AU7236794A - Isoflavone derivatives - Google Patents
Isoflavone derivativesInfo
- Publication number
- AU7236794A AU7236794A AU72367/94A AU7236794A AU7236794A AU 7236794 A AU7236794 A AU 7236794A AU 72367/94 A AU72367/94 A AU 72367/94A AU 7236794 A AU7236794 A AU 7236794A AU 7236794 A AU7236794 A AU 7236794A
- Authority
- AU
- Australia
- Prior art keywords
- general formula
- alkyl
- compounds
- group
- isoflavone
- 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.)
- Abandoned
Links
- 150000002515 isoflavone derivatives Chemical class 0.000 title description 8
- 229930012930 isoflavone derivative Natural products 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- -1 hydroxy, phenoxy, piperidino, morpholino Chemical group 0.000 claims description 13
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 claims description 11
- 235000008696 isoflavones Nutrition 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- DIORMHZUUKOISG-UHFFFAOYSA-N sulfoformic acid Chemical group OC(=O)S(O)(=O)=O DIORMHZUUKOISG-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 150000001983 dialkylethers Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910052987 metal hydride Inorganic materials 0.000 claims description 3
- 150000004681 metal hydrides Chemical class 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 2
- CPBYTAYFHIHDNI-UHFFFAOYSA-N 2-hydroxy-3-phenyl-2,3-dihydrochromen-4-one Chemical class OC1OC2=CC=CC=C2C(=O)C1C1=CC=CC=C1 CPBYTAYFHIHDNI-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 150000008051 alkyl sulfates Chemical class 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 150000002596 lactones Chemical class 0.000 claims description 2
- 229910000510 noble metal Inorganic materials 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 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
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 239000007858 starting material Substances 0.000 claims 2
- ROSLGMBGAIDTPC-UHFFFAOYSA-N 1,3-bis(2-hydroxy-4-propan-2-yloxyphenyl)-1,3-diphenylpropan-2-one Chemical compound OC1=CC(OC(C)C)=CC=C1C(C=1C=CC=CC=1)C(=O)C(C=1C(=CC(OC(C)C)=CC=1)O)C1=CC=CC=C1 ROSLGMBGAIDTPC-UHFFFAOYSA-N 0.000 claims 1
- 230000002152 alkylating effect Effects 0.000 claims 1
- 230000018044 dehydration Effects 0.000 claims 1
- 238000006297 dehydration reaction Methods 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 229910052759 nickel Inorganic materials 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- SFBODOKJTYAUCM-UHFFFAOYSA-N Ipriflavone Chemical compound C=1C(OC(C)C)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 SFBODOKJTYAUCM-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- WMKOZARWBMFKAS-UHFFFAOYSA-N 7-hydroxyisoflavone Chemical compound C=1C(O)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 WMKOZARWBMFKAS-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 229960005431 ipriflavone Drugs 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 210000002449 bone cell Anatomy 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- VGHVJQXWDXRTRJ-UHFFFAOYSA-N 1-(2-hydroxyphenyl)-2-phenylethanone Chemical class OC1=CC=CC=C1C(=O)CC1=CC=CC=C1 VGHVJQXWDXRTRJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- VFZIJLPRJAQGFO-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)-7-hydroxychromen-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O VFZIJLPRJAQGFO-UHFFFAOYSA-N 0.000 description 2
- WWSPUYCZWPFPLZ-UHFFFAOYSA-N 3-phenyl-7-propan-2-yloxy-3,4-dihydro-2h-chromene Chemical compound C1OC2=CC(OC(C)C)=CC=C2CC1C1=CC=CC=C1 WWSPUYCZWPFPLZ-UHFFFAOYSA-N 0.000 description 2
- QFWLLPSGSRVCSU-UHFFFAOYSA-N 4-oxo-3-phenylchromene-2-carboxylic acid Chemical class OC(=O)C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 QFWLLPSGSRVCSU-UHFFFAOYSA-N 0.000 description 2
- IFLFPBOUCZIKCG-UHFFFAOYSA-N 7-cyclohex-2-en-1-yloxy-3-phenylchromen-4-one Chemical compound C=1C=C2C(=O)C(C=3C=CC=CC=3)=COC2=CC=1OC1CCCC=C1 IFLFPBOUCZIKCG-UHFFFAOYSA-N 0.000 description 2
- MEIOIMGKPPMDKW-UHFFFAOYSA-N 7-ethoxy-3-phenylchromen-4-one Chemical compound C=1C(OCC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 MEIOIMGKPPMDKW-UHFFFAOYSA-N 0.000 description 2
- IECSQLKWZBEUGA-UHFFFAOYSA-N 7-methoxyisoflavone Chemical compound C=1C(OC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 IECSQLKWZBEUGA-UHFFFAOYSA-N 0.000 description 2
- QFOILJZOWCPCGC-UHFFFAOYSA-N 8-(chloromethyl)-3-phenyl-7-propan-2-yloxychromen-4-one Chemical compound ClCC=1C(OC(C)C)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 QFOILJZOWCPCGC-UHFFFAOYSA-N 0.000 description 2
- LNSBUEBEDMIYIC-UHFFFAOYSA-N 8-(chloromethyl)-7-methoxy-3-phenylchromen-4-one Chemical compound ClCC=1C(OC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 LNSBUEBEDMIYIC-UHFFFAOYSA-N 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000033558 biomineral tissue development Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- NNQSGBRGJHSRFN-UHFFFAOYSA-N isoflavan Chemical class C1OC2=CC=CC=C2CC1C1=CC=CC=C1 NNQSGBRGJHSRFN-UHFFFAOYSA-N 0.000 description 2
- RTRZOHKLISMNRD-UHFFFAOYSA-N isoflavanone Chemical compound C1OC2=CC=CC=C2C(=O)C1C1=CC=CC=C1 RTRZOHKLISMNRD-UHFFFAOYSA-N 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
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 210000000537 nasal bone Anatomy 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- BCRQJCOTVWIESL-UHFFFAOYSA-N (4-oxo-3-phenyl-7-propan-2-yloxychromen-8-yl)methyl acetate Chemical compound CC(=O)OCC=1C(OC(C)C)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 BCRQJCOTVWIESL-UHFFFAOYSA-N 0.000 description 1
- BRRLPFHLAAXZNA-UHFFFAOYSA-N (7-methoxy-4-oxo-3-phenylchromen-8-yl)methyl acetate Chemical compound CC(=O)OCC=1C(OC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 BRRLPFHLAAXZNA-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- OTKCEEWUXHVZQI-UHFFFAOYSA-N 1,2-diphenylethanone Chemical class C=1C=CC=CC=1C(=O)CC1=CC=CC=C1 OTKCEEWUXHVZQI-UHFFFAOYSA-N 0.000 description 1
- IBMIVKGDPUAYAV-UHFFFAOYSA-N 1,3-bis(2-hydroxyphenyl)-1,3-diphenylpropan-2-one Chemical class OC1=CC=CC=C1C(C=1C=CC=CC=1)C(=O)C(C=1C(=CC=CC=1)O)C1=CC=CC=C1 IBMIVKGDPUAYAV-UHFFFAOYSA-N 0.000 description 1
- YXZFFTJAHVMMLF-UHFFFAOYSA-N 1-bromo-3-methylbutane Chemical compound CC(C)CCBr YXZFFTJAHVMMLF-UHFFFAOYSA-N 0.000 description 1
- GJQCKJHVZVFNAN-UHFFFAOYSA-N 11-(4-oxo-3-phenylchromen-7-yl)oxyundecanoic acid Chemical compound C=1C(OCCCCCCCCCCC(=O)O)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 GJQCKJHVZVFNAN-UHFFFAOYSA-N 0.000 description 1
- LCLIEOLCBISQNO-UHFFFAOYSA-N 2-(4-oxo-3-phenylchromen-7-yl)oxybutanoic acid Chemical compound C=1C(OC(CC)C(O)=O)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 LCLIEOLCBISQNO-UHFFFAOYSA-N 0.000 description 1
- HYOLCSXLIWSQRX-UHFFFAOYSA-N 2-(4-oxo-3-phenylchromen-7-yl)oxyundecanoic acid Chemical compound C=1C(OC(CCCCCCCCC)C(O)=O)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 HYOLCSXLIWSQRX-UHFFFAOYSA-N 0.000 description 1
- DFNPNCXRHHHAAN-UHFFFAOYSA-N 2-(diethylamino)ethyl 2-(2-methyl-4-oxo-3-phenylchromen-7-yl)oxyacetate Chemical compound C=1C(OCC(=O)OCCN(CC)CC)=CC=C(C2=O)C=1OC(C)=C2C1=CC=CC=C1 DFNPNCXRHHHAAN-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 1
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 1
- UENRXLSRMCSUSN-UHFFFAOYSA-N 3,5-diaminobenzoic acid Chemical compound NC1=CC(N)=CC(C(O)=O)=C1 UENRXLSRMCSUSN-UHFFFAOYSA-N 0.000 description 1
- WCNGJVJPIUSCAQ-UHFFFAOYSA-N 3-phenyl-2-propan-2-yloxychromen-4-one Chemical compound CC(C)OC=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 WCNGJVJPIUSCAQ-UHFFFAOYSA-N 0.000 description 1
- OUUQNRSGMXTUBQ-UHFFFAOYSA-N 3-phenyl-7-(3-sulfonylpropoxy)chromen-4-one;sodium Chemical compound [Na].C=1OC2=CC(OCCC=S(=O)=O)=CC=C2C(=O)C=1C1=CC=CC=C1 OUUQNRSGMXTUBQ-UHFFFAOYSA-N 0.000 description 1
- XDECXCGUACYMSM-UHFFFAOYSA-N 3-phenyl-7-prop-2-enoxy-2,3-dihydrochromen-4-one Chemical compound C1OC2=CC(OCC=C)=CC=C2C(=O)C1C1=CC=CC=C1 XDECXCGUACYMSM-UHFFFAOYSA-N 0.000 description 1
- NTMRNGALJKIXQQ-UHFFFAOYSA-N 6-(4-oxo-3-phenylchromen-7-yl)oxyhexanoic acid Chemical compound C=1C(OCCCCCC(=O)O)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 NTMRNGALJKIXQQ-UHFFFAOYSA-N 0.000 description 1
- OKDRFVNZEWWZFN-UHFFFAOYSA-N 6-chloro-3-phenyl-7-(3-sulfonylpropoxy)chromen-4-one Chemical compound C1=C(OCCC=S(=O)=O)C(Cl)=CC(C2=O)=C1OC=C2C1=CC=CC=C1 OKDRFVNZEWWZFN-UHFFFAOYSA-N 0.000 description 1
- XPWZCEOSZNZTTC-UHFFFAOYSA-N 6-chloro-3-phenyl-7-propan-2-yloxychromen-4-one Chemical compound O=C1C=2C=C(Cl)C(OC(C)C)=CC=2OC=C1C1=CC=CC=C1 XPWZCEOSZNZTTC-UHFFFAOYSA-N 0.000 description 1
- UUCWXRKAXVAHKY-UHFFFAOYSA-N 6-chloro-7-(2-methylpropoxy)-3-phenylchromen-4-one Chemical compound O=C1C=2C=C(Cl)C(OCC(C)C)=CC=2OC=C1C1=CC=CC=C1 UUCWXRKAXVAHKY-UHFFFAOYSA-N 0.000 description 1
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- 230000000911 decarboxylating effect Effects 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
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- MOCJWLKVLAZYPH-UHFFFAOYSA-N ethyl 11-(4-oxo-3-phenylchromen-7-yl)oxyundecanoate Chemical compound C=1C(OCCCCCCCCCCC(=O)OCC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 MOCJWLKVLAZYPH-UHFFFAOYSA-N 0.000 description 1
- HCIHOQPRKMFGQO-UHFFFAOYSA-N ethyl 2-(2-methyl-4-oxo-3-phenylchromen-7-yl)oxyacetate Chemical compound C=1C(OCC(=O)OCC)=CC=C(C2=O)C=1OC(C)=C2C1=CC=CC=C1 HCIHOQPRKMFGQO-UHFFFAOYSA-N 0.000 description 1
- JZIGHFPBSMTISM-UHFFFAOYSA-N ethyl 2-(4-oxo-3-phenylchromen-7-yl)oxyacetate Chemical compound C=1C(OCC(=O)OCC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 JZIGHFPBSMTISM-UHFFFAOYSA-N 0.000 description 1
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- XPQZMCIJINJKKG-UHFFFAOYSA-N ethyl 2-(8-methyl-4-oxo-3-phenylchromen-7-yl)oxyacetate Chemical compound CC=1C(OCC(=O)OCC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 XPQZMCIJINJKKG-UHFFFAOYSA-N 0.000 description 1
- YIGSZRCGZXQNCD-UHFFFAOYSA-N ethyl 4-(4-oxo-3-phenylchromen-7-yl)oxybutanoate Chemical compound C=1C(OCCCC(=O)OCC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 YIGSZRCGZXQNCD-UHFFFAOYSA-N 0.000 description 1
- CPEVKZFHWKYMQI-UHFFFAOYSA-N ethyl 6-(4-oxo-3-phenylchromen-7-yl)oxyhexanoate Chemical compound C=1C(OCCCCCC(=O)OCC)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 CPEVKZFHWKYMQI-UHFFFAOYSA-N 0.000 description 1
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- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 235000010755 mineral Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
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- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- JJUATYUQJZKPIG-UHFFFAOYSA-M sodium;11-(4-oxo-3-phenylchromen-7-yl)oxyundecanoate Chemical compound [Na+].C=1C(OCCCCCCCCCCC(=O)[O-])=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 JJUATYUQJZKPIG-UHFFFAOYSA-M 0.000 description 1
- FSUXCMMRXDMAHL-UHFFFAOYSA-M sodium;3-(2-methyl-4-oxo-3-phenylchromen-7-yl)oxypropane-1-sulfonate Chemical compound [Na+].CC=1OC2=CC(OCCCS([O-])(=O)=O)=CC=C2C(=O)C=1C1=CC=CC=C1 FSUXCMMRXDMAHL-UHFFFAOYSA-M 0.000 description 1
- WPWGRSGSRZMLIQ-UHFFFAOYSA-M sodium;3-(5-methyl-4-oxo-3-phenylchromen-7-yl)oxypropane-1-sulfonate Chemical compound [Na+].O=C1C=2C(C)=CC(OCCCS([O-])(=O)=O)=CC=2OC=C1C1=CC=CC=C1 WPWGRSGSRZMLIQ-UHFFFAOYSA-M 0.000 description 1
- RPNSLHJHKVRQBG-UHFFFAOYSA-M sodium;4-(4-oxo-3-phenylchromen-7-yl)oxybutanoate Chemical compound [Na+].C=1C(OCCCC(=O)[O-])=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 RPNSLHJHKVRQBG-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- GINSRDSEEGBTJO-UHFFFAOYSA-N thietane 1-oxide Chemical compound O=S1CCC1 GINSRDSEEGBTJO-UHFFFAOYSA-N 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 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
- C07D311/34—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 3 only
- C07D311/36—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 3 only not hydrogenated in the hetero ring, e.g. isoflavones
-
- 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
- C07D311/34—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 3 only
- C07D311/38—2,3-Dihydro derivatives, e.g. isoflavanones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Description
ISOFLAVONE DERIVATIVES
The present invention relates to isoflavone, isoflavan-4-one and isoflavane derivatives of the general formula (I),
their salts, phaimaceutical compositions containing the compounds of the general formula (I), and to a process for preparing the same.
The isoflavone derivatives of the general formula
the isoflavane-4-one derivatives of the general formula
the isoflavane derivatives of the general formula
(IC)
form a narrower group of the compounds of the general formula (I).
In the general formula (I) if n is 0, R5 and R6 together stand for an oxo group and the dotted line means a double bond, R1 represents C^galkyl substituted by alkylcarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a
(C1.4alkyl)2N-(CH2)mCO(CH2)p- or by
(C1.4alkyl)2N-(CH2)mOCO(CH2)p- group; or stands for
C3.6cycloalkyl or cycloalkenyl; or if n is 1, R5 and R6 together stand for an oxo group and the dotted line means a double bond, R1 represents C1-.18alkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a (C1_.4al yl)2N-(CH2)mCO(CH2)p- group; or stands for C3.6-cycloalkyl or cycloalkenyl or C2_6alkenyl; or if n is 0 or 1, R5 and R6 together stand for an oxo group or stand separately for hydrogen and the dotted line does not mean a chemical bond, R1 represents C^galkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, alkoxy, phenyl optionally substituted by a halo atom, phenoxy, piperidino, morpholino or piridino or by a (C1-4alkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3.6-cycloalkyl or C2_6alkenyl; R stands for C-*_8alkyl, halogen, C^alkoxymethyl, C2.5-acyloxymethyl, or hydroxymethyl; R4 stands for hydrogen or C^alkyl;
R2 and R3 stand for hydrogen or C galkoxy;
R5 and R6 together stand for an oxo group or separately stand for hydrogen; the dotted line means a double bond being optionally present; n is 0 or 1; m is an integer from 1 to 4; and p is an integer from 1 to 4.
The compounds of the general formula (I) can be used for the prevention and treatment of osteoporosis.
According to the invention the compounds of the general formula (IA) can be prepared by reacting ketones of the general formula
wherein R, n, R1, R2 and R3 are as defined for the general formula (I), a) with alkyl orthoformate in the presence of a basic catalyst, or b) with hydrogen cyanide and/or cyanic salts in the presence of hydrohalides; or c) with alkyl formiate in the presence of an alkali metal; or d) with alkyloxalylhalide, and the isoflavone ester thus obtained is, if desired, saponified and/or decarboxylated; or e) with organic carboxylic anhydride; or f) with N,N-dialkyl acid amide in the presence of phosphorous chloride; or g) by dehydrating 2-hydroxy-isoflavanone derivatives of the general formula
and if desired, converting an R1 group into another R1 group, or forming an R group in a compound of the general formula (I), wherein R stands for hydrogen, and, if desired, converting a compound of the general formula (I) thus obtained into its salt or setting it free from its salt.
According to process variant a) of the present invention a suitably substituted ketone is reacted with alkyl orthoformiate, preferably ethyl ester, in an aprotic solvent having a high boiling point. As a solvent pyrrolidine, dimethyl formamide or diethylene glycol dimethyl ether is used. As a basic catalyst preferably " piperidine, morpholine, pyrrolidine and other secondary amines may be used.
According to process variant b) of the present invention the ketones are reacted with hydrogen cyanide in an aprotic solvent in the presence of dry gaseous hydrochloric acid or other hydrohalogenic acids or Lewis acids. Non-basic aprotic solvents may also be used in the reaction, preferably diethyl ether or other dialkyl ethers. As catalyst zinc chloride or other Lewis acids may be used.
The reaction is carried out with hydrogen cyanide or an appropriate salt thereof, preferably with zinc cyanide. The mixture may be saturated with dry gaseous hydrochloric acid and the substituted α-foπnimino-2-hydroxyphenylben2yl-ketone chlorohydrates thus obtained are decomposed with aqueous treatment.
According to process variant c) of the present invention the ketones of the formula (IH) are reacted with alkyl formiates in the presence of an alkali metal. One preferably proceeds by adding dropwise suitably substituted 2-hydroxyphenyl -benzyl-ketone dissolved in ethyl formiate onto pulverized metallic sodium, then by decomposing the reaction mixture with water and separating the isoflavone thus-obtained.
According to process variant d) of the present invention suitably substituted 2-hydroxy-phenyl benzyl ketones are reacted with alkyl oxalyl halides.
A 2-alkoxycarbonyl-isoflavone derivative is obtained, which is, if desired, converted into an isoflavone derivative unsubstituted in position 2 by hydrolyzing the ester group and by subsequent decarboxylation. This process variant can preferably be carried out with methyl- or ethyl oxalyl chloride in the presence of a basic acid binding agent in an appropriate aprotic solvent, preferably pyridine or another tertiary amine.
According to process variant e) of the present invention the suitably substituted 2-hydroxy-phenyl benzyl ketone is reacted with organic acid anhydrides in the presence of a basic catalyst. As an organic acid anhydride acetic, propionic or benzoic anhydride can be used. The anhydride is heated in the presence of a basic catalyst, suitably an alkali salt of the acid component of the acid anhydride, or in the presence of tertiary amines, without solvent or in an aprotic solvent having high boiling point, such as pyridine or dimethyl formamide.
According to process variant f) of the present invention the ketone is reacted with N,N-dialkyl acid amides in the presence of phosphorus oxychloride, preferably by heating the suitably substituted 2-hydroxy-phenyl benzyl ketone with
N,N-dialkyl acid amid (e.g. dimethyl formamide or dimethyl acetamide) and phosphorous oxychloride, using as solvent the N,N-dialkyl acid amide itself.
According to process variant g) of the present invention 2-hydroxy-isoflavones of the formula (IV) are dehydrated by heating or by warming in an acidic medium in polar solvent.
In the first step of the process according to the invention such derivatives may be obtained from the compounds of the formula (HI) or (TV) in which R1 stands for hydrogen or it is not the R1 group which is required in the target product.
In these cases the R1 group is introduced into the place of the hydrogen atom or, respectively, an R1 group is converted into another R1 group. This step can be carried out by the partial or total alkylation of the mono- or polyhydroxy-isoflavones, which alkylation can preferably be carried out by reacting with alkyl halides or substituted alkyl halides, alkyl sulfonic lactones, alkyl sulfates, olefines or epoxydes, preferably by heating the alkylating agent in a suitable solvent, e.g. ketones, dimethyl formamide or ethers containing a higher number of carbon atoms with the isoflavones to be alkylated. In case of halogens preferably an acid binding agent, such as alkali carbonate, and in case of alkyl bromides and alkyl chlorides preferably alkali iodide is present.
This step can be carried out by the partial or total desacylation or the partial and total desalkylation of acyloxy and polyacyloxy, alkyloxy and polyalkyloxy isoflavones. Acyloxy or polyacyloxy isoflavones are formed when process variant e) is carried out with di- or polyhydroxy phenyl benzyl ketones containing a hydroxy group in position 2. The desacylation is preferably carried out in an acidic or basic medium in the presence of a polar solvent. This step can also be carried out by decarboxylating isoflavone-2-carboxylic acids. Isoflavone-2- carboxylic acids are formed during process variant d) and their decarboxylation is preferably carried out by heating with or without the presence of a catalyst, such as copper dust.
The compounds of the general formula (IB), wherein R, n, R1, R2, R3 and R4 are as defined for general formula (I) are prepared by the reduction of the compounds of the general formula (IA), wherein R, n, R1, R2, R3 and R4 are as defined for general formula (I). The reduction is carried out by catalytic hydrogenation or by using metal hydrides.
In the case of the catalytic hydrogenation a nobel metal catalyst, preferably a palladium on charcoal catalyst is used and the reduction is carried out in an organic solvent, preferably in acetone.
As a complex metal hydride, preferably diisobutyl aluminum hydride is used and the reduction is carried out at a low temperature (-70 °C). The compounds of the general formula (IC), wherein R, n, R1, R2, R3 and R4 are as defined for general formula (I) are prepared aby the catalytic hydrogenation of the compounds of the general formula (IB), wherein R, n, R1, R2, R3 and R4 are as defined for general formula (I), in the presence of a noble metal or nickel catalyst. The reduction is preferably carried out in a polar solvent, preferably acetic acid or ethyl acetate.
The compounds of the general formula (I), wherein R1 stands for alkyl substituted by carboxy are prepared by hydrolysing the ester group of the compounds containing as R1 an alkyl group substituted by alkoxycarbonyl. The hydrolysis is preferably carried out in an acidic medium, preferably with lower organic acids in the presence of a strong acid catalyst.
The compounds of the general formula (IA) containing a methyl group in position 6 are prepared by the reduction of halomethyl isoflavones obtained from the compounds of the general formula (IA) containing a hydrogen atom in position by halomethylation. The reduction is carried out preferably in the presence of metals, preferably zinc.
The compounds of the general formula (I) containing an alkoxy or hydroxymethyl group in position 6 are prepared either by replacing the halo atom of the halomethyl isoflavones prepared as described above with an alkoxy group by the aid of alcohols or by replacing said halo atom with an 0-acetyl group by the aid of sodium acetate and by subsequently converting the acetoxy group into an OH group.
We have found that the compounds of the general formula (I) and salts thereof can effectively be used for the prophylaxis and the treatment of osteoporosis.
It is known that Ipriflavone (7-Isopropoxy-isoflavone) is able to inhibit bone resorption either in vitro or in vivo (Notoya, K. et al. Inhibitory effect of Ipriflavone on pit formation in mouse unfractionated bone cells, Calcif. Tissue Int. 51, (Supl. 1) 53-56 (1992); Notoya, K. et al. Inhibitory effect of Ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation in long-term
cultures of mouse unfractionated bone cells, Calcif Tissue Int. 50, 314-319 (1992). On the other hand, it is known that Ipriflavone also could increase the mineralization of the extracellular matrix of human bone cell cultures (Ref. Ecsedi, G.G. Model for in vitro investigation of bone mineralization, Agents and Actions 41, 84-85 (1994.)
To estimate the effectiveness of the compounds of the general Formula (I) on bone formation an in vitro mineralization model was developed. Under certain circumstances cultures of partially selected (osteoblast-enriched) human bone cells originated from either nasal bone of adults or foetus femur produce Type I collagene, bone specific proteins (e.g. osteocalcin), prostanoides (PGE2, PGF2α, PGI2, etc. and accumulate calcium into the synthesized matrix (Ref.: Ecsedi, G.G., Characterization of cells of human nasal bone cell cultures, 4th Int. Symposium on Osteoporosis, 27 March- 2 April, 1993 Hong Kong; Abstr. no. 534). Method, Cells of subcultures 8-12 (usually 8th or 9th) were drop-inoculated at a density of 2*10A4 cells per well 96-well plates. On the day 3 the treatments were started with the compound of the Formula I at two concentrations, 10A-8 and 10Λ-10 M. Because ethanolic 10Λ-5 and 10Λ-7 M stock solutions of the compounds were used in the treatments all culture media contained 0.1 % ethanol including the Controls. Media were changed on each 2-3 day. The treatments were finished on the day 21, the total calcium (Ca) and DNA content of the 6-parallel samples were measured by Boehringer Test Combination (MPR3) and the spectrofluoromerric 3,5-diaminobenzoic acid (DABA) method, respectively, then the ratios, Ca/DNA were calculated.
In the table of the compounds of Formula I below, data are given in percentages compared to the average of the Control value (100%)
Name of Concentration Ca DNA Ca/DN. Compound [-log M] % % %
Ipriflavone 8 121 100 121
(7-isopropoxy- 10 111 108 103 isoflavone)
CH- 16693 8 110 97 113
(7-(-l-cyclohex- 10 131 107 124
2-enyloxy)-isoflavone)
The compounds of the general formula (I) may be utilized in the therapy in the form of preparations containing the active ingredient together with inert, non-toxic, pharmaceutically acceptable solid or liquid diluents or carriers. If desired, the preparations can contain biologically active known substances such as vitamins, amino acids, choline chloride, salts of mineral acids, trace elements etc. As carriers talc, gelatine, calcium carbonate, magnesium stearate, starch, water, polyalkylene glycols etc. may be used. The compositions may be formulated as solid (e.g. tablets, dragees, capsules, suppositories etc.) or liquid (e.g. solution, suspension or emulsion) preparations.
The invention is elucidated in more detail in the following non-limiting examples.
Example 1
10 g of 7-hydroxy-isoflavone, 10 ml of chloroacetone and 8 g of potassium carbonate are stirred in 120 ml of acetone and the mixture is boiled for 5 hours. The reaction mixture is diluted with water, the precipitate is filtered off and recrystallized from acetic acid. 8.5 g of 7-(2-oxopropyl)-isoflavone are obtained, m.p.: 174-175 °C.
7-(2,3-dihydroxy-l-propyloxy)-isoflavone (FL 230), m.p.: 164-165 °C,
7-(3-ethoxycarbonyl-propyloxy)-isoflavone (FL 283), m.p.: 124-125 °C, 7-(2-phenoxyethoxy)-isoflavone (FL 273), m.p.: 195-197 °C, and
7-(l-ethoxycarbonyl-l-decyloxy)-isoflavone (FL 279), m.p.: 97-99 °C are prepared in a similar way from 7-hydroxy-isoflavone and the corresponding alkyl halide or substituted alkyl halide. 7-(3-methyl-l-butyloxy)-isoflavone (FL 191), m.p.: 107-108 °C, is prepared from 7-hydroxy-3',4'-dimethoxy-isoflavone by using 3-methyl-l-butylbromid.
7-ethoxy-8-methyl-isoflavone (FL 315), m.p.: 129-130 °C, 7-(carbethoxymethoxy)-8-methyl-isoflavone (FL 316), m.p.: 137-139 °C, and 7-(4-oxo-l-pentyloxy)-isoflavone (FL 501), m.p.: 143-145 °C, are obtained from 7-hydroxy-8-methyl-isoflavone.
Example 2
A mixture of 16 g of 6-n-hexyl-7-hydroxy-isoflavone, 14 ml of isopropylbromide and 70 ml of dimethylformamide are stirred for 4 hours at a temperature of 90 °C in the presence of 16 g of potassium carbonate.
The reaction mixture is poured into 500 ml of water, the product is separated, then recrystallized from 80% aqueous methanol. 15 g of 6-n-hexyl-7-(l-methylethoxy)-
-isoflavone are obtained, m.p. 37-39 °C.
6-n-hexyl-7-ethoxy-isoflavone (FL 319), m.p.: 57-59 °C, and 6-n-hexyl-7-
-(2-methyl-l-propyloxy)-isoflavone (FL 321), m.p.: 65-67 °C, are prepared in a similar way. By reacting 6-chloro-7-hydroxy-isoflavones with alkyl halides with the following compounds are prepared:
7-ethoxy-6-chloro-isoflavone (FL 322), m.p. : 162- 164 °C, 7-(l-methylethoxy)-6-chloro-isoflavone (FL 323), m.p.: 156-158 °C, 7-(2-methyl-l-propyloxy)-6-chloro-isoflavone (FL 324), m.p.: 170-172 °C, 7-(2-propen-l-yloxy)-isoflavan-4-one (FL 238), m.p.: 76-78 °C and
7-(4-nitro-benzyloxy)-isoflavan-4-one (FL 239), m.p.: 100-102 °C.
Example 3
6.5 g of 7-n-hexadecyloxy-isoflavone are hydrogenated in 1200 ml of acetone in the presence of 3.0 g of 10 % palladium on charcoal catalyst until a hydrogen uptake of 1.2 equimolar amount. The catalyst is filtered off and the solution is evaporated. The residue is recrystallized from a mixture of methanol and acetone to obtain 5.3 g of 7-n-hexadecyloxy-isoflavon-4-one, m.p.: 90-92 °C.
7-ethoxy-5-methyl-isoflavan-4-one (FL 299), m.p.: 97-98 °C, is prepared in a similar way from 7-ethoxy-5-methyl-isoflavone.
7-cyclohexyl-isoflavan-4-one (FL 312), m.p.: 119-120 °C, is prepared from 7-(l-cyclohex-2-enyloxy)-isoflavone (FL 286) by hydrogenation until a hydrogen ptake of 2.2 equimolar amount.
Example 4
A solution of 14 g of 7-isopropyloxy-isoflavone in 160 ml of acetic acid is hydrogenated in the presence of 5% palladium on charcoal catalyst until a hydrogen uptake of 3 equimolar amount. The catalyst is filtered off, the solvent is evaporated and the residue is recrystallized from methanol. 10 g of 7-(l- methylethoxy)-isoflavane (FL199) is obtained, m.p.: 93-95 °C
7-(2-methyl-l-propyloxy)-isoflavane (FL 248), m.p.: 97-99 °C, 7-(n- hexadecyloxy)-isoflavan, m.p.: 90-92 °C, are prepared in a similar way from the corresponding isoflavones.
7-cyclohexyl-isoflavane, m.p.: 90-92 °C, is prepared from 7-(l- -cyclohex-2-enyloxy)-isoflavone by hydrogenation until a hydrogen uptake of 4 equimolar amount.
Example 5
2.38 g of 7-hydroxy-isoflavone and 1.94 g of propane sulfone are dissolved in 25 ml of 1% methanolic sodium methylate. The mixture is let stand for 48 hours, then the precipitated product is separated by suction and recrystallized from water to obtain 3.0 g of 7-(3-sulfonyl- l-propyloxy)-isoflavone sodium salt which melts above 350 °C
7-(3-sulfonyl-l-propyloxy)-8-methyl-isoflavone sodium salt (FL 318), m.p.: above 350 °C,
6-chloro-7-(3-sulfonyl-l-propyloxy)-isoflavone (FL 346), m.p.: above 350 °C,
5-methyl-7-(3-sulfo-l-propyloxy)-isoflavone sodium salt (FL 502), m.p.: above 320 °C, and
7-(3-sulfo-l-propyloxy)-2-methyl-isoflavone sodium salt (FL 291), m.p.: above 350 °C are prepared in a similar way from the corresponding 7-hydroxy-isoflavone derivatives.
Example 6
16.5 g of 7-(3-carbomethoxy-l-proplyoxy)-isoflavone are boiled for 9 hours under reflux in a mixture of 165 ml of glacial acetic acid, 8.5 ml of water and
1.0 ml of concentrated sulfuric acid. The free acid (m.p.: 188-190 °C) precipitates when the mixture is cooled, said acid is removed by suction, dissolved in 300 ml of methanol and the solution is neutralized to pH-8 with IN sodium methylate solution. The precipitated 7-(3-carboxy-l-propyloxy)-isoflavone sodium salt is separated by suction in an amount of 13.1 g, m.p.: above 320 °C.
7-(l-carboxy-l-propyloxy)-isoflavone, m.p.: 197-200 °C and its sodium salt (FL 282) and
7-(l-carboxy-l-decyloxy)-isoflavone, m.p.: 124-126 °C, and its sodium salt (FL 280) are prepared in a similar way from the corresponding esters.
Example 7
9 g of 7-isopropyloxy-isoflavone and 3.2 g of paraformaldehyde are stirred for 3 hours at a temperature of 70 °C in a mixture of 80 ml of glacial acetic acid and 40 ml of concentrated hydrochloric acid under continuous introducing of anhydrous gaseous hydrochloric acid. On the next day the solution is partially evaporated, the precipitate is separated by suction and recrystallized from methanol. To the solution of the 7-isopropoxy-8-chloromethyl-isoflavone, m.p.: 123-124 °C, thus obtained with 50 ml of benzene an equivalent amount of
IN sodium methylate is added under boiling. The cooled solution is shaken several times with water and evaporated. The residue is recrystallized from methanol to obtain 7 g of 7-isopropoxy-8-methoxymethyl-isoflavone, m.p.: 92-93 °C. 7-methoxy-8-methoxymethyl-isoflavone (FL 308) is prepared from 7-methoxy-isoflavone in a similar way.
Example 8
To a suspension of 7.5 g of 7-methoxy-8-chloromethyl-isoflavone with 45 ml of glacial acetic acid 3.0 of zinc dust is added within 3 hours. After a further stirring for 8 hours the reaction mixture is diluted with warm water, the precipitate is separated by suction and recrystallized from ethanol. 5.1 g of 7-methoxy-8- -methyl-isoflavone are obtained, m.p.: 133-135 °C.
Example 9 36.2 g of 2-hydroxy-4-(3-phenoxy-l-propyloxy)-phenylbenzyl-ketone, 22 g of ethyl orthofoπniate and 5 g of morpholine are boiled in 200 ml of dimethyl formamide for 8 hours. The ethanol formed during the reaction is removed through a fractionating attachment, then a great part of the solvent is evaporated in vacuo and the residue is diluted with diluted aqueous hydrochloric acid. The raw product is filtered off and recrystallized from acetone to obtain 32 g of 7-(3-phenoxy-l-propyloxy)-isoflavone (FL 230), m.p.: 123-125 °C.
Example 10
9.8 g of 7-(3-chloro-l-propyloxy)-isoflavone are boiled with 4.1 ml of piperidine in 55 ml of 2-butanone in the presence of 5.5 g of potassium carbonate and 0.5 g of potassium iodide for 14 hours. The inorganic salts are filtered off while hot and after cooling the precipitated product is separated by suction and recrystallized from methanol. 7-[3-(l-piperidine)-propyloxy]-isoflavone (FL 118) is obtained in an amount of 6.0 g, m.p.: 138-139 °C. 7-[3-(l-morpholinyl)-propyloxy]-isoflavone (FL 117) is obtained in a similar way, m.p.: 162-163 °C.
Example 11
18.5 g of 7-(10-ethoxycarbonyl-l-decyloxy)-isoflavone are boiled in a mixture of 180 ml of glacial acetic acid, 10 ml of water and 3 ml of concentrated sulfuric acid for 4 hours. The next day the precipitated 7-(10-carboxy-l-decyloxy)- isoflavone, m.p.: 118-120 °C, is separated by suction, dissolved in a 4:1 mixture of acetone and methanol and the solution is adjusted to pH 8 by the aid of 10%
sodium hydroxyde. The precipitated salt is separated by suction and washed with the solvent mixture. 7-(10-carboxy-l-decyloxy)-isoflavone sodium salt (FL 295) is obtained in an amount of 10.6 g, which melts above 360 °C.
7-(5-carboxy-l-pentyloxy)-isoflavone, m.p.: 146-148 °C, is obtained from 7-(5-carbethoxy- l-pentyloxy)-isoflavone in a similar way and then the corresponding sodium salt (FL 302) which melts above 360 °C.
Example 12
3.0 g of 7-methoxy-isoflavone are dissolved in 30 ml of chloroform and then 2.0 g of sulfurylchloride are added to the solution. The mixture is boiled for an hour, evaporated, then the residue is recrystallized from a 1: 1 mixture of chloroform and ethanol. 8-chloro-7-methoxy-isoflavone (FL 501) is obtained in an amount of 22.5 g, m.p.: 181-182 °C.
In a similar way 7-ethoxy-isoflavone, m.p.: 144-145 °C, is prepared from 7- ethoxy-isoflavone, 8-chloro-7-(2-propyloxy)-isoflavone, m.p.: 167-169 °C, from 7-
(2-propyloxy)-isoflavone and 8-chloro-2-methyl-7-methoxy-isoflavone (FL 517), m.p.: 176-178 °C, from 2-methyl-7-methoxy-isoflavone.
Example 13 2.0 g of 7-(carbethoxymethoxy)-isoflavone are dissolved in 10 ml of diethylamino ethanol, 2.0 g of potassium carbonate are added to the solution and the mixture is boiled for 5 hours under stirring, then poured into a mixture of ice and 2% hydrochloric acid. The product is separated by suction and recrystallized from a mixture of methanol and acetone. 7-(N,N-chethylaπunoethoxy- -carbonylmethoxy)-isoflavone (FL 105) is obtained in an amount of 1.5 g, m.p.: 227-228 °C.
7-(N,N-diethylaminoethoxy-carbonylmethoxy)-2-methyl-isoflavone (FL 104), m.p.: 190-192 °C, is prepared in a similar way from 7-(carbethoxymethoxy)-2-methyl-isoflavone.
Example 14
16.0 g of 8-chloromethyl-7-methoxy-isoflavone and 11.4 g of anhydrous sodium acetate are boiled in 80 ml of acetic anhydride for 4 hours. The reaction mixture is poured onto water, the precipitated product is filtered off and recrystallized from acetic acid. 8-acetoxymethyl-7-methoxy-isoflavone (FL 509) is obtained in an amount of 11.7 g, m.p.: 195-197 °C.
8-acetoxymethyl-7-(2-propyloxy)-isoflavone (FL 521), m.p.: 107-109 °C, is prepared from 8-chloromethyl-7-(2-propyloxy)-isoflavone in a similar way.
Claims (17)
1. Process for the preparation of compounds of the general formula
and salts thereof, wherein if n is 0, R5 and R6 together stand for an oxo group and the dotted line means a double bond, R1 represents C-^galkyl substituted by alkylcarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a
(C alkyl)2N-(CH2)mCO(CH2)p- or by (CMalkyl)2N-(CH2)mOCO(CH2)p- group; or stands for C^cycloalkyl or cycloalkenyl; or if n is 1, R5 and R6 together stand for an oxo group and the dotted line means a double bond,
R1 represents optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or piridino or by a (Cι^alkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3.6-cycloalkyl or cycloalkenyl or C2.6alkenyl; or if n is 0 or 1, R5 and R6 together stand for an oxo group or stand separately for hydrogen and the dotted line does not mean a chemical bond, R1 represents C ^alkyl optionally substituted by alkyl-carbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, alkoxy, phenyl optionally substituted by a halo atom, phenoxy, piperidino, morpholino or piridino or by a (CMalkyl)2N-(CH2)mCO(CH2)p- group; or stands for C3.6-cycloalkyl or C2.galkenyl; or R stands for C galkyl, halogen, C-^alkoxymethyl, C2.5-acyloxymethyl, or hydroxymethyl; R4 stands for hydrogen or C-^alkyl; R2 and R3 stand for hydrogen or C1.6alkoxy;
R5 and R6 together stand for an oxo group or separately stand for hydrogen; the dotted line means a double bond being optionally present; n is 0 or 1; m is an integer from 1 to 4; and p is an integer from 1 to 4. characterized in that
1) for the preparation of compounds of the general formula
wherein R, n, R1, R2 and R3 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), ketones of the general formula
wherein R, n, R1, R2 and R3 are as defined for the general formula (I), are reacted a) with alkyl orthofoπnate in the presence of a basic catalyst, or b) with hydrogen cyanide and or cyanic salts in the presence of hydrohalogenic acid; or c) with alkyl formiate in the presence of an alkali metal; or d) with alkyloxalyl halide, and the isoflavone ester thus obtained is, if desired, saponified and/or decarboxylated; or e) with organic carboxylic anhydride; or f) with N,N-dialkyl acid amide in the presence of phosphorous chloride; or g) 2-hydroxy-isoflavanone derivatives of the general formula
(IV) ,
are dehydrated, or
2) for the preparation of compounds of the general formula
wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), compounds of the general formula (IA), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, are subjected to reduction, or
3) for the preparation of compounds of the general formula
wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, forming a narrower group of the compounds of the general formula (I), compounds of the general formula (IB), wherein R, n, R1, R2 R3 and R4 are as defined in the preamble, are reduced by catalytic hydrogenation, and, if desired, an R1 is converted into another R1 group within the definitions of the preamble, or an R group is formed in a compound of the general formula (I) containing a hydrogen atom in the place of R, and, if desired, a compound of the general formula (I) thus obtained is converted into its salt or is set free from its salt.
2. Processes according to variants a) to f) of claim 1, characterized by using 2-hydroxy-4-alkoxyphenylbenzyl-ketone as a starting material of the general formula (III).
3. A process as claimed in claim 2, characterized by using 2-hydroxy-4- isopropoxyphenylbenzyl-ketone as starting material of the general formula (El).
4. A process as claimed in variant a) of claim 1, characterized by using piperidine, morpholine or pyrrolidine as basic catalyst.
5. A process as claimed in variant b9 of claim 1, characterized by carrying out the reaction in an aprotic solvent, preferably in dialkyl ether or another dialkyl ether.
6. A process as claimed in claim 5, characterized by carrying out the reaction in the presence of Lewis acids, preferably in the presence of zinc chloride.
7. A process as claimed in variant c) of claim 1, characterized by using sodium as an alkali metal.
8. A process as claimed in variant e) of claim 1, characterized by using acetic anhydride, propionic anhydride or benzoic anhydride as organic acid anhydride.
9. A process as claimed in claim 8, characterized by carrying out the reaction in the presence of a basic catalyst, preferably in the presence of the alkali salt of the acid component of the acid anhydride or a tertiary amine.
10. A process as claimed in variant f) of claim 1, characterized by using dimethylformamide or dimethylacetamide as N,N-dialkyl acid amide.
11. A process as claimed in variant g) of claim 1, characterized by carrying out the dehydration in an acidic medium.
12. A process as claimed in claim 1, characterized by introducing the R1 group by alkylating the compounds of the general formula (I) containing a hydrogen atom in the place of R1 with alkyl halides, alkyl sulfates, alkyl sulfonic lactones, olefines or epoxydes.
13. A process as claimed in variant 2) of claim 1, characterized by carrying out the reduction by catalytic hydrogenation or by using metal hydrides.
14. A process as claimed in variant 3) of claim 1, characterized by using as catalyst nickel or a noble metal catalyst.
15. A process for the preparation of pharmaceutical compositions, characterized by admixing a compound of the general formula (I) wherein R1, R, R2, R3 R4, R5, R6, n, m, p and the dotted line are as defined in claim 1, or a salts thereof, with inert, non-toxic, pharmaceutically acceptable solid or liquid diluents or carriers and other excipients and formulating pharmaceutical compositions.
16. Compounds of the general formula
and salts thereof.
17. Pharmaceutical compositions containing compounds of the general formula (I).
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU2083/93 | 1993-07-20 | ||
HU9302083A HUT68558A (en) | 1993-07-20 | 1993-07-20 | Method for preparing isoflavon derivatives |
PCT/HU1994/000028 WO1995003293A1 (en) | 1993-07-20 | 1994-07-19 | Isoflavone derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
AU7236794A true AU7236794A (en) | 1995-02-20 |
Family
ID=10983803
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU72367/94A Abandoned AU7236794A (en) | 1993-07-20 | 1994-07-19 | Isoflavone derivatives |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0710234A1 (en) |
KR (1) | KR960703888A (en) |
CN (1) | CN1129445A (en) |
AU (1) | AU7236794A (en) |
CA (2) | CA2167597A1 (en) |
HU (1) | HUT68558A (en) |
WO (1) | WO1995003293A1 (en) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6087366A (en) * | 1996-03-07 | 2000-07-11 | The Trustees Of Columbia University In The City Of New York | Use of flavopiridol or a pharmaceutically acceptable salt thereof for inhibiting cell damage or cell death |
IT1289154B1 (en) * | 1997-01-03 | 1998-09-29 | Chiesi Farma Spa | ISOFLAVONE DERIVATIVES THEIR PREPARATION AND THEIR THERAPEUTIC USE |
US6146668A (en) | 1997-04-28 | 2000-11-14 | Novogen, Inc. | Preparation of isoflavones from legumes |
KR20000001793A (en) | 1998-06-13 | 2000-01-15 | 이경하 | Novel benzopyran or thiobenzopyran derivatives |
AUPP868599A0 (en) * | 1999-02-15 | 1999-03-11 | Novogen Research Pty Ltd | Production of isoflavone derivatives |
AUPQ266199A0 (en) | 1999-09-06 | 1999-09-30 | Novogen Research Pty Ltd | Compositions and therapeutic methods involving isoflavones and analogues thereof |
KR100408231B1 (en) * | 2000-08-14 | 2003-12-01 | 한국 한의학 연구원 | Flavonoid derivateives for prevention and treatment of osteoporosis |
AUPR363301A0 (en) | 2001-03-08 | 2001-04-05 | Novogen Research Pty Ltd | Dimeric isoflavones |
US7468445B2 (en) | 2002-08-07 | 2008-12-23 | University Of Mississippi | Antigiardial agents and use thereof |
GB0412769D0 (en) | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
GB0412768D0 (en) * | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
WO2007099432A2 (en) * | 2006-02-28 | 2007-09-07 | Council Of Scientific And Industrial Research | Pharmaceutical composition containing butea isoflavones for the prevention /treatment of bone disorders and a process for the preparation thereof |
TWI324514B (en) | 2008-02-26 | 2010-05-11 | Univ Kaohsiung Medical | Isoflavone derivatives and pharmaceutical compositions comprising the same |
CN102964322A (en) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | Isoflavone or flavonoid aliphatic ether derivates, preparation method and medical application thereof |
CN108264506B (en) * | 2018-01-17 | 2021-01-26 | 中国药科大学 | Isoflavone derivative, preparation method and medical application thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6054379A (en) * | 1983-09-05 | 1985-03-28 | Takeda Chem Ind Ltd | Novel 4h-1-benzopyran-4-one derivative, its preparation and its use |
EP0478558B1 (en) * | 1990-04-06 | 1994-02-02 | CHINOIN Gyògyszer és Vegyészeti Termékek Gyára RT. | An improved process for the preparation of substituted isoflavone derivatives |
-
1993
- 1993-07-20 HU HU9302083A patent/HUT68558A/en unknown
-
1994
- 1994-07-18 CA CA002167597A patent/CA2167597A1/en not_active Abandoned
- 1994-07-19 AU AU72367/94A patent/AU7236794A/en not_active Abandoned
- 1994-07-19 WO PCT/HU1994/000028 patent/WO1995003293A1/en not_active Application Discontinuation
- 1994-07-19 EP EP94921776A patent/EP0710234A1/en not_active Withdrawn
- 1994-07-19 CN CN94193107A patent/CN1129445A/en active Pending
- 1994-07-19 CA CA002167714A patent/CA2167714A1/en not_active Abandoned
-
1996
- 1996-01-19 KR KR1019960700364A patent/KR960703888A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
HUT68558A (en) | 1995-06-28 |
CA2167714A1 (en) | 1995-02-02 |
CN1129445A (en) | 1996-08-21 |
EP0710234A1 (en) | 1996-05-08 |
KR960703888A (en) | 1996-08-31 |
WO1995003293A1 (en) | 1995-02-02 |
CA2167597A1 (en) | 1995-02-02 |
HU9302083D0 (en) | 1993-10-28 |
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