JP2016509031A - Toleragliptin solid form and production method and use thereof - Google Patents

Abstract

The present invention relates to a solid form of trelagliptin, a method for producing the same, and application thereof. Specifically, the present invention relates to six novel solid forms of trelagliptin, which is a dipeptidyl peptidase IV inhibitor, and a method for producing the same. The present invention relates to drug compositions comprising a novel solid form and their application to the manufacture of drugs for treating diseases mediated by dipeptidyl peptidase IV of the novel solid form of trelagliptin. [Selection figure] None

Description

  The present invention relates to the fields of organic chemistry and pharmaceutics, and specifically, solid forms of trelagliptin, production methods and uses thereof, drug compositions containing these novel solid forms, and these novel solid forms It relates to the application to the manufacture of a medicament for treating diseases mediated by the form of dipeptidyl peptidase IV (DPP-IV).

Trelagliptin has the chemical name 2-[[6-[(3R) -3-amino-1-piperidino] -3,4-dihydro-3-methyl-2,4-dioxy-1 (2H)- Pyrimidyl] methyl] -4-fluoro-benzonitrile, which is a structure of formula I:

  Trelagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor. DPP-IV is a serine aminodipeptidase that removes the Xaa-Pro dipeptide from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, kidney and placenta), is also found in body fluids, and is also expressed on circulating T-lymphocytes. Is done. DPP-IV is already involved in many human disease states, including diabetes (especially type 2 diabetes), diabetic dyslipidemia, impaired glucose tolerance (IGT), fasting glycemic abnormalities (IFG) Including, but not limited to, metabolic acidosis, ketosis, appetite control and obesity; autoimmune diseases (eg, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, AIDS and cancer) and the like. A DPP-IV inhibitor can be used as a drug to prevent, delay and / or treat a condition mediated by DPP-IV.

  Trelagliptin is a long-acting DPP-IV inhibitor developed by the Japanese Takeda Company, currently undergoing Phase III clinical studies, used to treat type 2 diabetes, and administered once a week However, all currently marketed concomitant drugs are administered daily. Therefore, this pharmaceutical has excellent clinical value and market value.

  Patent Document 1, Patent Document 2, and the like disclose a method for producing trelagliptin, but none of the solid forms is disclosed. Trelagliptin is a poorly water-soluble compound and is usually used in the form of solids in pharmaceutical preparations. Therefore, studies on the solid form have sufficiently important significance.

  Through research on trelagliptin solid form, we have discovered a solid form that is characterized by a variety of distinct powder X-ray diffraction spectra that are simple to manufacture, convenient to store, and suitable for the manufacture of a wide variety of formulations.

Chinese Patent Application Publication No. 1926128 Chinese Patent Application No. 101360723

  An object of the present invention is to provide a novel solid form of trelagliptin and a method for producing the same.

  Another object of the present invention is to provide a pharmaceutical composition containing a novel solid form of trelagliptin.

  Another object of the present invention is to provide application of a novel solid form of trelagliptin to the manufacture of a drug for treating diseases mediated by DPP-IV.

  In order to achieve the above-mentioned invention object, the present invention first provides trelagliptin represented by the formula I in the crystalline state.

  Furthermore, the present invention provides crystalline form of trelagliptin, crystalline form A, crystalline form B, crystalline form C, crystalline form D and crystalline form E.

  Furthermore, the present invention provides trelagliptin in an amorphous state.

  Furthermore, the present invention provides a method for producing the crystalline trelagliptin and the amorphous trelagliptin.

  Furthermore, the present invention provides a mixture containing the crystalline trelagliptin.

  Furthermore, the present invention provides a pharmaceutical composition containing the novel solid form of trelagliptin.

  Furthermore, the present invention provides an application of the novel solid form of trelagliptin to the manufacture of a medicament for treating diseases mediated by DPP-IV.

Crystalline form A of trelagliptin
The powder X-ray diffraction spectrum of trelagliptin crystal form A provided by the present invention has 2θ values of 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 It has a characteristic diffraction peak corresponding to °, 22.5 ° ± 0.2 °, 22.9 ° ± 0.2 °, 29.1 ° ± 0.2 °, and the like.

  In one of the modes for carrying out the invention, the powder X-ray diffraction spectrum of crystal form A of treragliptin provided in the present invention has a 2θ value of 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 ° Characterized by having characteristic diffraction peaks corresponding to ± 0.2 °, 27.6 ° ± 0.2 °, 29.1 ° ± 0.2 °, 32.0 ° ± 0.2 °, etc. To do.

Furthermore, the crystalline form A of trelagliptin described in the present application has characteristic diffraction peaks and relative intensities at the following positions in the powder X-ray diffraction spectrum shown at 2θ angle:

  In one of the modes for carrying out the invention, the crystal form A of trelagliptin provided in the present invention has characteristics represented by a powder X-ray diffraction spectrum shown in FIG.

  In one form for carrying out the invention, the content (mass content) of trelagliptin crystalline form A in the prepared trelagliptin mixture provided in the present invention is usually greater than 70%, preferably Greater than 80%, most preferably greater than 90%.

  It is understood by those skilled in the art that the trelagliptin mixture described in the present application refers to trelagliptin that is produced by direct synthesis by a chemical synthesis method and contains other impurities.

The present invention
(1) A step of dissolving trelagliptin in isopropanol, tetrahydrofuran or ethyl acetate;
(2) crystallization step;
(3) a step of separating solids;
(4) Optionally, a method for producing trelagliptin crystal form A comprising the step of drying the separated solid.

  In the step (1) of the method, the mass / mass ratio of the solvent and trelagliptin is usually 4: 1 to 20: 1, and may be dissolved by heating.

In the step (2) of the above method, the crystallization may be performed under standing or may be performed under stirring. The crystallization method is a normal method in this technical field, and for example, methods such as cooling, evaporative removal of a part of the solvent, addition of an antisolvent, and addition of crystal seeds are used alone or in combination. “Anti-solvent” refers to a solvent that does not have good solubility in treragliptin at room temperature but can be co-dissolved with the solvent that dissolves trelagliptin in step (1). For example, n-hexane, n-heptane, and petroleum Ethers and the like.

  In the step (3) of the method, the separation can be performed by a usual method in this technical field such as filtration, and optionally the solid separated by the solvent in the step (1) is washed. can do.

  In step (4) of the method, the drying temperature is usually 30 to 120 ° C., preferably 40 to 70 ° C., and may be atmospheric drying or reduced pressure drying.

In one of the modes for carrying out the invention, the present invention comprises dissolving trelagliptin in 7-15 times by weight of isopropanol by heating and cooling and crystallizing with stirring;
Among them, it is preferably cooled to 0 to 10 ° C. for crystallization and filtration;
Optionally, a method for producing trelagliptin crystal Form A comprising drying the separated crystals at 40 to 70 ° C. under normal pressure or reduced pressure is provided.

In one of the modes for carrying out the invention, the present invention comprises dissolving trelagliptin in 7-15 times weight of tetrahydrofuran by heating and cooling and crystallizing with stirring;
Among them, it is preferably cooled to 0 to 10 ° C. for crystallization and filtration;
Optionally, a method for producing trelagliptin crystal Form A comprising drying the separated crystals at 40 to 70 ° C. under normal pressure or reduced pressure is provided.

In one of the modes for carrying out the invention, the present invention comprises dissolving trelagliptin by heating to 7-15 times the weight of ethyl acetate and cooling and crystallizing with stirring;
Among them, it is preferably cooled to 0 to 10 ° C. for crystallization and filtration;
Optionally, a method for producing trelagliptin crystal Form A comprising drying the separated crystals at 40 to 70 ° C. under normal pressure or reduced pressure is provided.

Crystalline form B of trelagliptin
The powder X-ray diffraction spectrum of crystal form B of trelagliptin provided in the present invention has 2θ values of 4.9 ° ± 0.2 °, 5.7 ° ± 0.2 °, and 9.9 ° ± 0.2. °, 11.4 ° ± 0.2 °, 14.8 ° ± 0.2 °, 20.2 ° ± 0.2 °, 22.7 ° ± 0.2 °, 27.0 ° ± 0.2 It has a characteristic diffraction peak corresponding to a location such as °.

  In one of the modes for carrying out the invention, the powder X-ray diffraction spectrum of the crystalline form B of trelagliptin described in the present application has a 2θ value of 4.9 ° ± 0.2 °, 5.7 ° ± 0. .2 °, 9.9 ° ± 0.2 °, 11.4 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.8 ° ± 0.2 °, 17.1 ° ± 0 2 °, 20.1 ° ± 0.2 °, 20.2 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.1 ° ± 0.2 °, 27.0 ° ± 0 It has characteristic diffraction peaks corresponding to .2 °, 29.6 ° ± 0.2 °, and the like.

Furthermore, the crystalline form B of trelagliptin described in the present application has characteristic diffraction peaks and relative intensities at the following positions in the powder X-ray diffraction spectrum shown at 2θ angle:

  In one of the modes for carrying out the invention, the crystalline form B of trelagliptin provided in the present invention has characteristics represented by a powder X-ray diffraction spectrum shown in FIG.

  In one of the modes for carrying out the invention, the content (mass content) of trelagliptin crystalline form B in the produced trelagliptin mixture provided in the present invention is usually greater than 70%, preferably Greater than 80%, most preferably greater than 90%.

The present invention
(1) a step of dissolving trelagliptin in methanol;
(2) crystallization step;
(3) a step of separating solids;
(4) Optionally, a method for producing trelagliptin crystalline form B comprising the step of drying the separated solid.

  In step (1) of the method, the mass / mass ratio of methanol to trelagliptin is usually 4: 1 to 20: 1; it may be dissolved by heating.

  In step (2) of the above method, the crystallization may be performed under standing or may be performed with stirring; the crystallization method is a normal method in this technical field, for example, cooling. A method such as evaporative removal of a part of the solvent or addition of crystal seeds may be used alone or in combination.

  In the step (3) of the method, the separation can be performed by a usual method in this technical field such as filtration, and optionally, the solid separated by an appropriate amount of methanol can be washed.

  In the step (4) of the method, the drying temperature is usually 30 to 120 ° C., preferably 40 to 70 ° C., and may be atmospheric drying or reduced pressure drying.

In one of the modes for carrying out the invention, the present invention comprises dissolving trelagliptin in 7-15 times by weight of methanol by heating and cooling and crystallizing with stirring;
Among them, it is preferably cooled to −10 to 10 ° C. for crystallization and filtration;
Optionally, the separated crystal is dried at 40 to 70 ° C. under normal pressure or reduced pressure, thereby producing trelagliptin crystal form B.

Crystalline form C of trelagliptin
The powder X-ray diffraction spectrum of crystal form C of trelagliptin provided in the present invention is 4.9 ° ± 0.2 °, 9.7 ° ± 0.2 °, 12.5 ° ± 0.2 as 2θ values. °, 12.9 ° ± 0.2 °, 14.6 ° ± 0.2 °, 16.7 ° ± 0.2 °, 20.3 ° ± 0.2 °, 22.0 ° ± 0.2 It is characterized by having characteristic diffraction peaks corresponding to °, 26.2 ° ± 0.2 °, 34.1 ° ± 0.2 °, and the like.

  In one form for carrying out the invention, the powder X-ray diffraction spectrum of crystal form C of trelagliptin described in the present application is 4.9 ° ± 0.2 °, 9.7 ° ± 0 as 2θ values. .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 °, 22.5 ° ± 0.2 °, 23.2 ° ± 0.2 °, 24.3 ° ± 0.2 °, 26.2 ° ± 0 It has a characteristic diffraction peak corresponding to .2 °, 34.1 ° ± 0.2 °, and the like.

Furthermore, the crystalline form C of trelagliptin described herein has a characteristic diffraction peak and relative intensity at the following positions in the powder X-ray diffraction spectrum shown at 2θ angle:

  In one of the modes for carrying out the invention, the crystal form C of trelagliptin provided in the present invention has characteristics represented by a powder X-ray diffraction spectrum shown in FIG.

In one of the modes for carrying out the invention, the crystalline form C of treragliptin provided in the present invention is an ethanol adduct of treragliptin; in one of the modes for carrying out the preferred invention, The crystalline form C of treragliptin is an ethanol adduct of treragliptin having a molar composition ratio of treragliptin to ethanol of about 1: 1, that is, having a structure represented by Formula II.

  In one form for carrying out the invention, the content (mass content) of trelagliptin crystalline form C in the prepared trelagliptin mixture provided in the present invention is usually greater than 70%, preferably Greater than 80%, most preferably greater than 90%.

The present invention
(1) a step of dissolving trelagliptin in ethanol;
(2) crystallization step;
(3) a step of separating solids;
(4) Optionally, a method for producing crystalline form C of treragliptin comprising the step of drying the separated solid.

  In step (1) of the method, the mass / mass ratio of ethanol and trelagliptin is usually 4: 1 to 20: 1; it may be dissolved by heating.

  In step (2) of the above method, the crystallization may be performed under standing or may be performed with stirring; the crystallization method is a normal method in this technical field, for example, cooling. A method such as evaporative removal of a part of the solvent or addition of crystal seeds may be used alone or in combination.

  In the step (3) of the above method, the separation can employ a usual method in this technical field such as filtration, and can optionally wash the solid separated with an appropriate amount of ethanol. .

  In the step (4) of the above method, the drying temperature is usually 10 to 120 ° C., preferably 10 to 50 ° C., normal pressure drying, or vacuum drying.

In one of the modes for carrying out the invention, the present invention comprises dissolving trelagliptin by heating in ethanol of 7 to 15 times weight and cooling and crystallizing with stirring;
Among them, it is preferably cooled to 0 to 10 ° C. for crystallization and filtration;
Optionally, a process for producing trelagliptin crystalline form C is provided which comprises drying the separated crystals at 10-50 ° C. at normal or reduced pressure.

Crystalline form D of trelagliptin
The powder X-ray diffraction spectrum of crystal form D of trelagliptin provided by the present invention is 5.5 ° ± 0.2 °, 12.2 ° ± 0.2 °, 15.7 ° ± 0.2 as 2θ values. Characteristic diffraction peaks corresponding to °, 16.8 ° ± 0.2 °, 19.7 ° ± 0.2 °, 22.2 ° ± 0.2 °, 22.5 ° ± 0.2 °, etc. It is characterized by having.

  In one of the modes for carrying out the invention, the powder X-ray diffraction spectrum of crystal form D of trelagliptin described in the present application is 5.5 ° ± 0.2 °, 12.2 ° ± 0 as 2θ value. .2 °, 12.5 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.8 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.4 ° ± 0 2 °, 22.2 ° ± 0.2 °, 22.5 ° ± 0.2 °, 25.0 ° ± 0.2 °, 26.4 ° ± 0.2 °, 28.7 ° ± 0 It has a characteristic diffraction peak corresponding to 2 ° or the like.

Furthermore, the crystalline form D of trelagliptin described in the present application has characteristic diffraction peaks and relative intensities at the following positions in the powder X-ray diffraction spectrum shown at 2θ angle:

  In one of the modes for carrying out the invention, the crystal form D of trelagliptin provided in the present invention has characteristics represented by a powder X-ray diffraction spectrum shown in FIG.

  In one form for carrying out the invention, the content (mass content) of trelagliptin crystalline form D in the manufactured trelagliptin mixture provided in the present invention is usually greater than 70%, preferably Greater than 80%, most preferably greater than 90%.

The present invention
(1) A step of dissolving trelagliptin in acetonitrile;
(2) crystallization step;
(3) a step of separating solids;
(4) Optionally, a method for producing trelagliptin crystalline form D, comprising the step of drying the separated solid.

  In step (1) of the method, the mass / mass ratio of acetonitrile to trelagliptin is usually 4: 1 to 20: 1; it may be dissolved by heating.

  In step (2) of the above method, the crystallization may be performed under standing or may be performed with stirring; the crystallization method is a normal method in this technical field, for example, cooling. A method such as evaporative removal of a part of the solvent or addition of crystal seeds may be used alone or in combination.

  In the step (3) of the above method, the separation can employ a usual method in this technical field such as filtration, and can optionally wash the solid separated with an appropriate amount of acetonitrile. .

  In the step (4) of the method, the drying temperature is usually 30 to 120 ° C., preferably 40 to 70 ° C., and may be atmospheric drying or reduced pressure drying.

In one of the modes for carrying out the invention, the present invention comprises dissolving trelagliptin in 7-15 times weight of acetonitrile by heating and cooling and crystallizing under standing;
Among them, it is preferably cooled to 0 to 20 ° C. for crystallization and filtration;
Optionally, a method for producing trelagliptin crystalline form D comprising drying the separated crystals at 40-70 ° C. under normal pressure or reduced pressure is provided.

Crystalline form E of trelagliptin
The powder X-ray diffraction spectrum of trelagliptin crystal form E provided by the present invention is 5.1 ° ± 0.2 °, 5.4 ° ± 0.2 °, 7.0 ° ± 0.2 as 2θ values. °, 9.3 ° ± 0.2 °, 11.0 ° ± 0.2 °, 16.3 ° ± 0.2 °, 23.9 ° ± 0.2 °, 25.4 ° ± 0.2 It has a characteristic diffraction peak corresponding to °, 26.5 ° ± 0.2 °, etc.

  In one of the modes for carrying out the invention, the powder X-ray diffraction spectrum of the crystalline form E of trelagliptin described in the present application is 5.1 ° ± 0.2 °, 5.4 ° ± 0 as 2θ values. .2 °, 7.0 ° ± 0.2 °, 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 It has characteristic diffraction peaks corresponding to .2 °, 26.5 ° ± 0.2 °, and the like.

Furthermore, the crystalline form E of trelagliptin described herein has characteristic diffraction peaks and relative intensities at the following positions in the powder X-ray diffraction spectrum shown at 2θ angle:

  In one of the modes for carrying out the invention, the crystalline form E of treragliptin provided in the present invention has characteristics represented by a powder X-ray diffraction spectrum shown in FIG.

  In one form for carrying out the invention, the content (mass content) of trelagliptin crystalline form E in the prepared trelagliptin mixture provided in the present invention is usually greater than 70%, preferably Greater than 80%, most preferably greater than 90%.

The present invention
(1) a step of dissolving trelagliptin in acetone;
(2) crystallization step;
(3) a step of separating solids;
(4) Optionally, a method for producing trelagliptin crystal form E, comprising the step of drying the separated solid.

  In step (1) of the method, the mass / mass ratio of acetone to trelagliptin is usually 4: 1 to 20: 1; it may be dissolved by heating.

  In step (2) of the above method, the crystallization may be performed under standing or may be performed with stirring; the crystallization method is a normal method in this technical field, for example, cooling. A method such as evaporative removal of a part of the solvent or addition of crystal seeds may be used alone or in combination.

  In the step (3) of the above method, the separation can be performed by a usual method in this technical field such as filtration, and optionally the solid separated with acetone can be washed.

  In the step (4) of the method, the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and may be atmospheric drying or reduced pressure drying.

In one form for carrying out the invention, the present invention comprises dissolving trelagliptin in 7-15 times weight acetone by heating, allowing to stand and cooling crystallization;
Among them, it is preferably cooled to 0 to 10 ° C. for crystallization and filtration;
Optionally, there is provided a process for producing trelagliptin crystalline form E comprising drying the separated crystals at 40-70 ° C. at normal or reduced pressure.

Amorphous Trelagliptin The present invention provides amorphous trelagliptin having the characteristics represented by the powder X-ray diffraction spectrum shown in FIG.

  In one mode for carrying out the invention, the content (mass content) of amorphous treragliptin in the prepared treragliptin mixture provided in the present invention is usually more than 70%, preferably Greater than 80%, most preferably greater than 90%.

The present invention provides a variety of methods for producing amorphous trelagliptin including the following methods:
Method one:
(1) dissolving trelagliptin in an appropriate organic solvent;
(2) Evaporate off the organic solvent and concentrate to obtain a residual solid;
(3) Optionally, drying the resulting residual solid.

  In step (1) of the method, suitable organic solvents include acetone, trichloromethane, and the like. The mass / mass ratio of solvent to trelagliptin is usually 4: 1 to 20: 1; it may be dissolved by heating.

  In step (2) of the above method, the organic solvent may be removed by evaporation / concentration at normal pressure or in vacuum.

In the step (3) of the method, the drying temperature is usually 30 to 120 ° C., preferably 40 to 70 ° C., and may be atmospheric drying or reduced pressure drying.
Method two:
(1) A step of heating and melting trelagliptin;
(2) Cooling and solidification process.

  In step (1) of the method, the temperature for melting by heating is usually 165 ° C or higher, preferably 165 to 175 ° C.

  In one mode for carrying out the invention, the present invention is to dissolve treragliptin in 7-15 times weight acetone by heating, and evaporate and remove the acetone by evaporation to obtain a residual solid. Optionally providing a method for producing treragliptin amorphous comprising drying the resulting solid at 40-70 ° C. at atmospheric or reduced pressure.

  In one of the modes for carrying out the invention, according to the present invention, there is provided another method for producing trelagliptin amorphous comprising melting and melting coagulation of trelagliptin at 165 ° C. to 170 ° C. Provided.

The powder X-ray diffraction analysis was carried out under the conditions of ambient temperature and humidity in the Netherlands PANalytical B.D. V. CuKα source (α = 1.54Å) of X-Pert PRO type powder X-ray diffractometer
). “Environmental temperature” is usually 0-40 ° C .; “Environmental humidity” is usually 30% -80% relative humidity.

  Representative powder X-ray diffraction spectra of crystal forms A, B, C, D, E and amorphous of trelagliptin provided in the present invention are shown in FIGS. "Representative powder X-ray diffraction spectrum" means that the crystalline or amorphous powder X-ray diffraction characteristics match the overall shape shown in the spectrum, and during the measurement process, Since it is influenced by various factors (for example, the particle size of the sample to be measured, the processing method of the sample at the time of measurement, the apparatus, the measurement parameters, the measurement operation, etc.), even in the same crystal form, the measured powder X-ray diffraction spectrum It is considered that the peak position or peak intensity may be slightly different. Generally, the experimental error of the 2θ value of the diffraction peak in the powder X-ray diffraction spectrum may be ± 0.2 °.

  Another object of the present invention provides a mixture comprising trelagliptin of any of the above crystalline forms wherein the mass content of the crystalline form is greater than 70%, preferably greater than 80%, more preferably greater than 90%. There is.

  It should be understood that the crystal form described herein is a single crystal form selected from crystal forms A, B, C, D or E, not a mixture of the above crystal forms; The mass content of one kind of crystal form selected from crystal form A, B, C, D or E contained in the mixture is greater than 70%, preferably greater than 80%, more preferably greater than 90%.

  Another object of the present invention is to provide a drug composition containing the novel solid form of trelagliptin and the application of trelagliptin to the manufacture of the human drug in the novel solid form.

  In an embodiment to achieve the object, the present invention provides an effective therapeutic amount of trelagliptin crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E or amorphous and a pharmaceutical additive. A pharmaceutical composition or formulation comprising is provided.

  In another embodiment, the present invention provides a drug for treating a disease mediated by DPP-IV, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or amorphous form of trelagliptin. Provide manufacturing application.

  The drug composition or preparation can be produced according to a normal production method in the pharmaceutical field. For example, trelagliptin crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or amorphous Alternatively, the desired dosage form is prepared after mixing a variety and one or a variety of carriers. In certain embodiments, the particle size distribution of trelagliptin crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or amorphous is 90% less than 100 μm, preferably less than 50 μm. More preferably, it is controlled to be less than 10 μm.

  The drug composition or preparation can be a long-term effective DPP-IV inhibitor and is used for the treatment of diseases mediated by DPP-IV. As those diseases, type 1 diabetes, type 2 diabetes, Diabetic sebology abnormality, glucose tolerance abnormality, fasting blood glucose abnormality, metabolic acidosis, ketosis, appetite regulation and obesity, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, AIDS or cancer And type 1 and 2 diabetes are preferred.

  Examples of the dosage form of the drug composition or formulation include tablets, pills, granules, powders, aerosols, dusts, sprays, suspensions, solutions, emulsions, sugar preparations, tinctures, suppositories, Includes injections, gelling agents, implants, membranes, milk creams, ointments, glues, patches and the like. They include oral, sublingual, injection, luminal, transpulmonary / tracheal or transdermal, etc., depending on the characteristics of their dosage form.

  The dosage of the composition or preparation is adjusted according to the pathological nature and severity of the patient, the administration route and the patient age, body weight, etc., and the dosage for one week is usually 1 mg to 2 g, preferably 1 mg. -1000 mg, more preferably 5 mg-700 mg; may be administered once a week, may be administered several times a week, or may be administered daily.

  In one embodiment, the drug composition provided by the present invention is an oral solid preparation, preferably a tablet. The oral solid preparation contains a pharmaceutical additive in addition to the active ingredient trelagliptin, and all of the above-mentioned pharmaceutical additives are ordinary pharmaceutical additives in this field, and are fillers, disintegrants, adhesives or wets. Agent, lubricant, surfactant, solubilizer or cosolvent.

  The fillers are lactose, microcrystalline cellulose, mannitol, alpha starch, starch, sucrose, dextrin, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium bicarbonate, sodium bicarbonate, sodium carbonate, hydroxypropyl Including methyl cellulose, ethyl cellulose, aluminum hydroxide and the like. They may be used alone or in combination, and lactose, microcrystalline cellulose, mannitol, alpha starch or calcium hydrogen phosphate are preferred.

  Such disintegrants usually include starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, low substituted hydroxypropylcellulose and hydroxypropyl starch. They may be used alone or in combination. Among them, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose or sodium carboxymethyl starch is preferred.

  The pressure-sensitive adhesive or wetting agent is usually polyvinylpyrrolidone (polyvinylpyrrolidone), hydroxypropylmethylcellulose, microcrystalline cellulose, hydroxypropylcellulose, ethylcellulose, polyethylene glycol, starch paste, gum arabic, water, ethanol solutions of various concentrations, etc. including. They may be used alone or in combination, and among them, polyvinylpyrrolidone (polyvinylpyrrolidone), microcrystalline cellulose or hydroxypropylcellulose is preferred.

  The lubricant is usually zinc stearate, magnesium stearate, calcium stearate, sodium stearyl fumarate, talcum powder, sucrose fatty acid ester, aerosil (including light silicon dioxide, hydrous silicon dioxide and colloidal silicon dioxide), Contains stearic acid, palmitic acid, aluminum silicate, solid polyethylene glycol and the like. They may be used alone or in combination, among which magnesium stearate, aerosil or talcum powder is preferred.

  The surfactants, solubilizers or cosolvents usually include sodium dodecyl sulfate, Tween-80, poloxamer, sodium laurel sulfate and the like. They may be used alone or in combination, and sodium dodecyl sulfate or Tween-80 is preferred among them.

  If necessary, other pharmaceutical additives can be added to the composition or formulation, such as sweeteners (eg, aspartame, steviocin, etc.), colorants (eg, yellow iron sesquioxide, red iron oxide) Etc.), stabilizers (for example, citric acid, lactic acid, malic acid, glycine and the like) and pH regulators (for example, calcium carbonate, sodium carbonate, sodium hydrogen carbonate, tartaric acid, fumaric acid, citric acid and the like).

  If necessary, the composition or formulation may contain other suitable active ingredients.

  The oral solid preparation can be produced according to a conventional method for producing a production oral solid preparation in this technical field. For example, in the case of a tablet, wet granulation tablet, dry granulation tablet, fluid bed granulation It can be produced by a method such as tableting or powder mixing direct tableting. When the oral solid preparation is a tablet or small round tablet, it is further coated as necessary, and a film-coated tablet or film-coated small round, sugar-coated tablet or sugar-coated small round, enteric-coated tablet or enteric-coated small round and sustained-release coated tablet or Sustained release coated small circles can be produced. Among them, as a coating material, cellulose-based, acrylic resin-based, and sugar-based include, for example, hydroxypropylmethylcellulose and sucrose, among which plasticizer, anti-tacking agent, opacifier and the like may be added. .

  As proved by experiments, the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E or amorphous form of trelagliptin provided in the present invention is easy to manufacture; In the HPLC relative area comparison method, the purity can reach 98%, 99% or 99.5% or more; it has advantages such as good stability and formulation suitability. Due to their advantages, they are advantageous in producing corresponding formulations, for example, they have good stability and efficacy in production and storage; It is advantageous in producing an adduct, for example, by using them, the purity reaches 98% or more, 99% or more, or 99.5% or more in the HPLC relative area comparison method. Less than 15%, less than 0.1% or less than 0.05% of acid adducts such as succinic acid adducts and benzoic acid adducts of trelagliptin can be produced.

  Hereinafter, the contents of the present invention will be described in more detail with reference to embodiments of the examples. However, it should not be construed that the scope of the subject matter is limited only to the following examples. Any substitution or change made by ordinary technical knowledge and conventional means in the field without departing from the above gist of the present invention should be included in the scope of the present invention.

1 is a powder X-ray diffraction spectrum of crystal form A of trelagliptin; 1 is a powder X-ray diffraction spectrum of crystal form B of trelagliptin; 1 is a powder X-ray diffraction spectrum of crystal form C of trelagliptin; FIG. 5 is a powder X-ray diffraction spectrum of crystal form D of trelagliptin; FIG. 4 is a powder X-ray diffraction spectrum of crystal form E of trelagliptin; It is a powder X-ray diffraction spectrum of trelagliptin amorphous.

  Hereinafter, the technical solutions of the present invention have been described in detail with reference to the drawings and embodiments, but these do not limit the scope claimed by the present invention and are included in the scope of the present invention.

  In Examples and Production Examples, nuclear magnetic measurements were performed using a Bruke AV-II 300 MHz or BRUKER AVANCE III HD 400 MHz nuclear magnetic resonance apparatus, dimethyl sulfoxide-d6 (DMSO-d6) as a measurement solvent, and tetramethylsilane as an internal standard. The material was completed at room temperature.

Preparation of crystal form A of treragliptin 2.5 g of trelagliptin is dissolved in 25 ml of isopropanol at 75 to 78 ° C., cooled to 5 to 10 ° C. with stirring, filtered with suction, and the resulting solid is reduced in pressure at 45 to 50 ° C. Drying afforded trelagliptin crystal form A, a white solid.

The measured powder X-ray diffraction spectrum is shown in FIG. 1, and the measured values are shown below (measured values corresponding to diffraction peaks having a relative intensity of greater than 1%):

Manufacture of crystal form A of trelagliptin At 70-75 ° C, 2.5 g of trelagliptin is dissolved in 48 ml of isopropanol, cooled to 0-5 ° C under stirring, filtered with suction, and the resulting solid is vacuumed at 55-60 ° C. Drying afforded trelagliptin crystal form A, a white solid.

Preparation of Trelagliptin Crystalline Form A At 60-63 ° C., 2.5 g of treragliptin is dissolved in 25 ml of tetrahydrofuran, cooled to 0-5 ° C. with stirring, and filtered with suction to obtain trelagliptin crystal Form A as a white solid. Obtained.

Manufacture of crystal form A of treragliptin At 58-63 ° C., 25 g of trelagliptin is dissolved in 200 ml of tetrahydrofuran, cooled to 5-10 ° C. with stirring, suction filtered, and the resulting solid is dried under reduced pressure at 40-45 ° C. Thus, crystal form A of trelagliptin, which is a white solid, was obtained.

Preparation of Trelagliptin Crystalline Form A At 71-74 ° C., 2.5 g of trelagliptin is dissolved in 25 ml of ethyl acetate, cooled to 0-10 ° C. with stirring, filtered with suction, and the resulting solid is filtered at 60-65 ° C. Was dried under reduced pressure to obtain crystal form A of trelagliptin as a white solid.

Preparation of Trelagliptin Crystalline Form B At 57-60 ° C, 2.5 g of trelagliptin is dissolved in 25 ml of methanol, cooled to -5-0 ° C under stirring, filtered with suction, and the resulting solid is obtained at 40-45 ° C. Drying under reduced pressure yielded a crystalline solid form B of trelagliptin that was a white solid.

The measured powder X-ray diffraction spectrum is shown in FIG. 2, and the measured values are shown in the following table (measured values corresponding to diffraction peaks having a relative intensity of greater than 0.4%):

Preparation of Trelagliptin Crystalline Form B At 55-58 ° C., 2.5 g of trelagliptin is dissolved in 32 ml of methanol, cooled to 5-10 ° C. with stirring, and filtered with suction to obtain trelagliptin crystal form B, which is a white solid. Obtained.

Manufacture of crystal form B of trelagliptin At 55-60 ° C, 25 g of trelagliptin is dissolved in 470 ml of methanol, cooled to 0-5 ° C under stirring, suction filtered, and the resulting solid is dried under reduced pressure at 60-65 ° C. Crystalline form B of trelagliptin, a white solid, was obtained.

Preparation of crystal form C of treragliptin At 72-75 ° C., 2.5 g of trelagliptin is dissolved in 25 ml of ethanol, cooled to 0-5 ° C. with stirring, filtered with suction, and the resulting solid is vacuumed at 45-50 ° C. Drying gave crystal form C of trelagliptin, a white solid.

¹ H NMR (300 MHz, DMSO-d6) δ: 7.85-7.89 (q, 1H), 7.25-7.31 (t, 1H), 7.11-7.14 (d, 1H) , 5.31 (s, 1H), 5.12 (s, 2H), 3.38-3.45 (q, 2H), 3.06 (s, 3H), 3.00-3.04 (d , 1H), 2.87-2.91 (d, 1H), 2.57-2.63 (m, 1H), 2.50 (s, 2H), 2.29-2.36 (t, 1H) ), 1.60-1.78 (q, 2H), 1.11-1.40 (m, 2H), 1.01-1.06 (t, 3H).

In the ¹ H NMR results, δ 5.12 (s, 2H) is attributed to H at the two benzylic positions of trelagliptin, and δ 3.38-3.45 (q, 2H) is two methylenes in ethanol. From the H number, the molar composition ratio of trelagliptin and ethanol in the sample was found to be about 1: 1.

The measured powder X-ray diffraction spectrum is shown in FIG. 3 and the measured values are shown in the following table (measured values corresponding to diffraction peaks with relative intensities greater than 1%):

Manufacture of crystal form C of treragliptin At 70-75 ° C., 2.5 g of trelagliptin is dissolved in 13 ml of ethanol, cooled to 5-10 ° C. with stirring, filtered by suction, and the resulting solid is reduced at 10-15 ° C. Drying gave crystal form C of trelagliptin, a white solid.

Manufacture of crystal form C of treragliptin At 68-72 ° C., 2.5 g of treragliptin is dissolved in 47 ml of ethanol, cooled to 0-5 ° C. with stirring, and filtered with suction to obtain trelagliptin crystal form C as a white solid. Obtained.

Manufacture of crystal form C of trelagliptin At 70-74 ° C, 25 g of trelagliptin is dissolved in 630 ml of ethanol, cooled to 5-10 ° C under stirring, filtered with suction, and the resulting solid was dried under reduced pressure at 15-20 ° C. Crystalline form C of trelagliptin, a white solid, was obtained.

Manufacture of crystal form D of treragliptin At 75-78 ° C, 2.5 g of trelagliptin is dissolved in 25 ml of acetonitrile, left to cool at 10-15 ° C, suction filtered, and the resulting solid is dried at 60-65 ° C under reduced pressure. Thus, crystal form D of trelagliptin, which is a white solid, was obtained.

The measured powder X-ray diffraction spectrum is shown in FIG. 4 and the measured values are shown in the following table (measured values corresponding to diffraction peaks with relative intensities greater than 1%):

Manufacture of crystal form D of treragliptin 2.5 g of treragliptin is dissolved in 32 ml of acetonitrile at reflux temperature, left to cool at 0 to 5 ° C., suction filtered, and the obtained solid is dried at 40 to 45 ° C. under reduced pressure. Thus, crystal form D of trelagliptin, which is a white solid, was obtained.

Manufacture of crystal form D of treragliptin At 75-78 ° C, 25 g of trelagliptin is dissolved in 470 ml of acetonitrile, left to cool to 5-10 ° C, and suction filtered to obtain crystal form D of trelagliptin, which is a white solid. It was.

Manufacture of crystal form E of treragliptin At 50-53 ° C., 2.5 g of trelagliptin is dissolved in 25 ml of acetone, left to cool to 0-10 ° C., filtered with suction, and the resulting solid is obtained at 40-45 ° C. Drying under reduced pressure gave Trelagliptin crystal form E as a white solid.

The measured powder X-ray diffraction spectrum is shown in FIG. 5 and the measured values are shown in the following table (measured values corresponding to diffraction peaks with relative intensities greater than 1%):

Preparation of Trelagliptin Crystal Form E Dissolve 2.5 g of treragliptin in 31 ml of acetone at reflux temperature, allow to stand, cool to 0-5 ° C., and filter with suction to obtain trelagliptin crystal form E as a white solid. Obtained.

Manufacture of crystal form E of trelagliptin At 48-50 ° C, 25 g of trelagliptin is dissolved in 470 ml of acetone, allowed to stand, cooled to 5-10 ° C, suction filtered, and the resulting solid is dried under reduced pressure at 55-60 ° C. Thus, crystalline form E of trelagliptin, which is a white solid, was obtained.

Manufacture of treragliptin amorphous A solution of trelagliptin 2.5 g in acetone 25 ml at 50 to 53 ° C. and concentrated under reduced pressure to obtain a white solid, and the resulting solid is dried under reduced pressure at 45 to 50 ° C. Amorphous was obtained.

  The measured powder X-ray diffraction spectrum is shown in FIG.

Manufacture of amorphous treragliptin 2.5 g of trelagliptin was dissolved in 22 ml of acetone at reflux temperature and concentrated under reduced pressure to obtain a white solid, thus obtaining trelagliptin amorphous.

Preparation of trelagliptin amorphous A 25 g of trelagliptin is dissolved in 480 ml of acetone at 50-53 ° C. and concentrated under reduced pressure to obtain a white solid. The obtained solid is dried under reduced pressure at 65-70 ° C. Got quality.

Manufacture of amorphous form of trelagliptin After 0.5 g of trelagliptin was heated and melted at 165 to 170 ° C., it was cooled to room temperature to obtain an amorphous form of trelagliptin.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ａ（実施例１の方法に従い製造されたもの）、微結晶性セルロース、乳糖、架橋カルボキシメチルセルロースナトリウム及びコロイド状二酸化ケイ素を均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablet containing 12.5 mg trelagliptin and its manufacture

Production: After the uniform mixing of trelagliptin crystalline form A (produced according to the method of Example 1), microcrystalline cellulose, lactose, cross-linked sodium carboxymethylcellulose and colloidal silicon dioxide in the components listed in the table above, Wet granulated with water, dried and sized, mixed uniformly with magnesium stearate, and compressed into tablets.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ａ（実施例１の方法に従い製造されたもの）、微結晶性セルロース、マンニトール、架橋カルボキシメチルセルロースナトリウム及びコロイド状二酸化ケイ素を均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablet containing 12.5 mg trelagliptin and its manufacture

Production: Toleragliptin crystalline form A (produced according to the method of Example 1), microcrystalline cellulose, mannitol, cross-linked sodium carboxymethylcellulose and colloidal silicon dioxide in the components listed in the above table were uniformly mixed, Wet granulated with water, dried and sized, mixed uniformly with magnesium stearate, and compressed into tablets.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｂ（実施例６の方法に従い製造されたもの）、微結晶性セルロース、乳糖、架橋カルボキシメチルセルロースナトリウム及びコロイド状二酸化ケイ素を均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablets containing 25 mg treragliptin and its manufacture

Production: Toleragliptin crystalline form B (produced according to the method of Example 6), microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and colloidal silicon dioxide in the components listed in the table above, Wet granulated with water, dried and sized, mixed uniformly with magnesium stearate, and compressed into tablets.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｂ（実施例６の方法に従い製造されたもの）、微結晶性セルロース、マンニトール及び架橋カルボキシメチルセルロースナトリウムを均一に混合した後、水で湿式造粒し、乾燥・整粒し、更にタルカムパウダー及びステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablets containing 25 mg treragliptin and its manufacture

Production: Trelagliptin crystal form B (produced according to the method of Example 6), microcrystalline cellulose, mannitol and crosslinked sodium carboxymethylcellulose in the components listed in the above table were uniformly mixed and wet granulated with water. Then, it was dried and sized, further uniformly mixed with talcum powder and magnesium stearate, and tableted to obtain the tablet.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｃ（実施例１２の方法に従い製造されたもの）、微結晶性セルロース、乳糖、架橋カルボキシメチルセルロースナトリウム及びコロイド状二酸化ケイ素を均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablets containing 50 mg treragliptin and its manufacture

Production: Toleragliptin crystalline form C (produced according to the method of Example 12), microcrystalline cellulose, lactose, cross-linked sodium carboxymethylcellulose and colloidal silicon dioxide in the components listed in the table above, Wet granulated with water, dried and sized, mixed uniformly with magnesium stearate, and compressed into tablets.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｃ（実施例９に従い製造されたもの）、微結晶性セルロース、マンニトール及び架橋ポリビニルピロリドンを均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablets containing 50 mg treragliptin and its manufacture

Manufacture: Trelagliptin crystal form C (manufactured according to Example 9), microcrystalline cellulose, mannitol and cross-linked polyvinyl pyrrolidone in the components listed in the above table are uniformly mixed, then wet granulated with water and dried. -The size was adjusted, mixed uniformly with magnesium stearate, and tableted to obtain the tablet.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｃ（実施例１２の方法に従い製造されたもの）、微結晶性セルロース、マンニトール、架橋ポリビニルピロリドン及びコロイド状二酸化ケイ素を均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablets containing 100 mg treragliptin and its manufacture

Production: Trelagliptin crystal form C (produced according to the method of Example 12), microcrystalline cellulose, mannitol, cross-linked polyvinyl pyrrolidone and colloidal silicon dioxide in the components listed in the above table, and then mixed with water Was wet granulated, dried and sized, mixed uniformly with magnesium stearate, and compressed into tablets.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｃ（実施例１２の方法に従い製造されたもの）、マンニトール及び低置換度ヒドロキシプロピルロースを均一に混合した後、水で湿式造粒し、乾燥・整粒し、更にステアリン酸マグネシウムと均一に混合し、分けて複合フィルム袋に入れて、該顆粒剤を得た。 Granules containing 100 mg treragliptin and its production

Manufacture: Trelagliptin crystal form C (manufactured according to the method of Example 12), mannitol, and low-substituted hydroxypropylulose in the components listed in the above table were uniformly mixed, then wet granulated with water and dried. -The size was adjusted, and further mixed uniformly with magnesium stearate, divided and placed in a composite film bag to obtain the granules.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｃ（実施例１２の方法に従い製造されたもの）、乳糖を粉砕して、１００目篩いにかけて、更にトレラグリプチンの結晶形Ｃ、乳糖、タルカムパウダー及びステアリン酸マグネシウムを均一に混合して、分けてパッキングして、該散剤を得た。 Powder containing 100 mg trelagliptin and its manufacture

Production: Trelagliptin crystal form C (produced according to the method of Example 12), lactose in the components listed in the above table, pulverized lactose, sieved through 100 mesh, further treragliptin crystal form C, lactose, talcum powder and The magnesium stearate was mixed uniformly and packed separately to obtain the powder.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｄ（実施例１３の方法に従い製造されたもの）、微結晶性セルロース、乳糖、架橋カルボキシメチルセルロースナトリウム及びコロイド状二酸化ケイ素を均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablets containing 100 mg treragliptin and its manufacture

Production: Toleragliptin crystalline form D (produced according to the method of Example 13), microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and colloidal silicon dioxide in the components listed in the table above, Wet granulated with water, dried and sized, mixed uniformly with magnesium stearate, and compressed into tablets.

製造：上表に記載の成分におけるトレラグリプチンの結晶形Ｅ（実施例１６の方法に従い製造されたもの）、微結晶性セルロース、乳糖、架橋カルボキシメチルセルロースナトリウム及びコロイド状二酸化ケイ素を均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablets containing 200 mg treragliptin and its manufacture

Manufacture: After uniformly mixing trelagliptin crystalline form E (produced according to the method of Example 16), microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and colloidal silicon dioxide in the components listed in the table above, Wet granulated with water, dried and sized, mixed uniformly with magnesium stearate, and compressed into tablets.

製造：上表成分におけるトレラグリプチン非晶質（実施例１９の方法に従い製造されたもの）、微結晶性セルロース、乳糖、架橋カルボキシメチルセルロースナトリウム及びコロイド状二酸化ケイ素を均一に混合した後、水で湿式造粒し、乾燥・整粒し、ステアリン酸マグネシウムと均一に混合し、打錠して、該錠剤を得た。 Tablets containing 400 mg treragliptin and its manufacture

Manufacture: Toleragliptin amorphous (manufactured according to the method of Example 19), microcrystalline cellulose, lactose, cross-linked sodium carboxymethylcellulose and colloidal silicon dioxide in the above table were uniformly mixed, and then wet prepared with water. Granulated, dried and sized, mixed uniformly with magnesium stearate, and compressed into tablets.

Production Example 1 Production of Trelagliptin (1) 2-[(6-Chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidyl) methyl] -4-fluoro-benzonitrile ( IV) Manufacture

  425 g of 3-methyl-6-chlorouracil (V, obtained as a commercial product), 714 g of 2-bromomethyl-4-fluorobenzonitrile (VI, obtained as a commercial product), 566 ml of N, N-diisopropylethylamine (DIEA) After mixing 1530 ml of N-methyl-pyrrolidinone (NMP), stirring at 15 to 20 ° C. and reacting for about 2 hours, then raising the temperature to 55 to 60 ° C., and monitoring the completion of the reaction by TLC After adding 2200 ml of water for dilution, the mixture was cooled to about 5 ° C., filtered, and the solid was dried under reduced pressure at 45-50 ° C. to give 697 g of the title compound (IV).

(2) 2-[[6-[(3R) -3-Amino-1-piperidino] -3,4-dihydro-3-methyl-2,4-dioxy-1 (2H) -pyrimidyl] methyl] -4 -Production of fluoro-benzonitrile (I, trelagliptin)

  2-[(6-Chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidyl) methyl] -4-fluoro-benzonitrile (IV) 684 g, (R) -3 -Mixing 441.8 g of amino-piperidine dihydrochloride (III, obtained as a commercial product), 6150 ml of isopropanol, 1420 g of potassium carbonate and 45 ml of water and stirring them at 55-60 ° C. to complete the reaction; completion of the reaction by TLC After monitoring, the mixture was added with 2000 ml of acetonitrile, cooled to room temperature, stirred for about 3 hours, filtered, washed with 2000 ml × 2 acetonitrile, and combined with the filtrate; the filtrate was 45-50 ° C. And concentrated under reduced pressure. The obtained concentrate was dissolved in 7500 ml of dichloromethane, and a 2 mol / L hydrochloric acid aqueous solution was added dropwise at 20 to 30 ° C. so that the pH was about 3. After completion of the addition of hydrochloric acid, the mixture was continuously stirred for about 1 hour, After filtration, the filter cake was washed successively with 4000 ml of dichloromethane and 2750 ml of tetrahydrofuran, and dried under reduced pressure at 45-50 ° C. The solid obtained by drying is added to a mixture of 4500 ml of dichloromethane and 9000 ml of water, adjusted to a pH> 12 with 50% aqueous sodium hydroxide solution and separated into liquid phases; the aqueous phase is 3700 ml of dichloromethane. The organic phase was sequentially washed with water 3700 ml × 2, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid; the resulting solid was 45 to 50 ° C. And dried under reduced pressure to obtain 502 g of trelagliptin (I).

¹ H NMR (400 MHz, DMSO-d6) δ: 7.94-7.97 (m, 1H), 7.32-7.37 (m, 1H), 7.16-7.19 (m, 1H) , 5.32 (s, 1H), 5.18 (s, 2H), 3.11 (s, 3H), 2.98-3.01 (m, 1H), 2.90-2.93 (m , 1H), 2.64-2.69 (m, 1H), 2.55-2.60 (m, 1H), 2.30-2.35 (m, 1H), 1.74-1.78. (M, 1H), 1.63-1.68 (m, 1H), 1.37-1.48 (m, 3H), 1.05-1.14 (m, 1H).

Production Example 2 Production of Trelagliptin Succinate 45.5 g of trelagliptin in 55 to 60 ° C. was dissolved in a mixed solvent consisting of 530 ml of tetrahydrofuran and 200 ml of isopropanol, and then a solution prepared from 15.8 g of oxalic acid and 250 ml of tetrahydrofuran was added dropwise. After the addition is complete, stir for 15 minutes, then cool to room temperature, continue to stir for 12 hours; filter, wash the filter cake with an appropriate amount of isopropanol, and dry under reduced pressure at 50-55 ° C. to give trelagliptin 49.4 g of oxalate was obtained.

¹ H NMR (400 MHz, DMSO-d6) δ: 8.59 (s, 4H), δ: 7.94-7.98 (q, 1H), 7.33-7.38 (m, 1H), 7 .16-7.19 (q, 1H), 5.39 (s, 1H), 5.10-5.22 (q, 2H), 3.13-3.16 (q, 1H), 3.09 (S, 3H), 3.05 (s, 1H), 2.89-2.92 (t, 1H), 2.61-2.68 (m, 2H), 2.30 (s, 4H), 1.73-1.87 (m, 2H), 1.33-1.50 (m, 2H).

In the ¹ H NMR results, δ 5.10-5.22 (q, 2H) is attributed to H at the two benzylic positions of trelagliptin, and δ 2.30 (s, 4H) is 4 of oxalic acid. It was attributed to H of methylene, and from the H number, the molar composition ratio of trelagliptin and succinic acid in the sample could be judged to be about 1: 1.

In vitro elution experiment The results of measuring the elution degree of the sample prepared according to Example 29 in the elution medium with different pH outside the body are shown below:

As shown from the above study, the preparations produced from crystalline form C of trelagliptin have a dissolution rate of more than 85% in 15 minutes in different dissolution media, and the crystalline form is suitable for formulation. It was what had.

Stability experiment The following is a test conducted under the conditions of high temperature, high humidity and strong light for each of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E and amorphous of trelagliptin. After days, related substances and crystal forms were measured.

流速０．８ｍｌ／ｍｉｎ； Related substances were measured by HPLC method, and the measurement conditions were as follows:
Chromatographic column: octadecylsilyl-bonded silica gel column (250 mm × 4.6 mm, 5 μm);
Column temperature: 40 ° C .;
Measurement wavelength: 225 nm;
Fluid phase: Gradient elution was performed according to the following table.

Flow rate 0.8 ml / min;

  Measurement method: Take an appropriate amount of sample, weigh accurately, add methanol to dissolve and dilute to a solution containing about 0.5 mg per ml to obtain a sample solution, and accurately weigh 10 μL. This was injected into a liquid chromatograph, a chromatogram was recorded, and the content of related substances was calculated according to the relative area comparison method.

The results of the measurement are as follows:

  According to the above research, it was found that the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E and amorphous of trelagliptin have good stability.

Solubility experiment First, the product form of trelagliptin crystal form C and trelagliptin amorphous was ground to a fine powder, added to an Erlenmeyer flask containing 10 ml of water, and the water temperature was controlled between 25 ° C. ± 2 ° C. The sample was vigorously rocked for 30 seconds every minute; the dissolution state of the sample was observed within 30 minutes, and its solubility was judged according to the Chinese drug standards. The experimental results are as follows.

  In general, the amorphous state of a substance has better solubility than the crystalline form, however, according to the above study, trelagliptin crystal form C is more soluble in water than amorphous. Turned out.

Animal pharmacokinetic experiment Sieves were screened using a μm sieve to produce trelagliptin crystal form A, crystal form B, crystal form C and trelagliptin succinate having a size corresponding to the crystal. Twenty-four 240-270 g male SD rats were selected and randomly divided into four groups, each of which was forcibly orally administered with trelagliptin crystal forms A, B, C and treragliptin succinate intragastrically. It was 10 mg / kg (trelagliptin). Before administration and about 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, blood was collected from the tail vein every time, and centrifuged at 3500 rpm for 10 minutes. After separation, the upper plasma layer was taken and quantitatively analyzed by LC-MS / MS. From the plasma drug concentration-time data, WinNonlin 6.2 software was employed to calculate the pharmacokinetic parameters of trelagliptin according to a non-compartmental model. The results of T-testing the main pharmacokinetic parameters are shown in the following table.

  According to the above study, the main pharmacokinetic parameters of trelagliptin crystalline form A, crystalline form B, and crystalline form C did not show a significant difference (P> 0.05) from trelagliptin succinate. Therefore, it was found that crystal form A, crystal form B, and crystal form C of trelagliptin have biological properties or medicinal effects similar to salts.

Claims (16)

  In the powder X-ray diffraction spectrum, 2θ values of 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 °, 22.5 ° ± 0.2 °, It has a characteristic diffraction peak corresponding to 22.9 ° ± 0.2 °, 29.1 ° ± 0.2 °, or a characteristic represented by a powder X-ray diffraction spectrum shown in FIG. Characteristic crystalline form A of trelagliptin. (1) A step of dissolving trelagliptin in isopropanol, tetrahydrofuran or ethyl acetate;
(2) crystallization step;
(3) a step of separating solids;
(4) A method for producing crystal form A of trelagliptin, which optionally comprises the step of drying the separated solid.   In the powder X-ray diffraction spectrum, the 2θ value is 4.9 ° ± 0.2 °, 5.7 ° ± 0.2 °, 9.9 ° ± 0.2 °, 11.4 ° ± 0.2 °, Characteristic diffraction peaks corresponding to 14.8 ° ± 0.2 °, 20.2 ° ± 0.2 °, 22.7 ° ± 0.2 °, 27.0 ° ± 0.2 ° Or a crystalline form B of trelagliptin characterized by having the characteristics represented by the powder X-ray diffraction spectrum shown in FIG. (1) a step of dissolving trelagliptin in methanol;
(2) crystallization step;
(3) a step of separating solids;
(4) A method for producing crystal form B of trelagliptin, which optionally comprises the step of drying the separated solid.   Ethanol adduct of trelagliptin.   The crystal form is crystal form C of trelagliptin, and in the powder X-ray diffraction spectrum, the 2θ value is 4.9 ° ± 0.2 °, 9.7 ° ± 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 Have characteristic diffraction peaks corresponding to °, 26.2 ° ± 0.2 °, 34.1 ° ± 0.2 °, or have characteristics represented by the powder X-ray diffraction spectrum shown in FIG. The ethanol adduct according to claim 5, wherein (1) a step of dissolving trelagliptin in ethanol;
(2) crystallization step;
(3) a step of separating solids;
(4) A method for producing crystalline form C of treragliptin ethanol adduct, optionally comprising the step of drying the separated solid.   In the powder X-ray diffraction spectrum, 2θ values of 5.5 ° ± 0.2 °, 12.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.8 ° ± 0.2 °, Powder X-ray diffraction with characteristic diffraction peaks corresponding to 19.7 ° ± 0.2 °, 22.2 ° ± 0.2 °, 22.5 ° ± 0.2 °, or shown in FIG. Crystal form D of trelagliptin characterized by having characteristics represented by a spectrum. (1) A step of dissolving trelagliptin in acetonitrile;
(2) crystallization step;
(3) a step of separating solids;
(4) A method for producing crystal form D of trelagliptin, which optionally comprises the step of drying the separated solid.   In the powder X-ray diffraction spectrum, 2θ values of 5.1 ° ± 0.2 °, 5.4 ° ± 0.2 °, 7.0 ° ± 0.2 °, 9.3 ° ± 0.2 °, 11.0 ° ± 0.2 °, 16.3 ° ± 0.2 °, 23.9 ° ± 0.2 °, 25.4 ° ± 0.2 °, 26.5 ° ± 0.2 ° Crystal form E of trelagliptin characterized by having a corresponding characteristic diffraction peak or a characteristic represented by the powder X-ray diffraction spectrum shown in FIG. (1) a step of dissolving trelagliptin in acetone;
(2) crystallization step;
(3) a step of separating solids;
(4) A method for producing crystal form E of trelagliptin, which optionally comprises the step of drying the separated solid.   An amorphous trelagliptin characterized by having characteristics represented by a powder X-ray diffraction spectrum shown in FIG. (1) dissolving trelagliptin in an appropriate organic solvent containing acetone and trichloromethane;
(2) Evaporate off the organic solvent and concentrate to obtain a residual solid;
(3) A method for producing amorphous trelagliptin, which optionally comprises drying the obtained residual solid.   11. The mass content of the crystalline form is greater than 70%, preferably greater than 80%, more preferably greater than 90%, any one of claims 1, 3, 6, 8, 10 A trelagliptin mixture comprising the crystalline form according to 1.   A drug composition of treragliptin, comprising a therapeutically effective amount of treragliptin according to any one of claims 1, 3, 5, 6, 8, 10, and 12, and a pharmaceutical additive.   Application to the manufacture of a drug for treating a disease mediated by dipeptidyl peptidase IV, wherein treragliptin according to any one of claims 1, 3, 5, 6, 8, 10, 12 is used.

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