Crystalline form of a SHP2 inhibitor
This Invention relates to a hemihydrate crystalline form of (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine free base (Form 1). The invention also relates to pharmaceutical compositions comprising this crystalline form, and to methods of using the crystalline form and such compositions for the treatment of abnormal cell growth, such as cancer, in a mammal.
1 . A hemihydrate crystalline form of(S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine free base characterized by a PXRD pattern comprising characterizing peaks at 2θ values of 10.9, 14.0, 15.4, and 16.0±0.2° 2θ.
2 . The hemihydrate crystalline form of claim 1 , further characterized by a 13 C ssNMR spectrum comprising resonance (ppm) values of 44.4, 47.7, 149.2, and 36.6=0.2 ppm.
3 . The hemihydrate crystalline form of claim 1 , further characterized by a FT-Raman spectrum comprising wavenumber (cm −1 ) values of 607, 1462, 1051, and 1573±0.2 cm −1 .
4 . The hemihydrate crystalline form of claim 1 , wherein the PXRD pattern further comprises a peak at the 2θ value of: 25.1=0.2° 2θ.
5 . The hemihydrate crystalline form of claim 1 , wherein the PXRD pattern further comprises a peak at the 2θ value of: 20.5±0.2° 2θ.
6 . The hemihydrate crystalline form of claim 1 , wherein the PXRD pattern further comprises a peak at the 2θ value of: 29.5±0.2° 2θ.
7 . The hemihydrate crystalline form of claim 2 , wherein the 13 C ssNMR spectrum further comprises a resonance (ppm) value of 26.9=0.2 ppm.
8 . The hemihydrate crystalline form of claim 1 , comprising less than 3% by weight of any other physical forms of(S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine.
9 . A pharmaceutical composition, comprising:
the hemihydrate crystalline form of claim 1 ; and
at least one pharmaceutically acceptable excipient.
10 . A method of treating cancer in subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of the hemihydrate crystalline form of claim 1 ,
wherein the subject is a human having cancer or diagnosed with cancer, and
wherein the cancer is non-small cell lung cancer or colorectal cancer.
11 . The method, of claim 10 , wherein the cancer is selected from the group consisting of ALK-positive non-small cell lung cancer, ROS1-positive non-small cell lung cancer, or B-type Raf proto-oncogene V600E mutation colorectal cancer.
12 . The method of claim 10 , further comprising:
administering one or more additional pharmaceutical compounds in combination with the hemihydrate crystalline form of claim 1 .
13 . The method of claim 12 , wherein the additional pharmaceutical compound is selected from the group consisting of lorlatinib, binimetinib, cetuximab, and encorafenib.
14 . The hemihydrate crystalline form of claim 2 , further characterized by a FT-Raman spectrum comprising wavenumber (cm −1 ) values of 607, 1462, 1051, and 1573±0.2 cm −1 .