CN108129468B - Aspirin derivatives and preparation method and application thereof - Google Patents

Aspirin derivatives and preparation method and application thereof Download PDF

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CN108129468B
CN108129468B CN201810084158.XA CN201810084158A CN108129468B CN 108129468 B CN108129468 B CN 108129468B CN 201810084158 A CN201810084158 A CN 201810084158A CN 108129468 B CN108129468 B CN 108129468B
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梁仁明
程纯儒
刘义
郑智
徐凯
杨蕊
丁杰
梁兴勇
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Sichuan University of Science and Engineering
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Abstract

The invention discloses an acetylsalicylic acid derivative with a structure shown as a formula I or a formula II

Description

Aspirin derivatives and preparation method and application thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to aspirin derivatives and a preparation method and application thereof.
Background
Heparanase (HPSE-1), the only endogenous beta-glucuronic acid esterase in mammals capable of recognizing Heparan Sulfate Proteoglycan (HSPG) side chain-HS structure, is closely related to tumor metastasis. Heparanase promotes the migration and infiltration process of cells by cutting HS chains on HSPG, causes the degradation of extracellular matrix and cell basement membrane, and thus destroys the barrier of cancer cell metastasis; the activation of plasminogen by the release of urokinase-type plasmin and tissue plasmin activators activates the metalloproteases in the matrix to promote the release of heparan sulfate-bound basic fibroblast growth factor and thus promote cell migration (Biochim Biophys Acta,2001,1471(3): M99-M108; Biochemistry,2005,44: 12103-. Heparanase is highly expressed in tumor cells of lung cancer, pancreatic cancer, esophageal cancer, ovarian cancer, breast cancer and the like, and promotes invasion and migration of the tumor cells. Meanwhile, HPSE can also release angiogenesis promoting factors such as VEGF, bFGF, HGF and the like bound on HS chains to the vicinity of tumor cells to induce angiogenesis of tumor tissues (Cancer Research,2010,70: 5649-. Therefore, heparanase plays an important role in tumor angiogenesis, tumor proliferation, infiltration and metastasis. Research and screening of heparanase inhibitors has become a new direction for human beings to find potential drugs for cancer treatment.
Heparanase inhibitors currently in the development front are all heparin analogues, and the development work of related small-molecule inhibitors has no breakthrough. PI-88 is a heparanase inhibitor produced by Progen, Australia, has a relative molecular mass of 2300, is a mixture of highly sulfated mannan-oligosaccharides, is a promising candidate anti-tumor drug, and has entered clinical research as an anti-tumor drug. The existing inhibitors such as heparin analogues and sulfated polysaccharides are difficult to prepare monoclonal antibodies and often have an anticoagulant effect, and the production process of antibodies and vaccine antagonists is complex, the production cost is high, and severe immune response is often caused. In order to further improve the selectivity and bioavailability of the heparanase inhibitor and reduce the toxic and side effects of the heparanase inhibitor, research and development of small-molecule heparanase inhibitors have become hot spots in the development of modern inhibitor drugs.
In recent years, research finds that heparanase is a potential target for resisting tumor metastasis of aspirin. Research shows that aspirin inhibits the enzyme activity function and regulates related signal paths by binding with key amino acid Glu225 for regulating the enzyme activity of heparanase, so that angiogenesis and metastasis of tumors are inhibited. Based on the discovery, in order to further improve the inhibitory activity of aspirin on heparanase and reduce the toxic and side effects of aspirin, the invention designs and synthesizes a new acetylsalicylic acid analogue which is used as a new small-molecular heparanase inhibitor for resisting tumors and has very important significance.
Disclosure of Invention
The technical problem solved by the invention is as follows: compared with aspirin, the aspirin derivative has stronger activity inhibition effect on heparanase and better activity and effect of inhibiting tumor cells.
The invention also provides a preparation method of the aspirin derivative.
The invention also provides the application of the aspirin derivative or the isomer, the prodrug, the pharmaceutically acceptable salt, the double salt and the solvate thereof in preparing the preparation for inhibiting the heparanase.
The technical scheme adopted by the invention is as follows:
aspirin derivatives with structure shown in formula I or formula II
Figure BDA0001561898740000021
Or an isomer, prodrug, pharmaceutically acceptable salt, double salt, solvate thereof, wherein X ═ C, N, O, or S; n is 0, 1, 2, 3, or > 3.
The preparation method of the aspirin derivative is characterized by comprising the following steps of:
step 1: under the action of an acylating agent, acetylsalicylic acid reacts to generate acetylsalicyloyl chloride, and the reaction formula is as follows:
Figure BDA0001561898740000022
step 2: diols of different chain lengths (X ═ O, S, or N) in (BoC)2Under the action of O, an intermediate a is generated by reaction, and the reaction formula is as follows:
Figure BDA0001561898740000023
and step 3: the intermediate a and acetylsalicyloyl chloride are subjected to acylation reaction under the alkalescent condition to obtain an intermediate b, and the reaction formula is as follows:
Figure BDA0001561898740000031
and 4, step 4: reacting the intermediate b with trifluoroacetic acid, and removing tert-butyl to obtain an intermediate c, wherein the reaction formula is as follows:
Figure BDA0001561898740000032
and 5: under the action of an acylating agent, an intermediate d is generated by reacting the intermediate c, and the reaction formula is as follows:
Figure BDA0001561898740000033
step 6: allowing propylidene andrographolide to perform nucleophilic reaction with the intermediate d under alkalescent condition to obtain a compound shown in formula I, wherein the reaction formula is as follows:
Figure BDA0001561898740000034
further, the compound of formula I obtained in step 6 is reacted in an aqueous acid solution, and acetonide is removed to obtain a compound of formula II, which has the following reaction formula:
Figure BDA0001561898740000041
further, in step 1 acetylsalicylic acid is dissolved in dichloromethane in N2Under protection, adding oxalyl chloride and DMF (dimethyl formamide) with a catalytic amount, and stirring at room temperature for reaction to ensure that carboxyl is acylated to form an intermediate acetylsalicyloyl chloride;
in step 2, glycols of different chain lengths (X ═ O, S, or N) were dissolved in DMF and triethylamine and (BoC) were added2O, in N2Under protection, the system is stirred and reacts for 2 to 5 hours at the temperature of between 40 and 50 ℃ to obtain an intermediate a;
in step 3, dissolving the intermediate a in dichloromethane, cooling to 0 ℃, adding triethylamine, and reacting in N2Slowly dropwise adding a dichloromethane solution of acetylsalicyloyl chloride under protection, and then stirring the system at room temperature for reacting for 2-3h to obtain a light yellow oily substance b;
in the step 4, the intermediate b is stirred and reacts for 1-2h at room temperature under the action of trifluoroacetic acid, and a white solid intermediate c is obtained after tert-butyl is removed;
in step 5, the intermediate c is dissolved in dichloromethane in N2Adding acylating agent oxalyl chloride or thionyl chloride under protection, stirring at room temperature for reaction for 30min, adding catalytic amount of DMF, reacting at 25-85 ℃ for 6-10h, and evaporating excessive oxalyl chloride or thionyl chloride under reduced pressure to obtain a yellowish oily intermediate d;
in step 6, the propylidene andrographolide is dissolved in dichloromethane, then the temperature is reduced to 0 ℃, triethylamine is added, and the mixture is added in N2Under protection, slowly dropwise adding a dichloromethane solution of the intermediate d, and then stirring the system at room temperature for reacting for 2-3h to obtain the compound of the formula I.
Further, the synthesis method of the propylidene andrographolide comprises the following steps: dissolving andrographolide in organic solvent, adding 2, 2-dimethoxypropane and p-toluenesulfonic acid pyridine for reaction, evaporating to dryness, dissolving residue with the organic solvent, washing with weak base, water and saturated salt solution in sequence, drying, concentrating, and performing column chromatography or recrystallization to obtain propylidene andrographolide; the weak base is sodium bicarbonate or sodium carbonate; the organic solvent is diethyl ether, dichloromethane, toluene, chloroform or acetone.
Further, the intermediate a with different lengths, namely different n values, is adopted to perform acylation reaction with the acetyl salicylic acid chloride under the weak alkaline condition, so as to obtain the intermediate b with different chain lengths.
The invention relates to an application of aspirin derivative or isomer, prodrug, pharmaceutically acceptable salt, double salt and solvate thereof in preparing a preparation for inhibiting heparanase.
Further, the heparanase-inhibiting preparation inhibits angiogenesis and metastasis of tumors including lung cancer, pancreatic cancer, esophageal cancer, ovarian cancer, breast cancer or prostate cancer by inhibiting heparanase activity.
Further, the application comprises the compatibility and combination of other therapeutic agents, and the other therapeutic agents are selected from any one or more of the following drugs or derivatives or salts thereof: vincristine, doxorubicin, colchicine, etoposide, paclitaxel, docetaxel, camptothecin, topotecan, thioguanine, melphalan, chlorambucil, cyclophosphamide, epirubicin, aclacinomycin, tamoxifen, doxazosin, tamsulosin, fluoropyridine, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, amprenavir, abacavir, ritonavir, saquinavir, rofecoxib, genistein, cytarabine, bortezomib, glitazobactam, rituximab, gemcitabine, lopinavir.
Further, the formulation is administered by a method comprising: oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
Compared with the prior art, the invention has the beneficial effects that:
the compound can obviously inhibit the activity of heparanase and is a good heparanase inhibitor. The compound inhibits the activity of heparanase so as to inhibit the angiogenesis and metastasis of tumors, has very strong inhibitory activity on various tumor cells, and can be used for preparing anti-tumor medicaments.
The compound of the invention has simple preparation method, simple and convenient operation, good purity of the obtained compound and high yield.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples.
The present invention is more specifically explained in the following examples. It should be understood, however, that these examples are intended to illustrate the present invention, and are not intended to limit the scope of the present invention in any way. All examples of the invention1H-NMR or13The C-NMR nuclear magnetic resonance instrument (Brucker company) records, chemical shifts are expressed in ppm, silica gel for separation is 200-300 meshes (Qingdao ocean chemical Co., Ltd.), and the mixture ratio of eluent is volume ratio. % represents the mass percentage of the composition unless otherwise specified.
Example 1
This example provides a preparation of propylidene andrographolide, with the reaction formula:
Figure BDA0001561898740000051
adding 100mL of acetone into 4g of andrographolide, stirring until the solid is dissolved, adding 13mL of 2, 2-dimethoxypropane into the system, stirring for 5min after the addition is finished, adding 0.14g of pyridine p-toluenesulfonate into the system, and stirring for reacting for 2h at room temperature after the addition is finished. After the reaction was completed, the system was distilled under reduced pressure until acetone was eliminated, and the residue was dissolved in dichloromethane, washed successively with a saturated sodium bicarbonate solution, washed with water, washed with a saturated common salt solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (ethyl acetate/cyclohexane ═ 3:7) to obtain 4.3g of a white solid with a yield of 94%.1H-NMR(400MHz,CDCl3)6.98(t,J＝8Hz,1H),5.04(d,J＝4Hz,1H),4.92(s,1H),4.62(s,1H),4.45-4.44(m,1H),4.28(d,J＝10Hz,1H),3.95(d,J＝10Hz,1H),3.50(dd,J1＝4Hz,J2＝8Hz,1H),3.18(d,J＝10Hz,1H),2.57–2.55(m,3H),2.43(d,J＝12Hz,1H),2.00–1.92(m,2H),1.8–1.77(m,6H),1.42(s,3H),1.37(s,3H),1.25(s,3H),0.97(s,3H).
Example 2
This example provides the preparation of acetylsalicyloyl chloride, of the formula:
Figure BDA0001561898740000061
acetylsalicylic acid (3.0g,16.65mmol), 30mL of methylene chloride was added to a 50mL single neck flask under N2Stirring at room temperature to dissolve under protection, adding oxalyl chloride (4.22g,33.3mmol), stirring at room temperature for reaction for 30min, adding 20-50 μ L DMF, stirring at room temperature for reaction for 6h, and evaporating excess oxalyl chloride under reduced pressure to obtain light yellow oil with yield of 90%.1H-NMR(400MHz,CDCl3)8.13(d,J＝8Hz,1H),7.62(t,J＝6Hz,1H),7.35(t,J＝6Hz,1H),7.15(d,J＝8Hz,1H),2.35(s,3H).
Example 3
This example provides the preparation of a compound of formula I (compound 1) where n ═ 0, according to the following reaction scheme:
Figure BDA0001561898740000062
propylidene andrographolide (0.40g,1.02mmol), 10mL of methylene chloride was charged into a 50mL single neck flask under N2The reaction was then placed in a low temperature reactor and cooled to 0 ℃ under protection with stirring at room temperature, followed by addition of triethylamine (0.56mL,4.0mmol), followed by dropwise addition of 10mL of a solution of acetylsalicylic acid chloride (0.285g,1.5mmol) in dichloromethane, and the mixture was stirred at room temperature for 1 h. After the reaction is completed, dichloromethane is added to dilute the reaction system, and then saturated NaHCO is used for sequential reaction3Washing with water, mixing water phases, extracting with dichloromethane, mixing organic phases, and washing with saturated brineAnhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ 2:5) to give compound 1 as a white solid in 85% yield.1H-NMR(400MHz,CDCl3)8.02(d,J＝8Hz,1H),7.62(t,J＝4Hz,1H),7.34(t,J＝4Hz,1H),7.14(d,J＝8Hz,2H),6.16(d,J＝4Hz,1H),4.87(s,1H),4.61(q,J＝10Hz,1H),4.54(s,1H),4.38(d,J＝12Hz,1H),3.95(d,J＝8Hz,1H),3.49(d,J＝12Hz,1H),3.18(d,J＝12Hz,1H),2.51(t,J＝10Hz,2H),2.42(d,J＝16Hz,3H),2.30(s,3H),1.98(t,J＝12Hz,2H),1.87(d,J＝8Hz,1H),1.73(t,J＝12Hz,3H),1.39(s,3H),1.36(s,3H),1.30–1.20(m,6H),0.85(s,3H).
Example 4
This example provides the preparation of a compound of formula II (compound 2) where n ═ 0, according to the following reaction scheme:
Figure BDA0001561898740000071
a compound of the formula I obtained in example 3 (0.1g,0.2mmol), 3mL of 70% aqueous acetic acid was placed in a 25mL single-neck flask under N2The reaction was stirred at room temperature for 20min under protection. After the reaction is completed, pouring the reaction system into a beaker, adding water to dilute the reaction system, and then adding saturated NaHCO3Neutralizing the reaction system with the solution until no bubbles are generated in the system, extracting with dichloromethane, combining organic phases, washing with saturated saline solution, and anhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ 3:1) to give compound 2 as a white solid in 93% yield.1H-NMR(400MHz,CDCl3)8.01(d,J＝8Hz,1H),7.62(t,J＝4Hz,1H),7.34(t,J＝4Hz,1H),7.14(d,J＝8Hz,2H),6.14(d,J＝4Hz,1H),4.85(s,1H),4.61(q,J＝10Hz,1H),4.51(s,1H),4.38(d,J＝12Hz,1H),4.17(d,J＝12Hz,1H),3.46(t,J＝12Hz,1H),3.31(d,J＝8Hz,1H),2.81(s,2H),2.50-2.41(m,3H),2.30(s,3H),1.83(t,J＝8Hz,1H),1.80(m,5H),1.23(m,6H),0.62(s,3H).
Example 5
This example provides a preparation of chloroacetylated propylidene andrographolide, with the reaction formula:
Figure BDA0001561898740000072
propylidene andrographolide (0.4g, 1.0mmol), 10mL of methylene chloride was added to a 50mL single neck flask in N2The reaction was then placed in a low temperature reactor and cooled to 0 ℃ under protection with stirring at room temperature, followed by addition of triethylamine (0.56mL,4.0mmol), followed by dropwise addition of chloroacetyl chloride (0.15mL,2.0mmol) in 15mL of dichloromethane, and the mixture was stirred at room temperature for 1 h. After the reaction is completed, dichloromethane is added to dilute the reaction system, and then saturated NaHCO is used for sequential reaction3Washing with water, mixing water phases, extracting with dichloromethane, mixing organic phases, washing with saturated saline solution, and anhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ 1:3) to obtain the chloroacetylated propylidene andrographolide as a pale yellow oily compound with a yield of 80%.
Example 6
This example provides the preparation of a compound of formula I (compound 3) where n ═ 1, X ═ C, according to the formula:
Figure BDA0001561898740000081
the compounds chloroacetylated propylidene andrographolide (0.20g, 0.43mmol), potassium iodide (0.14g, 0.86mmol), 10mL of acetone were added to a 25mL single-necked flask in N2The reaction is stirred for 2 hours at 30 ℃ under protection. After completion of the reaction, the acetone solvent was distilled off under reduced pressure, followed immediately by addition of acetylsalicylic acid (0.116g, 0.645mmol), triethylamine (0.23mL,1.72mmol) and 10mL of redistilled THF in N2The reaction was stirred at room temperature for 16h under protection. After completion of the reaction, the THF solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane and then successively saturated NaHCO3Washing with water, mixing water phases, extracting with dichloromethane, mixing organic phases, washing with saturated saline solution, and anhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ 1:3) to give compound 3 as a white solid in yield50％。1H-NMR(600MHz,CDCl3)8.07(d,J＝7.6Hz,1H),7.61(t,J＝7.5Hz,1H),7.34(t,J＝7.5Hz,1H),7.13(d,J＝7.9Hz,1H),7.06(s,1H),6.04(s,1H),4.83(d,J＝23.7Hz,3H),4.56(dd,J＝9.2,6.4Hz,1H),4.47(s,1H),4.30(d,J＝11.4Hz,1H),3.95(d,J＝11.5Hz,1H),3.48(d,J＝7.6Hz,1H),3.17(d,J＝11.7Hz,1H),2.51–2.37(m,3H),2.33(d,J＝11.5Hz,3H),1.97(dd,J＝27.9,13.2Hz,2H),1.82(d,J＝11.0Hz,1H),1.75–1.63(m,3H),1.40(s,3H),1.36(s,3H),1.25(s,3H),1.19(s,3H),0.93(s,3H).13C-NMR(150MHz,CDCl3)168.49,167.79,166.30,162.60,150.56,149.97,145.90,133.61,130.90,125.13,122.94,122.21,120.95,107.86,98.10,75.24,70.16,67.80,62.88,59.90,54.81,51.19,37.39,36.87,36.56,33.50,26.08,25.11,24.54,24.28,23.92,22.11,19.97,15.07.
Example 7
This example provides the preparation of a compound of formula ii (compound 4) where n ═ 1, x ═ C, according to the formula:
Figure BDA0001561898740000091
the compound of formula I (compound 3, 0.1g,0.2mmol) having N ═ 1 obtained by the method of example 6, and 3mL of 70% aqueous acetic acid were put into a 25mL single-neck flask, and the mixture was heated under vacuum in a nitrogen atmosphere2The reaction was stirred at room temperature for 20min under protection. After the reaction is completed, pouring the reaction system into a beaker, adding water to dilute the reaction system, and then adding saturated NaHCO3Neutralizing the reaction system with the solution until no bubbles are generated in the system, extracting with dichloromethane, combining organic phases, washing with saturated saline solution, and anhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ 3:1) to give compound 4 as a white solid in 93% yield.1H-NMR(600MHz,CDCl3)8.06(d,J＝7.4Hz,1H),7.61(t,J＝7.1Hz,1H),7.34(t,J＝6.7Hz,1H),7.13(d,J＝7.8Hz,1H),7.06(s,1H),6.03(s,1H),4.81(dd,J＝22.7,13.8Hz,3H),4.56(s,1H),4.44(s,1H),4.30(d,J＝11.3Hz,1H),4.17(d,J＝11.0Hz,1H),3.46(s,1H),3.31(s,1H),2.90(d,J＝3.9Hz,1H),2.66(s,1H),2.43(m,3H),2.32(s,3H),1.95(t,J＝12.2Hz,1H),1.78(m,5H),1.24(s,6H),0.66(s,3H).13C-NMR(150MHz,CDCl3)168.57,167.82,166.34,162.64,150.46,149.94,145.53,133.66,130.87,125.17,122.96,122.26,120.94,107.76,79.31,76.25,76.04,75.83,70.18,67.74,63.08,59.90,54.74,54.14,41.80,37.84,36.65,35.91,27.07,24.33,22.66,21.70,19.97,14.05.
Example 8
This example provides N ═ 1, X ═ N intermediate d (compound d)1) The reaction formula is as follows:
Figure BDA0001561898740000092
compound c1(4.66g,16.65mmol), 30mL of methylene chloride was charged into a 50mL single-neck flask under N2Stirring at room temperature to dissolve under protection, adding oxalyl chloride (4.22g,33.3mmol), stirring at room temperature for reaction for 30min, adding 20-50 μ L DMF, stirring at room temperature for reaction for 6h, and evaporating excess oxalyl chloride under reduced pressure to obtain light yellow oil d1The yield was 80%.
Example 9
This example provides the preparation of a compound of formula I (compound 5) where N ═ 1 and X ═ N, according to the formula:
Figure BDA0001561898740000101
propylidene andrographolide (0.40g,1.02mmol), 10mL of methylene chloride was charged into a 50mL single neck flask under N2Stirring at room temperature to dissolve under protection, placing the reaction in a low-temperature reactor, cooling to 0 ℃, adding triethylamine (0.56mL,4.0mmol), and dropwise adding d prepared by the method of example 81A10 mL solution of (0.45g,1.5mmol) in dichloromethane was added and the mixture was stirred at room temperature for 1 h. After the reaction is completed, dichloromethane is added to dilute the reaction system, and then saturated NaHCO is used for sequential reaction3Washing with water, mixing water phases, extracting with dichloromethane, mixing organic phases, washing with saturated saline solution, and anhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ PE)2:3) to give compound 5 as a pale yellow oil in 82% yield.1H-NMR(400MHz,CDCl3)8.03(s,1H),8.01(d,J＝8Hz,1H),7.59(t,J＝4Hz,1H),7.29(t,J＝4Hz,1H),7.13(d,J＝8Hz,2H),6.15(d,J＝4Hz,1H),4.85(s,1H),4.61(q,J＝10Hz,1H),4.51(s,1H),4.39(d,J＝12Hz,1H),4.31(t,J＝8Hz,2H),3.93(d,J＝8Hz,1H),3.48(d,J＝12Hz,1H),3.18(d,J＝12Hz,1H),3.13(t,J＝8Hz,2H),2.51(t,J＝10Hz,2H),2.42(d,J＝16Hz,3H),2.29(s,3H),2.03–1.98(m,2H),1.96(t,J＝12Hz,2H),1.86(d,J＝8Hz,1H),1.71(t,J＝12Hz,3H),1.36(s,3H),1.34(s,3H),1.34–1.28(m,6H),0.82(s,3H).
Example 10
This example provides the preparation of a compound of formula ii (compound 6) where N ═ 1 and X ═ N, according to the formula:
Figure BDA0001561898740000102
compound 5(0.1g,0.15mmol) obtained in example 9, 3mL of 70% aqueous acetic acid was placed in a 25mL single-neck flask under N2The reaction was stirred at room temperature for 30min under protection. After the reaction is completed, pouring the reaction system into a beaker, adding water to dilute the reaction system, and then adding saturated NaHCO3Neutralizing the reaction system with the solution until no bubbles are generated in the system, extracting with dichloromethane, combining organic phases, washing with saturated saline solution, and anhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ 3:1) to give compound 6 as a pale yellow solid in 65% yield.1H-NMR(400MHz,CDCl3)8.03(s,1H),8.02(d,J＝8Hz,1H),7.58(t,J＝4Hz,1H),7.32(t,J＝4Hz,1H),7.14(d,J＝8Hz,2H),6.12(d,J＝4Hz,1H),4.87(s,1H),4.61(q,J＝10Hz,1H),4.54(s,1H),4.38(d,J＝12Hz,1H),4.26(t,J＝8Hz,2H),3.95(d,J＝8Hz,1H),3.49(d,J＝12Hz,1H),3.18(d,J＝12Hz,1H),3.14(t,J＝8Hz,2H),2.51(t,J＝10Hz,2H),2.42(d,J＝16Hz,3H),2.33(s,3H),2.04–1.99(m,2H),1.98(t,J＝12Hz,2H),1.85(d,J＝8Hz,1H),1.73(t,J＝12Hz,3H),1.35–1.29(m,6H),0.81(s,3H).
Example 11
The embodiment is providedIntermediate d (compound d) provided with n ═ 1 and X ═ O2) The reaction formula is as follows:
Figure BDA0001561898740000111
compound c2(4.7g,16.65mmol), 30mL of methylene chloride was charged to a 50mL single neck flask in N2Stirring at room temperature to dissolve under protection, adding oxalyl chloride (4.22g,33.3mmol), stirring at room temperature for reaction for 30min, adding 20-50 μ L DMF, stirring at room temperature for reaction for 6h, and evaporating excess oxalyl chloride under reduced pressure to obtain light yellow oil d2The yield was 85%.
Example 12
This example provides the preparation of a compound of formula I (compound 7) where n ═ 1 and X ═ O, according to the formula:
Figure BDA0001561898740000112
propylidene andrographolide (0.40g,1.02mmol), 10mL of methylene chloride was charged into a 50mL single neck flask under N2The reaction was then cooled to 0 ℃ in a low temperature reactor under protection with stirring at room temperature, followed by addition of triethylamine (0.56mL,4.0mmol) and dropwise addition of the acid chloride d prepared as described in example 112A10 mL solution of (0.285g,1.5mmol) in dichloromethane was added and the mixture was stirred at room temperature for 1 h. After the reaction is completed, dichloromethane is added to dilute the reaction system, and then saturated NaHCO is used for sequential reaction3Washing with water, mixing water phases, extracting with dichloromethane, mixing organic phases, washing with saturated saline solution, and anhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ 1:2) to give compound 7 as a pale yellow oil in 75% yield.1H-NMR(400MHz,CDCl3)8.01(d,J＝8Hz,1H),7.61(t,J＝4Hz,1H),7.35(t,J＝4Hz,1H),7.16(d,J＝8Hz,2H),6.16(d,J＝4Hz,1H),4.87(s,1H),4.59(q,J＝10Hz,1H),4.54(s,1H),4.38(d,J＝12Hz,1H),4.29(t,J＝8Hz,2H),4.21(t,J＝8Hz,2H),3.95(d,J＝8Hz,1H),3.45(d,J＝12Hz,1H),3.18(d,J＝12Hz,1H),2.45(t,J＝10Hz,2H),2.41(d,J＝16Hz,3H),2.30(s,3H),2.16–2.12(m,2H),1.98(t,J＝12Hz,2H),1.87(d,J＝8Hz,1H),1.69(t,J＝12Hz,3H),1.39(s,3H),1.36(s,3H),1.32–1.21(m,6H),0.83(s,3H).
Example 13
This example provides the preparation of a compound of formula ii (compound 8) where n ═ 1 and X ═ O, according to the formula:
Figure BDA0001561898740000121
compound 7(0.1g,0.15mmol) obtained in example 12, 3mL of 70% aqueous acetic acid was placed in a 25mL single-neck flask under N2The reaction was stirred at room temperature for 30min under protection. After the reaction is completed, pouring the reaction system into a beaker, adding water to dilute the reaction system, and then adding saturated NaHCO3Neutralizing the reaction system with the solution until no bubbles are generated in the system, extracting with dichloromethane, combining organic phases, washing with saturated saline solution, and anhydrous NaSO4Drying, filtering, evaporating the solvent under reduced pressure, and purifying the residue by column chromatography (EA: PE ═ 3:1) to give compound 8 as a pale yellow solid in 83% yield.1H-NMR(400MHz,CDCl3)8.03(d,J＝8Hz,1H),7.62(t,J＝4Hz,1H),7.32(t,J＝4Hz,1H),7.15(d,J＝8Hz,2H),6.16(d,J＝4Hz,1H),4.87(s,1H),4.59(q,J＝10Hz,1H),4.54(s,1H),4.38(d,J＝12Hz,1H),4.30(t,J＝8Hz,2H),4.19(t,J＝8Hz,2H),3.95(d,J＝8Hz,1H),3.49(d,J＝12Hz,1H),3.18(d,J＝12Hz,1H),2.53(t,J＝10Hz,2H),2.42(d,J＝16Hz,3H),2.30(s,3H),2.16–2.12(m,2H),1.96(t,J＝12Hz,2H),1.87(d,J＝8Hz,1H),1.73(t,J＝12Hz,3H),1.29–1.18(m,6H),0.82(s,3H).
Example 14
This example provides a study of the biological activity of heparanase inhibitors according to the invention.
In this example, heparan degradation assay kit (insight, INS-26-4-0000-10) was used to detect the inhibitory effect of compounds on heparanase. Adding different concentrations of biological heparan in the reaction system of 50 μ L biological heparan and 31mIU/L human recombinant heparanase strictly according to the instruction of the kitThe reaction volume of the compound solution (1, 5, 15, 30, 60, 120, 180, 240) per well was 100. mu.L. Incubating at 37 deg.C for 45 min; transferring the reaction product to a color development plate of a hole, and incubating for 45min at 37 ℃; and (5) washing the plate. Adding horseradish enzyme-labeled ovalbumin and 100 mu L of horseradish enzyme substrate into each hole, and incubating for 30min at 37 ℃ for color development; the reaction was terminated by adding 100. mu.L of a stop solution, and the value was measured by a microplate reader. Three parallel wells were made for each drug concentration. IC calculation Using GraphPadprism 5 software50The value is obtained.
The experimental results are shown in table 1 below.
TABLE 1 Studies of biological Activity of heparanase inhibitors
Figure BDA0001561898740000131
As is clear from Table 1, all of Compound 1, Compound 3, Compound 6 and Compound 8 were effective in inhibiting heparanase activity and had higher inhibitory activity than aspirin, among which Compound 1 had the best inhibitory effect and IC50The value reaches 5.32 mu M, and the heparanase inhibitor is good.
Example 15
This example provides an anti-tumor activity assay of the invention.
In this example, prostate tumor cells (PC-3), breast cancer cells (MCF-7, MDA-MB-231) and lung cancer cells (A549) were used for pharmacological experiments, after the cells were neutralized with pancreatin-digested cells and 10 wt% FBS culture medium until the cells grew to the logarithmic phase, cells were collected by centrifugation at 800g for 5min, the supernatant was removed, the cell pellet was resuspended in 10% FBS-containing RPMI-1640 culture medium, the cell concentration was adjusted to 4 × 104/mL, 100. mu.L of cell suspension was added to a 96-well culture plate so that the number of cells per well became 4 × 103, and a blank group (containing no cells and no drug) and a control group (containing cells but no drug) were set at 37 ℃ and 5% CO were set2Culturing for 24h under the condition, allowing the cells to adhere to the wall, and entering the growth cycle again. The concentration gradient of 5 groups of medicines is set, each group has 5 compound holes, and the final concentration of the medicines is set to be 100, 50, 25, 12.5, 6.25ng/mL (the fat-soluble medicines are dissolved in 1mL of EtOH to be 3 mg)Diluting the mother liquor with 30mg/mL by using a cell culture solution according to needs to ensure that the content of EtOH does not exceed 1 percent), replacing the cell culture solution before adding the medicament, uniformly mixing the medicament with corresponding concentration with the cell culture solution, and adding the mixture into cells corresponding to a 96-well plate (100 mu L per well); the control group was added with the same volume of culture solution. At 37 ℃ 5% CO2Culturing under the condition for 48 hr, replacing with new cell culture solution, adding 10 μ L CCK-8 cell proliferation detection reagent into each well, culturing at 37 deg.C with 5% CO2After incubation for 3h under the conditions, the corresponding absorbance values (A values) were determined with a microplate reader at a wavelength of 450 nm. The positive control drug adopts clinical antitumor drugs of paclitaxel (taxol) and aspirin as control drugs.
The growth inhibition rate is (a value of control-a value of experimental group)/(a value of control-blank group) × 100%.
The experimental results are shown in table 2 below.
TABLE 2 inhibitory Effect of heparanase inhibitors on different tumor cells
Figure BDA0001561898740000141
As can be seen from Table 2, Compound 1, Compound 3, Compound 6 and Compound 8 of the present invention have significant inhibitory effects on tumor cells and are more potent than aspirin in tumor cells. Wherein, the inhibition effect of the compound 1 and the compound 6 on MDA-MB-231 and PC-3 tumor cells is equivalent to that of clinical antitumor drug taxol.
The above embodiments are merely illustrative and not restrictive of the present invention, and those skilled in the relevant art can make various changes and modifications without departing from the spirit and scope of the present invention. All equivalent solutions are therefore also within the scope of the present invention.

Claims (10)

1. Aspirin derivatives with structure shown in formula I or formula II
Figure FDA0002634993590000011
Or a pharmaceutically acceptable salt, double salt, wherein X ═ C, N, O, or S; n is 0, 1, 2, 3.
2. The process for producing an aspirin derivative according to claim 1, characterized by comprising the steps of:
step 1: dissolving acetylsalicylic acid in DCM, reacting with acylating agent oxalyl chloride under the action of DMF with a catalytic amount at room temperature to generate acetylsalicyloyl chloride, wherein the reaction formula is as follows:
Figure FDA0002634993590000012
step 2: will be provided with
Figure FDA0002634993590000013
Dissolved in DMF with (Boc)2O in Et3Under the action of N, reacting to generate an intermediate a, wherein X ═ O, S or N, and the reaction formula is as follows:
Figure FDA0002634993590000014
and step 3: intermediate a was dissolved in DCM and acetylsalicyloyl chloride in Et3Carrying out acylation reaction under the action of N to obtain an intermediate b, wherein the reaction formula is as follows:
Figure FDA0002634993590000015
and 4, step 4: dissolving the intermediate b in DCM to react with trifluoroacetic acid, and removing tert-butyl to obtain an intermediate c, wherein the reaction formula is as follows:
Figure FDA0002634993590000021
and 5: dissolving the intermediate c in DCM, reacting with acylating agent oxalyl chloride or thionyl chloride under the action of catalytic amount of DMF at room temperature to generate an intermediate d, wherein the reaction formula is as follows:
Figure FDA0002634993590000022
step 6: propylidene andrographolide was dissolved in DCM and reacted with intermediate d in Et3Carrying out nucleophilic reaction under the action of N to obtain a compound shown in a formula I, wherein the reaction formula is as follows:
Figure FDA0002634993590000023
3. a process for preparing aspirin derivatives according to claim 2, wherein the compound of formula I obtained in step 6 is reacted in an aqueous solution of acetic acid, removing acetonide to obtain a compound of formula II:
Figure FDA0002634993590000031
4. a process for preparing aspirin derivatives as claimed in claim 3, wherein in step 1 acetylsalicylic acid is dissolved in dichloromethane in N2Under protection, adding oxalyl chloride and DMF (dimethyl formamide) with a catalytic amount, and stirring at room temperature for reaction to ensure that carboxyl is acylated to form an intermediate acetylsalicyloyl chloride;
in step 2, the
Figure FDA0002634993590000032
Dissolved in DMF and added triethylamine and (Boc)2O, in N2Under protection, the system is stirred and reacts for 2 to 5 hours at the temperature of between 40 and 50 ℃ to obtain an intermediate a;
in step 3, dissolving the intermediate a in dichloromethane, cooling to 0 ℃, adding triethylamine, and reacting in N2Slowly dropwise adding a dichloromethane solution of acetylsalicyloyl chloride under protection, and then stirring the system at room temperature for reacting for 2-3h to obtain a light yellow oily substanceb；
In the step 4, the intermediate b is stirred and reacts for 1-2h at room temperature under the action of trifluoroacetic acid, and a white solid intermediate c is obtained after tert-butyl is removed;
in step 5, the intermediate c is dissolved in dichloromethane in N2Adding acylating agent oxalyl chloride or thionyl chloride under protection, stirring at room temperature for reaction for 30min, adding catalytic amount of DMF, reacting at 25-85 ℃ for 6-10h, and evaporating excessive oxalyl chloride or thionyl chloride under reduced pressure to obtain a yellowish oily intermediate d;
in step 6, the propylidene andrographolide is dissolved in dichloromethane, then the temperature is reduced to 0 ℃, triethylamine is added, and the mixture is added in N2Under protection, slowly dropwise adding a dichloromethane solution of the intermediate d, and then stirring the system at room temperature for reacting for 2-3h to obtain the compound of the formula I.
5. The method for preparing aspirin derivatives according to claim 4, wherein the synthesis method of propylidene andrographolide comprises: dissolving andrographolide in organic solvent, adding 2, 2-dimethoxypropane and p-toluenesulfonic acid pyridine for reaction, evaporating to dryness, dissolving residue with the organic solvent, washing with weak base, water and saturated salt solution in sequence, drying, concentrating, and performing column chromatography or recrystallization to obtain propylidene andrographolide; the weak base is sodium bicarbonate or sodium carbonate; the organic solvent is diethyl ether, dichloromethane, toluene, chloroform or acetone.
6. A process for preparing aspirin derivatives as claimed in claim 5, characterized in that different length intermediates a, i.e. different values of n, are used to perform acylation reaction with acetylsalicylic acid chloride under weakly alkaline conditions to obtain different chain length intermediates b.
7. Use of the aspirin derivative or the pharmaceutically acceptable salt or double salt according to claim 1 for preparing a preparation for inhibiting heparanase.
8. The use of claim 7, wherein the heparanase-inhibiting preparation inhibits angiogenesis and metastasis of tumors, including lung, pancreatic, esophageal, ovarian, breast or prostate cancer, by inhibiting heparanase activity.
9. The use according to claim 8, comprising the compatible co-administration with a further therapeutic agent selected from any one or more of the following: vincristine, doxorubicin, colchicine, etoposide, paclitaxel, docetaxel, camptothecin, topotecan, thioguanine, melphalan, chlorambucil, cyclophosphamide, epirubicin, aclacinomycin, tamoxifen, doxazosin, tamsulosin, fluoropyridine, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, amprenavir, abacavir, ritonavir, saquinavir, rofecoxib, genistein, cytarabine, bortezomib, glitazobactam, rituximab, gemcitabine, lopinavir.
10. The use of claim 9, wherein the formulation is administered by a method comprising: oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
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