CN113387872A - Preparation method and application of compound - Google Patents

Abstract

The invention relates to the technical field of medicines, relates to a preparation method and a new application of a compound, and particularly relates to a preparation method of a compound 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidine-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol and an application of the compound in preparation of a medicine for preventing and/or treating diseases related to SphK1 dysfunction. The invention discovers for the first time that 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol has the effect of selectively inhibiting SphK1, and can be used for preventing and/or treating diseases related to SphK1 dysfunction.

Description

Preparation method and application of compound

Technical Field

The invention relates to the technical field of medicines, relates to a new application of a compound, and particularly relates to an application of a compound 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol in preparation of a medicine for preventing and/or treating diseases related to SphK1 dysfunction.

Background

Sphingomyelin (sphingomyelin) is an important component of eukaryotic cell membranes, and is metabolized by various biological enzymes in turn to ceramide (Cer), sphingosine (Sp) and sphingosine-1-phosphate (S1-phosphate, 1P). These three metabolites have different roles in biology as bioeffective molecules. Cer and Sp are used as negative regulatory factors and can mediate cell growth arrest or apoptosis. S1P, which is functionally opposite, acts to promote cell proliferation and differentiation. On one hand, S1P can be used as a first messenger, acts on G protein coupled Receptors (S1P Receptors, S1PRs) on the cell surface, and plays roles in promoting cell proliferation, increasing angiogenesis and inhibiting apoptosis; on the other hand, it can mediate various biological effects by performing a second messenger function and acting on corresponding targets in the cell. The level of S1P activity in tumor cells directly determines the fate of the cells. There is a dynamic equilibrium between Cer, Sp, which promotes apoptosis, and S1P, which promotes survival, and this equilibrium is called sphingomyelin rheostat (sphingolipid rheostat). It is strictly controlled by various regulatory enzymes such as ceramidase, ceramide synthase, sphingosine kinases (sphiks), phosphorylase, and the like. The SphKs play a crucial role in this balance. It can rely on ATP to catalyze Sp phosphorylation to generate S1P, which acts to influence cell proliferation.

There are two species of SphKs in mammals, SphK1 and SphK2, which differ in structure and function. SphK1 has been shown to be highly expressed in a variety of cancer cells, such as ovarian, cervical, colon, gastric, lung, and brain cancers. Inhibition of SphK1 activity resulted in elevated levels of Sph and Cer in tumor cells, while levels of S1P decreased, resulting in inhibition of cell growth or apoptosis. Over-expressed SphK1 not only stimulates cell growth, but also causes malignant transformation of normal cells. Therefore, the expression and activity of SphK1 directly determine the fate of tumor cells. The major biological function of SphK1 is generally thought to be to promote cell survival and proliferation, and SphK1 is therefore an ideal target for cancer therapy. In recent years, SphK1-S1P-S1PRs signal pathways and the functions of the signal pathways in various diseases such as tumors, autoimmune system diseases, inflammations, atherosclerosis, nervous system diseases and the like are gradually clarified, and the design, development and research of SphK 1-targeted drugs also become one of the hot spots of domestic and foreign research. Since the incidence of cancer and inflammatory diseases tends to increase year by year and the mechanism of pathological process is very complicated, the structural diversity of the SphK1 inhibitor is found to alleviate cancer and inflammatory diseases.

1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol, CAS number 2125657-10-3, molecular formula C₂₈H₄₂N₂O₅The structural formula is as follows:

the literature data disclosed at present only have physicochemical properties of the compound, and no reports on the synthetic method and pharmacological efficacy of the compound are found, and no reports on the compound serving as an SphK1 inhibitor are found.

Disclosure of Invention

The first aspect of the technical scheme of the invention provides a preparation method of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol, which comprises the following steps:

dissolving 2- ((2-ethoxyphenoxy) methyl) ethylene oxide and 1- (3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) phenyl) -N-methyl methylamine in isopropanol, adding a catalytic amount of pyridine under the protection of nitrogen, heating and refluxing for 6h, and detecting the disappearance of raw materials by TLC (thin layer chromatography); diluting the reaction solution with ethyl acetate, washing the organic phase with water, saturated salt solution, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating the crude product by silica gel column chromatography.

The second aspect of the technical scheme of the invention provides application of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol in preparation of a medicine for preventing and/or treating diseases related to SphK1 dysfunction.

The disease associated with dysfunction of SphK1 is cancer.

The disease related to the dysfunction of SphK1 is inflammatory disease.

The clinical administration mode of the compound of the invention can adopt oral administration, injection and other modes.

The compound of the present invention is used in the clinical dosage of 0.01-1000 mg/day, and the dosage may be varied according to the severity of the disease or the dosage form.

The third aspect of the technical scheme of the invention provides a pharmaceutical composition of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol and one or more pharmaceutically acceptable carriers and/or diluents, which is any clinically or pharmaceutically acceptable dosage form, preferably an oral preparation or an injection. The composition contains 0.01g to 10g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.04g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g and the like of a physiologically effective amount of the compound represented by formula I.

1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol can be administered to a patient in need of such treatment orally or parenterally, and the like.

For parenteral administration, it can be made into injection. The injection is a sterile preparation of solution, emulsion or suspension for injection into the body and powder or concentrated solution for preparation or dilution into solution or suspension before use, and can be divided into injection, sterile powder for injection and concentrated solution for injection. The injection is sterile solution type injection, emulsion type injection or suspension type injection prepared from the medicine for injection into human body, and can be used for intramuscular injection, intravenous drip, etc.; the standard of the injection is 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml and the like, wherein the large-volume (generally not less than 100ml) injection for intravenous drip is also called intravenous infusion. The sterile powder for injection is sterile powder or sterile block which is prepared by proper sterile solution to be prepared into clear solution or uniform suspension before use, can be prepared by proper solvent for injection and then injected, and can also be prepared by intravenous infusion and then is subjected to intravenous drip; the sterile powder is prepared by solvent crystallization, spray drying or freeze drying. Concentrated solution for injection refers to sterile concentrated solution of the drug for dilution before use for intravenous drip.

The injection can be prepared by conventional method in pharmaceutical field, and can be aqueous solvent or non-aqueous solvent. The most commonly used aqueous solvent is water for injection, and 0.9% sodium chloride solution or other suitable aqueous solution can also be used; the common non-aqueous solvent is vegetable oil, which is mainly soybean oil for injection, and other aqueous solutions of ethanol, propylene glycol, polyethylene glycol and the like. When preparing the injection, the additive can be not added, and the proper additives can be added according to the property of the medicine, such as osmotic pressure regulator, pH value regulator, solubilizer, filler, antioxidant, bacteriostatic agent, emulsifier, suspending agent and the like. Commonly used osmo-regulators include sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol, etc., preferably sodium chloride or glucose; commonly used pH regulators include acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate-sodium carbonate, etc.; commonly used solubilizers include polysorbate 80, propylene glycol, lecithin, polyoxyethylene castor oil, and the like; common fillers include lactose, mannitol, sorbitol, dextran, and the like; common antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, and the like; common bacteriostats are phenol, cresol, chlorobutanol and the like. The common containers for injections include glass ampoules, glass bottles, plastic ampoules, plastic bottles and the like. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. The tablet is a round or special-shaped tablet solid preparation prepared by uniformly mixing and pressing the medicament and proper auxiliary materials, mainly takes an oral common tablet as a main part, and also comprises a buccal tablet, a sublingual tablet, an oral patch, a chewable tablet, a dispersible tablet, a soluble tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet, an enteric-coated tablet and the like. The capsule refers to a solid preparation prepared by filling a drug or an adjuvant into an empty capsule or sealing in a soft capsule material, and can be divided into hard capsules (generally called capsules), soft capsules (capsules), sustained-release capsules, controlled-release capsules, enteric capsules and the like according to the dissolution and release characteristics of the solid preparation. The pill refers to a spherical or spheroidal solid preparation prepared by mixing the medicine and proper materials uniformly and preparing the mixture by a proper method, and comprises a dropping pill, a sugar pill, a pellet and the like. The granules refer to dry granular preparations with certain granularity prepared by the medicines and proper auxiliary materials, and can be divided into soluble granules (generally called granules), suspension granules, effervescent granules, enteric granules, sustained-release granules, controlled-release granules and the like. Oral solution means that the drug is dissolved in a suitable solvent to make into a clear liquid preparation for oral administration. Oral suspensions refer to poorly soluble solid drugs dispersed in a liquid medium to form a suspension formulation for oral administration, including dry suspensions or concentrated suspensions. Syrup refers to a concentrated aqueous solution of sucrose containing the drug. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. Common fillers include starch, sugar powder, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, and the like; common binders include sodium carboxymethylcellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hypromellose, gelatinized starch, etc.; common disintegrants include dry starch, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and the like; common lubricants include magnesium stearate, talc, sodium lauryl sulfate, aerosil, and the like.

The compound can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, powder, syrup, liquid, suspending agents and injection, and common medicinal auxiliary materials such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added.

In the fourth aspect of the technical scheme, the invention provides application of a composition containing 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol in preparing a medicament for preventing and/or treating diseases related to SphK1 dysfunction.

The disease associated with dysfunction of SphK1 is cancer.

The disease related to the dysfunction of SphK1 is inflammatory disease.

The fifth aspect of the technical scheme of the invention provides application of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol in preparing anticancer drugs.

The sixth aspect of the technical scheme of the invention provides application of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol in preparing a medicine for treating colon cancer.

The beneficial technical effects are as follows:

(1) the invention provides a preparation method of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidine-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol, which is simple to operate and high in yield.

(2) Book (I)The invention discovers for the first time that 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol has the effect of selectively inhibiting SphK1, and can be used for preventing and/or treating diseases related to SphK1 dysfunction. IC of Compounds of the invention for SphK1 and SphK2₅₀The values show that the IC of compound SAMS10 for inhibition of SphK1₅₀The value is less than 10 mu M, has no inhibition effect on SphK2, is a selective SphK1 inhibitor, and is an ideal compound for intensive pharmacological research.

Detailed Description

The present invention will be further described with reference to specific embodiments so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.

Example 1: synthesis of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol (SAMS10)

2- ((2-ethoxyphenoxy) methyl) oxirane (194mg,1.0mmol) and 1- (3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) phenyl) -N-methylmethanamine (354mg,1.2mmol) were dissolved in isopropanol (15mL), and a catalytic amount of pyridine (8.0 μ L,0.1mmol) was added under nitrogen protection, heated under reflux for 6h, and the starting material was lost by TLC (developing solvent: dichloromethane-methanol ═ 10: 1). The reaction mixture was diluted with ethyl acetate, and the organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under the reduced pressure, and the crude product was separated and purified by silica gel column chromatography (mobile phase: dichloromethane-methanol ═ 20:1) to give a colorless oil (437.9mg, 90%).¹H NMR(CDCl₃,600MHz)δ(ppm):6.89(m,7H),4.09(m,7H), 3.84(s,3H),3.59(d,J＝19.80Hz,1H),3.47(d,J＝19.80Hz,1H),3.05(d,J＝17.40Hz,2H), 2.90(t,J＝9.60Hz,2H),2.61(m,2H),2.28(s,3H),2.19(m,2H),1.66(d,J＝21.0Hz,2H),1.38 (m,6H),0.94(d,J＝8.40Hz,3H).¹³C NMR(CDCl₃,150MHz)δ(ppm):149.49,149.39,148.72, 147.33,131.62,122.12,121.27,121.10,115.80,113.84,113.16,112.48,72.91,66.61(2C),64.51, 62.45,59.60,57.25,55.94,54.37(2C),42.43,33.84(2C),30.39,21.76,14.93.IR(KBr,cm^-1):2924, 2871,2851,2794,2360,2340,1592,1512,1494,1460,1419,1368,1321,1272,1217,1138,1035, 980,863,803,772,670.HRMS(ESI):m/z calcd for C₂₈H₄₃N₂O₅(M+H)⁺:487.3172.found: 487.3199.

Example 21 antagonistic Activity of- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol (SAMS10 for short in the test) against SphK1 and SphK2 kinase

1. Laboratory instruments and materials

The multifunctional microplate reader used for the experiment is a SpectraMax M5 multifunctional microplate reader manufactured by Molecular Devices of America.

TABLE 1 test reagents

2. Experimental methods

First 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol was made into 10mM stock solution with DMSO, accelerated dissolution was performed with ultrasound, and then DMSO and kinase buffer (pH 7.4, 40mM Tris, 10mM MgCl)₂0.1g/L BSA, 1mM DTT, 10. mu.M ATP) was diluted in a gradient with a final DMSO concentration of less than 1%. Concentration at preliminary screening was set to 10. mu.M, and IC was determined₅₀In order to ensure the accuracy of the results, 100, 33, 10, 3.33, 1, 0.33, 0.1, 0.03, 0.01 μ M9 concentration gradients were set. SphK1 and SphK2 were made up to 0.4. mu.g/mL and 1. mu.g/mL with kinase buffer and stored in a liquid nitrogen tank.

On the ELISA plate, the drug was added first, then the kinase buffer was added and mixed, the sphingosine substrate (0.2mM) was added, and finally SphK1/SphK2 was added and mixed so that the total volume was 50. mu.L, all the above operations were performed on ice. After incubating at 30 ℃ for 40 minutes, 50. mu.L of ATP detection solution was added, and the reaction was carried out at room temperature for 5 minutes, and a chemiluminescent signal (Luminescence, Lu) was immediately detected on a microplate reader, and the percentage of activity was calculated by substituting the value into the following equation:

% activity ═ 100% (Lu drug-Lu background)/(Lu enzyme-Lu background) ]

IC of the compound was calculated using Graphpad Prism5 software processing₅₀The value is obtained.

3. Results of the experiment

TABLE 2 inhibition of SphK1 and SphK2 by SAMS10

¹⁾PF-543 as positive control drug, and IC as measured result₅₀。

Preliminary screening results show that the compound SAMS10 has a certain inhibition effect on SphK1 when the concentration is 10 mu M, and has almost no inhibition effect on SphK2, and preliminary test results show that the compound has good selectivity on SphK 1.

Continuing the IC of the compounds to SphK1 and SphK2₅₀And (5) testing the value. The results are shown in Table 3.

TABLE 3 IC of SAMS10 for SphK1 and SphK2₅₀Value of

¹⁾PF-543 is positive control drug.

IC of Compounds of the invention for SphK1 and SphK2₅₀The values show that the IC of compound SAMS10 for inhibition of SphK1₅₀The value is less than 10 mu M, has no inhibition effect on SphK2, is a selective SphK1 inhibitor, and is an ideal compound for intensive pharmacological research.

Example 31- (2-Ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol (SAMS10 for short in the test) test for tumor cell growth inhibitory Activity

1. Laboratory instruments and materials

The multifunctional label analyzer used in the experiment was model Victor 1420 from Perkin Elmer, USA.

TABLE 4 test reagents

Cell lines: human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375), and human colon cancer (LOVO) cell lines were purchased from cell banks of Chinese academy of sciences, and cultured in DMEM (high glucose) medium containing 15% fetal bovine serum at 37 deg.C and 5% CO₂Culturing in an incubator.

2. Experimental methods

2.1 MTT principle and preparation method

MTT is an oxidative yellow dye with the chemical name of 3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2-H-tetrazolium bromide [3- (4, 5-dimethylthiazole-2) -2,5-diphenyl tetrazolium bromide. The MTT method is also called as MTT colorimetric method, can detect the survival and growth of cells, is simple and easy to operate, and is commonly used for screening substances with cytotoxic activity. The basic principle of detection is that succinate dehydrogenase can reduce exogenous MTT, so that MTT is reduced to water-insoluble blue-purple crystalline Formazan (Formazan), and the crystal is deposited in cells. Succinate dehydrogenase is present in mitochondria in living cells, and is absent in dead cells. Thus, the color reaction can only occur in living cells^[56]. Blue-violet formazan crystals in the cells were then dissolved in dimethyl sulfoxide (DMSO), and the absorbance thereof was measured with a microplate reader, thereby indirectly reflecting the number of living cells. In a certain range of cell numbers, the amount of blue-violet formazan crystals formed was positively correlated with the number of living cells.

The MTT method has the advantages of high efficiency, accuracy, simplicity, economy, good repeatability and the like, and is widely applied to screening of antitumor drugs, activity detection of medical bioactive factors, cytotoxic activity test determination and determination of tumor radiosensitivity.

Preparation of 5mg/mL MTT solution: weighing 500.0mg of MTT powder, dissolving in warm 100mL PBS, filtering with a microporous filter membrane with the aperture of 0.22 mu m to remove bacteria to obtain filtrate, subpackaging in a small amount into a centrifugal tube after autoclaving, and freezing and storing at the temperature of minus 20 ℃ in a dark place.

2.2 cell culture and Experimental methods

Taking out the cryopreservation tube with the tumor cells from the liquid nitrogen, quickly putting the tube into a37 ℃ incubator, and shaking continuously until the tube is melted. After wiping the edge of the cryopreserving tube cover with 75% alcohol, sucking the cell suspension, transferring the cell suspension into a 10mL centrifuge tube, and supplementing 5mL culture medium. Centrifuging at low speed (25 deg.C, 3000r/min, 5min), discarding supernatant, adding culture medium, and centrifuging once again. Diluting with appropriate amount of culture medium, blowing off cells with a pipette to obtain suspension, transferring into a culture flask, and placing at 37 deg.C and 5% CO₂Culturing in a cell culture box. The culture medium is replaced the next day and placed in 5% CO at 37 deg.C₂And continuing culturing in the cell culture box.

Human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cells are all adherent cells, adherent tumor cells in logarithmic growth phase are washed according to the growth rate of the tumor cells, and the number of the cells is adjusted to 1 × 10 by digesting with 0.25% EDTA pancreatin⁵Perml/mL in 96-well plates, 100. mu.L per well, at 37 ℃ in CO₂Culturing in incubator, and administering after 24 h. Administration groups were dosed with different concentrations of drug SAMS10, and 5 dose groups were set, 100, 10, 1, 0.1, 0.01. mu. mol/L, with three duplicate wells per concentration. A blank control, DMSO (0.8%) solvent control, and a cisplatin positive control were set. 5% CO at 37 ℃₂After culturing in an incubator for 48 hours, the OD value was measured by the MTT method, and the cell inhibition ratio was calculated.

2.3 cellular IC₅₀Calculation of values

Human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cells were cultured for 48h and terminated, then 10. mu.L of 0.5% MTT solution was added to each well and placed in CO₂After 4 hours in an incubator, the solution in each well was removed, 0.2mL of DMSO solution was added, followed by shaking sufficiently with low frequency on a shaker to dissolve formazan crystals sufficiently, and the resulting mixture was placed in the shakerRecording OD value at 490nm wavelength in enzyme labeling instrument, calculating average OD value of three parallel wells with different concentrations, and calculating cell inhibition rate and IC of tested drug at different concentrations according to average value₅₀The value is obtained.

Inhibition (%) [ 1-test sample OD value/negative control OD value ]. times.100%

3. Results of the experiment

TABLE 5 IC of SAMS10 against cancer cell proliferation₅₀Value of

¹⁾Cisplatin was used as a positive control.

Claims (10)

1. A process for the preparation of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol comprising the steps of:

   dissolving 2- ((2-ethoxyphenoxy) methyl) ethylene oxide and 1- (3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) phenyl) -N-methyl methylamine in isopropanol, adding a catalytic amount of pyridine under the protection of nitrogen, heating and refluxing for 6h, and detecting the disappearance of raw materials by TLC (thin layer chromatography); diluting the reaction solution with ethyl acetate, washing the organic phase with water, saturated salt solution, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating the crude product by silica gel column chromatography.
2. 2. Use of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol according to claim 1 for the preparation of a medicament for the prevention and/or treatment of a disease associated with dysfunction of SphK 1.
3. 3. Use according to claim 2, characterized in that: the disease associated with dysfunction of SphK1 is cancer.
4. 4. Use according to claim 2, characterized in that: the disease related to the dysfunction of SphK1 is inflammatory disease.
5. 5. A pharmaceutical composition comprising 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol of claim 1 and a pharmaceutically acceptable carrier and/or diluent.
6. 6. Use of a composition comprising 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol in the manufacture of a medicament for the prevention and/or treatment of a disease associated with dysfunction of SphK 1.
7. 7. The use of claim 6, wherein: the disease associated with dysfunction of SphK1 is cancer.
8. 8. The use of claim 6, wherein: the disease related to the dysfunction of SphK1 is inflammatory disease.
9. Application of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol in preparing anticancer drugs.
10. Application of 1- (2-ethoxyphenoxy) -3- ((3-methoxy-4- (2- (4-methylpiperidin-1-yl) ethoxy) benzyl) (methyl) amino) propan-2-ol in preparation of medicines for treating colon cancer.