WO2016124137A1 - Phosphate of epidermal growth factor receptor inhibitor, crystalline form of phosphate, and preparation method - Google Patents

Abstract

The present invention relates to a phosphate crystalline form A of the compound of formula (I), and a preparation method for the phosphate crystalline form A. The phosphate crystalline form A has advantageous properties such as good solubility, low hygroscopicity and process developability. The preparation method is simple and low-cost, and has significant value for the future optimisation and development of the drug.

Description

Phosphate of epidermal growth factor receptor inhibitor, crystal form thereof and preparation method thereof Technical field

The present invention relates to the field of chemical medicine, in particular to N-(2-(2-dimethylaminoethyl-methylamino)-4-methoxy-5-(4-(1-methylindol-3-yl) a pyrimidine-2-yl)aminophenyl)prop-2-enamide phosphate, a crystal form thereof, and a process for the preparation thereof.

Background technique

For patients with advanced non-small cell lung adenocarcinoma (NSCLC), targeted therapy with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations is the standard treatment option today. However, the efficacy of these drugs is generally very short, and drug resistance occurs in 9-11 months. This occurs because cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutation and altered growth patterns.

For the second mutation of EGFR in lung cancer patients, there is currently no suitable drug for treatment. The compound of formula (I) developed by AstraZeneca (also known as AZD9291) is an oral, irreversible, third-generation EGFR inhibitor. The preclinical model study has a significant effect on the existing epidermis. Growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has a better therapeutic effect in NSCLC patients with resistance and T790M mutations. The chemical name of the compound of formula (I) is N-(2-(2-dimethylaminoethyl-methylamino)-4-methoxy-5-(4-(1-methylindol-3-yl)pyrimidine 2-yl)aminophenyl)prop-2-enamide.

Chinese Patent Application CN103702990A discloses the structure of the compound of formula (I). Polymorphic forms of the compounds of formula (I) and their mesylate salts are also disclosed in this patent application.

Increasing the solubility of candidate compounds by salt formation has become an important means in drug development. Compared with the free form of the drug, a suitable drug salt can improve the solubility of the drug, increase the physicochemical stability, and improve the physical properties such as melting point, hygroscopicity, and crystallization type after the salt is formed, and has a further development of the pharmaceutical dosage form. Important role. The original research company used the mesylate salt of the compound of formula (I) for clinical research. However, methanesulfonic acid is highly biotoxic and, if selected, is not suitable for use in medicine. (P. Heinrich Stahl, Camille G. Wermuth (Eds.). (2002). Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 294-302)

Therefore, it is necessary to develop other salts with high bioavailability, low toxicity, and suitable for medicinal use.

Summary of the invention

It is an object of the present invention to provide phosphates of the compounds of formula (I). The phosphate provided by the invention has high solubility, low wettability, high biosafety, meets medicinal requirements, and has simple preparation method, and is suitable for drug research and industrial production.

The phosphate of the compound of formula (I) provided by the present invention is in a crystalline form and is designated as Form A in the present invention.

The X-ray powder diffraction pattern of Form A provided by the present invention has characteristic peaks at 2theta values of 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, and 16.4 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern of Form A provided by the present invention has a characteristic peak at a 2theta value of 7.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, and 24.5 ° ± 0.2 °.

Further, the X-ray powder diffraction pattern of Form A provided by the present invention has a value of 2theta in 2theta There are characteristic peaks at 8.2 ° ± 0.2 °, 16.7 ° ± 0.2 °, and 17.4 ° ± 0.2 °.

In a specific embodiment, the X-ray powder diffraction pattern of Form A provided by the present invention has a value of 7.5 ° ± 0.2 °, 8.2 ° ± 0.2 °, 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, 16.4 °. Characteristic peaks are present at ±0.2°, 16.7°±0.2°, 17.4°±0.2°, 19.5°±0.2°, and 24.5°±0.2°.

In another embodiment, the X-ray powder diffraction pattern of Form A provided by the present invention is substantially as shown in FIG.

Further, the crystal form A provided by the present invention begins to exhibit an endothermic peak when heated to about 235 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .

Further, the crystal form A provided by the present invention has a weight loss gradient of about 1.5% when heated to 200 ° C, and the thermogravimetric analysis chart is shown in FIG. 3 .

Another object of the present invention is to provide a process for the preparation of a crystalline form A of a compound of the formula (I), which comprises reacting a compound of the formula (I) with phosphoric acid in a ketone or an alcohol solvent, and stirring and crystallization.

Further, the alcohol solvent is preferably an alcohol having a carbon number of less than 6, more preferably methanol or ethanol.

Further, the ketone solvent is preferably a ketone having a carbon number of less than 6, more preferably acetone.

Further, the molar ratio of the compound of the formula (I) to phosphoric acid is 1:1.

The phosphate of the compound of the formula (I) provided by the present invention, in particular the crystalline form A of the phosphate of the compound of the formula (I), can be used for the preparation of a medicament for the treatment of cancer, in particular for the treatment of a medicament for the treatment of non-small cell lung cancer.

Still another object of the present invention is to provide a pharmaceutical composition which is prepared by using a crystalline form A of the compound of the formula (I) as an active ingredient and adding a usual excipient for the drug.

Another object of the present invention is to provide a use of the phosphate crystal form A of the compound of the formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of cancer.

The beneficial effects of the invention are:

The phosphate crystal form A of the compound of the formula (I) provided by the invention has higher biosafety, overcomes the problem of great toxicity of the methanesulfonate salt, and is more suitable for drug development;

The phosphate crystal form A of the compound of the formula (I) provided by the invention has lower hygroscopicity, and overcomes the problem that the mesylate salt has high wettability and high humidity is deliquescent;

The phosphate crystal form A of the compound of the formula (I) provided by the present invention has higher solubility than the free base of the compound of the formula (I), and satisfies the bioavailability and the efficacy requirement.

DRAWINGS

Figure 1 is an XRPD pattern of the crystalline form A of the compound of formula I;

Figure 2 is a DSC chart of the crystalline form A of the compound of formula I;

Figure 3 is a TGA diagram of the crystalline form A of the compound of formula I;

Figure 4 is a ¹ H NMR chart of the crystalline form A of the compound of formula I;

Figure 5 is a DVS diagram of the crystalline form A of the compound of formula I;

Figure 6 is a DVS diagram of the crystalline form B of the compound of formula I;

Figure 7 is a XRPD comparison of the one month stability test of the compound of formula I for the crystalline form A of the compound of formula I under different test conditions (from top to bottom, the starting sample is XRPD, 5 ° C, 25 ° C / 60% RH and XRPD of the sample after being placed at 40 ° C / 75% RH for 1 month;

Figure 8 is a comparison of XRPD of the 3-month stability test of the compound of the formula I for the phosphate crystal form A under different test conditions (from top to bottom, the starting sample is XRPD, 5 ° C, 25 ° C / 60% RH and XRPD of the sample after 3 months of placement at 40 ° C / 75% RH.

detailed description

The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art within the scope of the claims, and such modifications are also considered to be within the scope of the invention.

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

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric analysis

¹ H NMR: Nuclear Magnetic Resonance Spectroscopy

DVS: Dynamic moisture adsorption

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

X-ray reflection parameters: Cu, K-α radiation

Kα1

1.540598; Kα2

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV)

Current: 40 milliamps (mA)

Scan range: from 3.0 to 40.0 degrees

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture adsorber are as follows:

Temperature: 25 ° C

Carrier gas, flow rate: N ₂ , 200 ml / min

Unit time quality change: 0.002% / minute

Relative humidity range: 0%RH-95%RH

Example 1

Preparation method of compound crystal form A of formula (I):

10.1 mg of the free base of the compound of formula (I) was placed in a 1.5 mL glass vial, dissolved in 0.5 mL of acetone, and 0.1 mL of a 0.2 mol/L phosphoric acid solution was added, stirring under a magnetic stirrer (r= 500 r / min), the reaction was sealed at room temperature for 24 hours, crystallized, and the solid obtained by centrifugation was dried under vacuum at room temperature.

The phosphate product prepared by the above method has a ¹ H NMR as shown in Fig. 4, and the identification data is as follows: ¹ H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 9.03 (s, 1H), 8.63 (s) , 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.25 (dd , J=8.7, 6.3 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.55 (d, J = 10.3 Hz, 1H), 6.29 (dd, J = 16.9, 1.9 Hz, 1H), 5.84–5.71 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.04 (s, 2H), 2.69 (s, 3H), 2.62 (s, 2H), 2.41(s,6H).

Upon examination, the solid obtained in this example was a phosphate crystal form A of the compound of the formula (I), and the X-ray powder diffraction data thereof are shown in Table 1. 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 1 X-ray powder diffraction data of Form A

2theta	d interval	strength%
7.49	11.80	37.89
8.22	10.76	21.87
8.63	10.25	12.84
9.82	9.01	100.00
10.86	8.15	7.20
12.33	7.18	13.18
13.24	6.69	3.55
13.65	6.49	19.94
15.26	5.80	12.21
16.43	5.40	48.63
16.77	5.29	11.93
17.48	5.07	18.35
17.59	5.04	13.07
19.43	4.57	24.23
19.57	4.54	37.69
19.79	4.49	22.94
19.98	4.44	11.04

20.91	4.25	2.29
22.16	4.01	8.13
22.48	3.95	15.64
23.57	3.77	12.32
24.50	3.63	43.99
24.79	3.59	14.86
25.08	3.55	40.86
25.76	3.46	4.79
26.09	3.42	4.54
26.46	3.37	3.61
27.46	3.25	3.38
29.90	2.99	4.42
31.84	2.81	3.45
32.46	2.76	3.41
33.30	2.69	3.49
34.09	2.63	1.08

Example 2

Preparation method of compound crystal form A of formula (I):

10.2 mg of the free base of the compound of formula (I) was placed in a 1.5 mL glass vial, dissolved in 0.5 mL of ethanol, and 0.1 mL of a 0.2 mol/L phosphoric acid solution was added, with stirring under a magnetic stirrer (r= 500 r / min), the reaction was sealed at room temperature for 24 hours, crystallized, and the solid obtained by centrifugation was dried under vacuum at room temperature.

Upon examination, the solid obtained in this example was a phosphate crystal form A of the compound of the formula (I), and its X-ray powder diffraction data is shown in Table 2.

Table 2 X-ray powder diffraction data of Form A

2theta	d interval	strength%
7.43	11.91	31.68
8.17	10.83	28.63
8.57	10.32	16.45
9.76	9.06	100.00
10.70	8.27	57.18
11.85	7.47	7.92
12.25	7.22	13.48
12.85	6.89	3.59
13.60	6.51	22.65
15.20	5.83	15.23
16.37	5.41	35.12
16.78	5.28	19.18
17.49	5.07	17.43
19.51	4.55	41.64
21.51	4.13	24.69
22.56	3.94	20.93
23.55	3.78	13.26
24.47	3.64	37.67
25.06	3.55	31.75
25.64	3.47	16.14
29.97	2.98	2.23

Example 3

Comparative Study on Dynamic Solubility of Phosphate Form A and Free Base of Compound of Formula (I):

The phosphate crystal form A of the compound of the formula (I) and the free base were respectively made into a saturated solution by using H ₂ O and a simulated gastric fluid (SGF) of pH 1.8, respectively, after 1 hour, 4 hours and 24 hours, respectively. The content was determined by high performance liquid chromatography (HPLC) after an hour. The experimental results are shown in Table 3.

table 3

The results showed that the solubility of the crystalline form A of the compound of the formula (I) in water was much higher than that of the free base in water, and the free base was found to degrade in the SGF for 24 hours during the analysis, in the biological medium. Poor stability is not conducive to the preparation of medicine. The invention overcomes the problem that the free base has low solubility and is unstable in the biological medium by means of phosphate formation, and the effect of improving bioavailability is achieved.

Example 4

Comparative study on the wettability of the crystalline form A of the compound of the formula (I) and the crystalline form B of the compound of the formula (I):

10 mg of the phosphate crystal form A of the present invention and 10 mg of the methanesulfonate crystal form B of the Chinese patent application CN103702990A were respectively subjected to dynamic moisture adsorption (DVS) test. The DVS of the phosphate crystal form A is shown in Fig. 5, and the DVS of the methanesulfonate crystal form B is shown in Fig. 6, and the results are shown in Table 4.

Table 4

sample	80% humidity gain	95% humidity gain
Compound (I) phosphate crystal form A	2.82%	3.47%
Compound (I) mesylate salt form B	6.16%	55.17% (deliquescent)

The results show that the phosphate crystal form A of the compound of the formula (I) of the present invention has a weight gain of 2.82% after equilibrium at 80% relative humidity, a weight gain of 3.47% after equilibrium at 95% relative humidity, and a low wettability; Application CN103702990A The compound (I) mesylate salt Form B has a weight gain of 6.16% after equilibration at 80% relative humidity, a high wettability, and deliquescence occurs after equilibration at 95% relative humidity. The invention overcomes the problem that the mesylate salt has high wettability and deliquescent by means of phosphate formation.

Defining the characteristics of wettability and the definition of wettability weight gain (Chinese Pharmacopoeia 2010 edition Appendix XIX J drug wettability test guidelines, experimental conditions: 25 ° C ± 1 ° C, 80% relative humidity):

Deliquescence: absorbs a sufficient amount of water to form a liquid;

Very hygroscopic: the wetting weight gain is not less than 15%;

It has hygroscopicity: the wetting weight gain is less than 15% but not less than 2%;

Slightly hygroscopic: wetting gain is less than 2% but not less than 0.2%;

No or almost no wettability: wetting gain is less than 0.2%.

Example 5

The phosphate crystal A of the compound of the formula (I) obtained by the present invention is placed at 5 ° C, 25 ° C / relative humidity 60%, and 40 ° C / relative humidity of 75% for 3 months, respectively at the end of January and March Each sample was taken once, focusing on the stability of related substances and crystal forms. The test showed that Form A had good stability, the HPLC purity data is summarized in Table 5, and the XRPD comparison chart is shown in Figures 7 and 8.

table 5

	5 ° C, %	25°C/60%RH,%	40 ° C / 75% RH, %
0 days	98.82	98.82	98.82
30 days	98.87	98.85	98.88
90 days	98.81	98.76	98.78

After 3 months, the phosphate crystal A of the compound of the formula (I) was very stable. Stabilization refers to the analysis by liquid phase, XRPD, etc., that is, no degradation is found, and no transition to other crystal forms is detected.

Claims (10)

1. Phosphate Form A of the compound of formula (I),

   

   It is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, and 16.4 ° ± 0.2 °.
2. Crystalline form A of the phosphate of the compound of formula (I) according to claim 1, characterized in that its X-ray powder diffraction pattern is also 2theta values of 7.5 ° ± 0.2 °, 19.5 ° ± 0.2 °, 24.5 ° ± 0.2 There is a characteristic peak at °.
3. Crystalline form A of the phosphate of the compound of formula (I) according to claim 1, characterized in that its X-ray powder diffraction pattern is also 2theta values of 8.2 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 0.2 There is a characteristic peak at °.
4. The crystalline form A of the phosphate of the compound of the formula (I) according to any one of claims 1 to 3, characterized in that the X-ray powder diffraction pattern has a value of 7.5 ° ± 0.2 ° and 8.2 ° ± 0.2 ° at 2theta. Characteristic peaks are present at 9.8 ° ± 0.2 °, 10.9 ° ± 0.2 °, 16.4 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.4 ° ± 0.2 °, 19.5 ° ± 0.2 °, and 24.5 ° ± 0.2 °.
5. A process for the preparation of a phosphate crystal form A of a compound of the formula (I) according to any one of claims 1 to 4, which comprises reacting a compound of the formula (I) with phosphoric acid in a ketone or alcohol solvent , stirring and crystallization obtained.
6. The method according to claim 5, wherein said alcohol solvent has a small number of carbon atoms In the alcohol of 6, the ketone solvent is a ketone having a carbon number of less than 6.
7. The method according to claim 6, wherein the alcohol solvent is methanol or ethanol, and the ketone solvent is acetone.
8. The method according to any one of claims 5 to 7, wherein the molar ratio of the compound of the formula (I) to phosphoric acid is 1:1.
9. A pharmaceutical composition comprising the crystalline form A of the compound of formula (I) according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
10. Use of the compound crystal form A of the compound of the formula (I) according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 9 for the preparation of a medicament for treating cancer.

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