FI67080C - FRAMEWORK FOR THE FRAMEWORK OF PHARMACEUTICALS ACTIVE 5: -BENZO-NY-PYRONDERIVAT - Google Patents
FRAMEWORK FOR THE FRAMEWORK OF PHARMACEUTICALS ACTIVE 5: -BENZO-NY-PYRONDERIVAT Download PDFInfo
- Publication number
- FI67080C FI67080C FI3742/74A FI374274A FI67080C FI 67080 C FI67080 C FI 67080C FI 3742/74 A FI3742/74 A FI 3742/74A FI 374274 A FI374274 A FI 374274A FI 67080 C FI67080 C FI 67080C
- Authority
- FI
- Finland
- Prior art keywords
- carboxy
- flavone
- formula
- compound
- compounds
- Prior art date
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- 239000003814 drug Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 65
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- -1 morpholinoethyl ester Chemical class 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 5
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 15
- YLQMFQKRHQCFBI-UHFFFAOYSA-N 4-oxo-2-(2-propan-2-yloxyphenyl)chromene-6-carboxylic acid Chemical compound CC(C)OC1=CC=CC=C1C1=CC(=O)C2=CC(C(O)=O)=CC=C2O1 YLQMFQKRHQCFBI-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 159000000000 sodium salts Chemical class 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 230000003266 anti-allergic effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- NADDLRWCPPNNBA-UHFFFAOYSA-N 7-(2-hydroxyethoxy)-9-oxoxanthene-2-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2C(=O)C3=CC(OCCO)=CC=C3OC2=C1 NADDLRWCPPNNBA-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- FPYAQSSSRQZXMS-UHFFFAOYSA-N methyl 3-acetyl-4-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(O)C(C(C)=O)=C1 FPYAQSSSRQZXMS-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- WWZSEFGEROSCNG-UHFFFAOYSA-N 2-(3-fluorophenyl)-4-oxochromene-6-carboxylic acid Chemical compound C(=O)(O)C=1C=C2C(C=C(OC2=CC=1)C1=CC(=CC=C1)F)=O WWZSEFGEROSCNG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- GKWXNIZHVQLKQY-UHFFFAOYSA-N 2-[2-(2-ethoxyethoxy)phenyl]-4-oxochromene-6-carboxylic acid Chemical compound CCOCCOC1=CC=CC=C1C1=CC(=O)C2=CC(C(O)=O)=CC=C2O1 GKWXNIZHVQLKQY-UHFFFAOYSA-N 0.000 description 2
- QKVNNCNPDOJZJZ-UHFFFAOYSA-N 2-[4-(2-ethoxyethoxy)phenyl]-4-oxochromene-6-carboxylic acid Chemical compound C1=CC(OCCOCC)=CC=C1C1=CC(=O)C2=CC(C(O)=O)=CC=C2O1 QKVNNCNPDOJZJZ-UHFFFAOYSA-N 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- NTSMIVYANJBXBU-UHFFFAOYSA-N methyl 2-(2-hydroxyphenyl)-4-oxochromene-6-carboxylate Chemical compound C=1C(=O)C2=CC(C(=O)OC)=CC=C2OC=1C1=CC=CC=C1O NTSMIVYANJBXBU-UHFFFAOYSA-N 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- DZCBKUAAGVVLOX-UHFFFAOYSA-N 1-morpholin-4-ylethanol Chemical compound CC(O)N1CCOCC1 DZCBKUAAGVVLOX-UHFFFAOYSA-N 0.000 description 1
- FNOGVKQMXXVLIH-UHFFFAOYSA-N 2-(2-butoxyphenyl)-4-oxochromene-6-carboxylic acid Chemical compound CCCCOC1=CC=CC=C1C1=CC(=O)C2=CC(C(O)=O)=CC=C2O1 FNOGVKQMXXVLIH-UHFFFAOYSA-N 0.000 description 1
- FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 description 1
- VJTLVZSINHPNBX-UHFFFAOYSA-N 2-(2-ethoxyphenyl)-4-oxochromene-6-carboxylic acid Chemical compound CCOC1=CC=CC=C1C1=CC(=O)C2=CC(C(O)=O)=CC=C2O1 VJTLVZSINHPNBX-UHFFFAOYSA-N 0.000 description 1
- XZJLRTHIVFYYMZ-UHFFFAOYSA-N 2-(4-fluorophenyl)-4-oxochromene-6-carboxylic acid Chemical compound C=1C(=O)C2=CC(C(=O)O)=CC=C2OC=1C1=CC=C(F)C=C1 XZJLRTHIVFYYMZ-UHFFFAOYSA-N 0.000 description 1
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 1
- JVKRKMWZYMKVTQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JVKRKMWZYMKVTQ-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical class O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 1
- UWGVMPXQULQQMP-UHFFFAOYSA-N 3-[3-(4-fluorophenyl)-3-oxopropanoyl]-4-hydroxybenzoic acid Chemical compound OC1=C(C(=O)CC(C2=CC=C(C=C2)F)=O)C=C(C=C1)C(=O)O UWGVMPXQULQQMP-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- KNSPZJBQWIGKBI-UHFFFAOYSA-N 4-hydroxy-3-(3-oxo-3-pyrazin-2-ylpropanoyl)benzoic acid Chemical compound OC1=C(C(=O)CC(=O)C2=NC=CN=C2)C=C(C=C1)C(=O)O KNSPZJBQWIGKBI-UHFFFAOYSA-N 0.000 description 1
- GWZBOGOEJSMFIS-UHFFFAOYSA-N 4-hydroxy-3-[3-oxo-3-(2-propan-2-yloxyphenyl)propanoyl]benzoic acid Chemical compound OC1=C(C(=O)CC(C2=C(C=CC=C2)OC(C)C)=O)C=C(C=C1)C(=O)O GWZBOGOEJSMFIS-UHFFFAOYSA-N 0.000 description 1
- JPQLYHXMTDKJDF-UHFFFAOYSA-N 4-oxo-2-(2-propan-2-yloxyphenyl)chromene-6-carbonyl chloride Chemical compound CC(C)OC1=CC=CC=C1C1=CC(=O)C2=CC(C(Cl)=O)=CC=C2O1 JPQLYHXMTDKJDF-UHFFFAOYSA-N 0.000 description 1
- RWBCSOJJSOOSPA-UHFFFAOYSA-N 4-oxo-2-(2-propoxyphenyl)chromene-6-carboxylic acid Chemical compound CCCOC1=CC=CC=C1C1=CC(=O)C2=CC(C(O)=O)=CC=C2O1 RWBCSOJJSOOSPA-UHFFFAOYSA-N 0.000 description 1
- URZKEHHDMLOHJU-UHFFFAOYSA-N 4-oxo-2-phenyl-2-propan-2-yloxy-3h-chromene-6-carboxylic acid Chemical compound C1C(=O)C2=CC(C(O)=O)=CC=C2OC1(OC(C)C)C1=CC=CC=C1 URZKEHHDMLOHJU-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229920002055 compound 48/80 Polymers 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- LNDBOJKIDVIRQA-UHFFFAOYSA-N methyl 2-(4-hydroxyphenyl)-4-oxochromene-6-carboxylate Chemical compound C(=O)(OC)C=1C=C2C(C=C(OC2=CC=1)C1=CC=C(C=C1)O)=O LNDBOJKIDVIRQA-UHFFFAOYSA-N 0.000 description 1
- RDAALIJZJHPRRP-UHFFFAOYSA-N methyl 2-propan-2-yloxybenzoate Chemical compound COC(=O)C1=CC=CC=C1OC(C)C RDAALIJZJHPRRP-UHFFFAOYSA-N 0.000 description 1
- KLPRRBLWXBGSQG-UHFFFAOYSA-N methyl 4-hydroxy-3-[3-oxo-3-(2-phenylmethoxyphenyl)propanoyl]benzoate Chemical compound COC(=O)C1=CC=C(O)C(C(=O)CC(=O)C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=C1 KLPRRBLWXBGSQG-UHFFFAOYSA-N 0.000 description 1
- MDIBGPICHUESMF-UHFFFAOYSA-N methyl 4-hydroxy-3-[3-oxo-3-(2-propan-2-yloxyphenyl)propanoyl]benzoate Chemical compound COC(=O)C1=CC=C(O)C(C(=O)CC(=O)C=2C(=CC=CC=2)OC(C)C)=C1 MDIBGPICHUESMF-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960001238 methylnicotinate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
---KUULUTUSJULKAISU s π n o n •j8Tm W «"»UTLAGGNIMGSSWUFT 67080 q Pvlentti cyur.n;i,y 10 01 1983 (51) Kv.lt/totCI.3 C 07 D 311/22, 405/04 SUOMI—FINLAND (it) 37^2/7^ (22) H«k«mlipto* — AiUtaUmri·» 27.12.74 (Fi) (23) AHn^W-GIW^U, 27.12.74 (41) TuHut («IklMksi — BlMt offaMlf 28.06.75--- ANNOUNCEMENT s π non • j8Tm W «" »UTLAGGNIMGSSWUFT 67080 q Pvlentti cyur.n; i, y 10 01 1983 (51) Kv.lt/totCI.3 C 07 D 311/22, 405/04 FINLAND — FINLAND (it) 37 ^ 2/7 ^ (22) H «k« mlipto * - AiUtaUmri · »27.12.74 (Fi) (23) AHn ^ W-GIW ^ U, 27.12.74 (41) TuHut (« IklMksi - BlMt offaMlf 28.06.75
Ja rekisteri hallitut Niht^p^o.J. p**.- PMant» och reghtantyralMn v AnaBkan od*d och utLafcrlftan paMkarad 28.09.84 (32)(33)(31) fyydtty «cxXfc-t Bftod prtorttt 27.12.73 04.0/.74, 17.07.74 Itai ia-1 taiien(IT) 32089 A/73, 24777 A/74, 25244 A/74 (71) Farmitalia Carlo Erba S.p.A., Via Carlo Imbonati 24, 20159 Milano, I ta 1 ia-I ta 1 ien(IT) (72) Gianfederico Doria, Milano, Pier Nicola Giraldi, Milano, Francesco Lauria, Milano, Maria LuisaCorno, Milano, Piero Sberze, Varese,And the register managed Niht ^ p ^ o.J. p ** .- PMant »och reghtantyralMn v AnaBkan od * d och utLafcrlftan paMkarad 28.09.84 (32) (33) (31) fyydtty« cxXfc-t Bftod prtorttt 27.12.73 04.0 / .74, 17.07.74 Itai ia- 1 taiien (IT) 32089 A / 73, 24777 A / 74, 25244 A / 74 (71) Farmitalia Carlo Erba SpA, Via Carlo Imbonati 24, 20159 Milan, I ta 1 ia-I ta 1 ien (IT) (72) Gianfederico Doria, Milan, Pier Nicola Giraldi, Milan, Francesco Lauria, Milan, Maria LuisaCorno, Milan, Piero Sberze, Varese,
Marcello Tibolla, Milano, I taiia-l taiien(IT) (74) Munsterhielm Ky Kb (54) Menetelmä uusien, farmaseuttisesti aktiivisten 5:6-bentso-)f-pyroni-johdannaisten valmistamiseksi - Förfarande för framställning av nya, fa rmaceut i skt aktiva 5:6-benso-if-pyronder i vat Tämä keksintö koskee menetelmää 5:6-bentso-Y-pyronijohdannaisten valmistamiseksi, joiden yleinen kaava (I) on 0 H00C - I (I) jossa R on fenyyli, joka on substituoitu fluorilla tai C^-C^-alkok- silla, joka puolestaan on substituoimaton tai substituoitu C2“alkoksilla, tai R on pyridyyli tai pyratsinyyli, joka on substituoimaton tai substituoitu metyylillä, ja niiden farmaseuttisesti hyväksyttävien suolojen valmistamiseksi.Marcello Tibolla, Milan, I taiia-l taiien (IT) (74) Munsterhielm Ky Kb (54) Process for the preparation of new pharmaceutically active 5: 6-benzo) f-pyrone derivatives - Förfarande för framställning av nya, fa rmaceut i This invention relates to a process for the preparation of 5: 6-benzo-γ-pyrone derivatives of general formula (I) wherein O is phenyl which is substituted by fluoro or C 1 -C 4 alkoxy which in turn is unsubstituted or substituted by C 2 -C 4 alkoxy, or R is pyridyl or pyrazinyl which is unsubstituted or substituted by methyl, and pharmaceutically acceptable salts thereof.
Keksinnön mukaisesti valmistetuissa yhdisteissä kun R on fenyyli käytetään seuraavaa numerointia: 2 2' 3* 67080 ^Q·: 6* 5' kun R on pyridyyli (tai pyratsinyyli 2 heteroatomia) numerointi on seuraava: 1' 9« 1» 3' 2' <*· *0·· *· 3 » μ » *4’ 5' 5b jossa Z on heteroatomi, josta numerointi tavallisesti alkaa.In the compounds of the invention, when R is phenyl, the following numbering is used: 2 2 '3 * 67080 ^ Q ·: 6 * 5' when R is pyridyl (or pyrazinyl 2 heteroatoms) the numbering is as follows: 1 '9 «1» 3' 2 ' <* · * 0 ·· * · 3 »μ» * 4 '5' 5b where Z is the heteroatom from which numbering usually begins.
Keksinnön mukaisesti valmistetuissa yhdisteissä voivat ulkoksiryhmät olla haarautuneita tai suoraketjuisia.In the compounds of the invention, the oxy groups may be branched or straight-chain.
Esimerkkejä farmaseuttisesti hyväksyttävistä suoloista ovat natriumsuolat ja suolat 2-amino-etanolin ja 2-amino-2-hydroksimetyyli--1,3-propaanidiolin kanssa.Examples of pharmaceutically acceptable salts include sodium salts and salts with 2-aminoethanol and 2-amino-2-hydroxymethyl-1,3-propanediol.
Esimerkkejä edullisista, keksinnön mukaisesti valmistetuista yhdisteistä, ovat seuraavat: 6-karboksi-2’-isopropoksi-flavoni 6-karboksi-2’-butoksi-flavoni 6-karboksi-2'-(2-etoksi-etoksi)-flavoni 6-karboksi-H'-(2-etoksi-etoksi)-flavoni 6-karboksi-2-(2’-pyridyyli)-kromoni 6-karboksi-2-(3·-pyridyyli)-kromoni 6-karboksi-2-(2'-pyratsinyyli)-kromoni sekä niiden farmaseuttisesti hyväksyttävät suolat, erityisesti natriumsuolat ja dietyyliaminoetanolin ja morfolinoetanolin kanssa saatujen estereiden sekä glykoli- ja pivaloksimetyyliestereiden hydroklo-ridit.Examples of preferred compounds of the invention are as follows: 6-carboxy-2'-isopropoxy-flavone 6-carboxy-2'-butoxy-flavone 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone 6-carboxy -H '- (2-ethoxy-ethoxy) -flavone 6-carboxy-2- (2'-pyridyl) -chromone 6-carboxy-2- (3 · -pyridyl) -chromone 6-carboxy-2- (2' -pyrazinyl) chromone and their pharmaceutically acceptable salts, in particular the sodium salts and the hydrochlorides of esters with diethylaminoethanol and morpholinoethanol and of glycol and pivaloxymethyl esters.
5: 6-bentso-)f-pyronijohdannaiset voidaan valmistaa menetelmällä , j onka mukaan a) yhdiste, jonka kaava (II) on jj £ HOOC—^C1I2 Π i| i (m C(?The 5: 6-benzo [f] pyrone derivatives can be prepared by a process according to which a) a compound of formula (II) is: [HOOC-^ ClI2 Π i | i (m C (?
X RX R
3 67080 jossa R tarkoittaa samaa kuin edellä, syklisoidaan yleisen kaavan (I) mukaisten yhdisteiden valmistamiseksi, tai b) yhdiste, jonka kaava (III) on 0 H00\ (III)3 67080 wherein R is as defined above, is cyclized to give compounds of general formula (I), or b) a compound of formula (III) is O
I ]^0?l UiiJI] ^ 0? L UiiJ
saatetaan reagoimaan (^-C^-alkyylihalogenidin kanssa, joka on substi-tuoimaton tai substituoitu C2“alkoksilla, kaavan (I) mukaisen yhdisteen valmistamiseksi, jossa R on fenyyli, joka on substituoitu -alkoksilla, joka puolestaan on substituoimaton tai substituoitu C2--alkoksilla; ja/tai kaavan (I) mukaiset yhdisteet muutetaan pivaloksimetyyli-, glykoli-, dietyyliaminoetyyli- tai morfolinoetyyliesteriksi, ja/tai tällaisen esterin hydrokloridiksi tai maleaatiksi; ja/tai yleisen kaavan (I) mukainen yhdiste muutetaan sen farmaseuttisesti hyväksyttäväksi suolaksi.is reacted with a (C 1 -C 4) alkyl halide which is unsubstituted or substituted by C 2 -C 6 alkoxy to give a compound of formula (I) in which R is phenyl substituted by -alkoxy which in turn is unsubstituted or substituted by C 2 -C 4 alkoxy. and / or the compounds of formula (I) are converted into pivaloxymethyl, glycol, diethylaminoethyl or morpholinoethyl ester, and / or the hydrochloride or maleate of such an ester, and / or the compound of general formula (I) is converted into a pharmaceutically acceptable salt thereof.
Kaavan (II) mukaisen yhdisteen syklisointi suoritetaan mieluimmin happamien katalysaattoreiden, kuten esimerkiksi kloorivetyhapon, jodivetyhapon, rikkihapon, muurahaishapon läsnäollessa, mieluimmin 20--120°C:n lämpötilassa ja inertissä liuottimessa, jollaisena on esimerkiksi metanoli, etanoli, dioksaani, tetrahydrofuraani, bentseeni, to-lueeni, etikkahappo ja niiden seokset.The cyclization of a compound of formula (II) is preferably carried out in the presence of acid catalysts such as hydrochloric acid, hydroiodic acid, sulfuric acid, formic acid, preferably at a temperature of 20-120 ° C and in an inert solvent such as methanol, ethanol, ethanol, dioxane, dioxane to-read, acetic acid and mixtures thereof.
Kaavan (III) mukainen yhdiste voidaan saada syklisoimalla menetelmän a) mukaisesti kaavan (Ha) mukainen yhdiste 0 l| HOOC^^c— CH2 kJ) CO (Ha)The compound of formula (III) can be obtained by cyclizing a compound of formula (IIa) according to method a) 0 l | HOOC ^ ^ c - CH2 kJ) CO (Ha)
O^0HO ^ 0H
joka puolestaan voidaan saada kaavan (II) mukaiselle yhdisteelle esitetyn menetelmän mukaisesti.which in turn can be obtained according to the method described for the compound of formula (II).
Vapaat hydroksiryhmät voidaan eetteröidä käsittelemällä esim. alkyylihalogenideilla tai eetteröidyt hydroksiryhmät voidaan muuttaa vapaiksi hydroksiryhmiksi esim. käsittelemällä pyridiinisuolalla, mieluimmin hydrokloridilla, tai vahvalla hapolla tai Lewis-hapolla.The free hydroxy groups may be etherified by treatment with e.g. alkyl halides or the etherified hydroxy groups may be converted to free hydroxy groups e.g. by treatment with a pyridine salt, preferably the hydrochloride, or a strong acid or Lewis acid.
Kaavan (I) mukaisten yhdisteiden mahdollinen suolanmuodostus voi myös tapahtua tunnetuilla menetelmillä.The possible salt formation of the compounds of formula (I) can also take place by known methods.
6708067080
Kaavan (II) mukaiset yhdisteet voidaan valmistaa saattamalla yhdiste, jonka kaava (IV) on 0Compounds of formula (II) may be prepared by reacting a compound of formula (IV) 0
IIII
H00C —" i 3 I (IV) reagoimaan yhdisteen kanssa, jonka kaava (V) on R-jOOC-R (V) jossa R tarkoittaa samaa kuin edellä ja R^ on aryyli, mieluimmin fe-nyyli, tai alkyyli.H 3 C-3 i (IV) to react with a compound of formula (V) is R 1 -COO-R (V) wherein R is as defined above and R 1 is aryl, preferably phenyl, or alkyl.
Reaktio kaavan (IV) mukaisen yhdisteen ja kaavan (V) mukaisen yhdisteen välillä suoritetaan mieluimmin orgaanisessa liuottimessa, kuten esim. metanolissa, etanolissa, dioksaanissa ja pyridiinissä, vahvan emäksen, kuten esimerkiksi natriummetoksidin, natriumetoksidin, natriumhydridin läsnäollessa ja huoneen lämpötilan ja palautus lämpötilan välillä.The reaction between a compound of formula (IV) and a compound of formula (V) is preferably carried out in an organic solvent such as methanol, ethanol, dioxane and pyridine in the presence of a strong base such as sodium methoxide, sodium ethoxide, sodium hydride and at room temperature and reflux temperature.
Eräs vaihtoehtoinen menetelmä kaavan (II) mukaisten yhdisteiden valmistamiseksi käsittää sen, että tunnetulla tavalla saatetaan kaavan (IV) mukainen yhdiste reagoimaan yhdisteen kanssa, jonka kaava (VI) on M'OC-R (VI) jossa M' on halogeeni tai hydroksi ja R tarkoittaa samaa kuin edellä, yhdisteen valmistamiseksi, jonka kaava (VII) on 0An alternative process for the preparation of compounds of formula (II) comprises reacting a compound of formula (IV) in a known manner with a compound of formula (VI) is M'OC-R (VI) wherein M 'is halogen or hydroxy and R means the same as above to prepare a compound of formula (VII) 0
IIII
Hooc-r^^'^ (VII)Hooc-r ^^ '^ (VII)
0-C-R0-C-R
IIII
o jossa R tarkoittaa samaa kuin edellä, minkä jälkeen kaavan (VII) mukaisille yhdisteille suoritetaan toisiintumisreaktio inertissä liuottimessa, esim. pyridiinissä, tolueenissa, metyyli-etyyliketonissa, vahvan emäksen, esim. natriumin, natriumamidin, kaliumhydroksidin, kaliumkarbonaatin, läsnäollessa, huoneen lämpötilan ja palautusläm-pötilan välillä.o wherein R is as defined above, after which the compounds of formula (VII) are subjected to a rearrangement reaction in an inert solvent, e.g. pyridine, toluene, methyl ethyl ketone, in the presence of a strong base, e.g. sodium, sodium amide, potassium hydroxide, potassium carbonate, at room temperature and reflux. between.
67080 567080 5
Kaavan (IV) mukaiset yhdisteet voidaan valmistaa esimerkiksi lähtemällä sopivista substituoiduista fenoleista Friedel-Crafts--kondensaatiolla tai Fries'in uudelleenryhmittämisellä.Compounds of formula (IV) may be prepared, for example, by starting from suitable substituted phenols by Friedel-Crafts condensation or Fries regrouping.
Kaavan (III) mukaiset yhdisteet voidaan valmistaa lähtemällä yhdisteistä, joiden kaava (VIII) onCompounds of formula (III) may be prepared starting from compounds of formula (VIII)
0 H0 H
HOOC—^ C=CH-RHOOC- ^ C = CH-R
| (VIII) jossa R tarkoittaa samaa kuin edellä, saattamalla ne reagoimaan emäksisten kondensaatioaineiden, kuten esim. natrium- tai kaliumhydroksi-din, natriumamidin, natriumhydridin, natrium- tai kaliumkarbonaatin, kaliumasetaatin, tai happojen, esim. halogeenivetyhappojen, rikki-, fosfori-, p-tolueenisulfonihapon kanssa liuottimessa, esim. mieluimmin metanolissa, etanolissa, dioksaanissa, tetrahydrofuraanissa, bentseenissä, tolueenissa, dimetyylisulfoksidissa, huoneen lämpötilan ja palautuslämpötilan välillä.| (VIII) wherein R is as defined above, by reacting them with basic condensing agents such as sodium or potassium hydroxide, sodium amide, sodium hydride, sodium or potassium carbonate, potassium acetate, or acids, e.g. hydrohalic acids, sulfuric, phosphoric, with p-toluenesulfonic acid in a solvent, e.g. preferably methanol, ethanol, dioxane, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide, between room temperature and reflux temperature.
Kaavan (VIII) mukaiset yhdisteet voidaan puolestaan valmistaa kondensoimalla kaavan (V) mukainen yhdiste substituoidun aldehydin kanssa, jonka kaava on OCH-R (IX) jossa R tarkoittaa samaa kuin edellä.Compounds of formula (VIII) may in turn be prepared by condensing a compound of formula (V) with a substituted aldehyde of formula OCH-R (IX) wherein R is as defined above.
Kondensaatio voi tapahtua liuottimessa, jollaisena on esimerkiksi metanoli, etanoli, dioksaani, vesi ja niiden seokset, ja emäksisen katalysaattorin, kuten esim. piperidiinin, natriumhydroksidin, natriumhydridin, natriumalkoksidin läsnäollessa ja huoneen lämpötilan ja palautuslämpötilan välillä.The condensation may take place in a solvent such as methanol, ethanol, dioxane, water and mixtures thereof, and in the presence of a basic catalyst such as piperidine, sodium hydroxide, sodium hydride, sodium alkoxide and between room temperature and reflux temperature.
6 670806 67080
Keksinnön mukaisesti valmistetuilla yhdisteillä on antiallergi-nen aktiviteetti, mikä ilmenee siitä, että ne ovat aktiivisia passiivisessa kutaanisessa anafylaksia-kokeessa (PCA) rotissa, Goose Y ja Blair A.M.Y.N.'n mukaan (Immunology, 1969, )J5:749). Niitä voidaan täten käyttää bronkiaalisen astman, allergisen nuhan, heinänuhan, nokkos-kuumeen (urticaria) ja dermatosis'en estämiseksi ja käsittelemiseksi.The compounds of the invention have antiallergic activity, as evidenced by their activity in the passive cutaneous anaphylaxis (PCA) assay in rats, according to Goose Y and Blair A.M.Y.N. (Immunology, 1969, J5: 749). They can thus be used to prevent and treat bronchial asthma, allergic rhinitis, hay fever, urticaria and dermatosis.
Uusien yhdisteiden eräs tärkeä ominaisuus on, että niillä on antiallerginen aktiviteetti myös oraalisesti annettuina.An important property of the new compounds is that they have antiallergic activity even when administered orally.
FARMAKOLOGINEN K0ESEL0STUSPHARMACOLOGICAL PROPERTIES
Seuraavassa taulukossa on esitetty aktiviteettiarvot, jotka on saatu PCA-kokeessa rotilla, annostettaessa oraalisesti tämän keksinnön mukaisesti valmistettuja yhdisteitä.The following table shows the activity values obtained in the PCA experiment in rats after oral administration of the compounds of this invention.
Aktiviteettiarvot on esitetty K^:n arvoina, jotka määritellään aktiivisen yhdisteen annoksena (mg/kg), joka pystyy vähentämään her-kistykseen käytetyn seerumin aktiviteetin puoleen:Activity values are expressed as K i values, defined as the dose of active compound (mg / kg) capable of reducing the activity of the serum used for sensitization by:
BB
K = - B DR-1 jossa B = antagonistisen yhdisteen annos, ilmoitettuna mg/kg DR = annossuhde: antagonistisen aineen sisältävän seerumin ja ilman antagonistista ainetta olevan seerumin käyrien välisen etäisyyden antilogaritmi (J.H. Gaddum et ai. Exp. Physiol., 1955, 40, 49); K„ ollessa yhtä kuin antilogaritmi - , se on riippumaton B pA2 sekä lääkeannoksesta että herkitykseen käytetyn reagenssin kon-sentraatiosta, pA2 on antagonistisen yhdisteen (A) molaarisen konsentraation, jonka pienentää stimuloivan lääkeaineen vaikutuksen puoleen, negatiivinen logaritmi.K = - B DR-1 where B = dose of antagonist compound, expressed in mg / kg DR = dose ratio: antilogarithm of the distance between the curves of the serum containing the antagonist and the serum without the antagonist (JH Gaddum et al. Exp. Physiol., 1955, 40 , 49); When K is equal to the antilogarithm, it is independent of B pA2 both the dose of drug and the concentration of reagent used for sensitization, pA2 is the negative logarithm of the molar concentration of antagonist compound (A) reduced by half the effect of the stimulating drug.
Mitä alhaisempi on Kg-arvo, sitä korkeampi on antiallerginen aktiviteetti.The lower the Kg value, the higher the antiallergic activity.
Seuraavassa taulukossa keksinnön mukaisesti valmistettujen yhdisteiden antiallergista aktiviteettia on verrattu dinatrium-kromo-glykaattiin (DSCG), joka on tunnettu antiallerginen lääke; taulukossa yhdisteitä on merkitty seuraavilla koodeilla: 67080 K 10149 6-karboksi-2’-isopropoksi-flavoni; K 11056 6-karboksi-2'-butoksi-flavoni; K 11006 6-karboksi-2'-(2-etoksi-etoksi)-flavoni; K 10175 6-karboksi-4'-(2-etoksi-etoksi)-flavoni; K 11662 6-karboksi-4'-fluori-flavoni; K 11785 6-karboksi-3'-fluori-flavoni; K 11074 6-karboksi-2-(2'-pyridyyli)-kromoni; K 11054 6-karboksi-2-(3'-pyridyyli)-kromoni; K 11089 6-karboksi-2-(2'-pyratsinyyli)-kromoni; K 11166 6-karboksi-2-(5'-metyyli-2’-pyratsinyyli)-kromoni; K 11202 6-karboksi-2-(6,-metyyli-2,-pyratsinyyli)-kromoni.The following table compares the antiallergic activity of the compounds of the invention with disodium chromoglycate (DSCG), a known antiallergic drug; in the table the compounds are denoted by the following codes: 67080 K 10149 6-carboxy-2'-isopropoxy-flavone; K 11056 6-carboxy-2'-butoxy-flavone; K 11006 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone; K 10175 6-carboxy-4 '- (2-ethoxy-ethoxy) -flavone; K 11662 6-carboxy-4'-fluoro-flavone; K 11785 6-carboxy-3'-fluoro-flavone; K 11074 6-carboxy-2- (2'-pyridyl) chromone; K 11054 6-carboxy-2- (3'-pyridyl) chromone; K 11089 6-carboxy-2- (2'-pyrazinyl) -chromone; K 11166 6-carboxy-2- (5'-methyl-2'-pyrazinyl) -chromone; K 11202 6-Carboxy-2- (6, -methyl-2, -pyrazinyl) -chromone.
TAULUKKO ITABLE I
------------------------------------------------------------------------------------------------------------------------ --------------------
Yhdiste Esikäsittelyaika Antiallerginen aktiviteetti p.o. - Κβ (mg/kg) DSCG 15' > 200 K 10149 15’ 9,59 K 11056 15’ 11,51 K 11006 15’ 11,62 K 10175 15* 14,53 K 11662 15’ 5,51 K 11785 15' 16,34 K 11074 15’ 8,48 K 11054 15' 15,02 K 11089 15’ 5,71 K 11166 15’ 10,36 K 11202 15' 9,98 ! _ _________________________________________________________Compound Pretreatment time Antiallergic activity p.o. - Κβ (mg / kg) DSCG 15 '> 200 K 10149 15' 9.59 K 11056 15 '11.51 K 11006 15' 11.62 K 10175 15 * 14.53 K 11662 15 '5.51 K 11785 15 '16.34 K 11074 15' 8.48 K 11054 15 '15.02 K 11089 15' 5.71 K 11166 15 '10.36 K 11202 15' 9.98! _ _______________________________________________________
Antiallerginen aktiviteetti määritettiin IgE-välitetyn PCA:n inhibiitiona, menetelmän mukaan, jonka ovat esittäneet Goose J. ja Blair A.M.J.N. (Immunology, 1969, 16:749) käyttäen homosytotrooppisia vasta-aineita, jotka kohosivat rotilla, menetelmän mukaan, jonka on esittänyt Mota I., Immunology, 7, 681 (1964).Antiallergic activity was determined as inhibition of IgE-mediated PCA according to the method of Goose J. and Blair A.M.J.N. (Immunology, 1969, 16: 749) using homocytotropic antibodies raised in rats according to the method of Mota I., Immunology, 7, 681 (1964).
Testattavat yhdisteet annostettiin per os 15 minuuttia ennen antigeenin annostamista ja jokaiseen määritykseen käytettiin ainakin 6 rottaa.Test compounds were administered orally 15 minutes before antigen administration and at least 6 rats were used for each assay.
8 670808 67080
Seuraavassa taulukossa esitetään keksinnön mukaisesti valmistetulla, o-raalisesti annetulla yhdisteellä PCA-kokeessa rotissa saatu suoja verrattuna kahteen tunnettuun antiallergisesti vaikuttavaan lääkkeeseen, nimittäin dinatrium-kromoglykaattiin (DSCG) ja AH 7725’een, t.s. 2--karboksi-7-hydroksietoksiksantoniin (Fullarton, J., Martin,L.E. ja Vardey, C. Int. Arch. All. 1973 , 45:8*4).The following table shows the protection obtained with the o-orally administered compound of the invention in a PCA test in rats compared to two known antiallergic drugs, namely disodium cromoglycate (DSCG) and AH 7725, i. 2-carboxy-7-hydroxyethoxyxanthone (Fullarton, J., Martin, L.E. and Vardey, C. Int. Arch. All. 1973, 45: 8 * 4).
TAULUKKO IITABLE II
Yhdiste Annos %:nen esto verrattuna kontrolleihin (mg/kg/p o ) mitattuna eri käsittelyajan jälkeen 15 min. 30 min. 60 min. 120 min.Compound Dose% inhibition compared to controls (mg / kg / p o) measured after different treatment times of 15 min. 30 min. 60 min. 120 min.
I DSCG 50 6,0 5,5 3,2 2,5 i AH 7725 50 42,6 1*4,4 13,3 3,8 6-karboksi-2 '--isopropoksi- -flavoni 50 82,9 39,5 27,6 24,4 !_________________________________________________________________I DSCG 50 6.0 5.5 3.2 2.5 i AH 7725 50 42.6 1 * 4.4 13.3 3.8 6-carboxy-2'-isopropoxy-flavone 50 82.9 39 , 5 27.6 24.4! _______________________________________________________________
Antiallergisen aktiviteetin ohella ovat nämä keksinnön mukaisesti valmistetut yhdisteet tehokkaita ilmakanavan aiheuttaman resistanssin vähentämiseksi ja pulmonaarisen elastisiteetin lisäämiseksi, ja niitä voidaan näin ollen käyttää respiratoorisen insuffisienssin, kuten esimerkiksi akuuttisen pulmonaarisen insuffisienssin käsittelemiseksi, kuten käy ilmi rotissa saaduista tuloksista käyttäen tekniikkaa, jota ovat kuvanneet Palecek F., Palecekova M., ja Aviado D.M. (Arch. Environ. Health, 1967, 15: 332-342). Näissä kokeissa alentavat keksinnön mukaiset yhdisteet, erityisesti 6-karboksi-2 -isopropoksi-flavoni, ilmakanavan resistenssiä ja lisäävät pulmonaa-rista elastisiteettia niinkin pieninä annoksina kuin 3 mg/kg/i.v.; samansuuruisina annoksina ne ovat tehokkaita vastustamaan (50 %) 5-HT:n (5-hydroksi-triptamiinin, t.s. serotoniinin) ja yhdisteen 48/80 (histamiinia vapauttavan lääkkeen) bronkokonstriktiivista vaikutusta.In addition to antiallergic activity, these compounds of the invention are effective in reducing airway resistance and increasing pulmonary elasticity, and can therefore be used to treat respiratory insufficiency, such as acute pulmonary insufficiency, as shown by the results obtained in rats using the technique Palek. , Palecekova M., and Aviado DM (Arch. Environ. Health, 1967, 15: 332-342). In these experiments, the compounds of the invention, in particular 6-carboxy-2-isopropoxy-flavone, reduce airway resistance and increase pulmonary elasticity at doses as low as 3 mg / kg / i.v .; at equal doses, they are effective against the bronchoconstrictive effect of (50%) 5-HT (5-hydroxytryptamine, i.e. serotonin) and compound 48/80 (histamine releasing drug).
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Keksinnön mukaisesti valmistetuilla yhdisteillä on lisäksi vatsahaavoja vastustava aktiviteetti, mikä ilmenee siitä, että ne osoittautuivat aktiivisiksi stressi-indusoitujen vatsahaavojen estämiseksi rotissa, joita rasitettiin 25°:n vesihauteessa 40 minuutin aikana menetelmämuunnoksen mukaan, jota ovat kuvanneet Tagaki, K. ja Okabe, S. (Jap. J. of Pharmac., 1968, 18:9).The compounds of the invention further have antiulcer activity, as evidenced by their proven activity in preventing stress-induced gastric ulcers in rats challenged in a 25 ° water bath for 40 minutes according to a method modification described by Tagaki, K. and Okabe, S. (Jap. J. of Pharmac., 1968, 18: 9).
Tässä kokeessa estivät keksinnön mukaisesti valmistetut yhdisteet, erityisesti 6-karboksi-2’-isopropoksi-flavonin natriumsuola, 45-prosenttisesti stressi-indusoituja vatsahaavoja rotissa kun yhdisteitä annostettiin 50 mg/kg/i.v.:n annoksina.In this experiment, the compounds of the invention, especially the sodium salt of 6-carboxy-2'-isopropoxy-flavone, inhibited 45% of the stress-induced gastric ulcers in rats when administered at doses of 50 mg / kg / i.v.
Keksinnön mukaisesti valmistettuja yhdisteitä voidaan annostaa tavanomaiseen tapaan, esimerkiksi oraalisesti ja parenteraalises-ti päivittäisen annoksen ollessa mieluimmin 0,5 - 15 mg/kg, tai in-haloimalla päivittäisen annoksen ollessa mieluimmin 0,5 - 100 mg, mieluimmin 0,5 - 25 mg, tai topikaalisesti.The compounds of the invention may be administered in a conventional manner, for example orally and parenterally at a daily dose of preferably 0.5 to 15 mg / kg, or by inhalation at a daily dose of preferably 0.5 to 100 mg, more preferably 0.5 to 25 mg , or topically.
Keksinnön mukaisesti valmistettuja yhdisteitä ja farmaseuttisesti hyväksyttäviä kantaja-aineita ja/tai laimennusaineita sisältävien farmaseuttisten koostumusten luonne riippuu tietenkin halutusta annostustavasta.The nature of the pharmaceutical compositions containing the compounds of the invention and pharmaceutically acceptable carriers and / or diluents will, of course, depend on the desired route of administration.
Koostumukset voidaan valmistaa tavalliseen tapaan käyttäen tavanomaisia aineosia. Keksinnön mukaisesti valmistetut yhdisteet voidaan antaa esimerkiksi vetipitoisten tai öljymäisten liuosten tai suspensioiden, aerosolien sekä puutereiden, tablettien, pillereiden, liivatekapseleiden, siirappien tai voiteiden tai lotionien muodossa topikaalista käyttöä varten.The compositions may be prepared in a conventional manner using conventional ingredients. The compounds according to the invention can be administered, for example, in the form of aqueous or oily solutions or suspensions, aerosols and powders, tablets, pills, gelatin capsules, syrups or ointments or lotions for topical use.
Oraalista annostamista varten voidaan keksinnön mukaisesti valmistetuista yhdisteistä muodostaa sopivia farmaseuttisia koostumuksia, jotka ovat mieluimmin tabletteja, pillereitä tai liivatekap-seleita, jotka sisältävät aktiiviyhdistettä yhdessä laimennusainei-den, kuten esimerkiksi laktoosin, dekstroosin, sakkaroosin, mannito-lin, sorbitolin, selluloosan kanssa; voiteluaineita, esimerkiksi silikaa, talkkia, steariinihappoa, magnesium- tai kalsiumstearaattia, ja/tai polyetyleeniglykoleja; tai ne voivat sisältää myös sideaineita, kuten esimerkiksi tärkkelyksiä, liivatetta, metyyliselluloosaa, karboksimetyyliselluloosaa, arabikumia, traganttia, polyvinyyli-pyrrolidonia, hajottamisaineita, kuten esimerkiksi tärkkelyksiä, algiinihappoa, alginaatteja, natriumtärkkelysglykolaattia; kuohu-seoksia; väriaineita; makeuttamisaineita; kostutusaineita; kuten 67080 10 esimerkiksi lesitiiniä, polysorbaatteja, lauryylisulfaatteja; ja yleensä myrkyttömiä ja farmakologisesti inaktiivisia, farmaseuttisissa valmisteissa käytettyjä aineita. Mainitut farmaseuttiset valmisteet muodostetaan tavanomaiseen tapaan, esimerkiksi sekoittamalla, granuloimalla, tabletoimalla, päällystämällä sokerilla, tai käyttämällä kalvonpäällystämismenetelmiä,For oral administration, the compounds of the invention may be formulated into suitable pharmaceutical compositions, preferably tablets, pills or gelatin capsules, containing the active compound in association with diluents such as lactose, dextrose, sucrose, mannitol, cellbitol; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; or they may also contain binders such as starches, gelatin, methylcellulose, carboxymethylcellulose, acacia, tragacanth, polyvinylpyrrolidone, disintegrants such as starches, alginic acid, alginates, sodium starch glycolate; foam-based alloys; coloring agents; sweetening agents; wetting agents; such as 67080 10 for example lecithin, polysorbates, lauryl sulphates; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical preparations. Said pharmaceutical preparations are formed in a conventional manner, for example, by mixing, granulating, tableting, sugar-coating, or film-coating techniques.
Allergisen astman hoitoon annostetaan keksinnön mukaisesti valmistettuja yhdisteitä myös inhaloimalla. Tällaista käyttöä varten voivat sopivat koostumukset käsittää aktiivisen aineosan, mieluimmin suolan, kuten natriumsuolan muodossa, suspension tai liuoksen vedessä, jolloin sen annostamiseen käytetään tavanomaista sumu-tinta. Vaihtoehtoisesti voivat koostumukset olla aktiiviaineosan suspensiona tai liuoksena tavanomaisessa nesteytetyssä ponneaineessa, kuten diklooridifluorimetaanissa tai diklooritetrafluorietaa-nissa, jolloin niitä annostetaan painesäiliöstä, t.s. aerosolisäi-liöstä. Lääkkeen ollessa liukenematon ponneaineeseen voi olla välttämätöntä lisätä koostumukseen jotakin lisäliuotinta, kuten esimerkiksi etanolia, dipropyleeniglykolia, isopropyylimyristaattia ja/tai pinta-aktiivista ainetta lääkkeen suspensoimiseksi ponneaineeseen, ja tällainen pinta-aktiivinen aine voi olla mikä tahansa aine, jota tavallisesti käytetään tähän tarkoitukseen, kuten ei--ioninen pinta-aktiivinen aine, esim. lesitiini.For the treatment of allergic asthma, the compounds according to the invention are also administered by inhalation. Suitable compositions for such use may comprise the active ingredient, preferably in the form of a salt, such as the sodium salt, a suspension or solution in water, using a conventional nebulizer for administration. Alternatively, the compositions may be in the form of a suspension or solution of the active ingredient in a conventional liquefied propellant such as dichlorodifluoromethane or dichlorotetrafluoroethane, which is dispensed from a pressure vessel, i. aerosolisäi-container. When the drug is insoluble in the propellant, it may be necessary to add an additional solvent to the composition, such as ethanol, dipropylene glycol, isopropyl myristate, and / or a surfactant to suspend the drug in the propellant, and such a surfactant may be any substance commonly used for this purpose. --ionic surfactant, e.g. lecithin.
Keksinnön mukaisesti valmistettuja yhdisteitä voidaan käyttää myös puutereiden muodossa käyttäen sopivaa puhalluslaitetta, ja tässä tapauksessa voidaan aktiiviaineosan hienojakoiset puuterit sekoittaa laimennusaineen, kuten laktoosin kanssa.The compounds according to the invention can also be used in the form of powders using a suitable blowing device, in which case the fine powders of the active ingredient can be mixed with a diluent such as lactose.
Keksinnön mukaisesti valmistetut yhdisteet voidaan myös antaa intradermaalisena ruiskeena tai ruiskeena suoneen tavanomaiseen tapaan.The compounds of the invention may also be administered by intradermal injection or intravenous injection in a conventional manner.
Sisäisen annostamisen ohella voidaan keksinnön mukaisesti valmistettuja yhdisteitä käyttää topikaalisissa koostumuksissa, esim. voiteissa, lotioneissa tai tahnoissa dermatologisiin käsit-telyihin. Näitä koostumuksia varten voidaan aktiiviaine sekoittaa tavanomaisten öljymäisten tai emulgoimisaineiden kanssa.In addition to internal administration, the compounds of the invention may be used in topical compositions, e.g., creams, lotions or pastes for dermatological treatments. For these compositions, the active ingredient may be mixed with conventional oily or emulsifying agents.
6708067080
Seuraavat esimerkit havainnollistavat keksintöä.The following examples illustrate the invention.
ESIMERKKI 1EXAMPLE 1
Liuos, jossa oli metyyli-3-asetyyli-4-hydroksi-bentsoaattia (60 g) ja metyyli-2-isopropoksi-bentsoaattia (120 g) dioksaanissa (400 ml), lisättiin samalla hämmentäen huoneen lämpötilassa natrium-hydridin 50-pros. (45 g) suspensioon dioksaanissa (200 ml). Seos pidettiin 4 tuntia 80°C:ssa, jäähdytettiin ja laimennettiin sitten pet-rolieetterillä (600 ml), minkä jälkeen suodatettiin. Saatu sakka liuotettiin veteen, hapotettiin etikkahapolla ja uutettiin etyyliasetaatilla. Orgaaninen faasi pestiin 5-%:lla kaliumkarbonaatilla ja vedellä, ja haihdutettiin sitten kuiviin ja kiteytettiin etanolista, jolloin saatiin (2-hydroksi-5-karbometoksi-bentsoyyli)-(2-isopropoksi--bentsoyyli)-metaania (70 g; sul.p. 105-107°C), joka sitten keitettiin palautusjäähdyttäen 15 minuuttia 99-%:n muurahaishapon (280 ml) kanssa. Jäähdyttämisen ja vedellä (1 litra) laimentamisen ja suodattamisen jälkeen kerätty sakka kiteytettiin uudestaan asetonista, jolloin saatiin 6-karbometoksi-2 1 -isopropoksi-flavonia (60 g·, sul.p. 154-155°C), joka hydrolysoitiin l-%:lla kaliumhydroksidiliuoksella (1. 1,020) 95-%:ssa etanolissa palautuslämpötilassa 30 minuuttia.A solution of methyl 3-acetyl-4-hydroxybenzoate (60 g) and methyl 2-isopropoxybenzoate (120 g) in dioxane (400 ml) was added with stirring at room temperature over 50% sodium hydride. (45 g) in dioxane (200 ml). The mixture was kept at 80 ° C for 4 hours, cooled and then diluted with petroleum ether (600 ml), then filtered. The resulting precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with 5% potassium carbonate and water, then evaporated to dryness and crystallized from ethanol to give (2-hydroxy-5-carbomethoxy-benzoyl) - (2-isopropoxy-benzoyl) -methane (70 g; m.p. m.p. 105-107 ° C), which was then refluxed for 15 minutes with 99% formic acid (280 mL). After cooling and dilution with water (1 liter) and filtration, the precipitate collected was recrystallized from acetone to give 6-carbomethoxy-21-isopropoxy-flavone (60 g ·, m.p. 154-155 ° C), which was hydrolyzed with 1% with a solution of potassium hydroxide (1. 1.020) in 95% ethanol at reflux for 30 minutes.
Seos jäähdytettiin, hapotettiin etikkahapolla, väkevöitiin tyhjössä, jolloin saatiin sakka, joka suodatettiin, pestiin etanolilla (95%) ja vedellä, jolloin kiteyttämisen jälkeen etanolista saatiin 6-kar-boksi-2'-isopropoksi-flavonia (45 g; sul.p. 209-211°C).The mixture was cooled, acidified with acetic acid, concentrated in vacuo to give a precipitate which was filtered, washed with ethanol (95%) and water to give 6-carboxy-2'-isopropoxy-flavone (45 g; m.p. 209-211 ° C).
Menettelemällä vastaavalla tavalla saatiin seuraavia yhdisteitä: - 6-karboksi-2'-propoksi-flavoni, sul.p. 201-203°Cj - 6-karboksi-2'-butoksi-flavoni, sul.p. 204-206°C; - 6-karboksi-2'-etoksi-flavoni, sul.p. 225-227°C; - 6-karboksi-4'-isopropoksi-flavoni, sul.p. 263-265°C; - 6-karboksi-3'-isopropoksi-flavoni, sul.p. 235-237°Cv - 6-karboksi-2'-isopropoksi-4 '-(2-etoksi-etoksi)-flavoni, sul.p. 179-181°C; - 6-karboksi-2'-(2-etoksi-etoksi)-flavoni, sul.p. 198-200°C.By proceeding in a similar manner, the following compounds were obtained: - 6-carboxy-2'-propoxy-flavone, m.p. 201-203 ° C - 6-carboxy-2'-butoxy-flavone, m.p. 204-206 ° C; - 6-carboxy-2'-ethoxy-flavone, m.p. 225-227 ° C; - 6-carboxy-4'-isopropoxy-flavone, m.p. 263-265 ° C; - 6-carboxy-3'-isopropoxy-flavone, m.p. 235-237 ° C - 6-carboxy-2'-isopropoxy-4 '- (2-ethoxy-ethoxy) -flavone, m.p. 179-181 ° C; - 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone, m.p. 198-200 ° C.
ESIMERKKI 2 a) Liuos, jossa oli metyyli-3-asetyyli-4-hydroksi-bentsoaattia (54 g) ja metyyli-2-bentsyylioksi-bentsoaattia (135 g) dioksaanissa (400 ml), lisättiin hitaasti, samalla hämmentäen, huoneen lämpötilassa 67080 natriumhydridin 50-pros. (40 g) suspensioon dioksaanissa (150 ml).EXAMPLE 2 a) A solution of methyl 3-acetyl-4-hydroxybenzoate (54 g) and methyl 2-benzyloxybenzoate (135 g) in dioxane (400 ml) was added slowly, with stirring, at room temperature 67080 50% of sodium hydride. (40 g) suspension in dioxane (150 ml).
Seos pidettiin 5 tuntia 70°C:ssa, jäähdytettiin ja laimennettiin petrolieetterillä, minkä jälkeen suodatettiin. Kerätty sakka liuotettiin veteen, hapotettiin etikkahapolla ja uutettiin etyyliasetaatilla. Orgaaninen faasi pestiin 5-%:lla kaliumkarbonaatilla ja vedellä, ja haihdutettiin sitten kuiviin. Kiteyttämisen jälkeen metanolista saatiin (2-hydroksi-5-karbometoksi-bentsoyyli)-(2-bentsyylioksi-bent-soyyli)-metaania (74 g; sul.p. 95-97°C), joka sen jälkeen keitettiin palautusjäähdyttäen 24 tuntia 99-%:n muurahaishapon kanssa (500 ml). Jäähdyttämisen ja etanolilla (500 ml) laimentamisen jälkeen saatu sakka suodatettiin ja pestiin etanolilla, jolloin saatiin 6-karbometoksi--2'-hydroksi-flavonia (31 gi sul.p. 290-291°C).The mixture was kept at 70 ° C for 5 hours, cooled and diluted with petroleum ether, then filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with 5% potassium carbonate and water, and then evaporated to dryness. After crystallization from methanol, (2-hydroxy-5-carbomethoxy-benzoyl) - (2-benzyloxy-benzoyl) -methane (74 g; m.p. 95-97 ° C) was obtained, which was then refluxed for 24 hours. with% formic acid (500 ml). After cooling and dilution with ethanol (500 ml), the resulting precipitate was filtered and washed with ethanol to give 6-carbomethoxy-2'-hydroxy-flavone (31 g m.p. 290-291 ° C).
b) Edellä kohdassa a) selitetyn menetelmän mukaan saatua 6--karbometoksi-2’-hydroksi-flavonia (5 g) saatettiin reagoimaan dime-tyyliformamidissa (30 ml) /3 -etoksi-etyyli-bromidin (3,5 g) ja kaliumkarbonaatin (3,2 g) kanssa 80°C:ssa 16 tuntia. Seos jäähdytettiin, laimennettiin vedellä, suodatettiin ja pestiin vedellä. Kiteyttämisen jälkeen metanolista saatiin 6-karbometoksi-2’-(2-etoksi-etoksi)-fla-vonia (4,5 g), joka hydrolysoitiin kaliumhydroksidin l-%:lla liuoksella (90 ml) 95-%:ssa etanolissa palautuslämpötilassa 45 minuuttia. Jäähdytettiin, hapotettiin etikkahapolla, väkevöitiin, laimennettiin vedellä, suodatettiin ja kiteytettiin etanolista, minkä jälkeen saatiin 6-karboksi-2’-(2-etoksi-etoksi)-flavonia (3,1 g; sul.p. 198-200° C).b) 6-Carbomethoxy-2'-hydroxy-flavone (5 g) obtained according to the method described in a) above was reacted in dimethylformamide (30 ml) with 3-ethoxyethyl bromide (3.5 g) and potassium carbonate. (3.2 g) at 80 ° C for 16 hours. The mixture was cooled, diluted with water, filtered and washed with water. After crystallization from methanol, 6-carbomethoxy-2 '- (2-ethoxy-ethoxy) -flafonone (4.5 g) was obtained, which was hydrolyzed with a 1% solution of potassium hydroxide (90 ml) in 95% ethanol at reflux temperature. minutes. Cool, acidify with acetic acid, concentrate, dilute with water, filter and crystallize from ethanol to give 6-carboxy-2 '- (2-ethoxy-ethoxy) -flavone (3.1 g; m.p. 198-200 ° C) .
Käyttämällä sopivaa alkyylihalogenidia valmistettiin: 6-karboksi-2'-isopropoksi-flavoni, sul.p. 208-210°Cj ja vastaavasti lähtemällä 6-karbometoksi-4’-hydroksi-flavo-nista saatiin: 6-karboksi-4'-(2-etoksi-etoksi)-flavoni, sul.p. 221-223°C.Using the appropriate alkyl halide, the following was prepared: 6-carboxy-2'-isopropoxy-flavone, m.p. 208-210 ° C and starting from 6-carbomethoxy-4'-hydroxy-flavone, respectively: 6-carboxy-4 '- (2-ethoxy-ethoxy) -flavone, m.p. 221-223 ° C.
ESIMERKKI 3EXAMPLE 3
Liuos, jossa oli metyyli-3-asetyyli-4-hydroksi-bentsoaattia (16 g) ja metyylinikotinaattia (23 g) dioksaanissa (100 ml), lisättiin hitaasti huoneen lämpötilassa samalla hämmentäen natriumhydridin (12 g) 50-%:een suspensioon dioksaanissa (60 ml). Liuos pidettiin 6 tuntia 80°C:ssa, jäähdytettiin ja laimennettiin petrolieetterillä (200 ml) ja suodatettiin. Saatu tuote liuotettiin veteen ja käsiteltiin etikkahapollaj saatu sakka pestiin vedellä ja kiteytettiin metyleenikloridi/metanolista, jolloin saatiin (2-hydroksi-5-karbo- I3 67080 metoksi-bentsoyyli)-nikotinoyyli-metaania (17,2 g; sul.p. 200-202°C), jota sitten käsiteltiin 1 % väkevää kloorivetyä sisältävällä etanolilla (300 ml) palautuslämpötilassa 2 tuntia. Väkevöitiin tyhjössä-laimennettiin vedellä, neutraloitiin natriumasetaatilla, minkä jälkeen sakka suodatettiin. Raaka 6-karbometoksi-2-(3’-pyridyyli)-kromoni (15,1 g) hydrolysoitiin stökiömetrisellä määrällä l-%:sta kaliumhyd-roksidia 95-%:ssa etanolissa palautuslämpötilassa yhden tunnin ajan. Jäähdyttämisen, vedellä (600 ml) laimentamisen, etikkahapolla neutra-loimisen jälkeen sakka kerättiin ja kiteyttämisen jälkeen dimetyyli-formamidista saatiin 6-karboksi-2-(3'-pyridyyli)-kromonia (9,8 gi sul.p. 350°C); IR (KBr): ^ (karboksi) 1680 cm”*, 'f (kromoni) 1630 cm *, 1610 cm *, ^ ^^^(meta-substituoitu pyridiini) 770 cm *, 696 cm *.A solution of methyl 3-acetyl-4-hydroxybenzoate (16 g) and methyl nicotinate (23 g) in dioxane (100 ml) was added slowly at room temperature with stirring to a 50% suspension of sodium hydride (12 g) in dioxane ( 60 ml). The solution was kept at 80 ° C for 6 hours, cooled and diluted with petroleum ether (200 ml) and filtered. The resulting product was dissolved in water and treated with acetic acid, and the resulting precipitate was washed with water and crystallized from methylene chloride / methanol to give (2-hydroxy-5-carbo-1,37080 methoxybenzoyl) -nicotinoyl-methane (17.2 g; m.p. 202 ° C) which was then treated with ethanol (300 ml) containing 1% concentrated hydrogen chloride at reflux for 2 hours. Concentrated in vacuo-diluted with water, neutralized with sodium acetate, then the precipitate was filtered. The crude 6-carbomethoxy-2- (3'-pyridyl) chromone (15.1 g) was hydrolyzed with a stoichiometric amount of 1% potassium hydroxide in 95% ethanol at reflux for one hour. After cooling, dilution with water (600 ml), neutralization with acetic acid, the precipitate was collected and, after crystallization from dimethylformamide, 6-carboxy-2- (3'-pyridyl) -chromone (9.8 g, m.p. 350 ° C) was obtained. ; IR (KBr): δ (carboxy) 1680 cm -1, λ max (chromone) 1630 cm -1, 1610 cm -1, λmax (meta-substituted pyridine) 770 cm -1, 696 cm -1.
Menettelemällä vastaavalla tavalla valmistettiin seuraavia yhdisteitä: - 6-karboksi-2-(2'-pyridyyli)-kromoni, sul.p. > 300°C; IR (KBr):By proceeding in a similar manner the following compounds were prepared: 6-carboxy-2- (2'-pyridyl) -chromone, m.p. > 300 ° C; IR (KBr):
Yc_0( karboksi) cm ^ C~o(kromoni) 1650 cm *, ^c-H^orto“ -substituoitu pyridiini) 768 cm”*; - 6-karboksi-2-(4'-pyridyyli)-kromoni, sul.p. > 350°C; IR (KBr): V q_q(karboksi) 1690 cm”1, Ϋ^.Q(kromoni) 1630 cm”1, ^T^_^(para--substituoitu pyridiini) 825 cm *; - 6-karboksi-2-(2'-pyratsinyyli)-kromoni, sul.p. > 350°C; IR (KBr): V c_Q(karboksi) 1695 cm”*, £_0(kromoni) 1645 cm *; - 6-karboksi-2-(6'-metyyli-2'-pyratsinyyli)-kromoni, sul.p. 320°C (haj.] IR (KBr). q_q(karboksi) 1700 cm *, \^^_q(kromoni) 1655 cm *; - 6-karboksi-2-(5'-metyyli-2'-pyratsinyyli)-kromoni, sul.p. 316-319°C.Yc_O (carboxy) cm-2 (chromone) 1650 cm-1, (c-H (ortho-substituted pyridine)) 768 cm-1; - 6-carboxy-2- (4'-pyridyl) chromone, m.p. > 350 ° C; IR (KBr): ν max (carboxy) 1690 cm -1, λmax (chromone) 1630 cm -1, λmax (para-substituted pyridine) 825 cm -1; - 6-carboxy-2- (2'-pyrazinyl) -chromone, m.p. > 350 ° C; IR (KBr): ν max (carboxy) 1695 cm-1, ε-O (chromone) 1645 cm-1; - 6-carboxy-2- (6'-methyl-2'-pyrazinyl) -chromone, m.p. 320 DEG C. (dec.) IR (KBr), .delta. (Carboxy) 1700 cm @ -1, @ @ @ @ @ @ @ @ @ @ @ @ @ N-D - (chromone) - 1655 cm @ -1; chromone, mp 316-319 ° C.
ESIMERKKI 4 6-karboksi-2'-isopropoksi-flavonia (3,2 g) käsiteltiin natriumbikarbonaattia (800 mg) sisältävällä kuumalla vesiliuoksella.EXAMPLE 4 6-Carboxy-2'-isopropoxy-flavone (3.2 g) was treated with a hot aqueous solution containing sodium bicarbonate (800 mg).
Pieni liukenematon määrä happoa suodatettiin pois ja kirkas liuos väkevöitiin tyhjössä melkein kuiviin. Käsittelemällä asetonilla (200 ml) ja kiteyttämällä saatiin 6-karboksi-2'-isopropoksi-flavonin 67080 14 natriumsuolaa (3*1 g; sul.p. 300°C).A small insoluble amount of acid was filtered off and the clear solution was concentrated in vacuo to near dryness. Treatment with acetone (200 ml) and crystallization gave 6-carboxy-2'-isopropoxy-flavone 67080 14 sodium salt (3 * 1 g; m.p. 300 ° C).
Menettelemällä vastaavalla tavalla saatiin: 6-karboksi-2-(2'-pyratsinyyli)-kromonin natriumsuolaa, sul.p* > 300°C.By proceeding in a similar manner, the following was obtained: the sodium salt of 6-carboxy-2- (2'-pyrazinyl) -chromone, m.p.> 300 ° C.
ESIMERKKI 5 6-karboksi-2'-isopropoksi-flavonin esimerkin 4 mukaisesti valmistettua natriumsuolaa (5 g),suspensoituna dimetyyliformamidiin (50 ml), käsiteltiin kloorimetyyli-pivalaatilla (5 ml) ja trietyyli-amiinilla (1,5 ml) 70°C:ssa 16 tuntia. Sen jälkeen seos jäähdytettiin, laimennettiin vedellä (500 ml), uutettiin etyyliasetaatilla ja orgaaninen faasi pestiin 5-%:lla natriumbikarbonaatilla, sen jälkeen vedellä ja haihdutettiin kuiviin. Jäännös kiteytettiin isopropyyli-eetterillä, jolloin saatiin 6-karboksi-2'-isopropoksi-flavonin piva-loksimetyyliesteriä (3,9 g; sul.p. 102-104°C).EXAMPLE 5 The sodium salt of 6-carboxy-2'-isopropoxy-flavone prepared according to Example 4 (5 g) suspended in dimethylformamide (50 ml) was treated with chloromethyl pivalate (5 ml) and triethylamine (1.5 ml) at 70 ° C. at 16 hours. The mixture was then cooled, diluted with water (500 ml), extracted with ethyl acetate and the organic phase washed with 5% sodium bicarbonate, then with water and evaporated to dryness. The residue was crystallized from isopropyl ether to give pivaloxymethyl ester of 6-carboxy-2'-isopropoxy-flavone (3.9 g; m.p. 102-104 ° C).
Käyttämällä samaa menetelmää saatiin: 6-karboksi-2-(2'-pyratsinyyli)-kromonin pivaloksimetyyliesteri, sul.p. 137-142°C.Using the same procedure, the following was obtained: 6-carboxy-2- (2'-pyrazinyl) -chromone pivaloxymethyl ester, m.p. 137-142 ° C.
ESIMERKKI 6EXAMPLE 6
Esimerkin 4 mukaisesti valmistettua 6-karboksi-2'-isopropoksi--flavonin natriumsuolaa (4 g), suspensoituna dimetyyliformamidiin (40 ml), käsiteltiin klooriasetamidilla (1,25 g) ja muutamalla tipalla trietyyliamiinia 75°C:ssa 24 tuntia. Jäähdytettiin, laimennettiin vedellä, hapotettiin etikkahapolla ja suodatettiin, jolloin saatiin 6-karboksi-2'-isopropoksi-flavonin 6-glukoliamidiesteriä (4,2 g; sul.p. 230-232°C), joka hydrolysoitiin etikkahapossa (30 ml) ja 23-%:ssa kloorivetyhapossa (20 ml) 75°C:ssa yhden tunnin ajan. Laimennettiin vedellä, suodatettiin ja kiteytettiin etanolista, jolloin saatiin 6-karboksi-2’-isopropoksi-flavonin glykoliesteriä (3,1 g; sul.p. 210-212°C).The sodium salt of 6-carboxy-2'-isopropoxy-flavone (4 g) prepared according to Example 4, suspended in dimethylformamide (40 ml), was treated with chloroacetamide (1.25 g) and a few drops of triethylamine at 75 ° C for 24 hours. Cooled, diluted with water, acidified with acetic acid and filtered to give 6-glucolamide ester of 6-carboxy-2'-isopropoxy-flavone (4.2 g; m.p. 230-232 ° C) which was hydrolyzed in acetic acid (30 ml) and In 23% hydrochloric acid (20 ml) at 75 ° C for one hour. Diluted with water, filtered and crystallized from ethanol to give 6-carboxy-2'-isopropoxy-flavone glycol ester (3.1 g; mp 210-212 ° C).
ESIMERKKI 7 2'-isopropoksi-flavoni-6-karbonyylikloridia (5,6 g) \valmis-tus: 6-karboksi-2'-isopropoksi-flavonia suspendoidaan bentseeniin ja käsitellään tionyylikloridilla palautuslämpötilassa, liuos haihdutetaan kuiviin], joka oli liuotettu vedettömään bentseeniin (50 ml) käsiteltiin dietyyliaminoetanolilla (4,2 ml) ja trietyyliamiinilla (1 ml) huoneen lämpötilassa 4 tuntia. Bentseeniliuos pestiin 5-%:lla natriumbikarbonaatilla ja vedellä, ja haihdutettiin sitten kuiviin. Jäännös liuotettiin asetoniin (100 ml); lisäämällä stökiömetrinen 15 67080 määrä väkevää kloorivetyhappoa saatiin 6-karboksi-2'-isopropoksi--flavonin dietyyliaminoetyyliesterin hydrokloridia. Yhdiste (5,4 g; sul.p. 215-217°C) kerättiin suodattamalla ja pestiin huolellisesti asetonilla.EXAMPLE 7 2'-Isopropoxy-flavone-6-carbonyl chloride (5.6 g) Preparation: 6-Carboxy-2'-isopropoxy-flavone is suspended in benzene and treated with thionyl chloride at reflux, the solution is evaporated to dryness] dissolved in anhydrous benzene. (50 ml) was treated with diethylaminoethanol (4.2 ml) and triethylamine (1 ml) at room temperature for 4 hours. The benzene solution was washed with 5% sodium bicarbonate and water, and then evaporated to dryness. The residue was dissolved in acetone (100 ml); addition of a stoichiometric amount of concentrated hydrochloric acid gave 6-carboxy-2'-isopropoxy-flavone diethylaminoethyl ester hydrochloride. The compound (5.4 g; mp 215-217 ° C) was collected by filtration and washed thoroughly with acetone.
Käyttämällä samaa menetelmää valmistettiin esimerkin 5 lopussa mainitun 6-karboksi-2-(2*-pyratsinyyli)-kromonin dietyyliamino-etyyliesterin hydrokloridi, sul.p. 113-115°C.Using the same procedure, the hydrochloride of diethylaminoethyl ester of 6-carboxy-2- (2 * -pyrazinyl) chromone mentioned at the end of Example 5 was prepared, m.p. 113-115 ° C.
ESIMERKKI 8 2'-isopropoksi-flavoni-6-karbonyylikloridia (4,3 g), joka oli liuotettu vedettömään bentseeniin (40 ml), käsiteltiin N-hydroksietyy-li-morfoliinilla (3,2 g) ja pyridiinillä ¢1 ml) huoneen lämpötilassa 24 tuntia. Bentseeniliuos pestiin 40-%:11a vesipitoisella sitruuna-hapolla, natriumbikarbonaatilla ja vedellä ja haihdutettiin sitten kuiviin. Asetonista uudelleenkiteytetystä jäännöksestä saatiin 6--karboksi-2'-isopropoksi-flavonin morfolinoetyyliesteriä (3,6 g; sul.p. 133-135°C).EXAMPLE 8 2'-Isopropoxy-flavone-6-carbonyl chloride (4.3 g) dissolved in anhydrous benzene (40 ml) was treated with N-hydroxyethylmorpholine (3.2 g) and pyridine ¢ 1 ml) at room temperature. at 24 hours. The benzene solution was washed with 40% aqueous citric acid, sodium bicarbonate and water and then evaporated to dryness. The recrystallized residue from acetone gave 6-carboxy-2'-isopropoxy-flavone morpholinoethyl ester (3.6 g; m.p. 133-135 ° C).
ESIMERKKI 9 (2-hydroksi-5-karboksi-bentsoyyli)-pyratsinoyyli-metaania (27 g) käsiteltiin väkevöidyllä suolahapolla (20 ml) etikkahapossa (200 ml) palautuslämpötilassa 1 tunnin ajan. Jäähdyttämisen jälkeen sakka kerättiin suodattamalla ja pestiin vedellä ja sen jälkeen kuumassa etanolissa, jolloin saatiin 6-karboksi-2-(2'-pyratsinyyli)--kromonia 17,8 g, sul.p. > 350°C.EXAMPLE 9 (2-Hydroxy-5-carboxy-benzoyl) -pyrazinoyl-methane (27 g) was treated with concentrated hydrochloric acid (20 ml) in acetic acid (200 ml) at reflux for 1 hour. After cooling, the precipitate was collected by filtration and washed with water and then in hot ethanol to give 6-carboxy-2- (2'-pyrazinyl) chromone 17.8 g, m.p. > 350 ° C.
Vastaavalla tavalla menetellen valmistettiin seuraavat yhdisteet :Following a similar procedure, the following compounds were prepared:
6-karboksi-2-(2'-pyridyyli)-kromoni, sul.p. > 300°C 6-karboksi-2-(3,-pyridyyli)-kromoni, sul.p. > 350°C 6-karboksi-2-(4'-pyridyyli)-kromoni, sul.p. > 350°C6-carboxy-2- (2'-pyridyl) chromone, m.p. > 300 ° C 6-carboxy-2- (3'-pyridyl) -chromone, m.p. > 350 ° C 6-carboxy-2- (4'-pyridyl) chromone, m.p. > 350 ° C
6-karboksi-2-(6'-metyyli-2'-pyratsinyyli)-kromoni, sul.p. 320°C(haj.) 6-karboksi-2-(5'-metyyli-2'-pyratsinyyli)-kromoni, sul.p. 316-319°C.6-carboxy-2- (6'-methyl-2'-pyrazinyl) -chromone, m.p. 320 ° C (dec.) 6-carboxy-2- (5'-methyl-2'-pyrazinyl) -chromone, m.p. 316-319 ° C.
ESIMERKKI 10 (2-hydroksi-5-karboksi-bentsoyyli)-(2-isopropoksi-bentsoyyli)--metaania (13 g) käsiteltiin väkevöidyllä suolahapolla (10 ml) etanolissa (150 ml) palautuslämpötilassa 1 tunnin ajan. Jäähdyttämisen jälkeen sakka suodatettiin, pestiin vedellä ja kuumassa etanolissa, jolloin saatiin 6-karboksi-2'-isopropoksi-flavonia 7,5 g, sul.p. 209--211°C.EXAMPLE 10 (2-Hydroxy-5-carboxy-benzoyl) - (2-isopropoxy-benzoyl) -methane (13 g) was treated with concentrated hydrochloric acid (10 ml) in ethanol (150 ml) at reflux for 1 hour. After cooling, the precipitate was filtered, washed with water and hot ethanol to give 6-carboxy-2'-isopropoxy-flavone 7.5 g, m.p. 209 to -211 ° C.
67080 1667080 16
Vastaavasti saatiin seuraavat yhdisteet: 6-karboksi-2'-propoksi-flavoni, sul.p. 201-203°C; 6-karboksi-2 '-butoksi-f lavoni, sul.p. 204-206°C*, 6-karboksi-2'-etoksi-flavoni, sul.p. 225-227°C.Correspondingly, the following compounds were obtained: 6-carboxy-2'-propoxy-flavone, m.p. 201-203 ° C; 6-carboxy-2'-butoxy-f corone, m.p. 204-206 ° C *, 6-carboxy-2'-ethoxy-flavone, m.p. 225-227 ° C.
ESIMERKKI 11 (2-hydroksi-5-karboksi-bentsoyyli)-(4-fluori-bentsoyyli)-metaania (12 g) käsiteltiin 57-%:11a suolahapolla (15 ml) etikkahapossa (95 ml) palautuslämpötilassa 30 minuuttia. Jäähdyttämisen jälkeen sakka suodatettiin, pestiin vedellä ja kuumassa etanolissa, jolloin saatiin 6-karboksi-U’-fluori-flavonia 6,9 g, sul.p. 297-299°C.EXAMPLE 11 (2-Hydroxy-5-carboxy-benzoyl) - (4-fluoro-benzoyl) -methane (12 g) was treated with 57% hydrochloric acid (15 ml) in acetic acid (95 ml) at reflux for 30 minutes. After cooling, the precipitate was filtered, washed with water and hot ethanol to give 6-carboxy-U'-fluoro-flavone 6.9 g, m.p. 297-299 ° C.
Menettelemällä vastaavalla tavalla valmistettiin: 6-karboksi-3'-fluori-flavoni, sul.p. 314-316°C.By a similar procedure were prepared: 6-carboxy-3'-fluoro-flavone, m.p. 314-316 ° C.
ESIMERKKI 12 (koskee suolan valmistusta)EXAMPLE 12 (concerns the preparation of salt)
Esimerkin 7 mukaisesti valmistettua 6-karboksi-2'-isopropoksi--flavoni-dietyyliaminoetyyliesterin hydrokloridia (5,95 g) käsiteltiin ylimäärällä 5-%:sta natriumkarbonaattia huoneen lämpötilassa ja tuloksena saatu vapaa esteri uutettiin etyyliasetaatilla. Orgaaninen liuos haihdutettiin kuiviin*, jäännös kiteytettiin isopropyylieette-ristä, jolloin saatiin 3,4 g 6-karboksi-2'-isopropoksi-flavoni-di-etyyliaminoetyy liesteriä (sul.p. 76-78°C), joka liuotettiin aseto-nitriiliin (50 ml) ja käsiteltiin maleiinihapolla (0,93 g) huoneen lämpötilassa 1 tunnin ajan. Kun sakka oli suodatettu saatiin 3,35 g 6-karboksi-2'-isopropoksi-flavoni-dietyyliaminoetyyliesterin maleaat-tia (sul.p. 158-164°C).The 6-carboxy-2'-isopropoxy-flavone-diethylaminoethyl ester hydrochloride (5.95 g) prepared according to Example 7 was treated with an excess of 5% sodium carbonate at room temperature and the resulting free ester was extracted with ethyl acetate. The organic solution was evaporated to dryness *, the residue was crystallized from isopropyl ether to give 3.4 g of 6-carboxy-2'-isopropoxy-flavone-diethylaminoethyl ester (m.p. 76-78 ° C) which was dissolved in acetonitrile. (50 ml) and treated with maleic acid (0.93 g) at room temperature for 1 hour. After the precipitate was filtered, 3.35 g of 6-carboxy-2'-isopropoxy-flavone-diethylaminoethyl ester maleate (m.p. 158-164 ° C) were obtained.
Claims (1)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT3208973 | 1973-12-27 | ||
| IT3208973 | 1973-12-27 | ||
| IT2477774A IT1045480B (en) | 1974-07-04 | 1974-07-04 | 5,6-Benzo-gamma-pyrone derivs. - as anti-allergic and anti-ulcer agents |
| IT2477774 | 1974-07-04 | ||
| IT2524474 | 1974-07-17 | ||
| IT2524474 | 1974-07-17 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI374274A7 FI374274A7 (en) | 1975-06-28 |
| FI67080B FI67080B (en) | 1984-09-28 |
| FI67080C true FI67080C (en) | 1985-01-10 |
Family
ID=27273401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI3742/74A FI67080C (en) | 1973-12-27 | 1974-12-27 | FRAMEWORK FOR THE FRAMEWORK OF PHARMACEUTICALS ACTIVE 5: -BENZO-NY-PYRONDERIVAT |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5634595B2 (en) |
| AT (1) | AT345830B (en) |
| CA (1) | CA1061353A (en) |
| CH (2) | CH616934A5 (en) |
| CS (1) | CS202543B2 (en) |
| DE (1) | DE2461670A1 (en) |
| DK (1) | DK680474A (en) |
| FI (1) | FI67080C (en) |
| FR (1) | FR2255894B1 (en) |
| GB (1) | GB1479518A (en) |
| HU (1) | HU171874B (en) |
| IL (1) | IL46423A (en) |
| NL (1) | NL7416873A (en) |
| NO (1) | NO144110C (en) |
| SE (1) | SE417427B (en) |
| SU (1) | SU611590A3 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4160028A (en) * | 1977-08-02 | 1979-07-03 | Carlo Erba S.P.A. | Substituted 2-cyclopropyl-chromones and pharmaceutical compositions and use thereof |
| IT1134205B (en) * | 1980-11-11 | 1986-08-13 | Bonomelli Spa | PROCESS FOR THE PRODUCTION OF FLAVONIC DERIVATIVES FOR MEDICINAL ACTIVITY |
| FR2516922A1 (en) * | 1981-11-25 | 1983-05-27 | Lipha | ACIDS (OXO-4-4H- (1) -BENZOPYRAN-8-YL) ALKANOIC, SALTS AND DERIVATIVES, PREPARATION AND DRUG CONTAINING THEM |
| EP0108986A1 (en) * | 1982-11-02 | 1984-05-23 | Hokuriku Pharmaceutical Co.,Ltd | N-substituted flavone-8-carboxamides |
| IL108841A0 (en) * | 1993-03-10 | 1994-06-24 | Pfizer Res & Dev | Benzopyrans |
| JP3957795B2 (en) * | 1996-10-04 | 2007-08-15 | 興和株式会社 | Flavone derivative and pharmaceutical containing the same |
| IN2014MN02331A (en) * | 2012-04-27 | 2015-08-14 | Basf Se | |
| WO2014184073A1 (en) * | 2013-05-15 | 2014-11-20 | Basf Se | Substituted n-(tetrazol-5-yl)- and n-(triazol-5-yl)arylcarboxamide compounds and their use as herbicides |
-
1974
- 1974-12-17 GB GB54453/74A patent/GB1479518A/en not_active Expired
- 1974-12-23 SE SE7416231A patent/SE417427B/en unknown
- 1974-12-23 HU HU74EA00000142A patent/HU171874B/en unknown
- 1974-12-23 DK DK680474A patent/DK680474A/da not_active Application Discontinuation
- 1974-12-24 NL NL7416873A patent/NL7416873A/en not_active Application Discontinuation
- 1974-12-24 CH CH1731074A patent/CH616934A5/en not_active IP Right Cessation
- 1974-12-27 CA CA216,961A patent/CA1061353A/en not_active Expired
- 1974-12-27 SU SU742098258A patent/SU611590A3/en active
- 1974-12-27 AT AT1034174A patent/AT345830B/en not_active IP Right Cessation
- 1974-12-27 CS CS749033A patent/CS202543B2/en unknown
- 1974-12-27 FI FI3742/74A patent/FI67080C/en active
- 1974-12-27 NO NO744714A patent/NO144110C/en unknown
- 1974-12-27 FR FR7443125A patent/FR2255894B1/fr not_active Expired
- 1974-12-27 JP JP753008A patent/JPS5634595B2/ja not_active Expired
- 1974-12-27 DE DE19742461670 patent/DE2461670A1/en not_active Withdrawn
-
1975
- 1975-01-10 IL IL46423A patent/IL46423A/en unknown
-
1978
- 1978-03-13 CH CH388578A patent/CH616935A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2255894A1 (en) | 1975-07-25 |
| FI374274A7 (en) | 1975-06-28 |
| ATA1034174A (en) | 1978-02-15 |
| HU171874B (en) | 1978-04-28 |
| FI67080B (en) | 1984-09-28 |
| DK680474A (en) | 1975-08-25 |
| CA1061353A (en) | 1979-08-28 |
| FR2255894B1 (en) | 1978-07-21 |
| AU7687874A (en) | 1976-06-24 |
| CS202543B2 (en) | 1981-01-30 |
| SE417427B (en) | 1981-03-16 |
| CH616934A5 (en) | 1980-04-30 |
| SU611590A3 (en) | 1978-06-15 |
| SE7416231L (en) | 1975-06-30 |
| CH616935A5 (en) | 1980-04-30 |
| IL46423A (en) | 1979-03-12 |
| JPS50129568A (en) | 1975-10-13 |
| AT345830B (en) | 1978-10-10 |
| IL46423A0 (en) | 1975-05-22 |
| NL7416873A (en) | 1975-07-01 |
| DE2461670A1 (en) | 1975-07-10 |
| GB1479518A (en) | 1977-07-13 |
| NO144110C (en) | 1981-06-24 |
| NO744714L (en) | 1975-07-21 |
| NO144110B (en) | 1981-03-16 |
| JPS5634595B2 (en) | 1981-08-11 |
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