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Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione

a technology of methyl and thiazolidine, which is applied in the field of stable and novel type crystals of 5 6(2fluorobenzyl) oxy2naphthyl methyl)2, and 4thiazolidinedione, and achieves excellent stability and advantages in handling, storage, and manufactur

Inactive Publication Date: 2006-07-06
TAKAYUKI +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a new crystal form of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione that has improved stability and handling properties compared to existing crystals. The new crystal has characteristic absorption peaks in a powder X-ray diffraction pattern, making it easier to handle and manufacture pharmaceutical preparations. The invention also provides methods for preparing the new crystal and pharmaceutical compositions containing it. The new crystal has improved stability and can be easily handled, making it a more suitable form of the compound for use in pharmaceutical preparations."

Problems solved by technology

However, these patent documents are silent about the possibility of the polymorphism, and hence no information about the type A, B, C and D crystals are disclosed therein.

Method used

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  • Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
  • Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
  • Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione

Examples

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reference example 1

Preparation of a mixture of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione Polymorphic Forms

[0044] 50.0 g of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione (roughly purified product, prepared by the method described in the Japanese Patent Unexamined Publication No. (Hei) 6-247945 / 1994), was add to 375 ml of toluene and heated with stirring at refluxing temperature. After the solid was completely dissolved, the solution was cooled to 20° C. with stirring. The reaction mixture was filtered, and the filter cake was washed with toluene and dried under reduced pressure to obtain 48.8 g of a mixture of polymorphic forms comprising the type A and type D crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione (98% of theoretical yield). Melting point: 149-151° C.

[0045] Elemental analysis (as C21H16FNO3S):

Calculated (%)C, 66.13; H, 4.23; N, 3.67FoundC, 66.06; H, 4.08; N, 3.68

example 1

Preparation of MCC-555 (1)

[0046] The mixture of polymorphic forms of the type A and type D crystals obtained in Reference Example 1 (400 mg) was suspended in ethanol (4.0 ml), heated under reflux for one hour with stirring, and then cooled to room temperature with stirring. The reaction mixture was filtered, and the filter cake was washed with ethanol and dried under reduced pressure to obtain 361 mg of MCC-555 as white crystals (90% of theoretical yield). Melting point: 150-152° C.

example 2

Preparation of MCC-555 (2)

[0047] The mixture of polymorphic forms of the type A and type D crystals obtained in Reference Example 1 (15.0 g) was added to ethanol (68 ml) and suspended with heating under pressure in an autoclave at 78° C. for 3 hours. Then, the mixture was cooled to room temperature and further stirred for 1 hour. The reaction mixture was filtered, and the filter cake was washed with ethanol and dried under reduced pressure to obtain 14.6 g of MCC-555 as white crystals (97% of theoretical yield). Melting point: 150-152° C.

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Abstract

The invention relates to type A crystal of 5-[{6-(2-fluorobenzyl)oxy-2-naphtyl}methyl]-2,4-thiazolidinedione characterized to have characteristic absorption peaks (2θ) at 11.5°±0.3°, 14.5°±0.2°, 16.2°±0.3°, 17.0°±0.3°, 17.7°±0.2°, 18.6°±0.3°, 19.1°±0.2°, 21.3°±0.4°, 22.4°±0.5°, 25.7°±1.5° and 28.3°±10.5° in a powder X-ray diffraction pattern, and also to a method for preparation thereof, and a pharmaceutical composition comprising the same. The crystal is excellent in stability, and has advantages in handling, storage, and pharmaceutical preparation. The invention also relates to type B, C and D crystals of said compound.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a stable and novel type A crystal of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl)-2,4-thiazolidinedione (referred to as “MCC-555” in the specification), which is useful as an active ingredient of therapeutic medicaments for diabetes and a complication thereof, hyperlipidemia and a complication thereof and the like. BACKGROUND OF THE INVENTION [0002] Diabetes is a complicated disease caused by hyperglycemia, and the disease is brought by deficiency of insulin action which reduces blood glucose. Diabetes can be classified into several types based on their pathologic state. Among them, those regarded as important are insulin dependent diabetes (type I diabetes) which requires supplement of insulin because of its deficiency, and non-insulin dependent diabetes (type II diabetes) where insulin fails to effect due to abnormalities of receptors, saccharide transporting carriers and the like, although sufficient amount of insulin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D277/34C07D277/20A61K31/426A61P1/18A61P3/06A61P3/10A61P19/06A61P35/02
CPCC07D277/34A61P1/18A61P19/06A61P35/02A61P3/06A61P3/10
Inventor OE, TAKAYUKIUENO, HIROAKIMARUYAMA, AKIRAMASUDA, KATSUHIKO
Owner TAKAYUKI