers are used contemplated: [1BJKrone (6) (IUPAC nomenclature: 1,4,7,10,13,16-hexaoxacyclooctadecane); [152crown (5); 2,3-benzo-1, 4,7,10,13-pentaoxacyclopentadecene-2; 2,3-monocyclohexyl-1 , 4,7,10,13-pentaoxacyclopentadecane; [12] crown (4); 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene; 2,3,11,12-dicyclohexyl-1,4,7,10,13s16-hexaoxacyclooctadecane; 2,3,14,15-dibenzo-1 , 4,7,1O, 13,16,19,22-octaoxacyclotetracosane-2,14-diene; 2,3,14,15-dicyclohexyl-1, 4,7,10,13,16,19,22-octacyclotetracosane; 1, 4,10,13-tetraoxa-7,16-dithiacyclooctadecan Ol, 04> 04,010,013,57,516; 1,4,7,10,13,16-hexathiacyclooctadecane; Hexaoxadiazabicyclo [8.8.8.] Hexacosane (Kryptofi xC'222); 4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (Kryptofix 221); Heptaoxadiazabicycl o [8.8.11. loctacosan (Kryptofi x'322); Octaoxadiazabicyclo [8.11.11.] Dotriacontan (Kryptofix 332); Nonaoxodiazabicyclo [11/11/11] pentatriacontane (Krpytofix 333).
Bevorzugt kommen Kronenether in Betracht, deren Komplexbildungstendenzen mit Platin(II) durch die Anordnung der für die Ausbildung der koordinativen Bindungen verantwortlichen Heteroatome besonders ausgeprägt sind. Zur Bildung erfindungsgemäßer Platin-Kronenether-Komplexe sind u.a. insbesondere solche Kronenether geeignet, deren "innere Höhle" einen solchen Durchmesser aufweist, daß die Heteroatome ohne zu große sterische Hinderung mit dem Platin(II) koordinieren können. Bevorzugte erfindungsgemäße Platin-Kronenether-Komplexe sind daher solche, bei denen die Kronenether-Komponente einen inneren Durchmesser von 2,2 bis 4, vorzugsweise 2,6 bis 3,2 A aufweist.Crown ethers and their complex-forming tendencies are preferred with platinum (II) by the arrangement of the for the formation of the coordinative bonds responsible heteroatoms are particularly pronounced. To form inventive Platinum-crown ether complexes are particularly suitable, among others, those crown ethers, whose "inner cavity" has such a diameter that the heteroatoms without too great steric hindrance can coordinate with the platinum (II). Preferred Platinum crown ether complexes according to the invention are therefore those in which the crown ether component has an inner diameter of 2.2 to 4, preferably 2.6 to 3.2 Å.
Die Herstellung der erfindungsgeilìälSen Verbindungcn erfolgt durch Umsetzen des entsprechenden Cisdiamminplatin(II)dihalogenids mit dem entsprechenden Kronenether. Es ist vorteilhaft, die Umsetzung in einem Lösungsmittel am Rückfluß durchzuführen. In den meisten Fällen ist es günstiger, das Reaktionsprodukt aus dem Reaktionsgemisch durch vorsichtige Zugabe geeigneter inerter Lösungsmittel, wie beispielsweise n-Hexan oder Petrolether, auszufällen, als es durch Einengen des Reaktionsgemisches zu isolieren.The connections according to the invention are produced by Reacting the corresponding cisdiammine platinum (II) dihalide with the corresponding Crown ether. It is advantageous to reflux the reaction in a solvent perform. In most cases it is more beneficial to take the reaction product off the reaction mixture by carefully adding suitable inert solvents, such as n-hexane or petroleum ether, as it precipitates by concentration to isolate the reaction mixture.
Gegenstand der Erfindung ist auch ein Verfahren zur Herstellung der Platinkronenether-Komplexe der allgemeinen Formel I [A Pt X2]Y2 (I), worin A einen mono- oder bicyclischen Kronenether, X Ammoniak oder ein Mono- oder Di-C1-C4-alkylamin und Y Halogen bedeuten, dadurch gekennzeichnet, daß man den Kronenether A mit einer Verbindung PtX2Y2 umsetzt.The invention also provides a method for producing the Platinum crown ether complexes of the general formula I [A Pt X2] Y2 (I), wherein A is a mono- or bicyclic crown ether, X ammonia or a mono- or di-C1-C4-alkylamine and Y mean halogen, characterized in that the crown ether A with a Connection PtX2Y2 implements.
Die erfindungsgemäßen Arzneimittel werden vor allem i)t r4iv(iis , auch intramuskulär, intraperitoneal , stibkutan, rektal oder peroral vcrabreicht. Auch eine äußerliche Applikation ist mglichs Bevorzugt ist die Verabreichung durch intravenöse Injektion oder intravenöse Infusion.The medicaments according to the invention are primarily i) t r4iv (iis, also administered intramuscularly, intraperitoneally, stibcutaneously, rectally or orally. External application is also possible. Administration through is preferred intravenous injection or intravenous infusion.
Die Arzneimittel werden nach an sich bekannten Verfahren hergestellt, wobei die Komplexverbindungen als solche oder gegebenenfalls in Kombination mit geeigneten pharmazeutischen Tragerstoffen eingesetzt werden. Enthalten die neuen pharmazeutischen Zubereitungen neben dem Wirkstoff pharmazeutische Trägerstoffe, beträgt der Wirkstoffgehalt dieser Mischungen 0,1 bis 99,5, vorzugsweise 0,5 bis 95 Gewichtsprozent der Gesamtmischung.The pharmaceuticals are manufactured according to processes known per se, wherein the complex compounds as such or optionally in combination with suitable pharmaceutical carriers are used. Include the new pharmaceutical preparations in addition to the active ingredient pharmaceutical carriers, the active ingredient content of these mixtures is 0.1 to 99.5, preferably 0.5 to 95 percent by weight of the total mixture.
Die pharmazeutischen Zubereitungen gemäß der Erfindung können, wenn sie in Einheitsdosen vorliegen und für die Applikation z.B. am Menschen bestimmt sind, etwa 0,1 bis 500 mg, vorteilhafterweise 10 bis 200 mg und insbesondere 50 bis 150 mg Wirkstoff enthalten.The pharmaceutical preparations according to the invention can, if they are available in unit doses and are intended for use on humans, for example are, about 0.1 to 500 mg, advantageously 10 to 200 mg and especially 50 contain up to 150 mg of active ingredient.
Im allgemeinen erweist es sich in der Humanmedizin als vorteilhaft, Aen oder die Wirkstoffe bei parenteraler Gabe in einer Tagesdosis von etwa 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 zu verabreichen. Eine Einzelgabe enthält den oder die Wirkstoffe in zungen von etwa 0,1 bis etwa 5, vorzugsweise 1 bis 3 mg/kg Körpergewicht. Bei einer oralen Behandlung können ähnliche Dosierungen zur Anwendung kommen.In general, it is advantageous in human medicine to Aen or the active ingredients in the case of parenteral administration in a daily dose of about 0.1 to 5, preferably 1 to 3 mg / kg of body weight, optionally in the form of several, preferably Administer 1 to 3 single doses to achieve the desired results. One Single dose contains the active ingredient (s) in tongues from about 0.1 to about 5, preferably 1 to 3 mg / kg body weight. For oral treatment, similar dosages can be used come into use.
Wie bei der internistischen Tumortherapie üblich, kann zur Reduzierung des Nebenwirkungsrisikos die Behandlung mit den erfindungsgemäßen Arzneimitteln kombiniert werden mit der Verabreichung anderer Cytostatica mit unterschiedlichen Wirkungsspektren. Es kann auch zweckmäßig sein, die Behandlung nach dem Prinzip.der zyklischen Cytostaticatherapie durchzu- führen. Hierbei wird nach jeder Behandlung eine Erliolungsphase eingelegt. Man macht sich dabei die Erfahrung zunutze, daß gesundes Gewebe der meisten Organe schneller regeneriert als malignes Gewebe.As is usual with internal tumor therapy, it can be used to reduce the risk of side effects, treatment with the medicaments according to the invention can be combined with the administration of other cytostatics with different Spectra of activity. It can also be useful to treat the treatment according to the principle cyclic cytostatic therapy to lead. Here is after every treatment has a recovery phase. You get the experience take advantage of the fact that healthy tissue in most organs regenerates faster than malignant tissue Tissue.
Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoff kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.Determining the optimal dosage required in each case and The active ingredient can be administered by any person skilled in the art on the basis of his or her specialist knowledge easily done.
Die pharmazeutischen Zubereitungen bestehen in der Regel aus den Komplexverbindungen und nichttoxischen, pharmazeutisch verträglichen Arzneimittelträgern, die als Zumischung oder Verdünnungsmittel in fester, halbfester oder flüssiger Form oder als Umhüllungsmittel, beispielsweise in Form einer Kapsel, eines Tablettenüberzugs, eines Beuteis oder eines anderen Behältnisses, für den therapeutisch aktiven Bestandteil in Anwendung kommen. Ein Tragerstoff kann z.B. als Vermittler für die Arzneimittel aufnahme durch den Körper, als Formulierungshilfsmittel, als SüBungsmittel. als Geschmackskorrigens, -als Farbstoff oder als Konservierungsmittel dienen.The pharmaceutical preparations usually consist of the complex compounds and non-toxic, pharmaceutically acceptable excipients that are used as admixtures or diluents in solid, semi-solid or liquid form or as a coating agent, for example in the form of a capsule, a tablet coating, an egg or another container for the therapeutically active ingredient in use come. A carrier material can, for example, act as a mediator for drug absorption through the body, as a formulation aid, as a sweetener. as a taste corrector, - Serve as a coloring agent or as a preservative.
Wäßrige Suspensionen können Suspendiermittel, z.B. Natriumcarboxymethylcellulose, Methylcellulose, Hydroxypropylcellulose, Natriumalkinat, Polyvinylpyrrolidon, Traganthgummi oder Akaziengummi; Dispergier- und Benetzungsmittel, z.B. Polyoxyethylenstearat, Heptadecaethylenoxycetanol, Polyoxyethylensorbitanfettsäureester, wie z.B.Aqueous suspensions can contain suspending agents, e.g. sodium carboxymethyl cellulose, Methyl cellulose, hydroxypropyl cellulose, sodium alkynate, polyvinylpyrrolidone, gum tragacanth or acacia gum; Dispersing and wetting agents, e.g. polyoxyethylene stearate, Heptadecaethyleneoxycetanol, polyoxyethylene sorbitan fatty acid esters, e.g.
olyoxyethylensorbitanmonooleat, sowie Lecithin, Konservierungsmittel, z.B. Methyl- oder Propylhydroxybenzoate; Geschmacksmittel; Sußungsmittel, z.B. Saccharose, Lactose, Natriumcyclamat, Dextrose, Invertzuckersirup enthalten.olyoxyethylene sorbitan monooleate, as well as lecithin, preservatives, e.g., methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. sucrose, Contains lactose, sodium cyclamate, dextrose, invert sugar syrup.
Emulsionen können z.B. Oliven-, ErdnuB- oder Paraffinöl neben Emulgiermitteln, wie z.B. Akaziengummi, Traganthgummi, Phosphatiden, Sorbitanmonooleat, Polyoxyethylensorbitanmonooleat, und Si'ßungs- und Geschmacksmittel enthalten.Emulsions can e.g. olive, peanut or paraffin oil in addition to emulsifiers, such as gum acacia, gum tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and contain sweeteners and flavorings.
lur parcnteralcn Anwendung der Arzneistoffe dienen steril injizierbare zdDrige Suspensionen, isotonische Salzlösungen oder sonstige Lösungen, die Dispergier- oder Benetzungsmittel und/der pharmakologisch verträgliche Verdünnungsmittel, z.B. Propylen- oder Butylenglykol, und/oder Lösungsvermittler, z.B. Tweene, Cremophores oder Polyvinylpyrrolidon, enthalten.lur parcnteralcn application of the medicinal substances are used sterile injectable zdry suspensions, isotonic saline solutions or other solutions that disperse or wetting agents and / the pharmacologically acceptable diluents, e.g. Propylene or butylene glycol and / or solubilizers, e.g. Tweene, Cremophores or polyvinylpyrrolidone.
Die Wirkstoffe können gegebenenfalls mit einem oder mehreren der angegebenen Trager- oder Zusatzstoffe audh in mikroverkapselter Form formuliert werden.The active ingredients can optionally with one or more of the specified Carriers or additives can also be formulated in microencapsulated form.
Das folgende Beispiel erläutert die Erfindung näher, ohne sie einzuschränken.The following example explains the invention in more detail without restricting it.
Herstel 1 ungsbei spiel [18]Krone(6)cis-diammin-dichloroplatin(II) 2,09 g (7mMol)Cisdiammindichloroplatin(II) und 1,85 g (7mMol) t18]Krone(6) werden 10 Stunden in Aceton oder Chloroform am Rückfluß erhitzt. Die leicht gelbgefärbte Reaktionslösung wird von nicht umgesetzten Cisdiammindichloroplatin(II) abfiltriert und bis zur beginnenden Trübung mit n-Hexan oder Petrolether versetzt. Falls man zuviel n-Hexan oder Petrolether zusetzt, fällt die Titelverbindung als gelbes schmieriges U1 aus, das aber durch Zugabe von Methanol oder Aceton leicht wieder in Lösung gebracht werden kann. Man erhält gelbe Kristalle vom Schmelzpunkt 235°C.Production example [18] crown (6) cis-diammine-dichloroplatinum (II) 2.09 g (7 mmol) of cisdiammine dichloroplatinum (II) and 1.85 g (7 mmol) of t18] crown (6) Heated under reflux in acetone or chloroform for 10 hours. The slightly yellow-colored The reaction solution is filtered off from the unreacted cisdiammine dichloroplatinum (II) and n-hexane or petroleum ether are added until the cloud starts to become cloudy. If you too much n-hexane or petroleum ether is added, the title compound falls as a yellow greasy U1 from, but easily redissolved by adding methanol or acetone can be. Yellow crystals with a melting point of 235 ° C. are obtained.
Ausbeute: 0,4 g (10D der Titelverbindung) Analyse: C12H2806N2Cl2Pt Berechnet: 25,63% C; 5,02% H; 4,98% N; 34,71% Pt Gefunden: 25,82% C; 5,59% H; 4,75% N; 34,10% Pt.Yield: 0.4 g (10D of the title compound) Analysis: C12H2806N2Cl2Pt Calculated: 25.63% C; 5.02% H; 4.98% N; 34.71% Pt Found: 25.82% C; 5.59% H; 4.75% N; 34.10% pt.
P h I r r m a k o 1 o g i P 3t Leukäinie-Modell Ca. 4 Wochen alten 18 bis 20 g schweren weiblichen BDF1 -Mäusen werden ca.P h I r r m a k o 1 o g i P 3t Leukäinie model approx. 4 weeks old Female BDF1 mice weighing 18 to 20 g are approx.
106 P 388-Leukämiezellen in 0,2 ml physiologischer Kochsalzlösung intraperitoneal (i;p.) übertragen. Die Leukämie wird auf DBA/2-Mäusen in Passage gehalten. Die Leukämiezellen werden frisch getöteten Tieren unmittelbar vor der Transplantation entnommen. Beim Oberimpfen werden die Tiere randomisiert. Pro Dosierung werden 3 bis 6 Mäuse verwendet.106 P 388 leukemia cells in 0.2 ml of physiological saline solution transferred intraperitoneally (i; p.). The leukemia is in passage on DBA / 2 mice held. The leukemia cells are freshly sacrificed immediately before the animals Transplant removed. The animals are randomized when they are over-vaccinated. Per dosage 3 to 6 mice are used.
Die Anzahl der Kontrollgruppen (unbehandelte Tiere) wird bei umfangreicheren Versuchen so gewähit, daß sie in etwa der Quadratzahl aus der Gesamtzahl der Gruppen entspricht. Die Substanzen werden als wässrige Lösungen, falls notwendig unter Zuhilfenahme von Lösungsvermittlern beispielsweise Tween'"' (Polyoxyethylenderivate von Sorbitanestern), jeweils 24 Stunden nach der Transplantation intraperitoneal gespritzt.The number of control groups (untreated animals) is larger in the case of larger ones Try so that they are roughly the square number of the total number of groups is equivalent to. The substances are provided as aqueous solutions, if necessary with the aid of solubilizers, for example Tween '"' (polyoxyethylene derivatives of sorbitan esters), injected intraperitoneally 24 hours after transplantation.
Die Versuchsbedingungen entsprechen dem P 388-Leukämie-Modell des US-amerikanischen National Cancer Institute (NCI). Im Gegensatz zum Modell des NCI wird im vorliegenden Fall die Substanz nur einmal appliziert.The test conditions correspond to the P 388 leukemia model of the US National Cancer Institute (NCI). In contrast to the NCI model In the present case, the substance is applied only once.
In der nachfolgenden Tabelle I sind Ergebnisse aus dem beschriebenen P 388-Leukämiemodell zusammengestellt. Die angegebene Dosis wurde einmalig zu Beginn des Versuchs wle angegeben appliziert. Der in Prozent angegebene Faktor T/C bedeutet die prozentuale Verlängerung der medianen Oberlebenszeit der unbehandelten Kontrolltiere.In the following Table I are results from the described P 388 leukemia model compiled. The dose indicated was a one-off at the beginning of the experiment as indicated. The factor T / C given in percent means the percentage increase in the median survival time of the untreated control animals.
Der Versuch wird abgebrochen, sobald die mediane Oberlebenszeit T/C der behandelten Tiere 300 Z, der medianen Oberlebenszeit der unbehandelten Tiere erreicht hat. Zur Berechnung der medianen Oberlebenszeit werden die bei Versuchsende noch lebenden Tiere als bei Versuchsende gestorben berücksichtigt. Nach den T/C-Werten ist in Klammern die Zahl der bei Versuchsende geheilten Tiere und die Zahl der Tiere pro Gruppe angegeben.The experiment is terminated as soon as the median survival time T / C of the treated animals 300 Z, the median survival time of the untreated animals has reached. To calculate the median survival time, those at the end of the experiment animals still alive are considered as having died at the end of the experiment. According to the T / C values is in brackets the number of animals cured at the end of the experiment and the number of animals specified per group.
Tabelle I
Während bei den angewendeten Dosen mit Cisplatin keine Heilungen erreicht werden, werden durch die erfindungsgemäßen Verbindungen Heilungen beobachtet.While at the doses used with cisplatin no cures were achieved cures are observed by the compounds of the invention.
Claims (7)
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843400435 DE3400435A1 (en) | 1984-01-09 | 1984-01-09 | ANTINEOPLASTIC PLATINUM-KRONENETHER COMPLEXES AND MEDICINAL PRODUCTS CONTAINING THEM |
| EP85900629A EP0171401A1 (en) | 1984-01-09 | 1985-01-08 | Platinum and crown ether complexes with antineoplastic activity and drug containing them |
| PCT/DE1985/000001 WO1985003078A1 (en) | 1984-01-09 | 1985-01-08 | Platinum and crown ether complexes with antineoplastic activity and drug containing them |
| FI853426A FI853426A7 (en) | 1984-01-09 | 1985-01-08 | Anticancer platinum crown ether complexes and drugs containing them. |
| JP60500472A JPS61501029A (en) | 1984-01-09 | 1985-01-08 | Platinum-coronary ether complex having antitumor effect and pharmaceutical containing the same |
| DE19853524841 DE3524841A1 (en) | 1984-01-09 | 1985-07-09 | ANTINEOPLASTICALLY ACTIVE PLATIN (IV) -CRONENETHER COMPLEX COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| NO853448A NO853448L (en) | 1984-01-09 | 1985-09-02 | ANTINEOPLASTIC EFFECTIVE PLATINO CROONETS COMPLEX AND PHARMACEUTICALS CONTAINING THESE |
| DK405385A DK405385D0 (en) | 1984-01-09 | 1985-09-05 | ANTINEOPLASTIC EFFECTIVE PLATIN CRONEETHER COMPLEXES AND MEDICINES CONTAINING THESE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843400435 DE3400435A1 (en) | 1984-01-09 | 1984-01-09 | ANTINEOPLASTIC PLATINUM-KRONENETHER COMPLEXES AND MEDICINAL PRODUCTS CONTAINING THEM |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3400435A1 true DE3400435A1 (en) | 1985-07-18 |
Family
ID=6224506
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19843400435 Withdrawn DE3400435A1 (en) | 1984-01-09 | 1984-01-09 | ANTINEOPLASTIC PLATINUM-KRONENETHER COMPLEXES AND MEDICINAL PRODUCTS CONTAINING THEM |
| DE19853524841 Ceased DE3524841A1 (en) | 1984-01-09 | 1985-07-09 | ANTINEOPLASTICALLY ACTIVE PLATIN (IV) -CRONENETHER COMPLEX COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19853524841 Ceased DE3524841A1 (en) | 1984-01-09 | 1985-07-09 | ANTINEOPLASTICALLY ACTIVE PLATIN (IV) -CRONENETHER COMPLEX COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0171401A1 (en) |
| JP (1) | JPS61501029A (en) |
| DE (2) | DE3400435A1 (en) |
| DK (1) | DK405385D0 (en) |
| FI (1) | FI853426A7 (en) |
| NO (1) | NO853448L (en) |
| WO (1) | WO1985003078A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ306396B6 (en) * | 2014-12-16 | 2017-01-04 | Vuab Pharma A.S. | Soluble platinum (II) complex with pyridinecarboxamidine ligand and process for its preparation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0051946A1 (en) * | 1980-11-07 | 1982-05-19 | Imperial Chemical Industries Plc | Metal complexes |
-
1984
- 1984-01-09 DE DE19843400435 patent/DE3400435A1/en not_active Withdrawn
-
1985
- 1985-01-08 FI FI853426A patent/FI853426A7/en not_active Application Discontinuation
- 1985-01-08 JP JP60500472A patent/JPS61501029A/en active Pending
- 1985-01-08 WO PCT/DE1985/000001 patent/WO1985003078A1/en not_active Ceased
- 1985-01-08 EP EP85900629A patent/EP0171401A1/en not_active Withdrawn
- 1985-07-09 DE DE19853524841 patent/DE3524841A1/en not_active Ceased
- 1985-09-02 NO NO853448A patent/NO853448L/en unknown
- 1985-09-05 DK DK405385A patent/DK405385D0/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ306396B6 (en) * | 2014-12-16 | 2017-01-04 | Vuab Pharma A.S. | Soluble platinum (II) complex with pyridinecarboxamidine ligand and process for its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| FI853426A0 (en) | 1985-09-06 |
| DK405385A (en) | 1985-09-05 |
| WO1985003078A1 (en) | 1985-07-18 |
| DK405385D0 (en) | 1985-09-05 |
| JPS61501029A (en) | 1986-05-22 |
| FI853426L (en) | 1985-09-06 |
| DE3524841A1 (en) | 1987-01-15 |
| EP0171401A1 (en) | 1986-02-19 |
| NO853448L (en) | 1985-09-02 |
| FI853426A7 (en) | 1985-09-06 |
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