U.S. patent application number 16/313777 was filed with the patent office on 2019-05-23 for optically active pyranochromenyl phenol derivative and pharmaceutical composition comprising same.
The applicant listed for this patent is GLACEUM, INC.. Invention is credited to JIN WOOK CHUNG, JEONG HO IM, IN GEUN JO, KU SUK KANG, JIN YOUNG KIM, Jl YOUNG KIM, SANG KU YOO.
Application Number | 20190152984 16/313777 |
Document ID | / |
Family ID | 60787377 |
Filed Date | 2019-05-23 |
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United States Patent
Application |
20190152984 |
Kind Code |
A1 |
YOO; SANG KU ; et
al. |
May 23, 2019 |
OPTICALLY ACTIVE PYRANOCHROMENYL PHENOL DERIVATIVE AND
PHARMACEUTICAL COMPOSITION COMPRISING SAME
Abstract
The present invention relates to pyranochromenylphenol
derivatives having different efficacies depending on the direction
of optical activity and a pharmaceutical composition including the
same, and in the pyranochromenylphenol derivatives, an R-enantiomer
has excellent anti-diabetic efficacy by suppressing a rise in blood
sugar and an S-enantiomer has excellent anti-obesity efficacy by
suppressing an increase in body weight.
Inventors: |
YOO; SANG KU; (Suwon-si,
KR) ; CHUNG; JIN WOOK; (Seoul, KR) ; JO; IN
GEUN; (Cheonan-si, KR) ; KIM; Jl YOUNG;
(Seoul, KR) ; IM; JEONG HO; (Gwangju-si, KR)
; KANG; KU SUK; (Yongin-si, KR) ; KIM; JIN
YOUNG; (Suwon-si, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLACEUM, INC. |
Suwon-si Gyeonggi-do |
|
KR |
|
|
Family ID: |
60787377 |
Appl. No.: |
16/313777 |
Filed: |
June 29, 2017 |
PCT Filed: |
June 29, 2017 |
PCT NO: |
PCT/KR2017/006863 |
371 Date: |
December 27, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 493/04 20130101;
C07B 57/00 20130101; A61K 31/353 20130101; C07B 2200/07 20130101;
A61P 3/04 20180101; A61K 31/352 20130101 |
International
Class: |
C07D 493/04 20060101
C07D493/04; C07B 57/00 20060101 C07B057/00; A61P 3/04 20060101
A61P003/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 29, 2016 |
KR |
10-2016-0081674 |
Claims
1. An optically active pyranochromenylphenol compound of the
following Chemical Formula (I), a pharmaceutically acceptable salt,
or a solvate thereof: ##STR00020## wherein R.sub.1 is a straight or
branched C.sub.2 to C.sub.6 alkyl group unsubstituted or
substituted by a straight or branched C.sub.1 to C.sub.5 alkyl
group, a halogen atom, or a C.sub.1 to C.sub.5 thioalkyl group;
R.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or ethoxy; and
R.sub.3 and R.sub.4 are each independently a hydrogen atom or a
C.sub.1 to C.sub.2 alkyl group.
2. The optically active pyranochromenylphenol compound, the
pharmaceutically acceptable salt, or the solvate thereof of claim
1, wherein R.sub.1 is ethyl, n-propyl, isopropyl, n-butyl,
2-methylpropyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,
2-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, or 2-ethylbutyl; R.sub.2 is a hydrogen atom; and
R.sub.3 and R.sub.4 are each methyl.
3. The optically active pyranochromenylphenol compound, the
pharmaceutically acceptable salt, or the solvate thereof of claim
1, wherein R.sub.1 is ethyl, n-propyl, isopropyl, n-butyl,
2-methylpropyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,
2-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, or 2-ethylbutyl; R.sub.2 is methyl or methoxy; and
R.sub.3 and R.sub.4 are each methyl.
4. The optically active pyranochromenylphenol compound, the
pharmaceutically acceptable salt, or the solvate thereof of claim
1, wherein the compound of Chemical Formula (I) is any one of the
following compounds: ##STR00021## ##STR00022## ##STR00023##
5. An optically active pyranochromenylphenol compound of the
following Chemical Formula (II), a pharmaceutically acceptable
salt, or a solvate thereof: ##STR00024## wherein R.sub.1 is a
straight or branched C.sub.2 to C.sub.6 alkyl group unsubstituted
or substituted by a straight or branched C.sub.1 to C.sub.5 alkyl
group, a halogen atom, or a C.sub.1 to C.sub.5 thioalkyl group;
R.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or ethoxy; and
R.sub.3 and R.sub.4 are each independently a hydrogen atom or a
C.sub.1 to C.sub.2 alkyl group.
6. The optically active pyranochromenylphenol compound, the
pharmaceutically acceptable salt, or the solvate thereof of claim
5, wherein R.sub.1 is ethyl, n-propyl, isopropyl, n-butyl,
2-methylpropyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,
2-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, and 2-ethylbutyl; R.sub.2 is a hydrogen atom; and
R.sub.3 and R.sub.4 are each methyl.
7. The optically active pyranochromenylphenol compound, the
pharmaceutically acceptable salt, or the solvate thereof of claim
5, wherein R.sub.1 is ethyl, n-propyl, isopropyl, n-butyl,
2-methylpropyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,
2-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, or 2-ethylbutyl; R.sub.2 is methyl or methoxy; and
R.sub.3 and R.sub.4 are each methyl.
8. The optically active pyranochromenylphenol compound, the
pharmaceutically acceptable salt, or the solvate thereof of claim
5, wherein the compound of Chemical Formula (II) is any one of the
following compounds: ##STR00025## ##STR00026## ##STR00027##
9. A pharmaceutical composition for preventing or treating
diabetes, comprising an optically active pyranochromenylphenol
compound of the following Chemical Formula (I'), a pharmaceutically
acceptable salt, or a solvate thereof: ##STR00028## wherein
R'.sub.1 is a straight or branched C.sub.1 to C.sub.6 alkyl group
unsubstituted or substituted by a straight or branched C.sub.1 to
C.sub.5 alkyl group, a halogen atom, or a C.sub.1 to C.sub.5
thioalkyl group; R'.sub.2 is a hydrogen atom, methyl, ethyl,
methoxy, or ethoxy; and R'.sub.3 and R'.sub.4 are each
independently a hydrogen atom or a C.sub.1 to C.sub.2 alkyl
group.
10. The pharmaceutical composition of claim 9, wherein the
optically active pyranochromenylphenol compound of Chemical Formula
(I') is any one of the following compounds: ##STR00029##
##STR00030## ##STR00031##
11. A pharmaceutical composition for preventing or treating
obesity, comprising an optically active pyranochromenylphenol
compound of the following Chemical Formula (II'), a
pharmaceutically acceptable salt, or a solvate thereof:
##STR00032## wherein R'.sub.1 is a substituted or unsubstituted
straight or branched C.sub.1 to C.sub.6 alkyl group unsubstituted
or substituted by a straight or branched C.sub.1 to C.sub.5 alkyl
group, a halogen atom, or a C.sub.1 to C.sub.5 thioalkyl group;
R'.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or ethoxy; and
R'.sub.3 and R'.sub.4 are each independently a hydrogen atom or a
C.sub.1 to C.sub.2 alkyl group.
12. The pharmaceutical composition of claim 10, wherein the
optically active pyranochromenylphenol compound of Chemical Formula
(II') is any one of the following compounds: ##STR00033##
##STR00034## ##STR00035##
Description
TECHNICAL FIELD
[0001] The present specification claims priority to and the benefit
of Korean Patent Application No. 10-2016-0081674 filed in the
Korean Intellectual Property Office on Jun. 29, 2016, the entire
contents of which are incorporated herein by reference.
[0002] The present invention relates to pyranochromenylphenol
derivatives having different efficacies depending on the direction
of optical activity and a pharmaceutical composition including the
same, and to an R-enantiomer having excellent anti-diabetic
efficacy and an S-enantiomer having excellent anti-obesity efficacy
and a pharmaceutical composition including each of the
enantiomers.
BACKGROUND ART
[0003] Obesity, which about 30 to 40% of modern people have, is
defined as a state in which excessive fat tissues are accumulated
in the body, and obesity occurs when excessive energy is
accumulated due to imbalance of energy supply in the human body.
Due to improvement in the standard of living resulting from the
recent economic development, frequent ingestion of instant food
products and dietary habits of consumption of large amounts of meat
lead to a rapid increase in obesity ratio.
[0004] Meanwhile, diabetes is one of the metabolic disorders which
show a phenomenon in which the amount of insulin secreted is
insufficient or insulin does not perform normal functions, and
diabetes is characterized by hyperglycemia in which the
concentration of glucose in blood is increased, and is defined as a
disease in which various syndromes and symptoms are shown due to
hyperglycemia, and glucose is released in the urine. In order to
treat diabetes and prevent complications thereof, it is the most
important to adjust blood sugar, and there are glycated hemoglobin
(HbA1C), and the like as a primary efficacy endpoint which is
involved in the adjustment of blood sugar.
[0005] Since obesity is caused by imbalance of energy when more
excessive nutrients are absorbed than the amount of energy consumed
for a long period of time, it is known that obesity increases not
only the attack rate of diabetes, fatty liver, dyslipidemia, and
the like, but also the attack rate of sexual dysfunction,
arthritis, cardiovascular diseases, obstructive sleep apnea, and
the like, and is responsible for cholelithiasis and several
cancers. For this reason, the World Health Organization (WHO)
stipulates that obesity is responsible for causing various
metabolic diseases (adult diseases), and obesity is also
responsible for diabetes, and conversely, diabetic patients evolve
into an obese state, and the like due to insulin resistance, so
that obesity and diabetes can be said to be diseases affecting each
other.
[0006] However, for the correlation between diabetes and obesity,
it is estimated that the Europeans and the Africans have a
correlation of approximately 60% and the Asians such as Koreans,
Chinese, and Japanese have a correlation of approximately 30%, and
there are a considerable number of diabetic patients with normal
body weight or lean body build for various reasons (Non-Patent
Document 1). Further, since the target and indicator of a
therapeutic agent for obesity is to reduce the body weight, and the
target and indicator of a therapeutic agent for diabetes is to
adjust blood sugar, the targets and therapeutic methods of the two
diseases are different from each other in terms of the adjustment
of blood sugar.
[0007] Glabridin is a compound found from Glycyrrhiza glabra
extract, and is known to have whitening activity by suppressing the
activity of tyrosinase during the synthetic process of melanin, and
to help alleviate gastroenteric disorders. Recently, it was
confirmed that glabridin is effective for metabolic syndromes
including hyperlipidemia, fatty liver, impaired glucose metabolism,
diabetes, and obesity, and has anti-inflammatory actions,
anti-cancer actions, and the like (Patent Document 1). However,
inspite of useful medicinal efficacy, glabridin is easily broken
down by sunlight, moisture, acidity, basicity, oxygen, heat, and
the like due to low chemical stability, so that it is very
difficult to develop a product actually utilizing glabridin
(Non-Patent Document 2).
[0008] For the aforementioned reasons, the inventors of the present
invention suggested a new direction for treating various metabolic
diseases and inflammatory diseases by synthesizing a new
pyranochromenylphenol derivative of the following Chemical Formula
(I), which is stable under various physical conditions while
maintaining or improving the medicinal efficacy of glabridin
(Patent Document 2).
##STR00001##
[0009] In the chemical formula,
[0010] R.sup.1 is a hydrogen atom, methyl, methoxy, or a halogen
atom;
[0011] R.sup.2 is a hydrogen atom; a substituted or unsubstituted
straight or branched C.sub.1 to C.sub.6 alkyl group; a halogen
atom; a substituted or unsubstituted straight or branched C.sub.1
to c.sub.6 alkoxy group; or a substituted or unsubstituted straight
or branched C.sub.1 to C.sub.4 thioalkyl group;
[0012] R.sup.3 and R.sup.4 are each independently a hydrogen atom
or a C.sub.1 to C.sub.2 alkyl group; and
[0013] in the case of the substituted alkyl, the substituted
alkoxy, and the substituted thioalkyl, the substituent is a halogen
atom, a straight or branched C.sub.1 to c.sub.5 alkyl group, a
straight or branched C.sub.1 to c.sub.5 alkoxy group or a straight
or branched C.sub.1 to c.sub.3 thioalkyl group.
[0014] In the Patent Document 2, the compound of Chemical Formula
(I) has one asymmetric carbon, and the present invention is
intended to suggest that in the specific derivatives of these
compounds, an R-enantiomer has an excellent effect in treating
diabetes and an S-enantiomer has an excellent effect in treating
obesity.
REFERENCES OF THE RELATED ART
Patent Documents
[0015] (Patent Document 1) International Publication No. WO
07/058480
[0016] (Patent Document 2) Korean Patent Application Laid-Open No.
10-2015-0075030
Non-Patent Documents
[0017] (Non-Patent Document 1) "Lean diabetes mellitus: An emerging
entity in the era of obesity", George A., et al., World J Diabetes,
2015 May 15; 6(4): 613-620
[0018] (Non-Patent Document 2) M. Ao, Natural Product Communication
5 (2010), 1907-1912.
DETAILED DESCRIPTION OF THE INVENTION
Technical Problem
[0019] An aspect of the present invention is to provide an
optically active pyranochromenylphenol derivative which has
excellent anti-diabetic efficacy and is chemically stable, and a
pharmaceutical composition including the same.
[0020] Another aspect of the present invention is to provide an
optically active pyranochromenylphenol derivative which has
excellent anti-obesity efficacy and is chemically stable, and a
pharmaceutical composition including the same.
Technical Solution
[0021] An aspect of the present invention provides an optically
active pyranochromenylphenol compound of the following Chemical
Formula (I), a pharmaceutically acceptable salt, or a solvate
thereof, and a pharmaceutical composition including the same:
##STR00002##
[0022] wherein
[0023] R.sub.1 is a straight or branched C.sub.2 to C.sub.6 alkyl
group unsubstituted or substituted by a straight or branched
C.sub.1 to C.sub.5 alkyl group, a halogen atom, or a C.sub.1 to
C.sub.5 thioalkyl group;
[0024] R.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or
ethoxy; and
[0025] R.sub.3 and R.sub.4 are each independently a hydrogen atom
or a C.sub.1 to C.sub.2 alkyl group.
[0026] Another aspect of the present invention provides an
optically active pyranochromenylphenol compound of the following
Chemical Formula (II), a pharmaceutically acceptable salt, or a
solvate thereof, and a pharmaceutical composition including the
same:
##STR00003##
[0027] wherein
[0028] R.sub.1 is a straight or branched C.sub.2 to C.sub.6 alkyl
group unsubstituted or substituted by a straight or branched
C.sub.1 to C.sub.5 alkyl group, a halogen atom, or a C.sub.1 to
C.sub.5 thioalkyl group;
[0029] R.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or
ethoxy; and
[0030] R.sub.3 and R.sub.4 are each independently a hydrogen atom
or a C.sub.1 to C.sub.2 alkyl group.
Advantageous Effects
[0031] In the optically active pyranochromenylphenol derivatives of
the present invention, an R-enantiomer is more chemically stable
than glabridin and has excellent anti-diabetic efficacy, and an
S-enantiomer has excellent anti-obesity efficacy and is more
chemically stable than glabridin.
BRIEF DESCRIPTION OF DRAWINGS
[0032] FIG. 1 is a column chromatogram of optically active
pyranochromenylphenol compounds 1a and 1b prepared in Example 1 of
the present invention.
[0033] FIG. 2 is a column chromatogram of an R-enantiomer (Compound
1a) of a pyranochromenylphenol compound synthesized from
glabridin.
[0034] FIG. 3 is a graph illustrating the degree to which the body
weight of a DIO mouse is increased according to the administration
dose and administration period of a racemic compound of Compound 1
prepared in Example 1 of the present invention and Compound 1b,
which is an S-enantiomer of Compound 1 prepared in Example 1 of the
present invention.
[0035] FIG. 4 is a graph illustrating the degree to which the body
weight of a DIO mouse is increased according to the administration
period of Compound 2a, which is an R-enantiomer of Compound 2
prepared in Example 2 of the present invention, and Compound 2b,
which is an S-enantiomer of Compound 2 prepared in Example 2 of the
present invention.
[0036] FIG. 5 is a graph illustrating the measurement results of a
change in blood sugar of a db/db mouse according to the
administration of a racemic compound (racemate) of Compound 13,
Compound 13a, which is an R-enantiomer of Compound 13, and a
racemic compound of Compound 2, and Compound 2a, which is an
R-enantiomer of Compound 2.
[0037] FIG. 6 is a graph illustrating a change in glycated
hemoglobin of a db/db mouse according to the administration of a
racemic compound of Compound 13, Compound 13a, which is an
R-enantiomer of Compound 13, and a racemic compound of Compound 2,
and Compound 2a, which is an R-enantiomer of Compound 2.
[0038] FIG. 7 is a graph illustrating the results of a glucose
tolerance test of a db/db mouse administered with a racemic
compound of Compound 13, Compound 13a, which is an R-enantiomer of
Compound 13, a racemic compound of Compound 2, and Compound 2a,
which is an R-enantiomer of Compound 2.
MODE FOR INVENTION
[0039] Hereinafter, the present invention will be described in more
detail.
[0040] All the technical terms used in the present invention are
used in the same sense as those generally understood by the person
skilled in the related art of the present invention, unless
otherwise defined. Further, in the present specification, a
preferred method or sample is described, but those similar or
equivalent thereto also fall within the scope of the present
invention. The contents of all the publications described as a
reference document in the present specification are incorporated by
reference into the present specification.
[0041] According to an aspect of the present invention, provided is
an optically active pyranochromenylphenol compound of the following
Chemical Formula (I), a pharmaceutically acceptable salt, or a
solvate thereof:
##STR00004##
[0042] wherein
[0043] R.sub.1 is a straight or branched C.sub.2 to C.sub.6 alkyl
group unsubstituted or substituted by a straight or branched
C.sub.1 to C.sub.5 alkyl group, a halogen atom, or a C.sub.1 to
C.sub.5 thioalkyl group;
[0044] R.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or
ethoxy; and
[0045] R.sub.3 and R.sub.4 are each independently a hydrogen atom
or a C.sub.1 to C.sub.2 alkyl group.
[0046] According to an exemplary embodiment of the present
invention, in Chemical Formula (I), R.sub.1 may be ethyl, n-propyl,
isopropyl, n-butyl, 2-methylpropyl, n-pentyl, 2-methylbutyl,
3-methylbutyl, 2-ethylpropyl, n-hexyl, 2-methylpentyl,
3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl, R.sub.2 may be a
hydrogen atom, and R.sub.3 and R.sub.4 may be each methyl.
[0047] Further, according to an exemplary embodiment of the present
invention, in Chemical Formula (I), R.sub.1 may be ethyl, n-propyl,
isopropyl, n-butyl, 2-methylpropyl, n-pentyl, 2-methylbutyl,
3-methylbutyl, 2-ethylpropyl, n-hexyl, 2-methylpentyl,
3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl, R.sub.2 may be
methyl or methoxy, and R.sub.3 and R.sub.4 may be each methyl.
[0048] According to an exemplary embodiment, the optically active
pyranochromenylphenol compound of Chemical Formula (I) may be any
one of the following compounds:
##STR00005## ##STR00006## ##STR00007##
[0049] According to an exemplary embodiment of the present
invention, the optically active pyranochromenylphenol compound of
Chemical Formula (I) has an excellent effect of preventing and
treating diabetes due to the excellent ability to adjust blood
sugar, and simultaneously, is excellent in terms of chemical
stability.
[0050] According to another aspect of the present invention,
provided is an optically active pyranochromenylphenol compound of
the following Chemical Formula (II), a pharmaceutically acceptable
salt, or a solvate thereof:
##STR00008##
[0051] wherein
[0052] R.sub.1 is a straight or branched C.sub.2 to C.sub.6 alkyl
group unsubstituted or substituted by a straight or branched
C.sub.1 to C.sub.5 alkyl group, a halogen atom, or a C.sub.1 to
C.sub.5 thioalkyl group;
[0053] R.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or
ethoxy; and
[0054] R.sub.3 and R.sub.4 are each independently a hydrogen atom
or a C.sub.1 to C.sub.2 alkyl group.
[0055] According to an exemplary embodiment of the present
invention, in Chemical Formula (II), R.sub.1 may be ethyl,
n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl,
2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, n-hexyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl,
R.sub.2 may be a hydrogen atom, and R.sub.3 and R.sub.4 may be each
methyl.
[0056] Further, according to an exemplary embodiment of the present
invention, in Chemical Formula (II), R.sub.1 may be ethyl,
n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl,
2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, n-hexyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl,
R.sub.2 may be methyl or methoxy, and R.sub.3 and R.sub.4 may be
each methyl.
[0057] According to an exemplary embodiment, the optically active
pyranochromenylphenol compound of Chemical Formula (II) may be any
one of the following compounds:
##STR00009## ##STR00010## ##STR00011##
[0058] According to an exemplary embodiment of the present
invention, the optically active pyranochromenylphenol compound of
Chemical Formula (II) has an excellent effect of preventing and
treating obesity by suppressing an increase in body weight and
simultaneously, is excellent in terms of chemical stability.
[0059] According to an exemplary embodiment of the present
invention, the pharmaceutically acceptable salt may be present as
an acid addition salt because the compound of Chemical Formula (I)
or the compound of Chemical Formula (II) forms a salt with a free
acid. The compound of Chemical Formula (I) or the compound of
Chemical Formula (II) may form a pharmaceutically acceptable acid
addition salt according to the typical method publicly known in the
art. An organic acid or an inorganic acid may be used as the free
acid, hydrochloric acid, bromic acid, sulfuric acid, or phosphoric
acid, and the like may be used as the inorganic acid, and citric
acid, acetic acid, lactic acid, tartariac acid, maleic acid,
fumaric acid, formic acid, propionic acid, oxalic acid,
trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic
acid, glycolic acid, succinic acid, 4-toluenesulfonic acid,
galacturonic acid, embonic acid, glutamic acid or aspartic acid,
and the like as the organic acid.
[0060] The pharmaceutically acceptable salt may be present as an
inorganic salt of the compound of Chemical Formula (I) or the
compound of Chemical Formula (II). The compound of Chemical Formula
(I) or the compound of Chemical Formula (II) may form a
pharmaceutically acceptable inorganic salt according to the typical
method publicly known in the art. Examples of the inorganic salt
include salts with aluminum, ammonium, calcium, copper, iron,
lithium, magnesium, manganese, potassium, sodium, or zinc, but are
not limited thereto, and ammonium, calcium, magnesium, potassium,
or sodium salts are preferred.
[0061] Further, according to an exemplary embodiment of the present
invention, the compound of Chemical Formula (I) or the compound of
Chemical Formula (II) may include not only pharmaceutically
acceptable salts, but also all the salts and solvates including
hydrates, which may be prepared by typical methods.
[0062] A method of preparing the compound of Chemical Formula (I)
or the compound of Chemical Formula (II) is not particularly
limited, but the compound of Chemical Formula (I) or the compound
of Chemical Formula (II) may be prepared based on the preparation
method disclosed in Korean Patent Application Laid-Open No.
10-2015-0075030 (Patent Document 2). That is, it is possible to
obtain an R-enantiomer and an S-enantiomer, which are optically
active pyranochromenylphenol compounds, by separating a racemic
compound of the pyranochromenylphenol compound prepared by the
method disclosed in the document by means of a separation method
such as column chromatography.
[0063] According to another aspect of the present invention,
provided is a pharmaceutical composition for preventing or treating
diabetes, including an optically active pyranochromenylphenol
compound of the following Chemical Formula (I'), a pharmaceutically
acceptable salt, or a solvate thereof:
##STR00012##
[0064] wherein
[0065] R'.sub.1 is a straight or branched C.sub.1 to C.sub.6 alkyl
group unsubstituted or substituted by a straight or branched
C.sub.1 to C.sub.5 alkyl group, a halogen atom, or a C.sub.1 to
C.sub.5 thioalkyl group;
[0066] R'.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or
ethoxy; and
[0067] R'.sub.3 and R'.sub.4 are each independently a hydrogen atom
or a C.sub.1 to C.sub.2 alkyl group.
[0068] Further, according to an exemplary embodiment of the present
invention, in Chemical Formula (I'), R'.sub.1 may be ethyl,
n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl,
2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, n-hexyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl,
R'.sub.2 may be a hydrogen atom, and R'.sub.3 and R'.sub.4 may be
each methyl.
[0069] In addition, according to an exemplary embodiment of the
present invention, in Chemical Formula (I'), R'.sub.1 may be ethyl,
n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl,
2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, n-hexyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl,
R'.sub.2 may be methyl or methoxy, and R'.sub.3 and R'.sub.4 may be
each methyl.
[0070] According to an exemplary embodiment of the present
invention, the optically active pyranochromenylphenol compound of
Chemical Formula (I') may be any one of the following
compounds:
##STR00013## ##STR00014## ##STR00015##
[0071] According to still another aspect of the present invention,
provided is a pharmaceutical composition for preventing or treating
obesity, including an optically active pyranochromenylphenol
compound of the following Chemical Formula (II'), a
pharmaceutically acceptable salt, or a solvate thereof:
##STR00016##
[0072] wherein
[0073] R'.sub.1 is a substituted or unsubstituted straight or
branched C.sub.1 to C.sub.6 alkyl group unsubstituted or
substituted by a straight or branched C.sub.1 to C.sub.5 alkyl
group, a halogen atom, or a C.sub.1 to C.sub.5 thioalkyl group;
[0074] R'.sub.2 is a hydrogen atom, methyl, ethyl, methoxy, or
ethoxy; and
[0075] R'.sub.3 and R'.sub.4 are each independently a hydrogen atom
or a C.sub.1 to C.sub.2 alkyl group.
[0076] Further, according to an exemplary embodiment of the present
invention, in Chemical Formula (II'), R'.sub.1 may be ethyl,
n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl,
2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, n-hexyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl,
R'.sub.2 may be a hydrogen atom, and R'.sub.3 and R'.sub.4 may be
each methyl.
[0077] In addition, according to an exemplary embodiment of the
present invention, in Chemical Formula (II'), R'.sub.1 may be
ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl,
2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, n-hexyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl,
R'.sub.2 may be methyl or methoxy, and R'.sub.3 and R'.sub.4 may be
each methyl.
[0078] According to an exemplary embodiment of the present
invention, the optically active pyranochromenylphenol compound of
Chemical Formula (II') may be any one of the following
compounds:
##STR00017## ##STR00018## ##STR00019##
[0079] According to an exemplary embodiment of the present
invention, the pharmaceutical composition may be formulated into a
typical pharmaceutical dosage form publicly known in the art. The
dosage form includes orally administered preparations, injection
preparations, suppositories, percutaneous administration
preparations, and nasal administration preparations, but may also
be administered by being formulated into any dosage form which is
not limited thereto, but may be preferably formulated into a
preparation for oral administration and an injection
preparation.
[0080] When the pharmaceutical composition is formulated into each
dosage form, the dosage form may be prepared by adding a
pharmaceutically acceptable carrier required for the preparation of
each dosage form. In the present specification, the term
"pharmaceutically acceptable carrier" is used to refer to any
constituent ingredient excluding a pharmaceutically active
ingredient. The "pharmaceutically acceptable" means the properties
that do not cause any pharmaceutically undesirable change via
interaction with other ingredients present in a composition (for
example, interaction between carriers or interaction between the
pharmaceutically active ingredient and a carrier). Selection of the
pharmaceutically acceptable carrier may vary depending on factors
such as the properties and the administration method of a
particular dosage form, and the effects of the carrier on
solubility and stability of the dosage form.
[0081] According to an exemplary embodiment of the present
invention, a pharmaceutically acceptable carrier included in a
pharmaceutical composition for oral administration may be one
selected from a diluent, a binder, a glidant (or a lubricant), a
disintegrant, a stabilizer, a solubilizing agent, a sweetening
agent, a coloring agent, and a flavoring agent, but is not limited
thereto.
[0082] A diluent refers to any excipient that is added to increase
the volume of a composition to formulate the composition into a
dosage form with an appropriate size. As the diluent, it is
possible to use starch (for example, potato starch, corn starch,
wheat starch, pregelatinized starch), microcrystalline cellulose
(for example, low-hydration microcrystalline cellulose), lactose
(for example, lactose monohydrate, anhydrous lactose, spray
lactose), glucose, sorbitol, mannitol, sucrose, alginate, alkaline
earth metal salts, clay, polyethylene glycol, dicalcium phosphate,
anhydrous calcium hydrogenphosphate, or silicon dioxide, and the
like either alone or in a mixture thereof, but the diluent is not
limited thereto. In the present invention, the excipient may be
used within a range of 5 wt % to 50 wt % based on a total weight of
the pharmaceutical composition, and may be used, for example, in an
amount of 10 wt % to 35 wt % based on the total weight of the
pharmaceutical composition for tableting and quality
maintenance.
[0083] A binder refers to a material that is used to impart
adhesiveness to materials in a powder form so as to facilitate
compression of the materials and improve flowability. The binder
may be one or more selected from starch, microcrystalline
cellulose, highly dispersible silica, mannitol, lactose,
polyethylene glycol, polyvinylpyrrolidone, cellulose derivatives
(for example, hydroxypropyl methylcellulose, hydroxypropyl
cellulose, or low-substituted hydroxypropyl cellulose), natural
gum, synthetic gum, povidone, co-povidone, and gelatin, but is not
limited thereto. In the present invention, the binder may be used
in an amount of 2 wt % to 15 wt % based on a total weight of the
pharmaceutical composition, and may be used, for example, in an
amount of 1 wt % to 3 wt % based on the total weight of the
pharmaceutical composition for tableting and quality
maintenance.
[0084] A disintegrant refers to a material that is added to
facilitate breakup or disintegration of a solid dosage form after
being administered to a living body. As the disintegrant, it is
possible to use starch such as sodium starch glycolate, corn
starch, potato starch or pregelatinized starch, or modified starch,
clay such as bentonite, montmorillonite or veegum, cellulose such
as microcrystalline cellulose, hydroxypropyl cellulose or
carboxymethyl cellulose, algins such as sodium alginate or alginic
acid, a cross-linked cellulose such as croscarmellose sodium, gum
such as guar gum or xanthan gum, a cross-linked polymer such as
cross-linked polyvinylpyrrolidone (crospovidone), or an
effervescent preparation such as sodium bicarbonate or citric acid
either alone or in a mixture thereof, but the disintegrant is not
limited thereto. In the present invention, the disintegrant may be
used in an amount of 2 wt % to 15 wt % based on a total weight of
the pharmaceutical composition, and may be used, for example, in an
amount of 4 wt % to 10 wt % based on the total weight of the
pharmaceutical composition for tableting and quality
maintenance.
[0085] A glidant or lubricant refers to a material that performs a
function of preventing cohesion of powders to a compressing system
and improving flowability of granules. As the glidant, it is
possible to use hard anhydrous silicic acid, talc, stearic acid, a
metal salt (magnesium salt, calcium salt, or the like) of stearic
acid, sodium lauryl sulfate, hydrogenated vegetable oil, sodium
benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl
monostearate, or polyethylene glycol either alone or in a mixture
thereof, but the glidant is not limited thereto. In the present
invention, the glidant may be used in an amount of 0.1 wt % to 5 wt
% based on a total weight of the pharmaceutical composition, and
may be used, for example, in an amount of 1 wt % to 3 wt % based on
the total weight of the pharmaceutical composition for tableting
and quality maintenance.
[0086] As an adsorbent, it is possible to use hydrated silicon
dioxide, hard anhydrous silicic acid, colloidal silicon dioxide,
magnesium aluminometasilicate, microcrystalline cellulose, lactose,
or a cross-linked polyvinylpyrrolidone either alone or in a mixture
thereof, but the adsorbent is not limited thereto.
[0087] A stabilizer may be one or more selected from antioxidants
such as butylhydroxyanisole, butylhydroxytoluene, carotene,
retinol, ascorbic acid, tocopherol, tocopherol polyethylene glycol
succinic acid or propyl gallate, cyclic compounds of sugars such as
cyclodextrin, carboxyethyl cyclodextrin, hydroxypropyl
cyclodextrin, sulfobutyl ether or cyclodextrin, and organic acids
such as phosphoric acid, lactic acid, acetic acid, citric acid,
tartaric acid, succinic acid, maleic acid, fumaric acid, glycolic
acid, propionic acid, gluconic acid or glucuronic acid, but is not
limited thereto.
[0088] Selectively, a publicly known additive for enhancing the
taste by boosting the sense of taste may be included in the
pharmaceutical composition. For example, a sweetening agent such as
sucralose, sucrose, fructose, erythritol, acesulfame potassium,
sugar alcohol, honey, sorbitol, or aspartame may be added to more
effectively mask bitterness and maintain the stability and quality
of the preparation. Further, an acidifier such as citric acid or
sodium citrate, a natural flavor such as Japanese apricot flavor,
lemon flavor, pineapple flavor or herbal flavor, or a natural
pigment such as natural fruit juice, chlorophyllin, or flavonoid
may be used.
[0089] The pharmaceutical composition for oral administration may
be a solid preparation, a semi-solid preparation, or a liquid
preparation, for oral administration. Examples of the solid
preparation for oral administration include tablets, pills, hard or
soft capsules, powders, fine granules, granules, powders for
reconstitution of solution or suspension, lozenges, wafers, oral
strips, dragees and chewable gum, and the like, but are not limited
thereto. Examples of the liquid preparation for oral administration
include solution, suspension, emulsion, syrup, elixir, spirit,
aromatic waters, lemonade, extract, precipitant, tincture, and oily
medicine. Examples of the semi-solid preparation include aerosol,
cream, gel and the like, but are not limited thereto.
[0090] The pharmaceutical composition according to the present
invention may be formulated into an injection preparation, and when
the composition is formulated into an injection preparation, the
composition may include a non-toxic buffer solution, which is
isotonic to blood, as a diluent, and examples thereof include a
phosphoric acid buffer solution with a pH of 7.4, and the like. The
pharmaceutical composition may include other diluents or additives
in addition to the buffer solution.
[0091] A method of preparing a carrier used in the aforementioned
preparation and the preparation may be selected and performed as
widely known in the art, and the carrier and the preparation may be
prepared according to the methods described in, for example, the
Remington's Pharmaceutical Science latest edition.
[0092] The dosage and administration time of the pharmaceutical
composition according to the present invention may vary depending
on age, sex, status, and body weight of an administration subject,
administration route, administration frequency, and type of drug.
The daily dosage is about 0.1 mg/kg to about 1,000 mg/kg,
preferably mg/kg to 100 mg/kg. The dosage may be appropriately
increased and decreased according to a type of disease, progress of
disease, administration route, sex, age, body weight and the
like.
[0093] In order to obtain a target effect, the pharmaceutical
composition according to the present invention may be arbitrarily
administered several times such that the total daily dosage as an
effective ingredient is 0.1 mg/kg to 1,000 mg/kg as a compound
based on an adult. The dosage may be appropriately increased and
decreased according to a type of disease to be treated or
prevented, progress of disease, administration route, sex, age,
body weight, health status, and the like.
[0094] The pharmaceutical composition according to the present
invention may contain the compound of Chemical Formula (I') or the
compound of Chemical Formula (II') according to the present
invention in an amount of about 0.0001 wt % to about 10 wt %,
preferably 0.001 wt % to 1 wt % based on a total weight of the
entire composition.
[0095] Hereinafter, one or more specific examples will be described
in more detail through Examples. However, these Examples are
provided only for exemplarily explaining one or more specific
examples, and the scope of the present invention is not limited by
these Examples.
EXAMPLE 1
Preparation of
(R)-3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyran-
o[2,3-f]chromene (Compound 1a) and
(S)-3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyran-
o[2,3-f]chromene (Compound 1b)
[0096]
3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyr-
ano[2,3-f]chromene in the form of a racemic compound was
synthesized in accordance with the method exemplified in Korean
Patent Application Laid-Open No. 10-2015-0075030 (Patent Document
2).
1-1: Preparation of
2-(2-benzyloxy-4-ethoxyphenyl)-3-(2,2-dimethyl-5-hydroxy-2H-1-benzopyran--
6-yl)-acrylic acid methyl ester
[0097] A three-neck round flask was cooled in a dry ice-acetone
bath at -78.degree. C. while being maintained under a nitrogen
atmosphere, and 45 ml of a 1.0 M lithium diisopropyl amide
(LDA)-THF solution was added thereto. Thereafter, 8.10 g (30.0
mmol) of (2-benzyloxy-4-ethoxyphenyl)acetic acid methyl ester was
dissolved in 150 ml of THF, and then the resulting solution was
slowly added to the 1.0 M LDA-THF solution prepared above for 30
minutes, and the resulting mixture was additionally stirred for 30
minutes. Next, 9.24 g (30.0 mmol) of
5-benzoyloxy-2,2-dimethyl-6-formyl-2H-1-benzopyran was dissolved in
20 ml of THF, and then the solution was slowly added to the
reaction solution prepared above over 30 minutes, and the resulting
mixture was additionally stirred for 30 minutes. The round flask
was separated from the dry ice-acetone bath, and then left to
stand, and the reaction solution was slowly cooled at 0.degree. C.
In this state, 100 ml of brine was added thereto, the mixture was
vigorously stirred at room temperature for 30 minutes, and then the
organic layer was separated, and the aqueous layer was extracted
one more time with 200 ml of ethyl acetate (CH.sub.3COOC.sub.2H).
The organic layer extracted with ethyl acetate was combined with
the organic layer previously separated, and the combined organic
layer was dried over anhydrous magnesium sulfate, and then was
concentrated by being distilled under reduced pressure. The
concentrated solution was purified with silica gel column
chromatography to obtain 5.79 g (12.70 mmol) of
2-(2-benzyloxy-4-ethoxyphenyl)-3-(2,2-dimethyl-5-hydroxy-2H-1-benzopyran--
6-yl) acrylic acid methyl ester (Yield: 42.3%).
1-2: Preparation of
2-(2-benzyloxy-4-ethoxyphenyl)-3-(2,2-dimethyl-5-hydroxy-2H-1-benzopyran--
6-yl)-propan-1-ol
[0098] 4.56 g (10.0 mmol) of the
2-(2-benzyloxy-4-ethoxyphenyl)-3-(2,2-dimethyl-5-hydroxy-2H-1-benzopyran--
6-yl)-acrylic acid methyl ester obtained in Example 1-1 was
dissolved in 20 ml of THF, 60 ml of a 1.0 M THF solution of
LiBH.sub.4 was added thereto, and the resulting mixture was
refluxed for 5 hours. The reaction solution was cooled in an ice
bath, and then 50 ml of 1 N HCl was slowly added thereto, and
extraction was performed by using 100 ml of CH.sub.2Cl.sub.2. The
organic layer was dried over anhydrous magnesium sulfate, and then
was concentrated by being distilled under reduced pressure, and
then the concentrated solution was purified with silica gel column
chromatography to obtain 2.35 g (5.47 mmol) of
2-(2-benzyloxy-4-ethoxyphenyl)-3-(2,2-dimethyl-5-hydroxy-2H-1-benzopyran--
6-yl)-propan-1-ol (Yield: 54.7%).
1-3: Preparation of
3-(2-benzyloxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8-tetrahydropyrano[2,3--
f]chromen
[0099] 1.57 g (3.65 mmol) of the
2-(2-benzyloxy-4-ethoxyphenyl)-3-(2,2-dimethyl-5-hydroxy-2H-1-benzopyran--
6-yl)-propan-1-ol obtained in Example 1-2 was dissolved in 10 ml of
THF, 0.995 g (3.80 mmol) of triphenylphosphine (Ph.sub.3P) was
added to the solution, and the reaction solution was slowly
refluxed while being heated. While maintaining this state, 3.9 ml
of a 1.0 M toluene solution of diethylazodicaboxylate (DEAD) was
slowly added thereto, and the resulting mixture was vigorously
stirred for 1 hour. The reaction solution was cooled to room
temperature, and then concentrated by being distilled under reduced
pressure, and the concentrated solution was purified with silica
gel column chromatography to obtain 1.31 g (3.17 mmol) of
3-(2-benzyloxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8-tetrahydropy-
rano[2,3-f]chromene (Yield: 86.8%).
1-4: Preparation of
3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,-
3-f]chromen
[0100] 4.12 g (10.0 mmol) of the
3-(2-benzyloxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8-tetrahydropyrano[2,3--
f]chromene obtained in Example 1-3 was put into a 100-ml pressure
vessel, 50 ml of ethanol was added thereto, and the resulting
mixture was dissolved well. Thereafter, 150 mg of 5% palladium on
carbon (Pd/C) was mixed with the solution, and the resulting
mixture was vigorously stirred at room temperature for 25 hours
while maintaining a hydrogen state of 5 atm. The reaction solution
was filtered to remove the catalyst, and then concentrated by being
distilled under reduced pressure, and the concentrated solution was
purified with silica gel column chromatography to obtain 2.67 g
(8.23 mmol) of
3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,-
3-f]chromene (Yield=82%).
1-5: Preparation of Optical Isomer of
3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,-
3-f]chromene
[0101] The racemic compound obtained in Example 1-4 was separated
into each isomer by column chromatography, and the column
chromatography conditions are shown in the following Table 1.
TABLE-US-00001 TABLE 1 Conditions Column CHIRALPAK IA (Daicel) 0.46
cm I.D. .times. 25 cm L Volume of sample injected 2.0 .mu.l Sample
solution 1.0 mg/ml in Ethanol Mobile phase Hexane/Isopropanol =
95/5 (V/V) Flow rate 1.0 ml/min Wavelength UV 214 nm Temperature
35.degree. C.
[0102] FIG. 1 is a column chromatogram of optically active
pyranochromenylphenol compounds 1a and 1b prepared in Example
1-4.
[0103] For comparison, an R-enantiomer was synthesized from
glabridin (Daechon Chemical Co., Ltd., Korea), and then a result
was obtained by carrying out column chromatography under the same
conditions.
[0104] FIG. 2 is a column chromatogram of an R-enantiomer (Compound
1a) of a pyranochromenylphenol compound synthesized from
glabridin.
[0105] As a result of comparing the chromatogram of FIG. 2 with the
chromatogram of FIG. 1, it could be seen that in FIG. 1, the peak
in the 16.5 minute range is an R-enantiomer and the peak in the
20.5 minute range is an S-enantiomer.
[0106] The chromatography conditions for separating each of the R
and S enantiomers from the racemic compound were confirmed, and
then Daicel Chiral Technologies Co., Ltd. (China) was requested for
the separation and purification of the racemic compound sample
(37.0 g). As a result, 16.5 g of the R-enantiomer and 16.2 g of the
S-enantiomer with >99% ee were obtained, and the results of
.sup.1H-NMR, .sup.13C-NMR, optical rotation, and melting point
(M.P.) for the enantiomers are shown as follows.
[0107] .sup.1H-NMR (CDCl.sub.3): 6.995 (d, 1H, J=8.4 Hz), 6.832 (d,
1H, J=8.0 Hz), 6.465 (dd, 1H, J=8.0, 2.4 Hz), 6.388 (d, 1H, J=8.4
Hz), 6.331 (d, 1H, J=2.4 Hz), 5.170 (s, 1H), 4.389 (m, 1H, J=10.4,
3.2, 2.0 Hz), 4.009 (t, 1H, J=10.4 Hz), 3.960 (q, 2H, J=7.2 Hz),
3.483 (m, 1H), 3.010 (dd, 1H, J=15.6, 11.2 Hz), 2.858 (m, 1H,
J=15.6, 4.8, 1.6 Hz), 2.642 (m, 2H), 1.773 (t, 2H, J=6.8 Hz), 1.384
(t, 2H, J=6.8 Hz), 1.333 (s, 3H), 1.318 (s, 3H).
[0108] .sup.13C-NMR (CDCl.sub.3): 158.552, 154.340, 152.719,
152.091, 128.075, 127.465, 119.882, 112.909, 109.305, 109.248,
106.572, 102.504, 73.798, 70.018, 63.450, 32.311, 31.749, 30.614,
26.776, 26.390, 17.116, 14.781.
[0109] Optical Rotation Data
[0110] R-enantiomer--[a].sub.D.sup.20: -6.2.degree. (c=0.025,
ethanol); and
[0111] S-enantiomer--[a].sub.D.sup.20: +6.0.degree. (c=0.025,
ethanol).
[0112] M.P.
[0113] R-enantiomer: 132.5.degree. C.; and
[0114] S-enantiomer: 132.0.degree. C.
EXAMPLE 2
Preparation of
(R)-3-(2-hydroxy-4-propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyra-
no[2,3-f]chromene (Compound 2a) and
(S)-3-(2-hydroxy-4-propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyra-
no[2,3-f]chromene (Compound 2b)
[0115]
3-(2-hydroxy-4-propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropy-
rano[2,3-f]chromene was synthesized in the form of a racemic
compound by using the same method as in Example 1, except that in
Example 1-1, (2-benzyloxy-4-propoxyphenyl) acetic acid methyl ester
was used instead of (2-benzyloxy-4-ethoxyphenyl) acetic acid methyl
ester. Daicel Chiral Technologies Co., Ltd. was requested for the
separation and purification of the synthesized sample, 10 g of an
R-enantiomer and 10 g of an S-enantiomer with >99% ee were
provided, and the results of .sup.1H-NMR, .sup.13C-NMR, optical
rotation, and M.P. for the enantiomers are shown as follows.
[0116] .sup.1H-NMR (CDCl.sub.3): 6.976 (d, 1H, J=8.4 Hz), 6.817 (d,
1H, J=8.0 Hz), 6.452 (dd, 1H, J=8.0, 2.0 Hz), 6.392 (d, 1H, J=8.4
Hz), 6.316 (d, 1H, J=2.0 Hz), 5.600 (s, 1H), 4.380 (d, 1H, J=10.0
Hz), 4.000 (t, 1H, J=10.0 Hz), 3.812 (t, 2H, J=6.4 Hz), 3.488 (m,
1H), 2.997 (dd, 1H, J=15.6, 11.2 Hz), 2.837 (dd, 1H, J=15.6, 4.4
Hz), 2.640 (m, 2H), 1.782 (t, 2H, J=6.8 Hz), 1.765 (m, 2H), 1.329
(s, 3H), 1.314 (s, 3H), 0.994 (t, 3H, J=7.2 Hz).
[0117] .sup.13C-NMR (CDCl.sub.3): 158.678, 154.412, 152.596,
152.054, 128.015, 127.483, 119.827, 113.016, 109.299, 109.226,
106.588, 102.460, 73.888, 70.014, 69.537, 32.287, 31.702, 30.552,
26.728, 26.349, 22.453, 17.096, 10.458.
[0118] Optical Rotation Data
[0119] R-enantiomer--[a].sub.D.sup.20: -5.3.degree. (c=0.025,
ethanol); and
[0120] S-enantiomer--[a].sub.D.sup.20: +5.8.degree. (c=0.025,
ethanol).
[0121] M.P.
[0122] R-enantiomer: 153.6.degree. C.; and
[0123] S-enantiomer: 153.4.degree. C.
EXAMPLE 3
Preparation of
(R)-3-(2-hydroxy-4-butoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyran-
o[2,3-f]chromene (Compound 4a) and
(S)-3-(2-hydroxy-4-butoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyran-
o[2,3-f]chromene (Compound 4b)
[0124]
3-(2-hydroxy-4-butoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyr-
ano[2,3-f]chromene was synthesized in the form of a racemic
compound by using the same method as in Example 1, except that in
Example 1-1, (2-benzyloxy-4-butoxyphenyl) acetic acid methyl ester
was used instead of (2-benzyloxy-4-ethoxyphenyl) acetic acid methyl
ester. Daicel Chiral Technologies Co., Ltd. was requested for the
separation and purification of the synthesized sample, 10 g of an
R-enantiomer and 10 g of an S-enantiomer with >99% ee were
provided, and the results of .sup.1H-NMR, .sup.13C-NMR, optical
rotation, and M.P. for the enantiomers are shown as follows.
[0125] .sup.1H-NMR (CDCl.sub.3): 7.009 (d, 1H, J=8.4 Hz), 6.847 (d,
1H, J=8.0 Hz), 6.482 (dd, 1H, J=8.0, 2.0 Hz), 6.408 (d, 1H, J=8.4
Hz), 6.355 (d, 1H, J=2.0 Hz), 5.313 (s, 1H), 4.407 (m, 1H, J=10.0
Hz), 4.027 (t, 1H, J=10.0 Hz), 3.906 (t, 2H, J=6.4 Hz), 3.503 (m,
1H), 3.027 (dd, 1H, J=15.6, 11.2 Hz), 2.874 (dd, 1H, J=15.6, 4.4
Hz), 2.662 (m, 2H), 1.70-1.90 (m, 4H), 1.482 (m, 2H), 1.351 (s,
3H), 1.337 (s, 3H), 0.977 (t, 3H, J=7.2 Hz).
[0126] .sup.13C-NMR (CDCl.sub.3): 158.793, 154.331, 152.721,
152.092, 128.047, 127.461, 119.777, 112.909, 109.299, 109.248,
106.628, 102.511, 73.786, 70.023, 67.738, 32.317, 31.756, 31.227,
30.626, 26.777, 26.390, 19.193, 17.117, 13.807.
[0127] Optical Rotation Data
[0128] R-enantiomer--[a].sub.D.sup.20: -5.3.degree. (c=0.025,
ethanol); and
[0129] S-enantiomer--[a].sub.D.sup.20: +5.1.degree. (c=0.025,
ethanol).
[0130] M.P.
[0131] R-enantiomer: 115.9.degree. C.; and
[0132] S-enantiomer: 114.6.degree. C.
EXAMPLE 4
Preparation of
(R)-3-(2-hydroxy-4-isopentyloxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydr-
opyrano[2,3-f]chromene (Compound 8a) and
(S)-3-(2-hydroxy-4-isopentyloxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydr-
opyrano[2,3-f]chromene (Compound 8b)
[0133]
3-(2-hydroxy-4-isopentyloxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahy-
dropyrano[2,3-f]chromene was synthesized in the form of a racemic
compound by using the same method as in Example 1, except that in
Example 1-1, (2-benzyloxy-4-isopentyloxyphenyl) acetic acid methyl
ester was used instead of (2-benzyloxy-4-ethoxyphenyl) acetic acid
methyl ester.
[0134] Daicel Chiral Technologies Co., Ltd. was requested for the
separation and purification of the synthesized sample, 0.5 g of an
R-enantiomer and 0.5 g of an S-enantiomer with >99% ee were
provided, and the results of .sup.1H-NMR, .sup.13C-NMR, M.P., and
optical rotation for the enantiomers are shown as follows.
[0135] .sup.1H-NMR (CDCl.sub.3): 6.992 (d, 1H, J=8.4 Hz), 6.827 (d,
1H, J=8.4 Hz), 6.468 (dd, 1H, J=8.4, 2.0 Hz), 6.385 (d, 1H, J=8.4
Hz), 6.335 (d, 1H, J=2.0 Hz), 5.083 (s, 1H), 4.387 (m, 1H, J=10.0,
5.6, 2.4 Hz), 4.011 (t, 1H, J=10.0 Hz), 3.918 (t, 2H, J=6.8 Hz),
3.485 (m, 1H), 3.008 (dd, 1H, J=15.6, 11.2 Hz), 2.857 (dd, 1H,
J=15.6, 4.4 Hz), 2.643 (m, 2H), 1.806 (m, 1H), 1.772 (t, 2H, J=6.8
Hz), 1.644 (m, 2H), 1.331 (s, 3H), 1.316 (s, 3H), 0.944 (t, 3H,
J=6.4 Hz).
[0136] .sup.13C-NMR (CDCl.sub.3): 158.881, 154.197, 152.861,
152.137, 128.120, 127.459, 119.736, 112.789, 109.288, 109.284,
106.724, 102.561, 73.700, 70.031, 66.431, 37.940, 32.345, 31.805,
30.710, 26.836, 26.434, 25.031, 22.573, 17.150.
[0137] Optical Rotation Data
[0138] R-enantiomer--[a].sub.D.sup.20: -1.7.degree. (c=0.001,
methylene chloride)
[0139] S-enantiomer--[a].sub.D.sup.20: +1.5.degree. (c=0.001,
methylene chloride)
[0140] M.P.
[0141] R-enantiomer: 164.7.degree. C.; and
[0142] S-enantiomer: 164.1.degree. C.
EXAMPLE 5
Preparation of
(R)-3-(2-hydroxy-4-ethoxyphenyl)-5,8,8-trimethyl-2,3,4,8,9,10-hexahydropy-
rano[2,3-f]chromene (Compound 9a) and
(S)-3-(2-hydroxy-4-ethoxyphenyl)-5,8,8-trimethyl-2,3,4,8,9,10-hexahydropy-
rano[2,3-f]chromene (Compound 9b)
[0143]
3-(2-hydroxy-4-ethoxyphenyl)-5,8,8-trimethyl-2,3,4,8,9,10-hexahydro-
pyrano[2,3-f]chromene was synthesized in the form of a racemic
compound by using the same method as in Example 1, except that in
Example 1-1, 5-benzoyloxy-2,2,7-trimethyl-6-formyl-2H-1-benzopyran
was used instead of
5-benzoyloxy-2,2-dimethyl-6-formyl-2H-1-benzopyran. Daicel Chiral
Technologies Co., Ltd. was requested for the separation and
purification of the synthesized sample, 0.5 g of an R-enantiomer
and 0.5 g of an S-enantiomer with >99% ee were provided, and the
results of .sup.1H-NMR and .sup.13C-NMR for the enantiomers are
shown as follows.
[0144] .sup.1H-NMR (CDCl.sub.3): 7.011 (d, 1H, J=8.4 Hz), 6.475
(dd, 1H, J=8.4, 2.4 Hz), 6.341 (d, 1H, J=2.4 Hz), 6.311 (s, 1H),
5.189 (s, 1H), 4.353 (m, 1H, J=10.4, 3.2, 2.0 Hz), 4.007 (t, 1H,
J=10.4 Hz), 3.966 (q, 2H, J=6.8 Hz), 3.485 (m, 1H), 2.848 (dd, 1H,
J=16.0, 5.6 Hz), 2.757 (dd, 1H, J=16.0, 10.8 Hz), 2.566 (m, 2H),
2.138 (s, 3H), 1.760 (t, 2H, J=7.2 Hz), 1.385 (t, 2H, J=6.8 Hz),
1.325 (s, 3H), 1.309 (s, 3H).
[0145] .sup.13C-NMR (CDCl.sub.3): 158.598, 154.290, 152.245,
152.131, 135.428, 128.196, 120.218, 112.011, 110.471, 106.961,
106.722, 102.577, 73.700, 69.461, 63.521, 32.478, 31.938, 28.717,
26.845, 26.371, 19.031, 17.009, 14.786.
EXAMPLE 6
Preparation of
(R)-3-(2-hydroxy-4-propoxyphenyl)-5,8,8-trimethyl-2,3,4,8,9,10-hexahydrop-
yrano[2,3-f]chromene (Compound 10a) and
(S)-3-(2-hydroxy-4-propoxyphenyl)-5,8,8-trimethyl-2,3,4,8,9,10-hexahydrop-
yrano[2,3-f]chromene (Compound 10b)
[0146]
3-(2-hydroxy-4-propoxyphenyl)-5,8,8-trimethyl-2,3,4,8,9,10-hexahydr-
opyrano[2,3-f]chromene was synthesized in the form of a racemic
compound by using the same method as in Example 1, except that in
Example 1-1, 5-benzoyloxy-2,2,7-trimethyl-6-formyl-2H-1-benzopyran
was used instead of
5-benzoyloxy-2,2-dimethyl-6-formyl-2H-1-benzopyran, and
(2-benzyloxy-4-propoxyphenyl) acetic acid methyl ester was used
instead of (2-benzyloxy-4-ethoxyphenyl) acetic acid methyl
ester.
[0147] Daicel Chiral Technologies Co., Ltd. was requested for the
separation and purification of the synthesized sample, 0.5 g of an
R-enantiomer and 0.5 g of an S-enantiomer with >99% ee were
provided, and the results of .sup.1H-NMR and .sup.13C-NMR for the
enantiomers are shown as follows.
[0148] .sup.1H-NMR (CDCl.sub.3): 7.008 (d, 1H, J=8.4 Hz), 6.477
(dd, 1H, J=8.4, 2.4 Hz), 6.347 (d, 1H, J=2.4 Hz), 6.312 (s, 1H),
5.263 (s, 1H), 4.353 (m, 1H, J=10.4, 3.2, 2.0 Hz), 4.006 (t, 1H,
J=10.4 Hz), 3.850 (t, 2H, J=6.8 Hz), 3.512 (m, 1H), 2.826 (dd, 1H,
J=16.0, 6.0 Hz), 2.757 (dd, 1H, J=16.0, 10.8 Hz), 2.622 (m, 2H),
2.137 (s, 3H), 1.784 (t, 2H, J=7.2 Hz), 1.761 (m, 2H), 1.325 (s,
3H), 1.309 (s, 3H), 1.011 (t, 3H, J=7.2 Hz).
[0149] .sup.13C-NMR (CDCl.sub.3): 158.800, 154.324, 152.244,
152.112, 135.428, 128.163, 120.164, 112.043, 110.471, 106.958,
106.734, 102.593, 73.710, 69.584, 69.471, 32.482, 31.937, 28.717,
26.839, 26.368, 22.505, 19.025, 17.009, 10.470.
EXAMPLE 7
Preparation of
(R)-3-(2-hydroxy-4-ethoxyphenyl)-5-methoxy-8,8-dimethyl-2,3,4,8,9,10-hexa-
hydropyrano[2,3-f]chromene (Compound 11a) and
(S)-3-(2-hydroxy-4-ethoxyphenyl)-5-methoxy-8,8-dimethyl-2,3,4,8,9,10-hexa-
hydropyrano[2,3-f]chromene (Compound 11b)
[0150]
3-(2-hydroxy-4-ethoxyphenyl)-5-methoxy-8,8-dimethyl-2,3,4,8,9,10-he-
xahydropyrano[2,3-f]chromene was synthesized in the form of a
racemic compound by using the same method as in Example 1, except
that in Example 1-1,
5-benzoyloxy-7-methoxy-2,2-dimethyl-6-formyl-2H-1-benzopyran was
used instead of
5-benzoyloxy-2,2-dimethyl-6-formyl-2H-1-benzopyran.
[0151] Daicel Chiral Technologies Co., Ltd. was requested for the
separation and purification of the synthesized sample, 0.5 g of an
R-enantiomer and 0.5 g of an S-enantiomer with >99% ee were
provided, and the results of .sup.1H-NMR and .sup.13C-NMR for the
enantiomers are shown as follows.
[0152] .sup.1H-NMR (CDCl.sub.3): 7.008 (d, 1H, J=8.4 Hz), 6.441
(dd, 1H, J=8.4, 2.4 Hz), 6.310 (d, 1H, J=2.4 Hz), 6.009 (s, 1H),
5.439 (s, 1H), 4.358 (m, 1H, J=10.4, 3.2, 2.0 Hz), 3.978 (t, 1H,
J=10.4 Hz), 3.939 (t, 2H, J=6.8 Hz), 3.735 (s, 3H), 3.406 (m, 1H),
2.922 (dd, 1H, J=16.0, 5.6 Hz), 2.722 (dd, 1H, J=16.0, 10.8 Hz),
2.582 (m, 2H), 1.756 (t, 2H, J=6.8 Hz), 1.367 (t, 2H, J=7.2 Hz),
1.334 (s, 3H), 1.321 (s, 3H).
[0153] .sup.13C-NMR (CDCl.sub.3): 158.493, 156.541, 154.402,
152.710, 152.641, 128.191, 120.124, 106.585, 102.814, 102.474,
101.609, 92.026, 74.135, 69.806, 63.472, 55.315, 32.521, 31.376,
26.805, 26.369, 25.166, 16.643, 14.767.
EXAMPLE 8
Preparation of
(R)-3-(2-hydroxy-4-propoxyphenyl)-5-methoxy-8,8-dimethyl-2,3,4,8,9,10-hex-
ahydropyrano[2,3-f]chromene (Compound 12a) and
(S)-3-(2-hydroxy-4-propoxyphenyl)-5-methoxy-8,8-dimethyl-2,3,4,8,9,10-hex-
ahydropyrano[2,3-f]chromene (Compound 12b)
[0154]
3-(2-hydroxy-4-propoxyphenyl)-5-methoxy-8,8-dimethyl-2,3,4,8,9,10-h-
exahydropyrano[2,3-f]chromene was synthesized in the form of a
racemic compound by using the same method as in Example 1, except
that in Example 1-1,
5-benzoyloxy-7-methoxy-2,2-dimethyl-6-formyl-2H-1-benzopyran was
used instead of 5-benzoyloxy-2,2-dimethyl-6-formyl-2H-1-benzopyran,
and (2-benzyloxy-4-propoxyphenyl) acetic acid methyl ester was used
instead of (2-benzyloxy-4-ethoxyphenyl) acetic acid methyl
ester.
[0155] Daicel Chiral Technologies Co., Ltd. was requested for the
separation and purification of the synthesized sample, 0.5 g of an
R-enantiomer and 0.5 g of an S-enantiomer with >99% ee were
provided, and the results of .sup.1H-NMR and .sup.13C-NMR for the
enantiomers are shown as follows.
[0156] .sup.1H-NMR (CDCl.sub.3): 7.023 (d, 1H, J=8.4 Hz), 6.463
(dd, 1H, J=8.4, 2.4 Hz), 6.344 (d, 1H, J=2.4 Hz), 6.004 (s, 1H),
5.024 (s, 1H), 4.360 (m, 1H, J=10.4, 3.2, 2.0 Hz), 3.978 (t, 1H,
J=10.4 Hz), 3.858 (t, 2H, J=6.8 Hz), 3.744 (s, 3H), 3.403 (m, 1H),
2.930 (dd, 1H, J=16.0, 5.6 Hz), 2.722 (dd, 1H, J=16.0, 10.8 Hz),
2.584 (m, 2H), 1.786 (t, 2H, J=6.8 Hz), 1.761 (m, 2H), 1.336 (s,
3H), 1.323 (s, 3H), 1.014 (t, 3H, J=7.2 Hz).
[0157] .sup.13C-NMR (CDCl.sub.3): 158.795, 156.587, 154.296,
152.741, 152.720, 128.212, 119.988, 106.678, 102.732, 102.530,
101.567, 91.979, 74.076, 69.828, 69.557, 55.320, 32.547, 31.393,
26.846, 26.399, 25.229, 22.530, 16.658, 10.490.
EXAMPLE 9
Preparation of
(R)-3-(2-hydroxy-4-methoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyra-
no[2,3-f]chromene (Compound 13a) and
(S)-3-(2-hydroxy-4-methoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyra-
no[2,3-f]chromene (Compound 13b)
[0158]
3-(2-hydroxy-4-methoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropy-
rano[2,3-f]chromene was synthesized in the form of a racemic
compound by using the same method as in Example 1, except that in
Example 1-1, (2-benzyloxy-4-methoxyphenyl) acetic acid methyl ester
was used instead of (2-benzyloxy-4-ethoxyphenyl) acetic acid methyl
ester. Daicel Chiral Technologies Co., Ltd. was requested for the
separation and purification of the synthesized sample, 0.5 g of an
R-enantiomer and 0.5 g of an S-enantiomer with >99% ee were
provided, and the results of .sup.1H-NMR and .sup.13C-NMR for the
enantiomers are shown as follows.
[0159] .sup.1H-NMR (CDCl.sub.3): 7.022 (d, 1H, J=8.4 Hz), 6.837 (d,
1H, J=8.0 Hz), 6.488 (dd, 1H, J=8.0, 2.4 Hz), 6.388 (d, 1H, J=8.4
Hz), 6.364 (d, 1H, J=2.4 Hz), 5.059 (s, 1H), 4.392 (m, 1H, J=10.0,
2.0 Hz), 4.024 (t, 1H, J=10.0 Hz), 3.768 (s, 3H), 3.488 (m, 1H),
3.017 (dd, 1H, J=15.6, 11.2 Hz), 2.875 (m, 1H, J=15.6, 6.8, 2.0
Hz), 2.645 (m, 2H), 1.778 (t, 2H, J=6.8 Hz), 1.335 (s, 3H), 1.321
(s, 3H).
[0160] .sup.13C-NMR (CDCl.sub.3): 159.257, 154.516, 152.772,
152.160, 128.184, 127.546, 120.182, 112.994, 109.394, 109.340,
105.957, 102.118, 73.917, 70.069, 55.340, 32.391, 31.811, 30.671,
26.833, 26.459, 17.187.
EXPERIMENTAL EXAMPLE 1
Anti-Obesity Effect Experiment of R-Enantiomer (Compound 1a) and
S-Enantiomer (Compound 1b) of Optically Active
Pyranochromenylphenol Compound
[0161] For the anti-obesity efficacy of the R-enantiomer (Compound
1a) and the S-enantiomer (Compound 1b) of the optically active
pyranochromenylphenol compound prepared in Example 1, an experiment
was performed as follows.
[0162] Specifically, a 5- to 6-week-old female C57BL/6J mouse
(Jackson Lab., USA) were purchased and fed with only high-fat
fodder for at least 11 weeks to produce a diet induced obesity
(DIO) mouse. Samples were exactly taken from a control and the
racemic compound, the R-enantiomer (Compound 1a) and the
S-enantiomer (Compound 1b) in Example according to the
administration dose (0, 20, and 50 mg/kg) and put into Falcon
tubes, 3 ml of a 0.5% aqueous methyl cellulose solution was added
thereto, and the resulting mixture was gently mixed by means of a
vortex mixer. Thereafter, the mixture was homogenized by using a
homogenizer (30,000 rpm, Ultra-Turrax.RTM. T10 Basic, IKA) for 3
minutes while 1.5 ml of a 0.5% aqueous methyl cellulose solution
was added thereto. The sample thus prepared was administered
through the oral gavage once daily for 6 weeks by using a
disposable plastic syringe. The body weight was measured once a
week while the DIO mouse was bred in this manner.
[0163] Based on the data thus measured, the anti-obesity effect was
calculated according to the following Equation 1.
Anti-obesity effect (%)={(Body weight after compound is
administered)-(Body weight before compound is administered)}/(Body
weight before compound is administered)).times.100 [Equation 1]
[0164] As a result, as shown in the following Table 2, it could be
confirmed that in the optically active pyranochromenylphenol
compounds, Compound 1b being the S-enantiomer had a better effect
of suppressing an increase in body weight than the racemic
compound, and thus had an excellent anti-obesity activity.
TABLE-US-00002 TABLE 2 Control S-enantiomer (DIO Racemic (Compound
Experimental group mouse) compound 1b) Administration dose 0 20 50
50 (mg/kg) Anti-obesity effect (%) 35.02 16.11 2.29 -10.99
[0165] FIG. 3 is a graph illustrating the degree to which the body
weight of the DIO mouse is increased according to the
administration dose and administration period of a racemic compound
prepared in Example 1, and Compound 1b, which is an S-enantiomer
prepared in Example 1.
[0166] As illustrated in FIG. 3, it could be confirmed that the
racemic compound prepared in Example 1 had an effect of suppressing
an increase in body weight of the mouse, but Compound 1b being the
S-enantiomer of the present invention prepared in Example 1 had a
much better anti-obesity effect of suppressing an increase in body
weight than that of the racemic compound.
EXPERIMENTAL EXAMPLE 2
Anti-Obesity Effect Experiment of R-Enantiomer (Compound 2a) and
S-Enantiomer (Compound 2b) of Optically Active
Pyranochromenylphenol Compound
[0167] For the anti-obesity efficacy of the R-enantiomer (Compound
2a) and the S-enantiomer (Compound 2b) of the optically active
pyranochromenylphenol compound prepared in Example 2, an experiment
was performed in the same manner as in Experimental Example 1.
[0168] Based on the data thus measured, the anti-obesity effect was
calculated according to Equation 1.
[0169] As a result, as shown in the following Table 3, it could be
confirmed that in the optically active pyranochromenylphenol
compounds according to the present invention, Compound 2b being the
S-enantiomer had a better anti-obesity activity than Compound 2a
being the R-enantiomer.
TABLE-US-00003 TABLE 3 Normal R- S- control Control enantiomer
enantiomer Experimental (Normal (DIO (Compound (Compound group
mouse) mouse) 2a) 2b) Administration 0 0 200 200 dose (mg/kg)
Anti-obesity 5.7 4.0 -6.0 -19 effect (%)
[0170] FIG. 4 is a graph illustrating the degree to which the body
weight of the mouse is increased according to the administration
period of Compound 2a being an R-enantiomer and Compound 2b being
an S-enantiomer, which are prepared in Example 2 of the present
invention.
[0171] As illustrated in FIG. 4, it can be seen that Compound 2b
being the S-enantiomer has a better anti-obesity activity than
Compound 2a being the R-enantiomer, and the body weight of the
mouse administered with the S-enantiomer (Compound 3b) for 6 weeks
has an excellent anti-obesity activity to such an extent as to be
close to the body weight of the normal mouse.
EXPERIMENTAL EXAMPLE 3
Anti-Diabetes Effect Experiment of R-Enantiomer (Compound 2a) and
S-Enantiomer (Compound 2b) of Optically Active
Pyranochromenylphenol Compound
[0172] For the anti-diabetes efficacy of the R-enantiomer and the
S-enantiomer of the optically active pyranochromenylphenol compound
prepared in Example 2, an experiment was performed as follows.
[0173] Specifically, 5-week-old male C57BLKS/J-db/db mice (Central
Lab. Animal Inc., Korea) were purchased and acclimatized for 2
weeks, and then used in the present experiment. The R-enantiomer
(Compound 2a) and the S-enantiomer (Compound 2b) prepared in
Example 2 were weighed (CP423S, Sartorius, Germany) according to
the administration dose and put into 50 ml tubes, an excipient (10%
LM 2125 CS MCT solution) stored at room temperature was added
thereto, and then the resulting mixture was stirred by means of a
vortex mixer so as to dissolve the excipient. Thereafter, the
solution was ultrasonically treated for about 10 minutes, and a
stock solution was prepared by formulating the solution at a
predetermined concentration. A 0.5% aqueous MC solution as an
excipient was added to the prepared stock solution, the resulting
mixture was gently stirred by means of a vortex mixer, homogenized
and prepared by means of a homogenizer (PT-1600E, Kinematica,
Switzerland) at 30,000 rpm for 3 minutes, and then a solution was
prepared at a final predetermined concentration by performing
ultrasonic wave treatment for minutes. The sample thus prepared was
administered through the oral gavage once daily for 6 weeks by
using a disposable plastic syringe with a zonde for oral
administration attached.
[0174] While the C57BLKS/J-db/db mouse was bred, the mouse was
fasted for 14 to 16 hours on the 48th day after administration, and
then a glucose tolerance test was performed by orally administering
glucose (Lot No: SLBM9269V, Sigma-Aldrich, USA) at a dose of 2 g/kg
to the mice. Specifically, blood was collected from the caudal vein
seven times in total including before the administration of
glucose, at 15 minutes after the administration of glucose, at 30
minutes after the administration of glucose, at 60 minutes after
the administration of glucose, at 120 minutes after the
administration of glucose, at 180 minutes after the administration
of glucose, and at 240 minutes after the administration of glucose.
Thereafter, blood sugar was measured by using two blood sugar
meters (AGM-4000, Allmedicus Inc., Korea), and then an average
blood sugar was calculated by using each blood sugar measurement
value. The area under the blood concentration-time curve (AUC) for
the blood sugar value at each measurement time point was calculated
by using a Phoenix WinNonlin program.
[0175] As a result, as shown in the following Table 4, it could be
seen that in the pyranochromenylphenol derivatives according to the
present invention, the R-enantiomer (Compound 2a) adjusted blood
sugar well as compared to the S-enantiomer (Compound 2b).
TABLE-US-00004 TABLE 4 Blood sugar (mg/dl) Time after
administration of glucose (min) AUC Group 0 15 30 60 120 180 240
(mg/dl/min) Negative Average 321 636 595 634 442 414 349 764
control (mean) (0 mg/kg) Standard 218 148 120 103 246 309 270 279
deviation (S.D.) Standard 97 66 54 46 110 138 121 125 error (S.E.)
Number of 5 5 5 5 5 5 5 5 samples (number) R- Average 193 473 527
541 200 176 184 526 enantiomer - Standard 38 50 109 44 19 22 45 59
Compound deviation 2a Standard 19 25 54 22 9 11 23 29 (100 error
mg/kg) Number of 4 4 4 4 4 4 4 4 samples R- Average 175 440 469 460
234 153 163 481 enantiomer - Standard 25 43 74 94 26 20 18 55
Compound deviation 2a Standard 11 19 33 42 12 9 8 24 (150 error
mg/kg) Number of 5 5 5 5 5 5 5 5 samples R- Average 159 488 507 437
223 183 174 501 enantiomer - Standard 37 131 82 46 51 68 42 89
Compound deviation 2a Standard 16 59 37 21 23 30 19 40 (200 error
mg/kg) Number of 5 5 5 5 5 5 5 5 samples S- Average 392 595 616 628
472 422 397 782 enantiomer - Standard 215 185 110 150 227 298 231
292 Compound deviation 2b Standard 96 83 49 67 101 133 103 130 (100
error mg/kg) Number of 5 5 5 5 5 5 5 5 samples
EXPERIMENTAL EXAMPLE 4
Comparison of Anti-Diabetes Efficacies
[0176] By using the same method as in Experimental Example 3, a
normal group, a negative control, a racemic compound of Compound 13
prepared in Example 9, Compound 13a being an R-enantiomer, a
racemic compound of Compound 2 prepared in Example 2, and Compound
2a being an R-enantiomer were administered to the C57BLKS/J-db/db
mice, and then the anti-diabetes effects were confirmed.
[0177] FIG. 5 is a graph illustrating the measurement results of a
change in blood sugar of a db/db mouse according to the
administration of the racemic compound (racemate) of Compound 13,
Compound 13a, which is an R-enantiomer of Compound 13,the racemic
compound of Compound 2, and Compound 2a, which is an R-enantiomer
of Compound 2. Specifically, FIG. 5 is a view illustrating that the
racemic compound of Compound 13, Compound 13a being an
R-enantiomer, the racemic compound of Compound 2, and Compound 2a
being an R-enantiomer were each administered to the C57BLKS/J-db/db
mice at a dose of 150 mg/kg daily for days, by using the same
method as in Experimental Example 3, and the difference in
concentration of blood sugar in blood with respect to the db/db
mouse between before the administration and on the 43th day was
measured.
[0178] As a result of observing the concentration of blood sugar in
blood, as illustrated in FIG. 5, it could be seen that in the
optically active pyranochromenylphenol derivatives according to the
present invention, the R-enantiomer had excellent ability to adjust
blood sugar as compared to the racemic compound.
[0179] The following Table 5 is a result of measuring a change in
glycated hemoglobin of the db/db mouse according to the
administration of the normal group, the negative control, the
racemic compound of Compound 13 prepared in Example 9, Compound 13a
being the R-enantiomer, the racemic compound of Compound 2 prepared
in Example 2, and Compound 2a being the R-enantiomer.
TABLE-US-00005 TABLE 5 Glycated hemoglobin (HbAlc, %) Before
admini- 29th day after 43rd day after Group stration administration
administration Normal Average 4.3 4.1 4.2 group Standard 0.1 0.1
0.1 (0 mg/kg) deviation Number of 3 3 3 samples Negative Average
4.7 9.7 9.9 control Standard 0.2 1.0 1.0 (0 mg/kg) deviation Number
of 4 4 4 samples R- Average 4.7 9.0 7.6 enantiomer - Standard 0.1
0.6 1.8 Compound deviation 13a Number of 7.0 7.0 7 (300 mg/kg)
samples Racemic Average 4.7 10.6 9.7 compound - Standard 0.1 0.5
2.4 Compound deviation 13 Number of 7.0 7.0 7.0 (300 mg/kg) samples
R- Average 4.7 7.1 5.3 enantiomer - Standard 0.1 0.6 0.4 Compound
deviation 2a Number of 7.0 7.0 7.0 (300 mg/kg) samples Racemic
Average 4.7 6.7 6.2 compound - Standard 0.1 0.5 0.4 Compound 2
deviation (300 mg/kg) Number of 7.0 7.0 7.0 samples
[0180] FIG. 6 is a graph illustrating a change in glycated
hemoglobin of a db/db mouse according to the administration of a
racemic compound (racemate) of Compound 13, Compound 13a, which is
an R-enantiomer of Compound 13, a racemic compound of Compound 2,
and Compound 2a, which is an R-enantiomer of Compound 2.
Specifically, FIG. 6 is a view illustrating a value of a change in
glycated hemoglobin of the db/db mouse before administering the
racemic compound of Compound 13, Compound 13a being an
R-enantiomer, the racemic compound of Compound 2, and Compound 2a
being an R-enantiomer and 43 days after the administration in Table
5.
[0181] As illustrated in Table 5 and FIG. 6, it could be confirmed
that the racemic compounds prepared in Example 2 and Example 9 had
an effect of adjusting blood sugar, but Compound 2a and Compound
13a being the R-enantiomer of the present invention, which were
prepared in Example 2 and Example 9, respectively, had a much
better effect of adjusting blood sugar than each racemic
compound.
[0182] FIG. 7 is a graph illustrating the results of a glucose
tolerance test of a db/db mouse administered with the racemic
compound of Compound 13, Compound 13a, which is an R-enantiomer of
Compound 13, the racemic compound of Compound 2, and Compound 2a,
which is an R-enantiomer of Compound 2. Specifically, FIG. 7 is a
view illustrating blood sugar in blood of a db/db mouse according
to the time elapsed after the racemic compound of Compound 13,
Compound 13a, which is an R-enantiomer of Compound 13, the racemic
compound of Compound 2, and Compound 2a, which is an R-enantiomer
of Compound 2 were administered.
[0183] As illustrated in FIG. 7, it could be confirmed that the
racemic compounds prepared in Example 2 and Example 9 had
anti-diabetes efficacy, but Compound 2a and Compound 13a being the
R-enantiomer of the present invention, which were prepared in
Example 2 and Example 9, respectively, had much better
anti-diabetes efficacy than each racemic compound.
[0184] As described above, it could be confirmed that the optically
active pyranochromenylphenol derivative according to the present
invention had better anti-obesity activity or anti-diabetes
activity than the racemic compound, and it could be seen that the
respective optical isomers had different activities.
[0185] Hitherto, the present invention has been reviewed mainly in
the preferred examples thereof. A person with ordinary skill in the
art to which the present invention pertains will be able to
understand that the present invention may be implemented in a
modified form without departing from the essential characteristics
of the present invention. Therefore, the disclosed examples are to
be considered not from a restrictive viewpoint, but from an
explanatory viewpoint. It is to be interpreted that the scope of
the present invention is described not in the above-described
explanation, but in the claims, and all the differences within a
range equivalent thereto are included in the present invention.
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