Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-15
2002-07-16
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S315100
Reexamination Certificate
active
06420412
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a pharmaceutically active compound, a process for its production, compositions containing the compound and methods of using the compound in the treatment of certain disease states in mammals, in particular man. More specifically, the present invention relates to (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dihydrate, a wet granulation process for preparing said compound, compositions containing this compound, and methods of using (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dihydrate to block angiotensin II (AII) receptors and to treat hypertension, congestive heart failure and renal failure.
BACKGROUND OF THE INVENTION
The compound (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate is known by the name “eprosartan” and is the subject of U.S. Pat. No. 5,185,351 (the '351 patent), issued Feb. 9, 1993. This patent discloses in Example 41 a process for making the anhydrous form of (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate. Additionally, the '351 patent discloses conventional techniques for formulating (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate and Examples 108-111 specifically detail the preparation of certain formulations. This compound is claimed to have utility in blocking angiotensin II receptors and to be useful in the treatment of hypertension, congestive heart failure and renal failure.
Surprisingly, it has been found that the dihydrated form of (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate is formed in situ during the wet granulation process for preparing solid dosage forms of the anhydrous form of said compound. Additionally, it has been found that the dihydrate of eprosartan is obtained by recrysallizing the anhydrouus form from an aqueous acidic solution. The dihydrate has the improved property of being more compactible in the solid dosage form when compared to the corresponding anhydrous form of the compound. This is particularly important when formulating (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethane-sulfonate for therapeutic use.
SUMMARY OF THE INVENTION
The present invention provides a novel dihydrated form of (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate, in particular, in pharmaceutical compositions for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal failure.
The present invention also provides a process for preparing (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dihydrate during wet granulation of the anhydrous form of (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate.
Another aspect of this invention provides a process for preparing (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate dibydrate by recrystallizing the anhydrous form of (E)-&agr;[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate from an aqueous acidic solution, in particular, an aqueous solution of methanesulfonic acid.
REFERENCES:
patent: 5185351 (1993-02-01), Finkelstein et al.
Duddu Sarma
Palepu Nageswara R.
Venkatesh Gopadi M.
Kinzig Charles M.
Lambkin Deborah C.
Madden Laura K.
McCarthy Mary E.
SmithKline Beecham Corporation
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