CN115746017A - Thienopyrimidine compound and preparation method and application thereof - Google Patents
Thienopyrimidine compound and preparation method and application thereof Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a thienopyrimidine compound. The structural formula of the thienopyrimidine compound is shown as the following formula (I). The thienopyrimidine compound has simple preparation process, simple and feasible separation and purification steps and high product yield. The thienopyrimidine compound has antitumor activity on cervical cancer, colon cancer, breast cancer, lung cancer and liver cancer, and especially has higher activity on cervical cancer, colon cancer and breast cancer than colchicine, so that the thienopyrimidine compound has excellent antitumor effect and application prospect.
Description
Technical Field
The present invention is in the field of heterocyclic compounds. More particularly, relates to a thienopyrimidine compound, and a preparation method and application thereof.
Background
Malignant tumors are a serious disease seriously harming human health, surpass cardiovascular diseases at present, become the diseases with the highest global mortality rate, and overcoming the malignant tumors is still a great challenge in modern medicine. In recent years, with the progress of research on cellular carcinogenesis, various basic vital mechanisms of malignant tumor cells, such as signal transduction, cycle regulation, apoptosis induction, and angiogenesis, have been elucidated. However, although the clinically used antitumor drugs have a certain curative effect, the problems of poor selectivity, large toxic and side effects, easy occurrence of drug resistance and the like still exist, so that the search for an efficient, high-selectivity and low-toxicity broad-spectrum anticancer drug is a main direction for the development of the anticancer drugs at present.
The heterocyclic compound containing nitrogen and sulfur occupies an important position in the design and screening of drug molecules, wherein the thienopyrimidine is an important nitrogen and sulfur heterocyclic compound which is similar to purine in structure, and the derivative thereof has a plurality of biological activities of good cancer resistance, malaria resistance, bacteria resistance, oxidation resistance, virus resistance and the like, and plays a pharmacological potential in the aspects of sterilization, disinsection, weeding and medicine; in addition, it is also widely used for the development and screening of drug molecules. The compounds become hot spots of research of researchers in the field of pharmacy. The common synthetic method of thienopyrimidine and its derivatives is: firstly, the thienopyrimidine derivatives are synthesized from thiophene rings, and are prepared by cyclization of ortho-substituted aminothiophene and various electrophilic reagents. Secondly, a thiophene ring is condensed from a pyrimidine ring to obtain a thienopyrimidine derivative, the method is relatively less applied, mainly halogen atoms on the pyrimidine ring are replaced by sulfydryl to introduce sulfur or the sulfur is introduced through alkylation of thioketone on the pyrimidine ring, and a catalyst commonly used in the method is mainly transition metal Pd and hydroxide Pd (OH) thereof 2 。
Chinese patent CN200780024503.0 discloses a pharmaceutical compound based on a thienopyrimidine ring, which has activity as a PBK inhibitor and thus is useful for the treatment of diseases and disorders caused by abnormal cell growth, function or behavior associated with PI3 kinase, such as cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine disorders and neurological disorders.
However, at present, no approved antitumor drug is reported based on the thienopyrimidine derivatives. In addition, the anticancer effect of the existing thienopyrimidine compounds is still not ideal, and how to provide an acridine compound with excellent antitumor effect becomes a technical problem to be solved urgently.
Disclosure of Invention
In view of the above problems of the prior art, a primary object of the present invention is to provide a thienopyrimidine compound having excellent antitumor activity against cervical cancer, colon cancer, breast cancer, lung cancer and liver cancer, and particularly having excellent antitumor activity against cervical cancer, colon cancer and breast cancer higher than colchicine.
The second purpose of the invention is to provide a preparation method of the thienopyrimidine compound.
The third purpose of the invention is to provide the application of the thienopyrimidine compound in preparing anti-tumor drugs.
The fourth purpose of the invention is to provide the application of the thienopyrimidine compound and the PD-L1 inhibitor in preparation of antitumor drugs.
The above purpose of the invention is realized by the following technical scheme:
a thienopyrimidine compound, the structural formula of which is shown as the following formula (i):
further claimed is a process for the preparation of the thienopyrimidines of formula (i) above, comprising the following preparation steps:
(1) Dissolving 4-chloro-2-methylthiophene [3,2-d ] pyrimidine and 1-methyl-5-aminoindole in a first solvent, adding glacial acetic acid, reacting at 70-90 ℃, and performing suction filtration to obtain a crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidine-4-amine;
(2) Dissolving methyl iodide in a second solvent, mixing with the crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidin-4-amine in the step (1), reacting at normal temperature under the catalysis of sodium hydride, and extracting and then processing to obtain the thienopyrimidine compound;
the reaction formula of the preparation method is as follows:
preferably, the molar ratio of the 4-chloro-2-methylthiophene [3,2-d ] pyrimidine to the 1-methyl-5-aminoindole is 1:1 to 1.1.
Preferably, the molar ratio of the crude 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidin-4-amine to the methyl iodide is 1:1-1.5.
Further preferably, the molar ratio of the crude 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidin-4-amine and the methyl iodide is 1.5.
Preferably, the first solvent is absolute ethanol.
Preferably, the second solvent is anhydrous tetrahydrofuran.
Preferably, in the step (1), the reaction time is 1 to 3 hours.
Preferably, in the step (1), the reaction time is 2h.
Preferably, in the step (2), the normal-temperature reaction is performed at 20 to 25 ℃.
Preferably, in the step (2), the reaction time of the normal-temperature reaction is 1 to 3 hours.
Further preferably, in the step (2), the reaction time of the normal temperature reaction is 2 hours.
Further preferably, in the step (1), glacial acetic acid is added and then the reaction is carried out at 80 ℃.
Specifically, the post-extraction treatment is to extract the product obtained after the reaction in the step (2) by using a mixed solution of ethyl acetate and water, separate to obtain an organic phase, dry, exsolution, and separate and purify by using column chromatography to obtain the thienopyrimidine compound.
Specifically, as a specific embodiment of the present invention, the process for producing the thienopyrimidine compound of the above formula (i) comprises the following production steps: (1) Dissolving 4-chloro-2-methylthiophene [3,2-d ] pyrimidine and 1-methyl-5-aminoindole in absolute ethyl alcohol, adding glacial acetic acid, reacting at 70-90 ℃ for 1-3H, and performing suction filtration to obtain a crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidine-4-amine;
(2) Dissolving methyl iodide in anhydrous tetrahydrofuran, mixing with the crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidine-4-amine in the step (1), reacting at normal temperature for 1-3H under the catalysis of sodium hydride, extracting by using a mixed solution of ethyl acetate and water, separating to obtain an organic phase, drying, desolventizing, and then separating and purifying by adopting column chromatography to obtain the thienopyrimidine compound.
In addition, the application also claims the application of the thienopyrimidine compound shown as the formula (I) in preparing antitumor drugs.
Furthermore, the application of the thienopyrimidine compound shown as the formula (I) and the PD-L1 inhibitor in combination in preparing the antitumor drug is also within the protection scope of the application. The inventor finds that the combined use of the thienopyrimidine compound of the formula (I) and the PD-L1 inhibitor has obvious synergistic effect and can exert more excellent antitumor effect in vivo and obtain more excellent antitumor effect compared with the use of the thienopyrimidine compound of the formula (I) or the PD-L1 inhibitor alone.
Further preferably, the PD-L1 inhibitor is the PD-L1 inhibitor NP-19.
Preferably, the tumor is one or more of cervical cancer, colon cancer, breast cancer, lung cancer or liver cancer.
More preferably, the tumor is one or more of cervical cancer, colon cancer or breast cancer.
Compared with the prior art, the invention has the following beneficial effects: the invention provides a novel thienopyrimidine compound, which has simple and convenient preparation process, simple and easy separation and purification steps and high product yield. The thienopyrimidine compound has excellent antitumor activity on cervical cancer, colon cancer, breast cancer, lung cancer and liver cancer, and particularly has higher antitumor activity on the cervical cancer, the colon cancer and the breast cancer than colchicine, so the thienopyrimidine compound has excellent antitumor effect and application prospect.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a thienopyrimidine compound in example 1 of the invention.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of a thienopyrimidine compound of example 1 of the invention.
FIG. 3 is a graph showing the size of tumors in mice treated by different treatment groups.
FIG. 4 is a graph showing the tumor growth inhibition rate of mice treated by different treatment groups.
FIG. 5 is a graph of the body weight of mice as a function of time after treatment of the mice in different treatment groups.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
EXAMPLE 1 preparation of a thienopyrimidine Compound
The thienopyrimidine compound comprises the following preparation steps:
(1) Dissolving 4-chloro-2-methylthiophene [3,2-d ] pyrimidine (1mmol, 184.64mg) and 1-methyl-5-aminoindole (1mmol, 146.19mg) in absolute ethyl alcohol, adding 1 drop of glacial acetic acid, reacting at 80 ℃ for 30 minutes, separating out a solid after the reaction is finished, and performing suction filtration to obtain a crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidine-4-amine, and directly putting the crude product into the next step.
(2) Dissolving methyl iodide in anhydrous tetrahydrofuran, and mixing with the crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidin-4-amine obtained in step (1), wherein the molar ratio of methyl iodide to the crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidin-4-amine is 1.5:1, reacting for 2 hours at normal temperature under the catalysis of sodium hydride, extracting the reaction liquid by using a mixed solution of ethyl acetate and water, taking an organic phase, drying the organic phase by using anhydrous sodium sulfate, desolventizing, and separating and purifying by column chromatography to obtain a yellow solid 185mg. The overall yield of the process described in this example was calculated to be 60%.
The obtained yellow solid is identified by nuclear magnetic resonance spectrum,as shown in fig. 1 and fig. 2, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram of the yellow solid product respectively have the following identification results: 1 H NMR(400MHz,CDCl 3 )δ7.61(s,1H),7.40(d,J＝8.5Hz,1H),7.33(d,J＝5.5Hz,1H),7.19(dd,J＝7.6,4.5Hz,3H),6.55(d,J＝2.5Hz,1H),3.89(s,3H),3.67(s,3H),2.71(s,3H). 13 C NMR(101MHz,CDCl 3 )δ163.42,161.11,158.04,136.22,135.46,133.14,130.45,128.62,123.23,122.84,122.05,113.29,109.96,101.63,77.41,77.09,76.77,39.74,33.06,25.84.
according to the identification result, the obtained yellow solid is N, 2-dimethyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidine-4-amine, and the structural formula of the yellow solid is shown as the formula (I).
The preparation method of the thienopyrimidine compound has the following process route:
EXAMPLE 2 in vitro antitumor Activity test of thienopyrimidines
In this example, MTT method was used to detect the in vitro anti-tumor activity of the compound of formula (I) in example 1 (the tumor cells used in this example were human cervical cancer cell HeLa, human colon cancer cell HCT116, human breast cancer cell MCF7, human lung cancer cell H23 and human liver cancer cell HepG 2).
Cells were collected in log phase and cell suspension concentration was adjusted at 4X 10 3 -5×10 3 one/mL of the cells were inoculated in a 96-well plate and incubated for 12-24h. After the cells have adhered to the wall, the compound of formula (I) of example 1 is added in different concentrations, setting a total of 9 concentration gradients of 0.39,0.78,1.56,3.12,6.25,12.50,25,50,100nmol/L, each concentration being 3 duplicate wells. Standing at 37 deg.C and 5% CO 2 And an incubator for starting time-lapse culture. After 48h of drug addition, the 96-well plate was removed and 20. Mu.L of 5mg/mL MTT solution was added to each well and incubation was continued for 4h at 37 ℃. Then, get smallThe supernatant in the wells was removed by cardiac suction, 100. Mu.L DMSO was added to each well, and the mixture was shaken for 10min to dissolve the crystals. The absorbance (OD) of each well was measured on an enzyme linked immunosorbent assay (ELISA) using a 570nm wavelength. Finally, data statistics were performed, in which the OD value (570 nm) was taken as the ordinate and the treatment time was taken as the abscissa, to thereby plot the effect of the drug on the inhibition of cell growth. The inhibition rate was calculated according to the following formula = (1-addition drug OD value/control group OD value) × 100%. Colchicine was set as a positive control. Half maximal inhibitory IC was calculated using GraphPad Prism software 50 . The results of the measured activities are shown in table 1:
the antitumor activity (nM,
)
as can be seen from table 1 above, the anti-tumor activity of the compound of formula (i) in example 1 was significantly different from that of the positive control group by P <0.05 for human cervical cancer cells HeLa. For human colon cancer cells HCT116, the antitumor activity of the compound of formula (i) in example 1 was significantly different from that of the positive control group at P < 0.001. The antitumor activity of the compound of formula (i) in example 1 was significantly different from that of the positive control group by P <0.001 for human breast cancer cells MCF 7. In contrast, the antitumor activity of the compound of formula (I) in example 1 was slightly inferior to that of the positive control group in human lung cancer H23 and human liver cancer cell HepG 2.
The in vitro experiment results show that the compound in the formula (I) in the example 1 has stronger inhibition effects on five human tumor cells, namely the human cervical cancer cell HeLa, the human colon cancer cell HCT116, the human breast cancer cell MCF7, the human lung cancer cell H23 and the human liver cancer cell HepG2, wherein the inhibition activities on the human cervical cancer cell HeLa, the human colon cancer cell HCT116 and the human breast cancer cell MCF7 are obviously better than the inhibition activities on a positive control colchicine.
Example 3 in vivo antitumor Activity test of thienopyrimidines
Example 1 the in vivo anti-tumour activity of a compound of formula (i) was tested using the following method, in particular:
establishing a B16-F10 tumor model of a male C57 mouse: the B16-F10 tumor cells were implanted subcutaneously in mice for about one week, and the mice were intraperitoneally injected once daily for 12 days with 7mg/kg of the compound of formula (I) of example 1 and 7mg/kg of the PD-L1 inhibitor NP-19. To determine whether the compound of formula (I) of example 1 and the PD-L1 inhibitor NP-19 produced an antitumor synergistic effect, mice were injected intraperitoneally once daily for 12 days with a dose of 3.5mg/kg of the compound of formula (I) and 3.5mg/kg of the PD-L1 inhibitor NP-19. A blank control was set up in the experiment.
FIG. 3 is a graph showing the size of tumors in mice treated by different treatment groups; as shown in FIG. 3, the tumor size in mice was significantly smaller in the group treated with 7mg/kg of the compound of formula (I) and the group treated with 7mg/kg of the PD-L1 inhibitor, relative to the blank control group. In the treatment group combining the compound of formula (I) and the PD-L1 inhibitor, the tumor size in mice is obviously smaller than that in the treatment group using the compound of formula (I) alone, the treatment group using the PD-L1 inhibitor and the blank control group.
FIG. 4 is a graph showing the tumor growth inhibition rate of mice treated by different treatment groups; as shown in FIG. 4, the compound of formula (I) in example 1 was effective in inhibiting the growth of mouse B16-F10 tumor cells in vivo with a tumor growth inhibition ratio (TGI) of 59.4%; the Tumor Growth Inhibition (TGI) of mice in the group treated with PD-L1 inhibitor alone was 59.4%; the compound of formula (I) and PD-L1 inhibitor were used in combination to treat mice with a TGI of 73.1%. The treatment group with the compound of formula (i) in combination with the PD-L1 inhibitor showed a very significant difference of P <0.001 compared to the treatment group with the PD-L1 inhibitor alone, indicating that the compound of formula (i) in combination with the PD-L1 inhibitor resulted in an enhanced antitumor activity. The treatment group with the compound of formula (i) in combination with the PD-L1 inhibitor showed a significant difference compared to the treatment group with the compound of formula (i) alone, with P < 0.01. Compared with the blank control group, the # P is less than 0.001, and the difference is very significant.
FIG. 5 is a graph of the body weight of mice as a function of time after treatment of the mice in different treatment groups. As shown in fig. 5, after 12 days of culture, the body weight of the blank control group mice was about 26g; in the treatment group using the compound of formula (I), the body weight of the mice was about 23g; in the treatment group with the PD-L1 inhibitor, the body weight of the mice was about 25g; in the treatment group using the compound of formula (I) in combination with the PD-L1 inhibitor, the mice weighed about 22.5g. The data above demonstrate that none of the three treatment groups of mice experienced significant weight loss during the treatment period.
The results show that the thienopyrimidine compound provided by the invention has excellent antitumor activity on cervical cancer, colon cancer, breast cancer, lung cancer and liver cancer, and particularly has higher antitumor activity on cervical cancer, colon cancer and breast cancer than colchicine, so that the thienopyrimidine compound has excellent antitumor effect and good application prospect. Compared with the single use of the PD-L1 inhibitor or the single use of the thienopyrimidine compound, the thienopyrimidine compound and the PD-L1 inhibitor have obvious synergistic effect and enhanced antitumor activity when used in combination.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A thienopyrimidine compound having a structural formula shown by the following formula (I):
2. a process for producing a thienopyrimidine compound as claimed in claim 1, characterized by comprising the following production steps:
(1) Dissolving 4-chloro-2-methylthiophene [3,2-d ] pyrimidine and 1-methyl-5-aminoindole in a first solvent, adding glacial acetic acid, reacting at 70-90 ℃, and performing suction filtration to obtain a crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidine-4-amine;
(2) Dissolving methyl iodide in a second solvent, mixing with the crude product of 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidin-4-amine in the step (1), reacting at normal temperature under the catalysis of sodium hydride, and extracting and then processing to obtain the thienopyrimidine compound;
the reaction formula of the preparation method is as follows:
3. the method of claim 2, wherein the molar ratio of 4-chloro-2-methylthiophene [3,2-d ] pyrimidine to 1-methyl-5-aminoindole is 1:1 to 1.1.
4. The method according to claim 2 or 3, wherein the molar ratio of the crude 2-methyl-N- (1-methyl-1H-indol-5-yl) thieno [3,2d ] pyrimidin-4-amine to the methyl iodide is 1:1 to 1.5.
5. The method according to claim 2, wherein the first solvent is absolute ethanol.
6. The method according to claim 2, wherein the second solvent is anhydrous tetrahydrofuran.
7. The use of the thienopyrimidine compound of claim 1 for the preparation of an antitumor drug.
8. The use of the thienopyrimidine compound of claim 1 in combination with a PD-L1 inhibitor for the preparation of an antitumor medicament.
9. The use of claim 7 or 8, wherein the tumor is one or more of cervical cancer, colon cancer, breast cancer, lung cancer or liver cancer.
10. The use of claim 9, wherein the tumor is one or more of cervical cancer, colon cancer or breast cancer.
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| WO2003074529A2 (en) * | 2002-03-01 | 2003-09-12 | Pfizer Inc. | iNDOLYL-UREA DERIVATIVES OF THIENOPYRIDINES USEFUL AS ANTI-ANGIOGENIC AGENTS |
| US20070099877A1 (en) * | 2005-11-02 | 2007-05-03 | Cytovia, Inc. | N-aryl-thienopyrimidin-4-amines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
| CN101328186A (en) * | 1997-11-11 | 2008-12-24 | 辉瑞产品公司 | Thienopyrimidine and thienopyridine derivatives useful as anticancer agents |
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| CN101328186A (en) * | 1997-11-11 | 2008-12-24 | 辉瑞产品公司 | Thienopyrimidine and thienopyridine derivatives useful as anticancer agents |
| WO2003074529A2 (en) * | 2002-03-01 | 2003-09-12 | Pfizer Inc. | iNDOLYL-UREA DERIVATIVES OF THIENOPYRIDINES USEFUL AS ANTI-ANGIOGENIC AGENTS |
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