JPWO2020152629A5 - - Google Patents

Claims (21)

Formula (I), in the form of modification F :

crystalline form of the succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide. X-ray with peaks at 4.9°+/-0.2°, 11.9°+/-0.2° and 12.6°+/-0.2° (CuKα λ=1.5406 Å) 2. The crystalline form of claim 1 , in the form of said modification F, characterized by a powder diffraction pattern. 4.9°+/-0.2°, 11.9°+/-0.2°, 12.6°+/-0.2° and 22.8°+/-0 at a temperature of about 22°C 2. The form of Modification F characterized by an X-ray powder diffraction pattern comprising four or more 2-theta values (CuKα λ=1.5406 Å) selected from the group consisting of .2°. crystalline form. 4.9°+/-0.2°, 11.9°+/-0.2°, 12.6°+/-0.2°, 22.8°+/-0 at a temperature of about 22°C .2° and 26.6°+/-0.2°, characterized by an X-ray powder diffraction pattern comprising 5 or more 2-theta values (CuKα λ=1.5406 Å) selected from the group consisting of 2. The crystalline form of claim 1 in the form F. 4.9°+/-0.2°, 11.9°+/-0.2°, 12.6°+/-0.2°, 22.8°+/-0 at a temperature of about 22°C .2°, 26.6°+/-0.2° and 29.4°+/-0.2° with 6 or more 2θ values (CuKα λ=1.5406 Å) selected from the group consisting of 2. The crystalline form of claim 1 , in the form of said modification F, characterized by an X-ray powder diffraction pattern. 2. The crystalline form of claim 1 , in the form of said modification F, which exhibits an X-ray powder diffraction pattern substantially consistent with that shown in Figure 3 below .

2. The crystalline form of claim 1 in the form of said modification F characterized by a differential scanning calorimetry thermogram with an endotherm at 206.8 (±2.5)°C. A crystalline form according to any preceding claim comprising at least 80, 85, 90, 95% or 99% by weight of said modification. A pharmaceutical composition comprising the crystalline form of any one of claims 1-8 and a pharmaceutically acceptable carrier or excipient. Claim 9 , further comprising one or more additional therapeutic agents such as aromatase inhibitors (e.g., letrozole, anastrozole, exemestane) or estrogen receptor function inhibitors (e.g., fulvestrant) or combinations thereof. The pharmaceutical composition according to . A method of treating a disease responsive to inhibition of cyclin-dependent kinase activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of modification E of any one of claims 1-8 . used in a method comprising the step of administering
A pharmaceutical composition for treating diseases responsive to inhibition of cyclin-dependent kinase activity, comprising a crystalline form according to any one of claims 1-8 . A crystalline form according to any one of claims 1 to 8 or any of claims 9 to 11 for the manufacture of a medicament for treating or preventing a condition or disease responsive to inhibition of a cyclin dependent kinase. Use of the pharmaceutical composition according to item 1. optionally said crystalline form for use in treating breast cancer selected from the group consisting of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, The pharmaceutical composition according to any one of claims 9 to 11 , which is administered in combination with an aromatase inhibitor , an estrogen receptor function inhibitor, or a combination thereof. Formula (I) in the form of modification E:

preparation of the crystalline form of the succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide of A method to:
providing a solution of about 0.1 mg/mL to about 1.0 mg/mL of ribociclib monosuccinate in an organic solvent, wherein the solution is substantially free of water; maintained at a first temperature in the range of about 50° C. to about 80° C. for
mixing Modification A with said solution to form a mixture at a first temperature; and from said mixture after maintaining said mixture at said first temperature for a second period of time to obtain Modification E from said organic solvent. A manufacturing method including a step of removing Formula (I) in the form of modification E:

preparation of the crystalline form of the succinate salt of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide of A method to:
(a) providing a solution of succinic acid in a first organic solvent at a second temperature within the range of about 70°C to about 85°C;
(b) providing a solution of ribociclib free base in a second organic solvent at a third temperature within the range of about 60° C. to about 85° C.;
(c) transferring the solution of the free base of ribociclib to a crystallization vessel;
(d) adding said solution of succinic acid to said crystallization vessel at a fourth temperature within the range of about 60° C. to about 85° C.;
(e) immediately after the addition in (d) is complete, adding seed crystals of pure modification E to obtain a suspension mixture;
(f) cooling the turbid mixture to a fifth temperature within the range of about 0° C. to about 20° C. to obtain Modification E;
(g) optionally separating modification E from said mixture and optionally rinsing said filtered solids with an organic solvent; and (h) optionally resulting from step (g). A manufacturing method comprising a step of drying E. 11.0°+/-0.2°, 13.0°+/-0.2° and 17.2°+/-0.2° (CuKα λ= 1.5406 Å). 16. The manufacturing method according to claim 14 or 15 , characterized by an X-ray powder diffraction pattern comprising a peak at . at a temperature of about 22° C., 11.0° +/- 0.2°, 13.0° +/- 0.2°, 17.2° +/- 0.2°, X-ray powder diffraction containing four or more 2θ values (CuKα λ=1.5406 Å) selected from the group consisting of 20.0°+/-0.2° and 23.0°+/-0.2° 16. Manufacturing method according to claim 14 or 15 , characterized by a pattern. The morphology of said modification E is 8.8°+/-0.2°, 11.0°+/-0.2°, 13.0°+/-0.2°, 13° at a temperature of about 22°C. .7°+/-0.2°, 15.7°+/-0.2°, 17.2°+/-0.2°, 18.7°+/-0.2°, 20.0° selected from the group consisting of °+/-0.2°, 21.1°+/-0.2°, 23.0°+/-0.2° and 24.9°+/-0.2° 16. A process according to claim 14 or 15 , characterized by an X-ray powder diffraction pattern comprising 5 or more 2[theta] values (CuK[alpha][lambda] = 1.5406 A). The morphology of said modification E is 7.9°+/-0.2°, 8.8°+/-0.2°, 11.0°+/-0.2°, 12° at a temperature of about 22°C. .4°+/-0.2°, 13.0°+/-0.2°, 13.7°+/-0.2°, 15.7°+/-0.2°, 17.2° °+/-0.2°, 18.7°+/-0.2°, 20.0°+/-0.2°, 21.1°+/-0.2°, 23.0°+ characterized by an X-ray powder diffraction pattern comprising 6 or more 2-theta values (CuKα λ=1.5406 Å) selected from the group consisting of /−0.2° and 24.9°+/-0.2° , the manufacturing method according to claim 14 or 15 . 16. A process according to claim 14 or 15 , wherein the morphology of Modification E exhibits an X-ray powder diffraction pattern substantially consistent with that shown in Figure 2 below .

16. A process according to claim 14 or 15 , wherein the form of modification E is characterized by a differential scanning calorimetry thermogram with an endotherm at 210 (±2.5)°C.