CN105949151A - Cortisone acetate medicine composition and medical application thereof - Google Patents
Cortisone acetate medicine composition and medical application thereof Download PDFInfo
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- CN105949151A CN105949151A CN201610380372.0A CN201610380372A CN105949151A CN 105949151 A CN105949151 A CN 105949151A CN 201610380372 A CN201610380372 A CN 201610380372A CN 105949151 A CN105949151 A CN 105949151A
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- cortisone acetate
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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
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
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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)
- A61K36/39—Convolvulaceae (Morning-glory family), e.g. bindweed
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- Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a cortisone acetate medicine composition and medical application thereof. The cortisone acetate medicine composition contains cortisone acetate and a natural product compound (I) of a novel structure, and when cortisone acetate and the compound (I) work independently, the anti-inflammatory and analgesic functions are achieved; when cortisone acetate and the compound (I) work together, the anti-inflammatory and analgesic functions are further improved, and cortisone acetate and the compound (I) can be developed into anti-inflammatory and analgesic medicine. Compared with the prior art, the medicine composition has outstanding substantial characteristics and makes remarkable progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of cortisone acetate, be specifically related to the medicine of a kind of cortisone acetate
Compositions and medical usage thereof.
Background technology
Cortisone acetate is a kind of adrenocortical hormone, commonly uses hormonal system medication for clinic.
Up to now, there is not yet the dependency report of cortisone acetate and pharmaceutical composition thereof and anti-inflammatory and antalgic.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of cortisone acetate, containing cortisone acetate in this pharmaceutical composition
Anti-inflammatory and antalgic can be worked in coordination with the natural product of a kind of novel structure, cortisone acetate 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 cortisone acetate, including cortisone acetate, 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: Caulis Erycibes 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), described macroporous resin is D101 type macroporous adsorbent resin.
The above-claimed cpd (I) application in the medicine preparing anti-inflammatory and antalgic.
The application in the medicine preparing anti-inflammatory and antalgic of the pharmaceutical composition of above-mentioned cortisone acetate.
Advantages of the present invention:
Containing cortisone acetate and the natural product of a kind of novel structure in the pharmaceutical composition of the cortisone acetate that the present invention provides,
When cortisone acetate and this natural product independent role, there is anti-inflammatory and analgesic effect；During the two synergy, anti-inflammatory and analgesic effect
Improve further, the medicine of anti-inflammatory and antalgic can be developed into.The present invention compared with prior art have prominent substantive distinguishing features and
The most progressive.
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: Caulis Erycibes (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+Na]+For m/z415.2093, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C22H32O6, degree of unsaturation is 7.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-1a (1.29, m),
H-1b (1.54, m), H-2a (1.81, m), H-2b (1.92, m), H-3 (5.91, s), H-5 (2.25, m),
H-6a (2.21, m), H-6b (2.87, d, J=12.3Hz), H-9 (2.26, m, 2H), H-12 (1.83, s),
H-13 (2.04, s), H-14 (0.99, s), H-15 (1.58, s), H-3 ' (3.44, q, J=6.2Hz), H-4 ' (1.36,
D, J=6.2Hz), and H-5 ' (1.42, s), 4-AcO (1.96, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3,
125MHz): 33.5 (CH2, 1-C), 22.8 (CH2, 2-C), 71.4 (CH, 3-C), 83.3 (C, 4-C),
45.2 (CH, 5-C), 25.4 (CH2, 6-C), 130.2 (C, 7-C), 201.1 (C, 8-C), 59.8 (CH2,
9-C), 36.3 (C, 10-C), 145.3 (C, 11-C), 22.3 (CH3, 12-C), 23.1 (CH3, 13-C),
18.8(CH3, 14-C), 18.7 (CH3, 15-C), 168.7 (C, 1 '-C), 64.1 (C, 2 '-C), 61.6 (CH,
3 '-C), 13.1 (CH3, 4 '-C), 18.3 (CH3, 5 '-C), 169.9 (C, 4-AcO), 21.6 (CH3, 4-AcO).
1734cm in infrared spectrum-1With 1641cm-1Absorption band shows to there is carbonyl and double bond fragment in structure.13C-NMR、DEPT
With hsqc spectrum shows 22 carbon signals, including seven methyl (acetonyl), four methylene, three times
Methyl (two company's oxygen carbon), and eight quaternary carbons (three carbonyl carbon, two alkene carbon and two company's oxygen quaternary carbons).Above merit
Structure can show that this compound is tricyclic structure in conjunction with insatiable hunger sum.1H-NMR spectrum combines hsqc spectrum and shows six onychostromas
Subsignal δH1.83 (3H, s), 2.04 (3H, s), 0.99 (3H, s), 1.58 (3H, s), 1.36 (3H, d,
J=6.2Hz), 1.42 (3H, s), an acetylmethyl proton signal δH1.96 (3H, s), two company's oxygen methine matter
Subsignal δH5.91 (1H, s) with 3.44 (1H, q, J=6.2Hz)；Above NMR data can confirm that this compound is wealthy
Bud chrysanthanone derivant.In HMBC spectrum, the coherent signal of H-12/C-11, H-13/C-11, H-14/C-10, H-15/C-4 can be returned
Belonging to is the methyl fragment on fetid marsh fleabane ketone, and it is esterified that C-3 position proton signal shifts to low field explanation C-3 hydroxyl, is composed by HMBC
The dependency of middle H-3/C-1 ' is further confirmed that.HMBC spectrum in H-3 '/C-1 '/C-2 '/C-4 ', H-4 '/C-3 ',
The dependency of H-5 '/C-2 '/C-1 ' and C-2 ' and C-3 ' carbon chemical shifts can confirm that existence 2 '-methyl-2 in structure ', 3 '-epoxy-
Butyryl acyloxy side chain structure, and proton signal δH1.42 and 1.36 methyl signals that can be attributed to H-5 ' and the methyl of H-4 '
Signal.H in NOESY spectrumβ-1/H-14, Hβ-1/H-3, H-3/H-15 and H-14/H-15 coherent signal shows H-3, H-14
With H-15 at the homonymy of fetid marsh fleabane ketone skeleton, H in additionα-1/H-5 coherent signal hint different at H-3, H-14 and H-15 of H-5
Side.The relative configuration of this compound is confirmed by X-single crystal diffraction further, the absolute configuration of C-3 position by acidolysis reaction with
Mosher method can confirm that as R configuration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about relevant
Types of nuclear magnetic data, can determine that this compound is as follows substantially, and spatial configuration is determined by ECD test further, theoretical value
Basically identical with experiment value.This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 animal
Kun Ming mice, male and female half and half (Individual testwas is with male), weight (20 ± 2) g；Wistar rat, male,
Weight (200 ± 20) g, is provided by Heilongjiang University of Chinese Medicine's Experimental Animal Center.
1.2 reagent and sample
Cortisone acetate is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
Aspirin Enteric-coated Tablets (Henan Xin Hui pharmaceutical Co. Ltd product)；The chemical reagent such as dimethylbenzene, glacial acetic acid is analytical pure,
Ovum Gallus domesticus album solution is Fresh.
1.3 instrument
Self-control toes swelling analyzer
1.4 dimethylbenzene induced mice ear swelling experiments
Take mice 50, male, it is randomly divided into 5 groups by weight, often group 10, each group is respectively blank group, sun
Property matched group (aspirin, 500mg kg-1) and cortisone acetate group (80mg kg-1), compound (I) group (80mg kg-1)、
Cortisone acetate and compound (I) compositions group [40mg kg-1Cortisone acetate+40mg kg-1Compound (I)].Empty
White matched group gavages normal saline, and remaining is according to drug administration, and gastric infusion is for three days on end.After last is administered 30min,
Before and after the left ear of mice, dimethylbenzene 0.05mL is smeared on two sides immediately, mice takes off after 1h cervical vertebra and puts to death, cut left and right along auricle baseline
Two auricles, lay round auricle at same position respectively with 6mm diameter card punch, claim two ear weight, calculate ear swelling degree.
Rat paw edema experiment caused by 1.5 Ovum Gallus domesticus album
Take rat 50, male, it is randomly divided into 5 groups (packets same 1.4), often group 10 by weight.Each Mus before experiment
Right metapedes ankle is marked, and measures each Mus right metapedes volume twice with volumetry, averages as normal foot volume.
Blank group gavages normal saline, and remaining is according to drug administration, and for three days on end, last is administered every rat after 30min
Right metapedes sole of the foot portion subcutaneous injection 10% Fresh Egg clear normal saline solution 0.1mL causes inflammation, and after Yu Zhiyan, 2.0h measures rat foot appearance
Long-pending, continuous 2 times, meansigma methods is measured value, calculates each Mus and causes right metapedes sole of the foot volume changing value before and after inflammation, swelling rate and suppression ratio.
1.6 acetic acid induced mice Body writhing tests
Take mice 50, male and female half and half, be randomly divided into 5 groups (packet and dosages same 1.4) by weight, often group 10,
Respectively organizing gastric infusion for three days on end, last is administered 30min pneumoretroperitoneum injection 0.3%HAc solution 0.1mL/10g, after observing injection
In 15min, there is the number of times of writhing in mice.
1.7 statistical method
Representing with mean ± standard deviation (x ± s), data process SPSS13.0 statistical software carries out Group Design t inspection.
2, experimental result
The impact of 2.1 xylol induced mice ear swellings
Swelling degree=every Mus left auricle quality-auris dextra tablet quality
With blank group ratio, positive controls mice ear degree significantly reduces (P ＜ 0.01)；With blank group ratio,
Cortisone acetate group, compound (I) group mice ear degree reduces (P ＜ 0.05)；With blank group ratio, acetic acid can
Pine group and compound (I) compositions group mice ear degree significantly reduce (P ＜ 0.01).The results are shown in Table 1.
2.2 impacts on rat paw edema caused by Ovum Gallus domesticus album
Swelling rate=(causing the scorching front foot sole of the foot volume of scorching metapedes sole of the foot volume-cause)/cause scorching front foot sole of the foot volume × 100%；
Suppression ratio=(blank group swelling rate-administration group swelling rate)/blank group swelling rate × 100%.
With blank group ratio, positive controls rat paw edema degree significantly reduces (P ＜ 0.01)；With blank group ratio, vinegar
Acid cortisone group, compound (I) group rat paw edema degree reduce (P ＜ 0.05)；With blank group ratio, cortisone acetate
Group and compound (I) compositions group rat paw edema degree significantly reduce (P ＜ 0.01).The results are shown in Table 1.
The impact of 2.3 Dichlorodiphenyl Acetate induced mice writhing responses
With blank group ratio, positive controls mouse writhing number of times significantly reduces (P ＜ 0.01)；With blank group ratio, vinegar
Acid cortisone group, compound (I) group mouse writhing number of times reduce (P ＜ 0.05)；With blank group ratio, cortisone acetate
Group and compound (I) compositions group mouse writhing number of times significantly reduce (P ＜ 0.01).The results are shown in Table 1.
Table 1 is on mice ear, rat paw edema, the impact of mouse writhing reaction
The above results shows, when cortisone acetate, compound (I) independent role, has anti-inflammatory and analgesic effect；Acetic acid can
When pine and compound (I) synergy, anti-inflammatory pain-stopping effect improves further, can develop into anti-inflammation analgesis medicament.
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 (8)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a cortisone acetate, it is characterised in that: include cortisone acetate, as claimed in claim 1
Compound (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of cortisone acetate 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 cortisone acetate 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 Caulis Erycibes 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: described macroporous resin is D101
Type macroporous adsorbent resin.
7. the application in the medicine preparing anti-inflammatory and antalgic of the compound (I) described in claim 1.
8. the pharmaceutical composition of the arbitrary described cortisone acetate of claim 2～4 application in the medicine preparing anti-inflammatory and antalgic.
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| CN201610380372.0A CN105949151A (en) | 2016-05-31 | 2016-05-31 | Cortisone acetate medicine composition and medical application thereof |
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| CN201610380372.0A CN105949151A (en) | 2016-05-31 | 2016-05-31 | Cortisone acetate medicine composition and medical application thereof |
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Application publication date: 20160921 |