Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Peptides with at least one nonpeptide bond other than a...
Reexamination Certificate
2000-05-08
2002-02-12
Russel, Jeffrey E. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Peptides with at least one nonpeptide bond other than a...
C514S011400
Reexamination Certificate
active
06346603
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel crystals of depsipeptide derivative (IV) with an antiparasitic activity, and a method for producing the same.
BACKGROUND ART
The depsipeptide derivative (IV) represented by the following formula has been known as a compound with an excellent antiparasitic activity to animals and human beings, and WO 93/19053 and WO 97/02256 disclose a method for producing the same.
The former WO 93/19053 specifically discloses a method for producing amorphous depsipeptide derivative (IV) by way of the following processes (nine processes in total).
According to the method, however, all the intermediate products produced during the course by way of the compound (B) to the objective compound (IV) have basic morpholino groups within the molecules and therefore, they should be handled with precise caution and they are purified by re-crystallization with much difficulty. Because the resulting objective compound (IV) itself is poor in terms of crystallinity, the compound has a variety of disadvantages in terms of production efficiency and handle-ability such that the compound requires purification by column chromatography and the like. Hence, it cannot be said that the method is suitable for industrial scale.
So as to overcome such problems, thus, the method of the latter WO 97/02256 is proposed. According to the method, a depsipeptide derivative in crystal can be recovered, but the subsequent research works indicate that the crystal is poor in respect of filtration properties during crystallization and of fluidity and specific volume [referring the volume occupied by a unit mass (1 g), which is equal to the reciprocal of the density].
DISCLOSURE OF INVENTION
With attention focused on the aforementioned circumstance, the present invention has been attained, and the purpose of the present invention is to provide novel crystals of depsipeptide derivative with excellent filtration properties during crystallization, great fluidity, good specific volume and the like, thereby as a consequence of the improvement in the handle-ability during production, resulting in an enhanced production efficiency and an increased yield of the crystal, and to provide a method for producing such crystals at a high efficiency.
The crystals (I), (II) and (III) of the depsipeptide derivative (IV) according to the present invention capable of overcoming the problems described above, individually have the following physico-chemical properties.
Crystal (I): substantially having the powdery X-ray diffraction characteristic properties described in Table 1 and having an endothermic peak substantially at 155° C. by differential thermal analysis.
TABLE 1
Relative
2&thgr;
inten-
2&thgr;
Relative
2&thgr;
Relative
2&thgr;
Relative
value
sity
value
intensity
value
intensity
value
intensity
(°)
(%)
(°)
(%)
(°)
(%)
(°)
(%)
5.67
100.0
13.15
19.52
19.86
15.18
26.48
2.33
6.46
0.41
14.56
8.83
20.19
10.19
26.93
1.22
7.36
1.01
15.01
42.59
20.47
6.81
27.66
5.24
7.92
3.12
15.44
61.33
20.84
7.03
28.03
4.70
8.74
5.339
15.97
26.84
21.62
8.83
28.60
2.65
9.34
9.94
16.80
16.13
22.15
6.71
29.45
1.26
10.35
10.32
17.07
10.84
22.52
7.35
29.77
1.60
11.27
29.39
17.55
2.39
23.04
1.55
30.61
1.05
11.39
25.81
18.33
19.34
23.75
5.81
31.94
1.36
11.88
5.52
18.96
7.79
25.05
4.03
12.69
5.24
19.42
3.87
26.07
1.40
Crystal (II): substantially exerting the powdery X-ray diffraction characteristic properties described in Table 2 and having an endothermic peak substantially at 182° C. by differential thermal analysis.
TABLE 2
Relative
2 &thgr;
inten-
2 &thgr;
Relative
2 &thgr;
Relative
2 &thgr;
Relative
value
sity
value
intensity
value
intensity
value
intensity
(°)
(%)
(°)
(%)
(°)
(%)
(°)
(%)
4.79
35.86
13.56
47.83
19.10
47.83
25.00
6.48
4.89
35.50
14.20
32.70
19.51
32.02
25.36
6.63
5.58
14.69
14.64
30.02
19.91
17.57
26.06
4.65
7.00
1.16
15.75
41.82
21.39
23.82
27.31
8.61
9.09
8.79
15.56
52.50
22.02
13.34
27.95
8.61
9.69
5.45
16.26
66.32
22.54
14.01
29.06
6.48
10.52
100.0
16.63
40.67
22.84
16.58
29.60
3.12
10.85
31.10
17.07
40.29
23.16
17.32
30.38
3.79
11.49
7.10
18.34
32.70
23.82
26.21
31.75
2.07
12.40
11.86
18.73
24.40
24.44
9.51
Crystal (III): substantially exerting the powdery X-ray diffraction characteristic properties described in Table 3 and having an endothermic peak substantially at 194° C. by differential thermal analysis.
TABLE 3
Relative
2 &thgr;
inten-
2 &thgr;
Relative
2 &thgr;
Relative
2 &thgr;
Relative
value
sity
value
intensity
value
intensity
value
intensity
(°)
(%)
(°)
(%)
(°)
(%)
(°)
(%)
6.02
100.0
12.17
30.53
19.04
14.75
26.07
3.83
6.20
87.04
13.20
5.81
19.44
7.78
26.73
2.78
6.30
50.17
14.45
16.17
19.98
10.99
28.19
2.66
6.82
2.60
15.19
19.22
21.21
11.72
29.13
1.61
8.08
1.22
16.10
19.22
21.99
17.36
30.05
1.22
9.45
2.32
16.70
26.47
22.16
11.97
30.61
1.26
9.64
1.90
16.87
24.10
22.88
8.40
31.27
0.76
10.48
2.10
17.74
6.62
22.99
9.94
12.03
20.51
18.45
7.38
24.26
10.52
The methods for producing the crystals (I), (II) and (III) of the depsipeptide derivative (IV) according to the present invention, having overcome the problems, are individually as follows.
Crystal (I)
The following method (1) or (2) may essentially be used.
(1) The depsipeptide derivative (IV) is added to acetone and dissolved therein, followed by further addition of water for crystallization, or
(2) the depsipeptide derivative (IV) is added to tetrahydrofuran, acetonitrile or acetone and dissolved, followed by addition of isopropyl ether for crystallization.
Crystal (II)
The crystal (I) is added to ethanol and dissolved therein, followed by addition of isopropyl ether for crystallization.
Crystal (III)
The crystal (II) is added to ethyl acetate and dissolved therein, followed by further addition of isopropyl ether for crystallization.
REFERENCES:
patent: 5514773 (1996-05-01), Nishiyama et al.
patent: 5646244 (1997-07-01), Nishiyama et al.
patent: 5856436 (1999-01-01), Nishiyama et al.
patent: 6235875 (2001-05-01), Yamanishi et al.
patent: 93/01953 (1993-02-01), None
patent: 93/19053 (1993-09-01), None
patent: 94/19334 (1994-09-01), None
patent: 97/02256 (1997-01-01), None
Ikushima Muneharu
Yamamura Atsushi
Yamanishi Ryo
Fujisawa Pharmaceutical Co. Ltd.
Russel Jeffrey E.
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