CN105713065A - Azathioprine pharmaceutical composition and medical application thereof - Google Patents
Azathioprine pharmaceutical composition and medical application thereof Download PDFInfo
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- CN105713065A CN105713065A CN201610260396.2A CN201610260396A CN105713065A CN 105713065 A CN105713065 A CN 105713065A CN 201610260396 A CN201610260396 A CN 201610260396A CN 105713065 A CN105713065 A CN 105713065A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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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
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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Abstract
The invention discloses an azathioprine pharmaceutical composition and a medical application thereof. The azathioprine pharmaceutical composition provided by the invention contains azathioprine and a natural product compound (I) separated from dry rhizome of coptis chinensis with novel structure, azathioprine and the compound (I) respectively have good neuroinflammation inhibiting effect when being applied separately, and the neuroinflammation inhibiting effect is further enhanced when azathioprine and the compound (I) are in combined utilization, so that the azathioprine pharmaceutical composition can be developed into a neuroinflammation inhibitory medicine. Compared with the prior art, the azathioprine pharmaceutical composition disclosed by the invention has outstanding substantial characteristics and obvious progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of azathioprine, be specifically related to pharmaceutical composition and the medical usage thereof of azathioprine.
Background technology
Azathioprine is the imdazole derivatives of Ismipur, for having the antimetabolite of immunosuppressive action.Alkylating can be produced and block SH group, it is suppressed that the biosynthesis of nucleic acid, it is prevented that the hypertrophy of cell, and the infringement of DNA can be caused.Zoopery confirms, this medicine can make DNA, RNA in thymus, spleen reduce, and affects DNA, RNA and the synthesis of protein, mainly suppresses T-lymphocyte to affect immunity, so delayed anaphylaxis reaction can be suppressed, and the rejection of organ transplantation.The curative effect of this medicine just need to occur after treatment several weeks or several months.Absorb preferably in upper digestive tract.
Neuroinflamation is the innate immune response reaction of central nervous system, is mainly mediated by immunocyte microglia in brain and astrocyte.When cerebral tissue is subject to the damage of various pathological factor or stimulates, microglia and star spongiocyte can be changed into activated state by tranquillization state, and nervous tissue's fragment of degeneration is removed in phagocytosis, and neuron is shielded by the glial cell that therefore appropriateness activates.But under pathological conditions, glial cell can by excessive activation, cause neuroinflamation, discharge substantial amounts of inflammatory factor, such as tumor necrosis factor (TNF-α), interleukin (IL), glutamate, Glu and nitric oxide (NO) etc., cause that neuronal function forfeiture, degeneration are even dead, and then cause neuronic damage.Although the mechanism of neuroinflamation is clear but without studying completely, but generally believe that neuroinflamation is closely related with the morbidity of multiple nervous system degenerative disease.
Up to now, there is not yet the dependency of azathioprine and pharmaceutical composition thereof and neuroinflamation report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of azathioprine, containing the natural product of azathioprine and a kind of novel structure, azathioprine and this natural product in this pharmaceutical composition can Synergistic treatment neuroinflamation.
The above-mentioned purpose of the present invention is achieved by the techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of azathioprine, including azathioprine, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepares into the dosage form of needs.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form includes tablet, capsule, oral liquid, sucks 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), comprise following operating procedure: the dry rhizome of Rhizoma Coptidis is pulverized by (a), extract with 75～85% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum 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 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 85:1,45:1,25:1 and 15:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 20:1,15:1 and 1:1 methylene chloride-methanol gradient elution obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 10～16 column volume eluents, eluent concentrating under reduced pressure obtains 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) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
The above-claimed cpd (I) application in the medicine of preparation treatment neuroinflamation.
The application in the medicine of preparation treatment neuroinflamation of the pharmaceutical composition of above-mentioned azathioprine.
Advantages of the present invention:
Containing azathioprine and a kind of natural product separating the novel structure obtained from the dry rhizome of Rhizoma Coptidis in the pharmaceutical composition of azathioprine provided by the invention, when azathioprine and this natural product independent role, neuroinflamation had therapeutical effect；During the two synergy, the therapeutic effect of neuroinflamation is improved further, it is possible to develop into the medicine for the treatment of neuroinflamation.The present invention compared with prior art has prominent substantive distinguishing features and significant 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.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, it is possible to technical scheme is modified or equivalent replacement, 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: the dry rhizome (2kg) of Rhizoma Coptidis is pulverized by (a), (15L × 3 time) are extracted with 80% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (3L), extract with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated n-butyl alcohol (3L × 3 time) successively, 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 8 column volumes of 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 85:1 (10 column volumes), 45:1 (8 column volumes), 25:1 (10 column volumes) and 15:1 (8 column volumes) successively；D in () step (c), component 4 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 20:1 (10 column volumes), 15:1 (8 column volumes) and 1:1 (6 column volumes) successively；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collect 10～16 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (190mg, HPLC normalization purity is more than 98%).
Structural identification: yellow powder；HR-ESI-MS shows [M+H]+For m/z523.3021, can obtain molecular formula in conjunction with nuclear-magnetism feature is C32H42O6, degree of unsaturation is 12.Hydrogen nuclear magnetic resonance modal data δH(ppm, DMSO-d6, 600MHz): H-1 (6.07, d, J=12.8Hz), H-2 (5.89, d, J=12.9Hz), H-5 (2.15, d, J=3.1Hz), H-6 (1.22, m), H-6 (1.64, m), H-7 (1.13, m), H-7 (1.41, m), H-8 (1.77, dd, J=10.5, 6.6Hz), H-11 (1.50, m), H-11 (2.11, m), H-12 (1.64, m), H-12 (1.71, m), H-15 (1.28, m), H-15 (2.33, dd, J=14.9, 7.2Hz), H-16 (5.33, m), H-16b (2.06, s), H-17 (2.27, m), H-18 (1.11, s), H-19 (0.88, d, J=4.4Hz), H-19 (0.98, d, J=4.4Hz), H-20 (2.50, m), H-21 (0.88, d, J=6.9Hz), H-24a (5.89, s), H-24a (6.03, s), H-25 (2.99, m), H-26 (1.05, d, J=6.8Hz), H-27 (1.11, d, J=6.6Hz), H-28 (5.27, d, J=12.8Hz), H-28 (5.45, d, J=12.8Hz), H-30 (0.97, s)；Carbon-13 nmr spectra data δC(ppm, DMSO-d6, 150MHz): 150.5 (CH, 1-C), 119.6 (CH, 2-C), 160.2 (C, 3-C), 159.2 (C, 4-C), 44.7 (CH, 5-C), 23.2 (CH2, 6-C), 21.6 (CH2, 7-C), 45.9 (CH, 8-C), 30.2 (C, 9-C), 37.0 (C, 10-C), 28.5 (CH2, 11-C), 32.6 (CH2, 12-C), 45.2 (C, 13-C), 47.3 (C, 14-C), 46.9 (CH2, 15-C), 77.1 (CH, 16-C), 170.2 (C, 16a-C), 22.3 (CH3, 16b-C), 50.5 (CH, 17-C), 18.5 (CH3, 18-C), 32.5 (CH2, 19-C), 32.5 (CH, 20-C), 12.1 (CH3, 21-C), 203.7 (C, 22-C), 195.2 (C, 23-C), 154.3 (C, 24-C), 120.3 (CH2, 24a-C), 29.0 (CH, 25-C), 22.1 (CH3, 26-C), 21.9 (CH3, 27-C), 99.8 (CH2, 28-C), 20.2 (CH3, 30-C).1715cm in IR spectrogram-1With 1694cm-1Absorption band shows there is carbonyl and conjugation carbonyl in this compound structure；Absorption maximum 207nm and 245nm in UV spectrogram illustrates there is conjugated double bond in structure.Hydrogen spectrum nuclear magnetic data shows that in this structure, degree of unsaturation is by three C-C double bond structures, four carbonyl structures and five cyclic skeleton compositions.Carbon spectrum nuclear magnetic data shows in this compound structure containing 32 carbon with DEPT modal data, wherein there are six methyl, eight methylene (two olefinic methylene), eight methine (two olefinic methines, one company's oxygen methine), ten tertiary carbons (two ester carbonyl groups, two ketone carbonyls, two olefinic quaternary carbons).One group of High-Field methene proton signal δH0.88 and 0.98 and their coupling constant 4.4Hz, it was shown that this compound contains cyclopropane moiety.H in HMBC spectrum3-16b(δH2.06) with C-16a (δC170.2), and H-16 (δH5.33) C-16 (δ is shown with the dependency of C-16aC77.1) position is connected with an acetoxyl group.Additionally, H in HMBC spectrum2-28(δH5.27 and 5.45) with C-4 (δC159.2) and C-5 (δC44.7) dependency show that C-28 is exocyclic double bond.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 is determined by ECD test further, and theoretical value is basically identical with experiment value.
This compound chemistry formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 medicines and reagent
Azathioprine is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.DMEM culture medium purchased from American Gibco company；New fetal calf serum is purchased from Hangzhou Ilex purpurea Hassk.[I.chinensis Sims biological product company；Lipopolysaccharide (LPS) is purchased from Merck Millipore Corp.；Mice TNF-α, IL-6ELISA detection kit are Xin Bosheng bio tech ltd product.
1.2 instruments
MQX-200 microplate reader (Bio-TeK.InstrumentsInc., USA)；Sigma2K15 centrifuge；Vertical electrophoresis apparatus and electrotransfer system (Liuyi Instruments Plant, Beijing)；LAS4000 chemiluminescence system (GE company, USA)；FV1000MPEMultiphotonLaserScanningMicroscope (Olympus, Japan).
1.3 cells are cultivated
Microglia system BV2 cell is provided by Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences's cell centre, in the DMEM culture medium containing 10% hyclone, is placed in 37 DEG C, 5%CO2Cultivating in cell culture incubator, went down to posterity every 2～3 days, Digestive system used is 0.25% trypsin+0.02%EDTA.
1.4NO measures
Griess method is adopted to measure nitrite (NO2 -) content reflect the concentration of NO.Take the logarithm the BV2 cell of trophophase, after digestion counting, with 5 × 103Individual/hole is inoculated in 96 orifice plates, after cultivating 24h, adds azathioprine, compound (I), azathioprine and compound (I) compositions preincubate 1h, is subsequently adding LPS (1mg L-1) continue to cultivate 24h, collect supernatant 100 μ L, add equal-volume Griess reagent (prepare 0.1% how ethylenediamine with distilled water, prepare 1% p-aminobenzene sulfonic acid with 5% phosphoric acid, both are mixing with 1:1 equal-volume before use), room temperature stands 10min, distilled water returns to zero, and measures 540nm place absorbance, simultaneously with sodium nitrate for standard substance in microplate reader, measure absorbance, calculate the content of nitrite.
1.5 enzyme-linked immunosorbent assay (ELISA)
BV2 cell is with 5.0 × 104Individual/hole is inoculated in 24 orifice plates, after cell attachment, adds azathioprine, compound (I), azathioprine and compound (I) compositions preincubate 1h, adds LPS (1mg L-1) continue to cultivate, after 3h and 12h, collect cell conditioned medium liquid respectively, be operated according to ELISA kit description, measure the content of TNF-α and IL-6 in cell conditioned medium liquid.
1.6 statistical analysis
Statistical analysis is carried out with SPSS19.0 software.Each group result represents with x ± s, and the comparison in difference between each group adopts one factor analysis of variance (one-wayANOVA).
2, experimental result
The LPS BV2 cell stimulated is produced the impact of NO by 2.1
NO is as important physiological process such as messenger molecule important in cell, the release of participation neurotransmitter and reuptake, nerve conduction and synaptic plasticitys, but the NO of excessive generation can also cause serious neurotoxicity.Table 1 result shows, LPS (1mg L-1) jointly hatch 24h can activate microglia with BV2 cell, NO is made to produce substantial increase, and azathioprine, compound (I), azathioprine and compound (I) compositions can substantially suppress the generation (P < 0.05 of NO, P < 0.05, P < 0.01), show that LPS is stimulated the inflammatory factor that BV2 cell produces to have a significant inhibitory action by azathioprine and compound (I) compositions, and this inhibitory action is better than azathioprine or the independent inhibitory action of compound (I).
The LPS BV2 cell stimulated is produced the impact of NO by table 1
| Group | NO generation amount/(relative to blank %) |
| Blank group | 100 |
| LPS matched group | 200 |
| Azathioprine group | 160 |
| Compound (I) group | 150 |
| Azathioprine and compound (I) compositions group | 110 |
LPS is stimulated BV2 cell to produce the impact of TNF-α, IL-6 by 2.2
It is the principal element causing neuronal damage, causing delayed ischemic neurological deficits that the microglia activated discharges excessive inflammatory factor.TNF-α and IL-6 are the inflammatory factors that two classes are common, therefore have detected medicine in this experiment further and LPS stimulates the TNF-α of BV2 cell generation and the impact of IL-6.Result is as shown in table 2, TNF-α in matched group BV2 cell, IL-6 secretory volume very low, compared with matched group, LPS (1mg L-1) stimulate after BV2 cell, the burst size that can make the two is significantly raised, and prompting LPS have activated microglia, produces inflammatory reaction.Compare with model group, administration azathioprine, compound (I), azathioprine and compound (I) compositions can obviously reduce the release (P < 0.05 of the two, P < 0.05, P < 0.01), show that LPS is stimulated the inflammatory factor that BV2 cell produces to have a significant inhibitory action by azathioprine and compound (I) compositions, and inhibitory action when this inhibitory action is better than azathioprine or compound (I) individually application.
LPS is stimulated BV2 cell to produce the impact of TNF-α, IL-6 by table 2
| Group | TNF-α(ng/L) | IL-6(ng/L) |
| Blank group | 100 | 100 |
| LPS matched group | 1750 | 1100 |
| Azathioprine group | 1100 | 550 |
| Compound (I) group | 1000 | 500 |
| Azathioprine and compound (I) compositions group | 500 | 220 |
Result above shows, is respectively provided with, during the individually application of azathioprine, compound (I), the effect suppressing neuroinflamation preferably, inhibitory action to neuroinflamation is used in combination and further enhances, it is possible to develop into the medicine of suppression neuroinflamation.
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, it is possible to technical scheme is modified or equivalent replacement, without deviating from essence and the protection domain of technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of an azathioprine, it is characterised in that: include azathioprine, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of azathioprine according to claim 2, it is characterised in that: pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
4. the pharmaceutical composition of azathioprine according to claim 2, it is characterised in that: described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: the dry rhizome of Rhizoma Coptidis is pulverized by (a), extract with 75～85% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtains 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 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 85:1,45:1,25:1 and 15:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 20:1,15:1 and 1:1 methylene chloride-methanol gradient elution obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collecting 10～16 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
6. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) is extracted with 80% alcohol heat reflux, united extraction liquid.
7. the preparation method of compound according to claim 5 (I), it is characterised in that: described macroporous resin is D101 type macroporous adsorbent resin.
8. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
9. the application in the medicine of preparation treatment neuroinflamation of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described azathioprine of claim 2～4 application in the medicine of preparation treatment neuroinflamation.
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Application publication date: 20160629 |