CN108864089B - Indolopyridone drug molecule and preparation method and application thereof - Google Patents
Indolopyridone drug molecule and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a novel indolopyridone drug molecule, and a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The technical scheme provided by the invention has the key points that: a novel indolopyridone drug molecule having the structural formula:
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a novel indolopyridone medicine molecule and a preparation method and application thereof.
Background
Six-membered nitrogen containing heterocyclic compounds are backbone moieties of many pharmaceutically active molecules. Many molecules containing pyridine, pyridone, dihydropyridone and other skeletons show good pharmacological activity, for example, Nothapodytine B and Nothapodytine A are compounds separated from Nothapodytine B and Nothapodytine A, and pharmacological experiments prove that the compounds have good antiviral activity, while Mappicine and Camptothecin, derivatives of the compounds, are inhibitors of DNA topoisomerase I and have certain antitumor activity, and the compound Streptonigrone is separated from a culture solution of streptomyces and shows good antitumor activity. Lycoridine, Narciglane and Panceristatin are alkaloids separated from Narcissus plants, and all have good biological activity, such as insect anti-feeding activity, anti-tumor activity and the like.
The indolopyridine compounds are structural mother nuclei and important intermediates of a plurality of natural products, and have physiological activities of antianaphylaxis, anti-inflammation, anti-tumor, potent cathartic, fever reduction and the like. There are many reports on the activity of these compounds, and most of them can obtain compounds with different physiological activities by modifying the nitrogen of indole ring and pyridine ring.
The density of electron cloud on the pyrrole ring in the indole substance is higher, and chemical reaction is easy to carry out, so the indole and the derivatives thereof are not only important skeletons of natural products, but also important skeletons of pharmaceutically active molecules, and functional groups on the indole ring are always researched by people in the field of organic synthesis. Indole and derivatives thereof can also be used as heterocyclic alkaloids, and most of the heterocyclic alkaloids have obvious medicinal value and physiological activity. In the development of new drugs, indole structures are often considered as lead compounds for research, such as the synthesis of thiosemicarbazone Schiff base compounds from 5-methoxyindole-3-formaldehyde and thiosymmetric diaminourea. Indole and its derivatives can be used to synthesize antipyretic analgesic, stimulant, antihypertension agent, vasodilator, and antihistamine. Recently, researches in the biomedical field find that compounds containing indole structural frameworks have certain inhibition effects on the expression of certain kinases, have potential antitumor activity and good clinical development prospects, and the potential application value attracts people to search a great deal of synthetic routes, for example, each monofunctional enzyme of a bacterial fatty acid synthetase system becomes a research hotspot of a novel antibacterial drug target driven by genomics and the design of a novel 2-indolone c-Met kinase inhibitor; constructing a self-assembled micelle of the carrier indocyanine green and the doxorubicin; bis (1H-2-indolyl) methanones as a novel platinum group growth factor receptor kinase inhibitors; synthesizing the 2-aroylindole derivative as a novel effective tubular inhibition, anti-biological drug; 2-Aroylinoles and 2-acylphenylureas as a group of reasonably designed histone deacetylase inhibitors; 2, 4-diaminopyrimidine derivatives were investigated for their excellent antitumor activity. Indoles and their derivatives have a variety of pharmacological and biological properties, including: antibacterial, cytotoxic, antioxidant, and pesticidal activities, such as processes for preparing photoactive oxazolone derivatives.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method and application of indolopyridone drug molecules with simple synthesis method, low raw material price and novel structure.
The invention adopts the following technical scheme for solving the technical problems, and the molecular structure of the indolopyridone drug is as follows:
wherein R is fluorobenzene, quinoline and indole.
The invention adopts the following technical scheme for solving the technical problems, and the preparation method of the indolopyridone drug molecule is characterized by comprising the following specific steps:
A. adding 3, 5-dichloroaniline into a mixed solution of water and sulfuric acid, uniformly stirring, cooling to 0 ℃, dropwise adding an aqueous solution dissolved with sodium nitrite under the stirring condition, and performing diazotization to obtain a solution A; preparing an aqueous solution dissolved with barium hydroxide in another reaction bottle, slowly dropwise adding ethanol dissolved with ethyl pyruvate at the temperature of 0 ℃, and uniformly stirring after dropwise adding to prepare a solution B; slowly adding the solution A into the solution B dropwise at the temperature of 0 ℃, heating to 40 ℃ after dropwise adding, reacting for a period of time to carry out an amine-aldehyde condensation reaction, filtering the reaction liquid, extracting the filtrate with diethyl ether, combining organic phases, drying with anhydrous magnesium sulfate, concentrating, and recrystallizing with a mixed solution of n-hexane and acetone to obtain ethyl-2- (2- (3, 5-dichlorophenyl) hydrazono) propionic acid; the volume ratio of the n-hexane to the acetone is 2: 1.
B. Adding ethyl-2- (2- (3, 5-dichlorophenyl) hydrazono) propionic acid and polyphosphoric acid into toluene, heating to 45 ℃, stirring for reacting for a period of time, starting vacuum, removing toluene, adding ice water, stirring uniformly, filtering the reaction solution, and recrystallizing a filter cake by using n-hexane to obtain the 4, 6-dichloroindole ethyl formate.
C. Adding 4, 6-dichloroindole ethyl formate, sodium nitrite and potassium persulfate into formic acid, continuously stirring and reacting at 90 ℃ until the raw materials completely react, then pouring into water, extracting the reaction solution for multiple times by using ethyl acetate, merging organic phases, drying by using anhydrous sodium sulfate, concentrating the reaction solution, and carrying out silica gel column chromatography separation to obtain the 2-nitro-4, 6-dichloroindole ethyl formate.
D. Adding 2-nitro-4, 6-dichloroindole ethyl formate and a catalyst palladium carbon into methanol, introducing hydrogen into an autoclave, leading the pressure to reach 0.2MPa, leading the reaction temperature to be 40 ℃, reacting until the raw materials completely react, filtering the reaction solution, and concentrating the filtrate to obtain pure 2-amino-4, 6-dichloroindole ethyl formate.
E. Adding 2-amino-4, 6-dichloroindole ethyl formate into dichloromethane, adding triethylamine, cooling to 10 ℃, slowly dropwise adding 4-chloroformyl ethyl acetate, reacting at room temperature overnight, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, adding dichloromethane to dilute reaction liquid, washing with water twice, drying with anhydrous sodium sulfate, and spin-drying to obtain 2-formamidoethyl acetate-4, 6-dichloroindole ethyl formate.
F. Adding ethyl 2-formamidoacetate-4, 6-dichloroindole carboxylate into tetrahydrofuran, adding potassium tert-butoxide in batches, controlling the reaction temperature to be less than 25 ℃, adding ice water for quenching after reacting for a period of time, adjusting the pH of the reaction solution to 3 by using 2mol/L HCl, filtering, and drying in vacuum to obtain a white solid product, namely ethyl 7, 9-dichloro-4-hydroxy-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] indole-3-carboxylate.
G. Adding ethyl 7, 9-dichloro-4-hydroxy-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] indole-3-carboxylate into HCl solution in batches, heating to 100 ℃, reacting overnight, spin-drying the reaction solvent, washing with diethyl ether, and drying in vacuum to obtain the off-white solid 7, 9-dichloro-4-hydroxy-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] indole.
H. Adding 7, 9-dichloro-4-hydroxy-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] indole into phosphorus oxychloride in batches in a closed reaction bottle, slowly heating to 100 ℃, reacting overnight, performing TLC monitoring on the reaction of raw materials, performing vacuum spin-drying on the phosphorus oxychloride to obtain red oily concentrate, adding 10 times of ethyl acetate, washing for three times, separating an organic phase, washing with a sodium chloride solution, drying, and spinning the reaction solution to obtain 7, 9-dichloro-4-chloro-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] indole.
I. Reacting 7, 9-dichloro-4-chloro-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ]]Adding indole into tetrahydrofuran, adding potassium phosphate and boric acid derivative, heating to 100 deg.C, reacting for a period of time, extracting with ethyl acetate, concentrating, adding into mixed solution of methanol, dilute hydrochloric acid and 1, 4-dioxane, reacting at room temperature until the raw materials react completely, vacuum concentrating, and washing with diethyl ether to obtain the final product
The invention adopts the following technical scheme for solving the technical problems, and the preparation method of the indolopyridone drug molecule is characterized by comprising the following specific steps:
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Adding 48g (0.3mol) of 3, 5-dichloroaniline into a mixed solution of 500mL of water and 500mL of hydrochloric acid in a reaction flask, uniformly stirring, cooling to 0 ℃, dropwise adding 400mL of an aqueous solution in which 23g (0.34mol) of sodium nitrite is dissolved under the stirring condition, and uniformly mixing to obtain a solution A; preparing 1000mL of aqueous solution in which 67g (1.2mol) of potassium hydroxide is dissolved in another reaction bottle, slowly dropwise adding 250mL of ethanol in which 35g (0.3mol) of ethyl pyruvate is dissolved at 0 ℃, and uniformly stirring after dropwise adding to prepare solution B; slowly adding the solution A into the solution B at 0 deg.C, heating to 40 deg.C for 10min, extracting with diethyl ether 1000mL for three times, mixing organic phases, drying with anhydrous magnesium sulfate 100g, concentrating, and mixing with n-hexane and acetone solution (V)N-hexane： VAcetone (II)2:1) to obtain 78g of ethyl-2- (2- (3, 5-dichlorophenyl) hydrazono) propionic acid with a yield of 95%;1H NMR (600MHz,DMSO-d6):δ10.08(s,1H),7.23(d,J＝6.0Hz,2H),7.03(d,J＝6.0Hz,1H),4.22(q, J＝12.0Hz,2H),2.07(s,3H),1.28(t,J＝12.0Hz,3H)；13C NMR(150MHz,DMSO-d6):δ164.66, 146.98,135.32,134.79,119.75,112.16,61.06,14.39,12.33。
example 2
Adding 80g (0.29mol) of ethyl-2- (2- (3, 5-dichlorophenyl) hydrazono) propionic acid and 500 g (1.47mol) of polyphosphoric acid into 1000mL of toluene in a reaction bottle, heating to 45 ℃, stirring for reaction for 1h, then starting vacuum, removing the toluene, then adding 2000mL of ice water, stirring for 10min, then carrying out suction filtration on the reaction solution, and recrystallizing a filter cake with n-hexane to obtain 66g of ethyl 4, 6-dichloroindole carboxylate with the yield of 89%;1H NMR(600MHz,DMSO-d6):δ12.41(s,1H),7.46(s,1H),7.28 (s,1H),7.12(s,1H),4.37(dd,J1＝6.0Hz,J2＝6.0Hz,2H),1.35(t,J1＝6.0Hz,J2＝6.0Hz,3H).13CNMR(150MHz,DMSO-d6):δ161.03,138.04,129.54,129.20,127.34,124.82,120.51,111.84,105.78,61.44,14.66。
example 3
Adding 26g (0.1mol) of 4, 6-dichloroindole ethyl formate, 28g (0.4mol) of sodium nitrite and 100g (0.4mol) of potassium persulfate into 500mL of formic acid in a reaction bottle, continuously stirring and reacting for 2h at 90 ℃, monitoring the complete reaction of raw materials by TLC, pouring the raw materials into 600mL of water, extracting the reaction solution three times by 300mL of ethyl acetate, combining organic phases, drying by anhydrous sodium sulfate, concentrating the reaction solution, and separating by silica gel column chromatography (V petroleum ether: V ethyl acetate is 4:1) to obtain 28.5g of 2-nitro-4, 6-dichloroindole ethyl formate with the yield of 95%;1H NMR(600MHz,DMSO-d6):δ12.15(s, 1H),7.59(s,1H),7.04-7.03(m,1H),4.37(d,J＝6.0Hz,2H),1.28-1.27(m,3H)。
example 4
In a 500mL reaction bottle, 30g (0.1mol) of 2-nitro-4, 6-dichloroindole carboxylic acid ethyl ester and 3g of palladium carbon as a catalyst are added into 200mL of methanol, hydrogen is introduced into an autoclave, the pressure reaches 0.2MPa, the reaction temperature is 40 ℃, the raw materials are completely reacted after 12 hours of reaction, the reaction solution is filtered, the filtrate is concentrated to obtain 26g of pure 2-amino-4, 6-dichloroindole carboxylic acid ethyl ester, and the yield is 96%.
Example 5
In a 500mL reaction bottle, 30g (0.1mol) of ethyl 2-nitro-4, 6-dichloroindole carboxylate and 3g of palladium carbon as a catalyst are added into 200mL of methanol, hydrogen is introduced into an autoclave, the pressure reaches 0.05MPa, the reaction temperature is 40 ℃, the raw materials are monitored by TLC after 12 hours of reaction and completely reacted, the reaction solution is filtered, the filtrate is concentrated and then chromatographically separated by a silica gel column to obtain 22g of pure ethyl 2-amino-4, 6-dichloroindole carboxylate, and the yield is 81%.
Example 6
In a 500mL reaction bottle, 30g (0.1mol) of 2-nitro-4, 6-dichloroindole carboxylic acid ethyl ester and 3g of palladium carbon as a catalyst are added into 200mL of methanol, hydrogen is introduced into an autoclave, the pressure reaches 0.1MPa, the reaction temperature is 40 ℃, the raw materials are completely reacted after 12h of reaction, the reaction solution is filtered, and the filtrate is concentrated to obtain 24g of pure 2-amino-4, 6-dichloroindole carboxylic acid ethyl ester, wherein the yield is 88%.
Example 7
In a 500mL reaction bottle, 30g (0.1mol) of ethyl 2-nitro-4, 6-dichloroindole carboxylate and 3g of palladium carbon as a catalyst are added into 200mL of methanol, hydrogen is introduced into an autoclave, the pressure reaches 0.4MPa, the reaction temperature is 40 ℃, the raw materials are monitored by TLC after 12 hours of reaction and completely reacted, the reaction solution is filtered, the filtrate is concentrated and then chromatographically separated by a silica gel column to obtain 25g of pure ethyl 2-amino-4, 6-dichloroindole carboxylate, and the yield is 92%.
Example 8
Adding 27g (0.1mol) of ethyl 2-amido-4, 6-dichloroindole carboxylate into 250mL of dichloromethane in a reaction bottle, adding 11g (0.11mol) of triethylamine, cooling to 10 ℃, slowly adding 16g (0.105mol) of ethyl 4-chloroformylacetate dropwise, reacting at room temperature overnight, monitoring the reaction of raw materials by TLC (thin layer chromatography), adding 250mL of dichloromethane to dilute reaction solution, washing with water twice, drying with anhydrous sodium sulfate, and spin-drying to obtain 28g of ethyl 2-formamidoacetate-4, 6-dichloroindole carboxylate with the yield of 73%;1H NMR(600MHz,DMSO-d6):δ12.11(s,1H),7.79-7.78(m,1H),7.41(s,1H),7.09(s,1H), 4.92(d,J＝6.0Hz,3H),4.11(d,J＝12.0Hz,2H),3.35(s,2H),1.29(s,3H)。
example 9
Adding 37g (0.1mol) of ethyl 2-formamidoacetate-4, 6-dichloroindole carboxylate into 400mL of THF (tetrahydrofuran), adding 23g (0.2mol) of t-BuOK in batches, controlling the reaction temperature to be less than 25 ℃, adding 300mL of ice water after 1H of reaction for quenching, adjusting the pH of the reaction solution to 3 by using 2mol/L of HCl, filtering, and drying in vacuum to obtain a white-like solid product 7, 9-dichloro-4-hydroxy-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] -3]30g of indole-3-ethyl formate, wherein the yield is 88%;1H NMR(600MHz,DMSO-d6):δ15.98(s,1H),11.81(s,1H),7.66-7.65(m,1H),7.24-7.22(m,1H),4.44(d,J＝6.0Hz,2H),1.26(s,3H)。
example 10
In the reverse direction200mL of 6mol/L HCl solution was added to the flask, and 7, 9-dichloro-4-hydroxy-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] was added in portions]Indole-3-carboxylic acid ethyl ester 34g (0.1mol), heating to 100 deg.C, reacting overnight, spin-drying the reaction solvent, washing with diethyl ether, and vacuum drying to obtain off-white solid 7, 9-dichloro-4-hydroxy-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ]]Indole 22g, yield 82%; HRMS ((+) -ESI) m/z 268.9735(calcd.268.9743for C)11H6Cl2N2O2,[M+H]+)。
Example 11
Adding 7, 9-dichloro-4-hydroxy-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] dissolved in 50g (0.5mol) of phosphorus oxychloride into a closed reaction bottle in batches]Indole 27g (0.1mol) in toluene 150mL, slowly heated to 100 ℃, reacted overnight, TLC monitored raw materials reacted completely, vacuum dried phosphorus oxychloride and solvent toluene to get red oily product concentrate, adding concentrate 10 times volume of ethyl acetate, water washing three times, separating organic phase, drying and drying to get 7, 9-dichloro-4-chloro-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ] -2]22g of indole, wherein the yield is 77%;1H NMR(400M,CDCl3):δ12.02 (s,1H),7.68(s,1H),7.24(s,1H),6.69(s,1H)。
example 12
Reacting 7, 9-dichloro-4-chloro-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ]]Adding 30g (0.1mol) of indole into 600mL of THF, adding 330mL of 1mol/L potassium phosphate and 25g (0.12mol) of p-fluorobenzeneboronic acid, heating to 100 ℃, reacting for 24h, extracting with ethyl acetate, concentrating, adding into 300mL of methanol and 300mL of 12mol/L HCl/1, 4-dioxane, reacting for 5h at room temperature, monitoring the completion of the reaction of raw materials by TLC, concentrating in vacuum, and washing with diethyl ether to obtain the intermediate
20g, HPLC purity 98.7%, yield 58%;1H NMR(400M, CDCl3):11.98(s,1H),7.77-7.76(m,2H),7.65(d,J＝4.0Hz,1H),7.61(s,1H),7.41-7.39(m,2H), 7.16(t,J1＝8.0Hz,J2＝8.0Hz,1H),6.61(s,1H)；MS(ESI)m/z:347.7[M+H]+；Anal.Calcd for C17H9Cl2FN2O:C,58.81；H,2.61；N,8.07.Found:C,58.67；H,2.66；N,8.14。
example 13
Reacting 7, 9-dichloro-4-chloro-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ]]Adding 30g (0.1mol) of indole into 600mL of THF, adding 200mL of 1mol/L potassium phosphate and 25g (0.12mol) of p-fluorobenzeneboronic acid, heating to 100 ℃, reacting for 24h, extracting with ethyl acetate, concentrating, adding into 300mL of methanol and 300mL of 12mol/L HCl/1, 4-dioxane, reacting for 5h at room temperature, monitoring the reaction completion of raw materials by TLC, concentrating in vacuum, washing with ether, concentrating, and performing silica gel column chromatography (petroleum ether: ethyl acetate: 6: 1) to obtain the final product
12g, HPLC purity 99%, yield 35%;1H NMR(400M,CDCl3):11.98(s,1H),7.77-7.76(m,2H),7.65(d,J＝4.0Hz,1H), 7.61(s,1H),7.41-7.39(m,2H),7.16(t,J1＝8.0Hz,J2＝8.0Hz,1H),6.61(s,1H)；MS(ESI)m/z: 347.7[M+H]+；Anal.Calcd for C17H9Cl2FN2O:C,58.81；H,2.61；N,8.07.Found:C,58.67；H, 2.66；N,8.14。
example 14
Reacting 7, 9-dichloro-4-chloro-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ]]30g (0.1mol) of indole was added to 600mL of THF, and 400m of 1mol/L potassium phosphate was addedL and 25g (0.12mol) of p-fluorobenzeneboronic acid are heated to 100 ℃, after 24h of reaction, ethyl acetate is used for extraction and concentration, then the mixture is added into 300mL of methanol and 300mL of 12mol/L HCl/1, 4-dioxane, the mixture is reacted for 5h at room temperature, TLC monitors that the raw materials are completely reacted, the mixture is concentrated in vacuum, washed by ether, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 6: 1) after concentration to obtain the compound
18g, HPLC purity 99.6%, yield 52%;1H NMR(400M,CDCl3):11.98(s,1H),7.77-7.76(m,2H),7.65(d,J＝4.0Hz,1H), 7.61(s,1H),7.41-7.39(m,2H),7.16(t,J1＝8.0Hz,J2＝8.0Hz,1H),6.61(s,1H)；MS(ESI)m/z: 347.7[M+H]+；Anal.Calcd for C17H9Cl2FN2O:C,58.81；H,2.61；N,8.07.Found:C,58.67；H, 2.66；N,8.14。
example 15
Reacting 7, 9-dichloro-4-chloro-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ]]Adding 29g (0.1mol) of indole into 600mL of THF, adding 330mL of 1mol/L potassium phosphate and 20g (0.12mol) of quinoline-4-boric acid, heating to 100 ℃, reacting for 24h, extracting with ethyl acetate, concentrating, adding into 400mL of methanol and 400mL of 12mol/L HCl/1, 4-dioxane, reacting for 5h at room temperature, monitoring by TLC that the raw materials are completely reacted, concentrating in vacuum, and washing with diethyl ether to obtain the intermediate25g, HPLC purity 98.9%, yield 66%;1H NMR(400M, CDCl3):12.39(s,1H),8.32(d,J＝8.0Hz,1H),7.91(s,2H),7.76(s,1H),7.53-7.51(m,2H), 7.49-7.48(m,2H),6.97(t,J1＝12.0Hz,J2＝12.0Hz,1H),6.54(s,1H)，MS(ESI)m/z:380.2 [M+H]+；Anal.Calcd forC20H11Cl2N3O:C,63.18；H,2.92；N,11.05.Found:C,63.35；H,3.01； N,11.18。
example 16
Reacting 7, 9-dichloro-4-chloro-2-carbonyl-2, 5-dihydro-1H-pyrido [3,2-b ]]Adding 29g (0.1mol) of indole into 600mL of THF, adding 330mL of 1mol/L potassium phosphate and 19g (0.12mol) of indole-4-boric acid, heating to 100 ℃, reacting for 15h, extracting with 400mL of ethyl acetate for three times, concentrating, adding into 400mL of methanol and 400mL of 12mol/L HCl/1, 4-dioxane, reacting for 3h at room temperature, monitoring by TLC that the raw materials are completely reacted, concentrating in vacuum, washing with diethyl ether to obtain the final product28g, HPLC purity 99.2%, yield 76%;1H NMR(400M,CDCl3):12.21(s,1H),7.97-7.96(m,2H),7.74(s,1H),7.49-7.48(m,2H),7.25(d, J＝12.0Hz,2H),6.83(dd,J1＝8.0Hz,J2＝4.0Hz,1H),3.12(s,1H)，MS(ESI)m/z:368.3 [M+H]+；Anal.Calcdfor C19H11Cl2N3O:C,61.98；H,3.01；N,11.41.Found:C,62.26；H, 3.07；N,11.53。
example 17
Antitumor Activity test
The growth-stage breast cancer cells MCF-7 were collected, and the anticancer activity of the compound was measured by MTS method, and the cells were added at an appropriate concentration (4X 10/ml)4Individual cells) were added to a 96-well cell culture plate (culture solution containing 10% fetal calf serum was prepared as a single cell suspension), and after 24 hours of culture, CO was added at 37 ℃ in a volume concentration of 5%2After 72 hours of reaction with different concentrations of compound, a mixture of MTS (final concentration 2mg/mL) and DMS (final molarity 30. mu.M) was added directly to the cell-containing medium and the incubator was incubated for 4 h. After 4h of action, the supernatant is discarded, 150 mu LDMSO is added into each hole, the vibration is carried out, and the cell survival rate is determined by the absorption rate of the metabolites acting on MTS at 490nm of an enzyme linked immunosorbent assay.
Preliminary biological activity tests show that the compounds have an inhibiting effect on cancer cells in breast cancer cells MCF-7.
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.
Claims (6)
1. An indolopyridone drug molecule, characterized in that the structure of the indolopyridone drug molecule is:
wherein R is p-fluorophenyl, quinolyl and indolyl.
2. The method for preparing indolopyridone drug molecules according to claim 1, which is characterized by comprising the following steps:
A. adding 3, 5-dichloroaniline into a mixed solution of water and sulfuric acid, uniformly stirring, cooling to 0 ℃, dropwise adding an aqueous solution dissolved with sodium nitrite under the stirring condition, and performing diazotization to obtain a solution A; preparing an aqueous solution dissolved with barium hydroxide in another reaction bottle, slowly dropwise adding ethanol dissolved with ethyl pyruvate under the condition of 0 ℃, and uniformly stirring after dropwise adding to prepare a solution B; slowly adding the solution B into the solution A at 0 ℃, heating to 40 ℃ after dropwise adding, reacting for a period of time to carry out an amine-aldehyde condensation reaction, filtering the reaction liquid, extracting the filtrate with diethyl ether, combining organic phases, drying with anhydrous magnesium sulfate, concentrating, and recrystallizing with a mixed solution of n-hexane and acetone to obtain the formula I;
B. adding formula I and polyphosphoric acid into toluene, heating to 45 ℃, stirring for reacting for a period of time, then starting vacuum, evaporating to remove toluene, then adding ice water, filtering the reaction solution after stirring uniformly, and recrystallizing the filter cake with n-hexane to obtain formula II;
C. adding a formula II, sodium nitrite and potassium persulfate into formic acid, continuously stirring and reacting at 90 ℃ until the raw materials completely react, then pouring into water, extracting the reaction solution for multiple times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, concentrating the reaction solution, and separating by silica gel column chromatography to obtain a formula III;
D. adding the formula III and a catalyst palladium-carbon into methanol, introducing hydrogen into an autoclave, reacting until the pressure reaches a certain pressure and the reaction temperature is 40 ℃ until the raw materials completely react, filtering the reaction solution, and concentrating the filtrate to obtain a pure formula IV;
E. adding the formula IV into dichloromethane, adding triethylamine, cooling to 10 ℃, slowly adding ethyl chloroformylacetate dropwise, reacting at room temperature overnight, monitoring by TLC (thin layer chromatography) that the raw materials are completely reacted, adding dichloromethane to dilute the reaction solution, washing twice, drying with anhydrous sodium sulfate, and spin-drying to obtain a formula V;
F. adding the formula V into tetrahydrofuran, adding potassium tert-butoxide in batches, controlling the reaction temperature to be less than 25 ℃, adding ice water for quenching after reacting for a period of time, adjusting the pH of the reaction solution to 3 by using 2mol/L HCl, filtering, and drying in vacuum to obtain a white-like solid product of the formula VI;
G. adding the formula VI in batches into a hydrochloric acid solution, heating to 100 ℃, reacting overnight, spin-drying a reaction solvent, washing with diethyl ether, and vacuum-drying to obtain an off-white solid formula VII;
H. adding a toluene solution dissolved with the formula VII into phosphorus oxychloride in batches in a closed reaction bottle, slowly heating to 100 ℃, reacting overnight, after TLC monitors that the raw materials are completely reacted, carrying out vacuum spin-drying on the phosphorus oxychloride and a solvent toluene to obtain a red oily concentrate, adding ethyl acetate with the volume of 10 times that of the red oily concentrate, washing for three times, separating an organic phase, washing with a sodium chloride solution, drying, and carrying out rotary evaporation on a reaction solution to obtain the formula VIII;
I. adding formula VIII into tetrahydrofuran, adding potassium phosphate and boric acid derivative, heating to 100 deg.C, reacting for a period of time, extracting with ethyl acetate, and concentratingThen adding into mixed solution of methanol, dilute hydrochloric acid and 1, 4-dioxane, reacting at room temperature until the raw materials react completely, vacuum concentrating, washing with diethyl ether to obtain
The method comprises the following specific steps:
3. the method of claim 2, wherein the indolopyridone drug molecule is prepared by: the volume ratio of the n-hexane to the acetone in the step A is 2: 1.
4. The method of claim 2, wherein the indolopyridone drug molecule is prepared by: and D, the certain pressure in the step D is 0.05-0.4 MPa.
5. The method of claim 2, wherein the indolopyridone drug molecule is prepared by: the feeding amount molar ratio of the formula VIII to the potassium phosphate in the step I is 1: 2-4.
6. The use of the indolopyridone drug molecule of claim 1 in the preparation of an anti-tumor drug.
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| WO2015088564A1 (en) * | 2013-12-13 | 2015-06-18 | Sunovion Pharmaceuticals Inc. | P2x4 receptor modulating compounds |
| WO2016183115A1 (en) * | 2015-05-12 | 2016-11-17 | Bristol-Myers Squibb Company | 5h-pyrido[3,2-b]indole compounds as anticancer agents |
| WO2017133681A1 (en) * | 2016-02-05 | 2017-08-10 | 正大天晴药业集团股份有限公司 | Tricyclic compound for bromodomain-containing protein inhibitor and preparation, pharmaceutical composition, and application thereof |
| CN104693186B (en) * | 2014-12-31 | 2017-12-22 | 青岛黄海制药有限责任公司 | C F keys generation C N are bonded to the method that class medicine is dissolved in west in a kind of indole derivatives |
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| WO2015088564A1 (en) * | 2013-12-13 | 2015-06-18 | Sunovion Pharmaceuticals Inc. | P2x4 receptor modulating compounds |
| CN104693186B (en) * | 2014-12-31 | 2017-12-22 | 青岛黄海制药有限责任公司 | C F keys generation C N are bonded to the method that class medicine is dissolved in west in a kind of indole derivatives |
| WO2016183115A1 (en) * | 2015-05-12 | 2016-11-17 | Bristol-Myers Squibb Company | 5h-pyrido[3,2-b]indole compounds as anticancer agents |
| WO2017133681A1 (en) * | 2016-02-05 | 2017-08-10 | 正大天晴药业集团股份有限公司 | Tricyclic compound for bromodomain-containing protein inhibitor and preparation, pharmaceutical composition, and application thereof |
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