DE1518002C3 - Isoflavans and isoflavens and processes for their production and medicinal products containing them - Google Patents
Isoflavans and isoflavens and processes for their production and medicinal products containing themInfo
- Publication number
- DE1518002C3 DE1518002C3 DE1518002A DE1518002A DE1518002C3 DE 1518002 C3 DE1518002 C3 DE 1518002C3 DE 1518002 A DE1518002 A DE 1518002A DE 1518002 A DE1518002 A DE 1518002A DE 1518002 C3 DE1518002 C3 DE 1518002C3
- Authority
- DE
- Germany
- Prior art keywords
- acid
- general formula
- isoflavans
- isoflavane
- known per
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- NNQSGBRGJHSRFN-UHFFFAOYSA-N isoflavan Chemical class C1OC2=CC=CC=C2CC1C1=CC=CC=C1 NNQSGBRGJHSRFN-UHFFFAOYSA-N 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 3
- 229940126601 medicinal product Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 9
- -1 2 - pyrrolidinoethoxy Chemical group 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 235000002324 isoflavanes Nutrition 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 5
- 150000002902 organometallic compounds Chemical class 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- RTRZOHKLISMNRD-UHFFFAOYSA-N isoflavanone Chemical compound C1OC2=CC=CC=C2C(=O)C1C1=CC=CC=C1 RTRZOHKLISMNRD-UHFFFAOYSA-N 0.000 claims description 3
- KKBIDVILXNDFLH-UHFFFAOYSA-N 3-phenyl-3,4-dihydro-2h-chromen-4-ol Chemical compound C1OC2=CC=CC=C2C(O)C1C1=CC=CC=C1 KKBIDVILXNDFLH-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000012024 dehydrating agents Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 150000002641 lithium Chemical group 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- CNNBJLXLTIKXGJ-UHFFFAOYSA-N 3-phenyl-2h-chromene Chemical compound C1OC2=CC=CC=C2C=C1C1=CC=CC=C1 CNNBJLXLTIKXGJ-UHFFFAOYSA-N 0.000 claims 2
- 239000000969 carrier Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 206010067572 Oestrogenic effect Diseases 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 230000001076 estrogenic effect Effects 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000002254 contraceptive effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 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
- 238000002474 experimental method Methods 0.000 description 3
- 235000011007 phosphoric acid Nutrition 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 2
- JVMWFGYBGRWDEO-UHFFFAOYSA-N 7-methoxy-3-phenyl-2,3-dihydrochromen-4-one Chemical compound C1OC2=CC(OC)=CC=C2C(=O)C1C1=CC=CC=C1 JVMWFGYBGRWDEO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000003433 contraceptive agent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000725 suspension 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
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RMGFLMXDCGQKPS-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine Chemical compound ClCCN1CCCC1 RMGFLMXDCGQKPS-UHFFFAOYSA-N 0.000 description 1
- FSNGFFWICFYWQC-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine;hydron;chloride Chemical compound Cl.ClCCN1CCCC1 FSNGFFWICFYWQC-UHFFFAOYSA-N 0.000 description 1
- HWIJWVYJMZFHDN-UHFFFAOYSA-N 2-(4-chlorophenoxy)-n,n-diethylethanamine Chemical compound CCN(CC)CCOC1=CC=C(Cl)C=C1 HWIJWVYJMZFHDN-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- 125000000872 2-diethylaminoethoxy group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- TXDJEIPDIUUGFV-UHFFFAOYSA-N 7-methoxy-3-phenyl-3,4-dihydro-2h-chromene Chemical compound C1OC2=CC(OC)=CC=C2CC1C1=CC=CC=C1 TXDJEIPDIUUGFV-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- CQRVORXETHOPSY-UHFFFAOYSA-N [bromo-[bromo(diphenyl)methoxy]-phenylmethyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Br)OC(Br)(C=1C=CC=CC=1)C1=CC=CC=C1 CQRVORXETHOPSY-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
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- 230000000996 additive effect Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003509 anti-fertility effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- DQSHRNZTQWDMPJ-UHFFFAOYSA-N chlorosulfinyloxymethane Chemical compound COS(Cl)=O DQSHRNZTQWDMPJ-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 150000004707 phenolate Chemical class 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- ZGJADVGJIVEEGF-UHFFFAOYSA-M potassium;phenoxide Chemical class [K+].[O-]C1=CC=CC=C1 ZGJADVGJIVEEGF-UHFFFAOYSA-M 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 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
-
- 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
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
- C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Die Erfindung betrifft Isoflavane und Isoflavene der allgemeinen Formeln Ia und IbThe invention relates to isoflavans and isoflavens of the general formulas Ia and Ib
4-[p-(2-Diäthylaminoäthoxy)-phenyl]-4- [p- (2-diethylaminoethoxy) phenyl] -
7-methoxy-3-isoflaven (B) und
4-Hydroxy-4-[p-(2-Diäthylaminoäthoxy)-7-methoxy-3-isoflavene (B) and
4-hydroxy-4- [p- (2-diethylaminoethoxy) -
phenyl]-7-metnoxy-isoflavan (C).
5phenyl] -7-methoxy-isoflavane (C).
5
Folgende kontrazeptive Wirksamkeiten wurdenThe following contraceptive effects were found
ermittelt (angegeben wird in der Tabelle neben der Dosierung die Zahl der untersuchten Tiere in Prozent, bei denen keine Schwangerschaften festgestellt wurden): determined (in the table, in addition to the dosage, the number of animals examined is given in percent, in which no pregnancies were found):
(Ia)(Ia)
CH3OCH 3 O
Die Präparate waren also unter Berücksichtigung der Streuung etwa gleich stark kontrazeptiv wirksam.Taking into account the variance, the preparations were therefore about equally effective in contraceptive terms.
Die östrogene Wirkung wurde für die VerbindungenThe estrogenic effects were for the compounds
P und B im Vergleich zu D-im klassischen Allen-Doisy-Test an Ratten ermittelt (angegeben wird in der Tabelle neben der Dosierung die Zahl der untersuchten Tiere in Prozent, bei denen ein Ustrus nachgewiesen wurde; die Substanzen wurden oral appliziert):P and B compared to D in the classic Allen-Doisy test determined on rats (the table indicates the number of investigated in addition to the dosage Percent of animals in which ustrus was detected; the substances were administered orally):
(Ib)(Ib)
OCH2CH2NR1R2 OCH 2 CH 2 NR 1 R 2
in denen R1 und R2 entweder je eine Äthylgruppe oder zusammen mit dem Stickstoffatom den Pyrrolidinring bedeuten sowie deren physiologisch verträgliche Salze mit Säuren.in which R 1 and R 2 are either an ethyl group or, together with the nitrogen atom, the pyrrolidine ring and their physiologically acceptable salts with acids.
Diese Verbindungen besitzen neben einer geringen östrogenen Wirkung eine gute kontrazeptive Wirkung.In addition to a low estrogenic effect, these compounds have a good contraceptive effect.
So ist ihre kontrazeptive Wirkung (Antifertilitäts-Wirkung), welche in Anlehnung an die Versuchsmethodik von Martin und Mitarbeitern, beschrieben im J. of Reproduction and Fertility, Bd. 5, S. 239 (1963), und von Em me ns und Majr-tin, ibid., Bd. 9, S. 269 (1965), untersucht wurde, vergleichbar mit der der bekannten Verbindung 2-[p-(3,4-Dihydro-6 - methoxy - 2 - phenyl -1 -naphthyl) - phenoxy] - äthylpyrrolidin-hydrochlorid (D) (vgl. Duncan und Mitarbeiter in Proceedings of the Society for Experimental Biology and Medicine, Bd. 112, S. 439 bis 442 (1963), wie aus den folgenden Versuchen hervorgeht:This is how their contraceptive effect (anti-fertility effect) is described, based on the experimental method used by Martin and co-workers in J. of Reproduction and Fertility, Vol. 5, p. 239 (1963), and by Em me ns and Majr-tin, ibid., Vol. 9, p. 269 (1965), comparable to that of the known compound 2- [p- (3,4-dihydro-6 - methoxy - 2 - phenyl (1) -naphthyl) - phenoxy] - ethylpyrrolidine hydrochloride (D) (see Duncan et al. In Proceedings of the Society for Experimental Biology and Medicine, Vol. 112, pp. 439 to 442 (1963), as can be seen from the following experiments:
Die zu prüfenden Verbindungen werden oral in verschiedenen Dosierungen an Gruppen von je fünf weiblichen Ratten verabfolgt, und zwar am 1. bis 3. bzw. 4. bis 6. Tag nach der Konzeption; der Tag, an dem Spermatocyten im Vaginalabstrich (morgens entnommen) nachgewiesen werden können, gilt als erster Tag. Die Tiere werden bis zum 15. Tag beobachtet, dann getötet und auf etwa vorhandene (abgestorbene resorbierte oder lebende) Feten untersucht.The compounds to be tested are administered orally in various dosages to groups of five administered to female rats on the 1st to 3rd and 4th to 6th day after conception; the day on the spermatocytes can be detected in the vaginal swab (taken in the morning) is considered to be first day. The animals are observed up to the 15th day, then killed and checked for any (dead resorbed or live) fetuses are examined.
In den Vergleichsversuchen wurden folgende erfindungsgemäße Verbindungen verwendet:The following compounds according to the invention were used in the comparative experiments:
4-[p-(2-Pyrrolidinoäthoxy)-phenyl]-4- [p- (2-pyrrolidinoethoxy) phenyl] -
7-methoxy-3-isofiaven (P),
4-Hydroxy-4-[p-(2-Pyrrolidinoäthoxy)-phenyl]-7-methoxy-3-isofiaven (P),
4-hydroxy-4- [p- (2-pyrrolidinoethoxy) phenyl] -
7-methoxy-isoflavan (A),7-methoxy-isoflavan (A),
Während D eine starke östrogene Wirkung zeigte, wies P im untersuchten Bereich nur eine geringe bzw. keine und B eine geringere östrogene Wirkung auf.While D showed a strong estrogenic effect, P showed only a slight or none and B a lower estrogenic effect.
Die akute Toxizität der Verbindung P wurde bei oraler Verabreichung an männlichen und weiblichen
Ratten ermittelt; die LD50 betrug nach 24stündiger-Beobachtungszeit
> 320 mg/kg. Die bekannte Verbindung D besitzt (vgl. Duncan, I.e.) eine LD50
von 302 mg/kg.
Es ist von Vorteil, daß die erfindungsgemäßen Verbindungen eine geringe östrogene Wirkung besitzen,
da bei der Verabreichung von kontrazeptiven Mitteln mit stark östrogener Wirkung Komplikationen, wie
Blutungen, auftreten können.The acute toxicity of Compound P was determined when administered orally to male and female rats; the LD 50 after 24 hours of observation was> 320 mg / kg. The known compound D (cf. Duncan, Ie) has an LD 50 of 302 mg / kg.
It is advantageous that the compounds according to the invention have a low estrogenic effect, since complications, such as bleeding, can occur when contraceptive agents with a strong estrogenic effect are administered.
Die Isoflavane und Isoflavene der oben angegebenen allgemeinen Formeln Ia und Ib sowie deren physiologisch verträglichen Salze mit Säuren werden dadurch hergestellt, daß man in an sich bekannter Weise ein Isoflavanon der allgemeinen Formel IIThe isoflavans and isoflavens of the general formulas Ia and Ib given above and their physiological properties Compatible salts with acids are prepared by being known per se Way an isoflavanone of the general formula II
CH3OCH 3 O
mit einer metallorganischen Verbindung der allge-with an organometallic compound of the general
ι oiöuuzι oiöuuz
meinen Formel IIImy formula III
(III)(III)
0-CH7CH7-NR1R2 0-CH 7 CH 7 -NR 1 R 2
in der R1 und R2 die oben angegebene Bedeutung haben und M die MgCl-, MgBr- oder MgJ-Gruppe oder ein Lithiumatom bedeutet, umsetzt oder daß man ein Isofiavan oder Isoflaven der allgemeinen Formeln IVa oder IVbin which R 1 and R 2 have the meaning given above and M denotes the MgCl, MgBr or MgI group or a lithium atom, or that an isofavane or isoflavin of the general formulas IVa or IVb is reacted
HOHO
(IVa)(IVa)
0-CH2CH7NR1R2 0-CH 2 CH 7 NR 1 R 2
HOHO
(IVb)(IVb)
0-CH2CH2NR1R2 0-CH 2 CH 2 NR 1 R 2
in der R1 und R2 die oben angegebene Bedeutung haben, in an sich bekannter Weise mit einem Methylierungsmittel umsetzt oder daß man ein Isofiavan oder Isoflaven der allgemeinen Formeln Va oder Vbin which R 1 and R 2 have the meaning given above, are reacted in a manner known per se with a methylating agent, or an isofiavan or isoflavin of the general formulas Va or Vb
CH1OCH 1 O
CH, OCH, O
(Va)(Va)
(Vb)(Vb)
OHOH
in an sich bekannter Weise mit einer Verbindung der allgemeinen Formel VIin a manner known per se with a compound of general formula VI
Q — CH2CH2NR1R2 (VI)Q - CH 2 CH 2 NR 1 R 2 (VI)
in der R1 und R2 die oben angegebene Bedeutung
haben und Q eine Hydroxylgruppe oder ein Chloroder Brom- oder Jodatom bedeutet, umsetzt und daß
man gegebenenfalls das erhaltene 4-Hydroxy-isoflavan anschließend in an sich bekannter Weise mit einem
wasserabspaltenden Mittel behandelt und/oder das erhaltene Isofiavan oder Isoflaven durch Behandlung
mit einer Säure in ein physiologisch verträgliches Säureadditionssalz überführt.
Als metallorganische Verbindungen der allgemeinen Formel III kommen vor allem solche in Frage, die
sich von p-Chlorphenyl-(2-diäthylaminoäthyl)-äther, ρ - Bromphenyl - (2 - diäthylaminoäthyl) - äther,
ρ - Chlorphenyl - (2 - pyrrolidinoäthyl) - äther oder ρ - Bromphenyl - (2 - pyrrolidino - äthyl) - äther ableiten.in which R 1 and R 2 have the meaning given above and Q is a hydroxyl group or a chlorine, bromine or iodine atom, and that the 4-hydroxy-isoflavane obtained is then optionally treated in a manner known per se with a dehydrating agent and / or the isofiavan or isoflave obtained is converted into a physiologically acceptable acid addition salt by treatment with an acid.
As organometallic compounds of the general formula III, there are above all those which are derived from p-chlorophenyl (2-diethylaminoethyl) ether, ρ - bromophenyl (2 - diethylaminoethyl) ether, ρ - chlorophenyl - (2 - pyrrolidinoethyl) - ether or ρ - bromophenyl - (2 - pyrrolidino - ethyl) - ether.
Die Umsetzung eines Isoflavanons der Formel II mit einer Organometallverbindung der allgemeinen Formel III geschieht zweckmäßigerweise in einem indifferenten Lösungsmittel wie Äther, Anisol, Dibenzyläther, Dioxan, Benzol, Toluol, Methylenchlorid oder vorzugsweise Tetrahydrofuran oder in Gemischen dieser Lösungsmittel. In manchen Fällen ist der Zusatz einer zur Komplex bildung geeigneten*0 Lewis-Säure wie Magnesiumbromid vorteilhaft. Inder Regel wird das Keton in Lösung oder in fester Form zu einer Lösung der metallorganischen Verbin- y dung in einem der genannten Lösungsmittel zugege- ■ ben. Die Umsetzung ist meist exotherm; die Reak- / tionstemperatur liegt im allgemeinen zwischen —20; und + 70° C, vorzugsweise jedoch bei Raumtempera- ' tür. Zur Beendigung der Umsetzung kann man das Reaktionsgemisch noch einige Zeit bis zum Sieden des verwendeten Lösungsmittels erhitzen. Nach beendeter Umsetzung wird das Reaktionsprodukt, gegebenenfalls nach Abdampfen und Rückgewinnung des Lösungsmittels, hydrolysiert.The reaction of an isoflavanone of the formula II with an organometallic compound of the general formula III is expediently carried out in an inert solvent such as ether, anisole, dibenzyl ether, dioxane, benzene, toluene, methylene chloride or, preferably, tetrahydrofuran or in mixtures of these solvents. In some cases, the additive is a suitable for complex formation * 0 Lewis acid such as magnesium bromide advantageous. As a rule, the ketone is added in solution or in solid form to a solution of the organometallic compound in one of the solvents mentioned. The implementation is mostly exothermic; the reaction temperature is generally between -20; and + 70 ° C, but preferably at room temperature. To complete the reaction, the reaction mixture can be heated for some time until the solvent used has boiled. After the reaction has ended, the reaction product is hydrolyzed, if appropriate after evaporation and recovery of the solvent.
Führt man die Hydrolyse mit Wasser oder unter sauren Bedingungen, z. B. mit Hilfe von wäßriger Ammoniumchloridlösung oder verdünnter Salzsäure in der Kälte durch, so wiwi im Regelfalle kein Wasser abgespalten, und man efhält die Carbmole der allgemeinen Formel Ia.If the hydrolysis is carried out with water or under acidic conditions, e.g. B. with the help of aqueous Ammonium chloride solution or dilute hydrochloric acid in the cold, so usually no water split off, and the carb moles of the general formula Ia are obtained.
Will man dagegen die Dehydratisierungsprodukte der allgemeinen Formel I b (Isoflavene) erhalten, so kann man die erhaltenen Carbinole der allgemeinen Formel Ia dehydratisieren. Das kann durch "sauren Behandlung schon unter milden Bedingungen erfolgen. Zum Beispiel kann man die Carbinole mit verdünnter Mineralsäure wie wäßriger Schwefelsäure oder wäßriger Salzsäure in der Wärme oder längere Zeit in der Kälte behandeln. Auch andere der üblichen Wasserabspaltungsmethoden sind anwendbar, beispielsweise Behandlung mit Ameisensäure, Perchlorsäure, p-Toluolsulfonsäure, Essigsäure, Acetanhydrid, p-Toluolsulfonsäurechlorid oder mit Thionylchlorid, Phosphoroxychlorid, Methansulfonsäurechlorid oder Methylchlorsulfit in Pyridin. Es ist auch möglich, auf eine Isolierung der Carbinole (Ia) zu verzichten. Beispielsweise gelangt man direkt zu den Isoflavenen der allgemeinen Formel Ib, wenn man die Aufarbeitung der Grignard-Reaktion mit verdünnten Mineralsäuren in der Wärme vornimmt.If, on the other hand, the dehydration products of the general formula I b (isoflavens) are to be obtained, so the carbinols of the general formula Ia obtained can be dehydrated. That can be done by "sour Treatment can be done under mild conditions. For example you can use the carbinols dilute mineral acid such as aqueous sulfuric acid or aqueous hydrochloric acid in the warm or longer Treat time in the cold. Other common dehydration methods can also be used, for example Treatment with formic acid, perchloric acid, p-toluenesulfonic acid, acetic acid, acetic anhydride, p-toluenesulfonic acid chloride or with thionyl chloride, Phosphorus oxychloride, methanesulfonic acid chloride or methylchlorosulfite in pyridine. It is also possible on to forego isolation of the carbinols (Ia). For example, one arrives directly at the isoflavens of the general formula Ib when working up the Grignard reaction with dilute mineral acids in the warmth.
Es ist ferner möglich, freie Hydroxygruppen in einem Isoflavan oder Isoflaven der allgemeinen Formeln IVa oder IVb in an sich bekannter Weise zu methylieren.It is also possible to have free hydroxyl groups in an isoflavane or isoflavane of the general formulas To methylate IVa or IVb in a manner known per se.
Die Methylierung kann beispielsweise durch Umsetzung mit entsprechenden Methylhalogeniden, -sulfaten oder niederen Methylestern in Gegenwart vonThe methylation can be carried out, for example, by reaction with appropriate methyl halides or sulfates or lower methyl esters in the presence of
1 OiO1 OiO
Alkali wie Natrium- oder Kaliumhydroxid oder -carbonat erfolgen, wobei auch eines der üblichen inerten Lösungsmittel wie Aceton oder Methyläthylketon zugegen sein kann.Alkali such as sodium or potassium hydroxide or carbonate take place, with one of the usual inert solvents such as acetone or methyl ethyl ketone may be present.
Für die Umsetzung einer Verbindung der allgemeinen Formel Va oder Vb oder Vb mit einer Verbindung der allgemeinen Formel VI wird ein entsprechendes Chlorid, Bromid oder Jodid verwendet. Die Verätherungen von Verbindungen der Formeln Va oder Vb erfolgen beispielsweise nach dem Prinzip einer Williamson-Synthese, wobei man von den entsprechenden Alkaliphenolaten (Natrium- oder Kaliumphenolaten) ausgeht. Es ist aber auch möglich, die freie Phenolverbindung mit dem entsprechenden Aminoalkohol in Gegenwart saurer Katalysatoren wie Schwefelsäure, Phosphorsäure, p-Toluolsulfonsäure, umzusetzen.For the reaction of a compound of the general formula Va or Vb or Vb with a compound of the general formula VI, a corresponding chloride, bromide or iodide is used. The etherifications of compounds of the formulas Va or Vb take place, for example, according to the principle a Williamson synthesis, whereby one of the corresponding alkali phenolates (sodium or potassium phenolates) goes out. But it is also possible to combine the free phenolic compound with the corresponding Amino alcohol in the presence of acidic catalysts such as sulfuric acid, phosphoric acid, p-toluenesulfonic acid, to implement.
Für die Salzbildung kommen solche Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können organische und anorganische Säuren wie entsprechende aliphatische, alicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon- oder Sulfonsäuren, z. B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diäthylessigsäure, Oxalsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Aminocarbonsäuren, Sulfaminsäure, Benzoesäure, Salicylsäure, Phenylpropionsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Isonicotinsäure, Methansulfonsäure, Äthandisulfonsäure, /3-Hydroxyäthansulfonsäure, p-Toluolsulfonsäure, Naphthalin-mono- und -disulfonsäuren, Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren, oder Phosphorsäuren, wie Orthophosphorsäure, verwendet werden.For salt formation, those acids come into consideration that provide physiologically harmless salts. Organic and inorganic acids such as corresponding aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulfonic acids, e.g. B. formic acid, Acetic acid, propionic acid, pivalic acid, diethyl acetic acid, oxalic acid, malonic acid, succinic acid, Pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, Sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, Ascorbic acid, isonicotinic acid, methanesulphonic acid, ethane disulphonic acid, / 3-hydroxyethanesulphonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, Sulfuric acid, nitric acid, hydrohalic acids, or phosphoric acids, such as Orthophosphoric acid can be used.
Die neuen Verbindungen können im Gemisch mit üblichen Arzneimittelträgern in der Human- oder Veterinärmedizin eingesetzt werden. Als Trägersubstanzen kommen solche organischen oder anorganischen Stoffe in Frage, die für die parenterale, enterale oder topikale Applikation geeignet sind und die mit den neuen Verbindungen nicht in Reaktion treten, wie beispielsweise Wasser, pflanzliche öle, PoIyäthylenglykole, Gelatine, Milchzucker, Stärke, Magnesiumstearat, Talk, Vaseline, .Cholesterin. Zur. parenteralen Applikation dienen insbesondere Lösungen, vorzugsweise ölige oder wäßrige Lösungen, sowie Suspensionen, Emulsionen oder Implantate. Für die enterale Applikation können ferner Tabletten oder Dragees, für die topikale Anwendung Salben oder Cremes, die gegebenenfalls sterilisiert oder mit Hilfsstoffen, wie Konservierungs-, Stabilisierungs- oder Netzmitteln oder Salzen zur Beeinflussung des osmotischen Drucks oder mit Puffersubstanzen versetzt sind, angewendet werden.The new compounds can be mixed with conventional drug carriers in the human or Veterinary medicine can be used. The carrier substances used are organic or inorganic Substances in question that are suitable for parenteral, enteral or topical application and that contain the new compounds do not react, such as water, vegetable oils, polyethylene glycols, Gelatine, milk sugar, starch, magnesium stearate, talc, petroleum jelly, cholesterol. To the. parenteral administration are used in particular solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. Tablets can also be used for enteral administration or coated tablets, for topical application ointments or creams, which may or may not be sterilized or with Auxiliaries such as preservatives, stabilizers or wetting agents or salts to influence the osmotic Pressure or mixed with buffer substances are applied.
Die Dosierung der erfindungsgemäßen Substanzen beträgt vorzugsweise 1 bis 500 mg.The dosage of the substances according to the invention is preferably 1 to 500 mg.
B ei s piel 1Example 1
2,2 g 4-p-Hydroxyphenyl-7-methoxy-3-isoflaven werden in 50 ml absolutem Aceton gelöst und mit 2,5 g wasserfreiem Kaliumcarbonat sowie einer ätherischen Lösung von 2-Pyrrolidinoäthylchlorid versetzt (erhalten aus 7 g 2-Chloräthylpyrrolidiniumchlorid). Man kocht das Gemisch unter Rühren 24 Stunden am Rückfluß, engt dann ein, setzt Wasser und Äther hinzu, trennt die Ätherschicht ab, trocknet diese über Kaliumhydroxid, dampft ein und Chromatographien den Rückstand an 50 g basischem Aluminiumoxid, wobei man das erhaltene 4-p-(2-Pyrrolidinoäthoxy)-phenyl-7-methoxy-3-isoflaven mit Chloroform eluiert. Anschließend wird aus Äther umkristallisiert. Die Verbindung schmilzt bei 92 bis 93° C.2.2 g of 4-p-hydroxyphenyl-7-methoxy-3-isoflavene are dissolved in 50 ml of absolute acetone and mixed with 2.5 g of anhydrous potassium carbonate and an ethereal Solution of 2-pyrrolidinoethyl chloride added (obtained from 7 g of 2-chloroethylpyrrolidinium chloride). The mixture is refluxed with stirring for 24 hours, then concentrated and water is added and ether added, separates the ether layer, dries it over potassium hydroxide, evaporates and chromatographs the residue of 50 g of basic aluminum oxide, the 4-p- (2-pyrrolidinoethoxy) phenyl-7-methoxy-3-isoflavene obtained eluted with chloroform. Then it is recrystallized from ether. The compound melts at 92 to 93 ° C.
Analog wird hergestellt: 4-p-(2-Diäthylaminoäthoxy)-phenyl-7-methoxy-3-isoflaven, F. 72 bis 73° C.The following is prepared analogously: 4-p- (2-diethylaminoethoxy) -phenyl-7-methoxy-3-isoflavene, F. 72 to 73 ° C.
Das oben als Ausgangsmaterial verwendete 4-p-Hydroxyphenyl-7-methoxy-3-isoflaven ist wie folgt hergestellt worden:The 4-p-hydroxyphenyl-7-methoxy-3-isoflavene used as the starting material above is as follows manufactured:
0,76 g 7-Methoxy-isoflavanon, gelöst in 30 ml absolutem Benzol, werden zu einer ätherischen Grignardlösung aus 0,23 g Magnesium und 3,1 g Bromphenylbenzyläther zugetropft. Der Äther wird abdestilliert und das Gemisch 16 Stunden gekocht. Man kühlt ab, zersetzt das Reaktionsprodukt mit 100 ml 10%iger Salzsäure, trennt die Benzolschicht ab, wäscht sie nacheinander mit Wasser, 10%iger Natronlauge und wieder mit Wasser, trocknet sie über Natriumsulfat und entfernt das Lösungsmittel. Der Rückstand besteht aus 4-p-Benzyloxyphenyl-7-methoxy-3-isoflaven vom F. 109 bis Hl0C. -*.0.76 g of 7-methoxy-isoflavanone, dissolved in 30 ml of absolute benzene, are added dropwise to an ethereal Grignard solution of 0.23 g of magnesium and 3.1 g of bromophenylbenzyl ether. The ether is distilled off and the mixture is boiled for 16 hours. It is cooled, the reaction product is decomposed with 100 ml of 10% strength hydrochloric acid, the benzene layer is separated off, washed successively with water, 10% strength sodium hydroxide solution and again with water, dried over sodium sulfate and the solvent is removed. The residue consists of 4-p-Benzyloxyphenyl-7-methoxy-3-isoflaven from F. 109 to Hl 0 C. - *.
3,9 g des erhaltenen 4-p--Benzyloxyphenyl-7-meth-~=--~ oxy-isoflavens werden in 100 ml Äthylacetat mit 3 g· 5%iger Palladiumkohle katalytisch hydriert. Nach -; Aufnahme von 226 ml Wasserstoff bricht man die f Hydrierung ab, filtriert den Katalysator ab, destilliert j das Filtrat zur Trockne und chromatographiert das ; Rohprodukt an Kieselgel, wobei amorphes 4-p-Hy- '' droxyphenyl-7-methoxy-3-isoflaven vom F. 118° C . erhalten werden.3.9 g of the 4-p - benzyloxyphenyl-7-meth- ~ = - ~ oxy-isoflavene obtained are catalytically hydrogenated in 100 ml of ethyl acetate with 3 g of 5% palladium-on-carbon. After - ; Uptake of 226 ml of hydrogen to break the f hydrogenation and filtered off the catalyst, the filtrate was distilled j to dryness and chromatographed; Crude product on silica gel, with amorphous 4-p-Hy- '' droxyphenyl-7-methoxy-3-isoflavene with a melting point of 118 ° C. can be obtained.
B e i s ρ i e 1 2B e i s ρ i e 1 2
a) 18,6 g reines N-(p-Bromphenoxy-äthyl)-pyrrolidiniumchlorid werden in 240 ml Äthanol und 480 ml absolutem Tetrahydrofuran gelöst. Man filtriert die Lösung klar und leitet 30 Minuten gasförmigen Ammoniak ein. Nach nochmaliger Filtration werden die Lösungsmittel unter vermindertem Druck entfernt.a) 18.6 g of pure N- (p-bromophenoxy-ethyl) pyrrolidinium chloride are dissolved in 240 ml of ethanol and 480 ml dissolved in absolute tetrahydrofuran. The solution is filtered clear and gaseous ammonia is passed in for 30 minutes a. After filtering again, the solvents are removed under reduced pressure.
Man nimmt den Rückstand in 100 ml. absolutem Tetrahydrofuran auf, filtriert das Ammoniumchlorid ab und entfernt das Lösungsmittel unter vermindertem Druck. Das Gleiche wird nun mit 50 ml absolutem Tetrahydrofuran wiederholt. ~~ The residue is taken up in 100 ml. Of absolute tetrahydrofuran, the ammonium chloride is filtered off and the solvent is removed under reduced pressure. The same is now repeated with 50 ml of absolute tetrahydrofuran. ~~
Eine Lösung aus dem obigen N-(p-Bromphenoxy- _ äthyl)-pyrrolidin in 40 ml absolutem Tetrahydrofuran wird dann unter Feuchtigkeitsausschluß zu einer siedenden Suspension von 1,5 g Magnesium in 20 ml absolutem Tetrahydrofuran getropft, wobei man die Reaktion durch Zugabe von etwas Jod und wenig Äthylbromid startet. Man erhitzt das Ganze noch 15 Minuten zum Sieden, läßt dann abkühlen und tropft eine Lösung von 3,1 g 7-Methoxyisoflavanon in 30 ml absolutem Tetrahydrofuran zu, worauf nochmais 15 Minuten gekocht wird. Dann wird das erhaltene Produkt in der Kälte durch Zugabe von 100 ml gesättigter wäßriger Ammoniumchloridlösung zersetzt, das Ganze dreimal mit je 100 ml Äther extrahiert, der Extrakt nacheinander mit 100 ml Wasser, 100 ml 1 N-Natronlauge und dreimal mit je 50 ml Wasser gewaschen, hierauf mit Natriumsulfat getrocknet, filtriert und zur Trockne eingedampft. Das Rohprodukt wird an 250 g basischem Aluminiumoxid chromatographiert, wobei mit Benzol und Benzol/Chloroform-Gemischen eluiert wird. Mit Benzol/Chloroform 4:1 erhält man 3 g 4-p-(2-Pyrrolidinoäthoxy) - phenyl - 4 - hydroxy - 7 - methoxy - isoflavan aus der Säule, das dann aus Äther/Petroläther (1:2)A solution of the above N- (p-bromophenoxy- _ ethyl) pyrrolidine in 40 ml of absolute tetrahydrofuran is then converted into one with the exclusion of moisture boiling suspension of 1.5 g of magnesium in 20 ml of absolute tetrahydrofuran was added dropwise, whereby the The reaction starts by adding a little iodine and a little ethyl bromide. You still heat the whole thing 15 minutes to the boil, then allowed to cool and a solution of 3.1 g of 7-methoxyisoflavanone is added dropwise in 30 ml of absolute tetrahydrofuran, after which corn is boiled for another 15 minutes. Then the obtained Product in the cold by adding 100 ml of saturated aqueous ammonium chloride solution decomposed, the whole thing extracted three times with 100 ml of ether each time, the extract successively with 100 ml Water, 100 ml of 1N sodium hydroxide solution and washed three times with 50 ml of water each time, then with sodium sulfate dried, filtered and evaporated to dryness. The crude product is based on 250 g of basic aluminum oxide chromatographed, using benzene and benzene / chloroform mixtures is eluted. With benzene / chloroform 4: 1 you get 3 g of 4-p- (2-pyrrolidinoethoxy) - phenyl - 4 - hydroxy - 7 - methoxy - isoflavan from the column, which is then from ether / petroleum ether (1: 2)
409 684/18409 684/18
99 1010
umkristallisiert wird: F. 148 bis 1490C; λιηαχ 276 und b) Durch halbstündiges Kochen der nach a) erhal-is recrystallized: mp 148 to 149 0 C; λ ιηαχ 276 and b) By boiling the according to a) for half an hour
286 nm, E!*m 99 und 79, kein UV-Maximum oberhalb tenen Basen mit der 35fachen Menge 5%iger äthano-286 nm, E! * M 99 and 79, no UV maximum above ten bases with 35 times the amount of 5% ethano-
300 nm. lischer Salzsäure und übliche Aufarbeitung wird das300 nm. Lischer hydrochloric acid and the usual work-up is the
In analoger Weise erhält man: mit p-(2-Diäthyl- 4 - ρ - (2 - Pyrrolidinoäthoxy) - phenyl - 7 - methoxyaminoäthoxy)-phenylmagnesiumbromiddas4-p-(2-Di- 5 3-isoflaven (F. 92 bis 93° C) und 4-p-(2-Diäthylamino-In an analogous manner one obtains: with p- (2-diethyl- 4 - ρ - (2 - pyrrolidinoethoxy) - phenyl - 7 - methoxyaminoethoxy) -phenylmagnesium bromide the 4-p- (2-di- 5 3-isoflaves (m.p. 92 to 93 ° C) and 4-p- (2-diethylamino-
äthylammoäthoxy) - phenyl - 4 - hydroxy - 7 - methoxy- äthoxy)-phenyl-7-methoxy-3-isoflaven (F 72 bis 73° C)ethylammoethoxy) - phenyl - 4 - hydroxy - 7 - methoxy- ethoxy) -phenyl-7-methoxy-3-isoflave (F 72 to 73 ° C)
isoflavan vom F. 55°C (aus Ather/Petroläther [1:2]). erhaltenisoflavane with a temperature of 55 ° C (from ether / petroleum ether [1: 2]). obtain
Claims (4)
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DEM0063676 | 1965-01-02 |
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DE1518002A1 DE1518002A1 (en) | 1969-06-19 |
DE1518002B2 DE1518002B2 (en) | 1974-04-11 |
DE1518002C3 true DE1518002C3 (en) | 1975-01-23 |
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DE1518002A Expired DE1518002C3 (en) | 1965-01-02 | 1965-01-02 | Isoflavans and isoflavens and processes for their production and medicinal products containing them |
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US (1) | US3471520A (en) |
BE (1) | BE674534A (en) |
BR (1) | BR6576150D0 (en) |
CH (1) | CH469697A (en) |
DE (1) | DE1518002C3 (en) |
DK (1) | DK111268B (en) |
FR (1) | FR5046M (en) |
GB (1) | GB1102987A (en) |
IL (1) | IL24787A (en) |
NL (1) | NL6517021A (en) |
SE (1) | SE350040B (en) |
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US4053626A (en) * | 1973-03-13 | 1977-10-11 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Cholesterol level-lowering phenoxyacetic acids |
US4133883A (en) * | 1975-06-03 | 1979-01-09 | Beecham Group Limited | Polycyclic chromenes useful as antidepressants and anorexics |
GB1493998A (en) * | 1975-06-03 | 1977-12-07 | Beecham Group Ltd | Propanolamine derivatives |
US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
US5686465A (en) * | 1988-10-31 | 1997-11-11 | Endorecherche Inc. | Sex steroid activity inhibitors |
US5254568A (en) * | 1990-08-09 | 1993-10-19 | Council Of Scientific & Industrial Research | Benzopyrans as antiestrogenic agents |
US6060503A (en) * | 1991-12-02 | 2000-05-09 | Endorecherche, Inc. | Benzopyran-containing compounds and method for their use |
ATE275959T1 (en) * | 1992-05-19 | 2004-10-15 | Graham Edmund Kelly | USE OF ISOFLAVONE PHYTO-ESTROGEN EXTRACTS OF SOY OR CLOVER |
US5389646A (en) * | 1993-12-30 | 1995-02-14 | Zymogenetics, Inc. | Methods for treatment and prevention of bone loss using 2,3-benzopyrans |
AUPO203996A0 (en) | 1996-08-30 | 1996-09-26 | Novogen Research Pty Ltd | Therapeutic uses |
US6146668A (en) | 1997-04-28 | 2000-11-14 | Novogen, Inc. | Preparation of isoflavones from legumes |
EP0979074A4 (en) * | 1997-05-01 | 2003-07-09 | Novogen Inc | Treatment or prevention of menopausal symptoms and osteoporosis |
AUPP112497A0 (en) * | 1997-12-24 | 1998-01-22 | Novogen Research Pty Ltd | Compositions and method for protecting skin from UV induced immunosupression and skin damage |
AUPP260798A0 (en) | 1998-03-26 | 1998-04-23 | Novogen Research Pty Ltd | Treatment of medical related conditions with isoflavone containing extracts of clover |
AUPP868599A0 (en) * | 1999-02-15 | 1999-03-11 | Novogen Research Pty Ltd | Production of isoflavone derivatives |
US20090233999A1 (en) * | 1999-09-06 | 2009-09-17 | Novogen Research Pty Ltd | Compositions and therapeutic methods involving isoflavones and analogues thereof |
AUPQ266199A0 (en) * | 1999-09-06 | 1999-09-30 | Novogen Research Pty Ltd | Compositions and therapeutic methods involving isoflavones and analogues thereof |
AUPQ520300A0 (en) * | 2000-01-21 | 2000-02-17 | Novogen Research Pty Ltd | Food product and process |
JP4332349B2 (en) * | 2001-01-24 | 2009-09-16 | キエシ・フアルマチエウテイチ・ソチエタ・ペル・アチオニ | 2H-1-benzopyran derivatives, processes for their preparation and pharmaceutical compositions thereof |
AUPR363301A0 (en) * | 2001-03-08 | 2001-04-05 | Novogen Research Pty Ltd | Dimeric isoflavones |
US20050119301A1 (en) * | 2001-03-16 | 2005-06-02 | Alan Husband | Treatment of restenosis |
ES2377073T3 (en) * | 2004-09-21 | 2012-03-22 | Marshall Edwards, Inc. | Substituted Chroman Derivatives, Medicines and Therapy Use |
ATE532777T1 (en) * | 2004-09-21 | 2011-11-15 | Marshall Edwards Inc | SUBSTITUTED CHROMEDER DERIVATIVES, MEDICATIONS AND APPLICATIONS IN THERAPY |
US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
JP6013349B2 (en) | 2010-11-01 | 2016-10-25 | メイ ファーマ, インク.Mei Pharma, Inc. | Isoflavonoid compounds and methods for the treatment of cancer |
ES2877712T3 (en) | 2015-02-02 | 2021-11-17 | Mei Pharma Inc | Combination therapies for use in the treatment of breast cancer |
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US3142682A (en) * | 1961-11-21 | 1964-07-28 | Ciba Geigy Corp | Tertiary amino derivatives of chromans and homo-chromans |
US3340276A (en) * | 1964-04-01 | 1967-09-05 | Ciba Geigy Corp | 3, 4-diphenyl-chromans |
US3340277A (en) * | 1964-06-24 | 1967-09-05 | Ciba Geigy Corp | Phenyl-chromenes |
-
1965
- 1965-01-02 DE DE1518002A patent/DE1518002C3/en not_active Expired
- 1965-11-11 CH CH1556465A patent/CH469697A/en unknown
- 1965-12-07 GB GB51947/65A patent/GB1102987A/en not_active Expired
- 1965-12-14 IL IL24787A patent/IL24787A/en unknown
- 1965-12-28 NL NL6517021A patent/NL6517021A/xx unknown
- 1965-12-29 SE SE16891/65A patent/SE350040B/xx unknown
- 1965-12-29 DK DK667765AA patent/DK111268B/en unknown
- 1965-12-30 US US517782A patent/US3471520A/en not_active Expired - Lifetime
- 1965-12-30 BR BR176150/65A patent/BR6576150D0/en unknown
- 1965-12-30 BE BE674534D patent/BE674534A/xx unknown
- 1965-12-31 FR FR44499A patent/FR5046M/fr not_active Expired
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BR6576150D0 (en) | 1973-09-06 |
BE674534A (en) | 1966-06-30 |
US3471520A (en) | 1969-10-07 |
DE1518002A1 (en) | 1969-06-19 |
DE1518002B2 (en) | 1974-04-11 |
GB1102987A (en) | 1968-02-14 |
IL24787A (en) | 1969-11-30 |
NL6517021A (en) | 1966-07-04 |
FR5046M (en) | 1967-05-02 |
CH469697A (en) | 1969-03-15 |
SE350040B (en) | 1972-10-16 |
DK111268B (en) | 1968-07-15 |
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