CN111454229B

CN111454229B - Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs

Info

Publication number: CN111454229B
Application number: CN202010276756.4A
Authority: CN
Inventors: 颜建发
Original assignee: Individual
Current assignee: Xu Ying
Priority date: 2020-04-10
Filing date: 2020-04-10
Publication date: 2022-07-19
Anticipated expiration: 2040-04-10
Also published as: CN111454229A

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 by the international cancer research institute worldwide, about 1410 ten thousand cancer patients are newly added in 2012 worldwide 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 approaches to cancer treatment: 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 repaired by themselves 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, the 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 the 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, (C)₁-C₆) An alkyl group.

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

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 which may comprise formula I of the present invention may be synthesized by methods well known in the chemical arts, especially those prepared in accordance with the teachings of the present invention, all according to the route of condensation of the corresponding starting material 1 with diethyl oxalate under LiHMDS conditions to give intermediate 2; the intermediate 2 and hydroxylamine hydrochloride are subjected to ring closure reaction to obtain an intermediate 3; then obtaining an intermediate 4 by alkali liquor hydrolysis; finally, the target product is obtained by amide reaction with 5-aminoisoxazole.

The synthesis route of the dihydronaphthoisoxazole derivatives is as follows:

synthetic route reagents and conditions (a) Diethyl oxalate, LiHMDS; (b) hydroxylamine hydrochloride, EtOH, reflux,2 h; (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 either analytically or chemically pure, unless specified otherwise.

Example 1.

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

dissolving 1.5g (10.2mmol) of 1-tetralone and 1.8g (12.3mmol) of diethyl oxalate in tetrahydrofuran, reducing the temperature of the system to 0 ℃ in an ice bath under the protection of argon, then slowly dropwise adding 14.3mL (1MinTHF, 14.3mmol) of LiHMDS solution, heating to room temperature after dropwise adding, reacting for 6h, detecting by TLC to complete the reaction, and distilling under reduced pressure to remove the solvent to obtain a concentrate which is directly used for the next reaction.

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

The concentrate obtained in the previous step is dissolved in 40mL of glacial acetic acid, then 0.85g (12.3mmol) of hydroxylamine hydrochloride is added, and the temperature is raised to 80 ℃ for reaction for 10 h. TLC detection reaction was completed, the reaction solution was poured into 100mL of water, extracted with ethyl acetate, and the organic layer was washed with saturated brine and Na₂SO₄Dried 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 ]]2g (8.2mmol) of isoxazole-3-carboxylic acid ethyl ester was dissolved in 30mL of methanol, then 10mL of 2N NaOH solution was added and stirred at room temperature for 3 h. TLC detection reaction is completed, methanol is removed under reduced pressure, pH is adjusted to 5-7 by 1N hydrochloric acid, white solid is separated out, and the white solid is filtered and dried to obtain 1.62g, and the yield is 92.1%.¹H-NMR(600MHz,DMSO-d6)δ7.63(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) 1.0g (4.6mmol) of 4, 5-dihydronaphtho [2,1-d ] isoxazole-3-carboxylic acid was dissolved in dried DMF and EDCI2.20g (5.1mmol) and HOBt0.69g (5.1mmol) were added. After the reaction is carried out for 1h at room temperature, 0.43g (5.1mmol) of 5-aminoisoxazole and 2.5mL (15.2mmol) of DIEA are added, and the temperature is raised to 70 ℃ for reaction for 6 h. And (3) after TLC detection reaction, cooling the temperature to room temperature, pouring the reaction solution into 100mL of water, separating out a solid, filtering, drying, and performing column chromatography to obtain 0.86g of a white solid, namely the target product.

¹H-NMR(600MHz,DMSO-d₆)δ11.23(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).

Examples 2-4 were prepared according to the procedure of example 1, using substituted 1-tetralones as starting materials, respectively, via four reactions of condensation, ring closure, hydrolysis, and condensation.

Example 2.

¹H-NMR(600MHz,DMSO-d₆)δ11.24(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)δ11.22(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)δ11.22(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 inoculated into 96-well plates containing 5% of the totalCO₂100U/mL penicillin and 100 mu g/mL streptomycin in RPMI1640 complete medium at 37 ℃ for 24h, adding compounds with different concentrations, setting 5 multiple wells for each concentration, abandoning the culture solution after 48h of drug action, and determining the cell viability by 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. IC (integrated circuit)₅₀Refers 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.

Using 10g of the compound of claim 1 (exemplified by the compound of example 1), adsorbing with activated carbon, filtering through a 0.65 μm microporous membrane, and filling into nitrogen gas bottles to obtain water injection preparations, each containing 2mL, and filling into 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 present invention.

Claims

1. Dihydronaphthoisoxazole derivatives shown in a general formula I,

said R₁Selected from hydroxy, halogen, amino, (C)₁-C₆) Alkyl, (C)₁-C₆) An alkoxy group.

2. Dihydronaphthoisoxazoles derivatives according to claim 1, wherein R₁Selected from hydroxy, halogen, amino, (C)₁-C₆) An alkyl group.

3. The dihydronaphthoisoxazole derivative shown in the general formula I is selected from one of the following compounds:

4. the use of dihydronaphthoisoxazoles derivatives as claimed in claim 1 in the preparation of anti-tumor drugs, wherein the tumors are cervical cancer, breast cancer, lung tumor and colon cancer.