CN104788333B - 2-substituted-9,10-anthraquinone compounds, and preparation method and application thereof - Google Patents

2-substituted-9,10-anthraquinone compounds, and preparation method and application thereof Download PDF

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CN104788333B
CN104788333B CN201510121606.5A CN201510121606A CN104788333B CN 104788333 B CN104788333 B CN 104788333B CN 201510121606 A CN201510121606 A CN 201510121606A CN 104788333 B CN104788333 B CN 104788333B
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methyl
anthraquinones
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triazol
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CN104788333A (en
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孟繁浩
张廷剑
袁伟燕
杨苏
王琳
孙琦
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China Medical University
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China Medical University
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Abstract

The invention belongs to the technical field of medicine, and particularly relates to 2-substituted-9,10-anthraquinone compounds represented by the general formula I, the general formula II, the general formula III and the general formula IV, and pharmaceutically acceptable salts, hydrates or solvates and pharmaceutically acceptable carriers thereof. A preparation method comprises the steps: with phthalic anhydride as a starting material, carrying out a Friedel-Crafts reaction, concentrated sulfuric acid dehydration, NBS bromization and sodium azide substitution, generating a key intermediate 2-azide methyl-9,10-anthraquinone, and finally in the presence of copper sulfate pentahydrate and vitamin C, carrying out a Husigen cycloaddition reaction with substituted alkyne; or carrying out concentrated sulfuric acid dehydration, cyclization, chromium trioxide oxidation and thionyl chloride chlorination, to obtain anthraquinone-2-formyl chloride, then carrying out an acylation reaction with various L-amino acid methyl esters, further hydrolyzing, and thus obtaining the target compounds. The prepared compounds show good results in in-vitro antitumor activity tests.

Description

2- replaces -9,10- anthraquinone analog compounds, preparation method and its usage
Technical field：The invention belongs to pharmaceutical technology field, is related to, with anti-tumor activity such as formula I, formula II, lead to The 2- of formula III and general formulae IV replaces -9,10- anthraquinone analog compounds, compositionss and preparation method thereof.
Background technology：Malignant tumor is the disease for seriously threatening human health, and current malignant tumor has been over painstaking effort Pipe disease becomes the first killer for causing human death.World Health Organization, it is contemplated that the year two thousand thirty, will have 12,000,000 people to die from Malignant tumor.Although current antitumor drug has certain curative effect, there is poor selectivity, the shortcomings of toxic and side effects are big, medicine Thing treats the new breakthrough that waits in expectation.Therefore, efficient, low toxicity, wide spectrum are found and cheap antitumor drug has become current swelling The important content of tumor research.
Anthraquinone analog compound, is widely present in natural plant, with plants such as Rubiaceae, Rhamnaceae, pulse family and Polygonaceaes In have high level.Such compound has multiple biological activities, is wherein projected with anti-tumor activity the most.With amycin class There is stronger II inhibitory activity of Topo with the anthraquinone analog compound that mitoxantrone is representative, as antitumor drug clinically Widely use.
It is several antitumor drug for being applied to clinic above.
The content of the invention：
It is an object of the invention to provide a kind of such as formula I, formula II, the Anthraquinones shown in general formula III and general formulae IV are newly changed Compound, prepared compound have shown good result during anti-tumor activity is tested in vitro.
Another object of the present invention is to provide such as formula I, formula II, the new chemical combination of the anthraquinone shown in general formula III and general formulae IV The preparation method of thing.
For achieving the above object, the present invention is employed the following technical solutions：
A kind of 2- replaces -9,10- anthraquinone analog compounds, it is characterised in that：The compound includes formula I, formula II, formula III and general formulae IV, structural formula is as follows：
Wherein：
Integers of the m for 0-1；Integers of the n for 0-3；
Each X stands alone as O or OCO；
Each R1Stand alone as the fatty acyl group of H or 1-5 carbon atom；
Each R2Stand alone as H, F, Cl, Br, amino, nitro, cyano group, hydroxyl, methoxyl group, the alkyl of 1-5 carbon, 1-5 carbon The fatty acylamino- of atom, phenylacetyl group amino, tolysulfonyl amino, formoxyl, carboxyl, methoxyl group, acetoxyl group, diethyl Amido；
Each R3Stand alone as H, F, Cl, Br, amino, nitro, cyano group, hydroxyl, methoxyl group, benzyloxy, acetoxyl group, diethyl Amido；
Each R4Stand alone as H, isopropyl, isobutyl group, sec-butyl, phenyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamyl Ethyl, 3- indole methyls.
The compound of formula I and formula II, they are selected from：
2- (4- Phenoxymethyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones
2- (4- ((4- formoxyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- (2- formoxyl -5- fluorine Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- (2- formoxyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- (2- formoxyl -4- fluorine Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- (2- formoxyl -4- chlorine Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- (2- formoxyl -4- bromine Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- (2- formoxyl -4,6- dibromo-phenoxy methyl) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthracenes Quinone
2- (4- (2- formoxyl -4,6- di-t-butyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9, 10- anthraquinones
2- (4- (2- formoxyl -5- diethylin Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- Anthraquinone
2- (4- ((4- cyano group Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- ((2,6- Dichlorophenoxy methyl) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- ((4- formoxyl -2,6- dimethoxy Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9, 10- anthraquinones
2- (4- ((4- acetylamino Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- ((2- carboxyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- ((3- formoxyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- methylol -1,2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- acetyl-o-methyl -1,2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- benzoyloxymethy -1,2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- (2- carboxybenzoyl epoxides) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- (2- chlorobenzoyl epoxides) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- (2- acetoxyl group benzoyloxys) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- (4- nitrobenzoyl acyloxy) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- phenyl -1,2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- (4- (3- amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N- acetyl group) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N- propionos) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N- phenylacetyl groups) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N- cinnamoyls) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N- (2- picolinoyls)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N- (4- Methyl benzenesulfonyl bases)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- anthracenes Quinone.
The compound of the general formula III, they are selected from：
2- (4- (3- (N- benzoyls) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N- (2- chlorobenzene formacyls)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N-4- nitro benzoyls) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- anthraquinones
2- (4- (3- (N- (- 5 benzoyl bromide of 2- methoxyl groups)) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl - 9,10- anthraquinones
2- (4- (3- (N- (3,5 2 bromo- 4- anisoyl)) amino) phenyl -1,2,3-1H triazol-1-yls) first Base -9,10- anthraquinones
2- (4- (3- (N- (3,5 2 bromo- 4- benzyloxybenzoyls)) amino) phenyl -1,2,3-1H- triazol-1-yls) first Base -9,10- anthraquinones
2- (4- (3- (N- (2- methoxyl group -5- fluoro benzoyls)) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl - 9,10- anthraquinones
2- (4- (3- (N- (2- acetoxy benzoyls)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9, 10- anthraquinones
2- (4- (3- (N- (3,4,5- trimethoxybenzoys)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl - 9,10- anthraquinones.
The compound of the general formulae IV, they are selected from：
N-9,10- anthraquinone -2- formoxyl Phenylalanine
N-9,10- anthraquinone -2- formyl methionines
N-9,10- anthraquinone -2- formoxyl glutamic acid
N-9,10- anthraquinone -2- formoxyl L-Valine
N-9,10- anthraquinone -2- formoxyl leucines
N-9,10- anthraquinone -2- formoxyl glycine
N-9,10- anthraquinone -2- formyltryptophans
N-9,10- anthraquinone -2- formoxyl proline
N-9,10- anthraquinone -2- formoxyl aspartic acids
N-9,10- anthraquinone -2- formoxyl isoleucine
N-9,10- anthraquinone -2- formoxyl glutamine
N-9,10- anthraquinone -2- formoxyl agedoites.
A kind of Pharmaceutical composition, it is comprising the compound described in claim 1-4 any one and its can pharmaceutically connect Salt, hydrate or the solvate received and pharmaceutically acceptable carrier, used as preparing the application in antitumor drug.
A kind of 2- as above replaces the preparation method of -9,10- anthraquinone analog compounds, it is characterised in that：
Formula I, the preparation of compound shown in formula II and general formula III：With phthalic anhydride as initiation material, Jing Friedel-Crafts reacts, concentrated sulphuric acid dehydration, NBS bromos, sodium azide replace, and generate key intermediate 2- azido-methyl -9, 10- anthraquinones, finally copper sulfate pentahydrate and it is ascorbic in the presence of, with replace alkynes Jing Husigen cycloaddition reactions, Obtain formula I, the target compound shown in formula II and general formula III；
The preparation of the target compound shown in general formulae IV：With phthalic anhydride as initiation material, Jing Friedel- Crafts reacts, concentrated sulphuric acid dehydration, cyclization, chromic acid oxygen, and thionyl chloride chloro is obtained anthraquinone -2- formyl chlorides, then with it is various L-amino acid methyl ester carries out acylation reaction, further hydrolyzes, and obtains the target compound shown in general formulae IV.
Specific embodiment：The present invention is explained in detail by the following examples, these embodiments are merely illustrative, absolutely Do not limit the scope of the invention.
The present invention formula I, the compound shown in formula II and general formula III can pass course 1 synthesis obtain：
With phthalic anhydride as initiation material, Jing Friedel-Crafts reactions, concentrated sulphuric acid dehydration, NBS bromos are folded Nitrogen sodium replaces, and generates key intermediate 2- azido-methyl -9, and 10- anthraquinones, finally in copper sulfate pentahydrate and ascorbic presence Under, with the alkynes Jing Husigen cycloaddition reactions for replacing, obtain formula I and the target compound shown in formula II.
Compound shown in the general formulae IV of the present invention can pass course it is 2-in-1 into obtaining：
With phthalic anhydride as initiation material, Jing Friedel-Crafts reactions, concentrated sulphuric acid dehydration, cyclization, three oxidations Chromium oxygen, thionyl chloride chloro are obtained anthraquinone -2- formyl chlorides, then carry out acylation reaction, further water with various l-amino acid methyl ester Solution, obtains the target compound shown in general formula III.
Formula I provided by the present invention, formula II, the preparation side of the Anthraquinones noval chemical compound shown in general formula III and general formulae IV Method simple possible, yield are preferable.
Embodiment 1
The preparation of 2- methyl -9,10- anthraquinones
In 250mL Phthalic anhydride (14.8g, 0.1mol) and toluene (64mL) is added in reaction bulb, is dividedly in some parts anhydrous chlorination under 50 DEG C of stirrings Aluminum (26.7g, 0.2mol), continues reaction 4h, moves in beaker after completion of the reaction, is slowly added to 10% dilute sulfuric acid that ice bath crosses extremely Toluene is flung in no longer heat release, sucking filtration after cooling, massive laundering, drying, obtains whiteness 22.1g, yield 92.1%.
Above-mentioned whiteness and concentrated sulphuric acid (88mL, 4mL/g), 100 DEG C of reaction 1h, reaction is added in 250mL reaction bulbs Pour into after finishing in trash ice, sucking filtration, washing obtains yellow powder 15.3g, yield 75.2%.
Embodiment 2
The preparation of 2- bromomethyl -9,10- anthraquinones
Addition 2- methyl -9 in reaction bulb, 10- anthraquinones (5.55g, 25mmol), N- bromo-succinimides (4.95g, 27mmol), benzoyl peroxide 1g, carbon tetrachloride 50mL, back flow reaction 24h.Sucking filtration after cooling, obtains yellow substance, after being dried Filter cake is dissolved in 80mL 20%NaOH solution and is washed, sucking filtration washes to obtain product.
Embodiment 3
The preparation of 2- azido-methyl -9,10- anthraquinones
2- bromomethyl -9 are added in reaction bulb, and 10- anthraquinones (3.8g, 13mmol), sodium azide (1.69g, 26mmol) are few Amount potassium iodide, tetrahydrofuran 30mL are reacted under the conditions of 40 DEG C overnight, and reactant liquor is in brick-red, and dilute, sucking filtration are obtained slightly Product, acetone recrystallization obtain sterling.
Embodiment 4
Synthesize formula I, the compound shown in formula II and general formula III by the following technical programs
Concrete scheme is as follows：
(1) preparation of 2- (4- Phenoxymethyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones (TJA01)
In reaction bulb, add copper sulfate 0.18g and vitamin C 0.15g, plus 50 DEG C of microwave reaction 2min of 10mL water to make which Dissolving, adds h1 (1.1g, 69mmol) and g (1.5g, 57mmol), DMF 20mL, and 80 DEG C of microwave reaction 10min add water dilute Release, separate out crystallization, sucking filtration.Filter cake is washed and starched with 60% ethanol, then is concentrated to dryness with 10mL tetrahydrofurans and 40mL acetone extractions, Off-white color crystalline powder is obtained with 95% ethyl alcohol recrystallization afterwards.
1H-NMR(400MHz,DMSO-d6):δ8.41(s,1H,Ar-H),8.21(m,3H,Ar-H),8.13(s,1H,Ar- H), 7.93 (m, 2H, Ar-H), 7.82 (d, 1H, J=8Hz, Ar-H), 7.29 (t, 2H, J=7.56Hz, Ar-H), 7.03 (d, 2H, J=8.56Hz, Ar-H), 6.94 (t, 1H, J=7.32Hz, Ar-H), 5.89 (s, 2H, CH2),5.16(s,2H,CH2).
(2) 2- (4- ((4- formoxyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA02) preparation, method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ9.87(s,1H,CHO),8.47(s,1H,Ar-H),8.20(m,3H,Ar- ), H 8.11 (d, 1H, J=1.52Hz, Ar-H), 7.93 (m, 2H, Ar-H), 7.89 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.83 (dd, 1H, J=8.02Hz, J=1.68Hz, Ar-H), 7.25 (s, 1H, Ar-H), 7.23 (s, 1H, Ar-H), 5.90 (s, 2H,CH2),5.32(s,2H,CH2).
(3) 2- (4- (2- formoxyl -5- fluorine Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthracenes The preparation of quinone (TJA03), method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ10.23(s,1H,CHO),8.54(s,1H,Ar-H),8.20(m,3H,Ar- ), H 8.11 (d, 1H, J=1.4Hz, Ar-H), 7.93 (m, 2H, Ar-H), 7.79 (m, 2H, Ar-H), 7.40 (dd, 1H, J= 11.44Hz, J=2.24Hz, Ar-H), 6.95 (td, 1H, J=8.48Hz, J=2.12Hz, Ar-H), 5.91 (s, 2H, CH2), 5.41(s,2H,CH2).
(4) 2- (4- (2- formoxyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA04) preparation, method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ 10.35 (s, 1H, CHO), 8.51 (s, 1H, Ar-H), 7.81 (d, 1H, J= 7.96Hz, Ar-H), 7.44 (d, 1H, J=8.28Hz, Ar-H), 7.10 (t, 1H, J=7.2Hz, Ar-H), 5.89 (s, 2H, CH2),5.39(s,2H,CH2).
(5) 2- (4- (2- formoxyl -4- fluorine Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthracenes The preparation of quinone (TJA05), method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ 10.27 (d, 1H, J=3.2Hz, CHO), 8.51 (s, 1H, Ar-H), 8.20 (m, 3H, Ar-H), 8.09 (d, 1H, J=1.36Hz, Ar-H), 7.93 (d, 2H, J=3.32Hz, Ar-H), 7.80 (dd, 1H, J =8.04Hz, J=1.64Hz, Ar-H), 7.54 (m, 2H, Ar-H), 7.39 (dd, 1H, J=8.42Hz, J=3.24Hz, Ar- H),5.90(s,2H,CH2),5.39(s,2H,CH2).
(6) 2- (4- (2- formoxyl -4- chlorine Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthracenes The preparation of quinone (TJA06), method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ10.26(s,1H,CHO),8.50(s,1H,Ar-H),8.21(m,3H,Ar- ), H 8.09 (s, 1H, Ar-H), 7.93 (m, 3H, Ar-H), 7.79 (d, 1H, J=8Hz, Ar-H), 7.72 (dd, 1H, J= 8.96Hz, J=2.76Hz, Ar-H), 7.62 (t, 1H, J=2.44Hz, Ar-H), 5.89 (s, 2H, CH2),5.40(s,2H, CH2).
(7) 2- (4- (2- formoxyl -4- bromine Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthracenes The preparation of quinone (TJA07), method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ10.24(s,1H,CHO),8.50(s,1H,Ar-H),8.21(m,3H,Ar- H), 8.09 (d, 1H, J=1.32Hz, Ar-H), 7.94 (m, 2H, Ar-H), 7.84 (dd, 1H, J=8.72Hz, J=2.24Hz, Ar-H), 7.80 (dd, 1H, J=8.02Hz, J=1.6Hz, Ar-H), 7.73 (d, 1H, J=2.64Hz, Ar-H), 7.45 (d, 1H, J=8.92Hz, Ar-H), 5.89 (s, 2H, CH2),5.40(s,2H,CH2).
(8) 2- (4- (2- formoxyl -4,6- dibromo-phenoxy methyl) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9, The preparation of 10- anthraquinones (TJA08), method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ 9.93 (s, 1H, CHO), 8.43 (s, 1H, Ar-H), 8.25 (d, 1H, J= 2.48Hz, Ar-H), 8.22 (m, 3H, Ar-H), 8.10 (d, 1H, J=1.48Hz, Ar-H), 7.94 (m, 2H, Ar-H), 7.74 (d, 1H, J=2.48Hz, Ar-H), 7.72 (d, 1H, J=1.76Hz, Ar-H), 5.87 (s, 2H, CH2),5.30(s,2H,CH2).
(9) 2- (4- (2- formoxyl -4,6- di-t-butyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) - The preparation of 9,10- anthraquinones (TJA09), method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ10.35(s,1H,CHO),8.56(s,1H,Ar-H),8.20(m,5H,Ar- ), H 7.95 (m, 3H, Ar-H), 7.85 (dd, 1H, J=8.04Hz, J=1.68Hz, Ar-H), 7.66 (m, 2H, Ar-H), 5.93 (s,2H,Ar-H),5.08(s,2H,CH2),1.41(s,9H,CH3),1.30(s,9H,CH3).
(10) 2- (4- (2- formoxyl -5- diethylin Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) - The preparation of 9,10- anthraquinones (TJA10), method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ9.98(s,1H,CHO),8.48(s,1H,Ar-H),8.20(m,3H,Ar- ), H 8.12 (d, 1H, J=1.48Hz, Ar-H), 7.93 (m, 2H, Ar-H), 7.81 (dd, 1H, J=8Hz, J=1.72Hz, Ar- ), H 7.49 (d, 1H, J=8.88Hz, Ar-H), 6.36 (m, 2H, Ar-H), 5.90 (s, 2H, CH2),5.35(s,2H,CH2), 3.43(m,4H,CH2), 1.11 (t, 6H, J=7Hz, CH3).
(11) 2- (4- ((4- cyano group Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA11) preparation, method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ8.46(s,1H,Ar-H),8.20(m,3H,Ar-H),8.10(s,1H,Ar- ), H 7.92 (m, 2H, Ar-H), 7.82 (dd, 1H, J=8.06Hz, J=1.2Hz, Ar-H), 7.80 (s, 1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.22 (d, 2H, J=8.8Hz, Ar-H), 5.90 (s, 2H, CH2),5.30(s,2H,CH2).
(12) 2- (4- ((2,6- Dichlorophenoxy methyl) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA12) preparation, method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ8.49(s,1H,Ar-H),8.21(m,3H,Ar-H),8.13(s,1H,Ar- ), H 7.94 (d, 1H, J=3.44Hz, Ar-H), 7.93 (d, 1H, J=3.44Hz, Ar-H), 7.79 (dd, 1H, J=7.8Hz, J =1.32Hz, Ar-H), 7.50 (s, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.18 (t, 1H, J=8Hz, Ar-H), 5.90 (s,2H,CH2),5.16(s,2H,CH2).
(13) 2- (4- ((4- formoxyl -2,6- dimethoxy Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) first Base) -9,10- anthraquinones (TJA13) preparation, method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ9.85(s,1H,Ar-H),8.30(s,1H,Ar-H),8.20(m,3H,Ar- H), 8.10 (d, 1H, J=1.48Hz, Ar-H), 7.93 (m, 2H, Ar-H), 7.74 (dd, 1H, J=4.2Hz, J=1.68Hz, Ar-H),7.21(s,2H,Ar-H),5.86(s,2H,CH2),5.14(s,2H,CH2),3.80(s,6H,CH3).
(14) 2- (4- ((4- acetylamino Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA14) preparation, method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ9.80(s,1H,NH),8.40(s,1H,Ar-H),8.16(m,4H,Ar-H), 7.92 (m, 2H, Ar-H), 7.80 (dd, 1H, J=8Hz, J=1.6Hz, Ar-H), 7.48 (d, 2H, J=9Hz, Ar-H), 6.96 (d, 2H, J=9.04Hz, Ar-H), 5.88 (s, 2H, CH2),5.12(s,2H,CH2),2.00(s,3H,CH3).
(15) 2- (4- ((2- carboxyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA15) preparation, method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ12.59(s,1H,COOH),8.36(s,1H,Ar-H),8.21(m,3H,Ar- ), H 8.13 (d, 1H, J=1.24Hz, Ar-H), 7.93 (m, 2H, Ar-H), 7.79 (dd, 1H, J=8Hz, J=1.4Hz, Ar- H), 7.62 (d, 1H, J=7.32Hz, Ar-H), 7.49 (t, 1H, J=7.56Hz, Ar-H), 7.32 (d, 1H, J=8.28Hz, ), Ar-H 7.02 (t, 1H, J=7.2Hz, Ar-H), 5.90 (s, 2H, CH2),5.26(s,2H,CH2).
(16) 2- (4- ((3- formoxyl Phenoxymethyls) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA16) preparation, method is with (TJA01).
1H-NMR(400MHz,DMSO-d6):δ9.98(s,1H,CHO),8.45(s,1H,Ar-H),8.21(m,3H,Ar- H), 8.12 (d, 1H, J=1.52Hz, Ar-H), 7.93 (m, 2H, Ar-H), 7.82 (dd, 1H, J=7.2Hz, J=1.72Hz, Ar-H),7.54(m,3H,Ar-H),7.37(m,1H,Ar-H),5.90(s,2H,CH2),5.28(s,2H,CH2).
(17) 2- ((4- methylol -1,2,3-1H-- triazol-1-yls) methyl) -9,10- anthraquinones (TJA17).
1H NMR(600MHz,DMSO-d6) δ 8.22 8.17 (m, 3H), 8.14 (s, 1H), 8.09 (d, J=1.6Hz, 1H), 7.94 7.90 (m, 2H), 7.80 (dd, J=8.0,1.8Hz, 1H), 5.84 (s, 2H), 5.21 (t, J=5.7Hz, 1H), 4.54 (d, J=5.6Hz, 2H), 2.55 2.46 (m, 3H).
(18) 2- ((4- acetyl-o-methyl -1,2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA18)
1H NMR(600MHz,DMSO-d6) δ 8.33 (s, 1H), 8.23 8.17 (m, 3H), 8.11 (d, J=1.6Hz, 1H), 7.95 7.90 (m, 2H), 7.82 (dd, J=8.0,1.8Hz, 1H), 5.86 (s, 2H), 5.13 (s, 2H), 2.02 (s, 3H).
(19) 2- ((4- benzoyloxymethy -1,2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA19)
1H NMR(600MHz,DMSO-d6) δ 8.45 (s, 1H), 8.22 8.16 (m, 3H), 8.11 (d, J=1.5Hz, 1H), 7.95 (dd, J=8.2,1.1Hz, 2H), 7.92 (dd, J=5.8,3.3Hz, 2H), 7.83 (dd, J=8.0,1.7Hz, 1H), 7.65 (t, J=7.4Hz, 1H), 7.51 (t, J=7.8Hz, 2H), 5.88 (s, 2H), 5.40 (s, 2H).
(20) 2- ((4- (2- carboxybenzoyl epoxides) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA20)
1H NMR(600MHz,DMSO-d6)δ13.28(s,1H),8.39(s,1H),8.23–8.16(m,3H),8.12(d,J =1.5Hz, 1H), 7.94 7.90 (m, 2H), 7.81 (dd, J=8.0,1.7Hz, 1H), 7.78 7.75 (m, 1H), 7.66 7.60(m,3H),5.88(s,2H),5.36(s,2H).
(21) 2- ((4- (2- chlorobenzoyl epoxides) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA21)
1H NMR(600MHz,DMSO-d6) δ 8.22 8.17 (m, 3H), 8.15 (s, 1H), 8.09 (d, J=1.6Hz, 1H), 7.92 (dd, J=5.5,3.5Hz, 2H), 7.80 (dd, J=8.0,1.8Hz, 1H), 5.84 (s, 2H), 4.54 (s, 2H).
(22) 2- ((4- (2- acetoxyl group benzoyloxys) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthracenes Quinone (TJA22)
1H NMR(600MHz,DMSO-d6) δ 8.40 (s, 1H), 8.19 8.14 (m, 3H), 8.08 (d, J=1.5Hz, 1H), 7.93 7.88 (m, 2H), 7.77 (dd, J=8.0,1.7Hz, 1H), 5.86 (s, 2H), 5.13 (q, J=12.4Hz, 2H).
(23) 2- ((4- (4- nitrobenzoyl acyloxy) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA23)
1H NMR(600MHz,DMSO-d6) δ 8.48 (s, 1H), 8.32 (d, J=8.8Hz, 2H), 8.21 (d, J=8.0Hz, 1H), 8.18 (d, J=8.8Hz, 4H), 8.12 (d, J=0.9Hz, 1H), 7.95 7.89 (m, 2H), 7.84 (dd, J=8.0, 1.6Hz,1H),5.89(s,2H),5.49(s,2H).
(24) 2- ((4- phenyl -1,2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones (TJA24)
1H NMR(600MHz,DMSO-d6) δ 8.74 (s, 1H), 8.23 (d, J=8.0Hz, 1H), 8.21 8.18 (m, 2H), 8.13 (d, J=1.5Hz, 1H), 7.95 7.91 (m, 2H), 7.85 (td, J=8.5,1.5Hz, 3H), 7.45 (t, J=7.7Hz, 2H), 7.34 (t, J=7.4Hz, 1H), 5.92 (s, 2H).
(25) 2- (4- (3- amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones (YSA01)
With 3- acetylene aniline as raw material, preparation method obtains pale yellow powder with (TJA01).Yield：80.1%.1H NMR (400MHz,DMSO-d6) δ 8.58 (s, 1H), 8.25 8.16 (m, 3H), 8.11 (s, 1H), 7.92 (dd, J=5.5,3.5Hz, 2H), 7.83 (dd, J=8.0,1.2Hz, 1H), 7.08 (dd, J=15.5,7.8Hz, 2H), 6.93 (d, J=6.7Hz, 1H), 6.52 (d, J=6.9Hz, 1H), 5.88 (s, 2H), 5.29 (s, 2H).
(26) 2- (4- (3- (N- acetyl group) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones (YSA02)
With N- (3- acetylene phenyl) acetamide as raw material, preparation method obtains pale yellow powder with (TJA01).Yield： 90.05%.1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.70(s,1H),8.26–8.17(m,3H),8.17– 8.09 (m, 2H), 7.93 (dd, J=5.7,3.4Hz, 2H), 7.85 (dd, J=8.0,1.7Hz, 1H), 7.55 (d, J= 8.0Hz, 1H), 7.47 (d, J=7.8Hz, 1H), 7.35 (t, J=7.9Hz, 1H), 5.91 (s, 2H), 2.07 (d, J= 10.9Hz,3H).
(27) 2- (4- (3- (N- propionos) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones (YSA03) with N- (3- acetylene phenyl) propionic acid amide. as raw material, preparation method obtains pale yellow powder with (TJA01).Yield： 87.25%.1H NMR(600MHz,DMSO-d6) δ 10.21 (s, 1H), 8.73 (s, 1H), 8.33 (s, 1H), 8.23 (d, J= 8.0Hz, 1H), 8.19 (dd, J=5.5,3.3Hz, 2H), 8.15 (d, J=1.2Hz, 1H), 7.94 7.90 (m, 2H), 7.86 (dd, J=8.0,1.5Hz, 1H), 7.69 7.63 (m, 2H), 7.56 (d, J=7.7Hz, 1H), 7.52 7.48 (m, 1H), 7.41 (t, J=7.9Hz, 1H), 7.18 (d, J=8.3Hz, 1H), 7.07 (t, J=7.4Hz, 1H), 5.93 (s, 2H), 3.91 (s, 3H).
(28) 2- (4- (3- (N- phenylacetyl groups) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones (YSA04)
With N- (3- ethynyl phenyls) phenyl acetamide as raw material, preparation method obtains pale yellow powder with (TJA01).Yield： 87.21%.1H NMR(400MHz,DMSO-d6) δ 10.29 (s, 1H), 8.71 (s, 1H), 8.20 (ddd, J=9.7,8.0, 4.8Hz, 4H), 8.14 (d, J=1.5Hz, 1H), 7.93 (dd, J=5.5,3.6Hz, 2H), 7.85 (dd, J=8.0,1.7Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.49 (d, J=7.8Hz, 1H), 7.39 7.29 (m, 5H), 7.24 (dt, J=5.8, 1.9Hz,1H),5.91(s,2H),3.65(s,2H).
(29) 2- (4- (3- (N- cinnamoyls) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- anthraquinones (YSA05)
With N- (3- acetylene phenyl) cinnamamide as raw material, preparation method obtains yellow powder with (TJA01).Yield： 84.62%.MS m/z 597.15 [M+H]+.
(30) 2- (4- (3- (N- (2- picolinoyls)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- Anthraquinone (YSA06)
With N- (3- ethynyl phenyls) picolinamide as raw material, preparation method obtains brown powder with (TJA01).Yield： 80.24%.MS m/z 472.13 [M+H]+.
(31) 2- (4- (3- (N- (4- Methyl benzenesulfonyl bases)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9, 10- anthraquinones (YSA07)
With N- (3- acetylene phenyl) para toluene sulfonamide as raw material, preparation method obtains pale yellow powder with (TJA01).Receive Rate：81.20%.MS m/z 521.12 [M+H]+.
(31) 2- (4- (3- (N- benzoyls) amino) phenyl -1,2,3-1H- triazol-1-yls) methyl -9,10- anthraquinones (YSA08)
With N- (3- ethynyl phenyls) Benzoylamide as raw material, preparation method obtains pale yellow powder with (TJA01).Yield： 88.51%.1H NMR(600MHz,DMSO-d6) δ 10.36 (s, 1H), 8.73 (s, 1H), 8.38 (s, 1H), 8.23 (d, J= 8.0Hz, 1H), 8.19 (dd, J=5.5,3.4Hz, 2H), 8.15 (d, J=1.1Hz, 1H), 7.99 (d, J=7.3Hz, 2H), 7.94 7.90 (m, 2H), 7.87 (dd, J=8.0,1.4Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 7.57 (dq, J=15.0, 7.3Hz, 4H), 7.42 (t, J=7.9Hz, 1H), 5.93 (s, 2H).
(32) 2- (4- (3- (N- (2- chlorobenzene formacyls)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- Anthraquinone (YSA09)
With the chloro- N- of 2- (3- ethynyl phenyls) Benzoylamide as raw material, preparation method obtains pale yellow powder with (TJA01). Yield：85.23%.MS m/z 505.1, m/z 507.1 [M+H]+.
(33) 2- (4- (3- (N-4- nitro benzoyls) amino) phenyl -1,2,3-1H triazol-1-yls) methyl -9,10- Anthraquinone (YSA10)
With 4- nitro-N- (3- ethynyl phenyls) Benzoylamide as raw material, preparation method obtains yellowish toner with (TJA01) End.Yield：84.82%.MS m/z 516.1 [M+H]+.
(34) 2- (4- (3- (N- (- 5 benzoyl bromide of 2- methoxyl groups)) amino) phenyl -1,2,3-1H- triazol-1-yls) first Base -9,10- anthraquinones (YSA11)
With 2- methoxyl group -5- bromo- N- (3- ethynyl phenyls) Benzoylamides as raw material, preparation method obtains light with (TJA01) Yellow powder, yield：85.30%.1H NMR(600MHz,DMSO-d6)δ10.28(s,1H),8.73(s,1H),8.30(s, 1H), 8.27 8.17 (m, 3H), 8.15 (s, 1H), 7.93 (s, 2H), 7.86 (d, J=7.4Hz, 1H), 7.72 (s, 1H), 7.66 (s, 2H), 7.57 (d, J=7.0Hz, 1H), 7.41 (t, J=7.4Hz, 1H), 7.16 (d, J=8.6Hz, 1H), 5.93 (s, 2H),3.89(s,3H).
(35) 2- (4- (3- (N- (3,5 2 bromo- 4- anisoyl)) amino) phenyl -1,2,3-1H triazole -1- Base) methyl -9,10- anthraquinones (YSA12)
With 3,5 two bromo- 4- methoxyl groups-N- (3- ethynyl phenyls) Benzoylamide is raw material, preparation method with (TJA01), Obtain brown powder.Yield：85,71%.MS m/z 658.97, m/z 660.97, m/z 656.97 [M+H]+.
(36) 2- (4- (3- (N- (3,5 2 bromo- 4- benzyloxybenzoyls)) amino) phenyl -1,2,3-1H- triazole -1- Base) methyl -9,10- anthraquinones (YSA13)
With 3,5 two bromo- 4- benzyloxies-N- (3- ethynyl phenyls) Benzoylamide is raw material, preparation method with (TJA01), Pale yellow powder.Yield：86.11%.1H NMR(600MHz,DMSO-d6)δ10.47(s,1H),8.74(s,1H),8.33 (s, 1H), 8.31 (s, 2H), 8.24 (d, J=8.0Hz, 1H), 8.20 (dd, J=5.4,3.1Hz, 2H), 8.16 (d, J= 1.3Hz, 1H), 7.95 7.90 (m, 2H), 7.87 (d, J=8.0Hz, 1H), 7.78 (d, J=8.1Hz, 1H), 7.58 (t, J= 7.0Hz,3H),7.47–7.39(m,4H),5.93(s,2H),5.07(s,2H).
(37) 2- (4- (3- (N- (2- methoxyl group -5- fluoro benzoyls)) amino) phenyl -1,2,3-1H- triazol-1-yls) Methyl -9,10- anthraquinones (YSA14)
With 2- methoxyl group -5- bromo- N- (3- ethynyl phenyls) Benzoylamides as raw material, preparation method obtains light with (TJA01) Yellow powder.Yield：85.30%.1H NMR(600MHz,DMSO-d6)δ10.28(s,1H),8.73(s,1H),8.31(s, 1H), 8.23 (d, J=8.0Hz, 1H), 8.20 (ddd, J=6.1,2.7,1.0Hz, 2H), 8.15 (d, J=1.3Hz, 1H), 7.95 7.90 (m, 2H), 7.86 (dd, J=8.0,1.7Hz, 1H), 7.66 (d, J=9.0Hz, 1H), 7.57 (d, J= 7.8Hz, 1H), 7.46 (dd, J=8.7,3.2Hz, 1H), 7.42 (t, J=7.9Hz, 1H), 7.36 (td, J=8.6,3.3Hz, 1H), 7.20 (dd, J=9.1,4.2Hz, 1H), 5.93 (s, 2H), 3.89 (s, 3H).
(38) 2- (4- (3- (N- (2- acetoxy benzoyls)) amino) phenyl -1,2,3-1H triazol-1-yls) methyl - 9,10- anthraquinones (YSA15)
With 2- acetoxyl group-N- (3- ethynyl phenyls) Benzoylamide as raw material, preparation method obtains yellowish with (TJA01) Color powder.Yield：86.51%.MS m/z 529.14 [M+H]+.
(39) 2- (4- (3- (N- (3,4,5- trimethoxybenzoy)) amino), phenyl -1,2,3-1H triazol-1-yls) Methyl -9,10- anthraquinones (YSA16)
With 3,4,5- trimethoxy-N- (3- ethynyl phenyls) Benzoylamide to be prepared as method for preparing raw material same (TJA01), obtain pale yellow powder.Yield：87.65%.MS m/z 561.17 [M+H]+.
Embodiment 5
The preparation of 9,10- anthraquinone -2- formic acid
2- methyl -9,10- anthraquinones (8.9g, 40mmol) and glacial acetic acid (180mL, 20mL/ is added in 500mL reaction bulbs G), under 80 DEG C of stirrings, chromic acid (40g, 0.4mol) is slowly added in batches, be warming up to 120 DEG C of backflow 1h after temperature stabilization. After cooling, sucking filtration washing, obtains bluish yellow color cotton like solid 4.32g, yield 42.9%.
Embodiment 6
Synthesize the compound shown in general formulae IV by the following technical programs
(1) preparation of 9,10- anthraquinones -2- formyl chlorides
Add 9,10- anthraquinones -2- formic acid (1.86g, 7.4mmol) in 100mL reaction bulbs, thionyl chloride (1.05g, 8.9mmol), dichloromethane 30mL, catalytic amount DMF, back flow reaction overnight, obtain final product -9,10- anthraquinones-after solution is clarified completely The dichloromethane solution of 2- formyl chlorides, is directly used in next step reaction.
(2) preparation of 9,10- anthraquinones -2- formyl chlorides
Add 9,10- anthraquinones -2- formic acid (1.86g, 7.4mmol) in 100mL reaction bulbs, thionyl chloride (1.05g, 8.9mmol), dichloromethane 30mL, catalytic amount DMF, back flow reaction overnight, obtain final product -9,10- anthraquinones-after solution is clarified completely The dichloromethane solution of 2- formyl chlorides, is directly used in next step reaction.
(3) preparation of N-9,10- anthraquinones -2- formoxyl Phenylalanine (YWY01)
Phenyalanine methyl ester is added in reaction bulb, is dissolved in dichloromethane, add triethylamine (3g, 30mmol), low In the lower Deca 9 of 0 DEG C of stirring, the dichloromethane solution of 10- anthraquinone -2- formyl chlorides, after completion of dropping stirring several minutes, room temperature is moved on to Under continue to be stirred overnight, rotate out partial solvent, stand and separate out crystal, wash to obtain crude product, recrystallized from acetonitrile obtains sterling.
N-9,10- anthraquinones -2- formoxyl phenyalanine methyl esters (0.34g, 10mmol), 4% is added in reaction bulb NaOH solution 5mL, methanol 1mL, tetrahydrofuran 1mL stir 4h, dilute, plus dilute sulfuric acid and adjust pH to 3, have cotton-shaped at 50 DEG C Material is separated out, and sucking filtration washes to obtain product.
1H-NMR(300MHz,DMSO-d6):δ12.85(s,1H,COOH),9.26(s,1H,NH),8.62(s,1H,Ar- ), H 8.23 (m, 4H, Ar-H), 7.95 (m, 2H, Ar-H), 7.25 (m, 5H, Ph-H), 4.69 (t, 1H, J=2.4Hz, CH), 3.22(m,2H,CH2).
(4) preparation of N-9,10- anthraquinones -2- formyl alanines (YWY02)
With N-9,10- anthraquinone -2- formyl alanines methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(300MHz,DMSO-d6):δ12.67(s,1H,COOH),9.21(S,1H,NH),8.67(s,1H,Ar- H), 8.34 (d, 1H, J=7.8Hz, Ar-H), 8.22 (d, 3H, J=5.7Hz, Ar-H), 7.93 (s, 2H, Ar-H), 4.47 (q, 1H, J=7.5Hz, CH), 1.45 (d, 3H, J=7.2Hz, CH3).
(5) preparation of N-9,10- anthraquinones -2- formyl methionines (YWY03)
With N-9,10- anthraquinone -2- formyl methionines methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(300MHz,DMSO-d6):δ12.57(s,1H,COOH),9.17(s,1H,NH),8.69(s,1H,Ar- ), H 8.27 (m, 4H, Ar-H), 7.95 (s, 2H, Ar-H), 4.59 (q, 1H, J=7.5Hz, CH), 2.59 (m, 2H, CH2),2.1 (m,5H,CH3,CH2).
(6) prepared by N-9,10- anthraquinones -2- formoxyl glutamic acid (YWY04)
With N-9,10- anthraquinone -2- formoxyls glutamic acid methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(300MHz,DMSO-d6):δ12.54(s,1H,COOH),9.13(s,1H,NH),8.69(s,1H,Ar- ), H 8.36 (d, 1H, J=8.1Hz, Ar-H), 8.26 (m, 3H, Ar-H), 7.95 (m, 2H, Ar-H), 4.47 (t, 1H, J= 4.5Hz, CH), 2.40 (t, 2H, J=7.2Hz, CH2),2.07(m,2H,CH2).
(7) preparation of N-9,10- anthraquinones -2- formoxyl L-Valine (YWY05)
With N-9,10- anthraquinone -2- formoxyls valine methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(300MHz,DMSO-d6):δ 12.73 (s, 1H, COOH), 9.04 (d, 1H, J=8Hz, Ar-H), 8.68 (s, 1H, NH), 8.36 (d, 1H, J=8Hz, Ar-H), 8.26 (m, 3H, Ar-H), 7.96 (m, 2H, Ar-H), 4.35 (t, 1H, J =4.5Hz, CH), 2.24 (dd, 1H, J=13.2Hz, J=6.9Hz, CH), 1.01 (t, 6H, J=5.7Hz, CH3).
(8) preparation of N-9,10- anthraquinones -2- formoxyl leucines (YWY06)
With N-9,10- anthraquinone -2- formoxyls leucine methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(300MHz,DMSO-d6):δ 9.14 (s, 1H, NH), 8.69 (d, 1H, J=1.53Hz, Ar-H), 8.33 (m, 2H, Ar-H), 8.24 (m, 2H, Ar-H), 7.96 (m, 2H, Ar-H), 4.52 (t, 1H, J=7.8Hz, CH), 1.83 (m, 2H, CH2),1.65(m,1H,CH),0.93(m,6H,CH3).
(9) preparation of N-9,10- anthraquinones -2- formoxyl glycine (YWY07)
With N-9,10- anthraquinone -2- formoxyls glycine methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(300MHz,DMSO-d6):δ 12.71 (s, 1H, COOH), 9.36 (t, 1H, J=5.7Hz, Ar-H), 8.66 (d, 1H, J=1.4Hz, Ar-H), 8.28 (m, 4H, Ar-H), 7.94 (d, 2H, J=5.7Hz, Ar-H), 4.00 (d, 2H, J= 5.8Hz,CH2).
(10) preparation of N-9,10- anthraquinones -2- formyltryptophans (YWY08)
With N-9,10- anthraquinone -2- formyltryptophans methyl ester is raw material, and preparation method is with (YWY01).
1H NMR(300MHz,DMSO-d6):δ 10.86 (s, 1H, NH), 9.27 (d, 1H, J=7.7Hz, NH), 8.66 (s, 1H, Ar-H), 8.25 (m, 4H, Ar-H), 7.95 (m, 2H, Ar-H), 7.63 (d, 1H, J=7.65Hz, Ar-H), 7.17 (m, 3H, ), Ar-H 4.72 (t, 1H, J=4.5Hz, CH), 3.33 (m, 2H, CH2).
(11) preparation of N-9,10- anthraquinones -2- formoxyl proline (YWY09)
With N-9,10- anthraquinone -2- formoxyls proline methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(400MHz,DMSO-d6):δ12.76(s,1H,COOH),8.10(m,7H,Ar-H),4.42(m,1H, CH),3.60(m,2H,CH2),2.32(m,1H,CH2),1.92(m,3H,CH2).
(12) preparation of N-9,10- anthraquinones -2- formoxyl aspartic acids (YWY10)
With N-9,10- anthraquinone -2- formoxyls aspartate methylester is raw material, and preparation method is with (YWY01).
1H-NMR(400MHz,DMSO-d6):δ 12.73 (s, 2H, COOH), 9.31 (d, 1H, J=7.72Hz, Ar-H), 8.66 (d, 1H, J=1.32Hz, Ar-H), 8.28 (m, 4H, Ar-H), 7.95 (d, 2H, J=5.8Hz, Ar-H), 4.82 (q, 1H, J=7.6Hz, CH), 2.85 (m, 2H, CH2).
(13) preparation of N-9,10- anthraquinones -2- formoxyl isoleucine (YWY11)
With N-9,10- anthraquinone -2- formoxyls Isoleucine methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(600MHz,DMSO-d6):δ 12.72 (s, 1H, COOH), 9.01 (d, 1H, J=7.98Hz, Ar-H), 8.65 (d, 1H, J=1.68Hz, Ar-H), 8.34 (dd, 1H, J=8.01Hz, J=1.74Hz, NH), 8.27 (d, 1H, J= 8.04Hz, Ar-H), 8.23 (m, 2H, Ar-H), 7.95 (m, 2H, Ar-H), 4.39 (t, 1H, J=7.44Hz, CH), 1.99 (m, 1H,CH),1.54(m,1H,CH2),1.30(m,1H,CH2), 0.96 (d, 3H, J=6.84Hz, CH3), 0.89 (t, 3H, J= 7.38Hz,CH3).
(14) preparation of N-9,10- anthraquinones -2- formoxyl glutamine (YWY12)
With N-9,10- anthraquinone -2- formoxyl glutamine methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(600MHz,DMSO-d6):δ 12.54 (s, 1H, COOH), 9.12 (d, 1H, J=7.56Hz, Ar-H), 8.68 (d, 1H, J=1.68Hz, Ar-H), 8.35 (dd, 1H, J=8.1Hz, J=1.68Hz, NH), 8.29 (d, 1H, J= 8.04Hz, Ar-H), 8.23 (m, 2H, Ar-H), 7.94 (m, 2H, Ar-H), 4.47 (m, 1H, CH), 2.39 (t, 2H J= 7.56Hz,CH2),2.14(m,1H,CH2),2.00(m,1H,CH2).
(15) preparation of N-9,10- anthraquinones -2- formoxyl agedoites (YWY13)
With N-9,10- anthraquinone -2- formoxyl agedoites methyl ester is raw material, and preparation method is with (YWY01).
1H-NMR(600MHz,DMSO-d6):δ 12.74 (s, 1H, COOH), 9.30 (d, 1H, J=7.74Hz, Ar-H), 8.66 (d, 1H, J=1.68Hz, Ar-H), 8.33 (dd, 1H, J=8.04Hz, J=1.8Hz, NH), 8.29 (d, 1H, J= 8.04Hz,Ar-H),8.23(m,2H,Ar-H),7.95(m,2H,Ar-H),4.81(m,1H,CH),2.89(m,1H,CH2), 2.79(m,1H,CH2).
7 anti tumor activity in vitro of embodiment is tested
Screening technique：Tetrazolium (micoculture tetrozolium, MTT) reducing process
Cell strain：A549, MCF-7
Method of testing：After cell culture to exponential phase, attached cell is digested about with 0.25% pancreatin Digestive system 5min, adds 10% hyclone RMPI1640 culture medium to terminate digestion, blows and beats into cell suspension, move into 15mL centrifuge tubes, 1000 turns, (cell suspension is directly moved into 15mL centrifuge tubes, 1000 turns, is centrifuged without the need for digestion centrifugation 5min by suspension growth cell Supernatant 5min) is abandoned, is added 10% hyclone DMEM culture medium, piping and druming to mix, is prepared into single cell suspension, adjusts cell suspension Concentration is 5.0 × 104Individual/mL, above-mentioned cell suspension is laid in 96 orifice plates, per hole 200uL, sets 3 holes per group；3 are stayed separately Hole, it is each to add 10% hyclone RMPI1640 culture medium 200uL as blank control wells.After continuing culture 24h, experimental group is each Group adds test medicine 2uL, matched group to add RMPI16402uL；Continue culture 24h, 4h takes out culture plate before terminating culture, often Hole adds the MTT 20uL (lucifuge) of 5mg/mL, continues culture, and after terminating, culture medium is abandoned in suction, adds DMSO 150uL, shake per hole Swing and shake up, with the wavelength mensuration absorbance value of 570nm in microplate reader.It is repeated 3 times.Calculate growth inhibition ratio.Activity data storehouse It is shown in Table 1.
Anti-tumor activity test in 8 animal body of embodiment
Select the preferable compound TJA05 and compound YSA01 of external activity to carry out anti-tumor activity in animal body to survey Examination, model used are mice S-180 sarcoma models, and positive control medicine is clinical conventional antitumor drug 5-fluorouracil.
Experimental technique：From 18-22 gram of female KM mice and the S-180 tumor kinds of well-grown 7-11 days, by tumor group Knit and make cell suspension, it is subcutaneous to be seeded to right side of mice armpit, about 1.0-2.0 × 106 cell/only, it is random after inoculation 24 hours Divide cage, intraperitoneal injection is continuous 7 days.Put to death animal within 24 hours after drug withdrawal, weigh, knurl weight, calculate the average knurl weight of each group, press Equation below is obtained tumor control rate and carries out t inspections, and test result is shown in Table 2.
Tumor control rate=[(the average knurl weight of the average knurl weight-treatment group of blank control group)/(average tumor of blank control group Weight)] × 100%
1 anti-tumor activity list of table
2 anti tumor activity in vitro list of table
Pharmaceutically acceptable salt, hydrate or solvate to Anthraquinones noval chemical compound of the present invention, does same body Outer anti-tumor activity test, has also all shown good result.

Claims (4)

1. a kind of 2- replaces -9,10- anthraquinone analog compounds, it is characterised in that：The structural formula of the compound is as follows：
Wherein：
M is 1 integer；Integers of the n for 0-3；
Each X independences OCO；
Each R2Stand alone as H, F, Cl, Br, nitro, carboxyl, acetoxyl group.
2. 2- according to claim 1 replaces -9,10- anthraquinone analog compounds, it is characterised in that：Compound is selected from：
2- ((4- benzoyloxymethy -1,2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- (2- carboxybenzoyl epoxides) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- (2- chlorobenzoyl epoxides) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- (2- acetoxyl group benzoyloxys) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones
2- ((4- (4- nitrobenzoyl acyloxy) methyl isophthalic acid, 2,3-1H- triazol-1-yls) methyl) -9,10- anthraquinones.
3. a kind of compound and its pharmaceutically acceptable salt as described in claim 1 or 2 any one and can pharmaceutically connect The carrier received is used as preparing applying in antitumor drug.
4. a kind of 2- as claimed in claim 1 replaces the preparation method of -9,10- anthraquinone analog compounds, it is characterised in that：
The preparation of shown compound：With phthalic anhydride as initiation material, Jing Friedel-Crafts reactions, concentrated sulphuric acid take off Water, NBS bromos, sodium azide replace, and generate key intermediate 2- azido-methyl -9,10- anthraquinones, finally in copper sulfate pentahydrate and In the presence of ascorbic, with the alkynes Jing Husigen cycloaddition reactions for replacing, shown target compound is obtained.
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