CN104447721A - Canagliflozin anhydrous compound - Google Patents
Canagliflozin anhydrous compound Download PDFInfo
- Publication number
- CN104447721A CN104447721A CN201310415190.9A CN201310415190A CN104447721A CN 104447721 A CN104447721 A CN 104447721A CN 201310415190 A CN201310415190 A CN 201310415190A CN 104447721 A CN104447721 A CN 104447721A
- Authority
- CN
- China
- Prior art keywords
- clean
- anhydrous compound
- kan gelie
- kan
- gelie
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine, and in particular to a Canagliflozin anhydrous crystal form and a preparation method thereof. The Canagliflozin prepared by the invention has the advantages of chemical purity of 99.9%, maximum is less than 1 per thousand, optical purity of up to 99.96% ee and good stability. The invention also relates to application of the crystal form composition to preparation of medicaments for treating type 2 diabetes and related diseases.
Description
Technical field
The invention belongs to medical art, be specifically related to clean anhydrous crystal forms of Kan Gelie and preparation method thereof, the invention still further relates to the application of composition in the disease treatments such as diabetes B using this compound.
Background technology
Patent WO2005/012326 is disclosed as the compound group of sodium dependent glucose transporter (SGLT) inhibitor, and these compounds are for the therepic use of process diabetes, obesity, diabetic complication etc.Be described in 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzene of the formula (I) of patent WO2005/012326:
Generally speaking, in order to commercial use, importantly product should possess the good character of operation.In addition, also need this product manufacturing pure matter and crystal type, make formula can meet strict requirement pharmaceutically and specification.
And it is desirable to this product and should be and can be easy to filter and easily dry pattern.In addition, it is desirable to economically special preservation condition can be stable product within the time of an elongated segment.
But the crystal type that will obtain formula (I) compound from organic solvent has difficulties.
Have now found that and the reproducible method of commercial size can produce the anhydrous compound of crystalline form (I).
Summary of the invention
The invention provides the material of anhydrous compound crystal type as novelty of formula (I) compound, particularly with pharmaceutically acceptable pattern.
The present inventor has found from moisture solvent, crystallization to go out formula (I) compound, and this formula (I) compound crystal type possesses the good character of operation and characteristic.
Accordingly, the present invention relates to:
A kind of crystal type 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene anhydrous compound.
A kind of crystal type 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene anhydrous compound, be characterised in that powder x-ray diffraction collection of illustrative plates (powder x-ray diffraction pattern), this collection of illustrative plates comprises the following 2 θ values using CuKa radiation measurement: 3.780 ± 0.2,7.660 ± 0.2,15.360 ± 0.2,17.040 ± 0.2,17.900 ± 0.2,18.820 ± 0.2,21.640 ± 0.2,23.040 ± 0.2,24.280 ± 0.2,26.360 ± 0.2,27.400 ± 0.2.
A kind of in order to prepare the method for crystal type 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene semihydrate, it comprises the solution forming 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, and utilizes precipitation or recrystallize from this anhydrous compound of this solution crystallization.
A kind of medical composition, includes crystal type 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the benzene anhydrous compound of effective amount and pharmaceutically acceptable carrier.
One is used for the treatment of or delays diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, retardance wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, the blood level of lipid acid raises, the blood level of glycerine raises, hyperlipidemia, fat, hypertriglyceridemia, X syndrome (syndrome X), diabetic complication, the method of arteriosclerosis or hypertensive progress or morbidity, it comprises crystal type 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the benzene semihydrate of dispensing treatment significant quantity.
As mentioned above, the present invention comprises some solid state crystalline form.There is multiple method for characterizing this pattern, and the present invention not should by selected method or be used for characterization the compounds of this invention equipment and limit.Such as, with X-ray diffracting spectrum, in experimental patterns, this diffraction peak intensities can change to some extent, as being known in the art, mainly results from the preferred orientation (non-any orientation of this crystallization) of prepared sample.Therefore, person skilled in the art can understand, and category of the present invention must consider the change degree of feature.
The clean anhydrous compound crystal of this Kan Gelie, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value as follows.
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
When infrared spectrogram measures, the correction polystyrene film of instrument, meets the regulation of Chinese Pharmacopoeia.
This crystal formation infrared spectrogram (KBr pressed disc method mensuration), at 3422 ± 5cm
-1; 3099 ± 5cm
-1; 2875 ± 5cm
-1; 1547 ± 2cm
-1; 1437 ± 2cm
-1; 1158 ± 2cm
-1there is characteristic peak at place.
The fusing point of this crystal formation is 222 DEG C-222.5 DEG C, measures by the method for Chinese Pharmacopoeia, and this is that those skilled in the art are in common knowledge.
Another object of the present invention, discloses the preparation method of the clean anhydrous compound crystal of Kan Gelie,
Specifically comprise the following steps:
Kan Gelie adds in 4-5 times of (weigh-volume ratio) water only, and in the above-mentioned aqueous solution, add the dimethyl formamide (DMF) of the clean 0.5%-1% of Kan Gelie, stir 30 minutes, filter, filtrate is cooled to 10 DEG C-15 DEG C, for subsequent use.
The mixed solution of clean for Kan Gelie 18-20 times of acetonitrile-methyl ethyl ketone=5-6:5-4 is cooled to 10 DEG C-15 DEG C, adds above-mentioned stock solution, insulation 16-20 hour, crystallization, filter, drying obtains.Chemical purity is up to 99.9%, and maximum contaminant is less than 1 ‰, and optical purity is up to more than 99.9%ee.
Kan Gelie used is clean, and the method synthesis that reference WO2005/012326 provides, the Kan Gelie of synthesis is clean, and its chemical structure, through determination of elemental analysis, proves that chemical structure is correct.
Another object of the present invention, provides the composition comprising the clean anhydrate of Kan Gelie that Kan Gelie clean anhydrate crystal and one or more pharmaceutically acceptable carriers form.
Crystalline compound of the present invention has the activity as sodium dependent glucose transporter inhibitors, and shows splendid blood sugar decreasing effect.
Crystal type expection of the present invention is useful in the following areas: treatment, prevent or delay diabetes (1 type and diabetes B etc.), diabetic complication is (as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), post prandial hyperglycemia, retardance wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, the blood level of lipid acid raises, the blood level of glycerine raises, hyperlipidemia, fat, hypertriglyceridemia, X syndrome, arteriosclerosis or hypertensive progress or morbidity.
Crystal type of the present invention or its pharmaceutically acceptable salt can oral or parenteral administration, and pharmaceutical preparation pattern that can be suitable and using.Suitable pharmaceutical preparation for oral administration medicine supplying comprises, and such as, solid formulation is as tablet, granula, capsule and powder, or liquid formulation, suspension formulation, emulsification preparation etc.Suitable pharmaceutical preparation for parenteral administration comprises, such as, and suppository; Injection formulations or intravenous drip preparations, utilize distilled water for injection, physiological saline solution or D/W; And suction preparation.
Medical composition herein will in every dose unit, i.e. tablet, capsule, powder, injection, suppository, amounts (teaspoonful) etc., comprise oneself about 0.01 mg/kg of activeconstituents extremely about 100 mg/kg body weight (preferably oneself about 0.01 mg/kg extremely about 50 mg/kg; And more preferably from about 0.01 mg/kg extremely about 30 mg/kg), and dosage about 0.01 mg/kg/day extremely about 100 mg/kg/day (preferably from about 0.01 mg/kg/day extremely about 50 mg/kg/day, and more preferably from about 0.01 mg/kg/day extremely about 30 mg/kg/day) certainly can be given.The method that treatment is described in illness of the present invention also can use the medical composition of crystal type and the pharmaceutically acceptable carrier comprised as defined herein and implement.This dosage form will comprise oneself about 0.01 mg/kg of activeconstituents extremely about 100 mg/kg (preferably oneself about 0.01 mg/kg extremely about 50 mg/kg, and more preferably from about 0.01 mg/kg extremely about 30 mg/kg), and any pattern being applicable to selected dispensing pattern can be formed.But this dosage can be different according to the severity of dosing way, individual demand, wish treatment symptom and the compound used.The usage of dispensing every day or rear periodically medication (post-periodicdosing) can be used in.
If desired, time, crystal type of the present invention can use with one or more other antidiabetics, antihyperglycemic agents and/or other diseases therapeutic combination.The compounds of this invention and this other treatment agent can same dosage form or the oral dosage form separated or inject be offerd medicine.
The dosage of this therapeutical agent can be complied with, such as, the age, body weight, conditions of patients, dosing way, different from dosage forms.
This medical composition can oral administration medicine supplying to mammals, comprise the mankind, ape, dog, with such as tablet, capsule, granula or powder, or the dosage forms of the injection type of parenteral administration or interanasal administration or skin paste formulation.
Stability test
The stability of contriver to crystal formation of the present invention is studied, and investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), and high humidity (92.5% ± 5%) inspection target is outward appearance, content and related substance.
Result: from 0-10 days under high light, high temperature, super-humid conditions, outward appearance, related substance, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
Embodiment
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
In the 500ml reaction flask that stirring, thermometer, condenser are housed, add clean and 300 ml waters of 60 Ke Kangelie, in the above-mentioned aqueous solution, add 0.5 gram of dimethyl formamide (DMF), stirs 30 minutes, filtration, filtrate is cooled to 12 DEG C, for subsequent use.
The mixed solution of 1150ml acetonitrile-methyl ethyl ketone=5:5 is cooled to 13 DEG C, adds above-mentioned stock solution under stirring, be incubated 18 hours, crystallization, filter, drying obtains white crystals 54.4 grams.Purity 99.9% (HPLC normalization method), optical purity 99.96%ee (chirality HPLC).
INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer; CuKa, 40Kv, 100mA; 2 θ sweep limit: 0-50
°.
Claims (6)
1. the clean anhydrous compound of Kan Gelie shown in formula I,
The crystal of the clean anhydrous compound of described Kan Gelie, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and d value,
The error of 2 θ diffraction angle is ± 0.2.
2. the clean anhydrous compound crystal of Kan Gelie described in claim 1, infrared spectrogram, pellet technique measures, at 3422 ± 5cm
-1; 3099 ± 5cm
-1; 2875 ± 5cm
-1; 1547 ± 2cm
-1; 1437 ± 2cm
-1; 1158 ± 2cm
-1there is characteristic peak at place.
3. the preparation method of the clean anhydrous compound crystal of Kan Gelie described in claim 1, by Kan Gelie being added only in 4-5 times of (weight or measurement (WM) ratio) water, the dimethyl formamide (DMF) of the clean 0.5%-1% of Kan Gelie is added in the above-mentioned aqueous solution, stir 30 minutes, filter, filtrate is cooled to 10 DEG C-15 DEG C, for subsequent use, then, the mixed solution of clean for Kan Gelie 18-20 times of acetonitrile-methyl ethyl ketone=5-6:5-4 is cooled to 10 DEG C-15 DEG C, adds above-mentioned stock solution, insulation 16-20 hour, crystallization, filter, drying obtains.
4. the composition of the clean anhydrous compound of Kan Gelie formed containing the clean anhydrous compound crystal of Kan Gelie described in claim 1 and one or more pharmaceutically acceptable carriers.
5. composition according to claim 4, is characterized in that said composition is for the preparation of tablet.
6. the clean anhydrous compound crystal of Kan Gelie described in claim 1 is manufacturing the application in treatment diabetes B medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310415190.9A CN104447721A (en) | 2013-09-13 | 2013-09-13 | Canagliflozin anhydrous compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310415190.9A CN104447721A (en) | 2013-09-13 | 2013-09-13 | Canagliflozin anhydrous compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104447721A true CN104447721A (en) | 2015-03-25 |
Family
ID=52894540
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310415190.9A Pending CN104447721A (en) | 2013-09-13 | 2013-09-13 | Canagliflozin anhydrous compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104447721A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016136830A1 (en) * | 2015-02-27 | 2016-09-01 | 田辺三菱製薬株式会社 | Novel crystal of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene |
| WO2016191173A1 (en) * | 2015-05-22 | 2016-12-01 | Janssen Pharmaceutica Nv | Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol |
-
2013
- 2013-09-13 CN CN201310415190.9A patent/CN104447721A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016136830A1 (en) * | 2015-02-27 | 2016-09-01 | 田辺三菱製薬株式会社 | Novel crystal of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene |
| WO2016191173A1 (en) * | 2015-05-22 | 2016-12-01 | Janssen Pharmaceutica Nv | Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol |
| TWI710568B (en) * | 2015-05-22 | 2020-11-21 | 比利時商健生藥品公司 | Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101573368B (en) | Crystalline form of 1- (belta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate | |
| CN103260613B (en) | 3-methanesulfonylpropionitrile for treating inflammation and pain | |
| JPS5843996A (en) | Stable s-adenosylmethionine salts, manufacture and therapeutical composition containing them as active components | |
| EA016904B1 (en) | Novel choline cocrystal of epalrestat | |
| JP2022503890A (en) | A salt formed by 2- (1-acyloxy-N-pentyl) benzoic acid and a basic amino acid or aminoguanidine, and a method and use thereof. | |
| CN107311915A (en) | A kind of salicylic acid organic pharmaceutical co-crystal and preparation method thereof | |
| JP7362646B2 (en) | cocrystal | |
| EP3653603A1 (en) | Fenlean (flz) crystal g form, preparation method, and composition and use thereof | |
| CN103284991B (en) | Food compositions | |
| CN104447721A (en) | Canagliflozin anhydrous compound | |
| CN104447722A (en) | Canagliflozin compound | |
| CN104945455B (en) | Tonka bean camphor glycosides compounds, its preparation method and pharmaceutical composition and purposes | |
| CN114920743A (en) | Indole alkaloid and preparation method and application thereof | |
| EP3904335A1 (en) | Acetylsalicylic acid derivative and application thereof | |
| CN102234284B (en) | Fluorine-containing ticlopidine analogues, and preparation method and application thereof | |
| CN110872280B (en) | Application of flavone C-glycoside monomeric compound | |
| CN113214207A (en) | Hesperetin and betaine eutectic compound A, preparation method, composition and application thereof | |
| CN104876942B (en) | isosorbide mononitrate hemihydrate | |
| Mahwi et al. | Hypoglycemic, antihistaminic and diuretic effects of aqueous extract of Adiantum capillus. | |
| CN102731430B (en) | Novel febuxostat crystal form, its preparation method and application thereof | |
| RU2575923C2 (en) | Organic salts of bromfenac and method for producing them, composition containing them, and using them | |
| CN105541946A (en) | Adenosine cyclophosphate crystalline compound | |
| CN104447751A (en) | Tofacitinib compound | |
| CN105439889A (en) | Vanillylamine type new compound as well as preparation method and medical appliance thereof | |
| CN104945392A (en) | Crystal-type canagliflozin-hydrate as well as preparation method and application of crystal-type canagliflozin hydrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150325 |
|
| WD01 | Invention patent application deemed withdrawn after publication |