CN105859702A - Pharmaceutical composition containing celecoxib and pharmaceutical application of pharmaceutical composition - Google Patents
Pharmaceutical composition containing celecoxib and pharmaceutical application of pharmaceutical composition Download PDFInfo
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- CN105859702A CN105859702A CN201610340405.9A CN201610340405A CN105859702A CN 105859702 A CN105859702 A CN 105859702A CN 201610340405 A CN201610340405 A CN 201610340405A CN 105859702 A CN105859702 A CN 105859702A
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- compound
- pharmaceutical composition
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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
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- 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 pharmaceutical composition containing celecoxib and pharmaceutical application of the pharmaceutical composition. The pharmaceutical composition containing celecoxib contains celecoxib and a natural product compound (I) with a novel structure; the treatment effect on epilepsy is achieved when celecoxib and the compound (I) acts independently; the treatment effect on the epilepsy is further improved when celecoxib and the compound (I) jointly act, and therefore the pharmaceutical composition can be developed into a drug for treating the epilepsy. Compared with the prior art, the pharmaceutical composition has the outstanding substantial characteristics and the significant progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of Sai-Mi-Xi-Bu, be specifically related to the medicine group of Sai-Mi-Xi-Bu
Compound and medical usage thereof.
Background technology
Sai-Mi-Xi-Bu be clinically used for relief from osteoarthritis sings and symptoms, alleviate adult rheumatoid arthritis symptom and
Sign, treatment adult acute's pain.
Sai-Mi-Xi-Bu is non-steroid anti-inflammatory drug, observes its effect having anti-inflammatory, easing pain and bring down a fever in animal model.Plug
The mechanism of action carrying out former times cloth is to suppress prostaglandin to generate by suppression Transitional cell carcinomas (COX-2).And it is dense at human body therapy
Under degree, this product does not has inhibitory action to isodynamic enzyme-Cycloxygenase-1 (COX-1).
In animal colon tumor model, Sai-Mi-Xi-Bu slow down generation and the progress of tumour.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of Sai-Mi-Xi-Bu, this pharmaceutical composition carrys out former times containing plug
Cloth and the natural products of a kind of novel structure, Sai-Mi-Xi-Bu and this natural products can be with Synergistic treatment epilepsies.
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 Sai-Mi-Xi-Bu, including Sai-Mi-Xi-Bu, compound as claimed in claim 1 (I) and medicine
Acceptable carrier on, is prepared as the formulation needed.
Further, pharmaceutically acceptable carrier include diluent, excipient, filler, adhesive, wetting agent,
Disintegrant, sorbefacient, surfactant, absorption carrier or lubricant.
Further, described formulation include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, spray, drops or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: linseed is pulverized by (a), with 75～85% second
Alcohol circumfluence distillation, merges extract, is concentrated into without alcohol taste, successively by petroleum ether, ethyl acetate and water saturated n-butanol extraction
Take, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butanol takes thing use
Macroreticular resin removal of impurities, first with 8 column volumes of 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, collects 70% and washes
De-liquid, reduced pressure concentration 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 85:1,45:1,25:1 and 15:1 successively；(d) step
Suddenly in (c), component 4 separates further by purification on normal-phase silica gel, is the methylene chloride-methanol of 20:1,15:1 and 1:1 by volume ratio successively
Gradient elution obtains 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and uses volume
Percentage concentration is the methanol aqueous solution isocratic elution of 72%, collects 10～16 column volume eluents, and eluent reduced pressure concentration obtains
To compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 80% alcohol heat reflux, merges and extracts
Liquid.
Further, in the preparation method of compound (I), described macroreticular resin is D101 type macroporous absorbent 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 epilepsy.
The application in the medicine of preparation treatment epilepsy of the pharmaceutical composition of above-mentioned Sai-Mi-Xi-Bu.
Advantages of the present invention:
Containing Sai-Mi-Xi-Bu and the natural product of a kind of novel structure in the pharmaceutical composition of the Sai-Mi-Xi-Bu that the present invention provides
When thing, Sai-Mi-Xi-Bu and this natural products independent role, epilepsy had therapeutic action；During the two synergy, to epilepsy
Result for the treatment of improves further, can develop into the medicine for the treatment of epilepsy.
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.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, can be right
Technical scheme is modified 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: linseed (2kg) is pulverized by (a), extracts (15L × 3 time) with 80% alcohol heat reflux, merges and extracts
Liquid, is concentrated into without alcohol taste (3L), successively with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated n-butanol
(3L × 3 time) extract, and respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
Acetic acid ethyl ester extract D101 type macroreticular resin removal of impurities, first with 8 column volumes of 25% ethanol elution, then uses 70% ethanol elution
12 column volumes, collect 70% eluent, and reduced pressure concentration obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, successively with volume ratio be 85:1 (10 column volumes), 45:1 (8 column volumes), 25:1 (10
Individual column volume) and the methylene chloride-methanol gradient elution of 15:1 (8 column volumes) obtain 4 components；Component in (d) step (c)
4 separate further by purification on normal-phase silica gel, successively with volume ratio be 20:1 (10 column volumes), 15:1 (8 column volumes) and 1:1 (6
Column volume) methylene chloride-methanol gradient elution obtain 3 components；E in () step (d), component 2 is bonded by octadecylsilane
Reverse phase silica gel separate, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collect 10～16 column volumes and wash
De-liquid, eluent is concentrated under reduced pressure to give compound (I) (HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+Na]+For m/z 377.1467, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C21H22O5, degree of unsaturation is 11.Hydrogen nuclear magnetic resonance modal data δH(ppm, CD3COCD3, 500MHz): H-3 (7.12, s), H-4
(7.24, s), H-7 (6.75, s), H-2 ' (7.04, d, J=1.8Hz), H-4 ' (6.41, t, J=2.1Hz), H-6 ' (7.04, d,
J=1.8Hz), H-4 " (2.78, dd, J=15.6,8.4Hz), H-4 " (2.43, dd, J=15.6,9.0Hz), H-5 " (3.62,
Dd, J=8.4,9.0Hz), H-7 " (1.31, s), H-8 " (1.32, s), OCH3-3 ' (3.85, s), OCH3-5 ' (3.83, s)；Core
Magnetic resonance carbon modal data δC(ppm, CD3COCD3, 125MHz): 156.4 (C, 2-C), 103.5 (CH, 3-C), 122.1 (C, 3a-
C), 117.1 (CH, 4-C), 125.1 (C, 5-C), 161.2 (C, 6-C), 93.8 (CH, 7-C), 154.1 (C, 7a-C), 132.1
(C, 1 '-C), 107.4 (CH, 2 '-C), 162.2 (C, 3 '-C), 105.4 (CH, 4 '-C), 162.2 (C, 5 '-C), 107.4 (CH,
6 '-C), 35.5 (CH2, 4 " and-C), 66.7 (CH, 5 "-C), 71.4 (C, 6 "-C), 25.2 (CH3, 7 " and-C), 25.7 (CH3, 8 " and-C),
56.6(CH3, 3 '-OCH3), 56.6 (CH3, 5 '-OCH3).The hydrogen spectrum display two replacement 2-arylbenzofuran structures of this compound
[δH7.12 (1H, s, H-3), 7.24 (1H, s, H-4), 6.75 (1H, s, H-7), 7.04 (1H, d, J=1.8Hz, H-2 '), 6.41
(1H, t, J=2.1Hz, H-4 '), 7.04 (1H, d, J=1.8Hz, H-6 ')], two methoxyl group proton signal [δH3.85 (3H,
S) He 3.83 (3H, s)], and 2,3 epoxy-3-methyl-butvl substituent [2.78 (1H, dd, J=15.6,8.4Hz, H-
4 "), 2.43 (1H, dd, J=15.6,9.0Hz, H-4 "), 3.62 (1H, dd, J=8.4,9.0Hz, H-5 "), 1.31 (1H, s, H-
7 "), 1.32 (1H, s, H-8 ")].The carbon spectrum of this compound shows that this compound has 21 carbon spectrum signals, including four methyl
(two methoxyl groups), a methylene, seven methines and nine quaternary carbons.In HMBC spectrum methoxyl group proton signal and C-3 ' and
The correlation of C-5 ' shows that C-3 ' and C-5 ' position are connected with a methoxyl group respectively.In HMBC spectrum, H2-4 "/C-5 ", H3-7 "/C-5 ",
H3-8 "/C-5 " between correlation the C-5 of this compound is described " and C-6 " position is epoxy construction.Comprehensive hydrogen spectrum, carbon spectrum, HMBC
Spectrum and NOESY compose, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration
Being determined by ECD test further, 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 makes epilepsy model with rats by intraperitoneal injection penicillin 6,000,000 U/kg, observes drug therapy epilepsy
Effect.
1, materials and methods
1.1 animal
Wistar rat 90, male and female half and half, body weight 120 ± 20g, Heilongjiang University of Chinese Medicine's Experimental Animal Center carry
Supply.
1.2 reagent and sample
Sai-Mi-Xi-Bu is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Benzene
Appropriate English sodium: power raw pharmacy head factory in Tianjin produces；Penicillin: Harbin Pharmaceutical General Factory；Urethane: Harbin Pharmaceutical General Factory.
1.3 instrument
LMB-2B type two road physiograph: Chengdu Instruement Factory produces.
Prepared by 1.4 animal packets and model
Taking rat 50, male and female half and half, be randomly divided into 5 groups, often group 10, is respectively as follows: model control group, positive controls
(dilantin sodium 4.2mg kg-1), Sai-Mi-Xi-Bu group (80mg kg-1), compound (I) group (80mg kg-1), Sai-Mi-Xi-Bu with
Compound (I) composition group [40mg kg-1Sai-Mi-Xi-Bu+40mg kg-1Compound (I)].Each group administration group is according to respective agent
Amount is administered, and is oral administration gavage and is administered.Model group gavages consubstantiality ponding.Each treated animal is all being administered or after distilled water 1h, abdominal cavity
Injection penicillin 6,000,000 U/kg, observes rat behavior.
1.5 epileptic rat convulsions latency experiments
After lumbar injection penicillin, observe each group of mouse epilepsy outbreak behavior and the incubation period of epilepsy outbreak.
1.6 seizures in rats degree observation experiments
Epilepsy outbreak behavior observation, with reference to Racine standard: 0 grade: reactionless or stopping of twitching.I grade: rhythmicity mouth or face
Portion twitches.II grade: nod or whipping.III grade: single limb is twitched.IV grade: many limbs are twitched or tetanic.V grade: comprehensive tonic-clonic
Outbreak.
1.7 statistical method
Experimental data mean ± standard deviationRepresenting, application SPSS18.0 version statistical software carries out single factor test variance
Analyze and t checks, statistically significant for difference with P ＜ 0.05.
2, experimental result
2.1 on the penicillin induction epileptic rat preclinical impact of convulsions
Comparing with model control group, positive controls rat is fainted from fear and significantly extends (P ＜ 0.01) incubation period；With model comparison
Group is compared, and Sai-Mi-Xi-Bu is fainted from fear with compound (I) composition group rat and significantly extended (P ＜ 0.01) incubation period；With model comparison
Group compares, Sai-Mi-Xi-Bu group, compound (I) group rat convulsions prolongation of latency (P ＜ 0.05).The results are shown in Table 1.
2.2 impacts on penicillin induced rat epilepsy outbreak degree
Comparing with model control group, positive controls seizures in rats degree is substantially reduced (P ＜ 0.01)；With model pair
Comparing according to group, Sai-Mi-Xi-Bu and compound (I) composition group seizures in rats degree are substantially reduced (P ＜ 0.01)；With model
Control group compares, and Sai-Mi-Xi-Bu group, compound (I) group seizures in rats degree reduces (P ＜ 0.05).The results are shown in Table 2.
Table 1 is on the penicillin induction epileptic rat preclinical impact of convulsions
| Group | Incubation period (s) | Convulsions percentage (%) |
| Model control group | 46.4±16.4 | 100% |
| Positive controls | 88.5±17.5 | 70% |
| Sai-Mi-Xi-Bu group | 74.4±18.6 | 80% |
| Compound (I) group | 73.7±18.2 | 80% |
| Sai-Mi-Xi-Bu and compound (I) composition group | 86.2±18.7 | 70% |
The table 2 impact on penicillin induced rat epilepsy outbreak degree
Penicillin is classical cause epilepsy agent, and it is acute or lights animal epileptic model and has obtained generally acknowledged.Penicillin can suppress
GABA serotonergic neuron, causes inhibitory synapse activity to weaken or excitatory synapse activity strengthens, thus causes neuronal excitability
Increase.Paroxysmal depolarising drift can be produced when neuronal excitability postsynaptic potential (EPSP) comprehensively exceedes certain threshold value
(PDS)。
The above results shows, when Sai-Mi-Xi-Bu, compound (I) independent role, epilepsy is had therapeutic action；Sai-Mi-Xi-Bu
During with compound (I) synergy, the result for the treatment of of epilepsy is improved further, the medicine for the treatment of epilepsy can be developed into.
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 Sai-Mi-Xi-Bu, it is characterised in that: include Sai-Mi-Xi-Bu, chemical combination as claimed in claim 1
Thing (I) and pharmaceutically acceptable carrier, be prepared as the formulation needed.
The pharmaceutical composition of Sai-Mi-Xi-Bu the most according to claim 2, it is characterised in that: pharmaceutically acceptable carrier
Including diluent, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surfactant, absorption carrier
Or lubricant.
The pharmaceutical composition of Sai-Mi-Xi-Bu the most according to claim 2, it is characterised in that: described formulation includes tablet, glue
Wafer, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution, injection,
Suppository, spray, drops 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 Asia
Pockmarks pulverize, with 75～85% alcohol heat reflux extract, merge extract, be concentrated into without alcohol taste, successively use petroleum ether, acetic acid second
Ester and water saturated extracting n-butyl alcohol, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b)
In step (a), n-butanol takes thing macroreticular resin removal of impurities, first with 8 column volumes of 25% ethanol elution, then uses 70% ethanol elution
12 column volumes, collect 70% eluent, and reduced pressure concentration obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, successively by the methylene chloride-methanol gradient that volume ratio is 85:1,45:1,25:1 and 15:1
Afford 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1,15:1 by volume ratio successively
3 components are obtained with the methylene chloride-methanol gradient elution of 1:1；E in () step (d), component 2 is bonded by octadecylsilane
Reverse phase silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collects 10～16 column volume wash-outs
Liquid, 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 80% ethanol heat
Stream extracts, and merges extract.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroreticular resin is D101 type
Macroporous absorbent 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 epilepsy of the compound (I) described in claim 1.
10. pharmaceutical composition the answering in the medicine of preparation treatment epilepsy of the arbitrary described Sai-Mi-Xi-Bu of claim 2～4
With.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610340405.9A CN105859702A (en) | 2016-05-20 | 2016-05-20 | Pharmaceutical composition containing celecoxib and pharmaceutical application of pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610340405.9A CN105859702A (en) | 2016-05-20 | 2016-05-20 | Pharmaceutical composition containing celecoxib and pharmaceutical application of pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105859702A true CN105859702A (en) | 2016-08-17 |
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ID=56634409
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610340405.9A Withdrawn CN105859702A (en) | 2016-05-20 | 2016-05-20 | Pharmaceutical composition containing celecoxib and pharmaceutical application of pharmaceutical composition |
Country Status (1)
| Country | Link |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924413A (en) * | 2016-05-20 | 2016-09-07 | 江苏神龙药业有限公司 | Celecoxib drug composition and medical application of composition in cholelithiasis treatment |
| CN106279344A (en) * | 2016-08-14 | 2017-01-04 | 吴芊葭 | A kind of native compound separated from Radix Saposhnikoviae and preparation method thereof, medical applications |
-
2016
- 2016-05-20 CN CN201610340405.9A patent/CN105859702A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924413A (en) * | 2016-05-20 | 2016-09-07 | 江苏神龙药业有限公司 | Celecoxib drug composition and medical application of composition in cholelithiasis treatment |
| CN106279344A (en) * | 2016-08-14 | 2017-01-04 | 吴芊葭 | A kind of native compound separated from Radix Saposhnikoviae and preparation method thereof, medical applications |
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