CRYSTALS OF (2-AMINO-4,5,6,7-TETRAHYDROBENZO[b]THIEN-3-YL)(4-CHLOROPHENYL)METHANONE
The present invention provides crystal forms of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone of the formula processes for the production of such crystal forms; pharmaceutical compositions comprising such crystal forms; and methods of treating diseases or conditions modulated by the adenosine A 1 receptor, in particular neuropathic pain, in a mammal in need thereof, by employing such crystal forms, or pharmaceutical compositions comprising such.
1 . A crystal form of anhydrous (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (T-62) which crystal form (Form I) is substantially free of other polymorphic forms of T-62 and has at least one of the following properties:
(a) a melting point of about 143° C.;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (20) of about 19.6±0.2, 19.9±0.2, 20.8±0.2, 22.9±0.2 and 23.3±0.2;
(c) an infrared absorption spectrum with absorption bands at about 3330±2, 3239±2, 2943±2, 1908±2 and 927±2 cm −1 ; and
(d) a Raman spectrum with Raman shifts at about 3060±2, 2944±2, 1596±2, 1426±2 and 1391±2 cm −1 .
2 . A crystal form according to claim 1 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (20), and relative intensities (I/I 1 ) of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
11.9 ± 0.2
11
13.3 ± 0.2
13
13.9 ± 0.2
11
18.6 ± 0.2
14
19.6 ± 0.2
100
19.9 ± 0.2
40
20.8 ± 0.2
48
22.9 ± 0.2
37
23.3 ± 0.2
46
24.0 ± 0.2
22
25.7 ± 0.2
18
26.7 ± 0.2
20
27.6 ± 0.2
13
29.2 ± 0.2
23
38.2 ± 0.2
10
3 . A crystal form according to claim 1 , which crystal form has all four of the properties (a), (b), (c) and (d).
4 . A pharmaceutical composition comprising a therapeutically effective amount of a crystal form according to claim 1 and a pharmaceutically acceptable carrier.
5 . A crystal form of anhydrous (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (T-62) which crystal form (Form II) is substantially free of other polymorphic forms of T-62 and has at least one of the following properties:
(a) a melting point of about 135° C.;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (2θ) of about 16.5±0.2, 19.4±0.2, 20.3±0.2, 22.2±0.2, 23.6±0.2 and 26.2±0.2;
(c) an infrared absorption spectrum with absorption bands at about 3344±2, 3243±2, 2955±2, 2930±2, 1895±2 and 1172±2 cm −1 ; and
(d) a Raman spectrum with Raman shifts at about 3065±2, 2957±2, 1595±2, 1430±2 and 1394±2 cm −1 .
6 . A crystal form according to claim 5 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities (I/I 1 ) of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
6.7 ± 0.2
26
11.6 ± 0.2
24
13.5 ± 0.2
17
15.5 ± 0.2
10
16.5 ± 0.2
100
19.4 ± 0.2
52
20.3 ± 0.2
68
21.1 ± 0.2
24
21.6 ± 0.2
28
22.2 ± 0.2
37
22.8 ± 0.2
24
23.6 ± 0.2
40
24.6 ± 0.2
27
26.2 ± 0.2
34
28.5 ± 0.2
12
29.0 ± 0.2
18
30.0 ± 0.2
13
30.9 ± 0.2
24
33.4 ± 0.2
14
35.4 ± 0.2
20
37.5 ± 0.2
10
39.0 ± 0.2
19
7 . A crystal form according to claim 5 , which crystal form has all four of the properties (a), (b), (c) and (d).
8 . A pharmaceutical composition comprising a therapeutically effective amount of a crystal form according to claim 5 and a pharmaceutically acceptable carrier.
9 . A crystal form of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (T-62) which crystal form (Form III) is substantially free of other polymorphic forms of T-62 and has at least one of the following properties:
(a) a melting point in the range of about 126-135° C.;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (20) of about 15.5±0.2, 19.1±0.2, 19.4±0.2, 21.3±0.2 and 21.7±0.2;
(c) an infrared absorption spectrum with absorption bands at about 3247±2, 2941±2, 1908±2 and 922±2 cm −1 ; and
(d) a Raman spectrum with Raman shifts at about 3068±2, 2939±2, 1596±2 and 1436±2 cm −1 .
10 . A crystal form according to claim 9 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities (I/I 1 ) of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
15.5 ± 0.2
40
16.9 ± 0.2
12
19.1 ± 0.2
57
19.4 ± 0.2
34
21.3 ± 0.2
34
21.7 ± 0.2
100
22.9 ± 0.2
21
24.6 ± 0.2
12
29.4 ± 0.2
19
30.5 ± 0.2
18
11 . A crystal form according to claim 9 , which crystal form has all four of the properties (a), (b), (c) and (d).
12 . A pharmaceutical composition comprising a therapeutically effective amount of a crystal form according to claim 9 and a pharmaceutically acceptable carrier.
13 . A crystal form of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (T-62) which crystal form (Form IV) is substantially free of other polymorphic forms of T-62 and has at least one of the following properties:
(a) a melting point of about 138° C.; and
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (2θ) of about 7.4±0.2, 18.8±0.2, 20.4±0.2 and 21.3±0.2.
14 . A crystal form according to claim 13 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities (I/I 1 ) of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
7.4 ± 0.2
45
8.8 ± 0.2
15
13.2 ± 0.2
10
13.6 ± 0.2
21
16.1 ± 0.2
25
18.4 ± 0.2
11
18.8 ± 0.2
43
19.5 ± 0.2
21
20.4 ± 0.2
38
21.3 ± 0.2
100
22.1 ± 0.2
10
23.2 ± 0.2
25
24.5 ± 0.2
20
25.6 ± 0.2
15
26.8 ± 0.2
13
27.8 ± 0.2
24
15 . A crystal form according to claim 13 , which crystal form has both the properties (a) and (b).
16 . A pharmaceutical composition comprising a therapeutically effective amount of a crystal form according to claim 13 and a pharmaceutically acceptable carrier.
17 . A method for the production of Form I crystal form of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (T-62) which crystal form is substantially free of other polymorphic forms of T-62, wherein the method comprises:
(a) dissolving T-62, in any of its forms, in a solvent to form a solution in which solvent T-62 is suitably soluble at an elevated temperature ranging from about 30° C. to the boiling point of the solvent, and in which solvent T-62 is only poorly soluble at a lower temperature ranging from about −78° C. to about 30° C.;
(b) cooling the solution to the lower temperature to induce precipitation of the Form I crystal form of T-62; and
(c) isolating and drying the precipitated Form I crystal form of T-62.
18 . The method of claim 17 , wherein the solvent is a mixture of a lower alcohol and water.
19 . The method of claim 18 , wherein the lower alcohol is ethanol.
20 . The method of claim 19 , wherein the solvent contains about 95% of ethanol by volume.
21 . The method of claim 20 , wherein the elevated temperature ranges from about 60° C. to about 80° C.; and the lower temperature ranges from about 4° C. to about 30° C.
22 . The method of claim 21 , wherein the elevated temperature is about 78° C.
23 . A method for the production of Form I crystal form of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (T-62) which crystal form is substantially free of other polymorphic forms of T-62, wherein the method comprises:
(a) dissolving T-62, in any of its forms, in a first solvent to form a solution in which solvent T-62 is readily soluble at a temperature ranging from room temperature to the boiling point of the solvent;
(b) treating the solution with a second solvent which is miscible with the first solvent, and in which T-62 is only poorly soluble to induce precipitation of Form I crystal form of T-62;
(c) if desired, cooling the resulting mixture gradually to a temperature of about 10° C. to further induce precipitation of the Form I crystal form of T-62; and
(d) isolating and drying the precipitated Form I crystal form of T-62.
24 . The method of claim 23 , wherein the first solvent is selected from the group consisting of acetone, methanol, isopropanol, methylethylketone and tetrahydrofuran.
25 . The method of claim 23 , wherein the second solvent is selected from the group consisting of hexane and water.
26 . The method of claim 23 , wherein the first solvent is selected from the group consisting of acetone, methylethylketone and tetrahydrofuran; and the second solvent is hexane.
27 . The method of claim 23 , wherein the first solvent is selected from the group consisting of methanol, methylethylketone and tetrahydrofuran; and the second solvent is water.
28 . The method of claim 23 , wherein the first solvent is isopropanol; and the second solvent is water.
29 . A method for the production of Form I crystal form of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone (T-62) which crystal form is substantially free of other polymorphic forms of T-62, wherein the method comprises converting the Form III or Form IV crystal form of T-62 into the Form I crystal form of T-62 by storing the former crystal form of T-62 under atmospheric, super-atmospheric or reduced pressure at a temperature ranging from about 20° C. to about 104° C. and in relative humidity ranging from about 0% to about 95%.