Crystalline forms of N[4[4-(4-Morpholinyl)-7H-Pyrrolo[2-3-D]Pyrimidin-6-yl]Phenyl]-4-[[3(R)-[(1-Oxo-2-Protein-1-yl)Amino]-1-Piperidinyl]Methyl]2-Pyridinecarboxamide]
Described herein is N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) (Formula I), including crystalline forms, solvates, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions or pharmaceutical formulations that include the compound, as well as methods of using the compound, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, diabetes, and inflammatory diseases or conditions.
1. A crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2° 2θ, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.
2. The crystalline Form K according to claim 1 , wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern comprising one additional characteristic peak at an angle (° 2θ) of 24.254±0.2° 2θ.
3. The crystalline Form K according to claim 1 , wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9 .
4. The crystalline Form K according to claim 1 , wherein the crystalline Form K is further characterized by an infrared (IR) spectrum comprising one, two, three, four, five, six, seven, or eight characteristic peaks selected from the group consisting of 3676 cm −1 , 3332 cm −1 , 2970 cm −1 , 1581 cm −1 , 1515 cm −1 , 1340 cm −1 , 1279 cm −1 , and 1110 cm −1 .
5. The crystalline Form K according to claim 1 , wherein the crystalline Form K is further characterized by an infrared (IR) spectrum as shown in FIG. 5 .
6. The crystalline Form K according to claim 1 , wherein the crystalline Form K is further characterized by a melting temperature in the range of 275° C. to 277° C.
7. The crystalline Form K according to claim 1 , wherein the crystalline Form K is further characterized by a thermogravimetric analysis (TGA) thermogram as shown in FIG. 6 .
8. The crystalline Form K according to claim 1 , wherein the crystalline Form K is further characterized by a differential scanning calorimetry (DSC) thermogram with an endotherm having an onset at 275.4° C. and a peak at 277° C.
9. The crystalline Form K according to claim 1 , wherein the crystalline Form K is further characterized by a differential scanning calorimetry (DSC) thermogram as shown in FIG. 7 .
10. A pharmaceutical formulation comprising one or more diluents and crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2° 2θ, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.
11. The pharmaceutical formulation according to claim 10 , wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9 .
12. The pharmaceutical formulation according to claim 10 , wherein the pharmaceutical formulation further comprises at least one of (a), (b), (c), (d), and (e):
(a) 5 wt % to 70 wt % of Compound A;
(b) 25 wt % to 80 wt % of one or more diluents;
(c) 1 wt % to 10 wt % of one or more disintegrating agents;
(d) 0.2 wt % to 3 wt % of one or more glidants; and
(e) 0.2 wt % to 1.0 wt % of one or more lubricants.
13. The pharmaceutical formulation according to claim 12 , wherein the pharmaceutical formulation further comprises 10 mg to 500 mg of Compound A.
14. The pharmaceutical formulation according to claim 12 , wherein at least one diluent is selected from the group consisting of calcium phosphate, calcium sulfate, a cyclodextrin, a dextrate, dextrose, lactose, maltodextrin, mannitol, microcellulose, microcrystalline cellulose, sorbitol, sucrose, xylitol, a starch, modified starches, and talc.
15. The pharmaceutical formulation according to claim 14 , wherein the starch is a modified starch.
16. The pharmaceutical formulation according to claim 12 , wherein at least one diluent is lactose or a pregelatinized maize starch.
17. The pharmaceutical formulation according to claim 12 , wherein at least one disintegrating agent is selected from the group consisting of croscarmellose, croscarmellose sodium, cross-linked carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, methyl cellulose, methylcrystalline cellulose, a cross-linked starch, a natural starch, a pregelatinized starch, and a sodium starch.
18. The pharmaceutical formulation according to claim 17 , wherein the croscarmellose is cross-linked croscarmellose.
19. The pharmaceutical formulation according to claim 17 , wherein the cross-linked starch is a cross-linked polymer or sodium starch glycolate.
20. The pharmaceutical formulation according to claim 19 , wherein the cross-linked polymer is selected from the group consisting of a clay, crospovidone, cross-linked polyvinylpyrrolidone, a gum, and sodium alginate.
21. The pharmaceutical formulation according to claim 12 , wherein at least one glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, fumed silica, magnesium stearate, a starch, and talc.
22. The pharmaceutical formulation according to claim 12 , wherein at least one lubricant is selected from the group consisting of calcium hydroxide, corn starch, magnesium stearate, sodium stearyl fumarate, sodium stearate, stearic acid, talc, a wax, and zinc stearate.
23. The pharmaceutical formulation according to claim 12 , wherein the pharmaceutical formulation further comprises one or more binders.
24. The pharmaceutical formulation according to claim 23 , wherein at least one binder is hydroxypropyl cellulose.
25. The pharmaceutical formulation according to claim 12 , wherein the pharmaceutical formulation further comprises one or more surfactants.
26. The pharmaceutical formulation according to claim 25 , wherein at least one surfactant is cremophore or Poloxamer 407.
27. The pharmaceutical formulation according to claim 10 , wherein the pharmaceutical formulation is formulated for a route of administration selected from the group consisting of buccal administration, nasal administration, oral administration, parenteral administration, rectal administration, and topical administration.
28. A method for treating diabetes in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2° 28, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.
29. The method according to claim 28 , wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9 .
30. A method for treating diabetes in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising one or more diluents and crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2°2θ, 12.756°±0.2°2θ, and 19.071°±0.2°2θ.
31. The method according to claim 30 , wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9 .
32. A method for treating cancer in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2° 2θ, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.
33. The method according to claim 32 , wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9 .
34. A method for treating cancer in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising one or more diluents and crystalline Form K of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of formula (I):
wherein the crystalline Form K is characterized by an X-ray powder diffraction pattern comprising at least two characteristic peaks at angles (° 2θ) selected from the group consisting of 10.483°±0.2°2θ, 12.756°±0.2° 2θ, and 19.071°±0.2° 2θ.
35. The method according to claim 34 , wherein the crystalline Form K is further characterized by an X-ray powder diffraction pattern as shown in FIG. 9 .