Maleate salts of B-RAF kinase inhibitor, crystalline forms, methods of preparation, and uses therefore

一种马来酸盐、酮马来酸盐的技术，应用在B‑RAF激酶抑制剂的马来酸盐、其结晶形式、制备和用途领域，能够解决很难确信地预测等问题

Active Publication Date: 2018-01-02
BEIGENE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In practice, it is difficult to predict with confidence which salts of a particular compound will be stable and suitable for pharmaceutical processing

Method used

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  • Maleate salts of B-RAF kinase inhibitor, crystalline forms, methods of preparation, and uses therefore
  • Maleate salts of B-RAF kinase inhibitor, crystalline forms, methods of preparation, and uses therefore
  • Maleate salts of B-RAF kinase inhibitor, crystalline forms, methods of preparation, and uses therefore

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0266] Example 1: Formation of Salts of Compound 1 with Various Salt Forming Agents

Embodiment 1A

[0267] Example 1A: Preparation of the free base of Compound 1 and the crystalline Form A* of Compound 1 sesquimaleate

[0268] Step 1: Synthesis of Intermediate 1

[0269]

[0270] To a stirred solution of EtONa (154 kg) in DMF (989 kg) was added EtSH (68.6 kg) at an internal temperature 2 o 2 (129kg). The mixture was stirred for 30-60 min. After separation of the organic layer, the aqueous phase was extracted with EtOAc. The combined organic phases were washed twice with saturated brine, then the solvent was evaporated to dryness. A solution of MeOH and NaOH (44.5 kg) in water (185 kg) was added dropwise to the residue at below 40 °C. The mixture was stirred at 30-40°C for 5-7 hours. Activated carbon (74 kg) moistened with water (77 kg) was added. The mixture was stirred at 30-40 °C for 4-6 hours and filtered; and the filter cake was washed with MeOH and water. DCM was added to the filtrate and the pH was adjusted to 1 with 35% aq. HCl below 40°C. The aqueous p...

Embodiment 1B

[0295] Example 1B: Preparation of Salts of Compound 1 and Other Salt Forming Agents

[0296] About 150 mg of the free base of Compound 1 was dissolved in a 40 mL glass vial with 2 mL of IPA. The appropriate salt former was dissolved in IPA according to the molar ratios listed in Table 16 on a magnetic stirrer (the salt former was pre-dissolved in IPA, for those that could not be dissolved, the suspension was heated to dissolve) The solution of the solution was slowly titrated into the free base solution, and then kept stirring at room temperature for 24 hours to precipitate a solid. If a solid is not obtained, an antisolvent (eg, heptane) is slowly added to the solution, causing precipitation. The centrifuged solid was determined by XRPD to determine if a new crystalline form was obtained, and then dried under vacuum at 40°C overnight for further characterization. API suspended in IPA and pure solid acid were used as API control and pure solid salt former control to distin...

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PUM

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Abstract

The invention relates to 5- ( ( (1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [d] imidazol-2-yl) -1a,6b-dihydro-1H-cyclopropa [b] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one(Compound 1) maleate salts, in particular the sesqui-maleate salt and its crystalline forms, methods of preparation, pharmaceutical compositions, and therapeutic uses for treatment of diseases or disorders mediated by BRAF or other kinases.

Description

technical field [0001] The present invention relates to B-RAF kinase inhibitors, namely 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a , 6b-dihydro-1H-cyclopropane[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridine-2(1H)-one (thereafter Maleate salts of compound 1), in particular the sesquimaleate salts of compound 1, and crystalline forms (polymorphs) of said sesquimaleate salts, as well as processes for their preparation and use. Background technique [0002] B-RAF is a kinase that is part of the RAF-MEK-ERKMAPK pathway that is critical for cell proliferation and survival. B-RAF mutations have been found in more than 7% of human cancers, including melanoma (43%) (see H. Davies et al., Nature, 417 (2002), 949-54; D.R. English et al., Cancer Epidemiol Biomarkers Prev, 17(2008), 1774-80; G.V.Long et al., Lancet Oncol., 13(2012), 1087-95), thyroid cancer (27%) (see Y.Cohen, J Natl Cancer Inst, 95( 2003), 625-7; E.T.Kimura et al., Cancer Res, 63(2003)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D471/04A61K31/4184A61K31/4355A61K31/5585A61P35/00
CPCC07D471/04A61P35/00C07B2200/13A61K31/4184A61K31/4375A61K31/5585C07C51/43C07C57/145
Inventor 张国良周昌友
Owner BEIGENE LTD
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