KR940010296B1 - New pt(ñœ)complexes and process for the preparation thereof - Google Patents
New pt(ñœ)complexes and process for the preparation thereof Download PDFInfo
- Publication number
- KR940010296B1 KR940010296B1 KR1019910019969A KR910019969A KR940010296B1 KR 940010296 B1 KR940010296 B1 KR 940010296B1 KR 1019910019969 A KR1019910019969 A KR 1019910019969A KR 910019969 A KR910019969 A KR 910019969A KR 940010296 B1 KR940010296 B1 KR 940010296B1
- Authority
- KR
- South Korea
- Prior art keywords
- bis
- platinum
- dioxolane
- aminomethyl
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 38
- 238000002360 preparation method Methods 0.000 title description 39
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 150000004985 diamines Chemical class 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 150000001924 cycloalkanes Chemical class 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 93
- 229910052760 oxygen Inorganic materials 0.000 claims description 78
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 56
- 239000007864 aqueous solution Substances 0.000 claims description 32
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 32
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 31
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 26
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 20
- 229910001923 silver oxide Inorganic materials 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000003957 anion exchange resin Substances 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 10
- 229920001429 chelating resin Polymers 0.000 claims description 9
- 239000002609 medium Substances 0.000 claims description 9
- 229940023144 sodium glycolate Drugs 0.000 claims description 9
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012736 aqueous medium Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- IVKNYMXGZKPFOJ-UHFFFAOYSA-N [5-(aminomethyl)-1,3-dioxolan-4-yl]methanamine Chemical group NCC1OCOC1CN IVKNYMXGZKPFOJ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- LHTZGIZZJTZRLX-UHFFFAOYSA-N 4,5-bis(azidomethyl)-1,3-dioxolane Chemical compound [N-]=[N+]=NCC1OCOC1CN=[N+]=[N-] LHTZGIZZJTZRLX-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- UUOFRXDFODYHPC-RNFRBKRXSA-N [(4r,5r)-5-(aminomethyl)-2-propan-2-yl-1,3-dioxolan-4-yl]methanamine Chemical compound CC(C)C1O[C@H](CN)[C@@H](CN)O1 UUOFRXDFODYHPC-RNFRBKRXSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000001093 anti-cancer Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 67
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 17
- 230000000259 anti-tumor effect Effects 0.000 abstract description 11
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 abstract 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 abstract 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 abstract 1
- 229910052709 silver Inorganic materials 0.000 abstract 1
- 239000004332 silver Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 51
- 238000005481 NMR spectroscopy Methods 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- 239000007787 solid Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000000377 silicon dioxide Substances 0.000 description 18
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 16
- 229960004316 cisplatin Drugs 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 230000005526 G1 to G0 transition Effects 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 201000011510 cancer Diseases 0.000 description 9
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 9
- 231100000417 nephrotoxicity Toxicity 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 208000032839 leukemia Diseases 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- -1 propyl Butylaldehyde Chemical compound 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- XWDXJLFCNGJHKX-TYSVMGFPSA-N [Pt+2].NC[C@H]1OCO[C@@H]1CN Chemical compound [Pt+2].NC[C@H]1OCO[C@@H]1CN XWDXJLFCNGJHKX-TYSVMGFPSA-N 0.000 description 5
- NIJAWRIBIZBIIQ-UHFFFAOYSA-K [Pt](I)I.[I-].[K+] Chemical compound [Pt](I)I.[I-].[K+] NIJAWRIBIZBIIQ-UHFFFAOYSA-K 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- CBSOEMXPFCVLST-KGZKBUQUSA-N [(4R,5R)-5-(aminomethyl)-2-ethyl-1,3-dioxolan-4-yl]methanamine platinum(2+) Chemical compound [Pt+2].NC[C@H]1OC(O[C@@H]1CN)CC CBSOEMXPFCVLST-KGZKBUQUSA-N 0.000 description 4
- IELGANLONSBBOO-ZJLYAJKPSA-N [(4R,5R)-5-(aminomethyl)-2-propan-2-yl-1,3-dioxolan-4-yl]methanamine platinum(2+) Chemical compound [Pt+2].CC(C)C1O[C@H](CN)[C@@H](CN)O1 IELGANLONSBBOO-ZJLYAJKPSA-N 0.000 description 4
- GNTQMWAVHNZVNK-KGZKBUQUSA-N [Pt+2].NC[C@H]1OC(O[C@@H]1CN)C Chemical compound [Pt+2].NC[C@H]1OC(O[C@@H]1CN)C GNTQMWAVHNZVNK-KGZKBUQUSA-N 0.000 description 4
- BHGJETMSYBGAQM-SCLLHFNJSA-N [Pt].NC[C@H]1OC2(CCCC2)O[C@@H]1CN Chemical compound [Pt].NC[C@H]1OC2(CCCC2)O[C@@H]1CN BHGJETMSYBGAQM-SCLLHFNJSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YGHRJJRRZDOVPD-UHFFFAOYSA-N Isovaleric aldehyde Natural products CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- SINPFJGOXXNQDK-KGZKBUQUSA-N [Pt+2].NC[C@H]1OC(O[C@@H]1CN)(C)C Chemical compound [Pt+2].NC[C@H]1OC(O[C@@H]1CN)(C)C SINPFJGOXXNQDK-KGZKBUQUSA-N 0.000 description 3
- UXWRZHYZRJLIMH-ZJLYAJKPSA-N [Pt].NC[C@H]1OC(O[C@@H]1CN)(C)CC Chemical compound [Pt].NC[C@H]1OC(O[C@@H]1CN)(C)CC UXWRZHYZRJLIMH-ZJLYAJKPSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- ONDVNRNSHFNJHG-HTQZYQBOSA-N (4r,5r)-4,5-bis(azidomethyl)-2,2-diethyl-1,3-dioxolane Chemical compound CCC1(CC)O[C@H](CN=[N+]=[N-])[C@@H](CN=[N+]=[N-])O1 ONDVNRNSHFNJHG-HTQZYQBOSA-N 0.000 description 2
- INJUNLDNDNSXHM-HTQZYQBOSA-N (4r,5r)-4,5-bis(azidomethyl)-2-(2-methylpropyl)-1,3-dioxolane Chemical compound CC(C)CC1O[C@H](CN=[N+]=[N-])[C@@H](CN=[N+]=[N-])O1 INJUNLDNDNSXHM-HTQZYQBOSA-N 0.000 description 2
- ZYYGSQZNHAQJRG-RNFRBKRXSA-N (4r,5r)-4,5-bis(azidomethyl)-2-ethyl-2-methyl-1,3-dioxolane Chemical compound CCC1(C)O[C@H](CN=[N+]=[N-])[C@@H](CN=[N+]=[N-])O1 ZYYGSQZNHAQJRG-RNFRBKRXSA-N 0.000 description 2
- MBVUFTJTLQJBQM-RNFRBKRXSA-N (4r,5r)-4,5-bis(azidomethyl)-2-propyl-1,3-dioxolane Chemical compound CCCC1O[C@H](CN=[N+]=[N-])[C@@H](CN=[N+]=[N-])O1 MBVUFTJTLQJBQM-RNFRBKRXSA-N 0.000 description 2
- KEYOLTKQGFTWEB-RNFRBKRXSA-N (4r,5r)-4,5-bis(azidomethyl)-2-tert-butyl-1,3-dioxolane Chemical compound CC(C)(C)C1O[C@H](CN=[N+]=[N-])[C@@H](CN=[N+]=[N-])O1 KEYOLTKQGFTWEB-RNFRBKRXSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- YWUQXOIKJVOHMA-HTQZYQBOSA-N [(4r,5r)-5-(aminomethyl)-2-(2-methylpropyl)-1,3-dioxolan-4-yl]methanamine Chemical compound CC(C)CC1O[C@H](CN)[C@@H](CN)O1 YWUQXOIKJVOHMA-HTQZYQBOSA-N 0.000 description 2
- XLGDUOJUMJAUCP-RNFRBKRXSA-N [(4r,5r)-5-(aminomethyl)-2-propyl-1,3-dioxolan-4-yl]methanamine Chemical compound CCCC1O[C@H](CN)[C@@H](CN)O1 XLGDUOJUMJAUCP-RNFRBKRXSA-N 0.000 description 2
- JLIVTBLGMXYRQS-RNFRBKRXSA-N [(4r,5r)-5-(aminomethyl)-2-tert-butyl-1,3-dioxolan-4-yl]methanamine Chemical compound CC(C)(C)C1O[C@H](CN)[C@@H](CN)O1 JLIVTBLGMXYRQS-RNFRBKRXSA-N 0.000 description 2
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 2
- JTLOZZJMKKLWLJ-SCLLHFNJSA-N [Pt+2].NC[C@H]1OC(O[C@@H]1CN)(CC)CC Chemical compound [Pt+2].NC[C@H]1OC(O[C@@H]1CN)(CC)CC JTLOZZJMKKLWLJ-SCLLHFNJSA-N 0.000 description 2
- VBTYSHBDFXBBME-ZJLYAJKPSA-N [Pt+2].NC[C@H]1OC(O[C@@H]1CN)C(C)(C)C Chemical compound [Pt+2].NC[C@H]1OC(O[C@@H]1CN)C(C)(C)C VBTYSHBDFXBBME-ZJLYAJKPSA-N 0.000 description 2
- KJSFBBQCWIYHDP-SCLLHFNJSA-N [Pt+2].NC[C@H]1OC(O[C@@H]1CN)CC(C)C Chemical compound [Pt+2].NC[C@H]1OC(O[C@@H]1CN)CC(C)C KJSFBBQCWIYHDP-SCLLHFNJSA-N 0.000 description 2
- ZECGBCUGGSXNCK-ZJLYAJKPSA-N [Pt+2].NC[C@H]1OC(O[C@@H]1CN)CCC Chemical compound [Pt+2].NC[C@H]1OC(O[C@@H]1CN)CCC ZECGBCUGGSXNCK-ZJLYAJKPSA-N 0.000 description 2
- RDRLMVIPWWEWCS-SCLLHFNJSA-N [Pt].NC[C@H]1OC(O[C@@H]1CN)(CC)CC Chemical compound [Pt].NC[C@H]1OC(O[C@@H]1CN)(CC)CC RDRLMVIPWWEWCS-SCLLHFNJSA-N 0.000 description 2
- ZRSLIELZVCEETI-ZJLYAJKPSA-N [Pt].NC[C@H]1OC(O[C@@H]1CN)C(C)(C)C Chemical compound [Pt].NC[C@H]1OC(O[C@@H]1CN)C(C)(C)C ZRSLIELZVCEETI-ZJLYAJKPSA-N 0.000 description 2
- TXMSZRVQSJRHNG-SCLLHFNJSA-N [Pt].NC[C@H]1OC(O[C@@H]1CN)CC(C)C Chemical compound [Pt].NC[C@H]1OC(O[C@@H]1CN)CC(C)C TXMSZRVQSJRHNG-SCLLHFNJSA-N 0.000 description 2
- XLRHFEQYLWYFJB-ZJLYAJKPSA-N [Pt].NC[C@H]1OC(O[C@@H]1CN)CCC Chemical compound [Pt].NC[C@H]1OC(O[C@@H]1CN)CCC XLRHFEQYLWYFJB-ZJLYAJKPSA-N 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 229910000365 copper sulfate Inorganic materials 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000020095 red wine Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- LIGGTHHMIFMDSF-UHFFFAOYSA-N (2-ethyl-1,3-dioxolan-2-yl)methanamine Chemical compound CCC1(CN)OCCO1 LIGGTHHMIFMDSF-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
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Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 우수한 항종양활성을 나타내면서 수용성이며 독성이 낮은 신규의 플라티늄(Ⅱ) 착화합물에 관한 것이다. 본 발명은 또한, 상기의 플라티늄(Ⅱ) 착화합물을 제조하는 방법과 그러한 제조방법에 유용한 중간체에 관한 것이다.The present invention relates to a novel platinum (II) complex which is water soluble and has low toxicity while exhibiting good antitumor activity. The present invention also relates to a process for preparing the above-mentioned platinum (II) complex compounds and to intermediates useful for such preparation methods.
플라티늄 항암제는 일반적으로 핵산에 작용하여 악성세포의 생장 및 전파를 억제하는 것으로 알려져 있으며, 이에 대하여는 비. 로젠버그 등의 문헌[B. Rosenberg et al, Nature 222, 385(1969)]에 상세히 설명되어 있다. 가장 널리 알려진 플라티늄 항암제중의 하나는 시스-DDP 또는 시스플라틴(cisplatin)이라 불리워지는 시스-디클로로디아민플라티늄(Ⅱ)으로, 이러한 시스플라틴은 고환암, 난소암, 방광암 및 두부암과 같은 다양한 인체암에 대해 효과가 있음이 증명되었다. 그러나, 이 화합물은 심각한 투여량-제한 독성이 있어 다량 투여하는 경우에는 심한 신장 독성, 골수억압, 오심 및 구토와 신경독성, 특히 이(耳)독성 및 말초신경병의 증상을 나타낸다. 더우기, 시스플라틴은 물에 대한 용해성이 좋지 못할 뿐만 아니라 물에 천천히 용해되므로 정맥 투여가 어려운 문제점이 있었다. 이와 같은 시스플라틴의 결점 때문에 우수한 항종양활성을 유지하면서도 독성이 낮고 물에 대한 용해도가 개선된 다른 활성물질을 찾고자 수많은 유사체가 합성되어 왔다.Platinum anticancer agents are generally known to act on nucleic acids to inhibit the growth and spread of malignant cells. Rosenberg et al., B. Rosenberg et al, Nature 222, 385 (1969). One of the most well known platinum anticancer drugs is cis-dichlorodiamineplatinum (II), called cis-DDP or cisplatin, which is effective against various human cancers such as testicular cancer, ovarian cancer, bladder cancer and head cancer. It has been proven. However, this compound has severe dose-limiting toxicities, and when administered in high doses, it exhibits symptoms of severe renal toxicity, myelosuppression, nausea and vomiting and neurotoxicity, in particular toxic and peripheral neuropathy. Moreover, cisplatin is not only poorly soluble in water but also has a problem in that intravenous administration is difficult because it is slowly dissolved in water. Because of this drawback of cisplatin, numerous analogs have been synthesized to find other active substances with low toxicity and improved solubility in water while maintaining good antitumor activity.
이들 중 가장 대표적인 화합물로, 에이.에취.하이네스 등의 유럽 특허 출원 공보 제0 222 522호 및 그의 대응 특허인 미합중국 특허 제4,783,452호에는 다음 일반식(A)와 같은 화합물이 개시되어 있다.As the most representative of these compounds, European Patent Application Publication No. 0 222 522 to A. H. Heines et al. And its corresponding patent US Pat. No. 4,783,452 disclose compounds such as the following general formula (A).
여기서, X는 모두 염소이거나 모두 브롬이고, R은 모두 메틸이거나 혹은 하나가 수소이고 다른 하나가 페닐이며, n은 1이다.Wherein X is all chlorine or all bromine, R is all methyl or one is hydrogen and the other is phenyl and n is 1.
그러나, 상기 일반식(A)로 표시되는 플라티늄(Ⅱ) 착화합물 역시 신장독성을 나타내고 물에 대한 용해도도 낮은 단점을 갖으며, 기타 여러가지 플라티늄(Ⅱ) 착화합물 또한 상기 문제점을 해결하지 못하여 왔다.However, the platinum (II) complexes represented by the general formula (A) also have renal toxicity and low solubility in water, and various other platinum (II) complexes have not solved the above problems.
따라서, 본 발명의 목적은 이러한 종래의 시스플라틴 계열 플라티늄(Ⅱ) 착화합물의 문제점을 해결하여 우수한 항종양 활성을 갖으며 신장독성이 낮을 뿐만 아니라 물에 대한 용해성도 우수하여 인체암의 치료에 매우 유용한 신규의 플라티늄(Ⅱ) 착화합물을 제공하는 것이다.Accordingly, an object of the present invention is to solve the problems of the conventional cisplatin-based platinum (II) complex compound, which has excellent anti-tumor activity, low renal toxicity, and excellent solubility in water, which is very useful for the treatment of human cancer. It is to provide a platinum (II) complex compound.
또한, 본 발명의 목적은 상기 플라티늄(Ⅱ) 착화합물을 제조하는 방법을 제공하는 것이다.It is also an object of the present invention to provide a method for producing the platinum (II) complex.
또한, 본 발명의 목적은 상기 플라티늄(Ⅱ) 착화합물의 제조방법에서 유용하게 사용될 수 있는 중간체들을 제공하는 것이다.It is also an object of the present invention to provide intermediates that can be usefully used in the production method of the platinum (II) complex.
아울러, 본 발명은 상기 플라티늄(Ⅱ) 착화합물을 함유하는 항암제 조성물을 제공하는데 있다.In addition, the present invention is to provide an anticancer agent composition containing the platinum (II) complex compound.
본 발명의 플라티늄(Ⅱ) 착화합물은 다음의 일반식(1)로 표시된다.The platinum (II) complex compound of this invention is represented by following General formula (1).
상기식에서, R1과 R2는 같거나 다르고, 각각 수소원자 또는 C1내지 C4의 저급 알킬기를 나타내거나, 혹은 함께 사이클로알칸을 형성하며, 단 4,5-비스(아미노메틸)-1,3-디옥소란 부위에서 각 부재탄소(chiral carbon)의 절대 입체배위는 다음과 같이 표시되는 (4R, 5R)이거나 (4S, 5S)이다.Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group of C 1 to C 4 , or together form a cycloalkane, provided that 4,5-bis (aminomethyl) -1, The absolute steric coordination of each chiral carbon at the 3-dioxolane site is (4R, 5R) or (4S, 5S) represented as follows.
상기 일반식(1)의 화합물중 R1과 R2가 상이할 경우에는 다음과 같이 표시되는 두 개의 기하 이성질체가 존재할 수 있으며, 따라서 본 발명의 범위에는 이들 각각 및 이들의 혼합물 모두가 포함된다.When R 1 and R 2 in the compound of Formula (1) are different from each other, two geometric isomers represented as follows may exist, and thus, each of them and a mixture thereof are included in the scope of the present invention.
그러나, 상기 2개의 기하 이성질체는 제조과정에서 혼합물 상태로 얻어지며 분리가 극히 어려울 뿐만 아니라 각각의 이성질체의 항종양활성이 같은 수준으로 기대되므로, 본 발명에서는 이들을 구분하지 않았다.However, the two geometric isomers are obtained in a mixture during preparation and are extremely difficult to separate, and the antitumor activity of each isomer is expected to be at the same level, so the present invention did not distinguish them.
본 발명에 따른 상기 일반식(1)의 화합물은 일반적으로 4,5-비스(아미노메틸)-1,3-디옥소란 부위에서 부재탄소의 절대 입체배위가 (4R, 5R)일 때가 (4S, 5S)인 경우보다 우수한 항종양 활성을 나타내며, 그중에서도 사이클로펜탄 및 사이클로헥산과 같이 R1과 R2가 함께 고리를 형성하는 화합물과, R1과 R2가 모두 메틸 또는 에틸인 화합물, R1과 R2중 어느 하나가 에틸이고 나머지 하나가 메틸인 화합물, 및 R1과 R2중 어느 하나가 에틸 또는 이소프로필이고 나머지 하나가 수소인 화합물이 강력한 항종양 활성을 나타낸다. 한편, 물에 대한 용해도에 있어서는, R1과 R2가 상이한 것이, 그리고 지방족 사슬의 길이가 짧은 것일수록 높은 경향을 보이며, 거의 모든 화합물이 우수한 수용성을 가진다. 다른 한편, 상기 일반식(1)의 화합물은 혈중 요소질소농도(BUN값)의 측정 결과 신장독성이 없거나 낮은 것으로 나타났다.The compound of the general formula (1) according to the present invention generally has an absolute stereoconfiguration of (4R, 5R) in the 4,5-bis (aminomethyl) -1,3-dioxolane moiety at (4S). , 5S) shows better antitumor activity, among which R 1 and R 2 together form a ring together with cyclopentane and cyclohexane, and R 1 and R 2 are both methyl or ethyl, R 1 And a compound in which one of R 2 is ethyl and the other is methyl, and a compound in which one of R 1 and R 2 is ethyl or isopropyl and the other is hydrogen exhibits strong antitumor activity. On the other hand, in terms of solubility in water, the more different R 1 and R 2 , and the shorter the length of the aliphatic chain, the higher the tendency, and almost all compounds have excellent water solubility. On the other hand, the compound of formula (1) showed no or low renal toxicity as a result of the measurement of blood urea nitrogen concentration (BUN value).
상기 특성들을 종합하여 고려할 때 4,5-비스(아미노메틸)-1,3-디옥소란 부위에서 부재탄소의 절대 입체배위가 (4R, 5R)이면서 R1과 R2가 함께 사이클로펜탄 및 사이클로헥산을 형성하는 화합물과, R1과 R2가 모두 메틸 또는 에틸인 화합물, R1과 R2중 어느 하나가 에틸이고 나머지 하나가 메틸인 화합물, 및 R1과 R2중 어느 하나가 에틸 또는 이소프로필이고 나머지 하나가 수소인 화합물이 인체암의 치료에 유용한 것으로 판단된다. 그러나, 당업자들은 화합물의 사용목적에 따라 그 밖의 것들 중에서 적절한 것을 선택하여 사용할 수도 있을 것이다.Taking these properties together, the absolute steric coordination of the absent carbon in the 4,5-bis (aminomethyl) -1,3-dioxolane site is (4R, 5R) and R 1 and R 2 together are cyclopentane and cyclo A compound forming hexane, a compound in which R 1 and R 2 are both methyl or ethyl, a compound in which one of R 1 and R 2 is ethyl and the other is methyl, and either one of R 1 and R 2 is ethyl or Isopropyl and the other one, hydrogen, are believed to be useful for the treatment of human cancer. However, those skilled in the art will be able to select and use the appropriate ones depending on the intended use of the compounds.
본 발명에서 상기 일반식(1)로 표시되는 화합물의 대표적예는 다음과 같고, 이들의 제조방법은 각 실시예에 나타내었다. 그러나 본 발명이 다음의 예에 국한되는 것은 아니다.Representative examples of the compound represented by the general formula (1) in the present invention are as follows, and their preparation method is shown in each Example. However, the present invention is not limited to the following examples.
(글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2,2-디메틸-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란-2-스피로-1'-사이클로펜탄]플라티늄(Ⅱ) ; (글라이코레이토-O,O') {사이클로헥산스피로-2'-[(4'R,5'R)-4',5'-비스(아미노메틸)-1',3'-디옥소란]}플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-메틸-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-이소프로필-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2,2-디에틸-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-2-메틸-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-프로필-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-이소부틸-1,3-디옥소란]플라티늄(Ⅱ) ; (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-tert-부틸-1,3-디옥소란]플라티늄(Ⅱ).(Glycorayo-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane] platinum (II); (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2,2-dimethyl-1,3-dioxolane] platinum (II); (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane-2-spiro-1'-cyclopentane] platinum (II); (Glycoraito-O, O ') {cyclohexanespiro-2'-[(4'R, 5'R) -4 ', 5'-bis (aminomethyl) -1', 3'-dioxolane ]} Platinum (II); (Glycorayto-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-methyl-1,3-dioxolane] platinum (II); (Glycorayto-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-1,3-dioxolane] platinum (II); (Glycorayto-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-isopropyl-1,3-dioxolane] platinum (II); (Glycorayto-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2,2-diethyl-1,3-dioxolane] platinum (II); (Glycorayto-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-2-methyl-1,3-dioxolane] platinum (II); (Glycorayto-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-propyl-1,3-dioxolane] platinum (II); (Glycorayo-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-isobutyl-1,3-dioxolane] platinum (II); (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-tert-butyl-1,3-dioxolane] platinum (II).
이상에서 설명한 바와 같은 본 발명의 플라티늄(Ⅱ) 착화합물은 다음의 2가지 방법에 따라 제조될 수 있다.Platinum (II) complexes of the present invention as described above can be prepared according to the following two methods.
[방법 A][Method A]
상기 식들에서, R1과 R2및 절대 입체배위는 상기에서 정의한 바와 같고, Hal은 할로겐 원자이다.In the above formulas, R 1 and R 2 and absolute steric coordination are as defined above, and Hal is a halogen atom.
[방법 B][Method B]
단계 1 :Step 1:
단계 2 :Step 2:
상기식들에서, R1과 R2및 절대입체배위와 Hal은 상기에서 정의한 바와 같다.In the above formulas, R 1 and R 2 and absolute stereocoordination and Hal are as defined above.
상기 방법 A에 따르면, 상기 일반식(2)의 디할로게노디아민 플라티늄(Ⅱ) 착화합물을 글라이콜산 및 산화은(Ⅰ)과 반응시켜서 목적하는 일반식(1)의 화합물을 제조할 수 있다. 이때, 일반식(2)의 화합물과 글라이콜산 및 산화은(Ⅰ)은 1 : 0.5 : 0.5 내지 1 : 5 : 5의 당량비로 사용하여, 일반적으로 수성매질중에서 또는 수성매질과 메탄올이나 에탄올 등의 알코올성 매질과의 혼합매질 중에서 차광하에 반응을 실시하며, 반응온도는 0 내지 100℃, 바람직하게는 50 내지 70℃로 하는 것이 좋고, 반응시간은 반응조건에 따라 1시간 내지 3일간으로 한다.According to the said method A, the dihalogeno diamine platinum (II) complex compound of the said General formula (2) can be made to react with glycolic acid and silver oxide (I), and the compound of the general formula (1) can be manufactured. In this case, the compound of Formula (2), glycolic acid and silver oxide (I) are used in an equivalent ratio of 1: 0.5: 0.5 to 1: 5: 5, and are generally used in an aqueous medium or in an aqueous medium and methanol or ethanol. The reaction is carried out in a mixed medium with an alcoholic medium under light shielding, and the reaction temperature is preferably 0 to 100 ° C, preferably 50 to 70 ° C, and the reaction time is 1 hour to 3 days depending on the reaction conditions.
한편, 상기 방법 B에 따르면, 먼저 단계 1에서 상기 일반식(2)의 디할로게노디아민 플라티늄(Ⅱ) 착화합물을 질산은과 반응시켜서 상기 일반식(3)으로 표시되는 수화물의 수용액을 얻은 다음, 이를 음이온교환수지를 충진한 컬럼을 통과시켜서 상기 일반식(4) 화합물의 수용액을 얻는다. 이때, 일반식(2)의 화합물과 질산은은 약 1 : 2의 몰비로 사용하여, 일반적으로 수성 매질중에서 차광하에 반응을 실시하며, 반응온도는 0 내지 80℃로 하는 것이 바람직하고, 반응시간은 반응조건에 따라 20분 내지 3일간으로 한다. 이렇게 하여 얻어진 일반식(3)의 수용액을 음이온교환수지 컬럼을 통과시키는데, 여기서 사용되는 음이온교환수지는 OH-형의 앰버라이트 IRA-400, 도웩스 I 또는 다이아이온 SA-10A를 사용할 수 있다.Meanwhile, according to the method B, first, in step 1, the dihalogenodiamine platinum (II) complex of the general formula (2) is reacted with silver nitrate to obtain an aqueous solution of the hydrate represented by the general formula (3), and then An aqueous solution of the compound of formula (4) is obtained by passing through a column packed with an anion exchange resin. At this time, the compound of the formula (2) and silver nitrate are used in a molar ratio of about 1: 2, and the reaction is generally carried out under shading in an aqueous medium, and the reaction temperature is preferably 0 to 80 ° C, and the reaction time is 20 minutes to 3 days depending on reaction conditions. The aqueous solution of the formula (3) thus obtained is passed through an anion exchange resin column, in which the anion exchange resin used here may be an OH − type Amberlite IRA-400, Dow's I or Diaion SA-10A.
그런 다음, 단계 2에 따라 상기에서 얻어진 일반식(4) 화합물의 수용액을 글라이콜산 및 글라이콜산의 나트륨염과 반응시켜서 목적하는 일반식(1)의 화합물을 제조할 수 있다. 이때, 일반식(4)의 화합물과 글라이콜산 및 글라이콜산의 나트륨염은 1 : 1 : 1 내지 1 : 1 : 5의 몰비로 사용하여, 일반적으로 수성매질중에서 차광하에 반응을 실시하며, 반응온도는 0 내지 100℃, 바람직하게는 50 내지 70℃로 하는 것이 좋고, 반응시간은 반응조건에 따라 1시간 내지 3일간으로 한다.Then, according to step 2, an aqueous solution of the compound of formula (4) obtained above can be reacted with glycolic acid and sodium salt of glycolic acid to prepare the compound of formula (1). In this case, the compound of formula (4) and the sodium salt of glycolic acid and glycolic acid are used in a molar ratio of 1: 1: 1 to 1: 1: 5, and generally, the reaction is carried out under shading in an aqueous medium. The reaction temperature is preferably 0 to 100 ° C, preferably 50 to 70 ° C, and the reaction time is 1 hour to 3 days depending on the reaction conditions.
이와 같은 본 발명의 방법 A 및 B에서, 일반식(1)의 최종 생성물을 4,5-비스(아미노메틸)-1,3-디옥소란 부위의 절대 입체배위가 (4R,5R)인 형태로 얻기 위해서는 상기 일반식(2)의 출발물질로서 해당부위의 절대 입체배위가 (4R,5R)인 것을 사용하며, (4S,5S)형태의 최종 생성물을 얻기 위해서는 (4S,5S) 형태의 출발물질을 사용한다.In the above methods A and B of the present invention, the final product of general formula (1) is a form in which the absolute stereoconfiguration of the 4,5-bis (aminomethyl) -1,3-dioxolane site is (4R, 5R) In order to obtain as the starting material of the general formula (2), the absolute stereoconfiguration of the corresponding site is used (4R, 5R), and to obtain the final product of the (4S, 5S) form of the (4S, 5S) start Use substance.
이상에서 설명한 바와 같은 본 발명에 따른 플라티늄(Ⅱ) 착화합물의 제조방법에서 출발물질로 사용되는 상기 일반식(2)의 디할로게노디아민 플라티늄(Ⅱ) 착화합물은, 본 출원인의 1991년 3월 23일자 대한민국 특허출원 제4627호에 개시된 방법이나 다음에 도시된 반응들에 따라 제조될 수 있다.The dihalogenodiamine platinum (II) complex of the general formula (2) used as a starting material in the method for producing a platinum (II) complex compound according to the present invention as described above is the applicant's March 23, 1991 It may be prepared according to the method disclosed in Korean Patent Application No. 4627 or the reactions shown below.
상기 식들에서, R1과 R2및 절대입체배위는 상기에서 정의한 바와 같고, M은 1가의 양이온이 될 수 있는 원자이며, Hal은 할로겐 원자를 나타낸다.In the above formulas, R 1 and R 2 and absolute stereocoordination are as defined above, M is an atom capable of becoming a monovalent cation, and Hal represents a halogen atom.
먼저, 상기 구조식(5)의 트레이톨 1,4-비스(메탄술포네이트)를 피. 더블유. 페이트 등(P.W. Feit et al, J.Med.Chem. 7, 14(1964)]의 방법에 따라 알데하이드나 아세탈 또는 케톤과, 바람직하게는 메탄술폰산 또는 황산 등의 산 촉매존재하에 반응시켜, 상기 일반식(6)의 1,3-디옥소란-4,5-비스(메탄술포네이트)를 얻는다. 이때 알데하이드나 아세탈 또는 케톤은 치환되어질 R1과 R2에 따라 적절히 선정한다. 예컨대, R1과 R2가 모두 에틸일 때에는 3-펜타논 ; R1과 R2중 어느 하나는 메틸이고 나머지 하나가 에틸일 때에는 2-부타논 ; R1과 R2중 어느 하나는 수소이고 나머지 하나가 프로필일 때에는 부틸알데하이드 ; R1과 R2중 어느 하나는 수소이고 나머지 하나가 이소부틸 때에는 이소발레르알데하이드 ; R1과 R2중 어느 하나가 수소이고 나머지 하나가 tert-부틸일때는 트리메틸 아세트알데하이드를 사용할 수 있다.First, the traceol 1,4-bis (methanesulfonate) of the formula (5) was avoided. W. Pate et al. (PW Feit et al, J. Med. Chem. 7, 14 (1964)) according to the method of aldehyde, acetal or ketone, preferably reacted in the presence of an acid catalyst such as methanesulfonic acid or sulfuric acid, Obtain 1,3-dioxolane-4,5-bis (methanesulfonate) of formula (6), wherein aldehydes, acetals or ketones are appropriately selected depending on R 1 and R 2 to be substituted, eg R 1 3-pentanone when and R 2 are both ethyl; one of R 1 and R 2 is methyl and the other is 2-butanone when ethyl is one; one of R 1 and R 2 is hydrogen and the other is propyl Butylaldehyde when R 1 and R 2 are hydrogen and the other isobutyl isovaleraldehyde when either R 1 and R 2 is hydrogen and tert-butyl when trimethyl acetaldehyde is used Can be.
그런 다음, 상기 일반식(6)의 화합물을 아지드이온과 N,N-디메틸포름아미드 중에서, 일반적으로 20 내지 120℃의 온도를 유지하면서 1 내지 24시간 동안 반응시켜서 상기 일반식(7)의 4,5-비스(아지도메틸)-1,3-디옥소란을 얻는다.Thereafter, the compound of formula (6) is reacted with azide ion in N, N-dimethylformamide for 1 to 24 hours while maintaining the temperature of 20 to 120 ° C. 4,5-bis (azidomethyl) -1,3-dioxolane is obtained.
이어서, 상기 일반식(7)의 화합물을 메탄올이나 에탄올 등의 알코올성 매질중에서 팔라듐-목탄이나 플라티늄(4) 산화물등의 촉매 존재하에 수소로 환원시키는 등의 통상적인 환원 방법에 따라 상기 일반식(8)의 4,5-비스(아미노메틸)-1,3-디옥소란을 얻는다. 상기 환원반응은 일반적으로 15 내지 70psi의 압력하에 15 내지 50℃를 유지하면서 30분 내지 1일 동안 실시한다.Subsequently, the compound of formula (7) is reduced to hydrogen in an alcoholic medium such as methanol or ethanol in the presence of a catalyst such as palladium-charcoal or platinum (4) oxide. 4,5-bis (aminomethyl) -1,3-dioxolane of The reduction reaction is generally carried out for 30 minutes to 1 day while maintaining 15 to 50 ℃ under a pressure of 15 to 70 psi.
이렇게 하여 얻어진 상기 일반식(8)의 화합물을 사할로겐화 백금염과 반응시키는데, 이때 반응은 일반적으로 수성매질 중에서 온도를 0 내지 100℃, 바람직하게는 50 내지 70℃를 유지하면서, 대기하에서, 바람직하게는 질소 또는 아르곤 가스 등과 같은 불활성 가스를 유입하면서 진행시킴으로써, 상기 일반식(2)의 디할로게노 디아민 플라티늄(Ⅱ) 착화합물을 얻을 수 있다.The compound of formula (8) thus obtained is reacted with a tetrahalogenated platinum salt, wherein the reaction is generally carried out in air, while maintaining the temperature of 0 to 100 캜, preferably 50 to 70 캜 in an aqueous medium. Preferably, the dihalogeno diamine platinum (II) complex compound of the general formula (2) can be obtained by advancing while introducing an inert gas such as nitrogen or argon gas.
상기의 제조방법에서 목적물인 일반식(2)의 디할로게노디아민 플라티늄(Ⅱ) 착화합물을 그 4,5-비스(아미노메틸)-1,3-디옥소란 부위에서 부재탄소의 절대 입체배위가 (4R,5R)인 형태로 얻기 위해서는 구조식(5)의 출발물질로서 D-트레이톨 1,4-비스(메탄술포네이트)를 사용하여야 하며, 반대로 출발물질로서 L-트레이톨 1,4-비스(메탄술포네이트)를 사용하게 되면 (4S,5S)의 절대 입체배위를 갖는 일반식(2)의 화합물을 얻을 수가 있다.Absolute steric coordination of the absent carbon at the 4,5-bis (aminomethyl) -1,3-dioxolane site of the dihalogenodiamine platinum (II) complex of the general formula (2) To obtain in the form of (4R, 5R), D-thritol 1,4-bis (methanesulfonate) should be used as starting material of formula (5), and conversely, L-thritol 1,4-bis as starting material. When (methanesulfonate) is used, the compound of the general formula (2) having an absolute stereoconfiguration of (4S, 5S) can be obtained.
본 발명에 따른 상기 일반식(1)의 플라티늄(Ⅱ) 착화합물은 우수한 항 종양활성을 갖으며 신장 독성이 낮고 물에 대한 용해성이 양호하여 항암제로서 유용하다.Platinum (II) complexes of the general formula (1) according to the present invention have excellent antitumor activity, low renal toxicity and good solubility in water, and thus are useful as anticancer agents.
본 발명의 화합물은 약제학적으로 허용가능한 담체와 함께, 필요하다면 보조제와 함께 통상의 방법에 따라 제형화시킬 수 있다. 경구로 투여할 경우, 본 발명의 화합물은 정제, 환약, 과립, 분말 및 캡슐 등과 같은 고형제제나 용액, 현탁액 및 유화액 등과 같은 액상제제로 할 수 있으며, 비경구로 투여할 경우에는 주사액이나 정맥내 적주 주입액 등으로 제형화할 수 있다. 주사액은 화합물을 물이나 염화나트륨과 같은 수용액에 용해시켜서 제조할 수 있으며 정맥내 적주 주입액은 생리식염수나 글루코스-염화나트륨용액 등과 같은 적당한 치료용 유체에 용해시켜서 제조한다.The compounds of the present invention may be formulated according to conventional methods with pharmaceutically acceptable carriers, with adjuvant if necessary. In the case of oral administration, the compound of the present invention may be in the form of solid preparations such as tablets, pills, granules, powders, and capsules, or liquid preparations such as solutions, suspensions, and emulsions, and when administered parenterally, by injection or intravenous red wine. It may be formulated as an injection liquid or the like. Injectable solutions can be prepared by dissolving the compound in an aqueous solution such as water or sodium chloride, and intravenous red wine is prepared by dissolving it in a suitable therapeutic fluid such as saline solution or glucose-sodium chloride solution.
본 발명에 따른 화합물의 투여량은 투여하고자하는 대상의 성별, 연령, 체중과 종양의 위치, 종양의 심각도 및 투여경로 등에 따라 달라질 수 있으나, 일반적으로 체표면적 1㎡당 25 내지 500mg 사용한다.The dosage of the compound according to the present invention may vary depending on the sex, age, weight and location of the tumor, the severity of the tumor, and the route of administration, etc., but generally 25 to 500 mg per 1 m 2 of body surface area is used.
이하 본 발명을 실시예에 의거하여 보다 구체적으로 설명한다. 다음의 실시예는 본 발명을 예시하는 것으로서 본 발명을 한정하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples illustrate the invention but do not limit the invention.
본 발명에 따른 플라티늄(Ⅱ) 착화합물의 구조는 적외선 분광법,1H NMR분광법,13C NMR분광법 및 고속원자포격질량분광법 등의 다양한 분석 방법에 의해 확인하였다.The structure of the platinum (II) complex according to the present invention was confirmed by various analytical methods such as infrared spectroscopy, 1 H NMR spectroscopy, 13 C NMR spectroscopy, and high-speed atomic bomb mass spectrometry.
[실시예 1A]Example 1A
방법 A에 의한 (글리이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoyraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane] platinum (II) by Method A
시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.86mmol)과 글라이콜산(0.13g, 1.71mmol) 및 산화은(Ⅰ)(0.40g, 1.72mmol)을 물(30ml)에 혼합하고, 이 혼합물을 암조건하에서 60℃를 유지하면서 하룻밤동안 교반시켰다. 이 반응혼합물을 실온으로 냉각시킨 후, 셀라이트 패드를 통과시켜 여과하고, 그 잔사를 소량의 물로 세척하였다. 이어서, 여과물과 세척물의 혼합물을 감압하에서 농축하여 5ml가 되게한 다음, 그 농축액을 고정상으로 델타 팩 C18-100Å역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물을 사용하여 HPLC로 정제하였다. 그런 다음, 얻어진 용출액을 감압하에서 농축하고 동결건조하여서 백색고형의 목적화합물을 0.198g얻었다.Cis-dioiodo [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane] platinum (II) (0.50 g, 0.86 mmol) and glycolic acid (0.13 g, 1.71 mmol) and silver oxide (I) (0.40 g, 1.72 mmol) were mixed in water (30 ml), and the mixture was stirred overnight while maintaining 60 ° C under dark conditions. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the residue was washed with a small amount of water. The mixture of filtrate and wash was then concentrated under reduced pressure to 5 ml, and then the concentrate was purified by HPLC using Delta Pack C18-100Å reversed phase bound silica cartridge as stationary phase and water as mobile phase. Then, the obtained eluate was concentrated under reduced pressure and lyophilized to obtain 0.198 g of the target compound as a white solid.
수율 : 57%Yield: 57%
IR(KBr) : 3445, 3222, 3069cm-1(NH), 1645cm-1(C=O)IR (KBr): 3445, 3222, 3069cm -1 (NH), 1645cm -1 (C = O)
1H NMR(D2O/DSS) : δ 2.87(m, 2H, 2CHNH2), 3.38(m, 2H, 2CHNH2), 4.10(s, 2H, CH2), 4.59(m,2H,2CH), 5.05(s, 2H, OCH2O) 1 H NMR (D 2 O / DSS): δ 2.87 (m, 2H, 2CHNH 2 ), 3.38 (m, 2H, 2CHNH 2 ), 4.10 (s, 2H, CH 2 ), 4.59 (m, 2H, 2CH) , 5.05 (s, 2H, OCH 2 O)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
13C NMR(D2O/DSS) : δ 48.52, 48.82, 69.30, 79.49, 79.53, 95.42, 195.49 13 C NMR (D 2 O / DSS): δ 48.52, 48.82, 69.30, 79.49, 79.53, 95.42, 195.49
내부 표준으로 DSS사용 (D2O중에서 DSS δ=-1.600ppm)Use DSS as internal standard (DSS δ = -1.600ppm in D 2 O)
FAB-MS : (M＋H)+=401(194Pt, 33%), 402(195Pt, 34%) 및 403(196Pt, 25%)FAB-MS: (M + H) + = 401 ( 194 Pt, 33%), 402 ( 195 Pt, 34%) and 403 ( 196 Pt, 25%)
[실시예 1B]Example 1B
방법 B에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane] platinum (II) by Method B
[단계 1][Step 1]
시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.86mmol)을 물(15ml)에 현탁 및 교반시키고, 이 현탁액에 질산은(0.29g, 1.72mmol)을 물(15ml)에 용해시켜서된 용액을 첨가시킨 후, 이 혼합물을 암조건하에서 2시간 동안 60℃로 가열시켰다. 이 반응혼합물을 실온으로 냉각시킨 후, 셀라이트 패드를 통과시켜 여과하고, 그 잔사를 소량의 물로 세척하였다. 이어서, 여과물과 세척물의 혼합물을 감압하에서 농축하여 10ml가 되게한 다음, 그 농축액을 음이온 교환수지 앰버라이트 IRA-400(OH-형, 20ml) 컬럼을 통과시키고, 용리액으로 물을 사용하여 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란]플라티늄(Ⅱ)을 용출시켰다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane] platinum (II) (0.50 g, 0.86 mmol) is suspended and stirred in water (15 ml) To this suspension was added a solution by dissolving silver nitrate (0.29 g, 1.72 mmol) in water (15 ml), and then the mixture was heated to 60 ° C. for 2 hours under dark conditions. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the residue was washed with a small amount of water. The mixture of filtrate and wash was then concentrated under reduced pressure to 10 ml, and then the concentrate was passed through an anion exchange resin Amberlite IRA-400 (OH-type, 20 ml) column and cis- using water as eluent. Dihydroxy [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane] platinum (II) was eluted.
[단계 2][Step 2]
상기 단계 1에서 얻어진 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란]플라티늄(Ⅱ)의 수용액 30ml에 글라이콜산(0.07g, 0.92mmol)과 1M 글라이콜산 나트륨 수용액(3.44ml)을 첨가하고, 이 혼합물을 암조건하에서 60℃를 유지하면서 하룻밤동안 교반시켰다. 이 반응혼합물을 실온으로 냉각시키고, 감압하에서 농축하여 5ml가 되게 한 다음, 그 농축액을 고정상으로 델타 팩 C18-100Å역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물을 사용하여 HPLC로 정제하였다. 그런 다음, 얻어진 용출액을 감압하에서 농축하고 동결건조하여서 백색 고형의 목적화합물을 0.194g 얻었다.In 30 ml of an aqueous solution of cis-dihydroxy [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane] platinum (II) obtained in step 1, glycolic acid (0.07 g, 0.92 mmol) and 1 M aqueous sodium glycolate solution (3.44 ml) were added, and the mixture was stirred overnight while maintaining 60 ° C under dark conditions. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to 5 ml, and the concentrate was purified by HPLC using Delta Pack C18-100Å reversed phase bound silica cartridge as stationary phase and water as mobile phase. Then, the obtained eluate was concentrated under reduced pressure and lyophilized to obtain 0.194 g of a white solid target compound.
수율 : 56%Yield: 56%
[실시예 2A]Example 2A
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2,2-디메틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Of (glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2,2-dimethyl-1,3-dioxolane] platinum (II) by Method A Produce
상기 실시예 1A에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2,2-디메틸-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.82mmol)과 글라이콜산(0.13g, 1.71mmol) 및 산화은(Ⅰ)(0.38g, 1.64mmol)을 물(30ml)중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(9 : 1)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색고형의 목적화합물을 0.149g얻었다.Cis-diododo [(4R, 5R) -4,5-bis (aminomethyl) -2,2-dimethyl-1,3-dioxolane] platinum (II) ( 0.50 g, 0.82 mmol), glycolic acid (0.13 g, 1.71 mmol) and silver oxide (I) (0.38 g, 1.64 mmol) were reacted in water (30 ml), and then the product was fixed as a delta pack C18-100 Å reverse phase. The combined silica cartridge was employed and purified by HPLC using a mixture of water and methanol (9: 1) as mobile phase. In this way, 0.149g of white solid target compounds were obtained.
수율 : 42%Yield: 42%
IR(KBr) : 3430, 3142, 3085cm-1(NH), 1657cm-1(C=O)IR (KBr): 3430, 3142, 3085cm -1 (NH), 1657cm -1 (C = O)
1H NMR(D2O/DSS) : δ 1.47(s,6H,2CH3), 2.86(m,2H,2CHNH2), 3.32(m, 2H, 2CHNH2), 4.10(s,2H,CH2), 4.71(m,2H,2CH) 1 H NMR (D 2 O / DSS): δ 1.47 (s, 6H, 2CH 3 ), 2.86 (m, 2H, 2CHNH 2 ), 3.32 (m, 2H, 2CHNH 2 ), 4.10 (s, 2H, CH 2 ), 4.71 (m, 2H, 2CH)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
13C NMR(D2O/DSS) : δ 26.56, 49.36, 49.65, 69.27, 79.18, 111.35, 195.51 13 C NMR (D 2 O / DSS): δ 26.56, 49.36, 49.65, 69.27, 79.18, 111.35, 195.51
내부 표준으로 DSS사용 (D2O중에서 DSS δ=-1.600ppm)Use DSS as internal standard (DSS δ = -1.600ppm in D 2 O)
FAB-MS : (M＋H)+=429(194Pt, 33%), 430(195Pt, 34%) 및 431(196Pt, 25%)FAB-MS: (M + H) + = 429 ( 194 Pt, 33%), 430 ( 195 Pt, 34%) and 431 ( 196 Pt, 25%)
[실시예 2B]Example 2B
방법 B에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2,2-디메틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Of (glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2,2-dimethyl-1,3-dioxolane] platinum (II) according to Method B Produce
[단계 1][Step 1]
상기 실시예 1B의 단계 1에서와 동일한 방법으로 시스-디요오도[(4R, 5R)-4,5-비스(아미노메틸)-2,2-디메틸-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.82mmol)과 질산은(0.28g, 1.65mmol)을 반응시킨 다음, 음이온 교환수지 앰버라이트 IRA-400컬럼을 통과시켜서 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-2,2-디메틸-1,3-디옥소란]플라티늄(Ⅱ)을 수용액을 얻었다.Cis-diodo [[4R, 5R) -4,5-bis (aminomethyl) -2,2-dimethyl-1,3-dioxolane] platinum ( II) (0.50 g, 0.82 mmol) and silver nitrate (0.28 g, 1.65 mmol) were reacted, and then passed through an anion exchange resin Amberlite IRA-400 column to give cis-dihydroxy [(4R, 5R) -4,5 An aqueous solution of -bis (aminomethyl) -2,2-dimethyl-1,3-dioxolane] platinum (II) was obtained.
[단계 2][Step 2]
상기 실시예 1B의 단계 2에서와 동일한 방법으로 상기 단계 1에서 얻어진 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-2,2-디메틸-1,3-디옥소란]플라티늄(Ⅱ)의 수용액과 글라이콜산(0.06g, 0.79mmol) 및 글라이콜산 나트륨(1M수용액 3.3ml)을 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å역상 결합된 실리카 카트리지를 채용하고 이동상으로 물과 메탄올과의 혼합물(9 : 1)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적 화합물을 0.161g 얻었다.Cis-dihydroxy [(4R, 5R) -4,5-bis (aminomethyl) -2,2-dimethyl-1,3-di obtained in Step 1 in the same manner as in Step 2 of Example 1B above After reacting an aqueous solution of oxolane] platinum (II) with glycolic acid (0.06 g, 0.79 mmol) and sodium glycolate (3.3 ml of 1 M aqueous solution), the product was fixed as a delta pack C18-100Å reversed phase silica. The cartridge was employed and purified by HPLC using a mixture of water and methanol (9: 1) as mobile phase. In this way, 0.161g of white solid target compounds were obtained.
[실시예 3A]Example 3A
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란-2-스피로-1'-사이클로펜탄]플라티늄(Ⅱ)의 제조(Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane-2-spiro-1'-cyclopentane] platinum by Method A Preparation of (II)
상기 실시예 1A에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란-2-스피로-1'-사이클로펜탄]플라티늄(Ⅱ) (0.50g, 0.79mmol)과 글라이콜산(0.12g, 1.58mmol) 및 산화은(Ⅰ)(0.37g, 1.60mmol)을 물(55ml)과 메탄올(5ml)과의 혼합매질 중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(6 : 4)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.243g 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane-2-spiro-1'-cyclopentane] platinum in the same manner as in Example 1A above (II) (0.50 g, 0.79 mmol), glycolic acid (0.12 g, 1.58 mmol) and silver oxide (I) (0.37 g, 1.60 mmol) were reacted in a mixed medium of water (55 ml) and methanol (5 ml). The product was then purified by HPLC using a Delta Pack C18-100Å reversed phase bound silica cartridge as the stationary phase and a mixture of water and methanol (6: 4) as the mobile phase. Thus, 0.243 g of a white solid target compound was obtained.
수율 : 68%Yield: 68%
IR(KBr) : 3409, 3211, 3143cm-1(NH), 1635cm-1(C=O)IR (KBr): 3409, 3211, 3143cm -1 (NH), 1635cm -1 (C = O)
1H NMR(D2O/DSS) : δ 1.60-2.00(m,8H,사이클로펜틸), 2.86(m, 2H, 2CHNH2), 3.33(m, 2H, 2CHNH2), 4.10(s, 2H, CH2), 4.66(m, 2H, 2CH) 1 H NMR (D 2 O / DSS): δ 1.60-2.00 (m, 8H, cyclopentyl), 2.86 (m, 2H, 2CHNH 2 ), 3.33 (m, 2H, 2CHNH 2 ), 4.10 (s, 2H, CH 2 ), 4.66 (m, 2H, 2CH)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
13C NMR(D2O/DSS) : δ 23.88, 37.11, 49.22, 49.50, 69.29, 79.05, 121.09, 195.51 13 C NMR (D 2 O / DSS): δ 23.88, 37.11, 49.22, 49.50, 69.29, 79.05, 121.09, 195.51
내부 표준으로 DSS사용 (D2O중에서 DSS δ=-1.600ppm)Use DSS as internal standard (DSS δ = -1.600ppm in D 2 O)
FAB-MS : (M＋H)+=455(194Pt, 33%), 456(195Pt, 34%) 및 457(196Pt, 25%)FAB-MS: (M + H) + = 455 ( 194 Pt, 33%), 456 ( 195 Pt, 34%) and 457 ( 196 Pt, 25%)
[실시예 3B]Example 3B
방법 B에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란-2-스피로-1'-사이클로펜탄]플라티늄(Ⅱ)의 제조(Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane-2-spiro-1'-cyclopentane] platinum by Method B Preparation of (II)
[단계 1][Step 1]
상기 실시예 1B의 단계 1에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란-2-스피로-1'-사이클로펜탄]플라티늄(Ⅱ) (0.50g, 0.79mmol)과 질산은 (0.27g, 1.59mmol)을 반응시킨 다음, 음이온교환지수 앰버라이트 IRA-400컬럼을 통과시켜서 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란-2-스피로-1'-사이클로펜탄]플라티늄(Ⅱ)의 수용액을 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane-2-spiro-1'-cyclo in the same manner as in step 1 of Example 1B above Pentane] platinum (II) (0.50g, 0.79mmol) and silver nitrate (0.27g, 1.59mmol) were reacted, and then passed through anion exchange index Amberlite IRA-400 column to cis-dihydroxy [(4R, 5R). An aqueous solution of -4,5-bis (aminomethyl) -1,3-dioxolane-2-spiro-1'-cyclopentane] platinum (II) was obtained.
[단계 2][Step 2]
상기 실시예 1B의 단계 2에서와 동일한 방법으로 상기 단계 1에서 얻어진 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-1,3-디옥소란-2-스피로-1'-사이클로펜탄]플라티늄(Ⅱ)의 수용액과 글라이콜산(0.06g, 0.79mmol)과 글라이콜산 나트륨 수용액(1M수용액 3.2ml)을 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å역상 결합된 실라카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(6:4)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.178g 얻었다.Cis-dihydroxy [(4R, 5R) -4,5-bis (aminomethyl) -1,3-dioxolane-2-spiro obtained in step 1 in the same manner as in step 2 of Example 1B. After reacting an aqueous solution of -1'-cyclopentane] platinum (II) with glycolic acid (0.06 g, 0.79 mmol) and an aqueous sodium glycolate solution (3.2 ml of 1 M aqueous solution), the product was fixed as a delta pack C18-. A 100 cc reverse phase coupled silica cartridge was employed and the mobile phase was purified by HPLC using a mixture of water and methanol (6: 4). Thus, 0.178 g of a white solid target compound was obtained.
수율 : 50%Yield: 50%
[실시예 4A]Example 4A
방법 A에 의한 (글라이코레이토-O,O'){사이클로헥산스피로-2'-[(4'R,5'R)-4',5'-비스(아미노메틸)-1',3'-디옥소란]플라티늄(Ⅱ)의 제조(Glycoraito-O, O ') {cyclohexanespiro-2'-[(4'R, 5'R) -4 ', 5'-bis (aminomethyl) -1', 3 'by Method A -Dioxolane] Platinum (II) Preparation
상기 실시예 1A에서와 동일한 방법으로 시스-디요오도{사이클로헥산스피로-2'-[(4'R,5'R)-4',5'-비스(아미노메틸)-1',3'-디옥소란]}플라티늄(Ⅱ) (0.50g, 0.77mmol)과 글라이콜산(0.12g, 1.58mmol) 및 산화은(Ⅰ)(0.36g, 1.55mmol)을 물(110ml)과 메탄올(10ml)과의 혼합매질 중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(6 : 4)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.174g 얻었다.Cis-diiodo {cyclohexanespiro-2 '-[(4'R, 5'R) -4', 5'-bis (aminomethyl) -1 ', 3' in the same manner as in Example 1A Dioxolane]} platinum (II) (0.50g, 0.77mmol), glycolic acid (0.12g, 1.58mmol) and silver oxide (I) (0.36g, 1.55mmol) in water (110ml) and methanol (10ml) After reaction in a mixed medium with, the product was purified by HPLC using a delta pack C18-100Å reversed phase bound silica cartridge as the stationary phase and a mixture of water and methanol (6: 4) as the mobile phase. Thus, 0.174 g of a white solid target compound was obtained.
수율 : 48%Yield: 48%
IR(KBr) : 3417, 3218, 3143cm-1(NH), 1634cm-1(C=O)IR (KBr): 3417, 3218, 3143cm -1 (NH), 1634cm -1 (C = O)
1H NMR(DMSO-d62/TMS) : δ 1.34(br s,2H,사이클로헥실), 1.54(br s,8H,사이클로헥실), 2.55(m,2H,2CHNH2), 3.14(m,2H,CHNH2), 3.78(s,2H,CH2), 4.40(m,2H,2CH), 4.93(br s,1H,NH), 5.15(br s,2H,2NH), 5.24(br s,1H,NH) 1 H NMR (DMSO-d 62 / TMS): δ 1.34 (br s, 2H, cyclohexyl), 1.54 (br s, 8H, cyclohexyl), 2.55 (m, 2H, 2CHNH 2 ), 3.14 (m, 2H , CHNH 2 ), 3.78 (s, 2H, CH 2 ), 4.40 (m, 2H, 2CH), 4.93 (br s, 1H, NH), 5.15 (br s, 2H, 2NH), 5.24 (br s, 1H , NH)
13C NMR(DMSO-D6) : δ 23.79, 24.83, 35.96, 36.00, 48.92, 48.96, 69.70, 78.17, 78.21, 109.43, 191.91 13 C NMR (DMSO-D 6 ): δ 23.79, 24.83, 35.96, 36.00, 48.92, 48.96, 69.70, 78.17, 78.21, 109.43, 191.91
FAB-MS : (M+H)+=469(194Pt, 33%), 470(195Pt, 34%) 및 471(196Pt, 25%)FAB-MS: (M + H) + = 469 ( 194 Pt, 33%), 470 ( 195 Pt, 34%) and 471 ( 196 Pt, 25%)
[실시예 4B]Example 4B
방법 B에 의한 (글라이코레이토-O,O'){사이클로헥산스피로-2'-[(4'R,5'R)-4',5'-비스(아미노메틸)-1',3'-디옥소란]}플라티늄(Ⅱ)의 제조(Glycoraito-O, O ') {cyclohexanespiro-2'-[(4'R, 5'R) -4 ', 5'-bis (aminomethyl) -1', 3 'by Method B -Dioxolane]} Preparation of Platinum (II)
[단계 1][Step 1]
상기 실시예 1B의 단계 1에서와 동일한 방법으로 시스-디요오도{사이클로헥산스피로-2'-[(4'R,5'R)-4',5'-비스(아미노메틸)-1',3'-디옥소란]플라티늄(Ⅱ) (0.50g, 0.77mmol)과 질산은 (0.26g, 1.53mmol)을 반응시킨 다음, 음이온교환수지 앰버라이트 IRA-400컬럼을 통과시켜서 시스-디히드록시{사이클로헥산스피로-2'-[(4'R,5'R)-4',5'-비스(아미노메틸)-1',3'-디옥소란]}플라티늄(Ⅱ)의 수용액을 얻었다.Cis-diiodo {cyclohexanespiro-2 '-[(4'R, 5'R) -4', 5'-bis (aminomethyl) -1 'in the same manner as in step 1 of Example 1B (3) -dioxolane] platinum (II) (0.50g, 0.77mmol) and silver nitrate (0.26g, 1.53mmol) were reacted and then passed through anion exchange resin Amberlite IRA-400 column to give cis-dihydroxy An aqueous solution of {cyclohexanespiro-2 '-[(4'R, 5'R) -4', 5'-bis (aminomethyl) -1 ', 3'-dioxolane]} platinum (II) was obtained. .
[단계 2][Step 2]
상기 실시예 1B의 단계 2에서와 동일한 방법으로 상기 단계 1에서 얻어진 시스-디히드록시{사이클로헥산스피로-2'-[(4'R,5'R)-4',5'-비스(아미노메틸)-1',3'-디옥소란]}플라티늄(Ⅱ)의 수용액과 글라이콜산 (0.06g, 0.79mmol) 및 글라이콜산 나트륨 수용액 (1M수용액 3.1ml)을 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물 (6:4)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.084g 얻었다.Cis-dihydroxy {cyclohexanespiro-2 '-[(4'R, 5'R) -4', 5'-bis (amino) obtained in step 1 in the same manner as in step 2 of Example 1B Methyl) -1 ', 3'-dioxolane]} platinum (II) solution with glycolic acid (0.06 g, 0.79 mmol) and sodium glycolate aqueous solution (3.1 ml aqueous solution) were reacted. As a stationary phase, a Delta Pack C18-100Å reverse-phase bound silica cartridge was employed and the mobile phase was purified by HPLC using a mixture of water and methanol (6: 4). Thus, 0.084 g of a white solid target compound was obtained.
수율 : 23%Yield: 23%
[실시예 5A]Example 5A
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-methyl-1,3-dioxolane] platinum (II) by Method A
상기 실시예 1A에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-메틸-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.84mmol)과 글라이콜산(0.13g, 1.71mmol) 및 산화은(Ⅰ)(0.39g, 1.68mmol)을 물(30ml)중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(95 : 5)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.225g 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-methyl-1,3-dioxolane] platinum (II) (0.50 g) in the same manner as in Example 1A above , 0.84 mmol), glycolic acid (0.13 g, 1.71 mmol), and silver oxide (I) (0.39 g, 1.68 mmol) were reacted in water (30 ml), and the product was then bound to the Delta Pack C18-100 Å reverse phase by a fixed phase. The silica cartridge was employed and the mobile phase was purified by HPLC using a mixture of water and methanol (95: 5). Thus, 0.225 g of a white solid target compound was obtained.
수율 : 64%Yield: 64%
IR(KBr) : 3451, 3213, 3139cm-1(NH), 1634cm-1(C=O)IR (KBr): 3451, 3213, 3139 cm -1 (NH), 1634 cm -1 (C = O)
1H NMR(D2O/DSS) : δ 1.40(d,J=4.8Hz,3H,CH3), 2.87(m,2H,2CHNH2), 3.28(m,1H,CHNH2), 3.39(m,1H,CHNH2), 4.10(s,2H,CH2), 4.64(m,1H,CH), 4.71(m,1H,CH,HOD와 중복), 5.28(q,J=4.8Hz,1H,CH) 1 H NMR (D 2 O / DSS): δ 1.40 (d, J = 4.8 Hz, 3H, CH 3 ), 2.87 (m, 2H, 2CHNH 2 ), 3.28 (m, 1H, CHNH 2 ), 3.39 (m , 1H, CHNH 2 ), 4.10 (s, 2H, CH 2 ), 4.64 (m, 1H, CH), 4.71 (overlapping with m, 1H, CH, HOD), 5.28 (q, J = 4.8 Hz, 1H, CH)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
13C NMR(D2O/DSS) : δ 19.51, 48.57, 48.73, 48.86, 49.05, 69.29, 78.82, 80.77, 102.70, 195.46 13 C NMR (D 2 O / DSS): δ 19.51, 48.57, 48.73, 48.86, 49.05, 69.29, 78.82, 80.77, 102.70, 195.46
내부 표준으로 DSS사용 (D2O중에서 DSS δ=-1.600ppm)Use DSS as internal standard (DSS δ = -1.600ppm in D 2 O)
FAB-MS : (M+H)+=415(194Pt, 33%), 416(195Pt, 34%) 및 417(196Pt, 25%)FAB-MS: (M + H) + = 415 ( 194 Pt, 33%), 416 ( 195 Pt, 34%) and 417 ( 196 Pt, 25%)
[실시예 5B]Example 5B
방법 B에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-methyl-1,3-dioxolane] platinum (II) by Method B
[단계 1][Step 1]
상기 실시예 1B의 단계 1에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-메틸-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.84mmol)과 질산은(0.28g, 1.65mmol) 반응시킨 다음, 음이온 교환수지 앰버라이트 IRA-400컬럼을 통과시켜서 시스-디히드록시 [(4R,5R)-4,5-비스(아미노메틸)-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)의 수용액을 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-methyl-1,3-dioxolane] platinum (II) in the same manner as in step 1 of Example 1B above (0.50 g, 0.84 mmol) and silver nitrate (0.28 g, 1.65 mmol) were reacted and then passed through an anion exchange resin Amberlite IRA-400 column to give cis-dihydroxy [(4R, 5R) -4,5-bis ( An aqueous solution of aminomethyl) -2-methyl-1,3-dioxolane] platinum (II) was obtained.
[단계 2][Step 2]
상기 실시예 1B의 단계 2에서와 동일한 방법으로 상기 단계 1에서 얻어진 시스-히드록시[(4R,5R)-4,5-비스(아미노메틸)-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)의 수용액과 글라콜산 (0.06g, 0.79mmol) 및 글라이콜산 나트륨 수용액(1M수용액 3.4ml)을 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(95 : 5)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.273g 얻었다.Cis-hydroxy [(4R, 5R) -4,5-bis (aminomethyl) -2-methyl-1,3-dioxolane] obtained in step 1 in the same manner as in step 2 of example 1B; After reacting an aqueous solution of platinum (II) with glycolic acid (0.06 g, 0.79 mmol) and an aqueous sodium glycolate solution (3.4 ml of 1 M aqueous solution), the product was used as a stationary phase. The mobile phase was purified by HPLC using a mixture of water and methanol (95: 5). Thus, 0.273 g of a white solid target compound was obtained.
수율 : 78%Yield: 78%
[실시예 6A]Example 6A
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-1,3-dioxolane] platinum (II) by Method A
상기 실시예 1A에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.82mmol)과 글라이콜산(0.13g, 1.71mmol) 및 산화은(Ⅰ)(0.38g, 1.64mmol)을 물(30ml)중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(9 : 1)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.234g 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-1,3-dioxolane] platinum (II) (0.50 g) in the same manner as in Example 1A above , 0.82 mmol), glycolic acid (0.13 g, 1.71 mmol) and silver oxide (I) (0.38 g, 1.64 mmol) were reacted in water (30 ml), and then the product was bound to the delta pack C18-100Å reverse phase as a stationary phase. A silica cartridge was employed and the mobile phase was purified by HPLC using a mixture of water and methanol (9: 1). Thus, 0.234 g of a white solid target compound was obtained.
수율 : 66%Yield: 66%
IR(KBr) : 3431, 3132cm-1(NH), 1650cm-1(C=O)IR (KBr): 3431, 3132cm -1 (NH), 1650cm -1 (C = O)
1H NMR(D2O/DSS) : δ 0.93(t,J=7.5Hz,3H,CH3), 1.72(dq,J=4.5Hz,J=7.5Hz,2H,CH2CH3), 2.88(m,2H,2CHNH2), 3.29(m,1H,CHNH2), 3.39(m,1H,CHNH2), 4.10(s,2H,CH2), 4.61(m,1H,CH), 4.68(m,1H,CH,HOD와 중복), 5.15(t,J=4.5Hz,1H,CH) 1 H NMR (D 2 O / DSS): δ 0.93 (t, J = 7.5Hz, 3H, CH 3 ), 1.72 (dq, J = 4.5Hz, J = 7.5Hz, 2H, CH 2 CH 3 ), 2.88 (m, 2H, 2CHNH 2) , 3.29 (m, 1H, CHNH 2), 3.39 (m, 1H, CHNH 2), 4.10 (s, 2H, CH2), 4.61 (m, 1H, CH), 4.68 (m Duplicate with 1H, CH, HOD), 5.15 (t, J = 4.5Hz, 1H, CH)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
13C NMR(D2O/DSS) : δ 7.89, 26.90, 48.65, 48.70, 48.94, 49.00, 69.28, 78.85, 80.57, 106.43, 195.48 13 C NMR (D 2 O / DSS): δ 7.89, 26.90, 48.65, 48.70, 48.94, 49.00, 69.28, 78.85, 80.57, 106.43, 195.48
내부 표준으로 DSS사용 (D2O중에서 DSS δ=-1.600ppm)Use DSS as internal standard (DSS δ = -1.600ppm in D 2 O)
FAB-MS : (M+H)+=429(194Pt, 33%), 430(195Pt, 34%) 및 431(196Pt, 25%)FAB-MS: (M + H) + = 429 ( 194 Pt, 33%), 430 ( 195 Pt, 34%) and 431 ( 196 Pt, 25%)
[실시예 6B]Example 6B
방법 B에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-1,3-dioxolane] platinum (II) by Method B
[단계 1][Step 1]
상기 실시예 1B의 단계 1에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.82mmol)과 질산은(0.28g, 1.65mmol)을 반응시킨 다음, 음이온 교환수지 앰버라이트 IRA-400컬럼을 통과시켜 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-1,3-디옥소란]플라티늄(Ⅱ)의 수용액을 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-1,3-dioxolane] platinum (II) in the same manner as in step 1 of Example 1B above (0.50g, 0.82mmol) and silver nitrate (0.28g, 1.65mmol) were reacted and then passed through anion exchange resin Amberlite IRA-400 column to cis-dihydroxy [(4R, 5R) -4,5-bis An aqueous solution of (aminomethyl) -2-ethyl-1,3-dioxolane] platinum (II) was obtained.
[단계 2][Step 2]
상기 실시예 1B의 단계 2에서와 동일한 방법으로 상기 단계 1에서 얻어진 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-1,3-디옥소란]플라티늄(Ⅱ)의 수용액과 글라이콜산(0.06g, 079mmol)과 글라이콜산 나트륨 수용액(1M수용액 3.3ml)을 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(9 : 1)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.189g 얻었다.Cis-dihydroxy [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-1,3-dioxolane obtained in step 1 in the same manner as in step 2 of Example 1B. ] Aqueous solution of platinum (II), glycolic acid (0.06 g, 079 mmol) and sodium glycolate solution (3.3 ml of 1 M aqueous solution) are reacted, and then the product is fixed as a delta pack C18-100Å reverse phase bonded silica cartridge. As a mobile phase, the mixture was purified by HPLC using a mixture of water and methanol (9: 1). In this way, 0.189g of the target compound of white solid was obtained.
수율 : 54%Yield: 54%
[실시예 7A]Example 7A
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-이소프로필-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-isopropyl-1,3-dioxolane] platinum (II) by Method A
상기 실시예 1A에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-이소프로필-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.80mmol)과 글라이콜산(0.12g, 1.58mmol) 및 산화은(Ⅰ)(0.38g, 1.60mmol)을 물(55ml)과 메탄올(5ml)과의 혼합매질 중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(7:3)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.267g 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-isopropyl-1,3-dioxolane] platinum (II) (0.50) in the same manner as in Example 1A above g, 0.80 mmol), glycolic acid (0.12 g, 1.58 mmol) and silver oxide (I) (0.38 g, 1.60 mmol) were reacted in a mixed medium of water (55 ml) and methanol (5 ml), and then the product was reacted. As a stationary phase, a Delta Pack C18-100Å reversed phase bound silica cartridge was employed and the mobile phase was purified by HPLC using a mixture of water and methanol (7: 3). This obtained 0.267g of the target compound of white solid.
수율 : 75%Yield: 75%
IR(KBr) : 3425, 3218, 3143cm-1(NH), 1634cm-1(C=O)IR (KBr): 3425, 3218, 3143cm -1 (NH), 1634cm -1 (C = O)
1H NMR(D2O/DSS) : δ 0.94(d,J=6.9Hz,6H,2CH3), 1.89(m,1H,CH(CH3)2), 2.86(m,2H,2CHNH2), 3.30(m,1H,CHNH2), 3.39(m,1H,CHNH2), 4.10(s,2H,CH2), 4.58(m,1H,CH), 4.64(m,1H,CH, HOD와 중복), 4.98(d,J=4.2Hz,1H,CH) 1 H NMR (D 2 O / DSS): δ 0.94 (d, J = 6.9 Hz, 6H, 2CH 3 ), 1.89 (m, 1H, CH (CH 3 ) 2 ), 2.86 (m, 2H, 2CHNH 2 ) , 3.30 (m, 1H, CHNH 2 ), 3.39 (m, 1H, CHNH 2 ), 4.10 (s, 2H, CH 2 ), 4.58 (m, 1H, CH), 4.64 (m, 1H, CH, HOD and Redundancy), 4.98 (d, J = 4.2 Hz, 1H, CH)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
13C NMR(D2O/DSS) : δ 16.69, 16.79, 32.02, 48.66, 48.72, 48.96, 49.02, 69.28, 78.97, 80.48, 109.26, 195.50 13 C NMR (D 2 O / DSS): δ 16.69, 16.79, 32.02, 48.66, 48.72, 48.96, 49.02, 69.28, 78.97, 80.48, 109.26, 195.50
내부 표준으로 DSS사용 (D2O중에서 DSS δ=-1.600ppm)Use DSS as internal standard (DSS δ = -1.600ppm in D 2 O)
FAB-MS : (M+H)+=443(194Pt, 33%), 444(195Pt, 34%) 및 445(196Pt, 25%)FAB-MS: (M + H) + = 443 ( 194 Pt, 33%), 444 ( 195 Pt, 34%) and 445 ( 196 Pt, 25%)
[실시예 7B]Example 7B
방법 B에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-이소프로필-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-isopropyl-1,3-dioxolane] platinum (II) by Method B
[단계 1][Step 1]
상기 실시예 1B의 단계 1에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-이소프로필-1,3-디옥소란]플라티늄(Ⅱ) (0.50g, 0.80mmol)과 질산은 (0.27g, 1.59mmol)을 반응시킨 다음, 음이온교환수지 앰버라이트 IRA-400컬럼을 통과시켜서 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-2-이소프로필-1,3-디옥소란]플라티늄(Ⅱ)의 수용액을 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-isopropyl-1,3-dioxolane] platinum (II) in the same manner as in step 1 of Example 1B above ) (0.50 g, 0.80 mmol) and silver nitrate (0.27 g, 1.59 mmol) were reacted and then passed through anion exchange resin Amberlite IRA-400 column to give cis-dihydroxy [(4R, 5R) -4,5- An aqueous solution of bis (aminomethyl) -2-isopropyl-1,3-dioxolane] platinum (II) was obtained.
[단계 2][Step 2]
상기 실시예 1B의 단계 2에서와 동일한 방법으로 상기 단계 1에서 얻어진 시스-디히드록시[(4R,5R)-4,5-비스(아미노메틸)-2-이소프로필-1,3-디옥소란]플라티늄(Ⅱ)의 수용액과 글라이콜산 (0.06g, 079mmol)과 글라이콜산 나트륨 수용액(1M수용액 3.2ml)을 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(7 : 3)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.102g 얻었다.Cis-dihydroxy [(4R, 5R) -4,5-bis (aminomethyl) -2-isopropyl-1,3-dioxo obtained in step 1, in the same manner as in step 2 of Example 1B. After reacting an aqueous solution of lan] platinum (II) with glycolic acid (0.06 g, 079 mmol) and an aqueous sodium glycolate solution (3.2 ml of 1 M aqueous solution), the product was fixed as a delta pack C18-100 Å reversed phase silica cartridge. Was employed and the mobile phase was purified by HPLC using a mixture of water and methanol (7: 3). In this way, 0.102g of white solid target compounds were obtained.
수율 : 29%Yield: 29%
상기 실시예 1 내지 7에서 사용된 출발물질들은 상품화된 것을 구입하여 사용하거나 공지의 문헌 또는 본 출원인의 1991년 3월 23일자 대한민국 특허출원 제4627호에 개시된 방법에 따라 제조될 수 있다.The starting materials used in Examples 1 to 7 may be purchased and used commercially, or may be prepared according to a known method or a method disclosed in Korean Patent Application No. 4627 of March 23, 1991 of the present applicant.
[실시예 8]Example 8
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2,2-디에틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조(Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2,2-diethyl-1,3-dioxolane] platinum (II) by Method A Manufacture
시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2,2-디에틸-1,3-디옥소란]플라티늄(Ⅱ) (1.42g, 2.23mmol)과 글라이콜산(0.34g, 4.46mmol) 및 산화은(Ⅰ)(1.03g, 4.46mmol)을 물(100ml)과 메탄올(10ml)과의 혼합용매에 투입하고, 이를 암조건하에서 60℃를 유지하면서 하룻밤동안 교반시켰다. 이 반응혼합물을 실온으로 냉각시킨 후, 셀라이트 패드를 통과시켜 여과하고, 그 잔사를 소량의 물로 세척하였다. 이어서, 여과물과 세척물의 혼합물을 감압항서 농축하여 20ml가 되게한 다음, 그 농축액을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(6 : 4)을 사용하여 HPLC로 정제하였다. 그런 다음, 얻어진 용출액을 감압하에서 농축하고 동결 건조하여서 백색 고형의 목적화합물을 0.616g 얻었다.Cis-diiodo [(4R, 5R) -4,5-bis (aminomethyl) -2,2-diethyl-1,3-dioxolane] platinum (II) (1.42 g, 2.23 mmol) Lycolic acid (0.34 g, 4.46 mmol) and silver oxide (I) (1.03 g, 4.46 mmol) were added to a mixed solvent of water (100 ml) and methanol (10 ml), which were kept overnight at 60 ° C. under dark conditions. Stirred. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the residue was washed with a small amount of water. The mixture of filtrate and washings was then concentrated under reduced pressure to 20 ml, and then the concentrate was taken as a fixed phase using a delta pack C18-100Å reversed phase bound silica cartridge and as a mobile phase a mixture of water and methanol (6: 4). Purification was carried out by HPLC. Then, the obtained eluate was concentrated under reduced pressure and lyophilized to obtain 0.616 g of a white solid target compound.
수율 : 60%Yield: 60%
IR(KBr) : 3422, 3208cm-1(NH), 1640cm-1(C=O)IR (KBr): 3422, 3208cm -1 (NH), 1640cm -1 (C = O)
1H NMR(D2O/DSS) : δ 0.91(t,J=7.2Hz,6H,2CH3), 1.73(q,J=7.2Hz,4H,2CH2), 2.80-2.96(m,2H,2CHNH2), 3.29-3.42(m,2H,2CHNH2), 4.10(s,2H,CH2), 4.71(m,2H,2CH, HOD와 중복) 1 H NMR (D 2 O / DSS): δ 0.91 (t, J = 7.2Hz, 6H, 2CH 3 ), 1.73 (q, J = 7.2Hz, 4H, 2CH 2 ), 2.80-2.96 (m, 2H, 2CHNH 2 ), 3.29-3.42 (m, 2H, 2CHNH 2 ), 4.10 (s, 2H, CH 2 ), 4.71 (overlapping with m, 2H, 2CH, HOD)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
13C NMR(D2O/DSS) : δ 8.10, 30.64, 49.29, 49.57, 69.25, 79.65, 115.53, 195.46 13 C NMR (D 2 O / DSS): δ 8.10, 30.64, 49.29, 49.57, 69.25, 79.65, 115.53, 195.46
내부 표준으로 DSS사용 (D2O중에서 DSS δ=-1.600ppm)Use DSS as internal standard (DSS δ = -1.600ppm in D 2 O)
FAB-MS : (M+H)+=457(194Pt, 33%), 458(195Pt, 34%) 및 459(196Pt, 25%)FAB-MS: (M + H) + = 457 ( 194 Pt, 33%), 458 ( 195 Pt, 34%) and 459 ( 196 Pt, 25%)
[실시예 9]Example 9
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조(Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-2-methyl-1,3-dioxolane] platinum (II by Method A Manufacturing
상기 실시예 8에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)(1.22g, 1.96mmol)과 글라이콜산(0.30g, 3.92mmol)및 산화은(Ⅰ)(0.91g, 3.92mmol)을 물(90ml)과 메탄올(10ml)과의 혼합용매 중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(6 : 4)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.607g 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-2-methyl-1,3-dioxolane] platinum (II) in the same manner as in Example 8 above ) (1.22 g, 1.96 mmol), glycolic acid (0.30 g, 3.92 mmol) and silver oxide (I) (0.91 g, 3.92 mmol) were reacted in a mixed solvent of water (90 ml) and methanol (10 ml), The product was purified by HPLC using a Delta Pack C18-100Å reversed phase bound silica cartridge as the stationary phase and a mixture of water and methanol (6: 4) as the mobile phase. In this way, 0.607g of white solid target compounds were obtained.
수율 : 70%Yield: 70%
IR(KBr) : 3425, 3142cm-1(NH), 1645cm-1(C=O)IR (KBr): 3425, 3142cm -1 (NH), 1645cm -1 (C = O)
1H NMR(D2O/DSS) : δ 0.92(t,J=6.6Hz,3H,CH3), 1.43(s,3H,CH3), 1.75(q,J=6.6Hz,2H,CH2), 2.78-2.98(m,2H,2CHNH2), 3.28-3.42(m,2H,2CHCH2), 4.10(S,2H,CH2), 4.72(m,2H,2CH, HOD와 중복) 1 H NMR (D 2 O / DSS): δ 0.92 (t, J = 6.6 Hz, 3H, CH 3 ), 1.43 (s, 3H, CH 3 ), 1.75 (q, J = 6.6Hz, 2H, CH 2 ), 2.78-2.98 (m, 2H, 2CHNH 2 ), 3.28-3.42 (m, 2H, 2CHCH 2 ), 4.10 (S, 2H, CH 2 ), 4.72 (duplicate with m, 2H, 2CH, HOD)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
13C NMR(D2O/DSS) : δ 8.25, 24.66, 32.69, 49.42, 49.52, 69.27, 79.04, 79.64, 113.44, 195.44 13 C NMR (D 2 O / DSS): δ 8.25, 24.66, 32.69, 49.42, 49.52, 69.27, 79.04, 79.64, 113.44, 195.44
내부 표준으로 DSS사용 (D2O중에서 DSS δ=-1.600ppm)Use DSS as internal standard (DSS δ = -1.600ppm in D 2 O)
FAB-MS : (M+H)+=443(194Pt, 33%), 444(195Pt, 34%) 및 445(196Pt, 25%)FAB-MS: (M + H) + = 443 ( 194 Pt, 33%), 444 ( 195 Pt, 34%) and 445 ( 196 Pt, 25%)
[실시예 10]Example 10
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-프로필-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-propyl-1,3-dioxolane] platinum (II) by Method A
상기 실시예 8에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-프로필-1,3-디옥소란]플라티늄(Ⅱ) (1.00g, 1.91mmol)과 글라이콜산(0.29g, 3.82mmol) 및 산화은(Ⅰ) (0.89g, 3.82mmol)을 물(90ml)과 메탄올(10ml)과의 혼합용매 중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(5 : 5)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.470g 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-propyl-1,3-dioxolane] platinum (II) (1.00 g) in the same manner as in Example 8 above , 1.91 mmol), glycolic acid (0.29 g, 3.82 mmol) and silver oxide (I) (0.89 g, 3.82 mmol) were reacted in a mixed solvent of water (90 ml) and methanol (10 ml), and then the product was fixed. A delta pack C18-100Å reverse phase bound silica cartridge was employed and the mobile phase was purified by HPLC using a mixture of water and methanol (5: 5). Thus, 0.470 g of a white solid target compound was obtained.
수율 : 56%Yield: 56%
IR(KBr) : 3422, 3210, 3131cm-1(NH), 1630cm-1(C=O)IR (KBr): 3422, 3210, 3131cm -1 (NH), 1630cm -1 (C = O)
1H NMR(D2O/DSS) : δ 0.94(t,J=7.2Hz,3H,CH3), 1.41(m,2H,CH3), 1.68(m,2H,CH2), 2.81-2.97(m,2H,2CHNH2), 3.23-3.34(m,1H,CHNH2), 3.34-3.45(m,1H,CHNH2), 4.10(s,2H,CH2), 4.62(m,2H,2CH, HOD와 중복), 5.19(t,J=4.2Hz,1H,CH) 1 H NMR (D 2 O / DSS): δ 0.94 (t, J = 7.2 Hz, 3H, CH 3 ), 1.41 (m, 2H, CH 3 ), 1.68 (m, 2H, CH 2 ), 2.81-2.97 (m, 2H, 2CHNH 2 ), 3.23-3.34 (m, 1H, CHNH 2 ), 3.34-3.45 (m, 1H, CHNH 2 ), 4.10 (s, 2H, CH 2 ), 4.62 (m, 2H, 2CH , Redundant with HOD), 5.19 (t, J = 4.2 Hz, 1H, CH)
내부 표준으로 DSS사용 (D2O중에서 DSS δ=0.015ppm)Use DSS as internal standard (DSS δ = 0.015ppm in D 2 O)
FAB-MS : (M+H)+=443(194Pt, 33%), 444(195Pt, 34%) 및 445(196Pt, 25%)FAB-MS: (M + H) + = 443 ( 194 Pt, 33%), 444 ( 195 Pt, 34%) and 445 ( 196 Pt, 25%)
[실시예 11]Example 11
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-이소부틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of (Glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-isobutyl-1,3-dioxolane] platinum (II) by Method A
상기 실시예 8에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-이소부틸-1,3-디옥소란]플라티늄(Ⅱ) (1.00g, 1.86mmol)과 글라이콜산(0.28g, 3.72mmol) 및 산화은(Ⅰ) (0.86g, 3.72mmol)을 물(90ml)과 메탄올(10ml)과의 혼합용매 중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(5 : 5)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.257g 얻었다.Cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-isobutyl-1,3-dioxolane] platinum (II) (1.00) in the same manner as in Example 8 above g, 1.86 mmol) and glycolic acid (0.28 g, 3.72 mmol) and silver oxide (I) (0.86 g, 3.72 mmol) were reacted in a mixed solvent of water (90 ml) and methanol (10 ml), and then the product was reacted. As a stationary phase, a Delta Pack C18-100Å reversed phase bound silica cartridge was employed and the mobile phase was purified by HPLC using a mixture of water and methanol (5: 5). This obtained 0.257g of the target compound of white solid.
수율 : 30%Yield: 30%
IR(KBr) : 3430, 3140, 3082cm-1(NH), 1653cm-1(C=O)IR (KBr): 3430, 3140, 3082cm -1 (NH), 1653cm -1 (C = O)
FAB-MS : (M+H)+=457(194Pt, 33%), 458(195Pt, 34%) 및 459(196Pt, 25%)FAB-MS: (M + H) + = 457 ( 194 Pt, 33%), 458 ( 195 Pt, 34%) and 459 ( 196 Pt, 25%)
[실시예 12]Example 12
방법 A에 의한 (글라이코레이토-O,O')[(4R,5R)-4,5-비스(아미노메틸)-2-tert-부틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Of (glycoraito-O, O ') [(4R, 5R) -4,5-bis (aminomethyl) -2-tert-butyl-1,3-dioxolane] platinum (II) by Method A Produce
상기 실시예 8에서와 동일한 방법으로 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-tert-부틸-1,3-디옥소란]플라티늄(Ⅱ) (0.97g, 1.80mmol)과 글라이콜산(0.27g, 3.60mmol) 및 산화은(Ⅰ) (0.83g, 3.60mmol)을 물(90ml)과 메탄올(10ml)과의 혼합용매 중에서 반응시킨 다음, 그 생성물을 고정상으로 델타 팩 C18-100Å 역상 결합된 실리카 카트리지를 채용하고 이동상으로는 물과 메탄올과의 혼합물(5:5)을 사용하여 HPLC로 정제하였다. 이렇게 하여 백색 고형의 목적화합물을 0.402g 얻었다.Cis-diodo [(4R, 5R) -4,5-bis (aminomethyl) -2-tert-butyl-1,3-dioxolane] platinum (II) ( 0.97 g, 1.80 mmol), glycolic acid (0.27 g, 3.60 mmol) and silver oxide (I) (0.83 g, 3.60 mmol) were reacted in a mixed solvent of water (90 ml) and methanol (10 ml), and then the product. It was purified by HPLC using a Delta Pack C18-100Å reversed phase bound silica cartridge as the stationary phase and a mixture of water and methanol (5: 5) as the mobile phase. In this way, 0.402g of white solid target compounds were obtained.
수율 : 49%Yield: 49%
IR(KBr) : 3486, 3190, 3063cm-1(NH), 1645cm-1(C=O)IR (KBr): 3486, 3190, 3063cm -1 (NH), 1645cm -1 (C = O)
FAB-MS : (M+H)+=457(194Pt, 33%), 458(195Pt, 34%) 및 459(196Pt, 25%)FAB-MS: (M + H) + = 457 ( 194 Pt, 33%), 458 ( 195 Pt, 34%) and 459 ( 196 Pt, 25%)
상기 실시예 8 내지 12에서 사용된 출발물질들은 상품화된 것을 구입하여 사용하거나 공지문헌에 따라 제조될 수 있으며 일부 신규한 화합물들은 다음 제조예 1∼5에 따라 제조하였다.The starting materials used in Examples 8 to 12 may be purchased and used commercially or prepared according to the known literature, and some novel compounds were prepared according to Preparation Examples 1 to 5 below.
[제조예 1][Production Example 1]
시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2,2-디에틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2,2-diethyl-1,3-dioxolane] platinum (II)
[단계 1][Step 1]
D-트레이톨 1,4-비스(메탄술포네이트)(4.17g, 15.0mmol)와 3-펜타논(2.58g, 30.0mmol, 3.17ml) 및 메탄술폰산(3방울)을 벤젠(50ml)과 혼합시키고, 그 혼합물을 딘-스타크 연속 수분분리기로 수분을 제거하면서 16시간동안 환류시켰다. 반응 혼합물을 실온으로 냉각시킨후, 이 투명 용액에 무수탄산칼륨(0.20g)을 첨가하고 20분동안 더 교반시켰다. 그런 다음, 이 반응 혼합물을 여과하고 감압하에서 증발건조시킨 후 잔사를 100% 에탄올로부터 결정화시켜서 백색결정의 2,3-O-디에틸메틸렌-D-트레이톨 1,4-비스(메탄술포네이트)를 4.32g 얻었다.Mix D-thritol 1,4-bis (methanesulfonate) (4.17g, 15.0mmol), 3-pentanone (2.58g, 30.0mmol, 3.17ml) and methanesulfonic acid (3drops) with benzene (50ml) The mixture was refluxed for 16 hours with water removal with a Dean-Stark continuous moisture separator. After the reaction mixture was cooled to room temperature, anhydrous potassium carbonate (0.20 g) was added to this clear solution and further stirred for 20 minutes. The reaction mixture was then filtered and evaporated to dryness under reduced pressure, and the residue was crystallized from 100% ethanol to give 2,3-O-diethylmethylene-D-thritol 1,4-bis (methanesulfonate) as white crystals. 4.32 g was obtained.
수율 : 83%Yield: 83%
m.p. : 53.5℃m.p. : 53.5 ℃
IR(KBr) : 1351, 1170cm-1(O-SO2)IR (KBr): 1351, 1170cm -1 (O-SO2)
1H NMR(CDCl3) : δ 0.92(t,J=7.3Hz,6H,2CH3), 1.68(q,J=7.3Hz,4H,2CH2), 3.08(s,6H,2SO2CH3), 4.08-4.22(m,2H,2CH), 4.08-4.22(m,2H,2CH), 4.22-4.44(m,4H,2CH2) 1 H NMR (CDCl 3 ): δ 0.92 (t, J = 7.3Hz, 6H, 2CH 3 ), 1.68 (q, J = 7.3Hz, 4H, 2CH 2 ), 3.08 (s, 6H, 2SO2CH 3 ), 4.08 -4.22 (m, 2H, 2CH), 4.08-4.22 (m, 2H, 2CH), 4.22-4.44 (m, 4H, 2CH 2 )
[단계 2][Step 2]
상기 단계 1에서 얻어진 2,3-O-디에틸메틸렌-D-트레이톨 1,4-비스(메탄술포네이트) (4.26g, 12.3mmol)을 무수 N-N-디메틸포름아마이드(30ml)에 녹이고, 여기에 아지드화나트륨(3.20g, 49.2mmol)을 첨가한 다음, 그 혼합물을 질소충진하에서 16시간동안 80℃로 가열하였다. 그런 다음, 반응혼합물을 실온으로 냉각시키고 물(50ml)로 희석시킨 후 에테르(100ml)로 추출하였다. 이 에테르성 용액을 함수(20ml)로 세척하고 무수 황산마그네슘으로 건조한 다음 감압하에서 증발건조시켰다. 그 조성생물을 실리카겔을 통해 플래쉬 컬럼 크로마토그라피하여 정제하였다. 이때 용출액으로는 에테르-헥산(1 : 4)을 이용하였다. 그 결과 엷은 황색 오일상의 (4R,5R)-4,5-비스(아지도메틸)-2,2-디에틸-1,3-디옥소란을 2.65g 얻었다.2,3-O-diethylmethylene-D-thritol 1,4-bis (methanesulfonate) (4.26 g, 12.3 mmol) obtained in step 1 was dissolved in anhydrous NN-dimethylformamide (30 ml), and To sodium azide (3.20 g, 49.2 mmol) was added, the mixture was heated to 80 ° C. for 16 hours under nitrogen filling. The reaction mixture was then cooled to room temperature, diluted with water (50 ml) and extracted with ether (100 ml). The ethereal solution was washed with brine (20 ml), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The composition was purified by flash column chromatography on silica gel. At this time, ether-hexane (1: 4) was used as the eluent. As a result, 2.65 g of (4R, 5R) -4,5-bis (azidomethyl) -2,2-diethyl-1,3-dioxolane was obtained as a pale yellow oil.
수율 : 90%Yield: 90%
=+105.89°(아세톤) = + 105.89 ° (acetone)
IR(니트) : 2104cm-1(N3)IR (knit): 2104cm -1 (N 3 )
1H NMR(CDCl3) : δ 0.93(t,J=7.3Hz,6H,2CH3), 1.70(q,J=7.3Hz,4H,2CH2), 3.27-3.63(m,4H,2CH2), 3.89-4.10(m,2H,2CH) 1 H NMR (CDCl 3 ): δ 0.93 (t, J = 7.3Hz, 6H, 2CH 3 ), 1.70 (q, J = 7.3Hz, 4H, 2CH 2 ), 3.27-3.63 (m, 4H, 2CH 2 ) , 3.89-4.10 (m, 2H, 2CH)
13C NMR(CDCl3) : δ 7.91, 30.21, 51.75, 77.13, 114.16 13 C NMR (CDCl 3 ): δ 7.91, 30.21, 51.75, 77.13, 114.16
[단계 3][Step 3]
상기 단계 2에서 얻어진 (4R,5R)-4,5-비스(아지도메틸)-2,2-디에틸-1,3-디옥소란 (2.65g, 10.9mmol)을 에탄올(30ml)에 용해시킨 후 10% 팔라듐-활성탄소(0.25g)의 존재하에 50psi의 압력 및 40℃의 온도조건에서 2시간동안 수소화시켰다. 이 반응 혼합물을 셀라이트 패드를 통과시켜 여과하고 그 잔사를 감압하에서 증발건조시켜서 무색 오일상의 (4R,5R)-4,5-비스(아미노메틸)-2,2-디에틸-1,3-디옥소란을 2.05g을 얻었다.(4R, 5R) -4,5-bis (azidomethyl) -2,2-diethyl-1,3-dioxolane (2.65 g, 10.9 mmol) obtained in step 2 was dissolved in ethanol (30 ml). After hydrogenation was carried out for 2 hours at a pressure of 50 psi and a temperature of 40 ° C. in the presence of 10% palladium-activated carbon (0.25 g). The reaction mixture was filtered through a pad of celite and the residue was evaporated to dryness under reduced pressure to give a colorless oily (4R, 5R) -4,5-bis (aminomethyl) -2,2-diethyl-1,3- 2.05 g of dioxolane was obtained.
수율 : 100%Yield: 100%
IR(니트) : 3374, 3299cm-1(NH2)IR (knit): 3374, 3299 cm -1 (NH2)
1H NMR(CDCl3) : δ 0.91(t,J=7.3Hz,6H,2CH3), 1.39(s,4H,2NH2), 1.65(q,J=7.3Hz,4H,2CH2), 2.68-3.04(m,4H,2CH2), 3.60-3.87(m,2H,2CH) 1 H NMR (CDCl 3 ): δ 0.91 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.39 (s, 4H, 2NH 2 ), 1.65 (q, J = 7.3Hz, 4H, 2CH 2 ), 2.68 -3.04 (m, 4H, 2CH 2 ), 3.60-3.87 (m, 2H, 2CH)
13C NMR(CDCl3) : δ 8.01, 30.56, 44.24, 80.50, 112.41 13 C NMR (CDCl 3 ): δ 8.01, 30.56, 44.24, 80.50, 112.41
[단계 4][Step 4]
요오드화 칼륨(10.86g, 65.4mmol)을 물(25ml)에 녹여 교반시키면서, 여기에다 사염화백금(Ⅱ)칼륨(4.53g, 10.9mmol)을 물(160ml)에 용해시키고 여과하면서 얻은 용액을 첨가한 후, 질소로 충진하고 암조건하에 실온에서 40분동안 교반시켜서 흑색의 사요오드화백금(Ⅱ)칼륨의 용액을 얻었다. 플라스크에 120ml의 물을 채우고 질소로 충진한 후 60℃로 유지하면서 교반시켜 준 다음, 여기에 상기 사요오드화백금(Ⅱ)칼륨의 용액과 상기 단계 3에서 얻어진(4R,5R)-4,5-비스(아미노메틸)-2,2-디에틸-1,3-디옥소란(2.05g, 10.9mmol)을 물(180ml)에 용해시켜서된 용액을 동시에 2시간에 걸쳐 일정한 속도로 적가하였다. 1시간후 여과하여 황색의 침전을 모아, 물, 에탄올 및 에테르로 연이어 세척한 다음 진공건조시켜서, 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2,2-디에틸-1,3-디옥소란]플라티늄(Ⅱ)을 6.35g 얻었다.Potassium iodide (10.86 g, 65.4 mmol) was dissolved in water (25 ml) and stirred, while platinum (II) potassium tetrachloride (4.53 g, 10.9 mmol) was dissolved in water (160 ml), followed by addition of a solution obtained by filtration. Filled with nitrogen and stirred for 40 minutes at room temperature under dark conditions to obtain a solution of black potassium iodide (II) potassium iodide. The flask was filled with 120 ml of water, filled with nitrogen, and stirred at 60 ° C., followed by the solution of platinum (II) potassium iodide and obtained in step 3 (4R, 5R) -4,5- Bis (aminomethyl) -2,2-diethyl-1,3-dioxolane (2.05 g, 10.9 mmol) dissolved in water (180 ml) was added dropwise at a constant rate over 2 hours simultaneously. After 1 hour, the yellow precipitate was collected by filtration, washed successively with water, ethanol and ether, followed by vacuum drying to obtain cis-diiodo [(4R, 5R) -4,5-bis (aminomethyl) -2,2. 6.35 g of -diethyl-1,3-dioxolane] platinum (II) was obtained.
수율 : 91%Yield: 91%
[제조예 2][Production Example 2]
시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-2-methyl-1,3-dioxolane] platinum (II)
[단계 1][Step 1]
D-트레이톨 1,4-비스(메탄술포네이트)(3.50g, 12.6mmol)와 2-부타논(70ml), 무수황산구리(Ⅱ)(3.01g, 18.9mmol) 및 농축황산(0.1ml)을 혼합시키고, 질소충진하에서 16시간동안 환류시켰다. 반응 혼합물을 여과하고 그 여액을 28% 수산암모늄 하이록사이드 용액으로 중화시킨 다음, 증발건조시키고 100% 에탄올로 결정화시켜서 백색 결정의 2,3-O-(1-메틸프로필리덴)-D-트레이톨 1,4-비스(메탄술포네이트)를 3.69g 얻었다.D-thritol 1,4-bis (methanesulfonate) (3.50 g, 12.6 mmol), 2-butanone (70 ml), anhydrous copper sulfate (II) (3.01 g, 18.9 mmol) and concentrated sulfuric acid (0.1 ml) It was mixed and refluxed for 16 hours under nitrogen filling. The reaction mixture was filtered and the filtrate was neutralized with 28% ammonium hydroxide hydroxide solution, then evaporated to dryness and crystallized with 100% ethanol to give 2,3-O- (1-methylpropylidene) -D-thritol as white crystals. 3.69g of 1, 4-bis (methanesulfonate) were obtained.
수율 : 98%Yield: 98%
m.p. : 71.5-72.5℃m.p. : 71.5-72.5 ℃
IR(KBr) : 1352, 1332, 1182cm-1(O-SO2)IR (KBr): 1352, 1332, 1182cm -1 (O-SO2)
1H NMR(CDCl3) : δ 0.94(t,J=7.3Hz,3H,CH3), 1.38(s,3H,CH2), 1.70(q,J=7.3Hz,2H,CH2), 3.08(s,6H,2SO2CH3), 4.02-4.27(m,2H,2CH), 4.31-4.45(m,4H,2CH2) 1 H NMR (CDCl 3 ): δ 0.94 (t, J = 7.3 Hz, 3H, CH 3 ), 1.38 (s, 3H, CH 2 ), 1.70 (q, J = 7.3Hz, 2H, CH 2 ), 3.08 (s, 6H, 2SO 2 CH 3 ), 4.02-4.27 (m, 2H, 2CH), 4.31-4.45 (m, 4H, 2CH 2 )
13C NMR(CDCl3) : δ 8.01, 24.59, 32.69, 37.70, 67.74, 67.97, 75.02, 75.60, 112.90 13 C NMR (CDCl 3 ): δ 8.01, 24.59, 32.69, 37.70, 67.74, 67.97, 75.02, 75.60, 112.90
[단계 2][Step 2]
상기 단계 1에서 얻어진 2,3-O-(1-메틸프로필리덴)-D-트레이톨 1,4-비스(메탄술포네이트) (3.50g, 11.7mmol)을 제조예 1의 단계 2에서와 동일한 방법으로 아지드화 나트륨과 반응시켜서 엷은 황색오일상의 (4R,5R)-4,5-비스(아지도메틸)-2-에틸-2-메틸-1,3-디옥소란을 2.35g 얻었다.2,3-O- (1-methylpropylidene) -D-thritol 1,4-bis (methanesulfonate) (3.50 g, 11.7 mmol) obtained in step 1 was the same as in step 2 of Preparation Example 1. By reacting with sodium azide by the method, 2.35 g of (4R, 5R) -4,5-bis (azidomethyl) -2-ethyl-2-methyl-1,3-dioxolane as pale yellow oil was obtained.
수율 : 88%Yield: 88%
=+128.24°(아세톤) = + 128.24 ° (acetone)
IR(니트) : 2105cm-1(N3)IR (knit): 2105cm -1 (N 3 )
1H NMR(CDCl3) : δ 0.96(t,J=7.3Hz,3H,CH3), 1.41(s,.3H,CH3), 1.73(q,J=7.3Hz,2H,CH2), 3.23-3.65(m,4H,2CH2), 3.88-4.18(m,2H,2CH) 1 H NMR (CDCl 3 ): δ 0.96 (t, J = 7.3 Hz, 3H, CH 3 ), 1.41 (s, .3H, CH 3 ), 1.73 (q, J = 7.3 Hz, 2H, CH 2 ), 3.23-3.65 (m, 4H, 2CH 2 ), 3.88-4.18 (m, 2H, 2CH)
13C NMR(CDCl3) : δ 8.04, 24.53, 32.82, 51.61, 51.70, 76.65, 77.32, 112.28 13 C NMR (CDCl 3 ): δ 8.04, 24.53, 32.82, 51.61, 51.70, 76.65, 77.32, 112.28
[단계 3][Step 3]
상기 단계 2에서 얻어진 (4R,5R)-4,5-비스(아지도메틸)-2-에틸-2-메틸-1,3-디옥소란 (2.70g, 11.9mmol)을 제조예 1의 단계 3에서와 동일한 방법으로 환원시켜서 오일상의 (4R,5R)-4,5-비스(아미노메틸)-2-에틸-2-메틸-디에틸-1,3-디옥소란을 2.08g 얻었다.(4R, 5R) -4,5-bis (azidomethyl) -2-ethyl-2-methyl-1,3-dioxolane (2.70 g, 11.9 mmol) obtained in step 2 was prepared. Reduction was performed in the same manner as in 3. to obtain 2.08 g of (4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-2-methyl-diethyl-1,3-dioxolane in an oily state.
수율 : 100%Yield: 100%
IR(니트) : 3373, 3319cm-1(NH2)IR (knit): 3373, 3319cm -1 (NH2)
1H NMR(CDCl3) : δ 0.94(t,J=7.4Hz,3H,CH3), 1.35(br s,7H,CH3및 2NH2), 1.68(q,J=7.4Hz,2H,CH2), 2.71-3.03(m,4H,2CH2), 3.63-3.93(m,2H,2CH) 1 H NMR (CDCl 3 ): δ 0.94 (t, J = 7.4 Hz, 3H, CH 3 ), 1.35 (br s, 7H, CH 3 and 2NH 2 ), 1.68 (q, J = 7.4 Hz, 2H, CH 2 ), 2.71-3.03 (m, 4H, 2CH 2 ), 3.63-3.93 (m, 2H, 2CH)
13C NMR(CDCl3) : δ 8.10, 25.01, 33.01, 43.99, 44.24, 79.84, 80.55, 110.49 13 C NMR (CDCl 3 ): δ 8.10, 25.01, 33.01, 43.99, 44.24, 79.84, 80.55, 110.49
[단계 4][Step 4]
상기 단계 3에서 얻어진 (4R,5R)-4,5-비스(아미노메틸)-2-에틸-2-메틸-1,3-디옥소란(2.08g, 11.9mmol)을 제조예 1의 단계에서와 동일한 방법으로 사요오드화백금(Ⅱ) 칼륨의 수용액과 반응시켜서 황색 고형의 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-에틸-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)을 7.12g 얻었다.(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-2-methyl-1,3-dioxolane (2.08 g, 11.9 mmol) obtained in step 3 was prepared in the step of Preparation Example 1. Yellow solid cis-diiodo [(4R, 5R) -4,5-bis (aminomethyl) -2-ethyl-2-methyl-1 was reacted with an aqueous solution of platinum (II) potassium iodide in the same manner as 7.12 g of, 3-dioxolane] platinum (II) was obtained.
수율 : 96%Yield: 96%
[제조예 3][Manufacture example 3]
시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-프로필-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of cis-dioodo [(4R, 5R) -4,5-bis (aminomethyl) -2-propyl-1,3-dioxolane] platinum (II)
[단계 1][Step 1]
D-트레이톨 1,4-비스(메탄술포네이트)(3.50g, 12.6mmol)와 n-부틸알데하이드(1.00g, 13.8mmol, 1.25ml), 무수황산구리(Ⅱ) (3.01g, 18.9mmol) 및 메탄술폰산(3방울)을 무수 톨루엔(35ml)에 혼합시키고 질소 충진하에서 16시간동안 교반시켰다. 이 반응 혼합물을 무수 탄산칼륨(0.30g)을 첨가하고, 20분 동안 더 교반시켰다. 이를 여과하고 증발건조시킨 후 100% 에탄올로 결정화시켜서 백색 결정의 2,3-O-부틸리덴-D-트레이톨 1,4-비스(메탄술포네이트)를 4.10g 얻었다.D-thritol 1,4-bis (methanesulfonate) (3.50g, 12.6mmol) and n-butylaldehyde (1.00g, 13.8mmol, 1.25ml), anhydrous copper sulfate (II) (3.01g, 18.9mmol) and Methanesulfonic acid (3 drops) was mixed with anhydrous toluene (35 ml) and stirred for 16 hours under nitrogen filling. The reaction mixture was added anhydrous potassium carbonate (0.30 g) and further stirred for 20 minutes. It was filtered, evaporated to dryness and crystallized with 100% ethanol to give 4.10 g of 2,3-O-butylidene-D-thritol 1,4-bis (methanesulfonate) as white crystals.
수율 : 98%Yield: 98%
m.p. : 59-59.5℃m.p. : 59-59.5 ℃
IR(KBr) : 1360, 1332, 1178cm-1(O-SO2)IR (KBr): 1360, 1332, 1178cm -1 (O-SO2)
1H NMR(CDCl3) : δ 0.95(t,J=7.4Hz,3H,CH3), 1.45(m,2H,CH2), 1.66(m,2H,CH2), 3.08(s,6H,2SO2CH3), 4.10-4.27(m,2H,2CH), 4.27-4.50(m,4H,2CH2), 5.10(t,J=4.6Hz,1H,CH) 1 H NMR (CDCl 3 ): δ 0.95 (t, J = 7.4 Hz, 3H, CH 3 ), 1.45 (m, 2H, CH 2 ), 1.66 (m, 2H, CH 2 ), 3.08 (s, 6H, 2SO 2 CH 3 ), 4.10-4.27 (m, 2H, 2CH), 4.27-4.50 (m, 4H, 2CH 2 ), 5.10 (t, J = 4.6 Hz, 1H, CH)
13C NMR(CDCl3) : δ 13.88, 17.02, 35.83, 37.74, 67.80. 68.06, 75.06, 75.69, 105.49 13 C NMR (CDCl 3 ): δ 13.88, 17.02, 35.83, 37.74, 67.80. 68.06, 75.06, 75.69, 105.49
[단계 2][Step 2]
상기 단계 1에서 얻어진 2,3-O-부틸리덴-D-트레이톨 1,4-비스(메탄술포네이트) (4.01g, 12.1mmol)을 제조예 1의 단계 2에서와 동일한 방법으로 아지드화 나트륨과 반응시켜서 엷은 황색오일상의 (4R,5R)-4,5-비스(아지도메틸)-2-프로필-1,3-디옥소란을 2.45g 얻었다.2,3-O-butylidene-D-thritol 1,4-bis (methanesulfonate) (4.01 g, 12.1 mmol) obtained in step 1 was azide in the same manner as in step 2 of Preparation Example 1. 2.45 g of (4R, 5R) -4,5-bis (azidomethyl) -2-propyl-1,3-dioxolane as pale yellow oil was obtained by reacting with sodium sulfide.
수율 : 90%Yield: 90%
=+119.96°(아세톤) = + 119.96 ° (acetone)
IR(니트) : 2104cm-1(N3)IR (knit): 2104cm -1 (N 3 )
1H NMR(CDCl3) : δ 0.96(t,J=7.4Hz,3H,CH3), 1.46(m,.2H,CH2), 1.67(m,2H,CH2), 3.30-3.60(m,4H,2CH2), 4.01(br s,2H,2CH), 5.10(t,J=4.5Hz,1H,CH) 1 H NMR (CDCl 3 ): δ 0.96 (t, J = 7.4 Hz, 3H, CH 3 ), 1.46 (m, .2H, CH 2 ), 1.67 (m, 2H, CH 2 ), 3.30-3.60 (m , 4H, 2CH 2 ), 4.01 (br s, 2H, 2CH), 5.10 (t, J = 4.5Hz, 1H, CH)
13C NMR(CDCl3) : δ 13.92, 17.11, 36.09, 51.87, 51.96, 76.89, 77.90, 105.02 13 C NMR (CDCl 3 ): δ 13.92, 17.11, 36.09, 51.87, 51.96, 76.89, 77.90, 105.02
[단계 3][Step 3]
상기 단계 2에서 얻어진 (4R,5R)-4,5-비스(아지도메틸)-2-프로필-1,3-디옥소란 (2.37g, 10.5mmol)을 제조예 1의 단계 3에서와 동일한 방법으로 환원시켜서 오일상의 (4R,5R)-4,5-비스(아미노메틸)-2-프로필-1,3-디옥소란을 1.81g을 얻었다.(4R, 5R) -4,5-bis (azidomethyl) -2-propyl-1,3-dioxolane (2.37 g, 10.5 mmol) obtained in step 2 was the same as in step 3 of Preparation Example 1. It reduced by the method and 1.81g of oily (4R, 5R) -4,5-bis (aminomethyl) -2-propyl-1,3-dioxolane was obtained.
수율 : 99%Yield: 99%
IR(니트) : 3368, 3297cm-1(NH2)IR (knit): 3368, 3297cm -1 (NH 2 )
1H NMR(CDCl3) : δ 0.95(t,J=7.2Hz,3H,CH3), 1.45(m,2H,CH2), 1.63(m,2H,CH2), 1.68(s,4H,2NH2), 2.70-3.05(m,4H,2CH2), 3.75(br s, 2H,2CH), 5.03(t,J=4.2Hz,1H,CH) 1 H NMR (CDCl 3 ): δ 0.95 (t, J = 7.2 Hz, 3H, CH 3 ), 1.45 (m, 2H, CH 2 ), 1.63 (m, 2H, CH 2 ), 1.68 (s, 4H, 2NH 2 ), 2.70-3.05 (m, 4H, 2CH 2 ), 3.75 (br s, 2H, 2CH), 5.03 (t, J = 4.2Hz, 1H, CH)
13C NMR(CDCl3) : δ 14.01, 17.23, 36.27, 43.94, 44.24, 80.15, 81.01, 103.71 13 C NMR (CDCl 3): δ 14.01, 17.23, 36.27, 43.94, 44.24, 80.15, 81.01, 103.71
[단계 4][Step 4]
상기 단계 3에서 얻어진 (4R,5R)-4,5-비스(아미노메틸)-2-프로필-1,3-디옥소란(1.81g, 10.4mmol)을 제조예 1의 단계 4에서와 동일한 방법으로 사요오드화백금(Ⅱ) 칼륨의 수용액과 반응시켜서 황색 고형의 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-프로필-1,3-디옥소란]플라티늄(Ⅱ)을 4.73g 얻었다.(4R, 5R) -4,5-bis (aminomethyl) -2-propyl-1,3-dioxolane (1.81 g, 10.4 mmol) obtained in step 3 was prepared in the same manner as in step 4 of Preparation Example 1. Yellow cis-diiodo [(4R, 5R) -4,5-bis (aminomethyl) -2-propyl-1,3-dioxolane] by reacting with an aqueous solution of platinum (II) potassium iodide 4.73 g of platinum (II) was obtained.
수율 : 87%Yield: 87%
[제조예 4][Production Example 4]
시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-이소부틸-2-메틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of cis-diiodo [(4R, 5R) -4,5-bis (aminomethyl) -2-isobutyl-2-methyl-1,3-dioxolane] platinum (II)
[단계 1][Step 1]
D-트레이톨 1,4-비스(메탄술포네이트)(3.50g, 12.6mmol)와 이소발레르알데하이드(1.19g, 13.8mmol, 1.48ml)을 제조예 3의 단계 1에서와 동일한 방법으로 반응시켜서 백색 결정의 2,3-O-이소펜틸리덴-D-트레이톨 1,4-비스(메탄술포네이트)를 4.18g 얻었다.D-thritol 1,4-bis (methanesulfonate) (3.50g, 12.6mmol) and isovaleraldehyde (1.19g, 13.8mmol, 1.48ml) were reacted in the same manner as in step 1 of Preparation Example 3 to white 4.18 g of 2,3-O-isopentylidene-D-thritol 1,4-bis (methanesulfonate) as crystals was obtained.
수율 : 96%Yield: 96%
m.p. : 85.5-86℃m.p. : 85.5-86 ℃
IR(KBr) : 1356, 1333, 1181cm-1(O-SO2)IR (KBr): 1356, 1333, 1181cm -1 (O-SO 2 )
1H NMR(CDCl3) : δ 0.95(d,J=6.6Hz,6H,2CH3), 1.58(dd,J=4.9Hz,J=6.8Hz,2H,CH2), 1.79(m,1H,CH), 3.09(s,6H,2SO2CH3), 4.18(br s,2H,2CH), 4.27-4.50(m,4H,2CH2), 5.13(t,J=4.9Hz,1H,CH) 1 H NMR (CDCl 3 ): δ 0.95 (d, J = 6.6Hz, 6H, 2CH 3 ), 1.58 (dd, J = 4.9Hz, J = 6.8Hz, 2H, CH 2 ), 1.79 (m, 1H, CH), 3.09 (s, 6H, 2SO 2 CH 3 ), 4.18 (br s, 2H, 2CH), 4.27-4.50 (m, 4H, 2CH 2 ), 5.13 (t, J = 4.9 Hz, 1H, CH)
13C NMR(CDCl3) : δ 22.82, 22.88, 24.38, 37.80, 42.67, 67.75, 68.05, 74.98, 75.73, 104.91 13 C NMR (CDCl 3 ): δ 22.82, 22.88, 24.38, 37.80, 42.67, 67.75, 68.05, 74.98, 75.73, 104.91
[단계 2][Step 2]
상기 단계 1에서 얻어진 2,3-O-이소펜틸리덴-D-트레이톨 1,4-비스(메탄술포네이트) (4.08g)을 제조예 1의 단계 2에서와 동일한 방법으로 아지드화 나트륨과 반응시켜서 엷은 황색오일상의 (4R,5R)-4,5-비스(아지도메틸)-2-이소부틸-1,3-디옥소란을 2.78g 얻었다.2,3-O-isopentylidene-D-thritol 1,4-bis (methanesulfonate) (4.08 g) obtained in step 1 was prepared in the same manner as in step 2 of Preparation Example 1 2.78 g of (4R, 5R) -4,5-bis (azidomethyl) -2-isobutyl-1,3-dioxolane in the form of pale yellow oil was reacted with the reaction product.
수율 : 98%Yield: 98%
=+118.44°(아세톤) = + 118.44 ° (acetone)
IR(니트) : 2103cm-1(N3)IR (knit): 2103cm -1 (N 3 )
1H NMR(CDCl3) : δ 0.96(d,J=6.6Hz,6H,2CH3), 1.59(dd,J=5.1Hz,J=6.6Hz,2H,CH2), 1.83(m,1H,CH), 3.30-3.60(m,4H,2CH2), 4.01(br s,2H,2CH), 5.13(t,J=5.1Hz,1H,CH) 1 H NMR (CDCl 3 ): δ 0.96 (d, J = 6.6Hz, 6H, 2CH 3 ), 1.59 (dd, J = 5.1Hz, J = 6.6Hz, 2H, CH2), 1.83 (m, 1H, CH ), 3.30-3.60 (m, 4H, 2CH2), 4.01 (br s, 2H, 2CH), 5.13 (t, J = 5.1Hz, 1H, CH)
13C NMR(CDCl3) : δ 22.81, 22.89, 24.44, 42.89, 51.88, 51.96, 76.77, 77.85, 104.38 13 C NMR (CDCl 3 ): δ 22.81, 22.89, 24.44, 42.89, 51.88, 51.96, 76.77, 77.85, 104.38
[단계 3][Step 3]
상기 단계 2에서 얻어진 (4R,5R)-4,5-비스(아지도메틸)-2-이소부틸-1,3-디옥소란 (2.71g, 11.3mmol)을 제조예 1의 단계 3에서와 동일한 방법으로 환원시켜서 오일상의 (4R,5R)-4,5-비스(아미노메틸)-2-이소부틸-1,3-디옥소란을 2.12g을 얻었다.(4R, 5R) -4,5-bis (azidomethyl) -2-isobutyl-1,3-dioxolane (2.71 g, 11.3 mmol) obtained in step 2 was prepared in Step 3 of Preparation Example 1. Reduction was carried out in the same manner to obtain 2.12 g of (4R, 5R) -4,5-bis (aminomethyl) -2-isobutyl-1,3-dioxolane in oily form.
수율 : 100%Yield: 100%
IR(니트) : 3370, 3295cm-1(NH2)IR (knit): 3370, 3295cm -1 (NH 2 )
1H NMR(CDCl3) : δ 0.95(d,J=6.6Hz,6H,2CH3), 1.55(dd,J=4.9Hz,J=6.8Hz,2H,CH2), 1.81(m,1H,CH), 2.03(s,4H,2NH2), 2.73-2.93(m,4H,2NH2), 3.73(br s, 2H,2CH), 5.06(t,J=4.9Hz,1H,CH) 1 H NMR (CDCl 3 ): δ 0.95 (d, J = 6.6Hz, 6H, 2CH 3 ), 1.55 (dd, J = 4.9Hz, J = 6.8Hz, 2H, CH 2 ), 1.81 (m, 1H, CH), 2.03 (s, 4H, 2 NH 2 ), 2.73-2.93 (m, 4 H, 2 NH 2 ), 3.73 (br s, 2H, 2 CH), 5.06 (t, J = 4.9 Hz, 1 H, CH)
13C NMR(CDCl3) : δ 22.98, 24.46, 43.06, 43.78, 44.13, 79.88, 80.89, 103.07 13 C NMR (CDCl 3 ): δ 22.98, 24.46, 43.06, 43.78, 44.13, 79.88, 80.89, 103.07
[단계 4][Step 4]
상기 단계 3에서 얻어진 (4R,5R)-4,5-비스(아미노메틸)-2-이소부틸-1,3-디옥소란(2.11g, 11.2mmol)을 제조예 1의 단계 4에서와 동일한 방법으로 사요오드화백금(Ⅱ) 칼륨의 수용액과 반응시켜서 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-이소부틸-1,3-디옥소란]플라티늄(Ⅱ)을 5.36g 얻었다.(4R, 5R) -4,5-bis (aminomethyl) -2-isobutyl-1,3-dioxolane (2.11 g, 11.2 mmol) obtained in step 3 was the same as in step 4 of Preparation Example 1. By reacting with an aqueous solution of platinum (II) potassium iodide by means of cis-diodo [(4R, 5R) -4,5-bis (aminomethyl) -2-isobutyl-1,3-dioxolane] platinum 5.36g of (II) was obtained.
수율 : 89%Yield: 89%
[제조예 5]Production Example 5
시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-tert-부틸-1,3-디옥소란]플라티늄(Ⅱ)의 제조Preparation of cis-diiodo [(4R, 5R) -4,5-bis (aminomethyl) -2-tert-butyl-1,3-dioxolane] platinum (II)
[단계 1][Step 1]
D-트레이톨 1,4-비스(메탄술포네이트)(3.50g, 12.6mmol)와 트리메틸아세트알데하이드(1.19g, 13.8mmol, 1.50ml)을 제조예 3의 단계 1에서와 동일한 방법으로 반응시켜서 백색 결정의 2,3-O-네오펜틸리덴-D-트레이톨 1,4-비스(메탄술포네이트)를 2.08g 얻었다.D-thritol 1,4-bis (methanesulfonate) (3.50g, 12.6mmol) and trimethylacetaldehyde (1.19g, 13.8mmol, 1.50ml) were reacted in the same manner as in step 1 of Preparation Example 3 to white 2.08g of 2,3-O- neopentylidene-D-thritol 1,4-bis (methanesulfonate) of crystals were obtained.
수율 : 48%Yield: 48%
m.p. : 100℃m.p. : 100 ℃
IR(KBr) : 1358, 1331, 1181cm-1(O-SO2)IR (KBr): 1358, 1331, 1181 cm -1 (O-SO 2 )
1H NMR(CDCl3) : δ 0.92(s,9H,3CH3), 3.07(s,3H,SO2CH3), 3.08(s,3H,SO2CH3), 4.10-4.24(m,2H,2CH), 4.24-4.50(m,4H,2CH2), 4.74(s,1H,CH) 1 H NMR (CDCl 3 ): δ 0.92 (s, 9H, 3CH 3 ), 3.07 (s, 3H, SO 2 CH 3 ), 3.08 (s, 3H, SO 2 CH 3 ), 4.10-4.24 (m, 2H , 2CH), 4.24-4.50 (m, 4H, 2CH 2 ), 4.74 (s, 1H, CH)
13C NMR(CDCl3) : δ 24.06, 34.19, 37.74, 37.79, 67.81, 67.91, 75.49, 75.67, 110.98 13 C NMR (CDCl 3 ): δ 24.06, 34.19, 37.74, 37.79, 67.81, 67.91, 75.49, 75.67, 110.98
[단계 2][Step 2]
상기 단계 1에서 얻어진 2,3-O-네오펜틸리덴-D-트레이톨 1,4-비스(메탄술포네이트) (1.98g, 5.7mmol)을 제조예 1의 단계 2에서와 동일한 방법으로 아지드화 나트륨과 반응시켜서 엷은 황색오일상의 (4R,5R)-4,5-비스(아지도메틸)-2-tert-부틸-1,3-디옥소란을 1.36g 얻었다.2,3-O-neopentylidene-D-thritol 1,4-bis (methanesulfonate) (1.98 g, 5.7 mmol) obtained in step 1 was prepared in the same manner as in step 2 of Preparation Example 1. 1.36 g of (4R, 5R) -4,5-bis (azidomethyl) -2-tert-butyl-1,3-dioxolane as pale yellow oil was reacted with sodium zide.
수율 : 99%Yield: 99%
=+104.69°(아세톤) = + 104.69 ° (acetone)
IR(니트) : 2103cm-1(N3)IR (knit): 2103cm -1 (N 3 )
1H NMR(CDCl3) : δ 0.94(s,9H,3CH3), 3.32-3.49(m,.4H,2CH2), 3.92-4.04(m,2H,2CH), 4.74(s,1H,CH) 1 H NMR (CDCl 3 ): δ 0.94 (s, 9H, 3CH 3 ), 3.32-3.49 (m, .4H, 2CH 2 ), 3.92-4.04 (m, 2H, 2CH), 4.74 (s, 1H, CH )
13C NMR(CDCl3) : δ 24.05, 34.16. 51.73. 51.88, 77.31, 77.91, 110.53 13 C NMR (CDCl 3 ): δ 24.05, 34.16. 51.73. 51.88, 77.31, 77.91, 110.53
[단계 3][Step 3]
상기 단계 2에서 얻어진 (4R,5R)-4,5-비스(아지도메틸)-2-tert-부틸-1,3-디옥소란 (1.29g, 5.4mmol)을 제조예 1의 단계 3에서와 동일한 방법으로 환원시켜서 오일상의 (4R,5R)-4,5-비스(아미노메틸)-2-tert-부틸-1,3-디옥소란을 1.00g 얻었다.(4R, 5R) -4,5-bis (azidomethyl) -2-tert-butyl-1,3-dioxolane (1.29 g, 5.4 mmol) obtained in step 2 was prepared in step 3 of Preparation Example 1. Reduction was carried out in the same manner as in to obtain 1.00 g of oily (4R, 5R) -4,5-bis (aminomethyl) -2-tert-butyl-1,3-dioxolane.
수율 : 99%Yield: 99%
IR(니트) : 3366, 3295cm-1(NH2)IR (knit): 3366, 3295 cm -1 (NH 2 )
1H NMR(CDCl3) : δ 0.92(s,9H,3CH3), 1.49(s,4H,2NH2), 2.70-3.00(m,4H,2CH2), 3.66-3.80(m,2H,2CH), 4.66(s,1H,CH) 1 H NMR (CDCl 3 ): δ 0.92 (s, 9H, 3CH 3 ), 1.49 (s, 4H, 2NH 2 ), 2.70-3.00 (m, 4H, 2CH 2 ), 3.66-3.80 (m, 2H, 2CH ), 4.66 (s, 1H, CH)
13C NMR(CDCl3) : δ 24.31, 34.33, 44.03, 44.18, 80.43, 80.96, 109.50 13 C NMR (CDCl 3 ): δ 24.31, 34.33, 44.03, 44.18, 80.43, 80.96, 109.50
[단계 4][Step 4]
상기 단계 3에서 얻어진 (4R,5R)-4,5-비스(아미노메틸)-2-tert-부틸-1,3-디옥소란(0.99g, 5.3mmol)을 제조예 1의 단계 4에서와 동일한 방법으로 사요오드화백금(Ⅱ) 칼륨의 수용액과 반응시켜서 황색 고형의 시스-디요오도[(4R,5R)-4,5-비스(아미노메틸)-2-tert-부틸-1,3-디옥소란]플라티늄(Ⅱ)을 2.55g 얻었다.(4R, 5R) -4,5-bis (aminomethyl) -2-tert-butyl-1,3-dioxolane (0.99 g, 5.3 mmol) obtained in step 3 was prepared in step 4 of Preparation Example 1. In the same manner, yellow solid cis-diiodo [(4R, 5R) -4,5-bis (aminomethyl) -2-tert-butyl-1,3- is reacted with an aqueous solution of platinum (II) potassium iodide. 2.55 g of dioxolane] platinum (II) was obtained.
수율 : 90%Yield: 90%
상기 실시예에서 얻어진 화합물들에 대해 다음과 같이 실험하고, 비교를 위해 기지의 화합물인 시스플라틴 및 카보플라틴에 대하여 실험을 하였다.The compounds obtained in the above examples were tested as follows, and the known compounds cisplatin and carboplatin were tested for comparison.
쥐 백혈병 암세포 L1210에 대한 성장억제 활성의 생체외 시험In Vitro Testing of Growth Inhibitory Activity on Rat Leukemia Cancer Cell L1210
쥐 백혈병 암세포 L1210(1×105)를 10% 태아소혈청을 함유하는 RPMI 1640배지중에서 시험 화합물로 처리하고, 5% CO2급습 인큐베이터(humidified incubator)에서 37℃를 유지하면서 48시간 배양하였다. 이때 각 화합물의 농도를 적어도 6가지 이상으로 달리하여 실험하였다. 상기 쥐 백혈병암세포의 생존율을 0.17%트리판 블루로 염색하여 평가하고, 이를 화합물로 처리하지 않고 상기와 동일배지 및 배양조건에서 배양한 대조세포의 생존율과 비교하여, IC50값(성장을 50% 억제하는데 요구되는 농도, 단위 : ㎍/ml)을 구하였다. IC50값은 투여량-반응의 대수곡선을 그리고 이로부터 계산하였다. 그 결과를 다음의 표 1에 나타내었다.Rat leukemia cancer cells L1210 (1 × 10 5 ) were treated with test compounds in RPMI 1640 medium containing 10% fetal bovine serum and incubated for 48 hours at 37 ° C. in a 5% CO 2 humidified incubator. At this time, the concentration of each compound was experimented with at least six or more. The survival rate of the rat leukemia cancer cells was evaluated by staining with 0.17% trypan blue, and compared with the survival rate of control cells cultured in the same medium and culture conditions as above without treatment with the compound, IC50 value (50% inhibition of growth). Required concentration, unit: μg / ml). IC 50 values were calculated from and algebraic curves of dose-response. The results are shown in Table 1 below.
[표 1]TABLE 1
상기의 표 1에 나타난 바와 같이, 본 발명의 화합물은 낮은 농도에서도 암세포의 성장에 대해 탁월한 억제효과가 있었다.As shown in Table 1, the compound of the present invention had an excellent inhibitory effect on the growth of cancer cells even at low concentrations.
쥐 백혈병 암세포 L1210에 대한 항종양활성의 생체내 시험In Vivo Testing of Antitumor Activity against Rat Leukemia Cancer Cell L1210
쥐 백혈병 암세포 L1210를 생후 6주된 숫컷 DBA/2 쥐의 복강에 매주 이식배양하여 유지시켰다. 1×106백혈병 암세포를 시험개시일에 21±3g의 체중을 갖는 생후 6주된 수컷 BDF1쥐의 복강에 투여하여 실험하였다. 각 처리군은 7마리의 쥐로 구성하였다. 시험 화합물은 0.5% CMC용액(용매 : 물)에 용해 또는 현탁시켜, 이를 종양접종일로부터 1, 5 및 9일째되는 날에 복강내로 투여하였다. 한편, 대조군에는 상기 화합물을 함유하지 않는 0.5% CMC용액(용매 : 물)을 동일한 방법으로 주사하였다.Rat leukemia cancer cells L1210 were maintained by weekly transplantation into the abdominal cavity of male DBA / 2 mice 6 weeks old. 1 × 10 6 leukemia cancer cells were administered to the abdominal cavity of 6 week old male BDF 1 rats having a body weight of 21 ± 3 g at the start of the test. Each treatment group consisted of seven rats. Test compounds were dissolved or suspended in 0.5% CMC solution (solvent: water) and administered intraperitoneally on days 1, 5 and 9 from the day of tumor inoculation. Meanwhile, 0.5% CMC solution (solvent: water) containing no compound was injected into the control group in the same manner.
상기 쥐들을 50일동안 관찰한 후 생존한 쥐를 부검하여 종양이 발견되지 않으면 치료된 것으로 판정되었다. 항종양활성은 대조군의 평균 생존시간(C)과 화합물 처리군의 평균 생존시간(T)으로부터 다음의 식에 따라 T/C(%)값으로 구하고, 그 결과를 다음의 표 2에 나타내었다.After observing the mice for 50 days, the surviving mice were autopsied and determined to be treated if no tumors were found. Antitumor activity was calculated from T / C (%) values according to the following equation from the average survival time (C) of the control group and the average survival time (T) of the compound treatment group, the results are shown in Table 2 below.
[표 2a]TABLE 2a
[표 2b]TABLE 2b
상기 표 2에 나타난 바와 같이, 본 발명의 화합물은 쥐 백혈병 암세포 L1210로 접종한 쥐의 생명을 연장시키는데 매우 효과가 있었다.As shown in Table 2, the compound of the present invention was very effective in prolonging the life of mice inoculated with mouse leukemia cancer cells L1210.
[물에 대한 용해도 실험]Solubility Test in Water
화합물의 표준용액을 각 농도별로 만든후 220nm의 자외선(UV) 흡광도를 측정하여 표준검량선을 작성하였다. 표준용액은 물 또는 10% 에탄올 수용액(용해도가 낮은 화합물인 경우)으로 만들었다.A standard calibration curve was prepared by measuring the standard absorbance of the compound and measuring the absorbance of UV at 220 nm. The standard solution was made up of water or 10% aqueous ethanol solution (if low solubility compound).
용해도 측정을 위해, 화합물을 물에 혼합시킨 후 60초동안 교반한 다음, 60초동안 초음파 처리하고, 다시 180초 동안 교반하고, 60초 동안 초음파 처리한 후, 그리고 5분 동안 교반하여 충분히 용해시켜 포화용액을 준비하였다. 이 혼합물은 측정전에 0.45미크론의 일회용 필터막을 통과시키고 일정배수로 희석한 후 자외선 흡광도를 측정하여 작성된 표준검량선으로부터 농도를 산출한 뒤 희석배수를 곱하여서 이를 용해도로 하였다.For solubility measurement, the compound was mixed in water and stirred for 60 seconds, then sonicated for 60 seconds, stirred for 180 seconds again, sonicated for 60 seconds, and stirred for 5 minutes to dissolve sufficiently. Saturated solution was prepared. The mixture was passed through a 0.45 micron disposable filter membrane before dilution, diluted to a certain multiple, and the concentration was calculated from the standard calibration curve prepared by measuring ultraviolet absorbance.
이 용해도 측정 결과를 다음의 표 3에 나타내었다.The solubility measurement results are shown in Table 3 below.
[표 3]TABLE 3
상기 표 3에 나타난 바와 같이 본 발명의 화합물은 물에 대해 매우 높은 용해성을 나타내었다.As shown in Table 3, the compounds of the present invention showed very high solubility in water.
[신장독성 시험]Renal Toxicity Test
시험 화합물을 0.5% CMC용액(용매 : 물)에 용해 또는 현탁시켜서, 이를 생후 8주된 30±3g의 숫컷 ICR 쥐에 1회 복강투여하였다. 투여량은 상기 표 2에서 나타난 최적 투여량의 1.5배 또는 그 이상으로 하였다. 투여한지 1, 4 및 8일 후에 상기 쥐를 마취하여 채혈한 후, 이로부터 혈액중 요소질소 농도(BUN값)와 크레아티닌 농도를 측정하여, 그 결과를 다음의 표 4에 나타내었다.Test compounds were dissolved or suspended in 0.5% CMC solution (solvent: water) and were intraperitoneally administered to 30 ± 3 g of male ICR mice 8 weeks old. Dosage was 1.5 times or more than the optimal dose shown in Table 2 above. After 1, 4 and 8 days of administration, the rats were anesthetized and collected, and blood urea nitrogen concentration (BUN value) and creatinine concentration were measured therefrom, and the results are shown in Table 4 below.
[표 4]TABLE 4
주) a : 100ml혈액당 mg단위에서 평균치 프러스 또는 마이너스 표준 오차 값이다.Note: a: The mean prus or minus standard error in mg per 100 ml of blood.
b : 대조군과 통계학적으로 유의성 있는 차이를 가짐을 지적(p〈0.01)b: pointed out that there was a statistically significant difference from the control group (p <0.01)
c : 대조군과 통계학적으로 유의성 있는 차이를 가짐을 지적(p〈0.05)c: pointed out that there was a statistically significant difference from the control group (p <0.05)
상기 표 4에서 나타난 바와 같이, 본 발명의 화합물을 투여했을 때의 BUN값이 시스플라틴을 투여했을 때보다 낮았으며 화합물을 함유하지 않고 0.5% CMC 용액(용매 : 물)만 투여한 대조군에 근접하였는 바, 본 화합물의 신장독성이 매우 낮음을 알 수 있다.As shown in Table 4, the BUN value of the compound of the present invention was lower than that of cisplatin and was close to the control group containing only 0.5% CMC solution (solvent: water) without containing the compound. It can be seen that the nephrotoxicity of the compound is very low.
[급성독성실험][Acute Toxicity Test]
7주령된 ICR마우스(수컷 : 34±2.0g, 암컷 : 31±2.0g)을 투입하여, 실험전에 실온 23±1℃, 습도 65±5%의 조건에서 고형사료 및 물을 자유롭게 섭취하였다.Seven-week-old ICR mice (male: 34 ± 2.0 g, female: 31 ± 2.0 g) were injected and solid feed and water were ingested freely at the conditions of 23 ± 1 ° C and 65 ± 5% humidity before the experiment.
실험동물을 군당 6마리씩 사용하며, 약물을 복강내에 투입하였다. 7일간 관찰하여 외견상태와 생사여부를 기록하였고, 폐사 동물은 부검하여 육안적 병변을 관찰하였다. 모든 장기는 10% 중성 포르말린 용액에 넣어 고정하였다. LD50값은 리치필드-윌콕손(Litchfield-Wilcoxon)법에 의해 구하였다. 그 결과를 다음의 표 5에 나타내었다.Six animals were used per group, and drugs were injected intraperitoneally. Observation and appearance were observed for 7 days, and mortality was examined by necropsy. All organs were fixed in 10% neutral formalin solution. LD 50 value was calculated | required by the Litchfield-Wilcoxon method. The results are shown in Table 5 below.
[표 5a]TABLE 5a
[표 5b]TABLE 5b
[표 5c]TABLE 5c
주) a : 7일동안 폐사된 동물수의 총합임.A) The total number of animals killed in 7 days.
상기 표 1 내지 표 5의 내용을 요약하면 다음과 같이 본 발명에 따른 화합물의 효과를 설명할 수 있다.Summarizing the contents of Tables 1 to 5, the effects of the compounds according to the present invention can be described as follows.
본 발명의 화합물은 항종양활성이 생체외의 실험실적 조건(표 1)에서는 시스플라틴보다 약간 떨어지는 것이 확인되었으나 카보플라틴 보다는 다소 우수하였으며, 생체내 조건(표 2)에서는 다소의 화합물이 시스플라틴과 카보플라틴보다 우수함을 확인하였고, 특히 시스플라틴의 과량 투여시 독성이 극심한데 비하여 본 발명의 화합물은 안전함이 확인되었다.Anti-tumor activity of the compounds of the present invention was found to be slightly lower than cisplatin under laboratory conditions (Table 1) in vitro, but was slightly superior to carboplatin, and some compounds were cisplatin and carbople in vivo conditions (Table 2). It was confirmed that it is superior to Latin, in particular, the compound of the present invention was found to be safe compared to the extreme toxicity when cisplatin is excessively administered.
또한 본 발명의 화합물은 물에 대한 용해도(표 3)가 시스플라틴보다 대체적으로 높으며, 다수의 화합물이 카보플라틴보다도 우수한 것으로 확인되었다.In addition, the compounds of the present invention were found to have a higher solubility in water (Table 3) than cisplatin, and many compounds were superior to carboplatin.
또한 본 발명의 화합물은 신장 독성(표 4)이 시스플라틴 보다 작은 것을 확인하였으며, 특히 독성이 극심하게 되는 제 4 일째의 수치는 시스플라틴보다 월등히 작은 것이 확인되었다.In addition, the compounds of the present invention confirmed that the renal toxicity (Table 4) is less than cisplatin, especially the fourth day of the severe toxicity was found to be significantly less than cisplatin.
또한 본 발명의 화합물은 급성독성(표 5)에 있어서 시스플라틴보다 안전성이 월등하여 투약량 제한 독성에 있어서 선행기술의 화합물이 지니고 있던 문제점을 상당한 수준까지 극복하는 것을 확인하였다.In addition, the compounds of the present invention were found to overcome the problems of the prior art compounds in dose limiting toxicity in acute toxicity (Table 5) superior safety to cisplatin, to a considerable level.
따라서, 본 발명의 화합물은 종래 시스플라틴 항암제가 지니고 있던 단점인 투여량 제한 독성이나 물에 대한 용해도가 낮은점 및 신장독성을 모두 개선시키면서 항조양활성이 생체내의 실험적조건에서 시스플라틴 보다 우수하여 항암제로서 개발되는데 있어서의 모든 고려 조건을 상당한 수준까지 개량시킨 효과가 있음이 입증되었다.Accordingly, the compound of the present invention is developed as an anticancer agent because the anticoagulant activity is superior to cisplatin under experimental conditions in vivo, while improving both the dose limiting toxicity, the disadvantage of the conventional cisplatin anticancer agent, the low solubility in water and the renal toxicity. It has been proved that there is an effect of improving all the considerations in the process to a considerable level.
Claims (21)
Priority Applications (28)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019910019969A KR940010296B1 (en) | 1991-05-03 | 1991-11-11 | New pt(ñœ)complexes and process for the preparation thereof |
| JP4502604A JP2801965B2 (en) | 1991-03-23 | 1991-12-30 | Novel platinum (II) complex compound and method for producing the same |
| RU9193057869A RU2067099C1 (en) | 1991-03-23 | 1991-12-30 | Platinum (ii) complex compounds, method of their synthesis, intermediate compounds and methods of their synthesis |
| HU9302461A HUT65220A (en) | 1991-03-23 | 1991-12-30 | Process for producing new platinum(ii) complexes |
| CA002106679A CA2106679C (en) | 1991-03-23 | 1991-12-30 | Novel platinum (ii) complex and processes for preparing the same |
| HU9502323A HUT72890A (en) | 1991-03-23 | 1991-12-30 | Process for producing novel platinium complexes |
| BR9107299A BR9107299A (en) | 1991-03-23 | 1991-12-30 | New platinum II complex and processes for its preparation |
| AU91247/91A AU654990B2 (en) | 1991-03-23 | 1991-12-30 | Novel platinum(II) complex and processes for preparing the same |
| EP92902293A EP0586378B1 (en) | 1991-03-23 | 1991-12-30 | Novel platinum(ii) complex and processes for preparing the same |
| ES92902293T ES2124251T3 (en) | 1991-03-23 | 1991-12-30 | NEW PLATINUM (II) COMPLEX AND PROCEDURES FOR ITS PREPARATION. |
| HU9302461A HU220869B1 (en) | 1991-03-23 | 1991-12-30 | Platinum(ii) complexes, pharmaceutical compositions comprising thereof and processes for preparing the same |
| PCT/KR1991/000036 WO1992016539A1 (en) | 1991-03-23 | 1991-12-30 | Novel platinum(ii) complex and processes for preparing the same |
| AT92902293T ATE171455T1 (en) | 1991-03-23 | 1991-12-30 | PLATINUM COMPLEXES AND METHOD FOR THE PRODUCTION THEREOF |
| DE69130261T DE69130261T2 (en) | 1991-03-23 | 1991-12-30 | PLATINUM COMPLEXES AND METHOD FOR THE PRODUCTION THEREOF |
| NZ241824A NZ241824A (en) | 1991-03-23 | 1992-03-04 | Platinum (ii) complexes of 4,5-bis(aminomethyl)-1,3- dioxolane derivatives; pharmaceutical compositions and 4,5-bis(aminomethyl and azidomethyl)-1,3-dioxolane derivatives |
| IE068792A IE920687A1 (en) | 1991-03-23 | 1992-03-04 | Novel platinum(ii) complex and processes for preparing the¹same |
| IL10116792A IL101167A (en) | 1991-03-23 | 1992-03-06 | Platinum (II) complexes processes for the preparation thereof and pharmaceutical compositions containing the same |
| TW081101719A TW207542B (en) | 1991-03-23 | 1992-03-06 | |
| PT100272A PT100272B (en) | 1991-03-23 | 1992-03-20 | A NEW PLATINUM COMPLEX (II) AND PROCESS FOR THEIR PREPARATION |
| PH44095A PH30926A (en) | 1991-03-23 | 1992-03-23 | Platinum (II) complex and processes for preparing the same. |
| CS92873A CZ285904B6 (en) | 1991-03-23 | 1992-03-23 | Platinum(ii) complex compounds, process of their preparation as well as pharmaceutical composition containing thereof |
| CN92102045A CN1038590C (en) | 1991-03-23 | 1992-03-23 | Platinum complex and processes for preparing same |
| US08/117,096 US5395947A (en) | 1991-03-23 | 1993-09-14 | Platinum(II) complex and processes for preparing the same |
| NO932824A NO304652B1 (en) | 1991-03-23 | 1993-09-22 | Analogous methods for the preparation of therapeutically active platinum (II) complexes |
| FI934150A FI934150A (en) | 1991-03-23 | 1993-09-22 | NYA PLATINUM (II) COMPLEX OR FARING FARING FOR FRAMSTAELLNING AV DESSA |
| AU74439/94A AU7443994A (en) | 1991-03-23 | 1994-10-05 | Intermediates for the preparation of platinum (II) complexes |
| CN97120205A CN1063753C (en) | 1991-03-23 | 1997-10-31 | Method for preparing platinum compound |
| AU45338/97A AU704409B2 (en) | 1991-03-23 | 1997-11-24 | 4,5-bis(aminomethyl and azidomethyl)-1,3-dioxolane intermediates useful for the preparation of platinum (II) complexes |
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| KR91-7207 | 1991-05-03 | ||
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| KR1019910019969A KR940010296B1 (en) | 1991-05-03 | 1991-11-11 | New pt(ñœ)complexes and process for the preparation thereof |
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