CN1603318A - Genistein derivatives and their preparation process and use - Google Patents

Genistein derivatives and their preparation process and use Download PDF

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CN1603318A
CN1603318A CN 200410041157 CN200410041157A CN1603318A CN 1603318 A CN1603318 A CN 1603318A CN 200410041157 CN200410041157 CN 200410041157 CN 200410041157 A CN200410041157 A CN 200410041157A CN 1603318 A CN1603318 A CN 1603318A
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genistein
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genistein derivative
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CN100351248C (en
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谭仁祥
王世范
李洋
吴俊华
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Nanjing University
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Nanjing University
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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

Genistein derivative and method for making thereof and purposes
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
Figure A20041004115700061
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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