CN104557944B - A kind of hypoglycemic medicine and preparation method thereof - Google Patents
A kind of hypoglycemic medicine and preparation method thereof Download PDFInfo
- Publication number
- CN104557944B CN104557944B CN201410844655.7A CN201410844655A CN104557944B CN 104557944 B CN104557944 B CN 104557944B CN 201410844655 A CN201410844655 A CN 201410844655A CN 104557944 B CN104557944 B CN 104557944B
- Authority
- CN
- China
- Prior art keywords
- equivalent
- melbine
- hypoglycemic
- hypoglycemic medicine
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a kind of hypoglycemic medicine.Moreover, it relates to using the hypoglycemic medicine as active drug composition, the medicinal mixture of preferably one or more excipient or carrier merges fat pharmaceutical composition for treating diabetes.Moreover, it relates to the preparation method of the hypoglycemic medicine.
Description
Technical field
The present invention relates to hypoglycemic medicine, particularly A-Z-B types derivative, the more particularly hypoglycemic medicine containing amino（A）- the third
Alcohol diacid（Z）- melbine（B）Peptide bond derivative, the derivative and its salt can be used as hypoglycemic agent for treating diabetes；This
Invention further relates to the preparation method of the hypoglycemic medicine.
Background technology
Diabetes are one group of metabolic diseases being characterized with hyperglycaemia.Hyperglycaemia be then due to defect of insulin secretion or
Its biological agent is damaged, or both have concurrently and cause.Long-standing hyperglycaemia during diabetes, cause various tissues, particularly eye,
Kidney, heart, blood vessel, chronic lesion, the dysfunction of nerve.China's adult's diabetes prevalence of more than 20 years old is according to estimates
9.7%, Chinese Adult diabetes are total up to 92,400,000, wherein rural area 43,100,000, city 49,300,000 or so.China may turn into
The most country of diabetes number of patients in the world.
Diabetic neuropathy is one of most common chronic complicating diseases of diabetes, is diabetes that are lethal main with what is disabled
Reason.Diabetic neuropathy is most common with peripheral neuropathy and vegetative nerve lesion, shows as four limbs end slightly numb, scorching hot
Sense or ice-cold shouting pain, severe one are tossed about, are lain awake all night；Vegetative nerve lesion shows as perspiring exception（Lossless, hypohidrosis is more
Sweat）, abdominal distension, constipation or diarrhoea, erect position low blood pressure, tachycardia or too slow, urine retention or the urinary incontinence.Diabetic is except dynamic
Outside arteries and veins hardening, Retinopathy of Hypertension and cataract of old people, diabetic retinopathy is glycosuria with diabetic cataract
It is critically ill the main performance of ball of having eye trouble.The lighter's visual impairment, severe one can cause blindness, and current BDR has turned into
One of four big main blinding diseases.
Because diabetes harm is big, the incidence of disease is wide, therefore in the urgent need to more effective therapeutic modality, in the world Rezulin
The research of thing is always the focus of research, and new medicine is also constantly weeded out the old and bring forth the new.
Hydroxymalonic acid（Structural formula is as follows）It is a kind of chemical substance all contained in the foods such as cucumber, wax gourd.Hydroxymalonic acid
It is fat that can suppress saccharide converted in human body, prevents body fat from piling up, and has functions that coronary heart disease of losing weight and prevent.
Melbine（Structural formula is as follows）It is a kind of biguanide antidiabetic medicament, many large-scale experiments are proved, melbine is only
The hyperglycaemia of diabetic is reduced, influence is had no on physiological blood sugar, exclusive use does not result in hypoglycemia.It can improve pancreas
The sensitiveness of island element, promotes utilization of the peripheral tissues to glucose, and delay glucose therefore has certain drop in the absorption of intestines and stomach
Blood sugar is acted on.Melbine is often shared with other drugs, with synergy.But melbine drug effect is relatively weak, usually
Needs take heavy dose of specification 1g/ days, and to increase curative effect, biguanides is most strong organic base, after the medication of high concentration melbine,
The melbine of high concentration stick to stimulate on gastrointestinal mucosal cause in Nausea and vomiting, anorexia, mouth have Metal peculiar smell,
Diarrhoea etc..
Row spit of fland class medicine be it is a kind of can suppress β Apoptosis with selective, competitive, reversible DPP_4 inhibitor,
Promote β cell neogenesis, increase diabetes B patient's β cell quantities, hence it is evident that reduce patient blood glucose, and sulfa drugs is lost
The patient of effect still has significant blood sugar reducing function.Phosphoric acid Xi Gelieting（Structural formula is as follows）It is first to ratify for treating 2 types sugar
Urinate the DPP-4 inhibitor of disease.
We to compound during structure of modification is carried out, it has unexpectedly been found that compound of the invention（A-Z-B types）Tool
There is obvious blood sugar reducing function, significantly improved than the hypoglycemic effect before transformation, merge fat mouse especially for diabetes, not only
Blood sugar is controlled, body weight is also well controlled, be expected to turn into more preferably medicine.
The content of the invention
It is an object of the invention to provide a kind of high activity, hypotoxicity, can the effectively hypoglycemic medicine of control body weight and its preparation
Method.
In order to realize the above object the compound and its pharmaceutically acceptable salt of a kind of below formula of the invention：
A-Z-B
Wherein, A is the hypoglycemic medicine containing amino, including but not limited to Xi Gelieting, vildagliptin, BMS-477118, A Ge
Row spit of fland, melbine, voglibose, its amino part is connected with Z bases by C-N keys；
Wherein, Z is alkyl, aryl, aralkyl, alkyl-carbonyl, aryl carbonyl, aromatic alkyl carbonyl, carbonylic alkyl carbonyl, alkane
Epoxide, one or more hydrogen in Z can be replaced by amino or hydroxyl；
Wherein, B is melbine or other compounds that can be acted synergistically with A generations, and its amino part passes through C- with Z bases
N keys are connected.
" alkyl " refers to one to the direct-connected or branched saturated hydrocarbon group for specifying number carbon atom.Such as methyl, ethyl, different
Propyl group, n-propyl, normal-butyl, n-pentyl, n-heptyl, dodecyl, octadecyl etc..
" aryl " refers to from aromatic hydrocarbon and removes organic group derived from one or more hydrogen atoms.Preferred aryl is in aromatic hydrocarbons
In have 6-12 carbon atom as ring carbon atom.
" aralkyl " refers to the organic group derived from aryl alkane, and wherein alkyl hydrogen atom is replaced by aryl defined above.
Especially, Z is-carbonyl-methylol-carbonyl-, and structural formula is as follows：
More particularly, Z is-carbonyl-methylol-carbonyl-, and B is melbine structure, and structural formula is as follows：
This law it is bright provide more than one state compound as active drug composition, preferably one or more excipient or carrier
Mixture, the pharmaceutical composition for treating diabetes.
The preparation method of above-mentioned hypoglycemic medicine is：
The hydroxymalonic acid of 1 equivalent and the woodward's reagent K of 1.5 equivalents, plus 20 times of anhydrous acetonitriles of amount are taken, it is cold under stirring
But to 0 DEG C, the triethylamine of 1 equivalent is added, is stirred 1 hour at 0 DEG C.The compound and 1 equivalent of the another part A structure for taking 1 equivalent
Melbine, be dissolved in 20 times amount anhydrous acetonitriles and 5 times amount DMF, add 1 equivalent triethylamine, be well mixed, at 0 DEG C
Under be slowly dropped into above-mentioned reaction solution, be stirred at room temperature after completion of dropping 72 hours, HPLC monitoring reaction, subtract after the completion of reaction
Pressure is evaporated, and adds 5 times of water of amount, stirs 30 minutes, suction filtration, and filter cake is recrystallized with alcohol-water, is obtained final product.
Through NMR spectrum and mass spectral analysis, the product that confirmation synthesizes is the compound of above-mentioned object construction.
A-Z-B compounds of the invention, have following significant advantage compared with simple A+B compounds：
（1）For normal mouse blood sugar almost without influence, it is and more notable for the hypoglycemic effect of diabetic mice,
A+B compositions are substantially better than, effective dose is lower；
（2）Therapeutic effect for fat complication with diabetes mouse becomes apparent from, and not only controls blood sugar, body weight also under
Drop, may be relevant with propionic acid diol structure；
（3）Compound of the invention is single component, is easy to preparation processing and shaping, it is to avoid compound composition is possible to be had
The uneven dose deviations for causing of mixing and the prominent of a certain component for imitating composition release the adverse reaction for causing, and biguanides is tied
After structure transformation, the strong basicity of biguanides is reduced, advantageously reduce the GI irritation of melbine.
Specific embodiment
A kind of hypoglycemic medicine of the invention and preparation method thereof is described in further detail below by way of specific embodiment.
The SI-0220 of embodiment 1（A is Xi Gelieting）
Take hydroxymalonic acid 12.01g（0.1mol）、38.01g（0.15mol）Woodward's reagent K, plus 1L anhydrous acetonitriles, stir
Mix down and be cooled to 0 DEG C, add 13.36g（0.1mol）Triethylamine, stirs 1 hour at 0 DEG C.Separately take Xi Gelieting free alkalis
40.82g（0.1mol）With melbine free alkali 12.95g（0.1mol）, the DMF of 1L anhydrous acetonitriles and 200mL is dissolved in, add
13.36g（0.1mol）Triethylamine, is well mixed, and is slowly dropped at 0 DEG C in above-mentioned reaction solution, after completion of dropping at room temperature
Stirring 72 hours, HPLC monitoring reactions, evaporated under reduced pressure after the completion of reaction adds 200mL water, stirs 30 minutes, suction filtration, and filter cake is used
Alcohol-water（4:1）Recrystallization, obtains final product.
The preparation of free alkali：Xi Gelieting or melbine 100g, plus 500ml water and 1000ml dichloromethane are taken, is stirred
Under be slowly added to the 4M NaOH of 500ml, stir 10 minutes, stratification separates dichloromethane layer, with anhydrous sodium sulfate drying,
Suction filtration, takes filtrate decompression and is evaporated, and obtains final product.
Mass spectrum（+ ESI, m/z）：621.52[M+H]+；1H-NMR (DMSO-d6,600 MHz): δ 8.02 (brs,
1H), 6.79(m, 1H), 6.61 (m, 1H), 5.11(s, 1H), 4.46 (s, 2H), 4.20(m, 1H), 3.99
(t, 2H), 3.68 (m, 2H), 2.89 (m, 1H), 2.64-2.53(m, 2H), 2.47(s, 6H), 2.28 (m,
1H), 2.02(brs, 5H)；13C-NMR (DMSO-d6, 150 MHz): δ 174.7, 173.0, 171.4, 163.7,
163.2, 163.0, 157.9, 148.4, 145.2, 123.9, 118.4, 113.2, 106.4, 85.0, 46.0,
45.6, 43.5, 34.5, 32.5, 31.4, 26.9。
The SI-0221 of embodiment 2（A is vildagliptin）
Replace Xi Gelieting methods similar to Example 1 to prepare using vildagliptin, obtain target compound.Mass spectrum（+
ESI, m/z）：517.58[M+H]+。
The SI-0222 of embodiment 3（A is Egelieting）
Replace Xi Gelieting methods similar to Example 1 to prepare using Egelieting, obtain target compound.Mass spectrum（+
ESI, m/z）：686.74[M+H]+。
The SI-0223 of embodiment 4（A is melbine）
Replace Xi Gelieting methods similar to Example 1 to prepare using melbine, obtain target compound.Mass spectrum（+
ESI, m/z）：343.31[M+H]+。
The SI-0224 of embodiment 5（A is voglibose）
Replace Xi Gelieting methods similar to Example 1 to prepare using voglibose, obtain target compound.Mass spectrum（+
ESI, m/z）：481.47[M+H]+。
The validity and security of the compound provided the present invention below by test example make further comparative descriptions.
Test example 1
Influence to normal mouse blood sugar
Normal mouse is taken, water 12h is can't help in fasting, is grouped at random after surveying fasting blood sugar, every group 10, it is respectively normal right
According to group（Give 0.9% physiological saline）, positive controls（Give the glibenclamide of 50mg/kg）And administration group（Give 50mg/kg
SI-022 series compounds）, successive administration 10 days, once a day.The blood of each group mouse is determined after last dose with blood glucose meter
Sugar, observes the change of mouse fasting blood sugar（Mouse fasting 12h, free water before determining every time）.The results are shown in Table 1.
Influence of each compound of table 1 to normal mouse blood sugar
Result shows that each compound of the invention has little to no effect for the blood sugar of normal mouse, and glibenclamide substantially drops
Low blood sugar, its mechanism of action is unclear.Speculate that this product may be glucose dependency mechanism of action, only increase in hyperglycaemia
Plus insulin releasing, it is different from sulfonylureas mechanism of action, even if sulfonylureas is when glucose level is relatively low,
Increase insulin secretion, so as to cause hypoglycemia in diabetic and normal subjects's human body.
Test example 2
Blood sugar influence and weight loss effect to taking in the diabetic model rats of high lipid food
Mouse 100 is taken, is divided into 2 groups, blank group 20, getting fat group 80, blank group gives normal diet, and getting fat group is given
Give high lipid food（Normal diet 60%, lard 10%, glucose 5%, milk powder 5%, peanut 7%, yolk powder 10%, cod-liver oil 1%, salt
2%）, continuous 5 weeks, normal water.Water 16h then is can't help into mouse fasting after getting fat, the oxygen of tail vein injection four after fasting blood-glucose is surveyed
Pyrimidine 90mg/kg, the 7th day after injection, fasting 12h, free water, tail vein takes blood, and fasting blood-glucose is surveyed with blood glucose meter, selects blood
Sugar mouse of the value higher than 11.0mmol/L is diabetic mice.Naive mice gives 0.9% physiological saline.By diabetic mice
Random packet, respectively every group 10, model control group（Give 0.9% physiological saline）And administration group, successive administration 28 days,
Before administration, body weight is determined after last dose, investigate changes of weight, and determine the blood of each group mouse with blood glucose meter after last dose
Sugar, observes the change of mouse fasting blood sugar（Mouse fasting 12h, free water before determining every time）.The results are shown in Table 2, table 3.
The influence to Mouse Weight of each compound of table 2（g）（X±SD）
The influence to blood sugar of each compound of table 3（mmol/L）（X±SD）
Result shows, gives the weight loss of A-Z-B compounds apparently higher than A+B compounds, merges fat for diabetes
The body weight control effect of mouse is considerably better, and blood sugar reduction effect of the A-Z-B compounds to diabetic mice becomes apparent from,
This may be relevant with the unique texture of hydroxymalonic acid-biguanides.
The present invention can be made into various preparations, such as preparation example 1~4：
Preparation example 1
Hard capsule
10mg A-Z-B compounds, 80mg lactose, 70mg microcrystalline celluloses and 1mg magnesium stearates are taken, is mixed, by 60 mesh
After sieve, these powder No. 3 gelatine capsules of loading are made capsule.
Preparation example 2
Tablet
10mg A-Z-B compounds, 75mg lactose, 24mg microcrystalline celluloses and 1mg magnesium stearates are taken, by tablet press machine pressure
Piece, is made 1 tablet of tablet of 110mg.
The tablet can be coated as needed.
Preparation example 3
Solution
10mg A-Z-B compounds, sucrose 12mg, Sodium Benzoate 0.2mg are taken, water for injection 10ml is added, 0.1N hydrochloric acid is used
Regulation pH to about 6, through 0.22 μm of membrane filtration, loads vial, and 121 DEG C of autoclaving 10min are obtained final product.
Preparation example 4
Parenteral solution
10mg A-Z-B compounds are taken, physiological saline 100ml is added, with 0.1N salt acid for adjusting pH to about 6, through 0.22 μm of filter
Membrane filtration, loads vial, and 121 DEG C of autoclaving 15min are obtained final product.
The present invention is illustrated by specific embodiment above, it will be apparent that in the feelings without departing substantially from the disclosed invention theory
Under condition, can be using the method for various changes, change and accommodation.Therefore, all of such change, change and alternative are all wrapped
It is contained in the spirit and scope of appended claims.
Claims (3)
1. a kind of hypoglycemic medicine and its pharmaceutically acceptable salt, its structural formula of compound is：
Wherein, A is the hypoglycemic medicine containing amino, be Xi Gelieting, vildagliptin, BMS-477118, Egelieting, melbine,
One kind in voglibose, its amino part is connected with carbonyl by C-N keys；Wherein, B is melbine, its amino part
It is connected by C-N keys with carbonyl.
2. a kind of pharmaceutical composition comprising hypoglycemic medicine described in claim 1, it is characterized in that：With hypoglycemic described in claim 1
Medicine as active drug composition, the mixture of preferably one or more excipient or carrier, be made for treating diabetes
Pharmaceutical composition.
3. the preparation method of hypoglycemic medicine described in a kind of claim 1, it is characterized in that：Take the hydroxymalonic acid and 1.5 equivalents of 1 equivalent
2- ethyl -5- phenyl isoxazole -3'- sulfonate（Woodward's reagent K）, plus 20 times of amounts（Envelope-bulk to weight ratio, relative to propyl alcohol
The weight summation of diacid and woodward's reagent K）Anhydrous acetonitrile, be cooled to 0 DEG C under stirring, add the triethylamine of 1 equivalent,
0 DEG C is stirred 1 hour；The compound and the melbine of 1 equivalent of the another part A structure for taking 1 equivalent, are dissolved in 20 times of anhydrous second of amount
Nitrile and 5 times of DMF of amount, add the triethylamine of 1 equivalent, are well mixed, and are slowly dropped at 0 DEG C in above-mentioned reaction solution, drip
It is stirred at room temperature 72 hours after finishing, HPLC monitoring reactions, evaporated under reduced pressure after the completion of reaction adds 5 times of water of amount, stirs 30 points
Clock, suction filtration, filter cake is recrystallized with alcohol-water, is obtained final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410844655.7A CN104557944B (en) | 2014-12-31 | 2014-12-31 | A kind of hypoglycemic medicine and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410844655.7A CN104557944B (en) | 2014-12-31 | 2014-12-31 | A kind of hypoglycemic medicine and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104557944A CN104557944A (en) | 2015-04-29 |
| CN104557944B true CN104557944B (en) | 2017-05-31 |
Family
ID=53075107
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410844655.7A Active CN104557944B (en) | 2014-12-31 | 2014-12-31 | A kind of hypoglycemic medicine and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104557944B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543141A (en) * | 2015-09-21 | 2017-03-29 | 成都苑东生物制药股份有限公司 | Uracil derivative |
| WO2017088812A1 (en) * | 2015-11-26 | 2017-06-01 | 苏州晶云药物科技有限公司 | Composition and eutectic of saxagliptin and metformin, and preparation method and use thereof |
| CN113354561B (en) * | 2021-04-17 | 2023-03-28 | 中山大学 | Biguanide derivatives and their use and formulations |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101234105A (en) * | 2008-01-09 | 2008-08-06 | 北京润德康医药技术有限公司 | Pharmaceutical composition containing diabetosan and vildagliptin and preparation thereof |
| WO2008141021A1 (en) * | 2007-05-08 | 2008-11-20 | Concert Pharmaceuticals, Inc. | Deuterated derivatives of tetrahydrotriazolopyrazine compounds and their use as dpp-iv inhibitors |
| CN101897697A (en) * | 2009-05-27 | 2010-12-01 | 北京奥萨医药研究中心有限公司 | Sugar-lowering drug composition and application |
| US20120108598A1 (en) * | 2009-05-11 | 2012-05-03 | Mylan India Private Limited | Sitagliptin synthesis |
| CN102702300A (en) * | 2011-06-10 | 2012-10-03 | 四川大学华西医院 | Compound for preventing or treating autoimmune diabetes and preparation method and application thereof |
-
2014
- 2014-12-31 CN CN201410844655.7A patent/CN104557944B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008141021A1 (en) * | 2007-05-08 | 2008-11-20 | Concert Pharmaceuticals, Inc. | Deuterated derivatives of tetrahydrotriazolopyrazine compounds and their use as dpp-iv inhibitors |
| CN101234105A (en) * | 2008-01-09 | 2008-08-06 | 北京润德康医药技术有限公司 | Pharmaceutical composition containing diabetosan and vildagliptin and preparation thereof |
| US20120108598A1 (en) * | 2009-05-11 | 2012-05-03 | Mylan India Private Limited | Sitagliptin synthesis |
| CN101897697A (en) * | 2009-05-27 | 2010-12-01 | 北京奥萨医药研究中心有限公司 | Sugar-lowering drug composition and application |
| CN102702300A (en) * | 2011-06-10 | 2012-10-03 | 四川大学华西医院 | Compound for preventing or treating autoimmune diabetes and preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| 3-溴代香豆素二甲双胍类化合物的合成;祁刚，等;《盐城工学院学报(自然科学版)》;20060331;第19卷(第1期);第8页摘要、图，第9页第2.1-2.8段实验方法部分 * |
| 5-羟甲基-2-呋喃甲醛衍生物的合成及降血糖活性评价;张欣，等;《中国药物化学杂志》;20121031;第22卷(第5期);第349-355页 * |
| 二氢三嗪类化合物的合成与降糖活性;李志燕，等;《化学试剂》;20130228;第35卷(第2期);第114-116页 * |
| 拼合原理在降血糖新药研发中的应用设想;王忠雷，等;《中国实验方剂学杂志》;20130228;第19卷(第4期);第351-354页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104557944A (en) | 2015-04-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109381471A (en) | Combination product comprising limonoid and biguanide compound | |
| CN104557944B (en) | A kind of hypoglycemic medicine and preparation method thereof | |
| CN101880286B (en) | Water-soluble amino-acid ester derivative of ginkgolide B | |
| CN103402506A (en) | Combination for treatment of diabetes mellitus | |
| DK2992888T3 (en) | APPLICATION OF PENTACYCLIC TRITERPENOID SAPONE COMPOUND FROM SZECHUAN MELANDIUM ROOD TO PREPARATION OF HYPOGLYCEMIC MEDICINE | |
| CN106866652B (en) | Jamaicin 12- bit derivant with insulin-sensitizing activity and preparation method thereof | |
| CN110314233B (en) | Combination product comprising a limonoid and a DPP-4 inhibitor | |
| CN105646512A (en) | Preparation and medical application of glinides berberine coupling compound | |
| CN101347511B (en) | Medicament composition with function for reducing blood sugar | |
| CN116139127B (en) | Application of amide compound in preparation of medicament for preventing or treating metabolic syndrome | |
| CN101032534A (en) | Method of preparing jiubiying total saponins and the application thereof | |
| CN116115598B (en) | Application of isoflavone alcohol compound in preparation of medicament for preventing or treating metabolic syndrome | |
| CN108863943A (en) | Deuterated benznidazole | |
| CN103304504B (en) | Anti-diabetic compound, as well as preparation method and application thereof | |
| CN101735218A (en) | Piperidine carbamic acid ester derivative and application thereof | |
| US20240041964A1 (en) | Method for preparing gynostemma pentaphyllum leaf extract and gynostemma pentaphyllum leaf extract prepared thereby | |
| CN108101788A (en) | Composition and its application containing salvianolic acid salt | |
| WO2015134357A1 (en) | Modulators of insulin receptor | |
| CN115947731A (en) | Fused heterocyclic compound and application of amylase inhibitor thereof | |
| CN116098904A (en) | Application of acyl piperazine compound in preparation of medicament for preventing or treating metabolic syndrome | |
| CN101036637A (en) | Application of salvia miltiorrhiza bge I sodium sulfonate in the preparation of medicine and its medicine made by the same | |
| NO159588B (en) | ANALOGY PROCEDURES FOR THE PREPARATION OF THERAPEUTIC ACTIVE 5-OXO-2-PYRROLIDINE PROPANIC ACID DERIVATIVES. | |
| CN1267126C (en) | Chinese medicine for treating coronary heart disease and angina pectoris | |
| CN105777846A (en) | Preparation method and medical application of OA (oleanolic acid) and BBR (berberine) conjugate | |
| CN104997780B (en) | A kind of Rosuvastatin calcium composition and its application in reducing blood lipid hypoglycemic medicament is prepared |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220505 Address after: 230051 Room 802, building C, QingWang Science Park, No. 88, Lanzhou Road, Baohe Economic Development Zone, Hefei, Anhui Province Patentee after: Hefei little hedgehog Information Technology Co.,Ltd. Address before: 100094 No. a-2206, 2f, building a 19, nanmoliyuan, wangdezheng Road, northwest, Haidian District, Beijing Patentee before: BEIJING RUIDU PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220712 Address after: 266000 room a501-13, No. 5, Jiading Road, Shibei District, Qingdao, Shandong Patentee after: Qingdao Jiayuan Huimei Biotechnology Co.,Ltd. Address before: 230051 Room 802, building C, QingWang Science Park, No. 88, Lanzhou Road, Baohe Economic Development Zone, Hefei, Anhui Province Patentee before: Hefei little hedgehog Information Technology Co.,Ltd. |