Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-11-12
1995-04-04
Chang, Celia
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514278, C07D491107, A61K 31445
Patent
active
054039312
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to (-)-(S)-2,8-di-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (hereinafter referred to briefly as compound A) L-tartrate monohydrate which is of value as a medicament and to a process for producing the same compound.
BACKGROUND ART
It has been reported that compound A has a selective affinity for the muscarinic acetylcholine receptor (M1 receptor) and hydrochloride, fumarate, maleate and di-p-toluoyl-D-tartrate of compound A can be utilized in the treatment of diseases associated with a deficiency of acethylcholine-related functions, such as Alzheimer's disease (JP-A-2-36183; the term "JP-A" as used herein means an "unexamined published Japanese patent application").
JP-A-2-36183 enumerates various inorganic and organic acid addition salts which can be formed by heterocyclic spiro compounds such as compound A, including addition salts with tartaric acid. However, the literature contains no specific disclosure of the tartrate of compound A or its monohydrate.
On the other hand, compound A as the free base is oily and can be crystallized after conversion to certain acid addition salts. The research undertaken by the inventors of the present invention revealed that compound A does not form a crystallizable salt with D-tartaric acid, D- or L-malic acid, succinic acid, hydrobromic acid, sulfuric acid, phosphoric acid or the like. The hydrochloride gave a powdery compound which, however, underwent deliquescence within 24 hours when allowed to stand in the air, due to high hygroscopicity.
Meanwhile, stability of compound A is low even in the form of a solid salt and this instability has been a major drawback in the practical application of this compound as a medicinal material.
DISCLOSURE OF INVENTION
After extensive studies under these circumstances, the inventors of the present invention found surprisingly that the L-tartrate monohydrate of compound A is crystallizable and also highly stable. The present invention was accomplished based on this finding.
The present invention is, therefore, directed to compound A L-tartrate monohydrate. The invention is further directed to a process for producing compound A L-tartrate monohydrate comprising dissolving 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane and L-tartaric acid in an aqueous organic solvent and carrying out crystallization.
The aqueous organic solvent which can be used in the process of the present invention is any solvent that is capable of dissolving the starting compounds. Representative examples of the aqueous organic solvent includes aqueous alcohols such as aqueous methanol, aqueous ethanol, aqueous propanol, aqueous isopropyl alcohol, etc., aqueous acetonitrile, and mixtures thereof. Regarding the water content of said aqueous solvent, 9 parts by volume of the organic solvent or solvents to 1 part by volume of water is preferred, but the water content is not limited to this ratio.
For an enhanced solubility of the starting compounds, the system is preferably heated at a suitable temperature.
The starting compound, 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane, may be whichever of its optically active compounds and racemic compound. When the racemic compound is employed, the resulting L-tartrate can be recrystallized in repetition to isolate the desired pure compound A L-tartrate monohydrate.
The compound A L-tartrate monohydrate thus produced is remarkably superior to other salts of compound A in stability. Its shelf-life at room temperature is not less than 3 years, which is sufficient to insure the application of compound A as a treating agent.
INDUSTRIAL APPLICABILITY
The stability of the compound of the present invention is now described in further detail in comparison with the sesquifumarate which is the most stable salt of compound A heretofore available.
Test method
Under protection from light, the respective compounds were stored for 3 months in the open condition at 40.degree. C., 50.degree. C. and 60.degree. C. or in the condition of 75% RH at 40.degree. C.. The cha
REFERENCES:
patent: 4996210 (1991-02-01), Tsukamoto
patent: 5075317 (1991-12-01), Wu
Fujii Mitsuo
Kohinata Takeru
Tomizawa Sakiko
Tsukamoto Shin-ichi
Chang Celia
Yamanouchi Pharmaceutical Co. Ltd.
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