CN108912035B - Indole amide compound with anti-tumor activity - Google Patents
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Abstract
The invention discloses an indoleamide compound with anti-tumor activity, which can be used for treating cancers, particularly for treating gastric cancer, liver cancer, breast cancer, lung cancer cells and cervical cancer, and is particularly used for inhibiting human gastric cancer cells MGC-803, human liver cancer cells HepG2, human breast cancer cells MCF-7, human lung cancer cells A549 and human cervical cancer cells HELA cell strains. Therefore, the compound can be used as a broad-spectrum anti-tumor medicament and has good development and application prospects.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and particularly relates to a series of indoleamide compounds, and a preparation method and application thereof.
Background
Medically, cancer (cancer) refers to a malignant tumor that originates in epithelial tissue, and is the most common type of malignant tumor. Cancer has the biological characteristics of abnormal cell differentiation and proliferation, uncontrolled growth, infiltrative and metastatic properties and the like, is a multi-factor and multi-step complex process, is divided into three processes of carcinogenesis, cancer promotion and evolution, and is closely related to smoking, infection, occupational exposure, environmental pollution, unreasonable diet and genetic factors. The etiology of malignant tumors is not fully understood. The currently well-defined cancer-related factors can be classified into exogenous and endogenous types. Gastric cancer, liver cancer, breast cancer, lung cancer cells and cervical cancer are several types of cancers with high incidence in China. The current new drug development also aims at the cancers in most cases.
The indole compounds are important heterocyclic compounds and have wide biological activity. Indole secondary metabolites are widely present in cruciferous vegetables and in a large number of marine organisms and actinomycetes. In recent years, its activity against cancer has attracted general attention. At present, a small amount of indole-structure-containing varieties such as SU11248 (trade name: sunitinib), Vinblastine (VLB, Vinblastine), Vincristine (VCR, Vincristine), Vindesine (VDS, Vindesine), Vinorelbine (VBR, Vinorelbine), indirubin and the like are put into use on the market, and the characteristics of small toxic and side effects, strong selectivity and the like highlight the special effects of indole anticancer compounds (Liu Xiao Yu, Euro Yang Guiping, research progress of indole anticancer compounds, fine chemical intermediates, volume 40, pages 5-8 in 2010). Lixuelin et al (CN103214472A) report a class of acrylic acid indoleamide compounds
The compound has inhibitory activity on various cancer cells such as lung cancer, breast cancer, osteosarcoma, cervical cancer, etc. Sung et al (proceedings of university of science and technology in Huazhong, medical edition, 2004, 33, 6 th, page 720-723) reported that indole had a good chance of inducing apoptosis in gastric cancer cells, but the mechanism was unclear.
Therefore, the development and research of compounds with broad anticancer activity still has important significance.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provided is a class of indoleamide compounds which can broadly inhibit a variety of cancers.
In a first aspect of the present invention, there is provided a class of compounds of formula I:
wherein: r' is selected from Cl or Br;
each R is independently selected from halogen, -NO2, -CN, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl; n is selected from 1, 2,3 or 4.
Preferably, each R is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl;
more preferably, each R is independently selected from fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl;
most preferably, each R is independently selected from methyl, chloro, bromo.
Preferably, n is selected from 1 or 2;
more preferably, n is 1.
Preferably, the compounds of the present invention have the following structure:
in another aspect of the invention, there is provided a process for the preparation of a compound of formula I, the synthetic route for which is as follows:
wherein R', R and n are as defined in claim 1;
the specific reaction steps are as follows:
the method comprises the following steps: 4-substituted aniline and hydrochloric acid are added into a reaction vessel, and a sodium nitrite solution is added into the solution dropwise. Carrying out suction filtration after reacting for 1 hour, dropwise adding the filtrate into a sodium sulfite solution, reacting for 1-3 hours at 80 ℃, dropwise adding concentrated hydrochloric acid, reacting for 1-3 hours at 95 ℃, standing at normal temperature overnight, and separating out a 4-substituted phenylhydrazine hydrochloride solid;
step two: sequentially adding 4-substituted phenylhydrazine hydrochloride, 4-chloro-1-hydroxy-butane sodium sulfonate, ethanol and water into a reaction vessel, adjusting the pH value of the solution to 6-7, and reacting for 5-7 hours at 75 ℃; distilling under reduced pressure to remove ethanol and part of water, washing the residual solution with dichloromethane, adjusting the pH value to 8-10, washing with chloroform, and cooling in a refrigerator at 4 ℃ overnight to precipitate 5-substituted tryptamine hydrochloride solid;
step three: sequentially adding salicylic acid derivative, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and acetone into a reaction vessel, and stirring at normal temperature for 1-3 hours; then adding the 5-substituted tryptamine hydrochloride obtained in the second step and anhydrous potassium carbonate, and stirring at normal temperature until the reaction is complete; purifying by column chromatography to obtain the compound shown in formula I.
Preferably, the molar ratio of the 4-substituted aniline, the sodium nitrite and the sodium sulfite in the first step is 1:1-1.5:2-4.5, preferably 1:1.05: 3;
the molar ratio of the 4-substituted phenylhydrazine hydrochloride to the 4-chloro-1-hydroxy-butane sodium sulfonate in the second step is 1:1-1.5, preferably 1: 1-1.2;
the molar ratio of the salicylic acid derivative, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, the 1-hydroxybenzotriazole and the 5-substituted tryptamine hydrochloride in the third step is 1:1-2:1-2: 0.5-1.5; preferably 1:1-1.5:1-1.5: 0.8-1.2.
In another aspect of the present invention, a pharmaceutical composition is provided, which comprises a compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Another aspect of the invention relates to the use of a compound of formula I for the manufacture of a medicament, characterized in that said medicament is useful for the treatment of cancer; especially for the treatment of gastric cancer, liver cancer, breast cancer, lung cancer cells and cervical cancer; in particular to the cell strains for inhibiting human gastric cancer cells MGC-803, human liver cancer cells HepG2, human breast cancer cells MCF-7, human lung cancer cells A549 and human cervical cancer cells HELA.
Defining:
"alkyl" means consisting solely of carbon and hydrogen atoms, containing no unsaturation, and may be a C1-6 alkyl group. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Representative saturated straight chain alkyl groups include, but are not limited to-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and-n-hexyl; and saturated branched alkyl groups include, but are not limited to-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methyl-pentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethyl-butyl, and the like. The alkyl group is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl. In a non-limiting embodiment, the substituted alkyl group can be selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.
"alkoxy" means an "alkyl" group attached to the parent molecule through an oxygen atom, wherein "alkyl" has the meaning described above.
"haloalkyl" refers to an alkyl group wherein all hydrogen atoms are partially or fully replaced with a halogen selected from fluoro, chloro, bromo, and iodo. In some embodiments, all hydrogen atoms are each replaced with fluoro groups. In some embodiments, all hydrogen atoms are each replaced with a chloro group. Examples of haloalkyl groups include-CF 3, -CF2CF3, -CF2CF2CF3, -CFCl2, -CF2Cl, and the like.
In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt, which is well known in the art. Examples of pharmaceutically acceptable salts are such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, acetic, oxalic, maleic, tartaric, citric, succinic or malonic, acetic, propionic, glycolic, pyruvic, oxalic, lactic, trifluoroacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, and the like.
"pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a new indole amide compound with anticancer activity, widens the range of the existing anticancer compound, and can be continuously optimized as a lead compound;
(2) the compound of the invention introduces-Cl or-Br substituent at 5-position of indole ring, so that the compound has wide application range in treating cancer, and can be used for treating various cancers.
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention.
Example 1
N- (2- (5-chloro-1H-indol-3-yl) ethyl) -2-hydroxy-3-methylbenzamide (Compound R9)
The method comprises the following steps: 4-chloroaniline (12.75g, 0.1mol) and dilute hydrochloric acid were added to a 200ml round bottom flask and added dropwise to the solution with 30ml of a solution containing (7.3g, 0.105mol) sodium nitrite. After the reaction for about 1 hour, the clear liquid is filtered out by suction and dropped into 70ml of sodium sulfite solution (37.8g, 0.3mol), the reaction is carried out for about 2.5 hours at 80 ℃, 25ml (0.3mol) of concentrated hydrochloric acid is dropped into the solution, the solution is placed at normal temperature for overnight after the reaction is carried out for about 2 hours at 95 ℃, and 15.8g of 4-chlorophenylhydrazine hydrochloride solid is separated out. Yield: 88.3 percent.
Step two: adding the 4-chlorophenylhydrazine hydrochloride (15.8g, about 0.088mol) obtained in the step one, (22.2g, 0.106mol) 4-chloro-1-hydroxy-butanesulfonic acid sodium salt, 45ml ethanol and 45ml water into a 200ml round-bottom flask in turn, adjusting the pH of the solution to 6-7 by using a disodium hydrogen phosphate solution, and condensing and refluxing the solution at 75 ℃ for about 6 hours; and removing ethanol and a small amount of water by using a rotary evaporator, washing the residual solution by using dichloromethane, adjusting the pH value to 8-10 by using a sodium carbonate solution, washing by using chloroform, and cooling overnight in a refrigerator at 4 ℃ to precipitate 12.7g of 5-chlorotrimethylamine hydrochloride solid. Yield: 62.5 percent.
Step three: to a 50ml round bottom flask were added (0.912g, 6mmol) of 3-methylsalicylic acid, (1.15g, 9mmol) of EDCI (1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride), (1.215g, 9mmol) of HOBT (1-hydroxybenzotriazole) and 15ml of acetone in this order, and the mixture was stirred at room temperature for 2 hours; then adding the 5-chlorotrimethylamine hydrochloride (1.27g, 5.5mmol) obtained in the step two and anhydrous potassium carbonate, and stirring at normal temperature for about 24 hours; purifying by column chromatography, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether. 1.31g of compound R9 (yield: 75.8%) are obtained as a brown solid with a melting point: 164 ℃ and 165 ℃.1H NMR(400MHz,DMSO)13.30(s,1H),10.94(s,1H),8.99(t,J＝5.6Hz,1H),7.67(dd,J＝5.9,2.1Hz,1H),7.35(s,1H),7.34(d,J＝3.9Hz,1H),7.32–7.30(m,1H),7.28(d,J＝2.3Hz,1H),6.96(td,J＝9.3,2.5Hz,1H),6.79(t,J＝7.7Hz,1H),3.54(dd,J＝13.3,7.2Hz,2H),2.95(t,J＝7.4Hz,2H),2.16(s,3H)。
Examples 2 to 7
Referring to the procedure of example 1, the following compounds were prepared, with the corresponding data as shown below:
comparative examples 1 to 4
Referring to the procedure of example 1, comparative example compounds R30-R33 were prepared having the following structures:
r30 is a white solid with a melting point of 147-,1H NMR(400 MHz,DMSO)13.30(s,1H),10.94(s,1H),8.99(t,J＝5.6 Hz,1H),7.67(dd,J＝5.9,2.1 Hz,1H),7.35(s,1H),7.34(d,J＝3.9 Hz,1H),7.32–7.30(m,1H),7.28(d,J＝2.3 Hz,1H),6.91(td,J＝9.3,2.5 Hz,1H),6.78(t,J＝7.7 Hz,1H),3.56(dd,J＝13.3,7.2 Hz,2H),2.95(t,J＝7.4 Hz,2H),2.16(s,3H)。
r31 is a brown solid with a melting point of 144-148 ℃,1H NMR(400 MHz,DMSO)12.69(s,1H),10.94(s,1H),8.86(t,J＝5.6 Hz,1H),7.72(d,J＝8.0 Hz,1H),7.34(dd,J＝5.1,3.6 Hz,1H),7.32(d,J＝2.2 Hz,1H),7.27(d,J＝2.2 Hz,1H),6.91(td,J＝9.2,2.5Hz,1H),6.72(s,1H),6.70(s,1H),3.55(dd,J＝13.3,7.2Hz,2H),2.94(t,J＝7.4Hz,2H),2.27(s,3H)。
r32 is a white solid with a melting point of 175-180 ℃,1H NMR(400MHz,DMSO)12.93(s,1H),10.94(s,1H),8.97(t,J＝5.5Hz,1H),7.87(d,J＝8.4Hz,1H),7.36–7.33(m,1H),7.32–7.30(m,1H),7.27(d,J＝2.2Hz,1H),6.99(dd,J＝3.7,2.0Hz,1H),6.96(d,J＝2.1Hz,1H),6.91(td,J＝9.2,2.5Hz,1H),3.57(dd,J＝13.2,7.2Hz,2H),2.94(t,J＝7.3Hz,2H)。
r33 is a white solid with a melting point of 170-172 ℃,1H NMR(400MHz,DMSO)12.61(s,1H),10.95(s,1H),8.99(t,J＝5.4Hz,1H),7.93(d,J＝2.6Hz,1H),7.43(dd,J＝8.8,2.6Hz,1H),7.34(t,J＝4.3Hz,1H),7.32(d,J＝3.6Hz,1H),7.28(d,J＝2.2Hz,1H),6.96–6.92(m,1H),6.90(dd,J＝9.1,2.4Hz,1H),3.57(dd,J＝13.2,7.1Hz,2H),2.94(t,J＝7.3Hz,2H)。
example 8 in vitro Activity assay
The cell strain is selected from MGC-803 (human gastric cancer cell), HepG2 (human liver cancer cell), MCF-7 (human breast cancer cell), A549 (human lung cancer cell) and HELA (human cervical cancer cell).
The culture solution is DMEM + 15% NBS + double antibody
Preparing a sample solution: after dissolution in DMSO (Merck), the concentration was 33333.33. mu. mol/L
1. Adding the cell suspension into a 96-well plate in 100 μ l per well (the cell content in each well is about 8000 cells/well), and culturing in a 5% CO2 incubator at 37 deg.C for 24 h;
2. adding a drug culture medium to prepare a sample solution with gradient concentration (256, 128, 64, 32, 16, 8, 4, 2 mu mol/L), discarding the original culture medium on a 96-well plate, adding culture media with different concentrations of drugs, wherein each well is 100 mu L, and each concentration is provided with 5 auxiliary wells. Using 3 per mill DMSO-containing culture medium as control for the rest wells, and culturing in 5% incubator at 37 deg.C for 48 hr;
taking out a 96-well plate in an MTT method test, adding 10 mu of LMTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyl tetrazolium bromide, 5mg/mL) solution into each well in a dark condition, and placing the solution in an incubator for 4 hours; after 4 hours, the culture solution is discarded, 150 mu LDMSO is added into each hole for dissolution and oscillation, the 490nm OD value is measured by an MK-2 full-automatic enzyme standard instrument, and the half inhibitory concentration IC50 is calculated.
The test results were as follows:
as can be seen from the above table, after introducing Cl or Br at the 5-position of the indole ring, the compounds have a wider range of inhibiting cancer cells, and specifically, the compounds of the present invention can inhibit gastric cancer, liver cancer, breast cancer, lung cancer cells and cervical cancer. Although the 5-position of the indole ring is likewise halogen, the compounds of the present application have a significantly better cancer-inhibiting effect, with unexpected technical effects and significant advances compared to the comparative compounds R30-R33 (indole ring 5-position is F).
Claims (9)
1. A compound of formula I, or a pharmaceutically acceptable salt thereof, having the structure:
wherein: r' is selected from Cl or Br;
each R is independently selected from halogen, C1-C4 alkyl;
n is selected from 1.
2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from methyl, chloro, bromo; n is 1.
3. A compound according to any one of claims 1-2, selected from the following compounds:
R11 R12
4. a process for the preparation of a compound of formula I according to claim 1, which reaction scheme is as follows:
wherein R', R and n are as defined in claim 1;
the specific reaction steps are as follows:
the method comprises the following steps: 4-substituted aniline and hydrochloric acid are added into a reaction vessel, and a sodium nitrite solution is added into the solution dropwise. Carrying out suction filtration after reacting for 1 hour, dropwise adding the filtrate into a sodium sulfite solution, reacting for 1-3 hours at 80 ℃, dropwise adding concentrated hydrochloric acid, reacting for 1-3 hours at 95 ℃, standing at normal temperature overnight, and separating out a 4-substituted phenylhydrazine hydrochloride solid;
step two: sequentially adding 4-substituted phenylhydrazine hydrochloride, 4-chloro-1-hydroxy-butane sodium sulfonate, ethanol and water into a reaction vessel, adjusting the pH value of the solution to 6-7, and reacting for 5-7 hours at 75 ℃; distilling under reduced pressure to remove ethanol and part of water, washing the residual solution with dichloromethane, adjusting the pH value to 8-10, washing with chloroform, and cooling in a refrigerator at 4 ℃ overnight to precipitate 5-substituted tryptamine hydrochloride solid;
step three: sequentially adding salicylic acid derivative, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and acetone into a reaction vessel, and stirring at normal temperature for 1-3 hours; then adding the 5-substituted tryptamine hydrochloride obtained in the second step and anhydrous potassium carbonate, and stirring at normal temperature until the reaction is complete; purifying by column chromatography to obtain the compound shown in formula I.
5. The method of claim 4, wherein:
the mol ratio of the 4-substituted aniline, the sodium nitrite and the sodium sulfite in the first step is 1:1-1.5: 2-4.5;
the molar ratio of the 4-substituted phenylhydrazine hydrochloride to the 4-chloro-1-hydroxy-butane sodium sulfonate in the second step is 1: 1-1.5;
and step three, the molar ratio of the salicylic acid derivative, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, the 1-hydroxybenzotriazole and the 5-substituted tryptamine hydrochloride is 1:1-2:1-2: 0.5-1.5.
6. The method of claim 4, wherein:
the mol ratio of the 4-substituted aniline, the sodium nitrite and the sodium sulfite in the first step is 1:1.05: 3;
the molar ratio of the 4-substituted phenylhydrazine hydrochloride to the 4-chloro-1-hydroxy-butane sodium sulfonate in the second step is 1: 1-1.2;
and step three, the molar ratio of the salicylic acid derivative, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, the 1-hydroxybenzotriazole and the 5-substituted tryptamine hydrochloride is 1:1-1.5:1-1.5: 0.8-1.2.
7. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient.
8. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 7 for the preparation of a medicament for the treatment of gastric cancer, liver cancer, breast cancer, lung cancer cells and cervical cancer.
9. The pharmaceutical of claim 8, wherein said drug selectively inhibits human gastric cancer cell MGC-803, human hepatoma cell HepG2, human breast cancer cell MCF-7, human lung cancer cell a549, and human cervical cancer cell HELA.
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| CN108558732A (en) * | 2018-06-25 | 2018-09-21 | 南华大学 | A kind of indole amides class compound of alternative treatment gastric cancer and cervical carcinoma |
| CN108623511A (en) * | 2018-06-25 | 2018-10-09 | 南华大学 | A kind of indole amides class compound can be used for treating cancer |
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| CN108558732A (en) * | 2018-06-25 | 2018-09-21 | 南华大学 | A kind of indole amides class compound of alternative treatment gastric cancer and cervical carcinoma |
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