RXR agonist salt form, polymorphs thereof, and uses thereof

Patent metadata

Field	Value
Publication number	US-12325685-B2
Application number	US-202418416577-A
Country	US
Kind code	B2
Filing date	Jan 18, 2024
Priority date	Mar 15, 2022
Publication date	Jun 10, 2025
Grant date	Jun 10, 2025

Abstract

Provided herein are salt and solid forms of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, including a Tris salt form of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, and polymorphs thereof, methods of preparing the compounds, and their uses.

First claim

We claim:

1. A solid form of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, which is a a lysine salt or a glycine salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid.

2. The solid form of claim 1 , which is the lysine salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid.

3. A solid form of claim 2 , which is selected from:
Form A of the lysine salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, having an X-ray powder diffraction pattern comprising one or more signals, in terms of degrees 2θ, selected from 6.76±0.2°, 8.7±0.2°, 10.1±0.2°, or 10.3±0.2°, optionally having a differential scanning calorimetry thermogram comprising endothermic transitions at 46±3° C., 131±3° C., and 183±3° C.;
Form B of the lysine salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, having an X-ray powder diffraction pattern comprising one or more signals, in terms of degrees 2θ, selected from 3.1±0.2°, 5.1±0.2°, 18.7±0.2°, or 20.7±0.2°, optionally having a differential scanning calorimetry thermogram comprising endothermic transitions at 48±3° C., 117±3° C., 133±3° C., and 189±3° C.;
Form C of the lysine salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, having an X-ray powder diffraction pattern comprising one or more signals, in terms of degrees 2θ, selected from 10.1±0.2°, 11.0±0.2°, 13.6±0.2°, or 24.1±0.2°, optionally having a differential scanning calorimetry thermogram comprising endothermic transitions at 127±3° C. and 186±3° C.; or
Form D of the lysine salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, having an X-ray powder diffraction pattern comprising one or more signals, in terms of degrees 2θ, selected from 3.5±0.2°, 7.0±0.2°, 10.4±0.2°, or 14.9±0.2°, optionally having a differential scanning calorimetry thermogram comprising endothermic transitions at 93±3° C., 132±3° C., 166±3° C., and 181±3° C.

4. The solid form of claim 1 , which is the glycine salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid.

5. A solid form of claim 4 , which is Form A of the glycine salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, having an X-ray powder diffraction pattern comprising one or more signals, in terms of degrees 2θ, selected from 21.9±0.2°, 25.4±0.2°, 29.3±0.2°, or 40.0±0.2°.

6. A method for preparing a solid form which is Form A of the salt (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid mono-(tris (hydroxymethyl)aminomethane) having an X-ray powder diffraction pattern comprising a signal, in terms of 2θ, at 11.3±0.2°, the method comprising:
heating a solid Form C of tris(hydroxymethyl)aminomethane salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, optionally having an X-ray powder diffraction pattern comprising one or more signals, in terms of degrees 2θ, selected from 2.9±0.2°, 5.5±0.2°, 5.9±0.2°, or 28.9±0.2°, and optionally having a differential scanning calorimetry thermogram comprising endothermic transitions at 94±3° C. and 152±3° C. to obtain the solid Form A of the salt (25,4E)-3-methyl-5-((15,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic mono-acid (tris(hydroxymethyl)aminomethane).

7. A method for preparing a solid form which is Form A of the salt (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid mono-tris(hydroxymethyl)aminomethane) having an X-ray powder diffraction pattern comprising a signal, in terms of 2θ, at 11.3±0.2°, the method comprising:
heating a solid Form D of the tris(hydroxymethyl)aminomethane salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, optionally having an X-ray powder diffraction pattern comprising one or more signals, in terms of degrees 2θ, selected from 3.9±0.2°, 11.8±0.2°, 17.6±0.2°, or 32.7±0.2°, and optionally having a differential scanning calorimetry thermogram comprising endothermic transitions at 61±3° C., and 154±3° C. to obtain the solid Form A of the salt (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid mono-(tris(hydroxymethyl)aminomethane).

8. The method of claim 6 , wherein the obtained solid Form A of the salt (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid mono-(tris(hydroxymethyl)aminomethane) has an X-ray powder diffraction pattern comprising signals, in terms of 2θ, at 3.8±0.2°, 7.6±0.2°, 11.3±0.2°, 18.1±0.2°, and 19.6±0.2°.

9. The method of claim 7 , wherein the obtained solid Form A of the salt (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid mono-(tris(hydroxymethyl)aminomethane) has an X-ray powder diffraction pattern comprising signals, in terms of 2θ, at 3.8±0.2°, 7.6±0.2°, 11.3±0.2°, 18.1±0.2°, and 19.6±0.2°.

Assignees

• Io Therapeutics Inc

Inventors

• Vuligonda Vidyasagar
• Sanders Martin E
• Kuang Shanming
• Shah Harsh Shailesh

Classifications

• C07C215/10

  with one amino group and at least two hydroxy groups bound to the carbon skeleton · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07C51/43 Primary

  by change of the physical state, e.g. crystallisation · CPC title

• A61P35/00

  Antineoplastic agents · CPC title