CN109438365B - N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide derivative - Google Patents

N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide derivative Download PDF

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CN109438365B
CN109438365B CN201811484075.6A CN201811484075A CN109438365B CN 109438365 B CN109438365 B CN 109438365B CN 201811484075 A CN201811484075 A CN 201811484075A CN 109438365 B CN109438365 B CN 109438365B
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difluorobenzenesulfonamide
aminophenyl
trifluoromethyl
pyrimidinyl
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CN109438365A (en
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夏正策
张玉琪
罗忠峰
王辉
曾卓
朱孝峰
邓蓉
冯公侃
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South China Normal University
Sun Yat Sen University Cancer Center
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Sun Yat Sen University Cancer Center
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/42—One nitrogen atom
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Abstract

The invention discloses N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide with anti-tumor activity, derivatives thereof and a synthesis method thereof, wherein the N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide has a structural general formula shown in a formula I. The synthesis method of the invention adopts 2, 6-difluorobenzenesulfonyl chloride and m-phenylenediamine to carry out nucleophilic substitution to obtain the sulfonamide. Then the amino group in the N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide reacts with cyanamide to obtain guanidine salt. A series of differently substituted 1, 3-dione compounds were then prepared. Finally, guanidine salt reacts with 1, 3-diketone to generate a pyrimidine ring, and the active group of the pyrimidine ring is skillfully introduced into the molecular structure. The invention adjusts the anti-tumor proliferation inhibition activity, solubility and the like of the compound by changing the substituent on the pyrimidine ring, and has the advantages of simple and convenient adjustment.

Description

N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide derivative
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to N- (3- ((4-trifluoromethyl) -2-pyrimidyl) aminophenyl) -2, 6-difluorobenzenesulfonamide with anti-tumor activity, derivatives thereof, and synthesis methods and applications thereof.
Background
Cancer, also known as malignant tumor, has a very high morbidity and mortality rate and is a serious medical topic for the related treatment methods. In order to search for an effective method for treating cancer, scientists made continuous efforts to treat malignant lymphoma by using nitrogen mustard for the first time in the last 40 th century and obtain good curative effect, and the research and development and application of the antineoplastic medicine are marked to enter the rapid development period.
In the research of antitumor drugs, nitrogen-containing heterocyclic compounds, analogs and derivatives have attracted extensive attention because of having various biological and pharmacological activities. Meanwhile, after fluorine-containing groups or fluorine atoms are introduced into the drug molecules, the membrane permeability and lipid solubility of the molecules can be changed, so that the bioavailability and the drug effect of the drug are improved. The fluorine-containing medicine has the advantages of strong stability, difficult generation of drug resistance, high biological activity and the like, so the fluorine-containing medicine has wide prospects in the development of anti-tumor medicines, anti-inflammatory medicines, central nervous system medicines, antiviral medicines and other medicines.
Common derivatives of nitrogen-containing heterocyclic pyrimidine, thiazole, imidazole and the like have various biological activities such as bactericidal activity, anti-inflammatory activity, antitumor activity and the like, particularly 5-fluorouracil is the first antimetabolite designed and synthesized, is recognized as the most widely-applied anti-pyrimidine medicine clinically at present, has good curative effect on digestive tract cancer and other solid tumors, and plays an important role in the treatment of medical oncology. However, under the action of dihydropyrimidine reductase in liver, intestinal mucosa and other tissues, the pyrimidine ring of 5-fluorouracil is easily reduced to 5-fluoro-5, 6-dihydrouracil and inactivated, and if the human body lacks the enzyme due to heredity, the sensitivity to the drug is greatly enhanced, and few people lack the enzyme and show strong drug toxicity to the drug with the commonly used dosage. In addition, metabolites of 5-fluorouracil can also be doped into RNA and DNA in the form of pseudo metabolites, influence cell functions and generate cytotoxicity, so that the research on pyrimidine antitumor drugs with novel structures has important theoretical significance and practical value.
Disclosure of Invention
The primary object of the present invention is to provide N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof.
The invention also aims to provide a synthesis method of the N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof.
The invention further aims to provide application of the N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof in preparation of anti-cancer cell proliferation medicaments.
The purpose of the invention is realized by the following technical scheme:
the structure of N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof is shown in a formula I:
Figure BDA0001894034240000021
wherein R is CF3Alkyl, aryl, hydrogen;
the alkyl group is preferably an alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl group;
the aryl is halophenyl, phenyl methyl ether and phenylalkyl;
the halogenophenyl is preferably fluorophenyl or bromophenyl;
the alkyl moiety of the above phenylalkyl group is preferably an alkyl group having 1 to 6 carbon atoms, and particularly preferably a methyl group or a butyl group.
Specifically, the N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof are the following compounds:
Figure BDA0001894034240000031
in the process of synthesizing the compound of formula I, a key intermediate 1, 3-diketone is obtained, and the structure of the intermediate is shown as formula II:
Figure BDA0001894034240000032
specifically, the 1, 3-diketone is the following compound:
Figure BDA0001894034240000041
the synthesis method of the N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and the derivatives thereof comprises the following steps:
(1) m-phenylenediamine and 2, 6-difluorobenzenesulfonyl chloride are used as raw materials, 4-dimethylaminopyridine and anhydrous triethylamine are used as alkali, anhydrous tetrahydrofuran is used as a solvent, and the reaction is carried out for 2 hours at normal temperature to obtain light yellow solid N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide with the yield of 85%;
the molar ratio of the m-phenylenediamine to the 2, 6-difluorobenzenesulfonyl chloride is preferably 1.0: 1.1;
Figure BDA0001894034240000042
(2) taking N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide, cyanamide and hydrochloric acid as raw materials, taking acetonitrile as a solvent, heating to 82 ℃ and refluxing for 16h to obtain a white product guanidine salt (N- (3-guanidinophenyl hydrochloride) -2, 6-difluorobenzenesulfonamide), wherein the yield is 80%;
the molar ratio of the N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide to the cyanamide to the hydrochloric acid is preferably 1.0:2.5: 2.0;
Figure BDA0001894034240000043
(3) mixing ethyl trifluoroacetate with ketones, reacting for 12 hours by using anhydrous tetrahydrofuran as a solvent and sodium or sodium hydride as a catalyst to obtain an intermediate 1, 3-diketone with the yield of 80%;
the molar ratio of the ketones to the ethyl trifluoroacetate is preferably 1: 2;
the structure of the ketone is shown as the following formula:
Figure BDA0001894034240000051
(4) guanidine salt (N- (3-guanidinophenyl hydrochloride) -2, 6-difluorobenzenesulfonamide) and 1, 3-diketone are used as raw materials, sodium hydroxide or sodium carbonate is used as alkali, acetonitrile or methanol is used as a solvent, heating is carried out at 82 ℃ and refluxing is carried out for 12h, so as to obtain a final product, wherein the yield is 60%;
the molar ratio of the N- (3-guanidinophenyl hydrochloride) -2, 6-difluorobenzenesulfonamide to the sodium hydroxide to the 1, 3-butanedione is preferably 1.0:1.1: 2.0.
Figure BDA0001894034240000052
In the synthesis method, nucleophilic substitution is carried out on 2, 6-difluorobenzenesulfonyl chloride and m-phenylenediamine under the condition that 4-dimethylaminopyridine is used as a catalyst and anhydrous triethylamine is used as alkali, so as to obtain the sulfonamide. Then the amino group in the N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide reacts with cyanamide to obtain guanidine salt. A series of differently substituted 1, 3-dione compounds can then be obtained by reacting the esters with sodium metal, aryl ketones. Finally, guanidine salt and different substituted 1, 3-diketone compounds are subjected to ring closure under the catalysis of alkali to generate a pyrimidine ring, and the active group of the pyrimidine ring is skillfully introduced into a molecular structure.
The N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof can be applied to the preparation of anti-cancer cell proliferation medicaments;
the cancer cells comprise human nasopharyngeal carcinoma cells CNE1, CNE2, HONE1, SUNE1, human breast cancer cells MCF-7, human liver cancer cells Be17402 and SMMC7221, and have strong antiproliferative inhibition activity. The antiproliferative inhibitory activity of other antitumor cancer cells is to be examined.
Compared with the prior art, the invention has the following advantages and effects:
1. the synthesis method of the N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and the derivatives thereof is simple and easy, the raw materials are simple and easy to obtain, and the yield is high.
2. The N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and the derivatives thereof have stronger antiproliferative inhibition activity.
3. The N- (3- ((4-trifluoromethyl) -2-pyrimidyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and the derivatives thereof can adjust the antitumor proliferation inhibition activity, the solubility and the like of the compound by changing the substituent on the pyrimidine ring, and have the advantages of simple and convenient adjustment.
Drawings
FIG. 1 is a graph of the inhibition rate of YW-XB compound on tumor cells.
FIG. 2 is a graph showing the inhibition rate of YW-FB on tumor cells.
FIG. 3 is a compound YW-OCH3B inhibition rate of tumor cells.
FIG. 4 is a graph showing the inhibition rate of YW-TBUB compound on tumor cells.
FIG. 5 is compound YW-CH3B inhibition rate of tumor cells.
FIG. 6 is compound YW-CH3The inhibition rate of tumor cells is shown in a graph.
FIG. 7 is Compound YW-CF3The inhibition rate of tumor cells is shown in a graph.
FIG. 8 is a graph showing the inhibition rate of compound YW-B on tumor cells.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Examples of the Synthesis methods
A method for synthesizing N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof, comprising the following steps:
(1) synthesis of N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide
M-phenylenediamine (1.6g, 14.8mmol) and 4-dimethylaminopyridine (0.09g, 0.74mmol) were placed in a 100mL round-bottom flask, and after evacuation, 30mL of anhydrous tetrahydrofuran and 10mL of anhydrous triethylamine were added. Stirring at normal temperature to dissolve, then adding 2, 6-difluorobenzenesulfonyl chloride (3.13g,15mmol) dropwise, reacting at room temperature for 2h after the dropwise addition to obtain yellow turbid liquid, and distilling off part of the solvent under reduced pressure. Then 100mL of CH was added2Cl2The organic layer was washed with water (100 mL. times.3) and saturated brine (100 mL. times.2), and the organic layer was washed with anhydrous Na2SO4Drying, rotary steaming to remove CH2Cl2Column chromatography was performed with petroleum ether ethyl acetate ═ 2:1(Rf ═ 0.3) as the eluent to give a pale yellow solid (structure below) in 85% yield.
Figure BDA0001894034240000071
1H NMR(400MHz,DMSO-d6)δ(ppm):10.49(s,1H),7.79–7.57(m,1H),7.25(t,J＝9.0Hz,2H),6.84(t,J＝8.0Hz,1H),6.37(s,1H),6.28(d,J＝7.9Hz,1H),6.22(d,J＝8.0Hz,1H).19F NMR(400MHz,DMSO-d6)δ(ppm):-107.70(s,2F).13C NMR(101MHz,DMSO-d6)δ(ppm):160.33,157.92,157.63,149.71,138.21,136.28,130.42,116.76,115.65,113.70,111.08,107.14,105.36.HRMS:C12H10N2O2F2S for[M]+,calculated 284.0431,found 284.0435.
(2) Synthesis of N- (3-guanidinophenyl hydrochloride) -2, 6-difluorobenzenesulfonamide
N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide (1.68g,6mmol), cyanamide (0.62g,15mmol) and 30mL of acetonitrile were put in a 100mL round-bottomed flask, and the mixture was stirred at room temperature to dissolve a solid. Then slowly adding 1mL (12mmol) of hydrochloric acid, heating and refluxing for 16h, removing acetonitrile by rotary evaporation, adding Na2CO3The solution (20mL) was filtered at rest and the filter cake was washed with ethanol to give a white solid (structure below) in 80% yield.
Figure BDA0001894034240000072
1H NMR(400MHz,DMSO-d6)δ(ppm):11.18(s,1H),10.05(s,1H),7.79–7.67(m,1H),7.57(s,4H),7.31(dt,J＝12.7,8.6Hz,3H),7.04(d,J＝8.0Hz,1H),7.01(s,1H),6.93(d,J＝8.0Hz,1H).19F NMR(400MHz,DMSO-d6)δ(ppm):-107.77(s,2F).13C NMR(101MHz,DMSO-d6)δ(ppm):161.52,160.55,158.03,156.31,138.62,136.70,130.97,119.93,117.00,116.39,114.68,114.14,113.94.HRMS:C12H13O2N4F2S for[M+H+],calculated 327.0722,found 327.0721.
(3) Synthesis of key intermediates 1, 3- dione compounds 4 and 7
P-fluoroacetophenone (0.69g,5mmol) or p-bromoacetophenone (0.99g,5mmol) and ethyl trifluoroacetate (1.42g,10mmol) were placed in a 50mL round bottom flask and placed in an ice bath, and 30mL of anhydrous tetrahydrofuran was added, after which sodium (0.69g,30mmol) was cut into fine sodium chips, slowly added to the round bottom flask, stirred, and left overnight. The reaction solution was poured into anhydrous ethanol to completely remove the residual sodium, if any, by checking whether there was any residual sodium. If no residual sodium beads exist, distilling all solvents under reduced pressure, adding 20mL of water, then adding a hydrochloric acid solution to acidify until the pH value is 2-3, and then adding 50mL of CH2Cl2The organic layer was washed with water (30 mL. times.3) and saturated brine (30 mL. times.2), and the organic layer was washed with anhydrous Na2SO4Drying and spinningDistill off CH2Cl2Column chromatography was performed using petroleum ether and ethyl acetate (Rf ═ 0.3) as eluents to give red 4 and white 7 solids, respectively, in 80% yield.
Figure BDA0001894034240000081
Nuclear magnetic spectrum of compound 4:1H NMR(400MHz,CDCl3) δ (ppm) 8.05-7.93 (m,2H), 7.24-7.15 (m,2H),6.53(s, 1H.) nuclear magnetic spectrum of Compound 7:1H NMR(400MHz,CDCl3)δ(ppm):8.04–7.93(m,2H),7.24–7.13(m,2H),6.53(s,1H).
(4) antitumor target compounds YW-B, YW-FB and YW-CF3、YW-CH3、YW-XB、YW-OCH3B、YW-TBUB、YW-CH3Synthesis of B
N- (3-guanidinophenyl hydrochloride) -2, 6-difluorobenzenesulfonamide (0.5g,1.4mmol) and sodium hydroxide (0.064g, 1.6mmol) were put in a 50mL round-bottomed flask, 30mL of acetonitrile was added, and the mixture was stirred at room temperature for 30 min. Then 4,4, 4-trifluoro-1-phenyl-1, 3-butanedione (0.34g,1.6mmol), 4,4, 4-trifluoro-1- (4-fluorophenyl) butane-1, 3-dione, 1,1,1,5,5, 5-hexafluoroacetylacetone (0.33g,1.6mmol), 1,1, 1-trifluoro-acetylacetone (0.24g,1.6mmol), 4,4, 4-trifluoro-1- (4-bromophenyl) butane-1, 3-dione, 4,4, 4-trifluoro-1- (4-methoxyphenyl) butane-1, 3-dione (0.40g, 1.6mmol), 4,4, 4-trifluoro-1- (4-tert-butylphenyl) butane-1, 3-dione (0.44g, 1.6mmol) or 4,4, 4-trifluoro-1- (4-methylphenyl) butane-1, 3-dione (0.37g, 1.6mmol) was heated under reflux for 12 h. Acetonitrile was removed by rotary evaporation and then 100ml CH was added2Cl2The organic layer was washed with water (100 mL. times.3) and saturated brine (100 mL. times.2), and the organic layer was washed with anhydrous Na2SO4Drying, rotary evaporating dichloromethane, and performing column chromatography with petroleum ether and ethyl acetate (Rf ═ 0.3) as eluent to obtain white solid, yellow solid, white solid and white solid, respectively. The yields were 70%, 75%, 80%, 70%, 85%, 80%, respectively. The following products were respectively obtained:
Figure BDA0001894034240000091
YW-B:1H NMR(400MHz,DMSO-d6)δ(ppm):10.91(s,1H),10.30(s,1H),8.32(d,J＝6.8Hz,2H),7.84(s,1H),7.75(s,1H),7.72–7.55(m,4H),7.51(d,J＝8.2Hz,1H),7.35–7.10(m,3H),6.84(d,J＝8.0Hz,1H)；13C NMR(101MHz,DMSO-d6)δ(ppm):167.54,160.64,160.36,158.08,157.90,140.91,137.37,135.66,131.90,129.71,129.43,128.09,124.93,122.19,119.37,117.33,115.92,114.50,113.94,113.71,113.49,111.45,103.46；19F NMR(400MHz,DMSO-d6)δ(ppm):-68.86(s,3F),-107.58(s,2F)；HRMS:C23H16O2N4F5S for[M+H+],calculated 507.0909,found 507.0910.
Figure BDA0001894034240000092
YW-FB:1H NMR(400MHz,DMSO-d6)δ(ppm):10.88(s,1H),10.31(s,1H),8.26(d,J 8.7,2H),7.91–7.56(m,5H),7.45(d,J 8.1,1H),7.29–7.13(m,3H),6.81(d,J 7.9,1H)；13C NMR(400MHz,DMSO-d6)δ(ppm):166.37,166.11,163.62,160.61,160.28,158.07,140.88,137.62,136.28,132.39,130.71,129.72,116.47,116.26,114.42,113.96,113.70,111.73,103.67；19F NMR(400MHz,DMSO-d6)δ-68.90(s,3F),-107.63(dd,J＝9.6,6.2Hz,2F),-108.54(dq,J＝8.8,5.5Hz,1F)；HRMS:C23H19O2N4F8S for[M+H+],calculated 507.0814,found 507.0809.
Figure BDA0001894034240000101
YW-CF3:1H NMR(400MHz,DMSO-d6)δ(ppm):10.87(s,1H),10.15(s,1H),7.81(s,1H),7.74–7.60(m,1H),7.39(d,J＝8.2Hz,1H),7.30–7.07(m,4H),6.78(d,J＝8.0Hz,1H)；13C NMR(101MHz,DMSO-d6)δ(ppm):160.53,160.12,158.44,158.04,139.84,137.78,136.28,129.83,124.49,121.56,118.97,117.25,116.32,115.20,114.01,113.72,112.00,103.68.(s,2F)；19F NMR(400MHz,DMSO-d6)δ(ppm):-107.73(s,2F),δ-69.11；HRMS:C18H11O2N4F8S for[M+H+],calculated 499.0469,found 499.0468.
Figure BDA0001894034240000102
YW-CH3:1H NMR(400MHz,DMSO-d6)δ(ppm):10.87(s,1H),10.15(s,1H),7.81(s,1H),7.74–7.57(m,1H),7.39(d,J＝9.2Hz,1H),7.31–7.04(m,4H),6.78(d,J＝8.0Hz,1H),2.49(s,3H)；13C NMR(101MHz,DMSO-d6)δ(ppm):171.78,160.63,159.62,157.91,154.77,153.67,140.91,137.38,136.37,135.67,129.08,122.18,119.36,115.61,113.85,111.06,107.30,24.42；19F NMR(400MHz,DMSO-d6)δ(ppm):-69.15(s,3F),-107.64(s,2F)；HRMS:C18H14O2N4F5S for[M+H+],calculated 445.0752,found 445.0752.
Figure BDA0001894034240000103
YW-XB:1H NMR(400MHz,DMSO-d6)δ(ppm):10.88(1H,s),10.31(1H,s),8.26(2H,d,J8.7),7.91–7.56(5H,m),7.45(1H,d,J8.1),7.29–7.13(3H,m),6.81(1H,d,J7.9)；13C NMR((400MHz,DMSO-d6)δ(ppm):166.41,160.58,160.29,158.02,140.83,137.59,136.30,135.06,132.38,131.93,131.23,130.10,129.75,126.16,122.47,119.74,117.15,116.26,114.53,113.9,113.72,111.73,103.78；19F NMR(400MHz,DMSO-d6)δ(ppm):-68.91(s,3F),-107.63(s,2F)；HRMS:C23H15O2N4F5S for[M+H+],calculated 585.0014,found 585.0009.
Figure BDA0001894034240000111
1H NMR(400MHz,DMSO)δ10.89(s,1H),10.19(s,1H),8.29(d,J＝8.8Hz,2H),7.78–7.62(m,3H),7.51(d,J＝8.2Hz,1H),7.23(dd,J＝12.3,6.1Hz,3H),7.10(d,J＝8.8Hz,2H),6.82(d,J＝7.8Hz,1H),3.86(s,3H)；13C NMR(101MHz,DMSO)δ166.94,162.80,160.64,160.27,158.08,156.01,141.06,137.58,136.27,129.92,129.67,128.17,125.37,122.63,119.89,117.23,116.17,114.74,114.31,113.96,113.74,111.76,103.00；19F NMR(400MHz,DMSO-d6)δ(ppm):-68.63(s,3F),-107.81(s,2F)；HRMS:C24H18O3N4F5S for[M+H+],calculated 537.1014,found 537.1008.
Figure BDA0001894034240000112
YW-CH3B:1H NMR(400MHz,DMSO)δ10.92(s,1H),10.28(s,1H),8.25(d,J＝8.2Hz,2H),7.86–7.78(m,2H),7.69(td,J＝8.4,4.2Hz,1H),7.54(d,J＝8.2Hz,1H),7.41(d,J＝8.1Hz,2H),7.26(t,J＝8.7Hz,3H),6.86(d,J＝7.9Hz,1H),5.79(s,1H),2.44(s,3H)；13C NMR(101MHz,DMSO)δ167.39,160.60,160.32,158.04,156.22,142.51,141.00,137.59,136.26,133.12,130.01,129.68,128.04,122.58,119.84,117.23,116.19,114.40,113.92,113.69,111.80,103.43,55.33,21.48；19F NMR(376MHz,DMSO)δ-68.93(s,3F),-107.56(dd,2F)；HRMS:C24H18O3N4F5S for[M+H+],calculated 521.1065,found 521.1060.
Figure BDA0001894034240000121
YW-TBHB:1H NMR(400MHz,DMSO)δ10.87(s,1H),10.22(s,1H),8.20(d,J＝8.4Hz,2H),7.76(s,1H),7.68(s,1H),7.66–7.60(m,1H),7.56(d,J＝8.5Hz,2H),7.50(d,J＝8.4Hz,1H),7.23–7.15(m,3H),6.80(d,J＝7.8Hz,1H),1.32(s,9H)；13C NMR(101MHz,DMSO)δ167.37,160.59,160.34,158.07,156.35,156.00,155.30,140.97,137.58,136.29,133.19,129.69,127.93,126.23,122.57,116.20,114.37,113.96,113.93,113.73,113.70,111.82,103.53,35.16,31.35；19F NMR(376MHz,DMSO)δ-68.89(s),-107.57(dd,J＝9.6,6.3Hz)；HRMS:C27H24O2N4F5S for[M+H+],calculated 563.1535,found 563.1528.
effects of the embodiment
Research on in vitro antitumor activity of N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof
1. The MTT [3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide ] method is adopted to determine the minimum inhibitory bacteria concentration of the new compound. The specific operation is as follows:
placing a certain amount of tumor cells in culture medium, and culturing at 37 deg.C and 100% humidity with 5% CO2Culturing in an incubator. Then, 100 mu L of cell suspension with the concentration of 3-5 multiplied by 104/mL is added into each 96-hole of the cells in the logarithmic growth phase. Guanidine salt (a4) and 5 target products 6 samples were set up with 5 concentration gradients per sample, three replicate wells per concentration, and the corresponding controls were set up with DMSO solutions. The samples were added to the corresponding wells at 37 ℃ with 5% CO2Culturing in an incubator for 24h, adding 20mL of 5mg/mL MTT solution into each well, adding DMSO for dissolving after reacting for 4h, and measuring the OD value at 570nm by using a BIR-600 enzyme linked immunosorbent assay instrument.
The inhibition ratio was calculated, and the inhibition ratio IR (%) × 100% (1-drug-use group average OD value/control group average OD value). IR > 50% sensitive, positive; 30% < IR < 50% is moderately sensitive; IR > 30% was insensitive and negative.
The inhibition rates of N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and its derivatives are shown in table 1:
TABLE 1 inhibition rate IR of different functional group compound molecules on tumor cells
Figure BDA0001894034240000131
Figure BDA0001894034240000141
And (4) preparing a standard curve of the cell growth inhibition rate according to the calculated inhibition rate IR value, and obtaining the relation between the inhibition rate and the concentration of the corresponding compound on the standard curve.
The inhibition curves of N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and its derivatives are shown in FIGS. 1-8. As shown in the figure, compounds YW-FB, YW-XB, YW-B, YW-CF3、YW-OCH3B、YW-TBUB、YW-CH3B concentration and inhibition rate to tumor cells are in positive correlation, and YW-CH3Then a negative correlation is present. At optimum concentration, compound YW-CH3B is most sensitive to the inhibition of human nasopharyngeal carcinoma cells CNE2, and is sensitive to the inhibition of other 6 tumor cells; compound YW-CH3None were sensitive to the 7 tumor cell inhibitory activities tested. The inhibitory activity of other compounds on cancer cells is shown in table 2.
Computing IC50The value is obtained. IC (integrated circuit)50Defined as the concentration of compound at which 50% of the tumor cells are apoptotic, can be used as a measure of the ability of a compound to induce apoptosis. The stronger the induction, the IC50The lower the value. Through IC50Values may also inversely indicate the degree of tolerance of a certain cell to a compound.
The inhibition ratios of N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and its derivatives are shown in table 3.
As can be shown from the data in Table 3, when the R group is aromatic ring, the activity of the compound is the highest, and the compound has good activity on human nasopharyngeal carcinoma cells, human liver cancer cells and human breast cancer cells. Wherein the compounds YW-B, YW-XB, YW-FB and YW-CH3B. YW-TBUB has better inhibition effect on experimental tumor cells. From the data, it can be seen that the compound YW-TBUB inhibits the proliferation of human nasopharyngeal carcinoma cell CNE250The value is as low as 2.89 mu mol/L, and YW-TBUB can be seen to have stronger effect on human nasopharyngeal carcinoma cell CNE2Anti-proliferation inhibitory activity.
In conclusion, the invention systematically describes the synthesis of target products and the research of antitumor activity, eight brand-new compounds are designed and synthesized, and the structure is developed1H-NMR、19F-NMR and HRMS confirmation. In addition, the target compounds are subjected to in vitro anti-human nasopharyngeal carcinoma cells CNE2, HONE1 and SUNE1, human lung adenocarcinoma cells A549 and GLC82, human breast cancer cells MCF-7, and human liver cancer cells Be17402 and SMMC7221 for proliferation activity test, and the test proves that the target compounds have better anti-tumor activity.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Figure BDA0001894034240000161
Figure BDA0001894034240000171

Claims (9)

  1. N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof, characterized by the structure shown in formula I:
    Figure FDA0003498147340000011
    wherein R is phenyl, halophenyl, methyletherphenyl, alkylphenyl or CF3；
    The alkyl is an alkyl with 1-6 carbon atoms.
  2. 2. N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof according to claim 1, characterized in that: the halogenophenyl is phenyl substituted by F or Br.
  3. 3. N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof according to claim 1, characterized by the following compounds:
    Figure FDA0003498147340000012
    Figure FDA0003498147340000021
  4. 4. a process for the synthesis of N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide and derivatives thereof as claimed in any one of claims 1 to 3, characterized by comprising the steps of:
    (1) m-phenylenediamine and 2, 6-difluorobenzenesulfonyl chloride are used as raw materials, 4-dimethylaminopyridine and anhydrous triethylamine are used as alkali, anhydrous tetrahydrofuran is used as a solvent, and the reaction is carried out for 2 hours at normal temperature to obtain N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide;
    (2) taking N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide, cyanamide and hydrochloric acid as raw materials, taking acetonitrile as a solvent, heating to 82 ℃ and refluxing for 16h to obtain a guanidine salt (N- (3-guanidinophenyl hydrochloride) -2, 6-difluorobenzenesulfonamide);
    (3) mixing ethyl trifluoroacetate with ketones, reacting for 12 hours by taking anhydrous tetrahydrofuran as a solvent and sodium or sodium hydride as a catalyst to obtain an intermediate 1, 3-diketone;
    the structure of the ketone is shown as the following formula:
    Figure FDA0003498147340000022
    the structure of the intermediate 1, 3-diketone is shown as formula II:
    Figure FDA0003498147340000023
    (4) guanidine salt (N- (3-guanidinophenyl hydrochloride) -2, 6-difluorobenzenesulfonamide) and 1, 3-diketone are used as raw materials, sodium hydroxide or sodium carbonate is used as alkali, acetonitrile or methanol is used as a solvent, and the mixture is heated at 82 ℃ and refluxed for 12 hours to obtain a final product.
  5. 5. The method of synthesis according to claim 4, characterized in that:
    the molar ratio of the m-phenylenediamine to the 2, 6-difluorobenzenesulfonyl chloride in the step (1) is 1.0: 1.1;
    the molar ratio of the N- (3-aminophenyl) -2, 6-difluorobenzenesulfonamide, the cyanamide and the hydrochloric acid in the step (2) is 1.0:2.5: 2.0.
  6. 6. The method of synthesis according to claim 4, characterized in that:
    the molar ratio of the ketones to the ethyl trifluoroacetate in the step (3) is 1: 2;
    and (4) the molar ratio of the N- (3-guanidinophenyl hydrochloride) -2, 6-difluorobenzenesulfonamide to the sodium hydroxide to the 1, 3-diketone is 1.0:1.1: 2.0.
  7. 7. The method of synthesis according to claim 4, characterized in that: the intermediate 1, 3-diketone is the following compound:
    Figure FDA0003498147340000031
  8. 8. use of N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide or a derivative thereof according to any one of claims 1 to 3 for the preparation of a medicament for the proliferation of anticancer cells.
  9. 9. Use according to claim 8, characterized in that: the cancer cells are human nasopharyngeal carcinoma cells CNE1, CNE2, HONE1, SUNE1, human breast cancer cells MCF-7, human liver cancer cells Be17402 and SMMC 7221.
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