CN105287460A - Application of substituted diphenylamine compound in preparing anti-tumor drug - Google Patents
Application of substituted diphenylamine compound in preparing anti-tumor drug Download PDFInfo
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- CN105287460A CN105287460A CN201410348361.5A CN201410348361A CN105287460A CN 105287460 A CN105287460 A CN 105287460A CN 201410348361 A CN201410348361 A CN 201410348361A CN 105287460 A CN105287460 A CN 105287460A
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Abstract
The invention discloses application of a substituted diphenylamine compound shown as a general formula I in preparing anti-tumor drug. A definition of each substitutional group in the formula is shown in an instruction book. The compound shown as the general formula I has high anti-tumor activity, and has excellent activity especially for lung cancer A549.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of field of antineoplastic medicaments.Relate to the application of a kind of substituted diphenylamine aminated compounds as antitumor drug particularly.
Background technology
Prior art 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 ACSSymposiumSeries (1992), 504 (Synth.Chem.Agrochem. III), 336-48, JournaloftheChemicalSociety (1951), 110-15 etc. disclose the compound of following formula can as insecticide, acaricide, antibacterial, herbicide, rat poison or other purposes:
Patent WO2011116671 discloses the compound shown in following general formula as disinfectant use in agriculture:
Patent WO2013135147 discloses the compound shown in following general formula can as preparing antitumor drug:
In prior art, the compound of structure as shown in general formula I of the present invention has no the report as preparing antitumor drug application.
Summary of the invention
The object of the present invention is to provide substituted diphenylamine aminated compounds as the application preparing antitumor drug.
The technical solution used in the present invention is for achieving the above object:
Substituted diphenylamine aminated compounds is as the application preparing antitumor drug, and described compound is compound shown in general formula I;
Or, the salt of compound of 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
6, wherein X is selected from (CHR
6) p, CR
6=CR
7or C
6h
4;
P=0,1,2,3 or 4;
R
2be selected from trifluoromethyl or nitro;
R
3be selected from hydrogen, halogen, 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
8dialkyl amido, C
3-C
8alkene oxygen base, halo C
3-C
8alkene oxygen base, C
3-C
8alkynyloxy group or halo C
3-C
8alkynyloxy group;
R
4, R
5may be the same or different, be selected from nitro, cyano group, halo C respectively
1-C
8alkyl, C (=O) NR
6r
7, C (=S) NR
6r
7, C
1-C
8alkyl-carbonyl, C
1-C
8alkoxy carbonyl or C
1-C
8alkyl sulphonyl;
R is selected from halogen, cyano group, nitro, hydroxyl, amino, sulfydryl, COOH, C (=O) NR
6r
7, C
1-C
8alkyl, halo C
1-C
8alkyl, C
1-C
8alkoxyl, halo C
1-C
8alkoxyl, C
1-C
8alkylthio group, halo C
1-C
8alkylthio group, C
1-C
8alkyl amino, halo C
1-C
8alkyl amino, C
2-C
8thiazolinyl, halo C
2-C
8thiazolinyl, C
2-C
8alkynyl, halo C
2-C
8alkynyl, C
1-C
8alkyl sulphonyl, C
1-C
8alkyl-carbonyl, C
1-C
8alkoxy carbonyl, C
1-C
8alkyl-carbonyl oxygen base, C
1-C
8alkyl-carbonyl-amino, C
1-C
8alkoxy C
1-C
8alkyl, C
1-C
8alkoxy carbonyl C
1-C
8alkyl, unsubstituted or by 1-5 R
8the following radicals replaced: aryl, arylmethyl, aryloxy group, arylamino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl or heteroaryl oxygen base, and when substituent number is greater than 1, R
8may be the same or different;
N=0,1,2,3,4 or 5;
R
6, R
7may be the same or different, be selected from hydrogen, C respectively
1-C
6alkyl or C
3-C
6cycloalkyl;
R
8be 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 oxygen base, halo C
1-C
6alkyl-carbonyl oxygen base, C
1-C
6alkyl-carbonyl-amino or halo C
1-C
6alkyl-carbonyl-amino.
When applying as antitumor drug in above-mentioned substituted diphenylamine aminated compounds preferred compound for: described compound is compound shown in general formula I;
Or, the salt of compound of Formula I;
R
1be selected from hydrogen, C
1-C
4alkyl or C
1-C
4alkyl-carbonyl;
R
2be selected from trifluoromethyl or nitro;
R
3be 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
2-C
4dialkyl amido, C
3-C
4alkene oxygen base, halo C
3-C
4alkene oxygen base, C
3-C
4alkynyloxy group or halo C
3-C
4alkynyloxy group;
R
4, R
5may be the same or different, be selected from nitro or halo C respectively
1-C
4alkyl;
R is selected from halogen, cyano group, nitro, C (=O) NR
6r
7, 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
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
8the following radicals replaced: phenoxy group, phenylamino, phenylcarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl, phenyl amino carbonyl or pyridine radicals oxygen base, and when substituent number is greater than 1, R
8may be the same or different;
N=0,1,2,3 or 4;
R
6, R
7may be the same or different, be selected from hydrogen or C respectively
1-C
3alkyl;
R
8be 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, halo C
1-C
3alkylthio group, halo C
1-C
3alkyl-carbonyl, C
1-C
3alkyl amino or halo C
1-C
3alkyl amino.
When applying as antitumor drug in above-mentioned substituted diphenylamine aminated compounds further preferred compound for: compound be such as compound shown in general formula I,
Or, the hydrochlorate of compound of Formula I, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates;
R
1be selected from hydrogen;
R
2be selected from trifluoromethyl or nitro;
R
3be selected from hydrogen or halogen;
R
4, R
5be selected from nitro or trifluoromethyl;
R is selected from halogen, cyano group, nitro, 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
1-C
4alkyl sulphonyl, C
1-C
4alkyl-carbonyl or C
1-C
4alkoxy carbonyl;
N=2 or 3.
When applying as antitumor drug in above-mentioned substituted diphenylamine aminated compounds, preferred compound is further:
When in general formula I, R
2=CF
3, R
3=H, R
4=R
5=NO
2time, namely in general formula I A, R
1=H, Rn are selected from 2-chloro-4-trifluoromethyl, 2-chloro-4-nitro, 2,4,6-trichlorines, 2,6-dichlor-4-trifluoromethyls or the fluoro-4-nitro of the chloro-6-of 2-; Or, when in general formula I, R
2=R
5=NO
2, R
3=Cl, R
4=CF
3time, namely in general formula I B, R
1=H, Rn are selected from 2-chloro-4-nitro, 2,4,6-trichlorines, 2,6-bis-chloro-4-nitros, 2,6-dichlor-4-trifluoromethyls, 2,6-bis-chloro-4-cyano group or the fluoro-4-nitro of the chloro-6-of 2-.
The structure of general formula I A and general formula I B is as follows:
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, normal-butyl 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, the 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, the 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.Alkoxyalkyl: alkoxyl is connected in structure through alkyl.As-CH
2oCH
2,-CH
2oCH
2cH
3.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.Dialkyl amido: as-N (CH
3)
2,-N (CH
2cH
3)
2.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.Alkene oxygen base: straight or branched alkene class, is connected in structure through oxygen atom key.Haloalkene oxygen base: straight or branched alkene oxygen base, the hydrogen atom on these alkene oxygen bases can partly or entirely replace by halogen atom.Alkynyloxy group: straight or branched alkynes class, is connected in structure through oxygen atom key.Halo alkynyloxy group: straight or branched alkynyloxy group, the hydrogen atom on these alkynyloxy groups can partly or entirely replace by halogen atom.Alkyl sulphonyl: straight or branched alkyl is through sulfonyl (-SO
2-) be connected in structure, as methyl sulphonyl.Alkyl-carbonyl: alkyl is connected in structure, as-COCH through carbonyl
3,-COCH
2cH
3.Halogenated alkyl carbonyl: the hydrogen atom on the alkyl of alkyl-carbonyl can partly or entirely replace by halogen atom, as-COCF
3.Alkyl-carbonyl oxygen base: as-OCOCH
3,-OCOC (CH
3)
3.Alkyl-carbonyl-amino: as-NHCOCH
3,-NHCOC (CH
3)
3.Alkoxy carbonyl: alkoxyl is connected in structure through carbonyl.As-COOCH
3,-COOCH
2cH
3.Alkoxy carbonyl alkyl: as-CH
2cOOCH
3,-CH
2cOOCH
2cH
3.Aryl moiety in aryl, arylmethyl, aryloxy group, arylamino, aryl carbonyl, arylmethyl carbonyl, aryloxycarbonyl, aromatic yl aminocarbonyl comprises phenyl or naphthyl etc.Heteroaryl in heteroaryl oxygen base is containing the heteroatomic five-membered ring of one or more N, O, S or hexatomic ring.Such as pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, furyl, thiazolyl, quinolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazoles base, thiadiazolyl group, pyrazolyl, pyranose, triazolyl, tetrazole radical etc.
With the substituted diphenylamine aminated compounds shown in general formula I or its salt for active fraction preparation become oral, parenteral route or carry out the antitumor drug of administration by the form of transplant medicine pump in body.
Further, take the substituted diphenylamine aminated compounds shown in general formula I or its salt as the medicine of active fraction preparation treatment, prevention or tumor remission; Described pharmaceutical dosage form is tablet, pill, capsule, electuary, syrup, injection or freeze-dried powder dosage form.
The active component of said medicine is the substituted diphenylamine aminated compounds shown in one or more general formula Is or its salt.
Further say, the substituted diphenylamine aminated compounds shown in described general formula I or its salt are for the preparation for the treatment of, prevention or the medicine alleviating 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.
Table 1 and table 2 list R in general formula I
1substituent group concrete with the part of R.
Table 1R
1substituent group
Table 2R substituent group
| R | R | R | R |
| F | CH(CH 3) 2 | SCCl 3 | OCH 2C≡CH |
| Cl | (CH 2) 3CH 3 | NHCH 3 | OCH 2C≡C-I |
| Br | CH 2CH(CH 3) 2 | NHCH 2CH 3 | SO 2CH 3 |
| I | C(CH 3) 3 | NHCH(CH 3) 2 | SO 2CH 2CH 3 |
| CN | CF 3 | N(CH 3) 2 | COCH 3 |
| NO 2 | CHF 2 | N(C 2H 5) 2 | COCH 2CH 3 |
| OH | CH 2F | NHCH 2CF 3 | COCH 2C(CH 3) 3 |
| SH | CH 2CHF 2 | CH＝CH 2 | CO 2CH 3 |
| NH 2 | CH 2CF 3 | CH＝CCl 2 | CO 2CH 2CH 3 |
| COOH | CCl 3 | CH 2CH＝CH 2 | CO 2CH(CH 3) 2 |
| CONH 2 | OCH 3 | CH 2CH＝CCl 2 | OCOCH 3 |
| CONHCH 3 | OCH 2CH 3 | CH 2CH＝CF 2 | OCOCH 2CH 3 |
| CONHCH 2CH 3 | O(CH 2) 2CH 3 | CH 2CF＝CF 2 | NHCOCH 3 |
| CONHCH(CH 3) 2 | OCH(CH 3) 2 | C≡CH | NHCOCH 2CH 3 |
| CON(CH 3) 2 | OC(CH 3) 3 | C≡CCl | NHCOCH 2C(CH 3) 3 |
| CON(CH 2CH 3) 2 | OCF 3 | CH 2C≡CH | CH 2OCH 3 |
| CH 3 | OCH 2CF 3 | CH 2C≡CCl | CH 2OCH 2CH 3 |
| CH 2CH 3 | SCH 3 | OCH 2CH＝CH 2 | CH 2CO 2CH 3 |
| (CH 2) 2CH 3 | SCH 2CH 3 | OCH 2CH＝CCl 2 | CH 2CO 2CH 2CH 3 |
The compound that the present invention has anti-tumor activity is illustrated by the particular compound listed in table 3-table 10, but does not limit the present invention.
Work as R
2=CF
3, R
3=H, R
4=R
5=NO
2time, the R in representation compound IA-1 to IA-222
1with the concrete substituent group of Rn in table 3.
Table 3
| Numbering | R 1 | Rn |
| IA-1 | H | 2-Cl |
| IA-2 | H | 3-Cl |
| IA-3 | H | 4-Cl |
| IA-4 | H | 2-CN |
| IA-5 | H | 3-CN |
| IA-6 | H | 4-CN |
| IA-7 | H | 2-NO 2 |
| IA-8 | H | 3-NO 2 |
| IA-9 | H | 4-NO 2 |
| IA-10 | H | 2-CF 3 |
| IA-11 | H | 3-CF 3 |
| IA-12 | H | 4-CF 3 |
| IA-13 | H | 2-OCH 3 |
| IA-14 | H | 2-OCH 3 |
| IA-15 | H | 3-OCH 3 |
| IA-16 | H | 4-OCH 3 |
| IA-17 | H | 2-SCH 3 |
| IA-18 | H | 3-SCH 3 |
| IA-19 | H | 4-SCH 3 |
| IA-20 | H | 2-OCF 3 |
| IA-21 | H | 3-OCF 3 |
| IA-22 | H | 4-OCF 3 |
| IA-23 | H | 2-COCH 3 |
| IA-24 | H | 3-COCH 3 |
| IA-25 | H | 4-COCH 3 |
| IA-26 | H | 2-SO 2CH 3 |
| IA-27 | H | 3-SO 2CH 3 |
| IA-28 | H | 4-SO 2CH 3 |
| IA-29 | H | 2-CO 2CH 3 |
| IA-30 | H | 3-CO 2CH 3 |
| IA-31 | H | 4-CO 2CH 3 |
| IA-32 | H | 2-CONH 2 |
| IA-33 | H | 3-CONH 2 |
| IA-34 | H | 4-CONH 2 |
| IA-35 | H | 2,3-2Cl |
| IA-36 | H | 2,4-2Cl |
| IA-37 | H | 2,5-2Cl |
| IA-38 | H | 2,6-2Cl |
| IA-39 | H | 3,4-2Cl |
| IA-40 | H | 3,5-2Cl |
| IA-41 | H | 2,4-2NO 2 |
| IA-42 | H | 2-Cl-3-CH 3 |
| IA-43 | H | 2-CH 3-3-Cl |
| IA-44 | H | 2-Cl-4-CF 3 |
| IA-45 | H | 2-Cl-4-NO 2 |
| IA-46 | H | 2-Cl-4-CN |
| IA-47 | H | 2-CH 3-4-Cl |
| IA-48 | H | 2-CF 3-4-Cl |
| IA-49 | H | 2-NO 2-4-Cl |
| IA-50 | H | 2-CN-4-Cl |
| IA-51 | H | 2-NO 2-4-F |
| IA-52 | H | 2-NO 2-4-Br |
| IA-53 | H | 2-NO 2-4-CF 3 |
| IA-54 | H | 2-NO 2-4-CN |
| IA-55 | H | 2-NO 2-4-COCH 3 |
| IA-56 | H | 2-NO 2-4-CONH 2 |
| IA-57 | H | 2-NO 2-4-CH 3 |
| IA-58 | H | 2,4-2CF 3 |
| IA-59 | H | 2-CF 3-4-NO 2 |
| IA-60 | H | 2-CN-4-NO 2 |
| IA-61 | H | 2-COCH 3-4-NO 2 |
| IA-62 | H | 2-CONH 2-4-NO 2 |
| IA-63 | H | 2-CH 3-4-NO 2 |
| IA-64 | H | 2-Cl-5-CF 3 |
| IA-65 | H | 2-Cl-5-NO 2 |
| IA -66 | H | 2-Cl-5-CN |
| IA-67 | H | 2-CH 3-5-Cl |
| IA-68 | H | 2-CF 3-5-Cl |
| IA-69 | H | 2-NO 2-5-Cl |
| IA-70 | H | 2,3,4-3Cl |
| IA-71 | H | 2,3,5-3Cl |
| IA-72 | H | 2,3,6-3Cl |
| IA-73 | H | 2,4,5-3Cl |
| IA-74 | H | 2,4,6-3Cl |
| IA-75 | H | 3,4,5-3Cl |
| IA-76 | H | 2,4,6-3Br |
| IA-77 | H | 2,4,6-3NO 2 |
| IA-78 | H | 2,4-2Cl-6-NO 2 |
| IA-79 | H | 2,4-2Cl-6-CN |
| IA-80 | H | 2,4-2Cl-6-CF 3 |
| IA-81 | H | 2,4-2F-6-NO 2 |
| IA-82 | H | 2,4-2F-6-CN |
| IA-83 | H | 2,4-2F-6-CF 3 |
| IA-84 | H | 2NO 2-4,5-2Cl |
| IA-85 | H | 2,5-2Cl-4-NO 2 |
| IA-86 | H | 2,5-2Cl-6-NO 2 |
| IA-87 | H | 2,3-2Cl-4NO 2 |
| IA-88 | H | 2,3-2Cl-6-NO 2 |
| IA-89 | H | 2,6-2Cl-4-NO 2 |
| IA-90 | H | 2,6-2Cl-4-CF 3 |
| IA-91 | H | 2,6-2Cl-4-CN |
| IA-92 | H | 2,6-2Cl-4-COCH 3 |
| IA-93 | H | 2,6-2Cl-4-CONH 2 |
| IA-94 | H | 2,6-2F-4-NO 2 |
| IA-95 | H | 2,6-2Br-4-NO 2 |
| IA-96 | H | 2-Cl-6-F-4-NO 2 |
| IA-97 | H | 2-Br-6-Cl-4-NO 2 |
| IA-98 | H | 2-Cl-4-CF 3-6-NO 2 |
| IA-99 | H | 2-Cl-4,6-2NO 2 |
| IA-100 | H | 2-Cl-4-CN-6-NO 2 |
| IA-101 | H | 2-F-4-Cl-6-NO 2 |
| IA-102 | H | 2-CH 3-4-Cl-6-NO 2 |
| IA-103 | H | 2-CF 3-4-Cl-6-NO 2 |
| IA-104 | H | 2-CN-4-Cl-6-NO 2 |
| IA-105 | H | 4-Cl-2,6-2NO 2 |
| IA-106 | H | 4-CF 3-2,6-2NO 2 |
| IA-107 | H | 4-CN-2,6-2NO 2 |
| IA-108 | H | 4-CH 3-2,6-2NO 2 |
| IA-109 | H | 4-F-2,6-2NO 2 |
| IA-110 | H | 2-CF 3-4,6-2NO 2 |
| IA-111 | H | 2-CN-4,6-2NO 2 |
| IA-112 | H | 2-CH 3-4,6-2NO 2 |
| IA-113 | H | 2-F-4,6-2NO 2 |
| IA-114 | H | 3-CF 3-4-CN |
| IA-115 | H | 2-NO 2-4-CN-5-CF 3 |
| IA-116 | H | 4-OCF 3-2,6-2Br |
| IA-117 | H | 2,4-2Cl-3-CH 3 |
| IA-118 | H | 2,4-2Cl-3-CH 3-6-NO 2 |
| IA-119 | H | 2-CH 3-3-Cl-4,6-2NO 2 |
| IA-120 | H | 2-CH 3-3-Cl-4-NO 2 |
| IA-121 | H | 2-Cl-3-CH 3-4,6-2NO 2 |
| IA-122 | H | 2-Br-4-NO 2-6-CN |
| IA-123 | H | 3-Cl-4-CF 3-2,6-2NO 2 |
| IA-124 | H | 3,4-2Cl-2,6-2NO 2 |
| IA-125 | H | 2,5-2Cl-4,6-2NO 2 |
| IA-126 | H | 2,4,5-3Cl-6-NO 2 |
| IA-127 | H | 2,3,4-3Cl-5NO 2 |
| IA-128 | H | 2,3,4-3Cl-6-NO 2 |
| IA-129 | H | 2,3,5-3Cl-4,6-2CN |
| IA-130 | H | 2,5-2Cl-4-OCF 2OCF 3 |
| IA-131 | H | 2-CH 3-6-Cl-4-NO 2 |
| IA-132 | H | 2,3,4,5,6-5F |
| IA-133 | H | 2,3,4,5,6-5Cl |
| IA-134 | H | 2,4,6-3F-3,5-2Cl |
| IA-135 | H | 2,4,6-3Cl-3,5-2F |
| IA-136 | CH 3 | 2,4-2Cl |
| IA-137 | CH 3 | 2,4-2NO 2 |
| IA-138 | CH 3 | 2,4-2CF 3 |
| IA-139 | CH 3 | 2-CF 3-4-NO 2 |
| IA-140 | CH 3 | 2-NO 2-4-CF 3 |
| IA-141 | CH 3 | 2-CH 3-5-Cl |
| IA-142 | CH 3 | 2-CF 3-5-Cl |
| IA-143 | CH 3 | 2-Cl-5-CF 3 |
| IA-144 | CH 3 | 2,4,5-3Cl |
| IA-145 | CH 3 | 2,4,6-3Cl |
| IA-146 | CH 3 | 2,6-2Cl-4-NO 2 |
| IA-147 | CH 3 | 2,6-2Cl-4-CF 3 |
| IA-148 | CH 3 | 2,6-2Cl-4-CN |
| IA-149 | CH 3 | 2,6-2Br-4-NO 2 |
| IA-150 | CH 3 | 2-Cl-6-F-4-NO 2 |
| IA-151 | CH 3 | 2-Br-6-Cl-4-NO 2 |
| IA-152 | CH 3 | 2-CH 3-6-Cl-4-NO 2 |
| IA-153 | CH 3 | 4-CF 3-2,6-2NO 2 |
| IA-154 | CH 3 | 4-Cl-2,6-2NO 2 |
| IA-155 | CH 3 | 2-Br-4-NO 2-6-CN |
| IA-156 | CH 3 | 2-NO 2-4-CN-5-CF 3 |
| IA-157 | CH 3 | 2,5-2Cl-4-NO 2 |
| IA-158 | CH 3 | 2-Cl-4,6-2NO 2 |
| IA-159 | CH 3 | 2-Cl-4-CN-6-NO 2 |
| IA-160 | CH 3 | 2,4-2Cl-6-NO 2 |
| IA-161 | CH 3 | 2,4-2Cl-6-CN |
| IA-162 | CH 3 | 2,4-2Cl-6-CF 3 |
| IA-163 | CH 3 | 2,5-2Cl-4,6-2NO 2 |
| IA-164 | CH 3 | 2,4,5-3Cl-6-NO 2 |
| IA-165 | CH 2CH 3 | 2,4-2Cl |
| IA-166 | CH 2CH 3 | 2,4-2NO 2 |
| IA-167 | CH 2CH 3 | 2,4-2CF 3 |
| IA-168 | CH 2CH 3 | 2-CF 3-4-NO 2 |
| IA-169 | CH 2CH 3 | 2-NO 2-4-CF 3 |
| IA-170 | CH 2CH 3 | 2-CH 3-5-Cl |
| IA-171 | CH 2CH 3 | 2-CF 3-5-Cl |
| IA-172 | CH 2CH 3 | 2-Cl-5-CF 3 |
| IA-173 | CH 2CH 3 | 2,4,5-3Cl |
| IA-174 | CH 2CH 3 | 2,4,6-3Cl |
| IA-175 | CH 2CH 3 | 2,6-2Cl-4-NO 2 |
| IA-176 | CH 2CH 3 | 2,6-2Cl-4-CF 3 |
| IA-177 | CH 2CH 3 | 2,6-2Cl-4-CN |
| IA-178 | CH 2CH 3 | 2,6-2Br-4-NO 2 |
| IA-179 | CH 2CH 3 | 2-Cl-6-F-4-NO 2 |
| IA-180 | CH 2CH 3 | 2-Br-6-Cl-4-NO 2 |
| IA-181 | CH 2CH 3 | 2-CH 3-6-Cl-4-NO 2 |
| IA-182 | CH 2CH 3 | 4-CF 3-2,6-2NO 2 |
| IA-183 | CH 2CH 3 | 4-Cl-2,6-2NO 2 |
| IA-184 | CH 2CH 3 | 2-Br-4-NO 2-6-CN |
| IA-185 | CH 2CH 3 | 2-NO 2-4-CN-5-CF 3 |
| IA-186 | CH 2CH 3 | 2,5-2Cl-4-NO 2 |
| IA-187 | CH 2CH 3 | 2-Cl-4,6-2NO 2 |
| IA-188 | CH 2CH 3 | 2-Cl-4-CN-6-NO 2 |
| IA-189 | CH 2CH 3 | 2,4-2Cl-6-NO 2 |
| IA-190 | CH 2CH 3 | 2,4-2Cl-6-CN |
| IA-191 | CH 2CH 3 | 2,4-2Cl-6-CF 3 |
| IA-192 | CH 2CH 3 | 2,5-2Cl-4,6-2NO 2 |
| IA-193 | COCH 3 | 2,4,5-3Cl-6-NO 2 |
| IA-194 | COCH 3 | 2,4-2Cl |
| IA-195 | COCH 3 | 2,4-2NO 2 |
| IA-196 | COCH 3 | 2,4-2CF 3 |
| IA-197 | COCH 3 | 2-CF 3-4-NO 2 |
| IA-198 | COCH 3 | 2-NO 2-4-CF 3 |
| IA-199 | COCH 3 | 2-CH 3-5-Cl |
| IA-200 | COCH 3 | 2-CF 3-5-Cl |
| IA-201 | COCH 3 | 2-Cl-5-CF 3 |
| IA-202 | COCH 3 | 2,4,5-3Cl |
| IA-203 | COCH 3 | 2,4,6-3Cl |
| IA-204 | COCH 3 | 2,6-2Cl-4-NO 2 |
| IA-205 | COCH 3 | 2,6-2Cl-4-CF 3 |
| IA-206 | COCH 3 | 2,6-2Cl-4-CN |
| IA-207 | COCH 3 | 2,6-2Br-4-NO 2 |
| IA-208 | COCH 3 | 2-Cl-6-F-4-NO 2 |
| IA-209 | COCH 3 | 2-Br-6-Cl-4-NO 2 |
| IA-210 | COCH 3 | 2-CH 3-6-Cl-4-NO 2 |
| IA-211 | COCH 3 | 4-CF 3-2,6-2NO 2 |
| IA-212 | COCH 3 | 4-Cl-2,6-2NO 2 |
| IA-213 | COCH 3 | 2-Br-4-NO 2-6-CN |
| IA-214 | COCH 3 | 2-NO 2-4-CN-5-CF 3 |
| IA-215 | COCH 3 | 2,5-2Cl-4-NO 2 |
| IA-216 | COCH 3 | 2-Cl-4,6-2NO 2 |
| IA-217 | COCH 3 | 2-Cl-4-CN-6-NO 2 |
| IA-218 | COCH 3 | 2,4-2Cl-6-NO 2 |
| IA-219 | COCH 3 | 2,4-2Cl-6-CN |
| IA-220 | COCH 3 | 2,4-2Cl-6-CF 3 |
| IA-221 | COCH 3 | 2,5-2Cl-4,6-2NO 2 |
| IA-222 | COCH 3 | 2,4,5-3Cl-6-NO 2 |
Table 4: work as R
2=R
5=NO
2, R
3=Cl, R
4=CF
3time, the R in representation compound IB-1 to IB-222
1and R
nsubstituent group consistent with table 3 Compound I A-1 to IA-222.
Table 5: work as R
2=R
5=NO
2, R
3=OCH
3, R
4=CF
3time, the R in representation compound IC-1 to IC-222
1and R
nsubstituent group consistent with table 3 Compound I A-1 to IA-222.
Table 6: work as R
2=R
5=NO
2, R
3=OCH
2cF
3, R
4=CF
3time, the R in representation compound ID-1 to ID-222
1and R
nsubstituent group consistent with table 3 Compound I A-1 to IA-222.
Table 7: work as R
2=R
5=NO
2, R
3=NHCH
3, R
4=CF
3time, the R in representation compound IE-1 to IE-222
1and R
nsubstituent group consistent with table 3 Compound I A-1 to IA-222.
Table 8: work as R
2=R
5=NO
2, R
3=SCH
3, R
4=CF
3time, the R in representation compound IF-1 to IF-222
1and R
nsubstituent group consistent with table 3 Compound I A-1 to IA-222.
Table 9: work as R
2=R
5=NO
2, R
3=H, R
4=CF
3time, the R in representation compound IG-1 to IG-222
1and R
nsubstituent group consistent with table 3 Compound I A-1 to IA-222.
Table 10: work as R
2=R
5=NO
2, R
3=H, R
4during=CN, the R in representation compound IH-1 to IH-222
1and R
nsubstituent group consistent with table 3 Compound I A-1 to IA-222.
The highly preferred compound of the present invention is: Compound I A-44, Compound I A-74 and Compound I A-90.
Compound of Formula I involved in the present invention has been reported in the prior art, can obtain easily.Also can specifically the middle preparation method recorded such as referenced patent US4117167, US4152460, US4407820, US4187318 obtain simultaneously.
The present invention includes the preparation that compound that above-mentioned general formula I comprises is the formulation ingredients that is mixed with of 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 contained in 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 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 of normal saline or 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 or alleviates the preparation of 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.
Antitumor cytolytic activity
The external test experience to inhibiting tumour cells effect is as follows:
Institute's employment tumor cell strain: people pulmonary carcinoma A549 etc.
Embodiment 1: to the growth inhibition ratio of human lung cancer cell A549, adopt Cell culture invitro technology, about 1000 to 3000 cell kinds are entered in 24 orifice plates, then more every hole add 1 milliliter well known to those skilled in the art can the cell culture fluid of culture experiment tumor cell line, (CO in cell culture incubator
25%, 370 DEG C) cultivate after 24 hours, then the contrast medicine of debita spissitudo and above-mentioned gained material medicine to be measured of preparing are added in hand-hole, note, the volume adding liquid is no more than 0.5% of cumulative volume.Allow cell continue to grow in cell culture incubator, after the week, by cell culture fluid sucking-off, wash once with cold 1 milliliter of PBS.Then, fix 10 minutes by the formalin room temperature of 1%, then wash once with cold 1 milliliter of PBS.Add the violet staining 30 minutes of 0.1%.Crystal violet recycling.The cell deionized water of dye lechery slowly rinses, and after room temperature is dried, preserves.Remaining cell by each concentration process calculates cell inhibitory rate with the remaining cell of the matched group without medicine process.Contrast medicament is respectively fluazinam (fluazinam), department is beautiful for Buddhist nun (AZD6244), gefitinib (Gefitinib) and cisplatin (Cisplatin).
The remaining cell of suppression ratio=each concentration process/without remaining cell × 100% of the matched group of medicine process
Part of compounds test result is as follows:
Under 2.0 μMs of concentration, Compound I A-44, IA-45, IA-74, IA-90, IA-96, IB-74, IB-89, IB-90, IB-91 etc. are 100% to the growth inhibition ratio of human lung cancer cell A549; The growth inhibition ratio to human lung cancer cell A549 such as Compound I A-89, IA-91, IB-45, IB-96 is not less than 90%.
Under 1.0 μMs of concentration, Compound I A-44, IA-45, IA-74, IA-90, IB-74, IB-90, IB-91 etc. are 100% to the growth inhibition ratio of human lung cancer cell A549; The growth inhibition ratio to human lung cancer cell A549 such as Compound I A-96, IB-89 is not less than 90%.
Under 0.5 μM of concentration, Compound I A-44, IA-45, IA-74, IA-90 etc. are 100% to the growth inhibition ratio of human lung cancer cell A549; The growth inhibition ratio to human lung cancer cell A549 such as Compound I B-74, IB-90, IB-91 is not less than 70%.
Under 0.1 μM of concentration, Compound I A-44 etc. are 100% to the growth inhibition ratio of human lung cancer cell A549; The growth inhibition ratio to human lung cancer cell A549 such as Compound I A-74, IA-90 is not less than 70%.
Under 0.05 μM of concentration, Compound I A-44 etc. are 80% to the growth inhibition ratio of human lung cancer cell A549.
The test result correction data of part of compounds and contrast medicament is in table 11:
Table 11 part of compounds and control compound are to the growth inhibition ratio (%) of human lung cancer cell A549
Claims (5)
1. substituted diphenylamine aminated compounds is as the application preparing antitumor drug, it is characterized in that: compound is such as compound shown in general formula I,
Or, the hydrochlorate of compound of Formula I, sulfate, nitrate, bicarbonate, carbonate, phosphate, formates, acetate, trifluoroacetate, benzene sulfonate, tosilate, metilsulfate, benzoate, citrate, malate, tartrate, maleate, succinate, Ascorbate or oxalates;
In formula:
R
1be selected from hydrogen;
R
2be selected from trifluoromethyl or nitro;
R
3be selected from hydrogen or halogen;
R
4, R
5be selected from nitro or trifluoromethyl;
R is selected from halogen, cyano group, nitro, 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
1-C
4alkyl sulphonyl, C
1-C
4alkyl-carbonyl or C
1-C
4alkoxy carbonyl;
N=2 or 3.
2. application according to claim 1, is characterized in that: with the substituted diphenylamine aminated compounds shown in general formula I or its salt for active fraction preparation become oral, parenteral route or carry out the antitumor drug of administration by the form of transplant medicine pump in body.
3. application according to claim 1, is characterized in that: the medicine taking the substituted diphenylamine aminated compounds shown in general formula I or its salt as active fraction preparation treatment, prevention or tumor remission; Described pharmaceutical dosage form is tablet, pill, capsule, electuary, syrup, injection or freeze-dried powder dosage form.
4. application according to claim 3, is characterized in that: the active component of described medicine is the substituted diphenylamine aminated compounds shown in one or more general formula Is or its salt.
5. application according to claim 1, is characterized in that: the substituted diphenylamine aminated compounds shown in described general formula I or its salt are for the preparation for the treatment of, prevention or the medicine alleviating 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.
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Citations (3)
| 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 |
| CN103301096A (en) * | 2012-03-14 | 2013-09-18 | 中国中化股份有限公司 | Application of substituted diphenylamine compound to preparation of antitumor drugs |
| CN103301103A (en) * | 2012-03-14 | 2013-09-18 | 中国中化股份有限公司 | Application of cyano-containing diphenylamine compound to preparation of antitumor drugs |
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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 |
| CN103301096A (en) * | 2012-03-14 | 2013-09-18 | 中国中化股份有限公司 | Application of substituted diphenylamine compound to preparation of antitumor drugs |
| CN103301103A (en) * | 2012-03-14 | 2013-09-18 | 中国中化股份有限公司 | Application of cyano-containing diphenylamine compound to preparation of antitumor drugs |
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