CN101914084B - Derivative of diphenylpyrone nitrogen heterocyclic ring as well as preparation method and application thereof - Google Patents
Derivative of diphenylpyrone nitrogen heterocyclic ring as well as preparation method and application thereof Download PDFInfo
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- 0 CC=C(C[n]1nnc(CNC)c1)C=CC=*=C Chemical compound CC=C(C[n]1nnc(CNC)c1)C=CC=*=C 0.000 description 2
- OLELRAIMBYZQJO-UHFFFAOYSA-N CN(CC1)CCN1c1cc(C#N)ccc1 Chemical compound CN(CC1)CCN1c1cc(C#N)ccc1 OLELRAIMBYZQJO-UHFFFAOYSA-N 0.000 description 1
- UWEDYKKUTBCWQI-UHFFFAOYSA-N CNCCNc(cc1)ccc1Cl Chemical compound CNCCNc(cc1)ccc1Cl UWEDYKKUTBCWQI-UHFFFAOYSA-N 0.000 description 1
- HSXNBGOTBBCJIX-UHFFFAOYSA-N CNCCNc1cc(OCc2cc(C(F)(F)F)cc(NCCNC)c2)ccc1 Chemical compound CNCCNc1cc(OCc2cc(C(F)(F)F)cc(NCCNC)c2)ccc1 HSXNBGOTBBCJIX-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a derivative of a diphenylpyrone nitrogen heterocyclic ring with a general formula shown in the specification as well as a preparation method and application thereof. In the formula, R is heterocyclic radical and substituted phenyl piperazinyl, the number of R1 and R2 is 1-5, and R1 and R2 are one or combination of halogen, C1-6 alkyl, cyano group, nitryl, trifluoromethyl, methoxyl and ethoxyl. The derivative of the diphenylpyrone nitrogen heterocyclic ring has stronger inhibition activity to cervical-cancer cells and hepatic cancer cells and can be used for preparing medicaments for treating cervical cancer or hepatic cancer.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of active compound for anti tumor diphenyl pyrone nitrogen heterocyclic verivate and preparation method thereof and application.
Background technology
Tumour is one of disease of serious harm human health, and according to cma's data presentation in 2007, malignant tumour became first killer in all kinds of diseases that endanger China resident life, and state-owned 2,000,000 people die from tumour in every year.Chemotherapy is one of three big means of cancer therapy, and warp is made great efforts for many years, and a part of cancer can be cured through the medicine chemotherapy at present.
The diphenyl pyrone skeleton is simple tricyclic structure, and three rings are on same plane, forms π-pi-conjugated, and is similar with the chemical structure of anthrone series antineoplastic medicament, has notable antitumor activity.But with diphenyl pyrone is basic parent nucleus, introduces the different resulting verivates of nitrogen heterocyclic in the 7-position and does not also appear in the newspapers so far.
Summary of the invention
First purpose of the present invention is to provide a kind of diphenyl pyrone nitrogen heterocyclic verivate
Second purpose of the present invention is to provide the preparation method of this verivate.
The 3rd purpose of the present invention is to provide the application of this verivate.
Diphenyl pyrone nitrogen heterocyclic verivate provided by the invention, general structure does
Wherein R is:
(I) heterocyclic radical, said heterocyclic radical are piperidyl, piperazinyl, N-METHYL PIPERAZINE base, morpholinyl, imidazolyl or triazol radical;
(II) substituted phenylpiperazine base, said substituted-phenyl are monosubstituted phenyl or polysubstituted phenyl, and in each position of phenyl ring, substituting group is halogen, C
1～C
4Alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, oxyethyl group or amino;
(III) having general formula does
Substituting group, R in the formula
1Being positioned at each position of phenyl ring, can be single replacement, also can be polysubstituted, and quantity is 1～5, is halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination;
Or (IV) have general formula and do
Substituting group, wherein, R
2Being positioned at each position of phenyl ring, can be single replacement, also can be polysubstituted, and quantity is 1～5, is halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination.
The preparation method of diphenyl pyrone nitrogen heterocyclic verivate provided by the invention, general formula
Middle R is heterocyclic radical or substituted phenylpiperazine base; Said heterocyclic radical is piperidyl, piperazinyl, N-METHYL PIPERAZINE base, morpholinyl, imidazolyl or triazol radical; Said substituted-phenyl is monosubstituted phenyl or polysubstituted phenyl, and in each position of phenyl ring, substituting group is halogen, C
1～C
4Alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, oxyethyl group or when amino; Reaction scheme is:
May further comprise the steps:
(A): with 5 bromosalicylic acid and 1,3, the 5-trimethoxy-benzene is a raw material, and reaction obtains 1,3-dimethoxy-7-bromo-diphenyl pyrone in Eaton ' s reagent;
(B) 1,3-dimethoxy-7-bromo-diphenyl pyrone and replacement amine are at Pd
2(dba)
3, Xphos, Cs
2CO
3Under the effect, 1, in the 4-dioxane solvent, reaction obtains said verivate under argon shield, and said replacement amine is selected from piperidines, piperazine, N-METHYL PIPERAZINE, morpholine, imidazoles, triazole or substituted phenylpiperazine.
R does in the general formula
R in the formula
2Being positioned at each position of phenyl ring, can be single replacement, also can be polysubstituted, and quantity is 1～5, is halogen, C
1～C
6When a kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination, reaction scheme is:
The preparation method comprises:
(A) with 5-nitrosalicylic acid and 1,3, the 5-trimethoxy-benzene is a raw material, and reaction obtains 1,3-dimethoxy-7-nitro-diphenyl pyrone in Eaton ' s reagent;
(B) 1,3-dimethoxy-7-nitro-diphenyl pyrone and Hydrazine Hydrate 80 are under the Raney's nickel effect, and in alcoholic solvent, reaction obtains 1,3-dimethoxy-7-amino-diphenyl pyrone;
(C) 1,3-dimethoxy-7-amino-diphenyl pyrone and propargyl bromide back flow reaction in alkali, acetone solvent obtains 1,3-dimethoxy-7-(2-alkynyl third ammonia)-diphenyl pyrone;
(D) sodiumazide and benzyl br-derivatives react 12h in DMSO, add 1,3-dimethoxy-7-(2-alkynyl third ammonia)-diphenyl pyrone, and under cupric sulfate pentahydrate, xitix effect, reaction obtains said verivate, and the general formula of said benzyl br-derivatives is:
R wherein
2Being positioned at each position of phenyl ring, can be single replacement, also can be polysubstituted, and quantity is 1～5, is halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination.
R does in the general formula
R in the formula
1Being positioned at each position of phenyl ring, can be single replacement, also can be polysubstituted, and quantity is 1～5, is halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination, reaction scheme is:
The preparation method comprises:
(A) with 5-hydroxyl Whitfield's ointment and 1,3, the 5-trimethoxy-benzene is a raw material, and reaction obtains 1,3-dimethoxy-7-hydroxyl-diphenyl pyrone in Eaton ' s reagent;
(B) 1,3-dimethoxy-7-hydroxyl-diphenyl pyrone and propargyl bromide back flow reaction in alkali, acetone solvent obtains 1,3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone;
(C) sodiumazide and benzyl br-derivatives react 12h in DMSO, add 1,3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone, and under cupric sulfate pentahydrate, xitix effect, reaction obtains said verivate, and the general formula of said benzyl br-derivatives is:
R wherein
1Being positioned at each position of phenyl ring, can be single replacement, also can be polysubstituted, and quantity is 1～5, is halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination.
Diphenyl pyrone nitrogen heterocyclic verivate provided by the invention is used to prepare the medicine of treating cervical cancer or liver cancer.
Embodiment
Below in conjunction with specific embodiment, the present invention is further specified.Should be understood that following examples only are used to the present invention is described but not are used to limit scope of the present invention.
Embodiment 1 raw material is synthetic
1.1 1,3-dimethoxy-7-bromo-diphenyl pyrone synthetic
With 5 bromosalicylic acid 10.9g (0.5mol) and 1,3,5-trimethoxy-benzene 8.5g (0.53mol) is dissolved in 100mlEaton ' the s reagent, stirs 4 hours in 110 ℃; React completely, be cooled to room temperature, the adding frozen water is an amount of; Stirred 2.0 hours, and filtered, washing is to neutral; Recrystallizing methanol gets the 10g product, productive rate 70.5%.
1HNMR (300MHz, DMSO-d
6, TMS) data are: δ 8.38 (1H, s, Ar), 7.70 (1H, d, Ar), 7.25 (1H, d, Ar), 6.49 (1H, s, Ar), 6.35 (1H, s, Ar), 4.12 (s, 3H, OCH
3), 3.96 (3H, s, OCH
3).
1.2 1,3-dimethoxy-7-nitro-diphenyl pyrone synthetic
With 5-nitrosalicylic acid 9.1g (0.05mol) and 1,3,5-trimethoxy-benzene 8.5g (0.055mol) is dissolved among Eaton ' the s reagent 100ml, 110 ℃ of stirring reactions 4 hours; React completely, be chilled to room temperature, the adding frozen water is an amount of; Stirred 2 hours, and filtered, washing is to neutral; Recrystallizing methanol gets the 12g product, productive rate 79.2%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ9.14(1H，s，Ar)，8.47(1H，d，Ar)，7.50(1H，d，Ar)，6.55(1H，s，Ar)，6.42(1H，s，Ar)，4.01(3H，s，OCH
3)，3.95(3H，s，OCH
3).M+H+，302.90
1.31,3-dimethoxy-7-amino-diphenyl pyrone synthetic
According to 1 of embodiment 1.2 methods preparation, add 20ml methyl alcohol among 3-dimethoxy-7-nitro-diphenyl pyrone 3.01g (0.01mol), add the 0.5g Raney's nickel subsequently, slowly drip Hydrazine Hydrate 80 2mL, stirring at room 4 hours is filtered, and concentrates recrystallizing methanol.Get product 1.9g, yield: 69.2%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ7.52(1H，s，Ar)，7.22(1H，d，Ar)，7.00(1H，d，Ar)，6.47(1H，s，Ar)，6.32(1H，s，Ar)，3.98(3H，s，OCH
3)，3.91(3H，s，OCH
3)，3.77(2H，br，NH).2M+Na+，565.19
1.4 1,3-dimethoxy-7-(2-alkynyl third ammonia)-diphenyl pyrone synthetic
According to 1 of embodiment 1.3 methods preparation, 3-dimethoxy-7-amino-diphenyl pyrone 1g (3.7mmol) is dissolved in the acetone, adds salt of wormwood 1.5g (10.9mmol) and propargyl bromide 0.42g (3.6mmol) subsequently; Refluxed 6 hours, and poured in the water, have a large amount of depositions to produce; Filter; Ether, methyl alcohol filter wash cake get the 900mg product, yield: 53.6%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ7.22(1H，s，Ar)，7.12(1H，d，Ar)，7.05(1H，d，Ar)，6.61(1H，s，Ar)，6.42(1H，s，Ar)，6.28(1H，t，NH)，4.21(2H，s，CH
2)，3.98(3H，s，OCH
3)，3.91(3H，s，OCH
3)，3.19(1H，s，CH)。
1.5 1,3-dimethoxy-7-hydroxyl-diphenyl pyrone synthetic
With 5-hydroxyl Whitfield's ointment 7.7g (0.5mol) and 1,3,5-trimethoxy-benzene 8.5g (0.53mol) is dissolved in 100ml in the Eatons reagent, and 110 ℃ were stirred after 4 hours; React completely, be chilled to room temperature, the adding frozen water is an amount of; Stirred 2 hours, and filtered, washing is to neutral; Recrystallizing methanol gets the 10g product, productive rate 75%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ9.81(1H，s，OH)，7.93-7.35(3H，m，Ar)，6.70(1H，s，Ar)，6.50(1H，s，Ar)，3.89(3H，s，OCH
3)，3.85(3H，s，OCH
3).M-H+：271.64
1.6 1,3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone synthetic
Will be according to 1 of embodiment 1.5 methods preparation, 3-dimethoxy-7-hydroxyl-diphenyl pyrone 1g is dissolved among the acetone 15ml, adds Pottasium Hydroxide 1.5g and propargyl bromide 0.42g subsequently; Refluxed 6 hours, and poured in the water, have a large amount of depositions to produce; Filter; Ether, methyl alcohol filter wash cake get the 900mg product, yield: 79%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ7.57-7.37(3H，m，Ar)，6.67(1H，s，Ar)，6.50(1H，s，Ar)，4.90(2H，s，CH
2)，3.90(3H，s，OCH
3)，3.84(3H，s，OCH
3)，3.60(1H，s，CH)。
Embodiment 21,3-dimethoxy-7-nitrogen heterocyclic-diphenyl pyrone synthetic
The reaction scheme of embodiment 2.1～2.6 is:
The reaction scheme of embodiment 2.7～2.9 is:
The reaction scheme of embodiment 2.10～2.14 is:
2.1 1,3-dimethoxy-7-R-diphenyl pyrone synthetic
According to 1 of embodiment 1.1 methods preparation, 3-dimethoxy-7-bromo-diphenyl pyrone 100mg and piperidines 50ml, Pd
2(dba)
3(catalytic amount), X ligand phos (2-dicyclohexyl phosphorus-2 ', 4 ', 6 '-tri isopropyl biphenyl; Catalytic amount), cesium carbonate (200mg) is dissolved in and is suspended in 1,4-dioxane (5ml) is under the argon shield; 115 ℃ were stirred after 15 hours, filtered, and concentrated; The ether recrystallization gets the 89mg product, yield: 65%.
1HNMR (300MHz, DMSO-d
6, TMS) data are: δ 7.62 (1H, s, Ar), 7.31 (2H, d, Ar), 6.49 (1H, d, Ar), 6.34 (1H, d, Ar), 3.98 (3H, s, OCH
3), 3.92 (3H, s, OCH
3), 3.88 (3H, m, OCH
3), 3.71 (4H, br, CH
2), 1.79-1.56 (6H, m, CH
2).
2.2 1,3-dimethoxy-7-morpholine-diphenyl pyrone synthetic
According to 1 of embodiment 1.1 methods preparation, 3-dimethoxy-7-bromo-diphenyl pyrone 100mg and morpholine 65ml, Pd
2(dba)
3(catalytic amount), X ligand phos (catalytic amount), cesium carbonate (200mg) are dissolved in and are suspended in 1,4-dioxane (5ml), and under the argon shield, 115 ℃ were stirred after 15 hours, reacted completely, and filtered, and concentrated, and the ether recrystallization gets the 100mg product, yield: 70.8%.
1HNMR (300MHz, DMSO-d
6, TMS) data are: δ 7.70 (1H, s, Ar), 7.30 (2H, m, Ar), 6.48 (1H, d, Ar), 6.33 (1H, d, Ar), 3.98 (3H, s, OCH
3), 3.91 (4H, m, CH
2), 3.88 (3H, m, OCH
3), 3.22 (4H, m, CH
2).
2.3 1,3-dimethoxy-7-(4-N-METHYL PIPERAZINE)-diphenyl pyrone synthetic
According to 1 of embodiment 1.1 methods preparation, 3-dimethoxy-7-bromo-diphenyl pyrone 100mg and 4-N-METHYL PIPERAZINE 65ml, Pd
2(dba)
3(catalytic amount), X ligand phos (catalytic amount), cesium carbonate (200mg) are dissolved in and are suspended in 1,4-dioxane (5ml), and under the argon shield, 115 ℃ were stirred after 15 hours, filtered, and concentrated, and the ether recrystallization gets the 105mg product, yield: 71.8%.
1HNMR (300MHz, DMSO-d
6, TMS) data are: δ 7.71 (1H, s, Ar), 7.31 (2H, d, Ar), 6.48 (1H, d, Ar), 6.33 (1H, d, Ar), 3.98 (3H, s, OCH
3), 3.92 (3H, s, OCH
3), 3.88 (3H, m, OCH
3), 3.27 (4H, m, CH
2), 2.61 (4H, m, CH
2), 2.38 (3H, s, CH
3).
2.4 1,3-dimethoxy-7-(1,2, the 4-triazole)-diphenyl pyrone synthetic
According to 1 of embodiment 1.1 methods preparation, 3-dimethoxy-7-bromo-diphenyl pyrone 100mg and 1,2,4-triazole 55ml, Pd
2(dba)
3(catalytic amount), X ligand phos (catalytic amount), cesium carbonate (200mg) are dissolved in and are suspended in 1,4-dioxane (5ml), and under the argon shield, 115 ℃ were stirred after 15 hours, filtered, and concentrated, and the ether recrystallization gets the 95mg product, yield: 68.8%.
1HNMR (300MHz, DMSO-d
6, TMS) data are: δ 8.38 (1H, s, Ar), 8.23 (1H, s, Ar), 7.72 (1H, s, Ar), 7.30 (2H, m, Ar), 6.50 (1H, d, Ar), 6.36 (1H, d, Ar), 4.05 (3H, s, OCH
3), 3.92 (3H, m, OCH
3).
2.5 1,3-dimethoxy-7-imidazoles-diphenyl pyrone synthetic
According to 1 of embodiment 1.1 methods preparation, 3-dimethoxy-7-bromo-diphenyl pyrone 100mg and imidazoles 55ml, Pd
2(dba)
3(catalytic amount), X ligand phos (catalytic amount), cesium carbonate (200mg) are dissolved in and are suspended in 1,4-dioxane (5ml), and under the argon shield, 115 ℃ were stirred after 15 hours, filtered, and concentrated, and the ether recrystallization gets the 90mg product, yield: 65.8%.
1HNMR (300MHz, DMSO-d
6, TMS) data are: δ 8.11 (2H, m, Ar), 7.92-7.50 (4H, m, Ar), 6.69 (1H, d, Ar), 652 (1H, d, Ar), 4.05 (3H, s, OCH
3), 3.92 (3H, m, OCH
3).
2.6 1,3-dimethoxy-7-(4-(2-methoxyphenyl)-piperazine)-diphenyl pyrone synthetic
According to 1 of embodiment 1.1 methods preparation, 3-dimethoxy-7-bromo-diphenyl pyrone 100mg and 4-(2-p-methoxy-phenyl) piperazine 75ml, Pd
2(dba)
3(catalytic amount), X ligand phos (catalytic amount), cesium carbonate (200mg) are suspended in 1,4-dioxane (5ml), under the argon shield, 115 ℃ were stirred after 15 hours, reacted completely, and filtered, and concentrated, and the ether recrystallization gets the 121mg product, yield: 80.8%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ7.60-6.77(7H，m，Ar)，6.59-6.45(2H，m，Ar)，3.87(3H，s?OCH
3)，3.85(3H，s，OCH
3)，3.73(3H，s，OCH
3)，3.58-3.43(8H，m，CH
2).
2.7 1,3-dimethoxy-7-(synthesizing of (1-(2-methyl-benzyl)-1,2,3-triazole)-4-methylamino diphenyl pyrone
Sodiumazide 40mg (0.6mmol) is dissolved among the DMSO, adds adjacent methyl benzyl bromine 115mg (0.57mmol) stirring at room 12 hours, and disposable adding is according to 1 of the preparation of embodiment 1.4 methods; 3-dimethoxy-7-(2-alkynyl third ammonia)-diphenyl pyrone 130mg (0.42mmol) is dissolved in cupric sulfate pentahydrate (catalytic amount) in the 1ml water subsequently, adds sodium ascorbate (catalytic amount); Splash in the reaction solution fast; Stirring at room 16 hours is poured in the weak ammonia dichloromethane extraction into; Concentrate column chromatography (methylene dichloride: methyl alcohol=100: 1).Get the 150mg product, yield: 74.6%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ7.85(1H，s，CH＝C-)，7.30-6.97(7H，m，Ar)，6.59-6.42(2H，m，Ar)，6.36(1H，br，NH)，5.52(2H，s，CH
2)，4.34(2H，d，CH
2)，3.87(3H，s，OCH
3)，3.83(3H，s，OCH
3)，2.24(3H，s，CH
3).
2.8 1,3-dimethoxy-7-(synthesizing of (1-(4-luorobenzyl)-1,2,3-triazole)-4-methylamino diphenyl pyrone
Sodiumazide 40mg (0.6mmol) is dissolved among the DMSO, adds 4-fluorobenzyl bromide 110mg (0.57mmol) stirring at room 12 hours, and disposable adding is according to 1 of the preparation of embodiment 1.4 methods; 3-dimethoxy-7-(2-alkynyl third ammonia)-diphenyl pyrone 130mg (0.42mmol) is dissolved in cupric sulfate pentahydrate (catalytic amount) in the 1ml water subsequently, adds sodium ascorbate (catalytic amount); Splash in the reaction solution fast; Stirring at room 16 hours is poured in the weak ammonia dichloromethane extraction into; Concentrate column chromatography (methylene dichloride: methyl alcohol=100: 1).Get the 140mg product, yield: 70%.1HNMR(300MHz，DMSO-d6，TMS)：δ8.02(1H，s，CH＝C-)，7.35-7.11(7H，m，Ar)，6.62-6.46(2H，m，Ar)，6.45(1H，br，NH)，5.55(2H，s，CH
2)，4.36-4.34(2H，br，CH
2)，3.90(3H，s，OCH
3)，3.86(3H，s，OCH
3)。
2.9 1,3-dimethoxy-7-(synthesizing of (1-(2-nitrobenzyl)-1,2,3-triazole)-4-methylamino diphenyl pyrone
Sodiumazide 40mg (0.6mmol) is dissolved among the DMSO, adds adjacent nitrobenzyl bromine 118mg (0.57mmol) and adds 2-methyl benzyl bromine 115mg (0.57mmol) stirring at room 12 hours, and disposable adding is according to 1 of the preparation of embodiment 1.4 methods; 3-dimethoxy-7-(2-alkynyl third ammonia)-diphenyl pyrone 130mg (0.42mmol) is dissolved in cupric sulfate pentahydrate (catalytic amount) in the 1ml water subsequently, adds sodium ascorbate (catalytic amount); Splash in the reaction solution fast; Stirring at room 16 hours is poured in the weak ammonia dichloromethane extraction into; Concentrate column chromatography (methylene dichloride: methyl alcohol=100: 1).Get the 110mg product, yield: 64.6%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ8.12-8.01(2H，m，Ar)，7.69-7.11(5H，m，Ar)，6.87-6.43(4H，m，Ar)，5.92(2H，s，CH
2)，4.38(2H，br，CH
2)，3.86(6H，s，OCH
3)。
2.10 1,3-dimethoxy-7-(synthesizing of (1-(2-methyl-benzyl)-1,2,3-triazole)-4-methoxyl group diphenyl pyrone
Sodiumazide 40mg (0.6mmol) is dissolved among the DMSO, adds 2-methyl benzyl bromine 116mg (0.57mmol) stirring at room 12 hours, and disposable adding is according to 1 of the preparation of embodiment 1.6 methods; 3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone 135mg (0.43mmol) is dissolved in cupric sulfate pentahydrate (catalytic amount) in the 1ml water subsequently, adds sodium ascorbate (catalytic amount); Splash in the reaction solution fast; Stirring at room 16 hours is poured in the weak ammonia dichloromethane extraction into; Concentrate column chromatography (methylene dichloride: methyl alcohol=100: 1).Get the 150mg product, yield: 74.6%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ8.18(1H，s，CH＝C-)，7.59-7.05(7H，m，Ar)，6.67(1H，d，Ar)，6.50(1H，d，Ar)，5.61(2H，s，CH
2)，5.23(2H，s，CH
2)，3.90(3H，s，OCH
3)，3.87(3H，s，OCH
3)，2.30(3H，s，CH
3)。
2.11 1,3-dimethoxy-7-(synthesizing of (1-(2-luorobenzyl)-1,2,3-triazole)-4-methoxyl group diphenyl pyrone
Sodiumazide 40mg (0.6mmol) is dissolved among the DMSO, adds adjacent fluorobenzyl bromide 110mg (0.55mmol) stirring at room 12 hours, and disposable adding is according to 1 of the preparation of embodiment 1.6 methods; 3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone 135mg (0.43mmol) is dissolved in cupric sulfate pentahydrate (catalytic amount) in the 1ml water subsequently, adds sodium ascorbate (catalytic amount); Splash in the reaction solution fast; Stirring at room 16 hours is poured in the weak ammonia dichloromethane extraction into; Concentrate column chromatography (methylene dichloride: methyl alcohol=100: 1).Get the 125mg product, yield: 68.6%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ8.28(1H，s，CH＝C-)，7.60-7.18(7H，m，Ar)，6.67(1H，d，Ar)，6.49(1H，d，Ar)，5.71(2H，d，CH
2)，5.23(2H，s，CH
2)，3.90(3H，s，OCH
3)，3.87(3H，s，OCH
3)。
2.12 1,3-dimethoxy-7-(synthesizing of (1-(4-bromobenzyl)-1,2,3-triazole)-4-methoxyl group diphenyl pyrone
Sodiumazide 40mg (0.6mmol) is dissolved among the DMSO, adds bromobenzyl bromine 120mg (0.55mmol) stirring at room 12 hours, and disposable adding is according to 1 of the preparation of embodiment 1.6 methods; 3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone 130mg (0.42mmol) is dissolved in cupric sulfate pentahydrate (catalytic amount) in the 1ml water subsequently, adds sodium ascorbate (catalytic amount); Splash in the reaction solution fast; Stirring at room 16 hours is poured in the weak ammonia dichloromethane extraction into; Concentrate column chromatography (methylene dichloride: methyl alcohol=100: 1).Get the 130mg product, yield: 68.6%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ8.31(1H，s，CH＝C-)，7.58-7.24(7H，m，Ar)，6.68(1H，d，Ar)，6.50(1H，d，Ar)，5.61(2H，d，CH
2)，5.24(2H，s，CH
2)，3.90(3H，s，OCH
3)，3.87(3H，s，OCH
3)。
2.13 1,3-dimethoxy-7-(synthesizing of (1-(4-nitrobenzyl)-1,2,3-triazole)-4-methoxyl group diphenyl pyrone
Sodiumazide 40mg (0.6mmol) is dissolved among the DMSO, adds nitrobenzyl bromine 118mg (0.57mmol) stirring at room 12 hours, and disposable adding is according to 1 of the preparation of embodiment 1.6 methods; 3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone 130mg (0.42mmol) is dissolved in cupric sulfate pentahydrate (catalytic amount) in the 1ml water subsequently, adds sodium ascorbate (catalytic amount); Splash in the reaction solution fast; Stirring at room 16 hours is poured in the weak ammonia dichloromethane extraction into; Concentrate column chromatography (methylene dichloride: methyl alcohol=100: 1).Get the 130mg product, yield: 77.6%.
1HNMR(300MHz，DMSO-d
6，TMS)：δ8.38(1H，s，CH＝C-)，8.21(2H，m，Ar)，7.75-7.42(5H，m，Ar)，6.66(1H，d，Ar)，6.49(1H，d，Ar)，5.80(2H，s，CH
2)，5.24(2H，s，CH
2)，3.89(3H，s，OCH
3)，3.86(3H，s，OCH
3)。
2.14 1,3-dimethoxy-7-(synthesizing of (1-(3-cyanic acid benzyl)-1,2,3-triazole)-4-methoxyl group diphenyl pyrone
Sodiumazide 40mg (0.6mmol) is dissolved among the DMSO, adds 2-cyanic acid benzyl bromine 116mg (0.57mmol) stirring at room 12 hours, and disposable adding is according to 1 of the preparation of embodiment 1.6 methods; 3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone 130mg (0.42mmol) is dissolved in cupric sulfate pentahydrate (catalytic amount) in the 1ml water subsequently, adds sodium ascorbate (catalytic amount); Splash in the reaction solution fast; Stirring at room 16 hours is poured in the weak ammonia dichloromethane extraction into; Concentrate column chromatography (methylene dichloride: methyl alcohol=100: 1).Get the 130mg product, yield: 78.6%.1HNMR(300MHz，DMSO-d6，TMS)：δ8.35(1H，s，CH＝C-)，7.82-7.42(7H，m，Ar)，6.66(1H，d，Ar)，6.49(1H，d，Ar)，5.69(2H，s，CH
2)，5.24(2H，s，CH
2)，3.90(3H，s，OCH
3)，3.87(3H，s，OCH
3)。
Agents useful for same is commercially available analytical pure among the above embodiment.Enforcement of the present invention is not limited to above embodiment, and all the other target compounds are with different benzyl br-derivatives, and replacement amine is synthesis material, repeats the step among the above embodiment, just can synthesize required diphenyl pyrone analog derivative.The chemical structure of the preferred verivate of the present invention part, nuclear magnetic data shown in table 1, table 2, the nuclear magnetic data of verivate when table 1 is heterocyclic radical or substituted phenylpiperazine base for R, table 2 for R does
The nuclear magnetic data of verivate when
.
The nuclear magnetic data of table 1 diphenyl pyrone nitrogen heterocyclic verivate
The nuclear magnetic data of table 2 diphenyl pyrone nitrogen heterocyclic verivate
Embodiment 3 pharmacological evaluation
(1) experiment material
After given the test agent is used DMSO (Merck) dissolving respectively, add solution or uniform suspension that PBS (-) is made into 1000 μ g/ml, then with PBS (-) dilution that contains DMSO.
Cell strain adopts Hela (human cervical carcinoma cell), Bel7402 (human liver cancer cell).
Other materials and key instrument are:
Nutrient solution: RPMI1640+15%NBS+ is two anti-; MTT: available from Sigma company (St.Louis, MO, USA); Other reagent are homemade analytical pure.Full-automatic ELIASA WellscanMK-2 (Labsystems company), CO
2Constant incubator (SANYO GS company), import 96 well culture plates etc.
The inhibitor concentration of table 3 verivate half necrocytosis is IC
50Value
aZorubicin positive control (Doxorubicin, positive control)
(2) experimental technique
MTT (tetrazolium) method: it is 4～6 * 10 that the every hole of 96 orifice plates adds concentration
4The cell suspension 100 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid (diluting 100 times), two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds the DMSO lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is surveyed with the full-automatic ELIASA of MK-2 in the dissolving back.
(3) experimental result
Institute's synthetic compound has been carried out the test of cell strain vitro inhibition effect, from the primary dcreening operation result, select activity preferably 20 compounds carried out multiple sieve, obtaining the inhibitor concentration that makes the half necrocytosis is IC
50Value (μ M), the result is as shown in table 3.
The above results is represented; The verivate of the present invention's preparation has tumor cell proliferation inhibition activity preferably, the external activity of most compounds, particularly verivate A1; A5; A7, A10 has stronger inhibition cel l proliferation to Hela cell Bel7402 cell, and this analog derivative can be used as the medicine of preparation cervical cancer, liver cancer.
Claims (5)
1. diphenyl pyrone nitrogen heterocyclic verivate, general structure does
Wherein R is:
(I) heterocyclic radical, said heterocyclic radical are piperidyl, piperazinyl, N-METHYL PIPERAZINE base, morpholinyl, imidazolyl or triazol radical;
(II) substituted phenylpiperazine base, said substituted phenylpiperazine base is selected from:
R does
(III) having general formula does
Substituting group, R in the formula
1Quantity be 1～5, be halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination;
Or (IV) have general formula and do
Substituting group, wherein, R
2Quantity be 1～5, be halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination.
2. the preparation method of a diphenyl pyrone nitrogen heterocyclic verivate as claimed in claim 1, the general structure of said verivate does
Wherein R is heterocyclic radical or substituted phenylpiperazine base, and said heterocyclic radical is piperidyl, piperazinyl, N-METHYL PIPERAZINE base, morpholinyl, imidazolyl or triazol radical, and said substituted-phenyl is monosubstituted phenyl or polysubstituted phenyl, and substituting group is halogen, C
1Alkyl, trifluoromethyl, methoxyl group; It is characterized in that, may further comprise the steps:
(A): with 5 bromosalicylic acid and 1,3, the 5-trimethoxy-benzene is a raw material, and reaction obtains 1,3-dimethoxy-7-bromo-diphenyl pyrone in Eaton ' s reagent;
(B) 1,3-dimethoxy-7-bromo-diphenyl pyrone and replacement amine are at Pd
2(dba)
3, Xphos, Cs
2CO
3Under the effect, 1, in the 4-dioxane solvent, reaction obtains said verivate under argon shield, and said replacement amine is selected from piperidines, piperazine, N-METHYL PIPERAZINE, morpholine, imidazoles, triazole or substituted phenylpiperazine.
3. the preparation method of a diphenyl pyrone nitrogen heterocyclic verivate as claimed in claim 1, the general structure of said verivate does
Wherein R does
R in the formula
2Quantity be 1～5, be halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination is characterized in that, comprising:
(A) with 5-nitrosalicylic acid and 1,3, the 5-trimethoxy-benzene is a raw material, and reaction obtains 1,3-dimethoxy-7-nitro-diphenyl pyrone in Eaton ' s reagent;
(B) 1,3-dimethoxy-7-nitro-diphenyl pyrone and Hydrazine Hydrate 80 are under the Raney's nickel effect, and in alcoholic solvent, reaction obtains 1,3-dimethoxy-7-amino-diphenyl pyrone;
(C) 1,3-dimethoxy-7-amino-diphenyl pyrone and propargyl bromide back flow reaction in alkali, acetone solvent obtains 1,3-dimethoxy-7-(2-alkynyl third ammonia)-diphenyl pyrone;
(D) sodiumazide and benzyl br-derivatives react 12h in DMSO, add 1,3-dimethoxy-7-(2-alkynyl third ammonia)-diphenyl pyrone, and under cupric sulfate pentahydrate, xitix effect, reaction obtains said verivate, and the general formula of said benzyl br-derivatives is:
R wherein
2Quantity be 1～5, be halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination.
4. the preparation method of a diphenyl pyrone nitrogen heterocyclic verivate as claimed in claim 1, the general structure of said verivate does
Wherein R does
R in the formula
1Quantity be 1～5, be halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination is characterized in that, comprising:
(A) with 5-hydroxyl Whitfield's ointment and 1,3, the 5-trimethoxy-benzene is a raw material, and reaction obtains 1,3-dimethoxy-7-hydroxyl-diphenyl pyrone in Eaton ' s reagent;
(B) 1,3-dimethoxy-7-hydroxyl-diphenyl pyrone and propargyl bromide back flow reaction in alkali, acetone solvent obtains 1,3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone;
(C) sodiumazide and benzyl br-derivatives react 12h in DMSO, add 1,3-dimethoxy-7-(2-alkynes propoxy-)-diphenyl pyrone, and under cupric sulfate pentahydrate, xitix effect, reaction obtains said verivate, and the general formula of said benzyl br-derivatives is:
R wherein
1Quantity is 1～5, is halogen, C
1～C
6A kind of in alkyl, cyanic acid, nitro, trifluoromethyl, methoxyl group, the oxyethyl group or their combination.
5. the application of a diphenyl pyrone nitrogen heterocyclic verivate as claimed in claim 1 is characterized in that, is used to prepare the medicine of treatment cervical cancer or liver cancer.
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| CN101279967A (en) * | 2008-05-29 | 2008-10-08 | 武汉远大制药集团有限公司 | Medicinal composition of trimethyl xanthone-4-acetic acid for treating cancer and use thereof |
| CN101627989A (en) * | 2009-06-18 | 2010-01-20 | 中国人民解放军第二军医大学 | Novel anti-tumor application of organic small-molecular compound JFD-03169 |
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