CN1708490A - 胺化异黄酮类衍生物及其应用 - Google Patents
胺化异黄酮类衍生物及其应用 Download PDFInfo
- Publication number
- CN1708490A CN1708490A CNA2003801025650A CN200380102565A CN1708490A CN 1708490 A CN1708490 A CN 1708490A CN A2003801025650 A CNA2003801025650 A CN A2003801025650A CN 200380102565 A CN200380102565 A CN 200380102565A CN 1708490 A CN1708490 A CN 1708490A
- Authority
- CN
- China
- Prior art keywords
- compound
- derivative
- acceptable salt
- pharmacy acceptable
- alkyl
- 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
- 150000003817 isoflavonoid derivatives Chemical class 0.000 title abstract description 10
- 229930013035 isoflavonoid derivative Natural products 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims description 106
- 238000000034 method Methods 0.000 claims description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 44
- 201000010099 disease Diseases 0.000 claims description 42
- -1 sulfo- Chemical class 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 31
- DCTLJGWMHPGCOS-UHFFFAOYSA-N Osajin Chemical compound C1=2C=CC(C)(C)OC=2C(CC=C(C)C)=C(O)C(C2=O)=C1OC=C2C1=CC=C(O)C=C1 DCTLJGWMHPGCOS-UHFFFAOYSA-N 0.000 claims description 29
- 238000011282 treatment Methods 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 230000004083 survival effect Effects 0.000 claims description 16
- 239000003981 vehicle Substances 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 230000002265 prevention Effects 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 230000002159 abnormal effect Effects 0.000 claims description 14
- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 12
- 230000012292 cell migration Effects 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 10
- 235000013305 food Nutrition 0.000 claims description 10
- 239000003163 gonadal steroid hormone Substances 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 230000004663 cell proliferation Effects 0.000 claims description 8
- 230000014509 gene expression Effects 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- 230000004862 vasculogenesis Effects 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 6
- OUZCFMSJGDEXRT-UHFFFAOYSA-N Scandinone Natural products O=C1C=2C(OC)=C(CC=C(C)C)C=3OC(C)(C)C=CC=3C=2OC=C1C1=CC=C(O)C=C1 OUZCFMSJGDEXRT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 235000013361 beverage Nutrition 0.000 claims description 5
- 230000004064 dysfunction Effects 0.000 claims description 5
- 230000001076 estrogenic effect Effects 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 230000002792 vascular Effects 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 230000005786 degenerative changes Effects 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 230000001640 apoptogenic effect Effects 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 230000001934 delay Effects 0.000 claims description 2
- 230000005748 tumor development Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 6
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- 229930182558 Sterol Natural products 0.000 claims 1
- 230000007850 degeneration Effects 0.000 claims 1
- 150000003432 sterols Chemical class 0.000 claims 1
- 235000003702 sterols Nutrition 0.000 claims 1
- 229930013032 isoflavonoid Natural products 0.000 abstract description 9
- 235000012891 isoflavonoids Nutrition 0.000 abstract description 9
- RTRZOHKLISMNRD-UHFFFAOYSA-N isoflavanone Chemical compound C1OC2=CC=CC=C2C(=O)C1C1=CC=CC=C1 RTRZOHKLISMNRD-UHFFFAOYSA-N 0.000 abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 55
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 39
- 235000008696 isoflavones Nutrition 0.000 description 39
- 150000002515 isoflavone derivatives Chemical class 0.000 description 33
- 230000000694 effects Effects 0.000 description 32
- 238000005576 amination reaction Methods 0.000 description 29
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 23
- 102000004190 Enzymes Human genes 0.000 description 19
- 108090000790 Enzymes Proteins 0.000 description 19
- 150000002431 hydrogen Chemical class 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 17
- 239000000284 extract Substances 0.000 description 16
- 230000019491 signal transduction Effects 0.000 description 16
- 230000006870 function Effects 0.000 description 15
- 239000003960 organic solvent Substances 0.000 description 14
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 14
- 150000001721 carbon Chemical group 0.000 description 12
- 230000007246 mechanism Effects 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- 229960003604 testosterone Drugs 0.000 description 12
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 206010060862 Prostate cancer Diseases 0.000 description 11
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 102100032187 Androgen receptor Human genes 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 108010080146 androgen receptors Proteins 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 241000196324 Embryophyta Species 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000003013 cytotoxicity Effects 0.000 description 8
- 231100000135 cytotoxicity Toxicity 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 239000011737 fluorine Substances 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 150000003180 prostaglandins Chemical class 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- ZQSIJRDFPHDXIC-UHFFFAOYSA-N daidzein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC=C2C1=O ZQSIJRDFPHDXIC-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000001624 naphthyl group Chemical group 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 150000003431 steroids Chemical class 0.000 description 6
- ZDRVLAOYDGQLFI-UHFFFAOYSA-N 4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol;hydrochloride Chemical compound Cl.C1=CC(O)=CC=C1NC1=NC(C=2C=CC(Cl)=CC=2)=CS1 ZDRVLAOYDGQLFI-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 230000001093 anti-cancer Effects 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 210000001616 monocyte Anatomy 0.000 description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 210000002307 prostate Anatomy 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 108010035597 sphingosine kinase Proteins 0.000 description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 4
- 229960004039 finasteride Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 150000003515 testosterones Chemical class 0.000 description 4
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 description 3
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 201000009273 Endometriosis Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 3
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
- 206010046798 Uterine leiomyoma Diseases 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- WUADCCWRTIWANL-UHFFFAOYSA-N biochanin A Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O WUADCCWRTIWANL-UHFFFAOYSA-N 0.000 description 3
- 230000031018 biological processes and functions Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000004803 chlorobenzyl group Chemical group 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
- 239000012141 concentrate Substances 0.000 description 3
- 235000007240 daidzein Nutrition 0.000 description 3
- 230000003412 degenerative effect Effects 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- HKQYGTCOTHHOMP-UHFFFAOYSA-N formononetin Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O HKQYGTCOTHHOMP-UHFFFAOYSA-N 0.000 description 3
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 3
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 3
- 150000007857 hydrazones Chemical class 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 230000009245 menopause Effects 0.000 description 3
- 125000006178 methyl benzyl group Chemical group 0.000 description 3
- 230000000394 mitotic effect Effects 0.000 description 3
- 230000002969 morbid Effects 0.000 description 3
- 125000006502 nitrobenzyl group Chemical group 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 150000007659 semicarbazones Chemical class 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000002769 thiazolinyl group Chemical group 0.000 description 3
- 125000005425 toluyl group Chemical group 0.000 description 3
- 210000001215 vagina Anatomy 0.000 description 3
- 239000005418 vegetable material Substances 0.000 description 3
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- ZZUBHVMHNVYXRR-UHFFFAOYSA-N 3-(4-hydroxyphenyl)-2h-chromen-7-ol Chemical compound C1=CC(O)=CC=C1C1=CC2=CC=C(O)C=C2OC1 ZZUBHVMHNVYXRR-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CCOJFDRSZSSKOG-UHFFFAOYSA-N Angolensin Chemical compound C1=CC(OC)=CC=C1C(C)C(=O)C1=CC=C(O)C=C1O CCOJFDRSZSSKOG-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 2
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JHYXBPPMXZIHKG-CYBMUJFWSA-N Dihydrodaidzein Natural products C1=CC(O)=CC=C1[C@@H]1C(=O)C2=CC=C(O)C=C2OC1 JHYXBPPMXZIHKG-CYBMUJFWSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 241000220645 Leonotis nepetifolia Species 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010036618 Premenstrual syndrome Diseases 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000028990 Skin injury Diseases 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 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
- 239000002253 acid Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229960003473 androstanolone Drugs 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 238000011319 anticancer therapy Methods 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000012062 aqueous buffer Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- JHYXBPPMXZIHKG-UHFFFAOYSA-N dihydrodaidzein Chemical compound C1=CC(O)=CC=C1C1C(=O)C2=CC=C(O)C=C2OC1 JHYXBPPMXZIHKG-UHFFFAOYSA-N 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 150000002066 eicosanoids Chemical class 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 235000019126 equol Nutrition 0.000 description 2
- ADFCQWZHKCXPAJ-GFCCVEGCSA-N equol Chemical compound C1=CC(O)=CC=C1[C@@H]1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-GFCCVEGCSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000008105 immune reaction Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- ADFCQWZHKCXPAJ-UHFFFAOYSA-N indofine Natural products C1=CC(O)=CC=C1C1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-UHFFFAOYSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 208000000509 infertility Diseases 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 231100000535 infertility Toxicity 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- NNQSGBRGJHSRFN-UHFFFAOYSA-N isoflavan Chemical compound C1OC2=CC=CC=C2CC1C1=CC=CC=C1 NNQSGBRGJHSRFN-UHFFFAOYSA-N 0.000 description 2
- 235000002324 isoflavanes Nutrition 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 2
- 239000003104 tissue culture media Substances 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- XLWCIHPMASUXPI-UHFFFAOYSA-N 1,1'-(propane-1,2-diyl)dibenzene Chemical compound C=1C=CC=CC=1C(C)CC1=CC=CC=C1 XLWCIHPMASUXPI-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical class CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 241001044369 Amphion Species 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- CCOJFDRSZSSKOG-SNVBAGLBSA-N Angolensin Natural products C1=CC(OC)=CC=C1[C@@H](C)C(=O)C1=CC=C(O)C=C1O CCOJFDRSZSSKOG-SNVBAGLBSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 229930191576 Biochanin Natural products 0.000 description 1
- 208000013165 Bowen disease Diseases 0.000 description 1
- 208000019337 Bowen disease of the skin Diseases 0.000 description 1
- 208000033386 Buerger disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 241001432959 Chernes Species 0.000 description 1
- 241000370738 Chlorion Species 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 1
- 244000045195 Cicer arietinum Species 0.000 description 1
- 235000010523 Cicer arietinum Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 102000009058 Death Domain Receptors Human genes 0.000 description 1
- 108010049207 Death Domain Receptors Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 208000024720 Fabry Disease Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 101000919849 Homo sapiens Cytochrome c oxidase subunit 1 Proteins 0.000 description 1
- 101000725401 Homo sapiens Cytochrome c oxidase subunit 2 Proteins 0.000 description 1
- 101000605122 Homo sapiens Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 101000605127 Homo sapiens Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- SFBODOKJTYAUCM-UHFFFAOYSA-N Ipriflavone Chemical compound C=1C(OC(C)C)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 SFBODOKJTYAUCM-UHFFFAOYSA-N 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 244000043158 Lens esculenta Species 0.000 description 1
- 235000010666 Lens esculenta Nutrition 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 102100026933 Myelin-associated neurite-outgrowth inhibitor Human genes 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010036049 Polycystic ovaries Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036590 Premature baby Diseases 0.000 description 1
- 206010036631 Presenile dementia Diseases 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000003639 Student–Newman–Keuls (SNK) method Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 208000005485 Thrombocytosis Diseases 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000219793 Trifolium Species 0.000 description 1
- 235000015724 Trifolium pratense Nutrition 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 244000126002 Ziziphus vulgaris Species 0.000 description 1
- 235000008529 Ziziphus vulgaris Nutrition 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 208000009621 actinic keratosis Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000001548 androgenic effect Effects 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002634 anti-blastic effect Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 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
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 238000009360 aquaculture Methods 0.000 description 1
- 244000144974 aquaculture Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 229940110331 bextra Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000872 buffer Substances 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008294 cold cream Substances 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 235000021185 dessert Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 108700014361 due to increased aromatase activity Familial gynecomastia Proteins 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 208000008487 fibromuscular dysplasia Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- RIKPNWPEMPODJD-UHFFFAOYSA-N formononetin Natural products C1=CC(OC)=CC=C1C1=COC2=CC=CC=C2C1=O RIKPNWPEMPODJD-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000006539 genistein Nutrition 0.000 description 1
- 229940045109 genistein Drugs 0.000 description 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- NNUVCMKMNCKPKN-UHFFFAOYSA-N glycitein Natural products COc1c(O)ccc2OC=C(C(=O)c12)c3ccc(O)cc3 NNUVCMKMNCKPKN-UHFFFAOYSA-N 0.000 description 1
- 235000008466 glycitein Nutrition 0.000 description 1
- DXYUAIFZCFRPTH-UHFFFAOYSA-N glycitein Chemical compound C1=C(O)C(OC)=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 DXYUAIFZCFRPTH-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229960005431 ipriflavone Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N iso-butene Natural products CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229930012930 isoflavone derivative Natural products 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 230000009191 jumping Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 201000005857 malignant hypertension Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 210000002935 megaloblast Anatomy 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000003360 nephrocyte Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 208000025661 ovarian cyst Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 1
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000001686 pro-survival effect Effects 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- CBOMORHDRONZRN-QLOYDKTKSA-N prostaglandin E3 Chemical compound CC\C=C/C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O CBOMORHDRONZRN-QLOYDKTKSA-N 0.000 description 1
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 235000013526 red clover Nutrition 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 210000005000 reproductive tract Anatomy 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 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
- 230000028327 secretion Effects 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- YEENEYXBHNNNGV-XEHWZWQGSA-M sodium;3-acetamido-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoate;(2r,3r,4s,5s,6r)-2-[(2r,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound [Na+].CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I.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 YEENEYXBHNNNGV-XEHWZWQGSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000010009 steroidogenesis Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000002723 toxicity assay Methods 0.000 description 1
- 229940124279 traditional non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 206010055031 vascular neoplasm Diseases 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
-
- 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
- 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
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
通过胺化异黄烷酮和异黄烷酮环体系4-酮基合成的胺化异黄酮类化合物、含有它们的药用组合物及其作为治疗药物的应用。
Description
发明领域
本发明总的来说涉及基于异黄酮和异黄烷酮环体系4-酮基氮取代物的胺化异黄酮类衍生物。本发明还涉及胺化异黄酮类衍生物的合成、含有该成分的组合物及其作为治疗药物的应用。
发明背景
已知天然存在的植物异黄酮对人细胞具有广泛的基本生物学作用,包括抗氧化、上调和下调各种酶和信号转导机制。人癌细胞有丝分裂停止和细胞毒性、毛细血管通透性增加、细胞粘附增加、血管平滑肌细胞对血管松弛剂的反应增加以及雌激素受体的兴奋只是动物细胞响应天然存在的异黄酮类化合物生物学作用的几个实例。
作为这些生物学作用的结果,现在已经发现了多种治疗用途,包括治疗和预防绝经前症状(如月经前综合症)、子宫内膜异位、子宫肌瘤、高脂血症、心血管疾病、绝经症状(如骨质疏松症和老年性痴呆)、酒精中毒、良性前列腺肥大和癌症(如前列腺癌、乳腺癌和大肠癌)[参见WO 93/23069;WO 96/10341;US 5424331;JP 62-106017;JP 62-106016;US 5516528;JP 62-106016A2;JP 62-106017A2;JP61-246124;WO 98/50026;WO 99/43335;WO 00/49009;WO00/644438;WO 99/48496]。
尽管已经描述了700多种不同的天然存在的异黄酮,但是只有少数几种被确定为在动物(包括人)中具有潜在的治疗用途。它们包括黄豆苷元、金雀异黄素、芒柄花黄素、鹰嘴豆素和黄豆黄素。这些和所有天然存在的异黄酮以单体形式存在于自然界中,其处于游离状态或更可能与糖部分结合(糖苷)。异黄酮在变成生物活性前需要与糖部分分离。
一些具有天然存在的植物异黄酮相关结构的化合物也被描述为具有生物活性,对动物(包括人)有潜在的治疗用途。它们包括通过肠道菌群的细菌发酵产生的植物异黄酮天然存在的代谢物,并且包括化合物如雌马酚和O-去甲安哥拉紫檀素[WO 93/23069;WO98/08503;WO 01/17986;WO 00/66576]。这类化合物还包括合成异黄酮类化合物(如依普黄酮,开发用于治疗经绝后骨质疏松症[WO91/14429])和多种合成异黄酮类类似物[WO 98/08503]。
虽然对异黄酮类化合物及其衍生物进行了大量的研究,并积累了许多知识,但是在治疗上有用的异黄酮类化合物及其活性的全部情况仍然有待认识。而且,治疗、预防、缓解、抵抗和/或阻止各种疾病和失调持续需要新型改进的、或者至少是替代的活性药物。
因此,有对新一代化合物的需求,这种化合物对动物(尤其是人)的健康表现出重要生理性质,并且需要发现新方法,以开发它们治疗、缓解和预防疾病的性质。
发明概述
令人惊奇的是,本发明的发明人发现了一类基于胺化异黄-4-酮(isoflav-4-one)和异黄烷-4-酮(isoflavan-4-one)化合物的新分子。具体地说,本发明的胺化异黄酮类化合物涉及异黄-4-酮和异黄烷-4-酮的亚胺、腙、缩氨基脲、吖嗪、肟和胺衍生物。本发明化合物的活性令人惊讶和意想不到,即使是对于其来源的非胺化异黄-4-酮和异黄烷-4-酮化合物的已知情况也是如此。
因此,本发明的一个方面提供通式(I)的化合物:
其中
R1、R2、R3、R4、R5、R6、R7和R8独立地为氢、羟基、OR9、OC(O)H、OC(O)R9、OS(O)R9、OSi(R10)3、C(O)R11、CO2R12、烷基、卤代烷基、芳基、芳基烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤基,或者取代基R2、R3和R4中的任两个与连接它们的碳原子一起形成环烷基、杂环烷基、芳基或杂芳基结构,
R9为烷基、卤代烷基、芳基、芳基烷基或烷基芳基,
R10独立地为氢、烷基或芳基,
R11为氢、烷基、芳基、芳基烷基、芳基烷基或氨基酸,
R12为氢、烷基、卤代烷基、芳基、芳基烷基或烷基芳基,
X为O、NR12或S,
Z为R13、NR14R15、NR13CONR14R15、N=CR16R17或OR13,
R13、R14和R15独立地为氢、氨基、硫代、硝基、氰基,或者为任选取代的烷基、卤代烷基、酰基、芳基、杂芳基、芳基烷基或烷基芳基,或者取代基R14和R15与连接它们的氮原子一起形成任选取代的杂环烷基或杂芳基结构,
R16和R17独立地为氢、氨基、硫代、硝基、氰基,或者为任选取代的烷基、卤代烷基、酰基、芳基、杂芳基、芳基烷基或烷基芳基,或者取代基R16和R17与连接它们的碳原子一起形成任选取代的异黄酮类环体系,
或者当X为NR12时,取代基R12可以为化学键,从而R8和X与连接它们的碳原子一起形成下列结构之一:
其中Y为
其中
R1、R2、R3、R4、R5、R6、R7、R8和Z如上定义,
所述化合物包括其药学上可接受的盐和衍生物。
本发明的另一个方面提供制备式(I)化合物的方法,该方法包括使式(X)化合物的4-酮基与胺化剂反应的步骤:
其中
R1、R2、R3、R4、R5、R6、R7、R8和X如上定义,
符号
表示单键或双键。
本发明人惊讶地发现,通式(I)的胺化异黄酮类衍生物对调节动物细胞内的多种分子靶点具有特别的作用和效力,这些分子靶点紧密涉及重要细胞过程(如细胞生长、分化、迁移和死亡)中的基本信号转导途径。
本发明胺化化合物可调节动物细胞内的多种信号转导途径,这些信号转导途径涉及动物所有细胞存活和运作必须的多种功能。因此,这种化合物在动物、包括人中具有广泛和重要的健康益处,尤其有潜力预防和治疗重要和常见人类疾病、失调和功能。
本发明的具体益处在于:(a)化合物靶向多种信号转导途径,(b)对这些途径的调节包括对某些途径的上调和对其它途径的下调,以及(c)对信号转导途径有广泛和多样的效果,同时对多种重要的在代谢和类固醇生成作用中起基础作用的酶具有独立作用。
因此,本发明的另一个方面提供治疗、预防或缓解疾病或失调的方法,该方法包括给予患者治疗有效量的一种或多种式(I)化合物或其药学上可接受的盐或衍生物的步骤。
具体地说,本发明提供治疗、预防或缓解疾病的方法,这些疾病涉及反常细胞存活、反常细胞增殖、异常细胞迁移、异常血管生成、异常雌激素/雄激素平衡、类固醇生成机能障碍或异常、退化如血管壁退化性改变、炎症和免疫失调,该方法包括给予患者一种或多种任选与载体和/或赋形剂混和的式(I)化合物或其药学上可接受的盐或衍生物。
本发明的另一个方面提供诱导表达异常促存活(prosurvival)表型的细胞凋亡的方法,该方法包括使所述细胞接触一种或多种任选与载体或赋形剂混和的式(I)化合物或其药学上可接受的盐或衍生物。
本发明的另一个方面提供抑制具有异常细胞迁移表型细胞迁移的方法,该方法包括使所述细胞接触任选与载体或赋形剂混和的式(I)化合物或其药学上可接受的盐或衍生物。
本发明的另一个方面提供抑制表达异常血管生成表型的组织中的血管生成的方法,该方法包括使所述组织接触任选与载体或赋形剂混和的式(I)化合物或其药学上可接受的盐或衍生物。
本发明的另一个方面提供治疗、预防或缓解哺乳动物癌症的方法,该方法包括使式(I)化合物或其药学上可接受的盐或衍生物接触患肿瘤哺乳动物体内癌性组织的步骤,从而延缓或阻止所述癌性组织中的肿瘤发展。
本发明的另一个方面提供一种或多种式(I)化合物或其药学上可接受的盐或衍生物在制备疾病或失调治疗药物中的用途。
本发明的另一个方面提供治疗、预防或缓解疾病或失调的药物,该药物包含一种或多种式(I)化合物或其药学上可接受的盐或衍生物。
本发明的另一个方面提供药用组合物,所述药用组合物包含一种或多种式(I)化合物或其药学上可接受的盐或衍生物以及一种或多种药用载体、赋形剂、辅料和/或稀释剂。
本发明的另一个方面提供饮料或食品,所述饮料或食品包含一种或多种式(I)化合物或其药学上可接受的盐或衍生物。
在一个特别优选的实施方案中,本发明胺化化合物显示下列治疗活性:
1.通过抑制信号转导、调节细胞周期和诱导细胞凋亡直接抗癌。
2.通过抑制COX阻止癌症发生和增殖。
3.通过特异性抑制5′α-还原酶阻止癌症发生和增殖。
4.抗炎作用。
根据说明书、所附权利要求书和附图,本发明的这些方面和其它方面将会是显而易见的。
在本发明说明书和所附权利要求书中,除内容另有要求外,单词“包含”、“包括”及其各种变化应理解为包含整体或步骤的所指整体或步骤或基团,但不排除整体或步骤的任何其它整体或步骤或基团。
附图简述
图1表示Cpd.1和Cpd.3抗所选肿瘤系LNCaP、DU145和NCI-H460的细胞毒性曲线,如下述:
图A Cpd.1/LNCaP
图B Cpd.1/DU145
图C Cpd.3/LNCaP
图D Cpd.3/NCI-H460
图2表示Cpd.1(图A)和Cpd.2和Cpd.3(图B)抑制睾酮诱导LNCaP的增殖。
图3表示Cpd.1、Cpd.2和Cpd.3对睾酮诱导LNCaP增殖的抑制曲线。
图4表示Cpd.1、Cpd.2和Cpd.3对COS(PGE3)和血栓烷合酶(TBXZ)活性的抑制。
图5表示Cpd.1的1H NMR谱(d6-丙酮)。
图6表示Cpd.2的1H NMR谱(d3-乙腈)。
图7表示Cpd.3的1H NMR谱(d3-乙腈)。
发明详述
本发明胺化化合物基于异黄酮化合物及其衍生物。本文所用的术语“异黄酮”广义上包括环稠合的苯并吡喃分子,该吡喃环外伸出基于1,2-二苯基丙烷体系的苯基。因此,通常称为异黄酮、异黄烯(isoflavenes)、异黄烷、异黄烷酮、异黄烷醇等的这类化合物在本文中统称为异黄酮、异黄酮衍生物或异黄酮类分子、化合物或衍生物。
术语“烷基”包括1-10个碳原子、优选1-6个碳原子的直链、支链和环状(在5个或更多碳的情况下)饱和烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、环戊基等。烷基更优选为甲基、乙基、丙基或异丙基。烷基可任选被一个或多个下述基团取代:氟、氯、溴、碘、羧基、C1-C4-烷氧基羰基、C1-C4-烷基氨基-羰基、二-(C1-C4-烷基)-氨基-羰基、羟基、C1-C4-烷氧基、甲酰氧基、C1-C4-烷基-羰基氧基、C1-C4-烷硫基、C3-C6-环烷基或苯基。
术语“烯基”包括2-10个碳原子、优选2-6碳原子并带有至少一个双键的直链支链和环状(在5个或更多碳的情况下)烃基,如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、2-甲基-1-丙烯基(peopenyl)、2-甲基-2-丙烯基等。烯基更优选乙烯基、1-丙烯基或2-丙烯基。烯基可任选被一个或多个下述基团取代:氟、氯、溴、碘、羧基、C1-C4-烷氧基羰基、C1-C4-烷基氨基-羰基、二-(C1-C4-烷基)-氨基-羰基、羟基、C1-C4-烷氧基、甲酰氧基、C1-C4-烷基-羰基氧基、C1-C4-烷硫基、C3-C6-环烷基或苯基。
术语“炔基”包括2-10个碳原子、优选2-6个碳原子并带有至少一个三键的直链和支链烃,如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基等。炔基更优选乙炔基、1-丙炔基或2-丙炔基。炔基可任选被一个或多个下述基团取代:氟、氯、溴、碘、羧基、C1-C4-烷氧基羰基、C1-C4-烷基氨基-羰基、二-(C1-C4-烷基)-氨基-羰基、羟基、C1-C4-烷氧基、甲酰氧基、C1-C4-烷基-羰基氧基、C1-C4-烷硫基、C3-C6-环烷基或苯基。
术语“芳基”包括苯基、联苯基和萘基,可任选被一个或多个下述基团取代:C1-C4-烷基、羟基、C1-C4-烷氧基、羰基、C1-C4-烷氧基羰基、C1-C4-烷基羰基氧基、硝基或卤基。
术语“杂芳基”包括在环中含有至少一个氧、硫或氮的5元和6元环,该环可任选与其它芳环或杂芳环稠合,包括但不限于呋喃基、吡啶基、嘧啶基、噻吩基、咪唑基、四唑基、吡嗪基、苯并呋喃基、苯并噻吩基、喹啉基、异喹啉基、嘌呤基、吗啉基、噁唑基、噻唑基、吡咯基、黄嘌呤基、嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶和异噁唑基。杂芳基可任选被一个或多个下述基团取代:氟、氯、溴、碘、羧基、硝基、C1-C4-烷氧基羰基、C1-C4-烷基氨基-羰基、二-(C1-C4-烷基)-氨基-羰基、羟基、C1-C4-烷氧基、甲酰氧基、C1-C4-烷基-羰基氧基、C1-C4-烷硫基、C3-C6-环烷基或苯基。杂芳基可根据需要部分或完全氢化。
术语“卤基”包括氟基、氯基、溴基和碘基,优选氟基和氯基,更优选氟基。对实例“卤代烷基”的引用包括一卤代、二卤代和最多全卤代的烷基。优选卤代烷基为三氟甲基和五氟乙基。
任选取代基团为其中一个或多个氢独立被以下基团取代的基团:羟基、烷氧基、酰基、硫代、烷硫基、氰基、硝基、氨基、烷基氨基、二烷基氨基、卤基或羧基。
本发明发明人发现了一类新型基于胺化异黄酮类衍生物的分子。本发明涉及氮基部分对异黄酮和异黄烷酮类化合物4-酮基的取代物。具体地说,胺化异黄酮类衍生物涉及亚胺、腙、缩氨基脲、吖嗪和肟,如通式(II)-(VIII)所示:
其中
R1、R2、R3、R4、R5、R6、R7和R8独立地为氢、羟基、OR9、OC(O)R9、OS(O)R9、烷基、芳基、芳基烷基、硫代、烷硫基、溴基、氯基或氟基,
R9为烷基、氟烷基或芳基烷基,
R13、R14和R15独立地为氢、氨基、氰基、硫代、硝基,或者为任选取代的烷基、卤代烷基、酰基、芳基、芳基烷基或烷基芳基,或者取代基R14和R15与连接它们的氮原子一起形成任选取代的杂环烷基或杂芳基结构,
R16和R17独立地为氢、氨基、氰基、硫代、硝基或任选取代的烷基、卤代烷基、酰基、芳基、芳基烷基或烷基芳基,或者取代基R16和R17与连接它们的碳原子一起形成任选取代的异黄酮类环体系,
符号
表示单键或双键;
更优选它们具有以下取代基,其中
R1为氢,
R2、R3、R5、R6和R8独立地为氢、羟基、OR9、OC(O)R9、烷基、芳基或芳基烷基,
R4和R7独立地为羟基、OR9或OC(O)R9,
R9为甲基、乙基、丙基、异丙基或三氟甲基,
R13、R14和R15独立地为氢、甲基、乙基、丙基、异丙基、三氟甲基或任选取代的苯基、萘基或苄基,或者取代基R14和R15与连接它们的氮原子一起形成任选取代的杂环烷基或杂芳基结构,
R16和R17独立地为氢、甲基、乙基、丙基、异丙基、三氟甲基或任选取代的苯基、萘基或苄基,或者取代基R16和R17与连接它们的碳原子一起形成任选取代的异黄酮类环体系,
最优选它们具有以下取代基,其中
R1为氢,
R2、R3、R5、R6和R8独立地为氢、羟基、OR9、OC(O)R9或甲基,
R4和R7独立地为羟基、OR9或OC(O)R9,
R9为甲基,
R13为氢、甲基、乙基、三氟甲基、苯基、氯苯基、硝基苯基、甲苯甲酰基、萘基、苄基、氯苄基、硝基苄基或甲基苄基,
R14为氢,R15为氢、甲基、乙基、三氟甲基、苯基、氯苯基、硝基苯基、甲苯甲酰基、萘基、苄基、氯苄基、硝基苄基或甲基苄基,或者取代基R14和R15与连接它们的氮原子一起形成任选取代的杂环烷基或杂芳基结构,
R16和R17独立地为氢、甲基、乙基、三氟甲基、苯基、氯苯基、硝基苯基、甲苯甲酰基、萘基、苄基、氯苄基、硝基苄基或甲基苄基,或者取代基R16和R17与连接它们的碳原子一起形成任选取代的异黄酮类环体系,
最优选新型式(I)胺化异黄酮类化合物为下列(1)-(14)化合物:
本发明化合物包括其所有的盐,如酸式盐、阴离子盐和两性离子盐,尤其包括药学上可接受的盐。
化学官能团保护、去保护、合成子和其它本领域技术人员已知的技术可适当地用于帮助合成本发明化合物及其原料。
本发明优选化合物还包括所有带有生理学可裂解离去基团的衍生物,该基团可在体内从其连接的异黄酮或衍生物分子上脱落。离去基团包括酰基、磷酸根、硫酸根、磺酸根,优选为一、二和全酰基氧基取代化合物,其中一个或多个羟基侧基被酰基保护,优选被乙酰基保护。典型的酰基氧基异黄酮及其衍生物易于裂解为相应的羟基取代化合物。此外,本发明异黄酮类化合物和衍生物上官能团的保护可通过本领域已有的方法进行,例如T.W.Greene,ProtectiveGroups in Organic Synthesis,John Wiley & Sons,New York,1981中描述的方法。
最优选本发明使用的异黄酮和异黄烷酮起始化合物包括芒柄花黄素、鹰嘴豆素、金雀异黄素、黄豆苷元和雌马酚及其功能衍生物、等效物或类似物。类似的重要化合物为异黄酮代谢物,包括二氢黄豆苷元、顺式和反式四氢黄豆苷元和脱氢雌马酚及其衍生物和前药。
具体异黄酮的化学和功能等效物应理解为显示一种或多种异黄酮功能活性的分子,其可得自任何来源,如通过化学合成或通过筛选方法(如天然产物筛选)鉴定获得。
术语“药学上可接受的盐”指携带电荷并可与药物同时给予的有机或无机部分,例如盐中的相反阳离子(counter-cation)或相反阴离子(counter-anion)。药学上可接受的阳离子是本领域技术人员已知的,包括但不限于钠、钾、钙、锌和季铵。药物可接受的阴离子本领域技术人员已知的,包括但不限于氯离子、醋酸根、柠檬酸根、碳酸氢根和碳酸根。
术语“药学上可接受的衍生物”或“前药”指活性化合物的衍生物,其在给予接受者时,可直接或间接提供母体化合物或代谢物,或显示其自身活性。
本文所用的术语“治疗”、“预防”或“缓解”等应理解为其最广的含义。具体地说,术语“治疗”不是必须暗示受治疗动物完全痊愈。相应地,“治疗”包括具体疾病症状或严重性的减轻,或预防或降低具体疾病的发病风险。
本发明治疗性治疗中需要的一种或多种式(I)化合物的量取决于多种因素,其中包括具体的应用方法、所用具体化合物的性质、待治疗疾病、给药方式和病人的情况。式(I)化合物可按常规的使用方式和用量给药。例如可参见Goodman和Gihnan,″The pharmacologicalbasis of therapeutics″,第7版,(1985)。具体使用的剂量取决于待治疗疾病、患者情况、给药途径和其它上述熟知因素。通常,每个患者日剂量范围可以为0.1mg-5g;典型为0.5mg-1g;优选50mg-200mg。给药的时间长度可从每一日或两日给药一次,到每日给药两次或三次,可根据需要从一周到多个月到多年,这根据待治疗或待缓解疾病的严重性决定。更应该理解的是对于具体的患者,具体的给药方案应根据个体需要以及执行或监督给予组合物的人员的职业判断调整。用活性化合物进行的相对短期的治疗可用于稳定或减轻不能用血管成形术或手术治疗的冠状动脉疾病损害。长期治疗可用于在高危患者中预防晚期损害的进展。
通常通过将本发明化合物(为方便起见后面称为“活性化合物”)与一种或多种药学或兽医学可接受载体和/或赋形剂混合,生产本文所述治疗适应症的药用组合物,这是本领域所熟知的。
当然,载体必须与制剂中的任何其它成分相容,并且对患者无害。载体或赋形剂可以为固体或液体,或两种都有,优选与化合物制成单位剂量形式,例如片剂,其中最多含有100%(重量)的活性化合物,优选0.5%-59%(重量)的活性化合物。本发明制剂中可包含一种或多种活性化合物,可通过任何药学现有技术制备,主要由混合的各种成分组成,任选包含一种或多种辅料成分。药物组合物中活性化合物的优选浓度取决于药物的吸收、分布、灭活和排泄速率以及其它本领域技术人员已知的因素。
本发明制剂包括适合口服、直肠、眼、口含(例如舌下)、胃肠外(例如皮下、肌内、真皮内或静脉内)和透皮给药(包括通过鼻、口、阴道或直肠粘膜给药)的制剂和吸入剂,在任何特定的情况下最合适的途径取决于待治疗疾病的性质和严重性以及具体所用活性化合物的性质。
适合口服给药的制剂可以为分散单位,如胶囊剂、小药囊剂、锭剂或片剂,每单位含有预先决定量的活性化合物;可以为散剂或颗粒剂;可以为水或非水液体中的溶液剂或混悬剂;或者为水包油或油包水乳剂。制剂可通过任何合适的药学方法制备,其中包括混和活性化合物和合适载体(如上所述其中可包含一种或多种辅料成分)的步骤。通常,本发明制剂通过均匀和紧密地将活性化合物与液体载体或粉碎的固体载体或两者混合而制备,然后如果需要,使所得混合物成形,例如形成单位剂量。例如,可通过压制或模制含活性化合物的粉末或颗粒,任选还有一种或多种辅料成分,制备片剂。可通过在合适的机器中压缩自由流动的化合物,如任选与粘合剂、润滑剂、惰性稀释剂、和/或表面活性剂/分散剂混和的粉末或颗粒,制备压制片。可通过在合适的机器中用惰性液体粘合剂润湿粉状化合物,制备模制片。
适合口含(舌下)给药的制剂包括糖锭,其中包含活性化合物和调味后的基质,通常为蔗糖和阿拉伯胶或黄芪胶;以及软锭,其中包含化合物和隋性基质如明胶和甘油,或蔗糖和阿拉伯胶。
适合眼部给药的制剂包括液体、凝胶和软膏,其包含活性化合物和眼部可接受载体或稀释剂。
方便胃肠外给药的本发明组合物包括活性化合物的无菌水溶液制品,该制品优选与接受者的血液等渗。这种制品优选静脉内给药,但给药也可通过皮下、肌内或真皮注射完成。通过将化合物和水或甘氨酸缓冲液混合,使所得溶液无菌而且与血液等渗,可方便地制备这种制品。本发明可注射制剂通常含有0.1%-60%(w/v)的活性化合物,以0.1ml/分钟/kg的速度给药。
适合直肠给药的制剂优选为单位剂量的栓剂。适合阴道给药的制剂优选为单位剂量的阴道栓。可通过将活性化合物与一种或多种常用固体载体(如可可豆脂)混和,然后使所得混合物成形,制备这类制剂。
适合皮肤局部给药的制剂或组合物优选采用软膏剂、乳膏剂、洗剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂形式。可使用的载体包括凡士林、lanoline、聚乙二醇、乙醇和它们中两种或更多种的组合。活性化合物通常浓度为0.1%-5%(w/w),尤其是0.5%-2%(w/w)。这种组合物的实例包括美容用护肤膏。
适合透皮给药的制剂可以为不连续的贴剂,以长时间与接受者表皮保持紧密接触。这种贴剂适合包含任选缓冲水溶液形式的活性化合物,所述活性化合物浓度例如为0.1M-0.2M。参见例如Brown,L.等(1998)。
适合透皮给药的制剂还可通过离子电渗疗法给药(参见例如Panchagnula R等,2000),典型采用活性化合物的任选缓冲水溶液形式。合适的制剂包含柠檬酸或Bis/Tris缓冲液(pH 6)或乙醇/水,并含有0.1M-0.2M的活性成分。
适合吸入的制剂可作为溶液剂、混悬剂或乳剂形式的喷雾组合物给予。吸入的喷雾组合物可进一步包含药学上可接受的抛射剂如二氧化碳或一氧化二氮。
活性化合物可以食品的形式提供,如加入、混和、包衣、组合或以其它方式加入食品中。术语“食品”使用其最广泛的含义,包括液体制品如饮料(包括乳品)和其它食品,如保健食品、甜点等。包含本发明化合物的食品容易根据标准方法制备。
治疗方法、用途和组合物可给予人或动物,包括哺乳动物如伴侣动物和驯养动物(如狗和猫)、家畜(如牛、绵羊、猪和山羊)、家禽(如鸡、火鸡、鸭子)、水生动物包括水产养殖品种(如鱼、甲壳类和贝类)等。
活性化合物或其药学上可接受的衍生物、前药或盐还可与其它不妨碍所需作用的活性物质共同给予,或与补充所需作用的物质共同给予,如抗生素、抗真菌药、抗炎药或抗病毒化合物。活性药物可包含两种或更多异黄酮或其衍生物的组合或协同混合物。活性化合物还可与下述药物共同给予:降脂药,例如普罗布考和烟酸;血小板聚集抑制剂,例如阿斯匹林;抗血栓药,例如香豆定;钙通道阻滞药,例如维拉帕米、地尔硫和硝苯地平;血管紧张素转化酶(ACE)抑制剂,例如卡托普利和依那普利;以及β受体阻滞药,例如普萘洛尔、terbutalol和拉贝洛尔。化合物还可与非甾体类抗炎药联合给予,例如布洛芬、吲哚美辛、阿斯匹林、非诺洛芬、甲芬那酸、氟芬那酸和舒林酸。化合物还可与皮质类固醇共同给药。
共同给药可同时或依次进行。同时给药可给予同一单位剂量中的化合物,或同时或类似时间时给予在单独和不连续的单位剂量中的化合物。依次给予可以为需要的任何顺序,通常在给予第二或后面活性药物时需要出现第一种或最初的活性药物在前的生理学效应,尤其是需要累积或协同效应时。
用于本发明优选合成方法的异黄酮和异黄烷酮化合物可得自任何本领域技术人员容易鉴别的来源。优选异黄酮以植物来源浓缩物或提取物的形式获得。而且,本领域的技术人员容易确定合适的植物种类,但是,例如,本发明中特别有用的植物包括豆科植物。更优选异黄酮提取物得自鹰嘴豆、兵豆、菜豆、红车轴草或地下三叶草等。
异黄酮提取物可通过任何本领域已知的技术制备。例如,合适的异黄酮提取物可通过水/有机溶剂提取从植物来源制备。人们将会认识到,异黄酮提取物可从一种植物的任一组织中提取,或者从其两种或更多种不同组织的组合中提取。同样,提取物可以含有两种或更多种不同种类植物来源组织的不均一混合物为原料制备。
通常,从植物材料制备异黄酮提取物时,材料可被粉碎或切碎为小块,部分地粉碎或切碎为小块并接触水和有机溶剂,如水混溶性有机溶剂。或者,植物材料接触水和有机溶剂而无需任何预处理。水与有机溶剂的比值通常可以为1∶10~10∶1,例如可包含等比例的水和有机溶剂,或1%-30%(v/v)的有机溶剂。可使用任何有机溶剂或这类溶剂的混合物。有机溶剂优选为C2-10,更优选C1-4的有机溶剂(如甲醇、氯仿、乙醇、丙醇、丙二醇、赤藓醇、丁醇、丁二醇、乙腈、乙二醇、乙酸乙酯、缩水甘油、甘油二羟基丙酮或丙酮)。水/有机溶剂混合物可任选包括可裂解的异黄酮苷为糖苷配基形式的酶。混合物可剧烈搅拌以形成乳液。混和温度可改变,例如从环境温度到沸腾温度。暴露时间在1小时到几周之间。一种方便的提取周期为90℃下24小时。提取物可与未溶解的植物材料分离,并除去有机溶剂,例如用蒸馏、旋转蒸发或其它除去溶剂的标准方法。干燥含水溶性和水不溶性成分的所得提取物,获得含异黄酮提取物,该提取物可与一种或多种本发明药学上可接受的载体、赋形剂和/或辅料一起配制。
根据前一段所述制备的提取物可含有微量的油,其中包含异黄酮的糖苷配基形式(在本文称为异黄酮)。该富含异黄酮的油可用HPLC调整其异黄酮比例,或者,如果其异黄酮比例是所需的,可将其干燥(例如在二氧化硅的存在下),并与一种或多种载体、赋形剂和/或辅料配制成含异黄酮的提取物。或者,含在所述微量油中的异黄酮可通过向油中加入水不溶性有机溶剂进一步浓缩,这种有机溶剂例如为己烷、庚烷、辛烷、丙酮或一种或多种这类溶剂的混合物。一个实例为80%己烷,20%丙酮(w/w),其对油溶解度高而对异黄酮的溶解度低。油可轻易分配到有机溶剂中,富含异黄酮的提取物可从溶液中分离。回收提取物,干燥(例如在50℃至约120℃烘箱中),并与一种或多种药学上可接受的载体、赋形剂和/或辅料配制。
人们将会认识到,本发明还考虑通过本领域熟知的既定合成技术,生产合适的起始异黄酮或其功能衍生物、等效物或类似物。参见例如Chang等(1994),其中公开了作为原料的各种异黄酮的适当合成方法。
其它合适的方法可参见例如公开的国际专利申请WO 98/08503和WO 00/49009,以及其中引用的参考文献,它们通过整体引用结合到本文中。
细胞功能
所有细胞功能处于无数信号的控制之下,这种信号来自远基细胞(内分泌信号)或邻近细胞(旁分泌信号)或同一细胞内(自分泌信号)。这些不同的信号主要通过刺激细胞基因组(DNA)启动适当的细胞应答而起作用。信号传递到基因组的过程称为信号转导。这时,我们是指各种途径,大部分涉及不同的蛋白,其中一种蛋白的活化催化另一种蛋白的反应,最终导致某个特定基因或一组基因的转录。内环境稳定,我们指健康细胞、组织和器官的整体功能,是连续不断进入身体细胞的成百上千种不同信号的最终结果。
根据信号传递环境,可主观的将信号分为涉及“特殊功能”的信号和涉及细胞基本存活活动能力的信号。“特殊功能”的实例为神经细胞的痛觉、免疫细胞产生抗体、肝细胞的解毒反应或肾细胞的尿形成。“基本功能”的实例为细胞存活或细胞死亡、细胞增殖、细胞迁移和血管生成。可以看到,调节细胞能否执行“特殊功能”的关键是细胞“基本功能”的调节。
本发明申请人已发现,式(I)化合物调节细胞的许多“基本功能”。下面为本发明发明人发现的某些可由本发明胺化化合物调节的“基本功能”的实例。
1.细胞存活/死亡
为了持续发挥功能,包括响应特殊功能的能力,细胞需要持续活化促存活信号转导机制。促存活机制在两大水平上起作用-主动促进存活和主动抑制细胞死亡(凋亡)。
促存活机制涉及多种不同信号转导途径,这些途径最终导致某些其终产物促进细胞存活的基因转录。这些不同过程包括但不限于分子靶点如MEK、ERK和NFκB。Phenoxodiol被发现通过某些这种过程起作用。举例来具体地说,其中一个为酶,即鞘氨醇激酶。鞘氨醇激酶将底物鞘氨醇磷酸化为鞘氨醇-1-磷酸。鞘氨醇-1-磷酸是促存活机制的一种重要刺激物,在以细胞寿命延长为特征的各种疾病状态下过度表达。胺化异黄酮类衍生物下调鞘氨醇激酶的活性。
细胞凋亡可通过某些下列机制完成。
(a)其中一种机制涉及称为“死亡受体”的受体。它们包括例如Fas/Mort、TGF和TNRF等受体。受体的活化通常被阻遏蛋白如C-flip的产生抑制。胺化异黄酮类衍生物被发现可阻断C-flip的产生,从而促进细胞死亡。
(b)另一种机制涉及称为胱冬酶的蛋白水解酶的活化。一旦活化,这种酶自溶细胞。胺化异黄酮类衍生物被发现可上调胱冬酶的活性。
(c)另一种机制涉及线粒体的裂解,导致各种促死亡因子的产生。胺化异黄酮类衍生物被发现可通过线粒体上的直接新作用促进这种裂解。
由上述说明可以发现,胺化异黄酮类衍生物可通过多种不同途径,全面诱导细胞死亡。具有这种广泛和互补作用能力的单一化合物还是新化合物。但是,令人相当惊讶的是发现胺化异黄酮类衍生物仅在异常细胞中产生促死亡效果。
在正常健康细胞中,胺化异黄酮类衍生物对它们的调节过程没有可辨别的作用。这些常规过程表现异常活性的细胞包括但不限于涉及下列疾病状态的细胞:癌症、心血管疾病、自身免疫疾病和具有免疫性、炎性或高增殖性成分的疾病。
2.细胞增殖
响应生长信号而分裂的能力是正常健康细胞所必须的另一个基本功能。鞘氨醇-1-磷酸在促进细胞的分裂能力中起关键作用。细胞分裂的行为涉及各种不同的酶,如下述:
(a)拓扑异构酶(I和II)的活化,其作用为在有丝分裂前组织DNA;
(b)细胞周期蛋白依赖性激酶(CDK)的活化,其作用为在不同有丝分裂期移动基因组;
(c)细胞周期蛋白依赖性激酶抑制剂(CDKI)的失活,该抑制剂的作用为通过抑制CDK抑制有丝分裂。
胺化异黄酮类衍生物令人惊讶地抑制上述3种酶系统,即行为异常细胞中的拓扑异构酶II、CKD和CDKI,尤其是表达异常促存活表型或反常细胞增殖的细胞。
3.细胞迁移
应该理解,细胞迁移和与邻近细胞交互作用的能力是健康和疾病细胞的基本能力。鞘氨醇激酶和基质金属蛋白酶是该重要细胞功能的关键调节剂。胺化异黄酮类衍生物特异性下调这两种酶系统,因此降低疾病状态细胞迁移的能力。
4.血管生成
形成新血管的能力已知为许多涉及增生的疾病状态的基础关键事件。鞘氨醇激酶是该事件的关键促进物。当这种事件发生在疾病组织中而不是健康组织中时,胺化异黄酮类衍生物通过下调该酶选择性减少血管生成。
胺化异黄酮类衍生物对信号转导机制的这种广泛效应被其对多种酶的抑制作用补充,这种酶通常不被认为是信号转导途径的部分,而是更一般性的生理学的部分。这种作用还包括下面所述:
5.类固醇生成
胺化异黄酮类衍生物抑制多种涉及类固醇生成的酶。它们包括但不限于类固醇脱氢酶、5-α-还原酶和芳化酶。本领域技术人员将会认识到,这种作用对类固醇激素的产生具有显著的影响,这种激素包括雄激素、雌激素和皮质类固醇。这种作用被本领域某些技术人员认为对男性和女性生殖组织(包括乳房、卵巢、子宫、子宫内膜、子宫颈、阴道、前列腺和阴茎)的正常功能有影响。
总之,本发明发明人令人惊讶的发现,胺化异黄酮类衍生物调节特殊的一组涉及一般代谢、生理功能和信号转导途径的酶,该酶在细胞存活、细胞生长、细胞分化和细胞对炎症和免疫调节剂的反应中起关键作用。通过调节这组酶,本发明化合物能(a)预防或治疗许多形式的疾病而不考虑该疾病的原因或发病机理,和(b)影响机体组织的全部生物活性以及疾病、年龄、环境影响和其它药物影响这些活性的途径。
此外,令人惊讶的新发现是这种化合物可导致人乳腺癌细胞凋亡和死亡,同时可具有各种作用,如拮抗高血压、纠正炎性肠病中基础的免疫性和炎性失调、逆转I型糖尿病和逆转男性型秃头。
容易看到,本发明胺化异黄酮类衍生物尤其可用于预防和治疗下述各种疾病状态和失调。
A.涉及对生长信号异常反应、异常细胞增殖、凋亡机能障碍和异常
迁移形式(转移)的疾病和失调
它们包括:
1.机体所有组织中所有形式的癌症(癌前期、良性和恶性)。在这点上,本发明化合物可用作抗癌治疗的单一药物,或与其它抗癌疗法(包括但不限于放疗和化疗)联合应用;
2.丘疹结节性(papulonodular)皮肤损伤,包括但不限于肉样瘤病、血管肉瘤、Kaposi肉瘤和Fabry病。
3.丘疹鳞屑性皮肤损伤,包括但不限于牛皮癣、Bowen病和Reiter病;
4.骨髓增殖失调,包括但不限于巨成红细胞病、脊髓发育不良综合症、真性红细胞增多、血小板增多和骨髓纤维化;
5.生殖道增生性疾病,包括但不限于良性前列腺增生、子宫内膜异位、子宫肌瘤和多囊性卵巢疾病。
B.涉及异常血管生成的疾病和失调
它们包括:
1.与影响机体任何组织中异常血管生成有关的疾病和失调,包括但不限于转移性癌症、牛皮癣、血管瘤和毛细血管扩张。
C.涉及异常炎症反应/免疫反应的疾病和失调
它们包括:
1.涉及机体任何组织中异常或持续性炎症反应的疾病和失调,包括但不限于类风湿性关节炎、腱炎、炎性肠病、溃疡性结肠炎、节段性回肠炎、硬化性胆管炎;
2.涉及血管壁中退化性改变的疾病和失调,包括但不限于通常称为心血管病的综合症(包括动脉粥样硬化、动脉粥样化、冠状动脉病、中风、心肌梗塞、血管成形术后再狭窄、高血压性血管病、恶性高血压、闭塞性血栓性脉管炎、纤维肌性发育不良);
3.涉及异常免疫反应的疾病和失调,包括但不限于皮肤肌炎和硬皮病;
4.涉及H.I.V.或其它病毒传染物或细菌传染物的免疫失调(包括免疫缺陷),以及与未成熟或衰老有关的免疫缺陷。
D.涉及降低细胞功能(包括对生长信号的反应降低和细胞死亡速度增
加)的疾病和失调
它们包括:
1.以皮肤退化性改变为特征的光化性损伤,包括但不限于日光性角化病、光敏性疾病和皱纹;
2.以异常免疫反应为特征的自身免疫疾病,包括但不限于多发性硬化病、I型糖尿病、系统性红斑狼疮和胆汁性肝硬化;
3.以神经系统结构中退化性改变为特征的神经变性性疾病和失调,包括但不限于帕金森病、早老性痴呆、肌营养不良、Lou-Gehrig病、运动神经元疾病;
4.涉及眼中退化性改变的疾病和失调,包括但不限于白内障、黄斑变性和视网膜萎缩。
E.涉及类固醇生成和生殖激素功能异常或机能障碍的疾病和失调
它们包括:
1.女性中涉及异常雌激素/雄激素平衡的疾病,包括但不限于周期性乳腺痛、痤疮、痛经、子宫肌瘤、子宫内膜异位、卵巢囊肿、月经前综合症、急性绝经症、骨质疏松症、老年性痴呆、不育症;
2.男性中涉及异常雌激素/雄激素平衡的疾病,包括但不限于良性前列腺肥大、不育症、男子女性型乳房、遗传性脱发和各种其它型式的秃头。
本发明胺化异黄酮类衍生物的生理作用具体涉及通常的信号转导途径、抗癌应用和抗炎活性,并可作为心血管预防药物。更具体地说,本发明胺化异黄酮类衍生物表现出广泛的治疗适应症,包括并优选通过抑制信号转导的抗癌活性、细胞周期调节和诱导细胞凋亡、抗血管生成(MMP抑制)、干扰信号转导(受体蛋白酪氨酸激酶抑制剂)、抑制COX、抑制5′-α还原酶、心血管保护性质和抗炎作用。
使用本发明化合物的具体范围如下面的描述和举例说明:
抗癌:
在许多西方国家,前列腺癌是男性中最常见被诊断的恶性肿瘤(仅次于肺癌)和最常见的死因(Landis等,1999;Hsing等,2000)。局限性前列腺癌的已有治疗选择包括手术(前列腺根除术)和放射疗法,其治愈率仅为52-78%,剩余比例的患者则由于残留疾病而导致复发(Morris和Scher,2000;Papatsoris和Papavassiliou,2001)。由于雄激素在控制正常前列腺的生长中具有重要作用,它们还可通过反式激活细胞增殖基因,促进配体结合雄激素受体(AR),促进发生良性前列腺肥大(BPH),进而发展成前列腺癌(Amanatullah等,2000)。因此,在疾病早期,主要的治疗选择是利用手术和/或药物治疗方法消除雄激素(Papatsoris和Papavassiliou,2001)。
有趣的是,在缺乏5′-α还原酶的太监中进行前列腺癌流行的流行病学研究,结果表明这一类人群具有很低的发病率。在雄激素信号级联中,5′AR将睾酮转化为二氢睾酮,与睾酮相比,二氢睾酮与AR的结合亲和力强得多,可产生更强的增殖反应(Papatsoris和Papavassiliou,2001)。这种研究的结果是集中开发新型5′AR抑制剂。NADPH依赖的5′α还原酶有两种同工型,称为I型和II型,I型主要表达于人头皮、皮肤和肝,II型主要表达于前列腺。II型特异性抑制剂非那雄胺是目前仅有的5AR抑制剂,可用于治疗BPH,当其与抗雄激素(如醋酸甲地孕酮)联合应用时可治疗早期前列腺癌。但是,由于非那雄胺的类固醇结构和潜在副作用,许多研究集中于阐明其它临床可接受的5′α还原酶非类固醇抑制剂(Chen等,2001)。
从最近的证据推断,癌症开始和进展可被炎性组织中前列腺素的过度产生促进(Vainio,2001)。环加氧酶(COX)催化花生四烯酸(AA)转化为前列腺素和血栓烷。支持性流行病学研究和实验室研究提供足够的证据证明,传统的非甾体类抗炎药(NSAID,包括阿斯匹林)和COX-2抑制剂(塞来考昔)可降低结肠癌的风险(Koki等,2002)。对许多不同恶性肿瘤的实际临床活组织检查一致显示COX-2的明显过度表达。推测NSAID产生的抗癌作用机制是由于其通过COX-2抑制前列腺素产生的能力,而前列腺素可促使血管生成和防止癌细胞凋亡(Vaino,2001;Fosslien,2001)。
抗炎:
前列腺素如PGE2和PGI2以及血栓烷(TX)如TXA2是被称为类花生酸的脂肪酸衍生物(Penglis等,2000)。它们涉及正常生理反应和炎症反应。从膜磷脂释放的AA是COX酶的主要底物,因此产生类花生酸。无论哪种COX同工型(COX1和COX2),前列腺素(PGH2)是这种反应的主要中间体,它是下游前列腺素类(PGE2、PGI2和TXA2)生产的常见前体。可通过测定化合物在筛选测定中抑制PG和TX合成的能力,评价受试物表现抗炎活性的潜力。实施例中,根据本发明胺化异黄酮和它们抑制血栓烷合酶和COX的能力,给出的初步数据支持这类分子具有作为NSAID的治疗用途。
下面通过非限制性实施例和所附的图进一步说明本发明。
实施例1-通用合成方法
1.亚胺的合成
2.腙的合成
3.缩氨基脲的合成
4.吖嗪的合成
4.1吖嗪二聚物的合成
5.肟的合成
6.胺的合成(还原)
在上述通用方法中,其中结构可任选被所需取代基或其合成子或衍生物取代。反应性胺化合物例如可以其盐酸盐的形式存在,反应可在碱如乙酸钠的存在下进行,或在合成化学技术人员决定的合适条件下进行。
合成
二氢黄豆苷元(1mmol)与3摩尔当量的盐酸苯肼和3摩尔当量的乙酸钠(246mmol)在4ml甲醇中回流6小时。
过滤溶液,减压除去甲醇。产物用硅胶柱色谱纯化(10%乙醚,90%二氯甲烷),得到40%~60%的产物。
R=H
H-NMR:(d6-丙酮)8.046(s),8.018(s),7.787(s),7.194(t),7.088(d),6.762(m),6.542(dd),6.292(d),4.400(dd),4.3165(dd),4.198(s)
CI-MS(+):256
R=p-NO2
H-NMR:(d3-乙腈)8.685(s),8.638(s),8.239(d),8.079(d),7.247(t),7.046(m),6.817(dd),6.60(d),6.646(d),6.583(dd),4.546(d),4.392(d),4.309(s)
CI-MS(+):298
R=p-CH3
H-NMR:(d3-乙腈)8.028(s),7.999(s),7.689(s),7.085(d),7.000(d),6.45(d),6.529(dd),6.285(d),4.388(dd),4.321(dd),4.180(s),2.220(s)
CI-MS(+):361,344,256
类似地制备苄基取代化合物4、氯苯基取代化合物6-8、吡啶并化合物9和氰基化合物10。
通过标准吖嗪合成方法制备二聚化合物5。
二氢黄豆苷元(1mmol)与甲胺(3mmol)反应,得到甲基亚胺化合物11。类似地用羟胺制备羟基亚胺12。
用3当量乙酸酐和弱酸后处理还原胺化(氨/H2/阮内镍),酰化氨基衍生物13,得到产量近乎定量的N-乙酰衍生物14。
实施例2-方法
细胞毒性分析:
按照Alley等(1988)的方法进行。简短地说,在细胞毒性筛选前,为每个待筛选肿瘤系作生长曲线,以确定生长动力学;确定最佳接种密度以经5天达到对数生长期和相应的延迟期。从分会合贴壁单层培养物(T-75)中吸出用过的培养基,细胞用胰蛋白酶消化并重悬于最小体积培养基中。细胞计数后,以适当的密度(100μl)接种于96孔板,获得最佳生长参量,板在5%CO2下37℃孵育。在达到预先决定的延迟期后,板用溶媒处理(阴性对照)或用在培养基中连续稀释的受试化合物处理,然后再培养5天。向所有孔中加入PBS中的MTT(0.5mg/ml),37℃孵育约3小时。然后小心地吸出用过的培养基,加入DMSO(150μl)以溶解细胞和还原甲。用SpectraMax读板仪在570nm下读出吸光度,处理板中的活细胞表示为对照板中细胞的百分数。
雄激素抑制研究:
按照Negri-Cesi和Motta(1994)以及Negri-Cesi等(1999)的方法进行。简短地说,在补充10%胎牛血清和2mM L-谷氨酰胺的RPMI中,5%CO2下37℃培养LNCaP细胞。在第0天,分会合LNCaP培养瓶(80%)用胰蛋白酶消化后收集,洗涤,重悬于加入了经活性炭吸附的胎牛血清的RPMI培养基(RPMIi),以30,000细胞/孔(15,000细胞/mL)的密度接种于12孔板中。板在5%CO2下37℃培养48小时。在第2天,从所有的板中小心地吸出用过的培养基,然后用2mlRPMIi补足,RPMIi中含睾酮(0.5pM)的作为阳性对照,含睾酮加非那雄胺(1uM)的作为抑制剂对照,含溶媒的作为生长对照(同等浓度的DMSO)。受试板按上述处理,只是使用在RPMIi中连续稀释的受试化合物。基于受试化合物的细胞毒性曲线(在上一节细胞毒性分析方法中测定),选择它们的浓度,即在LNCaP增殖测定中使用的最高浓度是在细胞毒性曲线中存活率接近100%的浓度。选择该浓度以保受试物对增殖的抑制是由于其对5′AR的抑制而不是由于直接杀死细胞。重要的是在加入处理时不要破坏细胞单层。在第5天和第8天对所有板重复第2天的方法。在第11天从所有孔中吸出用过的培养基,用PBS(500μl)轻柔地洗涤细胞,胰蛋白酶消化,用血细胞计数仪计数每孔中的细胞。计算平均细胞数和标准偏差,结果表示为与溶媒对照相比,睾酮诱导增殖的%抑制。
血栓烷合酶和COX抑制筛选测定:
人血沉棕黄层获得自红十字会血库。血沉棕黄层(50ml)用无菌磷酸盐缓冲液(PBS)1∶2稀释,覆盖在Lymphoprep密度梯度介质上,800g离心20分钟。除去单核细胞(MNC)层,用PBS洗涤,用逆流离心淘析从MNC制备富含单核细胞的细胞。单核细胞以1.5×106细胞/ml的密度重悬于含10%胎牛血清的RPMI组织培养基。制备DMSO中的受试类似物,以10μM或100μM的浓度与单核细胞在37℃孵育30分钟。30分钟预孵育后,加入细菌脂多糖(LPS)(200ng/ml),细胞在5%CO2下37℃再孵育18小时。离心后,除去无细胞上清,用放射免疫分析测定前列腺素或血栓烷的产生。由于TXA2在水介质中不稳定,测定TXA2的稳定水解产物TXB2。对于每个剂量(0μM、10μM、100μM),一式三份进行孵育。结果表示为平均值±SD,n=3。ANOVA和其后的Newman-Keuls多重比较检验用于检验各种剂量和对照值之间的差异。
细胞毒性分析:
Cpd.1和Cpd.3显示出中等抗癌活性,Cpd.1表现出抗前列腺癌系LNCaP和DU-145活性(图1A和1B;表1)。与响应雄激素的LNCaP(16.25μM)相比,其对不依赖雄激素的前列腺癌系DU-145的IC50稍好(13.81μM)。它对其它细胞系也有中等活性(>20μM)。类似于Cpd.1,Cpd.3也表现出抗LNCaP(16.26μM)的中等活性(图1C;表1.),但是虽然表现出某些抗DU-145效力(19.2μM),Cpd.3具有抗大细胞肺癌系NCI-H460的活性(13.3μM)(图1D和表1)。Cpd.3对所有受试细胞系具有最佳的全面杀灭活性。与Cpd.3相反,在苯环4位有硝基而不是甲基的Cpd.2对所有受试细胞系具有最低的活性(表1)。
雄激素抑制研究:
在两种研究睾酮诱导LNCaP细胞增殖的研究中,可观察到这些细胞响应睾酮时的生长速度被诱导为2-4倍(图2A和B)。这种睾酮诱导增殖被非那雄胺(1μM)有效阻断(图2A和B)。这些数据共同表明,筛选模型是有效的。对于3种受试类似物,Cpd.1是效力最低的睾酮诱导增殖抑制剂(2.25μM),而Cpd.3的结果比Cpd.1好3倍(IC500.68μM)(图2、3和表2)。Cpd.2是抑制睾酮诱导增殖最有效的类似物,其在37nM时没有测定到IC50,比Cpd.1效力强约60倍(图2、3和表2)。可注意到,Cpd.2在4位有吸电子基团(-NO2),与给电子基团(-CH3)(Cpd.3)相比,这在该测定中增强了分子的抑制活性。
实施例3-结果和讨论
表1.Cpd.1、Cpd.2和Cpd.3对PC3(AR阴性前列腺癌)、LNCaP(AR阳性前列腺癌)、DU145(AR阴性前列腺癌)、MDA-MB-468(ER阴性乳腺癌)和NCI-H460(大细胞肺癌)的细胞毒性比较
类似物 | 细胞系(μM) | |||||||||
PC3 | LNCaP | DU-145 | MDA-MB-468 | NCI-H460 | ||||||
Avg. | St.dev | Avg. | St.dev | Avg. | St.dev | Avg. | St.dev | Avg. | St.dev | |
Cpd.1 | 33.9 | 2.26 | 16.2 | .074 | 13.8 | 2.12 | 34.9 | 19.3 | 27.6 | 0.60 |
Cpd.2 | 44.8 | 3.39 | 50.9 | 4.66 | 46.0 | 0.74 | 26.1 | 1.20 | 32.7 | 0.30 |
Cpd.3 | 27.9 | 6.43 | 16.2 | 3.88 | 19.1 | 1.62 | 22.4 | 5.52 | 13.3 | 1.62 |
表2.苯腙类似物对睾酮诱导LNCaP增殖的抑制分布型
类似物 | IC50(uM) |
Cpd.1 | 2.25 |
Cpd.2 | ND@0.035 |
Cpd.3 | 0.68 |
血栓烷合酶和COX的抑制:
Cpd.1和Cpd.3在10μM时显示100%抑制COX活性,而Cpd.2抑制77%的该活性(图4)。同样,10μM Cpd.1、Cpd.2和Cpd.3分别抑制血栓烷合酶33%、27%和60%,但它们的抑制作用比它们对COX的抑制作用弱。这些数据支持该发现,即胺化异黄酮类似物为血栓烷合酶和COX的抑制剂,并且具有该骨架的分子显示出作为抗炎药物的潜力。此外,作为COX活性NSAIDS抑制的治疗应用证实,苯腙类似物也显示出抗癌活性。
就其直接杀灭活性而论,Cpd.3和Cpd.1被发现是更有效的抗癌药物,但是,它们抑制睾酮诱导增殖的效力较低。最有效抑制睾酮诱导增殖的类似物是Cpd.2,在直接杀细胞测定中它是效力最低的类似物。这些结果表明,受试化合物经历的两种抗癌筛选其活性和作用方式上具有某些差异。此外,这种胺化类似物抑制COX的能力证实,这类分子具有多种抗癌用途,它们抑制血栓烷合酶的能力暗示其在抗炎中的作用。
为了使读者能实施本发明而无需过多的实验,在本文中结合某些优选实施方案描述了本发明。然而,本领域普通技术人员容易认识到,在不偏离本发明范围的情况下,可以对此中的许多组分和参数进行变化或修改。此外,给出大标题、小标题等以增强读者对本文本的理解,而不应当理解为是对本发明范围的限制。
本文引用的所有申请、专利和出版物(如果有的话)的完整公开内容通过整体引用结合到本文中。
本领域技术人员将会认识到,本文描述的发明除具体描述的方案外还可以进行变化和修改。不用说本发明包括所有这样的变化和修改。本发明也包括本发明说明书中单独或共同涉及或指出的所有步骤、特征、组合物和化合物,以及所述步骤或特征的任两个或更多个的任何和所有组合。
有关本说明书中的任何现有技术不是也不应理解为承认或以任何形式暗示,该现有技术构成本研究领域中的一般常识部分。
参考文献
Alley MC,Scudiero DA, Monks A,Hursey ML,Czerwinski MJ,Fine DL,Abbott BJ,Mayo JG,Shoemaker RH,Boyd MR.1988 Feasibility of drug screening with panels ofhuman tumor cell lines using a microculture tetrazolium assay.Cancer Res.48:589-601.Amauatullah DF,Reutens AT,Zafonte BT,Fu M,Mani S,Pestell RG.2000 Cell-cycledysregulation and the molecular mechanisms of prostate cancer.Front.Biosci.,5:D372-90.Chen GS,Chang CS,Kan WM,Chang CL,Wang KC,Chern JW 2001 Novelleadgeneration through hypothetical pharmacophore three-dimensional database searching:discovery of isoflavonoids as nonsteroidal inhibitors of rat 5 alpha-reductase.J Med Chem44,3759-63.
Hsing AW,Tsao L,Devesa SS.2000 International trends and patterns of prostate cancerincidenee and mortality.Int.J.Cancer 85,60-7.
Fosslien,E.2001 Molecular pathology of COX-2 in cancer-induced angiogenesis.Ann.Clin.Lab.Science.31,325-348.
Koki,A.T.and Masferrer,J.L.2002 Celecoxib:A specific COX-2 Inhibitor with anticancerproperties.Cancer Control 9,Supp.28-35.
Landis SH,Murray T,Bolden S,Wingo PA.1999 CA Cancer J.Clin.49,δ-31.Morris,M.J.and Scher,H.I 2000 Novel strategies and therapeutics for the treatment ofprostate careinoma.Cancer 89,1329-1348.
Negri-Cesi,P.,Motta,M.,1994 Androgen metabolism in the human prostatic cancer cellline LNCaP.1994 J.Steroid Biochem.Molec.Biol.51,89-96.
Negri-Cesi,P.,Colciago,A.,Poletti,A.and Motta,M.1999 5a-Reductase isozymes andaromatase are differentially expressed and active in the androgen-independent humanprostate cancer cell lines DU145 and PC3.The Prostate 41,224-232.
Papatsoris,A.G and Papavassiliou,A.G.2001 Prostate cancer:horizons in thedevelopment of novel anti-cancer strategies.Curr.Med.Chem.-Anti-cancer agents.1,47-70.
Penglis,P.S.,Cleland,L.G.,.Demasi,M.,Caughey,G.E.and James,M.J.2000.Differential regulation of prostaglandin E2 and thromboxane A2 production in humanmonocytes:implications for the use of COX inhibitors.J.Immunol.165,1605-11.Vaino,H.2001 Is Cox inhibition apanacea for cancerprevention.Int.J.Cancer 94,613-614.
Claims (14)
1.一种以下通式(I)的化合物:
其中
R1、R2、R3、R4、R5、R6、R7和R8独立地为氢、羟基、OR9、OC(O)H、OC(O)R9、OS(O)R9、OSi(R10)3、C(O)R11、CO2R12、烷基、卤代烷基、芳基、芳基烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤基,或者取代基R2、R3和R4中的任两个与连接它们的碳原子一起形成环烷基、杂环烷基、芳基或杂芳基结构,
R9为烷基、卤代烷基、芳基、芳基烷基或烷基芳基,
R10独立地为氢、烷基或芳基,
R11为氢,烷基、芳基、芳基烷基、芳基烷基或氨基酸,
R12为氢、烷基、卤代烷基、芳基、芳基烷基或烷基芳基,
X为O、NR12或S,
Z为R13、NR14R15、NR13CONR14R15、N=CR16R17或OR13,
R13、R14和R15独立地为氢、氨基、硫代、硝基、氰基,或者为任选取代的烷基、卤代烷基、酰基、芳基、杂芳基、芳基烷基或烷基芳基,或者取代基R14和R15与连接它们的氮原子一起形成任选取代的杂环烷基或杂芳基结构,
R16和R17独立地为氢、氨基、硫代、硝基、氰基,或者为任选取代的烷基、卤代烷基、酰基、芳基、杂芳基、芳基烷基或烷基芳基,或者取代基R16和R17与连接它们的碳原子一起形成任选取代的异黄酮类环体系,
或者当X为NR12时,取代基R12可以为化学键,从而R8和X与连接它们的碳原子一起形成下列结构之一:
其中Y为
其中
R1、R2、R3、R4、R5、R6、R7、R8和Z如上定义,
所述化合物包括其药学上可接受的盐和衍生物。
3.一种治疗、预防或缓解疾病的方法,所述方法包括给予患者治疗有效量的一种或多种式(I)化合物或其药学上可接受的盐或衍生物。
4.一种治疗、预防或缓解疾病的方法,所述疾病涉及反常细胞存活、反常细胞增殖、异常细胞迁移、异常血管生成、异常雌激素/雄激素平衡、机能障碍或异常类固醇生成、包括血管壁退化性改变的退化、炎症和免疫失调,所述方法包括给予患者一种或多种任选与载体和/或赋形剂混和的式(I)化合物或其药学上可接受的盐或衍生物。
5.一种诱导表达异常促存活表型的细胞凋亡的方法,所述方法包括使所述细胞接触一种或多种任选与载体或赋形剂混和的式(I)化合物或其药学上可接受的盐或衍生物。
6.一种抑制具有异常细胞迁移表型的细胞迁移的方法,所述方法包括使所述细胞接触任选与载体或赋形剂混和的式(I)化合物或其药学上可接受的盐或衍生物。
7.一种抑制表达异常血管生成表型的组织的血管生成的方法,所述方法包括使所述组织接触任选与载体或赋形剂混和的式(I)化合物或其药学上可接受的盐或衍生物。
8.一种治疗、预防或缓解哺乳动物的癌症的方法,所述方法包括使式(I)化合物或其药学上可接受的盐或衍生物接触患肿瘤哺乳动物体内癌性组织的步骤,从而延缓或阻止所述癌性组织中的肿瘤发展。
9.一种或多种式(I)化合物或其药学上可接受的盐或衍生物在制备治疗疾病的药物中的用途。
10.作为抗炎药的式(I)化合物或其药学上可接受的盐或衍生物的用途。
11.一种治疗、预防或缓解疾病的药物,所述药物包含一种或多种式(I)化合物或其药学上可接受的盐或衍生物。
12.一种药用组合物,所述组合物包含一种或多种式(I)化合物或其药学上可接受的盐或衍生物以及一种或多种药用载体、赋形剂、辅料和/或稀释剂。
13.一种饮料或食品,所述饮料或食品含有一种或多种式(I)化合物或其药学上可接受的盐或衍生物。
14.式I化合物或其药学上可接受的盐,其与本发明说明书中的实施例和/或附图描述的一致。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2002952453A AU2002952453A0 (en) | 2002-11-01 | 2002-11-01 | Aminated isoflavonoid derivatives and uses thereof |
AU2002952453 | 2002-11-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1708490A true CN1708490A (zh) | 2005-12-14 |
Family
ID=28795843
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2003801025650A Pending CN1708490A (zh) | 2002-11-01 | 2003-11-03 | 胺化异黄酮类衍生物及其应用 |
Country Status (10)
Country | Link |
---|---|
US (1) | US7714151B2 (zh) |
EP (1) | EP1556368A4 (zh) |
JP (1) | JP2006513997A (zh) |
CN (1) | CN1708490A (zh) |
AU (1) | AU2002952453A0 (zh) |
CA (1) | CA2504653A1 (zh) |
MX (1) | MXPA05004526A (zh) |
NO (1) | NO20052524L (zh) |
NZ (1) | NZ539034A (zh) |
WO (1) | WO2004039793A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101716135B (zh) * | 2010-01-08 | 2012-11-14 | 山西医科大学 | 大豆异黄酮固体分散体栓剂及其制备方法 |
CN106795135A (zh) * | 2014-09-10 | 2017-05-31 | 系统生物股份有限公司 | 异黄烷及其中间体的合成 |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1615906A1 (en) * | 2003-04-03 | 2006-01-18 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of protein kinases |
FR2873118B1 (fr) * | 2004-07-15 | 2007-11-23 | Sanofi Synthelabo | Derives de pyrido-pyrimidine, leur application en therapeutique |
JP2006146490A (ja) * | 2004-11-18 | 2006-06-08 | Ricoh Co Ltd | 印刷制御装置及び印刷制御プログラム |
US20060134243A1 (en) * | 2004-12-17 | 2006-06-22 | Bionovo, Inc. | Method of using extracts of epimedium species |
DE102005011822A1 (de) * | 2005-03-15 | 2006-09-21 | Merck Patent Gmbh | Phthalazinone |
JP2008533177A (ja) * | 2005-03-24 | 2008-08-21 | ノボジェン リサーチ ピーティーワイ リミテッド | 抗炎症治療法 |
US7482029B2 (en) | 2005-04-01 | 2009-01-27 | Bionovo, Inc. | Composition for treatment of menopause |
FR2887882B1 (fr) * | 2005-07-01 | 2007-09-07 | Sanofi Aventis Sa | Derives de pyrido[2,3-d] pyrimidine, leur preparation, leur application en therapeutique |
US7528267B2 (en) | 2005-08-01 | 2009-05-05 | Girindus America, Inc. | Method for enantioselective hydrogenation of chromenes |
US7700136B2 (en) * | 2005-11-14 | 2010-04-20 | Bionovo, Inc. | Scutellaria barbata extract for the treatment of cancer |
US20080319051A1 (en) * | 2007-06-22 | 2008-12-25 | Bionovo, Inc. | Liquiritigenin and derivatives as selective estrogen receptor beta agonists |
US20090042818A1 (en) * | 2007-06-22 | 2009-02-12 | Bionovo, Inc. | Liquiritigenin and Derivatives as Selective Estrogen Receptor Beta Agonists |
CA2696304A1 (en) * | 2007-08-08 | 2009-02-12 | Bionovo, Inc. | Estrogenic extracts of ligustrum lucidum ait. of the oleaceae family and uses thereof |
US9339523B2 (en) * | 2007-09-07 | 2016-05-17 | Bionovo, Inc. | Estrogenic extracts of Asparagus conchinchinensis (Lour.) Merr of the Liliaceae family and uses thereof |
CA2698739A1 (en) * | 2007-09-07 | 2009-03-12 | Bionovo, Inc. | Estrogenic extracts of pueraria lobata willd. ohwi of the leguminosae family and uses thereof |
AU2008296072A1 (en) * | 2007-09-07 | 2009-03-12 | Bionovo, Inc. | Estrogenic extracts of Astragalus membranaceus Fisch.Bge.Var.mongolicus Bge. of the Leguminosae Family and uses thereof |
WO2009033075A1 (en) * | 2007-09-07 | 2009-03-12 | Bionovo. Inc. | ESTROGENIC EXTRACTS OF Scuttelaria barbata D. DON OF THE LABIATAE FAMILY AND USES THEREOF |
CA2706326A1 (en) * | 2007-11-19 | 2009-05-28 | Bionovo, Inc. | Scutellaria barbata extract and combinations for the treatment of cancer |
US8197868B2 (en) | 2007-11-19 | 2012-06-12 | Bionovo, Inc. | Process of making purified extract of Scutellaria barbata D. Don |
US8512961B2 (en) | 2007-11-19 | 2013-08-20 | Bionovo, Inc. | Methods of detecting and treatment of cancers using Scutellaria barbata extract |
CA2706315A1 (en) * | 2007-11-19 | 2009-05-28 | Bionovo, Inc. | Anti-cancer therapy with an extract of scutellaria barbata |
TWI324514B (en) * | 2008-02-26 | 2010-05-11 | Univ Kaohsiung Medical | Isoflavone derivatives and pharmaceutical compositions comprising the same |
WO2009129260A2 (en) * | 2008-04-14 | 2009-10-22 | Bionovo, Inc. | Calycosin and analogs thereof for the treatment of estrogen receptor beta-mediated diseases |
AU2009244315A1 (en) * | 2008-05-06 | 2009-11-12 | Bionovo, Inc. | Estrogenic extracts for use in treating vaginal and vulvar atrophy |
EP2294402A2 (en) * | 2008-06-05 | 2011-03-16 | Bionovo Inc. | Method of quantification of multiple bioactives from botanical compositons |
AU2009255626A1 (en) * | 2008-06-06 | 2009-12-10 | Bionovo, Inc. | Anthraquinones and analogs from Rhuem palmatum for treatment of estrogen receptor beta-mediated conditions |
CA2734523A1 (en) * | 2008-09-03 | 2010-03-11 | Bionovo, Inc. | Methods and compositions for the treatment of cancer |
EP2389180A4 (en) * | 2009-01-26 | 2012-08-15 | Primus Pharmaceuticals Inc | METHODS FOR THE TREATMENT OF MUSCLE DYSTROPHIES |
US20100303936A1 (en) * | 2009-04-28 | 2010-12-02 | Bionovo, Inc. A Delaware Corporation | Method of reducing fat accumulation and inducing weight loss |
CN102453028B (zh) * | 2010-10-22 | 2014-07-30 | 沈阳药科大学 | 抗真菌剂—2-[(2,3-二氢-4H-苯并[b]噻喃-4-亚基)亚肼基]-4-氧代四氢噻(噁)唑-5-乙酸衍生物 |
US10568900B1 (en) | 2013-03-15 | 2020-02-25 | Suzanne Janine Paxton-Pierson | Androgen effectors |
AU2017247006B2 (en) * | 2016-04-06 | 2022-05-12 | Noxopharm Limited | Radiotherapy improvements |
AU2017247008B2 (en) | 2016-04-06 | 2022-04-07 | Noxopharm Limited | Isoflavonoid composition with improved pharmacokinetics |
JP2023519990A (ja) | 2020-03-30 | 2023-05-15 | ノクソファーム リミティド | 感染に関連する炎症の治療のための方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX18911A (es) * | 1988-12-27 | 1993-10-01 | Du Pont | Artropodicidas de semicarbazonas substituidas. |
DE68913706T2 (de) * | 1988-12-27 | 1994-08-04 | Du Pont | Substituierte Semicarbazon-Arthropodizide. |
WO1992018462A1 (en) | 1991-04-12 | 1992-10-29 | Schering Corporation | Bicyclic amides as inhibitors of acyl-coenzyme a: cholesterol acyl transferase |
CN1093086A (zh) | 1993-04-03 | 1994-10-05 | 华西医科大学药物研究所 | 异黄酮脂环烃醚及其肟衍生物 |
-
2002
- 2002-11-01 AU AU2002952453A patent/AU2002952453A0/en not_active Abandoned
-
2003
- 2003-11-03 MX MXPA05004526A patent/MXPA05004526A/es active IP Right Grant
- 2003-11-03 US US10/532,074 patent/US7714151B2/en not_active Expired - Fee Related
- 2003-11-03 EP EP03769053A patent/EP1556368A4/en not_active Withdrawn
- 2003-11-03 CN CNA2003801025650A patent/CN1708490A/zh active Pending
- 2003-11-03 JP JP2004547289A patent/JP2006513997A/ja active Pending
- 2003-11-03 NZ NZ539034A patent/NZ539034A/en unknown
- 2003-11-03 WO PCT/AU2003/001446 patent/WO2004039793A1/en active Application Filing
- 2003-11-03 CA CA002504653A patent/CA2504653A1/en not_active Abandoned
-
2005
- 2005-05-26 NO NO20052524A patent/NO20052524L/no not_active Application Discontinuation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101716135B (zh) * | 2010-01-08 | 2012-11-14 | 山西医科大学 | 大豆异黄酮固体分散体栓剂及其制备方法 |
CN106795135A (zh) * | 2014-09-10 | 2017-05-31 | 系统生物股份有限公司 | 异黄烷及其中间体的合成 |
CN106795135B (zh) * | 2014-09-10 | 2019-08-09 | 系统生物股份有限公司 | 异黄烷及其中间体的合成 |
Also Published As
Publication number | Publication date |
---|---|
MXPA05004526A (es) | 2005-07-26 |
US20060100238A1 (en) | 2006-05-11 |
JP2006513997A (ja) | 2006-04-27 |
EP1556368A1 (en) | 2005-07-27 |
WO2004039793A1 (en) | 2004-05-13 |
NO20052524D0 (no) | 2005-05-26 |
NZ539034A (en) | 2008-04-30 |
NO20052524L (no) | 2005-05-26 |
CA2504653A1 (en) | 2004-05-13 |
US7714151B2 (en) | 2010-05-11 |
AU2002952453A0 (en) | 2002-11-21 |
EP1556368A4 (en) | 2010-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1708490A (zh) | 胺化异黄酮类衍生物及其应用 | |
CN1301710C (zh) | 使用异黄酮的治疗方法和含有异黄酮的组合物 | |
CN1223595C (zh) | 雷公藤内酯醇衍生物及其应用 | |
CN1158274C (zh) | 苯并吡喃类化合物及其使用方法 | |
WO2017047769A1 (ja) | トール様受容体7またはトール様受容体9の活性化阻害剤 | |
CN1116288C (zh) | 用作肌苷-5'-一磷酸脱氢酶抑制剂的脲衍生物 | |
CN1946392A (zh) | 含有单乙酰基二酰基甘油衍生物的免疫调节剂、抗癌剂和健康食品 | |
CN1726034A (zh) | 亚甲基桥连的选择性雄激素受体调节剂及其应用方法 | |
CN1784221A (zh) | 影响体重减轻的组合物 | |
CN1694690A (zh) | 联合化疗组合物及方法 | |
CN1390126A (zh) | 治疗和/或抑制体重增加的方法 | |
CN1520290A (zh) | 含铜胺氧化酶的碳环肼基抑制剂 | |
CN1523982A (zh) | 减少体脂和调节脂肪酸代谢的方法、化合物和组合物 | |
CN1638765A (zh) | Hedgehog信号转导途径介质、其相关组合物以及应用 | |
CN1933818A (zh) | 用于治疗癌症的方法和组合物 | |
CN1250652A (zh) | 苯并噁嗪酮与核苷类似物的组合 | |
CN1496257A (zh) | 调控免疫球蛋白e及抑制细胞增殖的苯并咪唑化合物 | |
CN1505618A (zh) | 二聚体异黄酮类 | |
CN1492762A (zh) | 用作代谢调节剂的为丙二酸单酰辅酶a脱羧酶抑制剂的吡咯 | |
CN1281436A (zh) | 用于治疗肿瘤的n-苄基-3-茚乙酰胺衍生物 | |
CN1253172C (zh) | 抗变态反应剂、含有它的药品、食品或化妆品及它们的制备方法 | |
CN1960723A (zh) | 烷基呋喃在制备用于治疗肥胖症的药物和美容性处理超重中的用途 | |
Gao et al. | Chronic infusion of astaxanthin into hypothalamic paraventricular nucleus modulates cytokines and attenuates the renin–angiotensin system in spontaneously hypertensive rats | |
CN1627939A (zh) | 二环cb2大麻碱受体配体 | |
CN1294913C (zh) | 含有非那雄胺与环糊精或其衍生物的药物组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1084663 Country of ref document: HK |
|
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Open date: 20051214 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1084663 Country of ref document: HK |