U.S. patent application number 10/074772 was filed with the patent office on 2002-10-10 for agent for hypoalbuminaemia.
Invention is credited to Ienaga, Kazuharu, Mikami, Hiroki, Nishibata, Ryoji.
Application Number | 20020147228 10/074772 |
Document ID | / |
Family ID | 18898735 |
Filed Date | 2002-10-10 |
United States Patent
Application |
20020147228 |
Kind Code |
A1 |
Ienaga, Kazuharu ; et
al. |
October 10, 2002 |
AGENT FOR HYPOALBUMINAEMIA
Abstract
A highly safe and useful therapeutic agent for hypoalbuminaemia
contains a hydantoin derivative represented by the formula (I) or a
pharmaceutically acceptable salt thereof as an effective
ingredient: 1 wherein each of R.sub.1 and R.sub.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.
Administration of the compounds substantially increases the serum
albumin value of patients suffering from hypoalbuminaemia from
abnormal values, and significantly improves the condition of
hypoalbuminaemia.
Inventors: |
Ienaga, Kazuharu; (Osaka,
JP) ; Mikami, Hiroki; (Katoh-gun, JP) ;
Nishibata, Ryoji; (Katoh-gun, JP) |
Correspondence
Address: |
HOLLANDER LAW FIRM, P.L.C.
SUITE 305
10300 EATON PLACE
FAIRFAX
VA
22030
|
Family ID: |
18898735 |
Appl. No.: |
10/074772 |
Filed: |
February 12, 2002 |
Current U.S.
Class: |
514/389 |
Current CPC
Class: |
A61K 31/4166 20130101;
A61P 7/00 20180101; A61P 1/00 20180101 |
Class at
Publication: |
514/389 |
International
Class: |
A61K 031/4166 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 13, 2001 |
JP |
35262/2001 |
Claims
What is claimed is:
1. A method for the treatment of hypoalbuminaemia comprising
administering to a patient in need of such treatment a
pharmaceutically effective amount of at least one hydantoin
derivative represented by the formula (I) or a pharmaceutically
acceptable salt, hydrate or complex thereof, said hydantoin
derivative being represented by the formula (I): 4wherein, each of
R.sub.1 and R.sub.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 is an
oxo group.
2. A method as claimed in claim 1 wherein one of X and Y is
hydrogen.
3. A method as claimed in claim 2 wherein the other of X and Y is a
hydroxyl group.
4. A method as claimed in claim 3 wherein one of R.sub.1 and
R.sub.2 is an alkyl group and the other is hydrogen.
5. A method as claimed in claim 4 wherein R.sub.1 is alkyl.
6. A method as claimed in claim 5 wherein R.sub.1 is an alkyl
having 1 to 4 carbon atoms.
7. A method as claimed in claim 6 wherein R.sub.1 is methyl.
8. A method as claimed in claim 1 wherein said hypoalbuminaemia is
caused by hepatic disease.
9. A method as claimed in claim 1 wherein said hypoalbuminaemia is
caused by a nutrition disorder.
10. A method as claimed in claim 1 wherein said hypoalbuminaemia is
caused by renal failure.
11. A method as claimed in claim 1 wherein said hypoalbuminaemia is
caused by traumatic injury.
12. A method as claimed in claim 1 wherein said hypoalbuminaemia is
caused by protein-losing gastroenteropathy.
13. A method as claimed in claim 1 wherein said hypoalbuminaemia is
caused by heart failure.
14. A method as claimed in claim 1 wherein said hypoalbuminaemia is
caused by hypercatabolism.
15. A method as claimed in claim 1 wherein said at least one
hydantoin derivative is administered to substantially increase the
serum album value of said patient to at least 3.0 g/dL.
16. A method for treating hypoalbuminaemia comprising administering
to a patient in need of such treatment a pharmaceutical composition
comprising a pharmaceutically effective amount of at least one
hydantoin derivative represented by the formula (I) or a
pharmaceutically acceptable salt, hydrate or complex thereof, and a
pharmaceutically acceptable carrier, said hydantoin derivative
being represented by the formula (I): 5wherein, each of R.sub.1 and
R.sub.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 is an oxo group.
17. A method as claimed in claim 16 wherein one of X and Y is
hydrogen.
18. A method as claimed in claim 17 wherein the other of X and Y is
a hydroxyl group.
19. A method as claimed in claim 18 wherein one of R.sub.1 and
R.sub.2 is an alkyl group and the other is hydrogen.
20. A method as claimed in claim 19 wherein R.sub.1 is methyl.
21. A method as claimed in claim 12 wherein said hypoalbuminaemia
is caused by a disease or condition selected from the group
consisting of nutrition disorders, hepatic disease, renal failure,
traumatic injury, protein-losing gastroenteropathy, heart failure,
and accelerated catabolism by hyperthyroidism.
22. A method for the treatment of hypoalbuminaemia comprising
determining the serum albumin value of a patient and administering
to a patient in need of such treatment a pharmaceutically effective
amount of at least one hydantoin derivative represented by the
formula (I) or a pharmaceutically acceptable salt, hydrate or
complex thereof to substantially increase the serum albumin value,
said hydantoin derivative being represented by the formula (I):
6wherein, each of R.sub.1 and R.sub.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 is an oxo group.
23. A method as claimed in claim 22 wherein said hypoalbuminaemia
is caused by a disease or condition selected from the group
consisting of nutrition disorders, hepatic disease, renal failure,
traumatic injury, protein-losing gastroenteropathy, heart failure,
and accelerated catabolism by hyperthyroidism.
24. A method as claimed in claim 23 wherein said at least one
hydantoin derivative is administered to substantially increase the
serum album value of said patient to at least 3.0 g/dL.
Description
FIELD OF THE INVENTION
[0001] 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
[0002] 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.
[0003] 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.
[0004] 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 lenaga
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.
[0005] 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.
[0006] The present invention solves the above-mentioned problems
and provides a highly safe therapeutic agent for hypoalbuminaemia
which can be orally administered.
SUMMARY OF THE INVENTION
[0007] The hydantoin derivatives and their pharmaceutically
acceptable salts of the present invention may be used 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.
[0008] 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): 2
[0009] wherein each of R.sub.1 and R.sub.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.
[0010] 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
[0011] 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: 3
[0012] wherein each of R.sub.1 and R.sub.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.
[0013] In the above mentioned formula (I), each of R.sub.1 and
R.sub.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.
[0014] 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.
[0015] Preferred compounds of the present invention are:
[0016] [Compound 1] Hydantoin
[0017] [Compound 2] 1-Methylhydantoin
[0018] [Compound 3] 3-Methylhydantoin
[0019] [Compound 4] 1-Ethylhydantoin
[0020] [Compound 5] 1-Propylhydantoin
[0021] [Compound 6] 1-Butylhydantoin
[0022] [Compound 7] 1-t-Butylhydantoin
[0023] [Compound 8] 1-Hexylhydantoin
[0024] [Compound 9] 1-(1,3-Dimethylbutyl) hydantoin
[0025] [Compound 10] 1-Decylhydantoin
[0026] [Compound 11] 1-Stearylhydantoin
[0027] [Compound 12] 1,3-Dimethylhydantoin
[0028] [Compound 13] 1,5-Dimethylhydantoin
[0029] [Compound 14] 3,5-Dimethylhydantoin
[0030] [Compound 15] 1-Cyclopentylhydantoin
[0031] [Compound 16] 1-Cyclohexylhydantoin
[0032] [Compound 17] 1-Cyclohexyl-3-methylhydantoin
[0033] [Compound 18] 3-Cyclohexylhydantoin
[0034] [Compound 19] 1,3-Dicyclohexylhydantoin
[0035] [Compound 20] 5-Hydroxyhydantoin
[0036] [Compound 21] 5-Hydroxy-1-methylhydantoin
[0037] [Compound 22] 5-Hydroxy-3-methylhydantoin
[0038] [Compound 23] 5-Hydroxy-1-ethylhydantoin
[0039] [Compound 24] 5-Hydroxy-1-propylhydantoin
[0040] [Compound 25] 5-Hydroxy-1-butylhydantoin
[0041] [Compound 26] 5-Hydroxy-1-t-butylhydantoin
[0042] [Compound 27] 5-Hydroxy-1-hexylhydantoin
[0043] [Compound 28] 5-Hydroxy-1-(1,3-dimethylbutyl) hydantoin
[0044] [Compound 29] 5-Hydroxy-1-decylhydantoin
[0045] [Compound 30] 5-Hydroxy-1-stearylhydantoin
[0046] [Compound 31] 5-Hydroxy-1-cyclopentylhydantoin
[0047] [Compound 32] 5-Hydroxy-1-cyclohexylhydantoin
[0048] [Compound 33] 5-Hydroxy-1-cyclohexyl-3-methylhydantoin
[0049] [Compound 34] 5-Hydroxy-1,3-dimethylhydantoin
[0050] [Compound 35] 5-Hydroxy-1,5-dimethylhydantoin
[0051] [Compound 36] 5-Hydroxy-3,5-dimethylhydantoin
[0052] [Compound 37] 5-Hydroxy-1,3-dicyclohexylhydantoin
[0053] [Compound 38] 5-Methoxyhydantoin
[0054] [Compound 39] 5-Methoxy-1-methylhydantoin
[0055] [Compound 40] 5-Methoxy-3-methylhydantoin
[0056] [Compound 40] 5-Methoxy-1-ethylhydantoin
[0057] [Compound 43] 5-Methoxy-1-butylhydantoin
[0058] [Compound 44] 5-Methoxy-1-cyclohexylhydantoin
[0059] [Compound 45] 5-Methoxy-3-cyclohexylhydantoin
[0060] [Compound 46] 5-Ethoxyhydantoin
[0061] [Compound 47] 5-Ethoxy-1-methylhydantoin
[0062] [Compound 48] 5-Ethoxy-3-methylhydantoin
[0063] [Compound 49] 5-Ethoxy-1-ethylhydantoin
[0064] [Compound 50] 5-Ethoxy-1-propylhydantoin
[0065] [Compound 51] 5-Ethoxy-1-butylhydantoin
[0066] [Compound 52] 5-Propoxyhydantoin
[0067] [Compound 53] 5-Propoxy-1-methylhydantoin
[0068] [Compound 54] 5-Propoxy-3-methylhydantoin
[0069] [Compound 55] 5-Propoxy-1-ethylhydantoin
[0070] [Compound 56] 5-Propoxy-1-propylhydantoin
[0071] [Compound 57] 5-Propoxy-1-butylhydantoin
[0072] [Compound 58] 5-Butoxyhydantoin
[0073] [Compound 59] 5-Butoxy-1-methylhydantoin
[0074] [Compound 60] 5-Butoxy-3-methylhydantoin
[0075] [Compound 61] 5-t-Butoxyhydantoin
[0076] [Compound 62] 5-t-Butoxy-1-methylhydantoin
[0077] [Compound 63] 5-t-Butoxy-3-butylhydantoin
[0078] [Compound 64] Imidazolidinetrione
[0079] [Compound 65] 1-Methylimidazolidinetrione
[0080] [Compound 66] 1-Ethylimidazolidinetrione
[0081] [Compound 67] 1-Butylimidazolidinetrione
[0082] [Compound 68] 1-Isobutylimidazolidinetrione
[0083] [Compound 69] 1-t-Butylimidazolidinetrione
[0084] [Compound 70] 1-Hexylimidazolidinetrione
[0085] [Compound 71] 1-(1,3-Dimethylbutyl)imidazolidinetrione
[0086] [Compound 72] 1-Decylimidazolidinetrione
[0087] [Compound 73] 1-Cyclopentylimidazolidinetrione
[0088] [Compound 74] 1-Cyclopentyl-3-ethylimidazolidinetrione
[0089] [Compound 75] 1-Cyclohexylimidazolidinetrione
[0090] [Compound 76] 1,3-Dimethylimidazolidinetrione
[0091] [Compound 77] 1,3-Dicyclohexylimidazolidinetrione
[0092] The hydantoin derivatives of the present invention include
the pharmaceutically acceptable salts of the compounds represented
by the above given formula (I). Exemplary salts of the present
invention are acid addition salts of the hydantoin derivatives of
general formula (I) with hydrochloric acid, sulfuric acid, nitric
acid, hydrobromic acid, phosphoric acid, perchloric acid,
thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic
acid, propionic acid, glycolic acid, citric acid, tartaric acid,
succinic acid, gluconic acid, lactic acid, malonic acid, fumaric
acid, anthranilic acid, benzoic acid, cinnamic acid,
p-toluenesulfonic acid, naphthalenesulfonic acid, or sulfanilic
acid. Other salts of the present invention include salts of the
hydantoin derivatives of general formula (I) with: a) an alkali
metal such as sodium and potassium, b) an alkaline-earth metal such
as calcium, magnesium and barium, and c) other metals such as
aluminum and zinc.
[0093] The pharmaceutically acceptable salts may be manufactured by
conventional methods, starting from the hydantoin derivatives of
the present invention in a free state or free form, or by
conversion from one salt to another salt.
[0094] When there are steric isomers or stereoisomers such as
cis-trans isomers, optical isomers, or conformational isomers,
hydrates or complexes for the compounds of the present invention,
the present invention includes any and all of such isomers,
hydrates and complexes.
[0095] The compounds of the present invention may be manufactured
by conventional methods as disclosed, for example, in Japanese Laid
Open (Kokai) Nos. 61/122275 (published Jun. 10, 1986) and 62/14
(published Jan. 6, 1987) and their corresponding U.S. Pat. Nos.
4,647,574 and 4,683,240 each to lenaga et al, respectively. The
disclosures of each of said Japanese publications and U.S. Pat.
Nos. 4,647,574 and 4,683,240 are herein incorporated by reference
in their entireties. For example, hydantoin derivatives of the
present invention may be produced by methods as disclosed in U.S.
Pat. No. 4,647,574 at column 2 line 39 to column 3 line 32. Thus,
the hydantoin derivatives may be produced by first conventionally
esterifying a glyoxylic acid. For example, a glyoxylic acid is
reacted with an alcohol or 2-methoxyethanol, at room temperature or
at a suitable temperature above room temperature or under reflux,
for about several hours to about a day, with the produced water
being removed, in the presence of an organic acid catalyst such as
p-toluene-sulfonic acid or camphorsulfonic acid in an aprotic
solvent such as benzene, toluene, xylene or carbon tetrachloride.
Then the produced glyoxylic acid ester or an o-alkylglyoxylic acid
ester (glyoxylic acid ester alcoholate) is, without being isolated
or further purified, reacted at room temperature or heated under
reflux for about 1 hour to about several days with, e.g.,
N-alkylurea, N-cycloalkylurea, N,N'dialkylurea or
N,N'-dicycloalkylurea in an appropriate solvent such as water,
acetic acid or alcohol, such as butanol or mixtures thereof, to
give compounds of the present invention represented by the general
formula (I).
[0096] The above-mentioned reaction can also be carried out with an
.alpha.-ketocarbonic acid such as pyruvic acid as the starting
material instead of a glyoxylic acid.
[0097] The compounds of the present invention wherein X or Y is an
alkoxy group may be produced from a hydantoin derivative as
prepared, e.g., by the process described above, by a conventional
O-alkylation process. The hydantoin derivatives may be reacted with
p-toluenesulfonyl chloride or mesyl chloride to introduce a
removable residue into the hydroxy group at the 5-position, in the
presence of an organic base such as a lower alkylamine or an alkali
metal alkoxide in an appropriate solvent which does not inhibit the
reaction. During or after the reaction, the resultant product is
reacted with the alcohol corresponding to the X or Y substituent of
the desired hydantoin derivative to give the compound of the
present invention. This O-alkylation may be carried out at room
temperature or at a suitable temperature above room temperature or
under reflux, for about several hours to about several days.
[0098] The compounds of the present invention also include products
from the N-alkylation of the hydantoin derivatives. The hydantoin
derivative is reacted with a halogenated alkyl, a halogenated
cycloalkyl, a dialkylsulfuric acid such as dimethylsulfonic acid, a
p-toluenesulfonic acid alkyl ester or a p-toluenesulfonic acid
cycloalkyl ester, in the presence of a base such as a lower alkyl
amine, an alkali metal alkoxide or a hydroxyalkyl metal in an
appropriate solvent which does not inhibit the reaction such as
absolute alcohol, or dimethyl sulfoxide. The N-alkylation may be
carried out at room temperature or at a suitable temperature above
room temperature for about several hours to about several days.
[0099] When X and Y represent an oxo group, the hydantoin
derivatives or imidazolidinetrione derivatives of the present
invention may be produced by methods as disclosed in T. Yonezawa et
al, Nippon Kagaku Zasshi, 89, No. 8, pp 62-64 (1968), Tad L.
Patton, J. Org. Chem., 32, No. 2, 383-388 (1967), and U.S. Pat. No.
4,683,240 at column 3 lines 27-49. For example, as disclosed in
U.S. Pat. No. 4,683,240, oxalyl chloride and an N-substituted urea,
such as an N-alkylurea, or N-cycloalkylurea may be stirred in an
appropriate solvent such as tetrahydrofuran which does not inhibit
the reaction in an ice-water bath or at room temperature.
Alternatively, diethyl oxalate and the above-mentioned
N-substituted urea may be stirred in an appropriate solvent which
does not inhibit the reaction in the presence of an organic base
such as an amine or alkali metal alkoxide at room temperature, if
desired, by heating to higher temperatures to give the
imidazolidinetrione derivatives of the present invention.
[0100] The compounds of the invention can also be prepared by
conventional N-alkylation wherein unsubstituted, 1-alkylsubstituted
or 1-cycloalkylsubstituted imidazolidinetrione is reacted with
halogenated alkyl.
[0101] The compounds of the present invention prepared as described
above may be purified by conventional methods such as distillation,
chromatography and recrystallization. The compounds may be
identified by means of, for example, elementary analysis, melting
point measurement, infrared (IR), nuclear magnetic resonance (NMR),
ultraviolet (UV), and mass spectroscopy (MS).
[0102] The compounds of the present invention, which include the
hydantoin derivatives and their pharmaceutically acceptable salts
and complexes, can be made into pharmaceutical preparations by
combining one or more of the compounds with at least one
pharmaceutically acceptable carrier or diluent. Any of the known
methods for providing preparations, such as for oral
administrations (e.g. tablets, capsules, powders, liquids, etc.)
and for parenteral administrations (e.g. for subcutaneous,
intravenous, intramuscular, intrarectal and intranasal
administrations) may be used to produce the pharmaceutical
compositions of the present invention. In preparing the
preparations, the hydantoin derivatives of the present invention
may be used in the form of their pharmaceutically acceptable salts.
The compounds of the present invention may be used either solely or
jointly in pharmaceutically effective amounts for treating animals
or humans. The compounds of the invention can be used either solely
or jointly together in pharmaceutically acceptable amounts with
pharmaceutically effective amounts of other pharmaceutically active
components in pharmaceutical compositions or preparations.
[0103] In the case of preparations for oral administration, one or
more of the compounds of the present invention either alone or in
combination with commonly-used pharmaceutically acceptable
excipients in pharmaceutically acceptable amounts such as at least
one suitable pharmaceutically acceptable additive or carrier (e.g.
lactose, mannitol, corn starch, potato starch, potassium citrate,
etc.) may be mixed with one or more pharmaceutically acceptable:
(1) binders such as cellulose derivatives (e.g. crystalline
cellulose, hydroxypropylcellulose, etc.), gum arabicum, corn
starch, gelatin, etc., (2) disintegrating agents such as corn
starch, potato starch, calcium carboxymethylcellulose, etc., (3)
lubricating agents such as talc, magnesium stearate, etc. and (4)
other pharmaceutically acceptable excipients including
pharmaceutically acceptable bulking agents, moisturizing agents,
buffers, preservatives, perfumes and the like to obtain tablets,
diluted powders, granules or capsules.
[0104] In the case of injections, it is possible to prepare
solutions or suspensions of one or more compounds of the present
invention in pharmaceutically acceptable carriers such as an
aqueous or nonaqueous solvent. Examples of solvents which may be
used are distilled water for injection, physiological saline
solution, Ringer's solution, plant oil, synthetic fatty acid
glycerides, higher fatty acid esters, propylene glycol, etc.
[0105] It is also possible, depending upon the type of the disease,
to prepare pharmaceutical preparations other than the
above-mentioned ones which are suitable for therapy depending upon
the state of the patient. Exemplary of other pharmaceutical
preparations are syrups, suppositories, inhalations, aerosol
preparations, collyriums, medicines for external use (e.g.
ointments, gels, poultices), etc.
[0106] The preferred dosage of the compound of the present
invention varies depending upon the subject to be administered
(age, body weight, symptoms, etc. of the patient), form of the
preparation, method for the administration, term for the
administration, etc. To achieve the desired result, the compound
may be usually administered by the oral route with a daily dose of
1-1,000 mg per day, preferably 5-600 mg per day, to common adults.
In the case of a parenteral administration such as by injection,
the preferred dosage, may be from 1/3 to {fraction (1/10)} of the
above-mentioned oral dosages because of the effects of absorption,
etc. in the oral route.
[0107] Preferred embodiments of the improving agent for
hypoalbuminaemia of the present invention containing the compound
represented by the above formula (I) are:
[0108] (1) A improving agent for hypoalbuminaemia containing the
compound represented by the formula (I) wherein one of X and Y
represents hydrogen as an active ingredient.
[0109] (2) An agent according to the above subparagraph (1) wherein
the other of X and Y represents a hydroxyl group.
[0110] (3) An agent according to the above subparagraph (2) wherein
one of R.sub.1 and R.sub.2 represents an alkyl group and the other
represents hydrogen.
[0111] (4) An agent according to the above subparagraph (3) wherein
R.sub.1 represents an alkyl group.
[0112] (5) An agent according to the above subparagraph (4) wherein
R.sub.1 represents an alkyl group having 1 to 4 carbon atoms.
[0113] (6) An agent according to the above subparagraph (5) wherein
R.sub.1 represents methyl.
[0114] (7) An agent according to one of the above subparagraphs
(1)-(6) which is used for the therapy of hypoalbuminaemia owing to
hepatic disease.
[0115] (8) An agent according to one of the above subparagraphs
(1)-(6) which is used for the therapy of hypoalbuminaemia owing to
nutrition disorders.
[0116] (9) An agent according to one of the above subparagraphs
(1)-(6) which is used for the therapy of hypoalbuminaemia owing to
renal failure.
[0117] (10) An agent according to one of the above subparagraphs
(1)-(6) which is used for the therapy of hypoalbuminaemia owing to
traumatic injury.
[0118] (11) An agent according to one of the above subparagraphs
(1)-(6) which is used for the therapy of hypoalbuminaemia owing to
protein-losing gastroenteropathy.
[0119] (12) An agent according to one of the above subparagraphs
(1)-(6) which is used for the therapy of hypoalbuminaemia owing to
heart failure.
[0120] (13) An agent according to one of the above subparagraphs
(1)-(6) which is used for the therapy of hypoalbuminaemia owing to
hypercatabolism.
[0121] The most preferred compound for use in the present
invention, which has been clinically confirmed as having low
toxicity and lower side effects is 5-hydroxy-1-methylhydantoin
(Compound 21).
[0122] The present invention is illustrated by the following
non-limiting example wherein all parts, percentages and ratios are
by weight, unless indicated to the contrary:
EXAMPLE
[0123] In this example, the unexpected increase in albumin values
in patients in need of treatment for hypoalbuminaemia is
demonstrated by the results of a clinical test.
[0124] The compound of the present invention (Compound 21) was
administered to 6 patients suffering from hypoalbuminaemia (serum
albumin value was less than 3.0 g/dL) at the dose of 200 mg/day
(dosage for only Patient 1 was 400 mg/day). Serum albumin values
were compared between before and after administration for 24 weeks
(after 16 weeks in case of only Patient 2). The result wherein a
significant difference was statistically analyzed by a paired
t-test is shown in Table 1. The serum albumin values were
significantly increased by the administration of the compound of
the present invention and, therefore, it showed an improving effect
for hypoalbuminaemia. In another case of tested subjects showing a
normal value of serum albumin, any change of the value was not
noted by the administration of the compounds of the present
invention.
1 TABLE 1 After Administration Before Administration for 24 weeks
Patient 1 1.7 g/dL 2.1 g/dL Patient 2 2.0 g/dL 2.3 g/dL Patient 3
2.3 g/dL 3.4 g/dL Patient 4 2.4 g/dL 2.7 g/dL Patient 5 2.5 g/dL
3.2 g/dL Patient 6 2.7 g/dL 3.0 g/dL Mean Value 2.3 .+-. 0.2 g/dL
2.8 .+-. 0.2* g/dL p <0.01
[0125] It is apparent from the above-mentioned clinical test that
the administration of the compound of the present invention gave an
increase of serum albumin value in patients suffering from
hypoalbuminaemia and, therefore, an improving effect of the
compound of the present invention for hypoalbuminaemia was shown.
Consequently, the compounds of the present invention are very
useful as a therapeutic agent for hypoalbuminaemia. The compounds
of the present invention do not affect subjects with normal values
of serum albumin, and therefore it is considered that the compounds
of this invention show an effect only in a morbid or diseased state
wherein the serum albumin value is abnormally lowered. In addition,
it has been shown by both animal and clinical tests that the
compounds of the present invention have little side effect. Thus,
the compounds of the present invention have both high safety and
therapeutic effect, and accordingly, the compounds of this
invention are very useful as a drug for hypoalbuminaemia available
for oral and long-term administration.
[0126] In embodiments of the invention, hypoalbuminaemia and
diseases or conditions which cause it may be treated in a patient
in need of such treatment by measuring the serum albumin,
determining whether the serum albumin level of the patient is
present at an abnormal level, for example below about 3.5 g/dL,
generally below about 3.0 g/dL, and administering a hydantoin
derivative of the present invention to increase the albumin level
to a normal level so as to alleviate symptoms of the disease or
condition. In embodiments of the present invention, at least one
hydantoin derivative may administered to substantially increase the
serum album value of a patient, for example from an abnormally low
value of less than or equal to 2.5 g/dL to a value of at least 3.0
g/dL, preferably at least 3.5 g/dL.
[0127] Accordingly, the hydantoin derivatives of the present
invention may be employed in accordance with the present invention
for the treatment of diseases or conditions other than diabetes,
diabetic complications, intractable vasculitis, and those requiring
hypoglycemic or hypolipemic action, or lowering of uremic toxin.
Thus, the hydantoin derivatives of the present invention may be
used for the treatment of diseases or conditions which cause
hypoalbuminaemia, such as nutrition disorders, hepatic disease,
renal failure, such as nephritic syndrome, traumatic injury such as
burn, protein-losing gastroenteropathy, heart failure, accelerated
catabolism by hyperthyroidism, and the like by substantially
increasing serum albumin levels from abnormally low levels to near
normal or normal levels.
* * * * *