WO2014127735A1 - Formes solides de trélagliptine, leur procédé de préparation et leurs applications - Google Patents
Formes solides de trélagliptine, leur procédé de préparation et leurs applications Download PDFInfo
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- WO2014127735A1 WO2014127735A1 PCT/CN2014/072370 CN2014072370W WO2014127735A1 WO 2014127735 A1 WO2014127735 A1 WO 2014127735A1 CN 2014072370 W CN2014072370 W CN 2014072370W WO 2014127735 A1 WO2014127735 A1 WO 2014127735A1
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- WIPO (PCT)
- Prior art keywords
- crystal form
- troglitazone
- trotagliptin
- powder
- ray diffraction
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to the field of organic chemistry and the field of pharmacy, in particular to a solid form of trozastatin, a preparation method and use thereof, a pharmaceutical composition comprising the novel solid form, and the novel solid form for the preparation of a therapeutic dipeptide-based peptide Application of Enzyme IV (DPP-IV) Mediated Diseases in Drugs Background technique
- Trelaglittin chemical name: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4- Dioxy-1(2H)-pyrimidinyl]methyl]-4-fluoro-benzonitrile, structure as
- Tristatin is a dipeptidyl peptidase IV (DPP-IV) inhibitor
- DPP-IV is a serine amino dipeptidase that removes Xaa-Pro from the amino terminus (N-terminus) of peptides and proteins.
- Dipeptide is constitutively expressed on epithelial and endothelial cells of various tissues (intestine, liver, kidney, and placenta), also in body fluids, and is also expressed on circulating T-lymphocytes.
- DPP-IV has been implicated in many human diseases, including but not limited to diabetes (especially type 2 diabetes), diabetic dyslipidemia, impaired glucose tolerance (IGT), fasting plasma glucose damage (IFG), metabolic Acidosis, ketosis, appetite regulation and obesity; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, AIDS and cancer.
- DPP-IV inhibitors are useful as drugs for the prevention, delay and/or treatment of DPP-IV mediated conditions.
- Triglitastatin is a long-acting DPP-IV inhibitor developed by Takeda, Japan, and is currently being used in Phase III clinical studies.
- the treatment of type 2 diabetes is administered once a week, and the same drugs on the market are administered daily, so this product has excellent clinical value and market value.
- CN1926128A, CN101360723A and the like disclose a method for preparing troglitazone, but neither of them discloses a solid form.
- Trastatin is a poorly water-soluble compound, which is generally used in solid form in preparations, and is therefore of great significance for the study of its solid form.
- One of the objects of the present invention is to provide a novel solid form of troglitazone and a process for its preparation.
- Another object of the present invention is to provide a pharmaceutical composition comprising a new solid form of trozastatin. It is yet another object of the present invention to provide the use of a novel solid form of trozastatin for the manufacture of a medicament for the treatment of a disease mediated by DPP-IV.
- the present invention first provides a crystalline form of troglitazone of the formula I.
- the present invention provides crystalline form of crystalline trougliptin, Form B, Form C, Form D, and Form. Still further, the present invention provides an amorphous form of troglitazone.
- the present invention provides a process for the preparation of the above crystalline trougliptin and amorphous troglitazone.
- the present invention provides a mixture comprising the above crystalline troxliptin.
- the present invention provides a pharmaceutical composition comprising the above novel solid form of troglitazone.
- the present invention provides the use of the above novel solid form of troglitazone for the preparation of a medicament for the treatment of a disease mediated by DPP-IV.
- the powder X-ray diffraction pattern of the troglitazone crystal form A provided by the present invention is characterized by: a value of 5.7° ⁇ 0.2°, 11.4° ⁇ 0.2°, 12.5° ⁇ 0.2°, 16.8° ⁇ 0.2° at 2 ⁇ , 17.1. ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.9° ⁇ 0.2°, 20.5° ⁇ 0.2°, 22.5. ⁇ 0.2. 22.9. ⁇ 0.2. , 29.1. ⁇ 0.2. There are characteristic diffraction peaks at the same place.
- the powder X-ray diffraction pattern of troglitazone Form A is characterized by:
- the 2 ⁇ value is 5.7. ⁇ 0.2°, 11.4. ⁇ 0.2. , 12.5. ⁇ 0.2. 16.8. ⁇ 0.2. 17.1. ⁇ 0.2. 19.4. ⁇ 0.2. , 19.9. ⁇ 0.2. 20.5° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.5° ⁇ 0.2°, 22.9° ⁇ 0.2°, 25.2° ⁇ 0.2°, 27.6° ⁇ 0.2°, 29.1° ⁇ 0.2°, 32.0° ⁇ 0.2°, etc. Corresponding to characteristic diffraction peaks.
- the powder X-ray diffraction pattern of the troagliptin crystal form A of the present invention at a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
- the troglitazone Form A provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
- the treprostatine crystalline form A content of the prepared troglitin mixture provided by the present invention (mass content The amount) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
- troglitazone mixture of the present invention refers to troglitazone containing other impurities prepared by direct synthesis by chemical synthesis.
- the invention provides a preparation method of troglitazone crystal form A, which comprises:
- the separated solid is dried.
- the mass/mass ratio of the solvent to trozastatin is generally 4:1 to 20:1; and the dissolution can be carried out by heating.
- the crystallization may be carried out under standing or under stirring;
- the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding anti-solvent, and adding crystal Single or combined use of methods.
- the "anti-solvent” refers to a solvent which is poorly soluble in troglitazone at room temperature but which is miscible with the solvent which dissolves trozastatin in step (1), such as ruthenium, ruthenium and petroleum. Ether, etc.
- the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed by the solvent in the above step (1).
- the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
- the present invention provides a method for preparing troglitazone crystal form A, which comprises: dissolving statstatin in 7-15 times by weight of isopropanol, and cooling under stirring Crystallization
- the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
- the present invention provides a method for preparing troglitazone crystal form, which comprises: dissolving statastigine in 7-15 times by weight of tetrahydrofuran, and cooling and crystallization under stirring ;
- it is cooled to 0 to 10 ° C for crystallization and filtration;
- the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
- the present invention provides a method for preparing troglitazone crystal form, which comprises: dissolving statstatin in 7-15 times by weight of ethyl acetate, and cooling under stirring Crystallization
- it is cooled to 0 to 10 ° C for crystallization and filtration;
- the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
- the powder X-ray diffraction pattern of the troglitin crystal form of the present invention is characterized by a value of 4.9 ° ⁇ 0.2 ° and 5.7 at 2 ⁇ . ⁇ 0.2. , 9.9. ⁇ 0.2. , 11.4. ⁇ 0.2. , 14.8. ⁇ 0.2. 20.2. ⁇ 0.2. , 22.7 ° ⁇ 0.2 °, 27.0. ⁇ 0.2. There are characteristic diffraction peaks at the same place.
- the powder X-ray diffraction pattern of troglitazone Form B of the present invention is characterized by a value of 4.9 at 2 ⁇ . ⁇ 0.2. , 5.7. ⁇ 0.2. , 9.9. ⁇ 0.2°, 11.4. ⁇ 0.2.
- the powder X-ray diffraction pattern of the troagliptin crystal form B of the present invention represented by a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
- the troglitazone Form B provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
- the troxreline form B content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
- the invention provides a preparation method of troglitazone crystal form B, the method comprising:
- the separated solid is dried.
- the mass/mass ratio of methanol to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
- the crystallization may be carried out under standing or under stirring;
- the crystallization method is a conventional method in the art, such as cooling, distilling off a part of a solvent, adding a seed crystal, etc. Used alone or in combination.
- the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of methanol.
- the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
- the present invention provides a method for preparing troglitazone crystal form B, which comprises: dissolving statstatin in 7-15 times by weight of methanol, and cooling and crystallization under stirring ;
- the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
- the powder X-ray diffraction pattern of troigliptin crystal form C provided by the present invention is characterized by a value of 4.9 ° ⁇ 0.2 ° and 9.7 at 2 ⁇ . ⁇ 0.2. , 12.5. ⁇ 0.2. 12.9. ⁇ 0.2. 14.6. ⁇ 0.2. 16.7. ⁇ 0.2. 20.3. ⁇ 0.2. 22.0. ⁇ 0.2. 26.2. ⁇ 0.2. , 34.1 ° ⁇ 0.2 °, etc. correspond to characteristic diffraction peaks.
- the powder X-ray diffraction pattern of troigliptin Form C of the present invention is characterized by a value of 4.9 at 2 ⁇ . ⁇ 0.2°, 9.7. ⁇ 0.2°, 12.5. ⁇ 0.2°, 12.9. ⁇ 0.2°, 14.6. ⁇ 0.2°, 16.7. ⁇ 0.2°, 20.3. Characteristic diffraction peaks correspond to ⁇ 0.2°, 22.0° ⁇ 0.2°, 22.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.3° ⁇ 0.2°, 26.2° ⁇ 0.2°, 34.1° ⁇ 0.2°.
- the powder X-ray diffraction pattern of the troglitazone crystal form C of the present invention at a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
- the troglitazone crystal form C provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern shown in FIG.
- the troigliptin crystalline form C provided by the present invention is an ethanolate of trozastatin; in a preferred embodiment, the troigliptin crystalline form C is an ethanolate of trozastatin
- the molar composition ratio of trozastatin to ethanol is about 1:1, that is, having the structure shown in Formula II,
- the troglitazone form c content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
- the invention provides a preparation method of troglitazone crystal form C, the method comprising:
- the separated solid is dried.
- the mass/mass ratio of ethanol to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
- the crystallization may be carried out under static conditions or under stirring;
- the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
- the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of ethanol.
- the drying temperature is usually 10 to 120 ° C, preferably 10 to 50 ° C, and it may be dried at normal pressure or dried under reduced pressure.
- the present invention provides a method for preparing troglitazone crystal form c, which comprises: dissolving troglitazone in 7-15 times by weight of ethanol, and cooling and crystallization under stirring ;
- it is cooled to 0 to 10 ° C for crystallization and filtration;
- the separated crystals are dried at normal pressure or under reduced pressure at 10 to 50 Torr.
- the powder X-ray diffraction pattern of the troglitin crystal form D provided by the present invention is characterized by a value of 5.5 ° ⁇ 0.2 ° and 12.2 at 2 ⁇ . ⁇ 0.2. 15.7. ⁇ 0.2. 16.8. ⁇ 0.2. 19.7. ⁇ 0.2. 22.2. ⁇ 0.2. There are characteristic diffraction peaks at 22.5° ⁇ 0.2°.
- the powder X-ray diffraction pattern of troglitazone Form D of the present invention is characterized by a value of 5.5 at a pH of 5.5. Division 0.2. 12.2. Division 0.2. , 12.5. Division 0.2. 15.7. Division 0.2. 16.8. Division 0.2. 19.7. Division 0.2. 20.4. Division 0.2. 22.2° ⁇ 0.2°, 22.5° ⁇ 0.2°, 25.0° ⁇ 0.2°, 26.4° ⁇ 0.2°, 28.7° ⁇ 0.2° correspond to characteristic diffraction peaks.
- the powder X-ray diffraction pattern of the troagliptin crystal form D of the present invention represented by a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
- the troglitazone crystal form D provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
- the treprostatine crystal form D content (quality included) of the prepared troglitin mixture provided by the present invention The amount is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
- the invention provides a preparation method of troglitazone crystal form D, the method comprising:
- the separated solid is dried.
- the mass/mass ratio of acetonitrile to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
- the crystallization may be carried out under static conditions or under stirring;
- the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
- the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of acetonitrile.
- the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
- the present invention provides a method for preparing troglitazone crystal form D, which comprises: dissolving troglitazone in 7-15 times by weight of acetonitrile, and cooling it under standing.
- it is cooled to 0 to 20 ° C for crystallization and filtration;
- the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
- the powder X-ray diffraction pattern of the troglitazone crystal form provided by the present invention is characterized by: a value of 5.1 ° ⁇ 0.2 ° at 2 ⁇ ,
- the powder X-ray diffraction pattern of the troglitazone crystalline form of the present invention is characterized by: a value of 5.1 ⁇ ⁇ 0.2 °, 5.4 ° ⁇ 0.2 °, 7.0 ° ⁇ 0.2 at 2 ⁇ . °, 9.0 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 11.0 ° ⁇ 0.2 °, 13.1 ° ⁇ 0.2 °, 14.3 ° ⁇ 0.2 °, 16.3 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 23.9 ° ⁇ 0.2 °, 25.4° ⁇ 0.2°, 26.5° ⁇ 0.2°, etc. correspond to characteristic diffraction peaks.
- the powder X-ray diffraction pattern of the troglitazone crystal form of the present invention represented by a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
- the troglitazone Form E provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern shown in FIG.
- the troxreline Form E content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
- the invention provides a preparation method of troglitazone crystal form E, the method comprising:
- the separated solid is dried.
- the mass/mass ratio of acetone to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
- the crystallization may be carried out under static conditions or under stirring;
- the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
- the separation may be carried out by a conventional method in the art such as filtration, and optionally, the separated solid may be washed with acetone.
- the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
- the present invention provides a method for preparing troglitazone crystal form E, which comprises: dissolving statastigine in 7-15 times by weight of acetone, and cooling and crystallization. ;
- it is cooled to 0 to 10 ° C for crystallization and filtration;
- the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
- the present invention provides an amorphous troglitin which has the characteristics represented by the powder X-ray diffraction pattern shown in Fig. 6.
- the amount of statin statin (mass content) in the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
- the invention provides various preparation methods of amorphous troglitazone, including:
- suitable organic solvents include acetone, chloroform, and the like.
- the mass/mass ratio of solvent to trozastatin is generally from 4:1 to 20:1; dissolution can be carried out by heating.
- the concentrated organic solvent may be carried out under normal pressure or under reduced pressure.
- the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
- troglitazone is heated and melted
- the heating and melting temperature is generally 165 ° C or higher, preferably 165 to 175 ° C.
- the present invention provides a method for preparing an amorphous form of troglitazone, which comprises: dissolving statstatin in 7-15 times by weight of acetone, and distilling off under reduced pressure. Acetone is obtained as a residual solid; optionally, the obtained solid is dried at 40 to 70 Torr under normal pressure or reduced pressure.
- the present invention provides an alternative method of preparing triclinide amorphous comprising: heating and melting troglitazone at 165-170, followed by cooling and solidification.
- Representative powder X-ray diffraction patterns of the troagliptin crystal forms A, B, C, D, E and amorphous provided by the present invention are shown in Figures 1 to 6.
- "Representative powder X-ray diffraction pattern” means that the crystal form or amorphous powder X-ray diffraction characteristics conform to the overall morphology of the map, and it is understood that during the test, due to various factors ( If the particle size of the test sample, the method of processing the sample, the instrument, the test parameters, the test operation, etc., the peak position or peak intensity of the powder X-ray diffraction pattern measured by the same crystal form will be certain. difference. In general, the experimental error of the diffraction peak 2 ⁇ in the X-ray powder diffraction pattern can be ⁇ 0.2°.
- a further object of the present invention is to provide a troglitazone mixture comprising any of the above-described crystalline forms, said crystalline form having a mass content of greater than 70%, preferably greater than 80%, more preferably greater than 90%.
- the crystalline form described herein is a single crystal form selected from the group consisting of crystal forms A, B, C, D or E, rather than a mixture of the above crystal forms; that is, the mixture
- the crystalline form contained in one of the crystalline forms A, B, C, D or E has a mass content of greater than 70%, preferably greater than 80%, more preferably greater than 90%.
- a further object of the present invention is to provide a pharmaceutical composition comprising the above novel solid form of troglitazone and the use of the above novel solid form of troglitazone for the manufacture of a medicament for human use.
- the invention provides a medicament comprising a therapeutically effective amount of troglitazone Form A, Form B, Form (Formation Form D, Form E or amorphous and pharmaceutical excipients) A composition or formulation.
- the present invention provides the use of troglitazone Form A, Form B, Form C, Form D, Form E or amorphous in the manufacture of a medicament for the treatment of a disease mediated by DPP-IV.
- the above pharmaceutical composition or preparation can be prepared according to a conventional production method in the pharmaceutical field, for example, one or more of troigliptin crystal form A, crystal form B, crystal form (form, form D, form E or amorphous). Mix with one or more carriers and then form the desired dosage form.
- troglitazone Form A, Form B, Form C, Form D, Form E or none The shaped particle size distribution is controlled to be less than 90% less than ⁇ , preferably less than 50 ⁇ , more preferably less than 10 ⁇ .
- the above pharmaceutical composition or preparation can be used as a long-acting DPP-IV inhibitor for the treatment of diseases mediated by DPP-IV, including type I diabetes, type II diabetes, diabetic lipodystrophy, and impaired glucose tolerance. , fasting plasma glucose damage, metabolic acidosis, ketosis, appetite regulation and obesity, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, AIDS or cancer, etc., among which I, II are preferred Type 2 diabetes.
- the dosage form of the above pharmaceutical composition or preparation includes: tablets, pills, granules, powders, aerosols, powders, sprays, suspensions, solutions, emulsions, syrups, elixirs, suppositories, injections, coagulation Glues, implants, films, creams, ointments, pastes, patches, etc. They are administered according to the characteristics of the respective dosage form, including oral, sublingual, injection, luminal, transpulmonary/tracheal or transdermal.
- the amount of the above composition or preparation to be administered is adjusted depending on the nature and severity of the patient's condition, the route of administration, and the age, body weight, etc. of the patient, and the usual weekly dose is between 1 mg and 2 g, preferably between 1 mg and 1000 mg, more preferably 5 mg to Between 700 mg; it can be administered once a week, or it can be administered multiple times, or it can be administered daily.
- the pharmaceutical composition provided by the present invention is an oral solid preparation, preferably a tablet.
- the oral solid preparation contains, in addition to the active ingredient troglitazone, a pharmaceutically acceptable excipient, which is a conventional pharmaceutical excipient in the art, including a filler, a disintegrating agent, a binder or a wetting agent. , lubricants, surfactants, solubilizers or co-solvents.
- the filler generally comprises lactose, microcrystalline cellulose, mannitol, pregelatinized starch, starch, sucrose, dextrin, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium hydrogencarbonate, sodium hydrogencarbonate, Sodium carbonate, hydroxypropyl methylcellulose, ethyl cellulose, and aluminum hydroxide. They may be used singly or in combination, and among them, lactose, microcrystalline cellulose, mannitol, pregelatinized starch or calcium hydrogen phosphate is preferred.
- the disintegrant generally comprises starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl fiber. And hydroxypropyl starch and the like. They may be used singly or in combination, and among them, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose or sodium carboxymethyl starch is preferred.
- the binder or wetting agent generally comprises povidone (polyvinylpyrrolidone), hydroxypropyl methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene Alcohol, starch syrup, gum arabic, water and various concentrations of ethanol solution. They may be used singly or in combination, and among them, povidone (polyvinylpyrrolidone), microcrystalline cellulose or hydroxypropylcellulose is preferred.
- the lubricant generally comprises zinc stearate, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid, silica gel (including light silica, hydrated silica). And colloidal silica;), stearic acid, palmitic acid, aluminum silicate and solid polyethylene glycol. They may be used singly or in combination, and among them, magnesium stearate, micronized silica gel or talc is preferred.
- the surfactant, solubilizer or co-solvent generally includes sodium decyl sulfate, Tween-80, poloxamer, laurel sulfur Sodium and so on. They may be used singly or in combination, and among them, sodium dodecyl sulfate or Tween-80 is preferred.
- excipients such as sweeteners (such as aspartame, stevioside, etc.), coloring agents (such as yellow iron oxide, red iron oxide, etc.), stabilizers (or stabilizers) may be added to the above composition or formulation.
- sweeteners such as aspartame, stevioside, etc.
- coloring agents such as yellow iron oxide, red iron oxide, etc.
- stabilizers or stabilizers
- citric acid lactic acid, malic acid and glycine, etc.
- pH regulators such as calcium carbonate, sodium carbonate, sodium bicarbonate, tartaric acid, fumaric acid, citric acid, etc.
- the above oral solid preparation can be prepared according to a conventional method for preparing an oral solid preparation in the art, for example, the tablet can be directly subjected to wet granulation tableting, dry granulation tableting, fluidized bed granulation tableting, powder mixing directly Prepared by tableting or the like.
- the oral solid preparation is a tablet or pellet, it may be further coated as needed to prepare a film-coated tablet or pellet, a sugar-coated tablet or a pellet. Enteric coated tablets or pellets as well as sustained release tablets or pellets.
- the coating material includes cellulose, acrylic resin and sugars such as hydroxypropylmethylcellulose and sucrose, and a plasticizer, an anti-adhesive agent and an opacifier may be added thereto.
- the present invention provides a simple preparation method of troagliptin crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or amorphous; and can have high purity, such as HPLC area normalization.
- the purity of the method can reach 98%, 99% or more than 99.5%; it has the advantages of good stability and formulation adaptability.
- These advantages are advantageous on the one hand to make them into corresponding preparations, such as their formulations have good stability and effectiveness in preparation and storage; on the other hand, they are also advantageous for making high-purity acid adducts.
- they can be used to prepare HPLC area normalized purity of 98%, 99% or more, and individual impurities are less than 0.15%, 0.1% or 0.05% of tric succinic acid, benzoic acid, etc.
- adults can be used to prepare HPLC area normalized purity of 98%, 99% or more, and individual impurities are less than 0.15%, 0.1% or 0.05% of tric succinic acid, benzoic acid,
- Figure 1 is an X-ray diffraction pattern of troglitazone crystal form A powder
- Figure 2 is an X-ray diffraction pattern of troglitazone crystal form B powder
- Figure 3 is an X-ray diffraction pattern of troglitazone crystal form C powder
- Figure 4 is an X-ray diffraction pattern of troglitazone crystal form D powder
- Figure 5 is an X-ray diffraction pattern of troglitazone crystal form E powder
- Figure 6 is an X-ray diffraction pattern of trozastatin amorphous powder. detailed description
- the nuclear magnetic test in the examples and preparation examples is Bruke AV-II 300MHz or BRUKER AVANCEIII HD 400.
- DMSO-i/6 deuterated dimethyl sulfoxide
- tetramethylsilyl was used as an internal standard at room temperature.
- Example 1 Preparation of troglitazone Form A 2.5 g of troglitazone was dissolved in 25 ml of isopropanol at 75-78 ° C, cooled to 5-10 ° C with stirring, suction filtered, and the obtained solid was dried under reduced pressure at 45-50 Torr. Gliptin crystal form, white solid.
- the X-ray diffraction pattern of the measured powder is shown in Fig. 1.
- the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
- troglitazone 2.5g was dissolved in 48ml of isopropanol at 70 ⁇ 75 °C, cooled to 0 ⁇ 5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 55 ⁇ 60 ⁇ . Gliptin crystal form, white solid.
- troglitazone 2.5 g was dissolved in 25 ml of tetrahydrofuran at 60 to 63 ° C, cooled to 0 to 5 ° C with stirring, and suction filtered to obtain troglitin crystal form A, a white solid.
- Example 4 Preparation of troglitazone Form A 25g of troglitazone was dissolved in 200ml of tetrahydrofuran at 58 ⁇ 63 °C, cooled to 5 ⁇ 10 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 40 ⁇ 45 , to obtain Qugrid. Ting crystal type, white solid.
- troglitazone 2.5 g was dissolved in 25 ml of ethyl acetate at 71-74 ° C, cooled to 0-10 ° C with stirring, suction filtered, and the obtained solid was dried under reduced pressure at 60-65 Torr. Quagliptin crystal form, white solid.
- troglitazone 2.5g was dissolved in 25ml of methanol at 57 ⁇ 60°C, cooled to -5 ⁇ 0°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 40 ⁇ 45 ,. Gliptin crystal form, white solid.
- the measured X-ray diffraction pattern of the powder is shown in Fig. 2, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 0.4%):
- troglitazone 2.5 g was dissolved in 32 ml of methanol at 55 to 58 ° C, cooled to 5 to 10 ° C with stirring, and filtered to obtain troglitazone crystal form B, a white solid.
- troglitazone 25g was dissolved in 470ml of methanol at 55 ⁇ 60°C, cooled to 0 ⁇ 5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 60 ⁇ 65 , to obtain Qugrid. Ting crystal type, white solid.
- troglitazone 2.5g was dissolved in 25ml of ethanol at 72 ⁇ 75 °C, cooled to 0 ⁇ 5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 45 ⁇ 50 ⁇ to obtain Qugrid. Ting Form C, white solid.
- the X-ray diffraction pattern of the measured powder is shown in Fig. 3.
- the measured values are as follows (measured by the diffraction peaks with relative intensities greater than 1%):
- troglitazone 2.5g was dissolved in 13ml of ethanol at 70 ⁇ 75°C, cooled to 5 ⁇ 10°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 10 ⁇ 15 ⁇ to obtain Qugrid. Ting Form C, white solid.
- troglitazone 2.5 g was dissolved in 47 ml of ethanol at 68 to 72 ° C, cooled to 0 to 5 ° C with stirring, and suction filtered to obtain troglitazone crystal form C, a white solid.
- Example 12 Preparation of troglitazone Form C 25g of troglitazone was dissolved in 630ml of ethanol at 70 ⁇ 74°C, cooled to 5 ⁇ 10°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 15 ⁇ 20 ⁇ to obtain troglitazone. Form C, white solid.
- troglitazone 2.5 g was dissolved in 25 ml of acetonitrile at 75-78 ° C, and allowed to stand at 10 to 15 ° C, filtered, and the resulting solid was dried under reduced pressure at 60-65 Torr to obtain a grid.
- Retin form D white solid.
- the X-ray diffraction pattern of the measured powder is shown in Fig. 4, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
- troglitazone was dissolved in 32 ml of acetonitrile, allowed to stand for cooling to 0-5 Torr, suction filtered, and the obtained solid was dried under reduced pressure at 40 to 45 ° C to obtain troglitazone crystal form. D, white solid.
- troglitazone 25 g was dissolved in 470 ml of acetonitrile at 75 to 78 ° C, left to cool to 5 to 10 ° C, and filtered to obtain troglitazone crystal form D, a white solid.
- troglitazone 2.5 g was dissolved in 25 ml of acetone at 50-53 ° C, left to cool to 0-10 ° C, suction filtered, and the obtained solid was dried under reduced pressure at 40-45 Torr. Levin crystal form, white solid.
- the measured X-ray diffraction pattern of the powder is shown in Fig. 5, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
- troglitazone At a reflux temperature, 2.5 g of troglitazone was dissolved in 31 ml of acetone, allowed to stand to cool to 0 to 5 ° C, and suction filtered to obtain troglitazone crystal form E, a white solid.
- troglitazone 25g was dissolved in 470ml of acetone at 48 ⁇ 50°C, left to cool to 5 ⁇ 10°C, filtered by suction, and the obtained solid was dried under reduced pressure at 55 ⁇ 60 ⁇ to obtain troglitazone. Crystalline ⁇ , white solid.
- troglitazone 2.5 g was dissolved in 25 ml of acetone at 50 to 53 ° C, concentrated under reduced pressure to give a white solid, and the obtained solid was dried under reduced pressure at 45 to 50 Torr to obtain amorphous troglitazone.
- the measured powder X-ray diffraction pattern is shown in Fig. 6.
- troglitazone was dissolved in 22 ml of acetone, and concentrated under reduced pressure to give a white solid.
- troglitazone 25 g was dissolved in 480 ml of acetone at 50 to 53 ° C, concentrated under reduced pressure to give a white solid, and the obtained solid was dried under reduced pressure at 65 to 70 Torr to obtain amorphous troglitazone.
- troglitazone 0.5 g was heated and melted, and then cooled to room temperature to obtain troglitazone amorphous.
- Example 23 Tablet containing 12.5 mg of troglitazone and preparation thereof
- Example 24 Tablet containing 12.5 mg of troglitazone and preparation thereof
- troglitazone Form A prepared as in Example 1
- microcrystalline cellulose mannitol
- croscarmellose sodium and colloidal silica in the above components
- it is wet granulated with water, dried, granulated, mixed with magnesium stearate, and tableted.
- Example 26 Tablet containing 25 mg of troglitazone and preparation thereof
- Talc powder is listed as a phenolic acid, a phenolic acid, a vitamin 1.0
- Example 27 Tablet containing 50 mg of troglitazone and preparation thereof
- Example 28 Tablet containing 50 mg of troglitazone and preparation thereof
- Example 29 Tablet containing lOOmg of troglitazone and preparation thereof
- troglitazone crystal form C prepared according to the method of Example 12
- microcrystalline cellulose mannitol
- crospovidone s hard microemulsion f-curvature
- colloidal dioxide After the silicon is mixed, it is wet granulated with water, dried, granulated, mixed with magnesium stearate, and tableted.
- Example 31 Powder containing lOOmg of troglitazone and preparation thereof
- troglitazone crystal form C prepared according to the method of Example 12 in the above table components, lactose pulverized through a 100 mesh sieve, and then troglitazone crystal form (, lactose, talc and stearic acid) Mix the magnesium, sub-package, and get it.
- Example 32 Tablet containing lOOmg of troglitazone and preparation thereof
- Example 33 Tablet containing 200 mg of troglitazone and preparation thereof
- Example 34 Tablet containing 400 mg of troglitazone and preparation thereof
- the obtained concentrate is dissolved in 7500 ml of dichloromethane, and the pH is adjusted to about 3 by adding 2 mol/L hydrochloric acid aqueous solution at 20 to 30 ° C. After adding hydrochloric acid, stirring is continued for about 1 hour, followed by filtration, and the filter cake is sequentially used. The mixture was washed with 4000 ml of chloroformamidine and 2750 ml of tetrahydrofuran, and dried under reduced pressure at 45 to 50 °C.
- the dried solid was added to a mixture of 4,500 ml of dichloromethane and 9000 ml of water, and the pH was adjusted to 12 with 50% aqueous sodium hydroxide solution, and the aqueous phase was extracted with 3700 ml of dichloromethane, and the organic phase was combined.
- the organic phase was washed successively with water 3700 ml*2, dried over anhydrous sodium sulfate, and evaporated to dryness to give a white solid.
- the obtained solid was dried under reduced pressure at 45 to 50 Torr to obtain 502 g of troglitazone (I).
- trozastatin 45.5 g was dissolved in a mixed solvent consisting of 530 ml of tetrahydrofuran and 200 ml of isopropanol at 55 to 60 ° C, and then a solution of 15.8 g of succinic acid and 250 ml of tetrahydrofuran was added dropwise, and the addition was completed. After stirring for 15 minutes, it was cooled to room temperature and stirring was continued for 12 hours. After filtration, the cake was washed with an appropriate amount of isopropanol and dried under reduced pressure at 50 to 55 ° C to obtain 49.4 g of troglitazone succinate.
- troglitazone crystal form C has a dissolution rate of more than 85% in 15 minutes in different dissolution media, and the crystal form has good formulation suitability.
- the relevant substances are detected by HPLC method, and the detection conditions are as follows:
- Detection method Take the appropriate amount of sample, accurately weigh, add methanol to dissolve and dilute to make about 0.5mg solution per lml as the test solution, accurately measure ⁇ , inject into the liquid chromatograph, record the chromatogram, according to the area The law calculates the relevant substance content.
- test results are as follows: Time of investigation Investigation conditions Samples Related substances (%) Whether crystal form changes or not, troglitazone crystal form A 0.14%
- troglitazone crystal form A crystal form B
- crystal form C crystal form D
- form E amorphous have good stability.
- the product Quagstatin C and troglitazone were first ground into a fine powder and added to a conical flask containing 10 ml of water.
- the water temperature was controlled between 25 ⁇ ⁇ 2 ,, and the vibration was vigorously every 5 minutes. Shake for 30 seconds; observe the dissolution of the sample within 30 minutes, and judge its solubility according to Chinese Pharmacopoeia standards.
- the experimental results are as follows:
- the amorphous form of a substance has a better solubility than the crystal form, but the above studies show that the solubility of troglitazone form c in water is greater than that of amorphous.
- the trozaleadine crystal form, the crystalline form ⁇ , the crystalline form C and the troglitazone succinate having a comparable crystal size were prepared by sieving through a ⁇ sieve. Twenty-four male Sprague-Dawley rats, 240-270 g, were randomly divided into 4 groups. The trozastatin crystal forms A, B, C and troglitazone succinate were administered by gavage at a dose of 10 mg/kg. Quglitastatin).
- troglitazone crystal Type A, Form B, and Form C have similar biological properties or effects as salts.
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- Plural Heterocyclic Compounds (AREA)
Abstract
La présente invention concerne des formes solides de trélagliptine, leur procédé de préparation et leurs applications, et concerne spécifiquement six nouvelles formes solides de l'inhibiteur de dipeptidyl peptidase-4 trélagliptine et leurs procédés de préparation, ainsi que des compositions pharmaceutiques comprenant lesdites formes solides de trélagliptine, et leurs utilisations pour la préparation de médicaments pour le traitement de maladies médiées par la dipeptidyl peptidase-4.
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CN201480002130.7A CN104603123B (zh) | 2013-02-22 | 2014-02-21 | 曲格列汀的固态形式及其制备方法和用途 |
JP2015558339A JP2016509031A (ja) | 2013-02-22 | 2014-02-21 | トレラグリプチンの固形形式及びその製造方法と用途 |
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CN201310056368.5A CN104003975A (zh) | 2013-02-22 | 2013-02-22 | 曲格列汀新的固态形式及其制备方法和用途 |
CN201310056368.5 | 2013-02-22 |
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WO2014127735A1 true WO2014127735A1 (fr) | 2014-08-28 |
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PCT/CN2014/072370 WO2014127735A1 (fr) | 2013-02-22 | 2014-02-21 | Formes solides de trélagliptine, leur procédé de préparation et leurs applications |
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JP (1) | JP2016509031A (fr) |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106632241A (zh) * | 2016-12-06 | 2017-05-10 | 安徽省金楠医疗科技有限公司 | 一种琥珀酸曲格列汀制备方法 |
CN112552281A (zh) * | 2020-12-07 | 2021-03-26 | 石家庄市华新药业有限责任公司 | 一种琥珀酸曲格列汀原料药合成工艺 |
CN114983958A (zh) * | 2022-07-13 | 2022-09-02 | 青海夏都医药有限公司 | 一种琥珀酸曲格列汀片及其制备方法 |
Families Citing this family (9)
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CN105384724A (zh) * | 2014-09-01 | 2016-03-09 | 广东东阳光药业有限公司 | 一种氟代物的晶型及其制备方法 |
CN105524041A (zh) * | 2014-09-30 | 2016-04-27 | 四川海思科制药有限公司 | 曲格列汀新晶型及其制备方法和用途 |
CN105524044A (zh) * | 2014-10-22 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | 曲格列汀杂质及其组合物 |
CN105693691A (zh) * | 2014-11-25 | 2016-06-22 | 上海医药工业研究院 | 高纯度曲格列汀的新晶型及其制备 |
CN108794448B (zh) * | 2015-02-11 | 2021-01-26 | 四川科伦药物研究院有限公司 | 一种曲格列汀及其盐的制备方法 |
CN104829590B (zh) * | 2015-04-08 | 2020-04-24 | 重庆医药工业研究院有限责任公司 | 一种纯化曲格列汀的方法 |
CN104825413B (zh) * | 2015-05-25 | 2019-12-20 | 浙江华海药业股份有限公司 | 一种含有琥珀酸曲格列汀的口服片剂及其制备方法 |
CN105561326A (zh) * | 2015-12-31 | 2016-05-11 | 上海现代制药股份有限公司 | 一种曲格列汀包合物及其制备方法和应用 |
CN115785066B (zh) * | 2022-12-08 | 2024-05-31 | 广东工业大学 | 曲格列汀晶型f及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007035629A2 (fr) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Inhibiteurs de dipeptidylpeptidase |
WO2008067465A1 (fr) * | 2006-11-29 | 2008-06-05 | Takeda Pharmaceutical Company Limited | Polymorphes de sel de succinate de 2-[6-(3-amino-pipéridin-1-yl)-3-méthyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylméthy]-4-fluor-benzonitrile et leurs procédés d'utilisation |
WO2008114807A1 (fr) * | 2007-03-13 | 2008-09-25 | Takeda Pharmaceutical Company Limited | Administration hebdomadaire d'inhibiteurs de la dipeptidyle peptidase |
CN103030631A (zh) * | 2011-09-28 | 2013-04-10 | 江苏正大天晴药业股份有限公司 | 用于制备嘧啶二酮类dpp-iv抑制剂的化合物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1911754B1 (fr) * | 2003-08-13 | 2013-10-09 | Takeda Pharmaceutical Company Limited | Inhibiteurs de peptidase dipeptidyl |
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2013
- 2013-02-22 CN CN201310056368.5A patent/CN104003975A/zh active Pending
-
2014
- 2014-02-21 WO PCT/CN2014/072370 patent/WO2014127735A1/fr active Application Filing
- 2014-02-21 JP JP2015558339A patent/JP2016509031A/ja active Pending
- 2014-02-21 CN CN201480002130.7A patent/CN104603123B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007035629A2 (fr) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Inhibiteurs de dipeptidylpeptidase |
WO2008067465A1 (fr) * | 2006-11-29 | 2008-06-05 | Takeda Pharmaceutical Company Limited | Polymorphes de sel de succinate de 2-[6-(3-amino-pipéridin-1-yl)-3-méthyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylméthy]-4-fluor-benzonitrile et leurs procédés d'utilisation |
WO2008114807A1 (fr) * | 2007-03-13 | 2008-09-25 | Takeda Pharmaceutical Company Limited | Administration hebdomadaire d'inhibiteurs de la dipeptidyle peptidase |
CN103030631A (zh) * | 2011-09-28 | 2013-04-10 | 江苏正大天晴药业股份有限公司 | 用于制备嘧啶二酮类dpp-iv抑制剂的化合物 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106632241A (zh) * | 2016-12-06 | 2017-05-10 | 安徽省金楠医疗科技有限公司 | 一种琥珀酸曲格列汀制备方法 |
CN112552281A (zh) * | 2020-12-07 | 2021-03-26 | 石家庄市华新药业有限责任公司 | 一种琥珀酸曲格列汀原料药合成工艺 |
CN114983958A (zh) * | 2022-07-13 | 2022-09-02 | 青海夏都医药有限公司 | 一种琥珀酸曲格列汀片及其制备方法 |
Also Published As
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JP2016509031A (ja) | 2016-03-24 |
CN104603123A (zh) | 2015-05-06 |
CN104603123B (zh) | 2016-12-07 |
CN104003975A (zh) | 2014-08-27 |
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