Carbon monoxide prodrug and its preparation method and application

Abstract

The present invention discloses a carbon monoxide prodrug, its preparation method, and application. The carbon monoxide prodrug is obtained by coupling one or more oxalate structural fragments with a photosensitive CO prodrug. This type of organic small molecule can specifically release CO in response to hydrogen peroxide. Specifically, the oxalate fragment in the carbon monoxide prodrug reacts with hydrogen peroxide, causing proton transfer within the molecule. The resulting intermediate then undergoes a [2+3] cycloaddition reaction with hydrogen peroxide to form an epoxy bridge, which then releases carbon monoxide through electron transfer. Furthermore, the carbon monoxide prodrug provided by the present invention can achieve controlled release of CO in the absence of light and heavy metals, with a CO release efficiency of up to 100%. It has excellent application prospects in the preparation of drugs for CO delivery.

Description

Technical Field

[0001] The present invention relates to the fields of chemical synthesis and biomedicine, and in particular to a carbon monoxide prodrug and a preparation method and application thereof. Background Art

[0002] Carbon monoxide (CO) has long been recognized as a toxic gas that can bind to heme in the hemoglobin structure with an affinity 200 times that of oxygen, thereby blocking the oxygen supply function of hemoglobin. Endogenous CO is generated by heme through the catalysis of heme oxygenase. Over the past two or three decades, CO has been proven to be one of the most important gas messenger molecules in the body. Like nitric oxide (NO) and hydrogen sulfide (H2S), CO plays an important physiological regulatory role in mammals. It is reported that CO has shown good therapeutic effects in antibacterial, anti-inflammatory, anti-tumor, cardiovascular and cerebrovascular diseases, and organ transplantation and preservation. These findings have given CO broad clinical application prospects. However, there are major drawbacks in the use of gas as a clinical method for delivering CO: (1) Administration in the form of inhalation can only be performed in hospitals, which is inconvenient for patients to carry. (2) The CO gas dose is difficult to control, and the administration method is heavily dependent on whether the patient has healthy lung function. (3) The release of CO gas is uncontrollable, and the resulting off-target effects cannot be underestimated.

[0003] Early research on carbon monoxide prodrugs focused on transition metal carbonyl complexes, as shown below:

[0004]

[0005] This type of photoactivated organic small molecule carbon monoxide prodrug has developed rapidly in recent years, but it requires an external light source to provide light of the corresponding wavelength to enable the organic small molecule carbon monoxide prodrug to reach an excited state and then release CO.

[0006] Patent CN113559071B discloses a CO targeted delivery system and its construction method and application, as follows:

[0007]

[0008] This CO-targeted delivery system releases CO based on chemical energy-activated CO release. Specifically, the reaction of the oxalate polymer with hydrogen peroxide generates an excited high-energy intermediate, which, through energy transfer, activates the photosensitive CO prodrug to release CO. While this technology achieves targeted CO delivery in vivo, it still has some inherent drawbacks: 1) The system involves two components: the oxalate polymer and the CO prodrug, requiring specialized nanodelivery technology. During nanoparticle preparation, the ratio of the two components can vary significantly between batches. Furthermore, during the synthesis of the oxalate polymer, the degree of polymerization can vary significantly between batches, making batch-to-batch quality control a significant challenge. 2) Because the high-energy intermediate formed by the reaction of oxalate with H₂O₂ has an extremely short half-life (~ms), a large portion of it will directly degrade into CO₂, unable to effectively transfer energy to the CO prodrug. Therefore, a significant excess of the oxalate polymer is required to ensure efficient CO release. Even with this excess oxalate, the amount of oxalate polymer used must be significantly increased to ensure efficient CO release. The CO release efficiency is only about 60% (the maximum release amount is about 300 ppm), and the complete release of CO cannot be achieved.

[0009] Therefore, the development of new delivery forms of organic small molecule carbon monoxide prodrugs is a key issue that needs to be solved in the clinical application of carbon monoxide. Summary of the Invention

[0010] To address the above-mentioned problems, the present invention provides a carbon monoxide prodrug, a preparation method, and an application thereof. This type of carbon monoxide prodrug is obtained by coupling one or more oxalate structural fragments with a photosensitive CO prodrug. It has H2O2 response specificity and can achieve controlled release of CO in the absence of light and heavy metals. The CO release efficiency can reach 100%, and it has good application prospects in the preparation of drugs for CO delivery.

[0011] The present invention provides the following technical solutions:

[0012] The first aspect of the present invention provides a carbon monoxide prodrug having the general structural formula shown in Formula (I) to Formula (III):

[0013]

[0014] wherein R1, R2, R3, R4, R′1, R′2, R′4, R″1, R″2, R″3, and R″4 are independently selected from one of hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, acyl, C1-C10 alkyl, and C1-C10 alkoxy;

[0015] R5, R'5, R"5 are independently selected from C1-C10 alkyl, C3-C10 cycloalkyl, propargyl, butyl alkynyl, allyl, phenyl, benzyl, heteroaryl, saturated or unsaturated 7-11 membered cyclyl, One of the following;

[0016] R6 and R′6 are phenyl groups;

[0017] R″7 is hydrogen or

[0018] The above phenyl group is unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, n is any integer from 1 to 20,

[0019] X and Y are each selected from one of O, N, S, and N-CH3;

[0020] Z is selected from one of O, N, S, and -CH2-O-.

[0021] Furthermore, R1, R2, R3, R4, R'1, R'2, R'4, R"1, R"2, R"3, R"4 are independently selected from one of hydrogen and halogen; R5, R'5, R"5 are independently selected from methyl, ethyl, propargyl, cyclohexyl, allyl, Alkynyl, benzyl, methoxy substituted phenyl, halogen substituted phenyl, C1-C10 alkyl substituted phenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, cyano substituted phenyl, Substituted phenyl, Substituted phenyl, Substituted phenyl, n is any integer from 1 to 20.

[0022] Furthermore, the carbon monoxide prodrug is a compound shown in the following structure:

[0023]

[0024]

[0025] The second aspect of the present invention provides a method for preparing a carbon monoxide prodrug, wherein the carbon monoxide prodrug includes but is not limited to the compound shown in the above structure, which is prepared by method 1 or method 2, wherein:

[0026] The method 1 comprises the following steps: subjecting the compound represented by formula (IV) and the compound represented by formula (V) to a reflux reaction in the presence of a catalyst and a first solvent to obtain the carbon monoxide prodrug;

[0027] The method 2 comprises the following steps: reacting the compound represented by formula (VI) with the compound represented by formula (V) in the presence of an acid-binding agent and a second solvent to obtain the carbon monoxide prodrug;

[0028]

[0029] Wherein, X is O, S, N-CH3;

[0030] R5 is selected from methyl, ethyl, propargyl, cyclohexyl, allyl, Alkynyl, benzyl, methoxy substituted phenyl, halogen substituted phenyl, C1-C10 alkyl substituted phenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, cyano substituted phenyl, Substituted phenyl, Substituted phenyl, Substituted phenyl, n is any integer from 1 to 20;

[0031] When Q is phenyl, R″′1, R″′2, and R″′4 are hydrogen, and R″′3 is hydroxyl;

[0032] When Q is a hydroxy-substituted phenyl group, a 2-hydroxyethyl-substituted phenyl group or a 2-mercaptoethylene-substituted phenyl group, R'1, R'2, R'3 and R'4 are hydrogen.

[0033] Furthermore, in method 1: the catalyst is preferably 4-dimethylaminopyridine; the first solvent is selected from one or more of benzene, toluene, and xylene; the temperature of the reflux reaction is preferably 100-120° C., and the time is preferably 0.5-4 h.

[0034] Furthermore, in method 2: the acid binding agent is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, and potassium carbonate; the second solvent is selected from one or more of dichloromethane, tetrahydrofuran, and acetonitrile; the reaction temperature is preferably -20 to 25°C, and the reaction time is preferably 10 min to 3 h.

[0035] The third aspect of the present invention provides a carbon monoxide prodrug micelle, which is obtained by reacting the carbon monoxide prodrug described in the first aspect with an azide compound in the presence of a first solvent; or

[0036] Obtained by reacting the carbon monoxide prodrug described in the first aspect with a main chain compound in the presence of an initiator and a second solvent; or,

[0037] The method is prepared by dripping a mixed solution comprising the carbon monoxide prodrug described in the first aspect, the nanomaterial and the third solvent into deionized water under ultrasound;

[0038] Wherein, the structure of the azide compound is as follows:

[0039] n is any integer from 4 to 60;

[0040] The structure of the main chain compound is as follows:

[0041] m is 10-200;

[0042] The nanomaterial is one or more of PEG-PCL, PCL-PEG-PCL, PEG-PLGA, and PEG-DSPE.

[0043] Furthermore, the first solvent is a mixed solvent of an organic solvent and water, and the organic solvent includes but is not limited to acetonitrile and tert-butanol.

[0044] Furthermore, the carbon monoxide prodrug is obtained by reacting with an azide compound in the presence of a first solvent and a catalyst; the catalyst is copper sulfate and sodium ascorbate.

[0045] Furthermore, the initiator is azobisisobutyronitrile, and the second solvent is dimethyl sulfoxide.

[0046] Furthermore, the third solvent is selected from one or more of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, ethanol, and methanol.

[0047] The fourth aspect of the present invention provides a carbon monoxide delivery drug, comprising the carbon monoxide prodrug described in the first aspect and / or the carbon monoxide prodrug micelles described in the second aspect.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] 1. The present invention provides a carbon monoxide prodrug, which is an organic small molecule obtained by coupling one or more oxalate structural fragments with a photosensitive CO prodrug. The principle of CO release is different from the principle of CO release by the CO targeted delivery system described in the background art, and does not involve chemical energy transfer. Specifically, the oxalate fragment in the carbon monoxide prodrug organic small molecule can react with hydrogen peroxide to cause proton transfer within the molecule. The obtained intermediate further undergoes a [2+3] cycloaddition reaction with hydrogen peroxide to form an epoxy bridge, and then releases carbon monoxide through electron transfer. Because the carbon monoxide prodrug can specifically respond to hydrogen peroxide to release CO, controlled release of CO can be achieved under light and heavy metal-free conditions, solving the limitations of current photoactivated carbon monoxide prodrugs that require external light irradiation and the existence of heavy metal toxicity. In addition, the carbon monoxide prodrug is a small molecule with a precise structure, and the ratio of oxalate structural fragment to 3-hydroxyflavone is 1:1 to 1:2. Compared with the CO targeted delivery system composed of oxalate polymer and photosensitive carbon monoxide prodrug, the small molecule carbon monoxide prodrug provided by the present invention is easier to control quality, and the CO release amount is high, which can be close to 100%, and has good application prospects in the preparation of drugs for CO delivery.

[0050] 2. The present invention also provides a carbon monoxide prodrug micelle, which is obtained by reacting a carbon monoxide prodrug small molecule with a molecule containing a polyether chain, to solve the problem of applying water-insoluble carbon monoxide prodrug organic small molecules in a physiological environment, thereby achieving the release of CO targeted to specific disease tissues under physiological conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 : Mechanism diagram of carbon monoxide release from carbon monoxide prodrugs;

[0052] Figure 2 : The UV absorption curve of compound 6-11P solution after adding H2O2;

[0053] Figure 3 : Curve of UV absorption change of compound 6-21P solution after adding H2O2;

[0054] Figure 4 :(a) Detection results of CO release from 15@PEG-PCL and 22@PEG-PCL in response to endogenous H2O2 in 4T1 cells;(b) Quantitative analysis of the corresponding fluorescence in (a);

[0055] Figure 5 : Curves of 4T1 cell activity changing with the concentrations of 15@PEG-PCL and 22@PEG-PCL. DETAILED DESCRIPTION

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. The terms used herein in the specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the relevant listed items. The term "includes" or "comprising" described in the present invention means that in addition to the components described, it may also include or contain other components. The term "includes" or "comprising" described in the present invention may also be replaced by the closed form "for" or "consisting of..."

[0057] The present invention will be further described below with reference to specific embodiments and accompanying drawings so that those skilled in the art can better understand and implement the present invention. However, the embodiments are not intended to limit the present invention.

[0058] The raw materials 1-10 used in the following examples were prepared by the method shown in Reaction Scheme 1 or Reaction Scheme 2, as follows:

[0059]

[0060] The preparation process is as follows:

[0061] Compound A (3.0 mmol) was dissolved in ethanol (100 mL), and a 20% aqueous solution of NaOH (50 mL) was added. After stirring for 30 minutes, compound B (5.0 mmol) was added and the reaction was continued at room temperature with stirring for 12 hours. The reaction was then placed in an ice bath at 0°C, and H2O2 (1.3 mL, 30%) was slowly added dropwise. The reaction was continued for 2 hours. The reaction was monitored by TLC. After completion of the reaction, 1 M dilute hydrochloric acid solution (10 mL) was added at 0°C to acidify the solution. A yellow precipitate was precipitated, which was filtered to obtain a yellow solid. The resulting solid was washed three times with ethanol and dried under vacuum to obtain the target product C.

[0062] Under nitrogen, Lawesson's reagent (3.0 mmol, 0.6 equiv) and compound C (5.0 mmol) were dissolved in toluene (20 mL) and heated to 120°C under reflux for 1 hour, with the color gradually turning red. After completion of the reaction, the solvent was directly evaporated by TLC. The thiolated target product D was purified by column chromatography using petroleum ether:ethyl acetate as the eluent.

[0063]

[0064]

[0065] The preparation process is as follows:

[0066] Compound C (3.0 mmol, 1.0 equiv) and imidazole (2.5 equiv) were dissolved in DMF (100 mg / mL), and TBSCl was added in batches. The reaction was continued for 1 hour after the addition was completed. After TLC detection, the reaction was completed with ethyl acetate (50 mL × 3) and saturated NaCl solution (50 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The product was purified by flash column chromatography using (petroleum ether: ethyl acetate = 30:1) as eluent to obtain the target product E.

[0067] Under nitrogen, Lawesson's reagent (3.0 mmol, 0.6 equiv) and compound E (5.0 mmol) were dissolved in toluene (20 mL) and heated to 120°C under reflux for 2 hours, gradually turning red. After completion of the reaction, the solvent was directly evaporated by TLC. The thiolated target product F was purified by column chromatography using a (petroleum ether:ethyl acetate) system as the eluent.

[0068] Compound F (3.0 mmol, 1.0 equiv) was dissolved in methanol and iodine (0.45 mmol, 0.15 equiv) was added. The mixture was stirred at room temperature for 2 hours to precipitate a red solid. The product was filtered and washed with methanol and dried to obtain the target product G.

[0069]

[0070] Raw material 1 was synthesized according to the method shown in reaction scheme 1 with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ8.71(s,1H),8.57(d,J=8.1Hz,1H),8.38(d,J=7.1Hz,2H),7.7 1(t,J=7.4Hz,1H),7.64(d,J=8.3Hz,1H),7.59–7.51(m,3H),7.46(t,J=7.5Hz,1H); 13 C NMR(150MHz, CDCl3)δ188.2,150.5,146.3,141.4,133.3,131.0,130.9,128.9,128.8,128.1,125.9,118.5; HRMS(ESI)calcd C 15 H 10 O2S[M+H] + :255.0474,found:255.0484.

[0071]

[0072] Raw material 2 was synthesized according to the method shown in reaction scheme 1 with a yield of 75%.1 H NMR (500MHz, CDCl3) δ7.71–7.57(m,1H),7.41–7.37(m,2H),7.32–7.18(m,2H); 13 C NMR (125MHz, DMSO) δ198.9,174.8,137.4,135.8,134.5,131.2,130.8,130.6,130.3,128.7,128.7,127.6,127.1.

[0073]

[0074] Raw material 3 was synthesized according to the method shown in Reaction Scheme 1 with a yield of 78%. 1 H NMR (500MHz, CDCl3) δ7.75–7.67(m,2H),7.57–7.48(m,3H),7.42(td,J=15. 0,3.0Hz,1H),7.12(dd,J=14.5,3.0Hz,1H),6.79–6.67(m,2H),3.36(s,3H); 13 C NMR (125MHz, CDCl3) δ178.3,154.2,140.3,138.8,135.7,132.9,129.5,129.3,128.0,127.7,127.0,124.4,117.1,40.3.

[0075]

[0076] Raw material 4 was synthesized according to the method shown in Reaction Scheme 1 with a yield of 50%. 1 H NMR (300MHz, DMSO) δ11.18(s,1H),8.78(s,1H),8.35–8.18(m,3H),7.57(d,J=7.0Hz,3H),7.10–7.01(m,2H).

[0077]

[0078] Raw material 5 was synthesized according to the method shown in Reaction Scheme 1 with a yield of 30%. 1H NMR (400MHz, CDCl3) δ8.74(s,1H),8.62–8.56(m,1H),8.40(d,J=9.1Hz,1H),8.28(d,J=8.6Hz,1H),7.75–7.68( m,1H),7.64(d,J=8.1Hz,1H),7.47(t,J=8.0Hz,1H),7.42(d,J=8.6Hz,1H),7.08(d,J=9.1Hz,1H),3.92(s,2H).

[0079]

[0080] Raw material 6 was synthesized according to the method shown in Reaction Scheme 2 with a yield of 60%. 1 H NMR (600MHz, DMSO-d6) δ8.91(s,1H),8.42–8.27(m,3H),7.84(s,2H),7.58–7.47(m,3H),5.51(s,1H),4.59(s,2H); 13 CNMR(150MHz,DMSO-d6)δ187.1,149.8,146.3,145.9,141.7,133.8,128.6,128.5,127.7,127.5,126.6,126.3,119.0,62.5.HRMS(ESI)calcd C 16 H 12 O3S[M+H] + :285.0580,found:285.0576.

[0081]

[0082] The raw material 7 was synthesized according to the method shown in Reaction Scheme 1 with a yield of 20%. 1 H NMR(600MHz, CDCl3)δ8.71(s,1H),8.59–8.55(m,1H),8.34(d,J=8.3Hz,2H),7.71(dd,J=11.2,4.1Hz,1H),7.6 3(d,J=8.4Hz,1H),7.50(d,J=8.3Hz,2H),7.47(t,J=7.5Hz,1H),3.81(d,J=7.7Hz,2H),1.83(t,J=7.7Hz,1H); 13C NMR (150MHz, CDCl3) δ188.0,150.4,146.3,144.4,141.1,133.3,129.8,129.2,128.9,128.6,128.1,125.9,118.5,29.0; HRMS(ESI)calcd C 16 H 12 O2S2[M+H] + :301.0351,found:301.0343.

[0083]

[0084] The raw material 8 was synthesized according to the method shown in Reaction Scheme 1 with a yield of 30%. 1 H NMR (600MHz, DMSO) δ8.92(s,1H),8.82(s,1H),8.33(d,J=8.3Hz,2H),8.29(s,1H),8.14(d,J=8.4Hz,1H),7.9 9(d,J=8.4Hz,1H),7.61(t,J=7.4Hz,1H),7.55(d,J=8.3Hz,2H),7.52–7.49(m,1H),4.61(s,2H),3.81(s,1H); 13 C NMR(150MHz,DMSO)δ188.4,146.4(d,J=4.6Hz),144.9,142.1,135.0,131.6,130.4,1 29.3,128.8,128.8,128.2,127.1,126.5,126.3,126.0,114.9,62.5; HRMS(ESI)calcd C 20 H 16 O2S[M+H] + :335.0736,found:335.0741.

[0085]

[0086] The raw material 9 was synthesized according to the method shown in Reaction Scheme 1 with a yield of 15%. 1 H NMR (600MHz, DMSO) δ9.09 (s, 1H), 8.34 (s, 1H), 8.29 (d, J = 8.0Hz, 3H), 7.53 (d, J = 8.1Hz, 2H), 4.59 (s, 2H); 13C NMR (150MHz, DMSO) δ185.5,147.0,146.6,145.5,141.9,137.8,129.4,129.2,128.5,128.3,126.6,118.6,113.7,62.5; HRMS(ESI)calcd C 16 H 10 Br2O4[M+H] + :426.8998,found:426.9004.

[0087]

[0088] The raw material 10 was synthesized according to the method shown in Reaction Scheme 1 with a yield of 32%. 1 H NMR (600MHz, CDCl3) δ8.72(s,1H),8.57(d,J=8.1Hz,1H),8.36(s,1H),8.31(d,J=7.0Hz,1H),7.7 2(t,J=7.2Hz,1H),7.66(d,J=8.1Hz,1H),7.58–7.51(m,2H),7.47(t,J=7.5Hz,1H),4.84(s,2H); 13 C NMR (150MHz, CDCl3) δ188.3,150.5,146.3,141.6,141.2,133.4,131.3,129.6,129.2,128.9,128.2,128.1,127.1,126.0,118.6,65.3; HRMS(ESI)calcd C 16 H 12 O4[M+H] + :269.0808,found:269.0809.

[0089] The raw material acyl chloride used in the following examples was prepared according to the method shown in Reaction Scheme 3, as follows:

[0090]

[0091] The preparation process is as follows:

[0092] Under nitrogen protection, hydroxyl-containing compound H (3.0 mmol, 1.0 equiv) was added dropwise to oxalyl chloride (5.0 equiv) and the reaction was continued at 50°C for 4 hours. Bubbles continuously emerged during the reaction. After the reaction was completed, the remaining oxalyl chloride was dried under vacuum to obtain the target product I.

[0093] The following examples relate to carbon monoxide prodrugs prepared by Synthesis Method 1 or 2, wherein:

[0094] Synthesis method 1: Under a nitrogen atmosphere, compound 1-3 (1.0 equiv) and 4-dimethylaminopyridine (DMAP) (0.2 equiv) ethyl oxalyl chloride (1.5 equiv) were dissolved in toluene (benzene or xylene), and the mixture was refluxed at 100-120° C. for 0.5-4 hours. The reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction was quenched with water and diluted, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the corresponding target product.

[0095] Synthesis method 2: Under a nitrogen atmosphere, compound 4-10 (1.0 equiv) and triethylamine (or diisopropylethylamine, sodium carbonate, potassium carbonate, etc.) (2.0-5.0 equiv) are dissolved in dichloromethane (or tetrahydrofuran, acetonitrile, etc.), and ethyl oxalyl chloride (1.5-5 equiv) is added dropwise to the reaction at -20°C to 25°C. After the addition, the reaction is continued for 10 minutes to 3 hours, and the reaction is monitored by thin layer chromatography. After the reaction is complete, the reaction is quenched with water and diluted, extracted with dichloromethane, and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography (petroleum ether: dichloromethane = 1:1) is performed for separation and purification to obtain the corresponding target product.

[0096] Example 1

[0097] This example uses Synthesis Method 1 to prepare carbon monoxide prodrug 1P, specifically as follows:

[0098]

[0099] Characterization data of product 1P: 1 H NMR (500MHz, CDCl3) δ7.80–7.74(m,2H),7.53–7.44(m,4H),7.36(d,J=15.0,3.1Hz,1H),7.05(d, J=15.0,3.1Hz,1H),6.88(t,J=14.8,3.1Hz,1H),4.18(q,J=11.8Hz,2H),1.25(t,J=11.8Hz,3H); 13 C NMR (125MHz, CDCl3) δ200.2,160.0,153.6,151.4,150.1,137.3,132.0,131.7,130.9,129.2,128.8,128.5,128.4,125.3,117.6,61.4,14.7.

[0100] Example 2

[0101] This example uses Synthesis Method 1 to prepare carbon monoxide prodrug 1-2P, specifically as follows:

[0102]

[0103] Characterization data of product 1-2P: 1 H NMR (500MHz, CDCl3) δ7.80–7.73(m,2H),7.54–7.44(m,4H),7.36(d,J=15.0,3.1Hz,1H ),7.05(d,J=15.0,3.1Hz,1H),6.88(t,J=14.8,3.1Hz,1H),5.17(s,2H),3.37(s,1H); 13 C NMR (125MHz, CDCl3) δ200.2,160.2,153.6,151.4,150.1,137.3,132.0,131.7,130.9,129.2,128.8,128.5,128.4,125.3,117.6,79.0,75.5,55.7.

[0104] Example 3

[0105] This example uses Synthesis Method 1 to prepare carbon monoxide prodrug 1-3P, specifically as follows:

[0106]

[0107] Characterization data of product 1-3P: 1 H NMR (500MHz, CDCl3) δ7.78–7.75(m,2H),7.50–7.44(m,4H),7.36(d,J=7.5,1.4Hz,1H),7.05(d,J=7.5,1.4Hz,1H),6.88(t, J=7.5,1.4Hz,1H),4.57–4.41(m,1H),1.94(d,J=11.8,5.8Hz,2H),1.68–1.59(m,3H),1.27–1.21(m,2H),1.19–1.10(m,3H); 13 C NMR (125MHz, CDCl3) δ200.2,161.5,153.6,151.4,150.6,137.3,132.0,131. 7,130.9,129.2,128.8,128.5,128.4,125.3,117.6,75.7,30.7,25.9,24.6.

[0108] Example 4

[0109] This example uses Synthesis Method 1 to prepare carbon monoxide prodrug 1-4P, specifically as follows:

[0110]

[0111] Characterization data of product 1-4P: 1 H NMR (500MHz, CDCl3) δ7.79–7.74(m,2H),7.51–7.45(m,4H),7.36(d,J=15.0,3. 2Hz, 1H), 7.05 (d, J=15.0, 3.1Hz, 1H), 6.88 (t, J=14.8, 3.1Hz, 1H), 3.62 (s, 3H); 13 C NMR (125MHz, CDCl3) δ200.2,159.9,153.6,151.4,150.1,137.3,132.0,131.7,130.9,129.2,128.8,128.5,128.4,125.3,117.6,52.1.

[0112] Example 5

[0113] This example uses Synthesis Method 1 to prepare carbon monoxide prodrug 1-5P, specifically as follows:

[0114]

[0115] Characterization data of product 1-5P: 1 H NMR (500MHz, CDCl3) δ7.81–7.73(m,2H),7.53–7.43(m,4H),7.36(d,J=15.0,3.1Hz,1H),7.05(d,J=15.0,3 .1Hz,1H),6.88(t,J=14.8,3.1Hz,1H),6.07–5.89(m,1H),5.38–5.21(m,2H),4.58(d,J=12.4,1.9Hz,2H); 13 C NMR (125MHz, CDCl3) δ200.2,159.9,153.6,151.4,150.1,137.3,133.2,13 2.0,131.7,130.9,129.2,128.8,128.5,128.4,125.3,117.6,117.0,65.5.

[0116] Example 6

[0117] This example uses Synthesis Method 1 to prepare carbon monoxide prodrug 1-6P, specifically as follows:

[0118]

[0119] Characterization data of product 1-6P: 1 H NMR (500MHz, CDCl3) δ7.80–7.75(m,2H),7.51–7.45(m,4H),7.36(d,J=15.0,3.1Hz,1H),7.05(d,J=15.0,3.1Hz,1H),6.88(t,J=14.8 ,3.1Hz,1H),4.39(d,J=16.2Hz,2H),2.35–2.26(m,4H),2.05–1.91(m,2H),1.79–1.62(m,2H),0.61–0.45(m,1H),0.40–0.21(m,2H); 13 C NMR (125MHz, CDCl3) δ175.7,160.8,153.7,151.5,150.1,136.8,132.5,131.8,131 .0,129.3,128.6,128.5,126.5,125.4,117.7,93.9,66.0,30.8,27.0,25.4,16.8.

[0120] Example 7

[0121] This example uses Synthesis Method 1 to prepare carbon monoxide prodrug 2P, specifically as follows:

[0122]

[0123] Characterization data of product 2P: 1 H NMR (500MHz, CDCl3) δ7.73–7.53(m,2H),7.41–7.37(m,4H),7.33–7.15(m,3H),4.18(q,J=11.8Hz,2H),1.25(t,J=11.8Hz,3H); 13 C NMR (125MHz, CDCl3) δ195.2,167.7,160.0,150.1,137.3,135.4,135.0,134.7,131.7,131.4,130.5,128.8,128.6,127.9,127.5,61.4,14.7.

[0124] Example 8

[0125] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 3P, specifically as follows:

[0126]

[0127] Characterization data of product 3P:1 H NMR (500MHz, CDCl3) δ7.75–7.67(m,2H),7.55–7.48(m,3H),7.42(t,J=15.0,3.0Hz,1H),7.12(d,J =14.5,3.0Hz,1H),6.79–6.66(m,2H),4.18(q,J=11.8Hz,2H),3.36(s,3H),1.25(t,J=11.8Hz,3H); 13 C NMR (125MHz, CDCl3) δ174.3,160.0,150.1,146.,143.3,141.0,136.1,133.8,130.3,129.2,128.2,127.7,126.6,124.7,117.0,61.4,40.3,14.7.

[0128] Example 9

[0129] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 4P, specifically as follows:

[0130]

[0131] Characterization data of product 4P: 1 H NMR (300MHz, CDCl3) δ8.35(d,J=8.2Hz,1H),7.94(s,2H),7.53(s,3H),7.10–6.82(m,3H),4.57–4.33(m,2H),1.50–1.34(m,3H); 13 C NMR (125MHz, CDCl3) δ205.0,159.5,158.1,155.7,151.7,147.7,146.7,132.3,130.2,129.3,128.6,127.5,122.0,119.5,107.6,61.5,14.7.

[0132] Example 10

[0133] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 5P, as follows:

[0134]

[0135] Characterization data of product 5P: 1H NMR(300MHz, CDCl3) δ8.58(d,J=8.2Hz,1H),8.10(d,J=8.7Hz,2H),7.86–7.73( m,1H),7.60(d,J=8.1Hz,1H),7.43(d,J=8.8Hz,2H),4.97(s,3H),2.63(s,1H); 13 C NMR (125MHz, CDCl3) δ205,158.6,158.1,154.0,152.9,147.7,146.7,131.2,130.6,128.1,128.0,125.6,125.1,121.1,117.6,79.0,75.5,55.7.

[0136] Example 11

[0137] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6P, specifically as follows:

[0138]

[0139] Characterization data of product 6P: 1 H NMR (600MHz, CDCl3) δ8.72(s,1H),8.64–8.53(m,1H),8.40(d,J=8.5Hz,2H),7.76–7.70(m,1H),7.67–7.63( m,1H),7.59(d,J=8.5Hz,2H),7.51–7.45(m,1H),5.39(s,2H),4.38(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H); 13 C NMR (150MHz, CDCl3) δ188.6,157.8,157.6,150.5,146.4,140.6,137.0,133.5 ,131.5,129.1,128.9,128.1,126.0,118.6,67.9,63.5,14.1; HRMS(ESI)calcd C 20 H 16 O6S[M+Na] + :407.0560,found:407.0564.

[0140] Example 12

[0141] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-2P, as follows:

[0142]

[0143] Characterization data of product 6-2P: 1 H NMR(500MHz, CDCl3)δ7.48(t,J=14.9,3.0Hz,1H),7.36(d,J=15.0,3.1Hz,1H),7.29(s,4H)7.05(d,J=15.0,3.1Hz,1H),6. 88(t,J=14.8,3.1Hz,1H),6.50–6.46(m,1H),6.42–6.38(m,1H),5.13(s,2H),4.39(t,J=2.3Hz,4H),2.01(t,J=2.0Hz,6H); 13 C NMR (125MHz, CDCl3) δ205.0,167.2,160.0,159.5,152.9,147.7,146.7,137.7,137. 1,133.8,131.2,129.6,129.5,128.1,128.0,125.1,124.7,117.6,66.9,62.7,19.1.

[0144] Example 13

[0145] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-3P, as follows:

[0146]

[0147] Characterization data of product 6-3P: 1 H NMR(500MHz, CDCl3)δ7.48(t,J=14.9,3.1Hz,1H),7.36(d,J=15.0,3.1Hz,1H),7.29(s,4H)7.05(d,J=15.0,3.1Hz,1H),6.88(t,J= 14.8,3.1Hz,1H),6.48(t,J=4.0,2.0Hz,2H),6.40(t,J=4.0,2.0Hz,2H),5.13(s,2H),4.38(t,J=2.4Hz,8H),2.01(t,J=2.0Hz,6H); 13 C NMR (125MHz, CDCl3) δ200.2,167.2,160.4,160.0,159.5,153.6,152.0,150.1,137.7,137. 3,136.9,133.4,131.7,129.8,129.0,128.8,128.4,125.3,124.7,117.6,66.9,62.7,19.1.

[0148] Example 14

[0149] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-4P, as follows:

[0150]

[0151] Characterization data of product 6-4P: 1 H NMR (500MHz, CDCl3) δ7.48(t,J=14.9,3.0Hz,1H),7.36(d,J=15.0,3.1Hz,1H),7.29(s,4H),7.05(d,J=15.0,3.1Hz,1H ),6.88(t,J=14.8,3.1Hz,1H),5.13(s,2H),4.35(t,J=10.3Hz,2H),2.42(t,J=10.3,6.0Hz,2H),2.11(t,J=6.0Hz,1H); 1 3CNMR(125MHz,CDCl3)δ205.0,160.0,159.5,152.9,147.7,146.7,137.1,133.8 ,131.2,129.6,129.5,128.1,128.0,125.1,117.6,82.8,68.5,66.9,63.7,21.4.

[0152] Example 15

[0153] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-5P, as follows:

[0154]

[0155] Characterization data of product 6-5P: 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.57(dd,J=8.2,1.4Hz,1H),8.39(d,J=8.4Hz,2H),7.76–7.70(m,1H),7.64(d ,J=8.0Hz,1H),7.58(d,J=8.4Hz,2H),7.48(dd,J=11.1,4.0Hz,1H),7.45–7.36(m,5H),5.38(s,2H),5.33(s,2H); 13CNMR (100MHz, CDCl3) δ188.6,157.6,157.5,150.5,146.4,140.5,136.9,134.2,133.5, 131.5,129.1,129.1,128.9,128.9,128.1,126.0,118.6,68.9,68.0; HRMS(ESI)calcdC 25 H 18 O6S[M+H] + :447.0897,found:447.0900.

[0156] Example 16

[0157] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-6P, as follows:

[0158]

[0159] Characterization data of product 6-6P: 1 H NMR (600MHz, CDCl3) δ8.71(s,1H),8.54(d,J=8.2Hz,1H),8.40(d,J=8.3Hz,2H),7.71(t,J=7.7Hz,1 H),7.64–7.59(m,3H),7.48–7.39(m,3H),7.30(t,J=7.4Hz,1H),7.21(d,J=8.3Hz,2H),5.46(s,2H); 13 C NMR (150MHz, CDCl3) δ188.5,157.2,155.9,150.4,150.0,146.3,140.4,136.6,133.4,131 .6,129.8,129.1,128.9,128.8,128.0,127.0,126.0,121.0,118.5,68.4; HRMS(ESI)calcd C 24 H 16 O6S[M+H] + :433.0740,found:433.0742.

[0160] Example 17

[0161] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-7P, as follows:

[0162]

[0163] Characterization data of product 6-7P: 1H NMR (600MHz, CDCl3) δ8.72(s,1H),8.56(dd,J=8.2,1.2Hz,1H),8.41(d,J=8.4Hz,2H),7.73(dd,J=11.2,4.2Hz,1H), 7.64(t,J=8.6Hz,3H),7.47(t,J=7.5Hz,1H),7.13(d,J=9.1Hz,2H),6.92(d,J=9.1Hz,2H),5.46(s,2H),3.80(s,3H); 13 C NMR (150MHz, CDCl3) δ188.5,158.0,157.4,156.2,150.4,146.4,143.5,140.5,136.7,133.5, 131.6,129.2,129.0,128.9,128.1,126.0,121.8,118.6,114.8,68.3,55.7; HRMS(ESI)calcd C 25 H 18 O7S[M+H] + :463.0846,found:463.0856.

[0164] Example 18

[0165] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-8P, as follows:

[0166]

[0167] Characterization data of product 6-8P: 1 H NMR(600MHz, CDCl3)δ8.71(s,1H),8.55(dd,J=8.2,1.3Hz,1H),8.40(d,J=8.3Hz,2H),7.73–7.6 8(m,1H),7.64–7.60(m,3H),7.48–7.41(m,3H),7.13(d,J=8.8Hz,2H),5.45(s,2H),1.33(s,9H); 13 C NMR (150MHz, CDCl3) δ188.4,157.4,156.0,150.4,149.9,147.7,146.3,140.4,136.7,133.4,13 1.5,129.1,128.9,128.8,128.0,126.7,126.0,120.3,118.5,68.3,34.7,31.5.HRMS(ESI)calcd C 28 H 24 O6S[M+H]+ :489.1366,found:489.1377.

[0168] Example 19

[0169] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-9P, as follows:

[0170]

[0171] Characterization data of product 6-9P: 1 H NMR (600MHz, CDCl3) δ8.73 (s, 1H), 8.57 (d, J = 6.7Hz, 1H), 8.42 (d, J = 6.1Hz, 2H),7.74(s,1H),7.64(s,3H),7.48(s,1H),7.30–7.09(m,4H),5.47(s,2H); 13 C NMR (150MHz, CDCl3) δ188.5,157.1,155.8,150.4,146.3,145.8,140.3,136.6,133.4,131.6,129.1,128.9,128.8, 128.1,126.0,122.6(d,JC-F=8.2Hz),118.5,116.7(d,J=23.6Hz),116.6(d,JC-F=23.7Hz),68.4.HRMS(ESI)calcd C 24 H 15 FO6S[M+H] + :451.0646,found:451.0647.

[0172] Example 20

[0173] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-10P, specifically as follows:

[0174]

[0175] Characterization data of product 6-10P: 1 H NMR (600MHz, CDCl3) δ8.73(s,1H),8.58(d,J=8.2Hz,1H),8.43(d,J=8.2Hz,2H),7.74(t,J =7.6Hz,1H),7.65(t,J=7.8Hz,3H),7.48(t,J=7.6Hz,1H),7.32–7.16(m,4H),5.49(s,2H); 13C NMR (150MHz, CDCl3) δ188.6, 156.6, 154.8, 150.5, 146.4, 140.5, 137.3 (d, J = 13.0Hz), 136.6, 133.5, 131.7, 129.2, 12 9.0,128.9,128.4(d,J=7.0Hz),126.1,124.9(d,J=3.6Hz),123.2,118.6,117.2(d,J=18.2Hz),68.6; HRMS(ESI)calcd C 24 H 15 FO6S[M+H] + :451.0646,found:451.0655.

[0176] Example 21

[0177] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-11P, specifically as follows:

[0178]

[0179] Characterization data of product 6-11P: 1 H NMR (600MHz, CDCl3) δ8.71(s,1H),8.53(d,J=8.1Hz,1H),8.39(d,J=8.0Hz,2H),7.70(t,J=7.3Hz,1H),7.60 (d,J=8.1Hz,3H),7.44(t,J=7.5Hz,1H),7.28–7.18(m,3H),7.12(d,J=7.8Hz,1H),5.45(s,2H),2.24(s,3H); 13 C NMR (150MHz, CDCl3) δ188.4,157.3,155.8,150.3,148.6,146.3,140.3,136.8,133.4,131.6,131.5, 129.8,129.1,128.8,128.7,128.0,127.3,127.1,126.0,121.2,118.5,68.3,16.2.HRMS(ESI)calcd C 25 H 18 O6S[M+H] + :447.0897,found:447.0903.

[0180] Example 22

[0181] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-12P, specifically as follows:

[0182]

[0183] Characterization data of product 6-12P: 1 H NMR (600MHz, CDCl3) δ8.73(s,1H),8.58(d,J=8.1Hz,1H),8.44(d,J=8.3Hz,2H),7.74(t,J=7.7Hz,1H),7.65(t,J=8.2Hz,3H),7.49(t, J=7.6Hz,1H),7.37(d,J=6.8Hz,1H),7.30–7.22(m,2H),7.11(d,J=7.9Hz,1H),5.49(s,2H),3.11–3.03(m,1H),1.23(d,J=6.9Hz,6H); 13 C NMR (150MHz, CDCl3) δ188.6,157.4,156.3,150.5,147.5,146.4,140.5,140.0,136.8,133.5,131.7,12 9.2,128.9,128.9,128.2,127.4,127.3,127.0,126.1,121.6,118.6,68.3,27.6,23.1; HRMS(ESI)calcd C 27 H 22 O6S[M+H] + :475.1210,found:475.1212.

[0184] Example 23

[0185] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-13P, as follows:

[0186]

[0187] Characterization data of product 6-13P: 1 H NMR (600MHz, CDCl3) δ8.74(s,1H),8.58(dd,J=8.2,1.3Hz,1H),8.44(d,J=8.4Hz,2H),7.75–7.72( m,1H),7.65(t,J=8.5Hz,3H),7.49(t,J=7.2Hz,1H),7.11–7.09(m,3H),5.49(s,2H),2.20(s,6H); 13C NMR (150MHz, CDCl3) δ188.6,157.5,155.6,150.5,147.5,146.4,140.5,136.8,133.5,131.6, 129.8,129.2,129.0,128.9,128.8,128.1,126.9,126.1,118.6,68.3,16.4; HRMS(ESI)calcd C 26 H 20 O6S[M+H] + :461.1053,found:461.1064.

[0188] Example 24

[0189] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-14P, specifically as follows:

[0190]

[0191] Characterization data of product 6-14P: 1 H NMR (600MHz, CDCl3) δ8.72(s,1H),8.56(d,J=8.1Hz,1H),8.42(d,J=8.3Hz,2H),7.73(t, J=8.3Hz,2H),7.67–7.60(m,4H),7.49–7.38(m,2H),7.34(d,J=8.2Hz,1H),5.49(s,2H); 13 C NMR (150MHz, CDCl3) δ188.5,156.5,155.3,150.4,147.2,146.4,140.5,136.6,133.6,133.5,131.6,128.8,128. 6,128.1,127.5(q,JC-F=4.9Hz),127.2,126.0,123.6,122.3(q,JC-F=147.5Hz),118.6,68.5; HRMS(ESI)calcdC 25 H 15 F3O6S[M+H] + :501.0614,found:501.0626.

[0192] Example 25

[0193] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-15P, as follows:

[0194]

[0195] Characterization data of product 6-15P: 1 H NMR (600MHz, CDCl3) δ8.72(s,1H),8.56(dd,J=8.2,1.4Hz,1H),8.42(d,J=8.4 Hz,2H),7.75–7.70(m,1H),7.66–7.62(m,3H),7.49–7.45(m,1H),7.35–7.29(m ,2H),7.28–7.24(m,1H),7.20(dd,J=8.0,1.1Hz,1H),6.05(s,1H),5.52–5.51( m,1H),5.48(s,2H),4.34(t,J=7.0Hz,2H),2.97(t,J=7.0Hz,2H),1.89(s,3H); 13 CNMR (150MHz, CDCl3) δ188.5,167.3,157.1,155.9,150.4,148.6,146.4,140.5,136.7,136.3,133.4,131.6,131. 3,129.6,129.2,128.8,128.3,128.1,127.2,126.0,125.8,121.8,118.6,68.4,63.8,29.7,18.4; HRMS(ESI)calcd C 30 H 24 O8S[M+Na] + :567.1084,found:567.1099.

[0196] Example 26

[0197] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-16P, specifically as follows:

[0198]

[0199] Characterization data of product 6-16P: 1 H NMR (600MHz, CDCl3) δ8.72(s,1H),8.57(d,J=8.2Hz,1H),8.42(d,J=8.2Hz,2H),7.73(t,J=7.6Hz,1H),7.64(t,J=8.6Hz,3H),7.48(t,J=7.5Hz,1H ),7.28(d,J=8.4Hz,2H),7.15(d,J=8.4Hz,2H),6.07(s,1H),5.54(s,1H) ,5.46(s,2H),4.35(t,J=6.8Hz,2H),3.00(t,J=6.8Hz,2H),1.91(s,3H);13 C NMR (150MHz, CDCl3) δ188.6,167.4,157.3,155.9,150.5,148.7,146.4,140.5,136.9,136.7,136.3,133.5,13 1.7,130.3,129.2,129.0,128.9,128.1,126.0,125.8,121.0,118.6,68.4,65.0,34.6,18.4; HRMS(ESI)calcd C 30 H 24 O8S[M+H] + :545.1265,found:545.1263.

[0200] Example 27

[0201] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-17P, as follows:

[0202]

[0203] Characterization data of product 6-17P: 1 H NMR(600MHz, CDCl3)δ8.72(s,1H),8.57(dd,J=8.2,1.5Hz,1H),8.41(d,J=8.5Hz,2H),7.75–7.71(m,1H), 7.66–7.63(m,1H),7.61(d,J=8.5Hz,2H),7.49–7.46(m,3H),7.39–7.36(m,2H),5.43(s,2H),1.34(s,9H); 13 C NMR (150MHz, CDCl3) δ188.5,183.8,159.2,153.7,150.4,146.4,140.5,136.8,134.0,133.4,13 1.6,129.1,128.9,128.8,128.1,126.8,126.0,122.2,118.6,68.4,35.0,31.3; HRMS(ESI)calcd C28H 24 O5S2[M+H] + :505.1138,found:505.1143.

[0204] Example 28

[0205] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-18P, specifically as follows:

[0206]

[0207] Characterization data of product 6-18P: 1 H NMR (600MHz, CDCl3) δ8.71(s,1H),8.56(dd,J=8.2,1.1Hz,1H),8.25(d,J=8.3Hz,2H),7.75–7.71(m,1H),7.65(d ,J=8.4Hz,1H),7.47(t,J=7.5Hz,1H),7.29(dd,J=5.1,1.8Hz,3H),7.21–7.17(m,4H),5.04(s,2H),3.36(s,3H); 13 CNMR (150MHz, CDCl3) δ188.4,162.4,161.5,150.4,146.3,141.2,140.6,137.0,133.4,131.1 ,129.8,128.9,128.8,128.8,128.6,128.1,126.4,126.0,118.6,66.7,36.3; HRMS(ESI)calcd C 25 H 19 NO5S[M+Na] + :468.0876,found:468.0886.

[0208] Example 29

[0209] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-19P, specifically as follows:

[0210]

[0211] Characterization data of product 6-19P: 1 H NMR (500MHz, CDCl3) δ8.30(d,J=15.0Hz,2H),7.52(d,J=15.0Hz,2H),7.47(d,J=11.8Hz,1H),7.36 (dd,J=14.9,3.2Hz,1H),7.29(s,4H),7.05(d,J=14.9Hz,1H),6.88(t,J=14.8Hz,1H),5.13(s,2H); 13 C NMR (125MHz, CDCl3) δ205,158.6,158.1,156.3,152.9,147.7,146.7,144.5,137 .1,133.8,131.2,129.6,129.5,128.1,128.0,125.6,125.1,121.4,117.6,66.9.

[0212] Example 30

[0213] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-20P, as follows:

[0214]

[0215] Characterization data of product 6-20P: 1 H NMR(500MHz, CDCl3)δ7.89(d,J=15.0Hz,2H),7.48(t,J=14.8Hz,1H),7.41–7.33( m,3H),7.29(s,4H),7.04(d,J=14.9Hz,1H),6.88(t,J=14.8Hz,1H),5.13(s,2H); 13 C NMR (125MHz, CDCl3) δ205.0,158.6,158.1,156.6,152.9,147.7,146.7,137.1,133.8 ,133.2,131.2,129.6,129.5,128.1,128.0,125.1,123.8,118.9,117.6,109.9,66.9.

[0216] Example 31

[0217] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-21P, specifically as follows:

[0218]

[0219] Characterization data of product 6-21P: 1 H NMR (500MHz, CDCl3) δ7.53–7.44(m,3H),7.36(d,J=14.9Hz,1H),7.29(s,4H),7.14–7.02(m,3H),6.88(t,J=14.8Hz,1H),5.13(s,2H); 13 C NMR (125MHz, CDCl3) δ205,158.6,158.1,154.3,152.9,147.7,146.7,137.1,133.8,131.2,129.6,129.5,129.3(q,JC-F =32.3Hz), 128.1, 128.0, 127.4 (q, JC-F = 3.7Hz), 125.1, 123.6 (q, JC-F = 268.1Hz), 121.7 (q, JC-F = 1.5Hz), 117.6, 66.9.

[0220] Example 32

[0221] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-22P, as follows:

[0222]

[0223] Characterization data of product 6-22P: 1 H NMR (600MHz, CDCl3) δ8.71(s,1H),8.55(dd,J=8.1,1.1Hz,1H),8.40(d,J=8.3Hz ,2H),7.72(dd,J=11.2,4.1Hz,1H),7.64(d,J=8.4Hz,1H),7.61(d,J=8.3Hz,2H), 7.46(t,J=7.5Hz,1H),7.17(dd,J=8.5,2.0Hz,1H),7.09(d,J=2.0Hz,1H),6.89(d ,J=8.5Hz,1H),6.47(s,4H),5.44(s,2H),3.82(s,3H),3.81(s,3H),3.69(s,6H); 13 C NMR (150MHz, CDCl3) δ188.5,157.0,155.1,153.1,150.4,149.6,146.3,140.5,138.6,137.4,136.7,133.4,132.3,131. 5,130.4,130.2,129.1,128.9,128.8,128.7,128.2,128.1,126.0,122.5,118.6),112.4,105.9,68.3,61.0,56.1,56.0.

[0224] Example 33

[0225] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 6-23P, as follows:

[0226]

[0227] Characterization data of product 6-23P: 1H NMR (300MHz, CDCl3) δ11.61(s,1H),8.68(s,1H),8.50(d,J=7.8Hz,1H),8.37(d,J=7.5Hz,2H),7.74–7.39(m,6H),6.44(d,J=8 .6Hz,1H),5.43(s,2H),4.18(s,2H),3.85(s,2H),3.69(s,2H),3.61(s,28H),3.52(d,J=4.5Hz,2H),3.35(s,3H),2.07(s,3H).

[0228] Example 34

[0229] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 7P, as follows:

[0230]

[0231] Characterization data of product 7P: 1 H NMR (600MHz, CDCl3) δ8.72(s,1H),8.58(d,J=8.1Hz,1H),8.36(d,J=8.0Hz,2H),7.73(t,J=7.3Hz,1H),7.65 (d,J=8.3Hz,1H),7.54(d,J=7.9Hz,2H),7.50–7.46(m,3H),7.36(d,J=8.2Hz,2H),4.29(s,2H),1.33(s,9H); 13 C NMR (150MHz, CDCl3) δ188.3,188.2,187.1,153.8,150.5,146.4,140.8,139.2,134.1,133.4,130 .5,129.6,129.3,128.9,128.1,126.9,126.0,121.9,118.6,35.0,33.3,31.3; HRMS(ESI)calcdC 28 H 24 O4S3[M+H] + :521.0909,found:521.0912.

[0232] Example 35

[0233] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 7-2P, specifically as follows:

[0234]

[0235] Characterization data of product 7-2P: 1H NMR (600MHz, CDCl3) δ8.70(s,1H),8.56(d,J=8.1Hz,1H),8.22(d,J=8.2Hz,2H),7.72(t,J=7.6Hz,1H),7.63(d,J=8. 4Hz,1H),7.46(t,J=7.5Hz,1H),7.35–7.32(m,3H),7.27–7.22(m,2H),7.17–7.14(m,2H),4.07(s,2H),3.37(s,3H); 13 C NMR (150MHz, CDCl3) δ189.1,188.1,162.9,150.4,146.3,141.7,140.9,139.9,133.3,130.0, 129.7,129.3,129.0,128.8,128.3,128.0,126.6,126.0,118.5,37.9,32.6; HRMS(ESI)calcd C 25 H 19 NO4S2[M+H] + :462.0828,found:462.0831.

[0236] Example 36

[0237] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 8P, specifically as follows:

[0238]

[0239] Characterization data of product 8P: 1 H NMR (600MHz, CDCl3) δ9.10(s,1H),8.61(s,1H),8.49(d,J=8.2Hz,2H),8.10–8.06(m,2H),7.92(d,J=8.3Hz,1H),7.65(d,J=8. 1Hz,2H),7.63–7.59(m,1H),7.54–7.50(m,1H),7.46–7.41(m,2H),7.31(t,J=7.4Hz,1H),7.22(d,J=7.8Hz,2H),5.48(s,2H); 13C NMR (150MHz, CDCl3) δ190.0,157.3,155.9,150.1,147.3,145.3,141.0,136.9,135.7,131.9,131.1,129 .9,129.8,130.0,129.5,129.1,129.0,127.3,127.0,126.6,126.4,121.1,114.7,68.4; HRMS(ESI)calcd C 28 H 18 O6S[M+H] + :483.0897,found:483.0903.

[0240] Example 37

[0241] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 9P, as follows:

[0242]

[0243] Characterization data of product 9P: 1 H NMR (600MHz, CDCl3) δ8.63(s,2H),8.52(d,J=8.2Hz,2H),8.05(d,J=1.9Hz,1H),7.66(d,J=8 .1Hz,2H),7.43(t,J=7.9Hz,2H),7.30(t,J=7.5Hz,1H),7.21(d,J=7.8Hz,2H),5.48(s,2H); 13 C NMR (150MHz, CDCl3) δ186.8,157.3,155.9,150.0,146.9,146.1,140.9,138.6,137.3,131 .1,130.5,129.9,129.7,129.5,129.1,127.0,121.0,119.5,113.7,68.3; HRMS(ESI)calcd C 24 H 14 Br2O6S[M+H] + :588.8951,found:588.8951.

[0244] Example 38

[0245] This example uses Synthesis Method 2 to prepare carbon monoxide prodrug 10P, specifically as follows:

[0246]

[0247] Characterization data of product 10P: 1H NMR (600 MHz, CDCl3) δ8.71 (s, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 8.40–8.37 (m, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 4.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 5.42 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (150MHz, CDCl3) δ188.6,157.8,157.7,150.5,146.3,140.4,135.0,133.5,131.6,13 1.2,129.4,129.3,129.0,128.9,128.1,126.0,118.6,68.3,63.5,14.1; HRMS(ESI)calcd C 20 H 16 O6S[M+H] + :385.0740,found:385.0743.

[0248] Example 39

[0249] This embodiment relates to the preparation of carbon monoxide prodrug micelles 1-2P-NPs, as follows:

[0250]

[0251] Under a nitrogen atmosphere, compound 1-2P (2.0 equiv) and an azide compound (1.0 equiv) were dissolved in a 1:1 mixed solvent of tert-butanol:water, and copper sulfate (0.2 equiv) and sodium ascorbate (0.4 equiv) were added as catalysts. The reaction was allowed to react for 4 hours and monitored by thin-layer chromatography. After completion of the reaction, the reaction was quenched with water and diluted, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH=10:1) afforded the target product 1-2P-NPs.

[0252] Example 40

[0253] This embodiment relates to the preparation of carbon monoxide prodrug micelles 1-6P-NPs, as follows:

[0254]

[0255] Compound 1-6P (2.0 equiv) and an azide compound (1.0 equiv) were dissolved in a 1:1 mixed solvent of acetonitrile:water and stirred for 4 hours. The reaction was monitored by thin-layer chromatography. After completion of the reaction, the reaction was quenched with water and diluted, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography (DCM:MeOH = 10:1) was performed for separation and purification to obtain the corresponding target product 1-6P-NPs.

[0256] Example 41

[0257] This example relates to the preparation of carbon monoxide prodrug micelles 6-2P-NPs, as follows:

[0258]

[0259] The backbone compound (120 mg, 0.05 equiv), compound 6-2P (82 mg, 1.0 equiv), and azobisisobutyronitrile (6.6 mg, 0.05 equiv) used in the polymerization were placed in a 5 mL Schlenk tube. The atmosphere was replaced with nitrogen three times using a refrigerated, triple-evacuation, triple-cycle method to remove oxygen. Dimethyl sulfoxide (1 mL) was added, and the mixture was heated and stirred at 70°C for 24 hours. After completion of the reaction, the product was added dropwise to 50 mL of stirred diethyl ether, and the precipitated solid was collected. This reaction was repeated three times to obtain polymer 6-2P-NPs.

[0260] Example 42

[0261] This example relates to the preparation of carbon monoxide prodrug micelles 6-15P-NPs, as follows:

[0262]

[0263] The backbone compound (50 mg, 0.05 equiv), compound 6-15P (110 mg, 1.0 equiv), and azobisisobutyronitrile (3.3 mg, 0.05 equiv) used in the polymerization were placed in a 5 mL Schlenk tube. The atmosphere was replaced with nitrogen three times using a refrigerated, triple-evacuation, triple-cycle method to remove oxygen. Dimethyl sulfoxide (1 mL) was added, and the mixture was heated and stirred at 70°C for 24 hours. After completion of the reaction, the product was added dropwise to 50 mL of stirred diethyl ether, and the precipitated solid was collected. This reaction was repeated three times to obtain polymer 6-15P-NPs.

[0264] Example 43

[0265] This example relates to the preparation of carbon monoxide prodrug micelles 6-16P-NPs, as follows:

[0266]

[0267] The backbone compound (50 mg, 0.05 equiv), compound 6-16P (110 mg, 1.0 equiv), and azobisisobutyronitrile (3.3 mg, 0.05 equiv) used in the polymerization were placed in a 5 mL Schlenk tube. The atmosphere was replaced with nitrogen three times using a refrigerated, three-pump, three-cycle method to remove oxygen. Dimethyl sulfoxide (1 mL) was added, and the mixture was heated and stirred at 70°C for 24 hours. After completion of the reaction, the product was added dropwise to 50 mL of stirred diethyl ether, and the precipitated solid was collected. This reaction was repeated three times to obtain polymer 6-16P-NPs.

[0268] Example 44

[0269] The carbon monoxide prodrugs prepared in Examples 15 and 22 were dissolved in tetrahydrofuran (0.5 mL) along with the nanomaterial PEG-PCL. The solution was then added dropwise to deionized water (5 mL) under ultrasonic conditions, and sonication was continued for 5 minutes. The tetrahydrofuran was removed by evaporation under reduced pressure, and the resulting solution was concentrated to 200 μL using an ultrafiltration tube. Deionized water (3 mL) was added and the solution was centrifuged again to a final concentration of 200 μL, yielding 15@PEG-PCL and 22@PEG-PCL nanoparticles.

[0270] Test Example 1

[0271] Taking compound 6-11P and compound 6-21P as examples, the carbon monoxide prodrug was characterized by UV absorption. The specific operation is as follows:

[0272] (1) Compound 6-21P (40 μM) was dissolved in 60% CH 3 CN / PBS (pH=7.4), H 2 O 2 (1 mM) was added, and the changes in the UV absorption curve were measured.

[0273] (2) Compound 6-21P (40 μM) was dissolved in 60% CH 3 CN / PBS (pH=7.4), H 2 O 2 (1 mM) was added, and the changes in the UV absorption curve were measured.

[0274] The test results are as follows Figure 2 、 3 As shown: Figure 2 The ultraviolet absorption change curve of the compound 6-11P test group shows that the absorbance of the prodrug 6-11P gradually decreases, the characteristic peak of intramolecular proton transfer at 500 nm gradually increases from 0 to 10 minutes, and the characteristic peak at 500 nm gradually decreases from 15 to 60 minutes, indicating that the carbon monoxide prodrug is continuously decomposed into carbon monoxide; Figure 3The UV absorption curve for the compound 6-21P test group shows a similar characteristic absorption peak at 500 nm for intramolecular proton transfer, which gradually increases from 0 to 15 minutes and then gradually decomposes from 15 to 70 minutes. This further demonstrates that the carbon monoxide prodrug was successfully activated and formed an intermediate with a characteristic absorption at 500 nm.

[0275] Test Example 2

[0276] The carbon monoxide prodrug prepared in Example 1-38 was dissolved in 50 mL of (20% to 60% CH3CN / PBS) solution to a final concentration of 40 μM, and then H2O2 (1 mM) was added. The mixture was incubated at 37°C and CO release was detected using a CO detector. The maximum amount of carbon monoxide released was measured within 1-6 hours.

[0277] The test results are shown in Table 1 below:

[0278] Table 1 CO release test results

[0279]

[0280]

[0281]

[0282]

[0283] As shown in Table 1, the series of carbon monoxide prodrugs provided by the present invention can release carbon monoxide in the presence of hydrogen peroxide, and the release amount is high. For example, compound 6-11P can also achieve high carbon monoxide release when the ratio of oxalate fragment to prodrug is only 1:1, with the release amount reaching 525 ppm, which is close to 100% release efficiency.

[0284] Test Example 3

[0285] The carbon monoxide prodrug micelles prepared in Examples 39-43 were dissolved in tetrahydrofuran (1 mL) and added dropwise to deionized water (7 mL) under ultrasonic conditions. Ultrasonication was continued for 5 minutes after the addition. The tetrahydrofuran was removed by evaporation under reduced pressure, and the solution was concentrated by centrifugation to 200 μL using an ultrafiltration tube. Deionized water (3 mL) was added and the solution was further centrifuged to 200 μL. The solution was diluted to 40 μM (50 mL) with PBS (pH = 7.4). After the addition of H2O2 (1 mM), CO release was detected using a CO detector.

[0286] The test results are shown in Table 2 below:

[0287] Table 2 CO release test results

[0288]

[0289] As shown in Table 2, the carbon monoxide prodrug micelles can also release carbon monoxide in the presence of hydrogen peroxide. Therefore, it can be seen that the carbon monoxide prodrug prepared in the present invention can improve the problem of its application in physiological environment by preparing micelles.

[0290] Test Example 4

[0291] The 15@PEG-PCL and 22@PEG-PCL nanoparticles prepared in Example 44 were diluted to 40 μM (50 mL) with PBS (pH = 7.4), and CO release was detected using a CO detector after adding H2O2 (1 mM).

[0292] Table 3 CO release test results

[0293] number serial number CO (ppm) 1 15@PEG-PCL 52 2 22@PEG-PCL 98

[0294] As shown in Table 3, CO prodrugs 6-5P and 6-12P with different CO release amounts were respectively reacted with the nanomaterial PEG-PCL to prepare carbon monoxide prodrug micelles 15@PEG-PCL and 22@PEG-PCL. Both micelles can release carbon monoxide in the presence of hydrogen peroxide. It can be seen that the carbon monoxide prodrug prepared by the present invention can improve its application in physiological environments through the preparation of micelles.

[0295] Test Example 5

[0296] The ability of the 15@PEG-PCL and 22@PEG-PCL nanoparticles prepared in Example 44 to release CO in response to endogenous H2O2 in 4T1 cells was detected using the CO fluorescent probe NR-PdA. The specific operation was as follows:

[0297] 4T1 cells were seeded in 24-well plates (5 × 10 4 Cells were plated and incubated overnight in RPMI 1640 containing 10% FBS. After attachment, cells were first treated with 2 μM CO probe NR-PdA at 37°C. After 30 minutes, cells were washed twice with PBS and 30 μg mL -1 After 60 minutes of culture, the cell nuclei were stained with Hoechst dye. Fluorescence images of the cells were obtained using a laser confocal scanning microscope.

[0298] The results are as follows Figure 4As shown in the figure, compared with the PBS group, 15@PEG-PCL and 22@PEG-PCL have stronger fluorescence intensities, indicating that this type of CO prodrug micelles can well respond to endogenous H2O2 produced by 4T1 tumor cells and effectively release CO. In addition, the fluorescence intensity of the 22@PEG-PCL group is stronger than that of 15@PEG-PCL, mainly because the prodrug 6-12P has a stronger CO release ability than 6-5P. In summary, this experiment proves that this type of prodrug can respond to endogenous H2O2 in cells and release CO.

[0299] Test Example 6

[0300] Taking the 15@PEG-PCL and 22@PEG-PCL nanoparticles prepared in Example 44 as an example, the present invention further studied the effect of CO prodrug micelles on the antiproliferative activity of 4T1 breast cancer cells. The specific operation is as follows:

[0301] 4T1 cells in the logarithmic growth phase were seeded on 96-well plates (5×104 cells / mL-1). After adherence, the cells were treated with 15@PEG-PCL, 22@PEG-PCL, or PBS at doses of 1.5625, 3.125, 6.25, 12.5, 25, and 50 μM, respectively. After incubation at 37°C for 12 hours, the medium was discarded and 100 μL of MTT solution (0.5 mg mL-1) was added to each well. -1 After incubation at 37°C for 4 hours, the supernatant was discarded and 100 μL of dimethyl sulfoxide was added to each well and shaken for 10 minutes to dissolve the formed blue-purple crystals. Finally, the OD value was measured at a wavelength of 490 nm using a microplate reader. The cell viability value was calculated as follows: Cell viability % = OD administrationgroup / OD controlgroup ×100%.

[0302] The results are as follows Figure 5 As shown in the results, both 15@PEG-PCL and 22@PEG-PCL exhibited significant antiproliferative activity against 4T1 cells, and the effect of 22@PEG-PCL was significantly stronger than that of 15@PEG-PCL, which was mainly attributed to the higher CO release of prodrug 6-12, resulting in stronger cytotoxicity.

[0303] The above-described embodiments are merely preferred examples for the purpose of fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are within the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

Claims

1. A carbon monoxide prodrug, characterized in that The carbon monoxide prodrug has the general structural formula shown in formula (I) to formula (III): ， wherein R1, R2, R3, R4, R′1, R′2, R′4, R′′1, R′′2, R′′3, and R′′4 are independently selected from one of hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, acyl, C1-C10 alkyl, and C1-C10 alkoxy; R5, R'5, R''5 are independently selected from C1-C10 alkyl, C3-C10 cycloalkyl, propargyl, butyl alkynyl, allyl, phenyl, benzyl, 、 One of the following; R6 and R′6 are phenyl groups; R''7 is hydrogen or ; The above phenyl group is unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, , n is any integer from 1 to 20, 、 ; X and Y are each selected from one of O, N, S, and N-CH3; Z is selected from one of O, N, S, and -CH2-O-.

2. The carbon monoxide prodrug according to claim 1, characterized in that R1, R2, R3, R4, R'1, R'2, R'4, R''1, R''2, R''3, R''4 are independently selected from one of hydrogen and halogen; and R5, R'5, R''5 are independently selected from methyl, ethyl, propargyl, cyclohexyl, allyl, 、 , butyl alkynyl, benzyl, methoxy substituted phenyl, halogen substituted phenyl, C1-C10 alkyl substituted phenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, cyano substituted phenyl, Substituted phenyl, Substituted phenyl, Substituted phenyl, n is any integer from 1 to 20.

3. The carbon monoxide prodrug according to claim 1, characterized in that The carbon monoxide prodrug is a compound shown in the following structure: , , 。 4. A method for preparing the carbon monoxide prodrug according to claim 1, characterized in that: Prepared by method 1 or method 2, wherein, The method 1 comprises the following steps: subjecting the compound represented by formula (IV) and the compound represented by formula (V) to a reflux reaction in the presence of a catalyst and a first solvent to obtain the carbon monoxide prodrug; The method 2 comprises the following steps: reacting the compound represented by formula (VI) with the compound represented by formula (V) in the presence of an acid-binding agent and a second solvent to obtain the carbon monoxide prodrug; ； Wherein, X is O, S, N-CH3; R5 is selected from methyl, ethyl, propargyl, cyclohexyl, allyl, 、 , butyl alkynyl, benzyl, methoxy substituted phenyl, halogen substituted phenyl, C1-C10 alkyl substituted phenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, cyano substituted phenyl, Substituted phenyl, Substituted phenyl, Substituted phenyl, n is any integer from 1 to 20; When Q is phenyl, R'''1, R'''2, and R'''4 are hydrogen, and R'''3 is hydroxyl; When Q is a hydroxy-substituted phenyl group, a 2-hydroxyethyl-substituted phenyl group or a 2-mercaptoethylene-substituted phenyl group, R'''1, R'''2, R'''3 and R'''4 are hydrogen.

5. The preparation method according to claim 4, characterized in that In method 1, the catalyst is 4-dimethylaminopyridine; the first solvent is selected from one or more of benzene, toluene, and xylene; the reflux reaction temperature is 100-120° C., and the reaction time is 0.5-4 h.

6. The preparation method according to claim 4, characterized in that In method 2, the acid-binding agent is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, and potassium carbonate; the second solvent is selected from one or more of dichloromethane, tetrahydrofuran, and acetonitrile; the reaction temperature is -20 to 25°C, and the reaction time is 10 min to 3 h.

7. A carbon monoxide prodrug micelle, characterized in that The carbon monoxide prodrug micelles are obtained by reacting the carbon monoxide prodrug according to any one of claims 1 to 3 with an azide compound in the presence of a first solvent; or Obtained by reacting the carbon monoxide prodrug according to any one of claims 1 to 3 with a main chain compound in the presence of an initiator and a second solvent; or The method is prepared by dripping a mixed solution comprising the carbon monoxide prodrug according to any one of claims 1 to 3, a nanomaterial and a third solvent into deionized water under ultrasound; The structure of the azide compound is as follows: , n is any integer from 4 to 60; The structure of the main chain compound is as follows: , m is 10-200; The nanomaterial is one or more of PEG-PCL, PCL-PEG-PCL, PEG-PLGA, and PEG-DSPE.

8. The carbon monoxide prodrug micelle according to claim 7, characterized in that The carbon monoxide prodrug is obtained by reacting with an azide compound in the presence of a first solvent and a catalyst; the catalyst is copper sulfate and sodium ascorbate, and the first solvent is a mixed solvent of an organic solvent and water, and the organic solvent includes acetonitrile and tert-butanol.

9. The carbon monoxide prodrug micelle according to claim 7, characterized in that The initiator is azobisisobutyronitrile, and the second solvent is dimethyl sulfoxide; The third solvent is selected from one or more of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, ethanol, and methanol.

10. A carbon monoxide delivery drug, characterized in that The carbon monoxide delivery drug comprises the carbon monoxide prodrug according to any one of claims 1 to 3 and / or the carbon monoxide prodrug micelle according to any one of claims 7 to 9.

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