SYNTHESIS OF NIROGACESTAT
The present disclosures are directed to processes for synthesizing(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide (“nirogacestat”).
1 - 87 . (canceled)
88 . A composition comprising: 98.0% to 99.9% of a Compound 1:
or a pharmaceutically acceptable salt thereof; and one or more of the following:
(1) 0.7% to 0.01% of a compound of Formula II:
wherein:
R 1 is selected from the group consisting of hydrogen, fluoro, or chloro;
R 2 is selected from the group consisting of hydrogen or chloro;
R 3 is selected from the group consisting of fluoro, or chloro; and
R 4 is selected from the group consisting of −OH and −N(H)CH 2 C(CH 3 ) 3 ,
or a pharmaceutically acceptable salt thereof;
(2) 0.05% to 0.005% of imidazole, or a pharmaceutically acceptable salt thereof; or
(3) 0.7% to 0.01% of a compound of Formula II, or a pharmaceutically acceptable salt thereof, and 0.05% to 0.005% of imidazole, or a pharmaceutically acceptable salt thereof,
wherein the compound of Formula II is not Compound 1, and the percentages of Compound 1, the compound of Formula II, and/or imidazole are determined by high performance liquid chromatography.
89 . The composition of claim 88 , wherein the compound of Formula II is a hydrobromide salt.
90 . The composition of claim 88 , wherein the compound of Formula II is a compound of Formula II-A:
or a pharmaceutically acceptable salt thereof.
91 . The composition of claim 90 , wherein the compound of Formula II-A is a hydrobromide salt.
92 . The composition of claim 88 , wherein the compound of Formula II is a compound of Formula II-B:
or a pharmaceutically acceptable salt thereof.
93 . The composition of claim 92 , wherein the compound of Formula II-B is a hydrobromide salt.
94 . The composition of claim 88 , wherein the compound of Formula II is a compound of Formula II-C:
or a pharmaceutically acceptable salt thereof.
95 . The composition of claim 94 , wherein the compound of Formula II-C is a hydrobromide salt.
96 . The composition of claim 88 , wherein the compound of Formula II is a compound of Formula II-D:
or a pharmaceutically acceptable salt thereof.
97 . The composition of claim 96 , wherein the compound of Formula II-D is a hydrobromide salt.
98 . The composition of claim 88 , wherein R 4 is —N(H)CH 2 C(CH 3 ) 3 .
99 . The composition of claim 88 , wherein R 4 is —OH.
100 . The composition of claim 88 , wherein R 1 is fluoro; R 2 is hydrogen; and R 3 is chloro.
101 . The composition of claim 88 , wherein R 1 is chloro; R 2 is hydrogen; and R 3 is fluoro.
102 . The composition of claim 88 , wherein R 1 is hydrogen; R 2 is chloro; and R 3 is fluoro.
103 . The composition of claim 88 , wherein R 1 is fluoro, R 2 is hydrogen, and R 3 is fluoro.
104 - 139 . (canceled)
140 . A method of treating tumors or cancer in a subject in need thereof comprising administering to the subject a composition of claim 88 .
141 . The method of claim 140 , wherein the tumors are desmoid tumors.
142 . The method of claim 140 , wherein the cancer is multiple myeloma, a cancer having a mutation in a Notch pathway gene, adenoid cystic carcinoma, or T-cell acute lymphoblastic leukemia.