Psammulin A type and podophyllotoxin spliced compound and application of Psammulin A type and podophyllotoxin spliced compound

Abstract

The invention belongs to the field of biological medicines, and particularly relates to a Psammulin A and podophyllotoxin spliced compound and application thereof in preparation of a medicine for treating tumors. The compound is a compound as shown in a formula (I), a derivative, and pharmaceutically acceptable salt or hydrate thereof. The spliced compound is applied to the fields of preparation and tumor resistance; the invention also relates to application of the compound in preparation of drugs for resisting paclitaxel-resistant tumors. The invention also relates to application of the compound in anti-osimertinib drug-resistant tumors. The intracellular activity of the spliced compound disclosed by the invention is superior to that of Psammulin A and etoposide, and the spliced compound has no cross resistance with paclitaxel and osimertinib.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to a Psammaplin A-podophyllotoxin complex and its application in preparing a drug for treating tumors. Background Art

[0002] Histone deacetylase (HDAC) inhibitors regulate apoptosis, differentiation, and tumor cell proliferation by increasing the degree of histone acetylation in chromatin. Psammaplin A (PsA) is a natural product isolated from the sponge Psammaplysilla sp. It is a symmetrical compound with disulfide-linked bromotyrosine and cysteine ​​fragments that selectively inhibits Class I HDAC enzyme activity. To exert its activity, PsA requires glutathione (GSH)-catalyzed cleavage of the disulfide bond, converting it into two molecules of rPsA to exert enzyme inhibitory activity. PsA has inhibitory activity against both hematologic and solid tumors. HDAC inhibitors are often combined with other anti-tumor drugs to achieve synergistic anti-tumor efficacy.

[0003] Topoisomerase is one of the main targets of anti-tumor drugs due to its important role in cell proliferation, differentiation, and survival. Topoisomerase inhibitors are divided into Class I (Topo I) and Class II (Topo II) based on their catalytic function, reaction mechanism, amino acid sequence, and structure. Topoisomerase II is one of the main targets of anti-tumor drugs, and drugs such as amscrine, etoposide, and doxorubicin have been developed and are clinically used to treat patients with hematological and solid tumors. Podophyllotoxin (PPT), an active ingredient in plants of the genus Podophyllotoxin, exhibits various anti-tumor activities and has been extensively studied as a Topo II inhibitor. However, its high toxicity has limited its application. Etoposide and teniposide, which are structurally modified versions of podophyllotoxin, are less toxic than podophyllotoxin and are used as first-line drugs in chemotherapy for various tumors. Summary of the Invention

[0004] The present invention aims to provide a Psammaplin A-podophyllotoxin complex and its application in preparing a drug for treating tumors.

[0005] To achieve the above purpose, the present invention adopts the following technical solutions:

[0006] A Psammaplin A-podophyllotoxin complex, wherein the complex is a compound represented by formula (I), a derivative thereof, and a pharmaceutically acceptable salt or hydrate thereof.

[0007]

[0008] Where,

[0009] n is an integer from 1 to 3

[0010] R is selected from H or C1-C6 alkyl;

[0011] X is selected from N, O or Y is -SS-, -CONH- or -COS-.

[0012] Preferably, the complex is a compound represented by formula (I), a derivative, and a pharmaceutically acceptable salt or hydrate thereof, wherein n is 2 or 3;

[0013] R is selected from H, methyl, ethyl or propyl;

[0014] X is selected from N, O or Y is -SS-, -CONH- or -COS-.

[0015] More preferably, the composite is

[0016] (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}disulfanyl)butanoate (FA-1);

[0017] (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}thio)-4-oxobutanoic acid-(4-podophyllotoxin) ester (FB-1);

[0018] (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-(4-amino-4-deoxypodophyllotoxin)-4-oxobutane sulfate (FB-2);

[0019] (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-{4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}-4-oxobutane sulfate (FB-3);

[0020] (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}thio)-4-oxobutanoic acid-(4-O-demethyl-4-podophyllotoxin) ester (FB-4);

[0021] (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-(4-O-demethyl-4-amino-4-deoxypodophyllotoxin)-4-oxobutane sulfate (FB-5);

[0022] (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-{4-O-demethyl-4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}-4-oxobutane sulfate (FB-6);

[0023] (E)-N 1 -{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-N 4 -{4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}succinamide (FC-1);

[0024] (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}amino)-4-oxobutanoic acid-(4-O-demethyl-4-podophyllotoxin) ester (FC-2).

[0025] An application of the Psammaplin A class and podophyllotoxin complex, and an application of the compound represented by formula (I), derivatives, and pharmaceutically acceptable salts or hydrates thereof in the preparation of histone deacetylase inhibitors.

[0026] An application of the Psammaplin A class and podophyllotoxin complex, and the application of the compound represented by formula (I), its derivatives, and its pharmaceutically acceptable salts or hydrates in the preparation of drugs for treating diseases related to abnormal expression of histone deacetylase activity.

[0027] An application of the Psammaplin A class and podophyllotoxin complex, and an application of the compound represented by formula (I), derivatives, and pharmaceutically acceptable salts or hydrates thereof in the preparation of anti-tumor drugs.

[0028] The compound represented by formula (I), its derivatives, and its pharmaceutically acceptable salts or hydrates are used in the preparation of drugs for treating lung cancer, breast cancer or leukemia.

[0029] The compound represented by formula (I), its derivatives, and its pharmaceutically acceptable salts or hydrates are used in the preparation of drugs for treating osimertinib-resistant non-lung cancer and paclitaxel-resistant lung cancer.

[0030] The compound of the present invention can be used to prepare histone deacetylase inhibitors, and can be used to prepare drugs for treating diseases associated with abnormal expression of histone deacetylase activity, such as various cancers.

[0031] Through in vitro activity screening and in vivo pharmacodynamic studies, we found that the compounds of the present invention have anti-tumor activity. Therefore, the compounds of the present invention can be used to prepare drugs for treating and / or preventing various cancers, such as lung, breast, colon, rectum, stomach, prostate, bladder, uterus, pancreas, ovary and other cancers and leukemia.

[0032] The active compounds of the present invention can be used as the sole anticancer drug or in combination with one or more other antitumor drugs. Combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

[0033] A pharmaceutical composition comprising one or more of the compound represented by formula (I), derivatives, and pharmaceutically acceptable salts or hydrates thereof.

[0034] An application of the pharmaceutical composition is the application of the composition in preparing histone deacetylase inhibitors.

[0035] The above-mentioned compound or composition may be further mixed with a pharmaceutically acceptable excipient to obtain a corresponding dosage form. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and / or carrier that can be used in the pharmaceutical field. The compound of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0036] It is formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions, or injectable dry powders that can be used immediately by adding injection water before injection); topical preparations (such as ointments or solutions).

[0037] Carriers are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. Pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0038] The active compounds of the present invention can be used as the sole anticancer drug or in combination with one or more other antitumor drugs. Combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

[0039] The compound represented by formula (I) of the present invention is prepared according to the following method to prepare the target compound FA-1:

[0040]

[0041] According to the compound of formula 1 of the present invention, the target compounds FB-1, FB-2, FB-3, FB-4, FB-5, FB-6, FC-1, and FC-2 were prepared according to the following route, and each substituent is as defined in the summary of the invention.

[0042] DETAILED DESCRIPTION

[0043] The following examples and preparations are provided to further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations does not limit the scope of the present invention in any way.

[0044] The following synthetic schemes describe the preparation of the compounds of formula I of the present invention. All starting materials are prepared by the methods described in these schemes, by methods well known to those skilled in the art of organic chemistry, or are commercially available.

[0045] All final compounds of the present invention are prepared by the methods described in these routes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. All variables used in these routes are as defined below or as defined in the claims.

[0046] This invention links rPsA and podophyllotoxin via disulfide, thioester, and amide bonds to create a series of complexes that simultaneously exert HDAC / Topo II dual-target inhibitory activity. By exploiting the elevated levels of GSH expressed in drug-resistant tumor cells, these compounds overcome drug resistance and are subsequently used as histone deacetylase or topoisomerase inhibitors in the prevention and / or treatment of tumors and drug-resistant tumors.

[0047] Example 1: Preparation of (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}disulfanyl)butyric acid-(4-podophyllotoxin) ester (FA-1)

[0048]

[0049] Step A: Preparation of 4-bromobutyric acid-4-podophyllotoxin ester (A1)

[0050]

[0051] 1.0 g (2.4 mmol) of podophyllotoxin (Compound PPT) was placed in a 50 mL eggplant-shaped flask and 25 mL of DCM was added. 0.36 g (2.7 mmol) of HOBt and 0.48 mL (2.9 mmol) of 4-bromobutyric acid were added at 0°C and stirred for 5 min. 0.51 g (2.7 mmol) of EDCI and 0.89 g (7.2 mmol) of DMAP were added and stirred for 10 min. The mixture was then transferred to room temperature and allowed to react for 10 h. After the reaction was complete, the reaction solution was poured into 4 times the volume of water and extracted with DCM (20 mL x 3). The organic layers were combined, washed with water (20 mL x 2) and then with saturated sodium chloride solution (20 mL x 1). The concentrated crude product was separated and purified by column chromatography (200-300 mesh silica gel, MeOH / DCM = 1 / 50, V / V) to obtain 0.61 g of Compound A1 as a white solid in a yield of 44.9%.

[0052] Step B: Preparation of 4-(acetylthio)butyric acid-4-podophyllotoxin ester (A2)

[0053]

[0054] 0.5 g (0.89 mmol) of compound A1 was dissolved in 25 mL of EtOH, the temperature was raised to 60°C, 0.15 g (1.3 mmol) of potassium thioacetate was added, and the reaction was carried out for 5 h. EtOH was removed by rotary evaporation, and the residue was dissolved in 20 mL of DCM. The organic phase was washed with water (10 mL × 2) and saturated sodium chloride aqueous solution (10 mL × 1). After concentration, 0.42 g of the target compound A2 was obtained as a white solid with a yield of 84.2%. It was used directly in the next step without purification.

[0055] Step C: Preparation of 4-(pyridin-2-yldisulfanyl)butyric acid-4-podophyllotoxin ester (A3)

[0056]

[0057] Dissolve 0.5 g (0.90 mmol) of compound A2 in 10 mL of DMF, add 0.30 g (1.3 mmol) of 2,2'-disulfpyridine, and under N2 protection, slowly add 0.5 mL of a 70% aqueous solution of ethylamine dropwise at room temperature. Allow to react for 4 hours. After completion of the reaction, pour the reaction mixture into ice water, filter, and dry to obtain 0.50 g of crude target compound A3 as a white solid in an 89.6% yield. Use it directly in the next step without purification.

[0058] Step D: Preparation of (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}disulfanyl)butyrate (FA-1)

[0059]

[0060] 0.5 g (0.80 mmol) of compound A3 was dissolved in 20 mL of DCM. 0.29 g (0.88 mmol) of rPsA dissolved in 10 mL of anhydrous ethanol was added dropwise at room temperature. The reaction was allowed to react for 6 h. The reaction solution was evaporated to dryness, and the residue was dissolved in 50 mL of DCM. The organic phase was washed with water (10 mL x 2) and saturated sodium chloride solution (10 mL x 1). The crude product after concentration was purified by column chromatography (200-300 mesh silica gel, MeOH / DCM = 1 / 70, V / V) to obtain 0.23 g of the target compound FA-1 as a white solid in a yield of 34.2%. Mp: 81.6-83.4°C; LC-MS: 869.3 [M+Na] + ,845.0[MH] - ; 1 H-NMR (600MHz, DMSO-d6) δ: 11.84 (1H, s), 10.02 (1H, s), 8.08 (1H, t, J = 6.0Hz), 7.28 (1H, d, J = 1.8Hz), 7.01 (1H, dd, J1 = 1.8Hz,J2=8.4Hz),6.86(1H,s),6.83(1H,d,J=8.4Hz),6.58(1H,s),6.53(2H,s),5.99(2H,dd,J1=1.2Hz,J2=2.4Hz),5. 69(1H,d,J=8.4Hz),4.45-4.42(1H,m),4.30-4.27(2H,m),3.72(6H,s),3.68(2H,s),3.64(3H,s),3.61-3.59(1H,m),3. 43-3.40(2H,m),3.03-2.99(1H,m),2.79(2H,t,J=7.2Hz),2.67(2H,t,J=7.2Hz),2.36-2.27(2H,m),1.84-1.79(2H,m); 13 C-NMR(150MHz,DMSO-d6)δ:177.8,172.6,163.7,153.2,152.8,152.3,147.9,146.8,138.9,136.6,133.2,132.7,129.6,129.3, 127.2,116.6,109.5,109.3,108.4,106.2,101.7,72.6,71.0,60.4,56.4,44.2,43.9,40.5,38.7,37.3,37.2,32.4,28.1,24.2.

[0061] Example 2: Preparation of (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}thio)-4-oxobutanoic acid-(4-podophyllotoxin) ester (FB-1)

[0062]

[0063] Step A: Preparation of 4-podophyllotoxin-4-oxobutyric acid (F3-1)

[0064]

[0065] 1.0 g (2.4 mmol) of PPT was dissolved in 10 mL of pyridine, and 0.15 g (1.2 mmol) of DMAP and 0.29 g (2.9 mmol) of succinic anhydride were added. The mixture was reacted at 110°C for 1.2 h. The reaction solution was then poured into 4 times the amount of water and the pH was adjusted to 3-4 with 2N HCl solution. A white solid precipitated, which was filtered and dried to obtain 1.18 g of crude F3-1 as a white solid with a yield of 94.8%.

[0066] Step B: Preparation of (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}thio)-4-oxobutanoic acid-(4-podophyllotoxin) ester (FB-1)

[0067]

[0068] 0.5 g (0.97 mmol) of F3-1 was dissolved in 25 mL of THF. 0.14 g (1.1 mmol) of HOBt and 0.36 mL (1.1 mmol) of rPsA were added at 0°C and stirred for 5 min. 0.21 g (1.1 mmol) of EDCI and 0.36 g (2.9 mmol) of DMAP were added and stirred for 10 min. The mixture was then brought to room temperature and allowed to react for 10 h. The reaction solution was poured into 4 times the volume of water and extracted with DCM (20 mL x 3). The organic phases were combined, washed with water (20 mL x 2) and then with saturated sodium chloride (20 mL x 1). The concentrated crude product was purified by column chromatography (200-300 mesh silica gel, MeOH / DCM = 1 / 70, v / v) to obtain 0.30 g of the target compound FB-1 as a white solid in a yield of 37.4%. Mp: 94.6-96.5℃; LC-MS: 851.2[M+Na] + ,827.1[MH] - ; 1H-NMR (600MHz, DMSO-d6) δ: 11.84 (1H, s), 10.02 (1H, s), 8.10 (1H, t, J = 6.0Hz), 7.28 (1H, d, J = 2.4Hz), 7.01 (1H, dd, J 1=2.4Hz,J2=8.4Hz),6.90(1H,s),6.83(1H,d,J=8.4Hz),6.60(1H,s),6.33(2H,s),6.01(2H,d,J=9.0Hz),5.90(1H, d,J=9.0Hz),4.56(1H,d,J=4.8Hz),4.31(1H,t,J=7.8Hz),4.17-4.13(1H,m),3.68(2H,s),3.65(6H,s),3.63(2H,s) ,3.62(3H,s),3.39-3.35(1H,m),3.30-3.27(2H,m),2.97(2H,t,J=6.6Hz),2.92(2H,t,J=6.6Hz),2.77-2.72(1H,m); 13 C-NMR (150MHz, DMSO-d6) δ: 198.1, 174.4, 172.5, 163.8, 152.8, 152.5, 152.3, 147.8, 147.4, 136.9, 136.1, 133.2, 132.7, 129. 6,129.3,129.1,116.6,109.8,109.3,108.5,107.4,101.9,73.3,71.1,60.4,56.2,44.5,43.3,38.8,38.6,29.5,28.4,28.1.

[0069] Example 3: Preparation of (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-(4-amino-4-deoxypodophyllotoxin)-4-oxobutane sulfate (FB-2)

[0070]

[0071] Step A: Preparation of 2-chloro-N-4-deoxypodophyllotoxin acetamide (F1-2)

[0072]

[0073] 1.0 g (2.4 mmol) of compound PPT was dissolved in 8 mL of chloroacetonitrile, and a catalytic amount of concentrated sulfuric acid was added dropwise. The reaction was terminated after stirring at room temperature for 3 h. The reaction solution was evaporated to dryness, dissolved in a small amount of methanol, and poured into water to precipitate a white solid. Filtration gave 1.1 g of crude product F1-2 as a white solid in a yield of 95.7%.

[0074] Step B: Preparation of 4-amino-4-deoxypodophyllotoxin (F2-2)

[0075]

[0076] 1.0 g (2.0 mmol) of compound F1-2 was dissolved in 20 mL of glacial acetic acid, and 0.23 g (0.31 mmol) of thiourea was added. The reaction was carried out at 100° C. for 8 h. The reaction solution was poured into 4 times the amount of cold water, and the pH was adjusted to 7-8 with 2N NaOH solution. The mixture was extracted with AcOEt (30 mL×3). The organic phases were combined and washed with water (30 mL×2) and saturated sodium chloride aqueous solution (30 mL×1). The concentrated crude product was separated and purified by column chromatography (200-300 mesh silica gel, MeOH / DCM=1 / 70, V / V) to obtain 0.48 g of the target compound F2-2 as a white solid in a yield of 56.8%.

[0077] Step C: Preparation of 4-(4-amino-4-deoxypodophyllotoxin)-4-oxobutanoic acid (F3-2)

[0078]

[0079] Dissolve 0.5 g (1.2 mmol) of compound F2-2 in 25 mL of DCM, add 0.074 g (0.61 mmol) of DMAP and 0.18 g (1.8 mmol) of succinic anhydride, and react at room temperature for 3 h. Wash with 0.5N HCl (20 mL), water (30 mL x 2), and saturated sodium chloride solution (30 mL x 1). After concentration, 0.57 g of the target compound F3-2 was obtained as a white solid in a 91.3% yield.

[0080] Step D: Preparation of (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-(4-amino-4-deoxypodophyllotoxin)-4-oxobutane sulfate (FB-2)

[0081]

[0082] Using F3-2 as the starting material, the target compound FB-2 was obtained according to the synthesis method of FB-1 as a white solid in a yield of 32.8%. Mp: 113.7-116.8℃; LC-MS: 850.1[M+Na] + ; 1H-NMR (600MHz, DMSO-d6) δ: 11.84 (1H, s), 10.02 (1H, s), 8.36 (1H, s), 8.08 (1H, t, J = 6.0Hz), 7 .28(1H,d,J=1.8Hz),7.01(1H,dd,J1=1.8Hz,J2=8.4Hz),6.83-6.82(2H,m),6.46(1H,s),6.33 (2H,s),5.99-5.95(2H,m),4.23(1H,s),4.17(1H,s),4.09-4.06(1H,m),4.02-4.00(1H,m),3. 69-3.62(12H,m),3.30-3.25(2H,m),2.96-2.93(2H,m),2.80-2.77(3H,m),2.56-2.53(2H,m); 13 C-NMR (150MHz, DMSO-d6) δ: 197.7, 177.0, 171.8, 163.8, 153.2, 152.8, 152.2, 147.2, 145.7, 140.7, 136.7, 135.8, 133.2, 129.6, 129.3,128.8,116.6,111.6,109.3,107.4,106.4,101.4,64.0,60.4,56.4,55.4,50.3,45.9,41.9,38.6,38.6,29.1,28.4,28.1.

[0083] Example 4: Preparation of (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-{4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}-4-oxobutane sulfate (FB-3)

[0084]

[0085] Step A: Preparation of 4-azido-4-deoxypodophyllotoxin (F1-3)

[0086]

[0087] 1.0 g (2.4 mmol) of podophyllotoxin was dissolved in 50 mL of CHCl3, 0.31 g (4.8 mmol) of sodium azide was added, 0.5 mL of CF3COOH was added dropwise, and after stirring for 1 h, 1.5 mL of CF3COOH was added and the mixture was reacted for 3 h. The reaction solution was poured into four times the amount of saturated sodium bicarbonate solution and extracted with CHCl3 (20 mL × 2). The organic phases were combined, washed with water (10 mL × 2), and then washed with saturated sodium chloride aqueous solution (10 mL × 1). The organic phase was evaporated to dryness to obtain 1.0 g of crude product F1-3 as a white solid with a yield of 94.3%.

[0088] Step B: Preparation of [1-(4-deoxypodophyllotoxin)-1H-1,2,3-triazol-4-yl]methanamine (F2-3)

[0089]

[0090] 1.0 g (2.3 mmol) of compound F1-3 was dissolved in 50 mL of a THF / H2O / isopropanol (3:2:1) mixed solution, followed by the addition of 0.28 g (1.1 mmol) of copper sulfate, 0.74 g (2.5 mmol) of sodium citrate, and 0.18 mL (2.7 mmol) of propargylamine. The reaction was allowed to proceed at 45°C for 10 h, and then 30 mL of water was added to terminate the reaction. The mixture was extracted with AcOEt (30 mL × 3). The organic phases were combined, washed with water (30 mL × 2), and then washed with saturated sodium chloride aqueous solution (30 mL × 1). The concentrated crude product was separated and purified by column chromatography (200-300 mesh silica gel, MeOH / DCM = 1 / 70, V / V) to obtain 0.53 g of the target compound F2-3 as a white solid in a yield of 47.1%.

[0091] Step C: Preparation of 4-({[1-(4-deoxypodophyllotoxin)-1H-1,2,3-triazol-4-yl]methyl}amino)-4-oxobutanoic acid (F3-3)

[0092]

[0093] Using F2-3 as raw material and following the synthesis method of F3-2, the target compound F3-3 was obtained as a white solid with a yield of 93.2%.

[0094] Step D: Preparation of (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-{4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}-4-oxobutane sulfate (FB-3)

[0095]

[0096] Using F3-3 as starting material, the target compound FB-3 was obtained according to the synthetic method of FB-1. White solid, yield 30.1%. M.p.: 123.4-125.2°C; LC-MS: 931.1 [M+Na] + ,906.8 [M-H] - ; 1 H-NMR (600MHz, DMSO-d6) δ: 11.84 (1H, s), 10.02 (1H, s), 8.30 (1H, t, J = 6.6 Hz), 8.08 (1H, t, J = 6.0 Hz), 7.82 (1H, s), 7.28 (1H, d, J = 2.4 Hz), 7.01 (1H, dd, J1= 2.4 Hz, J2= 8.4 Hz), 6.83 (1H, d, J = 8.4 Hz), 6.75 (1H, s), 6.68 (1H, s), 6.32 (2H, s), 6.24 (1H, d, J = 5.4 Hz), 6.01 (1H, s), 6.01 (1H, s), 4.74 (1H, d, J = 5.4 Hz), 4.37 (1H, t, J = 7.8 Hz), 4.29 (2H, d, J = 5.4 Hz), 3.68 (2H, s), 3.67 (6H, s), 3.63 (3H, s), 3.47-3.44 (1H, m), 3.31-3.22 (3H, m), 2.97-2.93 (3H, m), 2.80 (2H, t, J = 6.6 Hz), 2.41 (2H, t, J = 6.6 Hz); 13 C-NMR (150MHz, DMSO-d6) δ: 198.1, 174.0, 170.6, 163.8, 152.8, 152.6, 152.3, 148.6, 147.4, 145.0, 137.0, 135.7, 133.3, 133.2, 129.6, 129.3, 126.5, 124.1, 116.6, 110.3, 109.3, 109.2, 108.6, 102.1, 67.6, 60.4, 57.8, 56.3, 55.4, 43.4, 41.2, 39.2, 37.0, 34.8, 30.4, 28.4, 28.2.

[0097] Example 5: Preparation of (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2- (hydroxyimino)propanamido]ethyl}thio)-4-oxobutanoic acid-(4-O-desmethyl-4- epipodophyllotoxin) ester (FB-4)

[0098] FB-4 was prepared according to the method of Example 2 using desmethyl epipodophyllotoxin as starting material.

[0099]

[0100] M.p.: 94.6-97.3 °C; LC-MS: 837.0 [M+Na] + ,812.8 [M-H] - ; 1 H-NMR (600 MHz, DMSO-d6) δ: 11.84 (1H, s), 10.02 (1H, s), 8.27 (1H, s), 8.09 (1H, t, J = 6.0 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.01

[0101] (1H, dd, J1= 2.4 Hz, J2= 8.4 Hz), 6.85 (1H, s), 6.83 (1H, d, J = 8.4 Hz), 6.60 (1H, s), 6.22 (2H, s), 6.04 (1H, d, J = 3.6 Hz), 6.03 (1H, s), 5.99 (1H, s), 4.56 (1H, d, J = 5.4 Hz), 4.28 (1H, t, J = 7.8 Hz), 3.88 (1H, dd, J1= 8.4 Hz, J2= 10.8 Hz), 3.68 (2H, s), 3.63 (6H, s), 3.29-3.26 (2H, m), 3.22-3.19 (1H, m), 3.05-3.00 (1H, m), 2.95 (2H, t, J = 6.6 Hz), 2.91-2.87 (2H, m), 2.73-2.68 (1H, m), 2.67-2.60 (1H, m); 13 C-NMR (150 MHz, DMSO-d6) δ: 198.0, 174.6, 171.9, 163.8, 152.8, 152.3, 148.5, 147.6, 147.0, 135.2, 133.8, 133.2, 130.1, 129.6, 129.3, 128.2, 116.6, 110.1, 109.9, 109.3, 108.8, 101.9, 68.8, 67.7, 56.5, 55.4, 43.3, 41.2, 38.6, 36.9, 29.3, 28.4, 28.2.

[0102] Example 6: Preparation of (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2- (hydroxyimino)propanamido]ethyl}-4-(4-O-demethyl-4-amino-4-deoxyvinka- toxinyl)-4-oxobutane sulfate (FB-5)

[0103]

[0104] FB-5 was prepared using demethylpodophyllotoxin as the starting material according to the method of Example 3. Mp: 113.7-115.3°C; LC-MS: 836.0 [M+Na] + ; 1 H-NMR (600MHz, DMSO-d6) δ: 11.84 (1H, s), 10.02 (1H, s), 8.33 (1H, d, J = 8.4Hz), 8.25 (1H, s), 8.10 (1H, t, J = 6.0Hz), 7.29 (1H, d, J = 1.8Hz), 7.01 (1H, dd,J1=1.8Hz,J2=8.4Hz),6.83(1H,d,J=8.4Hz),6.76(1H,s),6.53(1H,s) ,6.25(2H,s),6.00(1H,d,J=1.2Hz),5.97(1H,d,J=1.2Hz),5.16(1H,dd,J 1=4.8Hz,J 2=8.4Hz),4.50(1H,d,J=5.4Hz),4.25(1H,t,J=8.4Hz),3.78(1H,dd,J1=8.4Hz,J2=10.8Hz),3.68(2H,s),3 .63(6H,s),3.30-3.27(2H,m),3.18-3.13(1H,m),2.98-2.95(2H,m),2.92-2.82(3H,m),2.49-2.40(2H,m); 13 C-NMR (150MHz, DMSO-d6) δ: 198.1, 174.9, 170.6, 163.7, 152.7, 152.2, 147.5, 146.9, 135.1, 133.1, 132.5, 130.8, 130.5, 130. 0,129.5,129.2,116.5,109.7,109.4,109.2,108.8,101.6,68.7,56.4,55.3,47.1,43.3,41.3,39.2,38.6,36.9,30.4,28.3.

[0105] Example 7: Preparation of (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-{4-O-demethyl-4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}-4-oxobutane sulfate (FB-6)

[0106]

[0107] The target compound FB-6 was obtained according to the synthetic method of Example 4, using desmethyl podophyllotoxin as raw material. M.p.: 129.2-131.1 °C; LC-MS: 917.0 [M+Na] + ,892.8 [M-H] - ; 1 H-NMR (600MHz, DMSO-d6) δ: 11.84 (1H, s), 10.03 (1H, s), 8.31 (1H, s), 8.29 (1H, t, J=5.4 Hz), 8.08 (1H, t, J=6.0 Hz), 7.81 (1H, s), 7.28 (1H, d, J=1.8 Hz), 7.01 (1H, dd, J1=1.8 Hz, J2=7.8 Hz), 6.83 (1H, d, J=7.8 Hz), 6.73 (1H, s), 6.67 (1H, s), 6.28 (2H, s), 6.04 (1H, s), 6.00 (1H, s), 4.69 (1H, d, J=4.8 Hz), 4.36 (1H, t, J=7.8 Hz), 4.29 (2H, d, J=5.4 Hz), 4.10-4.07 (1H, m), 3.68 (2H, s), 3.65 (6H, s), 3.43-3.40 (1H, m), 3.30-3.28 (2H, m), 3.25-3.23 (1H, m), 2.97-2.93 (3H, m), 2.80 (2H, t, J=7.2 Hz), 2.41 (2H, t, J=6.6 Hz); 13 C-NMR (150MHz, DMSO-d6) δ: 198.1, 174.0, 170.5, 163.7, 152.7, 152.2, 148.5, 147.6, 147.2, 144.9, 135.3, 133.6, 133.1, 130.0, 129.5, 129.1, 126.4, 124.0, 116.5, 110.2, 109.2, 109.1, 108.8, 102.0, 67.5, 57.8, 56.4, 49.0, 43.1, 41.3, 39.1, 38.6, 36.8, 34.7, 30.3, 28.3.

[0108] Example 8: (E)-N 1 -{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-N 4 Preparation of {4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin} succinamide (FC-1)

[0109]

[0110] 0.5 g (0.84 mmol) of F3-3 was dissolved in 25 mL of THF. At 0°C, 0.13 g (0.93 mmol) of HOBt and 0.29 g (0.93 mmol) of (E)-N-(2-aminoethyl)-3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamide were added and stirred for 5 min. 0.20 g (0.93 mmol) of EDCI and 0.43 mL (2.5 mmol) of DIEA were added and stirred for ten minutes. The mixture was transferred to room temperature and reacted for 10 h. The reaction mixture was poured into 4 times the volume of water and extracted with DCM (20 mL x 3). The organic phases were combined and washed with water (20 mL x 2) and then with saturated sodium chloride (20 mL x 1). The concentrated crude product was purified by column chromatography (200-300 mesh silica gel, MeOH / DCM = 1 / 70, V / V) to obtain 0.24 g of the target compound FC-1 as a white solid in a yield of 32.6%. Mp: 89.4-92.2°C; LC-MS: 914.1 [M+Na] + ,890.0[MH] - ; 1 H-NMR (600MHz, DMSO-d6) δ: 11.84 (1H, s), 10.02 (1H, s), 8.23 ​​(1H, t, J = 5.4Hz), 7.97 (1H, t, J = 6.0Hz), 7.91 (1H, t, J = 5.4Hz), 7.83 (1H ,s),7.30(1H,d,J=1.8Hz),7.01(1H,dd,J1=1.8Hz,J2=8.4Hz),6.83(1H,d,J=8.4Hz),6.75(1H,s),6.68(1H,s),6.32(2H,s),6.24(1H ,d,J=5.4Hz),6.04(1H,s),6.01(1H,s),4.56(1H,t,J=5.4Hz),4.37(1H,t,J=7.8Hz),4.29(2H,d,J=5.4Hz),3.68(2H,s),3.67(6H,s ),3.63(3H,s),3.48-3.45(1H,m),3.29-3.24(1H,m),3.23-3.17(2H,m),3.13-3.09(2H,m),2.96-2.93(1H,m),2.31(4H,t,J=3.6Hz); 13C-NMR (150MHz, DMSO-d6) δ: 173.9, 172.0, 171.7, 163.7, 152.7, 152.5, 152.1, 148.5, 147.3, 145.2, 136.9, 135.6, 133.2, 133.2, 129.5, 129 .2,126.4,123.9,116.5,110.2,109.2,109.1,108.5,102.0,60.3,57 .7,56.2,55.3,43.3,41.1,40.4,39.1,38.7,36.9,34.6,31.0,28.1.

[0111] Example 9: Preparation of (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}amino)-4-oxobutanoic acid-(4-O-demethyl-4-podophyllotoxin) ester (FC-2)

[0112]

[0113] Using F3-4 as the starting material, the target compound FC-2 was obtained according to the synthesis method of FC-1 as a white solid in a yield of 30.1%. Mp: 95.1-97.4℃; LC-MS: 820.20 [M+Na] + ; 1 H-NMR (600MHz, DMSO-d6) δ: 11.82 (1H, s), 10.02 (1H, s), 8.27 (1H, s), 7.96 (2H, t, J = 6.0Hz), 7.30 (1H, d, J = 1.8Hz), 7.02(1H,dd,J1=1.8Hz,J2=8.4Hz),6.86(1H,s),6.83(1H,d,J=8.4Hz),6.55(1H,s),6.22(2H,s),6.03(2H,t,J=1. 8Hz), 5.99 (1H, d, J = 6.6Hz), 4.56 (1H, d, J = 5.4Hz), 4.27-4.25 (1H, m), 3.93 (1H, dd, J1 = 8.4Hz, J2 = 10.8Hz), 3.68 (2 H,s),3.63(6H,s),3.20-3.15(3H,m),3.11-3.08(2H,m),3.04-2.98(1H,m),2.61-2.52(2H,m),2.38-2.36(2H,m); 13C-NMR (150MHz, DMSO-d6) δ: 174.5, 172.6, 171.4, 163.7, 152.7, 152.1, 148.4, 147.5, 146.9, 135.1, 133.7, 133.2, 130.0, 129. 5,129.2,128.3,116.5,110.0,109.8,109.2,108.7,101.8,68.3,67.7,56.4,43.2,41.1,39.0,38.7,36.8,30.1,28.1,22.8.

[0114] Example 10: Study on the pharmacological effects of the invention product:

[0115] The experiment included a positive control group (etoposide), PsA, and rPsA. HDAC1, HDAC2, HDAC3, and HDAC6 proteins (BPS Bioscience, USA) served as isoform enzyme sources. All reactions were performed in 96-well plates. The reaction buffer contained 25 mM Tris HCl (pH 8.0), 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, and 0.1 mg / mL BSA. FA-1 + TCEP was vortexed for 20 minutes in the dark before use. The remaining gradient concentrations of the above examples and control compound solutions (5 μL) and each enzyme (5 μL) were preincubated at room temperature for 15 minutes. The fluorogenic substrate Boc-Lys(Ac)-AMC (5 μL) was then added to initiate the reaction, and the reaction was incubated at 37°C for 60 minutes. Finally, a stop buffer containing trypsin and SAHA (25 μL) was added to the system, and incubation continued at 37°C for 10 minutes. Fluorescence intensity was measured at an excitation wavelength of 355 nm and an emission wavelength of 460 nm (Thermo Scientific Varioskan Flash Station). IC was calculated using GraphPad. 50 The inhibitory activities of the target compounds against HDAC are shown in Table 1.

[0116] In vitro inhibition activity test of anti-tumor cell proliferation, blood tumor cells were selected from acute lymphoblastic leukemia Jurkat cells, B cell lymphoma Jeko-1 and Raji cells (Jurkat and Raji cells were obtained from Mount Sinai School of Medicine [2] Jeko-1 cells were obtained from the Cell Bank of the Chinese Academy of Sciences (catalog number: TCHu194).

[0117] The anti-tumor activity of the target compound was tested on Jurkat leukemia cells using trypan blue staining. Jurkat cells were cultured in RPMI1640 medium supplemented with 10% FBS, dual-antibody (100 units / mL penicillin G and 100 ng / mL streptomycin), sodium pyruvate, and glucose. The cells were cultured in a constant temperature incubator (5% CO2, 37°C, Thermo / Forma Scientific). 10×10 4 Jurkat leukemia cells were seeded in a 24-well plate, and then the test drugs at various concentrations were added. After 72 hours of culture, the cells were suspended with a 1ml pipette tip, and 50μl of the cell suspension was added to an EP tube containing 50μl of 0.4% trypan blue and stained for 2 minutes. 10μl of cell staining solution was injected between the blood cell counting plate and the coverslip, and the cells were counted under a ×10 objective lens. The total number of cells and the number of dead cells were counted separately. The cell growth inhibition rate was calculated, and then the IC was calculated using GraphPad. 50 Growth inhibition rate = (1-number of cells in drug group / number of cells in control group) × 100%.

[0118] Solid tumors were selected from lung cancer A549 cells and paclitaxel-resistant A549 / T cells (donated by Professor Wu Yingliang's research group at Shenyang Pharmaceutical University, and related cells have been published in the literature). [3] ), PC-9 cells, osimertinib-resistant PC-9 cells (PC-9 / AR) (gift from Professor Sun Shiyong, see published papers) [4] ), colon cancer HCT116 cells (purchased from the Chinese Academy of Sciences Cell Bank, catalog number: TCHu 99), and breast cancer MCF-7 cells (gifted from Mount Sinai School of Medicine, USA, related papers have been published [5] ).

[0119] The above-mentioned solid tumor cells were seeded in a 96-well plate at a number of 3500 cells / well. After overnight incubation, 50 μL volume was added with a final concentration of 10 mM NAC for pretreatment for 4 hours. 50 μL of PsA of different concentrations (0.15625-2.5 μM) was added to each well. After incubation for 96 hours, 50 μL (2 mg / mL) of methyl tetrazolium blue (MTT) solution was added to each well and incubated at 37°C for 4 hours. The culture medium was aspirated and the cells were dissolved in 200 μL DMSO. The absorbance at 570 nm was measured using a microplate reader. The growth inhibition rate IC was calculated using GraphPad Prism5. 50 .

[0120] The experimental results are shown in Tables 1, 2, and 3.

[0121] Table 1 In vitro HDAC1, 2, 3, 6 enzyme inhibitory activity results of target compounds

[0122]

[0123] From Table 1, it can be seen that the split compounds all maintain the inhibitory activity on HDAC1, HDAC2, HDAC3, or HDAC6. TCEP is a disulfide bond reducing agent that can break the disulfide bond in vitro, and TCEP itself has no HDAC inhibitory activity. Mixing TCEP with FA-1 at a molar ratio of 1:1.5, avoiding light, vortexing for 20 minutes (method see published article [1] ), TCEP can break the disulfide bond of FA-1 in vitro, and FA-1 shows HDAC inhibitory activity after the disulfide bond is broken. The split compound connected by other chemical bonds does not need TCEP pretreatment and shows HDAC inhibitory activity.

[0124] Table 2 Inhibitory activity of target compounds on Jurkat cells

[0125]

[0126] Table 2 shows that the split compounds have inhibitory activity on Jurkat cells, and FA-1 and FB-1 have better inhibitory activity than PsA and Etoposide.

[0127] Table 3 Inhibitory activity of FA-1 on other tumor cells

[0128]

[0129] Table 3 shows that the split compound FA-1 has inhibitory activity on various tumor cells, and is sensitive to paclitaxel-resistant cells and osimertinib-resistant tumor cells.

[0130] [1] BAO Y, XU Q, WANG L, et al. Studying Histone Deacetylase Inhibition and Apoptosis Induction of Psammaplin A Monomers with Modified Thiol Group [J]. ACS medicinal chemistry letters, 2021, 12(1): 39-47. [2]ZHU X H,SHEN Y L,JING Y K,et al.Apoptosis and growth inhibition inmalignant lymphocytes after treatment with arsenic trioxide at clinicallyachievable concentrations[J].Journal of the National Cancer Institute,1999,91(9):772-8.

[0131] [3]YANG J,SONG D,LI B,et al.Replacing the tropolonic methoxyl groupof colchicine with methylamino increases tubulin binding affinity withimproved therapeutic index and overcomes paclitaxel cross-resistance[J].DrugResist Updat,2023,68(100951.

[0132] [4]CHEN Z,VALLEGAK A,WANG D,et al.DNA topoisomerase II inhibitionpotentiates osimertinib's therapeutic efficacy in EGFR-mutant non-small celllung cancer models[J].The Journal of clinical investigation,2024,134(10):

[0133] [5]ZHONG H,ZHAO X,ZUO Z,et al.Combating P-glycoprotein-mediatedmultidrug resistance with10-O-phenyl dihydroartemisinin ethers in MCF-7cells[J].European journal of medicinal chemistry,2016,108(720-9.

Claims

1. A combination of Psammaplin A and podophyllotoxin, characterized in that: The complex is a compound represented by formula (I), a derivative, and a pharmaceutically acceptable salt or hydrate thereof, Where, n is an integer from 1 to 3; R is selected from H or C1-C6 alkyl; X is selected from N, O or Y is -SS-, -CONH- or -COS-.

2. The Psammaplin A class and podophyllotoxin complex according to claim 1, characterized in that: The composite is a compound represented by formula (I), a derivative, and a pharmaceutically acceptable salt or hydrate thereof, wherein n is 2 or 3; R is selected from H, methyl, ethyl or propyl; X is selected from N, O or Y is -SS-, -CONH- or -COS-.

3. The Psammaplin A class and podophyllotoxin complex according to claim 2, characterized in that: The conjugate is (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}disulfanyl)butyric acid-(4-podophyllotoxin) ester (FA-1); (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}thio)-4-oxobutanoic acid-(4-podophyllotoxin) ester (FB-1); (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-(4-amino-4-deoxypodophyllotoxin)-4-oxobutane sulfate (FB-2); (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-{4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}-4-oxobutane sulfate (FB-3); (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}thio)-4-oxobutanoic acid-(4-O-demethyl-4-podophyllotoxin) ester (FB-4); (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-(4-O-demethyl-4-amino-4-deoxypodophyllotoxin)-4-oxobutane sulfate (FB-5); (E)-S-{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-4-{4-O-demethyl-4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}-4-oxobutane sulfate (FB-6); (E)-N 1 -{2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}-N 4 -{4-[(4-aminomethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin}succinamide (FC-1); (E)-4-({2-[3-(3-bromo-4-hydroxyphenyl)-2-(hydroxyimino)propionamido]ethyl}amino)-4-oxobutanoic acid-(4-O-demethyl-4-podophyllotoxin) ester (FC-2).

4. A use of the Psammaplin A class and podophyllotoxin complex according to claim 1, characterized in that: Use of the compound represented by formula (I), derivatives, pharmaceutically acceptable salts or hydrates thereof, and pharmaceutically acceptable excipients in the preparation of histone deacetylase inhibitors.

5. A use of the Psammaplin A class and podophyllotoxin complex according to claim 1, characterized in that: The compound represented by formula (I), its derivatives, and pharmaceutically acceptable salts or hydrates thereof are used in the preparation of drugs for treating diseases associated with abnormal expression of histone deacetylase activity.

6. Use of the Psammaplin A class and podophyllotoxin complex according to claim 1, characterized in that: The use of the compound represented by formula (I), its derivatives, and its pharmaceutically acceptable salts or hydrates in the preparation of anti-tumor drugs.

7. The use of the complex of Psammaplin A and podophyllotoxin according to claim 6, characterized in that: The compound represented by formula (I), its derivatives, and its pharmaceutically acceptable salts or hydrates are used in the preparation of drugs for treating lung cancer, breast cancer or leukemia.

8. The use of the complex of Psammaplin A and podophyllotoxin according to claim 6, characterized in that: The compound represented by formula (I), its derivatives, and pharmaceutically acceptable salts or hydrates thereof are used in the preparation of drugs for treating osimertinib-resistant non-lung cancer and paclitaxel-resistant lung cancer.

9. A pharmaceutical composition, characterized in that: The composition contains one or more of the compound represented by formula (I) according to claim 1, its derivatives, and pharmaceutically acceptable salts or hydrates thereof.

10. Use of the pharmaceutical composition according to claim 9, characterized in that: The composition is used in preparing histone deacetylase inhibitors.

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