Pharmaceutical compositions comprising a MENIN inhibitor

Patent metadata

Field	Value
Publication number	US-12521396-B2
Application number	US-202418827538-A
Country	US
Kind code	B2
Filing date	Sep 6, 2024
Priority date	Jul 17, 2023
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

Described herein are crystalline forms of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof, methods of making such forms, and pharmaceutical composition comprising such forms.

First claim

We claim:

1 . A pharmaceutical composition comprising wet-milled crystalline of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof having a bulk density of at least 0.1 g/cm 3 .

2 . The pharmaceutical composition of claim 1 , wherein the wet-milled crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile Form 1 having an XRPD pattern with at least three characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta.

3 . The pharmaceutical composition of claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile Form 1 having an X-ray powder diffraction (XRPD) pattern with at least five characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta.

4 . The pharmaceutical composition of claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile Form 1 having a differential scanning calorimetry (DSC) thermogram with an endotherm having an onset at about 136° C. and/or a peak at about 149° C.

5 . The pharmaceutical composition of claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is obtained from methyl ethyl ketone (MEK) and isopropanol (IPA).

6 . The pharmaceutical composition of claim 5 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is obtained from a 1:1 mixture of MEK and IPA.

7 . The pharmaceutical composition of claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof has a bulk density from about 0.1 to about 0.15 g/cm 3 .

8 . The pharmaceutical composition of claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof has a particle size distribution of D 10 , 1.5 to 4.5 μm; D 50 , 5 to 11 μm; or D 90 , 13 to 50 μm; or a particle size distribution of D 90 equal to or below 50 μm.

9 . The pharmaceutical composition of claim 1 , comprising 15 to 800 mg of the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof.

10 . The pharmaceutical composition of claim 1 , comprising a pharmaceutically acceptable excipient.

11 . The pharmaceutical composition of claim 10 , wherein the pharmaceutically acceptable excipient is selected from a filler, a disintegrant, a surfactant, and a lubricant, and combinations thereof, optionally wherein the filler is mannitol and/or microcrystalline cellulose, optionally wherein the disintegrant is croscarmellose sodium, optionally wherein the surfactant is sodium lauryl sulfate, and optionally wherein the lubricant is magnesium stearate.

12 . The pharmaceutical composition of claim 10 , wherein the pharmaceutically acceptable excipient is selected from a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant, and combinations thereof, optionally where in the filler is microcrystalline cellulose, lactose, or mannitol, or a combination thereof, optionally wherein the binder is hydroxypropyl cellulose, optionally wherein the disintegrant is croscarmellose sodium or crospovidone, optionally wherein the surfactant is sodium lauryl sulfate, optionally wherein the glidant is colloidal silicon dioxide, and optionally wherein the lubricant is magnesium stearate.

13 . The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is a capsule.

14 . The pharmaceutical composition of claim 13 , wherein the capsule comprises:
a) 15 to 800 mg of the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof; b) 15% w/w to 75% w/w of a first filler, optionally wherein the first filler is mannitol; c) 10% w/w to 35% w/w of a second filler, optionally wherein the second filler is microcrystalline cellulose; d) 1% w/w to 10% w/w of a disintegrant, optionally wherein the disintegrant is croscarmellose sodium; e) 0.1% w/w to 1% w/w of a surfactant, optionally wherein the surfactant is sodium lauryl sulfate; and f) 0.1% w/w to 1% w/w of a lubricant, optionally wherein the lubricant is magnesium stearate; wherein the total % w/w of a) to f) is 100%.

15 . The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is a tablet.

16 . The pharmaceutical composition of claim 15 , wherein the tablet comprises:
a) 35% w/w to 75% w/w of the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof; b) 7% w/w to 40% w/w of a first filler, optionally wherein the first filler is microcrystalline cellulose; c) 5% w/w to 25% w/w of a second filler, optionally wherein the second filler is lactose anhydrous or mannitol; d) 2% w/w to 10% w/w of a binder; optionally wherein the binder is hydroxypropyl cellulose; e) 1% w/w to 10% w/w of a disintegrant, optionally wherein the disintegrant is croscarmellose sodium or crospovidone; f) 0.3% w/w to 2% w/w of a surfactant, optionally wherein the surfactant is sodium lauryl sulfate; g) 0.3% w/w to 2% w/w of a lubricant, optionally wherein the lubrican

Assignees

• Kura Oncology Inc

Inventors

• Tao Jing
• Bakale Roger Paul
• Bowe Craig Michael
• Sengupta Dipanjan
• Andres Patricia
• Deng Chaoyi

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• A61K9/4866

  Organic macromolecular compounds · CPC title

• A61K9/4858

  Organic compounds · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title