CN111454229A - Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs - Google Patents

Abstract

The invention belongs to the technical field of drug synthesis, and provides a dihydronaphthoisoxazole derivative shown in a general formula and a preparation method thereof.

Description

Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to novel dihydronaphthoisoxazole derivatives, a preparation method of the derivatives and application of the derivatives as antitumor drugs.

Technical Field

Cancer is a malignant tumor originating in epithelial tissues, and is characterized by rapid proliferation and metastasis of cells, with mortality among the first of all diseases. According to the latest cancer data published worldwide by the international cancer research institute, about 1410 ten thousand cancer patients are newly added worldwide in 2012 and will also increase at an annual growth rate of around 11%. Therefore, research in cancer treatment has been intensively focused worldwide.

Currently, there are four main clinical cancer treatments: surgical therapy, radiotherapy, chemotherapy and immunotherapy. Chemotherapy is generally painless and killing cancer cells is difficult to achieve with other approaches to cancer treatment, as compared to the other three approaches. Most of the chemical drugs are not specific, and can kill cancer cells and damage normal tissue cells around the tumor, and the tissues can be automatically repaired only after chemotherapy. Therefore, the search for antitumor drugs with strong targeting property, remarkable effect and high safety has become one of the hot spots of research of global medicine developers.

With the continuous development of tumor molecular biology technology, people further know the pathogenesis of malignant tumors, continuously disclose various carcinogenic ways and develop various molecular targeted therapeutic drugs. The molecular targeted therapy aims at target molecules playing a key role in the processes of tumor occurrence, development and metastasis and related signal pathways thereof to interfere or block the efficacy of the target molecules, so as to achieve the purpose of inhibiting tumor growth and metastasis. With the development of molecular biology, cancer therapy has entered the targeted therapeutic era. Therefore, further research and development of novel anticancer drugs with strong targeting property, high efficiency and low toxicity become an important direction for the research of current antitumor drugs.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provide a novel dihydronaphthoisoxazole derivative, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug of the compound, a preparation method of the derivative and application of the derivative.

In order to achieve the purpose, the novel dihydronaphthoisoxazole derivative is shown as a general formula I, and a geometric isomer or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,

said R₁Selected from 1-3 selected from hydroxyl, halogen, nitro, amino, cyano and (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) An alkoxy group.

Preferably, said R is₁Selected from 1-3 selected from hydroxyl, halogen, nitro, amino, cyano and (C)₁-C₆) An alkyl group.

"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl.

The compounds of formula I according to the invention and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs are preferably the following compounds, but these compounds are not meant to limit the invention in any way:

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.

The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule and dripping pill, etc.

The derivatives of formula I which may be present in the invention may be synthesized by methods well known in the chemical art, in particular according to the teachings of the present invention, and may be prepared according to the methods of the routes, i.e. by condensation of the corresponding starting material 1 with diethyl oxalate under the conditions of L iHMDS to give the intermediate 2, by ring closure of the intermediate 2 with hydroxylamine hydrochloride to give the intermediate 3, by hydrolysis in alkaline solution to give the intermediate 4, and finally by amide reaction with 5-aminoisoxazole to give the desired product.

The synthesis route of the dihydronaphthoisoxazole derivatives is as follows:

the synthetic route reagent and conditions are (a) Diethyl oxalate, L iHMDS, (b) Hydroxylamine hydrochloride, EtOH, reflux,2H, (c) NaOH, MeOH/H₂O,rt.,7h；(e)EDCI,HOBt,DIEA,rt.,7h.

The positive progress effects of the invention are as follows: the invention provides a dihydronaphthoisoxazole derivative, a preparation method, a pharmaceutical composition and application thereof. MTT results show that the dihydronaphthoisoxazole derivative has the advantage of strong 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 1.

(1) Synthesis of ethyl 1-oxo-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate (intermediate 2):

1.5g (10.2mmol) of 1-tetralone and 1.8g (12.3mmol) of diethyl oxalate are dissolved in tetrahydrofuran, the temperature of the system is reduced to 0 ℃ in an ice bath under the protection of argon, then L iHMDS solution 14.3m L (1MinTHF, 14.3mmol) is slowly dripped, the temperature is raised to room temperature after the dripping is finished, the reaction is detected to be finished at T L C, the solvent is distilled off under reduced pressure, and the obtained concentrate is directly used for the next reaction.

(2) Synthesis of ethyl 4, 5-dihydronaphtho [2,1-d ] isoxazole-3-carboxylate (intermediate 3).

Dissolving the above concentrate in 40m L glacial acetic acid, adding hydroxylamine hydrochloride 0.85g (12.3mmol), heating to 80 deg.C, reacting at 10 h.T L C to detect reaction completion, pouring the reaction solution into 100m L water, extracting with ethyl acetate, washing organic layer with saturated saline solution, and adding 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 1.70g of a white solid with a yield of 67.9%.

(3) Synthesis of 4, 5-dihydronaphtho [2,1-d ] isoxazole-3-carboxylic acid (intermediate 4).

4, 5-dihydronaphtho [2,1-d ]]Isoxazole-3-carboxylic acid ethyl esterDissolving 2g (8.2mmol) of ester in 30m L methanol, adding 10m L of 2N NaOH solution, stirring at room temperature for 3 h.T L C to detect reaction completion, removing methanol under reduced pressure, adjusting pH to 5-7 with 1N hydrochloric acid to precipitate white solid, filtering, and drying to obtain 1.62g of white solid with yield of 92.1%.¹H-NMR(600MHz,DMSO-d6)7.63(d,J＝6.5Hz,1H),7.14–7.08(m,2H),7.03(d,J＝6.8Hz,1H),2.64(t,J＝7.0Hz,2H),2.32–2.27(m,2H).

(4) Dissolving 1.0g (4.6mmol) of 4, 5-dihydronaphtho [2,1-d ] isoxazole-3-formic acid in DMF obtained by drying, adding EDCI2.20g (5.1mmol) and HOBt0.69g (5.1mmol), reacting at room temperature for 1h, adding 0.43g (5.1mmol) of 5-aminoisoxazole and DIEA2.5m L (15.2mmol), heating to 70 ℃, reacting at 6 h.T L C, detecting that the reaction is finished, cooling to room temperature, pouring the reaction liquid into 100m L water, separating out a solid, filtering, drying and carrying out column chromatography to obtain 0.86g of white solid, namely the target product.

¹H-NMR(600MHz,DMSO-d₆)11.23(s,1H),8.09(d,J＝7.5Hz,1H),7.68(d,J＝6.5Hz,1H),7.15–7.07(m,2H),7.04(d,J＝6.8Hz,1H),6.79(d,J＝7.5Hz,1H),2.62(t,J＝7.0Hz,2H),2.32–2.27(m,2H).

According to the method of the embodiment 1, the substituted 1-tetralone is used as the raw material, and four steps of reactions of condensation, ring closing, hydrolysis and condensation are carried out to prepare the embodiment 2-4.

Example 2.

¹H-NMR(600MHz,DMSO-d₆)11.24(s,1H),8.09(d,J＝7.5Hz,1H),7.80(d,J＝2.0Hz,1H),7.60(dd,J＝8.1,2.1Hz,1H),7.37(d,J＝8.1Hz,1H),7.20(s,1H),6.79(d,J＝7.5Hz,1H),2.63(t,J＝7.0Hz,2H),2.31–2.28(m,2H).

Example 3.

¹H-NMR(600MHz,DMSO-d₆)11.22(s,1H),8.09(d,J＝7.5Hz,1H),7.32(d,J＝8.4Hz,1H),7.19(d,J＝2.7Hz,1H),6.98(dd,J＝8.4,2.7Hz,1H),6.80(d,J＝7.5Hz,1H),3.82(s,3H),2.63(t,J＝7.0Hz,2H),2.31–2.28(m,2H).

Example 4.

¹H-NMR(600MHz,DMSO-d₆)11.22(s,1H),8.09(d,J＝7.5Hz,1H),7.60(d,J＝8.7Hz,1H),7.01(d,J＝2.2Hz,1H),6.93(dd,J＝8.4,2.5Hz,1H),6.81(d,J＝7.5Hz,1H),3.81(s,3H),2.63(t,J＝7.0Hz,2H),2.31–2.28(m,2H).

MTT method anticancer cell proliferation experiment

Cancer cells were seeded in 96-well plates using 5% CO₂100U/m L penicillin and 100 μ g/m L streptomycin in RPMI1640 complete medium at 37 ℃ for 24h, adding different concentrations of compounds, setting 5 multiple wells for each concentration, after 48h of drug action, abandoning the culture solution, and determining the cell viability by MTT reagent.

The determination method comprises adding pre-prepared MTT reaction solution into 15 μ L/well, culturing for 4h, removing supernatant, adding DMSO into 100 μ L/well to dissolve the reduction product, reacting for 5min in dark, reading absorbance at 490nm, calculating cell activity, and determining absorbance of intervention/control wells as cell activity₅₀Refers to the concentration of inhibitor at which cell growth is inhibited by half. The data of the inhibitory activity of the above compounds on cancer cells are shown in Table 1.

Table 1 MTT assay compounds were tested for their inhibitory activity against cancer cells.

The compounds of formula I of the present invention can be administered alone, but are usually administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, the following procedures for the preparation of various pharmaceutical dosage forms of the compounds, e.g. tablets, capsules, injections, drop pills, illustrate their novel use in the pharmaceutical field.

Example 5: and (4) tablets.

10g of the compound of claim 1 (taking the compound of example 1 as an example) is mixed with 20g of auxiliary materials according to a general pharmaceutical tabletting method, and then the mixture is pressed into 100 tablets, wherein each tablet is 300 mg.

Example 6: and (4) capsules.

10g of the compound containing the compound in claim 1 (taking the compound in the example 1 as an example) is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into empty capsules, wherein each capsule weighs 300 mg.

Example 7: can be made into injection.

10g of the compound of claim 1 (exemplified by the compound of example 1) was adsorbed by activated carbon in accordance with a conventional pharmaceutical method, filtered through a 0.65 μm microporous membrane, and filled in nitrogen gas bottles to prepare water-injection preparations each containing 2m L and filled in 100 bottles.

Example 8: a dripping pill.

10g of the compound containing the compound of claim 1 (taking the compound in example 1 as an example) is mixed with 50g of a matrix such as gelatin and the like, heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.

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. Dihydronaphthoisoxazole derivatives shown in a general formula I, geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

said R₁Selected from 1-3 selected from hydroxyl, halogen, nitro, amino, cyano and (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) An alkoxy group.

2. Dihydronaphthoisoxazole derivatives according to claim 1, and geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein R is₁Selected from 1-3 selected from hydroxyl, halogen, nitro, amino, cyano and (C)₁-C₆) An alkyl group.

3. Dihydronaphthoisoxazole derivatives shown in the general formula I, and geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, are selected from:

4. the use of dihydronaphthoisoxazole derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to claim 1 for the preparation of medicaments for the treatment of tumors.