CN103301103A - Application of cyano-containing diphenylamine compound to preparation of antitumor drugs - Google Patents
Application of cyano-containing diphenylamine compound to preparation of antitumor drugs Download PDFInfo
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- CN103301103A CN103301103A CN2012100675953A CN201210067595A CN103301103A CN 103301103 A CN103301103 A CN 103301103A CN 2012100675953 A CN2012100675953 A CN 2012100675953A CN 201210067595 A CN201210067595 A CN 201210067595A CN 103301103 A CN103301103 A CN 103301103A
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- 0 *c(cc1)ccc1Nc(c(Cl)c(c(C#N)c1Cl)Cl)c1C#N Chemical compound *c(cc1)ccc1Nc(c(Cl)c(c(C#N)c1Cl)Cl)c1C#N 0.000 description 3
- LBEKFAUAYVGHFP-UHFFFAOYSA-N COC(c(cc1Cl)cc(Cl)c1N)=O Chemical compound COC(c(cc1Cl)cc(Cl)c1N)=O LBEKFAUAYVGHFP-UHFFFAOYSA-N 0.000 description 1
- NWJOXHYISOGHHO-UHFFFAOYSA-N Cc(cc(c(C)c1)Cl)c1Nc(c(Cl)c(c(C#N)c1Cl)Cl)c1C#N Chemical compound Cc(cc(c(C)c1)Cl)c1Nc(c(Cl)c(c(C#N)c1Cl)Cl)c1C#N NWJOXHYISOGHHO-UHFFFAOYSA-N 0.000 description 1
- CRQQGFGUEAVUIL-UHFFFAOYSA-N N#Cc(c(Cl)c(c(Cl)c1C#N)Cl)c1Cl Chemical compound N#Cc(c(Cl)c(c(Cl)c1C#N)Cl)c1Cl CRQQGFGUEAVUIL-UHFFFAOYSA-N 0.000 description 1
- OCJPFYIYARGCPB-UHFFFAOYSA-N N#Cc(c(Cl)c(c(Cl)c1Cl)C#N)c1Nc(cc1)ccc1[N+]([O-])=O Chemical compound N#Cc(c(Cl)c(c(Cl)c1Cl)C#N)c1Nc(cc1)ccc1[N+]([O-])=O OCJPFYIYARGCPB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses application of a cyano-containing diphenylamine compound shown in a general formula I in the specification to preparation of antitumor drugs. The definition of each substituent group in the formula refers to 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 field of antineoplastic medicaments.Relate to particularly a kind of cyano-containing diphenylamine compound as the application of antitumor drug.
Background technology
Patent CN101391981A discloses the chemical compound shown in the following general formula and can be used as synthetic a kind of intermediate with new polyhaloacridones compound of fluorescence activity and potential drug activity, wherein mentioned compound K C1 (chemical compound code name IV-A), KC2 (chemical compound code name IV-B), KC3 (chemical compound code name IV-D), KC4 (chemical compound code name IV-E), KC5 (chemical compound code name IV-H), KC6 (chemical compound code name IV-C), but reported without any biological activity; Document Pesticide Science (1988), 24 (2), 111-21 has reported that compound K C1 (wherein code name is XXIX) has certain activity to relevant disease such as Plasmopara viticola (Plasmopora viticola) etc. under high dose.
The applicant had once applied for the chemical compound shown in the general formula I as disinfectant use in agriculture in 2011, and application number is 201110163457.0.
In the prior art, the chemical compound of structure shown in general formula I of the present invention has no the report as antitumor drug.
Summary of the invention
The object of the present invention is to provide the application of the cyano-containing diphenylamine compound of a class formation shown in general formula I in the preparation antitumor drug.
Technical scheme of the present invention is as follows:
The application of cyano-containing diphenylamine compound in the preparation antitumor drug, compound structure is shown in general formula I:
In the 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
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
2-C
8Thiazolinyl, C
2-C
8Alkynyl, halo C
2-C
8Thiazolinyl, halo C
2-C
8Alkynyl, aryl C
1-C
8Alkyl 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
2, R
3Can be identical or different, be selected from respectively hydrogen, halogen, hydroxyl, cyano group, nitro, COOH, 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
1-C
8Alkyl sulphonyl, 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 or C
1-C
8Alkoxy carbonyl C
1-C
8Alkoxyl;
R
4, R
8Can be identical or different, be selected from respectively hydrogen, halogen, cyano group, nitro, COOH, 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, unsubstituted or by 1-5 R
11The following radicals that replaces: aryl, arylmethyl, aryloxy group, virtue amino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl or heteroaryl oxygen base, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
5, R
7Can be identical or different, be selected from respectively hydrogen, halogen, cyano group, nitro, COOH, C (=O) NR
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 that replaces: aryl, arylmethyl, aryloxy group, virtue amino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl or heteroaryl oxygen base, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
6Be selected from hydrogen, halogen, cyano group, nitro, COOH, CO
2Na, CO
2NH
4, 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, C (=O) NR
9R
10, SO
2NR
9R
10, unsubstituted or by 1-5 R
11The following radicals that replaces: aryl, arylmethyl, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl or aromatic yl aminocarbonyl, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
9, R
10Can be identical or different, be selected from respectively hydrogen, C
1-C
6Alkyl or C
3-C
6Cycloalkyl;
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 using as antitumor drug in the above-mentioned cyano-containing diphenylamine compound more preferably chemical compound be: in the general formula I
R
1Be selected from hydrogen, C
1-C
4Alkyl, C
3-C
6Cycloalkyl, halo C
1-C
4Alkyl, C
1-C
4Alkyl-carbonyl, halo C
1-C
4Alkyl-carbonyl, C
1-C
4Alkoxy carbonyl, 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
2-C
4Thiazolinyl, C
2-C
4Alkynyl, halo C
2-C
4Thiazolinyl, halo C
2-C
4Alkynyl, benzyl, phenethyl, CO-X-CO
2R
9, wherein X is selected from (CHR
9) n, CR
9=CR
10Or C
6H
4, n=1-3;
R
2, R
3Can be identical or different, be selected from respectively chlorine, bromine, fluorine, hydroxyl, cyano group, nitro, 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
1-C
4Alkyl sulphonyl, C
1-C
6Dialkyl amido, C
3-C
4Alkene oxygen base, halo C
3-C
4Alkene oxygen base, C
3-C
4Alkynyloxy group, halo C
3-C
4Alkynyloxy 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 or C
1-C
4Alkoxy carbonyl C
1-C
4Alkoxyl;
R
4, R
8Can be identical or different, be selected from respectively hydrogen, chlorine, bromine, fluorine, cyano group, nitro, COOH, C (=O) NR
9R
10, C
1-C
4Alkyl, halo C
1-C
4Alkyl, C
1-C
4Alkoxyl, halo C
1-C
4Alkoxyl, C
1-C
4Alkylthio group, halo C
1-C
4Alkylthio group, C
2-C
4Thiazolinyl, C
2-C
4Alkynyl, 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 1-3 R
11The following radicals that replaces: phenoxy group, phenylamino, phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl, phenyl amino carbonyl or pyridine radicals oxygen base, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
5, R
7Can be identical or different, be selected from respectively hydrogen, chlorine, bromine, fluorine, cyano group, nitro, COOH, C (=O) NR
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
4Thiazolinyl, C
2-C
4Alkynyl, 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 1-3 R
11The following radicals that replaces: phenoxy group, phenylamino, phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl, phenyl amino carbonyl or pyridine radicals oxygen base, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
6Be selected from hydrogen, chlorine, bromine, fluorine, cyano group, nitro, COOH, CO
2Na, CO
2NH
4, C (=O) NR
9R
10, C
1-C
4Alkyl, halo C
1-C
4Alkyl, C
1-C
4Alkoxyl, halo C
1-C
4Alkoxyl, C
2-C
4Thiazolinyl, C
2-C
4Alkynyl, 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, SO
2NHCH
3, SO
2N (CH
3)
2, unsubstituted or by 1-3 R
11The following radicals that replaces: phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl or phenylamino carbonyl, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
9, R
10Can be identical or different, be selected from respectively hydrogen or C
1-C
4Alkyl;
R
11Be selected from fluorine, chlorine, bromine, nitro, cyano group, C
1-C
4Alkyl, halo C
1-C
4Alkyl, C
1-C
4Alkoxyl, halo C
1-C
4Alkoxyl, C
1-C
4Alkylthio group, C
1-C
4Alkyl-carbonyl, C
1-C
4Alkoxy carbonyl or C
1-C
4Alkyl amino-carbonyl;
Or the salt of compound of Formula I.
Further preferred chemical compound is when using as antitumor drug in the above-mentioned cyano-containing diphenylamine compound: in the general formula I
R
1Be selected from hydrogen, methyl, acetyl group, methyl sulphonyl, benzyl or phenethyl;
R
2, R
3Can be identical or different, be selected from respectively chlorine, fluorine, methoxyl group, CF
3O, CF
3CH
2O, methylamino, dimethylamino, diethylamino, CF
3CH
2NH, ClCH
2CH
2NH, methyl mercapto, ethylmercapto group, methyl sulphonyl, ethylsulfonyl, dimethylamino, CH
2=CHCH
2O, CH ≡ CCH
2O, ClC ≡ CCH
2O, IC ≡ CCH
2O, CH
3CO
2, CH
3CONH, CH
3OCH
2CH
2O, C
2H
5OCH
2CH
2O, CH
3OC (=O) CH
2O or CH
3OC (=O) CH
2CH
2O;
R
4, R
8Can be identical or different, be selected from respectively hydrogen, fluorine, chlorine, bromine, cyano group, nitro, COOH, CONH
2, methyl, ethyl, isopropyl, the tert-butyl group, chloromethyl, trifluoromethyl, methoxyl group, ethyoxyl, CF
3O, CF
3CH
2O, methyl mercapto, methoxycarbonyl, CH
3OCH
2, CONHCH
3, CON (CH
3)
2, CONHCH (CH
3)
2Or CONHC (CH
3)
3
R
5, R
7Can be identical or different, be selected from respectively hydrogen, fluorine, chlorine, bromine, cyano group, nitro, COOH, CONH
2, methyl, ethyl, isopropyl, the tert-butyl group, chloromethyl, trifluoromethyl, methoxyl group, ethyoxyl, CF
3O, CF
3CH
2O, methyl mercapto, methoxycarbonyl, CH
3OCH
2, CONHCH
3, CON (CH
3)
2, CONHCH (CH
3)
2Or CONHC (CH
3)
3
R
6Be selected from hydrogen, fluorine, chlorine, bromine, cyano group, nitro, COOH, CO
2Na, CO
2NH
4, CONH
2, CONHCH
3, CON (CH
3)
2, CONHCH (CH
3)
2, CONHC (CH
3)
3, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxy carbonyl, methyl sulphonyl, SO
2NHCH
3, SO
2N (CH
3)
2, phenyloxycarbonyl, phenylamino carbonyl, 4-methylbenzene amino carbonyl or 4-chlorobenzene amino carbonyl;
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 using as antitumor drug in the above-mentioned cyano-containing diphenylamine compound further preferred chemical compound be: in the general formula I
R
1Be selected from hydrogen;
R
2Be selected from chlorine, methoxyl group, NHCH
3, N (CH
3)
2Or N (C
2H
5)
2
R
3Be selected from chlorine, methoxyl group or NHCH
3
R
4Be selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, nitro or cyano group;
R
5Be selected from hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl;
R
6Be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, CO
2CH
3, cyano group, nitro, COOH, CO
2Na, phenylamino carbonyl or 4-chlorobenzene amino carbonyl;
R
7Be selected from hydrogen, chlorine, bromine, methyl or trifluoromethyl;
R
8Be selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, nitro or cyano group;
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 using as antitumor drug in the above-mentioned cyano-containing diphenylamine compound more further preferred chemical compound be: in the general formula I
R
1, R
5, R
7Be selected from hydrogen;
R
2, R
3Be selected from chlorine;
R
4, R
8Be selected from hydrogen or chlorine;
R
6Be selected from hydrogen, chlorine, bromine 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.
Most preferred chemical compound is when using as antitumor drug in the above-mentioned cyano-containing diphenylamine compound:
In the definition of the compound of Formula I that the above provides, compile the following substituent group of used term general proxy:
Halogen: refer to fluorine, chlorine, bromine or iodine.Alkyl: straight or branched alkyl, for example methyl, ethyl, propyl group, isopropyl or the tert-butyl group.Cycloalkyl: replace or unsubstituted cyclic alkyl, for example cyclopropyl, cyclopenta or cyclohexyl, substituent group such as methyl, halogen etc.Haloalkyl: the straight or branched alkyl, the hydrogen atom on these alkyl can partly or entirely be replaced by halogen atom, such as chloromethyl, dichloromethyl, trichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl etc.Alkoxyl: the straight or branched alkyl is connected on the structure through the oxygen atom key.Halogenated alkoxy: straight or branched alkoxyl, hydrogen atom on these alkoxyls can partly or entirely be replaced by halogen atom, such as chlorine methoxyl group, dichloro methoxyl group, trichlorine methoxyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, chlorine fluorine methoxyl group, trifluoro ethoxy etc.Alkylthio group: the straight or branched alkyl is connected on the structure through the sulphur atom key.Halogenated alkylthio: straight or branched alkylthio group, hydrogen atom on these alkyl can partly or entirely be replaced 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: the straight or branched alkyl is connected on the structure through the nitrogen-atoms key.Haloalkyl is amino: the straight or branched alkyl amino, the hydrogen atom on these alkyl can partly or entirely be replaced by halogen atom.Thiazolinyl: straight or branched alkene class, for example vinyl, 1-acrylic, 2-acrylic and different cyclobutenyl, pentenyl and hexenyl isomers.Thiazolinyl also comprises the polyenoid class, such 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 be replaced by halogen atom.Alkynyl: straight or branched alkynes class, for example acetenyl, 1-propinyl, 2-propynyl and different butynyl, pentynyl and the isomers of hexin base.Alkynyl also comprises the group that is comprised of a plurality of triple bonds, such as 2,5-hexadiine base.The halo alkynyl: straight or branched alkynes class, the hydrogen atom on these alkynyls can partly or entirely be replaced by halogen atom.Aryl moiety in aryl and aralkyl, aryloxy group and the aryloxy alkyl etc. comprises phenyl or naphthyl etc.Heteroaryl is to contain one or more N, O, the heteroatomic five-membered ring of 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 have been enumerated respectively R in the general formula I
1, R
2, R
3, 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
2(R
3) substituent group
| R 2(R 3) | R 2(R 3) | R 2(R 3) | R 2(R 3) | R 2(R 3) |
| H | CH 3 | OCH 3 | SCH 3 | OCOCH 3 |
| F | C 2H 5 | OCH 2CH 3 | SCH 2CH 3 | OCOCH 2CH 3 |
| Cl | n-C 3H 7 | OCF 3 | SO 2CH 3 | NHCOCH 3 |
| Br | i-C 3H 7 | OCH 2CF 3 | SO 2CH 2CH 3 | NHCOCH 2CH 3 |
| I | n-C 4H 9 | NHCH 3 | N(CH 3) 2 | OSO 2CH 3 |
| OH | t-C 4H 9 | NHCH 2CH 3 | N(C 2H 5) 2 | OSO 2CH 2CH 3 |
| CN | CH 2Cl | NH(CH 2) 2CH 3 | OCH 2CH＝CH 2 | OCH 2OCH 3 |
| NO 2 | CF 3 | NHCH(CH 3) 2 | OCH 2CH＝CCl 2 | OCH 2OCH 2CH 3 |
| COOH | CH 2CF 3 | NHCH 2CF 3 | OCH 2C≡CH | OCH 2CO 2CH 3 |
Table 3R
4(R
8) substituent group
Table 4R
5(R
7) substituent group
Table 5R
6Substituent group
| R 6 | R 6 | R 6 | R 6 |
| H | CHF 2 | CH 2C≡CH | CONHCH(CH 3) 2 |
| F | CH 2F | SO 2CH 3 | CON(CH 2CH 3) 2 |
| Cl | CH 2Cl | SO 2CH 2CH 3 | CONHC(CH 3) 3 |
| Br | CH 2Br | COCH 3 | SO 2NH 2 |
| I | CH 2CF 3 | COCH 2CH 3 | SO 2NHCH 3 |
| CN | CF 2CHF 2 | CO 2CH 3 | SO 2N(CH 3) 2 |
| NO 2 | CF 2CF 3 | CO 2CH 2CH 3 | Ph |
| COOH | OCH 3 | CH 2OCH 3 | CH 2Ph |
| CO 2Na | OCH 2CH 3 | CH 2OCH 2CH 3 | COPh |
| CO 2NH 4 | O(CH 2) 2CH 3 | CH 2CO 2CH 3 | COCH 2Ph |
| CH 3 | OCH(CH 3) 2 | CH 2CO 2CH 2CH 3 | CO 2Ph |
| CH 2CH 3 | OCF 3 | OCH 2OCH 3 | CO 2Ph-2-Cl-4-CF 3 |
| n-C 3H 7 | OCH 2CF 3 | OCH 2OCH 2CH 3 | CONHPh |
| i-C 3H 7 | OCF 2CF 3 | CONH 2 | CONHPh-4-Cl |
| n-C 4H 9 | CH＝CH 2 | CONHCH 3 | CONHPh-4-CH 3 |
| t-C 4H 9 | CH 2CH＝CH 2 | CON(CH 3) 2 | CONHPh-2-Cl-4-NO 2 |
| CF 3 | C≡CH | CONH(CH 2) 2CH 3 | CONHPh-2-Cl-4-CF 3 |
The chemical compound that the present invention has anti-tumor activity illustrates by the particular compound of listing among the table 6-21, but does not limit the present invention.
Table 6: in the general formula I, R
1Be H, R
2, R
3Be Cl, R
4, R
5, R
6, R
7, R
8(be designated hereinafter simply as R
4-R
8) specifically see the following form.
Table 6
| Numbering | R 4 | R 5 | R 6 | R 7 | R 8 |
| 1 | H | H | H | H | H |
| 2 | F | H | H | H | H |
| 3 | Cl | H | H | H | H |
| 4 | Br | H | H | H | H |
| 5 | I | H | H | H | H |
| 6 | CH 3 | H | H | H | H |
| 7 | OCH 3 | H | H | H | H |
| 8 | NO 2 | H | H | H | H |
| 9 | CF 3 | H | H | H | H |
| 10 | CN | H | H | H | H |
| 11 | H | F | H | H | H |
| 12 | H | Cl | H | H | H |
| 13 | H | Br | H | H | H |
| 14 | H | CF 3 | H | H | H |
| 15 | H | H | F | H | H |
| 16 | H | H | Cl | H | H |
| 17 | H | H | Br | H | H |
| 18 | H | H | CH 3 | H | H |
| 19 | H | H | t-C 4H 9 | H | H |
| 20 | H | H | OCH 3 | H | H |
| 21 | H | H | OCF 3 | H | H |
| 22 | H | H | NO 2 | H | H |
| 23 | H | H | CN | H | H |
| 24 | H | H | CF 3 | H | H |
| 25 | H | H | CO 2CH 3 | H | H |
| 26 | H | H | SO 2CH 3 | H | H |
| 27 | H | H | CONHPh | H | H |
| 28 | H | H | CONHPh-4-CH 3 | H | H |
| 29 | H | H | CONHPh-4-Cl | H | H |
| 30 | F | F | H | H | H |
| 31 | F | H | F | H | H |
| 32 | F | H | H | F | H |
| 33 | F | H | H | H | F |
| 34 | F | H | Cl | H | H |
| 35 | F | H | H | CF 3 | H |
| 36 | H | F | F | H | H |
| 37 | H | F | H | F | H |
| 38 | Cl | Cl | H | H | H |
| 39 | Cl | H | Cl | H | H |
| 40 | Cl | H | H | Cl | H |
| 41 | Cl | H | H | H | Cl |
| 42 | Cl | H | H | H | CH 3 |
| 43 | H | Cl | Cl | H | H |
| 44 | H | Cl | H | Cl | H |
| 45 | Cl | H | Br | H | H |
| 46 | Br | H | Cl | H | H |
| 47 | Cl | H | CF 3 | H | H |
| 48 | Cl | H | H | CF 3 | H |
| 49 | Cl | H | NO 2 | H | H |
| 50 | Cl | H | H | NO 2 | H |
| 51 | Cl | H | H | CN | H |
| 52 | Cl | H | H | CH 3 | H |
| 53 | NO 2 | H | H | Cl | H |
| 54 | CN | H | H | Cl | H |
| 55 | CH 3 | H | H | Cl | H |
| 56 | CF 3 | H | CN | H | H |
| 57 | F | H | CN | H | H |
| 58 | Cl | H | CN | H | H |
| 59 | Br | H | CN | H | H |
| 60 | NO 2 | H | CN | H | H |
| 61 | t-C 4H 9 | H | CN | H | H |
| 62 | OCH 3 | H | CN | H | H |
| 63 | CO 2CH 3 | H | CN | H | H |
| 64 | SO 2CH 3 | H | CN | H | H |
| 65 | H | F | CN | H | H |
| 66 | H | Cl | CN | H | H |
| 67 | H | Br | CN | H | H |
| 68 | H | NO 2 | CN | H | H |
| 69 | H | CH 3 | CN | H | H |
| 70 | H | OCH 3 | CN | H | H |
| 71 | CN | H | Cl | H | H |
| 72 | CF 3 | H | Cl | H | H |
| 73 | CO 2CH 3 | H | Cl | H | H |
| 74 | H | CN | Cl | H | H |
| 75 | H | CH 3 | Cl | H | H |
| 76 | H | CF 3 | Cl | H | H |
| 77 | CH 3 | H | Cl | H | H |
| 78 | CH 3 | Cl | H | H | H |
| 79 | CH 3 | H | CH 3 | H | H |
| 80 | CH 3 | H | H | CH 3 | H |
| 81 | CH 3 | H | CN | H | H |
| 82 | CH 3 | H | CF 3 | H | H |
| 83 | CH 3 | H | CO 2CH 3 | H | H |
| 84 | CH 3 | H | H | H | CO 2CH 3 |
| 85 | H | CF 3 | CN | H | H |
| 86 | H | CH 3 | CN | H | H |
| 87 | NO 2 | H | Cl | H | H |
| 88 | CN | H | NO 2 | H | H |
| 89 | F | F | F | H | H |
| 90 | F | H | F | H | F |
| 91 | F | H | NO 2 | H | F |
| 92 | Cl | Cl | Cl | H | H |
| 93 | Cl | H | Cl | H | Cl |
| 94 | Cl | Cl | H | Cl | H |
| 95 | Cl | H | CF 3 | H | Cl |
| 96 | Cl | H | OCF 3 | H | Cl |
| 97 | Cl | H | CH 3 | H | Cl |
| 98 | Cl | H | CN | H | Cl |
| 99 | Cl | H | NO 2 | H | Cl |
| 100 | Cl | H | CO 2CH 3 | H | Cl |
| 101 | Cl | H | SO 2CH 3 | H | Cl |
| 102 | Cl | H | t-C 4H 9 | H | Cl |
| 103 | Cl | H | CONHPh | H | Cl |
| 104 | Cl | H | CONHPh-4-Cl | H | Cl |
| 105 | Cl | H | CO 2Na | H | Cl |
| 106 | Cl | H | COOH | H | Cl |
| 107 | Cl | H | NO 2 | H | CH 3 |
| 108 | Cl | CH 3 | Cl | H | H |
| 109 | Cl | H | Cl | H | CN |
| 110 | Cl | H | NO 2 | H | F |
| 111 | Br | H | OCF 3 | H | Br |
| 112 | Br | H | Br | H | Br |
| 113 | Br | H | NO 2 | H | Cl |
| 114 | Br | H | NO 2 | H | Br |
| 115 | CH 3 | H | CH 3 | H | CH 3 |
| 116 | CH 3 | H | t-C 4H 9 | H | CH 3 |
| 117 | C 2H 5 | H | Cl | H | C 2H 5 |
| 118 | CH 3 | H | CO 2CH 3 | H | Br |
| 119 | CH 3 | H | CO 2CH 3 | H | NO 2 |
| 120 | CH 3 | H | CO 2CH 3 | H | CN |
| 121 | CH 3 | H | CO 2CH 3 | H | OCH 3 |
| 122 | CH 3 | H | CO 2CH 3 | H | CF 3 |
| 123 | CH 3 | H | CO 2CH 3 | H | Cl |
| 124 | CH 3 | H | Cl | H | NO 2 |
| 125 | C 2H 5 | H | NO 2 | H | F |
| 126 | C 2H 5 | H | NO 2 | H | Cl |
| 127 | C 2H 5 | H | NO 2 | H | Br |
| 128 | C 2H 5 | H | NO 2 | H | NO 2 |
| 129 | C 2H 5 | H | NO 2 | H | CN |
| 130 | C 2H 5 | H | NO 2 | H | OCH 3 |
| 131 | C 2H 5 | H | NO 2 | H | CF 3 |
| 132 | C 2H 5 | H | NO 2 | H | CO 2CH 3 |
| 133 | C 2H 5 | H | NO 2 | H | SO 2CH 3 |
| 134 | C 2H 5 | Cl | H | H | C 2H 5 |
| 135 | Cl | H | CN | H | F |
| 136 | Cl | H | CN | H | Br |
| 137 | Cl | H | CN | H | NO 2 |
| 138 | Cl | H | CN | H | OCH 3 |
| 139 | Cl | H | CN | H | CO 2CH 3 |
| 140 | F | H | CN | H | Br |
| 141 | F | H | CN | H | NO 2 |
| 142 | F | H | CN | H | OCH 3 |
| 143 | F | H | CN | H | CO 2CH 3 |
| 144 | Cl | H | SO 2NHCH 3 | H | Cl |
| 145 | Cl | H | SO 2N(CH 3) 2 | H | Cl |
| 146 | Cl | H | CO 2NH 4 | H | Cl |
| 147 | Cl | H | CONH 2 | H | Cl |
| 148 | Cl | H | CONHCH 3 | H | Cl |
| 149 | Cl | H | CON(CH 3) 2 | H | Cl |
| 150 | Cl | H | CONHCH(CH 3) 2 | H | Cl |
| 151 | Cl | H | CONHC(CH 3) 3 | H | Cl |
| 152 | CH 3 | H | Cl | CH 3 | H |
| 153 | NO 2 | H | Cl | H | NO 2 |
| 154 | CN | H | Cl | H | NO 2 |
| 155 | CN | H | Cl | H | CH 3 |
| 156 | CN | H | Cl | H | CN |
| 157 | CN | H | Cl | H | CF 3 |
| 158 | CO 2CH 3 | H | Cl | H | Cl |
| 159 | CH 3 | H | Cl | H | Cl |
| 160 | NO 2 | H | Cl | H | Cl |
| 161 | CF 3 | H | Cl | H | Cl |
| 162 | OCH 3 | H | Cl | H | Cl |
| 163 | NO 2 | H | Cl | H | F |
| 164 | NO 2 | H | Cl | H | Br |
| 165 | NO 2 | H | Cl | H | CF 3 |
| 166 | NO 2 | H | Cl | H | CO 2CH 3 |
| 167 | NO 2 | H | Cl | H | CH 3 |
| 168 | CN | H | NO 2 | H | NO 2 |
| 169 | COOH | H | CN | H | CH 3 |
| 170 | COOH | H | Cl | H | Cl |
| 171 | COOH | H | Cl | H | CH 3 |
| 172 | COOH | H | Br | H | CH 3 |
| 173 | COOH | H | CN | H | Cl |
| 174 | CO 2CH 3 | H | Cl | H | CH 3 |
| 175 | CO 2CH 3 | H | Br | H | CH 3 |
| 176 | CONHCH 3 | H | CN | H | CH 3 |
| 177 | CONHCH 3 | H | Cl | H | Cl |
| 178 | CONHCH 3 | H | Cl | H | CH 3 |
| 179 | CONHCH 3 | H | Br | H | CH 3 |
| 180 | CONHCH 3 | H | H | H | H |
| 181 | CONH 2 | H | CN | H | CH 3 |
| 182 | CONH 2 | H | Cl | H | Cl |
| 183 | CONH 2 | H | Cl | H | CH 3 |
| 184 | CONH 2 | H | Br | H | CH 3 |
| 185 | CONH 2 | H | CN | H | Cl |
| 186 | CON(CH 3) 2 | H | CN | H | CH 3 |
| 187 | CON(CH 3) 2 | H | Cl | H | Cl |
| 188 | CON(CH 3) 2 | H | Cl | H | CH 3 |
| 189 | CON(CH 3) 2 | H | Br | H | CH 3 |
| 190 | CON(CH 3) 2 | H | CN | H | Cl |
| 191 | CONHCH(CH 3) 2 | H | CN | H | CH 3 |
| 192 | CONHCH(CH 3) 2 | H | Cl | H | Cl |
| 193 | CONHCH(CH 3) 2 | H | Cl | H | CH 3 |
| 194 | CONHCH(CH 3) 2 | H | Br | H | CH 3 |
| 195 | CONHCH(CH 3) 2 | H | CN | H | Cl |
| 196 | CONHC(CH 3) 3 | H | CN | H | CH 3 |
| 197 | CONHC(CH 3) 3 | H | Cl | H | Cl |
| 198 | CONHC(CH 3) 3 | H | Cl | H | CH 3 |
| 199 | CO NHC(CH 3) 3 | H | Br | H | CH 3 |
| 200 | CO NHC(CH 3) 3 | H | CN | H | Cl |
| 201 | Cl | H | Br | H | Cl |
| 202 | Cl | H | SO 2NH 2 | H | Cl |
| 203 | Cl | H | SO 2NH 2 | H | Br |
| 204 | Br | H | SO 2NH 2 | H | Br |
| 205 | Cl | CH 3 | CN | Cl | H |
| 206 | CH 3 | Cl | NO 2 | H | NO 2 |
| 207 | NO 2 | CH 3 | Cl | H | NO 2 |
| 208 | CN | Cl | CN | Cl | Cl |
Table 7: in the general formula I, R
1Be CH
3, R
2, R
3Be Cl, R
4-R
8Specifically see Table 6.
Table 8: in the general formula I, R
1Be H, R
2, R
3Be F, R
4-R
8Specifically see Table 6.
Table 9: in the general formula I, R
1Be H, R
2Be N (C
2H
5)
2, R
3Be Cl, R
4-R
8Specifically see Table 6.
Table 10: in the general formula I, R
1Be H, R
2Be N (CH
3)
2, R
3Be Cl, R
4-R
8Specifically see Table 6.
Table 11: in the general formula I, R
1Be H, R
2Be NHCH
3, R
3Be Cl, R
4-R
8Specifically see Table 6.
Table 12: in the general formula I, R
1Be H, R
2Be OCH
3, R
3Be Cl, R
4-R
8Specifically see Table 6.
Table 13: in the general formula I, R
1Be H, R
2Be SCH
3, R
3Be Cl, R
4-R
8Specifically see Table 6.
Table 14: in the general formula I, R
1Be H, R
2, R
3Be OCH
3, R
4-R
8Specifically see Table 6.
Table 15: in the general formula I, R
1Be H, R
2, R
3Be N (CH
3)
2, R
4-R
8Specifically see Table 6.
Table 16: in the general formula I, R
1Be H, R
2, R
3Be NHCH
3, R
4-R
8Specifically see Table 6.
Table 17: in the general formula I, R
1Be H, R
2, R
3Be SCH
3, R
4-R
8Specifically see Table 6.
Table 18: in the general formula I, R
1Be H, R
2Be SO
2CH
3, R
3Be Cl, R
4-R
8Specifically see Table 6.
Table 19: in the general formula I, R
1Be H, R
2Be OCH
2CH=CH
2, R
3Be Cl, R
4-R
8Specifically see Table 6.
Table 20: in the general formula I, R
1Be H, R
2Be OCH
3, R
3Be F, R
4-R
8Specifically see Table 6.
Table 21: in the general formula I, R
1Be H, R
2Be N (CH
3)
2, R
3Be F, R
4-R
8Specifically see Table 6.
Compound of Formula I involved in the present invention has been reported in the prior art, can obtain easily or in accordance with the following methods self-control.Reaction equation is as follows, and each group unless otherwise indicated defines ditto in the formula:
Intermediate II and intermediate III are reacted under alkali condition and are obtained R in the general formula I
i=H, R
2=R
3Compound I-a of=Cl; With itself and X-R
1(R
1≠ H) reaction can obtain R in the general formula I
1≠ H, R
2=R
3Compound I-b of=Cl; With I-a and Y-R
2(R
2≠ Cl) reaction or with I-b and Y-R
2(R
2≠ Cl) reaction can obtain R in the general formula I
2≠ Cl, R
3Compound I-c of=Cl; With I-c again with Z-R
3(R
3≠ Cl) reaction can obtain R in the general formula I
2, R
3All be not compound I-d of Cl.
In the formula: X is selected from halogen atom; Y, Z are selected from alkali metal atom or hydrogen.
The suitable optional freely potassium hydroxide 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.
Reaction is carried out in suitable solvent, the suitable optional freely oxolane of solvent, Isosorbide-5-Nitrae-dioxane, acetonitrile, toluene, dimethylbenzene, benzene, DMF, N-Methyl pyrrolidone, dimethyl sulfoxine, acetone or butanone etc.
Reaction temperature can in room temperature between the solvent boiling point temperature, be generally 20-100 ℃.
Response time is 30 minutes to 20 hours, 1-10 hour usually.
Intermediate II is the commercial goods.
Intermediate III mostly is the commercial goods, also can prepare by known method reference literature Indian Journal of Chemistry for example, Section B:Organic Chemistry Including Medicinal Chemistry, 45B (4), 972-975; The method or the document Tetrahedron Letters that introduce in 2006,44 (21), 4085-4088; The methods of 2003 reports, and the method among the Poland Patent PL174903 etc. makes.
R in the general formula I
8=NO
2Or R
6=NO
2Chemical compound can also adopt corresponding substituted diphenylamine intermediate nitrated preparation, preparation method is referring to US4041172 etc.
Each group as previously mentioned in the formula.
R in the general formula I
4, R
6Or R
8Have one in three substituent groups at least and be the chemical compound of hydrogen, also can be by with its nitrated compound of Formula I that obtains increasing one or two nitros.
Can also be with R in the general formula I
4, R
6Or R
8Be not the substituted diphenylamine aminated compounds of halogen atom, obtain increasing the compound of Formula I of one or two halogen atoms by halogenation.
R in the general formula I
2, R
3Be the chemical compound of alkylamino, alkoxyl, alkylthio group etc., can be by corresponding R
2, R
3For compound of Formula I and the reaction preparations such as amine, alcohol or mercaptan (or its salt) of halogen atom, perhaps with reference to Journal of Medicinal Chemistry, the method preparation of describing among 1978,21 (9), the 906-913.
R in the general formula I
2, R
3Be the chemical compound of alkyl sulphonyl, alkyl-carbonyl oxygen base etc., can be with reference to Journal of Medicinal Chemistry, the method preparation of describing among 1978,21 (9), the 906-913.
The salt of compound of Formula I can be made 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.; Further preferred hydrochloric acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid or p-methyl benzenesulfonic acid etc.
The present invention includes preparation composition that the chemical compound that comprised take above-mentioned general formula I is mixed with as active component with and the preparation that forms of preparation.Formulation preparation method is: the compound dissolution that the present invention is contained makes formulation soln in the surfactant of water miscible organic solvent, nonionic, water miscible lipoid, various cyclodextrin, fatty acid, fatty acid ester, phospholipid or its combination solvent; The adding normal saline obtains the carbohydrate of 1-20%.Described organic solvent comprises Polyethylene Glycol (PEG), ethanol, the combination solvent of propylene glycol or these solvents.
The chemical compound of containing in the general formula I of the present invention and salt thereof 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 cyano-containing diphenylamine compound shown in one or more general formula Is.Be particularly useful for treating or alleviate the cancer that 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 chemical compound that the present invention synthesizes can be used for the active component of antitumor drug, can use separately, also can with other antitumor, antiviral drugs drug combination.In the drug combination therapeutic process of indication of the present invention, comprise use at least a the compounds of this invention with and reactive derivative use to increase general curative effect with other one or more anti-tumor virus drugs.Dose during drug combination should be decided according to rational therapy effect obtained in the different situations with administration time.
The medicament compatibility of containing comprises the effective dose of the chemical compound in the general formula I." effective dose " herein refers to the consumption that can produce required this chemical compound of therapeutic effect for institute's treatment target.This effective dose or dosage can be by experience person being arranged according to the suggestion of different situations and difference.Such as, the tumor kind for the treatment of is different, and the usage of medicine is different; Therapeutic Method such as other antitumor drug or antiviral drugs with other shares etc., and dosage all can change.Can make any spendable preparation formulation.If some has alkalescence or acid compound and can form avirulent acid or salt, can use the form of the salt of this chemical compound.Spendable acylate comprises spendable anion salt on the physiology in the pharmacy, such 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.; Can make the form of described salt if any the chemical compound of the alkalescence as amine and suitable acid; The chemical compound of carboxylic acids can form spendable salt with alkali metal or alkaline-earth metal.
The chemical compound of containing among the formula of I of the present invention is general 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 with and share.Described pure particular methanol, ethanol, isopropyl alcohol, glycerol or ethylene glycol.The compounds of this invention can mix with preparations carrier commonly used and make preparation.Compound dissolution is in water miscible organic solvent, non-protonic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or in the mixed solvent of these solvents and make drug solution; Add again normal saline and obtain the carbohydrate of 1-20%, such as the aqueous solution of glucose.The preparation stabilization that makes therefrom also is used for animal and clinical.
The product medicine that chemical compound becomes as active fraction preparation in the above-mentioned general formula I, can be by oral or parenteral route administration, also can be by transplant medicine pump in the body and additive method administration, the parenteral route administration of indication herein refers to subcutaneous Intradermal, intramuscular, intravenous, intra-arterial, atrium in, in the synovial membrane, in the breastbone, in the sheath, interior, the intracranial injection of wound site or drip infusion technique etc.Use conventional method proportioning by the technical staff, mixing finally becomes needed pharmaceutical dosage form.Can be the outstanding solution of tablet, pill, capsule, electuary, syrup, injection, freeze-dried powder dosage form, Emulsion, powder, lyophilized powder, drop pill, emulsion suspension liquid, water, aqueous solution, colloid, colloid solution, slow releasing preparation, nanometer formulation or be used for animal or clinical with other forms of dosage form.
Chemical compound in the general formula I of the present invention is used for the treatment of or alleviates the preparation of the cancer drug of a certain tissue or organ.The 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.
The specific embodiment
Following specific embodiment is used for further specifying the present invention, but the present invention is not limited to these examples.(except other have indicate, raw materials used all have commercially available)
Synthetic example
Embodiment 1: the preparation of table 6-1 chemical compound
40ml N to 0.35g (3.76mmol) aniline, in the dinethylformamide solution, add sodium hydroxide 0.30g (7.52mmol), slowly add 2 under stirring, 4,5,6-tetrachloro-1,3-benzene dicarbonitrile 1.00g (3.76mmol), add rear continuation stirring at room reaction 5h, after the TLC monitoring reaction is complete, reactant liquor is poured into water, the adularescent solid is separated out, sucking filtration, filter cake is washed twice with the 20ml petroleum ether with 30ml washing twice again, dry to get product 1.65g, namely show the 6-1 chemical compound.Pale solid, fusing point 226-228 ℃.
1H-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 7.22 (d, 2H, Ph-2,6-2H, J=7.5Hz), and 7.40-7.46 (m, 3H, Ph-3,4,5-3H).
Embodiment 2: the preparation of table 6-33 chemical compound
To 1.03g (8mmol) 2, in the 40ml DMF solution of 6-difluoroaniline, add sodium hydroxide 0.64g (16mmol), slowly add 2,4,5 under stirring, 6-tetrachloro-1,3-benzene dicarbonitrile 2.13g (8mmol) adds rear continuation stirring at room reaction 5h, after the TLC monitoring reaction is complete, reactant liquor is poured into water, ethyl acetate extraction, organic facies are successively through washing, and saturated salt is washed, dry, filter, precipitation, (eluant is ethyl acetate and petroleum ether (boiling range 60-90 ℃) to the residue column chromatography, volume ratio is 1: 4) purification gets product 1.65g, namely shows the 6-33 chemical compound.Light yellow solid, fusing point 264-266 ℃.
1H-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 6.70 (s, 1H, NH), 7.07 (t, 2H, Ph-3,5-2H, J=8.1Hz), 7.37 (m, 1H, Ph-4-1H).
Embodiment 3: the preparation of table 6-39 chemical compound
Synthetic method is with table 6-1 chemical compound, brownish black solid, fusing point 209-212 ℃.
1H-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 6.95 (s, 1H, NH), 7.20 (d, 1H, Ph-6-H, J=8.1Hz), 7.36 (dd, 1H, Ph-5-H,
3J=8.7Hz,
4J=2.7Hz), 7.54 (d, 1H, Ph-3-H, J=2.4Hz).
Embodiment 4: the preparation of table 6-91 chemical compound
20ml concentrated sulfuric acid solution with 0.68g (2mmol) table 6-33 chemical compound places ice bath first, stirs the lower nitration mixture (nitric acid and sulphuric acid amount of substance are respectively 4mmol and 6mmol) for preparing that slowly drips, and the control temperature is below 20 ℃.After dropwising, continue reaction 5min, after the TLC monitoring reaction is complete, reactant liquor is poured in the frozen water, stir.After being chilled to room temperature, ethyl acetate extraction, organic facies is washed through saturated salt successively, drying is filtered precipitation, residue column chromatography (eluant is ethyl acetate and petroleum ether (boiling range 60-90 ℃), and volume ratio is 1: 4) purification gets product 0.40g, namely shows the 6-91 chemical compound.Shallow white solid, fusing point 204-206 ℃.
1H-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 6.70 (s, 1H, NH), 7.97-8.01 (dd, 2H, Ph-3,5-2H,
3J=10.8Hz,
4J=3.0Hz).
Embodiment 5: the preparation of table 6-93 chemical compound
Synthetic method is with table 6-1 chemical compound, brown solid, fusing point 182-184 ℃.
1H-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 6.86 (s, 1H, NH), 7.48 (s, 2H, Ph-3,5-2H).
Embodiment 6: the preparation of table 6-99 chemical compound
To 0.35g (1.3mmol) 2, add sodium hydroxide 0.10g (2.6mmol) in the DMF solution of the 40ml of 6-Dichloro-4-nitroaniline, slowly add 2 under stirring, 4,5,6-tetrachloro-1,3-benzene dicarbonitrile 0.27g (1.3mmol), add rear continuation stirring at room reaction 5h, after the TLC monitoring reaction is complete, reactant liquor is poured into water ethyl acetate extraction, organic facies is successively through washing, the saturated salt washing, drying is filtered, precipitation, residue column chromatography (eluant is ethyl acetate and petroleum ether (boiling range 60-90 ℃), and volume ratio is 1: 4) purification gets product 0.48g, namely shows the 6-99 chemical compound.Light yellow solid, fusing point 250-252 ℃.
1H-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 6.93 (s, 1H, NH), 8.34 (s, 2H, Ph-3,5-2H).
Embodiment 7: the preparation of table 6-100 chemical compound
To 10.33g (39mmol) 4-amino-3, (preparation method is with reference to WO2010060379 for the 5-methyl p-dichlorobenzene, CN101337940) 60mlN, in the dinethylformamide solution, add sodium hydroxide 3.12g (78mmol), slowly add 2 under stirring, 4,5,6-tetrachloro-1,3-benzene dicarbonitrile 10.37g (39mmol), add rear continuation stirring at room reaction 5h, after the TLC monitoring reaction is complete, reactant liquor is poured into water ethyl acetate extraction, organic facies is successively through washing, the saturated salt washing, drying is filtered, precipitation, residue column chromatography (eluant is ethyl acetate and petroleum ether (boiling range 60-90 ℃), and volume ratio is 1: 5) purification gets product 13.65g, namely shows the 6-100 chemical compound.Light yellow solid, fusing point 229-231 ℃.
1H-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 3.96 (s, 3H, CH
3), 6.92 (s, 1H, NH), 8.11 (s, 2H, Ph-2,6-2H).
Embodiment 8: the preparation of table 6-104 chemical compound
(1) preparation of table 6-106 chemical compound
To the 120ml oxolane of 13.31g (31mmol) table 6-100 chemical compound and the middle sodium hydroxide 2.45g (61mmol) that adds of mixed solution (volume ratio is 1: 1) of water, place 50 ℃ oil bath stirring reaction 5h, after the TLC monitoring reaction is complete, reactant liquor is poured into water, ethyl acetate extraction, organic facies discards, and it is 5-6 that water is regulated pH value with dilute hydrochloric acid, has light yellow solid to separate out, filter, filter cake is table 6-106 chemical compound, and drying is for subsequent use.
(2) preparation of table 6-106a chemical compound
In the 100ml petroleum ether solution of the table 6-106 chemical compound of 5.54g (12.72mmol), add 2 DMF, then add thionyl chloride 2.27g (19.08mmol), place 85 ℃ oil bath back flow reaction 2h, after the TLC monitoring reaction is complete, with the reactant liquor precipitation that reduces pressure, products obtained therefrom is table 6-106a chemical compound.
(3) preparation of table 6-104 chemical compound
0.40g (0.91mmol) table 6-106a chemical compound is added dropwise in dry tetrahydrofuran (50ml) solution of parachloroanilinum 0.12g (0.91mmol) and triethylamine 0.23g (2.27mmol), place 45 ℃ of oil baths to react 5h, after the TLC monitoring reaction is complete, reactant liquor is poured into water, ethyl acetate extraction, organic facies is washed through saturated salt successively, dry, filter, precipitation, residue column chromatography (eluant is ethyl acetate and petroleum ether (boiling range 60-90 ℃), and volume ratio is 1: 3) purification gets chemical compound, white solid 0.23g, fusing point 275-276 ℃.
1H-NMR (300MHz, interior mark TMS, solvent DMSO) δ (ppm): 7.31-7.35 (m, 2H, 4-Cl-Ph-2,6-2H), 7.81 (d, 2H, 4-Cl-Ph-3,5-2H, J=9.0Hz), 8.13 (dd, 2H, Ph-2,6-2H,
3J=15.7Hz,
4J=1.2Hz), 10.50 (d, 1H, CONH, J=12.9Hz).
Embodiment 9: the preparation of table 14-99 chemical compound
In the 20ml DMSO solution of 0.55g (1.3mmol) table 6-99 chemical compound, add 0.14g (2.5mmol) Feldalat NM, place 95 ℃ oil bath to react 8h, after the TLC monitoring reaction is complete, reactant liquor is poured into water, ethyl acetate extraction, organic facies is successively through washing, the saturated salt washing, dry, filter, precipitation, (eluant is ethyl acetate and petroleum ether (boiling range 60-90 ℃) to the residue column chromatography, volume ratio is 1: 4) purification gets product 0.16g, namely shows the 14-99 chemical compound.Light yellow solid, fusing point 151-153 ℃.
1H-NMR (300MHz, interior mark TMS, solvent C DCl
3) δ (ppm): 4.23 (t, 6H, OCH
3, J=6.6Hz), 6.78 (br, 1H, NH), 8.31 (d, 2H, Ph-3,5-2H, J=3.9Hz).
Other chemical compounds of the present invention can be with reference to above embodiment preparation.
The physical data of part of compounds and nuclear magnetic data (
1HNMR, 300MHz, interior mark TMS, ppm) as follows:
Table 6-3 chemical compound: fusing point 208-210 ℃.δ(CDCl
3)：7.03(s，1H，NH)，7.27-7.38(m，3H，Ph-3，5，6-3H)，7.49-7.55(m，1H，Ph-4-H)。
Table 6-6 chemical compound: fusing point 212-214 ℃.δ(CDCl
3)：2.29(s，3H，CH
3)，7.00(s，1H，NH)，7.15(d，H，Ph-6-H，J＝7.5Hz)，7.28-7.34(m，3H，Ph-3，4，5-3H)。
Table 6-10 chemical compound: fusing point 258-260 ℃.δ(CDCl
3)：7.12(s，1H，NH)，7.24(d，1H，Ph-6-H，J＝7.5Hz)，7.47(t，1H，Ph-4-H，J＝7.2Hz)，7.68(t，1H，Ph-5-H，J＝7.5Hz)，7.78(d，1H，Ph-3-H，J＝7.8Hz)。
Table 6-14 chemical compound: fusing point 236-238 ℃.δ(CDCl
3)：7.12(s，1H，NH)，7.28-7.40(m，1H，Ph-6-H)，7.41-7.52(m，2H，Ph-2，4-2H)，7.54-7.62(m，1H，Ph-5-H)。
Table 6-19 chemical compound: fusing point 144-146 ℃.δ(CDCl
3)：1.30(s，9H，t-C
4H
9)，6.65(m，2H，Ph-2，6-2H)，7.16(s，1H，NH)，7.18(m，2H，Ph-3，5-2H)。
Table 6-21 chemical compound: fusing point 204-206 ℃.δ(CDCl
3)：7.09(s，1H，NH)，7.22-7.32(m，4H，Ph-2，3，5，6-4H)。
Table 6-23 chemical compound: fusing point 259-261 ℃.δ(CDCl
3)：7.00(s，1H，NH)，7.17(d，2H，Ph-2，6-2H，J＝8.7Hz)，7.42(d，2H，Ph-3，5-2H，J＝9.0Hz)。
Table 6-25 chemical compound: fusing point 246-248 ℃.δ(CDCl
3)：2.29(s，3H，COOCH
3)，7.08(s，1H，NH)，7.17(d，2H，Ph-3，5-2H，J＝8.7Hz)，8.10(d，2H，Ph-2，6-2H，J＝8.7Hz)。
Table 6-31 chemical compound: fusing point 206-208 ℃.δ(CDCl
3)：6.88(s，1H，NH)，6.99(t，2H，Ph-5，6-2H，J＝8.1Hz)，7.32(d，1H，Ph-3-H，J＝2.4Hz)。
Table 6-35 chemical compound: fusing point 209-212 ℃.6.93(s，1H，NH)，7.34(t，1H，Ph-3-H，J＝9.0Hz)，7.52(d，1H，Ph-4-H，J＝7.2Hz)，7.58-7.65(m，1H，Ph-3-H)。
Table 6-38 chemical compound: fusing point 218-220 ℃.δ(CDCl
3)：7.03(s，1H，NH)，7.13(dd，1H，Ph-6-H，
3J＝8.1Hz，
4J＝0.9Hz)，7.28(t，1H，Ph-5-H，J＝8.1Hz)，7.47(dd，1H，Ph-4-H，
3J＝8.1Hz，
4J＝0.9Hz)。
Table 6-41 chemical compound: fusing point 235-237 ℃.δ(CDCl
3)：6.61(s，1H，NH)，7.36(t，1H，Ph-4-H，J＝7.2Hz)，7.45(d，2H，Ph-3，5-2H，J＝7.2Hz)。
Table 6-42 chemical compound: fusing point 240-242 ℃.δ(CDCl
3)：2.32(s，3H，Ph-CH
3)，6.93(s，1H，NH)，7.22-7.35(m，3H，Ph-3，4，5-H)。
Table 6-44 chemical compound: fusing point 238-242 ℃.δ(CDCl
3)：6.95(s，1H，NH)，7.05(d，2H，Ph-2，6-2H，J＝1.8Hz)，7.32(d，1H，Ph-4-H，J＝1.5Hz)。
Table 6-47 chemical compound: fusing point 166-168 ℃.δ(CDCl
3)：7.00(s，1H，NH)，7.20(d，1H，Ph-6-H，J＝8.4Hz)，7.57(dd，1H，Ph-5-H，
3J＝8.4Hz，
4J＝1.5Hz)，7.78(s，1H，Ph-3-H)。
Table 6-48 chemical compound: fusing point 197-199 ℃.δ(CDCl
3)：7.02(s，1H，NH)，7.45(s，1H，Ph-6-H)，7.55(d，1H，Ph-4-H，J＝8.4Hz)，7.65(d，1H，Ph-3-H，J＝8.4Hz)。
Table 6-49 chemical compound: fusing point 220-222 ℃.7.04(d，1H，Ph-6-H，J＝8.7Hz)，7.07(s，1H，NH)，8.20(dd，1H，Ph-5-H，
3J＝9.0Hz，
4J＝2.7Hz)，8.42(d，1H，Ph-3-H，J＝2.7Hz)。
Table 6-77 chemical compound: fusing point 200-202 ℃.δ(CDCl
3)：2.27(s，3H，Ph-2-CH
3)，6.86(s，1H，NH)，7.07(d，1H，Ph-6-H，J＝8.4Hz)，7.23(dd，1H，Ph-5-H，
3J＝8.4Hz，
4J＝2.1Hz)，7.33(s，1H，Ph-3-H)。
Table 6-78 chemical compound: fusing point 140-142 ℃.δ(CDCl
3)：2.35(s，3H，CH
3)，6.99(s，1H，NH)，7.08(d，1H，Ph-6-H，J＝8.1Hz)，7.19-7.25(m，1H，Ph-5-H)，7.46(d，1H，Ph-4-H，J＝8.7Hz)。
Table 6-80 chemical compound: fusing point 198-200 ℃.δ(CDCl
3)：2.23(s，3H，CH
3)，2.34(s，3H，CH
3)，6.95(s，1H，NH)，6.95(s，1H，Ph-6-H)，7.13-7.22(m，2H，Ph-3，4-2H)。
Table 6-83 chemical compound: fusing point 204-205 ℃.δ(CDCl
3)：2.36(s，3H，COOCH
3)，3.92(s，3H，Ph-3-CH
3)，6.85(s，1H，NH)，7.12(d，1H，Ph-5-1H，J＝8.4Hz)，7.92(d，1H，Ph-6-1H，J＝8.4Hz)，8.02(s，1H，Ph-2-1H)。
Table 6-84 chemical compound: fusing point 216-218 ℃.δ(CDCl
3)：2.16(s，3H，CH
3)，3.89(s，3H，COOCH
3)，7.39(t，1H，Ph-4-H，J＝7.8Hz)，7.51(d，1H，Ph-5-H，J＝7.8Hz)，7.93(d，1H，Ph-3-H，J＝7.8Hz)。
Table 6-85 chemical compound: fusing point 242-243 ℃.δ(CDCl
3)：7.07(s，1H，NH)，7.25(d，1H，Ph-6-H，J＝2.1Hz)，7.42(d，1H，Ph-2-H，J＝2.4Hz)，7.83(d，1H，Ph-5-H，J＝8.4Hz)。
Table 6-87 chemical compound: fusing point 232-234 ℃.δ(CDCl
3)：6.94(d，1H，Ph-6-H，J＝9.3Hz)，7.58(dd，1H，Ph-5-H，
3J＝9.0Hz，
4J＝2.7Hz)，8.26(d，1H，Ph-3-H，J＝2.7Hz)，9.36(s，1H，NH)。
Table 6-88 chemical compound: fusing point 236-238 ℃.δ(DMSO)：7.02(dd，1H，Ph-6-H，
3J＝9.6Hz，
4J＝2.7Hz)，8.32(dd，1H，Ph-5-H，
3J＝9.3Hz，
4J＝2.7Hz)，8.63(d，1H，Ph-3-H，J＝2.7Hz)。
Table 6-95 chemical compound: fusing point 201-203 ℃.δ(CDCl
3)：6.91(s，1H，NH)，7.72(s，2H，Ph-3，5-2H)。
Table 6-98 chemical compound: fusing point 259-261 ℃.δ(CDCl
3)：6.91(s，1H，NH)，7.74(s，2H，Ph-3，5-2H)。
Table 6-103 chemical compound: fusing point 267-269 ℃.δ(CDCl
3)：7.28-7.30(m，1H，NHPh-4-H)，7.40(t，2H，NHPh-3，5-2H，J＝6.9Hz)，δ＝7.62(d，2H，NHPh-2，6-2H，J＝7.8Hz)，δ＝7.89-7.95(m，2H，NHCOPh-2，6-2H)。
Table 6-107 chemical compound: fusing point 232-234 ℃.δ(CDCl
3)：2.43(s，3H，Ph-CH
3)，6.86(s，1H，NH)，8.14(s，1H，Ph-5-1H)，8.26(s，1H，Ph-3-1H)。
Table 6-108 chemical compound: fusing point 196-198 ℃.δ(CDCl
3)：2.55(s，3H，CH
3)，6.99(s，1H，NH)，7.04(d，1H，Ph-6-H，J＝8.4Hz)，7.36(d，1H，Ph-5-H，J＝8.4Hz)。
Table 6-109 chemical compound: fusing point 194-196 ℃.δ(CDCl
3)：6.96(s，1H，NH)，7.67(d，1H，Ph-5-H，J＝2.1Hz)，7.77(d，1H，Ph-3-H，J＝2.4Hz)。
Table 6-110 chemical compound: fusing point 197-199 ℃.6.86(s，1H，NH)，8.05(dd，1H，Ph-5-H，
3J＝9.9Hz，
4J＝2.7Hz)，8.28(d，1H，Ph-3-H，J＝2.4Hz)。
Table 6-113 chemical compound: fusing point 248-250 ℃.δ(CDCl
3)：6.95(s，1H，NH)，8.37(d，1H，Ph-3-H，J＝2.7Hz)，8.49(d，1H，Ph-5-H，J＝2.4Hz)。
Table 6-114 chemical compound: fusing point 247-249 ℃.δ(CDCl
3)：6.96(s，1H，NH)，8.51(s，2H，Ph-3，5-2H)。
Table 6-134 chemical compound: fusing point 176-178 ℃.δ(CDCl
3)：115-1.27(m，6H，CH
3)，2.49(q，4H，CH
2，J＝7.5Hz)，6.98(s，1H，NH)，7.14(d，1H，Ph-5-H，J＝8.4Hz)，7.47(d，1H，Ph-3-H，J＝8.4Hz)。
Table 6-152 chemical compound: fusing point 222-223 ℃.δ(CDCl
3)：2.22(s，3H，CH
3)，2.34(s，3H，CH
3)，6.88(s，1H，NH)，7.00(s，1H，Ph-6-H)，7.30(s，1H，Ph-3-H)。
Table 6-176 chemical compound: fusing point 260-262 ℃.δ(CDCl
3)：2.06(s，3H，CH
3)，2.98(d，3H，NHCH
3，J＝4.8Hz)，6.38(s，1H，CONH)，7.67(s，2H，Ph-3，5-2H)，9.38(s，1H，NH)。
Table 6-178 chemical compound: fusing point 240-242 ℃.δ(CDCl
3)：2.08(s，3H，CH
3)，2.93(d，3H，NCH
3，J＝5.1Hz)，6.22(s，1H，CONH)，7.35-7.38(m，2H，Ph-3，5-2H)，8.59(s，1H，NH)。
Table 6-180 chemical compound: fusing point 180-182 ℃.δ(CDCl
3)：2.69(s，3H，CH
3)，7.12(s，1H，NH)，7.24-7.68(m，4H，Ph)。
Table 6-206 chemical compound: fusing point 156-158 ℃.δ(CDCl
3)：2.51(s，3H，CH
3)，8.67(s，1H，Ph)，8.89(s，1H，NH)。
Table 9-8 chemical compound: yellow oil.δ(CDCl
3)：1.13-1.21(m，6H，CH
3)，3.46(q，4H，CH
2，J＝7.2Hz)，6.90(s，1H，NH)，7.13(t，2H，Ph-2，6-2H，J＝7.5Hz)，7.31(d，1H，Ph-4-H，J＝7.5Hz)，7.42(t，2H，Ph-3，5-2H，J＝7.2Hz)。
Table 10-99 chemical compound: fusing point 127-129 ℃.δ(CDCl
3)：3.22(s，6H，CH
3)，6.85(s，1H，NH)，8.32(s，2H，Ph-3，5-2H)。
Table 12-99 chemical compound: fusing point 198-200 ℃.δ(CDCl
3)：4.25(s，3H，CH
3)，6.87(s，1H，NH)，8.32(s，2H，Ph-3，5-2H)。
Table 14-4 chemical compound: fusing point 142-144 ℃.δ(CDCl
3)：4.14(s，3H，OCH
3)，4.17(t，3H，OCH
3，J＝4.2Hz)，6.91(s，1H，Ph-NH-Ph)，7.18(d，2H，Ph-2，6-2H，J＝7.8Hz)，7.32(t，1H，Ph-4-H，J＝7.2Hz)，7.42(t，2H，Ph-3，5-2H，J＝7.5Hz)。
Table 16-2 chemical compound: fusing point 176-178 ℃.δ(CDCl
3)：3.26(d，3H，NCH
3，J＝8.7Hz)，3.37(d，3H，NCH
3J＝8.1Hz)，5.04(br，1H，Ph-NH-C)，5.26(br，1H，Ph-NH-C)，6.35(s，1H，Ph-NH-Ph)，7.04(d，2H，Ph-2，6-2H，J＝8.1Hz)，7.14(t，1H，Ph-4-H，J＝7.2Hz)，7.35(t，2H，Ph-3，5-2H，J＝7.5Hz)。
Antitumor cytolytic activity
Embodiment 10: external test experience to the inhibiting tumour cells effect is as follows:
Institute's employment tumor cell strain: people's pulmonary carcinoma A549, human leukemia HL-60 etc.
Design routinely five different concentration, i.e. 100,10,1,0.1,0.01 μ M.Adopt the cell in vitro culture technique, measure test sample to the suppression ratio of each one growth of cancer cells with conventional mtt assay.
Cell is taken out from incubator, with PBS liquid cleaning twice, with the digestion of 0.25% trypsin solution, add culture medium and stop digestion, centrifugal rear piping and druming with suction pipe makes it to form cell suspension, and counts under inverted microscope.It is 5x10 that cell is mixed with concentration
4The cell suspension of/ml, add cell 100 μ l in the every hole of 96 orifice plates, be positioned over 5% carbon dioxide, overnight incubation in 37 ℃ of humidifying air adds the above-mentioned medicine to be measured that is diluted to the variable concentrations gradient, after making its effect 48h, add MTT, through reacting 4 hours, living cells produces formazan with the reduction of MTT tetrazolium composition, add afterwards DMSO with dissolving formazan, at last to measure the light absorption value of 570nm on the 96 hole plate reader.
The partial test result is as follows:
Suppression ratio to human lung cancer cell A549's growth
Suppression ratio to human leukemia cell HL60 growth
Claims (10)
1. the cyano-containing diphenylamine compound is characterized in that as the application of preparation antitumor drug compound structure is shown in general formula I:
In the 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
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
2-C
8Thiazolinyl, C
2-C
8Alkynyl, halo C
2-C
8Thiazolinyl, halo C
2-C
8Alkynyl, aryl C
1-C
8Alkyl 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
2, R
3Can be identical or different, be selected from respectively hydrogen, halogen, hydroxyl, cyano group, nitro, COOH, 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
1-C
8Alkyl sulphonyl, 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 or C
1-C
8Alkoxy carbonyl C
1-C
8Alkoxyl;
R
4, R
8Can be identical or different, be selected from respectively hydrogen, halogen, cyano group, nitro, COOH, 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, unsubstituted or by 1-5 R
11The following radicals that replaces: aryl, arylmethyl, aryloxy group, virtue amino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl or heteroaryl oxygen base, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
5, R
7Can be identical or different, be selected from respectively hydrogen, halogen, cyano group, nitro, COOH, C (=O) NR
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 that replaces: aryl, arylmethyl, aryloxy group, virtue amino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl or heteroaryl oxygen base, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
6Be selected from hydrogen, halogen, cyano group, nitro, COOH, CO
2Na, CO
2NH
4, 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, C (=O) NR
9R
10, SO
2NR
9R
10, unsubstituted or by 1-5 R
11The following radicals that replaces: aryl, arylmethyl, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl or aromatic yl aminocarbonyl, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
9, R
10Can be identical or different, be selected from respectively hydrogen, C
1-C
6Alkyl or C
3-C
6Cycloalkyl;
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.
2. application according to claim 1 is characterized in that: in the general formula I
R
1Be selected from hydrogen, C
1-C
4Alkyl, C
3-C
6Cycloalkyl, halo C
1-C
4Alkyl, C
1-C
4Alkyl-carbonyl, halo C
1-C
4Alkyl-carbonyl, C
1-C
4Alkoxy carbonyl, 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
2-C
4Thiazolinyl, C
2-C
4Alkynyl, halo C
2-C
4Thiazolinyl, halo C
2-C
4Alkynyl, benzyl, phenethyl, CO-X-CO
2R
9, wherein X is selected from (CHR
9) n, CR
9=CR
10Or C
6H
4, n=1-3;
R
2, R
3Can be identical or different, be selected from respectively chlorine, bromine, fluorine, hydroxyl, cyano group, nitro, 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
1-C
4Alkyl sulphonyl, C
1-C
6Dialkyl amido, C
3-C
4Alkene oxygen base, halo C
3-C
4Alkene oxygen base, C
3-C
4Alkynyloxy group, halo C
3-C
4Alkynyloxy 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 or C
1-C
4Alkoxy carbonyl C
1-C
4Alkoxyl;
R
4, R
8Can be identical or different, be selected from respectively hydrogen, chlorine, bromine, fluorine, cyano group, nitro, COOH, C (=O) NR
9R
10, C
1-C
4Alkyl, halo C
1-C
4Alkyl, C
1-C
4Alkoxyl, halo C
1-C
4Alkoxyl, C
1-C
4Alkylthio group, halo C
1-C
4Alkylthio group, C
2-C
4Thiazolinyl, C
2-C
4Alkynyl, 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 1-3 R
11The following radicals that replaces: phenoxy group, phenylamino, phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl, phenyl amino carbonyl or pyridine radicals oxygen base, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
5, R
7Can be identical or different, be selected from respectively hydrogen, chlorine, bromine, fluorine, cyano group, nitro, COOH, C (=O) NR
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
4Thiazolinyl, C
2-C
4Alkynyl, 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 1-3 R
11The following radicals that replaces: phenoxy group, phenylamino, phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl, phenyl amino carbonyl or pyridine radicals oxygen base, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
6Be selected from hydrogen, chlorine, bromine, fluorine, cyano group, nitro, COOH, CO
2Na, CO
2NH
4, C (=O) NR
9R
10, C
1-C
4Alkyl, halo C
1-C
4Alkyl, C
1-C
4Alkoxyl, halo C
1-C
4Alkoxyl, C
2-C
4Thiazolinyl, C
2-C
4Alkynyl, 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, SO
2NHCH
3, SO
2N (CH
3)
2, unsubstituted or by 1-3 R
11The following radicals that replaces: phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl or phenylamino carbonyl, and when substituent number greater than 1 the time, R
11Can be identical or different;
R
9, R
10Can be identical or different, be selected from respectively hydrogen or C
1-C
4Alkyl;
R
11Be selected from fluorine, chlorine, bromine, nitro, cyano group, C
1-C
4Alkyl, halo C
1-C
4Alkyl, C
1-C
4Alkoxyl, halo C
1-C
4Alkoxyl, C
1-C
4Alkylthio group, C
1-C
4Alkyl-carbonyl, C
1-C
4Alkoxy carbonyl or C
1-C
4Alkyl amino-carbonyl;
Or the salt of compound of Formula I.
3. application according to claim 2 is characterized in that: in the general formula I
R
1Be selected from hydrogen, methyl, acetyl group, methyl sulphonyl, benzyl or phenethyl;
R
2, R
3Can be identical or different, be selected from respectively chlorine, fluorine, methoxyl group, CF
3O, CF
3CH
2O, methylamino, dimethylamino, diethylamino, CF
3CH
2NH, ClCH
2CH
2NH, methyl mercapto, ethylmercapto group, methyl sulphonyl, ethylsulfonyl, dimethylamino, CH
2=CHCH
2O, CH ≡ CCH
2O, ClC ≡ CCH
2O, IC ≡ CCH
2O, CH
3CO
2, CH
3CONH, CH
3OCH
2CH
2O, C
2H
5OCH
2CH
2O, CH
3OC (=O) CH
2O or CH
3OC (=O) CH
2CH
2O;
R
4, R
8Can be identical or different, be selected from respectively hydrogen, fluorine, chlorine, bromine, cyano group, nitro, COOH, CONH
2, methyl, ethyl, isopropyl, the tert-butyl group, chloromethyl, trifluoromethyl, methoxyl group, ethyoxyl, CF
3O, CF
3CH
2O, methyl mercapto, methoxycarbonyl, CH
3OCH
2, CONHCH
3, CON (CH
3)
2, CONHCH (CH
3)
2Or CONHC (CH
3)
3
R
5, R
7Can be identical or different, be selected from respectively hydrogen, fluorine, chlorine, bromine, cyano group, nitro, COOH, CONH
2, methyl, ethyl, isopropyl, the tert-butyl group, chloromethyl, trifluoromethyl, methoxyl group, ethyoxyl, CF
3O, CF
3CH
2O, methyl mercapto, methoxycarbonyl, CH
3OCH
2, CONHCH
3, CON (CH
3)
2, CONHCH (CH
3)
2Or CONHC (CH
3)
3
R
6Be selected from hydrogen, fluorine, chlorine, bromine, cyano group, nitro, COOH, CO
2Na, CO
2NH
4, CONH
2, CONHCH
3, CON (CH
3)
2, CONHCH (CH
3)
2, CONHC (CH
3)
3, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxy carbonyl, methyl sulphonyl, SO
2NHCH
3, SO
2N (CH
3)
2, phenyloxycarbonyl, phenylamino carbonyl, 4-methylbenzene amino carbonyl or 4-chlorobenzene amino carbonyl;
Or its hydrochlorate, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates.
4. application according to claim 3 is characterized in that: in the general formula I
R
1Be selected from hydrogen;
R
2Be selected from chlorine, methoxyl group, NHCH
3, N (CH
3)
2Or N (C
2H
5)
2
R
3Be selected from chlorine, methoxyl group or NHCH
3
R
4Be selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, nitro or cyano group;
R
5Be selected from hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl;
R
6Be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, CO
2CH
3, cyano group, nitro, COOH, CO
2Na, phenylamino carbonyl or 4-chlorobenzene amino carbonyl;
R
7Be selected from hydrogen, chlorine, bromine, methyl or trifluoromethyl;
R
8Be selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, nitro or cyano group;
Or its hydrochlorate, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates.
5. application according to claim 4 is characterized in that: in the general formula I
R
1, R
5, R
7Be selected from hydrogen;
R
2, R
3Be selected from chlorine;
R
4, R
8Be selected from hydrogen or chlorine;
R
6Be selected from hydrogen, chlorine, bromine 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.
6. application according to claim 5 is characterized in that the chemical compound of following structure:
Or its hydrochlorate, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates.
7. according to claim 1-6 described application of any one, it is characterized in that: become the form of oral or parenteral route to carry out administration take the cyano-containing diphenylamine compound shown in the general formula I as active fraction preparation, or carry out administration by the form of transplant medicine pump in the body.
8. application according to claim 7, it is characterized in that: the medicine take the cyano-containing diphenylamine compound shown in the general formula I as active fraction preparation treatment, prevention or tumor remission, pharmaceutical dosage form are tablet, pill, capsule, electuary, syrup or injection or freeze-dried powder dosage form.
9. application according to claim 8 is characterized in that: active constituents of medicine is the cyano-containing diphenylamine compound shown in one or more general formula Is.
10. application according to claim 9, it is characterized in that, be applied in preparation treatment, prevention or alleviation 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 the gastric cancer medicine.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210067595.3A CN103301103B (en) | 2012-03-14 | 2012-03-14 | Application of cyano-containing diphenylamine compound to preparation of antitumor drugs |
| US14/376,074 US9376376B2 (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 |
| 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 |
| JP2014561274A JP5959670B2 (en) | 2012-03-14 | 2013-03-06 | Use of substituted diphenylamine compounds in the preparation of antitumor agents |
| CA2859842A CA2859842C (en) | 2012-03-14 | 2013-03-06 | Substitute diphenylamine compounds use thereof as antitumor agents |
| KR1020147017304A KR101599300B1 (en) | 2012-03-14 | 2013-03-06 | Substitute diphenylamine compounds use thereof as antitumor agents |
| ARP130100821A AR090334A1 (en) | 2012-03-14 | 2013-03-13 | DIFENYLAMINE SUBSTITUTED COMPOUNDS; USE OF THEM AS ANTITUMOR AGENTS |
| TW102108792A TW201336808A (en) | 2012-03-14 | 2013-03-13 | Use of substituted diphenylamine compounds in preparing anti-tumor drugs |
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|---|---|---|---|
| CN201210067595.3A CN103301103B (en) | 2012-03-14 | 2012-03-14 | Application of cyano-containing diphenylamine compound to preparation of antitumor drugs |
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| CN105287460A (en) * | 2014-07-21 | 2016-02-03 | 沈阳化工研究院有限公司 | Application of substituted diphenylamine compound in preparing anti-tumor drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| 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 |
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|---|---|---|---|---|
| CN105287460A (en) * | 2014-07-21 | 2016-02-03 | 沈阳化工研究院有限公司 | Application of substituted diphenylamine compound in preparing anti-tumor drug |
| 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 |
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