Salt of arylaminoquinazoline-containing compound, and preparation method therefor and use thereof
Provided are a salt of an arylaminoquinazoline-containing compound as shown in formula 2, a solvate or hydrate thereof, a preparation method therefor and the use thereof. The prepared salt has good crystallinity, and compared to a compound in a free form, the water solubility is significantly improved, and preferably, the salt form and crystal form can stably exist. Therefore, compared to a compound in a free form or other salts, the salt has better druggability.
1 . A crystalline form of a salt of an arylaminoquinazoline-containing compound represented by Formula 2 or a hydrate thereof:
wherein,
HA is hydrochloric acid;
n is 2; and
the crystalline form of the salt of the arylaminoquinazoline-containing compound is a crystalline form I of a dihydrochloride salt represented by Formula 3-1 and having characteristic peaks at the following 2θ angles (°): 9.8±0.2°, 12.4±0.2°, 18.8±0.2°, 20.3±0.2°, and 24.6±0.2° in an X-ray powder diffraction spectrum with Cu-Kα radiation,
or
the crystalline form of the salt of the arylaminoquinazoline-containing compound is a crystal of a dihydrochloride salt tetrahydrate represented by Formula 3-2 and having characteristic peaks at the following 2θ angles (°): 6.0±0.2°, 6.8±0.2°, 12.4±0.2°, 15.5±0.2°, 25.4±0.2°, and 26.0±0.2° in an X-ray powder diffraction spectrum with Cu-Kα radiation,
2 . A pharmaceutical composition comprising the salt of the arylaminoquinazoline-containing compound or the hydrate thereof according to claim 1 , and one or more pharmaceutically acceptable carriers.
3 . A method for treating a receptor tyrosine kinase-related disease in a patient, comprising administering to the patient a therapeutically effective amount of the salt of the arylaminoquinazoline-containing compound or the hydrate thereof according to claim 1 , wherein the receptor tyrosine kinase is one or more of VEGFR, FLT, FGFR, RET, EGFR and mutants thereof.
4 . A method for preparing the salt of the arylaminoquinazoline-containing compound or the hydrate thereof according to claim 1 , comprising reacting an arylaminoquinazoline-containing compound represented by Formula 1 with HA in a solvent, isolating the salt of the arylaminoquinazoline-containing compound represented by Formula 2 or the hydrate thereof:
wherein,
HA is hydrochloric acid;
n is 2; and
a reaction temperature is 40-90° C.; and
the solvent is selected from one or a combination of two of ethyl acetate, methanol or water.
5 . The crystalline form of the salt of the arylaminoquinazoline-containing compound or the hydrate thereof according to claim 1 , wherein the crystalline form I of the dihydrochloride salt represented by Formula 3-1 has characteristic peaks at the following 20 angles (°): 8.1±0.2°, 9.8±0.2°, 12.4±0.2°, 18.8±0.2°, 20.3±0.2°, 24.6±0.2°, and 29.9±0.2° in an X-ray powder diffraction spectrum with Cu-Kα radiation.
6 . The crystalline form of the salt of the arylaminoquinazoline-containing compound or the hydrate thereof according to claim 1 , wherein the crystalline form I of the dihydrochloride salt represented by Formula 3-1 has characteristic peaks at the following 20 angles (°): 8.1±0.2°, 9.8±0.2°, 12.4±0.2°, 18.8±0.2°, 19.3±0.2°, 20.3±0.2°, 24.6±0.2°, 28.6±0.2°, and 29.9±0.2° in an X-ray powder diffraction spectrum with Cu-Kα radiation.
7 . The crystalline form of the salt of the arylaminoquinazoline-containing compound or the hydrate thereof according to claim 1 , wherein the crystalline form I of the dihydrochloride salt represented by Formula 3-1 has characteristic diffraction peaks at the following 2θ angles (°): 8.1±0.2°, 9.8±0.2°, 12.4±0.2°, 16.1±0.2°, 18.8±0.2°, 19.3±0.2°, 20.3±0.2°, 24.6±0.2°, 28.6±0.2°, 29.9±0.2°, and 30.9±0.2° in an X-ray powder diffraction spectrum with Cu-Kα radiation.
8 . The crystalline form of the salt of the arylaminoquinazoline-containing compound or the hydrate thereof according to claim 1 , wherein the crystal of the dihydrochloride salt tetrahydrate represented by Formula 3-2 has characteristic peaks at the following 2θ angles (°): 6.0±0.2°, 6.8±0.2°, 12.4±0.2°, 15.5±0.2°, 18.0±0.2°, 24.4±0.2°, 25.4±0.2°, and 26.0±0.2° in an X-ray powder diffraction spectrum with Cu-Kα radiation.
9 . The crystalline form of the salt of the arylaminoquinazoline-containing compound or the hydrate thereof according to claim 1 , wherein the crystal of the dihydrochloride salt tetrahydrate represented by Formula 3-2 has characteristic peaks at the following 2θ angles (°): 6.0±0.2°, 6.8±0.2°, 12.4±0.2°, 15.5±0.2°, 18.0±0.2°, 22.7±0.2°, 24.4±0.2°, 25.4±0.2°, and 26.0±0.2° in an X-ray powder diffraction spectrum with Cu-Kα radiation.
10 . The method according to claim 3 , wherein the receptor tyrosine kinase-related disease is a tumor.
11 . The method according to claim 10 , wherein the tumor is thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer or ovarian cancer.
12 . The method according to claim 11 , wherein the thyroid cancer is medullary thyroid cancer, and the lung cancer is non-small cell lung cancer.