U.S. patent application number 13/664173 was filed with the patent office on 2014-01-30 for new compounds for inhibiting differentiation of osteoclast and pharmaceutical composition comprising thereof.
This patent application is currently assigned to Metacine, Inc.. Invention is credited to Bae Keun Park, Ju-Young Park, Sung Hoon Park, Sung-Hwa Yoon.
Application Number | 20140031563 13/664173 |
Document ID | / |
Family ID | 47288102 |
Filed Date | 2014-01-30 |
United States Patent
Application |
20140031563 |
Kind Code |
A1 |
Park; Bae Keun ; et
al. |
January 30, 2014 |
New compounds for inhibiting differentiation of osteoclast and
pharmaceutical composition comprising thereof
Abstract
New compounds and pharmaceutical compositions comprising active
ingredients having inhibition effects on osteoclast differentiation
are provided. The pharmaceutical compositions comprising the new
compounds can be used as medicines for treating metabolic bone
diseases such as bone metastatic cancer, solid cancer bone
metastasis, musculoskeletal complication by solid cancer bone
metastasis, hypercalcemia by malignant tumor, multiple myeloma,
primary bone tumor, osteoporosis, rheumatoid arthritis,
osteoarthritis, periodontal disease, inflammatory resorption of
alveolar bone, inflammatory resorption of bone, and Paget's
disease.
Inventors: |
Park; Bae Keun; (Wonju,
KR) ; Yoon; Sung-Hwa; (Suwon, KR) ; Park;
Ju-Young; (Suwon, KR) ; Park; Sung Hoon;
(Gunpo, KR) |
Assignee: |
Metacine, Inc.
Wonju
KR
|
Family ID: |
47288102 |
Appl. No.: |
13/664173 |
Filed: |
October 30, 2012 |
Current U.S.
Class: |
548/548 ;
548/543; 548/549; 548/565 |
Current CPC
Class: |
C07D 207/456 20130101;
C07D 207/38 20130101; C07D 207/20 20130101; A61P 35/00 20180101;
C07D 207/408 20130101; A61K 31/4015 20130101; C07D 207/444
20130101; A61P 19/00 20180101; C07D 207/452 20130101; C07D 409/04
20130101; C07D 207/448 20130101 |
Class at
Publication: |
548/548 ;
548/549; 548/543; 548/565 |
International
Class: |
C07D 207/452 20060101
C07D207/452; C07D 207/20 20060101 C07D207/20; C07D 207/38 20060101
C07D207/38 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 27, 2012 |
KR |
10-2012-0082248 |
Claims
1. A compound comprising the following formula I-a, formula I-b, or
a pharmaceutically acceptable salt thereof, ##STR00053## wherein,
in Formula I-a or I-b, R.sub.1 represents phenyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl or 5-10 membered
heteroaryl including at least one selected from nitrogen atom,
oxygen atom and sulfur atom in a ring; wherein R.sub.2 and R.sub.3
each independently represent halogen, phenyl, hydroxy,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring; wherein X and
Y each independently represent hydrogen, oxo, hydroxy, S or
CH.sub.2; wherein Z represents hydrogen,
aminoC.sub.1-6alkyloraminoC.sub.1-6alkyl which is mono-, di- or
tri-substituted by C.sub.1-6alkyl; and wherein said C.sub.6-10aryl,
C.sub.3-10cycloalkyl and 5-10 membered heteroaryl including at
least one selected from nitrogen atom, oxygen atom and sulfur atom
in a ring can be substituted by at least one substituent selected
from the groups consisting of halogen, hydroxy, C.sub.1-6alkyl,
halogenated C.sub.1-6alkyl, alkoxy, amide and carboxy.
2. The compound according to claim 1, wherein: R.sub.1 represents
phenyl, C.sub.6-13aryl, C.sub.6-13arylC.sub.1-6alkyl,
C.sub.3-10cycloalkyl or 5-10 membered heteroaryl including at least
one selected from nitrogen atom, oxygen atom and sulfur atom in a
ring; R.sub.2 and R.sub.3 each independently represent halogen,
phenyl, hydroxy, C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl,
C.sub.3-10cycloalkyl or 5-10 membered heteroaryl including at least
one selected from nitrogen atom, oxygen atom and sulfur atom in a
ring; X and Y each independently represent hydrogen, oxo or
hydroxy; Z represents hydrogen or aminoC.sub.1-6alkyl which is
mono-, di- or tri-substituted by C.sub.1-6alkyl; and the above
C.sub.6-10aryl, C.sub.3-10cycloalkyl and 5-10 membered heteroaryl
including at least one selected from nitrogen atom, oxygen atom and
sulfur atom in a ring can be substituted by at least one
substituent selected from the groups consisting of halogen,
hydroxy, C.sub.1-3alkyl, halogenated C.sub.1-3alkyl, amide and
carboxy.
3. The compound according to claim 1, wherein the compound of
formula I-a or I-b is one of:
1-(2,6-diisopropylphenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1,3,4-triphenyl-1H-pyrrole-2,5-dione;
1-(2-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
3,4-diphenyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione;
1-cyclohexyl-3,4-diphenyl-1H-pyrrole-2,5-dione;
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid;
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenz-
oic acid; 3-chloro-1,4-diphenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-benzyl-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-phenethyl-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1,3-bis(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one;
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
; 3-hydroxy-1,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;
4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one;
1-(4-chlorophenyl)-3,4-diphenyl-2,5-dihydro-1H-pyrrole; or
1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione.
4. The compound according to claim 1, wherein the compound of
formula I-a or I-b is one of:
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid;
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenz-
oic acid;
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
;
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;
4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; or
1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione.
5. The compound according to claim 1, wherein the compound of
formula I-a or I-b is one of:
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid;
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenz-
oic acid;
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrole-2(5H)-one;
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
;
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;
4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; or
1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione.
6. A pharmaceutical composition for preventing or treating
metabolic bone disease, the composition comprising a compound of
the following formula I-a or I-b, or a pharmaceutically acceptable
salt thereof as an active ingredient, ##STR00054## Wherein, in
Formula I-a or I-b, R.sub.1 represents phenyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl or 5-10 membered
heteroaryl including at least one selected from nitrogen atom,
oxygen atom and sulfur atom in a ring; wherein R.sub.2 and R.sub.3
each independently represent halogen, phenyl, hydroxy,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring; wherein X and
Y each independently represent hydrogen, oxo, hydroxy, S or
CH.sub.2; wherein Z represents hydrogen, aminoC.sub.1-6alkyl or
aminoC.sub.1-6alkyl which is mono-, di- or tri-substituted by
C.sub.1-6alkyl; and wherein said C.sub.6-10aryl,
C.sub.3-10cycloalkyl and 5-10 membered heteroaryl including at
least one selected from nitrogen atom, oxygen atom and sulfur atom
in a ring can be substituted by at least one substituent selected
from the groups consisting of halogen, hydroxy, C.sub.1-6alkyl,
halogenated C.sub.1-6alkyl, alkoxy, amide and carboxy.
7. The pharmaceutical composition for preventing or treating
metabolic bone disease according to claim 6, wherein: R.sub.1
represents phenyl, C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl,
C.sub.3-10cycloalkyl or 5-10 membered heteroaryl including at least
one selected from nitrogen atom, oxygen atom and sulfur atom in a
ring; R.sub.2 and R.sub.3 each independently represent halogen,
phenyl, hydroxy, C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl,
C.sub.3-10cycloalkyl or 5-10 membered heteroaryl including at least
one selected from nitrogen atom, oxygen atom and sulfur atom in a
ring; X and Y each independently represent hydrogen, oxo or
hydroxy; Z represents hydrogen or aminoC.sub.1-6alkyl which is
mono-, di- or tri-substituted by C.sub.1-6alkyl; and said
C.sub.6-10aryl, C.sub.3-10cycloalkyl and 5-10 membered heteroaryl
including at least one selected from nitrogen atom, oxygen atom and
sulfur atom in a ring can be substituted by at least one
substituent selected from the groups consisting of halogen,
hydroxy, C.sub.1-3alkyl, halogenated C.sub.1-3alkyl, amide and
carboxy.
8. The pharmaceutical composition for preventing or treating
metabolic bone disease according to claim 6, wherein the compound
is selected from the groups consisting of
1-(2,6-diisopropylphenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1,3,4-triphenyl-1H-pyrrole-2,5-dione;
1-(2-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
3,4-diphenyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione;
1-cyclohexyl-3,4-diphenyl-1H-pyrrole-2,5-dione;
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid;
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenz-
oic acid; 3-chloro-1,4-diphenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-benzyl-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-phenethyl-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1,3-bis(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one;
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
; 3-hydroxy-1,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;
4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one;
1-(4-chlorophenyl)-3,4-diphenyl-2,5-dihydro-1H-pyrrole; and
1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or
pharmaceutically acceptable salts thereof as an active
ingredient.
9. The pharmaceutical composition for preventing or treating
metabolic bone disease according to claim 6, wherein the compound
is selected from the groups consisting of
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid;
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenz-
oic acid;
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione;
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
;
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;
4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; and
1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or
pharmaceutically acceptable salts thereof as an active
ingredient.
10. The pharmaceutical composition for preventing or treating
metabolic bone disease according to claim 6, comprising
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione as an active
ingredient.
11. The pharmaceutical composition for preventing or treating
metabolic bone disease according to claim 6, wherein the metabolic
bone disease is selected from the groups consisting of bone
metastatic cancer, solid cancer bone metastasis, musculoskeletal
complication by solid cancer bone metastasis, hypercalcemia by
malignant tumor, multiple myeloma, primary bone tumor,
osteoporosis, Rheumatoid Arthritis, Osteoarthritis, Periodontal
Disease, inflammatoryresorption of alveolar bone, inflammatory
resorption of boneand Paget's disease.
12. The pharmaceutical composition for preventing or treating
metabolic bone disease according to claim 6, wherein the metabolic
bone disease is selected from the groups consisting of bone
metastatic cancer, solid cancer bone metastasis, musculoskeletal
complication by solid cancer bone metastasis, hypercalcemia by
malignant tumor and multiple myeloma.
Description
CROSS-REFERENCES TO RELATED APPLICATION
[0001] This patent application claims the benefit of priority from
Korean Patent Application No. 10-2012-0082248 filed on Jul. 27,
2012, the contents of which are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to new compounds and
pharmaceutical compositions comprising them, which have inhibition
effects on osteoclast differentiation. The pharmaceutical
composition comprising new compounds according to the present
invention can be used as medicines for treating metabolic bone
diseases such as bone metastatic cancer, solid cancer bone
metastasis, musculoskeletal complication by solid cancer bone
metastasis, hypercalcemia by malignant tumor, multiple myeloma,
primary bone tumor, osteoporosis, rheumatoid arthritis,
osteoarthritis, periodontal disease, inflammatory resorption of
alveolar bone, inflammatory resorption of bone and Paget's
disease.
[0004] 2. Description of the Related Art
[0005] Breast cancer is one of the cancers known as the most
studies have made compared to all the other cancers. While the
studies researched that the breast cancer can be caused by
environmental and genetic factors, a certain cause of the cancer
has not yet been identified. However, various study results showed
possible certain causes of the cancer and there is no controversy
that the female hormone estrogen plays an important role in the
carcinogenesis of breast cancer. Since breast cells proliferate and
differentiate by estrogen stimulations, the risk of breast cancer
may be determined by the estrogen exposure period. It means that an
increased incidence of breast cancer depends on a longer exposure
period to estrogen. In addition, excess intakes of nutrients and
fat, genetic factors, obesity, and a hormonal imbalance caused by a
long-term administration of contraceptive and female hormone
therapy have also been suggested as a possible cause of breast
cancer.
[0006] The metastasis of cancer often leads to death in cancer
patients, especially the breast cancer is recurred by a bone
metastasis. According to the clinical cases, it has been reported
that the metastasis into the bone tissues was occurred in the
30%-40% of patients who have an early stage transition and in more
than 90% of patients who died from the transition. Roughly three
causes are considered to induce the bone metastasis. First, a high
blood stream mobility following to a lot of blood flow around the
red bone marrow of breast cancer cells causes to high access of
breast cancer cells to bone tissues. Second, the revelation of
surface molecules of orphan cancer cell, i.e., homing receptor of
breast cancer cell, and absorbance molecule of bone tissue matrix
cells, i.e., drawing ligand molecule may cause it. Finally,
existing calcium (Ca.sup.2+) and growth factor within the bone
tissues promote a proliferation of breast cancer cells. When the
bone metastasis occurred by a single or a few of breast cancer
cells, bone destruction (i.e., bone resorption) may be induced, and
the above factors released through the above processes stimulate
the proliferation of breast cancer (i.e., vicious cycle) and the
majority of patients eventually leads to death.
[0007] The bone resorption proceeds by the actions of osteoclasts.
The differentiation of osteoclasts may be initiated by the
revelation of PTHrP (paratyroid hormone-related protein) and GM-CSF
(granulocyte macrophage colony-stimulating factor) molecules which
were occurred by the regulated transcription action of activated
NF-kappa B (Nuclear Factor-kappa B) in the breast cancer. The PTHrP
increases RANKL (RANK ligand) which competes with OPG
(osteoprotegrin) in the RANK (receptor activator of NF-kappa B),
and concurrently decreases the revelation of OPG (i.e., RANKL
antagonist or RANK inhibitor), and thus the PTHrP facilitates the
binding of RANK and RANKL. When the RANKL binds to the RANK, the
revelation of osteoclast precursors increases. The GM-CSF helps to
the generation and differentiation of osteoclast precursors and
differentiation of osteoclasts. The NF-kappa B is one of proteins
which involved in the cell survival, regulation of immune response,
cancer or inflammation, and it has different functions depending on
the types of interacting cells and acting point of interaction,
like many other transcription factors. NF-kappa B always exists as
an active form in the breast cancer cells, and regulates the
mechanism of carcinogenesis, proliferation, and metastasis. The
activation of NF-kappa B is regulated by IKK (IkB kinase) which
phosphorylates IKB(Inhibitor-kB), the activated NF-kappa B is
translocated into the nucleus and transcription of target gene
initiated.
[0008] The only commercially used-medicine for bone disease (bone
metastasis of breast cancer and osteoporosis) is zoledronic acid of
Novartis. The zoledronic acid is one of bisphosphonates,
transformed form of pyrophosphate which used to prevent corrosion
of metal pipes etc.
[0009] Pharmacokinetically, pyrophosphates having P--O--P can be
easily hydrolyzed however, bisphosphonates having P--C--P cannot be
easily hydrolyzed and thus it has relatively long-term half-life.
Bisphosphonates is used as a treatment for osteoporosis since it
reduces bone resorption by inhibiting osteoclasts. R.sup.1 among
R.sup.1 and R.sup.2, two lateral chains, binding to carbon atom of
bisphosphonates can be binded to calcium of bone by hydroxide(--OH)
group, and R.sup.2 can be modified in the various forms to increase
the inhibition effect of bone resorption. Most of the
bisphosphonates are structurally highly hydrophilic and the
absorption rate is very low and thus they are formulated to the
intravenous injection dosage form. Bisphosphonates attach to the
bone surface which the bone formation actively made, and inhibit
the maturation of osteoclasts and prevent bone resorption. Also
bisphosphonates inhibit the recruitment of osteoclasts to the
region of bone resorption and reduce the generation of cytokines to
stimulate the bone resorption. Bisphosphonates prevent the invasion
of tumor cells and induce the apoptosis of tumor cells in the bone
matrix.
[0010] Bisphosphonates may have many side effects, such as stroke
and atrial fibrillation and the biggest rising problem is known as
a bisphosphonates induced osteonecrosis of the jaws(BIONJ), and the
exact mechanism of BIONJ is still unknown. BIONJ is a severe bone
disease that affects the maxilla, the mandible and the tooth root
and the definitive symptom is the exposure of mandibular or
maxillary bone. In healthy bone tissue there is a homeostasis
between bone resorption and bone apposition. Diseased or damaged
bone is resorbed through the osteoclasts mediated process and then
osteoblasts form new bone to replace it, thus maintaining healthy
bone density. This process is commonly called remodeling.
[0011] The main pharmacological action of bisphosphonates is
inhibition of the maturation of osteoclast driven bone resorption,
and thus bone resorption is inhibited by bisphosphonates, it
prevents bone formation by osteoblasts, bone generation is not
occurred and thereby micro-damage and fractures are cumulated.
Bisphosphonates may affect to the mucous membrane of the gingiva
and the tooth root to be exposed outside of the gingiva. Especially
in case of frequently masticated jaw bone, the bone turnover rate
of jaw is about 10 times higher than the one of normal bone, and
thus it is easily affected by bisphosphonates. Also, the
bisphosphonates increases the possibility of occurrence of BIONJ by
blocking a sufficient blood supply through the inhibition of blood
vessels by bisphosphonates.
SUMMARY OF THE INVENTION
[0012] The present invention provides new compounds and
pharmaceutical compositions comprising them, which have inhibition
effects on osteoclast differentiation and NF-.kappa.B
transcription.
[0013] To solve the above described technical problems, the present
invention provides a compound of the following formula I-a or I-b,
or pharmaceutically acceptable salts thereof.
##STR00001##
[0014] In Formula I-a or I-b, R.sub.1 represents phenyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-20cycloalkyl
or 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring. R.sub.2 and
R.sub.3 each independently represent halogen, phenyl, hydroxy,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring. X and Y each
independently represent hydrogen, oxo, hydroxy, S or CH.sub.2. Z
represents hydrogen, aminoC.sub.1-6alkyl or aminoC.sub.1-6alkyl
which is mono-, di- or tri-substituted by C.sub.1-6alkyl. The above
described C.sub.6-10aryl, C.sub.3-10cycloalkyl and 5-10 membered
heteroaryl including at least one selected from nitrogen atom,
oxygen atom and sulfur atom in a ring can be substituted by at
least one substituent selected from the groups consisting of
halogen, hydroxy, C.sub.1-6alkyl, halogenated C.sub.1-6alkyl,
alkoxy, amide and carboxy.
[0015] The pharmaceutical composition according to the present
invention has inhibitory effect on osteoclast differentiation and
the inhibitory effect on NF-.kappa.B transcription. Thus, they can
be used for preventing or treating metabolic bone disease selected
from the groups consisting of bone metastatic cancer, solid cancer
bone metastasis, musculoskeletal complication by solid cancer bone
metastasis, hypercalcemia by malignant tumor, multiple myeloma,
primary bone tumor, osteoporosis, rheumatoid arthritis,
osteoarthritis, periodontal disease, inflammatory resorption of
alveolar bone, inflammatory resorption of bone and Paget's
disease.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 depicts the dose-dependent inhibitory effect on
osteoclast differentiation by treating RAW 264.7 cells with the
compound of the invention, zoledronic acid.
[0017] FIG. 2 depicts the dose-dependent inhibitory effect on
osteoclast differentiation by treating RAW 264.7 cells with the
compounds of the invention, zoledronic acid in a graph.
[0018] FIG. 3 depicts the inhibitory effect on NF-.kappa.B
transcription when administering the compound of invention and
zoledronic acid.
[0019] FIG. 4 depicts the inhibitory effect on the binding of RNAKL
with RANK receptor when administering the compound of invention and
zoledronic acid.
[0020] FIG. 5 depicts the inhibitory effect on the binding of
osteoclast with bone matrix when administering the compound of
invention and zoledronic acid.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0021] The present invention relates to new compounds and
pharmaceutical compositions comprising them, which have inhibition
effects on osteoclast differentiation.
[0022] The present invention provides a compound of the following
formula I-a or I-b, or pharmaceutically acceptable salts
thereof
##STR00002##
[0023] wherein in Formula I-a or I-b, R.sub.1 represents phenyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring; R.sub.2 and
R.sub.3 each independently represent halogen, phenyl, hydroxy,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring; X and Y each
independently represent hydrogen, oxo, hydroxy, S or CH.sub.2; Z
represents hydrogen, aminoC.sub.1-6alkyl or aminoC.sub.1-6alkyl
which is mono-, di- or tri-substituted by C.sub.1-6alkyl; and the
above C.sub.6-10aryl, C.sub.3-10cycloalkyl and 5-10 membered
heteroaryl including at least one selected from nitrogen atom,
oxygen atom and sulfur atom in a ring can be substituted by at
least one substituent selected from the groups consisting of
halogen, hydroxy, C.sub.1-6alkyl, halogenated C.sub.1-6alkyl,
alkoxy, amide and carboxy.
[0024] As one aspect of the present invention, in the above
described Formula I-a or I-b,R.sub.1 represents phenyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring; R.sub.2 and
R.sub.3 each independently represent halogen, phenyl, hydroxy,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring; X and Y each
independently represent hydrogen, oxo or hydroxy; Z represents
hydrogen or aminoC.sub.1-6alkyl which is mono-, di- or
tri-substituted by C.sub.1-6alkyl; and the above C.sub.6-10aryl,
C.sub.3-10 cycloalkyl and 5-10 membered heteroaryl including at
least one selected from nitrogen atom, oxygen atom and sulfur atom
in a ring can be substituted by at least one substituent selected
from the groups consisting of halogen, hydroxy, C.sub.1-3alkyl,
halogenated C.sub.1-3alkyl, amide and carboxy.
[0025] As another aspect of the present invention, the compound of
the above described Formula I-a or I-b can be the compound selected
from the groups consisting of [0026]
1-(2,6-diisopropylphenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0027]
1,3,4-triphenyl-1H-pyrrole-2,5-dione; [0028]
1-(2-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0029]
1-(3-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0030]
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0031]
3,4-diphenyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione;
[0032] 1-cyclohexyl-3,4-diphenyl-1H-pyrrole-2,5-dione; [0033]
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0034]
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0035] 3-chloro-1,4-diphenyl-1H-pyrrole-2,5-dione; [0036]
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0037]
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0038]
3-chloro-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0039]
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0040]
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0041]
1-(4-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0042]
1-benzyl-3,4-diphenyl-1H-pyrrole-2,5-dione; [0043]
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0044]
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0045]
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0046]
1-phenethyl-3,4-diphenyl-1H-pyrrole-2,5-dione; [0047]
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0048]
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0049]
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0050]
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0051]
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dion-
e; [0052] 1,3-bis(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0053]
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0054]
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;
[0055] 1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one; [0056]
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
; [0057] 3-hydroxy-1,4-diphenyl-1H-pyrrole-2,5-dione; [0058]
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;
[0059] 4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; [0060]
1-(4-chlorophenyl)-3,4-diphenyl-2,5-dihydro-1H-pyrrole; and [0061]
1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or the
pharmaceutically acceptable salt thereof.
[0062] As another aspect of the present invention, the compound of
the above described Formula I-a or I-b can be the compound selected
from the groups consisting of
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0063]
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0064]
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0065]
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0066]
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0067]
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0068]
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0069]
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0070]
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0071]
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0072]
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0073]
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0074]
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0075]
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0076]
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dion-
e; [0077]
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,-
5-dione; [0078]
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;
[0079]
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
; [0080]
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dion-
e; [0081] 4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; and
[0082] 1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or the
pharmaceutically acceptable salt thereof.
[0083] As another aspect of the present invention, the compound of
the above described Formula I-a or I-b can be the compound selected
from the groups consisting of [0084]
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0085]
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0086]
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0087]
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0088]
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0089]
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0090]
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0091]
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0092]
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0093]
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0094]
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0095]
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0096]
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0097]
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dion-
e; [0098]
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,-
5-dione; [0099]
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrole-2(5H)-one;
[0100]
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
; [0101]
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dion-
e; [0102] 4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; and
[0103] 1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or the
pharmaceutically acceptable salt thereof.
[0104] The present invention provides a pharmaceutical composition
for preventing or treating metabolic bone disease comprising a
compound of the following formula I-a or I-b, or pharmaceutically
acceptable salts thereof as an active ingredient,
##STR00003##
[0105] wherein in Formula I-a or I-b, R.sub.1 represents phenyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring; R.sub.2 and
R.sub.3 each independently represent halogen, phenyl, hydroxy,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl
or 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring; X and Y each
independently represent hydrogen, oxo, hydroxy, S or CH.sub.2; Z
represents hydrogen, aminoC.sub.1-6alkyl or aminoC.sub.1-6alkyl
which is mono-, di- or tri-substituted by C.sub.1-6alkyl; and the
above C.sub.6-10aryl, C.sub.3-10cycloalkyl and 5-10 membered
heteroaryl including at least one selected from nitrogen atom,
oxygen atom and sulfur atom in a ring can be substituted by at
least one substituent selected from the groups consisting of
halogen, hydroxy, C.sub.1-6alkyl, halogenated C.sub.1-6alkyl,
alkoxy, amide and carboxy.
[0106] More specifically, in the above described Formula I-a or
I-b, R.sub.1 represents phenyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl or 5-10 membered
heteroaryl including at least one selected from nitrogen atom,
oxygen atom and sulfur atom in a ring; R.sub.2 and R.sub.3 each
independently represent halogen, phenyl, hydroxy, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-6alkyl, C.sub.3-10cycloalkyl or 5-10 membered
heteroaryl including at least one selected from nitrogen atom,
oxygen atom and sulfur atom in a ring; X and Y each independently
represent hydrogen, oxo or hydroxy; Z represents hydrogen or
aminoC.sub.1-6alkyl which is mono-, di- or tri-substituted by
C.sub.1-6alkyl; and the above C.sub.6-10aryl, C.sub.3-10cycloalkyl
and 5-10 membered heteroaryl including at least one selected from
nitrogen atom, oxygen atom and sulfur atom in a ring can be
substituted by at least one substituent selected from the groups
consisting of halogen, hydroxy, C.sub.1-3alkyl, halogenated
C.sub.1-3alkyl, amide and carboxy.
[0107] The compound of the above Formula I-a or I-b according to
the present invention can be the compound selected from the groups
consisting of [0108]
1-(2,6-diisopropylphenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0109]
1,3,4-triphenyl-1H-pyrrole-2,5-dione; [0110]
1-(2-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0111]
1-(3-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0112]
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0113]
3,4-diphenyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione;
[0114] 1-cyclohexyl-3,4-diphenyl-1H-pyrrole-2,5-dione; [0115]
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0116]
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0117] 3-chloro-1,4-diphenyl-1H-pyrrole-2,5-dione; [0118]
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0119]
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0120]
3-chloro-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0121]
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0122]
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0123]
1-(4-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0124]
1-benzyl-3,4-diphenyl-1H-pyrrole-2,5-dione; [0125]
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0126]
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0127]
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0128]
1-phenethyl-3,4-diphenyl-1H-pyrrole-2,5-dione; [0129]
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0130]
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0131]
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0132]
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0133]
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dion-
e; [0134] 1,3-bis(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0135]
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0136]
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;
[0137] 1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one; [0138]
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
; [0139] 3-hydroxy-1,4-diphenyl-1H-pyrrole-2,5-dione; [0140]
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dione;
[0141] 4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; [0142]
1-(4-chlorophenyl)-3,4-diphenyl-2,5-dihydro-1H-pyrrole; and [0143]
1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or the
pharmaceutically acceptable salt thereof. The present invention
provides pharmaceutical composition for preventing or treating
metabolic bone disease comprising at least one selected from the
above listed compounds or pharmaceutically acceptable salts thereof
as an active ingredient.
[0144] The compound of the above Formula I-a or I-b according to
the present invention can be the compound selected from the groups
consisting of [0145]
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0146]
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0147]
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid; [0148]
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0149]
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione; [0150]
1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0151]
1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0152]
1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0153]
1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0154]
1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0155]
1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0156]
1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0157]
1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione; [0158]
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione;
[0159]
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dion-
e; [0160]
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrole-2,-
5-dione; [0161]
1-(4-chlorophenyl)-5-hydroxy-3,4-diphenyl-1H-pyrrol-2(5H)-one;
[0162]
1-(4-chlorophenyl)-3-((dimethylamino)methyl)-3,4-diphenylpyrrolidin-2-one-
; [0163]
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrole-2,5-dion-
e; [0164] 4-chloro-5-hydroxy-1,3-diphenyl-1H-pyrrol-2(5H)-one; and
[0165] 1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione, or the
pharmaceutically acceptable salt thereof. The present invention
provides pharmaceutical composition for preventing or treating
metabolic bone disease comprising at least one selected from the
above listed compounds or pharmaceutically acceptable salts thereof
as an active ingredient.
[0166] The present invention provides the pharmaceutical
composition for preventing or treating metabolic bone disease
comprising 1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione as
an active ingredient.
[0167] As used herein, the term "alkyl" refers to a straight or
branched chain hydrocarbon having from one to five carbon atoms, or
from one to seven carbon atoms, or from five to nine carbon atoms,
or from six to twelve carbon atoms. Examples of "alkyl" as used
herein include, but are not limited to, methyl, ethyl, propyl,
n-butyl, n-pentyl, isobutyl, and isopropyl, tert-butyl, and the
like.
[0168] As used herein the term "aryl" refers to aromatic monocyclic
or multicyclic groups containing from 5 to 15 carbon atoms. When
referring to said aryl being substituted, said substitution may be
at any position on the ring, other than the point of attachment to
the other ring system of a compound of the invention. Therefore,
any hydrogen atom on the aryl ring may be substituted with a
substituent defined by the invention. In embodiments where the aryl
is a phenyl ring, said substitution may be at the meta- and/or
ortho- and/or para-position relative to the point of
attachment.
[0169] As used herein the term "heteroaryl" refers to a monocyclic
or multicyclic aromatic ring system, in certain embodiments, of
about 5 to about 15 members where one or more, in one embodiment 1
to 3, of the atoms in the ring system is a heteroatom, that is, an
element other than carbon, including but not limited to, nitrogen,
oxygen or sulfur. The heteroaryl group may be optionally fused to a
benzene ring.
[0170] The term "cycloalkyl" refers to a cyclic ring having from 6
to 12 carbon atoms connected via single bond only.
[0171] It is appreciated by a person skilled in the art that
certain compounds of the invention may possess at least one
stereogenic carbon atom. Thus, it should be noted that the present
invention encompasses all possible stereoisomers of such compounds
including all possible mixtures thereof, such as for example
racemic mixtures, diastereomeric mixtures, non-racemic mixtures
etc. It is further noted that compounds of the invention may
possess a double bond. Thus, the present invention encompasses any
stereoisomer, cis, trans, E or Z stereoisomers of such compounds
including any mixture thereof.
[0172] The pharmaceutical composition according to the present
invention can be used for preventing or treating metabolic bone
disease selected from the groups consisting of bone metastatic
cancer, solid cancer bone metastasis, musculoskeletal complication
by solid cancer bone metastasis, hypercalcemia by malignant tumor,
multiple myeloma, primary bone tumor, osteoporosis, rheumatoid
arthritis, osteoarthritis, periodontal disease, inflammatory
resorption of alveolar bone, inflammatory resorption of bone and
Paget's disease.
[0173] More specifically, the pharmaceutical composition comprising
the compound of Formula I-a or I-b, or the pharmaceutically
acceptable salt thereof according to the present invention can be
used for preventing or treating metabolic bone diseases selected
from the groups consisting of bone metastatic cancer, solid cancer
bone metastasis, musculoskeletal complication by solid cancer bone
metastasis, hypercalcemia by malignant tumor and multiple
myeloma.
[0174] When the above mentioned chemical compound is used as
pharmaceutically acceptable salt form, the salt can be selected
from the allowable salts for treating or preventing bone metabolic
diseases among the existing salt forms of active ingredient
compounds.
[0175] Pharmaceutically acceptable salts of the compounds of this
invention include, but are not limited to, acid addition salts
those derived from pharmaceutically acceptable free acids. Examples
of suitable acid addition salts include inorganic acids such as
hydrochloric acid, nitric acid, phosphoric acid, sulfurinc acid,
hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous and
the like; nontoxic organic acids such as aliphatic mono- and
dicarbolxylate, phenyl-substituted alkanoate, hydroxyalkanoate and
alkandioate, hetero-acids, aliphatic and hetero sulfonates.
[0176] Pharmaceutically nontoxic salts include sulfates,
pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,
mono-hydrogen phosphate, dihydrogen phosphate, metaphosphate,
pyrophosphate chloride, bromide, iodide, fluoride, acetate,
propionate, decanoate, caprylate, acrylate, formate, iso-butyrate,
caprate, heptanoate, propionic oleate, oxalate, malonate,
succinate,
[0177] suberate, sebacate, fumarate, maleate, Butin-1,4-dioate,
hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate,
dinitro benzoate, hydroxy benzoate, methoxy benzoate, phthalate,
terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene
sulfonate, xylene sulfonate, phenyl acetate, phenyl propionate,
phenyl butyrate, citrate, lactate, hydroxy butyrate, glycolate,
maleate, tartrate, methane sulfonate, propane sulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
[0178] The acid addition salts of the invention can be prepared by
using conventional methods, for example, the compounds of the
invention dissolved in an excess of aqueous acid solution, and the
salts are precipitated by using water-miscible organic solvents
such as methanol, ethanol, acetone or acetonitrile.
[0179] The compounds of the invention can be made as a
pharmaceutically acceptable metal salts by using bases. Alkali
metal or alkali earth metal salts can be prepared by conventional
methods, for example, the compounds are dissolved in an excess of
alkali metal hydroxide or alkali earth metal hydroxide solvent,
non-soluble compound is filtered, and then the filtrate is obtained
by evaporating and drying. Sodium, potassium or calcium salt is
preferable as a metal salt. Also, silver salt can be obtained by
reacting alkali metal or alkali earth metal salt with suitable
silver salt (e.g., silver nitrate).
[0180] The pharmaceutical composition of the invention may comprise
pharmaceutically acceptable carriers. The pharmaceutical
composition of the invention comprising pharmaceutically acceptable
carriers may be administrated in various oral or non-oral
administering formulations. When it is formulated, commonly used
diluents and excipients such as fillers, extenders, binders,
wetting agents, melting agents, surfactants, and the like are used
for the preparation.
[0181] As the solid formulations for oral administration, it may be
used in the formulations of tablets, pills, capsules (hard/soft),
granules, and the like. The solid oral formulations may be prepared
by mixing more than one its active ingredient compound(s) with more
than one excipient(s) such as starch, calcium carbonate, lactose,
and gelatin. In addition to the excipients, lubricants such as
stearic acid, magnesium and talc can also be used. As the liquid
formulations for oral administration, it may be used in the
formulations of suspensions, solutions, emulsions, syrups, and the
like. In addition to the commonly used diluents such as water and
liquid paraffin, excipients such as wetting agents, sweeteners,
fragrances, preservatives, and the like can be used. For non-oral
administration, it may be used in the formulations of sterilized
solution, non-aqueous solution, suspensions, emulsions,
lysophilized formulations, suppository and the like. For the
non-aqueous solutions and suspensions, propylene glycol,
polyethylene glycol, vegetable oil such as olive oil, and esters
such as injection capable ethyloleate can be used. The bases of
suppository may include witepsol, macrogol, tween 61, cacao butter,
laurin butter, glycerogelatin, and the like. The above stated
composition may be sterilized and/or to be sterilized, and contain
antiseptic agents, stabilizers, wettable agents or emulsifiers,
salts and/or buffers for controlling osmotic pressure, and
therapeutically useful agents. The composition may be formulated by
traditional methods such as mixing, granulating, or coating.
[0182] Pharmaceutically acceptable compositions of this invention
may be orally administered in any orally acceptable dosage form
including, but not limited to, tablets, pills, powders, granules,
capsules, suspensions, aqueous suspensions, solutions, emulsions,
syrups, sterilized solution, and the like.
[0183] The composition of invention is administered into a patient
as a pharmaceutically (therapeutically) effective doasage.
[0184] As used herein, "treatment" or "treating," is used
interchangeably herein. These terms refer to an approach for
obtaining beneficial or desired results including but not limited
to therapeutic benefit and/or a prophylactic benefit. By
therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions may be
administered to a patient at risk of developing a particular
disease, or to a patient reporting one or more of the physiological
symptoms of a disease, even though a diagnosis of this disease may
not have been made.
[0185] The term "therapeutically effective amount" refers to that
amount of a compound described herein that is sufficient to effect
the intended application including but not limited to disease
treatment, as defined below. The therapeutically effective amount
may vary depending upon the intended application (in vitro or in
vivo), or the subject and disease condition being treated, e.g.,
the weight, gender and age of the subject, the severity of the
disease condition, the manner of administration, formulation of the
product, health condition, and the like, which can readily be
determined by one of ordinary skill in the art. The specific dose
will vary depending on the particular compounds chosen, the dosing
regimen to be followed, whether it is administered in combination
with other compounds, timing of administration, the tissue to which
it is administered, and the physical delivery system in which it is
carried. In case of standardized to 70 Kg man, general dosage may
be 0.1 mg to 1,000 mg/day, preferably 1 to 500 mg/day, more
preferably 10 to 100 mg/day and the daily dosage may be
administered once or divided over a few times per day at a decision
made by a doctor or a pharmacist.
[0186] The pharmaceutical composition of the invention may be
administered to a patient independently or in a combination therapy
with the other therapeutic agents for treating metabolic bone
diseases. The composition may be administered to a patient
simultaneously or separately with the other therapeutic agents.
Also, the composition may be administered in single or multiple.
Considering all the above stated factors, it is important to
administer adequate dosage to get the maximum effect by the least
amount of the compound with minimal side effect and the dosage may
be determined easily by those skilled in the art.
[0187] The term "co-administration," "administered in combination
with," and their grammatical equivalents, as used herein, encompass
administration of two or more agents to an animal so that both
agents and/or their salts are present in the animal at the same
time. Co-administration includes simultaneous administration in
separate compositions, administration at different times in
separate compositions, or administration in a composition in which
both agents are present.
[0188] As used herein, the term "subject" (or patient) refers to
all animals including humans which have disease or have the
possibility to develop the disease to be prevented or treated by
inhibiting the differentiation of osteoclast. The above diseases
may be effectively prevented or treated by administering the
composition comprising the compound of the invention to the
subject.
[0189] The pharmaceutically acceptable compositions of the
invention can be administered to the subject in any conventional
administration routes as long as it can be reached to the target
tissues. Following to the administering object, the composition of
the invention can be administered to the subject in a way of
parenteral, intravenous, intramuscular, subcutaneous, intradermal,
oral, intranasal, intrapulmonary, and/or intra-rectum
administration, but not limited thereto. Also, the above
composition can be administered by using any device that can be
moved to the target cells.
[0190] In one embodiment, the invention may be added to food
directly, or used with another food or food ingredients following
to the ways of commonly used, but not limited thereto. The amount
of the active ingredient may be determined following to the purpose
of use (prevention or improvement).
[0191] In one embodiment, the invention provides health food
functions for preventing or improving metabolic bone disease
comprising a compound of the formula I-a or I-b, or its
pharmaceutically acceptable salts thereof.
[0192] The health food of the invention contains a compound of the
formula I-a or I-b, or its pharmaceutically acceptable salts
thereof, and further contain proper food supplements.
[0193] As used herein, the term, "food supplements" is a component
can be added to the various forms of health food and those skilled
in the art can be selected and used it properly. The food
supplement examples include nutrients, vitamins, minerals
(electrolytes), flavors such as synthetic flavors and natural
flavors, colorants, fillers, pectic acid and its salts, arginic
acid and its salts, organic acid, protective colloidal thickeners,
pH adjusters, stabilizer, glycerin, alcohols, carbonates for
carbonated beverages, and the like, but is not limited thereto.
[0194] In one embodiment, the food composition of the invention may
include functional health food. As used herein, the term
"functional health food" is the food manufactured or processed with
health useful functioning raw materials or ingredients in the forms
of tablets, capsules, powders, granules, liquid, pills and the
like. As used herein, the term "function" or "functional" refers to
functions to obtain the health useful effect for human bodies of
adjusting the nutrient and physiological health effects. The
functional health food of the invention can be manufactured by
commonly used method in the art, and the commonly used raw
materials or ingredients can be added to the food. Also, the
functional health food has its advantages of no side effect that
could happen when drugs are taken for a long term. Since it is also
highly portable, the functional health food of the invention can be
taken as a supplement for preventing or improving metabolic bone
diseases.
[0195] The amount of the active ingredient to be added to the food
may be determined following to the purpose of its use (prevention
or improvement or treatment). Generally, for the food use, the
compound of the formula I-a or I-b or its pharmaceutically
acceptable salts may be added into the food at the rate of 1-10 wt
%, preferably 5 to 10 wt %. However, in case of long-term intakes
for improving health and sanitation, or for regulating health
conditions, the above stated adding dosage rates can be lowered
while the active ingredients has no safety problems.
[0196] There are no specific limits in kinds to be the above stated
foods. For food examples, it includes commonly understandable
health foods such as all kinds of drinks, meat, sausages, breads,
biscuits, rice cakes, chocolates, candies, snacks, pizzas, noodles,
gums, ice creams, milk products, soups, alcohol/non-alcohol drinks,
and vitamin complex, but not limited thereto.
[0197] The health food composition can be further comprised of
various flavoring agents or natural carbonates as an additive in
common food, but is not limited thereto.
[0198] The above stated natural carbohydrate examples include
monosaccharides, such as glucose, fructose, and etc., disacharides
such as maltose, sucrose and etc., polysaccharides such as commonly
used sugars such as dextrin, cyclodextrin, and etc., and alcohol
sugars such as xylitol, sorbitol, erythrytol, and etc. As flavoring
agents, natural flavoring agents such as taumatin, stevia extract
(e.g., levaudioside A, glycyrrhyzine etc.), and synthetic flavoring
agents such as saccharine, aspartame, and etc.) may be beneficially
added. The above stated natural carbohydrates may be added at the
rate of 0.01-0.04 g/100 g of the invented composition, or desirably
0.02-0.03 g/100 g of the invented composition.
[0199] The compound according to the present invention can be
produced by the following schemes. Aryl or alkyl acetic acid(II)
and aryl or alkyl glyoxylic acid were reacted together in acetic
anhydride as a preferable solvent with triethylamine as a catalyst
for 3-5 hours at 100-120.degree. C. After that, diphenylmaleimide
(IV) was synthesized as an intermediate through the purification
method using silicagel column chromatography. Diphenylmaleimide
intermediate and amine compound were reacted together in toluene as
a solvent with triethylamine as a catalyst for 2-5 hours at 1200 to
produce diphenylmaleimide (I).
##STR00004##
##STR00005##
[0200] Hereinafter, the present invention can be more specifically
described by the following experimental examples and preparation
examples. However, they are provided for illustrative purposes
only, and the scope of the present invention should not be limited
thereto in any manner.
Example 1
The Preparation of Compound 4
##STR00006##
TABLE-US-00001 [0201] TABLE 1 Substituents of Compound 4 No R No R
a 2,6-diisopropylphenyl b phenyl c 2-chlorophenyl d 3-chlorophenyl
e 4-chorophenyl f 2-trifluoropentylphenyl g cyclohexyl h
4-carboxy-3-hydroxyphenyl i 3-caboxy-4-hydroxyphenyl j
2-fluorophenyl K 3-fluorophenyl l 4-fluorophenyl m benzyl n
2-fluorobenzyl o 3-fluorobenzyl p 4-fluorobenzyl q phenethyl r
2-fluorophenethyl s 3-fluorophenethyl t 4-fluorophenethyl
(1) 3,4-diphenylfuran-2,5-dione (3)
[0202] After dissolving compound 2 (19.6 g, 96.0 mmol) in acetic
anhydride (250 ml), Compound 1 (18.0 g, 80.0 mmol) is added
thereto. After 6 hours of reaction with reflux, the temperature was
reduced to room temperature, three times extractions were carried
out with EA and seven times washings were carried out with brine.
Water was removed with anhydrous sodium sulfate and to remove the
remaining phenyl acetic acid, the column chromatography was carried
out with EA/HX (1/2). After the distillation under the reduced
pressure for the removal of the solvents conducted, vacuum drying
was carried out to obtain compound 3.
[0203] pale solid(11.0 g, 37.0%); mp 183-184.degree. C.; IR (KBr,
cm.sup.-1) 1756; .sup.1H NMR (DMSO-d.sub.6) .delta. 7.437-7486 (m,
10H); .sup.13C NMR (DMSO-d.sub.6) .delta. 127.355, 128.568,
129.243, 130.434, 138.170, 164.873.
(2) Compound 4 (4a-4-t)
[0204] After dissolving compound 3 (0.50 g, 2.00 mmol) in toluene
(10 ml), TEA (0.420 ml, 3.00 mmol) and amine reagents (1.2
equivalents, 2.4 mmol) were added thereto. After 6 hours of the
reflux, solvents were removed by the distillation under the reduced
pressure. The crystallization was carried out with HX and the
column chromatography was carried out with EA/HX (1/8). After the
distillation under the reduced pressure for the removal of the
solvents, and suspension with HX conducted, vacuum filtration under
the reduced pressure and vacuum drying were carried out.
1) 1-(2,6-diisopropylphenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione
(4a)
[0205] fluorescence pale green solid (0.1 g 12.2%); mp
233-234.degree. C.; IR (KBr, cm.sup.-1) 1713; .sup.1H NMR
(CDCl.sub.2-d) .delta.1.199-1.126 (d, 2H), 2.758-2.826 (m 2H,
7.269-7.288 (d, 2H), 7.367-7.461 (m, 8H) 7.554-7.579 (m, 4H);
.sup.13C NMR (CDCl.sub.2-d) .delta. 24.392, 29.747, 124.038,
127.095, 128.627, 128.687, 129.014, 130.113, 130.174, 136.067,
147.549, 170.453.
2) 1,3,4-triphenyl-1H-pyrrole-2,5-dione (4b)
[0206] yellow solid (0.51 g, 39.2%); mp 173-174.degree. C.; IR
(KBr, cm.sup.-1) 1707; .sup.1H-NMR (CDCl.sub.3-d) .delta.
7.304-7.363 (m, 7H), 7.442-7.454 (m, 4H), 7.503-7.510 (m, 4H);
.sup.14C NMR (CDCl.sub.3-d) .delta. 126.132, 127.732, 128.430,
128.581, 129.036, 129.977, 129.999, 131.736, 136.188, 169.406.
3) 1-(2-chlorophenyl)-3,4-dipheyl-1H-pyrrole-2,5-dione (4c)
[0207] pale yellow solid (0.57 g, 40.7%); mp 213-214.degree. C.; IR
(KBr, cm.sup.-1) 1710; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.340-7.418 (m, 9H), 7.528-7.563 (m, 5H); .sup.13C NMR
(CDCl.sub.3-d) .delta. 127.777, 128.437, 128.687, 129.728, 130.091,
130.144, 130.477, 130591, 130.765, 133.276, 136.552, 168.860.
4) 1-(3-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione (4d)
[0208] dark yellow solid (0.47 g, 33.6%); mp 144-145.degree. C.; IR
(KBr, cm.sup.-1) 1713; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.309-7.407 (m, 10H), 7.487-7.511 (m, 4H); .sup.13C NMR
(CDCl.sub.3-d) .delta. 124.092, 126.185, 127.838, 128.255, 128.602,
130.015, 130.166, 132 866, 134.520, 136.332, 169.027.
5) 1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione (4e)
[0209] dark yellow solid (0.66 g, 47.1%); mp 198-199.degree. C.; IR
(KBr, cm.sup.-1) 1707; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.333-7.402 (m, 7H), 7.410-7.438 (m, 5H), 7.485-7.509 (m, 4H);
.sup.13C NMR (CDCl.sub.3-d) .delta. 127.247, 128.308, 128.687,
129.264, 130.022, 130.159, 130.326, 133.367, 136.347, 169.194.
6) 3,4-diphenyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione
(4f)
[0210] fluorescence pale green sold (0.3 g, 19.1%); mp
152-153.degree. C.; IR (KBr, cm.sup.-1) 1713; .sup.1H NMR
(CDCl.sub.3-d) .delta. 7.339-7.417 (m, 10H), 7.528-7.562 (m, 4H);
.sup.13C NMR (CDCl.sub.3-d) .delta. 127.777, 128.445, 128.687,
129.734, 130.091, 130.144, 130.477, 130.591, 130.765, 133.283,
136.560, 168.860.
7) 1-cyclohexyl-3,4-diphenyl-1H-pyrrole-2,5-dione (4g)
[0211] fluorescence pale green sold (0.4 g, 303%); mp
159-160.degree. C.; IR (KBr, cm.sup.-1) 1693; .sup.1H NMR
(CDCl.sub.3-d) .delta. 1.226-1.410 (m, 3H), 1.670-1.700 (m, 1H),
1.749-1.779 (d, 2H), 1.845, 1.877 (d, 2H), 1.121-2.207 (m, 2H),
4.028-4.089 (m, 1H), 7.327-7.458 (m, 10H); .sup.13C NMR
(CDCl.sub.3-d) .delta. 25.454, 26.326, 30.262, 51.389, 128.521,
128.794, 129.696, 129.954, 135.885, 170.642.
8)
4-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid (4h)
[0212] yellow solid (0.345 g, 22.4%); mp decomposed; IR (KBr,
cm.sup.-1) 3064, 1710, 1677; .sup.1H NMR (DMSO-d.sub.3) .delta.
6.710-6.767 (m, 2H), 7.361-7.462 (m, 10H), 7.782-7.803 (d, 1H);
.sup.13C NMR (DMSO-d.sub.6) .delta. 114.204, 114.500, 119.013,
128.318, 138.455, 129.547, 129.592, 129.534, 134.514, 136.031,
162.689, 168.832, 171.054.
9)
5-(2,5-dioxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-1-yl)-2-hydroxybenzoic
acid (41)
[0213] yellow solid (1.10 g, 71.4%); mp 249-250.degree. C.; IR
(KBr, cm.sup.-1) 3457, 1710, 1587; .sup.1H NMR (DMSO-d.sub.6)
.delta. 7.096-7.118 (d, 1H), 7.376-7.476 (m, 10H), 7.585-7.613 (m,
1H), 7.908-7.914 (d, 1H); .sup.13C NMR (DMSO-d.sub.3) .delta.
113.090, 117.534, 122.979, 128.333, 127.485, 128.834, 129.539,
160.178, 169.128, 170.689.
10) 1-(2-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione (4j)
[0214] yellow solid (100 mg, 14.6%); mp decomposed; IR (KBr,
cm.sup.-1) 1719, 3471; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.223-7.536 (m, 14H); .sup.13C NMR (CDCl.sub.3-d) .delta. 116.750,
116.947, 119.564, 124.683, 14.721, 128.445, 128.695, 129.871,
130.083, 130.151, 130.568, 130.652, 136.742, 156.650, 159.152
168.731.
11) 1-(3-fluorophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dione (4k)
[0215] yellow solid (324 mg, 46.4%); mp 157-158.degree. C.; IR
(KBr, cm.sup.-1) 1710, 3459; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.060-7.523 (m, 14H), .sup.13C NMR (CDCl.sub.3-d) .delta. 113.451,
113.694, 114.672, 114.877, 121.574, 128.346, 128.748, 130.091,
130.182, 130.235, 130.819, 136.431, 163.839, 169.133.
12) 1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione (4l)
[0216] yellow solid (352 mg, 50.7%); mp 188-189.degree. C.; IR
(KBr, cm.sup.-1) 1710, 3453; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.152-7.521 (m, 14H); .sup.13C NMR (CDCl.sub.3-d) .delta. 116.068,
116.295, 127.770, 128.012, 128.096, 128.430, 128.725, 130.075,
130.174, 136.340, 160.487, 162.944, 169.482.
13) 1-benzyl-3,4-diphenyl-1H-pyrrole-2,5-dione (4m)
[0217] pale yellow sold (180 mg, 442%); mp 123-124.degree. C.; IR
(KBr, cm.sup.-1) 1695, 3438; .sup.1H NMR (CDCl.sub.3-d) .delta.
4.783 (s, 2H), 7.242-7.461 (m, 15H); .sup.13C NMR (CDCl.sub.3-d)
.delta. 42.230, 127.891, 128.559, 128.604, 128.718, 128.877,
129.863, 129.901, 136.143, 137.446, 170.331.
14) 1-(2-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione (4n)
[0218] pale yellow solid (210 mg, 51.6%); mp 113-114.degree. C.; IR
(KBr, cm.sup.-1) 1704, 3444; .sup.1H NMR (CDCl.sub.3-d) .delta.
4.895 (s, 2H), 7.031-7.486 (m, 14H); .sup.13C NMR (CDCl.sub.3-d)
.delta. 35.950, 115.597, 115.810, 124.281, 124.312, 128.619,
129.666, 129.742, 129.977, 130.583, 130.621, 136.234, 170.202
15) 1-(3-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione (4o)
[0219] pale yellow sold (250 mg, 58.3%); mp 107-108.degree. C.; IR
(KBr, cm.sup.-1) 1708, 3438; .sup.1H NMR (CDCl.sub.3-d) .delta.
4.788 (s, 2H), 6.956-7.475 (m, 14H); .sup.13C NMR (CDCl.sub.3-d)
.delta. 41.760, 114.900, 115.105, 115.711, 115.924, 124,418,
128.543, 128.665, 129.954, 130.030, 130.288, 130.371, 136.271,
170.308.
16) 1-(4-fluorobenzyl)-3,4-diphenyl-1H-pyrrole-2,5-dione (4p)
[0220] pale yellow solid (271 mg, 65.2%); mp 124-125.degree. C.; IR
(KBr, cm.sup.-1) 1704, 3448; .sup.1H NMR (CDCl.sub.3-d) .delta.
4.759 (s, 2H), 6.981-7.024 (t, 2H), 7.302-7.463 (m, 12H); .sup.13C
NMR (CDCl.sub.3-d) .delta. 41.632, 115.537, 115.749 128.559,
128.619, 129.916, 129.969, 130.765, 130.841, 132.328, 136.211,
161.155, 163.597, 170.346.
17) 1-phenethyl-3,4-diphenyl-1H-pyrrole-2,5-dione (4q)
[0221] pale yellow solid (120 mg, 28.3%); mp 164-165.degree. C.; IR
(KBr, cm.sup.-1) 1697, 3444; .sup.1H NMR (CDCl.sub.3-d) .delta.
2.978-3.017 (m, 2H), 3.871-3.910 (m, 2H), 7.212-7.448 (m, 15H);
.sup.13C NMR (CDCl.sub.3-d) .delta. 34.964, 39.955, 126.746,
128.627, 128.665, 128.976, 129.886, 129.916, 136.188, 138.130,
170.559.
18) 1-(2-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione
(4r)
[0222] pale yellow sold (80.0 mg, 10.8%); mp 111-112.degree. C.; IR
(KBr, cm.sup.-1) 1697, 3442; .sup.1H NMR (CDCl.sub.3-d) .delta.
3.026-3.062 (t, 2H) 3.901-3.937 (t, 2H), 7.001-7.435 (m, 14H);
.sup.13C NMR(CODl.sub.3-d) .delta. 28.556, 38.529, 115.385,
115.605, 124.198, 124.198, 124.236, 125.100, 128.604, 128.680,
129.855, 129.893, 129.984, 131.145, 131.198, 136.165, 162.641,
170.445.
19) 1-(3-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione
(4s)
[0223] pale yellow solid (35.0 mg, 7.8%); mp 129-130.degree. C.; IR
(KBr, cm.sup.-1) 1702, 3448; .sup.1H NMR (CDCl.sub.3-d) .delta.
2.978-3.016 (t, 2H), 3.868-3.906 (m, 2H), 6.906-7.051 (m, 2H),
7.242-7.450 (m, 12H); .sup.13C NMR (CDCl.sub.3-d) .delta. 34.684,
39.629, 113.633, 113.846, 115.817, 116.030, 124.607, 128.665,
129.916, 129.954, 130.098, 130.182, 136.234, 170.506.
20) 1-(4-fluorophenethyl)-3,4-diphenyl-1H-pyrrole-2,5-dione
(4t)
[0224] pale yellow solid (32.0 mg, 7.2%); mp 153-154.degree. C.; IR
(KBr, cm.sup.-1) 1700, 3446; .sup.1H NMR (CDCl.sub.3-d) .delta.
2.953-2.992 (t, 2H), 3.847-3.885 (m, 2H), 6.971-7.014 (m, 2H),
7.202-7,451 (m, 12H); .sup.13C NMR (CDCl.sub.3-d) .delta. 34.130,
39.917, 115.415, 115.628, 128.665, 129.909, 129.954, 130.379,
130.462, 136.188, 162.967, 170.551.
Example 2
The preparation of Compounds 5, 6 and 7
##STR00007##
[0225] (1) The synthesis of N,2-diphenylacetamide (5a)
[0226] After dissolving compound 2 (1.00 g, 7.34 mmol) in MC (30
ml), the activation for 30 minutes was carried out by the addition
of DCC (1.82 g, 8.81 mmol). After the sufficient activation,
aniline (0.75 g, 8.07 mmol) was added thereto and the agitation for
6 hours was carried out at room temperature. After the
identification of the reaction progress with TLC, DCU was removed
by the filtration and solvents were removed by the distillation
under the reduced pressure. Then, the next reaction was followed
without the purification process.
(2) The synthesis of N-(2-chlorophenyl)-2-phenylacetamide (5b)
[0227] After dissolving compound 2 (5.00 g, 36.7 mmol) in MC (50
ml), the activation for 30 minutes was carried out by the addition
of DCC (9.10 g, 44.5 mmol). After the sufficient activation,
2-chloroaniline (5.15 g, 40.4 mmol) was added thereto and the
agitation for 6 hours was carried out at room temperature. After
the identification of the reaction progress with TLC, DCU was
removed by the filtration and solvents were removed by the
distillation under the reduced pressure. Then, the next reaction
was followed without the purification process.
(3) The synthesis of N-(3-chlorophenyl)-2-phenylacetamide (5c)
[0228] After dissolving compound 2 (1.00 g, 7.34 mmol) in MC (30
ml), the activation for 30 minutes was carried out by the addition
of DCC (1.82 g, 8.81 mmol). After the sufficient activation,
3-chloroaniline (1.03 g, 8.07 mmol) was added thereto and the
agitation for 6 hours was carried out at room temperature. After
the identification of the reaction progress with TLC, DCU was
removed by the filtration and solvents were removed by the
distillation under the reduced pressure. Then, the next reaction
was followed without the purification process.
(4) The synthesis of N-(4-chlorophenyl)-2-phenylacetamide (5d)
[0229] After dissolving compound 2 (1.00 g, 7.34 mmol) in DCM (30
ml), the activation for 30 minutes was carried out by the addition
of DCC (1.82 g, 8.81 mmol). After the sufficient activation,
4-chloroaniline (1.03 g, 8.07 mmol) was added thereto and the
agitation for 6 hours was carried out at room temperature. After
the identification of the reaction progress with TLC, DCU was
removed by the filtration and solvents were removed by the
distillation under the reduced pressure. Then, the next reaction
was followed without the purification process.
(5) The synthesis of 3-hydroxy-1,4-diphenyl-1H-pyrrole-2,5-dione
(6a)
[0230] After the addition of anhydride THF (20 ml) to compound 5a
(1.55 g, 7.34 mmol), the temperature was adjusted to 0.degree. C.
Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35
g, 11.9 mmol) were added thereto and the agitation for 3 hours was
carried out. After the identification of the reaction progress with
TLC, the solution was poured into the distilled water and acidified
with 1N HCL aqueous solution. Three times extractions were carried
out with EA and three times washings were carried out with brine.
Water was removed by using Na.sub.2SO.sub.4, solvents were removed
and then, the suspension was carried out by HX.
(6) The synthesis of
1-(2-chlorophenyl)-3-hydroxy-4-phenyl-1H-pyrrole-2,5-dione (6b)
[0231] After the addition of anhydride THF (20 ml) to compound 5b
(1.40 g, 7.34 mmol), the temperature was adjusted to 0.degree. C.
Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35
g, 11.9 mmol) were added thereto and the agitation for 3 hours was
carried out. After the identification of the reaction progress with
TLC, the solution was poured into the distilled water and acidified
with 1N HCL aqueous solution. Three times extractions were carried
out with EA and three times washings were carried out with brine.
Water was removed by using Na.sub.2SO.sub.4, solvents were removed
and then, crude purification was carried out by the column
chromatography (EA/HX, 1/5).
(7) The synthesis of
1-(3-chlorophenyl)-3-hydroxy-4-phenyl-1H-pyrrole-2,5-dione (6c)
[0232] After the addition of anhydride THF (20 ml) to compound 5c
(1.55 g, 7.34 mmol), the temperature was adjusted to 0.degree. C.
Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35
g, 11.9 mmol) were added thereto and the agitation for 3 hours was
carried out. After the identification of the reaction progress with
TLC, the solution was poured into the distilled water and acidified
with 1N HCL aqueous solution. Three times extractions were carried
out with EA and three times washings were carried out with brine.
Water was removed by using Na.sub.2SO.sub.4, solvents were removed
and then, the suspension was carried out by EA/HX (1/3).
(8) The synthesis of
1-(4-chlorophenyl)-3-hydroxy-4-phenyl-1H-pyrrole-2,5-dione (6d)
[0233] After the addion of anhydride THF (20 ml) to compound 5d
(1.40 g, 7.34 mmol), the temperature was adjusted to 0.degree. C.
Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35
g, 11.9 mmol) were added thereto and the agitation for 3 hours was
carried out. After the identification of the reaction progress with
TLC, the solution was poured into the distilled water and acidified
with 1N HCL aqueous solution. Three times extractions were carried
out with EA and three times washings were carried out with brine.
Water was removed by using Na.sub.2SO.sub.4 and solvents were
removed. Crude purification was carried out by the column
chromatography but the next reaction was followed since the
purified compound was small in quantity.
(9) The synthesis of 3-chloro-1,4-diphenyl-1H-pyrrole-2,5-dione
(7a)
[0234] After dissolving compound 6a (2.00 g, 7.54 mmol) in MC (10
ml) and anhydrous DMF (10 ml), oxalyl chloride (1.90 g, 15.0 mmoL)
was added thereto and the agitation for 30 minutes was carried out.
After the identification of the reaction progress with TLC, the
reaction was terminated. Then, three times extractions were carried
out with EA and three times washings were carried out with brine.
Water was removed by using Na.sub.2SO.sub.4, solvents were removed
and then, the column chromatography was carried out with EA/HX
(1/9). As the result, Compound 7a was obtained.
[0235] pale yellow solid (1.21 g, 56.1%); mp 82-83.degree. C.; IR
(KBr, cm.sup.-1) 1782, 1724; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.316-7.492 (m, 8H), 7.921-7.946 (m, 2H); .sup.13C NMR
(CDCl.sub.3-d) .delta. 126.025, 126.822, 128.103, 128.619, 129.097,
129.704, 130.940, 131.054, 131.372, 134.853, 163.976, 167.025.
(10) The synthesis of
3-chloro-1-(2-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione (7b)
[0236] After dissolving compound 6b (3.00 g, 10.0 mmol) in MC (10
ml) and anhydrous DMF (10 ml), oxalyl chloride (2.50 g, 20.0 mmoL)
was added thereto and the agitation for 30 minutes was carried out.
After the identification of the reaction progress with TLC, the
reaction was terminated. Then, three times extractions were carried
out with EA and three times washings were carried out with brine.
Water was removed by using anhydrous Na.sub.2SO.sub.4, solvents
were removed and then, the column chromatography was carried out
with EA/HX (1/15). The suspension was carried out with HX to obtain
compound 7b.
[0237] white solid (0.500 g, 15.7%); mp 132-133.degree. C.; IR
(KBr, cm.sup.-1) 1787, 1739; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.286-7.392 (m, 3H), 7.459-7.514 (m, 4H) 7.963-7.987 (m, 2H);
.sup.13C NMR (CDCl.sub.3-d) .delta. 126.739, 127.755, 128.642,
128.764, 129.704, 130.349, 130.561, 130.887, 131.062, 131.342,
133.003, 135.400, 163.400, 166.388.
(11) The synthesis of
3-chloro-1-(3-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione (7c)
[0238] After dissolving compound 6c (2.00 g, 6.67 mmol) in DCM (10
ml) and anhydrous DMF (10 ml), oxalyl chloride (1.69 g, 13.3 mmol)
was added thereto and the agitation for 30 minutes was carried out.
After the identification of the reaction progress with TLC, the
reaction was terminated. Then, three times extractions were carried
out with EA and three times washings were carried out with brine.
Water was removed by using Na.sub.2SO.sub.4, solvents were removed
and then, the column chromatography was carried out with EA/HX
(1/9). The suspension was carried out with EA/HX(1/3) to obtain
compound 7c.
[0239] yellow solid (1.02 g, 48.2%); mp 67-68.degree. C.; IR (KBr,
cm.sup.-1) 1778, 1722; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.289-7.494 (m, 7H), 7.924-7.949 (m, 2H); .sup.13C NMR
(CDCl.sub.3-d) .delta. 124.023, 126.094, 126.678, 128.286, 128.741,
129.757, 130.113, 131.183, 131.509, 132.161, 134.633, 135.081,
163.665, 166.691.
(12) The synthesis of
3-chloro-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-2,5-dione (7d)
[0240] After dissolving compound 6d (1.00 g, 3.33 mmol) in MC (10
ml) and anhydrous DMF (10 ml), oxalyl chloride (0.850 g, 6.66 mmoL)
was added thereto and the agitation for 30 minutes was carried out.
After the identification of the reaction progress with TLC, the
reaction was terminated. Then, three times extractions were carried
out with EA and three times washings were carried out with brine.
Water was removed by using Na.sub.2SO.sub.4, solvents were removed
and then, the column chromatography was carried out with EA/HX
(1/15). The suspension was carried out with HX to obtain compound
7d.
[0241] yellow solid (0.610 g, 55.5%); mp 116-117.degree. C.; IR
(KBr cm.sup.-1) 1780, 1727; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.320-7.508 (m, 7H), 7.921-7.945 (m, 2H); .sup.13C NMR
(CDCl.sub.3-d) .delta. 126.686, 127.148, 128.726, 129.348, 129.568,
129.727, 131.145, 131.471, 133.830, 135.066, 163.802, 166.836.
Example 3
The Preparation of Compound 8
##STR00008##
[0243] The synthesis of
5-hydroxy-1,3,4-triphenyl-1H-pyrrol-2(5H)-one(8)
[0244] After the addition of compound 4e (1.00 g, 2.78 mmol) in
methanol, NaBH.sub.4 was slowly added thereto in acetone-ice bath
and the agitation for 3 hours was carried out at room temperature.
After the identification of disappearance of compound 4e with TLC,
quenching was carried out with in HCL aqueous solution in the ice
bath. Then, three times extractions were carried out with EA and
three times washings were carried out with brine. Water was removed
by using Na.sub.2SO.sub.4, solvents were removed and then, the
column chromatography was carried out with EA/HX (1/4). After the
distillation under the reduced pressure, vacuum drying was carried
out to obtain compound 8
[0245] white solid (0.71 g, 70.9%); mp 186-187.degree. C.; IR (KBr,
cm.sup.-1) 3326, 1672; .sup.1H NMR (CDCl.sub.3-d) .delta.
6.325-6.503 (m, 1H), 7.279-7.476 (m, 12H), 7.847-7.869 (m, 2H);
.sup.13C NMR (CDCl.sub.3-d) .delta. 82.205, 121.498, 127.793,
127.884, 128.043, 128.187, 128.475, 128.521, 128.771, 129.120,
130.371, 131.152, 131.387, 131.801, 149.536, 167.244.
Example 4
The Preparations of Compounds 11, 12, 13 and 14
##STR00009##
[0246] (1) The synthesis of
2-((4-chlorophenyl)amino)-1-phenylethanone (11)
[0247] After the addition of compound 9 (2.00 g, 10.2 mmol) in
ethanol, NaHCO.sub.3 (854 mg, 10.2 mmol) was added thereto. After
the activation for 30 minutes at room temperature, compound 10
(1.30 g, 10.2 mmol) was added thereto and the agitation for 3 hours
was carried out. After the identification of the reaction progress
with TLC, three times extractions were carried out with EA and
three times washings were carried out with brine. Water was removed
by using Na.sub.2SO.sub.4 and distillation under the reduced
pressure and vacuum drying were carried out. Then, the next
reaction was followed without the purification process.
(2) The synthesis of 2-phenylacetyl chloride (12)
[0248] After dissolving compound 2 (2.00 g, 14.7 mmol) in
SOCl.sub.2 (30 ml), the droppings were carried out at 0.degree. C.
After the agitation for 1 hour at room temperature, solvents were
removed by the distillation under the reduced pressure. Then, the
next reaction was followed without the purification process.
(3) The synthesis of
N-(4-chlorophenyl)-N-(2-oxo-2-phenylethyl)-2-phenylacetamide
(13)
[0249] After dissolving compound 12 (2.27 g, 14.7 mmol) in THF,
compound 11 (1.5 g, 6.1 mmol) was added thereto. After the
agitation for 2 hours at room temperature, three times extractions
were carried out with EA and three times washings were carried out
with brine. Water was removed by using Na.sub.2SO.sub.4 and
distillation under the reduced pressure was carried out. After the
removal of a junk by column chromatography (EA/HX=1/9), the next
reaction was followed as a crude condition.
(4) The synthesis of
1-(4-chlorophenyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one (14)
[0250] After dissolving compound 13 (2.22 g, 6.1 mmol) in
ethanol/H.sub.2O (v/v=1/1) 40 ml, K.sub.2CO.sub.3 (1.70 g, 12.2
mmol) was added thereto and the activation was carried out at room
temperature. After the activation, the reflux was conducted. After
the identification of the reaction termination with TLC, the
solution was dropped in the distilled water. After the produced
solid was distilled under the reduced pressure, the washing was
conducted by diethyl ether.
[0251] white solid (1.57 g, 71.6%); mp 173.degree. C.; IR (KBr,
cm.sup.-1) 1673; .sup.1H NMR (CDCl.sub.3-d) .delta. 4.568 (s, 2H),
7.212-8.399 (m, 12H), 7.728-7.757 (m, 2H); .sup.13C NMR
(CDCl.sub.3-d) .delta. 52.436, 119.556, 127.641, 128.323, 128.430,
128.741, 128.778, 129.006, 129.522, 129.590, 131.281, 132.320,
132.972, 137.864, 147.056, 169.285.
Example 5
The Preparations of Compounds 16 and 17
##STR00010##
[0252] (1) The synthesis of compound 16(16a-16e)
[0253] After melting compound 1 (1.00 g, 7.11 mmol) inacetic
anhydride (30 ml), compound 15 (6.51 mmol) and TEA (1 ml) were
sequentially added thereto. After 6 hours of the reaction with the
reflux, the temperature was reduced to room temperature. Three
times extractions were carried out with EA and seven times washings
were carried out with brine. Water was removed by using
Na.sub.2SO.sub.4 and distillation under the reduced pressure was
carried out. Then, the next reaction was followed without the
purification process.
(2) The synthesis of compound 17 (17a-17e)
[0254] After melting compound 16 (4.00 mmol) in toluene (5 ml), TEA
(0.840 ml, 6.00 mmol) and 4-chloroaniline (600 mg, 4.80 mmol) were
added thereto. After the reflux for 6 hours, Three times
extractions were carried out with EA and five times washings were
carried out with distilled water and brine, respectively. Water was
removed by using Na.sub.2SO.sub.4 and column chromatography was
carried out with EA/HX (1/9).
(3) The synthesis of
3-(2-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrol-2,5-dione
(17a)
[0255] pale yellow solid (700 mg, 26%); mp 46.degree. C.; IR (KBr,
cm.sup.-1) 1716; .sup.1H NMR (CDCl.sub.3-d) .delta. 7.287-7.494 (m,
13H); .sup.13C NMR (CDCl.sub.3-d) .delta. 126.979, 128.154,
128.192, 128.412, 129.034, 129.481, 130.027, 130.353, 130.831,
130.922, 133.182, 133.486, 135.177, 138.605, 167.925, 168.584.
(4) The synthesis of
3-(3-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrol-2,5-dione
(17b)
[0256] pale yellow solid (300 mg, 11.4%); mp 51.degree. C.; IR
(KBr, cm.sup.-1) 1712; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.215-7.508 (m, 13H); .sup.13C NMR (CDCl.sub.3-d) .delta. 126.872,
127.517, 127.836, 128.511, 128.973, 129.587, 129.606, 129.762,
129.883, 130.240, 133.144, 134.305, 134.418, 137.020, 168.440,
168.509.
(5) The synthesis of
3-(4-chlorophenyl)-1-(4-chlorophenyl)-4-phenyl-1H-pyrrol-2,5-dione
(17c)
[0257] pale yellow solid (1.01 g, 38.1%); mp 157.degree. C.; IR
(KBr, cm.sup.-1) 17.10; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.290-7.476 (m, 13H); .sup.13C NMR (CDCl.sub.3-d) .delta. 126.470,
126, 903, 127.775, 128.541, 128.761, 128.988, 129.656, 129.929,
130.096, 131.104, 133.152, 134.752, 136.079, 126.352, 168.622.
(6) The synthesis of
1-(4-chlorophenyl)-3-(2,6-dichlorophenyl)-4-phenyl-1H-pyrrol-2,5-dione
(17d)
[0258] pale yellow solid (200 mg, 7.6%); mp 134.degree. C.; IR
(KBr, cm.sup.-1) 1718; .sup.1H NMR (CDCl.sub.3-d) .delta.
7.326-7.529 (m, 12H); .sup.13C NMR (CDCl.sub.3-d) .delta. 127.032,
127.919, 128.169, 128.594, 129.041, 129.102, 129.982, 130.748,
131.233, 133.334, 133, 364, 134.889, 140.99, 168.372.
(7) The synthesis of
1-(4-chlorophenyl)-3-phenyl-4-(thiophen-2-yl)-1H-pyrrol-2,5-dione
(17e)
[0259] Orange solid (1.24 g, 67.0%); mp 176-177.degree. C.; IR
(KBr, cm.sup.-1) 1704; .sup.1H NMR (DMSO-d.sub.6) .delta.
7.092-7.114 (t, 1H), 7.467-7.549 (m, 9H), 7.687-7.763 (m, 2H);
.sup.13C NMR (CDCl.sub.3-d) .delta. 127.856, 128.538, 128.842,
128.978, 129.183, 129.608, 129.942, 129.987, 130.526, 130.928,
131.929, 132.391, 132.543, 168.639, 159.064.
Example 6
The Preparations of Compounds 18, 19, 20 and 21
##STR00011##
[0260] (1) The synthesis of 3,4-diphenylfuran-2(5H)-one(18)
[0261] After dissolving compound 2 (5.00 g, 36.7 mmol) in ACN (30
ml), compound 10 (7.31 g, 36.7 mmol) and TEA (5.63 ml) were
sequentially added thereto. After the agitation for 30 minutes at
room temperature, the temperature was reduced to 0.degree. C., DBU
(16.5 ml) was dropped and the agitation for 1 hour was carried out.
After the termination of the reaction, EA and 1N HCL aqueous
solution were added thereto and the organic layer was washed three
times with brine. Water was removed by using anhydrous
Na.sub.2SO.sub.4 and the distillation under the reduced pressure
was carried out to obtain compound 18.
[0262] Pale yellow solid (7.12 g, 82.1%); mp 113.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta. 5.120 (s, 2H), 7.288-7.420 (m,
1H); .sup.13C NMR (DMSO-d.sub.6) .delta. 70.394, 125.605, 127.159,
128.312, 128.410, 128.630, 128.896, 129.851, 130.246, 130.390,
155.913, 173.024.
(2) The synthesis of (Z)-2,3-diphenylbut-2-ene-1,4-diol (19)
[0263] After dissolving compound 18 (1.00 g, 4.23 mmol) in THF (20
ml), the temperature was reduced to or and DIBAL-H (12.96 ml) was
dropped. After the agitation for 3 hours was carried out, the
reaction was terminated and the extraction was conducted with EA.
The organic layer was washed five times with brine and the column
chromatography was carried out to obtain compound 19.
[0264] White solid (512 mg, 50.7%); mp 79.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 2.930 (s, 2H), 4.599 (s, 4H), 7.026-7.129 (m,
10H); .sup.13C NMR (DMSO-d.sub.6) .delta. 64.151, 126.491, 127.758,
128.205, 128.342, 128.357, 129.108, 140.713, 140.956.
(3) The synthesis of (Z)-(1,4-dibromobut-2-ene-2,3-diyl)dibenzene
(20)
[0265] After dissolving compound 19 (300 mg, 1.25 mmol) in THF (10
ml), PBr3 (338 mg, 1.25 mmol) was dropped at 0.degree. C. After the
agitation for 10 minutes at room temperature, the reflux was
conducted for 3 hours. After the termination of the reaction, the
temperature was reduced to room temperature. EA and water were
added thereto and the organic layer was washed three times with
brine. Water was removed by using anhydrous Na.sub.2SO.sub.4 and
the distillation under the reduced pressure was carried out for the
removal of the solvent. Then, column chromatography was conducted
to obtain compound 20.
[0266] White solid (320 mg, 70.0%); mp 98.degree. C.; .sup.1H NMR
(CDCl.sub.3) 4.511 (s, 4H), 7.057-7.081 (m, 4H), 7.131-7.148 (m,
6H); .sup.13C NMR (CDCl.sub.3) 35.101, 126.403, 127.921, 128.643,
131.241, 139.402.
(4) The synthesis of
1-(4-chlorophenyl)-3,4-diphenyl-2,5-dihydro-1H-pyrrole (21)
[0267] After dissolving compound 20 (300 mg, 0.819 mmol) and
4-chloroaniline (105 mg, 0.819 mmol) in DCM (10 ml), TEA (457 l,
3.28 mmol) was added thereto and the reflux was conducted for 4
hours. After the termination of the reaction, the temperature was
reduced to room temperature and water was added thereto. The
organic layer was washed with water and water was removed by using
anhydrous Na.sub.2SO.sub.4. After the distillation under the
reduced pressure was carried out for the removal of the solvent,
column chromatography was conducted to obtain compound 21.
[0268] Pale yellow sold (80 mg, 30.0%); mp 158.degree. C.; .sup.1H
NMR (CDCl.sub.3) .delta. 4.291 (s, 4H), 6.370-6.392 (d, 2H),
6.892-7.188 (m, 12H); .sup.13C NMR (CDCl.sub.3) .delta. 66.410,
115.703, 127.231, 127.405, 127.928, 128.642, 129.302, 140.684,
144.986.
Example 7
The preparation of Compound 23
##STR00012##
[0270] The synthesis of
1-(4-chlorophenyl)-3,4-diphenylpyrrolidine-2,5-dione (23)
[0271] After dissolving compound 22 (200 mg, 0.740 mmol) in DCM (10
ml), EDC (284 mg, 1.48 mmol) and HOBt (200 mg, 1.48 mmol) were
added thereto and the agitation for 24 hours was conducted at room
temperature. After the termination of the reaction, the
distillation under the reduced pressure was carried out. The
produced solid was removed and compound 23 was obtained by the
column chromatography.
[0272] White solid (50 mg, 11.2%); mp 176.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 4.226 (s, 4H), 7.241-7.265 (m, 4H),
7.349-7.416 (m, 8H), 7.444-7.466 (d, 2H); .sup.13C NMR (CDCl.sub.3)
.delta. 55.322, 113.127, 127.508, 128.130, 129.214, 129.252,
130.147, 134.364, 135.988, 175.133.
[0273] Table 2 shows the structures and the properties of the
compounds that were synthesized by the above examples.
TABLE-US-00002 TABLE 2 The structures and the properties of
Compounds in Examples ##STR00013## ##STR00014## ##STR00015## ClogP
Property 348.36 30 mg 2.57 ##STR00016## 4a 409.52 30 mg 6.65
##STR00017## 4b 325.36 30 mg 4.60 ##STR00018## 4c 359.81 30 mg 5.19
##STR00019## 4d 359.81 30 mg 5.59 ##STR00020## 4e 359.81 30 mg 5.59
##STR00021## 4f 393.36 30 mg 5.97 ##STR00022## 4g 348.36 30 mg 2.57
##STR00023## 4h 343.72 30 mg 3.90 ##STR00024## 4i 343.72 30 mg 3.90
##STR00025## 7a 283.71 30 mg 4.35 ##STR00026## 7b 318.15 30 mg 4.75
##STR00027## 7c 318.15 30 mg 4.75 ##STR00028## 7d 318.15 30 mg 5.59
##STR00029## 4j 343.35 20 mg 4.848 ##STR00030## 4k 343.35 20 mg
5.018 ##STR00031## 4l 343.35 20 mg 5.018 ##STR00032## 4m 339.39 20
mg 3.634 ##STR00033## 4n 357.38 20 mg 3.777 ##STR00034## 4o 357.38
20 mg 3.777 ##STR00035## 4p 357.38 20 mg 3.777 ##STR00036## 4q
353.41 20 mg 4.263 ##STR00037## 4r 371.40 20 mg 4.406 ##STR00038##
4s 371.40 20 mg 4.406 ##STR00039## 4t 371.40 20 mg 4.406
##STR00040## 17a 394.25 20 mg 6.301 ##STR00041## 17b 394.25 20 mg
6.301 ##STR00042## 17c 394.25 20 mg 6.301 ##STR00043## 17d 428.70
20 mg 7.014 ##STR00044## 8 361.82 20 mg 4.9168 ##STR00045## 14
345.82 20 mg 8.027 ##STR00046## AJ-3036 404.93 20 mg 6.1121
##STR00047## 6a 265.26 20 mg 3.25 ##STR00048## 17e 365.84 20 mg
5.9628 ##STR00049## AJ-3039 385.72 20 mg 3.8688 ##STR00050## 21
331.84 20 mg 6.3168 ##STR00051## 23 361.82 20 mg 4.372
##STR00052##
Experimental Example 1
Inhibition Effect on Osteoclast Differentiation
[0274] RAW 264.7 cell, a mouse macrophage/monocyte cell line which
can be differentiated in various forms depends on its surrounding
environments and stimuli, is differentiated to multinucleated
osteoclast by the stimulus of RANKL (100 ng/ml). Inhibition effect
of each compound on osteoclast differentiation was analyzed by
comparing the degree of osteoclast differentiation when RAW 264.7
cell was treated with RANKL and the subject each compound
simultaneously.
[0275] The experiment procedures were more specifically described
as follows:
[0276] Inhibition activities of osteoclast differentiation in
respect of compounds 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k,
4l, 4m, 4n, 4o, 7a, 7b, 7c, and 7d were tested. Macrophage/monocyte
RAW 264.7 cell was used as a cell and 1.5.times.10.sup.3 cells were
seeded in a 96 well plate. The synthetized compound and zoledronic
acid as a control material were dissolved in 10% DMSO aqueous
solution and treated to cells according to each concentration
(0.5M, 1M, 5M and 10M).
[0277] After pre-treating each compound for 6 hours and then,
treating RANKL, the incubation was carried out for 7 days in a 5%
CO.sub.2 incubator. To observe osteoclasts well, they were stained
by TRAP(tartrate resistance acid phosphatase) stain method. The
number of cells differentiated to osteoclasts was counted and then,
a comparative analysis was conducted for the degree of each
compound's osteoclast differentiation. The results were shown in
the following table 3:
TABLE-US-00003 TABLE 3 Results of osteoclast differentiation
degrees of the compounds by concentration. concentration compounds
0.5 .mu.M 1 .mu.M 5 .mu.M 10 .mu.M control 51.5 51.5 51.5 51.5 ZA
21 58 20 57 25 27 12 20 4a 4 7 13 29 20 57 50 92 4b 29 39 18 30 14
25 16 43 4c 23 35 26 16 13 17 13 26 4d 50 45 38 33 27 34 13 37 4e
23 26 21 29 9 10 7 9 4f 23 26 21 29 9 10 7 9 4g 34 24 48 23 19 26
30 49 4h 48 39 45 38 37 28 31 15 4i 14 28 21 43 27 31 33 49 4j 23
22 45 23 29 42 21 35 4k 40 -- 25 -- 40 -- 28 -- 4l 7 18 14 22 9 42
24 25 4m 19 27 11 16 30 56 12 24 4n 15 13 23 18 14 24 52 55 4o 21
32 26 20 41 29 33 26 7a 18 29 10 31 31 24 37 38 7b 41 24 24 29 40
44 39 35 7c 26 18 13 15 32 20 27 24 7d 12 21 28 29 22 40 24 27
[0278] Only the osteoclasts containing nucleus number more than 4
were only counted as effective analysis targets in both control and
experiment groups (See FIGS. 1 and 2).
[0279] As the results, all synthetic compounds showed the
inhibition effects on osteoclast differentiation. Especially,
compound 4e showed more superior inhibition effect on osteoclast
differentiation than the control group of zoledronic acid.
Experimental Example 2
Inhibition of NF-kappa B
[0280] The compound 4e showed relatively high inhibition effect of
the differentiation of osteoclasts and the control zolendronic acid
(ZA) group were comparatively analyzed for the regulation function
of NF-kappa B. After the concentration of 10 .mu.M ZA and 10 .mu.M
compound 4e were treated to RAW264.7 cells for 12 hours, ALLN
(protease inhibitors, 50 .mu.g/ml) and RANKL were continuously
treated for 30 minutes respectively. It is confirmed that the
compound of 4e is suppressed the mechanism of NF-kappa B 2 times
more than ZA (FIG. 3)
Experimental Example 3
Analysis of Inhibition Activity of RANK Receptor Binding
[0281] After the human recombinant sRNAK receptor molecule (100
.mu.g/ml, PeproTech) was fixed to the protein chip(PeproTech),
human recombinant sRANK ligand(10 .mu.g/ml, PeproTech) was treated
and incubated for 1 hour. OPG molecule was used as a positive
control, and the compound and OPG are simultaneously treated. A
comparative analysis was conducted to compare the binding
inhibition effect of the compound using OPG as a control. Mouse
anti-human sRANK ligand monoclonal antibody coupled with
Cy5-fluorescent (1.0 .mu.g/ml, PeproTech) was treated for 30
minutes, and scanning the strength of luminescence by using image
analysis scanner and analyzed to the GraphPad Prism 4 software. Out
of the above stated compounds, compound 4e and ZA were
comparatively analyzed. The binding inhibitory activity upon to
RANK receptor of the positive control was 83.65% and that of ZA was
27.55%. That of the compound 4e was 46.70%. The binding inhibitory
activity upon to the RANK receptor of compound 4e showed superior
about 1.7 times to that of ZA (n=6)(FIG. 4)
Experimental Example 4
Analysis of Inhibition Activity of Osteopontin-Integrin Binding
[0282] Osteopontin(OPN) molecule is the one of bone phosphoproteins
and acts as an important factor of bone remodeling. The OPN
provides a role of that integrin molecule of osteoclasts can be
attached to the bone inorganic matrix with inducing osteoclasts to
develop the formation of tight junction to the bone surface (i.e.,
ruffled borders), and thus, it can initiate the bone resorption
eventually.
[0283] After the human integrin .alpha..sub..gamma..beta..sub.3(100
.mu.g/ml, Milipore) was fixed to the protein chip(PeproTech), the
human recombinant OPN (40 .mu.g/ml, PeproTech) molecule coupled
with Cy5-fluorescent was reacted for 1 hour. Echistatin molecule(40
.mu.g/ml, Sigma-Aldrich) was used as a positive control. The
samples were simultaneously treated to conduct a comparative
analysis for the binding inhibitory effect thereof. Finally, the
strength of luminescence is scanned by using image analysis scanner
and analyzed to the GraphPad Prism 4 software. The binding
inhibitory rate of the positive control with ingegrin molecule was
51.75%, that of ZA was 8.65%, and that of compound 4e was 26.45%.
The binding inhibitory activity of compound 4e of the invention was
about 3 times higher than that of ZA (n=6)(FIG. 5).
Preparation Example 1
The Preparation of the Powder Form
TABLE-US-00004 [0284] Compound 4e 10 mg Sucrose 100 mg Talc 10
mg
[0285] The above ingredients were mixed and filled in packs to
obtain the powder form.
Preparation Example 2
The Preparation of the Tablet Form
TABLE-US-00005 [0286] Compound 4e 10 mg Starch 100 mg Sucrose 100
mg Magnesium Stearate 2 mg
[0287] The above ingredients were mixed and the mixture was
formulated into tablets.
Preparation Example 3
The Preparation of the Capsule Form
TABLE-US-00006 [0288] Compound 4e 10 mg Crystalline Celluose 3 mg
Lactose 15 mg Magnesium Stearate 1 mg
[0289] The above ingredients were mixed and the mixture was
formulated into capsules by using gelatin capsule.
Preparation Example 4
The Preparation of the Granule Form
TABLE-US-00007 [0290] Compound 4e 10 mg Soybean extracts 50 mg
Glucose 200 mg Starch 500 mg
[0291] The above ingredients were mixed, 100 mL of 30% ethanol was
added and dried in 60.degree. C. to formulate granules.
Preparation Example 5
The Preparation of the Pill Form
TABLE-US-00008 [0292] Compound 4e 20 mg Lactose 1,500 mg Glycerin
1,500 mg Starch 980 mg
[0293] The above ingredients were mixed and the mixture was
formulated into pills by using conventional methods. The weight of
one pill was 4 g.
Preparation Example 6
The Preparation of the Injection
TABLE-US-00009 [0294] Compound 4e 10 mg Mannitol 180 mg Sterile
distilled water for injection 2,970 mg Na.sub.2HPO.sub.412H.sub.2O
30 mg
[0295] The above ingredients were mixed and the mixture was
formulated into injection by using conventional methods. The volume
of each of the ampules was 2 mL.
Preparation Example 7
The preparation of the Solution
TABLE-US-00010 [0296] Compound 4e 10 mg Isomerized glucose syrup
10,000 mg Mannitol 5,000 mg Purified water Properly
[0297] The above ingredients were mixed and dissolved into the
purified water by using conventional methods. Proper flavoring
agent was added to the above mixture and sterilized to formulated
into solutions.
* * * * *