US2004152758A1PendingUtilityA1
N-(indole-2-carbonyl)-b-alaninamide crystal forms
Est. expiryApr 15, 2022(expired)· nominal 20-yr term from priority
Inventors:Douglas J. M. AllenFrank R. BuschJoseph Francis KrzyzaniakZheng LiSusan OrrillPeter R. RoseDerek TicknerHarry Tobiassen
C07D 403/12
45
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The instant invention provides crystal forms of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (I) processes for the production of such crystal forms; pharmaceutical compositions comprising such crystal forms; and methods of treating glycogen phosphorylase dependent diseases, or conditions with such crystal forms, or such pharmaceutical compositions.
Claims
exact text as granted — not AI-modified1 . Amorphous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide.
2 . A crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-H-indole-2-carboxamide (Form A), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) of about 12.73, 16.82, 17.67, 20.24, 20.56, 20.96, 21.41, 25.61 and 25.85, and X-ray diffraction d-spacings (Å) of about 6.95, 5.27, 5.02, 4.38, 4.32, 4.23, 4.15, 3.48, and 3.44, respectively.
3 . A crystal form according to claim 2 , which crystal form further comprises characteristic diffraction peaks at diffraction angles (2-theta), X-ray diffraction d-spacings (Å), and intensities (I) of about:
d-
d-
d-
Angle
value
Angle
value
Angle
value
2-Theta
(Å)
I
2-Theta
(Å)
I
2-Theta
(Å)
I
6.48
13.62
20.9
22.54
3.94
5.2
30.46
2.93
6.0
12.73
6.95
80.4
24.44
3.64
9.8
31.10
2.87
8.9
14.11
6.27
6.7
24.72
3.60
11.9
31.44
2.84
6.9
16.82
5.27
34.4
25.01
3.56
14.0
32.39
2.76
10.1
17.67
5.02
35.0
25.61
3.48
32.4
33.24
2.69
6.7
18.69
4.74
12.3
25.85
3.44
30.4
35.76
2.51
5.0
19.12
4.64
8.0
26.76
3.33
23.2
36.09
2.49
6.6
20.24
4.38
32.8
27.47
3.24
7.7
36.87
2.44
6.2
20.56
4.32
100.0
28.08
3.18
6.5
37.12
2.42
6.8
20.96
4.23
30.1
28.55
3.12
13.8
38.85
2.32
7.3
21.41
4.15
74.7
30.04
2.97
5.3
4 . A crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, mono-ethanolate (Form C), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) of about 6.26, 8.70, 18.46, 19.22, 21.24, 23.27, 23.62, 23.87, and X-ray diffraction d-spacings of about 14.12, 10.16, 4.80, 4.61, 4.18, 3.82, 3.76, and 3.72, respectively.
5 . A crystal form according to claim 4 , which crystal form further comprises characteristic diffraction peaks at diffraction angles (2-theta), X-ray diffraction d-spacings (Å), and intensities (I) of about:
d-
d-
d-
Angle
value
Angle
value
Angle
value
2-Theta
(Å)
I
2-Theta
(Å)
I
2-Theta
(Å)
I
4.36
20.25
8.6
19.75
4.49
18.9
29.13
3.06
7.5
6.26
14.12
46.8
20.71
4.28
28.6
29.63
3.01
12.4
8.70
10.16
95.0
21.24
4.18
100.0
30.23
2.95
16.0
10.40
8.50
10.7
21.77
4.08
20.5
30.61
2.92
12.0
10.99
8.05
37.3
22.14
4.01
9.0
31.00
2.88
15.8
12.56
7.04
33.8
23.27
3.82
75.5
32.49
2.75
13.3
15.57
5.69
28.6
23.62
3.76
55.3
33.26
2.69
8.2
16.06
5.52
10.9
23.87
3.72
52.8
33.98
2.64
15.2
16.41
5.40
14.6
24.33
3.65
10.5
34.78
2.58
8.5
16.76
5.29
8.5
25.61
3.48
8.4
35.46
2.53
12.6
17.18
5.16
15.5
26.10
3.41
33.1
36.00
2.49
8.8
17.49
5.07
9.4
26.60
3.35
21.3
37.36
2.40
8.0
18.46
4.80
94.1
26.88
3.31
15.4
39.03
2.31
6.7
19.22
4.61
46.1
28.16
3.17
19.4
6 . A crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate (Form D), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) at about 4.90, 8.53, 14.38, 18.13, 21.74, 22.23, 22.46, 22.97 and 23.45, and X-ray diffraction d-spacings of about 18.02, 10.36, 6.15, 4.89, 4.08, 4.00, 3.96, 3.87, and 3.79, respectively.
7 . A crystal form according to claim 6 , which crystal form further comprises characteristic diffraction peaks at diffraction angles (2-theta), X-ray diffraction d-spacings (Å), and intensities (I) of about:
d-
d-
d-
Angle
value
Angle
value
Angle
value
2-Theta
(Å)
I
2-Theta
(Å)
I
2-Theta
(Å)
I
4.90
18.02
60.1
18.61
4.76
44.4
27.46
3.24
32.0
6.61
13.35
11.6
19.74
4.49
29.9
28.04
3.18
24.2
8.53
10.36
71.8
20.08
4.42
55.1
28.94
3.08
17.2
9.75
9.07
44.2
20.56
4.32
20.2
29.46
3.03
14.6
13.32
6.64
19.3
21.26
4.18
30.7
30.23
2.95
14.0
13.64
6.49
25.7
21.74
4.08
75.7
30.70
2.91
12.5
13.86
6.39
37.8
22.23
4.00
69.6
30.94
2.89
15.3
14.38
6.15
58.7
22.46
3.96
65.9
31.24
2.86
11.8
14.72
6.01
12.1
22.97
3.87
100.0
32.03
2.79
10.1
14.98
5.91
12.1
23.45
3.79
57.7
32.48
2.75
13.3
15.32
5.78
12.4
24.22
3.67
12.7
32.83
2.73
14.4
15.76
5.62
16.1
24.72
3.60
11.8
33.57
2.67
12.5
15.96
5.55
22.5
25.63
3.47
13.3
35.23
2.55
10.4
17.55
5.05
38.2
26.28
3.39
40.8
35.72
2.51
11.4
18.13
4.89
57.8
26.83
3.32
33.7
8 . A crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, hemi-ethanolate (Form E), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) at about 11.97, 16.80, 20.07, 21.06, 22.00, 23.89, and 26.27, and X-ray diffraction d-spacings of about 7.39, 5.27, 4.42, 4.22, 4.04, 3.72, and 3.39, respectively.
9 . A crystal form according to claim 8 , which crystal form further comprises characteristic diffraction peaks at diffraction angles (2-theta), X-ray diffraction d-spacings (Å), and intensities (I) of about:
d-
d-
d-
Angle
value
Angle
value
Angle
value
2-Theta
(Å)
I
2-Theta
(Å)
I
2-Theta
(Å)
I
4.75
18.60
7.2
17.88
4.96
19.5
26.90
3.31
46.8
6.57
13.45
10.4
18.65
4.75
32.7
27.97
3.19
22.5
6.82
12.94
9.5
19.62
4.52
34.7
28.66
3.11
18.4
7.53
11.74
25.2
20.07
4.42
52.8
29.98
2.98
17.8
9.81
9.01
5.8
21.06
4.22
96.4
31.19
2.87
30.3
10.47
8.44
7.8
22.00
4.04
100.0
32.60
2.74
17.4
11.97
7.39
75.1
22.72
3.91
27.7
36.72
2.45
12.7
13.00
6.80
9.8
23.89
3.72
50.1
37.03
2.43
12.2
13.54
6.54
9.9
24.86
3.58
26.6
16.80
5.27
64.3
26.27
3.39
65.9
10 . A crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, monohydrate (Form F), which crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) at about 4.30, 6.07, 9.67, 13.66, 17.88, 20.09, and 21.88, and X-ray diffraction d-spacings of about 20.54, 14.54, 9.14, 6.48, 4.96, 4.42, and 4.06, respectively.
11 . A crystal form according to claim 10 , which crystal form further comprises characteristic diffraction peaks at diffraction angles (2-theta), X-ray diffraction d-spacings (Å), and intensities (I) of about:
d-
d-
d-
Angle
value
Angle
value
Angle
value
2-Theta
(Å)
I
2-Theta
(Å)
I
2-Theta
(Å)
I
4.30
20.54
100.0
22.62
3.93
16.7
31.07
2.88
10.9
6.07
14.54
66.1
24.28
3.66
14.0
31.92
2.80
9.3
8.61
10.26
26.3
24.54
3.62
21.8
32.25
2.77
12.2
9.67
9.14
47.2
25.03
3.56
21.6
32.86
2.72
13.5
13.09
6.76
5.4
25.32
3.51
16.3
33.88
2.64
5.8
13.66
6.48
40.6
25.69
3.46
17.1
34.61
2.59
6.9
15.86
5.58
17.8
26.20
3.40
11.4
35.19
2.55
8.6
17.04
5.20
8.2
26.63
3.34
11.0
35.81
2.51
7.0
17.88
4.96
98.9
27.55
3.23
13.0
36.20
2.48
5.3
18.54
4.78
30.7
28.18
3.16
11.4
37.03
2.43
7.5
19.14
4.63
37.3
29.00
3.08
10.4
37.98
2.37
6.8
20.09
4.42
44.7
29.16
3.06
12.0
39.24
2.29
5.2
21.47
4.14
21.3
29.40
3.04
11.3
39.69
2.27
5.8
21.88
4.06
53.0
30.36
2.94
5.5
12 . A crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form G), crystal form comprises characteristic high intensity X-ray diffraction peaks at diffraction angles (2-theta) at about 18.2, 20.1, 24.3, 25.2, and 26.3, and X-ray diffraction d-spacings, expressed in Å, of about 4.9, 4.4, 3.7, 3.5, and 3.4, respectively.
13 . A crystal form according to claim 12 , which crystal form further comprises characteristic diffraction peaks at diffraction angles (2-theta), X-ray diffraction d-spacings (Å), and intensities (I) of about:
d-
d-
d-
Angle
value
Angle
value
Angle
value
2-Theta
(Å)
I
2-Theta
(Å)
I
2-Theta
(Å)
I
16.2
5.5
5.4
26.3
3.4
38.6
34.8
2.6
2.4
17.2
5.1
2.8
26.9
3.3
3.6
35.2
2.5
3.2
18.2
4.9
8.6
27.9
3.2
6.4
35.5
2.5
2.7
19.7
4.5
4.1
29.4
3.0
2.3
35.9
2.5
2.7
20.1
4.4
100.0
29.8
3.0
3.9
36.6
2.4
3.6
20.8
4.3
5.8
30.8
2.9
2.9
38.4
2.3
3.7
23.7
3.7
2.5
31.6
2.8
3.5
38.8
2.3
3.3
24.3
3.7
12.1
31.9
2.8
3.8
39.8
2.3
3.1
25.2
3.5
8.9
32.7
2.7
3.7
14 . A process for preparing anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form A), which process comprises azetropically distilling a solution prepared from 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate (Form D), in an aprotic solvent to substantially remove said water of hydration and crystallize said Form A crystal form.
15 . A process for preparing 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate (Form D), which process comprises the steps of:
(a) adding water to a suspension of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form A), or anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Form B) crystal forms in an aprotic solvent such that a water content of between about 5% and about 10% is achieved; (b) heating said suspension to substantially dissolve said Form A or said Form B crystal form to form a solution; and (c) diluting said solution with a non-polar, anti-solvent to crystallize said Form D crystal form.
16 . A pharmaceutical composition comprising a Form A crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, or a Form D crystal form of 5-chloro-N-[(1 S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate, and a pharmaceutically acceptable carrier, vehicle, or diluent.
17 . A method of treating a glycogen phosphorylase dependent disease or condition which method comprises administering to a mammal in need of such treatment a Form A crystal form of anhydrous 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, a Form D crystal form of 5-chloro-N-[(1S,2R)-3-[3R,4S]-3,4-dihydroxy-1-pyrrolidinyl]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide, dihydrate, or a pharmaceutical composition comprising such Form A or Form D crystal forms.
18 . A method according to claim 17 , wherein said glycogen phosphorylase dependent disease or condition is selected from the group consisting of hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis, diabetes, diabetic cardiomyopathy, infection, tissue ischemia, myocardial ischemia, and tumor growth.Join the waitlist — get patent alerts
Track US2004152758A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.