WO2002060440A1 - Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide - Google Patents

Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide Download PDF

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WO2002060440A1
WO2002060440A1 PCT/SE2002/000162 SE0200162W WO02060440A1 WO 2002060440 A1 WO2002060440 A1 WO 2002060440A1 SE 0200162 W SE0200162 W SE 0200162W WO 02060440 A1 WO02060440 A1 WO 02060440A1
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ethyl
imidazo
pyridine
dimethyl
methylbenzylamino
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PCT/SE2002/000162
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French (fr)
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Kosrat Amin
Mikael Dahlström
Peter Nordberg
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Astrazeneca Ab
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Publication of WO2002060440A1 publication Critical patent/WO2002060440A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to novel crystalline forms of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide. Further, the present invention also relates to use of said compounds for the treatment of gastrointestinal disorders, pharmaceutical compositions containing them and processes for obtaining them.
  • the active pharmaceutical ingredient In the formulation of drug compositions, it is important for the active pharmaceutical ingredient (API) to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations (e.g. oral dosage forms such as tablets) comprising the active pharmaceutical ingredient.
  • API active pharmaceutical ingredient
  • the active pharmaceutical ingredient, and compositions containing it should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active pharmaceutical ingredient, e.g. its chemical composition, density, hygroscopicity and solubility.
  • Amorphous materials may present problems in this regard. For example, such materials are typically more difficult to handle and to formulate, provide for unreliable dissolution, and are often found to be more unstable.
  • WO 99/55706 also contains a specific disclosure of the compound 2,3-dimethyl-8-(2-ethyl- 6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide.
  • a process for the synthesis of this compound is described in Example 1.4 of WO 99/55706, where the compound is crystallized from ethyl acetate. This process has. been shown later to give 2,3-dimethyl-8- (2-ethyl-6-memylbe ⁇ zylammo)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form A.
  • WO 99/55706 contains no information about the solid state properties of the prepared 2,3- dimemyl-8-(2-ethyl-6-methylbe ⁇ zylammo)-i ⁇ nidazo[l,2-a]pyridine-6-carboxamide. WO 99/55706 does further not disclose how different crystal forms may be obtained and does not predict the properties of such crystal forms.
  • Figure 1 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylberizylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A.
  • Figure 2 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form B.
  • Figure 3 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form C.
  • Figure 4 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form D.
  • Figure 5 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylberizylammo)-irmdazo[l,2-a]pyridine-6-carboxamide form E.
  • Figure 6 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylber ⁇ zylamino)-imidazo[l,2-a]pyridine-6-carboxamide form F.
  • Figure 7 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form G.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide can exist in more than one crystal form.
  • the compounds are hereinafter referred to as 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide forms A-G.
  • the notation A-G relates to the order in time in which the forms were created, not to their relative thermodynamic stability.
  • 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A is characterized in providing an X-ray powder diffraction pattern, as in figure 1, exhibiting substantially the following d-values and intensities;
  • DSC Differential scanning calorimetry
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
  • 2,3-dimethyl-8-(2-ethyl-6-me ylbenzylamino)-imidazo[l,2-a]pyridirie-6-carboxamide form B is characterized in providing an X-ray powder diffraction pattern, as in figure 2, exhibiting substantially the following d-values and intensities;
  • DSC on form B showed endotherms with extrapolated onset temperatures of ca 196°C (ca 68 J/g) and ca 213°C (ca 37 J/g).
  • 2,3 -Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form B is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form C is characterized in providing an X-ray powder diffraction pattern, as in figure 3, exhibiting substantially the following d-values and intensities;
  • DSC on form C showed endotherms with extrapolated onset temperatures of ca 201°C (ca 12 J/g) and ca 206°C (ca 121 J/g). TGA showed a decomposition starting around 250°C.
  • 2,3-Dimethyl-8-(2-emyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form C is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form D is characterized in providing an X-ray powder diffraction pattern, as in figure 4, exhibiting substantially the following d-values and intensities;
  • DSC on form D showed endotherms with extrapolated onset temperatures of ca 109°C (ca 89 J/g), ca 159°C (ca 19 J/g), ca 208°C (ca 62 J/g), and ca 217°C (ca 13 J/g).
  • TGA showed a decrease in mass of ca 17.9% (w/w) around 115°C, corresponding to a monobutanolate, and a decomposition starting around 250°C.
  • 2,3-Dimethyl-8-(2-ethyl-6-methylben ⁇ ylamino)-imidazo[l,2-a]pyridine-6-carboxamide form D is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridme-6-carboxamide form E is characterized in providing an X-ray powder diffraction pattern, as in figure 5, exhibiting substantially the following d-values and intensities;
  • DSC on form E showed an endotherm with extrapolated onset temperature of ca 144°C (ca 191. J/g).
  • TGA showed a decomposition starting around 165°C.
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form E is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
  • 2,3-dimethyl-8-(2-ethyl-6-memylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form F is characterized in providing an X-ray powder diffraction pattern, as in figure 6, exhibiting substantially the following d-values and intensities;
  • DSC on form F showed endotherms with extrapolated onset temperatures of ca 154°C (ca 92 J/g), ca 201°C (ca 45 J/g), ca 209°C (ca 13 J/g), and ca 217°C (ca 33 J/g).
  • TGA showed a decrease in mass of ca l l .9% (w/w) around 160°C, probably corresponding to a MEK- solvate, and a decomposition starting around 250°C.
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidaz ⁇ [l,2-a]pyridine-6-carboxamide form F is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylam o)-imidazo[l,2-a]pyridine-6-carboxamide form G is characterized in providing an X-ray powder diffraction pattern, as in figure 7, exhibiting substantially the following d-values and intensities;
  • DSC on form G showed endotherms with extrapolated onset temperatures of c ⁇ 115°C, ca 141°C, ca 203°C, and ca 219°C .
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form G is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
  • Crystallization of compounds of the present invention from an appropriate solvent system, containing at least one solvent may be achieved by attaining supersaturation in a solvent system by solvent evaporation, by temperature decrease, and/or via the addition of anti- solvent (i.e. a solvent in which the compounds of the invention are poorly soluble).
  • Crystallization may also be initiated and/or effected with or without seeding with crystals of the appropriate crystalline compound of the invention.
  • Crystallization of compounds of the present invention can be achieved starting from pure 10 2,3-dimemyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide of any form, or mixtures of any form.
  • Compounds of the invention may be prepared in the form of solvates, hydrates, and anhydrates.
  • one crystalline form may be more stable than another (or indeed any other).
  • crystalline forms that have a relatively low thermodynamic stability may be kinetically favored.
  • kinetic factors such as time, impurity profile, agitation, the presence or absence of seeds, etc. may also influence which form that
  • One object of the present invention is to provide processes for the preparation of 2,3- dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide forms A 30 to G.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A can be obtained upon crystallization from ethyl acetate.
  • 2,3-dimethyl-8-(2-ethyl-6-methylberizylammo)-imidazo[l,2-a]pvridme-6-carboxamide form B can be obtained upon crystallization from ethyl acetate.
  • 2,3 -dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form C can be obtained upon crystallization from methyl ethyl ketone containing methanol.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form D can be obtained upon crystallization from n-butanol.
  • 2,3-mmemyl-8-(2-emyl-6-methylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form F can be obtained upon crystallization from 2-butanone (methyl ethyl ketone).
  • crystallization is preferably carried out by seeding with seed crystals of the desired crystalline form. This applies particularly to each of the specific crystalline forms which are described in the Examples.
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide forms A to G obtained according to the present invention are substantially free from other crystal and non-crystal forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide.
  • substantially free from other crystal and non-crystal forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2- a]pyridine-6-carboxamide shall be understood to mean that the desired crystal form of 2,3- dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide contains less than 50%, preferably less than 10%, more preferably less than 5% of any other forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide.
  • the compounds of the invention may be administered and used as described in WO 99/55705 and WO 99/55706, the content of which is hereby incorporated by reference.
  • the compounds of the invention may be further processed before formulation into a suitable pharmaceutical formulation.
  • the crystalline form may be milled or ground into smaller particles.
  • a pharmaceutical formulation including a compound of the invention in admixture with at least one pharmaceutically acceptable adjuvant, diluent or carrier.
  • a method of treatment of a condition where inhibition of gastric acid secretion is required or desired which method includes administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment.
  • treatment we include the therapeutic treatment, as well as the prophylaxis, of a condition.
  • the compounds of the invention have the advantage that they are in a form that provides for improved ease of handling. Further, the compounds of the invention have the advantage that they may be produced in forms that have improved chemical and solid state stability as well as lower hygroscopicity. Thus, the compounds may be stable when stored over prolonged periods;
  • X-ray powder diffraction (XRPD) analysis was performed on samples prepared according to standard methods, for example those described in Giacovazzo, C. et al (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York;
  • DSC Differential scanning calorimetry
  • Thermogravimetric analysis was performed using a Mettler Toledo TGA850 instrument.
  • DSC onset temperatures may vary in the range ⁇ 5°C (e.g. ⁇ 2°C), and XRPD distance values may vary in the range ⁇ 2 on the last decimal place. It should be understood that the d-values of X-ray powder diffraction pattern exhibits variation depending on e.g. equipment used, sample preparation, and operator. However the precision and repeatability of said technique is found to be high and thus X-ray powder diffraction pattern exhibiting substantially the same d-values should be obtained if repeated.

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Abstract

The present invention relates to novel crystalline forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide. Further, the present invention also relates to use of said compounds for the treatment of gastrointestinal disorders, pharmaceutical compositions containing them and processes for obtaining them.

Description

Novel forms of 2 -dhuethyl-8-(2-ethyl-6-methylberιzylam o)-imidazo ( 1 ,2-a)pyridine-6-carboxamide
Field of the invention
The present invention relates to novel crystalline forms of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide. Further, the present invention also relates to use of said compounds for the treatment of gastrointestinal disorders, pharmaceutical compositions containing them and processes for obtaining them.
Background of the invention and prior art
In the formulation of drug compositions, it is important for the active pharmaceutical ingredient (API) to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations (e.g. oral dosage forms such as tablets) comprising the active pharmaceutical ingredient.
Further, in the manufacture of oral drug compositions, it is important that a reliable, reproducible and constant plasma concentration profile of the active pharmaceutical ingredient is provided following administration to a patient.
Chemical stability, solid state stability, and "shelf life" of the active pharmaceutical ingredient are also very important factors. The active pharmaceutical ingredient, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active pharmaceutical ingredient, e.g. its chemical composition, density, hygroscopicity and solubility. Amorphous materials may present problems in this regard. For example, such materials are typically more difficult to handle and to formulate, provide for unreliable dissolution, and are often found to be more unstable.
Thus, in the manufacture of commercially viable and pharmaceutically acceptable drug compositions, it is important, wherever possible, to provide the active pharmaceutical ingredient in a substantially crystalline and stable form.
International patent applications WO 99/55705 and WO 99/55706 disclose a number of compounds, referred to as imidazo pyridine derivatives, which are reversible acid pump inhibitors.
WO 99/55706 also contains a specific disclosure of the compound 2,3-dimethyl-8-(2-ethyl- 6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide. A process for the synthesis of this compound is described in Example 1.4 of WO 99/55706, where the compound is crystallized from ethyl acetate. This process has. been shown later to give 2,3-dimethyl-8- (2-ethyl-6-memylbeιιzylammo)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form A.
WO 99/55706 contains no information about the solid state properties of the prepared 2,3- dimemyl-8-(2-ethyl-6-methylbeτιzylammo)-iτnidazo[l,2-a]pyridine-6-carboxamide. WO 99/55706 does further not disclose how different crystal forms may be obtained and does not predict the properties of such crystal forms.
Brief description of the drawings
Figure 1 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylberizylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A.
Figure 2 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form B. Figure 3 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form C.
Figure 4 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form D.
Figure 5 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylberizylammo)-irmdazo[l,2-a]pyridine-6-carboxamide form E.
Figure 6 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylberιzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form F.
Figure 7 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form G.
Description of the invention
It has surprisingly been found that 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide can exist in more than one crystal form. The compounds are hereinafter referred to as 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide forms A-G. The notation A-G relates to the order in time in which the forms were created, not to their relative thermodynamic stability.
It is thus an object of the present invention to provide crystalline forms of 2,3-dimethyl-8- (2-ethyl-6-memylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide with advantageous properties.
It is an aspect of the present invention to provide 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 1, exhibiting substantially the following d-values and intensities;
Figure imgf000005_0001
The peaks, identified with d-values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo [l,2-a]pyridine-6-carboxamide form A. The relative intensities are less reliable and instead of numerical values the following definitions are used;
% Relative intensity* Definition 25- 100 vs (very strong)
10-25 s (strong) 3-10 m (medium)
1-3 . w (weak)
* The relative intensities are derived from diffractograms measured with variable slits.
, The definition above has also been used when identifying the peaks of 2,3-dimethyl-8-(2- ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide forms B to G, vide infra.
Differential scanning calorimetry (DSC) on form A showed endotherms with extrapolated onset temperatures of ca 143°C (ca 20 J/g), ca 163°C (ca 10 J/g), and ca 200°C (ca 89 J/g). TGA showed a decrease in mass of ca 4.7% (w/w) around 145°C, and a decomposition starting around 250°C.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
It is a further aspect of the present invention to provide 2,3-dimethyl-8-(2-ethyl-6- methylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form B.
2,3-dimethyl-8-(2-ethyl-6-me ylbenzylamino)-imidazo[l,2-a]pyridirie-6-carboxamide form B, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 2, exhibiting substantially the following d-values and intensities;
Figure imgf000007_0001
DSC on form B showed endotherms with extrapolated onset temperatures of ca 196°C (ca 68 J/g) and ca 213°C (ca 37 J/g).
2,3 -Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form B is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
It is a further aspect of the present invention to provide 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form C.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form C, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 3, exhibiting substantially the following d-values and intensities;
Figure imgf000008_0001
DSC on form C showed endotherms with extrapolated onset temperatures of ca 201°C (ca 12 J/g) and ca 206°C (ca 121 J/g). TGA showed a decomposition starting around 250°C.
2,3-Dimethyl-8-(2-emyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form C is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
It is a further aspect of the present invention to provide 2,3-dimethyl-8-(2-ethyl-6- memylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form D.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form D, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 4, exhibiting substantially the following d-values and intensities;
Figure imgf000009_0001
DSC on form D showed endotherms with extrapolated onset temperatures of ca 109°C (ca 89 J/g), ca 159°C (ca 19 J/g), ca 208°C (ca 62 J/g), and ca 217°C (ca 13 J/g). TGA showed a decrease in mass of ca 17.9% (w/w) around 115°C, corresponding to a monobutanolate, and a decomposition starting around 250°C.
2,3-Dimethyl-8-(2-ethyl-6-methylben^ylamino)-imidazo[l,2-a]pyridine-6-carboxamide form D is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
It is a further aspect of the present invention to provide 2,3-dimethyl-8-(2-ethyl-6- methylberιzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form E.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridme-6-carboxamide form E, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 5, exhibiting substantially the following d-values and intensities;
Figure imgf000010_0001
DSC on form E showed an endotherm with extrapolated onset temperature of ca 144°C (ca 191. J/g). TGA showed a decomposition starting around 165°C.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form E is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
It is a further aspect of the present invention to provide 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form F.
2,3-dimethyl-8-(2-ethyl-6-memylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form F, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 6, exhibiting substantially the following d-values and intensities;
Figure imgf000011_0001
DSC on form F showed endotherms with extrapolated onset temperatures of ca 154°C (ca 92 J/g), ca 201°C (ca 45 J/g), ca 209°C (ca 13 J/g), and ca 217°C (ca 33 J/g). TGA showed a decrease in mass of ca l l .9% (w/w) around 160°C, probably corresponding to a MEK- solvate, and a decomposition starting around 250°C.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazό[l,2-a]pyridine-6-carboxamide form F is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
It is a further aspect of the present invention to provide 2,3-dimethyl-8-(2-ethyl-6-. methylbenzylammo)-imidazo[l,2-a]pvridine-6-carboxamide form G.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylam o)-imidazo[l,2-a]pyridine-6-carboxamide form G, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 7, exhibiting substantially the following d-values and intensities;
Figure imgf000012_0001
DSC on form G showed endotherms with extrapolated onset temperatures of cα 115°C, ca 141°C, ca 203°C, and ca 219°C .
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form G is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
It is possible to crystallize 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2- a]pyridine-6-carboxamide, i.e. the compounds of the present invention in one single solvent or in a mixture of solvents. However, we prefer that the crystallization is from one single solvent. Crystallization of compounds of the present invention from an appropriate solvent system, containing at least one solvent, may be achieved by attaining supersaturation in a solvent system by solvent evaporation, by temperature decrease, and/or via the addition of anti- solvent (i.e. a solvent in which the compounds of the invention are poorly soluble). ' 5
Crystallization may also be initiated and/or effected with or without seeding with crystals of the appropriate crystalline compound of the invention.
Crystallization of compounds of the present invention can be achieved starting from pure 10 2,3-dimemyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide of any form, or mixtures of any form.
Compounds of the invention may be prepared in the form of solvates, hydrates, and anhydrates.
15
Whether an anhydrate or a solvate crystallizes is related to the kinetics and equilibrium conditions of the respective forms at the specific conditions. Thus, as maybe appreciated by the skilled person, the crystalline form that is obtained depends upon both the kinetics and the thermodynamics of the crystallization process. Under certain thermodynamic
20 conditions (e.g. solvent system, temperature, pressure and concentration of compound of the invention), one crystalline form may be more stable than another (or indeed any other). However, crystalline forms that have a relatively low thermodynamic stability may be kinetically favored. Thus, in addition, kinetic factors, such as time, impurity profile, agitation, the presence or absence of seeds, etc. may also influence which form that
25 crystallizes. Thus, the skilled person, in order to obtain different crystalline forms, may adapt the procedures discussed herein.
One object of the present invention is to provide processes for the preparation of 2,3- dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide forms A 30 to G. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form A can be obtained upon crystallization from ethyl acetate.
2,3-dimethyl-8-(2-ethyl-6-methylberizylammo)-imidazo[l,2-a]pvridme-6-carboxamide form B can be obtained upon crystallization from ethyl acetate.
2,3 -dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form C can be obtained upon crystallization from methyl ethyl ketone containing methanol.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form D can be obtained upon crystallization from n-butanol.
2,3-dime yl-8-(2-ethyl-6-methylbenzylanιino)-imidazo[l,2-a]pyridme-6-carboxamide form E can be obtained upon crystallization from n-propanol.
2,3-mmemyl-8-(2-emyl-6-methylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form F can be obtained upon crystallization from 2-butanone (methyl ethyl ketone).
2,3-dimethyl-8-(2-ethyl-6-methylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide form G can be obtained upon crystallization from water.
The preparation and characterization of different forms of compounds of the invention are described hereinafter. Different crystalline forms of the compounds of the invention may be readily characterized using X-ray powder diffraction (XRPD) methods or Raman spectroscopy.
In order to ensure that a particular crystalline form is prepared in the absence of other crystalline forms, crystallization is preferably carried out by seeding with seed crystals of the desired crystalline form. This applies particularly to each of the specific crystalline forms which are described in the Examples. 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide forms A to G obtained according to the present invention are substantially free from other crystal and non-crystal forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide. The term "substantially free from other crystal and non-crystal forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2- a]pyridine-6-carboxamide" shall be understood to mean that the desired crystal form of 2,3- dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide contains less than 50%, preferably less than 10%, more preferably less than 5% of any other forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide.
In accordance with the invention, the compounds of the invention may be administered and used as described in WO 99/55705 and WO 99/55706, the content of which is hereby incorporated by reference.
The compounds of the invention may be further processed before formulation into a suitable pharmaceutical formulation. For example, the crystalline form may be milled or ground into smaller particles.
According to a further aspect of the invention, there is provided a pharmaceutical formulation including a compound of the invention in admixture with at least one pharmaceutically acceptable adjuvant, diluent or carrier.
According to a further aspect of the invention there is provided a method of treatment of a condition where inhibition of gastric acid secretion is required or desired, which method includes administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment.
For the avoidance of doubt, by "treatment" we include the therapeutic treatment, as well as the prophylaxis, of a condition. The compounds of the invention have the advantage that they are in a form that provides for improved ease of handling. Further, the compounds of the invention have the advantage that they may be produced in forms that have improved chemical and solid state stability as well as lower hygroscopicity. Thus, the compounds may be stable when stored over prolonged periods;
The invention is illustrated, but in no way limited, by the following examples.
Examples
General Procedures
X-ray powder diffraction (XRPD) analysis was performed on samples prepared according to standard methods, for example those described in Giacovazzo, C. et al (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York;
Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York. X-ray analyses were performed using a Siemens D5000 diffractometer and/or a Philips X'Pert MPD.
Differential scanning calorimetry (DSC) was performed using a Mettler DSC820 instrument, according to standard methods, for example those described in Hδhne, G. W. H. et al (1996), Differential Scanning Calorimetry, Springer, Berlin.
Thermogravimetric analysis (TGA) was performed using a Mettler Toledo TGA850 instrument.
DSC onset temperatures may vary in the range ±5°C (e.g. ±2°C), and XRPD distance values may vary in the range ±2 on the last decimal place. It should be understood that the d-values of X-ray powder diffraction pattern exhibits variation depending on e.g. equipment used, sample preparation, and operator. However the precision and repeatability of said technique is found to be high and thus X-ray powder diffraction pattern exhibiting substantially the same d-values should be obtained if repeated.
Example 1 Preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6- carboxamide form B
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide (0.72g, 0.0021 mol) was suspended in ethyl acetate and the mixture was heated for a short while. When the temperature reached R.T. the precipitate was filtered off , washed with ethyl acetate and dried under reduced pressure. Yield: 0.61g (84%)
Example 2
Preparation of 2,3 -dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo [ 1 ,2-a]pyridine-6- carboxamide form C
2,3-mmethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide (44.2g, 0.13 mol) was solved in a refluxing mixture of methyl ethyl ketone (600 ml) and methanol (20 ml). 120 ml of the solvent was evaporated off and the mixture was stirred at 50 °C for 5 h. The mixture was cooled to R.T. and for 72 h. The mixture was cooled with a mixture of ice-water and the product was filtered off. The product was washed with methyl ethyl ketone (100 ml) and was dried at R.T. Yield: 34.4g, (78 %)
Example 3
Preparation of 2,3 -dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo [ 1 ,2-a]pyridine-6- carboxamide form D 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide was suspended in n-butanol and stirred at room temperature for 5 hours whereupon the product was filtered off.
Example 4
Preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6- carboxamide form E
2,3-dimethyl-8-(2-ethyl-6-methylbenzylammo)-imidazo[l,2-a]pyridine-6-carboxamide was suspended in n-propanol and stirred at room temperature for 5 hours whereupon the product was filtered off.
Example 5
Preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6- carboxamide form F
2,3-dimethyl-8-(2-ethyl-6-me ylbeιιzylammo)-imidazo[l,2-a]pyridine-6-carboxamide was suspended in 2-butanone and stirred at room temperature for 5 hours whereupon the product was filtered off.
Example 6
Preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6- carboxamide form G
To a mixture of 2,3-o^ethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6- carboxamide mesylate (6.0 g, 0.0139 mol) in water (120 ml) was added triethylamine (3. Ig, 0.031 mol). The reaction mixture was stirred at 80 °C for 45 min and the precipitate was filtered off. The solids were suspended in water (50 ml) and were then filtered off. The solids were once again suspended in water and the suspension was heated at 120 °C and a small amount of water was destilled off. The suspension was filtered warm and the solids were washed with water (50 ml). The product was dried under reduced pressure at 50 °C for 1 h.
Yield: 4.2g (90 %)

Claims

1. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form B, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000020_0001
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form C, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000021_0001
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form D, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000022_0001
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form E, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000023_0001
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[ 1 ,2-a]pyridine-6-carboxamide form F, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000024_0001
6. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide form G, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000025_0001
7. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyramino)- imidazo[l,2-a]pyridine-6-carboxamide form B as defined in claim 1 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide of any form, or a mixture of any form in ethyl acetate, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine- 6-carboxamide form B thus obtained.
8. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide form C as defined in claim 2 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridme-6-carboxamide of any form, or a mixture of any form in methyl ethyl ketone containing methanol, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine- 6-carboxamide form C thus obtained.
9. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-. imidazo[l,2-a]pyridine-6-carboxamide form D as defined in claim 3 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide of any form, or a mixture of any form in n- butanol, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine- 6-carboxamide form D thus obtained.
10. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide form E as defined in claim 4 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[ 1 ,2-a]pyridine-6-carboxamide of any form, or a mixture of any form in n- propanol, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimemyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine- 6-carboxamide form E thus obtained.
11. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide form F as defined in claim 5 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo [ 1 ,2-a]pyridine-6-carboxamide of any form, or a mixture of any form in methyl ethyl ketone, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-e yl-6-memylbenzylamino)-imidazo[l,2-a]pyridine- 6-carboxamide form F thus obtained.
12. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide form G as defined in claim 6 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo [ 1 ,2-a]pyridine-6-carboxamide of any form, or a mixture of any form in water, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine- 6-carboxamide form G thus obtained. -
13. A process according to any of claims 7-12, characterized in that seeds are added to the solution/suspension to induce crystallization.
14. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide prepared according to any of claims 7-13.
15. A pharmaceutical formulation comprising 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[l,2-a]pyridine-6-carboxamide as defined in any of claims 1-6 in admixture with at least one pharmaceutically acceptable excipient.
16. The use of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6- carboxamide as defined in any of claims 1-6 in therapy.
17. The use of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[l,2-a]pyridine-6- carboxamide as defined in claims 1-6 as active ingredient in the manufacture of a medicament for use in treatment of gastrointestinal disorders.
18. A method of treatment of gastrointestinal disorders which comprises administration of , a therapeutically effective amount of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[l,2-a]pyridine-6-carboxamide as defined in any of claims 1-6, to a patient suffering from gastrointestinal disorders.
PCT/SE2002/000162 2001-02-01 2002-01-30 Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide WO2002060440A1 (en)

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WO2005058895A1 (en) * 2003-12-18 2005-06-30 Astrazeneca Ab Novel crystalline forms of 2, 3 dimethyl-8- (2, 6-dimethylbenzylamino) -n-hydroxyethyl-imidazo [1, 2-a] pyridine-6-carboxamide mesylate salt.
WO2007043938A1 (en) * 2005-10-07 2007-04-19 Astrazeneca Ab NOVEL CRYSTALLINE FORM OF 3,5-DIBROMO-N- [ (2S) -2- (-4- FLUOROPHENYL) -4- (3-MORPHOLIN-4-YLAZTIDIN-l-YL) BUTYL] -N METHYLBENZAMIDE, MODIFICATION B
US7326718B2 (en) 2002-11-19 2008-02-05 Altana Pharma Ag 8-Substituted imidazopyridines
EP1974730A1 (en) 2003-11-03 2008-10-01 AstraZeneca AB Imidazo[1,2-a]pyridine derivatives for use in the treatment of sleep disturbance due to silent gastro-esophageal reflux

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WO1999055706A1 (en) * 1998-04-29 1999-11-04 Astrazeneca Ab Imidazo pyridine derivatives which inhibit gastric acid secretion

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7326718B2 (en) 2002-11-19 2008-02-05 Altana Pharma Ag 8-Substituted imidazopyridines
EP1974730A1 (en) 2003-11-03 2008-10-01 AstraZeneca AB Imidazo[1,2-a]pyridine derivatives for use in the treatment of sleep disturbance due to silent gastro-esophageal reflux
WO2005058895A1 (en) * 2003-12-18 2005-06-30 Astrazeneca Ab Novel crystalline forms of 2, 3 dimethyl-8- (2, 6-dimethylbenzylamino) -n-hydroxyethyl-imidazo [1, 2-a] pyridine-6-carboxamide mesylate salt.
JP2007514744A (en) * 2003-12-18 2007-06-07 アストラゼネカ・アクチエボラーグ Novel crystalline form of 2,3-dimethyl-8- (2,6-dimethylbenzylamino) -N-hydroxyethyl-imidazo [1,2-a] pyridine-6-carboxamide mesylate salt
US7459463B2 (en) 2003-12-18 2008-12-02 Astrazeneca Ab Crystalline forms of 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidazo[1,2-a] pyridine-6-carboxamide mesylate salt
WO2007043938A1 (en) * 2005-10-07 2007-04-19 Astrazeneca Ab NOVEL CRYSTALLINE FORM OF 3,5-DIBROMO-N- [ (2S) -2- (-4- FLUOROPHENYL) -4- (3-MORPHOLIN-4-YLAZTIDIN-l-YL) BUTYL] -N METHYLBENZAMIDE, MODIFICATION B

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