CN106045835A - Benserazide hydrochloride medicine composition and medical purpose therefore for decreasing blood glucose - Google Patents

Benserazide hydrochloride medicine composition and medical purpose therefore for decreasing blood glucose Download PDF

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Publication number
CN106045835A
CN106045835A CN201610459119.4A CN201610459119A CN106045835A CN 106045835 A CN106045835 A CN 106045835A CN 201610459119 A CN201610459119 A CN 201610459119A CN 106045835 A CN106045835 A CN 106045835A
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compound
blood glucose
elution
group
benserazide hydrochloride
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CN201610459119.4A
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不公告发明人
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Cui Kunfeng
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Publication of CN106045835A publication Critical patent/CN106045835A/en
Priority to PCT/CN2017/097789 priority patent/WO2017220051A2/en
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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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
    • C07C49/557—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings having unsaturation outside the rings

Abstract

The invention discloses a benserazide hydrochloride medicine composition and a medical purpose therefore for decreasing blood glucose. The benserazide hydrochloride medicine composition contains benserazide hydrochloride and a natural product compound (I), wherein the natural product compound (I) is separated from dried tubers of gastrodia elata and is of a novel structure; when the benserazide hydrochloride and the natural product compound (I) singly act, the function of decreasing blood glucose is realized; when the benserazide hydrochloride and the natural product compound (I) jointly act, the effect of decreasing blood glucose is further improved, and a medicine for decreasing blood glucose can be developed. Compared with the prior art, the benserazide hydrochloride medicine composition has outstanding substantive characteristics and obvious progress.

Description

The pharmaceutical composition of Ro-4-4602. and hypoglycemic medical usage thereof
Technical field
The invention belongs to biomedicine field, relate to the new application of Ro-4-4602., be specifically related to the medicine of Ro-4-4602. Compositions and hypoglycemic medical usage thereof.
Background technology
Ro-4-4602. is periphery decarboxylase inhibitor, makes compound preparation Benserazide with combined with levodopa application. Levodopa is to treat Parkinsonian active drug, and its pharmacological action is by being converted into DOPA through decarboxylation in brain Amine realizes, and the dopamine in brain can improve Parkinsonian symptoms.But most of levodopa in periphery through aromatic amino acid Decarboxylase (AADC) effect is converted into dopamine, can enter in brain the most on a small quantity, and Ro-4-4602. is as AADC inhibitor and a left side Rotation DOPA is used in combination, and levodopa can be suppressed to turn to dopamine in outer planet, so that the amount of the levodopa entered in brain Increase, effectively improve Parkinsonian symptoms.
Diabetes are a kind of common endocrine metabolism syndromes, are mainly characterized by carbohydrate metabolism disturbance, and clinical manifestation is many Drinking water copiously food, polyuria, lose weight.At present onset diabetes rate raises year by year, it has also become the malignant tumor that continues, cardiovascular and cerebrovascular vessel after being ill the The disease of 3 serious threat human healths.
Have not yet to see Ro-4-4602. to report with hypoglycemic dependency.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of Ro-4-4602., containing hydrochloric acid in this pharmaceutical composition Benserazide and a kind of natural product of the novel structure of isolated from draft, Ro-4-4602. and this natural product can be assisted Same blood sugar lowering.
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 Ro-4-4602., including Ro-4-4602., compound as above (I) and pharmaceutically Acceptable carrier.
The preparation method of compound (I) as above, comprises following operating procedure: (a) is by the dry tuber powder of Rhizoma Gastrodiae Broken, with 80～90% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water successively Saturated n-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b) step (a) Middle n-butyl alcohol takes thing macroporous resin remove impurity, first with 6 column volumes of 30% ethanol elution, then with 12 cylinders of 85% ethanol elution Long-pending, collect 85% eluent, concentrating under reduced pressure obtains 85% ethanol elution concentrate；85% ethanol elution concentrate in (c) step (b) Separate by purification on normal-phase silica gel, obtain with the methylene chloride-methanol gradient elution that volume ratio is 100: 1,50: 1,25: 1 and 12: 1 successively 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20: 1,12: 1 and 2: 1 by volume ratio successively Methylene chloride-methanol gradient elution obtains 3 components；E anti-phase silicon that in () step (d), component 2 is bonded by octadecylsilane Glue separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 88%, collects 13～16 column volume eluents, eluting Liquid is concentrated under reduced pressure to give compound (I).
Further, step (a) is extracted with 85% alcohol heat reflux, united extraction liquid.
Further, described macroporous resin is D101 type macroporous adsorbent resin.
The compound (I) application in preparing hypoglycemic medicine as above.
The application in preparing hypoglycemic medicine of the pharmaceutical composition of Ro-4-4602. as above.
Advantages of the present invention:
Containing Ro-4-4602. and a kind of being dried from Rhizoma Gastrodiae in the pharmaceutical composition of the Ro-4-4602. that the present invention provides When the natural product of the novel structure of isolated in tuber, Ro-4-4602. and this natural product independent role, there is fall blood Sugar effect；During the two synergy, blood sugar decreasing effect improves further, can develop into hypoglycemic medicine.The present invention is with existing There is technology to compare and there is prominent substantive distinguishing features and significantly progress.
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: the dry tuber (2kg) of Rhizoma Gastrodiae is pulverized by (a), extracts (15L × 3 time) with 85% alcohol heat reflux, United extraction liquid, is concentrated into without alcohol taste (3L), successively by petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated N-butyl alcohol (3L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b) step A acetic acid ethyl ester extract D101 type macroporous resin remove impurity in (), first with 6 column volumes of 30% ethanol elution, then uses 85% second 12 column volumes of alcohol eluting, collect 85% eluent, and concentrating under reduced pressure obtains 85% ethanol elution concentrate；In (c) step (b) 85% Ethanol elution concentrate purification on normal-phase silica gel separates, and is 100: 1 (12 column volumes), 50: 1 (10 cylinders by volume ratio successively Long-pending), the methylene chloride-methanol gradient elution of 25: 1 (8 column volumes) and 12: 1 (8 column volumes) obtain 4 components；(d) step Suddenly in (c), component 4 separates further by purification on normal-phase silica gel, is 20: 1 (6 column volumes), 12: 1 (8 cylinders by volume ratio successively Long-pending) and the methylene chloride-methanol gradient elution of 2: 1 (6 column volumes) obtain 3 components；E in () step (d), component 2 is with 18 The reverse phase silica gel of alkyl silane bonding separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 88%, collect 13～ 16 column volume eluents, eluent is concentrated under reduced pressure to give compound (I) (514mg, HPLC normalization purity is more than 98%).
Structural identification: white needles, HR-ESI-MS shows [M+H]+For m/z 293.1492, can obtain in conjunction with nuclear-magnetism feature Molecular formula is C20H20O2, degree of unsaturation is 11.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-3 (6.68, s), H-7 (5.53, dd, J=7.7,1.8Hz), H-8 (2.04, dt, J=11.5,7.2Hz), H-9 (3.26, d, J=11.5Hz), H- 12 (6.15, d, J=10.5Hz), H-13 (6.62, dd, J=10.5,6.7Hz), H-14 (2.42, dd, J=6.7,7.2Hz), H-16a (4.73, s), H-16b (4.74, s), H-17 (1.53, s), H-18a (5.03, s) H-18b (4.82, s), H-19 (1.88, s), H-20 (1.63, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 198.2 (C, 1-C), 144.2 (C, 2-C), 146.4 (CH, 3-C), 160.3 (C, 4-C), 207.2 (C, 5-C), 138.1 (C, 6-C), 133.9 (CH, 7-C), 47.4 (CH, 8-C), 42.8 (CH, 9-C), 151.5 (C, 10-C), 148.9 (C, 11-C), 129.7 (CH, 12-C), 135.8 (CH, 13-C), 51.4 (CH, 14-C), 146.4 (C, 15-C), 114.3 (CH2, 16-C), 18.5 (CH3, 17-C), 109.7 (CH2, 18-C), 10.5 (CH3, 19-C), 19.3 (CH3, 20-C).Infrared spectrum shows that this compound contains carbonyl (1735cm-1 With 1675cm-1) and alkene (1632cm-1) group；And it has uv absorption at 245nm, show containing α, beta-unsaturated carbonyl list Unit.13C-NMR, DEPT and hsqc spectrum show 20 carbon signals, including three methyl, two methylene (two alkene carbon), Seven methines (four alkene carbon), and eight quaternary carbons (two carbonyl carbon and six alkene carbon), function above structure is tied again Close insatiable hunger sum and show that this compound is tricyclic structure.1H-NMR spectrum combines hsqc spectrum and shows three methyl proton signal δH 1.53 (3H, s), 1.88 (3H, s), 1.63 (3H, s), two groups of terminal olefine proton signal δH4.73 (1H, s) with 4.74 (1H, s), 5.03 (1H, s) with 4.82 (1H, s), a pair olefinic proton signals δH6.15 (1H, d, J=10.5Hz) and 6.62 (1H, dd, J= 10.5,6.7Hz), two isolated olefinic proton signals δH6.68 (1H, s), 5.53 (1H, dd, J=7.7,1.8Hz).1H-1H There is H-12/H-13/H-14/H-8/H-7 and H-8/H-9 coherent signal in COSY spectrum, HMBC spectrum shows simultaneously H-3 with C-1, C-2 and C-4, H-7 Yu C-5, C-6, C-8 and C-14, H2-16 with C-14, C-15 and C-17, H3-17 and C-14, H2-18 with C-9, C-11 and C-12, H3-19 with C-1, C-2 and C-3, H3-20 with C-5, C-6 and C-7 coherent signal, by above-mentioned H NMR spectroscopy Relevant information can build the connected mode of this compound, and may determine that this compound is rhamnofolane type diterpene Compounds.By the carbon chemical shifts δ of C-4 Yu C-10CIt is double bond between C-4 and C-10 knowable to 160.3 and 151.5.Comprehensively Hydrogen spectrum, carbon spectrum, HMBC spectrum and ROESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows Shown in, spatial configuration is determined by ECD test further, and theoretical value is basically identical with experiment value.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 materials and instrument
Healthy male ICR mouse, Shenyang Medical College animal experimental center, body weight 18～22g；Ro-4-4602. is purchased from China Pharmaceutical biological product examines and determine institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Streptozotocin (STZ) U.S. Sigmaization Company, is made into 1%STZ solution with front citrate buffer solution；The domestic analytical pure of other reagent.The ultra-clean work of SW-CJ-2FD Platform Purifying Equipment Co., Ltd., Suzhou；It is that experimental apparatus manufactures limited public affairs that the large-scale bilayer of QYC-2112 temperature entirely cultivates sky, shaking table Shanghai Department；SHY-2A difunctional water-bath constant temperature oscillator Jiangsu Dong Peng instrument manufacturing company limited；TGL20W desk type high speed frozen centrifugation Machine Hunan Xiang Yi Laboratory Instruments development corporation, Ltd.；PB203-N electronic balance Switzerland, happy China of the Shenzhen limited public affairs of new electronics Department；FW177 crusher for Chinese herbal medicine Tianjin Stettlen Co., Ltd；Rotary Evaporators Japan, east, the Five continents, Beijing science and technology is sent out Exhibition company limited；Nereid's grand experimental facilities company limited on YRD-30.2A vacuum freeze drier；Glucose kit, super oxygen Compound dismutase (SOD) and malonaldehyde (MDA) measure test kit Sichuan mikey science and technology limited Company.
1.2STZ induced diabetes Establishment of mouse model
Randomly draw body weight (20 ± 2) g mice, fasting 16h, lumbar injection 1%STZ 150mg kg-1.Inject after 4h 20% glucose solution.Normal raise 3d after, fasting 3h, measure blood glucose value by glucose kit, blood glucose value >= 11.1mmol·L-1Person is defined as diabetic rat model.
1.3 experiment packet and administrations
Take diabetic rat model 40, be 4 groups at random, often group 10: model group, Ro-4-4602. group (100mg kg-1), compound (I) group (100mg kg-1), Ro-4-4602. and compound (I) compositions group [50mg kg-1Ro-4-4602. +50mg·kg-1Compound (I)], separately take healthy Mus 10, as Normal group.Each group gastric infusion respectively (model group and Normal group gavage equal-volume normal saline), successive administration 30d, surveys blood glucose value, monitors hair color, amount of drinking water, bedding and padding humidity journey Degree and the basic sign of body weight.
1.4 glucose tolerance test
Separately take a collection of mice, modeling and administration ibid, after last is administered 1h, gavage 2g kg-1Glucose solution, after gavage 0,30,60,120min measure blood glucose value, calculate Area under the curve of blood glucose (AUC).
Computational methods: mmol h L-1=12A+B+C+12D；
Wherein, A, B, C, D be respectively 0,30,60,120min blood glucose value.
The mensuration of 1.5 alpha-glucosidase activities
Mice is put to death in fasting, takes small intestinal epimere, and 0.01M PBS, pH7.4 rinse, and inverts small intestinal inner chamber, peels off small intestinal brush Velum, dries, by W: V=1: 9 add ice bath homogenate after PBS, and 4 DEG C centrifugal (4000r/min) take supernatant, and-34 DEG C of freezings are standby. Small intestinal mucosa alpha-glucosidase activity measures: measure extracting solution tissue protein content with Coomassie brilliant blue.Dilution mucous membrane of small intestine Extracting solution, to optium concentration, takes 0.2mL, is separately added into pH6.8 phosphate buffer 0.7mL, after 37 DEG C of water-bath 10min, adds 0.5mol·L-1Sucrose solution 0.1mL, 37 DEG C of water-bath 20min add 0.l mol L-1Na2CO31mL terminates reaction.Measure Portugal Grape sugar concentration, parallel assay 3 is managed, and averages, and calculates alpha-glucosaccharase enzyme activity.
The mensuration of 1.6 antioxidant activity
After being administered 20d, taking blood 3mL, 3500r/min is centrifuged 5min, extracts serum.Employing xanthine oxidase measures SOD activity, uses thiobarbituricacidα-method to measure MDA content, according to SOD, MDA detection kit description step operation.
1.7 data statistic analysis
Use SPSS17.0 software data processing, represent with x ± s.
2, experimental result
2.1 impacts on mice sugar dosis tolerata
After each group mouse stomach glucose, blood glucose starts to raise.Wherein Ro-4-4602. and compound (I) compositions group AUC is minimum, demonstrates the strongest carbohydrate tolerance effect (P < 0.01), next to that Ro-4-4602. group, compound (I) group (P < 0.05).Compositions sugar tolerance is better than single group.The results are shown in Table 1,0min, 30min, 60min and 120min blood glucose value unit For mmol L-1, AUC unit is mmol h L-1。
Table 1 mice sugar dosis tolerata
The mensuration of 2.2 diabetic mice alpha-glucosidase activities
Diabetic mice alpha-glucosidase activity after administration is shown in Table 2.Administration group alpha-glucosidase activity 0.3～ 0.7U·mg-1Between.Compared with model group, Ro-4-4602. and compound (I) compositions group mouse small intestine mucosa glucoside Enzymatic activity is significantly lowered (P < 0.01), and Ro-4-4602. group, compound (I) group mouse small intestine mucosa glucosidase activity also has Substantially lower (P < 0.05).By suppressing this enzymatic activity, reduce the suction of the carbohydrates such as the human body starch to taking in, sucrose Receive.
The mensuration of table 2 diabetic mice alpha-glucosidase activity
Group Alpha-glucosidase activity (U mg-1)
Normal group 0.8
Model group 1.4
Ro-4-4602. group 0.6
Compound (I) group 0.7
Ro-4-4602. and compound (I) compositions group 0.3
The mensuration of 2.3 antioxidant activity
Diabetic mice antioxidant activity is shown in Table 3.Compared with model group, Ro-4-4602. and compound (I) compositions group SOD activity significantly raised (P < 0.01), MDA content is decreased significantly (P < 0.01), and this effect is better than Ro-4-4602. Group or compound (I) group.
Table 3 is on diabetic mice SOD activity and the impact of MDA content
Group SOD(U·mL-1) MDA(nmol·mL-1)
Normal group 98.76±7.23 5.33±1.24
Model group 86.54±6.26 8.42±1.82
Ro-4-4602. group 93.25±6.21 6.21±1.66
Compound (I) group 92.33±4.28 6.39±1.53
Ro-4-4602. and compound (I) compositions group 99.87±6.38 5.04±1.42
Test shows, when Ro-4-4602. and compound (I) are used alone, can significantly improve diabetic mice Sugar dosis tolerata, Inhibiting α-glucosidase activity, improves the anti-oxidative damage ability of diabetic mice simultaneously.Hydrochloric acid benzyl silk When hydrazine and compound (I) synergy, having more preferable pharmacologically active, there is synergism in the two, can be developed into hypoglycemic medicine.
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 (7)

1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a Ro-4-4602., it is characterised in that: include Ro-4-4602., as claimed in claim 1 Compound (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) is by sky Fiber crops dry tuber pulverize, with 80～90% alcohol heat reflux extraction, united extraction liquid, be concentrated into without alcohol taste, use 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；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 6 column volumes of 30% ethanol elution, then with 85% 12 column volumes of ethanol elution, collect 85% eluent, and concentrating under reduced pressure obtains 85% ethanol elution concentrate；In (c) step (b) 85% ethanol elution concentrate purification on normal-phase silica gel separates, and is the dichloromethane of 100:1,50:1,25:1 and 12:1 by volume ratio successively Alkane-methanol elution gradient obtains 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, use volume ratio successively Methylene chloride-methanol gradient elution for 20:1,12:1 and 2:1 obtains 3 components；E in () step (d), component 2 uses octadecane The reverse phase silica gel of base silane bonding separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 88%, collects 13～16 Individual column volume eluent, 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: step (a) is returned by 85% ethanol heat Stream 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 D101 type Macroporous adsorbent resin.
6. the application in preparing hypoglycemic medicine of the compound (I) described in claim 1.
7. the pharmaceutical composition of the Ro-4-4602. described in claim 2 application in preparing hypoglycemic medicine.
CN201610459119.4A 2016-06-23 2016-06-23 Benserazide hydrochloride medicine composition and medical purpose therefore for decreasing blood glucose Pending CN106045835A (en)

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