NO750864L - - Google Patents
Info
- Publication number
- NO750864L NO750864L NO750864A NO750864A NO750864L NO 750864 L NO750864 L NO 750864L NO 750864 A NO750864 A NO 750864A NO 750864 A NO750864 A NO 750864A NO 750864 L NO750864 L NO 750864L
- Authority
- NO
- Norway
- Prior art keywords
- hydroxy
- nitrocoumarin
- added
- room temperature
- product
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000006396 nitration reaction Methods 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000000802 nitrating effect Effects 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 238000002156 mixing Methods 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
- 239000000725 suspension Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 238000001914 filtration Methods 0.000 description 33
- 239000000047 product Substances 0.000 description 33
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 239000011734 sodium Substances 0.000 description 17
- -1 aralkoxy Chemical group 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 13
- VXIXUWQIVKSKSA-UHFFFAOYSA-N 4-hydroxycoumarin Chemical compound C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 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
- 241001465754 Metazoa Species 0.000 description 8
- 230000004044 response Effects 0.000 description 6
- 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
- 241000700159 Rattus Species 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 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 3
- 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
- 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 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
- 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 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
- 108010058846 Ovalbumin Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 208000006673 asthma Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 229940092253 ovalbumin Drugs 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- DXMGZEOFDYHIIO-UHFFFAOYSA-N 4-hydroxy-3-nitro-6,7-dipropylchromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(CCC)C(CCC)=C2 DXMGZEOFDYHIIO-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
- 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 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
- CLSXJCRBXDOZJP-UHFFFAOYSA-N 6-ethyl-4-hydroxy-7-methyl-3-nitrochromen-2-one Chemical compound OC1=C([N+]([O-])=O)C(=O)OC2=C1C=C(CC)C(C)=C2 CLSXJCRBXDOZJP-UHFFFAOYSA-N 0.000 description 2
- LVZTYKPCDIGFBZ-UHFFFAOYSA-N 7-ethoxy-6-ethyl-4-hydroxy-3-nitrochromen-2-one Chemical compound O1C(=O)C([N+]([O-])=O)=C(O)C2=C1C=C(OCC)C(CC)=C2 LVZTYKPCDIGFBZ-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 241000700157 Rattus norvegicus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000000872 buffer Substances 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
- 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
- 239000000203 mixture Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000005303 weighing Methods 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
- 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
- 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 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
- 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
- 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
- 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 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
- 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
- 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 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
- 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
- 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 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241001239379 Calophysus macropterus Species 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
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali 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
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 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
- 238000012754 cardiac puncture Methods 0.000 description 1
- BPHHNXJPFPEJOF-UHFFFAOYSA-J chembl296966 Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)C1=CC(S([O-])(=O)=O)=C(N)C2=C(O)C(N=NC3=CC=C(C=C3OC)C=3C=C(C(=CC=3)N=NC=3C(=C4C(N)=C(C=C(C4=CC=3)S([O-])(=O)=O)S([O-])(=O)=O)O)OC)=CC=C21 BPHHNXJPFPEJOF-UHFFFAOYSA-J 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
- 239000000839 emulsion Substances 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
- 239000011521 glass 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
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 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
- 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
- 150000002828 nitro derivatives Chemical class 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
- 210000001672 ovary Anatomy 0.000 description 1
- 229940066827 pertussis vaccine Drugs 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
- 239000008363 phosphate buffer Substances 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
- 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
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 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
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Oppfinnelsen vedrører farmasøytiske preparater som er nyttige ved inhibering av effektene av visse typer av antigen/- antistoff-reaksjoner, og er derfor av verdi i profylaksen og behandlingen av sykdommer som er assosiert med allergiske eller The invention relates to pharmaceutical preparations which are useful in inhibiting the effects of certain types of antigen/antibody reactions, and are therefore of value in the prophylaxis and treatment of diseases which are associated with allergic or
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immunologiske reaksjoner, f.eks. visse typer av astma og høyfeber, og også ved behandling av rhinitt. Oppfinnelsen innbefatter også en rekke nye 3-nitrokumariner og en fremgangsmåte for fremstilling av slike. immunological reactions, e.g. certain types of asthma and hay fever, and also in the treatment of rhinitis. The invention also includes a number of new 3-nitrocoumarins and a method for producing such.
Det er oppdaget at visse 3-nitrokumariner har nyttig aktivitet hos pattedyr ved det at de inhiberer effektene av visse typer av antigen/antistoff-raksjoner. 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 beneficial 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^, IL,, 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^, R2, 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^, IL,, 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 1 , R 2 , R 1 and R 2 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: 4-hydroksy-3-nitrokumarin ^' ^''10Below are the compounds of formula (I) which have been found discussed in the literature, together with the relevant literature reference: 4-hydroxy-3-nitrocoumarin ^' ^''10
4-hydroksy-6-metyl-3-nitrokumarin 1 '2 4-hydroxy-6-methyl-3-nitrocoumarin 1 '2
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<5>6- klor-4-hydroksy-3-nitrokumarin<11>4-hydroxy-7-isopropyl-5-methyl-3-nitrocoumarin ^ 4-hydroxy-8-isopropyl-5-methyl-3-nitrocoumarin<5>6-chloro-4-hydroxy-3-nitrocoumarin<11>
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-dihydroksy-3,6-dinitrokumarin ^ 4,7-dihydroxy-3-nitrocoumarin 2 '7 4,7-dihydroxy-3,6-dinitrocoumarin ^
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
ReferanserReferences
1. J. Chem. Soc. C. (1971), 2181. J. Chem. Soc. C. (1971), 218
2. Proe' Ind. Acad. Sei. Sect A. (1968), 67, 422. Proe' Ind. Acad. Pollock. Sect A. (1968), 67, 42
3. J. Amer. Chem. Soc, (1945), 6J_, 993. J. Amer. Chem. Soc, (1945), 6J_, 99
4. Yakugaku Zassi (1966), 86, 1064 (Chemical Abstracts 1967, 66, I04869u) 5. Annalen (1961) , 64_3, 97 6. Pharmazie (1953) , 8, 221 (CA. 4_8, 7602g) 4. Yakugaku Zassi (1966), 86, 1064 (Chemical Abstracts 1967, 66, I04869u) 5. Annalen (1961) , 64_3, 97 6. Pharmazie (1953) , 8, 221 (CA. 4_8, 7602g)
7. Chem. Pharm. Bull., (1971), 19, 10467. Chem. Pharm. Bull., (1971), 19, 1046
8. Monatsh (1958), 8_9, 787 9. Monatsh (1958), 89_, 143 10. Arch. Pharm (1963), 296, 365 8. Monatsh (1958), 8_9, 787 9. Monatsh (1958), 89_, 143 10. Arch. Pharm (1963), 296, 365
11. Glas. Hem. Tehndl. Bosne, Hercegovine (1968), _16, 10911. Glass. Home. Tehndl. Bosne, Hercegovine (1968), _16, 109
(Chemical Abstracts 72, 43345V)(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 sli.ke 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^fR2, 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^fR2, R^ and R^ represent hydrogen or alkyl, alkoxy, aryloxy, aralkyl, aryl, aralkyl, heterocyclic, hydroxy, nitro or halogen groups and any two of
gruppene R^, ' R3°9R4sammen 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^, 'R3°9R4 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^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^ 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 R1og R2og 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 er angitt ovenfor. n-, sec- and tert-butoxy, phenoxy, benzyloxy, phenyl, benzyl, pyridyl, fluorine, chlorine, bromine, iodine. In addition, R1 and R2 and R^. or R^ and R^ together with the carbon atoms to which they are attached form a fused phenyl or fused 1,2-cyclohexenylene ring which may have one or more of the substituents indicated above.
Fortrinnsvis er R^og R^hydrogen, og R2og R^ er hver Preferably, R₂ and R₂ are hydrogen, and R₂ and R₂ are each
metyl, etyl, n-propyl, metoksy, etoksy eller n-propoksygrupper. 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
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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 anvendesThe 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<1>er hydrogen eller metyl, etyl, n-propyl, metoksy, etoksy eller n-propoksy og R er metyl, etyl, n-propyl, metoksy, etoksy eller n-propoksy. where R<1> is hydrogen or methyl, ethyl, n-propyl, methoxy, ethoxy or n-propoxy and R is methyl, ethyl, n-propyl, methoxy, ethoxy or n-propoxy.
Forbindelser av formel (IA) som er spesielt foretrukket, innbefatter de følgende, samt deres farmasøytisk akseptable salter: 6,7-dimetyl-4-hydroksy-3-nitrokumarin 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-dietyl-4-hydroksy-3-nitrokumarin 6,7-diethyl-4-hydroxy-3-nitrocoumarin
6,7-di-n-propyl-4-hydroksy-3-nitrokumarin 6,7-di-n-propyl-4-hydroxy-3-nitrocoumarin
6-mety1-7-etyl-4-hydroksy-3-nitrokumarin 6-methyl-7-ethyl-4-hydroxy-3-nitrocoumarin
6- ety1-7-metyl-4-hydroksy-3-nitrokumarin 6-ethyl-7-methyl-4-hydroxy-3-nitrocoumarin
7- metoksy-4-hydroksy-3-nitrokumarin 7- methoxy-4-hydroxy-3-nitrocoumarin
7-etoksy-4-hydroksy-3-nitrokumarin7-ethoxy-4-hydroxy-3-nitrocoumarin
r r
7-n-propoksy-4-hydroksy-3-nitrokumarin 7-n-propoxy-4-hydroxy-3-nitrocoumarin
6-metyl-7-metoksy-4-hydroksy-3-nitrokumarin 6-methyl-7-methoxy-4-hydroxy-3-nitrocoumarin
6-ety1-7-metoksy-4-hydroksy-3-nitrokumarin 6-ethyl-7-methoxy-4-hydroxy-3-nitrocoumarin
6-n-propy1-7-metoksy-4-hydroksy-3-nitrokumarin 6-metyl-7-etoksy-4-hydroksy-3-nitrokumarin 6-n-propyl-7-methoxy-4-hydroxy-3-nitrocoumarin 6-methyl-7-ethoxy-4-hydroxy-3-nitrocoumarin
6-ety1-7-etoksy-4-hydroksy-3-nitrokumarin 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-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 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-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), (HAVE),
hvor R^, R2, R^og R4er som definert for formel (I), og R<1>og R1"*" 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°, ;(CgH5N05 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. Filtréring og rekrystallisering fra etanol ga 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 250 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.). (C1QH7N05 krever 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^HgNO,- 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), (C1;LHgN05 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.), (Ci;LHgN05 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^H<g>NO,.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) 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,,HoN0cNa krever C 51,37, H 3,14, ;11 o 5 ;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° (spalt<n.>), (ci2HllN05 brever 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>° (C13H13N05 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>13H12NO,-Na.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. 262-4°, ;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.). (C10H7N06krever 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, ;H 3,18, N 5,47). ;(ii) 4- hy. droksy- 6- metoksy- 3- nitrokumarin- natriumsalt;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, ;N 5,41, Na 8,87. Funnet: C 46,32, H 2,44, N 5,50, Na 8,34) ;etter kort vasking med vann og tørkning under vakuum.;Eksempel 14;4- hydroksy- 5- metoksy- 3- nitrokumarin;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.), (C10H7N06krever C 50,64, H 2,97, ;N 5,91. Funnet: C 50,54, H 2,97, N 5,63). ;Eksempel 15;7- etoksy- 4- hydroksy- 3- nitrokumarin;25 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 7-etoksy-4-hydroksykumarin (sm.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). ;Eksempel 16;(i) 4- hydroksy- 3- nitro- 7- n- propoksykumarin;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>°, (C]_2HHN06 krever C 54,34, H 4,18, N 5,28. Funnet: C 54,38, H 4,28, N 5,24). ;(ii) 4- hydroksy- 3- nitro- 7- n- propoksykumarin- natriumsalt;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. ;Eksempel 17;6- benzyloksy- 4- hydroksy- 3- nitrokumarin- natriumsalt;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 ;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 30 ml vann og fortynnet natriumhydroksydløsning tilsatt til løsningens pH-verdi nådde 14. Filtrering ga produktet med sm.p. 262-4° (spalt<n.>). (<C>^<H>^<N>O^Na krever 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:;C 57,44, H 3,31, N 4,34, Na 6,67) etter vasking med vann og tørkning under vakuum. ;Eksempel 18;4- hydroksy- 7- metoksy- 8- metyl- 3- nitrokumarin;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 ;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). ;Eksempel 19;6- ety1- 4- hydroksy- 7- metoksy- 3- nitrokumarin;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° (spalt<n.>), (ci2HllN06 krever c 54'34, H 4,18, N 5,28, Funnet: C 54,03, H 4,16, H 5,21). ;Eksempel 20;(i) 3, 6- dinitro- 4- hydroksykumarin;10,0 g 4-hydroksykumarin ble oppløst i 20 ml konsentrert svovelsyre under omrøring og avkjøling. Til dette ble 20 ml rykende ;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, Hl,72, ;N 10,81). ;(ii) 3, 6- dinitro- 4- hydroksykumarin- natriumsalt;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. ;Eksempel 21;(i) 6- klor- 4- hydroksy- 3- nitrokumarin;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.), (CgH4N0[-Cl krever C 44,74, ;H 1,67, N 5,80, Cl 14,68. Funnet: C 44,47, H 1,63, N 5,72, ;Cl 15,02). ;(ii) 6- klor- 4- hydroksy- 3- nitrokumarin- natriumsalt;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, ;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. ;Eksempel 22;(i) 7- klor- 4- hydroksy- 3- nitrokumarin;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.), (CgH4N0,-Cl krever C 44,74, ;H 1,67, N 5,80, Cl 14,68. Funnet: C 44,64, H 1,81, N 5,62, ;Cl 14,96) . ;(ii) 7- klor- 4- hydroksy- 3- nitrokumarin- natriumsalt;Fortynnet natriumhydroksydløsning ble tilsatt til en;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°, (CnH-NOcClNa krever 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, ;Na 9,61) etter vasking med vann og tørkning under vakuum.;Eksempel 2 3;(i) 6- brom- 4- hydroksy- 3- nitrokumarin;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.), (C9H4N05Br krever C 37,79, ;H 1,41, N 4,90, Br 27,94. Funnet: C 37,86, H 1,63, N 5,05, ;Br 27,64). ;(ii) 6- brom- 4- hydroksy- 3- nitrokumarin- natriumsalt;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, ;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 ;og tørkning under vakuum.;Eksempel 2 4;(i) 7- brom- 4- hydroksy- 3- nitrokumarin;2 7 ml rykende salpetersyre ble tilsatt til en omrørt suspensjon av 7-brom-4-hydroksykumarin (sm.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°, (CgH^NO^Br krever 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). ;(Li) 7- brom- 4- hydroksy- 3- nitrokumarin- natriumsalt;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. ;Eksempel 25;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. ;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. ;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. ;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. ;Ved å følge samme generelle fremgangsmåte som angitt i eksempel 19, men under anvendelse av følgende utgangsmaterialer: 6-metyl-7-etoksy-4-hydroksykumarin ;6-ety1-7-etoksy-4-hydroksykumarin ;6-n-propy1-7-etoksy-4-hydroksykumarin ;6-mety1-7-n-propoksy-4-hydroksykumarin ;6-etyl-7-n-propoksy-4-hydroksykumarin ;6-n-propyl-7-n-propoksy-4-hydroksykumarin;oppnås følgende forbindelser: 6-metyl-7-etoksy-4-hydroksy-3-nitrokumarin ;6-etyl-7-etoksy-4-hydroksy-3-nitrokumarin ;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-propyl-7-n-propoksy-4-hydroksy-3-nitrokumarin ;Eksempel 26;Noen av de 4-hydroksykumariner som ble fremstilt i de foregående eksempler, ble testet i den passive kutane anafylakse-test for rotter (PCA-testen) som er beskrevet nedenunder. De ble administrert som sine natriumsalter, enten i fosfatbuffer pH 7,2 (for løselige salter) eller som en suspensjon i 1% metylcellulose (for uløselige salter). ;(i) Serum som inneholdt varmelabile homocytotropiske antistoffer,;r ;ble dyrket i rotter ved en metode som er lik den som ble anvendt av Mota. (I. Mota Immunology 1964, 7, 681). ;Hann-Wistar-rotter med vekt 250-300 g ble injisert intraperitonealt med 0,5 ml av Bordatella pertussis-vaksine (inneholdende 4 x IO<10>døde organismer pr. ml) og subkutant med ;0,5 ml av en emulsjon av 100 mg ovalbumin i 2 ml saltvann og 3 ml ufullstendig Freunds<*>hjelpestoff. Det ble tappet blod av rottene ved kardial punktur på dag 18, blodet ble samlet og separert og serumet lagret ved -20° og tinet bare én gang før bruk. where R 1 , R 2 , R 2 and R 4 are as defined for formula (I), and R< 1> and R 1"*" 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 over 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°, ;(CgH 5 NO 5 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 gave 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^HgNO,- 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° (spl. ), 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.), (C1;LHgN05 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 of 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 - within 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.), (Ci;LHgN05 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 of 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 added to the residue. Filtration gave the product with m.p. 200-201° (dec.) (C^H<g>NO,.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) 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 pH- value until the solution reached 14. Filtration gave the product, m.p. >300° (C,,HoN0cNa requires C 51.37, H 3.14, ;11 o 5 ;N 5.45, Na 8.94. Found: C 51.69, H 3.26, N 5.33 , N 8.92) after short 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° (slit<n.>), (ci 2 H 11 NO 5 leaves 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>° (C13H13N05 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 until the pH of the solution reached 14. Filtration gave the product as a monohydrate, m.p. 249-251° (dec.) (<C>13H12NO,-Na.H2O; 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. 262-4 °, ;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°;(spltn.), 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 of 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.). (C10H7N06 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 of 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). ;(ii) 4- hy. hydroxy- 6- methoxy- 3- nitrocoumarin sodium salt; 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 Found: C 46.32, H 2.44, N 5.50, Na 8.34) ;after short washing with water and drying under vacuum. ;Example 14; 4-hydroxy-5-methoxy-3-nitrocoumarin; 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 of chloroform at room temperature during 1 hour. After further After 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.), (C10H7N06 requires C 50.64, H 2.97, ;N 5.91. Found: C 50.54, H 2.97, N 5.63). ;Example 15;7-ethoxy-4-hydroxy-3-nitrocoumarin; 25 ml of fuming nitric acid was added to a stirred suspension of 7-ethoxy-4-hydroxycoumarin (m.p. 267-8°, 5.0 g); 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). Example 16 (i) 4-hydroxy-3-nitro-7-n-propoxycoumarin; 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 of chloroform at room temperature during 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>°, (C]_2HHN06 requires C 54.34, H 4.18, N 5.28. Found: C 54.38, H 4.28, N 5.24). ;(ii) 4-hydroxy-3-nitro-7-n-propoxycoumarin sodium salt; Dilute sodium hydroxide solution was added to a suspension of 4-hydroxy-3-nitro-7-n-propoxycoumarin (1.92 g) in 20 ml water until the pH of the solution reached 14. Filtration gave the product, cleaved at 212-220°, after washing with water and drying under vacuum. ;Example 17;6-benzyloxy-4-hydroxy-3-nitrocoumarin sodium salt;13 ml of fuming nitric acid was added to a stirred suspension of 6-benzyloxy-4-hydroxycoumarin (m.p. 226-8°, 3.13 g ) in 200 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 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 of water and dilute sodium hydroxide solution added until the pH of the solution reached 14. Filtration gave the product with m.p. 262-4° (split<n. >). (<C>^<H>^<N>O^Na requires C 57.32, H 3.01, N 4.18, ;Na 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) after washing with water and drying under vacuum. ;Example 18;4-hydroxy-7-methoxy-8-methyl-3-nitrocoumarin; 15 ml fuming nitric acid was added to a suspension of 4-hydroxy-7-methoxy-8-methylcoumarin (m.p. 261-4° (spaltn.), ;3.0 g) in 250 ml chloroform at room temperature during 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 with m.p. 195-7° (splitn.) ; (C-^HgNOg requires C 52.60, H 3.61, N 5.58. Found: C 52.34, H 3.77, N 5.65). ;Example 19;6-ethyl-1-4-hydroxy-7-methoxy-3-nitrocoumarin; 15 ml of fuming nitric acid was added to a suspension of 6-ethyl-4-hydroxy-7-methoxycoumarin (m.p. 262-5° (spaltn.), ;2.86 g) in 250 ml chloroform at room temperature during 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° (slit<n.>), (Cl 2 H 11 NO 6 requires c 54'34, H 4.18, N 5.28, Found: C 54.03, H 4.16, H 5.21). ;Example 20;(i) 3,6-dinitro-4-hydroxycoumarin; 10.0 g of 4-hydroxycoumarin was dissolved in 20 ml of concentrated sulfuric acid with stirring and cooling. To this, 20 ml fuming nitric acid was added over the course of 20 minutes, while cooling with ice water as necessary. 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.), (CgH4N2O7 requires C 42.87, H 1.60, N 11.11. Found: C 43.24, Hl.72, ;N 10.81). ;(ii) 3,6-dinitro-4-hydroxycoumarin sodium salt; 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. ;Example 21;(i) 6-chloro-4-hydroxy-3-nitrocoumarin;13.5 ml of fuming nitric acid was added to a stirred suspension of 6-chloro-4-hydroxycoumarin (m.p. 266-8°, 2 .33 g) in 200 ml of chloroform at room temperature during 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.), (CgH4N0[-Cl requires C 44.74, ;H 1.67, N 5.80, Cl 14.68. Found: C 44.47, H 1.63, N 5 .72, ;Cl 15.02). ;(ii) 6-chloro-4-hydroxy-3-nitrocoumarin sodium salt; 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 to the solution's pH- value reached 14. Filtration gave the product, m.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. ;Example 22;(i) 7-chloro-4-hydroxy-3-nitrocoumarin; 27 ml of fuming nitric acid was added to a stirred suspension of 7-chloro-4-hydroxycoumarin (m.p. 251-2°, 4.5 g) in 400 ml of chloroform at room temperature during 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.), (CgH4N0,-Cl requires C 44.74, ;H 1.67, N 5.80, Cl 14.68. Found: C 44.64, H 1.81, N 5 .62, ;Cl 14.96) . (ii) 7-chloro-4-hydroxy-3-nitrocoumarin sodium salt Dilute sodium hydroxide solution was added to a stirred suspension of 5.1 g of 7-chloro-4-hydroxy-3-nitrocoumarin in 60 ml of water to the pH of the solution -value reached 14. Filtration gave the product, which decomposes at 295°, (CnH-NOcClNa requires C 41.01, H 1.15, N 5.31, ;Cl 13.46, Na 8.72. Found: C 40 .41, H 1.13, N 4.90, Cl 13.64, ;Na 9.61) after washing with water and drying under vacuum. ;Example 2 3;(i) 6-bromo-4-hydroxy-3-nitrocoumarin; 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 during 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.), (C9H4N05Br requires C 37.79, ;H 1.41, N 4.90, Br 27.94. Found: C 37.86, H 1.63, N 5.05, ;Br 27.64). ;(ii) 6-bromo-4-hydroxy-3-nitrocoumarin sodium salt; 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 to the pH value of the solution reached 14. Filtration gave the product, m.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 and drying under vacuum. ;Example 2 4;(i) 7-bromo-4-hydroxy-3-nitrocoumarin;2 7 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) 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°, (CgH^NO^Br requires C 37.79, H 1.41,;N 4.90, Br 27.94. Found: C 37.46,. H 1.45, N 4.78 , Br 27,93). ;(Li) 7-bromo-4-hydroxy-3-nitrocoumarin sodium salt; 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; to the solution's pH- value reached 14. Filtration gave the product, m.p. 265-7° (dec.) after washing with water and drying under vacuum. ;Example 25;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, 6,7-di-n-propyl-4-hydroxy-3-nitrocoumarin is formed as the free acid and the sodium salt. 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. 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. ;By following the same general procedure as indicated in Example 19, but using 6-n-propyl-7-methoxy-4-hydroxycoumarin as. starting material, 6-n-propyl-7-methoxy-4-hydroxy-3-nitrocoumarin is obtained. ;By following the same general procedure as stated in Example 19, but using the following starting materials: 6-methyl-7-ethoxy-4-hydroxycoumarin ;6-ethy1-7-ethoxy-4-hydroxycoumarin ;6-n-propy1- 7-ethoxy-4-hydroxycoumarin ;6-methyl-7-n-propoxy-4-hydroxycoumarin ;6-ethyl-7-n-propoxy-4-hydroxycoumarin ;6-n-propyl-7-n-propoxy-4- hydroxycoumarin; 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-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 ;Example 26;Some of the 4-hydroxycoumarins prepared in the preceding examples were tested in the rat passive cutaneous anaphylaxis test (PCA test) described below. They were administered as their sodium salts, either in phosphate buffer pH 7.2 (for soluble salts) or as a suspension in 1% methylcellulose (for insoluble salts). (i) Serum containing heat-labile homocytotropic antibodies was cultured in rats by a method similar to that used by Mota. (I. Mota Immunology 1964, 7, 681). ;Male Wistar rats weighing 250-300 g were injected intraperitoneally with 0.5 ml of Bordatella pertussis vaccine (containing 4 x IO<10> dead organisms per ml) and subcutaneously with ;0.5 ml of an emulsion of 100 mg ovalbumin in 2 ml saline and 3 ml incomplete Freund's adjuvant. The rats were bled by cardiac puncture on day 18, the blood was collected and separated and the serum stored at -20° and thawed only once before use .
(ii) PCA-testen var lik den som er beskrevet av Ovary og Bier(ii) The PCA test was similar to that described by Ovary and Bier
(A. Ovary og O.E. Bier, Prod. Soc. Exp. Biol. Med. 1952, 8J., 584)(A. Ovary and O.E. Bier, Prod. Soc. Exp. Biol. Med. 1952, 8J., 584)
og Goose og Blair (J. Goose og A.M.J.N. Blair, Immunology 1969, 16, 769). and Goose and Blair (J. Goose and A.M.J.N. Blair, Immunology 1969, 16, 769).
0,1 ml av hver av 6 dobbelte seriefortynninger av serumet i 0,9% saltvann ble injisert intradermalt på forskjellige steder på den barberte ryggflate til hann-Wistar-rotter med vekt 250-350 g. 72 timer senere ble dyrene provosert ved i.v.-injeksjon av 0,3 ml av 1% ovalbumin blandet med 0,1 ml av en 5% løsning.av "pontamine sky blue"-farvestoff, begge i isotonisk saltvann bufret med Sørenson buffer, pH 7,2 (P.B.S.). Rottene ble slaktet etter 20 minutter, og diameteren på de blå opphovnede striper på antistoff-injeksjonsstedene ble målt. Utgangsfortynningen av serumet ble justert slik at det etter provoseringen ikke var noen respons ved injeksjonsstedet med den høyeste fortynning, og maksimal respons ved de to eller tre laveste fortynninger. Typisk ble det anvendt 6 dobbelte seriefortynninger av serumet 1/4 til 1/128. 0.1 ml of each of 6 two-fold serial dilutions of the serum in 0.9% saline was injected intradermally at various sites on the shaved dorsal surface of male Wistar rats weighing 250-350 g. 72 hours later the animals were challenged by i.v.- injection of 0.3 ml of 1% ovalbumin mixed with 0.1 ml of a 5% solution of "pontamine sky blue" dye, both in isotonic saline buffered with Sørenson buffer, pH 7.2 (P.B.S.). The rats were sacrificed after 20 minutes, and the diameter of the blue raised streaks at the antibody injection sites was measured. The initial dilution of the serum was adjusted so that after the challenge there was no response at the injection site with the highest dilution, and maximum response at the two or three lowest dilutions. Typically, 6-fold serial dilutions of the serum 1/4 to 1/128 were used.
Det ble testet forbindelser med hensyn på deres evne tilCompounds were tested for their ability to
å redusere diameteren til de opphovnede striper ved injeksjonsstedene for fortynninger av antistoff som ved alle kontroller har mindre enn maksimal respons. Det ble administrert mengder av forbindelsene til rotter ved subkutan injeksjon, inn i nakkeregionen, av en løsning av forbindelsen i P.B.S, eller som en suspensjon i 1% metylcellulose, hver mengde til en testgruppe bestående av 6 dyr på et bestemt tidspunkt før intravenøs provosering med ovalbumin. to reduce the diameter of the raised streaks at the injection sites for dilutions of antibody that in all controls have less than maximal response. Amounts of the compounds were administered to rats by subcutaneous injection, into the neck region, of a solution of the compound in P.B.S., or as a suspension in 1% methylcellulose, each amount to a test group consisting of 6 animals at a specified time before intravenous challenge with ovalbumin.
Diametrene til de blå, opphovnede striper som utvikler seg på The diameters of the blue, swollen streaks that develop on
testgruppen av dyr, ble sammenlignet med slike for en kontroll-gruppe på 6 dyr som var behandlet på samme måte som testgruppen, the test group of animals was compared with those for a control group of 6 animals that were treated in the same way as the test group,
men som hadde fått en ekvivalent subkutan injeksjon av bærevæsken i samme'volum, men som ikke inneholdt den forbindelse som skulle testes. but which had received an equivalent subcutaneous injection of the vehicle in the same volume, but which did not contain the compound to be tested.
a = gjennomsnittet av summen av diametrene av de opphovnede striper som ble frembragt i testgruppen av dyr ved de antistoffsteder hvor hele kontrollgruppen av dyr ga mindre enn maksimal respons. a = the average of the sum of the diameters of the raised streaks produced in the test group of animals at the antibody sites where the entire control group of animals gave less than maximal responses.
b = gjennomsnittet av summen av diametrene av de opphovnede striper frembragt hos kontrollgruppen av dyr ved de antistoffsteder hvor alle dyr i gruppen ga mindre enn maksimal respons. b = the average of the sum of the diameters of the raised stripes produced in the control group of animals at the antibody sites where all animals in the group gave less than maximal response.
Den foretrukne administreringsmetode var en løsning av testforbindelsen oppløst i buffer pH 7,2 og nøytralisert med natriumbikarbonat. For de forbindelser som har uløselige natriumsalter, ble saltene isolert ved omsetning av den frie nitro-forbindelse med 2,5n natriumhydroksyd og det filtrerte natriumsalt vasket fritt for alkali med vann. De tørkede salter ble så administrert som en suspensjon i 1% metylcellulose. The preferred method of administration was a solution of the test compound dissolved in buffer pH 7.2 and neutralized with sodium bicarbonate. For those compounds having insoluble sodium salts, the salts were isolated by reacting the free nitro compound with 2.5N sodium hydroxide and the filtered sodium salt washed free of alkali with water. The dried salts were then administered as a suspension in 1% methylcellulose.
Biologiske resultater Biological results
Claims (1)
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 |
|---|---|
| NO750864L true NO750864L (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 Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO750863A NO750863L (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 |
|---|---|
| NO750863L (en) | 1974-10-22 |
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