CN102172353B - Application of p-carboxy phenyl ferriporphyrin to prevention and treatment of atherosclerosis - Google Patents
Application of p-carboxy phenyl ferriporphyrin to prevention and treatment of atherosclerosis Download PDFInfo
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Abstract
The invention relates to application of p-carboxy phenyl ferriporphyrin to preparation of medicaments for preventing or treating atherosclerosis. As proved by an experimental research relevant to the application of the p-carboxy phenyl ferriporphyrin to the treatment of atherosclerosis of a mouse, the p-carboxy phenyl ferriporphyrin can be used for remarkably improving behavior symptoms caused by atherosclerosis of the mouse, reducing the influence on the serum lipid of the mouse and preparing medicaments, such as tablets and capsules, for preventing or treating the atherosclerosis.
Description
Technical field
The present invention relates to the application of carboxyl phenyl iron porphyrin in preparation prevention or treatment atherosclerosis medicine.
Background technology
Atherosclerosis (Atherosclerosis, AS) be a kind of cardiovascular and cerebrovascular disease of common serious harm human health, Epidemiological study, China suffers the patient of atherosclerosis puzzlement to surpass 7,000 ten thousand every year, and the prevalence of this disease and sickness rate are year by year ascendant trend, in the 40-49 crowd in year, recall rate is respectively 58.36% and 88.31%, has become one of main killer of middle-aged and elderly people death.Atherosclerosis is a kind of disease of invading the systemic arterial system, the asymptomatic stage that many decades can be arranged, the cause of disease is complicated, the course of disease is very long, comprise endothelial injury, low density lipoprotein, LDL (LDL) oxidative modification, high-density lipoprotein concentration (HDL) increases, Adherence of Monocytes, and smooth muscle cell increment and fibrous plaque form.Under the effect of Other Risk Factors (hypertension, high cholesterol count, hyperlipemia etc.), the arterial endothelial injury necrosis is peeled off, produce and release cells adhesion factor and somatomedin, so that platelet and mononuclear cell adhere at this place, and then mononuclear cell enters subcutaneous space and transfers macrophage to; Middle film smooth muscle cell migration is to inner membrance place propagation or apoptosis; Macrophage and smooth muscle cell picked-up cholesterol change into foam cell, and the early lesion that forms AS is the fat stricture of vagina.On this basis, progressively develop into the fibrous plaque that is consisted of by non-viable non-apoptotic cell fragment, cholesterol and ester thereof, vascular smooth muscle, macrophage and fine and close fibrous tissue.Unstable factor causes the fibrous cap formation blood vessel blockage of breaking behind the Mottling formation, is retarded by silt etc.Atherosclerosis and hypertension, coronary heart disease, apoplexy have close ties, and human health in serious threat, have brought huge economy and living burden also for society and family.Therefore, strengthening atherosclerotic control and treatment is China and even global problem demanding prompt solution, and the medicine of extensively seeking prevention has extremely far-reaching theoretical and practical significance.(Hoke?M，Schmidt?B，Schillinger?T，et?al.Evidence?of?carotid?atherosclerosis?in?orthopantomograms?and?the?risk?for?future?cardiovascular?events.Vasa-European?Journal?of?Vascular?Medicine.2010，39(4)：298-304.)
Porphyrin (Porphyrins) is the macrocyclic compounds that contains four pyrroles's molecules, when the pyrroles's proton in the parent be after metal replaces metalloporphyrin.Being a kind of of metalloporphyrin to the carboxyl phenyl iron porphyrin, is the conjugated backbone macrocyclic compound that is linked to each other and form by methine by four pyrrole rings, and pyrroles's proton is wherein replaced by iron ion, and its structural formula is as follows:
Porphyrin compound extensively exists in nature and life entity, bringing into play very important effect, all is porphyrin compound such as hemoglobin, electronics transmission and the cytochrome C of an oxygen catalytic action, the catalase that cytochrome P-450 has reached enzyme catalysis etc. that play the oxygen transfer function; Hemoporphyrin (porphyrin of a β substd); Chlorophyll (magnesium porphyrin); Vitamin B12 (cobalt porphyrin) etc.
Just because of the special nature of porphyrin with to the important function of life entity.Over several years, people pay much attention to the research of porphyrin always.Porphyrin has been used to diagnosis and the treatment of various diseases.As: utilize hemoporphyrin to the sensitization of light, used as photosensitizer treatment tumor.Hemoporphyrin has been applied to live body to the research of tumor, cancer, such as Mus body, human body.In the clinical practice of hemoporphyrin, Muner is expelled to an amount of hemoporphyrin in the malignant brain tumor patient body, confirms that in more than 100 observed patient photodynamic therapy is safe, and medicinal mortality rate is lower than 30%.(Muller P, Abrams J, Wilson BC, Lother LD, Yang V, Hetzel FW, Chen Q, Fenstermaker K, Selker R.Photofrin photodynamic therapy for malignant brain tumors.Proceedings of SPIE-The International Society for Optical Engineering.2001,4248:34-35.) in addition, by artificial extraction of prothetic group haemachrome warp of hemoglobin, the protoporphrin disodium that processes has the effect of anti-hepatitis B virus, is used for anti-hepatic-B virus medicine and has advantages of that toxic and side effects is little.(Chao?L，Xu?L，Liu?H，et?al.Extraction?of?proto-porphyrin?disodium?and?its?inhibitory?effects?on?HBV-DNA[J].World?Journal?of?Gastroenterology.2004，10(3)：433.)
Atherosclerosis is the pathologic basis of ischemic cardio cerebrovascular diseases.Up to the present, its pathogenesis still imperfectly understands, and therefore there is no effective and specific Drug therapy.Basis and clinical research show in a large number, and atherosclerotic pathogenesis is relevant with many factors, has various theories.
What widely approved at present is the lipid peroxidation theory.And the effect of lipid oxidation and oxygen-derived free radicals is closely related in the body, after wherein low density lipoprotein, LDL (LDL) is become oxidized ldl (ox-LDL) by the free-radical oxidation modification, can resist lysosomal enzyme and cathepsin to its degraded, cause LDL in cell, to pile up, AS has been played pivotal role.Free radical is by producing material impact to machine-processed genesis to AS such as the damage of vascular endothelial cell, short vascular smooth muscle cell proliferation, short blood inflammation-oxidative stresss in addition.The carboxyl phenyl iron porphyrin had very strong scavenging action to oxygen-derived free radicals.
Up to now, the application in preparation prevention or treatment atherosclerosis medicine there is not yet bibliographical information to the carboxyl phenyl iron porphyrin.
Summary of the invention
The object of the present invention is to provide the application of carboxyl phenyl iron porphyrin in preparation prevention or treatment atherosclerosis medicine.
The present invention also aims to provide to the application of carboxyl phenyl iron porphyrin in anti peroxidation of lipid.
Pharmaceutical preparation provided by the invention comprises oral administration drug-delivery preparation such as tablet, pill, drop pill, capsule etc.
The present invention is when preparation, and principal agent adds pharmaceutically acceptable carrier to the carboxyl phenyl iron porphyrin, adopts conventional preparation technique, is made into required dosage form.
The used pharmaceutical aids of the present invention comprises cellulose, polyvinylpyrrolidone, magnesium stearate, lactose and corn starch etc.The present invention tests by animal toxicology, determines the carboxyl phenyl iron porphyrin is had no side effect in dosage range, can long-term taking.
Below in conjunction with test example the present invention is described in further detail.
Test example 1: first prelibation
To the carboxyl phenyl iron porphyrin, oral administration gavage, 300mg/kg, large mice is movable normal, no abnormality seen.
Test example 2: to the resistant function of carboxyl phenyl iron porphyrin to the white mice lipid peroxidation
(1) material
The carboxyl phenyl iron porphyrin is pressed embodiment 1 preparation;
Peroxynitrite (PN), according to document (Uppu RM, Pryor WA.Synthesis of peroxynitrite in a two-phase system using isoamyl nitrite and hydrogen peroxide, Analytical Biochemistry.1996,236:242-249.) preparation;
Thiobarbituricacidα-(TBA), trichloroacetic acid (TCA) are available from U.S. Sigma company;
Phosphate buffered solution (pH 7.4), matching while using;
White mice is provided by BJ Union Hospital.
(2) method and result
List of references (Feng Qing, Liu Li, He Yongyan, Wang Hailong, Lu Yanzhen, Liu Yongming, Wei Lei. metalloporphyrin is as the research [J] of dual function mimicry enzyme, the journal .2000 of Tongji University, 31 (2): method 143-146.) is measured.
In the catabolite of lipid peroxide, malonaldehyde (MDA) can with thiobarbituricacidα-(TBA) condensation, form red product, at the 532nm place absorption maximum is arranged.Get white mice (quality is 18-25g), the 24h that goes on a hunger strike, the cervical vertebra dislocation is put to death, and uses the normal saline lavation, takes out liver after the collapse due to massive hemorrhage, uses 200gL
-1Acetate buffer solution to be mixed with mass concentration be 100gL
-1Liver homogenate, for subsequent use.Get homogenate 0.2mL and be loaded in the tool plug test tube, add 0.1mL to the carboxyl phenyl iron porphyrin, then incubation 0.5h in constant temperature (37 ℃) water bath adds 0.2mL SDS (81gL successively
-1), 1.5mL acetate buffer solution (200gL
-1), 1.5mLTBA aqueous solution (8gL
-1), boil 0.5h in the boiling water bath, to take out, the flowing water cooling adds the 4mL n-butyl alcohol, and vibration is with 3000 rmin
-1Centrifugal 15min gets n-butanol layer, measures absorbance A in the 532nm place.Blank with physiologic saline for substitute to the carboxyl phenyl iron porphyrin.Relevant data sees Table 1.
Table 1 pair carboxyl phenyl iron porphyrin is to the resistant function of white mice lipid peroxidation
*P＜0.01 (with respect to blank)
By table 1 data as can be known: to the carboxyl phenyl iron porphyrin lipid peroxidation product is obviously reduced, to the clearance rate of the lipid peroxide positive correlation that increases to self concentration, illustrate that they have good anti peroxidation of lipid ability.
3 pairs of carboxyl phenyl iron porphyrin of test example are to the reducing effect of cholesterol level in the atherosclerosis model rats tremulous pulse
(1) material
The carboxyl phenyl iron porphyrin is pressed embodiment 1 preparation;
The SD male rat is provided by BJ Union Hospital;
High lipid food is available from Beijing feed factory.
(2) Method and Process
Experimental technique:
1. get 40 of the SD male rat of 6 week body weight in age about 200g, under standard conditions, raise:
2. rat is divided into 4 groups at random, 10 every group.The grouping situation is:
A group 1: matched group: common SD rat feeding feedstuff;
B group 2: High cholesterol diet group (HCD);
C group 3: hypercholesterolemia adds low dosage to carboxyl phenyl iron porphyrin group, gives the carboxyl phenyl iron porphyrin with meal;
D group 4: hypercholesterolemia adds high dose to carboxyl phenyl iron porphyrin group, gives the carboxyl phenyl iron porphyrin with meal.
Wherein, the consisting of of High cholesterol diet in the group 2-group 4: 2% cholesterol, 2.5% Adeps Sus domestica, 0.5% bile acid and 0.2% propyl thiourea pyrimidine add in the normal diet:
Low dosage to the oral dose to the carboxyl phenyl iron porphyrin in the carboxyl phenyl iron porphyrin group is: 50 μ g/g/day;
High dose to the oral dose to the carboxyl phenyl iron porphyrin in the carboxyl phenyl iron porphyrin group is: 100 μ g/g/day.
Except matched group, every group of rat pressed the oral dose vitamin D2 of 300,000IU/kg/day to induce the formation of atheromatous plaque;
3. after raising for 12 weeks, measure the cholesterol level in the rat aorta tissue;
Get and respectively organize rat aorta, reject the outer fatty tissue of aorta wall and other connective tissues with ophthalmic tweezers, weigh after cleaning with PBS.Aorta is put into centrifuge tube, add the 2mL homogenate, carry out homogenate under 4 ℃, the centrifugal 5min of 1500g/min, supernatant are transferred in another clean tube, add 0.4mL 8.8g/L KCl solution, make supernatant be divided into water layer and fat layer.The fat layer is transferred in another centrifuge tube, after drying up with nitrogen under 37 ℃, adds the 0.2mL dehydrated alcohol to each pipe, to be measured in-20 ℃ of storages;
4. adopt enzyme linked immunosorbent assay to measure cholesterol level, the 0.1mL sample is joined 0.9mL cholesterol detection analytic liquid (0.1U/mL cholesterol oxidase, 1U/mL cholesteryl esterase, 0.5mL/L TritonX-100 (Triton X-100), 1mM sodium cholate, 0.6mg/mL phenethanol liquid, be dissolved in the 0.1M sodium phosphate buffer of pH 7.4,37 ℃ hatch 1h after, in fluorescence spectrophotometer (F-4500 type, HIT) fluorescence intensity, the excitation wavelength of measuring fluorescence intensity is 325nm, and emission wavelength is 410nm.The slit width excitation wavelength is 10nm, and emission wavelength is 5nm.
(3) experimental result and analysis
The aorta inner cholesterol content of matched group and each atherosclerosis group model rat experiment group as shown in Figure 1.
The result shows: compare with matched group 1, give High cholesterol diet and vitamin D in addition
2The aorta cholesterol level of the rat model of inducing (group 2) significantly increase (
##P＜0.01); 2 compare with group, give (group 3, group 4) significantly reduced cholesterol level in the atherosclerotic rat model tremulous pulse (
*P＜0.01), should effect and during high dose more obvious.
The above results shows: to the picked-up of carboxyl phenyl iron porphyrin energy establishment experimental group rat artery to cholesterol.
Test example 4 on the carboxyl phenyl iron porphyrin on the atherosclerotic impact of experimental rat
(1) material
The carboxyl phenyl iron porphyrin is pressed embodiment 1 preparation;
SOD, MDA test kit are available from U.S. Sigma company; High lipid food is available from Beijing feed factory.
Rat is provided by BJ Union Hospital.
(2) process and result
Get 24 of healthy rats, male and female half and half, body weight (200 ± 2g), be divided at random Normal group, the Atherosclerosis Model group, positive drug (simvastatin) matched group is to carboxyl phenyl iron porphyrin low dose group, to dosage group in the carboxyl phenyl iron porphyrin, to carboxyl phenyl iron porphyrin high dose group (every group of 4 rats).Except Normal group normal diet normal diet (the equal-volume water in the dosage is distilled water), all the other each groups all adopt high lipid food (1% cholesterol, 5% Adeps Sus domestica, 10% yolk powder, 84% normal feedstuff) to feed.Feed also continuously and gavage simultaneously medicine after 60 days, get fasting blood and on automatic clinical chemistry analyzer, measure respectively the content of serum total cholesterol (TC), triglyceride (TG), HDL-C (HDL-C), low-density lipoprotein cholesterol (LDL-C), detect serum superoxide dismutase (SOD) vigor and malonaldehyde (MDA) with test kit, put to death subsequently animal, get aorta and do the pathomorphology inspection.Result of the test sees Table 2,3.
Table 2 is on the impact of carboxyl phenyl iron porphyrin on experimental atherosclerosis rat blood serum lipid
Annotate: compare with Normal group:
aP＜0.01; Compare with model control group:
bP＜0.05,
cP＜0.01.
By as seen from Table 2, serum total cholesterol (TC), triglyceride (TG), HDL-C (HDL-C), low-density lipoprotein cholesterol (LDL-C) content and Atherosclerosis Model group to the basic, normal, high dosage group of carboxyl phenyl iron porphyrin compare, difference has statistical significance, prompting can obviously reduce serum TC, TG to the carboxyl phenyl iron porphyrin, the LDL-C level reduces, the remarkable elevating HDL-C level of energy reduces the risk that atherosclerosis occurs simultaneously.
Table 3 is on the impact of carboxyl phenyl iron porphyrin on experimental atherosclerosis rat blood serum SOD, NO, MDA
Annotate: compare with Normal group:
aP＜0.01; Compare with model control group:
bP＜0.01,
cP＜0.05.
By as seen from Table 3, activity of SOD in serum, NO content, MDA content and Atherosclerosis Model group to the basic, normal, high dosage group of carboxyl phenyl iron porphyrin compare, difference has statistical significance, prompting can improve activity of SOD in serum and NO content to the carboxyl phenyl iron porphyrin, can significantly raise simultaneously and reduce MDA content, reduce the risk that atherosclerosis occurs.
The morphological examination of aorta pathology is the result show: the rats in normal control group aortic tunica intima is smooth smooth, and it is greyish white that color is, there are no abnormality.Model group rat aorta visible vessels inner membrance is distributed with yellow speckle in various degree, and is more obvious with aortic arch, thoracic aorta and aortic arch crotch.Simvastatin matched group pathological changes is lighter, be confined to aortic arch and aorta crotch; pathological changes is take strip and streak speckle as main; also lighter to the basic, normal, high dosage group of carboxyl phenyl iron porphyrin rat pathological changes; that pathological changes is dispersed in aorta and crotch with strip and streak speckle, and lesion degree alleviates with the increase to carboxyl phenyl iron porphyrin dosage.
This experimental result shows: can obviously reduce serum TC, TG, LDL-C level to the carboxyl phenyl iron porphyrin, can significantly improve the HDL-C level simultaneously; Activity of SOD in serum and NO content can be improved, MDA content can be obviously reduced simultaneously; Can obviously reduce simultaneously formation and the damage of atheromatous plaque.Show the carboxyl phenyl iron porphyrin is had obvious antiatherogenic effect.
Test example 5: on the impact of carboxyl phenyl iron porphyrin on apolipoprotein E gene deficient mice AS plaque stability
(1) material
The carboxyl phenyl iron porphyrin is pressed embodiment 1 preparation;
Mice is provided by BJ Union Hospital.
Prepare before the experiment:
10 ages in week, healthy clean mice was 40, male and female half and half, and body weight 20-22g in sterile laminar flow frame sub-cage rearing, freely drinks water and ingests.Raised for 30 weeks with high lipid food (conventional mouse feedstuff+1% cholesterol+21% fat, sterilization treatment), room temperature keeps 25 ℃, relative humidity 50%, light application time 12 hours (early 8 are arrived late 8 points).Every other day use the ultraviolet lamp disinfection Animal House 1 time, to keep the gnotobasis of laminar-flow rack.
(2) Method and Process
Raise that mice after 15 weeks is random puts to death 5, get its aortic root, AS model copy situation is observed in HE dyeing (hematoxylin-eosin staining).All the other mices are divided into following 5 groups (n=35) at random.
A. model group: solvent;
B. to carboxyl phenyl iron porphyrin low dose group 20 μ g/g/day;
C. to the 40 μ g/g/day of dosage group in the carboxyl phenyl iron porphyrin;
D. to carboxyl phenyl iron porphyrin high dose group 80 μ g/g/day;
E. simvastatin matched group 10 μ g/g/day.
Above medicine is dissolved in first DMSO, then is suspended in 0.5% cmc soln, gavage behind the mixing, every day 1 time.Survey weekly 1 body weight and record food ration, adjust drug dose according to body weight, intervened for 15 weeks.All animals are all put to death for the 30th weekend.
(3) animal is drawn materials
Mice AS speckle histopathologic slide: the mice cervical vertebra is put to death, with the normal saline that contains 4% paraformaldehyde from the left ventricle retroperfusion fixedly behind the aorta, from aortic root section to the ventral aorta end from disconnected whole aorta.Get aortic root, the routine paraffin wax embedding, the section of getting continuously 5 μ m thickness from aortic root is used for analyzing respectively aortic valve cross section AS speckle morphological indexes after HE dyeing and MASSON dyeing (the gloomy dyeing of horse).
Pathological staining: 1. get 2 continuous sections from each tangent plane of every continuous paraffin section of mouse aorta root and carry out respectively HE dyeing and MASSON dyeing, observe under the light microscopic.2. get remaining aorta and be used for Sudan IV dyeing, observe under the light microscopic.
(4) detection method
The morphological indexes graphical analysis: the HE stained, under * 40 times of common light microscopics, utilize " Image Pro Plus 5.0 " image analysis software to measure the atherosclerosis area of each tangent plane.Measure plate area (PA), vessel cross-sections long-pending (CVA), lipid core area (LCA) and minimum fibrous cap thickness (mFCT), (plate area/vessel cross-sections is long-pending for the calculation correction plaque area, PA/CVA) and proofread and correct lipid core area (lipid core area/plaque area, LCA/PA), each specimen is got the meansigma methods of 4 tangent planes.MASSON dyeing utilizes " Image Pro Plus 5.0 " image analysis software to measure aortic root area of collagen (CA), calculates collagen blood vessel Area Ratio (CA/CVA).Sudan IV dyeing, whole plaque area of aortic tunica intima face are calculated in * 4 times of spectroscopic analysiies, and plaque area accounts for the ratio of whole endarterium area.
(5) statistical analysis
Data with
Expression is carried out variance analysis with SPSS12.0 statistics software between group.
(6) result
1. the carboxyl phenyl iron porphyrin is seen Table 4 to mouse aorta AS speckle and stable impact thereof.
The result shows: compare with model group, the basic, normal, high dosage group of carboxyl phenyl iron porphyrin is significantly reduced mouse aorta AS correction plaque area, and (plate area/vessel cross-sections is long-pending, PA/CVA), significantly reduce mouse aorta AS speckle inner lipid die area and proofread and correct lipid core area (lipid core area/plaque area, LCA/PA), (area of collagen/vessel cross-sections is long-pending to enlarge markedly mouse aorta AS speckle fibrous cap thickness and correction area of collagen, CA/CVA), stablize the AS speckle.
2. the carboxyl phenyl iron porphyrin is seen Table 5 to the impact of mouse aorta AS lesion degree.
The result shows: compare with model group: the basic, normal, high dosage group of carboxyl phenyl iron porphyrin is significantly reduced the percentage ratio that mouse aorta AS plaque area accounts for whole piece endarterium area, alleviate aortal AS lesion degree.
Table 4 on the carboxyl phenyl iron porphyrin on the impact of composition in mouse aorta AS speckle and the speckle (
N=35)
Annotate:
aCompare P＜0.05. with model group
bCompare P＜0.01 with model group.
Table 5 on the carboxyl phenyl iron porphyrin on the impact of mouse aorta AS lesion degree (
N=35)
Annotate: * compares P＜0.01 with model group
Description of drawings
Fig. 1 is the design sketch that the carboxyl phenyl iron porphyrin is reduced cholesterol level in the atherosclerosis model rats tremulous pulse
N=10), wherein
##P＜0.01, group 1, group 2 are compared;
*P＜0.01, group 3, group 4 are compared.
The specific embodiment
Embodiment 1: to the preparation of carboxyl phenyl iron porphyrin
1, synthesizing carboxyl phenyl iron porphyrin part
Agitator is being housed, in the 250mL three-neck flask of reflux condensing tube and Dropping funnel, add respectively 1.5g (0.01mol) to carboxyl benzaldehyde, the 40mL propanoic acid, the 10mL valeric acid, behind the reflux 30min, in flask, drip the 10mL meta-nitrotoluene solution that 0.7mL (0.01mol) newly steams the pyrroles, add in the 10min, after continuing reflux 1.5h, stopped heating is stirred to room temperature, leave standstill cooling 8h, with the propanoic acid washing, the propanoic acid cleaning mixture is to substantially colourless first for sucking filtration, filter cake, the reusable heat distilled water fully washs, vacuum drying gets bluish violet to carboxyl phenyl porphyrin part (its structural formula is as follows), the 0.69g that weighs, yield 35.1%.
UV-vis(CH
3CH
2OH)：λ
max，417nm，513nm，548nm，592nm，649nm；
IR (KBr): 3442cm
-1(COOH, stretching vibration), 1684cm
-1(C=O, stretching vibration), 1606～1419cm
-1(phenyl ring skeleton stretching vibration), 1288～1180cm
-1(C-O, stretching vibration), 964cm
-1(porphin ring N-H, stretching vibration), 800cm
-1(para-orientation phenyl ring C-H, bending vibration);
Elementary analysis C
48H
30N
4O
8, value of calculation: C 72.90, H 3.82, and N 7.09; Measured value: C 73.12, H 4.13, and N 6.92.
2, synthesizing the carboxyl phenyl iron porphyrin
With 0.15g to carboxyl phenyl porphyrin part, 30mL N, dinethylformamide, the adding of 5mL glacial acetic acid are equipped with in the reflux of magnetic agitation and drying tube, after the reflux, 0.2g Iron dichloride tetrahydrate (excessive 5 times) is divided in 5 batches of adding refluxes, behind the back flow reaction 1h, from reaction system, carry out the centre sampling with dropper, and detect to judge whether to reach reaction end by ultraviolet-visible spectrum.After question response reaches terminal point, stopped heating, be stirred to room temperature, leave standstill cooling 8h, sucking filtration, use first a small amount of N, the dinethylformamide washing leaching cake is to colourless, and then with the abundant washing leaching cake of hot distilled water, vacuum drying gets rufous to the carboxyl phenyl iron porphyrin, the 0.14g that weighs, metallization yield 88.6%.
UV-vis(CH
3COOH)：λ
max，413nm，507nm，676nm；
IR (KBr): 3421cm
-1(COOH, stretching vibration), 1700cm
-1(C=O, stretching vibration), 1605～1401cm
-1(phenyl ring skeleton stretching vibration), 1265～1176cm
-1(C-O, stretching vibration), 999cm
-1(Fe-N, stretching vibration), 774cm
-1(para-orientation phenyl ring C-H, bending vibration);
Elementary analysis C
48H
28FeN
4O
8, value of calculation: C 68.26, H 3.34, and N 6.63; Measured value: C 68.60, H 3.72, and N 6.41.
Embodiment 2
Prepare tablet according to methods known in the art, every contains following compositions:
To carboxyl phenyl iron porphyrin 65mg,
Lactose 45mg,
Magnesium stearate 4mg,
Polyvinylpyrrolidone 16mg,
Microcrystalline Cellulose 30mg,
Add up to 160mg.
Prepare capsule according to methods known in the art, each capsule contains following compositions:
To carboxyl phenyl iron porphyrin 65mg,
Lactose 45mg,
Corn starch 35mg,
Magnesium stearate 4mg,
Polyvinylpyrrolidone 16mg,
Add up to 160mg.
The accumulated dose that the present invention gives host's every day with dosage single or that separate can be 30-100mg/kg (body weight)/sky.The dosage device compositions can contain the amount of the part of every daily dose.Preferential every bu gives the 30mg/kg unit dosage form about one to three time.
Chemical compound of the present invention can be with unit formulation by oral, parenteral, suction spraying, rectum, topical, and preparation can contain nontoxic drug acceptable carrier, additive and excipient commonly used as required.
Topical also may relate to the use of percutaneous dosing such as percutaneous ointment.Chemical compound of the present invention carries out the administration except can be used as single active pharmaceutical ingredient, they can also with one or more to this disease effectively chemical compound use.
Claims (1)
- Suc as formula shown in (I) to the application of carboxyl phenyl iron porphyrin in preparation prevention or treatment atherosclerosis medicine。
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Non-Patent Citations (3)
| Title |
|---|
| Day, Brian J.等.Metalloporphyrins are potent inhibitors of lipid peroxidation.《Free Radical Biology & Medicine》.1999,第26卷(第5/6期), |
| Day, Brian J.等.Metalloporphyrins are potent inhibitors of lipid peroxidation.《Free Radical Biology & * |
| Medicine》.1999,第26卷(第5/6期), * |
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