CN1882526A - Process for the preparation of voglibose - Google Patents
Process for the preparation of voglibose Download PDFInfo
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- CN1882526A CN1882526A CNA2004800339960A CN200480033996A CN1882526A CN 1882526 A CN1882526 A CN 1882526A CN A2004800339960 A CNA2004800339960 A CN A2004800339960A CN 200480033996 A CN200480033996 A CN 200480033996A CN 1882526 A CN1882526 A CN 1882526A
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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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
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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
- A61P3/06—Antihyperlipidemics
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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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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
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Abstract
The invention relates to processes for the preparation of pure voglibose. The invention also relates to the preparation of acid addition salts of voglibose. More particularly, it relates to the preparation of crystalline hydrochloride salt of voglibose. The invention also relates to pharmaceutical compositions that include the pure voglibose or voglibose hydrochloride and use of said compositions for treatment or prevention of hyperglycemic symptoms and various disorders caused by hyperglycemia such as diabetes, obesity, and hyperlipemia.
Description
Invention field
The present invention relates to prepare the method for pure voglibose (voglibose).The invention still further relates to the method for the acid salt of preparation voglibose.More specifically, the present invention relates to prepare the crystalline hydrochloride of voglibose.The invention still further relates to the pharmaceutical composition and the purposes of described composition in treatment or prevention hyperglycemia and the various diseases that causes by hyperglycemia such as diabetes, obesity, obesity and hyperlipidaemia that comprise pure voglibose or crystallization voglibose hydrochloride.
Background of invention
Chemically, voglibose is (1S)-(1 (OH), 2,4,5/1,3)-5-[[2-hydroxyl-1-(methylol) ethyl] amino]-1-C-(methylol)-1,2,3, the 4-cyclohexanetetraol has fabulous inhibition activity to the heteroside lytic enzyme.Several methods that prepare voglibose have been reported, for example in United States Patent (USP) 4,701,559; 4,824,943; 4,898,986 and 6,150,568; J Org.Chem. has reported some preparation methods in 1992,57,3651 and J.Med.Chem., 1986,29,1038.
These methods generally comprise water and carry out ion exchange chromatography, then the aqueous solution is concentrated separating voglibose, and from ethyl alcohol recrystallization to obtain pure voglibose.Cause the sepn process difficulty owing to the big water gaging of recovery need prolong heating, the overall yield of product is low.Adopting the product of the several method acquisition of report is moisture absorption at first, becomes viscosity oily matter when being exposed to atmosphere.We have found that voglibose that the acid salt by voglibose obtains is pure, stable non-moisture absorption, separates without any need for chromatographic technique.
Summary of the invention
A total aspect provides pure voglibose.
Pure voglibose can have the X-ray diffracting spectrum of figure IV, the dsc figure of the infrared spectra of figure V and figure VI.
The aspect that another is total provides a kind of method for preparing pure voglibose.This method comprises the solution of acquisition voglibose in one or more solvents; Solution contacts with acid; The acid salt that separates the voglibose that is solid-state; And change the acid salt of this voglibose into pure voglibose.
This method can comprise the product that obtains further dry.
The aspect that another is total provides a kind of pharmaceutical composition, and said composition comprises the pure voglibose for the treatment of significant quantity; One or more pharmaceutically acceptable carriers, vehicle or thinner.
The aspect that another is total provides the disease that caused by hyperglycemia in treatment or the prevention warm-blooded animal such as diabetes, obesity, obesity, and the method for hyperlipidemia, and this method comprises and gives the warm-blooded animal a kind of pharmaceutical composition that comprises pure voglibose.
The aspect that another is total provides a kind of crystalline hydrochloride of voglibose, i.e. the hydrochloric acid voglibose.
The hydrochloric acid voglibose can have the X-ray diffracting spectrum of figure I, the dsc figure of the infrared spectra of figure II and figure III.
The aspect that another is total provides the method for preparing the hydrochloric acid voglibose.This method comprises the solution of acquisition voglibose in one or more solvents; This solution is contacted with hydrochloric acid; Separate the hydrochloric acid voglibose that is crystallized form.
The aspect that another is total provides a kind of pharmaceutical composition, and said composition comprises the hydrochloric acid voglibose crystallization for the treatment of significant quantity; One or more pharmaceutically acceptable carriers, vehicle or thinner.
The aspect that another is total, disease that treatment is provided or has prevented to cause by hyperglycemia in the warm-blooded animal such as diabetes, obesity, obesity, and the method for hyperlipidemia, this method comprises and gives warm-blooded animal a kind of hydrochloric acid voglibose crystalline pharmaceutical composition that comprises.
Describe one or more embodiments of the present invention below in detail.By these explanations and claims, other features, objects and advantages of the present invention will be conspicuous.
The accompanying drawing summary
Figure I is the X-ray powder diffraction of hydrochloric acid voglibose.
Figure II is the infrared spectra of hydrochloric acid voglibose.
Figure III is the dsc figure of hydrochloric acid voglibose.
Figure IV is the X-ray powder diffraction of voglibose.
Figure V is the infrared spectra of voglibose.
Figure VI is the dsc figure of voglibose.
Detailed Description Of The Invention
The inventor has worked out the method for the pure voglibose of preparation, and the method comprises: the preparation voigelibo The solution of sugar in one or more solvents; This solution is contacted with acid; Separate and be solid-state voigelibo saccharic acid Addition salts; Change this voglibose acid-addition salts into pure voglibose.
The present invention also develops the pharmaceutical composition that contains pure voglibose, is pure voglibose and a kind of or many The blend of the pharmaceutical diluents of kind solid or liquid, carrier, excipient.
Generally speaking, the solution of voglibose can make by voglibose is dissolved in the suitable solvent. Perhaps, this solution can directly obtain from the reaction that forms voglibose. Can heat and contain voglibose Solvent obtain solution.
Voglibose can adopt any method preparation known in the art, is included in United States Patent (USP) 4,701,559; 4,824,943; 4,898,986 and 6,150,568; J.Org.Chem., 1992,57,3651 and J.Med.Chem., 1986,29, those methods described in 1038. Voglibose can contain transisomer, polymeric impurities or At any other impurity such as the catabolite producing or occur between the storage life.
Term " suitable solvent " comprises any solvent or the solvent mixture that can dissolve voglibose, comprises example As: water, alcohols, ketone, nitrile, chlorinated hydrocabon, dipolar aprotic solvent, ester class, cyclic ethers, and they Mixture.
Suitable alcohols solvent comprises following one or more: methyl alcohol, ethanol and isopropyl alcohol. Ketone Example comprises acetone and methyl iso-butyl ketone (MIBK). The example of nitrile comprises acetonitrile. Suitable chlorinated hydrocabon comprises following One or more: chloroform, carrene and 1,2-dichloroethanes. The example of dipolar aprotic solvent comprises such as two The solvent of methyl sulfoxide and dimethyl formamide. The example of ester class comprises such as methyl acetate, ethyl acetate and acetic acid The solvent of isopropyl ester. The example of cyclic ethers comprises such as the solvent of diox and oxolane. Consider that also all these are molten The mixture of agent.
The solution of voglibose in a kind of solvent can adopt the combination of dissolving, slurrying, stirring or these modes Make.
Generally speaking, by adding organic acid or inorganic acid, can make voglibose change voglibose into Acid-addition salts. Can in suitable solvent, acid be added in the solution of voglibose. Perhaps, at preparation volt lattice Add acid in the final step of array wave sugar, directly separate the acid-addition salts of voglibose, and do not separate Fu Gelie Ripple sugar.
The example of inorganic acid comprises: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid. The organic acid example comprises: Formic acid, acetic acid, maleic acid, malic acid, oxalic acid, tartaric acid, citric acid, ascorbic acid, tussol, right Toluenesulfonic acid and methanesulfonic acid.
The mode of separating the acid-addition salts of voglibose comprises following one or more: distillation, vacuum distillation, Crystallization, precipitation, cooling, filtration, vacuum filtration, decant and centrifugal.
The acid-addition salts precipitation of voglibose can be spontaneous, depends on solvent for use and condition. All right Crystal seed by adding required salt or add molten to the acid-addition salts of voglibose of anti-solvent (anti-solvent) Promote precipitation in the agent, the acid-addition salts that described anti-solvent is voglibose can not be dissolved in or be slightly soluble in wherein Solvent. Perhaps, can also be by distilling out some solvents and/or reducing temperature and cause precipitation.
Can be before acid-addition salts change voglibose into, the recrystallization one or many.
The example of anti-solvent that is used for being settled out the acid salt of voglibose comprises: hydrocarbon such as hexane, hexanaphthene, toluene, heptane and octane; Lower alkyl ether, as diethyl ether and diisopropyl ether, and their mixture.
The acid salt of voglibose changes pure voglibose into and can reach by add alkali in suitable solvent.
Described alkali can be organic bases or mineral alkali.
The example of organic bases comprises: Trimethylamine 99, triethylamine, Tributylamine, tri-isopropyl amine, diisopropylethylamine, pyridine, morpholine, DBU (1,8-diazabicyclo-[5.4.0]-hendecene-7), DBN (1,5-diazabicyclo-[4.3.0]-nonene-5), 4-dimethylaminopyridine and their mixture.
The example of mineral alkali comprises alkaline carbonate, supercarbonate, oxyhydroxide and their mixture.The example of alkaline carbonate comprises: Quilonum Retard, yellow soda ash and salt of wormwood.The example of alkali metal hydrocarbonate comprises sodium bicarbonate and saleratus.The example of alkali metal hydroxide comprises sodium hydroxide and potassium hydroxide.
Be used for acid salt with voglibose change into pure voglibose solvent can with the above-mentioned solvent phase that is used for preparing the voglibose acid salt with.
The product that obtains can be further or drying in addition, to reach required moisture value.For example, this product can be in pan dryer further or dry in addition, vacuum-drying and/or at the fluidized bed dryer inner drying.
The purity of pure voglibose is greater than 99%.More specifically, the purity of voglibose is greater than 99.5%, for example greater than 99.8%.
The inventor finds a kind of new crystalline form of hydrochloric acid voglibose.This crystalline form can be by the X-ray powder diffraction shown in the figure I, and dsc figure characterizes shown in infrared spectra shown in the figure II and the figure III.
Usually, the crystallization of hydrochloric acid voglibose can be characterized at the X-ray diffraction peak of about 17.70,20.20,22.84 and 26.78 ± 0.2 degree by 2 θ.Can also characterize at the X-ray diffraction peak of about 14.10,15.70,23.04,26.02 and 27.54 ± 0.2 degree by 2 θ.
The inventor also works out a kind of method for preparing the crystallized form of hydrochloric acid voglibose, and this method comprises: the solution of preparation voglibose in one or more solvents; This solution is contacted with hydrogenchloride; The hydrochloric acid voglibose of fractional crystallization form.The inventor also develops a kind of pharmaceutical composition, and said composition comprises the crystallization of hydrochloric acid voglibose, for the blend of one or more solids or liquid medicine thinner, carrier and/or vehicle.
According to being similar to the mode that above-mentioned acid salt from voglibose prepares voglibose, make pure voglibose by the crystallization of hydrochloric acid voglibose.
Usually, the voigelibo sugar soln can make by voglibose is dissolved in one or more solvents.Perhaps, this solution can directly obtain from the reaction that forms voglibose.
Voglibose can adopt any method preparation known in the art, is included in United States Patent (USP) 4,701,559; 4,824,943; 4,898,986 and 6,150,568; J.Org.Chem., 1992,57,3651 and J.Med.Chem., 1986,29, those methods described in 1038.The voglibose directly solution from form the voglibose reaction obtains, and need not to separate.
The solution of voglibose in solvent can obtain by the combination of dissolving, slurrying, stirring or these modes.
Usually, in the solution of suitable solvent, hydrogenchloride is added to voglibose.Perhaps, can add hydrogenchloride at the final step of preparation voglibose, and the hydrochloric acid voglibose of crystallized form can separate directly, does not separate voglibose.
The hydrochloric acid voglibose method of fractional crystallization form comprises following one or more: distillation, vacuum distilling, crystallization, precipitation, cooling, filtration, vacuum filtration, decant and centrifugal.
The hydrogenchloride that uses in the salification process can be the aqueous solution or gaseous state.Hydrochloride aqueous solution can be buied.Gaseous hydrogen chloride can be buied or prepare by methods known in the art.Gaseous hydrogen chloride may be dissolved in the suitable solvent.
The solvent that is used to prepare the hydrochloric acid voglibose can be similar to the above-mentioned solvent that is used for preparing the acid salt of voglibose.
The product that obtains can be further or drying in addition.For example, product can be in pan dryer further or dry in addition, vacuum-drying and/or at the fluidized bed dryer inner drying.
The hydrochloric acid voglibose crystallization that produces can be mixed with common formulations, for example tablet, capsule, pill, solution etc.Under these situations, can adopt ordinary method, prepare medicament with conventional pharmaceutical excipient.
The hydrochloric acid voglibose can give warm-blooded animal, be used for preventing and treat hyperglycemia and the various diseases that causes by hyperglycemia as obesity, obesity, hyperlipidaemia (arteriosclerosis) and diabetes.
For the purpose of illustration, warm-blooded animal refers to it is the member of animal kingdom with homeostatic mechanism, comprises Mammals and birds.
This salt generally gives with pharmaceutically acceptable carrier, thinner or vehicle and optional other therapeutic component as part of pharmaceutical compositions.Described salt can be mixed with tablet, capsule, suspension, dispersion, injectable forms and other medicines form usually.Can adopt any suitable route of administration, for example oral or without intestines.
Further specify the present invention by the following examples, these embodiment are example of the present invention, do not constitute limitation of the scope of the invention.Some change and Equivalent it will be apparent to those skilled in the art that, and determine to be included within the scope of the invention.
Method
The X-ray powder diffraction
The X-ray powder diffraction adopts following instrument and parameter to carry out record:
X-ray diffractometer, Rigaku Coorperation, RU-H3R
Protractor CN2155A3
The X-x ray tube has Cu target anode
1 ° of divergent slit is accepted slit 0.15mm, 1 ° of scatter slit
Power: 40KV, 100mA
Sweep velocity: 2 °/min step: 0.02 °
Wavelength: 1.5406A
Infrared spectra
Instrument and parameter were carried out record below infrared spectra adopted:
SCAN:16 scanning, 4.0cm
-1
According to American Pharmacopeia (USP) 25, the 1920th page of general test method adopts Potassium Bromide method in blocks to obtain infrared absorption spectrum.
Dsc
Dsc figure adopts following instrument and parameter to carry out record:
DSC821e，Mettler?Toledo
Example weight: 3-5mg
Temperature range: 50-250 ℃
Heating rate: 10 ℃/min
Nitrogen: 80.0mL/min
Crucible mesopore numbering: 1
Embodiment 1: preparation four-o-benzyl-5-[[2-hydroxyl-1-(methylol) ethyl] amino]-1-C-(methylol)-1,2,3, the 4-cyclohexanetetraol
Envrionment temperature, with 2-amino-1, (20.1g 220mmol) is added to four-o-benzyl-5-oxygen-1-C-(methylol)-1,2,3 to ammediol, and (35.0g is in methyl alcohol 63.4mmol) (350ml) solution and stirred 60 minutes for the 4-cyclohexanetetraol.Then, in this reaction mixture, add sodium cyanoborohydride (sodium cyanoborohydride) (14g, 222mmol).Add concentrated hydrochloric acid and regulate pH, stir this reaction mixture and spend the night to about 8.0.This reaction mixture is distributed between water and the ethyl acetate.The ethyl acetate layer anhydrous sodium sulfate drying, and concentrate the faint yellow melicera title compound of acquisition.
Output: 38.6g
HPLC purity: 90.0%
1HNMR(CDCl
3)，δ：1.60(1H，dd，J＝2.1，15Hz)，1.92(1H，dd，J＝2.7，15Hz)，2.75(1H，m)，3.20(1H，d，J＝8.4Hz)，3.44(1H，m)，3.50-3.69(7H，m)，4.10(1H，m)，4.39(2H，s)，4.56-4.94(6H，m)，7.22-7.36(20H，m)
Embodiment 2: preparation hydrochloric acid voglibose
5% palladium carbon (13g) and 4% hydrogen chloride solution (20ml) are added to four-o-benzyl-5-[[2-hydroxyl-1-(methylol) ethyl] amino]-1-C-(methylol)-1,2,3,4-cyclohexanetetraol (13.0g, 20.73mmol) methyl alcohol and tetrahydrofuran (THF) (1: 1, solution 260ml), room temperature, 3.0-3.5Kg/cm
2This mixture vibration hydrogenation is 3 hours down.Methanol wash is removed and used to solid filtering.Concentrate the filtrate of merging and the liquid of washing.Then, in the resistates that obtains, add ethanol, reclaim solvent fully.This process repeats for several times, to remove trace water.Add methyl alcohol (35ml) then, stirring at room 1 hour.Filtration product obtains the hydrochloric acid voglibose into white crystalline solid.
Output: 5.0g
1HNMR(D
2O)，δ：1.94(1H，d，J＝3.0，16.2Hz)，2.33(1H，d，J＝2.1，16.2Hz)，3.60-3.70(4H，m)，3.80-4.0(7H，m)
XRD spectra, IR spectrum and DSC figure are similar to respectively shown in figure I, II and the III.
Embodiment 3: the preparation voglibose
The methanol solution of 20% triethylamine is added to the hydrochloric acid voglibose, and (5.0g 16.47mmol) in the suspension of 40ml methyl alcohol, regulates pH to about 8.8-9.0.It is limpid that this suspension becomes, and crystallization goes out free alkali then.Stirred 1 hour, filtration is also used methanol wash, obtains the voglibose into white crystalline solid, and this product can be from recrystallizing methanol.
Output: 3.0g
HPLC purity: 99.9%
1HNMR(D
2O)，δ：1.55(1H，dd，J＝2.1，15Hz)，2.10(1H，dd，J＝2.7，15Hz)，2.9(1H，m)，3.40-3.55(2H，m)，3.59(2H，m)，3.64-3.80(5H，m)3.88(1H，t，J＝9.6Hz)
XRD spectra, IR spectrum and DSC figure are similar to figure IV, V and VI respectively.
Though described the present invention with embodiment, some change and Equivalent are apparent to those skilled in the art, and are included within the scope of the invention.
Claims (57)
1. method for preparing pure voglibose, this method may further comprise the steps:
Obtain the solution of voglibose in one or more solvents;
This solution is contacted with acid;
The voglibose acid salt of separate solid;
And make the voglibose acid salt change pure voglibose into.
2. the method for claim 1 is characterized in that, directly being obtained by reaction mixture is the voglibose of solution.
3. the method for claim 1 is characterized in that, described solvent comprises following one or more: ketone, alcohols, ester class, nitrile, chlorinated hydrocarbon, cyclic ethers, dipolar aprotic solvent, or their mixture.
4. method as claimed in claim 4 is characterized in that ketone comprises one or both in acetone and the methyl iso-butyl ketone (MIBK).
5. method as claimed in claim 4 is characterized in that alcohols comprises one or more in methyl alcohol, ethanol and the Virahol.
6. method as claimed in claim 4 is characterized in that the ester class comprises one or more in methyl acetate, ethyl acetate and the isopropyl acetate.
7. method as claimed in claim 4 is characterized in that nitrile is an acetonitrile.
8. method as claimed in claim 4 is characterized in that, chlorinated hydrocarbon comprises chloroform, methylene dichloride and 1, in the 2-ethylene dichloride one or more.
9. method as claimed in claim 4 is characterized in that, cyclic ethers comprises in diox and the tetrahydrofuran (THF) one or both.
10. method as claimed in claim 4 is characterized in that, dipolar aprotic solvent comprises in dimethyl formamide and the dimethyl sulfoxide (DMSO) one or both.
11. the method for claim 1 is characterized in that, described acid is organic acid or mineral acid.
12. method as claimed in claim 11 is characterized in that, mineral acid comprises one or more in hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid and the nitric acid.
13. method as claimed in claim 11 is characterized in that, organic acid comprises one or more in acetate, toxilic acid, oxysuccinic acid, oxalic acid, tartrate, citric acid, xitix, tussol, tosic acid and the methylsulfonic acid.
14. also comprising, the method for claim 1, this method add the acid salt that anti-solvent precipitates voglibose.
15. method as claimed in claim 14 is characterized in that, anti-solvent comprises one or more in lower alkyl ether, hydrocarbon and their mixture.
16. method as claimed in claim 15 is characterized in that, alkyl oxide comprises in diethyl ether and the diisopropyl ether one or both.
17. method as claimed in claim 15 is characterized in that, hydrocarbon comprises one or more in hexane, hexanaphthene, toluene, heptane and the octane.
18. the method for claim 1 is characterized in that, by adding organic bases or mineral alkali, the acid salt that reaches voglibose changes pure voglibose into.
19. method as claimed in claim 18, it is characterized in that, organic bases comprises Trimethylamine 99, triethylamine, Tributylamine, tri-isopropyl amine, diisopropylethylamine, pyridine, morpholine, DBU (1,8-diazabicyclo-[5.4.0]-11-7-alkene), DBN (1,5-diazabicyclo-[4.3.0]-ninth of the ten Heavenly Stems-5-alkene), the mixture of one or more and they in the 4-dimethylaminopyridine.
20. method as claimed in claim 18 is characterized in that, mineral alkali comprises one or more in alkaline carbonate, alkali metal hydrocarbonate and the alkali metal hydroxide.
21. method as claimed in claim 20 is characterized in that, alkaline carbonate comprises one or more in Quilonum Retard, yellow soda ash and the salt of wormwood.
22. method as claimed in claim 20 is characterized in that, alkali metal hydrocarbonate comprises one or both in sodium bicarbonate and the saleratus.
23. method as claimed in claim 20 is characterized in that, alkali metal hydroxide comprises in sodium hydroxide and the potassium hydroxide one or both.
24. the method for claim 1, this method comprise that also the product to making carries out drying in addition.
25. the method for claim 1, this method also comprise the product that obtains is made finished dosage forms.
26. comprising, a method for the treatment of or preventing the disease that is caused by hyperglycemia in the warm-blooded animal, this method give warm-blooded animal a kind of formulation that makes voglibose by the described method of claim 1 that comprises.
27. method as claimed in claim 26 is characterized in that, described disease is diabetes, obesity, obesity and hyperlipidaemia.
28. voglibose is measured purity greater than 99.5% by HPLC.
29. voglibose is measured purity greater than 99.8% by HPLC.
30. pure voglibose as claimed in claim 29 is characterized in that described voglibose has the X-ray diffracting spectrum of figure IV.
31. pure voglibose as claimed in claim 29 is characterized in that described voglibose has the infrared spectra of figure V.
32. pure voglibose as claimed in claim 29 is characterized in that described voglibose has the dsc figure of figure VI.
33. a pharmaceutical composition comprises the pure voglibose for the treatment of significant quantity, one or more pharmaceutically acceptable carriers, vehicle or thinner.
34. comprising, a method for the treatment of or preventing the disease that is caused by hyperglycemia in the warm-blooded animal, this method supply with the formulation that warm-blooded animal comprises pure voglibose.
35. method as claimed in claim 34 is characterized in that, described disease is diabetes, obesity, obesity and hyperlipidaemia.
36. the crystalline hydrochloride of voglibose.
37. the crystalline hydrochloride of voglibose as claimed in claim 36 is characterized in that, described voglibose has the X-ray diffracting spectrum of figure I.
38. the crystalline hydrochloride of voglibose as claimed in claim 36 is characterized in that, described voglibose has the infrared spectra of figure II.
39. the crystalline hydrochloride of voglibose as claimed in claim 36 is characterized in that, described voglibose has the dsc figure of figure III.
40. the crystalline hydrochloride of a voglibose is characterized in that, the peak of X-ray diffracting spectrum is about 17.70,20.20,22.84 and 26.78 ± 0.2 degree at 2 θ.
41. the crystalline hydrochloride of voglibose as claimed in claim 40 is characterized in that, the peak of X-ray diffracting spectrum is about 14.10,15.70,23.04,26.02 and 27.54 ± 0.2 degree at 2 θ.
42. a pharmaceutical composition comprises the voglibose crystalline hydrochloride for the treatment of significant quantity; One or more pharmaceutically acceptable carriers, vehicle or thinner.
43. one kind prepares hydrochloric acid voglibose crystalline method, this method may further comprise the steps:
Make the solution of voglibose in one or more solvents;
This solution is contacted with hydrogenchloride;
The hydrochloric acid voglibose of fractional crystallization form.
44. method as claimed in claim 43 is characterized in that, voglibose can directly obtain with solution from the reaction that forms voglibose.
45. method as claimed in claim 43 is characterized in that, solvent comprises following one or more: ketone, alcohols, ester class, nitrile, chlorinated hydrocarbon, cyclic ethers, dipolar aprotic solvent, and their mixture.
46. method as claimed in claim 45 is characterized in that, described ketone comprises one or both in acetone and the methyl iso-butyl ketone (MIBK).
47. method as claimed in claim 45 is characterized in that, alcohols comprises one or more in methyl alcohol, ethanol and the Virahol.
48. method as claimed in claim 45 is characterized in that, described ester class comprises one or more in methyl acetate, ethyl acetate and the isopropyl acetate.
49. method as claimed in claim 45 is characterized in that, described nitrile is an acetonitrile.
50. method as claimed in claim 45 is characterized in that, described chlorinated hydrocarbon comprises chloroform, methylene dichloride and 1, one or more in the 2-ethylene dichloride.
51. method as claimed in claim 45 is characterized in that, described cyclic ethers comprises one or both in diox and the tetrahydrofuran (THF).
52. method as claimed in claim 45 is characterized in that, dipolar aprotic solvent comprises one or both in dimethyl formamide and the dimethyl sulfoxide (DMSO).
53. method as claimed in claim 43 is characterized in that, the hydrochloric acid voglibose of fractional crystallization form comprises following one or more mode: distillation, vacuum distilling, crystallization, precipitation, cooling, filtration, vacuum filtration, decant and centrifugal.
54. method as claimed in claim 43, this method also comprises the product that other drying makes.
55. method as claimed in claim 43, this method comprise that also the product that will obtain forms finished dosage forms.
56. the method for the disease that is caused by hyperglycemia in treatment or the prevention warm-blooded animal, this method comprise the hydrochloric acid voglibose that gives the crystallization shape that warm-blooded animal makes by the described method of claim 43.
57. method as claimed in claim 56 is characterized in that, described disease is diabetes, obesity, obesity and hyperlipidaemia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1210/DEL/2003 | 2003-09-26 | ||
| IN1210DE2003 | 2003-09-26 |
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| Publication Number | Publication Date |
|---|---|
| CN1882526A true CN1882526A (en) | 2006-12-20 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800339960A Pending CN1882526A (en) | 2003-09-26 | 2004-09-24 | Process for the preparation of voglibose |
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| Country | Link |
|---|---|
| CN (1) | CN1882526A (en) |
| WO (1) | WO2005030698A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101279925B (en) * | 2008-05-30 | 2011-10-19 | 雷云 | Tetrabenzyl voglibose, preparation and application thereof |
| CN105963280A (en) * | 2016-06-30 | 2016-09-28 | 合肥华方医药科技有限公司 | Voglibose oral instant film and preparation method thereof |
| CN111855841A (en) * | 2020-06-30 | 2020-10-30 | 辰欣药业股份有限公司 | Method for measuring related substances in voglibose raw material and preparation |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005092834A1 (en) * | 2004-03-29 | 2005-10-06 | Ranbaxy Laboratories Limited | Processes for the purification of voglibose and intermediates thereof |
| KR100714197B1 (en) * | 2006-04-05 | 2007-05-02 | 한미약품 주식회사 | Process for the preparation of voglibose |
| CN100393694C (en) | 2006-07-17 | 2008-06-11 | 深圳市药兴生物科技开发有限公司 | Tetrabenzyl voglibose crystallizing and preparing process |
| JO3353B1 (en) | 2012-04-20 | 2019-03-13 | Ono Pharmaceutical Co | Isolated solid form of anamorelin monohydrochloride with low molar ratio of chloride : anamolerin and low content of residual organic solvent |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4898986A (en) * | 1986-09-09 | 1990-02-06 | Takeda Chemical Industries, Ltd. | Inosose derivatives, production and use thereof |
-
2004
- 2004-09-24 CN CNA2004800339960A patent/CN1882526A/en active Pending
- 2004-09-24 WO PCT/IB2004/003120 patent/WO2005030698A1/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101279925B (en) * | 2008-05-30 | 2011-10-19 | 雷云 | Tetrabenzyl voglibose, preparation and application thereof |
| CN105963280A (en) * | 2016-06-30 | 2016-09-28 | 合肥华方医药科技有限公司 | Voglibose oral instant film and preparation method thereof |
| CN111855841A (en) * | 2020-06-30 | 2020-10-30 | 辰欣药业股份有限公司 | Method for measuring related substances in voglibose raw material and preparation |
| CN111855841B (en) * | 2020-06-30 | 2022-06-14 | 辰欣药业股份有限公司 | Method for measuring related substances in voglibose raw material and preparation |
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| Publication number | Publication date |
|---|---|
| WO2005030698A1 (en) | 2005-04-07 |
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