CN1738788A - 作为雌激素剂的取代的苯基萘 - Google Patents
作为雌激素剂的取代的苯基萘 Download PDFInfo
- Publication number
- CN1738788A CN1738788A CNA028247361A CN02824736A CN1738788A CN 1738788 A CN1738788 A CN 1738788A CN A028247361 A CNA028247361 A CN A028247361A CN 02824736 A CN02824736 A CN 02824736A CN 1738788 A CN1738788 A CN 1738788A
- Authority
- CN
- China
- Prior art keywords
- naphthol
- hydroxyphenyl
- compound
- chloro
- mmol
- 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.)
- Pending
Links
- 239000000262 estrogen Substances 0.000 title description 31
- IYDMICQAKLQHLA-UHFFFAOYSA-N 1-phenylnaphthalene Chemical class C1=CC=CC=C1C1=CC=CC2=CC=CC=C12 IYDMICQAKLQHLA-UHFFFAOYSA-N 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims description 292
- 238000000034 method Methods 0.000 claims description 143
- 229910052799 carbon Inorganic materials 0.000 claims description 45
- -1 3 - (3 - fluoro-4 - hydroxyphenyl) -7 - hydroxy-1 - naphthyl Chemical group 0.000 claims description 41
- 241000124008 Mammalia Species 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 230000005764 inhibitory process Effects 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 206010003246 arthritis Diseases 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 230000006378 damage Effects 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 230000000324 neuroprotective effect Effects 0.000 claims description 5
- 229930192474 thiophene Natural products 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 150000002632 lipids Chemical class 0.000 claims description 4
- 208000008423 pleurisy Diseases 0.000 claims description 4
- IPBYYNRPJBGKET-UHFFFAOYSA-N 1-bromo-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(Br)=C(O)C=C2)C2=C1 IPBYYNRPJBGKET-UHFFFAOYSA-N 0.000 claims description 3
- NLFWTSXMRSTIKQ-UHFFFAOYSA-N 2-chloro-4-naphthalen-2-ylphenol Chemical compound C1=C(Cl)C(O)=CC=C1C1=CC=C(C=CC=C2)C2=C1 NLFWTSXMRSTIKQ-UHFFFAOYSA-N 0.000 claims description 3
- JZAALJHRGIVUQB-UHFFFAOYSA-N 2-fluoro-4-naphthalen-2-ylphenol Chemical compound C1=C(F)C(O)=CC=C1C1=CC=C(C=CC=C2)C2=C1 JZAALJHRGIVUQB-UHFFFAOYSA-N 0.000 claims description 3
- QZUOTBJDFQFRGT-UHFFFAOYSA-N 2-hydroxy-6-(4-hydroxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(C#N)=C(O)C=C2)C2=C1 QZUOTBJDFQFRGT-UHFFFAOYSA-N 0.000 claims description 3
- VLJUOFGVEJAFFK-UHFFFAOYSA-N 6-(2,5-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=CC(F)=C(O)C=C1F VLJUOFGVEJAFFK-UHFFFAOYSA-N 0.000 claims description 3
- AUZLISXBMGKYGA-UHFFFAOYSA-N 6-(2,6-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=C(F)C=C(O)C=C1F AUZLISXBMGKYGA-UHFFFAOYSA-N 0.000 claims description 3
- FNSIACDWDZGUHN-UHFFFAOYSA-N 6-(2-chloro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound ClC1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 FNSIACDWDZGUHN-UHFFFAOYSA-N 0.000 claims description 3
- MAFQDFZNSVYFEW-UHFFFAOYSA-N 6-(2-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound FC1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 MAFQDFZNSVYFEW-UHFFFAOYSA-N 0.000 claims description 3
- DZGRIHNLLUZLTL-UHFFFAOYSA-N 6-(3,5-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=CC(F)=C(O)C(F)=C1 DZGRIHNLLUZLTL-UHFFFAOYSA-N 0.000 claims description 3
- MBESMLNJQCOTRU-UHFFFAOYSA-N 6-(4-hydroxyphenyl)naphthalen-1-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(O)=CC=C2)C2=C1 MBESMLNJQCOTRU-UHFFFAOYSA-N 0.000 claims description 3
- AOWCVRXIHIHAPN-UHFFFAOYSA-N 7-hydroxy-3-(4-hydroxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(O)=CC=C1C1=CC(C#N)=C(C=C(O)C=C2)C2=C1 AOWCVRXIHIHAPN-UHFFFAOYSA-N 0.000 claims description 3
- XSODNSMEBNRYBI-UHFFFAOYSA-N 8-bromo-7-hydroxy-3-(4-hydroxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(O)=CC=C1C1=CC(C#N)=C(C(Br)=C(O)C=C2)C2=C1 XSODNSMEBNRYBI-UHFFFAOYSA-N 0.000 claims description 3
- DGVWRZXKKCDNLS-UHFFFAOYSA-N 8-chloro-3-(3-fluoro-4-hydroxyphenyl)-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=C(F)C(O)=CC=C1C1=CC(C#N)=C(C(Cl)=C(O)C=C2)C2=C1 DGVWRZXKKCDNLS-UHFFFAOYSA-N 0.000 claims description 3
- ZOCBCFXUQAYMNS-UHFFFAOYSA-N 8-chloro-7-hydroxy-3-(4-hydroxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(O)=CC=C1C1=CC(C#N)=C(C(Cl)=C(O)C=C2)C2=C1 ZOCBCFXUQAYMNS-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 206010046851 Uveitis Diseases 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005466 alkylenyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 3
- LKNGKJDCKVVOLK-UHFFFAOYSA-N 1,5-dichloro-8-fluoro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1Cl LKNGKJDCKVVOLK-UHFFFAOYSA-N 0.000 claims description 2
- YTFVBUBYMJJWQZ-UHFFFAOYSA-N 1,8-dichloro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(Cl)=C(C(Cl)=C(O)C=C2)C2=C1 YTFVBUBYMJJWQZ-UHFFFAOYSA-N 0.000 claims description 2
- DZNMJDCCSRLHNP-UHFFFAOYSA-N 1-chloro-6-(2,5-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(O)=CC(F)=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 DZNMJDCCSRLHNP-UHFFFAOYSA-N 0.000 claims description 2
- LIGCNYLVJJWYIY-UHFFFAOYSA-N 1-chloro-6-(2,6-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound FC1=CC(O)=CC(F)=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 LIGCNYLVJJWYIY-UHFFFAOYSA-N 0.000 claims description 2
- LSVPDXDJCFTDSL-UHFFFAOYSA-N 1-chloro-6-(2-chloro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound ClC1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 LSVPDXDJCFTDSL-UHFFFAOYSA-N 0.000 claims description 2
- XIWROJLPONIAKV-UHFFFAOYSA-N 1-chloro-6-(2-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound FC1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 XIWROJLPONIAKV-UHFFFAOYSA-N 0.000 claims description 2
- AHELSLCUIPWEII-UHFFFAOYSA-N 1-chloro-6-(3,5-difluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=C(Cl)C(O)=CC=C2C=C1C1=CC(F)=C(O)C(F)=C1 AHELSLCUIPWEII-UHFFFAOYSA-N 0.000 claims description 2
- FWRUMAVROMTQMY-UHFFFAOYSA-N 1-chloro-6-(3-chloro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(Cl)C(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 FWRUMAVROMTQMY-UHFFFAOYSA-N 0.000 claims description 2
- HZPYQCSGTTZVLW-UHFFFAOYSA-N 1-chloro-6-(3-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 HZPYQCSGTTZVLW-UHFFFAOYSA-N 0.000 claims description 2
- GGWIHGXEDCXOIL-UHFFFAOYSA-N 1-chloro-6-(4-hydroxy-2-methylphenyl)naphthalen-2-ol Chemical compound CC1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 GGWIHGXEDCXOIL-UHFFFAOYSA-N 0.000 claims description 2
- YHEHVRSGKUYDON-UHFFFAOYSA-N 1-chloro-6-(4-hydroxyphenyl)-2-naphthol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 YHEHVRSGKUYDON-UHFFFAOYSA-N 0.000 claims description 2
- IPEUQNVORWKWRB-UHFFFAOYSA-N 1-chloro-6-phenylnaphthalen-2-ol Chemical compound C1=CC2=C(Cl)C(O)=CC=C2C=C1C1=CC=CC=C1 IPEUQNVORWKWRB-UHFFFAOYSA-N 0.000 claims description 2
- DXLDXLIYYQFLKD-UHFFFAOYSA-N 1-chloro-8-fluoro-6-(3-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(O)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1 DXLDXLIYYQFLKD-UHFFFAOYSA-N 0.000 claims description 2
- OYUGBGZDLCAQEA-UHFFFAOYSA-N 1-chloro-8-fluoro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1 OYUGBGZDLCAQEA-UHFFFAOYSA-N 0.000 claims description 2
- VQATUPWMFYRKSD-UHFFFAOYSA-N 1-fluoro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(F)=C(O)C=C2)C2=C1 VQATUPWMFYRKSD-UHFFFAOYSA-N 0.000 claims description 2
- NTESIIXLFNAOOM-UHFFFAOYSA-N 3-(3,5-difluoro-4-hydroxyphenyl)-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=C(C#N)C2=CC(O)=CC=C2C=C1C1=CC(F)=C(O)C(F)=C1 NTESIIXLFNAOOM-UHFFFAOYSA-N 0.000 claims description 2
- SCURDNNVFUOCIP-UHFFFAOYSA-N 3-bromo-1,8-dichloro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(Cl)=C(C(Cl)=C(O)C(Br)=C2)C2=C1 SCURDNNVFUOCIP-UHFFFAOYSA-N 0.000 claims description 2
- BXIITHSNGXGDCN-UHFFFAOYSA-N 6-(3-chlorophenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=CC=CC(Cl)=C1 BXIITHSNGXGDCN-UHFFFAOYSA-N 0.000 claims description 2
- QTDYCKGQBCKMGC-UHFFFAOYSA-N 6-(3-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=CC=C(O)C(F)=C1 QTDYCKGQBCKMGC-UHFFFAOYSA-N 0.000 claims description 2
- VHWBXEUHUQDHDH-UHFFFAOYSA-N 6-(3-hydroxyphenyl)naphthalen-2-ol Chemical compound OC1=CC=CC(C=2C=C3C=CC(O)=CC3=CC=2)=C1 VHWBXEUHUQDHDH-UHFFFAOYSA-N 0.000 claims description 2
- YIKDKHNOMWERET-UHFFFAOYSA-N 6-(4-hydroxy-2-methylphenyl)naphthalen-2-ol Chemical compound CC1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 YIKDKHNOMWERET-UHFFFAOYSA-N 0.000 claims description 2
- MYVOVZDBAWARDP-UHFFFAOYSA-N 6-(4-hydroxyphenyl)-1-nitronaphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(=C(O)C=C2)[N+]([O-])=O)C2=C1 MYVOVZDBAWARDP-UHFFFAOYSA-N 0.000 claims description 2
- INNGVLJQICTRAF-UHFFFAOYSA-N 6-(4-hydroxyphenyl)-1-phenylnaphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(=C(O)C=C2)C=3C=CC=CC=3)C2=C1 INNGVLJQICTRAF-UHFFFAOYSA-N 0.000 claims description 2
- PZOXFBPKKGTQDZ-UHFFFAOYSA-N 6-phenylnaphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=CC=CC=C1 PZOXFBPKKGTQDZ-UHFFFAOYSA-N 0.000 claims description 2
- IVJIWGTXXHDRCU-UHFFFAOYSA-N 8-chloro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(Cl)=C(C=C(O)C=C2)C2=C1 IVJIWGTXXHDRCU-UHFFFAOYSA-N 0.000 claims description 2
- TYSOZDHVMFAZKD-UHFFFAOYSA-N 8-fluoro-6-(3-fluoro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C2=CC(O)=CC=C2C=C1C1=CC=C(O)C(F)=C1 TYSOZDHVMFAZKD-UHFFFAOYSA-N 0.000 claims description 2
- KBQSRNQTSRTYGN-UHFFFAOYSA-N 8-fluoro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(F)=C(C=C(O)C=C2)C2=C1 KBQSRNQTSRTYGN-UHFFFAOYSA-N 0.000 claims description 2
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 208000004483 Dyspareunia Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000032456 Hemorrhagic Shock Diseases 0.000 claims description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 206010063837 Reperfusion injury Diseases 0.000 claims description 2
- 206010039966 Senile dementia Diseases 0.000 claims description 2
- 206010040047 Sepsis Diseases 0.000 claims description 2
- 206010049771 Shock haemorrhagic Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 230000006999 cognitive decline Effects 0.000 claims description 2
- 208000016018 endometrial polyp Diseases 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 230000027939 micturition Effects 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 201000007094 prostatitis Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 2
- 206010046811 uterine polyp Diseases 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 2
- 201000009273 Endometriosis Diseases 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- RIQUETWHZUIZKU-UHFFFAOYSA-N 3-bromo-8-chloro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC(Cl)=C(C=C(O)C(Br)=C2)C2=C1 RIQUETWHZUIZKU-UHFFFAOYSA-N 0.000 claims 1
- TWSSGPRRAGPVKD-UHFFFAOYSA-N 6-(4-hydroxy-2-methoxyphenyl)naphthalen-2-ol Chemical compound COC1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 TWSSGPRRAGPVKD-UHFFFAOYSA-N 0.000 claims 1
- FGIUXCLAHODWKV-UHFFFAOYSA-N 6-(4-hydroxyphenyl)-1-methylnaphthalen-2-ol Chemical compound C=1C=C2C(C)=C(O)C=CC2=CC=1C1=CC=C(O)C=C1 FGIUXCLAHODWKV-UHFFFAOYSA-N 0.000 claims 1
- VEQWNMMVQWDERW-UHFFFAOYSA-N 7-(3-hydroxyphenyl)naphthalen-2-ol Chemical compound OC1=CC=CC(C=2C=C3C=C(O)C=CC3=CC=2)=C1 VEQWNMMVQWDERW-UHFFFAOYSA-N 0.000 claims 1
- NSCZTZNRMFWAIY-UHFFFAOYSA-N 7-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C=CC(O)=C2)C2=C1 NSCZTZNRMFWAIY-UHFFFAOYSA-N 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 206010003694 Atrophy Diseases 0.000 claims 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- 201000004624 Dermatitis Diseases 0.000 claims 1
- 206010014733 Endometrial cancer Diseases 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims 1
- 208000035150 Hypercholesterolemia Diseases 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 claims 1
- 206010021639 Incontinence Diseases 0.000 claims 1
- 206010023232 Joint swelling Diseases 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010036774 Proctitis Diseases 0.000 claims 1
- 206010036783 Proctitis ulcerative Diseases 0.000 claims 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims 1
- 208000003251 Pruritus Diseases 0.000 claims 1
- 208000007156 Spondylarthritis Diseases 0.000 claims 1
- 208000024248 Vascular System injury Diseases 0.000 claims 1
- 208000012339 Vascular injury Diseases 0.000 claims 1
- 206010047163 Vasospasm Diseases 0.000 claims 1
- 206010047791 Vulvovaginal dryness Diseases 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N alpha-naphthol Natural products C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 230000037444 atrophy Effects 0.000 claims 1
- 150000007514 bases Chemical class 0.000 claims 1
- 235000012000 cholesterol Nutrition 0.000 claims 1
- 230000020335 dealkylation Effects 0.000 claims 1
- 238000006900 dealkylation reaction Methods 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000012976 endoscopic surgical procedure Methods 0.000 claims 1
- 230000003628 erosive effect Effects 0.000 claims 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- 230000009545 invasion Effects 0.000 claims 1
- 208000028867 ischemia Diseases 0.000 claims 1
- 230000007803 itching Effects 0.000 claims 1
- 210000001503 joint Anatomy 0.000 claims 1
- 208000002780 macular degeneration Diseases 0.000 claims 1
- 208000015122 neurodegenerative disease Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000035935 pregnancy Effects 0.000 claims 1
- 201000004240 prostatic hypertrophy Diseases 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- 208000037803 restenosis Diseases 0.000 claims 1
- 208000010485 smooth muscle tumor Diseases 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
- 230000002485 urinary effect Effects 0.000 claims 1
- 230000001457 vasomotor Effects 0.000 claims 1
- 239000002834 estrogen receptor modulator Substances 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 181
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 137
- 238000005160 1H NMR spectroscopy Methods 0.000 description 133
- 239000000243 solution Substances 0.000 description 117
- 238000004458 analytical method Methods 0.000 description 110
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 76
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- 241000700159 Rattus Species 0.000 description 51
- 239000000203 mixture Substances 0.000 description 51
- 238000012360 testing method Methods 0.000 description 49
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 46
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- 210000004027 cell Anatomy 0.000 description 41
- 239000002904 solvent Substances 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 150000001721 carbon Chemical group 0.000 description 35
- 239000000377 silicon dioxide Substances 0.000 description 34
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 32
- 241001465754 Metazoa Species 0.000 description 31
- 230000000694 effects Effects 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 229940011871 estrogen Drugs 0.000 description 25
- 238000010998 test method Methods 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- 102100029951 Estrogen receptor beta Human genes 0.000 description 21
- 101001010910 Homo sapiens Estrogen receptor beta Proteins 0.000 description 21
- 238000011156 evaluation Methods 0.000 description 21
- 210000001519 tissue Anatomy 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 238000004007 reversed phase HPLC Methods 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
- 229960005309 estradiol Drugs 0.000 description 17
- 239000007788 liquid Substances 0.000 description 17
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 17
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 17
- 210000004291 uterus Anatomy 0.000 description 17
- 150000000307 17β-estradiols Chemical class 0.000 description 16
- 238000011160 research Methods 0.000 description 16
- OVBICQMTCPFEBS-SATRDZAXSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical compound CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 OVBICQMTCPFEBS-SATRDZAXSA-N 0.000 description 15
- 229940122880 Estrogen receptor agonist Drugs 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 102000015694 estrogen receptors Human genes 0.000 description 15
- 108010038795 estrogen receptors Proteins 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 108700032141 ganirelix Proteins 0.000 description 15
- 108020004999 messenger RNA Proteins 0.000 description 15
- 238000012545 processing Methods 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
- 230000003203 everyday effect Effects 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- 238000010790 dilution Methods 0.000 description 10
- 239000012895 dilution Substances 0.000 description 10
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 10
- 239000012362 glacial acetic acid Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 8
- YLDFTMJPQJXGSS-UHFFFAOYSA-N 6-bromo-2-naphthol Chemical compound C1=C(Br)C=CC2=CC(O)=CC=C21 YLDFTMJPQJXGSS-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 239000000538 analytical sample Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 230000002441 reversible effect Effects 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 102000001775 Neurogranin Human genes 0.000 description 7
- 108010015301 Neurogranin Proteins 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 210000004204 blood vessel Anatomy 0.000 description 7
- 210000000988 bone and bone Anatomy 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000011694 lewis rat Methods 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 238000007920 subcutaneous administration Methods 0.000 description 7
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 239000000186 progesterone Substances 0.000 description 6
- 229960003387 progesterone Drugs 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- 125000002769 thiazolinyl group Chemical group 0.000 description 6
- IILGLPAJXQMKGQ-UHFFFAOYSA-N (3-fluoro-4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1F IILGLPAJXQMKGQ-UHFFFAOYSA-N 0.000 description 5
- ZKZURNPQTJONRQ-UHFFFAOYSA-N 1-bromo-2-methoxy-6-(4-methoxyphenyl)naphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(Br)=C(OC)C=C2)C2=C1 ZKZURNPQTJONRQ-UHFFFAOYSA-N 0.000 description 5
- AYFJBMBVXWNYLT-UHFFFAOYSA-N 2-bromo-6-methoxynaphthalene Chemical compound C1=C(Br)C=CC2=CC(OC)=CC=C21 AYFJBMBVXWNYLT-UHFFFAOYSA-N 0.000 description 5
- RGAMVVJGWSZBFJ-UHFFFAOYSA-N 3-bromo-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=C(Br)C=C(C#N)C2=CC(O)=CC=C21 RGAMVVJGWSZBFJ-UHFFFAOYSA-N 0.000 description 5
- PENOYHRWRASTMD-UHFFFAOYSA-N 3-bromo-8-chloro-6-(4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=CC(OC)=CC=C1C1=CC(Cl)=C(C=C(O)C(Br)=C2)C2=C1 PENOYHRWRASTMD-UHFFFAOYSA-N 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 102000052052 Casein Kinase II Human genes 0.000 description 5
- 108010010919 Casein Kinase II Proteins 0.000 description 5
- 102000012153 HLA-B27 Antigen Human genes 0.000 description 5
- 108010061486 HLA-B27 Antigen Proteins 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 210000000709 aorta Anatomy 0.000 description 5
- 235000019994 cava Nutrition 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- SLPJGDQJLTYWCI-UHFFFAOYSA-N dimethyl-(4,5,6,7-tetrabromo-1h-benzoimidazol-2-yl)-amine Chemical compound BrC1=C(Br)C(Br)=C2NC(N(C)C)=NC2=C1Br SLPJGDQJLTYWCI-UHFFFAOYSA-N 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- VIBJPUXLAKVICD-UHFFFAOYSA-N 4-bromo-2-chlorophenol Chemical compound OC1=CC=C(Br)C=C1Cl VIBJPUXLAKVICD-UHFFFAOYSA-N 0.000 description 4
- PYPBAWHTDYSLKJ-UHFFFAOYSA-N 7-methoxynaphthalen-1-amine Chemical compound C1=CC=C(N)C2=CC(OC)=CC=C21 PYPBAWHTDYSLKJ-UHFFFAOYSA-N 0.000 description 4
- CRRXABZDWHEWAP-UHFFFAOYSA-N 8-fluoro-6-(4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=CC(OC)=CC=C1C1=CC(F)=C(C=C(O)C=C2)C2=C1 CRRXABZDWHEWAP-UHFFFAOYSA-N 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 4
- 102000011632 Caseins Human genes 0.000 description 4
- 108010076119 Caseins Proteins 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 206010012735 Diarrhoea Diseases 0.000 description 4
- 241000699694 Gerbillinae Species 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 241001111421 Pannus Species 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 229910052796 boron Inorganic materials 0.000 description 4
- 239000005018 casein Substances 0.000 description 4
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 4
- 235000021240 caseins Nutrition 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 210000001072 colon Anatomy 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 150000002240 furans Chemical class 0.000 description 4
- 210000004124 hock Anatomy 0.000 description 4
- 210000005075 mammary gland Anatomy 0.000 description 4
- 235000012054 meals Nutrition 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- 235000016709 nutrition Nutrition 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 4
- 201000004595 synovitis Diseases 0.000 description 4
- 210000002303 tibia Anatomy 0.000 description 4
- 230000003442 weekly effect Effects 0.000 description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 4
- SSFFBVWGOVGZJB-UHFFFAOYSA-N (6-bromonaphthalen-2-yl)oxy-tert-butyl-dimethylsilane Chemical compound C1=C(Br)C=CC2=CC(O[Si](C)(C)C(C)(C)C)=CC=C21 SSFFBVWGOVGZJB-UHFFFAOYSA-N 0.000 description 3
- YXNHEYLZUGHRCD-UHFFFAOYSA-N 1-chloro-6-(3-fluoro-4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(OC)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 YXNHEYLZUGHRCD-UHFFFAOYSA-N 0.000 description 3
- MNBOGGWWWXXYKJ-UHFFFAOYSA-N 2-methoxy-6-(4-methoxyphenyl)naphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C=C(OC)C=C2)C2=C1 MNBOGGWWWXXYKJ-UHFFFAOYSA-N 0.000 description 3
- UOBYKYZJUGYBDK-UHFFFAOYSA-N 2-naphthoic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CC=C21 UOBYKYZJUGYBDK-UHFFFAOYSA-N 0.000 description 3
- ZVHAEOMHHOSTSB-UHFFFAOYSA-N 6-(3-fluoro-4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(OC)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 ZVHAEOMHHOSTSB-UHFFFAOYSA-N 0.000 description 3
- LUZJFMZQDLCIFR-UHFFFAOYSA-N 6-(4-methoxy-2-methylphenyl)naphthalen-2-ol Chemical compound CC1=CC(OC)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 LUZJFMZQDLCIFR-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 206010015548 Euthanasia Diseases 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 208000033830 Hot Flashes Diseases 0.000 description 3
- 206010060800 Hot flush Diseases 0.000 description 3
- 102000004895 Lipoproteins Human genes 0.000 description 3
- 108090001030 Lipoproteins Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- 102000003792 Metallothionein Human genes 0.000 description 3
- 108090000157 Metallothionein Proteins 0.000 description 3
- FRWVCDZCAVYORM-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC=C2C(Cl)=C(C=O)C=CC2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC=C2C(Cl)=C(C=O)C=CC2=C1 FRWVCDZCAVYORM-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000700157 Rattus norvegicus Species 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
- NVHHEADQQACSCJ-UHFFFAOYSA-N [4-[tert-butyl(dimethyl)silyl]oxyphenyl]boronic acid Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C(B(O)O)C=C1 NVHHEADQQACSCJ-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000003143 atherosclerotic effect Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 230000001413 cellular effect Effects 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
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 235000005687 corn oil Nutrition 0.000 description 3
- 239000002285 corn oil Substances 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 3
- 229960000452 diethylstilbestrol Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 3
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 201000003144 pneumothorax Diseases 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 230000008719 thickening Effects 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 3
- 210000001215 vagina Anatomy 0.000 description 3
- 238000004804 winding Methods 0.000 description 3
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 2
- DOBPHRADBWQSJX-UHFFFAOYSA-N (4-bromo-2,6-difluorophenoxy)-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=C(F)C=C(Br)C=C1F DOBPHRADBWQSJX-UHFFFAOYSA-N 0.000 description 2
- DLGZGLKSNRKLSM-UHFFFAOYSA-N (4-bromophenoxy)-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C(Br)C=C1 DLGZGLKSNRKLSM-UHFFFAOYSA-N 0.000 description 2
- GZFAVYWCPSMLCM-UHFFFAOYSA-N (6-methoxynaphthalen-2-yl)boronic acid Chemical compound C1=C(B(O)O)C=CC2=CC(OC)=CC=C21 GZFAVYWCPSMLCM-UHFFFAOYSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- WXOOBAUMMZAVDP-UHFFFAOYSA-N 1,5-dichloro-2-methoxy-6-(4-methoxyphenyl)naphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(Cl)=C(OC)C=C2)C2=C1Cl WXOOBAUMMZAVDP-UHFFFAOYSA-N 0.000 description 2
- UWYXMBNZRVLJNT-UHFFFAOYSA-N 1,5-dichloro-6-methoxynaphthalen-2-ol Chemical compound ClC1=C(O)C=CC2=C(Cl)C(OC)=CC=C21 UWYXMBNZRVLJNT-UHFFFAOYSA-N 0.000 description 2
- MKTMARDJUFIXBY-UHFFFAOYSA-N 1,5-dichloro-8-fluoro-6-(4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=CC(OC)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1Cl MKTMARDJUFIXBY-UHFFFAOYSA-N 0.000 description 2
- YESWBBOUYJZZPU-UHFFFAOYSA-N 1,8-dichloro-6-(4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=CC(OC)=CC=C1C1=CC(Cl)=C(C(Cl)=C(O)C=C2)C2=C1 YESWBBOUYJZZPU-UHFFFAOYSA-N 0.000 description 2
- COLPPPMPHPHUPC-UHFFFAOYSA-N 1-bromo-7-methoxynaphthalene Chemical compound C1=CC=C(Br)C2=CC(OC)=CC=C21 COLPPPMPHPHUPC-UHFFFAOYSA-N 0.000 description 2
- UBIJKBSGBOZSOE-UHFFFAOYSA-N 1-chloro-2-methoxy-6-(4-methoxyphenyl)naphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(Cl)=C(OC)C=C2)C2=C1 UBIJKBSGBOZSOE-UHFFFAOYSA-N 0.000 description 2
- QHBRHWSMPZXMFP-UHFFFAOYSA-N 1-chloro-6-methoxynaphthalen-2-ol Chemical compound ClC1=C(O)C=CC2=CC(OC)=CC=C21 QHBRHWSMPZXMFP-UHFFFAOYSA-N 0.000 description 2
- JDSWHTLMVDIJJD-UHFFFAOYSA-N 1-chloro-7-methoxynaphthalene Chemical compound C1=CC=C(Cl)C2=CC(OC)=CC=C21 JDSWHTLMVDIJJD-UHFFFAOYSA-N 0.000 description 2
- HHJAFHWKPPRSEF-UHFFFAOYSA-N 1-chloro-8-fluoro-6-(4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=CC(OC)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1 HHJAFHWKPPRSEF-UHFFFAOYSA-N 0.000 description 2
- WXGFIJSSEMRAGL-UHFFFAOYSA-N 1-fluoro-2-methoxy-6-(4-methoxyphenyl)naphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(F)=C(OC)C=C2)C2=C1 WXGFIJSSEMRAGL-UHFFFAOYSA-N 0.000 description 2
- UEDDMVOEGYUUGI-UHFFFAOYSA-N 1-fluoro-7-methoxynaphthalene Chemical compound C1=CC=C(F)C2=CC(OC)=CC=C21 UEDDMVOEGYUUGI-UHFFFAOYSA-N 0.000 description 2
- 108020004463 18S ribosomal RNA Proteins 0.000 description 2
- KKWDBDVGMIDKLP-UHFFFAOYSA-N 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dien-1-one Chemical compound [O-][N+](=O)C1(C)C(Br)=C(Br)C(=O)C(Br)=C1Br KKWDBDVGMIDKLP-UHFFFAOYSA-N 0.000 description 2
- RZCNLTHMEAUSJJ-UHFFFAOYSA-N 2-(2,5-difluoro-4-methoxyphenyl)-6-methoxynaphthalene Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C1=CC(F)=C(OC)C=C1F RZCNLTHMEAUSJJ-UHFFFAOYSA-N 0.000 description 2
- YLPUZABPRMZUAL-UHFFFAOYSA-N 2-(2,6-difluoro-4-methoxyphenyl)-6-methoxynaphthalene Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C1=C(F)C=C(OC)C=C1F YLPUZABPRMZUAL-UHFFFAOYSA-N 0.000 description 2
- SKNDLZCCIMRSMJ-UHFFFAOYSA-N 2-(2-fluoro-4-methoxyphenyl)-6-methoxynaphthalene Chemical compound FC1=CC(OC)=CC=C1C1=CC=C(C=C(OC)C=C2)C2=C1 SKNDLZCCIMRSMJ-UHFFFAOYSA-N 0.000 description 2
- DLUSYYKCQNXAPR-UHFFFAOYSA-N 2-(3-fluoro-4-methoxyphenyl)naphthalene Chemical compound C1=C(F)C(OC)=CC=C1C1=CC=C(C=CC=C2)C2=C1 DLUSYYKCQNXAPR-UHFFFAOYSA-N 0.000 description 2
- HMJIYPQPQDOHRP-UHFFFAOYSA-N 2-(4-methoxyphenyl)naphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C=CC=C2)C2=C1 HMJIYPQPQDOHRP-UHFFFAOYSA-N 0.000 description 2
- MTIDYGLTAOZOGU-UHFFFAOYSA-N 2-bromo-4-methylphenol Chemical compound CC1=CC=C(O)C(Br)=C1 MTIDYGLTAOZOGU-UHFFFAOYSA-N 0.000 description 2
- APSMUYYLXZULMS-UHFFFAOYSA-N 2-bromonaphthalene Chemical compound C1=CC=CC2=CC(Br)=CC=C21 APSMUYYLXZULMS-UHFFFAOYSA-N 0.000 description 2
- HQZVPGRVGAAUKR-UHFFFAOYSA-N 2-chloro-4-(6-methoxynaphthalen-2-yl)phenol Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C1=CC=C(O)C(Cl)=C1 HQZVPGRVGAAUKR-UHFFFAOYSA-N 0.000 description 2
- FCJHBXCQIOVMEM-UHFFFAOYSA-N 2-fluoro-4-methoxyphenol Chemical compound COC1=CC=C(O)C(F)=C1 FCJHBXCQIOVMEM-UHFFFAOYSA-N 0.000 description 2
- XXDSJAMLQLDCBU-UHFFFAOYSA-N 2-methoxy-6-(3-methoxyphenyl)naphthalene Chemical compound COC1=CC=CC(C=2C=C3C=CC(OC)=CC3=CC=2)=C1 XXDSJAMLQLDCBU-UHFFFAOYSA-N 0.000 description 2
- FFWFQWNNKJHLDR-UHFFFAOYSA-N 2-methoxy-6-(4-methoxyphenyl)-1-methylnaphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(C)=C(OC)C=C2)C2=C1 FFWFQWNNKJHLDR-UHFFFAOYSA-N 0.000 description 2
- LFBKGGUNNILPBD-UHFFFAOYSA-N 2-methoxy-6-(4-methoxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(C#N)=C(OC)C=C2)C2=C1 LFBKGGUNNILPBD-UHFFFAOYSA-N 0.000 description 2
- QMEQBOSUJUOXMX-UHFFFAOYSA-N 2h-oxadiazine Chemical compound N1OC=CC=N1 QMEQBOSUJUOXMX-UHFFFAOYSA-N 0.000 description 2
- LTQBZSDWSKDYKS-UHFFFAOYSA-N 3,6-dibromo-8-chloronaphthalen-2-ol Chemical compound C1=C(Br)C=C2C=C(Br)C(O)=CC2=C1Cl LTQBZSDWSKDYKS-UHFFFAOYSA-N 0.000 description 2
- NSSOSHDCWCMNDM-UHFFFAOYSA-N 3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile Chemical compound C1=C(C#N)C2=CC(O)=CC=C2C=C1C1=CC=C(O)C(F)=C1 NSSOSHDCWCMNDM-UHFFFAOYSA-N 0.000 description 2
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 2
- RXCBJNIIHBZSRT-UHFFFAOYSA-N 3-bromo-1,8-dichloro-6-(4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=CC(OC)=CC=C1C1=CC(Cl)=C(C(Cl)=C(O)C(Br)=C2)C2=C1 RXCBJNIIHBZSRT-UHFFFAOYSA-N 0.000 description 2
- AMXGXCGFMJCTHW-UHFFFAOYSA-N 3-bromo-8-chloro-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=C(Br)C=C(C#N)C2=C(Cl)C(O)=CC=C21 AMXGXCGFMJCTHW-UHFFFAOYSA-N 0.000 description 2
- BOLNYJLZQDSIKH-UHFFFAOYSA-N 3-chloro-4-(6-methoxynaphthalen-2-yl)phenol Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C1=CC=C(O)C=C1Cl BOLNYJLZQDSIKH-UHFFFAOYSA-N 0.000 description 2
- GPRPSJPFAAGLCA-UHFFFAOYSA-N 4-bromo-2,6-difluorophenol Chemical compound OC1=C(F)C=C(Br)C=C1F GPRPSJPFAAGLCA-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- SKPPZWVFPOQPOT-UHFFFAOYSA-N 6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1 SKPPZWVFPOQPOT-UHFFFAOYSA-N 0.000 description 2
- CMJIGLJKMWCPGF-UHFFFAOYSA-N 6-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-1-nitronaphthalen-2-ol Chemical compound C1=CC(O[Si](C)(C)C(C)(C)C)=CC=C1C1=CC=C(C(=C(O)C=C2)[N+]([O-])=O)C2=C1 CMJIGLJKMWCPGF-UHFFFAOYSA-N 0.000 description 2
- FREZGNRMOFFLRR-UHFFFAOYSA-N 6-bromo-1-nitronaphthalen-2-ol Chemical compound C1=C(Br)C=CC2=C([N+]([O-])=O)C(O)=CC=C21 FREZGNRMOFFLRR-UHFFFAOYSA-N 0.000 description 2
- UDGWTXRLMHXQKB-UHFFFAOYSA-N 7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=CC=C(C#N)C2=CC(O)=CC=C21 UDGWTXRLMHXQKB-UHFFFAOYSA-N 0.000 description 2
- GABLTKRIYDNDIN-UHFFFAOYSA-N 7-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CCC(=O)C2=CC(OC)=CC=C21 GABLTKRIYDNDIN-UHFFFAOYSA-N 0.000 description 2
- IBAXOSUDTXPJSA-UHFFFAOYSA-N 7-methoxy-3,4-dihydronaphthalene-1-carbonitrile Chemical compound C1CC=C(C#N)C2=CC(OC)=CC=C21 IBAXOSUDTXPJSA-UHFFFAOYSA-N 0.000 description 2
- CTAKVWPTULZNMM-UHFFFAOYSA-N 7-methoxynaphthalene-1-carbonitrile Chemical compound C1=CC=C(C#N)C2=CC(OC)=CC=C21 CTAKVWPTULZNMM-UHFFFAOYSA-N 0.000 description 2
- JGNLGAHBYIYVKI-UHFFFAOYSA-N 8-bromo-7-hydroxy-3-(4-methoxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(OC)=CC=C1C1=CC(C#N)=C(C(Br)=C(O)C=C2)C2=C1 JGNLGAHBYIYVKI-UHFFFAOYSA-N 0.000 description 2
- RKTCZJPBJNXBOV-UHFFFAOYSA-N 8-chloro-3-(3-fluoro-4-methoxyphenyl)-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C#N)=C(C(Cl)=C(O)C=C2)C2=C1 RKTCZJPBJNXBOV-UHFFFAOYSA-N 0.000 description 2
- DBJGSGXFSULKJN-UHFFFAOYSA-N 8-chloro-6-(4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=CC(OC)=CC=C1C1=CC(Cl)=C(C=C(O)C=C2)C2=C1 DBJGSGXFSULKJN-UHFFFAOYSA-N 0.000 description 2
- XSMAIDLOXKONHB-UHFFFAOYSA-N 8-chloronaphthalen-2-ol Chemical compound C1=CC=C(Cl)C2=CC(O)=CC=C21 XSMAIDLOXKONHB-UHFFFAOYSA-N 0.000 description 2
- GLRJXUHPMBWHNQ-UHFFFAOYSA-N 8-fluoro-6-(3-fluoro-4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(F)=C(C=C(O)C=C2)C2=C1 GLRJXUHPMBWHNQ-UHFFFAOYSA-N 0.000 description 2
- BBPLRENRRYYWPO-UHFFFAOYSA-N 8-fluoronaphthalen-2-ol Chemical compound C1=CC=C(F)C2=CC(O)=CC=C21 BBPLRENRRYYWPO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102000013918 Apolipoproteins E Human genes 0.000 description 2
- 108010025628 Apolipoproteins E Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010003693 Atrophic vulvovaginitis Diseases 0.000 description 2
- 229910014265 BrCl Inorganic materials 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-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
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 241000699684 Meriones unguiculatus Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- YNXWDNGKHFQYKP-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC(F)=C2C(Cl)=C(C=O)C=CC2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC(F)=C2C(Cl)=C(C=O)C=CC2=C1 YNXWDNGKHFQYKP-UHFFFAOYSA-N 0.000 description 2
- TZPAVDPVRQHVNB-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC=C(C=CC(C=O)=C2)C2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC=C(C=CC(C=O)=C2)C2=C1 TZPAVDPVRQHVNB-UHFFFAOYSA-N 0.000 description 2
- IYGSDPNPTIUKAK-UHFFFAOYSA-N OC(C=CC(C1=CC=C2C(Cl)=C(C=O)C=CC2=C1)=C1)=C1Cl Chemical compound OC(C=CC(C1=CC=C2C(Cl)=C(C=O)C=CC2=C1)=C1)=C1Cl IYGSDPNPTIUKAK-UHFFFAOYSA-N 0.000 description 2
- RAPGMEMAZMGJQL-UHFFFAOYSA-N OC1=CC=CC(C2=CC=C(C=CC(C=O)=C3)C3=C2)=C1 Chemical compound OC1=CC=CC(C2=CC=C(C=CC(C=O)=C3)C3=C2)=C1 RAPGMEMAZMGJQL-UHFFFAOYSA-N 0.000 description 2
- 206010030247 Oestrogen deficiency Diseases 0.000 description 2
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 2
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 102100025803 Progesterone receptor Human genes 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 235000021068 Western diet Nutrition 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- LKBREHQHCVRNFR-UHFFFAOYSA-K [B+3].[Br-].[Br-].[Br-] Chemical compound [B+3].[Br-].[Br-].[Br-] LKBREHQHCVRNFR-UHFFFAOYSA-K 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- UOIFTOBIGNZZSO-UHFFFAOYSA-N acetic acid;ethyl acetate;hexane Chemical compound CC(O)=O.CCCCCC.CCOC(C)=O UOIFTOBIGNZZSO-UHFFFAOYSA-N 0.000 description 2
- MOQOOKGPCBQMCY-UHFFFAOYSA-N acetic acid;hexane Chemical compound CC(O)=O.CCCCCC MOQOOKGPCBQMCY-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 210000000080 chela (arthropods) Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000005261 decarburization Methods 0.000 description 2
- 238000005238 degreasing Methods 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 2
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 2
- BTYPWVDULNVBHU-UHFFFAOYSA-N disodium;dinitrate Chemical compound [Na+].[Na+].[O-][N+]([O-])=O.[O-][N+]([O-])=O BTYPWVDULNVBHU-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 208000037906 ischaemic injury Diseases 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000005567 liquid scintillation counting Methods 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 230000009245 menopause Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 230000002969 morbid Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- ALNWQAFPXMGLTJ-UHFFFAOYSA-N n-(7-hydroxynaphthalen-1-yl)acetamide Chemical compound C1=C(O)C=C2C(NC(=O)C)=CC=CC2=C1 ALNWQAFPXMGLTJ-UHFFFAOYSA-N 0.000 description 2
- ROIBKRTYRRRTPJ-UHFFFAOYSA-N n-(7-methoxynaphthalen-1-yl)acetamide Chemical compound C1=CC=C(NC(C)=O)C2=CC(OC)=CC=C21 ROIBKRTYRRRTPJ-UHFFFAOYSA-N 0.000 description 2
- KPTRDYONBVUWPD-UHFFFAOYSA-N naphthalen-2-ylboronic acid Chemical compound C1=CC=CC2=CC(B(O)O)=CC=C21 KPTRDYONBVUWPD-UHFFFAOYSA-N 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 108090000468 progesterone receptors Proteins 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000036301 sexual development Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical compound O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 210000001258 synovial membrane Anatomy 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- ADBNMUAXSPOANR-UHFFFAOYSA-N tert-butyl-(3,6-dibromo-8-chloronaphthalen-2-yl)oxy-dimethylsilane Chemical compound C1=C(Br)C=C2C=C(Br)C(O[Si](C)(C)C(C)(C)C)=CC2=C1Cl ADBNMUAXSPOANR-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 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
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LTEHWCSSIHAVOQ-UHFFFAOYSA-N tripropyl borate Chemical compound CCCOB(OCCC)OCCC LTEHWCSSIHAVOQ-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- WZUVPPKBWHMQCE-XJKSGUPXSA-N (+)-haematoxylin Chemical compound C12=CC(O)=C(O)C=C2C[C@]2(O)[C@H]1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-XJKSGUPXSA-N 0.000 description 1
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- RRCMGJCFMJBHQC-UHFFFAOYSA-N (2-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1Cl RRCMGJCFMJBHQC-UHFFFAOYSA-N 0.000 description 1
- XELWCBVAXIEQLZ-UHFFFAOYSA-N (2-fluoro-4-methoxyphenyl) trifluoromethanesulfonate Chemical compound COC1=CC=C(OS(=O)(=O)C(F)(F)F)C(F)=C1 XELWCBVAXIEQLZ-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- NLLGFYPSWCMUIV-UHFFFAOYSA-N (3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1 NLLGFYPSWCMUIV-UHFFFAOYSA-N 0.000 description 1
- XSWCWQVOFJVATA-UHFFFAOYSA-N (4-bromo-3-methoxyphenyl) 4-methylbenzenesulfonate;[4-(6-hydroxynaphthalen-2-yl)-3-methoxyphenyl] 4-methylbenzenesulfonate Chemical compound C1=C(Br)C(OC)=CC(OS(=O)(=O)C=2C=CC(C)=CC=2)=C1.C=1C=C(C=2C=C3C=CC(O)=CC3=CC=2)C(OC)=CC=1OS(=O)(=O)C1=CC=C(C)C=C1 XSWCWQVOFJVATA-UHFFFAOYSA-N 0.000 description 1
- AMSQNQJCBXQYEX-UHFFFAOYSA-N (4-methoxy-2-methylphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C(C)=C1 AMSQNQJCBXQYEX-UHFFFAOYSA-N 0.000 description 1
- PXVDQGVAZBTFIB-UHFFFAOYSA-N (4-methoxy-3-methylphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1C PXVDQGVAZBTFIB-UHFFFAOYSA-N 0.000 description 1
- HBZBAMXERPYTFS-SECBINFHSA-N (4S)-2-(6,7-dihydro-5H-pyrrolo[3,2-f][1,3]benzothiazol-2-yl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)[C@H]1CSC(=N1)c1nc2cc3CCNc3cc2s1 HBZBAMXERPYTFS-SECBINFHSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WFLOTYSKFUPZQB-OWOJBTEDSA-N (e)-1,2-difluoroethene Chemical group F\C=C\F WFLOTYSKFUPZQB-OWOJBTEDSA-N 0.000 description 1
- BQCIDUSAKPWEOX-UHFFFAOYSA-N 1,1-Difluoroethene Chemical group FC(F)=C BQCIDUSAKPWEOX-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- AHFMSNDOYCFEPH-UHFFFAOYSA-N 1,2-difluoroethane Chemical compound FCCF AHFMSNDOYCFEPH-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YYRSVHXQHZEHFE-UHFFFAOYSA-N 1,5-dichloro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1Cl YYRSVHXQHZEHFE-UHFFFAOYSA-N 0.000 description 1
- ZXCATAQIUROCOY-UHFFFAOYSA-N 1,6-dibromo-8-fluoronaphthalen-2-ol Chemical compound C1=C(Br)C=C(F)C2=C(Br)C(O)=CC=C21 ZXCATAQIUROCOY-UHFFFAOYSA-N 0.000 description 1
- WWRCMNKATXZARA-UHFFFAOYSA-N 1-Isopropyl-2-methylbenzene Chemical compound CC(C)C1=CC=CC=C1C WWRCMNKATXZARA-UHFFFAOYSA-N 0.000 description 1
- OOTXNQBDWFJMNN-UHFFFAOYSA-N 1-bromo-2,5-difluoro-4-methoxybenzene Chemical compound COC1=CC(F)=C(Br)C=C1F OOTXNQBDWFJMNN-UHFFFAOYSA-N 0.000 description 1
- JTLAIKFGRHDNQM-UHFFFAOYSA-N 1-bromo-2-fluoroethane Chemical compound FCCBr JTLAIKFGRHDNQM-UHFFFAOYSA-N 0.000 description 1
- BLZNSXFQRKVFRP-UHFFFAOYSA-N 1-bromo-4-methoxy-2-methylbenzene Chemical compound COC1=CC=C(Br)C(C)=C1 BLZNSXFQRKVFRP-UHFFFAOYSA-N 0.000 description 1
- IMSNDBBRDWHYII-UHFFFAOYSA-N 1-chloro-6-(4-methoxy-2-methylphenyl)naphthalen-2-ol Chemical compound CC1=CC(OC)=CC=C1C1=CC=C(C(Cl)=C(O)C=C2)C2=C1 IMSNDBBRDWHYII-UHFFFAOYSA-N 0.000 description 1
- JCSOHQQDEQASQG-UHFFFAOYSA-N 1-chloro-6-methoxy-2-(4-methoxyphenyl)naphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C=C(OC)C=C2)C2=C1Cl JCSOHQQDEQASQG-UHFFFAOYSA-N 0.000 description 1
- NZRUFBUPRLIWCP-UHFFFAOYSA-N 1-chloro-8-fluoro-6-(3-fluoro-4-methoxyphenyl)naphthalen-2-ol Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(F)=C(C(Cl)=C(O)C=C2)C2=C1 NZRUFBUPRLIWCP-UHFFFAOYSA-N 0.000 description 1
- 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- PEOUMHZMJVTMBI-UHFFFAOYSA-N 2,6-difluoro-4-(6-methoxynaphthalen-2-yl)phenol Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C1=CC(F)=C(O)C(F)=C1 PEOUMHZMJVTMBI-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- GEJMNTXYFBBTFH-UHFFFAOYSA-N 2-bromo-1,3-difluoro-5-methoxybenzene Chemical compound COC1=CC(F)=C(Br)C(F)=C1 GEJMNTXYFBBTFH-UHFFFAOYSA-N 0.000 description 1
- IIRGBQTVRQCTDU-UHFFFAOYSA-N 2-methoxy-6-(4-methoxyphenyl)-1-phenylnaphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(=C(OC)C=C2)C=3C=CC=CC=3)C2=C1 IIRGBQTVRQCTDU-UHFFFAOYSA-N 0.000 description 1
- CNRLBMUETFJRMO-UHFFFAOYSA-N 2-methoxy-6-phenylnaphthalene Chemical compound C1=CC2=CC(OC)=CC=C2C=C1C1=CC=CC=C1 CNRLBMUETFJRMO-UHFFFAOYSA-N 0.000 description 1
- XYRQNLVGHSWINI-UHFFFAOYSA-N 2-methoxy-7-(4-methoxyphenyl)naphthalene Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C=CC(OC)=C2)C2=C1 XYRQNLVGHSWINI-UHFFFAOYSA-N 0.000 description 1
- FAOJNWOJCPKVTM-UHFFFAOYSA-N 2-methoxynaphthalen-1-amine Chemical compound C1=CC=CC2=C(N)C(OC)=CC=C21 FAOJNWOJCPKVTM-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- OTXUPCWFVTVAQM-UHFFFAOYSA-N 3-(3-fluoro-4-methoxyphenyl)-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C#N)=C(C=C(O)C=C2)C2=C1 OTXUPCWFVTVAQM-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- KWIVRAVCZJXOQC-UHFFFAOYSA-N 3h-oxathiazole Chemical compound N1SOC=C1 KWIVRAVCZJXOQC-UHFFFAOYSA-N 0.000 description 1
- RELAJOWOFXGXHI-UHFFFAOYSA-N 3h-oxathiole Chemical compound C1SOC=C1 RELAJOWOFXGXHI-UHFFFAOYSA-N 0.000 description 1
- DWNXGZBXFDNKOR-UHFFFAOYSA-N 4-bromo-2-fluoro-1-methoxybenzene Chemical compound COC1=CC=C(Br)C=C1F DWNXGZBXFDNKOR-UHFFFAOYSA-N 0.000 description 1
- RYVOZMPTISNBDB-UHFFFAOYSA-N 4-bromo-2-fluorophenol Chemical compound OC1=CC=C(Br)C=C1F RYVOZMPTISNBDB-UHFFFAOYSA-N 0.000 description 1
- FQEYHIPPYOSPLF-UHFFFAOYSA-N 4-bromo-3-chlorophenol Chemical compound OC1=CC=C(Br)C(Cl)=C1 FQEYHIPPYOSPLF-UHFFFAOYSA-N 0.000 description 1
- MPCCNXGZCOXPMG-UHFFFAOYSA-N 4-bromobenzene-1,3-diol Chemical compound OC1=CC=C(Br)C(O)=C1 MPCCNXGZCOXPMG-UHFFFAOYSA-N 0.000 description 1
- NIRHUNSXEDESLN-UHFFFAOYSA-N 4-naphthalen-2-ylphenol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C=CC=C2)C2=C1 NIRHUNSXEDESLN-UHFFFAOYSA-N 0.000 description 1
- JOGUPGIWMKIUQV-UHFFFAOYSA-N 5-chloro-6-(4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1Cl JOGUPGIWMKIUQV-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical class OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- UVRXGDFVCKYIGU-UHFFFAOYSA-N 6-(3-chloro-4-hydroxyphenyl)naphthalen-2-ol Chemical compound C1=CC2=CC(O)=CC=C2C=C1C1=CC=C(O)C(Cl)=C1 UVRXGDFVCKYIGU-UHFFFAOYSA-N 0.000 description 1
- DSBWWPDVDPKMHN-UHFFFAOYSA-N 6-(4-hydroxyphenyl)-1-methoxynaphthalen-2-ol Chemical compound C=1C=C2C(OC)=C(O)C=CC2=CC=1C1=CC=C(O)C=C1 DSBWWPDVDPKMHN-UHFFFAOYSA-N 0.000 description 1
- NBXFNIUSTYUSRR-UHFFFAOYSA-N 6-(4-hydroxyphenyl)-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC(O)=CC=C1C1=CC=C(C(=O)CCC2)C2=C1 NBXFNIUSTYUSRR-UHFFFAOYSA-N 0.000 description 1
- KSOKMKCLAWKUAK-UHFFFAOYSA-N 6-bromo-1-fluoronaphthalen-2-ol Chemical compound C1=C(Br)C=CC2=C(F)C(O)=CC=C21 KSOKMKCLAWKUAK-UHFFFAOYSA-N 0.000 description 1
- NDCOKFWKXFDSKD-UHFFFAOYSA-N 6-bromo-8-fluoronaphthalen-2-ol Chemical compound C1=C(Br)C=C(F)C2=CC(O)=CC=C21 NDCOKFWKXFDSKD-UHFFFAOYSA-N 0.000 description 1
- WWPKRXOOVICNJY-UHFFFAOYSA-N 6-methoxynaphthalen-2-ol Chemical compound C1=C(O)C=CC2=CC(OC)=CC=C21 WWPKRXOOVICNJY-UHFFFAOYSA-N 0.000 description 1
- JHRTUEXAHFMWID-UHFFFAOYSA-N 6-phenylnaphthalene-2-carbaldehyde Chemical compound C1=CC2=CC(C=O)=CC=C2C=C1C1=CC=CC=C1 JHRTUEXAHFMWID-UHFFFAOYSA-N 0.000 description 1
- ZNQNTFMRLVTHQY-UHFFFAOYSA-N 7-hydroxy-3-(4-methoxyphenyl)naphthalene-1-carbonitrile Chemical compound C1=CC(OC)=CC=C1C1=CC(C#N)=C(C=C(O)C=C2)C2=C1 ZNQNTFMRLVTHQY-UHFFFAOYSA-N 0.000 description 1
- USDTUDXPZDOQQC-UHFFFAOYSA-N 7-phenylnaphthalene-2-carbaldehyde Chemical compound C1(=CC=CC=C1)C1=CC=C2C=CC(=CC2=C1)C=O USDTUDXPZDOQQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KVHHMYZBFBSVDI-UHFFFAOYSA-N 8-aminonaphthalen-2-ol Chemical compound C1=C(O)C=C2C(N)=CC=CC2=C1 KVHHMYZBFBSVDI-UHFFFAOYSA-N 0.000 description 1
- FTNHSKRFRJSDLE-UHFFFAOYSA-N 8-chloro-7-hydroxynaphthalene-1-carbonitrile Chemical compound C1=CC=C(C#N)C2=C(Cl)C(O)=CC=C21 FTNHSKRFRJSDLE-UHFFFAOYSA-N 0.000 description 1
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 102100032187 Androgen receptor Human genes 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 206010002650 Anorexia nervosa and bulimia Diseases 0.000 description 1
- 206010065558 Aortic arteriosclerosis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 208000004746 Atrophic Vaginitis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- NVHNTEWDUMJHQW-UHFFFAOYSA-N CC1=C(C=O)C=CC2=CC(C(C=C3)=CC=C3O)=CC=C12 Chemical compound CC1=C(C=O)C=CC2=CC(C(C=C3)=CC=C3O)=CC=C12 NVHNTEWDUMJHQW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000005403 Casein Kinases Human genes 0.000 description 1
- 108010031425 Casein Kinases Proteins 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 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
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- RZSYLLSAWYUBPE-UHFFFAOYSA-L Fast green FCF Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC(O)=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 RZSYLLSAWYUBPE-UHFFFAOYSA-L 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 1
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Natural products C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000031953 Hereditary hemorrhagic telangiectasia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010021703 Indifference Diseases 0.000 description 1
- 206010060820 Joint injury Diseases 0.000 description 1
- 241000102542 Kara Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010024419 Libido decreased Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 206010027514 Metrorrhagia Diseases 0.000 description 1
- 102000003896 Myeloperoxidases Human genes 0.000 description 1
- 108090000235 Myeloperoxidases Proteins 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- WEMNFLMMUWXRDQ-UHFFFAOYSA-N O=CC(C=CC1=C2)=CC1=CC=C2C1=CC(Cl)=CC=C1 Chemical compound O=CC(C=CC1=C2)=CC1=CC=C2C1=CC(Cl)=CC=C1 WEMNFLMMUWXRDQ-UHFFFAOYSA-N 0.000 description 1
- QJPSVJMBPXHZRX-UHFFFAOYSA-N O=CC(C=CC1=CC(C2=CC=CC=C2)=CC=C11)=C1Cl Chemical compound O=CC(C=CC1=CC(C2=CC=CC=C2)=CC=C11)=C1Cl QJPSVJMBPXHZRX-UHFFFAOYSA-N 0.000 description 1
- CLRXBOGDDVYPGX-UHFFFAOYSA-N OC(C=C1)=CC(Cl)=C1C1=CC=C(C=C(C=O)C=C2)C2=C1 Chemical compound OC(C=C1)=CC(Cl)=C1C1=CC=C(C=C(C=O)C=C2)C2=C1 CLRXBOGDDVYPGX-UHFFFAOYSA-N 0.000 description 1
- OJDIMIPHDQOYOT-UHFFFAOYSA-N OC(C=C1)=CC(Cl)=C1C1=CC=C2C(Cl)=C(C=O)C=CC2=C1 Chemical compound OC(C=C1)=CC(Cl)=C1C1=CC=C2C(Cl)=C(C=O)C=CC2=C1 OJDIMIPHDQOYOT-UHFFFAOYSA-N 0.000 description 1
- ZWEXKCGATDJTBE-UHFFFAOYSA-N OC(C=C1)=CC(F)=C1C1=CC=C(C=C(C=O)C=C2)C2=C1 Chemical compound OC(C=C1)=CC(F)=C1C1=CC=C(C=C(C=O)C=C2)C2=C1 ZWEXKCGATDJTBE-UHFFFAOYSA-N 0.000 description 1
- XIHZAGIHQRKKPE-UHFFFAOYSA-N OC(C=C1)=CC(F)=C1C1=CC=C2C(Cl)=C(C=O)C=CC2=C1 Chemical compound OC(C=C1)=CC(F)=C1C1=CC=C2C(Cl)=C(C=O)C=CC2=C1 XIHZAGIHQRKKPE-UHFFFAOYSA-N 0.000 description 1
- XUDZWNHBTMIUQJ-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC(Cl)=C(C=C(C=O)C(Br)=C2)C2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC(Cl)=C(C=C(C=O)C(Br)=C2)C2=C1 XUDZWNHBTMIUQJ-UHFFFAOYSA-N 0.000 description 1
- KUGYJEFSJJZMCW-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC(Cl)=C(C=C(C=O)C=C2)C2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC(Cl)=C(C=C(C=O)C=C2)C2=C1 KUGYJEFSJJZMCW-UHFFFAOYSA-N 0.000 description 1
- JUKRIBCWTMZMPM-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC(F)=C(C=C(C=O)C=C2)C2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC(F)=C(C=C(C=O)C=C2)C2=C1 JUKRIBCWTMZMPM-UHFFFAOYSA-N 0.000 description 1
- HJJOKBUYNDEGKA-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC=C2C(Br)=C(C=O)C=CC2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC=C2C(Br)=C(C=O)C=CC2=C1 HJJOKBUYNDEGKA-UHFFFAOYSA-N 0.000 description 1
- DZGGUBQKSYJCFY-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC=C2C(C3=CC=CC=C3)=C(C=O)C=CC2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC=C2C(C3=CC=CC=C3)=C(C=O)C=CC2=C1 DZGGUBQKSYJCFY-UHFFFAOYSA-N 0.000 description 1
- MCGLRKIJSCKWND-UHFFFAOYSA-N OC(C=C1)=CC=C1C1=CC=C2C(F)=C(C=O)C=CC2=C1 Chemical compound OC(C=C1)=CC=C1C1=CC=C2C(F)=C(C=O)C=CC2=C1 MCGLRKIJSCKWND-UHFFFAOYSA-N 0.000 description 1
- UKMSKZBUVVZIRZ-UHFFFAOYSA-N OC(C=CC(C1=CC(F)=C(C=C(C=O)C=C2)C2=C1)=C1)=C1F Chemical compound OC(C=CC(C1=CC(F)=C(C=C(C=O)C=C2)C2=C1)=C1)=C1F UKMSKZBUVVZIRZ-UHFFFAOYSA-N 0.000 description 1
- VDXOYTDDWVQTHH-UHFFFAOYSA-N OC(C=CC(C1=CC(F)=C2C(Cl)=C(C=O)C=CC2=C1)=C1)=C1F Chemical compound OC(C=CC(C1=CC(F)=C2C(Cl)=C(C=O)C=CC2=C1)=C1)=C1F VDXOYTDDWVQTHH-UHFFFAOYSA-N 0.000 description 1
- LASOTYIHZWDNEO-UHFFFAOYSA-N OC(C=CC(C1=CC=C(C=C(C=O)C=C2)C2=C1)=C1)=C1F Chemical compound OC(C=CC(C1=CC=C(C=C(C=O)C=C2)C2=C1)=C1)=C1F LASOTYIHZWDNEO-UHFFFAOYSA-N 0.000 description 1
- WMHFGAPGEMWTIQ-UHFFFAOYSA-N OC1=CC=CC(C2=CC=C(C=C(C=O)C=C3)C3=C2)=C1 Chemical compound OC1=CC=CC(C2=CC=C(C=C(C=O)C=C3)C3=C2)=C1 WMHFGAPGEMWTIQ-UHFFFAOYSA-N 0.000 description 1
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 1
- 102000005891 Pancreatic ribonuclease Human genes 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000219098 Parthenocissus Species 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 206010036049 Polycystic ovaries Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 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
- 241000656145 Thyrsites atun Species 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 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
- LSNYXBYQGXHAEN-UHFFFAOYSA-N [3-bromo-8-chloro-1-(4-methoxyphenyl)naphthalen-2-yl]oxy-tert-butyl-dimethylsilane Chemical compound C1=CC(OC)=CC=C1C1=C(O[Si](C)(C)C(C)(C)C)C(Br)=CC2=CC=CC(Cl)=C12 LSNYXBYQGXHAEN-UHFFFAOYSA-N 0.000 description 1
- SKNGKLFZBUKMAJ-UHFFFAOYSA-N [4-(6-hydroxynaphthalen-2-yl)-3-methoxyphenyl] 4-methylbenzenesulfonate Chemical compound C=1C=C(C=2C=C3C=CC(O)=CC3=CC=2)C(OC)=CC=1OS(=O)(=O)C1=CC=C(C)C=C1 SKNGKLFZBUKMAJ-UHFFFAOYSA-N 0.000 description 1
- CUGZTZSJLKHQGS-UHFFFAOYSA-M [Na+].[SH-].OS(O)(=O)=O Chemical compound [Na+].[SH-].OS(O)(=O)=O CUGZTZSJLKHQGS-UHFFFAOYSA-M 0.000 description 1
- HPJJCHITJGXPPL-UHFFFAOYSA-N [O-][N+](C1=C(C=O)C=CC2=CC(C(C=C3)=CC=C3O)=CC=C12)=O Chemical compound [O-][N+](C1=C(C=O)C=CC2=CC(C(C=C3)=CC=C3O)=CC=C12)=O HPJJCHITJGXPPL-UHFFFAOYSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 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
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 201000001962 aortic atherosclerosis Diseases 0.000 description 1
- 210000002403 aortic endothelial cell Anatomy 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 201000010316 atrophic vulva Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 230000015624 blood vessel development Effects 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- ANYNYRPVUUZMGG-UHFFFAOYSA-N bromobenzene;magnesium Chemical compound [Mg].BrC1=CC=CC=C1 ANYNYRPVUUZMGG-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000005961 cardioprotection Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 210000003321 cartilage cell Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 229960003608 clomifene Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 238000011278 co-treatment Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 230000008828 contractile function Effects 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000005131 dialkylammonium group Chemical group 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940085363 evista Drugs 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 206010016629 fibroma Diseases 0.000 description 1
- 206010049444 fibromatosis Diseases 0.000 description 1
- 210000002082 fibula Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 210000004186 follicle cell Anatomy 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- HLUCICHZHWJHLL-UHFFFAOYSA-N hematein Chemical compound C12=CC=C(O)C(O)=C2OCC2(O)C1=C1C=C(O)C(=O)C=C1C2 HLUCICHZHWJHLL-UHFFFAOYSA-N 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 231100000546 inhibition of ovulation Toxicity 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000002189 macula lutea Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000024714 major depressive disease Diseases 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
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 230000003821 menstrual periods Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-WKUFJEKOSA-N oestradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-WKUFJEKOSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- JBPWRHDFVVEDTJ-UHFFFAOYSA-N oxadithiole Chemical compound O1SSC=C1 JBPWRHDFVVEDTJ-UHFFFAOYSA-N 0.000 description 1
- AZHVQJLDOFKHPZ-UHFFFAOYSA-N oxathiazine Chemical compound O1SN=CC=C1 AZHVQJLDOFKHPZ-UHFFFAOYSA-N 0.000 description 1
- CQDAMYNQINDRQC-UHFFFAOYSA-N oxatriazole Chemical compound C1=NN=NO1 CQDAMYNQINDRQC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000003209 petroleum derivative Substances 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- XPPWLXNXHSNMKC-UHFFFAOYSA-N phenylboron Chemical compound [B]C1=CC=CC=C1 XPPWLXNXHSNMKC-UHFFFAOYSA-N 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 201000010808 postmenopausal atrophic vaginitis Diseases 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 210000003456 pulmonary alveoli Anatomy 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- ZOKPDCKJLXVQPL-UHFFFAOYSA-N pyridine;hydrochloride Chemical compound Cl.C1=CC=NC=C1.C1=CC=NC=C1 ZOKPDCKJLXVQPL-UHFFFAOYSA-N 0.000 description 1
- NHDHVHZZCFYRSB-UHFFFAOYSA-N pyriproxyfen Chemical compound C=1C=CC=NC=1OC(C)COC(C=C1)=CC=C1OC1=CC=CC=C1 NHDHVHZZCFYRSB-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
- 239000002287 radioligand Substances 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000005000 reproductive tract Anatomy 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000004406 stave cell Anatomy 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000005186 women's health Effects 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
- A61K31/055—Phenols the aromatic ring being substituted by halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
- C07C205/25—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups bound to carbon atoms of six-membered aromatic rings being part of a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/26—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups and being further substituted by halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/14—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with at least one hydroxy group on a condensed ring system containing two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/38—Halogenated derivatives with at least one hydroxy group on a condensed ring system containing two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Reproductive Health (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Obesity (AREA)
- Rheumatology (AREA)
- Gynecology & Obstetrics (AREA)
- Emergency Medicine (AREA)
- Biochemistry (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Toxicology (AREA)
- Hospice & Palliative Care (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
Abstract
本发明提供了一种式(I)雌激素受体调节剂或其药学可接受的盐,具有结构(I),其中R1,R2,R3,R4,R5,R6,R7,R8,R9和R10如说明书所定义。
Description
发明背景
本发明涉及取代的苯基萘,其用作雌激素剂。
已经有文献充分证明了雌激素在哺乳动物组织中的多向性效应,现在认为雌激素会影响许多器官系统[Mendelsohn and Karas,NewEngland Journal of Medicine 340:1801-1811(1999),Epperson等人,Psychosomatic Medicine 61:676-697(1999),Crandall,Journal ofWomens Health & Gender Based Medicine 8:1155-1166(1999),Monkand Brodaty,Dementia & Geriatric Cognitive Disorders 11:1-10(2000),Hurn and Macrae,Journal of Cerebral Blood Flow &Metabolism 20:631-652(2000),Calvin,Maturitas 34:195-210(2000),Finking等人,Zeitschrift fur Kardiologie 89:442-453(2000),Brincat,Maturitas 35:107-117(2000),Al-Azzawi,Postgraduate MedicalJournal 77:292-304(2001)]。雌激素可能以若干方式影响组织,其作用机理的最大特征在于它们与雌激素受体相互作用,该受体导致在基因转录中的变化。雌激素受体是配体-触发的转录因子,属于核激素受体总科。该族的其它成员包括黄体酮受体、雄激素受体、糖皮质激素受体和盐皮质激素受体。当结合到配体上时,这些受体二聚然后可激活基因转录,即,通过直接与DNA上的特定序列(通常称为应答码)结合,或通过与其它转录因子(诸如AP1)相互作用,后者然后直接结合特定的DNA序列[Moggs and Orphanides,EMBO Reports 2:775-781(2001),Hall等人,Journal of Biological Chemistry 276:36869-36872(2001),McDonnell,Principles Of Molecular Regulation.p351-361(2000)]。一类″共同调节(coregulatory)″蛋白质还可以与配体结合的受体相互作用,进一步调节其转录活性[McKenna等人,EndocrineReviews 20:321-344(1999)]。还已经表明,雌激素受体可以配体-依赖型和独立型两种方式抑制NFκB-调节的转录作用[Quaedackers等人,Endocrinology 142:1156-1166(2001),Bhat等人,Journal of SteroidBiochemistry & Molecular Biology 67:233-240(1998),Pelzer等人,Biochemical & Biophysical Research Communications 286:1153-7(2001)]。
雌激素受体还可以被磷酸化作用激活。这种磷酸化作用通过诸如EGF的生长因子调节,并导致在没有配体存在的情况下基因转录的改变[Moggs and Orphanides,EMBO Reports 2:775-781(2001),Hall等人,Journal of Biological Chemistry 276:36869-36872(2001)]。
雌激素影响细胞的次要特征方式是通过所谓的膜受体。这种受体的存在是有争议的,但是已经充分证明了雌激素可引起来自细胞的非常快速的非基因组应答。负责转换这种效应的分子单元还没有最后被分离,但是有证据建议其至少与雌激素受体的中心形式有关[Levin,Journal of Applied Physiology 91:1860-1867(2001),Levin,Trends in Endocrinology & Metabolism 10:374-377(1999)]。
迄今为止已经发现了两种雌激素受体。第一种雌激素受体是在约15年前克隆的,目前被称为ERα[Green等人,Nature 320:134-9(1986)]。相比之下,第二种雌激素受体形式在最近发现,被称为ERβ[Kuiper等人,Proceedings of the National Academy of Sciences of the United Statesof America 93:5925-5930(1996)]。早期对ERβ的研究集中在确定其对于各种配体的亲合性,实际上发现了其与ERα的一些差别。ERβ的组织分布已经很好地在啮齿动物体内被标记,其与ERα不一致。组织,诸如小鼠和大鼠的子宫,主要表达了ERα,而小鼠和大鼠的肺主要表达ERβ[Couse等人,Endocrinology 138:4613-4621(1997),Kuiper等人,Endocrinology 138:863-870(1997)]。甚至在相同的器官内,可划分出ERα和ERβ的分布。例如,在小鼠的卵巢中,ERβ在卵泡细胞中被高度表达,ERα只限于膜和基质细胞[Sar and Welsch,Endocrinology 140:963-971(1999),Fitzpatrick等人,Endocrinology 140:2581-2591(1999)]。但是,有的实例中,受体是被共同表达的,体外试验证明ERα和ERβ可形成杂二聚物[Cowley等人,Journal of Biological Chemistry 272:19858-19862(1997)]。
已经公开了大量化合物,它们模拟或阻断17β-雌二醇的活性。具有大致和17β-雌二醇一样的生物效应的化合物,最有效的内源雌激素,被称为“雌激素受体拮抗剂”。那些在与17β-雌二醇联合使用时阻断其效应的化合物被称作“雌激素受体拮抗剂”。事实上,在雌激素受体激动剂和雌激素受体拮抗剂活性之间存在一种连续统一体,实际上一些化合物在一些组织中相当于雌激素受体激动剂,在其它组织中相当于雌激素受体拮抗剂。这些具有混合活性的化合物被称作选择性的雌激素受体调节剂(SERMS),它们是有用的治疗剂(例如EVISTA)[McDonnell,Journal of the Society for GynecologicInvestigation 7:S10-S15(2000),Goldstein等人,Human ReproductionUpdate 6:212-224(2000)]。为什么相同的化合物可具有特定的细胞效应,其确切的原因尚未阐明,但是已经暗示是受体构造的差别和/或共同调节(coregulatory)蛋白质的环境的差别。
已经了解了一段时间,当结合配体时,雌激素受体采用不同的构造。但是,仅在最近显示了这些变化的结果和细微差别。ERα和ERβ的三维结构通过与各种配体的共同析晶得到,并清楚地显示了在雌激素受体拮抗剂的存在下螺旋12的复位,所述的雌激素受体拮抗剂空间阻碍了受体-共同调节蛋白质相互作用需要的蛋白质序列[Pike等人,Embo 18:4608-4618(1999),Shiau等人,Cell 95:927-937(1998)]。另外,噬菌体显示技术已经用于确定在不同的配体存在下与雌激素受体相互作用的肽[Paige等人,Proceedings of the National Academy ofSciences of the United States of America 96:3999-4004(1999)]。例如,确定了一种肽,其在与完全的雌激素受体激动剂17β-雌二醇和二乙基己烯雌酚结合时不同。一种不同的肽显示了在与ERα和ERβ结合的氯美酚的区别。这些数据指出,各个配体可能以唯一的方式和不可预测的构造连接到受体上,后者似乎具有不同的生物活性。
如上所述,雌激素影响了生物过程的防护性覆盖物。另外,在已描述了有性别差异(例如疾病频率、对刺激的应答等)的情况下,解释说明可能涉及到男性和女性之间雌激素水平的差别。
发明概述
本发明提供了具有下述结构的式I雌激素化合物或其药学可接受的盐,
其中
R1、R2、R3和R4分别独立地选自氢、羟基、1-6个碳原子的烷基、1-6个碳原子的烷氧基或卤素;
R5、R6、R7、R8、R9和R10分别独立地是氢、1-6个碳原子的烷基、2-7个碳原子的烯基、2-7个碳原子的炔基、卤素、1-6个碳原子的烷氧基、-CN、-CHO、苯基或具有1-4个选自O、N或S的杂原子的5或6-元杂环;其中R5、R6、R7、R8、R9或R10的烷基或烯基部分可任选被羟基、-CN、卤素、三氟烷基、三氟烷氧基、-NO2或苯基取代;其中R5、R6、R7、R8、R9或R10的苯基部分可任选被一、二或三取代,取代基选自1-6个碳原子的烷基、2-7个碳原子的烯基、卤素、羟基、1-6个碳原子的烷氧基、-CN、-NO2、氨基、1-6个碳原子烷基氨基、每个烷基具有1-6个碳原子的二烷基氨基、巯基、1-6个碳原子的烷硫基、1-6个碳原子的烷基亚磺酰基、1-6个碳原子的烷基磺酰基、2-7个碳原子的烷氧羰基、2-7个碳原子的烷基羰基或苯甲酰基;
前提是R1、R2、R3、R4、R7、R8、R9或R10中的至少一个是羟基。
当本发明的化合物含有碱性片段时,可药用盐可由有机酸和无机酸形成,例如乙酸、丙酸、乳酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、邻苯二甲酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、甲磺酸、萘磺酸、苯磺酸、甲苯磺酸、樟脑磺酸和类似的已知的可接受的酸。当本发明的化合物含有酸性片段时,盐可由有机碱和无机碱形成,如碱金属盐(例如钠、锂或钾)、碱土金属盐、铵盐、含1-6的碳原子的烷基铵盐或每个烷基具1-6个碳原子的二烷基铵盐,以及每个烷基含有1-6个碳原子的三烷基铵基盐。
术语烷基和烯基包括支链和直链的片断,例如分别具有1-6个和2-7个碳原子。实例包括甲基、乙基、丙基、丁基、异丙基、仲丁基、叔丁基、乙烯基、烯丙基、1-甲基乙烯基等。当烷基或烯基片断是取代的时,它们可通常被一、二、三或多取代。卤素取代的例子包括1-溴乙烯基、1-氟乙烯基、1,2-二氟乙烯基、2,2-二氟乙烯基、1,2,2-三氟乙烯基、1,2-二溴乙烷、1、2-二氟乙烷、1-氟-2-溴基乙烷、CF2CF3、CF2CF2CF3等。术语卤素包括溴、氯、氟和碘。
优选的5-6元杂环包括呋喃、噻吩、吡咯、异吡咯、吡唑、咪唑、三唑、二硫杂环戊二烯、氧杂硫杂环戊二烯(oxathiole)、异噁唑、噁唑、噻唑、异噻唑、噁二唑、呋咱、噁三唑、二噁唑、噁噻唑(oxathiazole)、四唑、吡喃、吡啶、哒嗪、嘧啶、吡嗪、三嗪、噁秦、噁噻嗪(oxathiazine)或噁二嗪(oxadiazine)。更优选杂环是呋喃、噻吩或吡啶。
正如根据本发明使用的,术语″提供″就提供被发明所包括的化合物或物质而言,是指将这类化合物或物质直接给药,或使用前体药物、衍生物或同型物,其在体内能够形成有效量的所述化合物或物质。
对于本发明的化合物,优选具有下列结构的式I化合物或其药学可接受的盐:
其中
R1和R2分别独立地选自氢、羟基、1-6个碳原子的烷基、2-7个碳原子的烯基和2-7个碳原子的炔基、1-6个碳原子的烷氧基或卤素;
R5、R6、R7、R8和R9分别独立是氢、1-6个碳原子的烷基、2-7个碳原子的烯基、2-7个碳原子的炔基、卤素、1-6个碳原子的烷氧基、-CN、-CHO、三氟甲基、7-12个碳原子的苯基烷基、苯基或具有1-4个选自O、N或S的杂原子的5或6-元杂环;其中R5、R6、R7、R8、R9或R10的烷基或烯基部分可任选被羟基、-CN、卤素、三氟烷基、三氟烷氧基、-NO2或苯基取代;其中R5、R6、R7、R8、R9或R10的苯基部分可任选被一、二或三取代,取代基选自1-6个碳原子的烷基、2-7个碳原子的烯基、卤素、羟基、1-6个碳原子的烷氧基、-CN、-NO2、氨基、1-6个碳原子的烷基氨基、每个烷基具有1-6个碳原子的二烷基氨基、巯基、1-6个碳原子的烷硫基、1-6个碳原子的烷基亚磺酰基、1-6个碳原子的烷基磺酰基、2-7个碳原子的烷氧羰基、2-7个碳原子的烷基羰基或苯甲酰基;
前提是R5或R9中的至少一个不是氢,
或其药学上可接受的盐。
更优选具有下式结构的式I化合物或其药学可接受的盐,
特别优选具有1-4个选自O、N或S的杂原子的5或6-元杂环是呋喃、噻吩或吡啶。尤其优选R5、R6、R7、R8和R9分别独立地是氢、卤素、-CN或2-7个碳原子的炔基。
R1和R2的实例彼此独立地选自氢和氟。
例如,R5、R6、R7、R8和R9可分别独立地是氢、卤素、-CN或2-7个碳原子的炔基。
R5可以是例如选自氢、氟或氰基。
R9可选自氢、氟或氰基。
R6、R7和R8可以彼此独立地是氢。
特别优选具有1-4个选自O、N或S的杂原子的5或6-元杂环是例如呋喃、噻吩或吡啶。
包括上述结构(I)的本发明化合物的实例:
8-氟-6-(3-氟-4-羟基苯基)-2-萘酚;
1-氯-8-氟-6-(3-氟-4-羟基苯基)-2-萘酚;
3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈;
3-(3,5-二氟-4-羟基苯基)-7-羟基-1-萘甲腈;
6-(3-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(3-氯-4-羟基苯基)-2-萘酚;
1-氯-6-(2-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2,5-二氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2,6-二氟-4-羟基苯基)-2-萘酚;
6-(2,5-二氟-4-羟基苯基)-2-萘酚;
6-(3,5-二氟-4-羟基苯基)-2-萘酚;
1-氯-6-(3,5-二氟-4-羟基苯基)-2-萘酚;
6-(2,6-二氟-4-羟基苯基)-2-萘酚;或
8-氯-3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈;
7-(4-羟基苯基)-2-萘酚;
7-(3-羟基苯基)-2-萘酚;
6-(4-羟基苯基)-1-萘酚;
6-苯基-2-萘酚;
6-(3-羟基苯基)-2-萘酚;
6-(3-氯苯基)-2-萘酚;
2-氟-4-(2-萘基)酚;
6-(3-氯-4-羟基酚(phenol))-2-萘酚;
1-氯-6-苯基-2-萘酚;
1-溴-6-(4-羟基苯基)-2-萘酚;
1-氯-6-(4-羟基苯基)-2-萘酚;
1-氟-6-(4-羟基苯基)-2-萘酚;
2-羟基-6-(4-羟基苯基)-1-萘甲腈;
6-(4-羟基苯基)-1-苯基-2-萘酚;
6-(4-羟基苯基)-1-甲基-2-萘酚;
1-氯-6-(3-氯-4-羟基苯基)-2-萘酚;
6-(4-羟基苯基)-1-硝基-2-萘酚;
1-氯-6-(4-羟基-2-甲基苯基)-2-萘酚;
6-(4-羟基-2-甲基苯基)-2-萘酚;
6-(4-羟基-2-甲氧苯基)-2-萘酚;
6-(2-氯-4-羟基苯基)-2-萘酚;
1-氯-6-(2-氯-4-羟基苯基)-2-萘酚;
6-(2-氟-4-羟基苯基)-2-萘酚;
8-氟-6-(4-羟基苯基)-2-萘酚;
1-氯-8-氟-6-(4-羟基苯基)-2-萘酚;
8-氯-6-(4-羟基苯基)-2-萘酚;
1,5-二氯-8-氟-6-(4-羟基苯基)-2-萘酚;
2-氯-4-(2-萘基)苯酚;
3-溴-8-氯-6-(4-羟基苯基)-2-萘酚;
1,8-二氯-6-(4-羟基苯基)-2-萘酚;
3-溴-1,8-二氯-6-(4-羟基苯基)-2-萘酚;
7-羟基-3-(4-羟基苯基)-1-萘甲腈;
8-氯-3-(4-羟基苯基)-7-羟基-1-萘甲腈;
8-溴-7-羟基-3-(4-羟基苯基)-1-萘甲腈;或
其药学可接受的盐。
此外,提供了用于制备包括上述结构(I)的本发明化合物的方法。根据本发明提供了一种用于制备包括上述结构(I)的上述定义的萘基化合物的方法,其包括下述之一:
a)将下式化合物脱烷基或脱芳烷基
其中,R1-R10定义如上,条件是R1、R2、R3、R4、R7、R8、R9或R10中的至少一个是烷氧基或芳烷氧基,得到相应的式I化合物,其中R1、R2、R3、R4、R7、R8、R9或R10中的至少一个是羟基;{例如,下式化合物脱烷基或脱芳烷基,
其中,R和R′中的至少一个式烷基(例如1-6个碳的烷基)或芳烷基(例如7-12个碳的芳烷基),得到相应的式(I)化合物};
或
b)卤式I化合物
其中R10是羟基;{诸如下式化合物:
得到相应的1-卤代萘酚};
或
c)将式I的碱性化合物转化为其盐或反之亦然。
在任何在此描述的反应中,任何反应基团或位置可在反应前被保护,并在反应后将保护基除去。
在制备本发明化合物中使用的反应物可以是从市场购买的或可通过文献中所述的标准方法制备。
在下述路线1-15中描述了本发明一些代表性实例的制备。
路线2
路线3
路线4
路线5
路线7
路线9
路线11
路线12
路线13
路线15
可容易地获得标准药理学试验方法用以确定给定的试验化合物的活性。下面简略地概述若干代表性试验过程,并且可包括本发明典型化合物的数据。全部试验,除了放射性配体结合试验外,可用于测定化合物的雌激素受体激动剂或拮抗剂活性。通常,雌激素受体激动剂活性通过将所述化合物和参考雌激素(例如17β-雌二醇、17α-乙炔基、17β-雌二醇、雌甾酮、二乙基己烯雌酚等)比较进行。雌激素受体拮抗剂活性的测定通常是通过共同处理试验化合物和参考雌激素并与单独使用参考雌激素得到的结果比较进行。在美国专利4418068和5998402中也提供了用于SERMs的标准药理学试验方法,所述的文献引用在此作为参考。
对于ERα和ERβ的结合亲合性的评价
在常规放射性配体结合试验中,评价本发明代表实施例相对于17β-雌二醇对ERα和ERβ受体的亲和力。该试验方法提供了确定对ERα和ERβ受体相对结合亲合性的方法。使用的方法简述如下。
制备用于结合选择性表征的受体萃取物。配体结合区域,在此方便地定义为DNA结合区域的所有下游序列,通过PCR得到,使用了全长cDNA作为模板和引物,引物包含用于亚克隆的适合的限制位点,同时含有用于表达的适合的阅读框。这些模板包含人ERα的氨基酸M250-V595[Green等人,Nature 320:134-9(1986)]和人ERβ的M214-Q530[Ogawa,etal.,Biochemical & Biophysical Research Communications 243:122-6(1998)]。人ERβ被克隆到pET15b(Novagen,Madison WI),其作为Nco1-BamH1片段具有一个C-末端Flag标记物。人ERα被克隆为人ERβ,不同的是加入一个N-末端加了一个His标记物。使用的所有结构的序列通过两个链的全序列确定。
BL21(DE3)细胞用来表达人蛋白质。通常使用10ml过夜培养物接种含有100μg/ml氨苄青霉素的LB介质的1L培养物。在37℃培养过夜后,将IPTG加入得到1mM的最终浓度,培养在25℃进行2小时。离心(1500Xg)收集细胞,洗涤颗粒并将其再悬浮在100ml的50mM Tris-Cl(pH7.4)、150mM NaCl中。将细胞两次通过在12000psi的弗氏压碎器进行细胞溶解。通过在4℃在12,000Xg离心30分钟将溶胞产物澄清,并在-70℃存储。
评价萃取物对特定[3H]-雌二醇的结合。杜尔贝科磷酸盐缓冲盐水(Gibco,1x最后浓度)补充了1mM乙二胺四乙酸,将其用作本试验的缓冲剂。为了优化在分析中使用的受体的量,将[3H]-17β-雌二醇(NewEngland Nuclear;最终浓度=2纳米)±0.6μM二乙基己烯雌酚和100μL的各种稀释度的大肠杆菌溶菌产物加入到高结合掩蔽的微量滴定板的各个穴中(EG & G Wallac)。最终的分析体积是120μl,DMSO的浓度≤1%。在室温培养5-18小时后,吸出未结合的物质,用约300μl的分析缓冲剂冲洗三次滴定板。洗涤后,将135μl的闪烁鸡尾酒试剂(OptiphaseSupermix,EG & G Wallac)加入到各穴中,将板密封并振动至少5分钟,将闪烁剂与残留的洗涤缓冲剂混合。通过液体闪烁计数评价结合放射性(EG & G Wallac Microbeta Plus)。
在确定提供最大特异性结合的各受体制品的稀释度后,用各种稀释度的受体制品评价未标记17β-雌二醇的IC50,以此进一步优化分析。为各个受体制品选择最后的工作稀释度,在该稀释度下,未标记的17β-雌二醇的IC50是2-4纳米。
配体结合竞争试验方法。先将测试化合物溶解在二甲亚砜中,在结合分析中二甲亚砜的最终浓度为≤1%。每个测试化合物在8种稀释度下用作[3H]-17β-雌二醇的未标记竞争剂。通常,一系列稀释度的化合物会同时在人ERα和ERβ上进行测试。结果用测量DPM对测试化合物浓度的曲线图表示。为了拟合剂量-反应曲线,设置了基于转化的权重数据的四参数逻辑模型,IC50被定义为[3H]-雌二醇结合降低50%的化合物浓度。
对于本发明的典型实施例,对ERα和ERβ的结合亲合性(以IC50测定)列于表(1)。
表1:本发明典型化合物的ER结合亲合性 | ||
实施例 | ER-βIC50(nM) | ER-αIC50(nM) |
1a | 0.054 | 0.280 |
1b | 0.570 | 3.140 |
1c | 0.527 | 3.405 |
1d | 0.006 | 0.022 |
1e | 0.0175 | 0.180 |
1f | 0.245 | 0.638 |
1g | 0.374 | 1.345 |
1h | 0.030 | 0.230 |
1i | 0.519 | 1.360 |
1j | 0.242 | 2.120 |
1k | 0.006 | 0.092 |
1l | 0.011 | 0.107 |
1m | 0.468 | 1.785 |
1n | 1.360 | 3.070 |
1o | 0.0127 | 0.266 |
1p | 0.0025 | 0.091 |
1q | 0.114 | 0.884 |
1r | 0.007 | 0.077 |
1s | 0.081 | 1.402 |
1t | 0.657 | 1.720 |
1u | 0.017 | 0.282 |
1v | 0.004 | 0.143 |
1w | 0.032 | 0.356 |
1x | 0.206 | 0.802 |
1y | 0.013 | 0.140 |
1z | 0.0095 | 0.039 |
1aa | 0.027 | 0.074 |
1ab | 0.001 | 0.006 |
1ac | 0.0032 | 0.0032 |
1ad | 0.0020 | 0.024 |
表1:本发明典型化合物的ER结合亲合性 | ||
1ae | 0.0027 | 0.018 |
1af | 0.002 | 0.008 |
1ag | 0.0012 | 0.058 |
1ah | 0.011 | 0.131 |
1ai | 0.0025 | 0.038 |
1aj | 0.0016 | 0.022 |
1ak | 0.0015 | 0.021 |
1al | 0.0011 | 0.040 |
1am | 0.0025 | 0.125 |
1an | 0.0035 | 0.029 |
1ao | 0.0016 | 0.012 |
1ap | 0.002 | 0.029 |
1aq | 0.002 | 0.017 |
1ar | 0.004 | 0.052 |
1as | 0.0085 | 0.043 |
1at | 0.010 | 0.160 |
1au | 0.0023 | 0.105 |
1av | 0.0028 | 0.208 |
1aw | 0.006 | 0.109 |
1ax | 0.011 | 0.299 |
1ay | 0.0084 | 0.092 |
1az | 0.058 | 0.548 |
1ba | 0.011 | 0.519 |
1bb | 0.0095 | 0.095 |
在上述标准药理学试验方法中得到的结果证明本发明的化合物结合雌激素受体的两个亚型。对于ERβ,IC50通常较低,这表明这些化合物优选是ERβ的选择性配体,但是仍然认为其对ERα具有活性。本发明的化合物向显示出基于或至少是部分基于其受体亲和性选择性特征的许多活性。因为本发明化合物结合ERβ的亲合性高于结合ERα的亲合性,其将用于通过ERβ可调节的疾病的治疗或抑制。另外,因为各个受体配体配合物是唯一的,因此其与各种共同调节蛋白质的相互作用是唯一的,根据细胞组织,本发明化合物将显示不同的且不可预知的活性。例如,在一些细胞型中,一种化合物可起雌激素受体激动剂的作用,同时在其它组织中,其为雌激素受体拮抗剂。具有这种活性的化合物有时被称为SERM(选择性的雌激素受体调节剂)。但是,与许多雌激素不同,许多SERM不会导致子宫湿重的增加。这些化合物在子宫中是抗雌激素的,并且可完全对抗本在子宫组织中雌激素受体激动剂的营养效应。但是,这些化合物在骨骼、心血管和中枢神经系统中起雌激素受体激动剂的作用。由于这些化合物的这种组织选择性,其可用于治疗和抑制哺乳动物与雌激素缺乏(在某些组织中,如骨骼或心血管)或雌激素过量(在子宫或乳腺中)有关的疾病病症或综合征。另外,本发明的化合物还具有这样的可能性,其在一种受体类型中相当于雌激素受体激动剂,同时在其它类型上相当于雌激素受体拮抗剂。例如,已经证明了化合物可通过ERβ对抗17β-雌二醇的作用,同时其显示出与ERα的雌激素受体激动剂活性[Sun等人,Endocrinology 140:800-804(1999)]。在这系列化合物中,这种ERSAA(雌激素受体选择性激动剂拮抗剂)活性提供了药理学上明确的雌激素活性。
金属硫蛋白-II mRNA的调节
如Harris所述,雌激素通过ERβ而不是ERα作用,可向上调节金属硫蛋白II mRNA在Saos-2细胞中的水平[Endocrinology 142:645-652(2001)]。该试验方法得到的结果可与下述测试方法(ERE指示剂试验法)得到的结果结合,得到本发明化合物选择性的概况(也可参见WO00/37681)。本发明典型化合物的数据列于表(2)。
表2:在Saos-2细胞中金属硫蛋白-IImRNA的调节 | |
实施例1e | 17.0 |
实施例1l | 5.5 |
实施例1o | 5.7 |
实施例1p | 6.0 |
实施例1s | 4.9 |
使用ERE-指示剂试验法在MCF-7乳腺癌细胞中对测试化合物的评 价。在DMSO中制备试验化合物的原液(通常0.1M),然后用DMSO稀释10-100倍,制成1或10mM的工作溶液。二甲亚砜原液储藏在4℃(0.1M)或-20℃(<0.1M)。将MCF-7细胞用生长培养基[D-MEM/F-12介质,包括10%(vv)加热灭活的胎牛血清,1%(v/v)青霉素-链霉素和2mMglutaMax-1]每周两次继代移种。将细胞保存在有开口的烧瓶内,放置在37℃、5%CO2/95%湿度的有氧培养箱中。在处理前一天,将细胞和生长培养基以25,000细胞/穴的量植入96穴板然后在37℃培养过夜。
以50μl/穴的量用在实验介质[无酚红D-MEM/F-12介质,包括10%(v/v)加热灭活的脱碳(charcoal-stripped)胎牛血清、1%(v/v)青霉素-链霉素,2mM的glutaMax-1、1mM丙酮酸钠]中1∶10稀释的腺病毒5-ERE-tk-荧光素酶在37℃感染细胞2小时。然后用150μl的实验介质洗涤穴一次。最后,细胞在37℃用150μl/穴的载体(≤0.1%v/v二甲亚砜)或用实验介质≥1000倍稀释的化合物处理24小时,每次平行处理8个穴。
用一剂1μM单独的被测化合物(雌激素受体激动剂模式)或与0.1nM17β-雌二醇结合的被测化合物(EC80:雌激素受体拮抗剂模式)完成测试化合物的最初筛选。各个96穴板还包括载体对照组(0.1%v/v二甲亚砜)和雌激素受体激动剂对照组(0.1或1nM17β-雌二醇)。剂量-反应实验以雌激素受体激动剂和/或雌激素受体拮抗剂模式进行,活性化合物的记录从10-14增加到10-5M。由这些剂量-反应曲线,可分别得到EC50和IC50值。在各个试验组的最后一个穴,包括5μl的3×10-5M ICI-182,780(10-6M最终浓度)作为雌激素受体拮抗剂对照物。
处理后,在振荡器上用25μl/穴的1X细胞培养溶胞反应物(PromegaCorporation)溶解细胞15分钟。细胞溶菌产物(20μl)被转移到96穴光度计板上,在MicroLumat LB 96P光度计(EG & G Berthold)中测定荧光素酶活性,使用100μl/穴的荧光素酶基底(Promega Corporation)。在注射基底前,对每个穴进行1秒钟背景测量。在注射基底后,延迟1秒钟对荧光素酶活性进行10秒钟测试。数据从光度计传输到Macintosh个人计算机上,用JMP软件(SAS Institute)分析;该程序从每个穴的荧光素酶测量值中扣掉了背景读数,然后确定各次处理的平均和标准偏差。
荧光素酶数据转化为对数,用Huber M-估算器对外围转换测量进行下加权。JMP软件用来对单程ANOVA进行转换和加权数据分析(Dunnett′s试验)。在雌激素受体激动剂模式中,所述化合物处理可与载体对照组的结果比较,或在雌激素受体拮抗剂模式中,与正的雌激素受体激动剂对照结果(0.1nM17β-雌二醇)比较。对于最初的一剂实验,如果化合物处理结果与合适的对照显著不同(p<0.05),那么结果报告为相对于17β-雌二醇对照组的百分比[即,((化合物-载体对照)/(17β-雌二醇对照-载体对照))×100]。JMP软件此外用于从非线性的剂量-反应曲线确定EC50和/或IC50值。
子宫营养活性的评价
试验化合物的子宫营养活性可根据下面的标准药理学试验法测定。
过程1:从Taconic得到性发育未全的(18日龄)Sprague-Dawley大鼠,提供无限制的酪蛋白基饮食(Purina Mills 5K96C)和水。在19、20和21天,给大鼠皮下给药17α-乙炔基-17β-雌二醇(0.06μg/鼠/天)、测试化合物或载体(50%DMSO/50% Dulbecco′s PBS)。为了评价雌激素受体拮抗剂,化合物与17α-乙炔基-17β-雌二醇(0.06μg/鼠/天)共同给药。每组有6只大鼠,在最后一次注射约24小时后,通过CO2窒息和气胸施行安乐死。摘除子宫,在清理了结合的脂肪并挤出任何内部液体之后,将子宫称重。也可将组织样品急冻用于基因表达分析(例如,补体因子3mRNA)。从本发明典型化合物得到的结果列于表(3)。
表3:在大鼠子宫营养试验法中所选择化合物的评价 | |
化合物 | 平均子宫重量(mg)±SEM |
载体 | 21.4±1.6 |
17α-乙炔基-17β-雌二醇(0.06μg/大鼠/天) | 85.5±3.1 |
实施例1av(2mg/大鼠/天) | 23.3±1.3 |
实施例1 1av(2mg/大鼠/天)+17α-乙炔基-17β-雌二醇(0.06μg/大鼠/天) | 81.9±4.2 |
过程2:从Taconic得到性发育未全的(18日龄)129 SvE小鼠,提供无限制的酪蛋白基饮食(Purina Mills 5K96C)和水。在22、23、24和25天对小鼠在皮下给予化合物或载体(玉米油)。每组有6只小鼠,在最后一次注射约6小时后,通过CO2窒息和气胸施行安乐死。摘除子宫,在清理了结合的脂肪并挤出任何内部液体之后,将子宫称重。以下结果(表(4))得自本发明典型的化合物。
表4:在小鼠子宫营养试验法中所选择化合物的评价 | |
化合物 | 平均子宫重量(mg)±SEM |
载体 | 10.3±0.8 |
17β-雌二醇(50mg/kg/天) | 45.3±1.9 |
实施例1av(50mg/kg/天) | 12.6±0.8 |
骨质疏松症和脂类调节(心脏保护)的评价
切除卵巢或进行了假手术的雌性Sprague-Dawley大鼠在手术后1天从Taconic Farms得到(重量范围240-275克)。将其以每笼3或4只大鼠按照12/12(明/暗)时间表在室中饲养,提供无限制的食物(Purina 5K96C大鼠食物)和水。在到达后1天开始为所有的研究进行处理,大鼠每周给药7天,进行6周。年龄相匹配的、做了假手术的大鼠组不接受任何处理,其用作每个研究的无损伤、雌激素充足的对照组。
全部试验化合物在载体50%二甲亚砜(JT Baker,Phillipsburg,NJ)/1x Dulbecco′s磷酸盐生理盐水(GibcoBRL,Grand Island,NY)中制备成规定的浓度,从使处理体积是0.1ml/100克体重。17β-雌二醇溶于玉米油(20μg/ml)并皮下注射,0.1ml/大鼠。以三周为间隔根据组平均体重测量值调节全部剂量,皮下给药。
开始处理5周之后且在研究终止前1周,对每只大鼠进行骨骼矿物密度(BMD)评价。用XCT-960M(pQCT;Stratec Medizintechnik,Pforzheim,德国)评价被麻醉大鼠近端胫节的总密度和小梁密度。测量是进行如下:在扫描前15分钟,通过腹腔内注射45毫克/公斤氯胺酮、8.5毫克/公斤甲苯噻嗪和1.5毫克/公斤乙酰丙嗪麻醉每只大鼠。
将右后肢通过直径25mm的聚碳酸酯管,用胶带绑在丙烯酸框上,踝关节在90度角,膝关节在180度角。聚碳酸酯管被固定在滑台上,使其垂直于pQCT的窗孔。调节平台,从而使股骨的远端和胫节的近端处于扫描场中。双向探测观察持续10mm长度,谱线分辨度0.2mm。在探测视察显示在监视器上之后,固定胫节近端。从该点开始pqct扫描3.4毫米到末梢。pqct扫描为1mm厚度,具有voxel(三维的像素)尺寸0.140mm,从该部分的开始到结束由145个投影组成。
在完成pQCT扫描后,影像显示在监视器上。勾画了包括胫节但不包括腓骨的研究区域的轮廓。用迭代算法从数学上除去软组织。剩下的骨骼的密度(总密度)以mg/cm3报告。骨骼外面的55%按照同心螺线从数学上被剥离。剩下的骨骼密度(小梁密度)以mg/cm3报告。
BMD评价1周后,通过CO2窒息和气胸将大鼠安乐死,收集血液进行胆甾醇测定。另外,摘除子宫,在整理结合的脂肪并挤出任何腔内液体之后将子宫称重。总胆固醇通过Boehringer-Mannheim Hitachi911临床的分析仪用胆甾醇/HP试剂盒测定。用单向方差分析和Dunnet′s试验比较统计数字。
抗氧化活性评价
从屠宰场得到猪的主动脉,清洗,送到冷却的PBS,采集主动脉内皮细胞。为了采集所述细胞,结扎主动脉的脉间脉管,并将主动脉的一端夹住。将新鲜的、无菌的过滤的0.2%胶原酶(Sigma型I)置于血管中,并随后将血管的另一端夹住,形成一个封闭系统。该主动脉在37℃培养15-20分钟,随后收集胶原酶溶液并在2000Xg离心5分钟。各颗粒悬浮在7ml的内皮细胞培养介质中,所述介质由补充了脱碳FBS(5%)的无酚红DMEM/Ham′s F12介质、NuSerum(5%)、L-谷氨酸盐(4mM)、青霉素-链霉素(1000μg/ml,100μg/ml)和庆大霉素(75μg/ml)组成,将颗粒接种在100mm平皿中,在37℃在5%二氧化碳中培养。在20分钟后,细胞用PBS清洗,加入新鲜的介质,在24小时时再将此重复1次。约1周后细胞融合。内皮细胞通常每周加料两次,当融合时,胰蛋白酶化,并以在1∶7比例接种。在所述化合物存在下进行12.5μg/mLLDL的细胞介导的氧化,在37℃评价4小时(5μM)。结果可表示为氧化过程的抑制百分比,其通过用于分析游离醛的TBARS(丙二酰硫脲反应性物质)方法测定[Yagi,Biochemical Medicine 15:212-6(1976)]。
孕酮受体mRNA调节标准药理学试验法
该试验法可用于评价本发明化合物的雌激素活性或抗雌激素活性[Shμghrue等人,Endocrinology 138:5476-5484(1997)]。本发明典型化合物的数据列于表(5)。
表5.本发明典型化合物调节大鼠脑视前区孕酮mRNA的作用 | |
化合物 | 黄体酮受体mRNA(arbitrary units;mean±stdev) |
载体 | 55.4±9.4 |
17β-雌二醇(30μg/kg) | 557.1±80.6 |
实施例1av(10mg/kg) | 33.7±20.6 |
大鼠热潮红试验法
化合物在热潮红方面的作用可在标准药理学试验法中评价,所述方法测量被测化合物减弱尾部表皮温度增加的能力,所述的尾部表皮温度增加发生在咖啡上瘾的大鼠用纳洛酮急性脱离药物的情况下[Merchenthaler等人,Maturitas 30:307-16(1998)]。通过与对照雌激素共同给药,该方法还可以用来测定雌激素受体拮抗剂活性。
在分离的大鼠主动脉环中血管收缩功能的评价
Sprague-Dawley大鼠(240-260克)被分成4组:
1.正常的未切除卵巢的(无损伤的);
2.切除卵巢(ovex)用载体处理的;
3.切除卵巢用17β-雌二醇处理的(1毫克/公斤/天)
4.切除卵巢的动物用试验化合物(各种剂量)处理的。
在处理之前约3周将动物切除卵巢。每只动物接受17-β雌二醇硫酸盐(1毫克/公斤/天)或试验化合物,其悬浮在有1%吐温80的蒸馏去离子水中,通过胃强饲法施用。载体处理的动物接受适量在药物处理组所用的载体。
动物通过二氧化碳吸入和放血被处死。将胸主动脉迅速摘除,放入37℃的生理溶液中,所述生理溶液有以下组成(mM):NaCl(54.7)、KCl(5.0)、NaHCO3(25.0)、MgCl2 2H2O(2.5)、D-葡萄糖(11.8)和CaCl2(0.2),用CO2-O2充气,95%/5%,最终pH为7.4。将advantitia从外表面除去,血管被切成2-3mm宽的环。将环悬浮在10ml组织浴中,一端连接到池底,另一端连接测力传感器。将1克的静止张力施加到环上。将环平衡1小时,获取并分析信号。
在平衡后,将环暴露在浓度增加的苯肾上腺素(10-8至10-4M)下,记录张力。然后用新鲜的缓冲液冲洗三次浴。在冲洗后,将200mML-NAME加入组织浴中,并平衡30分钟。然后重复苯肾上腺素浓度反应曲线。
评价心脏保护活性
从Taconic Farms获得脱脂蛋白E-缺乏的C57/B1J(apo E KO)小鼠。全部动物操作严格按照IACUC指南进行。切除卵巢的雌性apo E KO小鼠,4-7周龄,在履带板-箱笼中饲养,允许自由进食和饮水。动物被随机按重量分成组(n=12-15小鼠/组)。用精确剂量方法在饮食中给动物施用测试化合物或雌激素(17β-雌二醇硫酸盐,1毫克/公斤/天),其中每周测定消耗的饮食的量,据此基于动物的体重调节剂量。使用的饮食是西式饮食(57U5),由Purina制备,含0.50%胆甾醇、20%猪油和25IU/KG维生素E。使用这种模式给动物用药/喂食12周。用西式饮食饲喂对照动物,不喂给化合物。在研究阶段末,将动物处死,得到血浆样品。就地灌注心脏,首先用盐水灌注,然后用中性缓冲剂10%甲醛液灌注。
为了测定血浆脂质和脂蛋白,分别用Boehringer Mannheim和Wako Biochemicals制造的市售试剂盒以酶促法确定总胆固醇和三酸甘油酯,然后用Boehringer Mannheim Hitachii 911分析仪分析。用FPLC尺寸精馏进行血浆脂蛋白的分离和定量评价。简而言之,过滤50-100ml的血清,将其注入Superose 12和Superose 6串连的柱中,以恒流速用1mM钠EDTA和0.15M NaCl洗脱。用Waters Millennium软件对表示VLDL、LDL和HDL的各个曲线的面积积分,通过用每个相应的色谱峰的相对百分比面积乘以总胆甾醇值确定各脂蛋白百分率。
为了定量评价主动脉的动脉粥样硬化,将主动脉小心分离并在处理前放入福尔马林固定剂中48-72小时。用油红O染色剂确定动脉粥样硬化损害。血管被略略脱色,然后用装有Sony 3CCD摄影体系的NikonSMU800显微镜成像,同时使用IMAQ Configuration Utility(NationalInstrument)作为影像俘获软件。用常规阈值实用软件包(ColemanTechnologies)沿着主动脉弓上面确定损害。在血管上用程序的阈函数进行自动操作损害评价,具体地说,在包含在主动脉弓内的区域上测试,所述的主动脉弓从头臂干的近边到左侧锁骨下动脉的远边。主动脉动脉粥样硬化数据可表示为在该定义的腔区域中确实牵连损害的百分比。
认识力增强的评价
使切除卵巢的大鼠(n=50)熟悉8-支路径向支路迷宫,连续5天每天10分钟。在熟习和测试前使动物失水。将100μl等分量的水置于各支路的末端作为补充。通过让动物能够达到有诱饵的支路,实现支路迷宫中得以成功完成轮班任务。在喝水后,动物离开支路重新进入中央室,在其中,动物现在可进入早先探访过的支路,或进入新的支路。当动物选择进入新的支路时,记录正确应答。各个动物每天可尝试5次,持续3天。在最后得到尝试后,将动物分成以下4组:
1.阴性对照:每天注入10%二甲亚砜/芝麻油载体一次,进行6天(1ml/kg,SC)
2.阳性对照:注入17β-苯甲酸雌二醇2天并在第二次注射(17β-苯甲酸雌二醇,10μg/0.1ml/大鼠)后4天测试
3.雌二醇:每天注入17β-雌二醇6天(20μg/kg,SC)
4.测试化合物:每天注入,进行6天(改变剂量)
在最后一天学习后开始所有的注射。在检验工作记忆前2小时对1、3和4组进行最后一次注射。
对工作记忆的检验采用15、30和60秒延迟的一种对样品的延迟的非对比作业(DNMS)。该工作是添加工作的变化,其中大鼠被置于中央场地中,并允许其如前所述进入一个支路中。一旦该大鼠沿着第一个支路移动到一半时,就打开第二个支路,并再次要求该大鼠选择该支路。当其已经沿着第二个支路通过一半时,将两个门均关闭,开始延时。一旦延时期满,将开始的两个门和第三个新的门同时打开。当该动物沿着第三个新的支路通过一半时,记录正确应答。当该动物沿着第一个或第二个支路移动过半时,记录不正确应答。在三个延时间隔时间,每只动物在每个时间进行5次尝试,每个受试者总共进行15次尝试。
对胸膜炎影响的评价
根据Cuzzocrea方法评价对大鼠的实验引起的胸膜炎症状的减轻能力[Endocrinology 141:1455-63(2000)]。
评价对谷氨酸盐引起细胞毒性的防护性能(神经保护)
本发明化合物的神经保护活性可在用谷氨酸盐诱导的体外标准药理学试验方法中评价[Zaulyanov等人,Cellular & MolecularNeurobiology 19:705-18(1999);Prokai等人,Journal of MedicinalChemistry 44:110-4(2001)]。
在乳腺末端芽体试验中的评价
乳腺管的完全导管延伸和分枝需要雌激素,随后在黄体酮的影响下发展成小叶蜂窝状末端芽体。在该试验法中,本发明所选择的化合物的激乳腺活性根据下述标准药理学试验方法评价。将28日龄的Sprague-Dawley大鼠(Taconic Farms,Germantown,NY)切除卵巢,然后休息9天。将动物饲养在12小时明/暗周期的环境中,并饲喂酪蛋白基的Purina Laboratory啮齿动物膳食5K96(Purina,Richmond,IN),允许自由饮水。然后给大鼠皮下注射6天载体(50%二甲亚砜(JT Baker,Phillipsburg,NJ)/50%1x Dulbecco′s磷酸盐缓冲盐水(GibcoBRL,Grand Island,NY)、17β-雌二醇(0.1毫克/公斤)或试验化合物(20毫克/公斤)。在最后三天,给大鼠皮下注射黄体酮(30毫克/公斤)。在第七天,将大鼠处死,切除乳房脂垫。对该脂垫分析酪蛋白激酶IImRNA,其作为末端芽体增殖的标示物。酪蛋白激酶II mRNA用实时RT-PCR分析。
简要地说,根据制备说明,按照Trizol(GibcoBRL,Grand Island,NY)分离RNA,使用无DNA的试剂盒(Ambion)用DNA酶I处理样品,用Taqman Gold方法(PE Applied Biosystems)通过实时RT-PCR测定酪蛋白激酶II mRNA水平。以酪蛋白激酶II特定引物对(5′引物,CACACGGATGGCGCATACT;3′引物,CTCGGGATGCACCATGAAG)和定制的探针(TAMRA-CGGCACTGGTTTCCCTCACATGCT-FAM)一式三次分析总共50ng RNA。酪蛋白激酶II mRNA水平被校正到18s核糖体RNA,其包括在使用引物和PE Applied Biosystems提供的探针的各个样品反应中。得到下述本发明典型的化合物的结果(表(6))。
表6:化合物在大鼠激乳腺分析中的评价 | |
化合物 | 酪蛋白激酶IImRNA/18S rRNA(mean±SEM) |
载体 | 2.66±0.13 |
黄体酮(30mg/kg)+17β-雌二醇(0.1mg/kg) | 39.0±5.4 |
黄体酮(30mg/kg)+实施例1av(20mg/kg) | 1.06±0.17 |
在HLA大鼠标准药理学试验中对炎症性肠病的评价
本发明的化合物可在模拟人炎症性肠病的HLA大鼠标准药理学试验中进行评价。以下简述所用的方法和得到的结果。从Taconic得到雄性HLA-B27大鼠(8-10周龄),给其提供无限制的食物(PMI Lab膳食5001)和水。在46天中,每天给大鼠口服载体(2%吐温-80/0.5%甲基纤维素)或实施例1av(10mg/公斤)。每天观察粪便特性,并根据以下标度分级:腹泻=3;软便=2;正常便=1。在研究结束时,收集血清并在-70℃储存。准备一段结肠用于组织分析,另一段用于对髓过氧物酶活性进行分析。得到下述结果(表(7)),表明在实施例1av给药21天内粪便的特征正常化。
表7:口服载体或实施例1av 46天处理的HLA大鼠的粪便记录。报道的数值是开始给药26天每组的平均值。 | ||
天 | 载体 | 实施例1av |
1 | 2.75 | 2.75 |
2 | 3 | 2.5 |
3 | 3 | 2.25 |
4 | 3 | 2.5 |
5 | 3 | 2.25 |
6 | 3 | 2.5 |
7 | 3 | 2.5 |
8 | 3 | 2 |
9 | 3 | 2 |
10 | 3 | 1.5 |
11 | 3 | 1.5 |
12 | 3 | 1.5 |
13 | 3 | 1.75 |
14 | 3 | 1.75 |
15 | 3 | 1.5 |
16 | 3 | 1.5 |
17 | 3 | 1.25 |
18 | 3 | 1.25 |
19 | 3 | 1.25 |
20 | 3 | 1.25 |
21 | 3 | 1.25 |
22 | 3 | 1 |
23 | 3 | 1 |
24 | 3 | 1 |
25 | 3 | 1 |
3=腹泻;2=软便;1=正常便 |
为了进行组织分析,将结肠组织浸于10%中性缓冲的福尔马林中。将各段结肠样品分成四份样品进行评价。将福尔马林固定的组织在Tissue Tek vacuum infiltration处理系统(Miles,Inc;West Haven,Connecticut)中处理进行石蜡包埋。将样品切成5μm的薄片,然后用苏木紫和曙红(H & E)着色,在Boμghton-Smith后用修正的标度进行组织的盲评价。在完成记录后,将样品明确,列表显示数据并用复合平均对比通过ANOVA线性模型进行分析。评价结肠组织薄片,用于指示多种疾病并得到相关数据。如表(8)所示,实施例1av在降低组织损伤的若干测量值方面有效。
表8:在口服载体或实施例1av46天后,HLA-B27大鼠模型的患病组织记录 | |||||
组别 | 溃疡(0-2) | 炎症(0-3) | 深度损伤(0-2) | 纤维化(0-2) | 总分 |
载体 | 1.19±0.69 | 2.38±0.32 | 1.0±0.54 | 0.94±0.75 | 5.50±2.1 |
实施例1av | 0.44±0.43 | 1.13±0.43* | 0.38±0.43 | 0.07±0.13* | 2.00±1.14* |
*信号<载体 |
在两个关节炎模型中的评价
佐剂引起关节炎的Lewis大鼠的分析。根据标准研究室操作方法饲养60只雌性12周龄Lewis大鼠。它们得到无限制的标准食物和水饲喂。各只动物通过标记项目组和动物数量的笼卡区分。每只大鼠的编号用持久性墨水标记在尾部。在研究前至少10-21天将其麻醉并用标准无菌外科术切除卵巢。
用弗氏完全佐剂(Freund′s Adjuvant-Complete)(Sigma ImmunoChemicals,St.Louis,MO)引起关节炎,每毫升含1毫克热灭活并干燥的结核分枝杆菌、0.85ml矿物油和0.15ml一油酸二缩甘露醇酯Lot No.084H8800。
下面是两个试验的实例。抑制试验方法:给30只大鼠在尾基真皮注射0.1ml的弗氏完全佐剂。将动物随机分组,每组6只。每天,各组接受载体(50%二甲亚砜(JT Baker,Phillipsburg,NJ)/1x Dulbecco′s磷酸盐生理盐水(GibcoBRL,Grand Island,NY))或试验化合物(皮下给药)。所有大鼠在第1天开始处理。实施例1av的数据列于表(9)。
治疗试验方法:给30只大鼠在尾基真皮注射0.1ml的弗氏完全佐剂。将动物随机分为四组,每组包括六只大鼠。每天,各组接受载体(50%二甲亚砜(JT Baker,Phillipsburg,NJ)/1x Dulbecco′s磷酸盐生理盐水(GibcoBRL,Grand Island,NY))或试验化合物(皮下给药)。在注射助剂后的第8天开始处理所有大鼠。实施例1av的数据列于表(10)、(11)和(12)。
用Abacus Concepts Super ANOVA(Abacus Concepts,Inc.,Berkeley,CA)进行统计分析。对所有感兴趣的参数在各组之间用邓肯新多程的后期测试(Duncan′s new multiple range post hoc testing)进行方差分析。全部数据以平均标准偏差(SD)表示,如果p<0.05,则认为差异显著。
每日监视关节炎的严重程度,折合成以下病情指数:后爪发红,后爪肿大,关节触痛以及运动和姿势。0至3的整数标度被用来量化红斑的级别(0=正常爪,1=轻微发红,2=中度发红,3=严重发红)和膨胀的级别(0=正常爪,1=轻微肿大,2=中度肿大,3=后爪严重肿大)。每天最多记录12次。
在研究结束时,将大鼠用CO2处死,从尸体上除去四肢,并在10%缓冲的福尔马林中固定,将跗关节脱钙,埋蜡。组织切片用苏木精和曙红或Saffranin O-坚牢绿着色。
将载玻片编号,从而检查员对试验组盲检。如下所述,对来自跗关节的滑膜组织在滑膜增生、炎性细胞浸润和血管翳形成方面进行评价[Poole and Coombs,International Archives of Allergy & AppliedImmunology 54:97-113(1977)]。
类型 | 分级 |
1.滑膜衬里细胞 | |
a.无变化 | 0 |
b.细胞扩大,稍微变厚 | 1 |
c.细胞扩大,数量增加,中等变厚。无绒毛存在 | 2 |
d.细胞扩大,变厚。存在绒毛 | 3 |
2.纤维组织形成 | |
a.无变化 | 0 |
b.在衬细胞下存在纤维增生 | 1 |
c.小面积的蜂窝组织被纤维组织代替 | 2 |
d.纤维组织代替蜂窝组织 | 3 |
3.炎性细胞 | |
a.偶而见到,散布在整个选择的区域 | 0 |
b.存在少量细胞,位于衬细胞层中或恰好在衬细胞层下和/或在血管周围 | 1 |
c.可存在细胞的小病灶聚集 | 2 |
d.大量细胞存在于包膜并在衬细胞层内或衬细胞层下。常见到大的病灶。 | 3 |
4.血管翳 | |
a.未检出 | 0 |
b.可检出 | 1 |
另外,如下所述,用Mankin′s组织分级系统评价关节软骨和骨骼[Mankin等人,Journal of Bone & Joint Surgery-American Volume 53:523-37(1971)]。
类型 | 分级 |
1.结构 | |
a.正常 | 0 |
b.表面不规则 | 1 |
c.血管翳和表面不规则 | 2 |
d.劈开过渡带 | 3 |
e.劈开放射带 | 4 |
f.劈开钙化带 | 5 |
g.完全解体 | 6 |
2.细胞 | |
a.正常 | 0 |
b.弥漫性细胞增殖 | 1 |
c.克隆化 | 2 |
d.细胞过少 | 3 |
3.番红精-O着色 | |
a.正常 | 0 |
b.稍微降低 | 1 |
c.少量降低 | 2 |
d.严重降低 | 3 |
e.无染色指示 | 4 |
4.潮标完整性 | |
a.无损伤 | 0 |
b.被血管交错 | 1 |
表9:Lewis大鼠关节炎症的评价:抑制方法
天 | 载体 | 实施例1av |
1 | 0.00 | 0.00 |
2 | 0.00 | 0.00 |
3 | 4.50 | 2.66 |
4 | 5.50 | 1.83 |
5 | 9.33 | 2.66 |
6 | 10.50 | 2.16 |
7 | 10.60 | 2.00 |
8 | 11.00 | 1.66 |
9 | 11.50 | 2.00 |
10 | 11.33 | 2.00 |
11 | 10.83 | 1.66 |
12 | 10.83 | 1.66 |
13 | 11.00 | 2.16 |
14 | 11.00 | 2.00 |
15 | 11.00 | 2.00 |
16 | 11.00 | 1.00 |
17 | 10.50 | 1.33 |
表10:Lewis大鼠关节炎症的评价:治疗方法
天 | 载体 | 实施例lav |
1 | 10.83 | 11.33 |
2 | 11.00 | 10.83 |
3 | 10.83 | 9.33 |
4 | 11.33 | 8.00 |
5 | 11.50 | 5.83 |
6 | 11.50 | 3.33 |
7 | 11.50 | 3.00 |
8 | 11.50 | 2.50 |
9 | 11.00 | 2.50 |
10 | 11.00 | 2.50 |
11 | 10.66 | 2.50 |
12 | 10.66 | 2.50 |
13 | 10.50 | 2.50 |
14 | 9.83 | 2.50 |
15 | 8.10 | 2.00 |
16 | 7.35 | 1.33 |
17 | 6.50 | 1.00 |
表11:Lewis大鼠跗关节滑膜炎的组织学得分(平均值±SD):治疗方案
组 | 滑膜结构(0-3) | 纤维增生(0-3) | 炎性细胞(0-3) | 血管翳(0-1) | 总滑膜炎得分(0-10) |
载体 | 2.58±0.38 | 1.75±0.42 | 2.92±0.20 | 1.00±0.89 | 8.25±1.57 |
实施例1av10mg/kg | 1.58±0.38* | 0.75±0.42* | 1.25±0.42* | 0.33±0.61* | 3.83±0.93* |
*信号<载体
表12:Lewis大鼠跗关节中软骨变化的组织学损伤(Mankin得分)(平均值±SD):治疗方法
组 | 软骨结构(0-6) | 软骨细胞(0-3) | Saffranin-O坚牢绿完整性(0-4) | 潮标着色(0-1) | 总Mankin得分(0-14) |
载体 | 2.83±0.26 | 2.58±0.38 | 2.50±0.32 | 0 | 7.92±0.74 |
实施例1av10mg/kg | 1.83±0.68* | 0.75±0.42* | 1.25±0.52* | 0 | 3.83±1.21* |
*信号<载体
在关节炎HLA-B27大鼠模型中评价。本发明的化合物可在模拟人关节炎的HLA-B27大鼠标准药理学试验中进行评价。以下简述所用的方法和得到的结果。从Taconic得到雄性HLA-B27大鼠,给其提供无限制的食物(PMI Lab膳食5001)和水。如上述佐剂引起的关节炎Lewis大鼠模型所述,评价关节损伤和组织结构。大鼠(8-10周龄)每天一次口服给予载体(2%吐温80/0.5%甲基纤维素)或实施例1av(10mg/公斤),进行46天。每组有4只大鼠,在处死前2小时给最后一剂。如表(13)所示,通过用实施例1av处理,减轻了关节炎症。此外,还减轻了滑膜炎和Mankin得分(表(14)),但是统计上没有不同于那些用载体处理的大鼠。
表13:用实施例1av口服处理46天的HLA大鼠关节炎症的评价
天 | 载体 | 实施例1av(10mg/kg) |
29 | 2.5 | 0.5 |
30 | 6 | 0.5 |
31 | 5 | 0.5 |
32 | 6.75 | 1 |
33 | 8 | 1.75 |
34 | 8 | 1.5 |
35 | 8 | 1 |
36 | 6 | 1.75 |
37 | 7.5 | 1.75 |
38 | 6.5 | 1.5 |
39 | 7.5 | 0.75 |
40 | 7.5 | 0.75 |
41 | 6.5 | 0.5 |
42 | 6.5 | 1.5 |
43 | 6 | 1.25 |
44 | 6.75 | 1.75 |
45 | 5.5 | 1.25 |
46 | 6 | 0.75 |
表14:用实施例1av口服处理46天的HLA大鼠关节组织学的评价
化合物 | 滑膜炎得分(平均值±SD) | Mankin得分(平均值±SD) |
载体 | 7.6±3.1 | 6.5±1.2 |
实施例lav(10mg/kg) | 5.0±2.5 | 4.5±1.8 |
在体内致癌模型中的评价
本发明化合物治疗和抑制各种恶性肿癌或hyperprolific病症的能力可在从文献容易得到的标准药理学试验法中评价,具体包括下面两个方法。
乳腺癌。从Charles River实验室(Wilmington,MA)获得切除卵巢的无胸腺nu/nu(裸)小鼠。在肿瘤细胞注入前一天,给动物植入缓释颗粒,所述颗粒含有0.36-1.7mg17β-雌二醇(60或90天释放,InnovativeResearch of America,Sarasota,FL)或安慰剂。用10-计量精度套针将颗粒皮下引入肩胛内区域。随后,在小鼠乳房组织中皮下注入1×107MCF-7细胞或1×107BG-1细胞。细胞与等体积的matrigel(一种基膜基料制品)以促进肿瘤的形成。试验化合物可通过在肿瘤细胞移植后一天给药(抑制方案)或者通过在肿瘤达到某个尺寸后给药(处理方案)进行评价。每天在含有1%吐温-80的生理盐水载体中将化合物经腹膜内给药或经口给药。每3天或7天评价肿瘤尺寸。
结肠癌。在Smirnoff试验法中可评价治疗或抑制结肠癌的能力[Oncology Research 11:255-64(1999)]。
在两种体内试验中评价神经保护
蒙古沙鼠中暂时脑局部缺血。用下述试验方法测定试验化合物在防止或治疗由于缺氧/再灌注造成的脑损伤的作用。
雌性蒙古沙鼠(60-80克;Charles River实验室,Kingston,NY)在Wyeth-Ayerst动物养护研究室(AAALAC认证)饲养,采用12小时光照,12-小时黑暗的光周期,可自由饮用自来水和摄取低雌激素酪蛋白膳食(Purina;Richmond,IN)。适应环境后(3-5天),将沙鼠用异氟烷(2-3%与O2的混合物)麻醉,切除卵巢(第0天)。从接下来的早晨开始(第1天),沙鼠每天用载体(10%EtOH/玉米油)、17β-雌二醇(1毫克/公斤,sc)或者实验化合物皮下处理。在第6天,用异氟烷麻醉沙鼠(n=4-5/组),用中线颈切割暴露共用的颈动脉干道,将两个动脉同时用无创微脑动脉瘤夹阻断5分钟。在阻断后,移动钳使得大脑再灌注,用创钳关闭颈部切口。在促进稳定缺血性伤害的大脑局部缺血手术前,所有的动物被禁食过夜。在第12天,将沙鼠暴露在致死量的CO2下,将脑在干冰中冷冻并储存在-80℃。评述用于这些研究的动物记录,并通过在Wyeth-AyerstResearch的Radnor/Collegeville Animal Care和Use Committee(RACUC/CACUC)审定。
通过原位杂交分析neurogranin mRNA评价神经元保护程度。简而言之,在涂有明胶的载玻片上聚积20μm冠状cryostat区,干燥并在-80℃储存。在处理的时候,将干贮的载玻片箱升温至室温,将载玻片在4%低聚甲醛中再固定,用乙酸酐处理,然后用氯仿和乙醇脱脂脱水。然后,将被测定的处理后切片的载玻片与200μl(6×106DPM/载玻片)用于Neurogranin(35S-UTP-标记的NG-241;基质99-340)的一种反义核糖探针(riboprobe)或感应(对照物)riboprobe在50%甲酰胺中杂交。杂交混合,然后在55℃,在增湿载玻片室中不加盖片地培养过夜。在接着的早晨,将载玻片收集在搁架上,浸于2x SSC(0.3M NaCl,0.03M柠檬酸钠;pH7.0)/10mM DTT,用核糖核酸酶A处理(20μg/ml),然后在67℃在0.1x SSC中洗涤(2X 30分钟),除去非特异性标记。脱水后,将载玻片与BioMax(BMR-1;Kodak)X线胶片对置过夜。
neurogranin杂交信号水平用来定量评价在损伤后CA1区域神经元损失的程度,以及用于评价17β-雌二醇和试验化合物的效果。neurogranin mRNA被选择用于这些研究是因为其在包括海马神经元的CA1中被高度表达,但是在神经胶质和该脑区的其它细胞类型中不存在。因此,neurogranin mRNA存在量的测定值表示了存活的神经元。neurogranin杂交信号的相对光密度测量值用基于计算机图象分析系统(C-Imaging Inc.,Pittsburgh,PA)的感光胶片放射自显影图获得。每只动物6个切片的结果(40μm间隔)进行平均,然后进行统计评价。数值报道为平均值±SEM。单向方差分析用来检验neurogranin mRNA水平的差异,在得到的切片中,所有无差异的描述表示为p>0.05。
小鼠大脑中动脉封闭。根据Dubal所述的测试方法可评价神经保护[见,Dubal等人,Proceedings of the National Academy of Sciences of theUnited States of America 98:1952-1957(2001),Dubal等人,Journal ofNeuroscience 19:6385-6393(1999)]。
排卵抑制标准药理学试验法
该试验法用于确定试验化合物是否可抑制或改变排卵时间。其还可以用来确定卵母细胞排卵的数目[Lundeen等人,J Steroid Biochem MolBiol 78:137-143(2001)]。
基于在该标准药理学试验中得到的结果,本发明的化合物是雌激素受体调节剂,用于治疗或抑制的状况、病症或疾病状况至少部分是由于雌激素缺乏或过量引起的,或者是通过使用雌激素剂可治疗或抑制的。本发明的化合物特别用于治疗绝经前、绝经或绝经后的患者,其体内产生的内源雌激素水平大大地减少。绝经期通常定义为最后的天然经期,特征在于卵巢功能的终止,导致了血流中循环雌激素的显著的减少。在这里使用的绝经期同时包括雌激素生成的减少,这可能是由于外科的、化学的或由疾病导致的,这些因素使得卵巢功能过早降低或终止。
本发明的化合物还用于抑制或治疗其它雌激素丧失现象,包括热潮红、阴道的或外阴萎缩、萎缩性阴道炎、阴道干燥、瘙瘁、性交疼痛、排尿困难、尿频、尿失禁、尿路感染。其它的生殖道用途包括治疗或抑制功能性月经失调。该化合物还用于治疗或抑制子宫内膜异位。
本发明的化合物还在脑部有活性,因此可用于抑制或治疗阿尔茨海默氏病、认知下降、性欲低下、老年性痴呆、神经变性病症、忧郁症、焦虑、失眠、精神分裂症和不育。本发明的化合物还适用于治疗或抑制良性的或恶性的异常组织长生,包括肾小球硬化症、前列腺肥大、子宫平滑肌瘤、乳腺癌、硬皮病、纤维瘤病、子宫内膜癌、多囊卵巢综合征、子宫内膜息肉、良性乳房疾病、子宫内膜异位、卵巢癌、黑瘤、前列腺癌、结肠癌、CNS癌(如神经胶质瘤或astioblastomia)。
本发明的化合物具有心脏保护作用,是抗氧化剂,并且适用于降低胆甾醇、三酸甘油酯、Lp(a)和LDL水平;抑制或治疗血胆甾醇过多、血脂质过多、心血管疾病、动脉粥样硬化、外周血管疾病、再狭窄和血管痉挛,抑制由于细胞间隙导致的、向免疫调节的血管损伤发展的血管壁破坏。
本发明的化合物还适用于治疗与炎症或自身免疫疾病有关的病症,包括炎性肠病(克罗恩氏病、溃疡性结肠炎、不确定的(indeterminate)结肠炎)、关节炎(类风湿性关节炎、脊柱关节炎、骨关节炎)、胸膜炎、局部缺血/再灌注损伤(例如中风、移植排斥反应、心肌梗死等)、哮喘、巨细胞动脉炎、前列腺炎、间质性膀胱炎、眼色素层炎、牛皮癣、多发性硬化、系统性红斑狼疮和脓血症。
本发明的化合物还可用于治疗或抑制眼部病症,包括白内障、眼色素层炎和黄斑衰退,并可用于治疗皮肤病症,如老化、脱发和痤疮。
本发明的化合物还可用于治疗或抑制代谢失调,诸如II型糖尿病、脂类代谢失调、食欲失调(例如神经性厌食症和食欲过盛)。
本发明的化合物还用于治疗或抑制出血病症,如遗传性出血性毛细血管扩张症、功能性月经失调以及对抗出血性休克。
本发明的化合物可用于闭经是有利的疾病状态,如白血病、子宫内膜烧蚀、慢性肾病或肝病或凝血疾病或病症。本发明的化合物可用作避孕药,特别是与孕酮结合使用。
当给药用于治疗或抑制特定的疾病状态或病症时,应认为有效剂量可根据所使用的特定化合物、给药模式、条件和疾病严重程度、要治疗的状况以及各种与被治疗个体有关的物理因素变化。可给出的本发明化合物的有效口服给药量是约0.1毫克/天至约1,000毫克/天。优选给药量是约10毫克/天至约600毫克/天,更优选约50毫克/天至约600毫克/天,以单剂给药或分两或多剂给药。设计的日剂量预计随给药途径变化。
这种剂量可以任何适用于将活性化合物引入患者血流的方式给药,包括口服、通过植入给药、非肠道给药(包括静脉内、腹膜内和皮下注射)、直肠给药、鼻内给药、局部给药,眼部给药(使用滴眼剂)、阴道给药和经皮肤给药。
含有本发明活性化合物的口服配方可包括任何通常所用的口服形式,包括片剂,胶囊,口腔用药剂形式、锭剂、糖锭和口服液体、悬浮液或溶液。胶囊可包括活性化合物和惰性填料和/或稀释剂的混合物,所述的稀释剂是诸如药学可接受的淀粉(例如玉米、马铃薯或木薯淀粉)、糖、人造甜味剂、粉末纤维素(如结晶纤维素和微晶纤维素)、面粉、明胶、树胶等。有用的片剂配方可以通过常规的压片、湿法造粒或干法造粒方法制备,使用药学可接受的稀释剂、粘合剂、润滑剂、崩解剂、表面改性剂(包括表面活性剂)、悬浮或稳定剂,非限制性地包括硬脂酸镁、硬脂酸、滑石、月桂基硫酸钠、微晶纤维素、羧甲基纤维素钙、聚乙烯吡咯烷酮、明胶、藻酸、金合欢胶、黄原胶、柠檬酸钠、复合硅酸盐、碳酸钙、甘氨酸、糊精、蔗糖,山梨醇、磷酸氢钙、硫酸钙、乳糖、高岭土、甘露糖醇、氯化钠、滑石、干淀粉和糖粉。首选的表面改性剂包括非离子和阴离子表面改性剂。表面改性剂的典型实例非限制性地包括泊洛沙姆188、氯化苯甲烃铵、硬脂酸钙、鲸蜡硬脂醇、cetomacrogol乳化蜡、脱水山梨糖醇酯、胶态二氧化硅、磷酸盐、十二烷基磺酸钠、镁铝硅酸盐和三乙醇胺。在此,口服配方可使用标准的延迟或定时释放的配方以改变活性化合物的吸收。口服配方还可构成活性成分在水中或果汁中给药的形式,如果需要,包括合适的增溶剂或乳化剂。
有时可能希望化合物直接以气雾剂的形式给药。
本发明的化合物还可不经肠道给药或在腹膜内给药。这些活性化合物作为游离碱或药学上可接受的盐的溶液或悬浮液可通过在水中适当地与表面活性剂(诸如羟基-丙基纤维素)混合制备。分散液还可在甘油、液体聚乙二醇和其在油中的混合物中制备。在普通的储存和使用条件下,这些制品含有抑制微生物生长的防腐剂。
适用于注射使用的药物形式包括无菌水溶液或分散液以及用于临时配制无菌可注射溶液或分散液的无菌粉末。在所有情况下,所述的形式必须是无菌的,并且必须是液体,从而具有容易注射的特性。其必须在生产和储存条件下稳定,并且必须防腐,以阻止诸如细菌和真菌的微生物的污染。载体可以是溶剂或分散介质,包括例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)或其适合的混合物,以及植物油。
出于公开的目的,认为透皮给药包括全部通过身体表面和身体通道内层(包括上皮组织和粘膜组织)的给药。这种给药可用所述化合物或其药学可接受盐以洗液、霜剂、泡沫剂、贴片、悬浮液、溶液和栓剂形式(直肠用和阴道用)进行。
透皮给药可以通过使用透皮贴剂实现,所述贴剂包括活性化合物和对活性化合物呈惰性的载体,对皮肤无毒,能够传递药剂,通过皮肤全身吸收进入血流。载体可采用多种形式,诸如霜剂或软膏、糊剂、凝胶剂和封闭装置。霜剂和软膏可以是粘性液体或水包油或油包水形式的半固体乳液。糊剂也是适合的,其由吸附粉末组成,所述粉末分散在含有活性成分的石油产品或亲水性石油产品中。各种封闭装置可用来将活性成分释放到血流中,诸如用半透膜覆盖在盛有含或不含载体的活性成分的容器上,或覆盖在含有活性成分的基料上。其它封闭装置是在文献中已知的。
栓剂配方可由常规材料制造,包括可可脂,添加或不添加蜡以改变栓剂的熔点,还可使用甘油。也可同时使用水溶性的栓剂基质,如各种分子量的聚乙二醇。
本发明典型实施例的的制备描述如下。
路线1中化合物的合成
中间体2
三氟甲磺酸(7-甲氧基-2-萘基)酯
向7-甲氧基-2-萘酚(4.75克,27.27毫摩尔)和吡啶(3.5毫升,44毫摩尔)在200毫升二氯甲烷的0℃溶液中加入三氟甲磺酸酐(10.0克,35毫摩尔)。将溶液缓慢温热至室温并搅拌过夜。将溶液冷却到0℃并与冰水一起搅拌,分解过量的酸酐。加入饱和碳酸氢钠溶液将混合物稍微碱化。分离得到的各层,水层用二氯甲烷(2×250毫升)萃取。将合并的有机层用水洗涤,用硫酸镁干燥,过滤,蒸发溶剂,得到红色的油,将其用二氧化硅色谱法(5%乙酸乙酯-己烷)提纯,得到8.08克(97%)标题化合物,为纯净无色的油。
1H NMR(DMSO-d6)δ3.92(3H,s),7.30(1H,dd,J=2.58Hz,J=8.93Hz),7.42(1H,dd,J=2.59Hz,J=8.93Hz),7.52(1H,d,J=2.38Hz),7.96(1H,d,J=9.12Hz),8.00(1H,d,J=2.38Hz),8.06(1H,d,J=8.73Hz);MS(EI)m/z306(M-)+.
对C12H9F3O4S的分析
计算值:C:47.06 H:2.96
实验值:C:46.62 H:2.84
中间体3
2-甲氧基-7-(4-甲氧苯基)萘
方法A
三氟甲磺酸(7-甲氧基-2-萘基)酯(3.15克,10.3毫摩尔)、4-甲氧基-苯基硼酸(2.2克,14毫摩尔)、碳酸钠(10毫升的2N水溶液)、四(三苯基膦)钯(0.59克,0.05毫摩尔)和100毫升乙二醇二甲醚的混合物加热回流8小时。冷却混合物至室温并倾入100毫升的1N NaOH中。混合物用乙酸乙酯(3×250毫升)萃取,用盐水(2×100毫升)洗涤,用硫酸镁干燥,过滤,蒸发溶剂,用二氧化硅色谱法(5%-10%乙酸乙酯-己烷)提纯,得到2.17克(79%)标题化合物,为白色固体:
mp 154℃;1H NMR(CDCl3):δ3.87(3H,s),3.94(3H,s),7.02(2H,d,J=8.72Hz),7.13(1H,dd,J=2.54Hz,J=9.09Hz),7.18(1H,d,J=2.55Hz),7.56(1H,dd,J=1.82Hz,J=8.36Hz),7.65(2H,d,J=8.72Hz),7.74(1H,d,J=9.09Hz),7.81(1H,d,J=8.36Hz),7.89(1H,d,J=1.09Hz);MS(EI)m/z264(M-).
对C18H16 2的分析:
计算值:C:81.79 H:6.10
实验值:C:81.78 H:6.17
中间体4
2-甲氧基-7-(3-甲氧苯基)萘
根据上述方法A,通过三氟甲磺酸7-甲氧基-2-萘基酯(2.20克,7.18毫摩尔)与3-甲氧基苯基硼酸(1.20克,7.90毫摩尔)反应制备标题化合物,得到白色固体:
mp 58-59℃;1H NMR(CDCl3):δ3.89(3H,s),3.93(3H,s),6.91-6.94(1H,m),7.15(1H,dd,J=2.42Hz,J=8.83Hz),7.191H,d,J=2.27Hz),7.23-7.25(1H,m),7.28-7.31(1H,m),7.37-7.42(1H,m),7.59(1H,dd,J=1.56Hz,J=8.46Hz),7.75(1H,d,J=8.84Hz),7.83(1H,d,J=8.45Hz),7.94(s1H,s);MS(ESI)m/z265(M+H)-.
对C18H16O2的分析:
计算值:C:81.79 H:6.10
实验值:C:81.61 H:5.99
中间体5
2-甲氧基-7-苯基萘根据上述方法A,通过三氟甲磺酸7-甲氧基-2-萘基酯(3.01克,9.83毫摩尔)与苯基硼酸(1.4克,12毫摩尔)反应制备标题化合物,得到1.95g(85%)白色固体:
mp 62-64℃;1H NMR(CDCl3)δ3.95(3H,s),7.15(1H,dd,J=2.56Hz,J=8.79Hz),7.20(1H,d,J=2.56Hz),7.36-7.39(1H,m),7.46-7.50(2H,m),7.60(1H,dd,J=1.83Hz,J=8.42Hz),7.70-7.73(2H,m),7.76(1H,d,J=8.79Hz),7.84(1H,d,J=8.42Hz),7.94(1H,d,J=1.46Hz);MS(EI)m/z 234(M-)+.
对C17H14O·0.1H2O的分析:
计算值:C:86.48 H:6.06
实验值:C:86.29 H:6.04
实施例1a
7-(4-羟基苯基)-2-萘酚
方法B
2-甲氧基-7-(4-甲氧基-苯基)萘(1.02克,3.86毫摩尔)在190℃加入到盐酸吡啶鎓(10g)中。溶液在190℃搅拌3小时,然后冷却至室温,与200毫升的1N HCl一起搅拌。过滤得到的悬浮液,溶于乙酸乙酯(500毫升)。合并的有机层用水(200毫升)洗涤,用硫酸镁干燥,过滤,在真空下除去溶剂,产品用二氧化硅色谱法(40%乙酸乙酯-己烷)提纯,得到0.36克(39%)白色固体:
mp 210℃;1HNMR(DMSO-d6):δ6.89(2H,d,J=8.58Hz),7.05(1H,dd,J=2.42Hz,J=8.77Hz),7.17(1H,d,J=2.24Hz),7.52(1H,dd,J=1.68Hz,J=8.40Hz),7.61(2H,d,J=8.58Hz),7.74(1H,d,J=8.58Hz),7.79(1H,d,J=8.58Hz),7.86(1H,d,J=1.12Hz),9.60(1H,bs),9.72(1H,bs);MS(ESI)m/z 235(M-H)-.
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:81.23 H:5.09
实施例1b
7-(3-羟基苯基)-2-萘酚
根据方法B,通过2-甲氧基-7-(3-甲氧苯基)-萘(0.52克,1.97毫摩尔)与盐酸吡啶鎓(8克)在190℃反应,得到0.13克(28%)白色固体:
mp 163-165℃;1H NMR(DMSO-d6):δ6.78-6.80(1H,m),7.08(1H,dd,J=2.56Hz,J=8.54Hz),7.13-7.14(1H,m),7.17-7.20(2H,m),7.27-7.30(1H,m),7.51(1H,dd,J=2.14Hz,J=8.54Hz),7.70(1H,d,J=8.97Hz),7.83(1H,d,J=8.54Hz),7.90(1H,d,J=1.28Hz),9.55(1H,s),9.78(1H,s);MS(ESI)m/z 235(M-H)-.
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:80.96 H:5.07
实施例1c
7-苯基-2-萘酚
根据方法B,通过2-甲氧基-7-苯基萘(0.53克,2.26毫摩尔)与盐酸吡啶鎓(10克)在190℃反应,得到0.36克(72%)白色固体:
mp 142-143℃;1H NMR(DMSO-d6):δ7.10(1H,dd,J=2.75Hz,J=8.70Hz),7.23(1H ,d,J=2.29Hz),7.37-7.40(1H,m),7.48-7.51(2H,m),7.58(1H,dd,J=1.83Hz,8.70Hz),7.78-7.90(3H,m),7.86(1H,d,J=8.24Hz),7.99(1H,d,J=0.92Hz)9.81(1H,s);MS(ESI)m/z 219(M-H)-.
对C16H12O·0.1H2O的分析:
计算值:C:86.66 H:5.47
实验值:C:86.72 H:5.62
路线2中化合物的合成
中间体6
6-(三氟甲烷磺酸盐)-1-四氢萘酮
在500毫升烧瓶中,6-羟基-1-四氢萘酮(4.8克,29.6毫摩尔)与二甲苯共沸,溶于无水CH2Cl2(220毫升)。然后将溶液冷却到0℃,加入无水吡啶(3.35毫升,41.4毫摩尔),再加入三氟甲磺酸酐(10.0克,35.5毫摩尔)。在0℃0.5小时后,反应用饱和碳酸氢钠淬灭,并用水洗涤。将有机层通过硅塞,浓缩得到8.39克(96%)产物,为浅黄色油:
1H NMR(300MHz,DMSO-d6)δ2.07(2H,m),2.65(2H,t,J=6.5Hz),3.03(2H,t,J=6.0Hz),7.47(1H,dd,J=8.7Hz,2.3Hz),7.57(1H,d,J=1.9Hz),8.03(1H,d,J=8.7Hz).
中间体7
6-(4-羟基苯基)-1-四氢萘酮
4-{[叔丁基(二甲基)甲硅烷基]氧基}苯基硼酸。在500毫升烧瓶中加入(4-溴代苯氧基)-叔丁基二甲基硅烷(15.0克,52.2毫摩尔)和无水THF(125毫升)。将混合物冷却至-78℃,用注射器缓慢加入正丁基锂(25毫升在己烷中2.5M的溶液,62.7毫摩尔)。在搅拌0.5小时后,加入三异丙基硼酸酯(60毫升,261毫摩尔),溶液在-78摄氏搅拌1.5小时,然后温热至室温。然后加入冰冷的2N HCl(150毫升),搅拌混合物10分钟。然后用乙酸乙酯(3x)萃取混合物,用硫酸钠干燥,减压浓缩至大约50毫升。将己烷加入到浓缩物中诱导结晶(3批),然后通过过滤收集,在真空下干燥,得到12.36克(89%)黄白色固体:
1H NMR(300MHz,DMSO-d6)δ0.19(6H,s),0.95(9H,s),6.80(2H,d,J=8.1Hz),7.67(2H,d,J=8.1Hz).
在500毫升烧瓶中加入6-(三氟甲烷磺酸盐)-1-四氢萘酮(5.0克,17.0毫摩尔)、4-{[叔丁基(二甲基)甲硅烷基]氧基}苯基硼酸(5.45克,20.4毫摩尔,如上制备)、碳酸钠(4.56克,2N水溶液,42.5毫摩尔)和在DME(200毫升)中的四(三苯基膦)钯(0)(0.98克,0.85毫摩尔),回流12小时。将反应冷却,用乙酸乙酯(3x)萃取,浓缩得到固体。固体用己烷洗涤,在真空下干燥,得到3.68克产物(92%)棕色固体。
mp 208-210℃;1HNMR(300MHz,DMSO-d6)δ2.06(2H,m),2.60(2H,t,J=6.5Hz),2.99(2H,t,J=5.9Hz),6.87(2H,d,J=8.6Hz),7.57(4H,m),7.86(1H,d,J=8.7Hz),9.74(1H,s);MSm/z237(M-H+);
对C16H14O2:的分析:
计算值:C:80.65 H:5.92
实验值:C:79.04 H:5.60
实施例1d
6-(4-羟基苯基)-1-萘酚
向25毫升烧瓶中加入6-(4-羟基苯基)-1-四氢萘酮(500毫克,2.12毫摩尔)、披钯碳(510毫克)和对异丙基苯甲烷(15毫升)。混合物加热回流24小时,冷却,用硅藻土过滤,用1M NaOH(2×25毫升)萃取。然后酸化水层,用乙醚(3x)萃取,通过硅塞。减压浓缩,得到260毫克(53%)产品,为棕色固体:
mp高于200℃(dec.);1H NMR(300MHz,DMSO-d6)δ6.82(1H,d,J=7.5Hz),6.87(2H,d,J=8.1Hz),7.29(1H,t,J=7.5Hz),7.38(1H,d,J=7.5Hz),7.63(2H,d,J=8.2Hz),7.70(1H,d,J=8.5Hz),7.99(1H,s)8.14(1H,d,J=8.5Hz),9.59(1H,s),10.09(1H,s);MS m/z 235(M-H+).
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:81.22 H:5.30
路线3中化合物的合成
中间体10
2-甲氧基-7-(4-甲氧苯基)萘
向2-溴-6-甲氧基萘(23.79克,100.3毫摩尔)和四(三苯基膦)钯(5.8克,5毫摩尔)的混合物中加入4-甲氧基苯基溴化镁在THF中的溶液(400毫升的0.5N溶液,200毫摩尔)。搅拌的溶液加热回流3小时,冷却到室温,然后在200毫升的1N HCl中搅拌。混合物用二氯甲烷萃取,通过短的硅塞和二氯甲烷一起过滤。除去溶剂得到粗黄色固体,将其进一步用二氧化硅色谱法提纯(20-50%乙酸乙酯-己烷),得到25.68克(97%)标题化合物白色固体:mp190℃;1H NMR(CDCl3):δ3.86(3H,s),3.93(3H,s),7.01(2H,d,J=8.57Hz),7.14-7.18(2H,m),7.63(2H,d,J=8.50Hz),7.67(1H,dd,J=1.68Hz,J=8.73Hz),7.76-7.80(2H,m),7.91(1H,d,J=0.94Hz);MS(ESI)m/z 265(M+H)+.
对C18H16O2的分析:
计算值:C:81.79 H:6.10
实验值:C:82.04 H:6.17
中间体11
2-(4-甲氧苯基)萘
通过2-溴萘(3.04克,14.7毫摩尔)和4-甲氧基苯基溴化镁根据制备中间体10所用的方法反应制备标题化合物,得到2.89克(89%)白色固体:
mp 114℃;1H NMR(CDCl3):δ3.86(3H,s),7.01(2H,d,J=9.06Hz),7.43-7.50(2H,m),7.65(2H,d,J=8.73Hz),7.71(1H,dd,J=1.84Hz,J=8.56Hz),7.83-7.89(3H,m),7.98(1H,d,J=0.67Hz);MS(EI)m/z234(M-)+.
对C17H14O的分析:
计算值:C:87.15 H:6.02
实验值:C:86.75 H:6.14
中间体12
2-甲氧基-6-苯基萘
通过2-溴-6-甲氧基萘(1.97克,8.31毫摩尔)和苯基溴化镁根据制备中间体10所用的方法反应制备标题化合物,得到1.59克(82%)白色固体:
mp 122-126℃;1HNMR(CDCl3):δ3.94(3H,s),7.16-7.18(2H,m),7.34-7.37(1H,m),7.46-7.49(2H,m),7.69-7.72(2H,m),7.78-7.82(2H,m),7.97(1H,s);MS(EI)m/z 234.2(M-)+.
对C17H14O的分析:
计算值:C:87.15 H:6.02
实验值:C:86.79 H:6.14
中间体13
2-甲氧基-6-(3-甲氧苯基)萘
通过6-甲氧基-2-溴萘(3.09克,13.0毫摩尔)和3-甲氧基苯基硼酸(2.18克,14.3毫摩尔)根据方法A反应制备标题化合物,得到1.18克(34%)白色固体:
mp 80℃;1H NMR(CDCl3):δ3.88(3H,s),3.92(3H,s),6.90(1H,dd,J=2.17Hz,J=7.76Hz),7.14-7.18(2H,m),7.22-7.24(1H,m),7.28(1H,d,J=7.45Hz),7.36-7.39,(1H,m),7.70(1H,dd,J=1.86Hz,J=8.70Hz),7.77-7.80(2H,m),7.96(1H,d,J=1.24Hz);MS(ESI)m/z265(M+H)+.
对C18H16O2的分析:
计算值:C:81.79 H:6.10
实验值:C:81.61 H:6.47
实施例1i
6-(3-氯苯基)-2-萘酚
6-溴-2-萘酚(1.78克,8.0毫摩尔)、2-氯苯基硼酸(1.5克,9.6毫摩尔)、碳酸钠(2.11g的2N水溶液,20.0毫摩尔)和四(三苯基膦)钯(0)(550毫克,0.48毫摩尔)在DME中(95毫升)的混合物根据方法A反应。柱色谱(30%乙酸乙酯-己烷)得到520毫克(26%)的产品,为黄褐色固体:
mp 116-118℃;1H NMR(300MHz,DMSO-d6)δ7.13(2H,m),7.42(1H,td,J=7.9Hz,0.9Hz),7.51(1H,t,J=7.6Hz),7.80(5H,m),8.16(1H,s),9.88(1H,s);MS m/z 253/255(Cl pattern)(M-H+);
对C16H11ClO的分析:
计算值:C:75.45 H:4.35
实验值:C:75.20 H:4.34
实施例1e
6-(4-羟基苯基)-2-萘酚
根据方法B,将2-甲氧基-6-(4-甲氧苯基)萘(5.61g,21.2毫摩尔)在190℃加入盐酸吡啶鎓(30克)中,得到4.88克(98%)白色固体:
mp>220(大于200℃失色);1H NMR(DMSO-d6):δ6.87(2H,d,J=8.54Hz),7.08(1H,dd,J=2.34Hz,J=8.76Hz),7.11(1H,d,J=2.14Hz),7.58(2H,d,J=8.54Hz),7.65(1H,dd,J=1.92Hz,J=8.76Hz),7.71(1H,d,J=8.54Hz),7.79(1H,d,J=8.97Hz),7.95(1H,s),9.56(1H,bs),9.70(1H,bs);MS(ESI)m/z 235(M-H)-.
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:81.05 H:5.18
实施例1f
4-(2-萘基)酚
根据方法B,在190℃,通过2-(4-甲氧苯基)-萘(1.01克,4.31毫摩尔)和10g盐酸吡啶鎓反应制备标题化合物,得到0.84克(89%)白色固体:
mp 148℃;1H NMR(DMSO-d6):δ6.92(2H,d,J=8.71Hz),7.46-7.53(2H,m),7.66(2H,d,J=8.71Hz),7.79(1H,dd,J=1.78Hz,J=8.51Hz),7.90(1H,d,J=8.31Hz),7.95(2H,d,J=8.31Hz),8.11(1H,d,J=1.19Hz),9.65(1H,s);MS(ESI)m/z219(M-H)-.
对C16H12O2的分析:
计算值:C:87.25 H:5.49
实验值:C:87.31 H:5.86
实施例1g
6-苯基-2-萘酚
根据方法B,在190℃通过2-甲氧基-6-苯基萘(0.54克,2.30毫摩尔)和盐酸吡啶鎓(10g)反应制备标题化合物,得到0.32克(63%),为浅粉色固体:
mp 169-170℃;1H NMR(DMSO-d6):δ7.12(1H,dd,J=2.56Hz,J=8.54Hz),7.16(1H,d,J=2.56Hz),7.35-7.38(1H,m),7.47-7.50(2H,m),7.73(1H,dd,J=1.71Hz,J=8.54Hz),7.76-7.79(3H,m),7.85(1H,d,J=8.54Hz),8.08(1H,d,J=1.28Hz),9.82(1H,s);MS(ESI)m/z 219(M-H)-.
对C16H12O的分析:
计算值:C:87.25 H:5.49
实验值:C:87.05 H:5.55
实施例1h
6-(3-羟基苯基)-2-萘酚
根据方法B,在190℃,通过2-甲氧基-6-(3-甲氧苯基)-萘(0.51克,1.90毫摩尔)和盐酸吡啶鎓(6克)反应制备标题化合物,得到0.21克(47%)的米色固体:
mp 192-194℃;1H NMR(DMSO-d6):δ6.75-6.78(1H,m),7.10-7.14(3H,m),7.16-7.18(1H,m),7.65(1H,dd,J=1.79Hz,J=8.57Hz),7.75(1H,d,J=8.77Hz),7.84(1H,d,J=8.77Hz),8.01(1H,d,J=1.59Hz),9.51(1H,s),9.78,(1H,s);MS(ESI)m/z 235(M-H)-.
对C16H12O2的分析:
计算值:C:81.34 H:5.12
实验值:C:80.94 H:5.09
路线4中化合物的合成
中间体14
1-溴-2-甲氧基-6-(4-甲氧苯基)萘
向2-甲氧基-6-(4-甲氧苯基)萘(9.68克,36.6毫摩尔)和冰醋酸(150毫升)的混合物中缓慢加入溴(5.85g,36.6毫摩尔)在冰醋酸(20毫升)中的溶液。混合物搅拌1小时,得到的悬浮液倾入水(200毫升)中,过滤收集固体产物。固体首先与水一起研磨,然后和乙酸乙酯一起研磨,得到11.25克(90%)标题化合物白色固体:
mp 172-174℃;1H NMR(CDC13):δ3.88(3H,s),4.05(3H,s),7.04(2H,d,J=8.56Hz),7.30(1H,d,J=9.01Hz),7.67(2H,d,J=8.65Hz),7.81(1H,dd,J=1.61Hz,J=8.84Hz),7.87(1H,d,J=9.04Hz),7.94(1H,d,J=1.47Hz),8.27(1H,d,J=8.92Hz);MS(EI)m/z 343(M)+.
对C18H15BrO2的分析:
计算值:C:62.99 H:4.41
实验值:C:62.66 H:4.57
中间体15
1-氯-2-甲氧基-6-(4-甲氧苯基)萘
方法C
2-甲氧基-6-(4-甲氧苯基)萘(0.51克,1.93毫摩尔)和NCS(0.28克,2.13毫摩尔)在乙腈(20毫升)中的悬浮液加热回流3小时。得到的溶液冷却到室温,过滤收集得到的固体,用乙腈冲洗,得到0.41g(72%)标题化合物,为白色固体:
mp 158-164℃;1H NMR(CDCl3):δ3.87(3H,s),4.05(3H,s),7.03(2H,d,J=8.62Hz),7.32(1H,d,J=9.02Hz),7.65(2H,d,J=8.55Hz),7.82(2H,d,J=9.01Hz),7.95(1H,d,J=1.36Hz),8.27(1H,d,J=8.81Hz);MS(EI)m/z 298(M-)+.
对C18H15ClO2的分析:
计算值:C:72.36 H:5.06
实验值:C:72.06 H:4.89
实施例1o
1-溴-6-(4-羟基苯基)-2-萘酚
在0℃向6-(4-羟基苯基)-2-萘酚(4.02克,17.0毫摩尔)在乙腈(150毫升)中的溶液中加入NBS(3.03克,17.0毫摩尔)。反应在0℃搅拌3小时,然后倾入水(200毫升)中,用乙酸乙酯(3×300毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,用二氧化硅柱色谱(20%乙酸乙酯-己烷)提纯,得到5.33克(100%)标题化合物,为黄褐色固体。进一步用逆向高压液相色谱法提纯标题化合物,得到白色固体:
mp 208-210℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.47Hz),7.28(1H,d,J=8.80Hz),7.63(2H,d,J=8.50Hz),7.85(2H,d,J=8.84Hz),8.02-8.06(2H,m),9.60(1H,s),10.54(1H,s);MS(ESI)m/z 313/315(M-H)-.
对C16H11BrO2的分析:
计算值:C:60.98 H:3.52
实验值:C:60.63 H:3.46
实施例1p
1-氯-6-(4-羟基苯基)-2-萘酚
根据方法B,在190℃,通过1-氯-2-甲氧基-6-(4-甲氧苯基)-萘(0.32克,1.07毫摩尔)和盐酸吡啶鎓(7g)反应制备标题化合物,得到0.12克(41%)的米色固体:
mp 222-224℃(dec.);1H NMR(DMSO-d6):δ6.88(2H,d,J=8.46Hz),7.29(1H,d,J=8.88Hz),7.63(2H,d,J=8.50Hz),7.81-7.88(2H,m),8.02-8.08(2H,m),9.59(1H,s),10.43(1H,s);MS(ESI)m/z 269/271(M-H)-.
对C16H11ClO2:的分析:
计算值:C:70.99 H:4.10
实验值:C:70.59 H:4.12
实施例1q
6-(4-羟基苯基)-1-甲氧基-2-萘酚
1-溴-6-(4-羟基苯基)-2-萘酚(0.41克,1.30毫摩尔)、CuBr(0.19克,0.13毫摩尔)、甲醇钠(3毫升4.4N在甲醇中的溶液)和DMF(6毫升)的混合物加热回流3小时。将反应混合物冷却至室温,倾入HCl(50毫升的1N水溶液),用乙酸乙酯(3×100毫升)萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸钠干燥,过滤,脱去溶剂,用二氧化硅柱色谱提纯(40%乙酸乙酯-己烷),得到0.31克(89%)标题化合物白色固体:
mp 204-206℃;1H NMR(DMSO-d6):δ6.88(2H,d,J=8.47Hz),7.19(1H,d,J=8.81Hz),7.57-7.60(3H,m),7.71(1H,dd,J=1.41Hz,J=8.78Hz),7.94-7.98(2H,m),9.54(2H,s);MS m/z(M-H)-=265;
对C17H14O3的分析:
计算值:C:76.68 H:5.30
实验值:C:76.46 H:5.13
路线5中化合物的合成
中间体16
2-甲氧基-6-(4-甲氧苯基)-1-氟萘
在-78℃向2-甲氧基-6-(4-甲氧苯基)-1-溴萘(1.28克,3.72毫摩尔)在THF(25毫升)中的溶液中缓慢加入正丁基锂(1.9毫升2.5N的在己烷中的溶液)得到的溶液在-78℃搅拌30分钟,加入N-氟苯磺酰亚胺(1.40克,4.5毫摩尔)在THF(10毫升)中的溶液。在-78℃再过2小时后,反应升温至室温,倾入水中,用乙酸乙酯(2×250毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,用二氧化硅色谱法(5%THF-己烷)提纯,得到0.66克(63%)的白色固体:
mp 150-155℃;1H NMR(CDCl3):δ3.88(3H,s),4.04(3H,s),7.02(2H,d,J=8.69Hz),7.28-7.34(1H,m),7.62-7.67(3H,m),7.74(1H,dd,J=1.60Hz,J=8.79Hz),7.93(1H,s),8.09(1H,d,J=8.77Hz).
对C18H15O2F的分析:
计算值:C:76.58 H:5.36
实验值:C:75.78 H:5.95
中间体17
2-甲氧基-6-(4-甲氧苯基)-1-萘甲腈
1-溴-2-甲氧基-6-(4-甲氧苯基)萘(0.76克,2.21克)、CuCN(0.24克,2.66毫摩尔)和DMF(10毫升)的混合物在120℃搅拌4小时。反应混合物冷却至室温,用乙酸乙酯制浆,通过二氧化硅过滤,蒸发溶剂,用二氧化硅柱色谱(20%乙酸乙酯-己烷)提纯,得到0.19g(30%)标题化合物,为浅黄固体:
1H NMR(CDCl3):δ3.88(3H,s),4.09(3H,s),7.03(2H,d,J=8.73Hz),7.29(1H,d,J=9.12Hz),7.63(2H,d,J=8.73Hz),7.88(1H,dd,J=1.98Hz,J=8.73Hz),7.97(1H,d,J=1.98Hz),8.09(1H,d,J=9.12Hz),8.14(1H,d,J=8.73Hz).
对C19H15O2N的分析:
计算值:C:78.87 H:5.23 N:4.84
实验值:C:79.06 H:7.27 N:2.91
中间体18
2-甲氧基-6-(4-甲氧苯基)-1-苯基萘
向2-甲氧基-6-(4-甲氧苯基)-1-溴萘(0.80克,2.33毫摩尔)和四(三苯基膦)钯(0.13克,0.12毫摩尔)在THF(10毫升)中的混合物中加入苯基溴化镁(2.2毫升3N在乙醚中的溶液)。反应混合物在回流下搅拌过夜,冷却至室温,倾入1N盐酸中(100毫升),用乙酸乙酯(3×200毫升)萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸镁干燥,过滤,蒸发溶剂,通过二氧化硅柱色谱(10%乙酸乙酯-己烷)提纯,得到0.42克(53%)灰色固体:
mp 157-160℃;1HNMR(CDCl3):δ3.85(3H,s),3.87(3H,s),7.01(2H,d,J=8.64Hz).7.38-7.46(4H,m),7.49-7.57(4H,m),7.64(2H,d,J=8.64Hz),7.92(1H,d,J=9.05Hz),7.97(1H,s);MS(ESI)m/z 341(M+H)+.
对C24H20O2·0.5H2O的分析:
计算值:C:82.50 H:6.06
实验值:C:82.60 H:5.66
中间体19
2-甲氧基-6-(4-甲氧苯基)-1-甲基萘
向2-甲氧基-6-(4-甲氧苯基)-1-溴萘在THF(25毫升)中的溶液中在0℃缓慢加入正丁基锂(2ml,2.5N)和TMEDA(0.60克,5.13毫摩尔,新从KOH蒸馏得到)。在0℃30分钟后,加入碘代甲烷(7.3克,51.3毫摩尔,通过碱性三氧化二铝),搅拌溶液使其升温至室温过夜。将反应物倾入水(100毫升)中,用乙酸乙酯(3×200毫升)萃取。合并的有机层用水洗涤,用硫酸镁干燥,过滤,蒸发溶剂,通过二氧化硅柱色谱(5%THF-己烷)提纯,得到0.63克(88%)白色固体:
mp 136-138℃;1H NMR(CDCl3):δ3.87(3H,s),3.96(3H,s),7.02(2H,d,J=8.74Hz),7.29(1H,d,J=9.01Hz),7.60-7.80(4H,m),7.95(1H,d,J=1.76Hz),8.00(1H,d,J=8.86Hz);MS(ESI)m/z279(M+H)+.
对C19H18O2·0.3H2O的分析:
计算值:C:80.43 H:6.61
实验值:C:80.20 H:6.33
实施例1r
1-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过2-甲氧基-6-(4-甲氧苯基)-1-氟萘(0.250克,0.886毫摩尔)与三溴化硼(2.7毫升1N溶液,2.7毫摩尔)反应制备标题化合物,得到0.13克(15%)白色固体:
mp219-224℃;1H NMR(DMSO-d6):δ(6.89(2H,d,J=8.49Hz),7.22-7.28(1H,m),7.61(2H,d,J=8.53Hz),7.65(1H,d,J=9.12Hz),7.79(1H,d,J=8.77Hz),7.92(1H,d,J=8.73Hz),8.05(1H,s),9.63(1H,bs),10.00(1H,bs);MS(ESI)m/z253(M-H)-.
对C16H11FO2:的分析:
计算值:C:75.58 H:4.36
实验值:C:75.13 H:4.40
实施例1s
2-羟基-6-(4-羟基苯基)-1-萘甲腈
根据方法D,通过2-甲氧基-6-(4-甲氧苯基)-萘甲腈(0.115g,0.397毫摩尔)与盐酸吡啶鎓(4g)在190℃反应,得到0.025g(24%)棕褐色固体:
mp>220℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.37Hz),7.28(1H,d,J=9.07Hz),7.63(2H,d,J=8.42Hz),7.88-7.98(2H,m),8.12-8.16(2H,m),9.63(1H,s),11.65(1H,bs);MS(ESI)m/z260(M-H)-
对C17H11NO2·0.4H2O的分析:
计算值:C:76.05 H:4.43 N:5.22
实验值:C:76.09 H:4.25 N:4.83.
实施例1t
6-(4-羟基苯基)-1-苯基-2-萘酚
方法D
向2-甲氧基-6-(4-甲氧苯基)-1-苯基萘(0.36克,1.06毫摩尔)在CH2Cl2(25毫升)中的混合物中在0℃缓慢加入三溴化硼(3.2毫升,1N在CH2Cl2中的溶液)。将混合物温热至室温并搅拌过夜。将得到的溶液倾入水(100毫升)中,用乙酸乙酯(3×150毫升)萃取。合并的有机层用饱和碳酸氢钠溶液洗涤,用硫酸镁干燥,蒸发溶剂,通过二氧化硅柱色谱(25%乙酸乙酯-己烷)提纯,然后用制备逆相HPLC法提纯,在真空下在105℃干燥,得到0.14克(42%)标题化合物,为白色固体:
mp 142-146℃;1H NMR(DMSO-d6):δ6.86(2H,d,J=8.50Hz),7.26-7.42(5H,m),7.48-7.61(5H,m),7.84(1H,d,J=8.96Hz),8.02(1H,d,J=1.46Hz),9.52(2H,s);MS(ESI)m/z 311(M-H)-.
对C22H16O2·0.1H2O的分析:
计算值:C:84.11 H:5.20
实验值:C:83.90 H:5.15
实施例1u
6-(4-羟甲基)-1-甲基-2-萘酚
根据方法D,通过2-甲氧基-6-(4-甲氧苯基)-1-甲基萘(0.35克,1.26毫摩尔)与三溴化硼(3.8毫升1N溶液,3.8毫摩尔)反应制备标题化合物,得到0.15克(48%)白色固体:
mp>170℃(dec.);1H NMR(DMSO-d6):δ2.42(3H,s),6.87(2H,k d,J=8.33Hz),7.15(1H,d,J=8.81Hz),7.59(2H,d,J=8.35Hz),7.65(1H,d,J=8.93Hz),7.71(1H,dd,J=1.24Hz,J=8.90Hz),7.88(1H,d,J=8.87Hz),7.95(1H,s),9.49(1H,s),9.52(1H,s);MS(ESI)249 m/z(M-H)-.
对C17H14O2的分析:
计算值:C:81.58 H:5.64
实验值:C:81.15 H:5.58
路线6中化合物的合成
中间体27
叔丁基[(6-溴-2-萘基)氧基]二甲基甲硅烷
方法E
向6-溴-2-萘酚(13.68克,61.33毫摩尔)和TBDMS-Cl(11.09克,73.6毫摩尔)在DMF(50毫升)中的溶液中加入咪唑(10.2克,150毫摩尔)。将溶液搅拌3小时,与碳酸氢钠溶液(250毫升)混合,用50%乙酸乙酯-己烷(3×250毫升)萃取。合并的有机层用水洗涤,用硫酸镁干燥,过滤,然后蒸发溶剂,得到棕褐色的油,其在真空下干燥,得到19.92g(97%)标题化合物,为白色固体:
1H NMR(CDCl3):δ0.24(6H,s),1.01(9H,s),7.08(1H,dd,J=2.26Hz,J=8.81Hz),7.14(1H,d,J=2.15Hz),7.46(1H,dd,J=1.80Hz,J=8.77Hz),7.54(1H,d,J=8.77Hz),7.61(1H,d,J=8.81Hz),7.90(1H,s);MS(EI)m/z 336/338(M-)+.
对C16H21BrO1Si·0.25H2O的分析:
计算值:C:56.97 H:6.27
实验值:C:56.81 H:6.43
中间体22
叔丁基(4-溴-2,6-二氟-苯氧基)二甲基甲硅烷
根据方法E,通过4-溴-2,6-二氟-酚(10.54克,50.4毫摩尔)与TBDMS-Cl(9.88克,150.7毫摩尔)反应制备标题化合物,得到14.61克(90%)的一种清澈无色的油:
1H NMR(CDCl3)δ0.17(6H,s),0.99(9H,s),7.02(H,d.J=7.13Hz).
中间体28
叔丁基[(2-(6-萘基硼酸)氧基]二甲基甲硅烷
方法F
向叔丁基[(6-溴-2-萘基)氧基]二甲基甲硅烷(19.18克,56.9毫摩尔)在THF(200毫升)中的溶液中在-78℃缓慢加入正丁基锂(25毫升,2.5N在己烷中的溶液)。搅拌溶液30分钟,然后加入三异丙基硼酸酯(53.5克,285毫摩尔)。在-78℃搅拌溶液1小时,然后升温至室温过夜。然后冷却溶液至0℃,与盐酸(200毫升1N溶液)一起搅拌10分钟。混合物用乙酸乙酯(3×250毫升)萃取。合并的有机层浓缩到25毫升体积。用己烷引导结晶,过滤收集固体产物,在真空下干燥,得到13.5克(79%)标题化合物,为米色固体:
1H NMR(DMSO-d6):δ0.25(6H,s),0.99(9H,s),7.10(1H,dd,J=2.56Hz.J=8.97Hz),7.26(1H,d,J=2.56Hz),7.73(1H,d,J=8.54Hz),7.82(1H,dd,J=1.07Hz,J=8.33Hz),7.83(1H,d,J=8.97Hz),8.30(1H,s);MS(ESI)m/z 303(M+H)+.
对C16H23BO3Si的分析:
计算值:C:63.58 H:7.67
实验值:C:46.97 H:6.78
中间体29
3-氟-4-甲氧基苯基硼酸
根据方法F,通过4-溴-2-氟茴香醚(10克,0.049摩尔)与正丁基锂(23.4毫升,2.5M在己烷中的溶液,0.059摩尔)反应,然后与三异丙基硼酸酯(45.2毫升,36.9g,0.196摩尔)反应制备标题化合物,得到7.1克(85.2%)白色固体:
MS(ESI)m/z 169(M-H)-:1H NMR(DMSO-d6):δ3.84(3H,s),7.10-7.16(1H,m),7.51-7.60(2H,m).
中间体30
3,5-二氟-4-叔丁基二甲基甲硅烷氧基硼酸
根据方法F,叔丁基(4-溴-2,6-二氟-苯氧基)二甲基甲硅烷(12.98克,40.19毫摩尔)与正丁基锂(27.6毫升,1.6N溶液,44.2毫摩尔)反应,然后与三异丙基硼酸酯(37.8克,200毫摩尔)反应制备标题化合物,得到4.38克(38%)白色固体:
1H NMR(DMSO-d6):δ0.25(6H,s),1.06(9H,s),7.54(2H,d,J=7.93Hz).
中间体31
4-甲氧基-2-甲基苯基硼酸
根据方法F,通过4-溴-3-甲基茴香醚(10克,0.050摩尔)与正丁基锂(24毫升2.5M在己烷中的溶液,0.055摩尔)反应,然后与三异丙基硼酸酯(57.7毫升,47.02g,0.25摩尔)反应制备标题化合物,得到5.7克(69%)白色固体:MS(ESI)m/z 313(2M-H2O-H)-.
中间体33
2-(3-氟-4-甲氧苯基)萘
根据方法A,通过2-溴萘(0.31克,1.50毫摩尔)与3-氟-4-甲氧基苯基硼酸(0.31克,1.80毫摩尔)反应制备标题化合物,得到0.30克(79%)白色固体:
mp 108-110℃;1H NMR(CDCl3):δ(3.96,3H,s),7.04-7.10(1H,m),7.43-7.52(4H,m),7.68(1H,dd,J=1.81Hz,J=8.57Hz),7.84-7.92(3H,m),7.97(1H,d,J=1.05Hz).
对C17H13FO的分析:
计算值:C:80.93 H:5.19
实验值:C:81.01 H:4.78
实施例1ay
6-(3,5-二氟-4-羟基苯基)-2-萘酚
根据方法A,通过6-溴-2-萘酚(0.165克,0.74毫摩尔)与3,5-二氟-4-叔丁基二甲基甲硅烷氧基硼酸(0.25克,0.87毫摩尔)反应制备标题化合物,得到0.14克(70%)棕褐色固体该原料进一步通过制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 216-220℃;1H NMR(DMSO-d6):δ7.09-7.13(2h,m),7.50(2H,d,J=10.00Hz),7.73(2H,s),7.78(1H,d,J=8.58Hz),8.10(1H,s),9.83(1H,s),10.2891H,s);MS(ESI)m/z 271(M-H)-.
对C16H10F2O2·0.25H2O的分析:
计算值:C:69.44 H:3.82
实验值:C:69.70 H:3.63
中间体34
6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法A,通过6-溴-2-萘酚(3.2克,18.8毫摩尔)与3-氟-4-甲氧基苯基硼酸(3.5g,15.7毫摩尔)反应制备标题化合物,得到3.3克(78%)白色固体:
mp 174-176℃;1H NMR(DMDO-d6):δ3.89(3H,s),7.11(1H,dd,J=8.79Hz,J=1.95Hz),7.13(1H,s),7.26(1H,J=8.79Hz),7.57(1H,d,J=8.79Hz),7.66(1H,dd,J=13.18Hz,J=1.95Hz),7.71(1H,dd,J=8.79Hz,J=1.46Hz),7.75(1H,d,J=8.79Hz),7.82(1H,d,J=8.79Hz),8.07(1H,s),9.81(1H,s);MS(ESI)m/z 267(M-H)-.
对C17H13FO2的分析:
计算值:C:76.11 H:4.88
实验值:C:76.03 H:4.78
中间体35
6-(4-甲氧基-2-甲基苯基)-2-萘酚
根据方法A,通过6-溴-2-萘酚(1.8克,5.4毫摩尔)与4-甲氧基-3-甲基苯基硼酸(1.74g,7.0毫摩尔)反应制备标题化合物,得到1.56克(73%)微黄的固体:
mp 124-126℃;1H NMR(DMDO-d6):δ2.25(3H,s),3.78(3H,s),6.85(1H,dd,J=8.35Hz,J=2.56Hz),6.90(1H,d,J=2.37Hz),7.09(1H,dd,J=8.75Hz,J=2.25Hz),7.13(1H,s),7.20(1H,d,J=8.33Hz),7.35(1H,dd,J=8.39Hz,J=1.37Hz),7.67(1H,s),7.70(1H,d,J=8.53Hz),7.78(1H,d,J=8.78Hz),9.74(1H,s);MS(ESI)m/z 263(M-H)-.
对C18H16O2的分析:
计算值:C:81.79 H:6.10
实验值:C:81.43 H:6.01
实施例1j
2-氟-4-(2-萘基)酚
根据方法D,通过2-(3-氟-4-甲氧苯基)-萘(0.22克,0.87毫摩尔)与三溴化硼(1.75毫升1N溶液,1.75毫摩尔)反应制备标题化合物,得到0.13克(63%)白色固体:
mp 110-112℃;1H NMR(DMSO-d6):δ7.05-7.11(1H,m),7.47-7.54(3H,m),7.65(1H,dd,J=2.20Hz,J=12.92Hz),7.82(1H,dd,J=1.80Hz,J=8.62),7.90-7.98(3H,m),8.17(1H,bs),10.07(1H,bs);MS(ESI)m/z 237(M-H)-.
对C16H11FO:的分析:
计算值:C:80.66 H:4.65
实验值:C:80.31 H:4.29
实施例1k
6-(3-氟-4-羟基苯基)-2-萘酚
根据方法D,通过6-(3-氟-4-甲氧苯基)-2-萘酚(600毫克,2.24毫摩尔)与三溴化硼(6.27毫升1.0M在CH2Cl2中的溶液,6.27毫摩尔)制备标题化合物,得到385毫克(68%)微黄固体:
mp 216-219℃;1H NMR(DMDO-d6):δ7.03-7.13(3H,m),7.43(1H,dd,J=8.37Hz,J=1.77Hz),7.58(1H,dd,J=12.92Hz,J=2.13Hz),7.68(1H,dd,J=8.68Hz,J=1.61Hz),7.74(1H,d,J=8.68Hz),8.03(1H,s),9.79(1H,s),9.98(1H,s);MS(ESI)m/z 253(M-H)-.
对C16H11FO2·0.13H2O的分析:
计算值:C:74.89 H:4.42
实验值:C:74.86 H:4.33
路线7中化合物的合成
中间体36
1-氯-6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法A,通过6-(3-氟-4-甲氧基苯基)-2-萘酚(1克,3.73毫摩尔)和NCS(748毫克,5.60毫摩尔)在THF(35毫升)中反应制备标题化合物,得到780毫克(69%)棕色固体:
mp 137-139℃;1H NMR(DMDO-d6):δ3.89(3H,s),7.26-7.33(2H,m),7.61(1H,d,J=8.63Hz),7.71(1H,dd,J=13.08Hz,J=2.16Hz),7.84(1H,d,J=8.93Hz),7.92(1H,dd,J=8.92Hz,J=1.80Hz),8.06(1H,d,J=8.86Hz),8.19(1H,d,J=1.55Hz),10.52(1H,s);MS(ESI)m/z301/303(M-H)-.
对C16H11ClO的分析:
计算值:C:67.45 H:4.00
实验值:C:67.35 H:3.78
中间体37
1-氯-6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法A,通过6-(4-甲氧基-2-甲基苯基)-2-萘酚(800毫克,3.03毫摩尔)和NCS(485毫克,3.61毫摩尔)在THF(35毫升)中反应制备标题化合物,得到640毫克(71%)黄色固体:
1H NMR(DMDO-d6):δ2.26(3H,s),3.79(3H,s),6.86(1H,dd,J=8.36Hz,J=2.63Hz),6.91(1H,d,J=2.51Hz),7.22(1H,d,J=8.34Hz),7.31(1H,d,J=8.89Hz),7.56(1H,dd,J=8.71Hz,J=1.71Hz),7.79-7.83(2H m),8.04(1H,J=8.91Hz),10.46(1H,s);13C NMR(DMDO-d6):δ20.54,55.07,111.48,112.21,115.71,118.73,121.94,127.92,128.15,128.35,129.34,130.12.130.87,133.26,136.14,136.36,150.99,158.49;MS(ESI)m/z 297/299(M-H)-.
对C18H15ClO2的分析:
计算值:C:72.36 H:5.06
实验值:C:72.02 H:5.03
实施例1v
1-氯-6-(3-氟-4-羟基苯基)-2-萘酚
根据方法D,通过1-氯-6-(3-氟-4-甲氧基苯基)-2-萘酚(420毫克,1.39毫摩尔)与三溴化硼(3.9毫升1.0M在CH2Cl2中的溶液,3.89毫摩尔)反应制备标题化合物,得到330毫克(82%)微黄固体:
mp 195-198℃;1H NMR(DMDO-d6):δ7.08(1H,t,J=8.86Hz),7.32(1H,d,J=8.89Hz),7.47(1H,dd,J=8.42Hz,J=1.52Hz),7.63(1H,dd,J=12.88Hz,J=1.98Hz),7.83(1H,d,J=8.95Hz),7.88(1H,dd,J=8.93Hz,J=1.61Hz),8.05(1H,d,8.86Hz),8.15(1H,d,J=1.25Hz),10.05(1H,s),10.50(1H,s);MS(ESI)m/z 287/289(M-H)-.
对C16H10ClFO2的分析:
计算值:C:66.56 H:3.49
实验值:C:66.37 H:3.65
实施例1y
1-氯-6-(4-羟基-2-甲基苯基)-2-萘酚
根据方法D,通过1-氯-6-(4-甲氧基-2-甲基苯基)-2-萘酚(400毫克,1.41毫摩尔)与三溴化硼(4.0毫升1.0M在CH2Cl2中的溶液,4.0毫摩尔)反应制备标题化合物,得到310毫克(77%)微黄固体:
mp 216-218℃;1H NMR(DMDO-d6):δ2.20(1H,s),6.68(1H,dd,J=8.19Hz,J=2.42Hz),6.72(1H,d,J=2.13Hz),7.10(1H,d,J=8.16Hz),7.29(1H,d,J=8.89Hz),7.29(1H,d,J=8.89Hz),7.53(1H,dd,J=8.78Hz,J=1.62Hz),7.76(1H,d,J=1.38Hz),7.80(1H,d,J=8.94Hz),8.02(1H,d,J=8.72Hz),9.4(1H,s),10.43(1H,s);13NMR(DMDO-d6):δ20.47,112.20,112.99,117.00,118.66,121.85,127.83,128.09,128.38,129.47,130.00,130.88,131.65,136.09,136.51,150.88,156.62;MS(ESI)m/z 283/285(M-H)-.
对C18H15ClO2的分析:
计算值:C:71.71 H:4.60
实验值:C:71.30 H:4.66
路线8中化合物的合成
中间体38
6-甲氧基-2-萘基硼酸
在500毫升烧瓶中加入2-溴-6-甲氧基萘(8.02克,33.8毫摩尔)、无水THF(125毫升)和一些1,10-菲咯啉结晶作为指示剂。将混合物冷却至-78℃,用注射器缓慢加入仲丁基锂(56毫升在己烷中1.3N的溶液,72.8毫摩尔)。在搅拌0.5小时后,加入三异丙基硼酸酯(47毫升,203.7毫摩尔),溶液在-78℃搅拌1小时,然后温热至室温。然后加入冰冷的2N盐酸(100毫升),混合物搅拌5分钟后,再加入2N盐酸(100毫升),再搅拌5分钟。然后将混合物用乙酸乙酯(3x)萃取,用硫酸镁干燥,浓缩到接近干燥。将己烷加入到浓缩液中,诱导结晶,然后过滤收集结晶,在真空下干燥,得到7.01克(约100%)浅橙色粉末。
1H NMR(500MHz,DMSO-d6)δ3.88(3H,s),7.15(1H,dd,J=8.9Hz,2.7Hz),7.29(1H,d,J=2.5Hz),7.75(1H,d,J=8.3Hz),7.83(2H,appt),8.30(1H,s);MS(EI)m/z 202.17(M+).
中间体39
2-氯-4-(6-甲氧基-2-萘基)酚
4-溴-2-氯酚(730毫克,3.5毫摩尔)、(6-甲氧基-2-萘基)硼酸(780毫克,3.85毫摩尔)、碳酸钠(930毫克的2N水溶液,8.8毫摩尔)和四(三苯基膦)钯(0)(203毫克,0.18毫摩尔)在DME(45毫升)中的混合物回流12小时。然后将反应冷却,用乙酸乙酯(3x)萃取,用硫酸钠干燥然后浓缩。柱色谱(30% EtOAc/己烷)得到360毫克(30%)的产物,为白色固体。
mp 129-130℃;1H NMR(300MHz,DMSO-d6)δ3.88(3H,s),7.08(1H,d,J=8.2Hz),7.17(1H,dd,J=8.6Hz,2.1Hz),7.34(1H,d,J=2.1Hz),7.59(1H,dd,J=8.6Hz,2.1Hz),7.75(2H,m),7.87(1H,d,J=8.8Hz),7.88(1H,d,J=8.6),8.09(1H,s),10.34(1H,s);MS m/z 283/285(Cl pattem)(M-H+);
对C17H13ClO2:的分析:
计算值:C:71.71 H:4.60
实验值:C:71.68 H:4.72
中间体40
3-氯-4-(6-甲氧基-2-萘基)酚
根据方法A,4-溴-3-氯酚(3.8克,18.3毫摩尔)和I12372-104(4.81g,23.8毫摩尔)反应制备标题化合物,得到5.09克(98%)白色固体:
mp 139-142℃;1H NMR(DMSO-d6):δ3.89(3H,s),6.87(1H,dd,J=8.39Hz,J=2.45Hz),6.98(1H,J=2.40Hz),7.19(1H,dd,J=8.98Hz,J=2.46Hz),7.32(1H,d,J=8.39Hz),7.35(1H,d,J=2.38Hz),7.50(1H,dd,J=8.47Hz,J=1.73Hz),7.83-7.88(3H,m),10.04(1H,s):MS(ESI)m/z 283/285(M-H)-.
对C16H11ClO:的分析:
计算值:C:71.71 H:4.60
实验值:C:71.50 H:4.62
中间体41
2,6-二氟-4-(6-甲氧基-2-萘基)酚
根据方法A,4-溴-2,6-二氟苯酚(3.5克,16.8毫摩尔)和中间体38(4.2克,20.2毫摩尔)反应制备标题化合物,得到1.1克(23%)白色固体:
mp 188-190℃;1H NMR(DMSO-d6):δ3.89(3H,s),7.19(1H,dd,J=8.92Hz,J=2.52Hz),7.34(1H,J=2.41Hz),7.48-7.59(2H,m),7.80(1H,dd,J=8.61Hz,J=1.76Hz),7.88(1H,d,J=8.65Hz),8.17(1H,d,J=1.25Hz),10.31(1H,s);MS(ESI)m/z 285(M-H)-.
对C17H12F2O2:的分析:
计算值:C:71.32 H:4.23
实验值:C:71.10 H:4.17
中间体42
4-甲基苯磺酸(4-(6-羟基-2-萘基)-3-甲氧苯基)酯4-甲基苯磺酸(4-溴-3-甲氧苯基)酯
4-溴-间苯二酚(4.92克,26.0毫摩尔)、对甲苯磺酰氯(5.95克,31.2毫摩尔)、碳酸钾(23克,167毫摩尔)和丙酮(300毫升)的混合物回流16小时。加入碘代甲烷(9.89克,70毫摩尔),混合物再回流12小时。将混合物冷却至室温,加入乙醚(200毫升),过滤悬浮液。将滤液脱除溶剂,在二氧化硅柱(10%乙酸乙酯-己烷)上提纯,得到6.49克(70%)标题化合物,为白色固体。
1H NMR(CDCl3):δ2.45(3H,s),3.78(3H,s),6.40(1H,dd,J=2.45Hz,J=8.60Hz),6.59(1H,d,J=2.48Hz),7.33(2H,d,J=8.30Hz),7.40(1H,d,J=8.69Hz),7.71(2H,d,J=8.23Hz);MS(ESI)m/z 355/357(M-H)-
对C14H13BrO4S的分析:
计算值:C:47.07 H:3.67
实验值:C:47.14 H:3.57
根据方法A,通过4-甲基苯磺酸(4-溴-3-甲氧苯基)酯(3.07克,8.60毫摩尔)和叔丁基[(2-(6-萘基硼酸)氧基]二甲基甲硅烷(2.86克,9.46毫摩尔)反应制备标题化合物,得到2.15克(53%)橙色固体:
1H NMR(CDCl3):δ2.44(3H,s),3.65(3H,s),6.69(1H,dd,J=2.10Hz,J=8.29Hz),6.74(1H,d,J=2.10Hz),7.06-7.11(2H,m),7.36(1H,d,J=8.27Hz),7.4569(1H,dd,J=1.32Hz,J=8.57Hz),7.51(1H,d,J=8.28Hz),7.67(1H,d,J=8.61Hz),7.77(1H,d,J=8.80Hz),7.80-7.85(3H,m),9.78(1H,s);MS(ESI)m/z 419(M-H)-.
对C24H20O5S·0.25H2O的分析:
计算值:C:67.82 H:4.86
实验值:C:67.75 H:4.56
实施例1aa
6-(4-羟甲基-2-甲氧苯基)-2-萘酚
4-甲苯磺酸(4-(6-羟基-2-萘基)-3-甲氧苯基)酯(1.74克,4.05毫摩尔)、氢氧化钾(5克)、水(85毫升)和乙醇(85毫升)的溶液在90℃搅拌2小时。将反应冷却至室温,浓缩至50%体积,用乙酸中和,用乙酸乙酯(3×200毫升)萃取。合并的有机层用盐水洗涤,用硫酸镁干燥,过滤,蒸发溶剂,通过二氧化硅柱色谱(25%乙酸乙酯-己烷)提纯,得到1.01克(94%)标题化合物,为棕褐色固体。样品进一步用制备逆相HPLC提纯,得到棕褐色固体:
mp 152-154℃;1H NMR(DMSO-d6):δ3.72(3H,s),6.46(1H,dd,J=1.52Hz,J=8.20Hz),6.52(1H,d,J=1.77Hz),7.04-7.09(2H,m),7.16(1H,d,J=8.23Hz),7.47(1H,d,J=8.50Hz),7.63(1H,d,J=8.57Hz),7.72-7.75(2H,m),9.56(1H,bs),9.68(1H,bs);MS(ESI)m/z 265(M-H)-.
对C17H14O3的分析:
计算值:C:76.68 H:5.30
实验值:C:76.68 H:5.30
实施例1l
6-(3-氯-4-羟基酚)-2-萘酚
2-氯-4-(6-甲氧基-2-萘基)酚(192毫克,0.71毫摩尔)和盐酸吡啶(3克,26毫摩尔)的混合物加热至200℃1小时,同时搅拌。将混合物冷却后,加入水溶解固体,水层用乙醚(3x)萃取。合并乙醚层,用硫酸钠干燥,通过二氧化硅填料。减压蒸发得到180毫克(98%)棕褐色固体产品。
mp 176-177℃;1H NMR(300MHz,DMSO-d6)δ7.09(3H,m),7.57(1H,dd,J=7.6Hz,1.5Hz),7.70(3H,m),7.82(1H,d,J=8.6Hz),8.02(1H,s),9.77(1H,s),10.28(1H,s);MS m/z 269/271(Clpattern)(M-H+);
对C16H11ClO2的分析:
计算值:C:70.99 H:4.10
实验值:C:70.64 H:4.16
实施例1ab
6-(2-氯-4-羟基苯基)-2-萘酚
根据方法D,通过3-氯-4-(6-甲氧基-2-萘基)酚(2.4g,8.43毫摩尔)和三溴化硼(21.9毫升,1.0M在CH2Cl2中的溶液,21.9毫摩尔)反应制备标题化合物,得到2.1克(92%)微黄固体:mp 209-210℃;1H NMR(DMDO-d6):δ6.86(1H,dd,J=8.42Hz,J=2.45Hz),6.97(1H,d,2.41Hz),7.11(1H,dd,J=8.78Hz,J=2.35Hz),7.16(1H,d,J=2.15Hz),7.30(1H,d,J=8.40Hz),7.42(1H,dd,J=8.51Hz,J=1.71Hz),7.71(1H,d,J=8.59Hz),7.76(1H,s),7.80(1H,d,J=8.82Hz),9.82(1H,s),10.01(1H,s);13C NMR(DMDO-d6):δ108.45,114.79,116.21,118.90,125.53,127.43,127.77,127.92,129.56,130.70,131.73,132.34,133.18,133.52,155.56,157.46;MS(ESI)m/z269/271(M-H)-.
对C16H11ClO2的分析:
计算值:C:70.99 H:4.10
实验值:C:70.68 H:4.09
实施例1w
1-氯-6-(3-氯-4-羟基苯基)-2-萘酚
根据方法A,通过6-(3-氯-4-羟基苯基)-2-萘酚(500毫克,1.85毫摩尔)和NCS(346毫克,2.59毫摩尔)在THF(37毫升)中反应制备标题化合物,得到380毫克(68%)微黄固体:
mp 174-175℃;1HNMR(DMDO-d6):δ7.09(1H,d,8.47Hz),7.31(1H,d,J=8.89Hz),7.60(1H,dd,J=8.20Hz,J=2.26Hz),7.78(1H,d,J=2.22Hz),7.84(1H,d,J=8.99Hz),7.88(1H,dd,J=9.00Hz,J=1.80Hz),8.05(1H,d,J=8.86Hz),8.14(1H,d,J=1.60Hz),10.37(1H,s),10.49(1H,s);MS(ESI)m/z 303/305/307(M-H)-.
对C16H10Cl2O2的分析:
计算值:C:62.98 H:3.30
实验值:C:62.65 H:3.21
实施例1ac
1-氯-6-(2-氯-4-羟基苯基)-2-萘酚
根据方法C,通过6-(2-氯-4-羟基苯基)-2-萘酚(500毫克,1.85毫摩尔)和NCS(321毫克,2.40毫摩尔)在THF(40毫升)中反应制备标题化合物,得到435毫克(77%)微黄固体:
mp 224-226℃;1HNMR(DMDO-d6):δ6.86(1H,dd,J=8.42Hz,J=2.41Hz),6.96(1H,d,J=2.44Hz),7.30(1H,d,J=3.19Hz),7.33(1H,d,J=2.65Hz),7.62(1H,dd,J=8.81Hz,J=1.71Hz),7.83(1H,d,J=8.93Hz),7.86(1H,d,J=1.54Hz),8.04(1H,J=8.76Hz),10.04(1H,s),10.51(1H,s);13C NMR(DMDO-d6):δ112.24,114.84,116.26,118.79,121.84,128.16,128.24,128.35,129.27,130.03,130.40,131.73,132.38,133.98,151.24,157.70;MS(ESI)m/z 303/305/307(M-H)-.
对C16H10Cl2O2的分析:
计算值:C:62.98 H:3.30
实验值:C:62.69 H:3.36
实施例1ba
1-氯-6-(3,5-二氟-4-羟基苯基)-2-萘酚
根据方法C,通过6-(3,5-二氟-4-羟基苯基)-2-萘酚(300毫克,1.10毫摩尔)和NCS(155毫克,1.16毫摩尔)在THF(30毫升)中反应制备标题化合物,得到264毫克(78%)灰色固体:
mp 209-210℃;1H NMR(DMSO-d6):δ7.32(1H,d,J=8.89Hz),7.50-7.61(2H,m),7.83(1H,d,J=8.96Hz),7.92(1H,dd.J=8.94Hz,J=1.59Hz),8.05(1H,d,J=8.88Hz),8.22(1H,d,J=1.19Hz),10.36(1H,s),10.54(1H,s);MS(ESI)m/z 305/307(M-H)-.
对C16H9ClF2O2的分析:
计算值:C:62.66 H:2.96
实验值:C:62.58 H:3.09
路线9中化合物的合成
中间体43
6-溴-1-氯萘-2-酚
根据方法C,通过6-溴-2-萘酚(3克,13.4毫摩尔)和NCS(2.47克,18.5毫摩尔)在THF(50毫升)中反应制备标题化合物,得到2.2g(64%)黄色固体:
1H NMR(DMDO-d6):δ7.34(1H,d,J=8.87Hz),7.69(1H,dd,J=1.75Hz,J=6.09Hz),7.79(1H,d,J=8.96Hz),7.96(1H,d,J=9.03Hz),8.17(1H,d,J=1.75Hz),10.68(1H,s);MS(ESI)m/z 255/257/259(M-H)-.
实施例1m
1-氯-6-苯基-2-萘酚
根据方法A,通过6-溴-1-氯-萘-2-酚(300毫克,1.17毫摩尔)和苯基硼酸(170.7毫克,1.40毫摩尔)反应制备标题化合物,得到240毫克(81%)白色固体:
mp 135-137℃;1H NMR(DMDO-d6):δ7.33(1H,d,J=8.85Hz),7.39(1H,td,J=7.25Hz,J=0.75Hz),7.51(2H,t,J=7.59Hz),7.80(2H,d,J=7.63Hz),7.88(1H,d,J=8.96Hz),7.93(1H,dd,J=8.85Hz,J=1.19.Hz),8.10(1H,d,J=8.84Hz),8.20(1H,s),10.53(1H,s);MS(ESI)m/z253/255(M-H)-.
对C16H11ClO的分析:
计算值:C:75.45 H:4.35
实验值:C:75.16 H:4.17
中间体44
6-溴-1-硝基-2-萘酚
将4-硝基-4-甲基-2,3,5,6-四溴-2,5-环己二烯-1-酮(2.53克,4.95毫摩尔,纯度:82.6%)加入到在40毫升无水乙醚中的6-溴-2-萘酚(1克,4.5毫摩尔)中。反应在室温进行1.5小时。过滤固体得到2,3,5,6-四溴-4-甲基苯酚(144毫克)。然后在真空下蒸发溶液。将粗混合物溶于乙酸乙酯并用水洗涤。用无水硫酸钠干燥有机层,在真空下除去溶剂。通过用乙酸乙酯-己烷重结晶粗产物得到2,3,5,6-四溴-4-甲基苯酚(1.2克)。母液浓缩到Florosil上,在二氧化硅柱(15%-20%乙酸乙酯-己烷)上提纯,得到0.731克(61%)标题化合物,为黄色固体:
mp 111-113℃;1H NMR(DMDO-d6):δ7.39(1H,d,J=9.07Hz),7.54(1H,d,J=9.05Hz),7.75(1H,dd,J=9.05Hz,J=1.70Hz),8.03(1H,d,J=9.14Hz),8.29(1H,d,J=1.84Hz),11.65(1H,s);MS(ESI)m/z 266/268(M-H)-;IR 1350cm-1,1490cm-1.
对C10H6BrNO3·0.18H2O的分析:
计算值:C:44.27 H:2.36 N:5.16
实验值:C:44.24 H:2.14 N:4.76.
中间体45
6-[4-(叔丁基-二甲基甲硅烷氧基)-苯基]-1-硝基-2-萘酚
根据方法A,通过6-溴-1-硝基-2-萘酚(560毫克,2.1毫摩尔)和4-叔丁基-二甲基甲硅烷氧基硼酸(688毫克,2.73毫摩尔)反应制备标题化合物,得到347毫克(42%)微黄固体:
1H NMR(DMDO-d6):δ0.23(6H,s),0.98(9H,s),6.99(2H,d,J=8.47Hz),7.35(1H,d,J=9.05Hz),7.64(1H,d,J=8.86Hz),7.70(2H,d,J=8.51Hz),7.94(1H,dd,J=6.62Hz,J=1.25Hz),8.08(1H,d,J=9.16Hz),8.22(1H,s),11.45(1H,s);MS(ESI)m/z 394(M-H)-.
实施例1x
6-(4-羟基苯基)-1-硝基-2-萘酚
向6-[4-(叔丁基-二甲基甲硅烷氧基)-苯基]-1-硝基-2-萘酚(302毫克,0.764毫摩尔)在THF(12毫升)中的溶液中加入TBAF(0.92毫升,0.917毫摩尔,1.0M在THF中的溶液)。溶液在室温搅拌10分钟,倾入水中。混合物用乙酸乙酯萃取。合并的有机层用盐水洗涤,用无水硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱上提纯(20%-40%乙酸乙酯-己烷),得到130毫克(61%)橙色固体。分析样品进一步用乙酸乙酯-己烷重结晶提纯,得到标题化合物,为橙色固体:
mp 199-201℃;1H NMR(DMDO-d6):δ6.89(2H,d,J=8.51Hz),7.33(1H,d,J=9.05Hz),7.62(1H,d,J=8.94Hz),7.63(2H,d,8.48Hz),7.91(1H,dd,J=8.87Hz,J=1.59Hz),8.06(1H,d,9.18Hz),8.17(1H,d,J=1.31Hz),9.64(1H,s),11.40(1H,s);MS(ESI)m/z 280(M-H)-.
对C16H11NO4的分析:
计算值:C:68.32 H:3.94 N:4.98
实验值:C:67.91 H:4.06 N:4.60
路线10中化合物的合成
中间体52
2-(2,5-二氟-4-甲氧苯基)-6-甲氧基萘
根据方法A,通过4-溴-2,5-二氟苯甲醚(4.06克,18.3毫摩尔)和中间体38(4.81克,23.8毫摩尔)反应制备标题化合物,得到5.18克(94.2%)白色固体:
mp 153-155℃;1H NMR(DMSO-d6):δ3.90(3H,s),3.91(3H,s),7.20(1H,dd,J=8.94Hz,J=2.50Hz),7.28(1H,dd,J=12.38Hz,J=7.47Hz),7.36(1H,d,J=2.42Hz),7.56(1H,dd,J=12.17Hz,J=7.53Hz),7.62-7.66(1H,m),7.89(2H,d,J=8.67Hz),8.02(1H,s);MS(ESI)m/z 301(M-H)+;HRMS:C18H14F2O2的计算值,300.0962;实验值(Cl(ISOBUTANE)),300.0953
对C18H14F2O2的分析:
计算值:C:71.99 H:4.70
实验值:C:73.00 H:4.62
中间体53
2-(2,6-二氟-4-甲氧苯基)-6-甲氧基萘
根据方法A,通过4-溴-3,5-二氟苯甲醚(4.06克,18.3毫摩尔)和中间体38(4.43克,22.0毫摩尔)反应制备标题化合物,得到3.4克(62%)白色固体:
mp 130-132℃;1H NMR(acetone-d6):δ3.91(3H,s),3.94(3H,s),6.72-6.80(2H,m),7.20(1H,dd,J=8.97Hz,J=2.54Hz),7.35(1H,d,J=2.48Hz),7.48-7.52(1H,m),7.85-7.90(3H,m);MS(ESI)m/z 301(M-H)+.
对C18H14F2O2的分析:
计算值:C:71.99 H:4.70
实验值:C:71.67 H:4.81
中间体50
三氟-甲磺酸(2-氟-4-甲氧基-苯基)酯
2-氟-4-甲氧基-苯酚
4-溴-2-氟苯酚(8克,41.9毫摩尔)、CuBr(6.0克,41.9毫摩尔)、甲醇钠(95.8毫升4.4M在甲醇中的溶液)和DMF(200毫升)的混合物在150℃加热4小时。反应混合物冷却到室温,倾入HCl(419毫升,2N水溶液)中,通过硅藻土过滤,然后用乙酸乙酯萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸钠干燥,过滤,蒸发溶剂,用二氧化硅柱色谱(5%-15%乙酸乙酯-己烷)提纯,得到5.63克(95%)标题化合物,为微黄色油:
1H NMR(DMDO-d6):δ3.67(3H,s),6.55(1H,m),6.78(1H,dd,J=12.97Hz,J=2.95Hz),6.85(1H,dd,J=10.14Hz,J=8.87Hz),9.24(1H,s)3.67(3H,s)
根据方法B,通过2-氟-4-甲氧基-苯酚(2.8克,19.7毫摩尔)与三氟甲磺酸酐(4.31毫升,7.23克,25.6毫摩尔)反应制备标题化合物,得到3.86克(68%)澄清的黄色油。
1H NMR(DMSO-d6):δ3.82(3H,s),6.89-6.94(1H,m),7.24(1H,dd,J=12.49Hz,J=2.98Hz),7.61(1H,t,J=9.09Hz).
中间体54
2-(2-氟-4-甲氧苯基)-6-甲氧基萘
根据方法A,通过三氟甲磺酸(2-氟-4-甲氧基-苯基)酯(3.86克,14.0毫摩尔)和中间体38(2.97克,14.8毫摩尔)反应制备标题化合物,得到2.27克(58%)的白色固体:
mp 104-106℃;1H NMR(DMSO-d6):δ3.83(3H,s),3.89(3H,s),6.92(1H,dd,J=8.46Hz,J=2.64Hz),6.98(1H,dd,J=12.92,J=2.48Hz),7.19(1H,dd,J=8.94Hz,J=2.46Hz),7.35(1H,J=2.38Hz),7.53-7.63(2H,m),7.90(2H,d,J=8.72Hz),7.97(1H,s);MS(ESI)m/z 283(M+H+).
对C18H15FO2的分析:
计算值:C:76.58 H:5.36
实验值:C:76.30 H:5.23
实施例1ar
2-氯-4-(2-萘基)苯酚
根据方法A,4-溴-2-氯苯酚(1.45克,6.98毫摩尔)、2-萘硼酸(1.0克,5.81毫摩尔)、碳酸钠(1.54克2N水溶液,14.53毫摩尔)和四(三苯基膦)钯(0)(340毫克,0.3毫摩尔)在DME(70毫升)中的混合物回流6小时。然后将反应冷却,用乙酸乙酯(3x)萃取,用硫酸钠干燥,然后浓缩。柱色谱(30%乙酸乙酯-己烷)得到610毫克(34%)白色固体产品。分析样品通过制备逆相HPLC(CH3CN/H2O,0.1%TFA)制备。
mp 99.5-100.0℃;1H NMR(300MHz,DMSO-d6)δ7.10(1H,d,J=8.4Hz),7.52(2H,m),7.63(1H,dd,J=8.5Hz,2.0Hz),7.81(2H,m),7.95(3H,m),8.17(1H,s),10.40(1H,s);MS m/z 253/255(Cl pattern)(M-H+);
对C16H11ClO.的分析:
计算值:C:75.45 H:4.35
实验值:C:75.24 H:4.34
实施例1z
6-(4-羟基-2-甲基苯基)-2-萘酚
根据方法D,通过6-(4-甲氧基-2-甲基苯基)-2-萘酚(420毫克,1.59毫摩尔)和三溴化硼(4.53毫升1.0M在CH2Cl2中的溶液,4.53毫摩尔)反应制备标题化合物,得到400毫克(定量得到)微黄固体:
mp 191-193℃;1H NMR(DMDO-d6):δ6.68(1H,dd,J=8.41Hz,J=2.21Hz),6.72(1H,d,J=2.21Hz),7.07-7.11(2H,m),7.14(1H,d,J=2.21Hz),7.33(1H,dd,J=8.41Hz,J=2.21Hz),7.64(1H,d,J=0.885Hz),7.68(1H,d,J=8.41Hz),7.77(1H,d,J=9.29Hz),9.33(1H,s),9.69(1H,s);13C NMR(DMDO-d6):δ108.34,112.82,116.84,118.68,125.47,127.13,127.56,128.02,129.26,130.71,132.26,133.02,135.63,135.90,155.11,156.31;MS(ESI)m/z 249(M-H)-.
对C17H14O2的分析:
计算值:C:81.58 H:5.64
实验值:C:81.36 H:5.53
实施例1ad
6-(2-氟-4-羟基苯基)-2-萘酚
根据方法D,通过2-(2-氟-4-甲氧苯基)-6-甲氧基-萘(1.12克,3.97毫摩尔)和三溴化硼(23.8毫升1.0M在CH2Cl2中的溶液,23.8毫摩尔)制备标题化合物,得到0.92克(91%)白色固体:mp208-209℃;1H NMR(DMSO-d6):δ6.66-6.75(2H,m),7.08-7.13(2H,m),7.41(1H,dd,J=9.37Hz,J=8.57Hz),7.49-7.53(1H,m),7.72(1H,d,J=8.64Hz),7.80(1H,d,J=8.76Hz),7.86(1H,s),9.79(1H,s),10.01(1H,s);MS(ESI)m/z 255(M+H)+,MS(ESI)m/z 253(M-H)-.
对C16H11FO2·0.15H2O的分析:
计算值:C:74.79 H:4.43
实验值:C:74.79 H:4.23
实施例1ae
6-(2,5-二氟-4-羟基苯基)-2-萘酚
根据方法D,通过2-(2,5-二氟-4-甲氧苯基)-6-甲氧基萘(1.5克,5.0毫摩尔)和三溴化硼(25毫升,1.0M在CH2Cl2中的溶液,25毫摩尔)制备标题化合物,得到1.28克(94%)的微黄固体:
mp 217-219℃;1H NMR(DMSO-d6):δ6.90(1H,dd,J=11.87Hz,J=7.51Hz),7.10-7.15(2H,m),7.45(1H,dd,J=11.87,J=7.61Hz),7.53-7.55(1H,m),7.74(1H,d,J=8.65Hz),7.92(1H,s),9.85(1H,s),10.50(1H,s);MS(ESI)m/z 271(M-H)-.
对C16H10F2O2的分析:
计算值:C:70.59 H:3.70
实验值:C:70.35 H:3.65
实施例1af
6-(2,6-二氟-4-羟基苯基)-2-萘酚
根据方法D,通过2-(2,6-二氟-4-甲氧苯基)-6-甲氧基萘(1.5克,5.0毫摩尔)和三溴化硼(25毫升1.0M在CH2Cl2中的溶液,25毫摩尔)反应制备标题化合物,得到1.35克(99%)的微黄固体:
mp>240℃;1H NMR(DMSO-d6):δ6.55-6.63(2H,m),7.11(1H,dd,J=8.76Hz,J=2.34Hz),7.15(1h,d,J=2.05Hz),7.36(1H,dd,J=8.58Hz,J=1.34Hz),7.39(1H,d,J=8.83Hz),7.79(1H,s),7.80(1H,d,J=8.74Hz),9.85(1H,s),10.48(1H,s);MS(ESI)m/z 271(M-H)-;MS(ESI)m/z 543(2M-H)-.
对C16H10F2O2的分析:
计算值:C:70.59 H:3.70
实验值:C:70.19 H:3.58
实施例1ag
1-氯-6-(2-氟-4-羟基苯基)-2-萘酚
根据方法C,通过6-(2-氟-4-羟基苯基)-2-萘酚(300毫克,1.18毫摩尔)和NCS(191毫克,1.43毫摩尔)在THF(30毫升)中反应制备标题化合物,得到170毫克(50%)微黄固体:
mp 179-180℃;1HNMR(DMSO-d6):δ6.73(1H,dd,J=12.69Hz,J=2.44Hz),6.75(1H,dd,J=8.30Hz,J=2.44Hz),7.31(1H,d,J=8.79Hz),7.45(1H,t,J=9.28Hz),7.70-7.72(1H,m),7.83(1H,d,J=8.79Hz),7.97(1H,s),8.06(1H,d,J=7.79Hz),10.06(1H,s),10.48(1H,s);MS(ESI)m/z 287/289(M-H)-.
对C16H10ClFO2的分析:
计算值:C:66.56 H:3.49
实验值:C:66.45 H:3.52
实施例1ah
1-氯-6-(2,5-二氟-4-羟基苯基)-2-萘酚
根据方法C,通过6-(2,5-二氟-4-羟基苯基)-2-萘酚(500毫克,1.84毫摩尔)和NCS(295毫克,2.21毫摩尔)在THF(37毫升)中反应制备标题化合物,得到370毫克(66%)微黄固体:
mp 203-204℃;1HNMR(DMSO-d6):δ6.90(1H,dd,J=11.90Hz,J=7.50Hz),7.32(1H,d,J=8.88Hz),7.49(1H,dd,J=11.87Hz,J=7.60Hz),7.72-7.76(1H,m),7.84(1H,d,J=8.97Hz),8.03(1H,s),8.06(1H,d,8.87Hz),10.58(2H,s);MS(ESI)m/z 305/307(M-H)-;HRMS C16H9ClF2O2的计算值306.02591,观察值305.01863(M-H)-.
对C16H9ClF2O2·0.4H2O的分析:
计算值:C:61.22 H:3.15
实验值:C:61.29 H:3.17
实施例1ai
1-氯-6-(2,6-二氟-4-羟基苯基)-2-萘酚
根据方法C,通过6-(2,6-二氟-4-羟基苯基)-2-萘酚(510毫克,1.86毫摩尔)和NCS(301毫克,2.25毫摩尔)在THF(30毫升)中反应制备标化合物,得到440毫克(77%)的微黄固体:
mp 213-214℃;1H NMR(丙酮-d6):δ6.71-6.78(2H,m),7.47(1H,d,J=8.85Hz),7.76(1H,dd,J=8.12Hz,J=1.52Hz),7.97(1H,d,J=8.90Hz),8.04(1H,s),8.29(1H,d,J=8.80Hz),9.26(1H,s),9.60(1H,s);MS(ESI)m/z 305/307(M-H)-;HRMS:C16H9ClF2O2的计算值,306.0259;实验值(ESI-),306.01991
对C16H9ClF2O2·0.25H2O的分析:
计算值:C:61.75 H:3.08
实验值:C:61.75 H:2.90
路线11中化合物的合成
中间体56
N-(7-羟基萘基)乙酰胺
向8-氨基2-萘酚(149.1克,0.937摩尔)在甲醇(1L)中的溶液中加入乙酸酐(93毫升,0.984摩尔)。反应回流90分钟,然后冷却至室温。除去溶剂,残余物通过硅塞与乙酸乙酯一起过滤。除去溶剂,得到175.8克(93%)标题化合物,为暗紫色固体。分析样品进一步通过逆相制备HPLC提纯,得到粉红色固体:
mp 161-162℃;1H NMR(DMSO-d6):δ2.15(3H,s),7.09(1H,dd,J=1.95Hz,J=8.79Hz),7.20-7.26(2H,m),7.49(1H,d,J=7.31Hz),7.63(1H,d,J=8.11Hz),7.77(1H,d,J=8.81Hz),9.76(1H,s),9.79(1H,s);MS(ESI)m/z 202(M+H)+.
对C12H11NO2.的分析:
计算值:C:71.63H:5.51 N:6.96
实验值:C:71.21H:5.45 N:6.89
中间体57
N-(7-甲氧基萘基)乙酰胺
向N-(7-羟基萘基)乙酰胺(175.4克,0.872摩尔)、碳酸钾(301克,2.18摩尔)和丙酮(1L)的混合物中加入碘代甲烷(270毫升,4.36摩尔)。反应混合物回流6小时,冷却至室温,除去溶剂。残余物与二氧化硅和乙酸乙酯一起过滤,与乙酸乙酯一起研磨,得到161.6克(86%)灰色固体。分析样品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 154-155℃;1H NMR(DMSO-d6):δ2.19(3H,s),3.90(3H,s),7.19(1H,dd,J=2.39Hz,J=8.94Hz),7.29-7.34(2H,m),7.39(1H,d,J=1.86Hz),7.75-7.68(2H,m),7.87(1H,d,J=8.96Hz),9.82(1H,s);MS(ESI)m/z 216(M+H)+.
对C13H13NO2的分析:
计算值:C:72.54 H:6.09 N:6.51
实验值:C:72.24 H:6.43 N:6.52.
中间体58
7-甲氧基萘胺
N-(7-甲氧基萘基)乙酰胺(160.6克,0.747摩尔)和HCl(1.51,1N溶液)的混合物回流5小时。冷却的反应物用固体碳酸氢纳中和,然后用二氯甲烷萃取直至UV澄清。合并的有机层通过二氧化硅过滤,蒸发溶剂,得到的89.5克(69%)棕色固体。分析样品通过制备HPLC制备,得到标题化合物白色固体:
mp 134-136℃;1HNMR(CDCl3):δ3.94(3H,s),4.01(2H,bs),6.80(1H,d,J=7.26Hz),7.05(1H,d,J=2.20Hz),7.12-7.19(2H,m),7.28(1H,d,J=8.17Hz),7.71(1H,d,J=8.93Hz);MS(ESI)m/z 174(M+H)+
对C11H11NO·CF3CO2H的分析:
计算值:C:54.55 H:3.87 N:4.89
实验值:C:54.39 H:4.28 N:4.78.
中间体59
1-氟-7-甲氧基萘
向冷却到10℃的7-甲氧基萘胺(10.94克,63.24毫摩尔)、HCl(15.8毫升,12N溶液,190毫摩尔)和水(50毫升)的混合物中用10分钟加入亚硝酸钠(4.58克,66.40毫摩尔)水中(25毫升)的溶液。将溶液搅拌30分钟,然后与氟硼酸(100毫升)合并。得到的绿色固体通过过滤收集,先用水洗涤,然后用乙醇洗涤,再用乙醚洗涤,得到黄固体[15.48克(90%)不典型的重氮氟硼酸盐中间体]。该黄色固体与二甲苯(250毫升)合并,回流1小时。除去溶剂,残余物在乙酸乙酯和碳酸氢钠溶液之间分配。有机层用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅上提纯(己烷),得到标题化合物,为浅黄色液体。
1H NMR(CDCl3):δ3.94(3H,s),7.10-7.28(3H,m),7.34(1H,d,J=2.50Hz),7.55(1H,d,J=8.12Hz),7.75(1H,dd,J=1.69Hz,J=9.00Hz);MS(EI)m/z 176(M)+.
对C11H9FO的分析:
计算值:C:74.99 H:5.15
实验值:C:74.84 H:5.14
中间体60
8-氯-2-甲氧基萘
将CuCl2(4.6克,24.6毫摩尔)和亚硝酸叔丁酯(4.46克,43.3毫摩尔)加入到0℃的乙腈(125毫升)中。向该混合物中缓慢地加入7-甲氧基萘胺(4.99克,28.8毫摩尔)在乙腈(25毫升)中的溶液。反应温热至室温,与HCl(400毫升,2N溶液)一起搅拌,用乙酸乙酯(3×200毫升)萃取。合并的有机层用2N的HCl洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(己烷)上提纯,得到2.27克(41%)的橙色液体。分析样品进一步用逆相制备HPLC提纯,得到标题化合物黄固体:
mp 32-34℃;1H NMR(CDCl3):δ3.98(3H,s),7.20(1H,dd,J=2.52Hz,J=8.96Hz),7.22-7.27(1H,m),7.52(1H,d,J=2.47Hz),7.55(1h,d,J=7.47Hz),7.69(1H,d,J=8.15Hz),7.75(1H,d,J=8.95Hz);MS m/z191/193(M-H)-.
对C11H9ClO的分析:
计算值:C:68.58 H:4.71
实验值:C:68.35 H:4.85
中间体61
1-溴-7-甲氧基萘
向CuBr2(15.7克,70.3毫摩尔)和TBN(9.05克,87.9毫摩尔)在乙腈(250毫升)中的0℃的溶液中缓慢加入2-甲氧基萘胺(10.14克,58.6毫摩尔)在乙腈(60毫升)中的溶液。深色的溶液在0℃搅拌2.5小时,在二氧化硅上浓缩,用二氧化硅柱提纯,得到4.03克(29%)白色固体。分析样品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 54-58℃;1H NMR(CDCl3):δ3.97(3H,s),7.15-7.21(2H,m),7.50(1H,d,J=2.42Hz),7.71-7.76(3H,m);MS(EI)m/z 236(M-)+.
对C11H9BrO的分析:
计算值:C:55.72 H:3.83
实验值:C:55.58 H:3.60
中间体62
7-甲氧基-1-萘甲腈
1-溴-7-甲氧基萘(3.26克,13.8毫摩尔)、Zn(CN)2(2.26克,19.2毫摩尔)和四(三苯基膦)钯(1.6克,1.4毫摩尔)在DMF(50毫升)中的混合物在120℃搅拌15小时。冷却的反应混合物倾入200毫升1N的氯化铵溶液中,然后用乙酸乙酯(3×350毫升)萃取。合并的有机层用盐水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(10%乙酸乙酯-己烷)上提纯,得到1.28克(51%)标题化合物,为白色固体:
mp 62-66℃;1H NMR(DMSO-d6):δ4.00(3H,s),7.25(1H,dd,J=2.48Hz,J=8.96Hz),7.36-7.47(1H,m),7.47(1H,d,J=2.39Hz),7.81(1H,d,J=9.00Hz),7.88(1H,dd,J=0.81Hz,J=7.23Hz),8.00(1H,d,J=8.21Hz);MS(EI)m/z 183(M-)+;
对C12H9NO:的分析:
计算值:C:78.67 H:4.95 N:7.65
实验值:C:78.83 H:4.60 N:6.80.
中间体64
7-甲氧基-3,4-二氢萘-1-甲腈
向7-甲氧基-1-四氢萘酮(39.65克,0.23摩尔)、碘化锌(1.73克,5.4毫摩尔)和苯(100毫升)的混合物中加入三甲基甲硅烷基氰(25.0克.0.25摩尔)。混合物在室温搅拌过夜。加入吡啶(350毫升),然后滴加磷酰氯(100毫升),同时稍微升高温度。混合物加热回流并保持6小时。TLC显示所需产物的mid-Rf点。混合物在室温搅拌过夜。将混合物小心地倾倒在冰/盐酸(约1.5升的10%HCl)上。总体积是2升。用乙酸乙酯(3×500毫升)萃取该混合物,合并有机物,用水洗涤(2×500毫升),然后用盐水(500毫升)洗涤。用硫酸镁干燥乙酸乙酯并蒸发,得到的液体静置时固化。该粗固体悬浮在在己烷中,过滤得到31.3克(74%)黄褐色固体。将一些这种物质用硅胶色谱法(10%乙酸乙酯-己烷)提纯,得到固体:
mp 47-49℃;1H NMR(DMSO-d6):δ2.44-2.50(2H,m),2.72(2H,t,J=8.4Hz),6.81(1H,d,J=2.6Hz),6.90(1H,dd,J=2.9Hz,J=8.2Hz),7.17-7.19(2H,m);MS m/z 168([M-H]-);
对C12H11NO的分析:
计算值:C:77.81 H:5.99 N:7.56
实验值:C:77.71 H:5.69 N:7.50
中间体62
7-甲氧基-1-氰基萘
向7-甲氧基-3,4-二氢萘-1-甲腈(9.95克,53.1毫摩尔)在对异丙基甲苯(100毫升)中的混合物中加入10%Pd/C(5克),搅拌反应混合物并加热到150℃过夜。冷却混合物,通过过滤助剂过滤除去催化剂。对异丙基甲苯用真空泵在转叶上除去,得到的液体静置时固化。将该固体悬浮在己烷中,过滤并干燥,得到白色固体(4.3克,44%)。将一部分用过硅胶(10%乙酸乙酯-己烷)提纯,得到白色固体:mp77-78℃;1H NMR(DMSO-d6):δ3.97(3H,s),7.36(1H,s),7.39(1H,d,J=2.5Hz),7.52(1H,t,J=7.4Hz),8.04-8.13(2H,m),8.24(1H,d,J=8.2Hz).
对C12H9NO的分析:
计算值:C:78.67 H:4.95 N:7.51
实验值:C:78.47 H:4.73 N:7.51
路线12中化合物的合成
中间体65
8-氟-2-萘酚
根据方法D,通过1-氟-7-甲氧基萘(7.99克,45.34毫摩尔)和三溴化硼(68毫升,1N溶液,68毫摩尔)反应制备标题化合物,得到3.99克(54%)的红色固体。分析样品通过制备逆相HPLC制备,得到白色固体:
mp 89-92℃;1H NMR(DMSO-d6):δ7.16(1H,dd,J=2.42Hz,J=8.90Hz),7.21-7.25(3H,m),7.62-7.65(1H,m),7.85(1H,dd,J=1.72Hz,J=8.87Hz),10.08(1H,s);MS(ESI)m/z 161(M-H)-.
对C10H7FO的分析:
计算值:C:74.07 H:4.35
实验值:C:73.90 H:4.30
中间体66
8-氯-2-萘酚
根据方法D,通过8-氯-2-甲氧基萘(10.25克,53.4毫摩尔)和三溴化硼(67毫升,1N溶液,67毫摩尔)反应制备标题化合物,得到8.76克(92%)黄色固体。分析样品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 95-100℃;1H NMR(DMSO-d6):δ7.18(1H,dd,J=2.37Hz,J=8.85Hz),7.23-7.28(1H,m),7.41(1H,d,J=2.28Hz),7.59(1H,d,J=7.37Hz),7.81(1H,d,J=8.15Hz),7.87(1H,d,J=8.86Hz),10.17(1H,s);MS m/z 177/179(M-H)-.
对C10H7ClO的分析:
计算值:C:67.24 H:3.95
实验值:C:66.99 H:4.06
中间体67
7-羟基-1-萘甲腈
根据方法D,通过7-甲氧基-1-萘甲腈(1.19克,6.50毫摩尔)和盐酸吡啶鎓(9克)反应制备标题化合物,得到0.88克(80%)白色固体:
mp 184-188℃;1H NMR(DMSO-d6):δ7.25(1H,dd,J=2.30Hz,J=8.88Hz),7.38(1H,d,J=2.20Hz),7.39-7.44(1H,m),7.98(1H,d,J=8.91Hz),8.04(1H,d,J=7.14Hz),8.17(1H,d,J=8.19Hz),10.48(1H,s);MS(ESI)m/z 170([M+H]+);MS(ESI)m/z 168(M-H)-.
对C11H7NO的分析:
计算值:C:78.09 H:4.17 N:8.28
实验值:C:77.99 H:3.99 N:8.47.
中间体68
6-溴-8-氟-2-萘酚
向8-氟-2-萘酚(3.24克,20.0毫摩尔)在冰醋酸(30毫升)中的溶液中缓慢加入溴(7.35克,46.0毫摩尔)在冰醋酸(30毫升)中的溶液。溶液在100℃搅拌1小时。冷却反应至室温,倾入水(50毫升)中,然后用乙酸乙酯(3×150毫升)萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(2.5%乙酸乙酯-己烷)上提纯,得到3.96克(12.4毫摩尔,62%)中间体1,6-二溴-8-氟-2-萘酚,黄色固体。将该固体与SnCl2(7.0克,31毫摩尔)、冰醋酸(35毫升)和HCl(35毫升,12N)合并,加热到100℃1小时。将得到的溶液冷却至室温,倾入水(100毫升)中,然后用乙酸乙酯(3×200毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,脱去溶剂,在二氧化硅上(2.5%乙酸乙酯-己烷)提纯,得到1.97克(41%)标题化合物,为白色固体:
mp 124-126℃;1H NMR(DMSO-d6):δ7.20(1H,s),7.23(1H,d,J=2.39Hz),7.48(1H,dd,J=1.78Hz,J=10.52Hz),7.84-7.88(1H,m),7.94(1H,d,J=0.79Hz),10.28(1H,s);MS(ESI)m/z 239/241(M-H)-.
对C10H6BrFO的分析:
计算值:C:49.83 H:2.51
实验值:C:49.86 H:2.46
中间体69
3,6-二溴-8-氯-2-萘酚
向8-氯-2-萘酚(4.92克,27.6毫摩尔)在冰醋酸(40毫升)中的溶液中缓慢加入溴(9.7克,60.7毫摩尔)在冰醋酸(40毫升)中的溶液。溶液在100℃搅拌1小时,冷却至室温,倾入水(250毫升)中,用乙酸乙酯萃取。合并的有机层用碳酸氢钠洗涤,用硫酸钠干燥,过滤,脱去溶剂,在二氧化硅柱(20%乙酸乙酯-己烷)上提纯,得到4.61克(50%)黄色固体。分析样品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 156-158℃;1H NMR(DMSO-d6):δ7.57(1H,s),7.82(1H,d,J=1.89Hz),8.11(1H,d,J=1.69Hz),8.31(1H,s),11.30(1H,bs);MS(ESI)m/z 333/335/337(M-H)-.
对C10H5Br2ClO的分析:
计算值:C:35.70 H:1.50
实验值:C:35.74 H:1.44
中间体70
3-溴-7-羟基-1-萘甲腈
向7-羟基-1-萘甲腈(26.03克,154.0毫摩尔)和冰醋酸(400毫升)的混合物中加入溴(51.8克,323毫摩尔)。混合物在100℃搅拌6小时。加入HCl(400毫升,12N溶液)和SnCl2(69克,308毫摩尔),混合物在100℃搅拌1小时。得到的溶液冷却至室温,倾入水(1升)中。得到的黄色沉淀通过过滤收集,在真空下干燥,与乙酸乙酯一起研磨,得到14.68克(38%)标题化合物,为黄白色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 222-224℃;1H NMR(DMSO-d6):δ7.28-7.35(2H,m),7.97(1H,d,J=8.73Hz),8.26(1H,s),8.47(1H,s),10.65(1H,s);MS(ESI)m/z246/247(M-H)-.
对C11H6BrNO的分析:
计算值:C:53.26 H:2.44 N:5.65
实验值:C:52.81 H:2.70 N:4.82.
中间体71
叔丁基[(3,6-二溴-8-氯-2-萘基)氧基]二甲基甲硅烷
根据方法F,通过3,6-二溴-8-氯-2-萘酚(3.00克,8.92毫摩尔)和TBDMS-Cl(1.75克,150.7毫摩尔)反应制备标题化合物,得到3.36克(84%)白色固体:
mp 58-64℃;1H NMR(CDCl3):δ0.34(6H,s),1.08(9H,s),7.57(1H,s),7.62(1H,d,J=1.72Hz),7.75(1H,d,J=1.24Hz),7.97(1H,s);MS(ESI)m/z 333/335/337(M-H)-.
对C16H19Br2ClOSi的分析:
计算值:C:42.64 H:4.25
实验值:C:42.73 H:4.08
中间体72
8-氟-6-(4-甲氧苯基)-2-萘酚
根据方法A,通过6-溴-8-氟-2-萘酚(0.39克,1.62毫摩尔)和4-甲氧苯基硼酸(0.34克,2.27毫摩尔)反应制备标题化合物,得到0.35克(81%)白色固体:
mp 150-151℃;1H NMR(DMSO-d6):δ3.81(3H,s),7.05(2H,d,J=8.75Hz),7.16-7.20(2H,m),7.57(1H,dd,J=1.21Hz,J=12.76Hz),7.74(214,d,J=8.74Hz),7.89-7.92(2H,m),10.10(1H,s);MS(ESI)m/z 269(M-H)+.
对C17H13FO2·0.1H2O的分析:
计算值:C:75.60 H:4.93
实验值:C:75.30 H:4.57
中间体73
8-氟-6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法A,通过6-溴-8-氟-2-萘酚(0.66克,2.73毫摩尔)和3-氟-4-甲氧苯基硼酸(0.56克,3.3毫摩尔)反应制备标题化合物,得到0.67克(85%)白色固体:
mp 138-140℃;1HNMR(DMSO-d6):δ3.90(3H,s),7.17-7.30(3H,m),7.60-7.65(2H,m),7.71(1H,dd,,J=2.19Hz),,J=13.14Hz),7.90(1H,d,,J=8.37Hz),7.99(1H,bs),10.15(1H,bs);MS(ES)m/z 285(M-H)-.
对C17H12F2O2的分析:
计算值:C:71.32 H:4.23
实验值:C:71.09 H:4.15
中间体74
叔丁基[(3-溴-8-氯-(4-甲氧苯基)-2-萘基)氧基]二甲基甲硅烷
叔丁基[(3,6-二溴-8-氯-2-萘基)氧基]二甲基甲硅烷(1.95克,4.32毫摩尔)、4-甲氧基苯基溴化镁(13.8毫升的0.5N溶液,6.9毫摩尔)和四(三苯基膦)钯(0.25克,0.21毫摩尔)在THF(10毫升)中的溶液回流搅拌8小时。反应用水(100毫升)淬灭,用乙酸乙酯(3×150毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(5%乙酸乙酯-己烷)上提纯,得到1.42克(69%)标题化合物,为白色固体:
1H NMR(CDCl3):δ0.36(6H,s),1.10(9H,s),3.87(3H,s),7.01(2H,d,J=8.78Hz),7.33(1H,d,J=1.36Hz),7.58(2H,d,J=8.75Hz),7.73(1H,s),7.78(1H,d,J=1.62Hz),8.10(1H,s).
中间体75
7-羟基-3-(4-甲氧苯基)-1-萘甲腈
根据方法A,通过3-溴-7-羟基-1-萘甲腈(0.249克,1.00毫摩尔)与4-甲氧基苯基硼酸(0.21克,1.4毫摩尔)反应制备标题化合物,得到0.19克(69%)浅黄色固体:
mp 226℃;1H NMR(DMSO-d6):δ3.82(3H,s),7.07(2H,d,J=8.82Hz),7.26(1H,dd,J=2.32Hz,J=8.90Hz),7.37(1H,d,J=2.27Hz),7.80(2H,d,J=8.80Hz),8.02(1H,d,J=8.96Hz),8.37(1H,d,J=1.85Hz),8.44(1H,d,J=1.43Hz),10.48(1H,bs);MS(ESI)m/z 274(M-H)-.
对C18H13NO2·0.1H2O的分析:
计算值:C:78.02 H:4.80 N:5.05
实验值:C:77.73 H:4.65 N:4.92.
中间体76
3-(3-氟-4-甲氧苯基)-7-羟基-1-萘甲腈
根据方法A,通过3-溴-7-羟基-1-萘甲腈(0.208克,0.839毫摩尔)与3-氟-4-甲氧基苯基硼酸(0.18克,1.1毫摩尔)反应制备标题化合物,得到0.16克(65%)浅黄色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物白色固体:
mp 214-216℃;1H NMR(DMSO-d6):δ3.90(3H,s),7.23-7.32(2H,m),7.37(1H,d,J=2.24Hz),7.65-7.70(1H,m),7.79(1H,dd,J=2.22Hz,J=13.10Hz),8.03(1H,d,J=8.96Hz),8.41(1H,d,J=1.86Hz),8.50(1H,d,J=1.43Hz),10.55(1H,s);MS(ESI)m/z 292(M-H)-.
对C18H12FNO2·0.1H2O的分析:
计算值:C:73.26 H:4.17 N:4.75
实验值:C:72.91 H:4.01 N:4.60.
中间体77
3-溴-8-氯-6-(4-甲氧苯基)-2-萘酚
方法I
向叔丁基[(3-溴-8-氯-(4-甲氧苯基)-2-萘基)-氧基]二甲基甲硅烷(0.50克,1.06毫摩尔)在THF(20毫升)中的溶液中加入TBAF(5毫升1N在THF中的溶液,55毫摩尔)。溶液在室温搅拌1小时,蒸发溶剂,置于水中(50毫升),用乙酸乙酯(3×150毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,脱去溶剂,在二氧化硅柱(10%乙酸乙酯-己烷)上提纯,得到0.34克(88%)白色色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 138-139℃;1H NMR(DMSO-d6):δ3.82(3H,s),7.06(2H,d,J=8.76Hz),7.5891H,s),7.73(2H,d,J=8.73Hz),7.94(1H,d,J=1.56Hz),8.07(H,bs),8.34(1H,s),11.05(1H,s);MS(ESI)m/z 361/363/365(M-H)-.
对C17H12BrClO2·0.6H2O的分析:
计算值:C:54.53 H:3.55
实验值:C:54.30 H:3.11
实施例1az
3-(3,5-二氟-4-羟基苯基)-7-羟基-1-萘甲腈
根据方法A,通过3-溴-7-羟基-1-萘甲腈(0.124克,0.50毫摩尔)和2,5-二氟-4-叔丁基二甲基甲硅烷氧基苯基硼酸(0.17克,0.59毫摩尔)反应制备标题化合物,得到0.090克(61%)黄色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为浅黄色固体:
mp 300-304℃(d);1H NMR(DMSO-d6):δ7.2791H,dd,J=2.26Hz,J=8.88Hz),7.36(1H,d,J=2.12Hz),7.63-7.66(2H,m),8.00(1H,d,J=8.95Hz),8.43(1H,d,J=1.77Hz),8.52(1H,s),10.44(1H,s),10.54(1H,s);MS(ESI)m/z 296(M-H)-.
对C17H9F2NO2·0.3H2O的分析:
计算值:C:67.46 H:3.20 N:4.63
实验值:C:67.18 H:2.89 N:4.55.
实施例1aj
8-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过8-氟-6-(4-甲氧苯基)-2-萘酚(0.10克,0.37毫摩尔)和三溴化硼(0.56毫升的1N溶液,0.56毫摩尔)反应制备标题化合物,得到0.10克(定量地)白色固体:
mp 236-238℃;1H NMR(DMSO-d6):δ6.87(2H,d,J=8.57Hz),7.14-7.18(2H,m),7.52(1H,dd,J=1.18Hz,J=12.78Hz),7.61(2H,d,J=8.59Hz,7.86-7.89(2H,m),9.61(1H,bs),10.05(1H,bs);MS(ESI)m/z 253(M-H)-.
对C16H11FO2·0.1H2O的分析:
计算值:C:75.06 H:4.41
实验值:C:75.01 H:4.11
实施例1ak
8-氟-6-(3-氟-4-羟基苯基)-2-萘酚
根据方法D,通过8-氟-6-(3-氟-4-甲氧苯基)-2-萘酚(0.10克,0.35毫摩尔)和三溴化硼(0.7毫升的1N溶液,0.7毫摩尔)反应制备标题化合物,得到0.020克(21%)白色固体:
mp 218-220℃d;1H NMR(DMSO-d6):δ7.01-7.07(1H,m),7.16-7.19(2H,m),7.46(1H,dd,,J=1.74Hz,,J=8.40Hz),7.56-7.65(2H,m),7.88(1H,d,,J=8.31Hz),7.93(1H,bs),10.04(1H,s),10.11(1H,s);MS(ESI)m/z 271(M-H)-.
对C16H10F2O2·0.25H2O的分析
计算值:C:69.44 H:3.82
实验值:C:69.13 H:3.45
实施例1au
7-羟基-3-(4-羟基苯基)-1-萘甲腈
根据方法B,通过7-羟基-3-(4-甲氧苯基)-1-萘甲腈(0.14克,0.51毫摩尔)和盐酸吡啶鎓(3克)反应制备标题化合物,得到0.10克(75%)白色固体:
mp 254-257℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.53Hz),7.25(1H,dd,J=2.15Hz,J=8.88Hz),7.36(1H,d,J=1.86Hz),7.67(2H,d,J=8.55Hz),8.00(1H,d,J=8.94Hz),8.31-8.38(2H,m),9.70(1H,bs),10.44(1H,bs);MS(ESI)m/z 260(M-H)-.
对C17H11NO2·0.25H2O的分析
计算值:C:76.83 H:4.36 N:5.27
实验值:C:76.85 H:4.31 N:5.10.
实施例1av
3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈
根据方法B,通过7-羟基-3-(3-氟-4-甲氧苯基)-1-萘甲腈(0.12克,0.41毫摩尔)和盐酸吡啶鎓(3克)反应制备标题化合物,得到0.085克(74%)白色固体:
mp 265-269℃;1H NMR(DMSO-d6):δ7.04-7.09(1H,m),7.26(1H,dd,J=2.31Hz,J=8.88Hz),7.36(1H,d,J=2.19Hz),6.52(1H,d,J=2.19Hz),6.52(1H,dd,J=1.76Hz,J=8.40Hz),6.71(1H,dd,J=2.22Hz,J=12.88Hz),8.01(1H,d,J=8.97Hz),8.37(1H,d,J=1.83Hz),8.45(1H,d,J=1.41Hz),10.33(2H,bs);MS(ESI)m/z278(M-H)-.
对C17H10FNO2.的分析:
计算值:C:73.11 H:3.61 N:5.02
实验值:C:72.75 H:3.45 N:4.82.
路线13中化合物的合成
中间体78和中间体79
1-氯-6-甲氧基-2-萘酚和1,5-二氯-6-甲氧基-2-萘酚
根据方法A,6-甲氧基-2-萘酚(5.43克,31.17毫摩尔)、NCS(4.58克,34.3毫摩尔)和乙腈(150毫升)的混合物在室温搅拌过夜。除去溶剂,得到的棕色固体残留物溶于乙酸乙酯(500毫升)中,用水洗涤,用硫酸钠干燥,蒸发溶剂,在二氧化硅柱(20%乙酸乙酯-己烷)上提纯,得到白色固体。该固体进一步用逆相制备HPLC提纯,得到3.91克(60%)中间体78,为白色固体:
mp 104-105℃;1H NMR(DMSO-d6):δ3.85(3H,s),7.22-7.26(2H,m),7.31(1H,d,J=2.42Hz),7.68(1H,d,J=8.91Hz),7.93(1H,d,J=9.17Hz);MS(ESI)m/z207/209(M-H)-.
对C11H9ClO2的分析:
计算值:C:63.32 H:4.35
实验值:C:63.21 H:4.50
HPLC分离进一步得到0.83克(3.43毫摩尔)的中间体79,为白色固体:
mp 152-158℃;1H NMR(DMSO-d6):δ3.97(3H,s),7.41(1H,d,J=9.22Hz),7.63(1H,d,J=9.17Hz),7.97(1H,d,J=9.23Hz),8.04(1H,d,J=9.34Hz),10.51(1H,s);MS(ESI)m/z 241/243(M-H)-.
对C11HXCl2O2的分析:
计算值:C:54.35 H:3.32
实验值:C:54.13 H:3.21
中间体80
三氟甲磺酸(1-氯-6-甲氧基-2-萘基)酯
根据中间体6,通过1-氯-6-甲氧基-2-萘酚(0.70克,3.36毫摩尔)和三氟甲磺酸酐(1.23克,4.4毫摩尔)反应制备标题化合物,得到1.02克(89%)白色固体:
mp 60-61℃;1HNMR(CDCl3):δ3.95(3H,s),7.17(1H,d,J=2.48Hz),7.35(1H,dd,J=2.50Hz,J=9.30Hz),7.39(1H,d,J=9.06Hz),7.71(1H,d,J=9.11Hz),8.21(1H,d,J=9.28Hz);MS(EI)m/z 340/342(M-)+.
对C12H8ClF3O4S的分析
计算值:C:42.30 H:2.37
实验值:C:42.20 H:2.37
中间体81
三氟甲磺酸(1,5-二氯6-甲氧基-2-萘基)酯
根据中间体6,通过1,5-二氯-6-甲氧基-2-萘酚(0.27克,1.11毫摩尔)和三氟甲磺酸酐(0.41克,1.44毫摩尔)反应制备标题化合物,得到0.37克(89%)白色固体:
mp 73-78℃;1H NMR(CDCl3):64.08(3H,s),7.48-7.52(2H,m),8.24-8.30(2H,m);MS(EI)m/z 374/376/378(M-)+.
对C12H7Cl2F3O4S的分析:
计算值:C:38.42 H:1.88
实验值:C:38.65 H:1.90
中间体82
1-氯-2-甲氧基-2-(4-甲氧苯基)萘
根据方法A,通过三氟甲磺酸(1-氯-6-甲氧基-2-萘基)酯(0.95克,2.79毫摩尔)和4-甲氧苯基硼酸(0.59克,3.9毫摩尔)反应制备标题化合物,得到0.71克(85%)白色固体:mp126-128℃;1H NMR(CDCl3):δ3.88(3H,s),3.95(3H,s),7.01(2H,d,J=8.60Hz),7.16(1H,d,J=2.49Hz),7.27(1H,dd,J=1.97Hz,J=8.99Hz),7.41(1H,d,J=8.45Hz),7.46(2H,d,J=8.61Hz),7.68(1H,d,J=8.48Hz),8.28(1H,d,J=9.27Hz);MS(ESI)m/z 299/301(M+H)+.
对C18H15ClO2·0.25H2O的分析
计算值:C:71.29 H:5.15
实验值:C:70.84 H:4.80
中间体83
1,5-二氯-2-甲氧基-6-(4-甲氧苯基)萘
根据方法A,通过三氟甲磺酸(1,5-二氯-6-甲氧基-2-萘基)酯(0.32克,0.85毫摩尔)和4-甲氧苯基硼酸(0.18克,1.2毫摩尔)反应制备标题化合物,得到0.27克(95%)白色固体:
mp 146-149℃;1H NMR(CDCl3):δ3.88(3H,s),4.07(3H,s),7.02(2H,d,J=8.73Hz),7.41(1H,d,J=9.52Hz),7.46(2H,d,J=8.83Hz),7.53(1H,d,J=8.73Hz),8.19(1H,d,J=8.73Hz),8.36(1H,d,J=9.12Hz);
对C18H14Cl2O2的分析:
计算值:C:64.88 H:4.23
实验值:C:64.63 H:4.28
实施例1ao
5-氯-6-(4-羟基苯基)-2-萘酚
根据方法D,通过1-氯-6-甲氧基-2-(4-甲氧基苯基)萘(0.65克,2.18毫摩尔)和三溴化硼(6.5毫升的1N溶液)反应制备标题化合物,得到0.44克(75%)白色固体:
mp>220℃;1H NMR(DMSO-d6):δ6.86(2H,d,J=8.33Hz),7.23-7.28(2H,m),7.30(2H,d,J=8.32Hz),7.37(1H,d,J=8.51Hz),7.72(1H,d,J=8.55Hz),8.13(1H,d,J=9.07Hz);MS(ESI)m/z 269/271(M-H)-.
对C16H11ClO2·0.1H2O的分析
计算值:C:70.52 H:4.14
实验值:C:70.52 H:4.05
实施例1ap
1,5-二氯6-(4-羟基苯基)-2-萘酚
根据方法D,通过1,5-二氯-2-甲氧基-6-(4-甲氧苯基)萘(0.15克,0.45毫摩尔)和三溴化硼(1.4毫升的1N溶液)反应制备标题化合物,得到0.10克(73%)白色固体:
mp 204-206℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.47Hz),7.33(2H,d,J=8.45Hz),7.46(1H,d,J=9.26Hz),7.56(1H,d,J=8.80Hz),8.06(1H,d,J=8.81Hz),8.17(1H,d,J=9.28Hz),9.68(1H,bs),10.84(1H,bs);MS(ESI)m/z 303/305/307(M-H)-.
对C16H10Cl2O2的分析
计算值:C:62.98 H:3.30
实验值:C:62.78 H:3.28
路线14中化合物的合成
中间体84
8-氯-6-(4-甲氧苯基)-2-萘酚
向3-溴-8-氯-6-(4-甲氧苯基)-2-萘酚(0.254克,0.698毫摩尔)在THF(25毫升)中的-78℃的溶液中缓慢加入叔丁基锂(1.65毫升的1.7N溶液,2.8毫摩尔)。得到的溶液在-78℃搅拌20分钟,加入2.5毫升水,混合物缓慢温热至室温同时进行搅拌。反应物倾入50毫升的水中,用乙酸乙酯(3×100毫升)萃取。合并的有机层用水洗涤,用硫酸钠干燥,过滤,蒸发溶剂,在二氧化硅柱(10%乙酸乙酯-己烷)上提纯,得到0.15克(88%)黄色固体。分析样品进一步用逆相制备HPLC制备,得到标题化合物,为浅黄色固体:
mp 116-118℃;1H NMR(DMSO-d6):δ3.81(3H,s),7.05(2H,d,J=8.75Hz),7.19(1H,dd,J=2.34Hz,J=8.84Hz),7.40(1H,d,J=2.25Hz),7.74(2H,d,J=8.73Hz),7.89(1H,d,J=1.65Hz),7.92(1H,d,J=8.93Hz),8.07(1H,s),10.19(1H,s);MS(ESI)m/z 283/285(M-H)-.
对C17H13ClO2·0.1H2O的分析:
计算值:C:71.26 H 4.64
实验值:C:71.18 H:4.43 N
中间体85
1-氟-8-氟-6-(3-氟-4-甲氧苯基)-2-萘酚
根据方法C,通过8-氟-6-(3-氟-4-甲氧基-苯基)-2-萘酚(0.30克,1.05毫摩尔)和NCS(0.17克,1.26毫摩尔)反应制备标题化合物,得到0.21克(62%)浅橙色固体:
mp 126-128℃;1H NMR(DMSO-d6):δ3.90(3H,s),7.25-7.31(1H,m),7.35(1H,d,,J=8.91Hz),7.64-7.67(1H,m),7.70-7.78(2H,m),7.87(1H,dd,,J=1.58Hz,,J=9.04Hz),10.68(1H,s);MS(ESI)m/z 319/321(M-H)-.
对C17H11ClF2O2的分析:
计算值:C:63.66 H:3.46
实验值:C:63.23 H:3.39
中间体86
1-氯-8-氟-6-(4-甲氧苯基)-2-萘酚
根据方法C,8-氟-6-(4-甲氧苯基)-2-萘酚(0.17克,0.63毫摩尔)和NCS(0.10克,0.76毫摩尔)在THF(20毫升)中的溶液在氮气下在室温搅拌过夜。将溶液浓缩到硅酸铝担体(Florosil)上,在二氧化硅柱上提纯(20%乙酸乙酯-己烷),得到0.16克(84%)标题化合物,为黄色固体。分析样品进一步通过制备逆相HPLC制备,得到浅黄色固体:
mp 120-124℃;1H NMR(DMSO-d6):δ3.82(3H,s),7.06(2H,d,,J=8.80Hz),7.34(1H,d,J=8.91Hz),7.67(1H,dd,J=1.69Hz,,J=15.48Hz),7.78(2H,d,J=8.78Hz),8.01(1H,d,J=1.54Hz),10.62(1H,s);MS(ESI)m/z 301/303(M-H)-.
对C17H12ClFO2的分析
计算值:C:67.45 H:4.00
实验值:C:67.23 H:3.65
中间体87
1,5-二氯-8-氟-6-(4-甲氧苯基)-2-萘酚
根据方法C,通过8-氟-6-(4-甲氧苯基)-2-萘酚(0.24克,0.90毫摩尔)和NCS(0.22克,1.6毫摩尔)在乙腈(20毫升)中反应制备标题化合物,得到0.22克(73%)黄色固体:
1H NMR(DMSO-d6):δ3.82(3H,s),7.06(2H,d,J=8.69Hz),7.39(1H,d,J=14.34Hz),7.47(2H,d,J=8.68Hz),7.53(1H,d,J=9.36Hz),8.22(1H,dd,J=1.65Hz,J=9.32Hz),11.01(1H,s);MS(ESI)m/z 335/337(M-H)-.
中间体88
3-溴-1,8-二氯-6-(4-甲氧苯基)-2-萘酚
根据方法C,通过3-溴-8-氯-6-(4-甲氧苯基)-2-萘酚(0.69克,1.90毫摩尔)和NCS(0.31克,2.3毫摩尔)在THF(25毫升)中反应制备标题化合物,得到0.61克(81%)黄色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 176-178℃(dec.);1H NMR(DMSO-d6):δ3.82(3H,s),7.08(2H,d,J=8.77Hz),7.77(2H,d,J=8.75Hz),8.00(1H,d,J=1.84Hz),8.19(1H,d,J=1.84Hz),8.39(1H,s),10.53(1H,bs);MS(ESI)m/z 395/397/399(M-H)-.
对C17H11BrCl2O2的分析
计算值:C:51.29 H:2.79
实验值:C:51.37 H:2.62
中间体89
8-溴-7-羟基-3-(4-甲氧苯基)-1-萘甲腈
根据方法C,通过7-羟基-3-(4-甲氧苯基)-1-萘甲腈(0.160克,0.58毫摩尔)和NBS(0.12克,0.70毫摩尔)在THF(10毫升)中反应制备标题化合物,得到0.080克(39%)黄色固体:
mp 145-146℃;1HNMR(DMSO-d6):δ3.83(3H,s),7.08(2H,d,J=8.79Hz),7.42(1H,d,J=8.79Hz),7.84(2H,d,J=8.79Hz),8.04(1H,d,J=8.79Hz),8.42(1H,d,J=1.95Hz),8.53(1H,d,J=1.95Hz),11.21(1H,s);MS(ESI)m/z 354/356(M+H+;MS(ESI)m/z352/354(M-H)-.
对C18H12BrNO2·0.25H2O的分析
计算值:C:60.27 H:3.51 N:3.90
实验值:C:60.27 H:3.51 N:3.46.
中间体90
1,8-二氯-6-(4-甲氧苯基)-2-萘酚
根据制备中间体84的方法,通过3-溴-1,8-二氯-6-(4-甲氧苯基)-2-萘酚(0.30克,0.754毫摩尔)和叔丁基锂(1.75毫升的1.7N溶液,3.0毫摩尔)反应并用水淬灭,制备标题化合物,得到0.19克(79%)的黄色固体。分析样品进一步用逆相制备HPLC制备,得到标题化合物,为浅黄色固体:
mp 132-134℃;1H NMR(DMSO-d6):δ3.82(3H,s),7.06(2H,d,J=8.77Hz),7.37(1H,d,J=8.90Hz),7.77(2H,d,J=8.75Hz),7.89-7.93(2H,m),8.15(1H,d,J=1.85Hz),10.68(1H,s);MS(ESI)m/z 317/319/321(M-H)-.
对C17H12Cl2O2的分析
计算值:C:63.97 H:3.79
实验值:C:63.57 H:3.65
实施例1al
1-氯-8-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过1-氯-8-氟-6-(4-甲氧基-苯基)-2-萘酚(0.14克,0.46毫摩尔)和三溴化硼(0.69毫升的1N溶液,0.69毫摩尔)反应制备标题化合物,得到0.050克(38%)白色固体:
mp 174-176℃;1H NMR(DMSO-d6):δ6.88(2H,d,J=8.62Hz),7.33(1H,d,J=8.92Hz),7.60-7.67(3H,m),7.86(1H,dd,,J=1.43Hz,J=9.02Hz),7.95(1H,d,J=1.37Hz),9.68(1H,s),10.59(1H,s);MS(ESI)m/z 287/289(M-H)-.
对C16H10ClFO2·0.25H2O的分析
计算值:C:65.54 H:3.61
实验值:C:65.52 H:3.19
实施例1am
1-氯-8-氟-6-(3-氟-4-羟基苯基)-2-萘酚
根据方法D,通过1-氯-8-氟-6-(3-氟-4-甲氧苯基)-2-萘酚(0.13克,0.41毫摩尔)和三溴化硼(0.8毫升的1N溶液,0.8毫摩尔)反应制备标题化合物,得到0.070克(56%)白色固体:
mp 198-200℃;1H NMR(DMSO-d6):δ7.03-7.09(1H,m)7.34(1H,d,J=8.92Hz),7.49-7.52(1H,m),7.68(2H,d,,J=15.0Hz),7.85-7.88(1H,m),8.02(1H,d,J=0.70Hz),10.13(1H,s),10.66(1H,s);MS(ESI)m/z 305/307(M-H)-.
对C16H9ClF2O2的分析
计算值:C:62.66 H:2.96
实验值:C:62.27 H:2.90
实施例1an
8-氯-6-(4-羟基苯基)-2-萘酚
根据方法D,通过8-氯-6-(4-甲氧苯基)-2-萘酚(0.10克,0.35毫摩尔)和三溴化硼(0.9毫升的1N溶液,0.9毫摩尔)反应制备标题化合物,得到0.080克(85%)的产品,将其进一步用逆相制备HPLC提纯,得到标题化合物,为白色固体:
mp 204-206℃;1H NMR(DMSO-d6):δ6.87(2H,d,J=8.61Hz),7.17(1H,dd,J=2.34Hz,J=8.83Hz),7.38(1H,d,J=2.26Hz),7.62(2H,d,J=8.59Hz),7.85(1H,d,J=1.64Hz),7.90(1H,d,J=8.92Hz),8.01(1H,bs),9.62(1H,s),10.14(1H,s);MS(ESI)m/z269/(M-H)-.
对C16H11ClO2·0.25H2O的分析
计算值:C:70.99 H:4.10
实验值:C:69.95 H:3.89
实施例1aq
1,5-二氯-8-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过1,5-二氯-8-氟-6-(4-甲氧苯基)-2-萘酚(0.15克,0.445毫摩尔)和三溴化硼(0.67毫升的1N溶液,0.67毫摩尔)反应制备标题化合物,得到0.12克(83%)浅黄色固体。
mp 206-216℃;1H NMR(DMSO-d6):δ6.88(2H,d,J=8.55Hz),7.34-7.39(3H,m),7.51(1H,d,J=9.34Hz),8.21(1H,dd,J=1.66Hz,J=9.34Hz),9.74(1H,bs),10.99(1H,bs);MS(ESI)m/z 321/323/326(M-H)-.
对C16H9Cl2FO2·0.1H2O的分析
计算值:C:59.13 H:2.85
实验值:C:58.88 H:2.85
实施例1ar
3-溴-8-氟-6-(4-羟基苯基)-2-萘酚
根据方法D,通过3-溴-8-氯-6-(4-甲氧苯基)-2-萘酚(0.24克,0.66毫摩尔)和三溴化硼(1.6毫升的1N溶液,1.6毫摩尔)反应制备标题化合物,得到0.14克(61%)黄色油。产品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 188-190℃;1H NMR(DMSO-d6):δ6.88(1H,d,J=8.60Hz),7.57(1H,s),7.71(2H,d,J=8.61Hz),7.89(1H,d,J=1.60Hz),8.02(1H,s),8.31(1H,s),9.67(1H,s),11.01(1H,s);MS(ESI)m/z 347/349/351(M-H)-.
对C16H10BrClO2的分析:
计算值:C:54.97 H:2.88
实验值:C:54.68 H:2.82
实施例1as
1,8-二氯-6-(4-羟基苯基)-2-萘酚
根据方法D,通过1,8-二氯-6-(4-甲氧苯基)-2-萘酚(0.12克,0.38毫摩尔)和三溴化硼(0.75毫升的1N溶液,0.75毫摩尔)反应制备标题化合物,得到0.10(86%)产物,将其进一步用逆相制备HPLC提纯,得到标题化合物,为白色固体:
mp 172-174℃(dec.);1H NMR(DMSO-d6):δ6.89(2H,d,J=8.54Hz),7.36(1H,d,J=8.90Hz),7.65(2H,d,J=8.56Hz),7.88-7.91(2H,m),8.10(1H,d,J=1.63Hz),9.69(1H,s),10.64(1H,s);MS(ESI)m/z 303/305/307(M-H)-.
对C16H10Cl2O2·0.25H2O的分析
计算值:C:62.98 H:3.30
实验值:C:61.80 H:3.08
实施例1at
3-溴-1,8-二氯-6-(4-羟基苯基)-2-萘酚
根据方法D,通过3-溴-1,8-二氯-6-(4-甲氧苯基)-2-萘酚(0.18克,0.45毫摩尔)和三溴化硼(0.9毫升的1N溶液,0.9毫摩尔)反应制备标题化合物,得到0.12克(69%)浅棕色固体。产品进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 184-188℃;1H NMR(DMSO-d6):δ6.89(2H,d,J=8.59Hz),7.65(2H,d,J=8.61Hz),7.95(1H,d,J=1.78Hz),8.13(1H,d,J=1.75Hz),8.37(1H,s),9.74(1H,s),10.50(1H,s);MS(ESI)m/z 381/383/385(M-H)-.
对C16H9BrCl2O2·0.25H2O的分析
计算值:C:50.04 H:2.36
实验值:C:49.10 H:2.14
实施例1bb
8-溴-7-羟基-3-(4-羟基苯基)-1-萘甲腈
根据方法D,通过8-溴-7-羟基-3-(4-甲氧苯基)-1-萘甲腈(0.13克,0.37毫摩尔)和三溴化硼(1.1毫升的1N溶液,1.1毫摩尔)反应制备标题化合物,得到0.050克(40%)米色固体:
mp 204-208℃(d);1H NMR(DMSO-d6):δ6.90(2H,d,J=8.30Hz),7.41(1H,d,J=8.79Hz),7.72(2H,d,J=8.79Hz),8.02(1H,d,J=9.23Hz),8.37(1H,d,J=1.95Hz),8.47(1H,d,J=2.44Hz),9.72(1H,s),11.16(1H,s);MS(ESI)m/z 338/340(M-H).
对C17H10BrNO2的分析
计算值:C:60.02 H:2.96 N:4.12
实验值:C:59.84 H:3.18 N:3.83.
路线15中化合物的合成
中间体91
3-溴-8-氯-7-羟基-1-萘甲腈
向在压力管中的8-氯-7-羟基-1-萘甲腈(0.127克,0.63毫摩尔)和冰醋酸(1毫升)的混合物中加入溴(0.24克,1.5毫摩尔)在冰醋酸(2毫升)中的溶液。将管密封,混合物在100℃搅拌过夜。冷却反应,倾入水(50毫升)中,然后用乙酸乙酯(3×100毫升)萃取。合并的有机层用碳酸氢钠溶液洗涤,用硫酸钠干燥,过滤,脱去溶剂,在二氧化硅柱上提纯(20%乙酸乙酯-己烷),得到0.10克(56%)标题化合物,为黄色固体。分析样品进一步用制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 148-150℃;1H NMR(DMSO-d6):δ7.47(1H,d,J=8.98Hz),7.95(1H,d,J=9.02Hz),8.32(1H,d,J=2.08Hz),8.55(1H,d,J=2.08Hz),11.33(1H,s);MS(ESI)m/z280/282/284(M-H)-.
对C11H5BrClNO·0.25H2O的分析:
计算值:C:46.03 H:1.93 N:4.88
实验值:C:45.92 H:1.75 N:4.78.
中间体91
3-溴-8-氯-7-羟基-1-萘甲腈
根据方法C,通过3-溴-7-羟基-1-萘甲腈(0.32克,1.28毫摩尔)和NCS(0.24克,1.8毫摩尔)在THF(25毫升)中在45℃反应3小时制备标题化合物,得到0.30克(83%)黄色固体。分析样品通过制备逆相HPLC制备,得到标题化合物,为白色固体:
mp 148-150℃;1H NMR(DMSO-d6):δ7.47(1H,d,J=8.98Hz),7.95(1H,d,J=9.02Hz),8.32(1H,d,J=2.08Hz),8.55(1H,d,J=2.08Hz),11.33(1H,s);MS(ESI)m/z 280/282/284(M-H)-
对C11H5BrClNO·0.25H2O的分析:
计算值:C:46.03 H:1.93 N:4.88
实验值:C:45.92 H:1.75 N:4.78.
中间体92
8-氯-3-(3-氟-4-甲氧苯基)-7-羟基-1-萘甲腈
根据方法A,通过3-溴-8-氯-7-羟基-1-萘甲腈(0.20克,0.71毫摩尔)与3-氟-4-甲氧基苯基硼酸(0.17克,1.0毫摩尔)反应制备标题化合物,得到0.14(60%)黄色固体:
mp 198-200℃;1H NMR(DMSO-d6):δ3.91(3H,s),7.27-7.33(1H,m),7.45(1H,d,J=8.93Hz),7.71-7.74(1H,m),7.85(1H,dd,J=2.23Hz,J=13.09Hz),8.00(1H,d,J=9.08Hz),8.48(1H,d,J=1.97Hz),8.57(1H,d,J=1.95Hz),11.18(1H,s);MS(ESI)m/z 326/328(M-H)-.
对C18H11ClFNO2的分析
计算值:C:65.97 H:3.38 N:4.27
实验值:C:65.76 H:3.36 N:4.11.
实施例1aw
8-氯-3-(4-羟基苯基)-7-羟基-1-萘甲腈
根据方法A,通过3-溴-8-氯-7-羟基-1-萘甲腈(0.10克,0.37毫摩尔)与4-叔丁基二甲基甲硅烷氧基苯基硼酸(0.13克,0.52毫摩尔)反应制备标题化合物,得到0.036克(33%)白色固体:
mp 254-256℃;1H NMR(DMSO-d6):δ6.90(2H,d,J=8.64Hz),7.43(1H,d,J=8.95Hz),7.72(2H,d,J=8.64Hz),7.99(1H,d,J=8.97Hz),8.38(1H,d,J=1.95Hz),8.47(1H,d,J=1.92Hz),9.73(1H,s),11.08(1H,s);MS(ESI)m/ z294/296(M-H)-.
对C17H10ClNO2的分析
计算值:C:69.05 :H3.41 N:4.74
实验值:C:69.01 H:3.63 N:4.31.
实施例1ax
8-氯-3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈
根据方法D,通过8-氯-3-(3-氟-4-甲氧苯基)-7-羟基-1-萘甲腈(0.042克,0.13毫摩尔)和盐酸吡啶鎓(1.8克)反应制备标题化合物,得到0.033克(78%)黄褐色固体。该物质进一步用制备逆相HPLC提纯,得到标题化合物,为白色固体:
mp 246-252℃;1H NMR(DMSO-d6):δ7.04-7.10(1H,m),7.4491H,d,J=8.94Hz),7.56(1H,dd,J=1.66Hz,J=8.37Hz),7.76(1H,dd,J=2.20Hz,J=12.88Hz),7.99(1H,d,J=9.09Hz),8.43(1H,d,J=1.98Hz),8.52(1H,d,J=1.94Hz),10.19(1H,bs),11.05(1H,bs);MS(ESI)m/z 312/314(M-H)-.
对C17H9ClFNO2·0.25H2O的分析:
计算值:C:64.16 H:3.01 N:4.40
实验值:C:63.75 H:2.84 N:4.20.
Claims (31)
1.具有下述结构的化合物或其药学可接受的盐,
其中
R1、R2、R3和R4分别独立地选自氢、羟基、1-6个碳原子的烷基、1-6个碳原子的烷氧基或卤素;
R5、R6、R7、R8、R9和R10分别独立地是氢、1-6个碳原子的烷基、2-7个碳原子的烯基、2-7个碳原子的炔基、卤素、1-6个碳原子的烷氧基、-CN、-CHO、苯基或具有1-4个选自O、N或S的杂原子的5或6-元杂环;其中R5、R6、R7、R8、R9或R10的烷基或烯基部分可任选被羟基、-CN、卤素、三氟烷基、三氟烷氧基、-NO2或苯基取代;其中R5、R6、R7、R8、R9或R10的苯基部分可任选被一、二或三取代,取代基选自1-6个碳原子的烷基、2-7个碳原子的烯基、卤素、羟基、1-6个碳原子的烷氧基、-CN、-NO2、氨基、1-6个碳原子烷基氨基、每个烷基具有1-6个碳原子的二烷基氨基、巯基、1-6个碳原子的烷硫基、1-6个碳原子的烷基亚磺酰基、1-6个碳原子的烷基磺酰基、2-7个碳原子的烷氧羰基、2-7个碳原子的烷基羰基或苯甲酰基;
前提是R1、R2、R3、R6、R7、R8、R9或R10中的至少一个是羟基。
3.根据权利要求1或权利要求2的化合物,其中R1和R2彼此独立地选自氢和氟。
4.根据权利要求1-3任一项的化合物,其中R5、R6、R7、R9和R9分别独立地是氢、卤素、-CN或2-7个碳原子的炔基。
5.根据权利要求1-4任一项的化合物,其中R5选自氢、氟或氰基。
6.根据权利要求1-5任一项的化合物,其中R9选自氢、氟或氰基。
7.根据权利要求1-6任一项的化合物,其中R6、R7和R8是氢。
8.根据权利要求1-7任一项的化合物,其中具有1-4个选自O、N或S的杂原子的5或6-元杂环是呋喃、噻吩或吡啶。
9.根据权利要求1的化合物,其为8-氟-6-(3-氟-4-羟基苯基)-2-萘酚或其药学可接受的盐。
10.根据权利要求1的化合物,其为1-氯-8-氟-6-(3-氟-4-羟基苯基)-2-萘酚或其药学可接受的盐。
11.根据权利要求1的化合物,其为3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈或其药学可接受的盐。
12.根据权利要求1的化合物,其为3-(3,5-二氟-4-羟基苯基)-7-羟基-1-萘甲腈或其药学可接受的盐。
13.萘酚化合物,其为下述化合物之一:
6-(3-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(3-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2-氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2,5-二氟-4-羟基苯基)-2-萘酚;
1-氯-6-(2,6-二氟-4-羟基苯基)-2-萘酚;
6-(2,5-二氟-4-羟基苯基)-2-萘酚;
6-(3,5-二氟-4-羟基苯基)-2-萘酚;
1-氯-6-(3,5-二氟-4-羟基苯基)-2-萘酚;
6-(2,6-二氟-4-羟基苯基)-2-萘酚;或
8-氯-3-(3-氟-4-羟基苯基)-7-羟基-1-萘甲腈;
或其药学可接受的盐。
14.化合物,其为下述之一:
7-(4-羟基苯基)-2-萘酚;
7-(3-羟基苯基)-2-萘酚;
6-(4-羟基苯基)-1-萘酚;
6-苯基-2-萘酚;
6-(3-羟基苯基)-2-萘酚;
6-(3-氯苯基)-2-萘酚;
2-氟-4-(2-萘基)苯酚;
6-(3-氯-4-羟基酚)-2-萘酚;
1-氯-6-苯基-2-萘酚;
1-溴-6-(4-羟基苯基)-2-萘酚;
1-氯-6-(4-羟基苯基)-2-萘酚;
1-氟-6-(4-羟基苯基)-2-萘酚;
2-羟基-6-(4-羟基苯基)-1-萘甲腈;
6-(4-羟基苯基)-1-苯基-2-萘酚;
6-(4-羟基苯基)-1-甲基-2-萘酚;
1-氯-6-(3-氯-4-羟基苯基)-2-萘酚;
6-(4-羟基苯基)-1-硝基2-萘酚;
1-氯-6-(4-羟基-2-甲基苯基)-2-萘酚;
6-(4-羟基-2-甲基苯基)-2-萘酚;
6-(4-羟基-2-甲氧苯基)-2-萘酚;
6-(2-氯-4-羟基苯基)-2-萘酚;
1-氯-6-(2-氯-4-羟基苯基)-2-萘酚;
6-(2-氟-4-羟基苯基)-2-萘酚;
8-氟-6-(4-羟基苯基)-2-萘酚;
1-氯-8-氟-6-(4-羟基苯基)-2-萘酚;
8-氯-6-(4-羟基苯基)-2-萘酚;
1,5-二氯-8-氟-6-(4-羟基苯基)-2-萘酚;
2-氯-4-(2-萘基)苯酚;
3-溴-8-氯-6-(4-羟基苯基)-2-萘酚;
1,8-二氯-6-(4-羟基苯基)-2-萘酚;
3-溴-1,8-二氯-6-(4-羟基苯基)-2-萘酚;
7-羟基-3-(4-羟基苯基)-1-萘甲腈;
8-氯-3-(4-羟基苯基)-7-羟基-1-萘甲腈;
8-溴-7-羟基-3-(4-羟基苯基)-1-萘甲腈
或其药学可接受的盐。
15.治疗或抑制哺乳动物前列腺炎或间质性膀胱炎的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
16.一种为需要的哺乳动物治疗或抑制炎症性肠病、克罗恩氏病、溃疡性直肠炎或结肠炎的方法,包括给所述的哺乳动物提供有效量的权利要求1-14任一项的化合物或其药学可接受的盐。
17.一种给需要的哺乳动物治疗或抑制前列腺肥大、子宫平滑肌瘤、乳腺癌、子宫内膜癌、多囊卵巢综合征、子宫内膜息肉、良性乳房疾病、子宫内膜异位、卵巢癌、黑瘤、前列腺(prostrate)癌、结肠癌,神经胶质瘤或astioblastomia的方法,其包括给所述哺乳动物提供有效量的权利要求1-14的化合物或其药学可接受的盐。
18.一种方法,用于给需要的哺乳动物降低胆甾醇、三酸甘油酯、Lp(a)或LDL水平;抑制或治疗高胆固醇血症;血脂质过多;心血管疾病;动脉粥样硬化;高血压;外周血管疾病;再狭窄或血管痉挛;或抑制血管壁由于细胞间隙导致免疫调节性血管损伤产生的损坏,该方法包括给所述哺乳动物提供有效量的权利要求1-14任一项的化合物或其药学可接受的盐。
19.一种方法,给需要的哺乳动物提供认识增强或神经保护;或治疗或抑制老年性痴呆、阿尔茨海默氏病、认知下降、中风、焦虑或神经变性疾病,该方法包括给所述哺乳动物提供有效量的权利要求1-14的化合物或其药学可接受的盐。
20.治疗或抑制哺乳动物自由基诱发性疾病的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
21.一种给需要的哺乳动物治疗或抑制阴道或外阴萎缩;萎缩性阴道炎;阴道干燥症;瘙痒;性交疼痛;排尿困难;尿频;尿失禁;尿路感染的方法,其包括给所述哺乳动物提供有效量的权利要求1-14的化合物或其药学可接受的盐。
22.一种给需要的哺乳动物治疗或抑制血管收缩症状的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
23.一种给需要的哺乳动物抑制妊娠的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
24.一种给需要的哺乳动物治疗或抑制关节炎的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
25.根据权利要求24的方法,其中所述的关节炎是类风湿性关节炎、骨关节炎或脊柱关节炎。
26.一种方法,用于给需要的哺乳动物治疗或抑制关节膨胀或侵蚀;或治疗或抑制在关节内窥过程或外科手术过程中伴随的关节损坏的方法,其包括给所述哺乳动物提供有效量的权利要求1-14的化合物或其药学可接受的盐。
27.一种治疗或抑制哺乳动物牛皮癣或皮肤炎的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
28.一种方法,用于需要的哺乳动物治疗或抑制局部缺血、再灌注损伤、哮喘、胸膜炎、多发性硬化、全身性红斑狼疮、眼色素层炎、脓血症、出血性休克、黄斑变性或II型糖尿病,其包括给所述哺乳动物提供有效量的权利要求1-14任一项的化合物或其药学可接受的盐。
29.一种给需要的哺乳动物治疗或抑制子宫内膜异位的方法,其包括给所述哺乳动物提供有效量的权利要求1-14任一项所述的化合物或其药学可接受的盐。
30.一种药物组合物,其包括权利要求1-14任一项的化合物或其药学可接受的盐和药物载体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US34116401P | 2001-12-13 | 2001-12-13 | |
US60/341,164 | 2001-12-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1738788A true CN1738788A (zh) | 2006-02-22 |
Family
ID=23336481
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA028247361A Pending CN1738788A (zh) | 2001-12-13 | 2002-12-12 | 作为雌激素剂的取代的苯基萘 |
Country Status (18)
Country | Link |
---|---|
US (2) | US6914074B2 (zh) |
EP (1) | EP1453782A2 (zh) |
JP (1) | JP4566561B2 (zh) |
KR (1) | KR20040071197A (zh) |
CN (1) | CN1738788A (zh) |
AR (1) | AR038019A1 (zh) |
AU (2) | AU2002361659A1 (zh) |
BR (1) | BR0215042A (zh) |
CA (1) | CA2470109C (zh) |
HU (1) | HUP0501025A2 (zh) |
IL (1) | IL161740A0 (zh) |
MX (1) | MXPA04005629A (zh) |
NO (1) | NO20042955L (zh) |
PL (1) | PL374300A1 (zh) |
RU (2) | RU2314283C2 (zh) |
TW (1) | TWI306450B (zh) |
WO (1) | WO2003051805A2 (zh) |
ZA (1) | ZA200405512B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102675056A (zh) * | 2012-05-24 | 2012-09-19 | 盛世泰科生物医药技术(苏州)有限公司 | 一种6-溴-8-氟-2-萘酚的制备方法 |
CN103193601A (zh) * | 2013-04-11 | 2013-07-10 | 山东大学 | 2-苯基萘衍生物及其在制备抗肿瘤药物中的应用 |
CN107474038A (zh) * | 2017-07-17 | 2017-12-15 | 苏州楚凯药业有限公司 | 一类靶向雌激素受体荧光探针及其制备和使用方法 |
Families Citing this family (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA007382B1 (ru) | 2001-11-19 | 2006-10-27 | Эли Лилли Энд Компани | Замещенные бензопираны в качестве селективных агонистов бета-рецептора эстрогена |
US6914074B2 (en) * | 2001-12-13 | 2005-07-05 | Wyeth | Substituted phenyl naphthalenes as estrogenic agents |
CA2518819A1 (en) | 2003-04-21 | 2004-11-04 | Eli Lilly And Company | Substituted benzopyrans as selective estrogen receptor-beta agonists |
ATE457308T1 (de) | 2003-04-21 | 2010-02-15 | Lilly Co Eli | Substituierte benzopyrane als selektive antagonisten am östrogenrezeptor-beta |
CL2004000985A1 (es) | 2003-05-16 | 2005-01-14 | Wyeth Corp | Compuestos derivados de fenilquinolinas; composicion farmaceutica, proceso de preparacion; y uso para tratar osteoporosis, enfermedad de paget, dano vascular, osteoartritis, cancer oseo, cancer ovarico, cancer prostatico, hipercolesterolemia, aterosc |
TW200500065A (en) * | 2003-05-21 | 2005-01-01 | Wyeth Corp | Antiarthritic combinations |
US7557237B2 (en) * | 2003-09-09 | 2009-07-07 | Wyeth | Process for the synthesis of 3-(3-fluoro-4-hydroxyphenyl)-7-hydroxynaphthonitrile |
US7196119B2 (en) * | 2003-10-21 | 2007-03-27 | The Regents Of The University Of California | Development of new selective estrogen receptor modulators |
EP1704856A4 (en) * | 2003-12-26 | 2009-08-19 | Kyowa Hakko Kirin Co Ltd | PROTEIN INHIBITOR OF THE HSP90 FAMILY |
US7157492B2 (en) * | 2004-02-26 | 2007-01-02 | Wyeth | Dibenzo chromene derivatives and their use as ERβ selective ligands |
US7425580B2 (en) * | 2004-05-19 | 2008-09-16 | Wyeth | (Diaryl-methyl)-malononitriles and their use as estrogen receptor ligands |
US20060004087A1 (en) * | 2004-07-01 | 2006-01-05 | Wyeth | Tetracyclic compounds as estrogen ligands |
US7145040B2 (en) * | 2004-07-02 | 2006-12-05 | Bristol-Myers Squibb Co. | Process for the preparation of amino acids useful in the preparation of peptide receptor modulators |
GT200500370A (es) * | 2004-12-17 | 2006-07-13 | Nuevos usos para los agonistas beta de estrogeno | |
MX2007006797A (es) * | 2004-12-31 | 2007-08-07 | Aventis Pharma Inc | Uso de ciertos compuestos de fenil-naftilo que no tienen afinidad significativa por er alfa o beta para la proteccion de neuronas y oligodendrocitos en el tratamiento de esclerosis multiple. |
AU2005323163A1 (en) * | 2005-01-04 | 2006-07-13 | Aventis Pharmaceuticals Inc. | Use of certain phenyl napthyl compounds for protection of neurons and oligodendrocytes in the treatment of multiple sclerosis (MS) |
JP2008530210A (ja) * | 2005-02-16 | 2008-08-07 | ワイス | 放射線または化学療法誘発粘膜炎および放射線膀胱炎のためのエストロゲン受容体−β選択性アゴニストの使用 |
EP1702558A1 (en) * | 2005-02-28 | 2006-09-20 | Euro-Celtique S.A. | Method and device for the assessment of bowel function |
WO2006092430A1 (de) | 2005-03-03 | 2006-09-08 | Universität des Saarlandes | Selektive hemmstoffe humaner corticoidsynthasen |
TW200800177A (en) * | 2006-02-14 | 2008-01-01 | Wyeth Corp | Aqueous pharmaceutical formulations of ERβ selective ligands |
EP2647376A1 (en) | 2007-01-22 | 2013-10-09 | Gtx, Inc. | Nuclear receptor binding agents |
US9623021B2 (en) * | 2007-01-22 | 2017-04-18 | Gtx, Inc. | Nuclear receptor binding agents |
US9604931B2 (en) | 2007-01-22 | 2017-03-28 | Gtx, Inc. | Nuclear receptor binding agents |
MX2009008121A (es) * | 2007-01-31 | 2009-08-12 | Wyeth Corp | Uso de ligados selectivos de receptores de estrogeno beta para tratar lesiones de pulmon agudas. |
AR065399A1 (es) * | 2007-02-21 | 2009-06-03 | Wyeth Corp | Mono- y di- fosfatos de 3- (3-fluoro-4-hidroxi-fenil) -7-hidroxi-naftalen-1-carbonitrilo |
DE102007015169A1 (de) | 2007-03-27 | 2008-10-02 | Universität des Saarlandes Campus Saarbrücken | 17Beta-Hydroxysteroid-Dehydrogenase-Typ1-Inhibitoren zur Behandlung hormonabhängiger Erkrankungen |
US20100215579A1 (en) * | 2007-04-10 | 2010-08-26 | The Trustees Of The University Of Pennsylvania | Phen-naphthalene and phen-quinoline derivatives and their use for binding and imaging amyloid plaques |
KR101101977B1 (ko) * | 2009-04-09 | 2012-01-02 | (주)에스메디 | 2-아릴나프탈렌, 2-아릴퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 퇴행성 뇌질환의 진단 또는 치료용 약학적 조성물 |
WO2010127307A1 (en) | 2009-04-30 | 2010-11-04 | Rutgers, The State University Of New Jersey | Antimicrobial agents |
US9102617B2 (en) * | 2010-06-25 | 2015-08-11 | Rutgers, The State University Of New Jersey | Antimicrobial agents |
WO2013048145A2 (ko) * | 2011-09-30 | 2013-04-04 | 부산대학교 산학협력단 | 6-(3-하이드록시페닐)-2-나프톨 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 염증성 질환 또는 골량 저하 관련 질환의 예방 또는 치료용 조성물 |
US9822108B2 (en) | 2012-01-13 | 2017-11-21 | Rutgers, The State University Of New Jersey | Antimicrobial agents |
US9475783B2 (en) | 2012-03-21 | 2016-10-25 | Rutgers, The State University Of New Jersey | Antimicrobial agents |
US9458150B2 (en) | 2013-11-08 | 2016-10-04 | Rutgers, The State University Of New Jersey | Antimicrobial agents |
WO2016037171A1 (en) * | 2014-09-05 | 2016-03-10 | The Cleveland Clinic Foundation | Flavonoid il-17a inhibitors |
WO2017120507A1 (en) * | 2016-01-06 | 2017-07-13 | The Board Of Trustees Of The University Of Illinois | Novel compounds which activate estrogen receptors and compositions and methods of using the same |
US10513528B2 (en) | 2016-02-25 | 2019-12-24 | Taxis Pharmaceuticals, Inc. | Synthetic processes and intermediates |
WO2018183917A1 (en) | 2017-03-30 | 2018-10-04 | Taxis Pharmaceuticals, Inc. | Synthetic processes and synthetic intermediates |
EP4036189A1 (en) * | 2021-02-02 | 2022-08-03 | Indian Oil Corporation Limited | Process for synthesis of polyhydrocarbons as heat transfer agents |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8410901D0 (en) | 1984-04-27 | 1984-06-06 | Ici Plc | Phenol derivatives |
IE58417B1 (en) | 1984-04-27 | 1993-09-22 | Ici Plc | Chemical derivatives |
LU85849A1 (fr) | 1985-04-11 | 1986-11-05 | Cird | Derives benzonaphtaleniques,leur procede de preparation et leur application dans les domaines pharmaceutiques et cosmetiques |
FR2676052B1 (fr) | 1991-05-02 | 1994-04-29 | Cird Galderma | Nouveaux composes polycycliques aromatiques et leur utilisation en medecine humaine ou veterinaire et en cosmetique. |
DK77393D0 (da) | 1993-06-29 | 1993-06-29 | Novo Nordisk As | Aktivering af enzymer |
US5998401A (en) | 1995-02-28 | 1999-12-07 | Eli Lilly And Company | Naphthyl compounds, intermediates, compositions, and methods |
US6448294B1 (en) | 1996-02-01 | 2002-09-10 | Aventis Pharma S.A. | Biphenyl compounds and their use as oestrogenic agents |
FR2744444B1 (fr) | 1996-02-01 | 1998-05-29 | Roussel Uclaf | Nouveaux composes biphenyles, procede et intermediaires de preparation, application a titre de medicaments et compositions pharmaceutiques les renfermant |
FR2747041B1 (fr) | 1996-04-05 | 1998-05-22 | Cird Galderma | Utilisation de derives benzonaphtaleniques pour la fabrication de medicaments destines au traitement des neuropathies |
US5916916A (en) * | 1996-10-10 | 1999-06-29 | Eli Lilly And Company | 1-aryloxy-2-arylnaphthyl compounds, intermediates, compositions, and methods |
CN1358091A (zh) | 1999-04-16 | 2002-07-10 | 阿斯特拉曾尼卡有限公司 | 雌激素受体-β配体 |
EP1361205A1 (en) | 1999-12-13 | 2003-11-12 | Chugai Seiyaku Kabushiki Kaisha | Compounds with hydroxycarbonyl-halogenalkyl side chains |
US6914074B2 (en) * | 2001-12-13 | 2005-07-05 | Wyeth | Substituted phenyl naphthalenes as estrogenic agents |
-
2002
- 2002-12-11 US US10/316,640 patent/US6914074B2/en not_active Expired - Fee Related
- 2002-12-11 TW TW091135871A patent/TWI306450B/zh not_active IP Right Cessation
- 2002-12-12 CN CNA028247361A patent/CN1738788A/zh active Pending
- 2002-12-12 EP EP02797299A patent/EP1453782A2/en not_active Withdrawn
- 2002-12-12 JP JP2003552695A patent/JP4566561B2/ja not_active Expired - Fee Related
- 2002-12-12 AU AU2002361659A patent/AU2002361659A1/en not_active Abandoned
- 2002-12-12 IL IL16174002A patent/IL161740A0/xx unknown
- 2002-12-12 WO PCT/US2002/039883 patent/WO2003051805A2/en active Application Filing
- 2002-12-12 BR BRPI0215042-5A patent/BR0215042A/pt not_active IP Right Cessation
- 2002-12-12 HU HU0501025A patent/HUP0501025A2/hu unknown
- 2002-12-12 PL PL02374300A patent/PL374300A1/xx unknown
- 2002-12-12 CA CA2470109A patent/CA2470109C/en not_active Expired - Fee Related
- 2002-12-12 KR KR10-2004-7009120A patent/KR20040071197A/ko not_active Application Discontinuation
- 2002-12-12 RU RU2004121227/04A patent/RU2314283C2/ru not_active Application Discontinuation
- 2002-12-12 MX MXPA04005629A patent/MXPA04005629A/es active IP Right Grant
- 2002-12-12 AR ARP020104829A patent/AR038019A1/es unknown
-
2004
- 2004-03-18 US US10/803,612 patent/US7067524B2/en not_active Expired - Fee Related
- 2004-07-12 ZA ZA200405512A patent/ZA200405512B/xx unknown
- 2004-07-12 NO NO20042955A patent/NO20042955L/no not_active Application Discontinuation
-
2007
- 2007-07-27 RU RU2007128958/04A patent/RU2007128958A/ru not_active Application Discontinuation
-
2009
- 2009-10-06 AU AU2009222567A patent/AU2009222567A1/en not_active Ceased
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102675056A (zh) * | 2012-05-24 | 2012-09-19 | 盛世泰科生物医药技术(苏州)有限公司 | 一种6-溴-8-氟-2-萘酚的制备方法 |
CN103193601A (zh) * | 2013-04-11 | 2013-07-10 | 山东大学 | 2-苯基萘衍生物及其在制备抗肿瘤药物中的应用 |
CN107474038A (zh) * | 2017-07-17 | 2017-12-15 | 苏州楚凯药业有限公司 | 一类靶向雌激素受体荧光探针及其制备和使用方法 |
CN107474038B (zh) * | 2017-07-17 | 2020-10-09 | 苏州楚凯药业有限公司 | 一类靶向雌激素受体荧光探针及其制备和使用方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2470109C (en) | 2010-12-21 |
EP1453782A2 (en) | 2004-09-08 |
RU2314283C2 (ru) | 2008-01-10 |
JP2005538924A (ja) | 2005-12-22 |
AU2009222567A1 (en) | 2009-10-22 |
RU2004121227A (ru) | 2006-01-10 |
PL374300A1 (en) | 2005-10-03 |
US7067524B2 (en) | 2006-06-27 |
US20030181519A1 (en) | 2003-09-25 |
TW200300668A (en) | 2003-06-16 |
MXPA04005629A (es) | 2004-12-06 |
WO2003051805A3 (en) | 2003-09-04 |
HUP0501025A2 (en) | 2006-03-28 |
TWI306450B (en) | 2009-02-21 |
WO2003051805A2 (en) | 2003-06-26 |
BR0215042A (pt) | 2006-06-06 |
RU2007128958A (ru) | 2009-02-10 |
AU2002361659A1 (en) | 2003-06-30 |
US6914074B2 (en) | 2005-07-05 |
ZA200405512B (en) | 2007-02-28 |
JP4566561B2 (ja) | 2010-10-20 |
IL161740A0 (en) | 2005-11-20 |
NO20042955L (no) | 2004-07-12 |
AR038019A1 (es) | 2004-12-22 |
US20040225123A1 (en) | 2004-11-11 |
CA2470109A1 (en) | 2003-06-26 |
KR20040071197A (ko) | 2004-08-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1738788A (zh) | 作为雌激素剂的取代的苯基萘 | |
CN1646504A (zh) | 作为雌激素药物的取代苯并噁唑和类似物 | |
CN100344610C (zh) | 芳基-甲醛肟衍生物及其作为雌激素药物的用途 | |
CN100344616C (zh) | 用于治疗代谢失调的化合物 | |
CN1649820A (zh) | 调节ppar活性的化合物及其制备方法 | |
CN1113873C (zh) | 新的任选取代的苯基咪唑烷、中间体及其制备方法,作为药物的应用和含有它们的药物组合 | |
CN1268614C (zh) | 用于治疗炎症的取代的吡唑基苯磺酰胺类化合物 | |
CN1154486C (zh) | 甲状腺素类似物的应用 | |
CN1606551A (zh) | 作为雌激素制剂的取代的2-苯基苯并呋喃 | |
CN1255396C (zh) | 含有稠环的羧酸衍生物 | |
CN101044126A (zh) | 作为雌激素药物的前药取代的苯并唑化合物 | |
CN1638776A (zh) | 取代的3-芳基-5-芳基-[1,2,4]-噁二唑和类似物 | |
CN1633296A (zh) | 糖皮质素模拟物、其制备方法、药物组合物及其用途 | |
CN101076336A (zh) | 新的姜黄素类似物及其用途 | |
CN1993320A (zh) | 作为11-β-羟基类固醇脱氢酶-1的抑制剂的磺酰化合物 | |
CN1578659A (zh) | 过氧化物酶体增殖剂激活的受体(ppar)的调节剂 | |
CN1113236A (zh) | 非肽基速激肽受体拮抗剂 | |
CN1489458A (zh) | 炎症性细胞因子产生游离抑制剂 | |
CN1699347A (zh) | 用于治疗炎症的取代的吡唑基苯磺酰胺类化合物 | |
CN1729157A (zh) | 取代的氨基苯乙酸、其衍生物、它们的制备以及它们作为环氧合酶-2 (co x-2)抑制剂的用途 | |
CN1258286A (zh) | 具有促孕激素和雄性激素之混合活性的非甾体(杂)环取代的酰基苯胺 | |
CN1775759A (zh) | 二环类雄激素和孕甾酮受体调节化合物和方法 | |
CN1630632A (zh) | 芳香族氨基酸衍生物及其药物组合物 | |
CN1747730A (zh) | 肝细胞生长因子(分散因子)活性的吡唑衍生物调节剂 | |
CN1816536A (zh) | 大麻素受体调节剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
AD01 | Patent right deemed abandoned | ||
C20 | Patent right or utility model deemed to be abandoned or is abandoned |