CN100500677C - Caffeoyl guinic acid-1-phosphate and its preparation and use - Google Patents
Caffeoyl guinic acid-1-phosphate and its preparation and use Download PDFInfo
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Abstract
This invention is about the synthesis and application of medicine precursor. Caffeoyl guinic acid derivation could have different subsalt on the phosphate group after phosphate esterification. Subsequently, it helps increase dissolvability from 4% to 20% above; reduce the difficulty in technical study for different agents. The increasing dissolvability could be in favour of compounds medicine adoption in vivo and bioavailability of the medicine. The phosphorus compounds here could also be used in target-oriented distribution with phospho-esterase in vivo. The trend of 1phosphorus compounds concentrating to ill tissues, achieve target-oriented administration, and focus Caffeoyl guinic acid derivation-1- phosphorus compounds to the ill tissue, hydrolyzing Caffeoyl guinic acid derivation to cure. For instance, the phospho-esterase in tumor cells is much higher than the nomal organs, so the parent compounds with tumor-oriented administration could work to cure.
Description
Technical field the present invention relates to medical compounds and synthetic method and application.Particularly caffeoyl guinic acid-1-phosphoric acid ester and preparation and pharmaceutical application.
The background technology caffeoyl guinic acid-1-phosphoric acid ester system is a compounds of pharmacy background with the pharmacological action of 3-caffeoyl guinic acid.Caffeoyl guinic acid is a Polyphenols organic acid acetic compound, poorly water-soluble, the solubleness in water be 4% (see the Merk index, 12 editions, 1996, p2199), as the 3-caffeoylquinic acids.Owing to have polyphenol group and ethylene linkage in the structure, see the auroral poles easy oxidation discoloration, show the unstable of compound.Give sizable difficulty of bringing of feedstock production and preparation production.Because of poorly soluble direct influence its absorption in vivo and distribution, make the interior bioavailability of body low simultaneously.In addition on the one hand, extensively distribute in vivo after the caffeoyl guinic acid administration and (see Ren Xia etc., the foundation and the pharmacokinetic thereof of chlorogenic acid intravenously administrable animal body inner analysis method, the outstanding Bo Shuoshilunwenji of China, 2005), lack target, make that the drug level that arrives the sufferer tissue is relatively low, necessary escalated dose can cause corresponding toxic side effect to increase the weight of to satisfy necessary treatment concentration thus during treatment, causes untoward reaction.
Summary of the invention the objective of the invention is in order to overcome above-mentioned weak point of the prior art, provide that a kind of solvability is better, the simpler caffeoyl guinic acid of preparation process-the 1-phosphate compound, and then develop the prodrug that is fit to clinical application.
Caffeoyl guinic acid-1-phosphate of the present invention, I is as follows for its general formula compound:
Wherein:
R represents H, C
1-5Alkyl or benzyl, when R is H, can form salt with following material: form inorganic salt with alkalies and alkaline earth, form organic salt with organic amine, organic amine is piperazine, piperidines, morpholine, trolamine, meglumine, amino acid, dipeptides, tripeptides or polypeptide;
R " expression H, C
1-5Alkyl or benzyl, as R " when being H; can form salt with following material: form inorganic salt with alkalies and alkaline earth, form organic salt with organic amine, organic amine is piperazine, piperidines, morpholine, trolamine, meglumine, amino acid, dipeptides, tripeptides or polypeptide;
R
1And R
2Can be identical or different, expression H, hydroxyl, C
1-5Alkoxyl group, alkyl, amido, fluorine, chlorine, bromine substituent or coffee acyl;
R
3And R
4Can be identical or different, expression H, hydroxyl, C
1-5Alkyl, amido, fluorine, chlorine or bromine substituting group.
The preparation of caffeoyl guinic acid-1-phosphate of the present invention; be with general formula compound III under protection of inert gas; add Phosphorus Oxychloride with general formula compound III equivalent; in～40 ℃～0 ℃ reaction; general formula compound III-1-phosphoric acid ester dichloro; add water decomposition generation 1-phosphoric acid ester by 10～20 times of amounts of reaction volume and slough 3 simultaneously; 4 acetone protecting group; concentrating under reduced pressure removes and desolvates; in case of necessity, separate with silica gel column chromatography, its moving phase is: ethanol: the ethyl acetate system; get general formula compound II, general formula compound II adds R " generates general formula compound I.
Wherein:
R represents H, C
1-5Alkyl or benzyl, when R is H, can form salt with following material: form inorganic salt with alkalies and alkaline earth, form organic salt with organic amine, organic amine is piperazine, piperidines, morpholine, trolamine, meglumine, amino acid, dipeptides, tripeptides or polypeptide;
R " expression H, C
1-5Alkyl or benzyl, as R " when being H; can form salt with following material: form inorganic salt with alkalies and alkaline earth, form organic salt with organic amine, organic amine is piperazine, piperidines, morpholine, trolamine, meglumine, amino acid, dipeptides, tripeptides or polypeptide;
R
1And R
2Can be identical or different, expression H, hydroxyl, C
1-5Alkoxyl group, alkyl, amido, fluorine, chlorine, bromine substituent or coffee acyl;
R
3And R
4Can be identical or different, expression H, hydroxyl, C
1-5Alkyl, amido, fluorine, chlorine or bromine substituting group.
The preparation of caffeoyl guinic acid-1-phosphate of the present invention, be injection liquid, aseptic powder injection, aseptic freeze-dried powder pin, tablet, capsule, various sustained-release preparation, eye drop, ointment, using the caffeoyl guinic acid-1-phosphate content of indication in these prescriptions is 1000 preparation unit voies, 1000 or, contain 1-3000mg among the 1000ml, 1000 bottles or 1000, the content of caffeoyl guinic acid-1-phosphate should be 90%～110% of labelled amount, w/w or w/v.
The application of caffeoyl guinic acid-1-phosphate of the present invention and preparation thereof is the application in anticancer, anti-AIDS field of preparation and analgesic preparation.
The present invention compared with prior art has following advantage:
1. improve the solvability caffeoyl guinic acid through 1 Phosphation after, can on phosphate-based, form different alkali salts, form the caffeoyl guinic acid-1-phosphate salt compounds and will improve the solvability of caffeoyl guinic acid greatly, former solubleness is brought up to more than 20% from 4%.Reduced the difficulty of different preparation process researchs.
2. improve the deliquescent increase of the bioavailability compound intravital absorption during that is highly advantageous to, improved bioavailability of medicament as medicine.
Drug targeting on the other hand the caffeoyl guinic acid-1-phosphate compounds not only can be used as the solvability that prodrug improves the low medicine of solvability, simultaneously, phosphate compounds also can utilize the character of phosphoesterase in the body to form the effect that target distributes.Though in extensive distribution of phosphoesterase and the body, when illness appears in body, sufferer tissue site phosphoesterase concentration will increase unusually, need phosphate compounds in the huge uptake body, so that body reparation needs to be provided.The trend of phosphate compounds in the sufferer set of organizations appears thus, the target of realizing medicine moves, the caffeoyl guinic acid-1-phosphate compounds is concentrated on the sufferer tissue in a large number, and hydrolysis goes out a large amount of caffeoyl guinic acids and gives full play to the pharmacological agent effect.Be far longer than the normal body tissue as phosphoesterase distribution in the tumour, thereby make parent compound produce the tumor tissues targeting, realize concentrated treatment tumour.
Embodiment the present invention is described in further detail below with reference to embodiment:
Synthesizing of embodiment 1. 3-caffeoylquinic acids-1-phosphoric acid ester
With 3-caffeoyl-4,5-o-isopropylidene quininic acid 10mmol, triethylamine (NEt
3) 10mmol, 20mlTHF joins in the round-bottomed flask of 100ml, the reaction system argon shield; with being cooled to below-30 ℃ of liquefied ammonia; slowly drip Phosphorus Oxychloride 10mmol, be warming up to room temperature then naturally, reaction is spent the night; remove by filter triethylamine hydrochloride; concentrating under reduced pressure falls THF, will concentrate oily matter and add in the 20g frozen water, and stirring reaction is 24 hours under argon shield; fall the aqueous solution in concentrating under reduced pressure below 40 ℃; with ethanol 20ml heating for dissolving, activated carbon decolorizing 20min; filter, be concentrated into about 10ml; add ethyl acetate 20ml; white solid is separated out in cooling, filters; drying under reduced pressure gets 3-caffeoylquinic acids-1-phosphoric acid ester white solid.
Embodiment 2. 3,5-dicaffeoylquinic acid-1-phosphoric acid ester synthetic
With 3,5-dicaffeoylquinic acid 10mmol, NEt
310mmol; 20ml THF joins in the round-bottomed flask of 100ml; the reaction system argon shield; with being cooled to below-30 ℃ of dry ice acetone; slowly drip the THF10ml solution of Phosphorus Oxychloride 10mmol; naturally be warming up to room temperature then; reaction is spent the night; remove by filter triethylamine hydrochloride, concentrating under reduced pressure falls THF, will concentrate oily matter and add in the 20g frozen water; stirring reaction is 24 hours under argon shield; fall the aqueous solution in concentrating under reduced pressure below 40 ℃, with ethanol 20ml heating for dissolving, activated carbon decolorizing 20min; filter; be concentrated into dried; (elutriant is an ethanol: ethyl acetate=1:2), get 3,5-dicaffeoylquinic acid-1-phosphoric acid ester white solid with the silica gel column chromatography separation.
Synthesizing of embodiment 3. 3-caffeoylquinic acids-1-Di-Sodium Phosphate
With 3-caffeoylquinic acids phosphoric acid ester 10mmol; 20ml ethanol joins in the round-bottomed flask of 100ml; the reaction system argon shield; be cooled to below 0 ℃ with icy salt solution, add the n-caprylic acid sodium of 20mmol, be warming up to room temperature then naturally; reaction is spent the night; filter white solid, drying under reduced pressure, 3-caffeoylquinic acids-1-Di-Sodium Phosphate white solid.
Embodiment 4. 3,5-dicaffeoylquinic acid-1-phosphoric acid glycinate synthetic
With 3,5-dicaffeoylquinic acid phosphoric acid ester 10mmol, 10ml ethanol joins in the round-bottomed flask of 100ml; the reaction system argon shield; but to below 0 ℃, add the glycine of 10mmol with icy salt solution, be warming up to room temperature then naturally; reaction is spent the night; the ethyl acetate that adds 10ml, filter white solid, drying under reduced pressure; get 3,5-dicaffeoylquinic acid-1-phosphoric acid ester glycinate white solid.
Synthesizing of embodiment 5. 3-caffeoylquinic acids-1-nitranol salt
3-caffeoylquinic acids-1-phosphoric acid ester 5.00g is added in the 100ml reaction flask, add acetone 20ml, be cooled to-30 ℃; under-30 ℃ of protections at argon gas; stir and drip the acetone soln of equivalent trolamine, about 20min dropwises, and is warming up to 60 ℃ of reactions 1 hour then.Concentrating under reduced pressure adds the 20ml ethyl acetate then, is heated to 80 ℃ of backflows, is cooled to 0 ℃, filters and drying, gets the white crystals of 3-caffeoylquinic acids-1-nitranol salt.
Embodiment 6. 3,5-dicaffeoylquinic acid-1-phosphoric acid meglumine salt synthetic
With 3,5-dicaffeoylquinic acid-1-phosphoric acid ester 5.00g adds in the 100ml reaction flask, adds acetone 20ml; be cooled to-30 ℃, under-30 ℃ of protections, stir and drip the acetone soln of equivalent meglumine at argon gas; about 20min dropwises, and is warming up to 60 ℃ of reactions 1 hour then.Concentrating under reduced pressure adds the 20ml ethyl acetate then, is heated to 80 ℃ of backflows, is cooled to 0 ℃, filters and drying, gets 3, the white crystals of 5-dicaffeoylquinic acid-1-phosphoric acid meglumine salt.
The injection liquid in use for intravenous injection and the eye drops of the sodium-chlor 0.9% of embodiment 7.3-caffeoylquinic acids-1-Di-Sodium Phosphate:
Prescription one:
Prescription two:
Prescription three:
Prevent the stablizer that 3-caffeoylquinic acids-1-Di-Sodium Phosphate decomposes: as cyclodextrin inclusion compound, tensio-active agent (anion surfactant, cats product, zwitterionics, nonionogenic tenside)
Antioxidant: S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine, xitix, halfcystine.
Physiology available pH value conditioning agent: citric acid, fumaric acid, L-glutamic acid, L-aspartic acid, lactic acid, lactobionic acid, galacturonic acid, glucuronic acid, xitix, hydrochloric acid, acetic acid.
Embodiment 8 contains 3, the sterile powder injection of 5-dicaffeoylquinic acid-1-phosphoric acid meglumine salt
Prescription one:
Prescription two:
Prescription three:
The aseptic freeze-dried powder injection of embodiment 9 3-caffeoylquinic acids-1-Di-Sodium Phosphate
Embodiment 7 each formulation product are made the aseptic freeze-dried powder injection of 3-caffeoylquinic acids-1-Di-Sodium Phosphate sodium-chlor through the freeze-drier lyophilize.
Embodiment 10 3,5% glucose injection liquid in use for intravenous injection and eye drops of 5-dicaffeoylquinic acid-1-phosphoric acid glycinate:
Prescription one:
Prescription two:
Prescription three:
Prevent 3, the stablizer that 5-dicaffeoylquinic acid-1-phosphoric acid glycinate decomposes: as cyclodextrin inclusion compound, tensio-active agent (anion surfactant, cats product, zwitterionics, nonionogenic tenside)
Antioxidant: S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine, xitix, halfcystine.
Physiology available pH value conditioning agent: citric acid, fumaric acid, L-glutamic acid, L-aspartic acid, lactic acid, lactobionic acid, galacturonic acid, glucuronic acid, xitix, hydrochloric acid, acetic acid.
Embodiment 11 contains the sterile powder injection of glucose
Prescription one:
Prescription two:
Embodiment 12 3,5-dicaffeoylquinic acid-1-phosphoric acid glycinate tablet:
Prescription:
3, the sweet ammonia 10.0g of 5-dicaffeoylquinic acid-1-phosphoric acid
Hydrochlorate (〉=95%)
Starch 184.00g
Polyvinylpyrrolidone 5.00g
Magnesium Stearate (120 order) 10.00g
Amount to 200.00g
Make 1000 altogether, every 3,5-dicaffeoylquinic acid-1-phosphoric acid glycine
Salt 10mg.
Weighting agent: as starch, dextrin, Icing Sugar, pregelatinized Starch, lactose, glucose, Microcrystalline Cellulose, lime carbonate, calcium sulfate, Calcium hydrogen carbonate.
Tamanori: as hypromellose, polyvidone, starch slurry, dextrin slurry, syrup, rubber cement, sodium alginate, polyoxyethylene glycol, peach gum, gum arabic.
Disintegrating agent: as croscarmellose sodium, polyvinylpolypyrrolidone, sodium starch glycolate, hydroxypropylated starch, low-substituted hydroxypropyl cellulose citric acid, tartrate, acid anhydrides, sodium bicarbonate, yellow soda ash.
Embodiment 13.3-caffeoylquinic acids-1-Di-Sodium Phosphate is right
60Co gammairradiation induced mice leucocytes reduction has treatment
1. method animal adaptability was raised 3 days, was divided into the high, medium and low dosage group of 3-caffeoylquinic acids-1-Di-Sodium Phosphate and positive controls, model control group and normal control group, 40 every group, male and female half and half at random according to body weight and sex.All the other animals are all used the full-body exposure of 60Co gamma-rays except that the normal control group, irradiation dose is that (dose rate is 256Gy/h to 4Gy, irradiation time is 2min), each group of irradiation back gives to be tried accordingly thing (control group and model group give the sodium chloride injection of volume) according to following table, once a day, successive administration is 14 days.Administration the 4th, 7,11,14 days, with the disposable blood vessel docking method blood sampling 20ul that quantitatively gets, blood slowly is blown into is added with the 500ul diluent in vitro, make blood and diluent mixing, with the full-automatic blood counting instrument detection of sea lion-18 type peripheral hemogram.Adopted behind the blood every group at every turn and randomly drawed 10 animals (minimum be not less than 8, male and female half and half), the cervical vertebra dislocation is put to death and is got femur immediately behind the animal and make the marrow push jack, and Wright's staining, mirror are checked bone marrow smear down.When getting marrow, get spleen and weigh and calculate the index and spleen index result and carry out single factor variance statistical study with the SPSS13.0 statistical software.
Grouping and dosage
| Group | Number of animals (n) | Dosage (mg/kg) | Concentration (mg/ml) | Administration volume (ml/kg) | Route of administration |
| The normal control group | 40 | - | - | 20 | Abdominal injection |
| Model control group | 40 | - | - | 20 | Abdominal injection |
| Positive controls | 40 | 100μg/kg | 5μg/ml | 20 | Abdominal injection |
| Low dose group | 40 | 5 | 0.25 | 20 | Abdominal injection |
| Middle dosage group | 40 | 10 | 0.5 | 20 | Abdominal injection |
| High dose group | 40 | 20 | 1 | 20 | Abdominal injection |
2. result
The body weight statistics (g) of test mice
3-caffeoylquinic acids-1-Di-Sodium Phosphate therapeutic administration is to the influence (* 10 of irradiation murine interleukin number
9/ L)
Compare with the normal control group: * P＜0.05, * P＜0.01; Compare with model control group:
aP＜0.05,
bP＜0.01 (down together).
3. conclusion
After the modeling, the animal white corpuscle obviously descends, and with the normal control group significant differences (P＜0.01) is arranged relatively, and administration is the rising of medicine high dose group white corpuscle after 11 days, with model control group significant difference (P＜0.05) is arranged relatively; The high, medium and low dosage group of medicine all raises at 7,11,17 days white corpuscles of administration, the myelosis that is suppressed is had the effect of certain promotion recovery.3-caffeoylquinic acids-1-Di-Sodium Phosphate is right
60Co gammairradiation induced mice leucocytes reduction has therapeutic action.
Embodiment 14 3, and 5-dicaffeoylquinic acid-1-phosphoric acid meglumine salt reduces to such an extent that treat to caused by cyclophosphamide Beagle canine leucocyte
Medication
1. method is except that the normal control group, endoxan (CY) 0.8ml/kg (8mg/kg) of other 5 groups of dog intravenous injection 8mg/ml, once a day, continuous 5 days.Began in the 6th day to respectively be subjected to reagent, model control group and normal control group are given physiological saline, continuous 13 days.The white corpuscle of getting each animal of invention Peripheral blood examination in 2,4,6,8,10,12,14 days respectively before modeling, after the modeling after every day, the treatment; (injection endoxan) before the modeling, modeling finish (injection endoxan the 5th day), treatment the 7th day and the 14th day, get clear-headed dog respectively and lie on one's side and bend over, and marrow is extracted in the ridge puncture on the ilium, smear, Wright's stain dyeing.Microscopically carries out differential count, granulocyte, red corpuscle, megalokaryocyte, monocyte system etc.Count 200 cells.The full sheet counting of megalokaryocyte summation, 25 of platelet counts (maturation has thrombocyte to form and ripe no thrombocyte forms), the result carries out statistical procedures.
2. detect index and detect frequency
1) overview
Every general situation of animal and behavioral activity before and after the every day observed and recorded administration, the feed situation, large and small just proterties, color, outward appearance sign, visual mucous membrane, body temperature etc. were weighed every 7 days.
2) peripheral hemogram
Preceding 1 time of administration, injection CY every day 1 time, treatment administration the 1st, 2,3,4,6,7,9,11 days, 15 days each 1 time.Get dog forelimb venous blood on an empty stomach, M-4000 Instrument measuring WBC (white corpuscle), LYM (lymphocyte count), MID (intermediate cell counting), GRAN (granulocyte count), LYM (lymphocyte percentage), MID (intermediate cell percentage), GRAN (granulocyte percentage), RBC (red corpuscle), HGB (oxyphorase), HCT (pcv), MCV (mean corpuscular volume (MCV)), MCH (mean corpuscular hemoglobin), MCHC (mean corpuscular hemoglobin), RDW-CV (Erythrocyte hemoglobin distribution width variance), RDW-SD (Erythrocyte hemoglobin distribution width standard deviation), PLT (platelet count), MPV (mean platelet volume), PCT (thrombocytocrit capacity), RCDW (the distribution control interval between red corpuscle and the thrombocyte), PDW (volume of platelets Tile Width), common light microscopic method counting RC (reticulocyte).
3) myelogram detects
Preceding 1 time of administration was injected CY6 days, treatment administration the 7th, 14 days each 1 time.Get clear-headed dog and lie on one's side and bend over, marrow is extracted in the ridge puncture on the ilium, smear, Wright's stain dyeing.Microscopically carries out differential count, granulocyte, red corpuscle, megalokaryocyte, monocyte system etc.Count 200 cells.The full sheet counting of megalokaryocyte summation, 25 of platelet counts (maturation has thrombocyte to form and ripe no thrombocyte forms), the result carries out statistical procedures.
4) data processing
Continuous data is all used x ± s (means standard deviation) expression, with the significance of t check comparative group differences.
3. result
1) to the influence of behavior sign
Heavy dose of group: in the modeling 5 days, the animal no abnormality seen, animal appetite reduces in the 3rd to 7 day of treatment, and movable the minimizing treats that animal recovers normal after the 7th day, and other each animal there is no unusually.
In the dosage group: animal no abnormality seen in the modeling 5 days, good than the day before yesterday in lazy 1/2, the 6 day each the animal mental status moving, that appetite only be normal appetite of the 2nd to the 8th day 3 animals of treatment, activity and appetite all have increase, recover normally behind the 8th day animal.
Small dose group: animal no abnormality seen in the modeling 5 days, beginning in the 3rd day of treatment, 2 animal appetite stimulators, spiritual not good enough, the movable minimizing are arranged, lazy moving, the appetite of the 3rd to the 5th day animal only is 1/2 of normal appetite, individual animal appetite only is that 1/4, the 6 day each animal mental status of normal appetite is good than the day before yesterday, and activity and appetite all have increase, the appetite of the 9th day animal, behavioral activity recover normally to there is no unusually until the off-test animal substantially.
Positive controls: animal no abnormality seen in the modeling 5 days, animal appetite reduces in the 2nd to 7 day of begin treatment, and the mental status is not good enough, and animal recovers normal after the 7th day, and other each animal there is no unusually.
Model control group: animal no abnormality seen in the endoxan modeling 5 days, give beginning in second day of physiological saline, an animal appetite stimulator, spiritual not good enough, the movable minimizing are arranged, death in the 5th day, all the other animals lazynesses are moving, appetite only is 1/4 of normal appetite, the phenomenon of not eating all day has appearred in individual animal, the animal mental status is more preceding good slightly after the 6th day, activity and appetite all have increase, appetite, the behavioral activity of remaining animal recovers normally to there is no unusually until the off-test animal substantially after the 9th day.
The normal control group: each animal health in process of the test, appetite appetite, behavioral activity, body temperature are all normal.
Each treated animal is in giving CY modeling process, behavioral activity, appetite appetite, stool and urine and body temperature (rectum) there is no unusually, in 3-6 days of drug treatment, except that the normal control group, other five groups individual animal body temperature all occurred and have obviously raise, and rising 40-41 ℃, animal appetite appetite goes down, spirit is owed Cui, symptoms such as movable minimizing.Finish to testing after 7 days in treatment, each treated animal body temperature recovers normally gradually, and the mental status, behavioral activity, appetite appetite all recover normal.
Each dosage treated animal is in 5 days of modeling (injection endoxan), significant reaction does not appear, treat beginning in second day, except that the normal control group, each group all has animal symptoms such as diet reduces, depressed, the movable minimizing of spirit to occur, wherein model control group is in the 5th a day dog (♀) death of treatment, and from treating the 8th day, it is normal that each treated animal recovers gradually.
2) to the influence of marrow
Myelogram hyperplasia situation is divided 6 grades, and 1 is extremely active, and 2 is obviously active, and 3 is active, and 4 lower, and 5 obviously lower, and 6 is extremely low.
Each treated animal medullary cell hyperplasia situation
The result shows: behind the injection endoxan, each is organized the dog myelosis and all lowers, 3, each the dosage group administration of 5-dicaffeoylquinic acid-1-phosphoric acid meglumine salt all obviously can be seen dog medullary cell hyperplasia on the 7th day, and its big or middle dosage group sees that slightly obviously, positive drug group and model group action effect are slightly poor, dead 1 dog of model group, the medicine group was recovered better in the 14th day, and it is low that model group still has 1 example to be in hyperplasia, normal control group no abnormality seen.
Normal bone marrow resembled microscopically observation, each dog medullary cell active proliferation, no abnormality seen before each organized the dog administration.
Neutrophil leucocyte is shaft-like to be main, accounts for full sheet sum 45-50%, secondly is middle children, late children, divides leaf cell.Accidental eosinophilic granulocyte is not seen original, promyelocyte.Children and metamyelocyte in not seeing.The red corpuscle system: based on acidophilic normoblast, accounting for full sheet counting about 25～30%, be polychromatophilic erythroblast secondly, do not see under the full sheet mirror former red, early the children is red, morning is huge, in huge, late megalocyte.Lymphsystem:, do not see original and inmature lymphocyte based on mature lymphocyte (accounting for 10～12%).The monokaryon system: each is organized each dog and is not seen that original, inmature, monocyte are arranged.Megalokaryocyte: have platelet-shaped to become the master with maturation, ripe no thrombocyte forms and takes second place, and does not see inmature megalokaryocyte.Other cell: do not see plasmocyte, do not see netted, endothelium, engulf, parasite, organize giant cells, not clear-cells and special cells.More equal no difference of science of statistics between each group of the ratio of granulocyte system and red corpuscle system (P〉0.05).
Except that the normal control group, all the other are respectively organized dog myelogram hyperplasia and obviously are suppressed, grain: the red severely subnormal that compares, non-hematopoietic cell lymphocytosis, grain is a cell, erythroid cells, the megalokaryocyte sum reduces, and does not see that maturation has thrombocyte to form and ripe no thrombocyte forms.Each cell counting standard deviation of mean of normal bone marrow picture increases,
Show injection CY8mg/kg4 days, granulocyte (WBC) system obviously is suppressed, and modeling is successful.
Treat the 7th day each dog myelogram hyperplasia of medicine group and recover substantially normally, granulocyte series, erythron, lymphocyte series, the megalokaryocyte sum, maturation has thrombocyte to form and ripe no thrombocyte forms, and mirror counting down is more or less the same with the normal control group.And 2 animal hyperplasia of model control group are still low, and non-hematopoietic cell lymphocytosis is drenched system and reduced.The result shows that medicine group dog myelogram is subjected to the acute inhibition of CY, recovers fast than model control group, and medicine has the effect of rising to leukopenia.
Treated the 14th day, 2 dogs of low dose group, 1 dog bone marrow smear of model group hyperplasia is low, non-hematopoietic cell lymphocytosis, grain is a cell, and the red corpuscle system reduces, and myelosis fails to recover, and all the other each dog medullary cell active proliferations recover normal.
3) the Cytometric influence of dialogue
(i.vCY) animal white corpuscle obviously descends after the modeling, and before control group and self modeling significant differences (P＜0.01) is arranged, and treats that medicine group and control group white corpuscle all raise after 6 days.The results are shown in Table.
White corpuscle (the x10 of each treated animal of different time
9/ L x ± s)
Annotate: pattern drawing treated animal number was 5 in the 6th day
Injection CY descends the WBC counting, the white blood cell count(WBC) of decline is obviously raise, and three are subjected to the reagent group to show that all medicine has the rising effect, and heavy dose of group is after the 12nd day, middle dosage group showed slightly after the 8th day obviously, and positive controls and model group are not obvious.The normal control group fluctuates in range of normal value.
4. conclusion
3,5-dicaffeoylquinic acid-1-phosphoric acid meglumine salt reduces caused by cyclophosphamide Beagle canine leucocyte certain therapeutic action, and the myelosis that is suppressed is had the effect that promotes recovery, and dose-effect relationship is arranged.
Experimental example 15 3-caffeoylquinic acids-1-Di-Sodium Phosphate influences the mouse analgesic
Adopt hot plate method research 3-caffeoylquinic acids-1-Di-Sodium Phosphate that the mouse analgesic is influenced.Get female kunming mice, 10 every group, establish chlorogenic acid administration group 100mg/kg; Positive controls pyramidon 50mg/kg; Negative control group physiological saline 10ml/kg.Route of administration is abdominal injection.Put 60 ℃ of hot plate temperatures.Mouse is dropped into hot plate, with stopwatch record mouse from drop into hot plate to the time of licking metapedes be threshold of pain (unit: second).
Measure the threshold of pain of every mouse before the administration earlier, survey altogether 2 times, average, it is defective surpassing 30 seconds persons, surveys once in per 30 minutes after the administration, continuous four times, surpasses 60 seconds as threshold of pain and promptly stops test, by 60 seconds.The threshold of pain is improved percentage and is by formula calculated.Percentage=[average threshold of pain before (the preceding average threshold of pain of average threshold of pain-medication after the medication)/medication] * 100% is improved in the threshold of pain.Result's (seeing Table) prompting 3-caffeoylquinic acids-1-Di-Sodium Phosphate has analgesic activity.
3-caffeoylquinic acids-1-Di-Sodium Phosphate is to mouse analgesic activity (hot plate method)
Experimental example 16 3-caffeoylquinic acids-1-Di-Sodium Phosphate is to the influence of rat anti-inflammatory action
Adopt of the influence of sufficient edema method research 3-caffeoylquinic acids-1-Di-Sodium Phosphate to the rat anti-inflammatory action.Get the SD rat, body weight 120 ± 10 grams, 10 every group, male and female half and half.If 3-caffeoylquinic acids-1-Di-Sodium Phosphate administration group 100mg/kg; Control group physiological saline 2.5ml/kg.Route of administration is abdominal injection.After the administration 30 minutes, left hind foot plantar subcutaneous injection 1% carrageen liquid 0.1ml measured the sufficient sole of the foot and ankle joint circumference every 1 hour with the moccasin chi, and right back foot compares, continuous 5 times.Swelling degree=left ankle joint and sufficient sole of the foot circumference-left ankle joint and sufficient sole of the foot circumference.
Result's (seeing Table) prompting 3-caffeoylquinic acids-1-Di-Sodium Phosphate has anti-inflammatory action.
3-caffeoylquinic acids-1-Di-Sodium Phosphate is to the influence of rat anti-inflammatory action
Claims (5)
1. caffeoyl guinic acid-1-phosphate, the feature of its general formula compound I is as follows:
Wherein:
R represents H, C
1-5Alkyl or benzyl when R is H, form salt with following material: form inorganic salt with alkalies and alkaline earth, form organic salt with organic amine, organic amine is piperazine, piperidines, morpholine, trolamine, meglumine, amino acid, dipeptides, tripeptides or polypeptide;
R " expression H, C
1-5Alkyl or benzyl are as R, and " when being H, form salt with following material: form inorganic salt with alkalies and alkaline earth, form organic salt with organic amine, organic amine is piperazine, piperidines, morpholine, trolamine, meglumine, amino acid, dipeptides, tripeptides or polypeptide;
R
1And R
2Identical or different, expression H, hydroxyl, C
1-5Alkoxyl group, alkyl, amido, fluorine, chlorine, bromine substituent or coffee acyl;
R
3And R
4Identical or different, expression H, hydroxyl, C
1-5Alkyl, amido, fluorine, chlorine or bromine substituting group.
2. according to the preparation of the described caffeoyl guinic acid-1-phosphate of claim 1; it is characterized in that: general formula compound III is under protection of inert gas; add Phosphorus Oxychloride with general formula compound III equivalent; in-40 ℃～0 ℃ reaction; general formula compound III-1-phosphoric acid ester dichloro; doubly measure by reaction volume 10-20 and to add water decomposition and produce the 1-phosphoric acid ester and slough 3 simultaneously; 4 acetone protecting group; concentrating under reduced pressure removes and desolvates; in case of necessity, separate with silica gel column chromatography, its moving phase is: ethanol: the ethyl acetate system; get general formula compound II, general formula compound II adds R " generation general formula compound I
Wherein:
R represents H or benzyl, when R is H, forms salt with following material: form inorganic salt with alkalies and alkaline earth, form organic salt with organic amine, organic amine is piperazine, piperidines, morpholine, trolamine, meglumine, amino acid, dipeptides, tripeptides or polypeptide;
R " expression H or benzyl; as R " when being H, form salt with following material: form inorganic salt with alkalies and alkaline earth, form organic salt with organic amine, organic amine is piperazine, piperidines, morpholine, trolamine, meglumine, amino acid, dipeptides, tripeptides or polypeptide;
R
1And R
2Identical or different, expression H, hydroxyl, C
1-5Alkoxyl group, alkyl, amido, fluorine, chlorine, bromine substituent or coffee acyl;
R
3And R
4Identical or different, expression H, hydroxyl, C
1-5Alkyl, amido, fluorine, chlorine or bromine substituting group.
3. according to the preparation of claim 1 and 2 described caffeoyl guinic acid-1-phosphates, it is characterized in that: be injection liquid, aseptic powder injection, aseptic freeze-dried powder pin, tablet, capsule, various sustained-release preparation, eye drop or ointment, using the caffeoyl guinic acid-1-phosphate content of indication in these prescriptions is 1000 preparation unit voies, 1000 or, contain 1-3000mg among the 1000ml, 1000 bottles or 1000, the content of caffeoyl guinic acid-1-phosphate should be 90%～110% of labelled amount, w/w or w/v.
4. according to the application of claim 1 and 3 caffeoyl guinic acid-1-phosphates and preparation thereof, it is characterized in that: the application in preparing anticancer or anti-AIDS field pharmaceutical preparation.
5. according to the application of claim 1 and 3 caffeoyl guinic acid-1-phosphates and preparation thereof, it is characterized in that: the application in preparation analgesic preparation.
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