CN105949044A - Imipramine hydrochloride pharmaceutical composition and medical application thereof - Google Patents
Imipramine hydrochloride pharmaceutical composition and medical application thereof Download PDFInfo
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- CN105949044A CN105949044A CN201610372938.5A CN201610372938A CN105949044A CN 105949044 A CN105949044 A CN 105949044A CN 201610372938 A CN201610372938 A CN 201610372938A CN 105949044 A CN105949044 A CN 105949044A
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- imipramine hydrochloride
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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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/647—Unsaturated compounds containing a keto groups being part of a ring having unsaturation outside the ring
- C07C49/653—Unsaturated compounds containing a keto groups being part of a ring having unsaturation outside the ring polycyclic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an imipramine hydrochloride pharmaceutical composition and medical application thereof. The Imipramine hydrochloride pharmaceutical composition provided by the invention contains imipramine hydrochloride and a chemical compound (I) of a natural product, and the chemical compound (I) has a novel structure; when the imipramine hydrochloride and the chemical compound (I) act independently, blood lipids can be regulated for curing atherosclerosis; when the imipramine hydrochloride and the chemical compound (I) act jointly, the action effect is further improved, and a drug used for curing the atherosclerosis can be developed; compared with the prior art, the composition has protruding substantial characteristics and significant progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of imipramine hydrochloride, be specifically related to the drug regimen of imipramine hydrochloride
Thing and medical usage thereof.
Background technology
Imipramine hydrochloride, it is adaptable to the endogenous depression for the treatment of slowness, reactive depression and involutional depression, also may be used
For children enuresis.Sedation and cholinolytic all belong to medium.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of imipramine hydrochloride, in this pharmaceutical composition hydrochloric imipramine and
The natural product of a kind of novel structure, imipramine hydrochloride and this natural product can Synergistic treatment atherosclerosiss.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
A kind of pharmaceutical composition of imipramine hydrochloride, including imipramine hydrochloride, compound as claimed in claim 1 (I) and
Pharmaceutically acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, collapses
Solve agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: Semen Nigellae is pulverized by (a), with 75～85%
Alcohol heat reflux extracts, and united extraction liquid is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butyl alcohol
Extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；N-butyl alcohol in (b) step (a)
Take thing macroporous resin remove impurity, first with 8 column volumes of 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, receive
Collecting 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate is used
Purification on normal-phase silica gel separates, and obtains 4 with the methylene chloride-methanol gradient elution that volume ratio is 85:1,45:1,25:1 and 15:1 successively
Component；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1,15:1 and 1:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 3 components；In (e) step (d) component 2 with octadecylsilane be bonded anti-
Phase silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collects 10～16 column volume eluents,
Eluent is concentrated under reduced pressure to give 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) replace ethyl acetate to extract with dichloromethane,
Obtain dichloromethane extract.
The above-claimed cpd (I) application in atherosclerotic medicine is treated in preparation.
The application in atherosclerotic medicine is treated in preparation of the pharmaceutical composition of above-mentioned imipramine hydrochloride.
Advantages of the present invention:
Containing imipramine hydrochloride and the natural product of a kind of novel structure in the pharmaceutical composition of the imipramine hydrochloride that the present invention provides,
When imipramine hydrochloride, compound (I) independent role, lipid therapy atherosclerosis can be regulated；Imipramine hydrochloride and change
During compound (I) synergy, action effect improves further, can develop into the atherosclerotic medicine for the treatment of.
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.To the greatest extent
The present invention is explained in detail by pipe with reference to preferred embodiment, it will be understood by those within the art that, can be to the present invention
Technical scheme modify 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: Semen Nigellae (2kg) is pulverized by (a), extracts (15L × 3 time) with 80% alcohol heat reflux, merges
Extracting solution, is concentrated into without alcohol taste (3L), satisfies with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water successively
N-butyl alcohol (3L × 3 time) extraction of sum, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；
Acetic acid ethyl ester extract D101 type macroporous resin remove impurity in (b) step (a), first with 8 column volumes of 25% ethanol elution,
Again with 12 column volumes of 70% ethanol elution, collecting 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；(c)
In step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 85:1 (10 column volumes),
45:1 (8 column volumes), 25:1 (10 column volumes) and the methylene chloride-methanol gradient elution of 15:1 (8 column volumes)
Obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1 (10 by volume ratio successively
Individual column volume), the methylene chloride-methanol gradient elution of 15:1 (8 column volumes) and 1:1 (6 column volumes) obtain 3 groups
Point；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and is 72% by concentration expressed in percentage by volume
Methanol aqueous solution isocratic elution, collect 10～16 column volume eluents, 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 341.2128, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C20H30O3, degree of unsaturation is 6.Hydrogen nuclear magnetic resonance modal data δH(ppm, DMSO-d6, 500MHz): H-1 (1.52,
M), and H-1 (1.78, m), H-2 (2.27, m), H-2 (2.31, m), H-5 (1.17, br, d, J=10.5),
H-6 (1.39, m), H-6 (1.43, m), H-7 (1.44, m), H-7 (1.51, m), H-9 (1.49, m),
H-11 (4.21, br, dd, J=12.0,6.5), H-12 (1.68, m), H-12 (1.82, ddd, J=13.0,9.0,1.5),
H-13 (2.63, m), H-14 (1.01, dd, J=12.0,4.5), H-14 (2.15, br, d, J=12.0), H-15 (1.96,
Dd, J=12.8,2.0), H-15 (2.08, d, J=12.8), H-17 (4.72, br, s), H-17 (4.81, br, s),
H-18 (3.19, d, J=11.4), and H-18 (3.45, d, J=11.4), H-19 (1.11, s), H-20 (0.82, s)；
Carbon-13 nmr spectra data δC(ppm, DMSO-d6, 125MHz): 40.5 (CH2, 1-C), 34.2 (CH2, 2-C),
216.3 (C, 3-C), 50.8 (C, 4-C), 53.1 (CH, 5-C), 20.4 (CH2, 6-C), 42.1 (CH2, 7-C),
46.5 (C, 8-C), 61.2 (CH, 9-C), 40.7 (C, 10-C), 70.3 (CH, 11-C), 42.1 (CH2, 12-C),
44.0 (CH, 13-C), 39.8 (CH2, 14-C), 49.2 (CH2, 15-C), 155.6 (C, 16-C), 102.7 (CH2,
17-C), 67.1 (CH2, 18-C), 18.4 (CH3, 19-C), 16.3 (CH3, 20-C).Infrared spectrum shows this change
Compound contains hydroxyl and carbonyl (3441cm-1And 1748cm-1)。1H-NMR spectrum show two methyl signals [δ H0.82 (s,
H3-20) and 1.11 (s, H3-19)], olefinic methylene signals [δ H4.72 (br, s, H-17) and 4.81 (br, s,
H-17)], an oxygen-containing methylene signals [δ H3.19 (d, J=11.4Hz, H-18) and 3.45 (d, J=11.4Hz, H-18)],
One oxygen-containing methine signals [δ H4.21 (br, dd, J=12.0,6.5Hz, H-11)].Additionally,13C-NMR spectrum demonstrates
20 carbon signals, including two methyl, nine methylene (an olefinic methylene base, contains Oxymethylene), four first
Base (an oxygen-containing methine), and five quaternary carbons (carbonyl carbon, an alkene quaternary carbon).H in HMBC spectrum2-17
With C-13 and C-15；H-14b (δ H2.15) and C-7, C-9, C-12, C-15 and C-16；And H-11 and C-9, C-10
Show that the outer methylene of ring is positioned at C-16/C-17, C-11 position and is connected with a hydroxyl with the dependency of C-13.Additionally, H2-18 and C-3,
The dependency of C-4, C-5 and C-19 shows that primary hydroxyl is positioned on C-18 position.By analyze H-11 coupling constant (br, dd,
J=12.0,6.5Hz) understand C-11 position hydroxyl be α configuration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, with
And document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration is tried by ECD further
Testing and determine, 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 uses VD3 and high lipid food to make atherosclerosis (AS) rat model, detects animal lipid content,
Observe the therapeutical effect of drugs on atherosclerotic.
1, materials and methods
1.1 animal
SD rat, male, 50～55d, weight (200 ± 20) g, medical animal experiment center, Guangdong Province provide.
1.2 reagent and sample
Imipramine hydrochloride is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
FUFANG DANSHEN PIAN: be ground by tablet, is dissolved in water, and makes suspension.VD3, sodium cholate, cholesterol, propylthio oxygen
Pyrimidine: upper sea blue season development in science and technology company limited.
1.3 instrument
Microplate reader (iMARK, BIO-RAD), microscope (OLYMPUS, DSX500), drying baker (Nanjing Lay cotton material
Skill Industrial Co., Ltd., DZF-6020)
Prepared by 1.4 rat packets and model
After 60 male SD rat routines are raised 1 week, observation experiment animal is in stable condition, is randomly divided into 6 groups, often
Organize 10, respectively blank group, model control group, positive controls (FUFANG DANSHEN PIAN solution, 25.92mg/mL)
With imipramine hydrochloride group (80mg kg-1), compound (I) group (80mg kg-1), imipramine hydrochloride and compound (I)
Compositions group [40mg kg-1Imipramine hydrochloride+40mg kg-1Compound (I)].Each group carries out lumbar injection according to weight
Modeling, wherein blank group injecting normal saline, remaining respectively organizes injection VD3.And in modeling same day in addition to blank group each
Group all gives high lipid food and feeds.High lipid food makes: normal diet is ground into powder, adds medicine according to formula: join
Fang Wei: 3% cholesterol, 0.5% sodium cholate, 0.2% propylthiouracil, 5% white sugar, 10% Adeps Sus domestica.Add water and mix well, make
It is in strip, puts in drying baker and dry.Each group presses weight gastric infusion, and blank group gives normal diet nursing every day,
Gavage is to normal saline；Model control group is to normal saline gavage；Remaining medicine group relative medicine gavage, administration time is 8 weeks.
1.5 test materials obtain
Fasting 24h after 8 weeks, 8h of intaking, weigh animal body quality, anaesthesia experiment animal, heart extracting blood, take tremulous pulse and heart
Tissue.Centrifugal serum, 5min, 5000r/min, take supernatant, be put in-20 DEG C standby.Tremulous pulse and heart tissue are placed in formaldehyde and fix
In liquid standby.
1.6 lipids contents detections
ELISA method detection lipids contents, middle step operates to specifications, observed result in microplate reader.
1.7 statistical method
Application SPSS software carries out data analysis, compares employing t inspection between group, and result is with mean ± standard deviationRepresent.
2, experimental result
2.1 impacts on AS rat model blood fat
Serum total cholesterol (TC), high density and low-density lipoprotein cholesterol (HDL-C and LDL-C) and triacylglycerol
(TG) it is 4 basic indexs of atherosclerosis.
With blank group ratio, model control group rat TG, TC, LDL-C level significantly raises (P ＜ 0.01), HDL-C
Level significantly reduces (P ＜ 0.01), and modeling success is described.With model control group ratio, positive controls rat TG, TC, LDL-C
Level significantly reduces (P ＜ 0.01), and HDL-C level significantly raises (P ＜ 0.01)；With model control group ratio, hydrochloric acid the third miaow
Piperazine group, compound (I) group rat TG, TC, LDL-C level reduces (P ＜ 0.05), and HDL-C level raises (P ＜
0.05)；Compared with model control group, imipramine hydrochloride and compound (I) compositions group rat TG, TC, LDL-C water
Putting down and significantly reduce (P ＜ 0.01), HDL-C level significantly raises (P ＜ 0.01).The results are shown in Table 1.
Table 1 on the impact of AS rat model blood fat (N=10, mmol/L)
The above results shows, when imipramine hydrochloride, compound (I) independent role, can regulate lipid therapy Atherosclerosis
Change；When imipramine hydrochloride and compound (I) synergy, action effect improves further, can develop into treatment tremulous pulse medicated porridge
The medicine of sample hardening.
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 (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of an imipramine hydrochloride, it is characterised in that: include imipramine hydrochloride, as claimed in claim 1
Compound (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of imipramine hydrochloride the most according to claim 2, it is characterised in that: pharmaceutically acceptable carries
Body includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, suction
Appendix body or lubricant.
The pharmaceutical composition of imipramine hydrochloride the most according to claim 2, it is characterised in that: described dosage form include tablet,
Capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution
Agent, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
By Semen Nigellae pulverize, with 75～85% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use 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 use 70% second
12 column volumes of alcohol eluting, 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 the dichloromethane that volume ratio is 85:1,45:1,25:1 and 15:1-
Methanol elution gradient obtains 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, use volume successively
3 components are obtained than the methylene chloride-methanol gradient elution for 20:1,15:1 and 1:1；E in () step (d), component 2 is used
The reverse phase silica gel of octadecylsilane bonding separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collects
10～16 column volume eluents, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) 80% second
Alcohol circumfluence distillation, united extraction liquid.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is D101
Type macroporous adsorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is used dichloromethane
Alkane replaces ethyl acetate to extract, and obtains dichloromethane extract.
9. the application in atherosclerotic medicine is treated in preparation of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described imipramine hydrochloride of claim 2～4 treats atherosclerotic medicine in preparation
In application.
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| CN201610372938.5A CN105949044A (en) | 2016-05-28 | 2016-05-28 | Imipramine hydrochloride pharmaceutical composition and medical application thereof |
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| CN201610372938.5A CN105949044A (en) | 2016-05-28 | 2016-05-28 | Imipramine hydrochloride pharmaceutical composition and medical application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US20210386754A1 (en) * | 2020-03-03 | 2021-12-16 | Augusta University Research Institute, Inc. | Compositions and methods for treating atherosclerotic vascular disease |
-
2016
- 2016-05-28 CN CN201610372938.5A patent/CN105949044A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US20210386754A1 (en) * | 2020-03-03 | 2021-12-16 | Augusta University Research Institute, Inc. | Compositions and methods for treating atherosclerotic vascular disease |
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Application publication date: 20160921 |