(4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p- tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone 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 method of inhibiting CCR2 activity in a patient suffering from pain, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula 1:
2. The method of claim 1 , wherein the pain is inflammatory pain.
3. The method of claim 1 , wherein the pain is chronic pain.
4. The method of claim 1 , wherein the pain is due to osteoarthritis.
5. The method of claim 1 , wherein the compound of Formula 1 is in crystalline form.
6. The method of claim 2 , wherein the compound of Formula 1 is in crystalline form.
7. The method of claim 3 , wherein the compound of Formula 1 is in crystalline form.
8. The method of claim 4 , wherein the compound of Formula 1 is in crystalline form.
9. The method of claim 5 , wherein the 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°.
10. The method of claim 6 , wherein the 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°.
11. The method of claim 7 , wherein the 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°.
12. The method of claim 8 , wherein the 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°.
13. The method of claim 5 , wherein the 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.
14. The method of claim 6 , wherein the 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.
15. The method of claim 7 , wherein the 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.
16. The method of claim 8 wherein the 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.
17. The method of claim 5 , wherein the 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.
18. The method of claim 6 , wherein the 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.
19. The method of claim 7 , wherein the 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.
20. The method of claim 8 , wherein the 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.