NO750863L - - Google Patents
Info
- Publication number
- NO750863L NO750863L NO750863A NO750863A NO750863L NO 750863 L NO750863 L NO 750863L NO 750863 A NO750863 A NO 750863A NO 750863 A NO750863 A NO 750863A NO 750863 L NO750863 L NO 750863L
- Authority
- NO
- Norway
- Prior art keywords
- hydroxy
- nitrocoumarin
- hydroxycoumarin
- added
- room temperature
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 20
- -1 methoxy, ethoxy Chemical group 0.000 claims description 18
- 150000003839 salts Chemical group 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- AYHZQBMBPNZPEY-UHFFFAOYSA-N 4-hydroxy-6,7-dimethylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(C)C(C)=C2 AYHZQBMBPNZPEY-UHFFFAOYSA-N 0.000 claims description 2
- SCILMMRZKMQNRK-UHFFFAOYSA-N 6-ethyl-4-hydroxy-7-methoxychromen-2-one Chemical compound OC1=CC(=O)OC2=C1C=C(CC)C(OC)=C2 SCILMMRZKMQNRK-UHFFFAOYSA-N 0.000 claims description 2
- DKDFRUJBZMZOEV-UHFFFAOYSA-N 6-ethyl-4-hydroxy-7-propoxychromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(OCCC)C(CC)=C2 DKDFRUJBZMZOEV-UHFFFAOYSA-N 0.000 claims description 2
- DVSUEIITDYMTFB-UHFFFAOYSA-N 7-ethyl-4-hydroxy-6-methylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(CC)C(C)=C2 DVSUEIITDYMTFB-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- 238000001914 filtration Methods 0.000 description 33
- 239000000047 product Substances 0.000 description 33
- 239000000725 suspension Substances 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 239000011734 sodium Substances 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 12
- VXIXUWQIVKSKSA-UHFFFAOYSA-N 4-hydroxycoumarin Chemical compound C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- NZQAQAUWFHMVEM-UHFFFAOYSA-N 4-hydroxy-3-nitrochromen-2-one Chemical compound C1=CC=CC2=C1OC(=O)C([N+]([O-])=O)=C2O NZQAQAUWFHMVEM-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- CEVVPXAFAUWIMW-UHFFFAOYSA-N 4-hydroxy-3,6-dinitrochromen-2-one Chemical compound C1=CC([N+]([O-])=O)=CC2=C1OC(=O)C([N+]([O-])=O)=C2O CEVVPXAFAUWIMW-UHFFFAOYSA-N 0.000 description 3
- WOZQGVWTWZLETB-UHFFFAOYSA-N 4-hydroxy-6,7-dimethyl-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(C)C(C)=C2 WOZQGVWTWZLETB-UHFFFAOYSA-N 0.000 description 3
- CPMOVDXRQYGPSF-UHFFFAOYSA-N 4-hydroxy-6-methoxy-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=CC(OC)=CC=C21 CPMOVDXRQYGPSF-UHFFFAOYSA-N 0.000 description 3
- QFTOEJKXJKAMNK-UHFFFAOYSA-N 6,7-diethyl-4-hydroxy-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(CC)C(CC)=C2 QFTOEJKXJKAMNK-UHFFFAOYSA-N 0.000 description 3
- UBDIXRVYJPYHNO-UHFFFAOYSA-N 6-chloro-4-hydroxy-3-nitrochromen-2-one Chemical compound C1=CC(Cl)=CC2=C1OC(=O)C([N+]([O-])=O)=C2O UBDIXRVYJPYHNO-UHFFFAOYSA-N 0.000 description 3
- ZLDUKGHXYIMWJP-UHFFFAOYSA-N 7-bromo-4-hydroxy-3-nitrochromen-2-one Chemical compound C1=C(Br)C=CC2=C1OC(=O)C([N+]([O-])=O)=C2O ZLDUKGHXYIMWJP-UHFFFAOYSA-N 0.000 description 3
- WLXORWBDJTUCLG-UHFFFAOYSA-N 7-chloro-4-hydroxy-3-nitrochromen-2-one Chemical compound C1=C(Cl)C=CC2=C1OC(=O)C([N+]([O-])=O)=C2O WLXORWBDJTUCLG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- YTCVPEZECJYZRK-UHFFFAOYSA-N 3-nitrochromen-2-one Chemical class C1=CC=C2OC(=O)C([N+](=O)[O-])=CC2=C1 YTCVPEZECJYZRK-UHFFFAOYSA-N 0.000 description 2
- VOBWYJZFRGXBFE-UHFFFAOYSA-N 4-hydroxy-3-nitro-7-propoxychromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=CC(OCCC)=CC=C21 VOBWYJZFRGXBFE-UHFFFAOYSA-N 0.000 description 2
- OERMPGGFPDGNOZ-UHFFFAOYSA-N 4-hydroxy-5-methoxy-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=CC=C2OC OERMPGGFPDGNOZ-UHFFFAOYSA-N 0.000 description 2
- KUALEWXMXRPRRL-UHFFFAOYSA-N 4-hydroxy-6-methyl-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=CC(C)=CC=C21 KUALEWXMXRPRRL-UHFFFAOYSA-N 0.000 description 2
- XANZFICLJFFUKG-UHFFFAOYSA-N 4-hydroxy-7-methoxy-3-nitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=CC(OC)=CC=C21 XANZFICLJFFUKG-UHFFFAOYSA-N 0.000 description 2
- GZKYQBNTSOFWPM-UHFFFAOYSA-N 4-hydroxy-7-methoxy-8-methyl-3-nitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C(C)C(OC)=CC=C21 GZKYQBNTSOFWPM-UHFFFAOYSA-N 0.000 description 2
- RASGTZZGBPNBLH-UHFFFAOYSA-N 6-bromo-4-hydroxy-3-nitrochromen-2-one Chemical compound C1=CC(Br)=CC2=C1OC(=O)C([N+]([O-])=O)=C2O RASGTZZGBPNBLH-UHFFFAOYSA-N 0.000 description 2
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N Arsenious Acid Chemical compound O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 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
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- JECYUBVRTQDVAT-UHFFFAOYSA-N 2-acetylphenol Chemical class CC(=O)C1=CC=CC=C1O JECYUBVRTQDVAT-UHFFFAOYSA-N 0.000 description 1
- XCLCBQOPVFPFBN-UHFFFAOYSA-N 4,7-dihydroxy-3,6,8-trinitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C([N+]([O-])=O)C(O)=C([N+]([O-])=O)C=C21 XCLCBQOPVFPFBN-UHFFFAOYSA-N 0.000 description 1
- SARRSDARCKJMPK-UHFFFAOYSA-N 4,7-dihydroxy-3,6-dinitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(O)C([N+]([O-])=O)=C2 SARRSDARCKJMPK-UHFFFAOYSA-N 0.000 description 1
- KKQAFZBJICXPRU-UHFFFAOYSA-N 4,7-dihydroxy-3,8-dinitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C([N+]([O-])=O)C(O)=CC=C21 KKQAFZBJICXPRU-UHFFFAOYSA-N 0.000 description 1
- UIBQLWQIGFZIID-UHFFFAOYSA-N 4,7-dihydroxy-3-nitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=CC(O)=CC=C21 UIBQLWQIGFZIID-UHFFFAOYSA-N 0.000 description 1
- KICKNBIKUUIDSK-UHFFFAOYSA-N 4,7-dihydroxychromen-2-one;hydrate Chemical compound O.OC1=CC(=O)OC2=CC(O)=CC=C21 KICKNBIKUUIDSK-UHFFFAOYSA-N 0.000 description 1
- WVVNGXKQLLKZPP-UHFFFAOYSA-N 4-hydroxy-3,6-dinitrochromen-2-one;sodium Chemical compound [Na].C1=CC([N+]([O-])=O)=CC2=C1OC(=O)C([N+]([O-])=O)=C2O WVVNGXKQLLKZPP-UHFFFAOYSA-N 0.000 description 1
- AWRMGCSUZGXDPQ-UHFFFAOYSA-N 4-hydroxy-3-nitro-6-phenylmethoxychromen-2-one;sodium Chemical compound [Na].C=1C=2C(O)=C([N+]([O-])=O)C(=O)OC=2C=CC=1OCC1=CC=CC=C1 AWRMGCSUZGXDPQ-UHFFFAOYSA-N 0.000 description 1
- QHIPEHKKGLLQRF-UHFFFAOYSA-N 4-hydroxy-3-nitro-7-propoxychromen-2-one;sodium Chemical compound [Na].OC1=C([N+]([O-])=O)C(=O)OC2=CC(OCCC)=CC=C21 QHIPEHKKGLLQRF-UHFFFAOYSA-N 0.000 description 1
- SKASSVARNXDRMC-UHFFFAOYSA-N 4-hydroxy-5,6,7-trimethylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(C)C(C)=C2C SKASSVARNXDRMC-UHFFFAOYSA-N 0.000 description 1
- LFFCJEOKCYTBDD-UHFFFAOYSA-N 4-hydroxy-5-methoxychromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=CC=C2OC LFFCJEOKCYTBDD-UHFFFAOYSA-N 0.000 description 1
- JOQLOWVQNWMIRK-UHFFFAOYSA-N 4-hydroxy-5-methyl-3-nitro-7-propan-2-ylchromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=CC(C(C)C)=CC(C)=C21 JOQLOWVQNWMIRK-UHFFFAOYSA-N 0.000 description 1
- NDOVCKMKZPJBBE-UHFFFAOYSA-N 4-hydroxy-5-methyl-3-nitro-8-propan-2-ylchromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C1C(C)=CC=C2C(C)C NDOVCKMKZPJBBE-UHFFFAOYSA-N 0.000 description 1
- YPKUPBACJZCZKA-UHFFFAOYSA-N 4-hydroxy-6,7-dimethyl-3-nitrochromen-2-one;sodium Chemical compound [Na].O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(C)C(C)=C2 YPKUPBACJZCZKA-UHFFFAOYSA-N 0.000 description 1
- CIBMJDFTKNIHKQ-UHFFFAOYSA-N 4-hydroxy-6,7-dipropylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(CCC)C(CCC)=C2 CIBMJDFTKNIHKQ-UHFFFAOYSA-N 0.000 description 1
- OIJLCRLAKRHBBN-UHFFFAOYSA-N 4-hydroxy-6,8-dimethyl-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=CC(C)=CC(C)=C21 OIJLCRLAKRHBBN-UHFFFAOYSA-N 0.000 description 1
- HVHIQQVTLCUBKA-UHFFFAOYSA-N 4-hydroxy-6,8-dimethylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=CC(C)=CC(C)=C21 HVHIQQVTLCUBKA-UHFFFAOYSA-N 0.000 description 1
- KNVVAFLWWDZVRA-UHFFFAOYSA-N 4-hydroxy-6-methoxy-3-nitrochromen-2-one;sodium Chemical compound [Na].O1C(=O)C([N+]([O-])=O)=C(O)C2=CC(OC)=CC=C21 KNVVAFLWWDZVRA-UHFFFAOYSA-N 0.000 description 1
- KFXXRRQBVLINPH-UHFFFAOYSA-N 4-hydroxy-6-methoxychromen-2-one Chemical compound O1C(=O)C=C(O)C2=CC(OC)=CC=C21 KFXXRRQBVLINPH-UHFFFAOYSA-N 0.000 description 1
- WIRGBZBGYNIZIB-UHFFFAOYSA-N 4-hydroxy-6-methylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=CC(C)=CC=C21 WIRGBZBGYNIZIB-UHFFFAOYSA-N 0.000 description 1
- OCVAZEDQAFICLI-UHFFFAOYSA-N 4-hydroxy-6-phenylmethoxychromen-2-one Chemical compound C=1C=2C(O)=CC(=O)OC=2C=CC=1OCC1=CC=CC=C1 OCVAZEDQAFICLI-UHFFFAOYSA-N 0.000 description 1
- AHIWTWINYJFZTJ-UHFFFAOYSA-N 4-hydroxy-7,8-dimethyl-3-nitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C(C)C(C)=CC=C21 AHIWTWINYJFZTJ-UHFFFAOYSA-N 0.000 description 1
- DZGDYAJCQWPAKE-UHFFFAOYSA-N 4-hydroxy-7,8-dimethylchromen-2-one Chemical compound OC1=CC(=O)OC2=C(C)C(C)=CC=C21 DZGDYAJCQWPAKE-UHFFFAOYSA-N 0.000 description 1
- NDQQBUKSTAUBFI-UHFFFAOYSA-N 4-hydroxy-7-methoxy-3-nitro-6-propylchromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C1C=C(CCC)C(OC)=C2 NDQQBUKSTAUBFI-UHFFFAOYSA-N 0.000 description 1
- AUWQRFLQKOBFJT-UHFFFAOYSA-N 4-hydroxy-7-methoxy-6-methyl-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(OC)C(C)=C2 AUWQRFLQKOBFJT-UHFFFAOYSA-N 0.000 description 1
- LERYPVGFHJAHPU-UHFFFAOYSA-N 4-hydroxy-7-methoxy-6-methylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(OC)C(C)=C2 LERYPVGFHJAHPU-UHFFFAOYSA-N 0.000 description 1
- BVEGTNLQOFTOIF-UHFFFAOYSA-N 4-hydroxy-7-methoxy-6-propylchromen-2-one Chemical compound OC1=CC(=O)OC2=C1C=C(CCC)C(OC)=C2 BVEGTNLQOFTOIF-UHFFFAOYSA-N 0.000 description 1
- ZPPACLOAXPSWDB-UHFFFAOYSA-N 4-hydroxy-7-methoxy-8-methylchromen-2-one Chemical compound OC1=CC(=O)OC2=C(C)C(OC)=CC=C21 ZPPACLOAXPSWDB-UHFFFAOYSA-N 0.000 description 1
- MJBHLQMPKBMZSF-UHFFFAOYSA-N 4-hydroxy-7-methoxychromen-2-one Chemical compound OC1=CC(=O)OC2=CC(OC)=CC=C21 MJBHLQMPKBMZSF-UHFFFAOYSA-N 0.000 description 1
- AHHFMOLSPQZAQT-UHFFFAOYSA-N 4-hydroxy-7-propoxy-6-propylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(OCCC)C(CCC)=C2 AHHFMOLSPQZAQT-UHFFFAOYSA-N 0.000 description 1
- USOPQJDZCBCFJG-UHFFFAOYSA-N 4-hydroxy-7-propoxychromen-2-one Chemical compound OC1=CC(=O)OC2=CC(OCCC)=CC=C21 USOPQJDZCBCFJG-UHFFFAOYSA-N 0.000 description 1
- NFFPEZYDUVHXIU-UHFFFAOYSA-N 4-hydroxy-8-methyl-3-nitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C1C=CC=C2C NFFPEZYDUVHXIU-UHFFFAOYSA-N 0.000 description 1
- SWTGXRICOTZSFY-UHFFFAOYSA-N 4-hydroxy-8-methylchromen-2-one Chemical compound OC1=CC(=O)OC2=C1C=CC=C2C SWTGXRICOTZSFY-UHFFFAOYSA-N 0.000 description 1
- JRSYUHVXYISMOU-UHFFFAOYSA-N 6,7-diethyl-4-hydroxychromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(CC)C(CC)=C2 JRSYUHVXYISMOU-UHFFFAOYSA-N 0.000 description 1
- JPYQLNZLTJDRNL-UHFFFAOYSA-N 6-bromo-4-hydroxy-3-nitrochromen-2-one;sodium Chemical compound [Na].C1=CC(Br)=CC2=C1OC(=O)C([N+]([O-])=O)=C2O JPYQLNZLTJDRNL-UHFFFAOYSA-N 0.000 description 1
- KNMCTCABMSGXGR-UHFFFAOYSA-N 6-bromo-4-hydroxychromen-2-one Chemical compound C1=CC(Br)=CC2=C1OC(=O)C=C2O KNMCTCABMSGXGR-UHFFFAOYSA-N 0.000 description 1
- AMBONCRHFJSJLA-UHFFFAOYSA-N 6-chloro-4-hydroxy-3-nitrochromen-2-one;sodium Chemical compound [Na].C1=CC(Cl)=CC2=C1OC(=O)C([N+]([O-])=O)=C2O AMBONCRHFJSJLA-UHFFFAOYSA-N 0.000 description 1
- HUMZENGQNOATEQ-UHFFFAOYSA-N 6-chloro-4-hydroxycoumarin Chemical compound C1=CC(Cl)=CC2=C1OC(=O)C=C2O HUMZENGQNOATEQ-UHFFFAOYSA-N 0.000 description 1
- UAADZDHLBGXZJC-UHFFFAOYSA-N 6-ethyl-4-hydroxy-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=CC(CC)=CC=C21 UAADZDHLBGXZJC-UHFFFAOYSA-N 0.000 description 1
- DBVBKQLWSBTXLT-UHFFFAOYSA-N 6-ethyl-4-hydroxy-7-methoxy-3-nitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C1C=C(CC)C(OC)=C2 DBVBKQLWSBTXLT-UHFFFAOYSA-N 0.000 description 1
- JZUXFVXCOFFNII-UHFFFAOYSA-N 6-ethyl-4-hydroxy-7-methylchromen-2-one Chemical compound OC1=CC(=O)OC2=C1C=C(CC)C(C)=C2 JZUXFVXCOFFNII-UHFFFAOYSA-N 0.000 description 1
- JYULRNGSVREOJU-UHFFFAOYSA-N 6-ethyl-4-hydroxychromen-2-one Chemical compound O1C(=O)C=C(O)C2=CC(CC)=CC=C21 JYULRNGSVREOJU-UHFFFAOYSA-N 0.000 description 1
- CFULEYDXZUKVNB-UHFFFAOYSA-N 7-bromo-4-hydroxy-3-nitrochromen-2-one;sodium Chemical compound [Na].C1=C(Br)C=CC2=C1OC(=O)C([N+]([O-])=O)=C2O CFULEYDXZUKVNB-UHFFFAOYSA-N 0.000 description 1
- UJWIUPBUKQLTTJ-UHFFFAOYSA-N 7-bromo-4-hydroxychromen-2-one Chemical compound C1=C(Br)C=CC2=C1OC(=O)C=C2O UJWIUPBUKQLTTJ-UHFFFAOYSA-N 0.000 description 1
- KXMUNKPRHFHESS-UHFFFAOYSA-N 7-chloro-4-hydroxy-3-nitrochromen-2-one;sodium Chemical compound [Na].C1=C(Cl)C=CC2=C1OC(=O)C([N+]([O-])=O)=C2O KXMUNKPRHFHESS-UHFFFAOYSA-N 0.000 description 1
- PKVBFOLFCIJRRE-UHFFFAOYSA-N 7-chloro-4-hydroxychromen-2-one Chemical compound C1=C(Cl)C=CC2=C1OC(=O)C=C2O PKVBFOLFCIJRRE-UHFFFAOYSA-N 0.000 description 1
- WRIWCTGCJAGBPC-UHFFFAOYSA-N 7-ethoxy-4-hydroxy-3-nitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=CC(OCC)=CC=C21 WRIWCTGCJAGBPC-UHFFFAOYSA-N 0.000 description 1
- WPWHOFJXRHXQGD-UHFFFAOYSA-N 7-ethoxy-4-hydroxy-6-methyl-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(OCC)C(C)=C2 WPWHOFJXRHXQGD-UHFFFAOYSA-N 0.000 description 1
- FCKZDVZDHOBNSC-UHFFFAOYSA-N 7-ethoxy-4-hydroxy-6-methylchromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(OCC)C(C)=C2 FCKZDVZDHOBNSC-UHFFFAOYSA-N 0.000 description 1
- IBCYZMVNMXAHHD-UHFFFAOYSA-N 7-ethoxy-4-hydroxy-6-propylchromen-2-one Chemical compound OC1=CC(=O)OC2=C1C=C(CCC)C(OCC)=C2 IBCYZMVNMXAHHD-UHFFFAOYSA-N 0.000 description 1
- BPWIJZQVCZRWTJ-UHFFFAOYSA-N 7-ethoxy-4-hydroxychromen-2-one Chemical compound OC1=CC(=O)OC2=CC(OCC)=CC=C21 BPWIJZQVCZRWTJ-UHFFFAOYSA-N 0.000 description 1
- IISGCEREQZLPMM-UHFFFAOYSA-N 7-ethoxy-6-ethyl-4-hydroxychromen-2-one Chemical compound O1C(=O)C=C(O)C2=C1C=C(OCC)C(CC)=C2 IISGCEREQZLPMM-UHFFFAOYSA-N 0.000 description 1
- WTAQDUQFXNCDKR-UHFFFAOYSA-N 7-ethyl-4-hydroxy-6-methyl-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(CC)C(C)=C2 WTAQDUQFXNCDKR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- XJYDDRXKAGBCBK-UHFFFAOYSA-N N-(4-hydroxy-3-nitro-2-oxochromen-7-yl)acetamide Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=CC(NC(=O)C)=CC=C21 XJYDDRXKAGBCBK-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Oppfinnelsen vedrører kjemiske mellomprodukter for fremstilling av antiallergene forbindelser som inngår i farma-søytiske preparater som er nyttige ved inhibering av effektene av visse typer av antigen/antistoff-reaksjoner, og som derfor. The invention relates to chemical intermediates for the production of antiallergenic compounds included in pharmaceutical preparations which are useful in inhibiting the effects of certain types of antigen/antibody reactions, and which therefore.
er av verdi i profylaksen og behandlingen av sykdommer som er assosiert med allergiske eller immunologiske reaksjoner, f.eks. visse typer av astma og høyfeber, og også ved behandling av (rjhinitt. is of value in the prophylaxis and treatment of diseases associated with allergic or immunological reactions, e.g. certain types of asthma and hay fever, and also in the treatment of (rjhinitis.
Det er oppdaget a;p visse 3-nitrokumariner har nyttig aktivitet hos pattedyr ved det at de inhiberer effekténe av visse typer av antigen/antistoff-reaksjoner. Spesielt viser de seg å inhibere frigjøringen av mediatorsubstanser, f.eks. histamin, som normalt frigjøres etter antigen/antistoff-kombinasjoner og som synes å mediere (formidle) den allergiske respons. Klassen av 3-nitrokumariner som har vist seg å være aktive på denne måte, har formel (I): It has been discovered that certain 3-nitrocoumarins have useful activity in mammals in that they inhibit the effects of certain types of antigen/antibody reactions. In particular, they are shown to inhibit the release of mediator substances, e.g. histamine, which is normally released after antigen/antibody combinations and which seems to mediate the allergic response. The class of 3-nitrocoumarins which have been shown to be active in this way have formula (I):
og saltene av forbindelsene (I) er også aktive. I formel (I) and the salts of the compounds (I) are also active. In formula (I)
betyr R^fIL, / R^og R^hver hydrogen eller alkyl-, alkoksy-, aryloksy-, aralkoksy-, aryl-, aralkyl-, heterocykliske, hydroksy-, nitro- eller halogen-grupper eller hvilke som helst to av gruppene R^, R^, R. og R^danner sammen med karbonatomene som de er knyttet til, et substituert eller usubstituert karbocyklisk eller hetero-cyklisk ringsystem. Imidlertid har en gjennomgåelse av den kjemiske litteratur avslørt at ikke alle medlemmene av klasse (I) er nye forbindelser. means R^fIL, / R^ and R^ are each hydrogen or alkyl, alkoxy, aryloxy, aralkoxy, aryl, aralkyl, heterocyclic, hydroxy, nitro or halogen groups or any two of the groups R^, R^, R^ and R^, together with the carbon atoms to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic ring system. However, a review of the chemical literature has revealed that not all members of class (I) are new compounds.
Nedenunder gjengis de forbindelser av formel (I) som er funnet omtalt i litteraturen, sammen med den aktuelle litteratur-henvisning: Below are the compounds of formula (I) that have been found mentioned in the literature, together with the relevant literature reference:
4-hydroksy-3-nitrokumarin ' 5, 6, ,0 4-hydroxy-3-nitrocoumarin ' 5, 6, ,0
1 2 1 2
4-hydroksy-6-metyl-3-nitrokumarin ' 4-hydroxy-6-methyl-3-nitrocoumarin'
6,8-dimetyl-4-hydroksy-3-nitrokumarin<9>6,8-dimethyl-4-hydroxy-3-nitrocoumarin<9>
4-hydroksy-7-isopropyl-5-metyl-3-nitrokumarin ^ 4-hydroksy-8-isopropyl-5-metyl-3-nitrokumarin ^ 6- klor-4-hydroksy-3-nitrokumarin ^ 4-hydroxy-7-isopropyl-5-methyl-3-nitrocoumarin ^ 4-hydroxy-8-isopropyl-5-methyl-3-nitrocoumarin ^ 6- chloro-4-hydroxy-3-nitrocoumarin ^
7- klor-4-hydroksy-3-nitrokumarin<2>7- Chloro-4-hydroxy-3-nitrocoumarin<2>
7-brom-4-hydroksy-3-nitrokumarin<2>7-bromo-4-hydroxy-3-nitrocoumarin<2>
4,7-dihydroksy-3-nitrokumarin 2 '<7>4,7-dihydroxy-3-nitrocoumarin 2 '<7>
4,7-dihydroksy-3,6-dinitrokumarin<7>4,7-dihydroxy-3,6-dinitrocoumarin<7>
4,7-dihydroksy-3,8-dinitrokumarin<7>4,7-dihydroxy-3,8-dinitrocoumarin<7>
4,7-dihydroksy-3,6,8-trinitrokumarin<7>4,7-dihydroxy-3,6,8-trinitrocoumarin<7>
4-hydroksy-5-metoksy-3-nitrokumarin<2>4-hydroxy-5-methoxy-3-nitrocoumarin<2>
4-hydroksy-6-metoksy-3-nitrokumarin<4>4-hydroxy-6-methoxy-3-nitrocoumarin<4>
4-hydroksy-7-metoksy-3-nitrokumarin 2 '4 4-hydroxy-7-methoxy-3-nitrocoumarin 2 '4
4-hydroksy-7-metoksy-8-metyl-3-nitrokumarin<4>4-hydroxy-7-methoxy-8-methyl-3-nitrocoumarin<4>
3,6-dinitro-4-hydroksykumarin<3>3,6-dinitro-4-hydroxycoumarin<3>
7-acetamido-4-hydroksy-3-nitrokumarin 2 ' 4 ' 127-acetamido-4-hydroxy-3-nitrocoumarin 2 ' 4 ' 12
Referanser References
1. J. Chem. Soc. C. (1971), 218 1. J. Chem. Soc. C. (1971), 218
2. Prpc. Ind. Acad. Sei. Sect A. (1968), 6J7, 42 2. Prpc. Ind. Acad. Pollock. Sect A. (1968), 6J7, 42
3. J. Amer. Chem. Soc, (1945), 6_7, 99 3. J. Amer. Chem. Soc, (1945), 6_7, 99
4. Yakugaku Zassi (1966), 86, 1064 (Chemical Abstracts 1967, 66, I04869u) 5. Annalen (1961) , 64_3, 97 6. Pharmazie (1953) , 8, 221 (CA. 48, 7602g) 4. Yakugaku Zassi (1966), 86, 1064 (Chemical Abstracts 1967, 66, I04869u) 5. Annalen (1961) , 64_3, 97 6. Pharmazie (1953) , 8, 221 (CA. 48, 7602g)
7. Chem. Pharm. Bull., (1971), 19_, 1046 7. Chem. Pharm. Bull., (1971), 19_, 1046
8. Monatsh (1958), 89>, 787 9. Monatsh (1958), 89_, 143 10. Arch. Pharm (1963) , 2_96 , 365 11. Glas. Hem. Tehndl. Bosne,Hercegovine (1968), lio, 109 (Chemical Abstracts 72, 43345V) 8. Monatsh (1958), 89>, 787 9. Monatsh (1958), 89_, 143 10. Arch. Pharm (1963) , 2_96 , 365 11. Glas. Home. Tehndl. Bosne, Herzegovina (1968), lio, 109 (Chemical Abstracts 72, 43345V)
12. Chemical Abstracts 6_7, P 43681y. 12. Chemical Abstracts 6_7, P 43681y.
Selv om de ovennevnte forbindelser er beskrevet i litteraturen, er de ikke blitt tilskrevet noen form for nyttig biologisk aktivitet. Likeledes er det i litteraturen ikke funnet noe forslag om at sLike forbindelser kan være i besittelse av noen form for nyttig biologisk aktivitet, og spesielt er oppdagelsen av at de har antiallergen aktivitet ikke på noen måte blitt forutsagt. Although the above compounds have been described in the literature, they have not been attributed any kind of useful biological activity. Likewise, no suggestion has been found in the literature that such compounds may possess any form of useful biological activity, and in particular the discovery that they have anti-allergenic activity was in no way predicted.
Følgelig tilveiebringer oppfinnelsen i sitt bredeste Accordingly, the invention provides in its widest
aspekt et farmasøytisk preparat som har antiallergen aktivitet, og som omfatter en forbindelse av formel (I) eller et farmasøytisk akseptabelt salt derav: aspect a pharmaceutical preparation which has antiallergenic activity, and which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:
sammen med en eller flere farmasøytisk akseptable bærere, i hvilken formel R^, R^, R^ og R^representerer hydrogen eller alkyl-, alkoksy-, aryloksy-, aralkoksy-, aryl-, aralkyl-, heterocykliske, hydroksy-, nitro- eller halogengrupper og hvilke som helst to av together with one or more pharmaceutically acceptable carriers, in which formula R^, R^, R^ and R^ represent hydrogen or alkyl, alkoxy, aryloxy, aralkyl, aryl, aralkyl, heterocyclic, hydroxy, nitro - or halogen groups and any two of
gruppene R^, R£/R^og R^sammen med karbonatomene som de er knyttet til, danner en substituert eller usubstituert karbocyklisk ring, idet dette preparat er tilpasset for administrering til mennesker. the groups R^, R£/R^ and R^ together with the carbon atoms to which they are attached form a substituted or unsubstituted carbocyclic ring, this preparation being adapted for administration to humans.
Eksempler på gruppene R^, R^, R^ og R^som kan være til-stede i'forbindelsene (I) er hydrogen, metyl, etyl, n- og isopropyl, n-, sek- og tert-butyl, metoksy, etoksy, n- og iso-propoksy, Examples of the groups R^, R^, R^ and R^ which may be present in the compounds (I) are hydrogen, methyl, ethyl, n- and isopropyl, n-, sec- and tert-butyl, methoxy, ethoxy, n- and iso-propoxy,
n-, sek- og tert-butoksy, fenoksy, benzyloksy, fenyl, benzyl, pyridyl, fluor, klor, brom, jod. I tillegg kan R^og R^og R^eller R^ og R^sammen med karbonatomene som de er knyttet til, danne en sammensmeltet fenyl- eller sammensmeltet 1,2-cyklo-.heksenylenring som kan ha en eller flere av de substituenter som n-, sec- and tert-butoxy, phenoxy, benzyloxy, phenyl, benzyl, pyridyl, fluorine, chlorine, bromine, iodine. In addition, R^ and R^ and R^ or R^ and R^, together with the carbon atoms to which they are attached, may form a fused phenyl or fused 1,2-cyclohexenylene ring which may have one or more of the substituents as
er angitt ovenfor. is indicated above.
Fortrinnsvis er R^ og R^hydrogen, og R^ og R^er hver metyl, etyl, n-propyl, metoksy, etoksy eller n-propoksygrupper. Preferably, R 1 and R 2 are hydrogen, and R 2 and R 3 are each methyl, ethyl, n-propyl, methoxy, ethoxy or n-propoxy groups.
Eksempler på egnede salter av forbindelser av formel (I) innbefatter alkalimetallsaltene, spesielt av kalium og natrium, og jordalkalimetallsaltene, f.eks. aluminium- og magnesiumsalter, såvel som salter med organiske baser så som aminer eller amino-forbindelser. Examples of suitable salts of compounds of formula (I) include the alkali metal salts, especially of potassium and sodium, and the alkaline earth metal salts, e.g. aluminum and magnesium salts, as well as salts with organic bases such as amines or amino compounds.
4-hydroksy-3-nitrokumariner kan forekomme i en rekke tautomere former: 4-Hydroxy-3-nitrocoumarins can occur in a number of tautomeric forms:
og det skal forstås at hvor det i denne beskrivelse refereres til 4-hydroksy-3-nitrokumariner, menes det også tautomere former av disse forbindelser. and it should be understood that where reference is made in this description to 4-hydroxy-3-nitrocoumarins, tautomeric forms of these compounds are also meant.
Preparatene i henhold til oppfinnelsen kan presenteres som et mikrofint pulver for innsnusning, f.eks. som et snusemiddel eller i kapsler av hård gelatin. De kan også presenteres med en steril, flytende bærer for injeksjon. Forbindelser av formel (I) som er aktive når de gis ad oral vei, kan være sammensatt i form av siruper, tabletter, kapsler, piller og lignende. Preparatene er fortrinnsvis i enhetsdoseform, eller de har en form som gjør det The preparations according to the invention can be presented as a microfine powder for sniffing, e.g. as a snuff or in hard gelatin capsules. They may also be presented with a sterile, liquid vehicle for injection. Compounds of formula (I) which are active when given orally can be formulated in the form of syrups, tablets, capsules, pills and the like. The preparations are preferably in unit dose form, or they have a form that does so
r r
mulig for pasienten å administrere en enkelt dose til seg selv. Eksempelvis, når preparatet er i form av en tablett, pille eller kapsel, kan en passende doseringsenhet inneholde fra 1 til 500 mg aktiv ingrediens. Om ønsket, kan en liten mengde av en bronkiodilatorforbindelse, f.eks. isoprenalin, innarbeides i preparatene i henhold til oppfinnelsen både for å inhibere hoste-respons hvis preparatet innsnuses, og for å gi øyeblikkelig lindring under et astmaanfall. Den effektive dose av forbindelse (I) er avhengig av den spesielle forbindelse som anvendes, men ligger generelt i området fra 0,1 mg/kg/dag til 100 mg/kg/dag. possible for the patient to self-administer a single dose. For example, when the preparation is in the form of a tablet, pill or capsule, a suitable dosage unit may contain from 1 to 500 mg of active ingredient. If desired, a small amount of a bronchodilator compound, e.g. isoprenaline, is incorporated into the preparations according to the invention both to inhibit the cough response if the preparation is inhaled, and to provide immediate relief during an asthma attack. The effective dose of compound (I) depends on the particular compound used, but generally ranges from 0.1 mg/kg/day to 100 mg/kg/day.
Den presise natur av den farmasøytiske bærer som anvendes The precise nature of the pharmaceutical carrier used
i preparatene i henhold til oppfinnelsen, er ikke av betydning. Standard farmasøytisk praksis kan følges. in the preparations according to the invention, is not important. Standard pharmaceutical practice can be followed.
Som vanlig i praksis, vil preparatene vanligvis være ledsaget av skrevne eller trykte veiledninger for bruk i denne aktuelle medisinske behandling, i dette tilfelle som et antiallergent middel for profylaktisk behandling av f.eks. astma, høyfeber eller rhinitt. As usual in practice, the preparations will usually be accompanied by written or printed instructions for use in this relevant medical treatment, in this case as an antiallergenic agent for prophylactic treatment of e.g. asthma, hay fever or rhinitis.
Oppfinnelsen innbefatter innen sin ramme en foretrukken klasse av nye substituerte 4-hydroksy-3-nitrokumariner av formel (IA) og farmasøytisk akseptable salter derav: The invention includes within its scope a preferred class of new substituted 4-hydroxy-3-nitrocoumarins of formula (IA) and pharmaceutically acceptable salts thereof:
hvor R"*" er hydrogen eller metyl, etyl, n-propyl, metoksy, etoksy eller n-propoksy og R^ er metyl, etyl, n-propyl, metoksy, etoksy eller n-propoksy. Forbindelser av formel (IA) som er spesielt foretrukket, innbefatter de følgende, samt deres farmasøytisk akseptable salter: 6,7-dimetyl-4-hydroksy-3-nitrokumarin ;6,7-dietyl-4-hydroksy-3-nitrokumarin ;6,7-di-n-propyl-4-hydroksy-3-nitrokumarin ;6-metyl-7-etyl-4-hydroksy-3-nitrokumarin ;6- etyl-7-metyl-4-hydroksy-3-nitrokumarin ;7- metoksy-4-hydroksy-3-nitrokumarin ;7-etoksy-4-hydroksy-3-nitrokumarin ;7-n-propoksy-4-hydroksy-3-nitrokumarin ;6-metyl-7-metoksy-4-hydroksy-3-nitrokumarin ;6-etyl-7-metoksy-4-hydroksy-3-nitrokumarin ;6-n-propy1-7-metoksy-4-hydroksy-3-nitrokumarin 6-metyl-7-etoksy-4-hydroksy-3-nitrokumarin ;6-etyl-7-etoksy-4-hydroksy-3-nitrokumarin ;6-n-propy1-7-etoksy-4-hydroksy-3-nitrokumarin 6-metyl-7-n-propoksy-4-hydroksy-3-nitrokumarin 6-etyl-7-n-propoksy-4-hydroksy-3-nitrokumarin ;.6-n-propyl-7-n-propoksy-4-hydroksy-3-nitrokumarin Forbindelser av formel (I) og naturligvis av formel (IIA) kan fremstilles ved nitrering av mor-4-hydroksykumarinet (II) eller ;(HA), ; hvor R^, R2, R^og R^er som definert for formel (I), og R1 og R11 er som definert for formel (IIA). Nitreringen kan utføres under anvendelse av et av de følgende nitreringsmidler: (i) De nitrøse gasser som utvikles med konsentrert salpetersyre og arsen(III)oksyd. ;(ii) Eddiksyre pluss konsentrert salptersyre ;(iii) Rykende salpetersyre i kloroform ;(iv) Konsentrert salpetersyre. ;Siden de er nyttige mellomprodukter, innbefatter oppfinnelsen forbindelser av formel IIA. ;Utgangsmaterialene av formel (II) kan fremstilles-ved hvilken som helst av de standardmetoder som er kjent fra litteraturen for fremstilling av 4-hydroksykumarin. Således er omsetningen av den passende fenol med malonsyre under anvendelse av fosforoksy-klorid pluss sinkklorid som kondenseringsmiddel, en mulig vei. ;Under anvendelse av denne fremgangsmåte gir 2- eller 4-substituerte fenoler bare ett kumarinprodukt, men 3-substituerte fenoler-kan gi en blanding av de to mulige isomerer. Disse kan vanligvis separeres under anvendelse av standardteknikker såsom fraksjonert krystallisasjon. En annen fremgangsmåte er kondenseringen av o-hydroksyacetofenoner med dietylkarbonat i nærvær av natrium eller natriumhydrid. ;Følgende eksempler illustrerer fremstillingen og egenskapene til en rekke forbindelser av formel (I). ;Eksempel 1 ;4- hydroksy- 3- nitrokumarin ;30 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 5,0 g 4-hydroksykumarin i 500 ml kloroform ved romtemperatur i løpet av 2 timer. Etter ytterligere 2 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 250 ml vann tilsatt til resten. Filtrering ga produktet, sm.p. 174-5°, (CgH5 N05 krever: C 52,18; H 2,43; N 6,76. Funnet: C 52,00; ;H 2,38; N 6,62). ;Eksempel 2 ;4- hydroksy- 8- metyl- 3- nitrokumarin ;18 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 4-hydroksy-8-metylkumarin (sm.p. 231-5°; 3,03 g) i 250 ml kloroform ved romtemperatur i løpet av 2 timer. Etter henstand i ytterligere 2 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 50 ml 6n saltsyre tilsatt til resten. Filtrering og rekrystallisering fra etanol gå produktet, sm.p. 177-9° ;(spaltn.), (C10H7N05 krever C 54,31, H 3,19, N 6,33. Funnet: ;C 54,12, H 3,35, N, 6,10). ;Eksempel 3 ;4- hydroksy- 6- metyl- 3- nitrokumarin ;15 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 4-hydroksy-6-metylkumarin (sm.p. 261-4°, 2,50 g) ;i 2 50 ml kloroform ved romtemperatur i løpet av 1,5 time. Etter henstand i ytterligere 3 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml vann tilsatt til resten. Filtrering ga produktet, sm.p. 171-171,5° (spaltn.). (C1QH7N05krever C 54,31; ;H 3,19, N 6,33. Funnet: 54,60, H 3,33, N 6,60). Rekrystallisering ;ut fra etanol hevet smeltepunktet til 172-173° (spaltn.). ;Eksempel 4 ;6- etyl- 4- hydroksy- 3- nitrokumarin ;>■ 33 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 6-etyl-4-hydroksykumarin (sm.p. 216-8°, 5,52 g) ;i 500 ml kloroform ved romtemperatur i løpet av 1 time. Etter henstand i ytterligere 1 time ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet, med sm.p. 114-5°, (C-^HgNOt- krever ;C 56,17, H 3,86, N 5,96. Funnet: C 55,86, H 3,80, N 5,86). Rekrystallisering fra benzen-petroleter (k.p. 40-60°) hevet smeltepunktet til 117-9°. ;Eksempel 5 ;. 7, 8- dimetyl- 4- hydroksy- 3- nitrokumarin ;26 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 7,8-dimetyl-4-hydroksykumarin (sm.p. 237-9° (spaltn.), 4,42 g) i 400 ml kloroform ved romtemperatur i løpet av 1,5 time. Etter henstand i ytterligere 2 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml 6n saltsyre ble tilsatt til resten. Filtrering og rekrystallisering fra etanol ga produktet med sm.p. 186-190° (spaltn), (C^HgNOg krever C 56,18, H 3,86, ;N 5,96. Funnet: C 56,38, H 4,10, N 5,80). ;Eksempel 6 ;6, 8- dimetyl- 4- hydroksy- 3- nitrokumarin ;13 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 6,8-dimetyl-4-hydroksykumarin (sm.p. 253-255°, ;2,21 g) i 200 ml kloroform ved romtemperatur i løpet av 2 timer. Etter henstand i ytterligere 2 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 50 ml 6n saltsyre satt til resten. Filtrering og rekrystallisering fra etanol ga produktet med sm.p. 169,5-170° (spaltn.), (C-^HgNOg krever C 56,18, H 3,86, N 5,96. Funnet: C 56,22, H 3,99, N 5,84). ;Eksempel 7 ;( i) 6, 7- dimetyl- 4- hydroksy- 3- nitrokumarin ;33 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 6,7-dimetyl-4-hydroksykumarin (sm.p. 252-3° (spaltn.), 5,52 g) i 500 ml kloroform ved romtemperatur i løpet av 1 time. Etter henstand i ytterligere 2 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet med sm.p. 200-201° (spaltn.) (C-^HgNOg krever C 56,18, H 3,86, N 5,96. Funnet: C 56,33, H 4,07, N 5,95). Rekrystallisering fra etanol hevet smeltepunktet til 203-4° (spaltn.). ;(ii) 6, 7- dimetyl- 4- hydroksy- 3- nitrokumarin- natriumsalt ;Fortynnet natriumhydroksydløsning ble tilsatt til en suspensjon av 4,32 g 6,7-dimetyl-4-hydroksy-3-nitrokumarin i 60 ml vann til pH-verdien til løsningen nådde 14. Filtrering ga produktet, sm.p. >300° (C^HgNOgNa krever C 51,37, H 3,14, ;N 5,45, Na 8,94. Funnet: C 51,69, H 3,26, N 5,33, N 8,92) etter kort vasking med vann og tørkning under vakuum. ;Eksempel 8 ;6- etyl- 4- hydroksy- 7- metyl- 3- nitrokumarin ;16 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 6-etyl-4-hydroksy-7-metylkumarin (sm.p. 234-7°, 3,17 g) i 250 ml kloroform ved romtemperatur i løpet av 1 time. Etter henstand i ytterligere 1 time ble løsningsmidlet fjernet i vakuum ved romtemperatur og 60. ml 6n saltsyre tilsatt til resten. Filtrering ga produktet, sm.p. 170-2° (spaltn.), (ci2HllN05 krever C 57,83, H 4,45, N 5,62. Funnet: C 58.07, H 4,54, N 5,76). ;Eksempel 9 ;(i) 6, 7- dietyl- 4- hydroksy- 3- nitrokumarin ;17 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 6,7-dietyl-4-hydroksykumarin (sm.p. 213-6°, 3,46 g). ;i 300 ml kloroform ved romtemperatur i løpet av 1,5 time. Etter ytterligere 1 time ble løsningsmidlet fjernet i vakuum ved romtemperatur og 70 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet med sm.p. 115-7° (Cn -.H, -.NO- krever C 59,31, H 4,98, ;N 5,32. Funnet: C 59,26, H 5,16, N 5,25). Rekrystallisering fra etanol hevet smeltepunktet til 119-120°. ;(ii) 6, 7- dietyl- 4- hydroksy- 3- nitrokumarin- natriumsalt ;Fortynnet natriumhydroksydløsning ble tilsatt til en suspensjon av 2,90 g 6,7-dietyl-4-hydroksy-3-nitrokumarin i 20 ml vann til løsningens pH-verdi nådde 14. Filtrering ga produktet som et monohydrat, sm.p. 249-251° (spaltn.) (C^H^NOgNa. H20 ;krever C 51,49, H 4,65, N 4,62, Na 7,58. Funnet: C 52,08, H 4,65 ;N 4,83, Na 7,81) etter vasking med vann og tørkning under vakuum. ;Eksempel 10 ;4- hydroksy- 3- nitro- 5, 6, 7- trimetylkumarin ;18 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 4-hydroksy-5,6,7-trimetylkumarin (sm.p. 2 62-4°, ;3,38 g)'i 250 ml kloroform ved romtemperatur i løpet av 1,5 time. Etter rytterligere 30 minutter ble løsningsmidlet fjernet i vakuum ved romtemperatur og 70 ml 6n saltsyre ble tilsatt til resten. Filtrering ga produktet med sm.p. 134-7° (spaltn.). (ci2HllN05krever C 57,83, H 4,45, N 5,62. Funnet: C 57,92, H 4,57, N 5,65). ;Eksempel 11 ;4, 7- dihydroksy- 3- nitrokumarin ;15 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 4,7-dihydroksykumarin-monohydrat (sm.p. 270-3° ;(spaltn.), 3,0 g) i 150 ml kloroform ved romtemperatur i løpet av ;1 time. Etter ytterligere 2 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 50 ml 6n saltsyre tilsatt til resten. Filtrering og rekrystallisering fra etanol ga produktet med sm.p. 253-6° (spaltn.), (CgHgNOg krever C 48,44, H 2,26, N 6,28. ;Funnet: C 47,78, H 2,44, N 6,07). ;Eksempel 12 ;4- hydroksy- 7- metoksy- 3- nitrokumarin ;17 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 4-hydroksy-7-metoksykumarin (sm.p. 258-260° (spaltn), 3,13 g) i 250 ml kloroform ved romtemperatur i løpet av 1,5 timer. Etter ytterligere 1,5 timer ble løsningsmidlet fjernet i vakuum ;ved romtemperatur og 70 ml 6n saltsyre tilsatt til resten. Filtrering og rekrystallisering fra etanol ga produktet med sm.p. 167-8° (spaltn.). (C1QH7N06 krever C 50,64, H 2,97, N 5,91. ;Funnet: C 50,37, H 3,15, N 5,60. ;Eksempel 13 ;( i) 4- hydroksy- 6- metoksy- 3- nitrokumarin ;30 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 4-hydroksy-6-metoksykumarin (sm.p. 271-2° (spaltn.), ;*C10H7N05 krever c 50»64/H 2,97, N 5,91. Funnet: C 50,78, where R"*" is hydrogen or methyl, ethyl, n-propyl, methoxy, ethoxy or n-propoxy and R^ is methyl, ethyl, n-propyl, methoxy, ethoxy or n-propoxy. Compounds of formula (IA) which are particularly preferred include the following, as well as their pharmaceutically acceptable salts: 6,7-dimethyl-4-hydroxy-3-nitrocoumarin ;6,7-diethyl-4-hydroxy-3-nitrocoumarin ;6 ,7-di-n-propyl-4-hydroxy-3-nitrocoumarin ;6-methyl-7-ethyl-4-hydroxy-3-nitrocoumarin ;6- ethyl-7-methyl-4-hydroxy-3-nitrocoumarin ;7 - methoxy-4-hydroxy-3-nitrocoumarin ;7-ethoxy-4-hydroxy-3-nitrocoumarin ;7-n-propoxy-4-hydroxy-3-nitrocoumarin ;6-methyl-7-methoxy-4-hydroxy-3 -nitrocoumarin ;6-ethyl-7-methoxy-4-hydroxy-3-nitrocoumarin ;6-n-propyl1-7-methoxy-4-hydroxy-3-nitrocoumarin 6-methyl-7-ethoxy-4-hydroxy-3- nitrocoumarin ;6-ethyl-7-ethoxy-4-hydroxy-3-nitrocoumarin ;6-n-propy1-7-ethoxy-4-hydroxy-3-nitrocoumarin 6-methyl-7-n-propoxy-4-hydroxy-3 -nitrocoumarin 6-ethyl-7-n-propoxy-4-hydroxy-3-nitrocoumarin ;.6-n-propyl-7-n-propoxy-4-hydroxy-3-nitrocoumarin Compounds of formula (I) and naturally of formula (IIA) can be prepared by nitration of the parent 4-hydroxycoumarin (II) or ;(HA), ; where R 1 , R 2 , R 2 and R 2 are as defined for formula (I), and R 1 and R 11 are as defined for formula (IIA). The nitration can be carried out using one of the following nitrating agents: (i) The nitrous gases evolved with concentrated nitric acid and arsenic (III) oxide. ;(ii) Acetic acid plus concentrated nitric acid ;(iii) Fuming nitric acid in chloroform ;(iv) Concentrated nitric acid. Since they are useful intermediates, the invention includes compounds of formula IIA. The starting materials of formula (II) can be prepared by any of the standard methods known from the literature for the preparation of 4-hydroxycoumarin. Thus, the reaction of the appropriate phenol with malonic acid using phosphorus oxychloride plus zinc chloride as a condensing agent is one possible route. Using this method, 2- or 4-substituted phenols give only one coumarin product, but 3-substituted phenols can give a mixture of the two possible isomers. These can usually be separated using standard techniques such as fractional crystallization. Another method is the condensation of o-hydroxyacetophenones with diethyl carbonate in the presence of sodium or sodium hydride. The following examples illustrate the preparation and properties of a number of compounds of formula (I). ;Example 1 ;4-hydroxy-3-nitrocoumarin ;30 ml of fuming nitric acid was added to a stirred suspension of 5.0 g of 4-hydroxycoumarin in 500 ml of chloroform at room temperature during 2 hours. After a further 2 hours, the solvent was removed in vacuo at room temperature and 250 ml of water was added to the residue. Filtration gave the product, m.p. 174-5°, (CgH5 NO5 required: C 52.18; H 2.43; N 6.76. Found: C 52.00; ;H 2.38; N 6.62). ;Example 2 ;4-hydroxy-8-methyl-3-nitrocoumarin ;18 ml of fuming nitric acid was added to a stirred suspension of 4-hydroxy-8-methylcoumarin (m.p. 231-5°; 3.03 g) in 250 ml of chloroform at room temperature during 2 hours. After standing for a further 2 hours, the solvent was removed in vacuo at room temperature and 50 ml of 6N hydrochloric acid was added to the residue. Filtration and recrystallization from ethanol give the product, m.p. 177-9° ;(dec.), (C10H7N05 requires C 54.31, H 3.19, N 6.33. Found: ;C 54.12, H 3.35, N, 6.10). ;Example 3 ;4-hydroxy-6-methyl-3-nitrocoumarin ;15 ml fuming nitric acid was added to a stirred suspension of 4-hydroxy-6-methylcoumarin (m.p. 261-4°, 2.50 g); in 250 ml of chloroform at room temperature during 1.5 hours. After standing for a further 3 hours, the solvent was removed in vacuo at room temperature and 100 ml of water was added to the residue. Filtration gave the product, m.p. 171-171.5° (dec.). (C1QH7N05 requires C 54.31; ;H 3.19, N 6.33. Found: 54.60, H 3.33, N 6.60). Recrystallization from ethanol raised the melting point to 172-173° (dec.). ;Example 4 ;6-ethyl-4-hydroxy-3-nitrocoumarin ;>■ 33 ml of fuming nitric acid was added to a stirred suspension of 6-ethyl-4-hydroxycoumarin (m.p. 216-8°, 5.52 g ) in 500 ml of chloroform at room temperature during 1 hour. After standing for a further 1 hour, the solvent was removed in vacuo at room temperature and 100 ml of 6N hydrochloric acid added to the residue. Filtration gave the product, m.p. 114-5°, (C-^HgNOt- requires; C 56.17, H 3.86, N 5.96. Found: C 55.86, H 3.80, N 5.86). Recrystallization from benzene-petroleum ether (b.p. 40-60°) raised the melting point to 117-9°. ;Example 5 ;. 7,8-Dimethyl-4-hydroxy-3-nitrocoumarin; 26 ml fuming nitric acid was added to a stirred suspension of 7,8-dimethyl-4-hydroxycoumarin (m.p. 237-9° (dec.), 4, 42 g) in 400 ml of chloroform at room temperature during 1.5 hours. After standing for a further 2 hours, the solvent was removed in vacuo at room temperature and 100 ml of 6N hydrochloric acid was added to the residue. Filtration and recrystallization from ethanol gave the product with m.p. 186-190° (dec.), (C^HgNOg requires C 56.18, H 3.86, ;N 5.96. Found: C 56.38, H 4.10, N 5.80). ;Example 6 ;6,8-dimethyl-4-hydroxy-3-nitrocoumarin ;13 ml fuming nitric acid was added to a stirred suspension of 6,8-dimethyl-4-hydroxycoumarin (m.p. 253-255°, ;2 .21 g) in 200 ml of chloroform at room temperature during 2 hours. After standing for a further 2 hours, the solvent was removed in vacuo at room temperature and 50 ml of 6N hydrochloric acid was added to the residue. Filtration and recrystallization from ethanol gave the product with m.p. 169.5-170° (dec.), (C-^HgNOg requires C 56.18, H 3.86, N 5.96. Found: C 56.22, H 3.99, N 5.84). ;Example 7 ;( i) 6,7-dimethyl-4-hydroxy-3-nitrocoumarin ;33 ml fuming nitric acid was added to a stirred suspension of 6,7-dimethyl-4-hydroxycoumarin (m.p. 252-3° (spaltn.), 5.52 g) in 500 ml chloroform at room temperature during 1 hour. After standing for a further 2 hours, the solvent was removed in vacuo at room temperature and 100 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product with m.p. 200-201° (dec.) (C-^HgNOg requires C 56.18, H 3.86, N 5.96. Found: C 56.33, H 4.07, N 5.95). Recrystallization from ethanol raised the melting point to 203-4° (dec.). ;(ii) 6,7-dimethyl-4-hydroxy-3-nitrocoumarin sodium salt ;Dilute sodium hydroxide solution was added to a suspension of 4.32 g of 6,7-dimethyl-4-hydroxy-3-nitrocoumarin in 60 ml of water to The pH of the solution reached 14. Filtration gave the product, m.p. >300° (C^HgNOgNa requires C 51.37, H 3.14, ;N 5.45, Na 8.94. Found: C 51.69, H 3.26, N 5.33, N 8.92 ) after brief washing with water and drying under vacuum. ;Example 8 ;6-ethyl-4-hydroxy-7-methyl-3-nitrocoumarin ;16 ml fuming nitric acid was added to a stirred suspension of 6-ethyl-4-hydroxy-7-methylcoumarin (m.p. 234-7 °, 3.17 g) in 250 ml of chloroform at room temperature during 1 hour. After standing for a further 1 hour, the solvent was removed in vacuo at room temperature and 60 ml of 6N hydrochloric acid added to the residue. Filtration gave the product, m.p. 170-2° (dec.), (Cl 2 H 11 NO 5 requires C 57.83, H 4.45, N 5.62. Found: C 58.07, H 4.54, N 5.76). ;Example 9 ;(i) 6,7-diethyl-4-hydroxy-3-nitrocoumarin ;17 ml of fuming nitric acid was added to a stirred suspension of 6,7-diethyl-4-hydroxycoumarin (m.p. 213-6° , 3.46 g). ;in 300 ml of chloroform at room temperature during 1.5 hours. After a further 1 hour, the solvent was removed in vacuo at room temperature and 70 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product with m.p. 115-7° (Cn -.H, -.NO- requires C 59.31, H 4.98, ;N 5.32. Found: C 59.26, H 5.16, N 5.25). Recrystallization from ethanol raised the melting point to 119-120°. ;(ii) 6,7-diethyl-4-hydroxy-3-nitrocoumarin sodium salt ;Dilute sodium hydroxide solution was added to a suspension of 2.90 g of 6,7-diethyl-4-hydroxy-3-nitrocoumarin in 20 ml of water to the pH value of the solution reached 14. Filtration gave the product as a monohydrate, m.p. 249-251° (dec.) (C^H^NOgNa. H20 ; requires C 51.49, H 4.65, N 4.62, Na 7.58. Found: C 52.08, H 4.65 ; N 4.83, Na 7.81) after washing with water and drying under vacuum. ;Example 10 ;4-hydroxy-3-nitro-5, 6,7-trimethylcoumarin ;18 ml of fuming nitric acid was added to a stirred suspension of 4-hydroxy-5,6,7-trimethylcoumarin (m.p. 2 62- 4°, ;3.38 g)'in 250 ml of chloroform at room temperature during 1.5 hours. After a further 30 minutes, the solvent was removed in vacuo at room temperature and 70 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product with m.p. 134-7° (split.). (Cl 2 H 11 NO 5 requires C 57.83, H 4.45, N 5.62. Found: C 57.92, H 4.57, N 5.65). ;Example 11 ;4,7-dihydroxy-3-nitrocoumarin ;15 ml of fuming nitric acid was added to a stirred suspension of 4,7-dihydroxycoumarin monohydrate (m.p. 270-3°;(dec.), 3.0 g) in 150 ml of chloroform at room temperature during ;1 hour. After a further 2 hours, the solvent was removed in vacuo at room temperature and 50 ml of 6N hydrochloric acid was added to the residue. Filtration and recrystallization from ethanol gave the product with m.p. 253-6° (dec.), (CgHgNOg requires C 48.44, H 2.26, N 6.28. ; Found: C 47.78, H 2.44, N 6.07). ;Example 12 ;4-hydroxy-7-methoxy-3-nitrocoumarin ;17 ml fuming nitric acid was added to a stirred suspension of 4-hydroxy-7-methoxycoumarin (m.p. 258-260° (split), 3.13 g) in 250 ml of chloroform at room temperature during 1.5 hours. After a further 1.5 hours, the solvent was removed in vacuo at room temperature and 70 ml of 6N hydrochloric acid added to the residue. Filtration and recrystallization from ethanol gave the product with m.p. 167-8° (spltn.). (C1QH7N06 requires C 50.64, H 2.97, N 5.91. ;Found: C 50.37, H 3.15, N 5.60. ;Example 13 ;( i) 4- hydroxy- 6- methoxy - 3-nitrocoumarin; 30 ml fuming nitric acid was added to a stirred suspension of 4-hydroxy-6-methoxycoumarin (m.p. 271-2° (dec.), ;*C10H7N05 requires c 50»64/H 2.97 , N 5.91 Found: C 50.78,
H 3,18, N 5,47) . H 3.18, N 5.47).
(ii) 4- hydroksy- 6- metoksy- 3- nitrokumarin- natriumsalt (ii) 4- hydroxy- 6- methoxy- 3- nitrocoumarin sodium salt
Fortynnet natriumhydroksydløsning ble tilsatt til en suspensjon av 2,0 g 4-hydroksy-6-metoksy-3-nitrokumarin i 40 ml vann til løsningens pH-verdi nådde 14. Filtrering ga produktet med sm.p. 277-8° (spaltn.), (C^HgNOgNa krever C 46,35, H 2,33, Dilute sodium hydroxide solution was added to a suspension of 2.0 g of 4-hydroxy-6-methoxy-3-nitrocoumarin in 40 ml of water until the pH of the solution reached 14. Filtration gave the product with m.p. 277-8° (dec.), (C^HgNOgNa requires C 46.35, H 2.33,
N 5,41, Na 8,87. Funnet: C 46,32, H 2,44, N 5,50, Na 8,34) N 5.41, Na 8.87. Found: C 46.32, H 2.44, N 5.50, Na 8.34)
etter kort vasking med vann og tørkning under vakuum. after brief washing with water and drying under vacuum.
Eksempel 14 Example 14
4- hydroksy- 5- metoksy- 3- nitrokumarin 4- hydroxy- 5- methoxy- 3- nitrocoumarin
10 ml rykende salpetersyre ble tilsatt til en omrørt løsning av 4-hydroksy-5-metoksykumarin (sm.p. 154,5-156°, 1,63 g) i 100 ml kloroform ved romtemperatur i løpet av 1 time. Etter ytterligere 1 time ble løsningsmidlet fjernet i vakuum og 35 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet med sm.p. 175-177,5° (spaltn.), (C1QH7N06 krever C 50,64, H 2,97, 10 ml fuming nitric acid was added to a stirred solution of 4-hydroxy-5-methoxycoumarin (m.p. 154.5-156°, 1.63 g) in 100 ml chloroform at room temperature over 1 hour. After a further 1 hour, the solvent was removed in vacuo and 35 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product with m.p. 175-177.5° (dec.), (C1QH7N06 requires C 50.64, H 2.97,
N 5,91. Funnet: C 50,54, H 2,97, N 5,63). N 5.91. Found: C 50.54, H 2.97, N 5.63).
Eksempel 15 Example 15
7- etoksy- 4- hydroksy- 3- nitrokumarin 7- ethoxy- 4- hydroxy- 3- nitrocoumarin
25 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 7-etoksy-4-hydroksykumarin (sm.p. 267-8°, 5,0 g) 25 ml of fuming nitric acid was added to a stirred suspension of 7-ethoxy-4-hydroxycoumarin (m.p. 267-8°, 5.0 g)
i 500 ml kloroform ved romtemperatur i løpet av 1,5 timer. Etter ytterligere 2 timer ble løsningsmidlet fjernet i vakuum og 100 ml 6n saltsyre tilsatt til resten. Filtrering og rekrystallisering fra etanol ga produktet med sm.p. 153-4° (spaltn.), (C-^HgNOg krever C 52,59, H 3,61, N 5,58. Funnet: C 52,48, H 3,36, N 5,29). in 500 ml of chloroform at room temperature during 1.5 hours. After a further 2 hours, the solvent was removed in vacuo and 100 ml of 6N hydrochloric acid was added to the residue. Filtration and recrystallization from ethanol gave the product with m.p. 153-4° (dec.), (C-^HgNOg requires C 52.59, H 3.61, N 5.58. Found: C 52.48, H 3.36, N 5.29).
Eksempel 16 Example 16
(i) 4- hydroksy- 3- nitro- 7- n- propoksykumarin (i) 4-hydroxy-3-nitro-7-n-propoxycoumarin
15 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 4-hydroksy-7-n-propoksykumarin (sm.p. 216-8°, 3,0 g) i 300 ml kloroform ved romtemperatur i løpet.av 1 time. Etter ytterligere 1 time, ble løsningsmidlet fjernet i vakuum og 60 ml 6n saltsyre tilsatt til resten. Filtrering og rekrystallisering fra etanol ga produktet med sm.p. 151-2°, (ci2HllN06 krever C 54,34, H 4,18, N 5,28. Funnet: C 54,38, H 4,28, N 5,24). 15 ml fuming nitric acid was added to a stirred suspension of 4-hydroxy-7-n-propoxycoumarin (m.p. 216-8°, 3.0 g) in 300 ml chloroform at room temperature over 1 hour. After an additional 1 hour, the solvent was removed in vacuo and 60 mL of 6N hydrochloric acid was added to the residue. Filtration and recrystallization from ethanol gave the product with m.p. 151-2°, (Cl 2 H 11 NO 6 requires C 54.34, H 4.18, N 5.28. Found: C 54.38, H 4.28, N 5.24).
(ii) 4- hydroksy- 3- nitro- 7- n- propoksykumarin- natriumsalt (ii) 4-hydroxy-3-nitro-7-n-propoxycoumarin sodium salt
Fortynnet natriumhydroksydløsning ble tilsatt til en suspensjon.av 4-hydroksy-3-nitro-7-n-propoksykumarin (1,92 g) i 20 ml vann til løsningens pH-verdi nådde 14. Filtrering ga produktet, spaltes ved 212-220°, etter vasking med vann og tørkning under vakuum. Dilute sodium hydroxide solution was added to a suspension of 4-hydroxy-3-nitro-7-n-propoxycoumarin (1.92 g) in 20 mL of water until the pH of the solution reached 14. Filtration gave the product, c.p. 212-220° , after washing with water and drying under vacuum.
Eksempel 17 Example 17
6- benzyloksy- 4- hydroksy- 3- nitrokumarin- natrlumsalt 6- benzyloxy- 4- hydroxy- 3- nitrocoumarin sodium salt
13 ml rykende.salpetersyre ble tilsatt til en omrørt suspensjon av 6-benzyloksy-4-hydroksykumarin (sm.p. 226-8°, 3,13 g) i 200 ml kloroform ved romtemperatur i løpet av 1,5 timer. Etter 13 ml fuming nitric acid was added to a stirred suspension of 6-benzyloxy-4-hydroxycoumarin (m.p. 226-8°, 3.13 g) in 200 ml chloroform at room temperature over 1.5 hours. After
r r
ytterligere 1,5 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml vann tilsatt til resten. Filtrering ga et oljeaktig, fast stoff som ble oppløst i benzen, filtrert, og filtratet ble inndampet til tørrhet slik at man fikk et gult, fast stoff som spaltes ved 170°. Det faste stoff ble suspendert i for a further 1.5 hours, the solvent was removed in vacuo at room temperature and 100 ml of water was added to the residue. Filtration gave an oily solid which was dissolved in benzene, filtered, and the filtrate evaporated to dryness to give a yellow solid which decomposed at 170°. The solid was suspended in
30 ml vann og fortynnet natriumhydroksydløsning tilsatt til 30 ml of water and dilute sodium hydroxide solution added to
løsningens pH-verdi nådde 14. Filtrering ga produktet med sm.p. 262-4° (spaltn.). (C^H^NOgNa krever C 57, 32, H 3,01, N 4,18, the pH value of the solution reached 14. Filtration gave the product with m.p. 262-4° (split.). (C^H^NOgNa requires C 57.32, H 3.01, N 4.18,
Na 6,86. Funnet: C 57,44, H 3,31, N 4,34, Na 6,86. Funnet: Well 6.86. Found: C 57.44, H 3.31, N 4.34, Na 6.86. Found:
C 57,44, H 3,31, N 4,34, Na 6,67) etter vasking med vann og tørkning under vakuum. C 57.44, H 3.31, N 4.34, Na 6.67) after washing with water and drying under vacuum.
Eksempel 18 Example 18
4- hydroksy- 7- metoksy- 8- metyl- 3- nitrokumarin 4- hydroxy- 7- methoxy- 8- methyl- 3- nitrocoumarin
15 ml rykende salpetersyre ble tilsatt til en suspensjon av 4-hydroksy-7-metoksy-8-metylkumarin (sm.p. 261-4° (spaltn.), 3,0 g) i 250 ml kloroform ved romtemperatur i løpet av 1 time. Etter ytterligere 1,5 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 60 ml 6n saltsyre tilsettes til resten. Filtrering og rekrystallisering fra benzen ga produktet med 15 ml fuming nitric acid was added to a suspension of 4-hydroxy-7-methoxy-8-methylcoumarin (m.p. 261-4° (dec.), 3.0 g) in 250 ml chloroform at room temperature over 1 hour. After a further 1.5 hours, the solvent was removed in vacuo at room temperature and 60 ml of 6N hydrochloric acid was added to the residue. Filtration and recrystallization from benzene gave the product
sm.p. 195-7° (spaltn.); (C-^HgNOg krever C 52,60, H 3,61, N 5,58. Funnet: C 52,34, H 3,77, N 5,65). sm.p. 195-7° (spltn.); (C-^HgNOg requires C 52.60, H 3.61, N 5.58. Found: C 52.34, H 3.77, N 5.65).
Eksempel 19 Example 19
6- etyl- 4- hydroksy- 7- metoksy- 3- nitrokumarin 6- ethyl- 4- hydroxy- 7- methoxy- 3- nitrocoumarin
15 ml rykende salpetersyre ble tilsatt til en suspensjon av 6-etyl-4-hydroksy-7-metoksykumarin (sm.p. 262-5° (spaltn.), 2,86 g) i 250 ml kloroform ved romtemperatur i løpet av 1 time. Etter ytterligere 1 time ble løsningsmidlet fjernet i vakuum ved romtemperatur og 60 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet med sm.p. 193-5° (spaltn.), (ci2HnN06 krever c 54,34, H 4,18, N 5,28, Funnet: C 54,03,. H 4,16, H 5,21). 15 ml fuming nitric acid was added to a suspension of 6-ethyl-4-hydroxy-7-methoxycoumarin (m.p. 262-5° (dec.), 2.86 g) in 250 ml chloroform at room temperature over 1 hour. After a further 1 hour, the solvent was removed in vacuo at room temperature and 60 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product with m.p. 193-5° (dec.), (Cl2HnN06 requires c 54.34, H 4.18, N 5.28, Found: C 54.03,. H 4.16, H 5.21).
Eksempel 20 Example 20
(i) 3, 6- dinitro- 4- hydroksykumarin (i) 3,6-dinitro-4-hydroxycoumarin
10,0 g 4-hydroksykumarin ble oppløst i 20 ml konsentrert svovelsyre under omrøring og avkjøling. Til dette ble 20 ml rykende 10.0 g of 4-hydroxycoumarin was dissolved in 20 ml of concentrated sulfuric acid with stirring and cooling. To this, 20 ml became fuming
salpetersyre tilsatt i løpet av 20 minutter, under avkjøling med isvann etter behov. Etter 1 time ble blandingen hellet ned i 100 g isvann og fikk henstå i 1 time. Filtrering og rekrystallisering fra benzen/etanol ga produktet, sm.p. 182-3° (spaltn.), (CgH4N207krever C 42,87, H 1,60, N 11,11. Funnet: C 43,24, H 1,72, nitric acid added over 20 minutes, cooling with ice water as needed. After 1 hour, the mixture was poured into 100 g of ice water and allowed to stand for 1 hour. Filtration and recrystallization from benzene/ethanol gave the product, m.p. 182-3° (dec.), (CgH4N2O7requires C 42.87, H 1.60, N 11.11. Found: C 43.24, H 1.72,
N 10,81). N 10.81).
(ii) 3, 6- dinitro- 4- hydroksykumarin- natriumsalt (ii) 3,6-dinitro-4-hydroxycoumarin sodium salt
Fortynnet natriumhydroksydløsning ble tilsatt til en omrørt løsning av 5,17 g 3,6-dinitro-4-hydroksykumarin i 150 ml vann til løsningens pH-verdi nådde 14. Filtrering ga produktet, sm.p. >310°, (C9H3N207Na krever C 39,43, H 1,10, N 10,22. Funnet: C 39,28, H 1,26, N 10,17) etter vasking med vann og tørkning under vakuum. Dilute sodium hydroxide solution was added to a stirred solution of 5.17 g of 3,6-dinitro-4-hydroxycoumarin in 150 ml of water until the pH of the solution reached 14. Filtration gave the product, m.p. >310°, (C9H3N207Na requires C 39.43, H 1.10, N 10.22. Found: C 39.28, H 1.26, N 10.17) after washing with water and drying under vacuum.
Eksempel 21 Example 21
(i) 6- klor- 4- hydroksy- 3- nitrokumarin (i) 6- chloro- 4- hydroxy- 3- nitrocoumarin
13,5 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 6-klor-4-hydroksykumarin (sm.p. 266-8°, 2,33 g) i 200 ml kloroform ved romtemperatur i løpet av 1 time. Etter ytterligere 2 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet, sm.p. 158-9° (spaltn.), (Cgl^NOgCl krever C 44,74, 13.5 ml fuming nitric acid was added to a stirred suspension of 6-chloro-4-hydroxycoumarin (m.p. 266-8°, 2.33 g) in 200 ml chloroform at room temperature over 1 hour. After a further 2 hours, the solvent was removed in vacuo at room temperature and 100 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product, m.p. 158-9° (dec.), (Cgl^NOgCl requires C 44.74,
H 1,67, N 5,80, Cl 14,68. Funnet: C 44,47, H 1,63, N 5,72, H 1.67, N 5.80, Cl 14.68. Found: C 44.47, H 1.63, N 5.72,
Cl 15,02). Cl 15.02).
(ii) 6- klor- 4- hydroksy- 3- nitrokumarin- natriumsalt (ii) 6- chloro- 4- hydroxy- 3- nitrocoumarin sodium salt
Fortynnet natriumhydroksydløsning ble tilsatt til en omrørt suspensjon av 2,30 g 6-klor-4-hydroksy-3-nitrokumarin i 40 ml vann til løsningens pH-verdi nådde 14. Filtrering ga produktet, Dilute sodium hydroxide solution was added to a stirred suspension of 2.30 g of 6-chloro-4-hydroxy-3-nitrocoumarin in 40 mL of water until the pH of the solution reached 14. Filtration gave the product,
sm.p. >300°, (CgH3N05ClNa krever C 41,01, H 1,15, N 5,31, Cl 13,45, Na 8,72. Funnet: C 40,97, H 1,29, N 5,34, Cl 12,68, Na 8,91) etter vasking med vann og tørkning under vakuum. sm.p. >300°, (CgH3N05ClNa requires C 41.01, H 1.15, N 5.31, Cl 13.45, Na 8.72. Found: C 40.97, H 1.29, N 5.34, Cl 12.68, Na 8.91) after washing with water and drying under vacuum.
Eksempel 22 Example 22
(i) 7- klor- 4- hydroksy- 3- nitrokumarin (i) 7-chloro-4-hydroxy-3-nitrocoumarin
27 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 7-klor-4-hydroksykumarin (sm.p. 251-2°, 4,5 g) i 400 ml kloroform ved romtemperatur i løpet av 1 time. Etter ytterligere 1,5 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet, sm.p. 174-5° (spaltn.), (CgH^OgCl krever C 44,74, 27 ml fuming nitric acid was added to a stirred suspension of 7-chloro-4-hydroxycoumarin (m.p. 251-2°, 4.5 g) in 400 ml chloroform at room temperature over 1 hour. After a further 1.5 hours, the solvent was removed in vacuo at room temperature and 100 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product, m.p. 174-5° (dec.), (CgH^OgCl requires C 44.74,
H 1,67, N 5,80, Cl 14,68. Funnet: C 44,64, H 1,81, N 5,62, H 1.67, N 5.80, Cl 14.68. Found: C 44.64, H 1.81, N 5.62,
Cl 14,96). Cl 14.96).
(ii) 7- klor- 4- hydroksy- 3- nitrokumarin- natriumsalt (ii) 7- chloro- 4- hydroxy- 3- nitrocoumarin sodium salt
Fortynnet natriumhydroksydløsning ble tilsatt til en Dilute sodium hydroxide solution was added to a
omrørt suspensjon av 5,1 g 7-klor-4-hydroksy-3-nitrokumarin i 60 ml vann til løsningens pH-verdi nådde 14. Filtrering ga produktet, som spaltes ved 295°, (CgH3N05ClNa krever C 41,01, H 1,15, N 5,31, stirred suspension of 5.1 g of 7-chloro-4-hydroxy-3-nitrocoumarin in 60 ml of water until the pH of the solution reached 14. Filtration gave the product, which decomposes at 295°, (CgH3N05ClNa requires C 41.01, H 1 ,15, N 5.31,
Cl 13,46, Na 8,72. Funnet: C 40,41, H 1,13, N 4,90, Cl 13,64, Cl 13.46, Na 8.72. Found: C 40.41, H 1.13, N 4.90, Cl 13.64,
Na 9,61) etter vasking med vann og tørkning under vakuum. Na 9.61) after washing with water and drying under vacuum.
Eksempel 2 3 Example 2 3
(i) 6- brom- 4- hydroksy- 3- nitrokumarin (i) 6- bromo- 4- hydroxy- 3- nitrocoumarin
17 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 6-brom-4-hydroksykumarin (sm.p. 275-7°, 3,25 g) i 200 ml kloroform ved romtemperatur i løpet av 1,5 timer. Etter ytterligere 2 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet, sm.p. 161-4° (spaltn.), (CgH^NOj-Br krever C 37,79, 17 ml of fuming nitric acid was added to a stirred suspension of 6-bromo-4-hydroxycoumarin (m.p. 275-7°, 3.25 g) in 200 ml of chloroform at room temperature over 1.5 hours. After a further 2 hours, the solvent was removed in vacuo at room temperature and 100 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product, m.p. 161-4° (dec.), (CgH^NOj-Br requires C 37.79,
H 1,41, N 4,90, Br 27,94. Funnet: C 37,86, H 1,63, N 5,05, H 1.41, N 4.90, Br 27.94. Found: C 37.86, H 1.63, N 5.05,
Br 27,64). Br 27,64).
(ii) 6- brom- 4- hydroksy- 3- nitrokumarin- natriumsalt (ii) 6- bromo- 4- hydroxy- 3- nitrocoumarin sodium salt
Fortynnet natriumhydroksydløsning ble tilsatt til en suspensjon av 2,80 g 6-brom-4-hydroksy-3-nitrokumarin i 20 ml vann til løsningens pH-verdi nådde 14. Filtrering ga produktet, Dilute sodium hydroxide solution was added to a suspension of 2.80 g of 6-bromo-4-hydroxy-3-nitrocoumarin in 20 ml of water until the pH of the solution reached 14. Filtration gave the product,
sm.p. >300°, (CgH-jNOj-BrNa krever C 35,09 , H 0,98, N 4,55, Na 7,46. Funnet: C 35,50, H 1,16, N 4,66, Na 6,98) etter vasking med vann sm.p. >300°, (CgH-jNOj-BrNa requires C 35.09 , H 0.98, N 4.55, Na 7.46. Found: C 35.50, H 1.16, N 4.66, Na 6 .98) after washing with water
og tørkning under vakuum. and drying under vacuum.
Eksempel 2 4 Example 2 4
(i) 7- brom- 4- hydroksy- 3- nitrokumarin (i) 7- bromo- 4- hydroxy- 3- nitrocoumarin
27 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 7-brom-4-hydroksykumarin (sm.p. 247,5-248,5°, 4,18 g) 27 ml of fuming nitric acid was added to a stirred suspension of 7-bromo-4-hydroxycoumarin (m.p. 247.5-248.5°, 4.18 g)
i 400 ml kloroform ved romtemperatur i løpet av 1,5 timer. Etter ytterligere 1,5 timer ble løsningsmidlet fjernet i vakuum ved romtemperatur og 100 ml 6n saltsyre tilsatt til resten. Filtrering ga produktet, sm.p. 155-7°, (Cgl^NOgBr krever C 37,79, H 1,41, in 400 ml of chloroform at room temperature during 1.5 hours. After a further 1.5 hours, the solvent was removed in vacuo at room temperature and 100 ml of 6N hydrochloric acid was added to the residue. Filtration gave the product, m.p. 155-7°, (Cgl^NOgBr requires C 37.79, H 1.41,
N 4,90, Br 27,94. Funnet: C 37,46, H 1,45, N 4,78, Br 27,93). N 4.90, Br 27.94. Found: C 37.46, H 1.45, N 4.78, Br 27.93).
(L i) 7- brom- 4- hydroksy- 3- nitrokumarin- natriumsalt (L i) 7- bromo- 4- hydroxy- 3- nitrocoumarin sodium salt
Fortynnet natriumhydroksydløsning ble tilsatt til en suspensjon av 4,3 g 7-brom-4-hydroksy-3-nitrokumarin i 50 ml vann til løsningens pH-verdi nådde 14. Filtrering ga produktet, sm.p..265-7° (spaltn.) etter vasking med vann og tørkning under vakuum.. Dilute sodium hydroxide solution was added to a suspension of 4.3 g of 7-bromo-4-hydroxy-3-nitrocoumarin in 50 ml of water until the pH of the solution reached 14. Filtration gave the product, m.p..265-7° (splitn .) after washing with water and drying under vacuum..
Eksempel 25 Example 25
r Ved tilsetning av rykende salpetersyre til en omrørt suspensjon av 6,7-di-n-propyl-4-hydroksykumarin i kloroform ved romtemperatur i løpet av 2 timer og under anvendelse av den samme fremgangsmåte som i eksemplene 7 og 9, dannes 6,7-di-n-propyl-4-hydroksy-3-nitrokumarin som den frie syre og natriumsaltet. r By adding fuming nitric acid to a stirred suspension of 6,7-di-n-propyl-4-hydroxycoumarin in chloroform at room temperature over 2 hours and using the same procedure as in Examples 7 and 9, 6 is formed, 7-di-n-propyl-4-hydroxy-3-nitrocoumarin as the free acid and the sodium salt.
Ved å følge samme generelle fremgangsmåte som angitt i eksempel 8, men under anvendelse av 6-metyl-7-etyl-4-hydroksykumarin som utgangsmateriale, oppnås 6-metyl-7-etyl-4-hydroksy-3-nitrokumarin. By following the same general procedure as stated in example 8, but using 6-methyl-7-ethyl-4-hydroxycoumarin as starting material, 6-methyl-7-ethyl-4-hydroxy-3-nitrocoumarin is obtained.
Ved å følge samme generelle fremgangsmåte som angitt i eksempel 19, men under anvendelse av 6-metyl-7-metoksy-4-hydroksykumarin som utgangsmateriale, oppnås 6-metyl-7-metoksy-4-hydroksy-3- nitrokumarin. By following the same general procedure as stated in example 19, but using 6-methyl-7-methoxy-4-hydroxycoumarin as starting material, 6-methyl-7-methoxy-4-hydroxy-3-nitrocoumarin is obtained.
Ved å følge samme generelle fremgangsmåte som angitt i eksempel 19, men under anvendelse .av 6-n-propyl-7-metoksy-4-hydroksykumarin som utgangsmateriale, oppnås 6-n-propyl-7-metoksy-4- hydroksy-3-nitrokumarin. By following the same general procedure as stated in example 19, but using 6-n-propyl-7-methoxy-4-hydroxycoumarin as starting material, 6-n-propyl-7-methoxy-4-hydroxy-3- nitrocoumarin.
Ved å følge samme generelle fremgangsmåte som angitt i eksempel 19, men under anvendelse av følgende utgangsmaterialer: 6-metyl-7-etoksy-4-hydroksykumarin By following the same general procedure as set forth in Example 19, but using the following starting materials: 6-methyl-7-ethoxy-4-hydroxycoumarin
6-etyl-7-etoksy-4-hydroksykumarin 6-ethyl-7-ethoxy-4-hydroxycoumarin
6-n-propyl-7-etoksy-4-hydroksykumarin 6-n-propyl-7-ethoxy-4-hydroxycoumarin
6-metyl-7-ri-propoksy-4-hydroksykumarin 6-methyl-7-ri-propoxy-4-hydroxycoumarin
6-etyl-7-n-propoksy-4-hydroksykumarin 6-Ethyl-7-n-propoxy-4-hydroxycoumarin
6-n-propyl-7-n-propoksy-4-hydroksykumarin 6-n-propyl-7-n-propoxy-4-hydroxycoumarin
oppnås følgende forbindelser: 6-metyl-7-etoksy-4-hydroksy-3-nitrokumarin 6-etyl-7-etoksy-4-hydroksy-3-nitrokumarin the following compounds are obtained: 6-methyl-7-ethoxy-4-hydroxy-3-nitrocoumarin 6-ethyl-7-ethoxy-4-hydroxy-3-nitrocoumarin
6-n-propyl-7-etoksy-4-hydroksy^3-nitrokumarin 6-metyl-7-n-propoksy-4-hydroksy-3-nitrokumarin 6-etyl-7-n-propoksy-4-hydroksy-3-nitrokumarin 6-n-propy1-7-n-propoksy-4-hydroksy-3-nitrokumarin 6-n-propyl-7-ethoxy-4-hydroxy^3-nitrocoumarin 6-methyl-7-n-propoxy-4-hydroxy-3-nitrocoumarin 6-ethyl-7-n-propoxy-4-hydroxy-3- nitrocoumarin 6-n-propy1-7-n-propoxy-4-hydroxy-3-nitrocoumarin
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1887673A GB1432809A (en) | 1973-04-19 | 1973-04-19 | Coumarin derivatives |
| NO741385 | 1974-04-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO750863L true NO750863L (en) | 1974-10-22 |
Family
ID=26253659
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO750863A NO750863L (en) | 1973-04-19 | 1975-03-13 | |
| NO750864A NO750864L (en) | 1973-04-19 | 1975-03-13 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO750864A NO750864L (en) | 1973-04-19 | 1975-03-13 |
Country Status (1)
| Country | Link |
|---|---|
| NO (2) | NO750863L (en) |
-
1975
- 1975-03-13 NO NO750863A patent/NO750863L/no unknown
- 1975-03-13 NO NO750864A patent/NO750864L/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO750864L (en) | 1974-10-22 |
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