CN101259127A - Sodium protoporphyrin production and application - Google Patents
Sodium protoporphyrin production and application Download PDFInfo
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- CN101259127A CN101259127A CNA2008100612144A CN200810061214A CN101259127A CN 101259127 A CN101259127 A CN 101259127A CN A2008100612144 A CNA2008100612144 A CN A2008100612144A CN 200810061214 A CN200810061214 A CN 200810061214A CN 101259127 A CN101259127 A CN 101259127A
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Abstract
The invention relates to applications of protoporphyrin in preparing medicines used for treating or preventing immunological liver injury or D-galatosamine induced acute liver injury; moreover, the invention also relates to a preparation method of the protoporphyrin and the preparations thereof.
Description
Technical field
The invention belongs to medical technical field, particularly, the present invention relates to protoporphyrin and be used for the treatment of or prevent application in the medicine of hepatic injury and preparation method and its product of protoporphyrin in preparation.
Background technology
The chemical name of protoporphyrin (English Protoporphyrin by name) is 7,12-divinyl-3,8,13,17-tetramethyl-21H, 23H-porphin-2, and the 18-dipropionic acid (7,12-Diethenyl-3,8,13,17-tetramethyl-21H, 23H-porphine-2,18-dipropanoic acid).Protoporphyrin is the initial liver function improving agent that extraction separation goes out from mammalian, and its (especially protoporphrin disodium) has the breathing of the cell tissue of promotion, improves protein and carbohydrate metabolism, and anticomplementary is in conjunction with the effect of grade.Animal experiment shows, protoporphyrin to hepatic injury due to the carbon tetrachloride have obvious reduction aminotransferase etc. effect (as referring to, the Ling Shu Lignum Rhamnellae. Acta Pharmacologica Sinica, 4 (4): 233-236), be applicable to acute hepatitis, various viral hepatitis clinically, also effective to liver cirrhosis, cholecystitis and cholelithiasis, indexs such as doing well,improving, liver swollenly dwindle, aminotransferase, turbidity test, icteric index are improved.
Yet, the origin cause of formation of hepatic injury is very complicated, except the viral hepatitis that carbon tetrachloride or the drug induced acute hepatitis of other liver toxicity and hepatitis virus cause, lymphocyte in the immune system (especially cytotoxic T cell) also can cause hepatocellular immunity damage in to antigenic replying, cause hepatocellular apoptosis, even can cause liver cirrhosis and hepatocellular carcinoma (as referring to, Nelson etc., J.Immunol, 158:1473-1481; Wong etc., J.Immunol., 160:1479-1488).Immunologic liver injury is different with the hepatic injury mechanism of action that virus causes with the liver toxicity medicine, the protoporphyrin that do not appear in the newspapers yet at present has treatment or preventive effect to immunologic liver injury, the protoporphyrin that also do not appear in the newspapers has treatment or preventive effect to the inductive acute liver damage of D-Gal amine, and this proves the new indication scope to the human body safe drugs once life-time service with the developing protoporphyrin therefore to need further research.
In addition, although Chen Wenhui etc. (referring to, Chinese Journal of Pharmaceuticals, 31 (7): 293-294) proposed a kind of improving one's methods of protoporphrin disodium that prepare, its raw material that needs is pure hemin; The haemachrome that the purity that the preparation method of some other bibliographical information also uses laboratory to use is high, rather than the purity of directly from animal blood, extracting do not reach that prepared in laboratory requires but low price many industrial haemachrome (as can referring to, Chinese patent application CN1300732A, CN1306002A, CN1450073A etc.), therefore be not suitable for suitability for industrialized production.
For this reason, the inventor proposed protoporphyrin preparation be used for the treatment of or prevent in the medicine of new indication application with and the preparation method that is suitable for suitability for industrialized production of crude drug, treatment and the preventive effect of protoporphyrin to immunologic liver injury and the inductive acute liver damage of D-Gal amine not only proposed in a creative way, and the preparation of its crude drug can the lower raw material of use cost, is more suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide protoporphyrin preparation be used for the treatment of or the medicine of epidemic prevention liver damage or the inductive acute liver damage of D-Gal amine in application with and preparation method and its goods of the suitable suitability for industrialized production of crude drug protoporphrin disodium.
Particularly, in first aspect, the invention provides protoporphyrin preparation be used for the treatment of or the medicine of epidemic prevention liver damage or the inductive acute liver damage of D-Gal amine in application.In this article, hepatic injury refers to the damage or the pathological changes of liver organization or cell appearance.The clinical manifestation of hepatic injury is to occur necrosis, liver angular vein inflammation in the hepatocellular degeneration, liver, reach the portal area cell infiltration occurs or fibroblast proliferation occurs or the liver enlargement in liver, therefore can examine under a microscope liver section judges the hepatic injury degree, determines the treatment or the preventive effect of medicine to hepatic injury with this.In addition, except assess hepatic injury by pathological phenomenon, when hepatocyte injury, cytolysis, the amount that is discharged into the transaminase in the blood circulation in the hepatocyte by damaged has increased, therefore by measuring the activity of these transaminases in serum, also can determine the degree that liver damage is hindered.
The medicine of a first aspect of the present invention preparation can be used for treatment or epidemic prevention liver damage, preferred epidemic prevention liver damage.Immunologic liver injury is induced generation by immunogen.Wherein, immunogen is not to cause the virus of viral hepatic injury, but can cause immune system to reply and attack hepatocellular antigenic substance.In a specific embodiment of the present invention, immunologic liver injury is bacillus calmette-guerin vaccine and lipopolysaccharide-induced immunologic liver injury.In addition, in another specific embodiment of the present invention, the medicine of first aspect present invention preparation also can be used for the treatment of or prevent the inductive acute liver damage of D-Gal amine.
In a first aspect of the present invention, protoporphyrin can be the water soluble salt of protoporphyrin, for example, and protoporphrin disodium, protoporphyrin potassium, preferably protoporphrin disodium.Since from healthy animal (as, cattle, pig etc.) although the haemachrome purity of extracting in the blood does not reach chemical pure requirement, its technical maturity, cost are lower, therefore protoporphyrin of the present invention can be that raw material prepares with this haemachrome.The preferred preferred protoporphrin disodium of the present invention is prepared by the method that may further comprise the steps:
A. haemachrome reduces under the condition that has formic acid and ferrum, adds Spirit of Mindererus. then and separates out crystal, obtains protoporphyrin coarse crystallization body;
B. with the esterification under the condition that has acid and methanol of protoporphyrin coarse crystallization body, add sal volatile then and separate out the protoporphyrin dimethyl ester crystalline solid and be dissolved in the chloroform, then solution is passed through Al
2O
3The chromatographic column purification distills the chromatography effluent, obtains the protoporphyrin dimethyl ester of purification; With
C. the protoporphyrin dimethyl ester of purification adds the acid decomposition, adds the sodium hydroxide neutralization then and separates out crystallization, obtains the protoporphrin disodium crystalline solid.
More preferably, protoporphrin disodium of the present invention is prepared by the method that may further comprise the steps:
A. add iron powder to the haemachrome that is dissolved in formic acid, reflux, cooling, filtration successively adds Spirit of Mindererus. in filtrate again, separate out crystalline solid, again crystalline solid is dissolved in ammonia, add the Spirit of Mindererus. crystallization then, again successively the washing, drying, obtain protoporphyrin coarse crystallization body;
B. add hydrochloric acid and methanol to protoporphyrin coarse crystallization body, reflux, cooling successively again adds sal volatile then and separates out the protoporphyrin dimethyl ester crystalline solid, after the washing protoporphyrin dimethyl ester crystalline solid is dissolved in the chloroform, then solution passed through Al
2O
3The chromatographic column purification, distillation chromatography effluent also washs, and obtains the protoporphyrin dimethyl ester of purification; With
C. the protoporphyrin dimethyl ester of purification adds hydrochloric acid and decomposes, add the sodium hydroxide neutralization then and separate out crystallization, washing successively again, dry, use the pyridine recrystallization, obtain the protoporphrin disodium crystalline solid.
Therefore, in second aspect, the invention provides the method for preparing protoporphrin disodium, it can use non-chemically pure other haemachrome raw material of level, and the protoporphrin disodium for preparing detects according to high performance liquid chromatography, ferrous porphyrin content 〉=90%, be preferably greater than 〉=95%, more preferably 〉=98%, most preferably 〉=99%: and water content≤2.0% wherein, preferably≤1.0%, more preferably≤0.5%.Particularly, a second aspect of the present invention provides the method for preparing protoporphrin disodium, it is characterized in that may further comprise the steps:
A. haemachrome reduces under the condition that has formic acid and ferrum, adds Spirit of Mindererus. then and separates out crystal, obtains protoporphyrin coarse crystallization body;
B. with the esterification under the condition that has acid and methanol of protoporphyrin coarse crystallization body, add sal volatile then and separate out the protoporphyrin dimethyl ester crystalline solid and be dissolved in the chloroform, then solution is passed through Al
2O
3The chromatographic column purification distills the chromatography effluent, obtains the protoporphyrin dimethyl ester of purification; With
C. the protoporphyrin dimethyl ester of purification adds the acid decomposition, adds the sodium hydroxide neutralization then and separates out crystallization, obtains the protoporphrin disodium crystalline solid.
More preferably, the method for second aspect present invention is characterized in that may further comprise the steps:
A. add iron powder to the haemachrome that is dissolved in formic acid, reflux, cooling, filtration successively adds Spirit of Mindererus. in filtrate again, separate out crystalline solid, again crystalline solid is dissolved in ammonia, add the Spirit of Mindererus. crystallization then, again successively the washing, drying, obtain protoporphyrin coarse crystallization body;
B. add hydrochloric acid and methanol to protoporphyrin coarse crystallization body, reflux, cooling successively again adds sal volatile then and separates out the protoporphyrin dimethyl ester crystalline solid, after the washing protoporphyrin dimethyl ester crystalline solid is dissolved in the chloroform, then solution passed through Al
2O
3The chromatographic column purification, distillation chromatography effluent also washs, and obtains the protoporphyrin dimethyl ester of purification; With
C. the protoporphyrin dimethyl ester of purification adds hydrochloric acid and decomposes, add the sodium hydroxide neutralization then and separate out crystallization, washing successively again, dry, use the pyridine recrystallization, obtain the protoporphrin disodium crystalline solid.
In the third aspect, the invention provides and be used for the treatment of or the goods of epidemic prevention liver damage or the inductive acute liver damage of D-Gal amine, it comprises the protoporphrin disodium of the method preparation of second aspect present invention.Particularly, a third aspect of the present invention provides and has been used for the treatment of or the pharmaceutical composition of epidemic prevention liver damage or the inductive acute liver damage of D-Gal amine, and it comprises the protoporphrin disodium of method preparation of second aspect present invention.This pharmaceutical composition is as the medicine in the application of first aspect present invention.
Pharmaceutical composition of the present invention also comprises pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier refers to nontoxic solid-state, semisolid or liquid filler, diluent, lapping or other pharmaceutical adjuncts.Known technology according to this area, can pharmaceutical composition be made various dosage forms according to the needs of therapeutic purposes, route of administration, preferred said composition is a unit dosage form, as tablet, capsule (comprise and continue to discharge or postpone releasing pattern), powder, Emulsion, injection, aerosol or liquid spray or suppository etc.For example, with oral administration, protoporphrin disodium can be combined with a kind of oral acceptable inert carrier of nontoxic materia medica, as cyclodextrin, etc. ooze glucose solution, glycerol, normal saline or its combination.This pharmaceutical composition can carry out administration by the known administering mode of one of ordinary skill in the art, for example oral, rectum, Sublingual, injection, transdermal, vagina and intranasal administration, preferred oral administration.Dosage changes to some extent according to the situation of action time of dosage form and expectation and treatment target, the required amount of actual therapeutic can by the doctor according to practical situation (as, patient's the state of an illness, body weight etc.) and determine easily.For general adult, the dosage of pharmaceutical composition of the present invention in protoporphrin disodium, can be that every kg becomes body weight for humans 1mg-1g, preferred 10mg-100mg.
In addition, the present invention also provides kit, and it comprises
A. container, it comprises the protoporphrin disodium of method preparation of second aspect present invention; With
B., the description that is used for the treatment of or prevents inductive immunologic liver injury of D-Gal amine or acute liver damage is described.Container is by not making with the inert material of protoporphrin disodium chemically reactive, and as vial, aluminum pool bag etc., preferred container seals." description " used herein refers to carry the entity of description.It can be a paper, is printed on the corresponding uses explanation on it; Can be container outer surface also, can be carved with or be printed on the corresponding uses explanation on it.
For the ease of understanding, below will be by of the description of concrete drawings and Examples to the present invention's property enumerated.It needs to be noted that these descriptions only are examples, do not constitute limitation of the scope of the invention.According to the argumentation of this description, many variations of the present invention, change all are conspicuous concerning one of ordinary skill in the art.In addition, the present invention has quoted open source literature, and these documents are in order more clearly to describe the present invention, and their full text content is all included this paper in and carried out reference, just looks like that repeated description is the same excessively in this article for their full text.
Description of drawings
Fig. 1 protoporphrin disodium is to the influence of serum biochemistry index in bacillus calmette-guerin vaccine and the lipopolysaccharide-induced immunologic liver injury model, and group shown in wherein * represents is with respect to the remarkable transaminase lowering level of model group.
Fig. 2 protoporphrin disodium is to the appraisal result of hepatic lesions degree in bacillus calmette-guerin vaccine and the lipopolysaccharide-induced immunologic liver injury model, and group shown in wherein * represents can significantly alleviate the lesion degree of liver with respect to model group.
Fig. 3 protoporphrin disodium is to the influence of serum biochemistry index in the inductive acute liver damage model of D-Gal amine, and group shown in wherein * represents is with respect to the remarkable transaminase lowering level of model group.
The specific embodiment
Following this paper will describe invention by specific embodiment.As do not specialize part, can carry out according to textbook and the laboratory manual that those skilled in the art were familiar with.Wherein, solute is liquid (comprising strong aqua ammonia, concentrated hydrochloric acid etc.) in the solution, and then percent concentration is a percent by volume; If solute is solid, then percent concentration is weight percentage.
The production method of embodiment 1 protoporphyrin
1, the preparation of thick protoporphyrin
Get haemachrome (available from Haining and field dragon bio tech ltd, it is according to Chinese patent application CN1450073A preparation) 100 grams, join among the 85% formic acid 5000ml, stirring, under the reflux condition, in 25 minutes, divide five addings with iron powder 30g, refluxed again 20 minutes, and be cooled to room temperature, filter, add 20% Spirit of Mindererus. 20000ml in the filtrate, placed 12 hours, and separated out crystallization, filtering for crystallizing, reuse 20% ammonia 1200ml dissolving, add 30% Spirit of Mindererus. 2000ml then, placed 12 hours, separate out crystallization, again with 2% acetic acid 1200ml washing 2 times, water 1 800ml washing 3 times, drying, altogether protoporphyrin coarse crystallization body 40g.
2, the protoporphyrin dimethyl ester preparation
Get protoporphyrin coarse crystallization body 100g, joining 2000ml contains in the methanol solution of 1% hydrochloric acid, refluxed 15 minutes, be cooled to and add 1% sal volatile 2000ml after the room temperature, crystallization is separated out in placement, filters, and washes crystallization with water 3 times, crystallization is dissolved in the 4000ml chloroformic solution, make gained solution by diameter be 10cm, length be 100cm, filler is the Al of 3000g
2O
3Chromatographic column, distillation chromatography effluent, the residue methanol wash after the distillation, protoporphyrin dimethyl ester 40g that must purification.Its molten point is that 228 degree decompose after measured.
3, the preparation of protoporphyrin sodium pure product
Get the protoporphyrin dimethyl ester 100g of purification, add 25% hydrochloric acid 3000ml dissolving after, room temperature was placed 6 hours, added water 6000ml dilution, with the neutralization of 30%NaOH solution, separated out crystallization, washed drying with water three times.Dry thing gets the protoporphrin disodium crystalline solid 50g of brown with the pyridine recrystallization.This protoporphrin disodium is the puce crystalline powder, and water-soluble and methanol is insoluble in diluted acid, is insoluble to chloroform, ether and acetone, detects ferrous porphyrin content 〉=98% according to high performance liquid chromatography.
1, laboratory animal
Wistar rat (body weight 1 80g～220g is available from Zhejiang Province's Experimental Animal Center) is divided into following 4 groups, 10 every group at random: (1) diammonium glycyrrhizinate group (the injection diammonium glycyrrhizinate is available from Jiangsu Zhengda Tianqing Drug Industry Co., Ltd); (2) protoporphrin disodium group (gastric infusion protoporphrin disodium); (3) blank group; (4) model group.
2, experimental technique
At the 0th day, in other 3 groups except the blank group, to rat tail vein injection 0.2ml BCG polyose nuclear acid injection (available from Hunan Jiuzhitang Siqi Biological Pharmaceutical Co., Ltd., dosage is counted 126 μ g/kg body weight with BCG-polysaccharide) sensitization; Meanwhile, blank group injection equal-volume normal saline.Then, in the diammonium glycyrrhizinate group, since the 5th day, every day, dosage was counted the 13.5mg/kg rat with diammonium glycyrrhizinate to the rats by intraperitoneal injection diammonium glycyrrhizinate, carried out altogether 7 days; In the protoporphrin disodium group, since the 5th day, every day, dosage was counted the 10mg/kg rat with protoporphrin disodium to rat oral gavage administration protoporphrin disodium, carried out altogether 7 days; Meanwhile, in blank group and model group, injection equal-volume normal saline.After the last administration 1 day, in other 3 groups except the blank group, inject 10 μ g lipopolysaccharide (LPS, can available from SIGMA company), damage hepatocyte to rat tail vein; Meanwhile, blank group injection equal-volume normal saline.
Behind the rat injection lipopolysaccharide 12 hours, rat is weighed, rat and blood sampling are put to death in the cervical vertebra dislocation then.Behind the separation of serum,, measure glutamate pyruvate transaminase in the serum (SGPT) activity, glutamic oxaloacetic transaminase, GOT (SGOT) activity respectively with glutamate pyruvate transaminase detection kit, glutamic oxaloacetic transaminase, GOT detection kit (all building up bio-engineering research institute) available from Nanjing by manufacturer's explanation.Simultaneously, get rat liver, through 10% formalin solution fix, after dehydration, paraffin embedding, film-making (4 μ m are thick), the HE dyeing, checked under optical microscope by the pathology professional and to have or not following pathological changes and to carry out pathological changes scoring: (1) has or not hepatocellular degeneration, as fat change, edema, have a liking for sour degeneration; (2) have or not hepatic necrosis, as spotty necrosis, kitchen range shape necrosis etc.; (3) have or not central vein and sinus hepaticus expansion, congestion, liver angular vein scorching on every side; (4) in the liver or portal area has or not connective tissue proliferation and cell infiltration.The pathological changes standards of grading are:, the necrosis of kitchen range shape occurs and double to keep the score by gently being labeled as 0 minute (normally), 0.5 minute (extremely slight), 1 minute (slightly), 2 minutes (moderate), 3 minutes (severe), 4 minutes (utmost point severe) respectively to heavy degree according to every pathological changes.Calculate the average mark of every treated animal pathological changes scoring, the high more expression lesion degree of score value is serious more.
3, experimental result
Active and the active experimental result of glutamic oxaloacetic transaminase, GOT (SGOT) of glutamate pyruvate transaminase (SGPT) as shown in Figure 1, the experimental result that pathological changes is marked is as shown in Figure 2.
In model group, rat blood serum glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, GOT significantly raise, and show that bacillus calmette-guerin vaccine and lipopolysaccharide have successfully caused the rat immunity liver damage; Protoporphrin disodium can significantly reduce the gpt level of hepatic injury rat, that is to say, concerning bacillus calmette-guerin vaccine and lipopolysaccharide-induced rat immunity liver damage model, protoporphrin disodium can significantly reduce the gpt level of immunologic liver injury rat.Damage does not have significant protective effect and diammonium glycyrrhizinate injection is to rats'liver.
Immunologic liver injury has been duplicated in histopathology research with also showing this Success in Experiment.In model group, liver tissue lesions shows as the hepatocyte spotty necrosis, and minority is the necrosis of kitchen range shape; Neutrophilic granulocyte quantity increases in the liver; There is slight cell infiltration the portal area.Liver tissue lesions's degree appraisal result shows that with respect to model group, the lesion degree significance of protoporphrin disodium group descends (P＜0.05), and damage does not have significant protective effect and diammonium glycyrrhizinate injection is to rats'liver.
1, laboratory animal
Wistar rat (body weight 180g～220g is available from Zhejiang Province's Experimental Animal Center) is divided into following 4 groups, 10 every group at random: (1) diammonium glycyrrhizinate group (the injection diammonium glycyrrhizinate is available from Jiangsu Zhengda Tianqing Drug Industry Co., Ltd); (2) protoporphrin disodium group (gastric infusion protoporphrin disodium); (3) blank group; (4) model group.
2, experimental technique
In the diammonium glycyrrhizinate injection group, since the 0th day, altogether carried out 7 day to rats by intraperitoneal injection diammonium glycyrrhizinate 13.5mg/kg rat every day; In the protoporphrin disodium group, since the 0th day, every day, dosage was counted the 10mg/kg rat with protoporphrin disodium to rat oral gavage administration protoporphrin disodium, carried out altogether 7 days; Meanwhile, in blank group and model group, injection equal-volume normal saline.Wherein, the 5th day (promptly putting to death rat before 48 hours), in other 3 groups except the blank group, to rats by intraperitoneal injection D-Gal amine (available from SIGMA company) 600mg/kg rat body weight; Meanwhile, blank group injection equal-volume normal saline.
The 7th day (injection D-Gal amine after 48 hours), rat and blood sampling were put to death in the cervical vertebra dislocation.Behind the separation of serum,, measure glutamate pyruvate transaminase in the serum (SGPT) activity, glutamic oxaloacetic transaminase, GOT (SGOT) activity respectively with glutamate pyruvate transaminase detection kit, glutamic oxaloacetic transaminase, GOT detection kit (all building up bio-engineering research institute) available from Nanjing by manufacturer's explanation.
3, experimental result
Experimental result as shown in Figure 3.In D-Gal amine model group, rat blood serum glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, GOT level significantly raise, and show that D-Gal amine successfully causes the rat acute hepatic injury.Protoporphrin disodium can reduce acute experiment liver damage rat glutamate pyruvate transaminase and glutamic oxaloacetic transaminase, GOT level by significance.Therefore, in the inductive rat acute liver injury model of D-Gal amine, peptide A can significantly reduce the inductive acute liver damage of D-Gal amine.In addition, diammonium glycyrrhizinate injection also has significant protective effect to this acute liver damage.
Claims (10)
1, protoporphyrin preparation be used for the treatment of or the medicine of epidemic prevention liver damage or the inductive acute liver damage of D-Gal amine in application.
2, the described application of claim 1, wherein protoporphyrin is a protoporphrin disodium.
3, claim 1 or 2 described application, its Chinese medicine is used for the treatment of or the epidemic prevention liver damage, and preferred described immunologic liver injury is bacillus calmette-guerin vaccine and lipopolysaccharide-induced immunologic liver injury.
4, claim 1 or 2 described application, its Chinese medicine is used for the treatment of or prevents the inductive acute liver damage of D-Gal amine.
5, the described application of claim 2, wherein protoporphrin disodium is prepared by the method that may further comprise the steps:
A. haemachrome reduces under the condition that has formic acid and ferrum, adds Spirit of Mindererus. then and separates out crystal, obtains protoporphyrin coarse crystallization body;
B. with the esterification under the condition that has acid and methanol of protoporphyrin coarse crystallization body, add sal volatile then and separate out the protoporphyrin dimethyl ester crystalline solid and be dissolved in the chloroform, then solution is passed through Al
2O
3The chromatographic column purification distills the chromatography effluent, obtains the protoporphyrin dimethyl ester of purification; With
C. the protoporphyrin dimethyl ester of purification adds the acid decomposition, adds the sodium hydroxide neutralization then and separates out crystallization, obtains the protoporphrin disodium crystalline solid.
6, the described application of claim 5, wherein protoporphrin disodium is prepared by the method that may further comprise the steps:
A. add iron powder to the haemachrome that is dissolved in formic acid, reflux successively again, cool off, filter, in filtrate, add Spirit of Mindererus., separate out crystalline solid, again crystalline solid is dissolved in ammonia, add the Spirit of Mindererus. crystallization then, again successively the washing, drying, obtain protoporphyrin coarse crystallization body;
B. add hydrochloric acid and methanol to protoporphyrin coarse crystallization body, reflux successively again, cool off, add sal volatile then and separate out the protoporphyrin dimethyl ester crystalline solid, after the washing protoporphyrin dimethyl ester crystalline solid is dissolved in the chloroform, then solution is passed through Al
2O
3The chromatographic column purification, distillation chromatography effluent also washs, and obtains the protoporphyrin dimethyl ester of purification; With
C. the protoporphyrin dimethyl ester of purification adds hydrochloric acid and decomposes, add the sodium hydroxide neutralization then and separate out crystallization, washing successively again, dry, use the pyridine recrystallization, with obtaining the protoporphrin disodium crystalline solid.
7. the method for preparing protoporphrin disodium is characterized in that may further comprise the steps:
A. haemachrome reduces under the condition that has formic acid and ferrum, adds Spirit of Mindererus. then and separates out crystal, obtains protoporphyrin coarse crystallization body;
B. with the esterification under the condition that has acid and methanol of protoporphyrin coarse crystallization body, add sal volatile then and separate out the protoporphyrin dimethyl ester crystalline solid and be dissolved in the chloroform, then solution is passed through Al
2O
3The chromatographic column purification distills the chromatography effluent, obtains the protoporphyrin dimethyl ester of purification; With
C. the protoporphyrin dimethyl ester of purification adds the acid decomposition, adds the sodium hydroxide neutralization then and separates out crystallization, obtains the protoporphrin disodium crystalline solid.
8. the described method of claim 7 is characterized in that may further comprise the steps:
A. add iron powder to the haemachrome that is dissolved in formic acid, reflux successively again, cool off, filter, in filtrate, add Spirit of Mindererus., separate out crystalline solid, again crystalline solid is dissolved in ammonia, add the Spirit of Mindererus. crystallization then, again successively the washing, drying, obtain protoporphyrin coarse crystallization body;
B. add hydrochloric acid and methanol to protoporphyrin coarse crystallization body, reflux successively again, cool off, add sal volatile then and separate out the protoporphyrin dimethyl ester crystalline solid, after the washing protoporphyrin dimethyl ester crystalline solid is dissolved in the chloroform, then solution is passed through Al
2O
3The chromatographic column purification, distillation chromatography effluent also washs, and obtains the protoporphyrin dimethyl ester of purification; With
C. the protoporphyrin dimethyl ester of purification adds hydrochloric acid and decomposes, add the sodium hydroxide neutralization then and separate out crystallization, washing successively again, dry, use the pyridine recrystallization, obtain the protoporphrin disodium crystalline solid.
9. be used for the treatment of or the pharmaceutical composition of epidemic prevention liver damage or the inductive acute liver damage of D-Gal amine, it comprises the protoporphrin disodium of claim 7 or 8 described methods preparations.
10. kit, it comprises
A. container, it comprises the protoporphrin disodium of claim 7 or 8 described methods preparations; With
B., the description that is used for the treatment of or prevents inductive immunologic liver injury of D-Gal amine or acute liver damage is described.
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| CNA2008100612144A CN101259127A (en) | 2008-03-18 | 2008-03-18 | Sodium protoporphyrin production and application |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012079232A1 (en) * | 2010-12-15 | 2012-06-21 | Lai Hung-Cheng | Compounds used for treating cancer and the use thereof |
| CN102697182A (en) * | 2012-06-15 | 2012-10-03 | 川渝中烟工业有限责任公司 | Preparation method of filter nozzle additive for lowering ammonia in smoke of cigarette and application thereof |
| CN103554115A (en) * | 2013-10-30 | 2014-02-05 | 吉安荣威生物科技有限公司 | Method for preparing protoporphyrin trimethyl ester |
| CN113546077A (en) * | 2020-04-23 | 2021-10-26 | 复旦大学 | Application of protoporphyrin in preparing medicine for resisting novel coronavirus SARS-CoV-2 |
| CN113893245A (en) * | 2021-11-17 | 2022-01-07 | 中国药科大学 | Use of compounds having ATP-citrate lyase inhibitory activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012079232A1 (en) * | 2010-12-15 | 2012-06-21 | Lai Hung-Cheng | Compounds used for treating cancer and the use thereof |
| CN102697182A (en) * | 2012-06-15 | 2012-10-03 | 川渝中烟工业有限责任公司 | Preparation method of filter nozzle additive for lowering ammonia in smoke of cigarette and application thereof |
| CN102697182B (en) * | 2012-06-15 | 2014-07-30 | 川渝中烟工业有限责任公司 | Preparation method of filter nozzle additive for lowering ammonia in smoke of cigarette and application thereof |
| CN103554115A (en) * | 2013-10-30 | 2014-02-05 | 吉安荣威生物科技有限公司 | Method for preparing protoporphyrin trimethyl ester |
| CN113546077A (en) * | 2020-04-23 | 2021-10-26 | 复旦大学 | Application of protoporphyrin in preparing medicine for resisting novel coronavirus SARS-CoV-2 |
| CN113893245A (en) * | 2021-11-17 | 2022-01-07 | 中国药科大学 | Use of compounds having ATP-citrate lyase inhibitory activity |
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