Polymorphic formsThe application is a divisional application of Chinese invention application (title of the invention: polymorphism; application date: 2007, month 4, and day 30; application number: 200780016135.5).
Technical Field
The present invention relates to polymorphic crystal modifications of a DPP-IV inhibitor, processes for their preparation and their use in the preparation of medicaments.
Background
The enzyme DPP-IV (also known as CD26) is a serine protease which promotes dipeptide cleavage in proteins having a proline or alanine group at the N-terminus. DPP-IV inhibitors thus affect plasma levels of biologically active peptides, including the peptide GLP-1. Such compounds are useful for the prevention or treatment of diseases or disorders associated with increased DPP-IV activity or which can be prevented or alleviated by decreasing DPP-IV activity, in particular type I or type II diabetes, prediabetes or low glucose tolerance.
WO2004/018468 describes DPP-IV inhibitors with valuable pharmacological properties. An example of an inhibitor disclosed therein is 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine.
Description of the invention
Within the scope of the present invention, it has been found that 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine can have various polymorphic crystal modifications and that the compound prepared in WO2004/018468 is present as a mixture of two tautomeric polymorphs at ambient temperature. The temperature at which the two polymorphic forms are converted to each other is 25 + -15 deg.C (see FIGS. 1 and 2).
The pure high temperature form (polymorph a), obtainable by heating the mixture to a temperature of more than 40 ℃, melts at 206 ± 3 ℃. In the X-ray powder diagram (see fig. 3), this morphology shows the characteristic diffraction at the following d-values:and(see also tables 1 and 2).
The anhydrous polymorph a can be prepared by the following steps:
(a) refluxing 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine in anhydrous ethanol and optionally filtering the mixture,
(b) cooling the hot solution or the hot filtrate until crystallization begins,
(c) it is diluted with a solvent such as t-butyl methyl ether,
(d) subjecting the solvent mixture to suction filtration, and
(e) the polymorph form a was dried under vacuum at 45 ℃.
The low temperature form (polymorph B) is obtained by cooling to a temperature of less than 10 ℃. In the X-ray powder diagram (see fig. 4), the morphology shows a characteristic diffraction at the following d-values:and(see also tables 3 and 4).
The anhydrous polymorph B can be prepared by the following steps:
(a) dissolving 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine in anhydrous ethanol and allowing it to reflux, and optionally filtering the mixture,
(b) cooling the hot solution or filtrate to a temperature below 10 ℃ to effect crystallization,
(c) it is diluted with a solvent such as t-butyl methyl ether,
(d) subjecting the solvent mixture to suction filtration, and
(e) the polymorph is dried under vacuum at a temperature below 10 ℃.
In the X-ray powder diagram (see fig. 5), another polymorph (polymorph C) shows the characteristic diffraction at the following d-values:and(see also Table 5).
Polymorph C was obtained as follows:
(a) dissolving 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine in methanol and refluxing it, and optionally filtering in the presence of activated carbon,
(b) cooling the methanol solution to a temperature of 40-60 ℃,
(c) a solvent such as t-butyl methyl ether or diisopropyl ether is added,
(d) the resulting suspension is first slowly cooled to 15-25 ℃ and then to 0-5 ℃,
(e) the crystals formed are suction-filtered and washed again with tert-butyl methyl ether or diisopropyl ether, and
(f) the crystals thus obtained were dried in a vacuum dryer at a temperature of 70 ℃.
The other polymorph (polymorph D) melts at 150 ± 3 ℃. Polymorph D is obtained if polymorph C is heated to or dried at a temperature of 30-100 ℃.
Finally, polymorph E also exists, which melts at 175 ± 3 ℃. If polymorph D melts, anhydrous polymorph E forms. After further heating, polymorph E crystallizes out of the melt.
The polymorph thus obtained can be used in the same way as the mixture of two polymorphs a and B described in WO2004/018468 for the preparation of a pharmaceutical composition suitable for the treatment of patients suffering from type I and type II diabetes, pre-diabetes or reduced glucose tolerance, rheumatoid arthritis, obesity or calcitonin induced osteoporosis, as well as patients who have undergone allograft transplantation. These medicaments contain, in addition to one or more inert carriers, at least 0.1% to 0.5%, preferably at least 0.5% to 1.5% and particularly preferably at least 1% to 3% of one of the polymorphic forms A, B or C.
Detailed description of the preferred embodiments
The following examples are intended to illustrate the invention in more detail.
Example 1: crystallization of polymorph A
The crude 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine was refluxed with 5-fold anhydrous ethanol and the hot solution was filtered clean via activated carbon. After the filtrate was cooled to 20 ℃ and crystallization started, the solution was diluted to two volumes with tert-butyl methyl ether. The suspension was then cooled to 2 ℃, stirred for 2 hours, suction filtered and dried in a vacuum desiccator at 45 ℃.
Polymorph A melts at 206. + -. 3 ℃. In the DSC plot, another slight endothermic signal is seen at about 25 ℃. This is a completely reversible solid-solid phase transition between the two tautomeric crystal modifications a and B. Form a is a thermodynamically stable variant above this transition temperature, while form B is a thermodynamically stable variant below this transition temperature.
FIG. 2 shows a cyclic DSC diagram in which a total of three phase transitions from-40 ℃ to 120 ℃ and vice versa are performed. During heating, the phase transition is observed as an endothermic signal, and correspondingly, during cooling it is observed as an exothermic signal. During the first heating cycle, this phase transition can be observed as a double endothermic signal or as a very broad signal, while in all other cycles this signal occurs as a very sharp endothermic or exothermic signal, depending on heating or cooling.
Table 1: marked X-ray reflection with intensity (normalized) to 30 ° 2 Θ (anhydrous polymorph A)
Table 2: lattice measurement of anhydrous form A
Example 2: crystallization of polymorph B
Polymorph B was obtained by cooling form a from example 1 to a temperature of less than 10 ℃.
Table 3: marked X-ray reflection with intensity (normalized) to 30 ° 2 Θ (anhydrous polymorph B)
Table 4: lattice measurement of anhydrous form B
Example 3: crystallization of polymorph C
The crude 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine (26kg) was refluxed with 157 liters of methanol (mixed with 1.3kg of activated carbon) and after stirring for 30 minutes the mixture was filtered and washed with 26 liters of methanol. 122 l of methanol were distilled off from the filtrate, and the residue was cooled to 45-55 ℃. To the residue was added 52 liters of tert-butyl methyl ether over 30 minutes. The mixture was then stirred at 45-55 ℃ for an additional 60 minutes. Crystallization occurs during this time. An additional 78 liters of tert-butyl methyl ether was added to the suspension over 30 minutes and then it was stirred again for an additional 60 minutes at 45-55 ℃. It was diluted to four times the volume. The suspension was slowly cooled to 15-25 ℃ and stirred at this temperature overnight. After the suspension had cooled to 0-5 ℃, the crystals were suction filtered, washed with 2 batches of tert-butyl methyl ether and dried in a vacuum desiccator at 70 ℃.
Table 5: marked X-ray reflection with intensity (normalized) to 30 ° 2 Θ (anhydrous polymorph C)
Example 4: crystallization of polymorph D
Polymorph D is obtained if polymorph C from example 3 is heated to or dried at a temperature of 30-100 ℃.
Example 5: crystallization of polymorph E
If polymorph D is melted, anhydrous polymorph E is obtained. After further heating, polymorph E crystallizes out of the melt.
In the DSC plot of form C, a full range of signals can be observed. The strongest signal is the melting point of the anhydrous form a at about 206 ℃, which form was generated in DSC experiments. Before this melting point, a number of other endothermic and exothermic signals were observed. Thus, for example, an extremely broad and weak endothermic signal can be seen between 30 ℃ and 100 ℃, which correlates with the major weight loss in Thermogravimetry (TR). The combined TG/IR experiment provides information that only moisture escapes from the sample in this temperature range.
The X-ray powder pattern measured for the sample maintained at a temperature of 100 ℃ shows a different X-ray diffraction from the starting material, indicating that form C is a hydrate phase, with the stoichiometry somewhere in the region of the hemihydrate or monohydrate. The temperature controlled sample is another anhydrous variant D, which is stable only under anhydrous conditions. The D form melts at about 150 ℃. Another anhydrous crystal modification E crystallizes from the melt and further melts when heated at about 175 ℃. Finally, form a crystallized from the melt of form E. Form E is also a metastable crystal modification, which is only present at high temperatures.
Brief Description of Drawings
FIG. 1: thermal analysis of the anhydrous form a/B;
FIG. 2: a cyclic DSC profile of the interconvertive phase transition;
FIG. 3: x-ray powder diagram of anhydrous form a;
FIG. 4: x-ray powder diagram of anhydrous form B;
FIG. 5: x-ray powder diagram of anhydrous form C;
FIG. 6: thermal analysis of form C.