POLYMORPH OF SYK INHIBITORS
Polymorphs of a bis-mesylate salt of a compound of Formula (I): or a hydrate thereof, are provided. The bis-mesylate salt may also be depicted as a compound of Formula (IA): Provided herein are also compositions thereof, methods for their preparation and methods for such polymorphs.
1 . A bis-mesylate salt of a compound of Formula I:
or a hydrate thereof.
2 . The bis-mesylate salt of claim 1 , wherein the bis-mesylate salt, or a hydrate thereof, is:
a compound of Formula IB:
or
a compound of Formula IC:
or
a compound of Formula ID:
wherein y is at least 0.5.
3 . The bis-mesylate salt of claim 1 , wherein the bis-mesylate salt, or a hydrate thereof, is crystalline.
4 . The bis-mesylate salt of claim 1 , wherein the bis-mesylate salt is a monohydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 13.8, 16.9, 22.9, and 26.1.
5 . The bis-mesylate salt of claim 4 , wherein the X-ray diffraction pattern further comprises 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.7, 12.9, 17.7, and 18.1.
6 . The bis-mesylate salt of claim 1 , wherein the bis-mesylate salt is a monohydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.7, 12.9, 17.7, and 18.1.
7 . The bis-mesylate salt of claim 6 , wherein the X-ray diffraction pattern further comprises 2θ-reflections, plus or minus 0.2 degrees 2θ, at 13.8, 16.9, 22.9, and 26.1.
8 . The bis-mesylate salt of claim 1 , wherein the bis-mesylate salt is a hydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 4.9, 9.8, and 26.7.
9 . The bis-mesylate salt of claim 8 , wherein the X-ray diffraction pattern further comprises 2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.0 and 18.0.
10 . The bis-mesylate salt of claim 1 , wherein the bis-mesylate salt is a hydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.0 and 18.0.
11 . The bis-mesylate salt of claim 10 , wherein the X-ray diffraction pattern further comprises 2θ-reflections, plus or minus 0.2 degrees 2θ, at 4.9, 9.8, and 26.7.
12 . The bis-mesylate salt of claim 1 , wherein the bis-mesylate salt is a monohydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern substantially as shown in FIG. 1A or 1B .
13 . The bis-mesylate salt of claim 1 , wherein the bis-mesylate salt is a hydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern substantially as shown in FIG. 2A or 2B .
14 . A polymorph of a bis-mesylate salt of a compound of Formula I:
or a hydrate thereof, wherein the polymorph is bioequivalent to the bis-mesylate salt of claim 2 , or a hydrate thereof.
15 . A method of producing polymorph Form 3 of monohydrate, bis-mesylate salt of compound of Formula I:
comprising:
adding an amount of polymorph Form 3 seeds and a solvent to polymorph Form 7 of a hydrate, bis-mesylate salt of a compound of Formula I to form a mixture; and
producing polymorph Form 3 in the mixture,
wherein the polymorph Form 3 has an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, selected from the group consisting of A: 13.8, 16.9, 22.9, and 26.1; B: 7.7, 12.9, 17.7 and 18.1; and C: 7.7, 12.9, 13.8, 16.9, 17.7, 18.1, 22.9, and 26.1; and
wherein the polymorph Form 7 has an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, selected from the group consist of A: 4.9, 9.8, and 26.7; B: 15.0 and 18.0; and C: 4.9, 9.8, 15.0, 18.0, and 26.7.
16 . The method of claim 15 , further comprising isolating the polymorph Form 3.
17 . The method of claim 16 , wherein the solvent comprises acetone.
18 . The method of claim 17 , wherein the solvent further comprises water.
19 . The method of claim 18 , wherein the ratio of water to acetone is about 1:15 to about 1:40.
20 . The method of claim 18 , wherein the ratio of water to acetone is about 1:18 to about 1:22.
21 . The method of claim 15 , further comprising:
agitating the mixture;
heating the agitated mixture; and
cooling the heated mixture.
22 . A method of producing polymorph Form 3 of a monohydrate, bis-mesylate salt of a compound of Formula I:
comprising:
a) adding a solvent to a compound of Formula I to form a mixture;
b) adding an amount of methanesulfonic acid to the mixture of step (a);
c) heating the mixture of step (b);
d) adding an amount of polymorph Form 3 seeds to the mixture of step (c); and
e) cooling the mixture of step (d) to produce polymorph Form 3;
wherein an X-ray diffraction pattern of the polymorph Form 3 comprises 2θ-reflections, plus or minus 0.2 degrees 2θ, selected from the group consisting of A: 13.8, 16.9, 22.9, and 26.1; B: 7.7, 12.9, 17.1, and 18.1; and C: 7.7, 12.9, 13.8, 16.9, 17.7, 18.1, 22.9, and 26.1.
23 . The method of claim 22 , further comprising isolating the polymorph Form 3.
24 . The method of claim 22 , wherein the amount of methanesulfonic acid added is between 2.0 and 2.4 molar equivalents with respect to 1 molar equivalent of the compound of Formula I.
25 . Polymorph Form 3 of a monohydrate bis-mesylate salt of a compound of Formula I
prepared by the method of claim 15 .
26 . A pharmaceutical composition comprising a therapeutically effective amount of
a bis-mesylate salt of a compound of formula I,
or a hydrate thereof; and
a pharmaceutical carrier, excipient, adjuvant, or vehicle.
27 . (canceled)
28 . A method of treating a condition in a human in need thereof, comprising administering to the human therapeutically effective amount of a bis-mesylate salt of a compound of formula I, or a hydrate thereof, according to claim 1 ; wherein the condition is selected from the group consisting of cancer and autoimmune disease.
29 . The method of claim 28 , wherein the condition is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, myelodysplastic syndrome, myeloproliferative disease, chronic myeloid leukemia, multiple myeloma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, Waldestrom's macroglobulinemia, T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma.
30 . The method of claim 29 , wherein the condition is non-Hodgkin's lymphoma.
31 . The method of claim 30 , wherein the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma.
32 . The method of claim 31 , wherein the indolent non-Hodgkin's lymphoma is refractory indolent non-Hodgkin's lymphoma.
33 . The method of claim 31 , wherein the indolent non-Hodgkin's lymphoma is non-follicular lymphoma indolent non-Hodgkin's lymphoma.
34 . The method of claim 28 , wherein the condition is selected from the group consisting of asthma, rheumatoid arthritis, multiple sclerosis, and lupus.
35 . The pharmaceutical composition of claim 26 wherein the bis-mesylate salt, or a hydrate thereof, is:
a compound of Formula IB:
or
a compound of Formula IC:
or
a compound of Formula ID:
wherein y is at least 0.5.
36 . The pharmaceutical composition of claim 26 wherein the bis-mesylate salt is a monohydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 13.8, 16.9, 22.9, and 26.1.
37 . The pharmaceutical composition of claim 36 wherein the X-ray diffraction pattern further comprises 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.7, 12.9, 17.7, and 18.1.
38 . The pharmaceutical composition of claim 26 wherein the bis-mesylate salt is a monohydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 7.7, 12.9, 17.7, and 18.1.
39 . The pharmaceutical composition of claim 38 wherein the X-ray diffraction pattern further comprises 2θ-reflections, plus or minus 0.2 degrees 2θ, at 13.8, 16.9, 22.9, and 26.1.
40 . The pharmaceutical composition of claim 26 wherein the bis-mesylate salt is a hydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 4.9, 9.8, and 26.7.
41 . The pharmaceutical composition of claim 40 wherein the X-ray diffraction pattern further comprises 2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.0 and 18.0.
42 . The pharmaceutical composition of claim 26 wherein the bis-mesylate salt is a hydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 15.0 and 18.0.
43 . The pharmaceutical composition of claim 42 wherein the X-ray diffraction pattern further comprises 2θ-reflections, plus or minus-0.2 degrees 2θ, at 4.9, 9.8, and 26.7.
44 . The pharmaceutical composition of claim 26 wherein the bis-mesylate salt is a monohydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern substantially as shown in FIG. 1A or 1B .
45 . The pharmaceutical composition of claim 26 wherein the bis-mesylate salt is a hydrate, bis-mesylate salt polymorph characterized by an X-ray diffraction pattern substantially as shown in FIG. 2A or 2B .