CN100351248C - 染料木素衍生物及其制法和用途 - Google Patents
染料木素衍生物及其制法和用途 Download PDFInfo
- Publication number
- CN100351248C CN100351248C CNB2004100411575A CN200410041157A CN100351248C CN 100351248 C CN100351248 C CN 100351248C CN B2004100411575 A CNB2004100411575 A CN B2004100411575A CN 200410041157 A CN200410041157 A CN 200410041157A CN 100351248 C CN100351248 C CN 100351248C
- Authority
- CN
- China
- Prior art keywords
- genistein
- hours
- derivative
- reaction
- isoflavones
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229930004065 genistein derivative Natural products 0.000 title claims description 28
- 150000002273 genistein derivatives Chemical class 0.000 title claims description 27
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 claims abstract description 23
- 235000006539 genistein Nutrition 0.000 claims abstract description 23
- 229940045109 genistein Drugs 0.000 claims abstract description 23
- 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 claims abstract description 23
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims description 43
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 21
- 229910052794 bromium Inorganic materials 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- -1 2-hydroxyl ethylmercapto group Chemical group 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 6
- 150000002367 halogens Chemical class 0.000 abstract description 5
- 125000004414 alkyl thio group Chemical group 0.000 abstract description 4
- 229910006069 SO3H Inorganic materials 0.000 abstract 1
- 125000003368 amide group Chemical group 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000013078 crystal Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 238000001953 recrystallisation Methods 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 210000000988 bone and bone Anatomy 0.000 description 15
- 241000700159 Rattus Species 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000004821 distillation Methods 0.000 description 11
- 238000003304 gavage Methods 0.000 description 10
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 9
- 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 8
- 150000002515 isoflavone derivatives Chemical class 0.000 description 8
- 235000008696 isoflavones Nutrition 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 230000037182 bone density Effects 0.000 description 6
- 229960005309 estradiol Drugs 0.000 description 6
- 230000001076 estrogenic effect Effects 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 229910014033 C-OH Inorganic materials 0.000 description 5
- 229910014570 C—OH Inorganic materials 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229930013032 isoflavonoid Natural products 0.000 description 5
- 235000012891 isoflavonoids Nutrition 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000004291 uterus Anatomy 0.000 description 5
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- 150000003817 isoflavonoid derivatives Chemical class 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229930182833 estradiol Natural products 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 206010025482 malaise Diseases 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 206010010582 Congenital osteodystrophy Diseases 0.000 description 1
- 208000007652 Dysostoses Diseases 0.000 description 1
- 201000001324 Dysostosis Diseases 0.000 description 1
- 102000007594 Estrogen Receptor alpha Human genes 0.000 description 1
- 108010007005 Estrogen Receptor alpha Proteins 0.000 description 1
- 102000000509 Estrogen Receptor beta Human genes 0.000 description 1
- 108010041356 Estrogen Receptor beta Proteins 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001164 Osteoporotic Fractures Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 239000003075 phytoestrogen Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 108010048734 sclerotin Proteins 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Cosmetics (AREA)
Abstract
一类染料木素衍生物,它有如下通式,式中:R1,R2,R3=-H或-(CH2)nX,其中:n=1~6,X=-H、卤素、烷硫基或三级氨基,R4=-H或-SO3H。它能应用于制备治疗骨质疏松症的药物。本发明公开了其制法。
Description
技术领域
本发明涉及异黄酮类化合物染料木素衍生物及其制法,以及它们在制备预防或治疗骨质疏松症药物中的应用。
背景技术
染料木素(Genistein)是一种异黄酮类化合物,它存在于豆科植物中。现有的研究表明,中国和日本乳腺癌和***癌发病率相对较低,可能与食用黄豆有关,日本人血浆总异黄酮水平比西方人高7~100倍,而黄豆是染料木素唯一的膳食来源。
骨质疏松症(Osteoporosis)是以骨组织显微结构退化,骨矿成分和骨基质等比例地逐渐减少,骨质变薄,骨小梁数量减少,骨脆性增加和骨折发生危险度升高的一种全身骨代谢障碍性疾病。骨质疏松症是危及老年人健康的最常见疾病,特别是绝经期和绝经期后的妇女。美国约有1400~2500万人患有骨质疏松症,医药开支每年在200亿美元以上(参见:Ray,N.F.;Chan,J.K.Medicalexpenditures for the treatment of osteoporosis fracture in the United States in 1995report from the National Osteoporosis Foundation.J.Bone Miner Res.1998,12:24-35.)。在中国,绝经后女性骨质疏松发病率可高达25%-50%,并随着年龄增大发病率增高(参见:Nguyen,T.V.;Center,J.R.;EismanJ.A.Association betweenbreaster cancer and bone mineral density.The Dubbo osteoporosis epidemiologystudy.Muturitas,2000,36(1):27-34.)。由于绝经后的女性容易患骨质疏松症,所以绝经后妇女骨质疏松症已成为原发性骨质疏松症的同义语,被称为是“一种使1/4妇女倒下的严重疾病”。因此,寻找治疗及预防骨质疏松的药物已成为当前医药的热门课题。
异黄酮类化合物是一类植物性激素,广泛存在于豆科植物中。作为植物***,异黄酮与17β***具有相似的结构。现已证明异黄酮类化合物是一种***样化合物,能与内源性***受体结合发挥***样作用。在内源性***水平较低时,表现为***促效剂(Estrogenic agonist)(参见:Rickard,D.J.;Monroe,D.G;Ruesink,T.J.;Khosla,S.;Riggs,B.L.;Spelsberg,T.C.Phytoestrogengenistein acts as an estrogen agonist on human osteoblastic cells through estrogenreceptors alpha and beta.Cell.Biochem.2003,89,633-646.,)而在内源性***水平较高时,又可表现为***拮抗剂(Estrogenic antagonist)(参见:Wang,D.H.;Gutkowska,J.;Marcinkiewicz,M.Genistein supplementation stimulates theoxytocin system in the aorta of ovariectomized rats.Cardiovascular Research 2003,57(1):186-194.)。这种双向生物调节作用被称为***受体调节剂(参见:Lonard,D.M.;Smith,C.L.Molecular perspectives on selective estrogen receptor modulators(SERMs):progress in understanding their tissue-specific agonist and antagonistactions,Steroids,2002,67(1):15-24.,)可用于治疗妇女更年期综合症和骨质疏松症,但不会诱导乳腺癌、子宫癌的发生(参见:Ishimi,Y.;Arai,N.;Wang,X.X.;Wu,J.;Umegaki,K.;Miyaura,C.;Takeda,A.;Ikegami,S.Diffference in effective dosageof genistein on bone and uterus in ovarietomized mice.Biochem.Biophys.Res.Commun.2000,274,69-701.)。从大量的研究文献看出,这种新型的***受体调节剂—异黄酮类化合物及其衍生物,将会成为市场上最具有潜力的治疗骨质疏松症药物之一。
发明内容
本发明的目的在于提供一类新的异黄酮类化合物,即染料木素衍生物以及它们的制法和用途。
本发明的技术方案如下:
一类染料木素衍生物,它有如下通式:
式中:R1,R2,R3=-H或-(CH2)nX,其中:n=1~6,X=-H、卤素、烷硫基或三级氨基,R4=-H或-SO3H。
上述的染料木素衍生物,所述的卤素是溴,所述的烷硫基是2-羟基乙硫基,所述的三级氨基是N-吡啶基。
一种染料木素衍生物的制法,它是将染料木素与α-卤代烷或α,ω-二卤代烷在40~80℃反应8~48小时,制得X为H或卤素的染料木素衍生物,将X为H或卤素的染料木素衍生物再与硫醇在48℃反应12小时或与三级胺在160℃反应2小时制得X为烷硫基或三级氨基的染料木素衍生物。
将上述制得的染料木素衍生物与浓硫酸在0℃反应8~10小时,制得R4为磺酸基的染料木素衍生物。
上述的染料木素衍生物的制法,可以用超声波辅助反应,以加快反应,缩短反应时间。
本发明的染料木素衍生物对卵巢切除的大鼠骨质疏松有明显的缓解作用,而且其子宫的增重不明显,本发明的染料木素衍生物几乎没有毒性,因此可以应用于制备治疗骨质疏松症的药物。
附图说明
图1为大鼠股骨的X-射线透视图,其中:Sham为假手术组,灌服试剂空白;Ovx为卵巢切除组,灌服试剂空白。10为卵巢切除组,每天灌服化合物10(25μmol/kg),E2为卵巢切除组每天灌服***(17β-Estradiol,E2)(0.5μmol/kg)作为阳性对照,G为卵巢切除组每天灌服母体化合物染料木素(genistein,25μmol/kg)作为阳性对照。
具体实施方式
本发明制备了表1所列的化合物。
实施例一:4′,5-二羟基-7-(2-溴乙氧基)-异黄酮(1)的制备染料木素(0.27g,1mmol),1,2-二溴乙烷(4.7g,25mmol),K2CO3(0.07g,0.5mmol)溶解在60ml的DMF中,40℃在40Hz超声波作用下,反应1.5小时(或在40℃下加热搅拌反应8小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到浅黄色针状晶体,产率86%。Mp 175-178℃;IR(KBr)cm-1:3421(OH),2922(CH2),1665(C=O);1H NMR(DMSO-d6):δ3.81(t,2H,CH2Br),4.43(t,2H,OCH2),6.41(m,1H,H-8),6.67(m,1H,H-6),6.82(d,2H,H-3′,H-5′),7.38(d,2H,H-2′,H-6′),8.39(s,1H,H-2),9.64(s,1H,4′-OH),12.95(s,1H,5-OH)。
表1.本发明的染料木素衍生物通式I中各R基团所代表的取代基
实施例二:5-羟基-4′,7-二-(2-溴乙氧基)-异黄酮(2)的制备
染料木素(0.27g,1mmol),1,2-二溴乙烷(9.4g,50mmol),K2CO3(0.14g,1mmol)溶解在60ml的DMF中,60℃在40Hz超声波作用下,反应3小时(或在60℃下加热搅拌反应16小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到浅黄色针状晶体,产率82%。Mp 140-142℃;IR(KBr)cm-1:3447(OH),2929(CH2),1663(C=O);1HNMR(DMSO-d6):δ3.80(m,4H,2(CH2Br)),4.34(t,2H,OCH2),4.44(t,2H,OCH2),6.44(t,1H,H-8),6.70(t,1H,H-6),7.03(d,2H,H-3′,H-5′),7.50(d,2H,H-2′,H-6′),8.42(s,1H,H-2),12.93(s,1H,5-OH)。
实施例三:4′,5-二羟基-7-(3-溴丙氧基)-异黄酮(3)的制备
染料木素(0.27g,1mmol),1,3-二溴丙烷(5.1g,25mmol),K2CO3(0.07g,0.5mmol)溶解在60ml的DMF中,40℃在40Hz超声波作用下,反应1.5小时(或在40℃下加热搅拌反应8小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到浅黄色针状晶体,产率85%。Mp 124-126℃;IR(KBr)cm-1:3423(OH),2934(CH2),1663(C=O);1H NMR(DMSO-d6):δ2.24(m,2H,CH2),3.65(t,2H,CH2Br),4.18(t,2H,OCH2),6.41(d,1H,H-8),6.67(s,1H,H-6),6.82(d,2H,H-3′,H-5′),7.38(d,2H,H-2′,H-6′),8.40(s,1H,H-2),9.63(s,1H,4′-OH),12.95(s,1H,5-OH)。
实施例四:5-羟基-4′,7-二-(3-溴丙氧基)-异黄酮(4)的制备
染料木素(0.27g,1mmol),1,3-二溴丙烷(10.2g,50mmol),K2CO3(0.14g,1mmol)溶解在60ml的DMF中,60℃在40Hz超声波作用下,反应3小时(或在60℃下加热搅拌反应16小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到浅黄色针状晶体,产率80%。Mp 128-130℃;IR(KBr)cm-1:3447(OH),2927,2875(CH2),1661(C=O);1H NMR(DMSO-d6):δ2.24(m,4H,2(CH2)),3.65(m,4H,2(CH2Br)),4.08(m,4H,2(OCH2)),6.41(s,1H,H-8),6.66(s,1H,H-6),6.97(d,2H,H-3′,H-5′),7.50(d,2H,H-2′,H-6′),8.43(s,1H,H-2),12.91(s,1H,5-OH)。
实施例五:4′,5,7-三-(3-溴丙氧基)-异黄酮(5)的制备
染料木素(0.27g,1mmol),1,3-二溴丙烷(15.3g,75mmol),K2CO3(0.49g,3.5mmol)溶解在60ml的DMF中,80℃在40Hz超声波作用下,反应4小时(或在80℃下加热搅拌反应48小时)。反应完成后,反应混合物冷却到室温,滤除不溶物后,滤液减压蒸馏得到淡黄色固体,丙酮中重结晶得到无色针状晶体,产率90%。Mp 110-112℃;IR(KBr)cm-1:3447(OH),2930,2874(CH2),1644(C=O);1H NMR(DMSO-d6):δ2.22(m,6H,3(CH2)),3.66(m,4H,2(CH2Br)),3.82(t,2H,CH2Br),4.08(m,4H,2(OCH2)),4.23(t,2H,OCH2),6.53(t,1H,H-8),6.69(d,1H,H-6),6.97(d,2H,H-3′,H-5′),7.41(d,2H,H-2′,H-6′),8.20(s,1H,H-2)。
实施例六:4′,5-二羟基-7-[2-(2-羟基乙硫基)-乙氧基]-异黄酮(6)的制备
将4′,5-二羟基-7-(2-溴乙氧基)-异黄酮(0.37g,1mmol),巯基乙醇(0.15g,2mmol),三乙胺(0.11g,1mmol)溶解在50ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在48℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到白色针状晶体,产率85%。Mp 132-135℃;IR(KBr)cm-1:3420(OH),2926(CH2),1664(C=O)1047(C-OH);1H NMR(DMSO-d6):δ2.66(t,2H,CH2-S),2.91(t,2H,S-CH2),3.55(q,2H,CH2-O),4.24(t,2H,OCH2),6.40(d,1H,H-8),6.66(t,1H,H-6),6.82(d,2H,H-3′,H-5′),7.38(d,2H,H-2′,H-6′),8.40(s,1H,H-2),9.62(s,1H,4′-OH),12.95(s,1H,5-OH);MS(ESI)calcd for C19H18O6S 374.0818,found,374.1095,[M+H]+375.1173,[2M+Na]+771.2198。
实施例七:5-羟基-4′,7-二-[2-(2-羟基乙硫基)-乙氧基]-异黄酮(7)的制备
将5-羟基-4′,7-二-(2-溴乙氧基)-异黄酮(0.48g,1mmol),巯基乙醇(0.30g.4mmol),三乙胺(0.22g.2mmol)溶解在50ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在48℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到白色针状晶体,产率80%。Mp 66-68℃;IR(KBr)cm-1:3431(OH),2924,2854(CH)2,1663(C=O),1048(C-OH);1H NMR(DMSO-d6):δ2.66(t,4H,2(CH2-S)),2.90(q,4H,2(S-CH2)),3.55(q,4H,2(CH2-O)),4.15(t,2H,OCH2),4.25(t,2H,OCH2),6.42(d,1H,H-8),6.69(d,1H,H-6),7.00(t,2H,H-3′,H-5′),7.50(d,2H,H-2′,H-6′),8.46(s,1H,H-2),12.92(s,1H,5-OH);MS(ESI)calcd for C23H26O7S2478.1111,found,478.1499,[M+H]+479.1577,[M+Na]+501.1599,[2M+Na]+979.2706,[2M+K]+995.2557。
实施例八:4′,5-二羟基-7-[3-(2-羟基乙硫基)-丙氧基]-异黄酮(7)的制备
将4′,5-二羟基-7-(3-溴丙氧基)-异黄酮(0.39g,1mmol),巯基乙醇(0.15g,2mmol),三乙胺(0.11g,1mmol)溶解在30ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在40℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到白色针状晶体,产率85%。Mp 152-154℃;IR(KBr)cm-1:3434(OH),2942,2920,2876(CH2),1664(C=O),1042(C-OH);1H NMR(DMSO-d6):δ1.95(m,2H,CH2),2.56(t,2H,CH2-S),2.64(t,2H,S-CH2),3.50(q,2H,CH2-O),4.14(t,2H,OCH2),6.39(q,1H,H-8),6.65(q,1H,H-6),6.80(m,2H,H-3′,H-5′),7.37(d,2H,H-2′,H-6′),8.40(s,1H,H-2),9.62(s,1H,4′-OH),12.95(s,1H,5-OH);MS(ESI)calcd for C20H20O6S388.0974,found,388.143,[M+H]+389.1221,[2M+Na]+799.1726。
实施例九:5-羟基-4′,7-二-[3-(2-羟基乙硫基)-丙氧基]-异黄酮(9)的制备
将5-羟基-4′,7-二-(3-溴丙氧基)-异黄酮(0.51g,1mmol),巯基乙醇(0.30g.4mmol),三乙胺(0.22g,2mmol)溶解在30ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在48℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到无色针状晶体,产率80%。Mp 102-105℃;IR(KBr)cm-1:3421(OH),2923,2877(CH2),1671(C=O),1049(C-OH);1H NMR (DMSO-d6):δ1.93(m,4H,2(CH2)),2.56(t,4H,2(CH2-S)),2.64(m,4H,2(S-CH2)),3.51(t,4H,2(CH2-O)),4.14(t,4H,2(OCH2)),6.39(t,1H,H-8),6.64(t,1H,H-6),6.80(d,2H,H-3′,H-5′),7.36(d,2H,H-2′,H-6′),8.39(s,1H,H-2);MS(ESI)calcd for C25H30O7S2506.1423,found,506.1587,[M+H]+507.1665,[M+Na]+529.1236,[2M+Na]+1035.6531。
实施例十:4′,5,7-三-[3-(2-羟基乙硫基)-丙氧基]-异黄酮(10)的制备
将4′,5,7-三-(3-溴丙氧基)-异黄酮(0.63g,1mmol),巯基乙醇(0.30g,4mmol),三乙胺(0.33g,3mmol)溶解在30ml的乙醇中,48℃在40Hz超声波作用下,反应2小时(或在48℃下加热搅拌反应12小时)。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用水洗涤后,丙酮中重结晶得到无色针状晶体,产率80%。Mp 78-80℃;IR(KBr)cm-1:3430(OH),2922,2872(CH)2,1639(C=O),1051(C-OH);1H NMR(DMSO-d6):δ1.96(m,6H,3(CH2)),2.56(m,6H,3(CH2-S)),2.66(m,4H,2(S-CH2)),2.78(t,2H,S-CH2),3.51(m,6H,3(CH2-O)),4.06(m,4H,2(OCH2)),4.16(t,2H,OCH2),6.50(s,1H,H-8),6.64(d,1H,H-6),6.95(d,2H,H-3′,H-5′),7.40(d,2H,H-2′,H-6′),8.16(s,1H,H-2);MS(ESI)calcd for C30H40O8S3624.1872,found,624.2096,[M+H]+625.2174,[M+Na]+647.1933,[2M+Na]+1272.3999。
实施例十一:三溴化-4′,5,7-三-[3-(N-吡啶基)-丙氧基]-异黄酮(11)的制备
将4′,5,7-三-(3-溴丙氧基)-异黄酮(0.63g,1mmol),无水吡啶10ml,160℃下反应2小时。反应完成后,反应混合物减压蒸馏得到淡黄色固体,用乙醇洗涤后,水中重结晶得到无色针状晶体,产率80%。Mp 260℃(dec.);1H NMR(D2O):δ2.45-2.51(m,6H,3(CH2)),4.06-4.13(m,6H,3(OCH2),4.70-4.80(m,6H,3(CH2-N+),6.24(d,1H,H-8),6.51(d,1H,H-6),6.85(d,2H,H-3′,H-5′),7.27(d,2H,H-2′,H-6′),8.32(s,1H,H-2);(吡啶环上)7.82(t,2H,2(H-4)),7.93(s,H,H-4),7.95(t,4H,2(H-3),2(H-5)),8.44(t,2H,H-3,H-5),8.73(d,2H,H-2,H-6),8.80(t,4H,2(H-2),2(H-6))。
实施例十二:4′,5-二羟基-7-甲氧基异黄酮-3′-磺酸(12)的制备
将98%的浓硫酸0.5ml,4′,5-二羟基-7-甲氧基异黄酮(0.28g,1mmol)放置在三角烧瓶中,在0℃,25Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率80%。Mp 365℃(dec.);IR(KBr)cm-1:3419(OH),2956(CH3),1655(C=O),1179(S=O);1H NMR(DMSO-d6):δ3.86(s,3H,7-OCH3),6.41(s,1H,H-8),6.66(s,1H,H-6),6.84(d,1H,H-5′),7.39(t,1H,H-6′),7.70(d,1H,H-2′),8.43(s,1H,H-2);MS(ESI)calcd for C16H12O8S 364.0248,found,364.0343,[M-H]-363.0256(negative ion mode)。化合物12用NaOH中和得到其相应的钠盐。
实施例十三:5-羟基-4′,7-二甲氧基异黄酮-3′-磺酸(13)的制备
将98%的浓硫酸0.5ml,4′,7-二甲氧基-5-羟基-异黄酮(0.30g,1mmol)放置在三角烧瓶中,在0℃,25Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率85%。mp 360℃(dec.);IR(KBr)cm-1:3421(OH),2957(CH3),1654(C=O),1199(S=O);1H NMR(DMSO-d6):δ3.78(s,3H,7-OCH3),3.86(s,3H,4′-OCH3),6.41(s,1H,H-8),6.67(s,1H,H-6),7.01(d,1H,H-5′),7.45(q,1H,H-6′),7.89(d,1H,H-2′),8.42(s,1H,H-2),12.92(s,1H,5-OH);MS(ESI)calcd for C17H14O8S 378.0404,found,378.0410,[M-H]-377.0332(negativeion mode)。化合物13用NaOH中和得到其相应的钠盐。
实施例十四:4′,5,7-三甲氧基异黄酮-3′-磺酸(14)的制备
将98%的浓硫酸0.5ml,4′,5,7-三甲氧基异黄酮(0.31g,1mmol)放置在三角烧瓶中,在0℃,25Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率85%。Mp 360℃(dec.);IR(KBr)cm-1:3431(OH),2955(CH3),1653(C=O)1180(S=O);1H NMR(DMSO-d6):δ3.66(s,3H,5-OCH3),3.72(s,3H,7-OCH3),3.81(s,3H,4′-OCH3),6.26(d,1H,H-8),6.36(d,1H,H-6),7.00(d,1H,H-5′),7.32(q,1H,H-6′),7.72(d,1H,H-2′),7.94(s,1H,H-2);MS(ESI)calcd for C18H16O8S 392.0560,found,392.0515,[M+H]+393.0593。化合物14用NaOH中和得到其相应的钠盐。
实施例十五:4′,5-二羟基-7-(2-溴乙氧基)-异黄酮-3′-磺酸(15)的制备
将98%的浓硫酸0.5ml,4′,5-二羟基-7-(2-溴乙氧基)-异黄酮(0.37g,1mmol)放置在三角烧瓶中,在0℃,25Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率78%。Mp 347℃(dec.);1H NMR(DMSO-d6+D2O):δ3.57(t,2H,CH2Br),4.17(t,2H,OCH2),6.12(s,1H,H-8),6.32(s,1H,H-6),6.88(d,1H,H-5′),7.29(d,1H,H-6′),7.65(s,1H,H-2′),7.98(s,1H,H-2)。化合物15用NaOH中和得到其相应的钠盐。
实施例十六:4′,5-二羟基-7-(3-溴丙氧基)-异黄酮-3′-磺酸(16)的制备
将98%的浓硫酸0.5ml,4′,5-二羟基-7-(3-溴丙氧基)-异黄酮(0.39g,1mmol)放置在三角烧瓶中,在0℃,40Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应10小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率76%。Mp 344℃(dec.);1H NMR(DMSO-d6):δ2.27(m,2H,CH2),3.64(t,2H,CH2Br),4.22(t,2H,OCH2),6.43(d,1H,H-8),6.70(d,1H,H-6),6.83(d,1H,H-5′),7.38(q,1H,H-6′),7.69(d,1H,H-2′),8.44(s,1H,H-2),10.65(s,1H,4-OH),12.90(s,1H,5OH)。化合物16用NaOH中和得到其相应的钠盐。
实施例十七:5-羟基-4′,7-二-(3-溴丙氧基)-异黄酮-3′-磺酸(17)的制备
将98%的浓硫酸0.5ml,5-羟基-4′,7-二(3-溴丙氧基)-异黄酮(0.51g,1mmol)放置在三角烧瓶中,在0℃,40Hz超声波作用下,反应0.5小时(或在0℃下加热搅拌反应8小时),反应完成后,反应混合物加水稀释得到白色固体,固体用水重结晶得到白色针状晶体,产率73%。Mp 312℃(dec.);1H NMR(D2O):δ2.33(m,4H,2CH2),3.65(t,2H,CH2Br),3.82(t,2H,CH2Br),4.22(t,2H,OCH2),4.30(t,2H,OCH2),6.40(d,1H,H-8),6.58(d,1H,H-6),7.18(d,1H,H-5′),7.69(q,1H,H-6′),8.10(d,1H,H-2′),8.20(d,1H,H-2。化合物17用NaOH中和得到其相应的钠盐。
实施例十八:本发明的染料木素衍生物对骨质疏松症的预防和治疗效果
为了评价通式(I)化合物对骨的作用效果,利用卵巢切除大鼠作为模型进行了体内活性评价,同时对活性好的化合物进行了急性毒性实验,实验结果如图1,表2和表3所示:
表2.染料木素及其衍生物对骨的作用效果
组别 | 化合物 | 右侧股骨的骨密度(g/cm2) | 右侧股骨的骨矿物含量(g) | 子宫重量(g) |
abcdefghijOvxSham | 678910121314染料木素E2-- | 0.284±0.0150.281±0.0060.287±0.0080.279±0.0160.290±0.0100.278±0.0070.286±0.0110.283±0.0140.268±0.0110.295±0.0070.233±0.0120.319±0.010 | 0.2589±0.0020.2614±0.0030.2577±0.0020.2592±0.0040.2674±0.0020.2516±0.0020.2602±0.0010.2641±0.0020.2411±0.0040.2620±0.0030.2045±0.0030.3010±0.003 | 0.0661±0.0080.0704±0.0060.0714±0.0070.0650±0.0040.0599±0.0060.0741±0.0080.0589±0.0080.0629±0.0090.0701±0.0050.2647±0.0300.0633±0.0080.3549±0.015 |
在表2中,卵巢切除组a到h组中的大鼠每天分别灌服相应的测试化合物(25μmol/kg),卵巢切除组i每天灌服母体化合物染料木素(25μmol/kg)作为阳性对照,卵巢切除j组每天灌服***(17β-Estradiol,E2)(0.5μmol/kg)作为阳性对照。Ovx组为卵巢切除组,灌服试剂空白。Sham组为假手术组,不切除卵巢,灌服试剂空白。实验进行两个月后大鼠被断颈处死,进行各项指标测定。骨密度使用Lunar DPX-IQ Dual-energy X-ray Densitometer进行测量,表中的数据结果表示为mean±SEM(n=6)。结果显示,Ovx组的大鼠相比于假手术组骨密度下降了27%,骨矿物含量下降了32%(p<0.01);e组(灌服测试化合物10)相比于Ovx组的大鼠骨密度增加了24%,骨矿物含量增加了31%(p<0.01);e组(灌服测试化合物10)的大鼠相比于i组(灌服母体化合物染料木素)骨密度增加了8%,骨矿物含量增加了11%(p<0.01)。结果同时显示,测试化合物对大鼠的子宫未产生显著的影响,但***显著地增加了大鼠的子宫重量。
表3.染料木素及其主要活性衍生物的急性毒性实验结果
组别 | 每组小鼠数目 | 受试化合物 | 给药量(mg/kg) |
123456 | 101010101010 | 染料木素6781013 | 72901009812906104761684810800 |
在表3中,测试化合物在限量实验中,给予表中相应的量,均无死亡例。表明这些化合物不但能够明显地增加骨密度和骨的矿物含量,而且是无毒的,很有希望成为预防和治疗骨质疏松的药物。
Claims (6)
2.一种权利要求1所述的染料木素衍生物的制法,其特征是:将染料木素与α-溴代烷或α,ω-二溴代烷在40~80℃反应8~48小时,制得X为H或溴的染料木素衍生物。
3.一种权利要求1所述的染料木素衍生物的制法,其特征是:将X为H或溴的染料木素衍生物与2-羟基乙硫醇在48℃反应12小时或与吡啶在160℃反应2小时制得X为2-羟基乙硫基或N-吡啶基的染料木素衍生物。
4.一种权利要求1所述的染料木素衍生物的制法,其特征是:将权利要求2或3制得的染料木素衍生物与浓硫酸在0℃反应8~10小时,制得R4为磺酸基的染料木素衍生物。
5.根据权利要求2、3或4所述的染料木素衍生物的制法,其特征是用超声波辅助反应,以缩短反应时间。
6.权利要求1所述的染料木素衍生物在制备治疗骨质疏松症药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2004100411575A CN100351248C (zh) | 2004-07-05 | 2004-07-05 | 染料木素衍生物及其制法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2004100411575A CN100351248C (zh) | 2004-07-05 | 2004-07-05 | 染料木素衍生物及其制法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1603318A CN1603318A (zh) | 2005-04-06 |
CN100351248C true CN100351248C (zh) | 2007-11-28 |
Family
ID=34664935
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004100411575A Expired - Fee Related CN100351248C (zh) | 2004-07-05 | 2004-07-05 | 染料木素衍生物及其制法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN100351248C (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2643973A1 (en) | 2006-02-28 | 2007-09-07 | Council Of Scientific And Industrial Research | Pharmaceutical composition containing butea isoflavones for the prevention /treatment of bone disorders and a process for the preparation thereof |
CN100462361C (zh) * | 2007-01-31 | 2009-02-18 | 陕西师范大学 | 芒柄花素-3′-磺酸钠、樱黄素-3′-磺酸钠及其制备方法和药物用途 |
TWI324514B (en) | 2008-02-26 | 2010-05-11 | Univ Kaohsiung Medical | Isoflavone derivatives and pharmaceutical compositions comprising the same |
CN102161648A (zh) * | 2011-02-18 | 2011-08-24 | 中国药科大学 | 具有选择性***受体调节活性的异黄酮类化合物的制备方法及其用途 |
CN104311519B (zh) * | 2014-09-23 | 2018-12-18 | 山东理工大学 | 具有胃黏膜损伤保护作用的功能性食品因子制备及其应用 |
CN104193717B (zh) * | 2014-09-25 | 2018-02-02 | 山东理工大学 | 含苯基哌嗪的染料木素衍生物的制备方法及其应用 |
CN104262313B (zh) * | 2014-09-25 | 2018-01-09 | 山东理工大学 | 含苯基哌嗪的染料木素衍生物制法及其抗菌活性 |
CN106281935A (zh) * | 2016-08-08 | 2017-01-04 | 山东理工大学 | 一种促进中性蛋白酶活性的方法及其在啤酒澄清中的应用 |
CN106065389A (zh) * | 2016-08-08 | 2016-11-02 | 山东理工大学 | 一种促进木瓜蛋白酶活性的方法及其在啤酒澄清中的应用 |
CN106674182B (zh) * | 2016-12-09 | 2018-09-04 | 郑州大学 | 含氨基二硫代甲酸酯的刺芒柄花素衍生物、制备方法及其在抗肿瘤药物中的应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES477270A1 (es) * | 1979-01-30 | 1979-10-16 | Farmasimes S A | Metodo para la preparacion de derivados de isoflavonas. |
CN1233173A (zh) * | 1996-08-30 | 1999-10-27 | 诺沃根研究有限公司 | 使用异黄酮的治疗方法和含有异黄酮的组合物 |
CN1306434A (zh) * | 1998-06-23 | 2001-08-01 | 希格马托保健科学股份公司 | 用于预防和/或治疗骨质疏松症和因绝经综合征所致病变的组合物 |
WO2002074308A1 (en) * | 2001-03-15 | 2002-09-26 | Roche Vitamins Ag | Composition for the prevention of osteoporosis comprising a combination of isoflavones and polyunsaturated fatty acids |
WO2003079965A2 (en) * | 2002-03-21 | 2003-10-02 | Yeda Research And Development Co. Ltd. | Derivatives of isoflavones |
-
2004
- 2004-07-05 CN CNB2004100411575A patent/CN100351248C/zh not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES477270A1 (es) * | 1979-01-30 | 1979-10-16 | Farmasimes S A | Metodo para la preparacion de derivados de isoflavonas. |
CN1233173A (zh) * | 1996-08-30 | 1999-10-27 | 诺沃根研究有限公司 | 使用异黄酮的治疗方法和含有异黄酮的组合物 |
CN1306434A (zh) * | 1998-06-23 | 2001-08-01 | 希格马托保健科学股份公司 | 用于预防和/或治疗骨质疏松症和因绝经综合征所致病变的组合物 |
WO2002074308A1 (en) * | 2001-03-15 | 2002-09-26 | Roche Vitamins Ag | Composition for the prevention of osteoporosis comprising a combination of isoflavones and polyunsaturated fatty acids |
WO2003079965A2 (en) * | 2002-03-21 | 2003-10-02 | Yeda Research And Development Co. Ltd. | Derivatives of isoflavones |
Non-Patent Citations (2)
Title |
---|
Isoflavone synthesis with 1,3,5-triazine..Jha,Hem Chandra,Zilliken,Fritz,Breitmaier,Eberhard.Angew.Chem,Vol.93 No.1. 1981 * |
Urinary and biliary metabolites of genistein in rats.Yasuda,Takaaki,Mizunuma,Shuichi,Kano,Yoshihiro,Saito,Ken.ichi,Ohsawa,Keisuke.Biol. Pharm. Bull.,Vol.19 No.3. 1996 * |
Also Published As
Publication number | Publication date |
---|---|
CN1603318A (zh) | 2005-04-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100351248C (zh) | 染料木素衍生物及其制法和用途 | |
CN100351250C (zh) | 对gsk3具有选择性抑制作用的新型化合物 | |
CN1034938C (zh) | 4H-萘并[1,2-b]吡喃化合物的制备方法 | |
CN104169266A (zh) | 新的苯并吡喃化合物、其组合物和用途 | |
RU2015107733A (ru) | Терапевтические средства на основе производных диглицилиловых простых эфиров и способы их применения | |
EP0144804A2 (en) | New 2,5-diaryl tetrahydrofurans and analogs thereof as paf-antagonists | |
EA010422B1 (ru) | Замещённые индол-о-глюкозиды | |
JP2016522179A (ja) | 腫瘍性疾患であって特に高her2タンパク質レベルの腫瘍性疾患を治療するためのタモキシフェン誘導体 | |
CN1231176A (zh) | 治疗心力衰竭的方法 | |
US7247646B2 (en) | Benzopyranone compounds, compositions thereof, and methods of treatment therewith | |
CN1101385C (zh) | 取代的苯并咪唑衍生物及其制法和药物用途 | |
CN1198802C (zh) | 具有抗增殖活性的查耳酮类化合物 | |
PT89269B (pt) | Processo para a preparacao de 2,5-diaril-tetra-hidrofuranos uteis como antagonistas do factor activador de plaquetas | |
ZA200408662B (en) | Benzopyranone compounds, compositions thereof and methods of treatment therewith | |
CN1301987C (zh) | 7-羧基-黄酮衍生物、其制备方法和应用 | |
JP2006515276A (ja) | 骨粗鬆症の予防及び治療効果を有するフラン誘導体並びにこれを含む薬学的組成物 | |
CN1425653A (zh) | 2,4,5-三取代咪唑类化合物及其制备方法和制药用途 | |
CN106389432A (zh) | 氯化两面针碱在制备抗骨质疏松和骨丢失疾病中的应用 | |
US6677373B2 (en) | Polymorphic B form of 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one | |
RU2678969C1 (ru) | Антиаритмическое средство на основе гибридной молекулы амлодипина с (7-метоксикумарин-4-ил)уксусной кислотой | |
Liu et al. | Computer-aided design, synthesis and biological assay of p-methylsulfonamido phenylethylamine analogues | |
CN1839831A (zh) | 染料木素与甲硝唑的复合物和其衍生物及其制备方法与用途 | |
KR102293709B1 (ko) | 신규한 퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 약학적 조성물 | |
CN106727463A (zh) | Harrisotone A的衍生物组合物用于抗骨质疏松 | |
CN1850815A (zh) | 一组长链烷氧烷基取代唾液酸衍生物及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20071128 Termination date: 20100705 |