CN1603318A - Genistein derivatives and their preparation process and use - Google Patents
Genistein derivatives and their preparation process and use Download PDFInfo
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- CN1603318A CN1603318A CN200410041157.5A CN200410041157A CN1603318A CN 1603318 A CN1603318 A CN 1603318A CN 200410041157 A CN200410041157 A CN 200410041157A CN 1603318 A CN1603318 A CN 1603318A
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- genistein
- hours
- derivative
- genistein derivative
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229930004065 genistein derivative Natural products 0.000 title claims description 31
- 150000002273 genistein derivatives Chemical class 0.000 title claims description 30
- 235000006539 genistein Nutrition 0.000 claims abstract description 21
- 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 20
- 229940045109 genistein Drugs 0.000 claims abstract description 20
- 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 20
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 19
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 43
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 19
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 9
- 150000003512 tertiary amines Chemical class 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- -1 2-hydroxyl ethylmercapto group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 6
- 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
- 239000013078 crystal Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 238000001953 recrystallisation Methods 0.000 description 17
- 210000000988 bone and bone Anatomy 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 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 10
- 238000003304 gavage Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 8
- 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 7
- 150000002515 isoflavone derivatives Chemical class 0.000 description 7
- 235000008696 isoflavones Nutrition 0.000 description 7
- 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
- 230000037182 bone density Effects 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
- 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
- 238000005160 1H NMR spectroscopy Methods 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
- 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
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- 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
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- 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
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Cosmetics (AREA)
Abstract
This invention discloses a kind of genistein derivate. It has the following general formula, in the formula R1, R2, R3 = - H OR - (CH2) n X, n = 1~6, X = - H, halogen, alkyl sulphide radical or third class amido, R4 = - H or - SO3H. It can be used to prepare medicine of curing osteoporosis. This invention discloses other preparations.
Description
Technical field
The present invention relates to isoflavonoid genistein derivative and method for making thereof, and their application in preparation prevention or treatment osteoporosis agents.
Background technology
Genistein (Genistein) is a kind of isoflavonoid, and it is present in the leguminous plants.Existing studies show that, Chinese and Japanese mammary cancer and prostate cancer sickness rate are relatively low, may be relevant with edible soya bean, Japanese's blood plasma total isoflavone level is higher 7～100 times than the westerner, and the soya bean meals that to be genistein unique source.
Osteoporosis (Osteoporosis) is to degenerate with the osseous tissue microstructure, bone ore deposit composition and ground substance of bone equal proportion ground reduce gradually, the sclerotin attenuation, bone trabecula quantity reduces, a kind of whole body dysostosis disease that bone fragility increases and fracture degree of causing danger raises.Osteoporosis is to jeopardize senior health and fitness's common disease, particularly climacteric and the women after climacteric.The U.S. has 1400～2,500 ten thousand people to suffer from osteoporosis approximately, medicine spending annual more than 20,000,000,000 dollars (referring to 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.).In China, postmenopausal women osteoporosis sickness rate can be up to 25%-50%, and along with the age increases sickness rate and increases (referring to 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.).Because postclimacteric women suffers from osteoporosis, so postmenopausal women's osteoporosis has become the synonym of primary osteoporosis, be known as " a kind of serious disease that 1/4 women is fallen down " easily.Therefore, the medicine of searching treatment and preventing osteoporosis has become the heat subject of current medicine.
Isoflavonoid is a class vegetalitas hormone, extensively is present in the leguminous plants.As phytoestrogen, isoflavones has similar structure to 17 β estradiol.Proved that now isoflavonoid is a kind of estrogen-like compound, can bring into play estrogen-like effects with the endogenous estrogen receptors bind.When the endogenous estrogen level is low, show as oestrogenic hormon agonist (Estrogenic agonist) (referring to 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.J.Cell.Biochem.2003,89,633-646.,) and when the endogenous estrogen level is higher, can show as estrogen antagonist (Estrogenic antagonist) again (referring to 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.).This two-way biological regulating effect is called as estrogenic agents (referring to 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.,) can be used for treating climacteric syndrome and osteoporosis, but the generation that can not induce mammary cancer, uterus carcinoma is (referring to Ishimi, Y.; Arai, N.; Wang, X.X.; Wu, J.; Umegaki, K.; Miyaura, C.; Takeda, A.; Ikegami, S.Difference in effective dosageof genistein on bone and uterus in ovarietomized mice.Biochem.Biophys.Res.Commun.2000,274,69-701.).Find out that from a large amount of research documents this novel estrogenic agents-isoflavonoid and derivative thereof will become one of treatment osteoporosis agents of potentialization on the market.
Summary of the invention
The object of the present invention is to provide the new isoflavonoid of a class, i.e. genistein derivative and their method for making and purposes.
Technical scheme of the present invention is as follows:
The genistein derivative, it has following general formula:
In the formula: R
1, R
2, R
3=-H or-(CH
2)
nX, wherein: n=1～6, X=-H, halogen, alkylthio or tertiary amine base, R
4=-H or-SO
3H.
Above-mentioned genistein derivative, described halogen is a bromine, and described alkylthio is a 2-hydroxyl ethylmercapto group, and described tertiary amine base is the N-pyridyl.
A kind of method for making of genistein derivative, it is with genistein and alpha-halogen alkane or α, ω-saturated dihalide was 40～80 ℃ of reactions 8～48 hours, making X is the genistein derivative of H or halogen, is that the genistein derivative of H or halogen 2 hour makes genistein derivative that X be alkylthio or tertiary amine base 48 ℃ of reactions 12 hours or with tertiary amine 160 ℃ of reactions with mercaptan again with X.
The above-mentioned genistein derivative that makes and the vitriol oil were reacted 8～10 hours at 0 ℃, make R
4Be sulfonic genistein derivative.
The method for making of above-mentioned genistein derivative can be used the ultrasonic wave assisted reaction, to add fast response, shortens the reaction times.
Genistein derivative of the present invention has tangible mitigation to OO osteoporosis rat, and the weightening finish in its uterus is not obvious, genistein derivative of the present invention does not almost have toxicity, therefore can be applied to prepare the medicine for the treatment of osteoporosis.
Description of drawings
Fig. 1 is the X-actinoscopy X figure of rat femur, and wherein: Sham is a sham operated rats, gavages reagent blank; Ovx is the oophorectomize group, gavages reagent blank.10 are the oophorectomize group, gavage compound 10 (25 μ mol/kg) every day, E
2For the oophorectomize group gavages estradiol (17 β-Estradiol, E every day
2) (0.5 μ mol/kg) as positive control, G is that the oophorectomize group gavages parent compound genistein (genistein, 25 μ mol/kg) as positive control every day.
Embodiment
The present invention has prepared the listed compound of table 1.
Embodiment one: 4 ', the preparation of 5-dihydroxyl-7-(2-bromine oxethyl)-isoflavones (1)
Genistein (0.27g, 1mmol), glycol dibromide (4.7g, 25mmol), K
2CO
3(0.07g 0.5mmol) is dissolved among the DMF of 60ml, 40 ℃ under the effect of 40Hz ultrasonic wave, react 1.5 hours (or 40 ℃ of following heated and stirred reactions 8 hours).After reaction is finished, the reaction mixture cool to room temperature, behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains light yellow needle-like crystal in the acetone, productive rate 86%.Mp?175-178℃；IR(KBr)cm
-1：3421(OH)，2922(CH
2)，1665(C＝O)；
1H?NMR(DMSO-d
6)：δ3.81(t，2H，CH
2Br)，4.43(t，2H，OCH
2)，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)。
The substituting group of each R group representative in the table 1. genistein derivative of the present invention general formula I
Change
Close R
1R
2R
3R
4
Thing
1 CH
2CH
2Br H H H
2 CH
2CH
2Br CH
2CH
2Br H H
3 CH
2CH
2CH
2Br H H H
4 CH
2CH
2CH
2Br CH
2CH
2CH
2Br H H
5 CH
2CH
2CH
2Br CH
2CH
2CH
2Br CH
2CH
2CH
2Br H
6 CH
2CH
2SCH
2CH
2OH H H H
7 CH
2CH
2SCH
2CH
2OH CH
2CH
2SCH
2CH
2OH H H
8 CH
2CH
2CH
2SCH
2CH
2OH H H H
9 CH
2CH
2CH
2SCH
2CH
2OH CH
2CH
2CH
2SCH
2CH
2OH H H
10 CH
2CH
2CH
2SCH
2CH
2OH CH
2CH
2CH
2SCH
2CH
2OH CH
2CH
2CH
2SCH
2CH
2OH H
12 CH
3 H H SO
3H
13 CH
3 CH
3 H SO
3H
14 CH
3 CH
3 CH
3 SO
3H
15 CH
2CH
2Br H H SO
3H
16 CH
2CH
2CH
2Br H H SO
3H
17 CH
2CH
2CH
2Br CH
2CH
2CH
2Br H SO
3H
Embodiment two: 5-hydroxyl-4 ' and, the preparation of 7-two-(2-bromine oxethyl)-isoflavones (2)
Genistein (0.27g, 1mmol), glycol dibromide (9.4g, 50mmol), K
2CO
3(0.14g 1mmol) is dissolved among the DMF of 60ml, 60 ℃ under the effect of 40Hz ultrasonic wave, react 3 hours (or 60 ℃ of following heated and stirred reactions 16 hours).After reaction is finished, the reaction mixture cool to room temperature, behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains light yellow needle-like crystal in the acetone, productive rate 82%.Mp?140-142℃；IR(KBr)cm
-1：3447(OH)，2929(CH
2)，1663(C＝O)；
1HNMR(DMSO-d
6)：δ3.80(m，4H，2(CH
2Br))，4.34(t，2H，OCH
2)，4.44(t，2H，OCH
2)，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)。
Embodiment three: 4 ', the preparation of 5-dihydroxyl-7-(3-bromine propoxy-)-isoflavones (3)
Genistein (0.27g, 1mmol), 1, the 3-dibromopropane (5.1g, 25mmol), K
2CO
3(0.07g 0.5mmol) is dissolved among the DMF of 60ml, 40 ℃ under the effect of 40Hz ultrasonic wave, react 1.5 hours (or 40 ℃ of following heated and stirred reactions 8 hours).After reaction is finished, the reaction mixture cool to room temperature, behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains light yellow needle-like crystal in the acetone, productive rate 85%.Mp?124-126℃；IR?(KBr)cm
-1：?3423(OH)，2934(CH
2)，1663(C＝O)；
1H?NMR(DMSO-d
6)：δ2.24(m，2H，CH
2)，3.65(t，2H，CH
2Br)，4.18(t，2H，OCH
2)，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)。
Embodiment four: 5-hydroxyl-4 ' and, the preparation of 7-two-(3-bromine propoxy-)-isoflavones (4)
Genistein (0.27g, 1mmol), 1, the 3-dibromopropane (10.2g, 50mmol), K
2CO
3(0.14g 1mmol) is dissolved among the DMF of 60ml, 60 ℃ under the effect of 40Hz ultrasonic wave, react 3 hours (or 60 ℃ of following heated and stirred reactions 16 hours).After reaction is finished, the reaction mixture cool to room temperature, behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains light yellow needle-like crystal in the acetone, productive rate 80%.Mp?128-130℃；IR(KBr)cm
-1：3447(OH)，2927，2875(CH
2)，1661(C＝O)；
1H?NMR(DMSO-d
6)：δ2.24(m，4H，2(CH
2))，3.65(m，4H，2(CH
2Br))，4.08(m，4H，2(OCH
2))，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)。
Embodiment five: 4 ', 5, the preparation of 7-three-(3-bromine propoxy-)-isoflavones (5)
Genistein (0.27g, 1mmol), 1, the 3-dibromopropane (15.3g, 75mmol), K
2CO
3(0.49g 3.5mmol) is dissolved among the DMF of 60ml, 80 ℃ under the effect of 40Hz ultrasonic wave, react 4 hours (or 80 ℃ of following heated and stirred reactions 48 hours).After reaction is finished, the reaction mixture cool to room temperature, behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains colourless acicular crystal in the acetone, productive rate 90%.Mp?110-112℃；IR(KBr)cm
-1：3447(OH)，2930，2874(CH
2)，1644(C＝O)；
1H?NMR(DMSO-d
6)：δ2.22(m，6H，3(CH
2))，3.66(m，4H，2(CH
2Br))，3.82(t，2H，CH
2Br)，4.08(m，4H，2(OCH
2))，4.23(t，2H，OCH
2)，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)。
Embodiment six: 4 ', 5-dihydroxyl-7-[2-(2-hydroxyl ethylmercapto group)-oxyethyl group]-preparation of isoflavones (6)
With 4 ', 5-dihydroxyl-7-(2-bromine oxethyl)-isoflavones (0.37g, 1mmol), mercaptoethanol (0.15g, 2mmol), triethylamine (0.11g, 1mmol) be dissolved in the ethanol of 50ml, 48 ℃ under the effect of 40Hz ultrasonic wave, react 2 hours (or 48 ℃ of following heated and stirred reactions 12 hours).After reaction was finished, the reaction mixture underpressure distillation obtained faint yellow solid, and after washing with water, recrystallization obtains white needle-like crystals in the acetone, productive rate 85%.Mp?132-135℃；IR(KBr)cm
-1：3420(OH)，2926(CH
2)，1664(C＝O)1047(C-OH)；
1H?NMR(DMSO-d
6)：δ?2.66(t，2H，CH
2-S)，2.91(t，2H，S-CH
2)，3.55(q，2H，CH
2-O)，4.24(t，2H，OCH
2)，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?C
19H
18O
6S?374.0818，found，374.1095，[M+H]
+375.1173，[2M+Na]
+771.2198。
Embodiment seven: 5-hydroxyl-4 ' and, the preparation of 7-two-[2-(2-hydroxyl ethylmercapto group)-oxyethyl group]-isoflavones (7)
With 5-hydroxyl-4 ', 7-two-(2-bromine oxethyl)-isoflavones (0.48g, 1mmol), mercaptoethanol (0.30g.4mmol), triethylamine (0.22g 2mmol) is dissolved in the ethanol of 50ml, 48 ℃ under the effect of 40Hz ultrasonic wave, react 2 hours (or 48 ℃ of following heated and stirred reactions 12 hours).After reaction was finished, the reaction mixture underpressure distillation obtained faint yellow solid, and after washing with water, recrystallization obtains white needle-like crystals in the acetone, productive rate 80%.Mp?66-68℃；IR(KBr)cm
-1：3431(OH)，2924，2854(CH
2)，1663(C＝O)，1048(C-OH)；
1H?NMR(DMSO-d
6)：δ2.66(t，4H，2(CH
2-S))，2.90(q，4H，2(S-CH
2))，3.55(q，4H，2(CH
2-O))，4.15(t，2H，OCH
2)，4.25(t，2H，OCH
2)，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?C
23H
26O
7S
2?478.1111，found，478.1499，[M+H]
+479.1577，[M+Na]
+501.1599，[2M+Na]
+979.2706，[2M+K]
+995.2557。
Embodiment eight: 4 ', 5-dihydroxyl-7-[3-(2-hydroxyl ethylmercapto group)-propoxy-]-preparation of isoflavones (7)
With 4 ', 5-dihydroxyl-7-(3-bromine propoxy-)-isoflavones (0.39g, 1mmol), mercaptoethanol (0.15g, 2mmol), triethylamine (0.11g, 1mmol) be dissolved in the ethanol of 30ml, 48 ℃ under the effect of 40Hz ultrasonic wave, react 2 hours (or 40 ℃ of following heated and stirred reactions 12 hours).After reaction was finished, the reaction mixture underpressure distillation obtained faint yellow solid, and after washing with water, recrystallization obtains white needle-like crystals in the acetone, productive rate 85%.Mp?152-154℃；IR(KBr)cm
-1：3434(OH)，2942，2920，2876(CH
2)，1664(C＝O)，1042(C-OH)；
1H?NMR(DMSO-d
6)：δ1.95(m，2H，CH
2)，2.56(t，2H，CH
2-S)，2.64(t，2H，S-CH
2)，3.50(q，2H，CH
2-O)，4.14(t，2H，OCH
2)，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?C
20H
20O
6S388.0974，found，388.143，[M+H]
+389.1221，[2M+Na]
+799.1726。
Embodiment nine: 5-hydroxyl-4 ' and, the preparation of 7-two-[3-(2-hydroxyl ethylmercapto group)-propoxy-]-isoflavones (9)
With 5-hydroxyl-4 ', 7-two-(3-bromine propoxy-)-isoflavones (0.51g, 1mmol), mercaptoethanol (0.30g, 4mmol), (0.22g 2mmol) is dissolved in the ethanol of 30ml triethylamine, 48 ℃ under the effect of 40Hz ultrasonic wave, react 2 hours (or 48 ℃ of following heated and stirred reactions 12 hours).After reaction was finished, the reaction mixture underpressure distillation obtained faint yellow solid, and after washing with water, recrystallization obtains colourless acicular crystal in the acetone, productive rate 80%.Mp?102-105℃；IR(KBr)cm
-1：3421(OH)，2923，2877(CH
2)，1671(C＝O)，1049(C-OH)；
1H?NMR(DMSO-d
6)：δ1.93(m，4H，2(CH
2))，2.56(t，4H，2(CH
2-S))，2.64(m，4H，2(s-CH
2))，3.51(t，4H，2(CH
2-O))，4.14(t，4H，2(OCH
2))，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?C
25H
30O
7S
2?506.1423，found，506.1587，[M+H]
+507.1665，[M+Na]
+529.1236，[2M+Na]
+1035.6531。
Embodiment ten: 4 ', 5, the preparation of 7-three-[3-(2-hydroxyl ethylmercapto group)-propoxy-]-isoflavones (10)
With 4 ', 5, and 7-three-(3-bromine propoxy-)-isoflavones (0.63g, 1mmol), mercaptoethanol (0.30g, 4mmol), triethylamine (0.33g, 3mmol) be dissolved in the ethanol of 30ml, 48 ℃ under the effect of 40Hz ultrasonic wave, react 2 hours (or 48 ℃ of following heated and stirred reactions 12 hours).After reaction was finished, the reaction mixture underpressure distillation obtained faint yellow solid, and after washing with water, recrystallization obtains colourless acicular crystal in the acetone, productive rate 80%.Mp?78-80℃；IR(KBr)cm
-1：3430?(OH)，2922，2872(CH
2)，1639(C＝O)，1051(C-OH)；
1H?NMR(DMSO-d
6)：δ1.96(m，6H，3(CH
2))，2.56(m，6H，3(CH
2-S))，2.66(m，4H，2(S-CH
2))，2.78(t，2H，S-CH
2)，3.51(m，6H，3(CH
2-O))，4.06(m，4H，2(OCH
2))，4.16(t，2H，OCH
2)，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?C
30H
40O
8S
3624.1872，found，624.2096，[M+H]
+625.2174，[M+Na]
+647.1933，[2M+Na]
+1272.3999。
Embodiment 11: tribromide-4 ', 5, the preparation of 7-three-[3-(N-pyridyl)-propoxy-]-isoflavones (11)
With 4 ', 5, and 7-three-(3-bromine propoxy-)-isoflavones (0.63g, 1mmol), anhydrous pyridine 10ml, 160 ℃ of reactions 2 hours down.After reaction was finished, the reaction mixture underpressure distillation obtained faint yellow solid, and after washing with alcohol, recrystallization obtains colourless acicular crystal in the water, productive rate 80%.260 ℃ of Mp (dec.);
1H NMR (D
2O): δ 2.45-2.51 (m, 6H, 3 (CH
2)), 4.06-4.13 (m, 6H, 3 (OCH
2), 4.70-4.80 (m, 6H, 3 (CH
2-N
+), 6.24 (d, 1H, H-8), 6.51 (d, 1H, H-6), and 6.85 (d, 2H, H-3 ', H-5 '), 7.27 (d, 2H, H-2 ', H-6 '), 8.32 (s, 1H, H-2); (on the pyridine ring) 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)).
Embodiment 12: 4 ') 5-dihydroxyl-7-methoxyl group isoflavones-3 '-preparation of sulfonic acid (12)
Vitriol oil 0.5ml with 98%, 4 ', (0.28g 1mmol) is placed in the Erlenmeyer flask 5-dihydroxyl-7-methoxyl group isoflavones, at 0 ℃, under the effect of 25Hz ultrasonic wave, react 0.5 hour (or 0 ℃ of following heated and stirred reaction 8 hours), after reaction was finished, the reaction mixture thin up obtained white solid, solid water recrystallization obtains white needle-like crystals, productive rate 80%.Mp?365℃(dec.)；IR(KBr)cm
-1：3419(OH)，2956(CH
3)，1655(C＝O)，1179(S＝O)；
1H?NMR(DMSO-d
6)：δ3.86(s，3H，7-OCH
3)，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?C
16H
12O
8S?364.0248，found，364.0343，[M-H]
-363.0256(negative?ion?mode)。Compound 12 usefulness NaOH neutralization obtains its corresponding sodium salts.
Embodiment 13: 5-hydroxyl-4 ', 7-dimethoxy isoflavones-3 '-preparation of sulfonic acid (13)
Vitriol oil 0.5ml with 98%, 4 ', (0.30g 1mmol) is placed in the Erlenmeyer flask 7-dimethoxy-5-hydroxyl-isoflavones, at 0 ℃, under the effect of 25Hz ultrasonic wave, react 0.5 hour (or 0 ℃ of following heated and stirred reaction 8 hours), after reaction was finished, the reaction mixture thin up obtained white solid, solid water recrystallization obtains white needle-like crystals, productive rate 85%.Mp360℃(dec.)；IR(KBr)cm
-1：3421(OH)，2957(CH
3)，1654(C＝O)，1199(S＝O)；
1H?NMR(DMSO-d
6)：δ3.78(s，3H，7-OCH
3)，3.86(s，3H，4′-OCH
3)，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?C
17H
14O
8S?378.0404，found，378.0410，[M-H]
-377.0332(negativeion?mode)。Compound 13 usefulness NaOH neutralization obtains its corresponding sodium salts.
Embodiment 14: 4 ', 5,7-trimethoxy isoflavones-3 '-preparation of sulfonic acid (14)
Vitriol oil 0.5ml with 98%, 4 ', 5,7-trimethoxy isoflavones (0.31g, 1mmol) be placed in the Erlenmeyer flask, at 0 ℃, under the effect of 25Hz ultrasonic wave, react 0.5 hour (or 0 ℃ of following heated and stirred reaction 8 hours), after reaction is finished, the reaction mixture thin up obtains white solid, and solid water recrystallization obtains white needle-like crystals, productive rate 85%.Mp?360℃(dec.)；IR(KBr)cm
-1：3431(OH)，2955(CH
3)，1653(C＝O)1180(S＝O)；
1H?NMR(DMSO-d
6)：δ3.66(s，3H，5-OCH
3)，3.72(s，3H，7-OCH
3)，3.81(s，3H，4′-OCH
3)，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?C
18H
16O
8S?392.0560，found，392.0515，[M+H]
+393.0593。Compound 14 usefulness NaOH neutralization obtains its corresponding sodium salts.
Embodiment 15: 4 ', the preparation of 5-dihydroxyl-7-(2-bromine oxethyl)-isoflavones-3 '-sulfonic acid (15)
Vitriol oil 0.5ml with 98%, 4 ', (0.37g 1mmol) is placed in the Erlenmeyer flask 5-dihydroxyl-7-(2-bromine oxethyl)-isoflavones, at 0 ℃, under the effect of 25Hz ultrasonic wave, react 0.5 hour (or 0 ℃ of following heated and stirred reaction 8 hours), after reaction was finished, the reaction mixture thin up obtained white solid, solid water recrystallization obtains white needle-like crystals, productive rate 78%.Mp?347℃(dec.)；
1H?NMR(DMSO-d
6+D
2O)：δ?3.57(t，2H，CH
2Br)，4.17(t，2H，OCH
2)，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)。Compound 15 usefulness NaOH neutralization obtains its corresponding sodium salts.
Embodiment 16: 4 ', the preparation of 5-dihydroxyl-7-(3-bromine propoxy-)-isoflavones-3 '-sulfonic acid (16)
Vitriol oil 0.5ml with 98%, 4 ', 5-dihydroxyl-7-(3-bromine propoxy-)-(0.39g 1mmol) is placed in the Erlenmeyer flask isoflavones, at 0 ℃, under the effect of 40Hz ultrasonic wave, react 0.5 hour (or 0 ℃ of following heated and stirred reaction 10 hours), after reaction was finished, the reaction mixture thin up obtained white solid, solid water recrystallization obtains white needle-like crystals, productive rate 76%.Mp?344℃(dec.)；
1H?NMR(DMSO-d
6)：δ2.27(m，2H，CH
2)，3.64(t，2H，CH
2Br)，4.22(t，2H，OCH
2)，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，5-OH)。Compound 16 usefulness NaOH neutralization obtains its corresponding sodium salts.
Embodiment 17: 5-hydroxyl-4 ' and, the preparation of 7-two-(3-bromine propoxy-)-isoflavones-3 '-sulfonic acid (17)
Vitriol oil 0.5ml with 98%, 5-hydroxyl-4 ', 7-two-(0.51g 1mmol) is placed in the Erlenmeyer flask (3-bromine propoxy-)-isoflavones, at 0 ℃, under the effect of 40Hz ultrasonic wave, react 0.5 hour (or 0 ℃ of following heated and stirred reaction 8 hours), after reaction was finished, the reaction mixture thin up obtained white solid, solid water recrystallization obtains white needle-like crystals, productive rate 73%.Mp312℃(dec.)；
1H?NMR(D
2O)：δ2.33(m，4H，2CH
2)，3.65(t，2H，CH
2Br)，3.82(t，2H，CH
2Br)，4.22(t，2H，OCH
2)，4.30(t，2H，OCH
2)，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。Compound 17 usefulness NaOH neutralization obtains its corresponding sodium salts.
Embodiment 18: genistein derivative of the present invention is to osteoporosis prevention and result of treatment
In order to estimate the action effect of general formula (I) compound to bone, utilize ovariectomized rat to carry out the activity in vivo evaluation as model, simultaneously the good compound of activity has been carried out acute toxicity test, experimental result such as Fig. 1, shown in table 2 and the table 3:
Table 2. genistein and derivative thereof are to the action effect of bone
The bone of the bone right side femur of right side femur
Group compound uterus weight (g)
Density (g/cm
2) mineral content (g)
a 6 0.284±0.015 0.2589±0.002 0.0661±0.008
b 7 0.281±0.006 0.2614±0.003 0.0704±0.006
c 8 0.287±0.008 0.2577±0.002 0.0714±0.007
d 9 0.279±0.016 0.2592±0.004 0.0650±0.004
e 10 0.290±0.010 0.2674±0.002 0.0599±0.006
f 12 0.278±0.007 0.2516±0.002 0.0741±0.008
g 13 0.286±0.011 0.2602±0.001 0.0589±0.008
h 14 0.283±0.014 0.2641±0.002 0.0629±0.009
I genistein 0.268 ± 0.011 0.2411 ± 0.004 0.0701 ± 0.005
j E
2 0.295±0.007 0.2620±0.003 0.2647±0.030
Ovx - 0.233±0.012 0.2045±0.003 0.0633±0.008
Sham - 0.319±0.010 0.3010±0.003 0.3549±0.015
In table 2, the rat of oophorectomize group a in the h group gavages corresponding test compounds (25 μ mol/kg) every day respectively, oophorectomize group i gavages parent compound genistein (25 μ mol/kg) as positive control every day, oophorectomize j organizes and gavages estradiol (17 β-Estradiol, E every day
2) (0.5 μ mol/kg) as positive control.The Ovx group gavages reagent blank for the oophorectomize group.The Sham group is sham operated rats, and spay does not gavage reagent blank.Experiment is carried out after two months, and rat is carried out every index determining by disconnected neck execution.Bone density uses Lunar DPX-IQ Dual-energy X-ray Densitometer to measure, and the data results in the table is expressed as mean ± SEM (n=6).The result shows that the rat of Ovx group has descended 27% than the sham operated rats bone density, bone mineral content 32% (p＜0.01) that descended; E group (gavaging test compounds 10) has increased by 24% than the rat bone density of Ovx group, and bone mineral content has increased by 31% (p＜0.01); The rat of e group (gavaging test compounds 10) has increased by 8% than i group (gavaging the parent compound genistein) bone density, and bone mineral content has increased by 11% (p＜0.01).The result shows that simultaneously test compounds does not produce remarkable influence to the uterus of rat, but estradiol has increased the uterus weight of rat significantly.
The acute toxicity test result of table 3. genistein and main reactive derivative thereof
Every group of mouse number of group test-compound dosage (mg/kg)
1 10 genisteins 7290
2 10 6 10098
3 10 7 12906
4 10 8 10476
5 10 10 16848
6 10 13 10800
In table 3, test compounds is measured in showing in the experiment of limiting the quantity of accordingly, does not all have dead example.Show the not only mineral content of bone density improving and bone significantly of these compounds, and be nontoxic, get a good chance of becoming prevention and treat osteoporotic medicine.
Claims (9)
1. genistein derivative is characterized in that it has following general formula:
In the formula: R
1, R
2, R
3=-H or-(CH
2)
nX, wherein: n=1～6, X=-H, halogen, alkylthio or tertiary amine base, R
4=-H or-SO
3H.
2. genistein derivative according to claim 1 is characterized in that described halogen is a bromine.
3. genistein derivative according to claim 1 is characterized in that described alkylthio is a 2-hydroxyl ethylmercapto group.
4. genistein derivative according to claim 1 is characterized in that described tertiary amine base is the N-pyridyl.
5. the method for making of the described genistein derivative of claim 1 is characterized in that: with genistein and alpha-halogen alkane or α, ω-saturated dihalide was 40～80 ℃ of reactions 8～48 hours, and making X is the genistein derivative of H or halogen.
6. the method for making of the described genistein derivative of claim 1 is characterized in that: with X is that the genistein derivative and the mercaptan of H or halogen made the genistein derivative that X is alkylthio or tertiary amine base 48 ℃ of reactions 12 hours or with tertiary amine in 2 hours 160 ℃ of reactions.
7. the method for making of the described genistein derivative of claim 1 is characterized in that: the genistein derivative that claim 5 and 6 is made and the vitriol oil make R 0 ℃ of reaction 8～10 hours
4Be sulfonic genistein derivative.
8. according to the method for making of claim 5,6 or 7 described genistein derivatives, it is characterized in that using the ultrasonic wave assisted reaction, to shorten the reaction times.
9. the application of the described genistein derivative of claim 1 in preparation treatment osteoporosis agents.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100411575A CN100351248C (en) | 2004-07-05 | 2004-07-05 | Genistein derivatives and their preparation process and use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100411575A CN100351248C (en) | 2004-07-05 | 2004-07-05 | Genistein derivatives and their preparation process and use |
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| CN100351248C CN100351248C (en) | 2007-11-28 |
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| Application Number | Title | Priority Date | Filing Date |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007099432A2 (en) | 2006-02-28 | 2007-09-07 | Council Of Scientific And Industrial Research | Pharmaceutical composition containing butea isoflavones for the prevention /treatment of bone disorders and a process for the preparation thereof |
| CN100462361C (en) * | 2007-01-31 | 2009-02-18 | 陕西师范大学 | Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use |
| US7618998B2 (en) | 2008-02-26 | 2009-11-17 | Kaosiung Medical University | Isoflavone derivatives and pharmaceutical compositions comprising the same |
| CN102161648A (en) * | 2011-02-18 | 2011-08-24 | 中国药科大学 | Preparation method and applications of isoflavone type compounds with selective estrogen receptor modulating activity |
| CN104193717A (en) * | 2014-09-25 | 2014-12-10 | 山东理工大学 | Preparation method and application of phenylpiperazine-containing genistein derivative |
| CN104262313A (en) * | 2014-09-25 | 2015-01-07 | 山东理工大学 | Preparation method of genistein derivative containing phenylpiperazine and antibacterial activity of genistein derivative containing phenylpiperazine |
| CN104311519A (en) * | 2014-09-23 | 2015-01-28 | 山东理工大学 | Preparation and application of functional food factor with gastric mucosal lesion protection effect |
| CN106065389A (en) * | 2016-08-08 | 2016-11-02 | 山东理工大学 | A kind of method promoting papain activity and the application in beer clarification thereof |
| CN106281935A (en) * | 2016-08-08 | 2017-01-04 | 山东理工大学 | A kind of method promoting neutral protease activity and the application in beer clarification thereof |
| CN106674182A (en) * | 2016-12-09 | 2017-05-17 | 郑州大学 | Formononetin derivative comprising dithiocarbamate, preparation method and application thereof to antitumor drugs |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES477270A1 (en) * | 1979-01-30 | 1979-10-16 | Farmasimes S A | Method for the preparation of derivatives of isoflavonas. (Machine-translation by Google Translate, not legally binding) |
| AUPO203996A0 (en) * | 1996-08-30 | 1996-09-26 | Novogen Research Pty Ltd | Therapeutic uses |
| IT1299191B1 (en) * | 1998-06-23 | 2000-02-29 | Sigma Tau Healthscience Spa | COMPOSITION TO PREVENT AND TREAT OSTEOPOROSIS AND ALTERATIONS RELATED TO MENOPAUSE |
| EP1370257B1 (en) * | 2001-03-15 | 2007-07-25 | DSM IP Assets B.V. | COMPOSITION FOR THE PREVENTION OF OSTEOPOROSIS consisting of A COMBINATION OF ISOFLAVONES AND POLYUNSATURATED FATTY ACIDS |
| IL148825A0 (en) * | 2002-03-21 | 2002-09-12 | Yeda Res & Dev | Derivatives of isoflavones |
-
2004
- 2004-07-05 CN CNB2004100411575A patent/CN100351248C/en not_active Expired - Fee Related
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007099432A3 (en) * | 2006-02-28 | 2007-11-22 | Council Scient Ind Res | Pharmaceutical composition containing butea isoflavones for the prevention /treatment of bone disorders and a process for the preparation thereof |
| WO2007099432A2 (en) | 2006-02-28 | 2007-09-07 | Council Of Scientific And Industrial Research | Pharmaceutical composition containing butea isoflavones for the prevention /treatment of bone disorders and a process for the preparation thereof |
| CN100462361C (en) * | 2007-01-31 | 2009-02-18 | 陕西师范大学 | Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use |
| US7618998B2 (en) | 2008-02-26 | 2009-11-17 | Kaosiung Medical University | Isoflavone derivatives and pharmaceutical compositions comprising the same |
| CN102161648A (en) * | 2011-02-18 | 2011-08-24 | 中国药科大学 | Preparation method and applications of isoflavone type compounds with selective estrogen receptor modulating activity |
| CN104311519A (en) * | 2014-09-23 | 2015-01-28 | 山东理工大学 | Preparation and application of functional food factor with gastric mucosal lesion protection effect |
| CN104311519B (en) * | 2014-09-23 | 2018-12-18 | 山东理工大学 | Functional food factor preparation and its application with mucosal lesion protective effect |
| CN104262313A (en) * | 2014-09-25 | 2015-01-07 | 山东理工大学 | Preparation method of genistein derivative containing phenylpiperazine and antibacterial activity of genistein derivative containing phenylpiperazine |
| CN104193717B (en) * | 2014-09-25 | 2018-02-02 | 山东理工大学 | The preparation method and applications of genistein derivative containing phenylpiperazine |
| CN104193717A (en) * | 2014-09-25 | 2014-12-10 | 山东理工大学 | Preparation method and application of phenylpiperazine-containing genistein derivative |
| CN106065389A (en) * | 2016-08-08 | 2016-11-02 | 山东理工大学 | A kind of method promoting papain activity and the application in beer clarification thereof |
| CN106281935A (en) * | 2016-08-08 | 2017-01-04 | 山东理工大学 | A kind of method promoting neutral protease activity and the application in beer clarification thereof |
| CN106674182A (en) * | 2016-12-09 | 2017-05-17 | 郑州大学 | Formononetin derivative comprising dithiocarbamate, preparation method and application thereof to antitumor drugs |
| CN106674182B (en) * | 2016-12-09 | 2018-09-04 | 郑州大学 | Formoononetin derivative, preparation method containing dithiocarbamates and its application in antitumor drug |
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| Publication number | Publication date |
|---|---|
| CN100351248C (en) | 2007-11-28 |
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