CN105712957A - Aripiprazole medicine composition and application of aripiprazole to prevent and treat diabetes - Google Patents
Aripiprazole medicine composition and application of aripiprazole to prevent and treat diabetes Download PDFInfo
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- CN105712957A CN105712957A CN201610167477.8A CN201610167477A CN105712957A CN 105712957 A CN105712957 A CN 105712957A CN 201610167477 A CN201610167477 A CN 201610167477A CN 105712957 A CN105712957 A CN 105712957A
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- aripiprazole
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- diabetes
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
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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)
- A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
- A61K36/704—Polygonum, e.g. knotweed
Abstract
The invention discloses an aripiprazole medicine composition and application of aripiprazole to prevent and treat diabetes. The aripiprazole medicine composition comprises aripirazole and a natural product compound (I) which is separated from dry tubers of polygonum multiflorum and is novel in structure, and when aripiprazole and the natural product act independently, the effect of preventing and treating diabetes is common; when aripiprazole and the natural product are combined to act, the effect of preventing and treating diabetes is remarkably improved, and aripiprazole and the natural product can be developed into a medicine for preventing and treating diabetes. Compared with the prior art, the aripiprazole medicine composition and the application of aripiprazole have prominent substantive features and remarkable progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of Aripiprazole, be specifically related to the pharmaceutical composition of a kind of Aripiprazole and prevent and treat the purposes of diabetes.
Background technology
Aripiprazole chemical name is 7-{4-[4-(2,3-Dichlorobenzene base)-l-piperazinyl] butoxy }-3,4-dihydro-2 (1H)-quinolinones.
Aripiprazole is a kind of novel atypia antipsychotic drug, and DA nervous system is had dual regulation, is the stabilizer of DA mediator.Significantly high affinity is had with D2, D3,5-HT1A and 5-HT2A receptor.Schizophrenia effect is produced by the partial agonist effect to D2 and 5-HT1A receptor and the antagonism to 5-HT2A receptor.After this product is oral, peak reaching time of blood concentration is 3～5 hours, and the half-life is 48～68 hours.DM-14857 is main active metabolites.For treating all types of schizophrenia.Overseas clinical trial shows, the schizoid positive and negative symptoms are all had obvious curative effects by this product, also can improve the affective symptom occurred together, and reduce schizoid relapse rate.
At present, the relevant report that there is not yet Aripiprazole and pharmaceutical composition thereof and prevent and treat diabetes.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of Aripiprazole, this pharmaceutical composition can be worked in coordination with prevent and treat diabetes containing Aripiprazole and a kind of natural product separating the novel structure obtained from Radix Polygoni Multiflori, Aripiprazole and this natural product.
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 Aripiprazole, including Aripiprazole, compound as above (I) and pharmaceutically acceptable carrier.
The preparation method of compound as above (I), comprise following operating procedure: the dried root of Radix Polygoni Multiflori is pulverized by (a), extract with 75% 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 10 column volumes of 8% ethanol elution, then with 12 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 40:1,20:1,10:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,5:1 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 75%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
Further, described macroporous resin is AB-8 type macroporous adsorbent resin.
Compound as above (I) prevents and treats the application in the medicine of diabetes in preparation.
The pharmaceutical composition of Aripiprazole as above prevents and treats the application in the medicine of diabetes in preparation.
Advantages of the present invention:
Containing Aripiprazole and a kind of natural product separating the novel structure obtained from Radix Polygoni Multiflori in the pharmaceutical composition of Aripiprazole provided by the invention, when Aripiprazole and this natural product independent role, prevent and treat diabetes effect general；During the two synergy, prevent and treat diabetes effect and significantly improve, it is possible to develop into the medicine preventing and treating diabetes.The present invention compared with prior art has prominent substantive distinguishing features and significant progressive.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, it is possible to technical scheme is modified or equivalent replacement, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: the dried root (5kg) of Radix Polygoni Multiflori 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 AB-8 type macroporous resin remove impurity in () step (a), first with 10 column volumes of 8% ethanol elution, then with 12 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 40:1 (8 column volumes), 20:1 (8 column volumes), 10:1 (8 column volumes) and 5:1 (10 column volumes) successively；D in () step (c), component 4 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 8:1 (8 column volumes), 5:1 (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 75%, collect 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (195mg, HPLC normalization purity is more than 98%).
Structural identification: colourless crystallization, HR-ESI-MS shows [M+H]+For m/z333.2027, can obtain molecular formula in conjunction with nuclear-magnetism feature is C20H28O4, degree of unsaturation is 7.Hydrogen nuclear magnetic resonance modal data δH(ppm, pyridine-d5, 500MHz): H-2a (3.66, dd, J=16.4, 11.2Hz), H-2b (3.33, ddd, J=16.4, 5.5, 1.1Hz), H-3 (6.99, m), H-5a (3.23, d, J=15.6Hz), H-5b (2.98, dd, J=15.6, 9.3Hz), H-6 (5.06, dd, J=9.3, 1.4Hz), H-7 (1.89, m), H-8 (1.48, m), H-9a (2.26, dd, J=16.5, 2.4Hz), H-9b (1.58, ddd, J=16.5, 7.6, 4.2Hz), H-10 (3.16, m), H-11 (1.80, m), H-12 (0.93, d, J=5.7Hz), H-13 (1.07, d, J=6.6Hz), H-14 (1.13, d, J=5.7Hz), H-3 ' (7.01, m), H-4 ' (1.65, d, J=7.3Hz), H-5 ' (1.84, s)；Carbon-13 nmr spectra data δC(ppm, pyridine-d5, 125MHz): 207.8 (C, 1-C), 42.6 (CH2, 2-C) and 130.9 (CH, 3-C), 132.4 (C, 4-C), 28.3 (CH2, 5-C), 77.4 (CH, 6-C), 52.7 (CH, 7-C), 22.4 (CH, 8-C), 34.8 (CH2, 9-C), 59.9 (CH, 10-C), 26.4 (CH, 11-C), 22.1 (CH3, 12-C), 23.8 (CH3, 13-C), 18.4 (CH3, 14-C), 171.2 (C, 15-C), 200.1 (C, 1 '-C), 129.3 (C, 2 '-C), 138.2 (CH, 3 '-C), 14.5 (CH3, 4 '-C), 13.1 (CH3, 5 '-C).1756cm-in infrared spectrum1With the 236nm absorption band in UV spectrum, absorption band shows that this compound contains α, β-unsaturated lactone structure, the 1715cm in infrared spectrum-1With 1680cm-1Absorption band shows there is ketone group and double bond fragment in structure.13C-NMR, DEPT and hsqc spectrum show 20 carbon signals, including five methyl, three methylene, seven methines (company's oxygen carbon and two alkene carbon), and five quaternary carbons (three carbonyl carbon and two alkene carbon), in conjunction with insatiable hunger sum, function above structure shows that this compound is twin nuclei.1H-NMR spectrum shows five methyl proton signal δ in conjunction with hsqc spectrumH0.93 (3H, d, J=5.7Hz), 1.07 (3H, d, J=6.6Hz), 1.13 (3H, d, J=5.7Hz), 1.65 (3H, d, J=7.3Hz), 1.84 (3H, s), two olefinic proton signals δH6.99 (1H, m) with 7.01 (1H, m), an even oxygen methine proton signal δH5.06 (1H, dd, J=9.3,1.4Hz), three groups of methene proton signal δH3.33 (1H, ddd, J=16.4,5.5,1.1Hz) with 3.66 (1H, dd, J=16.4,11.2Hz), 3.23 (1H, d, J=15.6Hz) and 2.98 (1H, dd, J=15.6,9.3Hz), 2.26 (1H, dd, J=16.5,2.4Hz) with 1.58 (1H, ddd, J=16.5,7.6,4.2Hz), four methine proton signal δH1.89 (1H, m), 1.48 (1H, m), 3.16 (1H, m), 1.80 (1H, m).1H-1There is H in HCOSY spectrum2-2/H-3、H2-5/H-6/H-7/H-8/H2-9/H-10、H-7/H-11/H3-12 and H-11/H3-13、H-8/H3-14 coherent signals, the H of display in composing in conjunction with HMBC2-2、H2-9 and H-10 and C-1 and H2-2、H2-5 and H-6 and C-4 coherent signal can build germacrane sesquiterpene skeleton.And1H-1H in HCOSY spectrum3-5’/H-3’/H3-4 ' in coherent signal and HMBC spectrum, H-3 ' and C-2 ', C-4 ' and C-5 ' coherent signal can build another part fragment, and in HMBC spectrum, the dependency of H-10 and C-1 ' shows the position that this fragment is connected with germacrane sesquiterpene skeleton simultaneously.Additionally H-3, H in HMBC spectrum2A lactonic ring structure is there is between-5 and H-6 and C-15 coherent signal hint C-6 and C-15.In NOESY spectrum, it is assumed that H-8 is beta comfiguration, then the dependency of H-8 and H-10 shows that H-10 is also beta comfiguration, therefore, O-2 '-methyl-2 '-butylene ketone group should be α configuration.Additionally, H-9b and H-8 exists coherent signal, so the dependency of H-9a and H-2a and H-9a and H-5a shows that H-2a, H-5a, H-9a are all α configuration, the coherent signal of H-2a and H-5a shows Δ simultaneously3(4)Double bond is E.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 chemical structure formula and carbon atoms numbered are as follows:
Embodiment 2: the impact on type 2 diabetes mellitus rat blood sugar
1, materials and methods
1.1 animals
Select healthy cleaning grade male Wistar rat 100, about 2 monthly age, body weight 150～180g (Hubei Province's epidemic prevention station), standard feed (Tongji Medical College, Huazhong Science and Technology Univ.'s Experimental Animal Center).
1.2 reagent and instrument
Aripiprazole is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in example 1.Metformin (Changzhou Ya Bang biological reagent company, purity 99.3%)；Streptozotocin (STZ, Sigma company), blood sugar kit (biological company limited is built up in Nanjing), blood fat test kit (Zhejiang Dong Ou biological engineering company limited).Serum insulin (INS) radioimmunological kit (Science and Technology Development Center of Chinese People's Liberation Army General Hospital puts and exempts from institute).Detecting instrument is Shandong Province of China rainbow analytical tool factory GF-D800 type semi-automation biochemistry analyzer；U.S.'s ELx800 microplate reader.
The foundation of 1.3 animal models and packet
After Rat Standard feedstuff adaptability feeds 2 weeks, selecting 10 Rat Standard forage feeds at random, ad lib, water inlet are as normal group.After remaining 90 rats give high fat, high-carbonhydrate diet (sucrose-lard-milk powder-egg-normal diet=30: 20: 4: 2: 63) feeds 8 weeks, rat presses 25mg kg-1Dosage tail vein injection streptozotocin, does OGTT experiment after feeding 2 weeks, screening impaired glucose tolerance person 50 only carries out random packet: model control group, positive controls (metformin group, 50mg kg-1), Aripiprazole group (280mg kg-1), compound (I) group (280mg kg-1), Aripiprazole and compound (I) compositions group, 5 groups altogether, often group 10.
1.4 animals process
Aripiprazole group every day is with 280mg kg-1Aripiprazole gavage；Compound (I) organizes every day with 280mg kg-1Compound (I) gavage；Aripiprazole and compound (I) compositions group every day are with 140mg kg-1Aripiprazole+140mg kg-1Compound (I) gavage；Positive controls every day is with 50mg kg-1Metformin gavage；Normal group and model control group every day are with equivalent 0.9% normal saline gavage.
1.5OGTT tests
Rat model all carries out OGTT experiment after screening and treating 6 weeks.After animal fasting 12h, press 2.5g kg with 25% G/W-1Dosage gavage.Before gavage and after gavage 60,120min cut tail and take blood, adopt each time point blood glucose (BG) of determination of glucose oxidase.
1.6 index determinings
After rat treats 6 weeks, using chloral hydrate intraperitoneal injection of anesthesia after animal fasting 12h, abdominal aortic blood also puts to death animal, detects by the explanation application of sample on test kit.Blood glucose value determination of glucose oxidase.
1.7 statistical methods
Measurement data x ± s represents, adopts SPSS19.0 software, compares with variance analysis, compare and check with q, compare employing paired t-test before and after treatment between two between many groups, and P < 0.05 is for there being significant difference.
2, experimental result
Pharmaceutical intervention is each comparison organizing blood sugar level after 6 weeks
Comparing with Normal group, model control group blood glucose significantly raises (P < 0.05), it was demonstrated that modeling success；Comparing with model control group, Aripiprazole group, compound (I) group blood glucose significantly reduces (P < 0.05)；Comparing with model control group, Aripiprazole and compound (I) compositions group blood glucose significantly reduce (P < 0.01), close to positive drug hypoglycemic effect.Result is in Table 1.
After table 1 pharmaceutical intervention, each group blood sugar level compares .mmol L-1, x ± s
| Group | Before gavage | 60min after gavage | 120min after gavage |
| Normal group | 4.35±0.37 | 5.20±0.25 | 6.14±0.19 |
| Model control group | 8.43±0.78 | 11.99±0.62 | 16.99±0.51 |
| Positive controls | 5.46±0.35 | 6.43±0.89 | 6.55±0.64 |
| Aripiprazole group | 6.48±0.50 | 6.99±0.57 | 7.17±0.65 |
| Compound (I) group | 6.32±0.82 | 6.94±0.68 | 6.99±0.91 |
| Aripiprazole and compound (I) compositions group | 5.35±0.68 | 6.50±0.52 | 6.54±0.65 |
The above results shows, when Aripiprazole and compound provided by the invention (I) independent role, the blood glucose of diabetes rat is had reduction effect；When Aripiprazole and compound provided by the invention (I) synergy, the hypoglycemic activity of diabetes rat is become apparent from, better effects if during than Aripiprazole or compound (I) independent role, it is possible to develop into the medicine preventing and treating diabetes.
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 (6)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of an Aripiprazole, it is characterised in that: include Aripiprazole, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier.
3. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: the dried root of Radix Polygoni Multiflori is pulverized by (a), extract with 75% 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 10 column volumes of 8% ethanol elution, then with 12 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 40:1,20:1,10:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,5:1 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 75%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
4. the preparation method of compound according to claim 3 (I), it is characterised in that: described macroporous resin is AB-8 type macroporous adsorbent resin.
5. the compound (I) described in claim 1 prevents and treats the application in the medicine of diabetes in preparation.
6. the pharmaceutical composition of the Aripiprazole described in claim 2 prevents and treats the application in the medicine of diabetes in preparation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106083771A (en) * | 2016-06-13 | 2016-11-09 | 崔坤峰 | The pharmaceutical composition of carbidopa and the medical usage for the treatment of liver cancer thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083771A (en) * | 2016-06-13 | 2016-11-09 | 崔坤峰 | The pharmaceutical composition of carbidopa and the medical usage for the treatment of liver cancer thereof |
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Application publication date: 20160629 |