AZD9291-2-indole carboxylate and its preparation method

Abstract

The present invention relates to the technical field of crystalline pharmaceutical molecules, and specifically provides an AZD9291-2-indolecarboxylate, its preparation method and application. The AZD9291-2-indolecarboxylate of the present invention has characteristic peaks at 5.77±0.2°, 8.55±0.2°, 12.37±0.2°, 15.32±0.2°, 17.34±0.2°, 18.62±0.2°, 19.87±0.2° in the X-ray diffraction pattern expressed in 2θ using Cu-Kα radiation. The preparation method of the AZD9291-2-indolecarboxylate provided by the present invention is simple, the solubility of the crystal form of the prepared salt is significantly improved, and the stability is good, which is suitable as a pharmaceutical active ingredient.

Description

Technical Field

[0001] The present invention relates to the technical field of crystalline pharmaceutical molecules, particularly to the technical field of AZD9291 crystal forms, specifically to AZD9291-2-indole carboxylate and its preparation method and application. Background Art

[0002] AZD9291 (Osimertinib), chemical name: N-[2-[[2-(dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide, English name: N-(2-{[2-(Dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino}phenyl)acrylamide. CAS number: 1421373-65-0 , and its structural formula is as follows:

[0003]

[0004] For lung cancer patients with EGFR or ALK gene mutations, the use of targeted drugs can achieve better survival benefits. However, the efficacy of these drugs is generally very short-lived, and drug resistance will occur within 9 - 11 months. This is because cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing their growth patterns.

[0005] ADZ9291 developed by AstraZeneca is a third-generation oral, irreversible selective EGFR mutation inhibitor, which can be used for both activating and resistant mutant EGFRs. That is to say, for advanced non-small cell lung cancer patients, 50% of acquired resistance to anti-EGFR therapy is caused by the T790M mutation, and ADZ9291 can render this challenging mutation ineffective. ADZ9291 has a better therapeutic effect on NSCLC patients with resistance to existing epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the T790M mutation.

[0006] Patent CN103702990A discloses the structure of the compound ADZ9291. This patent also discloses the polymorphs of this compound and its mesylate, including ADZ9291 mesylate polymorph A and ADZ9291 mesylate polymorph B. Patent CN104961731A discloses ADZ9291 phosphate; Patent CN106432231A discloses ADZ9291 pharmaceutical salts sulfate, p-toluenesulfonate, tartrate, acetate and citrate; Patent CN107915725A discloses its new pharmaceutical salts maleate, fumarate, gluconate, malonate, succinate and lactate.

[0007] The original research company used the mesylate of AZD9291 for clinical research. However, methanesulfonic acid has high biological toxicity and is not suitable for drug development when there are alternatives. And the mesylate has problems of high hygroscopicity and easy deliquescence in high humidity. Therefore, it is very necessary to develop other salts with high bioavailability, low toxicity and suitable for medicinal use. Although many polymorphs of AZD9291 have been disclosed in the existing literature, the systematic research on its polymorphs still needs to be improved. Summary of the Invention

[0008] In view of the deficiencies of the prior art, the present invention provides an AZD9291-2-indole carboxylate, which has good stability and high solubility; compared with the existing polymorphs, its excellent physical and chemical properties are suitable as the active ingredient of a drug.

[0009] The specific technical content of the present invention is as follows:

[0010] On the one hand, the present invention provides an AZD9291-2-indole carboxylate, and the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 5.77±0.2°, 8.55±0.2°, 12.37±0.2°, 15.32±0.2°, 17.34±0.2°, 18.62±0.2°, 19.87±0.2° when using Cu-Kα radiation.

[0011] Preferably, for the AZD9291-2-indole carboxylate, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 5.77±0.2°, 8.55±0.2°, 9.25±0.2°, 12.37±0.2°, 15.32±0.2°, 17.34±0.2°, 18.62±0.2°, 19.87±0.2°, 20.79±0.2°, 23.26±0.2°, 23.97±0.2°, 24.99±0.2°, 26.06±0.2°, 27.38±0.2°, 29.17±0.2°, 31.12±0.2° when using Cu-Kα radiation.

[0012] Preferably, the AZD9291-2-indolylformate, using Cu-Kα radiation, has Figure 1 the X-ray diffraction pattern shown below.

[0013] Preferably, the AZD9291-2-indolylformate has an endothermic peak at 202.85 - 230.33 °C in its differential scanning calorimetry curve (DSC), and the peak value is 218.63 °C.

[0014] On the other hand, the present invention provides a method for preparing the above-mentioned 2-indolylformate, comprising the following steps:

[0015] Dissolve AZD9291 and 2-indolylformic acid in a mixed solution of methanol and purified water, heat up, let stand, filter, evaporate, crystallize at room temperature, filter, and dry in vacuum to obtain the product.

[0016] Preferably, the molar feeding ratio of AZD9291 to 2-indolylformic acid is 1:1 - 2.

[0017] Preferably, the molar dosage of AZD9291 to the volume dosage of methanol is 1:30 - 50, where the molar unit is mol and the volume unit is L.

[0018] Preferably, the molar dosage of AZD9291 to the volume dosage of purified water is 1:2 - 10, where the molar unit is mol and the volume unit is L.

[0019] Preferably, the heating temperature is 45 - 60 °C.

[0020] Preferably, the standing time is 3 - 4 h.

[0021] Preferably, the vacuum drying temperature is 30 - 40 °C and the drying time is 4 - 8 h.

[0022] Confirmation of the crystal structure of AZD9291-2-indolylformate

[0023] The X-ray crystal data of the present invention was collected on a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K, using CuKa radiation, collecting data in ω-scan mode and performing Lp correction. The structure was solved by the direct method, and all non-hydrogen atoms were located by the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by the least squares method.

[0024] The X-ray powder diffraction test instrument and test conditions of the present invention are as follows: PANalytical Empyrean X-ray powder diffractometer; Cu target as the light source, flat sample stage, incident optical path: BBHD, diffraction optical path: PIXCEL, voltage 45 KV, current 40 mA, divergence slit 1 / 4°, anti-scattering slit 1°, Soller slit 0.04 rad, counting time per step 0.5 s, scanning range 3 - 50°.

[0025] The TGA / DSC thermal analysis test instrument and test conditions in the present invention are: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC3+; dynamic temperature range: 30 - 300 °C; heating rate: 10 °C / min; gas in the program segment: N2; gas flow rate: 50 mL / min; crucible: 40 μl aluminum crucible.

[0026] The crystallographic data obtained by testing and analyzing the AZD9291-2-indolecarboxylate prepared in the present invention are (see Table 1): Its crystallographic parameters are: monoclinic system, space group C2 / c; unit cell parameters are: α = 90°, β = 90.7340(10)°, γ = 90°, unit cell volume In the ORTEP diagram of the AZD9291-2-indolecarboxylate of the present invention, the occupancy rate of water molecules is 0.5, indicating that one molecule of osimertinib binds to one molecule of 2-indolecarboxylic acid and half a molecule of water, as Figure 2 shown.

[0027] Table 1 Main crystallographic data of AZD9291-2-indolecarboxylate

[0028]

[0029]

[0030] According to the crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) corresponding to the AZD9291-2-indolecarboxylate prepared in the present invention are shown in the appendix Figure 1 and Table 2. For the said AZD9291-2-indolecarboxylate, its differential scanning calorimetry curve (DSC) has an endothermic peak at 202.85 - 230.33 °C, and the peak value is 218.63 °C. The AZD9291-2-indolecarboxylate has a DSC / TGA pattern as Figure 3 shown.

[0031] Table 2 Main XRD peak data of AZD9291-2-indolecarboxylate

[0032]

[0033]

[0034] All AZD9291-2-indolylformate samples prepared by the present invention have the same crystallographic parameters, X-ray powder diffraction patterns and DSC / TGA spectra as described above.

[0035] In a third aspect, the present invention provides a pharmaceutical composition comprising the AZD9291-2-indolylformate prepared above, and containing other active ingredients that can be used in combination and / or pharmaceutically acceptable excipient components.

[0036] Preferably, the pharmaceutical composition can be made into sprays, tablets, capsules, powder injections, liquid injections, etc. using standard or conventional techniques.

[0037] In a fourth aspect, the present invention provides the use of the above-mentioned AZD9291-2-indolylformate in the preparation of drugs for treating lung cancer, especially in the preparation of drugs for treating non-small cell lung cancer.

[0038] Compared with the prior art, the AZD9291-2-indolylformate prepared by the present invention has good chemical stability and high solubility; the preparation method provided by the present invention has good reproducibility and is convenient to operate. Description of the Drawings

[0039] Figure 1 is the X-ray powder diffraction pattern of AZD9291-2-indolylformate;

[0040] Figure 2 is the ORTEP diagram of AZD9291-2-indolylformate;

[0041] Figure 3 is the TGA / DSC thermal analysis diagram of AZD9291-2-indolylformate. Detailed Embodiments

[0042] The present invention will be further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope of protection required by the present invention.

[0043] Example 1

[0044] Dissolve 2.5 g of AZD9291 and 1.2 g of 2-indolylformic acid in a mixed solution of 200 mL of methanol and 25 mL of purified water, heat to 55 °C, let stand for 4 h, filter, seal with a sealing film, punch holes, volatilize, crystallize at room temperature, filter, and vacuum dry at 35 °C for 6 h to obtain AZD9291-2-indolylformate, with a yield of 96.69% and HPLC: 99.98%.

[0045] Example 2

[0046] Dissolve 2.5 g of AZD9291 and 1.6 g of 2-indolecarboxylic acid in a mixed solution of 250 mL of methanol and 50 mL of purified water. Heat the solution to 60 °C, let it stand for 4 h, filter, seal it with a sealing film, punch holes, evaporate, crystallize at room temperature, filter, and dry it in vacuo at 40 °C for 8 h to obtain AZD9291-2-indolecarboxylate, with a yield of 95.76% and HPLC: 99.97%.

[0047] Example 3

[0048] Dissolve 2.5 g of AZD9291 and 0.8 g of 2-indolecarboxylic acid in a mixed solution of 150 mL of methanol and 10 mL of purified water. Heat the solution to 45 °C, let it stand for 3 h, filter, seal it with a sealing film, punch holes, evaporate, crystallize at room temperature, filter, and dry it in vacuo at 30 °C for 4 h to obtain AZD9291-2-indolecarboxylate, with a yield of 94.58% and HPLC: 99.96%.

[0049] Example 4

[0050] Dissolve 0.5 g of AZD9291 and 0.4 g of 2-indolecarboxylic acid in a mixed solution of 50 mL of methanol and 20 mL of purified water. Heat the solution to 60 °C, let it stand for 5 h, filter, seal it with a sealing film, punch holes, evaporate, crystallize at room temperature, filter, and dry it in vacuo at 45 °C for 9 h to obtain AZD9291-2-indolecarboxylate, with a yield of 91.32% and HPLC: 99.94%.

[0051] Verification test

[0052] (1) Stability test

[0053] The AZD9291-indolecarboxylate prepared in Examples 1 to 4 of the present invention was subjected to a stability test. The specific stability test method was carried out with reference to the guiding method for stability investigation in the fourth part of the Chinese Pharmacopoeia 2015 edition. Purity detection was carried out by HPLC method, and the specific test results are shown in Table 3.

[0054] Table 3 Stability test results of AZD9291-indolecarboxylate under light, high temperature and high humidity conditions

[0055]

[0056] As can be seen from Table 3, for the AZD9291-indolecarboxylate prepared in Examples 1 to 4 of the present invention, the purity did not change significantly under the conditions of light, high temperature and high humidity. It can be seen that the AZD9291-indolecarboxylate prepared by the present invention has good stability.

[0057] (2) Solubility test

[0058] A comparative study on the solubility of AZD9291-indole formate prepared in Examples 1-4 of the present invention and AZD9291 mesylate polymorph A and AZD9291 fumarate in the prior art was carried out. Method: 10 ml of media (water, 0.1 mol / L HCl solution and phosphate buffer solution with pH = 6.8) were respectively measured and placed in a vial, an excessive amount of the sample to be tested was added, the vial was sealed and placed in a constant temperature water bath at 25 °C and stirred for 1 hour, filtered through a 0.45 μm filter membrane, and the filtrate was taken; the absorbance was measured at a wavelength of 210 nm, and its solubility was calculated by measuring the absorbance of the standard reference substance.

[0059] Table 4 Solubility of osimertinib polymorphs in different media (mg / ml)

[0060]

[0061]

[0062] It can be seen from the above test data that, compared with AZD9291 mesylate polymorph A and AZD9291 fumarate in the prior art, the solubility of AZD9291-indole formate prepared in Examples 1-4 of the present invention has been significantly improved, indicating that the solubility of AZD9291-2-indole formate prepared in the present invention is good, and it is beneficial for human absorption when made into a pharmaceutical preparation.

Claims

1. An AZD9291-2-indolecarboxylate hemihydrate, characterized in that: Using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 5.77 ± 0.2°, 8.55 ± 0.2°, 12.37 ± 0.2°, 15.32 ± 0.2°, 17.34 ± 0.2°, 18.62 ± 0.2°, 19.87 ± 0.2°.

2. The AZD9291-2-indolecarboxylate hemihydrate according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at 5.77 ± 0.2°, 8.55 ± 0.2°, 9.25 ± 0.2°, 12.37 ± 0.2°, 15.32 ± 0.2°, 17.34 ± 0.2°, 18.62 ± 0.2°, 19.87 ± 0.2°, 20.79 ± 0.2°, 23.26 ± 0.2°, 23.97 ± 0.2°, 24.99 ± 0.2°, 26.06 ± 0.2°, 27.38 ± 0.2°, 29.17 ± 0.2°, 31.12 ± 0.2°.

3. The AZD9291-2-indolecarboxylate hemihydrate according to claim 1, characterized in that: The AZD9291-2-indolecarboxylate hemihydrate, using Cu-Kα radiation, has the X-ray diffraction pattern shown in Figure 1.

4. The AZD9291-2-indolecarboxylate hemihydrate according to claim 1, characterized in that: The AZD9291-2-indole carboxylate hemihydrate described above has the following crystallographic parameters: monoclinic system, space group C2 / c; unit cell parameters are: a = 29.8073(3) Å, b = 11.28020(10) Å, c = 20.1611(2) Å, α = 90°, β = 90.7340(10)°, γ = 90°, unit cell volume V = 6778.26(11) 3 .

5. A method for preparing the AZD9291-2-indolecarboxylate hemihydrate according to any one of claims 1 to 4, characterized in that, Comprising the following steps: Dissolve AZD9291 and 2-indolecarboxylic acid in a mixed solution of methanol and purified water, heat up, stand still, filter, volatilize, crystallize at room temperature, filter, and vacuum dry to obtain; The molar dosage of AZD9291 and the volume dosage of methanol are in a ratio of 1:30 - 50, where the molar unit is mol and the volume unit is L; the molar dosage of AZD9291 and the volume dosage of purified water are in a ratio of 1:2 - 10, where the molar unit is mol and the volume unit is L.

6. The preparation method according to claim 5, characterized in that: The molar feeding ratio of AZD9291 and 2-indolecarboxylic acid is 1:1 - 2.

7. A pharmaceutical composition, which comprises the AZD9291-2-indolecarboxylate hemihydrate according to any one of claims 1 to 4, and contains other active ingredients that can be used in combination and / or pharmaceutically acceptable excipient components.

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