Solid forms of macrocyclic compounds, salts and formulations thereof, and methods of preparing and using the same

Patent metadata

Field	Value
Publication number	US-12466835-B1
Application number	US-202418935332-A
Country	US
Kind code	B1
Filing date	Nov 1, 2024
Priority date	May 31, 2023
Publication date	Nov 11, 2025
Grant date	Nov 11, 2025

Abstract

The present disclosure relates to solid forms of Compound 1, or a pharmaceutically acceptable form thereof, a pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, pharmaceutical compositions comprising the same, methods of preparing the same, and methods of treating cancer dependent on a farnesylated protein, using the same.

First claim

What is claimed is:

1 . A solid form comprising Compound 1, or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof:

wherein the solid form is crystalline.

2 . The solid form of claim 1 , wherein the solid form comprises a free base of the Compound 1 or the pharmaceutically acceptable solvate thereof.

3 . The solid form of claim 1 , wherein the solid form is a non-solvate of the Compound 1 or the pharmaceutically acceptable salt thereof.

4 . The solid form of claim 1 , wherein the solid form is the pharmaceutically acceptable solvate of the Compound 1 or the pharmaceutically acceptable salt thereof, comprising (i) the Compound 1 or the pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable solvent.

5 . The solid form of claim 4 , wherein the pharmaceutically acceptable solvate is selected from the group consisting of: a hydrate, an iso-butyl acetate solvate, an iso-propyl acetate solvate, a tetrahydrofuran solvate, an acetone solvate, and an acetonitrile solvate, and combinations thereof.

6 . The solid form of claim 5 , wherein the pharmaceutically acceptable solvate comprises (i) the Compound 1 or the pharmaceutically acceptable salt thereof, and (ii) the pharmaceutically acceptable solvent, in a molar ratio in the range of about 2:1 to about 1:2.

7 . The solid form of claim 6 , wherein the pharmaceutically acceptable solvate is a hydrate.

8 . The solid form of claim 7 , wherein the hydrate comprises (i) the Compound 1 or the pharmaceutically acceptable salt thereof, and (ii) water, in a molar ratio in the range of about 2:1 to about 1:2.

9 . The solid form of claim 1 , wherein the solid form is a crystalline, free base, hemi-hydrate of the Compound 1.

10 . The solid form of claim 9 , wherein the solid form is Compound 1 (Form 1).

11 . The solid form of claim 9 , which is characterized by an X-ray power diffraction (XRPD) pattern, when measured using Cu Kα radiation, comprising peaks at approximately 9.0, 12.8, 16.6, and 18.4° 2θ.

12 . The solid form of claim 1 , wherein the solid form comprises the pharmaceutically acceptable salt of the Compound 1 or the pharmaceutically acceptable solvate thereof.

13 . The solid form of claim 12 , wherein the pharmaceutically acceptable salt is a benzoate salt, a besylate salt, a chloride salt, a citrate salt, a fumarate salt, a gentisate salt, a glycolate salt, a 1-hydroxy-2-naphthoate salt, a malate salt, a maleate salt, a mesylate salt, an oxalate salt, a phosphate salt, a tartrate salt, or a tosylate salt.

14 . The solid form of claim 1 , wherein the solid form is a free base of the Compound 1 or the pharmaceutically acceptable solvate thereof.

15 . The solid form of claim 11 , wherein the XRPD pattern comprises a peak selected from the group consisting of approximately 8.6, 12.0, 18.1, and 23.2° 2 θ.

16 . The solid form of claim 15 , wherein the XRPD pattern comprises a peak selected from the group consisting of approximately 16.1, 17.1, 24.1, and 25.6° 2 θ.

17 . The solid form of claim 9 , which is characterized by having approximately unit cell dimensions of a=15.2Å, b=7.9 Å, c=20.7 Å, α=90°, ß=107.8°, and γ=90°, and a unit cell of a space group of P2 1 .

18 . The solid form of claim 9 , which exhibits a thermal (endothermic) event with an onset temperature of about 83° C. and a thermal (endothermic, melting) event with an onset temperature of about 212° C., and/or an endothermic peak at about 137° C. and at about 221° C., as characterized by differential scanning calorimetry (DSC) with a temperature ramp of about 10° C./min.

19 . The solid form of claim 9 , which exhibits no weight loss upon heating below about 75° C. and a weight loss of about 1.8% upon heating from about 75° C. to about 170° C., as characterized by thermal gravimetric analysis (TGA).

20 . The solid form of claim 9 , wherein the solid form has a purity of at least 98%, 98.5%, 99%, or 99.5%.

21 . The solid form of claim 9 , wherein the solid form has:
(a) a solubility of about 4.69, 5.04, and 3.67 mg/mL in simulated gastric fluid (SGF) media, at 0.5 h, 2 h, and 24 h, respectively; or (b) a solubility of about 0.29, 0.31, and 0.33 mg/mL in fed state simulated intestinal fluid (FeSSIF) media, at 0.5 h, 2 h, and 24 h, respectively;
or a combination thereof.

22 . The solid form of claim 1 , wherein the solid form comprises a non-solvate of the Compound 1 or the pharmaceutically acceptable salt thereof.

23 . The solid form of claim 1 , wherein the solid form comprises the pharmaceutically acceptable solvate of the Compound 1 or the pharmaceutically acceptable salt thereof.

24 . The solid form of claim 1 , wherein the solid form is the pharmaceutically acceptable salt of the Compound 1 or the pharmaceutically acceptable solvate thereof.

25 . A solid form comprising a pharmaceutically acceptable solvate of Compound 1, or a pharmaceutically acceptable salt thereof:

wherein:
i) the pharmaceutically acceptable solvate is selected from the group consisting of: a hydrate, an iso-butyl acetate solvate, an iso-propyl acetate solvate, a tetrahydrofuran solvate, an acetone solvate, and an acetonitrile solvate, and combinations thereof; and
ii) the pharmaceutically acceptable solvate comprises (a) the Compound 1 or the pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable solvent, solvent are present in a molar ratio in the range of about 2:1 to about 1:2.

26 . The solid form of claim 25 , wherein the pharmaceutically acceptable solvate is a hydrate.

27 . The solid form of claim 26 , wherein the hydrate comprises (i) the Compound 1 or the pharmaceutically acceptable salt thereof, and (ii) water in a molar ratio of about 2:1 (hemi-hydrate).

28 . The solid form of claim 25 , wherein the pharmaceutically acceptable salt is a benzoate salt, a besylate salt, a chloride salt, a citrate salt, a fumarate salt, a gentisate salt, a glycolate salt, a 1-hydroxy-2-naphthoate salt, a malate salt, a maleate salt, a mesylate salt, an oxalate salt, a phosphate salt, a tartrate salt, or a tosylate salt.

Assignees

• Kura Oncology Inc

Inventors

• Bakale Roger Paul
• Liu Kenneth K
• Shan Yun
• Sun Xiufeng
• Andres Patricia
• Chen Song
• Lu Yue
• Song Licheng
• Ferrer Catalina
• Neves Ana Rita

Classifications

• A61K9/2095

  Tabletting processes · CPC title

• C07C59/265

  Citric acid · CPC title

• C07C59/255

  Tartaric acid · CPC title

• C07C65/03

  monocyclic and having all hydroxy or O-metal groups bound to the ring · CPC title

• C07C55/06

  Oxalic acid · CPC title