Novel salt forms of a 4h-pyran-4-one structured cyp11a1 inhibitor

Patent metadata

Field	Value
Publication number	US-2024158377-A1
Application number	US-202218548487-A
Country	US
Kind code	A1
Filing date	Feb 28, 2022
Priority date	Mar 1, 2021
Publication date	May 16, 2024
Grant date	—

Abstract

The present invention relates to novel salts, particularly crystalline salts, of 2-(isoindolin-2-ylmethyl)-5-((1-(methyl sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) which are particularly suitable for use in the manufacture of pharmaceutical 5 compositions. Furthermore, the invention relates to pharmaceutical compositions comprising such novel salts. Compound (I) is a selective inhibitor of CYP11A1 enzyme and is useful in the treatment of hormonally regulated cancers, such as prostate cancer and breast cancer.

First claim

1 . A salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)-methoxy)-4H-pyran-4-one (I) with an acid selected from the group consisting of
p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, hydrobromic acid, nitric acid, benzenesulfonic acid, hydrochloride acid, maleic acid, 1,2-ethanedisulfonic acid, oxalic acid, ethanesulfonic acid, sulfuric acid and methanesulfonic acid.

2 . The salt according to claim 1 , which is a salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) with an acid selected from the group consisting of
p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid and hydrobromic acid.

3 . The salt according to claim 1 which is crystalline.

4 . The salt according to claim 2 , which is a crystalline p-toluenesulfonic acid salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)-methoxy)-4H-pyran-4-one (I).

5 . The salt according to claim 4 , which is of crystalline form 1 having an X-ray powder diffraction pattern comprising peaks, expressed in degrees 2-theta (±0.2), at 4.4, 15.2, 18.4, 19.1, 20.8 and 22.4.

6 . The salt according to claim 5 , wherein the crystalline form 1 has an X-ray powder diffraction pattern comprising y peaks, expressed in degrees 2-theta (±0.2), at 4.4, 8.8, 11.4, 15.2, 16.5, 17.1, 18.4, 19.1, 20.8 and 22.4.

7 . The salt according to claim 4 , wherein the crystalline form 1 has the following unit cell parameters at T=293(2) K:

Crystal system
Monoclinic

Space group
P2 1

Unit cell dimensions
a = 6.02369(10) Å
α = 90°

b = 12.21533(19) Å
β = 92.5099(16)°

c = 20.1514(4) Å
γ = 90°

Volume
V = 1481.35(4) Å 3

Z
2

Goodness-of-fit
1.030

R factor
0.0657

Morphology
Prismatic

8 . The salt according to claim 2 , which is a crystalline 2-naphthalenesulfonic acid salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)-methoxy)-4H-pyran-4-one (I).

9 . The salt according to claim 8 , which is of crystalline form 1 having an X-ray powder diffraction pattern comprising peaks, expressed in degrees 2-theta (±0.2), at 4.3, 8.7, 13.0, 18.8 and 27.1.

10 . The salt according to claim 9 , wherein the crystalline form 1 has an X-ray powder diffraction pattern comprising peaks, expressed in degrees 2-theta (±0.2), at 4.3, 8.7, 13.0, 18.8, 21.7, 27.1 and 35.8.

11 . The salt according to claim 2 , which is a crystalline 1,5-naphthalenedisulfonic acid salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I).

12 . The salt according to claim 11 , which is of crystalline form 1 having an X-ray powder diffraction pattern comprising peaks, expressed in degrees 2-theta (±0.2), at 10.6, 17.6, 20.2, 20.4, 22.8 and 24.8.

13 . The salt according to claim 12 , wherein the crystalline form 1 has an X-ray powder diffraction pattern comprising peaks, expressed in degrees 2-theta (±0.2), at 5.9, 9.2, 10.6, 15.5, 17.1, 17.6, 20.2, 20.4, 22.8 and 24.8.

14 . The salt according to claim 2 , which is a crystalline hydrobromic acid salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)-methoxy)-4H-pyran-4-one (I).

15 . The salt according to claim 14 , which is of crystalline form 1 having an X-ray powder diffraction pattern comprising peaks, expressed in degrees 2-theta (±0.2), at 5.3, 10.5, 13.6, 18.3, 21.4 and 26.9.

16 . The salt according to claim 15 , wherein the crystalline form 1 has an X-ray powder diffraction pattern comprising peaks, expressed in degrees 2-theta (±0.2), at about 5.3, 10.5, 13.6, 16.9, 18.3, 18.8, 21.4, 22.6 and 26.9.

17 . A method of preparing a crystalline salt according to claim 4 , comprising dissolving compound (I) and p-toluenesulfonic acid in a mixture of acetonitrile and water, cooling the mixture and isolating the crystalline product.

18 . A method of preparing a crystalline salt according to claim 8 , comprising dissolving compound (I) and 2-naphthalenesulfonic acid in ethanol or a mixture of ethanol and water, cooling the mixture and isolating the crystalline product.

19 . A method of preparing a crystalline salt according to claim 11 , comprising dissolving compound (I) and 1,5-naphthalenedisulfonic acid in ethanol, a mixture of ethanol and water or a mixture of acetonitrile and water, cooling the mixture and isolating the crystalline product.

20 . A method of preparing a crystalline salt according to claim 14 , comprising dissolving compound (I) and hydrobromic acid in ethanol, or a mixture of water with ethanol or isopropanol, cooling the mixture and isolating the crystalline product.

21 . A pharmaceutical composition comprising the salt according to claim 1 as an active ingredient together with one or more excipients.

22 . The pharmaceutical composition according to claim 21 , which is in the form of a tablet, capsule, granule, powder or suspension.

23 . The pharmaceutical composition according to claim 22 , which is in the form of a tablet or capsule.

24 . The pharmaceutical composition according to claim 23 , which is in the form of a tablet.

25 . A method for the treatment of a hormonally regulated cancer, wherein the method comprises administering a therapeutically effective amount of the salt according to claim 1 .

26 . The method of claim 25 , wherein the cancer is prostate cancer or breast cancer.

Assignees

• Orion Corp

Inventors

• Karjalainen Oskari
• Mäkelä Mikko
• Pop Mihaela
• Rummakko Petteri
• Shevchenko Anna
• Sinervo Kai
• Tiainen Eija

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K9/20

  Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)} · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title