CN100395242C - Naphthalene alkoxy and naphthaquinone kind pyrane carbonic glucoside compound and preparation process thereof - Google Patents

Naphthalene alkoxy and naphthaquinone kind pyrane carbonic glucoside compound and preparation process thereof Download PDF

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CN100395242C
CN100395242C CNB2006100273911A CN200610027391A CN100395242C CN 100395242 C CN100395242 C CN 100395242C CN B2006100273911 A CNB2006100273911 A CN B2006100273911A CN 200610027391 A CN200610027391 A CN 200610027391A CN 100395242 C CN100395242 C CN 100395242C
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naphthalene
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naphthaquinone
ethanoyl
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CN1861589A (en
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陈国荣
林丽
唐燕辉
薛佳
贺晓鹏
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East China University of Science and Technology
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Abstract

The present invention relates to a (hydrogen) naphthaquinone pyran carbon glucoside compound, an intermediate body for preparing the carbon glucoside compound and a of the naphthaquinone pyran carbon glucoside compound and the intermediate body. The carbon glucoside compound has the structures disclosed in the formula (1) or the formula (2); the intermediate body has the structure disclosed in the formula (3). through invitro pharmacological activity tests, a plurality of compounds display PTP1B inhibitory activity and good antineoplasmic activity; therefore, the naphthaquinone pyran carbon glucoside compound can be possibly used as a primer for further structural optimization to obtain a novel high efficiency low toxicity bioactive compound; the naphthaquinone pyran carbon glucoside compound has potential development prospect of new antidiabetic and antitumor medicines, wherein R1 is alkoxyl groups of C1 to Cx, and R is the formula.

Description

Alkoxynaphtalene and naphthaquinone kind pyrane carbonic glucoside compound and preparation method thereof
Technical field
The present invention relates to a kind of naphthoquinones class (naphthoquinones or naphthalene quinhydrones) carbon glycoside compound, the intermediate of the said naphthoquinones class carbon glycoside compound of preparation and their preparation method, specifically, relate to a kind of naphthoquinones class (naphthoquinones or naphthalene quinhydrones) pyrane glycoside compounds, the intermediate of the said naphthaquinone kind pyrane carbonic glucoside compound of preparation and their preparation method.
Background technology
Regianin (structure is suc as formula shown in the A for 5-hydroxyl-1,4-naphthoquinones) is present in the Chinese olive skin of walnut Chinese catalpa, and the Chinese olive skin that walnut is seized often uses as a kind of cancer therapy drug in traditional Chinese medical science prescription among the people.The regianin that extraction separation goes out from Juglans mandshurica is for S 180Solid tumor, mouse hydroperitoneum type liver cancer and spontaneous mammary cancer have obvious inhibiting activity.Regianin also has been applied to treat digestive system tumor, especially esophagus cancer, cancer of the stomach is all had significant curative effect.Regianin and its derivative 5,8-dihydroxyl naphthoquinones is a kind of toxin to fish, its LD 50Extremely low, it can play restraining effect in mitochondrial oxidative phosphorylation process, all is the inhibitor that energy shifts.Regianin can also add in makeup and the toothpaste in addition, uses as sterilant.Obviously the application of regianin is very extensive, more and more is subject to people's attention.
From the structure of regianin, the phenolic hydroxyl group of existing hydrogen-bond donor has the carbonyl of hydrogen bond receptor again, can good with acceptor in vivo interaction.But experimentation on animals finds that body weight obviously descended after mouse was taken such medicine, and the phenomenon of diarrhoea takes place.This shows,, limited its application clinically greatly, simultaneously because organism absorbs the relatively poor performance that also influences drug effect to it owing to the toxic side effect of himself although regianin has shown a lot of special physiologically actives.If it is carried out suitable structural modification, then might obtain low toxicity cancer therapy drug guide thing efficiently.
Figure C20061002739100061
According to document Chinese Chemical Letters, 2003,14 (5), 489-490 report, a kind of α that extracts in the skunk bush plant-Tetralone an intermediate of Sertraline analog derivative (suc as formula compound shown in the B) have good PTP1B and suppress active, IC 50Value is 66.7 μ mol/L, is the medicine of class potential treatment type ii diabetes and obesity.Journal of Pharmaceutical Science, 1978,67 (4), 562-563 has reported a class 1, the tetra-acetylated glycosides derivative of 4-naphthoquinones (suc as formula compound shown in C, D or the E) has good anti-Ehrilich ascites tumour activity.
Figure C20061002739100071
The carbon glycoside compound compound that to be glycosyl link to each other by " C-C " key with aglucon is compared with being connected with keys such as " C-S " by " C-O ", " C-N ", its stability higher (especially show resistance to enzymolysis and antimetabolic in vivo, and the external antiacid aspect of separating).
Given this, the present invention has designed and synthesized naphthoquinones class (naphthoquinones or naphthalene quinhydrones) pyrane glycoside compounds, for the exploitation of naphthoquinones class carbon glycoside new drug lays the foundation.
Summary of the invention
One of the object of the invention is, a kind of naphthoquinones class (naphthoquinones or naphthalene quinhydrones) pyrane glycoside compounds is provided;
Two of the object of the invention is, a kind of intermediate that is used to prepare said naphthaquinone kind pyrane carbonic glucoside compound is provided;
Three of the object of the invention is, a kind of method for preparing above-mentioned naphthaquinone kind pyrane carbonic glucoside compound is provided.
The said naphthoquinones class of the present invention (naphthoquinones or naphthalene quinhydrones) pyrane glycoside compounds, its structure is suc as formula shown in (1) or the formula (2):
Figure C20061002739100072
Or
Figure C20061002739100073
In formula (1) or the formula (2), R is
Figure C20061002739100074
Or
Wherein: Ac represents ethanoyl
Figure C20061002739100076
Below if no special instructions, Ac all represents ethanoyl.
A kind of intermediate that is used to prepare the said naphthaquinone kind pyrane carbonic glucoside compound of the present invention, its structure be as the formula (3):
In the formula (3), R is
Figure C20061002739100082
Or
R 1Be C 1-C 6Alkoxyl group.
In the present invention, preferred R 1Be C 1～C 3Alkoxyl group, best R 1Be methoxyl group (CH 3O).
The synthetic route of the synthetic said naphthaquinone kind pyrane carbonic glucoside compound of the present invention is as follows:
Figure C20061002739100084
Or
Figure C20061002739100091
Wherein: R 1Be C 1～C 6Alkoxyl group;
R aFor
Figure C20061002739100092
Or
Figure C20061002739100093
R bFor
Figure C20061002739100094
Or
Figure C20061002739100095
The method for preparing the said naphthaquinone kind pyrane carbonic glucoside compound of the present invention, its key step is: at first by 1,2,3,4,6-five-O-ethanoyl-β-D-Glucopyranose [compound (4)] or 1,2,3,4, reaction makes compound (3a) (one of said intermediate of the present invention) to dialkoxy naphthalene [compound (6)] for 6-five-O-ethanoyl-β-D-galactopyranose [compound (5)] and 1,4-; Then compound (3a) is made one of target compound, compound (1a) through oxidation, with compound (1a) through reduction make target compound two, compound (2a); At last with compound (1a) and compound (2a) respectively through alcoholysis make target compound three, compound (1b) and compound (2b).
Or, compound (3a) is earlier made compound (3b) (the said intermediate of the present invention two) through alcoholysis, and then compound (3b) is made target compound compound (1b) through oxidation.
Embodiment
(1) 1,4-dialkoxy-2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene and 1, the reaction of 4-dialkoxy-2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose) naphthalene:
With 1,2,3,4,6-five-O-ethanoyl-β-D-Glucopyranose or 1,2,3,4,6-five-O-ethanoyl-β-D-galactopyranose and 1,4-is dissolved in CH to dialkoxy naphthalene (recommend to use 1,4-is to dimethoxy-naphthalene) 2Cl 2Or CHCl 3, stir down and drop into trifluoroacetic acid silver (AgOTfa), drip SnCl then 4CH 2Cl 2Solution reacted 4-8 hour down at 15-60 ℃, and reaction product is through extraction, column chromatography and recrystallization separation and purification; obtain pale red brown solid 1 respectively; 4-dialkoxy-2-(2,3,4; 6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene or 1; 4-dialkoxy-2-(2,3,4; 6-four-O-ethanoyl-β-D-galactopyranose) naphthalene
Wherein, 1,2,3,4,6-five-O-ethanoyl-β-D-Glucopyranose or 1,2,3,4,6-five-O-ethanoyl-β-D-galactopyranose and 1,4-is to dialkoxy naphthalene, AgOTfa and SnCl 4Mol ratio be 1: (1.6～2.2): (1.0～1.6): (0.1～0.5), preferred mol ratio is 1: 2: 1.5: 0.1; Preferred temperature of reaction is 25 ℃～60 ℃; Recrystallization adopts mixed solvent: ether: sherwood oil is 2: 1 or methylene dichloride: ether is 3: 1 (volume ratio).
(2) 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthoquinones and 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthoquinones synthetic:
Will be by step (1) institute synthetic 1,4-dialkoxy-2-(2,3,4; 6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene or 1,4-dialkoxy-2-(2,3; 4,6-four-O-ethanoyl-β-D-galactopyranose) naphthalene is dissolved in acetonitrile or tetrahydrofuran (THF), adds ceric ammonium nitrate ((NH 4) 2Ce (NO 3) 6, aqueous solution CAN), stirring at room 40～100 minutes obtains target product 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1 respectively, 4-naphthoquinones or 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthoquinones.
Wherein, 1,4-dialkoxy-2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene or 1, the mol ratio of 4-dialkoxy-2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose) naphthalene and ceric ammonium nitrate is 1: (3～5), preferred 1: 3.
(3) 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene quinhydrones and 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthalene quinhydrones synthetic:
With step (2) the synthetic 2-of institute (2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthoquinones or 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1, the 4-naphthoquinones is dissolved in CHCl 3, add Sodium Hydrosulphite (Na 2S 2O 4) the aqueous solution; vigorous stirring is 15～45 minutes under the room temperature, and reactant gets pale red brown spumescence product behind extraction, column chromatography purification, and promptly 2-(2; 3; 4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene quinhydrones or 2-(2; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthalene quinhydrones.
Wherein, 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthoquinones or 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthoquinones and Na 2S 2O 4Mol ratio be 1: (4～8); Preferred mol ratio is 1: 6.
(4) 2-(β-D-Glucopyranose)-1,4-naphthalene (hydrogen) quinone and 2-(β-D-galactopyranose)-1,4-naphthalene (hydrogen) quinone synthetic:
A) remove protecting group under the alkaline condition:
With step (3) the synthetic 2-of institute (2; 3; 4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene (hydrogen) quinone or 2-(2; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthalene (hydrogen) quinone adds the methanol solution of sodium methylate under argon shield; stirred under the room temperature 30～90 minutes, and added excessive acidic cation-exchange resin IR-120 then +, agitation and filtration, filtrate decompression concentrate the back column chromatography purification and get sorrel syrupy shape product, i.e. 2-(β-D-Glucopyranose)-1,4-naphthalene (hydrogen) quinone or 2-(β-D-galactopyranose)-1,4-naphthalene (hydrogen) quinone;
Wherein, 2-(2,3,4; 6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene (hydrogen) quinone or 2-(2,3,4; 6-four-O-ethanoyl-β-D-galactopyranose)-1, the mol ratio of 4-naphthalene (hydrogen) quinone and sodium methylate is (5～8): 1, and preferred mol ratio is 6: 1.
B) remove protecting group under the acidic conditions:
With step (3) the synthetic 2-of institute (2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene (hydrogen) quinone or 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthalene (hydrogen) quinone adds the methanol solution of the Acetyl Chloride 98Min. of prepared fresh under argon shield, leave standstill or stir a week under the room temperature, removal of solvent under reduced pressure, residue gets sorrel syrupy shape product through column chromatography purification, i.e. 2-(β-D-Glucopyranose)-1,4-naphthalene (hydrogen) quinone or 2-(β-D-galactopyranose)-1,4-naphthalene (hydrogen) quinone;
Wherein, 2-(2,3,4; 6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene (hydrogen) quinone or 2-(2,3,4; 6-four-O-ethanoyl-β-D-galactopyranose)-1, the mol ratio of 4-naphthalene (hydrogen) quinone and Acetyl Chloride 98Min. is (6～10): 1, and preferred mol ratio is 8: 1.
Or:
With step (1) institute synthetic 1; 4-dialkoxy-2-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene or 1; 4-dialkoxy-2-(2,3,4; 6-four-O-ethanoyl-β-D-galactopyranose) naphthalene is dissolved in methyl alcohol; argon shield adds the methanol solution of sodium methylate down, stirring at room 30～60 minutes, and methyl alcohol is removed in decompression; residue through column chromatography purify white solid; promptly 1,4-dialkoxy-2-(β-D-Glucopyranose) naphthalene or 1,4-dimethoxy-2-(β-D-galactopyranose) naphthalene.
Wherein: 1,4-dialkoxy-2-(2,3,4; 6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene or 1,4-dimethoxy-2-(2,3; 4,6-four-O-ethanoyl-β-D-galactopyranose) mol ratio of naphthalene and sodium methylate is (6～10): 1, and preferred molar ratio is 8: 1.
With 1,4-dialkoxy-2-(β-D-Glucopyranose) naphthalene or 1,4-dimethoxy-2-(β-D-galactopyranose) naphthalene can make 2-(β-D-Glucopyranose)-1 through ceric ammonium nitrate (CAN) oxidation respectively, 4-naphthoquinones or 2-(β-D-galactopyranose)-1, the 4-naphthoquinones, specific as follows:
With 1,4-dialkoxy-2-(β-D-Glucopyranose) naphthalene or 1,4-dialkoxy-2-(β-D-galactopyranose) naphthalene adds the aqueous solution of ceric ammonium nitrate (CAN), stirring at room 40～90 minutes, decompression removes and anhydrates, and residue gets yellow solid through column chromatography purification, i.e. target product 2-(β-D-Glucopyranose)-1,4-naphthoquinones or 2-(β-D-galactopyranose)-1, the 4-naphthoquinones.
Wherein, 1,4-dialkoxy-2-(β-D-Glucopyranose) naphthalene or 1, the mol ratio of 4-dialkoxy-2-(β-D-galactopyranose) naphthalene and cerous ammonium nitrate is 1: (3～5), preferred mol ratio is 1: 3.
The biological activity glucosides of design of the present invention and synthetic carbon glycoside compound and natural or chemosynthesis has better chemical and structural similarity, glycosyl is naturally occurring glucose that has no side effect or semi-lactosi, and aglucon is the naphthoquinones with active carbonyl group, the naphthalene quinhydrones with hydrogen-bond donor effect phenolic hydroxyl group.Through external pharmacologically active test, wherein a plurality of compound exhibits PTP1B suppress activity and good antitumor activity, therefore be expected to carry out further composition optimizes as guide's thing, obtain the bioactive compounds of novel high-efficiency low-toxicity thus, have potential anti-diabetic, anti-cancer agent DEVELOPMENT PROSPECT.
Below will the invention will be further elaborated by embodiment, its purpose only is better to understand content of the present invention and unrestricted protection scope of the present invention.
Embodiment 1
Synthesizing of (1) 1,4-dimethoxy-2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene
With 342.1mg (0.8766mmol) 1,2,3,4,6-five-O-ethanoyl-β-D-Glucopyranose and 330.0mg (1.753mmol) 1,4-is dissolved in 10mL CH to methoxynaphthalene 2Cl 2, 25 ℃ of following lucifuge stirred for several minute to raw material dissolves fully, adds trifluoroacetic acid silver (AgOTfa) 290.44mg (1.315mmol) then, keeps 25 ℃, and argon shield drips SnCl down 4CH 2Cl 2Solution; sustained reaction 4～5 hours; TLC detects and shows the basic end of reaction; add the 14mL saturated sodium bicarbonate aqueous solution and stir 10～15min, suction filtration removes inorganics, and filtrate with dichloromethane extraction for several times; dichloromethane extraction liquid washs with saturated nacl aqueous solution; add anhydrous magnesium sulfate drying, suction filtration is removed sal epsom, and filtrate decompression is removed the rear pillar chromatographic separation of desolvating; eluent is for being followed successively by sherwood oil: ethyl acetate=2: 1 or 3: 2 (V/V) carry out elution; get 1,4-dimethoxy-2-(2,3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene gets pale red brown solid 274.1mg, yield 59.6% with the mixed solvent recrystallization of ether and sherwood oil.
The product test data are as follows:
Pale red brown solid, m.p.70-73 ℃ (ether/sherwood oil), [α] D 23.3=-17.3084 (c=0.5350, CHCl 3), Rf=0.45 (sherwood oil: ethyl acetate=2: 1, V/V)
1H-NMR (CDCl 3, 500.13MHz): δ 8.23,8.05 (2d, 2H, J=8.28 and 8.15Hz, Ar-H 5 ', H 8 '), 7.53 (m, 2H, Ar-H 6 ', H 7 '), 6.76 (s, 1H, Ar-H 3 '), 5.56 (t, 1H, J=9.41 and 10.07Hz, H 3), 5.44 (t, 1H, J=9.22 and 9.41Hz, H 4), 5.30 (t, 1H, J=10.15 and 9.22Hz, H 2), 5.13 (d, 1H, J=10.15Hz, H 1), 4.27 (dd, 1H, J=5.19 and 12.44Hz, H 6a), 4.15 (dd, 1H, J=1.95 and 12.44Hz, H 6b), 4.01 (s, 3H, OCH 3), 3.97 (m, 1H, H 5), 3.94 (s, 3H ,-OCH 3), 2.08,2.05,2.05,2.03 (4s, 12H ,-OAc).
13C-NMR(CDCl 3，125.77MHz)：171.35，171.02，170.33，169.78(4C，-C＝O，-OAc)，153.04(C 4’，Ar)，149.49(C 1’，Ar)，128.80，127.82，127.50，126.91，124.07，123.26，122.90(7C，C 3’，C 5’-C 10’，Ar)，102.12(C 2’)，77.08(C 5)，75.48(C 3)，74.88(C 1)，71.58(C 2)，69.60(C 4)，64.04，63.28(2C，-OCH 3)，56.42(C 6)，21.42，21.36，21.36，21.13(4C，-CH 3，-OAc)
MS(ESI)m/e[M+23] +541.1
HRMS (ESI) m/e[M+23] +541.1684, calculated value 541.1686
This compound inhibiting rate to protein-tyrosine-phosphatase 1B (PTP1B) when concentration is 500 μ M is 24.16%
Synthesizing of (2) 1,4-dimethoxy-2-(β-D-Glucopyranose) naphthalene
It is resulting 1 to get step (1), and 4-dimethoxy-2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene 91.5mg (0.1765mmol) is dissolved in 3mLCH 3OH adds 0.5mL0.1M CH 3The CH of ONa 3OH solution, stirring at room 35min, TLC show that reaction finishes.Column chromatography for separation behind the reaction solution concentrating under reduced pressure, eluent is: ethyl acetate: methyl alcohol=8: 1 (V/V), get 1,4-dimethoxy-2-(β-D-Glucopyranose) naphthalene is with the white crystal 60.1mg behind the anhydrous diethyl ether recrystallization, productive rate 97.17%.
The product test data are as follows:
White crystal, m.p.80-83 ℃ (ether), [α] D 22.6=2.3333 (c=0.54, CH 3OH), and Rf=0.40 (ethyl acetate: methyl alcohol=8: 1, V/V)
1H-NMR (D 2O, 500.13MHz): δ 8.20,8.07 (2d, 2H, J=8.26 and 8.30Hz, Ar-H 5 ', H 8 '), 7.60 (m, 2H, Ar-H 6 ', H 7 '), 6.96 (s, 1H, Ar-H 3 '), 4.87 (d, 1H, J=9.71Hz, H 1), 3.98 (s, 3H ,-OCH 3), 3.90 (s, 3H ,-OCH 3), 3.85～3.56 (2m, overlapping, 6H, H 2, H 3, H 4, H 5, H 6a, H 6b)
13C-NMR(D 2O，125.77MHz)：154.95(C 4’，Ar)，150.87(C 1’，Ar)，130.56，130.22，129.57，129.09，128.36，124.99，124.73(7C，C 3’，C 5’-C 10’，Ar)，105.36(C 2’，Ar)，83.12(C 5)，80.26(C 3)，78.27(C 1)，75.70(C 2)，72.64(C 4)，66.11，63.66(2C，-OCH 3)，58.77(C 6)
MS(ESI)m/e[M+23] +373.1
HRMS (ESI) m/e[M+23] +373.1259, calculated value 373.1263
(3) 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthoquinones synthetic:
Get step (1) resulting 1; 4-dimethoxy-2-(2; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose) naphthalene 280.0mg (0.5400mmol) is dissolved in the 2mL acetonitrile, adds cerous ammonium nitrate (CAN) 956.7mg (1.745mmol, aqueous solution 3mL 3eq); about 60 minutes of stirring at room, TLC shows that reaction finishes.Reaction solution organic phase behind dichloromethane extraction is washed anhydrous magnesium sulfate drying with saturated sodium-chloride water solution.Filter, filtrate decompression is removed the rear pillar chromatographic separation (sherwood oil: ethyl acetate=3: 2 (V/V)), obtain product 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthoquinones 219.8mg, productive rate 83.32% that desolvates.
The product test data are as follows:
Yellow needle-like crystal, m.p.159-162 ℃ (ether/sherwood oil), [α] D 23.1=-10.8966 (c=0.58, CHCl 3), Rf=0.55 (sherwood oil: ethyl acetate=3: 2, V/V)
1H-NMR (CDCl 3, 500.13MHz): δ 8.08 (m, 2H, Ar-H 5 ', H 8 '), 7.56 (m, 2H, Ar-H 6 ', H 7 '), 7.12 (s, 1H, Ar-H 3 '), 5.41 (t, 1H, J=10.17 and 8.57Hz, H 3), 5.18 (t, 1H, J=9.34 and 10.17Hz, H 4), 5.05 (t, 1H, J=9.78 and 9.34Hz, H 2), 4.87 (d, 1H, J=9.78Hz, H 1), 4.27 (dd, 1H, J=4.87 and 12.48Hz, H 6a), 4.16 (dd, 1H, J=2.0 and 12.48Hz, H 6b), 3.86 (m, 1H, H 5 '), 2.10,2.05,2.02,1.87 (4s, 12H ,-OAc).
13C-NMR (CDCl 3, 125.77MHz): 185.23,184.13 (2C ,-C=O, naphthoquinones), 171.35,170.78,170.33,170.21 (4C ,-C=O ,-OAc), 146.70 (C 2 '), 136.70,134.85,134.72,132.52,127.18,127.09 (6C, Ar), 77.01 (C 5), 74.50 (C 3), 73.33 (C 2), 72.88 (C 1), 69.06 (C 4), 62.77 (C 6), 21.44,21.31,21.30,21.14 (4C ,-CH 3,-OAc)
MS(ESI)m/e[M+23] +511.1
HRMS (ESI) m/e[M+23] +511.1218, calculated value 511.1216
Growth has good restraining effect, IC to this compound to 7402 (tumor cell lines) 50Value is 60 μ g/mL; Effective rapidly to A375 JEG-3 restraining effect, IC 50Value is 22.6 μ g/mL; Inhibiting rate to PTP1B when concentration is 500 μ M is 31.56%.
(4) 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene quinhydrones synthetic
Get the 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1 of step (3) gained, 4-naphthoquinones 103.6mg (0.2121mmol) is dissolved in the 5mL chloroform, adds Na 2S 2O 4256.9mg (vigorous stirring is 40～60 minutes under the room temperature for 1.475mmol, 7eq) aqueous solution 5mL, and TLC shows that reaction finishes.Isolate organic phase, water chloroform extraction 2 times, organic phase is washed through saturated sodium-chloride water solution, anhydrous MgSO 4Drying is filtered, filtrate decompression remove desolvate after column chromatography (methylene dichloride: ethyl acetate=4: 1 V/V) obtains 2-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene quinhydrones 47.6mg, productive rate 45.76%.
The product test data are as follows:
The light tan pulverulent solids, and Rf=0.32 (methylene dichloride: ethyl acetate=4: 1, V/V).
1H-NMR (CDCl 3, 500.13MHz): δ 8.24,8.04 (2m, 2H, Ar-H 5 ', H 8 '), 7.53 (m, 2H, Ar-H 6 ', H 7 '), 6.49 (s, 1H, Ar-H 3 '), 5.37 (m, 3H, H 2, H 3, H 4), 4.69 (d, 1H, J=9.54Hz, H 1), 4.37 (dd, 1H, J=3.76 and 12.56Hz, H 6a), 4.20 (dd, 1H, J=2.05 and 12.56Hz, H 6b), 3.93 (m, 1H, H 5), 2.16,2.08,2.01,1.84 (4s, 12H ,-OAc).
(5) 2-(β-D-Glucopyranose)-1,4-naphthalene quinhydrones synthetic
A) remove protecting group under the alkaline condition:
Get the 2-(2 of step (4) gained; 3; 4; 6-four-O-ethanoyl-β-D-Glucopyranose)-1; 4-naphthalene quinhydrones 129.4mg (0.2638mmol) adds the methanol solution of 0.5mL 0.1M sodium methylate under argon shield; stirred under the room temperature 30～40 minutes, TLC shows that reaction finishes, and adds slightly excessive acidic cation-exchange resin IR-120 then +, stir 15 minutes after-filtration, filtrate decompression concentrates after column chromatography purification (eluent is an ethyl acetate: methyl alcohol=8: 1) 2-(β-D-Glucopyranose)-1,4-naphthalene quinhydrones 78.3mg, productive rate 92.1%.
B) remove protecting group under the acidic conditions:
Get the 2-(2 of step (4) gained, 3,4,6-four-O-ethanoyl-β-D-Glucopyranose)-1,4-naphthalene quinhydrones 321.5mg (0.6555mmol) is dissolved in 10mL methyl alcohol, the Acetyl Chloride 98Min. that under argon shield, adds the 0.8mL prepared fresh, leave standstill or stir a week under the room temperature, removal of solvent under reduced pressure, residue is through column chromatography purification (ethyl acetate: methyl alcohol=8: 1) get 2-(β-D-Glucopyranose)-1,4-naphthalene quinhydrones 146.9mg, productive rate 69.53%;
The product test data are as follows:
The sorrel syrup, and Rf=0.38 (ethyl acetate: methyl alcohol=8: 1, V/V)
1H-NMR (D 2O, 500.13MHz): δ 8.13 (m, 2H, Ar-H 5 ', H 8 '), 7.56 (m, 2H, Ar-H 6 ', H 7 '), 6.89 (s, 1H, Ar-H 3 '), 4.88 (d, 1H, J=9.71Hz, H 1), 3.85 (m, 1H, H 6b), 3.77 (dd, 1H, J=4.53 and 8.85Hz, H 6a), 3.75～3.57 (2m, overlapping, 4H, H 2, H 3, H 4, H 5).
(6) 2-(β-D-Glucopyranose)-1,4-naphthoquinones synthetic
A) ceric ammonium nitrate (CAN) oxidation style:
Get 1 of step (2) gained, 4-dimethoxy-2-(β-D-Glucopyranose) naphthalene 392.6mg (1.121mmol), add CAN (1.843g, 3.362mmol) the aqueous solution, stirring at room 60～90 minutes, decompression removes anhydrates, the residue column chromatography purification (chloroform: methyl alcohol=8: 1) again through the preparation plate layer chromatography separate 2-(β-D-Glucopyranose)-1,4-naphthoquinones (formula 7), red-brown soup compound 285.8mg, productive rate 79.5%.
B) silver suboxide oxidation style:
Get the 2-(β-D-Glucopyranose)-1 of step (5) gained, 4-naphthalene quinhydrones 141.9mg (O.4403mmol) is dissolved in 2mL Virahol (or trimethyl carbinol), adds the silver suboxide (Ag of prepared fresh 2O) (3.742mmol 8.5eq), stirred under the room temperature 2～4 hours 867.2mg, solids removed by filtration, filtrate decompression is concentrated, and (ethyl acetate: methyl alcohol=8: 1 V/V) gets 2-(β-D-Glucopyranose)-1 through the column chromatography purification, 4-naphthoquinones 15.2mg, productive rate 10.78%.
The product test data are as follows:
The red-brown soup compound, and Rf=0.42 (chloroform: methyl alcohol=6: 1, V/V)
1H-NMR (D 2O, 500.13MHz): δ 8.03,7.98 (2m, 2H, Ar-H 5 ', H 8 '), 7.81 (m, 2H, Ar-H 6 ', H 7 '), 7.13 (s, 1H, Ar-H 3 '), 4.64 (d, 1H, J=9.52Hz, H 1), 3.88 (dd, 1H, J=1.28 and 11.37Hz, H 6a), 3.75 (dd, 1H, J=5.05 and 12.40Hz, H 6b), 3.61 (t, 1H, J=8.72Hz, H 3), 3.57～3.50 (m, overlapping, 3H, H 2, H 4, H 5).
13C-NMR (D 2O, 125.77MHz): 189.56,187.52 (2C ,-C=O, naphthoquinones), 150.50 (C 2 ', Ar), 138.98 (C 3 ', Ar), 137.50,137.29 (2C, C 7 ', C 8 ', Ar), 134.21,133.79 (2C, C 9 ', C 10 ', Ar), 129.41,128.77 (2C, C 5 ', C 6 ', Ar), 82.96 (C 5), 79.98 (C 3), 77.18 (C 2), 76.44 (C 1), 72.40 (C 4), 63.63 (C 6)
MS(ESI)m/e[M+23] +343.1
HRMS (ESI) m/e[M+23] +343.0793, calculated value 343.0794
This compound inhibiting rate to PTP1B when concentration is 20 μ g/mL is 23.9%.
Embodiment 2
Synthesizing of (1) 1,4-dimethoxy-2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose) naphthalene
Operate identically, obtain 1 with embodiment 1 corresponding part step (1), 4-dimethoxy-2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose) naphthalene, productive rate is 65.0%.
The product test data are as follows:
Pale red brown solid, m.p.109-112 ℃ (ether/sherwood oil), [α] D 23.1=+6.9453 (c=3.855, CHCl 3), Rf=0.45 (sherwood oil: ethyl acetate=2: 1, V/V)
1H-NMR (CDCl 3, 500.13MHz): δ 8.24,8.06 (2d, 2H, J=8.21 and 8.10Hz, Ar-H 5 ', H 8 '), 7.63 (m, 2H, Ar-H 6 ', H 7 '), 6.81 (s, 1H, Ar-H 3 '), 5.73 (t, 1H, J=9.91 and 10.07Hz, H 2), 5.58 (d, 1H, J=3.09Hz, H 4), 5.29 (dd, 1H, J=3.09 and 9.91Hz, H 3), 5.10 (d, 1H, J=10.07Hz, H 1), 4.21～4.13 (m, overlapping, 3H, H 5, H 6a, H 6b), 4.02,3.95 (2s, 6H ,-OCH 3), 2.26,2.02,2.01,1.73 (4s, 12H ,-OAc).
13C-NMR(CDCl 3，125.77MHz)：171.11，171.01，170.86，169.84(4C，-C＝O，-OAc)，152.94(C 4’，Ar)，149.51(C 1’，Ar)，128.82，127.79，127.44，126.84，124.35，123.24，122.89(7C，C 3’，C 5’-C 10’，Ar)，102.54(C 2’)，75.72(C 5)，75.57(C 1)，73.36(C 3)，68.88(C 2)，68.73(C 4)，64.00，62.55(2C，-OCH 3)，56.40(C 6)，21.50，21.34，21.31，21.21(4C，-CH 3，-OAc)
MS(ESI)m/e[M+23] +541.1
HRMS (ESI) m/e[M+Na] +541.1685, calculated value 541.1686
Synthesizing of (2) 1,4-dimethoxy-2-(β-D-galactopyranose) naphthalene
Operate identically, obtain 1 with embodiment 1 corresponding part step (2), 4-dimethoxy-2-(β-D-Glucopyranose) naphthalene, productive rate is 58.91%.
The product test data are as follows:
White crystal, m.p.70-72 ℃ (ether), [α] D 22.7=+5.1524 (c=1.05, CH 3OH), and Rf=0.40 (be ethyl acetate: methyl alcohol=8: 1, V/V)
1H-NMR (D 2O, 500.13MHz): δ 8.21,8.08 (2d, 2H, J=8.43 and 8.21Hz, Ar-H 5 ', H 8 '), 7.60 (m, 2H, Ar-H 6 ', H 7 '), 7.09 (s, 1H, Ar-H 3 '), 4.83 (d, 1H, J=9.76Hz, H 1), 4.08 (d, 1H, J=3.3Hz, H 4), 4.02 (t, 1H, J=9.76 and 11.4Hz, H 2), 4.00,3.91 (2s, 6H ,-OCH 3), 3.89 (m, 1H, H 5), 3.83 (dd, 1H, J=7.5 and 3.37Hz, H 3), 3.72 (d, overlapping, 2H, H 6a, H 6b)
13C-NMR(D 2O，125.77MHz)：154.87(C 4’，Ar)，150.68(C 1’，Ar)，130.46，129.87，129.14，128.97，128.67，124.80，124.73(7C，C 3’，C 5’-C 10’，Ar)，105.47(C 2’，Ar)，82.00(C 5)，78.68(C 3)，77.11(C 1)，73.10(C 2)，72.00(C 4)，65.97，63.83(2C，-OCH 3)，58.68(C 6)
MS(ESI)m/e[M+23] +373.0
HRMS (ESI) m/e[M+23] +373.1265, calculated value 373.1263
(3) 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthoquinones synthetic
Operate identically with embodiment 1 corresponding part step (3), obtain 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthoquinones, productive rate are 94.85%.
The product test data are as follows:
Yellow needle-like crystal, m.p.109-112 ℃ (ether/sherwood oil), [α] D 23.3=+4.8684 (c=0.5850, CHCl 3), Rf=0.55 (sherwood oil: ethyl acetate=3: 2, V/V)
1H-NMR (CDCl 3, 500.13MHz): δ 8.09 (m, 2H, Ar-H 5 ', H 8 '), 7.77 (m, 2H, Ar-H 6 ', H 7 '), 7.21 (s, 1H, Ar-H 3 '), 5.53 (d, 1H, J=2.67Hz, H 4), 5.25 (dd, 1H, J=10.14 and 3.2Hz, H 3), 5.19 (t, 1H, J=10.14and 9.21Hz, H 2), 4.86 (d, 1H, J=9.21Hz, H 1), 4.19～4.06 (m, overlapping, 3H, H 6a, H 6b, H 5), 2.21,2.05,2.00,1.88 (4s, 12H ,-OAc).
13C-NMR (CDCl 3, 125.77MHz): 185.43,184.28 (2C ,-C=O, naphthoquinones), 171.09,170.88,170.64,170.59 (4C ,-C=O ,-OAc), 147.24 (C 2 '), 136.89,134.81,134.69,132.53,127.14,127.04 (6C, Ar), 75.48 (C 5), 72.95 (C 3), 72.45 (C 2), 70.86 (C 1), 68.20 (C 4), 62.43 (C 6), 21.38,21.38,21.26,21.22 (4C ,-CH 3,-OAc)
MS(ESI)m/e[M+23] +511.1
HRMS (ESI) m/e[M+23] +511.1172, calculated value 511.1216
This compound obviously suppresses 7402 (tumor cell lines) growth, and hexyl originally killed all cells when concentration was 50 μ g/ml, its IC 50Value is 33 μ g/mL; Restraining effect to the survival of A375 JEG-3 is effective rapidly, IC 50Value is 30.38 μ g/mL; Inhibiting rate to PTP1B when concentration is 20 μ g/mL is 10.8%.
(4) 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthalene quinhydrones synthetic
Operate identically with embodiment 1 corresponding part step (4), obtain 2-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose)-1,4-naphthalene quinhydrones, productive rate are 69.81%.
The product test data are as follows:
The light tan pulverulent solids, and Rf=0.32 (methylene dichloride: ethyl acetate=4: 1, V/V).
1H-NMR (CDCl 3, 500.13MHz): δ 8.25,8.04 (2m, 2H, Ar-H 5 ', H 8 '), 7.53 (m, 2H, Ar-H 6 ', H 7 '), 6.50 (s, 1H, Ar-H 3 '), 5.66 (t, 1H, J=10.08 and 9.88Hz, H 2), 5.58 (d, 1H, J=3.12Hz, H 4), 5.20 (dd, 1H, J=10.08 and 3.2Hz, H 3), 4.57 (d, 1H, J=9.88Hz, H 1), 4.22 (dd, 2H, J=1.57 and 7.21Hz, H 6a, H 6b), 4.13 (m, 1H, H 5), 2.27,2.21,2.06,1.84 (4s, 12H ,-OAc).
(5) 2-(β-D-galactopyranose)-1,4-naphthalene quinhydrones synthetic
Remove protecting group under the alkaline condition:
Operate identical with embodiment 1 corresponding part step (5), 2-(β-D-galactopyranose)-1,4-naphthalene quinhydrones, productive rate are 90.0%.
Remove protecting group under the acidic conditions:
Operate identical with embodiment 1 corresponding part step (5), 2-(β-D-galactopyranose)-1,4-naphthalene quinhydrones, productive rate are 87.97%.
The product test data are as follows:
The sorrel soup compound, and Rf=0.38 (ethyl acetate: methyl alcohol=8: 1, V/V)
1H-NMR (CDCl 3, 500.13MHz): δ 8.14 (m, 2H, Ar-H 5 ', H 8 '), 7.57 (m, 2H, Ar-H 6 ', H 7 '), 7.01 (s, 1H, Ar-H 3 '), 4.83 (d, 1H, J=9.71Hz, H 1), 4.05 (d, 1H, J=2.92Hz, H 4), 3.96 (t, 1H, J=9.71 and 9.58Hz, H 2), 3.86～3.73 (3m, overlapping, 4H, H 3, H 5, H 6a, H 6b).
(6) 2-(β-D-galactopyranose)-1,4-naphthoquinones synthetic
A) ceric ammonium nitrate (CAN) oxidation style:
Operate identical with embodiment 1 corresponding part step (6), 2-(β-D-galactopyranose)-1,4-naphthoquinones, productive rate are 78.3%.
B) silver suboxide oxidation style:
Operate identical with embodiment 1 corresponding part step (6), 2-(β-D-galactopyranose)-1,4-naphthoquinones, productive rate are 8.9%.
The product test data are as follows:
Pale brown look diploma thing, and Rf=0.42 (chloroform: methyl alcohol=6: 1, V/V)
1H-NMR (D 2O, 500.13MHz): δ 7.98 (m, 2H, Ar-H 5 ', H 8 '), 7.81 (m, 2H, Ar-H 6 ', H 7 '), 7.18 (s, 1H, Ar-H 3 '), 4.60 (s, 1H, H 1), 4.04 (d, 1H, J=2.72Hz, H 4), 3.83～3.71 (m, overlapping, 5H, H 2, H 3, H 5, H 6a, H 6b).
13C-NMR (D 2O, 125.77MHz): 189.65,187.61 (2C ,-C=O, naphthoquinones), 150.82 (C 2 ', Ar), 139.00 (C 3 ', Ar), 137.54,137.31 (2C, C 7 ', C 8 ', Ar), 134.21,133.77 (2C, C 9 ', C 10 ', Ar), 129.45,128.80 (2C, C 5 ', C 6 ', Ar), 82.25 (C 5), 76.81 (C 3), 76.72 (C 1), 74.60 (C 2), 71.97 (C 4), 64.04 (C 6)
MS(ESI)m/e[M+23] +343.1
HRMS (ESI) m/e[M+23] +343.0793, calculated value 343.0794
This compound inhibiting rate to PTP1B when concentration is 20 μ g/mL is 7.7%.

Claims (8)

1. naphthaquinone kind pyrane carbonic glucoside compound, it has suc as formula structure shown in (1) or the formula (2):
Figure C2006100273910002C1
In formula (1) or the formula (2), R is
Figure C2006100273910002C2
Wherein, Ac represents ethanoyl.
2. intermediate that is used to prepare as the said naphthaquinone kind pyrane carbonic glucoside compound of claim 1, it has structure as the formula (3):
Figure C2006100273910002C3
In the formula (3), R is
R 1Be C 1-C 6Alkoxyl group.
3. as the said intermediate of claim 2, it is characterized in that, wherein R 1Be C 1～C 3Alkoxyl group.
4. as the said intermediate of claim 3, it is characterized in that, wherein R 1Be methoxyl group.
5. a method for preparing as the said naphthaquinone kind pyrane carbonic glucoside compound of claim 1 is characterized in that, said preparation method's key step is: at first make compound (3a) by compound (4) or compound (5) and compound (6) reaction; Then compound (3a) is made one of target compound, compound (1a) through oxidation, optional with compound (1a) through reduction make target compound two, compound (2a); Optional with compound (1a) and compound (2a) respectively through alcoholysis make target compound three, compound (1b) and compound (2b);
Figure C2006100273910003C1
Wherein: R 1Be C 1～C 6Alkoxyl group;
R aFor
Figure C2006100273910003C2
R bFor
Figure C2006100273910003C3
6. as the said preparation method of claim 5, it is characterized in that said preparation method comprises the steps:
(1) compound (4) or compound (5) and compound (6) are dissolved in CH 2Cl 2Or CHCl 3, stir down and drop into trifluoroacetic acid silver, drip SnCl then 4CH 2Cl 2Solution reacted 4-8 hour down at 15-60 ℃, and reaction product obtains compound (3a) through extraction, column chromatography and recrystallization separation and purification;
Wherein, compound (4) or compound (5), compound (6), trifluoroacetic acid silver and SnCl 4Mol ratio be 1: (1.6～2.2): (1.0～1.6): (0.1～0.5);
(2) compound (3a) is dissolved in acetonitrile or tetrahydrofuran (THF), adds the aqueous solution of ceric ammonium nitrate, stirring at room 40～100 minutes obtains compound (1a);
Wherein, compound (3a) is 1 with the mol ratio of ceric ammonium nitrate: (3～5);
(3) optional compound (1a) is dissolved in CHCl 3, the aqueous solution of adding Sodium Hydrosulphite stirred under the room temperature 15～45 minutes, and reactant gets compound (2a) behind extraction, column chromatography purification;
Wherein, compound (1a) and Na 2S 2O 4Mol ratio be 1: (4～8);
(4) optional compound (1a) or compound (2a) are added the methanol solution of sodium methylate under argon shield, stirred under the room temperature 30～90 minutes, add excessive acidic cation-exchange resin IR-120 then +, agitation and filtration, filtrate decompression concentrate the back column chromatography purification and get compound (1b) or compound (2b);
Wherein, compound (1a) or compound (2a) are (5～8) with the mol ratio of sodium methylate: 1;
Or,
Optional compound (1a) or compound (2a) are added the methanol solution of freshly prepd Acetyl Chloride 98Min. under argon shield, leave standstill or stir a week under the room temperature, removal of solvent under reduced pressure, residue gets compound (1b) or compound (2b) through column chromatography purification;
Wherein, compound (1a) or compound (2a) are (6～10) with the mol ratio of Acetyl Chloride 98Min.: 1.
7. a method for preparing as the said intermediate of claim 2 is characterized in that, said preparation method's key step is: at first make compound (3a) by compound (4) or compound (5) and compound (6) reaction; Choose wantonly compound (3a) alcoholysis is obtained compound (3b);
Figure C2006100273910004C1
Wherein: R 1Be C 1～C 6Alkoxyl group;
R aFor
Figure C2006100273910005C1
R bFor
Figure C2006100273910005C2
8. as the said preparation method of claim 7, it is characterized in that said preparation method comprises the steps:
(1) compound (4) or compound (5) and compound (6) are dissolved in CH 2Cl 2Or CHCl 3, stir down and drop into trifluoroacetic acid silver, drip SnCl then 4CH 2Cl 2Solution reacted 4-8 hour down at 25 ℃～60 ℃, and reaction product obtains compound (3a) through extraction, column chromatography and recrystallization separation and purification;
Wherein, compound (4) or compound (5), compound (6), trifluoroacetic acid silver and SnCl 4Mol ratio be 1: 2: 1.5: 0.1;
(2) optional compound (3a) is dissolved in methyl alcohol, argon shield adds the methanol solution of sodium methylate down, stirring at room 30～60 minutes, methyl alcohol is removed in decompression, residue through column chromatography purify compound (3b);
Wherein: compound (3a) is (6～10) with the mol ratio of sodium methylate: 1.
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CN1206403A (en) * 1996-02-16 1999-01-27 教堂山北卡罗莱纳州大学 Naphthoquinone antitumor compound and method
CN1344264A (en) * 1999-03-19 2002-04-10 默克.夏普-道姆公司 Tetrahydropyran derivatives and their use as therapeutic agents
JP2003238585A (en) * 2002-02-08 2003-08-27 Ogawa & Co Ltd Naphthol glycoside and bleaching composition for external use containing the same
JP2004224762A (en) * 2003-01-27 2004-08-12 Ogawa & Co Ltd Naphthol glycoside and bleaching external preparation composition containing the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1206403A (en) * 1996-02-16 1999-01-27 教堂山北卡罗莱纳州大学 Naphthoquinone antitumor compound and method
CN1344264A (en) * 1999-03-19 2002-04-10 默克.夏普-道姆公司 Tetrahydropyran derivatives and their use as therapeutic agents
JP2003238585A (en) * 2002-02-08 2003-08-27 Ogawa & Co Ltd Naphthol glycoside and bleaching composition for external use containing the same
JP2004224762A (en) * 2003-01-27 2004-08-12 Ogawa & Co Ltd Naphthol glycoside and bleaching external preparation composition containing the same

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