CN105906494A - Cinildipine medicine composition and medicinal application of same for myocardial protection - Google Patents
Cinildipine medicine composition and medicinal application of same for myocardial protection Download PDFInfo
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- CN105906494A CN105906494A CN201610250520.7A CN201610250520A CN105906494A CN 105906494 A CN105906494 A CN 105906494A CN 201610250520 A CN201610250520 A CN 201610250520A CN 105906494 A CN105906494 A CN 105906494A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
- C07C47/46—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing hydroxy groups
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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
- A61K31/11—Aldehydes
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
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Abstract
The invention discloses a cinildipine medicine composition, and a medicinal application of the same for myocardial protection. The cinildipine medicine composition contains the cinildipine and a natural product compound (I), which has a novel structure and is separated from dry roots of scutellaria baicalensis. When the cinildipine and the natural product compound are used separately, myocardial ischemia-reperfusion injury is reduced, and when the two components are used together, the effect of prevention on the myocardial ischemia-reperfusion injury is enhanced. The composition can be developed into a medicine for prevention on the myocardial ischemia-reperfusion injury. Compared with the prior art, the composition has outstanding substantive features and significant improvement.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of cilnidipine, be specifically related to cilnidipine pharmaceutical composition and
The medical usage of its myocardial preservation.
Background technology
Cilnidipine i.e. 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzophenone)-3,5-dipicolinic acid 2-methoxy acrylate Cinoxolone.
Cilnidipine is lipophilic dihydropyridine type calcium antagonists, can be with the dihydro of L-type calcium channel on vascular smooth muscle cell film
Pyridine site combines, and suppresses Ca2+By the influx across membrane of L-type calcium channel, thus lax, expansion vascular smooth muscle, play fall
Pressure effect.It is also by suppression Ca2+Sympathetic nerve is suppressed by the influx across membrane of N-type calcium channel on sympathetoblast film
The release of tip norepinephrine and sympathetic activity.
Up to now, there is not yet the dependency report of cilnidipine and pharmaceutical composition thereof and myocardial ischemia reperfusion injury.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of cilnidipine, containing cilnidipine and in this pharmaceutical composition
Planting the natural product of the novel structure of isolated, cilnidipine and this natural product from draft can be with coordinating protection cardiac muscle.
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 cilnidipine, including cilnidipine, compound as above (I) and pharmaceutically can connect
The carrier being subject to.
The preparation method of compound (I) as above, comprises following operating procedure: the dry root of Radix Scutellariae is pulverized by (a),
With 60～70% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water saturation successively
N-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b) step (a)
Middle n-butyl alcohol extract macroporous resin remove impurity, first with 12 column volumes of 10% ethanol elution, then with 70% ethanol elution 15
Column volume, collects 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 55:1,25:1,15:1 and 1:1 successively
Take off and obtain 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 20:1,
The methylene chloride-methanol gradient elution of 15:1 and 1:1 obtains 3 components；Component 2 octadecyl silicon in (e) step (d)
The reverse phase silica gel of alkane bonding separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 70%, collects 7～13 column volumes
Eluent, eluent is concentrated under reduced pressure to give compound (I).
Further, step (a) is extracted with 65% alcohol heat reflux, united extraction liquid.
Further, described macroporous resin is AB-8 type macroporous adsorbent resin.
The compound (I) application in the medicine preparing myocardial preservation as above.
The application in the medicine preparing myocardial preservation of the pharmaceutical composition of cilnidipine as above.
Advantages of the present invention:
The present invention provide cilnidipine pharmaceutical composition in containing cilnidipine and a kind of from draft the structure of isolated new
When the natural product of grain husk, cilnidipine and this natural product independent role, myocardial ischemia reperfusion injury can be reduced；The two connection
The cooperation used time, more excellent to the preventive and therapeutic effect of myocardial ischemia reperfusion injury, preventing and treating myocardial ischemia reperfusion injury can be developed into
Medicine.
Detailed description of the invention
The essentiality content of the present invention is further illustrated below in conjunction with embodiment.
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 chemistry
Reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: the dry root (2kg) of Radix Scutellariae is pulverized by (a), extracts (20L × 3 time) with 65% 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) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butanol extraction
Thing；B n-butyl alcohol extract AB-8 type macroporous resin remove impurity in () step (a), first with 12 cylinders of 10% ethanol elution
Long-pending, then with 15 column volumes of 70% ethanol elution, collect 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 55:1 (8 column volumes),
The methylene chloride-methanol gradient elution of 25:1 (8 column volumes), 15:1 (8 column volumes) and 1:1 (5 column volumes) obtains
To 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, be 20:1 (8 by volume ratio successively
Column volume), the methylene chloride-methanol gradient elution of 15:1 (10 column volumes) and 1:1 (5 column volumes) obtain 3 components；
E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and is the first of 70% by concentration expressed in percentage by volume
Alcohol-water solution isocratic elution, collects 7～13 column volume eluents, eluent be concentrated under reduced pressure to give compound (I) (345mg,
HPLC normalization purity is more than 98%).
Structural identification: pale yellow powder, HR-ESI-MS shows [M+H]+For m/z 253.1761, can score in conjunction with nuclear-magnetism feature
Minor is C15H24O3, degree of unsaturation is 4.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-3 (2.54,
M), H-4a (1.82, m), H-4b (1.62, m), H-5a (1.77, m), H-5b (1.69, m), H-6 (2.07,
M), H-7 (2.66, br, d, J=8.7Hz), H-8 (3.54, d, J=9.2Hz), H-10a (2.37, d, J=15.4Hz),
H-10b (1.90, d, J=15.4Hz), H-11 (9.87, s), H-12a (3.93, dd, J=9.2,4.5Hz), H-12b
(3.58, dd, J=9.2,2.7Hz), and H-13 (0.88, d, J=7.4Hz), H-14 (0.86, s), H-15 (1.05, s)；
Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 171.2 (C, 1-C), 128.3 (C, 2-C) 51.2
(CH, 3-C), 24.5 (CH2, 4-C), 32.1 (CH2, 5-C), 29.3 (CH, 6-C), 53.5 (CH, 7-C),
83.1 (CH, 8-C), 39.6 (C, 9-C), 43.7 (CH2, 10-C), 194.3 (CH, 11-C), 51.4 (CH2,
12-C), 12.5 (CH3, 13-C), 19.5 (CH3, 14-C), 25.8 (CH3, 15-C).Infrared spectrum shows this change
Compound contains hydroxyl (3340cm-1), carbonyl (1735cm-1)。13C-NMR, DEPT and hsqc spectrum show 15
Individual carbon signal, including three methyl, four methylene (company's oxygen carbon), five methines (an aldehyde radical carbon and companies
Oxygen carbon), and three quaternary carbons (two alkene carbon), in conjunction with insatiable hunger sum, function above structure shows that this compound is dicyclo
Structure.1H-NMR spectrum combines hsqc spectrum and shows three methyl proton signal δH0.88 (3H, d, J=7.4Hz), 0.86 (3H,
S), 1.05 (3H, s), three groups of methene proton signal δH1.82 (1H, m) with 1.62 (1H, m), 1.77 (1H,
M) with 1.69 (1H, m), 2.37 (1H, d, J=15.4Hz) and 1.90 (1H, d, J=15.4Hz), one group of hydroxyl first
Proton signal δH3.93 (1H, dd, J=9.2,4.5Hz) and 3.58 (1H, dd, J=9.2,2.7Hz), three first
Proton signal δH2.54 (1H, m), 2.07 (1H, m) with 2.66 (1H, br, d, J=8.7Hz), company's oxygen
Methyl proton signal δH3.54 (1H, d, J=9.2Hz), an aldehyde radical proton signal δH9.87 (1H, s).1H-1H COSY
Spectrum exists H-3/H2-12、H-3/H2-4/H2-5/H-6/H-7/H-8 coherent signal, shows H in HMBC spectrum simultaneously2-4 with
C-2 and C-3, H2-5 and C-3, H-6 and C-8, H-7 and C-1, H2-10 with C-1, C-2, C-7, C-8 and C-14,
H-11 Yu C-1, C-2 and C-3, H2-12 and C-2, H3-13 with C-5 and C-7, H3-14 with C-8, C-9 and C-10,
H3-15 with C-9 and C-10 coherent signal, the connection side of this compound can be built by the relevant information in above-mentioned H NMR spectroscopy
Formula, and above-mentioned spectral data shows that this compound is tremulane type sesquiterpene.H in HMBC spectrum3-14 and C-8 and C-9
Dependency show that C-8 position is connected with a hydroxyl.In tremulane type sesquiterpene, H-6 Yu H-7 position is beta comfiguration, H3-14
The usual place of configuration is β position, H3-15 are configured as α position.H-6 Yu H-7 embodied in the NOE of this compound tests and H-7
With H3-14 coherent signals meet the configuration relationship of tremulane type sesquiterpene.Meanwhile, H in NOESY spectrum2-12 with H-7 with
And H3The dependency of-15 and H-8 shows that methylol is beta comfiguration, and H-8 is α configuration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and
NOESY composes, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, and spatial configuration enters one
Walking and determined by ECD test, theoretical value is basically identical with experiment value.
Chemical structural formula and carbon atoms numbered are as follows:
Embodiment 2: the protective effect to myocardial ischemia-reperfusion injury model
1, materials and methods
1.1 animal
SD rat 70, body weight 180～200g, male and female half and half, cleaning grade, limited by Beijing dimension tonneau China laboratory animal technology
Company provides.Cleaning grade Animal House is raised, and timing gives full nutrition feed feeding, room temperature 22～25 DEG C, humidity 50%～70%.
1.2 reagent and sample
Cilnidipine is purchased from Ji Wei bio tech ltd, Shanghai.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
DANHONG ZHUSHEYE (protocatechualdehyde 0.05g L-1, it is approximately equivalent to crude drug 1g mL-1), raw by Jinan, Shandong Province step-length pharmaceutical Co. Ltd
Produce.TnT (Cardiac troponin T, cTnT) test kit is produced by U.S. Rapid Bio Lab company, Beijing Lay
Bo Teli biomedicine scientific & technical corporation provides；Creatine kinase isozyme (CK-MB) test kit is controlled biotechnology by Beijing Zhong Shengbei
Limited company provides；Nitro blue tetrazolium (NBT), Shanghai advance chemical reagent work produces.Thromboxane (TXB2) and 6-
Ketone-PGF1α (6-keto-PGF1 α) radioimmunoassay kits, is provided by Beijing pul great achievement Bioisystech Co., Ltd；
Adenosine diphosphate (ADP) (adenosine diphosphate, ADP), is produced by CHRO-NOLOG company of the U.S., Beijing modern times prestige
Shi Da Medical Devices Co., Ltd. provides, concentration 0.2mmol L-1。
1.3 instrument
SC-3 artificial respirator (Shanghai Medical Equipment Factory)；ECG-6511 electrocardiograph (Shanghai photoelectric instrument company limited)；
RX-2000 full automatic biochemical apparatus (Technicon company of the U.S.)；LBY-NJ2 platelet aggregation instrument (the raw company of Beijing Puli)；
SN-682 radioimmunity γ calculating instrument (Shanghai radioprotective Instrument Ltd.).
Prepared by 1.4 rat packets and model
20% amino methyl ethyl ester (urethane) intraperitoneal injection of anesthesia (0.7mL kg-1), rat is fixed on special plank, gas
Cannula, (tidal volume is 20mL kg to artificial respiration-1, respiratory frequency is 50 times/min) and suck room air, open breast, cut
Pericardium, extruding rat thoracic cavity right side wall, extrudes heart gently.At left auricle lower edge, pulmonary conus left border and the left heart
Inserting needle between ear, with Coronary vein trunk for mark, (pads 1 semicircle silica gel with silk thread ligation at 2～3mm below left auricle
Pipe) anterior descending coronary causes myocardial ischemia in rats, cardiac monitoring display following coronary artery occlusion success (continuing 2min) 10min afterwards
It is administered through femoral vein iv.The dosage normal saline such as sham operated rats threading does not ligatures, injection；After model group ligation, give to wait agent
Amount normal saline.In experimentation, animal method of disposal meets animal ethics requirement standard.Blank is made in experiment packet respectively
(sham-operation) group, model control group, cilnidipine group (80mg kg-1), compound (I) group (80mg kg-1), west
Buddhist nun's Horizon and compound (I) compositions group [40mg kg-1Cilnidipine+40mg kg-1Compound (I)] and positive drug pair
According to group.Positive drug control group: DANHONG ZHUSHEYE (50mg kg-1)。
1.5 collection of specimens
40min after rat modeling ischemia, cuts off silk thread Reperfu-sion 60min.40min and cut off silk thread before record ligation, after ligation
(Reperfu-sion) 60min II leads electrocardiogram afterwards.After observing 60min, abdominal aortic blood, a part puts into 3.8% sodium citrate
Solution 1:9 anticoagulant vacuum tube and sorbitrate+2%EDTANa2It is centrifuged after solution anticoagulant tube, measures Platelet and TXB2,
6-keto-PGF1αContent.Another part not anticoagulant is centrifugal after putting into vacuum tube measures serum cTnT, CK-MB content.Then,
Take out heart, normal saline flushing, weigh and weigh whole-heartedly, below heart ligature, be parallel to coronary sulcus equably by left ventricle
Partial cross section is cut into 5, is placed in NBT solution 37 DEG C dyeing 15min.Measure with DeltaPix (Denmark) image analysis system
Every myocardial area, ventricle area and Infarct area, then obtain infarcted region and account for the percentage ratio of ventricle and district's area whole-heartedly.
1.6 index detection method
Measured by radioimmunoassay TXB2, 6-keto-PGF α 1；Full automatic biochemical apparatus Electrochemiluminescince and performance rate method measure
CTnT, CK-MB；Turbidimetry for Determination platelet aggregation rate, derivant is ADP, and concentration is 0.2mmol L-1, take 1,3,
5min and maximum agglutination rate.
1.7 statistical method
All data x ± s represents, compares for one factor analysis of variance between group, compares employing LSD method between group, and P < 0.05 is
Difference is statistically significant, uses SPSS19.0 software kit to carry out statistical procedures.
2, experimental result
2.1 on the impact of CK-MB and cTnT after rat MI area and I/R damage
After rat heart muscle I/R damage, model group Serum CK-MB activity is significantly raised, and sham operated rats compares, and there were significant differences
(P<0.01).Model group cTnT level also has certain rising, but compares without significant difference with sham operated rats, punctures cardiac muscle group
Knitting also is a kind of damage.Compare with model control group, cilnidipine and compound (I) compositions group and the equal energy of positive controls
Significantly reduce rat MI area and animal serum CK-MB level and cTnT content (P < 0.01)；Compare with model control group,
Cilnidipine group, compound (I) group rat MI area and Serum CK-MB level and cTnT content reduce (P ＜ 0.05).
The results are shown in Table 1.
Platelet, 6-keto-PGF after 2.2 pairs of rat heart muscle I/R damages1αAnd TXB2Impact
Comparing with Normal group, model control group mouse platelets aggregation raises (P ＜ 0.05), TXB2Raise (P ＜ 0.05),
(P ＜ 0.05), 6-keto-PGF1αReduce；Compare with model control group, cilnidipine and compound (I) compositions group and
Positive controls maximum platelet aggregation rate and TXB2Significantly reduce (P ＜ 0.01), 6-keto-PGF1αNotable rising (P ＜ 0.01)；
Compare with model control group, cilnidipine group, compound (I) group maximum platelet aggregation rate and TXB2Reduce (P ＜ 0.05),
6-keto-PGF1αRaise (P ＜ 0.05).The results are shown in Table 2.
Table 1 is on the impact of CK-MB and cTnT after rat MI area and I/R damage
| Group | Myocardial infarction area/% | cTnT/mg·L-1 | CK-MB/U·L-1 |
| Blank group | / | 0.97±0.17 | 437.17±154.82 |
| Model control group | 29.13±3.18 | 1.04±0.14 | 1268.17±256.50 |
| Positive controls | 24.97±5.94 | 0.63±0.14 | 386.39±107.71 |
| Cilnidipine group | 21.56±2.08 | 0.74±0.14 | 762.92±118.55 |
| Compound (I) group | 21.13±2.89 | 0.77±0.81 | 758.14±160.19 |
| Cilnidipine and compound (I) compositions group | 19.85±6.74 | 0.62±0.18 | 385.32±117.05 |
Table 2 is to Platelet, 6-keto-PGF after rat heart muscle I/R damage1αAnd TXB2Impact
The above results shows, when cilnidipine or compound (I) independent role, myocardial ischemia/reperfusion injury is had protection
Effect；When cilnidipine and compound (I) synergy, the protective effect to myocardial ischemia/reperfusion injury becomes apparent from,
The medicine of Ischemic myocardium/reperfusion injury can be developed into.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.
It will be understood by those within the art that, technical scheme can be modified or equivalent, and not take off
Essence and protection domain from technical solution of the present invention.
Claims (7)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a cilnidipine, it is characterised in that: include cilnidipine, chemical combination as claimed in claim 1
Thing (I) and pharmaceutically acceptable carrier.
3. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
The dry root of Radix Scutellariae is pulverized, with 60～70% alcohol heat reflux extraction, united extraction liquid, is concentrated into without alcohol taste, uses oil successively
Ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extraction
Take thing；N-butyl alcohol extract macroporous resin remove impurity in (b) step (a), first with 12 column volumes of 10% ethanol elution, then
With 15 column volumes of 70% ethanol elution, collecting 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；(c) step
Suddenly in (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, and is 55:1,25:1,15:1 and 1:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtains 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, depend on
Secondary volume ratio is that the methylene chloride-methanol gradient elution of 20:1,15:1 and 1:1 obtains 3 components；In (e) step (d)
The reverse phase silica gel that component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 70%,
Collecting 7～13 column volume eluents, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 3 (I), it is characterised in that: with 65% in step (a)
Alcohol heat reflux extracts, united extraction liquid.
The preparation method of compound the most according to claim 3 (I), it is characterised in that: described macroporous resin is AB-8
Type macroporous adsorbent resin.
6. the application in the medicine preparing myocardial preservation of the compound (I) described in claim 1.
7. the pharmaceutical composition of the cilnidipine described in claim 2 application in the medicine preparing myocardial preservation.
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Cited By (1)
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Application publication date: 20160831 |