US2021269446A1PendingUtilityA1

Forms of a pi3k delta selective inhibitor for use in pharmaceutical formulations

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Assignee: RHIZEN PHARMACEUTICALS SAPriority: May 27, 2014Filed: Dec 23, 2020Published: Sep 2, 2021
Est. expiryMay 27, 2034(~7.9 yrs left)· nominal 20-yr term from priority
Inventors:Swaroop K. Vakkalanka
Y02A50/30C07C 309/30C07B 2200/13A61P 29/00A61K 45/06A61K 31/519A61K 31/352A61P 35/00C07D 487/04
69
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Claims

Abstract

The present invention relates to solid state forms of a p-toluenesulfonic acid salt (PTSA) of the selective PI3K delta inhibitor (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (TGR-1202). The present invention also relates to methods of preparing the same, pharmaceutical compositions containing them, and methods of treating a PI3K kinase mediated disease or disorder, such as cancer, by administering the same.

Claims

exact text as granted — not AI-modified
1 - 43 . (canceled) 
     
     
         44 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt has a d(0.9) of from about 5 to about 50 μm. 
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein the solubilizer is hydroxypropyl betadex. 
     
     
         46 . The pharmaceutical composition of  claim 44 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5. 
     
     
         47 . The pharmaceutical composition of  claim 45 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5. 
     
     
         48 . The pharmaceutical composition of  claim 44 , wherein the tablet further comprises one or more excipients selected from suspending agents, dispersing agents, disintegrants, lubricants, and any combination of any of the foregoing. 
     
     
         49 . The pharmaceutical composition of  claim 44 , wherein the salt has a d(0.9) of from about 5 to about 25 μm. 
     
     
         50 . The pharmaceutical composition of  claim 44 , wherein the salt has a d(0.9) of from about 5 to about 15 μm. 
     
     
         51 . The pharmaceutical composition of  claim 44 , wherein the salt has a d(0.5) of from about 1 to about 10 μm. 
     
     
         52 . The pharmaceutical composition of  claim 44 , wherein the salt has a d(0.5) of from about 2 to about 5 μm. 
     
     
         53 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt exhibits a XRPD pattern having one or more peaks selected from 5.0, 10.1, 22.1, and 24.5±0.2° 2Θ. 
     
     
         54 . The pharmaceutical composition of  claim 44 , wherein the ratio of p-toluenesulfonic acid to (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one is about 1:1. 
     
     
         55 . A pharmaceutical composition comprising (i) 200 mg of a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt has a d(0.9) of from about 5 to about 50 μm. 
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein the solubilizer is hydroxypropyl betadex. 
     
     
         57 . The pharmaceutical composition of  claim 55 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5. 
     
     
         58 . The pharmaceutical composition of  claim 56 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5. 
     
     
         59 . The pharmaceutical composition of  claim 55 , wherein the tablet further comprises one or more excipients selected from suspending agents, dispersing agents, disintegrants, lubricants, and any combination of any of the foregoing. 
     
     
         60 . The pharmaceutical composition of  claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.9) of from about 5 to about 25 μm. 
     
     
         61 . The pharmaceutical composition of  claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.9) of from about 5 to about 15 μm. 
     
     
         62 . The pharmaceutical composition of  claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.5) of from about 1 to about 10 μm. 
     
     
         63 . The pharmaceutical composition of  claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.5) of from about 2 to about 5 μm. 
     
     
         64 . The pharmaceutical composition of  claim 55 , wherein the p-toluenesulfonic acid salt exhibits a XRPD pattern having one or more peaks selected from 5.0, 10.1, 22.1, and 24.5±0.2°2Θ. 
     
     
         65 . The pharmaceutical composition of  claim 55 , wherein the ratio of p-toluenesulfonic acid to (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one is about 1:1. 
     
     
         66 . A method of treating indolent non-Hodgkin's lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of  claim 44 . 
     
     
         67 . A method of treating B-cell lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of  claim 44 . 
     
     
         68 . A method of treating follicular lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of  claim 44 . 
     
     
         69 . A method of treating indolent non-Hodgkin's lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of  claim 55 . 
     
     
         70 . A method of treating B-cell lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of  claim 55 . 
     
     
         71 . A method of treating follicular lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of  claim 55 . 
     
     
         72 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer.

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