THERAPEUTIC AGENT FOR DYSLIPIDEMIA
Technical Field
[0001]
The present invention relates to a composition containing
a compound (1) selectively activating an -type (PPAR) of
peroxisome proliferator-activated receptors (PPARs), and a
cholesterol absorption inhibitor, which are intended to prevent
and/or treat atherosclerosis, and a lipemia condition such as
hypercholesterolemia; and a combination thereof.
Background Art
[0002]
In recent years, due to the westernization of diet,
patients with hypercholesterolemia, hypertriglyceridemia,
hypo-HDL chloesterolemia, and the like, which are in the category
of a so-called lifestyle-related diseases, are in an increasing
trend. Further, recently, patients with mixed or combined
dyslipidemia, which has both hypercholesterolemia and
hypertriglyceridemia, have been increased. Especially in
patients with mixed dyslipidemia, LDL cholesterol (LDL-C) and
triglyceride (TG) are increased, and HDL cholesterol (HDL-C)
is decreased. Such a high TG and low HDL-C condition is also
observed in patients with metabolic syndrome or diabetes. It
has been proved that hyper LDL-cholesterolemia, hypo-HDL
2
cholesterolemia, and hypertriglyceridemia are risk factors for
coronary artery disease (CAD) or cerebral vascular disorder and
the like. The importance of the management of dyslipidemia is
described in “Guidelines for Preventing Arteriosclerotic
Diseases, 2012 edition” released by Japan Atherosclerosis
Society.
[0003]
Dyslipidemia, in particular, hypercholesterolemia has
already fallen into a disease area of high medical satisfaction
with the advent of statins. However, from the results of a large
number of large-scale clinical trials, it has been found that
the further decrease of blood LDL cholesterol level leads to
the prevention of coronary artery disease (the lower the better),
and the more strict lipid control is recommended. There are
a large number of patients who cannot reach the intended level
of blood LDL-C only by the statins, and treatment with a
combination of multiple agents has been required. On the other
hand, for the hypertriglyceridemia, it has been indicated that
fibrate-based agents more effectively reduce the level, and for
the hypo-HDL cholesterolemia, research and development of CETP
inhibitors, apo A-I increasing agents, and the like has been
carried out. In particular, it has been expected that blood
HDL-C increasing drugs are increasingly important in the future
from the viewpoint of reverse transfer of cholesterol, and
3
evolution suppression and regression of arteriosclerosis,
(Non-Patent Document 1).
[0004]
PPAR is one of the receptors that belong to a nuclear
receptor family. It has been known of the presence of three
subtypes (, , and ) in the receptor (Non-Patent Document 2).
Among them, PPAR is mainly expressed in the liver, and when
PPAR is activated, production of apo C-III is suppressed, and
then lipoprotein lipase (LPL) is activated, as a result, fat
is decomposed. As the PPAR agonist, unsaturated fatty acids;
fibrate-based agents such as fenofibrate, bezafibrate, and
gemfibrozil; and the like have been known (Non-Patent Document
3). Further, in recent years, a compound, which has a PPAR
activating effect more strongly and selectively than the
conventional fibrate-based agent does, has been reported (Patent
Documents 1 to 10).
[0005]
A cholesterol absorption inhibitor is an agent suppressing
the absorption of dietary cholesterol from the small intestine.
As to the factors to determine the blood cholesterol level, it
is considered that contribution of de novo synthesized
cholesterol in the liver is 70%, and contribution of the dietary
cholesterol is 30%, therefore, the blood cholesterol levels can
be reduced by the suppression of the absorption of dietary
cholesterol from the small intestine, independently from the
4
cholesterol synthesis inhibition by statins. As the
cholesterol absorption inhibitor, for example, ezetimibe (Zetia
(registered trademark)) has been known. The mechanism of its
action was unknown for a long time, however, recently the
mechanism that the absorption of cholesterol is suppressed by
the inhibition of a cholesterol transporter (Niemann-Pick
C1-like 1, NPC1-L1) expressed in the small intestinal epithelial
cells has been elucidated. In addition to ezetimibe, multiple
compounds having an inhibitory effect on the cholesterol
transporter have been reported (Patent Documents 11 to 14).
[0006]
Treatments with a combination of the above-described
fibrate-based agent with ezetimibe have been investigated for
patients with mixed dyslipidemia who have a feature that the
blood LDL-C level and the blood TG level are increased, and the
blood HDL-C level is decreased (Patent Document 15, and
Non-Patent Documents 4 and 5). Meanwhile, it has not been known
what kind of effect is exerted on the dyslipidemia if a compound
(1) of the present invention is used in combination with
ezetimibe.
Citation List
Patent Document
[0007]
Patent Document 1: WO 2005/023777
Patent Document 2: WO 2009/080248
5
Patent Document 3: WO 2009/047240
Patent Document 4: WO 2008/006043
Patent Document 5: WO 2006/049232
Patent Document 6: WO 2006/033891
Patent Document 7: WO 2005/009942
Patent Document 8: WO 2004/103997
Patent Document 9: WO 2005/097784
Patent Document 10: WO 2003/043997
Patent Document 11: WO 2007/008541
Patent Document 12: WO 2007/008529
Patent Document 13: WO 2008/033464
Patent Document 14: WO 2008/104875
Patent Document 15: WO 2002/058732
Non-Patent Document
[0008]
Non-Patent Document 1: Folia Pharmacol. Jpn., 129, 267-270 (2007)
Non-Patent Document 2: J. Lipid Research 37, 907-925 (1996)
Non Patent Document 3: Trends in Endocrinology and Metabolism,
15(7), 324-330 (2004)
Non-Patent Document 4: European Heart Journal, 26, 897-905 (2005)
Non-Patent Document 5: Clinical Medicine: Therapeutics, 1,
1703-1713 (2009)
Summary of the Invention
6
Problems to be Solved in the Invention
[0009]
An object of the present invention is to provide a
pharmaceutical combination composition and a drug combination
for prevention and/or treatment of atherosclerosis, or a
dyslipidemic condition such as hypercholesterolemia, and
hypo-HDL cholesterolemia, and the like.
Means for Solving the Problems
[0010]
As a result of intensive study, in view of the above
circumstances, the present inventors found the fact that a strong
blood HDL cholesterol increasing effect is exerted by a
combination of a phenoxyacetic acid derivative represented by
the following general formula (1) or a salt thereof, with
ezetimibe that is a cholesterol absorption inhibitor, wherein
the phenoxyacetic acid derivative represented by the following
general formula (1) is disclosed in the Patent Document 1 to
have a selective PPAR activating effect, not to be accompanied
by weight gain or obesity in mammals including human beings,
and to be useful as a prophylactic and/or therapeutic agent for
dyslipidemia, arteriosclerosis, diabetes, diabetic
complication (diabetic nephropathy and the like), inflammation,
heart disease, and the like, and thus have completed the present
invention.
7
[0011]
That is, the present invention is to provide a
pharmaceutical composition for preventing and/or treating
dyslipidemia, including:
a) a compound represented by the following general formula (1):
[0012]
[Chemical formula 1]
[0013]
wherein R1 and R2, which may be identical or different, each
represents a hydrogen atom, a methyl group, or an ethyl group;
R3a, R3b, R4a and R4b, which may be identical or different, each
represents a hydrogen atom, a halogen atom, a nitro group, a
hydroxyl group, a C1-4 alkyl group, a trifluoromethyl group, a
C1-4 alkoxy group, a C1-4 alkylcarbonyloxy group, a di-C1-4
alkylamino group, a C1-4 alkylsulfonyloxy group, a C1-4
alkylsulfonyl group, a C1-4 alkylsulfinyl group, or a C1-4
alkylthio group, or R3a and R3b, or R4a and R4b are joined to represent
an alkylenedioxy group; X represents an oxygen atom, a sulfur
atom, or N-R5 (wherein R5 represents a hydrogen atom, a C1-4 alkyl
8
group, a C1-4 alkylsulfonyl group, or a C1-4 alkyloxycarbonyl
group); Y represents an oxygen atom, a S(O)l group (wherein l
represents 0, 1 or 2), a carbonyl group, a carbonylamino group,
an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl
group, or an NH group; Z represents CH, or N; n represents a
number from 1 to 6; and m represents a number from 2 to 6,
or a salt thereof, or a solvate of the compound, or a solvate
of the salt of the compound; and
b) a cholesterol absorption inhibitor.
[0014]
In more detail, the present invention is to provide a
pharmaceutical composition for preventing and/or treating mixed
dyslipidemia, metabolic syndrome, dyslipidemia complicated by
diabetes, hypo-HDL cholesterolemia, or hypertriglyceridemia,
including: a) a compound represented by the general formula (1)
or a salt thereof, or a solvate of the compound, or a solvate
of the salt of the compound; and b) a cholesterol absorption
inhibitor.
[0015]
The more detailed description of the present invention
is as follows.
(1) A pharmaceutical composition for preventing and/or treating
dyslipidemia, including: a compound represented by the general
formula (1) or a salt thereof, or a solvate of the compound,
9
or a solvate of the salt of the compound; and a cholesterol
absorption inhibitor.
(2) The pharmaceutical composition according to (1), wherein
the compound represented by the general formula (1) is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid.
(3) The pharmaceutical composition according to (1) or (2),
wherein the cholesterol absorption inhibitor is ezetimibe.
(4) The pharmaceutical composition according to any one of (1)
to (3), wherein the dyslipidemia is a disease selected from the
group consisting of mixed dyslipidemia, metabolic syndrome,
dyslipidemia complicated by diabetes, hypo-HDL chloesterolemia
(hypo HDL-C-emia), and hypertriglyceridemia (hyper TG-emia).
(5) The pharmaceutical composition according to any one of (1)
to (4), wherein a mass ratio of the compound represented by the
general formula (1) to the cholesterol absorption inhibitor is
1 : 200 to 3 : 1.
(6) A pharmaceutical composition for increasing HDL cholesterol
(HDL-C), including: a compound represented by the general formula
(1) or a salt thereof, or a solvate of the compound, or a solvate
of the salt of the compound; and a cholesterol absorption
inhibitor.
(7) The pharmaceutical composition according to (6), wherein
the compound represented by the general formula (1) is
10
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid.
(8) The pharmaceutical composition according to (6) or (7),
wherein the cholesterol absorption inhibitor is ezetimibe.
(9) The pharmaceutical composition according to any one of (6)
to (8), wherein a disease requiring increase of HDL cholesterol
(HDL-C) is a disease selected from the group consisting of mixed
dyslipidemia, metabolic syndrome, dyslipidemia complicated by
diabetes, hypo-HDL chloesterolemia (hypo HDL-C-emia), and
hypertriglyceridemia (hyper TG-emia).
(10) The pharmaceutical composition according to any one of (6)
to (9), wherein a mass ratio of the compound represented by the
general formula (1) to the cholesterol absorption inhibitor is
1 : 200 to 3 : 1.
[0016]
(11) A method for preventing and/or treating dyslipidemia in
a subject, comprising: administering to a subject with
dyslipidemia or a subject with a risk of dyslipidemia an effective
amount of a pharmaceutical composition containing a compound
represented by the general formula (1) or a salt thereof, or
a solvate of the compound, or a solvate of the salt of the compound,
and a cholesterol absorption inhibitor.
(12) The method for preventing and/or treating dyslipidemia in
a subject according to (11), wherein the compound represented
by the general formula (1) is
11
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid.
(13) The method for preventing and/or treating dyslipidemia in
a subject according to (11) or (12), wherein the cholesterol
absorption inhibitor is ezetimibe.
(14) The method for preventing and/or treating dyslipidemia with
a subject according to any one of (11) to (13), wherein the
dyslipidemia is selected from the group consisting of mixed
dyslipidemia, metabolic syndrome, dyslipidemia complicated by
diabetes, hypo-HDL chloesterolemia (hypo HDL-C-emia), and
hypertriglyceridemia (hyper TG-emia).
(15) The method for preventing and/or treating dyslipidemia in
a subject according to any one of (11) to (14), wherein a mass
ratio of the compound represented by the general formula (1)
to the cholesterol absorption inhibitor in the pharmaceutical
composition is 1 : 200 to 3 : 1.
(16) A method for increasing HDL cholesterol (HDL-C) in a subject,
comprising: administering to a subject requiring increase of
HDL cholesterol (HDL-C) an effective amount of a pharmaceutical
composition containing a compound represented by the general
formula (1) or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound, and a cholesterol
absorption inhibitor.
(17) The method according to (16), wherein the compound
represented by the general formula (1) is
12
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid.
(18) The method according to (16) or (17), wherein the cholesterol
absorption inhibitor is ezetimibe.
(19) The method according to any one of (16) to (18), wherein
a disease in a subject requiring increase of HDL cholesterol
(HDL-C) is selected from the group consisting of mixed
dyslipidemia, metabolic syndrome, dyslipidemia complicated by
diabetes, hypo-HDL chloesterolemia (hypo HDL-C-emia), and
hypertriglyceridemia (hyper TG-emia).
(20) The method according to any one of (16) to (19), wherein
a mass ratio of the compound represented by the general formula
(1) to the cholesterol absorption inhibitor in the pharmaceutical
composition is 1 : 200 to 3 : 1.
[0017]
(21) A compound represented by the general formula (1) or a salt
thereof, or a solvate of the compound, or a solvate of the salt
of the compound, for use as a pharmaceutical combination
composition for preventing and/or treating dyslipidemia in
combination with a cholesterol absorption inhibitor.
(22) The compound or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound for use according to
(21), wherein the compound represented by the general formula
(1) is
13
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid.
(23) The compound or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound for use according to
(21) or (22), wherein the cholesterol absorption inhibitor is
ezetimibe.
(24) The compound or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound for use according to
any one of (21) to (23), wherein the dyslipidemia is selected
from the group consisting of mixed dyslipidemia, metabolic
syndrome, dyslipidemia complicated by diabetes, hypo-HDL
chloesterolemia (hypo HDL-C-emia), and hypertriglyceridemia
(hyper TG-emia).
(25) The compound or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound for use according to
any one of (21) to (24), wherein a mass ratio of the compound
represented by the general formula (1) to the cholesterol
absorption inhibitor in the pharmaceutical composition is 1 :
200 to 3 : 1.
(26) A compound represented by the general formula (1) or a salt
thereof, or a solvate of the compound, or a solvate of the salt
of the compound, for use as a pharmaceutical combination
composition for increasing HDL cholesterol (HDL-C) in
combination with a cholesterol absorption inhibitor.
14
(27) The compound or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound for use according to
(26), wherein the compound represented by the general formula
(1) is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid.
(28) The compound or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound for use according to
(26) or (27), wherein the cholesterol absorption inhibitor is
ezetimibe.
(29) The compound or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound for use according to
any one of (26) to (28), wherein a disease in a subject requiring
increase of HDL cholesterol (HDL-C) is selected from the group
consisting of mixed dyslipidemia, metabolic syndrome,
dyslipidemia complicated by diabetes, hypo-HDL chloesterolemia
(hypo HDL-C-emia), and hypertriglyceridemia (hyper TG-emia).
(30) The compound or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound for use according to
any one of (26) to (29), wherein a mass ratio of the compound
represented by the general formula (1) to the cholesterol
absorption inhibitor in the pharmaceutical composition is 1 :
200 to 3 : 1.
Effects of the Invention
15
[0018]
The agent and pharmaceutical composition of the present
invention have an excellent blood HDL cholesterol increasing
effect, and are useful in the prevention and/or treatment of
dyslipidemia, particularly mixed dyslipidemia, metabolic
syndrome, dyslipidemia complicated by diabetes, hypo-HDL
cholesterolemia, or hypertriglyceridemia.
Brief Description of Drawings
[0019]
FIG. 1 illustrates plasma HDL-C levels when compound A
and ezetimibe are administered each alone or in combination.
FIG. 2 illustrates plasma TC levels when compound A and
ezetimibe are administered each alone or in combination.
FIG. 3 illustrates plasma VLDL-C levels when compound A
and ezetimibe are administered each alone or in combination.
FIG. 4 illustrates plasma LDL-C levels when compound A
and ezetimibe are administered each alone or in combination.
FIG. 5 illustrates plasma HDL-C levels when compound A
and ezetimibe are administered each alone or in combination.
FIG. 6 illustrates plasma HDL-C levels when fenofibrate
and ezetimibe are administered each alone or in combination.
Modes for Carrying Out the Invention
[0020]
16
Examples of the halogen atom of R3a, R3b, R4a, and R4b in
the general formula (1) include a fluorine atom, a chlorine atom,
and a bromine atom. Among them, a fluorine atom and a chlorine
atom are particularly preferable.
[0021]
Examples of the C1-4 alkyl group of R3a, R3b, R4a, R4b, and
R5 include a methyl group, an ethyl group, an n-propyl group,
an isopropyl group, and a butyl group. Among them, a methyl
group is particularly preferable.
[0022]
Examples of the C1-4 alkoxy group of R3a, R3b, R4a and R4b
include a methoxy group, an ethoxy group, an n-propoxy group,
an isopropoxy group, and a butoxy group. Among them, a methoxy
group is particularly preferable.
[0023]
Examples of the C1-4 alkylcarbonyloxy group of R3a, R3b,
R4a and R4b include a methylcarbonyloxy group, an ethylcarbonyloxy
group, an n-propylcarbonyloxy group, an isopropylcarbonyloxy
group, and a butylcarbonyloxy group. Among them, a
methylcarbonyloxy group is particularly preferable.
[0024]
Examples of the di-C1-4 alkylamino group of R3a, R3b, R4a
and R4b include a dimethylamino group, a diethylamino group,
and a diisopropylamino group. Among them, a dimethylamino group
is particularly preferable.
17
[0025]
Examples of the C1-4 alkylsulfonyloxy group of R3a, R3b,
R4a and R4b include a methylsulfonyloxy group, and an
ethylsulfonyloxy group. Among them, a methylsulfonyloxy group
is particularly preferable.
[0026]
Examples of the C1-4 alkylsulfonyl group of R3a, R3b, R4a,
R4b, and R5 include a methylsulfonyl group, and an ethylsulfonyl
group. Among them, a methylsulfonyl group is particularly
preferable.
[0027]
Examples of the C1-4 alkylsulfinyl group of R3a, R3b, R4a
and R4b include a methylsulfinyl group, and an ethylsulfinyl
group. Among them, a methylsulfinyl group is particularly
preferable.
[0028]
Examples of the C1-4 alkylthio group of R3a, R3b, R4a and
R4b include a methylthio group, and an ethylthio group. Among
them, a methylthio group is particularly preferable.
[0029]
Examples of the alkylenedioxy group in which R3a and R3b,
or R4a and R4b are bonded to each other include a methylenedioxy
group, and an ethylenedioxy group. Among them, a methylenedioxy
group is particularly preferable.
[0030]
18
Examples of the C1-4 alkyloxycarbonyl group of R5 include
a methyloxycarbonyl group, and an ethyloxycarbonyl group.
Among them, a methyloxycarbonyl group is particularly
preferable.
[0031]
R1 and R2 are particularly preferably hydrogen atoms at
the same time, or methyl groups at the same time; or a methyl
group and a hydrogen atom, or an ethyl group and a hydrogen atom.
[0032]
X represents an oxygen atom, a sulfur atom, or N-R5, and
is preferably an oxygen atom. Further, Y represents an oxygen
atom, a S(O)l group, a carbonyl group, a carbonylamino group,
an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl
group, or an NH group, and is preferably an oxygen atom. Z
represents CH or N, and is preferably CH. l represents 0, 1
or 2, and is preferably 2. n represents a number from 1 to 6,
and is preferably from 1 to 3. m represents a number from 2
to 6, is preferably 2 to 4, and is particularly preferably 2
or 3.
[0033]
Preferable examples of the compound represented by the
general formula (1) of the present invention include a compound
in which X and Y are oxygen atoms, Z is CH, n is 1, and m is
3. More preferable examples of the compound include a compound
in which X and Y are oxygen atoms; Z is CH; n is 1; m is 3; R3a
19
and R3b, which may be identical or different, each of which is
a hydrogen atom, a halogen atom, a hydroxyl group, a C1-4 alkyl
group, a trifluoromethyl group, or a C1-4 alkoxy group; R4a and
R4b, which may be identical or different, each of which is a
halogen atom, a hydroxyl group, a C1-4 alkyl group, a
trifluoromethyl group, or a C1-4 alkoxy group. More preferable
examples of the compound represented by the general formula (1)
of the present invention include
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid (hereinafter, may be
referred to as “compound A”).
[0034]
Usually, in an amount of around 400 to 500 mg of cholesterol
from the diet, and in an amount of around 800 to 2,000 mg of
cholesterol from the bile are drawn into the small intestine
per day, and around 50% of the cholesterol drawn into the small
intestine is absorbed. In the present invention, the
cholesterol absorption inhibitor is not particularly limited
as long as being able to inhibit the absorption of the cholesterol
drawn into the small intestine, and examples of the cholesterol
absorption inhibitor include, for example, an anion exchange
resin such as cholestyramine, and cholestyramide, and an agent
suppressing the absorption of cholesterol by the inhibition of
a cholesterol transporter (NPC1-L1), such as ezetimibe, and a
compound described in the Patent Documents 11 to 14. Preferable
20
examples of the cholesterol absorption inhibitor of the present
invention include, for example, an agent suppressing the
absorption of cholesterol by the inhibition of a cholesterol
transporter (NPC1-L1), and among them, ezetimibe is more
preferable.
[0035]
A compound represented by the general formula (1) of the
present invention can be produced, for example, in accordance
with a method described in Patent Document 1.
In addition, in the present invention, a salt or solvate
of the compound represented by the general formula (1) can be
used. The salt and solvate can be produced by routine procedures.
[0036]
The salt of the compound represented by the general formula
(1) of the present invention is not particularly limited as long
as being pharmacologically acceptable, and examples of the salt
include, for example, an alkali metal salt such as a sodium salt,
and a potassium salt; an alkaline earth metal salt such as a
calcium salt, and a magnesium salt; an organic base salt such
as an ammonium salt, and a trialkylamine salt; a mineral acid
salt such as a hydrochloride, and a sulfate; and an organic acid
salt such as an acetate.
[0037]
Examples of the solvate of the compound represented by
the general formula (1) or the salt thereof of the present
21
invention include a hydrate, and an alcohol solvate (for example,
an ethanol solvate).
[0038]
The compound represented by the general formula (1) of
the present invention has an asymmetric carbon atom, and
therefore has optical isomers of a R-isomer and a S-isomer, and
all the optical isomers are included in the present invention.
[0039]
Ezetimibe (chemical name:
(3R,4S)-1-(4-fluorophenyl)-3-{(3S)-3-(4-fluorophenyl)-3-hyd
roxypropyl}-4-(4-hydroxyphenyl)azetidin-2-one (IUPAC)) can be
produced by a method described in J. Org. Chem., 64(10), 3714-3718
(1999), Tetrahedron Lett., 44(4), 801-804 (2003), and the like.
Further, a pharmaceutical product available on the market may
be used.
[0040]
As indicated in Examples below, when a compound represented
by the general formula (1) is used in combination with a
cholesterol absorption inhibitor, each plasma lipid parameter
is improved and particularly a strong HDL-C increasing effect
is exerted in an evaluation system using a rat loaded with high
cholesterol diet. Therefore, an agent of the present invention
is useful in the prevention and/or treatment of mixed
dyslipidemia, metabolic syndrome, dyslipidemia complicated by
diabetes, hypo-HDL cholesterolemia, or hypertriglyceridemia.
22
[0041]
The dyslipidemia in the present invention means that any
one or two or more of the total triglyceride (TG) level, the
total cholesterol (TC) level, the VLDL cholesterol (VLDL-C) level,
the LDL cholesterol (LDL-C) level, or the HDL cholesterol (HDL-C)
level, in the blood deviate from a range of the normal level.
In addition, the disease in a subject requiring increase
of HDL cholesterol (HDL-C) in the present invention means the
case where the HDL-C level in the blood is lower than the normal
level.
[0042]
The compound represented by the general formula (1) or
a salt thereof, or a solvate of the compound, or a solvate of
the salt of the compound of the present invention can be prepared
alone or in combination with other pharmaceutically acceptable
carriers, into a dosage form of a tablet, a capsule, granules,
powders, lotion, ointment, an injection, a suppository, and the
like. These pharmaceutical preparations can be produced by a
known method. For example, a preparation for oral
administration can be produced by the formulation of a
solubilizer such as tragacanth gum, gum arabic, sucrose fatty
acid ester, lecithin, olive oil, soybean oil, and PEG 400; an
excipient such as starch, mannitol, and lactose;
a binder such as methylcellulose, carboxymethylcellulose sodium,
and hydroxypropylcellulose; a disintegrant such as crystalline
23
cellulose, and carboxymethylcellulose calcium; a lubricant such
as talc, and magnesium stearate; a fluidity-improving agent such
as light silicic anhydride; and the like, in appropriate
combination.
[0043]
As to the usage form of the pharmaceutical composition
of the present invention, a) a compound represented by the general
formula (1) or a salt thereof, or a solvate of the compound,
or a solvate of the salt of the compound is used in combination
with b) a cholesterol absorption inhibitor, and the
pharmaceutical composition can be used in a form in which a
prophylactic and/or therapeutic effect for dyslipidemia such
as mixed dyslipidemia, metabolic syndrome, dyslipidemia
complicated by diabetes, hypo-HDL cholesterolemia, and
hypertriglyceridemia is exerted with the use of the synergistic
blood HDL-C increasing effect by the administration of both
agents in addition to each effect of agents, however, is not
limited to these usage forms. The compound represented by the
general formula (1) and the cholesterol absorption inhibitor
may be administered at the same time, or may be administered
separately at intervals.
[0044]
The compound represented by the general formula (1) and
the cholesterol absorption inhibitor may be prepared together
into a single preparation, or may be prepared separately into
24
each preparation and used as a kit. That is, the pharmaceutical
composition of the present invention may be a kit composed of
an agent containing as an active component at least one kind
selected from a compound represented by the general formula (1)
or a salt thereof, or a solvate of the compound, or a solvate
of the salt of the compound, and an agent containing at least
one kind of cholesterol absorption inhibitors in combination.
When both agents are administered as a single preparation
in the present invention, the mixing ratio of the compound
represented by the general formula (1) to the cholesterol
absorption inhibitor can be appropriately selected in the range
of effective dose of each active component, however, the mixing
ratio is generally preferably in the range of 5 : 1 to 1 : 30,000
by mass ratio, and more preferably in the range of 5 : 1 to 1 :
1,000 by mass ratio. In particular, in a case where the
cholesterol absorption inhibitor is an agent such as ezetimibe,
which suppresses the absorption of cholesterol by the inhibition
of a cholesterol transporter (NPC1-L1), the mixing ratio is
preferably in the range of 5 : 1 to 1 : 300, and more preferably
3 : 1 to 1 : 200 by mass ratio from the viewpoint that the
particularly excellent synergistic effect is obtained.
[0045]
In a case where the compound represented by the general
formula (1) and the cholesterol absorption inhibitor are
separately prepared, the dosage forms of both preparations may
25
be the same as or different from each other. Further, the number
of administrations of each component may vary.
[0046]
The compound represented by the general formula (1) or
a salt thereof, or a solvate of the compound, or a solvate of
the salt of the compound of the present invention is orally or
parenterally administered. The dosage of the pharmaceutical
of the present invention varies depending on the body weight,
age, sex, symptoms and the like of a subject, however, usually
in a case of an adult human, the dosage of 0.001 to 100 mg, and
preferably 0.01 to 10 mg is preferably administered while being
divided into 1 to 3 times per day as for the compound of the
general formula (1). Further, the cholesterol absorption
inhibitor is preferably administered in a dosage of 0.01 to 1,000
mg, and preferably 1 to 100 mg while being divided into 1 to
3 times per day as the ezetimibe.
Examples
[0047]
Hereinafter, the present invention will be more
specifically explained by way of Examples, Comparative Example,
and Preparation Example, however should not be limited at all
by these Examples.
[0048]
26
Example 1 Combined effect of compound A and ezetimibe for on
high-cholesterol diet-fed rats
1. Procedure
SD rats (6 weeks old, male, CHARLES RIVER LABORATORIES
JAPAN, INC.) were used in the experiments. Blood was collected
from the jugular vein of chow-fed rat, and divided into 4 groups
(N = 8) base on the levels of TG and TC in the plasma, and the
body weight. From the next day, a solid chow containing 2%
cholesterol and 0.5% sodium cholate (MF-based, Oriental Yeast
Co., Ltd.) was loaded to rats for one week. In parallel to the
loading with the high cholesterol diet, a vehicle (an aqueous
solution of 0.5% methylcellulose: MC), or
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid (compound A) and/or
ezetimibe was orally administered once a day. In the afternoon
of the last day of the administration, blood was collected under
pentobarbital anesthesia after the fasting period of 4 hours,
and the HDL-C levels in the plasma were measured. The synergistic
effect was determined by using Bürgi’s formula (if the relative
level in the combined group is larger than the value of the product
of the relative level of single agent A and the relative level
of single agent B, the synergistic effect is positive).
2. Group Configuration
Group 1: Control
Group 2: Compound A 0.1 mg/kg
27
Group 3: Ezetimibe 0.003 mg/kg
Group 4: Compound A 0.1 mg/kg and ezetimibe 0.003 mg/kg
3. Statistical Analysis and Data Processing Method
The results were shown as the mean  standard deviation.
Comparison between the control group and the drug administration
group was performed using Dunnett’s multiple comparison test,
and the risk rate of less than 5% was determined to have a
significant difference.
4. Results
The results are shown in FIG. 1 and Table 1. In addition,
the average level of each group of HDL-C is shown in Table 1.
In the single administration group of compound A or ezetimibe,
apparent effects were not recognized for the HDL-C level.
However, in the combined administration group of 0.1 mg/kg of
compound A and 0.003 mg/kg of ezetimibe, significant (*: p<0.05,
to the control) and synergistic (the relative level (1.167) in
the combined group is larger than the value of the product (1.010
 1.022 = 1.032) of the relative level in the single agent A
administration group to the control group and the relative level
in the single agent B administration group to the control group)
increase of HDL-C level was recognized (FIG. 1, and Table 1).
[0049]
[Table 1]
28
Control Compound A
0.1mg/kg
Ezetimibe
0.003mg/kg
Compound A 0.1mg/kg +
Ezetimibe 0.003mg/kg
Ave. 24.1 24.3 24.6 28.1
SD 1.6 3.0 2.4 2.9
HDL-C
Rate of Change － 1.0% 2.2% 16.7%
[0050]
Example 2 Combined effect of compound A and ezetimibe on
high-cholesterol diet-fed rats
1. Procedure
SD rats (6 weeks old, male, CHARLES RIVER LABORATORIES
JAPAN, INC.) were used in the experiments. Blood was collected
from the jugular vein of chow-fed rat, and divided into 6 groups
(N = 6, 8) base on the levels of TG and TC in the plasma, and
the body weight. From the next day, a solid food containing
2% cholesterol and 0.5% sodium cholate (MF-based, Oriental Yeast
Co., Ltd.) was loaded to rats for one week. In parallel to the
loading with the high cholesterol diet, a vehicle (0.5% MC),
or compound A and/or ezetimibe was orally administered once a
day. In the afternoon of the last day of the administration,
blood was collected under pentobarbital anesthesia after the
fasting period of 4 hours, and the TG levels and TC levels in
the plasma, and lipid levels in the lipoprotein (VLDL-C, LDL-C
and HLDL-C) were measured. The synergistic effect was
determined by using Bürgi’s formula (in a case where a level
lower than that in the control group is indicated in a drug
29
administration group, that is, when the evaluation of an agent
to the TC, VLDL-C, or LDL-C is performed, if the relative level
in the combined group is smaller than the value of the product
of the relative level of single agent A and the relative level
of single agent B, the synergistic effect exists. In a case
where a level higher than that in the control group is indicated
in a drug administration group, that is, when the evaluation
of an agent to the HDL-C is performed, if the relative level
in the combined group is larger than the value of the product
of the relative level of single agent A and the relative level
of single agent B, the synergistic effect exists).
2. Group Configuration
Group 1: Control
Group 2: Compound A 0.1 mg/kg
Group 3: Ezetimibe 0.01 mg/kg
Group 4: Combination of compound A 0.1 mg/kg and ezetimibe
0.01 mg/kg
Group 5: Ezetimibe 0.1 mg/kg
Group 6: Combination of compound A 0.1 mg/kg and ezetimibe
0.1 mg/kg
3. Statistical Analysis and Data Processing Method
The results were shown as the mean  standard deviation.
Comparison between the control group and the drug administration
group was performed using Dunnett’s multiple comparison test,
30
and the risk rate of less than 5% was determined to have a
significant difference.
4. Results
The results are shown in Table 2 and FIGS. 2 to 5. FIG.
2 shows the results of the total cholesterol (TC) levels, FIG.
3 shows the VLDL cholesterol (VLDL-C) levels, FIG. 4 shows the
LDL cholesterol (LDL-C) levels, and FIG. 5 shows the HDL
cholesterol (HDL-C) levels. The symbol in FIGS means as follows:
*: p<0.05, **: p<0.01, and ***: p<0.001.
[0051]
Synergistic effects by the combination of compound A with
ezetimibe on the high-cholesterol diet-fed rats
[0052]
[Table 2]
Compound A (mg/kg) 0.1 - 0.1 - 0.1
Ezetimibe (mg/kg) - 0.01 0.01 0.1 0.1
TC Relative Level（to Control) 0.956 0.898 0.635 0.555 0.462
Bürgi’s Formula 0.859 0.530
VLDL-C Relative Level（to Control) 0.827 0.719 0.374 0.262 0.179
Bürgi’s Formula 0.595 0.217
LDL-C Relative Level（to Control) 0.971 0.955 0.713 0.720 0.529
Bürgi’s Formula 0.927 0.698
HDL-C Relative Level（to Control) 1.021 0.910 1.204 1.100 1.326
Bürgi’s Formula 0.929 1.123
[0053]
As to each numerical value, the value in the upper shows
a relative level to the control group, and the value in the lower
shows the product of the relative levels in the compound A single
administration group and the ezetimibe single administration
31
group by using Bürgi’s formula. The values in the underlined
part show that the synergistic effect is recognized.
[0054]
Firstly, when the attention was focused on TC (Table 2
and FIG. 2), the relative level of the compound A single
administration group was 0.956, the relative level of the 0.01
mg/kg single administration group of ezetimibe was 0.898, and
the product of both relative levels was 0.859. On the other
hand, the relative level of the combined administration group
of compound A and 0.01 mg/kg of ezetimibe was 0.635, and was
significantly decreased as compared with the product of levels
in the single administration groups, therefore, the synergistic
TC lowering effect was confirmed.
Further, the relative level of 0.1 mg/kg single
administration group of ezetimibe was 0.555, and the product
of the relative level 0.555 and the relative level 0.956 of the
compound A administration group was 0.530, whereas the relative
level of 0.1 mg/kg combined administration group of the compound
A and the ezetimibe was 0.462, therefore, it was revealed that
the synergistic TC lowering effect was recognized also in the
high-dose group of ezetimibe.
In the same manner, by the combined administration of the
compound A and the ezetimibe, the synergistic lowering effect
for the VLDL-C level and LDL-C level, and the synergistic
increasing effect for the HDL-C level were recognized.
32
[0055]
Comparative Example Combined effect of fenofibrate and
ezetimibe on high-cholesterol diet-fed rats
1. Procedure
SD rats (6 weeks old, male, CHARLES RIVER LABORATORIES
JAPAN, INC.) were used in the experiments. Blood was collected
from the jugular vein of chow-fed rat, and divided into 4 groups
(N = 8) base on the levels of TG and TC in the plasma, and the
body weight. From the next day, a solid chow containing 2%
cholesterol and 0.5% sodium cholate (MF-based, Oriental Yeast
Co., Ltd.) was loaded to rats for one week. In parallel to the
loading with the high cholesterol diet, a vehicle (0.5% MC),
or fenofibrate (FF) and/or ezetimibe (Ezeti) was orally
administered once a day. In the afternoon of the last day of
the administration, blood was collected under pentobarbital
anesthesia after the fasting period of 4 hours. The HDL-C levels
in the plasma were measured.
2. Group Configuration
Group 1: Control
Group 2: Fenofibrate 10 mg/kg
Group 3: Ezetimibe 0.1 mg/kg
Group 4: Combination of fenofibrate 10 mg/kg and ezetimibe
0.1 mg/kg
3. Statistical Analysis and Data Processing Method
33
The results were shown as the average level  standard
deviation. Comparison between the control group and the drug
administration group was performed using Dunnett’s multiple
comparison test, and the risk rate of less than 5% was determined
to have a significant difference.
4. Results
The results are shown in FIG. 6. Fenofibrate has also
been known as a PPAR agonist, however, the synergistic
increasing effect for the HDL-C level was not recognized in the
combination of fenofibrate with ezetimibe.
[0056]
Preparation Example Tablets for administration containing
compound A and ezetimibe
The tablets for administration, in which compound A and
ezetimibe are contained, can be produced as in the following.
[0057]
[Table 3]
Component Dosage
Compound A 0.05mg
Ezetimibe 10mg
Microcrystalline Cellulose 37.25mg
Modified food Grade Cornstarch 37.25mg
Magnesium Stearate 0.5mg
[0058]
All of the compound A and ezetimibe (mass ratio 1 : 200)
and part of the cellulose and cornstarch were mixed, and the
34
mixture was granulated, as a result, 10% cornstarch paste was
obtained. The obtained granules were sieved and dried, and the
dried granules were mixed with the remaining part of the
cornstarch, and the magnesium stearate. Next, the obtained
granules were compressed into a tablet containing 0.05 mg of
compound A and 10 mg of ezetimibe per tablet.
Industrial Applicability
[0059]
The agent and pharmaceutical composition of the present
invention have an excellent blood HDL cholesterol increasing
effect, and are useful in the prevention and/or treatment of
dyslipidemia, particularly mixed dyslipidemia, metabolic
syndrome, dyslipidemia complicated by diabetes, hypo-HDL
cholesterolemia, or hypertriglyceridemia, therefore have
industrial applicability.

CLAIMS
1. A pharmaceutical composition for preventing and/or
treating dyslipidemia, comprising:
a) a compound represented by the following general formula
(1):
[Chemical formula 1]
, wherein R1 and R2, which may be identical or different, each
represents a hydrogen atom, a methyl group, or an ethyl group;
R3a, R3b, R4a and R4b, which may be identical or different, each
represents a hydrogen atom, a halogen atom, a nitro group, a
hydroxyl group, a C1-4 alkyl group, a trifluoromethyl group, a
C1-4 alkoxy group, a C1-4 alkylcarbonyloxy group, a di-C1-4
alkylamino group, a C1-4 alkylsulfonyloxy group, a C1-4
alkylsulfonyl group, a C1-4 alkylsulfinyl group, or a C1-4
alkylthio group, or R3a and R3b, or R4a and R4b are joined to represent
an alkylenedioxy group; X represents an oxygen atom, a sulfur
atom, or N-R5 (wherein R5 represents a hydrogen atom, a C1-4 alkyl
group, a C1-4 alkylsulfonyl group, or a C1-4 alkyloxycarbonyl
group); Y represents an oxygen atom, a S(O)l group (wherein l
36
represents 0, 1 or 2), a carbonyl group, a carbonylamino group,
an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl
group, or an NH group; Z represents CH, or N; n represents a
number from 1 to 6; and m represents a number from 2 to 6,
or a salt thereof, or a solvate of the compound, or a solvate
of the salt of the compound; and
b) a cholesterol absorption inhibitor.
2. The pharmaceutical composition according to Claim 1,
wherein the compound represented by the general formula
(1) is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid.
3. The pharmaceutical composition according to Claim 1 or
2,
wherein the cholesterol absorption inhibitor is
ezetimibe.
4. The pharmaceutical composition according to any one of
Claims 1 to 3,
wherein the dyslipidemia is a disease selected from the
group consisting of mixed dyslipidemia, metabolic syndrome,
dyslipidemia complicated by diabetes, hypo-HDL chloesterolemia
(hypo HDL-C-emia), and hypertriglyceridemia (hyper TG-emia).
37
5. The pharmaceutical composition according to any one of
Claims 1 to 4,
wherein a mass ratio of the compound represented by the
general formula (1) to the cholesterol absorption inhibitor is
1 : 200 to 3 : 1.
6. A pharmaceutical composition for increasing HDL
cholesterol (HDL-C), comprising:
a) a compound represented by the following general formula
(1):
[Chemical formula 1]
, wherein R1 and R2, which may be identical or different, each
represents a hydrogen atom, a methyl group, or an ethyl group;
R3a, R3b, R4a and R4b, which may be identical or different, each
represents a hydrogen atom, a halogen atom, a nitro group, a
hydroxyl group, a C1-4 alkyl group, a trifluoromethyl group, a
C1-4 alkoxy group, a C1-4 alkylcarbonyloxy group, a di-C1-4
alkylamino group, a C1-4 alkylsulfonyloxy group, a C1-4
38
alkylsulfonyl group, a C1-4 alkylsulfinyl group, or a C1-4
alkylthio group, or R3a and R3b, or R4a and R4b are joined to represent
an alkylenedioxy group; X represents an oxygen atom, a sulfur
atom, or N-R5 (wherein R5 represents a hydrogen atom, a C1-4 alkyl
group, a C1-4 alkylsulfonyl group, or a C1-4 alkyloxycarbonyl
group); Y represents an oxygen atom, a S(O)l group (wherein l
represents 0, 1 or 2), a carbonyl group, a carbonylamino group,
an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl
group, or an NH group; Z represents CH, or N; n represents a
number from 1 to 6; and m represents a number from 2 to 6,
or a salt thereof, or a solvate of the compound, or a solvate
of the salt of the compound; and
b) a cholesterol absorption inhibitor.
7. The pharmaceutical composition according to Claim 6,
wherein the compound represented by the general formula
(1) is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl
]aminomethyl]phenoxy]butyric acid.
8. The pharmaceutical composition according to Claim 6 or
7,
wherein the cholesterol absorption inhibitor is
ezetimibe.
39
9. The pharmaceutical composition according to any one of
Claims 6 to 8,
wherein a disease requiring increase of HDL cholesterol
(HDL-C) is a disease selected from the group consisting of mixed
dyslipidemia, metabolic syndrome, dyslipidemia complicated by
diabetes, hypo-HDL chloesterolemia (hypo HDL-C-emia), and
hypertriglyceridemia (hyper TG-emia).
10. The pharmaceutical composition according to any one of
Claims 6 to 9,
wherein a mass ratio of the compound represented by the
general formula (1) to the cholesterol absorption inhibitor is
1 : 200 to 3 : 1.