CN106008638A - Medicine composition with ketamine hydrochloride and biomedical application of medicine composition - Google Patents
Medicine composition with ketamine hydrochloride and biomedical application of medicine composition Download PDFInfo
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- CN106008638A CN106008638A CN201610335393.0A CN201610335393A CN106008638A CN 106008638 A CN106008638 A CN 106008638A CN 201610335393 A CN201610335393 A CN 201610335393A CN 106008638 A CN106008638 A CN 106008638A
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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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
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention discloses a medicine composition with ketamine hydrochloride and biomedical application of the medicine composition. The medicine composition with the ketamine hydrochloride contains the ketamine hydrochloride and a compound (I). The compound (I) is a natural product and is of a novel structure. Effects of treating acute gouty arthritis can be realized when the ketamine hydrochloride and the compound (I) are individually used; the effects of treating the acute gouty arthritis further can be improved when the ketamine hydrochloride and the compound (I) are jointly used, and accordingly the ketamine hydrochloride and the compound (I) can be developed to obtain medicines for treating the acute gouty arthritis. Compared with the prior art, the medicine composition and the biomedical application have the advantages of outstanding substantial characteristics and obvious progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of ketalar, be specifically related to the medicine of ketalar
Compositions and the application in biological medicine thereof.
Background technology
The most selective inner side core suppressing thalamus of ketalar, retardance spinal cord is to cancellated up biography
Lead, excited limbic system, and the opiate receptor in nervus centralis and spinal cord is had affinity.Produce anesthetic action, mainly press down
Excitatory neurotransmitter processed (acetylcholine, Pidolidone) and the result of N-methyl-D-aspartate winter acid acceptor；Analgesic activity
Mainly due to retardance spinal cord to network structure to the incoming signal of the pain sensation and with the combination of opiate receptor, and spinal cord thalamus is conducted
Without impact, therefore visceral pain is improved limited.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of ketalar, containing hydrochloric acid in this pharmaceutical composition
Ketamine and the natural product of a kind of novel structure, ketalar and this natural product can close with Synergistic treatment acute gout
Joint inflammation.
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 ketalar, including ketalar, compound as claimed in claim 1 (I)
Pharmaceutically acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier include diluent, excipient, filler, binding agent, wetting agent,
Disintegrating 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: Fructus Phyllanthi is pulverized by (a), with 65～85% 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；N-butyl alcohol extract in (b) step (a)
Use macroporous resin remove impurity, first with 8 column volumes of 6% ethanol elution, then with 8 column volumes of 70% ethanol elution, collect 70% and wash
De-liquid, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel is divided
From, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 50:1,25:1,15:1 and 5:1 successively；(d) step
Suddenly in (c), component 4 separates further by purification on normal-phase silica gel, successively with the methylene chloride-methanol ladder that volume ratio is 10:1,5:1 and 2:1
Degree affords 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with volume hundred
Point concentration is the methanol aqueous solution isocratic elution of 75%, collects 8～14 column volume eluents, being concentrated under reduced pressure to give of eluent
Compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 75% alcohol heat reflux, united extraction
Liquid.
Further, in the preparation method of compound (I), described macroporous resin is AB-8 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane
Take, obtain dichloromethane extract.
The above-claimed cpd (I) application in the medicine of preparation treatment acute gouty arthritis.
The application in the medicine of preparation treatment acute gouty arthritis of the pharmaceutical composition of above-mentioned ketalar.
Advantages of the present invention:
Containing ketalar and the sky of a kind of novel structure in the pharmaceutical composition of the ketalar that the present invention provides
So product, when ketalar, compound (I) independent role, has therapeutical effect to acute gouty arthritis；Hydrochloric acid chloramines
When ketone and compound (I) synergy, the therapeutic effect of acute gouty arthritis is improved further, treatment can be developed into
The medicine of acute gouty arthritis.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit the present invention with this and protect model
Enclose.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: Fructus Phyllanthi (3kg) is pulverized by (a), extracts (20L × 3 time) with 75% alcohol heat reflux, united extraction
Liquid, is concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol
(4L × 3 time) extract, and respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol extract AB-8 type macroporous resin remove impurity, first with 8 column volumes of 6% ethanol elution, then with 70% ethanol elution 8
Column volume, collects 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution is dense
Contracting thing with purification on normal-phase silica gel separate, successively with volume ratio be 50:1 (8 column volumes), 25:1 (8 column volumes), 15:1 (8 cylinders
Long-pending) and the methylene chloride-methanol gradient elution of 5:1 (10 column volumes) obtain 4 components；D in () step (c), component 4 is with just
Phase silica gel separates further, successively with volume ratio be 10:1 (8 column volumes), 5:1 (10 column volumes) and 2:1 (5 cylinders
Long-pending) methylene chloride-methanol gradient elution obtain 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 75%, collects 8～14 column volume eluents,
Eluent is concentrated under reduced pressure to give compound (I) (purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 425.2978, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C28H40O3, degree of unsaturation is 9.Hydrogen nuclear magnetic resonance modal data δH(ppm, CD3OD, 500MHz): H-1a (1.94, m), H-1b
(1.78, m), H-2 (6.03, ddd, J=12.0,7.3,5.4Hz), H-3 (6.25, dd, J=12.0,7.5Hz), H-4a
(2.22, dd, J=11.6,7.5Hz), and H-4b (1.89, d, J=11.6Hz), H-7 (6.15, s), H-11 (5.76, s), H-12a
(2.33, dd, J=17.8,3.7Hz), and H-12b (1.89, dd, J=17.8,4.5Hz), H-15a (2.11, m), H-15b
(1.65, m), H-16a (1.53, m), H-16b (1.44, m), H-17 (1.61, m), H-18 (0.95, s), H-19 (1.21, s),
H-20 (2.14, m), H-21 (1.06, d, J=6.7Hz), H-22 (5.23, dd, J=15.3,7.8Hz), H-23 (5.25, dd, J
=15.3,7.3Hz), and H-24 (1.83, m), H-25 (1.47, m), H-26 (0.85, d, J=7.5Hz), H-27 (0.84, d, J=
7.5Hz), H-28 (0.93, d, J=6.6Hz)；Carbon-13 nmr spectra data δC(ppm, CD3OD, 125MHz): 35.3 (CH2, 1-
C), 132.1 (CH, 2-C) 131.7 (CH, 3-C), 43.4 (CH2, 4-C), 79.9 (C, 5-C), 196.8 (C, 6-C), 160.4
(CH, 7-C), 124.5 (C, 8-C), 131.2 (C, 9-C), 42.3 (C, 10-C), 116.5 (CH, 11-C), 39.7 (CH2, 12-
C), 46.4 (C, 13-C), 82.5 (C, 14-C), 34.6 (CH2, 15-C), 27.6 (CH2, 16-C), 53.3 (CH, 17-C), 18.9
(CH3, 18-C), 23.7 (CH3, 19-C), 41.7 (CH, 20-C), 23.1 (CH3, 21-C), 136.6 (CH, 22-C), 132.5
(CH, 23-C), 44.5 (CH, 24-C), 34.7 (CH, 25-C), 20.1 (CH3, 26-C), 20.6 (CH3, 27-C), 18.7 (CH3,
28-C).Infrared absorption band (1645cm-1) show that this compound contains conjugated diene knot with ultraviolet maximum absorption wavelength (242nm)
Structure.Hydrogen spectrum demonstrates two unimodal methyl signals [δH0.95 (3H, s, Me-18) and 1.21 (3H, s, Me-19)], four are bimodal
Methyl signals [δH1.06 (3H, d, J=6.7Hz, Me-21), 0.85 (3H, d, J=7.5Hz, Me-26), 0.84 (3H, d, J=
7.5Hz, Me-27) and 0.93 (3H, d, J=6.6Hz, Me-28)], six olefinic methine proton signal [δH6.03 (1H,
Ddd, J=12.0,7.3,5.4Hz, H-2), 6.25 (1H, dd, J=12.0,7.5Hz, H-3), 6.15 (1H, s, H-7), 5.76
(1H, s, H-11), 5.23 (1H, dd, J=15.3,7.8Hz, H-22) and 5.25 (1H, dd, J=15.3,7.3Hz, H-23)].
The carbon spectrum of this noval chemical compound demonstrates 28 carbon signals, including six methyl, five methylene, ten methine (six alkene
Carbon) and seven quaternary carbons (a ketone carbonyl carbon, two alkene quaternary carbons and two oxygen-containing quaternary carbons).Synthetic nucleus magnetic spectrum diagram data with
And high score mass spectrometric data, this compound may be the steroid compound of a pregnane type.Consulting literatures can reason out this
Compound has similar structure with known compound Fomentarol A.Relatively both nuclear magnetic datas find, both is unique
Difference is, loses and had more one group of double bond and a ketone carbonyl while C-3 and C-6 position connects oxygen carbon signal in noval chemical compound
Signal.Accordingly, the derivant that noval chemical compound may be a Fomentarol A can be deduced.In HMBC spectrum, H-7 and C-6
And the dependency of H-4 Yu C-6 may certify that the C-6 position in this compound is a ketone carbonyl carbon.Meanwhile, H-1 and C-3, H-3
With the dependency explanation of C-2 and H-4 and C-2, there is a cyclic olefinic bond in this compound between C-2 and C-3.NOESY composes
In, this compound being done in pyridine again spectrum and finds, Hax-4, H-7 and Hax-12 are to low field displacement, and this point demonstrates 5
The configurations such as α and 14 α.By the nuclear magnetic data of C-26, C-27 and C-28 in comparative compound and there is (24R)-22E-
Or (24S) compound of-22E-side chain compares discovery, the absolute configuration of noval chemical compound C-24 position is still that 24R type.
Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine this compound
As follows, 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 is as follows:
Embodiment 2: pharmacological action
This example uses Monosodium urate to prepare acute gouty arthritis rat model, observes tested joint before and after Drug therapy
Prostaglandin E in Zhou Jing, articular cavity tissue2(PGE), tumor necrosis factor-alpha (TNF-α) content and arthroedema leukocyte
Number.
1, materials and methods
1.1 animal
SD rat, male, cleaning grade, body weight 200～250g, by Guangdong Medical College Experimental Animal Center provide (.In experiment
Room supplies examination after normally raising 3d.
1.2 reagent and sample
Ketalar is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
Monosodium urate (offer of Sigma company), prostaglandin E2(PGE2) (Beijing East immunological technique institute carries radioimmunoassay kits
For), tumor necrosis factor-alpha (TNF-α) test kit (Military Medical Science Institute's institute provides).
Prepared by 1.3 rat packets and model
Rat is randomly divided into 5 groups, often group 12, respectively Normal group (not modeling), model control group and hydrochloric acid chlorine
Amine ketone group (80mg kg-1), compound (I) group (80mg kg-1), ketalar and compound (I) compositions group
【40mg·kg-1Ketalar+40mg kg-1Compound (I)].Modeling method: with No. 6 entry needles on the right side of tested rat
Ankle joint dorsal part inserts inside tibia tendon with 45° angle, and 10% Monosodium urate solution is only injected ankle joint intracavity by 0.2mL/.
Modeling second day, administration group is according to above-mentioned dosage gastric infusion, once a day, for three days on end；Normal group and mould
The normal saline of type matched group gavage equivalent.
1.4 rat articular swelling determination experiments
Each group rat before modeling, after modeling 3h (before administration) and last be administered after 3d, respectively at tested ankle joint
Same area measures its girth with nonelastic tape, before observing modeling and the change of rat ankle joint girth before and after treatment.
PGE in 1.5 articular cavity2, TNF-α, determination of white cells experiment
Sacrificed by decapitation after each group rat drug treatment 72h the last time, opens tested articular cavity and takes hydrarthrosis, be coated with
Sheet, carries out numeration of leukocyte；Take off articular cavity surrounding soft tissue, use in radioimmunoassay method tissue after homogenate
PGE2, TNF-α, by test kit description operate.
1.6 statistical method
Application 18.0 editions statistical softwares of SPSS carry out one factor analysis of variance and t inspection, have system with P ＜ 0.05 for difference
Meter meaning.
2, experimental result
2.1 impacts on gouty arthritis ankle swelling in rat
Comparing with Normal group, model control group ankle swelling in rat degree substantially increases (P ＜ 0.01).With model pair
Comparing according to group, ketalar group, compound (I) group rat articular swelling degree is obviously reduced (P ＜ 0.05), ketalar
(P0.01) is reduced with compound (I) compositions group arthroncus degree.The results are shown in Table 1.
PGE in 2.2 pairs of gouty arthritis rat articular cavity tissues2, TNF-α level and the impact of numeration of leukocyte
With Normal group ratio, PGE in model group rats articular cavity tissue2, TNF-α content significantly raise (P ＜ 0.01)；
Compare with model control group, PGE in ketalar group, compound (I) group rat articular cavity tissue2, TNF-α content reduce (P
＜ 0.05)；Compare with model control group, ketalar and PGE in compound (I) compositions group articular cavity tissue2、TNF-α
Content significantly reduces (P ＜ 0.01).Compared with Normal group, in model control group rat joint cavity hydrops, quantity of leucocyte is bright
Aobvious rising (P ＜ 0.01)；With model control group ratio, leukocyte in ketalar group, compound (I) group rat joint cavity hydrops
Quantity reduces (P ＜ 0.05), and ketalar and compound (I) compositions group significantly reduce (P ＜ 0.01).The results are shown in Table 2.
The comparison (mm) of Articular swelling change respectively organized by table 1
PGE in rat articular cavity tissue respectively organized by table 22, TNF-α content and numeration of leukocyte
Gout is heritability and (or) the acquired underexcretion caused and (or) disorders of purine metabolism, acute gout
The arthritic basic cause of disease of property is hyperuricemia and the precipitation of local joint sodium urate crystals caused thereof.Application Monosodium urate office
Portion's joint injection causes the modeling method that gouty arthritis model is considered as the gouty arthritis of classics, can be used for evaluating
The curative effect of gout arthritis drug.
When Monosodium urate deposits to around articular cavity, lure into monocytes/macrophages phagocytosis crystal, mastocyte, polymorphonuclear addicted to
Neutrophil accumulation is to about, and discharges that cause is scorching, algogenic substance, such as histamine, prostaglandin (PG), leukotriene
The inflammatory mediator such as B4, TNF-α, produces the strongest inflammatory effector and induced pain effect.PG is as the weight that third messenger is inflammatory reaction
Wanting mediator, the generation development of inflammation has substantial connection with local PG content.It is generally believed that in arthritic pathogenic process,
PGE2Effect the strongest.TNF-α as Chemokines and activity factor gouty arthritis generation, developed
Journey also plays an important role.Analyze PGE in tested articular cavity tissue2, quantity of leucocyte is favourable in TNF-α content and hydrarthrosis
In clinical diagnosis and the treatment of instructing gout.
The above results shows, when ketalar, compound (I) independent role, has acute gouty arthritis and controls
Treatment effect；When ketalar and compound (I) synergy, the therapeutic effect of acute gouty arthritis is carried further
Height, can develop into the medicine for the treatment of acute gouty arthritis.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit the protection of the present invention with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent,
Essence and protection domain without deviating from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a ketalar, it is characterised in that: include ketalar, as claimed in claim 1
Compound (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of ketalar the most according to claim 2, it is characterised in that: pharmaceutically acceptable carries
Body includes that diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carry
Body or lubricant.
The pharmaceutical composition of ketalar 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, injection
Agent, 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) is by remaining
Sweet sub-pulverizing, with 65～85% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, acetic acid second
Ester and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b)
N-butyl alcohol extract macroporous resin remove impurity in step (a), first with 8 column volumes of 6% ethanol elution, then uses 70% ethanol elution
8 column volumes, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, and washes by the methylene chloride-methanol gradient that volume ratio is 50:1,25:1,15:1 and 5:1 successively
Take off and obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 10:1,5:1 and
The methylene chloride-methanol gradient elution of 2:1 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 75%, collects 8～14 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) is returned by 75% ethanol heat
Stream extracts, united extraction liquid.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is AB-8 type
Macroporous adsorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) uses dichloromethane generation
Extract for ethyl acetate, obtain dichloromethane extract.
9. the application in the medicine of preparation treatment acute gouty arthritis of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described ketalar of claim 2～4 is at preparation treatment acute gouty arthritis
Medicine in application.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906647A (en) * | 2016-05-19 | 2016-08-31 | 江苏神龙药业有限公司 | Pharmaceutical composition of pramipexole dihydrochloride and application of pharmaceutical composition in biomedicine |
| CN110183507A (en) * | 2019-06-21 | 2019-08-30 | 华侨大学 | A kind of triterpene compound and its preparation method and application |
-
2016
- 2016-05-15 CN CN201610335393.0A patent/CN106008638A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906647A (en) * | 2016-05-19 | 2016-08-31 | 江苏神龙药业有限公司 | Pharmaceutical composition of pramipexole dihydrochloride and application of pharmaceutical composition in biomedicine |
| CN110183507A (en) * | 2019-06-21 | 2019-08-30 | 华侨大学 | A kind of triterpene compound and its preparation method and application |
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Application publication date: 20161012 |