CN106188077A - The Preparation method and use of 9 substituted double-functional group berberinc derivates - Google Patents
The Preparation method and use of 9 substituted double-functional group berberinc derivates Download PDFInfo
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- CN106188077A CN106188077A CN201610519467.6A CN201610519467A CN106188077A CN 106188077 A CN106188077 A CN 106188077A CN 201610519467 A CN201610519467 A CN 201610519467A CN 106188077 A CN106188077 A CN 106188077A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention provides the preparation method of a kind of 9 substituted double-functional group berberinc derivates, belong to the field of chemical synthesis, found by the experiment of pharmacology's aspect, this analog derivative has the pharmaceutically active of various value, particularly its performance easily absorbed is not available for simple function group medicine, and specifically this analog derivative demonstrates excellent regulation type 2 diabetes mellitus rat blood sugar effect in zoopery.Its Main Function is embodied in can improve oral glucose tolerance, promote insulin secretion, improve insulin resistant etc..
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to 9-position substituted double-functional group berberinc derivate in system
Application in the product of standby prevention or treatment diabetes and hyperlipidemia and relevant disease or symptom.
Background technology
At present, China's diabetics increases increasingly, in city, small towns and rich rural population, and the sugar of more than 20 years old
Urine patient has reached 11%, separately has people's impaired glucose regulation of 15%, and sum of the two accounts for the 1/4 of above-mentioned population.2006-2007
Year, only repaglinide is 4.5 hundred million dollars in the sales volume in the whole world, it can be seen that, research and development hypoglycemic drug has great society
Benefit and market prospect.Arrange the non-sulfonylurea Drugs Promoting Insulin Secretion (Non-how class hypoglycemic medicine is a class synthetic
Sulfonylureas, NSUR), the complication of the development and minimizing diabetes that delay diabetes there is is positive meaning.Wherein,
Repaglinide, as typically arranging how class medicine, is to drop one of hypoglycemic choice drug, to type 2 diabetes mellitus and metabolism syndrome
Treatment also have preferably effect, good market prospects.
Berberine BBR (Berberine, BBR) is the main active of Rhizoma Coptidis, and in Rhizoma Coptidis, BBR content is the highest, accounts for 5.2-
7.69%.Rhizoma Coptidis bitter in the mouth, has heat clearing away, removing toxic substances, pathogenic fire purging and controls effect of diabetes.Thought more in the past and be difficult to absorb after being administered orally,
Intestinal infection that dysentery bacterium, escherichia coli, staphylococcus aureus are caused, eye conjunctivitis, suppurative otitis media etc. effectively,
Clinic is mainly used in the treatment of intestinal infection.Along with going deep into of research, find that it has arrhythmia, diastole the most successively
The pharmacological actions such as blood vessel, protection cardiac muscle, antiplatelet aggregation, blood sugar lowering, blood fat reducing, antiinflammatory, antiviral, antitumor.Animal is real
Test research it was also found that berberine can reduce normal mouse, alloxan diabetes mice and Spontaneous Diabetic KK mice
Blood glucose, effect is relatively strong, the persistent period is the longest, has the feature of sulfonylureas and biguanide compound concurrently；Fruitlet alkali can change simultaneously
The glucose tolerance of kind KK mice.Reducing blood glucose study mechanism to show, berberine can suppress gluconeogenesis and promote glycogen degradation,
And strengthen secretion and the sensitivity of insulin, thus improve insulin and play hypoglycemic activity.Clinical research in recent years also demonstrates that,
Berberine has treatment diabetes effect, is particularly suited for the treatment of type 2 diabetes mellitus.
Water solublity yet with repaglinide is poor, and oral administration biaavailability is low, limits giving full play to of its drug effect.
And berberine hydrochloride water solublity is the least, fat-soluble less, gastrointestinal absorption is bad, causes its oral administration biaavailability low, impact
Its whole body therapeutic effect.Although arranging how class medicine, berberine has many similar pharmacologically actives, but all because of biological profit
The low use limited to a certain extent clinically of expenditure, therefore finds a kind of raising and arranges how class medicine and the biology of berberine
Availability also plays both synergistic method and will have very important meaning clinically.
Summary of the invention
The present invention provides the preparation method of a kind of 9-position substituted double-functional group berberinc derivate, belongs to chemosynthesis neck
Territory, is found by the experiment of pharmacology's aspect, and this analog derivative has the pharmaceutically active of various value, and particularly it easily absorbs
Performance is not available for simple function group medicine, and specifically this analog derivative demonstrates excellent regulation 2 type sugar in zoopery
The sick rat blood sugar effect of urine.Its Main Function is embodied in can improve oral glucose tolerance, promote insulin secretion, improve pancreas
Insulin resistance etc..The present invention provides the derivant of formula (I), and structure is as follows:
It is characterized in that, in formula (I), wherein m, n are the integer of 1-10；
X is the one in C, O, S, NH, C=O, COO, C=ONH；Z is F-、Cl-、Br-、I-Or physiology can accept into salt
Other anion；R is
In one
Kind.
The preparation method of described formula (I) compound, comprises the following steps:
(1) berberine hydrochloride is taken off 9 methyl and prepare berberrubine；
(2) to the berberrubine of step (1) gained withEtherificate prepares compound
(3) to the berberrubine etherate of step (2) gained withCondensation preparation formula (I) compound.Described step
Suddenly in (2) structural formula, m, n are the integer of 1-10, and X is the one in C, O, S, NH, C=O, COO, C=ONH, Y is F, Cl, Br,
I, Z are F-、Cl-、Br-、I-Or physiology can accept into other anion of salt.
In described step (3) structural formula, R is
In one
Kind.
Described formula (I) compound is made clinically may be used through common process or the pharmaceutically acceptable excipient of indirect addition
Accept dosage form, including injection, oral agents, preferred oral preparation.
Described formula (I) compound is made clinically may be used through common process or the pharmaceutically acceptable excipient of indirect addition
Accept dosage form, be used for clinically treating type 2 diabetes mellitus, regulation blood glucose and blood fat.
Specific embodiment
By following example to better illustrate the present invention.But the present invention is not limited by following embodiment.
Embodiment 1
A) synthesis of berberrubine
Adding berberine 7.4g in 250mL circle flask is 20-30mmHg in vacuum, heats under the conditions of 190-200 DEG C
About 30min, the most dimmed redness of yellow solid, vacuum desiccator is cooled to room temperature, silica gel column chromatography purification, obtains dark red toner
End 4.7g, yield 75%.
B) synthesis of 9-O-3-hydroxy-ethyl berberine hydrobromate
In 25mL round-bottomed flask, add berberrubine 3.2g (10mmol), add 30mLDMF and dissolve, 70 DEG C of heating, add
Entering ethylene bromohyrin 4.4g (20mmol), TLC follows the tracks of reaction, adds 100mL absolute ether, separates out solid, filter after reaction completely,
Silica gel column chromatography purification, obtains 9-O-3-hydroxy-ethyl berberine hydrobromate 3.3g, yield 76%
C) synthesis of repaglinide-9-O-acetas berberine
453mg (1mmol) repaglinide, dichloromethane 20ml, 178mg (1.1mmol) is added in 25mL round-bottomed flask
CDI, stir 10min, add 9-O-3-hydroxy-ethyl berberine hydrobromate 446mg (1mmol), be stirred at room temperature, TLC with
Track reacts, and adds 20ml water, stirring, extraction, organic facies, is dried, filter after reaction completely, and concentrating under reduced pressure, silica gel column chromatography is pure
Change, obtain repaglinide-9-O-acetas berberine 685mg, yield 87%.ESI-MS(M+H)+m/z calcd C47H52N3O8S+
for 787.37found787.37。
Embodiment 2
A) synthesis of berberrubine
A) identical with embodiment 1
B) synthesis of 9-O-3-hydroxy-ethyl berberine hydrobromate
B) identical with embodiment 1
C) synthesis of Nateglinide-9-O-acetas berberine
436mg (1mmol) Nateglinide, dichloromethane 20ml, 178mg (1.1mmol) is added in 25mL round-bottomed flask
CDI, stir 10min, add 9-O-3-hydroxy-ethyl berberine hydrobromate 446mg (1mmol), be stirred at room temperature, TLC with
Track reacts, and adds 20ml water, stirring, extraction, organic facies, is dried, filter after reaction completely, and concentrating under reduced pressure, silica gel column chromatography is pure
Change, obtain Nateglinide-9-O-acetas berberine 672mg, yield 88%.ESI-MS(M+H)+m/z calcd C39H41N2O7 +
for 650.29found650.30。
Embodiment 3
A) synthesis of berberrubine
A) identical with embodiment 1
B) synthesis of 9-O-3-hydroxy-ethyl berberine hydrobromate
B) identical with embodiment 1
C) synthesis of Mitiglinide-9-O-acetas berberine
317mg (1mmol) Mitiglinide, dichloromethane 20ml, 178mg (1.1mmol) is added in 25mL round-bottomed flask
CDI, stir 10min, add 9-O-3-hydroxy-ethyl berberine hydrobromate 446mg (1mmol), be stirred at room temperature, TLC with
Track reacts, and adds 20ml water, stirring, extraction, organic facies, is dried, filter after reaction completely, and concentrating under reduced pressure, silica gel column chromatography is pure
Change, obtain Mitiglinide-9-O-acetas berberine 553mg, yield 85%.ESI-MS(M+H)+m/z calcd C39H43N2O7 +
for651.31found651.31。
The hypoglycemic activity of embodiment 4 9-position substituted double-functional group berberinc derivate
Blood sugar lowering is tested: choose clean level mice 100, after balance is fed 3 days, tail vein injections alloxan；3 days
After, take blood measuring blood glucose.Choosing the mice that blood glucose value is 10-25 μm ol/mL is modeling success mice, then by modeling success
Mice be divided into totally 6 groups (often group 10).Distilled water (normal group) is fed for one group for filling；Two groups is high sugar model (matched group)；Its
His group is administration group, fills and feeds trial drug (100mg/Kg)；Fill continuously after feeding 15 days, measure blood blood sugar content.
Blood sugar lowering experimental result
Experimental result shows, 9-position substituted double-functional group berberinc derivate hypoglycemic effect is substantially better than berberine list
Body.
Claims (6)
1. the present invention provides the derivant of formula (I), and structure is as follows:
It is characterized in that, in formula (I), wherein m, n are the integer of 1-10；X is C, O,
One in S, NH, C=O, COO, C=ONH；Z is F-、Cl-、Br-、I-Or physiology can accept into other anion of salt；R
For
In
A kind of.
2. the preparation method of formula (I) compound described in claim 1, comprises the following steps:
(1) berberine hydrochloride is taken off 9 methyl and prepare berberrubine；
(2) to the berberrubine of step (1) gained withEtherificate prepares compound
(3) to the berberrubine etherate of step (2) gained withCondensation preparation formula (I) compound.
3., in step (2) structural formula described in claim 2, m, n are the integer of 1-10, and X is C, O, S, NH, C=O, COO, C=
One in ONH, Y is F, Cl, Br, I, and Z is F-、Cl-、Br-、I-Or physiology can accept into other anion of salt.
4., in step (3) structural formula described in claim 2, R is
In one
Kind.
5. formula (I) compound described in claim 1 is made through common process or the pharmaceutically acceptable excipient of indirect addition
Can accept dosage form clinically, including injection, oral agents, preferred oral preparation.
6. formula (I) compound described in claim 1 is made through common process or the pharmaceutically acceptable excipient of indirect addition
Can accept dosage form clinically, be used for clinically treating type 2 diabetes mellitus, regulation blood glucose and blood fat.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055413A (en) * | 2015-07-23 | 2015-11-18 | 上海市第六人民医院 | Medicine composition of berberine and repaglinide |
| CN105566353A (en) * | 2016-01-13 | 2016-05-11 | 北京宜生堂医药科技研究有限公司 | Compound and preparation method thereof |
| CN105566317A (en) * | 2016-01-13 | 2016-05-11 | 北京宜生堂医药科技研究有限公司 | Compound and preparation method thereof |
| CN105646512A (en) * | 2016-01-30 | 2016-06-08 | 合肥华方医药科技有限公司 | Preparation and medical application of glinides berberine coupling compound |
-
2016
- 2016-06-30 CN CN201610519467.6A patent/CN106188077A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055413A (en) * | 2015-07-23 | 2015-11-18 | 上海市第六人民医院 | Medicine composition of berberine and repaglinide |
| CN105566353A (en) * | 2016-01-13 | 2016-05-11 | 北京宜生堂医药科技研究有限公司 | Compound and preparation method thereof |
| CN105566317A (en) * | 2016-01-13 | 2016-05-11 | 北京宜生堂医药科技研究有限公司 | Compound and preparation method thereof |
| CN105646512A (en) * | 2016-01-30 | 2016-06-08 | 合肥华方医药科技有限公司 | Preparation and medical application of glinides berberine coupling compound |
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Application publication date: 20161207 |