CN101492427A - Pentabromo-thiazole derivative, preparation method and application thereof - Google Patents
Pentabromo-thiazole derivative, preparation method and application thereof Download PDFInfo
- Publication number
- CN101492427A CN101492427A CNA2009100680131A CN200910068013A CN101492427A CN 101492427 A CN101492427 A CN 101492427A CN A2009100680131 A CNA2009100680131 A CN A2009100680131A CN 200910068013 A CN200910068013 A CN 200910068013A CN 101492427 A CN101492427 A CN 101492427A
- Authority
- CN
- China
- Prior art keywords
- compound
- amino
- bromo
- ethanoyl
- methyl
- 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.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of drugs related to the diabetes, in particular to dipeptidyl peptidase-IV inhibitor with a general formula I and having curative effect on the diabetes and containing a 5-bromothiazole structure, a preparation method thereof, a drug combination containing the dipeptidyl peptidase-IV inhibitor and the application of the dipeptidyl peptidase-IV inhibitor to preparing the diabetes drugs, wherein, the group definition is described in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant with diabetes.Particularly, the present invention relates to dipeptidyl peptidase-iv inhibitor to the medicative 5-of the containing bromethiazole of diabetes structure and preparation method thereof, and the pharmaceutical composition that contains them.
Background technology
According to statistics, global diabetic subject in 2007 is nearly about 2.5 hundred million, and wherein exhausted big number is II type (being non-insulin-depending type) diabetic subjects.Antidiabetic medicine in clinical use mainly contains sulfonylurea, N1,N1-Dimethylbiguanide class and trypsin class medicine at present, the medicament of insulin sensitizer and the alpha-glucosidase inhibitor etc. in addition of listing in recent years.These medicines have good therapeutic action, but serious side effects such as ubiquity hypoglycemia, and there is safety issue in long-term treatment, as problems such as liver toxicity and weight increase.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can be effectively and the glucagon-like peptide 1 (GLP-1) of degrading apace, GLP-1 is one of the most effective stimulant of insulin production and secretion, therefore suppress the effect that DPP-IV can strengthen endogenous GLP-1, thereby improve the level (CN200480017355.6) of Regular Insulin in the blood.Medical science has confirmed that the DPP-IV inhibitor is a kind of novel antidiabetic treatment medicine (Deacon C.F. at present, Holst J.J., Dipeptidyl Peptidase IV Inhibitors:A Promising NewTherapeutic Approach for the Management of Type 2 Diabetes.The InternationalJournal of Biochemistry ﹠amp; Cell Biology, 2006,38 (5-6): 831-844).Clinical effectiveness shows that such medicine has good hypoglycemic effect, untoward reaction things such as common weight increase of simultaneously not finding other diabetes medicaments and being produced and hypoglycemia.
The major structural types of existing DPP-IV inhibitor has: divides from the chemical structure type and mainly is divided into piperazine and triazole species, 2-cyano group-pyrrolidines, thiazolidines, Pyrimdinone, and the other types structure medicament.
The invention discloses the 5-bromethiazole class DPP-IV inhibitor that reduces plasma glucose levels very effectively, these compounds lay the foundation for the medicine that further can be used for the treatment of diabetes, particularly non insulin dependent diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of excellent activity that has is provided, have the compound and the pharmacy acceptable salt thereof of general formula I.
Another object of the present invention provides the method that preparation has the compound and the pharmacy acceptable salt thereof of general formula I.
A further object of the present invention provide contain general formula I compound as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment diabetes.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The compound that the present invention has general formula I has following structural formula:
Wherein,
R
1Be selected from H, F, Cl, Br, I, C
1-C
5Alkyl and phenyl,
R
2Be selected from phenyl, by F, Cl, Br, I, C
1-C
5Alkyl, CN and NO
2With the phenyl that single replacement, two replaces or trisubstituted mode replaces, the 2-furyl is by F, Cl, Br, I, C
1-C
5Alkyl with single 2-furyl that replaces or under the situation that space requirement allows, replace in dibasic mode, the 2-thienyl is by F, Cl, Br, I, C
1-C
5Alkyl with single 2-thienyl that replaces or under the situation that space requirement allows, replace in dibasic mode.
Preferred following compound of Formula I or its pharmacy acceptable salt,
Wherein,
R
1Be selected from H, Cl, Br and C
1-C
5Alkyl,
R
2Be selected from phenyl, by F, Cl, Br and C
1-C
3Alkyl, CN and NO
2With the phenyl that single replacement or dibasic mode replace, the 2-furyl is by F, Cl, Br and C
1-C
3Alkyl replace or 2-furyl that dibasic mode replaces with single, the 2-thienyl is by F, Cl, Br and C
1-C
3Alkyl replace or 2-thienyl that dibasic mode replaces with single.
It is as shown in the table that preferred the present invention has the compound of general formula I:
| Code name | The compound title |
| I-1 | The 2-{2-[(benzyl) amino] ethanoyl } amino-5-bromo thiazole |
| I-2 | 4,5-two bromo-2-{2-[(2-benzyl chloride bases) amino] ethanoyl } aminothiazole |
| I-3 | 5-bromo-2-{2-[(2-fluoro-4-methyl-benzyl) amino] ethanoyl } amino-4-methylthiazol |
| I-4 | 5-bromo-2-{2-[(2-cyano group-3-nitro-4-Ethylbenzyl) amino] ethanoyl } amino-4-phenyl thiazole |
| I-5 | 5-bromo-2-{2-[(2-methyl-benzyl) amino] ethanoyl } amino-4-phenyl thiazole |
| I-6 | 5-bromo-2-{2-[(thiophene-2-methyl) amino] ethanoyl } aminothiazole |
| I-7 | 5-bromo-4-methyl-2-{2-[(thiophene-2-methyl) amino] ethanoyl } aminothiazole |
| I-8 | 4,5-two bromo-2-{2-[(4-bromothiophene-2-methyl) amino] ethanoyl } aminothiazole |
| I-9 | 5-bromo-2-{2-[(furans-2-methyl) amino] ethanoyl } aminothiazole |
| I-10 | 5-bromo-4-methyl-2-{2-[(3-nitrofuran-2-methyl) amino] ethanoyl } aminothiazole |
| I-11 | 5-bromo-2-{2-[(3-chloro-5-cyano group-4-methyl furan-2-methyl) amino] ethanoyl } amino-4-methylthiazol |
Compound of Formula I of the present invention is synthetic by following steps:
Compound I I reacts with chloroacetyl chloride in the presence of organic bases, obtains compound III.Organic bases comprises triethylamine, diisopropyl ethyl amine and 2,6-lutidine etc.
Compound III is reacted with compound IV in the presence of organic bases, obtains Compound I.Organic bases described as defined above.
Wherein, R
1And R
2Described as defined above.
The pharmacy acceptable salt of formula I compound of the present invention comprises, but be not limited to and various mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, for example pharmacy acceptable salt that generated such as formic acid, acetate, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid.
Formula I compound of the present invention or its pharmacy acceptable salt can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, injection liquid drugs injection, injection powder pin and infusion solutions, primary infusion.
Composition of the present invention can be accepted auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, lime carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I of the present invention or its salt have the restraining effect of DPP-IV, can be used as the medicine that effective constituent is used to prepare the diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in the body.
Compound of Formula I of the present invention is effective in quite wide dosage range.For example the dosage of taking every day is divided into once or administration for several times in 1mg-1000mg/ people's scope.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situations comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.Need to prove that following embodiment is used for explanation, and is not to be used to limit the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
5-bromo-2-(2-chloracetyl) aminothiazole (III-1)
Add 1.79g (10mmol) Compound I I-1 in the round-bottomed flask of a 100mL, 1.01g (13mmol) exsiccant triethylamine and 50mL exsiccant CH
2Cl
2, this mixture under agitation with the ice-water bath cooling, then slowly drips 1.24g (11mmol) chloroacetyl chloride and is dissolved in 5mL exsiccant CH
2Cl
2The solution of making, after dropwising, reaction mixture at room temperature stirred 1 hour.Reaction mixture 50mL CH
2Cl
2After the dilution, use the saturated common salt water washing again, the organic phase anhydrous Na
2SO
4Drying is sloughed solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains the pure product of compound III-1,2.30g, productive rate 90%.Clear crystal, fusing point 203-204 ℃,
1H NMR (DMSO-d
6, 400MHz), δ 12.74 (s, 1H), 7.60 (s, 1H), 4.40 (s, 2H).
Compound I I-1 and III-1 have general formula I I and have in the compound of general formula III one.
Embodiment 2
4,5-bromo-2-(2-chloracetyl) aminothiazole (III-2)
Add 2.58g (10mmol) Compound I I-2 in the round-bottomed flask of a 100mL, 1.29g (13mmol) exsiccant diisopropyl ethyl amine and 50mL exsiccant CH
2Cl
2, this mixture under agitation with the ice-water bath cooling, then slowly drips 1.24g (11mmol) chloroacetyl chloride and is dissolved in 5mL exsiccant CH
2Cl
2The solution of making, after dropwising, reaction mixture at room temperature stirred 1 hour.Reaction mixture 50mL CH
2Cl
2After the dilution, use the saturated common salt water washing again, the organic phase anhydrous Na
2SO
4Drying is sloughed solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains the pure product of compound III-2,2.84g, productive rate 85%.Clear crystal, IR (KBr), 3327,1694cm
-1
Compound I I-2 and III-2 have general formula I I and have in the compound of general formula III one.
Embodiment 3
5-bromo-2-(2-chloracetyl) amino-4-methylthiazol (III-3)
Add 1.93g (10mmol) Compound I I-3 in the round-bottomed flask of a 100mL, 1.07g (13mmol) exsiccant 2,6-lutidine and 50mL exsiccant CH
2Cl
2, this mixture under agitation with the ice-water bath cooling, then slowly drips 1.24g (11mmol) chloroacetyl chloride and is dissolved in 5mL exsiccant CH
2Cl
2The solution of making, after dropwising, reaction mixture at room temperature stirred 1 hour.Reaction mixture 50mL CH
2Cl
2After the dilution, use the saturated common salt water washing again, the organic phase anhydrous Na
2SO
4Drying is sloughed solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains the pure product of compound III-3,2.45g, productive rate 91%.Clear crystal, IR (KBr), 3332,1690cm
-1
Compound I I-3 and III-3 have general formula I I and have in the compound of general formula III one.
Embodiment 4
5-bromo-2-(2-chloracetyl) amino-4-phenyl thiazole (III-4)
Add 2.55g (10mmol) Compound I I-4 in the round-bottomed flask of a 100mL, 1.01g (13mmol) exsiccant triethylamine and 50mL exsiccant CH
2Cl
2, this mixture under agitation with the ice-water bath cooling, then slowly drips 1.24g (11mmol) chloroacetyl chloride and is dissolved in 5mL exsiccant CH
2Cl
2The solution of making, after dropwising, reaction mixture at room temperature stirred 1 hour.Reaction mixture 50mL CH
2Cl
2After the dilution, use the saturated common salt water washing again, the organic phase anhydrous Na
2SO
4Drying is sloughed solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains the pure product of compound III-4,3.12g, productive rate 94%.Clear crystal, IR (KBr), 3324,3031,1687cm
-1
Compound I I-4 and III-4 have general formula I I and have in the compound of general formula III one.
Embodiment 5
The 2-{2-[(benzyl) amino] ethanoyl } amino-5-bromo thiazole (I-1)
Add 2.55g (10mmol) compound III-1 in the round-bottomed flask of a 100mL, 1.07g (10mmol) compound IV-1 and 1.01g (10mmol) triethylamine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-1, and this crude product obtains the pure product of Compound I-1 through column chromatography purification.Clear crystal, 3.10g, productive rate 95%.IR(KBr)，3239，3156，3031，1685cm
-1。
Compound IV-the 1st has in the compound of general formula I V.
Embodiment 6
4,5-two bromo-2-{2-[(2-benzyl chloride bases) amino] ethanoyl } aminothiazole (I-2)
Add 3.34g (10mmol) compound III-2 in the round-bottomed flask of a 100mL, 1.42g (10mmol) compound IV-2 and 1.01g (10mmol) triethylamine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-2, and this crude product obtains the pure product of Compound I-2 through column chromatography purification.Clear crystal, 4.22g, productive rate 96%.IR(KBr)，3245，3167，3030，1692cm
-1。
Compound IV-the 2nd has in the compound of general formula I V.
Embodiment 7
5-bromo-2-{2-[(2-fluoro-4-methyl-benzyl) amino] ethanoyl } amino-4-methylthiazol (I-3)
Add 2.70g (10mmol) compound III-3 in the round-bottomed flask of a 100mL, 1.39g (10mmol) compound IV-3 and 1.07g (13mmol) exsiccant 2, the 6-lutidine then adds the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-3, and this crude product obtains the pure product of Compound I-3 through column chromatography purification.Clear crystal, 3.39g, productive rate 91%.IR(KBr)，3244，3161，3031，1690cm
-1。
Compound IV-the 3rd has in the compound of general formula I V.
Embodiment 8
5-bromo-2-{2-[(2-cyano group-3-nitro-4-Ethylbenzyl) amino] ethanoyl } amino-4-phenyl thiazole (I-4)
Add 3.32g (10mmol) compound III-4 in the round-bottomed flask of a 100mL, 2.05g (10mmol) compound IV-4 and 1.01g (10mmol) triethylamine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-4, and this crude product obtains the pure product of Compound I-4 through column chromatography purification.Clear crystal, 4.70g, productive rate 94%.IR(KBr)，3241，3189，3030，2223，1679cm
-1。
Compound IV-the 4th has in the compound of general formula I V.
Embodiment 9
5-bromo-2-{2-[(2-methyl-benzyl) amino] ethanoyl } amino-4-phenyl thiazole (I-5)
Add 3.32g (10mmol) compound III-4 in the round-bottomed flask of a 100mL, 1.21g (10mmol) compound IV-5 and 1.01g (10mmol) triethylamine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-5, and this crude product obtains the pure product of Compound I-5 through column chromatography purification.Clear crystal, 3.75g, productive rate 90%.IR(KBr)，3237，3177，3030，1681cm
-1。
Compound IV-the 5th has in the compound of general formula I V.
Embodiment 10
5-bromo-2-{2-[(thiophene-2-methyl) amino] ethanoyl } aminothiazole (I-6)
Add 2.56g (10mmol) compound III-1 in the round-bottomed flask of a 100mL, 1.13g (10mmol) compound IV-6 and 1.07g (10mmol) 2, the 6-lutidine then adds the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-6, and this crude product obtains the pure product of Compound I-6 through column chromatography purification.Clear crystal, fusing point 143-144 ℃, 2.89g, productive rate 87%.
1H NMR(DMSO-d
6，400MHz)，δ7.55(s，1H)，7.38-7.40(dd，1H，J＝1.6Hz and 4.4Hz)，6.94-6.96(m，2H)，3.94(s，2H)，3.48(s，2H)。
Compound IV-the 6th has in the compound of general formula I V.
Embodiment 11
5-bromo-4-methyl-2-{2-[(thiophene-2-methyl) amino] ethanoyl } aminothiazole (I-7)
Add 2.70g (10mmol) compound III-3 in the round-bottomed flask of a 100mL, 1.13g (10mmol) compound IV-6 and 1.01g (10mmol) triethylamine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-7, and this crude product obtains the pure product of Compound I-7 through column chromatography purification.Clear crystal, 2.94g, productive rate 85%.IR(KBr)，3224，3171，3028，1680cm
-1。
Embodiment 12
4,5-two bromo-2-{2-[(4-bromothiophene-2-methyl) amino] ethanoyl } aminothiazole (I-8)
Add 3.34g (10mmol) compound III-2 in the round-bottomed flask of a 100mL, 1.92g (10mmol) compound IV-7 and 1.01g (10mmol) triethylamine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-8, and this crude product obtains the pure product of Compound I-8 through column chromatography purification.Clear crystal, 4.51g, productive rate 92%.IR(KBr)，3243，3177，3028，1683cm
-1。
Compound IV-the 7th has in the compound of general formula I V.
Embodiment 13
5-bromo-2-{2-[(furans-2-methyl) amino] ethanoyl } aminothiazole (I-9)
Add 2.56g (10mmol) compound III-1 in the round-bottomed flask of a 100mL, 0.97g (10mmol) compound IV-8 and 1.01g (10mmol) triethylamine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-9, and this crude product obtains the pure product of Compound I-9 through column chromatography purification.Clear crystal, 2.62g, productive rate 83%.IR(KBr)，3279，3156，3030，1676cm
-1。
Compound IV-the 8th has in the compound of general formula I V.
Embodiment 14
5-bromo-4-methyl-2-{2-[(3-nitrofuran-2-methyl) amino] ethanoyl } aminothiazole (I-10)
Add 2.70g (10mmol) compound III-3 in the round-bottomed flask of a 100mL, 1.42g (10mmol) compound IV-9 and 1.01g (10mmol) triethylamine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-10, and this crude product obtains the pure product of Compound I-10 through column chromatography purification.Clear crystal, 3.41g, productive rate 91%.IR(KBr)，3265，3153，3031，1672cm
-1。
Compound IV-the 9th has in the compound of general formula I V.
Embodiment 15
5-bromo-2-{2-[(3-chloro-5-cyano group-4-methyl furan-2-methyl) amino] ethanoyl } amino-4-methylthiazol (I-11)
Add 2.70g (10mmol) compound III-3 in the round-bottomed flask of a 100mL, 1.71g (10mmol) compound IV-10 and 1.29g (13mmol) exsiccant diisopropyl ethyl amine then add the dissolving of 25mL dry THF.Resulting compound of reaction at room temperature stirs and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, obtain the crude product of Compound I-11, and this crude product obtains the pure product of Compound I-11 through column chromatography purification.Clear crystal, 3.75g, productive rate 93%.IR(KBr)，3269，3158，2224，1681cm
-1。
Compound IV-the 10th has in the compound of general formula I V.
Embodiment 16
Consumption/sheet
Embodiment 5 samples (I-1) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 17
Consumption/sheet
Embodiment 6 samples (I-2) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 18
Consumption/grain
Embodiment 7 samples (I-3) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, and the system wet granular is in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly.
Embodiment 19
Consumption/grain
Embodiment 8 samples (I-4) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, and the system wet granular is in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly.
Embodiment 20
Consumption/50mL
Embodiment 10 samples (I-6) 50mg
Citric acid 100mg
NaOH an amount of (transferring pH 4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 21
Consumption/50mL
Embodiment 11 samples (I-7) 50mg
Citric acid 100mg
NaOH an amount of (transferring pH 4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 22
Embodiment 13 samples (I-9) 3.0g
Poloxamer 1.0g
Sodium hydroxide 0.2g
Citric Acid QS
N.F,USP MANNITOL 26.0g
Lactose 23.0g
Water for injection 100ml
Preparation technology: get water for injection 80ml, add main ingredient, N.F,USP MANNITOL, lactose, poloxamer stir make dissolving after, the Citric Acid that adds 1mol/L is regulated PH to 7.0-9.0, mends and adds water to 100ml.Add the 0.5g gac, stirred 20 minutes down, take off charcoal, adopt the filtering with microporous membrane degerming at 30 ℃, filtrate is carried out packing by every 1ml, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 12 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal promptly.
Embodiment 23
100 bags of granules
Embodiment 14 samples (I-10) 30.0g
Lactose 55.0g
N.F,USP MANNITOL 14.0g
The sweet 0.05g of A Siba
Essence 0.05g
2% hypromellose (pure water preparation) QS
Preparation technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 14 mesh sieves are granulated, 55 ℃ of dryings, and the whole grain of 12 mesh sieves is measured heavily packing of bag.
Embodiment 24
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and the administration capacity is the 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy ICR mouse, male and female half and half, body weight 20-24g meets primary standard.Animal fasting 16 hours, the dextrose in saline solution of 2h abdominal injection 2g/kg behind the medicine (1.5h injectable dextrose monohydrate behind the gliclazide medicine), 0.5h, 1h, 2h, 3h and 4h regularly take kapillary and get blood from mouse ball rear vein beard after modeling, centrifugation serum is with each time point serum glucose level of determination of glucose oxidase.The results are shown in down page table:
Above result shows that each administration all can significantly reduce the mouse blood sugar dosis tolerata that glucose causes.
Claims (9)
1. has pharmaceutically acceptable salt of the compound of general formula I or its
Wherein,
R
1Be selected from H, F, Cl, Br, I, C
1-C
5Alkyl and phenyl,
R
2Be selected from phenyl, by F, Cl, Br, I, C
1-C
5Alkyl, CN and NO
2With the phenyl that single replacement, two replaces or trisubstituted mode replaces, the 2-furyl is by F, Cl, Br, I, C
1-C
5Alkyl with single 2-furyl that replaces or under the situation that space requirement allows, replace in dibasic mode, the 2-thienyl is by F, Cl, Br, I, C
1-C
5Alkyl with single 2-thienyl that replaces or under the situation that space requirement allows, replace in dibasic mode.
2. the defined compound with general formula I of claim 1 or its acceptable salt pharmaceutically,
Wherein,
R
1Be selected from H, Cl, Br and C
1-C
5Alkyl,
R
2Be selected from phenyl, by F, Cl, Br and C
1-C
3Alkyl, CN and NO
2With the phenyl that single replacement or dibasic mode replace, the 2-furyl is by F, Cl, Br and C
1-C
3Alkyl replace or 2-furyl that dibasic mode replaces with single, the 2-thienyl is by F, Cl, Br and C
1-C
3Alkyl replace or 2-thienyl that dibasic mode replaces with single.
3. the defined compound of Formula I of claim 2 or its pharmacy acceptable salt are selected from:
The 2-{2-[(benzyl) amino] ethanoyl } amino-5-bromo thiazole
4,5-two bromo-2-{2-[(2-benzyl chloride bases) amino] ethanoyl } aminothiazole
5-bromo-2-{2-[(2-fluoro-4-methyl-benzyl) amino] ethanoyl } amino-4-methylthiazol
5-bromo-2-{2-[(2-cyano group-3-nitro-4-Ethylbenzyl) amino] ethanoyl } amino-4-phenyl thiazole
5-bromo-2-{2-[(2-methyl-benzyl) amino] ethanoyl } amino-4-phenyl thiazole
5-bromo-2-{2-[(thiophene-2-methyl) amino] ethanoyl } aminothiazole
5-bromo-4-methyl-2-{2-[(thiophene-2-methyl) amino] ethanoyl } aminothiazole
4,5-two bromo-2-{2-[(4-bromothiophene-2-methyl) amino] ethanoyl } aminothiazole
5-bromo-2-{2-[(furans-2-methyl) amino] ethanoyl } aminothiazole
5-bromo-4-methyl-2-{2-[(3-nitrofuran-2-methyl) amino] ethanoyl } aminothiazole
5-bromo-2-{2-[(3-chloro-5-cyano group-4-methyl furan-2-methyl) amino] ethanoyl } amino-4-methylthiazol
4. synthesize the method for the defined compound of Formula I of claim 1-3, may further comprise the steps:
(1) Compound I I reacts with chloroacetyl chloride in the presence of organic bases, obtains compound III.Organic bases comprises triethylamine, diisopropyl ethyl amine and 2,6-lutidine etc.
(2) compound III is reacted with compound IV in the presence of organic bases, obtains Compound I.Organic bases described as defined above.
5. the described method of claim 4, wherein the organic bases of step (1), step (2) is selected from triethylamine, diisopropyl ethyl amine and 2, one or more in the 6-lutidine respectively.
6. the defined compound of Formula I of claim 1-3 or its pharmacy acceptable salt application aspect preparation treatment diabetes medicament.
7. pharmaceutical composition contains compound of Formula I or its pharmacy acceptable salt of one of claim 1-3 and appropriate carriers or vehicle.
8. the described pharmaceutical composition of claim 7, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
9. described according to Claim 8 solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100680131A CN101492427A (en) | 2009-03-03 | 2009-03-03 | Pentabromo-thiazole derivative, preparation method and application thereof |
| CN2009101392201A CN101550112B (en) | 2009-03-03 | 2009-04-29 | 4,5-disubstituted thiazole derivative, preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100680131A CN101492427A (en) | 2009-03-03 | 2009-03-03 | Pentabromo-thiazole derivative, preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101492427A true CN101492427A (en) | 2009-07-29 |
Family
ID=40923238
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009100680131A Pending CN101492427A (en) | 2009-03-03 | 2009-03-03 | Pentabromo-thiazole derivative, preparation method and application thereof |
| CN2009101392201A Expired - Fee Related CN101550112B (en) | 2009-03-03 | 2009-04-29 | 4,5-disubstituted thiazole derivative, preparation method and use thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101392201A Expired - Fee Related CN101550112B (en) | 2009-03-03 | 2009-04-29 | 4,5-disubstituted thiazole derivative, preparation method and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN101492427A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010069124A1 (en) * | 2008-12-16 | 2010-06-24 | 天津药物研究院 | Amide thiazole derivative, preparation method and uses thereof |
| CN105254585A (en) * | 2015-11-18 | 2016-01-20 | 泰山医学院 | Thiazole amide compound and preparation method and application thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664930B (en) * | 2012-09-20 | 2016-02-10 | 天津药物研究院有限公司 | One class is containing compound, the Preparation Method And The Use of thiazole structure |
-
2009
- 2009-03-03 CN CNA2009100680131A patent/CN101492427A/en active Pending
- 2009-04-29 CN CN2009101392201A patent/CN101550112B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010069124A1 (en) * | 2008-12-16 | 2010-06-24 | 天津药物研究院 | Amide thiazole derivative, preparation method and uses thereof |
| US8481577B2 (en) | 2008-12-16 | 2013-07-09 | Tianjin Institute Of Pharmaceutical Research | Amide thiazole derivative, preparation method and uses thereof |
| CN105254585A (en) * | 2015-11-18 | 2016-01-20 | 泰山医学院 | Thiazole amide compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101550112A (en) | 2009-10-07 |
| CN101550112B (en) | 2011-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101445492B (en) | Amide thiazole derivant, preparation method and use thereof | |
| CN101445527B (en) | Five-membered heteroaromatics tolylene glucoside and preparation method and use thereof | |
| US9655852B2 (en) | Tablets containing a 1-(β-D-glucopyranosyl)-3-(phenylthienylmethyl)benzene compound | |
| CN101508712A (en) | Glucoside containing tetrazole structure, preparation method and application | |
| CN101550112B (en) | 4,5-disubstituted thiazole derivative, preparation method and use thereof | |
| JP4854158B2 (en) | Formulations containing benzamide derivatives as active ingredients | |
| CN101445528A (en) | Sulpho-glucosan derivative and preparation method and application thereof | |
| US20230218563A1 (en) | Methods for treating or preventing chronic kidney disease | |
| CN101684103B (en) | Compound with 1,2,4-triazole structure and preparation method and application thereof | |
| CN101463055B (en) | O-indican compounds, preparation and use thereof | |
| CN101684088B (en) | Cyanomethyl pyrrole derivative and preparation method and application thereof | |
| CN103012314B (en) | Sulfonamide compound and preparation method as well as application thereof | |
| CN104513188A (en) | Cyano pyrrolidine derivative and preparation method and application thereof | |
| CN111195247B (en) | Alpha-glucosidase inhibitor and application thereof in hypoglycemic drugs | |
| CN103664930B (en) | One class is containing compound, the Preparation Method And The Use of thiazole structure | |
| CN103626722A (en) | Hypoglycemic compound of nitric oxide donor type, preparation method and purpose thereof | |
| CN101508713A (en) | Glucoside containing 1,2,3-triazole structure, preparation method and application | |
| CN114835767B (en) | Arbutin conjugate and application thereof | |
| CN102241644A (en) | Alpha-azyl-3-aryl propionamido thiazole derivative, preparation method and purpose thereof | |
| CN102875567B (en) | Piperazine compound and preparation and usage thereof | |
| CN114349665B (en) | Metformin pyroglutamic acid crystal and preparation method and application thereof | |
| CN101805308B (en) | Compound containing tyrosine and isoxazole skeleton and preparation method and application thereof | |
| CN103467405B (en) | Tetrazole carboxylic acid compounds, and preparation method and application thereof | |
| CN101805336B (en) | Compound containing tryptophane and isoxazole skeleton and preparation method and application thereof | |
| CN101955502A (en) | thiogalactosiTtderivatives, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |