CN109350617A - Purposes of the compound in the drug of preparation treatment diabetes - Google Patents
Purposes of the compound in the drug of preparation treatment diabetes Download PDFInfo
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- CN109350617A CN109350617A CN201810363848.9A CN201810363848A CN109350617A CN 109350617 A CN109350617 A CN 109350617A CN 201810363848 A CN201810363848 A CN 201810363848A CN 109350617 A CN109350617 A CN 109350617A
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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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- 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
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- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
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- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to purposes of the compound in the drug of preparation treatment diabetes, the compound has having structure:
Description
Technical field
The present invention relates to field of medicaments, and specifically, the present invention relates to compounds in the drug of preparation treatment diabetes
Purposes.
Background technique
Insulin resistance and β cell functional disorders are two big pathological characteristics of diabetes B.For a long time, due to majority
Diabetic has fat and hyperinsulinemia symptom, makes insulin resistance and Related Insulin sensitizer drug once
As the research hotspot in diabetes field, and β cell functional disorders are then ignored.Some researches show that with non-diabetic patients phase
Than, there is impaired glucose tolerance and diabetes do not occur patient in β cell function oneself decreased about 80%；And diabetic
Oneself reduction about 40%~65%, β cell function state of middle β cell quantity is to determine whether impaired glucose tolerance develops as diabetes
Key factor.Moreover, there are also the study found that β cell function state and glycemic control and medication effect are closely related,
The failure of drug therapy with β cell function carry out sexual exhaustion.Therefore, protecting and restoring p cell function becomes prevention and controls
Treat the important channel of diabetes.
Summary of the invention
The purpose of the present invention is to provide purposes of the compound in the drug of preparation treatment diabetes.
In order to achieve the object of the present invention, the present invention provides purposes of the compound in the drug of preparation treatment diabetes,
The compound has having structure:
Preferably, the drug may further include pharmaceutically acceptable carrier, excipient or adjuvant.
Preferably, the dosage form of the drug can be sustained-release dosage type, enteric dosage form and injection type.
After drug of the present invention, the blood sugar reducing function time of single-dose is obviously prolonged, so that medicine frequency is reduced；For a long time
Administration can obviously control the blood glucose fluctuation of type 2 diabetic patient, reduce glycated hemoglobin levels, and improve beta Cell of islet
Function, to enhance the Sugar metabolism ability of patient.Therefore drug of the present invention can be used as the depot drug product for the treatment of diabetes.
Detailed description of the invention
Fig. 1 is that drug long term administration of the present invention acts on the reduction of MSG mouse random blood sugar.
A.d2；B.d5；C.d11；D.d19；A. the P < 0.001 compared with model group；B. the P < 0.01 compared with model group.
Fig. 2 is influence of the drug long term administration of the present invention to MSG Mouse oral glucose tolerance.
The blood glucose curve and AUG of A~B. administration d8 oral glucose load；D29 oral glucose load is administered in C~D.
Blood glucose curve and AUG；A. the P < 0.05 compared with model group；B. the P < 0.01 compared with model group；C. the P < compared with model group
0.001。
Fig. 3 is influence of the drug long term administration of the present invention to MSG lipid of mice level.
D8 blood TG and TC is administered in A~B.；D23 blood TG and TC is administered in C~D.；A. the P < 0.05 compared with model group；B. with mould
Type group compares P < 0.01；C. the P < 0.001 compared with model group.
Specific embodiment
To better understand the essence of the present invention, below with drug in embodiment 1 in obese model In-vivo test in mice
The present invention will be described in detail, but the scope of protection of the present invention is not limited thereto.
The synthesis of the drug of the present invention of experimental example 1
Route:
Step A:1,5- naphthyridines -1,5- dioxide
At room temperature, 85% m-chloro is added portionwise into the methylene chloride (100mL) of 1,5- naphthyridines (5.00g, 0.038mol)
Benzoyl hydroperoxide (16.38g, 0.081mol) adds room temperature reaction overnight.End of reaction is added methylene chloride (100mL), according to
It is secondary dry with saturated sodium bicarbonate solution, water and saturated common salt washing, anhydrous sodium sulfate.Be concentrated under reduced pressure to give product (5.80g,
93%).
1H NMR(400MHz,d6-DMSO)δ7.68-7.71(m,2H),8.29(d,2H),8.73(d,2H)。
The chloro- 1,5- naphthyridines of step B:2,6- bis-
At 0 DEG C, phosphorus oxychloride (80mL) is added dropwise in 1,5- naphthyridines -1,5- dioxide (5.80g, 0.030mol), adds
Complete heating reflux reaction is stayed overnight.End of reaction is concentrated under reduced pressure, and excess pours into ice water, and saturated sodium bicarbonate solution is added, uses second
Acetoacetic ester extracts three times, and combined ethyl acetate phase is washed with saturated sodium chloride solution, and anhydrous sodium sulfate is dry, concentration.Excess warp
Silicagel column carries out chromatogram purification and obtains product (3.20g, 46%).
1H NMR(400MHz,CDCl3)δ7.63(d,2H),8.25(d,2H)。
Step C: bis- (tetrazole is simultaneously) [1,5-a:1', 5'-f] [1,5] naphthyridines
At 0 DEG C, NaN is added portionwise into the DMF (50mL) of chloro- 1, the 5- naphthyridines (3.20g, 0.016mol) of 2,6- bis-3
(4.18g, 0.064mol) adds reaction solution and is slowly heated to 120 DEG C of reactions overnight.End of reaction, it is cooling, it depressurizes dense
Contracting, excess pours into ice water, and saturated sodium bicarbonate solution is added, is extracted with ethyl acetate three times, combined ethyl acetate phase, with full
It is washed with sodium chloride solution, anhydrous sodium sulfate is dry, concentration.Excess through silicagel column carry out chromatogram purification obtain product (1.00g,
29%).
1H NMR(400MHz,CDCl3)δ7.92(d,1H),8.95(d,1H)。
Therapeutic effect of the drug of the present invention of experimental example 2 for diabetes
Modeling
Start within second day that L-sodium (4gkg is subcutaneously injected after the birth of Neonatal Female ICR mouse-1), continuous 7d breaks
Sub-cage rearing after cream.It is aged fat sodium glutamate (MSG) mouse of induced synthesis after 12 months.
Animal packet and administration
12 monthly age obesity MSG mouse decline percentage, fasting blood-glucose, blood TG according to insulin tolerance tests 40min blood glucose
5 indexs such as (blood triglyceride), blood TC (total cholesterol) and weight are randomly divided into 5 groups (every group 10): model control group,
Exenatide positive drug control group (2 μ gkg-1) and embodiment 1 drug low, middle and high dose groups (1,2 and 4mg of the present invention
kg-1).The daily subcutaneous administrations of Exenatide, the daily gastric infusion of drug of the present invention, model control group are given in equal volume
0.9%NaCl solution, continuous 46d.
Influence of the drug of the present invention to fat MSG mouse glycolipid metabolism
Groups of animals is respectively in administration d2, d5, d11 and d19 tail point blood sampling, and (grape is glycoxidative for measurement random blood glucose level
Enzyme process, similarly hereinafter)；Oral glucose tolerance test is carried out in administration d8 and d29.Groups of animals while fasting 4h (free water),
Tail point blood sampling measurement fasting blood-glucose (0min), then glucose load (2gkg is given in stomach-filling-1), respectively at 30,60 and
It takes a blood sample when 120min, measure blood glucose and calculates Area under the curve of blood glucose (AUC)；In administration d8 and d23, fasting blood TG and TC are measured
It is horizontal.
Influence (hyperglycemia clamp experiment) of the drug of the present invention to fat MSG mouse islets β cell function
With yellow Jackets (60~90mgkg before experiment-1Weight) intraperitoneal injection of anesthesia mouse, row jugular vein is inserted later
Pipe, and glucose infusion solution (10% and 20%, give first dosage glucose load (100mgkg-1Weight) so that blood glucose exists
Reach (14.0 ± 0.5mmolL in short time-1It is horizontal.Dynamic (every 5min) monitoring mouse blood sugar variation in experimentation, and
Glucose infusion rate (Rate) is adjusted with this.Blood glucose leaves and takes blood sample when reaching stable state, blood insulin levels, i.e. pancreas when measuring stable state
Island element maximal secretory capacity；The Rate value at 5~6 time points when recording stable state, calculates glucose infusion rate (GIR), GIR=is steady
State is averaged Rate (μ Lmin-1) × concentration of glucose (mg μ L-1)/weight (kg).The size and islet beta cell function of GIR
It is positively correlated.
Data processing
Test data is indicated with x ± s, is examined using t and is carried out statistics comparison, comparison among groups P < 0.05 is considered as difference
It is statistically significant.
Influence result of the drug of the present invention to aged obesity MSG mouse random blood sugar
As shown in Figure 1, compared with model control group, each dosage of drug (1,3 and 9mgkg of the present invention-1) administration d2 and
D5 can significantly reduce the random blood sugar (P < 0.01) of fat MSG mouse, and imitate relationship in a certain amount；In administration d11, originally
Invention drug is in 3 and 9mgkg-1Fat MSG mouse random blood sugar can be made to be substantially reduced (P < 0.01) under dosage；But it is being administered
D19, each dosage of drug of the present invention are showed no the effect of the reduction to blood glucose.Positive control Exenatide (2 μ gkg-1) given for a long time
During medicine, the random blood sugar of fat MSG mouse is had no significant effect, this may be shorter related with its Half-life in vivo.
Influence result of the drug of the present invention to aged obesity MSG mouse fasting blood-glucose and oral glucose tolerance
As shown in Fig. 2, compared with model control group, in administration d8, each dosage group of drug (1,3 and 9mgkg of the present invention-1)
Can significantly reduce 30,60 and 120min blood glucose and AUC after the fasting blood-glucose (0min) of fat MSG mouse, glucose load (P <
0.01)；D29 is being administered, only drug high dose group (9mgkg of the present invention-1) keep fat MSG mouse fasting blood-glucose, glucose negative
Blood glucose and AUC are substantially reduced (P < 0.05) after lotus.Positive control Exenatide can reduce fat MSG in administration d8 and d29
AUC (P < 0.05) after mouse fasting blood-glucose and glucose glucose load.
Influence result of the drug of the present invention to aged obesity MSG lipid of mice level
As shown in figure 3, in administration d8, drug of the present invention is in 1,3 and 9mgkg compared with model control group-1Under dosage,
The blood TG and TC that MSG mouse can be substantially reduced are horizontal (P < 0.05), and dose-effect relationship is significant；But in administration d23, medicine of the present invention
Object 3 and 9mgkg-1It is horizontal to can reduce MSG mouse TG, 9mgkg-1It is horizontal (P < 0.05) that TC can be reduced.Positive control Chinese mugwort
MSG mouse blood TG level (P < 0.05) can be substantially reduced in administration d8 and d23 by filling in that peptide, to blood TC level without obvious shadow
It rings.
Influence result of the drug of the present invention to aged obesity MSG mouse islets β cell function
Hyperglycemia clamp experiment is the golden index of current evaluation islet beta cell function.As can be seen that and model from following table
Group is compared, and drug of the present invention is in 1,3 and 9mgkg-1Under dosage, GIR is made to obviously increase (P < 0.05), secretes insulin maximum
Ability also obviously increases (P < 0.001).Positive control Exenatide can also be such that GIR and insulin maximum secretion capacity obviously increases
(P<0.001)。
| Group | Stable state blood insulin/ngmL-1 | GIR/mg·kg-1·min-1 |
| Model group | 90.1±49.2 | 37.0±7.5 |
| Low dose group | 533.2±16.3b | 56.5±8.7a |
| Middle dose group | 536.9±10.1b | 63.2±18.4a |
| High dose group | 545.8±6.7b | 55.3±8.5a |
| Positive controls | 544.6±4.2b | 79.5±6.6b |
Wherein: with model group ratio, a:P < 0.05, b:P < 0.001.
Claims (3)
1. purposes of the compound in the drug of preparation treatment diabetes, which is characterized in that the compound has having structure:
2. purposes according to claim 1, which is characterized in that the drug may further include pharmaceutically acceptable
Carrier, excipient or adjuvant.
3. purposes according to claim 2, which is characterized in that the dosage form of the drug can be sustained-release dosage type, enteric agents
Type and injection type.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810363848.9A CN109350617A (en) | 2018-04-22 | 2018-04-22 | Purposes of the compound in the drug of preparation treatment diabetes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810363848.9A CN109350617A (en) | 2018-04-22 | 2018-04-22 | Purposes of the compound in the drug of preparation treatment diabetes |
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| Publication Number | Publication Date |
|---|---|
| CN109350617A true CN109350617A (en) | 2019-02-19 |
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ID=65349695
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810363848.9A Pending CN109350617A (en) | 2018-04-22 | 2018-04-22 | Purposes of the compound in the drug of preparation treatment diabetes |
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| Country | Link |
|---|---|
| CN (1) | CN109350617A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103619841A (en) * | 2011-01-11 | 2014-03-05 | 桑诺维恩药品公司 | Heteroaryl compounds and methods of use thereof |
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2018
- 2018-04-22 CN CN201810363848.9A patent/CN109350617A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103619841A (en) * | 2011-01-11 | 2014-03-05 | 桑诺维恩药品公司 | Heteroaryl compounds and methods of use thereof |
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Application publication date: 20190219 |
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