CN104814952B - A kind of method for promoting carbon monoxide emitter release carbon monoxide and preventing from being formed precipitation - Google Patents
A kind of method for promoting carbon monoxide emitter release carbon monoxide and preventing from being formed precipitation Download PDFInfo
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- CN104814952B CN104814952B CN201510180597.7A CN201510180597A CN104814952B CN 104814952 B CN104814952 B CN 104814952B CN 201510180597 A CN201510180597 A CN 201510180597A CN 104814952 B CN104814952 B CN 104814952B
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- carbon monoxide
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Abstract
Promote carbon monoxide emitter release carbon monoxide and the method that prevents from being formed precipitation the invention discloses a kind of, belong to technical field of medical chemistry, methods described it is specific as follows：CO releasing agents are dissolved in dimethyl sulfoxide, add amino acid or derivatives thereof or drug molecule and the EDTA aqueous solution.Carbon monoxide generation can be effectively facilitated after adding EDTA, and can quickly remove the precipitation in reaction.The inventive method has good universality, and the compound for reacting involved has good bio-compatibility, and discharging the precipitation after CO can fast and effeciently remove, and the opportunity of release carbon monoxide and speed are easily-controllable.
Description
Technical field
The present invention relates to technical field of medical chemistry, more particularly to a kind of promotion carbon monoxide emitter release carbon monoxide
And the method for preventing from being formed precipitation.
Technical background
Carbon monoxide (CO) is a kind of biological micromolecule for having in human body bioactivity.It is the same with its analog NO,
CO plays very important physiology and pathological role in organism, such as vasodilator, suppress reperfusion injury, anti-apoptotic,
Antiproliferative, anti-oxidant, antibacterial etc..In order to explore the pharmaceutical potential of this diatomic molecule, its accurate scene is discharged right and wrong
The problem of Chang Guanjian.Transition metal carbonyl compound is a big metalloid-organic compound, can cause carbonyl under suitable condition
Base (CO's) leaves away, such as illumination, substitution reaction, redox induction.Can be with using these properties of metal carbonyl
Design, synthesize some specific transition metal carbonyl compounds, be allowed to discharge CO under suitable conditions, i.e., a so-called oxidation
Carbon emissions agent (carbon monoxide-releasing molecules, CORM).The advantages of CORM is need not both to pass through body
Metabolic process, CO directly is discharged in agents area drug administration by injection without being sucked through respiratory system, in addition, dosage size and use
Medicine opportunity is easily controlled.Metal carbonyl can realize safely controllable CO releases, be a kind of medicine with application prospect
Thing molecule, paid much attention in past ten years by people.
Mann etc. is to take the lead in carrying out one of researcher of metal carbonyl CORM researchs.Animal model test result
Show that the CORM based on metal carbonyl has fabulous application prospect.Research shows CORM-2 ([RuCl2(CO)3]2) and
CORM-3(fac-[Ru(CO)3Cl (glycinate)]) CO can be discharged under certain condition, vasodilator can be played, mitigated
Inflammatory reaction；Adjust vasoactive, mitigate myocardial ischemia-reperfusion injury；Suppress the effect such as cardiac transplant rejection episode.Nearly ten years
The relevant CORM of report compound is concentrated mainly on the metallic elements such as Ru, Mn, Mo, Re, Fe up to tens kinds, but these
Some metals such as Ru, Mo etc. are not the necessary element of organism in compound, and majority of compounds also generally existing is stable in addition
The problems such as property or poorly water-soluble and improper rate of release.Iron is the essential element of many organisms, and organism is to it
With perfect metabolic mechanism, but the report for being currently based on iron molybdenum cofactor CORM is also fewer.
We have synthesized two kinds of iron molybdenum cofactor [Fe recently2{μ-SCH2CH(OH)CH2-(OH)}2(CO)6] (1) and
[Fe2(μ-SCH2CH2-CH2)2(CO)6(2)), they can decompose release carbon monoxide under mercaptoethylmaine effect.But the mistake
Journey can produce a certain amount of precipitation, may be the corresponding iron compound not soluble in water of generation.In addition to strengthen an oxidation
The bio-compatibility of carbon emissions system, we select to form the material of Life Base matter protein elementary cell, i.e. amino acid
And its derivative or some drug molecules are used as substitution induction agent, and it have studied an oxidation of the iron molybdenum cofactor of its induction
Carbon emissions ability.But amino acid and its carbon monoxide rate of release of derivative or drug molecule induction are comparatively relatively slow, and
And a certain amount of precipitation can be also produced in course of reaction.It is well known that really if the compound as medicine is in body metabolism
During produce precipitation and can trigger a series of side reactions, such as aggregation is difficult to discharge in vivo, or even blocks blood vessel and cause some its
His disease.Therefore finding one kind can promote carbon monoxide to discharge, and can remove the method precipitated in drug metabolism reaction simultaneously
Tool is of great significance.
The content of the invention
Carbon monoxide can be promoted to discharge and simultaneously can be removed in drug metabolism reaction to precipitate the invention provides a kind of
Method.This method can promote the progress of reaction, and can is effective using the method that EDTA is added in carbon monoxide delivery systme
Ground removes caused precipitation in reaction.
The present invention adopts the following technical scheme that：
The promotion carbon monoxide emitter release carbon monoxide of the present invention simultaneously prevents from forming the method detailed process of precipitation such as
Under：CO releasing agents are dissolved in dimethyl sulfoxide, add amino acid or derivatives thereof or drug molecule and the EDTA aqueous solution.
Described CO releasing agents are transition metal carbonyl compound.
As one of preferable technical scheme：Described CO releasing agents are [Fe2{μ-SCH2CH
(OH)CH2(OH)}2(CO)6] (compound 1).
As one of preferable technical scheme：Described CO releasing agents are [Fe2(μ-SCH2CH2-CH2)2(CO)6] (chemical combination
Thing 2).
Described amino acid or derivatives thereof is proline.
Described drug molecule is Tiopronin.
The concentration that CO releasing agents are dissolved in dimethyl sulfoxide is 0.001mol/L~0.02mol/L, adds three times mole
Amino acid or derivatives thereof or drug molecule, and the EDTA of one times of mole.
Iron molybdenum cofactor 1 and 2 can decompose life under bio-compatible amino acid and its effect of derivative or drug molecule
Into carbon monoxide, reach the purpose for slowly discharging CO, but the reaction rate is slow, and precipitation is had during the course of the reaction
Generation.The system has obvious facilitation after EDTA is added to reaction, but also can effectively remove what is generated in reaction
Precipitation.
Compared with prior art, the inventive method has the beneficial effect that:
(1) this method can be effectively facilitated the generation of carbon monoxide；
(2) this method promotes the opportunity of release carbon monoxide and speed easily-controllable；
(3) compound involved by this method has good bio-compatibility；
(4) this method can quickly remove caused precipitation in reaction.
Brief description of the drawings
Fig. 1 is compound 1- [Fe2{μ-SCH2CH(OH)CH2(OH)}(CO)6] infrared spectrum after proline is added becomes
Change figure and its dynamics lnA-t linear relationship chart (interior illustration).
Fig. 2 is compound 1- [Fe2{μ-SCH2CH(OH)CH2(OH)}(CO)6] infrared after proline and EDTA is added
Spectrum change figure and its dynamics lnA-t linear relationship chart (interior illustration).
Fig. 3 is compound 1- [Fe2{μ-SCH2CH(OH)CH2(OH)}(CO)6] adding bio-compatible drug molecule (sulphur
The linear relationship chart (interior illustration) of infrared spectrum variation diagram and its dynamics lnA-t after Pu Luoning).
Fig. 4 is compound 1- [Fe2{μ-SCH2CH(OH)CH2(OH)}(CO)6] adding bio-compatible drug molecule (sulphur
Pu Luoning) and EDTA after infrared spectrum variation diagram and its dynamics lnA-t linear relationship chart (interior illustration).
Fig. 5 is compound 2- [Fe2{μ-SCH2CH2)}2(CO)6] adding bio-compatible drug molecule (Tiopronin)
Infrared spectrum variation diagram and its dynamics lnA-t linear relationship chart (interior illustration).
Fig. 6 is compound 2- [Fe2{μ-SCH2CH2)}2(CO)6] add bio-compatible drug molecule (Tiopronin) and
The linear relationship chart (interior illustration) of infrared spectrum variation diagram and its dynamics lnA-t after EDTA.
Embodiment
The present invention is further elaborated below by specific embodiment, but not to the limit of the scope of the present invention
System, on the basis of technical scheme, those skilled in the art need not pay creative work can make it is each
Kind modification is deformed still within protection scope of the present invention.
Embodiment 1：
Compound 1 (17mg, 34mmol) adds 2.4mL DMSO, adds in reaction tube after dissolving, is separately added at 37 DEG C
Appropriate amino acid or the drug molecule aqueous solution (0.1mL, 1.035mol L-1, [compound 1]：[amino acid or drug molecule]=1:
3) and the 0.5mL aqueous solution, survey at regular intervals once infrared (Varian Scimitar 600).Added in the system
EDTA experimentation is similar with said process, simply needs to add the 0.1mL EDTA-2Na aqueous solution (3.45mol L-1),
And the aqueous solution added is then 0.4mL, guarantee final solution is 3.0mL.
After adding proline or Tiopronin in compound 1, significant change occurs for infrared spectrum, as shown in figs. 1 and 3,
Compound 1 is in 2068,2031,1989cm-1Have three obvious carbonyl absorption peaks, these infrared signature peaks add proline or
Substantially weaken after Tiopronin.It can thus be appreciated that the carbonyl after proline or Tiopronin is added of compound 1 gradually decreases and conduct
Carbon monoxide discharges, and illustrates that the process can discharge carbon monoxide.Other amino acid and drug molecule act on compound 1
Infrared spectrum it is similar.These results illustrate that amino acid or drug molecule can promote compound 1 to decompose release carbonyl.Reaction is dynamic
Mechanics shows that these reactions meet first order kinetics process (illustration in Fig. 1 and 3), and the difference of its reaction rate depends on ammonia
The difference of base acid or drug molecular structure.
But precipitation is always had in above-mentioned carbon monoxide delivery systme and is produced, it may be possible to some insoluble iron chemical combination
Thing.In order to avoid such case, we are added in above-mentioned system from the EDTA with stronger coordination ability as part, are wished
Prestige can reduce precipitation generation.Additionally, it is desirable that EDTA can precipitate to form corresponding complex with iron compound, it is anti-so as to accelerate
The progress answered.It is envisioned that EDTA is added in above-mentioned system can accelerate the decomposition (Fig. 2 and 4) of compound 1, and can substantially reduce
Precipitation generation, can finally form settled solution substantially.And also to belong to one-level anti-for carbon monoxide release process after adding EDTA
Answer dynamic process (illustration in Fig. 2 and 4).In addition, by table 1 it can also be seen that adding EDTA in carbon monoxide delivery systme
Really the progress of reaction can be accelerated, its reaction half-time substantially shortens.
Embodiment 2：
Compound 2 (14mg, 34mmol) adds 2.4mL DMSO, adds in reaction tube after dissolving, is separately added at 37 DEG C
The appropriate amount of drug molecule aqueous solution (0.1mL, 1.035mol L-1, [compound 1]：[amino acid or drug molecule]=1:3) and
The 0.5mL aqueous solution, survey at regular intervals once infrared (Varian Scimitar 600).EDTA reality is added in the system
It is similar with said process to test process, simply needs to add the 0.1mL EDTA-2Na aqueous solution (3.45mol L-1), and add
The aqueous solution is 0.4mL, and guarantee final solution is 3.0mL.
After compound 2 adds Tiopronin, significant change occurs for infrared spectrum, as shown in figure 5, compound 2 is 2068,
2031,1989cm-1There are three obvious carbonyl absorption peaks, these infrared signature peaks substantially weaken after Tiopronin is added.This
Illustrate that the carbonyl characteristic peak of compound 2 gradually weakens and discharged as carbon monoxide after adding Tiopronin, i.e., the process can
To discharge carbon monoxide.Other drugs molecule is similar with the infrared spectrum that compound 2 acts on.Kinetics result shows, this
A little reactions meet first order kinetics process (illustration in Fig. 5).
Similar with compound 1, addition EDTA can accelerate the decomposition (Fig. 6) of compound 2 in above-mentioned system, and can significantly subtract
Few precipitation generation.The carbon monoxide release process that EDTA is added in above-mentioned system falls within first-order kinetics process (in Fig. 6
Illustration).In addition by table 2 it can also be seen that in above-mentioned carbon monoxide delivery systme add EDTA can accelerate reaction progress, its
Reaction half-time substantially shortens.
Two above example illustrates to add in the decomposable process of the compound 1 or 2 in amino acid or drug molecule promotion
EDTA can accelerate reaction to carry out, that is, accelerate the release of carbon monoxide, and can substantially reduce precipitation generation.
The compound 1 of table 1 discharges the half-life period of carbon monoxide under amino acid or derivatives thereof or drug molecule effect
The compound 2 of table 2 discharges the half-life period of carbon monoxide under amino acid derivativges or drug molecule effect
Although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of changes, modification can be carried out to these embodiments, replace without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (3)
- A kind of 1. method for promoting carbon monoxide emitter release carbon monoxide and preventing from being formed precipitation, it is characterised in that：It is described Method it is specific as follows：By CO releasing agents [Fe2{μ-SCH2CH(OH)CH2(OH)}2(CO)6] or [Fe2(μ-SCH2CH2-CH2)2 (CO)6] be dissolved in dimethyl sulfoxide, add amino acid or cysteine hydrochloride or aminobutyric acid or Tiopronin or mercaptoethylmaine Or mercapto glycerol and the EDTA aqueous solution.
- 2. promote carbon monoxide emitter release carbon monoxide and the method for preventing from being formed precipitation as claimed in claim 1, its It is characterised by：Described amino acid is proline or histidine.
- 3. promote carbon monoxide emitter release carbon monoxide and the method for preventing from being formed precipitation as claimed in claim 1, its It is characterised by：CO releasing agents [Fe2{μ-SCH2CH(OH)CH2(OH)}2(CO)6] or [Fe2(μ-SCH2CH2-CH2)2(CO)6] be dissolved in Concentration in dimethyl sulfoxide is 0.001mol/L~0.02mol/L, adds the amino acid or cysteine hydrochloric acid of three times mole Salt or aminobutyric acid or Tiopronin or mercaptoethylmaine or mercapto glycerol, and the EDTA of one times of mole.
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| CN109134551B (en) * | 2018-06-15 | 2021-01-05 | 嘉兴学院 | Water-soluble iron carbonyl compound and preparation method and application thereof |
| CN111505211A (en) * | 2020-05-07 | 2020-08-07 | 嘉兴学院 | Method for regulating and controlling carbon monoxide releasing rate of carbon monoxide releasing agent |
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| WO2001022960A1 (en) * | 1999-09-30 | 2001-04-05 | Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center | Treatment of carbon monoxide poisoning |
| CN1561207A (en) * | 2001-05-15 | 2005-01-05 | 北威克公园医学研究所 | Therapeutic delivery of carbon monoxide |
| WO2006134474A2 (en) * | 2005-06-17 | 2006-12-21 | Ge Healthcare Limited | Method for the use of [11c] carbon monoxide in labeling synthesis of 11c-labelled acids by photo-induced free radical carbonylation under mild conditions using sulfoxides |
| CN101642570A (en) * | 2008-08-07 | 2010-02-10 | 江苏大学附属医院 | Application of carbon monoxide-releasing molecules and heparin in preparing medicament for treating sepsis |
| CN102813925A (en) * | 2012-07-30 | 2012-12-12 | 江苏大学附属医院 | Application of carbon monoxide releasing molecules in preparing medicines for inhibiting blood coagulation activation diseases |
| CN102850403A (en) * | 2012-05-29 | 2013-01-02 | 嘉兴学院 | Water-soluble iron carbonyl compound, and preparation method and application thereof |
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- 2015-04-16 CN CN201510180597.7A patent/CN104814952B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001022960A1 (en) * | 1999-09-30 | 2001-04-05 | Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center | Treatment of carbon monoxide poisoning |
| CN1561207A (en) * | 2001-05-15 | 2005-01-05 | 北威克公园医学研究所 | Therapeutic delivery of carbon monoxide |
| WO2006134474A2 (en) * | 2005-06-17 | 2006-12-21 | Ge Healthcare Limited | Method for the use of [11c] carbon monoxide in labeling synthesis of 11c-labelled acids by photo-induced free radical carbonylation under mild conditions using sulfoxides |
| CN101642570A (en) * | 2008-08-07 | 2010-02-10 | 江苏大学附属医院 | Application of carbon monoxide-releasing molecules and heparin in preparing medicament for treating sepsis |
| CN102850403A (en) * | 2012-05-29 | 2013-01-02 | 嘉兴学院 | Water-soluble iron carbonyl compound, and preparation method and application thereof |
| CN102813925A (en) * | 2012-07-30 | 2012-12-12 | 江苏大学附属医院 | Application of carbon monoxide releasing molecules in preparing medicines for inhibiting blood coagulation activation diseases |
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