U.S. patent application number 16/313360 was filed with the patent office on 2019-06-06 for novel aryl ethene derivative and pharmaceutical composition containing same as active ingredient.
The applicant listed for this patent is Sung Yeoun HWANG, KEMIMEDI CO.LTD. Invention is credited to Jungwook CHIN, Sung Jin CHO, Hayoung HWANG, Sung Yeoun HWANG, Jae-Han JEON, Yong-Hyun JEON, Jina KIM, Sang Wook KIM, In-Kyu LEE, Jaetae LEE.
Application Number | 20190167820 16/313360 |
Document ID | / |
Family ID | 60786973 |
Filed Date | 2019-06-06 |
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United States Patent
Application |
20190167820 |
Kind Code |
A1 |
HWANG; Sung Yeoun ; et
al. |
June 6, 2019 |
NOVEL ARYL ETHENE DERIVATIVE AND PHARMACEUTICAL COMPOSITION
CONTAINING SAME AS ACTIVE INGREDIENT
Abstract
The present invention relates to an aryl ethene derivative, for
inhibiting an estrogen-related receptor gamma (ERR.gamma.)
activity, a prodrug of same, a solvate of same, a stereoisomer of
same or pharmaceutically acceptable salts of same, and a
pharmaceutical composition containing same as an active
ingredient.
Inventors: |
HWANG; Sung Yeoun; (Incheon,
KR) ; CHO; Sung Jin; (Daegu, KR) ; KIM;
Jina; (Daegu, KR) ; CHIN; Jungwook; (Daegu,
KR) ; HWANG; Hayoung; (Daegu, KR) ; LEE;
In-Kyu; (Daegu, KR) ; JEON; Yong-Hyun; (Daegu,
KR) ; LEE; Jaetae; (Daegu, KR) ; JEON;
Jae-Han; (Daegu, KR) ; KIM; Sang Wook; (Seoul,
KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HWANG; Sung Yeoun
KEMIMEDI CO.LTD |
Incheon
Andong-si |
|
KR
KR |
|
|
Family ID: |
60786973 |
Appl. No.: |
16/313360 |
Filed: |
September 13, 2016 |
PCT Filed: |
September 13, 2016 |
PCT NO: |
PCT/KR2016/010369 |
371 Date: |
December 26, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 265/28 20130101;
A61K 51/025 20130101; A61K 31/4192 20130101; A61K 31/407 20130101;
A61K 31/495 20130101; A61K 31/5375 20130101; C07D 241/04 20130101;
A61K 31/397 20130101; A61K 31/445 20130101; A61K 31/403 20130101;
A61K 31/454 20130101; C07D 203/08 20130101; A61K 31/535 20130101;
A61K 31/396 20130101; A61K 31/695 20130101; A61K 31/40 20130101;
A61K 31/496 20130101; A61P 35/00 20180101; A61K 31/404
20130101 |
International
Class: |
A61K 51/02 20060101
A61K051/02; A61K 31/495 20060101 A61K031/495; A61K 31/445 20060101
A61K031/445; A61K 31/5375 20060101 A61K031/5375; A61K 31/40
20060101 A61K031/40; A61K 31/396 20060101 A61K031/396; A61K 31/397
20060101 A61K031/397; A61K 31/454 20060101 A61K031/454; A61K 31/404
20060101 A61K031/404; A61K 31/695 20060101 A61K031/695; A61K 31/407
20060101 A61K031/407; A61K 31/403 20060101 A61K031/403; A61K 31/496
20060101 A61K031/496; A61K 31/4192 20060101 A61K031/4192; A61P
35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 27, 2016 |
KR |
10-2016-0080124 |
Sep 12, 2016 |
KR |
10-2016-0117200 |
Claims
1. A pharmaceutical composition for treating thyroid cancer,
comprising: the arylethene derivative represented by the following
Chemical Formula 1: ##STR00400## wherein L is (C6-C20)arylene,
(C3-C20)heteroarylene, or (C3-C20)fused heterocycle; R.sup.1 is
(C3-C20)heterocycloalkyl, (C3-C20)heteroaryl,
--O--(CH.sub.2).sub.m--R.sup.11, --(CH.sub.2).sub.m--R.sup.12,
--NH--(CH.sub.2).sub.m--R.sup.13,
--NHCO--(CH.sub.2).sub.n--R.sup.14, or
--SiR.sup.16R.sup.17--(CH.sub.2).sub.m--R.sup.15; R.sup.11 to
R.sup.15 are independently of one another (C3-C20)heterocycloalkyl;
R.sup.16 and R.sup.17 are independently of each other
(C1-C20)alkyl; m is an integer of 1 to 3; and n is an integer of 0
or 1; Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl
or heteroaryl of Ar may be further substituted by one or more
selected from the group consisting of hydroxy, halogen,
(C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano,
--NR.sup.21R.sup.22, (C1-C20)alkylcarbonyloxy,
(C1-C20)alkylcarbonylamino, guanidino, --SO.sub.2--R.sup.23, and
--OSO.sub.2--R.sup.24; R.sup.21 and R.sup.22 are independently of
each other hydrogen, (C1-C20)alkylsulfonyl, or
(C3-C20)cycloalkylsulfonyl; R.sup.23 and R.sup.24 are independently
of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or
(C3-C20)cycloalkyl; R.sup.2 is hydroxy, halogen,
(C1-C20)alkylcarbonyloxy, or (C1-C20)alkylsulfonyloxy; the
heterocycloalkyl or heteroaryl of R.sup.1 and the heterocycloalkyl
of R.sup.11 to R.sup.15 may be further substituted by one or more
selected from the group consisting of (C1-C20)alkyl,
(C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino,
(C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl, and
di(C1-C20)alkylamino(C1-C20)alkyl; and the heterocycloalkyl and
heteroaryl contains one or more heteroatoms selected from the group
consisting of N, O and S, and the heterocycloalkyl is a saturated
or unsaturated mono-, bi-, or spirocycle having a carbon atom or
nitrogen atom in a ring as a binding site, or a prodrug, solvate,
stereoisomer, or pharmaceutically acceptable salt thereof, as an
effective component, and a pharmaceutically acceptable carrier, and
being used in combination of radioactive iodine.
2. The pharmaceutical composition of claim 1, wherein the thyroid
cancer is analpastic thyroid cancer.
3. The pharmaceutical composition of claim 1, wherein the
arylethene derivative is an arylethene derivative represented by
the following Chemical Formulae 2 to 5: ##STR00401## wherein
denotes a single bond or a double bond; and R.sup.1, Ar and R.sup.2
are as defined in claim 1.
4. The pharmaceutical composition of claim 1, wherein R.sup.1 is
(C3-CO.sub.1)heterocycloalkyl, (C3-C10)heteroaryl,
--O--(CH.sub.2).sub.m--R.sup.11, --(CH.sub.2).sub.m--R.sup.12,
--NH--(CH.sub.2).sub.m--R.sup.13,
--NHCO--(CH.sub.2).sub.n--R.sup.14, or
--SiR.sup.16R.sup.17--(CH.sub.2).sub.m--R.sup.15; R.sup.11 to
R.sup.15 are independently of one another (C3-C10)heterocycloalkyl;
R.sup.16 and R.sup.17 are independently of each other
(C1-C10)alkyl; m is an integer of 1 to 3; n is an integer of 0 or
1; Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl or
heteroaryl of Ar may be further substituted by one or more selected
from the group consisting of hydroxy, halogen, (C1-C10)alkyl,
halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino,
(C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino,
di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy,
(C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl,
(C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and
(C3-C10)cycloalkylsulfonyloxy; R.sup.2 is hydroxy, fluoro,
(C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy; and the
heterocycloalkyl or heteroaryl of R.sup.1 and the heterocycloalkyl
of R.sup.11 to R.sup.15 may be further substituted by one or more
selected from the group consisting of (C1-C10)alkyl,
(C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino,
(C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and
di(C1-C10)alkylamino(C1-C10)alkyl.
5. The pharmaceutical composition of claim 4, wherein R.sup.1 is
(C3-C10)heterocycloalkyl or --O--(CH.sub.2).sub.m--R.sup.11;
R.sup.11 is (C3-C10)heterocycloalkyl; m is an integer of 1 to 3;
and the heterocycloalkyl of R.sup.1 and R.sup.11 may be further
substituted by one or more selected from the group consisting of
(C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino,
(C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and
di(C1-C10)alkylamino(C1-C10)alkyl.
6. The pharmaceutical composition of claim 1, wherein the
heterocycloalkyl of R.sup.1 and R.sup.11 to R.sup.15 is
independently of each other selected from the following structures:
##STR00402## wherein R.sup.31 and R.sup.32 are independently of
each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl,
(C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl,
hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L
is O or S.
7. The pharmaceutical composition of claim 3, wherein the
arylethene derivative is an arylethene derivative represented by
the following Chemical Formula 6: ##STR00403## wherein R.sup.1 is
(C3-C10)heterocycloalkyl or --O--(CH.sub.2).sub.m--R.sup.1;
R.sup.11 is (C3-C10)heterocycloalkyl; m is an integer of 1 to 3;
the heterocycloalkyl of R.sup.1 and R.sup.11 may be further
substituted by one or more selected from the group consisting of
(C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino,
(C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and
di(C1-C20)alkylamino(C1-C20)alkyl; Ar is (C6-C12)aryl or
(C3-C12)heteroaryl, in which the aryl or heteroaryl of Ar may be
further substituted by one or more selected from the group
consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl,
(C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino,
(C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino,
(C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino,
(C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy,
halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy;
and R.sup.2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or
(C1-C10)alkylsulfonyloxy.
8. The pharmaceutical composition of claim 7, wherein R.sup.2 is
hydroxy; and R.sup.1 is heterocycloalkyl selected from the
following structures: ##STR00404## wherein R.sup.31 and R.sup.32
are independently of each other hydrogen, (C1-C10)alkyl,
(C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino,
(C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or
di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
9. The pharmaceutical composition of claim 7, wherein R.sup.2 is
hydroxy; R.sup.1 is --O--(CH.sub.2).sub.m--R.sup.11; m is an
integer of 1 or 2; and R.sup.11 is heterocycloalkyl selected from
the following structures: ##STR00405## wherein R.sup.31 and
R.sup.32 are independently of each other halogen, (C1-C100)alkyl,
(C1-C10)alkoxycarbonyl, or hydroxy(C1-C10)alkyl; and L is O or
S.
10. The pharmaceutical composition of claim 3, wherein the
arylethene derivative is selected from the following structures:
##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410##
##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415##
##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420##
##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425##
##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430##
##STR00431## ##STR00432## ##STR00433## ##STR00434## ##STR00435##
##STR00436## ##STR00437## ##STR00438## ##STR00439## ##STR00440##
##STR00441## ##STR00442## ##STR00443## ##STR00444##
11. The pharmaceutical composition of claim 7, wherein the
arylethene derivative is selected from the following structures:
##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449##
##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454##
##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459##
##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464##
##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469##
##STR00470## ##STR00471## ##STR00472## ##STR00473##
12. A kit for treating thyroid cancer, comprising: an arylethene
derivative represented by the following Chemical Formula 1:
##STR00474## wherein L is (C6-C20)arylene, (C3-C20)heteroarylene,
or (C3-C20)fused heterocycle; R.sup.1 is (C3-C20)heterocycloalkyl,
(C3-C20)heteroaryl, --O--(CH.sub.2).sub.m--R.sup.11,
--(CH.sub.2).sub.m--R.sup.12, --NH--(CH.sub.2).sub.m--R.sup.13,
--NHCO--(CH.sub.2).sub.n--R.sup.14, or
--SiR.sup.16R.sup.17--(CH.sub.2).sub.m--R.sup.15; R.sup.11 to
R.sup.15 are independently of one another (C3-C20)heterocycloalkyl;
R.sup.16 and R.sup.17 are independently of each other
(C1-C20)alkyl; m is an integer of 1 to 3; n is an integer of 0 or
1; Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl or
heteroaryl of Ar may be further substituted by one or more selected
from the group consisting of hydroxy, halogen, (C1-C20)alkyl,
halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano,
--NR.sup.21R.sup.22, (C1-C20)alkylcarbonyloxy,
(C1-C20)alkylcarbonylamino, guanidino, --SO.sub.2--R.sup.23 and
--OSO.sub.2--R.sup.24; R.sup.21 and R.sup.22 are independently of
each other hydrogen, (C1-C20)alkylsulfonyl, or
(C3-C20)cycloalkylsulfonyl; R.sup.23 and R.sup.24 are independently
of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or
(C3-C20)cycloalkyl; R.sup.2 is hydroxy, halogen,
(C1-C20)alkylcarbonyloxy, or (C1-C20)alkylsulfonyloxy; the
heterocycloalkyl or heteroaryl of R.sup.1 and the heterocycloalkyl
of R.sup.11 to R.sup.15 may be further substituted by one or more
selected from the group consisting of (C1-C20)alkyl,
(C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino,
(C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl, and
di(C1-C20)alkylamino(C1-C20)alkyl; and the heterocycloalkyl and
heteroaryl contains one or more heteroatoms selected from the group
consisting of N, O and S, and the heterocycloalkyl is a saturated
or unsaturated mono-, bi-, or spirocycle having a carbon atom or
nitrogen atom in a ring as a binding site, or a prodrug, solvate,
stereoisomer, or pharmaceutically acceptable salt thereof, and
radioactive iodine.
Description
TECHNICAL FIELD
[0001] The present invention relates to an arylethene derivative
inhibiting an activity of an estrogen-related receptor gamma
(hereinafter, referred to as ERR.gamma.), or a prodrug, solvate,
stereoisomer, or pharmaceutically acceptable salt thereof, and a
pharmaceutical composition comprising the compound as an active
ingredient.
BACKGROUND ART
[0002] A hormone receptor which responds to the hormone is required
for regulating development, growth or differentiation of cells
through change in intracellular gene expression, and is largely
classified into a cell membrane receptor and a nuclear receptor.
Among them, there is an increasing interest in an orphan nuclear
receptor which is the nuclear receptor and of which the binding
ligand has not been revealed.
[0003] Estrogen-related receptor (ERR) which is one of the orphan
nuclear receptors has three types which are ERR.alpha., ERR.beta.,
and ERR.gamma., and each position to be activated is different.
[0004] In particular, ERR.gamma. shows an activity in spinal cords
and a central nervous system, and is a nuclear hormone receptor
which is a transcriptional regulatory protein involved in glucose
biosynthesis in a liver, and has an increased transcriptional
activity for itself when bound to a ligand, thereby helping gene
expression related to glucose synthesis. That is, ERR.gamma. is
directly involved in glucose metabolism.
[0005] In addition, ERR.gamma. is a human nuclear receptor protein
called NR3B3, and is encoded by a ESRRG gene. ERR.gamma. functions
as a constitutive activator in transcription. ERR.gamma. is a
member of a nuclear hormone receptor family of a steroid hormone
receptor.
[0006] An ERR.gamma. protein is known as a main modulator of
various genes related to fatty acid oxidation and mitochondria
biogenesis in a myocardium, and also known to be involved in
glucose production in a liver.
[0007] Meanwhile, diabetic retinopathy is a disease developed by
occurrence of circulatory failure in a retina which is specific to
diabetic patients, and belongs to one of the three major
microvascular complications of diabetes together with diabetic
neuropathy and diabetic nephropathy. Occurrence of diabetic
retinopathy is related to a disease period during which a patient
suffers from diabetes, and in the case of the diabetes diagnosed
before the age of 30 corresponding to type 1, the diabetic
retinopathy occurs in 17% when the disease period is 5 years or
less, and in 98% when the disease period is 15 years or more, and
among them, worsening proliferative diabetic retinopathy occurs in
about 1% when the disease period is 10 years or less, and in 67%
when the disease period is 35 years or more. In the case of type 2
diabetes, it is known that the diabetic retinopathy occurs in 29%
when the disease period is 5 years or less, and in 78% when the
disease period is 15 years or more, and the proliferative diabetic
retinopathy occurs in 2% when the disease period is 5 years or
less, and in 16% when the disease period is 15 years or more. In a
diabetic patient's retina, it is known that vascular change in a
capillary such as hypertrophy of a retinal capillary basement
membrane, loss of perivascular cells, and occurrence of
microaneurysm occurs, and as time passes, retinal
neovascularization subsequent to a wide range of capillary
nonperfusion may also occur. This diabetic retinopathy is a kind of
diabetes complications, but once develops, the progression thereof
is difficult to be prevented by glycemic control, and a treatment
method specific to retinopathy is demanded.
[0008] It has been reported from a recent study that a low
molecular organic compound known as GSK5182 which is
(Z)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-5-hydroxy-2-phenylpent-1-en--
1-yl)phenol functions as a ligand in ERR.gamma. to inhibit the
ERR.gamma. activity, thereby showing an anti-diabetes effect such
as relieving hyperglycemia and insulin resistance, and a treatment
effect of retinopathy.
##STR00001##
[0009] Development of a new material which significantly inhibits a
transcriptional activity of ERR.gamma. as compared with previously
reported GSK5182 is demanded.
[0010] Meanwhile, anaplastic thyroid cancer (ATC) is one of the
most aggressive and deadly cancers known to develop in humans. ATC
rapidly metastasizes from a thyroid gland to lungs, bones, focal
lymph nodes, and the brain. This is in contrast with the nature of
well-differentiated benign thyroid cancer which explains most of
the thyroid cancer, and thus, treatment of ATC which is surgery, a
radiation therapy, and a chemotherapy alone or in combination
thereof has not exhibited an effect on patient survival. As a
result, development of a novel treatment method is urgently
demanded.
[0011] A sodium iodide symporter (NIS) is a plasma membrane
glycoprotein which mediates intracellular active inflow of iodine.
In the treatment of thyroid cancer, endogenous NIS accepts a wide
range of application of a radioiodine therapy in a clinical
situation, which is known as an effective treatment method to
remove malignant cells with minimal side effects over the years.
Low-differentiated cancer cells including ATC cells tend to
represent gradual dedifferentiation leading to a decrease in a NIS
level. This prevents ATC cells from accumulating iodine in the
cells with a high concentration, and accordingly, causes cell
resistance to the radioiodine therapy, leading to a poor prognosis.
Therefore, there has been many attempts to recover an NIS function
from ATC cells, using several methods such as epigenetic regulation
using gene transfer, an epigenome-altering drug, and the like,
however, no satisfactory result has been obtained so far.
[0012] The biological effect of ERR.gamma. has been extensively
studied in various disease models (type 2 diabetes mellitus,
alcohol-derived oxidative stress, microbial infection by liver
damage and gluconeogenesis of the damaged liver, some metabolic
diseases such as liver insulin signaling and iron metabolism),
however, the role of ERR.gamma. for the NIS function in ATC has not
been clearly studied so far. It has been reported from a recent
study that a low molecular organic compound known as GSK5182 which
is
(Z)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-5-hydroxy-2-phenylpent-1-en--
1-yl)phenol functions as a ligand in ERR.gamma. to inhibit the
ERR.gamma. activity, thereby improving the function of NIS to
increase an ATC intracellular radioiodine uptake and finally
exhibit an effect of increasing radioiodine treatment. However,
when GSK5182 was administered to an ATC mouse tumor model, a
radioiodine uptake in the tumor was not increased. Accordingly,
development of a new material which may specifically and
significantly inhibit ERR.gamma. transcriptional activity as
compared with GSK5182, and as a result, cause a radioactive isotope
uptake increase from a cellular level to an animal level is
demanded.
DISCLOSURE
Technical Problem
[0013] Thus, the inventors of the present invention found that by
introducing a specific substituent to an arylethene derivative, an
activity to inhibit ERR.gamma. is better as compared with the
conventionally reported activity of GSK5182, and at the same time,
drug stability, a pharmacological activity, and toxicity were
improved, thereby completing the present invention.
[0014] An object of the present invention is to provide a novel
arylethene derivative which may effectively inhibit an ERR.gamma.
activity, or a prodrug, solvate, stereoisomer, or pharmaceutically
acceptable salt thereof.
[0015] Another object of the present invention is to provide a
pharmaceutical composition for preventing or treating
ERR.gamma.-mediated diseases, comprising the arylethene derivative,
or the prodrug, solvate, stereoisomer, or pharmaceutically
acceptable salt thereof as an active ingredient.
[0016] Another object of the present invention is to provide a
pharmaceutical composition for preventing or treating retinopathy,
comprising the arylethene derivative, or the prodrug, solvate,
stereoisomer, or pharmaceutically acceptable salt thereof as an
active ingredient.
[0017] Another object of the present invention is to provide a
pharmaceutical composition for treating thyroid cancer, comprising
the arylethene derivative, or the prodrug, solvate, stereoisomer,
or pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, and being used in combination of radioactive
iodine.
[0018] Another object of the present invention is to provide a kit
for treating thyroid cancer, comprising the arylethene derivative,
or the prodrug, solvate, stereoisomer, or pharmaceutically
acceptable salt thereof, and radioiodine.
Technical Solution
[0019] In one general aspect, an arylethene derivative represented
by the following Chemical Formula 1, as a novel compound which may
effectively inhibit an activity of ERR.gamma., or a prodrug,
solvate, stereoisomer, or pharmaceutically acceptable salt
thereof:
##STR00002##
[0020] wherein
[0021] L is (C6-C20)arylene, (C3-C20)heteroarylene, or
(C3-C20)fused heterocycle;
[0022] R.sup.1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl,
--O--(CH.sub.2).sub.mR.sup.11, --(CH.sub.2).sub.m--R.sup.12,
NH--(CH.sub.2).sub.m--R.sup.13, --NHCO--(CH.sub.2).sub.n--R.sup.14,
or --SiR.sup.16R.sup.17--(CH.sub.2).sub.m--R.sup.15;
[0023] R.sup.11 to R.sup.15 are independently of one another
(C3-C20)heterocycloalkyl;
[0024] R.sup.16 and R.sup.17 are independently of each other
(C1-C20)alkyl;
[0025] m is an integer of 1 to 3;
[0026] n is an integer of 0 or 1;
[0027] Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl
or heteroaryl of Ar may be further substituted by one or more
selected from the group consisting of hydroxy, halogen,
(C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano,
--NR.sup.21R.sup.22, (C1-C20)alkylcarbonyloxy,
(C1-C20)alkylcarbonylamino, guanidino, --SO.sub.2--R.sup.23, and
--OSO.sub.2--R.sup.24;
[0028] R.sup.21 and R.sup.22 are independently of each other
hydrogen, (C1-C10)alkylsulfonyl, or (C6-C20)cycloalkylsulfonyl;
[0029] R.sup.23 and R.sup.24 are independently of each other
(C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl;
[0030] R.sup.2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy, or
(C1-C20)alkylsulfonyloxy;
[0031] the heterocycloalkyl or heteroaryl of R.sup.1 and the
heterocycloalkyl of R.sup.11 to R.sup.15 may be further substituted
by one or more selected from the group consisting of (C1-C20)alkyl,
(C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino,
(C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl, and
di(C1-C20)alkylamino(C1-C20)alkyl; and
[0032] the heterocycloalkyl and heteroaryl contains one or more
heteroatoms selected from the group consisting of N, O and S, and
the heterocycloalkyl is a saturated or unsaturated mono-, bi-, or
spirocycle having a carbon atom or nitrogen atom in a ring as a
binding site.
[0033] In another general aspect, a pharmaceutical composition for
preventing or treating ERR.gamma.-mediated diseases includes: the
arylethene derivative, or a prodrug, solvate, stereoisomer, or
pharmaceutically acceptable salt thereof as an active ingredient,
by confirming an excellent ERR.gamma. inhibitory activity of the
arylethene derivative represented by Chemical Formula 1.
[0034] In another general aspect, a pharmaceutical composition for
preventing or treating retinopathy includes: the arylethene
derivative of Chemical Formula 1 which may effectively inhibit an
ERR.gamma. activity, or a prodrug, solvate, stereoisomer, or
pharmaceutically acceptable salt thereof as an active
ingredient.
[0035] In another general aspect, a pharmaceutical composition for
treating thyroid cancer includes: the arylethene derivative of
Chemical Formula 1 which may specifically and significantly inhibit
an ERR.gamma. transcriptional activity, or a prodrug, solvate,
stereoisomer, or pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier, and is used in combination of
radioactive iodine.
[0036] In still another general aspect, a kit for treating thyroid
cancer includes: the arylethene derivative of Chemical Formula 1
which may specifically and significantly inhibit an ERR.gamma.
transcriptional activity, or a prodrug, solvate, stereoisomer, or
pharmaceutically acceptable salt thereof, and radioactive
iodine.
Advantageous Effects
[0037] The arylethene derivative of the present invention is a
novel compound, and exhibits very high inhibitory activity to
ERR.gamma. as compared with a conventional GSK5182 compound, and at
the same time, shows an effect of improved drug stability,
pharmacological activity and toxicity. Thus, the arylethene
derivative may be useful as efficient prophylactic agent and
therapeutic agent for diseases mediated by ERR.gamma., in
particular, metabolic diseases such as obesity, diabetes,
hyperlipidemia, fatty liver, or atherosclerosis, as well as
retinopathy, without side effects.
[0038] In addition, the arylethene derivative of the present
invention may specifically and significantly inhibit ERR.gamma.
transcriptional activity as compared with GSK5182, and as a result,
cause a radioactive isotope uptake increase from a cellular level
to an animal level. Accordingly, the arylethene derivative of the
present invention may significantly increase a treatment effect of
radioactive iodine therapy for treating cancer, and when
administered to cancer cells, may effectively produce cancer cells
having an improved sodium iodide symporter (NIS) function, thereby
having an excellent effect of being more easily applied to related
research and clinical practice for treating anaplastic thyroid
cancer.
DESCRIPTION OF DRAWINGS
[0039] FIGS. 1 to 3 illustrate an effect of compound 18a for a
radioactive iodine uptake in anaplastic thyroid cancer cells.
[0040] FIGS. 4 and 5 illustrate an effect of compound 18a for
regulating endogenous ERR.gamma. and NIS mRNA expression in
anaplastic thyroid cancer cells.
[0041] FIGS. 6 and 7 illustrate an effect of compound 18a for
regulating endogenous ERR.gamma. protein expression in anaplastic
thyroid cancer cells.
[0042] FIGS. 8 and 9 illustrate a compound 18a-derived MAP kinase
activity in anaplastic thyroid cancer cells.
[0043] FIGS. 10 and 11 illustrate a degree of iodine uptake
inhibition in compound 18a-treated anaplastic thyroid cancer cells,
by PD98059 or U0126.
[0044] FIGS. 12 and 13 illustrate a degree of inversion of
activated MAK kinase signaling, by PD98059 or U0126.
[0045] FIGS. 14 and 15 illustrate an increase aspect of an amount
of membrane-localized NIS protein in anaplastic thyroid cancer
cells by compound 18a.
[0046] FIGS. 16 and 17 illustrate results showing increased
cytotoxicity of increased .sup.131I after treating anaplastic
thyroid cancer cells with compound 18a.
[0047] FIGS. 18 to 22 illustrate an effect of compound 18a for a
radioactive iodine uptake by administrating compound 18a in an ATC
tumor model.
BEST MODE
[0048] Hereinafter, the present invention will be described in
detail. Technical terms and scientific terms used in the present
specification have the general meaning understood by those skilled
in the art to which the present invention pertains unless otherwise
defined, and a description for the known function and configuration
obscuring the present invention will be omitted in the following
description.
[0049] The present invention provides an arylethene derivative
represented by the following Chemical Formula 1, or a prodrug,
solvate, stereoisomer, or pharmaceutically acceptable salt
thereof:
##STR00003##
[0050] wherein
[0051] L is (C6-C20)arylene, (C3-C20)heteroarylene, or
(C3-C20)fused heterocycle;
[0052] R.sup.1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl,
--O--(CH.sub.2).sub.m--R.sup.11, --(CH.sub.2).sub.m--R.sup.12,
NH--(CH.sub.2).sub.m--R.sup.13, --NHCO--(CH.sub.2).sub.n--R.sup.14,
or --SiR.sup.16R.sup.17--(CH.sub.2).sub.m--R.sup.15;
[0053] R.sup.11 to R.sup.15 are independently of one another
(C3-C20)heterocycloalkyl;
[0054] R.sup.16 and R.sup.17 are independently of each other
(C1-C20)alkyl;
[0055] m is an integer of 1 to 3;
[0056] n is an integer of 0 or 1;
[0057] Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl
or heteroaryl of Ar may be further substituted by one or more
selected from the group consisting of hydroxy, halogen,
(C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano,
--NR.sup.21R.sup.22, (C1-C20)alkylcarbonyloxy,
(C1-C20)alkylcarbonylamino, guanidino, --SO.sub.2--R.sup.23, and
--OSO.sub.2--R.sup.24;
[0058] R.sup.21 and R.sup.22 are independently of each other
hydrogen, (C1-C10)alkylsulfonyl, or (C6-C20)cycloalkylsulfonyl;
[0059] R.sup.23 and R.sup.24 are independently of each other
(C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl;
[0060] R.sup.2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy, or
(C1-C20)alkylsulfonyloxy;
[0061] the heterocycloalkyl or heteroaryl of R.sup.1 and the
heterocycloalkyl of R.sup.11 to R.sup.15 may be further substituted
by one or more selected from the group consisting of (C1-C20)alkyl,
(C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino,
(C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl, and
di(C1-C20)alkylamino(C1-C20)alkyl; and
[0062] the heterocycloalkyl and heteroaryl contains one or more
heteroatoms selected from the group consisting of N, O and S, and
the heterocycloalkyl is a saturated or unsaturated mono-, bi-, or
spirocycle having a carbon atom or nitrogen atom in a ring as a
binding site.
[0063] The arylethene derivative of Chemical Formula 1 according to
the present invention which is a novel compound, has a very high
inhibitory activity to ERR.gamma., and thus, is useful as a
therapeutic agent and a prophylactic agent of ERR.gamma.-mediated
diseases, in particular, metabolic diseases such as obesity,
diabetes, hyperlipidemia, fatty liver or arteriosclerosis, and also
may be used as an active ingredient for preventing or treating
retinopathy.
[0064] In addition, the arylethene derivative of Chemical Formula 1
according to the present invention regulates expression of
endogenous ERR.gamma. protein to regulate mitogen-activated protein
(MAP) kinase, and improves a sodium iodide symporter (NIS) function
to increase membrane-localized NIS, thereby increasing a
radioactive iodine uptake when treating thyroid cancer.
[0065] The term of the present invention, "alkyl" refers to a
monovalent straight-chain or branched-chain saturated hydrocarbon
radical consisting of only carbon and hydrogen atoms, and an
example of the alkyl radical includes methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, nonyl,
or the like, but not limited thereto.
[0066] The term of the present invention, "aryl" refers to a
monovalent organic radical of an aromatic ring derived from
aromatic hydrocarbon by removal of one hydrogen, including a
single- or fused ring system containing appropriately 4 to 7,
preferably 5 or 6 ring atoms in each ring, and even a form in which
a plurality of aryls are linked by a single bond. A specific
example thereof includes phenyl, naphthyl, biphenyl, anthryl,
indenyl, fluorenyl, or the like, but not limited thereto.
[0067] The term of the present invention, "heteroaryl" refers to a
monovalent radical of a heteroaromatic ring which is an aryl group
containing 1 to 4 heteroatoms selected from the group consisting of
N, O, and S as an aromatic ring backbone atom, and carbons as
remaining aromatic ring backbone atoms, and is a 5- or 6-membered
monocyclic heteroaryl and a polycyclic heteroaryl fused with one or
more benzene rings, which may be partially saturated. In addition,
the heteroaryl in the present invention also includes a form in
which one or more heteroaryls are linked by a single bond. An
example of the heteroaryl group includes pyrrolyl, pyrazolyl,
quinolyl, isoquinolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl,
thiadiazolyl, triazolyl, imidazolyl, benzimidazolyl, isoxazolyl,
benzisoxazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, or
the like, but not limited thereto.
[0068] The term of the present invention, "arylene" and
"heteroarylene" refer to divalent radicals of aromatic ring and
heteroaromatic ring.
[0069] The term of the present invention, "fused heterocycle"
refers to a divalent radical of a fused ring in which a
non-aromatic heterocycle containing 1 to 4 heteroatoms selected
from the group consisting of N, O, and S, and an aromatic ring are
fused, and has a carbon atom or a nitrogen atom in the fused
heterocycle as a bonding site. An example of the fused heterocycle
includes indoline, dihydrobenzofuran, dihydrobenzothiophene, or the
like, but not limited thereto.
[0070] The term of the present invention, "heterocycloalkyl" is a
monovalent radical of a non-aromatic heterocycle containing 1 to 4
heteroatoms selected from the group consisting of N, O, and S, and
the non-aromatic heterocycle includes a saturated or unsaturated
monocycle, polycycle or spirocycle form, and may be bonded via a
heteroatom or a carbon atom. An example of the heterocycloalkyl
radical may include monovalent radicals of non-aromatic
heterocycles such as aziridine, pyrrolidine, azetidine, piperidine,
tetrahydropyridine, piperazine, morpholine, thiomorpholine,
3-azabicyclo[3.1.0]hexane, octahydropyrrolo[3,4-c]pyrrole,
2,7-diazispiro[4.4]nonane, 2-azaspiro[4.4]nonane, or the like.
[0071] The term of the present invention, "halo" or "halogen"
refers to fluorine, chlorine, bromine or iodine atom.
[0072] The term or the present invention, "haloalkyl" refers to
alkyl substituted by one or more halogens, and an example thereof
may include trifluoromethyl, or the like.
[0073] The term of the present invention, "alkenyl" is a monovalent
radical of a straight chain or branched chain unsaturated
hydrocarbon including one or more double bonds between two or more
carbon atoms, and specifically includes ethenyl, propenyl,
prop-1-en-2-yl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl,
2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,
2,3-dimethyl-2-butenyl, or the like, but not limited thereto.
[0074] The term of the present invention, "alkoxy" refers to an
--O-alkyl radical, wherein the alkyl is as described above. An
example of the alkoxy radical includes methoxy, ethoxy, isopropoxy,
butoxy, isobutoxy, t-butoxy, or the like, but not limited
thereto.
[0075] The term of the present invention, "alkylcarbonyloxy" refers
to an --OC(.dbd.O)alkyl radical, wherein the alkyl is as described
above. An example of the alkylcarbonyloxy radical includes
methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy,
propylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy,
t-butylcarbonyloxy, or the like, but not limited thereto.
[0076] The term of the present invention, "alkylcarbonylamino"
refers to a --NHC(.dbd.O)alkyl radical, wherein the alkyl is as
described above. An example of the alkylcarbonylamino radical
includes methylcarbonylamino, ethylcarbonylamino,
isopropylcarbonylamino, propylcarbonylamino, butylcarbonylamino,
isobutylcarbonylamino, t-butylcarbonylamino, or the like, but not
limited thereto.
[0077] The term of the present invention, "alkoxycarbonyl" refers
to a --C(.dbd.O)alkoxy radical, wherein the alkoxy is as described
above. An example of the alkoxycarbonyl radical includes
methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
t-butoxycarbonyl, or the like, but not limited thereto.
[0078] The term of the present invention, "cycloalkyl" refers to a
monovalent saturated carbocyclic radical composed of one or more
rings. An example of the cycloalkyl radical includes cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like, but
not limited thereto.
[0079] The term of the present invention, "alkylsulfonyl" refers to
a --SO.sub.2-alkyl radical, wherein the alkyl is as described
above. An example of the alkylsulfonyl radical includes
methylsulfonyl, ethylsulfonyl, or the like, but not limited
thereto.
[0080] The term of the present invention, "cycloalkylsulfonyl"
refers to a --SO.sub.2-cycloalkyl radical, wherein the cycloalkyl
is as described above. An example of the cycloalkylsulfonyl radical
includes cyclopropylsulfonyl, cyclohexylsulfonyl, or the like, but
not limited thereto.
[0081] The term of the present invention, "alkylsulfonyloxy" refers
to a --OSO.sub.2-alkyl radical, wherein the alkyl is as described
above. An example of the alkylsulfonyloxyl radical includes
methylsulfonyloxy, ethylsulfonyloxy, or the like, but not limited
thereto.
[0082] The term or the present invention, "hydroxyalkyl" refers to
alkyl substituted by one or more hydroxys, and an example thereof
may include hydroxymethyl or the like.
[0083] In the arylethene derivative according to an exemplary
embodiment of the present invention, the arylethene derivative may
be represented by the following Chemical Formulae 2 to 5:
##STR00004##
[0084] wherein denotes a single bond or a double bond; and R.sup.1,
Ar and R.sup.2 are as defined in the above Chemical Formula 1.
[0085] In the arylethene derivative according to an exemplary
embodiment of the present invention, R.sup.1 is
(C3-C10)heterocycloalkyl, (C3-C10)heteroaryl,
--O--(CH).sub.m--R.sub.11, --(CH.sub.2).sub.m--R.sup.2,
NH--(CH.sub.2).sub.m--R.sup.13, --NHCO--(CH.sub.2).sub.n--R.sup.14,
or --SiR.sup.16R.sup.17--(CH.sub.2).sub.m--R.sup.15; R.sup.11 to
R.sup.15 are independently of one another (C3-C10)heterocycloalkyl;
R.sup.16 and R.sup.17 are independently of each other
(C1-C10)alkyl; m is an integer of 1 to 3; n is an integer of 0 or
1; Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl or
heteroaryl of Ar may be further substituted by one or more selected
from the group consisting of hydroxy, halogen, (C1-C10)alkyl,
halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino,
(C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino,
di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy,
(C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl,
(C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and
(C3-C10)cycloalkylsulfonyloxy; R.sup.2 is hydroxy, fluoro,
(C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy; and the
heterocycloalkyl or heteroaryl of R.sup.1 and the heterocycloalkyl
of R.sup.11 to R.sup.15 may be further substituted by one or more
selected from the group consisting of (C1-C10)alkyl,
(C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino,
(C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and
di(C1-C10)alkylamino(C1-C10)alkyl.
[0086] In the arylethene derivative according to an exemplary
embodiment of the present invention, it is preferred that R.sup.1
is (C3-C10)heterocycloalkyl or --O--(CH.sub.2).sub.m--R.sup.11;
R.sup.11 is (C3-C10)heterocycloalkyl; m is an integer of 1 to 3;
and the heterocycloalkyl of R.sup.1 and R.sup.11 may be further
substituted by one or more selected from the group consisting of
(C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino,
(C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and
di(C1-C10)alkylamino(C1-C10)alkyl.
[0087] In the arylethene derivative according to an exemplary
embodiment of the present invention, it is more preferred that
heterocycloalkyl of the R.sup.1 and R.sup.11 to R.sup.15 may be
independently of each other selected from the following
structures:
##STR00005##
[0088] wherein R.sup.31 and R.sup.32 are independently of each
other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl,
amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or
di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
[0089] In the arylethene derivative according to an exemplary
embodiment of the present invention, the arylethene derivative may
be more preferably represented by the following Chemical Formula
6:
##STR00006##
[0090] wherein
[0091] R.sup.1 is (C3-C10)heterocycloalkyl or
--O--(CH.sub.2).sub.m--R.sup.11;
[0092] R.sup.11 is (C3-C10)heterocycloalkyl;
[0093] m is an integer of 1 to 3;
[0094] the heterocycloalkyl of R.sup.1 and R.sup.11 may be further
substituted by one or more selected from the group consisting of
(C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino,
(C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and
di(C1-C20)alkylamino(C1-C20)alkyl;
[0095] Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl
or heteroaryl of Ar may be further substituted by one or more
selected from the group consisting of hydroxy, halogen,
(C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano,
amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino,
di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy,
(C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl,
(C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and
(C3-C10)cycloalkylsulfonyloxy; and
[0096] R.sup.2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or
(C1-C10)alkylsulfonyloxy.
[0097] In the arylethene derivative according to an exemplary
embodiment of the present invention, R.sup.1 and R.sup.11 may be
independently of each other heterocycloalkyl selected from the
following structures:
##STR00007##
[0098] wherein R.sup.31 and R.sup.32 are independently of each
other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl,
amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or
di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
[0099] In the arylethene derivative according to an exemplary
embodiment of the present invention, Ar is (C6-C20)aryl, in which
the aryl of Ar may be further substituted by one or more selected
from the group consisting of hydroxy, halogen, (C1-C10)alkyl,
halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino,
(C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino,
di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy,
(C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl,
(C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and
(C3-C10)cycloalkylsulfonyloxy.
[0100] In the arylethene derivative according to an exemplary
embodiment of the present invention, R.sup.2 may be hydroxy.
[0101] In the arylethene derivative according to an exemplary
embodiment of the present invention, R.sup.2 may be hydroxy, and
R.sup.1 may be heterocycloalkyl selected from the following
structures:
##STR00008##
[0102] wherein R.sup.31 and R.sup.32 are independently of each
other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl,
amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or
di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
[0103] In the arylethene derivative according to an exemplary
embodiment of the present invention, it is more preferred that
R.sup.2 is hydroxy and R.sup.1 is --O--(CH.sub.2).sub.m--R.sup.11;
m is an integer of 1 or 2; and R.sup.11 is heterocycloalkyl
selected from the following structures:
##STR00009##
[0104] wherein R.sup.31 and R.sup.32 are independently of each
other hydrogen, (C1-C10)alkyl, (C1-C10)alkoxycarbonyl, or
hydroxy(C1-C10)alkyl; and L is O or S.
[0105] In the arylethene derivative according to an exemplary
embodiment of the present invention, it is more preferred that Ar
is (C6-C12)aryl, in which the aryl of Ar may be further substituted
by one or more selected from the group consisting of hydroxy,
halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro,
cyano, amino, (C1-C10)alkylsulfonylamino,
(C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino,
(C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino,
(C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy,
halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy;
R.sup.2 is hydroxy; and R.sup.1 is heterocycloalkyl selected from
the following structures:
##STR00010##
[0106] wherein R.sup.31 and R.sup.32 are independently of each
other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl,
amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or
di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
[0107] In the arylethene derivative according to an exemplary
embodiment of the present invention, it is still more preferred
that Ar is (C6-C12)aryl, in which the aryl of Ar may be further
substituted by one or more selected from the group consisting of
hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy,
nitro, cyano, amino, (C1-C10)alkylsulfonylamino,
(C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino,
(C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino,
(C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy,
halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy;
R.sup.2 is hydroxy; R.sup.1 is --O--(CH.sub.2).sub.mR.sup.11, m is
an integer of 1 or 2, R.sup.11 is heterocycloalkyl selected from
the following structures:
##STR00011##
[0108] wherein R.sup.31 and R.sup.32 are independently of each
other hydrogen, (C1-C20)alkyl, (C1-C10)alkoxycarbonyl, or
hydroxy(C1-C10)alkyl; and L is O or S.
[0109] In the arylethene derivative according to an exemplary
embodiment of the present invention, the arylethene derivative may
be specifically selected from the following structure, but not
limited thereto:
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021##
##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026##
##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041##
##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047## ##STR00048## ##STR00049## ##STR00050##
##STR00051##
[0110] In the arylethene derivative according to an exemplary
embodiment of the present invention, the arylethene derivative may
be preferably selected from the following structures:
##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##
##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##
##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076##
##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081##
##STR00082## ##STR00083## ##STR00084##
[0111] In the arylethene derivative according to an exemplary
embodiment of the present invention, the arylethene derivative may
be more preferably selected from the following structures:
##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089##
##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094##
##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099##
##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104##
##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109##
##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114##
##STR00115##
[0112] In the arylethene derivative according to an exemplary
embodiment of the present invention, the arylethene derivative may
be still more preferably selected from the following
structures:
##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120##
##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125##
##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140##
##STR00141## ##STR00142## ##STR00143##
[0113] Since the arylethene derivative according to the present
invention may be used in the form of a prodrug, solvate, and
pharmaceutically acceptable salt thereof for increasing in vivo
absorption or increasing solubility, the prodrug, the solvate, and
the pharmaceutically acceptable salt also fall within the scope of
the present invention. In addition, since the arylethene derivative
has a chiral carbon, the stereoisomer thereof exists, and the
stereoisomer also falls within the scope of the present
invention.
[0114] The arylethene derivative according to the present invention
may be prepared by various methods known in the art depending on
the kinds of substituents, and as an example thereof, the following
Reaction Formulae 1 to 21 are illustrated, and the following
preparation methods do not limit a method of preparing the
arylethene derivative of the present invention. The specific
details will be described in the following Examples 1 to 121. The
preparation methods presented in the following Reaction Formulae 1
to 21 are only illustrative, and it is apparent to a person skilled
in the art that the preparation methods may be easily modified by a
person skilled in the art depending on certain substituents.
##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148##
##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153##
##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158##
##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163##
##STR00164## ##STR00165## ##STR00166## ##STR00167##
[0115] In addition, the present invention provides an ERR.gamma.
inhibitor composition comprising the arylethene derivative of
Chemical Formula 1, or the prodrug, solvate, stereoisomer, or
pharmaceutically acceptable salt thereof as an active
ingredient.
[0116] In addition, the present invention provides a pharmaceutical
composition for preventing or treating an ERR.gamma.-mediated
disease, comprising the arylethene derivative of Chemical Formula
1, or the prodrug, solvate, stereoisomer, or pharmaceutically
acceptable salt thereof as an active ingredient, and further a
pharmaceutically acceptable carrier.
[0117] As described above, since the arylethene derivative of
Chemical Formula 1, or the prodrug, solvate, stereoisomer, or
pharmaceutically acceptable salt thereof exhibits a high inhibitory
activity to ERR.gamma., a pharmaceutically acceptable composition
comprising them as an active ingredient may be useful for treating
or preventing ERR.gamma.-mediated diseases, for example, metabolic
diseases such as obesity, diabetes, hyperlipidemia, fatty liver, or
atherosclerosis.
[0118] In another general aspect, a pharmaceutical composition for
preventing or treating retinopathy includes: the arylethene
derivative of Chemical Formula 1 which may effectively inhibit an
ERR.gamma. activity, or a prodrug, solvate, stereoisomer, or
pharmaceutically acceptable salt thereof as an active
ingredient.
[0119] The "retinopathy" is a disease caused by chronic or acute
damage to a retina of an eye. The retinopathy may involve ongoing
inflammation and vascular remodeling. In addition, retinopathy also
appears as visual manifestation of a systemic disease such as
diabetes or hypertension. The kind of retinopathy includes diabetic
retinopathy, retinopathy of prematurity (ROP), or the like.
[0120] Here, the diabetic retinopathy refers to an eye complication
in which decreased visual acuity occurs due to a disorder following
a peripheral circulatory disorder caused by diabetes which is a
systemic disease. Diabetic retinopathy has no symptoms at the
beginning, but as macular invasion occurs, decreased visual acuity
appears. Diabetic retinopathy involves various pathological
features such as microaneurysm, phlebectasia, retinal hemorrhage,
retinal infarction, macular edema, neovascularization, vitreous
hemorrhage, traction membrane, or the like, and when these
phenomena are observed as ocular fundus symptoms, diabetic
retinopathy is diagnosed. The diabetic retinopathy is a disease
caused by a complex combination of various symptoms as described
above, and it is unclear whether the disease is treated when one of
these symptoms is alleviated.
[0121] In addition, retinopathy of prematurity is proliferative
retinopathy which may occur in premature babies, in particular low
birth weight infants. When a premature baby whose retinal blood
vessels are not completely formed at birth has failure in
angiogenesis process after birth, abnormal fibrovascular
proliferation occurs at a border of an angiogenic site and a
non-angiogenic site of a retina, whereby the retina is detached,
eventually leading to blindness.
[0122] The arylethene derivative according to the present invention
may be used in the form of a pharmaceutically acceptable salt, and
the pharmaceutically acceptable salt may be prepared by a
conventional method in the art, and may include for example, a salt
with an inorganic acid such as a hydrochloric acid, a bromic acid,
a sulfuric acid, sodium hydrogen sulfate, a phosphoric acid, a
nitric acid, or a carbonic acid, a salt with an organic acid such
as a formic acid, an acetic acid, a trifluoroacetic acid, a
propionic acid, an oxalic acid, a succinic acid, a benzoic acid, a
citric acid, a maleic acid, a malonic acid, a mandelic acid, a
cinnamic acid, a stearic acid, a palmitic acid, a glycolic acid, a
glutamic acid, a tartaric acid, a gluconic acid, a lactic acid, a
fumaric acid, a lactobionic acid, an ascorbic acid, a salicylic
acid, or an acetylsalicylic acid (aspirin), a salt with an amino
acid such as glycine, alanine, vanillin, isoleucin, serine,
cysteine, cystine, an asparaginic acid, glutamine, lysine,
arginine, tyrosine, or proline, a salt with a sulfonic acid such as
a methanesulfonic acid, an ethanesulfonic acid, a benzenesulfonic
acid, or a toluenesulfonic acid, a metal salt by a reaction with an
alkali metal such as sodium or potassium, a salt with an ammonium
ion, or the like.
[0123] The arylethene derivative of the present invention may exist
in a solvated form, for example, a hydrated form and a non-solvated
form, and the solvate of the arylethene derivative according to the
present invention includes all solvated forms having a
pharmaceutical activity. That is, the arylethene derivative of the
present invention is dissolved in water-compatible solvent such as
methanol, ethanol, acetone, and 1,4-dioxane, and then a free acid
or a free base is added thereto to perform crystallization or
recrystallization, thereby forming a solvate including a hydrate.
Accordingly, as a novel compound of the present invention,
stoichiometric solvates including hydrates may be included, in
addition to a compound containing various amounts of water which
may be prepared by a method such as lyophilization.
[0124] The arylethene derivative of the present invention may have
a chiral center, and exist as a racemate, a racemic mixture, and
individual enantiomer or diastereomer. These isomers may be
separated or resolved by a common method, and an optional
predetermined isomer may be obtained by a common synthesis method
or stereospecific or asymmetric synthesis. These isomer forms and
mixtures thereof are all included in the scope of the present
invention.
[0125] The arylethene derivative of the present invention may be
administered in the form of a prodrug which is decomposed in a
human or animal body to provide the compound of the present
invention. The prodrug may be used for modifying or improving a
physical and (or) pharmacokinetic profile of a parent compound, and
may be formed when the parent compound contains an appropriate
group or substituent which may be derived to form the prodrug.
[0126] In addition, the pharmaceutical composition of the present
invention may be formulated into a conventional preparation in the
pharmaceutical field, for example, a preparation for oral
administration such as a tablet, a pill, a hard/soft capsule, a
liquid, a suspension, an emulsion, syrup, granules, and elixirs, or
a preparation for parenteral administration of a sterile aqueous or
oily solvent for intravenous, subcutaneous, sublingual,
intramuscular, or intradermal administration, by adding
conventional non-toxic pharmaceutically acceptable carrier,
excipient, and the like to the arylethene derivative represented by
Chemical Formula 1, or the prodrug, solvate, stereoisomer, or
pharmaceutically acceptable salt thereof.
[0127] The pharmaceutically acceptable carrier which may be used in
the pharmaceutical composition of the present invention is commonly
used in formulation, and includes lactose, dextrose, sucrose,
sorbitol, mannitol, starch, acacia gum, calcium phosphate,
alginate, gelatin, calcium silicate, microcrystalline cellulose,
polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose,
hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate,
and/or mineral oil, and the like, but not limited thereto.
[0128] The excipient which may be used in the pharmaceutical
composition of the present invention may be a sweetener, a binder,
a solubilizer, a solubilizing aid, a wetting agent, an emulsifier,
an isotonic agent, an adsorbent, a disintegrant, an antioxidant, a
preservative, a lubricant, a filler, a fragrance, or the like, and
a ratio and properties of the excipient may be determined by
solubility and chemical properties of a selected tablet, a selected
administration route, and standard pharmaceutical practice. An
example of the excipient may include lactose, dextrose, sucrose,
mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid,
sterin, magnesium stearate, magnesium aluminum silicate, starch,
gelatin, tragacanth gum, alginic acid, sodium alginate, methyl
cellulose, sodium carboxymethyl cellulose, agar, water, ethanol,
polyethyleneglycol, polyvinylpyrrolidone, sodium chloride, calcium
chloride, orange essence, strawberry essence, vanilla flavor, or
the like.
[0129] In addition, the pharmaceutical composition of the present
invention may be formulated into a parenteral administration form,
and in this case, intravenous administration, intraperitoneal
administration, intramuscular administration, subcutaneous
administration, topical administration, or the like may be used,
and ocular administration or the like may be used, in that the
composition is a therapeutic agent for retinopathy, but not limited
thereto. Here, in order to be formulated into a formulation for
parenteral administration, the pharmaceutical composition may be
produced into a solution or suspension by mixing the active
ingredient, that is, the arylethene derivative of Chemical Formula
1, or the prodrug, solvate, stereoisomer, or pharmaceutically
acceptable salt thereof with water together with a stabilizer or a
buffer, and the solution or suspension may be produced into a unit
dosage form of an ampoule or vial.
[0130] In addition, the pharmaceutical composition of the present
invention may be sterilized, or further include an adjuvant such as
a preservative, a stabilizer, a hydrating agent or an emulsifying
accelerator, a salt for regulating osmotic pressure, and/or a
buffer, and other therapeutically useful materials, and may be
formulated according to a conventional method of mixing,
granulating or coating.
[0131] In addition, a dosage of the arylethene derivative
represented by Chemical Formula 1, or the prodrug, solvate,
stereoisomer, or pharmaceutically acceptable salt thereof as the
active ingredient in the pharmaceutical composition according to
the present invention for mammals including a human may be varied
depending on the age, weight, gender, dosage form, health status,
and disease severity of a patient. Generally, an effective amount
of 0.001 to 100 mg/kg (body weight), preferably 0.01 to 100 mg/kg
(body weight) per day may be included in the pharmaceutical
composition, and the pharmaceutical composition may be divided into
once or twice per day, and administered via an oral or parenteral
route. However, the amount may be increased or decreased depending
on the administration route, severity of the disease, gender,
weight, age, and the like, and thus, the administration amount in
no way limits the scope of the present invention.
[0132] In addition, the present invention provides a pharmaceutical
composition for treating thyroid cancer comprising the arylethene
derivative of Chemical Formula 1 which may specifically and
significantly inhibit an ERR.gamma. transcriptional activity, or
the prodrug, solvate, stereoisomer, or pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier, and used
in combination of radioactive iodine.
[0133] In addition, the present invention provides a kit for
treating thyroid cancer comprising the arylethene derivative of
Chemical Formula 1 which may specifically and significantly inhibit
an ERR.gamma. transcriptional activity, or the prodrug, solvate,
stereoisomer, or pharmaceutically acceptable salt thereof, and
radioactive iodine.
[0134] The arylethene derivative according to the present invention
regulates expression of endogenous ERR.gamma. protein to regulate
mitogen-activated protein (MAP) kinase, and improves a sodium
iodide symporter (NIS) function to increase membrane-localized NIS,
thereby increasing a radioactive iodine uptake when treating
thyroid cancer.
[0135] Hereinafter, the present invention will be described in more
detail by way of the Examples and the Experimental Examples.
However, the following Examples and Experimental Examples are only
illustrative of the present invention, and do not limit the
disclosure of the present invention in any way.
[Example 1] Preparation of (E)-tert-butyl
4-(2-(4-(5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl-
)phenoxy)ethyl)piperazine-1-carboxylate (6a)
##STR00168## ##STR00169##
[0136] Step 1: Preparation of
[4-[4-(2,2-dimethylpropanoyloxy)benzoyl]phenyl]
2,2-dimethylpropanoate (A-1)
[0137] 4,4-Hydroxybenzophenone (10 g, 46.6 mmol) was dissolved in
140 mL of dichloromethane and 40 mL of tetrahydrofuran, pivaloyl
chloride (19.7 g, 186 mmol) and triethylamine (26 mL, 186 mmol)
were slowly added thereto, and then a reaction was carried out at
room temperature for 12 hours. Saturated sodium hydrogen carbonate
and dichloromethane were further added to the reaction solution and
an organic layer was extracted. The organic layer was dried with
anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was distilled
under reduced pressure to obtain a residue, which was purified
using column chromatography, thereby obtaining 16 g of the desired
compound A-1 (91%).
Step 2: Preparation of [4-(4-hydroxybenzoyl)phenyl]
2,2-dimethylpropanoate (A-2)
[0138] Compound A-1 (12.4 g, 32.3 mmol) and potassium carbonate
(2.2 g, 16.2 mmol) were dissolved in methanol (360 mL) and
dichloromethane (60 mL), and a reaction was carried out at room
temperature for 12 hours. A 1 M aqueous citric acid solution (16.2
mL, 16.2 mmol) was added to the reaction solution, and extraction
was performed with ethyl acetate. The organic layer was dried with
anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was distilled
under reduced pressure to obtain a residue, which was purified
using column chromatography, thereby obtaining 5.6 g of the desired
compound A-2 (58%).
Step 3: Preparation of
(E)-5-[4-(2,2-dimethylpropanoyloxy)phenyl]-5-(4-hydroxyphenyl)-4-phenyl-p-
ent-4-enoate (A-3)
[0139] Zinc (8.8 g, 134 mmol) was added to tetrahydrofuran (130
mL), the temperature was lowered to 0.degree. C., and titanium
chloride (7.35 mL, 67 mmol) was slowly added thereto. The reaction
solution was heated at 60.degree. C. for 2 hours, and then compound
A-2 (5 g, 16.8 mmol) and methyl-3-benzoylpropionate (4.8 g, 25.1
mmol) were added thereto. The reaction solution was heated at
50.degree. C. for 1 hour. The reaction mixture was poured into a
10% aqueous potassium carbonate solution, stirring was performed
for 30 minutes, and filtration was performed using celite. The
filtrate was extracted with ethyl acetate and the organic layer was
dried with anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was
distilled under reduced pressure to obtain a residue, which was
purified using column chromatography, thereby obtaining 5.4 g of
the desired compound A-3 (70%).
Step 4: Preparation of (E)-tert-butyl
4-(2-(4-(5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl-
)phenoxy)ethyl)piperazine-1-carboxylate (A-4)
[0140] To dichloromethane (3 mL), compound A-3 (0.05 g, 0.11 mmol),
2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)ethanol (30 mg, 0.13
mmol), and triphenylphosphine (86 mg, 0.33 mmol) were added, the
temperature was lowered to 0.degree. C., and diisopropyl
azodicarboxylate (0.064 mL, 0.33 mmol) was slowly added thereto.
After 15 minutes, the temperature was raised to room temperature,
and stirring was performed for 12 hours. Water and ethyl acetate
were further added to the reaction solution and an organic layer
was extracted. The organic layer was dried with anhydrous
Na.sub.2SO.sub.4 and filtered. The solvent was distilled under
reduced pressure to obtain a residue, which was purified using
column chromatography, thereby obtaining 73 mg of the desired
compound A-4 (99%).
Step 5: Preparation of
(Z)-4-(5-hydroxy-1-(4-(2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)ethoxy)-
phenyl)-2-phenylpent-1-en-1-yl)phenol (6a)
[0141] Compound C (0.34 g, 0.05 mmol) was added to tetrahydrofuran
(10 mL), the temperature was lowered to 0.degree. C., and 1 M
lithium aluminum hydride (LiAlH.sub.4, 1.5 mL, 1.51 mmol) was
slowly added thereto. The temperature was raised to room
temperature, and stirring was performed for 1 hour. Water and ethyl
acetate were further added to the reaction solution and an organic
layer was extracted. The organic layer was dried with anhydrous
Na.sub.2SO.sub.4 and filtered. The solvent was distilled under
reduced pressure to obtain a residue, which was purified using
column chromatography, thereby obtaining 0.28 g of the desired
compound 6a (99%).
Examples 2 to 13
[0142] Compounds 6b to 6m were prepared according to the process of
Example 1. Compounds 6b to 6m were prepared by the same process,
except that in step 4 of Example 1,
2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)ethanol was replaced
with different ethanol. Identification data of the thus-prepared
compounds 6a to 6m is shown in the following Table 1.
TABLE-US-00001 TABLE 1 ##STR00170## Cmpd Example No. R
Identification data 1 6a ##STR00171## .sup.1H-NMR (CD.sub.3OD, 400
MHz) .delta. 7.22-7.11 (m, 7H), 7.05 (d, J = 4.1 Hz, 2H), 6.80 (d,
J = 6.5 Hz, 2H), 3.77 (s, 4H), 3.43 (m, 6H), 2.56 (m, 2H), 1.59 (m,
2H), 1.49 (s, 9H). MS (ESI) m/z: 515 [M + H].sup.+. 2 6b
##STR00172## .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.19-7.08
(m, 5H), 7.05-7.02 (m, 2H), 6.85-6.78 (m, 4H), 6.66-6.63 (m, 2H),
4.19 (t, J = 4.6 Hz, 2H), 3.50-3.37 (m, 12H), 2.94 (s, 3H), 2.53
(t, J = 2.8 Hz, 2H), 1.53 (m, 2H). MS (ESI) m/z: 473 [M + H].sup.+.
3 6c ##STR00173## .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.17
(m, 2H), 7.10 (m, 3H), 6.97 (d, J = 8.5 Hz, 2H), 6.75 (m, 4H), 6.66
(d, J = 8.8 Hz, 2H), 4.24 (t, J = 4.3 Hz, 2H), 3.93 (m, 2H), 3.74
(m, 2H), 3.24 (t, J = 6.7 Hz, 2H), 3.15 (s, 2H), 2.54 (s, 4H), 2.39
(m, 2H), 1.38 (m, 2H). MS (ESI) m/z: 460 [M + H].sup.+. 4 6d
##STR00174## .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.18-7.09
(m, 5H), 7.04 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.79
(d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 4.25 (t, J = 4.8 Hz,
2H), 3.58 (m, 2H), 3.50 (t, J = 4.9 Hz, 2H), 3.45 (t, J = 6.8 Hz,
2H), 3.04 (m, 2H), 2.54 (m, 2H), 1.96 (m, 2H), 1.82 (m, 3H), 1.55
(m, 3H). MS (ESI) m/z: 458 [M + H].sup.+. 5 6e ##STR00175##
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.18-7.09 (m, 5H), 7.04
(d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.5 Hz,
2H), 6.68 (d, J = 8.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 3.69 (m,
2H), 3.59 (t, J = 4.9 Hz, 2H), 3.43 (t, J = 6.8 Hz, 2H), 3.18 (m,
2H), 2.54 (m, 2H), 2.18 (m, 2H), 2.04 (m, 2H), 1.56 (m, 2H). MS
(ESI) m/z: 444 [M + H].sup.+. 6 6f ##STR00176## .sup.1H-NMR
(CD.sub.3OD, 400 MHz) .delta. 7.17-1.08 (m, 5H), 7.04 (d, J = 8.5
Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 6.68
(d, J = 8.7 Hz, 2H), 4.20 (t, J = 4.5 Hz, 2H), 3.91 (t, J = 5.5 Hz,
2H), 3.50 (m, 4H), 3.44 (t, J = 6.8 Hz, 2H), 2.53 (m, 2H), 1.55 (m,
2H). MS (ESI) m/z: 416 [M + H].sup.+. 7 6g ##STR00177## .sup.1H-NMR
(CD.sub.3OD, 400 MHz) .delta. 7.18-7.09 (m, 5H), 7.04 (d, J = 8.5
Hz, 2H), 6.80 (m, 4H), 6.62 (d, J = 8.6 Hz, 2H), 4.09-3.97 (m, 2H),
3.67 (m, 1H), 3.52 (m, 1H), 3.43 (t, J = 6.7 Hz, 2H), 3.16 (m, 1H),
2.94 (s, 3H), 2.53 (t, J = 7.8 Hz, 2H), 2.38 (m, 2H), 2.19-2.01 (m,
3H), 1.85 (m, 1H), 1.54 (m, 2H). MS (ESI) m/z: 458 [M + H].sup.+. 8
6h ##STR00178## .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.17-7.08
(m, 5H), 7.05 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.79
(d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H), 4.30 (m, 1H), 4.09
(m, 1H), 3.82 (m, 1H), 3.68 (m, 1H), 3.43 (t, J = 6.7 Hz, 2H), 3.21
(m, 1H), 3.02 (s, 3H), 2.54 (m, 2H), 2.35 (m, 1H), 2.20 (m, 1H),
2.02 (m, 2H), 1.56 (m, 2H). MS (ESI) m/z: 444 [M + H].sup.+. 9 6i
##STR00179## .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.17-7.08
(m, 5H), 7.05 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.79
(d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 4.28 (m, 1H), 4.09
(m, 1H), 3.83 (m, 1H), 3.69 (m, 1H), 3.43 (t, J = 6.7 Hz, 2H), 3.21
(m, 1H), 3.02 (s, 3H), 2.54 (m, 2H), 2.35 (m, 1H), 2.22 (m, 1H),
1.99 (m, 2H), 1.56 (m, 2H). MS (ESI) m/z: 444 [M + H].sup.+. 10 6j
##STR00180## .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.16-7.07
(m, 5H), 7.02 (d, J = 8.6 Hz, 2H), 6.78 (m, 4H), 6.60 (d, J = 8.8
Hz, 2H), 4.03 (m, 2H), 3.67 (m, 1H), 3.51 (m, 1H), 3.41 (t, J = 6.8
Hz, 2H), 3.15 (m, 1H), 2.92 (s, 3H), 2.51 (m, 2H), 2.38 (m, 1H),
2.08 (m, 4H), 1.84 (m, 1H), 1.55 (m, 2H). MS (ESI) m/z: 458 [M +
H].sup.+. 11 6k ##STR00181## .sup.1H-NMR (CD.sub.3OD, 400 MHz)
.delta. 7.16-7.07 (m, 5H), 7.02 (d, J = 6.6 Hz, 2H), 6.78 (m, 4H),
6.60 (d, J = 8.8 Hz, 2H), 4.01 (m, 2H), 3.67 (m, 1H), 3.50 (m, 1H),
3.41 (t, J = 6.7 Hz, 2H), 3.15 (m, 1H), 2.92 (s, 3H), 2.51 (m, 2H),
2.37 (m, 1H), 2.07 (m, 4H), 1.84 (m, 1H), 1.54 (m, 2H). MS (ESI)
m/z: 458 [M + H].sup.+. 12 6l ##STR00182## .sup.1H-NMR (CD.sub.3OD,
400 MHz) .delta. 7.18-7.09 (m, 5H), 7.05 (d, J = 8.6 Hz, 2H), 6.85
(d, J = 8.8, Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.8
Hz, 2H), 3.63 (m, 1H), 3.49 (m, 2H), 3.43 (t, J = 6.8 Hz, 2H), 3.25
(m, 1H), 3.04 (m, 1H), 2.87 (s, 3H), 2.54 (m, 2H), 2.04 (m, 2H),
2.04 (m, 2H), 1.79 (m, 1H), 1.66 (m, 1H), 1.55 (m, 2H). MS (ESI)
m/z: 444 [M + H].sup.+. 13 6m ##STR00183## .sup.1H-NMR (CD.sub.3OD,
400 MHz) .delta. 7.17-7.09 (m, 5H), 7.04 (d, J = 2H), 6.84 (m, 2H),
6.78 (m, 2H), 6.71 (m, 2H), 3.62 (m, 1H), 3.43 (m, 4H), 3.26 (m,
1H), 3.04 (m, 1H), 2.87 (s, 3H), 2.53 (m, 2H), 2.05 (m, 2H), 1.77
(m, 1H), 1.69 (m, 1H), 1.54 (m, 2H). MS (ESI) m/z: 444 [M +
H].sup.+.
[Example 14] Preparation of
(Z)-4-(5-hydroxy-2-phenyl-1-(4-(2-(piperazin-1-yl)ethoxy)phenyl)pent-1-en-
-1-yl)phenol 2hydrochloride salt (7a)
##STR00184##
[0144] Compound 6a (28 mg, 0.05 mmol) was added to dichloromethane
(5 mL), the temperature was lowered to 0.degree. C., and
trifluoroacetic acid (0.08 mL, 1.00 mmol) was added thereto. The
temperature was raised to room temperature, and stirring was
performed for 1 hour. Water and ethyl acetate were further added to
the reaction solution and an organic layer was extracted. The
organic layer was dried with anhydrous Na.sub.2SO.sub.4 and
filtered. The solvent was distilled under reduced pressure to
obtain a residue, which was purified using column chromatography
and then dissolved in methanol:dichloromethane (1:1), the
temperature was lowered to 0.degree. C., a 1M aqueous HCl solution
was slowly added thereto, and distillation under reduced pressure
was performed, thereby obtaining 4 mg of the desired compound 7a
(17%).
[0145] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.16-7.07 (m, 5H),
7.01 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.6 Hz,
2H), 4.31 (t, J=4.2 Hz, 2H), 3.66 (m, 10H), 3.41 (t, J=6.8 Hz, 2H),
2.51 (m, 2H), 1.54 (m, 2H). MS (ESI) m/z: 459 [M+H].sup.+.
[Example 15] Preparation of
(E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent--
4-en-1-ol hydrochloride salt (13a)
##STR00185## ##STR00186##
[0146] Step 1: Preparation of
(4-bromophenyl)(4-methoxyphenyl)methanone (B-1)
[0147] 4-Bromobenzoyl chloride (8.2 g, 50.9 mmol) and aluminum
chloride (6.1 g, 50.9 mmol) were dissolved in dichloromethane (90
mL), and anisole (5 g, 46.2 mmol) was slowly added thereto.
Stirring was performed for 3 hours, the temperature was lowered to
0.degree. C., and 1N HCl (50 mL) was added thereto. Ethyl acetate
was added to extract an aqueous layer, which was dried with
anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was distilled
under reduced pressure to obtain a residue, which was purified
using column chromatography, thereby obtaining 11 g of the desired
compound B-1 (99%).
Step 2: Preparation of (4-bromophenyl)(4-hydroxyphenyl)methanone
(B-2)
[0148] Compound B-1 (10 g, 34.3 mmol) was added to toluene (80 mL),
the temperature was lowered to 0.degree. C., and aluminum chloride
(11.5 g, 86 mmol) was slowly added thereto. Heating was performed
at 70.degree. C. for 4 hours. The reaction solution was cooled to
room temperature, 1 N hydrochloric acid was added thereto, ethyl
acetate was added thereto, and extraction was performed. The
organic layer was dried with anhydrous Na.sub.2SO.sub.4 and
filtered. The solvent was distilled under reduced pressure to
obtain a residue, which was purified using column chromatography,
thereby obtaining 8.1 g of the desired compound B-2 (85%).
Step 3: Preparation of (E)-methyl
5-(4-bromophenyl)-5-(4-hydroxyphenyl)-4-phenylpent-4-enoate
(B-3)
[0149] 0.61 g of the desired compound B-3 (39%) was obtained by the
same process as step 3 of Example 1
Step 4: Preparation of (E)-methyl
5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-en-
oate (B-4)
[0150] 44 mg of the desired compound B-4 (54%) was obtained, using
compound B-3 and 2-(aziridin-1-yl)ethanol by the same process as
step 4 of Example 1.
Step 5: Preparation of
(E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent--
4-en-1-ol hydrochloride salt (13a)
[0151] Compound B-4 (44 mg, 0.09 mmol) was added to tetrahydrofuran
(2 mL), the temperature was lowered to 0.degree. C., and 1 M
diisobutylaluminum hydride (0.26 mL, 0.26 mmol) was slowly added
thereto. The temperature was raised to room temperature, and
stirring was performed for 1 hour. Water and ethyl acetate were
further added to the reaction solution and an organic layer was
extracted. The organic layer was dried with anhydrous
Na.sub.2SO.sub.4 and filtered. The solvent was distilled under
reduced pressure to obtain a residue, which was purified using
column chromatography, thereby obtaining 0.3 mg of the desired
compound 13a (0.7%).
Examples 16 to 18
[0152] Compounds 13b to 13d were prepared according to the process
of Example 15. Compounds 13b to 13d were prepared by the same
process, except that in step 4 of Example 15,
2-(aziridin-1-yl)ethanol was replaced with different ethanol.
Identification data of the thus-prepared compounds 13a to 13d is
shown in the following Table 2.
TABLE-US-00002 TABLE 2 ##STR00187## Cmpd Example No. R
Identification data 15 13a ##STR00188## .sup.1H-NMR(CD.sub.3OD, 400
MHz) .delta. 7.51 (d, J = 8.4 Hz, 2H), 7.16-7.09 (m, 7H), 6.83 (d,
J = 8.8 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 4.18 (t, J = 4.7 Hz,
2H), 3.89 (t, J = 5.6 Hz, 2H), 3.49 (m, 4H), 3.41 (t, J = 6.6 Hz,
2H), 2.49 (m, 2H), 1.53 (m, 2H). MS (ESI) m/z: 479 [M + H].sup.+.
16 13b ##STR00189## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.51
(d, J = 8.4 Hz, 2H), 7.16-7.09 (m, 7H), 6.84 (d, J = 8.8 Hz, 2H),
6.70 (d, J = 8.8 Hz, 2H), 4.27 (m, 1H), 4.08 (m, 1H), 3.80 (m, 1H),
3.66 (m, 1H), 3.41 (t, J = 6.5 Hz, 2H), 3.19 (m, 1H), 3.00 (s, 3H),
2.50 (m, 2H), 2.33 (m, 1H), 2.20 (m, 1H), 1.98 (m, 2H), 1.52 (m,
2H). MS (ESI) m/z: 507 [M + H].sup.+. 17 13c ##STR00190##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.52 (d, J = 8.4 Hz, 2H),
7.17-7.12 (m, 7H), 6.84 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.6 Hz,
2H), 3.61 (m, 1H), 3.41 (m, 4H), 3.23 (m, 1H), 3.02 (m, 1H), 2.85
(s, 3H), 2.49 (m, 2H), 2.02 (m, 2H), 1.77 (m, 1H), 1.65 (m, 2H),
1.53 (m, 2H). MS (ESI) m/z: 507 [M + H].sup.+. 18 13d ##STR00191##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.52 (d, J = 8.4 Hz, 2H),
7.15 (m, 7H), 6.80 (m, 2H), 6.64 (m, 2H), 4.05 (m, 1H), 3.50 (m,
2H), 3.43 (m, 2H), 3.15 (m, 2H), 2.92 (m, 3H), 2.50 (m, 2H), 2.09
(m, 6H), 1.55 (m, 2H). MS (ESI) m/z: 520 [M + H].sup.+.
[Example 19] Preparation of
(E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent--
4-en-1-ol hydrochloride salt (18t)
##STR00192##
[0153] Step 1: Preparation of methyl
5-(4-(pivaloyloxy)phenyl)pent-4-ynoate (C-1)
[0154] 4-Iodophenyl pivalate (2 g, 6.6 mmol), copper (I) chloride
(0.13 g, 0.66 mmol), bis(triphenylphosphine)palladium (II)
dichloride (PdCl.sub.2(PPh.sub.3).sub.2, 0.23 g, 0.33 mmol), and
methyl pent-4-ynoate (0.74 g, 0.66 mmol) were dissolved in
trimethylamine (15 mL), and the reaction was carried out at
50.degree. C. for 12 hours. The reaction solution was concentrated
under reduced pressure, and 1.1 g of the desired compound C-1 (58%)
was obtained using column chromatography.
Step 2: Preparation of (E)-tert-butyl
3-(4-(5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl)ph-
enyl)azetidin-1-carboxylate (C-2)
[0155] tert-Butyl
3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)azetidin-1-carboxy-
late (0.27 g, 0.75 mmol), compound C-1 (0.14 g, 0.5 mmol), and
iodobenzene (84 .mu.L, 0.75 mmol) were dissolved in DMF (8 mL) and
water (4 mL), 0.025 M PdCl.sub.2(PhCN).sub.2 (0.2 mL, 5 .mu.mol)
was added thereto, and heating was performed at 45.degree. C. for
10 minutes. Cesium carbonate (0.24 g, 0.75 mmol) was added thereto,
and heating was performed at 45.degree. C. for 12 hours. When the
reaction was completed, brine and ethyl acetate was further added
to the reaction solution, and an organic layer was extracted. The
organic layer was dried with anhydrous Na.sub.2SO.sub.4 and
filtered. The solvent was distilled under reduced pressure to
obtain a residue, which was purified using column chromatography,
thereby obtaining 81 mg of the desired compound C-2 (27%).
Step 3: Preparation of tert-butyl
(E)-3-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)aze-
tidine-1-carboxylate (18t)
[0156] Compound C-2 (0.021 mmol) was added to tetrahydrofuran (2
mL), the temperature was lowered to 0.degree. C., and 1 M lithium
aluminum hydride, diisobutylaluminum hydride, or lithium
borohydride (0.024 mL, 0.024 mmol) was added thereto. The
temperature was raised to room temperature, and stirring was
performed for 1 hour. Water and ethyl acetate were further added to
the reaction solution and an organic layer was extracted. The
organic layer was dried with anhydrous Na.sub.2SO.sub.4 and
filtered. The solvent was distilled under reduced pressure to
obtain a residue, which was purified using column chromatography
and then dissolved in methanol:dichloromethane (1:1), the
temperature was lowered to 0.degree. C., a 1M aqueous HCl solution
was slowly added thereto, and distillation under reduced pressure
was performed, thereby obtaining 24 mg of the desired compound 18t
(78%).
Examples 20 to 39
[0157] Compounds 18a to 18s and 18u were prepared using the process
of Example 19. Identification data of the thus-prepared compounds
18a to 18u is shown in the following Table 3.
TABLE-US-00003 TABLE 3 ##STR00193## Example Cmpd No. ##STR00194## R
Identification data 19 18t ##STR00195## ##STR00196## .sup.1H-NMR
(CD.sub.3OD, 400 MHz) .delta. 7.18-7.10 (m, 5H), 7.05 (d, J = 8.4
Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.79
(d, J = 8.4 Hz, 2H), 4.25 (t, J = 8.4 Hz, 2H), 3.81 (t, J = 6.6 Hz,
2H), 3.66 (m, 1H), 3.43 (t, J = 6.8 Hz, 2H), 2.55 (m, 2H), 1.57 (m,
2H), 1.45 (s, 9H). MS (ESI) m/z: 386 [M + H].sup.+. 20 18a
##STR00197## ##STR00198## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.14-7.07 (m, 5H), 7.02 (d, J = 8.0 Hz, 2H), 6.78 (m, 4H), 6.69 (d,
J = 8.3 Hz, 2H), 3.76 (m, 2H), 3.52 (m, 3H), 3.41 (t, J = 6.4 Hz,
2H), 3.23 (m, 2H), 2.96 (m, 2H), 2.51 (m, 2H), 1.53 (m, 2H), 1.39
(d, J = 6.5 Hz, 6H). MS (ESI) m/z: 457 [M + H].sup.+. 21 18b
##STR00199## ##STR00200## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.18-7.13 (m, 5H), 7.08 (m, 4H), 6.79 (d, J = 8.7 Hz, 2H), 6.67 (d,
J = 8.7 Hz, 2H), 3.75 (m, 2H), 3.53 (m, 3H), 3.39 (t, J = 6.8 Hz,
2H), 3.21 (m, 2H), 2.92 (m, 2H), 2.48 (m, 2H), 2.35 (s, 3H), 1.53
(m, 2H), 1.38 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 455 [M + H].sup.+.
22 18c ##STR00201## ##STR00202## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 8.25 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H),
7.21-7.13 (m, 5H), 6.81 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.8 Hz,
2H), 3.74 (m, 2H), 3.54 (m, 2H), 3.42 (t, J = 6.4 Hz, 2H), 3.19 (t,
J = 9.8 Hz, 2H), 2.93 (m, 5H), 2.50 (m, 2H), 1.55 (m, 2H). MS (ESI)
m/z: 458 [M + H].sup.+. 23 18d ##STR00203## ##STR00204##
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.20-7.07 (m, 7H), 7.04
(d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.5 Hz,
2H), 6.73 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.6 Hz, 2H), 3.74 (m,
2H), 3.57 (m, 2H), 3.42 (t, J = 6.7 Hz, 2H), 3.33 (m, 2H), 3.23 (m,
2H), 2.95 (s, 3H), 2.53 (m, 2H), 1.55 (m, 2H). MS (ESI) m/z: 429 [M
+ H].sup.+. 24 18e ##STR00205## ##STR00206##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.49 (d, J = 8.4 Hz, 2H),
7.14-7.12 (m, 7H), 6.72 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.9 Hz,
2H), 3.40 (t, J = 6.6 Hz, 2H), 3.07 (m, 4H), 2.55 (m, 4H), 2.47 (m,
2H), 2.31 (s, 3H), 1.52 (m, 2H). MS (ESI) m/z: 492 [M + H].sup.+.
25 18f ##STR00207## ##STR00208## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.19-7.09 (m, 9H), 6.81 (d, J = 8.6 Hz, 2H), 6.68 (d, J =
8.8 Hz, 2H), 3.70 (m, 2H), 3.55 (m, 2H), 3.42 (t, J = 6.8 Hz, 2H),
3.20 (m, 2H), 2.00 (m, 2H), 2.93 (s, 3H), 2.50 (m, 2H), 2.36 (s,
3H), 1.55 (m, 2H). MS (ESI) m/z: 427 [M + H].sup.+. 26 18g
##STR00209## ##STR00210## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
8.25 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.21-7.13 (m,
5H), 6.81 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 3.78 (m,
2H), 3.53 (m, 3H), 3.42 (t, J = 6.5 Hz, 2H), 3.21 (m, 2H), 2.93 (m,
2H), 2.50 (m, 2H), 1.55 (m, 2H), 1.39 (d, J = 6.6 Hz, 6H). MS (ESI)
m/z: 486 [M + H].sup.+. 27 18h ##STR00211## ##STR00212##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.49 (d, J = 8.4 Hz, 2H),
7.16-7.11 (m, 7H), 6.74 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz,
2H), 3.40 (t, J = 6.6 Hz, 2H), 3.16 (m, 4H), 2.96 (m, 5H), 2.47 (m,
2H), 1.54 (m, 2H), 1.19 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 520 [M +
H].sup.+. 28 18i ##STR00213## ##STR00214## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.16-7.07 (m, 5H), 7.01 (d, J = 7.6 Hz, 2H), 6.77
(m, 4H), 6.67 (d, J = 8.5 Hz, 2H), 3.73 (m, 2H), 3.58 (m, 2H), 3.41
(t, J = 6.8 Hz, 2H), 3.23 (m, 2H), 3.14 (m, 2H), 2.93 (m, 2H), 2.51
(m, 2H), 1.53 (m, 2H), 1.37 (t, J = 7.3 Hz, 3H). MS (ESI) m/z: 443
[M + H].sup.+. 29 18j ##STR00215## ##STR00216##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.19-7.15 (m, 5H), 7.10
(m, 4H), 6.8 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.9 Hz, 2H), 3.75
(m, 2H), 3.60 (m, 2H), 3.41 (t, J = 6.8 Hz, 2H), 3.25 (q, J = 7.4
Hz, 2H), 3.14 (m, 2H), 2.93 (m, 2H), 2.50 (m, 2H), 2.37 (s, 3H),
1.55 (m, 2H), 1.38 (t, J = 7.3 Hz, 2H). MS (ESI) m/z: 441 [M +
H].sup.+. 30 18k ##STR00217## ##STR00218## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.19-7.09 (m, 6H), 6.81 (d, J = 8.7 Hz, 2H), 6.69
(m, 4H), 6.63 (m, 1H), 3.76 (m, 2H), 3.53 (m, 3H), 3.40 (t, J = 5.6
Hz, 2H), 3.21 (m, 2H), 2.91 (m, 2H), 2.50 (m, 2H), 1.53 (m, 2H),
1.38 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 457 [M + H].sup.+. 31 18l
##STR00219## ##STR00220## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.17-7.07 (m, 7H), 6.89 (d, J = 8.7 Hz, 2H), 6.85 (m, 2H), 6.65 (d,
J = 8.8 Hz, 2H), 3.73 (m, 2H), 3.50 (m, 2H), 3.35 (m, 2H), 3.20 (m,
2H), 2.91 (m, 2H), 2.39 (t, J = 7.9 Hz, 2H), 1.57 (m, 2H), 1.38 (d,
J = 6.6 Hz, 6H). MS (ESI) m/z: 457 [M + H].sup.+. 32 18m
##STR00221## ##STR00222## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.22-7.11 (m, 7H), 7.05 (m, 4H), 6.80 (d, J = 8.6 Hz, 2H), 3.77 (m,
4H), 3.42 (m, 6H), 2.55 (m, 2H), 1.59 (m, 2H), 1.49 (s, 9H). MS
(ESI) m/z: 515 [M + H].sup.+. 33 18n ##STR00223## ##STR00224##
.sup.1H-NMR(CD.sub.3OD 400 MHz) .delta. 7.49 (d, J = 8.4 Hz, 2H),
7.16-7.12 (m, 7H), 6.72 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.8 Hz,
2H), 3.47 (s, 4H), 3.39 (t, J = 6.6 Hz, 2H), 2.98 (m, 4H), 2.47 (m,
2H), 1.52 (m, 2H), 1.44 (s, 9H). MS (ESI) m/z: 478 [M + H].sup.+.
34 18o ##STR00225## ##STR00226## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.42 (d, J = 8.7 Hz, 2H), 7.20-7.12 (m, 7H), 7.07 (d, J =
8.5 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.07 (m, 4H), 3.62 (m, 4H),
3.44 (t, J = 6.6 Hz, 2H), 2.56 (m, 2H), 1.57 (m, 2H). MS (ESI) m/z:
416 [M + H].sup.+. 35 18p ##STR00227## ##STR00228##
.sup.1H-NMR(CD.sub.3OD 400 MHz) .delta. 8.23 (d, J = 8.8 Hz, 2H),
7.46 (d, J = 8.6 Hz, 2H), 7.22-7.12 (m, 5H), 6.66 (d, J = 8.8 Hz,
2H), 6.23 (d, J = 8.7 Hz, 2H), 3.42 (t, J = 6.5 Hz, 2H), 3.27 (m,
2H), 3.13 (m, 2H), 2.48 (m, 2H), 1.90 (m, 4H), 1.54 (m, 4H), 1.35
(m, 2H), 1.29 (s, 9H). MS (ESI) m/z: 484 [M + H].sup.+. 36 18q
##STR00229## ##STR00230## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.52 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.17-7.10 (m,
5H), 7.03 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 3.54 (s,
2H), 3.42 (t, J = 6.6 Hz, 2H), 2.52 (m, 6H), 1.62-1.48 (m, 8H). MS
(ESI) m/z: 492 [M + H].sup.+. 37 18r ##STR00231## ##STR00232##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.38 (m, 2H), 7.31 (m,
1H), 7.22 (m, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz,
2H), 6.51 (s, 1H), 6.43 (s, 1H), 4.03 (m, 3H), 3.35 (t, J = 6.9 Hz,
2H), 2.32 (m, 2H), 1.81 (m, 2H), 1.59 (m, 6H), 1.44 (s, 9H). MS
(ESI) m/z: 404 [M + H].sup.+. 38 18s ##STR00233## ##STR00234##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.93 (s, 1H), 7.05-7.12
(m, 9H), 6.85 (d, J = 10.0 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.47
(s, 1H), 3.61 (m, 2H), 3.48 (m, 4H), 3.25 (t, J = 7.6 Hz, 2H), 3.01
(t, J = 10.4 Hz, 2H), 2.59 (m, 2H), 1.99 (m, 2H), 1.77-1.87 (m,
3H), 1.51- 1.61 (m, 3H). MS (ESI) m/z: 482 [M + H].sup.+. 39 18u
##STR00235## ##STR00236## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
8.22 (s, 1H), 7.34 (d, J = 8.2 Hz, 2H), 6.99 (m, 5H), 6.93 (d, J =
8.5 Hz, 2H), 6.82 (d, J = 8.2 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H),
4.78 (m, 2H), 3.66 (t, J = 5.8 Hz, 2H), 3.29 (t, J = 6.7 Hz, 2H),
2.84 (s, 6H), 2.42 (m, 2H), 1.43 (m, 2H). MS (ESI) m/z: 469 [M +
H].sup.+.
[Example 40] Preparation of
(E)-5-(4-bromophenyl)-4-phenyl-5-(4-(piperazin-1-yl)phenyl)pent-4-en-1-ol
(20a)
##STR00237##
[0158] Step 1: Preparation of methyl
(E)-5-(4-bromophenyl)-4-phenyl-5-(4-(piperazin-1-yl)phenyl)pent-4-enoate
(D-2)
[0159] Compound D-1 (6 mg, 0.01 mmol) was added to dichloromethane
(2 mL), the temperature was lowered to 0.degree. C., and
trifluoroacetic acid (0.05 mL, 0.65 mmol) was slowly added thereto.
The temperature was raised to room temperature, and stirring was
performed for 12 hours. Water and ethyl acetate were further added
to the reaction solution and an organic layer was extracted. The
organic layer was dried with anhydrous Na.sub.2SO.sub.4 and
filtered. The solvent was distilled under reduced pressure to
obtain a residue, which was purified using column chromatography,
thereby obtaining 5 mg of the desired compound D-2 (99%).
Step 2: Preparation of
(E)-5-(4-bromophenyl)-4-phenyl-5-(4-(piperazin-1-yl)phenyl)pent-4-en-1-ol
(20a)
[0160] 7 mg of the desired compound 20a (41%) was obtained by the
same process as step 3 of Example 19, using compound D-2.
Examples 41 to 51
[0161] Compounds 20b to 201 were prepared, using the process of
Example 40. Identification data of the thus-prepared compounds 20a
to 201 is shown in the following Table 4.
TABLE-US-00004 TABLE 4 ##STR00238## Example Cmpd No. ##STR00239## R
Identification data 40 20a ##STR00240## ##STR00241##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.50 (d, J = 8.4 Hz, 2H),
7.17-7.09 (m, 7H), 6.76 (m, 2H), 6.66 (d, J = 8.8 Hz, 2H), 3.39 (m,
2H), 3.22 (s, 8H), 2.48 (m, 2H), 1.52 (m, 2H). MS (ESI) m/z: 478 [M
+ H].sup.+. 41 20b ##STR00242## ##STR00243##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.16-7.06 (m, 9H), 6.71
(d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 3.38 (t, J = 6.8 Hz,
2H), 3.19 (s, 8H), 2.47 (m, 2H), 2.34 (s, 3H), 1.52 (m, 2H). MS
(ESI) m/z: 413 [M + H].sup.+. 42 20c ##STR00244## ##STR00245##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.20-7.11(m, 7H), 7.04 (m,
4H), 6.80 (d, J = 8.5 Hz, 2H), 3.83 (m, 2H), 3.70 (m, 6H), 3.62 (t,
J = 5.2 Hz, 2H), 2.51 (m, 2H), 1.56 (m, 2H). MS (ESI) m/z: 415 [M +
H].sup.+. 43 20d ##STR00246## ##STR00247## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.17-7.07 (m, 9H), 7.03 (d, J = 8.3 Hz, 2H), 6.92
(d, J = 8.4 Hz, 2H), 4.24 (m, 2H), 4.07 (m, 3H), 3.39 (t, J = 6.8
Hz, 2H), 2.49 (m, 2H), 2.34 (s, 3H), 1.53 (m, 2H). MS (ESI) m/z:
384 [M + H].sup.+. 44 20e ##STR00248## ##STR00249## .sup.1H-NMR
(CD.sub.3OD, 400 MHz) .delta. 7.17-7.09 (m, 5H), 7.05 (m, 4H), 6.95
(d, J = 7.4 Hz, 2H), 6.79 (d, J = 7.8 Hz, 2H), 4.29 (m, 2H), 4.12
(m, 3H), 3.44 (t, J = 6.6 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 1.57
(m, 2H). MS (ESI) m/z: 386 [M + H].sup.+. 45 20f ##STR00250##
##STR00251## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.51 (d, J =
8.4 Hz, 2H), 7.16-7.11 (m, 7H), 7.04 (d, J = 8.2 Hz, 2H), 6.91 (d,
J = 8.2 Hz, 2H), 4.18 (m, 2H), 4.02 (m, 3H), 3.41 (t, J = 6.6 Hz,
2H), 2.50 (m, 2H), 1.53 (m, 2H). MS (ESI) m/z: 449 [M + H].sup.+.
46 20g ##STR00252## ##STR00253## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.93 (s, 1H), 7.05-7.12 (m, 9H), 6.85 (d, J = 10.0 Hz, 2H),
6.79 (d, J = 8.6 Hz, 2H), 6.47(s, 1H), 3.61 (m, 2H), 3.48 (m, 4H),
3.25 (t, J = 7.6 Hz, 2H), 3.01 (t, J = 10.4 Hz, 2H), 2.59 (m, 2H),
1.99 (m, 2H), 1.77-1.87 (m, 3H), 1.51-1.61 (m, 3H). MS (ESI) m/z:
443 [M + H].sup.+. 47 20h ##STR00254## ##STR00255##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.93 (s, 1H), 7.05-7.12
(m, 9H), 6.85 (d, J = 10.0 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H),
6.47(s, 1H), 3.61 (m, 2H), 3.48 (m, 4H), 3.25 (t, J = 7.6 Hz, 2H),
3.01 (t, J = 10.4 Hz, 2H), 2.59 (m, 2H), 1.99 (m, 2H), 1.77-1.87
(m, 3H), 1.51-1.61 (m, 3H). MS (ESI) m/z: 483 [M + H].sup.+. 48 20i
##STR00256## ##STR00257## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.93 (s, 1H), 7.05-7.12 (m, 9H), 6.85 (d, J = 10.0 Hz, 2H), 6.79
(d, J = 8.6 Hz, 2H), 6.47(s, 1H), 3.61 (m, 2H), 3.48 (m, 4H), 3.25
(t, J = 7.6 Hz, 2H), 3.01 (t, J = 10.4 Hz, 2H), 2.59 (m, 2H), 1.99
(m, 2H), 1.77-1.87 (m, 3H), 1.51-1.61 (m, 3H). MS (ESI) m/z: 481 [M
+ H].sup.+. 49 20j ##STR00258## ##STR00259##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.15-7.07 (m, 5H), 7.02
(d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.0 Hz,
2H), 6.77 (d, J = 8.1 Hz, 2H), 3.41 (m, 4H), 3.06 (m, 2H), 2.74 (m,
1H), 2.52 (m, 2H), 1.96 (m, 2H), 1.76 (m, 2H), 1.54 (m, 2H). MS
(ESI) m/z: 414 [M + H].sup.+. 50 20k ##STR00260## ##STR00261##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.17 (d, J = 7.8 Hz, 2H),
7.12-7.06 (m, 5H), 6.96 (m, 4H), 6.86 (m, 2H), 3.46 (m, 2H), 3.40
(t, J = 6.8 Hz, 2H), 3.10 (m, 2H), 2.82 (m, 1H), 2.50 (m, 2H), 2.35
(s, 3H), 2.02 (m, 2H), 1.83 (m, 2H), 1.53 (m, 2H). MS (ESI) m/z:
412 [M + H].sup.+. 51 20l ##STR00262## ##STR00263##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 8.26 (d, J = 8.6 Hz, 2H)
7.47 (d, J = 8.6 Hz, 2H), 7.21-7.09 (m, 5H), 6.64 (d, J = 8.4 Hz,
2H), 6.30 (d, J = 8.7 Hz, 2H), 3.48 (m, 2H), 3.25 (m, 2H), 3.15 (m,
2H), 2.51 (m, 2H), 2.12 (m, 4H), 1.59 (m, 4H), 1.15 (m, 2H). MS
(ESI) m/z: 484 [M + H].sup.+.
[Example 52] Preparation of
(E)-4-(5-hydroxy-1-(4-(1-isopropylazetidin-3-yl)phenyl)-2-phenylpent-1-en-
-1-yl)phenol (22a)
##STR00264##
[0162] Step 1: Preparation of methyl
(E)-5-(4-(1-isopropylazetidin-3-yl)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phe-
nyl)pent-4-enoate (E-2)
[0163] Compound E-1 (0.03 g, 0.06 mmol), acetone (0.14 mL, 1.9
mmol), and sodium triacetoxyborohydride (NaBH(OAc).sub.3, 41 mg,
0.19 mmol) were added to dichloroethane (3 mL), and stirred at room
temperature for 1 hour. Water and ethyl acetate were further added
to the reaction solution and an organic layer was extracted. The
organic layer was dried with anhydrous Na.sub.2SO.sub.4 and
filtered. The solvent was distilled under reduced pressure to
obtain a residue, which was purified using column chromatography,
thereby obtaining 18 mg of the desired compound E-2 (54%).
Step 2: Preparation of
(E)-4-(5-hydroxy-1-(4-(1-isopropylazetidin-3-yl)phenyl)-2-phenylpent-1-en-
-1-yl)phenol (22a)
[0164] 4 mg of the desired compound 22a (27%) was obtained by the
same process as step 3 of Example 19, using compound E-2.
Examples 53 to 82
[0165] Compounds 22b to 22a e were prepared, using the process of
Example 52. Identification data of the thus-prepared compounds 22b
to 22ae is shown in the following Table 5.
TABLE-US-00005 TABLE 5 ##STR00265## Example Cmpd No. ##STR00266## R
Identification data 52 22a ##STR00267## ##STR00268##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.17-7.08 (m, 5H),
7.08-7.02 (m, 4H), 6.94 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 8.5 Hz,
2H), 4.38 (t, J = 8.3 Hz, 2H), 4.21 (m. 1H), 4.10 (t, J = 9.8 Hz,
2H), 3.98 (m, 1H), 3.43 (t, J = 7.5 Hz, 2H), 2.55 (m, 2H), 1.56 (m,
2H), 1.24 (d, J = 6.4 Hz, 6H). MS (ESI) m/z: 428 [M + H].sup.+. 53
22b ##STR00269## ##STR00270## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.15-7.07 (m, 5H), 7.05-7.01 (m, 4H), 6.94 (m, 2H), 6.76
(d, J = 8.4 Hz, 2H), 4.46 (m, 2H), 4.34 (m, 1H), 4.22 (m, 1H), 4.02
(m, 2H), 3.41 (t, J = 6.7 Hz, 2H), 2.91 (s, 3H), 2.53 (m, 2H), 1.54
(m, 2H). MS (ESI) m/z: 400 [M + H].sup.+. 54 22c ##STR00271##
##STR00272## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.17-7.03 (m,
9H), 6.96 (d, J = 8.1 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 4.46 (m,
4H), 4.32 (m, 1H), 3.43 (t, J = 6.7 Hz, 2H), 3.35 (s, 3H), 3.21 (s,
3H), 2.55 (m, 2H), 1.55 (m, 2H). MS (ESI) m/z: 415 [M + H].sup.+.
55 22d ##STR00273## ##STR00274## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.15-7.09 (m, 5H), 7.06-7.00 (m, 4H), 6.94 (d, J = 8.04,
2H), 6.76 (d, J = 8.6 Hz, 2H), 4.42 (t, J = 9.3 Hz, 2H), 4.32 (m,
1H), 4.19 (m, 1H), 3.98 (m, 1H), 3.41 (t, J = 6.7 Hz, 2H), 2.53 (m,
2H), 1.54 (m, 2H), 0.86 (m, 4H). MS (ESI) m/z: 426 [M + H].sup.+.
56 22e ##STR00275## ##STR00276## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.17-7.07 (m, 9H), 6.98 (d, J = 8.2 Hz, 2H), 6.88 (d, J =
8.2 Hz, 2H), 4.07 (t, J = 8.2 Hz, 2H), 3.76 (m, 1H), 3.65 (t, J =
8.8 Hz, 2H), 3.39 (t, J = 6.7 Hz, 2H), 3.01 (m, 1H), 2.49 (m, 2H),
2.34 (s, 3H), 1.54 (m, 2H), 1.09 (d, J = 6.4 Hz, 6H). MS (ESI) m/z:
426 [M + H].sup.+. 57 22f ##STR00277## ##STR00278##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.17 (d, J = 7.8 Hz, 2H),
7.12-7.06 (m, 4H), 6.97 (m, 2H), 6.85 (m, 2H), 3.58 (m, 2H), 3.40
(t, J = 6.8 Hz, 2H), 3.12 (m, 2H), 2.90 (s, 3H), 2.80 (m, 1H), 2.50
(m, 2H), 2.35 (s, 3H), 2.07 (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H). MS
(ESI) m/z: 426 [M + H].sup.+. 58 22g ##STR00279## ##STR00280##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.17-7.07 (m, 5H), 7.02
(d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.2 Hz,
2H), 6.77 (d, J = 8.6 Hz, 2H), 3.48 (m, 3H), 3.41 (t, J = 6.7 Hz,
2H), 3.13 (m, 2H), 2.74 (m, 1H), 2.52 (m, 2H), 2.05 (m, 2H), 1.86
(m, 2H), 1.54 (m, 2H), 1.37 (d, J = 6.7 Hz, 6H). MS (ESI) m/z: 456
[M + H].sup.+. 59 22h ##STR00281## ##STR00282## 1H-NMR(CD3OD, 400
MHz) .delta. 7.19-7.09 (m, 6H), 6.85 (m, 4H), 6.71 (m, 2H), 6.64
(m, 1H), 3.77 (m, 2H), 3.58 (m, 3H), 3.41 (t, J = 6.8 Hz, 2H), 3.34
(m, 2H), 3.21 (m, 2H), 2.50 (m, 2H), 1.53 (m, 2H), 1.40 (d, J = 6.6
Hz, 6H). MS (ESI) m/z: 456 [M + H]+. 60 22i ##STR00283##
##STR00284## 1H-NMR(CD3OD, 400 MHz) .delta. 7.15-7.06 (m, 5H), 7.01
(d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.2 Hz,
2H), 6.75 (d, J = 8.5 Hz, 2H), 3.68 (m, 2H), 3.41 (t, J = 6.6 Hz,
2H), 3.24 (m, 2H), 2.79 (m, 2H), 2.52 (m, 2H), 2.02 (m, 2H), 1.78
(m, 2H), 1.54 (m, 2H), 0.97 (m, 4H). MS (ESI) m/z: 454 [M + H]+. 61
22j ##STR00285## ##STR00286## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.17-7.10 (m, 7H), 7.05 (d, J = 8.4 Hz, 2H), 6.91 (d, J =
8.2 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 6.06 (s, 1H), 4.02 (m, 2H),
3.53 (m, 2H), 3.44 (t, J = 6.7 Hz, 2H), 2.96 (m, 1H), 2.81 (s, 2H),
2.55 (m, 2H), 1.56 (m, 2H), 1.03 (m, 4H). MS (ESI) m/z: 452 [M +
H].sup.+. 62 22k ##STR00287## ##STR00288## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.17-7.10 (m, 7H), 7.05 (d, J = 8.4 Hz, 2H), 6.91
(d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.07 (s, 1H), 3.88
(s, 2H), 3.64 (m, 2H), 3.44 (t, J = 6.6 Hz, 2H), 3.23 (m, 1H), 2.81
(m, 2H), 2.56 (m, 2H), 1.55 (m, 2H), 1.42 (d, J = 6.6 Hz, 6H). MS
(ESI) m/z: 454 [M + H].sup.+. 63 22l ##STR00289## ##STR00290##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.22-7.12 (m, 8H), 6.92
(d, J = 8.3 Hz, 2H), 6.73 (m, 2H), 6.66 (s, 1H), 6.06 (s, 1H), 4.02
(m, 2H), 3.48 (m, 2H), 3.43 (t, J = 6.8 Hz, 2H), 2.95 (m, 1H), 2.81
(s, 2H), 2.54 (m, 2H), 1.56 (m, 2H), 1.04 (m, 4H). MS (ESI) m/z:
452 [M + H].sup.+. 64 22m ##STR00291## ##STR00292##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.22-7.12 (m, 9H), 6.93
(d, J = 6.8 Hz, 2H), 6.73 (d, J = 7.6 Hz, 2H), 6.08 (s, 1H), 3.88
(s, 2H), 3.64 (m, 2H), 3.44 (t, J = 6.6 Hz, 2H), 3.23 (m, 1H), 2.80
(m, 2H), 2.54 (m, 2H), 1.56 (m, 2H), 1.41 (d, J = 6.4 Hz, 6H). MS
(ESI) m/z: 454 [M + H].sup.+. 65 22n ##STR00293## ##STR00294##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.17-7.07 (m, 6H), 7.03
(m, 2H), 6.77 (m, 2H), 6.66 (m, 2H), 3.39 (d, J = 8.6 Hz, 1H), 3.89
(m, 1H), 3.72 (m, 2H), 3.63 (m, 2H), 3.41 (t, J = 6.7 Hz, 2H), 3.16
(m, 3H), 2.95 (m, 1H), 2.50 (m, 2H), 2.21 (m, 2H), 1.86 (m, 2H),
1.74 (m, 4H), 1.55 (m, 2H). MS (ESI) m/z: 483 [M + H].sup.+. 66 22o
##STR00295## ##STR00296## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
8.14 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.07-7.03 (m,
5H), 6.86 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 8.2 Hz, 2H), 3.57 (m,
2H), 3.32 (t, J = 6.4 Hz, 2H), 3.14 (m, 2H), 2.68 (m, 2H), 2.41 (m,
2H), 1.88 (m, 2H), 1.76 (m, 2H), 1.46 (m, 2H), 0.87 (m, 4H). MS
(ESI) m/z: 483 [M + H].sup.+. 67 22p ##STR00297## ##STR00298##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.18-7.08 (m, 5H), 7.02
(m, 2H), 6.65 (m, 2H), 6.39 (m, 2H), 3.81 (m, 2H), 3.64 (m, 2H),
3.41 (t, J = 6.7 Hz, 2H), 3.23 (m, 2H), 2.96 (m, 2H), 2.51 (m, 3H),
2.17 (m, 2H), 1.97 (m, 2H), 1.72 (m, 2H), 1.53 (m, 2H), 1.42 (m,
2H), 1.29 (m, 2H). MS (ESI) m/z: 497 [M + H].sup.+. 68 22q
##STR00299## ##STR00300## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.16-7.07 (m, 5H), 7.02 (d, J = 8.8 Hz, 2H), 6.78 (m, 2H), 6.66 (m,
2H), 3.72 (m, 2H), 3.49 (m, 2H), 3.41 (t, J = 6.7 Hz, 2H), 2.95 (m,
4H), 2.51 (m, 2H), 2.34 (m, 2H), 2.25 (m, 2H), 1.91 (m, 2H), 1.53
(m, 2H). MS (ESI) m/z: 469 [M + H].sup.+. 69 22r ##STR00301##
##STR00302## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.21-7.10 (m,
7H), 6.90 (m, 4H), 6.72 (d, J = 7.9 Hz, 2H), 3.71 (m, 2H), 3.43 (t,
J = 6.8 Hz, 2H), 3.27 (m, 2H), 2.80 (m, 2H), 2.52 (m, 2H), 2.01 (m,
2H), 1.79 (m, 2H), 1.52 (m, 2H), 0.98 (m, 4H). MS (ESI) m/z: 454 [M
+ H].sup.+. 70 22s ##STR00303## ##STR00304##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.04-6.86 (m, 9H), 6.78
(d, J = 8.1 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.61-6.58 (m, 2H),
3.61-3.51 (m, 2H), 3.36-3.28 (m, 5H), 2.96-2.90 (m, 1H), 2.43- 2.39
(m, 2H), 2.33-2.28 (m, 1H), 2.01-1.96 (m, 1H), 1.45-1.41 (m, 2H),
1.26-1.24 (m, 6H). MS (ESI) m/z: 442 [M + H].sup.+. 71 22t
##STR00305## ##STR00306## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.18-7.09 (m, 5H), 7.05-7.02 (m, 4H), 6.94-6.89 (m, 2H), 6.80-6.78
(m, 2H), 4.28-4.25 (m, 1H), 3.90- 3.73 (m, 3H), 3.55-3.51 (m, 1H),
3.45-3.41 (m, 3H), 3.28-3.23 (m, 1H), 3.05-2.96 (m, 1H), 2.56-2.52
(m, 2H), 2.44-2.39 (m, 1H), 2.25- 2.19 (m, 1H), 1.59-1.53 (m, 2H),
1.00-0.95 (m, 4H). MS (ESI) m/z: 440 [M + H].sup.+. 72 22u
##STR00307## ##STR00308## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.08-6.97 (m, 6H), 6.92-6.88 (m, 2H), 6.83-6.79 (m, 2H), 6.61-6.58
(m, 2H), 6.53 (s, 1H), 3.59-3.51 (m, 2H), 3.38-3.29 (m, 5H),
2.96-2.91 (m, 1H), 2.42-2.38 (m, 2H), 2.34-2.24 (m, 1H), 2.05- 1.97
(m, 1H), 1.47-1.39 (m, 2H), 1.26-1.24 (m, 6H). MS (ESI) m/z: 442 [M
+ H].sup.+. 73 22v ##STR00309## ##STR00310##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.20-7.09 (m, 6H),
7.04-7.00 (m, 2H), 6.93-6.91 (m, 2H), 6.71 (d, J = 7.8 Hz, 2H),
6.55 (s, 1H), 3.91-3.65 (m, 2H), 3.54-3.50 (m, 2H), 3.42 (t, J =
6.7 Hz, 2H), 3.27-3.22 (m, 1H), 3.01-2.96 (m, 1H), 2.54-2.50 (m,
2H), 2.45-2.42 (m, 1H), 2.23- 2.21 (m, 1H), 1.58-1.51 (m, 2H),
0.99-0.90 (m, 4H). MS (ESI) m/z: 440 [M + H].sup.+. 74 22w
##STR00311## ##STR00312## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.20-7.11 (m, 5H), 7.07 (d, J = 8.2 Hz, 2H), 7.01-6.98 (m, 1H),
6.80 (d, J = 8.2 Hz, 2H), 6.76-6.70 (m, 1H), 6.62-6.53 (m, 2H),
3.54-3.42 (m, 7H), 3.22-3.13 (m, 2H), 2.96-2.90 (m, 2H), 2.57- 2.54
(m, 2H), 1.61-1.55 (m, 2H), 1.40 (d, J = 6.3 Hz, 6H). MS (ESI) m/z:
457 [M + H].sup.+. 75 22x ##STR00313## ##STR00314##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.21-7.11 (m, 6H),
7.04-7.00 (m, 1H), 6.75-6.69 (m, 4H), 6.62-6.57 (m, 2H), 3.58-3.42
(m, 7H), 3.20- 3.15 (m, 2H), 2.97-2.92 (m, 2H), 2.56-2.52 (m, 2H),
1.61-1.53 (m, 2H), 1.41 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 457 [M +
H].sup.+. 76 22y ##STR00315## ##STR00316## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.17-6.98 (m, 8H), 6.89 (d, J = 7.6 Hz, 1H),
6.79-6.77 (m, 4H), 3.54-3.32 (m, 5H), 3.12-3.06 (m, 2H), 2.66-2.60
(m, 1H), 2.59-2.54 (m, 2H), 1.87- 1.84 (m, 2H), 1.77-1.71 (m, 2H),
1.60-1.53 (m, 2H), 1.37 (d, J = 6.5 Hz, 6H). MS (ESI) m/z: 456 [M +
H].sup.+. 77 22z ##STR00317## ##STR00318## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.17-6.99 (m, 8H), 6.91-6.88 (m, 1H), 6.80-6.78
(m, 4H), 3.68-3.64 (m, 2H), 3.44 (dd, J = 6.7 Hz, 2H), 3.26-3.20
(m, 2H), 2.81-2.77 (m, 1H), 2.69- 2.62 (m, 1H), 2.58-2.54 (m, 2H),
1.86-1.82 (m, 2H), 1.68-1.59 (m, 2H), 1.58-1.53 (m, 2H), 1.00-0.98
(m, 4H). MS (ESI) m/z: 454 [M + H].sup.+. 78 22aa ##STR00319##
##STR00320## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.22-7.09 (m,
6H), 7.05-7.00 (m, 1H), 6.93-6.90 (m, 1H), 6.83-6.80 (m, 2H),
6.75-6.71 (m, 2H), 6.67- 6.65 (m, 1H), 3.49-3.42 (m, 5H), 3.15-3.06
(m, 2H), 2.67-2.60 (m, 1H), 2.56-2.53 (m, 2H), 1.89-1.85 (m, 2H),
1.79-1.67 (m, 2H), 1.60- 1.53 (m, 2H), 1.38 (d, J = 7.7 Hz, 6H). MS
(ESI) m/z: 456 [M + H].sup.+. 79 22ab ##STR00321## ##STR00322##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.21-7.09 (m, 6H), 7.01
(dd, J = 7.9 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.81-6.80 (m, 1H),
6.74-6.71 (m, 2H), 6.68-6.67 (m, 2H), 3.67-3.64 (m, 2H), 3.44 (dd,
J = 6.8 Hz, 2H), 3.26-3.20 (m, 2H), 2.81-2.78 (m, 1H), 2.69-2.63
(m, 1H), 2.56-2.53 (m, 2H), 1.84-1.81 (m, 2H), 1.75-1.65 (m, 2H),
1.59- 1.53 (m, 2H), 1.04-0.95 (m, 4H). MS (ESI) m/z: 454 [M +
H].sup.+. 80 22ac ##STR00323## ##STR00324## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.15-7.07 (m, 6H), 6.93-6.85 (m, 4H), 6.70 (m,
2H), 6.63 (s, 1H), 3.53 (m, 2H), 3.41 (t, J = 6.8 Hz, 2H), 3.08 (m,
2H), 2.87 (s, 3H), 2.72 (m, 1H), 2.51 (m, 2H), 2.02 (m, 2H), 1.86
(m, 2H), 1.56 (m, 2H). MS (ESI) m/z: 428 [M + H].sup.+. 81 22ad
##STR00325## ##STR00326## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.21-7.11 (m, 7H), 6.85 (m, 2H), 6.71 (m, 4H), 3.70 (m, 4H), 3.42
(t, J = 6.7 Hz, 2H), 3.18 (m, 3H), 2.53 (m, 2H), 1.53 (m, 2H), 1.00
(m, 4H). MS (ESI) m/z: 455 [M + H].sup.+. 82 22ae ##STR00327##
##STR00328## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.19-7.09 (m,
6H), 6.97-6.85 (m, 4H), 6.69 (m, 2H), 6.63 (s, 1H), 3.60 (m, 2H),
3.41 (t, J = 6.7 Hz, 2H), 3.16 (m, 2H), 3.00 (m, 2H), 2.74 (m, 1H),
2.51 (m, 2H), 2.02 (m, 2H), 1.85 (m, 2H), 1.52 (m, 2H), 1.36 (m,
3H). MS (ESI) m/z: 442 [M + H].sup.+.
[Example 83] Preparation of
(Z)-5-(4-aminophenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)-4-phenylpent-4-
-en-1-ol (26a)
##STR00329##
[0167] Compound F-1 (0.01 g, 0.02 mmol) and ammonium chloride (11
mg, 0.21 mmol) were added to methanol (0.5 mL) and tetrahydrofuran
(0.5 mL), the temperature was lowered to 0.degree. C., and zinc (13
mg, 0.21 mmol) was added thereto Stirring was performed at room
temperature for 12 hours. Filtration was performed using celite,
and the solvent was distilled under reduced pressure to obtain a
residue, which was purified using column chromatography, thereby
obtaining 9 mg of the desired compound 26a (99%).
Examples 84 to 86
[0168] Compounds 26b to 26d were prepared, using the process of
Example 83. Identification data of the thus-prepared compounds 26a
to 26d is shown in the following Table 6.
TABLE-US-00006 TABLE 6 ##STR00330## Cmpd Example No. R
Identification data 83 26a ##STR00331## .sup.1H-NMR(CD.sub.3OD, 400
MHz) .delta. 7.43 (s, 4H), 7.21-7.14 (m, 5H), 6.82 (d, J = 8.8 Hz,
2H), 6.71 (d, J = 8.8 Hz, 2H), 3.70 (m, 2H), 3.55 (m, 2H), 3.44 (m,
2H), 3.17 (m, 2H), 3.14 (m, 5H), 2.49 (m, 2H), 1.55 (m, 2H). MS
(ESI) m/z: 428 [M + H].sup.+. 84 26b ##STR00332##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.42 (m, 2H), 7.25-7.09
(m, 7H), 7.05 (m, 2H), 6.82 (m, 2H), 3.96 (m, 2H), 3.79 (m, 2H),
3.61 (m, 2H), 3.42 (m, 3H), 3.17 (m, 2H), 2.47 (m, 2H), 1.54 (m,
2H), 1.41 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 456 [M + H].sup.+. 85
26c ##STR00333## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.44 (m,
4H), 7.25-7.11 (m, 5H), 6.97 (m, 2H), 6.68 (m, 2H), 3.59 (m, 4H),
3.42 (t, J = 6.6 Hz, 2H), 3.14 (m, 2H), 2.52 (m, 2H), 2.01 (m, 4H),
1.56 (m, 2H), 1.39 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 455 [M +
H].sup.+. 86 26d ##STR00334## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.32 (s, 4H), 7.08-7.01 (m, 5H), 6.85 (d, J = 8.1 Hz, 2H),
6.76 (d, J = 8.1 Hz, 2H), 3.59 (m, 2H), 3.30 (t, J = 6.5 Hz, 2H),
3.15 (m, 2H), 2.69 (m, 2H), 2.38 (m, 2H), 1.88 (m, 2H), 1.78 (m,
2H), 1.44 (m, 2H), 0.86 (m, 4H). MS (ESI) m/z: 453 [M +
H].sup.+.
[Example 87] Preparation of
(E)-N-(4-(5-hydroxy-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylpent--
1-en-1-yl)phenyl)methanesulfonamide (27a)
##STR00335##
[0170] Compound 26b (5 mg, 10 .mu.mol) and triethylamine (3 .mu.L,
0.02 mmol) were added to dichloromethane (2 mL), the temperature
was lowered to 0.degree. C., and methanesulfonyl chloride (1 .mu.L,
0.01 mmol) was added thereto. Stirring was performed at room
temperature for 12 hours. Saturated sodium hydrogen carbonate and
dichloromethane were further added to the reaction solution and an
organic layer was extracted. The organic layer was dried with
anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was distilled
under reduced pressure to obtain a residue, which was purified
using column chromatography and then dissolved in
methanol:dichloromethane (1:1), the temperature was lowered to
0.degree. C., a 1M aqueous HCl solution was slowly added thereto,
and distillation under reduced pressure was performed, thereby
obtaining 1 mg of the desired compound 27a (17%).
Examples 87 to 94
[0171] Compounds 27b to 27h were prepared, using the process of
Example 87. Identification data of the thus-prepared compounds 27a
to 27h is shown in the following Table 7.
TABLE-US-00007 TABLE 7 ##STR00336## R.sup.a R.sup.b R.sup.c R.sup.d
87 27a ##STR00337## H H ##STR00338## .sup.1H-NMR(CD.sub.3OD, 400
MHz) .delta. 7.43 (s, 4H), 7.19-7.13 (m, 5H), 6.82 (d, J = 7.6 Hz,
2H), 6.71 (d, J = 8.1 Hz 2H), 4.10 (t, J = 5.8 Hz, 2H), 3.76 (m,
2H), 3.54 (m, 3H), 3.21 (m, 2H), 2.98 (m, 5H), 2.56 (m, 2H), 1.74
(m, 2H), 1.39 (d, J = 6.5 Hz, 6H). MS (ESI) m/z: 534 [M + H].sup.+.
88 27b ##STR00339## ##STR00340## H ##STR00341##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.26 (d, J = 8.4 Hz, 2H),
7.21-7.14 (m, 7H), 6.82 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 7.5 Hz,
2H), 4.10 (t, J = 5.8 Hz, 2H), 3.77 (m, 2H), 3.54 (m, 3H), 3.21 (m,
2H), 2.96 (m, 8H), 2.59 (m, 2H), 1.73 (m, 2H), 1.39 (d, J = 6.6 Hz,
6H). MS (ESI) m/z: 612 [M + H].sup.+. 89 27c ##STR00342## H H
##STR00343## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.43 (d, J =
8.5 Hz, 2H), 7.07-6.98 (m, 7H), 6.82 (d, J = 8.2 Hz, 2H), 6.75 (d,
J = 8.2 Hz, 2H), 3.57 (m, 2H), 3.32 (t, J = 6.7 Hz, 2H), 3.14 (m,
2H), 2.70 (m, 2H), 2.41 (m, 2H), 2.03 (s, 3H), 1.92 (m, 2H), 1.68
(m, 2H), 1.44 (m, 2H), 0.83 (m, 4H). MS (ESI) m/z: 495 [M +
H].sup.+. 90 27d ##STR00344## H ##STR00345## ##STR00346##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.45 (d, J = 8.5 Hz, 2H),
7.06-7.01 (m, 7H), 6.82 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 8.3 Hz,
2H), 3.84 (t, J = 6.3 Hz, 2H), 6.70 (m, 2H), 3.13 (m, 2H), 2.67 (m,
2H), 2.43 (m, 2H), 2.03 (s, 3H), 1.92 (m, 2H), 1.83 (s, 3H), 1.72
(m, 2H), 1.51 (m, 2H), 0.84 (m, 4H). MS (ESI) m/z: 537 [M +
H].sup.+. 91 27e ##STR00347## H H ##STR00348##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.27 (d, J = 8.5 Hz, 2H),
7.19-7.09 (m, 7H), 6.81 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.7 Hz,
2H), 3.76 (m, 2H), 3.51 (m, 2H), 3.41 (t, J = 6.5 Hz, 2H), 3.21 (m,
2H), 2.92 (m, 2H), 2.57 (m, 1H), 2.50 (m, 2H), 1.52 (m, 2H), 1.39
(d, J = 6.6 Hz, 6H), 1.29 (s, 1H), 1.04 (m, 2H), 0.96 (m, 2H). MS
(ESI) m/z: 560 [M + H].sup.+. 92 27f ##STR00349## H H ##STR00350##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.33 (m, 4H), 7.19-7.12
(m, 5H), 6.83 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.11
(t, J = 6.0 Hz, 2H), 3.77 (m, 2H), 3.53 (m, 3H), 3.20 (m, 2H), 2.95
(m, 5H), 2.58 (m, 2H), 1.73 (m, 2H), 1.38 (d, J = 6.6 Hz, 6H). MS
(ESI) m/z: 498 [M + H].sup.+. 93 27g ##STR00351## H H ##STR00352##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.27 (d, J = 8.4 Hz, 2H),
7.19-7.09 (m, 7H), 6.90 (m, 4H), 3.67 (m, 3H), 3.41 (t, J = 6.4 Hz,
2H), 2.77 (m, 2H), 2.55 (m, 3H), 2.02 (m, 2H), 1.76 (m, 2H), 1.54
(m, 2H), 0.96 (m, 4H). MS (ESI) m/z: 557 [M + H].sup.+. 94 27h
##STR00353## H H ##STR00354## .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.28-7.11 (m, 9H), 6.96 (m 4H), 3.73 (m, 4H), 3.50 (m, 2H),
2.83 (m, 2H), 2.54 (mf 2H), 2.18 (m, 1H), 1.98 (m, 1H), 1.54(m,
2H), 0.95 (m, 4H). MS (ESI) m/z: 531 [M + H].sup.+.
[Example 95] Preparation of
(E)-4-(5-hydroxy-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylpent-1-e-
n-1-yl)phenyl methanesulfonate (28a)
##STR00355##
[0173] Compound G-1 (10 mg, 22 .mu.mol) and diisopropylethylamine
(8 .mu.L, 0.04 mmol) were added to dichloromethane (2 mL), the
temperature was lowered to 0.degree. C., and methanesulfonyl
chloride (3 .mu.L, 0.02 mmol) was added thereto. Stirring was
performed at room temperature for 12 hours. Saturated sodium
hydrogen carbonate and dichloromethane were further added to the
reaction solution and an organic layer was extracted. The organic
layer was dried with anhydrous Na.sub.2SO.sub.4 and filtered. The
solvent was distilled under reduced pressure to obtain a residue,
which was purified using column chromatography, thereby obtaining 1
mg of the desired compound 28a (9%).
Examples 96 to 101
[0174] Compounds 28b to 28g were prepared, using the process of
Example 95. Identification data of the thus-prepared compounds 28a
to 28g is shown in the following Table 8.
TABLE-US-00008 TABLE 8 ##STR00356## Cmpd Example No. R.sup.a
R.sup.b R.sup.c Identification data 95 28a ##STR00357## H
##STR00358## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.32 (m, 4H),
7.19- 7.10 (m, 5H), 6.81 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.8 Hz,
2H), 3.77 (m, 2H), 3.53 (m, 3H), 3.41 (t, J = 6.6 Hz, 2H), 3.25 (s,
3H), 3.20 (m, 2H), 2.92 (m, 2H), 2.49 (m, 2H), 1.54 (m, 2H), 1.38
(d, J = 6.6 Hz, 6H). MS (ESI) m/z: 535 [M + H].sup.+. 96 28b
##STR00359## ##STR00360## ##STR00361## .sup.1H-NMR(CD.sub.3OD, 400
MHz) .delta. 7.45 (d, J = 8.5 Hz, 2H), 7.06-6.99 (m, 7H), 6.82 (d,
J = 8.3 Hz, 2H), 6.76 (d, J = 8.3 Hz, 2H), 3.84 (t, J = 6.3 Hz,
2H), 3.59 (m, 2H), 3.14 (m, 2H), 2.68 (m, 2H), 2.43 (m, 2H), 2.03
(s, 3H), 1.92 (m, 2H), 1.83 (s, 3H), 1.55 (m, 2H), 1.52 (m, 2H),
0.84 (m, 4H). MS (ESI) m/z: 613 [M + H]+. 97 28c ##STR00362## H
##STR00363## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.35-7.29 (m,
4H), 7.19-7.10 (m, 5H), 6.81 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8
Hz, 2H), 3.77 (m, 2H), 3.54 (m, 3H), 3.41 (t, J = 6.6 Hz, 2H), 3.21
(m, 2H), 2.97 (m, 2H), 2.82 (m, 1H), 2.49 (m, 2H), 1.53 (m, 2H),
1.38 (d, J = 6.6 Hz, 6H), 1.14 (m, 4H). MS (ESI) m/z: 561 [M +
H].sup.+. 98 28d ##STR00364## H ##STR00365##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.38 (m, 4H), 7.18- 7.11
(m, 5H), 6.81 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 3.77
(m, 2H), 3.51 (m, 3H), 3.41 (t, J = 6.4 Hz, 2H), 3.21 (m, 2H), 2.92
(m, 2H), 2.48 (m, 2H), 1.53 (m, 2H), 1.38 (d, J = 6.6 Hz, 6H). MS
(ESI) m/z: 589 [M + H].sup.+. 99 28e ##STR00366## H ##STR00367##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.25 (d. J = 8.6 Hz, 2H),
7.15 (m, 5H), 7.05 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H),
6.68 (d, J = 8.8 Hz, 2H), 3.72 (m, 2H), 3.52 (m, 2H), 3.39 (t, J =
6.7 Hz, 2H), 3.18 (m, 2H), 2.92 (m, 5H), 2.51 (m, 2H), 1.54 (m,
2H), 1.36 (s, 9H). MS (ESI) m/z: 513 [M + H].sup.+. 100 28f H
##STR00368## ##STR00369## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta.
7.20-7.16 (m, 5H), 7.12 (d, J = 7.2 Hz, 2H), 7.04 (d, J = 8.7 Hz,
2H), 6.68 (d, J = 8.7 Hz, 2H), 3.89 (m, 2H), 3.62 (m, 2H), 3.48 (m,
2H), 3.42 (t, J = 6.7 Hz, 2H), 3.07 (m, 2H), 2.98 (s, 3H), 2.54 (m,
2H), 1.56 (m, 2H), 1.28 (s, 9H). MS (ESI) m/z: 513 [M + H].sup.+.
101 28g ##STR00370## ##STR00371## ##STR00372##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.24 (m, 2H), 7.18- 7.06
(m, 7H), 6.82 (d, J = 6.9 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 3.93
(t, J = 6.1 Hz, 2H), 3.72 (m, 2H), 3.52 (m, 2H), 3.19 (m, 2H), 2.95
(m, 5H), 2.52 (m, 2H), 1.63 (m, 2H), 1.37 (s, 9H), 1.08 (s, 9H). MS
(ESI) m/z: 597 [M + H].sup.+.
[Example 102] Preparation of
(E)-4-(5-hydroxy-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-phenylpen-
t-1-en-1-yl)phenol (30a)
##STR00373##
[0175] Step 1: Preparation of methyl
(E)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-phenyl-5-(4-(pivaloylo-
xy)phenyl)pent-4-enoate (H-2)
[0176] Compound H-1 (0.01 g, 0.02 mmol), 1-methylpiperizine (7
.mu.L, 0.06 mmol), and sodium triacetoxyborohydride
(NaBH(OAc).sub.3, 14 mg, 0.06 mmol) were added to dichloroethane (3
mL), and heated at 50.degree. C. for 12 hour. Water and ethyl
acetate were further added to the reaction solution and an organic
layer was extracted. The organic layer was dried with anhydrous
Na.sub.2SO.sub.4 and filtered. The solvent was distilled under
reduced pressure to obtain a residue, which was purified using
column chromatography, thereby obtaining 12 mg of the desired
compound H-2 (99%).
Step 2: Preparation of
(E)-4-(5-hydroxy-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-phenylpen-
t-1-en-1-yl)phenol (30a)
[0177] 2 mg of the desired compound 30a (18%) was obtained by the
same process as step 3 of Example 19, using compound H-2.
Example 103
[0178] Compound 30b was prepared, using the process of Example 102.
Identification data of the thus-prepared compounds 30a and 30b is
shown in the following Table 9.
TABLE-US-00009 TABLE 9 ##STR00374## Cmpd Example No. R
Identification data 102 30a OH .sup.1H-NMR(CD.sub.3OD, 400 MHz)
.delta. 7.19 (m, 2H), 7.16-7.10 (m, 5H), 7.07 (d, J = 8.4 Hz, 2H),
7.02 (d, J = 7.8 Hz, 2H), 6.80 (d, J = 8.3 Hz, 2H), 4.17 (s, 2H),
3.55 (m, 8H), 3.43 (t, J = 6.7 Hz, 2H), 2.96 (s, 3H), 2.55 (m, 2H),
1.56 (m, 2H). MS (ESI) m/z: 443 [M + H].sup.+. 103 30b NO.sub.2
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 8.26 (d, J = 7.9 Hz, 2H),
7.53 (d, J = 8.1 Hz, 2H), 7.31 (m, 2H), 7.17 (m, 5H), 7.06 (d, J =
7.2 Hz, 2H), 4.32 (s, 2H), 3.61 (m, 8H), 3.43 (t, J = 6.2 Hz, 2H),
2.98 (s, 3H), 2.53 (m, 2H), 1.56 (m, 2H). MS (ESI) m/z: 472 [M +
H].sup.+.
[Example 104] Preparation of
(Z)-4-(5-hydroxy-2-phenyl-1-(1-(2-(pyrrolidin-1-yl)ethyl)indolin-5-yl)pen-
t-1-en-1-yl)phenol (33)
##STR00375## ##STR00376##
[0179] Step 1: Preparation of methyl
(Z)-5-(indolin-5-yl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate
(I-2)
[0180] 0.2 g of the desired compound I-2 (99%) was obtained by the
same process as step 1 of Example 40, using compound I-1.
Step 2: Preparation of methyl
(Z)-4-phenyl-5-(4-(pivaloyloxy)phenyl)-5-(1-(2-(pyrrolidin-1-yl)ethyl)ind-
olin-5-yl)pent-4-enoate (I-3)
[0181] Compound I-2 (20 mg, 0.04 mmol), potassium carbonate (17 mg,
0.12 mmol), and sodium iodide (0.06 mg, 0.414 .mu.mol) were added
to dimethylformamide (1 mL), and stirred at room temperature for 12
hour. Saturated sodium hydrogen carbonate and ethyl acetate were
added to the reaction solution and an organic layer was extracted.
The organic layer was dried with anhydrous Na.sub.2SO.sub.4 and
filtered. The solvent was distilled under reduced pressure to
obtain a residue, which was purified using column chromatography,
thereby obtaining 3 mg of the desired compound I-3 (11%).
Step 3: Preparation of
(Z)-4-(5-hydroxy-2-phenyl-1-(1-(2-(pyrrolidin-1-yl)ethyl)indolin-5-yl)pen-
t-1-en-1-yl)phenol (33)
[0182] 1 mg of the desired compound 33 (55%) was obtained by the
same process as step 5 of Example 1, using compound I-3.
[0183] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.19-6.97 (m, 7H),
6.77 (d, J=8.5 Hz, 2H), 6.64 (m, 2H), 6.41 (d, J=8.7 Hz, 2H), 3.67
(m, 2H), 3.41 (m, 2H), 3.51 (m, 2H), 2.06 (m, 6H), 1.55 (m, 2H),
0.89 (m, 4H). MS (ESI) m/z: 469 [M+H].sup.+.
[Example 105] Preparation of
(Z)-4-(5-hydroxy-2-phenyl-1-(1-(2-(piperidin-1-yl)ethyl)-1H-indol-5-yl)pe-
nt-1-en-1-yl)phenol (36)
##STR00377## ##STR00378##
[0184] Step 1: Preparation of methyl
(Z)-5-(1H-indol-5-yl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate
(J-2)
[0185] 24 mg of the desired compound J-2 (99%) was obtained by the
same process as step 2 of Example 40, using compound J-1.
Step 2: Preparation of methyl
(Z)-4-phenyl-5-(1-(2-(piperidin-1-yl)ethyl)-1H-indol-5-yl)-5-(4-(pivaloyl-
oxy)phenyl)pent-4-enoate (J-3)
[0186] 9 mg of the desired compound J-3 (31%) was obtained by the
same process as step 1 of Example 104, using compound J-2.
Step 3: Preparation of
(Z)-4-(5-hydroxy-2-phenyl-1-(1-(2-(piperidin-1-yl)ethyl)-1H-indol-5-yl)pe-
nt-1-en-1-yl)phenol (36)
[0187] 2 mg of the desired compound 36 (18%) was obtained by the
same process as step 5 of Example 1, using compound J-3.
[0188] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.30-6.95 (m,
14H), 4.41 (m, 2H), 3.61 (m, 4H), 3.44 (m, 2H), 3.11 (m, 2H), 2.56
(m, 2H), 1.93 (m, 6H), 1.57 (m, 2H). MS (ESI) m/z: 481
[M+H].sup.+.
[Example 106] Preparation of
(Z)-4-(1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)phenyl)-5-hydroxy-2--
phenylpent-1-en-1-yl)phenol (38a)
##STR00379##
[0189] Step 1: Preparation of methyl
(E)-5-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)phenyl)-4-phenyl-5-(4-(-
pivaloyloxy)phenyl)pent-4-enoate (K-2)
[0190] Compound K-1 (10 mg, 0.02 mmol), 3-azabicyclo[3,1,0]hexane
(7 mg, 0.06 mmol), sodium iodide (0.3 mg, 2 .mu.mol), and
triethylamine (11 .mu.L, 0.08 mmol) were added to dimethylformamide
(1 mL), and heated at 80.degree. C. for 12 hours. The solvent was
distilled under reduced pressure to obtain a residue, which was
purified using column chromatography, thereby obtaining 6 mg of the
desired compound K-2 (53%).
Step 2: Preparation of
(Z)-4-(1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)phenyl)-5-hydroxy-2--
phenylpent-1-en-1-yl)phenol (38a)
[0191] 3 mg of the desired compound 38a (62%) was obtained by the
same process as step 5 of Example 1, using compound K-2.
Examples 107 to 109
[0192] Compounds 38b to 38d were prepared, using the process of
Example 106. Identification data of the thus-prepared compounds 38a
to 38d is shown in the following Table 10.
TABLE-US-00010 TABLE 10 ##STR00380## Cmpd Example No. R
Identification data 106 38a ##STR00381## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.16-7.07 (m, 5H), 7.02 (d, J = 8.4 Hz, 2H), 6.83
(d, J = 8.7 Hz, 2H), 6.76 (d, J = 2H), 6.65 (m, 2H), 4.17 (t, J =
4.4 Hz, 2H), 3.70 (m, 2H), 3.57 (t, J = 4.6 Hz, 2H), 3.46 (m, 2H),
3.41 (t, J = 6.7 Hz, 2H), 2.52 (m, 2H), 1.86 (m, 2H), 1.54 (m, 2H),
0.84 (m, 1H), 0.63 (m, 1H). MS (ESI) m/z: 456 [M + H].sup.+. 107
38b ##STR00382## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.16-7.07
(m, 5H), 7.02 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.76
(d, J = 8.5 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 4.19 (t, J = 4.7 Hz,
2H), 3.72 (m, 1H), 3.60 (m, 2H), 3.50 (m, 1H), 3.41 (t, J = 6.8 Hz,
2H), 3.15 (m, 1H), 2.52 (m, 2H), 2.06 (m, 1H), 1.92 (m, 1H), 1.69
(m, 9H), 1.54 (m, 2H). MS (ESI) m/z: 498 [M + H].sup.+. 108 38c
##STR00383## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.93 (s, 1H),
7.13-7.15 (m, 5H), 7.05 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz,
2H), 6.79 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 4.28 (t, J
= 10.0 Hz, 2H), 3.90 (m, 2H), 3.75 (m, 4H), 3.50 (m, 1H), 3.44 (t,
J = 6.8 Hz, 2H), 2.55 (m, 2H), 1.90-2.22 (m, 4H), 1.57 (m, 2H). MS
(ESI) m/z: 474 [M + H].sup.+. 109 38d ##STR00384##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.93 (s, 1H), 7.13-7.22
(m, 5H), 7.04 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.79
(d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 4.23 (m, 1H),
4.08-4.16 (m , 3H), 3.93 (m, 1H), 3.81 (m, 1H), 3.63 (m, 1H), 3.44
(t, J = 6.8 Hz, 3H), 2.55 (m, 2H), 1.92 (m, 1H), 1.79 (m, 1H), 1.59
(m, 2H), 0.93 (m, 2H). MS (ESI) m/z: 486 [M + H].sup.+.
[Example 110] Preparation of
(Z)-4-(1-(4-(2-(2,7-diazaspiro[4.4]nonan-2-yl)ethoxy)phenyl)-5-hydroxy-2--
phenylpent-1-en-1-yl)phenol (39)
##STR00385##
[0194] 0.8 mg of the desired compound 39 (24%) was obtained by the
same process as step 1 of Example 40, using compound Q.
[0195] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.18-7.07 (m, 5H),
7.0 (d, J=7.0 Hz, 2H), 6.83 (d, J=7.2 Hz, 2H), 6.76 (d, J=7.0 Hz,
2H), 6.68 (d, J=7.6 Hz, 2H), 4.23 (s, 2H), 3.81 (m, 2H), 3.66 (m,
2H), 3.41 (m, 8H), 2.51 (m, 2H), 2.21 (m, 4H), 1.54 (m, 2H). MS
(ESI) m/z: 499 [M+H].sup.+.
[Example 111] Preparation of
4-((Z)-1-(4-(2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethoxy)p-
henyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol (40)
##STR00386##
[0197] 2 mg of the desired compound 40 (19%) was obtained by the
same process as step 1 of Example 40, using compound R.
[0198] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.08-7.16 (m, 5H),
7.04 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.0 Hz, 2H), 6.79 (d, J=8.8 Hz,
2H), 6.70 (d, J=8.0 Hz, 2H), 4.31 (m, 2H), 4.04 (m, 2H), 3.83 (m,
1H), 3.68 (m, 3H), 3.36-3.49 (m, 8H), 2.55 (m, 2H), 1.57 (m, 2H).
MS (ESI) m/z: 485 [M+H].sup.+.
[Example 112] Preparation of
(Z)-4-(1-(4-(dimethyl((4-methylpiperazin-1-yl)methyl)silyl)phenyl)-5-hydr-
oxy-2-phenylpent-1-en-1-yl)phenol (42a)
##STR00387##
[0199] Step 1: Preparation of methyl
(Z)-5-(4-(dimethyl((4-methylpiperazin-1-yl)methyl)silyl)phenyl)-4-phenyl--
5-(4-(pivaloyloxy)phenyl)pent-4-enoate (L-2)
[0200] 8 mg of the desired compound I-2 (34%) was obtained by the
same process as step 1 of Example 106, using compound L-1.
Step 2: Preparation of
(Z)-4-(1-(4-(dimethyl((4-methylpiperazin-1-yl)methyl)silyl)phenyl)-5-hydr-
oxy-2-phenylpent-1-en-1-yl)phenol (42a)
[0201] 3 mg of the desired compound 42a (44%) was obtained by the
same process as step 5 of Example 1, using compound L-2.
Examples 113 to 116
[0202] Compounds 42b to 42e were prepared, using the process of
Example 112. Identification data of the thus-prepared compounds 42a
to 42e is shown in the following Table 11.
TABLE-US-00011 TABLE 11 ##STR00388## Cmpd Example No. R
Identification data 112 42a ##STR00389## .sup.1H-NMR(CD.sub.3OD,
400 MHz) .delta. 7.34 (d, J = 7.6 Hz, 2H), 7.20- 7.13 (m, 5H), 7.05
(d, J = 8.4 Hz, 2H), 7.00 (d, J = 7.6 Hz, 2H), 6.79 (d, J = 8.4 Hz,
2H), 3.67 (m, 8H), 3.43 (t, J = 6.7 hZ, 2H), 3.01 (m, 5H), 2.55 (m,
2H), 1.56 (m, 2H), 0.52 (s, 6H). MS (ESI) m/z: 501 [M + H].sup.+.
113 42b ##STR00390## .sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.29
(m, 2H), 7.12 (m, 5H), 7.00 (m, 4H), 6.77 (m, 2H), 3.42 (m, 2H),
3.25 (m, 2H), 2.83 (m, 4H), 2.54 (m, 2H), 1.77 (m, 4H), 1.55 (m,
2H). MS (ESI) m/z: 486 [M + H].sup.+. 114 42c ##STR00391##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.31 (m, 2H), 7.15-6.99
(m, 9H), 6.79 (d, J = 8.6 Hz, 2H), 3.44 (m, 4H), 2.93 (s, 2H), 2.83
(m, 2H), 2.56 (m, 2H), 2.06 (m, 2H), 1.93 (m, 2H), 1.57 (m, 2H),
0.44 (s, 6H). MS (ESI) m/z: 472 [M + H].sup.+. 115 42d ##STR00392##
.sup.1H-NMR(CD.sub.3OD, 400 MHz) .delta. 7.34 (d, J = 8.0 Hz, 2H),
7.17- 7.12 (m, 5H), 7.05 (m, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.79
(d, J = 8.5 Hz, 2H), 3.56 (s, 8H), 3.43 (t, J = 6.7 Hz, 2H), 3.02
(s, 2H), 2.55 (m, 2H), 1.56 (m, 2H), 0.52 (s, 6H). MS (ESI) m/z:
487 [M + H].sup.+. 116 42e ##STR00393## .sup.1H-NMR(CD.sub.3OD, 400
MHz) .delta. 7.30 (m, 2H), 7.13 (m, 5H), 7.01 (m, 4H), 6.77 (m,
2H), 4.26 (t, J = 6.2 Hz, 2H), 3.74 (m, 2H), 3.52 (m, 2H), 3.40 (m,
2H), 3.25 (m, 2H), 3.12 (m, 2H), 2.99 (s, 2H), 2.60 (m, 2H), 1.75
(m, 2H), 1.54 (m, 2H), 0.44 (s, 6H). MS (ESI) m/z: 513 [M +
H].sup.+.
[Example 117] Preparation of
(E)-N-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)-2--
(piperidin-1-yl)acetamide (44)
##STR00394##
[0203] Step 1: Preparation of methyl
(E)-4-phenyl-5-(4-(2-(piperidin-1-yl)acetamido)phenyl)-5-(4-(pivaloyloxy)-
phenyl)pent-4-enoate (M-2)
[0204] 7 mg of the desired compound M-2 (80%) was obtained by the
same process as step 1 of Example 106, using compound M-1.
Step 2: Preparation of
(E)-N-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)-2--
(piperidin-1-yl)acetamide (44)
[0205] 2 mg of the desired compound 44 (28%) was obtained by the
same process as step 5 of Example 1, using compound M-2.
[0206] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.25 (d, J=7.8 Hz,
2H), 7.17-7.10 (m, 5H), 7.05 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.6 Hz,
2H), 6.79 (d, J=8.5 Hz, 2H), 4.01 (s, 2H), 3.57 (m, 2H), 3.44 (t,
J=6.7 Hz, 2H), 3.05 (m, 2H), 2.55 (m, 2H), 1.90 (m, 6H), 1.56 (m,
2H). MS (ESI) m/z: 471 [M+H].sup.+.
[Example 118] Preparation of
(E)-4-(5-hydroxy-2-phenyl-1-(4-((2-(piperidin-1-yl)ethyl)amino)phenyl)pen-
t-1-en-1-yl)phenol (45)
##STR00395##
[0208] Compound 44 (10 mg, 0.02 mmol) was added to tetrahydrofuran
(2 mL), the temperature was lowered to 0.degree. C., and 1 M
lithium aluminum hydride (0.051 mL, 0.05 mmol) was added thereto.
Heating was performed at 60.degree. C. for 12 hour. Water and ethyl
acetate were further added to the reaction solution and an organic
layer was extracted. The organic layer was dried with anhydrous
Na.sub.2SO.sub.4 and filtered. The solvent was distilled under
reduced pressure to obtain a residue, which was purified using
column chromatography and then dissolved in
methanol:dichloromethane (1:1), the temperature was lowered to
0.degree. C., a 1M aqueous HCl solution was slowly added thereto,
and distillation under reduced pressure was performed, thereby
obtaining 0.5 mg of the desired compound 45 (6%).
[0209] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.15-7.07 (m, 5H),
7.01 (d, J=8.4 Hz, 2H), 6.74 (m, 4H), 6.50 (d, J=8.4 Hz, 2H), 3.61
(m, 2H), 3.48 (m, 2H), 3.40 (m, 6H), 2.51 (m, 2H), 1.81 (m, 4H),
1.55 (m, 4H). MS (ESI) m/z: 457 [M+H].sup.+.
[Example 119] Preparation of
2-((3aR,6aS)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(4-(-
(E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)acetamide
(46)
##STR00396## ##STR00397##
[0210] Step 1: Preparation of tert-butyl
(3aR,6aS)-5-(2-((4-((E)-5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl-
)pent-1-en-1-yl)phenyl)amino)-2-oxoethyl)-3a,6a-dimethylhexahydropyrrolo[3-
,4-c]pyrrole-2(1H)-carboxylate (N-1)
[0211] 11 mg of the desired compound N-1 (99%) was obtained by the
same process as step 1 of Example 106, using compound M-1.
Step 2: Preparation of tert-butyl
(3aR,6aS)-5-(2-((4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-
-yl)phenyl)amino)-2-oxoethyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrole-
-2(1H)-carboxylate (N-2)
[0212] 4 mg of the desired compound N-2 (39%) was obtained by the
same process as step 5 of Example 1, using compound N-1.
Step 3: Preparation of
2-((3aR,6aS)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(4-(-
(E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)acetamide
(46)
[0213] 1 mg of the desired compound 46 (38%) was obtained by the
same process as step 1 of Example 40, using compound N-2.
[0214] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.23 (d, J=8.4 Hz,
2H), 7.17-7.08 (m, 5H), 7.03 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.5 Hz,
2H), 6.77 (d, J=8.4 Hz, 2H), 4.24 (s, 2H), 3.43 (m, 8H), 2.52 (m,
2H), 1.52 (m, 4H). MS (ESI) m/z: 498 [M+H].sup.+.
[Example 120] Preparation of
(Z)-1-(4-(5-hydroxy-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylpent--
1-en-1-yl)phenyl)guanidine (50)
##STR00398##
[0215] Step 1: Preparation of
(Z)-5-(4-aminophenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpen-
t-4-en-1-ol (O-1)
[0216] Compound 26b (5 mg, 11 .mu.mol), N,N'-di-boc-thiourea (3 mg,
0.01 mmol), mercury (II) chloride (3 mg, 0.01 mmol), and
triethylamine (5 .mu.L, 0.03 mmol) were added to dimethylformamide
(1 mL), and heated at room temperature for 12 hours. The solvent
was distilled under reduced pressure to obtain a residue, which was
purified using column chromatography, thereby obtaining 6 mg of the
desired compound O-1 (84%).
Step 2: Preparation of
(Z)-1-(4-(5-hydroxy-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylpent--
1-en-1-yl)phenyl)guanidine (50)
[0217] 0.5 mg of the desired compound 50 (9%) was obtained by the
same process as step 1 of Example 40, using compound O-1.
[0218] MS (ESI) m/z: 498 [M+H].sup.+.
[Example 121] Preparation of
(E)-4-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)pip-
erazine-1-carboximidamide (52)
##STR00399##
[0219] Step 1: Preparation of tert-butyl
((E)-((tert-butoxycarbonyl)imino)(4-(4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-
-2-phenylpent-1-en-1-yl)phenyl)piperazin-1-yl)methyl)carbamate
(P-1)
[0220] 5 mg of the desired compound P-1 (36%) was obtained by the
same process as step 1 of Example 120, using compound 20c.
Step 2: Preparation of
(E)-4-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-i-en-1-yl)phenyl)pip-
erazine-1-carboximidamide (52)
[0221] 0.7 mg of the desired compound 52 (23%) was obtained by the
same process as step 1 of Example 40, using compound P-1.
[0222] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.16-7.07 (m, 5H),
7.01 (m, 2H), 6.78 (m, 2H), 6.67 (m, 2H), 6.40 (d, J=8.6 Hz, 2H),
3.67 (m, 2H), 3.28 (m, 2H), 3.48 (m, 1H), 3.41 (t, J=6.7 Hz, 2H),
3.19 (m, 2H), 3.13 (m, 1H), 2.51 (m, 2H), 1.54 (m, 2H). MS (ESI)
m/z: 457 [M+H].sup.+.
[Experimental Example 1] ERR.gamma., ERR.alpha., ERR.beta.,
ER.alpha. Binding Assay
[0223] 1) ERR.gamma. Binding Assay (Inverse Agonist Assay)
[0224] The arylethene derivative of the present invention was
sequentially added to a 384 well plate from a concentration of 10
.mu.M to a final concentration of two-fold dilution. Then, a
GST-bound ERR gamma ligand-binding domain (LBD) was added to a
final concentration of 5 nM, and a fluorescein-conjugated
coactivator PGC1a and a Tb-a-GST antibody were added to 500 nM and
5 nM, respectively. After all reagents were added, a reaction was
carried out with gentle shaking at 20.degree. C. for 1 hour, and
after the reaction, a binding activity was measured by a TR-FRET
method. That is, excitation at 340 nm was performed, each emission
value at 495 nm and 520 nm was measured, the result assay was a
value measured at 490 nm/a value measured at 520 nm, and an
analysis program was Prism 6.
[0225] 2) ERR.alpha./ERR.beta./ER.alpha. Binding Assay (Selectivity
Test)
[0226] In an ERR alpha binding assay, GST-bound ERR alpha LBD was
used, and all experiments other than that was the same as the ERR
gamma binding assay.
[0227] In an ERR beta binding assay, GST-bound ERR alpha LBD was
used so that a final concentration was 10 nM and a
fluorescein-conjugated coactivator PGC1a was 250 nM, and all
experiments other than that was the same as the ERR gamma binding
assay.
[0228] In an ER alpha binding assay, a GST-bound ER alpha
ligand-binding domain (LBD) was added to a 384 well plate to which
the arylethene derivative of the present invention was added to a
final concentration of 7.3 nM. Then, a fluorescein-conjugated
coactivator PGC1a and a Tb-a-GST antibody were added to 250 nM and
5 nM, respectively, and beta-estradiol as an agonist was added to a
final concentration of 4 nM. All subsequent experiments was the
same as the ERR gamma binding assay.
[0229] The results of Experiment Example 1 are shown in the
following Table 12.
TABLE-US-00012 TABLE 12 Binding Assay, IC50 (.mu.M) Example Cmpd
No. ERR.gamma. ERR.alpha. ERR.beta. ER.alpha. 4 6d 0.093 >10
0.262 5 6e 0.067 >10 0.408 6 6f 0.059 >10 0.296 7 6g 0.030
>10 0.331 8 6h 0.042 >10 1.1 10 6j 0.034 11 6k 0.026 16 13b
0.064 >10 3.928 >10 20 18a 0.040 >10 1.33 1.24 21 18b
0.017 >10 0.861 >10 23 18d 0.060 >10 1.7 24 18e 0.060
>10 2.8 >10 25 18f 0.026 >10 1.017 >10 27 18h 0.032
>10 0.99 >10 28 18i 0.050 >10 3.04 1.142 29 18j 0.025
>10 1.045 >10 30 18k 0.035 >10 >10 1.943 33 18n 0.029
8.25 1.09 8.8 40 20a 0.028 8.65 0.98 >10 41 20b 0.027 >10
2.097 >10 49 20j 0.048 >10 4.93 0.992 58 22g 0.095 >10
6.766 4.371 60 22i 0.056 >10 1.665 2.093 62 22k 0.049 >10
4.822 1.381 64 22m 0.078 >10 7.818 >10 67 22p 0.099 9.7 1.648
2.116 68 22q 0.053 >10 2.002 1.658 71 22t 0.096 >10 3.564
5.94 87 27a 0.026 4.318 0.07 0.413 106 38a 0.079 >10 8.13 0.437
107 38b 0.050 >10 3.07 0.256 108 38c 0.091 >10 >10 0.408
109 38d 0.083 >10 8.8 0.276 GSK5182 0.107 >10 >10 2
[Experimental Example 2] ERR.gamma. Inverse Agonist Functional
Assay
[0230] AD293 was cultured in a 24-well plate for 24 hours, using a
DMEM High glucose culture medium (Hyclone, USA) to which 0.5% FBS
was added at a concentration of 9.times.10.sup.4/well. The culture
medium was replaced with a DMEM High glucose culture medium to
which 10% FBS was added, treatment was performed with a mixture of
a TransIT-LT1 transfection reagent (Mirus, USA) and
pCMX-Gal4-ERR.gamma., pFR-luciferase reporter plasmid,
pCMV-.beta.-gal, and culturing was performed for 24 hours.
Thereafter, a luciferase activity assay and a .beta.-gal assay were
performed, respectively, with a lysate obtained after treatment
with the arylethene derivative of the present invention for 24
hours. All results were derived from three or more independent
repetitive experiments.
[0231] The results are shown in the following Table 13, in which
"Cpds" refers to an inverse agonist functional activity when the
compound was treated, "Ref 5182" refers to an activity of a
reference compound GSK5182 for data verification for every essay,
and "Cpds/Ref 5182" refers to an activity degree of the arylethene
derivative of the present invention, relative to the reference
compound.
TABLE-US-00013 TABLE 13 Functional Assay at 10 .mu.M (% of control)
Example Cmpd No. Cpds Ref 5182 Cpds/Ref 5182 2 6b 7.97 3.08 2.59 3
6c 4.64 3.08 1.51 4 6d 5.2 3.08 1.69 5 6e 5.61 3.08 1.82 6 6f 6.75
3.08 2.19 7 6g 4.94 3.08 1.60 8 6h 5.49 3.08 1.78 9 6i 5 3.08 1.62
10 6j 2.44 3.15 0.77 11 6k 2.5 3.15 0.79 14 7a 2.71 3.15 0.86 16
13b 1.5 3.15 0.48 17 13c 10.58 3.15 3.36 20 18a 4.83 4.09 1.18 21
18b 2.45 3.15 0.78 22 18c 1.31 3.15 0.42 23 18d 9.65 9.97 0.97 24
18e 2.6 2.93 0.89 25 18f 2.57 3.15 0.82 26 18g 1.62 1.93 0.84 27
18h 4.47 4.09 1.09 28 18i 1.88 1.93 0.97 29 18j 3.28 2.72 1.21 30
18k 1.08 0.95 1.14 32 18m 2.97 2.93 1.01 33 18n 3.36 4.09 0.82 34
18o 23.2 9.97 2.33 38 18s 2.92 2.93 1.00 19 18t 11.1 9.97 1.11 39
18u 5.33 0.95 5.61 40 20a 3.15 4.09 0.77 41 20b 3.58 4.09 0.88 42
20c 2.72 2.93 0.93 43 20d 3.32 4.09 0.81 44 20e 10.8 9.97 1.08 45
20f 5.76 2.93 1.97 47 20h 3.57 3.15 1.13 49 20j 1.41 1.02 1.38 52
22a 3.1 4.09 0.76 53 22b 2.94 4.09 0.72 55 22d 1.96 3.15 0.62 56
22e 1.93 3.15 0.61 58 22g 1.84 1.93 0.95 59 22h 0.6 0.93 0.65 60
22i 3.37 2.72 1.24 62 22k 0.77 0.93 0.83 64 22m 0.75 0.93 0.81 65
22n 3.47 2.72 1.28 69 22r 0.64 0.95 0.67 70 22s 6.33 5.97 71 22t
6.19 5.97 72 22u 5.12 5.97 73 22v 5.51 5.97 80 22ac 0.61 0.93 0.66
82 22ae 0.67 0.93 0.72 83 26a 2.66 3.15 0.84 85 26c 4.56 0.95 4.80
87 27a 2.1 2.72 0.77 95 28a 1.14 0.95 1.20 98 28d 1.69 0.95 1.78 99
28e 4.76 4.09 1.16 100 28f 4 4.09 0.98 101 28g 5.1 4.09 1.25 102
30a 2.94 0.95 3.09 106 38a 1.45 1.02 1.42 107 38b 1.27 1.02 1.25
108 38c 4.06 4.09 0.99 109 38d 3.16 4.09 0.77 110 39 3.38 1.02 3.31
111 40 2.8 2.93 0.96 112 42a 4.37 2.93 1.49 113 42b 11.6 9.97 1.16
114 42c 2.6 2.93 0.89 115 42d 11.7 2.93 3.99 116 42e 26.04 4.09
6.37 117 44 12.94 4.09 3.16 118 45 1.58 1.02 1.55 119 46 78.46 3.15
24.91 GSK5182 3~10
[Experimental Example 3] In Vitro Absorption, Distribution,
Metabolism, Excretion, and Toxicity (ADME)/Tox Evaluation
[0232] 1) Cytochrome P450 (CYP450) Activity Inhibition
Evaluation
[0233] Human liver microsomes (0.25 mg/ml) with 0.1 M phosphate
buffer solution (pH 7.4), a substrate drug cocktail of five drug
metabolizing enzymes (Phenacetin 50 .mu.M, Diclofenac 10 .mu.M,
S-mephenytoin 100 .mu.M, Dextromethorphan 5 .mu.M, Midazolam 2.5
.mu.M), and the arylethene derivative of the present invention were
added at concentrations of 0 .mu.M and 10 .mu.M, respectively,
culturing was performed at 37.degree. C. for 5 minutes in advance,
a NADPH generation system solution was added, and culturing was
performed at 37.degree. C. for 15 minutes. Thereafter, in order to
complete the reaction, an acetonitrile solution containing an
internal standard material (Terfenadine) was added thereto,
centrifugation (14,000 rpm, 4.degree. C.) was performed for 5
minutes, and a supernatant was injected into a LC-MS/MS system to
analyze the metabolites of the substrate drug, thereby evaluating
drug metabolism enzyme inhibition by the arylethene derivative of
the present invention.
[0234] The results are shown in the following Table 14.
TABLE-US-00014 TABLE 14 Cmpd CYP inhibition (% of control) Example
No. 1A2 2C9 2C19 2D6 3A4 3 6c 91.9 77.9 81.6 96.4 81.3 5 6e 79.6
51.6 64.1 80.6 68.1 7 6g 97.8 75.4 81.8 81.7 83.7 8 6h 103 62.8
83.2 90.7 75.4 9 6i 98.1 86.7 82.6 93.6 79.4 10 6j 98.7 85.6 89.1
85.2 74.6 18 13d >100 97 89.4 >100 90.2 20 18a 88 86.1 81.2
63.5 66.4 21 18b 89.8 73.4 69.7 68.9 53 22 18c 92.2 81.7 80 75.6
64.1 23 18d 88 67.7 81.2 98.4 64 24 18e >100 91.3 84.6 >100
84 25 18f >100 62.3 72.8 68.2 70.9 27 18h 93.5 96.9 86.3 71.5
64.5 29 18j >100 87 74 86.6 77.6 38 18s >100 81.8 82.4
>100 77.9 19 18t 100 83 93 98 106 40 20a 85 76 61.9 70.7 55 49
20j 93.6 77.1 62 89.3 66.2 50 20k 79.3 87.6 78.9 96.2 83.6 53 22b
100.4 98.4 96.6 93.5 90.8 55 22d >100 >100 >100 82.5 66.1
56 22e 94.9 61.3 58.4 71.8 58.2 59 22h >100 97.9 >100 69.1
72.2 61 22j 95.7 88 89.6 97.1 85 62 22k >100 97 >100 73.7
74.7 63 22l 96.2 88.3 97 99 80.7 64 22m 97 80.3 >100 70.7 58.1
65 22n 99 97.4 83 82.6 88.3 67 22p 88.1 81.8 61.5 79.6 90.6 68 22q
99.9 77.7 92.8 77.6 81 69 22r >100 >100 >100 91.8 82.7 80
22ac >100 >100 >100 86.2 85 82 22ae 59.4 >100 >100
68.4 81.5 83 26a >100 53.2 89 85.5 75.4 84 26b 99.2 92.5 98.7
81.9 60.9 86 26d >100 96.6 >100 86.1 57.3 108 38c 79.2 55.3
58.8 54.3 61.5 109 38d 79.2 55.3 58.8 54.3 57.6 110 39 82.5 74.4
73.9 67.8 59 GSK5182 84.6 72.9 78.2 82.3 83
[0235] 2) Microsomal Stability Evaluation
[0236] Four liver microsomes (Human, Dog, Rat, Mouse 0.5 mg/ml)
with a 0.1 M phosphate buffer solution (pH 7.4), and the arylethene
derivative of the present invention were added to a concentration
of 1 .mu.M, culturing was performed at 37.degree. C. for 5 minutes
in advance, a NADPH regeneration system solution was added thereto,
and culturing was performed at 37.degree. C. for 30 minutes.
Thereafter, in order to complete the reaction, an acetonitrile
solution containing an internal standard material (chlorpropamide)
was added thereto, centrifugation (14,000 rpm, 4.degree. C.) was
performed for 5 minutes, and a supernatant was injected into a
LC-MS/MS system to analyze the substrate drug, thereby evaluating
metabolism stability to the arylethene derivative of the present
invention.
[0237] The results are shown in the following Table 15.
TABLE-US-00015 TABLE 15 MS (Microsomal Stability) (%) Example Cmpd
No. human dog rat mouse 3 6c 128.0 45.2 14 7a 49.0 64.7 59.5 32.1
16 13b 61.2 66.2 18 13d 67.3 59.9 21 18b 54.2 40.0 19.7 22 18c 96.9
72.8 25 18f 79.2 65.7 47.6 26 18g 87.9 84.9 85.3 84.1 27 18h
>100 64.4 74.2 48.5 29 18j 67.9 58.0 62.8 54.9 30 18k 65.4 61.2
54.9 26.9 19 18t 66.9 80.5 40 20a 65.1 84.7 41 20b 44 58 71.5 28.8
42 20c 55.8 53.7 43 20d 83 54 11.3 44 20e 78.1 82.1 45 20f 83.9
99.5 49 20j 76.8 68.3 84.5 25.3 50 20k 93.6 84.9 89.0 81.3 53 22b
63.0 28.1 42.5 6.4 55 22d 57.6 60.2 57 22f 97.0 78.1 80.0 66.3 58
22g 42.8 54.3 43.2 10.7 59 22h 46.9 22.4 43.8 16.2 60 22i 36.0 91.5
92.6 83.6 61 22j 65.2 54.9 65.5 34.9 62 22k 59.7 59.6 69.0 23.4 63
22l 71.8 67.9 53.4 25.8 64 22m 55.3 55.0 53.5 24.2 65 22n 56.3 72.0
47.8 37.8 67 22p 72.3 77.7 75.3 40.4 68 22q 63.7 43.8 67.6 17.6 69
22r 62.0 56.9 49.9 24.5 70 22s 34.9 35.4 75.6 21.7 72 22u 40.0 10.0
44.3 17.2 82 22ae 48.4 33.7 32.2 21.5 83 26a 72.3 46.7 84 26b 49.1
40.6 31.4 14.3 86 26d 77.5 51.5 72.2 38.3 87 27a 66.2 50.3 65.0
32.7 89 27c 83.5 81.2 79.4 42.1 90 27d 63.7 43.8 67.6 17.6 99 28e
56.4 59.6 107 38b 41.8 41.8 53.4 38.4 109 38d 6.9 11.7 11.8 110 39
71.1 88.4 69.9 63.1 111 40 64.7 72.0 GSK5182 42.8-45.1 9.6
26.0-29.1 6.8
[0238] 3) Parallel Artificial Membrane Permeability Assay (PAMPA)
Evaluation
[0239] PAMPA is a method which has been developed for testing cell
membrane permeability of a material in a test tube, and has been
performed using a lipid tri-layer PVDF membrane available from
Corning Gentest (NY, US), the used reagents were all purchased from
Sigma (MO, US). First, a test material is diluted in PBS (pH 7.4)
to a final concentration of 10 mM, 300 mL of the solution is added
to the bottom well of a 96-transwell equipped with a PVDF membrane,
and 200 mL of PBS is added to the upper well. Then, a plate is
reacted at 25.degree. C. for 5 hours, 20 mL of the solution in each
well is transferred to a new container, and 80 mL of acetonitrile
containing an internal standard material (4 mM chloropropamide) is
added thereto. A concentration of the material in the solution is
analyzed using LC-MS/MS (ThermoFisher Scientific, MO, US), and the
transmittance of the material is calculated according to the
equation reported in the reference document.
[0240] Reference document: A novel design of artificial membrane
for improving the PAMPA model. Chen X, Murawski A, et al.
Pharmaceutical Research. 25:1511, 2007
[0241] The results are shown in the following Table 16.
TABLE-US-00016 TABLE 16 Permeability Example Cmpd No. Pampa
(10.sup.-6 cm/s) 11 6k 0.12 16 13b 0.93 18 13d 0.14 20 18a 0.46 21
18b 2.09 22 18c 5.73 23 18d 0.14 24 18e 1.11 25 18f 4.84 26 18g 4.8
27 18h 0.37 28 18i 1.16 29 18j 1.61 30 18k 1.29 33 18n 0.63 38 18s
0.18 40 20a 0.52 41 20b 3.61 43 20d 0.23 45 20f 0.14 55 22d 0.38 56
22e 6.16 57 22f 3.96 60 22i 0.35 67 22p 0.2 68 22q 0.77 83 26a 1.58
86 26d 1.04 87 27a 2.22 89 27c 0.68 90 27d 0.34 113 42b 0.1 GSK5182
0.11~0.82
[0242] 4) hERG channel binding inhibition evaluation
[0243] An E-4031 (effective IC50: 10-90 nM) compound as a positive
control was diluted stepwise with 3-fold, a pre-prepared membrane
containing a hERG channel and a fluorescent tracer were mixed and
reacted for 4 hours, and then a polarization values for each
concentration were measured to obtain IC.sub.50. For the arylethene
derivative of the present invention, fluorescence intensity
(excitation at 530 nm, emission at 590 nm) at a concentration of
stepwise diluted 16 points was measured and compared with a DMSO
solvent control.
[0244] A hERG fluorescence polarization assay (Invitrogen: PV5365)
kit was used.
[0245] The results are shown in the following Table 17.
TABLE-US-00017 TABLE 17 Example Cmpd No. hERG IC50 (.mu.M) 4 6d
>30 6 6f >30 7 6g 5.4 8 6h 18.0 9 6i >30 20 18a 18.7 21
18b >30 22 18c 11.6 23 18d >20 25 18f 18.9 26 18g 17.9 27 18h
15.3 28 18i >30 29 18j 17.0 30 18k 24.6 41 20b 7.1 43 20d 15.0
49 20j 12.7 50 20k 26.1 55 22d 6.0 56 22e 20.7 57 22f 5.8 58 22g
22.0 60 22i >30 61 22j 8.8 65 22n 14.6 68 22q 10.9 69 22r 16.4
70 22s 10.6 72 22u 6.1 73 22v 5.8 83 26a >30 86 26d 26.0 106 38a
16.1 110 39 9.5 GSK5182 >30
[Experimental Example 4] In Vivo Pharmacokinetics (In Vivo PK)
Evaluation
[0246] In order to investigate pharmacokinetic behavior when
intravenously or orally administrating the compound of the present
invention to a rat, rats weighing at least 200 g were used to
perform the following experiment, and the results are shown in the
following Table 18.
[0247] A. Experimental Method
[0248] 1. An oral administration group fasts the day before.
[0249] 2. Blood of each animal is collected at 0 hour.
[0250] 3. Into a tail vein of an intravenous administration group
(IV), a drug is injected at a dose of 1 mg/kg (syringe).
[0251] 4. To an oral administration group (PO), a drug is orally
administered at a dose of 10 mg/kg (oral zondec)
[0252] 5. After administration, blood of the intravenous
administration group was collected through a jugular vein 8 times
at 0.08, 0.25, 0.5, 1, 2, 4, 6, and 8 hours. One collected blood
amount is 400 to 500 ul.
[0253] 6. After administration, blood of the oral administration
group was collected through a jugular vein 6 times at 0.25, 0.5, 1,
4, 6 and 8 hours. One collected blood amount is 400 to 500 ul.
[0254] 7. Each blood is mixed with a 3.8% sodium citrate solution
and stored on ice.
[0255] 8. Supernatant plasma is collected by a centrifuge.
[0256] 9. The supernatant plasma was injected into a LC-MS/MS
system and the drug is analyzed.
TABLE-US-00018 TABLE 18 Cmpd Administration AUC.sub.all AUC.sub.INF
BA C.sub.max Cl(observed)/F T.sub.max t.sub.1/2 V.sub.SS Example
No. group (.mu.Mh) (.mu.Mh) (%) (.mu.M) (mL/min/kg) (h) (h) (L/Kg)
GSK5182 IV 0.89 0.94 44 2.3 9.1 PO 0.68 0.78 8.4 0.13 134 1.9 20
18a IV 0.42 0.49 75 3.8 25.2 PO 0.81 1.29 21.4 0.21 277 1.1 21 18b
IV 0.58 0.64 58 3.1 9.8 PO 0.31 0.36 8.7 0.12 1065 0.6 24 18e IV
0.06 0.06 546 0.8 39.1 PO 0.07 0.09 11.5 0.01 430 2.8 25 18f IV
0.28 0.29 139 2.5 30.3 PO 2.93 7.00 41.2 0.45 2.4 29 18j IV 0.55
0.60 59 3.2 9.8 PO 1.07 1.61 19.6 0.21 3 30 18k IV 0.99 1.00 37 1.2
3.0 PO 4.18 4.71 42.4 0.97 1.7 2.4 44 20e IV 0.28 0.34 139 4.4 52.8
PO -- -- -- -- 60 22i IV 0.49 0.54 69 3.0 11.7 PO 2.24 4.52 45.3
0.38 2.2 64 22m IV 0.34 0.00 110 2.4 19.9 PO 0.73 0.00 24.3 0.13
2.4 4.3 69 22r IV 0.85 0.87 45 1.8 4.6 PO 4.93 5.29 58.2 1.51 1 2.3
70 22s IV 0.44 81.1 2.2 13.2 PO 0.09 0.11 18.5 0.02 2855 1.3
[Experimental Example 5] Experiment on Anaplastic Thyroid
Cancer
[0257] 1. Materials and Method
[0258] 1.1. Cells
[0259] CAL-62 which is an anaplastic thyroid cancer cell line was
purchased from Deutsche Sammlung von Mikroorganismen und
Zellkulturen. The cell lines were all maintained in a DMEM medium
highly supplemented with 10% FBS, 1% antibiotic-antifungal agent
(Hyclone), at 37.degree. C. under the atmosphere of 5% CO.sub.2. A
retrovirus from which an enhanced firefly luciferase gene (effluc)
is expressed was treated with CAL-62 cells to establish cell lines
in which the effluc genes are stably expressed. The
thus-established cell lines were referred to as CAL-62/effluc
cells.
[0260] 1.2. .sup.125I Uptake Assay
[0261] The cells were plated in a 24-well plate for 24 hours,
treated with compound 18a, produced into a 100 mM stock solution in
DMSO, and stored at -80.degree. C. for 24 hours. After adsorbing a
drug-containing medium, the cells were washed with 1 mL of HBSS,
and incubated with 500 t of a Hank' balanced salt solution (HBSS)
containing 0.5% bovine serum albumin (bHBSS), 3.7 kBq carrier-free
.sup.125I (Perkin-Elmer), and 10 .mu.mol/L of sodium iodide
(inactive 740 MBq/mmol) at 37.degree. C. for 30 minutes.
Thereafter, the cells were washed twice with ice-cold bHBSS, and
lysed with 500 .mu.l of 2% sodium dodecyl sulfate (SDS).
Radioactivity was measured using a gamma counter (Cobra II;
Canberra Packard, Packard Bioscience). The radioactivity of the
cells was normalized using a total protein concentration determined
by a BCA kit (Pierce Protein Biology).
[0262] 1.3. .sup.125I Uptake Assay Depending on Compound 18a Drug
Concentration
[0263] The cells were treated with compound 18a at various
concentrations (vehicle, 6, 12 uM), and then a .sup.125I uptake
test was performed as described above.
[0264] 1.4. .sup.125I uptake inhibition assay by KClO.sub.4
[0265] The cells were pre-incubated with 300 .mu.M KClO.sub.4 (as a
specific inhibitor to NIS) for 30 minutes to inhibit iodine uptake,
and then a .sup.125I uptake test was performed as described
above.
[0266] 1.5. .sup.125I uptake inhibition assay by MAK kinase
inhibitor The cells were pre-incubated with PD98059 or U0126 (as a
specific inhibitor to MAP kinase) for 30 minutes to inhibit iodine
uptake, and then a 125I uptake test was performed as described
above.
[0267] 1.6 Quantitative RT-PCR
[0268] Total RNA was separated using Trizol (Invitrogen, Carlsbad,
Calif.). Total RNA (2 ug) was reverse-transcribed into cDNA with
RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific,
Pittsburgh, Pa.). Genes were amplified with a ViiA 7 Real-Time PCR
System instrument (Applied Biosystems) using the primer of each
target gene and YBR Green PCR master mix (Applied Biosystems,
Foster City, Calif.), using a cDNA template. The primer sequence of
each target gene is as follows: ERR.gamma. (forward, 5'-CAG ACG CCA
GTG GGA GCT A-3'; reverse, 5'-TGG CGA GTC AAG TCC GTT CT-3'), NIS
(forward, 5'-TCT AAC CGA TGC TCA CCT CTT CTG-3'; reverse, 5'-AGA
TGA TGG CAC CTC CTT GAA CC-3'), and acidic ribosomal protein 36B4
(forward, 5'-CCA CGC TGC TGA ACA TGC T-3'; reverse, 5'-TCG AAC ACC
TGC TGG ATG AC-3'). Each target gene was normalized using a 36B4
gene.
[0269] 1.7. Clonogenic Assay
[0270] The cells were plated in a 6-well plate, and allowed to
stand for 24 hours. The cells were treated with 12 .mu.M compound
18a for 24 hours, the drug-containing medium was discarded, and the
cells were washed twice with PBS. Thereafter, the medium was
replaced with DMEM for 6 hours in the presence or absence of 50
.mu.Ci .sup.131I (KIRAMS, Korea). The cells were washed with cold
bHBSS, and allowed to stand in a normalized culture medium for a
time corresponding to six doublings. Finally, the cells were fixed
in a 4% paraformaldehyde (PFA) solution and stained with 0.05%
crystal violet. Control colonies having more than 50 cells and
.sup.131I-treated colonies were counted.
[0271] 1.8. Western Blot
[0272] The cells were treated with or without compound 18a for 24
hours, washed twice with cold PBS, and lysed with a RIPA (Roche)
buffer containing a complete protease inhibitor cocktail. In the
case of cell membrane protein for NIS, samples were prepared using
a protein biotinylation kit (EZ-Link.TM. Sulfo-NHS-Biotin, Thermo
Scientific) according to the manufacturer's instruction. Briefly,
any one of non-treated cells or treated cells were washed twice
with ice-cold PBS/CM (PBS containing 0.1 mM calcium chloride and 1
mM magnesium chloride, pH 7.3), and incubated with EZ link
NHS-sulfo-SS-biotin in PBS/CM (1 mg/mL) at 4.degree. C. for 30
minutes. The reaction was quenched by washing twice using cold 100
mM glycine in PBS/CM, and further incubated with 100 mM glycine in
PBS/CM at 4.degree. C. for 20 minutes. Thereafter, the cells were
constantly shaken at 4.degree. C. for 1 hour, and rapidly washed
twice using PBS/CM before being lysed using a RIPA buffer (Roche)
containing a protease inhibitor cocktail and a phosphatase
inhibitor. The lysate was centrifuged at 16,000 g, at 4.degree. C.
for 30 minutes. A portion of the supernatant was used for a total
cell protein immune blot. The remaining sample was incubated with
100 .mu.L streptavidin beads (Thermo Scientific) at room
temperature for 1 hour to be used for obtaining membrane protein.
The beads were washed three times using a RIPA buffer, the bound
protein was eluted using 50 .mu.L of Laemmli buffer (62.5M Tris, pH
6.8; 20% glycerol; 2% SDS; 5% b-mercaptoethanol; and 0.01%
bromophenol blue) at room temperature for 30 minutes. Equivalent
amounts of the total cell membrane protein and biotinylated cell
membrane protein were loaded on each lane, and resolved by a
Bis-Tris gel (Invitrogen) with a 4-12% slope. The protein was moved
to a 0.2 .mu.m PVDF membrane (Invitrogen). The membrane was
incubated with a primary rat monoclonal human NIS-specific antibody
(dilution 1:1000, Thermo Scientific, Catalog#: MS-1653-P1, clone:
FP5A), and then incubated with a HRP-conjugated secondary antibody
at room temperature. ECL-Plus (Amersham Pharmacia) was used for
detecting a peroxidase activity, depending on the manufacturer's
method. Similarly, even in the case of other protein, an equivalent
amount of protein was loaded to each lane, and resolved by a
Bis-Tris gel (Invitrogen) with a 4-12% slope. The protein was moved
to a 0.2 .mu.m PVDF membrane (Invitrogen). The membrane was
incubated with a primary antibody (ERR.gamma., pERK1/2,
.beta.-actin) at 4.degree. C. for one night, and then incubated
with an appropriate HRP-conjugated secondary antibody at room
temperature. According to the manufacturer's protocol, the
peroxidase activity was detected using ECL-Plus. A band density was
determined using an ImageJ software.
[0273] 1.9. Animal Experiment
[0274] Nude mice (Balb/c nu/nu, female, 6 weeks old) were used, and
all animals were normally raised in DMRC center animal laboratory
of Kyungbuk National University Hospital in Chilgok.
5.times.10.sup.6 CAL-62/effluc cells were subcutaneously injected
into the left femoral region of the nude mouse to form a tumor. The
tumor was extracted, divided into small pieces (20 mg or more), and
then intradermally injected into the nude mouse to form a
tumor.
[0275] After forming the tumor, the CAL-62/effluc mouse tumor model
was divided into the following groups: Group 1: vehicle, Group 2:
100 mpk compound 18a, Group 3: 100 mpk compound 18a. To the mice of
each group, the vehicle (100% PEG) and compound 18a (100 mpk, 200
mpk) were orally administered daily for 6 days. In order to observe
a difference in tumor growth between before administration and
after administration, optical imaging (bioluminescent imaging) was
performed. While the drug was administered, a weight change of the
mouse was observed every other day.
[0276] In addition, in order to confirm a change in a 125I uptake
increase in the CAL-62/effluc tumor, an organ distribution study
(Bio-distribution study) was performed as follows. After finally
administrating the drug, .sup.125I (5 uCi/mouse) was administered
to the mouse by intravenous injection on the next day. After 4
hours of administration, all organs including a parent tumor were
extracted, and each organ was weighed. Thereafter, each organ was
transferred to a 5 mL test tube, and radioactivity in the organ was
measured using a gamma counter. A .sup.125I uptake degree in the
organ was expressed by percentage injected dose per gram (%
ID/g).
[0277] 1.10. Animal Image
[0278] For obtaining an optical image, D-luciferin (3 mg/mouse) was
intraperitoneally injected to the mouse. After about 10 minutes of
injection, the mouse was anesthetized by inhalation (1-2%
isoflurane gas), and then positioned on a IVIS Lumina III
(PerkinElmer) imaging bed. The time for obtaining the image was
automatically set, and then an optical image was obtained. A Living
imaging software (version 2.12, PerkinElmer) was used to quantify
an optical image signal from the tumor.
[0279] 1.11. Statistical Analysis
[0280] All data was represented as an average .+-., and statistical
significance was determined using a Student test of GraphPad Prism
5. A P value <0.05 was regarded as being statistically
significant.
[0281] 2. Results
[0282] 2.1 Increased Radioactive Iodine Uptake in ATC Cells by
Compound 18a
[0283] After treatment with compound 18a, a significant increase of
radioactive iodine uptake in CAL62 cells was confirmed for each
concentration and each time (FIGS. 1 and 2). A maximum increase of
iodine uptake was observed at a concentration of 12 uM of compound
18a. In order to test whether the increased radioactive iodine
uptake is related to regulation of a NIS function by compound 18a,
KClO.sub.4 which is an inhibitor specific to NIS was co-incubated
with compound 18a-treated CAL62 cells, and a change in a
radioactive iodine uptake level was observed. KClO.sub.4 completely
blocks radioactive iodine uptake which was increased in the
compound 18a-treated cells (FIG. 3), which implies that the
increased iodine uptake is directly related to the improved
functional activity of NIS mediated by compound 18a.
[0284] 2.2 Endogenous ERR.gamma. and NIS mRNA Expression Regulation
by Compound 18a in ATC Cells
[0285] In order to determine the effect of compound 18a on an
ERR.gamma. mRNA level in ATC cells, real-time PCR was performed
using ERR.gamma.- and NIS-specific primers. As a result of
treatment with compound 18a, it was confirmed that ERR.gamma. mRNA
expression in CAL62 cells were significantly decreased (FIG. 4),
and when compared with the vehicle treated group, the expression
was decreased by about 16 times. However, it was confirmed that NIS
mRNA expression was increased by about 2 times when compared with
the vehicle-treated group.
[0286] 2.3 Endogenous ERR.gamma. Protein Regulation by Compound 18a
in ATC Cells
[0287] In order to determine the effect of compound 18a on an
ERR.gamma. protein level in ATC cells, immune blotting assay was
performed using ERR.gamma.-specific antibody. As a result of
treatment with compound 18a, it was confirmed that ERR.gamma.
protein expression in CAL62 cells were significantly decreased
(FIG. 6), and when compared with the vehicle treated group, the
expression was decreased by about 2.8 times (FIG. 7).
[0288] 2.4 Increase of Membrane-Localized NIS Protein in ATC Cells
Through Activation of Endogenous MPA Kinase Signaling by Compound
18a in ATC Cells
[0289] A significant increase in a phosphorylated MPP kinase level
such as p44 and p42 ERK was found in ATC cells treated with
compound 18a (FIG. 8). The relative increase of the phosphorylated
forms oERK1 and ERK2f was 2.2 times and 2.8 times, respectively
(FIG. 9).
[0290] The radioactive iodine uptake increase (FIGS. 10 and 11) and
the relative increase of the phosphorylated form of ERK1 and ERK2
by compound 18a were completely inhibited by selective MEK
inhibitors, PD98059 and U0126 (FIGS. 12 and 13).
[0291] In order to determine the effect of compound 18a on an
ERR.gamma. protein level in ATC cells, immune blotting assay was
performed using NIC-specific antibody. As a result of treatment
with compound 18a, it was confirmed that total NIS protein (fully
or partially glycosylated form) expression in CAL62 cells were
significantly increased (FIGS. 14 and 15), and when compared with
the vehicle treated group, the expression was decreased by about
1.9 times. In order to determine the effect of compound 18a on the
state of NIS membrane protein, a change in a level of membranous
total NIS protein collected from compound 18a-treated CAL 62 cells
using a cell membrane biotinylated kit was examined using an immune
blotting examination using an NIS-specific antibody. Compound 18a
derived a sharp increase in cell membrane-localized NIS protein
having mature and immature forms in ATC cells, as compared with
control cells (FIG. 14). Qualitative analysis of band intensity
showed increases in membrane fully glycosylated and partially
glycosylated NIS protein in CAL62 cells by 8.1 times and 6.4 times,
respectively (FIG. 15).
[0292] 2.5 Modification of I-131 Mediated Cytotoxicity by Compound
18a in ATC Cells
[0293] A clone formation assay using I-131 showed a minimal
cytotoxic effect in CAL62 cells treated with any one of compounds
18a and I-131 alone (FIG. 16). Relative colony formability of I-131
or GSK5182 group was 92.9.+-.5.8% and 94.5.+-.10.8%, respectively
in CAL62 cells (FIG. 17). However, as a result of combining
.sup.131I and GSK5182, colony-formability was significantly
decreased to about 58.5.+-.7.4% in CAL-62 (FIG. 17).
[0294] 2.6 Increase of Radioactive Iodine Uptake by Administration
of Compound 18a in ATC Tumor Model
[0295] The CAL62-effluc mouse tumor model was divided into the
following groups (FIG. 18, Group 1: vehicle, Group 2: 100 mpk
compound 18a, Group 3: 200 mpk compound 18a). To the mice of each
group, the vehicle (100% PEG) and compound 18a (100 mpk, 200 mpk)
were orally administered daily for 6 days. In order to observe a
difference in tumor growth between before administration and after
administration, optical imaging (bioluminescent imaging) was
performed. After finally administering the drug, a radioactive
isotope (1-125) was administered to the mice on the next day, and
after 2 hours, the mice were sacrificed, all organs thereof were
extracted, and a radiation level was measured with a gamma counter.
It was confirmed that radioactive iodine uptake in CAL62 tumor was
concentration-dependently increased by treatment with compound 18a
(FIG. 19). When compared with the vehicle group, the radioactive
uptake was increased by 4.4 times and 16.2 times in the 100 mpk and
200 mpk compound 18a groups, respectively. When observing the
difference in tumor growth using optical imaging, significant tumor
growth inhibitory efficiency was shown in the compound 18a group
(FIG. 20). Drug concentration-dependent tumor growth inhibitory
efficiency was shown (FIG. 21). An abrupt weight change in the mice
was not shown in all groups (FIG. 22).
[0296] Hereinabove, although the present invention has been
described in detail with reference to the exemplary embodiments, it
will be apparent to those skilled in the art that various
modifications and alterations may be made without departing from
the scope and spirit of the present invention. It should be
understood that these modifications and alterations fall within the
scope defined by the following claims.
INDUSTRIAL APPLICABILITY
[0297] The arylethene derivative of the present invention is a
novel compound, and exhibits very high inhibitory activity to
ERR.gamma. as compared with a conventional GSK5182 compound, and at
the same time, shows an effect of improved drug stability,
pharmacological activity and toxicity. Thus, the arylethene
derivative may be useful as efficient prophylactic agent and
therapeutic agent for diseases mediated by ERR.gamma., in
particular, metabolic diseases such as obesity, diabetes,
hyperlipidemia, fatty liver, or atherosclerosis, as well as
retinopathy, without side effects.
[0298] In addition, the arylethene derivative of the present
invention may specifically and significantly inhibit ERR.gamma.
transcriptional activity as compared with GSK5182, and as a result,
cause a radioactive isotope uptake increase from a cellular level
to an animal level. Accordingly, the arylethene derivative of the
present invention may significantly increase a treatment effect of
radioactive iodine therapy for treating cancer, and when
administered to cancer cells, may effectively produce cancer cells
having an improved sodium iodide symporter (NIS) function, thereby
having an excellent effect of being more easily applied to related
research and clinical practice for treating anaplastic thyroid
cancer.
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