CN111875601A - Synthetic method and application of indolizine compound - Google Patents
Synthetic method and application of indolizine compound Download PDFInfo
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Abstract
A synthetic method of indolizine compounds comprises the following steps: mixing the benzopyrone derivative, the bromopyridinium salt derivative, the base and the solvent in a 10ml round-bottom flask, and stirring for 2-48 hours at 25-100 ℃; after the reaction is finished, the crude product is purified by silica gel chromatography to obtain a target compound, the structural formula of which is shown as formula I,
Description
Technical Field
The invention belongs to the technical field of chemistry and medicine, and particularly relates to a preparation method of a novel indolizine compound and application of the compound in treating tumors.
Background
Cancer (malignant tumor) is one of the diseases that seriously threaten the global human health, and is also a great problem facing the medical field all over the world. According to epidemiological investigation, the global cancer incidence rate is up to 2 per thousand in 2018. In China, about 380 million new cancer cases and about 229 million deaths are caused each year, the average annual incidence rate of the cancer is increased by about 3.9 percent, the incidence rate and the mortality rate are on the annual increasing trend, and the treatment and the prevention of the cancer are widely regarded. At present, the treatment methods of tumors mainly comprise surgical excision, radiotherapy and chemotherapy, but mainly comprise chemical drug treatment. The current clinical chemical drugs for treating cancer are in a wide variety, such as platinum, nitrogen mustard, triazole and the like, but most drugs are limited in application due to high toxicity, multiple adverse reactions and low bioavailability. Therefore, the development of highly effective and low toxic anticancer drugs has become a key research topic in the field of current medicinal chemistry.
In view of the potential application of indolizine anticancer drugs in tumor treatment, research surrounding small molecule drugs with indolizine skeleton as core pharmacophore is the current hotspot. Among the indolizines found, the known biological activities are antibacterial, antitubercular, anticancer, anti-inflammatory, antioxidant, antihistaminic and uterotrophic activities, and may also be useful as aromatase inhibitors, phosphodiesterase inhibitors, phosphatase inhibitors and Angiotensin Converting Enzyme (ACE) inhibitors. In combination with the research work, the novel indolizine compound is further found to have potential value in the treatment of malignant tumors.
Disclosure of Invention
The invention aims to solve the technical problem that a novel substituted indolizine compound can effectively inhibit various cancers or tumors.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthetic method of indolizine compounds comprises the following steps: the benzopyrone derivative, bromopyridinium salt derivative, base and solvent were mixed in a 10ml round bottom flask and stirred at 25 ℃ to 100 ℃ for 2 to 48 hours. After the reaction is finished, the crude product is purified by silica gel chromatography to obtain a target compound, the structural formula of which is shown as formula I,
in the above structural formula:
R1independently selected from one or more of H, halogen, alkyl, hydroxyl, amino, carboxyl, carbonyl, ester group, cyano, alkynyl, alkenyl, phenyl and aryl;
R2is independently selected from one or more of H, hydroxyl, alkoxy, phenyl, pyridyl and aryl;
X1selected from C and N;
X2selected from OH and SH;
R3independently selected from H, halogenAnd one or more of an element, an alkyl group, a hydroxyl group, an amino group, a carboxyl group, a carbonyl group, an ester group, a cyano group, an alkynyl group, an alkenyl group, a phenyl group, a pyridine, a thiophene, a heterocycle and an aryl group.
The aromatic group is selected from phenyl, naphthyl, anthryl, phenanthryl, pyridyl, thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, indolizinyl, quinolyl, indolinyl, benzothiazolyl, benzisothiazolyl, triazolopyridyl, indolizinyl, benzoxazolyl, triazolopyridyl, pyridopyrazinyl, quinazolinyl, benzooxadiazolyl, benzothiadiazolyl, benzoindazinyl; the alkyl group is C1-10A straight or branched chain saturated carbon chain; the halogen is selected from fluorine, chlorine, bromine and iodine.
The synthetic method of indolizine compound comprises the steps of mixing benzopyrone, bromopyridinium salt, alkali and solvent in a 10ml round-bottom flask, and stirring for 12 hours at 80 ℃; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.
The alkali is selected from one of DBU, DIPEA, potassium carbonate, sodium carbonate, potassium acetate, potassium hydroxide and sodium hydroxide; the solvent is selected from one of 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, toluene, NMP and THF.
The base is preferably DBU; the solvent is preferably 1, 4-dioxane.
The synthetic method of indolizine compound comprises the steps of mixing benzopyrone, bromopyridinium salt and DBU in a 10ml round-bottom flask, and stirring for 6 hours at 80 ℃; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.
The synthetic method of indolizine compound comprises the steps of mixing benzopyrone, bromopyridinium salt, metal catalyst, alkali and 1, 4-dioxane in a 10ml round-bottom flask, and stirring for 6 hours at 60 ℃; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound. The metal catalyst is selected from one of cuprous iodide, cuprous bromide, cuprous chloride, cupric chloride and cupric sulfate; the base is selected from DBU, DIPEA, potassium carbonate, sodium carbonate, potassium acetate, potassium hydroxide, and sodium hydroxide.
The metal catalyst is preferably cuprous iodide; the base is preferably DBU.
The indolizine compound used for tumor or cancer is gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, intestinal cancer, nasopharyngeal cancer, breast cancer, lymph cancer, kidney cancer, pancreatic cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngeal cancer, leukemia, prostate cancer, brain tumor, squamous carcinoma, skin cancer, hemangioma, lipoma, cervical cancer and thyroid cancer.
The invention also provides methods for treating tumors or cancers, limited to in vitro cell testing.
The invention relates to the inhibitory activity of the compound on human liver cancer cells and ovarian cancer cells.
Tumor cell inhibition rate ═ 100% for [1- (experimental-blank)/(control-blank). Interpretation of terms: "alkyl" is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. "halogen" refers to fluorine, chlorine, bromine and iodine atoms. "indolizine" may also be referred to as indolizine or indolizine.
English abbreviation: DBU refers to 1, 8-diazabicycloundecen-7-ene; DIPEA refers to N, N-diisopropylethylamine; NMP refers to N-methylpyrrolidone; THF means tetrahydrofuran.
The beneficial effect of adopting above-mentioned technical scheme is:
the invention provides three different preparation methods for synthesizing novel indolizine antitumor compounds, and activity tests show that the compounds have tumor cell inhibitory activity, so that the types of candidate drugs for treating tumors are further widened.
Detailed Description
It must be noted that the examples of the present invention are for illustrating the present invention and not for limiting the present invention. Simple modifications of the invention in accordance with its spirit fall within the scope of the claimed invention.
While the foregoing specification illustrates the invention, examples are provided to illustrate the practice and significance of the invention.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The specific conditions in the examples are not limited to a certain one, and the solvent used in the preparation of the compounds 1 to 10 may be 1, 4-dioxane, N-dimethylformamide, thionyl chloride, methanol, ethanol, etc., the temperature may be in the range of 25 to 100 ℃, and the base may be DBU, triethylamine, potassium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, among which DBU is most preferable. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
In each example, NMR spectra were determined by Bruker Ascend III 400M NMR (TMS as internal standard); high resolution mass spectrometry was determined using Bruker micrtof Q II; the melting point is measured by using an X-6 precise microscopic melting point tester; the silica gel is 200-300 meshes.
Wherein, the Chinese name table of the reagent represented by the chemical formula or English letter abbreviation is as follows:
the first embodiment is as follows:
preparation of ethizole:
o-hydroxyacetophenone (10mmol) and dimethylformamide dimethyl acetal (10ml) were heated at 90 ℃ under reflux for 1 hour. The reaction was monitored on thin layer plates. After completion of the reaction, the residual solvent was removed by rotary evaporator. Then, a mixed reagent of concentrated hydrochloric acid and dichloromethane (V: V ═ 1:10) was added to the mixture, and heated under reflux at 45 ℃ for 2 hours. After cooling, the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, then brine, dried over magnesium sulfate, filtered, concentrated, and column chromatographed to give the desired ethizole. If not otherwise stated, other derivatives of ethizole are prepared by this method.
Preparation of Bromide onium salt:
ethyl bromoacetate (1.2equiv) was reacted with pyridine (1.0equiv) in THF solution at room temperature for 6 hours, and the resulting precipitate was filtered and washed twice with petroleum ether. Finally, the prepared pyridinium salt was dried under vacuum for 2 hours. If not otherwise stated, other bromonium salts are prepared in this way.
Preparation of ethyl- (2-hydroxybenzoyl) indolizine-3-carboxylate (compound 1):
the method comprises the following steps:
4H-benzopyran-4-one (0.5mmol), ethyl bromopyridylacetate onium salt (0.55mmol), 1, 8-diazabicycloundec-7-ene (DBU, 1.0mmol) and 1, 4-dioxane (3.0ml) were dissolved in a 10ml round-bottom flask and stirred at 80 ℃ for 12 hours. The reaction was detected by thin layer silica gel plate. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated in vacuo to give a crude product, which was further purified by silica gel chromatography (ethyl acetate: petroleum ether ═ 1:5) to finally obtain the objective compound 1. Yellow solid (126mg, 81%), M.p.107-108 deg.C.1H NMR (400MHz, CDCl)3)12.03(s,1H),9.58(d,J＝7.0Hz,1H),8.46(dt,J＝9.0,1.1Hz,1H),7.95–7.83(m,2H),7.52–7.45(m,1H),7.41(m,1H),7.12–7.03(m,2H),7.01–6.92(m,1H),4.42(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)193.02,162.23,161.10,140.17,134.81,131.81,128.05,127.05,125.56,120.94,120.32,118.72,118.22,115.57,115.18,112.10,60.57,14.53.HRMS(ESI+)calculated for C18H16NO4[M+H]+:310.1079,found:310.1074。
Method two
4H-benzopyran-4-one (0.5mmol), bromopyridylacetic acid ethyl ester onium salt (0.55mmol) and 1, 8-diazabicycloundecen-7-ene (DBU, 2ml) were mixed in a 10ml round-bottom flask, sealed with a rubber plug and then stirred at 80 ℃ for 6 hours. The reaction was detected by thin layer silica gel plate. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated in vacuo to give a crude product, which was further purified by silica gel chromatography (ethyl acetate: petroleum ether ═ 1:5) to finally give the target compound 1 as a yellow solid (138mg, 89%).
Method III
4H-benzopyran-4-one (0.5mmol), ethyl bromopyridylacetate onium salt (0.55mmol), cuprous iodide (0.025mmol), 1, 8-diazabicycloundec-7-ene (DBU, 1.0mmol) and 1, 4-dioxane (3.0ml) were dissolved in a 10ml round bottom flask and stirred at 80 ℃ for 12 hours. The reaction was detected by thin layer silica gel plate. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product, which was further purified by silica gel chromatography (ethyl acetate: petroleum ether ═ 1:5) to finally give the title compound 1 as a yellow solid (147mg, 95%).
Example two
Preparation of ethyl- (4-hydroxy-4 '-methoxy- [1, 1' -diphenyl ] -3-carbonyl) indolizine-3-carboxylate (compound 2):
referring to method one of example 1, the target compound 2 was prepared by replacing 4H-benzopyran-4-one (0.5mmol) with 6- (4-methoxyphenyl) -4H-benzopyran-4-one (0.5mmol) under otherwise unchanged conditions. Yellow solid (170mg, 82%), m.p.169-171 ° c.1H NMR (400MHz, CDCl3)11.87(s,1H),9.61(d, J ═ 7.0Hz,1H),8.48(d, J ═ 9.0Hz,1H),8.05(d, J ═ 2.3Hz,1H),7.99(s,1H),7.69(dd, J ═ 8.6,2.3Hz,1H), 7.51-7.47 (M,2H),7.44(M,1H), 7.15-7.08 (M,2H), 6.99-6.94 (M,2H),4.41(q, J ═ 7.1Hz,2H),3.85(s,3H),1.41(t, J ═ 7.1H), 3H), 13.101 (q, J ═ 7.1Hz,2H),3.85(s,3H),1.41(t, 13H), 13H, 13 c.57C, 54H, 3655C, 3619 # 19, 3619H +, 3619 # 3H +).34H.
EXAMPLE III
Preparation of ethyl- (2-hydroxy-4, 5-dimethoxybenzoyl) indolizine-3-carboxylate (compound 3):
referring to method one of example 1, the target compound 3 was prepared by replacing 4H-chromen-4-one (0.5mmol) with 6, 7-dimethoxy-4H-chromen-4-one (0.5mmol) under otherwise unchanged conditions. Yellow solid (143mg, 78%), m.p.142-144 ℃.1H NMR (400MHz, CDCl3) 12.61(s,1H),9.58(d, J ═ 7.1Hz,1H),8.38(d, J ═ 8.1Hz,1H),7.95(s,1H), 7.51-7.33 (m,2H), 7.14-6.95 (m,1H),6.58(s,1H),4.41(q, J ═ 7.1Hz,2H),3.96(s,3H),3.84(s,3H),1.40(t, J ═ 7.1Hz,3H), 13C NMR (101MHz, CDCl3) 191.74,161.13,160.05,155.71,141.64,139.71,127.93,126.43,124.73,120.20,115.31,114.98,113.66,112.36,112.31,100.86,60.46,56.60,56.20,14.50 HRMSs (ESI for C +) 191.74,161.13,160.05,155.71,141.64,139.71,127.93,126.43,124.73,120.20,115.31,114.98,113.66,112.36,112.31,100.86, m.p.142 ℃. c.1H, 5H, 3H, hrcl 3H20H20NO6[M+H]+:370.1291,found:370.1284。
Example four
Preparation of ethyl-1- (1-hydroxy-2-naphthoyl) indolizine-3-carboxylate (compound 4):
referring to method one of example 1, 4H-benzopyran-4-one (0.5mmol) was replaced with 4H-benzo [ H ]]Chromone-4-one (0.5mmol) under otherwise unchanged conditions to afford the target compound 4. Yellow solid (135mg, 75%), m.p.120-122 ℃.1H NMR (400MHz, CDCl3) 14.06(s,1H),9.58(d, J ═ 7.0Hz,1H),8.50(d, J ═ 8.3Hz,1H),8.47(d, J ═ 9.0Hz,1H),7.98(s,1H),7.91(d, J ═ 8.8Hz,1H),7.79(d, J ═ 8.1Hz,1H), 7.67-7.58 (m,1H),7.54(ddd, J ═ 8.1,7.0,1.1Hz,1H),7.40(ddd, J ═ 8.9,6.8,1.1, 1H),7.33(d, J ═ 8.8, 1H, 7.3H, 7.9, 7.3H, 3H, 13.93,112.42,60.55,14.55.HRMS(ESI+)calculated forC22H18NO4[M+H]+:360.1236,found:360.1229。
EXAMPLE five
Preparation of ethyl 3- (2-hydroxybenzoyl) pyrrolo [1, 2-a ] quinoline-1-carboxylate (Compound 5):
by following the procedure one of example 1, ethyl bromopicolinoacetate onium salt (0.55mmol) was replaced with ethyl bromoquinolineacetate onium salt (0.55mmol) under otherwise unchanged conditions, crude compound 5 was prepared. Further purification by silica gel chromatography (ethyl acetate: petroleum ether ═ 1:3) finally afforded the target compound 5. Yellow solid (108mg, 60%), m.p.135-137 ℃.1HNMR (400MHz, CDCl3) 12.10(s,1H),8.41(d, J ═ 8.7Hz,1H),8.28(d, J ═ 9.3Hz,1H),7.90(dd, J ═ 7.9,1.5Hz,2H),7.85(s,1H),7.82(dd, J ═ 7.9,1.2Hz,1H),7.66(m,2H), 7.56-7.47 (m,2H),7.08(dd, J ═ 8.3,0.7Hz,1H), 7.01-6.95 (m,1H),4.46(q, J ═ 7.1Hz,2H),1.44(t, J ═ 7.1H, 2H), 2H, 13.13C ═ 35C, 13C-22H18NO4[M+H]+:360.1236,found:360.1233。
EXAMPLE six
Preparation of Ethyl 5- (2-hydroxybenzoyl) pyrrolo [1, 2-b ] pyridazine-7-carboxylate (Compound 6):
by following the procedure one of example 1, ethyl bromopyridylacetate onium salt (0.55mmol) was replaced with ethyl bromopyridazineacetate onium salt (0.55mmol), and the other conditions were not changed, crude compound 6 was prepared. Further purification by silica gel chromatography (dichloromethane: methanol ═ 50:1) finally afforded the target compound 6. Yellow solid (85mg, 55%), m.p.100-102 deg.c.1 HNMR (400MHz, CDCl3) 11.92(s,1H),8.71(dd,J＝9.2,1.9Hz,1H),8.60(dd,J＝4.5,1.8Hz,1H),7.94(s,1H),7.93(dd,J＝8.0,1.6Hz,1H),7.55–7.49(m,1H),7.18(dd,J＝9.1,4.5Hz,1H),7.09(dd,J＝8.4,0.7Hz,1H),7.03–6.97(m,1H),4.47(q,J＝7.1Hz,2H),1.43(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl 3)193.18,162.53,159.12,144.92,135.52,134.17,131.90,128.66,123.39,120.36,118.97,118.45,117.45,111.91,99.99,60.92,14.47.HRMS(ESI+)calculated for C17H15N2O4[M+H]+:311.1032,found:311.1026。
EXAMPLE seven
Preparation of ethyl 1- (2-hydroxybenzoyl) pyrrolo [2, 1-a ] phthalazine-7-carboxylate (Compound 7):
according to the first preparation method of example 1, ethyl bromopyridylacetate onium salt (0.55mmol) was replaced with ethyl bromophthalazine acetate onium salt (0.55mmol) under otherwise unchanged conditions to prepare crude compound 7. Further purification by silica gel chromatography (dichloromethane: methanol ═ 60:1) finally afforded the target compound 7. Yellow solid (90mg, 50%), m.p.230-232 ℃.1HNMR (400MHz, CDCl3) 12.15(s,1H),8.83(s,1H),8.65(d, J ═ 8.3Hz,1H),7.91(d, J ═ 7.2Hz,1H),7.79(td, J ═ 8.4,1.4Hz,2H), 7.74-7.68 (m,1H),7.66(s,1H), 7.58-7.52 (m,1H),7.12(dd, J ═ 8.4,0.8Hz,1H), 6.98-6.91 (m,1H),4.45(q, J ═ 7.1Hz,2H),1.42(t, J ═ 7.1Hz,3H), 13C (101MHz, 60.82 MHz, hrc 84C + (hrc +) NMR (t, 3H), 3.42 c.8514C +)21H17N2O4[M+H]+:361.1188,found:361.1182。
Example eight
Preparation of (1- (2-hydroxybenzoyl) indolizin-3-yl) (4-methoxyphenyl) methadone (compound 8):
with reference to the procedure one of example 1, ethyl bromopyridylacetate onium salt (0.55mmol) was replaced with 1- (2- (4-methoxyphenyl) -2-oxoethyl) pyridine-1-bromoonium salt (0.55mmol), and the other conditions were not changed to prepare a crude compound 8. The crude product was further purified by silica gel chromatography (ethyl acetate: petroleum ether ═ 1:3) to finally obtain the target compound 8. Yellow solid (136mg, 58%), m.p.123-125 ℃.1H NMR (400MHz, CDCl3) 11.98(s,1H),9.92(d, J ═ 7.0Hz,1H),8.47(d, J ═ 8.9Hz,1H),7.83(d, J ═ 8.7Hz,2H),7.77(dd, J ═ 7.9,1.4Hz,1H),7.70(s,1H), 7.54-7.47 (M,1H),7.44(t, J ═ 7.8Hz,1H),7.15(t, J ═ 6.9Hz,1H),7.05(d, J ═ 8.3Hz,1H),6.99(d, J ═ 8.7Hz,2H),6.88(t, J ═ 6.88, 1H),7.05(d, J ═ 8.3Hz,1H), 19H ++ (M, 3H, 8652H, 52H, 35C, 3H, 8652H, 52C, 3H, 52C + 8652C, 52C + 35C, 3H, 3C, n + 3, n.
Example nine
Preparation of ethyl 1- (2- (acryloyloxy) benzoyl) indolizine-3-carboxylate (compound 9):
compound 1(155mg,0.5mmol) was dissolved in 20ml of chloroform under ice bath, and then acryloyl chloride (136mg,1.5mmol) and trimethylamine (253mg,2.5mmol) were sequentially added dropwise. The reaction was kept at 0 ℃ for 2h with continuous stirring, and then the temperature was allowed to return to room temperature. The reaction was monitored on thin layer plates. After completion of the reaction, the reaction solution was extracted with ethyl acetate (20 ml. times.3). Na for organic phase2SO4Dried and concentrated under reduced pressure. The crude material was purified by chromatography column (petroleum ether/ethyl acetate 5:1) to give compound 9(131mg, 72%) as a pale yellow solid. Yellow solid (131mg, 72%), m.p.112-114 ℃.1H NMR (400MHz, CDCl3) 9.55(d, J ═ 7.0Hz,1H),8.57(d, J ═ 8.9Hz,1H),7.66(s,1H),7.60(dd, J ═ 7.6,1.5Hz,1H),7.54(td, J ═ 7.9,1.6Hz,1H), 7.43-7.33 (m,2H),7.28(d, J ═ 7.4Hz,1H),7.06(td, J ═ 7.0,1.2Hz,1H),6.43(dd, J ═ 17.3,1.1Hz,1H),6.15(dd, J, 17.3,10.4, 1H), 1.5 (ddh), 1.85 (ddh, 1H), 1.35H), 1.5 (ddh, 1H), 1.5H, 1H), 1H, 1.5 (ddh, 1H), 1H6(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl 3)187.94,164.20,161.13,147.87,139.58,133.66,132.74,131.18,129.72,127.99,127.46,127.36,126.15,125.73,123.17,120.52,115.59,115.05,113.27,60.41,14.49.HRMS(ESI+)calculated for C 21H 18NO 5[M+H]+364.1185,found:364.1189。
Example ten
Preparation of ethyl-1- (2- ((methanesulfonyl) oxy) benzoyl) indolizine-3-carboxylate (compound 10):
compound 1(155mg,0.5mmol) was dissolved in CH2Cl2(20ml) and Et was added3N (84. mu.L, 0.6 mmol). To the mixture was added dropwise methanesulfonyl chloride (63. mu.L, 0.81mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 4 hours, then water (20ml) was added to the mixture, and the product was extracted with ethyl acetate (50 ml). The separated organic phase was washed with sodium chloride solution and with anhydrous Na2SO4And (5) drying. Concentration in vacuo to remove the solvent gave title compound 10(165mg, 85%) as a pale yellow solid. White solid (165mg, 85%), M.p.118-200 ℃ C.1H NMR (400MHz, CDCl)3)9.60(d,J＝7.0Hz,1H),8.61(d,J＝8.9Hz,1H),7.56(m,4H),7.52–7.41(m,2H),7.13(t,J＝7.0Hz,1H),4.36(q,J＝7.1Hz,2H),3.12(s,3H),1.37(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl 3)187.48,161.02,146.06,139.57,134.35,131.32,129.71,128.26,127.93,127.00,126.23,123.73,120.41,115.90,115.48,113.24,60.57,37.98,14.47.HRMS(ESI+)calculated for C19H18NO6S[M+H]+388.0854,found:388.0853。
EXAMPLE eleven
Research on antitumor activity of the compounds 1-10.
The detection method comprises the following steps: CCK8 kit;
materials: tumor cells: HEPG2 (human hepatoma blasts), NCI-H460 (human non-small cell lung carcinoma cells), CCK-8 kit;
the experimental method comprises the following steps: with CC containing 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazole monosodium saltThe K-8 kit detects the influence of the compound on the proliferation of tumor cells: tumor cells in logarithmic growth phase, HEPG2 or NCI-H460, were digested with 0.25% trypsin and made into single cell suspension in medium containing 10% FBS, inoculated into 96-well plates at 5000 cells/100. mu.l/well, containing 5% CO at 37 ℃2The incubation period in the incubator is 24 h. Cells were treated with 10 μ M of different compounds and the same concentration of DMSO for 72 h. After completion of the culture, CCK8 solution was added thereto, and after 3 hours, absorbance at 450nm of each well was measured by a microplate reader, and the inhibition (%) was determined by the following method.
The cell inhibition rate is 100 percent [1- (experimental well-blank well)/(control well-blank well) ];
TABLE 1 results of Activity test for Compounds 1-10
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A synthetic method of indolizine compounds is characterized by comprising the following steps: it comprises the following steps: mixing the benzopyrone derivative, the bromopyridinium salt derivative, the base and the solvent in a 10ml round-bottom flask, and stirring for 2-48 hours at 25-100 ℃; after the reaction is finished, the crude product is purified by silica gel chromatography to obtain a target compound, the structural formula of which is shown as formula I,
in the above structural formula:
R1independently selected from one or more of H, halogen, alkyl, hydroxyl, amino, carboxyl, carbonyl, ester group, cyano, alkynyl, alkenyl, phenyl and aryl；
R2Is independently selected from one or more of H, hydroxyl, alkoxy, phenyl, pyridyl and aryl;
X1selected from C and N;
X2selected from OH and SH;
R3independently selected from one or more of H, halogen, alkyl, hydroxyl, amino, carboxyl, carbonyl, ester group, cyano, alkynyl, alkenyl, phenyl, pyridine, thiophene, heterocycle and aryl.
2. The synthetic method of indolizine compound according to claim 1, wherein: the aromatic group is selected from phenyl, naphthyl, anthryl, phenanthryl, pyridyl, thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, indolizinyl, quinolyl, indolinyl, benzothiazolyl, benzisothiazolyl, triazolopyridyl, indolizinyl, benzoxazolyl, triazolopyridyl, pyridopyrazinyl, quinazolinyl, benzooxadiazolyl, benzothiadiazolyl, benzoindazinyl; the alkyl group is C1-10A straight or branched chain saturated carbon chain; the halogen is selected from fluorine, chlorine, bromine and iodine.
3. The synthetic method of indolizine compound according to claim 1, wherein: benzopyrone derivative, bromopyridinium salt derivative, base and solvent were mixed in a 10ml round bottom flask and stirred at 80 ℃ for 12 hours; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.
4. The synthetic method of indolizine compound according to claim 3, characterized in that: the alkali is selected from one of DBU, DIPEA, potassium carbonate, sodium carbonate, potassium acetate, potassium hydroxide and sodium hydroxide; the solvent is selected from one of 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, toluene, NMP and THF.
5. The synthetic method of indolizine compound according to claim 3 or 4, characterized in that: the base is DBU; the solvent is 1, 4-dioxane.
6. The synthetic method of indolizine compound according to claim 1, wherein: benzopyrone, bromopyridinium salt and DBU were mixed in a 10ml round bottom flask and stirred at 80 ℃ for 6 hours; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.
7. The synthetic method of indolizine compound according to claim 1, wherein: benzopyrone, bromopyridinium salt, metal catalyst, base and 1, 4-dioxane were mixed in a 10ml round bottom flask and stirred at 60 ℃ for 6 hours; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.
8. The synthetic method of indolizine compound according to claim 7, wherein: the metal catalyst is selected from one of cuprous iodide, cuprous bromide, cuprous chloride, cupric chloride and cupric sulfate; the base is selected from DBU, DIPEA, potassium carbonate, sodium carbonate, potassium acetate, potassium hydroxide, and sodium hydroxide.
9. The synthesis method of indolizine compounds according to claim 7 or 8, characterized in that: the metal catalyst is cuprous iodide; the base is DBU.
10. The use of indolizine compounds according to claim 1, characterized in that: the indolizine compound used for tumor or cancer is gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, intestinal cancer, nasopharyngeal cancer, breast cancer, lymph cancer, kidney cancer, pancreatic cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngeal cancer, leukemia, prostate cancer, brain tumor, squamous carcinoma, skin cancer, hemangioma, lipoma, cervical cancer and thyroid cancer.
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| US11530217B1 (en) | 2022-06-29 | 2022-12-20 | King Faisal University | Antitubercular compounds |
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