CN113896718A

CN113896718A - Crystal of trifluoroethyl substituted indole aniline pyrimidine compound and salt thereof

Info

Publication number: CN113896718A
Application number: CN202111339855.3A
Authority: CN
Inventors: 王路路; 汤剑秋; 朱益忠; 刘飞; 朱岩; 张传玉; 杨利民
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Yifang Biotechnology Shanghai Co ltd; Betta Pharmaceuticals Co Ltd
Priority date: 2016-10-21
Filing date: 2016-10-21
Publication date: 2022-01-07
Also published as: CN107973782B; CN107973782A; CN113999209A; CN113896717A

Abstract

The application belongs to the field of medical chemistry, and relates to a crystal of trifluoroethyl substituted indole aminopyrimidine compound and a salt thereof serving as an EGFR inhibitor, in particular to a crystal of a compound shown in formula I, a mesylate crystal of the compound shown in formula I or a mesylate crystal of the compound shown in formula I, a preparation method of the crystal, a crystal composition containing the crystal, a pharmaceutical composition containing the crystal or the crystal composition, and other crystalsTheir medical application. The crystal has the advantages of high purity, high crystallinity, good stability and the like.

Description

Crystal of trifluoroethyl substituted indole aniline pyrimidine compound and salt thereof

The present application is a divisional application with the title "crystal of a trifluoroethyl substituted indole anilinopyrimidine compound and a salt thereof" having application number 201610921631.6 and application date 2016, 10.21.2016.

Technical Field

The application belongs to the field of medicinal chemistry, and particularly relates to crystal of a trifluoroethyl substituted indole anilinopyrimidine compound (I) and salt thereof.

Background

Egfr (epidermal Growth Factor receptor) is a receptor for cell proliferation and signaling of the Epithelial Growth Factor (EGF), also known as HER1, ErbB 1. EGFR belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3(ErbB-3) and HER4 (ErbB-4). EGFR is a glycoprotein belonging to tyrosine kinase type receptor, and has a penetrating cell membrane and a molecular weight of 170 KDa.

EGFR is located on the surface of cell membranes and is activated by binding to ligands, including EGF and TGF α, and following activation EGFR is converted from monomers to dimers. The dimer includes both the binding of two cognate receptor molecules (homodimerization) and the binding of different members of the human EGF-related receptor (HER) tyrosine kinase family (heterodimerization). EGFR dimerization can activate its intracellular kinase pathways, including phosphorylation of key tyrosine residues in the intracellular domain, and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival.

There is high or abnormal expression of EGFR in many solid tumors. EGFR is involved in the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis. It may be made with: high expression of EGFR leads to enhancement of downstream signaling; increased expression of mutant EGFR receptors or ligands results in sustained activation of EGFR; the effect of the autocrine loop is enhanced; disruption of receptor down-regulation mechanisms; activation of abnormal signaling pathways, etc. Overexpression of EGFR plays an important role in the progression of malignant tumors, and overexpression of EGFR has been found in all tissues such as glial cells, kidney cancer, lung cancer, prostate cancer, pancreatic cancer, and breast cancer.

Among them, abnormal expression of EGFR and Erb-B2 plays a critical role in tumor transformation and growth. In lung cancer as an example, EGFR is expressed in 50% of cases of non-small cell lung cancer (NSCLC), and its expression is poorly correlated with prognosis. These two factors make EGFR and its family members the main candidates for targeted therapy. Two small molecule inhibitors targeting EGFR, gefitinib and erlotinib, have received rapid FDA approval in the united states for the treatment of advanced NSCLC patients who have lost response to conventional chemotherapy.

Early clinical data indicated that 10% of NSCLC patients responded to gefitinib and erlotinib. Molecular biological analysis showed that in most cases, drug-responsive patients harbored specific mutations in the gene encoding EGFR: the deletion of 747-750 amino acids in exon19 accounts for 45% of the mutation, and 10% of the mutations occur in

exons

18 and 20. The most common EGFR activating mutations (L858R and del e746_ a750) result in increased affinity for small molecule Tyrosine Kinase Inhibitors (TKIs) and decreased affinity for Adenosine Triphosphate (ATP) relative to wild-type (WT) EGFR. The T790M mutation is a point mutation in exon 20 of EGFR that results in acquired resistance to gefitinib or erlotinib treatment. Recent studies have shown that L858R combined with the T790M mutation has stronger affinity for ATP than L858R alone, and TKI is an ATP competitive kinase inhibitor, resulting in a decreased binding rate of TKI to the kinase domain.

Because the mutation plays an important role in targeting the drug resistance mechanism of EGFR treatment, it is necessary to provide EGFR-L858R/T790M double mutant inhibitors for clinical treatment. Meanwhile, since inhibiting EGFR-WT results in various clinical toxic and side effects, it is also necessary to provide an inhibitor that exhibits selectivity for activating mutant forms of EGFR (e.g., EGFR-L858R mutant, del E746_ A750 mutant, or Exon19 deletion EGFR mutant) and/or resistant mutant forms of EGFR (e.g., EGFR-T790M mutant) relative to EGFR-WT for clinical treatment.

At present, a plurality of selective EGFR inhibitors have been reported, and WO2016070816 discloses a trifluoroethyl substituted indole anilinopyrimidine compound shown in formula I:

in addition to therapeutic efficacy, drug developers have attempted to provide suitable forms of active molecules with properties that are drugs. Therefore, finding a form with the desired properties is crucial for drug development.

Summary of The Invention

The application provides a compound crystal A shown in a formula I, a preparation method of the crystal, a crystal composition containing the crystal, a pharmaceutical composition containing the crystal or the crystal composition, and medical applications of the crystal A and the crystal A.

In another aspect, the present application provides a mesylate crystal B of the compound of formula I, and a preparation method of the crystal, a crystalline composition comprising the crystal, a pharmaceutical composition comprising the crystal or the crystalline composition thereof, and medical uses thereof.

In another aspect, the present application provides crystals C, D, E, F and G of the bis-mesylate salt of the compound of formula I, as well as methods for the preparation of said crystals, crystalline compositions comprising the crystals, pharmaceutical compositions comprising the crystals or crystalline compositions thereof, and their pharmaceutical uses.

Disclosure of Invention

In one aspect, the present application provides crystalline form a of a compound of formula I:

characterized by having diffraction peaks at 2 θ of 8.58 °, 13.10 °, 18.32 °, 19.39 °, 21.29 ° ± 0.2 ° in an X-ray diffraction (XRD) pattern; typically having diffraction peaks at 2 θ ═ 8.58 °, 9.98 °, 13.10 °, 17.53 °, 18.32 °, 19.39 °, 21.29 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ ═ 8.58 °, 9.98 °, 13.10 °, 17.53 °, 18.32 °, 19.39 °, 20.57 °, 21.29 °, 23.04 °, 23.76 ° ± 0.2 °.

In some embodiments of the present application, the X-ray diffraction peak of the crystal a has the following characteristics:

serial number	2θ±0.2(°)	Relative Strength (%)	Serial number	2θ±0.2(°)	Relative Strength (%)
						1	8.58	100	8	19.39	20.3
2	9.98	11.4	9	19.93	8.6
						3	13.10	14.8	10	20.57	13.2
4	14.10	6.1	11	21.29	18.2
						5	14.87	8.4	12	23.04	14.7
6	17.53	10.0	13	23.76	13.5
						7	18.32	33.2	14	24.80	8.0

In some embodiments of the present application, the crystal a according to the present application has an X-ray diffraction pattern as shown in fig. 1.

In some embodiments of the present application, the DSC pattern of crystal a described herein is shown in figure 2.

In another aspect, the present application provides a method for preparing crystal a, comprising the steps of:

1) dissolving a compound of formula I in a crystallization solvent;

2) cooling, crystallizing and filtering;

wherein the crystallization solvent is selected from acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetone, dichloromethane or a mixed solvent of any two or more solvents.

In some embodiments herein, the crystallization solvent is selected from acetonitrile.

In another aspect of the present application, there is provided a crystalline composition of the crystal a. In some embodiments of the present invention, the amount of the crystal a is 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystalline composition.

Another aspect of the present application provides a pharmaceutical composition of said crystal a, which comprises a therapeutically effective amount of said crystal a, or said crystalline composition of crystal a, and which may or may not further comprise pharmaceutically acceptable excipients.

Another aspect of the present application provides a use of the crystal a or the crystalline composition thereof or the pharmaceutical composition thereof for the preparation of a medicament for treating an EGFR-mediated disease.

In one aspect, the present application provides crystalline monomethanesulfonate salt B of a compound of formula I:

characterized by having diffraction peaks at 2 θ ═ 8.05 °, 11.08 °, 14.17 °, 17.98 °, 19.20 °, 20.78 °, and 24.18 ° ± 0.2 ° in an X-ray diffraction (XRD) pattern; typically have diffraction peaks at 2 θ of 8.05 °, 10.46 °, 11.08 °, 11.48 °, 14.17 °, 17.98 °, 19.20 °, 20.78 °, 24.18 °, 25.15 ° ± 0.2 °; more typically, diffraction peaks at 2 θ of 8.05 °, 10.46 °, 11.08 °, 11.48 °, 14.17 °, 16.65 °, 17.98 °, 18.61 °, 19.20 °, 20.03 °, 20.78 °, 24.18 °, 25.15 ° ± 0.2 °; further typically have diffraction peaks at 2 θ of 8.05 °, 10.46 °, 11.08 °, 11.48 °, 13.86 °, 14.17 °, 16.65 °, 17.98 °, 18.61 °, 19.20 °, 19.40 °, 20.03 °, 20.78 °, 21.12 °, 24.18 °, 25.15 °, 27.96 ° ± 0.2 °.

In some embodiments of the present application, the X-ray diffraction peaks of crystal B described herein have the following characteristics:

serial number	2θ±0.2(°)	Relative Strength (%)	Serial number	2θ±0.2(°)	Relative Strength (%)
						1	8.05	48.3	10	19.20	78.0
2	10.46	50.7	11	19.40	49.5
						3	11.08	56.0	12	20.03	62.5
4	11.48	30.8	13	20.78	86.3
						5	13.86	45.1	14	21.12	48.9
6	14.17	50.3	15	24.18	100.0
						7	16.65	58.2	16	25.15	63.6
8	17.98	99.7	17	27.96	44.0
						9	18.61	55.8	--	----	----

In some embodiments of the present application, the crystal B of the present application has an X-ray diffraction pattern as shown in fig. 3.

In some embodiments of the present application, the DSC pattern of crystal B described herein is shown in figure 4.

In another aspect, the present application provides a method for preparing crystal B, comprising the steps of:

1) dissolving a compound of formula I in a crystallization solvent;

2) adding methane sulfonic acid;

3) cooling, crystallizing and filtering;

wherein the crystallization solvent is selected from acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetone, dichloromethane, water or a mixed solvent of any two or more solvents; the ratio of the amount of the substance of methane sulfonic acid to the amount of the substance of the compound of formula I is 1: 1.

In some embodiments of the present application, the crystallization solvent is selected from acetonitrile, ethyl acetate, isopropanol, acetone, dioxane, water, or a mixed solvent of any two or more solvents. In some embodiments of the present application, the solvent is selected from acetonitrile.

Another aspect of the present application provides a crystalline composition of the crystal B. In some embodiments of the present invention, the amount of the crystal B is 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystalline composition.

Another aspect of the present application provides a pharmaceutical composition of said crystal B, which comprises a therapeutically effective amount of said crystal B, or a crystalline composition of said crystal B, and which may or may not further comprise a pharmaceutically acceptable excipient.

Another aspect of the present application provides the use of said crystal B or a crystalline composition thereof or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of an EGFR-mediated disease.

In one aspect, the present application provides crystalline bis-mesylate salt C of the compound of formula I:

characterized by having diffraction peaks at 2 θ of 6.64 °, 8.48 °, 17.25 °, 20.40 °, 21.87 ° ± 0.2 ° in an X-ray diffraction (XRD) pattern; typically have diffraction peaks at 2 θ ═ 6.64 °, 8.48 °, 13.70 °, 15.16 °, 17.25 °, 20.07 °, 20.40 °, 21.87 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ of 6.64 °, 8.48 °, 13.70 °, 15.16 °, 17.25 °, 19.65 °, 20.07 °, 20.40 °, 21.87 °, 23.53 °, 25.90 ° ± 0.2 °.

In some embodiments of the present application, the X-ray diffraction peaks of crystal C described herein have the following characteristics:

in some embodiments of the present application, the crystal C of the present application has an X-ray diffraction pattern as shown in fig. 5.

In some embodiments of the present application, the DSC profile of crystal C described herein is shown in figure 6.

In another aspect, the present application provides a method for preparing crystal C, comprising the steps of:

1) dissolving a compound of formula I in a crystallization solvent;

2) adding methane sulfonic acid;

3) cooling, crystallizing and filtering;

wherein the crystallization solvent is selected from acetonitrile; the ratio of the amount of the substance of methane sulfonic acid to the amount of the substance of the compound of formula I is 2: 1.

Another aspect of the present application provides a crystalline composition of the crystal C. In some embodiments of the present invention, the amount of the crystal C is 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystal composition.

Another aspect of the present application provides a pharmaceutical composition of said crystal C, which comprises a therapeutically effective amount of said crystal C, or said crystalline composition of crystal C, and which may or may not further comprise pharmaceutically acceptable excipients.

Another aspect of the present application provides a use of the crystal C or the crystal composition thereof or the pharmaceutical composition thereof for the preparation of a medicament for treating an EGFR-mediated disease.

In one aspect, the present application provides crystalline dimesylate salt of a compound of formula I:

characterized in that, in an X-ray diffraction (XRD) pattern, the diffraction peak of 2 theta is 8.04 degrees, 9.35 degrees, 14.42 degrees, 16.23 degrees, 18.64 degrees, 21.83 degrees and 23.30 degrees +/-0.2 degrees; typically have diffraction peaks at 2 θ ═ 8.04 °, 9.35 °, 11.86 °, 14.42 °, 16.23 °, 18.64 °, 20.32 °, 21.83 °, 23.30 °, 23.65 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ of 7.12 °, 8.04 °, 9.35 °, 11.86 °, 12.37 °, 14.42 °, 16.23 °, 18.64 °, 18.98 °, 20.32 °, 21.83 °, 23.30 °, 23.65 °, 24.45 ° ± 0.2 °; further typically have diffraction peaks at 2 θ ═ 7.12 °, 8.04 °, 9.35 °, 10.37 °, 11.86 °, 12.37 °, 14.42 °, 16.23 °, 17.79 °, 18.64 °, 18.98 °, 20.32 °, 20.82 °, 21.83 °, 23.30 °, 23.65 °, 24.22 °, 24.45 ° ± 0.2 °.

In some embodiments of the present application, the X-ray diffraction peak of crystal D described herein has the following characteristics:

serial number	2θ±0.2(°)	Relative Strength (%)	Serial number	2θ±0.2(°)	Relative Strength (%)
						1	7.12	27.7	13	18.64	56.4
2	8.04	97.5	14	18.98	33.1
						3	9.35	100.0	15	20.32	46.3
4	10.37	28.0	16	20.82	28.3
						5	10.80	21.5	17	21.83	58.6
6	11.86	33.2	18	23.30	58.2
						7	12.37	30.5	19	23.65	52.5
8	14.42	47.8	20	24.22	34.4
						9	15.08	22.3	21	24.45	31.9
10	15.91	18.3	22	24.80	21.8
						11	16.23	58.3	23	29.60	23.5
12	17.79	27.3	--	----	----

In some embodiments of the present application, the crystal D according to the present application has an X-ray diffraction pattern as shown in fig. 7.

In some embodiments of the present application, the DSC profile of crystal D described herein is shown in figure 8.

In another aspect, the present application provides a method for preparing crystal D, comprising the steps of:

1) dissolving a compound of formula I in a crystallization solvent;

2) adding methane sulfonic acid;

3) cooling, crystallizing and filtering;

wherein the crystallization solvent is selected from ethyl acetate; the ratio of the amount of the substance of methane sulfonic acid to the amount of the substance of the compound of formula I is 2: 1.

Another aspect of the present application provides a crystalline composition of the crystalline D. In some embodiments of the present invention, the amount of the crystal D is 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystal composition.

Another aspect of the present application provides a pharmaceutical composition of said crystal D, which comprises a therapeutically effective amount of said crystal D, or a crystalline composition of said crystal D, and which may or may not further comprise a pharmaceutically acceptable excipient.

Another aspect of the present application provides a use of the crystalline form D or the crystalline composition thereof or the pharmaceutical composition thereof for the preparation of a medicament for the treatment of an EGFR-mediated disease.

In one aspect, the present application provides crystalline bis-mesylate salt E of the compound of formula I:

characterized in that, in an X-ray diffraction (XRD) pattern, the diffraction peaks of 2 theta which is 6.98 degrees, 11.85 degrees, 17.83 degrees, 18.76 degrees, 20.29 degrees, 23.26 degrees and 23.99 degrees +/-0.2 degrees are provided; typically have diffraction peaks at 2 θ ═ 6.98 °, 10.98 °, 11.85 °, 17.00 °, 17.83 °, 18.76 °, 20.29 °, 22.84 °, 23.26 °, 23.99 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ ═ 6.98 °, 10.98 °, 11.85 °, 12.30 °, 17.00 °, 17.83 °, 18.76 °, 20.29 °, 21.65 °, 22.84 °, 23.26 °, 23.99 °, 25.69 ° ± 0.2 °.

In some embodiments of the present application, the crystal E has the following X-ray diffraction peaks:

serial number	2θ±0.2(°)	Relative Strength (%)	Serial number	2θ±0.2(°)	Relative Strength (%)
						1	6.98	100.0	11	19.39	14.6
2	10.98	17.1	12	20.29	28.2
						3	11.85	54.8	13	21.65	31.3
4	12.30	22.8	14	22.84	36.1
						5	13.70	16.2	15	23.26	54.9
6	14.31	10.8	16	23.67	18.7
						7	15.63	13.1	17	23.99	47.2
8	17.00	28.0	18	24.82	17.9
						9	17.83	42.0	19	25.69	23.0
10	18.76	36.6	20	27.11	19.3

In some embodiments of the present application, the crystal E described herein has an X-ray diffraction pattern as shown in fig. 9.

In some embodiments of the present application, the DSC profile of crystal E described herein is shown in figure 10.

In another aspect, the present application provides a method for preparing crystalline E, comprising the steps of:

1) dissolving a compound of formula I in a crystallization solvent;

2) adding methane sulfonic acid;

3) cooling, crystallizing and filtering;

wherein the crystallization solvent is selected from dichloromethane; the ratio of the amount of the substance of methane sulfonic acid to the amount of the substance of the compound of formula I is 2: 1.

Another aspect of the present application provides a crystalline composition of the crystalline E. In some embodiments of the present invention, the amount of the crystalline E is 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystalline composition.

Another aspect of the present application provides a pharmaceutical composition of said crystalline E, which comprises a therapeutically effective amount of said crystalline E, or a crystalline composition of said crystalline E, and which may or may not further comprise pharmaceutically acceptable excipients.

Another aspect of the present application provides the use of said crystalline E or a crystalline composition thereof or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of an EGFR-mediated disease.

In one aspect, the present application provides crystalline bis-mesylate salt F of the compound of formula I:

characterized by having diffraction peaks at 2 θ of 6.53 °, 7.52 °, 11.84 °, 19.02 °, 19.41 °, 20.16 °, 23.50 ° ± 0.2 ° in an X-ray diffraction (XRD) pattern; typically have diffraction peaks at 2 θ ═ 6.53 °, 7.52 °, 11.84 °, 14.29 °, 19.02 °, 19.41 °, 20.16 °, 21.96 °, 23.50 °, 24.90 °, 27.26 ° ± 0.2 °; more typically, there are diffraction peaks at 2 θ ═ 6.53 °, 7.52 °, 11.84 °, 13.17 °, 14.29 °, 15.17 °, 18.60 °, 19.02 °, 19.41 °, 20.16 °, 21.51 °, 21.96 °, 23.50 °, 24.90 °, 27.26 ° ± 0.2 °.

In some embodiments of the present application, the crystalline form F described herein has the following X-ray diffraction peaks:

serial number	2θ±0.2(°)	Relative Strength (%)	Serial number	2θ±0.2(°)	Relative Strength (%)
						1	6.53	49.4	10	19.41	41.7
2	7.52	64.7	11	20.16	83.9
						3	11.84	60.6	12	21.51	27.8
4	13.17	31.2	13	21.96	37.7
						5	14.29	39.8	14	23.00	21.1
6	15.17	36.5	15	23.50	57.3
						7	17.23	19.2	16	24.90	34.1
8	18.60	29.6	17	26.67	17.0
						9	19.02	100.0	18	27.26	26.3

In some embodiments of the present application, crystalline form F described herein has an X-ray diffraction pattern as shown in fig. 11.

In some embodiments of the present application, the DSC pattern of crystal F described herein is shown in figure 12.

In another aspect, the present application provides a method for preparing crystalline F, comprising the steps of:

1) dissolving a compound of formula I in a crystallization solvent;

2) adding methane sulfonic acid;

3) cooling, crystallizing and filtering;

wherein the crystallization solvent is selected from acetone; the ratio of the amount of the substance of methane sulfonic acid to the amount of the substance of the compound of formula I is 2: 1.

Another aspect of the present application provides a crystalline composition of the crystalline F. In some embodiments of the present invention, the amount of the crystalline F is 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more by weight of the crystalline composition.

Another aspect of the present application provides a pharmaceutical composition of said crystalline F, which comprises a therapeutically effective amount of said crystalline F, or a crystalline composition of said crystalline F, and which may or may not further comprise pharmaceutically acceptable excipients.

Another aspect of the present application provides a use of the crystalline F or the crystalline composition thereof or the pharmaceutical composition thereof for the preparation of a medicament for treating an EGFR-mediated disease.

In one aspect, the present application provides crystalline G of the bis-mesylate salt of the compound of formula I:

characterized in that, in an X-ray diffraction (XRD) pattern, diffraction peaks of 6.80 degrees, 9.71 degrees, 15.11 degrees, 18.35 degrees, 19.91 degrees and 25.48 degrees +/-0.2 degrees are provided; typically have diffraction peaks at 2 θ ═ 6.80 °, 9.71 °, 12.32 °, 15.11 °, 17.64 °, 18.35 °, 19.91 °, 21.26 °, 23.60 °, 25.48 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ ═ 6.80 °, 9.71 °, 12.32 °, 13.32 °, 15.11 °, 17.64 °, 18.35 °, 18.72 °, 19.91 °, 21.26 °, 23.11 °, 23.60 °, 24.51 °, 25.48 ° ± 0.2 °.

In some embodiments of the present application, the crystal G has the following X-ray diffraction peaks:

in some embodiments of the present application, crystal G as described herein has an X-ray diffraction pattern as shown in fig. 13.

In some embodiments of the present application, the DSC profile of crystal G described herein is shown in figure 14.

In another aspect, the present application provides a method for preparing crystal G, comprising the steps of:

1) dissolving a compound of formula I in a crystallization solvent;

2) adding methane sulfonic acid;

3) cooling, crystallizing and filtering;

wherein the crystallization solvent is selected from dioxane; the ratio of the amount of the substance of methane sulfonic acid to the amount of the substance of the compound of formula I is 2: 1.

Another aspect of the present application provides a crystalline composition of the crystal G. In some embodiments of the present invention, the amount of the crystal G is 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystalline composition.

Another aspect of the present application provides a pharmaceutical composition of said crystal G, which comprises a therapeutically effective amount of said crystal G, or said crystalline composition of crystal G, and which may or may not further comprise pharmaceutically acceptable excipients.

Another aspect of the present application provides the use of said crystal G or a crystalline composition thereof or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of an EGFR-mediated disease.

In the present application, the X-ray diffraction pattern is determined by the following method: the instrument comprises the following steps: bruker D2X-ray diffractometer; the method comprises the following steps: the target is Cu; the tube Voltage is 30 kV; pipe flow Current: 10 mA; scanning range: 4-40 degrees; scanning speed: 0.1 second per step and 0.02 degree per step.

In the present application, Differential Scanning Calorimetry (DSC) is measured by the following method: the instrument comprises the following steps: a Mettler DSC-1 differential scanning calorimeter; the method comprises the following steps: a sample (-5 mg) was placed in a DSC aluminum pan for testing by the method: 30-300 ℃ and the heating rate is 10 ℃/min.

In the present application, ion chromatography can be used to detect the amount ratio of the compound of formula I to the salt-forming substance of the acid ion, and the determination method can refer to: the instrument comprises the following steps: DIONEX ICS-2100 ion chromatograph; a detector: a DIONEX conductivity detector; a workstation: chromeleon 7.2; a chromatographic column: DIONEX RFIC^TM

AS11-HC (4X 250 mm); mobile phase: 10mmol potassium hydroxide leacheate; flow rate: 1.0 mL/min; detecting current: 25 mA; column temperature: 30 ℃; the method comprises the following steps: taking a proper amount of the product, precisely weighing, adding ultrapure water for dissolving and diluting to prepare a solution containing about 40 mu g of the product per 1mL, and shaking uniformly to obtain a test solution. An appropriate amount of methanesulfonic acid was weighed out precisely and diluted with ultrapure water to prepare a solution containing about 10. mu.g of methanesulfonic acid per 1mL as a control solution. Precisely measuring 10 μ L of each of the reference solution and the sample solution, injecting into an ion chromatograph, recording chromatogram, and calculating according to external standard method by peak area.

It is noted that in X-ray diffraction spectroscopy, the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystalline form, where the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question, and when judging whether the diffraction peaks are the same as the known crystal form, the relative positions of the peaks rather than their relative intensities should be noted. In addition, there may be slight errors in the position of the peaks for any given crystalline form, which is also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, movement of the sample, calibration of the instrument, or the like, and the measurement error of the 2 θ value may be about ± 0.2 °. Therefore, this error should be taken into account when determining each type of structure. The peak position is usually expressed in the XRD pattern by 2 θ angle or plane distance d, with a simple conversion relationship between: d ═ λ/2sin θ, where d represents the interplanar spacing, λ represents the wavelength of the incident X-rays, and θ is the diffraction angle. For the same crystal form of the same compound, the peak positions of the XRD spectrum have similarity on the whole, and the error of relative intensity is likely to be larger. It should also be noted that in the identification of mixtures, the loss of a portion of the diffraction lines may be due to, for example, a reduction in the amount of the compound, in which case it is not necessary to rely on all the bands observed in the high purity sample, and even one band may be characteristic of a given crystal.

In addition, DSC measures a transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystal form of the same compound, the thermal transition temperature and melting point errors in successive analyses are typically within about 5 ℃, which when we say a compound has a given DSC peak or melting point means that the DSC peak or melting point is ± 5 ℃. DSC provides an auxiliary method to distinguish different crystal forms. Different crystal morphologies can be identified by their different transition temperature characteristics.

The term "pharmaceutical composition" as used herein refers to a mixture of one or more compounds of the present application in a particular form or salt thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

In some embodiments of the present application, the EGFR-mediated disease is selected from EGFR-L858R activating mutation-mediated diseases. In some embodiments of the present application, the EGFR-mediated disease is selected from the group consisting of EGFR-T790M activating mutation-mediated diseases. In some embodiments of the present application, the EGFR-mediated disease is selected from the group consisting of EGFR-L858R combined with EGFR-T790M double mutation activation mediated diseases. In some embodiments of the present application, the EGFR-mediated disease is cancer; the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma; the lung cancer may be selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma.

In examining the stability of the crystals described herein, the crystals may be subjected to high temperature, high humidity, or light conditions. The high temperature condition can be selected from 40-60 ℃, the high humidity condition can be selected from 75-92.5% RH of relative humidity, and the illumination condition can be selected from 5000 Lux. When the crystallization stability is evaluated, a plurality of data such as content, total impurities, water content and the like in a sample can be considered, and the parameters are comprehensively evaluated according to the product properties.

All solvents used herein are commercially available and can be used without further purification. The reaction is generally carried out under inert nitrogen in an anhydrous solvent.

In the present application, proton nmr data are recorded on a BRUKER AVANCE iii HD 500M spectrometer with chemical shifts expressed in (ppm) at tetramethylsilane low field; mass spectra were measured at Waters ACQUITY UPLC + XEVO G2 QTof. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in either positive or negative mode.

The compound crystal shown in the formula I has the advantages of high purity, high crystallinity, good stability and the like; meanwhile, the preparation method of the compound crystal shown in the formula I is simple, the solvent is cheap and easy to obtain, the crystallization condition is mild, and the method is suitable for industrial production.

Drawings

Figure 1 XRD pattern of crystalline a compound of formula I.

FIG. 2 DSC profile of crystalline A of the compound of formula I.

Figure 3 XRD pattern of monomethanesulfonate salt crystalline B of the compound of formula I.

FIG. 4 DSC of crystalline B monomethanesulfonate salt of the compound of formula I.

Figure 5 XRD pattern of crystalline C bis (mesylate) salt of compound of formula I.

FIG. 6 DSC of crystalline C bis-mesylate salt of the compound of formula I.

Figure 7 XRD pattern of crystalline D bis (mesylate) salt of compound of formula I.

FIG. 8 is a DSC of crystalline D of the bis-mesylate salt of the compound of formula I.

Figure 9 XRD pattern of crystalline bis (mesylate) salt E of the compound of formula I.

FIG. 10 is a DSC of crystalline E of the bis-mesylate salt of the compound of formula I.

Figure 11 XRD pattern of crystalline form F of the bis-mesylate salt of the compound of formula I.

FIG. 12 DSC of crystalline bis-mesylate salt F of the compound of formula I.

Figure 13 XRD pattern of crystalline G bis (mesylate) salt of the compound of formula I.

FIG. 14 DSC of crystalline G bis-mesylate salt of the compound of formula I.

Detailed Description

The following examples further illustrate the present invention in non-limiting detail. They should not be considered limiting the scope of the application, but merely as being exemplary illustrations and representative of the application. The solvents, reagents, raw materials and the like used in the present application are all commercially available chemically pure or analytically pure products.

EXAMPLE 1 amorphous Compound of formula I

Adding a compound shown in formula 2 (18.9g, 0.037mol), DIEA (9.6g, 0.074mol) and DCM (400mL) into a 1L three-neck flask, magnetically stirring for dissolving, replacing system air with nitrogen, cooling a reaction solution to-20 to-10 ℃, dropwise adding acryloyl chloride (3.4g, 0.037mol), and reacting at-20 to-10 ℃ for 20min after dropwise adding. After completion of the reaction, water (300mL) was added to the reaction system for liquid separation, and the organic phase was dried over anhydrous sodium sulfate using saturated brine (200mL × 2), followed by suction filtration, and the residue obtained by concentrating the filtrate was purified by column chromatography (DCM/MeOH 50/1-20/1) to obtain a compound represented by the formula I (10.0g, 47.6%).

EXAMPLE 2 Crystal A of the Compound of formula I

Adding the product (0.5g) obtained in example 1 and acetonitrile (2.5mL) into a glass reaction bottle, stirring at room temperature under the protection of nitrogen, dissolving the solid clearly after 5min, then separating out the solid, continuing stirring at room temperature for 3h to ensure that the solid content is gradually increased, filtering, and drying the obtained solid at 45 +/-5 ℃ in vacuum to obtain an off-white solid with the yield of 98%.

EXAMPLE 3 Monomesylate salt Crystal B of the Compound of formula I

Adding acetonitrile (2.5mL) into a glass reaction bottle, stirring at room temperature under the protection of nitrogen, then adding the product (0.5g) obtained in example 1, dissolving the product clearly after about 5min, wherein the reaction solution is light yellow and clear, immediately dropwise adding an acetonitrile (0.5mL) solution of methane sulfonic acid (84.7mg) into the reaction system, after the dropwise adding is completed for 2min, after about 0.5h, separating out a white-like solid, keeping the reaction system to be stirred for 3h at room temperature, filtering, and drying the obtained solid at 45 +/-5 ℃ in vacuum to obtain the white-like solid with the yield of 90.7%.

EXAMPLE 4 Crystal C of the Dimethanesulfonic acid salt of the Compound of formula I

Adding the product (0.25g) obtained in example 1 and acetonitrile (1.25mL) into a glass reaction bottle, stirring at room temperature under the protection of nitrogen, dissolving the mixture clear after about 5min, immediately and slowly dropwise adding 0.5mL of methanesulfonic acid (2 times of molar weight) acetonitrile solution into a reaction system, after the dropwise adding is finished for 2min, enabling the reaction solution to be in a dark yellow clear state, stirring the reaction system at room temperature for 15h, separating out yellow solid, filtering, and drying the obtained solid at 45 +/-5 ℃ in vacuum to obtain orange solid, wherein the yield is 44.9%.

EXAMPLE 5 Crystal D of Dimethanesulfonic acid salt of Compound represented by formula I

Adding ethyl acetate (1.5mL) into a glass reaction bottle, stirring at room temperature under the protection of nitrogen, then adding the product (0.25g) obtained in example 1, immediately dropwise adding 0.5mL of methanesulfonic acid (85.0mg) ethyl acetate solution after dissolving, separating out orange viscous solid after dropwise adding for 2min, stirring at room temperature for 15h, filtering, and drying the obtained solid at 45 +/-5 ℃ in vacuum to obtain light yellow solid with the yield of 79.3%.

EXAMPLE 6 Crystal E of the Dimethanesulfonic acid salt of the Compound of formula I

Adding dichloromethane (1.5mL) into a glass reaction bottle, stirring at room temperature under the protection of nitrogen, then adding the product (0.25g) obtained in example 1, immediately dropwise adding 0.5mL of methane sulfonic acid (85.0mg) dichloromethane solution after dissolving, after dropwise adding for 2min, stirring at room temperature for 15h to separate out a large amount of yellow solid, filtering, and drying the obtained solid at 45 +/-5 ℃ in vacuum to obtain a light yellow solid with the yield of 83.8%.

EXAMPLE 7 Crystal F of the Dimethanesulfonic acid salt of the Compound of formula I

Adding acetone (1.5mL) into a glass reaction bottle, stirring at room temperature under the protection of nitrogen, then adding the product (0.25g) obtained in example 1, dissolving the product clear after about 2min, immediately dropwise adding 0.5mL of methanesulfonic acid (85.0mg) acetone solution after dissolving the product clear, stirring at room temperature for 15h to separate out a large amount of yellow solid, filtering, and drying the obtained solid at 45 +/-5 ℃ in vacuum to obtain the yellow solid with the yield of 82.0%.

EXAMPLE 8 Crystal G of the Dimethanesulfonic acid salt of the Compound of formula I

Adding dioxane (1.5mL) into a glass reaction bottle, stirring at room temperature under the protection of nitrogen, then adding the product (0.25g) obtained in example 1, dissolving the product clear after about 2min, immediately dropwise adding 0.5mL of methane sulfonic acid (85.0mg) dioxane solution after dissolving the clear product, immediately precipitating orange viscous solid after dropwise adding the solution for 2min, stirring at room temperature for 15h, filtering, and drying the obtained solid at 45 +/-5 ℃ in vacuum to obtain yellow solid with the yield of 94.9%.

Experimental example 1 Crystal stability test of Compound of formula I, Monomethanesulfonate Crystal and Dimethanesulfonate Crystal

According to the guiding principle of stability test of bulk drugs and pharmaceutical preparations, the stability of the crystal under the accelerated test condition is investigated. The crystals obtained in examples 1 to 8 were placed in a 5000Lx ± 500Lx light environment, a 60 ℃ ± 2 ℃ high temperature environment, and a 75% RH ± 5% RH high humidity environment, respectively, and stability tests were performed on the 5 th day, the 10 th day, and the 30 th day, respectively, and the samples were taken to record appearance properties, moisture content, and total impurities of related substances, and compared with initial data. The comparison results show that the crystals obtained in examples 1 to 8 of the present application have better stability, and particularly, the crystals obtained in examples 3, 6 and 7 have better stability.

Claims

1. Crystalline form a of a compound of formula I:

characterized in that, in the X-ray diffraction pattern, the diffraction peaks with 2 theta equal to 8.58 degrees, 13.10 degrees, 18.32 degrees, 19.39 degrees and 21.29 degrees plus or minus 0.2 degrees are provided; typically having diffraction peaks at 2 θ ═ 8.58 °, 9.98 °, 13.10 °, 17.53 °, 18.32 °, 19.39 °, 21.29 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ ═ 8.58 °, 9.98 °, 13.10 °, 17.53 °, 18.32 °, 19.39 °, 20.57 °, 21.29 °, 23.04 °, 23.76 ° ± 0.2 °.

2. Crystalline monomesylate of a compound of formula I:

characterized in that, in the X-ray diffraction pattern, the diffraction peak of 2 theta is 8.05 degrees, 11.08 degrees, 14.17 degrees, 17.98 degrees, 19.20 degrees, 20.78 degrees and 24.18 degrees +/-0.2 degrees; typically have diffraction peaks at 2 θ of 8.05 °, 10.46 °, 11.08 °, 11.48 °, 14.17 °, 17.98 °, 19.20 °, 20.78 °, 24.18 °, 25.15 ° ± 0.2 °; more typically, diffraction peaks at 2 θ of 8.05 °, 10.46 °, 11.08 °, 11.48 °, 14.17 °, 16.65 °, 17.98 °, 18.61 °, 19.20 °, 20.03 °, 20.78 °, 24.18 °, 25.15 ° ± 0.2 °; further typically have diffraction peaks at 2 θ of 8.05 °, 10.46 °, 11.08 °, 11.48 °, 13.86 °, 14.17 °, 16.65 °, 17.98 °, 18.61 °, 19.20 °, 19.40 °, 20.03 °, 20.78 °, 21.12 °, 24.18 °, 25.15 °, 27.96 ° ± 0.2 °.

3. Crystalline bis-mesylate salt C of the compound of formula I:

the compound is characterized by having diffraction peaks with 2 theta of 6.64 degrees, 8.48 degrees, 17.25 degrees, 20.40 degrees and 21.87 degrees +/-0.2 degrees in an X-ray diffraction pattern; typically have diffraction peaks at 2 θ ═ 6.64 °, 8.48 °, 13.70 °, 15.16 °, 17.25 °, 20.07 °, 20.40 °, 21.87 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ of 6.64 °, 8.48 °, 13.70 °, 15.16 °, 17.25 °, 19.65 °, 20.07 °, 20.40 °, 21.87 °, 23.53 °, 25.90 ° ± 0.2 °.

4. Crystalline bis-mesylate salt D of the compound of formula I:

the compound is characterized by having diffraction peaks with 2 theta being 8.04 degrees, 9.35 degrees, 14.42 degrees, 16.23 degrees, 18.64 degrees, 21.83 degrees and 23.30 degrees +/-0.2 degrees in an X-ray diffraction pattern; typically have diffraction peaks at 2 θ ═ 8.04 °, 9.35 °, 11.86 °, 14.42 °, 16.23 °, 18.64 °, 20.32 °, 21.83 °, 23.30 °, 23.65 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ of 7.12 °, 8.04 °, 9.35 °, 11.86 °, 12.37 °, 14.42 °, 16.23 °, 18.64 °, 18.98 °, 20.32 °, 21.83 °, 23.30 °, 23.65 °, 24.45 ° ± 0.2 °; further typically have diffraction peaks at 2 θ ═ 7.12 °, 8.04 °, 9.35 °, 10.37 °, 11.86 °, 12.37 °, 14.42 °, 16.23 °, 17.79 °, 18.64 °, 18.98 °, 20.32 °, 20.82 °, 21.83 °, 23.30 °, 23.65 °, 24.22 °, 24.45 ° ± 0.2 °.

5. Crystalline bis-mesylate salt E of the compound of formula I:

the compound is characterized by having diffraction peaks with 2 theta of 6.98 degrees, 11.85 degrees, 17.83 degrees, 18.76 degrees, 20.29 degrees, 23.26 degrees and 23.99 degrees +/-0.2 degrees in an X-ray diffraction pattern; typically have diffraction peaks at 2 θ ═ 6.98 °, 10.98 °, 11.85 °, 17.00 °, 17.83 °, 18.76 °, 20.29 °, 22.84 °, 23.26 °, 23.99 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ ═ 6.98 °, 10.98 °, 11.85 °, 12.30 °, 17.00 °, 17.83 °, 18.76 °, 20.29 °, 21.65 °, 22.84 °, 23.26 °, 23.99 °, 25.69 ° ± 0.2 °.

6. Crystalline bis-mesylate salt F of the compound of formula I:

characterized in that, in the X-ray diffraction pattern, the diffraction peak of 2 theta is 6.53 degrees, 7.52 degrees, 11.84 degrees, 19.02 degrees, 19.41 degrees, 20.16 degrees and 23.50 degrees +/-0.2 degrees; typically have diffraction peaks at 2 θ ═ 6.53 °, 7.52 °, 11.84 °, 14.29 °, 19.02 °, 19.41 °, 20.16 °, 21.96 °, 23.50 °, 24.90 °, 27.26 ° ± 0.2 °; more typically, there are diffraction peaks at 2 θ ═ 6.53 °, 7.52 °, 11.84 °, 13.17 °, 14.29 °, 15.17 °, 18.60 °, 19.02 °, 19.41 °, 20.16 °, 21.51 °, 21.96 °, 23.50 °, 24.90 °, 27.26 ° ± 0.2 °.

7. Crystalline bis-mesylate salt G of the compound of formula I:

the compound is characterized by having diffraction peaks with 2 theta of 6.80 degrees, 9.71 degrees, 15.11 degrees, 18.35 degrees, 19.91 degrees and 25.48 degrees +/-0.2 degrees in an X-ray diffraction pattern; typically have diffraction peaks at 2 θ ═ 6.80 °, 9.71 °, 12.32 °, 15.11 °, 17.64 °, 18.35 °, 19.91 °, 21.26 °, 23.60 °, 25.48 ° ± 0.2 °; more typically, it has diffraction peaks at 2 θ ═ 6.80 °, 9.71 °, 12.32 °, 13.32 °, 15.11 °, 17.64 °, 18.35 °, 18.72 °, 19.91 °, 21.26 °, 23.11 °, 23.60 °, 24.51 °, 25.48 ° ± 0.2 °.

8. Use of the crystal of any one of claims 1-7 in the manufacture of a medicament for treating an EGFR-mediated disease.