CN105646493B

CN105646493B - It is a kind of to be used to prevent and treat compound of organ damage and its production and use

Info

Publication number: CN105646493B
Application number: CN201410746440.1A
Authority: CN
Inventors: 李玉明; 周欣; 冉瑞琼
Original assignee: Individual
Current assignee: Beijing An Jianxi Medical Science And Technology Co ltd
Priority date: 2014-12-08
Filing date: 2014-12-08
Publication date: 2018-02-02
Anticipated expiration: 2034-12-08
Also published as: CN105646493A

Abstract

The present invention provides a kind of compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or Metabolic Intermediate that for preventing and treating compound of organ damage and its production and use, the compound represents for formula 1,Wherein, R1 is selected from=O, NH₂, OH, or NH₂Or the C of OH substitutions_1‑4Straight or branched alkyl；R2 is not present or selected from H, C_1‑4Straight or branched alkyl, CHO, or the C of CHO substitutions_1‑4Straight or branched alkyl；R3 is selected from H, C_1‑4Straight or branched alkyl, or OH；N is 0 13 positive integer.Compound provided by the invention is derived from folic acid, acts on Mutiple Targets, the different organ damage conduction path of comprehensive suppression, can be used to prepare prevention and/or treat a variety of causes to cause the medicine of organ damage.

Description

It is a kind of to be used to prevent and treat compound of organ damage and its production and use

Technical field

The invention belongs to medical science and medicinal chemistry art, be related to a kind of compound for being used to prevent and treat organ damage and Preparation method and use.More particularly, Mutiple Targets, comprehensive suppression are acted on derived from folic acid the invention provides a kind of Different Organs processed damage compound of conduction path and preparation method thereof, and it is used for preventing and/or treating various in preparation Purposes in the medicine of organ damage caused by reason.

Background technology

Make a general survey of seriously disease clinically, including myocardial infarction, headstroke, serious hepatitis, necrotizing pancreatitis and each Kind of wound etc., its common pathomechanism are all that the histocyte as caused by a variety of causes is quick, mortality.Therefore, for The treatment of these diseases, in addition to eliminating the cause of disease and symptomatic treatment, the key for the treatment of, which also resides in, effectively prevents cell death.Face Bed practice have shown that, the treatment for above-mentioned disease is of no avail using antioxidant, anti-apoptotic or antiinflammatory merely, only Have while dead transduction pathways are blocked in all directions, lifting histoorgan could effectively control the tolerance of damage Cell death, it is really achieved effective armour and reduces the purpose of the death rate.

Folic acid as an important carbon-based group carrier, it is synthesized in nucleotides, homocysteine methylate again etc. it is all Played an important role in terms of more important physiological metabolism, therefore folic acid is material necessary to body growth and development.Folic acid Have been used for cardiovascular disease caused by treating Homocysteine accumulation.Have been reported that and find that folic acid is not changing hemorheology spy While sign, iNOS activity, strong excitation ERK2 signal paths can be significantly inhibited.The present inventor etc. are once by folic acid as load Chemotherapeutics is deliverrf into tumour cell by body, it has been found that folic acid can substantially mitigate killing effect of the chemotherapeutics to tumour cell Should, these results of study imply that folic acid has the function of suppressing cell death.A large amount of documents delivered also fully show leaf Acid has the function that potent anti-oxidation stress and suppresses Apoptosis.What is more important, widely known is physiological dose Folic acid function, but also have numerous not known functions more than the folic acid of physiological requirements amount.For example, human hair of the present invention Now when folic acid concentration is up to 10 micromole with the function of removing free radical；The folic acid of high concentration can reduce vasopermeability, swash ERK2 living, suppresses GSK-3 β conduction paths, activates PPAR γ and suppresses inflammatory reaction etc..In addition, folic acid stable in physicochemical property, Abundance, it is cheap, therefore folic acid is expected to for preventing and treating the diseases such as myocardial infarction.

However, folic acid is water soluble vitamin, mainly absorbed by folacin receptor mediated active transport, few portion Divide with concentration gradient Passive intake.The folic acid absorbed by active transport can only maintain the amount that organism physiology needs, and do not reach and control Treat the drug concentration needed for purpose.Have been reported that, the folic acid (100-1000 times that exceedes usual amounts) of ultrahigh dose can be effectively pre- Anti- and treatment Rat Experimental acute myocardial infarction AMI.However, this is extremely unrealistic in clinical practice, the folic acid of over much dosage has sternly The side effect of weight, such as causes acute renal failure.Therefore, folic acid will reach the medicine for producing response to treatment in vivo Concentration, it is necessary to change its bioavilability and absorption pattern.Folic acid is non-fat-soluble highly polar compound, LogP values for- 0.68, body Passive intake it is extremely inefficient.

Therefore, the bioavilability for how effectively improving folic acid has become this area technical problem urgently to be resolved hurrily.

The content of the invention

In view of the problem of folic acid present in prior art is present in terms of its bioavilability cause its application by The defects of limitation, method of the present invention by being performed the derivatization to folic acid, there is provided one kind is used to prevent and/or treating organs damage Compound of wound and its production and use, the compound are derived from folic acid, and it acts on Mutiple Targets, and comprehensive suppression is not The conduction path of same organ damage, it can be used to prepare organ damage caused by effectively preventing and/or treating a variety of causes Medicine.

For realizing that the technical scheme of above-mentioned purpose is as follows：

In a kind of compound of expression of formula 1 or its pharmaceutically acceptable salt, ester, hydrate, solvate or metabolism Mesosome,

Wherein, R1 is selected from=O ,-NH₂,-OH, or-NH₂Or the C of-OH substitutions_1-4Straight or branched alkyl；

R2 is not present or selected from-H, C_1-4Straight or branched alkyl ,-CHO, or the C of-CHO substitutions_1-4Straight or branched alkane Base；

R3 is selected from-H, C_1-4Straight or branched alkyl, or-OH；

N is 0-13 positive integer.

Preferably, R1 is selected from=O ,-NH₂, or-OH；R2 is not present or selected from-H ,-CH₃Or-CHO；R3 is selected from-H ,- CH₃, or-OH.

Preferably, the compound that n 0,1,2,3,4,5 or 13, i.e. formula 1 represent is the pharmaceutically acceptable ester of folic acid (folate), it includes but is not limited to, such as folic acid propionic ester, folic acid butyrate, folic acid valerate, folic acid capronate, folic acid Heptanoate, folic acid caprylate or folic acid palmitate, it is within.

Preferably, the compound is represented by formula 2,

Wherein, R1, R2 and R3 are defined as above.

It is further preferred that the compound is selected from the compound represented by below formula a-e,

It is highly preferred that the compound is selected from the compound represented by below formula a-c,

More preferably, described compound is selected from the compound represented by below formula a or b,

Most preferably, the compound is selected from the compound represented by below formula b,

Metabolic Intermediate of the present invention refer to can by the standard biologic metabolism in the mankind or animal body, by The compound or its pharmaceutically acceptable salt, ester, hydrate, solvate that formula 1 represents, particularly by chemical formula a-e institutes The Metabolic Intermediate that the compound of expression is transformed.For example, formula 1 represent compound or its pharmaceutically acceptable salt, It is Metabolic Intermediate 1-3 as shown below that ester, hydrate or solvate are degradable under esterase effect after entering in vivo, these Metabolic Intermediate still has the effect that certain armour damages.

Present invention also offers a kind of pharmaceutical composition for being used to prevent and/or treating organs damage, the drug regimen Thing is included among the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or metabolism of therapeutically effective amount Body.

Preferably, described pharmaceutical composition is also comprising other medicines for being used to prevent and/or treating organs damage；It is preferred that Ground, it is described other to be used to prevent and/or the medicines for the treatment of organs damage are selected from heparin, hirudin, argatroban, warfarin, general One or more in top Cali or Valsartan, but other medicines for being used to prevent and/or treating organs damage of the present invention Be not limited to it is described these.

Preferably, described pharmaceutical composition also includes pharmaceutically acceptable auxiliary material.It is further preferred that it is described pharmaceutically Acceptable auxiliary material is selected from soybean oil, olive oil, medium chain triglyceride, soybean lecithin, phosphatidyl choline, polyethylene glycol stearic acid One or more in ester or polyoxyethylene sorbitan fatty acid ester, but pharmaceutically acceptable auxiliary material of the present invention is simultaneously Be not limited to it is described these.It is further preferred that the compound or its pharmaceutically acceptable salt, ester, hydrate, solvation The mass ratio of thing or Metabolic Intermediate and pharmaceutically acceptable auxiliary material is 1：10~90, preferably 1：15~50, more preferably 1：17~30, most preferably 1：20~25.

Any formulation can be made in pharmaceutical composition of the present invention, and is given with appropriate administering mode and be subjected to important device The treatment target of official's acute injury.Preferably, described pharmaceutical composition can be solution, suspension, emulsion, tablet, pill or Implant.For example, can by compound of the present invention or its pharmaceutically acceptable salt, ester, hydrate, solvate or The formulations such as solution, suspension, emulsion, tablet, pill, implant are made in Metabolic Intermediate, before organ acute injury, process In or afterwards, by modes such as oral, muscle, intravenous injection, percutaneous absorbtion, mucosa absorption, et al. Kes, by the change of the present invention Compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or Metabolic Intermediate give patient.People in the art Member can properly select chemical combination of the present invention according to factors such as the symptom species, health situation, specific therapeutic scheme of patient Thing or its pharmaceutically acceptable salt, ester, hydrate, the dosage and method of administration of solvate or Metabolic Intermediate.Daily Dosage can disposably give, can also be divided into and repeatedly give.In a preferred embodiment of the present invention, it is of the invention Protective agent is administered by oral or intravenous mode.

Those skilled in the art can select as the case may be the compounds of this invention or its pharmaceutically acceptable salt, Ester, hydrate, solvate or Metabolic Intermediate give the dosage of patient.In one embodiment, the compounds of this invention Dosage is 0.1-100 mg/kg body weight, preferably 1-50 mg/kgs body weight, more preferably 1.5-20 mg/kgs body Weight, most preferably 1-10 mg/kgs body weight.

Present invention also offers described compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or generation Thank to purposes of the intermediate in preparing for the medicine of prevention and/or treating organs damage.Preferably, the organ damage is selected from Myocardial infarction, headstroke, acute renal failure, serious hepatitis, hemorrhagic necrotizing pancreatitis, ALI, marrow are acute Damage, acute necrotizing enteritis, acute radiation damage, organ damage, the multiple organ dysfunction of septicemia or caused by radiotherapy and chemotherapy decline Exhaust, rheumatism, liver decline, rheumatoid, osteoarthritis, Respiratory Distress Syndrome(RDS), plasma homocysteine, Percutaneous coronary interventions (PCI) the one or more in complication or megaloblastic anemia.

Compound of the present invention or its pharmaceutically acceptable salt, ester, hydrate, solvate or Metabolic Intermediate Preparation method may comprise steps of：

The compound and C that formula 3 represents_3-16Fatty acid chloride methyl esters, for example, butyric acid chloromethyl ester in the presence of a base, organic molten The compound that reaction generation formula 1 represents in agent,

In described preparation method, it is preferable that the alkali is triethylamine；Preferably, the organic solvent is dimethyl Formamide.

The present invention it has been investigated that, by folic acid esterification be improve its bioavilability most effective means, the esterification of folic acid By the drug absorption for forming dose dependent and blood-brain barrier can be passed through enter brain tissue.And for existing in the prior art A large amount of alternative methods and reagent for folic acid esterification, the present inventor tries hard to by a large amount of designs and screening test Find a kind of best folic acid esterification mode.In this process, the present inventors have noted that a kind of acetylation of histone enzyme presses down Preparation (histone deacetylase inhibitor/HDAC Inhibitors), such as sodium butyrate can induced strong cell Express heat shock protein 70 (Hsp70).It is well known that Hsp70 is cytoprotection albumen, its height expression can effectively be protected thin Born of the same parents are from oxidative damage；Acetylation of histone enzyme inhibitor can also effectively block the cell death signal conduction way that P53 is mediated Footpath.Also it has been reported that acetylation of histone enzyme inhibitor can block the cytokine mediated inflammation such as TNF-alpha and TGF-beta Disease is reacted.Largely report that acetylation of histone enzyme inhibitor can also increase the level of glutathion inside cell, strengthened with this The oxidation resistance of cell.

Above result of study fully shows, acetylation of histone enzyme inhibitor can anti-apoptotic (up-regulation protected protein and Block the pathway of dead signal) it is and can anti-inflammatory, anti-oxidant, it is expected to for caused by treating ischemia-reperfusion or other reasons Organ damage.Also there are many brain damages for reporting sodium butyrate and can effectively mitigating the initiation of experimental rat ischemia-reperfusion. However, acetylation of histone enzyme inhibitor, particularly sodium butyrate, because its molecular weight very little (is removed rapidly, thus half by kidney Phase of declining is extremely short), polar group, particularly carboxyl are carried again, it is more difficult in the environment of meta-alkali effectively to be absorbed by cell, so Its poor bioavailability, plasma concentration will more than 10 mMs level special talents there is effect, only when lasting heavy dose gives butyric acid Effective treatment concentration is can be only achieved during sodium.But lasting heavy dose gives sodium butyrate and certainly will aggravate inflammatory edema, and cranium can be induced Inner high voltage and heart failure.

Therefore, the present inventor attempts the strategy using collaboration prodrug, the different types of compound of above two is passed through suitable When form coupling (esterification) and formed cooperate with prodrug.Surprisedly, pharmacological evaluation shows, the present invention obtains this prodrug and shown Work improves bioavilability, and collaboration and complementary synergistic effect are formd in terms of pharmacodynamics, enhances therapeutic effect, expands Big treatment indication.

Specifically, the therapeutic value for folic acid and sodium butyrate great potential and the limitation as medicine.The present invention Using organic synthesis technology dexterously with ester bond by folic acid and C_3-16Aliphatic acid (such as butyric acid) coupling turns into hybrid molecule, overcomes The limitations of two kinds of compounds pharmaceutically, and collaboration and complementation are produced in pharmacodynamics, it thereby is achieved the institute of formula 1 The compound shown or its pharmaceutically acceptable salt, ester, hydrate, solvate or Metabolic Intermediate.These compounds can be with As wide spectrum, superpower cell-protecting and antiinflammatory, it is used for preventing carefully in the case where acute severe disease occurs for patient The death of born of the same parents' rapid, high volume.The compound integrates anti-oxidant, anti-inflammatory, anti-apoptotic, overcomes folic acid and this kind of group of sodium butyrate Histone acetylation enzyme inhibitor is in terms of pharmacokinetics the defects of, therefore its internal anti-oxidative damage, anti-inflammatory and anti-apoptotic Ability, all similar drugs are significantly better than particularly in terms of security.

Experiment shows, compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or generation shown in formula 1 Thanking to intermediate has following feature：

1st, there is optimal lipid, LogP is changed into 2.18 from -0.65, in the absorption side of dose-dependent drug Formula, the significant increase bioavilability of medicine, and can pass through blood-brain barrier；

2nd, C is greatly extended_3-16The half-life period of aliphatic acid (such as butyric acid), dramatically increase C_3-16Aliphatic acid (such as fourth Acid) membrane permeability；

3rd, cooperative effect is presented in hybrid molecule drug effect, greatly strengthens therapeutic effect；

4th, hybrid molecule drug effect is in complementary effect, greatly extends treatment indication；

5th, after the compound enters in vivo, hybrid molecule is hydrolyzed to folic acid and C in the presence of lipase_3-16Aliphatic acid Played a role after (such as butyric acid), the material of toxic side effect is caused without any generation, therefore the compound has very high safety Property；

6th, cost is cheap, and synthetic technology is simple, is easy to industrialization etc..

In conventional all documents and patent delivered, being only mentioned to folic acid and acetylation of histone enzyme inhibitor may divide Not Ju You organ protection, but all do not solve the defects of these medicines itself fundamentally, be not carried out clinically yet Effectively application.Therefore, those skilled in the art can not possibly predict shows according to the folic acid of the present invention and the hybrid molecule ratio of butyric acid There are the active component of technology and preparation that there is following more prominent technique effect：Greatly enhance Organoprotective effect；Add Antiinflammatory action；The bioavilability of medicine is fundamentally improved, effectively passes through blood-brain barrier.

Brief description of the drawings

Hereinafter, embodiment of the present invention is described in detail with reference to accompanying drawing, wherein：

Fig. 1 shows the cell survival rate test result of the compounds of this invention；

Fig. 2 shows protection result of the compounds of this invention to nerve cell anoxia-induced apoptosis；

Fig. 3 shows protection result of the compounds of this invention to human embryonic kidney cell (HEK293) oxidative damage；

Fig. 4 shows protection result of the compounds of this invention to cardiac muscle cell's Injury by Adriamycin；

Fig. 5 shows the influence of the compounds of this invention pair and cell survival and death-associated protein；

Fig. 6 shows potent inhibitory activity of the compounds of this invention to Caspase-3.

Embodiment

Illustrate the present invention referring to specific embodiment.It will be appreciated by those skilled in the art that these embodiments are only For illustrating the present invention, its scope not limiting the invention in any way.

Synthesis and the cytoprotection function of some specific examples of the compounds of this invention are specifically described in following examples Test, it should be understood that protection scope of the present invention is not limited in these embodiments.

The present invention will be further described in detail in herein below.In the present invention, unless otherwise indicated, All ratios are mass ratio, and all percentage is mass percent, the unit of temperature for DEG C, the unit of pressure is Pa.Room temperature refers to environment temperature conventional in laboratory, usually 25 DEG C.In addition, all number ranges that the present invention describes are wrapped End value is included, and including the upper and lower bound of scope of disclosure is combined mutually into obtained new number range.

Following abbreviation is used in the present invention：RT- room temperatures；Min- minutes；H- hours；Biotin- biotins；DCM- dichloros Methane；FA- folic acid；5-Me-4H-FA-5- methyl tetrahydrofolates；DMF- dimethylformamides；DMSO- dimethyl sulfoxides；LPS- is thin Bacterium lipopolysaccharides；EtOAc- ethyl acetate, MeOH- methanol；K₂CO₃- potassium carbonate；TEA/Et₃N- triethylamines；NBT- chlorinations nitro four Nitrogen azoles is blue；The dUTP Nick Ends mark of TUNEL- terminal deoxynucleotidyl transferases mediation；HPLC- high pressure lipuid chromatography (HPLC)s； IR- infrared spectrums；¹H NMR- magnetic resonance Proton spectroscopy is analyzed；MIS%- infarct ratio；LVEDP- left ventricular end diastolic presssures；LDH- Lactic dehydrogenase；ALT- glutamic-pyruvic transaminase；AST- glutamic-oxalacetic transamineases；SOD- superoxide dismutases；GSH-Px- glutathione oxygen Change enzyme；MDA- propane diamine；CK- creatine phosphokinases；CK-MB- CPK-MBs；TNF- TNFs；IL- 1- interleukin 1s；IL-6- interleukin-6s；Z-VAD-fmk- apoptosis inhibitors；IC₅₀- effective dose 50； Caspase- cystine proteolytic enzymes；Apoptosis- apoptosis；

Unless otherwise indicated, chemical reagent used in following synthetic example is strange purchased from SIGMA-Ai Er Delhis (Sigma-Aldrich) analytical grade reagent of company, used water are deionization double distilled water.

Embodiment 1

Compound a has been synthesized in this embodiment, and its building-up process is as follows：

By methyl tetrahydrofolate (457mg, 1mmol), butyric acid chloromethyl ester 301mg (2.2mol), Et₃N (triethylamine, 202mg, 2.2mmol) add in 50mL dimethylformamides (DMF), 6h is reacted at 60 DEG C, reaction is cooled to 40 DEG C after terminating, Filtration, filtrate decompression are drained, and obtain yellow crude, and ethyl alcohol recrystallization obtains target compound a, yellow solid, purity 95%, received Rate is 68%.Or filtrate decompression drain after be dissolved in 50mL ethyl hexylates, with 50mL saturations Na₂CO₃, 5% acetic acid, saturation chlorine Change sodium, distilled water is washed 3 times, product purity 96%, yield 69%.Or purify (dichloromethane with silica gel column chromatography With the mixture of methanol, gradient elution (v/v=97：3 to 9：1)), product purity 97%, yield 67%.

¹H-NMR(CDCl₃):δ=8.69 (1H, bs, H-7), 8.17 (1H, m, CONHGlu), 7.65,6.70 (4H, 2m, virtue Fragrant H), 7.31 (2H, s, NH), 4.82 (2H, s, 9-CH), 4.22 (4H, q, 2CH), 4.23 (2H, m, 2a-CH), 3.20 (3H, s),1.79-1.75(4H,m),1.60(4H,s,3CH)。

LC-MS：C₃₀H₄₀N₇O₈,m/z(M-H)660.5803。

Embodiment 2

Compound b has been synthesized in this embodiment, and its building-up process is as follows：

By folic acid (441mg, 1mmol), butyric acid chloromethyl ester 301mg (2.2mol), Et₃N (triethylamine) 202mg (2.2mmol) is added in 50mL dimethylformamides (DMF), and 6h is reacted at 60 DEG C, and reaction is cooled to 40 DEG C after terminating, filter, Filtrate decompression is drained, and obtains yellow crude, and ethyl alcohol recrystallization obtains target compound b, yellow solid, purity 95%, and yield is 68%.Or filtrate decompression drain after be dissolved in 50mL ethyl hexylate, with 50mL saturations Na₂CO₃, 5% acetic acid, saturation chlorination Sodium, distilled water are washed 3 times, product purity 95%, yield 67%.Or purified with silica gel column chromatography (dichloromethane and The mixture of methanol, gradient elution (v/v=97：3 to 9：1)), product purity 97%, yield 62%.

¹H-NMR(CDCl₃):δ=8.65 (1H, bs, H-7), 8.15 (1H, m, CONHGlu), 7.70,6.70 (4H, 2m, virtue Fragrant H), 7.36 (2H, s, NH), 4.80 (2H, s, 9-CH), 4.25 (4H, q, 2CH), 4.23 (2H, m, 2a-CH), 3.20 (3H, s,),1.79-1.75(4H,m),1.43(4H,s,2CH)。

LC-MS：C₂₉H₃₅N₇O₈,m/z(M-H)642.5637。

Embodiment 3

Compound c has been synthesized in this embodiment, and its building-up process is as follows：

By folinic acid (473mg, 1mmol), butyric acid chloromethyl ester 301mg (2.2mol), Et₃N (triethylamine, 202mg, 2.2mmol) add in 50mL dimethylformamides (DMF), 6h is reacted at 60 DEG C, reaction is cooled to 40 DEG C after terminating, filter, filter Liquid decompressing and extracting, obtains yellow crude, and ethyl alcohol recrystallization obtains target compound c, yellow solid, purity 95%, and yield is 68%.Or filtrate decompression drain after be dissolved in 50mL ethyl hexylates, with 50mL saturations Na₂CO₃, 5% acetic acid, saturation chlorination Sodium, distilled water are washed 3 times, product purity 96%, yield 69%.Or purified with silica gel column chromatography (dichloromethane and The mixture of methanol, gradient elution (v/v=97：3 to 9：1)), product purity 97%, yield 67%.

¹H-NMR(CDCl₃):δ=8.65 (1H, bs, H-7), 8.15 (1H, m, CONHGlu), 7.70,6.70 (4H, 2m, virtue Fragrant H), 7.36 (2H, s, NH), 4.80 (2H, s, 9-CH), 4.25 (4H, q, 2CH), 4.23 (2H, m, 2a-CH), 3.20 (3H, s),1.79-1.75(4H,m),1.69(4H,s,3CH)。

LC-MS：C₃₀H₃₉N₇O₉,m/z(M-H)674.6131。

Embodiment 4

Compound e has been synthesized in this embodiment, and its building-up process is as follows：

In the case of logical nitrogen and stirring, compound a (661mg, 1mmol), sodium borohydride that embodiment 1 is synthesized (189mg, 5mol) is dissolved in 20mL DMF, reacts 30 minutes at room temperature.Then 5mL 5% hydrochloric acid and 100mL acetic acid second is added Ester, then with 5% glacial acetic acid, 10% Na₂CO₃Washed with saturated nacl aqueous solution, filtration, filtrate decompression is drained, and obtains Huang Color crude product, ethyl alcohol recrystallization obtain target compound e, yellow solid, purity 97%, yield 81%.Or filtrate decompression is taken out 50mL ethyl hexylates are dissolved in after dry, with 50mL saturations Na₂CO₃, 5% acetic acid, saturated sodium-chloride, distilled water wash 3 times, product Purity is 92%, yield 83%.Or purify (mixture of dichloromethane and methanol, gradient elution with silica gel column chromatography (v/v=97：3 to 9：1)), product purity 97%, yield 79%.

¹H-NMR(CDCl₃):δ=8.71 (1H, bs, H-7), 8.19 (1H, m, CONHGlu), 7.63,6.71 (4H, 2m, virtue Fragrant H), 7.31 (2H, s, NH), 4.82 (2H, s, 9-CH), 4.22 (4H, q, 2CH), 4.22 (2H, m, 2a-CH), 3.83 (dd1H),3.20(3H,s,),1.8–1.76(4H,m),1.61(4H,s,3CH)。

LC-MS：C₃₀H₄₀N₇O₈,m/z(M-H)660.5803。

Embodiment 5

Compound d has been synthesized in this embodiment, and its building-up process is as follows：

Logical nitrogen and stirring in the case of, by embodiment it is 2-in-1 into compound b (643mg, 1mmol), sodium borohydride (189mg, 5mol) is dissolved in 20mL DCM, reacts 30 minutes at room temperature.Then 5mL 5% hydrochloric acid and 100mL second are added Acetoacetic ester, then with 5% glacial acetic acid, 10% Na₂CO₃Washed with saturated nacl aqueous solution, filtration, filtrate decompression is drained, obtained To yellow crude, ethyl alcohol recrystallization obtains target compound d, yellow solid, purity 97%, yield 79%.Or filtrate subtracts Pressure is dissolved in 50mL ethyl hexylates after draining, with 50mL saturations Na₂CO₃, 5% acetic acid, saturated sodium-chloride, distilled water wash 3 times, Product purity is 93%, yield 81%.Or purify (mixture of dichloromethane and methanol, gradient with silica gel column chromatography Elute (v/v=97：3 to 9：1)), purity 96%, yield 75%.

¹H-NMR(CDCl₃)：δ=8.67 (1H, bs, H-7), 8.16 (1H, m, CONHGlu), 7.71-7.65 (4H, 2m, virtue Fragrant H), 7.36 (2H, s, NH), 4.80 (2H, s, 9-CH), 4.25 (4H, q, 2CH), 4.23 (2H, m, 2a-CH), 3.81 (dd1H),3.20(3H,s),1.79-1.75(4H,m),1.45(4H,s,2CH)。

LC-MS：C₂₉H₃₅N₇O₈,m/z(M-H)642.5637。

Among compound provided by the present invention or its pharmaceutically acceptable salt, ester, hydrate, solvate or metabolism Technique effect of the present invention can be achieved in body, and the compound a-e especially obtained by embodiment 1~5 has more obvious Technique effect.

The present invention has carried out cell protection activity experiment to compound a-e, and the folic acid with not modified, sodium butyrate, Methyl tetrahydrofolate and existing general Caspase inhibitor Z-VAD-fmk are compared.Caspase detection kits include Inhibitor (Z-VAD-fmk) and Caspase activation products be available from the analysis of Pu Luomaige companies of the U.S. (Promega) company Level reagent.

Caspase determinations of activity are carried out below in an example and cell in vitro survival experiment, every kind of experiment repeat Three times, each concentration sets three wells.Measurement data is represented with means standard deviation, is compared between group using one-way analysis of variance, Enumeration data uses x²Examine, between group the comparison of accumulative survival rate p value is worked as using Kaplan-Meier analyses<When 0.05, it is believed that Difference is statistically significant.Statistical analysis uses SPSS11.0 softwares.

Test example 1

1. experiment in vitro

1) inhibitory activity using colorimetric method cell free system measure compound to Caspase-1 and Caspase-3

Operated according to kit specification.Specifically, test and carried out in 96 hole elisa Plates, by above-mentioned synthesis Compound a-e (0.10,0.5,2.50,12.5 μM) and Caspases inhibitor Z-VAD-fmk (positive control) respectively with work The substrate of Caspases-1 and Caspase-3 and the pNA mark of change is directly added into hole, after being reacted 1 hour at 37 DEG C, On ELIASA OD values are surveyed with 405nm wavelength.Blank control is carried out using the sample for not adding cell-protecting simultaneously, by each experiment Outcome measurement value draws the degree of Caspase activity inhibiteds compared with blank control, calculates its IC₅₀(μM), i.e., Caspase vigor is suppressed the concentration of compound needed for half.It the results are shown in Table 1 the 2nd row and the 3rd row.

2) protection of Apoptosis is caused to Caspase-3 activation

By the cell of the Caspase-3 stable transfections of the activation of tetracycline induction, (HEK293-Caspase-3, HEK293 are thin Born of the same parents are purchased from Co., Ltd of clontech laboratories (Clontech Laboratories, Inc.)) it is seeded in 96 porocyte culture plates In (5000 cells/well), after culture 24 hours, by the compound a-e (0.5,2.5,12.5,62.5 μM) of above-mentioned synthesis and Caspases inhibitor Z-VAD-fmk, folic acid, methyl tetrahydrofolate, sodium butyrate, methyl tetrahydrofolate+sodium butyrate are respectively with four Ring element (being used to induce Caspase-3 expression to cause Apoptosis) is applied directly in cell culture medium together, and culture 48 is small Shi Hou, OD values are surveyed with mtt assay to reflect cell survival：Each hole adds MTT 0.1mg (100 μ l), and culture abandons supernatant after 3 hours Liquid, to every hole add dimethyl sulfoxide (DMSO) (DMSO) 150 μ l, after vibration with enzyme-linked instrument survey OD values (450nm), cell survival rate= (test group OD values-blank control group OD values)/(control group OD values-blank control group OD values).Control group：It is not added with medicine；Blank Control group：Nutrient solution, MTT, DMSO, without cell.Its IC is calculated according to cell survival rate₅₀(μM) is (needed for 50% cytoprotection Metering), the results are shown in Table 1 the 4th row.

As shown in Table 1, folic acid and its how high concentration of derivative and sodium butyrate are all any directly suppression Caspase-1 or 3 function, compound a-e of the invention in vitro also without directly suppress Caspase-1 or 3 activity function, but Apoptosis caused by the Caspase-3 of activation can effectively be suppressed.

Inhibition of the compound of the present invention of table 1 to Caspase

Note："-" represents unrestraint activity

3) to the protection of cardiomyocytes ischemical reperfusion injury

The cardiac muscle cell of rat primary culture is seeded in 96 porocyte culture plates (10000 cells/well), trained completely Support after being cultivated 24 hours in base (calf serum for containing 10%), use serum free medium instead and continue to cultivate 8 hours (ischemic cell membranes Type), then use complete medium instead and continue to cultivate (cell model for making ischemical reperfusion injury).3 hours after ischemic, will Compound a-e and control drug (Z-VAD-fmk, sodium butyrate, folic acid and folic acid derivatives (5-methyltetrahydrofolate)) are added to carefully In born of the same parents' culture medium, cultivate 48 hours, detect cell survival rate with mtt assay (being same as above), as a result see Fig. 1.As shown in Figure 1, folic acid exists The myocardial cell injury of in vitro culture caused by ischemia-reperfusion can be protected when dosage is more than 25 μM, but when folic acid concentration is less than Myocardial cell injury (p caused by ischemia-reperfusion can not be effectively protected at 10 μM>0.05)；When butyric acid na concn is less than 2000 μM To cell without obvious protective function (p>0.05) not reaching when, folic acid shares with sodium butyrate, which reduces dosage, still can effectively protect Protect the purpose (p of cell<0.05), but under respective effective dose, coordinating protection effect is presented；Compound a-the e of the present invention, For particularly a and b compared with control drug Z-VAD-fmk etc., its protective effect generates surprising enhancing：When concentration is up to 5 μM, Protection (the p of myocardial cell injury caused by ischemia-reperfusion (reaching 80%) can almost be blocked<0.001)；Alone folic acid or four During hydrogen folic acid, just there is certain protecting effect when concentration is up to 50 μM；And Z-VAD-fmk is when at concentrations up to 25 μM, it protects effect It should be only capable of improving 10-15%, when Z-VAD-fmk concentration is more than 50 μM, remarkably promote cell death on the contrary (result is not shown). Strikingly, 3 hours after ischemic, the compound a of the present invention is given, b, c, d or e remain to effectively protect ischemic Myocardial cell injury (p caused by Reperfu- sion<0.05) Fig. 1, is as a result seen.

4) to the protection of nerve cell anoxia-induced apoptosis

Rat cell (PC12) is seeded in 12 porocyte culture plates containing slide, in complete medium After being cultivated 24 hours in (NGF containing 10% calf serum and containing 10ng/ml), use low-oxygen environment (3% oxygen) instead and continue to cultivate 12 hours, then continue to cultivate in home.3 hours after anoxic, by compound a, b and control drug (Z-VAD- Fmk, folic acid and its derivative (5-methyltetrahydrofolate), sodium butyrate) it is added in cell culture medium, after cultivating 48 hours, cell With Hoechst 33342 and the double dyeing of propidium iodide, detection apoptotic cell (red) and survivaling cell (blueness), Fig. 2 is as a result seen. As shown in Figure 2, folic acid is 10 μM and when sharing sodium butyrate (100 μM) in dosage, it is impossible to protects nerve cell caused by anoxic to damage Hinder (p>0.05)；The compound a and b of the present invention, when concentration is up to 5 μM, nerve cell caused by effectively protecting anoxic damages Hinder (p<0.01).

5) to the protection of human embryonic kidney cell (HEK293) oxidative damage

Human embryonic kidney cell (HEK293) is seeded in 12 porocyte culture plates containing slide (30000 cells/ Hole), after being cultivated 24 hours in complete medium (calf serum for containing 10%), 200 μM of peroxidating is added into culture medium Hydrogen (H₂O₂) continue to cultivate.Adding hydrogen peroxide (H₂O₂) after 3 hours, by the compound a of various concentrations and b and difference Folic acid+sodium butyrate of concentration is added in cell culture medium, is cultivated 48 hours, and cell density is observed simultaneously directly under inverted microscope Take pictures.As a result Fig. 3 is seen.From the figure 3, it may be seen that folic acid is when dosage is 25 μM and sharing sodium butyrate (2500 μM) can protect hydrogen peroxide to draw Embryonic kidney cell damage (the p risen<0.05), but when folic acid concentration is less than 5 μM, it is impossible to protect embryo kidney caused by hydrogen peroxide Cellular damage (p>0.05)；To the only slight protective effect of cell (p=0.0518), this hair when butyric acid na concn is less than 500 μM Bright compound a is in dose-dependent protective effect, and compound b is similar to compound a to the protecting effect of cell, compound b Result do not show.

6) to the protection of cardiac muscle cell's Injury by Adriamycin

The cardiac muscle cell of rat primary culture is seeded in 96 porocyte culture plates (10000 cells/well), trained completely Support after being cultivated 24 hours in base (calf serum for containing 10%), 1 μM of adriamycin is added into culture medium and continues to cultivate.Adding 3 hours after adriamycin, by compound a-e and control drug (Z-VAD-fmk, folic acid and derivative (5-methyltetrahydrofolate), Sodium butyrate etc.) it is added in cell culture medium, cultivate 48 hours.Cell is dyed with Hoechst 33342, detection cell survival rate and Apoptosis incidence, is as a result shown in Fig. 4.As shown in Figure 4, folic acid in dosage more than 25 μM and when sharing sodium butyrate (500 μM), can be slight Cardiac muscle cell's cellular damage caused by adriamycin is protected, not reaching when folic acid shares with sodium butyrate, which reduces dosage, still can have The purpose of effect protection cell, but under respective effective dose, coordinating protection effect is presented；The present invention compound a and b with it is right Compared according to medicine Z-VAD-fmk etc., its protective effect generates great enhancing：When concentration is up to 5 μM, Ah mould can be almost blocked Myocardial cell injury (p caused by element<0.001), and Caspase inhibitor Z-VAD-fmk maximum protection effect is only capable of improving 10-15% (p<0.05).Strikingly, behind 3 hours after adriamycin processing, the compound of the present invention is given still Myocardial cell injury (p caused by adriamycin can effectively be protected<0.005).As a result Fig. 4 is seen.

Test example 2 is directed to the treatment of acute myocardial infarction AMI

A. the foundation of ami model

Coronary ligation method：From Sprague-Dawly (SD) male rat, 200~250g of body weight, by SD rats with penta bar Than appropriate sodium (40mg/kg) after intraperitoneal injection of anesthesia, rat MI/R (30min/3h) model is prepared according to a conventional method.Dorsal position is consolidated Due on animal surgery plate, conventional preserved skin, sterilization, otch, blunt separation and exposure tracheae are done in neck median line first, along 3,4 Cartilagines tracheales interannular carries out tracheotomy, after being intubated and connecting meiofauna lung ventilator, cuts 2 ribs, opens the wall of the chest, cruelly Reveal heart, carefully cut off pericardium, left coronary arteries descending anterior branch and posterior descending branch crotch hurtless measure about 3~4mm under left auricle of heart Silk thread passes through left coronary artery descending anterior branch, visible left room antetheca and apex colour-darkening, beating decrease after knotting.Synchronous electrocardio Whether figure engenders that the ST sections back of a bow is raised upwards, Q ripples and QRS wave peak reduce.After ligation 30 minutes, ligature is unclamped, it is extensive Multiple hemoperfusion 120 minutes, is then shut off thoracic cavity, then sutures muscle and skin successively.Heart infarction face is detected after Reperfu- sion 24h Product, heart function, cardiac muscle cell apoptosis and oxidation/nitrification stress, the Indexs measure such as inflammation.Sham-operation group is using at same method Reason, simply without coronary ligation art.

B. Experiment on therapy (dividing three parts)

1. the compound of the acute myocardial infarction of rat model measurement present invention obtained using test example 2A is to Acute myocardial The effect of infarct rat model.Rat is randomly divided into 7 groups (every group includes 8 rat models) that following numbering is a-g：A. it is false Operation group (SHAM), coronary artery underpass do not ligature；B. Ischemic/reperfusion (MI/R) group；Positive treatment group includes：c.Z- VAD-fmk (23mg/kg Z-VAD-fmk=50 μM)；D. nicorandil (0.1mg/kg)；E. folic acid+sodium butyrate group (FA： 3.2mg/kg=8 μM of+BA-Na：36mg/kg=200 μM)；F. compound a (a of the invention：5mg/kg=8 μM)；G. it is of the invention Compound b (b：5.1mg/kg=8 μM).Half an hour after acute myocardial infarction rat model causes (after ischemic), from stock The slow drug administration by injection of vein or abdominal cavity, successive administration 2 days, daily administration 2 times.

2. in another therapeutic test, using the compound b of the present invention basic, normal, high three concentration：

It is low：1mg/kg=1.7 μM；

In：3mg/kg=5 μM；

It is high：9mg/kg=15 μM；

Basic, normal, high three concentration of methyl tetrahydrofolate (MTFA)+sodium butyrate (BA) group：

It is low：FA：1mg/kg=2.7 μM of+BA:12.7mg/kg=67 μM；

In：FA：3mg/kg=7 μM of+BA：37.3mg/kg=200 μM；

It is high：FA：9mg/kg=21 μM of+BA：112mg/kg=600 μM；

Carry out therapeutic test.

3. in another therapeutic test, the change of the high dose of the present invention is given in vein or abdominal cavity after Reperfu- sion 3 is small Compound b (9mg/kg) and FA+BA (30mg/kg+336mg/kg).

Observation index

1. cardiac function investigation：Rat Ecg and blood flow are continued to monitor by polygraph (RM-4200) Each index of mechanics.Electrocardiogram, left ventricular developed pressure (LVDP), left room etc. hold contraction/relaxation phase pressure and rise or fall maximum rate (± dP/dtmax) etc. by computer-automatic collection, record and is calculated by data analysis system.

2. myocardial infarct size determines：Rat heart is taken out after taking blood within 5th day, removes atrial tissue and fat, weighs, will Crosscutting 5 of myocardium of left ventricle, it is then immersed in NBT (NBT) phosphate buffer, puts 37 DEG C of water bath with thermostatic control dyes Color takes out section after 30 minutes, normal structure dyeing, ischemic tissue does not dye, and cuts ischemic myocardium and weighs, with ischemic myocardium with The percentage of left ventricle weight in wet base calculates infarct ratio (MIS%).

3. blood biochemistry index includes the detection of inflammation index：Whole blood full-automatic biochemical was extracted at the 3rd hour and 24 hours Analytical instrument (UniCel DxC 600Synchron, Beckman, the U.S.) measure serum myocardial enzyme spectrum (glutamic-oxalacetic transaminease/AST, Lactic dehydrogenase/LDH, creatine kinase isozyme/CKMB)；Using double antibody sandwich ELISA detection blood TNF, IL-6 change Change.

4. the detection with cell survival and death-associated protein：The heart is detected with Western blotting (Western Blots) method Muscular tissue P53, nitric oxide synthase type (iNOS), heat shock protein 70 (Hsp70), Metallothionein 1 The change of (Metallothionein 1, MT1) expression.

5. cardiac muscle cell apoptosis index (AI) and caspase-3 activity:The detection end-labelling of cardiac muscle cell apoptosis, Caspase-3 determinations of activity Western Blots, with the cut situations of anti-PARP TPPA PARP.

6. the detection of Antioxidant Indexes：Propane diamine (MDA) content thiobarbituricacidα- colorimetric method, super oxygen oxide disproportionation Enzyme (SOD) content is determined using xanthine oxidase, and glutathione peroxidase (GSH-Px) content uses two thio two Nitrobenzoyl acid system detects.

As a result

1. the change of cardiac function：Whether there is protective effect to Ischemic Heart function for observation research and development medicine, monitor The hemodynamic index of rat.The basic value no significant difference of each index before ischemic.After Reperfu- sion, heart rate (HR) nothing between each group Significant difference；LVDP value SHMA Normal groups are that (20 ± 2) kPa, MI/R group significantly reduces [(5 ± 1.1) than SHAM group Vs (20 ± 2) kPa, n=8, P<0.01]；FA [(6.1 ± 1.1) kPa, n=8, P ＞ 0.05]；MTFA [(6.7 ± 1.3) kPa, n =8, P ＞ 0.05]；Nicorandil [(10.9 ± 1.2) kPa, n=8, P ＞ 0.05]；FA+BA [(7.3 ± 1.6) kPa, n=8, P ＞ 0.05]；Z-VAD-fmk [(6.9 ± 1.1) kPa, n=8, P ＞ 0.05]；A [(15.8 ± 1.7) kPa, n=8, P<0.01]；b [(17.1 ± 1.9) kPa, n=8, P<0.01].

In addition to the compound a and b of the present invention, other medicines group can not be such that LVDP is significantly raised compared with I/R groups.Make us impression It is deep, although Z-VAD-fmk can effectively protect ischemic caused by vitro culture cardiac muscle cell damage, but Z- VAD-fmk not can effectively improve the heart function of animal ischemic myocardium but, and nicorandil, which plays the role of moderate, improves LVDP.

2. the change of myocardial infarct size and myocardium serum enzyme：Myocardial infarction area and serum enzyme index result collect 2 are shown in Table, it shows that the compound that the present invention synthesizes has strong protective effect to myocardial ischemia-reperfusion injury, hence it is evident that better than Z-VAD- Fmk groups, nicorandil and folic acid+butyric acid group, wherein (the FA under the concentration that this experiment gives：5 μM, BA：200 μM) do not have it is bright Aobvious protective effect.The compound a or b that the present invention is given after ischemic half an hour still can reduce infarct size nearly 3 Times, the dead conduction path activated can be blocked by showing the compound of the present invention, there is critically important clinical value.

Therapeutic effect of the compound of table 2 to acute myocardial infarction AMI

Compared with infarct group,¹P<0.05；²P>0.05；³P>0.05；⁴P<0.001；⁵P<0.001；

^*P<0.05；^#P>0.05

3. the detection of inflammation index：The result of variations for the treatment of group and control group serum levels of inflammatory cytokines, which collects, is shown in Table 3.After wound 3h Plasma TNFs-α, IL-1, IL-6 reach peak value.Compound a or b are given before Reperfu- sion can block TNF-α, IL-1, IL-6 water Flat rise, almost nearly normal level.Z-VAD-FMK only reduces IL-1, and nicorandil only reduces TNF, it is impossible to reduces other inflammation Disease medium.Result above shows that the compound energy significant effective of the present invention suppresses the inflammatory reaction after myocardial damage, has wide spectrum Antiinflammatory action.

Influence of the compound of table 3 to acute myocardial infarction AMI area and inflammatory factor

^*P<0.05；^#P>0.05；**P<0.05；^##P<0.05

4. the change with cell survival and death-associated protein：Compound a and b can effectively suppress death protein and inflammation The expression of disease albumen, while increase has the expression of the albumen of defencive function；Sodium butyrate slightly increases Hsp70, MT1 expression.The heart Situation of change such as Fig. 5 of muscular tissue P53, iNOS, Hsp70, COX2 and Metallothionein (MT1) expression.

The change of 5.Caspase-3 activity:The detection end-labelling of cardiac muscle cell apoptosis, Caspase-3 activity are surveyed Surely Western Blots are used, situation about being cut with anti-PARP TPPA PARP, as a result as shown in fig. 6, the change of the present invention The potent suppression Caspase-3 of compound energy activity.

6. the change of Antioxidant Indexes：Cardiac muscular tissue's MDA contents, SOD, GSH-Px determination of activity result show, compound a SOD and GSH-Px activity can be significantly increased with b, compound a or b enhancement of SOD and GSH-Px activity are substantially better than the positive The combination application of control drug and folic acid and sodium butyrate.Compound a and b can significantly reduce MDA content.Illustrate compound A or b has strong anti-oxidation function, and its result is as shown in table 4.

Change horizontal table 4 cardiac muscular tissue SOD, GSH-Px, MDA

Compared with infarct group,¹P<0.05；²P>0.05；³P>0.05；⁴P<0.001；⁵P<0.001

7. compound b dose-dependently protects myocardial damage caused by ischemia-reperfusion:The compound b of high dose is again It is administered before perfusion, can almost recovers Left Ventricular Ejection Fraction completely, myocardial infarction area reduces nearly 5 times.Corresponding high concentration Folic acid (9mg/kg) is only capable of making myocardial infarction area reduce 20% plus the sodium butyrate (112mg/kg) of high concentration, as a result such as table 5 It is shown.

The Cardioprotective of the compound b dose dependents of table 5

Compared with infarct group,¹P>0.05；²P>0.05；³P<0.001；⁴P<0.001

8. giving compound b after 3 hours in Reperfu- sion still can effectively protect myocardial damage：Given in Reperfu- sion after 3 hours Giving the compound b of high dose still can effectively protect myocardial damage, make infarct size reduce 40% or so, nicorandil, Caspase inhibitor (Z-VAD-FMK) can effectively protect myocardial damage before Reperfu- sion, be administered after 3 hours, do not have in Reperfu- sion There is protective effect, therefore the compound of the present invention has important clinical value, as a result as shown in table 6.

Therapeutic effect of the compound of table 6 to acute myocardial infarction AMI

Compared with infarct group,¹P>0.05；²P>0.05；³P<0.001

The experiment mice median lethal dose LD of test example 9₅₀Measure

The present inventor also measured were the median lethal dose LD of experiment mice₅₀.Specifically, the present inventor have selected 10 bodies Weight is 20 grams or so of Swiss mouse, is divided into five groups, the respective sheet disposably through 5 kinds of various doses of intraperitoneal injection of every group of mouse Invention compound b DMSO solution, used five kinds of injection volumes are respectively 11mg, 33mg, 100mg, 300mg and 900mg.Note The dosage used and body weight based on mouse is converted when recording half dead mouse.The experiment measures the median lethal dose of mouse For 470-520mg/kg.

In summary, compound provided by the invention or its pharmaceutically acceptable salt, ester, hydrate, solvate or Metabolic Intermediate has the effect of superpower anti-apoptotic, anti-inflammatory and anti-oxidative damage, can be used for treating vitals damage Wound.Zoopery is shown, for myocardial infarction, is administered in a few houres after seizure of disease, chemical combination of the invention Thing remains to effectively suppress the damage of organ, is therefore particularly suited for the organ acute injury disease of therapeutic window stenostomia, such as heart The treatment of flesh infarct, headstroke etc..We also note that the effect of compound protection myocardial infarction of the invention will be substantially better than Current maximally effective medicine, therefore be excellent first-aid medicine.It is easily real meanwhile the preparation technology of the compounds of this invention is simple Now industrialization large-scale production.

In a word, specific description of embodiments of the present invention is not intended to limit the present invention for the above, and those skilled in the art can be with It is variously modified or is deformed according to the present invention, without departing from the spirit of the present invention, all should belong to right appended by the present invention will The scope asked.

Claims

1. compound or its pharmaceutically acceptable salt represented by chemical formula a-e,

2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：Described compound choosing Compound represented by free below formula a-c,

3. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：Described compound choosing Compound represented by free below formula a or b,

4. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：Described compound is Compound represented by below formula b,

5. a kind of pharmaceutical composition for being used to prevent and/or treating organs damage, described pharmaceutical composition include therapeutically effective amount Compound according to any one of claim 1 to 4 or its pharmaceutically acceptable salt.

6. pharmaceutical composition according to claim 5, it is characterised in that described pharmaceutical composition is also used in advance comprising other The medicine of anti-and/or treating organs damage.

7. pharmaceutical composition according to claim 6, it is characterised in that described other for prevention and/or treating organs One or more of the medicine of damage in heparin, hirudin, argatroban, warfarin, Putuo Cali or Valsartan.

8. the pharmaceutical composition according to any one of claim 5 to 7, it is characterised in that described pharmaceutical composition is also wrapped Containing pharmaceutically acceptable auxiliary material.

9. pharmaceutical composition according to claim 8, it is characterised in that the pharmaceutically acceptable auxiliary material is selected from soybean Oil, olive oil, medium chain triglyceride, soybean lecithin, phosphatidyl choline, polyethylene glycol stearate or polyoxyethylene sorbitol One or more in acid anhydride fatty acid ester.

10. pharmaceutical composition according to claim 8, it is characterised in that the compound or its is pharmaceutically acceptable The mass ratio of salt and pharmaceutically acceptable auxiliary material is 1：10~90.

11. pharmaceutical composition according to claim 10, it is characterised in that the compound or its is pharmaceutically acceptable The mass ratio of salt and pharmaceutically acceptable auxiliary material is 1：15~50.

12. pharmaceutical composition according to claim 11, it is characterised in that the compound or its is pharmaceutically acceptable The mass ratio of salt and pharmaceutically acceptable auxiliary material is 1：17~30.

13. pharmaceutical composition according to claim 12, it is characterised in that the compound or its is pharmaceutically acceptable The mass ratio of salt and pharmaceutically acceptable auxiliary material is 1：20~25.

14. the pharmaceutical composition according to any one of claim 5 to 7, it is characterised in that described pharmaceutical composition is molten Liquid, suspension, emulsion, tablet, pill or implant.

15. the compound or its pharmaceutically acceptable salt according to any one of claim 1-4 are being prepared for preventing And/or the purposes in the medicine for the treatment of organs damage.

16. purposes according to claim 15, it is characterised in that the organ damage is selected from myocardial infarction, headstroke, urgency Property renal failure, serious hepatitis, hemorrhagic necrotizing pancreatitis, ALI, marrow acute injury, acute necrotizing intestines Scorching, acute radiation damage, the organ damage of septicemia or caused by radiotherapy and chemotherapy, MOF, rheumatism, liver decline, class wind Wet, osteoarthritis, Respiratory Distress Syndrome(RDS), Homocysteine mass formed by blood stasis, the complication or huge of Percutaneous coronary interventions (PCI) One or more in erythroblastic anemia.