Solid Forms of BCL-2 Inhibitors, Method of Preparation, and Use Thereof
The present invention relates to a solid form, particularly a crystalline forms of Bcl-2 inhibitor 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, pharmaceutical compositions comprising the solid form, processes for preparing the solid form, and methods of use therefore.
1 - 2 . (canceled)
3 . A crystalline form of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1) is an EtOAc solvate, containing about 1 mol of EtOAc per mol, said form is designated as Form A.
4 - 16 . (canceled)
17 . A crystalline form of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1) is an anhydrate, said form is designated as Form B.
18 - 27 . (canceled)
28 . An anhydrous crystalline form of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having °2θ angle values at 11.3±0.1° and 24.3±0.1°.
29 . (canceled)
30 . The crystalline form according to claim 28 , wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having °2θ angle values at 11.3±0.1°, 15.6±0.1° and 24.3±0.1°.
31 . The crystalline form according to claim 28 , wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having ° 2θ angle values at 11.3±0.1°, 15.6±0.1°, 21.2±0.1° and 24.3±0.1.
32 . The crystalline form according to claim 28 , wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having ° 2θ angle values at 11.3±0.1°, 13.5±0.1°, 15.6±0.1°, 21.2±0.1° and 24.3±0.1°.
33 . The crystalline form according to claim 28 , wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having ° 2θ angle values at 11.3±0.1°, 13.5±0.1°, 15.6±0.1°, 17.0±0.1°, 21.2±0.1° and 24.3±0.1°.
34 . The crystalline form according to claim 28 , wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having ° 2θ angle values at 11.3±0.1°, 13.5±0.1°, 15.6±0.1°, 17.0±0.1°, 19.5±0.1°, 21.2±0.1° and 24.3±0.1°.
35 . The crystalline form according to claim 28 , wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having ° 2θ angle values at 7.0±0.1°, 11.3±0.1°, 13.5±0.1°, 15.6±0.1°, 17.0±0.1°, 19.5±0.1°, 21.2±0.1° and 24.3±0.1°.
36 . The crystalline form according to claim 28 , wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having ° 2θ angle values at 7.0±0.1°, 11.3±0.1°, 13.5±0.1°, 15.6±0.1°, 17.0±0.1°, 19.5±0.1°, 20.0±0.1°, 21.2±0.1° and 24.3±0.1°.
37 . The crystalline form according to claim 28 , wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks having ° 2θ angle values at 7.0±0.1°, 9.4±0.1, 11.3±0.1°, 13.5±0.1°, 15.6±0.1°, 17.0±0.1°, 19.5±0.1°, 20.0±0.1°, 21.2±0.1° and 24.3±0.1°.
38 - 39 . (canceled)
40 . The crystalline form according to claim 28 , having an X-ray powder diffraction pattern substantially as shown in FIG. 21 A .
41 . The crystalline form according to claim 28 , which has a differential scanning calorimetry (DSC) thermogram comprising one endotherm peak at about 171° C.
42 . (canceled)
43 . An amorphous form of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1).
44 - 45 . (canceled)
46 . A pharmaceutical composition comprising the anhydrous crystalline form of claim 28 and one or more pharmaceutically acceptable excipients.
47 . (canceled)
48 . A method of treating a disease related to Bcl-2 proteins inhibition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the anhydrous crystalline form of claim 28 .
49 - 52 . (canceled)
53 . The crystalline form according to claim 3 , obtained by the process comprising any one of the following procedures:
a) dissolving Compound 1 in DCM, removing DCM, charging with EA, to obtain Form A;
b) dissolving Compound 1 in DCM, concentrating, charging with EA, exchanging DCM with EA, MeOH and EA separately, to obtain Form A;
c) dissolving Compound 1 in EA, heating and cooling, to obtain Form A; or
d) dissolving Compound 1 in THF/EtOAc (1:2, v/v) solvent mixture, evaporating, to obtain Form A.
54 . The crystalline form according to any one claim 17 , obtained by the process comprising any one of the following procedures:
a) dissolving Compound 1 in acetone, evaporating the solvent, to obtain Form B;
b) heating Form A, Form C, Form O to about 160° C. and cooling, to obtain Form B;
c) heating Form A stepwise isothermally to about 100° C., to obtain Form B;
d) heating Form D or Form J to about 130° C. and being isothermal, to obtain Form B; or
c) adding Form K into heptane, heating to about 100° C. and cooling, to obtain Form B.
55 . The anhydrous crystalline form according to claim 28 , obtained by the process comprising any one of the following procedures:
a) dissolving Compound 1 in DCM, adding n-heptane in batches and stirring, to obtain the anhydrous crystalline form; or
b) dissolving Compound 1 in the mixture of DCM/n-heptane (1:1, v/v) and stirring, to obtain the anhydrous crystalline form.
56 . (canceled)
57 . The amorphous form according to claim 43 , obtained by the process comprising any one of the following procedures:
a) dissolving Compound 1 in DCM, drying, to obtain the amorphous form; or
b) dissolving Compound 1 in a mixture of solvent containing DCM, drying, to obtain the amorphous form.
58 . (canceled)
59 . A process for preparing a pharmaceutical composition comprising Compound 1, the process comprising mixing the solid form of Compound 1 according to claim 28 with at least one pharmaceutically acceptable excipient.