(4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-y1)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-citrate
The invention provides a salt of a tetrahydropyranylmethylaminopyrimidine amide, such as the citrate salt of (4-((3R,4R)-3-methoxytetrahydropyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone, pharmaceutical compositions containing the same, processes for preparing the same, and methods of medical treatment using the same.
1. A pharmaceutical composition comprising:
(a) a citrate salt of compound I:
having the formula
and
(b) one or more inert carriers and/or diluents;
wherein the pharmaceutical composition is formulated for oral administration.
2. The pharmaceutical composition according to claim 1 , wherein the salt is in crystalline form.
3. The pharmaceutical composition according to claim 2 , wherein the salt in crystalline form is characterized by a X-ray powder diffraction pattern comprising peaks at the following 2-theta values measured using monochromatic CuKα1 radiation of λ=1.54056 Å, 40 kV, 40 mA: 19.1° and 22.4°.
4. The pharmaceutical composition according to claim 3 , wherein the salt in crystalline form is characterized in that the X-ray powder diffraction pattern further comprises a peak at 12.2°.
5. The pharmaceutical composition according to claim 4 , wherein the salt in crystalline form is characterized in that the X-ray powder diffraction pattern further comprises a peak at 13.7°.
6. The pharmaceutical composition according to claim 5 , wherein the salt in crystalline form is characterized in that the X-ray powder diffraction pattern further comprises a peak at 14.6°.
7. The pharmaceutical composition according to claim 6 , wherein the salt in crystalline form is characterized in that the X-ray powder diffraction pattern further comprises a peak at 18.7°.
8. The pharmaceutical composition according to claim 2 , wherein the salt in crystalline form exhibits a X-ray powder diffraction pattern comprising peaks at the following 2-theta values measured using monochromatic CuKα1 radiation of λ=1.54056 Å, 40 kV, 40 mA: 12.2±0.2, 13.7±0.2, 14.6±0.2, 19.1±0.2, and 22.4±0.2.
9. The pharmaceutical composition according to claim 2 , wherein the salt in crystalline form exhibits a X-ray powder diffraction pattern comprising peaks at the following 2-theta values measured using monochromatic CuKα1 radiation of λ=1.54056 Å, 40 kV, 40 mA: 12.2±0.2, 13.7±0.2, 14.6±0.2, 18.7±0.2, 19.1±0.2, 22.4±0.2, 24.6±0.2, and 26.3±0.2.
10. The pharmaceutical composition according to claim 8 , wherein the relative intensity of the peak at said diffraction angles 2-theta is at least 10%.
11. The pharmaceutical composition according to claim 9 , wherein the relative intensity of the peak at said diffraction angles 2-theta is at least 15%.
12. The pharmaceutical composition according to claim 2 , wherein the salt in crystalline form has a X-ray powder diffraction pattern substantially as shown in FIG. 2 .
13. The pharmaceutical composition according to claim 2 , wherein the salt in crystalline form is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):
2-theta [°]
d-value [Å]
Intensity I/I 0 [%]
4.36
20.24
17
12.17
7.27
41
12.51
7.07
6
13.13
6.74
7
13.66
6.48
39
14.20
6.23
14
14.60
6.06
32
15.03
5.89
5
15.25
5.81
4
15.97
5.54
11
16.51
5.37
13
17.05
5.20
13
17.54
5.05
4
17.88
4.96
5
18.65
4.75
22
19.05
4.66
100
19.68
4.51
11
20.42
4.35
6
20.84
4.26
4
21.25
4.18
3
21.90
4.06
5
22.42
3.96
92
23.19
3.83
9
23.70
3.75
16
24.34
3.65
4
24.56
3.62
23
24.89
3.57
16
25.20
3.53
7
25.36
3.51
7
25.67
3.47
6
26.26
3.39
23
26.59
3.35
12
27.51
3.24
6
27.71
3.22
6
28.01
3.18
7
28.23
3.16
5
28.57
3.12
3
29.44
3.03
12
30.15
2.96
4.
14. The pharmaceutical composition according to claim 13 , wherein the salt in crystalline form has a Raman spectrum comprising peaks at any one or all of the following Raman shifts expressed in wavenumbers in cm −1 : 1718, 1242, 731, 662, 553.
15. The pharmaceutical composition according to claim 13 , wherein the salt in crystalline form has a melting point of 212±5° C.
16. The pharmaceutical composition according to claim 13 , wherein the salt in crystalline form has a differential scanning calorimetry curve substantially the same as shown in FIG. 3 .
17. A method of treating a condition selected from pain, osteoarthritis, diabetic nephropathy, and diabetic polyneuropathy, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 1 to treat the condition.
18. The method of claim 17 , wherein the condition is pain.
19. The method of claim 18 , wherein the condition is inflammatory pain.
20. The method of claim 17 , wherein the condition is chronic pain.
21. The method of claim 17 , wherein the condition is pain due to osteoarthritis.
22. A tablet or capsule, comprising a pharmaceutical composition according to claim 1 .
23. A tablet or capsule, comprising a pharmaceutical composition according to claim 2 .
24. A tablet or capsule, comprising a pharmaceutical composition according to claim 9 .