JPS6379830A - Antibiotic diazaquionomycin a derivative - Google Patents
Antibiotic diazaquionomycin a derivativeInfo
- Publication number
- JPS6379830A JPS6379830A JP61224153A JP22415386A JPS6379830A JP S6379830 A JPS6379830 A JP S6379830A JP 61224153 A JP61224153 A JP 61224153A JP 22415386 A JP22415386 A JP 22415386A JP S6379830 A JPS6379830 A JP S6379830A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- chloroform
- reduced pressure
- under reduced
- 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.)
- Granted
Links
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003944 tolyl group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 21
- 239000002904 solvent Substances 0.000 abstract description 17
- 239000002253 acid Substances 0.000 abstract description 9
- 239000003513 alkali Substances 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 abstract description 6
- 239000011707 mineral Substances 0.000 abstract description 6
- 238000001816 cooling Methods 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 150000002084 enol ethers Chemical class 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 125000005207 tetraalkylammonium group Chemical group 0.000 abstract description 2
- YYFLDZZDOUDZQM-UHFFFAOYSA-N 3-[1-[[4-(3-phenylquinolin-2-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=NC2=CC=CC=C2C=C1C1=CC=CC=C1 YYFLDZZDOUDZQM-UHFFFAOYSA-N 0.000 abstract 1
- 102000004190 Enzymes Human genes 0.000 abstract 1
- 108090000790 Enzymes Proteins 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 108
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 238000004519 manufacturing process Methods 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 28
- 239000013078 crystal Substances 0.000 description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 25
- 239000012156 elution solvent Substances 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- -1 nitro, carboxy group Chemical group 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 229910001923 silver oxide Inorganic materials 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004342 Benzoyl peroxide Substances 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 108010022394 Threonine synthase Proteins 0.000 description 3
- 102000005497 Thymidylate Synthase Human genes 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- OOKPOQDUQHQVNX-UHFFFAOYSA-N quinoline-3,7-dicarboxylic acid Chemical compound C1=C(C(O)=O)C=NC2=CC(C(=O)O)=CC=C21 OOKPOQDUQHQVNX-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- GQOJGBVTUSRBPQ-UHFFFAOYSA-N 2-quinolin-3-ylacetic acid Chemical compound C1=CC=CC2=CC(CC(=O)O)=CN=C21 GQOJGBVTUSRBPQ-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- PZAGQUOSOTUKEC-UHFFFAOYSA-N acetic acid;sulfuric acid Chemical compound CC(O)=O.OS(O)(=O)=O PZAGQUOSOTUKEC-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910000423 chromium oxide Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- KPVWDKBJLIDKEP-UHFFFAOYSA-L dihydroxy(dioxo)chromium;sulfuric acid Chemical compound OS(O)(=O)=O.O[Cr](O)(=O)=O KPVWDKBJLIDKEP-UHFFFAOYSA-L 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical group C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 description 1
- PCZOZSATUTWXIC-UHFFFAOYSA-N tetraethylazanium;cyanide Chemical compound N#[C-].CC[N+](CC)(CC)CC PCZOZSATUTWXIC-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は抗生物質リアザキノマイシン人の新規誘導体に
関する。DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel derivatives of the antibiotic riazachinomycin.
従来の技術
抗生物質ジアザΦノマイシン人は特開昭５８−２０５４
９７号公報に「抗生物質０Ｍ−７０４−ＡＪとして記載
された公知化合物で、ダラム陽性菌に活性を示す。Conventional technology Antibiotic diaza Φnomycin was published in Japanese Patent Publication No. 58-2054
A known compound described in Publication No. 97 as "Antibiotic 0M-704-AJ, which exhibits activity against Durham-positive bacteria.
本発明者は、上記ジアザキノマイクンＡから多くの誘導
体を製造、これらが抗菌活性のほかにチミジル酸合成酵
素阻害作用を有することを見出し、この発明を完成した
。The present inventor has produced many derivatives from the above-mentioned diazaquinomicun A, found that these have not only antibacterial activity but also thymidylate synthetase inhibitory action, and has completed the present invention.
発明が解決しようとする問題演
本発明の目的は、抗菌活性とチミジル酸合成酵素を阻害
する活性とを有する新規なジアザキノマイシンＡＲ導体
を提供することにある。Problems to be Solved by the Invention An object of the present invention is to provide a novel diazachinomycin AR conductor having antibacterial activity and thymidylate synthetase inhibiting activity.
問題点を解決するための手段
本発明によシ提供されるジアザキノマイシン人誘導体は
下記の一般式（１）で表わされる。Means for Solving the Problems The diazachinomycin human derivative provided by the present invention is represented by the following general formula (1).
υ
〔式中、Ｒ１とＲ２の一方はメチル基で、他方は（１）
−（ＣＨ，）、−Ｇｏ、Ｒ”または−ＣＨ，−０Ｈ
（Ｇｏ、ＴＬ”）、 （ただしｎは０−２の整数を表
わし、几３は炭素数１−５の低級アルキル基を表わす）
または（ｂ） −ＯＨ，ＯＲ’ または−ＯＨ，Ｑ
Ｃ：ＯＲ（ただしＲは水素、炭素数１−５の飽和または
不飽和アルキル基、置換または未置換アリール基または
アラルキル基を表わす）であるか、あるいはＴＬｌ
とＲ２は同一でも異なってもよく、上記（＆）着たは（
ｂ）を表わす。、〕Ｒ４のアリール基はフェニル、トリ
ルまたはナフチルである。アリール基の置換基はたとえ
ば低級アルキル基（例、メチル）、低級アルコキシ基（
例、メトキシ）、ハロゲン（例、フッ素、塩素、臭素）
、ニトロ、カルボキシ基などである。Ｒ４のアラル命ル
基はアリールアルキル基で、アリールとしてフェニル、
トリル、ナチルなどがあげられ、アル中ルとして炭素数
１−３のもの（例、メチル、エチル、プロピル）があげ
られる。υ [In the formula, one of R1 and R2 is a methyl group, and the other is (1)
-(CH,), -Go, R" or -CH, -0H
(Go, TL"), (where n represents an integer of 0-2, and 3 represents a lower alkyl group having 1-5 carbon atoms)
or (b) -OH,OR' or -OH,Q
C:OR (wherein R represents hydrogen, a saturated or unsaturated alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aryl group, or an aralkyl group), or TLl
and R2 may be the same or different, and the above (&) or (
b) represents. , ] The aryl group of R4 is phenyl, tolyl or naphthyl. Substituents for aryl groups include, for example, lower alkyl groups (e.g. methyl), lower alkoxy groups (
e.g., methoxy), halogens (e.g., fluorine, chlorine, bromine)
, nitro, carboxy group, etc. The aral group of R4 is an arylalkyl group, and the aryl is phenyl,
Examples include tolyl and natyl, and examples of alkyl include those having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl).
本発明の化合物は、たとえば次に記載する方法によって
収率よく得ることができる。The compound of the present invention can be obtained in good yield, for example, by the method described below.
本発明による化合物は、公知のジアザ中ノマイシン人〔
式（［）において几１−ＦＬ２−メチル〕を出発原料と
して製造される。ジアザ中ノマイシン人をクロロホルム
のような溶媒中で０−２５゜Ｃの温度でヨウ化メチルお
よび酸化銀と反応させて得られる化合物（２） 、”！
たは公知の化合物（３） （Ｔｅｔｒａｈｅｄｒｏｎ
Ｌ＠ｔｔ＠ｒｓ、 Ｖｏｌ、 ２４． ｐｐ３６４３−
３６４６．１９８３） を四塩化炭素のような溶媒中
で２５−８０℃の温度で過剰モル量のＮ−ブロムコハク
酸イミｒと触媒量の過酸化ベンゾイルと反応させて得ら
れた式（４）および式（５）で表わされる中間体から製
造する。The compounds according to the invention can be used in combination with the known diazanomycin
It is produced using the formula ([), 1-FL2-methyl] as a starting material. Compound (2), obtained by reacting diazatomycin with methyl iodide and silver oxide in a solvent such as chloroform at a temperature of 0-25°C.
or known compound (3) (Tetrahedron
L@tt@rs, Vol, 24. pp3643-
3646.1983) with an excess molar amount of imir N-bromosuccinate and a catalytic amount of benzoyl peroxide at a temperature of 25-80°C in a solvent such as carbon tetrachloride. It is produced from an intermediate represented by formula (5).
化合物（４）あるいは化合物（５）と、以下に示すよう
な求核試薬とを反応させ、目的の置換基をメチル基の位
置に導入することができる。A desired substituent can be introduced into the position of a methyl group by reacting compound (4) or compound (5) with a nucleophilic reagent as shown below.
製造方法人
化合物（５）をクロロホルムのような溶媒中、テトラア
ルキルアンモニウムシアニｒと水冷下に反応させ、化合
物（６）とし、次に一般式（７）（Ｒは炭素数１−５の
低級アルキル基を意味する）で表わされるアルコール類
と濃硫酸のようた鉱酸を触媒として反応させ、エノール
エーテルの加水分解と同時にエステル化を行ない化合物
（８）を製造する。相当するカルボン酸（９）は、化合
物（８）を含水アルコール溶媒中で、水酸化ナトリウム
のようなアルカリで処理して得られ化合物（４）からも
同様の方法により、相当する化合物（１０）、（１１）
、（１２）を製造することができる。Production method Compound (5) is reacted with tetraalkylammonium cyanide r in a solvent such as chloroform under water cooling to obtain compound (6), which is then expressed by the general formula (7) (R has 1 to 5 carbon atoms). A lower alkyl group) is reacted with a mineral acid such as concentrated sulfuric acid as a catalyst, and the enol ether is hydrolyzed and simultaneously esterified to produce compound (8). The corresponding carboxylic acid (9) can be obtained by treating compound (8) with an alkali such as sodium hydroxide in a hydroalcoholic solvent, and the corresponding compound (10) can also be obtained from compound (4) by the same method. , (11)
, (12) can be manufactured.
（ｌｔ） （１２）製造方法Ｂ
化合物（５）と乾燥テトラヒ？ロフランのような溶媒中
で、ジアルキルマロン酸ニステルト水素ナトリウムのよ
うな塩基から調製したマロン酸エステルのアニオンとを
室温で反応させ、化合物（１３）とする。化合物（１３
）を、含水アルコールのような溶媒中、濃硫酸のような
鉱酸を触媒として加水分解し、化合物（１４）を製造す
る。相当するカルボン酸（１５）は化合物（１４）を含
水アルコール溶媒中で水酸化ナトリウムのようなアルカ
リで処理して得られる。(lt) (12) Production method B Compound (5) and dry tetrahedron? Compound (13) is reacted with an anion of a malonic ester prepared from a base such as sodium dialkylmalonate nystertehydrogen in a solvent such as lofuran at room temperature. Compound (13
) is hydrolyzed in a solvent such as hydrous alcohol using a mineral acid such as concentrated sulfuric acid as a catalyst to produce compound (14). The corresponding carboxylic acid (15) can be obtained by treating compound (14) with an alkali such as sodium hydroxide in a hydroalcoholic solvent.
化合物（１３）を、含水アルコールのような溶媒中で、
水酸化ナトリウムのようなアルカリによって加水分解し
て化合物（１６）とし、これをピリジンのような溶媒中
、ｌＯＯ１２０”Ｃ程度に加熱し、化合物（１７）を製
造する。化合物（１７）を、一般式（７）で表わされる
アルコールと、硫酸のような鉱酸を触媒として反応させ
、エステル化と、エノールエーテルの加水分解を同時に
行ない、化合物（１８）を製造する。相当するカルボン
酸（１９）は、化合物（１８）を含水アルコール溶媒中
、水酸化ナトリ９ムのようなアルカリで処理して得られ
る。Compound (13) in a solvent such as hydroalcohol,
Compound (16) is produced by hydrolysis with an alkali such as sodium hydroxide, and this is heated to about 100"C in a solvent such as pyridine to produce compound (17). Compound (18) is produced by reacting the alcohol represented by formula (7) with a mineral acid such as sulfuric acid as a catalyst to simultaneously perform esterification and hydrolysis of the enol ether.The corresponding carboxylic acid (19) is obtained by treating compound (18) with an alkali such as sodium hydroxide in a hydroalcoholic solvent.
化合物を、含水テトラヒドロフラン中、８〇−９０℃程
度に約４８時間加熱し、化合物（２０）とし、これをア
セトンのような溶媒中、クロム酸−硫酸のような酸化剤
で酸化して化合物（２１）とする。化合物（２１）と、
一般式（７）で表わされるアルコールを、硫職のような
鉱酸を触媒として反応させ、エステル化と同時にエノー
ルエーテルの加水分解を行ない化合物（２２）を製造す
る。The compound is heated to about 80-90°C for about 48 hours in aqueous tetrahydrofuran to form compound (20), which is oxidized with an oxidizing agent such as chromic acid-sulfuric acid in a solvent such as acetone to form compound (20). 21). Compound (21) and
The alcohol represented by the general formula (7) is reacted with a mineral acid such as sulfuric acid as a catalyst, and enol ether is hydrolyzed at the same time as esterification to produce compound (22).
相当するカルボン酸（２３）は化合物（２２）を、含水
アルコール溶媒中、水酸化ナトリウムのようなアルカリ
で処理して得られる。The corresponding carboxylic acid (23) can be obtained by treating compound (22) with an alkali such as sodium hydroxide in a hydroalcoholic solvent.
製造方法り
化合物（５）を一般式（２４）（Ｒは水素、炭素数１−
５の飽和または不飽和アルキル基、アリ−ル基またはア
ラル中ル基を表わす）で表わされるカルボン酸類と、基
質に対して過剰量の該当ナトリクム塩と、室温から１１
０℃程度の温度で反応させ化合物（２５）とする。化合
物（２５）を酢酸−硫酸で室温から１００℃程度の温度
で処理し、化合物（２６）を製造する。化合物（２６）
は、メタノールのような溶媒中、触媒量の水酸化リチウ
ムのようなアルカリで処理し、化合物（２７）へ変換で
きる。According to the production method, compound (5) is represented by the general formula (24) (R is hydrogen, carbon number 1-
5 (representing a saturated or unsaturated alkyl group, aryl group, or aral group), an excess amount of the corresponding sodium salt relative to the substrate, and 11
The reaction is carried out at a temperature of about 0°C to obtain compound (25). Compound (25) is treated with acetic acid-sulfuric acid at a temperature from room temperature to about 100°C to produce compound (26). Compound (26)
can be converted to compound (27) by treatment with a catalytic amount of an alkali such as lithium hydroxide in a solvent such as methanol.
化合物（４）からも前記と同様の方法で化合物（２８）
、（２９） 、（３０）を屓次製造できる。Compound (28) was also obtained from compound (4) in the same manner as above.
, (29) and (30) can be produced sequentially.
製造方法Ｅ
化合物（５）と、一般式（３１）（Ｒは炭素数１−５の
低級アルキル基を意味する）で表わされるアルコール類
を溶媒とし、硫酸のような鉱酸を触媒として室温から溶
媒の沸点程度の温度で反応させ、化合物（３２）を製造
する。Production method E Compound (5) and an alcohol represented by the general formula (31) (R means a lower alkyl group having 1 to 5 carbon atoms) are used as solvents, and a mineral acid such as sulfuric acid is used as a catalyst from room temperature. Compound (32) is produced by reacting at a temperature around the boiling point of the solvent.
化合物（４）からも同様の方法で化合物（３３）が製造
できる。Compound (33) can also be produced from compound (4) in a similar manner.
次に実施例を示し、本発明を具体的に説明するが、本発
明はこれらの実施例のみに限定されるものではない口
実施例１
２．８−ジフト中シー３，７−シメチルー４，６−ジプ
ロピルビリＦ（３ｅ２−ｇ：ｌキノリン−５１１Ｏ−ジ
オン〔化合物（３）〕の製造。Next, the present invention will be specifically explained with reference to examples, but the present invention is not limited to these examples.Example 1 Production of 6-dipropylbiriF (3e2-g:l quinoline-511O-dione [compound (3)]).
ジアザキノマイシン人（式ＩＫおイテｎ、ｇＲ，２電メ
チル）２５０１１Ｔ９をクロロホルム２５＋ａＪに溶解
し、ヨウ化メチル５ゴ、酸化銀５００ダを加え、２時間
加熱還流する。反応液をろ過し、酸化銀を除去後、ろ液
を減圧下濃縮する。残査をシリカゲルカラムクロマトグ
ラフィー（溶出溶媒：クロロホルム）で精製し、黄色結
晶２３５■（収率８７チ）を得た。Diazachinomycin (formula IK, gR, dimethyl) 25011T9 was dissolved in 25+aJ of chloroform, 5g of methyl iodide and 500d of silver oxide were added, and the mixture was heated under reflux for 2 hours. After filtering the reaction solution and removing silver oxide, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform) to obtain 235 cm of yellow crystals (yield: 87 cm).
実施例２
３．７−’）ブロモメチル−２，８−ジメトキシ−４，
６−ジプロピルビリ）’（３，７−ｇ）−？ノリンー
５．１０−ジオン〔化合物（５）〕の製造。Example 2 3.7-') Bromomethyl-2,8-dimethoxy-4,
6-dipropylbiri)'(3,7-g)-? Norin
5. Production of 10-dione [compound (5)].
化合物（３） ５００■を四塩化炭素４０１に溶解し、
Ｎ−プロムフハク醒イミド７００■、過酸化ベンゾイル
１０！Ｒ９を加え、２．５時間加熱還流する。反応液を
水４ｏｍｃ注いで有機層を分離し、水層をサラに、クロ
ロホルム（４０ｙｎｌ Ｘ ３ ）で抽出する。Compound (3) 500μ was dissolved in carbon tetrachloride 401,
N-promufuhaku imide 700■, benzoyl peroxide 10! Add R9 and heat to reflux for 2.5 hours. 4 omc of water was poured into the reaction solution to separate the organic layer, and the aqueous layer was thoroughly extracted with chloroform (40ynl x 3).
有機層を無水硫酸す） ＩＪウムで乾燥し、減圧下濃縮
する。残査をシリカゲルカラムクロマトグラフィー（溶
出溶媒：クロロホルム）で精製し、黄色結晶５２０Ｉｎ
９（収率７４チ）を得た。The organic layer is dried over anhydrous sulfuric acid (IJ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform) to give yellow crystals of 520In.
9 (yield: 74 cm).
実施例３
２−メトキシ−３，７−シメチルー４，６−ジプロピル
ピリｒ（３，７−ｇ）キノリン−５，８，１０（９Ｈ）
−）ジオン〔化合物（２）〕の製造。Example 3 2-Methoxy-3,7-dimethyl-4,6-dipropylpyryr(3,7-g)quinoline-5,8,10(9H)
-) Production of dione [compound (2)].
ジアザキノマイシン人〔化合物（Ａ） ） ２１２■を
クロロホルム２８フに溶解し、ヨウ化メチル４ゴ、酸化
銀４２３■を加え、室温で９時間攪拌する。反応液をろ
過し、酸化銀を除去した後、ろ液を減圧下濃縮する。残
査をシリカゲルカラムクロマトグラフィー（溶出溶媒：
クロロホルム）で製製し、埋包結晶１６６■（収率７５
％）を得た。212 ml of diazachinomycin [compound (A)] was dissolved in 28 ml of chloroform, 4 ml of methyl iodide and 423 ml of silver oxide were added, and the mixture was stirred at room temperature for 9 hours. After filtering the reaction solution to remove silver oxide, the filtrate is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent:
chloroform), and the embedded crystals were 166 cm (yield: 75
%) was obtained.
実施例４
３−ブロモメチル−２−メトキシ−７−メチ／Ｌ／−４
，６−ジプロピルビリ）”（３，２−ｇ：ｌ＊／リン−
５，８，１０（９Ｈ） −）ジオン〔化合物（４）〕の
製造。Example 4 3-bromomethyl-2-methoxy-7-methy/L/-4
,6-dipropylbiri)” (3,2-g:l*/phosphorus-
Production of 5,8,10(9H)-)dione [Compound (4)].
化合物（２）ＩＩｉを四塩化炭素２００１に溶解し・Ｎ
−プロムフハク酸イミｒ２ｇ、過酸化ベンゾイル２０１
ｎ９を加え、２．５時間加熱還流する。反応液を水１５
０ 、ｄに注いで有機層を分離し、水層なサラにクロロ
ホルム（１５０１１１ｊＸ ３ ）で抽出スる。Compound (2) IIi was dissolved in carbon tetrachloride 2001, N
-Promfusuccinic acid imirr 2g, benzoyl peroxide 201
Add n9 and heat to reflux for 2.5 hours. Add 15% of the reaction solution to water.
The organic layer was separated, and the aqueous layer was extracted with chloroform (150111jX 3 ).
有機層を無水硫酸ナトリウムで乾燥し、減圧上濃縮する
。残査をシリカゲルカラムクロマトグラフィー（溶出溶
媒：ベンゼン／アセトン喘１０７１）で精製し、黄色結
晶５６８■（収率４４％）を得た。The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: benzene/acetone 1071) to obtain 568 cm of yellow crystals (yield: 44%).
実施例５
２．８−ジメトキシ−４，６−ジプロピル−５゜ｌＯ−
ジオキソ−５，１０−ジヒｒロビＩＪ）’（３，２−ｇ
）キノリン−３，７−ジアセドニトリル〔化合物（６）
〕の製造。Example 5 2,8-dimethoxy-4,6-dipropyl-5゜lO-
dioxo-5,10-dihyrobi IJ)' (3,2-g
) Quinoline-3,7-diacedonitrile [Compound (6)
〕Manufacturing of.
化合物（５） ５００■をジクロロメタン５０ｍに済解
し、０℃に冷却する。この溶液中に、テトラエチルアン
モニウムシアニド２８９１Ｒ９のジクロロメタン（５０
１ｔ）溶液を、４時間かけて滴下する０滴下後、水５０
ｍを加え、クロロホルムで抽出し、有機層を無水硫酸ナ
トリウムで乾燥し、減圧上濃縮する。浅査をシリカゲル
クロマトグラフィー（溶出溶媒：クロロホルム）で′１
ｎＩＩ製し、黄色結晶３０６ダ（収率７７％ ）を得た
、実施例６
４．６−ジプロビルー２．５，８．１０−テトラオキソ
−１，２，５，８，９，１０−ヘキサヒドロピリド（３
，２−ｇ〕キノリン−３，７−ジ酢酸ジエチル〔化合物
（３４） ：ｌの製造。500 ml of compound (5) was dissolved in 50 ml of dichloromethane and cooled to 0°C. In this solution, tetraethylammonium cyanide 2891R9 was added in dichloromethane (50
1t) Add the solution dropwise over 4 hours.After adding 0 drops, add 50% water.
m and extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. A shallow scan was performed using silica gel chromatography (elution solvent: chloroform).
Example 6 4.6-diprobyl-2.5,8.10-tetraoxo-1,2,5,8,9,10-hexahydro Pyrid (3
, 2-g] Diethyl quinoline-3,7-diacetate [Compound (34): Production of l.
化合物（６） ５２１Ｒ１ｙをエタノール４ＷＬｔに溶
解し、濃硫酸２−を加え、２時間加熱還流する。反応液
を水５４に注ぎ、クロロホルムで抽出し、有機層を無水
硫酸す） ＩＪウムで乾燥し、減圧上濃縮する。残査を
シリカゲルカラムクロマトグラフィー（溶出溶媒：クロ
ロホルム／メタノール＝＝５０／１）で精製し、赤色結
晶３３■（収率５５％）を得た。Compound (6) 521R1y was dissolved in ethanol 4WLt, concentrated sulfuric acid 2- was added, and the mixture was heated under reflux for 2 hours. The reaction solution was poured into water 54, extracted with chloroform, and the organic layer was dried over anhydrous sulfuric acid and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol = 50/1) to obtain 33 cm of red crystals (yield: 55%).
実施例７
４．６−ジプロピル−２＋ ５ ＋ ８−１０−テトラ
オキソ−１，２，５，８，９，１０−へキサヒドロピリ
￥〔３，ｚ−ｇ〕キノリン−３，７−：）酢酸〔化合物
（９）〕の製造。Example 7 4.6-dipropyl-2+ 5 + 8-10-tetraoxo-1,2,5,8,9,10-hexahydropyri[3,z-g]quinoline-3,7-:)acetic acid[ Production of compound (9)].
化合物（３４）３０ｒｎ９を８０チェタ／−ル水１２ゴ
に溶解し、水酸化ナトリウム３０１ｎ９を加えて５０℃
、３０分間反応する。反応液を塩酸酸性にし、沈殿物を
ろ過し、ろ過物を水で洗浄する。減圧下乾燥して赤色結
晶２１η（収率８２％）を得た。Compound (34) 30rn9 was dissolved in 80 liters of water and 301n9 of sodium hydroxide was added thereto at 50°C.
, react for 30 minutes. The reaction solution is acidified with hydrochloric acid, the precipitate is filtered, and the filtrate is washed with water. It was dried under reduced pressure to obtain red crystals 21η (yield: 82%).
実施例８
２．８− ：）メトキシ−３，７−：）メチル−４，６
−ジプロビルー５，１０−ジオキソ−５，１０−ジヒ「
ロビリげＣ３，２−ｇ ］］キノリンー３１．７１−シ
マロン酸テトラエチル化合物（３５）の製造。Example 8 2.8-:)methoxy-3,7-:)methyl-4,6
-diprobyl-5,10-dioxo-5,10-dihi
Robirige C3,2-g]] Production of quinoline-31.71-cimaronate tetraethyl compound (35).
水酸化ナトリウム（６０％油性）３８８：ｎ９を乾燥テ
トラヒＰロアラン１００ｍ１にけん濁し、これにジェチ
ルマロネー）１．８ｍＪを滴下する。滴下後、室温で３
０分間攪拌し、ジエチルマロネートのアニオンを調製す
る。この溶液中に化合物（５）１．５．＠のテトラヒＦ
’Ｄ７ラン溶液（６０ｍｌ）を加える。室温で３０分間
反応し、反応液にエタノール０．５コを加え反応を停止
させる。反応液を冷却後、減圧上濃縮し、水６０ｍ７を
加え、塩酸酸性とした後、クロロホルムで抽出する。有
機層を無水硫酸ナトリウムで乾燥し、減圧上濃縮し、残
査をシリカゲルカラムクロマトグラフィー（溶出溶媒：
へ中サン／酢酸エチル＝２／１）で精製する。黄色結晶
１．３ Ｎ （収率７４チ）を得た。Sodium hydroxide (60% oily) 388:n9 is suspended in 100 ml of dry TetrahyP-Loalane, and 1.8 mJ of Jethyl Maloney is added dropwise thereto. After dropping, at room temperature
Stir for 0 minutes to prepare diethyl malonate anion. In this solution compound (5) 1.5. @tetrahi F
'Add D7 run solution (60ml). React at room temperature for 30 minutes, then add 0.5 liters of ethanol to the reaction solution to stop the reaction. After cooling the reaction solution, it was concentrated under reduced pressure, and 60 m7 of water was added to make it acidic with hydrochloric acid, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent:
Purify with ethyl acetate/ethyl acetate = 2/1). 1.3N of yellow crystals (yield: 74cm) were obtained.
実施例９
３．７−シメチルー４，６−ジプロビルー２．５，８゜
１０−テトラオキソ−１，２，５，８，９，１０−へキ
サヒドロピリ）’（３，２−ｇ）キ／す７−３’ 、
７’−Ｑ−ｒロン酸テトラエチル〔化合物（３６） ）
の製造。Example 9 3.7-dimethyl-4,6-diprobyl-2.5,8゜10-tetraoxo-1,2,5,8,9,10-hexahydropyri)'(3,2-g)kis/su7 -3',
7'-Q-r Tetraethyl ronate [Compound (36)]
Manufacturing of.
化合物（３５） １００１１１９をエタノール４ｒｌＬ
ｔに溶解し、浸硫ｒＩＲ２，ｄを加え、１２時間加熱還
流する。Compound (35) 1001119 in 4 rlL of ethanol
t, add sulfurized rIR2,d, and heat under reflux for 12 hours.
反応液を冷却後、減圧上濃縮し、水５Ｍを加え、クロロ
ホルムで抽出する。有機層を無水硫酸ナトリウムで乾燥
後、減圧下濃縮し、残査をシリカゲルカラムクロマトグ
ラフィー（溶出溶媒：クロロホルム／メタノール−１０
７１）で精製し、赤色結晶９１り（収率９５％）を得た
。After cooling the reaction solution, it was concentrated under reduced pressure, 5M water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: chloroform/methanol-10
71) to obtain red crystal 91 (yield 95%).
実施例１０
３．７−シメチルー４，６−ジプロビルー２．５，８゜
ｌＯ−テトラオキソ−１？２１ｓ Ｉ８，９．１０−
ヘキサヒドロヒｌＪ ）’（３，２−ｇ ）’Ｐ／ Ｉ
） ン−３’、７’−ジカルボン酸〔化合物（１５）
）の製造。Example 10 3.7-dimethyl-4,6-diprobyl-2.5,8゜lO-tetraoxo-1?21s I8,9.10-
HexahydrohylJ)'(3,2-g)'P/I
) N-3',7'-dicarboxylic acid [Compound (15)
)Manufacturing of.
化合物（３６） ４９１ｖを８０％！タ／−ル水１５ｍ
ｊに溶解し、水酸化ナトリウム３０■を加えて５０℃、
３００分間反応る。反応液を塩酸酸性和シ、水１５―を
加え、クロロホルムで抽出する。有機層を無水硫酸す）
ＩＪウムで乾燥し、波圧下濃縮して赤色結晶３３■（
収率８０％）を得た。Compound (36) 491v at 80%! Tar/water 15m
Add 30μ of sodium hydroxide and heat at 50°C.
React for 300 minutes. Add hydrochloric acid and water to the reaction solution, and extract with chloroform. The organic layer is treated with anhydrous sulfuric acid)
Dry with IJum and concentrate under wave pressure to obtain 33cm red crystals (
A yield of 80% was obtained.
実施例】１
２．８−ジメトキシ−３，７−シメチルー４．６−ジプ
ロビルー５，１ｏ−ジオキン−５，１ｏ−ジヒドロピ！
Ｊ ）’（Ｌ２− ｇ ］ ｇ？／ ＩＪ ン−３’、
７’−９７ｏ７酸〔化合物（１６） ）の製造。Examples 1 2,8-dimethoxy-3,7-dimethyl-4,6-diprobyl-5,1o-dioquine-5,1o-dihydropi!
J)'(L2-g] g?/IJn-3',
Production of 7'-97o7 acid [Compound (16)].
化合物（３５） ５０ｒＲ９を８０係エタノール水１０
ゴに溶解し、水酸化ナトリウム３６ｒｎ９を加えて１時
間加熱還流する。反応液を塩酸酸性にして、水１０ゴを
加え、クロロホルムで抽出する。有機層を無水硫酸ナト
リウムで乾燥し、減圧下濃縮して黄色結晶３４■（収率
８２％）を得た。Compound (35) 50rR9 to 80% ethanol water 10%
Add 36rn9 sodium hydroxide and heat under reflux for 1 hour. The reaction solution is acidified with hydrochloric acid, 10 g of water is added, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 34 cm of yellow crystals (yield: 82%).
実施例１２
２．８− ：）メト會シー４．６−ジプロビルー５゜１
０−ジオキン−５，１０−’）ヒドロビリｌｊ［”３．
２−ｇ）−＃ノリノー３．フーブロビオン酸〔化合物（
１７） ）の製造。Example 12 2.8-:)Methocy4.6-Diprovir-5゜1
0-dioquine-5,10-') hydrovirylj["3.
2-g)-#Norino3. Fubrobionic acid [compound (
17) Manufacture of ).
化合物（１６）５０１ｎ９をピリジン１０ｍに溶解し、
１ｚｏｉ、４時間加熱還流する。反応液中のピリジンを
減圧留去し、塩酸酸性にしてから、水１゜１を加え、ク
ロロホルムで抽出する。有機層を無水硫酸ナトリウムで
乾燥し、減圧下ｍ縮して残査をシリカゲルカラムクロマ
トクラフィー（溶出溶媒：クロロホルム）で精製し、黄
色結晶３４ダ（収率９４俤）を得た。Compound (16) 501n9 was dissolved in 10m pyridine,
1 zoi and heat under reflux for 4 hours. The pyridine in the reaction mixture was distilled off under reduced pressure, the mixture was made acidic with hydrochloric acid, 1.1° of water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform) to obtain 34 da of yellow crystals (yield: 94 yen).
実施例１３
４．６−ジプロピル−２，５，８，１０−テトラオキソ
−１，２，５，８，９，１０−ヘ＃サヒトロビリ）”（
３，２−ｔｌキノリン−３，７−ジプロピオン酸ジエチ
ル〔化合物（３７） ）の製造。Example 13 4.6-dipropyl-2,5,8,10-tetraoxo-1,2,5,8,9,10-he
Production of diethyl 3,2-tlquinoline-3,7-dipropionate [compound (37)].
化合物（１７）３４１ｎ９をエタノールｌｏｍｊに溶解
し、濃硫酸５Ｍを加え、８０℃、４時間加熱還流する。Compound (17) 341n9 is dissolved in ethanol lomj, 5M concentrated sulfuric acid is added, and the mixture is heated under reflux at 80°C for 4 hours.
減圧下濃縮して水１０−を加え、クロロホルムで抽出す
る。有機層を無水硫酸ナトリウムで乾燥し、残査をシリ
カゲルカラムクロマトグラフィー（溶出溶媒：クロロホ
ルム）で精製し、赤色結晶１９ダ（収率５３％）を得た
。Concentrate under reduced pressure, add 10-mL of water, and extract with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (elution solvent: chloroform) to obtain 19 d of red crystals (yield: 53%).
実施例１４
４．６−ジプロビルー２．５，８．１０−テトラオキソ
−１，２，５，８，９，１０−へキサヒドロビリｒ（３
，２−ｇ〕キノリン−３，７−ジプロピオン酸〔化合物
（１９））の製造。Example 14 4.6-diprobyl-2.5,8.10-tetraoxo-1,2,5,8,9,10-hexahydrobylyr(3
, 2-g] Production of quinoline-3,7-dipropionic acid [Compound (19)].
化合物（３７３５０〜を８０％エタノール水に溶解し、
水酸化ナトリウム３０ダを加え、室温で４５分間反応す
る。反応液を塩酸酸性とし、水１０１１１１７を加え、
クロロホルムで抽出する。有機層を無水硫酸す） ＩＪ
ウムで乾燥し、減圧下濃縮して赤色結晶３６〜（収率８
０％）を得た。Dissolve the compound (37350 ~ in 80% ethanol water,
Add 30 Da of sodium hydroxide and react at room temperature for 45 minutes. The reaction solution was acidified with hydrochloric acid, water 1011117 was added,
Extract with chloroform. The organic layer is sulfuric anhydride) IJ
dried over 100 ml and concentrated under reduced pressure to give 36 ~ (yield 8) red crystals.
0%) was obtained.
実施例１５
３．７−：）ｌ：： ｆｒ：ｔｄＦ’／ｌ−Ｐ’に−２
，８−’）ｉｔ ）＄シー４，６−ジプロピルビリｐ（
３，ｚ−ｇ〕キノリン−５，１０−ジオン〔化合物（２
０） ’Ｉの製造。Example 15 3.7-:)l::fr:tdF'/l-P'-2
, 8-')it)$cy4,6-dipropylbilip(
3,z-g] Quinoline-5,10-dione [Compound (2
0) Manufacture of 'I.
化合物（５）８０１１１ｐをテトラヒｒロフランー水（
２： １ ）４８ｄＫ溶解し、８０℃、２日間加熱還流
する。減圧下濃縮し、水３０ｍＪを加え、クロロホルム
で抽出する。有機層を無水硫酸ナトリウムで乾燥し、減
圧下濃縮後、残査をシリカゲルカラムクロマトクラフィ
−（溶出溶媒：クロロホルム／メタノール−＝２０／１
）でＮ ＨＬ 、ｉＲ色結晶２７■（収率４４％）を得
た。Compound (5) 80111p was dissolved in tetrahydrofuran-water (
2:1) Dissolve at 48dK and heat under reflux at 80°C for 2 days. Concentrate under reduced pressure, add 30 mJ of water, and extract with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: chloroform/methanol = 20/1
) to obtain N HL , iR color crystals 27 cm (yield 44%).
実施例１６
２．８−ジフト中シー４．６−ジプロビルー５゜１０−
ジオ中ソ−５，１ｏ−ジヒーロピリ）Ｐ〔３，２−ｇ）
キノリン−３，７−ジカルボン酸〔化合物（２１） ）
の製造。Example 16 2.8-dift medium sea 4.6-diprobyl-5°10-
So-5,1o-dihydropyly)P[3,2-g]
Quinoline-3,7-dicarboxylic acid [Compound (21)]
Manufacturing of.
化合物（２０） ｓｓｏｍｐをアセトン５１Ｍ＋ｊに溶
解し、０℃に冷却する。酸化りａムー硫酸（酸化クロム
／濃硫酸／水＝ ２６ 、７ Ｊ／ ／ ２３ｍ１５０
ｍｊ ）を３ｄ加え、０℃、１０分間反応する。イソプ
ロパツールを加えて反応を中止し、減圧上濃縮後、水５
０Ｍを加え、クロロホルムで抽出する。有機層を無水硫
酸ナトリウムで乾燥し、減圧上濃縮して黄色結晶５１０
■（収率８７チ）を得た。Compound (20) ssomp is dissolved in acetone 51M+j and cooled to 0°C. Oxidized amu sulfuric acid (chromium oxide/concentrated sulfuric acid/water = 26,7 J//23m150
Add 3d of mj) and react at 0°C for 10 minutes. The reaction was stopped by adding isopropanol, and after concentrating under reduced pressure, 5% of water was added.
Add 0M and extract with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give yellow crystals.
(yield: 87 cm) was obtained.
実施例１７
４．６−：）プロピル−２，５ｐ８ｐｌｏ−テトｄオ中
シー １，２，５，８，９．１０− ヘ＊サヒｒｔ＝＋
ピリＦ’（３，２−ｇ〕キノリン−３，７−ジカルボン
酸ジエチル〔化合物（３８） ）の製造。Example 17 4.6-:) Propyl-2,5p8plo-TetdO Nakashi 1,2,5,8,9.10-He*Sahirt=+
Production of diethyl piriF'(3,2-g)quinoline-3,7-dicarboxylate [compound (38)].
化合物（２１） ２１０７１１ｐを！ 夕／ −ｋ２０
１ｄ Ｋ溶解し、濃硫酸１０ｍを加え、１００℃、５時
間還流する。反応液を減圧上濃縮し、水２０ｍを加え、
クロロホルムで抽出する。有機層を無水硫酸ナトリウム
で乾燥し、減圧下嬢縮後、残査をシリカゲルカラムクロ
マトグラフィー（溶出溶媒：クロロホルム／メタノール
−２５／ １ ）で精製シ、赤色結晶５３■（収率５０
％）を得た。Compound (21) 210711p! Evening/-k20
Dissolve 1d K, add 10 m of concentrated sulfuric acid, and reflux at 100°C for 5 hours. The reaction solution was concentrated under reduced pressure, and 20 m of water was added.
Extract with chloroform. The organic layer was dried over anhydrous sodium sulfate, condensed under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol-25/1) to give 53 cm of red crystals (yield: 50
%) was obtained.
実施例１８
４．６−ジプロピル−２，５，８，１０−テトラオキシ
−１，２，５，８，９，１０−ヘ＄サヒｙａピリド（：
３，２−ｇ〕キノリン−３，７−ジカルボン酸〔化合
物（２３） ）の製造。Example 18 4.6-dipropyl-2,5,8,10-tetraoxy-1,2,5,8,9,10-he$sahyyapyrido (:
3,2-g] Production of quinoline-3,7-dicarboxylic acid [Compound (23)].
化合物（３８）６０ダを８０チエタノール水１０ Ｉｌ
ｌに溶解し、水酸化ナトリウム３０ＷＩ９を加え、５０
℃で１時間反応する。反応液に水１０−を加え、減圧上
濃縮し、ろ過後、ろ液を塩酸酸性とする。沈殿物□をろ
過し、ろ過動を水で洗浄後、減圧下乾燥して赤色粉末３
８１１に？（収率７２俤）を得た。Compound (38) 60 Da to 80 diethanol water 10 Il
Dissolve in 50ml of sodium hydroxide, add 30WI9 of sodium hydroxide,
React for 1 hour at ℃. Add 10% of water to the reaction solution, concentrate under reduced pressure, and after filtration, the filtrate is acidified with hydrochloric acid. Filter the precipitate □, wash the filtrate with water, and dry under reduced pressure to obtain red powder 3.
To 811? (Yield 72 yen) was obtained.
実施例１９
３．７−ジアセト中ジメチルー２，８−ジメトキシ−４
，６−ジプロピルビリ’（３ｅ２− ｇ ）キノリン−
５，１０−ジオン〔化合物（３９） ）の製造。Example 19 Dimethyl-2,8-dimethoxy-4 in 3.7-diacetate
,6-dipropylbi'(3e2-g)quinoline-
Production of 5,10-dione [Compound (39)].
化合物（５） ５０１１１を酢ｒＲ６ｍに溶解し、水酸
化ナトリウム３０〜を加え、１００℃で３時間反応する
。反応液を減圧上濃縮し、残査に水５ｄを加え、クロロ
ホルムで抽出し、有機層を無水硫酸す） ＩＪウムで乾
燥する。減圧上濃縮後、残査をシリカゲルカラムクロマ
トグラフィー（溶出溶媒：クロロホルム／メタノール＝
２０７１）で精製し、黄色結晶４２〜（収率９１％）を
得た。Compound (5) 50111 is dissolved in vinegar rR6m, 30~ of sodium hydroxide is added, and the mixture is reacted at 100°C for 3 hours. The reaction solution was concentrated under reduced pressure, 5 d of water was added to the residue, extracted with chloroform, and the organic layer was washed with anhydrous sulfuric acid and dried over IJum. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: chloroform/methanol =
2071) to obtain yellow crystals 42~ (yield 91%).
実施例２０
３．７−アセドキシメチルー４，６−ジプロピルビリ）
（３，２−ｇ〕＊／すｙ −２，５，８，１０（ＩＨ。Example 20 3.7-acetoxymethyl-4,6-dipropyl bili)
(3,2-g]*/sy -2,5,8,10 (IH.
９トＩ）−テトロン〔化合物（４０） ）の製造。9. Production of I)-tetron [Compound (40)].
化合物（３９） ４２ｍ９を酢酸４−に溶解し、濃硫酸
０．２Ｍを加え、クロロホルムで抽出し、有機層を無水
硫酸す） ＩＪウムで乾燥する。減圧上濃縮後、残青を
シリカゲルカラムクロマトグラフィー（溶出溶媒：クロ
ロホルム／メタノール＝２０７１）で精製し、赤色結晶
２５〜（収率６３％）を得た。Compound (39) 42m9 was dissolved in 4-acetic acid, 0.2M concentrated sulfuric acid was added, extracted with chloroform, and the organic layer was washed with anhydrous sulfuric acid and dried over IJum. After concentration under reduced pressure, the residual blue color was purified by silica gel column chromatography (elution solvent: chloroform/methanol = 2071) to obtain red crystals 25~ (yield 63%).
実施例２１
３−アセトキシメチル−２−メトキシ−７−メチル−４
，ｓ−：）プロピルピリｐ（３，ｚ−ｇ）中ノリンー５
．８．１０（９Ｈ） −）ジオン〔化合物（４１） ）
の製造。Example 21 3-acetoxymethyl-2-methoxy-7-methyl-4
,s-:)propylpyri p(3,z-g)Norin-5
．． 8.10(9H)-)dione [Compound (41)]
Manufacturing of.
化合物（４） １１４ダを酢酸１０ｍｊに溶解し、水酸
化ナトリウム３０りを加え、１００℃で５時間反応する
。反応液を減圧上濃縮し、残査に水１０ｍを加え、クロ
ロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥
し、減圧上濃縮する。残査をシリカゲルカラムクロマト
グラフィー（溶出溶媒：クロロホルム／メタノール＝２
５７１）で精製し、黄色結晶１０４■（収率９６４）を
得た。Compound (4) 114 da was dissolved in 10 mj of acetic acid, 30 mj of sodium hydroxide was added, and the mixture was reacted at 100°C for 5 hours. The reaction solution is concentrated under reduced pressure, 10 ml of water is added to the residue, extracted with chloroform, the organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: chloroform/methanol = 2
571) to obtain 104 cm of yellow crystals (yield: 964).
実施例２２
３−アセトキシメチル−７−メチル−４，６−ジプロピ
ル♂すｈｃ３＋２−ｇ、ｌキノリン−２゜５．８．１０
（Ｉ Ｈ，９Ｈ）−テトロン〔化合物（４２））の製造
。Example 22 3-acetoxymethyl-7-methyl-4,6-dipropyl♂hc3+2-g,lquinoline-2゜5.8.10
Production of (I H,9H)-tetron [Compound (42)].
化合物（４１） １０４Ｗ９を酢酸ｌＯ属に溶解し、濃
硫酸１１Ｌｔを加え、５時間加熱還流する。反応液に水
１０Ｍを加え、クロロホルムで抽出し、有機層を無水硫
酸ナトリウムで乾燥する。減圧上濃縮後、残査をシリカ
ゲルカラムクロマトグラフィー（溶出溶媒：クロロホル
ム〕で精製し、赤色結晶６５■（収率６５チ）を得た。Compound (41) 104W9 is dissolved in lO acetic acid, 11 Lt of concentrated sulfuric acid is added, and the mixture is heated under reflux for 5 hours. 10M water is added to the reaction solution, extracted with chloroform, and the organic layer is dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform) to obtain 65 cm of red crystals (yield: 65 cm).
実施例２３
３．７− ：）ヒドロキシメチル−４，６−ジプロピル
ピリド（Ｌ２− ｇ ）キノリン−２，５，８，１０（
１）ＩＨ９Ｈ）−テトロン〔化合物（２７） ）の製造
。Example 23 3.7-:)Hydroxymethyl-4,6-dipropylpyride (L2-g)quinoline-2,5,8,10 (
1) Production of IH9H)-tetron [compound (27)].
化合物（４０）６７１１１９をメタノール３０■に溶解
し、水酸化リチ９ム５０■を加え、室温で３時間攪拌す
る。反応液に水３０−を加え、塩酸酸性にした後、クロ
ロホルムで抽出する。抽出液を無水硫酸ナトリウムで乾
燥する。減圧上濃縮後、残査をシリカゲルカラムクロマ
トグラフィー（溶出溶媒：クロロホルム／メタノール＝
４０７１ ） テ精製し、赤色結晶４４■（収率８０％
）を得た。Compound (40) 671119 was dissolved in 30 μm of methanol, 50 μm of lithium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. Add 30% of water to the reaction solution, make it acidic with hydrochloric acid, and then extract with chloroform. The extract is dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: chloroform/methanol =
4071) was purified to give 44 red crystals (yield 80%).
) was obtained.
実施例２４
３−ヒ「ロキシメチル−７−メチル−４，６−ジプロピ
ルピリｐ（ａ、２−ｓｒ）キノリン−２゜５．８．１０
（Ｉ Ｈ，９Ｈ）−テトロン〔化合物（３０） ）の製
造。Example 24 3-hydroxymethyl-7-methyl-4,6-dipropylpyri p(a,2-sr)quinoline-2゜5.8.10
Production of (I H,9H)-tetron [Compound (30)].
化合物（４２） ２０”ｆをメタノール１５−に溶解し
、水酸化リチウム１５Ｍ９を加え、室温で３時間攪拌す
る。反応液に水１５１１１７を加え、塩酸酸性にした後
、クロロホルムで抽出する。抽出液を無水硫酸ナトリウ
ムで乾燥し、減圧下濃縮する。残査をシリカゾルカラム
クロマトグラフィー（溶出溶媒：クロロホルム／メタノ
ール−４０７１）で精製し、赤色結晶１０〜（収率５６
チ）を得た。Compound (42) 20"f is dissolved in methanol 15", lithium hydroxide 15M9 is added, and the mixture is stirred at room temperature for 3 hours. Water 151117 is added to the reaction solution, acidified with hydrochloric acid, and then extracted with chloroform. Extract liquid is dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue is purified by silica sol column chromatography (elution solvent: chloroform/methanol-4071) to give red crystals from 10 to 10 (yield: 56
h) was obtained.
実施例２５
３．７−ジエト午ジメチルー４，６−リプロピルピリ）
”（３，２−ｇ ） ＃／ ＩＪ ７−２．５，８．１
０ （ＩＨ。Example 25 3.7-dimethyl-4,6-lipropylpyri)
”(3,2-g) #/IJ 7-2.5,8.1
0 (IH.
９Ｈ）−テトロン〔化合物（４３） ）の製造。Production of 9H)-tetron [Compound (43)].
化合物（５） ５０１ｎ９をエタノール６ｍｌに溶解し
、浸硫敢２ゴを加え、１０時間加熱遣鬼才る。反応液を
減圧下濃縮し、水６ゴを加え、クロロホルムで抽出する
。有機層を無水硫酸す） ＩＪウムで乾燥し、減圧上濃
縮後、残査をシリカゲルカラムクロマトグラフィー（溶
出溶媒：クロロホルム）で精製し、赤色結晶１３１Ｆｉ
ｐ（収率３２係）を得た。Compound (5) 501n9 was dissolved in 6 ml of ethanol, 2 sulfuric acid salts were added, and the mixture was heated for 10 hours. The reaction solution was concentrated under reduced pressure, 6 g of water was added, and the mixture was extracted with chloroform. After drying the organic layer with anhydrous sulfuric acid and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform) to give red crystals of 131Fi.
p (yield: 32%) was obtained.
実施例２６
３−エトキシメチル−７−メチル−４，６−ジプロピル
ピリｒ（３，２−ｇ ）−？ノリノー２，５゜８．１０
（Ｉ Ｈ，９Ｈ）−テトロン〔化合物（４４）］の製造
。Example 26 3-Ethoxymethyl-7-methyl-4,6-dipropylpyryr(3,2-g)-? Nolino 2.5゜8.10
Production of (I H,9H)-tetron [Compound (44)].
化合物（４）３２０１１１９をエタノール８０コに溶解
し、濃硫酸４０コを加え、９０℃で１０時間反応する□
反応液を減圧下濃縮し、水８０−を加え、クロロホルム
で抽出する。有機層を無水硫酸ナトリウムで乾燥し、減
圧上濃縮後、残査をシリカゲルカラムクロマトグラフィ
ー（溶出溶媒：クロロホルム）で精製し、赤色結晶１０
０ダ（収率３５％）を得た。Dissolve compound (4) 3201119 in 80 parts of ethanol, add 40 parts of concentrated sulfuric acid, and react at 90°C for 10 hours.
The reaction solution was concentrated under reduced pressure, 80% of water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform) to obtain red crystals.
0 da (yield 35%) was obtained.
実施例２７
２−メトキシ−７−メチル−４，６−ジプロビルー５．
８．１０−トリオキソ−５，８，９，１０−テトラヒド
ロピリ） （Ｌ２− ｇ 〕〕キノリンー３−アセトニ
トリル化合物（１０） ）の製造。Example 27 2-Methoxy-7-methyl-4,6-diprobyl-5.
8. Production of 10-trioxo-5,8,9,10-tetrahydropyri) (L2-g]]quinoline-3-acetonitrile compound (10)).
化合物（４）１３５１１９をジクロロメタン１５−に溶
解し、テトラエチルアンモニクムシアニＰ４４１ｖを水
冷下３時間で滴下する。滴下後、反応液に水１５−を加
え、クロロホルムで抽出し、有機層を無水硫酸ナトリ９
ムで乾燥する。減圧下濃縮し、残査をシリカゲルカラム
クロマトグラフィー（溶出溶媒：クロロホルム／メタノ
ール−５０７１）で精製し、黄色結晶８２■（収率７０
チ）を得た。Compound (4) 135119 is dissolved in dichloromethane 15-, and tetraethylammonicum cyani P441v is added dropwise over 3 hours while cooling with water. After dropping, water was added to the reaction solution, extracted with chloroform, and the organic layer was dissolved in anhydrous sodium sulfate.
Dry in a vacuum. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol-5071) to give 82 cm of yellow crystals (yield: 70
h) was obtained.
実施例２８
７−１ ＋ルー ４．６−ジプロピ！Ａ／ −２，５，
８，１０−テトラオキソ−１，２，５，８，９，１０−
へキサヒｒロビリｒ（３，２−ｆ”）キノリン−３−酢
酸エチル〔化合物（４５） ）の製造。Example 28 7-1 + Roux 4.6-dipropy! A/-2,5,
8,10-tetraoxo-1,2,5,8,9,10-
Production of ethyl hexahyrobili(3,2-f'')quinoline-3-acetate [compound (45)].
化合物（１０）８２１Ｗをエタノール２０ｍに溶解し、
濃硫酸１０フを加え、９０℃で５時間反応する。反応液
を減圧下濃縮し、水２０ｍを加え、クロロホルムで抽出
する。有機層を無水硫酸す） ＩＪウムで乾燥し、減圧
上濃縮後、残査をシリカゲルカラムクロマトグラフィー
（溶出溶媒：クロロホルム）で精製し、赤色結晶６０！
ｎ９（収率６８％）を得た。Compound (10) 821W was dissolved in 20m of ethanol,
Add 10 ml of concentrated sulfuric acid and react at 90°C for 5 hours. The reaction solution was concentrated under reduced pressure, 20 ml of water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sulfuric acid (IJ) and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform) to give red crystals (60%).
n9 (yield 68%) was obtained.
実施例２９
７−メチル−４，６−ジプロビルー２．５，８．１０−
テトラオキソ−１，２，５，８，９，１０−へキサヒド
ロビリｒ（３，ｚ−＋ｒ）キノリン−３−酢酸〔化合物
（１２） ］の製造。Example 29 7-methyl-4,6-diprobyl-2.5,8.10-
Production of tetraoxo-1,2,5,8,9,10-hexahydrobiri r(3,z-+r)quinoline-3-acetic acid [Compound (12)].
化合物（４５）６０■を８０チエタノール水２４ゴに溶
解し、水酸化す） Ｕラム３０１ｖを加え、５０℃で２
時反応する。反応液を減圧下濃縮し、水２０Ｍを加え、
塩酸酸性とした後、クロロホルムで抽出する。有機層を
無水硫酸ナトリウムで乾燥し、減圧下濃縮する。残査を
シリカゲルカラムクロマトグラフィー（溶出溶媒：クロ
ロホルム／メタノール＋２０７１）で精製し、赤色結晶
３１Ｗ９（収率５５チ）を得た。Dissolve 60 ml of compound (45) in 80 ml of ethanol water and hydroxylate.) Add 301 ml of Uram and heat at 50°C for 2
react when The reaction solution was concentrated under reduced pressure, 20M water was added,
After acidifying with hydrochloric acid, extract with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol+2071) to obtain red crystals 31W9 (yield: 55 cm).
実施例１−２９で得られた化合物の構造式、融点、高分
解能質量分析値、元素分析値および赤外吸収スペクトル
を第１表およびＭ２表に示す。The structural formula, melting point, high-resolution mass analysis value, elemental analysis value, and infrared absorption spectrum of the compound obtained in Example 1-29 are shown in Table 1 and Table M2.
第 ２ 表
２ ３３５０，２９６０．１６４５３ ２
９７０．２８８０，１６９５．１６５５４ ３３
５０．２９６０，２９２５，１６５５．１６００５
２９７５．１７３０，１７００，１６７０．１５８
５６ ２９５５．１７００，１６６５．１５８５
９ ３６００−２５００．２９７５，２９４５，
２８８０，１７１０，１６４５１０ ３３５０．
２９７５．１６６０１２ （ＫＢｒ）２９８０
，１６７０．１６３５１５ ３７００ −２５０
０．２９７５．１６４５１６ （ＫＢｒ）３７
００ −２５００．２９７５，１７１０，１６７０．１
５８５１７ ３６００−２５００．２９６０，１
７０５，１６６５，１５８５１９ ３６００−２
５００．２９５０，１７３０．１６６０２０ ３
４００．２９５５，１７００，１６７０．１５８５２１
３６００−２５００．２９８０，１７４５，１
７１０，１６７０．１５８５２３ ３６００−２
５００，３３５０，２９７５，１７３５．１６６０２７
（ＫＢｒｌ ３３２５，２９５５．１６６
５３０ ３４５０．２９５０，１６７０，１６３
０３４ ３３６０．１７３５，１６６０３５
３０１０．１７４０，１７０５，１６７５，１５９
５３６ ３３５０．２９７５，１７２５，１６５
５３７ ３３５５．２９７５，１７３０，１６５
０３８ ３３５０．２９７５，１７３５．１６５
０３９ ２９４５．１７４０，１６６０．１５７
５４０ ３３５０．２９４５，１７４０．１６６
５４１ ３３５０．２９４５，１７４０，１６５
５．１５７５４２ ３３５０．２９４５，１７４
０．１６５５４３ ３３５０．２９８０，１６５
５．１６３０４４ ２９７５．１６７０．１６３
０４５ ３３５０．２９８０，１７４０，１６７
０．１６３５本発明による化合物の溶剤に対する溶解性
は一般（、有機溶媒に溶解する。水にも溶解するが、そ
の程度は化合物によシ異なる。クロロホルムおよび水に
対する溶解性を第３表に示す。2nd Table 2 3350,2960.16453 2
970.2880, 1695.16554 33
50.2960, 2925, 1655.16005
2975.1730, 1700, 1670.158
56 2955.1700, 1665.1585
9 3600-2500.2975, 2945,
2880, 1710, 164510 3350.
2975.166012 (KBr)2980
,1670.163515 3700 -250
0.2975.164516 (KBr)37
00 -2500.2975,1710,1670.1
58517 3600-2500.2960,1
705,1665,158519 3600-2
500.2950,1730.166020 3
400.2955, 1700, 1670.158521
3600-2500.2980,1745,1
710,1670.158523 3600-2
500, 3350, 2975, 1735.166027
(KBrl 3325, 2955.166
530 3450.2950,1670,163
034 3360.1735, 166035
3010.1740, 1705, 1675, 159
536 3350.2975,1725,165
537 3355.2975,1730,165
038 3350.2975, 1735.165
039 2945.1740, 1660.157
540 3350.2945, 1740.166
541 3350.2945,1740,165
5.157542 3350.2945,174
0.165543 3350.2980,165
5.163044 2975.1670.163
045 3350.2980,1740,167
0.1635 The solubility of the compounds according to the present invention in solvents is generally (dissolved in organic solvents. Also soluble in water, but the degree differs depending on the compound. Table 3 shows the solubility in chloroform and water. .
有機溶媒の例としてクロロホルムの他にジクロロメタン
、メタノール、エタノール、プロパツール、ブタノール
、テトラヒドロフラン、ジオキサン、ジメチルスルホキ
シｒ、ジメチルホルムアミｒなどがあげられる。Examples of organic solvents include dichloromethane, methanol, ethanol, propatool, butanol, tetrahydrofuran, dioxane, dimethylsulfoxyr, dimethylformamyl, and the like in addition to chloroform.
第 ３ 表
化合物陰 クロロホルム（μｍ１／１ｊＬｔ）
水ＣμＩＩＡＩＬＩ ＞ジアザキノマイシンＡ Ｏ
，６４Ｘ １０” Ｏ・１５３４
５．９８ Ｘ １０” ！、８３
６ ４．３６ Ｘ １０”
０，６２４０ ３．１８ Ｘ １０”
０．５１４３ ３．５０ Ｘ １
０’ ０．２２１２ ＜０．１
２４．０９ ＜ ０．１
１６．０本発明による化合物（３４）および化合物（４
３）では、１００ ｍｐ／ＫＰ ｉｐ（マウス）で急性
毒性は認められなかった。Table 3 Compound shade Chloroform (μm1/1jLt)
Water CμIIAILI > Diazachinomycin A O
,64X 10” O・1534
5.98 x 10”!, 83
6 4.36 x 10"
0,6240 3.18 x 10"
0.5143 3.50 X 1
0' 0.2212 <0.1
24.09 < 0.1
16.0 Compound (34) and compound (4) according to the invention
In 3), no acute toxicity was observed at 100 mp/KP ip (mouse).
本発明罠よる。化合物は、マウスエーリツヒ腹水癌細胞
から調型したチミジル酸合成酵素を阻害する作用を示す
。ジアザ争ノマイシン人（化合物人）および代表的な化
合物の５０チ阻害、濃度を第４表（示す。This invention is a trap. The compound exhibits an inhibitory effect on thymidylate synthase, which was prepared from Mauerrich ascites carcinoma cells. Table 4 shows the 50% inhibitory concentration of diazacomycin (compounds) and representative compounds.
第 ４ 表
Ａ４．２
９ １．５１２
１．３
１５ １．３
２７ １．０
３４ １．１３６
１．６３７
２．１３８１．０
４０ １．０
４２ ２．０
４３ ０．４
４４０・７
４５ １．４化合物
（４０）によって、Ｍ＠ｔｈ−Ａ癌細胞に対する治療試
験を行なった結果、下記に示すように延命効果が認めら
れた。Table 4 A4.2 9 1.512
1.3 15 1.3 27 1.0 34 1.136
1.637
2.1381.0 40 1.0 42 2.0 43 0.4 440・7 45 1.4 As a result of a therapeutic test on M@th-A cancer cells using compound (40), as shown below. A life-prolonging effect was observed.
ＢＡＬＢ／Ｃマウスでｔｐ継代されているＭ＠ｔｈ−Ａ
細胞（ＩＸ ｔｏ’細胞／マウス）を１群６匹の雌性Ｃ
ＤＦＩ系マウス（６週令）の腹腔内に接種し、翌日から
、ジメチルスルホキシ「とアラビアゴムにけん濁した化
合物（４０）を腹腔内に投与し、延命率を求めた。結果
を第５表に示す。M@th-A being tp passaged in BALB/C mice
Cells (IX to' cells/mouse) were transferred to a group of 6 female C
DFI mice (6 weeks old) were inoculated intraperitoneally, and from the next day, the compound (40) suspended in dimethyl sulfoxy and gum arabic was administered intraperitoneally to determine the survival rate. Shown in the table.
第 ５ 表
ＩＸＡ日 ９９
１０×４日 １４１
１００ Ｘ １日 １７５
対照群の平均生存日数： １２．３日
発明の効果
以上のように、本発明に係る化合物は優れたチミジル酸
合成酵素阻害作用および制癌効果を示し、これらを含有
する製剤は、抗腫瘍剤として有利に用いられることが期
待される。Table 5 IXA days 99 10×4 days 141 100 It is expected that preparations containing these substances, which exhibit anticancer effects, will be advantageously used as antitumor agents.
手続補正書（方式）
％式％
１、事件の表示
昭和６１年 特許 願第２２４１５３号３、 補正を
する者
事件との関係 特許出願人
住 所 東京都港区白金五丁目９番１号氏 名（名
称）北里研究所 （社団法人）代表者水之江公 英
４・ 代 理 人 電話 。３−３５３−５５２
１５、補正命令の日付 昭和６１年１１月５日（同年
１１月２５日発送）６、 補正により増加する発明の数
なし７° 補１′）”象 明細書、委任状（１）
Ｊｌｌｆに最初に添付した明細書の浄書・別紙のと
おり（内容に変更なし）。Procedural amendment (method) % formula % 1. Indication of the case 1986 Patent Application No. 224153 3. Person making the amendment Relationship to the case Patent applicant Address 9-1 Shirokane 5-chome, Minato-ku, Tokyo Name (Name) Kitasato Research Institute (Incorporated Association) Representative Mizunoe Kimi Ei 4. Agent Telephone. 3-353-552
15. Date of amendment order: November 5, 1985 (shipped on November 25, 1985) 6. Number of inventions increased by amendment: None 7° Supplement 1')" Specification, Power of attorney (1)
As per the engraving and attachment of the specification originally attached to Jllf (no changes to the contents).
（２） 別紙のとおり委任状を提出する。(2) Submit a power of attorney as shown in the attached document.
（自発的）手続補正書
昭和６１年１１月２７日
特許庁長官 黒田明雄 殿 °−蔓１、事件の表示
昭和６１年 特許 願第２２４１５３号３、 補正を
する者
事件との関係 特許出願人
住 所 東京都港区白金五丁目９番１号氏 名（名
称）北里研究所 （社団法人）代表者水之江公 英
４° 代 理 人 電話 ０３−３５３−５５２
１住 所 東京都新宿区信濃町１１番地５、補正命
令の日付
６、 補正により増加する発明の詳細な説明細書を次の
とおシ補正する。(Voluntary) procedural amendment November 27, 1985 Akio Kuroda, Commissioner of the Patent Office °-Tsuru 1, Indication of the case 1986 Patent Application No. 224153 3, Person making the amendment Relationship to the case Patent applicant residence Address: 5-9-1 Shirokane, Minato-ku, Tokyo Name: Kitasato Research Institute (incorporated association) Representative: Mizunoe Hide 4° Representative Telephone: 03-353-552
1 Address: 11-5 Shinanomachi, Shinjuku-ku, Tokyo, Date of amendment order: 6 The detailed description of the invention, which will be increased by the amendment, will be amended as follows.
（１）特許請求の範囲の記載を別紙のとおり補正する。(1) The statement of the claims shall be amended as shown in the attached sheet.
（２）第３頁１１行、「製造」を「製造し」に補正する
。(2) On page 3, line 11, "manufacturing" is amended to "manufacturing".
（３）第４頁下から１３行、ｒ −Ｃ：Ｈ，−ＣＨ（Ｃ
ｏ２Ｒ”）、 Ｊを「−Ｃ：Ｈ，−ＣＩ（（Ｃｏ□Ｒ”
）２Ｊに補正する。(3) Page 4, line 13 from the bottom, r -C:H, -CH(C
o2R"), J as "-C:H, -CI((Co□R")
) Corrected to 2J.
（４）同上から１２行、「ａ３は」の後に「水素、Ｊを
加入する。(4) Line 12 from above, add ``hydrogen, J'' after ``a3''.
（５）同最下行、「ニトロ」の後に「基」を加入する。(5) At the bottom of the same line, add "Ki" after "Nitro".
（６）第５頁１４−１５行、「（３）・・・・・・・・
・・・・１９８３）Ｊをｒｆ３）（テトラへｒロン・レ
ターズ（’ｐｅｔｒａｈ＠ｄｒｏｎＬ＠ｔｔｅｒｓ
）、、 Ｖｏｌ、２４．ｐｐ ３６４３−３６４６．
１９８３）Ｊに補正する。(6) Page 5, lines 14-15, “(3)...
...1983) J rf3) ('petrah@dronL@tters
),, Vol, 24. pp 3643-3646.
1983) corrected to J.
（７）第６頁の式（２）を次のとおり補正する。(7) Correct equation (2) on page 6 as follows.
（２）」 （８） 第６頁の式（４）を次のとおり補正する。(2)” (8) Modify equation (4) on page 6 as follows.
」
（９） ＩＸ ７ 頁１行、ｒクロロホルム」を「ジ
クロロメタン」に補正する。(9) IX page 7, line 1, r chloroform” is corrected to “dichloromethane”.
（ｌＯ） 第８頁の式（１２）を次のとおり補正する
。(lO) Correct equation (12) on page 8 as follows.
（１２ン 」（１１）第
１０頁２−３行、「水素ナトリウム」を「水素化ナトリ
ウム」に補正する。(12) (11) Page 10, lines 2-3, "sodium hydride" is corrected to "sodium hydride."
（１２）第１３頁下から５行、「化会物」の後にｒ（５
）Ｊを加入する。(12) Page 13, 5 lines from the bottom, r (5
) Add J.
（１３）第１４頁の式（２７）を次のとおり補正する。(13) Formula (27) on page 14 is corrected as follows.
（２７） Ｊ
（１４） 第１６頁５行、「Ｂは炭素数１−５の低級
アルキル基を意味する」を「Ｒは炭素数１−５の飽和ま
たは不飽和アルキル基、アリール基またはアラルキル基
を表わす」に補正する。(27) J (14) Page 16, line 5, "B means a lower alkyl group having 1 to 5 carbon atoms" to "R means a saturated or unsaturated alkyl group having 1 to 5 carbon atoms, an aryl group or an aralkyl group""represents a group".
（１５）鋼上から２行、式 を次のとおり補正する。(15) Two lines from the top of the steel, formula shall be corrected as follows.
（３３） Ｊ
（１６） 第１７頁９行、「Ｒ１＝Ｒ２ＪをｒＲ’＝
Ｒ，”Ｊに補正する。(33) J (16) Page 17, line 9, “R1=R2J to rR’=
Correct to R,”J.
（１７） 同上から２行、「ジプロピルピクｒ（３，
７−ｇ〕Ｊを「ジゾロピルピリｒ（３４−＋ｒ）Ｊに補
正する。(17) Two lines from the above, “dipropylpicr(3,
7-g] Correct J to "dizolopylpyri r(34-+r)J.
（１８） 第１８頁１２行、ｒ ３，７− ｇ Ｊを
ｒ３．２−ｇＪに補正する。(18) Page 18, line 12, correct r3,7-gJ to r3.2-gJ.
（１９） 同最下行、「製製」をｒｆｆｌｉ！ Ｊに
補正する。(19) At the bottom of the same line, rffli for “manufactured”! Correct to J.
（２０） 第２０頁７行、「浅査」を「残査」に補正
する。(20) On page 20, line 7, "shallow survey" is corrected to "residue".
（２１）第２１頁下から３行、「水酸化ナトリウム」を
「水素化ナトリウム」に補正する。(21) On page 21, 3 lines from the bottom, "sodium hydroxide" is corrected to "sodium hydride."
（２２）第１７頁９行行、「テトラオキシ」を「テトラ
オキソ」に補正する。(22) On page 17, line 9, "tetraoxy" is corrected to "tetraoxo."
（２３） 第２８頁３行、「テトラオキシ」を「テト
ラオキソ」に補正する。(23) Page 28, line 3, "tetraoxy" is corrected to "tetraoxo".
（２４）第２９頁６行、「アセトキシメチル」を「ジア
セトキシメチル」に補正する。(24) Page 29, line 6, "acetoxymethyl" is corrected to "diacetoxymethyl".
（２５）同ｌＯ行、「加え、」の後に「１００℃、３時
間反応する。反応液に水５１を加え、」を加入する。(25) In the same line 1O, after "Add," add "React at 100° C. for 3 hours. Add 51 parts of water to the reaction solution."
（２６） 第３１頁５行、ｒ３０１ｎ９Ｊを［３０ｍ
ｊＪに補正する。(26) Page 31, line 5, r301n9J [30m
Correct to jJ.
（２７）第３３頁下から４行、「４４ｆｔ９ｊの後に「
のジクロロメタン溶液１５−」を加入する。(27) Page 33, 4 lines from the bottom, “After 44ft9j”
A dichloromethane solution of 15-' is added.
（２８）第３５頁５行、「２時」を「２時間」に補正す
る。(28) Page 35, line 5, "2 o'clock" is corrected to "2 hours".
（２９）第４１頁の第４表中、化合物ｍ１２の欄の数値
「１．３ Ｊを「１．４ Ｊに補正し、化合物階４５の
欄を数値とともに削除する。(29) In Table 4 on page 41, the numerical value "1.3 J" in the column for compound m12 is corrected to "1.4 J, and the column for compound level 45 is deleted together with the numerical value.
（３０） 第２１頁下から４行、「Ｈｓ）Ｊの後に「
〕」を特徴する
特許請求の範囲
（１） 次の一般式（１）で表わされる抗生物質ジア
ザキノマイシン人誘導体。(30) Page 21, 4 lines from the bottom, “Hs) After J”
Claim (1): An antibiotic diazachinomycin human derivative represented by the following general formula (1).
〔式中、Ｒ１とＲ２の一方はメチル基で、他方は＜ａ）
−（Ｃ）（２）ｎ−Ｇ：０２Ｒ”または−Ｃ，Ｈ，
−ＣＨ（Ｃｏｏ 、几３）２（ただしｎはＯ−２の整数
を表わし、Ｒ３は水素、炭素数１−５の低級アルキル基
を表わす）または（ｂｌ −０Ｈ２０Ｒ’または−Ｃ
Ｈ，０００几４（ただしＲ４は水素、炭素数１−５の飽
和または不飽和アルキル基、置換または未置換アリール
基またはアラルキル基を表わす）であるか、あるいはＲ
１と几２は同一でも異なってもよく、と記ｔａ＋または
（ｂ）を表わす。〕（２７Ｒ’ のアリール基がフェニ
ル、トリルまたはナフチルである特許請求の範囲第１項
記載の化合物。[In the formula, one of R1 and R2 is a methyl group, and the other is <a)
-(C)(2)n-G:02R" or -C,H,
-CH(Coo, 几3)2 (where n represents an integer of O-2, R3 represents hydrogen or a lower alkyl group having 1-5 carbon atoms) or (bl -0H20R' or -C
H,000 4 (wherein R4 represents hydrogen, a saturated or unsaturated alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aryl group, or an aralkyl group), or R
1 and 几2 may be the same or different, and represent ta+ or (b). (27) The compound according to claim 1, wherein the aryl group of R' is phenyl, tolyl or naphthyl.
（３３Ｒ’ のアリール基の置換基が低級アルキル基、
低級アルコキシ基、ハロゲン、ニトロ基またはカルボキ
シ基である特許請求の範囲第１項記載の化合物。(The substituent of the aryl group of 33R' is a lower alkyl group,
The compound according to claim 1, which is a lower alkoxy group, halogen, nitro group or carboxy group.
（４） Ｒ，’ のアラル中ル基がアリールアルキル
基である特許請求の範囲第１項記載の化合物。(4) The compound according to claim 1, wherein the aral group in R,' is an arylalkyl group.
（５） 几４のアリールアルキル基の１リールがフェ
ニル、トリルまたはナフチルで、アルキルが炭素数１−
３である特許請求の範囲第４項記載の化合物。(5) 1 aryl of the arylalkyl group of 几4 is phenyl, tolyl, or naphthyl, and the alkyl has 1-carbon number
3. The compound according to claim 4, which is
（６）炭ｇ数ｔ−３のアルキル基がメチル、エチルまた
はプロピルである特許請求の範超第５項記載の化合物。(6) The compound according to claim 5, wherein the alkyl group of the carbon g number t-3 is methyl, ethyl or propyl.
Claims (6)
キノマイシンＡ誘導体。 ▲数式、化学式、表等があります▼（ I ） 〔式中、Ｒ＾１とＲ＾２の一方はメチル基で、他方は（
ａ）−（ＣＨ＿２）＿ｎ−ＣＯ＿２Ｒ＾３または−ＣＨ
＿３−ＣＨ（ＣＯ＿２Ｒ＾３）＿２（ただしｎは０−２
の整数を表わし、Ｒ＾３は炭素数１−５の低級アルキル
基を表わす）または（ｂ）−ＣＨ＿２ＯＲ＾４または−
ＣＨ＿２ＯＣＯＲ＾４（ただしＲ＾４は水素、炭素数１
−５の飽和または不飽和アルキル基、置換または未置換
アリール基またはアラルキル基を表わす）であるか、あ
るいはＲ＾１とＲ＾２は同一でも異つてもよく、上記（
ａ）または（ｂ）を表わす。〕(1) An antibiotic diazachinomycin A derivative represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, one of R^1 and R^2 is a methyl group, and the other is (
a) -(CH_2)_n-CO_2R^3 or -CH
_3-CH(CO_2R^3)_2 (where n is 0-2
(b) -CH_2OR^4 or -
CH_2OCOR^4 (However, R^4 is hydrogen, carbon number is 1
-5 saturated or unsaturated alkyl group, substituted or unsubstituted aryl group or aralkyl group), or R^1 and R^2 may be the same or different and the above (
Represents a) or (b). ]
フチルである特許請求の範囲第１項記載の化合物。(2) The compound according to claim 1, wherein the aryl group of R^4 is phenyl, tolyl or naphthyl.
低級アルコキシ基、ハロゲン、ニトロ基またはカルボキ
シ基である特許請求の範囲第２項記載の化合物。(3) The substituent of the aryl group of R^4 is a lower alkyl group,
The compound according to claim 2, which is a lower alkoxy group, halogen, nitro group or carboxy group.
る特許請求の範囲第１項記載の化合物。(4) The compound according to claim 1, wherein the aralkyl group of R^4 is an arylalkyl group.
ル、トリルまたはナフチルで、アルキルが炭素数１−３
である特許請求の範囲第４項記載の化合物。(5) The aryl of the arylalkyl group in R^4 is phenyl, tolyl, or naphthyl, and the alkyl has 1 to 3 carbon atoms.
The compound according to claim 4, which is
はプロピルである特許請求の範囲第５項記載の化合物。(6) The compound according to claim 5, wherein the alkyl group having 1 to 3 carbon atoms is methyl, ethyl or propyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61224153A JPH085880B2 (en) | 1986-09-22 | 1986-09-22 | Antibiotic diazaquinomycin A derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61224153A JPH085880B2 (en) | 1986-09-22 | 1986-09-22 | Antibiotic diazaquinomycin A derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6379830A true JPS6379830A (en) | 1988-04-09 |
| JPH085880B2 JPH085880B2 (en) | 1996-01-24 |
Family
ID=16809365
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61224153A Expired - Lifetime JPH085880B2 (en) | 1986-09-22 | 1986-09-22 | Antibiotic diazaquinomycin A derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH085880B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2130831A1 (en) | 2008-06-06 | 2009-12-09 | InterMed Discovery GmbH | CDC25 inhibitors |
-
1986
- 1986-09-22 JP JP61224153A patent/JPH085880B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2130831A1 (en) | 2008-06-06 | 2009-12-09 | InterMed Discovery GmbH | CDC25 inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH085880B2 (en) | 1996-01-24 |
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