Platinum and aza-pyrrolidone complex as well as preparation method and application thereof

Abstract

The invention provides a platinum-coordination aza-pyrrolidone complex as well as a preparation method and application thereof, and belongs to the technical field of biological materials. The chemical structure of the platinum-coordination aza-pyrrolidone complex provided by the invention is as shown in a formula I in the specification. According to the invention, the electron-donating group is connected to the aza-pyrrolidone dye with near-infrared absorption, so that the complex can be excited by both light and ultrasound, and has excellent photodynamic therapy and sonodynamic therapy effects.

Description

Technical Field

[0001] The invention belongs to the technical field of biomaterials, and in particular relates to a platinum-azapyrrolidone complex and a preparation method and application thereof. Background Art

[0002] As a disease with a high mortality rate, tumors seriously threaten human health. Although traditional tumor treatment methods, such as surgery, chemotherapy, and radiotherapy, have achieved certain results in tumor treatment, they are often accompanied by side effects during implementation. With the continuous development of science and technology, researchers have gradually developed a variety of new treatment options, such as photothermal and photodynamic therapy or sonodynamic therapy.

[0003] Azapyrrolidine compounds have relatively good photostability and adjustable near-infrared absorption, making them widely used in optical technology, bioimaging and other fields. When combined with metals such as silver and iridium, they have good photodynamic therapy effects. However, existing azapyrrolidine complexes generally only have photodynamic effects, which limits their scope of application.

[0004] Therefore, there is an urgent need for a pyrrolidine complex with a wider range of applications. Summary of the invention

[0005] The purpose of the present invention is to provide a platinum-azapyrrolidone complex and its preparation method and application. The platinum-azapyrrolidone complex provided by the present invention has both photodynamic effect and sonodynamic effect, and has a wider application range.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a platinum-coordinated azopyrrolidone complex, the chemical structure of which is shown in Formula I:

[0008]

[0009] In the formula I, R 1 and R 2 Independently One of the following; among them, R 3 is H or a linear, branched or cyclic alkyl alkane having 1 to 16 carbon atoms.

[0011] The present invention also provides a method for preparing the platinum-coordinated nitrogen-pyrrolidone complex described in the above technical solution, comprising the following steps:

[0012] (1) R 1 The aldehyde and R 2The ketone, the first solvent and the alkali solution are mixed and subjected to a condensation reaction to obtain an intermediate product 1;

[0013] (2) mixing the intermediate product 1 obtained in step (1) with nitromethane, diethylamine and a second solvent, and performing an addition reaction to obtain an intermediate product 2;

[0014] (3) mixing the intermediate product 2 obtained in step (2) with ammonium acetate and a third solvent and performing a Hofmann rearrangement reaction to obtain an intermediate product 3;

[0015] (4) The intermediate product 3 obtained in step (3) is mixed with a chloro complex of platinum, a catalyst and a fourth solvent, and then subjected to coordination reaction to obtain a platinum-coordinated nitrogen-pyrrolidone complex.

[0016] Preferably, in step (1), R 1 The aldehyde and R 2 The molar ratio of ketone is (0.8~1.2):1.

[0017] Preferably, the temperature of the condensation reaction in step (1) is 20 to 30° C., and the time of the condensation reaction is 8 to 16 hours.

[0018] Preferably, in step (2), the molar ratio of the intermediate product 1, nitromethane and diethylamine is 15:(200-250):(200-250).

[0019] Preferably, the temperature of the addition reaction in step (2) is 80 to 90° C., and the time of the addition reaction is 12 to 36 hours.

[0020] Preferably, in step (3), the molar ratio of the intermediate product 2 to ammonium acetate is 8:(100-150).

[0021] Preferably, in step (4), the molar ratio of the intermediate product 3 to the chloro complex of platinum is (1-3):1.

[0022] Preferably, the temperature of the coordination reaction in step (4) is 100-120° C., and the time of the coordination reaction is 3-5 h.

[0023] The present invention also provides the use of the platinum-azapyrrolidone complex described in the above technical solution or the platinum-azapyrrolidone complex prepared according to the preparation method described in the above technical solution in preparing photodynamic therapy or sonodynamic therapy drugs.

[0024] The present invention provides a platinum-coordinated azapyrrolidone complex, the chemical structure of which is shown in Formula I. The present invention connects an electron-donating group to an azapyrrolidone dye having near-infrared absorption, so that the complex can be excited by both light and ultrasound, and has excellent photodynamic therapy and sonodynamic therapy effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The present invention is a process flow chart for preparing the platinum-azapyrrolidone complex;

[0026] Figure 2 This is a process flow chart for preparing the platinum-nitrogen-pyrrolidone complex in Example 1 of the present invention;

[0027] Figure 3 The mass spectrum of the platinum-coordinated nitrogen-pyrrolidone complex prepared in Example 1 of the present invention;

[0028] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the platinum-nitrogen-pyrrolidone complex prepared in Example 1 of the present invention;

[0029] Figure 5 The UV-visible absorption spectrum of the platinum-nitrogen-pyrrolidone complex prepared in Example 1 of the present invention;

[0030] Figure 6 This is a diagram of the sonodynamic effect of the platinum-nitrogen-pyrrolidone complex prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0031] The present invention provides a platinum-coordinated azopyrrolidone complex, the chemical structure of which is shown in Formula I:

[0032]

[0033] In the formula I, R 1 and R 2 Independently

[0034]

[0035] In the present invention, the R 1 Preferably The R 2 Preferably The present invention converts R 1 and R 2 Respectively limited to The sonodynamic therapy effect and photodynamic therapy effect of the complex can be further improved.

[0036] In the present invention, the R 3 is H or a linear, branched or cyclic alkyl alkane having 1 to 16 carbon atoms.

[0037] The present invention controls the specific structure of the platinum-coordinated azapyrrolidone complex and connects the electron-donating group to the azapyrrolidone dye with near-infrared absorption, so that the complex can be excited by both light and ultrasound, and has excellent photodynamic therapy and sonodynamic therapy effects.

[0038] The present invention also provides a method for preparing the platinum-coordinated nitrogen-pyrrolidone complex described in the above technical solution, comprising the following steps:

[0039] (1) R 1 The aldehyde and R 2 The ketone, the first solvent and the alkali solution are mixed and subjected to a condensation reaction to obtain an intermediate product 1;

[0040] (2) mixing the intermediate product 1 obtained in step (1) with nitromethane, diethylamine and a second solvent, and performing an addition reaction to obtain an intermediate product 2;

[0041] (3) mixing the intermediate product 2 obtained in step (2) with ammonium acetate and a third solvent and performing a Hofmann rearrangement reaction to obtain an intermediate product 3;

[0042] (4) The intermediate product 3 obtained in step (3) is mixed with a chloro complex of platinum, a catalyst and a fourth solvent, and then subjected to coordination reaction to obtain a platinum-coordinated nitrogen-pyrrolidone complex.

[0043] Unless otherwise specified, the present invention has no particular limitation on the sources of the raw materials, and commercially available products known to those skilled in the art may be used.

[0044] The present invention converts R 1 The aldehyde and R 2 The ketone, the first solvent and the alkali solution are mixed and subjected to a condensation reaction to obtain an intermediate product 1.

[0045] In the present invention, the R 1 The structural formula of the aldehyde is

[0046] In the present invention, the R 2 The structural formula of the ketone is

[0047] In the present invention, the R 1 The aldehyde and R 2 The molar ratio of the ketone is preferably (0.8-1.2):1, more preferably 1:1. 1 The aldehyde and R 2The molar ratio of the ketone is limited to the above range, so that the two can react fully.

[0048] In the present invention, the first solvent is preferably an alcohol solvent, more preferably methanol.

[0049] In the present invention, the R 1 The volume ratio of the amount of the aldehyde to the first solvent is preferably 20 mmol: (10-30) mL, more preferably 20 mmol: 20 mL. 1 The volume ratio of the amount of the aldehyde substance to the first solvent is limited to the above range, so that the raw material can be fully dissolved.

[0050] In the present invention, the alkali solution is preferably a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution; the mass concentration of the alkali solution is preferably 10-30%, more preferably 20%.

[0051] In the present invention, the R 1 The aldehyde and R 2 The mixture of ketone, the first solvent and the alkali solution is preferably: 1 The aldehyde and R 2 The ketone is added to the first solvent, and then the alkali solution is added dropwise.

[0052] The present invention has no particular limitation on the amount of the alkali solution added, as long as the amount of the alkali solution added is sufficient to prevent the flocculent precipitate in the mixed system from changing.

[0053] In the present invention, the temperature of the condensation reaction is preferably 20-30°C, more preferably 25°C; the time of the condensation reaction is preferably 8-16h, more preferably 12h. The present invention limits the temperature and time of the condensation reaction to the above ranges, so that the condensation reaction can be fully carried out.

[0054] After the condensation reaction is completed, the present invention preferably sequentially adjusts the pH value of the product of the condensation reaction, filters, washes and dries it to obtain an intermediate product 1.

[0055] The present invention preferably adds dilute hydrochloric acid to adjust the pH value. The present invention has no special restrictions on the concentration and amount of the dilute hydrochloric acid, as long as the pH value of the system is adjusted to neutral.

[0056] The present invention has no special limitation on the filtering operation, and any filtering technical solution well known to those skilled in the art may be used.

[0057] In the present invention, the washing is preferably water washing. The present invention has no particular limitation on the amount of water used and the number of washing times during the water washing, and it is sufficient to wash away impurities such as unreacted raw materials and solvents.

[0058] The present invention has no particular limitation on the drying operation, as long as the moisture is sufficiently removed.

[0059] In the present invention, the structure of the intermediate product 1 is

[0060] After obtaining the intermediate product 1, the present invention mixes the intermediate product 1 with nitromethane, diethylamine and a second solvent and performs an addition reaction to obtain the intermediate product 2.

[0061] In the present invention, the ratio of the amount of the intermediate product 1, nitromethane and diethylamine is preferably 15: (200-250): (200-250), more preferably 15: 225: 225. In the present invention, the diethylamine provides an alkaline environment. The present invention limits the ratio of the amount of the intermediate product 1, nitromethane and diethylamine to the above range, so that the raw materials can react fully, and the reaction has a suitable alkaline environment, which is more conducive to the reaction.

[0062] In the present invention, the second solvent is preferably an alcohol solvent, more preferably methanol or ethanol.

[0063] In the present invention, the ratio of the amount of the intermediate product 1 to the volume of the second solvent is preferably 15 mmol: (10-30) mL, more preferably 15 mmol: 20 mL. The present invention limits the ratio of the amount of the intermediate product 1 to the volume of the second solvent within the above range, so that the raw materials can be fully dissolved.

[0064] In the present invention, the mixing of the intermediate product 1 with nitromethane, diethylamine and the second solvent is preferably as follows: the intermediate product 1 is mixed with the second solvent, and then nitromethane and diethylamine are added in sequence.

[0065] In the present invention, the temperature of the addition reaction is preferably 80-90°C, more preferably 85°C; the time of the addition reaction is preferably 12-36h, more preferably 24h. The present invention limits the temperature and time of the addition reaction within the above ranges, so that the addition reaction can be fully carried out.

[0066] After the addition reaction is completed, the present invention preferably spin-drys the product of the addition reaction, extracts to obtain an organic phase, dries and performs silica gel column chromatography to obtain an intermediate product 2.

[0067] In the present invention, the spin drying is preferably performed under reduced pressure; the spin drying temperature is preferably 50-60° C., more preferably 55° C. The present invention has no particular limitation on the spin drying time and pressure, as long as the solvent can be fully removed.

[0068] The present invention preferably uses dichloromethane and deionized water for extraction. The present invention has no special limitation on other operations of the extraction, and the organic phase can be obtained by using extraction technical solutions well known to those skilled in the art.

[0069] In the present invention, anhydrous sodium sulfate is preferably added to the organic phase for drying. The present invention has no particular limitation on the amount of anhydrous sodium sulfate used, as long as the water in the organic phase can be fully removed.

[0070] In the present invention, the eluent of the silica gel column chromatography is preferably a mixture of dichloromethane and petroleum ether in a volume ratio of 1:1; the developing solvent of the silica gel column chromatography is preferably a mixture of dichloromethane and petroleum ether in a volume ratio of 1:1. The present invention has no special restrictions on other operations of the silica gel column chromatography, and conventional silica gel column chromatography operations can be used.

[0071] In the present invention, the structure of the intermediate product 2 is

[0072] After obtaining the intermediate product 2, the present invention mixes the intermediate product 2 with ammonium acetate and a third solvent and then performs a Hofmann rearrangement reaction to obtain the intermediate product 3.

[0073] In the present invention, the molar ratio of the intermediate product 2 to ammonium acetate is preferably 8: (100-150), more preferably 8: 120. The present invention limits the molar ratio of the intermediate product 2 to ammonium acetate within the above range, so that the raw materials can be fully reacted.

[0074] In the present invention, the third solvent is preferably n-butanol.

[0075] In the present invention, the volume ratio of the amount of the intermediate product 2 to the third solvent is preferably 8 mmol: (10-30) mL, more preferably 8 mmol: 20 mL. The present invention limits the volume ratio of the amount of the intermediate product 2 to the third solvent within the above range, so that the raw materials can be fully dissolved.

[0076] The present invention has no special limitation on the operation of mixing the intermediate product 2 with ammonium acetate and the third solvent. The components can be uniformly mixed using a material mixing technical solution well known to those skilled in the art.

[0077] In the present invention, the temperature of the Hofmann rearrangement reaction is preferably 100-120°C, more preferably 110-115°C; the time of the Hofmann rearrangement reaction is preferably 12-36h, more preferably 24h. The present invention limits the temperature and time of the Hofmann rearrangement reaction to the above ranges, so that the reaction can proceed fully.

[0078] After the Hofmann rearrangement reaction is completed, the present invention preferably sequentially performs reduced pressure distillation, cooling, filtering, washing and drying on the product of the Hofmann rearrangement reaction to obtain an intermediate product 3.

[0079] The present invention has no special limitation on the operation of the vacuum distillation, and the solvent can be fully removed by using the vacuum distillation technical scheme well known to those skilled in the art.

[0080] The present invention has no special limitation on the cooling operation, and cooling to room temperature may be performed using cooling technical solutions well known to those skilled in the art.

[0081] In the present invention, the filtration is preferably suction filtration. The present invention has no special limitation on the operation of the suction filtration, and the solid-liquid separation can be carried out by using the suction filtration technical solution well known to those skilled in the art.

[0082] In the present invention, the solvent for washing is preferably cold ethanol; the temperature of the cold ethanol is preferably 0° C. The present invention has no particular limitation on the amount of cold ethanol used for washing and the number of washing times, and it is sufficient to remove impurities such as unreacted raw materials.

[0083] The present invention has no particular limitation on the drying temperature and time, and the product can be fully dried using a drying technical solution well known to those skilled in the art.

[0084] In the present invention, the structure of the intermediate product 3 is

[0085] After obtaining the intermediate product 3, the present invention mixes the intermediate product 3 with a chloro complex of platinum, a catalyst and a fourth solvent and then performs a coordination reaction to obtain a platinum-azapyrrolidone complex.

[0086] In the present invention, the structural formula of the platinum chloride complex is

[0087] In the present invention, the molar ratio of the intermediate product 3 to the chloro complex of platinum is preferably (1-3): 1, more preferably 2: 1. The present invention limits the molar ratio of the intermediate product 3 to the chloro complex of platinum to the above range, so that the raw materials can react fully.

[0088] In the present invention, the catalyst preferably includes sodium carbonate or potassium carbonate.

[0089] In the present invention, the molar ratio of the platinum chloride complex to the catalyst is preferably 1: (2-4), more preferably 1: 3. The present invention limits the molar ratio of the platinum chloride complex to the catalyst to the above range, so that the reaction can proceed sufficiently.

[0090] In the present invention, the fourth solvent is preferably ethylene glycol ethyl ether.

[0091] In the present invention, the volume ratio of the amount of the intermediate product 3 to the fourth solvent is preferably 1.6 mmol: (10-30) mL, more preferably 1.6 mmol: 20 mL. The present invention limits the volume ratio of the amount of the intermediate product 3 to the fourth solvent within the above range, so that the raw material can be fully solventized.

[0092] The present invention has no special limitation on the mixing operation of the intermediate product 3 with the chloro complex of platinum, the catalyst and the fourth solvent. The raw materials can be uniformly mixed using a material mixing technical scheme well known to those skilled in the art.

[0093] In the present invention, the temperature of the coordination reaction is preferably 100-120°C, more preferably 110°C; the time of the coordination reaction is preferably 3-5h, more preferably 4h; the coordination reaction is preferably carried out under a nitrogen atmosphere. The present invention limits the temperature and time of the coordination reaction to the above ranges, so that the reaction can be fully carried out.

[0094] After the coordination reaction is completed, the present invention preferably spin-drys the product of the coordination reaction, extracts to obtain an organic phase, dries and performs silica gel column chromatography to obtain a platinum-coordinated nitrogen-pyrrolidone complex.

[0095] In the present invention, the spin drying is preferably carried out under reduced pressure. The present invention has no particular limitation on the temperature, time and pressure of the spin drying, as long as the solvent can be fully removed.

[0096] The present invention preferably uses dichloromethane and deionized water for extraction. The present invention has no special limitation on other operations of the extraction, and the organic phase can be obtained by using extraction technical solutions well known to those skilled in the art.

[0097] In the present invention, anhydrous sodium sulfate is preferably added to the organic phase for drying. The present invention has no particular limitation on the amount of anhydrous sodium sulfate used, as long as the water in the organic phase can be fully removed.

[0098] In the present invention, the eluent of the silica gel column chromatography is preferably a mixture of dichloromethane and petroleum ether in a volume ratio of 5:1; the developing agent is preferably a mixture of dichloromethane and petroleum ether in a volume ratio of 21:1. The present invention has no special limitation on other operations of the silica gel column chromatography, and conventional silica gel column chromatography operations can be used.

[0099] The process flow chart for preparing the platinum-coordinated nitrogen-pyrrolidone complex of the present invention is preferably as follows: Figure 1 As shown. Compound 1 (R 1 Aldehyde) and compound 2 (R 2The product is then reacted with nitromethane to obtain compound 4 (intermediate product 2), which is then reacted with a chloro complex of platinum to obtain compound 6 (platinum-complexed nitrogen-pyrrolidone complex).

[0100] The preparation method and parameters of the present invention can ensure that the product has good purity and yield.

[0101] The present invention also provides the use of the platinum-azapyrrolidone complex described in the above technical solution or the platinum-azapyrrolidone complex prepared according to the preparation method described in the above technical solution in preparing photodynamic therapy or sonodynamic therapy drugs.

[0102] The present invention has no special limitation on the operation of the application, and the technical solutions of the application well known to those skilled in the art may be adopted.

[0103] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0104] Example 1

[0105] A platinum-coordinated nitrogen-pyrrolidone complex (PoDipy) having the structural formula:

[0106]

[0107] The preparation method of the platinum-azapyrrolidone complex is as follows:

[0108] (1) Under nitrogen protection, potassium tetrachloroplatinate (2 mmol) was dissolved in a mixed solution of deionized water and ethylene glycol ether (the volume ratio of deionized water to ethylene glycol ether was 1:3), and 2-phenylpyridine (4.4 mmol) was added dropwise to the reaction solution under reflux stirring at 80°C, and the oil bath stirring was continued for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then filtered, the filter cake was washed three times with cold water, and three times with cold ethanol, and the filter cake was placed in a vacuum drying oven for drying to obtain a crude product of compound A (yellow-green solid), i.e., the chloro complex of platinum, which was directly used in subsequent reactions;

[0109] (2) Under stirring at room temperature, 4-diphenylaminobenzaldehyde (20 mmol, compound B) and acetylnaphthalene (20 mmol, compound C) were added to 20 mL of methanol to dissolve them (the molar ratio of 4-diphenylaminobenzaldehyde to acetylnaphthalene was 1:1, and the volume ratio of the molar ratio of 4-diphenylaminobenzaldehyde to methanol was 20 mmol:20 mL), and then a 20 wt% NaOH aqueous solution was added dropwise. When the flocculent precipitate no longer changed, the addition of the NaOH aqueous solution was stopped, and stirring was continued at room temperature for 12 h. After the reaction was completed, the pH of the reaction solution was adjusted to neutral with a dilute hydrochloric acid solution, the solvent was filtered out, the product was washed with water and then dried to obtain an orange-yellow oily compound D, i.e., intermediate product 1, with a yield of 85%;

[0110] (3) Nitromethane (225 mmol) and diethylamine (225 mmol) were added to 20 mL of ethanol containing intermediate product 1 (15 mmol) at 85° C. under reflux stirring (the molar ratio of intermediate product 1, nitromethane and diethylamine was 15:225:225, and the volume ratio of the molar ratio of intermediate product 1 to ethanol was 15 mmol:20 mL), and reflux stirring was continued at 85° C. for 24 h. After the reaction was completed, ethanol was dried under reduced pressure at 55° C., extracted with dichloromethane and deionized water, and the organic phase was collected. After the organic phase was dried over anhydrous sodium sulfate, it was further purified by silica gel column chromatography (developing solvent was a mixture of dichloromethane and petroleum ether in a volume ratio of 1:1, and eluent was a mixture of dichloromethane and petroleum ether in a volume ratio of 1:1) to obtain a colorless oil compound E, i.e., intermediate product 2, with a yield of 55%;

[0111] (4) The intermediate product 2 (8 mmol) and ammonium acetate (120 mmol) were dissolved in 20 mL of n-butanol (the molar ratio of the intermediate product 2 and ammonium acetate was 8:120, and the volume ratio of the molar ratio of the intermediate product 2 and n-butanol was 8 mmol:20 mL), the reaction temperature was set to 115°C, and refluxed with stirring for 24 h. After the reaction was completed, the n-butanol was removed by vacuum distillation, and the mixture was cooled to room temperature and filtered. The filter cake was washed with 0°C cold ethanol and dried in a vacuum drying oven to obtain a crude product (dark solid) containing compound F, i.e., the intermediate product 3, which was directly used in the next step of the reaction;

[0112] (5) Under nitrogen protection, 20 mL of ethylene glycol ether was added to a reaction bottle containing intermediate product 3 (1.6 mmol), platinum chloride complex (0.8 mmol) and sodium carbonate (2.4 mmol) (the molar ratio of intermediate product 3 to platinum chloride complex was 2:1, the molar ratio of platinum chloride complex to sodium carbonate was 1:3, and the volume ratio of the amount of intermediate product 3 to ethylene glycol ether was 1.6 mmol:20 mL). The oil bath temperature was set to 110° C. and the reaction was stirred for 4 h. After the reaction was completed, the solvent was dried under reduced pressure, extracted with dichloromethane and deionized water, and the organic phase was collected. After the organic phase was dried with anhydrous sodium sulfate, it was further purified by silica gel column chromatography (the developing solvent was a mixture of dichloromethane and petroleum ether in a volume ratio of 21:1, and the eluent was a mixture of dichloromethane and petroleum ether in a volume ratio of 5:1) to obtain PoDipy (dark solid, yield: 46%).

[0113] The preparation process of the platinum-coated nitrogen-pyrrolidone complex in Example 1 is preferably as follows: Figure 2 shown.

[0114] The hydrogen spectrum of compound D in Example 1 is: 1 H NMR (400 MHz, CDCl 3 )δ8.32-8.29(m,1H),8.00(d,J=8.0Hz,1H),7.94-7.92(m,1H),7.75(dd,J=7.1,1.0Hz,1H),7.59-7.54(m,3H ), 7.53 (d, J = 4.2Hz, 1H), 7.43 (d, J = 8.8Hz, 2H), 7.36-7.29 (m, 4H), 7.21-7.09 (m, 7H), 7.02 (d, J = 8.7Hz, 2H).

[0115] The hydrogen spectrum of compound E in Example 1 is: 1 H NMR (400 MHz, DMSO-d 6 )δ8.19-8.13(m,2H),8.01(d,J=7.5Hz,2H),7.62-7.53(m,3H),7.29-7.24(m,6H),7.02(t,J=7.5Hz,2H),6.91-6.85(m ,6H), 5.03(dd,J=13.0,6.1Hz,1H), 4.90(dd,J=12.8,9.4Hz,1H), 4.05(dt,J=15.4,8.0Hz,1H), 3.59(d,J=7.4Hz,2H).

[0116] The mass spectrum of the platinum-coordinated nitrogen-pyrrolidone complex prepared in Example 1 is as follows: Figure 3 As shown. Figure 3 It can be seen that the relative molecular mass (Mr) = 1232.39, MALDI-TOF-MS m / z: 1232.006 [M] + .

[0117] The H NMR spectrum of the platinum-coated nitrogen-pyrrolidone complex prepared in Example 1 is as follows Figure 4 As shown. Figure 4 It can be seen that 1 H NMR (400 MHz, CDCl 3 )δ8.86(d,J=8.5Hz,1H),8.81(d,J=8.5Hz,1H),8.55(d,J=7.0Hz,1H),8.51(d,J=7.0Hz,4H),8.09(d,J=5.4Hz,1H),8 .03(dd,J=8.6Hz,4.7Hz,4H),7.88(d,J=8.1Hz,1H),7.80(d,J=8.0Hz,2H),7.76-7.66(m,4H),7.58(t,J=7.5Hz,1H),7 .53(t,J=7.5Hz,1H),7.43(t,J=7.6Hz,1H),7.39-7.35(m,3H),7.24-7.20(m,8H),7.14-7.07(m,13H),7.04-6.97(m, 5H), 6.92 (d, J = 7.5Hz, 1H), 6.86 (d, J = 7.4Hz, 1H), 6.40 (t, J = 7.3Hz, 1H), 5.96 (t, J = 7.3Hz, 1H), 5.53 (t, J = 6.2Hz, 1H).

[0118] The UV-visible absorption spectrum of the platinum-coordinated nitrogen-pyrrolidone complex prepared in Example 1 was tested. The results are as follows: Figure 5 As shown, the test concentration is 10 μmol / L and the test solvent is tetrahydrofuran. Figure 5 It can be seen that the complex shows strong absorption in the ultraviolet region of 400-500nm and in the near-infrared region of 600-800nm. In particular, the complex can be excited by near-infrared light, which greatly reduces the damage of the excitation light source to the cells during cell imaging experiments.

[0119] The platinum-coated azopyrrolidone complex prepared in Example 1 was dissolved in THF, and the generation of singlet oxygen was confirmed by using the active oxygen indicator DPBF. 2 ) for different irradiation times, and the changes in the DPBF absorption peaks at different irradiation times (0min, 1min, 2min, 3min, 4min, 5min, 6min) were recorded using UV-visible spectroscopy. The results are shown in Figure 6As shown. Figure 6 As can be seen in the figure, with the extension of irradiation time, the indicator DPBF is consumed, proving the generation of reactive oxygen species.

[0120] In summary, the platinum-azapyrrolidone complex provided by the present invention can simultaneously have photodynamic therapy effects and sonodynamic therapy effects.

[0121] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A platinum-azapyrrolidone complex, the chemical structure of which is shown in Formula I: In the formula I, R1 and R2 are independently One of the following; R3 is H or a linear, branched or cyclic alkyl alkane having 1 to 16 carbon atoms.

2. The method for preparing the platinum-azapyrrolidone complex according to claim 1, comprising the following steps: (1) mixing the aldehyde of R1 with the ketone of R2, a first solvent and an alkali solution and performing a condensation reaction to obtain an intermediate product 1; (2) mixing the intermediate product 1 obtained in step (1) with nitromethane, diethylamine and a second solvent, and performing an addition reaction to obtain an intermediate product 2; (3) mixing the intermediate product 2 obtained in step (2) with ammonium acetate and a third solvent and performing a Hofmann rearrangement reaction to obtain an intermediate product 3; (4) The intermediate product 3 obtained in step (3) is mixed with a chloro complex of platinum, a catalyst and a fourth solvent, and then subjected to coordination reaction to obtain a platinum-coordinated nitrogen-pyrrolidone complex.

3. The preparation method according to claim 2, characterized in that: In the step (1), the molar ratio of the aldehyde of R1 to the ketone of R2 is (0.8-1.2):

1.

4. The preparation method according to claim 2, characterized in that: The temperature of the condensation reaction in step (1) is 20 to 30° C., and the time of the condensation reaction is 8 to 16 hours.

5. The preparation method according to claim 2, characterized in that: In the step (2), the molar ratio of the intermediate product 1, nitromethane and diethylamine is 15:(200-250):(200-250).

6. The preparation method according to claim 2, characterized in that: The temperature of the addition reaction in step (2) is 80 to 90° C., and the time of the addition reaction is 12 to 36 hours.

7. The preparation method according to claim 2, characterized in that: In the step (3), the molar ratio of the intermediate product 2 to ammonium acetate is 8:(100-150).

8. The preparation method according to claim 2, characterized in that: In the step (4), the molar ratio of the intermediate product 3 to the chloro complex of platinum is (1-3):

1.

9. The preparation method according to claim 2, characterized in that: The temperature of the coordination reaction in step (4) is 100-120° C., and the time of the coordination reaction is 3-5 hours.

10. Use of the platinum-azapyrrolidone complex according to claim 1 or the platinum-azapyrrolidone complex prepared by the preparation method according to any one of claims 2 to 9 in the preparation of photodynamic therapy or sonodynamic therapy drugs.

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