JPH0267217A - Antitumor agent - Google Patents
Antitumor agentInfo
- Publication number
- JPH0267217A JPH0267217A JP63219266A JP21926688A JPH0267217A JP H0267217 A JPH0267217 A JP H0267217A JP 63219266 A JP63219266 A JP 63219266A JP 21926688 A JP21926688 A JP 21926688A JP H0267217 A JPH0267217 A JP H0267217A
- Authority
- JP
- Japan
- Prior art keywords
- group
- antitumor agent
- hydrogen atom
- formula
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 13
- -1 amine compound Chemical class 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 7
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 30
- 229910052697 platinum Inorganic materials 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 3
- 238000007796 conventional method Methods 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 abstract description 2
- 206010029155 Nephropathy toxic Diseases 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 230000007694 nephrotoxicity Effects 0.000 abstract 1
- 231100000417 nephrotoxicity Toxicity 0.000 abstract 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- 238000004519 manufacturing process Methods 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- VGUWZCUCNQXGBU-UHFFFAOYSA-N 3-[(4-methylpiperazin-1-yl)methyl]-5-nitro-1h-indole Chemical compound C1CN(C)CCN1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 VGUWZCUCNQXGBU-UHFFFAOYSA-N 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- WLTCKEHCTUYJGI-UHFFFAOYSA-N Diethyl aminomalonate Chemical compound CCOC(=O)C(N)C(=O)OCC WLTCKEHCTUYJGI-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 208000007093 Leukemia L1210 Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000006268 Sarcoma 180 Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 2
- GLFVNTDRBTZJIY-UHFFFAOYSA-N diethyl 2-aminopropanedioate;hydron;chloride Chemical compound Cl.CCOC(=O)C(N)C(=O)OCC GLFVNTDRBTZJIY-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 231100001095 no nephrotoxicity Toxicity 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- HGTBAIVLETUVCG-UHFFFAOYSA-N (methylthio)acetic acid Chemical compound CSCC(O)=O HGTBAIVLETUVCG-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- DLDTUYIGYMNERN-UHFFFAOYSA-N 2-[(2-chloroacetyl)amino]acetic acid Chemical compound OC(=O)CNC(=O)CCl DLDTUYIGYMNERN-UHFFFAOYSA-N 0.000 description 1
- GEVGRLPYQJTKKS-UHFFFAOYSA-N 3-(phenylmethoxycarbonylamino)propanoic acid Chemical compound OC(=O)CCNC(=O)OCC1=CC=CC=C1 GEVGRLPYQJTKKS-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 description 1
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- JINBYESILADKFW-UHFFFAOYSA-N aminomalonic acid Chemical compound OC(=O)C(N)C(O)=O JINBYESILADKFW-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- POQBJIOLWPDPJE-UHFFFAOYSA-N cyclohexane-1,2-diamine;platinum Chemical compound [Pt].NC1CCCCC1N POQBJIOLWPDPJE-UHFFFAOYSA-N 0.000 description 1
- SGLJYTWMWIAGEU-UHFFFAOYSA-N cyclohexane-1,2-diamine;platinum(2+) Chemical compound [Pt+2].NC1CCCCC1N SGLJYTWMWIAGEU-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- UDUAGQWLJWQUJU-UHFFFAOYSA-N diethyl 2-[(2-aminoacetyl)amino]propanedioate Chemical compound CCOC(=O)C(NC(=O)CN)C(=O)OCC UDUAGQWLJWQUJU-UHFFFAOYSA-N 0.000 description 1
- NISGHTRPZFQYLP-UHFFFAOYSA-N diethyl 2-[(2-aminoacetyl)amino]propanedioate;hydrochloride Chemical compound Cl.CCOC(=O)C(NC(=O)CN)C(=O)OCC NISGHTRPZFQYLP-UHFFFAOYSA-N 0.000 description 1
- PXQUPULSKNTWQI-UHFFFAOYSA-N diethyl 2-[[2-(carbamoylamino)acetyl]amino]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)NC(=O)CNC(N)=O PXQUPULSKNTWQI-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000004013 groin Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical class [*:1]O[*:2] 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 230000008085 renal dysfunction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【発明の詳細な説明】 、（産業上の利用分野） 本発明は抗ａｍ剤に関する。[Detailed description of the invention] , (industrial application field) TECHNICAL FIELD The present invention relates to anti-ambulatory agents.
（従来技術）
シスプラチン〔化学名：シス−ジクロロジアンミン白金
（■）〕に抗腫瘍作用が見出されて以来〔ネイチャー
（Ｎａｔｕｒｅ） 、第２２２巻、３８５頁（１９６９
年）〕、有機白金系抗腫瘍剤の抗腫瘍作用が検討されて
いる。しかしながら、これら白金錯体には腎臓及び聴覚
器官に対し毒性があったり、水に対する溶解度が低く、
製剤化が困難であるといった難点があること等から、未
だ臨床応用しうるものが少ないのが現状である。(Prior art) Since the discovery of antitumor effects in cisplatin [chemical name: cis-dichlorodiammine platinum (■)] [Nature
(Nature), Vol. 222, p. 385 (1969
)], the antitumor effects of organoplatinum-based antitumor agents have been investigated. However, these platinum complexes are toxic to the kidneys and auditory organs, have low solubility in water,
At present, there are still very few products that can be used clinically due to problems such as difficulty in formulation.
従って、抗腫瘍作用が強く、毒性が低いと共に水に対す
る溶解度の高い有機白金錯体の開発が望まれている。Therefore, it is desired to develop an organic platinum complex that has a strong antitumor effect, low toxicity, and high solubility in water.
（発明の構成及び効果）
本発明は次の一般式で示される新規有機白金錯体を有効
成分とする抗ｍｓ剤に関する。(Structure and Effects of the Invention) The present invention relates to an anti-MS agent containing a novel organic platinum complex represented by the following general formula as an active ingredient.
（但し、Ｒ１は水素原子又は低級アルキル基、Ｒ２は水
素原子、置換基を有することもある低級アルキル基、低
級アルケニル基、低級アルキニル基、低級アルコキシ基
、低級アルカノイル基、アミノ基、置換基を有すること
もある含窒素複素単環式基又は含酸素複素単環式基、Ａ
ｌｋは低級アルキレン基、Ｘはカルボニル基又はスルホ
ニルＬ ｎは１又は２を表す。）
本発明の抗腫瘍剤は各種腫瘍に対し優れた腫瘍増殖抑制
効果を示す有用な医薬組成物である。例えば、本発明の
抗腫瘍剤は固形腫瘍、腹水肝癌及び白血病等のいずれに
対しても優れた抗Ｉｌ！Ｉ１ｗＩ作用を示し、これら腫
瘍に罹患した温血動物の生存期間を効果的に延長し及び
／又はｍｇ細胞の増殖を効果的に抑制することができる
。またその有効成分であるを機白金錯体（１）は高い水
溶性を存し、さらには従来の白金錯体にみられたような
腎毒性をほとんど示さないという特長も有する。(However, R1 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkanoyl group, an amino group, a substituent. A nitrogen-containing heteromonocyclic group or an oxygen-containing heteromonocyclic group, which may have
lk represents a lower alkylene group, X represents a carbonyl group or sulfonyl L, and n represents 1 or 2. ) The antitumor agent of the present invention is a useful pharmaceutical composition that exhibits excellent tumor growth inhibiting effects on various tumors. For example, the antitumor agent of the present invention has excellent anti-Il! It exhibits an I1wI effect and can effectively prolong the survival period of warm-blooded animals afflicted with these tumors and/or effectively suppress the proliferation of mg cells. In addition, its active ingredient, platinum complex (1), has high water solubility, and furthermore, it exhibits almost no nephrotoxicity as seen in conventional platinum complexes.
本発明の有効成分は１，２−ジアミノシクロヘキサンと
マロン酸誘導体をリガンドとする有機白金錯体であり、
具体例としては、一般式（１）において、Ｒ２が水素原
子；水酸基、低級アルコキシ基、低級アルキルスルフィ
ニル基、低級アルキルスルホニル基、低級アルカノイル
基、低級アルコキシ−低級アルコキシ基、ハロゲン原子
、モルホリノカルボニル基等の５〜６員含窒素複素単環
弐基置換カルボニル基、及びテトラヒドロピラニルオキ
シ基等の５〜６Ｒ含酸素複素単環式基置換オキシ基から
選ばれる１つもしくは２つの基で置換されていてもよい
低級アルキル基；低級アルケニル基；低級アルキニル基
；低級アルコキシ基；低級アルカノイル基；アミノ基；
オキソ基、低級アルカノイル基、低級アルコキシ−低級
アルカノイル基及びテトラヒドロフリルカルボニル基等
の５〜６Ｒ含酸素複素単環弐基置換カルボニル基で置換
されていてもよいピロリジニル基等の５〜６員含富含窒
素複素単環〔例えば、２−オキソピロリジニル基、Ｎ−
（低級アルコキシ−低級アルカノイル）ピロリジニル基
、Ｎ−（低級アルカノイル）ピロリジニル基、Ｎ−（テ
トラヒドロフリルカルボニル）ピロリジニル基等〕 ；
又はフリル基、テトラヒドロフリル基等含酸素複素単環
式基であるものをあげることができる。The active ingredient of the present invention is an organic platinum complex having 1,2-diaminocyclohexane and a malonic acid derivative as ligands,
Specific examples include, in general formula (1), R2 is a hydrogen atom; hydroxyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoyl group, lower alkoxy-lower alkoxy group, halogen atom, morpholinocarbonyl group Substituted with one or two groups selected from a 5- to 6-membered nitrogen-containing heteromonocyclic group-substituted carbonyl group such as, and a 5-6R oxygen-containing heteromonocyclic group-substituted oxy group such as a tetrahydropyranyloxy group. a lower alkyl group which may be present; a lower alkenyl group; a lower alkynyl group; a lower alkoxy group; a lower alkanoyl group; an amino group;
Contains 5- to 6-membered pyrrolidinyl groups that may be substituted with 5- to 6R oxygen-containing heteromonocyclic carbonyl groups such as oxo groups, lower alkanoyl groups, lower alkoxy-lower alkanoyl groups, and tetrahydrofuryl carbonyl groups. Nitrogen-containing heteromonocyclic ring [e.g., 2-oxopyrrolidinyl group, N-
(lower alkoxy-lower alkanoyl)pyrrolidinyl group, N-(lower alkanoyl)pyrrolidinyl group, N-(tetrahydrofurylcarbonyl)pyrrolidinyl group, etc.;
Alternatively, oxygen-containing heteromonocyclic groups such as furyl group and tetrahydrofuryl group can be mentioned.
この内、薬効上好ましい白金錯体は、Ｒ１が水素原子、
Ｒ２が水素原子；ハロゲン原子で置換されていてもよい
低級アルキル基；アミノ基；テトラヒドロフリルカルボ
ニル−ピロリジニル基、Ｘがカルボニル基、ｎが１であ
るものをあげることができる。Among these, the medicinally preferable platinum complex has R1 as a hydrogen atom,
Examples include those in which R2 is a hydrogen atom; a lower alkyl group optionally substituted with a halogen atom; an amino group; a tetrahydrofurylcarbonyl-pyrrolidinyl group; X is a carbonyl group; and n is 1.
また、本発明の有効成分である白金錯体には、低級アル
キル基、低級アルコキシ基、低級アルキレン基、低級ア
ルケニル基、低級アルキニル基及び低級アルカノイル基
の炭素数が６以下であるものが含まれるが、とりわけ炭
素数が３以下であるものが好ましい。Furthermore, the platinum complex that is an active ingredient of the present invention includes those in which the number of carbon atoms in the lower alkyl group, lower alkoxy group, lower alkylene group, lower alkenyl group, lower alkynyl group, and lower alkanoyl group is 6 or less. In particular, those having 3 or less carbon atoms are preferred.
尚、本発明の有効成分である有機白金錯体（１）には、
１．２−ジアミノシクロヘキサン、２−（置換アミノ）
マロン酸、その他の不斉炭素原子に基づく異性体及び／
又はＲ２のスルフィニル基による異性体並びにそれらの
混合物がいずれも含まれるが、トランス体、とりわけト
ランス−１体の１．２−ジアミノシクロヘキサンをリガ
ンドとする錯体が好ましい。In addition, the organic platinum complex (1) which is the active ingredient of the present invention includes:
1.2-diaminocyclohexane, 2-(substituted amino)
Malonic acid, other isomers based on asymmetric carbon atoms and/or
or an isomer with a sulfinyl group of R2 and a mixture thereof, but a complex having trans-1, particularly trans-1, 1,2-diaminocyclohexane as a ligand is preferred.
本発明の抗腫瘍剤は各種腫瘍に対し幅広い抗腫瘍効果を
有するため前立腺ガン、畢丸腫瘍、卵巣ガン、悪性リン
パ腫、白血病、乳ガン等の各種腫瘍の治療に効果的に用
いることができる。また、サルコーマ１８０、エールリ
ッヒ癌、古註肉腫、腹水肝癌及び白血病Ｌ １２１０、
Ｐ２Ｓ５などの実験腫瘍のいずれに対しても、優れた抗
腫瘍作用を有する。The anti-tumor agent of the present invention has a wide range of anti-tumor effects against various tumors, and therefore can be effectively used for the treatment of various tumors such as prostate cancer, Amaru tumor, ovarian cancer, malignant lymphoma, leukemia, and breast cancer. In addition, Sarcoma 180, Ehrlich carcinoma, old sarcoma, ascites liver cancer and leukemia L 1210,
It has excellent antitumor activity against all experimental tumors such as P2S5.
さらに、本発明の抗腫瘍剤は、腎毒性をほとんど示さな
いという特長も有する０例えば、〔２−（（Ｎ−（ホル
ミル）グリシル）アミノコマロナト〕（トランス−ｆ−
１，２−ジアミノシクロヘキサン）白金（ＩＩ）を白血
病Ｌ １２１０罹患マウスに工ＯＯ％の延命効果をもた
らし得る必要量だけ投与した場合にも、腎機能障害の指
標となる血中尿素窒素及びクレアチニンの濃度に影響を
与えなかった。Furthermore, the antitumor agent of the present invention also has the feature of showing almost no nephrotoxicity. For example, [2-((N-(formyl)glycyl)aminocomalonato](trans-f-
Even when platinum (II) (1,2-diaminocyclohexane) was administered to mice with leukemia L 1210 in the required amount to prolong the survival of OO%, blood urea nitrogen and creatinine levels, which are indicators of renal dysfunction, decreased. It did not affect the concentration.
また本発明の抗腫瘍剤の有効成分である有機白金錯体（
１）はシスプラチンに較べて約２０倍の水溶性を示し、
製剤化が容易であるため経口的にも非経口的にも好適に
投与することができるが、とりわけ非経口的に投与する
のが好ましい。In addition, the organic platinum complex (
1) is about 20 times more water-soluble than cisplatin,
Since it is easy to formulate a formulation, it can be suitably administered either orally or parenterally, but parenterally is particularly preferred.
投与剤型としては錠剤、カプセル剤等の固形剤であって
もよく、また溶液、懸濁液、乳液等の液剤であってもよ
い、また、非経口的に投与する場合には注射剤として用
いるのが好ましい。The dosage form may be a solid dosage form such as a tablet or capsule, or a liquid dosage form such as a solution, suspension, or emulsion, or as an injection when administered parenterally. It is preferable to use
上記の如き製剤は適宜、賦形剤、結合剤、滑沢剤、崩壊
剤、湿潤剤等の添加剤を含んでいてもよ（、これら添加
剤としては、例えば、乳糖、デンプン、カルボキシメチ
ルセルロース、ゼラチン、ステアリン酸マグネシウム、
精製タルク、アルコール、単シロップ等を好適に用いる
ことができる。The above-mentioned preparations may contain additives such as excipients, binders, lubricants, disintegrants, wetting agents, etc. (These additives include, for example, lactose, starch, carboxymethylcellulose, gelatin, magnesium stearate,
Purified talc, alcohol, simple syrup, etc. can be suitably used.
更に、注射剤としては、等張溶液の形で使用することが
でき、この場合の等張化剤としては、マンニトール、塩
化ナトリウム、グルコース、ソルビトール等をいずれも
好適に用いることができる。Further, as an injection, it can be used in the form of an isotonic solution, and in this case, any of mannitol, sodium chloride, glucose, sorbitol, etc. can be suitably used as the isotonic agent.
また当該製剤は殺菌し、及び／または安定化剤を含むも
のであってもよい。The formulation may also be sterilized and/or contain stabilizing agents.
本発明の有効成分錯体の投与量は投与方法、患者の年齢
、体重、状態及び疾患の程度によっても変動するが、通
常１日当たりの投与量は約２０〜１０００ｍｇ／ｍ、と
りわけ約４０〜３００■／ｄであるのが好ましい。Although the dosage of the active ingredient complex of the present invention varies depending on the administration method, patient's age, weight, condition, and degree of disease, the daily dosage is usually about 20 to 1000 mg/m, particularly about 40 to 300 mg/m. /d is preferred.
本発明の有効成分である有機白金錯体（１）は、例えば
−形式
％式％）
（但し、ｈはｎをこえない０、ｌもしくは２の整数を表
し、他の記号は前記と同一意味を有する。）で示される
アミン化合物又はそのエステルと一般式
％式％
（但し、記号は前記と同一意味を有する。）で示される
酸化合物とをペプチド合成の常法に従って反応させ、必
要により加水分解し、得られた一般式
（但し、記号は前記と同一意味を有する。）で示される
２−（置換アミノ）マロン酸又はその塩（例えば、アル
カリ金属塩又は銀塩）と−形式（但し、ＸＩ及びＸ２は
反応性残基を表す。）で示される１、２−ジアミノシク
ロヘキサン白金錯体とを、常法に従い、必要ならば、遮
光下で反実験例
サルコーマ１８０ に る
（方法）
一群５匹の雌性マウス（ＩＣＲ系、５週令）の鼠践部皮
下にサルコーマ１８０細胞（１，５Ｘ１０６個）を移植
した。移植２４時間後からマウスの腹腔内に検体溶液を
１日１回５日間連続投与し、投与終了から５日後の腫瘍
重量を測定した。The organic platinum complex (1) which is the active ingredient of the present invention is, for example, in the form % (%) (where h represents an integer of 0, 1 or 2 not exceeding n, and other symbols have the same meanings as above). ) or its ester is reacted with an acid compound represented by the general formula % (however, the symbols have the same meanings as above) according to a conventional method for peptide synthesis, and if necessary hydrolyzed. 2-(substituted amino)malonic acid or its salt (e.g., alkali metal salt or silver salt) represented by the obtained general formula (however, the symbols have the same meanings as above) and -form (however, 1,2-diaminocyclohexane platinum complex represented by Sarcoma 180 cells (1.5 x 106 cells) were subcutaneously transplanted into the groin area of a female mouse (ICR strain, 5 weeks old). Starting from 24 hours after transplantation, the sample solution was intraperitoneally administered to mice once a day for 5 consecutive days, and the tumor weight was measured 5 days after the end of administration.
（結果） 下記第１表に示す通りである。(result) It is as shown in Table 1 below.
第
表
注） ：（ｆｆｉ）及び（ｄｌ）は立体配置を表す、
（以下同様）注ａ）：抑制率＝ Ｃ−Ｔ Ｘ１００
注ｂ）？ＭＴＤ＝最大耐量
ＥＤ、。＝３０％の腫瘍増殖抑制効果を示す投与量
製造例 １
（１）２−アミノマロン酸ジエチルエステル・塩酸塩４
．２ｇのテトラヒドロフラン懸濁液にトリニーＪ−７Ｌ
／７ミン２．ＩｇＳ １−ヒドロキシベンゾトリアゾー
ル２．７ｇ及びＮ−（クロロアセチル）グリシン３．０
ｇを加え、０〜５°Ｃに冷却する。さらにＮ、Ｎ’−ジ
シクロへキシルカルボ、ジイミド４゜３ｇを加え、同温
で２時間撹拌後、室温で一夜放置する０反応液から不溶
物をろ去し、ろ液を減圧濃縮する。残香に酢酸エチルを
加え不溶物をろ去後、ろ液を炭酸水素ナトリウム水溶液
で洗浄、乾燥し、減圧濃縮する。残香を酢酸エチル−イ
ソプロピルエーテルから再結晶して２− （（Ｎ−（ク
ロロアセチル）グリシル）アミノコマロン酸ジエチルエ
ステル５．１ｇを得る。Table Note): (ffi) and (dl) represent the steric configuration,
(Same below) Note a): Suppression rate = C-T X100
Note b)? MTD=maximum tolerance ED. Dose production example showing =30% tumor growth inhibiting effect 1 (1) 2-Aminomalonic acid diethyl ester/hydrochloride 4
．． Triny J-7L in 2g of tetrahydrofuran suspension
/7 min 2. IgS 2.7 g of 1-hydroxybenzotriazole and 3.0 g of N-(chloroacetyl)glycine
g and cool to 0-5°C. Further, 4.3 g of N,N'-dicyclohexylcarbodiimide was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was allowed to stand overnight at room temperature. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. After adding ethyl acetate to the residual aroma and removing insoluble matter by filtration, the filtrate is washed with an aqueous sodium bicarbonate solution, dried, and concentrated under reduced pressure. The residual aroma is recrystallized from ethyl acetate-isopropyl ether to obtain 5.1 g of 2-((N-(chloroacetyl)glycyl)aminocomalonic acid diethyl ester.
Ｍ、ｐ、 １０４．５〜１０５°Ｃ
（２）上記（１）の生成物０．６８ｇをＩＮ水酸化ナト
リウム水溶液４．７−に加え、室温で１０時間反応させ
る０反応液を微圧下濃縮し、残香をメタノールで洗浄す
ることにより、２− （（Ｎ−（クロロアセチル）グリ
シル）アミノマロン酸・２ナトリウム塩０．６５ｇを得
る。M, p, 104.5 ~ 105 °C (2) Add 0.68 g of the product from (1) above to IN sodium hydroxide aqueous solution 4.7- and allow to react at room temperature for 10 hours. Concentrate the reaction solution under slight pressure. By washing the residual aroma with methanol, 0.65 g of 2-((N-(chloroacetyl)glycyl)aminomalonic acid disodium salt is obtained.
１６２０ （ｂｒｏａｄ）
（３）ジニトラト（トランス−ｊ！！−１，２−ジアミ
ノシクロヘキサン）白金（ＩＩ）０．８７ｇの水溶液３
０Ｉｄに上記（２）の生成物０．６５ｇの水溶液５ｄを
加え、室温にて５時間放置する。反応液を減圧濃縮後、
冷却して析出晶をろ取し、冷水及びエタノールで洗浄後
乾燥することにより、〔２−〔（Ｎ−（クロロアセチル
）グリシル）アミノコマロナト〕（トランス−１−１，
２−ジアミノシクロヘキサン）白金（ＩＩ）０．８１ｇ
を淡黄色結晶性粉末として得る。1620 (broad) (3) Dinitrato(trans-j!!-1,2-diaminocyclohexane)platinum(II) 0.87g aqueous solution 3
Add 5 d of an aqueous solution of 0.65 g of the product (2) above to 0Id and leave at room temperature for 5 hours. After concentrating the reaction solution under reduced pressure,
After cooling, the precipitated crystals were collected by filtration, washed with cold water and ethanol, and dried to obtain [2-[(N-(chloroacetyl)glycyl)aminocomalonato](trans-1-1,
2-diaminocyclohexane) platinum(II) 0.81g
is obtained as a pale yellow crystalline powder.
Ｍ、ｐ、＞２５０°Ｃ
製造例 ２
（１）２−アミノマロン酸ジエチルエステル・塩酸塩及
びＮ−（ベンジルオキシカルボニル）グリシンを製造例
１−（１）と同様に処理して２−（（Ｎ−ベンジルオキ
シカルボニルグリシルアミノ）〕マロン酸ジエチルエス
テルを得る。M, p, >250°C Production Example 2 (1) 2-Aminomalonic acid diethyl ester hydrochloride and N-(benzyloxycarbonyl)glycine were treated in the same manner as in Production Example 1-(1) to obtain 2-( (N-benzyloxycarbonylglycylamino)] Malonic acid diethyl ester is obtained.
Ｍ、ｐ、９４．５〜９５．５°Ｃ
（２）上記（１）の生成物１５．８ｇの１％塩酸−メタ
ノール溶液にパラジウム−炭素を加え、常圧水素中で一
夜還元する０反応液より不溶物をろ去し、ろ液を減圧濃
縮する。残香をエタノール−イソプロピルエーテルから
再結晶して２−（グリシルアミノ）マロン酸ジエチルエ
ステル・塩酸塩１０゜０ｇを得る。M, p, 94.5-95.5°C (2) Palladium-carbon is added to a 1% hydrochloric acid-methanol solution of 15.8 g of the product from (1) above, and the reaction is reduced overnight in hydrogen at atmospheric pressure. Insoluble materials are filtered off from the solution, and the filtrate is concentrated under reduced pressure. The residual aroma was recrystallized from ethanol-isopropyl ether to obtain 10.0 g of 2-(glycylamino)malonic acid diethyl ester hydrochloride.
Ｍ、ｐ、９７．５〜９８．５°Ｃ
（３）上記（２）の生成物５．４ｇの塩化メチレン溶液
にトリエチルアミン５ｇを加え、撹拌下、０〜５°Ｃに
てアセチルクロリド１．７ｇを滴下する。混合物を同温
で１時間、室温で２時間撹拌し、反応液を水洗、乾燥後
濃縮し、残香をクロロホルム−イソプロピルエーテルか
ら再結晶して２−（（Ｎ−アセチルグリシル）アミン）
マロン酸ジエチルエステル４．５ｇを得る。M, p, 97.5-98.5°C (3) 5 g of triethylamine was added to a methylene chloride solution of 5.4 g of the product from (2) above, and 1.5 g of acetyl chloride was added under stirring at 0-5°C. Drop 7g. The mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours, the reaction solution was washed with water, dried and concentrated, and the residual aroma was recrystallized from chloroform-isopropyl ether to give 2-((N-acetylglycyl)amine).
4.5 g of malonic acid diethyl ester are obtained.
Ｍ、Ｐ、１０２〜１０４°Ｃ
（４）ジニトラト（トランス−ｆｆｉ−１，２−ジアミ
ノシクロヘキサン）白金（Ｉ［）０．８７ｇの水溶液３
０ｄに２−（（Ｎ−アセチルグリシル）アミノコマロン
酸・２ナトリウム塩（対応するジエチルエステルから製
造例１−（２）と同様にして調製）０．６０ｇの水溶液
５ｄを加え、室温で５時間放置する０反応液をハイポー
ラス樹脂ＨＰ−２０（三菱化成工業社製）に吸着させ、
水洗後、メタノール−水（１： １）で溶出し、溶出液
を減圧濃縮し、残香にエタノール−アセトン（１：１）
を加えて析出品をろ取し、乾燥することにより、〔２−
〔（Ｎ−アセチルグリシル）アミノコマロナト） （
）ランス−ｆ−１，２−ジアミノシクロヘキサン）白金
（ＩＩ）０．７０ｇを淡黄色粉末として得る。M, P, 102-104°C (4) Aqueous solution of 0.87 g of dinitrato(trans-ffi-1,2-diaminocyclohexane)platinum (I[) 3
0d was added with 5d of an aqueous solution of 0.60g of 2-((N-acetylglycyl)aminocomalonic acid disodium salt (prepared from the corresponding diethyl ester in the same manner as in Production Example 1-(2)), and the mixture was heated at room temperature for 5 hours. The reaction solution to be left is adsorbed on high porous resin HP-20 (manufactured by Mitsubishi Chemical Industries, Ltd.),
After washing with water, elute with methanol-water (1:1), concentrate the eluate under reduced pressure, and add ethanol-acetone (1:1) to the residual aroma.
[2-
[(N-acetylglycyl)aminocomalonato) (
0.70 g of lance-f-1,2-diaminocyclohexane) platinum(II) are obtained as a pale yellow powder.
ｍ、Ｐ、 ２５７°Ｃ（分解）
製造例 ３〜２７
対応原料化合物を製造例１又は２と同様に処理して、下
記第２〜６表記載の錯体を得る。m, P, 257°C (decomposition) Production Examples 3 to 27 The corresponding raw material compounds are treated in the same manner as in Production Example 1 or 2 to obtain the complexes listed in Tables 2 to 6 below.
第２表
（Ａ１に＝−〇ＩＩｘ−、ｎ□１ 、χ；Ｃ０）３２２
０．３０７０． １６８０． １６４０第３表
（八Ｉｋ＝
−０１１□Ｃ１ｌ□−
ｎ＝１
Ｘ丑ＣＯ）
第４表
（ＡＩｋ＝−ＣＩｌ□−
ｎ＝１
Ｘ＝ＳＯｚ）
第５表
（Ａ１に＝−Ｃ１ｌ（ＣＩｌｚ）−１
ｎ＝１
Ｘ、ＣＯ）
第６表
（Ａｌｋ−−ＣＨｚ−
ｎ・２
Ｘ＝ＣＯ）
製造例３０
（グリシルアミノ）
マロン酸ジエチルエ
ステル・塩酸塩２゜
７ｇの水溶液にイソシアン酸
カリウムｌ。Table 2 (A1=-〇IIx-, n□1, χ; C0) 322
0.3070. 1680. 1640 Table 3 (8Ik= -011□C1l□- n=1 X OxCO) Table 4 (AIk=-CIl□- n=1 -1 n=1 X, CO) Table 6 (Alk--CHz- n.2
６ｇを加えて１ ０分間撹拌する。Add 6g to 1 Stir for 0 minutes.
反
応液に酢酸０゜
７成を加え、
さらに５時間撹拌す
る０反応液をクロロホルムで抽出し、抽出液を減圧濃縮
する。残香を酢酸エチルから再結晶して２−（Ｎ−カル
バモイルグリシル）アミノマロン酸ジエチルエステル１
．５８ｇを得る。Acetic acid solution was added to the reaction solution, and the mixture was further stirred for 5 hours. The reaction solution was extracted with chloroform, and the extract was concentrated under reduced pressure. The residual aroma was recrystallized from ethyl acetate to obtain 2-(N-carbamoylglycyl)aminomalonic acid diethyl ester 1.
．． Obtain 58g.
Ｍ、ｐ、１４０〜１４１．５°Ｃ
（２）上記（１）の生成物を製造例２−（４）と同様に
処理して、（２−（Ｎ−カルバモイルグリシル）アミノ
マロナト〕（トランス−ｆｆｉ−１，２−ジアミノシク
ロヘキサン）白金（ｎ）を白色粉末として得る。M, p, 140-141.5°C (2) The product of (1) above was treated in the same manner as in Production Example 2-(4) to obtain (2-(N-carbamoylglycyl)aminomalonato) (trans -ffi-1,2-diaminocyclohexane) platinum (n) is obtained as a white powder.
Ｍ、ｐ、＞２５０°Ｃ
３２２０，３０８０、１６８０、１６４０製造例３１及
び３２
（１）２−（グリシルアミノ）マロン酸ジエチルエステ
ル及びメチルスルフェニル酢酸を実施例１−（１）と同
様に処理して２− （（Ｎ−（メチルスルフェニルアセ
チル）グリシル）アミノコマロン酸ジエチルエステルを
得る。M, p, >250°C 3220, 3080, 1680, 1640 Production Examples 31 and 32 (1) 2-(Glycylamino)malonic acid diethyl ester and methylsulfenyl acetic acid were treated in the same manner as in Example 1-(1). to obtain 2-((N-(methylsulfenylacetyl)glycyl)aminocomalonic acid diethyl ester.
Ｍ、ｐ、８７〜８８．５°Ｃ
（２）上記（１）の生成物２．６４ｇの塩化メチレン溶
液に０〜５°Ｃでｍ−クロロ過安息香酸２．５ｇを加え
、同温で２０分間撹拌する。反応液を洗浄、乾燥後溶媒
を留去する。残香をシリカゲルカラムクロマトグラフィ
ーに付して２− ［（Ｎ−（メチルスルフィニルアセチ
ル）グリシル）アミノゴマロン酸ジエチルエステル（ｍ
、Ｐ、１２７〜１２９°Ｃ）１．３１ｇ及び２− （（
Ｎ−（メチルスルホニルアセチル）グリシル）アミノコ
マロン酸ジエチルエステル（ｍ、ｐ、 １７８〜１７
９． ５°Ｃ）１．２１ｇを得る。M, p, 87 to 88.5 °C (2) To a methylene chloride solution of 2.64 g of the product from (1) above was added 2.5 g of m-chloroperbenzoic acid at 0 to 5 °C, and at the same temperature. Stir for 20 minutes. After washing and drying the reaction solution, the solvent is distilled off. The residual aroma was subjected to silica gel column chromatography to obtain 2-[(N-(methylsulfinyl acetyl)glycyl)aminogomalonic acid diethyl ester (m
, P, 127-129 °C) 1.31 g and 2- ((
N-(methylsulfonylacetyl)glycyl)aminocomalonic acid diethyl ester (m, p, 178-17
9. 5°C) 1.21 g is obtained.
（３）上記（２）で得た生成物を製造例２−（４）と同
様に処理して下記第７表記載の錯体を得る。(3) The product obtained in (2) above is treated in the same manner as in Production Example 2-(4) to obtain the complexes listed in Table 7 below.
第７表
製造例３３
（１）２−アミノマロン酸ジエチルエステル及びＮ−ベ
ンジルオキシカルボニル−β−アラニンヲ製造例１−（
１１及び２−（２）と同様に処理して２−〔（β−アラ
ニル）アミノコマロン酸ジエチルエステル・塩酸塩を得
る。Table 7 Production Example 33 (1) 2-Aminomalonic acid diethyl ester and N-benzyloxycarbonyl-β-alanine Production Example 1-(
11 and 2-(2) to obtain 2-[(β-alanyl)aminocomalonic acid diethyl ester hydrochloride.
Ｍ、ｐ、 ｓａ〜９２℃
（２）上記（１）の生成物とグリコール酸とを製造例１
−（１）と同様に処理して２−（（Ｎ−（ヒドロキシア
セチル）−β−アラニル）アミノコマロン酸ジエチルエ
ステルを得る。M, p, sa ~ 92°C (2) The product of (1) above and glycolic acid were prepared in Production Example 1.
- Treat in the same manner as in (1) to obtain 2-((N-(hydroxyacetyl)-β-alanyl)aminocomalonic acid diethyl ester.
Ｍ、ｐ、 ９４．５〜９６°Ｃ
（３）上記（２）の生成物１．３０ｇの塩化メチレン溶
液にジヒドロピラン１．Ｏｇ及びｐ−トルエンスルホン
酸２０■を加えて室温で一夜撹拌する。反応液を洗浄、
乾燥し、溶媒を留去する。残香をシリカゲルカラムで精
製して２−（（Ｎ−（テトラヒドロピラン−２−イルオ
キシアセチル）−β−アラニル）アミノコマロン酸ジエ
チルエステル１３２ｇを油状物として得る。M, p, 94.5-96°C (3) Add 1.30 g of the product from (2) above in methylene chloride to a solution of 1.5 g of dihydropyran. Add Og and 20 μl of p-toluenesulfonic acid and stir overnight at room temperature. Wash the reaction solution,
Dry and evaporate the solvent. The residual aroma is purified using a silica gel column to obtain 132 g of 2-((N-(tetrahydropyran-2-yloxyacetyl)-β-alanyl)aminocomalonic acid diethyl ester as an oil.
１７４０、 １６６０
（４）上記（３）の生成物を製造例２−（４）と同様に
処理して、（２−（（Ｎ−（テトラヒドロピラン−２−
イルオキシアセチル）−β−アラニル）アミノマロナト
〕（トランス−ｆｆｉ−１，２−ジアミノシクロヘキサ
ン）白金（ｎ）を白色粉末として得る。1740, 1660 (4) The product of (3) above was treated in the same manner as in Production Example 2-(4) to obtain (2-((N-(tetrahydropyran-2-
yloxyacetyl)-β-alanyl)aminomalonato](trans-ffi-1,2-diaminocyclohexane)platinum (n) is obtained as a white powder.
Ｍ、ｐ、２２１〜２２３°Ｃ（分解）
３２２０．３０８０、１６９０、１６４０製造例３４
（１）２−（Ｎ−ベンジルオキシカルボニル）アミノマ
ロン酸ジエチルエステル（２−アミノマロン酸ジエチル
エステル・塩酸塩とベンジルオキシカルボニルクロリド
から製造例２−（３）と同様にして調製、 ｍ、ｐ、
３６．５〜３７°Ｃ）１２．４ｇをテトラヒドロフラン
１００Ｉｄに溶解し、６３％−水素化ナトリウム１．７
ｇを加え、室温で１時間撹拌後、ヨウ化メチル６．８ｇ
を滴下する。室温で２０時間反応後、濃縮し、残香に酢
酸エチル及び水を加えて有機層を分取し、乾燥後、溶媒
を留去する。M, p, 221-223°C (decomposition) 3220.3080, 1690, 1640 Production Example 34 (1) 2-(N-benzyloxycarbonyl)aminomalonic acid diethyl ester (2-aminomalonic acid diethyl ester hydrochloride and benzyloxycarbonyl chloride in the same manner as in Production Example 2-(3), m, p,
36.5-37°C) was dissolved in 100Id of tetrahydrofuran, 63%-sodium hydride 1.7
After stirring at room temperature for 1 hour, add 6.8 g of methyl iodide.
drip. After reacting at room temperature for 20 hours, it is concentrated, ethyl acetate and water are added to the residual aroma to separate the organic layer, and after drying, the solvent is distilled off.
残香をシリカゲルカラムクロマトグラフィー〔溶媒；ｎ
−ヘキサン−酢酸エチル＝（３１））で精製して油状物
１１．７４ｇが得られる。この油状物を酢酸エチル−メ
タノール混液に溶解し、１０％−塩酸メタノール溶液１
６ｄを加え、パラジウム−炭素を触媒として常圧上還元
を行う、ろ過し、濃縮することにより、２−アミノ−２
−メチルマロン酸ジエチルエステル塩酸塩７．２５ｇを
得る。The residual aroma was removed by silica gel column chromatography [solvent; n
-hexane-ethyl acetate=(31)) to obtain 11.74 g of an oil. Dissolve this oil in a mixture of ethyl acetate and methanol, and dissolve 10% hydrochloric acid in methanol solution.
2-amino-2-2-amino-2
- 7.25 g of methylmalonic acid diethyl ester hydrochloride are obtained.
ＮＭＲ（ｄ、−ＤＭＳＯ）δｉ １．２３（６＋１．
Ｌ）。NMR (d, -DMSO) δi 1.23 (6+1.
L).
１．７Ｈ３１１，ｓ）、 ４．２５（４１１，ｑ）、
９．４２（３１１゜ｂｒｏａｄ＋ ５）
（２）上記（１）の生成物とホルミルグリシンとを実施
例１−（１）と同様に処理して２−Ｎ−ホルミルグリシ
ル）アミノ−２−メチルマロン酸ジエチルエステルを得
る。1.7H311,s), 4.25(411,q),
9.42 (311° broad+ 5) (2) The product of (1) above and formylglycine were treated in the same manner as in Example 1-(1) to obtain 2-N-formylglycyl)amino-2-methyl. Malonic acid diethyl ester is obtained.
Ｍ、Ｐ、９８〜９９°Ｃ
（３）ジニトラト（トランス−ｊＩ！−１，２−ジアミ
ノシクロヘキサン）白金（ＩＩ）０．８７ｇの水？容液
３０ｄに２−（Ｎ−ホルミルグリシル）アミノ−２−メ
チルマロン酸・２ナトリウム塩（対応するジエチルエス
テルから製造例１−（２）と同様にして調製）０．６８
ｇの水溶液５ｄを加え、５０〜６０°Ｃで４時間加温し
、炭末を加え、ろ過する。M, P, 98-99°C (3) Dinitrato(trans-jI!-1,2-diaminocyclohexane)platinum(II) 0.87 g of water? 2-(N-formylglycyl)amino-2-methylmalonic acid disodium salt (prepared from the corresponding diethyl ester in the same manner as in Production Example 1-(2)) 0.68 to 30 d of solution
Add 5d of an aqueous solution of 1.g, heat at 50 to 60°C for 4 hours, add charcoal powder, and filter.
以律製造例２−（４）と同様に処理することにより、（
２−（Ｎ−ホルミルグリシル）アミノ−２−メチルマロ
ナト〕（トランス−ｆｆｉ−１，２−ジアミノシクロヘ
キサン）白金（ＩＩ）０．５５ｇを白色粉体として得る
。By treating in the same manner as in Production Example 2-(4), (
0.55 g of 2-(N-formylglycyl)amino-2-methylmalonato](trans-ffi-1,2-diaminocyclohexane)platinum(II) is obtained as a white powder.
Ｍ、Ｐ、 ２４９〜２５２°Ｃ（分解）３１００、
１６５０、 ｌ ５９０M, P, 249-252°C (decomposition) 3100,
1650, l 590
Claims (1)
は水素原子、置換基を有することもある低級アルキル基
、低級アルケニル基、低級アルキニル基、低級アルコキ
シ基、低級アルカノイル基、アミノ基、置換基を有する
こともある含窒素複素単環式基又は含酸素複素単環式基
、Ａｌｋは低級アルキレン基、Ｘはカルボニル基又はス
ルホニル基、ｎは１又は２を表す。） で示される有機白金錯体を有効成分とする抗腫瘍剤。 ２、Ｒ＾２が水素原子；水酸基、低級アルコキシ基、低
級アルキルスルフィニル基、低級アルキルスルホニル基
、低級アルカノイル基、低級アルコキシ−低級アルコキ
シ基、ハロゲン原子、モルホリノカルボニル基及びテト
ラヒドロピラニルオキシ基から選ばれる１つもしくは２
つの基で置換されていてもよい低級アルキル基；低級ア
ルケニル基；低級アルキニル基；低級アルコキシ基；低
級アルカノイル基；アミノ基；オキソ基、低級アルカノ
イル基、低級アルコキシ−低級アルカノイル基及びテト
ラヒドロフリルカルボニル基から選ばれる基で置換され
ていてもよいピロリジニル基；フリル基；又はテトラヒ
ドロフリル基である請求項１記載の抗腫瘍剤。 ３、Ｒ＾１が水素原子、Ｒ＾２が水素原子；ハロゲン原
子で置換されていてもよい低級アルキル基；アミノ基；
又はテトラヒドロフリルカルボニル−ピロリジニル基、
Ｘがカルボニル基、ｎが１である請求項２記載の抗腫瘍
剤。 ４、Ｒ＾２が水素原子、Ａｌｋがメチレン基である請求
項３記載の抗腫瘍剤。 ５、Ｒ＾２がクロロメチル基、Ａｌｋがメチレン基であ
る請求項３記載の抗腫瘍剤。 ６、Ｒ＾２がアミノ基、Ａｌｋがメチレン基である請求
項３記載の抗腫瘍剤。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a hydrogen atom or a lower alkyl group, R^2
is a hydrogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkanoyl group, an amino group, a nitrogen-containing heteromonocyclic group that may have a substituent, or a nitrogen-containing heteromonocyclic group that may have a substituent. An oxygen heteromonocyclic group, Alk represents a lower alkylene group, X represents a carbonyl group or a sulfonyl group, and n represents 1 or 2. ) An antitumor agent containing an organic platinum complex as an active ingredient. 2, R^2 is a hydrogen atom; selected from hydroxyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoyl group, lower alkoxy-lower alkoxy group, halogen atom, morpholinocarbonyl group, and tetrahydropyranyloxy group one or two
lower alkyl group which may be substituted with two groups; lower alkenyl group; lower alkynyl group; lower alkoxy group; lower alkanoyl group; amino group; oxo group, lower alkanoyl group, lower alkoxy-lower alkanoyl group and tetrahydrofurylcarbonyl group The antitumor agent according to claim 1, which is a pyrrolidinyl group optionally substituted with a group selected from; a furyl group; or a tetrahydrofuryl group. 3, R^1 is a hydrogen atom, R^2 is a hydrogen atom; a lower alkyl group that may be substituted with a halogen atom; an amino group;
or a tetrahydrofurylcarbonyl-pyrrolidinyl group,
The antitumor agent according to claim 2, wherein X is a carbonyl group and n is 1. 4. The antitumor agent according to claim 3, wherein R^2 is a hydrogen atom and Alk is a methylene group. 5. The antitumor agent according to claim 3, wherein R^2 is a chloromethyl group and Alk is a methylene group. 6. The antitumor agent according to claim 3, wherein R^2 is an amino group and Alk is a methylene group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63219266A JPH0267217A (en) | 1988-09-01 | 1988-09-01 | Antitumor agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63219266A JPH0267217A (en) | 1988-09-01 | 1988-09-01 | Antitumor agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0267217A true JPH0267217A (en) | 1990-03-07 |
Family
ID=16732835
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63219266A Pending JPH0267217A (en) | 1988-09-01 | 1988-09-01 | Antitumor agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0267217A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049696A1 (en) * | 2000-01-04 | 2001-07-12 | Access Pharmaceuticals, Inc. | N,o-amidomalonate platinum complexes |
| JP2007522244A (en) * | 2004-02-13 | 2007-08-09 | アクセス ファーマシューティカルズ， インコーポレイテッド | O, O'-amidmalonate and N, O-amidmalonate platinum complexes |
-
1988
- 1988-09-01 JP JP63219266A patent/JPH0267217A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049696A1 (en) * | 2000-01-04 | 2001-07-12 | Access Pharmaceuticals, Inc. | N,o-amidomalonate platinum complexes |
| KR100729015B1 (en) * | 2000-01-04 | 2007-06-14 | 어섹스 팔마큐티칼스 인코포레이티드 | N,o-amidomalonate platinum complexes |
| JP2007522244A (en) * | 2004-02-13 | 2007-08-09 | アクセス ファーマシューティカルズ， インコーポレイテッド | O, O'-amidmalonate and N, O-amidmalonate platinum complexes |
| JP2011105736A (en) * | 2004-02-13 | 2011-06-02 | Access Pharmaceuticals Inc | O,o'-amidomalonate and n,o-amidomalonate platinum complex |
| JP4717016B2 (en) * | 2004-02-13 | 2011-07-06 | アクセス ファーマシューティカルズ， インコーポレイテッド | O, O'-amidmalonate and N, O-amidmalonate platinum complexes |
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