U.S. patent application number 11/572251 was filed with the patent office on 2008-02-21 for progression inhibitor for disease attributed to abnormal accumulation of liver fat.
Invention is credited to Yoshikazu Fujimori, Masayuki Isaji, Kenji Katsuno.
Application Number | 20080045466 11/572251 |
Document ID | / |
Family ID | 35785257 |
Filed Date | 2008-02-21 |
United States Patent
Application |
20080045466 |
Kind Code |
A1 |
Katsuno; Kenji ; et
al. |
February 21, 2008 |
Progression Inhibitor For Disease Attributed To Abnormal
Accumulation Of Liver Fat
Abstract
The present invention provides pharmaceutical compositions
useful as agents for the inhibition of progression of diseases
associated with abnormal accumulation of liver lipids. In
particular, the pharmaceutical compositions of the present
invention which comprise as an active ingredient a sodium/glucose
co-transporter 2 inhibitor are highly suitable as an agent for the
inhibition of progression of not only common fatty liver but also
non-alcholic fatty liver disease (NAFL), non-alcholic
steatohepatitis (NASH), hypernutritive fatty liver, diabetic fatty
liver, alcholic fatty liver disease toxic fatty liver or the
like.
Inventors: |
Katsuno; Kenji; (Nagano,
JP) ; Fujimori; Yoshikazu; (Nagano, JP) ;
Isaji; Masayuki; (Nagano, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W.
SUITE 800
WASHINGTON
DC
20037
US
|
Family ID: |
35785257 |
Appl. No.: |
11/572251 |
Filed: |
July 19, 2005 |
PCT Filed: |
July 19, 2005 |
PCT NO: |
PCT/JP05/13262 |
371 Date: |
January 17, 2007 |
Current U.S.
Class: |
514/25 |
Current CPC
Class: |
A61K 31/4427 20130101;
A61P 1/16 20180101; A61P 43/00 20180101; A61P 3/10 20180101; A61K
31/155 20130101; A61K 31/7028 20130101; A61P 3/04 20180101; A61P
35/00 20180101; A61P 3/00 20180101; A61K 31/57 20130101; A61P 3/06
20180101; A61K 31/7036 20130101 |
Class at
Publication: |
514/025 |
International
Class: |
A61K 31/7004 20060101
A61K031/7004; A61P 1/16 20060101 A61P001/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 21, 2004 |
JP |
2004-213675 |
Claims
1. A pharmaceutical composition for the inhibition of progression
of a disease associated with abnormal accumulation of liver lipids,
which comprises as an active ingredient a sodium/glucose
co-transporter 2 inhibitor.
2. A pharmaceutical composition for the inhibition of progression
as claimed in claim 1 wherein the sodium/glucose co-transporter 2
inhibitor is 2-(4-methoxybenzyl)phenyl .beta.-D-glucopyranoside or
a pharmaceutically acceptable salt thereof, or a prodrug
thereof.
3. A pharmaceutical composition as claimed in claim 1 which is used
in combination with one or more selected from a group consisting of
metformin, troglitazone, pioglitazone hydrochloride, bezafibrate
and voglibose.
4. A pharmaceutical composition as claimed in claim 2 which is used
in combination with one or more selected from a group consisting of
metformin, troglitazone, pioglitazone hydrochloride, bezafibrate
and voglibose.
1. A pharmaceutical composition for the inhibition of progression
of a disease associated with abnormal accumulation of liver lipids,
which comprises as an active ingredient a sodium/glucose
co-transporter 2 inhibitor.
2. A pharmaceutical composition for the inhibition of progression
as claimed in claim 1 wherein the sodium/glucose co-transporter 2
inhibitor is 2-(4-methoxybenzyl)phenyl .beta.-D-glucopyranoside or
a pharmaceutically acceptable salt thereof, or a prodrug
thereof.
3. A pharmaceutical composition as claimed in claim 1 or 2 which is
used in combination with one or more selected from a group
consisting of metformin, troglitazone, pioglitazone hydrochloride,
bezafibrate and voglibose.
Description
TECHNICAL FIELD
[0001] The present invention relates to an agent for the inhibition
of progression of diseases associated with abnormal accumulation of
liver lipids, which comprises as an active ingredient a
sodium/glucose co-transporter 2 (hereinafter referred to as
SGLT2).
BACKGROUND ART
[0002] The patients with disorders in which lipids are abnormally
accumulated in liver, such as non-alcoholic steatohepatitis (NASH),
hypernutritive fatty liver, diabetic fatty liver, alcoholic fatty
liver, and toxic fatty liver as well as common fatty liver are
increasing year by year. Above all, non-alcoholic steatohepatitis
(NASH) is particularly acknowledged as a problem, because it
exhibits serious symptoms (see non-Patent Reference 1 or 2).
Moreover, it has been pointed out that abnormal lipid accumulation
in liver causes liver inflammation or fibril formation in liver
(liver cirrhosis) and makes shifts to serious disorders such as
liver cancer (see non-Patent References 1 to 4), and thus,
inhibiting this lipid accumulation is extremely important.
[0003] It is believed that various factors including recent
lifestyle changes overlap each other and abnormalities in liver
energy metabolism are caused and as a consequence, lipid
accumulation in liver occurs. Therefore therapeutic modality is not
uniform (see non-Patent Reference 5). Although presently, dietary
therapy, exercise therapy, pharmacotherapy and the like are tried
as remedies for lipid accumulation in liver, these modalities have
difficulties in control or continuing implementation. Therefore,
therapeutic effects are not always satisfied. Meanwhile, in
pharmacotherapy, polyene-phosphatidyl choline preparation is only
listed under coverage. As described above, satisfied treatment
modality for lipid accumulation in liver has not been established,
and thus development of more effective drug for lipid accumulation
has been desired.
[0004] It is known that SGLT2 inhibitors are drugs which exhibit
blood glucose-lowering action by inhibiting sugar reabsorption in
kidney, and are useful as drugs for the prevention or treatment of
diabetes mellitus (for example, see Patent References 1 to 19). In
addition, as to SGLT2 inhibitor, it has been also proposed that
concurrent use of T1095 represented by formula: ##STR1## and a
peroxisome proliferator-activated receptor (hereinafter referred to
as PPAR) agonist or a retinoid X receptor (hereinafter referred to
as RXR) agonist can suppress the onset of side effects such as
fatty liver caused by PPAR agonists or RXR agonists, and therefore
the dosage of PPAR agonist or RXR agonist can be reduced (see
Patent Reference 20 or 21). However, it has not ever been known
that SGLT2 inhibitors exhibit suppressive effects on abnormal
accumulation of liver lipids as described in the present
invention.
[0005] In the treatment of diabetic fatty liver, use of
hypoglycemic agents has been studied (see non-Patent Reference 6).
However, usefulness of diabetic drugs with blood glucose-lowering
actions has been not confirmed, for example, it has been pointed
out that tolbutamide does not exhibit suppressive effects on lipid
accumulation in liver (see non-Patent Reference 7), and may
adversely cause exacerbation of lipid accumulation in liver (see
non-Patent Reference 6).
[0006] In addition, it has been reported that clofibrate of an
antihyperlipidemic agent causes lipid accumulation in liver as a
side effect, while it lowers neutral fat or cholesterol in blood
(see Patent Reference 22). Furthermore, it has been reported that
microsomal triglyceride transfer protein (hereinafter referred to
as MTP) inhibitor of an antihyperlipidemic agent causes lipid
accumulation in liver, while it lowers neutral fat or cholesterol
blood (See Patent References 23 and 24 and non-Patent References 8
and 9). As described above, in use of these antihyperlipidemic
drugs, no correlation is observed in the amount of neutral fat or
cholesterol between in blood and in liver, but induction of fatty
liver is observed in some cases.
Patent Reference 1: International Publication WO02/28872
pamphlet;
Patent Reference 2: International Publication WO02/44192
pamphlet;
Patent Reference 3: International Publication WO02/53573
pamphlet;
Patent Reference 4: International Publication WO01/16147
pamphlet;
Patent Reference 5: International Publication WO01/68660
pamphlet;
Patent Reference 6: International Publication WO03/11880
pamphlet;
Patent Reference 7: International Publication WO03/00712
pamphlet;
Patent Reference 8: International Publication WO02/068440
pamphlet;
Patent Reference 9: International Publication WO02/68439
pamphlet;
Patent Reference 10: International Publication WO02/64606
pamphlet;
Patent Reference 11: International Publication WO03/80635
pamphlet;
Patent Reference 12: International Publication WO02/88157
pamphlet;
Patent Reference 13: International Publication WO02/36602
pamphlet;
Patent Reference 14: International Publication WO03/20737
pamphlet;
Patent Reference 15: International Publication WO01/74835
pamphlet;
Patent Reference 16: International Publication WO01/74834
pamphlet;
Patent Reference 17: Japanese Patent Publication 2003-012686;
Patent Reference 18: International Publication WO01/27128
pamphlet;
Patent Reference 19: International Publication WO03/99836
pamphlet;
Patent Reference 20: International Publication WO02/080936
pamphlet;
Patent Reference 21: International Publication WO02/080935
pamphlet;
Patent Reference 22: Japanese Patent Publication H8-119860;
Patent Reference 23: Japanese Patent Publication 2002-220345;
Patent Reference 24: International Publication WO03/075232
pamphlet;
Non-patent Reference 1: Hiromasa Ishii IGAKU NO AYUMI (Journal of
Clinical and Experimental Medicines, 2003, Vol. 206, No. 5, pp.
323-325;
Non-patent Reference 2: Naoki Tanaka and one person, KANZO (Acta
Hepatologica Japonica), 2002, Vol. 43, No. 12, pp. 539-549;
Non-patent Reference 3: Kazuhiko Koike, IGAKU NO AYUMI (Journal of
Clinical and Experimental Medicine), Vol. 206, No. 5, pp.
385-388;
Non-patent Reference 4: Koutaro Uchimura and three persons, RINSHO
TO KENKYU (The Japanese Journal of Clinical and Experimental
Medicine), 2003, Vol. 80, No. 3, pp. 503-506;
Non-patent Reference 5: Kenichiro Iwamura, KANZO (Acta Hepatologica
Japonica), 1971, Vol. 12, No. 12, pp. 659-669;
Non-patent Reference 6: Kenichiro Iwamura, SAISIN-IGAKU (The
Medical Frontline), 1979, Vol. 33, No 3, pp. 524-531;
Non-Patent Reference 7: A. Beringer and three persons, Deutsche
Medizinische Wochenschrift, 1967, vol. 92, No., pp. 2388-2392;
Non-patent Reference 8: Ken Ohashi, Annual review. NAIBUNPI, TAISHA
2000 (Internal Secretion, Metabolism 2000), Chugaiigaku Co.
publication, pp. 17-23;
Non-Patent Reference 9: JunichiOsuga, NAIKA (Internal Medicine),
2002, vol. 89 No. 5, pp. 875-881.
DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
[0007] The object of the present invention is to provide useful
pharmaceutical compositions for the inhibition of progression of
the diseases associated with abnormal accumulation of liver
lipids.
Means of Solving the Problems
[0008] In view of the above object, the present inventors have
studied earnestly to find a compound having an effect to inhibit
lipid accumulation in liver, and they acquired the surprising
knowledge that SGLT2 inhibitor had an excellent effect inhibiting
lipid accumulation, thereby forming the bases of the present
[0009] That is, the present invention relates to:
[0010] 1 a pharmaceutical composition for the inhibition of
progression of a disease associated with abnormal accumulation of
liver lipids, which comprises as an active ingredient a SGLT2
inhibitor;
[0011] [2] a pharmaceutical composition as described in the above 1
wherein the SGLT2 inhibitor is 2-(4-methoxybenzyl)-phenyl
.beta.-D-glucopyranoside or a pharmaceutically acceptable salt
thereof, or a prodrug thereof;
[0012] [3 a pharmaceutical composition as described in the above 1]
or [2] which is used in combination with one or more selected from
a group consisting of metformin, troglitazone, pioglitazone
hydrochloride, bezafibrate and voglibose; and the like.
[0013] The term "SGLT2 inhibitor" as an active ingredient of the
present invention means a compound inhibiting sugar reabsorption in
kidney by inhibiting SGLT2 activity. As the SGLT2 inhibitor of the
present invention, SGLT2 inhibitors described in the above Patent
References 1 to 19 can be illustrated, and concrete examples of
desirable execution mode include compounds selected from the
following group and pharmaceutically acceptable salts thereof.
[0014] 2-(4-Methoxybenzyl)phenyl .beta.-D-glucopyranoside,
2-(4-methylbenzyl)phenyl .beta.-D-glucopyranoside,
2-(4-ethyl-benzyl)phenyl-D-glucopyranoside,
2-(4-isobutylbenzyl)-phenyl .beta.-D-glucopyranoside,
2-(4-ethoxybenzyl)phenyl .beta.-D-glucopyranoside,
2-(4-isopropoxybenzyl)phenyl .beta.-D-glucopyranoside,
5-hydroxymethyl-2-(4-propoxybenzyl)-phenyl
.beta.-D-glucopyranoside, 2-(4-ethylbenzyl)-5-hydroxy-methylphenyl
.beta.-D-glucopyranoside,
2-[4-(2-hydroxyethyl)-benzyl]-5-hydroxymethylphenyl
.beta.-D-glucopyranoside, 2-[4-(2-hydroxyethyl)benzyl]phenyl
.beta.-D-glucopyranoside, 2-[4 (3-hydroxypropyl)benzyl]phenyl
.beta.-D-glucopyranoside, 2-(4-ethylthiobenzyl) phenyl
.beta.-D-glucopyranoside, 2-(4-methoxybenzyl)phenyl
6-O-ethoxycarbonyl-.beta.-D-gluco-pyranoside,
2-(4-methoxybenzyl)phenyl
6-O-methoxy-carbonyl-.beta.-D-glucopyranoside,
2-(4-methoxybenzyl)phenyl-6-O-[2-(methoxy)ethyloxycarbonyl]-.beta.-D-gluc-
opyranoside, 2-(4-methoxybenzyl phenyl
6-O-hexanoyl-.beta.-D-glucopyranoside, 2-(4-methoxybenzyl)phenyl
6-O-propionyl-.beta.-D-glucopyranoside, 2-(4-methoxybenzyl)phenyl
6-C-butyryl-.beta.-D-glucopyranoside, 2-(4-methoxybenzyl)phenyl
6-o-acetyl-.beta.-D-glucopyranoside, 2-(4-methoxybenzyl)phenyl
6-O-isobutyryl .beta.-D-glucopyranoside, 2-(4-methoxybenzyl)phenyl
6-O-ethylsuccinyl-.beta.-D-gluco-pyranoside,
2-(4-methoxybenzyl)phenyl
6-O-isopropyloxy-carbonyl-.beta.-D-glucopyranoside,
2-(4-methylbenzyl)phenyl-6-O-ethoxycarbonyl-.beta.-D-glucopyranoside,
2-(4-methylbenzyl)-phenyl 6-O-methoxycarbonyl-.beta.-D
glucopyranoside, 2-(4-ethylbenzyl)phenyl
6-O-ethoxycarbonyl-.beta.-D-glucopyranoside,
2-(4-ethylbenzyl)phenyl
6-O-methoxycarbonyl-.beta.-D-gluco-pyranoside,
5-amino-2-(4-ethylbenzyl)phenyl .beta.-D-gluco-pyranoside,
2-[4-(3-hydroxypropyl)benzyl]-3,5-dimethyl-phenyl
.beta.-D-glucopyranoside,
2-[4-(2-hydroxyethyl)benzyl]-3,5-dimethylphenyl
.beta.-D-glucopyranoside,
2-(4-methoxybenzyl-3,5-dimethylphenyl-D-glucopyranoside,
2-(4-ethylbenzyl)-5-hydroxymethylphenyl
6-O-ethoxycarbonyl-.beta.-D-glucopyranoside,
2-(4-ethylbenzyl)-5-pivaloyloxymethylphenyl
.beta.-D-gluco-6-O-butyryl-.beta.-D-glucopyranoside,
5-acetoxy-2-(4-ethyl-benzyl) phenyl
6-O-acetyl-.beta.-D-glucopyranoside,
2-(4-ethylbenzyl)-5-(ethoxycarbonyloxymethyl) phenyl
.beta.-D-gluco-pyranoside, 2-(4-ethylbenzyl)-5-hydroxymethylphenyl
6-O-hexanoyl-.beta.-D-glucopyranoside,
2-(4-ethylbenzyl)-5-hydroxy-methylphenyl
6-O-pivaloyl-.beta.-D-glucopyranoside
2-(4-ethyl-benzyl)-5-hydroxymethylphenyl-O-isobutyloxycarbonyl-.beta.-D-g-
lucopyranoside,
2-(4-ethylbenzyl)-5-hydroxymethylphenyl-O-isopropyloxycarbonyl-.beta.-D-g-
lucopyranoside, 2-[4-(2-benzyl-oxyethyl)benzyl]phenyl
6-O-ethoxycarbonyl-.beta.-D-gluco-pyranoside,
2-[4-(2-benzyloxyethyl)benzyl]phenyl
6-O-acetyl-.beta.-D-glucopyranoside,
2-[4-(2-acetoxyethyl)benzyl]phenyl
6-O-acetyl-.beta.-D-glucopyranoside,
2-(4-pyrazole-1-ylbenzyl)-phenyl .beta.-D-glucopyranoside,
2-[4-(4-hydroxypiperidin-1-yl-benzyl]3-D-glucopyranoside,
3-(.beta.-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-
-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-5-methyl-4-[(4-propylphenyl)meth-
yl]-1H-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-[(4-isobutylphenyl)-methyl]-5-methyl-1H--
pyrazole,
3-(.beta.-D-glucopyranosyloxy)-5-methyl-4-[(4-propoxyphenyl)meth-
yl]-1H-pyrazole,
4-[(4-ethoxyphenyl)methyl]-3-(.beta.-D-glucopyranosyloxy)-5-methyl-1H-pyr-
azole,
3-(.beta.-D-glucopyranosyloxy)-5-methyl-4-[(4-methyl-thiophenyl)met-
hyl]-1H-pyrazole,
5-ethyl-3-(.beta.-D-gluco-pyranosyloxy)-4-[(4-methylthiophenyl)methyl]-1H-
-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-[(4-isopropylphenyl)methyl]-5--
methyl-1H-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-[(4-methyl-thiophenyl)methyl]-5-trifluor-
omethyl-1H-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-[4-methoxyphenyl)methyl]-5-trifluoro-met-
hyl-1H-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-py-
razole,
3-(.beta.-D-gluco-pyranosyloxy)-1-methyl-4-[(4-methylthiophenyl)me-
thyl]-5-trifluoromethylpyrazole,
3-(.beta.-D-glucopyranosyloxy)-5-methyl-4-[(4-methylphenyl)methyl]-1H-pyr-
azole,
4-[(4-ethyl-phenyl)methyl]-3-(.beta.-D-glucopyranosyloxy)-5-methyl--
1H-pyrazole,
4-[(4-ethylphenyl)methyl]-3-(.beta.-D-glucopyranosyl-oxy)-5-trifluorometh-
yl-1H-pyrazole,
3-(1-D-glucopyranosyl-oxy)-4-[(4-methoxyphenyl)methyl]-1,5-dimethylpyrazo-
le,
3-(.beta.-D-glucopyranosyloxy)-1-methyl-[(4(4-methylthiophenyl)-methyl-
]-5-trifluoromethylpyrazole,
1-ethyl-3-(.beta.-D-gluco-pyranosyloxy)-4-[(4-methylthiophenyl)
methyl]-5-trifluoro-methylpyrazole,
3-(.beta.-D)-glucopyranosyloxy)-4-[(4-methyl-thiophenyl)methyl]1-propyl-5-
-trifluoromethylpyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1--
propylpyrazole,
1-ethyl-3-(.beta.-D-glucopyranosyl-oxy)-4-[(4-isopropoxyphenyl)methyl]-5--
methylpyrazole,
1-ethyl-3-(.beta.-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)-methyl]-5-met-
hylpyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1-pro-
pylpyrazole,
1-ethyl-4-[(4-ethoxyphenyl)methyl]-3-(.beta.-D-glucopyranosyl-oxy)-5-meth-
yl-1-propylpyrazole,
1-ethyl-4-[(4-ethylphenyl)-methyl]-3-(.beta.-D-glucopyranosyloxy)-5-methy-
lpyrazole,
4-[(4-ethylphenyl)methyl]-3-(.beta.-D-glucopyranosyloxy)-5-meth-
yl-1-propylpyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-[(4-isopropoxy-phenyl)methyl]1-isopropyl-
-5-methylpyrazole,
3-(.beta.-D-gluco-pyranosyloxy)-5-methyl-4-([4-(cyclopropylidenemethyl)-p-
henyl]methyl)-1H-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-5-methyl-4-[(4-cyclopropylphenyl)methyl]-1-
H-pyrazole,
(E)-4-{[4-(buta-1-en-1-yl)phenyl]methyl}-3-(.beta.-D-glucopyranosyl-oxy)--
5-methyl-1H-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-5-methyl-4-{[4-thiazole-2-yl)phenyl]methyl-
}-1H-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropyl)phenyl]-methyl}-5-t-
rifluoromethyl-1H-pyrazole,
3-(.beta.-D-gluco-pyranosyloxy)-5-methyl-4-{[4-(2-methylpropa-1-en-1-yl)--
phenyl]methyl}-1H-pyrazole,
4-[4-(4-fluorophenyl)phenyl]-methyl}-3-(.beta.-D-glucopyranosyloxy)-5-met-
hyl-1H-pyrazole,
4-{[4-(cyclobutyloxy)phenyl]methyl}-3-(.beta.-D-glucopyranosyl-oxy)-5-met-
hyl-H-pyrazole,
3-(.beta.-D-glucopyranosyloxy)-5-methyl-1-(cyclopropylmethyl)-4-[(4-cyclo-
propylphenyl)-methyl]-1H-pyrazole,
1-(cyclopropylmethyl)-3-(.beta.-D-gluco-pyranosyloxy)-5-methyl-4-[(4-meth-
ylthiophenyl)methyl]-1H-1-pyrazole,
4-[(4-ethylphenyl)methyl]-3-(.beta.-D-glucopyranosyl-oxy)-1-(3-hydroxypro-
pyl)-5-methyl-1H-pyrazole, 2-(4-pyrazole-1-ylbenzyl)
.beta.-D-glucopyranoside,
2-(4-[(4-hydroxy-piperidin-1-yl)benzyl]phenyl
.beta.-D-glucopyranoside,
4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-3-(.beta.-O-methoxycarbony-.be-
ta.-D-glucopyranosyloxy)-5-methylpyrazole,
3-(6-O-ethoxy-carbonyl-.beta.-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl-
)-methyl]-1-isopropyl-5-methylpyrazole,
3-(6-O-isopropoxy-carbonyl-.beta.-D-glucopyranosyloxy)-4-[(4-isopropoxyph-
enyl)-methyl]-1-isopropyl-5-methylpyrazole,
3-(6-O-isobutoxy-carbonyl-.beta.-D-glucopyranosyloxy)-4-[(4-isopropoxyphe-
nyl)-methyl]-1-isopropyl-5-methylpyrazole,
4-[(4-ethylphenyl)-methyl]-1-isopropyl-3-(6-O-methoxycarbonyl-.beta.-D-gl-
ucopyranos yloxy)-5-methylpyrazole,
3-(6-O-ethoxycarbonyl-.beta.-D-gluco-pyranosyloxy)-4-[(4-ethylphenyl)meth-
yl]-1-isopropyl-5-methylpyrazole,
4-[(4-ethylphenyl)methyl]-3-(6-O-iso-propoxycarbonyl-.beta.-D-glucopyrano-
syloxy)-1-isopropyl-5-methylpyrazole,
4-[(4-ethylphenyl)methyl]-3-(6-O-isobutoxy-carbonyl-.beta.-D-glucopyranos-
yloxy)-1-isopropyl-5-methyl-pyrazole, 4-L
(4-ethloxyphenyl)methyl-1-isopropyl-5-methyl-methoxycarbonyl-.beta.-D-glu-
copyranosyloxy)-5-methylpyrazole,
3-(6-O-ethoxycarbonyl-.beta.-D-glucopyranosyloxy)-4-[4-ethoxy-phenyl)meth-
yl]-1-isopropyl-5-methylpyrazole,
4-[(4-ethoxy-phenyl)methyl]-3-(6-O-isopropoxycarbonyl-.beta.-D-gluco-pyra-
nosyloxy)-1-isopropyl-5-methylpyrazole, 3-(6-O-
ethoxycarbonyl-.beta.-D-glucopyranosyloxy)-1-isopropyl-4-[(4-methoxypheny-
l)methyl]-5-methylpyrazole,
4-[(4-ethoxyphenyl)-methyl]-3-(6-O-isobutoxycarbonyl-.beta.-D-glucopyrano-
syloxy)-1-isopropyl-5-methylpyrazole,
1-isopropyl-3-(6-O-methoxy-carbonyl-.beta.-D-glucopyranosyloxy)-4-[(4-met-
hoxyphenyl)-methyl]-5-methylpyrazole,
3-(6-O-isopropoxycarbonyl-D-D-glucopyranosyloxy)-1-isopropyl-4-[(4-methox-
yphenyl)-methyl]-5-methylpyrazole,
3-(6-O-isopropoxycarbonyl-.beta.-D-glucopyranosyloxy)-1-isopropyl-4-[(4-m-
ethoxyphenyl)-methyl]-5-methylpyrazole,
2-[(4-ethoxyphenyl)methyl]-4-(.beta.-D-glucopyranosyl)-1-chlorobenzene,
1-isopropyl-3-(6-D-methoxycarbonyl-.beta.-D-glucopyranosyloxy)-5-methyl-4-
-[(4-methylthiophenyl)methyl]pyrazole,
3-(6-O-ethoxycarbonyl-.beta.-D-glucopyranosyloxy)-1-isopropyl-5-methyl-4--
[(4-methyl-thiophenyl)methyl]pyrazole,
3-(6-O-isopropoxycarbonyl-.beta.-D-glucopyranosyloxy)-1-isopropyl-5-methy-
l-4-[(4-methyl-thiophenyl)methyl]pyrazole,
3-(6-O-isobutoxycarbonyl-.beta.-D-glucopyranosyloxy)-1-isopropyl-5-methyl-
-4-[(4-methyl-thiophenyl)methyl]pyrazole,
3-(4-ethylbenzyl)-2-(.beta.-D-gluco-pyranosyloxy)-4,6-dimethylpyridine,
2-(.beta.-D-glucopyranosyl-oxy)-3-(4-methoxybenzyl)-4,6-dimethylpyridine,
2-(.beta.-D-glucopyranosyloxy)-3-(4-(2-hydroxyethyl)benzyl)-4,6-dimethylp-
yridine and
2-(.beta.-D-glucopyranosyloxy)-6-methoxy-3-(4-methoxybenzyl)-4-methylpyri-
dine
[0015] For example, the above compounds can be prepared according
to method described in the above Patent References 1 to 1.9 or an
analogous method thereof.
[0016] In the present invention, the term "disease associated with
abnormal accumulation of liver lipids" means a disease wherein the
lipids including triglyceride accumulate abnormally in liver, a
disease wherein the ratio of the amount of lipids to healthy cells
of the liver and the liver weight increase abnormally, and the size
of the liver increases abnormally. A progressive type wherein the
accumulative amount of lipids further increases is also included.
Moreover, a disease that shifts to other diseases because of the
accumulation of lipids, and a disease with inflammation are also
included. Concretely besides common fatty liver, non-alcholic fatty
liver disease (NAFL), non-alcholic steatohepatitis (NASH),
hypernutritive fatty liver, alcholic fatty liver disease, toxic
fatty liver, diabetic fatty liver, acute fatty liver of pregnancy
and the like can be illustrated.
[0017] The inhibitory effect on progression of the disease
associated with abnormal accumulation of liver lipids can be
confirmed by, for example, the examination that uses the KKA.sup.y
mouse bearing the fatty liver. The present inventors confirmed that
when 2-(4-methoxybenzyl)phenyl
6-O-ethoxycarbonyl-b-D-glucopyranoside of a SGLT2 inhibitor was
orally administered to rat, the symptom that the lipid accumulative
amount in rat liver increases is inhibited significantly in
comparison with the case where the present compound is not
administered. The above-mentioned result proves that a
pharmaceutical composition comprising as an active ingredient a
SGLT2 inhibitor is extremely useful as an agent for the inhibition
of progression of a disease associated with abnormal accumulation
of liver lipids.
[0018] In the present invention, it is possible to use the SGLT2
inhibitor of the active ingredient optionally in combination with
one or more other drugs used for the fatty liver. For example,
polyenphosphatidyl choline preparation, daisaikoto and the like can
be illustrated as other drugs that can be used in combination. In
addition, as far as the purpose of the present invention can be
achieved, the SGLT2 inhibitor can be used in combination with a
drug other than the above-mentioned drugs. In the case, metformin,
troglitazone, pioglitazone hydrochloride, bezafibrate, voglibose
and the like are illustrated as examples of the other drugs.
[0019] In the case of uses of the SGLT2 inhibitor in combination
with the above one or more other drugs, either dosage form of
simultaneous administration as a single preparation or separated
preparations in way of the same or different administration route,
and administration at different dosage intervals as separated
preparations in way of the same or different administration route
can be adopted.
[0020] The pharmaceutical compositions of the present invention can
be prepared by suitably admixing with or by diluting and dissolving
with an appropriate pharmaceutical additive pharmaceutically used
depending on the compositions or the dosage form such as
excipients, disintegrators, binders, lubricants, diluents, buffers,
isotonicities, antiseptics, moistening agents, emulsifiers,
dispersing agents, stabilizing agents, dissolving aids and the
like, by formulating the mixture in accordance with conventional
methods in dosage forms such as powders, granules, fine granules,
dry syrups, tablets, capsules, solutions, injections, ointments,
suppositories, poultices and the like, which can be orally or
parenterally administered. The pharmaceutical compositions of the
present invention also include a sustained release formulation
including gastrointestinal mucoadhesive formulation (see, for
example, International publications Nos. WO99/10010 and WO99/26606,
and Japanese patent publication No. 2001-2567).
[0021] The dosage of a SGLT2 inhibitor in a pharmaceutical
composition of the present invention is appropriately decided
depending on the age, sex, body weight and degree of symptoms and
treatment of each patient or the like, which is approximately
within the range of from 0.1 to 1,000 mg per day per adult human in
the case of oral administration and approximately within the range
of from 0.0.1 to 300 mg per day per adult human in the case of
parenteral administration. The daily dose can be divided into one
to several doses per day and administered suitably. Also, in case
of the uses of the drug(s) in combination with the other drug(s)
other than SGLT2 inhibitors, the dosage of the SGLT2 inhibitor can
be decreased depending on the dosage of the other drug(s) other
than SGLT2 inhibitors.
EFFECT OF THE INVENTION
[0022] As mentioned above, the pharmaceutical compositions of the
present invention which comprises as an active ingredient a SGLT2
inhibitor have an effect of the inhibition of progression of the
disease associated with abnormal accumulation of liver lipids, and
are highly suitable as an agent for the inhibition of progression
of the disease associated with abnormal accumulation of liver
lipids. Thence, the present invention can provide excellent
pharmaceutical compositions that can inhibit the progression of the
disease associated with abnormal accumulation of liver lipids by
using a SGLT2 inhibitor without compelling patients the
conventional dietary restriction by impossible diet therapy and the
exercise therapy difficult to continue.
BEST MODE TO PRACTICE THE INVENTION
[0023] The present invention is further illustrated in more detail
by way of the following Example. However, the present invention is
not limited thereto.
Example 1
Test to Confirm Inhibitory Effect on Accumulation of Liver
Lipids
[0024] Using KKA.sup.y mice (KKAy/Ta Jcl, CLEA Japan, Inc.) as
experimental animals, inhibitory effects on accumulation of lipids
in liver based on SGLT2 inhibitory effects were evaluated.
KKA.sup.y mice bearing fatty liver were prepared as follows.
[0025] Female 10-week-old KKA.sup.y mice were bred preparatorily
for 4 weeks. During preparatory breeding until 4 days before
grouping, the mice were fed on a pellet CE-2 diet for laboratory
animal (CLEA Japan, Inc.) under free feeding. From 4 days before
grouping, the food was changed to a powdered CE-2 diet for
laboratory animal (CLEA Japan, Inc.). At the age of 14 weeks, body
weight, blood glucose level and plasma alanine aminotransferase
level (ALT) were measured for grouping. The mice were grouped (5
animals in each group) so that in any of these three laboratory
values no significant difference was observed between the two
groups. In the second group, the mice were fed on a powdered CE-2
diet for laboratory animal (CLEA Japan, Inc.) containing 1000 ppm
of 2-(4-methoxybenzyl) phenyl
6-O-ethoxycarbonyl-.beta.-D-glucopyranoside (hereinafter referred
to as Compound A) as a SGLT2 inhibitor for 11 days, and then
triglyceride contents in liver were measured. The results of the
measurement were shown in Table 1. As, a consequence, it was
demonstrated that lipid accumulation in liver was significantly
suppressed by administration of Compound A to KKA.sup.y mice
bearing fatty liver, compared to drug-untreated mice. This
indicates that SGLT2 inhibitors exhibit inhibitory effects on the
progression of diseases associated with by abnormal lipid
accumulation in liver.
[0026] Method of measurement of liver triglyceride content was
described as follows.
1) Ice-cold saline (Otsuka Pharmaceutical Co., Ltd.) was added to
liver in the proportion of 4 mL of ice-cold saline to 1 g of the
liver, and then a homogenized suspension was prepared in a pestle
homogenizer.
2) To 100 .mu.L of the suspension 1), 800 .mu.L of Folch reagent
(chloroform:methanol=2:1) was added and mixed vigorously, and total
lipids was extracted.
3) The mixture 2) was centrifuged (3000 rpm, for 1 min, at room
temperature) using a cooled centrifuge (KUBOTA8900, KUBOTA
Corporation).
4) The lower layer after centrifugation in 3) was collected and
transferred to another containers and that is referred to as
Solution (A).
5) To the upper layer after centrifugation in 3) 150 .mu.UL of
Folch reagent was added and mixed vigorously, and centrifugation by
the operation identical to that in 3) was performed. The lower
layer was added to the Solution (A) described above.
6) To the Solution (A) obtained in 5), 250 .mu.L of saline was
added and mixed vigorously, and centrifugation by the operation
identical to that in 3) was performed again.
7) The upper layer after centrifugation in 6) was removed by
suction, and the solvent of the lower layer was removed under a
nitrogen flow.
8) The residue 7) was dissolved by adding of 300 .mu.L of Folch
reagent.
9) From the solution 8), 10 .mu.L of that was transferred to a
RIAbeads tube (Dainabot Co., Ltd.), and the solvent was removed
under a nitrogen flow.
10) Triglyceride was measured in a reaction in which 1.5 mL of a
coloring reagent of Triglyceride E-test Wako (Wako Pure Chemical
Industries, Ltd.) was added to the residue 9).
[0027] 11) The liver triglyceride content per gram was calculated
from the results obtained in 10). The data were expressed as the
mean .+-.standard error of the mean. TABLE-US-00001 TABLE 1 Liver
triglyceride content Group Matter (mg/g liver) The 1.sup.st group
Drug-untreated 43.0 .+-. 5.7 The 2.sup.nd group Drug-treated 25.4
.+-. 3.6* (Compound A) The symbol "*" in Table 1 means that there
is a statistically significant difference (significance level is 5%
or less) from the 1.sup.st group.
INDUSTRIAL APPLICABILITY
[0028] The pharmaceutical compositions of the present invention
which comprises as an active ingredient a SGLT2 inhibitor have an
effect of the inhibition of progression of the disease associated
with abnormal accumulation of liver lipids, and are useful as an
agent for the inhibition progression of a disease associated with
abnormal accumulation of liver lipids.
* * * * *