CN111533735A - Oxo-dihydropyridazine thiazole derivative and application thereof in antitumor drugs - Google Patents
Oxo-dihydropyridazine thiazole derivative and application thereof in antitumor drugs Download PDFInfo
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to oxo-dihydropyridazine and application thereof in antitumor medicines. MTT results show that the oxo-dihydropyridazine derivative has the advantage of stronger anti-tumor activity, can be used for preparing anti-tumor drugs,
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an oxo-dihydropyridazine thiazole derivative and application thereof in antitumor medicines.
Background
Cancer is one of the major causes of death faced by humans, and it seriously harms human life and health. The occurrence and development of most malignant tumors are related to the dysfunction of cell cycle regulation, and the regulation or the blockage of the cell cycle is one of the important ways for treating tumors. With the progress of scientific medical treatment, the tumor molecular targeted therapy becomes a novel therapeutic means. It uses some molecules capable of making specific expression on the cell membrane of tumor cell or in the cell as action target point, and directly blocks its cell signal conduction channel so as to inhibit the growth of tumor cell, induce its apoptosis and finally attain the goal of clinical treatment.
Cyclin-dependent kinases (CDKs) belong to the serine/threonine protein kinase family, and directly participate in regulation of the cell cycle to promote ordered growth, proliferation and apoptosis of cells. The cell division cycle is divided into 4 stages, namely G1 stage, S stage, G2 stage and M stage, wherein the G1-S regulatory point is the most important, and the regulation is closely related to CDKs. CDKs form protein kinase complexes by binding to cyclins, which catalyze substrate phosphorylation, control cell cycle progression, and in turn, complete DNA replication and mitosis, leading to cell division and proliferation.
Within the CDKs family, the crystal structure of CDK2 has distinct properties, both structurally and biochemically, as kinases are critical in cell mitosis. The over-activation of CDK2 caused by mutation, and the abnormal expression of CDK2 and cyclin E can all cause the occurrence of tumors. Abnormal expression of CDK2 is frequently found in tumor tissues of breast cancer, ovarian cancer, muscle cancer of the shoulder, endometrial cancer and gastric cancer. In view of the relevance and importance of CDK2 in the development of tumorigenesis, modulation of the activity of CDK2 to inhibit cell division opens new avenues for the treatment of tumors. Currently, the finding of more selective drugs with less side effects on patients to inhibit the activity of CDK2, thereby preventing the proliferation of tumor cells, has become a new direction for tumor treatment.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an oxo-dihydropyridazine thiazole derivative and application thereof in antitumor drugs.
In order to achieve the above object, the present invention provides oxodihydropyridazine thiazoles represented by the general formula (I):
r in the general formula1Is hydrogen radical, halogen, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl or (C)1-C6) An alkoxy group.
Said R2Is (C)1-C6) Alkyl, phenyl or substituted phenyl; the substituted phenyl is halogen substituted phenyl or alkoxy substituted phenyl.
The compounds of the general formula I according to the invention are preferably the following compounds, but these are not intended to limit the invention in any way:
the compound and the pharmaceutically acceptable salt, hydrate and solvate thereof can be applied to antitumor drugs.
The anti-tumor comprises anti-breast cancer, osteosarcoma, thyroid cancer, lung cancer and the like.
The derivatives of the invention comprising formula I may be synthesized by methods well known in the chemical arts, including, inter alia, methods according to the routes disclosed herein, in particular: diazotizing different substituted anilines, reacting with ethyl acetoacetate to obtain an intermediate 2, condensing with N, N-dimethyl phthalein amine dimethyl acetal (DMF-DMA) to obtain an intermediate 3, performing cyclization reaction on the intermediate 3 under the condition of weak base, performing hydrolysis reaction with strong base to obtain an intermediate 5, and performing amide reaction with substituted 2-amino-4-methylthiazole or substituted 2-amino-4-phenylthiazole to obtain a target product. The specific synthetic route is shown as follows:
synthetic scheme 1 reagents and conditions: (a) ethyl acetate, NaNO2,EtOH,0℃；(b) DMF-DMA,80℃；(c)EtOH,5％NaOH,80℃；(d)2N NaOH,MeOH/H2O；(e) EDCI,HOBt,DIEA,rt。
The positive progress effects of the invention are as follows: the invention provides oxo-dihydropyridazine thiazole derivative derivatives, a preparation method, a pharmaceutical composition and application thereof. MTT results show that the oxo-dihydropyridazine thiazole derivative has the advantage of stronger antitumor activity and can be used for preparing antitumor drugs.
Detailed Description
The examples provided below are intended to illustrate but not limit the scope of the invention. The starting materials may generally be obtained from commercial sources or prepared using methods well known to those skilled in the art, or prepared according to the methods described herein. The reagents used are, without particular reference, analytically or chemically pure.
Example 1N- (4-Methylthiazol-2-yl) -4-oxo-1-phenyl-1, 4-dihydropyridazine-3-carboxamide
Step 1 Synthesis of intermediate 2
Aniline (4.00g,42.95mmol) was added to 100mL of a mixed solution of water and hydrochloric acid (1:1), stirred for 30 minutes, and then an aqueous solution of sodium nitrite (3.11g,45.10mmol) was slowly added dropwise to the reaction mixture, stirred at room temperature for 20 minutes to form a diazonium salt solution, which was used in the next reaction without purification.
Ethyl acetoacetate (5.59g,42.95mmol) and potassium acetate (42.15g,429.15mmol) were added to 100mL of ethanol, and the mixture was stirred at room temperature for 10 minutes, and then the diazonium salt solution prepared above was slowly added dropwise to the reaction mixture, and after the addition, the reaction was continued at room temperature for 2 hours, and the reaction was completed by TLC. The reaction solution was poured into water to precipitate a large amount of solid, which was filtered under suction to give 6.20g of a yellow solid with a yield of 61.62%.
Step 2 Synthesis of intermediate 3
Adding the intermediate 2(4g,17.08mmol) into 60mL DMF-DMA, heating to 80 ℃ for reaction, detecting the reaction completion by TLC after the reaction is carried out for 6h, cooling the reaction liquid to room temperature, adding 200mL petroleum ether, precipitating a large amount of solid, and filtering to obtain a yellow solid 4.50g with the yield of 91.08%.
Step 3 Synthesis of intermediate 4
Intermediate 3(5.0g,17.28mmol) was dissolved in 100mL ethanol, 10mL 5% aqueous NaOH was added, the temperature was raised to reflux and the progress of the reaction was checked by TLC. After the reaction is finished, the solvent is evaporated under reduced pressure, a large amount of solid is precipitated by adding water, and the white solid is obtained by suction filtration, wherein the yield is 85.3%.
Step 4 Synthesis of intermediate 5
Dissolving intermediate 4(2g,8.19mmol) in 10mL ethanol, adding 10mL 2N sodium hydroxide solution, stirring at room temperature for 2h, detecting by TLC that the reaction is completed, evaporating the solvent under reduced pressure, adding water, adjusting pH to 4-5 with 3N hydrochloric acid, precipitating a large amount of solid, filtering to obtain 1.62g white solid with the yield of 91.51%.
Step 5 Synthesis of N- (2-hydroxy-1-phenylethyl) -4-oxo-1-phenyl-1, 4-dihydropyridazine-3-carboxamide
Intermediate 5(1.0g,4.63mmol) was dissolved in dry DMF and EDCI (0.98g, 5.09mmol) and HOBt (0.69g,4.4mmol) were added. After reacting at room temperature for 1h, adding phenylglycinol (0.63g,4.63mmol) and DIEA (1.20g,9.25mmol), and heating to 70 ℃ for reacting for 8 h. TLC detection reaction is completed, the temperature is reduced to room temperature, the reaction liquid is poured into 100mL of water, solid is separated out, filtration and drying are carried out, and the crude product is purified by silica gel column chromatography to obtain 0.96g of white solid with the yield of 61.9%.
1H-NMR(400MHz,DMSO-d6)12.43(s,1H),9.00(d,J＝7.8Hz,1H),7.85 (d,J＝8.5Hz,2H),7.61(t,J＝7.9Hz,2H),7.32(dt,J＝7.6,1.5Hz,1H),6.91 (d,J＝7.8Hz,1H),6.70(s,1H),2.52(s,3H).ESI-MS m/z:313.1[M+H]+.
Examples 2-9 were prepared according to the procedure for example 1, using differently substituted anilines as starting materials, respectively, and following 5 steps of diazotization, condensation, ring closure, hydrolysis, condensation, and the like.
Example 2N- (4-Methylthiazol-2-yl) -4-oxo-1- (4-chlorophenyl) -1, 4-dihydropyridazine-3-carboxamide
1H-NMR(400MHz,DMSO-d6)12.45(s,1H),9.01(d,J＝7.9Hz,1H),7.61 (d,J＝8.0Hz,2H),7.44(d,J＝7.6Hz,2H),6.90(d,J＝7.8Hz,1H),6.52(s,1H), 1.95(s,3H).ESI-MS m/z:347.1[M+H]+.
Example 3N- (4-Methylthiazol-2-yl) -4-oxo-1- (4-fluorophenyl) -1, 4-dihydropyridazine-3-carboxamide
1H-NMR(400MHz,DMSO-d6)12.40(s,1H),9.02(d,J＝7.6Hz,1H),7.51 (d,J＝8.5Hz,2H),7.42(d,J＝8.0Hz,2H),6.90(d,J＝7.8Hz,1H),6.52(s,1H), 1.96(s,3H).ESI-MS m/z:331.2[M+H]+.
Example 4N- (4-Methylthiazol-2-yl) -4-oxo-1- (4-methylphenyl) -1, 4-dihydropyridazine-3-carboxamide
1H-NMR(400MHz,DMSO-d6)12.43(s,1H),9.00(d,J＝7.8Hz,1H),7.49 (d,J＝8.2Hz,2H),7.30(d,J＝7.9Hz,2H),6.92(d,J＝7.8Hz,1H),6.50(s,1H), 2.32(s,3H),1.98(s,3H).ESI-MS m/z:327.1[M+H]+.
Example 5N- (4-Methylthiazol-2-yl) -4-oxo-1- (4-methoxyphenyl) -1, 4-dihydropyridazine-3-carboxamide
1H-NMR(400MHz,DMSO-d6)12.45(s,1H),9.01(d,J＝7.8Hz,1H),7.51 (d,J＝7.7Hz,2H),7.12(d,J＝8.1Hz,2H),6.91(d,J＝7.8Hz,1H),6.51(s,1H), 3.80(s,3H),1.97(s,3H).ESI-MS m/z:343.1[M+H]+.
Example 6N- (4-Methylthiazol-2-yl) -4-oxo-1- (3-chloro-4-fluorophenyl) -1, 4-dihydropyridazine-3-carboxamide
1H-NMR(400MHz,DMSO-d6)12.43(s,1H),9.00(d,J＝7.8Hz,1H),7.73 (d,J＝2.4Hz,1H),7.56(d,J＝7.9Hz,1H),7.36(d,J＝7.6Hz,1H),6.91 (d,J＝7.8Hz,1H),6.51(s,1H),1.98(s,3H).ESI-MS m/z:365.2[M+H]+.
Example 7N- (4-phenylthiazol-2-yl) -4-oxo-1- (4-chlorophenyl) -1, 4-dihydropyridazine-3-carboxamide
1H-NMR(400MHz,DMSO-d6)12.43(s,1H),9.00(d,J＝7.8Hz,1 H),8.08(d,J＝7.4Hz,2H),7.61(d,J＝8.0Hz,2H),7.51(t,J＝7.6Hz, 2H),7.44-7.42(m,3H),7.26(s,1H),6.91(d,J＝7.8Hz,1H).ESI-MS m/z:4 09.2[M+H]+.
EXAMPLE 8N- [4- (4-fluorophenyl) thiazol-2-yl ] -4-oxo-1- (4-chlorophenyl) -1, 4-dihydropyridazine-3-carboxamide
1H-NMR(400MHz,DMSO-d6)12.43(s,1H),9.00(d,J＝7.8Hz,1 H),7.86(d,J＝7.4Hz,2H),7.61(d,J＝8.0Hz,2H),7.44(d,J＝7.6Hz, 2H),7.31(d,J＝7.4Hz,2H),7.25(s,1H),6.92(d,J＝7.8Hz,1H).ESI- MS m/z:427.1[M+H]+.
Example 9N- [4- (4-methoxyphenyl) thiazol-2-yl ] -4-oxo-1- (4-chlorophenyl) -1, 4-dihydropyridazine-3-carboxamide
1H-NMR(400MHz,DMSO-d6)12.43(s,1H),9.00(d,J＝7.8Hz,1 H),7.56(d,J＝7.4Hz,2H),7.60(d,J＝8.0Hz,2H),7.42(d,J＝7.6Hz, 2H),7.26(s,1H),7.05(d,J＝7.4Hz,2H),6.92(d,J＝7.8Hz,1H),3.81 (s,3H).ESI-MS m/z:339.3[M+H]+.
Firstly, testing pharmacological activity:
CDK2 kinase inhibitory activity evaluation:
(1) compound preparation the compound powder was dissolved in 100% DMSO to prepare a 10mM stock solution.
(2) Preparation of Kinase 1 XKinase buffer was prepared and used to prepare a CDK2 Kinase solution at 2.5 fold final concentration.
(3) Add 10. mu.L of CDK2 kinase solution at 2.5 fold final concentration to the compound wells and positive control wells, respectively; mu.L of 1 XKinase buffer was added to the negative control wells. The mixture was centrifuged at 1000rpm for 30 seconds, shaken and mixed, and then incubated at room temperature for 10 minutes.
(4) A mixture of ATP and Kinase substrate 18 was made up to a final concentration of 25/15 times using a 1 XKinase buffer, and 10. mu.L was added to the well to initiate the reaction. The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken well and incubated at room temperature for 30 minutes.
(5) And (3) stopping the reaction, namely adding 30 mu L of termination detection solution to stop the kinase reaction, centrifuging at 1000rpm for 30 seconds, shaking and uniformly mixing, and reading the conversion rate by using an enzyme-linked immunosorbent assay (ELISA) instrument. Calculating the formula:
Inhibition％＝(Conversion％max-Conversion％sample) /(Conversion％max-Conversion％min)×100，
wherein Conversion%maxIndicates positive control well Conversion reading, Conversion%sampleIndicates the sample Conversion reading, Conversion%minThe negative control well conversion readings are shown in table 1.
Table 1 CDK2 kinase inhibitory activity.
| Compound (I) | IC50(μM) |
| Example 1 | 2.9 |
| Example 2 | 0.8 |
| Example 3 | 0.7 |
| Example 4 | 10.2 |
| Example 5 | 12.6 |
| Example 6 | 0.9 |
| Example 7 | 2.2 |
| Example 8 | 0.6 |
| Example 9 | 1.5 |
Secondly, MTT method anticancer cell proliferation experiment:
cancer cells are inoculated to a 96-well plate, the cells are cultured for 24h at 37 ℃ by using an RPMI 1640 complete medium containing 5% CO2, 100U/mL penicillin and 100 mu g/mL streptomycin, compounds with different concentrations are added, 5 multiple wells are set for each concentration, after the drugs act for 48h, culture solution is discarded, and the cell viability is measured by using an MTT reagent.
The determination method comprises the following steps: adding a pre-prepared MTT reaction solution into 15 mu L/hole, continuously culturing for 4h, sucking and removing the supernatant, adding DMSO into 100 mu L/hole to dissolve the reduction product, reacting for 5min in a dark place, reading the absorbance value at 490nm, calculating the cell activity, and taking the absorbance value of the test compound intervention hole/the control hole as the cell activity.
IC50Refers to the concentration of inhibitor at which cell growth is inhibited by half, as shown in Table 2.
Table 2 MTT assay compounds were tested for their inhibitory activity against cancer cells.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (4)
1. Oxo-dihydropyridazine derivatives shown in a general formula I,
r in the general formula1Is hydrogen radical, halogen, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, or substituted by halogen (C)1-C6) Alkyl or (C)1-C6) An alkoxy group;
said R2Is (C)1-C6) Alkyl, phenyl or substituted phenyl.
2. Oxodihydropyridazine derivatives represented by the general formula I, selected from:
n- (2-hydroxy-1-phenylethyl) -4-oxo-1-phenyl-1, 4-dihydropyridazine-3-carboxamide,
N- (2-hydroxy-1-phenylethyl) -4-oxo-1- (4-fluorophenyl) -1, 4-dihydropyridazine-3-carboxamide,
N- (2-hydroxy-1-phenylethyl) -4-oxo-1- (4-chlorophenyl) -1, 4-dihydropyridazine-3-carboxamide,
N- (2-hydroxy-1-phenylethyl) -4-oxo-1- (4-bromophenyl) -1, 4-dihydropyridazine-3-carboxamide,
N- (2-hydroxy-1-phenylethyl) -4-oxo-1- (4-methoxyphenyl) -1, 4-dihydropyridazine-3-carboxamide,
N- (2-hydroxy-1-phenylethyl) -4-oxo-1- (3-chloro-4-fluorophenyl) -1, 4-dihydropyridazine-3-carboxamide,
N- [1- (4-fluorophenyl) -2-hydroxyethyl) -4-oxo-1- (4-chlorophenyl) -1, 4-dihydropyridazine-3-carboxamide,
N- [1- (4-chlorophenyl) -2-hydroxyethyl) -4-oxo-1- (4-chlorophenyl) -1, 4-dihydropyridazine-3-carboxamide,
N- [1- (4-fluorophenyl) -2-hydroxyethyl) -4-oxo-1- (4-methoxyphenyl) -1, 4-dihydropyridazine-3-carboxamide.
3. An application of the oxo-dihydro-pyridazine derivative shown in the general formula I as an anti-tumor drug.
4. The oxodihydropyridazine derivative according to claim 3, for use as an antitumor agent, wherein the tumor is breast cancer, osteosarcoma, thyroid cancer or lung cancer.
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