Classifications

• • 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-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate 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. 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.
• WO 99/55706 discloses 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.
• WO 99/55705 discloses the compound 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt.
• 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt is used as the starting material in Example 2.5 to produce the corresponding carboxylic acid by alkaline hydrolysis.
• WO 99/55705 contains no information about the solid state properties of the mesylate salt compounds. WO 99/55705 does further not disclose how the different crystal forms of the mesylate salt compounds 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 mesylate salt form A.
• Figure 2 is an X-ray powder diffractogram of 2,3-dimethyl-8-(2-ethyl-6-methylbenzyl- amino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt form A'.
• 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo- [1 ,2-a]pyridine-6-carboxamide mesylate salt can exist in more than one crystal form.
• the compounds are hereinafter referred to as 2,3-dimethyl-8-(2-ethyl-6-methylbenzyIamino)- imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt forms A and A'.
• 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate 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
• 2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt form A is a crystalline form exhibiting advantageous properties, such as convenient handling as well as chemical and solid-state stability.
• a ' 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
• A' 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 mesylate 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.
• 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.
• 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 mesylate 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 mesylate 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 mesylate 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), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L.
• X-ray analyses were performed using a Siemens D5000 diffractometer and/or a Philips X'Pert MPD.
• 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)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Cited By (4)

Citations (1)

• 2001
  • 2001-02-01 SE SE0100296A patent/SE0100296D0/sv unknown
• 2002
  • 2002-01-25 AR ARP020100273A patent/AR032519A1/es unknown
  • 2002-01-30 WO PCT/SE2002/000163 patent/WO2002060441A1/en not_active Application Discontinuation

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