CN105669621A - Pharmaceutical composition of chlortetracycline hydrochloride and medical application of pharmaceutical composition - Google Patents
Pharmaceutical composition of chlortetracycline hydrochloride and medical application of pharmaceutical composition Download PDFInfo
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- CN105669621A CN105669621A CN201610257756.3A CN201610257756A CN105669621A CN 105669621 A CN105669621 A CN 105669621A CN 201610257756 A CN201610257756 A CN 201610257756A CN 105669621 A CN105669621 A CN 105669621A
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- compound
- chlortetracycline hydrochloride
- pharmaceutical composition
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- 0 C1C2C*CC1C2 Chemical compound C1C2C*CC1C2 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
Abstract
The invention discloses a pharmaceutical composition of chlortetracycline hydrochloride and medical application of the pharmaceutical composition. The pharmaceutical composition of the chlortetracycline hydrochloride, disclosed by the invention, contains the chlortetracycline hydrochloride and a natural product compound (I) with a novel structure; when the chlortetracycline hydrochloride and the compound (I) independently act, the glucose consumption of HepG2 cells can be promoted, and the blood glucose of a diabetic model mice can be reduced; when the chlortetracycline hydrochloride and the compound (I) jointly act, the pharmacologic action is further enhanced and is superior to that generated when the chlortetracycline hydrochloride and the compound (I) independently act; as a synergistic effect exists between the chlortetracycline hydrochloride and the compound (I), a drug for reducing the blood glucose can be developed; compared with the prior art, the pharmaceutical composition has prominent substantive features and significant progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of chlortetracycline hydrochloride, be specifically related to the pharmaceutical composition of chlortetracycline hydrochloride and the application in hyperglycemia thereof.
Background technology
The same tetracycline of chlortetracycline hydrochloride antimicrobial spectrum, to penicillin resistant, the curative effect of staphylococcus aureus is slightly stronger than tetracycline. Existing primary treatment conjunctivitis, trachoma.
Up to now, there is not yet the dependency of chlortetracycline hydrochloride and pharmaceutical composition thereof and hyperglycemia report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of chlortetracycline hydrochloride, containing chlortetracycline hydrochloride and a kind of natural product in this pharmaceutical composition, chlortetracycline hydrochloride and this natural product can Synergistic treatment hyperglycemia.
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 chlortetracycline hydrochloride, including chlortetracycline hydrochloride, 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: Herba Artemisiae Annuae is pulverized by (a), extract with 70～80% 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 n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 6 column volumes of 15% ethanol elution, then with 10 column volumes of 70% ethanol elution, collects 70% eluent, 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 80:1,30:1,15:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components;D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 25:1,15:1 and 2:1 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 8～14 column volume eluents, eluent concentrating under reduced pressure obtains pure 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 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 hyperglycemia.
The application in the medicine of preparation treatment hyperglycemia of the pharmaceutical composition of above-mentioned chlortetracycline hydrochloride.
Advantages of the present invention:
The pharmaceutical composition of chlortetracycline hydrochloride provided by the invention contains the natural product of chlortetracycline hydrochloride and a kind of novel structure, when chlortetracycline hydrochloride and this natural product independent role, there is hypoglycemic activity; During the two synergy, hypoglycemic activity further enhances, it is possible to develop into hypoglycemic medicine. 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
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, purchased from Shanghai Ling Feng chemical reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: Herba Artemisiae Annuae (2kg) is pulverized by (a), (20L × 3 time) are extracted with 75% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (4L), extract with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol (4L × 3 time) successively, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract; B n-butyl alcohol extract D101 type macroporous resin remove impurity in () step (a), first with 6 column volumes of 15% ethanol elution, then with 10 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 80:1 (8 column volumes), 30:1 (8 column volumes), 15:1 (8 column volumes) and 5:1 (10 column volumes) successively; D in () step (c), component 3 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 25:1 (8 column volumes), 15:1 (10 column volumes) and 2:1 (5 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%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z289.1392, can obtain molecular formula in conjunction with nuclear-magnetism feature is C17H20O4, degree of unsaturation is 8. Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-1 (5.62, s), H-3 (5.53, s), H-5 (2.61, d, J=11.7Hz), H-6 (3.93, dd, J=11.7, 10.6Hz), H-7 (2.54, dt, J=3.2, 10.6Hz), H-8 α (2.05, m), H-8 β (1.65, ddt, J=12.3, 3.6, 13.2Hz), H-9 α (2.01, dt, J=4.1, 13.2Hz), H-9 β (1.83, dt, J=13.2, 3.6Hz), H-13 (5.46, d, J=3.1Hz), H-13 (6.08, d, J=3.1Hz), H-14 (0.98, s), H-15 (1.93, d, J=1.3Hz), 2-OAc (2.03, s), carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 126.2 (CH, 1-C), (151.2 C, 2-C), 121.7 (CH, 3-C), 153.6 (C, 4-C), (51.6 CH, 5-C), 80.3 (CH, 6-C), (49.4 CH, 7-C), 20.9 (CH2, 8-C), 38.2 (CH2, 9-C), 31.0 (C, 10-C), 138.3 (C, 11-C), 170.3 (C, 12-C), 117.9 (CH2, 13-C), 17.8 (CH3, 14-C), 24.1 (CH3, 15-C), 167.9 (C, 2-OAc), 21.3 (CH3, 2-OAc). 1716cm in infrared spectrum-1236nm absorption band in absorption band and UV spectrum shows that this compound contains α, β-unsaturated gamma lactone structure, further and by analysis13δ in C-NMR spectrumC80.3, the carbon signal of 49.4,138.3,170.3,117.9 is known exists the outer methylene gamma lactone structure of ring.13C-NMR, DEPT and hsqc spectrum show 17 carbon signals, including three methyl (acetonyl), three methylene (an alkene carbon), five methines (company's oxygen carbon and two alkene carbon), and six quaternary carbons (three alkene carbon and two carbonyl carbon). In conjunction with insatiable hunger sum, function above structure shows that this compound is tricyclic structure.1H-NMR spectrum shows three methyl proton signal δ in conjunction with hsqc spectrumH0.98 (3H, s), 1.93 (3H, d, J=1.3Hz), 2.03 (3H, s), pair of end olefinic proton signals δH6.08 (1H, d, J=3.1Hz) and 5.46 (1H, d, J=3.1Hz), a company oxygen methine proton signal δH3.93 (1H, dd, J=11.2,10.6Hz), two olefinic methine proton signal δH5.62 (1H, s) with 5.53 (1H, s).13δ in C-NMR spectrumC167.9 with 21.3 signals and1δ in H-NMR spectrumH2.06 (1H, s) signal, in composing in conjunction with HMBC, the known acetoxyl group of dependency of acetyl methyl proton signals and C-2 is positioned at C-2 position. Pass through1H-1H-5/H-6/H-7/H in HCOSY spectrum2-8/H2-9 coherent signals, and H-1 and the C-2, C-3 and the C-10 that show in HMBC spectrum, H-3 and C-1, C-2, C-4 and C-5, H-5 and C-6 and C-10, H-6 and C-7, C-8, C-11 and C-12, H-7 and C-6, C-11, C-12 and C-13, H2-13 with C-7 and C-12, H3-14 and C-10; OAc and C-2 coherent signal; the connected mode of this compound can be built; and above-mentioned spectral data shows that this compound is eudesmane; and there is the outer methylene gamma lactone structure of ring; acetyl group is connected to C-2 position, and the C-5 in this compound, C-6, C-7 and C-10 are chiral carbon, confirms relative configuration by NOESY test with H-H coupling constant. In NOESY spectrum, H-6/H-8 β, H-6/H-14 and H-8 β/H-14 coherent signal shows that these hydrogen are in the same side, another H-5/H-7, H-5/H-9 α and H-7/H-9 α coherent signal shows that these hydrogen are in the same side, these coherent signals are consistent to the result of relevant coupling constant, and also indicating that the trans connection of A/B and B/C ring, therefore above coherent signal may indicate that the C-5 of this compound, C-6, C-7 and C-10 are configured as 5S, 6S, 7S and 10R.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 test apparatuses
Thermo6500 CO2 gas incubator, EosBravoW automatic clinical chemistry analyzer, the clean JJ-CJ-2F clean bench of gold, BioTekELX800 microplate reader, ZEISSAxiovert40CFL inverted microscope.
1.2 materials and reagent
Chlortetracycline hydrochloride is purchased from National Institute for Food and Drugs Control. Compound (I) is made by oneself, and preparation method is shown in embodiment 1. People hepatocarcinoma embryonic germ HepG2 is purchased from China typical culture collection center. Superfine hyclone, RPMI1640 culture medium, Gibco company. Glucose enzymatic assays test kit, builds up Bioengineering Research Institute purchased from Nanjing. Trypsin, available from Sigma. People's insuline pro injection, purchased from ten thousand biochemistry pharmaceuticals of nation. Cleaning grade Kunming mouse, weight 18～22g, animal housing of Third Military Medical University provides.
1.3 cell blood sugar lowering tests
The HepG2 cell digested and diluted is joined in 96 orifice plates, treats that cell is paved with rate and reaches 80%, change former culture medium, clean 1 time with PBS, by 96 orifice plate random packet, respectively Normal group and chlortetracycline hydrochloride group (5mg L-1), compound (I) group (5mg L-1), chlortetracycline hydrochloride and compound (I) compositions group [2.5mg L-1Chlortetracycline hydrochloride+2.5mg L-1Compound (I)]. Often organize every hole and add the culture fluid of 250 μ l pastilles or not pastille. Utilize glucose enzymatic assays test kit to utilize end-point method in automatic clinical chemistry analyzer after 24h, under 505nm wavelength, detect glucose surplus in culture fluid.
1.4 animal blood sugar lowering experiments
Cleaning grade Kunming mouse, weight 18～22g, purchased from animal housing of Third Military Medical University. After mice balance raises 3d, hungry 12h, then tail vein injections alloxan (70mg kg-1). After 3d, detect blood glucose. Take mice that blood glucose is 10～25mmol/L as hyperglycemia model mice, be divided into 6 groups according to blood glucose, often group 10. Respectively Normal group, model control group, positive controls (gastric hydrochloric acid guanidine, 100mg kg-1·d-1) and chlortetracycline hydrochloride group (100mg kg-1·d-1), compound (I) group (100mg kg-1·d-1), chlortetracycline hydrochloride and compound (I) compositions group [50mg kg-1·d-1Chlortetracycline hydrochloride+50mg kg-1·d-1Compound (I)]. High sugar model control group gavage distilled water, gavage medicine 7d, hungry 12h, measure fasting blood sugar.
1.5 statistical method
Significance test is done with SPSS19.0.
2, experimental result
2.1 impacts on the experiment of HepG2 blood sugar lowering
Comparing with Normal group, the consumption of glucose is substantially increased (P < 0.01) by chlortetracycline hydrochloride and compound (I) compositions group; Comparing with Normal group, the consumption of glucose is also increased (P < 0.05) by chlortetracycline hydrochloride group, compound (I) group, it is shown that significantly blood sugar reducing function. Result is in Table 1.
2.2 impacts on diabetic mice blood glucose
After mice gives alloxan, it can be observed that mouse blood sugar increases. Comparing with Normal group, model control group mouse blood sugar raises (P < 0.01); Comparing with model control group, chlortetracycline hydrochloride significantly reduces (P < 0.01 or P < 0.05) with compound (I) compositions group and positive drug control group blood glucose;Comparing with model control group, chlortetracycline hydrochloride group, compound (I) group blood glucose reduces (P < 0.05), and the blood glucose of mice reduces.
Result is in Table 1.
The table 1 impact (x ± s) on HepG2 glucose utilization and blood glucose in diabetic mice
The above results shows, when chlortetracycline hydrochloride, compound (I) independent role, it is possible to promote the consumption to glucose of the HepG2 cell, reduces diabetic mice blood glucose; When chlortetracycline hydrochloride and compound (I) synergy, pharmacological action is strengthened further, being better than chlortetracycline hydrochloride, compound (I) independent role effect, there is synergism in chlortetracycline hydrochloride and compound (I), it is possible to develops into hypoglycemic medicine.
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 a chlortetracycline hydrochloride, it is characterised in that: include chlortetracycline hydrochloride, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of chlortetracycline hydrochloride 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 chlortetracycline hydrochloride 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: Herba Artemisiae Annuae is pulverized by (a), extract with 70～80% 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 n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 6 column volumes of 15% ethanol elution, then with 10 column volumes of 70% ethanol elution, collects 70% eluent, 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 80:1,30:1,15:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components; D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 25:1,15:1 and 2:1 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 8～14 column volume eluents, eluent concentrating under reduced pressure obtains pure compound (I).
6. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) is extracted with 75% 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 hyperglycemia of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described chlortetracycline hydrochloride of claim 2～4 application in the medicine of preparation treatment hyperglycemia.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105837656A (en) * | 2016-04-01 | 2016-08-10 | 胡文杰 | Cycloartane triterpene and medical application thereof |
| CN105837422A (en) * | 2016-04-20 | 2016-08-10 | 宋晓梅 | Pharmaceutical composition of buprenorphine hydrochloride and application thereof in biomedicine |
| CN106243065A (en) * | 2016-09-09 | 2016-12-21 | 中国科学院西北高原生物研究所 | A kind of new sesquiterpenoid and biomedical uses thereof |
-
2016
- 2016-04-23 CN CN201610257756.3A patent/CN105669621A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105837656A (en) * | 2016-04-01 | 2016-08-10 | 胡文杰 | Cycloartane triterpene and medical application thereof |
| CN105837422A (en) * | 2016-04-20 | 2016-08-10 | 宋晓梅 | Pharmaceutical composition of buprenorphine hydrochloride and application thereof in biomedicine |
| CN106243065A (en) * | 2016-09-09 | 2016-12-21 | 中国科学院西北高原生物研究所 | A kind of new sesquiterpenoid and biomedical uses thereof |
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Application publication date: 20160615 |