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CN-121991038-A - Salts of 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivatives, preparation method and application thereof

CN121991038ACN 121991038 ACN121991038 ACN 121991038ACN-121991038-A

Abstract

The invention discloses a salt of a 1-methyl-6- ((5- (phenylethynyl) pyrazine-2-yl) oxy) -1H-indole derivative, a preparation method and application thereof, wherein the structure of the 1-methyl-6- ((5- (phenylethynyl) pyrazine-2-yl) oxy) -1H-indole derivative is as follows: the invention discloses hydrochloride, benzenesulfonate, maleate and fumarate of the compound, and also provides the hydrochloride, benzenesulfonate, maleate and fumarate of the compound which can obviously inhibit proliferation of cells such as breast cancer, liver cancer, pancreatic cancer, gastric cancer, lung cancer, esophageal cancer, cervical cancer, multiple myeloma and diffuse large B cell lymphoma at low dosage (nanomolar), and can inhibit expression level of downstream target proteins C-MYC and CyclinD1 of STAT3, so that the compound has the prospect of being developed into antitumor drugs.

Inventors

  • XU XUEJUN
  • YANG YUPO
  • XU HONGYUN
  • LIU YAQING
  • Tang Shanshun
  • XU CHUNPING

Assignees

  • 河南省锐达医药科技有限公司

Dates

Publication Date
20260508
Application Date
20241106

Claims (6)

  1. 1. A salt of a 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative, characterized by a salt formed from a 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative with hydrochloric acid, benzenesulfonic acid, maleic acid or fumaric acid, the 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative having the structure: 。
  2. 2. A process for the preparation of a salt of a 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative according to claim 1, characterised in that the process is as follows: (1) Adding the derivative into a solvent to obtain a solution A, directly adding hydrochloric acid, benzenesulfonic acid, maleic acid and fumaric acid into the solution A or dissolving the derivative into the solvent, then adding the solution A, stirring the solution A to 40-50 h at room temperature or stirring the solution A for 1-5 h at room temperature, stirring the solution A for 20-30 h at 45-55 ℃, naturally cooling the solution A to room temperature and stirring the solution A for 3-12 h; (2) Filtering, and leaching the solid by using a solvent; (3) And drying the leached solid for 15-25 hours at 45-55 ℃ to obtain the solid.
  3. 3. The process according to claim 2, wherein the molar ratio of the derivative to hydrochloric acid, benzenesulfonic acid, maleic acid or fumaric acid is 1 (1.0-1.2).
  4. 4. The method of claim 2, wherein the solvent is at least one of dichloromethane, acetone, and ethyl acetate.
  5. 5. The use of the salt of 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative according to claim 1 for preparing an anti-tumor drug, wherein the anti-tumor drug is a drug for treating breast cancer, liver cancer, pancreatic cancer, gastric cancer, lung cancer, esophageal cancer, cervical cancer, multiple myeloma and diffuse large B-cell lymphoma.
  6. 6. Use of a salt of a 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative according to claim 1 for the preparation of a STAT3 protein inhibitor.

Description

Salts of 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivatives, preparation method and application thereof Technical Field The invention relates to a salt and a crystal form of a compound, in particular to a salt of a 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative, a preparation method and application thereof. Background In the patent application number 202310682118.6, the following compounds (1-methyl-6- ((5- ((4- (trifluoromethyl) phenyl) ethynyl) pyrazin-2-yl) oxy) -1H-indol-2-yl) (4- (4- (2, 2-trifluoroethoxy) benzyl) piperazin-1-yl) methanone) are described: The compounds are useful as STAT3 inhibitors for the treatment of diseases responsive to inhibition of STAT3 targets. The 202310682118.6 patent does not disclose any specific salts and crystalline forms of the compound. Disclosure of Invention The invention relates to a salt of a 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative, a preparation method and application thereof. Based on the above purpose, the invention adopts the following technical scheme: a salt of a 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative formed from a salt of a 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative with hydrochloric acid, benzenesulfonic acid, maleic acid or fumaric acid, the 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative having the structure: The preparation method of the salt of the 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative comprises the following steps of: (1) Adding the derivative into a solvent to obtain a solution A, directly adding hydrochloric acid, benzenesulfonic acid, maleic acid and fumaric acid into the solution A or dissolving the derivative into the solvent, then adding the solution A, stirring the solution A to 40-50 h at room temperature or stirring the solution A for 1-5 h at room temperature, stirring the solution A for 20-30 h at 45-55 ℃, naturally cooling the solution A to room temperature and stirring the solution A for 3-12 h; (2) Filtering, and leaching the solid by using a solvent; (3) And drying the leached solid for 15-25 hours at 45-55 ℃ to obtain the solid. Further, the molar ratio of the derivative to hydrochloric acid, benzenesulfonic acid, maleic acid or fumaric acid is 1 (1.0-1.2). Further, the solvent is at least one of dichloromethane, acetone and ethyl acetate. Specifically, the preparation process of the hydrochloride of the 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative is as follows: (1) Dissolving concentrated hydrochloric acid in dichloromethane to obtain a solution B, adding the solution B into the solution A, and stirring at room temperature for 40-50 h; (2) Filtering, eluting the solid with dichloromethane; (3) And drying the leached solid for 15-25 hours at 45-55 ℃ to obtain the solid. In the preparation process of the hydrochloride, the concentration of the derivative in the solution A is 0.1-0.2 mmol/mL, and the concentration of the concentrated hydrochloride in the solution is 0.05-0.15 mmol/mL. Specifically, the preparation process of the benzenesulfonate, maleate and fumarate of the above-mentioned 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative is as follows: (1) Adding the derivative into acetone or ethyl acetate to obtain a solution A, directly adding benzenesulfonic acid, maleic acid and fumaric acid into the solution A, stirring for 1-5 h at room temperature, stirring for 20-30 h at 45-55 ℃, naturally cooling to room temperature and stirring for 3-12 h; (2) Filtering, eluting the solid with acetone or ethyl acetate; (3) And drying the leached solid for 15-25 hours at 45-55 ℃ to obtain the solid. The concentration of the derivative in the solution A in the preparation process of the benzenesulfonate, the maleate and the fumarate is 0.05-0.1 mmol/mL. The application of the salt of the 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative in preparing an anti-tumor drug, wherein the anti-tumor drug is used for treating breast cancer, liver cancer, pancreatic cancer, gastric cancer, lung cancer, esophageal cancer, cervical cancer, multiple myeloma and diffuse large B cell lymphoma. Use of a salt of the above-described 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative in the preparation of a STAT3 protein inhibitor. Specifically, the invention synthesizes four salts of 1-methyl-6- ((5- (phenylethynyl) pyrazin-2-yl) oxy) -1H-indole derivative- (1-methyl-6- ((5- ((4- (trifluoromethyl) phenyl) ethynyl) pyrazin-2-yl) oxy) -1H-indol-2-yl) (hydrochloride crystal form A, besylate crystal form A, maleate crystal form A and fumarate crystal form A of 4- (4- (2, 2-trifluoro-ethoxy) benzyl) piperazine-1-yl) methanone. The proliferation inhibition effect of the compound on various cancer cells is detected by a CCK-8 method, and the phosphorylation of