WO2002060442A1 - Nouvelles formes de 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide - Google Patents

Nouvelles formes de 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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WO
WIPO (PCT)
Prior art keywords
ethyl
pyridine
imidazo
dimethyl
methylbenzylamino
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PCT/SE2002/000164
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English (en)
Inventor
Mikael Dahlström
Karin Lövqvist
Bengt Malm
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Astrazeneca Ab
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Publication date
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Publication of WO2002060442A1 publication Critical patent/WO2002060442A1/fr

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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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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

La présente invention concerne des nouvelles formes de chlorhydrate de 2, 3-diméthyl-8-(2-éthyl-6-méthylbenzylamino-imidazo[1, 2-a]pyridine-6-carboxamide. L'invention concerne également l'utilisation desdits composés pour le traitement de troubles gastro-intestinaux, des compositions pharmaceutiques renfermant ces composés et des méthodes de préparation de ces composés.
PCT/SE2002/000164 2001-02-01 2002-01-30 Nouvelles formes de 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide WO2002060442A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0100295A SE0100295D0 (sv) 2001-02-01 2001-02-01 New compounds
SE0100295-5 2001-02-01

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WO2002060442A1 true WO2002060442A1 (fr) 2002-08-08

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AR (1) AR032520A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058895A1 (fr) * 2003-12-18 2005-06-30 Astrazeneca Ab Formes cristallines de sel mesylate de 2, 3 dimethyl-8- (2, 6-dimethylbenzylamino) -n-hydroxyethyl-imidazo [1, 2-a] pyridine-6-carboxamide.
US7326718B2 (en) 2002-11-19 2008-02-05 Altana Pharma Ag 8-Substituted imidazopyridines
EP1974730A1 (fr) 2003-11-03 2008-10-01 AstraZeneca AB Dérivés d'imidazo[1,2-a]pyridine pour l'utilisation dans le traitement des troubles du sommeil provoqués par un reflux gastro-oesophagien silencieux

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055705A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055705A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique
WO1999055706A1 (fr) * 1998-04-29 1999-11-04 Astrazeneca Ab Derives d'imidazo pyridine qui inhibent la secretion d'acide gastrique

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 (fr) 2003-11-03 2008-10-01 AstraZeneca AB Dérivés d'imidazo[1,2-a]pyridine pour l'utilisation dans le traitement des troubles du sommeil provoqués par un reflux gastro-oesophagien silencieux
WO2005058895A1 (fr) * 2003-12-18 2005-06-30 Astrazeneca Ab Formes cristallines de sel mesylate de 2, 3 dimethyl-8- (2, 6-dimethylbenzylamino) -n-hydroxyethyl-imidazo [1, 2-a] pyridine-6-carboxamide.
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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AR032520A1 (es) 2003-11-12

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