CN111116451A - A kind of polysubstituted tryptamine benzamide compound and its preparation method and use - Google Patents
A kind of polysubstituted tryptamine benzamide compound and its preparation method and use Download PDFInfo
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- CN111116451A CN111116451A CN202010047543.4A CN202010047543A CN111116451A CN 111116451 A CN111116451 A CN 111116451A CN 202010047543 A CN202010047543 A CN 202010047543A CN 111116451 A CN111116451 A CN 111116451A
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Abstract
The invention discloses a polysubstituted tryptamine benzamide compound and a preparation method and application thereof, which are characterized in that the compound is a polysubstituted tryptamine benzamide compound with a structural formula shown in a formula I or a pharmaceutically acceptable salt, ester or solvate of the polysubstituted tryptamine benzamide compound with the structural formula shown in the formula I, and the preparation method comprises the following steps: (1) carrying out amide synthesis reaction on the compound shown as the formula II and the compound shown as the formula III so as to obtain a compound shown as a formula IV; (2) reacting a compound shown as a formula IV with a compound shown as a formula V to perform Michael addition reaction so as to obtain a compound shown as a formula I; the advantages are that it can effectively inhibit tumor growth, so as to induce tumor cell growth arrest, differentiation or apoptosis, thereby achieving the effect of inhibiting tumor cell proliferation.
Description
Technical Field
The invention relates to the field of medicines, in particular to a polysubstituted tryptophane benzamide compound and a preparation method and application thereof.
Background
In recent years, the incidence and mortality of malignant tumors is still rising, and relevant data show that about 1810 million new cancer cases and 960 ten thousand cancer death cases worldwide in 2018. In china, there are approximately 286 tumor patients, with 181 deaths, in average every 10 million people. Therefore, it is very important to develop a novel effective anti-tumor drug with proprietary intellectual property rights. The tryptamine or indole compounds generally have relatively obvious anti-tumor effect, and in addition, the benzamide structural fragments also have relatively wide application in anti-tumor small molecule drugs. Therefore, the benzamide structural fragment has important guiding significance for researching and developing novel anti-tumor small molecule drugs by carrying out structural modification and structure effect research.
Disclosure of Invention
The invention aims to solve the technical problem of providing a polysubstituted tryptophane benzamide compound which can effectively inhibit the growth of tumors so as to achieve the effects of inducing the growth arrest, differentiation or apoptosis of tumor cells and inhibiting the proliferation of the tumor cells, and a preparation method and application thereof.
The technical scheme adopted by the invention for solving the technical problems is as follows: a polysubstituted tryptophane benzamide compound has a structural formula shown in formula I, or pharmaceutically acceptable salt, ester or solvate of the polysubstituted tryptophane benzamide compound having the structural formula shown in formula I,
Wherein R is1is-H, -OCH3、-CH3、-F、-Cl、-Br、-NH2、-NO2、-CF3Or a linear alkyl group having 2 to 5 carbon atoms, R2is-H, -NO2or-NH2，R3is-H, -CH3、-CH(CH3)2Or a linear alkyl group having 2 to 5 carbon atoms, R4is-H or-CH3，R5is-H, -OCH3、-CH3、-F、-Cl、-Br、-NH2、-NO2、-CF3Or a linear alkyl group having 2 to 5 carbon atoms, n = 0, 1, 2 or 3; the compound shown in the formula I can be pharmaceutically acceptable salts, esters or solvates, wherein the salts are inorganic acid salts or organic acid salts, and the inorganic acid salts are salts formed by any one of inorganic acids of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.
Preferably, the compound of formula I is
。
The preparation method of the polysubstituted tryptophane benzamide compound comprises the following steps:
(1) carrying out amide synthesis reaction on the compound shown as the formula II and the compound shown as the formula III so as to obtain a compound shown as a formula IV;
(2) reacting a compound shown as a formula IV with a compound shown as a formula V to carry out Michael addition reaction so as to obtain a compound shown as a formula I.
Wherein R is1is-H, -OCH3、-CH3、-F、-Cl、-Br、-NH2、-NO2、-CF3Or a linear alkyl group having 2 to 5 carbon atoms, R2is-H, -NO2or-NH2，R3is-H, -CH3、-CH(CH3)2Or a linear alkyl group having 2 to 5 carbon atoms, R4is-H or-CH3，R5is-H, -OCH3、-CH3、-F、-Cl、-Br、-NH2、-NO2、-CF3Or a linear alkyl group having 2 to 5 carbon atoms, n = 0, 1, 2 or 3; the pharmaceutically acceptable salt, ester or solvate of the compound shown as the formula I, wherein the salt is inorganic acid salt or organic acid salt, and the inorganic acid salt is any one of hydrochloric acid, sulfuric acid and phosphoric acidA salt formed with an inorganic acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.
The step (1) is specifically as follows: and (2) at the temperature of 0-30 ℃, using triethylamine as an acid-binding agent to ensure that the compound shown in the formula II and the compound shown in the formula III are mixed according to a molar ratio of 1.08: 1, slowly dripping the compound shown as the formula III into the compound shown as the formula II, and transferring to room temperature to react for 2-12 hours after the compound shown as the formula II is finished, thus obtaining the compound shown as the formula IV.
The step (2) is specifically as follows: at 60-100 deg.C with CaCO3Reacting the compound shown in the formula IV with the compound shown in the formula V for 12-24 hours by using alkali or dilute hydrochloric acid as acid to obtain the compound shown in the formula I.
If in the compound of formula I R2is-NO2Then, a reduction reaction is carried out to obtain R2is-NH2The compound of (1).
The method comprises the following specific steps: at 50-70 deg.C, using concentrated hydrochloric acid as catalyst to make R2is-NO2The molar ratio of the compound shown in the formula I to the iron powder is 1: 5.7 for 3-12 hours to obtain R2is-NH2A compound of formula I.
The polysubstituted tryptophane benzamide compound is used for preparing a medicament for preventing and/or treating tumors.
The polysubstituted tryptophane benzamide compound is used for preparing the medicine for inhibiting the proliferation of the tumor cells of the eukaryote.
Compared with the prior art, the invention has the advantages that: the invention relates to a polysubstituted tryptophanyl benzamide compound, a preparation method and application thereof, wherein the compound can effectively inhibit the proliferation of eukaryotic tumor cells and prevent and/or treat tumors. The compound provided by the invention is proved to be a potential anti-tumor medicament with stronger anti-tumor cell proliferation activity by various tumor cell line tests (including leukemia cells, lymphoma cells and the like), tumor cell apoptosis experiments, compound cell cycle block detection and the like. The compound provided by the invention has the advantages of easily available raw materials and simple preparation method, a series of micromolecule inhibitors with novel structures are designed and synthesized, and experiments prove that the compound has good anticancer effect and good application prospect in the field of design and research of antitumor drugs.
Drawings
Figure 1 shows an apoptosis assay for compound 6 according to the invention;
FIG. 2 shows a cell cycle arrest pattern for Compound 6 according to the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. Herein, the "compound represented by the formula N" is sometimes also referred to as "compound N" herein, and N is any integer of 1 to 12 herein, for example, the "compound represented by the formula 6" may also be referred to as "compound 6" herein.
Detailed description of the preferred embodiment
The invention provides a compound, which is a compound with a structural formula shown in a formula I or a pharmaceutically acceptable salt, ester or solvate of the compound with the structural formula shown in the formula I,
Wherein R is1is-H, -OCH3、-CH3、-F、-Cl、-Br、-NH2、-NO2、-CF3Or a linear alkyl group having 2 to 5 carbon atoms, R2is-H, -NO2or-NH2，R3is-H, -CH3、-CH(CH3)2Or a linear alkyl group having 2 to 5 carbon atoms, R4is-H or-CH3，R5is-H, -OCH3、-CH3、-F、-Cl、-Br、-NH2、-NO2、-CF3Or a linear alkyl group having 2 to 5 carbon atoms, n = 0, 1, 2 or 3. The compound shown in the formula I can be pharmaceutically acceptable salts, esters or solvates, wherein the salt is inorganic acid salt or organic acid salt, and the inorganic acid salt is formed by any one of inorganic acids of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.
The polysubstituted tryptophanyl benzamide compound shown in the formula I is preferably any one of the following compounds:
the compound can effectively inhibit the proliferation of eukaryotic tumor cells and prevent and/or treat tumors. The compound provided by the invention is proved to be a potential anti-tumor medicament with stronger anti-tumor cell proliferation activity by various tumor cell line tests (including leukemia cells, lymphoma cells and the like), tumor cell apoptosis experiments, compound cell cycle block detection and the like. The compound provided by the invention has the advantages of easily available raw materials and simple preparation method, a series of micromolecule inhibitors with novel structures are designed and synthesized, and experiments prove that the compound has good anticancer effect and good application prospect in the field of design and research of antitumor drugs.
Detailed description of the invention
The preparation method of the polysubstituted tryptophanyl benzamide compound in the first specific embodiment comprises the following steps:
(1) carrying out amide synthesis reaction on the compound shown as the formula II and the compound shown as the formula III so as to obtain a compound shown as a formula IV; according to the embodiment of the present invention, it may further specifically be: and (2) at the temperature of 0-30 ℃, using triethylamine as an acid-binding agent to ensure that the compound shown in the formula II and the compound shown in the formula III are mixed according to a molar ratio of 1.08: 1, slowly dripping the compound shown as the III into the compound shown as the II, and transferring to room temperature for reaction for 2-12 hours;
(2) carrying out Michael addition reaction on a compound shown as a formula IV and a compound shown as a formula V so as to obtain a compound shown as a formula I; according to the embodiment of the present invention, it may further specifically be: at 60-100 deg.C with CaCO3Reacting a compound shown in a formula IV with a compound shown in a formula V for 12-24 hours by using alkali or dilute hydrochloric acid as acid;
(3) a compound of formula I: if R is2is-NO2Then, a reduction reaction is carried out to obtain R2is-NH2A compound of (1); according to the embodiment of the present invention, it may further specifically be: reacting a compound (R) shown as a formula I at 50-70 ℃ by using concentrated hydrochloric acid as a catalyst2is-NO2) The mol ratio of the iron powder to the iron powder is 1: 5.7 for 3 to 12 hours. Therefore, each reactant can react under the conditions of the most suitable temperature, the most suitable proportion and the like, side reactions are reduced, and the yield and the reaction efficiency are improved.
Wherein R is1is-H, -OCH3、-CH3、-F、-Cl、-Br、-NH2、-NO2、-CF3Or a linear alkyl group having 2 to 5 carbon atoms, R2is-H, -NO2or-NH2，R3is-H, -CH3、-CH(CH3)2Or a linear alkyl group having 2 to 5 carbon atoms, R4is-H or-CH3，R5is-H, -OCH3、-CH3、-F、-Cl、-Br、-NH2、-NO2、-CF3Or a linear alkyl group having 2 to 5 carbon atoms, n = 0, 1, 2 or 3. The compound can be quickly and effectively prepared and obtained by the preparation method, and the method is simple to operate, convenient and quick, and suitable for large-scale production.
Example 1:
preparation of (Compound 1)
1. Preparation ofN-（2-aminophenyl) acrylamides
2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) were added to dichloromethane (20mL) and acryloyl chloride (7.5 mmol) dissolved in dichloromethane (10mL) was slowly added dropwise while cooling on ice. After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Purifying and separating by column chromatography to obtain light yellow solidN- (2-aminophenyl) acrylamide, yield 60%. The compound structure confirmation data is:1H NMR (500 MHz,Chloroform-d) δ 8.09 (s, 1H), 7.89 (dd, J = 7.5, 2.0 Hz, 1H), 7.35 (td, J =7.5, 2.1 Hz, 1H), 6.95-6.85 (m, 2H), 6.48 (dd, J = 16.7, 10.2 Hz, 1H), 6.28(dd, J = 13.9, 10.0 Hz, 1H), 5.74 (dd, J = 16.7, 13.7 Hz, 1H), 4.35 (s, 2H)。
2. preparation of 3- ((2- (5-methoxy-1)H-indol-3-yl) ethyl) amino) -substitutedN- (2-nitrophenyl) propanamide
To ethylene glycol Ether (30mL)N- (2-aminophenyl) acrylamide (3.65 mmol), 5-methoxytryptamine (4.38 mmol) and a small amount of dilute hydrochloric acid were reacted at 70 ℃ overnight. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. 3- ((2- (5-methoxy-1)H-indol-3-yl) ethyl) amino) -substitutedN- (2-nitrophenyl) propanamide, yield 25%. The compound structure confirmation data is:1H NMR (500 MHz, Chloroform-d) δ 9.50 (s, 1H), 8.04 (dd, J = 7.5, 2.1 Hz, 1H), 7.75-7.70 (m, 1H), 7.69(d, J = 8.5 Hz, 1H), 7.63 (dd, J = 7.4, 2.0 Hz, 1H), 7.57 (td, J = 7.4, 1.9Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.09 (s, 1H), 7.01 (d, J = 1.5 Hz, 1H),6.70 (dd, J = 7.5, 1.5 Hz, 1H), 3.87 (s, 3H), 2.93 (t, J = 7.9 Hz, 2H), 2.72(t, J = 7.5 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.35 (t, J = 7.9 Hz, 2H), 1.43(s, 1H)。
3. preparation of Compound 1
Adding iron powder (17.8 mmol) into water (20mL), heating to 50 deg.C, adding concentrated hydrochloric acid (1 mL), heating to 70 deg.C, stabilizing for ten minutes, adding 3- ((2- (5-methoxy-1)H-indoleIndole-3-yl) ethyl) amino) -substituted ketoneNA solution of (2-nitrophenyl) propionamide (3.1 mmol) in ethanol (10mL) was reacted for 5 hours. TLC detection of the end of the reaction, NaHCO3The solution was adjusted to pH 9. Ethyl acetate was added, stirred for 10 minutes and filtered with suction (filtration assisted with celite). The organic phase was retained and purified by column chromatography to give compound 1 as a yellow oily liquid in 80% yield. The compound structure confirmation data is:1H NMR (500 MHz, DMSO-d6) δ 10.63(d, J = 8.2 Hz, 1H), 9.36 (d, J = 21.9 Hz, 1H), 7.45 (dq, J = 7.0, 3.2 Hz,2H), 7.23-7.19 (m, 1H), 7.10 (ddd, J = 6.0, 4.3, 3.1 Hz, 2H), 7.04-6.97 (m,1H), 6.89 (tdd, J = 7.5, 3.3, 1.6 Hz, 1H), 6.71 (dq, J = 8.7, 2.1 Hz, 2H),6.51 (td, J = 7.5, 1.5 Hz, 1H), 3.73 (s, 3H), 3.13 (d, J = 7.3 Hz, 2H), 3.02(t, J = 7.2 Hz, 4H), 2.65-2.54 (m, 2H), 1.23 (d, J = 4.0 Hz, 1H).13C NMR (126MHz, DMSO-d6) δ 170.83, 154.34, 153.40, 142.77, 142.69, 131.80, 127.98,126.36, 126.31, 126.06, 126.01, 123.83, 123.67, 121.58, 116.46, 116.13,112.45, 111.45, 100.59, 55.80, 54.24, 52.06, 50.17, 45.91, 27.01, 26.74,22.76, 9.08。
example 2:
preparation of (Compound 2)
1. Preparation ofN- (2-aminophenyl) methacrylamide
2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) were added to dichloromethane (20mL) and methacryloyl chloride (7.5 mmol) dissolved in dichloromethane (10mL) was slowly added dropwise while cooling on ice. After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Column chromatography purification gave a pale yellow solid, i.e., N- (2-aminophenyl) methacrylamide, 45% yield. The compound structure confirmation data is:1H NMR (500 MHz,Chloroform-d) δ 8.09 (s, 1H), 7.81 (dd, J = 7.2, 2.0 Hz, 1H), 7.35 (td, J =7.4, 1.9 Hz, 1H), 6.78-6.70 (m, 2H), 5.74- 5.69 (m, 1H), 5.33 (t, J = 1.5 Hz,1H), 4.35 (s, 2H), 1.98 (d, J = 1.3 Hz, 3H)。
2. preparation of 3- ((2- (1)H-indol-3-yl) ethyl) amino) -substitutedN- (2-aminophenyl) -2-methylpropanamide
To ethylene glycol Ether (30mL)N- (2-aminophenyl) methacrylamide (3.65 mmol) and tryptamine (4.38 mmol) in a small amount of dilute hydrochloric acid were reacted at 70 ℃ overnight. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. 3- ((2- (1)H-indol-3-yl) ethyl) amino) -substitutedN- (2-aminophenyl) -2-methylpropanamide, yield 25%. The compound structure confirmation data is:1H NMR (500 MHz, Chloroform-d)δ 9.50(s, 1H), 8.58 (dd, J = 7.5, 2.1 Hz, 1H), 8.04 (dd, J = 7.5, 2.1 Hz,1H), 7.76-7.67 (m, 2H), 7.61-7.50 (m, 2H), 7.32 (dd, J = 7.4, 1.6 Hz, 1H),7.19 (td, J = 7.5, 1.5 Hz, 1H), 7.11 (s, 1H), 6.98 (td, J = 7.4, 1.5 Hz, 1H),3.45-3.29 (m, 2H), 3.28-3.17 (m, 1H), 3.07-2.91 (m, 3H), 2.91-2.84 (m, 1H),1.74 (s, 1H), 1.34 (d, J = 6.5 Hz, 3H)。
3. preparation of Compound 2
Iron powder (17.8 mmol) was added to water (20mL) and heated to 50 ℃ followed by concentrated hydrochloric acid (1 mL) and allowed to warm to 70 ℃ for ten minutes and then a solution of 3- ((2- (1H-indol-3-yl) ethyl) amino) -N- (2-aminophenyl) -2-methylpropanamide (3.1 mmol) in ethanol (10mL) was added and allowed to react for 5 hours. TLC detection of the end of the reaction, NaHCO3The solution was adjusted to pH 9. Ethyl acetate was added, the mixture was stirred for 10 minutes, and the mixture was suction-filtered (through Celite). The organic phase was retained and purified by column chromatography to give compound 2 as a yellow oily liquid in 80% yield. The compound structure confirmation data is:1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.52(d, J = 7.9 Hz, 1H), 7.48-7.43 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.15 (d, J= 2.2 Hz, 1H), 7.14 – 7.09 (m, 2H), 7.08-7.03 (m, 1H), 6.95 (t, J = 7.4 Hz,1H), 3.25 (q, J = 6.9 Hz, 1H), 3.12 (dd, J = 11.8, 7.7 Hz, 1H), 3.00-2.94 (m,2H), 2.93 (s, 1H), 2.91-2.87 (m, 2H), 2.62 (t, J = 7.3 Hz, 2H), 1.35 (d, J =7.0 Hz, 3H), 1.29-1.16 (m, 1H).13C NMR (126 MHz, DMSO-d6) δ 158.13, 136.73,127.61, 123.24, 121.66, 121.38, 118.76, 118.67, 112.17, 111.84, 53.76, 49.97,46.08, 33.75, 24.95, 18.01, 11.07。
example 3:
preparation of (Compound 3)
1. Preparation ofN- (2-aminophenyl) methacrylamide
Prepared according to step 1 of example 2N- (2-aminophenyl) methacrylamide.
2. Preparation of 2- ((2- (1)H-indol-3-yl) ethyl) amino) -2-methyl-N- (2-nitrophenyl) propanamide
To ethylene glycol Ether (30mL)N- (2-aminophenyl) methacrylamide (3.65 mmol) and tryptamine (4.38 mmol) in a small amount of dilute hydrochloric acid were reacted at 70 ℃ overnight. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. 2- ((2- (1)H-indol-3-yl) ethyl) amino) -2-methyl-N- (2-nitrophenyl) propanamide, yield 15%. The compound structure confirmation data is:1H NMR (500 MHz, Chloroform-d)δ 9.50 (s, 1H), 8.46 (dd, J = 7.4, 2.1 Hz, 1H), 8.04 (dd, J = 7.5, 2.1 Hz,1H), 7.81 (s, 1H), 7.71 (td, J = 7.4, 1.9 Hz, 1H), 7.61 – 7.50 (m, 2H), 7.32(dd, J = 7.4, 1.6 Hz, 1H), 7.19 (td, J = 7.6, 1.5 Hz, 1H), 7.13 (s, 1H), 6.98(td, J = 7.4, 1.5 Hz, 1H), 2.82 (t, J = 5.4 Hz, 2H), 2.53 (t, J = 5.3 Hz,2H), 1.66 (s, 1H), 1.55 (s, 6H)。
3. preparation of Compound 3
Adding iron powder (17.8 mmol) into water (20mL), heating to 50 deg.C, adding concentrated hydrochloric acid (1 mL), heating to 70 deg.C, stabilizing for 10 min, and adding 2- ((2- (1)H-indol-3-yl) ethyl) amino) -2-methyl-N- (2-nitrophenyl) propanamide (3.1 mmol) in ethanol (10mL) and reacted for 5 hours. TLC detection of the end of the reaction, NaHCO3The solution was adjusted to pH 9. Adding ethyl acetate, stirring for ten minutes, and performing suction filtration (using diatomite to assist filtration)). The organic phase was retained and purified by column chromatography to give compound 3 as a yellow oily liquid in 80% yield. The compound structure confirmation data is:1H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H),9.43 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.18 (d, J= 2.4 Hz, 1H), 7.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.09-7.05 (m, 1H), 6.98 (t, J= 7.4 Hz, 1H), 6.90 (td, J = 7.6, 1.5 Hz, 1H), 6.71 (dd, J = 8.0, 1.4 Hz,1H), 6.52 (td, J = 7.6, 1.4 Hz, 1H), 3.17 (s, 2H), 2.96 – 2.94 (m, 2H), 2.82-2.79 (m, 2H), 1.27-1.21 (m, 1H), 1.14 (d, J = 6.7 Hz, 3H), 1.09 (t, J = 7.2Hz, 3H).13C NMR (126 MHz, DMSO-d6) δ 173.68, 143.05, 136.74, 129.17, 127.51,126.51, 126.34, 123.60, 123.32, 121.45, 119.59, 118.75, 116.30, 115.96,111.89, 52.49, 52.06, 49.66, 49.06, 45.97, 24.33, 16.53, 10.12, 7.67. HR-MS(ESI): Calcd for [M+H]+337.1984; Found: 337.2024。
example 4:
preparation of (Compound 4)
1. Preparation ofN- (2-amino-4-methylphenyl) methacrylamide
To dichloromethane (20mL) was added 4-methyl-2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) in an ice bath and methacryloyl chloride (7.5 mmol) dissolved in dichloromethane (10mL) was slowly added dropwise. After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Separating with column to obtain light yellow solidN- (2-amino-4-methylphenyl) methacrylamide, yield 45%. The compound structure confirmation data is:1H NMR (500MHz, Chloroform-d) δ 8.09 (s, 1H), 7.71 (d, J = 7.4 Hz, 1H), 6.57 (dd, J =7.7, 1.4 Hz, 2H), 5.79 (t, J = 1.5 Hz, 1H), 5.51-5.47 (m, 1H), 4.35 (s, 2H),2.22-2.18 (m, 3H), 1.98 (d, J = 1.3 Hz, 3H)。
2. preparation of 3- ((2- (5-methoxy-1)H-indol-3-yl) ethyl) amino) -2-methyl-N- (4-methyl-2-nitrophenyl)) Propionamide
To ethylene glycol Ether (30mL)N- (2-amino-4-methylphenyl) methacrylamide (3.65 mmol) and 5-methoxytryptamine (4.38 mmol) in dilute hydrochloric acid were reacted overnight at 70 ℃. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. 3- ((2- (5-methoxy-1)H-indol-3-yl) ethyl) amino) -2-methyl-N- (4-methyl-2-nitrophenyl) propanamide, yield 40%. The compound structure confirmation data is:1H NMR(500 MHz, Chloroform-d) δ 9.50 (s, 1H), 8.29-8.19 (m, 2H), 7.68 (s, 1H),7.55-7.49 (m, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.10 (s, 1H), 7.01 (d, J = 1.5Hz, 1H), 6.70 (dd, J = 7.5, 1.5 Hz, 1H), 3.87 (s, 3H), 3.43-3.30 (m, 2H),3.29-3.20 (m, 1H), 3.00 (tdd, J = 11.6, 8.9, 5.9 Hz, 3H), 2.89 (ddd, J =12.3, 10.3, 4.9 Hz, 1H), 2.44 (d, J = 1.3 Hz, 3H), 1.68 (s, 1H), 1.35 (d, J =6.6 Hz, 3H)。
3. preparation of Compound 4
Adding iron powder (17.8 mmol) into water (20mL), heating to 50 deg.C, adding concentrated hydrochloric acid (1 mL), heating to 70 deg.C, stabilizing for 10 min, adding 3- ((2- (5-methoxy-1)H-indol-3-yl) ethyl) amino) -2-methyl-N(4-methyl-2-nitrophenyl) propanamide (3.1 mmol) in ethanol (10mL) and reacted for 5 hours. TLC detection of the end of the reaction, NaHCO3The solution was adjusted to pH 9. Add EtOAc and stir for ten minutes, suction filter (aid filter with celite). The organic phase was retained and purified by column chromatography to give compound 4 as a yellow oily liquid in 87% yield. The compound structure confirmation data is:1H NMR (500 MHz, DMSO-d6) δ10.82 (d, J = 2.5 Hz, 1H), 9.46 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.18 (d, J= 2.4 Hz, 1H), 7.12 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.73 (dd,J = 8.7, 2.4 Hz, 1H), 6.55 – 6.50 (m, 1H), 6.37-6.31 (m, 1H), 3.77 (s, 3H),3.17 (s, 2H), 3.04 (q, J = 7.3 Hz, 7H), 2.15 (s, 3H), 1.26 (d, J = 7.0 Hz,3H), 1.23 (s, 1H).13C NMR (126 MHz, DMSO-d6) δ 172.52, 153.61, 142.55,135.49, 131.85, 127.60, 126.08, 124.27, 120.91, 117.16, 116.56, 112.64,111.75, 109.74, 100.68, 55.93, 49.57, 49.06, 48.36, 45.80, 37.59, 22.16,21.28, 17.36, 8.94. HR-MS(ESI): Calcd for [M+H]+381.2246; Found: 381.2288。
example 5:
preparation of (Compound 5)
1. Preparation ofN- (2-amino-4-methylphenyl) acrylamide
To dichloromethane (20mL) was added 4-methyl-2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) in an ice bath and slowly dropwise added acryloyl chloride (7.5 mmol) dissolved in dichloromethane (10 mL). After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Purifying by column chromatography to obtain light yellow solidN- (2-amino-4-methylphenyl) acrylamide, yield 60%. The compound structure confirmation data is:1H NMR (500 MHz,Chloroform-d) δ 8.09 (s, 1H), 7.74- 7.68 (m, 1H), 6.61 (dd, J = 6.2, 1.8 Hz,2H), 6.48 (dd, J = 16.7, 10.2 Hz, 1H), 6.26 (dd, J = 13.9, 10.0 Hz, 1H), 5.73(dd, J = 16.7, 13.7 Hz, 1H), 4.35 (s, 2H), 2.22-2.18 (m, 3H).
2. preparation of 3- ((2- (5-methoxy-1)H-indol-3-yl) ethyl) amino) -substitutedN- (4-methyl-2-nitrophenyl) propanamide (Compound 12)
To ethylene glycol Ether (30mL)N- (2-amino-4-methylphenyl) acrylamide (3.65 mmol) and 5-methoxytryptamine (4.38 mmol) in a small amount of dilute hydrochloric acid were reacted at 70 ℃ overnight. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. 3- ((2- (5-methoxy-1)H-indol-3-yl) ethyl) amino) -substitutedN- (4-methyl-2-nitrophenyl) propanamide (compound 12) in 20% yield. The compound structure confirmation data is:1H NMR (500MHz, DMSO-d6) δ 10.82-10.76 (m, 1H), 7.77 (s, 1H), 7.52 (s, 2H), 7.24 (d, J =8.6 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.73 (dd, J= 8.7, 2.4 Hz, 1H), 3.77 (s, 3H), 3.13 (dt, J = 16.4, 7.6 Hz, 4H), 3.01 (t, J= 7.8 Hz, 2H), 2.79 (t, J = 7.1 Hz, 2H), 2.36 (s, 3H).13C NMR (126 MHz, DMSO-d6) δ 169.32, 153.58, 142.98, 135.89, 134.90, 131.88, 128.76, 127.68, 126.00,125.19, 124.25, 112.60, 111.71, 110.16, 100.66, 55.90, 48.22, 43.39, 33.13,22.98, 20.48. HR-MS(ESI): Calcd for [M+H]+397.1831; Found: 397.1877。
3. preparation of Compound 5
Iron powder (17.8 mmol) was added to water (20mL) and heated to 50 ℃ and concentrated hydrochloric acid (1 mL) was added and the mixture was allowed to warm to 70 ℃ and stabilize for 10 minutes, and then a solution of compound 12 (3.1 mmol) in ethanol (10mL) was added and reacted for 5 hours. TLC detection of the end of the reaction, NaHCO3The solution was adjusted to pH 9. Ethyl acetate was added, stirred for 10 minutes and filtered with suction (filtration assisted with celite). The organic phase was retained and purified by column chromatography to give compound 5 as a yellow oily liquid in 84% yield. The compound structure confirmation data is:1H NMR (500 MHz,DMSO-d6) δ 10.67 (d, J = 2.4 Hz, 1H), 9.31 (s, 1H), 7.23 (d, J = 8.7 Hz, 1H),7.12 (d, J = 2.4 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H),6.71 (dd, J = 8.7, 2.4 Hz, 1H), 6.52 (d, J = 1.9 Hz, 1H), 6.33 (dd, J = 8.0,1.9 Hz, 1H), 4.86 (s, 2H), 3.75 (s, 3H), 2.93 (t, J = 6.7 Hz, 2H), 2.91-2.87(m, 2H), 2.86 (d, J = 6.3 Hz, 2H), 2.51-2.49 (m, 2H), 2.15 (s, 3H), 0.96 (t,J = 7.1 Hz, 1H).13C NMR (126 MHz, DMSO-d6) δ 170.62, 153.43, 142.63, 135.34,131.88, 127.95, 126.02, 123.85, 121.37, 117.25, 116.49, 112.48, 112.14,111.51, 100.63, 55.82, 49.82, 46.15, 45.66, 35.91, 25.28, 21.28, 11.82. HR-MS(ESI): Calcd for [M+H]+367.2089; Found: 367.2132。
example 6:
preparation of (Compound 6)
1. Preparation ofN-phenylacrylamide
In methylene chloride (20mL)2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) were added slowly dropwise under ice bath to acryloyl chloride (7.5 mmol) dissolved in dichloromethane (10 mL). After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Separating by column chromatography to obtain light yellow solidN-phenyl acrylamide, yield 60%. The compound structure confirmation data is:1H NMR (500 MHz, DMSO-d6) δ 10.14 (s,1H), 7.89-7.54 (m, 2H), 7.43-7.26 (m, 2H), 7.14-6.95 (m, 1H), 6.46 (dd, J =17.0, 10.1 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 5.76 (dd, J = 10.1, 2.0Hz, 1H)。
2. preparation of Compound 6
To ethylene glycol Ether (30mL)N-phenylacrylamide (3.65 mmol), 5-chlorotryptamine (4.38 mmol), CaCO3(3.65 mmol) and reacted at 70 ℃ overnight. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. compound 6, with yield of 45%. The compound structure confirmation data is:1H NMR (500 MHz,DMSO-d6) δ 11.07 (s, 1H), 10.21 (s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.54-7.51(m, 2H), 7.38 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 14.9, 6.9 Hz, 3H), 7.07 (dd,J = 8.6, 2.2 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 3.21 (s, 1H), 2.86 (d, J =18.8 Hz, 6H), 2.48 (t, J = 6.6 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.09,139.62, 135.17, 129.10, 128.91, 124.99, 123.47, 123.43, 121.25, 119.54,118.07, 113.35, 113.07, 50.24, 45.73, 37.23, 25.63. HR-MS(ESI): Calcd for [M+H]+342.1328; Found: 342.1370。
example 7:
preparation of (Compound 7)
1. Preparation ofN-phenyl methacrylamide
2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) were added to dichloromethane (20mL) and methacryloyl dissolved in dichloromethane (10mL) was slowly added dropwise under ice bathChlorine (7.5 mmol). After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Purifying by column chromatography to obtain light yellow solidNPhenyl methacrylamide, yield 70%. The compound structure confirmation data is: 1H NMR (500 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.59-7.53 (m, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.07 (tt, J =7.4, 2.0 Hz, 1H), 6.48 (dd, J = 16.6, 10.0Hz, 1H), 6.23 (dd, J = 13.9, 10.0Hz, 1H), 5.71 (dd, J = 16.7, 13.7 Hz, 1H).
2. Preparation of Compound 7
To ethylene glycol Ether (30mL)NPhenyl methacrylamide (3.65 mmol), amine (4.38 mmol), CaCO3(3.65 mmol) and reacted at 70 ℃ overnight. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. compound 7, with 30% yield. The compound structure confirmation data is:1H NMR (500 MHz,DMSO-d6) δ 11.06-10.68 (m, 1H), 10.21 (s, 1H), 7.54-7.48 (m, 3H), 7.33 (d, J= 8.1 Hz, 1H), 7.28-7.23 (m, 2H), 7.13 (d, J = 2.3 Hz, 1H), 7.05 (ddd, J =8.1, 6.9, 1.2 Hz, 1H), 7.01 (dd, J = 8.1, 6.8 Hz, 1H), 6.97-6.92 (m, 1H),3.17 (s, 1H), 2.93-2.79 (m, 5H), 2.69-2.58 (m, 2H), 1.08 (d, J = 6.6 Hz, 3H).13C NMR (126 MHz, DMSO-d6) δ 174.35, 139.81, 136.73, 129.09, 127.71, 123.36,123.06, 121.31, 119.54, 118.78, 118.61, 112.85, 111.80,53.05, 50.46, 49.08,46.18, 25.80, 16.20. HR-MS(ESI): Calcd for [M+H]+322.1875; Found: 322.1917。
example 8:
preparation of (Compound 8)
1. Preparation ofN-phenyl methacrylamide
Prepared according to step 1 of example 7N-phenyl methacrylamide.
2. Preparation of Compound 8
To ethylene glycol Ether (30mL)N-benzeneMethylmethacrylamide (3.65 mmol), 5-methoxytryptamine (4.38 mmol), CaCO3(3.65 mmol) and reacted at 70 ℃ overnight. After TLC detection, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. compound 8, with a yield of 25%. The compound structure confirmation data is:1HNMR (500 MHz, DMSO-d6) δ 10.68-10.60 (m, 1H), 10.23 (s, 1H), 7.52 (d, J = 8.0Hz, 2H), 7.26 (t, J = 7.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 2.2Hz, 1H), 7.03-6.98 (m, 2H), 6.71 (dd, J = 8.7, 2.4 Hz, 1H), 3.74 (s, 3H),2.87-2.79 (m, 5H), 2.70-2.62 (m, 2H), 1.09 (d, J = 6.4 Hz, 3H).13C NMR (126MHz, DMSO-d6) δ 174.35, 153.39, 139.80, 131.87, 129.08, 128.02, 123.75,123.36, 119.55, 112.62, 112.44, 111.47, 100.60, 55.78, 53.03, 50.37, 46.17,25.77, 16.21, 11.89. HR-MS(ESI): Calcd for [M+H]+352.1980; Found: 352.2023。
example 9:
preparation of (Compound 9)
1. Preparation ofN-phenylacrylamide
2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) were added to dichloromethane (20mL) and acryloyl chloride (7.5 mmol) dissolved in dichloromethane (10mL) was slowly added dropwise while cooling on ice. After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Separating with column to obtain light yellow solidN-phenyl acrylamide, yield 60%. The compound structure confirmation data is:1H NMR (500 MHz, DMSO-d6) δ 10.14 (s,1H), 7.89-7.54 (m, 2H), 7.43-7.26 (m, 2H), 7.14-6.95 (m, 1H), 6.46 (dd, J =17.0, 10.1 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 5.76 (dd, J = 10.1, 2.0Hz, 1H)。
2. preparation of Compound 9
To ethylene glycol Ether (30mL)N-phenylacrylamide (3.65 mmol), 5-methoxytryptamine (4.38 mmol), CaCO3（3.65mmol) was added, and the reaction was carried out at 70 ℃ overnight. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. compound 9, with 40% yield. The compound structure confirmation data is:1H NMR (500MHz, DMSO-d6) δ 10.62 (s, 1H), 10.18 (d, J = 5.3 Hz, 1H), 7.51 (d, J = 8.4Hz, 2H), 7.26 (q, J = 9.2, 8.4 Hz, 3H), 7.10 (d, J = 2.3 Hz, 1H), 7.04-6.99(m, 2H), 6.72 (dd, J = 8.8, 2.4 Hz, 1H), 3.76 (s, 1H), 3.19 (s, 3H), 2.87-2.81 (m, 6H), 2.46 (t, J = 6.7 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 171.10,153.39, 139.61, 136.73, 131.88, 129.12, 128.04, 127.72, 123.72, 123.48,123.02, 121.33, 119.53, 118.78, 118.65, 113.02, 112.79, 112.47, 111.81,111.46, 100.62, 55.78, 50.33, 50.25, 49.08, 37.28, 25.89.HR-MS(ESI): Calcdfor [M+H]+338.1824; Found: 338.1869。
example 10:
preparation of (Compound 10)
1. Preparation ofN- (2-amino-4-methylphenyl) acrylamide
To dichloromethane (20mL) was added 4-methyl-2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) in an ice bath and slowly dropwise added acryloyl chloride (7.5 mmol) dissolved in dichloromethane (10 mL). After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Separating by column chromatography to obtain light yellow solidN- (2-amino-4-methylphenyl) acrylamide, yield 40%. The compound structure confirmation data is:1H NMR (500 MHz,Chloroform-d) δ 10.46 (s, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.04 (s, 1H), 7.48(d, J = 8.6 Hz, 1H), 6.46 (d, J = 16.9 Hz, 1H), 6.33 (dd, J = 16.9, 10.2 Hz,1H), 5.87 (d, J = 10.2 Hz, 1H), 2.40 (s, 3H).
2. preparation of 3- ((2- (1)H-indol-3-yl) ethyl) amino) -substitutedN- (4-methyl-2-nitrophenyl) propanamide
To ethylene glycol Ether (30mL)N-（2-amino-4-methylphenyl) acrylamide (3.65 mmol) and tryptamine (4.38 mmol) in a small amount of diluted hydrochloric acid were reacted at 70 ℃ overnight. After TLC detection reaction is finished, extracting for 2-3 times by using water and ethyl acetate, and purifying by column chromatography to obtain a yellow oily substance, namely 3- ((2- (1)H-indol-3-yl) ethyl) amino) -substitutedN- (4-methyl-2-nitrophenyl) propanamide, yield 30%. The compound structure confirmation data is:1H NMR (500 MHz, Chloroform-d) δ9.50 (s, 1H), 8.28-8.19 (m, 2H), 7.74 (s, 1H), 7.53 (ddd, J = 8.4, 4.3, 1.4Hz, 2H), 7.32 (dd, J = 7.4, 1.6 Hz, 1H), 7.19 (td, J = 7.5, 1.5 Hz, 1H), 7.10(s, 1H), 6.98 (td, J = 7.4, 1.5 Hz, 1H), 2.93 (t, J = 7.9 Hz, 2H), 2.72 (t, J= 7.5 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.44 (d, J = 1.4 Hz, 3H), 2.35 (t, J= 7.9 Hz, 2H), 1.47 (s, 1H)。
3. preparation of Compound 10
Adding iron powder (17.8 mmol) into water (20mL), heating to 50 deg.C, adding concentrated hydrochloric acid (1 mL), heating to 70 deg.C, stabilizing for 10 min, adding 3- ((2- (1)H-indol-3-yl) ethyl) amino) -substitutedN(4-methyl-2-nitrophenyl) propanamide (3.1 mmol) in ethanol (10mL) and reacted for 5 hours. TLC detection of the end of the reaction, NaHCO3The solution was adjusted to pH 9. Ethyl acetate was added, stirred for 10 minutes and filtered with suction (filtration assisted with celite). The organic phase is retained and purified by column chromatography to give a yellow oily liquid, i.e. 3- ((2- (1)HIndol-3-yl) amino) -N- (2-amino-4-methylbenzoyl) alanyl in 85% yield. The compound structure confirmation data is:1H NMR (500 MHz, DMSO-d6) δ 10.94-10.70 (m, 1H), 9.29 (s, 1H),7.54 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H),7.07 (t, J = 7.5 Hz, 1H), 7.00-6.95 (m, 2H), 6.53 (d, J = 1.8 Hz, 1H), 6.34(dd, J = 8.0, 1.9 Hz, 1H), 4.83 (s, 2H), 2.93-2.84 (m, 4H), 2.54-2.43 (m,4H), 2.15 (s, 3H), 0.96 (t, J = 7.2 Hz, 1H).13C NMR (126 MHz, DMSO-d6) δ170.84, 142.63, 136.72, 135.47, 127.62, 126.09, 123.13, 121.39, 121.30,118.76, 118.69, 117.33, 116.52, 112.48, 111.84, 49.96, 46.11, 45.73, 36.03,25.38, 21.26, 11.67. HR-MS(ESI): Calcd for [M+H]+337.1984; Found: 337.2027。
example 11:
preparation of (Compound 11)
1. Preparation ofN- (2-amino-4-fluorophenyl) acrylamides
To dichloromethane (20mL) was added 4-fluoro-2-nitroaniline (8.1 mmol) and triethylamine (24.4 mmol) in an ice bath and slowly dropwise added acryloyl chloride (7.5 mmol) dissolved in dichloromethane (10 mL). After the dropwise addition, the reaction mixture is turned to room temperature and stirred for 5 to 12 hours. The reaction was run to completion by TLC and the remaining organic phase was extracted with water and dichloromethane. Purifying by column chromatography to obtain light yellow solidN- (2-amino-4-fluorophenyl) acrylamide, yield 45%. The compound structure confirmation data is:1H NMR (500 MHz,Chloroform-d) δ 8.09 (s, 1H), 7.77 (dd, J = 7.5, 5.7 Hz, 1H), 6.63 (ddd, J =9.3, 7.6, 2.1 Hz, 1H), 6.48 (dd, J = 16.8, 10.2 Hz, 1H), 6.38 (dd, J = 8.9,2.0 Hz, 1H), 6.29 (dd, J = 13.7, 9.9 Hz, 1H), 5.74 (dd, J = 16.7, 13.7 Hz,1H), 4.35 (s, 2H)。
2. preparation of 3- ((2- (1)H-indol-3-yl) ethyl) amino) -substitutedN- (4-fluoro-2-nitrophenyl) propanamide
To ethylene glycol Ether (30mL)N-(2-amino-4-fluorophenyl) acrylamide (3.65 mmol) and tryptamine (4.38 mmol) in a small amount of diluted hydrochloric acid were reacted at 70 ℃ overnight. After TLC detection reaction, extracting with water and ethyl acetate for 2-3 times, and purifying by column chromatography to obtain yellow oily substance, i.e. 3- ((2- (1)H-indol-3-yl) ethyl) amino) -substitutedN- (4-fluoro-2-nitrophenyl) propanamide, yield 25%. The compound structure confirmation data is:1H NMR (500 MHz, Chloroform-d)δ 9.50 (s, 1H), 8.45 (dd, J = 7.6, 5.6 Hz, 1H), 8.01 (dd, J = 8.8, 2.0 Hz,1H), 7.74 (s, 1H), 7.53 (dd, J = 7.4, 1.4 Hz, 1H), 7.45 (ddd, J = 9.3, 7.4,1.9 Hz, 1H), 7.32 (dd, J = 7.4, 1.6 Hz, 1H), 7.19 (td, J = 7.5, 1.5 Hz, 1H),7.10 (s, 1H), 6.98 (td, J = 7.4, 1.5 Hz, 1H), 2.93 (t, J = 7.9 Hz, 2H), 2.72(t, J = 7.5 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.35 (t, J = 7.9 Hz, 2H), 1.43(s, 1H)。
3. preparation of Compound 11
Adding iron powder (17.8 mmol) into water (20mL), heating to 50 deg.C, adding concentrated hydrochloric acid (1 mL), heating to 70 deg.C, stabilizing for ten minutes, and adding 3- ((2- (1)H-indol-3-yl) ethyl) amino) -substitutedN(4-fluoro-2-nitrophenyl) propanamide (3.1 mmol) in ethanol (10mL) and reacted for 5 hours. TLC detection of the end of the reaction, NaHCO3The solution was adjusted to pH 9. Ethyl acetate was added, stirred for 10 minutes and filtered with suction (filtration assisted with celite). The organic phase was retained and purified by column chromatography to give compound 11 as a yellow oily liquid in 80% yield. The compound structure confirmation data is:1H NMR (500 MHz, DMSO-d6) δ 10.97-10.88 (m, 1H),9.37 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 (d, J= 2.4 Hz, 1H), 7.11-7.06 (m, 2H), 7.00 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.48(dd, J = 11.3, 2.9 Hz, 1H), 6.28 (td, J = 8.5, 2.9 Hz, 1H), 5.32 (s, 2H),3.11 (t, J = 6.9 Hz, 2H), 3.09-3.05 (m, 2H), 3.02- 2.98 (m, 2H), 2.69 (t, J =6.8 Hz, 2H), 1.24 (s, 1H).13C NMR (126 MHz, DMSO-d6) δ 169.82, 162.13,160.24, 145.23, 145.13, 136.75, 127.93, 127.85, 127.40, 123.51, 121.54,119.46, 118.83, 118.71, 111.94, 110.89, 102.18, 102.00, 101.64, 101.43,49.06, 48.70, 46.02, 44.34, 33.63, 23.51. HR-MS(ESI): Calcd for [M+H]+341.1733; Found: 341.1775。
example 12:
preparation of (Compound 12)
1. Preparation ofN- (2-amino-4-methylphenyl) acrylamide
Prepared according to step 1 of example 5N- (2-amino-4-methylphenyl) acrylamide.
2. Preparation of Compound 12
Compound 12 was prepared according to step 2 of example 5.
Detailed description of the preferred embodiment
Use of a compound prepared according to the above embodiment one or embodiment two in the manufacture of a medicament. The medicine is a potential medicine for inhibiting the proliferation of eukaryotic tumor cells and preventing and/or treating tumors.
The above eukaryote is a mammal; the tumor cell is a cancer cell; the cancer cells are leukemia cells, lymphoma cells, breast cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, stomach cancer cells, nasopharyngeal cancer cells, colon cancer cells, bladder cancer cells or rectal cancer cells, wherein the leukemia cells are preferably human chronic myelogenous leukemia cells and human acute lymphocytic leukemia cells, and the lymphoma cells are preferably human histiocytic lymphoma cells.
It is to be noted that the above-mentioned drug of the present invention can be introduced into the body, such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue, by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or can be mixed or coated with other materials and introduced into body. If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field. In addition, the medicine of the invention can be prepared into various forms such as injection, tablets, powder, granules, capsules, oral liquid, ointment, cream and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
Example 1
Screening of tumor cell proliferation inhibitory Activity by MTT method
The in vitro cell proliferation inhibitory activity of the compounds prepared in examples 1 to 12 of the second embodiment was examined by the MTT method using human Chronic myelocytic leukemia cell line K562 cells (suspension cells), human acute lymphoblastic leukemia cells CCRF-CEM (suspension cells) and human histiocytic lymphoma cells U937 (suspension cells) in logarithmic growth phaseAnd (4) sex. Wherein, the positive control drugs are: cydapamide. Tumor cells are cultured in RPIM-1640 culture medium containing 10% fetal calf serum at 37 deg.C with 5% CO2Culturing under conventional conditions; the specific steps of the cell proliferation inhibition activity test are as follows: (a) preparing a dimethyl sulfoxide DMSO solution with an initial concentration of 5mM from the tested compounds respectively, and performing gradient dilution on the obtained initial concentration solution to obtain compound solutions with multiple concentration gradients of 2.5 mM, 1mM, 0.5 mM, 0.1 mM, 0.01 mM and the like; (b) tumor cells were added at 1.5X 10/ml5The cell density of each (suspension cells) was seeded in a 96-well plate (99. mu.L per well), and then 1. mu.L of the test compound solution was added to each well to give final concentrations of the compounds of 0.1. mu.M, 1. mu.M, 5. mu.M, 10. mu.M, 25. mu.M and 50. mu.M, respectively. Three replicates per concentration of each compound were set. In addition, a blank was set in the 96-well plate, without test compound added to the blank; (c) the 96-well plate was left in the incubator for 72 hours, then MTT solution (10. mu.L per well) was added thereto, followed by further incubation in the incubator for 4 hours and centrifugation at 4 ℃ and a centrifugation speed of 2000 rpm for 5 minutes. The supernatant was aspirated off, and DMSO (100 μ L per well) was added, followed by shaking the 96-well plate with a micro-shaker for about 3-5 minutes; (d) finally, OD was measured at 490 nm with a microplate reader, and the inhibition rate of cell proliferation (IR%) was calculated. The calculation formula is as follows: IR% ((positive control OD-drug sample OD)/(positive control OD-blank OD) × 100%). The results are shown in Table 1.
TABLE 1 screening results for antiproliferative Activity of Compounds 1-12
Note: IC (integrated circuit)50The median inhibitory concentration is indicated.
Table 1 showsNMTT results of- (2-substituted phenyl) benzamide-4-methylaminoacridine compounds. As can be seen from the results, some of the compounds showed outstanding anti-cancer activity in vitro on leukemia CCRF-CEM cells, leukemia K562 cells and lymphoma U937 cells, wherein compound 6 was on trioThe anti-proliferation activity of the seed tumor cell is the best, and the seed tumor cell deserves subsequent intensive research.
Example 2
And (3) detecting cell apoptosis: whether Compound 6 induces apoptosis in tumor cells (U937 cells, CCRF-CEM cells, and K562 cells) was verified by using Annexin V-FITC apoptosis assay kit. The results are shown in figure 1, taking leukemia CCRF-CEM cells as an example (compound 6 treated cells for 48 h), compound 6 increased from 0 μ M to 8 μ M, significantly causing early and late apoptosis of U937 cells (percentage of apoptosis increased from 0.021% to 23.1% when not dosed). Thus, compound 6 was shown to induce apoptosis of tumor cells by the above biological tests.
Example 3
Cell cycle arrest detection: it was further found by experiments that the test results are shown in FIG. 2, the increase of the compound 6 from 0 μ M to 8 μ M significantly induces cycle arrest of the leukemia CCRF-CEM cells in the G0/G1 phase, as shown in the following Table 2, the compound 6 treated cells for 48h, and the drug concentration at 8 μ M reaches 92.3% of the ratio of G0/G1 phase.
TABLE 2 CCRF-CEM cells 48h
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also realize that changes, modifications, additions and substitutions can be made without departing from the true spirit and scope of the invention.
Claims (9)
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