CN104961681B - The rich mucate and its crystal formation for Buddhist nun of card - Google Patents

Abstract

The present invention relates to N-(4-{[6,7-bis(methyloxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1, Mucic acid salt of 1-dicarboxamide, its crystal form and preparation method. The mucic acid salt of the compound of the formula (I) of the present invention has higher solubility than the malic acid salt, which is of great significance for improving the bioavailability, curative effect and safety of the drug. .

Description

Mucate salt of cabozantinib and its crystal form

technical field

The invention relates to the field of chemical medicine, in particular to N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorobenzene base) mucate salt of cyclopropane-1,1-dicarboxamide and its crystal form.

Background technique

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di Formamide, also known as cabozantinib, was developed by Exelixis for the treatment of metastatic medullary thyroid cancer. It was approved by the FDA in November 2012 and marketed in the form of malate. The structure of cabozantinib is shown in formula (I):

Nearly half of the drug molecules are present and administered in the form of salts. Salt formation can improve some undesirable physicochemical or biopharmaceutical properties of drugs, such as changing the solubility or dissolution rate of drugs, reducing hygroscopicity, improving stability, changing melting point, improving grinding performance, facilitating preparation and purification, and improving permeability.

According to the report in the patent US7579473, the solubility of the free base of the compound formula (I) is extremely low. Therefore, the original research company conducted a large number of salt screening experiments in the patent CN102388024A, and finally chose the form of malate to be marketed, and the patent disclosed malate N-1 crystal form, N-2 crystal form and amorphous form. Surprisingly, the inventors have found that the mucate salt of the compound of formula (I) has high crystallinity and good stability, and its solubility is higher than that of malate, which is useful for improving the biological properties of the drug. Utilization, drug efficacy and safety are of great significance.

Contents of the invention

It is an object of the present invention to provide mucic acid salts of compounds of formula (I). Preferably, the ratio of the compound of formula (I) to mucic acid is 1:1. Preferably, the mucate salt is a crystalline salt.

The mucic acid salt of the compound of formula (I) provided by the present invention is easy to obtain, and its preparation method only needs to dissolve the compound of formula (I) and mucic acid in a solvent respectively, and make the two react to obtain the formula ( I) Mucic acid salts of compounds. The solvent may be acetonitrile, alcohols, ketones, ethers and a mixed solvent system of the above solvents and water respectively. When the two react in a solvent system, a stable salt form can be obtained by crystallization without recrystallization.

The mucate salt of the compound of formula (I) of the present invention has higher solubility, which is beneficial to improving the bioavailability and curative effect of the drug.

The mucic acid salt of the compound of formula (I) provided by the invention has low hygroscopicity, does not need special drying conditions in the preparation process, simplifies the preparation and post-treatment process of medicines, and is easy for industrial production. Moreover, the water content of the crystal form remains basically unchanged under different humidity conditions, which is convenient for long-term storage of medicines. Since the storage conditions are not strictly required, the cost of material storage and quality control is greatly reduced, and it has strong economic value.

The mucate salt of the compound of formula (I) provided by the invention has good stability. Moreover, the currently discovered mucic acid salts only have a single crystal form, which can reduce the changes in the efficacy and safety of drugs caused by polymorphic drugs due to crystal transformation.

The mucic acid salt of the compound of formula (I) provided by the invention can be used in the preparation of medicines for treating cancer, especially for the preparation of medicines for treating metastatic medullary thyroid carcinoma.

The pharmaceutical composition is prepared by taking the mucate salt of the compound of formula (I) as an active ingredient and adding common auxiliary materials for medicines.

Another object of the present invention is to provide a crystalline form of the mucate salt of the compound of formula (I), named Form A in the present invention.

The crystal form A provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 13.4°±0.2°, 25.5°±0.2°, and 19.6°±0.2°.

Furthermore, the crystal form A provided by the present invention is also characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 24.8°±0.2°, 26.6°±0.2°, and 17.3°±0.2°.

Furthermore, the crystal form A provided by the present invention is also characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 23.1°±0.2°, 22.5°±0.2°, and 21.8°±0.2°.

Furthermore, the crystal form A provided by the present invention is characterized in that its X-ray powder diffraction pattern is basically as shown in FIG. 1 .

Furthermore, the crystal form A provided by the present invention is characterized in that an endothermic peak begins to appear when heated to around 208.8°C, and its differential scanning calorimetry diagram is basically shown in FIG. 2 .

Furthermore, the crystal form A provided by the present invention is characterized in that it has a weight loss gradient of about 1.50% when heated to 179.0° C., and its thermogravimetric analysis chart is basically shown in FIG. 3 .

Furthermore, the crystal form A is an anhydrous crystal form.

Another object of the present invention is to provide a preparation method of crystal form A, which is characterized in that the preparation method comprises reacting the compound of formula (I) with mucic acid, stirring and crystallizing to obtain it.

Further, the reaction is carried out in a solvent, and the solvent is acetonitrile, alcohols, ethers or a mixed solvent thereof with water.

Furthermore, the mixed system of acetonitrile, alcohols, ketones, ethers and water respectively, preferably the ratio of acetonitrile, alcohols, ketones, ethers and water is 10:1-20 in volume ratio :1.

Furthermore, the alcohols are preferably methanol, the ketones are preferably acetone, and the ethers are preferably tetrahydrofuran.

Description of drawings

Figure 1 is the XRPD pattern of mucate salt crystal form A

Figure 2 is the DSC chart of mucate salt crystal form A

Figure 3 is the TGA diagram of mucate salt crystal form A

Figure 4 is the XRPD comparison diagram of the stability experiment of mucate salt crystal form A (a is the XRPD pattern before storage; b is the XRPD pattern after storage at 4°C for 30 days; c is the XRPD pattern at 25°C/60% relative humidity XRPD pattern after 30 days of storage; d is the XRPD pattern of 30 days after storage at 40°C/75% relative humidity)

Figure 5 is the DVS diagram of mucate salt crystal form A

detailed description

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermal Gravimetric Analysis

DVS: Dynamic Moisture Sorption

NMR: nuclear magnetic resonance

The X-ray powder diffraction pattern described in the present invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameter of X-ray powder diffraction of the present invention is as follows:

X-ray reflection parameters: Cu, Kα

1.540598; 1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 kilovolts (kV)

Current: 40 milliamps (mA)

Divergence Slit: Automatic

Scan mode: continuous

Scanning range: from 3.0 to 40.0 degrees

Sampling step size: 0.013 degrees

The differential scanning calorimetry (DSC) diagrams described in the present invention were collected on TA Q2000. The method parameter of differential scanning calorimetry (DSC) of the present invention is as follows:

Scanning rate: 10°C/min

Protective gas: nitrogen

The thermogravimetric analysis (TGA) figure of the present invention is collected on TA Q5000. The method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:

Scanning rate: 10°C/min

Protective gas: nitrogen

The Dynamic Water Sorption (DVS) graph of the present invention was collected on an Intrinsic Dynamic Water Sorption Instrument produced by SMS Company (Surface Measurement Systems Ltd.). The method parameter of described dynamic water adsorption instrument is as follows:

Example 1

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di The preparation method of formamide mucate:

200mg N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1 - The powder of diformamide was dissolved in 8.0 mL of acetonitrile solvent system, then 84 mg of mucic acid solid was added to the solution, and magnetically stirred at room temperature to obtain it.

The mucic acid salt product prepared by the above-mentioned method has the following NMR identification data:

¹ H NMR (400MHz, DMSO) δ10.18(s, 1H), 10.05(s, 1H), 8.47(d, J=5.2Hz, 1H), 7.76(d, J=9.0Hz, 2H), 7.64( dd,J=9.1,5.1Hz,2H),7.50(s,1H),7.39(s,1H),7.23(d,J=9.0Hz,2H),7.15(t,J=8.9Hz,2H), 6.43(d,J=5.2Hz,1H),4.22(s,2H),3.94(d,J=4.8Hz,6H),3.77(s,2H),1.47(s,4H).

Example 2

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1 of the present invention, Comparative study on the solubility of 1-dicarboxamide mucate and malate in CN102388024A:

The two salts were prepared as saturated solutions with pH 1.8 SGF (simulated gastric juice) and pH 6.5 FaSSIF (artificial intestinal fluid in fasting state) buffers. After 4 hours, measure the concentration of the sample in the saturated solution by high performance liquid chromatography, and the experimental results are as shown in table 1:

Table 1 Comparative study on solubility of cabozantinib mucate and CN102388024A malate

Detection limit: 0.03 μg/ml

As can be seen from the above comparison results, N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxyl}benzene of the present invention after being placed in SGF and FaSSIF for 4 hours Base)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide mucate salt has higher solubility than CN102388024A malate.

Example 3

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di The preparation method of formamide mucate salt crystal form A:

10mg N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1 - Diformamide powder was dissolved in 0.4 mL of methanol solvent system, then 4.2 mg of mucic acid solid was added, and stirred at room temperature to obtain Form A. Table 2 shows the X-ray powder diffraction data of Form A obtained in this example. Its XRPD diagram is shown in Figure 1, its DSC diagram is shown in Figure 2, and its TGA diagram is shown in Figure 3.

Table 2 X-ray powder diffraction data of crystal form A

2theta d interval Relative Strength% 3.28 26.91 6.51 6.81 12.97 17.59 7.22 12.24 4.15 8.79 10.06 7.33

13.28 6.67 82.93 13.41 6.60 100.00 15.16 5.84 6.40 16.72 5.30 9.18 17.32 5.12 19.17 17.67 5.02 4.61 18.41 4.82 5.75 19.61 4.53 39.96 20.53 4.33 13.50 21.86 4.07 13.98 22.23 4.00 6.44 22.57 3.94 12.24 23.20 3.83 9.92 23.53 3.78 5.95 24.13 3.69 2.99 24.81 3.59 17.61 25.22 3.53 0.94 25.51 3.49 21.97 26.13 3.41 3.87 26.68 3.34 14.82 26.85 3.32 11.26 27.47 3.25 7.97 27.98 3.19 4.68 28.69 3.11 7.15 29.65 3.01 4.21 30.03 2.98 4.48

Example 4

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di The preparation method of formamide mucate salt crystal form A:

200mg N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1 - Diformamide powder was dissolved in 8.0 mL of methanol solvent system, then 84 mg of mucic acid solid was added, and stirred at room temperature to obtain Form A. Table 3 shows the X-ray powder diffraction data of Form A obtained in this example.

Table 3 X-ray powder diffraction data of crystal form A

2theta d interval Relative Strength% 6.77 13.05 10.21 7.18 12.32 3.52 8.75 10.10 4.77 12.06 7.34 1.77 13.35 6.63 100.00 14.53 6.09 1.90 15.13 5.86 6.57 15.87 5.58 1.23 16.68 5.31 8.26 17.31 5.12 18.76 17.62 5.03 5.70 18.07 4.91 3.31 18.37 4.83 8.13 19.55 4.54 28.21 20.50 4.33 13.28 21.25 4.18 4.56 21.82 4.07 15.28 22.20 4.00 8.23 22.52 3.95 15.95 22.97 3.87 13.92 23.14 3.84 16.05 23.50 3.79 8.53 24.14 3.69 5.11 24.77 3.59 25.83 25.45 3.50 30.81 26.03 3.42 6.34 26.64 3.35 21.19 27.43 3.25 12.12 27.98 3.19 7.54 28.65 3.12 11.19

Example 5

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di Study on the stability of the mucate salt form A of formamide:

Take three samples of mucate salt crystal form A prepared in Example 4 and place them under the conditions of 25°C/60% relative humidity, 40°C/75% relative humidity and 4°C for 30 days, and then take samples to measure XRPD and Purity, the results are shown in Table 4.

Table 4 Stability study of Form A

From the above table, it can be seen that the crystal form A remains unchanged after being placed for 30 days under the conditions of 25°C/60% relative humidity, 40°C/75% relative humidity and 4°C, and the purity reaches 99.70% or above. The results show that , the crystal form A of the present invention has good stability.

Example 6

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di Study on the hygroscopicity of the mucate salt crystal form A of formamide:

Take about 10 mg of the crystal form A of the present invention and use a dynamic water sorption (DVS) instrument to test its hygroscopicity. The experimental results are shown in Table 5. The DVS diagram of the wetness experiment is shown in Figure 5.

Hygroscopicity experiment of table 5 crystal form A

About the definition of hygroscopic characteristic description and hygroscopic weight gain (Chinese Pharmacopoeia 2010 edition appendix XIX J drug hygroscopic test guidelines, experimental conditions: 25 ° C ± 1 ° C, 80% relative humidity):

Deliquescence: the absorption of sufficient water to form a liquid

Extremely hygroscopic: the weight gain of moisture is not less than 15%

Moisture-absorbing: the weight gain of moisture-absorbing is less than 15% but not less than 2%

Slight hygroscopicity: the weight gain of moisture is less than 2% but not less than 0.2%

No or almost no hygroscopicity: the weight gain of moisture is less than 0.2%

The results show that the crystal form A of the present invention has a weight gain of 0.28% after equilibrium at 80% humidity, and has slight hygroscopicity.

Claims (9)

1. The crystal form A of the mucate salt of the compound of formula (I), It is characterized in that its X-ray powder diffraction pattern is at 2theta values of 13.4°±0.2°, 25.5°±0.2°, 19.6°±0.2°, 24.8°±0.2°, 26.6°±0.2°, 17.3°±0.2° have characteristic peaks. 2. The crystal form A of formula (I) compound mucate salt according to claim 1 is characterized in that its X-ray powder diffraction pattern is 23.1 ° ± 0.2 °, 22.5 ° ± 0.2 °, 21.8 ° at 2theta values °±0.2° has a characteristic peak. 3. The crystal form A of the mucate salt of the formula (I) compound according to claim 2, characterized in that its X-ray powder diffraction pattern is basically consistent with that shown in Figure 1. 4. A method for preparing the mucic acid salt of the compound of formula (I) according to claim 1, which comprises reacting the compound of formula (I) with mucic acid, stirring and crystallizing to obtain it. 5. The method according to claim 4, wherein said reaction is carried out in a solvent, and said solvent is acetonitrile, alcohols, ethers or a mixed solvent thereof with water. 6. The method according to claim 5, wherein said alcohols are methyl alcohol, and said ethers are THF. 7. The method according to claim 6, wherein the volume ratio of the acetonitrile, alcohols, ethers and water is between 10:1-20:1. 8. A pharmaceutical composition comprising the crystalline form of the mucate salt of the compound of formula (I) according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier. 9. According to the crystal form of the mucate salt of the compound of formula (I) according to any one of claims 1 to 3, or the pharmaceutical composition according to claim 8 in the preparation of drugs for the treatment of metastatic medullary thyroid cancer use.