CN1583717A - Biguanide derivative and preparing method thereof - Google Patents
Biguanide derivative and preparing method thereof Download PDFInfo
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- CN1583717A CN1583717A CN 03134126 CN03134126A CN1583717A CN 1583717 A CN1583717 A CN 1583717A CN 03134126 CN03134126 CN 03134126 CN 03134126 A CN03134126 A CN 03134126A CN 1583717 A CN1583717 A CN 1583717A
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- biguanide
- biguanides
- derivative
- amino acid
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This patent concerns a novel method to produce the ramification of biguanide. The ramification is low toxicity and can decrease the concentration of blood sugar. The method use biguanide and inartificial or synthetical amino acid/sulfamic acid. The detal chemical structure is shown in the fig. Dissociative biguanide and amino acid-sulfamic acid is used as raw and processed materials, and reacted in organic acid generate ramification of biguanide. This novel ramification adapt to diabetes 2 treatment.
Description
Technical field:
The present invention relates to the ofhypoglycemic medicine technical field, exactly it is a kind of biguanides derivative and preparation method thereof.
Background technology:
Diabetes are common disease and frequently-occurring diseases of serious threat people ' s health, and China has patient more than 3,000 ten thousand now, and also will increase newly millions of every year.This sick sickness rate has the trend that rises year by year according to statistics.Therefore, the medicine of developing and develop new treatment diabetes is one of emphasis of current the world of medicine research and development.
Diabetes are broadly divided into two types: type i diabetes---be the insulin-dependent disease; Because it is hypoinsulinism causes, must supplementation with insulin normal to keep blood sugar.Type ii diabetes---be the non-insulin-dependent disease; Patient's insulin secretion level is not low, because intravital insulin resistant effect causes the susceptibility of Regular Insulin to descend, can not normally combine the effect of performance blood sugar regulation with acceptor.The latter accounts for more than 85% of patient's sum, must rely on non-insulin class hypoglycemic drug.Biguanides antidiabetic drug such as N1,N1-Dimethylbiguanide, phenformin etc. are choice drugs commonly used clinically.But this class medicine is toxic to organs such as liver, kidneys, has limited its range of application.The patient who suffers from the hepatic and renal function disease simultaneously should not take, and other patients take also restricted for a long time.Such drug price is welcome by the patient cheaply deeply, reduces its toxic side effect to satisfy the demand that the patient takes for a long time, is the task of top priority.China Patent No.: 97103536 disclose the patent of invention that a kind of name is called " a kind of medicine for the treatment of diabetes and preparation method thereof ", and it is a kind of Chinese medicine compound prescription, wherein contains N1,N1-Dimethylbiguanide.China Patent No.: 98806224 disclose the patent of invention that a kind of name is called " with thiazolidinedione and N1,N1-Dimethylbiguanide treatment diabetes ", and it relates to the pharmaceutical composition that comprises insulin sensitizer and biguanides antihyperglycemic agents.China Patent No.: 99801362 disclose the patent of invention that a kind of name is called " solid oral dosage form that contains N1,N1-Dimethylbiguanide and Glyburide ", it has improved the bioavailability of Glyburide, the Glyburide bioavailability that is equivalent to separately to take N1,N1-Dimethylbiguanide and Glyburide and is obtained.China Patent No.: 99802904 disclose the patent of invention that a kind of name is called " containing the pharmaceutical composition and the application in preparation reduction hyperglycemia medicine thereof of N1,N1-Dimethylbiguanide and Bei Te associating ", and it also is the form of therapy non-insulin-dependent diabetes mellitus (NIDDM) with a kind of pharmacologically acceptable salt.
Summary of the invention:
The amino acid (or thionamic acid) that the present invention will have a cytoprotection combines with biguanide antidiabetic medicament, and hope can obtain that toxicity is low, hypoglycemic effect good and have the new drug of protection β-islet cells.Under this thought guidance, designed, synthesized a series of biguanide compounds and combined double salt or the acid amides (or sulphonamide) that forms with natural or synthetic amino acid (or thionamic acid).And proved that by pharmacological evaluation their blood sugar reducing function is better than Metformin, and the β-islet cells to damage has certain repair simultaneously, and acute toxicity is lower than Metformin.Realized original design philosophy.
The structural formula of described compound is shown in (1) and (2):
R
1＝H，CH
3，PhCH
2CH
2，......
R
2＝H，CH
3
R
3＝Gly.，Ala.，Phe.，Glu.，CysH.，Met.，Taurine，......
R
4＝H，CH
3，PhCH
2CH
2，......
R
5＝H，CH
3
R
6＝Glycyl，Alanyl，Phenylalanyl，Glutaminyl，Methionyl，Cysteinyl，Tauryl，......
Structural formula synthesizes route as the compound of (1):
Free biguanide compound+amino acid or thionamic acid → double salt
This reaction can be carried out also can carrying out in the aqueous solution in organic solvent.
Structural formula synthesizes route as the compound of (2):
Acyl chlorides → the acid amides of free biguanide compound+amino acid or thionamic acid or sulphonamide
Advantage of the present invention is: toxicity of the present invention is low, and hypoglycemic effect is good.Its blood sugar reducing function is better than the blood sugar reducing function of N1,N1-Dimethylbiguanide, and the β-islet cells to damage has certain repair simultaneously, and acute toxicity is lower than Metformin.Be a kind of treatment type ii diabetes---the good medicine of non-insulin-dependent disease.
Embodiment:
Embodiment: composite part
Synthetic (a method) of N1,N1-Dimethylbiguanide taurate (I): free N1,N1-Dimethylbiguanide 12.9g (0.1Mol) is dissolved in the 100ml water; add heated and stirred dissolving (temperature is controlled at 40-50 ℃) in water-bath in the 250ml three-necked bottle that induction stirring is housed; add 12.5g (0.1Mol) taurine simultaneously; after treating the solution clarification, filtration, concentrated, static, cool overnight.Leach colourless needle crystal, dry, weigh.Get 16.5g (I) yield about 90%.mp：206-208℃。H
1NMR：(δppm)2.96(6H?2CH
3)，3.15-3.19(2HCH
2)，3.32-3.36(2H?CH
2)
Synthetic (the b method) of compound (I): N1,N1-Dimethylbiguanide and the taurine with 0.1Mol is dissolved in the 50ml ethanol respectively, after the mixing, and backflow 0.5h.Static, cool off, spend the night.Suction filtration gets white solid 16.5g yield about 90%.mp：206-208℃。
Utilization can make taurate and other amino acid whose salt of phenformin with quadrat method.
The pharmacological evaluation part
Compound (I) is to the LD of mouse stomach administration
50Be 4627 ± 604mg/kg (fiducial limit is 95%); LD to the mouse vein administration
50Be 392.13 ± 51.25mg/kg (fiducial limit is 95%).
Utilize that diabetes rat model carries out the hypoglycemic pharmacological evaluation due to the tetraoxypyrimidine.Compound (I) administration component is basic, normal, high three dosage groups; Control drug is a Metformin.The hypoglycemic experimental result is as shown in table 1.
Table 1 compound (I) is to the influence of blood glucose in diabetic rats due to the tetraoxypyrimidine
| Group dosage tetraoxypyrimidine number of animals blood-sugar content (mg/kg) is (mol/dl x ± s) (mg/kg) before (only) administration after the administration |
| (I) group 100 200 6 22.48 ± 0.35 10.33 ± 0.30 in the low group 30 200 6 22.62 ± 0.30 15.79 ± 0.39 (I) **(I) high group 300 200 6 23.23 ± 0.64 7.46 ± 0.45 **N1,N1-Dimethylbiguanide group 100 200 6 23.87 ± 0.23 13.44 ± 0.37 model group 200 6 22.40 ± 0.17 21.50 ± 0.58 normal group 6 3.86 ± 0.11 4.04 ± 0.37 |
*P＜0.01 (comparing) with model group
Compound (I) shows histopathology research (by the observing pathological section) result of diabetes rat β-islet cells due to the tetraoxypyrimidine: it has certain repair to the β-islet cells damage due to the tetraoxypyrimidine.
Claims (4)
1, biguanides derivative is characterized in that: its adopts biguanide compound and natural or synthetic amino acid/thionamic acid, and the composite structure formula is as (I) with the compound (II),
R
1＝H，CH
3，PhCH
2CH
2，......
R
2＝H，CH
3
R
3＝Gly.，Ala.，Phe.，Glu.，CysH.，Met.，Taurine，......
R
4＝H，CH
3，PhCH
2CH
2，......
R
5＝H，CH
3
R
6＝Glycyl，Alanyl，Phenylalanyl，Glutaminyl，Methionyl，Cysteinyl，Tauryl。
2, biguanides derivative according to claim 1 is characterized in that: biguanide compound is biguanide compounds such as N1,N1-Dimethylbiguanide or phenformin.
3, a kind of preparation method of biguanides derivative as claimed in claim 1 is characterized in that: with free biguanide compound and amino acid thionamic acid carries out in organic solvent or the aqueous solution in react and produce the biguanides derivative.
4, a kind of preparation method of biguanides derivative as claimed in claim 1 is characterized in that: the acyl chloride reaction of free biguanide compound and amino acid or thionamic acid is produced the biguanides derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031341268A CN100486960C (en) | 2003-08-20 | 2003-08-20 | Biguanide derivative and preparing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031341268A CN100486960C (en) | 2003-08-20 | 2003-08-20 | Biguanide derivative and preparing method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1583717A true CN1583717A (en) | 2005-02-23 |
| CN100486960C CN100486960C (en) | 2009-05-13 |
Family
ID=34597129
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031341268A Expired - Fee Related CN100486960C (en) | 2003-08-20 | 2003-08-20 | Biguanide derivative and preparing method thereof |
Country Status (1)
| Country | Link |
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| CN (1) | CN100486960C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014053962A2 (en) * | 2012-10-02 | 2014-04-10 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
| CN106278956A (en) * | 2016-08-04 | 2017-01-04 | 山西大学 | A kind of sulphation metformin closes Cr (III) acid potassium complexes and preparation method thereof |
-
2003
- 2003-08-20 CN CNB031341268A patent/CN100486960C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014053962A2 (en) * | 2012-10-02 | 2014-04-10 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
| WO2014053962A3 (en) * | 2012-10-02 | 2014-07-10 | Mahesh Kandula | Compositions and methods for treatment of diabetes and pre-diabetes |
| CN106278956A (en) * | 2016-08-04 | 2017-01-04 | 山西大学 | A kind of sulphation metformin closes Cr (III) acid potassium complexes and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100486960C (en) | 2009-05-13 |
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Granted publication date: 20090513 |
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