CN105884727A - Pharmaceutical composition of kanamycin sulfate and medical application of pharmaceutical composition - Google Patents
Pharmaceutical composition of kanamycin sulfate and medical application of pharmaceutical composition 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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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)
- A61K36/75—Rutaceae (Rue family)
- A61K36/756—Phellodendron, e.g. corktree
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Abstract
The invention discloses a pharmaceutical composition of kanamycin sulfate and a medical application of the pharmaceutical composition. The pharmaceutical composition of kanamycin sulfate contains kanamycin sulfate and a natural product compound (I) with a novel structure; kanamycin sulfate and the compound (I) have a treatment effect on a chronic cerebral ischemia injury caused by cerebral arteriosclerosis when separately act; the treatment effect on the chronic cerebral ischemia injury caused by cerebral arteriosclerosis is further improved when kanamycin sulfate and the compound (I) act jointly; and kanamycin sulfate and the compound (I) can be developed into a medicine for treating the chronic cerebral ischemia injury caused by cerebral arteriosclerosis; compared with the prior art, the pharmaceutical composition has outstanding substantial characteristics and significant progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of kanamycin sulfate, be specifically related to a kind of kanamycin sulfate
Pharmaceutical composition and medical usage thereof.
Background technology
Kanamycin sulfate is aminoglycosides broad ectrum antibiotic, and antimicrobial spectrum is similar with neomycin.Mainly to gram-negative bacteria as big
The severe infections that the uncommon bacterium of intestinal angstrom, Klebsiella, Proteus, pneumobacillus, clostridium perfringen and Shigella etc. cause,
Drug resistance S. aureus L-forms also there is good antibacterial action.Be mainly used in clinically the pulmonary infection caused by sensitive organism, urinary tract infection,
Biliary tract infection septicemia and abdominal cavity infection etc., both normal and other antimicrobial drug use in conjunction rear.Can also be used for other antibiotic resistance to
Medicine and the S. aureus L-forms that this product is sensitive is infected.To treatment lungy, this product can be as Second line Drug.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of kanamycin sulfate, in this pharmaceutical composition containing sulphuric acid card that
Mycin and the natural product of a kind of novel structure, kanamycin sulfate and this natural product can be slow with Synergistic treatment cerebral arteriosclerosis
Property cerebral ischemia.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of kanamycin sulfate, including kanamycin sulfate, compound as claimed in claim 1 (I)
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: Cortex Phellodendri is pulverized by (a), with 70～90% second
Alcohol circumfluence distillation, united extraction liquid, it is concentrated into without alcohol taste, successively by petroleum ether, ethyl acetate and water saturated n-butyl alcohol extraction
Take, 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 12 column volumes of 20% ethanol elution, then with 15 column volumes of 80% ethanol elution, collects
80% eluent, concentrating under reduced pressure obtains 80% ethanol elution concentrate；C in () step (b), 80% ethanol elution concentrate is with just
Phase silica gel separates, and obtains 4 groups with the methylene chloride-methanol gradient elution that volume ratio is 80:1,40:1,20:1 and 10:1 successively
Point；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 25:1,20:1 and 15:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtains 3 components；In (e) step (d) component 2 with octadecylsilane be bonded anti-phase
Silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 65%, collects 13～17 column volume eluents, washes
De-liquid is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 80% 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 the medicine of preparation treatment cerebral arteriosclerosis chronic cerebral ischemia damage.
The application in preparation treatment cerebral arteriosclerosis chronic cerebral ischemia damage medicine of the above-mentioned kanamycin sulfate pharmaceutical composition.
Advantages of the present invention:
Containing kanamycin sulfate and the natural product of a kind of novel structure in the pharmaceutical composition of the kanamycin sulfate that the present invention provides
Thing, when kanamycin sulfate, compound (I) independent role, has treatment to the damage of cerebral arteriosclerosis chronic cerebral ischemia and makees
With；Therapeutic effect when kanamycin sulfate and compound (I) synergy, to the damage of cerebral arteriosclerosis chronic cerebral ischemia
Improve further, the medicine for the treatment of cerebral arteriosclerosis chronic cerebral ischemia damage can be developed into.
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.To the greatest extent
The present invention is explained in detail by pipe with reference to preferred embodiment, it will be understood by those within the art that, can be to the present invention
Technical scheme modify or equivalent, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: Cortex Phellodendri (2kg) is pulverized by (a), extracts (15L × 3 time) with 80% alcohol heat reflux, and merging carries
Take liquid, be concentrated into without alcohol taste (3L), successively with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturation
N-butyl alcohol (3L × 3 time) extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b)
Acetic acid ethyl ester extract D101 type macroporous resin remove impurity in step (a), first with 12 column volumes of 20% ethanol elution, then
With 15 column volumes of 80% ethanol elution, collecting 80% eluent, concentrating under reduced pressure obtains 80% ethanol elution concentrate；(c) step
Suddenly in (b), 80% ethanol elution concentrate purification on normal-phase silica gel separates, and is 80:1 (10 column volumes), 40:1 by volume ratio successively
The methylene chloride-methanol gradient elution of (8 column volumes), 20:1 (8 column volumes) and 10:1 (9 column volumes) obtains 4
Individual component；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 25:1 (7 cylinders by volume ratio successively
Long-pending), the methylene chloride-methanol gradient elution of 20:1 (8 column volumes) and 15:1 (7 column volumes) obtain 3 components；(e)
The reverse phase silica gel that in step (d), component 2 is bonded by octadecylsilane separates, water-soluble with the methanol that concentration expressed in percentage by volume is 65%
Liquid isocratic elution, collects 13～17 column volume eluents, and eluent is concentrated under reduced pressure to give compound (I) (HPLC normalizing
Change purity more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 421.1421, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C21H24O9, degree of unsaturation is 10.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-1 (2.68, s),
H-3 (4.11, s), H-5 (2.54, t, J=6.8Hz), H-6 (4.69, dd, J=6.8,9.6Hz), H-7 (3.13,
Ddt, J=9.6,3.5,3.3Hz), H-8 (5.02, ddd, J=9.6,4.7,4.7Hz), H-9a (2.64, dd, J=14.0,
4.7Hz), H-9b (2.31, dd, J=14.0,4.7Hz), H-13a (6.12, d, J=3.5Hz), H-13b (5.64, d,
J=3.5Hz), and H-14a (5.27, br, s), H-14b (5.10, br, s), H-15a (4.76, d, J=12.5Hz),
H-15b (4.28, d, J=12.5Hz), H-3 ' a (6.11, br, s), H-3 ' b (5.63, br, s), H-4 ' (1.94, s),
15-OAc (2.11, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 57.2 (CH, 1-C),
219.8 (C, 2-C), 82.5 (CH, 3-C), 83.2 (C, 4-C), 55.3 (CH, 5-C), 76.9 (CH, 6-C),
48.9 (CH, 7-C), 74.2 (CH, 8-C), 38.4 (CH2, 9-C), 137.2 (C, 10-C), 135.3 (C,
11-C), 167.8 (C, 12-C), 122.5 (CH2, 13-C), 117.1 (CH2, 14-C), 65.2 (CH2, 15-C),
165.4 (C, 1 '-C), 136.2 (C, 2 '-C), 124.1 (CH2, 3 '-C), 18.4 (CH3, 4 '-C), 173.1 (C,
15-OAc), 21.5 (CH3, 15-OAc).Infrared spectrum shows that this compound contains lactone ring five membered (1765cm-1) and
Hydroxyl (3600cm-1).The carbon spectrum of this compound combines hsqc spectrum, demonstrates 21 carbon signals, including two methyl (
Individual acetonyl), five methylene (company's Oxymethylene, three olefinic methylene), six methine (three company's oxygen
Carbon) and eight quaternary carbons (three ester carbonyl groups, a ketone carbonyl, three alkene quaternary carbons and company's oxygen quaternary carbon).1H-NMR
Show two distinctive single protons doublets signal [δH6.12 (1H, d, J=3.5Hz, H-13a) and 5.64 (1H, d, J=3.5Hz,
H-13b)], and all with H-7 [δH3.13 (1H, ddt, J=9.6,3.5,3.3Hz)] it is connected it was confirmed alpha-methylene-gamma lactone
The existence of structure.Additionally, the coupling constant (J of H-6 and H-76,7=9.6Hz) and H-7 and H-13 pi-allyl coupling often
Number (J7,13=3.5Hz) show that lactone is trans connection.Heptatomic ring exocyclic double bond signal [δH5.27 (1H, br, s, H-14a) and
5.10 (1H, br, s, H-14b)].Two unimodal proton signal δH6.11 and 5.63 (H-3 ' a and H-3 ' b), and three
The sharp-pointed unimodal signal δ that proton is formedH1.94(CH3-4 ') show that this compound contains a 2-methacryloxy side chain.
H-8 (δ in HMBC spectrumH5.02) with carbonyl carbon C-1 ' (δC165.4) dependency shows that side chain is positioned at C-8 position.Meanwhile,
H2-15 and C-COCH3Dependency explanation C-15 position be connected with an acetoxyl group.This change can be guessed according to above-mentioned nuclear magnetic data
Compound is a sesquiterpenoids.By consulting literatures it appeared that this compound and known compound
2α3β4α-trihydroxy-4β-(acetoxymethyl)-8α(4-methacrylate)-1αH,5αH,6βH,7αH-guai-10(14),11(1
3)-dien-6,12-olide has similar structure.Relatively both nuclear magnetic datas are it is found that this noval chemical compound and known compound
Difference be, noval chemical compound has had more a ketone carbonyl signals.Further HMBC spectrum resolves, H-1 and C-2, H-3
Illustrate that additional ketone carbonyl signals is in C-2 position with the dependency of C-2 and H-5 and C-2.So far, this compound
Planar structure resolved out.In NOESY spectrum, H-3 and H-1, H-1 and the coherent signal of H-5 and H-5 and H-7
Illustrate that the group on 3-OH and the C-7 position in this compound is in β position.Additionally, H-15 and H-6, H-6 and H-13
And the group on dependency explanation 4-OH, the C-6 position of H-8 Yu H-6 and the group on C-8 position are in α position.Combine
Close hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine this change
Compound is as follows, and spatial configuration is determined by ECD test further, and theoretical value is basically identical with experiment value.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
The present embodiment uses double kidney double fastener method replicate renal hypertension and then set up cerebral arteriosclerosis rat model model, observes medicine
Thing is on each group of rat fat, serology index of correlation, the impact of cerebral tissue VEGF (VEGF) content.
1, materials and methods
1.1 animal
9～12 week old cleaning grade Wistar rats, weight (250 ± 20) g, Gansu Chinese of Traditional Chinese Medicine's animal center provide.
1.2 reagent and sample
Kanamycin sulfate is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
Normal saline (Gansu Fuzheng Pharmaceutical Sci & Tech Co., Ltd.；Dehydrated alcohol (Kingsoft, Chengdu chemical reagent factory)；10% water
Close chloral (Pharmacy department of the Lan great Second Academy)；Gentamicin injection liquid (Gansu Lanyao Pharmaceutical Industry Group Co., Ltd.'s production)；
SOD test kit, MDA test kit, GSH-PX test kit (be purchased from Nanjing and build up Bioisystech Co., Ltd)；VEGF
Test kit, PDGF test kit (be purchased from Wuhan doctor and obtain Bioisystech Co., Ltd)；High lipoprotein emulsion: be made into containing 7% gallbladder solid
Alcohol, 15% Adeps Sus domestica, 2% sodium cholate and the lipomul of 1% propylthiouracil, 4 DEG C of Refrigerator stores are standby.
1.3 instrument
FT-630G microcomputer Multi probe r enumerator (Beijing Nuclear Instrument Factory)；(University of Science and Technology Innovations is limited for low speed refrigerated centrifuge
Zhong Jia branch company of company, KDC-2044)；Automatic clinical chemistry analyzer (HIT, 7010)；Uv-spectrophotometric
Meter (Shimadzu company limited of Japan, SHIMADZU UV-2401PC)；Paraffin slicing machine (Leica company of Germany)；From
Dynamic tissue processor, full-automatic cell embedding machine (SAKURA company of Japan)
Prepared by 1.4 rat packets and model
Rat, fasting 12 hours (can't help water), after 10% chloral hydrate intraperitoneal injection of anesthesia, row Bilateral Renal aorta is narrow
Narrow operation so that it is narrow 3/4, causes Rat Experimental hypertension model.After performing the operation 1 week, rat oral gavage gives high lipoprotein emulsion
L0mL/kg, 1 time/d, totally 14 weeks, makes the cerebral arteriosclerosis model of hypertension complicated with hyperlipemia, selects modeling successful 60
Only, it is divided into Normal group, model control group, kanamycin sulfate group (80mg kg according to table of random number-1), change
Compound (I) group (80mg kg-1), kanamycin sulfate and compound (I) compositions group [40mg kg-1That is mould for sulphuric acid card
Element+40mg kg-1Compound (I)].After modeling success, model group gavage normal saline 3mL/d, remaining is respectively organized by phase
Answer dosed administration, continuous 14 weeks.
1.5 method of drawing material and observation index
1.5.1 method of drawing material
After gavage 14 weeks, fasting on the same day, femoral artery blood sampling 3～4mL in 10mL test tube, 3000r/min low-temperature centrifugation,
Taking serum, low temperature (＜ 20 DEG C) preserves, and carries out blood fat, Serum markers detection.After femoral artery blood sampling, with 10% hydration
Chloral intraperitoneal injection of anesthesia, opens breast exposed Rats heart and aortic arch, uses normal saline, 4% paraformaldehyde row perfusion respectively,
Until animal is stiff state, then broken end takes brain, puts in 4% paraformaldehyde solution fixing, put after being taken out by cerebral hippocampal tissue
Preserve to be measured in 4 DEG C of refrigerators.
1.5.2 observation index
1.5.2.1 the mensuration of blood lipids
Use OLYMPUS AU2700 type automatic clinical chemistry analyzer measure T-CHOL (TC), triacylglycerol (TG),
HDL-C (HDL-C), low-density lipoprotein cholesterol (LDL-C) level.Unit: mmol/L.
1.5.2.2 the mensuration of Serum markers
According to test kit operating procedure use colorimetry row serum superoxide dismutases (SOD), Serum MDA (MDA),
The detection of glutathion peroxidase (GSH-PX) level content.
1.5.2.3 the mensuration of cerebral tissue VEGF (VEGF) content
Using the expression of the VEGF immunoreactive cell of immunohistochemical method detection cerebral hippocampal tissue, SABC process is all pressed
Description operates.
1.6 statistical method
Experimental data mean ± standard deviation (x ± s) represents, application 18.0 editions statistical softwares of SPSS carry out one factor analysis of variance
Check with t, statistically significant for difference with P ＜ 0.05.
2, experimental result
2.1 respectively organize rat fat changes of contents
Treating for the 14th weekend, compare with model group, TC, TG that kanamycin sulfate group, compound (I) are organized all have reduction
(P ＜ 0.05), HDL-C raises (P ＜ 0.05)；Compare with model group group, kanamycin sulfate and compound (I) group
Two blood lipids index of TC, TG of compound group significantly reduce (P ＜ 0.01), and HDL-C significantly raises (P ＜ 0.01).
Result of the test is shown in Table 1.
2.2 respectively organize rat blood serum index of correlation
14th weekend, with model group ratio, kanamycin sulfate group, compound (I) group SOD in serum content, GSH-PX
Activity raises (P ＜ 0.05), and MDA content reduces (P ＜ 0.05)；With model group ratio, kanamycin sulfate and compound (I)
Compositions group SOD content, GSH-PX activity significantly raised (P ＜ 0.01), MDA content substantially reduces (P ＜ 0.01).
Result of the test is shown in Table 2.
After table 1 treatment, each group Serum Lipids in Experimental HypercholesterolemicRats compares
| Group | TC | TG | HDL-C |
| Normal group | 1.28±0.27 | 0.59±0.09 | 0.72±0.10 |
| Model control group | 19.36±1.85 | 1.88±0.24 | 0.37±0.04 |
| Kanamycin sulfate group | 10.34±0.66 | 0.93±0.06 | 0.59±0.07 |
| Compound (I) group | 9.85±0.86 | 0.87±0.05 | 0.60±0.06 |
| Kanamycin sulfate and compound (I) compositions group | 4.63±0.78 | 0.58±0.07 | 0.71±0.09 |
After table 2 treatment, each group rat blood serum index of correlation compares
| Group | SOD | MDA | GSH-PX |
| Normal group | 90.32±4.58 | 1.78±0.72 | 13.58±2.17 |
| Model control group | 72.43±5.92 | 8.75±2.15 | 6.45±1.06 |
| Kanamycin sulfate group | 80.69±7.49 | 5.43±2.17 | 9.16±2.02 |
| Compound (I) group | 82.70±3.36 | 5.84±0.77 | 10.7±1.83 |
| Kanamycin sulfate and compound (I) compositions group | 89.95±9.86 | 2.77±0.91 | 13.22±1.88 |
One of approach that atheromatous plaque is formed is the endothelial cell damage that a variety of causes causes, and abnormal hemodynamics must
Vascular remodeling mechanism will be started, cause vascular remodeling and dysfunction, occur that blood flow rate is slow, Peripheral resistance increases and complies with
Property variation etc., thus promote atherosclerotic process.Also research data is had to show, substantial amounts of lipid peroxide and decomposition
Product such as MDA can damaged arterial wall and cause atherosclerosis.SOD in body can scavenging activated oxygen, raw to cell
Thing film shields, thus suppresses atherosclerotic formation.GSH-PX as one of main free radical scavenger,
Lipid peroxide chain reaction can be blocked, to alleviating brain injury, blocking-up by the Peroxide metabolism product in scavenger cell
Excitatory toxicity, prevent Cascade of Injury.
The above results shows, when kanamycin sulfate, compound (I) independent role, to cerebral arteriosclerosis chronic cerebral ischemia
Damage has therapeutical effect；When kanamycin sulfate and compound (I) synergy, to cerebral arteriosclerosis chronic cerebral ischemia
The therapeutic effect of damage improves further, can develop into the medicine for the treatment of cerebral arteriosclerosis chronic cerebral ischemia damage.
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 kanamycin sulfate, it is characterised in that: include kanamycin sulfate, such as claim 1 institute
The compound (I) stated and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of kanamycin sulfate the most according to claim 2, it is characterised in that: pharmaceutically acceptable
Carrier include diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant,
Absorption carrier or lubricant.
The pharmaceutical composition of kanamycin sulfate 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)
By Cortex Phellodendri pulverize, with 70～90% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, second
Acetoacetic ester 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 12 column volumes of 20% ethanol elution, then with 80%
15 column volumes of ethanol elution, collect 80% eluent, and concentrating under reduced pressure obtains 80% ethanol elution concentrate；(c) step (b)
In 80% ethanol elution concentrate purification on normal-phase silica gel separate, be the dichloromethane of 80:1,40:1,20:1 and 10:1 by volume ratio successively
Alkane-methanol elution gradient obtains 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, use body successively
The methylene chloride-methanol gradient elution that long-pending ratio is 25:1,20:1 and 15:1 obtains 3 components；Component 2 in (e) step (d)
Separate with the reverse phase silica gel of octadecylsilane bonding, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 65%, collect
13～17 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) 80% 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 compound (I) described in claim 1 is in the medicine of preparation treatment cerebral arteriosclerosis chronic cerebral ischemia damage
Application.
10. the pharmaceutical composition of the arbitrary described kanamycin sulfate of claim 2～4 is chronic in preparation treatment cerebral arteriosclerosis
Application in the medicine of cerebral ischemia.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008539A (en) * | 2016-05-18 | 2016-10-12 | 江苏神龙药业有限公司 | Ferric carboxyl maltose injection and application thereof |
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Application publication date: 20160824 |