Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making

Patent metadata

Field	Value
Publication number	US-2021147433-A1
Application number	US-202117153727-A
Country	US
Kind code	A1
Filing date	Jan 20, 2021
Priority date	Apr 12, 2019
Publication date	May 20, 2021
Grant date	—

Abstract

Crystalline Forms of Compound (I):

pharmaceutically acceptable salts thereof and solvates of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating disorders and conditions associated with oncogenic KIT and PDGFRA alterations using the same, and methods for making Compound (I) and crystalline forms thereof are also disclosed.

First claim

1 . Crystalline Form A of Compound (I):

characterized by an X-ray powder diffractogram having a signal at least three two-theta values chosen from 11.5±0.2, 15.4±0.2, 16.7±0.2, 18.1±0.2, 20.0±0.2, 21.6±0.2, 23.1±0.2, 23.9±0.2, 25.9±0.2, and 30.7±0.2.

2 . Crystalline Form A according to claim 1 , characterized by an X-ray powder diffractogram having a signal at least three two-theta values chosen from 11.5±0.2, 15.4±0.2, 16.7±0.2, 20.0±0.2, and 21.6±0.2.

3 . Crystalline Form A according to claim 1 , characterized by an X-ray powder diffractogram having a signal at least six two-theta values chosen from 11.5±0.2, 15.4±0.2, 16.7±0.2, 18.1±0.2, 20.0±0.2, 21.6±0.2, 23.1±0.2, 23.9±0.2, 25.9±0.2, and 30.7±0.2.

4 . A method of preparing crystalline Form A of Compound (I) according to claim 1 , comprising
dissolving Compound (I) in a mixture of acetone and water to obtain a suspension;

heating the suspension to a temperature ranging from 40° C. to 50° C. to obtain a solution; and
cooling the solution.

5 . Crystalline Form C of Compound (I):

characterized by an X-ray powder diffractogram having a signal at least three two-theta values chosen from 5.3±0.2, 9.4±0.2, 10.4±0.2, 12.0±0.2, 13.9±0.2, 16.1±0.2, 17.4±0.2, 22.8±0.2, 24.0±0.2, 24.8±0.2, and 25.8±0.2.

6 . Crystalline Form O of Compound (I):

characterized by an X-ray powder diffractogram having a signal at least three two-theta values chosen from 7.2±0.2, 10.8±0.2, 12.3±0.2, 14.5±0.2, 14.7±0.2, 16.1±0.2, 19.0±0.2, 20.4±0.2, and 23.7±0.2.

7 . Crystalline Form T of a tosylate salt of Compound (I):

characterized by an X-ray powder diffractogram having a signal at least three two-theta values chosen from 5.9±0.2, 6.1±0.2, 9.6±0.2, 11.7±0.2, 16.0±0.2, 19.2±0.2, 20.8±0.2, 21.2±0.2, 22.0±0.2, 24.1±0.2, and 24.5±0.2.

8 . Crystalline Form Tr of a tartrate salt of Compound (I):

characterized by an X-ray powder diffractogram having a signal at least three two-theta values chosen from 6.3±0.2, 10.6±0.2, 11.1±0.2, 12.5±0.2, 13.3±0.2, 13.7±0.2, 14.2±0.2, 14.9±0.2, 16.2±0.2, 19.0±0.2, 22.5±0.2, 24.1±0.2, and 27.9±0.2.

9 . Crystalline Form H of a hydrochloride salt of Compound (I):

characterized by an X-ray powder diffractogram having a signal at least three two-theta values chosen from 4.8±0.2, 8.1±0.2, 8.5±0.2, 9.6±0.2, 11.1±0.2, 20.7±0.2, 21.5±0.2, 23.3±0.2, 23.7±0.2, 24.1±0.2, and 27.6±0.2.

10 . A pharmaceutical composition comprising:
at least one pharmaceutically acceptable excipient; and Crystalline Form A of Compound (I) according to claim 1 .

11 . A method of treating mastocytosis comprising administering to a patient in need thereof a therapeutically effective amount of Crystalline Form A of Compound (I) according to claim 1 .

12 . The method of claim 11 , wherein the mastocytosis is selected from cutaneous mastocytosis (CM) and systemic mastocytosis (SM).

13 . The method of claim 12 , wherein the mastocytosis is systemic mastocytosis and the systemic mastocytosis is selected from indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), and advanced systemic mastocytosis (AdvSM).

14 . The method of claim 13 , wherein the systemic mastocytosis is advanced systemic mastocytosis (AdvSM).

15 . The method of claim 14 , wherein the therapeutically effective amount is 200 mg to 300 mg of Crystalline Form A of Compound (I) administered once daily.

16 . The method of claim 14 , wherein the systemic mastocytosis is indolent systemic mastocytosis (ISM) or smoldering systemic mastocytosis (SSM).

17 . The method of claim 16 , wherein the therapeutically effective amount is 10 mg to 25 mg of Crystalline Form A of Compound (I) administered once a daily.

18 . A method of treating gastrointestinal stromal tumor, comprising administering to a patient in need thereof a therapeutically effective amount of Crystalline Form A of Compound (I) according to claim 1 .

19 . The method of claim 18 , wherein the gastrointestinal stromal tumor is characterized by an exon 18 mutation in PDGFRα.

20 . A method of treating acute myeloid leukemia comprising administering to a patient in need thereof a therapeutically effective amount of Crystalline Form A of Compound (I) according to claim 1 .

21 . A process for the preparation of Compound (I)

comprising forming a salt of Compound (I) with D-quinic acid in an organic solvent and crystallizing the salt from a solvent mixture.

Assignees

• Blueprint Medicines Corp

Inventors

• Waetzig Joshua D
• Mar Brenton
• Heinrich Brian
• Wilkie Gordon
• Maceachern Lauren

Classifications

• A61K31/155 Primary

  Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2) · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title