3-Aminobenzamide-platinum(IV) complexes, their preparation methods and applications

Abstract

The present invention relates to a 3-aminobenzamide-platinum(IV) complex, its preparation method and application. By introducing a 3-aminobenzamide compound on the basis of platinum(IV), it is expected to improve the efficacy of platinum drugs, and the structure is shown in formula (1) or formula (2). The 3-aminobenzamide-platinum(IV) complex has strong cytotoxic effects on a variety of human tumor cells and shows good potential for anti-tumor medicinal value.

Description

Technical Field

[0001] The present invention belongs to the technical field of anti-cancer chemical drugs, and particularly relates to a 3-aminobenzamide-platinum(IV) complex, a preparation method thereof and an application thereof. Background Art

[0002] The divalent platinum-based anticancer drug cisplatin has been approved for clinical use globally and is widely used in the first line of cancer treatment. Cisplatin mainly acts on the N7 position of guanine in DNA, forms Pt-DNA adducts by cross-linking with DNA, affects DNA replication and transcription, promotes DNA damage, and ultimately leads to cell death. During clinical use, the adverse reactions and tumor drug resistance caused by platinum-based drugs are the key issues restricting the development of platinum-based drugs. Divalent platinum-based drugs designed according to the classical structure-activity relationship of platinum-based antitumor drugs proposed by Cleare and Hoeschele will produce cell behaviors almost the same as cisplatin and are difficult to overcome the disadvantages of cisplatin-based drugs. Therefore, the research and development of non-classical platinum-based antitumor drugs are of great significance. Compared with divalent platinum complexes, tetravalent platinum complexes have an octahedral configuration, possess substitution kinetic inertness, can reduce reactions with nucleophilic substances in the body, can reach cancer cells relatively intact, and exert anti-cancer effects. In addition, tetravalent platinum complexes are easy to chemically modify. Lipophilic groups can be introduced at their axial positions to increase the uptake of platinum drugs, or active pharmacodynamic groups can be introduced to synergistically enhance the effect, or target molecules can be introduced to improve targeting. Divalent platinum drugs and axial ligands are released in the form of prodrugs, showing great development potential. Synthetic lethality is a forward-looking direction in the research and development of anticancer drugs, referring to the phenomenon that the simultaneous inhibition of two non-lethal genes leads to cell death. Currently, the only product approved in this field is the Poly(ADP-ribose)polymerase (PARP) inhibitor, which has a synthetic lethal effect on BRCA-mutated tumors. PARP is a DNA repair enzyme that plays a key role in the DNA repair pathway. PARP inhibitors can inhibit PARP activity, enhance the anti-cancer effects of DNA damage-based chemotherapy drugs (such as platinum-based antitumor drugs like cisplatin), and are particularly sensitive to patients with BRCA gene-mutated tumors. Currently, a variety of PARP inhibitors have been marketed or are in the clinical research stage. In 2018, the FDA officially approved the PARP inhibitor Olaparib for the treatment of BRCA-mutated Her2-negative metastatic breast cancer. The small molecule compound 3-aminobenzamide is an effective PARP inhibitor. Compared with other PARP inhibitors, 3-aminobenzamide is inexpensive, easy to synthesize, and is easy to industrialize. Introducing 3-aminobenzamide into the design of platinum drugs to develop novel 3-aminobenzamide-based platinum(IV) complexes can further promote DNA damage by inhibiting PARP activity on the basis of platinum drug-induced DNA damage, thereby improving the anti-tumor effect. In addition, based on the synthetic lethal effect of PARP and BRCA in the DNA damage response, 3-aminobenzamide-based platinum(IV) complexes are expected to precisely treat BRCA gene-mutated tumors. Summary of the Invention

[0003] To solve the above technical problems, the present invention provides a 3-aminobenzamide-platinum(IV) complex, its preparation method and application. By introducing a 3-aminobenzamide compound and a lipophilic long carbon chain group on the basis of platinum(IV), it is expected to improve the anti-tumor efficacy of platinum drugs.

[0004] The technical solution adopted by the present invention is: a 3-aminobenzamide-platinum(IV) complex, the structure of which is shown in formula (1) or formula (2),

[0005]

[0006] wherein, is selected from cisplatin, oxaliplatin, carboplatin, heptaplatin, nedaplatin or miriplatin;

[0007] R 1 is -C n H 2n -, n is an integer and ≥1;

[0008] R 2 is -C m H 2m+1 or -NHC m H 2m+1 -, m is an integer and ≥1.

[0009] Preferably, is cisplatin.

[0010] Preferably, R 1 is -C n H 2n -, n ≤ 10, preferably, n ≤ 6, more preferably, n ≤ 4;

[0011] Further preferably, R 1 is -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 -.

[0012] Preferably, R 2 is -C m H 2m+1 or -NHC m H 2m+1 -, m ≤ 20, preferably, m ≤ 17, more preferably, m ≤ 12;

[0013] Further preferably, R 2 is -NH-(CH2 ) 5 -CH 3 、-NH-(CH 2 ) 7 -CH 3 、-NH-(CH 2 ) 11 -CH 3 、-(CH 2 ) 14 -CH 3 or -(CH 2 ) 16 -CH 3 .

[0014] Preferably, it is represented by any one of the following structural formulas (3) to (19):

[0015]

[0016]

[0017]

[0018]

[0019] A method for preparing a 3-aminobenzamide-platinum (IV) complex, comprising dissolving a compound of formula (20) in a first solvent, and subjecting the compound to an esterification reaction with a compound of formula (21) in the presence of a condensing agent and an acid binding agent to obtain the compound of formula (1);

[0020]

[0021] Preferably, the compound of formula (1) is mixed with one of hexyl isocyanate, octyl isocyanate, dodecyl isocyanate, palmitic anhydride and stearic anhydride and dissolved in a second solvent, and heated to react to obtain the compound of formula (2).

[0022] Preferably, the molar ratio of the compound of formula (20) to the compound of formula (21) is 1:1-1.2;

[0023] The first solvent is a mixture of one or more of dichloromethane, acetone, acetonitrile, DMSO and DMF; preferably, the first solvent is DMSO;

[0024] The condensing agent is HOBT or TBTU, preferably, the condensing agent is TBTU;

[0025] The acid binding agent is triethylamine.

[0026] Preferably, the molar ratio of the compound of formula (1) to one of hexyl isocyanate, octyl isocyanate, dodecyl isocyanate, palmitic anhydride and stearic anhydride is 1:2-5;

[0027] The second solvent is one or a mixture of dichloromethane, acetone, acetonitrile, DMSO and DMF. Preferably, the second solvent is DMF;

[0028] The heating reaction temperature is 50-70 °C and the reaction time is 12-36 h.

[0029] Preferably, after the reaction is completed, it is separated by a preparative thin-layer chromatography plate, and the developing agent is dichloromethane:methanol = 10:1.

[0030] Application of 3-aminobenzamide-platinum(IV) complexes in anti-tumor drugs.

[0031] The advantages and positive effects of the present invention are: The 3-aminobenzamide-platinum(IV) complexes have good inhibitory effects on the growth and proliferation of various human tumor cells, showing high potential for medicinal value; the main reason for platinum drugs to kill cells is to cause DNA damage. Therefore, the DNA damage repair ability of tumor cells closely affects the efficacy of platinum drugs. Compared with platinum(II) complexes, platinum(IV) complexes have substitution kinetic inertness, reducing the deactivation of platinum drugs and improving the therapeutic effect. 3-Aminobenzamide, as a PARP inhibitor, plays an important role in DNA damage repair. Introducing 3-aminobenzamide into the design of tetravalent platinum drugs helps the body promote the death of tumor cells by inhibiting the repair of DNA damage; in addition, the introduction of the long carbon chain group R 2 can effectively increase the liposolubility of platinum drugs, promote the passive uptake of platinum drugs, and improve the efficacy of platinum drugs; especially for BRCA gene mutant tumors, using platinum drugs to damage their cellular DNA and combining with the PARP inhibitor 3-aminobenzamide to initiate the synthetic lethal effect of PARP and BRCA in the DNA damage response, inducing the collapse of the tumor cell DNA repair mechanism and selectively killing tumor cells, while normal cells can survive by repairing DNA damage through the BRCA pathway, thus precisely treating BRCA gene mutant tumors. Specific embodiments

[0032] The following describes the embodiments of the present invention.

[0033] On the basis of platinum(IV), the present invention introduces 3-aminobenzamide compounds in order to improve the efficacy of platinum drugs and constructs a 3-aminobenzamide-platinum(IV) complex, the structure of which is shown in formula (1) or formula (2),

[0034]

[0035] Among them, selected from cisplatin, oxaliplatin, carboplatin, heptaplatin, nedaplatin or miboplatin;

[0036] R 1 is -C n H 2n -, n is an integer and ≥1; preferably, n≤10, more preferably, n≤6, even more preferably, n≤4; R 2 is -C m H 2m+1 or -NHC m H 2m+1 , m is an integer and ≥1, preferably, m≤20, more preferably, m≤17, even more preferably, m≤12; preferably cisplatin. In certain embodiments of the present invention, R 1 is -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, or -CH 2 -CH 2 -CH 2 -CH 2 -; R 2 is -NH-(CH 2 ) 5 -CH 3 , -NH-(CH 2 ) 7 -CH 3 , -NH-(CH 2 ) 11 -CH 3 , -(CH 2 ) 14 -CH 3 , or -(CH 2 ) 16 -CH 3 .

[0037] Compared with the compound of formula (1), the introduction of R 2 in the compound of formula (2) helps to increase the liposolubility of 3-aminobenzamide-platinum(IV) complexes, facilitate the passive uptake of the complexes by cells, and improve the antitumor effect of platinum drugs. Especially for BRCA gene-mutated tumors, using platinum drugs to damage DNA and combining with PARP inhibitors can produce a synthetic lethal effect, selectively killing tumor cells, while normal cells can repair DNA damage through the BRCA pathway and survive, improving its antitumor specificity.

[0038] Method for preparing 3-aminobenzamide-platinum(IV) complexes:

[0039] Dissolve the compound of formula (20) in the first solvent, and carry out an esterification reaction with the compound of formula (21) in the presence of a condensing agent and an acid-binding agent to obtain the compound of formula (1); wherein, the molar ratio of the compound of formula (20) to the compound of formula (21) is 1:1 - 1.2; the first solvent is one or a mixture of more of dichloromethane, acetone, acetonitrile, DMSO, and DMF; preferably, the first solvent is DMSO; the condensing agent is HOBT or TBTU, preferably, the condensing agent is TBTU; the acid-binding agent is triethylamine. The compound of formula (1) is a 3-aminobenzamide-platinum(IV) complex.

[0040]

[0041]

[0042] In order to further modify the compound of formula (1), a second reaction is also included. Mix and dissolve the compound of formula (1) with one of hexyl isocyanate, octyl isocyanate, dodecyl isocyanate, palmitic anhydride, and stearic anhydride in the second solvent, and heat the reaction to obtain the compound of formula (2), which is also used as a 3-aminobenzamide-platinum(IV) complex. The molar ratio of the compound of formula (1) to one of hexyl isocyanate, octyl isocyanate, dodecyl isocyanate, palmitic anhydride, and stearic anhydride is 1:2 - 5; the second solvent is one or a mixture of more of dichloromethane, acetone, acetonitrile, DMSO, and DMF, preferably, the second solvent is DMF; the heating reaction temperature is 50 - 70 °C, and the reaction time is 12 - 36 h.

[0043] After the completion of the first-step reaction or the second-step reaction, the 3-aminobenzamide-platinum(IV) complex can be separated by a preparative thin-layer chromatography plate, and the developing agent is dichloromethane:methanol = 10:1.

[0044] The 3-aminobenzamide-platinum(IV) complex can be applied to anti-tumor drugs. The 3-aminobenzamide-platinum(IV) complex has a good inhibitory effect on the growth and proliferation of various human tumor cells, showing high potential for medicinal value. The following illustrates the solution of the present invention through specific examples. Among them, for the experimental methods without specific operation steps, they are all carried out according to the corresponding product instructions. The instruments, reagents, and consumables used in the examples can be purchased from commercial companies without special instructions.

[0045] Example 1

[0046] The structural formula of the 3-aminobenzamide-platinum(IV) complex a in this example is as follows:

[0047]

[0048] The synthetic route of the preparation method of the 3-aminobenzamide-platinum(IV) complex a described in this example is as follows:

[0049]

[0050] 1. Preparation of compound a1

[0051] Accurately weigh 1000 mg (0.67 mmol) of cisplatin and place it in a 25 mL round-bottom flask. Add 8 mL of hydrogen peroxide and heat to 70 °C for 6 h. After the reaction is completed, keep the reaction solution away from light and place it in a refrigerator at 4 °C overnight. Centrifuge to obtain a pale yellow precipitate, wash it once with absolute ethanol and once with anhydrous ether, and then dry it. 956.99 mg of pale yellow powder is obtained, and the yield is 87%.

[0052] Characterize the product obtained by IR, and the data obtained are as follows:

[0053] IR(KBr): 3461(s,OH stretch), 1075(m,Pt-OH bend), 539(m,Pt-N(O)stretch).

[0054] 2. Preparation of compound a2

[0055] Accurately weigh 3-aminobenzamide (500 mg, 3.67 mmol) and dissolve it in 25 mL of tetrahydrofuran (or acetonitrile). Add succinic anhydride (550 mg, 5.505 mmol) and stir at room temperature for 24 h. During the reaction, the clear solution gradually becomes turbid and a large amount of white precipitate appears. Wash with tetrahydrofuran and dry to obtain 788 mg of white powder, and the yield is 91%.

[0056] By 1 1H NMR and 13 characterize the product obtained by 13C NMR, and the data obtained are as follows:

[0057] 1 1H NMR(400MHz,DMSO-d 6 6): δppm 12.14(s,1H), 10.08(s,1H), 8.04(s,1H), 7.92(s,1H), 7.74(dd,J=8.1,1.2Hz,1H), 7.51(d,J=7.8Hz,1H), 7.41 - 7.28(m,2H), 2.55(dt,J=11.2,4.7Hz,4H).

[0058] 13 13C NMR(101MHz,DMSO-d 6): δ 174.25, 170.69, 168.39, 139.73, 135.54, 128.95, 122.15, 122.08, 119.00, 31.47, 29.22.

[0059] From the above 1 1H NMR and 13 13C NMR characterization results, it can be confirmed that the prepared product is compound a2.

[0060] 3. Preparation of compound a

[0061] Dissolve a2 (84 mg, 0.36 mmol) and TBTU (144 mg, 0.45 mmol) in 1 mL of DMSO, add TEA (57 μL, 0.45 mmol), and stir for 15 min. Then add a1 (100 mg, 0.3 mmol), and react at room temperature in the dark for 24 h. Add chloroform to the above reaction solution to precipitate a white solid, centrifuge to remove the supernatant, and obtain a white precipitate. Purify by recrystallization with methanol and wash with anhydrous ether to obtain 158.98 mg of a white powder with a yield of 80%.

[0062] By characterizing the product obtained from 1 1H NMR, 13 13C NMR and HR-MS, the following data are obtained:

[0063] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 10.05 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.38 - 7.29 (m, 2H), 5.97 (t, J = 50.6 Hz, 6H), 2.51 (d, J = 3.8 Hz, 4H).

[0064] 13 13C NMR (101 MHz, DMSO-d 6 6): δ 180.46, 171.38, 168.43, 139.80, 135.46, 128.88, 122.25, 122.12, 119.11, 33.11, 32.05;

[0065] HR-MS (m / z): calcd for C 11 1 18 1 l2 1 4 1 5 1 +), 552.2720; found, 552.0350.

[0066] From the above 1 1H NMR, 13 13C NMR and HR-MS characterization results can confirm that the prepared product is compound a.

[0067] Example 2

[0068] The structural formula of the 3-aminobenzamide-platinum(IV) complex b in this example is as follows:

[0069]

[0070] The synthetic route of the preparation method of the 3-aminobenzamide-platinum(IV) complex b described in this example is as follows:

[0071] 1. Preparation of compound b1

[0072] Accurately weigh 3-aminobenzamide (500 mg, 3.67 mmol) and dissolve it in 25 mL of tetrahydrofuran (or acetonitrile). Add glutaric anhydride (627 mg, 5.505 mmol) and stir at room temperature for 24 h. During the reaction, the clear solution gradually becomes turbid and a large amount of white precipitate appears. Wash with tetrahydrofuran and dry to obtain 734 mg of white powder, with a yield of 86%.

[0073] By characterizing the product obtained from 1 1H NMR and 13 13C NMR, the obtained data are as follows:

[0074] 1 1H NMR (400 MHz, DMSO-d 6 ) : δ ppm 12.09 (s, 1H), 10.03 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.75 (dd, J = 8.0, 1.2 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.42 - 7.26 (m, 2H), 2.36 (t, J = 7.4 Hz, 2H), 2.28 (t, J = 7.3 Hz, 2H), 1.81 (p, J = 7.4 Hz, 2H).

[0075] 13 13C NMR (101 MHz, DMSO-d 6):δ 174.60, 171.34, 168.41, 139.69, 135.50, 128.93, 122.27, 122.22, 119.18, 35.82, 33.43, 20.87。

[0076] From the above 1 1H NMR and 13 13C NMR characterization results, it can be confirmed that the prepared product is compound b1.

[0077] 2. Preparation of compound b

[0078] Dissolve b1 (90 mg, 0.36 mmol) and TBTU (144 mg, 0.45 mmol) in 1 mL of DMSO, add TEA (57 μL, 0.45 mmol), and react for 15 min. Then add hydroxy platinum (100 mg, 0.3 mmol), and react for 24 h at room temperature in the dark. Add chloroform to the above reaction solution to precipitate a white solid, and centrifuge to remove the supernatant (excess TBTU and TEA, dissolved in a mixed solvent of DMSO and dichloromethane) to obtain a white precipitate. Recrystallize the crude product with methanol and wash with anhydrous ether to obtain 86.64 mg of white powder, with a yield of 85%.

[0079] By characterizing the product obtained from 1 1H NMR, 13 13C NMR and HR-MS, the following data are obtained:

[0080] 1 1H NMR (400 MHz, DMSO-d 6 ):δ ppm 9.94 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.39 - 7.26 (m, 2H), 5.99 (t, J = 51.8 Hz, 6H), 2.34 (t, J = 7.3 Hz, 2H), 2.23 (t, J = 7.5 Hz, 2H), 1.86 - 1.72 (m, 2H).

[0081] 13 13C NMR (101 MHz, DMSO-d 6 ):δ 180.96, 171.82, 168.43, 139.71, 135.49, 128.92, 122.28, 122.20, 119.15, 36.34, 36.23, 22.29;

[0082] HR-MS (m / z): calcd for C 12 H20 Cl 2 N 4 O 5 Pt(M + H + ), 566.2990; found, 566.0509。

[0083] From the above 1 H NMR, 13 C NMR and HR-MS characterization results, it can be confirmed that the prepared product is compound b.

[0084] Example 3

[0085] The structural formula of the 3-aminobenzamide-platinum(IV) complex c in this example is as follows:

[0086]

[0087] The synthesis route of the preparation method of the 3-aminobenzamide-platinum(IV) complex c described in this example is as follows:

[0088] Preparation of compound c

[0089] Put a (100 mg, 0.18 mmol) and hexyl isocyanate (46 mg, 0.36 mmol) into a 10 mL round-bottom flask, add 1 mL of DMF, protect from light, heat up to 60 °C, and react for 24 h. After the reaction is complete, spin-dry the DMF, dissolve the crude product with a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The eluent is dichloromethane:methanol = 10:1. 72.16 mg of white powder is obtained, and the yield is 59%.

[0090] By characterizing the product obtained from 1 H NMR, 13 C NMR and HR-MS, the obtained data are as follows:

[0091] 1 H NMR (400 MHz, DMSO-d 6δ ppm 10.23 (s, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.38 - 7.29 (m, 2H), 6.63 (d, J = 103.0 Hz, 6H), 2.88 (d, J = 7.6 Hz, 2H), 2.57 (d, J = 5.8 Hz, 2H), 2.51 - 2.49 (m, 2H), 1.34 (s, 2H), 1.27 - 1.19 (m, 6H), 0.85 (t, J = 6.8 Hz, 3H).

[0092] 13 C NMR (101 MHz, DMSO-d 6 ):δ 180.24, 171.09, 168.43, 164.38, 139.83, 135.44, 128.85, 122.23, 122.15, 119.14, 40.90, 32.78, 31.58, 31.25, 30.26, 26.58, 22.57, 14.42;

[0093] HR-MS (m / z): calcd for C 18 H 31 Cl 2 N 5 O 6 Pt (M + H + ), 679.4590; found, 679.1353。

[0094] From the above 1 H NMR, 13 C NMR and HR-MS characterization results, it can be confirmed that the prepared product is compound c.

[0095] Example 4

[0096] The structural formula of the 3-aminobenzamide-platinum(IV) complex d in this example is as follows:

[0097]

[0098] The synthetic route of the preparation method of the 3-aminobenzamide-platinum(IV) complex d described in this example is as follows:

[0099] Preparation of compound d

[0100] a (100 mg, 0.18 mmol) and octyl isocyanate (56 mg, 0.36 mmol) were placed in a 10 mL round-bottom flask, 1 mL of DMF was added, protected from light, and the temperature was raised to 60 °C. The reaction was carried out for 24 h. After the reaction was complete, the DMF was evaporated to dryness, and the crude product was dissolved in a mixed solution of dichloromethane and methanol, loaded onto a column, and separated by preparative thin-layer chromatography. The eluent was dichloromethane:methanol = 10:1. 71.32 mg of white powder was obtained, and the yield was 56%.

[0101] By 1 1H NMR, 13 13C NMR and HR-MS, the product was characterized, and the obtained data were as follows:

[0102] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 10.10 (s, 1H), 8.05 (s, 1H), 7.94 (d, J = 13.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.40 - 7.27 (m, 2H), 6.88 - 6.52 (m, 6H), 6.54 - 6.50 (m, 1H), 2.88 (d, J = 7.9 Hz, 2H), 2.59 (t, J = 6.2 Hz, 2H), 2.55 - 2.51 (m, 2H), 1.43 - 1.27 (m, 2H), 1.23 (s, 10H), 0.85 (t, J = 6.8 Hz, 3H).

[0103] 13 13C NMR (101 MHz, DMSO-d 6 6): δ 180.26, 171.05, 168.41, 164.39, 139.78, 135.47, 128.88, 122.23, 122.14, 119.12, 41.46, 32.75, 31.73, 31.16, 30.31, 29.32, 29.19, 26.93, 22.56, 14.43;

[0104] HR-MS (m / z): calcd for C 20 24 35 17 2 Cl 5 2 6 N + 2

[0105] From the above 1 1H NMR, 13The characterization results of \(^{13}\)C NMR and HR-MS can confirm that the prepared product is compound d.

[0106] Example 5

[0107] The structural formula of the 3-aminobenzamide-platinum(IV) complex e in this example is as follows:

[0108]

[0109] The synthesis route of the preparation method of the 3-aminobenzamide-platinum(IV) complex e described in this example is as follows:

[0110] Preparation of compound e

[0111] Put a (100 mg, 0.18 mmol) and dodecyl isocyanate (76 mg, 0.36 mmol) into a 10 mL round-bottom flask, add 1 mL of DMF, avoid light, heat up to 60 °C, and react for 24 h. After the reaction is complete, spin-dry the DMF, dissolve the crude product with a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The eluent is dichloromethane:methanol = 10:1. 80.23 mg of white powder is obtained, washed with anhydrous ether, and the yield is 63%.

[0112] By 1 \(^{1}\)H NMR, 13 characterize the product obtained by \(^{13}\)C NMR and HR-MS, and the data obtained are as follows:

[0113] 1 \(^{1}\)H NMR (400 MHz, DMSO-d 6 ):δ ppm 10.10 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 6.83 - 6.53 (m, 6H), 6.55 - 6.51 (m, 1H), 2.88 (d, J = 6.1 Hz, 2H), 2.58 (d, J = 6.2 Hz, 2H), 1.34 (s, 2H), 1.23 (s, 20H), 0.85 (t, J = 6.7 Hz, 3H).

[0114] 13 \(^{13}\)C NMR (101 MHz, DMSO-d 6): δ 179.75, 170.55, 167.89, 163.88, 139.28, 134.95, 128.39, 121.70, 121.62, 118.59, 40.96, 32.23, 31.28, 30.63, 29.83, 29.06, 29.03, 29.01, 28.89, 28.70, 26.45, 22.08, 13.94;

[0115] HR-MS (m / z): calcd for C 24 H 43 Cl 2 N 5 O 6 PtNa + (M + Na) + , 785.21303; found, 785.21307.

[0116] From the above 1 H NMR, 13 C NMR and HR-MS characterization results, it can be confirmed that the prepared product is compound e.

[0117] Example 6

[0118] The structural formula of the 3-aminobenzamide-platinum(IV) complex f in this example is as follows:

[0119]

[0120] The synthesis route of the preparation method of the 3-aminobenzamide-platinum(IV) complex f described in this example is as follows:

[0121] Preparation of compound f

[0122] Put a (100 mg, 0.18 mmol) and palmitic anhydride (178 mg, 0.36 mmol) into a 10 mL round-bottom flask, add 1 mL of DMF, keep away from light, heat up to 60 °C, and react for 24 h. After the reaction is complete, spin-dry the DMF, dissolve the crude product with a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The developing agent is dichloromethane:methanol = 10:1. Obtain 65.47 mg of white powder, wash it with anhydrous ether, and the yield is 46%.

[0123] By 1 H NMR, 13 C NMR and HR-MS to characterize the obtained product, the data obtained are as follows:

[0124] 11H NMR (400 MHz, DMSO-d 6 ): δ ppm 10.10 (s, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 6.57 (s, 6H), 2.62 - 2.55 (m, 2H), 2.54 (d, J = 5.5 Hz, 2H), 2.20 (t, J = 7.4 Hz, 2H), 1.49 - 1.40 (m, 2H), 1.24 (s, 24H), 0.86 (t, J = 6.7 Hz, 3H).

[0125] 13 13C NMR (101 MHz, DMSO-d 6 ): δ 181.37, 180.33, 171.05, 168.41, 139.79, 135.47, 128.86, 122.23, 122.15, 119.12, 36.17, 32.72, 31.75, 31.26, 29.52, 29.47, 29.45, 29.39, 29.17, 29.10, 25.92, 22.55, 14.42;

[0126] HR-MS (m / z): calcd for C 27 H 48 Cl 2 N 4 O 6 Pt (M + H + ), 790.6870; found, 790.2658.

[0127] From the above 1 1H NMR, 13 13C NMR and HR-MS characterization results, it can be confirmed that the prepared product is compound f.

[0128] Example 7

[0129] The structural formula of the 3-aminobenzamide-Pt(IV) complex g in this example is as follows:

[0130]

[0131] The synthetic route of the preparation method of the 3-aminobenzamide-Pt(IV) complex g described in this example is as follows:

[0132] Preparation of compound g

[0133] Place a (100 mg, 0.18 mmol) and stearic anhydride (198 mg, 0.36 mmol) in a 10 mL round-bottom flask, add 1 mL of DMF, protect from light, heat to 60 °C, and react for 24 h. After the reaction is complete, rotary evaporate the DMF, dissolve the crude product with a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The eluent is dichloromethane:methanol = 10:1. Obtain 58.95 mg of white powder, wash it with anhydrous ether, and the yield is 41%.

[0134] By 1 1H NMR, 13 13C NMR and HR-MS to characterize the obtained product, and the data obtained are as follows:

[0135] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 10.12 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.27 (s, 1H), 6.62 (s, 6H), 2.58 (d, J = 5.4 Hz, 2H), 2.53 (d, J = 6.8 Hz, 2H), 2.20 (t, J = 6.8 Hz, 2H), 1.44 (d, J = 5.7 Hz, 2H), 1.24 (s, 28H), 0.86 (t, J = 5.8 Hz, 3H).

[0136] 13 13C NMR (101 MHz, DMSO-d 6 6): δ 181.36, 180.34, 171.06, 168.41, 139.80, 135.46, 128.86, 122.22, 122.14, 119.12, 36.18, 32.73, 31.75, 31.29, 29.50, 29.46, 29.40, 29.16, 29.11, 25.92, 22.55, 14.42;

[0137] HR-MS (m / z): calcd for C 29 32 52 H 2 4 4 Cl 6 N + 2

[0138] From the above 1 1H NMR,13 The characterization results of 13C NMR and HR-MS can confirm that the prepared product is compound g.

[0139] Example 8

[0140] The structural formula of the 3-aminobenzamide-platinum(IV) complex h in this example is as follows:

[0141]

[0142] The synthesis route of the preparation method of the 3-aminobenzamide-platinum(IV) complex h described in this example is as follows:

[0143] Preparation of compound h

[0144] Put b (100 mg, 0.18 mmol) and hexyl isocyanate (46 mg, 0.36 mmol) into a 10 mL round-bottom flask, add 1 mL of DMF, protect from light, heat to 60 °C, and react for 24 h. After the reaction is complete, spin-dry the DMF, dissolve the crude product with a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The eluent is dichloromethane:methanol = 10:1. 87.38 mg of white powder is obtained, washed with anhydrous ether, and the yield is 70%.

[0145] By 1 1H NMR, 13 13C NMR and HR-MS to characterize the obtained product, the data obtained are as follows:

[0146] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 9.97 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.41 - 7.30 (m, 2H), 6.88 - 6.52 (m, 6H), 6.53 (d, J = 4.9 Hz, 1H), 2.88 (d, J = 6.0 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 2.29 (t, J = 7.4 Hz, 2H), 1.85 - 1.71 (m, 2H), 1.34 (s, 2H), 1.26 (dd, J = 15.6, 8.1 Hz, 6H), 0.85 (t, J = 6.8 Hz, 3H).

[0147] 13 13C NMR (101 MHz, DMSO-d 6): δ 180.67, 171.68, 168.40, 164.44, 139.70, 135.51, 128.91, 122.25, 122.21, 119.15, 41.47, 36.13, 35.38, 31.58, 30.27, 26.58, 22.57, 22.05, 14.42;

[0148] HR-MS (m / z): calcd for C 19 H 33 Cl 2 N 5 O 6 Pt(M + H + ), 693.4860; found, 693.1511.

[0149] From the above 1 H NMR, 13 C NMR and HR-MS characterization results, it can be confirmed that the prepared product is compound h.

[0150] Example 9

[0151] The structural formula of the 3-aminobenzamide-platinum(IV) complex i in this example is as follows:

[0152]

[0153] The synthesis route of the 3-aminobenzamide-platinum(IV) complex h described in this example is as follows:

[0154] Preparation of compound i

[0155] Put b (100 mg, 0.18 mmol) and octyl isocyanate (56 mg, 0.36 mmol) into a 10 mL round-bottom flask, add 1 mL of DMF, protect from light, heat to 60 °C, and react for 24 h. After the reaction is complete, spin-dry the DMF, dissolve the crude product with a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The developing agent is dichloromethane:methanol = 10:1. Obtain 97.41 mg of white solid, wash with anhydrous ether, and the yield is 75%.

[0156] By characterizing the product obtained from 1 H NMR, 13 C NMR and HR-MS, the obtained data are as follows:

[0157] 1 H NMR (400 MHz, DMSO-d 6):δ ppm 10.01 (s, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.40 - 7.27 (m, 2H), 6.59 (d, J = 57.1 Hz, 6H), 6.52 (s, 1H), 2.88 (d, J = 6.0 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 2.28 (t, J = 7.4 Hz, 2H), 1.85 - 1.73 (m, 2H), 1.34 (s, 2H), 1.23 (s, 8H), 0.85 (t, J = 6.7 Hz, 3H).

[0158] 13 C NMR (101 MHz, DMSO - d 6 ):δ 180.68, 171.69, 168.42, 164.45, 139.72, 135.50, 128.90, 122.25, 122.20, 119.15, 41.50, 36.15, 35.38, 31.74, 30.27, 29.32, 29.19, 26.93, 22.56, 22.06, 14.43;

[0159] HR - MS (m / z): calcd for C 21 H 37 Cl 2 N 5 O 6 Pt (M + H + ), 721.5400;found, 721.1816。

[0160] From the above 1 H NMR, 13 C NMR and HR - MS characterization results, it can be confirmed that the prepared product is compound i.

[0161] Example 10

[0162] The structural formula of the 3 - aminobenzamide - platinum(IV) complex j in this example is as follows:

[0163]

[0164] The synthetic route of the preparation method of the 3 - aminobenzamide - platinum(IV) complex j described in this example is as follows:

[0165] Preparation of compound j

[0166] b (100 mg, 0.18 mmol) and dodecyl isocyanate (76 mg, 0.36 mmol) were placed in a 10 mL round-bottom flask, 1 mL of DMF was added, protected from light, and the temperature was raised to 60 °C. The reaction was carried out for 24 h. After the reaction was complete, the DMF was rotary evaporated, and the crude product was dissolved in a mixed solution of dichloromethane and methanol, loaded onto a column, and separated by preparative thin-layer chromatography. The eluent was dichloromethane:methanol = 10:1. 93.78 mg of white solid was obtained, washed with anhydrous ether, and the yield was 67%.

[0167] By 1 1H NMR, 13 13C NMR and HR-MS, the product was characterized, and the obtained data are as follows:

[0168] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 10.04 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 6.1 Hz, 2H), 6.94 - 6.44 (m, 6H), 6.54 (d, J = 4.5 Hz, 1H), 2.88 (d, J = 5.7 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.28 (t, J = 7.3 Hz, 2H), 1.86 - 1.69 (m, 2H), 1.47 - 1.02 (m, 20H), 0.85 (t, J = 6.6 Hz, 3H).

[0169] 13 13C NMR (101 MHz, DMSO-d 6 6): δ 180.15, 171.20, 167.91, 163.95, 139.23, 134.98, 128.41, 121.73, 121.69, 118.62, 40.95, 35.59, 34.85, 31.28, 29.83, 29.06, 29.03, 29.00, 28.89, 28.70, 26.45, 22.08, 21.55, 13.94;

[0170] HR-MS (m / z): calcd for C 25 34 45 H 2 2 5 Cl 6 N + 2 + O

[0171] From the above 1 1H NMR, 13 13C NMR, and HR-MS characterization results can confirm that the prepared product is compound j.

[0172] Example 11

[0173] The structural formula of the 3-aminobenzamide-platinum(IV) complex k in this example is as follows:

[0174]

[0175] The synthetic route of the preparation method of the 3-aminobenzamide-platinum(IV) complex k described in this example is as follows:

[0176] Preparation of compound k

[0177] Place b (100 mg, 0.18 mmol) and stearic anhydride (198 mg, 0.36 mmol) in a 10 mL round-bottom flask, add 1 mL of DMF, protect from light, heat to 60 °C, and react for 24 h. After the reaction is complete, rotary evaporate the DMF, dissolve the crude product with a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The developing solvent is dichloromethane:methanol = 10:1. Obtain 66.63 mg of white solid, wash with anhydrous ether, and the yield is 46%.

[0178] By 1 1H NMR, 13 13C NMR, and HR-MS characterization of the obtained product, the data obtained are as follows:

[0179] 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.03 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 10.1, 5.2 Hz, 2H), 6.58 (s, 6H), 2.35 (t, J = 7.2 Hz, 2H), 2.29 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.4 Hz, 2H), 1.85 - 1.72 (m, 2H), 1.52 - 1.38 (m, 2H), 1.24 (s, 24H), 0.85 (t, J = 6.6 Hz, 3H).

[0180] 13 13C NMR (101 MHz, DMSO-d 6):δ180.89,180.22,171.18,167.90,139.22,134.98,128.41,121.73,121.69,118.63,35.69,35.59,34.93,31.27,29.05,29.00,28.98,28.92,28.69,28.63,25.43,22.08,21.51,13.93;

[0181] HR-MS(m / z): calcd for C 28 H 50 Cl 2 N 4 O 6 PtNa + (M + Na) + 826.26474; found, 826.26489。

[0182] From the above 1 H NMR, 13 C NMR and HR-MS characterization results, it can be confirmed that the prepared product is compound k.

[0183] Example 12

[0184] The structural formula of the 3-aminobenzamide-Pt(IV) complex l in this example is as follows:

[0185]

[0186] The synthetic route of the preparation method of the 3-aminobenzamide-Pt(IV) complex l described in this example is as follows:

[0187] Preparation of compound l

[0188] Put b (100 mg, 0.18 mmol) and stearic anhydride (198 mg, 0.36 mmol) into a 10 mL round-bottom flask, add 1 mL of DMF, keep away from light, heat up to 60 °C, and react for 24 h. After the reaction is complete, spin-dry the DMF, dissolve the crude product with a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The eluent is dichloromethane:methanol = 10:1. Obtain 55.46 mg of white solid, wash it with anhydrous ether, and the yield is 37%.

[0189] By 1 H NMR, 13 C NMR and HR-MS characterization of the obtained product, the data obtained are as follows:

[0190] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 9.98 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.39 - 7.29 (m, 2H), 6.55 (s, 6H), 2.35 (t, J = 7.3 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.78 (p, J = 7.4 Hz, 2H), 1.50 - 1.38 (m, 2H), 1.23 (s, 28H), 0.85 (t, J = 6.8 Hz, 3H).

[0191] 13 13C NMR (101 MHz, DMSO-d 6 6): δ 181.40, 180.76, 171.67, 168.40, 139.70, 135.50, 128.91, 122.25, 122.21, 119.15, 36.19, 36.12, 35.47, 31.75, 29.52, 29.51, 29.46, 29.40, 29.16, 29.12, 25.92, 22.55, 22.01, 14.41;

[0192] HR-MS (m / z): calcd for C 30 1 54 H 2 N 4 O 6 Pt (M + H + +), 832.7680; found, 832.3134.

[0193] From the above 1 1H NMR, 13 13C NMR and HR-MS characterization results, it can be confirmed that the prepared product is compound l.

[0194] Example 13

[0195] The structural formula of the 3-aminobenzamide-platinum(IV) complex m in this example is as follows:

[0196]

[0197] The synthetic route of the preparation method of the 3-aminobenzamide-platinum(IV) complex m described in this example is as follows:

[0198] 1. Preparation of Compound m1

[0199] Accurately weigh 3-aminobenzamide (500 mg, 3.67 mmol) and dissolve it in 25 mL of tetrahydrofuran (or acetonitrile). Add adipic anhydride (470 mg, 3.67 mmol) and stir the reaction at room temperature for 24 h. During the reaction, the reaction solution remained clear all the time. After rotary evaporation, a light pink solid powder was obtained. Wash the precipitate with tetrahydrofuran to obtain 589.45 mg of a white solid, and the yield was 61.27%.

[0200] Through 1 HNMR and 13 CNMR to characterize the obtained product, and the data obtained are as follows:

[0201] 1 H NMR (400 MHz, DMSO-d 6 6): δ ppm 12.07 (s, 1H), 7.74 (s, 1H), 7.16 (s, 1H), 7.06 (dd, J = 9.2, 6.2 Hz, 2H), 7.01 - 6.96 (m, 1H), 6.68 (ddd, J = 8.0, 2.3, 1.0 Hz, 1H), 5.28 (s, 1H), 2.33 - 2.09 (m, 4H), 1.66 - 1.44 (m, 4H).

[0202] 13 C NMR (101 MHz, DMSO-d 6 6): δ 174.33, 168.68, 167.92, 148.42, 135.15, 128.51, 116.49, 114.70, 113.13, 33.33, 23.98.

[0203] From the above 1 HNMR and 13 CNMR characterization results, it can be confirmed that the obtained product is Compound m1.

[0204] 2. Preparation of Compound m

[0205] Dissolve m1 (95 mg, 0.36 mmol) and TBTU (144 mg, 0.45 mmol) in 1 mL of DMSO, add TEA (57 μL, 0.45 mmol), and stir for 15 min. Then add hydroxy platinum (100 mg, 0.3 mmol), and react for 24 h at room temperature in the dark. Add chloroform, squeeze out the white solid, centrifuge to obtain a brown precipitate C. Place the brown precipitate C (100 mg, 0.18 mmol) and hexyl isocyanate (46 mg, 0.36 mmol) in a 10 mL round-bottom flask, add 1 mL of DMF, react at 60 °C in the dark for 24 h. After the reaction is complete, evaporate the DMF, dissolve the crude product in a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The eluent is dichloromethane:methanol = 10:1. Obtain 25.47 mg of white solid, wash with anhydrous ether, and the yield is 20%.

[0206] By 1 1H NMR, 13 13C NMR and HR-MS to characterize the obtained product, and the data obtained are as follows:

[0207] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 10.06 (s, 1H), 8.04 (s, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 6.55 (dd, J = 37.6, 32.7 Hz, 6H), 6.51 (t, J = 5.1 Hz, 1H), 2.94 - 2.84 (m, 2H), 2.28 (dt, J = 23.1, 7.1 Hz, 4H), 1.65 - 1.42 (m, 4H), 1.39 - 1.18 (m, 12H), 0.85 (t, J = 6.8 Hz, 3H).

[0208] 13 13C NMR (101 MHz, DMSO-d 6 6): δ 171.28, 167.88, 163.93, 139.26, 134.98, 128.44, 121.69, 121.65, 118.59, 40.94, 36.12, 35.27, 31.10, 29.78, 26.09, 25.00, 24.66, 22.09, 13.94;

[0209] HR-MS (ESI): m / z calcd for C 20 1H35 Cl 2 N 5 O 6 PtNa + (M + Na) + 728.12389.found, 728.14813。

[0210] From the above 1 1H NMR, 13 13C NMR and HR-MS characterization results, it can be confirmed that the prepared product is compound m.

[0211] Example 14

[0212] The structural formula of the 3-aminobenzamide-platinum(IV) complex n in this example is as follows:

[0213]

[0214] The synthesis route of the 3-aminobenzamide-platinum(IV) complex n described in this example is as follows:

[0215]

[0216] Preparation of compound n

[0217] Dissolve m1 (95 mg, 0.36 mmol) and TBTU (144 mg, 0.45 mmol) in 1 mL of DMSO, add TEA (57 μL, 0.45 mmol), and stir for 15 min. Then add hydroxy platinum (100 mg, 0.3 mmol), and react at room temperature in the dark for 24 h. Add chloroform, expel the white solid, and centrifuge to obtain a brown precipitate C. Place the brown precipitate C (100 mg, 0.18 mmol) and octyl isocyanate (56 mg, 0.36 mmol) in a 10 mL round-bottom flask, add 1 mL of DMF, heat to 60 °C in the dark, and react for 24 h. After the reaction is complete, evaporate the DMF, dissolve the crude product in a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The eluent is dichloromethane:methanol = 10:1. Obtain 29.13 mg of white solid, wash with anhydrous ether, and the yield is 22%.

[0218] By 1 1H NMR, 13 13C NMR and HR-MS characterization of the obtained product, the data obtained are as follows:

[0219] 1 1H NMR (400 MHz, DMSO-d 6):δ ppm 10.06 (s, 1H), 8.04 (s, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 6.59 (d, J = 65.9 Hz, 6H), 2.94 - 2.84 (m, 2H), 2.28 (dt, J = 23.1, 7.1 Hz, 4H), 1.65 - 1.42 (m, 4H), 1.23 (s, 10H), 0.85 (t, J = 6.8 Hz, 3H).

[0220] 13 C NMR (101 MHz, DMSO - d 6 ):δ 180.50, 171.31, 167.92, 163.94, 139.26, 134.95, 128.44, 121.71, 121.67, 118.59, 40.93, 36.11, 35.30, 31.24, 29.81, 28.82, 28.70, 26.43, 24.99, 24.66, 22.07, 13.94;

[0221] HR - MS (ESI):m / z calcd for C 22 H 39 Cl 2 N 5 O 6 PtNa + (M + Na) + 757.15519. found, 757.18201。

[0222] From the above 1 H NMR, 13 C NMR and HR - MS characterization results, it can be confirmed that the prepared product is compound n.

[0223] Example 15

[0224] The structural formula of the 3 - aminobenzamide - platinum(IV) complex o in this example is as follows:

[0225]

[0226] The synthetic route of the preparation method of the 3 - aminobenzamide - platinum(IV) complex o described in this example is as follows:

[0227]

[0228] Preparation of compound o

[0229] Dissolve m1 (95 mg, 0.36 mmol) and TBTU (144 mg, 0.45 mmol) in 1 mL of DMSO, add TEA (57 μL, 0.45 mmol), and stir for 15 min. Then add hydroxy platinum (100 mg, 0.3 mmol), and react for 24 h at room temperature in the dark. Add chloroform, squeeze out the white solid, and centrifuge to obtain a brown precipitate C. Place the brown precipitate C (100 mg, 0.18 mmol) and dodecyl isocyanate (76 mg, 0.36 mmol) in a 10 mL round-bottom flask, add 1 mL of DMF, react at 60 °C in the dark for 24 h. After the reaction is complete, evaporate the DMF under reduced pressure, dissolve the crude product in a mixed solution of dichloromethane and methanol, load the sample, and separate by preparative thin-layer chromatography. The eluent is dichloromethane:methanol = 10:1. Obtain 48.45 mg of white solid, wash with anhydrous ether, and the yield is 34%.

[0230] By 1 1H NMR, 13 13C NMR and HR-MS to characterize the product obtained, and the data obtained are as follows:

[0231] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 10.11 (s, 1H), 8.01 (d, J = 12.7 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.43 - 7.32 (m, 2H), 6.64 (s, 6H), 6.46 (d, J = 3.4 Hz, 1H), 2.89 (s, 2H), 2.40 - 2.14 (m, 4H), 1.68 - 1.42 (m, 4H), 1.23 (s, 20H), 0.85 (t, J = 5.9 Hz, 3H).

[0232] 13 13C NMR (101 MHz, DMSO-d 6 6): δ 171.57, 168.21, 168.18, 163.94, 139.12, 134.75, 128.57, 121.94, 121.85, 118.57, 40.91, 36.05, 36.01, 31.22, 29.75, 28.98, 28.95, 28.94, 28.81, 28.63, 26.36, 24.94, 24.61, 22.03, 13.90

[0233] HR-MS (ESI): m / z calcd for C 26 25 47 H2 N 5 O 6 PtNa + (M + Na) + 813.21779.found, 813.24438。

[0234] From the above 1 1H NMR, 13 13C NMR and HR-MS characterization results can confirm that the prepared product is compound o.

[0235] Example 16

[0236] The structural formula of the 3-aminobenzamide-platinum(IV) complex p in this example is as follows:

[0237]

[0238] The synthesis route of the preparation method of the 3-aminobenzamide-platinum(IV) complex p described in this example is as follows:

[0239]

[0240] Preparation of compound p

[0241] Dissolve m1 (95 mg, 0.36 mmol) and TBTU (144 mg, 0.45 mmol) in 1 mL of DMSO, add TEA (57 μL, 0.45 mmol), and stir for 15 min. Then add hydroxyplatinum (100 mg, 0.3 mmol), and react for 24 h at room temperature in the dark. Add chloroform, expel the white solid, and centrifuge to obtain a brown precipitate C. Place the brown precipitate C (100 mg, 0.18 mmol) and stearic anhydride (198 mg, 0.36 mmol) in a 10 mL round-bottom flask, add 1 mL of DMF, heat to 60 °C in the dark, and react for 24 h. After the reaction is complete, evaporate the DMF, dissolve the crude product in a mixed solution of dichloromethane and methanol, load the sample, and separate it on a preparative thin-layer chromatography plate. The eluent is dichloromethane:methanol = 10:1. Obtain 28.00 mg of white solid, wash with anhydrous ether, and the yield is 19%.

[0242] By 1 1H NMR, 13 13C NMR and HR-MS characterization of the obtained product, the data obtained are as follows:

[0243] 1 1H NMR (400 MHz, DMSO-d 6):δ ppm 10.06 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.40 - 7.32 (m, 2H), 6.55 (s, 6H), 2.31 (t, J = 7.2 Hz, 2H), 2.23 (dt, J = 25.5, 7.4 Hz, 4H), 1.80 (s, 2H), 1.68 - 1.57 (m, 2H), 1.52 - 1.40 (m, 4H), 1.23 (s, 22H), 0.85 (t, J = 6.8 Hz, 4H).

[0244] 13 C NMR (101 MHz, DMSO - d 6 ):δ 171.42, 171.40, 168.00, 167.87, 139.19, 134.89, 128.50, 121.79, 121.73, 118.58, 36.08, 35.67, 35.64, 35.34, 31.24, 29.00, 28.92, 28.87, 28.65, 28.57, 25.40, 24.95, 24.63, 22.05, 13.93;

[0245] HR - MS (ESI):m / z calcd for C 29 H 52 Cl 2 N 4 O 6 PtNa + (M + Na) + 840.28039. found, 840.28027。

[0246] From the above 1 H NMR, 13 C NMR and HR - MS characterization results, it can be confirmed that the prepared product is compound p.

[0247] Example 17

[0248] The structural formula of the 3 - aminobenzamide - platinum(IV) complex q in this example is as follows:

[0249]

[0250] The synthesis route of the preparation method of the 3 - aminobenzamide - platinum(IV) complex q described in this example is as follows:

[0251]

[0252] Preparation of compound q

[0253] Dissolve m1 (95 mg, 0.36 mmol) and TBTU (144 mg, 0.45 mmol) in 1 mL of DMSO, add TEA (57 μL, 0.45 mmol), and stir for 15 min. Then add hydroxyplatinum (100 mg, 0.3 mmol), and react for 24 h at room temperature in the dark. Add chloroform, expel the white solid, and centrifuge to obtain a brown precipitate C. Place the brown precipitate C (100 mg, 0.18 mmol) and stearic anhydride (198 mg, 0.36 mmol) in a 10 mL round-bottom flask, add 1 mL of DMF, and react at 60 °C for 24 h in the dark. After the reaction is complete, evaporate the DMF under reduced pressure, dissolve the crude product in a mixed solution of dichloromethane and methanol, load the sample, and separate it by preparative thin-layer chromatography. The eluent is dichloromethane:methanol = 10:1. Obtain 22.86 mg of white solid, wash it with anhydrous ether, and the yield is 15%.

[0254] By 1 1H NMR, 13 13C NMR and HR-MS to characterize the obtained product, and the data obtained are as follows:

[0255] 1 1H NMR (400 MHz, DMSO-d 6 6): δ ppm 10.06 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.77 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.32 (s, 2H), 6.57 (s, 6H), 2.29 (dt, J = 14.7, 7.1 Hz, 4H), 2.19 (t, J = 7.4 Hz, 2H), 1.64 - 1.55 (m, 2H), 1.52 - 1.41 (m, 4H), 1.23 (s, 28H), 0.84 (d, J = 7.0 Hz, 3H).

[0256] 13 13C NMR (101 MHz, DMSO-d 6 6): δ 180.87, 180.56, 171.29, 167.89, 139.28, 134.97, 128.42, 121.69, 121.65, 118.60, 36.11, 35.69, 35.37, 31.27, 29.02, 28.98, 28.92, 28.68, 28.62, 25.42, 24.98, 24.67, 22.07, 13.94;

[0257] HR-MS (ESI): m / z calcd for C 31 25H56 Cl 2 N 4 O 6 PtNa + (M + Na) + 868.31169.found, 868.31165。

[0258] From the above 1 1H NMR, 13 13C NMR and HR-MS characterization results can confirm that the prepared product is compound q.

[0259] Example 18

[0260] In vitro antitumor activity assay of 3-aminobenzamide-platinum(IV) complexes

[0261] This example was completed using the MTT method (tetramethylthiazolyl diphenyl-tetrazolium bromide colorimetric method), and human non-triple-negative breast cancer cells MCF-7, human triple-negative breast cancer cells MDA-MB-231, human BRCA-mutated triple-negative breast cancer cells HCC-1937, and human normal liver tissue-derived cells LO2 were selected. MCF-7, MDA-MB-231, and LO2 were cultured in DMEM medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 U / mL streptomycin. HCC-1937 was cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 U / mL streptomycin. All cell lines were routinely cultured in an incubator with 5% CO 2 at a concentration, under saturated humidity conditions, at a temperature of 37 °C. The specific experimental steps are as follows:

[0262] Collect cells in the logarithmic growth phase, adjust the cell concentration, and inoculate them into a 96-well plate (3000 cells / well), 100 μL per well. The outermost peripheral wells of the 96-well plate were filled with sterile PBS to reduce the influence of edge effects. The cells were cultured overnight at 37 °C and 5% CO 2 conditions until the cells adhered, and then drugs with a concentration gradient were added, with 3 replicate wells set for each concentration. After the drugs acted for 72 h, 10 μL of 5 mg / mL MTT was added, and the cells were cultured for another 4 h in the dark. Then, the culture medium was discarded, and 100 μL of DMSO was added to each well to dissolve the formazan crystals. The absorbance A value of each well was measured at 570 nm using an enzyme-linked immunosorbent assay detector. Three independent repeated experiments were carried out. Table 1 shows the half-maximal inhibitory concentration (IC 50 ) of the present invention, and the results are shown in Table 1.

[0263] Table 1 IC 50 (μM) of the 3-aminobenzamide-platinum(IV) complexes prepared in the present invention against different cells

[0264]

[0265]

[0266] From the IC 50 activity screening results, the 3-aminobenzamide-platinum(IV) complexes have good killing effects on the above-mentioned several tumor cells. The cell growth inhibitory effect of compound b on MDA-MB-231 and HCC-1937 is better than that of the positive drug cisplatin, and its toxicity to MCF-7 cells is lower than that of cisplatin. The cell growth inhibitory effect of compound m on MCF-7 and MDA-MB-231 is better than that of the positive drug cisplatin, and its toxicity to HCC-1937 cells is slightly lower than that of cisplatin. In addition, the cytotoxicities of other 3-aminobenzamide-platinum(IV) complexes involved in the present invention to the three tumor cell lines MCF-7, MDA-MB-231 and HCC-1937 are all higher than those of the positive control drugs 3-aminobenzamide, cisplatin and their combined administration. Among them, the anti-tumor activities of compound f against MCF-7, MDA-MB-231 and HCC-1937 are 72.86, 404 and 50.73 times that of cisplatin respectively; the anti-tumor activities of compound q against MCF-7, MDA-MB-231 and HCC-1937 are 56.67, 269.33 and 6.55 times that of cisplatin respectively. Moreover, compared with the LO2 cells derived from normal liver tissue, the selectivity index of compound f for the tumor cell MDA-MB-231 is 20.59 times that of cisplatin, and the selectivity indices of compound q for the tumor cells MCF-7, MDA-MB-231 and HCC-1937 are 105.94 times, 503 times and 12.24 times that of cisplatin respectively, showing good selectivity for tumor cells and being beneficial to reducing the toxic side effects caused by the non-selective killing of platinum drugs. The 3-aminobenzamide-platinum(IV) complexes d, e, f, g, i, j, k, l, n, o, p and q involved in formula (2) have greater toxicity to the three tumor cells than the 3-aminobenzamide-platinum(IV) complexes a and b involved in formula (1), which is closely related to the introduction of the lipophilic long carbon chain group R 2 in it. R 2 is -NH-(CH 2 ) 5 -CH 3 When it is, the activities of the corresponding formula (2) complexes c, h and m are similar to the anti-tumor activities of the formula (1) complexes a and b without the introduction of the R 2 group, while when R 2 is a long carbon chain group -NH-(CH 2 ) 7 -CH 3 with greater lipophilicity, -NH-(CH 2) 11 -CH 3 、-(CH2) 14 -CH 3 or -(CH 2 ) 16 -CH 3 When it is, the anti-tumor activity is significantly improved.

[0267] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A 3-aminobenzamide-platinum(IV) complex, characterized in that: it is represented by any one of the structural formulas of Formula (6)-Formula (9), Formula (11)-Formula (14), and Formula (16)-Formula (19): 。 2. A method for preparing the 3-aminobenzamide-platinum(IV) complex according to Claim 1, characterized in that: dissolve the compound of Formula (20) in a first solvent, and carry out an esterification reaction with the compound of Formula (21) in the presence of a condensing agent and an acid-binding agent to obtain the compound of Formula (1); mix the compound of Formula (1) with octyl isocyanate and dissolve it in a second solvent, and heat and react to obtain the compound of Formula (6), Formula (11), or Formula (16); mix the compound of Formula (1) with dodecyl isocyanate and dissolve it in a second solvent, and heat and react to obtain the compound of Formula (7), Formula (12), or Formula (17); mix the compound of Formula (1) with palmitic anhydride and dissolve it in a second solvent, and heat and react to obtain the compound of Formula (8), Formula (13), or Formula (18); mix the compound of Formula (1) with stearic anhydride and dissolve it in a second solvent, and heat and react to obtain the compound of Formula (9), Formula (14), or Formula (19); Formula (1); Formula (20); Formula (21); Among them, R 1 is -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, or -CH 2 -CH 2 -CH 2 -CH 2 -; is cisplatin.

3. The method for preparing the 3-aminobenzamide-platinum(IV) complex according to Claim 2, characterized in that: the molar ratio of the compound of Formula (20) to the compound of Formula (21) is 1:1 - 1.2; the first solvent is one or a mixture of more than one of dichloromethane, acetone, acetonitrile, DMSO, and DMF; the condensing agent is HOBT or TBTU; the acid-binding agent is triethylamine.

4. The method for preparing the 3-aminobenzamide-platinum(IV) complex according to Claim 2, characterized in that: the molar ratio of the compound of Formula (1) to one of octyl isocyanate, dodecyl isocyanate, palmitic anhydride, and stearic anhydride is 1:2 - 5; the second solvent is one or a mixture of more than one of dichloromethane, acetone, acetonitrile, DMSO, and DMF, the heating reaction temperature is 50 - 70 °C, and the reaction time is 12 - 36 h.

5. The method for preparing the 3-aminobenzamide-platinum(IV) complex according to Claim 2, characterized in that: after the reaction is completed, separate it using a preparative thin-layer chromatography plate, and the developing agent is dichloromethane:methanol = 10:

1.

6. The application of the 3-aminobenzamide-platinum(IV) complex according to Claim 1 in the preparation of anti-tumor drugs.

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