CN111943947B - 1H-pyrrole [2,3-b ] pyridine derivative and synthesis method and application thereof - Google Patents

1H-pyrrole [2,3-b ] pyridine derivative and synthesis method and application thereof Download PDF

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CN111943947B
CN111943947B CN202010725627.9A CN202010725627A CN111943947B CN 111943947 B CN111943947 B CN 111943947B CN 202010725627 A CN202010725627 A CN 202010725627A CN 111943947 B CN111943947 B CN 111943947B
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pyrrolo
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CN111943947A (en
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高丽霞
丁勇
唐艳
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Chongqing Chushengdu Technology Co.,Ltd.
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Abstract

The invention relates to the technical field of organic synthesis, in particular to a 1H-pyrrole [2,3-b ] pyridine derivative, a synthesis method and application thereof, wherein the synthesis method comprises the steps of taking p-aminophenylacetic acid and Boc anhydride as initial raw materials, carrying out five-step reaction, adding a compound substituted amine in the second step of reaction, and adding 1H-pyrrolo [2,3-b ] pyridine-6-carboxylic acid in the fourth step of reaction to prepare and synthesize the 1H-pyrrole [2,3-b ] pyridine derivative. The 1H-pyrrolo [2,3-b ] pyridine derivatives 5a-5d have a certain inhibition effect on cell viability of head and neck squamous cell carcinoma, breast cancer, pancreatic cancer, colon cancer and liver cancer, and particularly the compound 5a has a good inhibition effect on the head and neck squamous cell carcinoma cells. Therefore, the 1H-pyrrole [2,3-b ] pyridine derivative synthesized by the invention can inhibit or kill tumor cells, has good anti-tumor activity, can be applied to preparation of anti-tumor drugs, and is particularly used for preparing anti-tumor drugs for treating head and neck squamous cell carcinoma.

Description

1H-pyrrole [2,3-b ] pyridine derivative and synthesis method and application thereof
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a 1H-pyrrole [2,3-b ] pyridine derivative and a synthesis method and application thereof.
Background
Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the leading causes of cancer morbidity and mortality worldwide, accounting for approximately 4% of all cancers, with approximately 60 million new cases and 40 million cases of death each year. HNSCC accounts for 95% of head and neck cancers, occurring in the mouth, oropharynx, hypopharynx, and larynx. Alcohol, tobacco and HPV infections are common causative factors of HNSCC. Although improvements in surgical and radiological techniques have resulted in significant improvement in the efficacy of some types of patients with early stage HNSCC, the early symptoms of HNSCC are not evident and there is a lack of effective screening means, and most patients with HNSCC are in late local stage (stage III or IV). Currently, the overall effective treatment regimen for this malignancy is not complete, resulting in a 5-year survival rate of less than 50% for patients with HNSCC. Therefore, the development of effective antitumor drugs is of great significance in improving the treatment effect of patients with HNSCC.
The pyrrolopyridine compound is an important nitrogen-containing fused heterocyclic compound, and the special structural characteristics of the pyrrolopyridine compound show potential biological activity. On the one hand, the integrase inhibitor plays an important role in the field of medicine, such as HIV-1 integrase inhibitors, which have the characteristics of high selectivity, low toxicity, capability of well blocking virus replication and the like (J.int.pharm.Res., 2016,43(5), 940-946). On the other hand, the catalyst can be used as a metal-organic concerted catalysis catalyst in the field of organic synthesis, and has been successfully applied to direct C (sp2) -H functional hydrogenation acylation reaction of olefin and aldehyde (J.Am.chem.Soc.2015,137, 6279-6291). In addition, it can be an important intermediate and an important raw material in the synthesis of drugs. With the progress of research, the flexible construction of polysubstituent pyrrolopyridine derivatives is found to be a very important research field through the exploration of the structure-activity relationship.
1H-pyrrolo [2,3-b ] pyridine derivatives form the backbone of many compounds as parent nucleus analogs, for example, WO2010092489 discloses a compound having the following structural formula:
Figure GDA0002982463850000011
JP5652417 discloses a compound having the following structural formula:
Figure GDA0002982463850000021
however, the development of new 1H-pyrrolo [2,3-b ] pyridine derivatives is relatively low, and particularly, the related reports of the initial evaluation of the antitumor activity of the currently newly synthesized 1H-pyrrolo [2,3-b ] pyridine derivatives are relatively low.
Disclosure of Invention
In view of the above, the present invention aims to provide 1H-pyrrolo [2,3-b ] pyridine derivatives, and a synthesis method and an application thereof, wherein the synthesized 1H-pyrrolo [2,3-b ] pyridine derivatives have a certain degree of inhibitory effect on cell viability of head and neck squamous cell carcinoma, breast cancer, pancreatic cancer, colon cancer and liver cancer, and particularly, the compound 5a has a good inhibitory effect on head and neck squamous cell carcinoma cells, has good antitumor activity, and can be applied to preparation of antitumor drugs.
The invention solves the technical problems by the following technical means:
the invention provides a 1H-pyrrole [2,3-b ] pyridine derivative, which has the following structure:
Figure GDA0002982463850000022
wherein R is R1-CH2-, p-bromophenyl, cyclopentyl.
Preferably, R is1Is thienyl or furyl.
Preferably, the derivative is selected from:
n- (4- (2-oxo-2- ((thienyl-2-methyl) amino) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide;
n- (4- (2-oxo-2- ((furanyl-2-methyl) amino) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide;
n- (4- (2-oxo-2- ((4-bromophenyl) amino) -2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide;
n- (4- (2-oxo-2- (cyclopentylamino) -2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide.
In another aspect, the present invention provides a method for synthesizing the above 1H-pyrrolo [2,3-b ] pyridine derivative, wherein the method comprises the following steps:
Figure GDA0002982463850000031
preferably, the preparation method of the compound 2 comprises the following steps:
weighing p-aminophenylacetic acid, adding dioxane, placing in an ice water bath, adding a sodium hydroxide solution, stirring, dropwise adding Boc anhydride, then moving to room temperature for reaction for 12 hours, after the reaction is finished, adjusting the pH to 7 by using dilute hydrochloric acid, extracting by using ethyl acetate, collecting an ethyl acetate layer, washing by using water and saturated saline solution, then drying by using anhydrous sodium sulfate, and distilling under reduced pressure to obtain a compound 2, wherein the molar ratio of the p-aminophenylacetic acid to the sodium hydroxide to the Boc anhydride is 1:1.5: 1.05.
Preferably, the preparation method of the compound 3 comprises the following steps:
adding a compound 2 and dichloromethane into a reaction tube, placing the reaction tube in an ice-water bath, adding 1-hydroxybenzotriazole and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, stirring, adding diisopropylethylamine and substituted amine, then moving the reaction tube to room temperature for further reaction for 12 hours, after the reaction is finished, extracting the reaction tube by using ethyl acetate, collecting an ethyl acetate layer, washing the ethyl acetate layer by using water and saturated saline water, then drying the ethyl acetate layer by using anhydrous sodium sulfate, distilling the anhydrous sodium sulfate layer under reduced pressure, and purifying the ethyl acetate layer by using silica gel column chromatography to obtain a compound 3, wherein the molar ratio of the compound 2, the 1-hydroxybenzotriazole, the 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, the diisopropylethylamine and the substituted amine is 1:1.2:1.5:3: 1.5.
Preferably, the preparation method of the compound 4 comprises the following steps:
adding compound 3 and 30% TFA/DCM into a reaction tube, reacting for 4h at room temperature, monitoring the reaction by TLC spot plate, distilling off the organic solvent under reduced pressure after the reaction is finished, adding dichloromethane for dissolution, and dissolving with saturated NaHCO3The remaining acid was neutralized with the solution, extracted with ethyl acetate, and the ethyl acetate layer was collected, washed with water and saturated brine, and then dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under the reduced pressure to give compound 4.
Preferably, the preparation method of the compound 5 comprises the following steps:
adding a compound 4 and 1H-pyrrolo [2,3-B ] pyridine-6-carboxylic acid into a reaction tube, adding dichloromethane, placing the reaction tube in an ice-water bath, adding dicyclohexylcarbodiimide and 4-dimethylaminopyridine, then moving the reaction tube to room temperature for further reaction, extracting the reaction product with ethyl acetate after the reaction is finished, collecting an ethyl acetate layer, washing the ethyl acetate layer with water and saturated saline water, drying the ethyl acetate layer with anhydrous sodium sulfate, distilling the dried ethyl acetate layer under reduced pressure, and purifying the ethyl acetate layer by silica gel column chromatography to obtain a compound 5, wherein the molar ratio of the compound 4, 1H-pyrrolo [2,3-B ] pyridine-6-carboxylic acid, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is 1:1:1.2: 0.2.
The invention also provides application of the 1H-pyrrole [2,3-b ] pyridine derivative in preparing an antitumor drug, wherein the antitumor drug comprises the 1H-pyrrole [2,3-b ] pyridine derivative or pharmaceutically acceptable salt, hydrate or combination thereof and auxiliary materials thereof.
Preferably, the 1H-pyrrolo [2,3-b ] pyridine derivative is used for preparing a medicament for treating squamous cell carcinoma of head and neck.
The invention takes aminobenzene acetic acid and Boc anhydride as initial raw materials, and prepares and synthesizes 1H-pyrrolo [2,3-B ] pyridine derivatives 5a-5d by five-step reaction, adding compound substituted amine in the second step reaction and adding 1H-pyrrolo [2,3-B ] pyridine-6-carboxylic acid in the fourth step reaction. The 1H-pyrrolo [2,3-b ] pyridine derivatives 5a-5d have a certain inhibition effect on cell viability of head and neck squamous cell carcinoma, breast cancer, pancreatic cancer, colon cancer and liver cancer, and particularly the compound 5a has a good inhibition effect on the head and neck squamous cell carcinoma cells. Therefore, the 1H-pyrrole [2,3-b ] pyridine derivative synthesized by the invention can inhibit or kill tumor cells, has good anti-tumor activity, can be applied to preparation of anti-tumor drugs, and is particularly used for preparing anti-tumor drugs for treating head and neck squamous cell carcinoma.
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FIG. 1 is a graph showing the effect of compounds 5a, 5b, 5c, 5d on the cell viability of head and neck squamous cell carcinoma cell lines, breast carcinoma cell lines, pancreatic carcinoma cell lines, colon carcinoma cell lines and liver carcinoma cell lines;
FIG. 2 is a graph of the effect of different concentrations of Compound 5a on SCC15, Cal33, Cal27, UM-1, HSC3 and SCC25 cell lines;
FIG. 3 is a graph showing the results of the inhibitory ability of 0.5. mu.M Compound 5a against the growth of SCC15 and Cal33 cells;
FIG. 4 is a graph of the effect of Compound 5a on the growth capacity of SCC15 and Cal33 cell lines;
FIG. 5 is a graph showing the effect of treatment with Compound 5a on the expression levels of cell proliferation and apoptosis marker proteins by Western blotting.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The English abbreviation used in the present invention is defined as follows:
HOBt: 1-hydroxybenzotriazole; edci: 1-ethyl-3 (3-dimethylpropylamine) carbodiimide; dipea: diisopropylethylamine; TFA: trifluoroacetic acid; DCM: dichloromethane; DCC: dicyclohexylcarbodiimide; DMAP: 4-dimethylaminopyridine.
The 1H-pyrrole [2,3-b ] pyridine derivative has the following structure:
Figure GDA0002982463850000051
wherein R is R1-CH2-, p-bromophenyl, cyclopentyl, or a pharmaceutically acceptable salt thereof, R1Is thienyl or furyl.
The synthetic route of the 1H-pyrrole [2,3-b ] pyridine derivative is as follows:
Figure GDA0002982463850000052
specifically, the preparation method of each derivative is as follows:
the product testing conditions in the following examples are as follows: recording on a 400MHz solid nuclear magnetic resonance spectrometer (Bruker AVANCE III400MHz) with Tetramethylsilicon (TMS) as an internal standard1H and13C NMR。1h NMR data are reported below: chemical shifts, in ppm (δ), multiplicity (s ═ singlet, d ═ doublet, t ═ triplet, m ═ multiplet), coupling constant (Hz), relative intensity;13the C NMR data are reported below: chemical shift (ppm).
Example 1
1H-pyrrolo [2,3-b ] of this example]R in pyridine derivatives is R1-CH2-，R1Is thienyl, i.e. of this example1H-pyrrole [2,3-b ]]The pyridine derivative is N- (4- (2-oxo-2- ((thienyl-2-methyl) amino) ethyl) phenyl) -1H-pyrrole [2,3-b]Pyridine-6-amides, abbreviated as compound 5a, compound 5a has the following structural formula:
Figure GDA0002982463850000053
the preparation of N- (4- (2-oxo-2- ((thienyl-2-methyl) amino) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide of this example is as follows:
(1) the synthesis of compound 2 is as follows:
the structural formula of compound 2 is as follows:
Figure GDA0002982463850000061
adding 3.02g (20mmol, 1equiv) of p-aminophenylacetic acid into a 100mL round-bottom flask, adding 25mL of dioxane, adding 30mL (1.5equiv) of 1M sodium hydroxide solution at the temperature of 0 ℃, stirring for 1h, dropwise adding 4.58g (21mmol, 1.05equiv) of Boc anhydride, then moving to the room temperature condition to continue reacting for 12h, adjusting the pH to 7 by using dilute hydrochloric acid after the reaction is finished, extracting with 50mL of ethyl acetate for 3 times, collecting an ethyl acetate layer, washing with water and saturated saline water, drying by using anhydrous sodium sulfate, and distilling under reduced pressure to obtain 4.06g of white solid, namely the compound 2, wherein the calculated yield is 81%.
(2) The synthesis of compound 3a is as follows:
the structural formula of compound 3a is as follows:
Figure GDA0002982463850000062
after stirring for 30min, adding 507 μ L (3mmol, 3equiv) of dipepa and 1.5mmol of thiophenamine (1.5equiv) into 5mL of dichloromethane, extracting for 3 times with 20mL of ethyl acetate after the reaction is finished, collecting an ethyl acetate layer, washing with water and saturated brine water, drying with anhydrous sodium sulfate, distilling under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography (30% Ea/hex developer) to obtain 221mg of a light yellow solid, namely the compound 3 a.
(3) The synthesis of compound 4a is as follows:
the structural formula of compound 4a is as follows:
Figure GDA0002982463850000063
adding compound 3a (0.64mmol,1equiv) into a 10mL reaction tube, adding 5mL 30% TFA/DCM, reacting at room temperature for 4h, monitoring the reaction by TLC dot plate, distilling off the organic solvent under reduced pressure after the reaction is finished, adding dichloromethane for dissolution, and dissolving with saturated NaHCO3The remaining acid was neutralized with the solution, extracted 3 times with 20mL of ethyl acetate, the ethyl acetate layer was collected, washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off under reduced pressure to obtain 148mg of a white solid, which was Compound 4 a.
(4) The synthesis of compound 5a is as follows:
adding the compound 4a (0.6mmol,1equiv) and 97mg (0.6mmol,1equiv) of 1H-pyrrolo [2,3-b ] pyridine-6-carboxylic acid into a 10mL reaction tube, adding 3mL of dichloromethane, moving to 0 ℃, adding 148mg (0.72mmol, 1.2equiv) of DCC and 15mg (0.12mmol, 0.2equiv) of DMAP, moving to room temperature, continuing to react for 12H, extracting 3 times with 20mL of ethyl acetate after the reaction is finished, collecting an ethyl acetate layer, washing with water and saturated saline water, drying with anhydrous sodium sulfate, distilling under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography (a developer is 40-60% Ea/hex) to obtain 113mg of a white solid, namely the compound 5 a.
1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.64(s,1H),8.18(d,J＝8.0Hz,1H),7.90(d,J＝8.1Hz,1H),7.79(d,J＝8.2Hz,2H),7.73(d,J＝3.0Hz,1H),7.39(s,1H),7.27(d,J＝8.2Hz,2H),6.96(s,2H),6.60(dd,J＝3.4,1.7Hz,1H),4.44(d,J＝5.7Hz,2H),3.44(s,2H).13C NMR(101MHz,DMSO)δ170.47,163.85,147.04,143.52,142.98,137.40,131.92,130.16,129.81,129.52,128.29,127.80,127.09,125.74,125.44,124.96,123.04,120.12,120.02,119.62,119.10,114.49,110.05,100.92,42.16,40.67,40.46,40.25,40.04,39.84,39.62,39.42,37.78.
Example 2
1H-pyrrolo [2,3-b ] of this example]R in pyridine derivatives is R1-CH2-，R1Is furyl. I.e. 1H-pyrrolo [2,3-b ] of the present example]The pyridine derivative is N- (4- (2-oxo-2- ((furyl-2-methyl) amino) ethyl) phenyl) -1H-pyrrole [2,3-b]Pyridine-6-amides, abbreviated as compound 5b, compound 5b has the following structural formula:
Figure GDA0002982463850000071
the preparation of N- (4- (2-oxo-2- ((furyl-2-methyl) amino) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide of this example is as follows:
(1) the synthesis method of compound 2 was the same as that of example 1.
(2) The synthesis of compound 3b is as follows:
the structural formula of compound 3b is as follows:
Figure GDA0002982463850000072
after stirring for 30min, adding 507 μ L (3mmol, 3equiv) of diapa and 1.5mmol of 2-furanmethanamine (1.5equiv), moving to room temperature for further reaction for 12h, after the reaction is finished, extracting with 20mL of ethyl acetate for 3 times, collecting an ethyl acetate layer, washing with water and saturated saline water, drying with anhydrous sodium sulfate, distilling under reduced pressure to obtain a crude product, and purifying with a silica gel column chromatography (a developer is 30% Ea/hex) to obtain 228mg of a light yellow solid, namely the compound 3 b.
(3) The synthesis of compound 4b is as follows:
the structural formula of compound 4b is as follows:
Figure GDA0002982463850000081
adding compound 3b (0.64mmol,1equiv) into a 10mL reaction tube, adding 5mL 30% TFA/DCM, reacting at room temperature for 4h, monitoring the reaction by TLC dot plate, distilling off the organic solvent under reduced pressure after the reaction is finished, adding dichloromethane for dissolution, and dissolving with saturated NaHCO3The remaining acid was neutralized with the solution, extracted 3 times with 20mL of ethyl acetate, the ethyl acetate layer was collected, washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off under reduced pressure to obtain 144mg of a white solid, which was Compound 4 b.
(4) The synthesis of compound 5b is as follows:
adding the compound 4b (0.6mmol,1equiv) and 97mg (0.6mmol,1equiv) of 1H-pyrrolo [2,3-b ] pyridine-6-carboxylic acid into a 10mL reaction tube, adding 3mL of dichloromethane, moving to 0 ℃, adding 148mg (0.72mmol, 1.2equiv) of DCC and 15mg (0.12mmol, 0.2equiv) of DMAP, moving to room temperature, continuing to react for 12H, extracting for 3 times by using 20mL of ethyl acetate after the reaction is finished, collecting an ethyl acetate layer, washing by using water and saturated saline water, drying by using anhydrous sodium sulfate, distilling under reduced pressure to obtain a crude product, and purifying by using a silica gel column chromatography (a developing agent is 40-60% Ea/hex) to obtain 107mg of white solid, namely the compound 5 b.
1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.27(s,1H),8.51(s,1H),8.18(d,J＝8.1Hz,1H),7.90(d,J＝8.1Hz,1H),7.78(d,J＝8.1Hz,2H),7.76–7.68(m,1H),7.58(s,1H),7.27(d,J＝8.1Hz,2H),6.60(d,J＝3.5Hz,1H),6.39(t,J＝2.4Hz,1H),6.22(d,J＝3.1Hz,1H),4.27(d,J＝5.6Hz,2H),3.44(s,2H).13C NMR(101MHz,DMSO)δ170.53,163.85,152.75,147.04,143.51,142.55,137.39,131.97,130.16,129.79,129.52,123.04,120.13,114.49,110.90,107.23,100.92,42.11,40.67,40.46,40.25,40.04,39.84,39.63,39.50,39.42,36.09,29.04.
Example 3
In the 1H-pyrrolo [2,3-b ] pyridine derivative of this example, R is p-bromophenyl. That is, the 1H-pyrrolo [2,3-b ] pyridine derivative of this example is N- (4- (2-oxo-2- ((4-bromophenyl) amino) -2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide, referred to as compound 5c, and the structural formula of compound 5c is as follows:
Figure GDA0002982463850000082
the preparation of N- (4- (2-oxo-2- ((4-bromophenyl) amino) -2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide of this example is as follows:
(1) the synthesis method of compound 2 was the same as that of example 1.
(2) The synthesis of compound 3c is as follows:
compound 3c has the following structural formula:
Figure GDA0002982463850000091
after stirring for 30min, adding HOBt 162mg (1.2mmol, 1.2equiv) and edci 287mg (1.5mmol, 1.5equiv) to a 10mL reaction tube, adding HOBt 162mg (1.2mmol, 1.2equiv) and epci 287mg (1.5mmol, 1.5equiv), moving to room temperature to continue the reaction for 12h, after the reaction is completed, extracting with 20mL ethyl acetate for 3 times, collecting an ethyl acetate layer, washing with water and saturated brine, drying with anhydrous sodium sulfate, distilling under reduced pressure to obtain a crude product, and purifying with silica gel column chromatography (30% Ea/hex developer) to obtain 231mg of a light yellow solid, namely the compound 3 c.
(3) The synthesis of compound 4c is as follows:
compound 4c has the following structural formula:
Figure GDA0002982463850000092
adding compound 3c (0.64mmol,1equiv) into a 10mL reaction tube, adding 5mL 30% TFA/DCM, reacting at room temperature for 4h, monitoring the reaction by TLC dot plate, distilling off the organic solvent under reduced pressure after the reaction is finished, adding dichloromethane for dissolution, and dissolving with saturated NaHCO3The remaining acid was neutralized with the solution, extracted 3 times with 20mL of ethyl acetate, the ethyl acetate layer was collected, washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off under reduced pressure to obtain 152mg of a white solid, which was Compound 4 c.
(4) The synthesis of compound 5c was as follows:
adding the compound 4c (0.6mmol,1equiv) and 97mg (0.6mmol,1equiv) of 1H-pyrrolo [2,3-b ] pyridine-6-carboxylic acid into a 10mL reaction tube, adding 3mL of dichloromethane, moving to 0 ℃, adding 148mg (0.72mmol, 1.2equiv) of DCC and 15mg (0.12mmol, 0.2equiv) of DMAP, moving to room temperature, continuing to react for 12H, extracting for 3 times by using 20mL of ethyl acetate after the reaction is finished, collecting an ethyl acetate layer, washing by using water and saturated saline water, drying by using anhydrous sodium sulfate, distilling under reduced pressure to obtain a crude product, and purifying by using a silica gel column chromatography (a developing agent is 40-60% Ea/hex) to obtain 78mg of a white solid, namely the compound 5 c.
1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.29(s,2H),8.18(d,J＝8.1Hz,1H),7.90(d,J＝8.1Hz,1H),7.82(d,J＝8.2Hz,2H),7.73(t,J＝3.0Hz,1H),7.59(d,J＝8.6Hz,2H),7.48(d,J＝8.6Hz,2H),7.33(d,J＝8.1Hz,2H),6.60(dd,J＝3.4,1.7Hz,1H),3.64(s,2H).13C NMR(101MHz,DMSO)δ169.86,163.90,147.03,143.48,139.06,137.61,132.00,131.39,130.19,129.93,129.53,123.03,121.49,120.24,115.20,114.51,100.92,43.23,40.62,40.42,40.21,40.00,39.79,39.58,39.37.
Example 4
In the 1H-pyrrolo [2,3-b ] pyridine derivative of this example, R is cyclopentyl. That is, the 1H-pyrrolo [2,3-b ] pyridine derivative of this example is N- (4- (2-oxo-2- (cyclopentylamino) -2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide, referred to as compound 5d, and the structural formula of compound 5d is as follows:
Figure GDA0002982463850000101
the preparation of N- (4- (2-oxo-2- (cyclopentylamino) -2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide of this example is as follows:
(1) the synthesis method of compound 2 was the same as that of example 1.
(2) The synthesis of compound 3d was as follows:
the structural formula of compound 3d is as follows:
Figure GDA0002982463850000102
after stirring for 30min, adding HOBt 162mg (1.2mmol, 1.2equiv) and edci 287mg (1.5mmol, 1.5equiv) to 10mL of reaction tube, adding 1mg (1mmol,1equiv) of compound, adding 3 μ L (3mmol, 3equiv) and 1.5mmol cyclopentylamine (1.5equiv), moving to room temperature to continue the reaction for 12h, extracting with 20mL ethyl acetate for 3 times, collecting ethyl acetate layer, washing with water and saturated brine, drying with anhydrous sodium sulfate, distilling under reduced pressure to obtain crude product, and purifying with silica gel column chromatography (30% Ea/hex) to obtain 175mg of light yellow solid, namely compound 3 d.
(3) The synthesis of compound 4d was as follows:
the structural formula of compound 4d is as follows:
Figure GDA0002982463850000103
adding the compounds 3a-3d (0.64mmol,1equiv) into a 10mL reaction tube, adding 5mL 30% TFA/DCM, reacting for 4h at room temperature, monitoring the reaction by TLC dot plate, distilling the organic solvent under reduced pressure after the reaction is finished, adding dichloromethane for dissolution,with saturated NaHCO3The remaining acid was neutralized with the solution, extracted 3 times with 20mL of ethyl acetate, the ethyl acetate layer was collected, washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off under reduced pressure to obtain 104mg of a white solid, which was Compound 4 d.
(4) The synthesis of compound 5d was as follows:
adding the compound 4d (0.6mmol,1equiv) and 97mg (0.6mmol,1equiv) of 1H-pyrrolo [2,3-b ] pyridine-6-carboxylic acid into a 10mL reaction tube, adding 3mL of dichloromethane, moving to 0 ℃, adding 148mg (0.72mmol, 1.2equiv) of DCC and 15mg (0.12mmol, 0.2equiv) of DMAP, moving to room temperature, continuing to react for 12H, extracting for 3 times by using 20mL of ethyl acetate after the reaction is finished, collecting an ethyl acetate layer, washing by using water and saturated saline water, drying by using anhydrous sodium sulfate, distilling under reduced pressure to obtain a crude product, and purifying by using a silica gel column chromatography (a developing agent is 40-60% Ea/hex) to obtain 49mg of white solid, namely the compound 5 d.
1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.26(s,1H),8.18(d,J＝8.0Hz,1H),8.01(d,J＝7.3Hz,1H),7.89(d,J＝8.1Hz,1H),7.77(d,J＝8.2Hz,2H),7.72(t,J＝2.9Hz,1H),7.25(d,J＝8.2Hz,2H),6.60(d,J＝1.7Hz,1H),3.97(q,J＝6.9Hz,1H),3.36(s,2H),1.79(dd,J＝12.6,6.1Hz,2H),1.67–1.59(m,2H),1.50(dd,J＝7.4,4.4Hz,2H),1.41–1.33(m,2H).13C NMR(101MHz,DMSO)δ169.99,163.85,147.03,143.51,137.27,132.40,130.17,130.00,129.72,129.67,129.53,123.02,120.13,114.50,114.22,100.91,50.78,50.66,42.27,42.12,40.67,40.62,40.46,40.41,40.21,40.00,39.79,39.58,39.37,32.79,23.93.
Example 5
In this example, compounds 5a, 5b, 5c and 5d prepared in examples 1 to 4 were tested for anti-tumor activity using SCC15, Cal27, MCF-7, MDA-MB-231, AsPC-1, PANC-1, HCT116, SW480, HepG2 and MHCC-97H, all of which were obtained from ACTT, USA. Wherein, SCC15, Cal27, MDA-MB-231, SW480, MHCC97H and HepG2 cell lines are cultured in DMEM medium, MCF-7 cell lines are cultured in MEM medium,HCT116 cell line was cultured in MCCoy's 5A medium, which contained 10% fetal bovine serum and 1% penicillin-streptomycin solution (100U/ml Penicillium and 100. mu.g/ml streptomycin), MEM medium and MCCoy's 5A medium. The cell culture conditions were 37 ℃ and 5% CO2The constant temperature incubator. The culture steps are as follows:
(1) after counting the cells with a hemocytometer, each tumor cell line was diluted to 3X 10 with the corresponding medium4Obtaining cell suspension of each tumor cell per mL;
(2) adding 100 mu L of cell suspension into each well of a 96-well plate, blowing, uniformly mixing, and incubating overnight in an incubator at 37 ℃;
(3) the compounds 5a, 5b, 5c and 5d prepared in examples 1 to 4 were diluted to a concentration of 2. mu.M, added to each tumor cell line, and incubated at 37 ℃ for 72 hours in an incubator;
(4) the cell survival ability is detected by an MTT experiment, after the drug treatment is finished, MTT with the concentration of 5mg/mL is added, and the mixture is cultured for 4 hours in an incubator at 37 ℃;
(5) adding DMSO to dissolve the cells, and then measuring the OD value (namely OD570) at 570nm by using an enzyme labeling instrument;
(6) the data were processed and the inhibition ratios were calculated from the OD values.
The experimental results are as follows: the effects of 2. mu.M of compounds 5a-5d on the cell viability of head and neck squamous cell carcinoma cell lines, breast carcinoma cell lines, pancreatic carcinoma cell lines, colon carcinoma cell lines and liver carcinoma cell lines are shown in FIG. 1. The data in fig. 1 show that compounds 5a-5d all have a certain degree of inhibition effect on cell viability of head and neck squamous cell carcinoma, breast cancer, pancreatic cancer, colon cancer and liver cancer, and especially compound 5a shows a good inhibition effect on head and neck squamous cell carcinoma cells. Therefore, the 5a described by the invention can inhibit or kill tumor cells, has good antitumor activity, and can be applied to preparation of antitumor drugs, especially used for preparing antitumor drugs for treating squamous cell carcinoma of head and neck.
To test the viability of the squamous cell carcinoma cells of the head and neck with different concentrations of Compound 5aEffect, SCC15, Cal33, Cal27, UM-1, HSC3 and SCC25 cell lines were diluted to 3X 10 with DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution (100U/ml Penicillium and 100. mu.g/ml streptomycin), respectively4One cell per mL, then inoculating 100 μ l cell suspension into 96-well plate, adding compound 5a at concentration of 0 μ M, 0.05 μ M, 0.1 μ M, 0.25 μ M, 0.5 μ M, 1 μ M, 2 μ M and 5 μ M to treat cells for 72h during incubation, and testing the effect of compound 5a at different concentrations on the cell growth ability of SCC15, Cal33, Cal27, UM-1, HSC3 and SCC25, the results are shown in FIG. 2. The data in figure 2 show that different head and neck squamous cell carcinoma cells are sensitive to compound 5a, with SCC15 and Cal33 cells being most sensitive to compound 5a compared to other cell lines. The half lethal concentration of the compound 5a in the head and neck squamous cell carcinoma is 0.5 mu M, the compound has obvious inhibition effect on various cell lines of the head and neck squamous cell carcinoma, and the activity of the head and neck squamous cell carcinoma can be effectively inhibited. In order to more truly reflect the effect of compound 5a on the growth of head and neck squamous cell carcinoma cells, the process of cell growth was photographed in real time by a high content drug screening platform, and the inhibitory ability of 0.5 μ M of compound 5a on the growth of SCC15 and Cal33 cells was examined, and the results are shown in fig. 3. The test results in fig. 3 show that 0.5 μ M compound 5a can significantly inhibit cell proliferation and induce cell death by treating SCC15 and Cal33 cells for 72 h. To further investigate the effect of 5a on the proliferative capacity of squamous cell cancer of the head and neck, on the basis of the experimental results presented in FIG. 3, 1X 10 cells were each separately examined3SCC15 and Cal33 cells were placed in a 6-well plate, incubated overnight at 37 ℃ in a 5% carbon dioxide cell incubator, treated with 0. mu.M, 0.2. mu.M, and 0.5. mu.M compounds 5a, respectively, and the incubation was terminated when the colony of cells grew to about 50 cells, fixed and stained with a 1% solution of crystal violet, and the effect of compound 5a on cell growth was examined, as shown in FIG. 4. The assay data in figure 4 show that compound 5a can significantly inhibit the proliferative capacity of SCC15 and Cal33 cells.
In addition, on the basis of the data, 0.5 μ M, 1 μ M and 2 μ M of compound 5a was added to SCC15 and Cal33 cells, respectively, and the cells were treated for 48h, and the expression levels of cell proliferation and apoptosis marker proteins were detected by western blotting, and as a result, as shown in fig. 5, p-ERK and p-AKT were significantly decreased, indicating that compound 5a can significantly inhibit the proliferation of SCC15 and Cal33 cells. Meanwhile, western blot experimental data show that the protein level of c-PARP is remarkably increased, and the result shows that the compound 5a can induce SCC15 and Cal33 cells to undergo apoptosis. In conclusion, the compound 5a has a remarkable inhibitory effect on the head and neck squamous cell carcinoma cells.
Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims. The techniques, shapes, and configurations not described in detail in the present invention are all known techniques.

Claims (9)

1.1H-pyrrolo [2,3-b ] pyridine derivatives characterized in that said derivatives have the following structure:
Figure FDA0002982463840000011
wherein R is R1-CH2-, p-bromophenyl, cyclopentyl, or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom1Is thienyl or furyl.
2. The 1H-pyrrolo [2,3-b ] pyridine derivative according to claim 1, wherein the derivative is selected from the group consisting of:
n- (4- (2-oxo-2- ((thienyl-2-methyl) amino) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide;
n- (4- (2-oxo-2- ((furanyl-2-methyl) amino) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide;
n- (4- (2-oxo-2- ((4-bromophenyl) amino) -2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide;
n- (4- (2-oxo-2- (cyclopentylamino) -2-oxoethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-6-amide.
3. A method of synthesis of 1H-pyrrolo [2,3-b ] pyridine derivatives according to claims 1-2, characterized in that it is as follows:
Figure FDA0002982463840000012
4. the method for synthesizing 1H-pyrrolo [2,3-b ] pyridine derivatives according to claim 3, wherein the compound 2 is prepared by the following method:
weighing p-aminophenylacetic acid, adding dioxane, placing in an ice water bath, adding a sodium hydroxide solution, stirring, dropwise adding Boc anhydride, then moving to room temperature for reaction for 12 hours, after the reaction is finished, adjusting the pH to 7 by using dilute hydrochloric acid, extracting by using ethyl acetate, collecting an ethyl acetate layer, washing by using water and saturated saline solution, then drying by using anhydrous sodium sulfate, and distilling under reduced pressure to obtain a compound 2, wherein the molar ratio of the p-aminophenylacetic acid to the sodium hydroxide to the Boc anhydride is 1:1.5: 1.05.
5. The method for synthesizing 1H-pyrrolo [2,3-b ] pyridine derivatives according to claim 4, wherein the compound 3 is prepared by the following method:
adding a compound 2 and dichloromethane into a reaction tube, placing the reaction tube in an ice-water bath, adding 1-hydroxybenzotriazole and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, stirring, adding diisopropylethylamine and substituted amine, then moving the reaction tube to room temperature for further reaction for 12 hours, after the reaction is finished, extracting the reaction tube by using ethyl acetate, collecting an ethyl acetate layer, washing the ethyl acetate layer by using water and saturated saline water, then drying the ethyl acetate layer by using anhydrous sodium sulfate, distilling the anhydrous sodium sulfate layer under reduced pressure, and purifying the ethyl acetate layer by using silica gel column chromatography to obtain a compound 3, wherein the molar ratio of the compound 2, the 1-hydroxybenzotriazole, the 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, the diisopropylethylamine and the substituted amine is 1:1.2:1.5:3: 1.5.
6. The 1H-pyrrolo [2,3-b ] pyridine derivatives, the synthesis methods and the uses thereof according to claim 5, wherein the compound 4 is prepared by the following method:
adding compound 3 and 30% TFA/DCM into a reaction tube, reacting for 4h at room temperature, monitoring the reaction by TLC spot plate, distilling off the organic solvent under reduced pressure after the reaction is finished, adding dichloromethane for dissolution, and dissolving with saturated NaHCO3The remaining acid was neutralized with the solution, extracted with ethyl acetate, and the ethyl acetate layer was collected, washed with water and saturated brine, and then dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under the reduced pressure to give compound 4.
7. The 1H-pyrrolo [2,3-b ] pyridine derivatives, the synthesis methods and the uses thereof according to claim 6, wherein the compound 5 is prepared by the following method:
adding a compound 4 and 1H-pyrrolo [2,3-b ] pyridine-6-carboxylic acid into a reaction tube, adding dichloromethane, placing the reaction tube in an ice-water bath, adding dicyclohexylcarbodiimide and 4-dimethylaminopyridine, then moving the reaction tube to room temperature for further reaction, extracting the reaction product with ethyl acetate after the reaction is finished, collecting an ethyl acetate layer, washing the ethyl acetate layer with water and saturated saline water, drying the ethyl acetate layer with anhydrous sodium sulfate, distilling the dried ethyl acetate layer under reduced pressure, and purifying the ethyl acetate layer by silica gel column chromatography to obtain a compound 5, wherein the molar ratio of the compound 4, 1H-pyrrolo [2,3-b ] pyridine-6-carboxylic acid, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is 1:1:1.2: 0.2.
8. The use of a 1H-pyrrolo [2,3-b ] pyridine derivative according to claims 1-2 for the preparation of an antitumor medicament comprising a 1H-pyrrolo [2,3-b ] pyridine derivative or a pharmaceutically acceptable salt, hydrate or combination thereof and an adjuvant thereof.
9. Use of a 1H-pyrrolo [2,3-b ] pyridine derivative according to claim 8 for the preparation of an antitumoral drug, characterized in that said derivative is used for the preparation of a drug for the treatment of squamous cell carcinoma of the head and neck.
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CN103429589A (en) * 2011-01-12 2013-12-04 诺瓦提斯公司 Oxazine derivatives and their use in the treatment of neurological disorders
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