Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-27
2001-02-20
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06191281
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to crystals of a salt of (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1, 3-thiazolidin-4-one which are useful as therapeutic agents for ischemic diseases and processes for preparing them.
PRIOR ART
JP No. 7-70023/1995 discloses benzene derivatives which are useful as therapeutic agents for ischemic diseases, especially 2-phenyl-1,3-thiazolidin-4-one derivatives. JP No. 8-225449/1996 discloses therapeutic agents for ischemic diseases containing such a 2-phenyl-1,3-thiazolidin-4-one derivative as an active ingredient. These patent publications disclose (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxy-phenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one as one of such derivatives. However, this compound is an oil around room temperature so that it has problems with handling and storage when it is to be prepared and formulated as a medicament.
A known solution to these problems is conversion of the active ingredient into a salt for ease of handling. We tried to prepare a salt of (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxy-phenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one using various acids, but no salt was obtained in a crystalline form. For example, the hydrochloride of this compound is described in Example 71 of the above-cited patent publication as an example of the salt thereof and generally considered as a stable salt. However, even this salt is amorphous and difficult to purify by crystallization. Therefore, it is not suitable for preparing a medicament since the preparation requires a bulk supply of the compound having a high quality.
An object of the present invention is to provide an acid addition salt which can be purified by crystallization to allow a stable and bulk production of (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one having a high quality, and a process for preparing it.
DISCLOSURE OF THE INVENTION
As a result of extensive research, we found that the fumaric acid salt of (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxy-phenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one can be purified by crystallization among various acid addition salts.
We also found that (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxy-phenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one hydrogen fumarate includes two crystal forms, i.e. low-melting crystal (hereinafter referred to as type I crystal) and high-melting crystal (hereinafter referred to as type II crystal), and that said type II crystal can be obtained by either heating said type I crystal or directly crystallizing said fumarate from a solution.
Accordingly, the present invention provides a crystalline fumaric acid salt of (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one represented by the formula:
The present invention also provides a process for preparing type II crystals comprising crystallizing (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one hydrogen fumarate from an organic solvent.
The present invention also provides a process for preparing type II crystals comprising heating type I crystals of (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one hydrogen fumarate.
JP No. 8-225449/1996 mentions fumaric acid as an acid capable of forming a salt with 2-phenyl-1,3-thiazolidin-4-one derivatives. However, it merely mentions fumaric acid as one of a number of such acids. It neither discloses nor suggests that (S)-(−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one (hereinafter sometimes referred to as free form) should be chosen from a number of 2-phenyl-1,3-thiazolidin-4-one derivatives to form a salt with fumaric acid and that the resulting fumaric acid salt (hereinafter referred to as compound A) can be purified by crystallization unlike other acid addition salts.
Type I crystal of compound A is a hemi- to mono- hydrate having a melting point of 108-120° C., while type II crystal is an anhydride having a melting point of 142-145° C. According to differential scanning calorimetric analysis (hereinafter abbreviated as DSC), type I crystal shows an endothermic peak around an onset temperature of 105° C. while type II crystal shows an endothermic peak around an onset temperature of 140° C.
REFERENCES:
patent: 5998452 (1999-12-01), Ohi et al.
patent: 0799614A1 (1997-10-01), None
patent: 8-225449 (1996-09-01), None
Tamura et al, European Journal of Pharmacology, 1996, vol. 312, pp. 195-202.
Kato Tatsuya
Kumagai Yoshikazu
Nakagomi Kazuya
Ozaki Tomokazu
Birch & Stewart Kolasch & Birch, LLP
Chugai Seiyaku Kabushiki Kaisha
Stockton Laura L.
LandOfFree
Crystalline fumarate of 2-phenyl-1, 3-thiazolidine-4-on... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Crystalline fumarate of 2-phenyl-1, 3-thiazolidine-4-on..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Crystalline fumarate of 2-phenyl-1, 3-thiazolidine-4-on... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2602411