CN102850403B - Water-soluble iron carbonyl compound, and preparation method and application thereof - Google Patents

Abstract

The invention discloses a water-soluble iron carbonyl compound, and a preparation method and an application thereof. The compound has a structural formula represented by the formula (1). When the compound is subjected to a reaction with mercaptoethylamine, CO can be released. The compound provided by the invention has good water solubility and appropriate stability. Metal ions and organic ligands involved in the reaction have good biocompatibility. Residual substances after CO releasing are harmless or slightly toxic to bodies. The timing and rate of CO releasing are easy to control.

Description

A kind of water-soluble iron carbonyl compound and its preparation method and application

technical field

The invention relates to the technical field of medicinal chemistry, in particular to a water-soluble iron carbonyl compound, a preparation method thereof and an application in controlled release of carbon monoxide.

Background technique

Carbon monoxide (CO) is a well-known toxic gas, but studies have shown that it, like nitric oxide (NO), is an important messenger molecule in the body, which can relax blood vessels and bronchial smooth muscles, inhibit platelet aggregation, inhibit Inflammatory response, anti-oxidation, anti-apoptosis, anti-proliferation and other physiological effects; in physiological processes such as nerves, respiration, and circulation, and in pathological processes such as acute lung injury, organ ischemia-reperfusion injury, and organ transplant rejection also play an important regulatory role.

The disadvantages of direct inhalation of CO gas are obvious: the inhaled CO must pass through the entire respiratory system, and then reach the relevant tissues through the blood circulation, which is not suitable for the situation where only local effects are required; the concentration and dose are not easy to control; at the same time, this The method also has the risk of poisoning patients and medical staff by accidentally inhaling high doses of CO.

Transition metal carbonyl compounds are a class of metal-organic compounds in which the carbonyl (CO) can leave under appropriate conditions, such as light irradiation, substitution reaction, redox induction, etc. Utilizing these properties of metal carbonyl compounds, some specific transition metal carbonyl compounds can be designed and synthesized to release CO under suitable conditions, that is, carbon monoxide-releasing molecules (CORM). Using CORM to provide CO through local administration does not need to pass through the body's metabolic process or the respiratory system; the dosage, timing and release rate of the drug are easy to control, and it is also safer than direct inhalation of CO.

The results of animal model experiments show that CORM based on metal carbonyl compounds has excellent application prospects. So far, the reported metal carbonyl compound CORM is mainly based on metal elements such as Ru, Mn, Mo, etc. However, some metals in these compounds such as Ru, Mo, etc. are not essential elements for organisms, and most of the compounds generally have stability or Problems such as poor water solubility and unsuitable release rate. Therefore, the study of CORM with good water solubility and moderate stability, and the residual substance after releasing CO is harmless to the body has practical significance for the development of new CORM drugs with independent intellectual property rights and low toxicity.

Iron is an essential element for life in many organisms, and organisms have complete metabolic mechanisms for it. Therefore, carbon monoxide releasing agents (CORMs) based on iron carbonyl compounds may have less or no toxicity, but currently iron-based There are relatively few reports on carbonyl compounds CORM. Moreover, the ligands used in these compounds, such as cyclopentadiene, pyrone and their derivative ligands, acyloxycyclohexadiene, etc., are not common organic molecules in organisms, and their metabolites may have adverse effects on the organism.

At present, the traditional method of synthesizing carbon monoxide releasing agents is to assemble metal complexes that can release carbon monoxide through the reaction of ligands and metal ions. It is very difficult to obtain the compound, because the compound is too stable to release carbon monoxide, and the compound is too unstable to be synthesized and not easy to obtain. Therefore, it is of great significance to study the CORM of biocompatible metal ions and ligands, and to find a suitable method to release carbon monoxide.

Contents of the invention

The invention provides a compound that can release carbon monoxide, the compound has good water solubility and moderate stability, and the metal ions and organic ligands involved in the reaction also have good biocompatibility, and the residual substance after releasing CO Harmless or less toxic to the body.

A kind of compound, its structural formula is as shown in formula (1):

Described compound has following three kinds of isomers:

The above three isomers can react with mercaptoethylamine to generate CO, achieving the purpose of slow and controllable release of CO.

The present invention also provides a preparation method of the compound, comprising:

dissolving Fe ₃ (CO) ₁₂ and 1-mercaptoglycerol in an organic solvent, reacting at a temperature lower than 120°C, preferably 60-80°C, until the reaction liquid turns red, and then separating and purifying to obtain the compound, The specific reaction process is shown in Figure 1.

The organic solvent disperses the raw materials in the same reaction system, preferably tetrahydrofuran, which is a medium-polar aprotic solvent, which does not react with the components in the reaction system, and has a small molecular weight, which is easy to separate from the product.

Appropriate ratio of raw materials is helpful for sufficient reaction of raw materials and formation of products. Preferably, the molar ratio of Fe ₃ (CO) ₁₂ and 1-mercaptoglycerol is 1:1-2:7.

If the reaction time is too short, the reaction cannot proceed sufficiently, and the reaction time is preferably 1 to 4 hours.

The process of separation and purification is mainly to remove the solvent and unreacted raw materials. Preferably, the organic solvent in the reaction solution is removed by rotary evaporation, and then the red oily product is recrystallized. This method is simple to operate and can keep the product stable.

The present invention further provides the application of the compound in the sustained release of CO.

A method for slow release of CO, comprising: dissolving the compound in dimethyl sulfoxide, and adding an aqueous solution of mercaptoethylamine.

Preferably, the concentration of the compound dissolved in dimethyl sulfoxide is 0.001mol/L-0.02mol/L.

The amount of mercaptoethylamine added affects the release rate of CO. The larger the amount added, the faster the release rate. Preferably, the concentration of the mercaptoethylamine aqueous solution is 4-5 mol/L, and the added amount is 10-120 μL.

Compared with prior art, the beneficial effect of compound of the present invention is:

(1) The compound has good water resistance and moderate stability;

(2) The metal ions and organic ligands involved in the compound have good biocompatibility;

(3) The timing and rate of the compound releasing carbon monoxide are easy to control.

Description of drawings

Fig. 1 is a flow diagram of the reaction of compound 1 of the present invention.

Figure 2 is the infrared spectrum of compound 1.

Figure 3 is the NMR spectrum of compound 1 (including three isomers of compound 1); wherein Figure 3a and Figure 3b are the NMR spectra of compound 1 prepared at different times, and Figure 3c is the compound after adding D ₂ O 1 NMR spectrum.

Fig. 4 is the infrared diagram of two products of compound 1 after adding mercaptoethylamine.

Figure 5 is the infrared change diagram of compound 1 after adding 6eq mercaptoethylamine; wherein, (a) is the infrared change diagram of compound 1 after 0~25min after adding mercaptoethylamine; (b) is the 45~175min compound after adding mercaptoethylamine 1’s infrared change map.

Detailed ways

1. Preparation of compounds

Add 2.81g Fe ₃ (CO) ₁₂ and 0.94g 1-mercaptoglycerol to tetrahydrofuran (THF), and react at 70°C for 2h to obtain a red solution, remove the solvent (THF) by rotary evaporation, and then redo the oily product. For crystallization, the solvent used was a mixed solvent of dichloromethane/cyclohexane, and finally a pure red oily substance was obtained, tentatively named compound 1.

2. Characterization of compounds

Varian Scimitar 600 was used to collect the infrared spectrum of compound 1, as shown in Figure 2, compound 1 was at 3367cm ^-1 (OH stretching vibration), 2876, 2928cm ^-1 (CH ₂ stretching vibration), 1415cm ^-1 (CH ₂ bending vibration ), 1992~2073cm ^-1 (C=O stretching vibration), 1262~1334cm ^-1 (OH in-plane bending), 561~617cm ^-1 (OH out-of-plane bending), 1031~1071cm ^-1 (CO stretching vibration) The obvious absorption peaks can confirm that compound 1 contains OH, CH ₂ , C=O and CO structures.

Figure 3 is the nuclear magnetic resonance spectrum of compound 1, which contains the structural information of three isomers, and the structural formulas of the three isomers are:

There are three configurations of bridged mercaptoglycerol in compound 1, two cis (aa), one cis-trans (ae), two trans (ee), and the compound with aa configuration in the ligand part is symmetrical Structure, OH has two peaks in ¹ HNMR, which are doublets and triplets. There are four peaks in the ae configuration, which are two doublets and two triplets. The ee configuration is also a symmetrical structure. There are also two peaks, doublet and triplet, so the ratio of doublet to triplet is 1:1.

It can also be deduced from the structural formula that the ratio of OH to CH is 2:5. According to Figures 3a and 3b, it can be seen that compound 1 has four doublets and two quintets, and the two quintets are obtained by coupling four triplets. The ratio of the doublet and the quintet is 1:1. Since Figures 3a and 3b were prepared at different times, there are slight differences in the environment, so the ratios of the three isomers are different. When a drop of D ₂ O is added to the compound of 3b, the NMR changes to Figure 3c, the OH peak disappears, and the water peak also moves. Combined with Figure 3b, the ratio of OH to CH is calculated to be 7.38:19.68≈2:5.

3. Application of compounds

Add the prepared compound 1 (17mg, 34mmol) into 3mL DMSO, dissolve and add to the reaction tube, add 20 (3eq), 40 (6eq), 80 (12eq) μL mercaptoethylamine (1g/2.5ml) at 37°C Aqueous solution, measure infrared (Varian Scimitar 600) every once in a while.

After adding mercaptoethylamine to compound 1, the infrared spectrum changes significantly, as shown in Figure 4, compound 1, product 1 and product 2 are respectively at 2068,2031,1989cm ^-1 (three); 2015,1974,1942 ,1907cm ^-1 (four); 2004,1941cm ^-1 (two) have obvious carbonyl absorption peaks, indicating that they are hexacarbonyl, pentacarbonyl and dicarbonyl compounds. It can be seen that the carbonyl group of compound 1 is gradually reduced and released as carbon monoxide after adding mercaptoethylamine, indicating that this process can release carbon monoxide.

As shown in Figure 5(a), the hexacarbonyl peak of compound 1 gradually weakens after the addition of mercaptoethylamine, and the pentacarbonyl peak gradually increases, indicating that the compound is gradually converted into product 1. During this process, the carbonyl group leaves, that is, carbon monoxide is released. As shown in Figure 5(b), the pentacarbonyl peak gradually weakens and the dicarbonyl peak gradually strengthens as time changes, indicating that product 1 is gradually converted into product 2, and carbonyl leaves during this process, that is, carbon monoxide is released.

Table 1 Compound 1 releases carbon monoxide half-life at different ratios of mercaptoethylamine

Compound 1 half-life 3eq Mercaptoethylamine 6eq Mercaptoethylamine 12eq Mercaptoethylamine t _1/2 (min) 62 7.1 4.4

It can be seen from Table 1 that the rate of release of carbon monoxide by compound 1 is related to the amount of mercaptoethylamine, that is, as the amount of mercaptoethylamine increases, the reaction rate is significantly accelerated. It follows that the rate at which this compound releases carbon monoxide can be adjusted as desired.

Claims (10)

1. a compound, is characterized in that, structural formula is such as formula shown in (1):

2. a preparation method for compound as claimed in claim 1, comprising:

By Fe ₃(CO) ₁₂be dissolved in organic solvent with 1-mercapto glycerol, react under lower than the condition of 120 DEG C, take on a red color to reaction solution, separation and purification obtains described compound.

3. preparation method as claimed in claim 2, it is characterized in that, described organic solvent is tetrahydrofuran (THF).

4. preparation method as claimed in claim 2, is characterized in that, Fe ₃(CO) ₁₂be 1:2 ~ 2:3 with the mol ratio of 1-mercapto glycerol.

5. preparation method as claimed in claim 2, it is characterized in that, the reaction times is 1 ~ 4 hour.

6. preparation method as claimed in claim 2, it is characterized in that, the method for described separation and purification is: rotary evaporation removes the organic solvent in reaction solution, then carries out recrystallization to Red oil product.

7. the application of compound in slowly-releasing CO as claimed in claim 1.

8. a method of slowly-releasing CO, comprising:

Compound according to claim 1 is dissolved in dimethyl sulfoxide (DMSO), adds the mercaptoethylamine aqueous solution.

9. method as claimed in claim 8, it is characterized in that, the described compound concentration be dissolved in methyl-sulphoxide is 0.001 ~ 0.02mol/L.

10. method as claimed in claim 8, it is characterized in that, the concentration of the described mercaptoethylamine aqueous solution is 4 ~ 5mol/L, and add-on is 10 ~ 120 μ L.