Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-12
2002-09-17
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S390000
Reexamination Certificate
active
06451831
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an improving agent for hypoalbuminaemia containing a hydantoin derivative or a pharmaceutically acceptable salt thereof as an effective ingredient.
BACKGROUND OF THE INVENTION
The concentration of serum albumin is 3.5-5.5 g/dL in healthy subjects. When the concentration is lowered to less than 3.5 g/dL, such condition is diagnosed as hypoalbuminaemia. Serious hypoalbuminaemia with less than 3.0 g/dL of serum albumin concentration is clinically significant. Hypoalbuminaemia causes symptoms such as edema and ascites, and worsens disorders by hyperbilirubinemia. This disease occurs from various causes such as a decrease in albumin synthesis, loss of albumin from blood and dilution of plasma. Albumin is synthesized only by hepatocytes and a decrease in their synthesis causes hypoalbuminaemia. The main causes of a decrease in the synthesis of albumin are a deficiency of amino acid supply by nutrition disorders and a lowered ability for albumin synthesis by hepatic disease. The loss of albumin from blood is caused by renal failure such as nephritic syndrome, traumatic injury such as burn and protein-losing gastroenteropathy. Dilution of plasma owing to heart failure, accelerated catabolism by hyperthyroidism and the like also cause hypoalbuminaemia. As a remedy for hypoalbuminaemia, dietetic therapy using a high protein diet and drug therapy by total amino acid preparations have been performed. However, in the case of intravenous administration of amino acids, caution is needed against an exhibition of side effects such as acid-base balance disorder, hyperammonaemia, imbalance of amino acids and azotemia. Also, when blood protein preparations are used, there are characteristic problems with such preparations such as contamination with virus.
As mentioned above, amino acid preparations and blood preparations for intravenous administration are mainly used at present as a therapeutic drug for hypoalbuminaemia. There is a strong demand in the clinical field for a therapeutic agent having higher safety and which can be orally administrated.
Several hydantoin compounds of the present invention were found as novel substances having plant growth controlling action. As a result of investigations thereafter for the compounds including analogs thereof, they have been found to have pharmacological actions such as hypoglycemic and hypolipemic actions, and also exhibit low toxicity resulting in almost no side effects. See U.S. Pat. Nos. 4,647,574 and 4,683,240, each to Ienaga et al, and Japanese Laid-Open Patent Publications Sho-57/114578, Sho-60/188373, Sho-61/122275, Sho-62/45525, Sho-62/14, Hei-01/75473, Hei-01/299276, etc.). It has been also disclosed that the compounds of the present invention are useful as: 1) agents for lowering uremic toxin (Japanese Laid-Open Patent Publication Hei-03/72463), 2) eliminating agents of active oxygen and free radicals (Japanese Laid-Open Patent Publication Hei-09/227377), and 3) therapeutic agents for intractable vasculitis (Japanese Laid-Open Patent Publication 2000/212083 and U.S. Pat. No. 6,251,929 B1). However, the therapeutic effect of the compounds of the present invention for hypoalbuminaemia has not ever been found.
The present inventors have carried out intensive investigations and have found that the hydantoin derivatives of the present invention have a therapeutic effect for hypoalbuminaemia whereupon the present invention has been accomplished. The compounds of the present invention are less toxic and have almost no side effect, and accordingly they are quite useful as an improving agent for hypoalbuminaemia having higher safety and are capable of oral administration.
The present invention solves the above-mentioned problems and provides a highly safe therapeutic agent for hypoalbuminaemia which can be oral administration.
SUMMARY OF THE INVENTION
The hydantoin derivatives and their pharmaceutically acceptable salts of the present invention may be us ed as therapeutic agents for the treatment of hypoalbuminaemia in patients known to be in need of such treatment. In embodiments of the present invention patients may be treated for hypoalbuminaemia caused by: 1) a deficiency of amino acid supply caused by nutrition disorders, 2) a lowered ability for albumin synthesis due to hepatic disease, 3) loss of albumin from blood due to renal failure such as nephritic syndrome, 4) traumatic injury such as burn, 5) protein-losing gastroenteropathy, 6) dilution of plasma owing to heart failure, and 7) accelerated catabolism by hyperthyroidism, and the like.
The pharmaceutical compositions employed in the present invention include at least one hydantoin derivative represented by the general formula (I) or pharmaceutically acceptable salts of the derivatives represented by the general formula (I):
wherein each of R
1
and R
2
, which may be the same or different, is hydrogen, an alkyl group or a cycloalkyl group; and each of X and Y, which may be the same or different, is hydrogen, a hydroxyl group, an alkyl group or an alkoxy group, or X and Y together represent an oxo group.
The hydantoin derivatives and their pharmaceutically acceptable salts may be administered orally or parenterally to patients in need of treatment in pharmaceutically effective amounts with little, if any side effects, low toxicity, and high safety to substantially increase serum albumin levels or values in patients diagnosed with hypoalbuminaemia.
DETAILED DESCRIPTION OF THE INVENTION
The effective ingredient of the improving agent for hypoalbuminaemia according to the present invention is a hydantoin derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein each of R
1
and R
2
, which may be the same or different, represents hydrogen, an alkyl group or a cycloalkyl group; and each of X and Y, which may be the same or different, represents hydrogen, a hydroxyl group, an alkyl group or an alkoxy group, or X and Y together represent an oxo group.
In the above mentioned formula (I), each of R
1
and R
2
, which may be the same or different, represents hydrogen, an alkyl group, preferably a straight or branched alkyl group having 1 to 20 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl or stearyl; or a cycloalkyl group, preferably a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
Each of X and Y, which may be the same or different, represents hydrogen, a hydroxyl group, an alkyl group, preferably a straight or branched alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl, isopropyl; or an alkoxy group, preferably a straight or branched alkoxy group having 1 to 5 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy; or X and Y together represent an oxo group.
Preferred compounds of the present invention are:
[Compound 1] Hydantoin
[Compound 2] 1-Methylhydantoin
[Compound 3] 3-Methylhydantoin
[Compound 4] 1-Ethylhydantoin
[Compound 5] 1-Propylhydantoin
[Compound 6] 1-Butylhydantoin
[Compound 7] 1-t-Butylhydantoin
[Compound 8] 1-Hexylhydantoin
[Compound 9] 1-(1,3-Dimethylbutyl)hydantoin
[Compound 10] 1-Decylhydantoin
[Compound 11] 1-Stearylhydantoin
[Compound 12] 1,3-Dimethylhydantoin
[Compound 13] 1,5-Dimethylhydantoin
[Compound 14] 3,5-Dimethylhydantoin
[Compound 15] 1-Cyclopentylhydantoin
[Compound 16] 1-Cyclohexylhydantoin
[Compound 17] 1-Cyclohexyl-3-methylhydantoin
[Compound 18] 3-Cyclohexylhydantoin
[Compound 19] 1,3-Dicyclohexylhydantoin
[Compound 20] 5-Hydroxyhydantoin
[Compound 21] 5-Hydroxy-1-methylhydantoin
[Compound 22] 5-Hydroxy-3-methylhydantoin
[Com
Ienaga Kazuharu
Mikami Hiroki
Nishibata Ryoji
Henley III Raymond
Hollander Law Firm, P.L.C.
Nippon Zoki Pharmaceutical Co. Ltd.
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