Polymorph of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-D]pyrimidin-7-yl)cyclopentane-1,2-diol
This invention relates to crystalline free base forms of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol, and to compositions and therapeutic uses thereof.
1 . Crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol.
2 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 1 characterized by a PXRD pattern measured using Cu K-alpha radiation comprising peaks at about 5.6, 13.1 and 19.6 degrees 2-theta (+/−0.2 degrees 2-theta).
3 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 2 characterized by a PXRD pattern measured using Cu K-alpha radiation comprising peaks at about 5.6, 13.1, 15.3 and 19.6 degrees 2-theta (+/−0.2 degrees 2-theta).
4 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 3 characterized by a PXRD pattern measured using Cu K-alpha radiation comprising peaks at about 5.6, 10.5, 13.1, 15.3 and 19.6 degrees 2-theta (+/−0.2 degrees 2-theta).
5 .- 6 . (canceled)
7 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 1 characterized by a 13C-ssNMR spectrum comprising peaks at about 56.0, 72.5 and 101.6 ppm±0.2 ppm.
8 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 7 characterized by a 13C-ssNMR spectrum comprising peaks at about 56.0, 72.5, 76.3 and 101.6 ppm±0.2 ppm.
9 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 8 characterized by a 13C-ssNMR spectrum comprising peaks at about 37.1, 56.0, 72.5, 76.3 and 101.6 ppm±0.2 ppm.
10 .- 11 . (canceled)
12 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 1 characterized by a FT Raman spectrum comprising peaks at about 576, 1258 and 1561 cm-1±2 cm-1.
13 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 12 characterized by a FT Raman spectrum comprising peaks at about 576, 1258, 1561 and 3129 cm-1±2 cm-1.
14 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 13 characterized by a FT Raman spectrum comprising peaks at about 576, 1023, 1258, 1561 and 3129 cm-1±2 cm-1.
15 .- 16 . (canceled)
17 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 1 characterized by a PXRD pattern measured using Cu K-alpha radiation comprising peaks at about 19.6 and 13.1 degrees 2-theta (+/−0.2 degrees 2-theta), and by a 13C-ssNMR spectrum comprising peaks at about 56.0 and 72.5 ppm±0.2 ppm.
18 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 1 characterized by a PXRD pattern measured using Cu K-alpha radiation comprising peaks at about 19.6 and 13.1 degrees 2-theta (+/−0.2 degrees 2-theta), and by a FT Raman spectrum comprising characterizing peaks at about 1561 and 576 cm-1±2 cm-1.
19 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 1 characterized by a 13C-ssNMR spectrum comprising peaks at about 56.0 and 72.5 ppm±0.2 ppm and by a FT Raman spectrum comprising characterizing peaks at about 1561 and 576 cm-1±2 cm-1.
20 . The crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol of claim 1 characterized by a PXRD pattern measured using Cu K-alpha radiation comprising a peak at about 19.6 degrees 2-theta (+/−0.2 degrees 2-theta), by a 13C-ssNMR spectrum comprising a peak at about 72.5 ppm±0.2 ppm, and by a FT Raman spectrum comprising a peak at about 1561 cm-1±2 cm-1.
21 . A pharmaceutical composition comprising crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as claimed in claim 1 and a pharmaceutically acceptable carrier or excipient.
22 .- 25 . (canceled)
26 . A method of treatment of abnormal cell growth in a mammal comprising administering to the mammal a therapeutically effective amount of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as claimed in claim 1 .
27 . (canceled)
28 . A combination of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as claimed in claim 1 , with another anti-cancer agent.