CN113292554A - Dihydronaphtho [2,1-d ] isoxazole amide derivatives and application thereof in antitumor drugs - Google Patents
Dihydronaphtho [2,1-d ] isoxazole amide derivatives and application thereof in antitumor drugs Download PDFInfo
- Publication number
- CN113292554A CN113292554A CN202110709903.7A CN202110709903A CN113292554A CN 113292554 A CN113292554 A CN 113292554A CN 202110709903 A CN202110709903 A CN 202110709903A CN 113292554 A CN113292554 A CN 113292554A
- Authority
- CN
- China
- Prior art keywords
- dihydronaphtho
- cyp1b1
- drug
- antitumor
- isoxazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a dihydronaphtho [2,1-d ] isoxazole amide derivative, a preparation method thereof, and application thereof as a CYP1B1 inhibitor in antitumor medicaments. The research of the CYP1B1 inhibitor in tumor treatment provides a new idea for developing antitumor drugs with targeting property and low toxic and side effects. The CYP1B1 enzyme inhibitor and the traditional antitumor drug are combined to be used, so that the antitumor activity of the drug can be obviously improved, the specificity and the effectiveness are improved, and the development prospect is wider. The experimental results show that the dihydronaphtho [2,1-d ] isoxazole amide derivatives synthesized by the subject combination have the prospect of developing the anti-tumor drug sensitizer.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a dihydronaphtho [2,1-d ] isoxazole amide derivative, a preparation method thereof, and application thereof as a CYP1B1 inhibitor in antitumor medicaments.
Background
Cytochrome CYP1B1 is a CYP450 enzyme which is specifically and highly expressed in a plurality of tumor tissues related to hormone, can metabolize estrogen into carcinogenic products, activates aromatic hydrocarbon precancerogen, and causes the development of various tumors. Research shows that CYP1B1 is an important CYP450 oxidative metabolism enzyme, participates in the metabolism of exogenous compounds and precancerogen, and is related to the susceptibility of tumors. It is widely present in extrahepatic tissues such as breast, stomach, uterus, ovary, lung, etc., and is expressed at high frequency in various malignant tumor tissues, but is not expressed or expressed at a very low level in corresponding normal tissues. The results of many studies suggest that CYP1B1 may be a new cancer marker protein, and provide a new target for tumor treatment.
In recent years, research and development of CYP1B1 inhibitors become a hotspot in the field of drug research and development, and a plurality of researches show that the CYP1B1 inhibitor can enhance the chemotherapy effect of anticancer drugs docetaxel or adriamycin on cancer cell lines of lung cancer, breast cancer, liver cancer, prostate, colorectal cancer, gastric cancer, leukemia and the like. More importantly, some inhibitors have been proved to overcome the drug resistance of cancer cell lines with docetaxel or adriamycin resistance. McFadyen et al showed that: docetaxel was exposed to the cell with CYP1B1 expression and the cell without CYP1B1 expression, respectively, and it was found that docetaxel produced cytotoxicity more than 4 times higher in the cell without CYP1B1 expression than in the cell with CYP1B1 expression. In addition, co-incubation with alpha-naphthoflavone, a known inhibitor of CYP1B1, and docetaxel, was found to result in diametrically opposite cytotoxic results. It is therefore speculated that inactivation of docetaxel by CYP1B1 may be responsible for resistance to docetaxel drugs. Sissung et al believe that estrogen-3, 4-quinone and methoxyestradiol catalyzed by CYP1B1 may be responsible for the decreased efficacy of docetaxel.
CYP1B1 participates in the activation of precancerogen and the metabolic inactivation of anticancer drugs, and is an important factor for inducing cancers and causing the invalidation of the anticancer drugs, so the CYP1B1 inhibitor is used for inhibiting the activity of the anticancer drug, can play a role in chemoprotection, reduces the generation of tumor drug resistance, and plays an important role in the treatment of tumors. Therefore, the research on the novel CYP1B1 inhibitor with stronger specificity is very important for the clinical treatment of tumor drug patients and the reversal of the multi-drug resistance phenomenon of chemotherapeutic drugs.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel dihydronaphtho [2,1-d ] isoxazole amide derivative; and a preparation method of the derivative and application of the derivative as a CYP1B1 enzyme inhibitor in antitumor drugs.
In order to achieve the purpose, the invention adopts the technical scheme that: the invention provides a novel dihydronaphtho [2,1-d ] isoxazole amide derivative shown in a general formula (I), and a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;
the R is1Selected from hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Cycloalkyl, alkenyl, alkynyl or aryl.
And X or Y is selected from N or S.
Preferably, said R is1Selected from hydrogen, halogen or C1-C6An alkyl group.
The dihydronaphtho [2,1-d ] isoxazole amide derivative shown in the general formula (I) is selected from:
the invention also includes prodrugs of the derivatives of the invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
"alkyl" in the context of the present invention means a straight or branched chain alkyl group, wherein C1-C6By a group is meant a moiety having 1 to 6 carbon atoms, i.e. the group contains 1, 2, 3, 4,5 or 6 carbon atoms.
The "alkoxy group" in the present invention means an alkyl ether group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The "halogen" as used herein means fluorine, chlorine, bromine or iodine.
The compounds of formula I can be synthesized according to the method of the scheme 1, different substituted 1-tetralone and diethyl oxalate are condensed under LiHMDS condition to obtain an intermediate 2, the intermediate 2 and hydroxylamine hydrochloride undergo a ring closing reaction to obtain an intermediate 3, the intermediate 3 undergoes a DDQ oxidative dehydrogenation reaction to obtain an intermediate 4, the intermediate 4 is hydrolyzed by sodium hydroxide to obtain an intermediate 4, and finally the intermediate and substituted benzo heterocyclic methylamine undergo condensation under the action of condensation reagents EDCI and HOBt to obtain a target compound.
Route 1 is as follows.
Synthetic scheme 1 reagents and conditions: (a) diethyl oxalate, LiHMDS; (b) hydroxylamine hydrochloride, EtOH, reflux,2 h; (c) DDQ,1, 4-dioxane; (d) NaOH, MeOH/H2O,r.t.,7h；(e)EDCI,HOBt,DIEA,r.t.,7h.
The dihydronaphtho [2,1-d ] isoxazole amide derivative can be used as an antitumor drug, and particularly as a sensitizer for a CYP1B1 inhibitor to enhance a clinical first-line antitumor drug paclitaxel or adriamycin.
The tumor cell of the invention can be MCF-7/ADM or A549/TAX.
The invention has obvious technical effect.
The research of the CYP1B1 inhibitor in tumor treatment provides a new idea for developing antitumor drugs with targeting property and low toxic and side effects. The CYP1B1 enzyme inhibitor and the traditional antitumor drug are combined to be used, so that the antitumor activity of the drug can be obviously improved, the specificity and the effectiveness are improved, and the development prospect is wider. The experimental results show that the dihydronaphtho [2,1-d ] isoxazole amide derivatives synthesized by the subject combination have the prospect of developing the anti-tumor drug sensitizer.
Detailed Description
The following examples are intended to illustrate but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by BrukeraRx-400, and the mass spectrum is measured by Agilent 1100 LC/MS; all reagents used were analytically or chemically pure.
Example 1.
The preparation method comprises the following steps:
step 1, synthesis of an intermediate 2:
dissolving 1-tetralone (2.0g,13.7mmol) in tetrahydrofuran, adding diethyl oxalate (3.0g,20.5mmol), cooling the reaction temperature to 0 ℃ in an ice bath under the protection of nitrogen, then slowly dropwise adding LiHMDS solution (20.5mL of 1M in THF, 20.5mmol), heating to 40 ℃ after dropwise adding, reacting for 4h, completing TLC detection reaction, and evaporating the solvent under reduced pressure to obtain an intermediate 2 which is directly used for the next reaction without purification.
Step 2, synthesis of an intermediate 3(4, 5-dihydronaphtho [2,1-d ] isoxazole-3-ethyl formate):
intermediate 2 was dissolved in 60mL of glacial acetic acid, hydroxylamine hydrochloride (1.4g,20.5mmol) was added and the temperature was raised to 80 ℃. After 10 hours of reaction, TLC was carried out to detect completion of the reaction, and 100mL of water was poured into the reaction solution, followed by extraction with ethyl acetate, washing of the organic layer with saturated brine, and addition of Na2SO4Dry overnight. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2.10g of a white solid with a yield of 63.1%.
And 3, synthesizing the naphtho [2,1-d ] isoxazole-3-ethyl formate.
4, 5-dihydronaphtho [2,1-d ]]Isoxazole-3-carboxylic acid ethyl ester (1.5g,6.2mmol) was dissolved in 60mL1, 4-dioxane, dichlorodicyanobenzoquinone (DDQ) (5.6g,24.7mmol) was added, and the temperature was raised to reflux. After 12h, TLC detection is carried out, sodium bicarbonate is added to quench the reaction, the precipitate is removed by filtration, the filtrate is extracted with ethyl acetate and saturatedThe organic layer was washed with brine, Na2SO4Dry overnight. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1.18g of a white solid with a yield of 79.3%.
And 4, synthesizing an intermediate 4 (naphtho [2,1-d ] isoxazole-3-formic acid).
Mixing naphtho [2,1-d ]]Isoxazole-3-carboxylic acid ethyl ester (1.0g, 4.2mmol) was dissolved in 25mL of methanol, and then 10mL of 2N NaOH solution was added to the reaction solution. After stirring at room temperature for 4h, the methanol was evaporated under reduced pressure, the pH was adjusted to 5-7 with 1N hydrochloric acid, a white solid was precipitated, filtered and dried to give 0.79g of intermediate 4 with a yield of 89.9%.1H-NMR(600MHz,DMSO-d6)δ8.11(d,J＝8.1Hz,1H),7.42(d,J＝7.7Hz,1H),7.32–7.25(m,1H),7.11(t,J＝7.5Hz,1H),6.96(d,J＝8.4Hz,1H),6.25(d,J＝8.4Hz,1H)。
Step 5, synthesis of example 1.
Naphtho [2,1-d ] isoxazole-3-carboxylic acid (0.5g,2.4mmol) was dissolved in 30mL DMF and EDCI (0.49g,2.6mmol) and HOBt (0.35g,2.6mmol) were added sequentially. After stirring at room temperature for 1h, 1, 3-benzothiazole-2-methanamine (0.46g,2.8mmol) and DIEA (0.61mg,4.7mmol) were added and the reaction was allowed to warm to 70 ℃ in an oil bath for 8 h. And (3) stopping heating after TLC detection reaction is finished, cooling the temperature to room temperature, pouring the reaction liquid into 60mL of water, separating out a solid, filtering, and purifying the residue by silica gel column chromatography to obtain 0.61g of white solid with the yield of 72.4%.
1H-NMR(600MHz,DMSO-d6)δ9.29(s,1H),8.45(dd,J＝6.0,3.4Hz,1H),8.24–8.16(m,2H),8.01-7.94(m,3H),7.85–7.80(m,2H),7.54-7.51(m,2H),4.26(s,2H).ESI-MS m/z:360.1[M+H]+.
Examples 2-8 were prepared according to the procedure of example 1, using substituted 1-tetralones as starting materials, respectively, via four-step reactions of condensation, ring closure, hydrolysis, and condensation.
Example 2.
1H-NMR(600MHz,DMSO-d6)δ9.60(s,1H),8.44(dd,J＝6.6,3.0Hz,1H),8.25–8.18(m,1H),7.94–7.90(m,3H),7.84–7.79(m,3H),7.49–7.45(m,2H),7.31(dd,J＝7.0,2.4Hz,1H),4.48(s,2H).ESI-MS m/z:359.1[M+H]+.
Example 3.
1H-NMR(600MHz,DMSO-d6)δ12.18(s,1H),9.54(s,1H),8.42(dd,J＝6.8,2.4Hz,1H),8.25–8.19(m,1H),7.94-7.90(m,2H),7.85–7.80(m,2H),7.53(d,J＝7.8Hz,2H),7.18(d,J＝8.0Hz,2H),4.28(s,2H).ESI-MS m/z:343.1[M+H]+.
Example 4.
1H-NMR(600MHz,DMSO-d6)δ9.48(s,1H),8.44(dd,J＝7.8,2.8Hz,1H),8.26–8.18(m,2H),7.94–7.89(m,2H),7.88–7.82(m,3H),7.56(dd,J＝7.0,2.8Hz,1H),4.22(s,2H).ESI-MS m/z:394.1[M+H]+.
Example 5.
1H-NMR(600MHz,DMSO-d6)δ12.16(s,1H),9.42(s,1H),8.45(dd,J＝6.0,3.4Hz,1H),8.24–8.16(m,1H),7.94–7.90(m,2H),7.85–7.80(m,2H),7.53-7.48(m,2H),7.12(d,J＝2.6Hz,1H),4.26(s,2H),2.44(s,3H).ESI-MS m/z:357.1[M+H]+.
Example 6.
1H-NMR(600MHz,DMSO-d6)δ9.29(s,1H),8.14–8.05(m,2H),7.68-7.64(m,2H),7.53–7.48(m,3H),7.35(s,1H),7.13(dd,J＝7.0,2.8Hz,1H),7.54-7.51(m,2H),4.26(s,2H),3.82(s,3H).ESI-MS m/z:390.3[M+H]+.
Example 7.
1H-NMR(600MHz,DMSO-d6)δ9.29(s,1H),8.67(s,1H),8.16–8.04(m,3H),7.59(d,J＝7.8Hz,1H),7.53–7.48(m,4H),4.26(s,2H).ESI-MS m/z:439.4[M+H]+.
Example 8.
1H-NMR(600MHz,DMSO-d6)δ9.29(s,1H),8.24(s,1H),7.88(d,J＝7.4Hz,1H),7.64-7.48(m,4H),7.35(s,1H),7.13(dd,J＝7.0,2.8Hz,1H),4.24(s,2H),3.82(s,3H).ESI-MS m/z:424.1[M+H]+.
Pharmacological research of partial product of the invention
1. CYP1B1/CYP1A1 enzyme inhibitory Activity assay (EROD assay)
The test principle is as follows: the 7-ethoxy-3H-phenoxazin-3-one deethyl (EROD) assay is commonly used to evaluate the activity of CYP1A1 and CYP1B1 enzymes. The 7-ethoxy-3H-phenoxazin-3-one is a substrate for CYP1A1 and CYP1B1 enzymes, and is converted into a metabolite, 7-hydroxy-3H-phenoxazin-3-one, through an enzyme-mediated O-deethylation reaction. The latter emits fluorescence with wavelength of 590nm under excitation wavelength of 544nm, and is read by a microplate reader. The inhibitory activity on CYP1A1 and CYP1B1 is judged by the intensity of the compound inhibiting the EROD.
The test method comprises the following steps: the reaction system (200. mu.L) contained 10fmol CYP1A1 or 20fmol CYP1B1 enzyme, varying concentrations of test compound, NADPH regenerating system (1.3mM NADP +,3.3mM glucose-6-phosphate, 0.5U/ml glucose-6-phosphate dehydrogenase), 3.3mM MgCl2And 150nmol 7-ethoxy-3H-phenoxazine-3-ketone. The reaction buffer was 50mM Tris-HC1(pH 7.4) buffer containing 1% BSA. After the reaction system is preheated at 37 ℃ for L0min, an NADPH regeneration system is added to start the reaction, and after the reaction is finished, 100 mu L of precooled acetonitrile is added to stop the reaction. The excitation wavelength and the emission wavelength are 544nm and 590nm respectively by using a multifunctional microplate reader for detection.
TABLE 1 CYP1B1/CYP1A1 enzyme inhibition assay results.
Experimental results show that the compounds in examples 1-8 have obvious CYP1B1 inhibitory activity, the activity of the optimal compound is equivalent to that of a positive control drug alpha-naphthoflavone, and the selectivity of the optimal compound on CYP1A1 is better.
2. Antitumor cell activity and reverse drug resistance activity
Examples 1-8 compounds were screened separately by combination with the anticancer drug paclitaxel on sensitive beads and paclitaxel resistant beads using the CCK8 method (cell lines: a549 and a 549/Tax). First to confirm that the enhanced cytotoxicity of the compounds of examples 1-9 was due to pharmacodynamic effects and not to the cytotoxicity of the compounds themselves, we determined the inhibitory activity of the compounds of examples on a549 and a549/Tax cells.
A549 and A549/Tax cells in logarithmic growth phase at 6X 103One/well inoculation in 96-well plates at 37 ℃ and 5% CO2Culturing for 24h under the condition; then, the compound of example was added to each well to a final concentration of 10. mu.M, 3 wells were set, and after 48 hours of incubation, 10. mu.L of CCK-8 reagent was added to each well, and the incubation was continued for 1 hour, and the absorbance at a wavelength of 450nm was measured for each well, and the survival rate of the compound against tumor cells was calculated. The results of the experiment show that the test compound has no obvious toxicity to the test cells when the concentration of the test compound is 10 mu M.
Table 2 survival of tumor cells at 10.0 μ M for the compounds of examples 1-8.
| Compound (I) | A549 | A549/Tax | Compound (I) | A549 | A549/Tax |
| Example 1 | 98.1 | 97.6 | Example 6 | >99.0 | >99.0 |
| Example 2 | 94.2 | 95.2 | Example 7 | 94.8 | 96.2 |
| Example 3 | 90.3 | 96.5 | Example 8 | 94.2 | 92.9 |
| Example 4 | 89.2 | 94.1 | |||
| Example 5 | >99.0 | >99.0 |
According to the experimental data in table 1, the test compound concentration is 10.0 μ M, and the study experiment of the test compound reversing drug resistance of drug-resistant cells (cells are a549/Tax) is carried out, specifically: cancer cells were seeded in 96-well plates using DMEM complete medium with 100U/mL penicillin and 100. mu.g/mL streptomycin at 6X 103One/well inoculated in 96-well plates at 37 ℃ and 5% CO2Culturing for 24h under the condition; then adding the compound to be tested (10.0 μ M) and paclitaxel with different concentrations into each well, incubating, setting 3 multiple wells, incubating for 48h, adding 10 μ L CCK-8 reagent into each well, culturing for 1h, and measuring absorbance value and IC at 450nm wavelength of each well50The concentration of inhibitor at which cell growth was inhibited by half, and the results are shown in Table 3.
Table 3 experimental results for reversal of drug resistant cells by the compounds of examples 1-8.
| Compound (I) | IC50/Tax | RF | Compound (I) | IC50/Tax | RF |
| Example 1 | 33.3 | 2.6 | Example 6 | 38.4 | 2.3 |
| Example 2 | 41.2 | 2.1 | Example 7 | 40.1 | 2.1 |
| Example 3 | 22.1 | 3.9 | Example 8 | 38.9 | 2.2 |
| Example 4 | 19.4 | 4.5 | Paclitaxel | 86.6 | |
| Example 5 | 29.4 | 2.9 |
Experimental results show that the compound of the embodiment 1-8 can be used together with paclitaxel drugs to enhance the antitumor activity of paclitaxel.
Claims (5)
1. The dihydronaphtho [2,1-d ] isoxazole amide derivative is characterized by having a structural formula as follows:
wherein, R is1Selected from hydrogen, halogen, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Cycloalkyl, alkenyl, alkynyl or aryl;
and X or Y is selected from N or S.
2. Dihydronaphtho [2,1-d ] as claimed in claim 1]The isoxazole amide derivative is characterized in that R is1Selected from hydrogen, halogen or C1-C6An alkyl group.
3. A dihydronaphtho [2,1-d ] isoxazoleamide derivative according to claim 1, which is selected from:
4. a process for the preparation of dihydronaphtho [2,1-d ] isoxazoleamide derivatives as claimed in any of claims 1 to 3, which comprises: can be synthesized according to the method of the scheme 1, the differently substituted 1-tetralone and diethyl oxalate are condensed under the condition of LiHMDS to obtain an intermediate 2, the intermediate 2 and hydroxylamine hydrochloride are subjected to a ring closing reaction to obtain an intermediate 3, the intermediate 3 is subjected to a DDQ oxidative dehydrogenation reaction to obtain an intermediate 4, the intermediate 4 is hydrolyzed by sodium hydroxide to obtain an intermediate 4, and finally the intermediate and substituted benzo heterocyclic methylamine are condensed under the action of condensation reagents EDCI and HOBt to obtain a target compound;
route 1 is as follows:
route 1 reagents and conditions: (a) diethyl oxalate, LiHMDS; (b) hydroxylamine hydrochloride, EtOH, reflux,2 h; (c) DDQ,1, 4-dioxane; (d) NaOH, MeOH/H2O,r.t.,7h；(e)EDCI,HOBt,DIEA,r.t.,7h。
5. A dihydronaphtho [2,1-d ] isoxazolamide derivative as claimed in any one of claims 1 to 3 can be used as an antitumor drug, in particular as a CYP1B1 inhibitor for enhancing the sensitivity of paclitaxel or doxorubicin, a first-line clinical antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110709903.7A CN113292554A (en) | 2021-06-25 | 2021-06-25 | Dihydronaphtho [2,1-d ] isoxazole amide derivatives and application thereof in antitumor drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110709903.7A CN113292554A (en) | 2021-06-25 | 2021-06-25 | Dihydronaphtho [2,1-d ] isoxazole amide derivatives and application thereof in antitumor drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113292554A true CN113292554A (en) | 2021-08-24 |
Family
ID=77329699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110709903.7A Withdrawn CN113292554A (en) | 2021-06-25 | 2021-06-25 | Dihydronaphtho [2,1-d ] isoxazole amide derivatives and application thereof in antitumor drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113292554A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114790166A (en) * | 2022-04-28 | 2022-07-26 | 周口市公共检验检测中心 | Tetrahydrocarbazole derivative and application thereof in preparing antitumor drugs |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2399402A1 (en) * | 2000-02-09 | 2001-08-16 | The University Court Of The University Of Aberdeen | Use of cyp1b1 inhibitors for treating cancer |
| US20040138246A1 (en) * | 2001-02-22 | 2004-07-15 | Mark Searcey | Benz-indole and benzo-quinoline derivatives as prodrugs for tumor treatment |
| CN102993157A (en) * | 2012-11-21 | 2013-03-27 | 上海交通大学 | Alpha-naphthoflavone derivative, preparation method and application thereof |
| CN111454229A (en) * | 2020-04-10 | 2020-07-28 | 颜建发 | Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs |
-
2021
- 2021-06-25 CN CN202110709903.7A patent/CN113292554A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2399402A1 (en) * | 2000-02-09 | 2001-08-16 | The University Court Of The University Of Aberdeen | Use of cyp1b1 inhibitors for treating cancer |
| US20040138246A1 (en) * | 2001-02-22 | 2004-07-15 | Mark Searcey | Benz-indole and benzo-quinoline derivatives as prodrugs for tumor treatment |
| CN102993157A (en) * | 2012-11-21 | 2013-03-27 | 上海交通大学 | Alpha-naphthoflavone derivative, preparation method and application thereof |
| CN111454229A (en) * | 2020-04-10 | 2020-07-28 | 颜建发 | Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs |
Non-Patent Citations (1)
| Title |
|---|
| 靖铮 等: ""萘查耳酮类化合物的设计合成及对CYP1B1酶"", 《现代生物医学进展》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114790166A (en) * | 2022-04-28 | 2022-07-26 | 周口市公共检验检测中心 | Tetrahydrocarbazole derivative and application thereof in preparing antitumor drugs |
| CN114790166B (en) * | 2022-04-28 | 2023-06-23 | 周口市公共检验检测中心 | Tetrahydrocarbazole derivative and application thereof in preparation of antitumor drugs |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108524482B (en) | Use of 2- (substituted phenylamino) benzoic acid FTO inhibitors for treating leukemia | |
| CN103992336A (en) | Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof | |
| CN110590796B (en) | Camptothecin derivative and preparation method and application thereof | |
| CN110627801A (en) | HDAC inhibitor and application thereof | |
| CN114195814B (en) | Hydroxy naphthalenone-phenylboronic acid compound, preparation method and application | |
| CN109970679B (en) | Paeonol thiazole derivative and preparation method and application thereof | |
| CN111704646A (en) | Steroid compound and preparation method and application thereof | |
| CN113292554A (en) | Dihydronaphtho [2,1-d ] isoxazole amide derivatives and application thereof in antitumor drugs | |
| CN111454229B (en) | Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs | |
| CN101863766B (en) | Beta-hydroxyisovalerylshikonin derivative and preparation method thereof | |
| CN110156817B (en) | Anti-tumor derivative of bi-evodiamine molecule and preparation and application thereof | |
| Zhu et al. | Design and synthesis of NAD (P) H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties | |
| CN108715589B (en) | Coumarin derivative used as caspase-3 activator and application thereof | |
| CN114031523B (en) | Synthesis method and application of histone deacetylase and microtubule double-target inhibitor | |
| CN112500412B (en) | Penamine A alkaloid structure simplification compound and application thereof | |
| CN111808101B (en) | Application of gamma-carboline hydroxamic acid anti-tumor metastasis compound and preparation method thereof | |
| CN111423379B (en) | Substituted 3-indazole Mcl-1 protein inhibitor, preparation method and application | |
| CN110526854B (en) | Alpha, beta-unsaturated ketone derivative, preparation method and application thereof as medicine | |
| CN113416171A (en) | 4, 5-dihydronaphthoisoxazole derivatives and application thereof in antitumor drugs | |
| CN111057004B (en) | N-o-substituted phenyl benzamide-4-methylaminoacridine compound and preparation method and application thereof | |
| CN108383837B (en) | Amino-substituted tetrahydropyridopyrimidine compound or available salt thereof, and preparation method and application thereof | |
| CN112028831A (en) | Benzopyrazolyl compound, preparation method thereof and application of benzopyrazolyl compound as antitumor drug | |
| US20220024916A1 (en) | Heterocyclic comipound as cdk-hdac dual pathway inhibitor | |
| CN115572247B (en) | Vitamin K 3 Derivatives and medical use thereof | |
| CN109776411B (en) | Nitrogen mustard carbostyril derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20210824 |
|
| WW01 | Invention patent application withdrawn after publication |