JPH0122276B2 - - Google Patents
Info
- Publication number
- JPH0122276B2 JPH0122276B2 JP53052407A JP5240778A JPH0122276B2 JP H0122276 B2 JPH0122276 B2 JP H0122276B2 JP 53052407 A JP53052407 A JP 53052407A JP 5240778 A JP5240778 A JP 5240778A JP H0122276 B2 JPH0122276 B2 JP H0122276B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- coch
- chain
- ethyl
- 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
Links
- 150000001875 compounds Chemical class 0.000 claims description 111
- -1 methoxy, propyl Chemical group 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 150000002148 esters Chemical group 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- LYYKXLNKDJVDPU-UHFFFAOYSA-N pyrano[2,3-h]quinolin-2-one Chemical class O1C=CC=C2C3=NC(=O)C=CC3=CC=C21 LYYKXLNKDJVDPU-UHFFFAOYSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- BILCUFMIUQDGEV-UHFFFAOYSA-N 4,6-dioxo-10-propyl-9h-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1N=C(C(O)=O)C=C(O)C1=C2 BILCUFMIUQDGEV-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002560 nitrile group Chemical group 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000004949 mass spectrometry Methods 0.000 description 16
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 239000003921 oil Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000012024 dehydrating agents Substances 0.000 description 8
- 239000012362 glacial acetic acid Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 229920000137 polyphosphoric acid Polymers 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 3
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 3
- 150000004820 halides Chemical group 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XOMFTESSIFMXOX-UHFFFAOYSA-N 10-bromo-4,6-dioxo-9h-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid Chemical compound BrC1=C2NC(C(=O)O)=CC(=O)C2=CC2=C1OC(C(O)=O)=CC2=O XOMFTESSIFMXOX-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 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 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 201000005298 gastrointestinal allergy Diseases 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- CYVYLVVUKPNYKL-UHFFFAOYSA-N quinoline-2,6-dicarboxylic acid Chemical compound N1=C(C(O)=O)C=CC2=CC(C(=O)O)=CC=C21 CYVYLVVUKPNYKL-UHFFFAOYSA-N 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical compound [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- AVSPCFCYVWNKGR-UHFFFAOYSA-N 2-ethoxycarbonyl-9-ethyl-4,6-dioxo-10-propylpyrano[3,2-g]quinoline-8-carboxylic acid Chemical compound C(C)OC(=O)C1=CC(C=2C=C3C(C=C(N(C3=C(C=2O1)CCC)CC)C(=O)O)=O)=O AVSPCFCYVWNKGR-UHFFFAOYSA-N 0.000 description 1
- QLVKECUOHNDWOI-UHFFFAOYSA-N 2-oxo-1,3,2$l^{5}-diazaphosphonan-2-amine Chemical compound NP1(=O)NCCCCCCN1 QLVKECUOHNDWOI-UHFFFAOYSA-N 0.000 description 1
- ZGKVRYOUJKEBAL-UHFFFAOYSA-N 2h-chromen-2-amine Chemical compound C1=CC=C2C=CC(N)OC2=C1 ZGKVRYOUJKEBAL-UHFFFAOYSA-N 0.000 description 1
- QVSKZDSGYNUVEC-UHFFFAOYSA-N 3-(ethylamino)-2-propylphenol Chemical compound CCCC1=C(O)C=CC=C1NCC QVSKZDSGYNUVEC-UHFFFAOYSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- STUCPXSXUYEBDJ-UHFFFAOYSA-N 4,10-dioxo-7h-pyrano[2,3-f]quinoline-2,8-dicarboxylic acid Chemical compound C1=CC(C(C=C(O2)C(O)=O)=O)=C2C2=C1NC(C(=O)O)=CC2=O STUCPXSXUYEBDJ-UHFFFAOYSA-N 0.000 description 1
- FXISCIQPTMQJSW-UHFFFAOYSA-N 4,9-dioxo-6h-pyrano[2,3-g]quinoline-2,7-dicarboxylic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=C1C(=O)C=C(C(=O)O)NC1=C2 FXISCIQPTMQJSW-UHFFFAOYSA-N 0.000 description 1
- XVWUGFWCTRLQBS-UHFFFAOYSA-N 5-methoxy-4,7-dioxo-10H-pyrano[3,2-h]quinoline-2,9-dicarboxylic acid Chemical compound COC1=CC=2C(C=C(NC=2C2=C1C(C=C(O2)C(=O)O)=O)C(=O)O)=O XVWUGFWCTRLQBS-UHFFFAOYSA-N 0.000 description 1
- HFVLQFQRPKKIKN-UHFFFAOYSA-N 7-(3-methylbutyl)-4,10-dioxopyrano[2,3-f]quinoline-2,8-dicarboxylic acid Chemical compound CC(CCN1C(=CC(C2=C3C(=CC=C12)C(C=C(O3)C(=O)O)=O)=O)C(=O)O)C HFVLQFQRPKKIKN-UHFFFAOYSA-N 0.000 description 1
- JZOZWPOCSWDJKR-UHFFFAOYSA-N 9-(3-methylbutyl)-4,6-dioxopyrano[3,2-g]quinoline-2,8-dicarboxylic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=C1N(CCC(C)C)C(C(O)=O)=CC(=O)C1=C2 JZOZWPOCSWDJKR-UHFFFAOYSA-N 0.000 description 1
- 208000000884 Airway Obstruction Diseases 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010006440 Bronchial obstruction Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102100039875 Histone H3-7 Human genes 0.000 description 1
- 102100038736 Histone H3.3C Human genes 0.000 description 1
- 101001035307 Homo sapiens Histone H3-7 Proteins 0.000 description 1
- 101001031505 Homo sapiens Histone H3.3C Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000009793 Milk Hypersensitivity Diseases 0.000 description 1
- 206010028748 Nasal obstruction Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- MVNOAWRGRYKESB-UHFFFAOYSA-L [Na+].N1=C(C=CC2=CC=CC(=C12)C(=O)[O-])C(=O)[O-].[Na+] Chemical compound [Na+].N1=C(C=CC2=CC=CC(=C12)C(=O)[O-])C(=O)[O-].[Na+] MVNOAWRGRYKESB-UHFFFAOYSA-L 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-N butynedioic acid Chemical compound OC(=O)C#CC(O)=O YTIVTFGABIZHHX-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- DZXIKYRDMDEUMX-UHFFFAOYSA-N diethyl 4,6-dioxo-10-propyl-9h-pyrano[3,2-g]quinoline-2,8-dicarboxylate Chemical compound O1C(C(=O)OCC)=CC(=O)C2=C1C(CCC)=C1NC(C(=O)OCC)=CC(=O)C1=C2 DZXIKYRDMDEUMX-UHFFFAOYSA-N 0.000 description 1
- VLZRJBNJUAUWAE-UHFFFAOYSA-N diethyl 9-ethyl-4,6-dioxo-10-propylpyrano[3,2-g]quinoline-2,8-dicarboxylate Chemical compound CCN1C(C(=O)OCC)=CC(=O)C2=C1C(CCC)=C1OC(C(=O)OCC)=CC(=O)C1=C2 VLZRJBNJUAUWAE-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- LDCRTTXIJACKKU-ARJAWSKDSA-N dimethyl maleate Chemical compound COC(=O)\C=C/C(=O)OC LDCRTTXIJACKKU-ARJAWSKDSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- KMGOZYUDCZKQGE-UHFFFAOYSA-N ethyl 7-amino-4-oxo-8-propylchromene-2-carboxylate Chemical compound O1C(C(=O)OCC)=CC(=O)C2=C1C(CCC)=C(N)C=C2 KMGOZYUDCZKQGE-UHFFFAOYSA-N 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000002237 fumaric acid derivatives Chemical class 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960002523 mercuric chloride Drugs 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- ZSSHNMZQDWSUJJ-UHFFFAOYSA-N n-(4-acetyl-3-hydroxyphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(C(C)=O)C(O)=C1 ZSSHNMZQDWSUJJ-UHFFFAOYSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009158 reflex pathway Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940066769 systemic antihistamines substituted alkylamines Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Description
【発明の詳細な説明】
本発明は新規ピラノキノリノン誘導体およびそ
の製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyranoquinolinone derivative and a method for producing the same.
本発明によれば、式：
〔式中、R5，R6，R7およびR8の隣接する一対
は連鎖−COCH＝CEO−を形成しており、R5，
R6，R7およびR8の残りは同一でも異つてもよく、
かつ各々、水素、ヒドロキシル基、C1−C8アル
キル基、ハロゲン、C2−C8アルケニル基、C1−
C8アルコキシ基またはNH2基を表わし；Rgは水
素または低級アルキル基を表わし；そしてＥは−
COOHを表わす〕で表わされる新規ピラノキノ
リノン誘導体およびその薬学的に許容し得る誘導
体が提供される。 According to the invention, the formula: [In the formula, an adjacent pair of R 5 , R 6 , R 7 and R 8 form a chain -COCH=CEO-, and R 5 ,
The remainder of R 6 , R 7 and R 8 may be the same or different,
and each hydrogen, hydroxyl group, C1 - C8 alkyl group, halogen, C2 - C8 alkenyl group, C1-
represents a C8 alkoxy group or an NH2 group; Rg represents hydrogen or a lower alkyl group; and E represents -
COOH] and pharmaceutically acceptable derivatives thereof are provided.
本発明のピラノキノリノン誘導体およびその薬
学的に許容し得る誘導体は下記(a)〜(c)の方法によ
り製造し得る。 The pyranoquinolinone derivatives and pharmaceutically acceptable derivatives thereof of the present invention can be produced by the following methods (a) to (c).
すなわち、(a)式
〔式中、Rgは前記の意義を有し、；R5a，R6a，
R7aおよびR8aは、R5a，R6a，R7aおよびR8aの
隣接する一対が式：−COCH＝Ｃ（D1）Ｏ−の連
鎖を表わし得るという条件で前記R5，R6，R7お
よびR8と同一の意義を有し；そして、Ｄおよび
D1は、その両方が−COOH基に加水分解または
酸化され得る基を表わすか、あるいはＤおよび
D1の一方が上記の基を表わし他方が−COOH基
を表わす〕の化合物を選択的に加水分解するかま
たは酸化することにより、前記式においてＥが
−COOHである化合物を製造するか、または、
(b)式または：
〔式中、Rgは前記の意義を有し、；R5b，R6b，
R7bおよびR8bは、R5b，R6b，R7bおよびR8bの
隣接する一対が、一対の基−Ｈおよび−Ｏ−Ｃ
（COOH）＝CH−COOHを表わすという条件で、
前記R5，R6，R7およびR8と同一の意義を有す
る〕の化合物またはそのエステルを環化すること
により、前記式においてＥが−COOHである
化合物を製造するか、または、
(c)式：
〔式中、Rgは前記の意義を有し、；R5c，R6c，
R7cおよびR8cは、下記の条件、すなわち、R5c，
R6c，R7cおよびR8cの隣接する一対が連鎖−
COCH＝Ｃ（COOH）−Ｏ−を形成する代りに、
下記の基の対：
(i) −COCH2COCOR″または−COCH＝Ｃ
（COOH）−NL1L2、またはこれらの基の適当
な誘導体；および−OMまたはハロゲン原子、
または、
(ii) −Ｈおよび−Ｏ−Ｃ（COR″）＝CH−
COR″（R″は−OMまたは、−OMに加水分解さ
れ得る基を表わし、L1およびL2は同一でも異
つてもよく、かつ、各々水素、アリール基また
はアルキル基を表わすか、またはL1およびL2
が一緒になつて飽和または不飽和アルキレン鎖
を表わし、Ｍは水素またはアルカリ金属を表わ
す）を表わすという条件で、前記R5，R6，R7
およびR8と同一の意義を有する〕の化合物ま
たはそのエステルを環化し、ついで、必要に応
じかつ所望の場合には、基−COR″を基−
COOMに転化させることにより、前記式に
おいてＥが−COOHである化合物を製造する。 In other words, equation (a) [In the formula, Rg has the above meaning; R 5 a, R 6 a,
R 7 a and R 8 a are defined as above with the condition that an adjacent pair of R 5 a, R 6 a, R 7 a and R 8 a can represent a chain of the formula: -COCH=C(D 1 )O-. have the same meaning as R 5 , R 6 , R 7 and R 8 ; and D and
D 1 represents a group, both of which can be hydrolyzed or oxidized to a -COOH group, or D and
one of D 1 represents the above-mentioned group and the other represents a -COOH group] to produce a compound in which E is -COOH in the above formula, or ,
(b) Formula or: [In the formula, Rg has the above meaning; R 5 b, R 6 b,
R 7 b and R 8 b are such that an adjacent pair of R 5 b, R 6 b, R 7 b and R 8 b is a pair of groups -H and -O-C
Provided that (COOH) = CH−COOH,
having the same meaning as the above R 5 , R 6 , R 7 and R 8 or an ester thereof to produce a compound in which E is -COOH in the above formula, or (c )formula: [In the formula, Rg has the above meaning; R 5 c, R 6 c,
R 7 c and R 8 c meet the following conditions: R 5 c,
Adjacent pairs of R 6 c, R 7 c and R 8 c are chained −
Instead of forming COCH=C(COOH)-O-,
Pairs of the following groups: (i) -COCH 2 COCOR'' or -COCH=C
(COOH)-NL 1 L 2 or suitable derivatives of these groups; and -OM or a halogen atom,
or (ii) -H and -OC(COR'')=CH-
COR''(R'' represents -OM or a group that can be hydrolyzed to -OM, L 1 and L 2 may be the same or different, and each represents hydrogen, an aryl group, or an alkyl group, or L 1 and L 2
together represent a saturated or unsaturated alkylene chain and M represents hydrogen or an alkali metal) .
and R 8 ] or its ester, and then, if necessary and desired, convert the group -COR'' into a group -
By converting to COOM, a compound in the above formula in which E is -COOH is prepared.
方法(a)において、基Ｄは、−COOH基に転化さ
れ得る基、例えばエステル基、酸ハライド基、ア
ミド基またはニトリル基であり得る。加水分解は
慣用の方法、例えば、炭酸ナトリウム、水酸化ナ
トリウム、炭酸水素ナトリウムを使用して温和な
塩基性条件下で、あるいはジオキサン水溶液と塩
酸の混合物または臭化水素酸と酢酸の混合物を使
用して、酸性条件下で行い得る。加水分解は使用
される化合物に応じて約25〜120℃の温度で行い
得る。また基Ｄはアルキル基、例えばメチル基の
ごとき低級アルキル基、ヒドロキシメチル基、ア
ラルケニル基、例えばスチリル基、アシル基、例
えばアセチル基のごとき低級アルカノイル基また
はホルミル基であり得る。酸化反応は、所望の化
合物の収率が経済的に好ましくないものになる程
度まで原料化合物の分子を変化させることのない
慣用の方法に従つて行うことができ、例えばアル
キル基またはヒドロキシメチル基の酸化は二酸化
セレンを使用してジオキサン水溶液中において還
流下で、あるいはクロム酸を使用して、酢酸水溶
液中において還流下で行い得る。アラルケニル基
の酸化は例えばエタノール水溶液中において中性
または塩基性過マンガン酸カリウムを使用して行
うことができ、アシル基の酸化は例えば、クロム
酸または次亜塩素酸水溶液、例えば次亜塩素酸ナ
トリウム水溶液を使用して行い得る。ホルミル基
の酸化は例えばクロム酸または酸化銀を使用して
行い得る。 In method (a), the group D can be a group that can be converted into a -COOH group, such as an ester group, an acid halide group, an amide group or a nitrile group. Hydrolysis can be carried out by conventional methods, for example under mild basic conditions using sodium carbonate, sodium hydroxide, sodium bicarbonate, or using a mixture of aqueous dioxane and hydrochloric acid or a mixture of hydrobromic acid and acetic acid. It can be carried out under acidic conditions. Hydrolysis may be carried out at temperatures of about 25-120°C depending on the compound used. The group D can also be an alkyl group, for example a lower alkyl group such as a methyl group, a hydroxymethyl group, an aralkenyl group, such as a styryl group, an acyl group, a lower alkanoyl group such as an acetyl group, or a formyl group. The oxidation reaction can be carried out according to conventional methods that do not alter the molecule of the starting compound to such an extent that the yield of the desired compound becomes economically unfavorable, e.g. Oxidation may be carried out using selenium dioxide in aqueous dioxane under reflux or using chromic acid in aqueous acetic acid under reflux. Oxidation of aralkenyl groups can be carried out, for example, using neutral or basic potassium permanganate in aqueous ethanol, and oxidation of acyl groups can be carried out, for example, using aqueous chromic acid or hypochlorous acid, e.g. sodium hypochlorite. This can be done using an aqueous solution. Oxidation of formyl groups can be carried out using, for example, chromic acid or silver oxide.
方法(b)において、環化は式またはの化合物
を環化剤、例えばクロルスルホン酸、硫酸または
ポリリン酸のごとき脱水剤により処理することに
より行い得る。反応は無水条件下で行うことが好
ましく、約25〜150℃、好ましくは75〜150℃の温
度で行い得る。式のマレイン酸誘導体の、式
のマレイン酸誘導体への異性化は、ポリりん酸を
使用してこれらの化合物を環化して式の化合物
にした場合に生起し、通常は好ましくないと思わ
れる式との化合物の混合物から、式の化合
物が満足すべき収率で得られる。式の化合物は
該化合物を上昇温度、例えば、200〜250℃の温度
で、場合により、反応条件下で不活性な高沸点溶
剤、例えばジフエニルエーテルの存在下で加熱す
ることによつても環化し得る。 In method (b), cyclization may be carried out by treating a compound of formula or with a cyclizing agent, for example a dehydrating agent such as chlorosulfonic acid, sulfuric acid or polyphosphoric acid. The reaction is preferably carried out under anhydrous conditions and may be carried out at a temperature of about 25-150°C, preferably 75-150°C. Isomerization of maleic acid derivatives of formula to maleic acid derivatives of formula occurs when polyphosphoric acid is used to cyclize these compounds to compounds of formula, which would normally be considered undesirable. From a mixture of compounds with, compounds of formula are obtained in satisfactory yields. Compounds of formula can also be prepared by heating the compound at elevated temperatures, e.g. 200-250° C., optionally in the presence of a high-boiling solvent inert under the reaction conditions, e.g. diphenyl ether. can be converted into
方法(c)において、一対の基(i)の一方が−OMで
ある場合には、環化反応は加熱により、あるい
は、塩基性または中性条件下で行われ得る。しか
しながら、環化反応を酸、例えば塩酸の存在下、
反応条件下で不活性な液体、例えば、エタノール
中で行うことが好ましい。反応は約20〜150℃で
行われる。基−COR″はエステル基であることが
好ましく、例えばR″は低級アルコキシ基であり
得る。一対の基(i)の一方が−COCH＝Ｃ
（COOH）−NL1L2である場合には、−COOH基の
誘導体基は基−CONL1L2（L1およびL2は前記の
意義を有する）であり得る。L1およびL2は水素、
フエニル基、炭素数１〜６個のアルキル基である
かL1とL2が一緒になつて４〜５員のアルキレン
鎖例えば窒素原子と一緒になつてピペリジン環を
形成していることが好ましい。一対の基(i)の一方
がハロゲンである場合には、環化は反応条件下で
不活性な溶剤、好ましくは高沸点極性溶剤、例え
ばピリジン、ジメチルホルムアミドまたはヘキサ
メチレンホスホルアミド中で行われ得る。反応は
強塩基、例えばアルカリ金属水素化合物、例えば
水素化ナトリウムの存在下で行うことが好まし
い。反応は約80〜200℃の温度において、遊離の
酸素の存在下、窒素のごとき不活性雰囲気で行う
ことが好ましい。 In method (c), when one of the pair of groups (i) is -OM, the cyclization reaction can be carried out by heating or under basic or neutral conditions. However, if the cyclization reaction is carried out in the presence of an acid, e.g.
Preference is given to carrying out in a liquid which is inert under the reaction conditions, for example ethanol. The reaction is carried out at approximately 20-150°C. The group -COR'' is preferably an ester group, for example R'' can be a lower alkoxy group. One of the pair of groups (i) is -COCH=C
In the case of (COOH)-NL 1 L 2 , the derivative group of the —COOH group can be the group —CONL 1 L 2 (L 1 and L 2 have the meanings given above). L 1 and L 2 are hydrogen,
It is preferable that it is a phenyl group, an alkyl group having 1 to 6 carbon atoms, or L 1 and L 2 are combined to form a piperidine ring with a 4- to 5-membered alkylene chain, for example, a nitrogen atom. . When one of the groups (i) of the pair is halogen, the cyclization is carried out in a solvent that is inert under the reaction conditions, preferably a high-boiling polar solvent, such as pyridine, dimethylformamide or hexamethylene phosphoramide. obtain. Preferably, the reaction is carried out in the presence of a strong base, such as an alkali metal hydrogen compound, such as sodium hydride. Preferably, the reaction is carried out at a temperature of about 80 DEG to 200 DEG C. in the presence of free oxygen and an inert atmosphere such as nitrogen.
方法(c)において一対の基が(ii)である場合には、
環化は式の化合物を環化剤、例えばクロルスル
ホン酸、ポリりん酸または硫酸のごとき脱水剤で
処理することにより行われる。反応は無水条件下
で行われることが好ましく、０〜100℃の温度で
行われる。別法として、環化は式の化合物の遊
離のカルボキシル基をアシルハライドに転化しつ
いで得られたアシルハライドを分子内フリーデル
ークラフト反応にかけることにより行い得る。 In method (c), when the pair of groups is (ii),
Cyclization is carried out by treating the compound of formula with a cyclizing agent, such as a dehydrating agent such as chlorosulfonic acid, polyphosphoric acid or sulfuric acid. The reaction is preferably carried out under anhydrous conditions and at a temperature of 0 to 100<0>C. Alternatively, cyclization may be carried out by converting the free carboxyl group of the compound of formula to an acyl halide and subjecting the resulting acyl halide to an intramolecular Friedel-Crafts reaction.
前記方法(b)で使用される出発物質は、式：
（式中、Rg，R5b，R6b，R7bおよびR8bは前
記と同一の意義を有する）の化合物を式：
Da−Ｃ≡Ｃ−Da
（式中、Daはエステル基を表わす）と反応さ
せて、式XIおよびXII：
（式中、Rg，Da，R5b，R6b，R7bおよびR8b
は前記と同一の意義を有する）の化合物の混合物
を製造することにより製造し得る。 The starting material used in said method (b) has the formula: (wherein, Rg, R 5 b, R 6 b, R 7 b and R 8 b have the same meanings as above), a compound of the formula: D a -C≡C-D a (wherein, D a represents an ester group) to form formulas XI and XII: (In the formula, Rg, D a , R 5 b, R 6 b, R 7 b and R 8 b
has the same meaning as above)).
式XIおよびXIIの化合物を加水分解することによ
り式および式の化合物が得られる。別法とし
て、式XIおよび式XIIの化合物中の基Daをそれ自
体慣用の方法により他の基Ｄに転化させついで得
られた化合物を前記方法(b)と同一の条件下で環化
することにより式の化合物を得ることもでき
る。他の好ましい方法は、式XIおよびXIIの化合物
を前記方法(b)と同一の条件下で環化してＤがエス
テル基である式の化合物を得、ついで得られた
式の化合物を、それ自体、前記方法(a)で使用す
るか、または、基Ｄをそれ自体既知の方法により
他の基Ｄ、例えば酸ハライド基、アミド基または
ニトリル基に転化させる方法である。 Hydrolysis of compounds of formulas XI and XII provides compounds of formulas and formulas. Alternatively, the group D a in the compounds of formulas XI and XII is converted into other groups D by methods customary per se and the resulting compounds are cyclized under the same conditions as in process (b) above. Compounds of formula can also be obtained by Another preferred method is to cyclize compounds of formulas XI and XII under the same conditions as in method (b) above to obtain compounds of formula in which D is an ester group, and then to , in process (a) above, or by converting the group D into another group D, for example an acid halide group, an amide group or a nitrile group, by methods known per se.
式XIIのフマル酸エステル異性体（またはDaが
Ｄに転化されている対応する化合物）は、環化し
て所望の式の化合物を与え得る唯一の異性体で
ある。２種の異性体の割合は核磁気共鳴スペクト
ルにより容易に測定することができるが、所望の
フマル酸誘導体は前記反応により得られる混合物
中に極めて僅かな割合でしか存在しないことが認
められている。 The fumarate ester isomer of formula XII (or the corresponding compound in which D a is converted to D) is the only isomer that can be cyclized to give a compound of the desired formula. Although the proportion of the two isomers can be easily determined by nuclear magnetic resonance spectroscopy, it has been observed that the desired fumaric acid derivative is present in only a very small proportion in the mixture obtained by said reaction. .
R5c，R6c，R7cおよびR8cの隣接する一対の基
が基−COCH2COCOR″と−OMまたはハロゲン
である式の化合物は、式：
式中、Rgは前記と同一の意義を有し、R5g，
R6g，R7gおよびR8gは、R5g，R6g，R7gおよび
R8gの隣接する対が連鎖−COCH＝CH（COOH）
−Ｏ−を形成する代りに基−COCH3および−
OMまたはハロゲン（Ｍは前記と同一の意義を有
する）を表わすという条件で、前記R5，R6，R7
およびR8と同一の意義を有する）の化合物また
はそのエステルと、式：
R′CZ−CZR″
（式中、R″は前記と同一の意義を有し、R′は
式の化合物の−COCH3基のカルバニオンと
反応性の適当な脱離基、例えばアルコキシ基、ハ
ロゲン、アミノ基、アルキルアミノ基、置換アミ
ノ基（例えばアリールスルホニルアミノ基）また
は置換アルキルアミノ基を表わし、Ｚは、各々、
カルボニル酸素原子を表わすか、あるいは、一方
のＺが２個のハロゲン原子を表わし、他方がカル
ボニル酸素原子を表わす）の化合物とを反応さ
せ、ついで必要に応じて、得られた化合物を加水
分解して式の化合物を得ることにより製造され
る。好ましい式Ｘの化合物は蓚酸ジアルキル例
えば蓚酸ジエチルである。 A compound of the formula in which a pair of adjacent groups of R 5 c, R 6 c, R 7 c and R 8 c is a group -COCH 2 COCOR'' and -OM or a halogen is a compound of the formula: In the formula, Rg has the same meaning as above, R 5 g,
R 6 g, R 7 g and R 8 g are R 5 g, R 6 g, R 7 g and
Adjacent pairs of R 8 g are linked −COCH=CH(COOH)
The groups -COCH 3 and - instead of forming -O-
The above R 5 , R 6 , R 7 with the proviso that they represent OM or halogen (M has the same meaning as above)
and R8 ) or its ester, and the compound of the formula: each represents a suitable leaving group reactive with the three carbanions, such as an alkoxy group, a halogen, an amino group, an alkylamino group, a substituted amino group (e.g. an arylsulfonylamino group) or a substituted alkylamino group;
or one Z represents two halogen atoms and the other represents a carbonyl oxygen atom), and then, if necessary, the resulting compound is hydrolyzed. It is produced by obtaining a compound of the formula: Preferred compounds of formula X are dialkyl oxalates such as diethyl oxalate.
−COCH＝Ｃ（COOH）−NL1L2基を有する式
の化合物またはその誘導体は、既知の化合物か
ら、それ自体既知の方法に従つて一工程または数
工程で製造し得る。 Compounds of the formula having the group -COCH=C(COOH)-NL 1 L 2 or derivatives thereof can be prepared from known compounds according to methods known per se in one or several steps.
式の化合物は、前記したごとき方法または前
記方法(c)（一対の基が(i)の場合の方法）に類似の
方法に従つて製造し得る。 Compounds of formula may be prepared according to methods as described above or analogous to method (c) above (method in which the pair of groups is (i)).
別法として、式の化合物は、例えば、酸ハラ
イド、アミドおよびニトリルの場合には、式の
化合物から慣用の方法に従つて、例えば式の化
合物とエステルとアンモニアとを反応させてアミ
ドを得、ついでこのアミドを脱水してニトリルを
得ることにより製造し得る。 Alternatively, compounds of the formula, for example in the case of acid halides, amides and nitrites, can be obtained from compounds of the formula according to conventional methods, for example by reacting a compound of the formula with an ester and ammonia to give an amide; The amide can then be prepared by dehydrating to obtain the nitrile.
置換基として−Ｈと−Ｏ−Ｃ（COR″）＝CH−
COR″を有する式の化合物は、式：
（式中、Rgは前記と同一の意義を有し、R5h，
R6h，R7hおよびR8hは、R5h，R6h，R7hおよび
R8hの隣接する対が連鎖−COCH＝Ｃ（COOH）−
Ｏ−を形成する代りに、基−Ｈおよび−OHを表
わすという条件で、R5，R6，R7およびR8と同一
の意義を有する）の化合物またはそのエステル
と、アセチレンジカルボン酸ジアルキルエステル
とを慣用の方法で反応させついで必要に応じて、
反応生成物を加水分解することにより製造し得
る。 -H and -OC(COR'')=CH- as substituents
Compounds of the formula with COR'' are of the formula: (In the formula, Rg has the same meaning as above, R 5 h,
R 6 h, R 7 h and R 8 h are R 5 h, R 6 h, R 7 h and
Adjacent pairs of R 8 h are linked −COCH=C(COOH)−
(having the same meaning as R 5 , R 6 , R 7 and R 8 with the proviso that instead of forming O-, the groups -H and -OH are represented) or their esters, and acetylene dicarboxylic acid dialkyl esters are reacted in a conventional manner and, if necessary,
It can be produced by hydrolyzing the reaction product.
式の化合物は：
（式中、Rgは前記と同一の意義を有し、R5i，
R6i，R7iおよびR8iは、R5i，R6i，R7iおよびR8i
の隣接する対が連鎖−COCH＝Ｃ（COOH）−Ｏ
−を形成する代りに、一対の基、−OHおよび−
COO−アルキルを表わすという条件で、前記R5，
R6，R7およびR8と同一の意義を有する）の化合
物またはそのエステルと、メチルアルキルスルホ
キシドアニオン例えばジメチルスルホキシドのア
ニオンとを反応させ、ついで得られたＯ−ヒドロ
キシ−２−アルキルスルフイニル化合物とグリオ
キシル酸またはそのエステルとを反応させること
により製造し得る。 A compound with the formula: (In the formula, Rg has the same meaning as above, R 5 i,
R 6 i, R 7 i and R 8 i are R 5 i, R 6 i, R 7 i and R 8 i
Adjacent pairs of are chained -COCH=C(COOH)-O
Instead of forming -, a pair of groups, -OH and -
On the condition that it represents COO-alkyl, the above R 5 ,
(having the same meaning as R 6 , R 7 and R 8 ) or an ester thereof with a methylalkyl sulfoxide anion, such as an anion of dimethyl sulfoxide, and then the obtained O-hydroxy-2-alkylsulfinyl It can be produced by reacting a compound with glyoxylic acid or its ester.
Ｄが−CNである式の化合物は、対応するピ
ラノキノリノンアミドを例えばオキシ塩化りんを
脱水剤として使用して脱水することにより製造し
得る。反応はピラノキノリノンアミド１モル当
り、少なくとも１モル当量の脱水剤を使用して行
うことが好ましい。脱水剤がR5，R6，R7または
R8の１個（例えば−OH基からなる置換基）と反
応する場合には、副反応と主反応の両者を満足さ
せるのに十分な脱水剤を使用すべきである。反応
は、所望ならば、酸結合剤、例えばトリエチルア
ミンの存在下で行い得る。反応は溶剤、例えば、
Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホ
キシド、ピリジン、ベンゼンまたはヘキサメチル
ホスホルアミドを存在下で行うことができ、ま
た、過剰の脱水剤を反応媒体として使用し得る。
反応は使用される脱水剤に応じて約０〜200℃の
温度で行い得る。オキシ塩化りんを使用した場合
には０〜100℃の温度が好ましい。 Compounds of the formula in which D is -CN may be prepared by dehydrating the corresponding pyranoquinolinone amide using, for example, phosphorus oxychloride as a dehydrating agent. The reaction is preferably carried out using at least one molar equivalent of dehydrating agent per mole of pyranoquinolinone amide. The dehydrating agent is R 5 , R 6 , R 7 or
When reacting with one of R 8 (e.g. a substituent consisting of an -OH group), sufficient dehydrating agent should be used to satisfy both the side and main reactions. The reaction may be carried out in the presence of an acid binder, such as triethylamine, if desired. The reaction takes place in a solvent, e.g.
It can be carried out in the presence of N,N-dimethylformamide, dimethylsulfoxide, pyridine, benzene or hexamethylphosphoramide and an excess of dehydrating agent can be used as reaction medium.
The reaction may be carried out at temperatures of about 0-200°C depending on the dehydrating agent used. When using phosphorus oxychloride, a temperature of 0 to 100°C is preferred.
クロモンアミド出発原料は対応するピラノキノ
リノンエステルとアンモニアとを、エステルから
アミドを製造する際の慣用の方法に従つて、例え
ば溶剤としてアルカノールを使用して、０〜120
℃の温度で反応させることにより製造し得る。 The chromon amide starting material is prepared by combining the corresponding pyranoquinolinone ester and ammonia in the range 0 to 120, according to conventional methods for preparing amides from esters, e.g. using an alkanol as the solvent.
It can be produced by reacting at a temperature of °C.
式，，，，，およびの
化合物は既知の化合物であるか、既知の化合物か
らそれ自体既知の方法により製造し得る。 The compounds of the formulas, , , , and are known compounds or can be prepared from known compounds by methods known per se.
上記したごとき方法により式の化合物または
その誘導体を製造し得る。かく得られた工程の誘
導体を処理して遊離の式の化合物を得ることお
よび一つの誘導体を他の誘導体に転化させること
も本発明の範囲に包含される。 Compounds of formula or derivatives thereof may be prepared by methods such as those described above. It is also within the scope of this invention to process the derivatives of the process thus obtained to obtain the free formula compounds and to convert one derivative to another.
式の化合物およびその中間体はその反応混合
物から任意の方法により単離し得る。 Compounds of formula and intermediates thereof may be isolated from the reaction mixture by any method.
式の化合物の薬学的に許容し得る誘導体は薬
学的に許容し得る塩類およびＥが−COOH基で
ある場合は２−カルボン酸基のエステルおよびア
ミドを包含する。適当な塩はアンモニウム塩、ア
ルカリ金属塩（例えば、ナトリウム、カリウムお
よびリチウム塩）およびアルカリ土類金属塩（例
えばウルシウムまたはマグネシウム塩）ならびに
適当な有機塩基との塩、例えばヒドロキシルアミ
ンとの塩；メチルアミンまたはエチルアミンのご
とき低級アルキルアミンとの塩；置換低級アルキ
ルアミン、例えばトリス（ヒドロキシメチル）メ
チルアミンのごときヒドロキシ置換アルキルアミ
ンとの塩または簡単な単環式窒素含有複素環化合
物、例えば、ピペリジンまたはモルホリンとの塩
を包含する。適当なエステルは、簡単な低級アル
キルエステル、例えばメチルエステル；塩基性基
を含有するアルコール、例えばジ−低級アルキル
アミノ置換アルカノールから誘導されるエステ
ル、例えばβ−（ジエチルアミノ）−エチルエステ
ル；およびアシルオキシアルキルエステル例えば
ピバロイルオキシメチルエステルのごとき低級ア
ルコキシ−低級アルキルエステル、またはジヒド
ロキシ化合物から誘導されるビス−エステル、例
えば、ビス−２−オキサプロパン−１，３−ジイ
ルエステルのごときジ（ヒドロキシ−低級アルキ
ル）エステルを包含する。塩基性エステルおよび
R5，R6，R7およびR8の一つが基NH2である式
の化合物の薬学的に許容し得る酸付加塩、例えば
塩酸塩、臭化水素酸塩、蓚酸塩、マレイン酸塩ま
たはフマル酸塩も使用し得る。上記エステルは慣
用の方法、例えばエステル化またはエステル交換
により製造し得る。アミドは例えば不飽和または
モノ−またはジ−アルキル（炭素数１〜６個）ア
ミドであることができ、そして、慣用の方法、例
えば対応する酸のエステルとアンモニアまたは適
当なアミンとの反応により製造し得る。 Pharmaceutically acceptable derivatives of compounds of formula include pharmaceutically acceptable salts and esters and amides of the 2-carboxylic acid group when E is a -COOH group. Suitable salts are ammonium salts, alkali metal salts (for example sodium, potassium and lithium salts) and alkaline earth metal salts (for example ursium or magnesium salts) and salts with suitable organic bases, for example salts with hydroxylamine; methyl salts with amines or lower alkyl amines such as ethylamine; salts with substituted lower alkyl amines, e.g. hydroxy-substituted alkyl amines such as tris(hydroxymethyl)methylamine, or simple monocyclic nitrogen-containing heterocycles, e.g. piperidine or Includes salts with morpholine. Suitable esters are simple lower alkyl esters, such as methyl esters; esters derived from alcohols containing basic groups, such as di-lower alkylamino-substituted alkanols, such as β-(diethylamino)-ethyl ester; and acyloxyalkyl esters. esters such as lower alkoxy-lower alkyl esters, such as pivaloyloxymethyl ester, or bis-esters derived from dihydroxy compounds, such as di(hydroxy-lower alkyl) esters. basic ester and
Pharmaceutically acceptable acid addition salts of compounds of formula wherein one of R 5 , R 6 , R 7 and R 8 is the group NH 2 , such as hydrochloride, hydrobromide, oxalate, maleate or Fumarate salts may also be used. The esters mentioned above may be prepared by conventional methods such as esterification or transesterification. Amides can be, for example, unsaturated or mono- or di-alkyl (1 to 6 carbon atoms) amides and are prepared in conventional manner, for example by reaction of an ester of the corresponding acid with ammonia or a suitable amine. It is possible.
式の化合物および薬学的に許容し得る誘導体
は、動物に対して薬学的活性を有するという理由
で有用である。特に上記化合物は、ある種の抗体
と特定の抗原、例えばレアジン的（reaginic）抗
体と特定の抗原の体内での結合により生ずる薬理
的調停器（mediatiors）の解放（release）およ
び（または）作用を抑制するという理由で有用で
ある（英国特許第1292601号明細書の実施例27参
照）。本発明の新規化合物は被験動物および人の
反射系統、特に肺の機能に附随する反射系統を抑
制することも認められた。人においては、特定の
抗原が感作された被験者によつて吸入されること
により生ずる自覚的および客観的変化が、本発明
の新規化合物を予め投与することにより阻止され
る。従つて本発明の化合物は可逆性気道閉塞症の
処置及び／又は過度の粘度の分泌の抑制に有用で
ある。従つて上記化合物はアレルギー性喘息、い
わゆる“内存性”（intrinsic）喘息（この場合に
は外性抗原に対する感応性は示されない）、気管
支炎、咳および普通の風邪に伴う鼻および気管支
の閉塞症の処置に使用される。本発明の新規化合
物は、また、抗原−抗体反応または過度の粘液の
分泌が病気の原因であるかまたはこれらの現象を
伴う病気、例えば枯草喘息、ある種の眼病、例え
ばトラホーム；食餌性アレルギー、例えばじんま
しん、および過敏性湿疹；および胃腸秒、例え
ば、特に子供の胃腸アレルギー、例えばミルクア
レルギーまたは潰瘍性大腸炎の処理にも有用であ
る。 Compounds of formula and pharmaceutically acceptable derivatives are useful because they have pharmaceutical activity in animals. In particular, the compounds mentioned above may stimulate the release and/or action of pharmacological mediatiors resulting from the binding of certain antibodies and certain antigens, such as reaginic antibodies and certain antigens, in the body. It is useful for inhibiting reasons (see Example 27 of GB 1292601). The novel compounds of the present invention have also been found to inhibit reflex systems in test animals and humans, particularly reflex systems associated with lung function. In humans, the subjective and objective changes caused by inhalation of specific antigens by sensitized subjects are prevented by prior administration of the novel compounds of the invention. The compounds of the present invention are therefore useful in treating reversible airway obstruction and/or inhibiting excessively viscous secretions. The above-mentioned compounds may therefore be used to treat allergic asthma, so-called "intrinsic" asthma (in which no sensitivity to exogenous antigens is shown), bronchitis, nasal and bronchial obstruction associated with coughs and the common cold. used for the treatment of The novel compounds of the invention may also be used to treat diseases in which antigen-antibody reactions or excessive mucus secretion are the cause of or are accompanied by these phenomena, such as hay fever, certain eye diseases, such as trachoma; dietary allergies; It is also useful in the treatment of gastrointestinal allergies, such as urticaria, and hypersensitivity eczema; and gastrointestinal allergies, especially in children, such as milk allergies or ulcerative colitis.
上記したごとき用途については、投与量は勿
論、使用される化合物、投与形態および所望の処
理に応じて変動するであろう。しかしながら、通
常、英国特許第1292601号明細書の実施例27に記
載される試験においては動物の体重１Kg当り
0.001〜50mgを投与した場合に満足すべき結果が
得られる。人については、指示された一日の全投
与量は0.01〜1000mg、好ましくは0.01〜200mg、
より好ましくは１〜60mgであり、これを１日１〜
６回に分けて投与するか、持効性投与形態で投与
し得る。例えば（吸引または食道経由の）適当な
単位投与薬剤は、前記化合物の0.01〜50mg、好ま
しくは0.01〜20mg、より好ましくは0.01〜10mg
を、好ましくは、固体または液体の薬学的に許容
し得る稀釈剤、担体または助剤と混合したものか
らなる。 For such uses as described above, the dosage administered will, of course, vary depending on the compound used, the mode of administration and the treatment desired. However, usually in the test described in Example 27 of GB 1292601,
Satisfactory results are obtained when doses of 0.001 to 50 mg are administered. For humans, the total daily dose indicated is 0.01-1000mg, preferably 0.01-200mg,
More preferably 1 to 60 mg, 1 to 60 mg per day.
It may be administered in six divided doses or in a sustained release dosage form. For example, suitable unit dosages (by inhalation or via the esophagus) include 0.01 to 50 mg, preferably 0.01 to 20 mg, more preferably 0.01 to 10 mg of said compound.
, preferably mixed with solid or liquid pharmaceutically acceptable diluents, carriers or auxiliaries.
式の化合物および薬学的に許容し得る誘導体
は、ある種の薬理学的製剤においては、式の化
合物に構造の類似する化合物に比べて効果がより
大きくあるいはより長時間効果を示すという利点
を有する。更に、式の化合物およびその薬学的
に許容し得る誘導体は、式の化合物に構造が類
似する化合物に比べて、反射経路を抑制する効果
および粘液の分泌を阻止する効果がより大きいと
いう利点を有する。 The compounds of the formula and their pharmaceutically acceptable derivatives have the advantage in certain pharmacological formulations of greater or longer-lasting effects than compounds structurally similar to the compounds of the formula. . Furthermore, the compounds of formula and their pharmaceutically acceptable derivatives have the advantage that they are more effective in inhibiting reflex pathways and in inhibiting mucus secretion than compounds structurally similar to compounds of formula .
Rg，R5，R6，R7およびR8の各々が炭素原子を
含有している場合には、その炭素数は８個まで、
好ましくは４個まであることが好ましい。特に、
R5，R6，R7およびR8は水素、メトキシ基、プロ
ピル基、アリル基、メチル基、エチル基、塩素、
臭素およびヒドロキシ基から選ばれることが好ま
しい。連鎖−COCH＝CE−Ｏ−は、いかなる意
味においても、また、隣接する位置R5，R6，R7
およびR8のいずれにおいても、ベンゼン環に結
合し得る。しかしながら、上記の連鎖がR6とR7
の位置で結合しており、そして連鎖の−Ｏ−の部
分がR7の位置であることが好ましい。 When each of Rg, R 5 , R 6 , R 7 and R 8 contains a carbon atom, the number of carbon atoms is up to 8,
Preferably, there are up to four pieces. especially,
R 5 , R 6 , R 7 and R 8 are hydrogen, methoxy group, propyl group, allyl group, methyl group, ethyl group, chlorine,
Preferably it is selected from bromine and hydroxy groups. The chain -COCH=CE-O- in any sense also includes the adjacent positions R 5 , R 6 , R 7
and R 8 can be bonded to a benzene ring. However, if the above chain is R 6 and R 7
and the -O- portion of the chain is preferably at the R7 position.
本発明によれば、更に、式ｃ；
（式中、Rgは前記と同一の意義を有し、R5j，
R6j，R7jおよびR8jは、R5j，R6j，R7jおよびR8j
の隣接する一対が連鎖−Ｏ−Ｃ（Ｘ）＝CHCO−を
表わし得るという条件で、前記R5，R6，R7およ
びR8と同一の意義を有し、Ｘはカルボン酸基ま
たはそのエステル基または他の塩を表わす）の化
合物を、利用し得る、薬学的に許容され得るカチ
オンを含有する、かつ、基ＸをＥ基の薬学的に許
容し得る塩に転化し得る化合物で処理することを
特徴とする、式の化合物の薬学的に許容し得る
塩の製造方法が提供される。 According to the invention, furthermore, formula c; (In the formula, Rg has the same meaning as above, R 5 j,
R 6 j, R 7 j and R 8 j are R 5 j, R 6 j, R 7 j and R 8 j
have the same meaning as R 5 , R 6 , R 7 and R 8 above, with the proviso that an adjacent pair of can represent the chain -O-C(X)=CHCO-, and X is a carboxylic acid group or its (representing an ester group or other salt) with a compound containing an available pharmaceutically acceptable cation and capable of converting the group X into a pharmaceutically acceptable salt of the group E. There is provided a method for preparing a pharmaceutically acceptable salt of a compound of formula:
基ＸをＥ基の薬学的に許容し得る塩に転化させ
得る化合物は、塩基および薬学的に許容し得るカ
チオン、例えばナトリウム、カリウム、カルシウ
ム、アンモニウムおよび適当な窒素含有有機カチ
オンを含有するイオン交換樹脂を包含する。 Compounds capable of converting the group Includes resin.
式の遊離の酸を適当な塩基、例えばアルカリ
土類金属またはアルカリ金属水酸化物、炭酸塩ま
たは重炭酸塩を使用して水溶液中で処理すること
により、あるいは適当な塩を使用して複分解を行
うことにより薬学的に許容し得る塩を形成させる
ことが好ましい。強塩基性化合物を使用する場合
には、温度を十分に低く保持して式の化合物が
加水分解あるいは分解されないように注意する必
要がある。薬学的に許容し得る塩は、例えば溶剤
沈澱および（または）蒸発による溶剤の除去、例
えば凍結乾燥により反応混合物から回収し得る。 By treating the free acid of the formula with a suitable base such as an alkaline earth metal or alkali metal hydroxide, carbonate or bicarbonate in aqueous solution, or by metathesis using a suitable salt. It is preferred to form a pharmaceutically acceptable salt by doing so. When using strongly basic compounds, care must be taken to keep the temperature low enough to prevent hydrolysis or decomposition of the compound of formula. The pharmaceutically acceptable salt may be recovered from the reaction mixture by removal of the solvent, eg, by solvent precipitation and/or evaporation, eg, lyophilization.
本発明によれば、更に、（好ましくは80重量％
以下、より好ましくは50重量％以下の）式の化
合物またはその薬学的に許容し得る誘導体と、薬
学的に許容し得る助剤、稀釈剤または担体とから
なる薬剤組成物が提供される。適当な助剤、稀釈
剤または担体の例としては、つぎのものが挙げら
れる；錠剤、カプセルおよび糖剤については、微
晶質セルロース、りん酸カルシウム、ケイソウ
土、ラクトース、デキストロースまたはマニトー
ルのごとき蔗糖、タルク、ステアリン酸、でんぷ
ん、炭酸水素ナトリウムおよび（または）ゼラチ
ン；坐薬については、天然または硬化油、または
ワツクス；吸引用組成物いついては粗大なラクト
ース。 According to the invention, furthermore, (preferably 80% by weight)
There is provided a pharmaceutical composition comprising a compound of formula (hereinafter more preferably 50% by weight or less) or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable auxiliary, diluent or carrier. Examples of suitable auxiliaries, diluents or carriers include; for tablets, capsules and dragees, microcrystalline cellulose, calcium phosphate, diatomaceous earth, sucrose such as lactose, dextrose or mannitol; , talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories, natural or hydrogenated oils, or wax; for inhalable compositions, coarse lactose.
式の化合物またはその薬学的に許容し得る誘
導体は、0.01〜10ミクロンの平均直径
（massmedian diameter）を有することが好まし
い。薬剤組成物は適当な防腐剤、安定剤および湿
潤剤、可溶化剤、甘味料、着色剤および香料も含
有し得る。組成物は所望に応じ、持効性形態のも
のであり得る。薬剤組成物は食道を経由して摂取
され、胃腸管内でその内容物を放出する形態であ
ることが好ましい。 Preferably, the compound of formula or a pharmaceutically acceptable derivative thereof has a mass median diameter of 0.01 to 10 microns. The pharmaceutical compositions may also contain suitable preservatives, stabilizing and wetting agents, solubilizing agents, sweetening agents, coloring agents, and flavoring agents. The compositions can be in sustained release form, if desired. Preferably, the pharmaceutical composition is in a form that is ingested via the esophagus and releases its contents within the gastrointestinal tract.
以下に本発明の実施例を示す。 Examples of the present invention are shown below.
実施例 １
６，９−ジヒドロ−４，６−ジオキソ−10−プ
ロピル−4H−ピラノ［３，２−ｇ］キノリン
−２，８−ジカルボン酸
(a) ４−アセトアミド−２−アリルオキシアセト
フエノン
４−アセトアミド−２−ヒドロキシアセトフエ
ノン（19.3ｇ）、臭化アリル（12.1ml）および無
水炭酸カリウム（21.5ｇ）を無水ジメチルホルム
アミド（250ml）中において24時間室温で撹拌し
た。反応混合物を水に注入し、ついで生成物を酢
酸エチルで抽出した。ついで有機溶液を水で十分
洗浄し、硫酸マグネシウム上で乾燥した後、溶剤
を蒸発乾固させた。かくして、上記目的化合物(a)
の淡黄色固体（20.5ｇ）を得た。この化合物の構
造はN.M.Rおよび質量スペクトル分析により確
認した。Example 1 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid (a) 4-acetamido-2-allyloxyacetophenone 4-acetamido-2-hydroxyacetophenone (19.3 g), allyl bromide (12.1 ml) and anhydrous potassium carbonate (21.5 g) were dissolved in anhydrous dimethylformamide (250 ml). ) for 24 hours at room temperature. The reaction mixture was poured into water and then the product was extracted with ethyl acetate. The organic solution was then thoroughly washed with water, dried over magnesium sulphate and the solvent was evaporated to dryness. Thus, the above target compound (a)
A pale yellow solid (20.5 g) was obtained. The structure of this compound was confirmed by NMR and mass spectrometry.
(b) ４−アセトアミド−３−アリル−２−ヒドロ
キシアセトフエノン
工程(a)で得たアリルエーテル（18.4ｇ）を200
〜210℃で４時間加熱した。かくして熱転位化合
物(b)の褐色結晶を得た。同様に構造をN.M.Rお
よび質量スペクトル分析により確認した。(b) 4-acetamido-3-allyl-2-hydroxyacetophenone The allyl ether (18.4 g) obtained in step (a) was
Heated at ~210°C for 4 hours. In this way, brown crystals of thermally rearranged compound (b) were obtained. Similarly, the structure was confirmed by NMR and mass spectrometry.
(c) ４−アセトアミド−２−ヒドロキシ−３−プ
ロピルアセトフエノン
工程(b)の生成物（17ｇ）を氷酢酸中に溶解し、
アダムス触媒（Adams catalyst）の存在下で、
水素の吸収が止むまで水添した。触媒をケイソウ
土により濾別した後、濾液を蒸発させて、殆んど
無色の固体13.0ｇを得た。この生成物の構造をN.
M.Rおよび質量スペクトル分析により確認した。(c) 4-acetamido-2-hydroxy-3-propylacetophenone The product of step (b) (17 g) was dissolved in glacial acetic acid;
In the presence of Adams catalyst,
Hydrogenation was continued until hydrogen absorption stopped. After filtering off the catalyst through diatomaceous earth, the filtrate was evaporated to give 13.0 g of an almost colorless solid. The structure of this product is N.
Confirmed by MR and mass spectrometry.
(d) ７−アセトアミド−４−オキソ−８−プロピ
ル−4H−１−ベンゾピラン−２−カルボン酸
エチルエステル
蓚酸ジエチル（19.3ｇ、17.9ml）、工程(c)の生
成物（12.4ｇ）および無水エタノール（100ml）
からなる混合物を、ナトリウムエトキシドとエタ
ノールからなる撹拌されている溶液（ナトリウム
6.1ｇをエタノール200mlに溶解して調製）に添加
した。反応混合物を３時間還流させついで稀塩酸
とクロロホルムからなる溶液中に注入した。クロ
ロホルム層を分離し、水洗しついで乾燥した。溶
剤を蒸発させて褐色固体を得、これを濃塩酸（３
ml）を含有するエタノール（300ml）中に溶解し、
全体を１時間還流させた。反応混合物を水に注入
し、ついで酢酸エチルで抽出し、抽出液を水洗
し、乾燥させた。溶剤を蒸発させて10ｇの粘着性
固体を得た。この生成物のN.M.Rおよび質量ス
ペクトル分析の結果は所望の化合物のものと一致
した。(d) 7-acetamido-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid ethyl ester diethyl oxalate (19.3 g, 17.9 ml), the product of step (c) (12.4 g) and anhydrous Ethanol (100ml)
A stirred solution of sodium ethoxide and ethanol (sodium
(prepared by dissolving 6.1 g in 200 ml of ethanol). The reaction mixture was refluxed for 3 hours and then poured into a solution consisting of dilute hydrochloric acid and chloroform. The chloroform layer was separated, washed with water and dried. Evaporation of the solvent gave a brown solid, which was dissolved in concentrated hydrochloric acid (3
ml) in ethanol (300 ml) containing
The whole was refluxed for 1 hour. The reaction mixture was poured into water, then extracted with ethyl acetate, and the extract was washed with water and dried. Evaporation of the solvent gave 10 g of sticky solid. NMR and mass spectrometry analysis of this product were consistent with the desired compound.
(e) ７−アミノ−４−オキソ−８−プロピル−
4H−１−ベンゾピラン−２−カルボン酸エチ
ルエステル
工程(d)で得られたアミド（10ｇ）、エタノール
（300ml）および濃塩酸（５ml）からなる溶液を８
時間還流させた。反応混合物を水で稀釈しついで
酢酸エチルで抽出した。抽出液を水洗し、乾燥し
ついで溶剤を蒸発させて、黒褐色半固体を得た。
この生成物を溶離剤としてエーテルを使用してシ
リカゲルカラム上でクロマトグラフイーにかけて
目的化合物4.8ｇを得た。この化合物の構造をN.
M.Rおよび質量スペクトル分析により確認した。
融点84〜87℃。(e) 7-amino-4-oxo-8-propyl-
4H-1-Benzopyran-2-carboxylic acid ethyl ester A solution consisting of the amide (10 g) obtained in step (d), ethanol (300 ml) and concentrated hydrochloric acid (5 ml) was
Refluxed for an hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated to give a dark brown semi-solid.
The product was chromatographed on a silica gel column using ether as eluent to obtain 4.8 g of the desired compound. The structure of this compound is N.
Confirmed by MR and mass spectrometry.
Melting point 84-87℃.
(f) ２−エトキシカルボニル−８−メトキシカル
ボニル−10−プロピル−4H−ピラノ［３，２
−ｇ］キリノン−４，６−（9H）−ジオン
工程(e)で得られたアミノベンゾピラン（2.0ｇ）
とアセチレンジカルボン酸ジメチルエステル
（1.24ｇ；1.01ml）をエタノール（30ml）中で26
時間還流させた。反応混合物を０℃に冷却して不
溶性黄褐色固体を濾過により捕集し、ついで洗浄
し、乾燥して、アミンをアセチレンに付加させる
ミカエル（Michael）付加反応で得られるマレイ
ン酸エステルとフマル酸エステルの混合物である
生成物2.0ｇを得た。(f) 2-ethoxycarbonyl-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2
-g] Quirinone-4,6-(9H)-dione Aminobenzopyran obtained in step (e) (2.0g)
and acetylene dicarboxylic acid dimethyl ester (1.24 g; 1.01 ml) in ethanol (30 ml) at 26
Refluxed for an hour. The reaction mixture is cooled to 0° C. and the insoluble yellow-brown solid is collected by filtration, then washed and dried to form maleate and fumarate esters obtained by a Michael addition reaction in which an amine is added to acetylene. 2.0 g of product was obtained which is a mixture of.
このエステル混合物（2.0ｇ）とポリりん酸
（30ml）を水蒸気浴上で攪拌しながら20分間加熱
した。ついで反応混合物を水上に注入しついで酢
酸エチルと共に攪拌した。有機層を分離し、水洗
しついで乾燥した。溶剤を蒸発させて、橙黄色固
体1.6ｇを得た。この固体を酢酸エチルから再結
晶させて綿毛状の黄色針状結晶（融点187〜188
℃）を得た。 This ester mixture (2.0 g) and polyphosphoric acid (30 ml) were heated on a steam bath with stirring for 20 minutes. The reaction mixture was then poured onto water and stirred with ethyl acetate. The organic layer was separated, washed with water and dried. Evaporation of the solvent gave 1.6 g of an orange-yellow solid. This solid was recrystallized from ethyl acetate to form fluffy yellow needles (melting point 187-188).
°C) was obtained.
分析値
実測値 C62.0 H5.1 N3.7％
C20H19NO7の
理論値 C62.3 H4.9 N3.6％
(g) ６，９−ジヒドロ−４，６−ジオキソ−10−
プロピル−4H−ピラノ［３，２−ｇ］キノリ
ン−２，８−ジカルボン酸
工程(f)で得たビスエステル（2.5ｇ）を炭酸水
素ナトリウム（1.64ｇ）とともに、エタノール
（100ml）と水（50ml）中で1.5時間還流させた。
反応混合物を水に注入し、酸性化して、ゼラチン
状固体を得た。この生成物を濾過により捕集しつ
いでエタノールとともに還流させ、ついで遠心分
離により分離した（1.4ｇ、融点303〜304℃−分
解）。この生成物の構造を質量およびN.M.Rスペ
クトル分析により確認した。Analytical value Actual value C62.0 H5.1 N3.7% C 20 H 19 Theoretical value of NO 7 C62.3 H4.9 N3.6% (g) 6,9-dihydro-4,6-dioxo-10-
Propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid The bisester (2.5 g) obtained in step (f) was mixed with sodium bicarbonate (1.64 g), ethanol (100 ml) and water ( 50 ml) for 1.5 hours.
The reaction mixture was poured into water and acidified to give a gelatinous solid. The product was collected by filtration and refluxed with ethanol, then separated by centrifugation (1.4 g, mp 303-304 DEG - decomposed). The structure of this product was confirmed by mass and NMR spectroscopy.
(h) ６，９−ジヒドロ−４，６−ジオキソ−10−
プロピル−4H−ピラノ［３，２−ｇ］キノリ
ン−２，８−ジカルボン酸二ナトリウム
工程(g)で得られたジカルボン酸（1.35ｇ）と炭
酸水素ナトリウム（0.661ｇ）を水（150ml）中で
攪拌しつつ加温して透明な溶液を得た。この溶液
を濾過し、濾液を凍結乾燥して、所望の二ナトリ
ウム塩1.43ｇを得た。(h) 6,9-dihydro-4,6-dioxo-10-
Propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid disodium Dicarboxylic acid (1.35 g) obtained in step (g) and sodium hydrogen carbonate (0.661 g) in water (150 ml) A clear solution was obtained by heating with stirring. The solution was filtered and the filtrate was lyophilized to yield 1.43 g of the desired disodium salt.
分析値
実測値 C46.1 H4.0 N2.9％
C17H11NO7Na212.5％H2Oについての
理論値 C46.1 H3.8 N3.15％
実施例 ２
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−
ｇ］キリノン−２，８−ジカルボン酸
(a) ４−（Ｎ−アセチル−Ｎ−エチル）アミノ−
２−アリルオキシアセトフエノン
４−（Ｎ−アセチル−Ｎ−エチル）アミノ−２
−ヒドロキシアセトフエノン（92.6ｇ）、臭化ア
リル（51ml）および無水炭酸カリウム（90.4ｇ）
を無水ジメチルホルムアミド（500ml）中で17時
間、攪拌した。反応混合物を水に注入しついで生
成物をエーテルで抽出した。ついで有機層を十分
水洗し、硫酸マグネシウム上で乾燥しついで溶剤
を蒸発させて、油状生成物（102.5ｇ）を得た。
この生成物の構造はN.M.Rおよび質量スペクト
ル分析により確認した。Analytical value Actual value C46.1 H4.0 N2.9% C 17 H 11 NO 7 Na 2 12.5% Theoretical value for H 2 O C46.1 H3.8 N3.15% Example 2 9-ethyl-6, 9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g] Quirinone-2,8-dicarboxylic acid (a) 4-(N-acetyl-N-ethyl)amino-
2-allyloxyacetophenone 4-(N-acetyl-N-ethyl)amino-2
-Hydroxyacetophenone (92.6g), allyl bromide (51ml) and anhydrous potassium carbonate (90.4g)
was stirred in anhydrous dimethylformamide (500ml) for 17 hours. The reaction mixture was poured into water and the product was extracted with ether. The organic layer was then thoroughly washed with water, dried over magnesium sulphate and the solvent was evaporated to give an oily product (102.5g).
The structure of this product was confirmed by NMR and mass spectrometry.
(b) ４−（Ｎ−アセチル−Ｎ−エチル）アミノ−
３−プロロピル−２−ヒドロキシアセトフエノ
ン
工程(a)で得られたアリルエーテル（100.5ｇ）
をジエチルアニリン（300ml）中で３時間還流さ
せた。反応混合物を冷却させた後、稀塩酸中に注
入しついでエーテルで抽出し、抽出物を稀塩酸お
よびついで水で洗浄した。有機溶液を10％水酸化
ナトリウム溶液で抽出しついで酸性化した。沈澱
した生成物をエーテルで抽出し、硫酸マグネシウ
ム上で乾燥した。得られたエーテル溶液を蒸発乾
固させて黄褐色油状物（78.7ｇ）を得た。この油
状物は４−（Ｎ−アセチル−Ｎ−エチル）アミノ
−３−アリル−２−ヒドロキシアセトフエノンと
６−（Ｎ―アセチル−Ｎ−エチル）アミノ−３−
アリル−２−ヒドロキシアセトフエノンの混合物
であつた。(b) 4-(N-acetyl-N-ethyl)amino-
3-Prolopyl-2-hydroxyacetophenone Allyl ether obtained in step (a) (100.5g)
was refluxed in diethylaniline (300ml) for 3 hours. After the reaction mixture was cooled, it was poured into dilute hydrochloric acid and extracted with ether, and the extract was washed with dilute hydrochloric acid and then water. The organic solution was extracted with 10% sodium hydroxide solution and then acidified. The precipitated product was extracted with ether and dried over magnesium sulfate. The resulting ether solution was evaporated to dryness to give a tan oil (78.7g). This oil consists of 4-(N-acetyl-N-ethyl)amino-3-allyl-2-hydroxyacetophenone and 6-(N-acetyl-N-ethyl)amino-3-
It was a mixture of allyl-2-hydroxyacetophenones.
上記混合物をエタノール（500ml）と氷酢酸と
の混合物中に溶解しついでアダム触媒の存在下
で、水素の吸収が止むまで水添した。触媒をケイ
ソウ土により濾別し、ついで濾液を蒸発させて
79.9ｇの褐色油状物を得た。この油状物は混合物
であり、これを溶離剤としてエーテル／石油エー
テル（１：１）混合物を使用して高圧液相クロマ
トグラフイーにより分離して、化合物(b)44.2ｇと
６−（Ｎ−アセチル−Ｎ−エチル）アミノ−３−
プロピル−２−ヒドロキシアセトフエノン23.8ｇ
を得た。 The above mixture was dissolved in a mixture of ethanol (500ml) and glacial acetic acid and hydrogenated in the presence of Adam's catalyst until hydrogen uptake ceased. The catalyst was filtered off through diatomaceous earth and the filtrate was evaporated.
79.9 g of brown oil was obtained. This oil was a mixture which was separated by high pressure liquid phase chromatography using an ether/petroleum ether (1:1) mixture as eluent to give 44.2 g of compound (b) and 6-(N- acetyl-N-ethyl)amino-3-
Propyl-2-hydroxyacetophenone 23.8g
I got it.
(c) ４−Ｎ−エチルアミノ−３−プロピル−２−
ヒドロキシアセトフエノン
４−（Ｎ−アセチル−Ｎ−エチル）アミノ−３
−プロピル−２−ヒドロキシアセトフエノン（44
ｇ）を、氷酢酸（100ml）中の臭化水素酸の48％
溶液、氷酢酸（500ml）および水（20ml）中で６
時間還流させた。反応混合物を氷水中に注入しつ
いで酢酸エチル中で抽出し、抽出液を水、炭酸水
素ナトリウム溶液および水で順次洗浄し、ついで
硫酸マグネシウム上で乾燥した。有機溶剤を蒸発
乾固させて、化合物(b)の赤色油状物（34ｇ）を得
た。この生成物の構造をN.M.Rおよび質量スペ
クトル分析で確認した。(c) 4-N-ethylamino-3-propyl-2-
Hydroxyacetophenone 4-(N-acetyl-N-ethyl)amino-3
-Propyl-2-hydroxyacetophenone (44
g), 48% of hydrobromic acid in glacial acetic acid (100ml)
solution, 6 in glacial acetic acid (500 ml) and water (20 ml)
Refluxed for an hour. The reaction mixture was poured into ice water and extracted into ethyl acetate, the extract was washed successively with water, sodium bicarbonate solution and water, and then dried over magnesium sulfate. The organic solvent was evaporated to dryness to obtain compound (b) as a red oil (34 g). The structure of this product was confirmed by NMR and mass spectrometry analysis.
(d) ６−アセチル−１−エチル−７−ヒドロキシ
―８−プロピル−１，４−ジヒドロ−４−オキ
ソ−キノリン−２−カルボン酸メチルエステル
工程(c)で得られたアミン化合物（17ｇ）とアセ
チレンジカルボン酸ジメチルエステル（11.3ml）
をエタノール（300ml）中で17時間還流させた。
反応混合物を冷却しついで溶剤を蒸発乾固させて
深赤色油状物を得た。この油状物を溶離剤として
エーテル／石油エーテル（１：１）混合物を使用
してシリカゲルカラム上でクロマトグラフにかけ
て、１−［Ｎ−（４−アセチル−３−ヒドロキシ−
２−プロピルフエニル）−Ｎ−エチルアミノ］マ
レイン酸ジメチルエステル19.1ｇ（融点83−87
℃）を得た。このマレイン酸エステル（５ｇ）と
ポリりん酸（100ml）を水蒸気浴上で10分間、加
熱攪拌した。反応混合物を冷却した後、氷水と酢
酸エチル混合物中に注入した。有機溶液を分離し
た後、水洗しついで硫酸マグネシウム上で乾燥し
た。溶剤を蒸発乾固させて淡黄色固体を得た。こ
の生成物を高圧液体クロマトグラフイーにより精
製して化合物(d)（融点121〜123℃）2.6ｇを得た。(d) 6-acetyl-1-ethyl-7-hydroxy-8-propyl-1,4-dihydro-4-oxo-quinoline-2-carboxylic acid methyl ester Amine compound obtained in step (c) (17 g) and acetylenedicarboxylic acid dimethyl ester (11.3ml)
was refluxed in ethanol (300ml) for 17 hours.
The reaction mixture was cooled and the solvent was evaporated to dryness to give a deep red oil. This oil was chromatographed on a silica gel column using an ether/petroleum ether (1:1) mixture as eluent and 1-[N-(4-acetyl-3-hydroxy-
2-propylphenyl)-N-ethylamino]maleic acid dimethyl ester 19.1 g (melting point 83-87
°C) was obtained. This maleic acid ester (5 g) and polyphosphoric acid (100 ml) were heated and stirred on a steam bath for 10 minutes. After the reaction mixture was cooled, it was poured into a mixture of ice water and ethyl acetate. After separating the organic solution, it was washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to give a pale yellow solid. This product was purified by high pressure liquid chromatography to obtain 2.6 g of compound (d) (melting point 121-123°C).
分析値
実測値 C65.5 H6.6 N4.2％
C18H21NO5についての
理論値 C65.3 H6.34 N4.23％
上記の精製を行うことにより、６−アセチル−
１−エチル−５−ヒドロキシ−４−オキソ−4H
−キノリン−２−カルボン酸メチルエステルの淡
黄色固体（100mg）が得られた。Analytical value Actual value C65.5 H6.6 N4.2% C 18 H 21 Theoretical value for NO 5 C65.3 H6.34 N4.23% By performing the above purification, 6-acetyl-
1-ethyl-5-hydroxy-4-oxo-4H
A pale yellow solid (100 mg) of -quinoline-2-carboxylic acid methyl ester was obtained.
(e) ９−エチル−６，９−ジヒドロ４，６−ジオ
キソ−10プロピル−4H−ピラノ［３，２−ｇ］
−キノリン−２，８−ジカルボン酸ジエチルエ
ステル
工程(d)で得られたヒドロキシケトン化合物
（1.0ｇ）、蓚酸ジエチル（3.3ml）および無水ジメ
チルホルムアミド（25ml）の混合物を、ジメチル
ホルムアミド（20ml）中のエーテルで洗浄した50
％水素化ナトリウム（0.581ｇ）に添加しついで
反応混合物を４時間攪拌した。ついで反応混合物
を水に注入し、酸性化し、ついで酢酸エチルで抽
出し、抽出液を水洗した後硫酸マグネシウム上で
乾燥した。溶剤を蒸発・乾固させて油状物を得、
ついでこれをエタノール（100ml）に溶解させた
後濃塩酸（数滴）を添加した。この溶液を1.5時
間還流させた後冷却し、ついで水に注入した後酢
酸エチルで抽出し、ついで抽出液を水洗し、硫酸
マグネシウム上で乾燥した。溶剤を蒸発乾固させ
て油状物を得、これを40〜60゜石油エーテル（1.2
ｇ）と研和して固体化した。この生成物の構造は
N.M.R.により確認した。(e) 9-ethyl-6,9-dihydro 4,6-dioxo-10propyl-4H-pyrano [3,2-g]
-Quinoline-2,8-dicarboxylic acid diethyl ester A mixture of the hydroxyketone compound (1.0 g) obtained in step (d), diethyl oxalate (3.3 ml) and anhydrous dimethylformamide (25 ml) was added in dimethylformamide (20 ml). 50 washed with ether of
% sodium hydride (0.581 g) and the reaction mixture was stirred for 4 hours. The reaction mixture was then poured into water, acidified, extracted with ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. Evaporate the solvent to dryness to obtain an oily substance,
This was then dissolved in ethanol (100 ml) and concentrated hydrochloric acid (several drops) was added. The solution was refluxed for 1.5 hours, then cooled, poured into water and extracted with ethyl acetate, then the extract was washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to obtain an oil, which was dissolved in 40-60° petroleum ether (1.2
g) to solidify. The structure of this product is
Confirmed by NMR.
(f) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸
工程(e)で得られたビスエステル（1.0ｇ）と炭
酸水素ナトリウム（0.787ｇ）をエタノール（85
ml）と水（32ml）からなる溶液中で４時間還流さ
せた。反応混合物を水に注入し、酸性化しついで
沈澱を濾過により捕集し、乾燥した。生成物を沸
騰エタノールおよびついで沸騰アセトンと２回研
和して精製した。各溶剤との研和を行つた後に混
合物を遠心分離し、上澄液を傾潟により除去し
た。残留固体を乾燥して、目的化合物のジカルボ
ン酸の黄色粉末（融点298−300℃、分解）0.547
ｇを得た。(f) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2
-g] Quinoline-2,8-dicarboxylic acid The bisester (1.0 g) obtained in step (e) and sodium hydrogen carbonate (0.787 g) were mixed with ethanol (85
ml) and water (32 ml) for 4 hours. The reaction mixture was poured into water, acidified and the precipitate was collected by filtration and dried. The product was purified by trituration twice with boiling ethanol and then boiling acetone. After trituration with each solvent, the mixture was centrifuged and the supernatant liquid was removed by decanting. Dry the residual solid to obtain a yellow powder of the target compound dicarboxylic acid (melting point 298-300℃, decomposition) 0.547
I got g.
分析値
実測値 C61.3 H5.0 N3.6％
C19H17NO7についての
理論値 C61.5 H4.6 N3.79％
(g) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸二ナト
リウム
工程(f)で得られたジカルボン酸（4.098ｇ）を
水（100ml）中に懸濁させ、ついで炭酸水素ナト
リウム（1.82ｇ）で処理した。得られた溶液を濾
過しついで濾液をアセトンで処理して、生成物を
完全に沈澱させた。所望の二ナトリウム塩を濾別
し、乾燥して、淡黄色粉末3.39ｇを得た。Analytical value Actual value C61.3 H5.0 N3.6% C 19 H 17 Theoretical value for NO 7 C61.5 H4.6 N3.79% (g) 9-Ethyl-6,9-dihydro-4,6 -dioxo-10-propyl-4H-pyrano[3,2
-g] Disodium quinoline-2,8-dicarboxylate The dicarboxylic acid obtained in step (f) (4.098g) was suspended in water (100ml) and then treated with sodium bicarbonate (1.82g). The resulting solution was filtered and the filtrate was treated with acetone to completely precipitate the product. The desired disodium salt was filtered off and dried to yield 3.39 g of pale yellow powder.
分析値
実測値 C51.1 H4.3 N3.0％
C19H15Na2O7についての
理論値 C51.1 H4.1 N3.1％
（水6.9％）
実施例 ３
上記と同様の方法に従つて、下記の化合物を得
た。Analytical value Actual value C51.1 H4.3 N3.0% C 19 H 15 Theoretical value for Na 2 O 7 C51.1 H4.1 N3.1% (6.9% water) Example 3 Same method as above Therefore, the following compound was obtained.
(i) ５−エチル−５，８−ジヒドロ−４，８−ジ
オキソ−10−プロピル−4H−ピラノ［２，３
−ｈ］キノリン−２，６−ジカルボン酸、
NMR（δ，DMSO−d6）：1.1（3H，ｔ）；
1.6（2H，ｍ）；2.2（2H，ｔ）；6.6（1H，
ｓ）；6.8（1H，ｓ）；7.8（1H，ｓ）
(ii) ７，10−ジヒドロ−４，10−ジオキソ−4H
−ピラノ［２，３−ｆ］キノリン−２，８−ジ
カルボン酸、
NMR（δ，DMSO−d6）：6.6（1H，ｓ）；
6.8（1H，ｓ）；7.6（1H，ｄ，Ｊ＝８Hz）；
8.1（1H，ｄ，Ｊ＝８Hz）
(iii) 10−ブロモ−６，９−ジヒドロ−４，６−ジ
オキソ−4H−ピラノ［３，２−ｇ］キノリン
−２，８−ジカルボン酸、
NMR（δ，DMSO−d6）：6.6（1H，ｓ）；
6.8（1H，ｓ）；8.9（1H，ｓ）
(iv) ６，９−ジヒドロ−５−ヒドロキシ−４，６
−ジオキソ−10−プロピル−4H−ピラノ［３，
２−ｇ］キノリン−２，８−ジカルボン酸、
NMR（δ，DMSO−d6）：1.1（3H，ｔ）；
1.6（2H，ｍ）；2.2（2H，ｔ）；6.3（1H，
ｓ）；6.9（2H，ｓ）
(v) ６，９−ジヒドロ−４，９−ジオキソ−4H
−ピラノ［２，３−ｇ］キノリン−２，７−ジ
カルボン酸、
NMR（δ，DMSO−d6）：6.6（1H，ｓ）；
6.9（1H，ｓ）；7.6（1H，ｓ）；8.6（1H，ｓ）
実施例 ４
前記と同様の方法に従つて下記の化合物を製造
した。(i) 5-ethyl-5,8-dihydro-4,8-dioxo-10-propyl-4H-pyrano[2,3
-h]quinoline-2,6-dicarboxylic acid, NMR (δ, DMSO-d 6 ): 1.1 (3H, t);
1.6 (2H, m); 2.2 (2H, t); 6.6 (1H,
s); 6.8 (1H, s); 7.8 (1H, s) (ii) 7,10-dihydro-4,10-dioxo-4H
-Pyrano[2,3-f]quinoline-2,8-dicarboxylic acid, NMR (δ, DMSO- d6 ): 6.6 (1H, s);
6.8 (1H, s); 7.6 (1H, d, J=8Hz);
8.1 (1H, d, J = 8 Hz) (iii) 10-bromo-6,9-dihydro-4,6-dioxo-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid, NMR ( δ, DMSO−d 6 ): 6.6 (1H, s);
6.8 (1H, s); 8.9 (1H, s) (iv) 6,9-dihydro-5-hydroxy-4,6
-dioxo-10-propyl-4H-pyrano[3,
2-g] Quinoline-2,8-dicarboxylic acid, NMR (δ, DMSO-d 6 ): 1.1 (3H, t);
1.6 (2H, m); 2.2 (2H, t); 6.3 (1H,
s); 6.9(2H, s) (v) 6,9-dihydro-4,9-dioxo-4H
-Pyrano[2,3-g]quinoline-2,7-dicarboxylic acid, NMR (δ, DMSO- d6 ): 6.6 (1H, s);
6.9 (1H, s); 7.6 (1H, s); 8.6 (1H, s) Example 4 The following compound was produced according to the same method as above.
(i) ７，10−ジヒドロ−７−（３−メチルブチル）
−４，10−ジオキソ−4H−ピラノ［２，３−
ｆ］キノリン−２，８−ジカルボン酸−融点
246−248℃（分解）
(ii) ６，９−ジヒドロ−９−（３−メチルブチル）
−４，６−ジオキソ−4H−ピラノ［３，２−
ｇ］キノリン−２，８−ジカルボン酸−融点
302−304℃（分解）
(iii) ７−エチル−７，10−ジヒドロ−４，10−ジ
オキソ−4H−ピラノ［２，３−ｆ］キノリン
−２，８−ジカルボン酸二ナトリウム
分析値
実測値 C44.1％，H3.5％，N3.3％
C16H9NNa2O7，14.4％，H2Oについての
理論値 C44.1％，H3.7％，N3.2％
実施例 ５
前記の方法に従つて下記の化合物を製造した。(i) 7,10-dihydro-7-(3-methylbutyl)
-4,10-dioxo-4H-pyrano[2,3-
f] Quinoline-2,8-dicarboxylic acid - melting point
246-248℃ (decomposition) (ii) 6,9-dihydro-9-(3-methylbutyl)
-4,6-dioxo-4H-pyrano[3,2-
g] Quinoline-2,8-dicarboxylic acid - melting point
302-304℃ (decomposition) (iii) Disodium 7-ethyl-7,10-dihydro-4,10-dioxo-4H-pyrano[2,3-f]quinoline-2,8-dicarboxylate Analysis value Actual value Theoretical values for C44.1%, H3.5%, N3.3% C 16 H 9 NNa 2 O 7 , 14.4%, H 2 O C44.1%, H3.7%, N3.2% Example 5 The following compounds were prepared according to the method described above.
(a) ７，10−ジヒドロ−５−メトキシ−４，７−
ジオキソ−4H−ピラノ［３，２−ｈ］キノリ
ン−２，９−ジカルボン酸、融点294−296℃
（分解）
(b) ６，９−ジヒドロ−４，６−ジオキソ−10−
（２−プロペニル−4H−ピラノ［３，２−ｇ］
キノリン−２，８−ジカルボン酸、構造はN.
M.Rにより確認
(c) ５，８−ジヒドロ−４，８−ジオキソ−4H
−ピラノ［２，３−ｈ］キノリン−２，６−ジ
カルボン酸、融点200℃
(d) 10−ヒドロキシ−１−オキソ−1H−ピラノ
［３，２−ｆ］キノリン−３，８−ジカルボン
酸二ナトリウム
分析値
C14H15NNa2O7.6.11H2Oについての
理論値：C45.74 H2.1 N3.8％
実測値：C45.74 H2.45 N3.6％
(e) ７，10−ジヒドロ−４，10−ジオキソ−4H
−ピラノ［２，３−ｆ］キノリン−２，８−ジ
カルボン酸二ナトリウム
分析値
C14H5NNa2O7.2H2Oについての
理論値：C44.1 ％ H2.38％ N3.67％
実測値：C44.36％ H2.18％ N3.54％
(f) ６，９−ジヒドロ−10−メチル−４，６−ジ
オキソ−4H−ピラノ［３，２−ｇ］キノリン
−２，８−ジカルボン酸、融点302℃
(g) ６，９−ジヒドロ−４，６−ジオキソ−10−
プロピル−4H−ピラノ［３，２−ｇ］キノリ
ン−２，８−ジカルボン酸ジエチルエステルの
融点211−212℃。(a) 7,10-dihydro-5-methoxy-4,7-
Dioxo-4H-pyrano[3,2-h]quinoline-2,9-dicarboxylic acid, melting point 294-296°C
(Decomposition) (b) 6,9-dihydro-4,6-dioxo-10-
(2-propenyl-4H-pyrano [3,2-g]
Quinoline-2,8-dicarboxylic acid, the structure is N.
Confirmed by MR (c) 5,8-dihydro-4,8-dioxo-4H
-Pyrano[2,3-h]quinoline-2,6-dicarboxylic acid, melting point 200°C (d) 10-hydroxy-1-oxo-1H-pyrano[3,2-f]quinoline-3,8-dicarboxylic acid Disodium analysis value C 14 H 15 NNa 2 O 7 .6.11Theoretical value for H 2 O: C45.74 H2.1 N3.8% Actual value: C45.74 H2.45 N3.6% (e) 7, 10-dihydro-4,10-dioxo-4H
-pyrano[2,3-f]quinoline-2,8-dicarboxylic acid disodium analytical value C 14 H 5 NNa 2 O 7 .Theoretical value for 2H 2 O: C44.1% H2.38% N3.67% Actual value: C44.36% H2.18% N3.54% (f) 6,9-dihydro-10-methyl-4,6-dioxo-4H-pyrano[3,2-g]quinoline-2,8- Dicarboxylic acid, melting point 302°C (g) 6,9-dihydro-4,6-dioxo-10-
Propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid diethyl ester melting point 211-212°C.
(h) ６−アミノ−７，10−ジヒドロ−５−メトキ
シ−４，７−ジオキソ−4H−ピラノ［３，２
−ｈ］キノリン−２，９−ジカルボン酸
NMRδDMSO：3.95（3H，ｓ）；6.95（1H，
ｓ）；7.4（1H，ｓ），9.6（brs−4H）。(h) 6-amino-7,10-dihydro-5-methoxy-4,7-dioxo-4H-pyrano[3,2
-h]quinoline-2,9-dicarboxylic acid NMRδDMSO: 3.95 (3H, s); 6.95 (1H,
s); 7.4 (1H, s), 9.6 (brs-4H).
(i) 10−ブロモ−６，９−ジヒドロ−４，６−ジ
オキソ−4H−ピラノ［３，２−ｇ］キノリン
−２，８−ジカルボン酸
NMRδDMSO：6.95（1H，ｓ）；7.0（1H，
ｓ）；8.6（1H，ｓ）
実施例 ６
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−
ｇ］キノリン−２，８−ジカルボン酸
(a) ６−アセチル−１−エチル−１，４−ジヒド
ロ−７−ヒドロキシ−４−オキソ−８−プロピ
ルキノリン−２−カルボン酸
６−アセチル−１−エチル−１，４−ジヒドロ
−７−ヒドロキシ−４−オキソ−８−プロピルキ
ノリン−２−カルボン酸メチル（20ｇ）を、48％
HBγ水溶液（20ml）を含有する氷酢酸（150ml）
中で還流下加熱した。18時間後、混合物を冷却
し、水に注入した。PH３になるまでアンモニアを
添加した。沈澱を捕集し、真空下で乾燥して目的
化合物(a)（14.3ｇ）を得、これをN.M.R分析およ
び質量スペクトル分析により同定した。(i) 10-Bromo-6,9-dihydro-4,6-dioxo-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid NMRδDMSO: 6.95 (1H, s); 7.0 (1H,
s); 8.6 (1H,s) Example 6 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g] Quinoline-2,8-dicarboxylic acid (a) 6-acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylic acid 6-acetyl-1- Methyl ethyl-1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylate (20 g), 48%
Glacial acetic acid (150ml) containing HBγ aqueous solution (20ml)
The mixture was heated under reflux. After 18 hours, the mixture was cooled and poured into water. Ammonia was added until pH was 3. The precipitate was collected and dried under vacuum to obtain the target compound (a) (14.3 g), which was identified by NMR analysis and mass spectrometry analysis.
(b) ２−エトキシカルボニル−９−エチル−６，
９−ジヒドロ−４，６−ジオキソ−10−プロピ
ル−4H−ピラノ［３，２−ｇ］キノリン−８
−カルボン酸
工程(a)の化合物（14.2ｇ）をエタノール（200
ml）中のナトリウム（5.2ｇ）の溶液に添加しつ
いで蓚酸ジエチル（16ｇ）を添加した。混合物を
還流下で５時間加熱しついで冷却した後、クロロ
ホルム（１）中に注入した。混合物を稀塩酸
（150ml）と共に振盪した後、有機相を乾燥しつい
で真空下で蒸発させた。残渣を濃塩酸（２ml）を
含有するエタノール（200ml）中に溶解し、18時
間還流させた。溶剤を蒸発させ、残渣をエタノー
ルから再結晶させて目的化合物(b)（3.2ｇ）を得、
その構造をN.M.R.分析および質量スペクトル分
析により確認した。(b) 2-ethoxycarbonyl-9-ethyl-6,
9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-8
- Carboxylic acid The compound of step (a) (14.2 g) was mixed with ethanol (200 g).
ml) followed by diethyl oxalate (16 g). The mixture was heated under reflux for 5 hours and after cooling was poured into chloroform (1). After shaking the mixture with dilute hydrochloric acid (150ml), the organic phase was dried and evaporated under vacuum. The residue was dissolved in ethanol (200ml) containing concentrated hydrochloric acid (2ml) and refluxed for 18 hours. The solvent was evaporated and the residue was recrystallized from ethanol to obtain the target compound (b) (3.2 g),
Its structure was confirmed by NMR analysis and mass spectrometry analysis.
(c) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸
工程(b)の生成物を工程(a)の方法により加水分解
して、薄層クロマトグラフイー分析により実施例
２(f)の化合物と同一であると同定された化合物
（1.1ｇ）を得た。(c) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2
-g] Quinoline-2,8-dicarboxylic acid The product of step (b) is hydrolyzed by the method of step (a) and is identical to the compound of Example 2(f) by thin layer chromatography analysis. A compound (1.1 g) was obtained.
実施例 ７
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−
ｇ］キノリン−２，８−ジカルボン酸
(a) ９−エチル−６，９−ジヒドロ−２−メチル
−４，６−ジオキソ−10−プロピル−4H−ピ
ラノ［３，２−ｇ］キノリン−８−カルボン酸
メチル
６−アセチル−１−エチル−７−ヒドロキシ−
４（1H）−オキソ−８−プロピルキノリン−２−
カルボン酸（3.15ｇ）を水素化ナトリウム（1.05
ｇ）を含有する無水ジメチルホルムアミド（50
ml）中に溶解した後、酢酸エチル（4.4ｇ）を添
加した。一夜撹拌した後、混合物に氷冷しながら
飽和するまでガス状塩化水素を通送した。混合物
を75℃で８時間加温した後、冷却しついで水中に
注入しついで混合物を酢酸エチルで抽出した。有
機相を乾燥し、蒸発させた後クロマトグラフイー
（SiO2／酢酸エチル）にかけて目的化合物(a)（0.8
ｇ）を得た。その構造をN.M.R分析および質量
スペクトル分析により確認した。Example 7 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g] Quinoline-2,8-dicarboxylic acid (a) 9-ethyl-6,9-dihydro-2-methyl-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-8 -Methyl carboxylate 6-acetyl-1-ethyl-7-hydroxy-
4(1H)-oxo-8-propylquinoline-2-
Carboxylic acid (3.15g) was dissolved in sodium hydride (1.05g).
g) of anhydrous dimethylformamide (50
ml) and then ethyl acetate (4.4 g) was added. After stirring overnight, gaseous hydrogen chloride was passed through the mixture with ice cooling until saturation. After warming the mixture to 75° C. for 8 hours, it was cooled and poured into water, and the mixture was extracted with ethyl acetate. The organic phase was dried, evaporated and chromatographed (SiO 2 /ethyl acetate) to obtain the target compound (a) (0.8
g) was obtained. Its structure was confirmed by NMR analysis and mass spectrometry analysis.
(b) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸
工程(a)の生成物（0.75ｇ）を氷酢酸（50ml）中
で二酸化セレン（1.5ｇ）と共に還流下48時間加
熱した。“セライト”（“Celite”）を通過させて濾
過して透明な濾液を得、これを濃塩酸（25ml）で
処理しかつ還流下で12時間加熱した。冷却後水中
に注入して沈澱（0.1ｇ）を得た。このものは薄
層クロマトグラフイーにより実施例２(f)の化合物
と同一であると同定された。(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2
-g] Quinoline-2,8-dicarboxylic acid The product of step (a) (0.75g) was heated under reflux with selenium dioxide (1.5g) in glacial acetic acid (50ml) for 48 hours. Filtration through "Celite" gave a clear filtrate, which was treated with concentrated hydrochloric acid (25 ml) and heated under reflux for 12 hours. After cooling, it was poured into water to obtain a precipitate (0.1 g). This was identified by thin layer chromatography to be identical to the compound of Example 2(f).
実施例 ８
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−
ｇ］キノリン−２，８−ジカルボン酸
(a) ２−［Ｎ−［３−（１，２−ジカルボキシエテ
ニルオキシ）−２−プロピルフエニル］−Ｎ−エ
チルアミノ］−２−ブテン−１，４−ジオン酸
３−エチルアミノ−２−プロピルフエノール
（17.9ｇ）、ジメチルアセチレンジカルボキシレー
ト（35ｇ）、水酸化カリウム（0.56ｇ）、水（50
ml）およびエタノール（100ml）を還流下で24時
間加熱した。水酸化カリウム（1.65ｇ）を添加し
た後、実に24時間還流を行つた。Example 8 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g] Quinoline-2,8-dicarboxylic acid (a) 2-[N-[3-(1,2-dicarboxyethenyloxy)-2-propylphenyl]-N-ethylamino]-2-butene- 1,4-Dionic acid 3-ethylamino-2-propylphenol (17.9g), dimethylacetylenedicarboxylate (35g), potassium hydroxide (0.56g), water (50g)
ml) and ethanol (100 ml) were heated under reflux for 24 hours. After addition of potassium hydroxide (1.65 g), reflux was carried out for 24 hours.
濃塩酸（４ml）を添加した後、溶剤を蒸発させ
た。残渣を真空下で蒸発させた後、エーテル中に
抽出した。エーテルを蒸発させて目的化合物(a)
（3.6ｇ）を得た。その構造をN.M.R.分析および
質量スペクトル分析により確認した。 After adding concentrated hydrochloric acid (4ml) the solvent was evaporated. The residue was evaporated under vacuum and then extracted into ether. Evaporate the ether to obtain the target compound (a)
(3.6g) was obtained. Its structure was confirmed by NMR analysis and mass spectrometry analysis.
(b) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸
工程(a)の生成物（3.55ｇ）を撹拌下、−78℃に
冷却したクロルスルホン酸（100ml）中に少量づ
つ添加した。溶液を室温までゆつくり昇温させつ
いで１時間で50℃まで加温した。反応混合物を氷
（１）中に注意深く注入しついで酢酸エチルで
抽出した。乾燥後、酢酸エチルを蒸発させついで
残渣を高圧液体クロマトグラフイーにより分離し
て、クロマトグラフイーにより実施例２(f)の化合
物と同一であると同定された目的化合物（0.2ｇ）
を得た。(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2
-g] Quinoline-2,8-dicarboxylic acid The product of step (a) (3.55 g) was added portionwise under stirring to chlorosulfonic acid (100 ml) cooled to -78°C. The solution was slowly warmed to room temperature and then to 50° C. over 1 hour. The reaction mixture was carefully poured into ice (1) and extracted with ethyl acetate. After drying, the ethyl acetate was evaporated and the residue was separated by high pressure liquid chromatography to give the desired compound (0.2 g) which was identified by chromatography to be identical to the compound of Example 2(f).
I got it.
実施例 ９
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−
ｇ］キノリン−２，８−ジカルボン酸
(a) １−エチル−６−（３−カルボキシ−３−ジ
エチルアミノ−１−オキソ−２−プロペニル）
−１，４−ジヒドロ−７−ヒドロキシ−４−オ
キソ−８−プロピルキノリン−２−カルボン酸
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−ｇ］
キノリン−２，８−ジカルボン酸（１ｇ）とジエ
チルアミン（５ml）とをオートクレーブ中で100
℃で12時間加熱しついで揮発物質を60℃で蒸発さ
せた。残渣をエーテルと研和して目的化合物(a)
（0.78ｇ）を得た。その構造をN.M.R.および質量
スペクトル分析により確認した。Example 9 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g] Quinoline-2,8-dicarboxylic acid (a) 1-ethyl-6-(3-carboxy-3-diethylamino-1-oxo-2-propenyl)
-1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylic acid 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3, 2-g]
Quinoline-2,8-dicarboxylic acid (1 g) and diethylamine (5 ml) were mixed in an autoclave at 100%
℃ for 12 hours and the volatiles were evaporated at 60.degree. The residue is triturated with ether to obtain the target compound (a).
(0.78g) was obtained. Its structure was confirmed by NMR and mass spectrometry.
(b) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸
工程(a)の生成物（0.77ｇ）を塩化水素含有エタ
ノール（20ml）中に懸濁させた後、還流下で24時
間加熱した。溶剤を蒸発させ、残渣を高圧液体ク
ロマトグラフイーにより分離して、クロマトグラ
フイーにより実施例２(f)の化合物と同一であると
同定された目的化合物（0.2ｇ）を得た。(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2
-g] Quinoline-2,8-dicarboxylic acid The product of step (a) (0.77 g) was suspended in ethanol containing hydrogen chloride (20 ml) and then heated under reflux for 24 hours. The solvent was evaporated and the residue was separated by high pressure liquid chromatography to give the desired compound (0.2 g) which was identified by chromatography to be identical to the compound of Example 2(f).
実施例 10
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−
ｇ］キノリン−２，８−ジカルボン酸
(a) ジエチル９−エチル−６，９−ジヒドロ−10
−プロピル−４，６−ジチオキソ−4H−ピラ
ノ［３，２−ｇ］キノリン−２，８−ジカルボ
キシレート
ジエチル９−エチル−６，９−ジヒドロ−４，
６−ジオキソ−10−プロピル−4H−ピラノ［３，
２−ｇ］キノリン−２，８−ジカルボキシレート
（10ｇ）と十硫化五燐
（pentaphosphorusdecasulfide）（20ｇ）を160℃
で６時間溶融させついで冷却した後、生成物の混
合物を酢酸エチル中に抽出した。クロマトグラフ
イー（シリカゲル／酢酸エチル）にかけて目的化
合物（5.6ｇ）を得た。その構造をN.M.R.および
質量スペクトル分析により確認した。Example 10 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g] Quinoline-2,8-dicarboxylic acid (a) Diethyl 9-ethyl-6,9-dihydro-10
-propyl-4,6-dithioxo-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate diethyl 9-ethyl-6,9-dihydro-4,
6-dioxo-10-propyl-4H-pyrano[3,
2-g] Quinoline-2,8-dicarboxylate (10 g) and pentaphosphorusdecasulfide (20 g) at 160°C.
After melting for 6 hours and cooling, the product mixture was extracted into ethyl acetate. The target compound (5.6 g) was obtained by chromatography (silica gel/ethyl acetate). Its structure was confirmed by NMR and mass spectrometry.
(b) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸
工程(a)の生成物を濃塩酸（５ml）を含有する氷
酢酸（50ml）中で100℃で24時間加熱した。酢酸
溶剤を蒸発させ、残渣をエーテルで研和した。固
体残渣を水（１ml）を含有するアセトニトリル
（50ml）中に溶解し、塩化第二水銀（２ｇ）と共
に激しく撹拌した。48時間後、溶液を濾過し、濾
液を水（250ml）で稀釈しついで酸性化した。沈
澱した固体を高圧液体クロマトグラフイーにより
精製して目的化合物(b)（2.1ｇ）を得た。この化
合物はクロマトグラフイーにより実施例２(f)の化
合物と同一であると同定された。(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2
-g] Quinoline-2,8-dicarboxylic acid The product of step (a) was heated at 100°C for 24 hours in glacial acetic acid (50ml) containing concentrated hydrochloric acid (5ml). The acetic acid solvent was evaporated and the residue was triturated with ether. The solid residue was dissolved in acetonitrile (50ml) containing water (1ml) and stirred vigorously with mercuric chloride (2g). After 48 hours, the solution was filtered and the filtrate was diluted with water (250ml) and acidified. The precipitated solid was purified by high pressure liquid chromatography to obtain the target compound (b) (2.1 g). This compound was identified by chromatography to be identical to the compound of Example 2(f).
実施例 11
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−
ｇ］キノリン−２，８−ジカルボン酸
(a) ９−エチル−２，３，６，９−テトラヒドロ
−４，６−ジオキソ−10−プロピル−4H−ピ
ラノ［３，２−ｇ］キノリン−２，８−ジカル
ボン酸
ジエチル９−エチル−６，９−ジヒドロ−４，
６−ジオキソ−10−プロピル−4H−ピラノ［３，
２−ｇ］キノリン−２，８−ジカルボキシレート
（５ｇ）を氷酢酸（100ml）中でアダムス
（Adams）触媒（0.5ｇ）の存在下、４気圧で、
水素の吸収が止むまで水素添加した。触媒を除去
した後、濃塩酸（５ml）を添加した。溶液を24時
間還流させた後、蒸発させた。残渣を高圧液体ク
ロマトグラフイーにかけて目的化合物(a)（0.9ｇ）
を得た。その構造をN.M.R.および質量スペクト
ル分析により確認した。Example 11 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g] Quinoline-2,8-dicarboxylic acid (a) 9-ethyl-2,3,6,9-tetrahydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-2 , 8-dicarboxylic acid diethyl 9-ethyl-6,9-dihydro-4,
6-dioxo-10-propyl-4H-pyrano[3,
2-g] quinoline-2,8-dicarboxylate (5 g) in glacial acetic acid (100 ml) in the presence of Adams catalyst (0.5 g) at 4 atm.
Hydrogenation was continued until hydrogen absorption stopped. After removing the catalyst, concentrated hydrochloric acid (5ml) was added. The solution was refluxed for 24 hours and then evaporated. Target compound (a) (0.9 g) was obtained by subjecting the residue to high-pressure liquid chromatography.
I got it. Its structure was confirmed by NMR and mass spectrometry.
(b) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸
工程(a)の生成物（0.85ｇ）をシメン（10ml）に
懸濁させた後、10％Pd／Ｃ触媒を用いて還流下、
６時間処理した。溶剤を蒸発させ、濾過してゴム
状物を得、これを高圧液体クロマトグラフイーに
より精製して、目的化合物(b)（0.15ｇ）を得た。
この化合物はクロマトグラフイーにより実施例２
(f)の化合物と同一であると同定された。(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2
-g] Quinoline-2,8-dicarboxylic acid The product of step (a) (0.85 g) was suspended in cymene (10 ml) and then refluxed using a 10% Pd/C catalyst.
It was treated for 6 hours. The solvent was evaporated and filtered to obtain a gum, which was purified by high pressure liquid chromatography to obtain the target compound (b) (0.15 g).
This compound was obtained by chromatography in Example 2.
It was identified as the same compound as (f).
実施例 12
９−エチル−６，９−ジヒドロ−４，６−ジオ
キソ−10−プロピル−4H−ピラノ［３，２−
ｇ］キノリン−２，８−ジカルボン酸
(a) １−エチル−１，４−ジヒドロ−７−ヒドロ
キシ−６−メトキシカルボニル−４−オキソ−
８−プロピルキノリン−２−カルボン酸
ジエチル９−エチル−６，９−ジヒドロ−４，
６−ジオキソ−10−プロピル−4H−ピラノ［３，
２−ｇ］キノリン−２，８−ジカルボキシレート
（4.27ｇ）と水素化ナトリウム（1.6ｇ）とを水
（10ml）中で還流下、24時間加熱した後、水を蒸
発させついで残渣を塩化水素ガスを飽和させたエ
タノール（50ml）中に懸濁させ、１時間還流させ
た。溶剤を蒸発させ、残渣をクロマトグラフイー
（シリカゲル／エーテル）にかけてジエステル
（1.3ｇ）を得、これを水酸化ナトリウム（0.139
ｇ）と水（20ml）とからなる水溶液と共に沸騰さ
せた。酸性化して目的化合物(a)（0.93ｇ）を沈澱
させた。その構造はN.M.R.および質量スペクト
ル分析により確認した。Example 12 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g] Quinoline-2,8-dicarboxylic acid (a) 1-ethyl-1,4-dihydro-7-hydroxy-6-methoxycarbonyl-4-oxo-
8-propylquinoline-2-carboxylic acid diethyl 9-ethyl-6,9-dihydro-4,
6-dioxo-10-propyl-4H-pyrano[3,
2-g] Quinoline-2,8-dicarboxylate (4.27 g) and sodium hydride (1.6 g) were heated under reflux in water (10 ml) for 24 hours, then the water was evaporated and the residue was chlorinated. It was suspended in ethanol (50 ml) saturated with hydrogen gas and refluxed for 1 hour. The solvent was evaporated and the residue was chromatographed (silica gel/ether) to give the diester (1.3 g), which was dissolved in sodium hydroxide (0.139
g) and water (20 ml). The target compound (a) (0.93 g) was precipitated by acidification. Its structure was confirmed by NMR and mass spectrometry.
(b) ９−エチル−６，９−ジヒドロ−４，６−ジ
オキソ−10−プロピル−4H−ピラノ［３，２
−ｇ］キノリン−２，８−ジカルボン酸
工程(a)の生成物（0.9ｇ）を無水ジメチルスル
ホキシド（10ml）に溶解しついでこの溶液を窒素
雰囲気下、40℃でジムシルナトリウム
（dimsylsodium）（１ｇ）とジメチルスルホキシ
ド（50ml）とからなる溶液に添加した。48時間
後、反応混合物を水（500ml）に注入しついでエ
ーテルで抽出した。乾燥および蒸発を行つて赤色
油状物を得、ついでこれをトルエン（20ml）中に
懸濁させた後、ピペリジン（1.1ｇ）と水和グリ
オキシル酸（1.5ｇ）とにより処理した。５時間
還流させた後、混合物を冷却し、酢酸エチル
（100ml）中に注入しついで炭酸水素ナトリウム飽
和溶液で洗浄した。炭酸水素ナトリウム溶液を酸
性化した後、酢酸エチルで抽出した。乾燥および
蒸発を行つてゴム状物を得、これを高圧液体クロ
マトグラフイーにより分離して目的化合物（0.13
ｇ）を得た。この化合物はクロマトグラフイーに
より実施例２(f)の化合物と同一であると同定され
た。(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2
-g] Quinoline-2,8-dicarboxylic acid The product of step (a) (0.9 g) was dissolved in anhydrous dimethyl sulfoxide (10 ml) and the solution was mixed with dimsylsodium (dimsylsodium) at 40°C under nitrogen atmosphere. 1g) and dimethyl sulfoxide (50ml). After 48 hours the reaction mixture was poured into water (500ml) and extracted with ether. Drying and evaporation gave a red oil which was then suspended in toluene (20ml) and treated with piperidine (1.1g) and hydrated glyoxylic acid (1.5g). After refluxing for 5 hours, the mixture was cooled, poured into ethyl acetate (100ml) and washed with saturated sodium bicarbonate solution. After acidifying the sodium bicarbonate solution, it was extracted with ethyl acetate. Drying and evaporation give a rubbery substance, which is separated by high pressure liquid chromatography to obtain the target compound (0.13
g) was obtained. This compound was identified by chromatography to be identical to the compound of Example 2(f).
Claims (1)
R7 aおよびR8 aは、R5 a，R6 a，R7 aおよびR8 aの隣
接する一対が式：−COCH＝Ｃ（D1）Ｏ−の連鎖
を表わし得るという条件で後記R5，R6，R7およ
びR8と同一の意義を有し；そして、ＤおよびD1
は、その両方が−COOH基に加水分解され得る
基を表わすか、あるいはＤおよびD1の一方が上
記の基を表わし他方が−COOH基を表わす〕 の化合物を選択的に加水分解することを特徴とす
る、式： （式中、R5，R6，R7およびR8の隣接する一対
は連鎖−COCH＝CEO−を形成しており、R5，
R6，R7およびR8の残りは同一でも異つてもよく、
かつ各々、水素、ヒドロキシル基、C1−C8アル
キル基、ハロゲン、C2−C8アルケニル基、C1−
C8アルコキシ基またはNH2基を表わし；Rgは水
素又は低級アルキル基を表わし、そしてＥは−
COOHを表わす）で表わされる新規ピラノキノ
リノン誘導体またはその薬学的に許容し得る塩又
は低級アルキルエステルの製造方法。 ２ 基Ｄがエステル基、アミド基またはニトリル
基であり、加水分解を温和な塩基性条件下または
酸性条件下で行う、特許請求の範囲第１項に記載
の方法。 ３ R5，R6，R7およびR8の隣接する一対は連鎖
−COCH＝CEO−を形成しており、R5，R6，R7
およびR8の残りは同一でも異つてもよく、かつ
各々、水素、メトキシ基、プロピル基、アリル
基、メチル基、エチル基、塩素、臭素およびヒド
ロキシ基からなる群から選ばれる特許請求の範囲
第１項又は第２項に記載の方法。 ４ 式ｃ： （式中、Rgは後記の意義を有し、；R5j，R6j，
R7jおよびR8jは、R5j，R6j，R7jおよびR8jの隣接
する一対が連鎖−COCH＝Ｃ（Ｘ）−Ｏ−を表わし
得るという条件で、後記R5，R6，R7およびR8と
同一の意義を有し、Ｘはカルボン酸基又はそのエ
ステル又は他の塩を表わす）の化合物を、薬学的
に許容され得るカチオンを含有する、かつ、基Ｘ
を薬学的に許容し得る塩に転化し得る化合物で処
理することを特徴とする式： （式中、R5，R6，R7およびR8の隣接する一対
は連鎖−COCH＝CEO−を形成しており、R5，
R6，R7およびR8の残りは同一でも異つてもよく、
かつ各々、水素、ヒドロキシル基、C1−C8アル
キル基、ハロゲン、C2−C8アルケニル基、C1−
C8アルコキシ基又はNH2基を表わし；Rgは水素
又は低級アルキル基を表わし；そしてＥは
COOHを表わす）で表わされる新規ピラノキノ
リノン誘導体の薬学的に許容し得る塩の製造方
法。 ５ 式： 〔式中、R5，R6，R7およびR8の隣接する一対
は連鎖−COCH＝CEO−を形成しており、R5，
R6，R7およびR8の残りは同一でも異つてもよく、
かつ各々、水素、ヒドロキシル基、C1−C8アル
キル基、ハロゲン、C2−C8アルケニル基、C1−
C8アルコキシ基またはNH2基を表わし；Rgは水
素または低級アルキル基を表わし；そしてＥは−
COOHを表わす〕で表わされる新規ピラノキノ
リノン誘導体、またはその薬学的に許容し得る塩
又は低級アルキルエステル。 ６ 連鎖−COCH＝CEO−がR6とR7の位置に結
合しており、該連鎖の−Ｏ−部がR7の位置にあ
る、特許請求の範囲第５項に記載の化合物。 ７ R5，R6，R7およびR8の隣接する一対は連鎖
−COCH＝CEO−を形成しており、R5，R6，R7
およびR8の残りは同一でも異つてもよく、かつ
各々、水素、メトキシ基、プロピル基、アリル
基、メチル基、エチル基、塩素、臭素およびヒド
ロキシ基から選ばれる、特許請求の範囲第５項ま
たは第６項に記載の化合物。 ８ ６，９−ジヒドロ−４，６−ジオキソ−10−
プロピル−4H−ピラノ［３，２−ｇ］キノリン
−２，８−ジカルボン酸又は９−エチル−６，９
−ジヒドロ−４，６−ジオキソ−10−プロピル−
4H−ピラノ［３，２−ｇ］キノリン−２，８−
ジカルボン酸である、特許請求の範囲第５項に記
載の化合物。[Claims] 1 Formula: [In the formula, Rg has the meaning below; R 5 a , R 6 a ,
R 7 a and R 8 a are described below with the condition that an adjacent pair of R 5 a , R 6 a , R 7 a and R 8 a can represent a chain of the formula: -COCH=C(D 1 )O- have the same meaning as R 5 , R 6 , R 7 and R 8 ; and D and D 1
both represent groups that can be hydrolyzed to a -COOH group, or one of D and D 1 represents the above group and the other represents a -COOH group. Characterized by the formula: (In the formula, an adjacent pair of R 5 , R 6 , R 7 and R 8 forms a chain -COCH=CEO-, and R 5 ,
The remainder of R 6 , R 7 and R 8 may be the same or different,
and each hydrogen, hydroxyl group, C1 - C8 alkyl group, halogen, C2 - C8 alkenyl group, C1-
represents a C 8 alkoxy group or an NH 2 group; Rg represents hydrogen or a lower alkyl group, and E represents -
A method for producing a novel pyranoquinolinone derivative represented by (representing COOH) or a pharmaceutically acceptable salt or lower alkyl ester thereof. 2. The method according to claim 1, wherein the group D is an ester group, an amide group or a nitrile group, and the hydrolysis is carried out under mild basic conditions or acidic conditions. 3 An adjacent pair of R 5 , R 6 , R 7 and R 8 forms a chain -COCH=CEO-, and R 5 , R 6 , R 7
and the remainder of R 8 may be the same or different, and each is selected from the group consisting of hydrogen, methoxy, propyl, allyl, methyl, ethyl, chlorine, bromine, and hydroxy. The method according to item 1 or 2. 4 Formula c: (In the formula, Rg has the meaning below; R 5 j, R 6 j,
R 7 j and R 8 j can be expressed as R 5 j below with the condition that an adjacent pair of R 5 j, R 6 j, R 7 j and R 8 j can represent the chain -COCH=C(X)-O-. , R 6 , R 7 and R 8 and X represents a carboxylic acid group or an ester or other salt thereof) containing a pharmaceutically acceptable cation and a group X
is characterized in that it is treated with a compound capable of converting it into a pharmaceutically acceptable salt: (In the formula, an adjacent pair of R 5 , R 6 , R 7 and R 8 forms a chain -COCH=CEO-, and R 5 ,
The remainder of R 6 , R 7 and R 8 may be the same or different,
and each hydrogen, hydroxyl group, C1 - C8 alkyl group, halogen, C2 - C8 alkenyl group, C1-
C8 represents alkoxy group or NH2 group; Rg represents hydrogen or lower alkyl group; and E represents
A method for producing a pharmaceutically acceptable salt of a novel pyranoquinolinone derivative represented by COOH. 5 Formula: [In the formula, an adjacent pair of R 5 , R 6 , R 7 and R 8 form a chain -COCH=CEO-, and R 5 ,
The remainder of R 6 , R 7 and R 8 may be the same or different,
and each hydrogen, hydroxyl group, C1 - C8 alkyl group, halogen, C2 - C8 alkenyl group, C1-
represents a C8 alkoxy group or an NH2 group; Rg represents hydrogen or a lower alkyl group; and E represents -
COOH], or a pharmaceutically acceptable salt or lower alkyl ester thereof. 6. The compound according to claim 5, wherein the chain -COCH=CEO- is bonded at the R6 and R7 positions, and the -O- part of the chain is at the R7 position. 7 Adjacent pairs of R 5 , R 6 , R 7 and R 8 form a chain -COCH=CEO-, and R 5 , R 6 , R 7
and the remainder of R 8 may be the same or different and each is selected from hydrogen, methoxy, propyl, allyl, methyl, ethyl, chlorine, bromine, and hydroxy. or a compound according to item 6. 8 6,9-dihydro-4,6-dioxo-10-
Propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid or 9-ethyl-6,9
-dihydro-4,6-dioxo-10-propyl-
4H-pyrano[3,2-g]quinoline-2,8-
6. A compound according to claim 5, which is a dicarboxylic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1859777 | 1977-05-04 | ||
| GB4586577 | 1977-11-04 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63322239A Division JPH01199909A (en) | 1977-05-04 | 1988-12-22 | Pharmaceutical composition containing novel pyranoquinoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS53137969A JPS53137969A (en) | 1978-12-01 |
| JPH0122276B2 true JPH0122276B2 (en) | 1989-04-25 |
Family
ID=26253475
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5240778A Granted JPS53137969A (en) | 1977-05-04 | 1978-05-02 | Novel pyranoquinoline derivative and method for its production and composition containing same |
| JP63322239A Pending JPH01199909A (en) | 1977-05-04 | 1988-12-22 | Pharmaceutical composition containing novel pyranoquinoline derivative |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63322239A Pending JPH01199909A (en) | 1977-05-04 | 1988-12-22 | Pharmaceutical composition containing novel pyranoquinoline derivative |
Country Status (16)
| Country | Link |
|---|---|
| JP (2) | JPS53137969A (en) |
| AU (1) | AU520816B2 (en) |
| CA (1) | CA1112644A (en) |
| CH (1) | CH634071A5 (en) |
| DE (1) | DE2819215A1 (en) |
| DK (1) | DK158266C (en) |
| ES (1) | ES469391A1 (en) |
| FR (1) | FR2389627B1 (en) |
| IE (1) | IE47051B1 (en) |
| IL (2) | IL54614A (en) |
| IT (1) | IT1158699B (en) |
| LU (2) | LU79579A1 (en) |
| NL (2) | NL184896C (en) |
| NO (1) | NO154497C (en) |
| NZ (1) | NZ187156A (en) |
| SE (2) | SE443561B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2440371A1 (en) * | 1978-10-31 | 1980-05-30 | Fisons Ltd | NOVEL HETEROCYCLIC NITROGEN COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND METHODS FOR PREPARING THE SAME |
| EP0030423B1 (en) * | 1979-12-07 | 1985-02-13 | FISONS plc | A process for the production of 1,4-dihydro-4-oxo-quinoline-2-carboxylic acids, or salts, esters or amides thereof and intermediates therefor |
| EP0162556B1 (en) * | 1984-04-13 | 1991-11-06 | FISONS plc | Novels forms and formulations of nedocromil sodium |
| DE3787274T2 (en) * | 1986-12-23 | 1994-01-27 | Fisons Plc | Pharmaceutical preparations containing an aqueous solution of a pyranoquinoline. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2054503A1 (en) * | 1969-07-18 | 1971-04-23 | Bellon Labor Sa Roger | 1, 4-dihydro-4-oxo quinolyl-3-carboxylic aci |
-
1978
- 1978-05-01 IL IL54614A patent/IL54614A/en unknown
- 1978-05-02 DK DK190178A patent/DK158266C/en not_active IP Right Cessation
- 1978-05-02 DE DE19782819215 patent/DE2819215A1/en active Granted
- 1978-05-02 IT IT7822918A patent/IT1158699B/en active Protection Beyond IP Right Term
- 1978-05-02 CA CA302,479A patent/CA1112644A/en not_active Expired
- 1978-05-02 JP JP5240778A patent/JPS53137969A/en active Granted
- 1978-05-02 NO NO781549A patent/NO154497C/en unknown
- 1978-05-03 AU AU35731/78A patent/AU520816B2/en not_active Expired
- 1978-05-03 NL NLAANVRAGE7804749,A patent/NL184896C/en not_active IP Right Cessation
- 1978-05-03 SE SE7805105A patent/SE443561B/en not_active IP Right Cessation
- 1978-05-03 NZ NZ187156A patent/NZ187156A/en unknown
- 1978-05-03 ES ES469391A patent/ES469391A1/en not_active Expired
- 1978-05-03 CH CH482978A patent/CH634071A5/en not_active IP Right Cessation
- 1978-05-03 IE IE890/78A patent/IE47051B1/en not_active IP Right Cessation
- 1978-05-03 LU LU79579A patent/LU79579A1/en unknown
- 1978-05-03 FR FR7813169A patent/FR2389627B1/fr not_active Expired
-
1980
- 1980-12-30 IL IL61826A patent/IL61826A0/en unknown
-
1986
- 1986-06-02 SE SE8602492A patent/SE463920B/en not_active IP Right Cessation
-
1988
- 1988-12-22 JP JP63322239A patent/JPH01199909A/en active Pending
-
1993
- 1993-06-03 LU LU88281C patent/LU88281I2/en unknown
- 1993-06-09 NL NL930050C patent/NL930050I2/en unknown
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