CN103467452B - A kind of benzamide compound and application thereof - Google Patents
A kind of benzamide compound and application thereof Download PDFInfo
- Publication number
- CN103467452B CN103467452B CN201310413643.4A CN201310413643A CN103467452B CN 103467452 B CN103467452 B CN 103467452B CN 201310413643 A CN201310413643 A CN 201310413643A CN 103467452 B CN103467452 B CN 103467452B
- Authority
- CN
- China
- Prior art keywords
- compound
- hnmr
- cell
- mcf
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 FN1CC*CC1 Chemical compound FN1CC*CC1 0.000 description 1
Abstract
The invention belongs to medical art, relate to a kind of new benzamides compounds, its pharmaceutically acceptable acid adding salify.The Pharmacological Activity Screening result of part of compounds shows it has good restraining effect to MCF-7 (human breast cancer cell) and HeLa (human cervical carcinoma cell), has good anti-tumor aspect development prospect.
Description
Technical field:
The invention provides a series antineoplastic medicament structure, belong to medical art.
Background technology:
Malignant tumour as one of larger public health problem in the whole world, the greatly health of harm humans, and will first killer of the new millennium mankind be become.From world wide, global new cancer cases 1,010 ten thousand, dead 6,200,000 in 2000, existing cancer stricken case 2,240 ten thousand, pathogenesis of cancer numbers in 2008 and death toll rise to 1,266 ten thousand and 7,560,000 respectively, and estimating 2015 will have 15,000,000 new cases.Meanwhile, malignant tumour is no longer the serious disease of advanced industrial country, and developing country is faced with larger Disease Spectrum.Within 2008, Incidence number developing country accounts for 56%; The cancer patients of 2009 80% concentrates on middle and low income country, and by 2015, developing country estimated at 9,000,000 people and dies from cancer.China is as a developing power, and due to the quickening of industrialization, urbanization and aging population process, the existence of the problems such as bad mode of life and environmental pollution, the situation that malignant tumour faces is also more severe.The invention provides one and there is anti-tumor activity benzamides medicines structure, there is important development prospect.
Summary of the invention:
The object of the present invention is to provide new benzamides compounds, this compounds pharmacologically active result shows it and has good restraining effect to tumor cell line.
A kind of benzamide compound, it is characterized in that, its structural formula is as shown in general formula (1):
Wherein:
R
1and R
2be selected from hydrogen, halogen, cyano group, hydroxyl, haloalkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl; Described haloalkyl is selected from the cyclic saturated hydrocarbon that 3 ~ 10 saturated carbon atoms are formed or the straight or branched saturated hydrocarbyl with 1 ~ 10 saturated carbon Sauerstoffatom formation, and halogen is fluorine, chlorine, the substituting group of bromine or iodine.R
3and R
4be selected from alkyl, the phenyl of phenyl or replacement.
Described haloalkyl is selected from the cyclic saturated hydrocarbon that 3 ~ 6 saturated carbon atoms are formed or the straight or branched saturated hydrocarbyl with 1 ~ 6 saturated carbon atom formation.
Described R
3and R
4following radicals is formed: imidazolidyl, 2-imidazolidyl, 3-imidazolidyl, pyrryl together with the N that they connect, 2H-pyrryl, 2-pyrrolinyl, pyrrolidyl, triazolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl, thio-morpholinyl, described group can optionally by hydroxyl, halogen, alkyl, amino, haloalkyl, alkylthio alkyl, alkoxyalkyl, pyrimidyl replace or group as follows
wherein Y is S, O, NH or N-alkyl; R
1and R
2can be identical or different.
Described benzamide compound can be used for antitumor drug;
The application of foregoing benzamide compound in antitumor monomer medicine or pharmaceutical composition.
A kind of pharmaceutical composition, is characterized in that comprising foregoing benzamide compound.
One or more pharmaceutical carriers or vehicle, is characterized in that comprising foregoing benzamide compound.
The conjunction of this compound is that starting raw material route via I obtains with 2-(2-amino-5-(dimethylamino) phenyl)-N-(3-(trifluoromethyl) phenyl) Isonicotinamide, and concrete synthetic route is as follows:
According to above-mentioned route of synthesis, the medicine of following structure can be obtained:
Said medicine can add one or more pharmaceutical carriers or vehicle, is prepared into tablet, capsule, powder, pill, granule or emulsion.Show that it has good restraining effect to tumor cell line by pharmacological activity test.
Description of drawings
Fig. 1 is compound (1) HNMR collection of illustrative plates;
Fig. 2 is compound (2) HNMR collection of illustrative plates;
Fig. 3 is compound (3) HNMR collection of illustrative plates;
Fig. 4 is compound (4) HNMR collection of illustrative plates;
Fig. 5 is compound (5) HNMR collection of illustrative plates;
Fig. 6 is compound (6) HNMR collection of illustrative plates;
Fig. 7 is compound (7) HNMR collection of illustrative plates;
Fig. 8 is compound (8) HNMR collection of illustrative plates.
Embodiment:
To contribute to understanding the present invention by following example, but content of the present invention can not be limited to.
Embodiment 1: the synthesis of compound (1)
Adopt the mode of synthetic route I:
By 2-(2-amino-5-(dimethylamino) phenyl)-N-(3-(trifluoromethyl) phenyl) Isonicotinamide (4.42g, 10mmol) be dissolved in 100mL round-bottomed flask with 20mL methylene dichloride, add triethylamine (5.05g again, 50mmol), frozen water is cooled to-20 DEG C.Simultaneously by 3-(chloromethyl) Benzoyl chloride (2.27g, 12mmol) be dissolved in the methylene dichloride of 30mL, and by its slowly above-mentioned round-bottomed flask of instillation, time for adding is 25min, control temperature is at-20 ~-30 DEG C, dropping terminates rear continuation and stirs 2h, then naturally rises to stirred overnight at room temperature, and reaction is finished.With pure water 50mL × 3 washing reaction liquid; anhydrous sodium sulfate drying; concentrating under reduced pressure organic phase; silica gel column chromatography separate mode is finally adopted to purify; eluent is that petrol ether/ethyl acetate=3:1 obtains brown oil 2-(2-(3-(chloromethyl) benzoyl)-5-(dimethylamino) phenyl)-N-(3-(trifluoromethyl) phenyl) easily niacinamide 4.90g; productive rate 82.41%; (ES, m/z): 595.2 [M+H]
+ 1, 597.2 [M+H+2]
+ 1.
Above-mentioned brown oil is dissolved in containing N, in the round-bottomed flask of dinethylformamide 50mL, add sodium hydride 200mg respectively again, 5mmol, 2.00N, 60% and 4-(2, 5, 8, 11, 14, 17, 20, the pungent oxo penta-25 of 23-)-1H-indoles 4.94g, 2.9.88mmol, 1.2N, whole system stirs 2h at ambient temperature, add ethyl acetate 100mL dilution, saturated aqueous common salt 100mL × 2 are used to extract again, anhydrous sodium sulfate drying, concentrating under reduced pressure organic phase, finally adopt silica gel column chromatogram separating purification, eluent is petrol ether/ethyl acetate=3:1, obtain brown oil product (1) 14.17g, productive rate 47.82%, (ES, m/z): 1058.2 [M+H]
+ 1, 1010.2 [M+H+2]
+ 1.HNMR(300MHz,CD
3OD)δ:8.85(s,1H),8.33(s,1H),8.18(s,J=5.4,1H),7.91(s,2H),7.54～7.73(m,9H),7.25(s,1H),6.99～7.07(m,2H),6.68(d,J=2.7,1H),6.59(d,J=7.2,1H),5.50(s,2H),4.72(s,2H),4.28(s,2H),3.93(s,2H),3.50～3.75(m,35H),1.31(s,2H)，1.20～1.25(m,6H)。See Fig. 1.
Adopt suitable raw material and reagent, according to synthetic method and the synthetic route I of embodiment 1, new benzamides compounds in embodiment 2 ~ 8 can be obtained.
Embodiment 2: the synthesis of compound (2)
(ES,m/z):1036.2[M+H]
+1，1038.2[M+H+2]
+1;HNMR(300MHz,CDCl
3)δ:8.87～8.97(m,2H),8.46(s,1H),8.17(s,1H),7.91～8.00(m,3H),7.84(s,2H),7.49～7.68(m,10H),4.72(s,2H),3.73～3.80(m,5H),3.47～3.61(m,23H),3.33(d,J=1.2,1H),2.81～2.86(m,2H),2.43～2.47(m,2H),1.92～1.97(m,2H),1.21～1.26(m,6H)。See Fig. 2.
Embodiment 3: the synthesis of compound (3)
(ES,m/z):974.2[M+H]
+1，976.2[M+H+2]
+1;HNMR(300MHz,CDCl
3)δ:8.98(d,J=5.1,1H),8.83(d,J=8.7,1H),8.43(s,1H),8.06(s,1H),7.92(d,J=5.1,1H),7.81～7.84(m,2H),7.50～7.72(m,7H),4.72(s,2H),3.70～3.77(m,5H),3.51～3.63(m,21H),3.22(s,3H),2.82～2.87(m,2H),2.52～2.56(m,2H),1.57～2.00(m,8H),1.24～1.41(m,9H)。See Fig. 3.
Embodiment 4: the synthesis of compound (4)
(ES,m/z):924.2[M+H]
+1，926.2[M+H+2]
+1;HNMR(300MHz,CDCl
3)δ:14.03(s,1H),13.68(s,1H),9.50(s,1H),9.35(s,1H),9.18(d,J=8.7Hz,1H),8.92(s,1H),8.35(d,J=3.9Hz,1H),8.01～7.92(m,3H),7.74～7.66(m,2H),7.53～7.43(m,3H),7.53～7.43(m,3H),7.38～7.30(m,2H),7.18～7.13(m,3H),7.00(d,J=6.3Hz,1H),6.68(d,J=2.4Hz,1H),5.45(s,2H),4.76(d,J=5.1Hz,2H),3.70～3.64(m,16H),3.57～3.53(m,5H),3.40(s,5H),3.02(t,J=7.2Hz,2H),2.83(s,1H),2.07(t,J=6.9Hz,2H),1.29(t,J=6.0Hz,2H)。See Fig. 4.
Embodiment 5: the synthesis of compound (5)
(ES,m/z):1012.2[M+H]
+1，1014.2[M+H+2]
+1;HNMR(300MHz,CDCl
3)δ:8.82(d,J=6.6Hz,1H),8.42(s,1H),8.24(d,J=11.1Hz,2H),8.04(s,1H),7.90(d,J=4.2Hz,1H),7.80～7.69(m,4H),7.66～7.49(m,6H),7.41(d,J=7.8Hz,1H),7.33(d,J=3.0Hz,1H),7.22(d,J=8.4Hz,1H),7.09(t,J=6.3Hz,1H),6.93(d,J=7.2Hz,1H),6.65(d,J=3.0Hz,1H),5.51(d,J=3.3Hz,2H),4.71(s,2H),4.71(s,2H),3.73(d,J=7.2Hz,4H),3.66～3.46(m,29H),2.98(t,J=7.5Hz,2H),1.98(t,J=7.2Hz,2H),1.22(t,J=3.9Hz,6H)。See Fig. 5.
Embodiment 6: the synthesis of compound (6)
(ES,m/z):1101.2[M+H]
+1，1103.2[M+H+2]
+1;HNMR(300MHz,CDCl
3)δ:8.73(d,J=9.6Hz,1H),8.37(s,1H),8.27(s,1H),8.04(s,1H),7.90(d,J=4.2Hz,1H),7.80～7.69(m,4H),7.66～7.49(m,6H),7.41(d,J=7.8Hz,1H),7.33(d,J=3.0Hz,1H),7.22(d,J=8.4Hz,1H),7.09(t,J=6.3Hz,1H),6.93(d,J=7.2Hz,1H),6.65(d,J=3.0Hz,1H),5.51(d,J=3.3Hz,2H),4.71(s,2H),3.72(d,J=7.2Hz,4H),3.66～3.46(m,28H),2.98(t,J=7.5Hz,2H),1.98(t,J=7.2Hz,2H),1.20(t,J=3.9Hz,6H)。See Fig. 6.
Embodiment 7: the synthesis of compound (7)
(ES,m/z):1026.2[M+H]
+1，1028.2[M+H+2]
+1;HNMR(300MHz,CDCl
3)δ:8.76(d,J=9.0Hz,1H),8.35(s,1H),8.24(d,J=5.1Hz,1H),8.03(s,1H),7.90(d,J=7.2Hz,1H),7.72～7.66(m,4H),7.63～7.53(m,5H),7.34(d,J=3.3Hz,1H),7.22(d,J=8.1Hz,1H),7.09(t,J=6.3Hz,1H),6.93(d,J=7.2Hz,1H),6.65(d,J=3.0Hz,1H),5.52(s,2H),4.71(s,2H),3.78～3.66(m,6H),3.63～3.58(m,10H),3.56～3.53(m,10H),3.49～3.34(m,2H),2.98(t,J=7.5Hz,2H),2.51(t,J=6.0Hz,2H),1.97(t,J=7.5Hz,2H),1.20(t,J=7.2Hz,6H)。See Fig. 7.
Embodiment 8: the synthesis of compound (8)
(ES,m/z):1159.2[M+H]
+1，11597.2[M+H+2]
+1;HNMR(300MHz,CDCl
3)δ:8.78(d,J=9.0Hz,1H),8.37(s,1H),8.25(d,J=5.1Hz,1H),8.14(s,1H),7.88(d,J=7.2Hz,1H),7.72(m,1H),7.65(m,4H),7.61(m,1H),;7.48(m,5H),7.30(d,J=3.0Hz,1H),7.20(d,J=8.1Hz,1H),7.06(t,J=7.8Hz,1H),6.90(d,J=6.9Hz,1H),6.63(d,J=3.0Hz,1H),5.48(s,2H),4.70(s,2H),3.75(m,1H),3.68(m,6H),3.61(m,1H),3.51(m,30H),3.47(m,1H),3.43(m,2H),2.95(t,J=7.5Hz,2H),2.53(t,J=6.3Hz,2H),1.96(t,J=7.2Hz,2H),1.20(t,J=7.2Hz,6H)。See Fig. 8.
Embodiment 6: compound pharmacological evaluation
Testing compound as research object, adopts tetrazolium-based colorimetric assay, i.e. mtt assay to MCF-7 (human breast cancer cell) and HeLa (human cervical carcinoma cell) tumour cell.Active half-inhibition concentration (IC
50) represent, unit is μM.
For MCF-7 cell:
Get the MCF-7 cell of 0.25% tryptic digestion monolayer culture, be made into single cell suspension, be inoculated in 96 orifice plates with the RPMI1640 nutrient solution containing 10% foetal calf serum, every hole 200 μ L(is containing 3 × 10
4~ 5 × 10
4individual cell).Culture plate is put into CO2 incubator, at 37 DEG C, 5%CO
2under condition, add the testing compound of different concns after culturing cell is adherent, each compound tests 4 concentration (1 × 10
-5, 1 × 10
-6, 1 × 10
-7, 1 × 10
-8mol/L), control group adds solvent isopyknic with administration group.Continue at CO
2in 37 DEG C, 5%CO in incubator
272h is cultivated under condition.Every hole adds 20 μ LMTT solution (5mg/mL), continue to hatch 4h in 37 DEG C, stop to cultivate, discard culture supernatant in hole, every hole adds 150 μ LDMSO, gentle agitation 10min, select 570nm wavelength, microplate reader measures each hole absorbance value (OD value), with the inhibiting rate of formulae discovery compound on tumor cell the following, and calculates IC
50.Repeated test 3 times, averages as net result.
| Compound | MCF-7(IC 50μM) | HeLa(IC 50μM) |
| (1) | 4.28 | 7.21 |
| (2) | 14.63 | ＞100 |
| (3) | 19.44 | ＞100 |
| (4) | 8.25 | 10.09 |
| (5) | 7.55 | 7.38 |
| (6) | 6.28 | 9.41 |
| (7) | 10.48 | 13.56 |
| (8) | 10.55 | 12.16 |
Known by above-mentioned data, compound 1 pair of MCF-7 and HeLa tumour cell has obvious inhibit activities, has the value of research further; Compound 2 and 3 pairs of MCF-7 tumour cells all show more weak suppression and live, and to HeLa tumour cell, almost unrestraint is active; Compound 8 and 10 shows poor inhibit activities to two kinds of tumour cells; All the other compounds also show different inhibit activities to two kinds of tumour cells.Structure-activity Relationship shows the-NR on pyrazole ring
3r
4for indole structure is the anti-tumor activity being conducive to improving compound, but be connected into alkylsulfonyl again or carboxyl likely reduces its anti-tumor activity when it.
Should be understood that, for those of ordinary skills, can be improved according to the above description or convert, and all these improve and convert the protection domain that all should belong to claims of the present invention.
Claims (1)
1. a benzamide compound, is characterized in that, its structural formula is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310413643.4A CN103467452B (en) | 2013-09-11 | 2013-09-11 | A kind of benzamide compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310413643.4A CN103467452B (en) | 2013-09-11 | 2013-09-11 | A kind of benzamide compound and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103467452A CN103467452A (en) | 2013-12-25 |
| CN103467452B true CN103467452B (en) | 2015-11-18 |
Family
ID=49792528
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310413643.4A Expired - Fee Related CN103467452B (en) | 2013-09-11 | 2013-09-11 | A kind of benzamide compound and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103467452B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772262B (en) * | 2014-02-24 | 2015-10-14 | 陕西理工学院 | A kind of different phthalimide derivatives and application thereof with anti-tumor activity |
| CN108997176B (en) * | 2018-07-27 | 2021-07-02 | 温州医科大学 | 4-chloro-N-substituted phenyl-3-sulfonyl aminobenzamide compound, and preparation and anti-tumor application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7119120B2 (en) * | 2001-12-26 | 2006-10-10 | Genzyme Corporation | Phosphate transport inhibitors |
| EP2591354B1 (en) * | 2010-07-07 | 2016-09-07 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| JP5823514B2 (en) * | 2010-07-07 | 2015-11-25 | アーデリクス，インコーポレーテッド | Compounds and methods for inhibiting phosphate transport |
-
2013
- 2013-09-11 CN CN201310413643.4A patent/CN103467452B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN103467452A (en) | 2013-12-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102295635B (en) | Antitumor medicament tetralin amide compounds and pharmaceutically acceptable salts thereof as well as preparation method and application of antitumor medicament tetralin amide compounds | |
| CA2884832C (en) | Means and method for treating solid tumours | |
| CN103181922A (en) | Application of piperidone-containing single-carbonyl curcumin compound in preparation of anti-inflammatory drug | |
| CN103467452B (en) | A kind of benzamide compound and application thereof | |
| Bu et al. | Cocrystallization-driven self-assembly with vanillic acid offers a new opportunity for surmounting fast and excessive absorption issues of antifungal drug 5-fluorocytosine: a combined theoretical and experimental research | |
| CN110922415B (en) | Synthesis and application of novel anti-tumor active compound | |
| CN104725372B (en) | Tetracyclic indole alkaloid derivative as well as preparation method and application thereof | |
| CN104892707B (en) | A kind of controlled syntheses compound CLCN and its application in medicines resistant to liver cancer | |
| CN103864776B (en) | A kind of Tegafur derivative containing 1,3,4-thiadiazoles heterocycle and amide group | |
| CN103483187B (en) | 4-ethyoxyl-2-hydroxyl-6-methyl benzoic acid and Pharmaceutical composition thereof and application | |
| CN103664972B (en) | Diamino dihydrogen triazine derivative, its salt, preparation method, composition and application | |
| CN104327083A (en) | Substituted-indanyl amide-type compounds and pharmaceutically acceptable salt and preparation method and application thereof | |
| CN103396400A (en) | Pyrazole amide compounds, and preparation method and application thereof | |
| CN103145739A (en) | Pyrimido thiazole type compounds with anti-inflammatory effect and application thereof in preparation of anti-inflammatory medicaments | |
| CN107501219A (en) | Asymmetric ginger-colored chlorins compound and its application in anti-gastric cancer medicament is prepared | |
| CN102702116B (en) | 4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound or pharmaceutically-acceptable salt thereof and preparation methods and applications thereof | |
| CN101759692B (en) | Preparation and use of thiocarbonyl compound | |
| CN103772262B (en) | A kind of different phthalimide derivatives and application thereof with anti-tumor activity | |
| CN103833651B (en) | Weary oxygen selective anti-tumor predrug indenes (1,2-b) quinoxaline-5,10-dioxy-11-ketoxime ether derivative | |
| CN102746173A (en) | Emodin derivative and preparation method and application thereof | |
| CN104326965B (en) | Indole-containing amine compounds, and preparation method and application thereof | |
| CN102276554B (en) | 4-((2-amino-5-sulfydryl-1,3,4-thiadiazole)-methyl)-benzamide derivative as well as preparation method and application thereof | |
| CN103408541A (en) | Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof | |
| CN103382198B (en) | Pyrazole amide compound, and preparation method thereof and application | |
| CN103387568B (en) | Compounds, preparation method thereof and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20151118 Termination date: 20160911 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |