CN1321120C - Phenoxazones, preparing process and pharmaceutical uses thereof - Google Patents

Phenoxazones, preparing process and pharmaceutical uses thereof Download PDF

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CN1321120C
CN1321120C CNB031468470A CN03146847A CN1321120C CN 1321120 C CN1321120 C CN 1321120C CN B031468470 A CNB031468470 A CN B031468470A CN 03146847 A CN03146847 A CN 03146847A CN 1321120 C CN1321120 C CN 1321120C
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oxine
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CN1524859A (en
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古练权
阮继武
符立梧
黄志纾
陈新滋
马林
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Sun Yat Sen University
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Abstract

The present invention relates to phenoxazone compounds shown as formulas I to IV, a preparing method thereof and an application thereof in preparing anti-tumor medicines. Experiments prove that the phenoxazone compounds referred by the present invention have strong inhibiting effects on various tumor cell strains and small toxicity on normal cells. Thus, the phenoxazone compounds can be used for preparing anti-tumor medicines. R1, R2, R3 X and Y in the formulas I to IV are defined in the specifications.

Description

Thiophene evil hexazinone compounds and preparation method thereof and pharmaceutical applications
Technical field
The present invention relates to thiophene evil hexazinone compounds and preparation method thereof, and this compounds is used for the purposes of antitumor drug in preparation.
Technical background
Tumour is the principal disease of prestige association's human health and life security.The research and development of antitumor drug are the focuses that chemist and medicine scholar pay close attention to always.Because the complicacy and the singularity of tumour mechanism, seek more efficient, highly selective and the little antitumor drug of side effect does not achieve satisfactory results more.
Design synthesizing antineoplastic medicament with DNA for target spot, particularly synthetic to the design of DNA intercalator, be the important method of development new type antineoplastic medicine.DNA intercalator common constitutional features mainly is: three or more coplanar aromatic ring structures is arranged; Energy salify under physiological condition; Hydrogen bond receptor or donor are arranged, can form hydrogen bond etc. with the region of interest of DNA.The mechanism that they produce antitumor action mainly is by the DNA of embedding tumour cell, influences it and duplicates and transcribe, thus the growth and the breeding of obstruction tumour cell.
Dactinomycin (AMD) is a DNA intercalator best in the known compound, also is one of the strongest compound of anti-tumor activity, and shortcoming is to have side effects such as extremely strong bone marrow depression and cardiac toxic.Recent studies show that, the toxic side effect of AMD is mainly from its two peptide side chains, and its precursor structure — thiophene evil hexazinone-be active essential part, also be the essential part of the intercalation of DNA.Therefore, Yi thiophene evil hexazinone precursor structure compound carries out structural modification as lead compound, is to seek a new effective way efficient, the low toxicity antitumor drug.
Summary of the invention
The purpose of this invention is to provide new thiophene evil hexazinone compounds of a class and preparation method thereof, and this compounds is used for the purposes of antitumor drug in preparation.
The chemical structural formula of thiophene evil hexazinone compounds of the present invention is as (to be designated hereinafter simply as formula I～IV compound) shown in following formula I～IV:
Figure C0314684700041
Formula I formula II
Figure C0314684700042
Formula III formula IV
R in the formula 1, R 2, R 3, X and Y representative group as described in the and the following:
(1) R 1, R 2Can be identical, also can be different, be selected from one of the following stated group: H, F, Cl, Br, NH 2, NO 2, CN, COOH, R 4CO, C 1-6Alkyl, C 3-6Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylamino, C 1-6Alkylthio, phenyl, benzyl, benzyloxy, benzoyl, pyridyl, imidazolyl, thienyl, piperidyl, piperazinyl, morpholinyl, oxazolyl, wherein R 4Be H, C 1-6Alkyl or phenyl;
(2) R 3Be selected from one of the following stated group: H, F, Cl, Br, C 1-6Alkyl;
(3) X, Y can be identical, also can be different, be selected from C or N.
The compounds of De thiophene evil hexazinone shown in formula I of the present invention～IV can make by two kinds of methods.Its building-up process is suc as formula shown in VIII～XI:
Figure C0314684700051
Formula VIII
Figure C0314684700052
Formula IX
Formula X
Figure C0314684700054
Formula XI
Concrete preparation method's step is:
Method one: a certain amount of o-aminophenol or 2-amino-4-chlorophenol or 2-amino-3-pyridone or 5-chloro-7-amino-oxine be dissolved in (concentration is 0.01～1M) usually in the solvent; 0～30 ℃ and stir the aqueous solution that adds the equimolar amount oxygenant down (concentration is 0.001～1M) usually, after 1～10 minute, neighbour-the p-aminophenol derivative or 2-amino-3-Tetrahydrothienopyriderivatives derivatives or the 7-amino-oxine derivative that add equimolar amount again, 0.5 after～3 hours, the aqueous solution that adds 2 molar weight oxygenants again, filter collection solid is filtered in stirring at room reaction 5～30 hours, wash filter cake with water, oven dry is after column chromatographic isolation and purification promptly obtains corresponding thiophene evil hexazinone compounds.
Method two: with a certain amount of o-aminophenol or 2-amino-4-chlorophenol or 2-amino-3-pyridone or 5-chloro-7-amino-oxine grind into powder, or with grind into powder again behind silica gel or aluminum oxide or the diatomite adsorption, the oxygenant that adds equimolar amount, after grinding this mixture evenly, microwave 100～800w reaction is after 0.5～10 minute, neighbour-the p-aminophenol derivative or 2-amino-3-Tetrahydrothienopyriderivatives derivatives or the 7-amino-oxine derivative that add equimolar amount again, after grinding evenly, microwave 100～800w reaction 1～10 minute, add 2 molar weight oxygenants again, after grinding evenly, microwave 100～800w reaction promptly obtained corresponding thiophene evil hexazinone compounds through column chromatographic isolation and purification after 10～60 minutes.
Neighbour-p-aminophenol derivative, 2-amino-3-Tetrahydrothienopyriderivatives derivatives and 7-amino-oxine derivative used in the aforesaid method are respectively shown in following formula V, VI, VII:
Figure C0314684700061
Formula V formula VI formula VII
R among formula V and the formula VI 1, R 2Can be identical, also can be different, be selected from one of following radicals: H, F, Cl, Br, NH 2, NO 2, CN, COOH, R 4CO, C 1-6Alkyl, C 3-6Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylamino, C 1-6Alkylthio, phenyl, benzyl, benzyloxy, benzoyl, pyridyl, imidazolyl, thienyl, piperidyl, piperazinyl, morpholinyl, oxazolyl, wherein R 4Be H, C 1-6Alkyl or phenyl;
R among the formula VII 3Be selected from one of following radicals: H, F, Cl, Br, C 1-6Alkyl.
Used solvent can be one or more the mixture that is selected from water, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), dioxane, acetonitrile, methyl-sulphoxide, the dimethyl formamide.Can arbitrary proportion between each composition in this mixture.
Used oxygenant can be sodium iodate, the Tripotassium iron hexacyanide, potassium permanganate, potassium bichromate, iron trichloride or Potassium Persulfate.
Aforesaid method of the present invention institute synthetic compound structure is MS, 1HNMR, conclusive evidences such as IR and ultimate analysis.
The present invention has proved that by external, the interior inhibition test to various tumor cell strains of body thiophene evil hexazinone compounds of the present invention has the effect of very strong inhibition growth of tumour cell.
Studies show that with GM63 (osteosarcoma cell line) thiophene evil hexazinone compounds of the present invention all has significant inhibitory effect to them with four kinds of tumor cell line KB (JEG-3 at the bottom of the oral cavity), KBv200 (to JEG-3 at the bottom of the drug-fast oral cavity of vincristine(VCR)), GLC-82 (lung adenocarcinoma cell line).And this compounds is very little to Normocellular toxicity, and therefore, thiophene evil hexazinone compounds of the present invention can be used for preparing anti-tumor drug.
Embodiment
The present invention is described further by the following examples.
Embodiment one: 2-amino-8-chloro-3H-phenoxazine-3-ketone (compound 1) synthetic
0.36g (2.5mmol) 2-amino-4-chlorophenol is dissolved in the 10mL acetone, the 50mL aqueous solution that adds 0.50g (2.5mmol) sodium iodate under the stirring at room, after 2 minutes, add 0.36g (2.5mmol) 2-amino-4-chlorophenol again, the stirring at room reaction adds the 100mL aqueous solution of 0.99g (5.0mmol) sodium iodate again after 2 hours, filter collection solid is filtered in stirring at room reaction 15 hours, wash filter cake with water, oven dry is after column chromatography (pure CHCl 3Wash-out) separation and purification obtains burgundy solid product 1, heavy 0.42g, and productive rate is 68.12%. 1H NMR(500MHz，DMSO-d 6)δ：6.35(s，1H)，6.36(s，1H)，7.04(s，2H)，7.51(d，J＝7.5Hz，1H)，7.60(d，J＝7.5Hz，1H)，7.77(s，1H)；IR ν max/cm -1：3423.0，3365.5，3294.6，1594.0，1557.8，1204.2；MS(FAB)m/z：247(M+H)+∶249(M+2+H) +＝3∶1。
Compound 1
Embodiment two: 2-amino-9-azepine-3H-phenoxazine-3-ketone (compound 2) synthetic
0.36g (2.5mmol) 2-amino-4-chlorophenol is dissolved in the 10mL acetone, the 50mL aqueous solution that adds 0.50g (2.5mmol) sodium iodate under the stirring at room, after 2 minutes, add 0.28g (2.5mmol) 2-amino-3-pyridone again, the stirring at room reaction adds the 100mL aqueous solution of 0.99g (5.0mmol) sodium iodate again after 2 hours, filter collection solid is filtered in stirring at room reaction 20 hours, wash filter cake with water, oven dry is after column chromatography (CHCl 3/ CH 3The OH=40/1 wash-out) separation and purification obtains orange red solid product 2, heavy 0.23g, and productive rate is 43.13%. 1H NMR(500MHz，DMSO-d 6)δ：6.42(s，1H)，6.55(s，1H)，7.06(s，2H)，7.80(dd，J＝8.5，4.5Hz，1H)，8.60(d，J＝8.5Hz，1H)，9.10(d，J＝4.5Hz，1H)；IR ν max/cm -1：3424.8，3364.5，1635.7，1584.0，1205.2；MS(ESI)m/z：214(M+H) +。
Figure C0314684700072
Compound 2
Embodiment three: and 2-amino-10-chloro-3H-pyrido [2,3-h] phenoxazine-3-ketone (compound 3) synthetic
Change 2-amino-3-pyridone into 5-chloro-7-amino-oxine reaction by embodiment two same methods and obtain crude product, through column chromatography (CHCl 3/ CH 3The OH=30/1 wash-out) separation and purification obtains orange red solid product 3, heavy 0.29g, and productive rate is 38.97%. 1H NMR(500MHz，DMSO-d 6)δ：6.44(s，1H)，6.53(s，1H)，7.03(s，2H)，7.80(dd，J＝8，4.5Hz，1H)，7.96(s，1H)，8.60(d，J＝8Hz，1H)，9.10(d，J＝4.5Hz，1H)；IR ν max/cm -1：3425.3，3258.2，1633.4，1572.9，1359.4，1214.8；MS(ESI)m/z：298(M+H) +∶300(M+2+H) +＝3∶1。
Figure C0314684700073
Compound 3
Embodiment four: 2-amino-1-azepine-3H-phenoxazine-3-ketone (compound 4) synthetic
0.28g (2.5mmol) 2-amino-3-pyridone is dissolved in the 10mL acetone, the 50mL aqueous solution that adds 0.50g (2.5mmol) sodium iodate under the stirring at room, after 2 minutes, add 0.27g (2.5mmol) 2-amino-phenol again, the stirring at room reaction adds the 100mL aqueous solution of 0.99g (5.0mmol) sodium iodate again after 2 hours, filter collection solid is filtered in stirring at room reaction 20 hours, wash filter cake with water, oven dry is after column chromatography (CHCl 3/ CH 3The OH=40/1 wash-out) separation and purification obtains orange/yellow solid product 4, heavy 0.28g, and productive rate is 52.53%. 1H NMR(500MHz，DMSO-d 6)δ：6.49(s，1H)，7.41(dd，J＝7.5，7.5Hz，1H)，7.47(dd，J＝7.5，7.5Hz，1H)，7.52(d，J＝7.5Hz，1H)，7.68(d，J＝7.5Hz，1H)，7.86(s，1H)，8.40(s，1H)；IR ν max/cm -1：3424.3，3050.0，3017.0，1626.6，1576.8，1449.5，1302.4，1208.2；MS(ESI)m/z：214(M+H) +。
Figure C0314684700081
Compound 4
Embodiment five: 2-amino-8-methyl isophthalic acid-azepine-3H-phenoxazine-3-ketone (compound 5) synthetic
Change the 2-amino-phenol into 2-amino-4-methylphenol reaction by embodiment four same methods and obtain crude product, through column chromatography (CHCl 3/ CH 3The OH=30/1 wash-out) separation and purification, orange red solid product 5, productive rate are 68.35%. 1H NMR(500MHz，DMSO-d 6)δ：2.40(s，3H)，6.48(s，1H)，7.30(d，J＝8Hz，1H)，7.42(d，J＝8Hz，1H)，7.50(s，1H)，7.89(s，1H)，8.51(s，1H)；IR ν max/cm -1：3364.4，3136.2，1666.8，1600.3，1568.0，1286.4，1179.9：MS(ESI)m/z：228(M+H) +。
Compound 5
Embodiment six: 2-amino-8-chloro-1-azepine-3H-phenoxazine-3-ketone (compound 6) synthetic
Change the 2-amino-phenol into 2-amino-4-chlorophenol reaction by embodiment four same methods and obtain crude product, through column chromatography (CHCl 3/ CH 3The OH=30/1 wash-out) separation and purification, orange/yellow solid product 6, productive rate are 59.78%. 1H NMR(500MHz，DMSO-d 6)δ：6.51(s，1H)，7.47(d，J＝8.5Hz，1H)，7.55(d，J＝8.5Hz，1H)，7.69(s，1H)，8.07(s，1H)，8.59(s，1H)；IR ν max/cm -1：3384.0，3175.3，1668.6，1614.4，1570.0，1448.3，1274.2，1183.8；MS(ESI)m/z：248(M+H) +∶250(M+2+H) +＝3∶1。
Figure C0314684700083
Compound 6
Embodiment seven: 2-amino-8-nitro-1-azepine-3H-phenoxazine-3-ketone (compound 7) synthetic
Change the 2-amino-phenol into 2-amino-4-nitrophenols reaction by embodiment four same methods and obtain crude product, through column chromatography (CHCl 3/ CH 3The OH=30/1 wash-out) separation and purification, pale brown look solid product 7, productive rate are 65.59%. 1H NMR(500MHz，DMSO-d 6)δ：6.60(s，1H)，7.71(d，J＝9Hz，1H)，8.22(s，1H)，8.24(d，J＝9Hz，1H)，8.36(s，1H)，8.75(s，1H)；IR ν max/cm -1：3354.8，3088.0，1629.0，1591.2，1529.6，1341.2，1175.7；MS(ESI)m/z：259(M+H) +。
Compound 7
Embodiment eight: 2-amino-1,8-diaza-3H-phenoxazine-3-ketone (compound 8) synthetic
By obtaining crude product behind the same method oxidation 2-amino-3-pyridone of embodiment one, through column chromatography (CHCl 3/ CH 3The OH=30/1 wash-out) separation and purification obtains pale brown look solid product 8, and productive rate is 60.28%. 1H NMR(500MHz，DMSO-d 6)δ：6.56(s，1H)，7.46(dd，J＝7.5，4.5Hz，1H)，7.96(d，J＝7.5Hz，1H)，8.29(s，1H)，8.55(d，J＝4.5Hz，1H)，8.77(s，1H)；IR ν max/cm -1：3423.2，3039.8，1620.5，1568.1，1423.9，1296.4，1201.9；MS(FAB)m/z：215(M+H) +。
Figure C0314684700092
Compound 8
Embodiment nine: and 2-amino-10-chloro-1-azepine-3H-pyrido [2,3-h] phenoxazine-3-ketone (compound 9) synthetic
Change the 2-amino-phenol into 5-chloro-7-amino-oxine reaction by embodiment four same methods and obtain crude product, through column chromatography (CHCl 3/ CH 3The OH=20/1 wash-out) separation and purification, orange/yellow solid product 9, productive rate are 39.76%. 1H NMR(500MHz，DMSO-d 6)δ：6.71(s，1H)，7.81(dd，J＝8.5，4.5Hz，1H)，7.98(s，1H)，8.12(s，1H)，8.61(d，J＝8.5Hz，1H)，8.67(s，1H)，9.11(d，J＝4.5Hz，1H)；IR ν max/cm -1：3426.1，3076.1，1622.1，1590.0，1560.3，1410.5，1196.9；MS(ESI)m/z：297(M-H) +∶299(M+2-H) +＝3∶1。
Figure C0314684700093
Compound 9
Embodiment ten: and 6-amino-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 10) synthetic
0.49g (2.5mmol) 5-chloro-7-amino-oxine is dissolved in the 10mL acetone, the 50mL aqueous solution that adds 0.50g (2.5mmol) sodium iodate under the stirring at room, after 2 minutes, add 0.27g (2.5mmol) 2-amino-phenol again, the stirring at room reaction adds the 100mL aqueous solution of 0.99g (5.0mmol) sodium iodate again after 2 hours, filter collection solid is filtered in stirring at room reaction 30 hours, wash filter cake with water, oven dry is after column chromatography (CHCl 3/ CH 3The OH=20/1 wash-out) separation and purification obtains amaranth solid product 10, heavy 0.27g, and productive rate is 41.02%. 1HNMR(500MHz，DMSO-d 6)δ：5.82(s，2H)，7.28(m，2H)，7.45(dd，J＝8，8.0Hz，1H)，7.66(d，J＝8Hz，1H)，7.81(dd，J＝7.5，4.5Hz，1H)，8.89(d，J＝7.5Hz，1H)，8.97(d，J＝4.5Hz，1H)；IR ν max/cm -1：3452.9，3351.6，2923.7，1625.3，1557.6，1383.6，1289.6；MS(FAB)m/z：264(M+H) +。
Compound 10
Embodiment 11: and 6-amino-10-methyl-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 11) synthetic
Change the 2-amino-phenol into 2-amino-4-methylphenol reaction by embodiment ten same methods and obtain amaranth solid product 11, productive rate is 48.39%. 1H NMR(500MHz，DMSO-d 6)δ：2.49(s，3H)，5.81(s，2H)，7.16(d，J＝8.5Hz，1H)，7.24(d，J＝8.5Hz，1H)，7.47(s，1H)，7.79(dd，J＝8，4.5Hz，1H)，8.86(d，J＝8Hz，1H)，8.96(d，J＝4.5Hz，1H)：IR ν max/cm -1：3468.0，3252.1，2922.6，1629.1，1605.0，1558.5，1505.6，1379.3，1284.3；MS(ESI)m/z：278(M+H) +。
Figure C0314684700102
Compound 11
Embodiment 12: and the 6-amino-10-tertiary butyl-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 12) synthetic
Change the 2-amino-phenol into 2-amino-4-tert.-butyl phenol reaction by embodiment ten same methods and obtain amaranth solid product 12, productive rate is 50.65%. 1H NMR(500MHz，DMSO-d 6)δ：1.38(s，9H)，6.61(s，2H)，7.26(d，J＝8.5Hz，1H)，7.55(d，J＝8.5Hz，1H)，7.80(s，1H)，7.83(dd，J＝8，4.5Hz，1H)，8.82(d，J＝8Hz，1H)，8.95(d，J＝4.5Hz，1H)；IR ν max/cm -1：3440.0，3277.1，2956.2，1678.8，1615.9，1546.0，1359.4，1279.7；MS(ESI)m/z：320(M+H) +。
Compound 12
Embodiment 13: 6-amino-10-chloro-5H-pyrido [3, the synthetic of 2-a] phenoxazine-5-ketone (compound 13) can be synthetic according to following two kinds of methods:
Method one: change the 2-amino-phenol into 2-amino-4-chlorophenol reaction by embodiment ten same methods and obtain amaranth solid product 13, productive rate is 40.06%.
Method two: 0.49g (2.5mmol) 5-chloro-7-amino-oxine is dissolved in the 5mL acetone, after 2g silica gel adsorption oven dry, add 0.50g (2.5mmol) sodium iodate, after this mixture grinding evenly, microwave 160w reaction 1 minute, add 0.36g (2.5mmol) 2-amino-4-chlorophenol again, after the grinding evenly, microwave 480w reaction 15 minutes, add 0.99g (5.0mmol) sodium iodate again, after grinding evenly, microwave 640w reaction is after 30 minutes, through column chromatography (CHCl 3/ CH 3The OH=10/1 wash-out) separation and purification obtains amaranth solid product 13, and productive rate is 45.86%.
1H NMR(500MHz，DMSO-d 6)δ：6.00(s，2H)，7.25(d，J＝8.5Hz，1H)，7.45(d，J＝8.5Hz，1H)，7.65(s，1H)，7.81(dd，J＝8，4.5Hz，1H)，8.83(d，J＝8Hz，1H)，8.97(d，J＝4.5Hz，1H)；IRν max/cm -1：3486.5，3260.5，2923.1，1630.6，1600.2，1566.0，1398.2，1288.1；MS(ESI)m/z：298(M+H) +∶300(M+2+H) +＝3∶1。
Figure C0314684700111
Compound 13
Embodiment 14: and 6-amino-10-nitro-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 14) synthetic
Change the 2-amino-phenol into 2-amino-4-nitrophenols reaction by embodiment ten same methods and obtain amaranth solid product 14, productive rate is 55.85%. 1H NMR(500MHz，DMSO-d 6)δ：7.01(s，2H)，7.58(d，J＝9Hz，1H)，7.95(dd，J＝8，4.5Hz，1H)，8.30(d，J＝9Hz，1H)，8.52(s，1H)，8.57(d，J＝8Hz，1H)，8.86(d，J＝4.5Hz，1H)；IR ν max/cm -1：3447.6，3215.0，3090.0，2920.5，1684.1，1604.2，1546.5，1336.4，1277.0，1257.5；MS(ESI)m/z：309(M+H) +。
Compound 14
Embodiment 15: and 6-amino-5H-pyrido [3,2-a] phenoxazine-5-ketone-10-formic acid (compound 15) synthetic
Change the 2-amino-phenol into 3-amino-4-hydroxy benzoic acid by embodiment ten same methods and obtain amaranth solid product 15, productive rate is 40.78%. 1H NMR(500MHz，DMSO-d 6)δ：6.59(s，2H)，7.50(d，J＝8Hz，1H)，7.65(d，J＝8Hz，1H)，7.88(dd，J＝8，4.5Hz，1H)，8.39(s，1H)，8.90(d，J＝8Hz，1H)，8.98(d，J＝4.5Hz，1H)；IR ν max/cm -1：3447.5，2954.8，2925.2，1733.1，1623.9，1454.7，1240.5，1147.2；MS(ESI)m/z：308(M+H) +。
Compound 15
Embodiment 16: and 6-amino-10-phenyl-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 16) synthetic
Change the 2-amino-phenol into 2-amino-4-phenylphenol reaction by embodiment ten same methods and obtain amaranth solid product 16, productive rate is 46.86%. 1H NMR(500MHz，DMSO-d 6)δ：6.63(s，2H)，7.40(d，J＝8Hz，1H)，7.42(d，J＝9Hz，1H)，7.50(dd，J＝8，8Hz，2H)，7.77(d，J＝8Hz，2H)，7.82(d，J＝9Hz，1H)，7.84(dd，J＝8，4.5Hz，1H)，8.10(s，1H)，8.84(d，J＝8Hz，1H)，8.96(d，J＝4.5Hz，1H)；IR ν max/cm -1：3435.0，3266.8，2952.0，1678.6，1614.5，1543.4，1358.6，1278.7；MS(ESI)m/z：340(M+H) +。
Figure C0314684700122
Compound 16
Embodiment 17: and 6-amino-10-benzyl-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 17) synthetic
Change the 2-amino-phenol into 2-amino-4-benzylphenol reaction by embodiment ten same methods and obtain amaranth solid product 17, productive rate is 50.21%. 1H NMR(500MHz，DMSO-d 6)δ：4.05(s，2H)，6.60(s，2H)，7.25(d，J＝8Hz，1H)，7.27～7.34(m，5H)，7.38(d，J＝8Hz，1H)，7.67(s，1H)，7.82(dd，J＝8，4Hz，1H)，8.81(d，J＝8Hz，1H)，8.94(d，J＝4Hz，1H)；IR ν max/cm -1：3435.0，3272.3，2954.9，1678.8，1615.8，1547.3，1363.3，1280.6；MS(ESI)m/z：354(M+H) +。
Figure C0314684700123
Compound 17
Embodiment 18: and 6-amino-10-benzoyl-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 18) synthetic
Change the 2-amino-phenol into 2-amino-4-benzoyl phenol reaction by embodiment ten same methods and obtain amaranth solid product 18, productive rate is 43.59%. 1H NMR(500MHz，DMSO-d 6)δ：6.67(s，2H)，7.47(d，J＝8Hz，1H)，7.61(dd，J＝8，8Hz，2H)，7.71(d，J＝8Hz，1H)，7.79(d，J＝8Hz，2H)，7.84(dd，J＝8，4.5Hz，1H)，7.86(d，J＝8Hz，1H)，8.08(s，1H)，8.81(d，J＝8Hz，1H)，8.96(d，J＝4.5Hz，1H)；IR ν max/cm -1：3435.0，3269.5，2952.0，1680.7，1614.8，1547.2，1360.4，1259.4，1223.0；MS(ESI)m/z：368(M+H) +
Figure C0314684700131
Compound 18
Embodiment 19: and 6-amino-9-methyl-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 19) synthetic
Change the 2-amino-phenol into 2-amino-5-methylphenol reaction by embodiment ten same methods and obtain amaranth solid product 19, productive rate is 45.69%. 1H NMR(500MHz，DMSO-d 6)δ：2.36(s，3H)，5.97(s，2H)，7.06(s，1H)，7.25(d，J＝8Hz，1H)，7.66(d，J＝8Hz，1H)，7.88(dd，J＝8，4.5Hz，1H)，8.88(d，J＝8Hz，1H)，8.97(d，J＝4.5Hz，1H)；IR ν max/cm -1：3438.1，3363.0，2953.0，2924.4，1730.6，1620.4，1559.7，1350.5，1279.4，1250.0；MS(ESI)m/z：278(M+H) +。
Figure C0314684700132
Compound 19
Embodiment 20: and 6-amino-9-nitro-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 20) synthetic
Change the 2-amino-phenol into 2-amino-5-nitrophenols reaction by embodiment ten same methods and obtain amaranth solid product 20, productive rate is 43.67%. 1H NMR(500MHz，DMSO-d 6)δ：6.67(s，2H)，7.84(dd，J＝8，4.5Hz，1H)，8.01(d，J＝8.5Hz，1H)，8.08(s，1H)，8.17(d，J＝8.5Hz，1H)，8.80(d，J＝8Hz，1H)，8.95(d，J＝4.5Hz，1H)；IR ν max/cm -1：3471.5，3275.4，1674.9，1615.0，1547.7，1340.3，1282.1，1227.3；MS(ESI)m/z：309(M+H) +。
Figure C0314684700133
Compound 20
Embodiment 21: and 6-amino-5H-pyrido [3,2-a] phenoxazine-5-ketone-9-formic acid (compound 21) synthetic
Change the 2-amino-phenol reaction of into 4-amino-3-hydroxy formic acid by embodiment ten same methods and obtain amaranth solid product 21, productive rate is 38.56%. 1H NMR(500MHz，DMSO-d 6)δ：6.60(s，2H)，7.50(d，J＝8Hz，1H)，7.68(d，J＝8Hz，1H)，7.88(dd，J＝8，4.5Hz，1H)，8.18(s，1H)，8.88(d，J＝8Hz，1H)，8.97(d，J＝4.5Hz，1H)；IR ν max/cm -1：3414.8，2956.0，2923.0，1732.2，1623.6，1462.5，1377.0，1283.0；MS(ESI)m/z：308(M+H) +。
Figure C0314684700141
Compound 21
Embodiment 22: and 6-amino-11-azepine-5H-pyrido [3,2-a] phenoxazine-5-ketone (compound 22) synthetic
Change the 2-amino-phenol into 2-amino-3-pyridone reaction by embodiment ten same methods and obtain amaranth solid product 22, productive rate is 42.43%. 1H NMR(500MHz，DMSO-d 6)δ：5.97(s，2H)，7.66(dd，J＝8，4.5Hz，1H)，7.88(dd，J＝8，4.5Hz，1H)，8.61(d，J＝8Hz，1H)，8.88(d，J＝8Hz，1H)，8.95(d，J＝4.5Hz，1H)，8.97(d，J＝4.5Hz，1H)；IR ν max/cm -1：3446.0，3333.5，2952.0，2924.4，1729.3，1619.1，1558.3，1350.2，1279.4；MS(ESI)m/z：265(M+H) +。
Figure C0314684700142
Compound 22
Embodiment 23: and 6-amino-12-chloro-5H-pyrido [3,2-a] pyrido [2,3-h] phenoxazine-5-ketone (compound 23) synthetic
Change the 2-amino-phenol into 5-chloro-7-amino-oxine reaction by embodiment ten same methods and obtain intense violet color solid product 23, productive rate is 58.30%. 1H NMR(500MHz，CDCl 3)δ：5.71(s，2H)，7.67(dd，J＝8，4.5Hz，1H)，7.71(dd，J＝8.5，4.5Hz，1H)，7.97(s，1H)，8.66(d，J＝8Hz，1H)，9.00(d，J＝8.5Hz，1H)，9.04(d，J＝4.5Hz，1H)，9.08(d，J＝4.5Hz，1H)；IR ν max/cm -1：3257.2，3149.0，1632.4，1562.9，1357.4，1284.8；MS(FAB)m/z：349(M+H) +∶351(M+2+H) +＝3∶1。
Compound 23
Embodiment 24: thiophene evil hexazinone compounds (formula I～IV compound) are to the restraining effect of growth of tumour cell
Select the representative compound of part, with four kinds of tumor cell line KB (JEG-3 at the bottom of the oral cavity), KBv200 (to JEG-3 at the bottom of the drug-fast oral cavity of vincristine(VCR)), GLC-82 (lung adenocarcinoma cell line) and GM63 (osteosarcoma cell line), adopt mtt assay to carry out the cell in vitro poison and measure.The logarithmic phase cell adds different concns De thiophene evil hexazinone compounds, acts on after 72 hours, measures its absorbancy.Calculate the compound concentration that cell growth inhibiting reaches at 50% o'clock respectively, with IC 50Value representation, the result is as shown in table 1.The result shows that formula I～IV compound all has very strong restraining effect in external growth to these four kinds of tumor cell lines.
Select the restraining effect of 1 pair of interior tumor cell of compound to test, the result shows, when low dosage (50mg/Kg) medication, tumour inhibiting rate is 10.68%, when middle dosage (100mg/Kg) medication, tumour inhibiting rate is 28.95%, when high dosage (200mg/Kg) medication, tumour inhibiting rate is 50.94%, demonstrates good tumor killing effect.Because this compounds is not to Normocellular toxicity very little (still can detecting toxicity) under the situation of high dosage 200mg/Kg, therefore, thiophene evil hexazinone compounds of the present invention has DEVELOPMENT PROSPECT, can be used for preparing anti-tumor drug.
Table 1. formula I～IV compound is to the restraining effect (IC of tumor cell line growth 50/ μ M)
KB KBv200 GLC-82 GM63
Compound 1 4.65 3.94 2.41 0.81
Compound 4 7.15 28.55 1.66 NT
Compound 8 ＞100 ＞100 12.67 8
Compound 9 2.25 6.91 4.34 0.78
Compound 10 0.47 0.83 1.42 NT
Compound 11 0.16 1.55 2.09 0.08
Compound 13 0.10 3.18 0.62 NT
Compound 23 5.54 48.66 NT NT
Annotate: NT represents not survey.

Claims (7)

1. the thiophene evil hexazinone of De shown in formula III compounds:
Figure C031468470002C1
Formula III
R in the formula 1, R 2With the group of X representative as described in the and the following:
(1) R 1, R 2Can be identical, also can be different, be selected from one of the following stated group: H, F, Cl, Br, NO 2, COOH, C 1-6Alkyl, phenyl, benzyl, benzoyl;
(2) X is selected from C or N.
2. the preparation method of the described formula III compound of claim 1, step is: o-aminophenol or 2-amino-3-pyridone or 5-chloro-7-amino-oxine are dissolved in the solvent, 0～30 ℃ is also stirred the aqueous solution that adds the equimolar amount oxygenant down, after 1～10 minute, neighbour-the p-aminophenol derivative or 2-amino-3-Tetrahydrothienopyriderivatives derivatives or the 7-amino-oxine derivative that add equimolar amount again, 0.5 after～3 hours, the aqueous solution that adds 2 times of molar weight oxygenants again, stirring at room reaction 5～30 hours, filter filter collection solid, wash filter cake with water, oven dry is after column chromatographic isolation and purification promptly obtains corresponding thiophene evil hexazinone compounds; Used neighbour-p-aminophenol derivative, 2-amino-3-Tetrahydrothienopyriderivatives derivatives and 7-amino-oxine derivative are respectively shown in following formula V, VI, VII:
Figure C031468470002C2
Formula V formula VI formula VII
R among formula V and the formula VI 1, R 2Can be identical, also can be different, be selected from one of following radicals: H, F, Cl, Br, NO 2, COOH, C 1-6Alkyl, phenyl, benzyl, benzoyl;
R among the formula VII 3Be Cl.
3. in accordance with the method for claim 2, it is characterized in that used solvent is selected from one or more the mixture in water, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), dioxane, acetonitrile, methyl-sulphoxide, the dimethyl formamide.
4. according to claim 2 or 3 described methods, it is characterized in that used oxygenant is sodium iodate, the Tripotassium iron hexacyanide, potassium permanganate, potassium bichromate, iron trichloride or Potassium Persulfate.
5. each method of system of the described formula III compound of claim 1, step is: with o-aminophenol or 2-amino-3-pyridone or 5-chloro-7-amino-oxine grind into powder, or with grind into powder again behind silica gel or aluminum oxide or the diatomite adsorption, the oxygenant that adds equimolar amount, after grinding this mixture evenly, microwave 100～800w reaction is after 0.5～10 minute, neighbour-the p-aminophenol derivative or 2-amino-3-Tetrahydrothienopyriderivatives derivatives or the 7-amino-oxine derivative that add equimolar amount again, after grinding evenly, microwave 100～800w reaction 1～10 minute, add 2 times of molar weight oxygenants again, after grinding evenly, microwave 100～800w reaction promptly obtained corresponding thiophene evil hexazinone compounds through column chromatographic isolation and purification after 10～60 minutes; Used neighbour-p-aminophenol derivative, 2-amino-3-Tetrahydrothienopyriderivatives derivatives and 7-amino-oxine derivative are respectively shown in following formula V, VI, VII:
Formula V formula VI formula VII
R among formula V and the formula VI 1, R 2Can be identical, also can be different, be selected from one of following radicals: H, F, Cl, Br, NO 2, COOH, C 1-6Alkyl, phenyl, benzyl, benzoyl;
R among the formula VII 3Be Cl.
6. in accordance with the method for claim 5, it is characterized in that used oxygenant is sodium iodate, the Tripotassium iron hexacyanide, potassium permanganate, potassium bichromate, iron trichloride or Potassium Persulfate.
7. the described formula III compound of claim 1 is as the application of preparation antitumor drug.
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