JPH085880B2 - Antibiotic diazaquinomycin A derivative - Google Patents
Antibiotic diazaquinomycin A derivativeInfo
- Publication number
- JPH085880B2 JPH085880B2 JP61224153A JP22415386A JPH085880B2 JP H085880 B2 JPH085880 B2 JP H085880B2 JP 61224153 A JP61224153 A JP 61224153A JP 22415386 A JP22415386 A JP 22415386A JP H085880 B2 JPH085880 B2 JP H085880B2
- 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.)
- Expired - Lifetime
Links
- WZZGVUSWZMBPPL-UHFFFAOYSA-N Diazaquinomycin A Chemical class N1C(=O)C(C)=C(CCC)C2=C1C(=O)C(NC(=O)C(C)=C1CCC)=C1C2=O WZZGVUSWZMBPPL-UHFFFAOYSA-N 0.000 title claims description 20
- 230000003115 biocidal effect Effects 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 112
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 102
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000002904 solvent Substances 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 239000013078 crystal Substances 0.000 description 29
- 238000004519 manufacturing process Methods 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- -1 malonic acid ester Chemical class 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 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
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- 229910001923 silver oxide Inorganic materials 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 108010022394 Threonine synthase Proteins 0.000 description 4
- 102000005497 Thymidylate Synthase Human genes 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000706 filtrate 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
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000002084 enol ethers Chemical class 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000012156 elution solvent Substances 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
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- PCZOZSATUTWXIC-UHFFFAOYSA-N tetraethylazanium;cyanide Chemical compound N#[C-].CC[N+](CC)(CC)CC PCZOZSATUTWXIC-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
- UPTAAVKOIJDMNU-UHFFFAOYSA-N 2-methoxy-3,7-dimethyl-4,6-dipropyl-9H-pyrido[3,2-g]quinoline-5,8,10-trione Chemical compound C1(=O)C=2NC(=O)C(=C(CCC)C=2C(=O)C2=C(CCC)C(C)=C(OC)N=C12)C UPTAAVKOIJDMNU-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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 208000003468 Ehrlich Tumor Carcinoma Diseases 0.000 description 1
- 241000192125 Firmicutes Species 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
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 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
- 230000000259 anti-tumor effect 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
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910000423 chromium oxide Inorganic materials 0.000 description 1
- ZVODSTJKZOOBPY-UHFFFAOYSA-N chromium(3+) oxygen(2-) sulfuric acid Chemical compound S(O)(O)(=O)=O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3] ZVODSTJKZOOBPY-UHFFFAOYSA-N 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
- 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
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012038 nucleophile 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
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は抗生物質ジアザキノマイシンＡの新規誘導体
に関する。TECHNICAL FIELD The present invention relates to novel derivatives of the antibiotic diazaquinomycin A.
従来の技術 抗生物質ジアザキノマイシンＡは特開昭58−205497号
公報に「抗生物質OM−704−Ａ」として記載された公知
化合物で、グラム陽性菌に活性を示す。2. Description of the Related Art The antibiotic diazaquinomycin A is a known compound described as "antibiotic OM-704-A" in JP-A-58-205497 and shows activity against Gram-positive bacteria.
本発明者は、上記ジアザキノマイシンＡから多くの誘
導体を製造し、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 diazaquinomycin A, found that these have an antibacterial activity and a thymidylate synthase inhibitory action, and completed the present invention.
発明が解決しようとする問題点 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Ａ誘導
体を提供することにある。Problem to be Solved by the Invention An object of the present invention is to provide a novel diazaquinomycin A derivative having antibacterial activity and thymidylate synthase inhibitory activity.
問題点を解決するための手段 本発明により提供されるジアザキノマイシンＡ誘導体
は下記の一般式（Ｉ）で表わされる。Means for Solving Problems The diazaquinomycin A derivative provided by the present invention is represented by the following general formula (I).
〔式中、R1とR2の一方はメチル基で、他方は（ａ）‐
（CH2）n‐CO2R3または ‐CH2‐CH（CO2R3）2（ただしｎは０−２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（ｂ）‐CH2OR4または‐CH2OCOR4（ただしR4
は水素、炭素数１−５の飽和又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R1とR2は同一でも異なつてもよ
く、上記（ａ）または（ｂ）を表わす。〕 R4のアリール基がフエニル、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、フツ素、塩素、臭素）、ニトロ
基、カルボキシ基などである。R4のアラルキル基はアリ
ールアルキル基で、アリールとしてフエニル、トリル、
ナチルなどがあげられ、アルキルとして炭素数１−３の
もの（例、メチル、エチル、プロピル）があげられる。 [In the formula, one of R 1 and R 2 is a methyl group, and the other is (a)-
(CH 2 ) n -CO 2 R 3 or -CH 2 -CH (CO 2 R 3 ) 2 (where n represents an integer of 0-2, R 3 represents hydrogen, a lower alkyl group having 1 to 5 carbon atoms) Or (b) -CH 2 OR 4 or -CH 2 OCOR 4 (provided that R 4
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 R 2 may be the same or different, and the above (a) Or represents (b). ] The aryl group of R 4 is phenyl, tolyl or naphthyl. The substituent of the aryl group is, for example, a lower alkyl group (eg, methyl), a lower alkoxy group (eg, methoxy), a halogen (eg, fluorine, chlorine, bromine), a nitro group, a carboxy group, etc. The aralkyl group of R 4 is an arylalkyl group, and aryl such as phenyl, tolyl,
Examples thereof include natyl and the like, 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つ
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 by, for example, the method described below.
本発明による化合物は、公知のジアザキノマイシンＡ
〔式（Ｉ）においてR1＝R2＝メチル〕を出発原料として
製造される。ジアザキノマイシンＡをクロロホルムのよ
うな溶媒中で０−25℃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）、または公知の化
合物（３）〔テトラヘドロン・レターズ（Tetrahedron
Letters）,Vol.24,pp 3643−3646、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
ロムコハク酸イミド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 are known diazaquinomycin A
It is produced by using [in the formula (I), R 1 = R 2 = methyl] as a starting material. Compound (2) obtained by reacting diazaquinomycin A with methyl iodide and silver oxide at a temperature of 0 to 25 ° C. in a solvent such as chloroform, or a known compound (3) [tetrahedron letters ( Tetrahedron
Letters), Vol. 24, pp 3643-3646, 1983] in a solvent such as carbon tetrachloride at a temperature of 25-80 ° C. with an excess molar amount of N-bromosuccinimide and a catalytic amount of benzoyl peroxide. It is produced from the intermediates represented by the formulas (4) and (5) thus obtained.
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。 Compound (4) or compound (5) can be reacted with a nucleophile as shown below to introduce a desired substituent at the position of the methyl group.
製造方法Ａ 化合物（５）をジクロロメタンのような溶媒中、テト
ラアルキルアンモニウムシアニドと氷冷下に反応させ、
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な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る。Production Method A Compound (5) is reacted with a tetraalkylammonium cyanide in a solvent such as dichloromethane under ice cooling,
The compound (6), then the general formula (7) (where R is 1-carbon)
(Meaning a lower alkyl group of 5) and a mineral acid such as concentrated sulfuric acid as a catalyst to react with each other to hydrolyze the enol ether and simultaneously esterify the compound (8). The corresponding carboxylic acid (9) is
It is obtained by treating the compound (8) with an alkali such as sodium hydroxide in a hydroalcoholic solvent.
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。 Corresponding compounds (10), (11) and (12) can be produced from compound (4) by the same method.
製造方法Ｂ 化合物（５）と乾燥テトラヒドロフランのような溶媒
中で、ジアルキルマロン酸エステルと水素化ナトリウム
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（1
3）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。 Manufacturing method B Compound (5) is reacted with a dialkylmalonic acid ester and the anion of malonic acid ester prepared from a base such as sodium hydride in a solvent such as dry tetrahydrofuran at room temperature to give compound (13). Compound (1
Compound (14) is produced by hydrolyzing 3) in a solvent such as hydroalcohol using a mineral acid such as concentrated sulfuric acid as a catalyst. The corresponding carboxylic acid (15) can be obtained by treating the 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つて加水分解し
て化合物（16）とし、これをピリジンのような溶媒中、
100−120℃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、水酸化ナトリウ
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 hydrous alcohol,
Hydrolyze with an alkali such as sodium hydroxide to give compound (16), which is added to a solvent such as pyridine,
The compound (17) is produced by heating to about 100-120 ° C. The compound (17) is reacted with an alcohol represented by the general formula (7) using a mineral acid such as sulfuric acid as a catalyst to simultaneously perform esterification and hydrolysis of an enol ether to produce a compound (18). The corresponding carboxylic acid (19) is
It is obtained by treating the compound (18) with an alkali such as sodium hydroxide in a hydroalcoholic solvent.
製造方法Ｃ 化合物（５）を、含水テトラヒドロフラン中、80−90
℃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、硫酸のような鉱酸
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。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。Manufacturing method C Compound (5) was added to 80-90 in water-containing tetrahydrofuran.
The compound (20) is heated to about 48 ° C. for about 48 hours and is oxidized with an oxidizing agent such as chromic acid-sulfuric acid in a solvent such as acetone to give a compound (21). The compound (21) is reacted with the alcohol represented by the general formula (7) using a mineral acid such as sulfuric acid as a catalyst to effect esterification and hydrolysis of the enol ether to produce a compound (22). The corresponding carboxylic acid (23) can be obtained by treating the compound (22) with an alkali such as sodium hydroxide in a hydroalcoholic solvent.
製造方法Ｄ 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、アリール基またはア
ラルキル基を表わす）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ウム塩と、室温から110
℃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。Manufacturing method D The compound (5) is converted into the compound represented by the general formula (24) (R is hydrogen, carbon number 1-
5 represents a saturated or unsaturated alkyl group, an aryl group or an aralkyl group), an excess amount of the corresponding sodium salt with respect to the substrate, and room temperature to 110
The compound (25) is obtained by reacting at a temperature of about ℃. The compound (25) is treated with acetic acid-sulfuric acid at room temperature to a temperature of about 100 ° C to give the compound (26). Compound (26) can be converted to compound (27) by treating 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（2
8）、（29）、（30）を順次製造できる。 From the compound (4), the compound (2
8), (29), and (30) can be manufactured sequentially.
製造方法Ｅ 化合物（５）と、一般式（31）（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）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。Manufacturing method E Using a compound (5) and an alcohol represented by the general formula (31) (R represents a saturated or unsaturated alkyl group having 1 to 5 carbon atoms, an aryl group or an aralkyl group) as a solvent, a mineral acid such as sulfuric acid is used. Is used as a catalyst to react from room temperature to a temperature around the boiling point of the solvent to produce the compound (32).
化合物（４）からも同様の方法で化合物（33）が製造
できる。 The compound (33) can be produced from the compound (4) by the same method.
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。Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
実施例１ 2,8-ジメトキシ‐3,7-ジメチル‐4,6-ジプロピルピリ
ド〔3,2-g〕キノリン‐5,10-ジオン〔化合物（３）〕の
製造。Example 1 Production of 2,8-dimethoxy-3,7-dimethyl-4,6-dipropylpyrido [3,2-g] quinoline-5,10-dione [compound (3)].
ジアザキノマイシンＡ（式ＩにおいてR1＝R2＝メチ
ル）250mgをクロロホルム25mlに溶解し、ヨウ化メチル5
ml、酸化銀500mg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イー（溶出溶媒：
クロロホルム）で精製し、黄色結晶235mg（収率87％）
を得た。250 mg of diazaquinomycin A (R 1 = R 2 = methyl in the formula I) was dissolved in 25 ml of chloroform to give methyl iodide 5
Add 500 ml of silver oxide and heat to reflux for 2 hours. The reaction solution is filtered to remove silver oxide, and then the filtrate is concentrated under reduced pressure. Silica gel column chromatography (eluting solvent:
Chloroform) and yellow crystals 235mg (87% yield)
I got
実施例２ 3,7-ジプロモメチル‐2,8-ジメトキシ‐4,6-ジプロピ
ルピリド〔3,2-g〕キノリン‐5,10-ジオン〔化合物
（５）〕の製造。Example 2 Production of 3,7-dipromomethyl-2,8-dimethoxy-4,6-dipropylpyrido [3,2-g] quinoline-5,10-dione [compound (5)].
化合物（３）500mgを四塩化炭素40mlに溶解し、N-ブ
ロムコハク酸イミド700mg、過酸化ベンゾイル10mgを加
え、2.5時間加熱還流する。反応液を水40mlに注いで有
機層を分離し、水層をさらに、クロロホルム（40ml×
３）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
グラフイー（溶出溶媒：クロロホルム）で精製し、黄色
結晶520mg（収率74％）を得た。500 mg of the compound (3) is dissolved in 40 ml of carbon tetrachloride, 700 mg of N-bromosuccinimide and 10 mg of benzoyl peroxide are added, and the mixture is heated under reflux for 2.5 hours. The reaction solution was poured into 40 ml of water to separate the organic layer, and the aqueous layer was further added with chloroform (40 ml x
Extract in 3). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: chloroform) to obtain 520 mg (yield 74%) of yellow crystals.
実施例３ 2-メトキシ‐3,7-ジメチル‐4,6-ジプロピルピリド
〔3,2-g〕キノリン‐5,8,10（9H）‐トリオン〔化合物
（２）〕の製造。Example 3 Preparation of 2-methoxy-3,7-dimethyl-4,6-dipropylpyrido [3,2-g] quinoline-5,8,10 (9H) -trione [compound (2)].
ジアザキノマイシンＡ（化合物（Ａ）〕212mgをクロ
ロホルム28mlに溶解し、ヨウ化メチル4ml、酸化銀423mg
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イー（溶出溶媒：クロロホル
ム）で精製し、橙色結晶166mg（収率75％）を得た。212 mg of diazaquinomycin A (compound (A)) was dissolved in 28 ml of chloroform, and 4 ml of methyl iodide and 423 mg of silver oxide were dissolved.
And stir at room temperature for 9 hours. After the reaction solution is filtered to remove silver oxide, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: chloroform) to obtain 166 mg of orange crystals (yield 75%).
実施例４ 3-ブロモメチル‐2-メトキシ‐7-メチル‐4,6-ジプロ
ピルピリド〔3,2-g〕キノリン‐5,8,10（9H）‐トリオ
ン〔化合物（４）〕の製造。Example 4 Production of 3-bromomethyl-2-methoxy-7-methyl-4,6-dipropylpyrido [3,2-g] quinoline-5,8,10 (9H) -trione [compound (4)].
化合物（２）1gを四塩化炭素200mlに溶解し、N-ブロ
ムコハク酸イミド2g、過酸化ベンゾイル20mgを加え、2.
5時間加熱還流する。反応液を水150mlに注いで有機層を
分離し、水層をさらにクロロホルム（150ml×３）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。残渣をシリカゲルカラムクロマトグラフイー
（溶出溶媒：ベンゼン／アセトン＝10/1）で精製し、黄
色結晶568mg（収率44％）を得た。1 g of the compound (2) was dissolved in 200 ml of carbon tetrachloride, 2 g of N-bromosuccinimide and 20 mg of benzoyl peroxide were added, and 2.
Heat to reflux for 5 hours. The reaction solution is poured into 150 ml of water to separate the organic layer, and the aqueous layer is further extracted with chloroform (150 ml × 3). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: benzene / acetone = 10/1) to obtain 568 mg of yellow crystals (yield 44%).
実施例５ 2,8−ジメトキシ‐4,6,ジプロピル‐5,10-ジオキソ‐
5,10-ジヒドロピリド〔3,2-g〕キノリン‐3,7-ジアセト
ニトリル〔化合物（６））〕の製造。Example 5 2,8-Dimethoxy-4,6, dipropyl-5,10-dioxo-
Production of 5,10-dihydropyrido [3,2-g] quinoline-3,7-diacetonitrile [compound (6)]].
化合物（５）500gをジクロロメタン50mlに溶解し、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289mgのジクロロメタン（50ml）溶液を、４
時間かけて滴下する。滴下後、水50ml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、
減圧下濃縮する。残査をシリカゲルクロマトグラフイー
（溶出溶媒：クロロホルム）で精製し、黄色結晶306mg
（収率77％）を得た。Dissolve 500 g of compound (5) in 50 ml of dichloromethane and
Cool to ° C. Into this solution, a solution of 289 mg of tetraethylammonium cyanide in dichloromethane (50 ml) was added 4 times.
Drop over time. After the dropping, 50 ml of water was added and extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate,
Concentrate under reduced pressure. The residue was purified by silica gel chromatography (eluting solvent: chloroform) to give 306 mg of yellow crystals.
(Yield 77%) was obtained.
実施例６ 4,6−ジプロピル‐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）〕の製造。Example 6 4,6-Dipropyl-2,5,8,10-tetraoxo-1,2,5,8,
Production of 9,10-hexahydropyrido [3,2-g] quinoline-3,7-diacetate diethyl (compound (34)).
化合物（６）52mgをエタノール4mlに溶解し、濃硫酸2
mlを加え、２時間加熱還流する。反応液を水5mlに注
ぎ、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、減圧下濃縮する。残査をシリカゲルカラム
クロマトグラフイー（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33mg（収率55％）を得
た。Dissolve 52 mg of compound (6) in 4 ml of ethanol, and add concentrated sulfuric acid 2
Add ml and heat to reflux for 2 hours. The reaction solution is poured into 5 ml of water, extracted 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 (eluting solvent: chloroform / methanol = 50/1) to obtain 33 mg 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-ヘキサヒドロピリド〔3,2-g〕キノリン‐3,7-ジ酢
酸（化合物（９）〕の製造。Example 7 4,6-Dipropyl-2,5,8,10-tetraoxo-1,2,5,8,
Production of 9,10-hexahydropyrido [3,2-g] quinoline-3,7-diacetic acid (compound (9)).
化合物（34）30mgを80％エタノール水12mlに溶解し、
水酸化ナトリウム30mg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21mg（収率82％）を
得た。Dissolve 30 mg of compound (34) in 12 ml of 80% ethanol water,
Add 30 mg of sodium hydroxide and react at 50 ° C for 30 minutes.
The reaction solution is acidified with hydrochloric acid, the precipitate is filtered, and the filtered product is washed with water. The crystals were dried under reduced pressure to give 21 mg of red crystals (yield 82%).
実施例８ 2,8−ジメトキシ‐3,7-ジメチル‐4,6-ジプロピル‐
5,10-ジオキソ‐5,10-ジヒドロピリド〔3,2-g〕キノリ
ン‐３′,7′‐ジマロン酸テトラエチル〔化合物（3
5）〕の製造。Example 8 2,8-Dimethoxy-3,7-dimethyl-4,6-dipropyl-
5,10-Dioxo-5,10-dihydropyrido [3,2-g] quinoline-3 ', 7'-tetraethyl dimalonate [Compound (3
5)] Manufacturing.
水素化ナトリウム（60％油性）388mgを乾燥テトラヒ
ドロフラン100mlにけん濁し、これにジエチルマロネー
ト1.8mlを滴下する。滴下後、室温で30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）1.5gのテトラヒドロフラン溶液（60ml）を
加える。室温で30分間反応し、反応液にエタノール0.5m
lを加え反応を停止させる。反応液を冷却後、減圧下濃
縮し、水60ml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
圧下濃縮し、残査をシリカゲルカラムクロマトグラフイ
ー（溶出溶媒：ヘキサン／酢酸エチル＝2/1）で精製す
る。黄色結晶1.3g（収率74％）を得た。388 mg of sodium hydride (60% oily) is suspended in 100 ml of dry tetrahydrofuran, to which 1.8 ml of diethyl malonate is added dropwise. After the dropping, the mixture is stirred at room temperature for 30 minutes to prepare the anion of diethyl malonate. A tetrahydrofuran solution (60 ml) of 1.5 g of the compound (5) is added to this solution. React at room temperature for 30 minutes, add 0.5m ethanol to the reaction mixture
Add l to stop the reaction. After cooling the reaction mixture, it is concentrated under reduced pressure, 60 ml of water is added to acidify the hydrochloric acid, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1). 1.3 g (74% yield) of yellow crystals were obtained.
実施例９ 3,7-ジメチル‐4,6-ジプロピル‐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′‐ジマロン酸テトラエチル〔化合物（3
6）〕の製造。Example 9 3,7-Dimethyl-4,6-dipropyl-2,5,8,10-tetraoxo-1,2,5,8,9,10-hexahydropyrido [3,2-g] quinoline- Tetraethyl 3 ', 7'-dimalonate [Compound (3
6)] Manufacturing.
化合物（35）100mgをエタノール4mlに溶解し、濃硫酸
2mlを加え、12時間加熱還流する。反応液を冷却後、減
圧下濃縮し、水5ml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イー（溶出溶
媒：クロロホルム／メタノール＝10/1）で精製し、赤色
結晶91mg（収率95％）を得た。Dissolve 100 mg of compound (35) in 4 ml of ethanol and add concentrated sulfuric acid.
Add 2 ml and heat to reflux for 12 hours. The reaction mixture is cooled, concentrated under reduced pressure, added with 5 ml of water, and extracted with chloroform.
The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (eluting solvent: chloroform / methanol = 10/1) to obtain 91 mg of red crystals (yield 95%).
実施例10 3,7-ジメチル‐4,6-ジプロピル‐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′‐ジマロン酸〔化合物（15）〕の製造。Example 10 3,7-Dimethyl-4,6-dipropyl-2,5,8,10-tetraoxo-1,2,5,8,9,10-hexahydropyrido [3,2-g] quinoline- Production of 3 ', 7'-dimalonic acid [compound (15)].
化合物（36）49mgを80％エタノール水15mlに溶解し、
水酸化ナトリウム30mgを加えて50℃、30分間反応する。
反応液を塩酸酸性にし、水15ml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
下濃縮して赤色結晶33mg（収率80％）を得た。Dissolve 49 mg of compound (36) in 15 ml of 80% ethanol water,
Add 30 mg of sodium hydroxide and react at 50 ° C for 30 minutes.
The reaction solution is acidified with hydrochloric acid, added with 15 ml of water, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 33 mg of red crystals (yield 80%).
実施例11 2,8-ジメトキシ‐3,7-ジメチル‐4,6-ジプロピル‐5,
10-ジオキソ‐5,10-ジヒドロピリド〔3,2-g〕キノリン
‐３′,7′‐ジマロン酸〔化合物（16）〕の製造。Example 11 2,8-Dimethoxy-3,7-dimethyl-4,6-dipropyl-5,
Production of 10-dioxo-5,10-dihydropyrido [3,2-g] quinoline-3 ', 7'-dimalonic acid [compound (16)].
化合物（35）50mgを80％エタノール水10mlに溶解し、
水酸化ナトリウム36mgを加えて１時間加熱還流する。反
応液を塩酸酸性にし、水10ml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34mg（収率82％）を得た。Dissolve 50 mg of compound (35) in 10 ml of 80% ethanol water,
Add 36 mg of sodium hydroxide and heat to reflux for 1 hour. The reaction mixture is acidified with hydrochloric acid, 10 ml of water is added, and the mixture is extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 34 mg (yield 82%) of yellow crystals.
実施例12 2,8-ジメトキシ‐4,6-ジプロピル‐5,10-ジオキソ‐
5,10-ジヒドロピリド〔3,2-g〕キノリン‐3,7-プロピオ
ン〔化合物（17）〕の製造。Example 12 2,8-Dimethoxy-4,6-dipropyl-5,10-dioxo-
Production of 5,10-dihydropyrido [3,2-g] quinoline-3,7-propione [compound (17)].
化合物（16）50mgをピリジン10mlに溶解し、120℃、
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10ml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
圧下濃縮して残査をシリカゲルカラムクロマトグラフイ
ー（溶出溶媒：クロロホルム）で精製し、黄色結晶34mg
（収率94％）を得た。Compound (16) 50mg is dissolved in pyridine 10ml, 120 ℃,
Heat to reflux for 4 hours. Pyridine in the reaction solution was distilled off under reduced pressure, acidified with hydrochloric acid, 10 ml 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 (eluting solvent: chloroform) to give 34 mg of yellow crystals.
(Yield 94%) was obtained.
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-ヘキサヒドロピリド〔3,2-g〕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,
Production of 9,10-hexahydropyrido [3,2-g] quinoline-3,7-dipropionate diethyl [compound (37)].
化合物（17）34mgをエタノール10mlに溶解し、濃硫酸
5mlを加え、80℃、４時間加熱還流する。減圧下濃縮し
て水10ml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
ロマトグラフイー（溶出溶媒：クロロホルム）で精製
し、赤色結晶19mg（収率53％）を得た。34 mg of compound (17) was dissolved in 10 ml of ethanol and concentrated sulfuric acid was added.
Add 5 ml and heat to reflux for 4 hours at 80 ° C. 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 (eluting solvent: chloroform) to obtain 19 mg of red crystals (yield 53%).
実施例14 4,6-ジプロピル‐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-ジプ
ロピオン酸〔化合物（19）〕の製造。Example 14 4,6-dipropyl-2,5,8,10-tetraoxo-1,2,5,8,
Production of 9,10-hexahydropyrido [3,2-g] quinoline-3,7-dipropionic acid [compound (19)].
化合物（37）50mgを80％エタノール水に溶解し、水酸
化ナトリウム30mgを加え、室温で45分間反応する。反応
液を塩酸酸性とし、水10ml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
縮して赤色結晶36mg（収率80％）を得た。50 mg of compound (37) is dissolved in 80% ethanol water, 30 mg of sodium hydroxide is added, and the mixture is reacted at room temperature for 45 minutes. The reaction mixture is acidified with hydrochloric acid, 10 ml of water is added, and the mixture is extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 36 mg of red crystals (yield 80%).
実施例15 3,7-ジヒドロキシメチル‐2,8-ジメトキシ‐4,6-ジプ
ロピルピリド〔3,2-g〕キノリン‐5,10-ジオン〔化合物
（20）〕の製造。Example 15 Production of 3,7-dihydroxymethyl-2,8-dimethoxy-4,6-dipropylpyrido [3,2-g] quinoline-5,10-dione [compound (20)].
化合物（５）80mgをテトラヒドロフラン‐水（2:1）4
8mlに溶解し、80℃、２日間加熱還流する。減圧下濃縮
し、水30ml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グラフイー（溶出溶媒：クロロ
ホルム／メタノール＝20/1）で精製し、黄色結晶27mg
（収率44％）を得た。80 mg of compound (5) was added to tetrahydrofuran-water (2: 1) 4
Dissolve in 8 ml and heat to reflux for 2 days at 80 ° C. Concentrate under reduced pressure, add 30 ml of water, and extract 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 (eluting solvent: chloroform / methanol = 20/1) to give 27 mg of yellow crystals.
(Yield 44%) was obtained.
実施例16 2,8-ジメトキシ‐4,6-ジプロピル‐5,10-ジオキソ‐
5,10-ジヒドロピリド〔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-Dimethoxy-4,6-dipropyl-5,10-dioxo-
Production of 5,10-dihydropyrido [3,2-g] quinoline-3,7-dicarboxylic acid [compound (21)].
化合物（20）550mgをアセトン50mlに溶解し、０℃に
冷却する。酸化クロム‐硫酸（酸化クロム／濃硫酸／水
＝26.7g/23ml/50ml）を3ml加え、０℃、10分間反応す
る。イソプロパノールを加えて反応を中止し、減圧下濃
縮後、水50ml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、減圧下濃縮した黄色結
晶510mg（収率87％）を得た。550 mg of compound (20) is dissolved in 50 ml of acetone and cooled to 0 ° C. Add 3 ml of chromium oxide-sulfuric acid (chromium oxide / concentrated sulfuric acid / water = 26.7 g / 23 ml / 50 ml) and react at 0 ° C. for 10 minutes. Isopropanol is added to stop the reaction, the mixture is concentrated under reduced pressure, 50 ml of water is added, and the mixture is extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 510 mg of yellow crystals (yield 87%).
実施例17 4,6-ジプロピル‐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-ジカ
ルボン酸ジエチル〔化合物（38）〕の製造。Example 17 4,6-dipropyl-2,5,8,10-tetraoxo-1,2,5,8,
Production of 9,10-hexahydropyrido [3,2-g] quinoline-3,7-dicarboxylic acid diethyl [compound (38)].
化合物（21）210mgをエタノール20mlに溶解し、濃硫
酸10mlを加え、100℃、５時間還流する。反応液を減圧
下濃縮し、水20ml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グラフイー（溶出溶媒：
クロロホルム／メタノール＝25/1）で精製し、赤色結晶
53mg（収率50％）を得た。210 mg of compound (21) is dissolved in 20 ml of ethanol, 10 ml of concentrated sulfuric acid is added, and the mixture is refluxed at 100 ° C. for 5 hours. The reaction mixture is concentrated under reduced pressure, 20 ml of water is added, and the mixture is 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:
Purified with chloroform / methanol = 25/1), red crystals
53 mg (yield 50%) was obtained.
実施例18 4,6-ジプロピル‐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-ジカ
ルボン酸〔化合物（23）〕の製造。Example 18 4,6-Dipropyl-2,5,8,10-tetraoxo-1,2,5,8,
Production of 9,10-hexahydropyrido [3,2-g] quinoline-3,7-dicarboxylic acid [compound (23)].
化合物（38）60mgを80％エタノール10mlに溶解し、水
酸化ナトリウム30mgを加え、50℃で１時間反応する。反
応液に水10mlを加え、減圧下濃縮し、ろ過後、ろ液を塩
酸酸性とする。沈殿物をろ過し、ろ過物を水で洗浄後、
減圧下乾燥して赤色粉末38mg（収率72％）を得た。60 mg of the compound (38) is dissolved in 10 ml of 80% ethanol, 30 mg of sodium hydroxide is added, and the mixture is reacted at 50 ° C. for 1 hour. 10 ml of water is added to the reaction solution, concentrated under reduced pressure, filtered, and the filtrate is acidified with hydrochloric acid. After filtering the precipitate and washing the filtrate with water,
It was dried under reduced pressure to obtain 38 mg of red powder (yield 72%).
実施例19 3,7-ジアセトキシメチル‐2,8-ジメトキシ‐4,6-ジプ
ロピルピリド〔3,2-g〕キノリン‐5,10-ジオン〔化合物
（39）〕の製造。Example 19 Production of 3,7-diacetoxymethyl-2,8-dimethoxy-4,6-dipropylpyrido [3,2-g] quinoline-5,10-dione [compound (39)].
化合物（５）50mgを酢酸6mlに溶解し、水酸化ナトリ
ウム30mgを加え、100℃で３時間反応する。反応液を減
圧下濃縮し、残査に水5ml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。減圧下濃
縮後、残査をシリカゲルカラムクロマトグラフイー（溶
出溶媒：クロロホルム／メタノール＝20/1）で精製し、
黄色結晶42mg（収率91％）を得た。50 mg of the compound (5) is dissolved in 6 ml of acetic acid, 30 mg of sodium hydroxide is added, and the mixture is reacted at 100 ° C. for 3 hours. The reaction mixture is concentrated under reduced pressure, 5 ml of water is added to the residue, the mixture is 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 / methanol = 20/1),
42 mg (91% yield) of yellow crystals were obtained.
実施例20 3,7-ジアセトキシメチル‐4,6-ジプロピルピリド〔3,
2-g〕キノリン‐2,5,8,10（1H,9H）‐テトロン〔化合物
（40）〕の製造。Example 20 3,7-diacetoxymethyl-4,6-dipropylpyrido (3,
Preparation of 2-g] quinoline-2,5,8,10 (1H, 9H) -tetron [compound (40)].
化合物（39）42mgを酢酸4mlに溶解し、濃硫酸0.2mlを
加え、100℃、３時間反応する。反応液に水5ml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。減圧下濃縮後、残査をシリカゲルカラムクロ
マトグラフイー（溶出溶媒：クロロホルム／メタノール
＝20/1）で精製し、赤色結晶25mg（収率63％）を得た。42 mg of compound (39) is dissolved in 4 ml of acetic acid, 0.2 ml of concentrated sulfuric acid is added, and the mixture is reacted at 100 ° C. for 3 hours. Add 5 ml of water to the reaction mixture,
Extract with chloroform and dry the organic layer over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: chloroform / methanol = 20/1) to obtain 25 mg of red crystals (yield 63%).
実施例21 3-アセトキシメチル‐2-メトキシ‐7-メチル‐4,6-ジ
プロピルピリド〔3,2-g〕キノリン‐5,8,10（9H）‐ト
リオン〔化合物（41）〕の製造。Example 21 Production of 3-acetoxymethyl-2-methoxy-7-methyl-4,6-dipropylpyrido [3,2-g] quinoline-5,8,10 (9H) -trione [compound (41)].
化合物（４）114mgを酢酸10mlに溶解し、水酸化ナト
リウム30mgを加え、100℃で５時間反応する。反応液を
減圧下濃縮し、残査に水10ml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、減圧下濃
縮する。残査をシリカゲルカラムクロマトグラフイー
（溶出溶媒：クロロホルム／メタノール＝25/1）で精製
し、黄色結晶104mg（収率96％）を得た。114 mg of the compound (4) is dissolved in 10 ml of acetic acid, 30 mg of sodium hydroxide is added, and the mixture is 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 purified by silica gel column chromatography (eluting solvent: chloroform / methanol = 25/1) to obtain 104 mg of yellow crystals (yield 96%).
実施例22 3-アセトキシメチル‐7-メチル‐4,6-ジプロピルピリ
ド〔3,2-g〕キノリン‐2,5,8,10（1H,9H）‐テトロン
〔化合物（42）〕の製造。Example 22 Preparation of 3-acetoxymethyl-7-methyl-4,6-dipropylpyrido [3,2-g] quinoline-2,5,8,10 (1H, 9H) -tetron [compound (42)].
化合物（41）104mgを酢酸10mlに溶解し、濃硫酸1mlを
加え、５時間加熱還流する。反応液に水10ml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。減圧下濃縮後、残査をシリカゲルカラムクロマ
トグラフイー（溶出溶媒：クロロホルム）で精製し、赤
色結晶65mg（収率65％）を得た。Compound (41) 104 mg is dissolved in acetic acid 10 ml, concentrated sulfuric acid 1 ml is added, and the mixture is heated under reflux for 5 hours. 10 ml of 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 (eluting solvent: chloroform) to obtain 65 mg of red crystals (yield 65%).
実施例23 3-7-ジヒドロキシメチル‐4,6-ジプロピルピリド〔3,
2-g〕キノリン‐2,5,8,10（1H,9H）‐テトロン〔化合物
（27）〕の製造。Example 23 3-7-Dihydroxymethyl-4,6-dipropylpyrido [3,
Preparation of 2-g] quinoline-2,5,8,10 (1H, 9H) -tetron [compound (27)].
化合物（40）67mgをメタノール30mlに溶解し、水酸化
ナトリウム50mgを加え、室温で３時間攪拌する。反応液
に水30ml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
下濃縮後、残査をシリカゲルカラムクロマトグラフイー
（溶出溶媒：クロロホルム／メタノール＝40/1）で精製
し、赤色結晶44mg（収率80％）を得た。67 mg of the compound (40) is dissolved in 30 ml of methanol, 50 mg of sodium hydroxide is added, and the mixture is stirred at room temperature for 3 hours. 30 ml of water is added to the reaction solution, acidified with hydrochloric acid, and extracted with chloroform. The extract is dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent: chloroform / methanol = 40/1) to obtain 44 mg of red crystals (yield 80%).
実施例24 3-ヒドロキシメチル‐7-メチル‐4,6-ジプロピルピリ
ド〔3,2-g〕キノリン‐2,5,8,10（1H,9H）‐テトロン
〔化合物（30）〕の製造。Example 24 Preparation of 3-hydroxymethyl-7-methyl-4,6-dipropylpyrido [3,2-g] quinoline-2,5,8,10 (1H, 9H) -tetron [compound (30)].
化合物（42）20mgをメタノール15mlに溶解し、水酸化
ナトリウム15mgを加え、室温で３時間攪拌する。反応液
に水15ml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。残査をシリカゲルカラムクロマトグラフイー
（溶出溶媒：クロロホルム／メタノール＝40/1）で精製
し、赤色結晶10mg（収率56％）を得た。20 mg of the compound (42) is dissolved in 15 ml of methanol, 15 mg of sodium hydroxide is added, and the mixture is stirred at room temperature for 3 hours. Water (15 ml) is added to the reaction solution to acidify it with hydrochloric acid and then extracted with chloroform. The extract is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: chloroform / methanol = 40/1) to obtain 10 mg of red crystals (yield 56%).
実施例25 3,7-ジエトキシメチル‐4,6-ジプロピルピリド〔3,2-
g〕キノリン‐2,5,8,10（1H,9H）‐テトロン〔化合物
（43）〕の製造。Example 25 3,7-Diethoxymethyl-4,6-dipropylpyrido (3,2-
g] Preparation of quinoline-2,5,8,10 (1H, 9H) -tetron [compound (43)].
化合物（５）50mgをエタノール6mlに溶解し、濃硫酸2
mlを加え、10時間加熱還流する。反応液を減圧下濃縮
し、水6ml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グラフイー（溶出溶媒：クロロ
ホルム）で精製し、赤色結晶13mg（収率32％）を得た。50 mg of compound (5) is dissolved in 6 ml of ethanol, and concentrated sulfuric acid 2
Add ml and heat to reflux for 10 hours. The reaction mixture is concentrated under reduced pressure, 6 ml of water is added, and the mixture is 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 (eluting solvent: chloroform) to obtain 13 mg of red crystals (yield 32%).
実施例26 3-エトキシメチル‐7-メチル‐4,6-ジプロピルピリド
〔3,2-g〕キノリン‐2,5,8,10（1H,9H）‐テトロン〔化
合物（44）〕の製造。Example 26 Preparation of 3-ethoxymethyl-7-methyl-4,6-dipropylpyrido [3,2-g] quinoline-2,5,8,10 (1H, 9H) -tetron [compound (44)].
化合物（４）320mgをエタノール80mlに溶解し、濃硫
酸40mlを加え、90℃で10時間反応する。反応液を減圧下
濃縮し、水80ml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グラフイー（溶出溶媒：ク
ロロホルム）で精製し、赤色結晶100mg（収率35％）を
得た。320 mg of compound (4) is dissolved in 80 ml of ethanol, 40 ml of concentrated sulfuric acid is added, and the mixture is reacted at 90 ° C. for 10 hours. The reaction mixture is concentrated under reduced pressure, 80 ml of water is added, and the mixture is 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 (eluting solvent: chloroform) to obtain 100 mg of red crystals (yield 35%).
実施例27 2-メトキシ‐7-メチル‐4,6-ジプロピル‐5,8,10-ト
リオキソ‐5,8,9,10-テトラヒドロピリド〔3,2-g〕キノ
リン‐3-アセトニトリル〔化合物（10）〕の製造。Example 27 2-Methoxy-7-methyl-4,6-dipropyl-5,8,10-trioxo-5,8,9,10-tetrahydropyrido [3,2-g] quinoline-3-acetonitrile [Compound (10)] Manufacturing.
化合物（４）135mgをジクロロメタン15mlに溶解し、
テトラエチルアンモニウムシアニド44mgのジクロロメタ
ン溶液15mlを氷冷下３時間で滴下する。滴下後、反応液
に水15ml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。減圧下濃縮し、残査をシリ
カゲルカラムクロマトグラフイー（溶出溶媒：クロロホ
ルム／メタノール＝50/1）で精製し、黄色結晶82mg（収
率70％）を得た。Dissolve 135 mg of compound (4) in 15 ml of dichloromethane,
15 ml of a dichloromethane solution containing 44 mg of tetraethylammonium cyanide was added dropwise over 3 hours under ice cooling. After the dropping, 15 ml of 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 (eluting solvent: chloroform / methanol = 50/1) to obtain 82 mg of yellow crystals (yield 70%).
実施例28 7-メチル‐4,6-ジプロピル‐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-酢酸エチル〔化合物（45）〕の製造。Example 28 7-Methyl-4,6-dipropyl-2,5,8,10-tetraoxo-1,2,5,8,9,10-hexahydropyrido [3,2-g] quinoline-3- Production of ethyl acetate [compound (45)].
化合物（10）82mgをエタノール20mlに溶解し、濃硫酸
10mlを加え、90℃で５時間反応する。反応液を減圧下濃
縮し、水20ml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グラフイー（溶出溶媒：クロ
ロホルム）で精製し、赤色結晶60mg（収率68％）を得
た。Dissolve 82 mg of compound (10) in 20 ml of ethanol and add concentrated sulfuric acid.
Add 10 ml and react at 90 ° C. for 5 hours. The reaction mixture is concentrated under reduced pressure, 20 ml of water is added, and the mixture is 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 (eluting solvent: chloroform) to obtain 60 mg of red crystals (yield 68%).
実施例29 7-メチル‐4,6-ジプロピル‐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-酢酸〔化合物（12）〕の製造。Example 29 7-Methyl-4,6-dipropyl-2,5,8,10-tetraoxo-1,2,5,8,9,10-hexahydropyrido [3,2-g] quinoline-3- Production of acetic acid [compound (12)].
化合物（45）60mgを80％エタノール水24mlに溶解し、
水酸化ナトリウム30mgを加え、50℃で２時間反応する。
反応液を減圧下濃縮し、水20ml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
ムクロマトグラフイー（溶出溶媒：クロロホルム／メタ
ノール＝20/1）で精製し、赤色結晶31mg（収率55％）を
得た。Dissolve 60 mg of compound (45) in 24 ml of 80% ethanol water,
Add 30 mg of sodium hydroxide and react at 50 ° C for 2 hours.
The reaction mixture is concentrated under reduced pressure, 20 ml of water is added to acidify the hydrochloric acid, and the mixture is extracted 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 (eluting solvent: chloroform / methanol = 20/1) to obtain 31 mg of red crystals (yield 55%).
実施例１−29で得られた化合物の構造式、触点、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表および第２表に示す。Tables 1 and 2 show the structural formulas, contact points, high-resolution mass analysis values, elemental analysis values, and infrared absorption spectra of the compounds obtained in Example 1-29.
本発明による化合物の溶剤に対する溶解性は一般に、
有機溶媒に溶解する。水にも溶解するが、その程度は化
合物により異なる。クロロホルムおよび水に対する溶解
性を第３表に示す。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
ノール、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ド、ジメチルホルムアミドなど
があげられる。 The solubility of the compounds according to the invention in solvents is generally
It dissolves in organic solvents. It also dissolves in water, but the degree depends on the compound. The solubility in chloroform and water is shown in Table 3. Examples of organic solvents include chloroform, dichloromethane, methanol, ethanol, propanol, butanol, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, and the like.
本発明による化合物（34）および化合物（43）では、
100mg/Kg ip（マウス）で急性毒性は認められなかつ
た。 In the compound (34) and the compound (43) according to the present invention,
No acute toxicity was observed at 100 mg / Kg ip (mouse).
本発明による化合物は、マウスエーリツヒ腹水癌細胞
から調製したチミジル酸合成酵素を阻害する作用を示
す。ジアザキノマイシンＡ（化合物Ａ）および代表的な
化合物の50％阻害濃度を第４表に示す。The compound according to the present invention exhibits an action of inhibiting thymidylate synthase prepared from mouse Ehrlich ascites tumor cells. The 50% inhibitory concentrations of diazaquinomycin A (Compound A) and representative compounds are shown in Table 4.
化合物（40）によつて、Meth-A癌細胞に対する治療試
験を行なつた結果、下記に示すように延命効果が認めら
れた。 As a result of conducting a therapeutic test on Meth-A cancer cells with the compound (40), a life prolonging effect was observed as shown below.
BALB/Cマウスでip継代されているMeth-A細胞（１×10
6細胞／マウス）を１群６匹の雌性CDFI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
ド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。Meth-A cells (1 × 10 6) that have been passaged ip in BALB / C mice
6 cells / mouse) were intraperitoneally inoculated into 6 female CDFI mice (6 weeks old) per group, and from the next day, a compound (40) suspended in dimethyl sulfoxide and gum arabic was intraperitoneally administered, I calculated the life extension rate. The results are shown in Table 5.
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。 Average survival time of the control group: 12.3 days Effect of the invention As described above, the compound according to the present invention exhibits excellent thymidylate synthase inhibitory activity and antitumor effect, and formulations containing these are advantageous as antitumor agents. It is expected to be used for.
Claims (6)
アザキノマイシンＡ誘導体。 〔式中、R1とR2の一方はメチル基で、他方は（ａ）‐
（CH2）n‐CO2R3または ‐CH2‐CH（CO2R3）2（ただしｎは０−２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（ｂ）‐CH2OR4または‐CH2OCOR4（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R1とR2は同一でも異なつてもよ
く、上記（ａ）または（ｂ）を表わす。〕1. An antibiotic diazaquinomycin A derivative represented by the following general formula (I). [In the formula, one of R 1 and R 2 is a methyl group, and the other is (a)-
(CH 2 ) n -CO 2 R 3 or -CH 2 -CH (CO 2 R 3 ) 2 (where n represents an integer of 0-2, R 3 represents hydrogen, a lower alkyl group having 1 to 5 carbon atoms) Or (b) -CH 2 OR 4 or -CH 2 OCOR 4 (provided that R 4
Is 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 R 2 may be the same or different and represent the above (a) or (b). ]
ナ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.
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。3. The compound according to claim 1, wherein the substituent of the aryl group of R 4 is a lower alkyl group, a lower alkoxy group, a halogen, a nitro group or a carboxy group.
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 aralkyl group of R 4 is an arylalkyl group.
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. The aryl of the arylalkyl group of R 4 is phenyl, tolyl or naphthyl, and the alkyl is 1 to 1 carbon atoms.
The compound of claim 4 which is 3.
ルまた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 JPS6379830A (en) | 1988-04-09 |
| JPH085880B2 true 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) |
Families Citing this family (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
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6379830A (en) | 1988-04-09 |
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