WO2002060441A1 - 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 PDFInfo
- Publication number
- WO2002060441A1 WO2002060441A1 PCT/SE2002/000163 SE0200163W WO02060441A1 WO 2002060441 A1 WO2002060441 A1 WO 2002060441A1 SE 0200163 W SE0200163 W SE 0200163W WO 02060441 A1 WO02060441 A1 WO 02060441A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyridine
- imidazo
- ethyl
- dimethyl
- methylbenzylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
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.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 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.
Description
Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylberιzylamh o)-inιidazo ( 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[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.
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 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.
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 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'.
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 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'.
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 mesylate salt with 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 mesylate salt form A.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate 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;
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 mesylate 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 d iff ractog rams 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 mesylate salt form A', vide infra.
Differential Scanning Calorimetry (DSC) on form A showed a single melting endotherm with extrapolated onset of ca 300°C ( ca 135 J/g). TGA showed that decomposition starts at ca 250°C and that there is no weight loss up to this temperature.
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.
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 mesylate salt form A'.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt form A', 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;
Differential Scanning Calorimetry (DSC) on form A' showed a single melting endotherm with extrapolated onset of ca 297°C (ca 131 J/g).
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.
It is possible to crystallize 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide mesylate 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 mesylate 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 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 obtained upon crystallization from ethanol.
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt form A' is obtained upon crystallization from acetonitrile in the presence of methanol.
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-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt forms A and A' 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[1 ,2-a]pyridine-6-carboxamide mesylate 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 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.
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 Hohne, 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-dimethyI-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide
10 g (0.0331 mol) of 8-amino-2,3-dimethylimidazo[1 ,2-a]pyridine-6-carboxamide hydrobromide was suspended in isopropanol (50 ml). 1.01 g (0.00674 mol, 0.2 eq.) of Nal and 11.46 g (0.0829 mol, 2.5 eq.) of K2CO3 were added. The suspension was heated to 81 °C inner temperature. A solution of 7J2 g (0.0458 mol, 1.38 eq.) 2-ethyl-6- methylbenzylchloride diluted in isopropanol (50 ml) was added over 6 h. Stirring was continued for 1 h at 81 °C. 80% of the solvent wasdistilled off (rotary evaporator, 45°C, 80 mbar). The suspension was cooled to 20°C over 2 h. The solid was filtered off .
The material was suspended in water (100 ml) and stirred for 3 h at 40°C. The solid was filtered off and washed with water (2 x 50 ml). The material was dried on the rotary evaporator (45-50°C, 20-1 mbar, 18 h) to give 9.49 g. Yield: 84.8%
Example 2
Preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide mesylate salt form A
12.35 g (0.0367 mol) of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2- a]pyridine-6-carboxamide was suspended in n-butanol (120 ml). The mixture was heated to 80-83°C (solution). Methanesulfonic acid (3.05 g, 0.0317 mol, 1.1 eq.) was added over 10 min. Precipitation started immediately. Heating was continued for 40-50 min, the suspension was cooled to 20°C over 3 h. The suspension was filtered off and washed with butanol (25 ml). The solid was suspended in ethanol (100 ml) and heated to reflux for
30 min, cooled to 20°C over 2 h, stirred an additional hour at 20°C, filtered off and washed with ethanol (2x30 ml) to obtain 11.61 g of a white solid (0.0268 mol). Yield: 93%
Example 3
Preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide mesylate salt form A'.
50 mg of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide mesylate salt was added to 40 ml acetonitrile with ca 0.24 ml methanol in a beaker covered with plastic film. The suspension was left to stir for two months. When the volume had decreased to ca 5 ml, the plastic film was removed and the sample evaporated to dryness in one day. The sample was analyzed with pXRD, DSC, and HPLC.
Claims
1. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt being in a substantially crystalline form.
2. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt form A according to claim 1 , characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
3. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt form A' according to claim 1 , characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following d-values:
4. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt form A as defined in claim 2 comprising the steps of: a) dissolving or suspending 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt of any form, or a mixture of any form in etanol, 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 mesylate salt form A thus obtained.
5. A process for the preparation of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)- imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt form A' 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 mesylate salt of any form, or a mixture of any form in acetonitrile containing some 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 mesylate salt form A' thus obtained.
6. A process according to claims 4 or 5, characterized in that seeds are added to the solution/suspension to induce crystallization.
7. 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide mesylate salt prepared according to any of claims 3 to 6.
8. The use of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide mesylate salt as defined in claims 1 to 3 in therapy.
9. A pharmaceutical formulation comprising 2,3-dimethyl-8-(2-ethyl-6- methylbenzylamino)-imidazo[1 ,2-a]pyridine-6-carboxamide as defined in claims 1 to 3 in admixture with at least one pharmaceutically acceptable excipient.
10. The use of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1 ,2-a]pyridine-6- carboxamide mesylate as defined in claims 1 to 3, as active ingredient in the manufacture of medicament for use in treatment of gastrointestinal disorders.
11. 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[1 ,2-a]pyridine-6-carboxamide mesylate as defined in claims 1 to 3, to a patient suffering from gastrointestinal disorders.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0100296-3 | 2001-02-01 | ||
| SE0100296A SE0100296D0 (en) | 2001-02-01 | 2001-02-01 | New compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002060441A1 true WO2002060441A1 (en) | 2002-08-08 |
Family
ID=20282798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE2002/000163 Ceased WO2002060441A1 (en) | 2001-02-01 | 2002-01-30 | Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide |
Country Status (3)
| Country | Link |
|---|---|
| AR (1) | AR032519A1 (en) |
| SE (1) | SE0100296D0 (en) |
| WO (1) | WO2002060441A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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. |
| WO2007043939A1 (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-ylazetidin-1-yl)butyl] -n-methylbenzamide, modification a |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999055705A1 (en) * | 1998-04-29 | 1999-11-04 | Astrazeneca Ab | Imidazo pyridine derivatives which inhibit gastric acid secretion |
-
2001
- 2001-02-01 SE SE0100296A patent/SE0100296D0/en unknown
-
2002
- 2002-01-25 AR ARP020100273A patent/AR032519A1/en unknown
- 2002-01-30 WO PCT/SE2002/000163 patent/WO2002060441A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (8)
| 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 |
| AU2004299435B2 (en) * | 2003-12-18 | 2008-04-17 | 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 |
| RU2376306C2 (en) * | 2003-12-18 | 2009-12-20 | Астразенека Аб | NEW CRYSTALLINE FORMS OF SALT OF MESYLATE 2,3-DIMETHYL-8-(2,6-DIMETHYLBENZYLAMINO)-K-HYDROXYETHYL-IMIDASO[1,2-a]PYRIDINE-6-CARBOXAMIDE, METHODS OF THEIR PREPARATION, PHARMACEUTICAL AGENT, WHICH CONTAINS THEM, THEIR APPLICATION AND METHOD OF TREATMENT |
| WO2007043939A1 (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-ylazetidin-1-yl)butyl] -n-methylbenzamide, modification a |
Also Published As
| Publication number | Publication date |
|---|---|
| SE0100296D0 (en) | 2001-02-01 |
| AR032519A1 (en) | 2003-11-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2586782B2 (en) | Crystalline salts of sitagliptin | |
| CN102448963B (en) | 7-[(3R,4R)-3-Hydroxy-4-hydroxymethyl-pyrrolidin-1-ylmethyl]-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one useful pharmaceutical salts of | |
| JP3493341B2 (en) | Crystal Form of EtO2C-CH2- (R) Cgl-Aze-Pab-OH | |
| US20090076272A1 (en) | Polymorphs of eszopiclone malate | |
| EP2524921A1 (en) | Novel Crystalline Salts of Asenapine | |
| EP0703915B1 (en) | Xamoneline tartrate | |
| WO2002060441A1 (en) | Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide | |
| JP2008174551A (en) | Crystalline form of rabeprazole sodium | |
| CA2579119A1 (en) | Crystalline forms of the mono-sodium salt of d-isoglutamyl-d-tryptophan | |
| WO2002060440A1 (en) | Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide | |
| WO2002060442A1 (en) | Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide | |
| JP2012102143A (en) | NEW CRYSTAL FORM OF 2,3-DIMETHYL-8-(2,6-DIMETHYLBENZYLAMINO)-N-HYDROXYETHYL-IMIDAZO[1,2-a]PYRIDINE-6-CARBOXAMIDE MESYLATE | |
| SK283188B6 (en) | Preparation method for crystalline form of 3/2 hydrate 7-[(7- (S)-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1- [(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3- carboxylic acid | |
| TWI648278B (en) | Cysteine protease inhibitor salt | |
| SI21616A (en) | New crystal forms of carvedilol | |
| MXPA01012328A (en) | Polymorphs of crystalline (2-benzhydryl-1-azabicyclo[2.2. 2]oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine citrate as nk-1 receptor antagonists. | |
| EP1858847A1 (en) | Stable form i donepezil hydrochloride and process for its preparation and use in pharmaceutical compositions | |
| WO2006051340A1 (en) | Novel form of celecoxib | |
| HK1095810B (en) | Novel crystalline forms of 2, 3 dimethyl-8- (2, 6-dimethylbenzylamino) -n-hydroxyethyl-imidazo 1, 2-a pyridine-6-carboxamide mesylate salt | |
| EP2109613A2 (en) | Polymorphs of eszopiclone malate | |
| WO2004007484A1 (en) | Fumarate salts |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| NENP | Non-entry into the national phase |
Ref country code: JP |
|
| WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |