RXR agonist salt form, polymorphs thereof, and uses thereof

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°.