Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-02-25
2000-05-16
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548186, A61K 31425, C07D27704
Patent
active
060637994
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a novel physical form of (.+-.)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl}-4-thiazolidi none useful in the treatment of inflammation, inflammatory bowel disease (hereinafter IBD), allergies, arthritis, hypoglycemia and muscular dystrophy and in preventing ischemia induced cell damage.
Benzyl-substituted rhodanine derivatives are known to be active in treating inflammation, inflammatory bowel disease (hereinafter IBD), allergies, arthritis, hypoglycemia and muscular dystrophy and in preventing ischemia induced cell damage. For example, U.S. Pat. No. 5,216,002 discloses that certain benzyl-substituted rhodanine derivatives are useful for treating IBD. EPO Publication No. 391644, on the other hand, discloses the effectiveness of such compounds for treating inflammation, arthritis, and muscular dystrophy and for preventing ischemia induced cell damage. EPO Publication No. 343643 describes the use of such compounds for treating allergies and inflammation, while EPO Publication No. 587377 discloses these compounds as being effective in treating hypoglycemia.
Tazofelone is a generic term used to identify the chemical compound (.+-.)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl}-4-thiazolidi none represented by the structural formula: ##STR1##
Tazofelone is particularly useful in treating inflammatory bowel diseases (IBD), ulcerative colitis and Chrohn's disease.
Tazofelone has a chiral center and, as such, can exist either as individual stereoisomers or in racemic form. Both the racemate and stereoisomers may be obtained according to procedures well known in the art. as described in U.S. Pat. No. 5,356,917 and U.S. Pat. No. 5,216,002, herein incorporated by reference.
It is desirable to prepare therapeutic agents of uniform and defined composition.
This invention provides a new, substantially pure crystalline form II of (.+-.)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl}-4-thiazolidi none having a typical x-ray powder diffraction pattern with characteristic d spacing at 5.64 .ANG..
The method of this invention also provides a process for producing this substantially pure form II of (.+-.)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl}-4-thiazolidi none.
In another embodiment of this invention, there is provided a pharmaceutical formulation containing the substantially pure form II Tazofelone as an active ingredient.
Finally, the present invention provides a method of using the new substantially pure form to prevent and/or treat inflammation, inflammatory bowel disease, allergies, arthritis, hypoglycemia and muscular dystrophy and in preventing ischemia-induced cell damage.
Applicants have discovered that the 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl}-4-thiazolidinone racemate exists in two different physical forms which are distinguishable by x-ray powder diffractometry, solid-state Nuclear Magnetic Resonance (NMR) or differential scanning calorimetry. The two polymorphic forms of the racemate are hereinafter designated Form I and Form II.
Both forms of Tazofelone are non-solvated and stable indefinitely at room temperature.
Form I is the predominant crystal form at temperatures from about 60.degree. C. to about 155.degree. C. Substantially pure Form I can be obtained in a laboratory setting by refluxing 3,5-di-tert-butyl-4-hydroxybenzaldehyde with rhodanine in glacial acetic acid using fused sodium acetate as a catalyst to form 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]}-methylene-2-thioxo-4-thia zolidinone. The resultant 2-thioxo-4-thiazolidinone can then be reduced with hydrogen in the presence of palladium on carbon. The product is isolated by chromatography, and the solvent is removed to afford Form I Tazofelone. In an alternate preparation, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]}-methylene-2-thioxo-4-thia zolidinone can be refluxed with diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and activated silica gel to form (.+-.)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methyl}-2-thioxo-4- thiazolidinone. T
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Hansen Marvin M
Harkness Allen R
Reutzel Susan M
Eli Lilly and Company
Harvey Suzanne M.
Henley III Raymond
Lentz Nelsen L.
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