CN115636863A

CN115636863A - Dexamethasone derivative containing maleimide segment and preparation method thereof

Info

Publication number: CN115636863A
Application number: CN202211276232.0A
Authority: CN
Inventors: 刘明亮; 刘秀均; 汪阿鹏; 李毅; 吕凯; 甄永苏
Original assignee: Institute of Medicinal Biotechnology of CAMS
Current assignee: Institute of Medicinal Biotechnology of CAMS
Priority date: 2022-10-19
Filing date: 2022-10-19
Publication date: 2023-01-24
Anticipated expiration: 2042-10-19
Also published as: CN115636863B

Abstract

The invention relates to a dexamethasone prodrug compound and an anti-tumor application thereof. In particular to a group of novel dexamethasone derivatives with antitumor activity and containing maleimide fragments, a preparation method thereof and application in the aspect of tumor resistance. The compound of the invention has a chemical structure shown in the following formula (I) and formula (II), wherein each substituent group is described in the specification. The compound prepared by the invention has excellent tumor inhibition effect on various tumors.

Description

Dexamethasone derivative containing maleimide segment and preparation method thereof

Technical Field

The invention belongs to the field of medicinal chemistry, relates to a method for improving the antitumor activity of dexamethasone, and particularly relates to a group of dexamethasone derivatives containing maleimide fragments, a preparation method thereof, and application thereof in the antitumor aspect.

Background

Dexamethasone (Dexamethasone), chemical name of 16 alpha-methyl-11 beta, 17 alpha, 21-trihydroxy-9 alpha-fluoropregna-1, 4-diene-3, 20-dione, CAS number 50-02-2, molecular formula C ₂₂ H ₂₉ FO ₅ Molecular weight 392.47, whose chemical structure is shown in the following formula (III):

dexamethasone is a glucocorticoid drug which is artificially synthesized (1957), is listed in a WHO basic drug standard list and is accepted by vast clinicians. The product has antiinflammatory, antiallergic, and antishock effects, and can be used for treating allergic and autoimmune diseases, such as connective tissue disease, rheumatoid arthritis, severe bronchial asthma, allergic diseases such as dermatitis, and ulcerative colitis, and can be made into tablet, injection, suspension, eye drop, and ointment. In addition, dexamethasone is also often used in combination with chemotherapeutic drugs to reduce the toxic side effects of the latter (e.g., dehydration, nausea, acute toxicity, edema, pain). Dexamethasone has been found to have some anti-tumor activity, but at the same time, it can reduce the sensitivity of cancer cells to chemotherapeutic drugs, so it must be strictly carefully used clinically (Sau S, et al. European Journal of Medicinal Chemistry,83 (2014) 433-447).

In recent years, a major breakthrough is made in the research of endogenous Human Serum Albumin (HSA) as a targeting carrier of a cytotoxic drug. Among them, as an HSA-binding prodrug of doxorubicin (DNA topoisomerase II inhibitor), aldoxoubicin (6-maleimidocaprohydrazide derivative of doxorubicin) has been approved by the U.S. FDA for marketing in 2014. It was found that, after intravenous administration, the maleimide fragment of the aldoxoubicin molecule could be covalently bound to the thiol group of HAS for targeted transport to tumor tissues and released from albumin under the acidic conditions of the tumor microenvironment. Compared with the original drug doxorubicin, aldoxorubicin has stronger curative effect and lower toxic and side effects (Moon H, et al. Biomacromolecules,2014,15, 3794-3801).

Based on the above results, the present inventors have conducted extensive studies to design and synthesize dexamethasone derivatives containing maleimide fragments, and measured their antitumor activities. Finally, it was found that compounds in which the hydroxyl group at the 21-position of dexamethasone was linked to the maleimide fragment via a different linker had unexpectedly strong antitumor activity. These prodrugs have superior in vivo antitumor efficacy when administered intravenously compared to the parent dexamethasone and gemcitabine already on the market.

Disclosure of Invention

The object of the present invention is to provide compounds of the following formulae (I) and (II),

or a pharmaceutically acceptable salt, solvate or solvate thereof,

wherein:

x represents O or is absent;

n represents 2 to 6.

A compound according to the first aspect of the invention, wherein the pharmaceutically acceptable salt is a salt with an inorganic acid or with an organic acid.

The compound according to the first aspect of the present invention, wherein the inorganic acid is selected from: hydrochloric acid, sulfuric acid, phosphoric acid.

A compound according to the first aspect of the invention, wherein the organic acid is selected from: acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, amino acids (e.g. alanine, aspartic acid, lysine), sulfonic acids (e.g. methanesulfonic acid, p-toluenesulfonic acid).

The compounds according to the first aspect of the invention may also exist in the form of solvates (e.g. hydrates), and therefore such solvates (e.g. hydrates) are also included in the compounds of the invention.

A compound according to the first aspect of the invention, which is a compound 1 to compound 10 selected from:

compound 1: dexamethasone-21- (3-maleimide) n-propionate

Compound 2: dexamethasone-21- (4-maleimide) n-butyrate

Compound 3: dexamethasone-21- (5-maleimide) pivalate

Compound 4: dexamethasone-21- (6-maleimide) n-hexanoate

Compound 5: dexamethasone-21- (2-maleimido) ethyl carbonate

Compound 6: dexamethasone-21- (3-maleimide) n-propyl carbonate

Compound 7: dexamethasone-21- (5-maleimide) n-pentylcarbonate

Compound 8: dexamethasone-21- (3-maleimide) n-propyl phosphate

Compound 9: dexamethasone-21- (5-maleimide) n-pentyl phosphate

Compound 10: dexamethasone-21- (6-maleimide) n-hexyl phosphate.

Further, the second aspect of the present invention provides a process for preparing a compound of formula (I) and a compound of formula (ii) according to the following reaction scheme one and reaction scheme two, respectively:

the reaction scheme I:

in scheme one, n and X are as defined above.

In particular, the preparation of the compound of formula (I) comprises the steps of:

a compound of formula (IV) or formula (IV) ^/ ) Dissolving the compound in a nonpolar solvent (such as dichloromethane, trichloromethane, tetrahydrofuran and dioxane), adding 0.5-1 equivalent of the compound of formula (III) in the presence of an organic base (such as triethylamine, N-dimethylpyridine, pyridine and 4-dimethylaminopyridine), and stirring at 0-room temperature for reaction for 5-15 hours to obtain the compoundA compound of formula (I).

In scheme one, the compound of formula (IV) used as starting material ^/ ) The compounds are known compounds and can be prepared readily by methods known from prior publications. For example, huicong Zhang et al, j.med.chem.,2018, 61.

In scheme one, the compounds of formula (III) and (IV) used as starting materials are common chemical reagents and are commercially available in China.

Reaction scheme two:

in scheme two, n is as previously defined.

Specifically, the preparation of the compound of formula (II) comprises the steps of:

dissolving the compound of formula (III) in a non-polar solvent (e.g. dichloromethane, chloroform, tetrahydrofuran, dioxane), adding pyrophosphoryl chloride (P) at-40 deg.C to-5 deg.C ₂ O ₃ Cl ₄ ) Continuously stirring and reacting for 0.5-3 h at the same temperature; then adding 1-2 times of equivalent of the compound of formula (V) and an organic base (such as triethylamine, N-dimethylpyridine, pyridine and 4-dimethylaminopyridine) into the reaction system, and continuously stirring and reacting for 4-6 hours at the same temperature to obtain the compound of formula (II).

In scheme two, the compounds of formula (III) and formula (V) used as starting materials are common chemical reagents and are commercially available in China.

Further, in a third aspect, the present invention provides the use of a compound according to any one of the first aspect of the present invention or a compound prepared by the method according to any one of the second aspect of the present invention in the manufacture of a medicament for the treatment of a tumour.

The use according to the third aspect of the invention, wherein the tumor is a solid tumor and leukemia.

At present, the reports OF the related documents are mostly the research on the treatment OF some solid tumors by the combination OF dexamethasone and other chemotherapeutic drugs, such as the combination OF dexamethasone and gemcitabine for treating breast cancer (YIN YUAN et al, j ournal OF pharmaceuticucal SCIENCES,2015, 104; or the study of the hybrid formed by dexamethasone and other chemotherapeutic drugs, such as the application of dexamethasone-gemcitabine hybrid in tumor treatment (Liu Ming et al, CN 202110507994.6), but the dexamethasone is rarely used for tumor therapists based on the structural modification of dexamethasone. The invention connects dexamethasone and maleimide segments through different linkers (ester bonds, carbonate bonds and phosphate bonds) for the first time, the corresponding compound can target tumor tissues, and the in vivo anti-tumor curative effect of the compound is obviously superior to that of dexamethasone or a positive control drug-gemcitabine.

Any feature of any aspect of the invention or any embodiment of any aspect thereof is equally applicable to any other embodiment or any embodiment of any other aspect thereof, provided that they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. Various aspects and features of the disclosure are described further below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

Detailed Description

The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention generally and/or specifically describes the materials used in the tests, as well as the test methods. Although many materials and methods of operation are known in the art for the purposes of this invention, the invention is nevertheless described herein in as detail as possible.

Example 1 dexamethasone-21- (3-maleimido) n-propionate

3-Maleimidopropionic acid (254mg, 1.5mmol) and HATU (1.14g, 1.5mmol) were dissolved in a dichloromethane solution, triethylamine (417mL, 3mmol) was added, and after stirring at room temperature for 30 minutes, dexamethasone (392mg, 1mmol) compound III was added, and the reaction was completed for 8 hours. And (3) post-treatment: the reaction solution was spin-dried and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 2).

¹ H NMR(500MHz,DMSO)δ7.24(s,1H),6.61(s,1H),6.27(s,1H),6.04(s,1H),4.95(d,J＝16.2Hz,2H),4.37(s,1H),4.32(s,1H),3.98(d,J＝13.0Hz,2H),2.75(d,J＝4.6Hz,2H),2.62(s,1H),2.50(s,1H),2.45(s,1H),2.31(d,J＝7.6Hz,1H),2.09(s,1H),1.82(d,J＝14.3Hz,2H),1.72(s,1H),1.51(s,3H),1.28(s,1H),1.00(s,4H),0.89(s,3H).MS-ESI(m/z):544.2(M+H) ⁺ .

Example 2 dexamethasone-21- (4-Maleimide) n-Butanoate

Referring to example 1, compound III was reacted with 4-maleimido-n-butyric acid to obtain a white solid.

¹ H NMR(500MHz,DMSO)δ7.24(s,1H),6.70(s,1H),6.27(s,1H),6.04(s,1H),4.95(d,J＝5.0Hz,2H),4.37(s,1H),4.32(s,1H),4.07(d,J＝12.3Hz,2H),2.62(s,1H),2.50(s,1H),2.46–2.43(m,3H),2.31(d,J＝7.6Hz,1H),2.09(s,1H),2.01(d,J＝5.2Hz,2H),1.97(s,0H),1.82(d,J＝14.3Hz,2H),1.72(s,1H),1.51(s,3H),1.28(s,1H),1.00(s,4H),0.89(s,4H).MS-ESI(m/z):558.2(M+H) ⁺ .

Example 3 dexamethasone-21- (5-maleimido) n-pentanoate

Referring to example 1, compound III was reacted with 5-maleimido-n-pentanoic acid to give a white solid.

¹ H NMR(500MHz,CDCl ₃ )δ7.24(s,1H),6.70(s,1H),6.27(s,1H),6.04(s,1H),4.96(d,J＝6.2Hz,2H),4.37(s,1H),4.32(s,1H),3.71(d,J＝12.9Hz,2H),2.62(s,1H),2.50(s,1H),2.43(d,J＝17.0Hz,3H),2.31(d,J＝7.6Hz,1H),2.09(s,1H),1.82(d,J＝14.3Hz,2H),1.73(d,J＝0.8Hz,2H),1.62(s,1H),1.56(d,J＝1.5Hz,2H),1.51(s,3H),1.28(s,1H),1.00(s,4H),0.89(s,4H).MS-ESI(m/z):572.2(M+H) ⁺ .

Example 4 dexamethasone-21- (6-maleimido) n-hexanoate

Referring to example 1, compound III was reacted with 6-maleimide n-hexanoic acid to give a white solid.

¹ H NMR(500MHz,DMSO)δ7.29(d,J＝10.2Hz,1H),7.00(s,2H),6.22(dd,J＝10.1,1.9Hz,1H),6.00(s,1H),5.39(d,J＝4.7Hz,1H),5.13(s,1H),5.01(d,J＝17.6Hz,1H),4.79(d,J＝17.6Hz,1H),4.19–4.12(m,1H),3.39(t,J＝7.0Hz,2H),3.10(dt,J＝11.1,5.6Hz,1H),2.87(ddd,J＝11.9,8.0,4.4Hz,1H),2.69(s,1H),2.61(dt,J＝13.6,6.8Hz,1H),2.34(tt,J＝12.8,5.6Hz,4H),2.21–2.06(m,2H),1.77(dt,J＝11.7,5.2Hz,1H),1.64(t,J＝11.8Hz,1H),1.58–1.54(m,2H),1.49(s,3H),1.26(p,J＝7.6,7.2Hz,2H),1.18(t,J＝7.3Hz,2H),1.07(tt,J＝8.8,3.8Hz,1H),0.88(s,3H),0.78(d,J＝7.2Hz,3H).MS-ESI(m/z):586.2(M+H) ⁺ .

Example 5 dexamethasone-21- (2-maleimido) ethyl carbonate

2-Maleimidoethanol (141mg, 1mmol) was dissolved in anhydrous chloroform (10 mL) at-10 deg.C, triethylamine (139. Mu.L, 1 mmol) was added, and triphosgene (90mg, 0.3mmol) was added after the pH test became basic. After 20min of reaction, triethylamine (139. Mu.L, 1 mmol) was added again, and triphosgene (90mg, 0.3mmol) was added after the pH paper became basic. Stirring is carried out at room temperature for 1h, triethylamine (167 mu L,1.2 mmol) and dexamethasone (393mg, 1mmol) are added into the reaction liquid in sequence, and the reaction is finished for 4h. And (3) performing column chromatography (PE: EA = 1) to obtain a white solid.

¹ H NMR(500MHz,CDCl ₃ )δ7.24(s,1H),6.70(s,2H),6.27(s,1H),6.04(s,1H),5.07(d,J＝18.0Hz,2H),4.48(d,J＝5.3Hz,2H),4.39–4.34(m,3H),4.32(s,1H),2.62(s,1H),2.50(s,1H),2.45(s,1H),2.31(d,J＝7.6Hz,1H),2.09(s,1H),1.82(d,J＝14.3Hz,2H),1.72(s,1H),1.51(s,3H),1.28(s,1H),1.00(s,4H),0.89(s,4H).MS-ESI(m/z):560.2(M+H) ⁺ .

Example 6 dexamethasone-21- (3-maleimide) n-propyl carbonate

Referring to example 5, compound III was reacted with 3-maleimido-n-propoxycarbonylchloride to give a white solid.

¹ H NMR(500MHz,CDCl ₃ )δ7.24(s,1H),6.70(s,1H),6.27(s,1H),6.04(s,1H),5.07(d,J＝18.0Hz,2H),4.37(s,1H),4.32(s,1H),4.23(s,2H),3.98(d,J＝7.8Hz,2H),2.62(s,1H),2.50(s,1H),2.45(s,1H),2.31(d,J＝7.6Hz,1H),2.10(d,J＝11.1Hz,2H),1.82(d,J＝14.3Hz,2H),1.72(s,1H),1.62(s,1H),1.51(s,3H),1.28(s,1H),1.00(s,4H),0.89(s,4H).MS-ESI(m/z):574.2(M+H) ⁺ .

Example 7 dexamethasone-21- (5-maleimide) n-pentylcarbonate

Referring to example 5, compound III was reacted with 5-maleimido-n-pentyloxy-acyl chloride to give a white solid.

¹ H NMR(500MHz,CDCl ₃ )δ7.24(s,1H),6.70(s,1H),6.27(s,1H),6.04(s,1H),5.07(d,J＝18.0Hz,2H),4.38(s,1H),4.32(s,1H),4.17(d,J＝4.2Hz,2H),3.55(d,J＝5.6Hz,2H),2.62(s,1H),2.50(s,1H),2.45(s,1H),2.31(d,J＝7.6Hz,1H),2.09(s,1H),1.82(d,J＝14.2Hz,2H),1.75–1.68(m,5H),1.51(s,3H),1.46(d,J＝4.6Hz,2H),1.28(s,1H),1.00(s,4H),0.89(s,3H).MS-ESI(m/z):602.2(M+H) ⁺ .

Example 8: dexamethasone-21- (3-maleimide) n-propyl phosphate

Compound III dexamethasone (392mg, 1mmol) dissolved in 10mL of ultra dry THF, pyrophosphate chloride (P) added at-40 deg.C ₂ O ₃ Cl ₄ 301mg, 1.2mmol) and stirred for 0.5 h. Compound V3-Maleimidopropanol (155mg, 1mmol) and ultra-dry pyridine (79mg, 1mmol) were then added and stirring continued for 4 hours. And (3) post-treatment: the reaction was quenched with water, washed with sodium bicarbonate solution, extracted with dichloromethane, the organic phase was spun dry and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 2).

¹ H NMR(500MHz,CD ₃ OD)δ7.41(d,J＝10.1Hz,1H),6.80(s,2H),6.29(d,J＝9.9Hz,1H),6.07(s,1H),4.91–4.86(m,1H),4.68-4.64(m,1H),4.28-3.92(m,3H),3.48(t,J＝7.1Hz,2H),3.10–2.67(m,2H),2.53–2.16(m,3H),1.91–1.87(m,1H),1.78–1.48(m,7H),1.40–1.28(m,3H),1.02(s,3H),0.87(d,J＝7.2Hz,3H).MS-ESI(m/z):610.2(M+H) ⁺ .

Example 9: dexamethasone-21- (5-maleimide) n-pentyl phosphate

Referring to example 8, compound III was reacted with 5-maleimido-n-pentanol to give a white solid.

¹ H NMR(500MHz,CD ₃ OD)δ7.41(d,J＝10.0Hz,1H),6.82(s,2H),6.39–6.17(m,1H),6.08(s,1H),4.94–4.86(m,1H),4.68-4.63(m,1H),4.27(d,J＝10.7Hz,1H),3.91-3.92(m,2H),3.49(t,J＝7.1Hz,2H),3.11–3.04(m,1H),2.75–2.68(m,1H),2.50–2.18(m,3H),1.90–1.85(m,1H),1.78–1.48(m,11H),1.40–1.35(m,2H),1.22–1.18(m,1H),1.02(s,3H),0.87(d,J＝7.2Hz,3H).MS-ESI(m/z):638.2(M+H) ⁺ .

Example 10: dexamethasone-21- (6-maleimide) n-hexyl phosphate

Referring to example 8, compound III was reacted with 6-maleimidon-butanol to give a white solid.

¹ H NMR(500MHz,CD ₃ OD)δ7.42(d,J＝10.1Hz,1H),6.80(s,2H),6.30(d,J＝10.1Hz,1H),6.10(s,1H),4.94–4.70(m,2H),4.26(d,J＝10.5Hz,1H),3.91-3.92(m,2H),3.50(t,J＝7.1Hz,2H),3.11–3.04(m,1H),2.75–2.28(m,4H),1.91–1.85(m,1H),1.78–1.48(m,13H),1.40–1.25(m,3H),1.01(s,3H),0.87(d,J＝7.2Hz,3H).MS-ESI(m/z):652.2(M+H) ⁺ .

Biological example 1 evaluation of antitumor Activity in vitro

The growth state of adherent cells is observed under an inverted microscope, and passage is required when the cell confluence degree in the culture bottle is found to reach 80% -90%. And (3) absorbing and removing the culture solution in the bottle, adding 1-2mL of sterile PBS to wash the cells gently, removing the PBS, adding 1mL of 0.25% trypsin, shaking the culture bottle gently to cover the cells uniformly, removing the trypsin after a while, and placing the culture bottle in an incubator for 2-3 min. After the cells became larger and round and the gaps increased under the lens, the flask was gently tapped and a small amount of culture medium was added to stop digestion. The cell suspension was gently pipetted to disperse it evenly and the appropriate ratio was inoculated into cell culture flasks with about 5mL of fresh medium per flask. The cells in the bottle are dispersed evenly according to the method of drawing 8, the bottle is placed in a cell incubator for culture, and the cell density and the growth state thereof are observed after 2 to 3 days.

(1) Preparation of MTT (5 mg/ml) solution: 250mg of MTT powder was weighed, dissolved in 50ml of 1 × PBS and mixed well, the solution was filtered on a clean bench using a 0.22 μm microporous membrane and dispensed into brown EP tubes and stored at-20 ℃.

(2) MTT method for detecting proliferation inhibition effect of compound on tumor cells

1) Plate paving: aspC-1 cells, H460 cells, hepG2 cells, U266 cells, HCT116 cells and GEM-R (gemcitabine-resistant strain) AspC-1 in the logarithmic growth phase are digested with trypsin, collected, counted, inoculated into a 96-well plate at 3000-5000/well, and placed in an incubator at a constant temperature for 24 hours. To prevent the effects of edge effects, only 200. Mu.L of sterile PBS was added around the perimeter of the 96-well plate.

2) Adding medicine: according to the experimental requirements, drugs with various concentrations are added, and a blank control group is arranged at the same time. Three multiple holes are arranged at each concentration, and the conditions are the same except the types and the concentrations of the medicines.

3) And (3) terminating the reaction: after a period of drug action, 10. Mu.L of MTT solution was added to each well in a super clean bench, the culture was continued in an incubator for 4 hours, after which the liquid in the wells was aspirated by a suction pump, 150. Mu.L of DMSO was added to each well, and shaking was carried out for 15min. The microplate reader detects the absorbance value at the wavelength of 570 nm.

4) Calculation of cell viability

TABLE 1 in vitro antitumor Activity of some of the example Compounds [ IC ₅₀ (μg/mL)]

GEM-R ^a Gemcitabine drug-resistant strain

Therefore, the compounds of the patent show definite in vitro broad-spectrum activity on 6 solid tumors, and more importantly, the compounds are still sensitive to gemcitabine-resistant strain GEM-R AspC-1.

Biological example 2 evaluation of antitumor Activity in vivo

Cells in logarithmic growth phase are counted according to the cell number of 1 multiplied by 10 ⁶ Inoculating to axillary part of BALB/c mouse, and treating tumor under aseptic condition after tumor grows to a certain volume. Cutting the tumor mass into pieces of 1.5mm ³ The small blocks with uniform size are inoculated to the axillary part of BALB/c mice subcutaneously, and the inoculation day is 0 day. The tumor length is 200mm ³ On the left and right sides, the mice were grouped according to tumor volume, and each group had 6 BALB/c mice, which were divided into 6 groups: blank control, example 1 compound 3mg/kg (5 mmol/kg), example 4 compound 3mg/kg (5 mmol/kg), example 8 compound 3mg/kg (5 mmol/kg), dexamethasone 2mg/kg (5 mmol/kg) and gemcitabine hydrochloride 8.71mg/kg (30 mmol/kg). The gemcitabine hydrochloride group was administered intraperitoneally 1 time/3 days for 7 times, and the remaining gemcitabine hydrochloride groups were administered via tail vein 5 times/week for 3 weeks and 15 times. Mouse body weight and tumor volume were measured weekly and tumor growth curves were plotted. After the experiment, the mice were euthanized, tumor masses were stripped and weighed, and the tumor inhibition rates of the groups were calculated.

TABLE 2 growth inhibition of H460 (human large cell lung carcinoma cell) nude mouse transplanted tumor by some of the example compounds

Test results showed that 1) all mice in each group survived except gemcitabine hydrochloride group (1 death on each of day 5 and day 7 of the test); 2) Compared with a blank control group, the weight of mice in other treatment groups has no obvious change except that the weight of mice in a gemcitabine hydrochloride group is obviously reduced; 3) The tumor inhibition rates (by mass) of the 3 example compound treatment groups are respectively 80.36%, 72.09% and 69.35%, which are respectively significantly larger than the original dexamethasone hydrochloride (20.9%) with equal molar dosage and the gemcitabine hydrochloride (42.94%) with 6 times molar dosage. Therefore, the in-vivo curative effect of the compound of the embodiment of the invention on H460 nude mouse transplanted tumor is obviously greater than that of the original drug control group and the positive control group, and the systemic toxicity is lower than that of the positive control group.

The growth inhibitory effect of some of the compounds of the examples on AspC-1 (human metastatic pancreatic cancer cells) nude mouse transplanted tumors was tested as described above and the results are shown in Table 3.

TABLE 3 growth inhibitory Effect of some of the example Compounds on AspC-1 (human metastatic pancreatic cancer cells) nude mouse transplantable tumors

The results of the experiments show that 1) the compound of example 7 and the compound of example 9 treatment groups have a dose-correlation; 2) The tumor inhibition rate (mass) of the compound of example 7 and the compound of example 9 is significantly higher than that of the original dexamethasone group; 3) The tumor inhibition rate (mass) of the remaining 5 treatment groups except the compound 2.5mg/kg group of example 7 was also greater than that of the positive control group, gemcitabine hydrochloride.

The above experiments demonstrate that the compounds of the present invention are effective in the treatment of solid tumors, such as lung cancer (table 2), pancreatic cancer (table 3). More importantly, the pancreatic cancer which is the King of life-taking cancer has high death rate, and the treatment medicines are few and have poor effect. The data in table 3 demonstrate that the compounds of the present invention have superior in vivo efficacy in pancreatic cancer over the first-line drug, gemcitabine, of pancreatic cancer, and thus the compounds of the present invention may provide an alternative clinical choice for the treatment of pancreatic cancer.

Although only some of the examples of the above experiments have been tested, other compounds of the present invention can achieve the same or similar therapeutic effects as the above compounds.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, it is intended that all such modifications and alterations be included within the scope of this invention as defined in the appended claims.

Claims

1. A compound shown in a formula (I) and/or a formula (II) or a pharmaceutically acceptable salt and a solvate thereof, and the structure of the compound is shown as follows:

wherein:

x represents O or is absent;

n represents 2 to 6.

2. The compound according to claim 1, characterized in that said pharmaceutically acceptable salt is a salt with an inorganic acid or with an organic acid; the inorganic acid is selected from: hydrochloric acid, sulfuric acid, phosphoric acid; the organic acid is selected from: acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, amino acids (e.g. alanine, aspartic acid, lysine), sulfonic acids (e.g. methanesulfonic acid, p-toluenesulfonic acid).

3. A compound according to claim 1, characterized in that it is in the form of a solvate (e.g. hydrate).

4. Compound according to claim 1, characterized in that it is a compound 1 to a compound 10 selected from:

compound 1: dexamethasone-21- (3-maleimide) n-propionate;

compound 2: dexamethasone-21- (4-maleimide) n-butyrate;

compound 3: dexamethasone-21- (5-maleimide) pivalate;

compound 4: dexamethasone-21- (6-maleimide) hexanoate;

compound 5: dexamethasone-21- (2-maleimido) ethyl carbonate;

compound 6: dexamethasone-21- (3-maleimide) n-propyl carbonate;

compound 7: dexamethasone-21- (5-maleimide) n-pentylcarbonate;

compound 8: dexamethasone-21- (3-maleimide) n-propyl phosphate;

compound 9: dexamethasone-21- (5-maleimide) n-pentyl phosphate;

compound 10: dexamethasone-21- (6-maleimide) n-hexyl phosphate.

5. A process for the preparation of a compound of formula (I) as claimed in any one of claims 1 to 4,

the first reaction route is as follows:

6. a process for the preparation of a compound of formula (II) as claimed in any of claims 1 to 4,

reaction scheme two:

wherein X and n are as defined in claim 1.

7. The process according to claim 5, wherein the preparation of the compound of formula (I) comprises the steps of:

a compound of formula (IV) or formula (IV) ^/ ) Dissolving the compound in a non-polar solvent (such as dichloromethane, trichloromethane, tetrahydrofuran and dioxane), adding 0.5-1 equivalent of the compound shown in the formula (III) in the presence of an organic base (such as triethylamine, N-dimethylpyridine, pyridine and 4-dimethylaminopyridine), and stirring and reacting at 0-room temperature for 5-15 hours to obtain the compound shown in the formula (I).

8. The process according to claim 6, characterized in that the preparation of the compound of formula (II) comprises the following steps:

9. Use of a compound of formula (I) and formula (II) as defined in any one of claims 1 to 4 in the manufacture of a medicament for the treatment of tumours.

10. The use according to claim 9, wherein the tumor is a solid tumor or leukemia.