Egfr inhibitor free base or acid salt polycrystalline form, preparation method therefor, and application

Abstract

Disclosed are an EGFR inhibitor free base or acid salt polycrystalline form, a preparation method therefor, and an application thereof. The present invention specifically relates to an N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)actylamide free base or acid salt polycrystalline form, a preparation method therefor, and an application of the polycrystalline form in preparing a drug for treating an EGFR mutant activity-mediated disease. The present invention is used for inhibiting the activity of an L858R EGFR mutant, a T790M EGFR mutant and an exon 19 deletion activating mutant etc., may be widely applied in preventing and treating cancer, especially non-small cell lung cancer and other related diseases, and is expected to develop into a new generation of EGFR inhibitors.

What is claimed is: 
     
         1 . A acid salt of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)actylamide (a compound of formula I), wherein the acid salt comprises an inorganic acid salt or an organic acid salt; wherein the inorganic acid salt is selected from the group consisting of hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide and phosphate; wherein the organic acid salt is selected from the group consisting of acetate, propionate, hexanoate, caprylate, fumarate, maleate, malonate, succinate, glutamate, adipate, sebacate, dichloroacetate, trichloroacetate, acetohydroxamate, salicylate, 4-aminosalicylate, benzoate, 4-acetylaminobenzoate, 4-aminobenzoate, caprate, cinnamate, citrate, aspartate, camphorate, gluconate, glucuronate, glutamate, erythorbate, lactate, aspartate, malate, mandelate, pyroglutamate, tartrate, lauryl sulfate, dibenzoyltartrate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, mesylate, ethyl-1,2-disulfonate, ethanesulfonate, benzenesulfonate, 4-chlorobenzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, camphorsulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, formate, galactonate, gentisate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, stearate, thiocyanate, undecylenate, trifluoroacetate and succinate. 
     
     
         2 . The acid salt of the compound of formula I according to  claim 1 , wherein the acid salt polymorph is a mesylate salt polymorph, selected from the group consisting of crystal form I of a mesylate salt, crystal form II of a mesylate salt, crystal form III of a mesylate salt, crystal form IV of a mesylate salt, crystal form V of a mesylate salt, and crystal form VI of a mesylate crystal, wherein an X-ray powder diffraction spectrum of crystal form I of the mesylate salt comprises peaks at diffraction angles (2θ) of 19.1±0.2°, 25.6±0.2°, 15.0±0.2° and 25.0±0.2°; wherein an X-ray powder diffraction spectrum of crystal form II of the mesylate salt comprises peaks at diffraction angles (2θ) of 24.3±0.2°, 20.1±0.2°, 11.0±0.2° and 20.6±0.2°, preferably, further comprises peaks at diffraction angles (2θ) of 17.4±0.2°, 22.7±0.2°, 23.8±0.2°, 12.1±0.2° and 15.7±0.2°, more preferably, further comprises peaks at diffraction angles (2θ) of 8.7±0.2°, 16.7±0.2°, 15.1±0.2, 18.5±0.2°, 17.7±0.2° and 6.5±0.2°; wherein an X-ray powder diffraction spectrum of crystal form III of the mesylate salt comprises peaks at diffraction angles (2θ) of 24.5±0.2°, 22.6±0.2°, 6.1±0.2° and 18.8±0.2°; wherein an X-ray powder diffraction spectrum of crystal form IV of the mesylate salt comprises peaks at diffraction angles (2θ) of 21.0±0.2°, 18.0±0.2°, 25.1±0.2° and 13.6±0.2°; wherein an X-ray powder diffraction spectrum of crystal form V of the mesylate salt comprises peaks at diffraction angles (2θ) of 24.6±0.2°, 23.3±0.2°, 14.9±0.2° and 20.1±0.2°; wherein an X-ray powder diffraction spectrum of crystal form VI of the mesylate salt comprises peaks at diffraction angles (2θ) of 11.7±0.2°, 19.8±0.2°, 17.2±0.2° and 6.8±0.2°. 
     
     
         3 . The acid salt of the compound of formula I according to  claim 1 , wherein the acid salt polymorph is a fumarate salt polymorph, selected from the group consisting of crystal form I of a fumarate salt and crystal form II of a fumarate salt, wherein an X-ray powder diffraction spectrum of crystal form I of the fumarate salt comprises peaks at diffraction angles (2θ) of 7.1±0.2°, 12.0±0.2°, 14.9±0.2° and 17.1±0.2°; wherein an X-ray powder diffraction spectrum of crystal form II of the fumarate salt comprises peaks at diffraction angles (2θ) of 6.0±0.2°, 22.7±0.2°, 25.1±0.2° and 23.3±0.2°. 
     
     
         4 . The acid salt of the compound of formula I according to  claim 1 , wherein the acid salt polymorph is a maleate salt, preferably selected from the group consisting of crystal form I of a maleate salt, crystal form II of a maleate salt and crystal form III of a maleate salt; wherein an X-ray powder diffraction spectrum of crystal form I of the maleate salt comprises peaks at diffraction angles (2θ) of 7.9±0.2°, 24.6±0.2°, 7.5±0.2° and 18.2±0.2°; wherein an X-ray powder diffraction spectrum of crystal form II of the maleate salt comprises peaks at diffraction angles (2θ) of 20.3±0.2°, 24.9±0.2°, 23.4±0.2° and 16.8±0.2°; wherein an X-ray powder diffraction spectrum of crystal form III of the maleate salt comprises peaks at diffraction angles (2θ) of 21.6±0.2°, 22.4±0.2°, 17.9±0.2° and 25.8±0.2° 
     
     
         5 . The acid salt of the compound of formula I according to  claim 1 , wherein the acid salt polymorph is selected from an acetate salt, selected from the group consisting of crystal form I of an acetate salt and crystal form II of an acetate salt; wherein an X-ray powder diffraction spectrum of crystal form I of the acetate salt comprises peaks at diffraction angles (2θ) of 23.0±0.2°, 11.8±0.2°, 16.3±0.2° and 7.4±0.2°; wherein an X-ray powder diffraction spectrum of crystal form II of the acetate salt comprises peaks at diffraction angles (2θ) of 8.4±0.2°, 19.9±0.2°, 23.0±0.2° and 24.8±0.2°. 
     
     
         6 . A method for preparing the acid salt of the compound of formula I according to  claim 1 , comprises the following step of:
 preparing the acid salt of the compound of formula I as follows: dissolving or dispersing the free base of the compound in an aqueous solvent or a suitable organic solvent, and then adding a liquid or solid or solution of inorganic acid or organic acid to the above system to prepare the acid salt of the compound of formula I; or, adding the free base solid to an acid solution to prepare the acid salt of the compound of formula I.   
     
     
         7 . A method for preparing the acid salt of the compound of formula I according to  claim 6 , wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, toluene, n-butanol, cyclohexane, dichloromethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dioxane, ethyl ether, n-heptane, n-hexane, methyl ethyl ketone, isooctane, pentane, dipropanol, tetrahydrofuran, dimethyl tetrahydrofuran, trichloroethane, and dimethylbenzene, or a mixture thereof. 
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of the acid salt of the compound of formula I according to any one of  claims 1 , and a pharmaceutically acceptable carrier. 
     
     
         9 . The acid salt of the compound of formula I according to  claim 1 , the acid salt selected from the group consisting of mesylate, fumarate, maleate, and acetate. 
     
     
         10 . The acid salt of the compound of formula I according to  claim 1 , wherein the acid salt is mesylate. 
     
     
         11 . A method for treating a disease mediated by the activity of an EGFR mutant or the activity of a mutant activated by exon 19 deletion in a subject, the method comprising administering to the subject the pharmaceutical composition according to  claim 8 . 
     
     
         12 . The method according to  claim 11 , wherein the EGFR mutant is selected from the group consisting of EGFR-L858R mutant and EGFR-T790M mutant. 
     
     
         13 . A method for treating a cancer in a subject, the method comprising administering to the subject the pharmaceutical composition according to  claim 8 , wherein the cancer is selected from the group consisting of 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 tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, and non-small cell lung cancer. 
     
     
         14 . The method according to  claim 13 , wherein the cancer is non-small cell lung cancer. 
     
     
         15 . The acid salt of the compound of formula I according to  claim 1 , wherein the acid salt of the compound of formula I is crystal form.