CN105837653A - Pharmaceutical composition of candesartan cilexetil and application of pharmaceutical composition to biological medicine - Google Patents
Pharmaceutical composition of candesartan cilexetil and application of pharmaceutical composition to biological medicine Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/26—Aristolochiaceae (Birthwort family), e.g. heartleaf
- A61K36/268—Asarum (wild ginger)
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Abstract
The invention discloses a pharmaceutical composition of candesartan cilexetil and application of the pharmaceutical composition to biological medicine .The pharmaceutical composition of candesartan cilexetil contains candesartan cilexetil and a natural product compound (I) which is novel in structure and is separated from dry rhizomes of asarum .When candesartan cilexetil and the compound (I) act independently, lipid and glucose metabolism of a T2DM rat can be remarkably improved, the thoracic aorta eNOS protein expression and serum SOD activity of the rat are improved, NO synthesis is increased, NO damage is relieved, and endothelial function damage caused by diabetes is avoided .When candesartan cilexetil and the compound (I) act jointly, the pharmacologic action is further enhanced, it is shown that candesartan cilexetil and the compound (I) coordinate and can be developed into medicine for avoiding endothelial damage caused by diabetes, and compared with the prior art, outstanding substantial advantages and remarkable progress are achieved .
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of candesartan Cilexetil, be specifically related to the drug regimen of candesartan Cilexetil
Thing and the application in biological medicine thereof.
Background technology
Candesartan Cilexetil chemical name be (±)-1-[[(hexamethylene oxo) carbonyl] oxo] ethyl-2-ethyoxyl-1-[[2'-(1H-tetrazole base
-5)-[1,1'-xenyl]-4-base] methyl]-1H-benzimidazole-7-carboxylate, it is adaptable to essential hypertension.
Candesartan Cilexetil is hydrolyzed into the most rapidly active metabolite Candesartan, and Candesartan is selectivity angiotensinⅡ
Receptor (ATl) antagonist, by being combined and the vasoconstrictor effects of antagonizing angiotensin II with vascular smooth muscle ATl receptor,
Thus reduce peripheral vascular resistance.Separately having and think, Candesartan can play certain fall by suppression acth secretion aldosterone
Pressure effect.Candesartan does not suppress kininaseⅡ, does not affect Kallidin I degraded.
Up to now, there is not yet candesartan Cilexetil and pharmaceutical composition thereof to report with the dependency that diabetes cause endothelial injury.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of candesartan Cilexetil, containing candesartan Cilexetil in this pharmaceutical composition
Endothelial injury can be caused with coordinating protection diabetes with the natural product of a kind of novel structure, candesartan Cilexetil and this natural product.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
A kind of pharmaceutical composition of candesartan Cilexetil, including candesartan Cilexetil, compound as claimed in claim 1 (I) and
Pharmaceutically acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, collapses
Solve agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: the dry rhizome of Herba Asari is pulverized by (a), uses
85~95% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water saturated successively
N-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract;In (b) step (a)
N-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 35% ethanol elution, then with 12 cylinders of 90% ethanol elution
Long-pending, collect 90% eluent, concentrating under reduced pressure obtains 90% ethanol elution concentrate;C in () step (b), 90% ethanol elution is dense
Contracting thing purification on normal-phase silica gel separates, successively with the methylene chloride-methanol gradient elution that volume ratio is 120:1,60:1,30:1 and 15:1
Obtain 4 components;D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 40:1,30:1 by volume ratio successively
3 components are obtained with the methylene chloride-methanol gradient elution of 10:1;Component 2 octadecylsilane key in (e) step (d)
The reverse phase silica gel closed separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 85%, collects 14~18 column volumes and washes
De-liquid, eluent is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane,
Obtain dichloromethane extract.
The above-claimed cpd (I) application in preparation protection diabetes cause the medicine of endothelial injury.
The application in preparation protection diabetes cause the medicine of endothelial injury of the pharmaceutical composition of above-mentioned candesartan Cilexetil.
Advantages of the present invention: contain candesartan Cilexetil and one in the pharmaceutical composition of the candesartan Cilexetil that the present invention provides from Herba Asari
Dry rhizome in the natural product of novel structure of isolated, when candesartan Cilexetil and this natural product independent role, to sugar
Urine disease causes endothelial injury and has protective effect;During the two synergy, the protected effect that diabetes cause endothelial injury carries further
Height, can develop into protection diabetes and cause the medicine of endothelial injury.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: the dry rhizome (2kg) of Herba Asari is pulverized by (a), extracts (15L × 3 time) with 90% alcohol heat reflux,
United extraction liquid, is concentrated into without alcohol taste (3L), successively with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and
Water saturated n-butyl alcohol (3L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butanol extraction
Thing;B acetic acid ethyl ester extract D101 type macroporous resin remove impurity in () step (a), first with 8 posts of 35% ethanol elution
Volume, then with 12 column volumes of 90% ethanol elution, collect 90% eluent, concentrating under reduced pressure obtains 90% ethanol elution concentrate;
C in () step (b), 90% ethanol elution concentrate purification on normal-phase silica gel separates, be 120:1 (11 cylinders by volume ratio successively
Long-pending), 60:1 (9 column volumes), 30:1 (9 column volumes) and the methylene chloride-methanol gradient of 15:1 (8 column volumes)
Afford 4 components;D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 40:1 by volume ratio successively
The methylene chloride-methanol gradient elution of (6 column volumes), 30:1 (8 column volumes) and 10:1 (6 column volumes) obtains 3
Individual component;E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and by concentration expressed in percentage by volume is
The methanol aqueous solution isocratic elution of 85%, collects 14~18 column volume eluents, and eluent is concentrated under reduced pressure to give compound (I)
(322mg, HPLC normalization purity is more than 98%).
Structural identification: white powder, HR-ESI-MS shows [M+H]+For m/z 469.3233, molecule can be obtained in conjunction with nuclear-magnetism feature
Formula is C30H44O4, degree of unsaturation is 9.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 600MHz): H-1 (1.62,
Dd, J=12.4,8.9Hz), H-1 (2.11, dd, J=12.4,3.6Hz), H-2 (5.82, ddd, J=10.9,8.9,3.6Hz),
H-3 (5.68, d, J=10.9Hz), H-5 (0.93, d, J=11.2Hz), H-6 (1.68, m), H-6 (1.93, m),
H-7 (1.73, m), H-7 (1.87, m), H-9 (1.60, d, J=9.4Hz), H-11 (4.17, d, J=9.1Hz),
H-16 (2.21, d, J=13.1Hz), H-16 (2.43, d, J=13.1Hz), H-18 (2.46, d, J=8.4Hz),
H-19 (1.41, m), H-20 (1.10, m), H-21 (1.28, m), H-21 (1.48, m), H-22 (1.36,
M), H-22 (1.51, m), H-23 (1.32, s), H-24 (9.82, s), H-25 (1.06, s), H-26 (1.17,
S), and H-27 (1.24, s), H-28 (0.87, s), H-29 (0.90, d, J=6.3Hz), H-30 (0.93, d, J=6.1Hz),
OH-11 (3.13, s), OH-12 (4.73, br, s);Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz):
40.3(CH2, 1-C), 124.3 (CH, 2-C), 133.6 (CH, 3-C), 48.3 (C, 4-C), 60.2 (CH,
5-C), 20.4 (CH2, 6-C), 40.9 (CH2, 7-C), 49.8 (C, 8-C), 51.6 (CH, 9-C), 41.2
(C, 10-C), 71.9 (CH, 11-C), 146.7 (C, 12-C), 119.2 (C, 13-C), 58.6 (C, 14-C),
209.9 (C, 15-C), 52.5 (CH2, 16-C), 53.9 (C, 17-C), 47.3 (CH, 18-C), 40.1 (CH,
19-C), 40.7 (CH, 20-C), 30.7 (CH2, 21-C), 39.2 (CH2, 22-C), 22.3 (CH3, 23-C),
201.1 (CH, 24-C), 15.7 (CH3, 25-C), 19.4 (CH3, 26-C), 20.9 (CH3, 27-C), 19.1
(CH3, 28-C), 17.2 (CH3, 29-C), 21.3 (CH3, 30-C).Infrared spectrum shows that this compound contains hydroxyl
(3478cm-1), carbonyl (1760cm-1), double bond (1663cm-1) and aldehyde radical (1641cm-1)。13C-NMR、DEPT
With hsqc spectrum shows 30 carbon signals, including seven methyl, six methylene, nine methines (an even oxygen carbon,
Two alkene carbon and an aldehyde radical), and eight quaternary carbons (a ketone carbonyl, company's oxygen olefinic quaternary carbon, an olefinic quaternary carbon),
In conjunction with insatiable hunger sum, function above structure shows that this compound is five ring structures.1H-NMR spectrum combines five that hsqc spectrum shows
Individual unimodal methyl proton signal δH1.32 (3H, s), 1.06 (3H, s), 1.17 (3H, s), 1.24 (3H, s) and
0.87 (3H, s), two bimodal methyl proton signal δH0.90 (3H, d, J=6.3Hz), 0.93 (3H, d, J=6.1Hz)
And1H-NMR data show that this compound is Ursane triterpenoid compound.In this Ursane compound, have one
Individual aldehyde radical proton signal δH9.82 (1H, s), H-3, H-5 and H in HMBC spectrum3The dependency of-23 and C-24 shows C-4
Position is connected with an aldehyde radical, H-24 and H in NOESY spectrum3-25 coherent signal hint aldehyde radicals are in β position.Knot is understood from ultrared spectrum
Containing hydroxyl in structure, and from1H-NMR data understand and contain 2 hydroxyls, H-9 and H-18 and C-12 in HMBC composes,
H-18 and H3With C-12 coherent signal and their carbon chemical shifts ,-27 show that this compound exists with C-13 and OH-12
Enol-type structure, hydroxyl is connected to the double bond composition enol-type structure that C-12 position is formed with C-12 and C-13.Additionally, according to
In HMBC spectrum, coherent signal and the chemical shift of OH-11 Yu C-11 confirm that another-OH is connected on C-11 position.Another C-2
Also form double bond structure with C-3, C-15 position forms ketone group, H in HMBC composes2-16 and H3-27 with C-15 coherent signal
And their carbon chemical shifts confirm further C-15 formed ketone group.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum,
And document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration passes through ECD further
Test determines, theoretical value is basically identical with experiment value.This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
The method that the present embodiment uses low dose of streptozotocin lumbar injection to increase fat forage feed sets up type 2 diabetes mellitus rat
(T2DM) model, detect fasting glucose (FPG) in each treated animal serum, T-CHOL (TC), triglyceride (TG),
The level of Diagnostic Value of Fasting Serum insulin (FINS);Detection Serum Nitric Oxide (NO) and superoxide dismutase (SOD) contain
Amount.Observe the medicine protective effect to diabetes rat thoracic aorta endothelial injury
1, materials and methods
1.1 animals and feedstuff
Select healthy cleaning grade male Wistar rat, body weight 160~180g, Jilin University's Experimental Animal Center provide.Commonly
Feed ingredient and heat thereof: fat 5%, carbohydrate 53%, protein 23%, its including cellulose and moisture
His composition accounts for 19%, and total amount of heat is 25kJ/kg;High lipid food composition and heat thereof: fat 22%, carbohydrate 48%,
Protein 20%, other compositions including cellulose and moisture account for 10%, and total amount of heat is 44.3kJ/kg.
1.2 reagent and sample
Candesartan Cilexetil is purchased from National Institute for Food and Drugs Control.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
Streptozotocin (STZ) is Sigma Products;The detection examination of glucose, T-CHOL (TC), triglyceride (TG)
Agent box is Beijing Northization safe clinical reagent company limited product;Insulin radioimmunoassay immunoassay medicine box is biological purchased from Tianjin nine ancient cooking vessel
Technology Co., Ltd.;Nitric oxide (NO) and superoxide dismutase (SOD) detection kit are purchased from Nanjing and build up biological skill
Art company limited;Other reagent are domestic analytical pure.
1.3 instrument
Microplate reader Model550, for Bio-Rad Products.755B type ultraviolet-uisible spectrophotometer, fastens the close section of Nereid
Learn Instrument Ltd.'s analytical tool head factory product;Desk type high speed refrigerated centrifuge, U.S.'s Suo Fu Products;1261 types γ are put
Penetrate immunity calculating instrument, LKB Products.
Prepared by 1.4 mice group and model
60 Wistar male rats, are randomly divided into 5 groups, often group 12, separate Normal group and feed with normal diet;
Remaining is used for setting up type 2 diabetes mellitus rat (T2DM) model, feeds with high lipid food.After rat high lipid food feeds 4w,
Lumbar injection low dose STZ (30mg/kg) 2 times, is spaced 1w;Fasting glucose (FPG) is detected, with FPG >=7.8mmol/L after 2w
As the successful standard of judgment models.The T2DM rat 40 being successfully prepared only is randomly divided into model control group, Candesartan
Ester group (100mg kg-1), compound (I) group (100mg kg-1), candesartan Cilexetil and compound (I) compositions group
【50mg·kg-1Candesartan Cilexetil+50mg kg-1Compound (I)].Gavage 8w, Normal group and model comparison continuously
Group gives equal-volume solvent gavage 8w.
FPG, TG, TC and the detection of Diagnostic Value of Fasting Serum insulin (FINS) in 1.5 serum
After rat treatment 8w, fasting 12~16h, urethane (100mg/kg) intraperitoneal injection of anesthesia, abdominal aortic blood is also located
Dead animal.Every rat about can take blood 4~5ml, separates serum, is distributed into Eppendorf pipe, and-70 DEG C frozen, is used for examining
Survey FPG, TG, TC and FINS.FPG, TG and TC use Enzymology method detection.FINS is by hospital of Jilin University the 3rd
Nuclear Medicine Department uses to put and exempts from method detection.
1.6 serum NO and the detection of SOD
Serum NO and the content of SOD is measured respectively according to NO and SOD test kit description method.
1.7 statistical method
Experimental data x ± s represents, statistical analysis uses SPSS13.0 software processes, compares and divide by single factor test variance between many groups
Analysis (OneWayANOVA) method, compares employing least significant difference (LSD) t inspection between two groups.
2, experimental result
2.1 on the impact on biochemical indicator of the T2DM rat model
Model control group FPG, TC, TG content are higher than blank group (P < 0.05), and insulin content is less than blank
Group (P < 0.05), illustrates modeling success.Comparing with model control group, candesartan Cilexetil is little with compound (I) compositions group
After Mus experiment, FPG, TC, TG content substantially increases (P < 0.01), and insulin content substantially reduces (P < 0.01);With mould
Type matched group compares, and candesartan Cilexetil group, compound (I) group FPG, TC, TG content increases (P < 0.05), islets of langerhans
Cellulose content reduces (P < 0.05).The results are shown in Table 1.
The table 1 impact on T2DM rat model changes of biochemical indexes (x ± s)
2.2 on T2DM rat model serum NO levels and the impact of SOD activity
Model control group NO content and SOD activity, less than blank group (P < 0.05), illustrate modeling success.With model pair
Compare according to group, NO content and the significantly raised (P of SOD activity after candesartan Cilexetil and compound (I) compositions group mouse experiment
< 0.01);Comparing with model control group, candesartan Cilexetil group, compound (I) group NO content and SOD activity raise (P
< 0.05).The results are shown in Table 2.
Table 2 is on T2DM rat model serum NO levels and the impact of SOD activity
Group | NO(μmol/L) | SOD(U/ml) |
Normal group | 25.59±1.27 | 136.41±2.18 |
Model control group | 11.11±1.41 | 103.95±5.72 |
Candesartan Cilexetil group | 18.96±1.22 | 126.15±2.81 |
Compound (I) group | 18.51±1.19 | 125.84±4.11 |
Candesartan Cilexetil and compound (I) compositions group | 24.25±1.51 | 138.29±1.14 |
Vascular endothelial injury is one of main pathogenesis of diabetic vascular complications.Hyperglycemia, hyperlipidemia, hyperinsulinemia
Disease all can make oxidative stress increase, and oxygen-derived free radicals produces and increases, and causes vascular endothelial cell damage.Therefore, want to maintain T
The normal function of 2DM vascular endothelial, improves the sugar of patient, fat, insulin metabolism are highly important simultaneously.
NO is the most important vascular relaxing factor in endothelium source, the delivery of vascular tension force that main regulation is bigger.NO is except having
Outside strong arterial dilation, also there is antiplatelet aggregation, anti-smooth muscle cell proliferation and suppression mononuclear phagocyte to blood
Pipe transfers etc. act on.Therefore, the decline of NO biological activity may result in endothelium-dependent vasodilatation function infringement and promotes tremulous pulse medicated porridge
The formation of sample hardening.NO is considered as an atherosclerotic most important protective factors, is body fight Atherosclerosis
The first line of defence changed.During diabetes, NO minimizing is probably synthesis minimizing and inactivates what increase caused.Endotheliocyte NO comes
Source is mainly catalyzed L-arginine and takes off guanidine radicals and produce NO by being present in the eNOS of intracellular.Research shows, height blood during diabetes
The many factors such as sugar, the secretion rise of IR state, Anomalous lipid metablism, inflammatory cytokine all can cause eNOS activity decrease or table
Reach reduction, so that NO synthesis and secretion reduce, cause diabetes endothelium-dependent vasodilatation function obstacle that painstaking effort occur
Pipe complication.SOD is one of Major Enzymes system of internal removing free radical, can be O by superoxide anion rapid oxidation2And H2O2,
Effectively the oxygen-derived free radicals in purged body, alleviates tissue injury.Diabetes hyperglycemia can with the Lysine binding in SOD active center,
Producing glycosylation, make SOD activity decrease, Scavenging ability declines.
Above-mentioned result of the test shows, when candesartan Cilexetil, compound (I) independent role, can significantly improve T2DM rat
Glucose-lipid metabolism, improve rat chest aorta eNOS protein expression and activity of SOD in serum, increase NO synthesis, reduce
NO destroys, the endothelial injury that protection diabetes cause;When candesartan Cilexetil and compound (I) synergy, pharmacology
Effect further enhances, and illustrates that candesartan Cilexetil and compound (I) exist synergism, can develop into protection diabetes and cause
The medicine of endothelial injury.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.
It will be understood by those within the art that, technical scheme can be modified or equivalent, and not take off
Essence and protection domain from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a candesartan Cilexetil, it is characterised in that: include candesartan Cilexetil, as claimed in claim 1
Compound (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of candesartan Cilexetil the most according to claim 2, it is characterised in that: pharmaceutically acceptable carries
Body includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, suction
Appendix body or lubricant.
The pharmaceutical composition of candesartan Cilexetil the most according to claim 2, it is characterised in that: described dosage form include tablet,
Capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution
Agent, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
The dry rhizome of Herba Asari is pulverized, with 85~95% alcohol heat reflux extraction, united extraction liquid, is concentrated into without alcohol taste, uses stone successively
Oil ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol
Extract;B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 35% ethanol elution, then
With 12 column volumes of 90% ethanol elution, collecting 90% eluent, concentrating under reduced pressure obtains 90% ethanol elution concentrate;(c) step
Suddenly in (b), 90% ethanol elution concentrate purification on normal-phase silica gel separates, and is 120:1,60:1,30:1 and 15:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 4 components;D in () step (c), component 3 separates further by purification on normal-phase silica gel,
3 components are obtained successively with the methylene chloride-methanol gradient elution that volume ratio is 40:1,30:1 and 10:1;(e) step (d)
The reverse phase silica gel that middle component 2 is bonded by octadecylsilane separates, and washes with the methanol aqueous solution that concentration expressed in percentage by volume is 85% is isocratic
De-, collect 14~18 column volume eluents, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) 90% second
Alcohol circumfluence distillation, united extraction liquid.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is D101
Type macroporous adsorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is used dichloromethane
Alkane replaces ethyl acetate to extract, and obtains dichloromethane extract.
9. the application in preparation protection diabetes cause the medicine of endothelial injury of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described candesartan Cilexetil of claim 2~4 causes endothelial injury in preparation protection diabetes
Application in medicine.
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CN105924490A (en) * | 2016-04-23 | 2016-09-07 | 徐月苗 | Candesartan cilexetil medicinal composition and application thereof in biomedicines |
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