Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-03
2001-01-30
Kight, John (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S273700
Reexamination Certificate
active
06180652
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel acetone complex of a sulfoxide compound or of a pharmacologically acceptable salt thereof useful as medicines such as inhibitors of gastric acid secretion and anti-ulcer agents or as intermediates for production of medicines, as described in JP-A 1-6270 (Example 32), JP-A 61-50978 (Example 2), JP-A 54-141783 (Example 21) or JP-A 61-22079 (Example 2), a process for producing the same and a purification method using the same.
PRIOR ART
Heretofore, sulfoxide compounds have been prepared by oxidizing thioether compounds with an oxidizing agent such as hydrogen peroxide, m-chloroperbonzoic acid, sodium hypochlorite, sodium hypobromite etc., as described in JP-A 1-6270 (EP 268956, U.S. Pat. No. 5,045,552), JP-A 61-50978 (EP 174726, U.S. Pat No. 4,628,098), JP-A 54-141783 (EP 5129, U.S. Pat. No. 4,255,431), JP-A 61-22079 (EP 166287, U.S. Pat. No. 4,758,579) etc.
(See the following reaction scheme wherein R
1
to R
4
have the same meanings as defined below.)
Among the oxidizing agents described above, m-chloroperbenzoic acid is frequently used from the viewpoint of easiness of weighing, storage stability, reaction activity etc.
For example, in Example 32 of JP-A 1-6270, thioether is oxidized with 0.96 equivalent (in terms of the amount of a purified product) of m-chloroperbenzoic acid, but in some cases, the reaction does not stop at the stage of sulfoxide, so there is the problem of the side reaction of further oxidation of a part of the formed sulfoxide into sulfone, as shown in the following reaction. As a matter of course, formation of the sulfone brings about the drawback of lower yield of the desired sulfoxide, and another problem is that it is difficult to separate and purify the 2 compounds because of their very similar physicochemical properties.
(In the following reaction, R
1
to R
4
have the same meanings as defined above.)
Further, many sulfoxide compounds or their pharmacologically acceptable salt (III) are unstable to air, humidity, heat, light, pH etc., and their decomposition reaction occurs during purification procedures in conventional purification methods such as column chromatography etc., so there is the problem that the purity of their product can be lowered on the contrary. Further, during storage as raw material (bulk), they may also be partially decomposed to lower their purity, but no method for stable storage thereof for a prolonged period of time has been established.
Under the present circumstances as described above, there are no established methods for purifying and stabilizing industrially superior high-purity sulfoxide compounds or their pharmaceutically acceptable salts (III), so there is a need for new superior purification and stabilization methods.
DISCLOSURE OF THE INVENTION
The present inventors made extensive study to solve the problems described above. As a result, they have unexpectedly found the novel acetone complexes described below and that by using these complexes, the objective sulfoxide compounds or their pharmacologically acceptable salts (III) can be purified in high yield and high purity and further they can be stored as raw material (bulk) stably for a prolonged period of time, to arrive at completion of the present invention.
Accordingly, the present invention is to provide novel acetone complexes (I) of sulfoxide compounds or of their pharmacologically acceptable salts (III) useful as medicines such as inhibitors of gastric acid secretion and anti-ulcer agents or as intermediates for production of medicines, a purification method using the same and a method capable of storing sulfoxides or their pharmacologically acceptable salts (III) stably for a prolonged period of time.
Hereinafter, the present invention is described in detail.
First, the acetone complex (I) of a sulfoxide compound or of a pharmacologically acceptable salt thereof according to the present invention is represented by the following formula:
wherein R
1
represents a hydrogen atom, a methoxy group or a difluoromethoxy group, R
2
represents a methyl group or a methoxy group, R
3
represents a 3-methoxypropoxy group, a methoxy group or a 2,2,2-trifluoroethoxy group, and R
4
represents a hydrogen atom or a methyl group;
n represents an integer of 1 to 4, and
m represents an integer of 1 to 4,
whereupon n and m can vary within the above-described range, depending on reaction conditions such as treatment method, the amount of acetone used, solvent used in combination, treatment temperature, treatment time and stirring rate; and
B represents a hydrogen atom, an alkali metal atom or ½alkaline earth metal atom.
In the above definition, the alkali atom includes e.g. sodium atom, potassium atom, lithium atom etc., and the alkaline earthmetal atom includes e.g. calciumatom, magnesium atom etc., among which sodium atom or magnesium atom is more preferable.
The acetone complex (I) of a sulfoxide compound or of a pharmaceutically acceptable salt thereof includes e.g. acetone complex of Rabeprazole, Lansoprazole, Omeprazole or Pantoprazole, or acetone complexes of pharmaceutically acceptable salts thereof.
The acetone complex (I) of a sulfoxide compound or of a pharmaceutically acceptable salt thereof according to the present invention is a novel compound characterized by patterns or absorption peaks in powder X-ray analysis, NMR, IR etc. Further, the acetone complex (I) of a sulfoxide compound or of a pharmaceutically acceptable salt thereof has industrially very superior characters such as stability to conditions such as air, humidity, heat, light, pH etc., thus making the conventionally impossible long-term storage or long-distance transport of the raw material (bulk) possible.
For example, the 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole sodium salt acetone complex (II) according to the present invention is specifically characterized in that it has peaks at the following angles expressed in terms of 2
&thgr;
, in a powder X-ray diffraction pattern (see FIG. 1), and/or peaks at wavelengths of 745.4, 803.1, 1010.2, 1093.0, 1268.1, 1298.5, 1381.4, 1465.2, 1584.5, 1710.6 and 2930.7 cm
−1
in an infrared absorption spectrum in potassium bromine (see FIG. 2), and/or peaks at
&dgr;
(ppm) 1.83-2.05 (m, 2H), 2.17 (s, 3H), 3.24 (s, 3H), 3.48 (t, J=6.2 Hz, 2H), 4.09 (t, J=6.2 Hz, 2H), 4.40 (dd, J=13.2 Hz, J=5.7, 1H), 4.72 (dd, J=13.2 Hz, J=5.7, 1H), 6.86 (m, 2H), 6.93 (d, J=5.7, 1H), 7.45 (m, 2H), and 8.27 (d, J=5.7 Hz, 1H) in a
1
H-NMR (400 MHz, DMSO-d
6
) spectrum (see FIG. 3).
Diffractive angles (2
&thgr;
, °)
Intensity (I/I
0
)
6.72
100
7.70
55
8.14
50
10.22
34
14.70
37
15.98
46
16.76
64
17.88
80
19.68
34
21.00
45
21.12
48
21.32
41
22.28
34
22.40
35
23.06
44
23.26
53
23.44
55
23.74
53
23.94
57
24.06
50
24.26
36
Method for Measurement of Powder X-Ray Diffraction Pattern, and Conditions
(1) Measurement Method
About 100 mg sample was measured for its powder X-ray diffraction pattern under the following measurement conditions.
(2) Measurement Conditions
Target: Cu
Filter: monochro
Voltage: 40 KV
Current: 2 mA
Slit: DS 1; RS 0.15, SS 1
Scan speed: 2 deg/min.
Range: 5-30°
Method for Measurement of IR Absorption Spectrum, and Conditions
Measured in FT-IR in accordance with the Japanese Pharmacopoeia, general test methods, infrared absorption spectrum, and a potassium bromide tablet method.
Next, the sulfoxide compound of the present invention or its pharmacologically acceptable salt (III) is represented by the following formula:
wherein R
1
, R
2
, R
3
, R
4
and B have the same meanings as defined above.
The sulfoxide compound or its pharmacologically acceptable salt (III) is a known compound, and more specifically, mention can be made of 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole (general name: Rabeprazole free base) described in JP-A 1-6270 (Example 32), a compound (R
1
=H, R
2
=CH
3
, R
3
Niikawa Nobuo
Nochi Shigeharu
Takayanagi Keizo
Tsujii Masahiko
Birch & Stewart Kolasch & Birch, LLP
Eisai Co. Ltd.
Kight John
Robinson Binta
LandOfFree
Sulfoxide compounds and acetone complexes, and a process for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Sulfoxide compounds and acetone complexes, and a process for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Sulfoxide compounds and acetone complexes, and a process for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2435321