Camcillate salt of triazolopyrazine derivative

Abstract

Salts of D(+)10-camphorsulfonic acid and triazolopyrazine derivatives of Chemical Formula 1 (camcylate salts), pharmaceutical compositions containing said salts, methods for producing said salts, and therapeutic uses of said salts. [Chemical Formula 1] JPEG2025522502000022.jpg60115

Description

Technical Field

[0001] Triazolopyrazine derivatives are, as is known, substances used in treating hyperproliferative diseases by suppressing the activity of c-Met kinase. However, in conventional literature, many free base forms, which are not the salt forms of such triazolopyrazine derivatives, are presented.

[0002] A salt form is required to improve the pharmacological utility of the free base form of triazolopyrazine derivatives. Therefore, in the present invention, it is desired to provide camcillate salts that maintain the pharmacokinetics and pharmacological activity of the free base form and improve useful physical properties, as well as a method for producing the same.

Background Art

[0003] The present invention relates to a novel camcillate salt compound of a triazolopyrazine derivative represented by the following Chemical Formula 1, a method for producing the same, and a pharmaceutical composition containing the same.

[0004]

Chem.

[0005] The present inventors diligently conducted research efforts to develop a composition for efficiently preventing or treating various hyperproliferative disorders induced by abnormal tyrosine kinase activity by discovering the above-mentioned compound having inhibitory activity against tyrosine kinase. As a result, the present inventors found that the novel salt compound of the compound of Chemical Formula 1, which has not been known heretofore, improves the storage stability and photo stability of the compound while maintaining the function of suppressing the activity of the c-Met kinase of the compound, and thus completed the present invention.

[0006] According to the present invention, the novel camcillate compound of the compound of Chemical Formula 1 of the present invention binds to hepatocyte growth factor (HGF) and activates phosphorylation, thereby promoting cell proliferation, migration, and neovascularization, and significantly suppressing the activity of c-Met kinase.

[0007] Therefore, the salt compound of the present invention can be usefully utilized for the treatment or prevention of various abnormal proliferative diseases mediated by excessive angiogenesis due to abnormal proliferation activation of cells.

[0008] In addition, the novel camcillate compound of the compound of Chemical Formula 1 exhibits physical properties different from those of a pure compound, such as melting point, hygroscopicity, solubility, flow characteristics, or thermodynamic safety.

[0009] Thereby, the salt compound of the compound of Chemical Formula 1 provided by the present invention can be used to select the most suitable form for pharmacological use in the drug manufacturing process or the manufacturing process of separate drug dosage forms such as purification, capsules, ointments, suspensions, etc., or the manufacturing of a drug form having optimal pharmacokinetic properties.

[0010] According to another aspect of the present invention, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the novel camcillate compound of Chemical Formula 1. For example, the present invention provides a pharmaceutical composition for the prevention or treatment of a hyperproliferative disorder containing the novel salt compound of the compound of Chemical Formula 1 described above as an active ingredient.

[0011] As used herein, the term "abnormal proliferative disease" refers to a pathological condition resulting from excessive cell growth, division, and migration that is not regulated by the general regulatory means in a normally growing animal body. The abnormal proliferative diseases that can be prevented or treated with the compositions of the present invention include, for example, cancer, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, iritis, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, autoimmune diseases, Crohn's disease, restenosis, atherosclerosis, intestinal adhesions, ulcers, liver diseases, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, tracheal transplant rejection, and renal glomerular diseases, but are not limited thereto, and include all abnormal proliferative diseases caused by abnormal cell proliferation and excessive angiogenesis.

[0012] More preferably, one of the cancers of abnormal proliferative diseases that can be prevented and treated with the compositions of the present invention is lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, ovarian cancer, renal cell carcinoma, prostate cancer, or brain tumor.

[0013] When the composition of the present invention is manufactured as a pharmaceutical composition, the pharmaceutical composition of the present invention contains a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers contained in the pharmaceutical composition of the present invention are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, etc., but are not limited thereto. The pharmaceutical composition of the present invention can further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. in addition to the above components.

[0014] The pure substance of the triazolopyrazine derivative represented by the above Chemical Formula 1 often has aspects where physical properties such as solubility and thermal stability are not suitable for manufacturing general pharmaceutical compositions.

[0015] Therefore, the inventors of the present invention conducted various salt screenings in order to develop a salt compound suitable for producing a pharmaceutical dosage form such as improving the solubility and safety of the triazolopyrazine derivative, and through this, a novel camsylate compound with high solubility and excellent safety while continuously maintaining the pharmacological activity of the compound was developed.

Prior Art Documents

Patent Documents

[0016]

Patent Document 1

Summary of the Invention

[0017] In the present invention, in order to improve the problems that the storage stability and photo stability of the pure substance of the triazolopyrazine derivative represented by the chemical formula 1 are low and the processability is not good in pharmaceutical manufacturing, salt screening was carried out on the compound, and by developing a novel camsylate compound of the compound, the above problems were solved.

Means for Solving the Problems

[0018] In the present invention, by developing a novel camsylate (Camsylate, Camphosulfonic acid) compound of the triazolopyrazine derivative, the storage stability and photo stability of the triazolopyrazine derivative (ABN401) represented by the chemical formula 1 were improved.

[0019] In addition, the present invention provides a method for producing the camsylate compound and a pharmaceutical composition containing the salt compound as an active ingredient.

Effects of the Invention

[0020] The present invention relates to a novel camcillate compound of a triazolopyrazine derivative represented by the above Chemical Formula 1 and a method for producing the same. The novel camcillate compound provided by the present invention improves storage stability and photo stability, which were problems of pure substances, and improves the pharmaceutical manufacturability and processability of the compound.

[0021] By efficiently suppressing the activity of c-Met tyrosine kinase, the camcillate compound can be usefully utilized as a therapeutic agent for various abnormal proliferative diseases related to excessive cell proliferation and growth caused by abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, and the like. In addition, a pharmaceutical composition for suppressing c-Met tyrosine kinase activity containing the novel salt compound as an active ingredient and a pharmaceutical composition for preventing or treating hyper proliferative disorders are provided.

Brief Description of the Drawings

[0022]

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[0023] The novel salts of the compound can be usefully utilized as therapeutic agents for various abnormal proliferative diseases related to excessive cell proliferation and growth due to abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc., by efficiently suppressing the activity of c-Met tyrosine kinase. Also provided are a pharmaceutical composition for suppressing c-Met tyrosine kinase activity containing the novel salt compound as an active ingredient and a pharmaceutical composition for preventing or treating hyperproliferative disorders.

[0024] On one side, the camsylate is an S - enantiomer of the triazolopyrazine derivative represented by the formula 1. Desirably, the triazolopyrazine derivative represented by the formula 1 is optically pure. On the other side, the optical purity is at least 95%, at least 97%, at least 99% or essentially 100%.

[0025] On one side, the camcillate is formed in the salt form of any one of Camp1, Camp2, Camp4, Camp5 or Camp6. Probably, the camcillate is likely to exist in the form of Camp2. On one side, the camcillate is physically stable at a temperature of 20 - 50 °C and a relative humidity of 35 - 80% for at least 2 days. On one side, the camcillate is physically stable for 24 months under ambient environmental conditions. Also, the camcillate has a purity of the active ingredient of at least 95%, and it is desirable that the purity is about 97.9%.

[0026] On one side, the camcillate is composed of characteristic peaks at 14 - 14.5 2θ (deg) and 16 - 17 2θ (deg) in a high-efficiency X-ray diffraction grating (HT-XRPD) pattern. Desirably, the HT-XRPD of the camcillate has characteristic peaks substantially corresponding to the following.

[0027] [Table 1] Or

[0028] [Table 2]

[0029] On one side, the present invention provides a method for producing the camcillate. The production method includes: a) a step of adding the compound of Chemical Formula 1 to a reactor containing a solvent; b) a step of stirring the solvent in the reactor and the compound; c) a step of adding 10-camphorsulfonic acid to the solution adjusted in step b); and d) a step of cooling the solution adjusted in step c) to precipitate the camcillate.

[0030] On one side, the solvent can be selected from acetonitrile, acetone, 1,2-dimethoxyethane, n-heptane, isopropyl alcohol, water or tetrahydrofuran (THF). On one side, the 10-camphorsulfonic acid added to the solution adjusted in step b) is added in an equivalent amount of 1:0.5 to 1:1.5 relative to the compound of Chemical Formula 1. Desirably, the equivalent ratio is 1:1.0 to 1:1.2 and the solvent is acetonitrile. On one side, step b) is carried out at about 45 to 55 °C for at least 1 hour.

[0031] On one side, the present invention provides a pharmaceutical composition comprising the camcylate and a pharmaceutical carrier. The pharmaceutically acceptable carrier contained in the pharmaceutical composition is one or more components selected from the group including lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, the pharmaceutical composition provided by the present invention may further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. in addition to the above components.

[0032] On one side, the present invention provides a method for reducing the activity of c-Met kinase by administering to a patient in need of a pharmaceutical composition obtained by adding an effective amount of the camcylate. On one side, the patient is suffering from a disease associated with hyperproliferative activation of cells. As an example, the disease is lung cancer, visceral cancer, pancreatic cancer, rectal cancer, ovarian cancer, kidney cancer, prostate cancer or brain tumor. On one side, the method is a method for treating or preventing hyperproliferative activation of cells.

[0033] <General>

Table 3

[0034] <Solvent>

Table 4

[0035] <Counterion>

[0036]

Table 5

[0037] The present invention will be described in detail by the following examples, but the technical scope of the present invention is not limited to those examples.

Examples

[0038] The compound of Chemical Formula 1 (ABN-401) was supplied by Abion, and the other compounds were supplied by Fisher Scientific, Sigma Aldrich or VWR. The compounds used were of research grade, and the solvents used for LCMS analysis were of LCMS grade.

[0039] Determination of Solubility Solubility was determined by adding small aliquots of solvent (50 μL up to 1 mL and 100 μL above 1 mL) to the solid starting material until it was completely dissolved or the maximum volume of 4 mL was reached.

[0040] The solvent was then evaporated, and the resulting solid was analyzed by HT-XRPD. The experimental results and detailed content are shown in Table 6.

[0041]

Table 6

[0042] Thermal Stability The thermal stability experiment of ABN-401 was conducted to confirm the chemical stability of the starting material that dissolved when exposed to high temperature.

[0043] The ABN-401 solution was adjusted to a concentration of about 0.3 mg / mL in a solvent consisting of acetone, 1,2-dimethoxyethane, and acetonitrile. The solution was exposed to room temperature for 1 hour, and then two sample aliquots were sequentially heated at 50 °C and 80 °C for 1 hour each. These solutions were analyzed by LCMS.

[0044] Furthermore, the samples placed at room temperature for 24 hours were re-measured by LCMS to confirm chemical alterations over time.

[0045] No significant chemical alterations were confirmed in the samples held at 50 °C and 80 °C. The results are summarized in Table 7.

[0046] LCMS analysis results in the thermal stability experiment

Table 7

[0047] Salt screening experiment The salt screening experiment was initiated by adjusting the concentrations of the ABN-401 solution in acetone, 1,2-dimethoxyethane, and acetonitrile to about 25, 13, and 8 mg / ml, respectively.

[0048] Counter ions were added to the API solution, and the content ratios were such that API:counter ion was 1:1.1, 1:2.1, and 1:3.1, respectively. The experiment derived a temperature profile including three heating-cooling cycles between 5 - 50 °C and was deteriorated at 25 °C for 3 days (Figure 1).

[0049] After the deterioration time, since solid particles were separated from the liquid phase, they were analyzed by HT-XRPD after drying under reduced pressure at 50 °C.

[0050] The solution and mother liquor were evaporated at room temperature, and the remaining solid particles were analyzed through HT-XRPD. Subsequently, all the solid particles were exposed to accelerated degradation conditions of 40 °C / 75% RH for 48 hours and re-measured by HT-XRPD to confirm their physical stability.

[0051] Scale-up of salts The camsylate, Camp2, was scaled up on a 0.5 gram scale (Experiment ID: SSm71). 300 mg of the free base form was dissolved in 15 ml of ACN at 50 °C to a concentration of 20 mg / ml.

[0052] Camphor-10-sulfonic acid (136 mg) was added such that the molar ratio of API:CI was 1:1.1. The suspension was heated to 50 °C and continuously stirred at 50 °C for 1 hour. The salt suspension was cooled to 25 °C and deteriorated for 72 hours. The precipitation of the salt occurred during the cooling process. After separating the solid particles and drying them under reduced pressure at 50 °C and 10 mbar, they were analyzed by HT- / HR-XRPD, TGA / TGMS, DSC, LCMS, 1H-NMR, and DVS.

[0053] The camsylate Mes2 was scaled up to a 0.5 gram scale (Experiment ID: SSm71). 500 mg of the free base form was dissolved in 23 ml of acetone to a concentration of 26 mg / ml. Methanesulfonic acid (1 M aqueous solution) was added such that the molar ratio of API:CI was 1:2.1. The precipitation of the salt was observed upon the addition of the counter ion. The suspension was heated to 50 °C and continuously stirred at 50 °C for 8 hours. The salt suspension was cooled to 25 °C. After separating the solid particles and drying them under reduced pressure at 50 °C and 10 mbar, they were analyzed by HT- / HR-XRPD, TGA / TGMS, DSC, LCMS, 1H-NMR, and DVS.

[0054] The maleate Mae2 was scaled up to a 0.3 gram scale (Experiment ID: SSm75). 300 mg of the base form was dissolved in 5 ml of acetone at 50 °C to a concentration of 60 mg / ml. A maleic acid suspension (130 mg) was added to the base form such that the molar ratio of API:CI was 1:2.1. The suspension was heated to 50 °C and continuously stirred at 50 °C for 1 hour. The salt suspension was cooled to 25 °C and aged for 72 hours. The salt suspension had a high viscosity and was shaken with 2 ml of acetonitrile to remove unreacted API or maleic acid. The solid particles were separated and dried under reduced pressure at 50 °C and 10 mbar, and then analyzed by HT- / HR-XRPD, TGA / TGMS, DSC, LCMS, 1H-NMR, and DVS.

[0055] Physical and Chemical Stability Physical stability experiments for the camsylate (Mes2), camsylate (Camp2), and maleate (Mae2) were conducted at specific temperatures and relative humidities (25 °C / 60%RH and 40 °C / 75%RH) for 2 years.

[0056] Similarly, the above stability experiments were also carried out on the base form of ABN-401 as a reference substance.

[0057] To confirm whether there were any special changes in the above solid particles and the content of water and solvent, and also to confirm whether there was any deterioration of the compound in the storage state stored under other conditions, XRPD, TGMS, and HPLC tests were performed on the vials containing the particles at the 1, 3, 15, and 24-month time points.

[0058] Conditions for Experimenting the Stability of Camsylate (Camp2), Maleate (Mae2), Camsylate (Mes2), and the Base Form (FB) of ABN-401

[0059]

Table 8

[0060] Crystalline form screening of maleate and camcillate The crystalline form changes of maleate and camcillate were evaluated through thermal cycling of 15 solvents. The salts were lyophilized to calculate the amorphous salts, and thus multiple tests were conducted. The experimental conditions are described in Table 9.

[0061] Experimental conditions for the lyophilization test to calculate amorphous inflammation. The symbol lc means that a minimal crystalline form was generated.

[0062] [Table 9]

[0063] Based on the above results, the most appropriate conditions were reproduced on a large scale to generate substances for crystalline form screening. The scale-up conditions are as follows.

[0064] The ABN-401 (735 mg) solution was dissolved in a 1,4-dioxane / water (50 / 50) solvent containing 1 molar equivalent of camphor-1-0 sulfonic acid and prepared to a concentration of 147 mg / ml (experimental ID: GEN10). The solution was divided into 16 vials.

[0065] The ABN-401 (722 mg) solution was dissolved in a tetrahydrofuran (THF) / water (50 / 50) solvent containing 2 molar equivalents of maleic acid and prepared to a concentration of 60 mg / ml (experimental ID: GEN11). The solution was divided into 16 vials.

[0066] The solution was frozen in liquid nitrogen and placed in a vacuum using a lyophilizer. To confirm the solvent content, the lyophilized solid samples were analyzed by HT-XRPD and TGMA, and H-NMR was analyzed to confirm the salt form.

[0067] To the vial containing the low crystals, aliquots of the solvent were added until a thin suspension was obtained.

[0068] To obtain the temperature profile of the vial, the vial was subjected to three thermal cycles from 50 to 5 °C and allowed to deteriorate at room temperature for two days. The results are shown in Figure 2.

[0069] After performing the temperature profile, the solid phase and the liquid phase were separated. The solid phase was analyzed after vacuum drying at 50 °C and 10 mbar overnight. The liquid phase fractionated from the mother liquor of each experiment was filtered and analyzed by HPLC. Two stock solutions were prepared by measuring the concentration of API in the solution through a calibration curve.

[0070] The solvent of the liquid phase was evaporated at room temperature, and the resulting solid was analyzed by XRPD. All the solids were gradually exposed to accelerated aging conditions (AAC, 40 °C / 75% RH) for two days and re-analyzed by HT-XRPD.

[0071] High-efficiency X-ray powder diffraction analysis The HT-XRPD patterns were collected by a crystal T2 high-efficiency XRPD instrument.

[0072] The plate was mounted on a Bruker General Area Detector Diffraction System (GADDS), and the system was equipped with a VANTEC-500 gas area detector to correct for changes in intensity and shape. The correction for the accuracy of the peak position was performed using NIST SRM1976 standard (Corundum).

[0073] Data collection was performed using Cu Kα monochromatic radiation in the 2θ range between 1.5 ° and 41.5 ° at room temperature, and the method is the most unique for XRPD patterns. The diffraction pattern of each well was collected through an exposure of 90 seconds per frame in two 2θ ranges (1.5 ° ≤ 2θ ≤ 21.5 °, first frame; 19.5 ° ≤ 2θ ≤ 41.5 °, second frame).

[0074] No background removal or curve smoothing operations were performed on the XRPD patterns.

[0075] The carrier material used in the HT-XRPD measurement was transparent to X-rays and had a very fine effect on the background.

[0076] High-resolution X-ray powder diffraction analysis The powder data was collected by a D8 diffractometer, where Cu K1 (1.54056 Å) using germanium monochromator at room temperature was used.

[0077] The data was collected for the solid using a LynxEye detector over a 2θ range between 4° and 45° with a 2θ step of 0.016° at a rate of 22 seconds / step. The sample was measured using a glass capillary with an outer diameter of 0.3 mm and a length of 8 mm.

[0078] TGMS analysis The mass loss due to the loss of water and solvent from the crystal was measured through TGA. The weight of the sample was monitored and heated in a TGA / DSC3+ STARe system, resulting in a weight-temperature curve and a heat flow signal. The TGA / DSC3+ results were corrected for temperature using indium and aluminum samples. The sample (circa 2 mg) was placed in a 100 μL aluminum crucible and sealed. A fill hole was formed for sealing, and the crucible was heated from 25 °C to 300 °C at a heating rate of 10 °C / min during the TGA process. Dry nitrogen gas was used during the purging process.

[0079] The gas evolved from the TGA sample was analyzed by an Omnistar GSD301 T2 (Pfeiffer Vacuum GmbH, Germany) mass spectrometer. The spectrometer is capable of mass spectrometry at temperatures in the range of 0 - 200 amu.

[0080] DSC analysis DSC temperature recording was performed through a heat flux DSC3+ STARe system. The DSC3+ was corrected for temperature and enthalpy using trace amounts of indium (m.p. = 156.6 °C; δHf = 28.45 J / g) and zinc (m.p. = 419.6 °C; δHf = 107.5 J / g).

[0081] The sample was sealed in a standard 40 μL aluminum pan with a pinhole opened, and heated from 25 to 300 °C at a heating rate of 10 °C / min in a DSC process. Dry nitrogen gas with a flow rate of 50 mL / min was used during the purging process.

[0082] H-NMR analysis The 1H-NMR spectra were recorded at room temperature through a 500 MHz spectrometer. The samples were dissolved in DMSO for analysis. The data were processed by ACD Labs software spectrum processor.

[0083] LCMA analysis Characterization of starting materials and purification of new crystalline forms in the prebase form Method name: S19061_0.3M Sample: concentration 0.3 mg / ml, diluent: acetonitrile

[0084] [Table 10]

[0085] Assay and purification of the new crystalline form salt Method name: S19061_01.M Sample: concentration 0.3 mg / ml, diluent: acetonitrile / water (50 / 50)

[0086] [Table 11]

[0087] DVS analysis The difference in the moisture absorption of various forms of solid substances serves as a measure of the relative stability of each substance in a situation where the relative humidity is increased. The isothermal moisture absorption of a trace amount of sample was obtained using a DVS-1 system. This apparatus is suitable for measuring very small amounts of sample with an accuracy of 0.1 μg. The relative humidity was changed during the moisture absorption-desorption-moisture absorption process at a constant temperature of 25°C (40-95-40%RH) and typically held for 60 minutes at each step (10% relative humidity step). At the end of the DVS experiment, the sample was measured by XRPD.

[0088] The hygroscopicity was classified according to the European Pharmacopoeia hygroscopicity classification.

[0089] The classification of the moisture absorption rate at 25°C / 80%RH (24 hours) is as follows.

[0090] Mass change < 0.2% - Non-hygroscopic Mass change > 0.2% and < 2% - Slight hygroscopicity Mass change > 2% and < 15% - Moderate hygroscopicity Mass change > 15% - High hygroscopicity Camcylate Figure 5 shows the XRPD patterns of all camcylates with respect to the prebase form (Form A).

[0091] Camp1 is a camcylate obtained from an experiment in which camphor-10-sulfonic acid was added so that the molar ratio of API:CI was 1:1 with acetone and 1,2-dimethoxyethane as crystallization solvents.

[0092] Table 12 shows the experimental conditions for obtaining Camp1. The solid selected for the subsequent characterization process is a crystalline form salt formed when camphor-10-sulfonic acid was added in 1 molar equivalent with acetone (Experiment ID: SSm14). Camp1 showed physical stability when exposed to AAC (40°C / 75%RH) for 2 days (Figure 6).

[0093] Experimental conditions for obtaining Camp1

Table 12

[0094] The TGA / TGMS analysis results for Camp1 showed a 3.3% mass loss due to water at 25 - 120 °C (equivalent to 1.5 water molecules per 3.3% salt molecule). Thermal decomposition was observed at 240 °C and above. The heat flow signal showed a distinct endothermic reaction around 160 °C, which is thought to be due to the melting of the salt anhydride.

[0095] The heat flow signal of the TGA showed a broad endothermic reaction due to mass loss around 160 °C, which is associated with the melting of the anhydrous form.

[0096] The DSC analysis results for Camp1 showed a broad endothermic reaction up to 25 - 120 °C, which may probably be associated with the loss of water. A double endothermic reaction, presumably due to the melting of the potential anhydrous salt, was observed around 164 °C.

[0097] The chemical purity of said Camp1 as determined by LCMS analysis appeared to be 100%, which means that the API is present in the solid phase of Camp1.

[0098] The 1H-NMR analysis results for Camp1 are presented in Figure 10. The shift of the API resonance visible in the spectrum of Camp1 implies that proton transfer occurred with the free base with an acidic counterion. The ratio of said API:CI appeared to be 1:1, and residual acetone was observed at 2.2 ppm.

[0099] Camp2 is a camcillate obtained from a crystallization experiment in which camphor-10-sulfonic acid was added in an ACN solvent so that the molar ratio of API:CI was 1:1 (Experiment ID: SSm60). Table 13 shows the experimental conditions for obtaining Camp2. Camp2 showed physical stability when exposed to AAC (40 °C / 75% RH) for 2 days.

[0100] Experimental conditions for obtaining Camp2

Table 13

[0101] The TGA / TGMS analysis results for Camp2 showed a 1.6% mass loss between 25 - 150 °C due to water based on the MS signal (1.6% corresponds to 0.7 water molecules per salt molecule). Thermal decomposition was observed at temperatures above 240 °C.

[0102] The heat flow signal of the TGA showed a broad endothermic reaction due to the melting of the salt anhydride at approximately 200 °C, followed by decomposition.

[0103] The DSC analysis results for Camp2 showed a broad endothermic reaction from 25 to 70 °C, which may possibly be related to water loss. An endothermic reaction presumably due to the melting of a potential anhydrous salt occurred near approximately 208.9 °C.

[0104] To separate the potential anhydrous salt melting at 208.9 °C shown by DSC, the Camp2 sample (Experiment ID: SSm60) was vacuum dried at 80 °C. HT-XRPD and TGMS analyses were performed on the obtained solid. The residual Camp2 solid contained 1.9% water.

[0105] The chemical purity of the Camp2 measured by LCMS was 100%, confirming the presence of the API in the solid phase.

[0106] The 1H-NMR analysis results for Camp2 are presented in Figure 16. The shift of the API resonance seen in the spectrum of Camp2 implies that proton transfer occurred with the acidic counterion in the free base form. The API:CI ratio appeared to be 1:1.

[0107] Characterization analysis results of Camp2 The HT-XRPD analysis results confirm the crystallization of Camp2 (Experiment ID: SSm73) in the scale-up experiment (Figure 17). The high-resolution XRPD (HR-XRPD) pattern of Camp2 is not indexed.

[0108] The TGA / TGMS analysis results of dried Camp2 showed a 1.6% mass loss between 25 - 80 °C (Figure 18). This is presumably due to the loss of water based on the MS signal (1.6% corresponds to 0.7 water molecules per salt molecule). The thermal decomposition of Camp2 was observed at temperatures above 240 °C.

[0109] The DSC analysis results of Camp2 showed one broad endothermic reaction related to the loss of water at 25 - 80 °C (Figure 19). The second distinct endothermic reaction was observed at 208.6 °C, which is presumably related to the melting process of the anhydrous salt.

[0110] The chemical purity of Camp2 measured by LCMS was 99.7%, which confirms the presence of API in the solid phase of Camp2.

[0111] The 1H-NMR analysis results of Camp2 are shown in Figure 21. The shift of the API resonance observed in the Camp2 spectrum implies that the proton shift occurred with the free base and the acidic counterion. The API:CI ratio was 1:1.

[0112] Figure 22 shows the DVS measurement results for Camp2. The first moisture absorption in the half cycle indicates that water absorption reached from a relative humidity of 95% to 15.6% (a 14.1% mass change appears with a change in relative humidity from 40 - 95%). The graph showing the mass change indicates that water absorption did not reach equilibrium at relative humidities of 90 - 95%. Water was ejected during the desorption cycle at relative humidities of 95 - 0%. The mass change in the last half absorption cycle (relative humidity 0 - 40% interval) was 6.6%. The water absorption is irreversible, which implies a change in form. A new form of Camp4 was confirmed in the solid phase by HT-XRPD (Figure 23).

[0113] The DVS analysis results show that the mass change is about 1.4% at a relative humidity of 80%, which implies that the substance is slightly hygroscopic according to the European Pharmacopoeia hygroscopicity classification.

[0114] Stability of the free base form For the 3-month TGA analysis, Form A was exposed to 25°C / 60%RH and 40°C / 75%RH, and the results are presented in Figures 25A and 25B. Mass losses of 4.1% and 4.4% were observed in the samples exposed to 25°C / 60%RH and 40°C / 75%RH for 3 months, respectively. The heat flow analysis results showed a broad endothermic reaction due to water loss at 140°C corresponding to the melting of Form A. Thermal decomposition was observed at 230°C in both samples.

[0115] For the 15-month TGA analysis, Form A was exposed to 25°C / 60%RH and 40°C / 75%RH, and the results are presented in Figures 26A and 26B. Mass losses of 3.3% and 3.7% were observed in the samples exposed to 25°C / 60%RH and 40°C / 75%RH for 15 months, respectively. The heat flow analysis results showed a broad endothermic reaction due to water loss at 140°C corresponding to the melting of Form A. Thermal decomposition was observed at 230°C in both samples.

[0116] For the 24-month TGA analysis, Form A was exposed to 25°C / 60%RH and 40°C / 75%RH, and the results are presented in Figures 27A and 27B. Mass losses of 5.3% and 5.2% were observed in the samples exposed to 25°C / 60%RH and 40°C / 75%RH for 24 months, respectively. The heat flow analysis results showed a broad endothermic reaction due to water loss at 140°C corresponding to the melting of Form A. No thermal decomposition occurred below 200°C.

[0117] After exposing the Form A to 25°C / 60%RH (Experiment ID: GEN81) and 40°C / 75%RH (Experiment ID: GEN76) for 24 months, the chemical purities measured by LCMS were 87.2% and 90.7% respectively (Figures 28 and 29). This confirms that the compound deteriorated under both conditions.

[0118] Stability of camsilate The HT-XRPD analysis results confirm that no solid form conversion occurred after exposing Camp2 to 25 °C / 60% RH for 24 months.

[0119] However, at 40 °C / 75% RH, solid phase conversion was observed after 3 months. The new powder pattern is named Camp4 powder pattern. After 24 months, more conversions occurred, indicating the possibility of mixing of camsilate and form E of the free base form. Figure 30 shows the superposition of the powder patterns after scale-up of Camp2 and exposure to 25 °C / 60% RH and 40 °C / 75% RH for 1, 3, 15, and 24 months.

[0120] Figures 31A and 31B show the TGA analysis results of Camp2 after exposure to 25 °C / 60% RH and 40 °C / 75% RH for 1 month. A 1.6% mass loss was observed in the sample exposed to 25 °C / 60% RH for 1 month, and a 1.8% mass loss was shown in the sample exposed to 40 °C / 75% RH for 1 month. Thermal decomposition occurred at 240 °C or higher in both samples.

[0121] The Camp2 sample incubated at 25 °C / 60% RH for 3 months showed a water content similar to that recorded after 1 month, meaning that there was no significant water absorption under the said conditions. However, at 40 °C / 75% RH, solid form conversion from Camp2 to Camp4 was observed. As a result, the TGA analysis results showed a water content of 7.1% (corresponding to 3.3 water molecules per camsilate molecule). The thermal changes recorded by the heat flow signal showed a wide endothermic reaction due to water elution, followed by an endothermic reaction at 150 °C (200 °C in Camp2) caused by the melting of the anhydride.

[0122] The Camp2 sample incubated at 25°C / 60%RH for 15 months showed the same water content as that recorded after 1 and 3 months, which means that there was no significant water absorption under the said conditions. At 40°C / 75%RH, Camp4 was maintained for 15 months. Similarly, the content of the remaining water was the same as the result after 3 months. The TGA analysis result of the said salt showed a water content of 6.9% (equivalent to 3.3 water molecules per camcillic acid molecule).

[0123] The thermal behavior recorded by the heat flow signal showed a wide endothermic reaction due to the elution of water, followed by an endothermic reaction due to the melting of the anhydride at about 150°C (Camp2 has a melting point different from 200°C).

[0124] The Camp2 sample incubated at 25°C / 60%RH for 24 months showed a mass loss of 1.9% similar to that measured at the above time (Figure 34A), which means that there was no significant water absorption under the said conditions. The TGA analysis result of the solid obtained after exposure to 40°C / 75%RH for 24 months showed a moisture content of 6.7% (equivalent to 3.2 water molecules per camcillate molecule). The thermal behavior recorded by the heat flow signal showed a wide endothermic reaction due to the elution of water, followed by an endothermic reaction due to the melting of the anhydride at about 150°C (Camp2 has a melting point different from 200°C).

[0125] After exposing the said Camp2 to 25°C / 60%RH (Experiment ID: GEN50) and 40°C / 75%RH (Experiment ID: GEN54) for 1 month, the chemical purity measured by LCMS was 99.8% for both samples (Figure 35, Figure 36). This means that the API is present in the solid phase of Camp2. The chemical purity after 3 months can be compared with that of the 1-month sample (Figure 37, Figure 38).

[0126] After exposure to 25°C / 60% RH for 15 months, the chemical purity of Camp2 (Experiment ID: GEN52) was 99.5% (Figure 39), which means that Camp2 was stable for at least 15 months under the said conditions. After 15 months at 40°C / 75% RH, the chemical purity of the Camp4 sample (Experiment ID: GEN56) was 93.7% (Figure 40). This means that Camp2 is converted to Camp4 at 40°C / 75% RH.

[0127] After exposing Camp2 (Experiment ID: GEN53) to 25°C / 60% RH for 24 months, the chemical purity was 100% (Figure 41), which confirms that Camp2 is stable for at least 24 months under the said conditions. After exposing camcillate to 40°C / 75% RH for 24 months, the chemical purity was 88.6% (Figure 42), which means that chemical deterioration occurs at 40°C / 75% RH when Camp2 is converted to a different form.

[0128] Form of camcillate Camp1 Camp1 was obtained from a crystallization form screening through thermal cycling of the small crystalline camcillate obtained after lyophilization. The crystallization solvents that led to Camp1 were ethyl acetate, p-xylene and MTBE. The solid phase for which an additional characterization process was carried out was the salt crystal obtained from MTBE. Camp1 obtained by drying at room temperature was exposed to AAC (40°C / 75% RH) for 2 days and was physically stable during the simultaneous vacuum drying process (Figure 43).

[0129] The TGA / TGMA analysis results of the said Camp1 (Figure 44) showed a mass loss of 4.1% from 40 to 200°C, which, according to the MS signal, was mostly due to water and MTBE. Thermal decomposition occurred at around 240°C or higher, and the heat flow signal showed an endothermic reaction at around 155°C. This is due to the melting of the anhydrous form of the said salt.

[0130] The TGA / TGMS analysis results for the second sample of Camp1 obtained from water (Experiment ID: GEN23) showed a 3.8% mass loss between 25 - 200 °C (3.8% corresponds to 1.8 water molecules per camcillate molecule), and according to the MS signal, this was due to water. Thermal decomposition was shown at approximately 240 °C and above.

[0131] According to the thermal analysis results for Camp1, Camp1 seems to be hydrated by lattice - combined water or organic solvent molecules, or a mixture of hydrates / solvates. According to the gradual loss of water in the TGA analysis results, it seems that water and organic solvent molecules are located in the channels or exist in a structurally vacant form so that Camp1 appears non - stoichiometrically.

[0132] The DSC analysis results of Camp1 obtained from Experiment ID: GEN21 showed a wide endothermic reaction from 25 to 120 °C (Figure 46), which is thought to be due to the loss of water and solvent. It gradually showed an endothermic reaction at approximately 158.8 °C, which is due to the melting of potential camcillate anhydride.

[0133] The DSC analysis results of Camp1 obtained from Experiment ID: GEN23 showed a wide endothermic reaction from 25 to 80 °C (Figure 47), which is thought to be due to the loss of water. It gradually showed two endothermic reactions at 130 - 180 °C, which is due to the elution of water strongly fixed in the crystal lattice of the salt.

[0134] The purity of the said Camp1 measured by LCMS is 98.6%, which means that the API exists in the solid phase of the said Camp1.

[0135] The H - NMR analysis results of Camp1 obtained from Experiment ID: GEN21 are presented in Figure 49. This spectrum overlaps with the results of Camp1 obtained from the said Experiment ID: SSm14. From the above similarity, it can be seen that proton transfer occurred, and at this point, the ratio of API:CI was shown to be 1:1.

[0136] Crystal Forms of Camp2 Camcylate Camp2 is the form most frequently seen in the screening for camcylate, especially in vacuum-dried solids. In some experiments, a mixed form of Camp4 and Camp2 was detected, which is due to the conversion of Camp2 during the AAC exposure in the vacuum-drying process. In the tetrahydrofuran (THF) experiment, it was seen as Camp5 in solids dried at room temperature, which is due to the conversion of Camp2 during the vacuum-drying process. Table 14 shows the experimental conditions for generating Camp2. Camp2 is physically stable upon exposure to AAC (40 °C / 75% RH) for 2 days (Figure 50).

[0137] The TGA / TGMS analysis results for Camp2 showed a 1.7% mass loss from 25 to 180 °C, which, according to the MS signal, is mostly due to water (1.7% corresponds to 0.7 water molecules per salt molecule). Thermal decomposition occurred at around 240 °C or higher, and the heat flow signal showed a distinct endothermic reaction around 200 °C. This is due to the melting of the anhydrous form of the salt, followed by decomposition.

[0138] Experimental Conditions for Generating Camp2

Table 14

[0139] The DSC analysis results for Camp2 showed a broad endothermic reaction from 25 to 70 °C (Figure 52), which is thought to be due to water loss. An endothermic reaction appeared at 208.9 °C, which is related to the melting of the anhydrous form of the salt.

[0140] The purity of the Camp2 measured by LCMS was 97.9% (Figure 53), which means that the API is present in the solid phase of the Camp2.

[0141] The H-NMR analysis results of Camp2 obtained from Experiment ID: GEN17 are presented in Figure 54 together with Camp2 obtained from Experiment ID: SSm73. It was found that proton transfer occurred from the similarity of the spectra, and at this point, the ratio of API:CI showed 1:1.

[0142] Crystal form of Camp4 camcillate Camp4 was obtained from several thermal cycling experiments conducted on camcillate. The experimental conditions for generating Camp4 are shown in Table 15. Camp4 selected for further analysis was obtained from Experiment ID: GEN19 (from heptane). Camp4 is physically stable as it was exposed to AAC (40 °C / 75% RH) for two days (Figure 55).

[0143] The TGA / TGMA analysis results of Camp4 (Figure 56) show a 3.8% mass loss from 25 to 200 °C. According to the MS signal, most of this is due to water and heptane. Thermal decomposition occurred at about 240 °C or higher. The TGMS analysis results for the second Camp4 (Figure 57) were obtained from tetrahydrofuran (THF) / water (95 / 5). The TGA / TGMS analysis results showed a 9.1% mass loss between 40 - 230 °C. Of this, 3.2% is due to water (corresponding to 1.5 water molecules per camcillate molecule), and 5.9% is due to tetrahydrofuran (THF) (0.7 tetrahydrofuran molecules). Thermal decomposition was shown at about 240 °C or higher.

[0144] Experimental conditions for generating Camp4. lc means small crystals. Camp4 is a camcillate obtained through the crystallization process by evaporation when no crystal form appeared after the thermal profile.

Table 15

[0145] The DSC analysis results of Camp4 obtained from the experiment conducted with heptane (Figure 58) showed an extensive endothermic reaction from 25 to 100 °C, which is thought to be due to the loss of water. An endothermic reaction was recorded at 150.4 °C, which is gradually thought to be due to the loss of heptane. No other thermal reactions were visible before thermal decomposition, which implies that the crystal structure of Camp4 collapsed after the loss of water and the solvent.

[0146] The DSC analysis results for Camp4 obtained from the experiment conducted with tetrahydrofuran (THF) / water (95 / 5) showed an extensive endothermic reaction between 25 - 140 °C due to the loss of water. Subsequently, an extensive endothermic reaction between 160 - 220 °C, which is thought to be due to the loss of tetrahydrofuran (THF), was recorded. No other thermal reactions appeared before thermal decomposition.

[0147] The purities of the two Camp4s measured by LCMS were 98.5% and 95.4% respectively (Figure 60, Figure 61). Thus, it can be confirmed that the API exists in the solid phase of the said Camp4. However, in the presence of water, partial chemical alteration seems to occur.

[0148] The H-NMR analysis results for Camp4 obtained from Experiment ID: GEN19 are shown in Figure 62. From the similarity with the results for Camp2, it can be confirmed that proton transfer occurred. The ratio of API:CI was calculated to be 1:1.

[0149] The H-NMR analysis results for Camp4 obtained from Experiment ID: GEN26 are shown in Figure 63. From the similarity with the results for Camp2, it can be confirmed that proton transfer occurred. The ratio of API:CI was calculated to be 1:1. Additional resonance shifts were confirmed in the Camp4 obtained from GEN26, but according to the HPLC results, this was due to potential impurities.

[0150] Although the present invention has been described by citing the special embodiments and the like, it is obvious that various modifications can be made without departing from the technical idea of the present invention. Therefore, it is a well-known fact that the present invention is not limited to the described embodiments, but includes those based on the claims and equivalent substances and the like.

Claims

1. A camcillate salt composed of 10-camphorsulfonic acid and a triazolopyrazine derivative represented by the following Chemical Formula 1. 【Chemical 1】

2. The camcillate salt according to Claim 1, wherein the triazolopyrazine derivative of Chemical Formula 1 is an S optical isomer.

3. The camcillate salt according to Claim 2, wherein the camcillate salt is characterized in that the triazolopyrazine derivative of Chemical Formula 1 is optically pure.

4. The camcillate salt according to any one of Claims 1 to 3, wherein the camcillate salt is any one of Camp1, Camp2, Camp4, Camp5, and Camp6.

5. The camcillate salt according to Claim 4, wherein the camcillate salt is Camp2.

6. The camcillate salt according to Claim 1, wherein the camcillate salt is physically stable at 20 - 50 °C and a relative humidity of 35 - 80% for at least 2 days.

7. The camcillate salt according to Claim 1, wherein the camcillate salt has an API purity of at least 95%.

8. The camcillate salt according to Claim 7, wherein the camcillate salt has an API purity of at least 97.9%.

9. The camcillate salt according to Claim 1, wherein the high-efficiency XRPD (HT-XRPD) pattern of the camcillate salt shows characteristic peaks at 14 - 14.5 ° 2θ and 16 - 17.0 ° 2θ.

10. The camcillate salt according to Claim 1, wherein the HT-XRPD pattern of the camcillate salt shows the following characteristic peaks. Or,

11. It relates to a method for producing the camcillate salt of Claim 1, and the production method includes: a) A step of adding a compound of the following Chemical Formula 1 to a reactor containing a solvent; 【Chemical 1】 b) A step of stirring the compound and the solvent in the reactor; c) A step of adding 10-camphorsulfonic acid to the solution in step b); d) A step of cooling the solution in step c) to obtain a precipitate of the camcillate salt. A method for producing a camcillate salt, characterized by including these steps.

12. The production method according to Claim 11, wherein the solvent contains any one selected from acetonitrile, acetone, 1,2-dimethoxyethane, n-heptane, isopropyl alcohol, water, or tetrahydrofuran (THF).

13. The manufacturing method according to claim 12, wherein the 10-camphorsulfonic acid added in the step b) is added in an equivalent amount of 1:0.5 to 1:1.5 with respect to the compound of the chemical formula 1.

14. The manufacturing method according to claim 13, wherein the equivalent amount is 1:1.0 to 1:1.2, and the solvent is acetonitrile.

15. The manufacturing method according to any one of claims 11 to 14, wherein the step b) is carried out at 45 to 55 °C for at least 1 hour.

16. A pharmaceutical composition comprising the camcillate of claim 1 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16, wherein the pharmaceutically acceptable carrier is one or more selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, green powder, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, amorphous cellulose, polyvinylpyrrolidone, cellulose, water, sealant, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition further comprises one or more selected from the group consisting of lubricants, wetting agents, sweeteners, spices, emulsifiers, suspending agents and preservatives.

19. As a method for suppressing the activity of c-Met kinase, the method is characterized by injecting an effective amount of the camcillate of claim 1 into a subject.

20. The method according to claim 19, wherein the subject exhibits a proliferative disorder.

21. The method according to claim 20, wherein the proliferative disorder is any one selected from lung cancer, colon cancer, pancreatic cancer, rectal cancer, ovarian cancer, renal cell carcinoma, prostate cancer and brain tumor.

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