CN103301096B - Application of substituted diphenylamine compound to preparation of antitumor drugs - Google Patents
Application of substituted diphenylamine compound to preparation of antitumor drugs Download PDFInfo
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- CN103301096B CN103301096B CN201210067267.3A CN201210067267A CN103301096B CN 103301096 B CN103301096 B CN 103301096B CN 201210067267 A CN201210067267 A CN 201210067267A CN 103301096 B CN103301096 B CN 103301096B
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- 0 Cc(cc1Cl)cc(II)c1Nc(c(**)c1)c(*)c(Cl)c1[N+](C)[O-] Chemical compound Cc(cc1Cl)cc(II)c1Nc(c(**)c1)c(*)c(Cl)c1[N+](C)[O-] 0.000 description 3
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Abstract
The invention discloses application of a substituted diphenylamine compound shown in a general formula I to preparation of antitumor drugs. Each substituent group in the formula is defined in the specification. The compound in the general formula I has good antitumor activity and especially has excellent activities on human lung cancer A549, human leukemia HL-60 and the like.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of antitumor drug.Relate to the application of a kind of substituted diphenylamine aminated compounds as antitumor drug particularly.
Background technology
Prior art reports the compound shown in following general formula can as insecticide, acaricide, antibacterial, herbicide, rat poison or other purposes:
Such as patent BR7900462, CH626323, CN1188757, DE2509416, DE2642147, DE2642148, EP26743, EP60951, GB1544078, GB1525884, JP58113151, JP64001774, JP01186849, WO2002060878, WO2005035498, WO2009037707, US3948957, US3948990, US4041172, US4152460, US4187318, US4215145, US4304791, US4316988, US4407820, US4459304, US4670596 etc., and ACS Symposium Series (1992), 504 (Synth.Chem.Agrochem.III), 336-48, Journal of the Chemical Society (1951), 110-15 etc. disclose the compound of above-mentioned formula.
In addition, magazine Chemische Berichte (1962), 95 1711-21; Chemische Berichte (1963), 96 (7), 1936-44; Journal of Organic Chemistry (1954), 19,1641-5, Journal of the Chemical Society, Transactions (1913), 103 982-8 and Journal of the Chemical Society, Transactions (1921), 119,187-92 etc. disclose following compound, but report without any biological activity.
Patent WO2011116671 discloses compound as shown in general formula I as disinfectant use in agriculture:
In prior art, the compound of structure as shown in general formula I of the present invention has no the report as antitumor drug.
Summary of the invention
The substituted diphenylamine aminated compounds of structure as shown in general formula I is the object of the present invention is to provide to prepare the application in antitumor drug.
Technical scheme of the present invention is as follows:
Substituted diphenylamine aminated compounds is preparing the application in antitumor drug, and compound structure is as shown in general formula I:
In formula:
R
1be selected from hydrogen, C
1-C
8alkyl, C
3-C
8cycloalkyl, halo C
1-C
8alkyl, C
1-C
8alkyl-carbonyl, halo C
1-C
8alkyl-carbonyl, C
1-C
8alkoxy carbonyl, C
1-C
8alkyl amino-carbonyl, C
1-C
8alkylthio group, halo C
1-C
8alkylthio group, C
1-C
8alkyl sulphonyl, C
1-C
8alkoxy C
1-C
8alkyl, C
1-C
8alkoxy C
1-C
8alkyl-carbonyl, C
1-C
8alkoxy carbonyl C
1-C
8alkyl, C
1-C
8alkyl amino sulfenyl, C
2-C
8dialkyl amido sulfenyl or CO-X-CO
2r
9, wherein X is selected from (CHR
9) n, CR
9=CR
10or C
6h
4, n=1-6;
R
2be selected from hydrogen, halogen, halo C
1-C
8alkyl, C
1-C
8alkoxyl, halo C
1-C
8alkoxyl, C
1-C
8alkyl amino, halo C
1-C
8alkyl amino, C
1-C
8alkylthio group, halo C
1-C
8alkylthio group, C
1-C
8alkyl sulphonyl, C
3-C
8cycloalkyl, C
2-C
8dialkyl amido, C
3-C
8alkene oxygen base, halo C
3-C
8alkene oxygen base, C
3-C
8alkynyloxy group, halo C
3-C
8alkynyloxy group, C
1-C
8alkyl-carbonyl oxygen base, C
1-C
8alkyl-carbonyl-amino, C
1-C
8alkyl sulphonyl oxygen base, C
1-C
8alkoxy C
1-C
8alkoxyl, C
1-C
8alkoxy carbonyl C
1-C
8alkoxyl, unsubstituted or by 1-5 R
11the following radicals replaced: aryloxy group, virtue amino, arylmethyl oxygen base, arylmethyl amino, heteroaryl oxygen base or heteroaryl amino, and when substituent number is greater than 1, R
11may be the same or different;
R
3be selected from hydrogen, halogen, nitro, cyano group, C (=O) NR
9r
10, C (=S) NR
9r
10, C
1-C
8alkyl amino-carbonyl, C
1-C
8alkoxy carbonyl, halo C
1-C
8alkyl or C
1-C
8alkyl sulphonyl;
R
4, R
8may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, C (=O) NR respectively
9r
10, C
1-C
8alkyl, halo C
1-C
8alkyl, C
1-C
8alkoxyl, halo C
1-C
8alkoxyl, C
2-C
8thiazolinyl, C
2-C
8alkynyl, C
1-C
8alkyl sulphonyl, C
1-C
8alkyl-carbonyl, C
1-C
8alkoxy carbonyl, C
1-C
8alkoxy C
1-C
8alkyl, C
1-C
8alkoxy carbonyl C
1-C
8alkyl, unsubstituted or by 1-5 R
11the following radicals replaced: aryl, arylmethyl, aryloxy group, virtue amino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl or heteroaryl oxygen base, and when substituent number is greater than 1, R
11may be the same or different;
R
5, R
7may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, C (=O) NR respectively
9r
10, C
1-C
8alkyl, halo C
1-C
8alkyl, C
1-C
8alkoxyl, halo C
1-C
8alkoxyl, C
1-C
8alkyl amino, halo C
1-C
8alkyl amino, C
1-C
8alkylthio group, halo C
1-C
8alkylthio group, C
2-C
8thiazolinyl, C
2-C
8alkynyl, C
1-C
8alkyl sulphonyl, C
1-C
8alkyl-carbonyl, C
1-C
8alkoxy carbonyl, C
1-C
8alkoxy C
1-C
8alkyl, C
1-C
8alkoxy carbonyl C
1-C
8alkyl, C
1-C
8alkyl-carbonyl oxygen base, C
1-C
8alkoxy-carbonyl oxy, C
1-C
8alkyl amino carbonyl oxy, C
1-C
8alkyl sulphonyl oxygen base, C
1-C
8alkoxy C
1-C
8alkoxyl, halo C
1-C
8halogenated alkoxy C
1-C
8alkoxyl, C
1-C
8alkoxy carbonyl C
1-C
8alkoxyl, unsubstituted or by 1-5 R
11the following radicals replaced: aryl, arylmethyl, aryloxy group, virtue amino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl or heteroaryl oxygen base, and when substituent number is greater than 1, R
11may be the same or different;
R
6be selected from hydrogen, halogen, cyano group, nitro, carboxyl, C (=O) NR
9r
10, C
1-C
8alkyl, halo C
1-C
8alkyl, C
1-C
8alkoxyl, halo C
1-C
8alkoxyl, C
2-C
8thiazolinyl, C
2-C
8alkynyl, C
1-C
8alkyl sulphonyl, C
1-C
8alkyl-carbonyl, C
1-C
8alkoxy carbonyl, C
1-C
8alkoxy C
1-C
8alkyl, C
1-C
8alkoxy carbonyl C
1-C
8alkyl, C
1-C
8alkoxy C
1-C
8alkoxyl, halo C
1-C
8halogenated alkoxy C
1-C
8alkoxyl, unsubstituted or by 1-5 R
11the following radicals replaced: aryl, arylmethyl, aryloxy group, virtue amino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl or heteroaryl oxygen base, and when substituent number is greater than 1, R
11may be the same or different;
R
9, R
10may be the same or different, be selected from hydrogen or C respectively
1-C
6alkyl;
R
11be selected from halogen, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl, halo C
1-C
6alkoxyl, C
1-C
6alkylthio group, C
1-C
6alkyl-carbonyl, C
1-C
6alkoxy carbonyl, C
2-C
6thiazolinyl, halo C
2-C
6thiazolinyl, C
3-C
6alkene oxygen base, halo C
3-C
6alkene oxygen base, C
2-C
6alkynyl, halo C
2-C
6alkynyl, C
3-C
6alkynyloxy group, halo C
3-C
6alkynyloxy group, halo C
1-C
6alkylthio group, halo C
1-C
6alkyl-carbonyl, C
1-C
6alkyl amino, halo C
1-C
6alkyl amino, C
2-C
8dialkyl amido, C
1-C
6alkyl-carbonyl-amino, halo C
1-C
6alkyl-carbonyl-amino, C
1-C
6alkyl amino-carbonyl or halo C
1-C
6alkyl amino-carbonyl;
Or the salt of compound of Formula I.
When applying as antitumor drug in above-mentioned substituted diphenylamine aminated compounds, more preferably compound is: in general formula I
R
1be selected from hydrogen, C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkyl-carbonyl, halo C
1-C
4alkyl-carbonyl, C
1-C
4alkoxy carbonyl, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
1-C
4alkyl sulphonyl, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkoxy C
1-C
4alkyl-carbonyl, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, C
1-C
4alkyl amino sulfenyl, C
2-C
4dialkyl amido sulfenyl or CO-X-CO
2r
9, wherein X is selected from (CHR
9) n, CR
9=CR
10or C
6h
4, n=1-3;
R
2be selected from hydrogen, halogen, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkyl amino, halo C
1-C
4alkyl amino, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
1-C
4alkyl sulphonyl, C
2-C
4dialkyl amido, C
3-C
4alkene oxygen base, halo C
3-C
4alkene oxygen base, C
3-C
6alkynyloxy group, C
1-C
4alkyl-carbonyl oxygen base, C
1-C
4alkyl-carbonyl-amino, C
1-C
4alkyl sulphonyl oxygen base, C
1-C
4alkoxy C
1-C
4alkoxyl, C
1-C
4alkoxy carbonyl C
1-C
4alkoxyl, unsubstituted or by 1-3 R
11the following radicals replaced: phenoxy group, phenylamino, benzyl oxygen base, benzylamino, pyridine radicals oxygen base or pyridinylamino;
R
3be selected from chlorine, bromine, fluorine, nitro, cyano group, C (=O) NR
9r
10, C (=S) NR
9r
10, CO
2cH
3, trifluoromethyl or methyl sulphonyl;
R
4, R
8may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, C (=O) NR respectively
9r
10, C
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
4alkyl sulphonyl, C
1-C
4alkyl-carbonyl, C
1-C
4alkoxy carbonyl, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, unsubstituted or by 1-4 R
11the following radicals replaced: phenoxy group, phenylamino, phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl, phenyl amino carbonyl or pyridine radicals oxygen base;
R
5, R
7may be the same or different, be selected from hydrogen, halogen, cyano group, nitro, C (=O) NR respectively
9r
10, C
1-C
4alkyl, halo C
1-C
4alkyl, C
1-C
4alkoxyl, halo C
1-C
4alkoxyl, C
1-C
4alkyl amino, halo C
1-C
4alkyl amino, C
1-C
4alkylthio group, halo C
1-C
4alkylthio group, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
4alkyl sulphonyl, C
1-C
4alkyl-carbonyl, C
1-C
4alkoxy carbonyl or C
1-C
4alkoxy C
1-C
4alkyl;
R
6be selected from hydrogen, halogen, cyano group, nitro, carboxyl, C (=O) NR
9r
10, C
1-C
4alkyl, halo C
1-C
4alkyl, halo C
1-C
4alkoxyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
4alkyl sulphonyl, C
1-C
4alkyl-carbonyl, C
1-C
4alkoxy carbonyl, C
1-C
4alkoxy C
1-C
4alkyl, C
1-C
4alkoxy carbonyl C
1-C
4alkyl, C
1-C
4alkoxy C
1-C
4alkoxyl, unsubstituted or by 1-4 R
11the following radicals replaced: phenoxy group, phenylamino, phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl, anilinocarbonyl or pyridine radicals oxygen base;
R
9, R
10may be the same or different, be selected from hydrogen or C respectively
1-C
3alkyl;
R
11be selected from halogen, nitro, cyano group, C
1-C
3alkyl, halo C
1-C
3alkyl, C
1-C
3alkoxyl, halo C
1-C
3alkoxyl, C
1-C
3alkylthio group, C
1-C
3alkyl-carbonyl, C
1-C
3alkoxy carbonyl, C
1-C
3alkyl amino, C
2-C
4dialkyl amido, C
1-C
3alkyl-carbonyl-amino or C
1-C
3alkyl amino-carbonyl;
Or the salt of compound of Formula I.
When applying as antitumor drug in above-mentioned substituted diphenylamine aminated compounds, preferred compound is further: in general formula I
R
1be selected from hydrogen, methyl, ethyl, cyclopropyl, formoxyl, acetyl group, trifluoroacetyl group, methoxycarbonyl, ethoxy carbonyl, trichloro-methylthio, methyl sulphonyl, ethylsulfonyl, methoxy, ethoxyl methyl, methoxy ethyl, methoxymethylcarbonyl, Methoxycarbonylmethyl, methylamino sulfenyl, dimethylamino sulfenyl, COCH
2cO
2h, COCH
2cO
2cH
3, COCH
2cH
2cO
2h, COCH
2cH
2cO
2cH
3, COCHCH
3cO
2h, COCHCH
3cO
2cH
3, COC
6h
4cO
2h, COC
6h
4cO
2cH
3, COCH=CHCO
2h or COCH=CHCO
2cH
3;
R
2be selected from hydrogen, chlorine, bromine, fluorine, C
1-C
3alkoxyl, halo C
1-C
3alkoxyl, C
1-C
3alkyl amino, halo C
1-C
3alkyl amino, methyl mercapto, ethylmercapto group, dimethylamino, diethylamino, methoxymethoxy, phenoxy group, phenylamino, benzyl oxygen base, benzylamino, to chlorophenoxy, amino to chloroanilino, 2-chloro-trifluoromethyl phenoxy, 2-chloro-4-trifluoromethyl phenylamino, the chloro-5 5-flumethiazine-2-base oxygen bases of 3-or 3-chloro-5-trifluoromethylpyridine-2-base;
R
3be selected from nitro;
R
4, R
8may be the same or different, be selected from hydrogen, chlorine, bromine, fluorine, cyano group, nitro, C (=O) NH respectively
2, C (=O) NHCH
3, C (=O) N (CH
3)
2, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, trifluoromethoxy, methyl sulphonyl, ethylsulfonyl, formoxyl, acetyl group, methoxycarbonyl, ethoxy carbonyl, phenoxy group, phenylamino, phenyloxycarbonyl or anilinocarbonyl;
R
5, R
7may be the same or different, be selected from hydrogen, chlorine, bromine, fluorine, cyano group, nitro, C (=O) NH respectively
2, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, methylamino, methyl mercapto, methyl sulphonyl, ethylsulfonyl, formoxyl, acetyl group, methoxycarbonyl, ethoxy carbonyl or methoxy;
R
6be selected from hydrogen, chlorine, bromine, fluorine, cyano group, nitro, carboxyl, C (=O) NH
2, C (=O) NHCH
3, C (=O) N (CH
3)
2, methyl, trifluoromethyl, seven fluorine isopropyls, trifluoromethoxy, trifluoro ethoxy, OCF
2cHFCF
3, methyl sulphonyl, ethylsulfonyl, formoxyl, acetyl group, methoxycarbonyl, ethoxy carbonyl, phenoxy group, phenylamino, phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl, anilinocarbonyl, pyridine radicals oxygen base or 3-chloro-5-trifluoromethylpyridine-2-base oxygen base;
Or its hydrochlorate, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates.
When applying as antitumor drug in above-mentioned substituted diphenylamine aminated compounds, further preferred compound is: in general formula I
R
1be selected from hydrogen or methyl;
R
2be selected from hydrogen, chlorine, methoxyl group, OCH
2cF
3, methylamino, methyl mercapto or dimethylamino;
R
3be selected from nitro;
R
4, R
8may be the same or different, be selected from hydrogen, chlorine, bromine, fluorine, cyano group, nitro, carboxyl, C (=O) NH respectively
2, C (=O) NHCH
3, C (=O) N (CH
3)
2, methyl, trifluoromethyl, methoxycarbonyl or phenyloxycarbonyl;
R
5, R
7may be the same or different, be selected from hydrogen, chlorine, bromine, fluorine, cyano group, nitro, methyl, trifluoromethyl or methoxyl group respectively;
R
6be selected from hydrogen, chlorine, bromine, fluorine, cyano group, nitro, carboxyl, C (=O) NH
2, C (=O) NHCH
3, methyl, trifluoromethyl, OCF
2cHFCF
3, methoxycarbonyl or 3-chloro-5-trifluoromethylpyridine-2-base oxygen base;
Or its hydrochlorate, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates.
When applying as antitumor drug in above-mentioned substituted diphenylamine aminated compounds, preferred compound is further again: in general formula I
R
1, R
5, R
7be selected from hydrogen;
R
2be selected from chlorine;
R
3be selected from nitro;
R
4be selected from chlorine;
R
6be selected from chlorine, cyano group, nitro or trifluoromethyl;
R
8be selected from chlorine, cyano group or nitro;
Or its hydrochlorate, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates.
When applying as antitumor drug in above-mentioned substituted diphenylamine aminated compounds, most preferred compound is:
In the definition of the compound of Formula I provided, collect the following substituent group of term general proxy used above:
Halogen: refer to fluorine, chlorine, bromine or iodine.Alkyl: straight or branched alkyl, such as methyl, ethyl, propyl group, isopropyl or the tert-butyl group.Cycloalkyl: substituted or unsubstituted cyclic alkyl, such as cyclopropyl, cyclopenta or cyclohexyl, substituent group is as methyl, halogen etc.Haloalkyl: straight or branched alkyl, the hydrogen atom on these alkyl can partly or entirely replace by halogen atom, such as chloromethyl, dichloromethyl, trichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl etc.Alkoxyl: straight or branched alkyl, is connected in structure through oxygen atom key.Halogenated alkoxy: straight or branched alkoxyl, hydrogen atom on these alkoxyls can partly or entirely replace by halogen atom, such as chlorine methoxyl group, dichloro methoxyl group, trichloromethoxy, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, chlorine fluorine methoxyl group, trifluoro ethoxy etc.Alkylthio group: straight or branched alkyl, is connected in structure through sulphur atom key.Halogenated alkylthio: straight or branched alkylthio group, hydrogen atom on these alkyl can partly or entirely replace by halogen atom, such as chloromethane sulfenyl, dichloromethane sulfenyl, trichloro-methylthio, fluorine methyl mercapto, difluoro methyl mercapto, trifluoromethylthio, chlorine fluorine methyl mercapto etc.Alkyl amino: straight or branched alkyl, is connected in structure through nitrogen-atoms key.Haloalkylamino: straight or branched alkyl amino, the hydrogen atom on these alkyl can partly or entirely replace by halogen atom.Thiazolinyl: straight or branched alkene class, such as vinyl, 1-acrylic, 2-acrylic and different cyclobutenyls, pentenyl and hexenyl isomers.Thiazolinyl also comprises polyenoid class, as 1,2-allene base and 2,4-hexadienyl.Haloalkenyl group: straight or branched alkene class, the hydrogen atom on these thiazolinyls can partly or entirely replace by halogen atom.Alkynyl: straight or branched alkynes class, such as acetenyl, 1-propinyl, 2-propynyl and different butynyl, pentynyl and hexynyl isomers.Alkynyl also comprises the group be made up of multiple triple bond, as 2,5-hexadiine base.Halo alkynyl: straight or branched alkynes class, the hydrogen atom on these alkynyls can partly or entirely replace by halogen atom.Aryl moiety in aryl and aralkyl, aryloxy group and aryloxy alkyl etc. comprises phenyl or naphthyl etc.Heteroaryl is containing the heteroatomic five-membered ring of one or more N, O, S or hexatomic ring.Such as furyl, pyrazolyl, thiazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, quinolyl etc.
Table 1, table 2, table 3, table 4, table 5 list R in general formula I respectively
1, R
2, R
4, R
5, R
6, R
7and R
8the concrete substituent group of part, but they are not limited only to these substituent groups.
Table 1R
1substituent group
Table 2R
2substituent group
Table 3R
4(R
8) substituent group
Table 4R
5(R
7) substituent group
Table 5R
6substituent group
The compound of Formula I in the present invention with anti-tumor activity is illustrated by the particular compound listed in table 6-14, but the present invention is only limitted to this absolutely not.
Table 6: in general formula I, R
1for H, R
2for Cl, R
3for NO
2, R
4, R
5, R
6, R
7, R
8(hereinafter referred to as R
4-R
8) specifically see the following form.
Table 6
Table 7: in general formula I, R
1, R
3be H, R
2for Cl, R
4-R
8specifically in table 6.
Table 8: in general formula I, R
1for CH
3, R
2for Cl, R
3for NO
2, R
4-R
8specifically in table 6.
Table 9: in general formula I, R
1for H, R
2for OCH
3, R
3for NO
2, R
4-R
8specifically in table 6.
Table 10: in general formula I, R
1for H, R
2for SCH
3, R
3for NO
2, R
4-R
8specifically in table 6.
Table 11: in general formula I, R
1for H, R
2for NHCH
3, R
3for NO
2, R
4-R
8specifically in table 6.
Table 12: in general formula I, R
1for H, R
2for N (CH
3)
2, R
3for NO
2, R
4-R
8specifically in table 6.
Table 13: in general formula I, R
1for H, R
2for OCH
2cF
3, R
3for NO
2, R
4-R
8specifically in table 6.
Table 14: in general formula I, R
1, R
2be H, R
3for NO
2, R
4-R
8specifically in table 6.
Compound of Formula I involved in the present invention has been reported in the prior art, can obtain easily or make by oneself in accordance with the following methods.Reaction equation is as follows, and in formula, each group unless otherwise indicated defines ditto:
In formula: X with Y is different, be selected from halogen atom or amino respectively; Z is selected from halogen atom; R
2, R
3, R
4, R
5, R
6, R
7, R
8respectively as previously mentioned; R
1as previously mentioned, but R
1≠ H.
According to above preparation method, intermediate II and intermediate III are obtained by reacting R in general formula I in the basic conditions
1compound I-a of=H; By itself and Z-R
1reaction, can obtain R in general formula I
1compound I-the b of ≠ H.
The suitable optional potassium hydroxide freely of alkali, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine, Feldalat NM, Sodium ethylate, sodium hydride, potassium tert-butoxide or sodium tert-butoxide etc.
React and carry out in suitable solvent, the suitable optional oxolane freely of solvent, acetonitrile, toluene, dimethylbenzene, benzene, DMF, N-Methyl pyrrolidone, dimethyl sulfoxine, acetone or butanone etc.
Reaction temperature between room temperature to solvent boiling point temperature, can be generally 20-100 DEG C.
Response time is 30 minutes to 20 hours, usual 1-10 hour.
Intermediate II mostly is commercial goods, also can prepare by known method, such as reference literature Indian Journal of Chemistry, Section B:Organic Chemistry Including Medicinal Chemistry, 45B (4), 972-975; 2006, or document Tetrahedron Letters, 44 (21), 4085-4088; 2003, and in Poland Patent PL174903 etc., the method for report obtains.
Intermediate III can be prepared by known method, and the method such as introduced with reference to JP2003292476, US2010160695 etc. obtains.
Additive method can also be adopted to prepare compound of Formula I of the present invention, such as, can by substituted diphenylamine intermediate (as shown in general formula I V) by the nitrated compound of Formula I obtained containing nitro, preparation method is see US4041172 etc.
In formula: R
1, R
2, R
4, R
5, R
6, R
7and R
8respectively as previously mentioned; R
3be selected from hydrogen or nitro.
For R in general formula I
4, R
6or R
8a compound for hydrogen is had at least in three substituent groups, also can by it be nitratedly obtained the compound of Formula I increasing one or two nitros.
Can also by R in general formula I
4, R
6or R
8be not the substituted diphenylamine aminated compounds of halogen atom, obtain by halogenation the compound of Formula I increasing one or two halogen atoms.
By R
2for the reaction such as compound of Formula I and amine, alcohol or mercaptan (or its salt) of halogen atom, R can be obtained
2for the compound of Formula I of alkylamino, alkoxyl or alkylthio group etc.
The salt of compound of Formula I can be obtained with corresponding acid according to a conventional method by compound of Formula I.Suitable acid is selected from hydrochloric acid, sulphuric acid, nitric acid, carbonic acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, pyrovinic acid, benzoic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, ascorbic acid or oxalic acid etc.; Preferred hydrochloric acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid or p-methyl benzenesulfonic acid etc. further.
The present invention includes the preparation of formulation ingredients that the compound that comprises with above-mentioned general formula I is mixed with for active component and its preparation composition.Formulation preparation method for: obtain formulation soln in compound dissolution the present invention contained to the surfactant of water miscible organic solvent, nonionic, water miscible lipoid, various cyclodextrin, fatty acid, fatty acid ester, phospholipid or its combination solvent; Add the carbohydrate that normal saline obtains 1-20%.Described organic solvent comprises Polyethylene Glycol (PEG), ethanol, the combination solvent of propylene glycol or these solvents.
The compound or its salt contained in general formula I of the present invention and prodrug are for the preparation for the treatment of, prevention or alleviate antitumor drug or pharmaceutical preparation, and active constituents of medicine is the substituted diphenylamine aminated compounds shown in one or more general formula Is.Be particularly useful for the cancer that treatment or alleviation tissue or organ tumor cell cause.The preferred colon cancer of indication cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer etc.
The compound of the present invention's synthesis can be used for the active component of antitumor drug, can be used alone, also can with other antitumor, antiviral drugs drug combination.In the drug combination therapeutic process of indication of the present invention, comprise using together with at least one the compounds of this invention and one or more anti-tumor virus drugs of its reactive derivative and other and use to increase general curative effect.Dose during drug combination and administration time should be determined according to most rational therapy effect acquired when different.
The medicament compatibility contained comprises the effective dose of the compound in general formula I." effective dose " herein refers to the consumption that can produce this compound required for therapeutic effect for institute's treatment target.This effective dose or dosage can by there being experience person different according to the suggestion of different situations.Such as, the tumor class for the treatment of is different, and the usage of medicine is different; Whether share with other Therapeutic Method such as other antitumor drug or antiviral drugs, dosage all can change.Any spendable preparation formulation can be made.If some has alkalescence or acid compound also can form avirulent acid or salt, the form of the salt of this compound can be used.In pharmacy, spendable acylate comprises spendable anion salt on physiology, as toluenesulfonate, metilsulfate, acetate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or glycerophosphate etc.; Spendable inorganic salt comprises chloride, bromide, fluoride, iodide, sulfate, nitrate, bicarbonate, carbonate or phosphate etc.; The form of described salt can be made if any the compound of the alkalescence as amine and suitable acid; The compound of carboxylic acids can form spendable salt with alkali metal or alkaline-earth metal.
The compound contained in formula of I of the present invention is generally readily soluble in the mixed solvent of organic solvent, water-soluble solvent and organic solvent and water-soluble solvent and water.Water-soluble solvent preferred alcohols, poly ethylene glycol, N-methyl-2-pyrrolinone, N,N-dimethylacetamide, DMF, dimethyl sulfoxine, acetonitrile and its share.Described alcohol particular methanol, ethanol, isopropyl alcohol, glycerol or ethylene glycol.The compounds of this invention can mix with conventional preparations carrier and make preparation.Drug solution is obtained in compound dissolution to water miscible organic solvent, non-protonic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or in the mixed solvent of these solvents; Add the carbohydrate that normal saline obtains 1-20% again, as the aqueous solution of glucose.Preparation stabilization obtained therefrom for animal and clinical.
With the product medicine that compound in above-mentioned general formula I becomes for active fraction preparation, oral or parenteral administration can be passed through, also by transplant medicine pump in body and additive method administration, herein the parenteral administration of indication refer in subcutaneous Intradermal, intramuscular, intravenous, intra-arterial, atrium, in synovial membrane, in breastbone, in sheath, in wound site, intracranial injection or drip infusion technique etc.Use conventional method proportioning by technical staff, mixing finally becomes required pharmaceutical dosage form.Can be tablet, pill, capsule, electuary, syrup, injection, freeze-dried powder dosage form, Emulsion, powder, lyophilized powder, drop pill, emulsion suspension liquid, water hang solution, aqueous solution, colloid, colloid solution, slow releasing preparation, nanometer formulation or with other forms of dosage form for animal or clinical.
Compound in general formula I of the present invention is used for the treatment of, prevents or alleviates the preparation of the cancer drug of a certain tissue or organ.Indication cancer comprises but is not only limited to colon cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer etc.
Detailed description of the invention
Following specific embodiment is used for further illustrating the present invention, but the present invention is not limited to these examples.(except as otherwise indicate outside, raw materials used all have commercially available)
Synthetic example
Embodiment 1: the preparation of table 6-39 compound
Table 6-39 compound
By 0.81g (0.005mol) 2,4-dichloroaniline joins in the 20mL oxolane suspension of the sodium hydride of 0.4g (0.01mol) 60% in batches, add rear stirring at room temperature 30min, instill 1.56g (0.006mol) 2 wherein, 6-bis-chloro-3, the 30mL tetrahydrofuran solution of 5-dinitrotoluene (DNT), about 30min drips, and continues stirring at room temperature 5 hours.TLC monitors after completion of the reaction, by reacting liquid filtering, and filtrate decompression precipitation, (eluant is ethyl acetate and petroleum ether (boiling range 60-90 DEG C) to column chromatography, volume ratio is 1: 20) purification must show 6-39 compound, yellow solid 1.37g, fusing point 136-137 DEG C.
1H-NMR (300MHz, interior mark TMS, solvent C DCl3) δ (ppm): 2.14 (s, 3H), 6.53 (d, 1H), 7.17 (d, 1H), 7.49 (s, 1H), 8.68 (s, 1H), 8.93 (s, 1H).
Embodiment 2: the preparation of table 6-101 compound
Table 6-101
Synthetic method is with showing 6-39 compound, fusing point 143-144 DEG C.
1h-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (CDCl
3): 1.98 (s, 3H), 7.66 (s, 2H), 8.70 (s, 1H), 9.10 (s, 1H).
Embodiment 3: the preparation of table 6-105 compound
Table 6-105 compound
By 0.83g (0.004mol) 2,6-Dichloro-4-nitroaniline joins the 10mL N of the sodium hydride of 0.32g (0.008mol) 60% in batches, in dinethylformamide (DMF) suspension, add rear stirred at ambient temperature 30min, then in 30min, add 1.20g (0.0048mol) 2 in batches, chloro-3, the 5-dinitrotoluene (DNT)s of 6-bis-, continue reaction 3 hours under room temperature.TLC monitoring after completion of the reaction, reactant liquor is poured in 50mL saturated aqueous common salt, extraction into ethyl acetate, extract anhydrous magnesium sulfate drying reduces pressure precipitation, (eluant is ethyl acetate and petroleum ether (boiling range 60-90 DEG C) to column chromatography, volume ratio is 1: 10) purification must show 6-105 compound, yellow solid 1.20g, fusing point 157-158 DEG C.
1h-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 2.02 (s, 3H), 8.29 (s, 2H), 8.65 (s, 1H), 8.95 (s, 1H).
Embodiment 4: the preparation of table 6-120 compound
Table 6-120
Synthetic method is with showing 6-39 compound, fusing point 148-150 DEG C.
1h-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 2.07 (s, 3H), 7.53 (s, 1H), 7.72 (s, 1H), 8.71 (s, 1H), 8.97 (s, 1H).
Embodiment 5: the preparation of table 6-121 compound
Table 6-39 compound table 6-121 compound
0.56g (0.0015mol) is shown 6-39 compound to be dissolved in 5mL concentrated sulphuric acid (96%, lower with) and to be cooled to 0 DEG C, add reaction bulb by after 0.15g fuming nitric aicd (95%) and 3mL concentrated sulphuric acid mix homogeneously, continue to stir 5min, TLC monitoring reaction is complete, is poured into by reactant liquor in frozen water, has solid to separate out, filter, use water flush cake, dry, 6-121 compound must be shown, brown solid 0.59g, fusing point 156-158 DEG C.
1h-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 2.09 (s, 3H), 7.66 (s, 1H), 8.01 (s, 1H), 8.60 (s, 1H), 9.75 (s, 1H).
Embodiment 6: the preparation of table 6-153 compound
Table 6-153
Synthetic method is with showing 6-39 compound, fusing point 204-206 DEG C.
1h-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 2.23 (s, 3H), 7.87 (s, 1H), 8.38 (s, 1H), 8.51 (s, 1H), 10.00 (s, 1H).
Embodiment 7: the preparation of table 6-206 compound
Intermediate M shows 6-206 compound
Obtain intermediate M according to the method for embodiment 3, then according to the method for example 5, obtain table 6-206 compound, red brown solid, fusing point 136-138 DEG C by nitrated for intermediate M.
1h-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 2.41 (s, 3H), 8.50 (s, 1H), 8.72 (s, 1H), 10.10 (s, 1H).
Embodiment 8: the preparation of table 8-39 compound
Table 6-39 compound table 8-39 compound
0.38g (0.001mol) being shown 6-39 compound joins in the 10mL DMF suspension of the sodium hydride of 0.10g (0.0025mol) 60%, stirs 1 hour, adds 0.43g (0.003mol) iodomethane, reacts 5 hours.TLC monitoring after completion of the reaction, reactant liquor is poured in 50mL saturated aqueous common salt, extraction into ethyl acetate, extract anhydrous magnesium sulfate drying, decompression precipitation, column chromatography (eluant is ethyl acetate and petroleum ether (boiling range 60-90 DEG C), and volume ratio is 1: 10) purification must show 8-39 compound, yellow solid 0.15g, fusing point 142-144 DEG C.
1h-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 2.54 (s, 3H), 3.31 (s, 3H), 7.09 (d, 1H), 7.25 (d, 2H), 8.04 (s, 1H).
Embodiment 9: the preparation of table 11-105 compound
Table 6-105 compound table 11-105 compound
Get 0.42g and show 6-105 compound (0.001mol) in microwave reaction bottle, dissolved with the dimethyl sulfoxide (DMSO) of 2.5mL, add cover lid after the methylamine water solution 1mL of 25%, put into Biotage Microwave synthesize instrument, at 150 DEG C, react 40min.Reactant liquor is poured in 50mL saturated aqueous common salt, extraction into ethyl acetate, extract anhydrous magnesium sulfate drying, decompression precipitation, (eluant is ethyl acetate and petroleum ether (boiling range 60-90 DEG C) to column chromatography, volume ratio is 1: 20) purification must show 11-105 compound, yellow solid 0.25g, fusing point 218-219 DEG C.
1h-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 1.70 (s, 3H), 3.09 (d, 3H), 8.25 (d, 1H), 8.31 (s, 2H), 9.12 (s, 1H), 9.58 (s, 1H).
Other compounds of the present invention can be prepared with reference to above embodiment.
The physical data of part of compounds and nuclear magnetic data (
1hNMR, 300MHz, interior mark TMS, ppm) as follows:
Table 6-11 compound: fusing point 158-160 DEG C.δ(CDCl
3)：2.10(s，3H)，6.83(d，4H)，7.12(m，2H)，7.34(m，4H)，8.56(s，1H)。
Table 6-22 compound: fusing point 172-174 DEG C.δ(DMSO)：2.34(s，3H)，6.83(d，2H)，8.06(d，2H)，8.64(s，1H)，9.49(s，1H)。
Table 6-23 compound: fusing point 184-186 DEG C.δ(CDCl
3)：2.22(s，3H)，6.87(d，2H)，7.62(d，2H)，8.66(s，1H)，8.93(s，1H)。
Table 6-24 compound: fusing point 91-94 DEG C.δ(CDCl
3)：2.14(s，3H)，6.91(d，2H)，721(d，2H)，8.71(s，1H)，9.20(s，1H)。
Table 6-31 compound: fusing point 136-138 DEG C.δ(CDCl
3)：2.12(s，3H)，7.21(m，2H)，7.26(m，1H)，8.72(s，1H)，9.00(s，1H)。
Table 6-47 compound: fusing point 106-108 DEG C.δ(CDCl
3)：2.22(s，3H)，6.55(d，1H)，7.43(d，1H)，7.75(s，1H)，8.65(s，1H)，8.87(s，1H)。
Table 6-48 compound: fusing point 110-112 DEG C.δ(CDCl
3)：2.03(s，3H)，2.50(s，3H)，6.50(d，1H)，7.05(t，1H)，7.24(d，1H)，8.73(s，1H)，9.06(s，1H)。
Table 6-50 compound: fusing point 191-193 DEG C.δ(CDCl
3)：2.29(s，3H)，6.48(d，1H)，8.06(d，1H)，8.41(s，1H)，8.62(s，1H)，8.79(s，1H)。
Table 6-56 compound: fusing point 146-148 DEG C.δ(CDCl
3)：1.86(s，3H)，2.40(s，3H)，7.18(m，2H)，7.28(m，1H)，8.80(s，1H)，9.52(s，1H)。
Table 6-58 compound: fusing point 133-135 DEG C.δ(CDCl
3)：2.03(s，3H)，2.50(s，3H)，6.53(d，1H)，7.06(t，1H)，7.21(d，1H)，8.74(s，1H)，9.08(s，1H)。
Table 6-61 compound: fusing point 206-208 DEG C.δ(CDCl
3)：2.25(s，3H)，6.48(d，1H)，7.47(d，1H)，7.77(s，1H)，8.62(s，1H)，8.80(s，1H)。
Table 6-63 compound: fusing point 259-261 DEG C.δ(CDCl
3)：2.38(s，3H)，6.54(d，1H)，7.70(d，1H)，8.50(s，1H)，8.62(s，1H)，10.51(s，1H)。
Table 6-80 compound: fusing point 121-123 DEG C.δ(CDCl
3)：2.02(s，3H)，2.40(s，3H)，6.53(d，1H)，7.10(d，1H)，7.27(s，1H)，8.74(s，1H)，9.03(s，1H)。
Table 6-86 compound: Chinese red grease.δ(DMSO)：2.33(s，3H)，6.92(d，1H)，7.26(s，1H)，7.78(d，1H)，8.63(s，1H)，9.54(s，1H)。
Table 6-88 compound: fusing point 204-205 DEG C.δ(CDCl
3)：2.31(s，3H)，6.48(d，1H)，7.43(d，1H)，8.26(s，1H)，8.54(s，1H)，10.36(s，1H)。
Table 6-89 compound: fusing point 185-186 DEG C.δ(CDCl
3)：2.41(s，3H)，6.56(d，1H)，8.31(d，1H)，8.52(s，1H)，9.23(s，1H)，10.59(s，1H)。
Table 6-93 compound: fusing point 148-150 DEG C.δ(CDCl
3)：2.12(s，3H)，7.04(d，2H)，8.70(s，1H)，8.87(s，1H)。
Table 6-94 compound: fusing point 154-156 DEG C.δ(CDCl
3)：2.21(s，3H)，7.20(m，1H)，7.80(m，1H)，8.59(s，1H)，9.94(s，1H)。
Table 6-95 compound: fusing point 140-142 DEG C.δ(CDCl
3)：2.17(s，3H)，7.19(d，2H)，8.71(s，1H)，8.94(s，1H)。
Table 6-97 compound: fusing point 142-143 DEG C.δ(CDCl
3)：2.20(s，3H)，6.59(s，1H)，7.58(s，1H)，8.67(s，1H)，8.80(s，1H)。
Table 6-98 compound: fusing point 160-162 DEG C.δ(CDCl
3)：1.95(s，3H)，7.41(s，2H)，8.72(s，1H)，9.19(s，1H)。
Table 6-104 compound: fusing point 180-182 DEG C.δ(CDCl
3)：1.99(s，3H)，7.69(s，2H)，8.67(s，1H)，9.00(s，1H)。
Table 6-106 compound: fusing point 169-171 DEG C.δ(CDCl
3)：2.32(s，3H)，6.42(s，1H)，8.20(s，1H)，8.60(s，1H)，8.62(s，1H)。
Table 6-107 compound: fusing point 132-134 DEG C.δ(CDCl
3)：1.95(s，3H)，3.96(s，3H)，8.05(s，2H)，8.70(s，1H)，9.13(s，1H)。
Table 6-116 compound: fusing point 216-219 DEG C.δ(CDCl
3)：2.30(s，3H)，7.88(s，2H)，8.48(s，1H)，8.85(s，1H)。
Table 6-118 compound: fusing point 169-171 DEG C.δ(CDCl
3)：2.26(s，3H)，8.50(d，2H)，8.99(s，1H)，10.14(s，1H)。
Table 6-119 compound: fusing point 160-161 DEG C.δ(CDCl
3)：2.13(s，3H)，2.54(s，3H)，6.40(d，1H)，7.19(d，1H)，8.68(s，1H)，8.96(s，1H)。
Table 6-122 compound: fusing point 135-137 DEG C.δ(CDCl
3)：2.16(s，3H)，7.95(dd，1H)，8.26(t，1H)，8.63(s，1H)，8.82(s，1H)。
Table 6-123 compound: fusing point 151-153 DEG C.δ(CDCl
3)：1.99(s，3H)，8.31(d，1H)，8.47(d，1H)，8.66(s，1H)，9.00(s，1H)。
Table 6-124 compound: fusing point 96-97 DEG C.δ(CDCl
3)：2.21(s，3H)，5.08(m，1H)，6.59(s，1H)，7.49(s，1H)，8.66(s，1H)，8.78(s，1H)。
Table 6-125 compound: fusing point 192-194 DEG C.δ(CDCl
3)：2.20(s，3H)，7.05(s，2H)，8.04(s，1H)，8.22(s，1H)，9.07(s，1H)，9.43(s，1H)。
Table 6-126 compound: fusing point 125-127 DEG C.δ(CDCl
3)：1.94(s，3H)，7.53(s，2H)，8.75(s，1H)，9.29(s，1H)。
Table 6-129 compound: fusing point 151-154 DEG C.δ(CDCl
3)：1.97(s，3H)，8.49(s，2H)，8.68(s，1H)，9.03(s，1H)。
Table 6-130 compound: fusing point 172-175 DEG C.δ(DMSO)：2.32(s，3H)，8.49(s，1H)，8.68(s，2H)，9.50(s，1H)。
Table 6-133 compound: fusing point 131-132 DEG C.δ(CDCl
3)：2.10(s，3H)，6.99(t，2H)，7.17(m，1H)，8.72(s，1H)，8.98(s，1H)。
Table 6-139 compound: fusing point 158-161 DEG C.δ(CDCl
3)：2.16(s，3H)，2.61(s，3H)，6.47(d，1H)，7.67(d，1H)，8.69(s，1H)，8.85(s，1H)。
Table 6-140 compound: fusing point 137-139 DEG C.δ(CDCl
3)：1.91(s，3H)，2.31(s，3H)，8.10(s，1H)，821(s，1H)，8.73(s，1H)，9.20(s，1H)。
Table 6-152 compound: fusing point 160-162 DEG C.δ(CDCl
3)：2.18(s，3H)，7.88(d，1H)，8.32(d，1H)，8.55(s，1H)，9.97(s，1H)。
Table 6-163 compound: fusing point 241-243 DEG C.δ(CDCl
3)：1.97(s，3H)，7.83(s，2H)，8.69(s，1H)，9.11(s，1H)。
Table 6-164 compound: δ (CDCl
3): 1.94 (s, 3H), 3.03 (d, 3H), 7.78 (s, 2H), 8.70 (s, 1H), 9.14 (s, 1H).
Table 6-169 compound: fusing point 187-190 DEG C.δ(CDCl
3)：2.18(s，3H)，8.23(s，2H)，8.57(s，1H)，10.39(s，1H)。
Table 6-170 compound: red oil.δ(CDCl
3)：2.27(s，3H)，8.52(s，1H)，9.09(s，2H)，10.93(s，1H)。
Table 6-171 compound: fusing point 93-95 DEG C.δ(CDCl
3)：2.19(s，3H)，8.14(s，2H)，8.56(s，1H)，10.42(s，1H)。
Table 6-172 compound: fusing point 204-206 DEG C.δ(DMSO)：2.32(s，3H)，7.03(s，1H)，8.73(s，1H)，8.86(s，1H)，10.40(s，1H)。
Table 6-180 compound: fusing point 127-129 DEG C.δ(CDCl
3)：2.36(s，3H)，6.55(s，1H)，8.40(s，1H)，8.54(s，1H)，10.31(s，1H)。
Table 6-207 compound: fusing point 159-162 DEG C.δ(CDCl
3)：2.16(s，3H)，8.23(s，1H)，8.63(s，1H)，8.91(s，1H)。
Table 6-208 compound: fusing point 133-135 DEG C.δ(CDCl
3)：2.07(s，3H)，7.70(s，1H)，8.69(s，1H)，9.22(s，1H)。
Table 7-22 compound: fusing point 136-138 DEG C.δ(CDCl
3)：2.22(s，3H)，6.70(d，2H)，7.41(d，1H)，8.00(d，1H)，8.16(d，2H)，8.22(s，1H)。
Table 7-23 compound: fusing point 146-148 DEG C.δ(CDCl
3)：2.19(s，3H)，6.70(d，2H)，7.36(d，1H)，7.53(d，2H)，7.96(d，1H)，820(s，1H)。
Table 7-24 compound: fusing point 72-74 DEG C.δ(CDCl
3)：2.12(s，3H)，6.75(d，2H)，7.12(d，2H)，7.25(d，1H)，7.98(d，1H)，8.46(s，1H)。
Table 7-63 compound: fusing point 158-160 DEG C.δ(CDCl
3)：2.30(s，3H)，6.47(d，1H)，7.59(m，2H)，7.94(d，1H)，8.60(s，1H)，10.21(s，1H)。
Table 7-77 compound: fusing point 136-138 DEG C.δ(CDCl
3)：2.22(s，3H)，6.75(d，1H)，7.03(s，1H)，7.45(d，1H)，7.67(d，1H)，7.99(d，1H)，8.16(s，1H)。
Table 7-80 compound: red oil.δ(CDCl
3)：2.02(s，3H)，2.38(s，3H)，6.34(d，1H)，7.00(d，1H)，7.18(m，2H)，7.98(d，1H)，8.30(s，1H)。
Table 7-97 compound: fusing point 112-114 DEG C.δ(CDCl
3)：2.18(s，3H)，6.38(s，1H)，7.38(d，1H)，7.50(s，1H)，7.97(d，1H)，8.11(s，1H)。
Table 7-101 compound: brown oil.δ(CDCl
3)：1.92(s，3H)，7.22(d，1H)，7.58(s，2H)，7.93(d，1H)，8.39(s，1H)。
Table 8-47 compound: fusing point 138-140 DEG C.δ(CDCl
3)：2.58(s，3H)，3.37(s，3H)，7.23(d，1H)，7.48(s，1H)，7.57(d，1H)，8.08(s，1H)。
Table 8-170 compound: fusing point 140-142 DEG C.δ(CDCl
3)：2.58(s，3H)，3.30(s，3H)，8.38(s，1H)，8.57(s，2H)。
Table 9-105 compound: fusing point 134-136 DEG C.δ(CDCl
3)：1.79(s，3H)，3.96(s，3H)，8.29(s，2H)，8.74(s，1H)，9.18(s，1H)。
Table 10-105 compound: fusing point 132-134 DEG C.δ(CDCl
3)：2.11(s，3H)，2.39(s，3H)，8.29(s，2H)，8.47(s，1H)，8.95(s，1H)。
Table 11-164 compound: fusing point 216-218 DEG C.δ(CDCl
3)：1.56(s，3H)，3.04(m，6H)，7.80(s，2H)，8.18(s，1H)，9.13(s，1H)，9.58(s，1H)。
Table 12-105 compound: fusing point 178-180 DEG C.δ(CDCl
3)：1.71(s，3H)，2.86(s，6H)，8.29(s，2H)，8.66(s，1H)，9.45(s，1H)。
Table 13-105 compound: fusing point 126-128 DEG C.δ(CDCl
3)：1.83(s，3H)，4.42(q，2H)，8.30(s，2H)，8.85(s，1H)，9.20(s，1H)。
Antitumor cytolytic activity
Embodiment 10: the external test experience to inhibiting tumour cells effect is as follows:
Institute's employment tumor cell strain: people pulmonary carcinoma A549, human leukemia HL-60 etc.
The concentration that design five is different routinely, namely 100,10,1,0.1,0.01 μMs.Adopt Cell culture invitro technology, measure test sample to the suppression ratio of each one growth of cancer cells with conventional mtt assay.
Taken out from incubator by cell, with PBS liquid cleaning twice, with 0.25% trypsin solution digestion, add culture medium and stop digestion, centrifugal rear suction pipe piping and druming makes it to form cell suspension, and counts under inverted microscope.Cell being mixed with concentration is 5x10
4the cell suspension of/ml, cell 100 μ l is added in the 96 every holes of orifice plate, be positioned over 5% carbon dioxide, overnight incubation in 37 DEG C of humidified air, add the above-mentioned medicine to be measured being diluted to variable concentrations gradient, after making its effect 48h, add MTT, through reacting 4 hours, the reduction of MTT tetrazolium composition is produced formazan by living cells, add DMSO afterwards to dissolve formazan, finally 96 hole plate reader to be measured the light absorption value of 570nm.
Partial test result is as follows:
To the suppression ratio of human lung cancer cell A549's growth
To the suppression ratio that human leukemia cell HL60 grows
Claims (7)
1. substituted diphenylamine aminated compounds is as the application preparing antitumor drug, it is characterized in that compound structure is as shown in general formula I:
In formula:
R
1, R
5, R
7be selected from hydrogen;
R
2be selected from hydrogen, chlorine, OCH
2cF
3;
R
3be selected from nitro;
R
4be selected from chlorine;
R
6be selected from hydrogen, fluorine, chlorine, cyano group, nitro or trifluoromethyl;
R
8be selected from fluorine, chlorine, cyano group or nitro;
Or its hydrochlorate, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates.
2. application according to claim 1, is characterized in that: in compound of Formula I
R
1, R
5, R
7be selected from hydrogen;
R
2be selected from chlorine;
R
3be selected from nitro;
R
4be selected from chlorine;
R
6be selected from chlorine, cyano group, nitro or trifluoromethyl;
R
8be selected from chlorine, cyano group or nitro;
Or its hydrochlorate, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates.
3. application according to claim 2, is characterized in that following structural compounds:
4. the application according to claim 1-3 any one, it is characterized in that: become oral with the substituted diphenylamine aminated compounds shown in general formula I for active fraction preparation or the form of parenteral route carries out administration, or carry out administration by the form of transplant medicine pump in body.
5. application according to claim 4, is characterized in that: active constituents of medicine is the substituted diphenylamine aminated compounds shown in one or more general formula Is.
6. application according to claim 5, it is characterized in that: be active fraction preparation treatment, prevention or the medicine of tumor remission with the substituted diphenylamine aminated compounds shown in general formula I, pharmaceutical dosage form is tablet, pill, capsule, electuary, syrup, injection or freeze-dried powder dosage form.
7. application according to claim 6, is characterized in that: be applied to preparation treatment, prevention or alleviate in colon cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer medicament.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210067267.3A CN103301096B (en) | 2012-03-14 | 2012-03-14 | Application of substituted diphenylamine compound to preparation of antitumor drugs |
| KR1020147017304A KR101599300B1 (en) | 2012-03-14 | 2013-03-06 | Substitute diphenylamine compounds use thereof as antitumor agents |
| EP13761044.0A EP2826474B1 (en) | 2012-03-14 | 2013-03-06 | Use of substituted diphenylamine compounds in preparing anti-tumour drugs |
| CN201380007479.5A CN104136021B (en) | 2012-03-14 | 2013-03-06 | Substituted diphenylamine aminated compounds is as the application preparing antitumor drug |
| US14/376,074 US9376376B2 (en) | 2012-03-14 | 2013-03-06 | Substitute diphenylamine compounds use thereof as antitumor agents |
| CA2859842A CA2859842C (en) | 2012-03-14 | 2013-03-06 | Substitute diphenylamine compounds use thereof as antitumor agents |
| PCT/CN2013/072232 WO2013135147A1 (en) | 2012-03-14 | 2013-03-06 | Use of substituted diphenylamine compounds in preparing anti-tumour drugs |
| JP2014561274A JP5959670B2 (en) | 2012-03-14 | 2013-03-06 | Use of substituted diphenylamine compounds in the preparation of antitumor agents |
| TW102108792A TW201336808A (en) | 2012-03-14 | 2013-03-13 | Use of substituted diphenylamine compounds in preparing anti-tumor drugs |
| ARP130100821A AR090334A1 (en) | 2012-03-14 | 2013-03-13 | DIFENYLAMINE SUBSTITUTED COMPOUNDS; USE OF THEM AS ANTITUMOR AGENTS |
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| CN103539681B (en) * | 2012-07-11 | 2016-04-20 | 沈阳中化农药化工研发有限公司 | A kind of diphenylamine compound of replacement and application thereof |
| CN105287460B (en) * | 2014-07-21 | 2019-03-22 | 沈阳化工研究院有限公司 | Substituted diphenylamine amine compound is as the application for preparing anti-tumor drug |
| CN105724398B (en) * | 2014-12-11 | 2018-12-14 | 沈阳中化农药化工研发有限公司 | A kind of Fungicidal composition and its application |
| CN106316861B (en) * | 2015-06-26 | 2018-04-24 | 沈阳中化农药化工研发有限公司 | A kind of method for preparing double benzene bacterium amine |
| CN112745237B (en) * | 2019-10-29 | 2023-06-20 | 中国科学院上海药物研究所 | 2-arylamine compound and preparation method and application thereof |
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|---|---|---|---|---|
| CN1333698A (en) * | 1998-12-22 | 2002-01-30 | 沃尼尔·朗伯公司 | Combination chemotherapy |
| CN101407467A (en) * | 2007-10-12 | 2009-04-15 | 中国人民解放军军事医学科学院毒物药物研究所 | N-substituted arene aniline / polysubstituted diaryl ether compound, preparation and anti-tumor use thereof |
| CN102199095A (en) * | 2010-03-22 | 2011-09-28 | 中国中化股份有限公司 | Substituted diphenylamine compounds and preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1333698A (en) * | 1998-12-22 | 2002-01-30 | 沃尼尔·朗伯公司 | Combination chemotherapy |
| CN101407467A (en) * | 2007-10-12 | 2009-04-15 | 中国人民解放军军事医学科学院毒物药物研究所 | N-substituted arene aniline / polysubstituted diaryl ether compound, preparation and anti-tumor use thereof |
| CN102199095A (en) * | 2010-03-22 | 2011-09-28 | 中国中化股份有限公司 | Substituted diphenylamine compounds and preparation and application thereof |
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