Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-07
2003-11-11
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S157000, C546S158000
Reexamination Certificate
active
06645982
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate (1:1) salts having the formula shown below:
The invention further relates to a method of making 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxybutanedioate (1:1) salts. The compounds of the present invention are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals, especially humans. The invention further relates to pharmaceutical compositions containing such compounds.
The free base, 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, is described in co-pending U.S. Ser. No. 09/383,755, filed Aug. 26, 1999, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing application is assigned in common with the present application. The aforementioned free base is useful in the treatment of hyperproliferative diseases such as cancers.
SUMMARY OF THE INVENTION
The present invention relates to crystalline tartrate salts of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one having the formula shown below:
Two crystal forms of formula I have been identified. The crystal forms of formula I are herein referred to as crystal form A and crystal form B. Crystal form A is an anhydrous crystalline salt of formula 1, while crystal form B is a sesquihydrate crystalline salt of formula 1.
The present invention relates to 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate salts. The 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl))-1-methyl-1H-quinolin-2-one has a chiral center at the 6-postion. Thus, the free base, 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinol in-2-one, may have specific rotations of (+) or (−). The tartrate salt may be L-tartaric acid or D-tartaric acid. L-tartaric acid is also known as (2R,3R)-(+)-tartaric acid, while D-tartaric acid is (2S,3S)-(−)-tartaric acid. Both acids are available from Aldrich Chemical Company, Inc., Milwaukee, Wis.
Particularly preferred salts include (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate salt and (−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate salt. Other particularly preferred salts include 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (−)-2,3-dihydroxy butanedioate salt and 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate salt.
More particularly preferred salts include (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (−)-2,3-dihydroxy butanedioate salt and (−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate salt. The salts of the present invention may be present in anhydrous or hydrous form.
The present invention further relates to (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate salt. The invention also relates to (−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (−)-2,3-dihydroxy butanedioate salt.
The present invention further comprises pharmaceutical compositions of crystal forms A and B of the compound of formula I and a method for the production of crystal forms A and B of the compound of formula I.
It is a further object of the present invention to provide crystal forms A and B in a pharmaceutically orally administered composition. Crystal forms A and B of the compound of formula I are useful for the oral administration of the drug in solid form, such as tablets. Crystal form A is preferred for use in the preparation of pharmaceutical compositions containing the compound of formula I in tablet form for oral administration.
Crystal forms A and B have been characterized by powder X-ray diffractometry. The anhydrous crystal form of the present invention is identified in this application as crystal form A. The second crystal form of formula I is a sesquihydrate having approximately 5.5% water and is identified herein as crystal form B.
The anhydrous crystal form A of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (−)-2,3-dihydroxy butanedioate is characterized by high-intensity diffraction peaks at diffraction angles (2&thgr;) of about 3.6, 17.2, 17.6, 18.8, 19.2, 20.4 and 22.1 in a powder X-ray diffraction pattern. The experimental conditions under which the powder X-ray diffraction was conducted are as follows: Cu anode; wavelength 1: 1.54056; wavelength 2: 1.54439 (Rel Intensity: 0.500); range #1-coupled: 3.000 to 40.000; step size: 0.040; step time: 1.00; smoothing width: 0.300; and threshold: 1.0. The characteristic diffraction peaks at diffraction angles (2&thgr;) in a powder X-ray diffraction analysis for the crystal form A are shown in Table 1.
The hydrate crystal form B of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4(3-ethynyl-phenyl)-1-methyl-1-H-quinolin-2-one, (−)-2,3-dihydroxy butanedioate is characterized in that the crystal provides high-intensity diffraction peaks at diffraction angles (2&thgr;) of about 5.1, 8.1, 18.2, 18.8, 20.2, 20.8, 23.6, 25.8 and 26.0 in a powder X-ray diffraction pattern. The experimental conditions under which the powder X-ray diffraction was conducted are as follows: Cu anode; wavelength 1: 1.54056; wavelength 2: 1.54439 (Rel Intensity: 0.500); range #1-coupled: 3.000 to 40.000; step size: 0.040; step time: 1.00; smoothing width: 0.300; and threshold: 1.0. The characteristic diffraction peaks at diffraction angles (2&thgr;) in a powder X-ray diffraction analysis for crystal form B are shown in Table 2.
The characteristic d-spacings, intensities, and 2-theta (2&thgr;) values for the diffraction pattern of crystal forms A and B are shown below in Tables 1 and 2, respectively.
TABLE 1
Crystal Form A
d-
d-
Angle
value
I*
Angle
value
I*
Angle
d-value
I*
2 theta
Å
(rel.)
2 theta
Å
(rel.)
2 theta
Å
(rel.)
3.6
24.7
100
16.9
5.3
1.3
23.4
3.8
2.4
6.2
14.2
3.3
17.2
5.2
9.7
25.1
3.5
3.7
7.2
12.3
1.9
17.6
5.1
9.2
25.5
3.5
2.0
9.5
9.3
1.5
18.8
4.7
5.6
26.0
3.4
1.5
10.8
8.2
1.7
19.2
4.6
5.2
26.7
3.3
2.2
12.3
7.2
1.2
19.7
4.5
2.0
27.6
3.2
1.8
12.5
7.1
1.4
20.4
4.4
10.0
28.2
3.2
2.0
13.8
6.4
1.3
21.7
4.1
1.3
28.5
3.1
2.1
14.5
6.1
1.4
22.1
4.0
6.0
29.0
3.1
1.8
16.0
5.5
4.8
22.6
3.9
2.2
29.9
3.0
2.0
*The relative intensities may change depending on the crystal size and morphology.
TABLE 2
Crystal Form B
d-
d-
Angle
value
I*
Angle
value
I*
Angle
d-value
I*
2 theta
Å
(rel.)
2 theta
Å
(rel.)
2 theta
Å
(rel.)
5.1
17.2
45
19.9
4.5
28.5
26.0
3.4
42.9
8.1
10.9
30
20.2
4.4
45.3
26.7
3.3
10.4
12.7
7.0
10.1
20.8
4.3
100
27.6
3.2
11.0
13.9
6.4
20.7
21.4
4.2
20.3
28.1
3.2
10.5
14.6
6.1
28.0
21.7
4.1
16.5
28.7
3.1
13.4
15.2
5.9
17.2
22.8
3.9
20.8
30.2
3.0
25.9
15.3
5.8
11.9
23.6
3.8
39.3
31.2
2.9
10.3
16.4
5.4
20.6
24.1
3.7
19.2
32.1
2.8
16.6
16.8
5.3
12.1
24.4
3.6
19.6
3
Li Zheng J.
Lyssikatos Joseph P.
Meltz Clifford N.
Newton Linda S.
Tickner Derek L.
Ginsburg Paul H.
Looney Adrian G.
Morris Patricia L.
Pfizer Inc
Richardson Peter C.
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