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WO2002060442A1 - 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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Publication number
WO2002060442A1
WO2002060442A1 PCT/SE2002/000164 SE0200164W WO02060442A1 WO 2002060442 A1 WO2002060442 A1 WO 2002060442A1 SE 0200164 W SE0200164 W SE 0200164W WO 02060442 A1 WO02060442 A1 WO 02060442A1
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Prior art keywords
ethyl
pyridine
imidazo
dimethyl
methylbenzylamino
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PCT/SE2002/000164
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French (fr)
Inventor
Mikael Dahlström
Karin Lövqvist
Bengt Malm
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Astrazeneca Ab
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Publication of WO2002060442A1 publication Critical patent/WO2002060442A1/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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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-ethy!-6- methylbenzylamino)-imidazo[i ,2-a]pyridine-6-carboxamide hydrochloride salt. 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[1 ,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.
  • WO 99/55706 contains no information about the corresponding hydrochloride salt of 2,3- Dimethyl-8-(2-ethyl-6-methylbenzylamino)-i.midazo[1 ,2-a]pyridine-6-carboxamide. WO 99/55706 does further not disclose how different crystal forms of 2,3-dimethyl-8-(2-ethyl- 6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride 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-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form A.
  • Figure 2 is an X-ray powder diffractogram of di [2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide] hydrochloride salt form B.
  • Figure 3 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form C.
  • Figure 4 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form D.
  • Figure 5 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form E.
  • Figure 6 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form F.
  • Figure 7 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate.
  • Figure 8 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt aceton solvate.
  • Figure 9 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt etanol solvate.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo- [1 ,2-a]pyridine-6-carboxamide hydrochloride salt can exist in more than one crystal form.
  • the compounds are hereinafter referred to as 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt forms A to F.
  • the notation A to F 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[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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
  • Di [2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide] hydrochloride salt 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 Differential Scanning Calorimetry
  • Di [2 ) 3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide] hydrochloride salt 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[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form C.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt form C is characterized in providing an X-ray powder diffraction pattern, as in figure 3, exhibiting substantially the following rivals, and intensities;
  • DSC Differential Scanning Calorimetry
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt form C is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
  • 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 Differential Scanning Calorimetry
  • TGA showed an decrease in mass of approximately 3.5%, by weight.
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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]pyridine-6-carboxamide hydrochloride salt form E is characterized in providing an X-ray powder diffraction pattern, as in figure 5, exhibiting substantially the following d- values and intensities;
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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 Differential Scanning Calorimetry
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate is characterized in providing an X-ray powder diffraction pattern, as in figure 7, exhibiting substantially the following d-values and intensities;
  • DSC Differential Scanning Calorimetry
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate 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]pyridine-6-carboxamide hydrochloride salt acetone solvate is characterized in providing an X-ray powder diffraction pattern, as in figure 8, exhibiting substantially the following d-values and intensities;
  • DSC Differential Scanning Calorimetry
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt acetone solvate 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]pyridine-6-carboxamide hydrochloride salt ethanol solvate is characterized in providing an X-ray powder diffraction pattern, as in figure 9, exhibiting substantially the following d-values and intensities;
  • DSC Differential Scanning Calorimetry
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt ethanol solvate 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 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt of any form, or mixtures of any form.
  • anhydrate or a solvate crystallizes is related to the kinetics and equilibrium conditions of the respective forms at the specific conditions.
  • the crystalline form that is obtained depends upon both the kinetics and the thermodynamics of the crystallization process.
  • 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 crystallizes.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form D is obtained upon crystallization from methanol/water (5:7, by volume).
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form E is obtained upon crystallization from methanol.
  • 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-methyibenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form A is a crystalline form exhibiting advantageous properties, such as being well-defined, being thermodynamically more stable (and less hygroscopic) than other crystalline forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide hydrochloride salt, especially at room temperature.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine- 6-carboxamide hydrochloride salt can under certain conditions, completely or partly, be converted into form A.
  • 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide hydrochloride salt form A is thereby characterized in being thermodynamically more stable than other crystalline forms of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt.
  • Examples of other forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide hydrochloride salt include, but are not limited to, anhydrates, hydrates, solvates, amorphous forms, and other polymorphs, of which some may be more or less crystalline.
  • 2,3-Dimethyl-8-(2-ethyl-6-methylbenzyiar ⁇ ino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt forms A-F obtained according to the present invention is substantially free from other crystal and non-crystal forms of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt.
  • substantially free from other crystal and non-crystal forms of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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 hydrochloride salt contains less than 50%, preferably less than 10%, and more preferable less than 5% of any other forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide hydrochloride salt.
  • 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),
  • 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 forms of 2, 3-dimethyl-8-(2-ethyl-6-methylbenzylamino-imidazo[1, 2-a]pyridine-6-carboxamide hydrochloride salt. 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 2,3-dimethyl-8-(2-ethyl-6-methylben2yl-- ino)-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-ethy!-6- methylbenzylamino)-imidazo[i ,2-a]pyridine-6-carboxamide hydrochloride salt. 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 discloses 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[1 ,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.
WO 99/55706 contains no information about the corresponding hydrochloride salt of 2,3- Dimethyl-8-(2-ethyl-6-methylbenzylamino)-i.midazo[1 ,2-a]pyridine-6-carboxamide. WO 99/55706 does further not disclose how different crystal forms of 2,3-dimethyl-8-(2-ethyl- 6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride 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-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form A.
Figure 2 is an X-ray powder diffractogram of di [2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide] hydrochloride salt form B.
Figure 3 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form C.
Figure 4 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form D.
Figure 5 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form E.
Figure 6 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form F. Figure 7 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate.
Figure 8 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt aceton solvate.
Figure 9 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt etanol solvate.
Description of the invention
It has surprisingly been found that 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo- [1 ,2-a]pyridine-6-carboxamide hydrochloride salt can exist in more than one crystal form. The compounds are hereinafter referred to as 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt forms A to F. The notation A to F 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-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride saltswith advantageous properties.
It is an aspect of the present invention to provide 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form A.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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[1,2-a]pyridine-6-carboxamide hydrochloride salt form B to F, vide infra.
Differential Scanning Calorimetry (DSC) on form A showed a single melting endotherm with extrapolated onset of ca 247°C. 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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 di [2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide] hydrochloride salt form B.
Di [2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide] hydrochloride salt 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 imgf000006_0001
Differential Scanning Calorimetry (DSC) on form B showed DSC onset 241 °C.
Di [2)3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide] hydrochloride salt 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[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form C.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt 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 rivals, and intensities;
Figure imgf000007_0001
Differential Scanning Calorimetry (DSC) on form C showed DSC onset 237, 244 °C
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt 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- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt Form D.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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 imgf000008_0001
Differential Scanning Calorimetry (DSC) on the form D showed DSC onset 210°C and
230°C.
TGA showed an decrease in mass of approximately 3.5%, by weight.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form E.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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 imgf000009_0001
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form F.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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 imgf000010_0001
Differential Scanning Calorimetry (DSC) on the methanol water solvate showed DSC onset 126°C, 142°C, 151°C, and 167°C. TGA showed an decrease in mass of approximately 4.8%, by weight.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate, 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 imgf000011_0001
Differential Scanning Calorimetry (DSC) on the n-propanol solvate showed DSC onset 163 °C TGA showed a weight loss of approximately 0.96 eq. n-propanol, which was confirmed by NMR.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate 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[1 ,2-a]pyridine-6-carboxamide hydrochloride salt acetone solvate.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt acetone solvate, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 8, exhibiting substantially the following d-values and intensities;
Figure imgf000012_0001
Differential Scanning Calorimetry (DSC) on the acetone solvate showed DSC onset 159 °C TGA showed a weight loss of approximately 1.02 eq. acetone, which was confirmed with NMR.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt acetone solvate 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[1 ,2-a]pyridine-6-carboxamide hydrochloride salt ethanol solvate.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt ethanol solvate, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in figure 9, exhibiting substantially the following d-values and intensities;
Figure imgf000013_0001
Differential Scanning Calorimetry (DSC) on the ethanol solvate showed DSC onset 147 °C TGA showed an decrease in mass of approximately 0.96 eq. ethanol, weight loss was confirmed by NMR.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt ethanol solvate 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[1 ,2- a]pyridine-6-carboxamide hydrochloride salts, 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). 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 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt of any form, or mixtures of any form.
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 may be 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 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 crystallizes.
According to the invention there is further provided a process for the preparation of 2,3- dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt forms A to F.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form A is obtained upon suspending from ethyl acetate.
Di [2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide] hydrochloride salt form B is obtained upon crystallization from water.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form C is obtained upon crystallization from butanol.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form D is obtained upon crystallization from methanol/water (5:7, by volume). 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form E is obtained upon crystallization from methanol.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form F is obtained upon crystallization from methanol/water (1 :1 , by volume).
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate is obtained upon crystallization from n-propanol.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt acetone solvate is obtained upon crystallization from acetone.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt ethanol is obtained upon crystallization from ethanol.
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 e.g. 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-methyibenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form A is a crystalline form exhibiting advantageous properties, such as being well-defined, being thermodynamically more stable (and less hygroscopic) than other crystalline forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide hydrochloride salt, especially at room temperature. Other crystalline forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine- 6-carboxamide hydrochloride salt can under certain conditions, completely or partly, be converted into form A. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide hydrochloride salt form A is thereby characterized in being thermodynamically more stable than other crystalline forms of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt. Other crystalline forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine- 6-carboxamide hydrochloride salt can therefore be used as intermediates for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- • carboxamide hydrochloride salt form A.
Examples of other forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide hydrochloride salt include, but are not limited to, anhydrates, hydrates, solvates, amorphous forms, and other polymorphs, of which some may be more or less crystalline.
2,3-Dimethyl-8-(2-ethyl-6-methylbenzyiarηino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt forms A-F obtained according to the present invention is substantially free from other crystal and non-crystal forms of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt. The term "substantially free from other crystal and non-crystal forms of 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt" 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 hydrochloride salt contains less than 50%, preferably less than 10%, and more preferable less than 5% of any other forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide hydrochloride salt.
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[1 ,2-a]pyridine-6- carboxamide hydrochloride Form A
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide (57.61 g, 0.17 mol) was dissolved in 1-butanol (850 ml) and heated to 60°C. At 60°C hydrogenchloride gas (40 g, 10 eq.) was added through a dip pipe. The solution was cooled to 5°C and stirred overnight. During stirring overnight, a solid precipitated. The solid was filtered off and washed with 1-butanol (50 ml). The solid was dried at 45°C / 1 mbar for 20 h. Yield was 59.99 g. The material was suspended in ethyl acetate ( 400 ml) and heated to reflux. After cooling to room temperature the solid was filtered and washed with ethyl acetate (150 ml). The solid was dried at 45°C / 0.3 mbar for 25 h. Yield: 52.41 g,
Example 2
Preparation of di [2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide] hydrocloride form B
To a solution of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide (3.4 g, 0.01 mol) in 50 ml boiling ethanol a solution of 0.86 g acetylchloride dissolved in 10 ml ethanol was added. The solution was stirred over night at room temperature. The reaction mixture was cooled on ice and filtered, the crystals was washed with cold ethanol. Yield 0.9 g.
The crystals were suspended in 100 ml boiling acetonitrile, cooled and filtered. Yield 0.86
9- The crystals were suspended in 20 ml water. During 15 min reflux the crystals first dissolves and then the final product crystallises. The crystals are cooled first in room temperature and then on ice water. The crystals are filtered and washed with water. Yield 0.59 g
Example 3
Preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide form C
To a refluxing solution of 17 g 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide in 10 ml 2-propanol, a solution of acetylchloride (1 ekv) in 15 ml 2-propanol was added. The HCI salt was precipitating. The product was filtered and washed with 2-propanol. Yield 1.4 g. NMR Vi eqv IPA. The product was refluxed and dissolved in 15 ml butanol. During reflux the crystals first dissolved and then crystallised again. The suspension was stirred at 80 °C for 1 hour. The mixture was left at room temperature to cool. The crystals were filtered off and washed with butanol and ether. The crystals were dried in vacuum at 65 °C for 30 min. Yield 0.85 g.
Example 4
Preparation of an n-propanol solvate
200 mg of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide was refluxed in 4 ml n-propanol until dissolved. 80 mg pyridine hydrochloride was added. The temperature was lowered to 85 °C and seeds of 2,3-dimethyl-8-(2-ethyl- 6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride was added. The crystallisation starts immediately. The temperature was raised to 95 °C for 1 h. The stirred suspension was then left at 80 °C for 16 h. The mixture was allowed to cool to room temperature and then filtered and the crystals were washed with n-propanol. Yield 226 mg. Example 5
Preparation of an acetone solvate 200 mg of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide was refluxed in 5 ml acetone. 80 mg pyridine hydrochloride was added. The mixture was refluxed for 20 h. The mixture was allowed to cool to room temperature and then filtered and the crystals were washed with acetone. Yield 241 mg.
Example 6
Preparation of an ethanol solvate
200 mg of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide was refluxed in 4 ml ethanol until dissolved. 80 mg pyridine hydrochloride was added. The mixture was allowed to cool to room .temperature, crystallisation starts. The stirred suspension was then left at room temperature over night. The mixture was then filtered and the crystals were washed with ethanol. Yield 97 mg.
Example 7 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 hydrochloride (0.5 g, 0.001 mol) was solved in a mixture of methanol (5 ml) and water (5 ml) at 60°C. An additional amount of water (2 ml) was added and the mixture was left for 3 days at room temperature. The crystals were filtered off and washed with methanol (30%) and dried at room temperature. Yield: 0.21 g
Example 8 Preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide form E
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride was dissolved in methanol and left without cover at 4°C. After three days methanol had evaporated and crystals had formed. Example 9
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-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride was dissolved in methanol and water (1 :1) and left without cover at 4°C. After seven days crystals had formed in the solution.

Claims

1. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt in a substantially crystalline form.
2. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form A according to claim 1, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000022_0001
Di [2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide] hydrochloride salt form B according to claim 1, 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 hydrochloride salt form C according to claim 1, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000024_0001
5. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt form D according to claim 1 , characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000025_0001
6. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt form E according to claim 1, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000026_0001
7. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt form F according to claim 1 , characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000027_0001
8. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate according to claim 1 , characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000028_0001
9. 2,3-dimethyl-8-(2-ethyl-6-methyibenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt acetone solvate according to claim 1 , characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000029_0001
10. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt ethanol solvate according to claim 1 , characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
Figure imgf000030_0001
11. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form A as defined in claim 2 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzyIamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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[1,2-a]pyridine-6- carboxamide hydrochloride salt form A thus obtained.
12. A process for the preparation of di [2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide] hydrochloride salt form B as defined in claim 3 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt of any form, or a mixture of any form in acetonitrile, b) allowing the solution or suspension to crystallize, and c) isolating the di [2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide] hydrochloride salt form B thus obtained.
13. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form C 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 hydrochloride salt of any form, or a mixture of any form in butanol b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6- carboxamide hydrochloride salt form C thus obtained.
14. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form D 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 hydrochloride salt of any form, or a mixture of any form in methanol/water (5:7, by volume) b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyi-8-(2-ethyl-6-methylbenzyiamino)-imidazo[1 ,2-a]pyridine-6- carboxamide hydrochloride salt form D thus obtained.
15. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt form E 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-carbqxamide hydrochloride salt of any form, or a mixture of any form in methanol, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6- carboxamide hydrochloride salt form E thus obtained.
16. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt form F as defined in claim 7 . comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt of any form, or a mixture of any form in methanol/water (1 :1 , by volume) b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide hydrochloride salt form F thus obtained.
17. A process for the preparation of 2,3-dimethyl-8-(2-ethyl 6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt n-propanol solvate as defined in claim 8 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt 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-dimethyl-8-(2-ethyl-6-methyibenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide hydrochloride salt n-propanol solvate thus obtained.
18. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1,2-a]pyridine-6-carboxamide hydrochloride salt acetone solvate as defined in claim 9 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt of any form, or a mixture of any form in acetone, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide hydrochloride salt acetone solvate thus obtained.
19. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt ethanol solvate as defined in claim 10 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt of any form, or a mixture of any form in ethanol, b) allowing the solution or suspension to crystallize, and c) isolating the 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6- carboxamide hydrochloride salt ethanol solvate thus obtained.
20. A process according to any of claims 11 to 19, characterized in that seeds are added to the solution/suspension to induce crystallization,
21. 2,3-dimethyl-.8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride salt prepared according to any of claims 11 to 20.
22. The use of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide hydrochloride salt as defined in any of claims 1 to 10 in therapy.
23. A pharmaceutical formulation comprising 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide as defined in any of claims 1 to 10 in admixture with at least one pharmaceutically acceptable excipient.
24. The use of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide hydrochloride as defined in any of claims 1 to 10, as active ingredient in the manufacture of medicament for use in treatment of gastrointestinal disorders.
25. A method of treatment of gastrointestinal disorders which. comprises administration of a therapeutically effective amount of 2,3-dimethyl-8-(2-ethyl-6-methy)benzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide hydrochloride as defined in any of claims 1 to 10, to a patient suffering from gastrointestinal disorders.
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Cited By (3)

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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.
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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WO1999055705A1 (en) * 1998-04-29 1999-11-04 Astrazeneca Ab Imidazo pyridine derivatives which inhibit gastric acid secretion

Patent Citations (2)

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WO1999055705A1 (en) * 1998-04-29 1999-11-04 Astrazeneca Ab Imidazo pyridine derivatives which inhibit gastric acid secretion
WO1999055706A1 (en) * 1998-04-29 1999-11-04 Astrazeneca Ab Imidazo pyridine derivatives which inhibit gastric acid secretion

Cited By (4)

* 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.
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

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