TECHNICAL FIELD
[0001] The present invention relates to a novel substituted biaryl compound, or a
pharmacologically acceptable salt thereof, that is useful as pharmaceuticals. More
particularly, the substituted biaryl compound of the present invention is useful as a
therapeutic agent andlor prophylactic agent for interstitial pneumonia and pulmonary
10 fibrosis since the substituted biaryl compound has an excellent inhibition effect of
pulmonary fibroblast proliferation.
BACKGROUND ART
[0002] Pulmonary fibrosis is characterized by hyperplasia of stromal cells due to
15 formation of bundles of collagen and the like produced by proliferative fibroblasts in
alveolar walls, and is a disease whose cardinal symptoms are dry cough and exertional
dyspnea. This disease is caused by progression from interstitial pneumonia, and in
many cases, interstitial pneumonia can be the preliminary symptom. Prognosis of
interstitial pneumonia is poor and, in many cases, interstitial pneumonia progresses to
20 pulmonary fibrosis. There are many cases where the interstitial pneumonia, in which
the cause can be identified, is cured by removing the cause or by administering
anti-inflammatory agents such as steroids; however, for the case of unexplained
idiopathic interstitial pneumonia, no radical treatments currently exist, and treatments,
such as administration of steroids, azathioprine, cyclophosphamide and the like when
25 the symptoms worsen, and oxygen therapy when hypoxemia is caused, are performed at
the best. If unexplained idiopathic interstitial pneumonia progresses to pulmonary
fibrosis, about the half of the pulmonary fibrosis patients die within 5 years from
occurrence of the symptoms. Because of this, interstitial pneumonia is designated as
one of the specified intractable diseases in Japan.
30 [0003] On the other hand, it has been known that prostaglandin E2 (hereinafter,
abbreviated as "PGE2") has a wide variety of bioactivities as a metabolic product in the
arachidonic acid cascade, and acts as an agonist against four receptors that are EP1, EP2,
EP3, and EP4. Recently, it has been reported that the EP2 receptor is a receptor that is
related to inhibition of pulmonary fibroblast proliferation and collagen formation via
35 PGE2 (see Non-Patent Document 1). Furthermore, it has been suggested that the EP2
receptor is also a receptor that is related to inhibition of apoptosis of alveolar epithelial
cells via PGE2 (see Non-Patent Document 2). Therefore, a compound that exhibits
agonistic effect like that of PGE2, and in particular, a compound that exhibits effect of
EP2 selective agonist is expected to be a therapeutic agent andlor prophylactic agent for
interstitial pneumonia and pulmonary fibrosis.
5 [0004] So far, it has been disclosed that a prostanoid-based compound exhibiting EP2
agonistic effect is useful for prophylaxis andlor therapy of respiratory diseases including
pulmonary fibrosis (see Patent Documents 1 and 2). Furthermore, a
non-prostanoid-based compound exhibiting EP2 agonistic effect has been also known
(see Patent Documents 3 to 17). Among these, various diseases that are exemplified as
10 the targets of the medical use of the compounds described in Patent Documents 9 and
11 to 17 include pulmonary fibrosis. However, in Patent Documents 9 and 11 to 17,
there are no specific descriptions regarding pharmacological test examples in which
these compounds are useful for pulmonary fibrosis. Furthermore, there are no specific
descriptions in any of these Patent Documents regarding working examples of a
15 sulfonamide compound related to the present invention having, as its partial structure, a
biaryl group in which a particular substituent is substituted at a particular part.
PRIOR ART DOCUMENTS
Patent Documents
20 [0005] Patent Document 1 : W02003174483
Patent Document 2: W020061043655
Patent Document 3 : W098128264
Patent Document 4: W099119300
Patent Document 5: W020041078 169
Patent Document 6: W0200810 155 17
Patent Document 7: W020051080367
Patent Document 8: W0200710 17687
Patent Document 9: W020091113600
Patent Document 10: W02010/113957
Patent Document 1 1 : W020 1 11030864
Patent Document 12: W020111030865
Patent Document 13: W020111030868
Patent Document 14: W02011/030871
Patent Document 15: W020111030872
Patent Document 16: W020111030873
Patent Document 17: W020111078303
Non-Patent Documents
[0006] Non-Patent Document 1 : American Journal of Physiology-Lung Cellular and
Molecular Physiology, 292, LA05 (2007)
5 Non-Patent Document 2: American Journal of Respiratory Cell and Molecular
Biology, 45,445 (201 1)
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
10 [0007] For the purpose of developing an excellent therapeutic agent and/or
prophylactic agent for interstitial pneumonia and pulmonary fibrosis, the present
inventors conducted intensive research on various sulfonamide compounds exhibiting
EP2 agonistic effect. As a result, it was found that introduction of a particular
substituent having a particular length to a particular part of a terminal aryl group of a
15 sulfonamide compound having a biaryl group significantly increased the inhibition
effect of pulmonary fibroblast proliferations, thereby making it particularly useful as a
therapeutic agent andlor prophylactic agent for interstitial pneumonia and pulmonary
fibrosis, and thus leading to completion of the present invention.
The present invention provides a substituted biaryl compound or a
20 pharmacologically acceptable salt thereof that exhibits excellent inhibition effect of
pulmonary fibroblast proliferation and, in particular, that exhibits EP2 agonistic effect
that is useful as a therapeutic agent and/or prophylactic agent for interstitial pneumonia
and pulmonary fibrosis.
25 Means for Solving the Problems
[0008] The present invention provides the following.
[0009] (1) A substituted biaryl compound of general formula (I):
[OO 101 wherein
30 R' represents a protected or unprotected carboxy group,
W represents a nitrogen atom or -CH= group,
R2 represents an ethoxy group, 1-propenyl group, or 1-propynyl group, and
Z represents a phenyl group, 3-fluorophenyl group, pyridin-2-yl group,
pyridin-3-yl group, thiophen-2-yl group, or thiophen-3-yl group;
or a pharmacologically acceptable salt thereof.
5 [0011] (2) The substituted biaryl compound according to (I), where in general formula
(11,
R1 represents a carboxy group or C1-C6 alkoxycarbonyl group,
or a pharmacologically acceptable salt thereof.
[0012] (3) The substituted biaryl compound according to (I), where in general formula
10 (I),
R' represents a carboxy group, ethoxycarbonyl group, isopropoxycarbonyl
group, or hexyloxycarbonyl group,
or a pharmacologically acceptable salt thereof.
[0013] (4) The substituted biaryl compound according to (I), where in general formula
15 (11,
R' represents a carboxy group, ethoxycarbonyl group, isopropoxycarbonyl
group, or hexyloxycarbonyl group,
W represents a nitrogen atom or -CH= group,
R~ represents a 1-propenyl group or 1-propynyl group, and
20 Z represents a phenyl group, 3-fluorophenyl group, pyridin-2-yl group,
pyridin-3-yl group, thiophen-2-yl group, or thiophen-3-yl group,
or a pharmacologically acceptable salt thereof.
[0014] (5) The substituted biaryl compound according to (I), where the substituted
biaryl compound of general formula (I) is
25 ethyl (6- {[3'-(1 -propenyl)biphenyl-4-ylmethyl](p yridin-2-ylsulfony1)-
aminomethy1)pyridin-2-ylamino)acetate,
){]lyhtemly-4-lynehpib)1yneporp-1(-'3[{ (6- -
pyridin-2-y1amino)acetic acid,
ethyl (6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfony1)-
30 aminomethy1)pyridin-2-ylamino)acetate,
(6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](py } -
pyridin-2-y1amino)acetic acid,
ethyl (6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl](pyridin-3-ylsulfonyl)-
aminomethy1)pyridin-2-ylamino)acetate,
35 (6- {[3 '-(1 -propynyl)biphenyl-4-ylmethyl](pyridin-3-ylsulfonyl)aminomethyl} -
pyridin-2-y1amino)acetic acid,
{6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-y1su1fony1)aminomethy1]-
pyridin-2-ylamino)a cetic acid,
hexyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsu1fony1)inomethy1]-
pyridin-2-ylamino)a cetate,
5 (6-[(3 '-ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]-
pyridin-2-ylamino) acetic acid,
{6-[(benzenesulfonyl)(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-
ylamino) acetic acid,
(6-[(3 '-ethoxybiphenyl-4-ylmethyl)(thiophen-2-ylsulfonyl)aminomethyl]-
10 pyridin-2-ylamino)a cetic acid,
(6-{ [4-(6-ethoxypyridin-2-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl)-
pyridin-2-y1amino)acetic acid,
ethyl (6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl](thiophen-2-ylsulfonyl)-
aminomethy1)pyridin-2-ylamino)acetate,
15 (6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl] (thiophen-2-ylsulfony1)-
aminomethy1)pyridin-2-y1amino)acetic acid,
ethyl (6- {(benzenesulfonyl)[3'-(1 -propynyl)biphenyl-4-ylmethyllaminomethy1)
pyridin-2-ylamino)acetate,
(6-{ (benzenesulfonyl)[3 '-(1 -propynyl)biphenyl-4-ylmethyl]aminomethyl}-
20 pyridin-2-y1amino)acetic acid,
ethyl (6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl](thiophen-3-ylsulfonyl)-
aminomethyl) pyridin-2-ylamino)acetate,
(6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](thiophen-3-ylsulfonyl)-
aminomethy1)pyridin-2-y1amino)acetic acid,
25 (6- ((3-fluorobenzenesulfonyl)[3'-(1 -propynyl)biphenyl-4-ylmethyllaminomethy1)
pyridin-2-y1amino)acetic acid, or
isopropyl(6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)-
aminomethyl) pyridin-2-ylamino)acetate,
or a pharmacologically acceptable salt thereof.
30 [0015] (6) A pharmaceutical composition comprising the substituted biaryl compound
according to any of (1) to (5), or a pharmacologically acceptable salt thereof, as an
active ingredient.
[OO 161 (7) The pharmaceutical composition according to (6), for prophylaxis or
treatment of interstitial pneumonia andlor pulmonary fibrosis.
35
Effect of the Invention
[0017] The substituted biaryl compound of general formula (I) or the
pharmacologically acceptable salt thereof of the present invention is useful as
pharmaceuticals, especially as a therapeutic agent andlor prophylactic agent for
interstitial pneumonia and pulmonary fibrosis, by exhibiting EP2 agonistic effect and
5 excellent inhibition effect of pulmonary fibroblast proliferation.
MODE FOR CARRYING OUT THE INVENTION
[OO 181 Preferred embodiments of each substituent in the substituted biaryl compound
of general formula (I) above are described below.
10 [0019] The protected or unprotected carboxy group represented by R' of general
formula (I) refers to a carboxy group or a carboxyl group protected by a protective
group. Examples of such a protective group include ester-type protective groups.
Examples of the partial structure of the ester-type protective group include C1-C12 alkyl
groups, such as a methyl group, ethyl group, propyl group, isopropyl group,
15 1-ethylpropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group,
3,3-dimethylbutyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl
group, 1 -methylbutyl group, hexyl group, 1 -methylpentyl group, 2-methylpentyl group,
3-methylpentyl group, 1 -ethylbutyl group, 2-ethylbutyl group, heptyl group, octyl group,
nonyl group, decyl group, undecyl group, and dodecyl group; C7-CI8 aralkyl groups,
20 such as a benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group,
phenylpentyl group, phenylhexyl group, phenylheptyl group, phenyloctyl group,
phenylnonyl group, phenyldecyl group, phenylundecyl group, and phenyldodecyl
group; C1-C4 alkyl groups substituted with a C2-C5 alkanoyloxy group, such as an
acetoxymethyl group, 1 -acetoxyethyl group, 1 -acetoxypropyl group, 1 -acetoxybutyl
25 group, propanoyloxymethyl group, 1 -propanoyloxyethyl group, butanoyloxymethyl
group, 1 -butanoyloxyethyl group, pivaloyloxymethyl group, 1 -pivaloyloxyethyl group,
1 -pivaloyloxypropyl group, and 1-pivaloyloxybutyl group; C1-C4 alkyl groups
substituted with a (C1-C4 alkoxy)carbonyloxy group, such as a
methoxycarbonyloxymethyl group, 1 -methoxycarbonyloxyethyl group,
3 0 ethoxycarbonyloxymethyl group, 1 -ethoxycarbonyloxyethyl group,
propoxycarbonyloxymethyl group, 1 -propoxycarbonyloxyethyl group,
isopropoxycarbonyloxymethyl group, 1-isopropoxycarbonyloxyethyl group,
butoxycarbonyloxymethyl group, 1-butoxycarbonyloxyethyl group,
tert-butoxycarbonyloxymethyl group, and 1-tert-butoxycarbonyloxyethyl group;
35 N,N-dialkylaminocarbonylalkyl groups, such as an N,N-dimethylaminocarbonylmethyl
group and N,N-diethylaminocarbonylmethyl group; 2-(N,N-dialky1amino)ethyl groups,
such as a 2-(N,N-dimethy1amino)ethyl group and 2-(N,N-diethy1amino)ethyl group;
C1-C4 alkyl groups substituted with a 5-membered or 6-membered saturated
heteromonocyclic group having 1 or 2 hetero atoms selected from N, 0, or S, such as a
2-(morpholin-4-y1)ethyl group, 2-piperidinoethyl group, and
5 2-(4-methy1piperidino)ethyl group; and groups that is readily deprotected in vivo to be
converted to a carboxy group, such as a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl
group and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyglr oup. The partial structure of
the ester-type protective group is preferably a C1-C12 alkyl group, C7-C18 aralkyl group,
C1-C2 alkyl group substituted with a C2-C5 alkanoyloxy group, C1-C2 alkyl group
10 substituted with a (C1-C4 alkoxy)carbonyloxy group,
N,N-dimethylaminocarbonylmethyl group, 2-(morpholin-4-y1)ethyl group,
(5-methyl-2-0x0- 1,3 -dioxolen-4-y1)methyl group, or
(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyglr oup. The partial structure of the
ester-type protective group is more preferably a C1-C6 alkyl group, and particularly
15 preferably an ethyl group, isopropyl group, or hexyl group.
[0020] Therefore, in general formula (I) of the present invention, R' is preferably a
carboxy group or a C1-C6 alkoxycarbonyl group. In a specific embodiment of general
formula (I) of the present invention, R' is a carboxy group, ethoxycarbonyl group,
isopropoxycarbonyl group, or hexyloxycarbonyl group.
20 [0021] In general formula (I) of the present invention, W is a nitrogen atom or -CH=
group. That is, in general formula (I) of the present invention, the aromatic ring
containing W is a pyridine ring or benzene ring. In a specific embodiment of general
formula (I) of the present invention, W is a -CH= group. In another specific
embodiment of general formula (I) of the present invention, W is a nitrogen atom.
25 [0022] In general formula (I) of the present invention, R2 is an ethoxy group,
1-propenyl group, or 1-propynyl group. In a specific embodiment of general formula
(I) of the present invention, R~ is an ethoxy group. In another specific embodiment of
general formula (I) of the present invention, R2 is a 1-propenyl group or 1-propynyl
group.
30 [0023] In general formula (I) of the present invention, Z is a phenyl group,
3-fluorophenyl group, pyridin-2-yl group, pyridin-3-yl group, thiophen-2-yl group, or
thiophen-3-yl group. In a specific embodiment of general formula (I) of the present
invention, Z is a phenyl group, 3-fluorophenyl group, pyridin-2-yl group, or
pyridin-3-yl group, and preferably a phenyl group, pyridin-2-yl group, or pyridin-3-yl
35 group. In another specific embodiment of general formula (I) of the present invention,
Z is a thiophen-2-yl group or thiophen-3-yl group, and preferably a thiophen-2-yl group.
[0024] When the compound of general formula (I) of the present invention has a
geometrical isomer or a rotational isomer, these isomers are also included in the scope
of the present invention. Furthermore, when the compound has a proton tautomer,
such tautomer is also included in the scope of the present invention.
5 [0025] The compound of general formula (I) of the present invention can be converted
to, as necessary, a pharmacologically acceptable salt by a conventional method;
however, the pharmacologically acceptable salt can be also directly separated from the
reaction mixture as a salt.
LO0261 The compound of general formula (I) of the present invention is converted to a
10 pharmacologically acceptable acid addition salt by treating it with an acid. Examples
of such a salt include, for example, inorganic acid salts, such as hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate, or phosphate; or organic acid salts, such as
acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate,
tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate,
15 benzenesulfonate, p-toluenesulfonate, glutamate, or aspartate.
[0027] When R' in the compound of general formula (I) of the present invention is a
carboxy group, the compound is converted to a pharmacologically acceptable basic salt
by treating it with a base. Examples of such a salt include metal salts, such as sodium
salt, potassium salt, calcium salt, or magnesium salt; inorganic salts, such as ammonium
20 salt; or organic amine salts, such as triethylamine salt or guanidine salt.
[0028] For cases where R' of the compound of general formula (I) of the present
invention is a carboxy group protected by a protective group, when administered
intravitally (in vivo test or the like), the compound is easily hydrolyzed by a
biochemical reaction (e.g., esterase or the like) in vivo, and thus can be converted to a
25 pharmacologically active compound in which R' is a carboxy group.
[0029] A representative method for producing the compound of the present invention
is described below. Note that specific method for producing each compound of the
present invention is described in detail in Examples described below.
[0030]
L I
Compound (a)
f
Compound (d) -
Compound (c) d route 3-1)
x'
?' / Oz~'.l 1 (Synthetic route 4)
Compound (e) RZyW,yB.OH Compound (i)
f R3 0 A,,kO0. ~~ Comp~und(g ) / HNW' A o e R 1 '
(Synthetic route 3-2) R2&
Compound (f) / Compound (h)
Wherein R2, W, and Z are as defined in the above. R" represents a protective
group of the carboxy group, R3 represents a tert-butoxycarbonyl group or hydrogen
atom, X represents a hydroxy group, chloro group, bromo group, iodo group,
5 methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, or
trifluoromethanesulfonyloxy group, and X' represents a chloro group, bromo group, or
iodo group.
[003 11 By any method of synthetic routes 1 to 4, the compound of general formula (I)
of the present invention can be obtained as a compound (Ia) in which R3 is a hydrogen
10 atom for cases where R' is a carboxy group, or can be obtained as a compound (I9) in
which R3 is a hydrogen atom for cases where R' is a carboxy group protected by a
protective group.
[0032] Synthetic route 1
When X is a hydroxy group in the compound (a), the compound (Iy) can be
15 obtained by reacting the compound (a) with the compound (b) in an inert organic
solvent in the presence of an azo compound-based condensing agent and a phosphine
reagent.
The inert organic solvent used is not particularly limited as long as it does not
inhibit the reaction and dissolves the raw materials at certain degrees. Examples of the
20 inert organic solvent include aromatic hydrocarbons, such as benzene, toluene, and
xylene; ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and
1,2-dimethoxyethane; amides, such as N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methylpynolidone; nitriles, such as acetonitrile and
propionitrile; esters, such as methyl acetate, ethyl acetate, and isopropyl acetate; and
arbitrary mixed solvents thereof, and preferably tetrahydrofuran,
5 N,N-dimethylformamide, acetonitrile, or a mixed solvent thereof.
Examples of the azo compound-based condensing agent used include diethyl
azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD),
N,N,N',N'-tetraisopropylazodicarboxamide (TIPA), 1,l '-(azodicarbony1)dipiperidine
(ADDP), N,N,N',NY- tetramethylazodicarboxamide( TMAD), or
10 1,6-dimethyl-1 ,5,7-hexahydro-l ,4,6,7-tetrazocine-2,5-dion(eD HTD), and preferably
diethylazodicarboxylate (DEAD) or N,N,N',NY -tetramethylazodicarboxamide (TMAD).
A molar amount of the azo compound-based condensing agent used is typically 0.9 to
10-fold, and preferably 1 to 5-fold based on 1 mole of the compound (b).
Examples of the phosphine reagent used include trimethylphosphine,
1 5 triethylphosphine, tri-n-butylphosphine, or triphenylphosphine, and preferably
tri-n-butylphosphine or triphenylphosphine. A molar amount of the phosphine
compound used is typically 0.9 to 10-fold, and preferably 1 to 5-fold based on 1 mole of
the compound (b).
A molar amount of the compound (a) used is typically 0.8 to 2-fold, and
20 preferably 0.9 to 1.5-fold based on 1 mole of the compound (b).
Although varying depending on types and amounts used of raw materials,
solvents, and the like, the reaction temperature is typically -20°C to 100°C, and
preferably -5°C to 50°C.
Although varying depending on the reaction temperature and the like, the
25 reaction time is typically 30 minutes to 48 hours, and preferably 1 hour to 24 hours.
[0033] When X in the compound (a) is a chloro group, bromo group, iodo group,
methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, or
trifluoromethanesulfonyloxy group, the compound (1') can be obtained by reacting the
compound (a) with the compound (b) in an inert organic solvent in the presence of a
30 base.
The inert solvent used is not particularly limited as long as it does not inhibit
the reaction and dissolves the raw materials at certain degrees. Examples of the inert
solvent include ethers, such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane;
halogenated aliphatic hydrocarbons, such as methylene chloride, chloroform, and
35 1,2-dichloroethane; nitriles, such as acetonitrile and propionitrile; esters, such as methyl
formate, ethyl formate, methyl acetate, and ethyl acetate; aromatic hydrocarbons, such
as benzene and toluene; amides, such as N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methylpyrrolidone; sulfoxides, such as dimethyl
sulfoxide; and arbitrary mixed solvents thereof, and preferably tetrahydrofuran,
N,N-dimethylformamide, methylene chloride, or 1,2-dichloroethane.
5 Examples of the base used include alkali metal hydrides, such as sodium
hydride and potassium hydride; alkali metal amides, such as lithium amide, sodium
amide, lithium diisopropylamide, and lithium bis(trimethylsily1)amide; alkali metal
alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, and
potassium tert-butoxide; alkali metal carbonates, such as sodium carbonate and
10 potassium carbonate; amines, such as triethylamine, tributylamine,
diisopropylethylamine, pyridine, picoline, 2,6-lutidine, and 4-dimethylaminopyridine,
and preferably sodium hydride, potassium carbonate, triethylamine, or
diisopropylethylamine. However, when the inert solvent used is an ester, nitrile, or
halogenated aliphatic hydrocarbon, the base is preferably triethylamine or
15 diisopropylethylamine.
A molar amount of the base used is typically 1 to 5-fold, and preferably 1 to
2.5-fold based on 1 mole of the compound (b).
A molar amount of the compound (a) used is typically 0.5 to 3-fold, and
preferably 0.5 to 1.5-fold based on 1 mole of the compound (b).
20 Although varying depending on types and amounts used of raw materials,
solvents, and the like, the reaction temperature is typically -80°C to 100°C, and
preferably 0°C to 80°C.
Although varying depending on the reaction temperature and the like, the
reaction time is typically 10 minutes to 48 hours, and preferably 1 hour to 24 hours.
25 [0034] Synthetic route 2
When X is a hydroxy group in the compound (d), the compound (1') can be
obtained by reacting the compound (c) with the compound (d) in an inert organic
solvent in the presence of an azo compound-based condensing agent and a phosphine
reagent. This step is performed in accordance with the case where X in the compound
30 (a) is a hydroxy group in "Synthetic route 1" described above except for using the
compound (d) in place of the compound (a) and using the compound (c) in place of the
compound (b).
When X in the compound (d) is a chloro group, bromo group, iodo group,
methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, or
35 trifluoromethanesulfonyloxy group, the compound (1') can be obtained by reacting the
compound (c) with the compound (d) in an inert organic solvent in the presence of a
base. This step is performed in accordance with the case where X in the compound (a)
is a chloro group, bromo group, iodo group, methanesulfonyloxy group,
benzenesulfonyloxy group, p-toluenesulfonyloxy group, or trifluoromethanesulfonyloxy
group in "Synthetic route 1" described above except for using the compound (d) in place
5 of the compound (a) and using the compound (c) in place of the compound (b).
[0035] Synthetic route 3
Synthetic route 3-1 is a step of obtaining the compound (f) by reacting the
compound (c) with the compound (e) in an inert organic solvent in the presence of a
base. This step is performed in accordance with the case where X in the compound (a)
10 is a chloro group, bromo group, iodo group, methanesulfonyloxy group,
benzenesulfonyloxy group, p-toluenesulfonyloxy group, or trifluoromethanesulfonyloxy
group in "Synthetic route 1" described above except for using the compound (e) in place
of the compound (a) and using the compound (c) in place of the compound (b).
In Synthetic route 3-2, the compound (1') can be obtained by reacting the
15 compound (f) obtained in Synthetic route 3-1 with the compound (g) in an inert solvent
under inert gas atmosphere in the presence of a palladium catalyst and either a base or a
fluoride.
The inert solvent used is not particularly limited as long as it does not inhibit
the reaction and dissolves the raw materials, catalyst, and base (or fluoride) at certain
20 degrees. Examples of the inert solvent include aromatic hydrocarbons, such as
benzene and toluene; ethers, such as tetrahydrofuran, 1,2-dimethoxyethane, and
1,4-dioxane; alcohols, such as methanol, ethanol, propanol, and isopropanol; esters,
such as methyl acetate and ethyl acetate; amides, such as N,N-dimethylformamide,
N,N-dimethylacetamide, and N-methylpyrrolidone; sulfoxides, such as dimethyl
25 sulfoxide; nitriles, such as acetonitrile; water; and arbitrary mixed solvents thereof, and
preferably toluene, toluene-ethanol-water mixed solvent, or toluene-water mixed
solvent.
Examples of the inert gas used include nitrogen, helium, argon, and the like.
Examples of the palladium catalyst used include metal palladiums, such as
30 palladium-activated carbon and palladium black; organopalladium complexes, such as
tetrakis(triphenylphosphine)palladium, bis(tripheny1phosphine)palladium chloride,
1,l '-bis(dipheny1phosphino)ferrocene palladium chloride, and
tris(dibenzylideneacetone)dipalladium; palladium salts, such as palladium chloride and
palladium acetate, and preferably tetrakis(tripheny1phosphine)palladium or palladium
35 acetate. A molar amount of palladium used as the catalyst is typically 0.0001 to 1-fold,
and preferably 0.005 to 0.3-fold based on 1 mole of the compound (f).
When tris(dibenzylideneacetone)dipalladium, palladium chloride, or palladium
acetate is used as the catalyst, it is preferably used in the presence of an organophosphine
compound. Examples of the organophosphine compound used include
tri-n-butylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine,
5 butyldi-1-adamantylphosphine, triphenylphosphine, tri(o-tolyl)phosphine,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl,
1,l '-bis(diphenylphosphino)ferrocene, or
1,2,3,4,5-pentaphenyl- 1 '-(di-tert-butylphosphino)ferrocene, and preferably
tricyclohexylphosphine, butyldi- 1 -adamantylphosphine, triphenylphosphine, or
10 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl. A molar amount of the
organophosphine compound used is typically 1 to 5-fold, and preferably 1.5 to 2.5-fold
based on 1 mole of the palladium.
Examples of the base or fluoride used include alkali metal acetates, such as
sodium acetate and potassium acetate; alkali metal carbonates, such as sodium
15 carbonate, potassium carbonate, and cesium carbonate; alkali metal phosphates, such as
trisodium phosphate and tripotassium phosphate; alkali metal hydroxides, such as
lithium hydroxide, sodium hydroxide, and potassium hydroxide; quaternary ammonium
hydroxides, such as tetramethylammonium hydroxide, tetraethylammonium hydroxide,
and tetrabutylammonium hydroxide; fluorides, such as cesium fluoride,
20 tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium
fluoride, and preferably sodium carbonate or tripotassiurn phosphate. A molar amount
of the base or fluoride used is typically 1 to 10-fold, and preferably 1.5 to 5-fold based
on 1 mole of the compound (f).
A molar amount of the compound (g) used is typically 1 to 3-fold, and
25 preferably 1 to 2-fold based on 1 mole of the compound (0.
Although varying depending on types and amounts used of raw materials,
solvents, and the like, the reaction temperature is typically 0°C to 200°C, and preferably
50°C to 150°C.
Although varying depending on the reaction temperature and the like, the
30 reaction time is typically 10 minutes to 120 hours, and preferably 1 hour to 48 hours.
[0036] Synthetic route 4
The compound (Iy) can be obtained by reacting the compound (h) with the
compound (i) in an inert organic solvent in the presence or absence of (preferably in the
presence of) a base.
35 The inert organic solvent used is not particularly limited as long as it does not
inhibit the reaction and dissolves the raw materials at certain degrees. Examples of the
inert organic solvent include aromatic hydrocarbons, such as benzene, toluene, and
xylene; halogenated aliphatic hydrocarbons, such as methylene chloride, chloroform,
and 1,2-dichloroethane; ethers, such as 1,4-dioxane, tetrahydrofuran, diethyl ether, and
1,2-dimethoxyethane; amides, such as N,N-dimethylformamide,
5 N,N-dimethylacetamide, and N-methylpyrrolidone; nitriles, such as acetonitrile and
propionitrile, and arbitrary mixed solvents thereof, and preferably methylene chloride,
1,2-dichloroethane, N,N-dimethylformamide, acetonitrile, and a mixed solvent thereof.
Examples of the base used include organic bases, such as triethylamine and
diisopropylethylamine; inorganic bases such as sodium bicarbonate, potassium
10 bicarbonate, sodium carbonate, and potassium carbonate, and preferably triethylamine
and diisopropylethylamine. A molar amount of the base used is typically 0.9 to
20-fold, and preferably 1 to 10-fold based on 1 mole of the compound (i).
A molar amount of the compound (h) used is typically 0.7 to 5-fold, and
preferably 0.8 to 1.5-fold based on 1 mole of the compound (i).
15 Although varying depending on types and amounts used of raw materials,
solvents, and the like, the reaction temperature is typically -20°C to 100°C, and
preferably -5°C to 50°C.
Although varying depending on the reaction temperature and the like, the
reaction time is typically 1 minute to 36 hours, and preferably 1 hour to 18 hours.
20 [0037] Synthetic route 5
When R3 in the compound (I9) is a tert-butoxycarbonyl group, the compound of
general formula (I), in which R' is a carboxy group protected by the ester-type
protective group, can be obtained by deprotecting the compound (Iy) via acid treatment.
However, when R" is a tert-butyl group and R3 is a tert-butoxycarbonyl group in the
25 compound (Iy), the compound of general formula (I), in which R' is a carboxy group,
can be obtained by deprotection via acid treatment with hydrochloric acid,
trifluoroacetic acid, or the like. Similarly, when R3 in the compound (I7) is a hydrogen
atom, the compound of general formula (I), in which R' is a carboxy group, can be
obtained by suitably deprotecting the compound (1') via alkaline hydrolysis or the like.
30 [0038] For the substituent R2, a desired substituent may be introduced at the beginning,
or a desired substituent may be introduced, after its basic structure is produced by the
method described above, using a general synthesizing method including oxidation,
reduction, alkylation, esterification, amidation, dehydration reaction, deprotection
reaction, hydrolysis, coupling reaction, cyclization reaction, andlor a combination of
35 these reactions.
The starting compound of the compound of the present invention is
commercially available or can be produced by a production method that is publicly
known by those slulled in the art. The methods for producing the starting compound
and an intermediate compound of the compound of the present invention are described
in detail in Reference Examples described below.
5 [0039] The target compound formed in each of the reactions can be obtained fi-om the
reaction mixture in accordance with conventional methods. For example, after
suitably neutralizing the reaction mixture, or removing insolubles by filtration in the
case such insolubles are present, an organic solvent such as ethyl acetate that is
immiscible with water is added followed by washing with water, separating the organic
10 layer containing the target compound, drylng using a drying agent such as anhydrous
magnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent to
obtain the target compound.
If necessary, the obtained target compound can be separated andlor purified by
suitably combining conventional methods, such as recrystallization; reprecipitation; and
15 typical methods that have been commonly used for separation and purification of
organic compounds (e.g., adsorption column chromatography methods using silica gel,
alumina, or the like as a carrier; ion-exchange chromatography methods; or normal
phaselreversed phase column chromatography methods using silica gel or alkylated
silica gel (preferably high performance liquid chromatography)).
20 [0040] When the compound of general formula (I) or the pharmacologically
acceptable salt thereof in the present invention is used as pharmaceuticals, the
compound can be administered alone (as bulk powder), or the compound can be
administered orally or parenterally (intravenous administration, intramuscular
administration, intraperitoneal administration, dermal administration, transnasal
25 administration, intrabronchial administration, pulmonary administration, intracutaneous
administration, subcutaneous administration, or the like) in the dosage form, such as a
tablet, capsule, powder, syrup, granule, fine granule, pill, suspension, emulsion,
percutaneous absorption agent, suppository, ointment, lotion, aerosol, powder inhalation
agent, or injection, that is produced by mixing with suitable pharmacologically
30 acceptable excipients or diluents and the like.
These dosage forms are prepared by commonly known methods using additives,
such as excipients, lubricants, binders, disintegrators, emulsions, stabilizers, flavoring
agents, diluents, or the like.
[004 11 Examples of the excipients include organic excipients and inorganic excipients.
35 Examples of the organic excipients include sugar derivatives, such as lactose, sucrose,
glucose, mannitol, and sorbitol; starch derivatives, such as cone starch, potato starch,
a-starch, and dextrin; cellulose derivatives, such as crystalline cellulose; gum arabic;
dextran; pullulan; and the like. Examples of the inorganic excipients include light
anhydrous silicic acid; sulfates, such as calcium sulfate; and the like.
[0042] Examples of the lubricants include stearic acid; stearic acid metal salts, such as
5 calcium stearate and magnesium stearate; talc; colloidal silica; waxes, such as beeswax
and spermaceti wax; boric acid; adipic acid; sulfates, such as sodium sulfate; glycol;
fbmaric acid; sodium benzoate; D,L-leucine; sodium lauryl sulfate; silicic acids, such as
silicic acid anhydride and silicic acid hydrate; starch derivatives described above for the
excipients; and the like.
10 [0043] Examples of the binders include hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, polyvinylpyrrolidone, macrogol, or compounds described above for
the excipients, and the like.
COO441 Examples of the disintegrators include cellulose derivatives, such as low
substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl
15 cellulose, and internally crosslinked calcium carboxymethyl cellulose; crosslinked
polyvinylpyrrolidone; chemically modified starch or cellulose derivatives, such as
carboxymethyl starch and sodium carboxymethyl starch; and the like.
[0045] Examples of the emulsifiers include colloidal clays, such as bentonite and
Veegum; anionic surfactants, such as sodium lauryl sulfate; cationic surfactants, such as
20 benzalkonium chloride; nonionic surfactants, such as polyoxyethylene alkyl ether,
polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester; and the like.
[0046] Examples of the stabilizers include para-hydroxybenzoates, such as
methylparaben and propylparaben; alcohols, such as chlorobutanol, benzyl alcohol, and
phenylethyl alcohol; benzalkonium chloride; phenols, such as phenol and cresol;
25 thimerosal; acetic anhydride; sorbic acid; and the like.
[0047] Examples of the corrigents include sweeteners, such as saccharin sodium and
aspartame; acidulants, such as citric acid, malic acid, and tartaric acid; flavorings, such
as menthol, lemon extract, and orange extract; and the like.
[0048] Examples of diluents include compounds commonly used as diluents, such as
30 lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropyl cellulose,
microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol,
glycerol, starch, polyvinylpyrrolidone, mixtures thereof, and the like.
[0049] In addition, suitable additives can be used depending on the dosage form. For
example, when the compound of general formula (I) or the pharmacologically
35 acceptable salt of the present invention is formed into an aerosol for transnasal
administration or intrabronchial administration, chlorofluorocarbons (CFCs), such as
dichlorodifluoromethane, trichlorofluoromethane, and dichlorotetrafluoroethane; carbon
dioxide, and the like can be used as a propellant.
[0050] Although the dosage of the compound of general formula (I) or the
pharmacologically acceptable salt of the present invention can be varied depending on
5 the conditions such as symptoms, age, and weight of the patient, the dosage for an adult
in the case of oral administration has the lower limit of 0.001 mglkg (preferably 0.01
mglkg) and the upper limit of 20 mglkg (preferably 10 mglkg), while the dosage for an
adult in the case of parenteral administration has the lower limit of 0.0001 mglkg
(preferably 0.0005 mglkg) and the upper limit of 10 mglkg (preferably 5 mglkg), which
10 can be administered corresponding to symptoms for 1 to 6 times per day.
EXAMPLES
[005 11 Although the following provides a more detailed explanation of the present
invention through Examples, Reference Examples, Comparative Examples, and Test
15 Examples; however, the present invention is not limited to these.
[0052] Example 1
Ethyl (6- { T3'-( 1 -propenyl)biphenyl-4-ylmethy11 (pyridin-2-y1~~1fony1~-
aminomethy1)pyridin-2-y1amino)acetate
[0053] To a solution of 205 mg (0.913 mmol) of
20 3'-(1-propeny1)biphenyl-4-ylmethanol obtained in Reference Example 3-(b) in 9.4 mL
of tetrahydrofuran, 320 mg (0.913 mmol) of ethyl
(6-[(pyridin-2-ylsulfonyl)aminomethyl]p~inoa)c etate obtained in the same
manner as in Reference Example 1-(g), 570 pL (2.3 1 mmol) of tri-n-butylphosphine,
and 236 mg (1.37 mmol) of N,N,NY,N'-tetramethylazodicarboxamidwe ere added and
25 stirred for 5 hours at room temperature. After the completion of the reaction, water
was added to the reaction solution, followed by extraction with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then concentrated under reduced pressure. The
residue was subjected to silica gel column chromatography (elution solvent;
30 n-hexane:ethyl acetate = 2:3 (VIV)), and fractions containing the target product were
concentrated under reduced pressure to afford 5 10 mg of the title compound as a
slightly yellow oil. (Quantitative)
Mass spectrum (FAB, mlz): 557 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 8.62 (ddd, J = 4.7, 1.8, 1 .O Hz, 1 H), 7.83
35 (ddd, J = 7.8, 1.0, 1.0 Hz, lH), 7.75 (ddd, J = 7.8,7.6, 1.8 Hz, lH), 7.52-7.43 (m, 3H),
7.41-7.30 (my 6H), 7.27-7.20 (my lH), 6.51 (d, J = 7.3 Hz, lH), 6.50-6.42 (my lH),
6.38-6.26 (my lH), 6.23 (d, J = 8.3 Hz, lH), 4.80 (s, 2H), 4.70 (t, J = 5.4 Hz, 0.9H), 4.42
(sy2H),4.22(q,J =7.1 HzY2H),3.96( d, J=5.4HzY2H)1, .91 (dd, J=6.3, 1.5HzY3H),
1.28 (t, J = 7.1 Hz, 3H)
[0054] Example 2
5 /6- { r3 '-( 1 -Propenyl)biphenyl-4-ylmethyll (pyridin-2-ylsulfonv1)aminomethyl) -
pvridin-2-y1amino)acetic acid
[0055] To a solution of 220 mg (0.395 mmol) of ethyl
(6- {[3'-(1 -propenyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl)pyidin-2-
y1amino)acetate obtained in Example 1 in 2.0 mL of ethanol, 1.98 mL (1.98 mmol) of 1
10 mol/L aqueous sodium hydroxide solution was added and stirred for 2.5 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution, and pH of the solution was adjusted to 4.5 with 1 mol/L hydrochloric acid.
The precipitated solid was collected by filtration and then dried under reduced pressure
to afford 146 mg of the title compound as a white solid. (Yield: 70%)
15 Mass spectrum (FAB, rnlz): 529 ( ~ + + 1 )
'H-NMR spectrum (DMSO-ds, 6 ppm): 8.64 (ddd, J = 4.8, 1.7,0.9 Hz, lH),
7.95 (ddd, J = 7.7,7.7, 1.7 Hz, lH), 7.80 (ddd, J = 7.7, 1.0, 0.9 Hz, lH), 7.61-7.56 (my
4H), 7.48-7.44 (my lH), 7.39-7.37 (my 2H), 7.35-7.32 (my 2H), 7.19 (dd, J = 8.3,7.2 Hz,
IH), 6.61 (brs, 0.8H), 6.52-6.47 (my lH), 6.44-6.37 (my lH), 6.33 (d, J = 8.3 Hz, lH),
20 6.28 (d, J = 7.2 Hz, lH), 4.74 (s, 2H), 4.24 (s, 2H), 3.76 (d, J=4.0 Hz, 2H), 1.87 (dd, J
= 6.2, 1.5 Hz, 3H)
[0056] Example3
Ethyl (6- { r3'-(1 -prop~yl)biphenyl-4-ylmethyl1(pyridin-2-y1~~lf0ny1)-
aminomethy1)pyridin-2-v1amino)acetate
25 [0057] To a solution of 200 mg (0.900 mmol) of
3'-(1 -propynyl)biphenyl-4-ylmethanol obtained in Reference Example 4-(b) in 4.0 mL
of tetrahydrofuran, 3 15 mg (0.900 mmol) of ethyl (6-[(pyidin-2-ylsulfony1)-
aminomethyllpyridin-2-y1amino)acetate obtained in the same manner as in Reference
Example 1-(g), 450 pL (1.82 mmol) of tri-n-butylphosphine, and 3 10 mg (1.80 mmol)
30 of N,N,N',NY-tetramethylazodicarboxamidew ere added and stirred for 3 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution, followed by extraction with ethyl acetate. The organic layer was washed
with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue was subjected to
35 silica gel column chromatography (elution solvent; n-hexane:ethyl acetate = 3:2 + 2:3
(VIV)), and fractions containing the target product were concentrated under reduced
pressure to afford 483 mg of the title compound as a white foam. (Yield: 97%)
Mass spectrum (FAB, d z ) : 555 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 8.62 (ddd, J = 4.6, 1.7, 1.0 Hz, lH), 7.83
(ddd, J = 7.7, 1.3, 1.0 Hz, lH), 7.75 (ddd, J = 7.7, 7.7, 1.7 Hz, lH), 7.59-7.58 (my lH),
5 7.47-7.43(m,3H),7.41-7.31(m,5H),7.23(dd,J=8.2,7.1Hz,1H),6.51(d7J=7.1Hz,
lH), 6.23 (d, J = 8.2 Hz, lH), 4.79 (s, 2H), 4.70 (t, J = 5.4 Hz, lH), 4.42 (s, 2H), 4.22 (q,
J=7.1 Hzy2H),3.96(d, J=5.4Hz72H),2.08 (s, 3H), 1.28 (t, J=7.1 Hz,3H)
[0058] Example 4
(6- fr3 ' 41- Pro~vn~l)biphenyl-4-~lmethyll(pvridin-2-vlsulfony1)aminometh-y l)
10 pvridin-2-v1amino)acetic acid
[0059] To a solution of 476 mg (0.858 mmol) of ethyl
(6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl] (pyridin-2-ylsulfony1)aminomethyl)pyridin-2-
y1amino)acetate obtained in Example 3 in 3.0 mL of ethanol, 3.43 mL (3.43 mmol) of 1
molIL aqueous sodium hydroxide solution was added and stirred for 5 hours at room
15 temperature. After the completion of the reaction, water was added to the reaction
solution. Then, pH of the solution was adjusted to 4.5 with 1 molIL hydrochloric acid,
followed by extraction with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate,
and then concentrated under reduced pressure. The residue was subjected to silica gel
20 column chromatography (elution solvent; methylene ch1oride:methanol = 15: 1 + 10: 1
(VIV)), and fractions containing the target product were concentrated under reduced
pressure to afford 444 mg of the title compound as a white foam. (Yield: 98%)
Mass spectrum (FAB, d z ) : 527 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.42 (brs, 0.6H), 8.64 (ddd, J = 4.7,
25 1.8,1.0Hz71H),7.95(ddd,J=7.7,7.7,1.8Hz,1H),7.80(ddd,J=7.7,1.0,1.0Hz,
lH), 7.63-7.56 (my 5H), 7.43 (dd, J = 7.9, 7.9 Hz, lH), 7.38-7.36 (my lH), 7.35-7.32 (my
2H), 7.19 (dd, J = 8.4,7.0 Hz, lH), 6.75 (t, J = 5.9 Hz, lH), 6.34 (d, J = 8.4 Hz, lH),
6.28 (d, J = 7.0 Hz, lH), 4.74 (s, 2H), 4.24 (s, 2H), 3.82 (d, J = 5.9 Hz, 2H), 2.07 (s, 3H)
[0060] Example 5
30 Ethyl (6- f r3 '-(I -propvnvl)biphenyl-4-ylmethyll( pyridin-3-vlsulfony1)-
aminomethyl] pyridin-2-y1amino)acetate
[0061] To a solution of 178 mg (0.800 mmol) of
3'-(1 -propynyl)biphenyl-4-ylmethanol obtained in the same manner as in Reference
Example 4-(b) in 4.0 mL of tetrahydrofuran, 280 mg (0.800 mmol) of ethyl
35 {6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-ylamino}a cetate obtained in the same
manner as in Reference Example 2-(b), 395 pL (1.60 mmol) of tri-n-butylphosphine,
and 276 mg (1.60 mmol) of N,N,NY,N'-tetramethylazodicarboxamidew ere added and
stirred for 3 hours at room temperature. After the completion of the reaction, water
was added to the reaction solution, followed by extraction with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride solution, dried over
5 anhydrous magnesium sulfate, and then concentrated under reduced pressure. The
residue was subjected to silica gel column chromatography (elution solvent;
n-hexane:ethyl acetate = 3:7 + 0:l (VN))a, nd fractions containing the target product
were concentrated under reduced pressure to afford 400 mg of the title compound as a
slightly yellow oil. (Yield: 90%)
10 Mass spectrum (ESI', d z ) : 555 (M++l)
'H-NMR spectrum (CDC13, 6 ppm): 8.97 (dd, J = 2.3,0.7 Hz, lH), 8.69 (dd, J
= 4.9, 1.7 Hz, lH), 7.92 (ddd, J = 8.0,2.3, 1.7 Hz, lH), 7.61-7.60 (my lH), 7.52-7.49 (m,
2H), 7.48-7.46 (m, lH), 7.38-7.35 (m, 4H), 7.32-7.27 (m, 2H), 6.46 (d, J = 7.0 Hz, lH),
6.28 (d, J = 8.2 Hz, lH), 4.74 (t, J = 5.4 Hz, lH), 4.66 (s, 2H), 4.34 (s, 2H), 4.22 (q, J =
15 7.2 Hz, 2H), 3.87 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H)
[0062] Example 6
(6- { r3 '-( 1- Pro~vnyl)biphenyl-4-ylmethyll~pvridin-3-ylsulfonyl)aminometh-y l)
pvridin-2-y1amino)acetic acid
COO631 To a solution of 395 mg (0.712 rnrnol) of ethyl (6-{[3'-(1-propyny1)-
20 biphenyl-4-ylmethyl](pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetate
obtained in Example 5 in 3.0 mL of ethanol, 3.0 mL (3.0 mmol) of 1 mol/L aqueous
sodium hydroxide solution was added and stirred for 16 hours at room temperature.
After the completion of the reaction, water was added to the reaction solution. Then,
pH of the solution was adjusted to 4.5 with 1 mol/L hydrochloric acid, followed by
25 extraction with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated
under reduced pressure. To the residue were added 10 mL of tert-butyl methyl ether
and 0.5 mL of methanol, followed by sonication. The precipitated solid was collected
by filtration and dried under reduced pressure to afford 340 mg of the title compound as
30 a white solid. (Yield: 91%)
Mass spectrum (ESI', d z ) : 527 (M++l)
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.42 (brs, 0.6H), 8.83 (dd, J = 2.4, 0.6
HZ, lH), 8.72 (dd, J = 4.8, 1.6 Hz, lH), 8.02 (ddd, J = 8.1,2.4, 1.6 Hz, lH), 7.65-7.61
(m, 4H), 7.47 (ddd, J = 8.1,4.8,0.6 Hz, lH), 7.44 (dd, J = 7.9,7.9 Hz, lH), 7.39-7.36
35 (m,3H),7.24(dd,J=8.3,7.1Hz,1H),6.78(t,J=5.9Hz71H),6.37(d,J=8.3Hz,1H),
6.33 (d, J = 7.1 Hz, lH), 4.71 (s, 2H), 4.21 (s, 2H), 3.71 (d, J = 5.9 Hz, 2H), 2.07 (s, 3H)
[0064] Example 7
(6-~(3'-Ethoxybiphenvl-4-ylmeth~l)(p~idin-2-ylsulfon~l)aminomethyllpyridin-
2-ylamino) acetic acid
[0065] 7-(a): tert-Butyl (tert-butoxycarbon~l16-~(3'-ethoxybiphenyl-4-ylmethyl~-
5 [pvridin-2-ylsulfonyl~aminomethyllpvridin-a2m1 ino)acetate
To a solution of 183 mg (0.800 mmol) of 3'-ethoxybiphenyl-4-ylmethanol
obtained in Reference Example 5 in 4.0 mL of tetrahydrofuran, 422 mg (0.880 mmol) of
tert-butyl (tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]-pyridin-2-y1}-
amino)acetate obtained in the same manner as in Reference Example 1-(f), 395 pL (1.60
10 mmol) of tri-n-butylphosphine, and 276 mg (1.60 mmol) of
N,N,Ny,N'-tetramethylazodicarboxamidew ere added and stirred for 3 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution, followed by extraction with ethyl acetate. The organic layer was washed
with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
15 sulfate, and then concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography (elution solvent; to1uene:ethyl acetate = 8: 1 + 6: 1
(VIV)), and fractions containing the target product were concentrated under reduced
pressure to afford 537 mg of the title compound as a white foam. (Yield: 98%)
Mass spectrum (FAB, rnlz): 689 (M++l)
20 'H-NMR spectrum (CDC13, 6 ppm): 8.60 (ddd, J = 4.6, 1.8, 1.0 Hz, lH), 7.82
(ddd, J = 7.7, 1.0, 1.0 Hz, lH), 7.77 (ddd, J = 7.7, 7.6, 1.8 Hz, IH), 7.65 (d, J = 8.3 Hz,
lH), 7.48-7.26 (my 7H), 7.1 1 (ddd, J = 7.9, 1.7,O.g Hz, lH), 7.07 (dd, J = 2.3, 1.7 Hz,
lH), 6.91 (d, J = 7.3 Hz, lH), 6.88 (ddd, J = 7.9,2.3,0.9 Hz, lH), 4.74 (s, 2H), 4.51 (s,
2H), 4.46 (s, 2H), 4.10 (q, J = 6.9 Hz, 2H), 1.52 (s, 9H), 1.45 (t, J = 6.9 Hz, 3H), 1.42 (s,
25 9H)
[0066] 7-(b): ~6-~(3'-Ethoxybiphenyl-4-ylmethyl)(p~din-2-y1~~lf0nyl)-
aminomethyllpyridin-2-ylamino 1 acetic acid
To a solution of 525 mg (0.762 mmol) of tert-butyl
(tert-butoxycarbonyl(6-[(3 '-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)-
30 aminomethyllpyridin-2-yl}amino)acetate obtained in Example 7-(a) in 4.0 mL of
1,4-dioxane, 3.2 mL (19.2 mmol) of 6 molIL hydrochloric acid and 0.8 mL of water
were added, and stirred at 70°C for 2 hours. After the completion of the reaction, the
reaction solution was concentrated under reduced pressure, followed by addition of
water. Then, pH of the solution was adjusted to 4.4 with 1 molIL aqueous sodium
35 hydroxide solution, followed by extraction with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (elution solvent; methylene
ch1oride:methanol = 15:l + 10: 1 (VN)), and fractions containing the target product
ware concentrated under reduced pressure to afford 369 mg of the title compound as a
5 white foam. (Yield: 91%)
Mass spectrum (FAB, d z ) : 533 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.41 (brs, 0.4H), 8.64 (ddd, J = 4.6,
1.8,O.g Hz, lH), 7.95 (ddd, J = 7.8,7.8, 1.8 Hz, lH), 7.80 (ddd, J = 7.8, 1.0,0.9 Hz,
lH), 7.59-7.56 (my 3H), 7.36 (dd, J = 8.1, 8.1 Hz, lH), 7.33-7.31 (my 2H), 7.20 (dd, J =
10 8.2,7.1Hz,1H),7.18(ddd,J=8.1,1.8,0.8Hz,1H),7.14(dd,J=2.3,1.8Hz,1H),
6.92 (ddd, J=8.1,2.3,0.8 Hz, lH), 6.75 (t, J=5.9HzY lH), 6.34 (d, J = 8.2HzY IH),
6.28 (d, J= 7.1 Hz, lH), 4.74 (s, 2H), 4.24 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.82 (d, J =
5.9HzY2 H), 1.35 (t, J=7.0HzY3 H)
[0067] Example 8
15 Hexvl ~6-~(3'-ethoxvbiphenvl-4-vlmethyl)(pyridin-2-ylsulfonyl)aminomethvllpyridin-
2-vlamino acetate
[0068] To a solution of 171 mg (0.750 mmol) of 3'-ethoxybiphenyl-4-ylmethanol
obtained in Reference Example 5 in 4.0 mL of tetrahydrofuran, 305 mg (0.750 mmol) of
hexyl (6-[(pyridin-2-ylsulfonyl)aminomethyl]p~inoa)c etate obtained in
20 Reference Example 6,280 pL (1.14 mmol) of tri-n-butylphosphine, and 196 mg (1.14
mmol) of N,N,N',N'-tetramethylazodicarboxamide were added and stirred for 16 hours
at room temperature. After the completion of the reaction, water was added to the
reaction solution, followed by extraction with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride solution, dried over anhydrous
25 magnesium sulfate, and then concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (elution solvent; n-hexane:ethyl acetate
= 3:2 + 2:3 (VIV)), and fractions containing the target product were concentrated under
reduced pressure to afford 429 mg of the title compound as a colorless oil. (Yield:
93 %)
30 Mass spectrum (FAB, d z ) : 617 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 8.61 (ddd, J = 4.7, 1.7, 1.0 Hz, lH), 7.82
(ddd, J = 7.7, 1.1, 1.0 Hz, lH), 7.75 (ddd, J = 7.7,7.7, 1.7 Hz, lH), 7.47-7.45 (my 2H),
7.38 (ddd, J = 7.7,4.7, 1.1 Hz, IH), 7.35-7.31 (my 3H), 7.23 (dd, J = 8.4,7.3 Hz, lH),
7.12(dddYJ =8.1, 1.8, l.OHz, 1H),7.08 (dd, J=2.4, 1.8HzY1 H),6.88(dddYJ =8.1,
35 2.4, l.OHz, 1H),6.51 (d, J=7.3HzY 1H),6.23 (d, J=8.4HzY lH),4.79(~,2H),4.70(t,
J = 5.3 Hz, lH), 4.42 (s, 2H), 4.15 (t, J = 6.8 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.96 (d,
J = 5.3 Hz, 2H), 1.66-1.60 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H), 1.34-1.25 (m, 6H), 0.87 (t,
J = 7.0 Hz, 3H)
[0069] Example 9
j6-[(3 '-Ethoxybiphenyl-4-ylmethy1)(p~din-3-ylsulfonyl)aminomethyl-
5 pwidin-2-ylamino ) acetic acid
[0070] 9-(a): tert-Butyl (tert-butox~carbon~l{6-r(3'-ethoxybiphenyl-
4-~lmethyl~~~~~-iydlsiunl-f3o n~l)aminometh~llpwidin-2-ayml)i no)acetate
To a solution of 183 mg (0.800 mmol) of 3'-ethoxybiphenyl-4-ylmethanol
obtained in Reference Example 5 in 4.0 mL of tetrahydrofuran, 422 mg (0.880 mmol) of
10 tert-butyl (tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]-
pyridin-2-y1)amino)acetate obtained in the same manner as in Reference Example 2-(a),
395 pL (1.60 mmol) of tri-n-butylphosphine, and 276 mg (1.60 mmol) of
N,N,N',N'-tetrarnethylazodicarboxamide were added and stirred for 3 hours at room
temperature. After the completion of the reaction, water was added to the reaction
15 solution, followed by extraction with ethyl acetate. The organic layer was washed
with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography (elution solvent; n-hexane:ethyl acetate = 7:3 + 1: 1
(VIV)), and fi-actions containing the target product were concentrated under reduced
20 pressure to afford 550 mg of the title compound as a white foam. (Quantitative)
Mass spectrum (FAB, mlz): 689 (Mf+l)
'H-NMR spectrum (CDC13, 6 ppm): 8.96 (dd, J = 2.4, 0.7 Hz, lH), 8.71 (dd, J
=4.8, 1.6Hz, lH), 7.87 (ddd, J=7.9,2.4, 1.6Hz, 1H),7.71 (d, J=8.5Hz, lH),
7.54-7.47 (m, 3H), 7.36-7.26 (m, 4H), 7.13 (ddd, J = 7.9, 1.9, 1.0 Hz, lH), 7.08 (dd, J =
25 2.3, 1.9 Hz, lH), 6.89 (ddd, J = 8.3,2.3, 1.0 Hz, lH), 6.87 (d, J = 7.3 Hz, lH), 4.62 (s,
2H),4.42(s,2H),4.37 (s,2H),4.10(q, J=7.0Hz,2H), 1.52(s, 9H), 1.45 (t, J=7.0Hz,
3H), 1.42 (s, 9H)
[0071] 9-(b): {6-~(3'-Ethoxybiphenyl-4-y1methy1)(p~idin-3-y1su1fony1)aminomethy11-
pwidin-2-ylamino) acetic acid
3 0 To a solution of 540 mg (0.784 mmol) of tert-butyl (tert-butoxycarbonyl-
(6- [(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-3- ylsulfonyl)aminomethyl]pyridin-2-yl)-
amino)acetate obtained in Example 9-(a) in 4.0 mL of 1,4-dioxane, 3.3 mL (20 mmol)
of 6 mol/L hydrochloric acid and 1.0 mL of water were added, and stirred at 70°C for 2
hours. After the completion of the reaction, the reaction solution was concentrated
35 under reduced pressure, followed by addition of water. Then pH of the solution was
adjusted to 4.4 with 1 mol/L aqueous sodium hydroxide solution, followed by extraction
with ethyl acetate. The organic layer was washed with saturated aqueous sodium
chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under
reduced pressure. The residue was subjected to silica gel column chromatography
(elution solvent; methylene ch1oride:methanol = 15: 1 + 10: 1 (VN)), and fractions
5 containing the target product were concentrated under reduced pressure. To the
concentrated product were added 2 mL of ethyl acetate and 8 mL of n-hexane, and the
precipitated solid was collected by filtration, followed by drying under reduced pressure
to afford 388 mg of the title compound as a white solid. (Yield: 93%)
Mass spectrum (FAB, d z ) : 533 (M++1)
10 'H-NMR spectrum (DMSO-d6, 6 ppm): 12.43 (brs, 0.4H), 8.83 (dd, J = 2.4, 0.7
HZ, IH), 8.72 (dd, Jz4.8, 1.7 Hz, lH), 8.02 (ddd, J = 8.0,2.4, 1.7 Hz, lH), 7.64-7.61
(m, 2H), 7.47 (ddd, J = 8.0,4.8,0.7 Hz, lH), 7.38-7.34 (m, 3H), 7.24 (dd, J = 8.3,7.2
Hz, lH), 7.20 (ddd, J = 7.8, 1.7,O.g Hz, lH), 7.16 (dd, J = 2.3, 1.7 Hz, lH), 6.92 (ddd, J
= 8.2,2.3, 0.9 Hz, lH), 6.78 (t, J = 5.9 Hz, lH), 6.37 (d, J = 8.3 Hz, lH), 6.33 (d, J = 7.2
15 Hz,1H),4.70(s,2H),4.21(s,2H),4.10(q,J=7.0Hz,2H),3.71(d,J=5.9Hz,2H),
1.36 (t, J = 7.0 Hz, 3H)
[0072] Example 10
{6-T(Benzenesulfon~l)(3'- ethoxybiphenyl-4-~lmethy1)aminomethyl~pvridin-2-
ylamino) acetic acid
20 [0073] 1 0-(a): tert-Butyl ( {6-~(benzenesulfonvl)(3'-ethoxybiphenvl-4-ylmethyl)-
aminomethyllpyridin-2-yl) tert-butoxycarbony1amino)acetate
To a solution of 350 mg (0.639 mmol) of tert-butyl (tert-butoxycarbonyl-
{6-[(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-yla) mino)acetate obtained
in Reference Example 7-(b) in 1.8 mL of methylene chloride, 178 pL (1.28 mmol) of
25 triethylamine and 98 pL (0.77 mmol) of benzenesulfonyl chloride were added under ice
cooling and then stirred for 1 hour at room temperature. After the completion of the
reaction, the reaction solution was subjected to silica gel column chromatography
(elution solvent; n-hexane:ethyl acetate = 4: 1 + 7:3 (VN)), and fractions containing
the target product were concentrated under reduced pressure to afford 392 mg of the
30 title compound as a white foam. (Yield: 89%)
Mass spectrum (CI, d z ) : 688 (M++1)
'H-NMR spectrum (CDC13, 6 ppm): 7.77-7.73 (m, 2H), 7.67 (d, J = 8.3 Hz,
lH), 7.56-7.41 (m, 6H), 7.33 (dd, J = 7.9, 7.7 Hz, lH), 7.24-7.19 (m, 2H), 7.11 (ddd, J =
7.7, 1.7, 0.9 Hz, lH), 7.07 (dd, J = 2.3, 1.7 Hz, lH), 6.88 (ddd, J = 7.9,2.3, 0.9 Hz, lH),
35 6.86 (d, J = 7.5 Hz, lH), 4.54 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 4.09 (q, J = 7.1 Hz, 2H),
1.51 (s,9H), 1.44(t, J=7.1 Hz,3H), 1.41 (s,9H)
[0074] 1 0-(b): j6-r(Benzenesulfonyl)(3 '-ethoxybiphenyl-4-y1methvl)aminomethvllpyridin-
2-ylamino) acetic acid
To a solution of 389 mg (0.566 mmol) of tert-butyl
((6-[(benzenesulfony1)(3 '-ethoxybiphenyl-4-ylmethyl)aminomethyl]pidin-2-y1-}
5 tert-butoxycarbony1amino)acetate obtained in Example 10-(a) in 5.8 mL of methylene
chloride, 5.8 mL (76 mmol) of trifluoroacetic acid was added at room temperature and
allowed to stand undisturbed for 3.5 hours. After the completion of the reaction, the
reaction solution was concentrated under reduced pressure, followed by addition of
water. Then pH of the solution was adjusted to 4.4 with saturated aqueous sodium
10 bicarbonate solution and 1 mol/L hydrochloric acid, followed by extraction with ethyl
acetate. The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate, and then concentrated under reduced
pressure. To the concentrated product was added 3.9 mL of diisopropyl ether, and the
precipitated solid was collected by filtration, followed by drying under reduced pressure
15 to afford 293 mg of the title compound as a white solid. (Yield: 97%)
Mass spectrum (FAB, mlz): 532 (M++l)
'H-NMR spectrum (DMSO-d6, 6 ppm): 12.41 (brs, 0.8H), 7.74-7.72 (m, 2H),
7.61-7.59 (my 3H), 7.52-7.48 (my 2H), 7.35 (dd, J = 7.8,7.8 Hz, lH), 7.31-7.29 (my 2H),
7.23 (dd, J = 8.4,7.2 Hz, lH), 7.19 (ddd, J = 7.8, 1.7, 0.9 Hz, lH), 7.14 (dd, J = 2.3, 1.7
20 Hz,lH),6.91(ddd,J=7.8,2.3,0.9Hz,lH),6.76(t,J=5.9Hz,lH),6.37(d,J=8.4
Hz, lH), 6.29 (d, J = 7.2 Hz, lH), 4.59 (s, 2H), 4.16 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H),
3.77 (d, J = 5.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H)
[0075] Example 11
{6-r(3 '-Ethoxybiphenyl-4-~lmethyl)(thiophen-2-vlsulfonyl~aminomethyll-
25 pyridin-2-ylamino) acetic acid
[0076] 1 1 -(a): tert-Butyl (tert-butoxvcarbonyl{6-r(3 '-ethoxybiphenyl-4-ylmethy1)-
Jthiophen-2-ylsulfony1)aminomethvllpyridin-2-yla]m ino)acetate
To a solution of 350 mg (0.639 mmol) of tert-butyl (tert-butoxycarbonyl-
(6-[(3 '-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-yla}m ino)acetate obtained
30 in Reference Example 7-(b) in 1.8 mL of methylene chloride, 178 1L (1.28 mmol) of
triethylamine and a solution of 141 mg (0.772 mmol) of 2-thiophenesulfonyl chloride in
0.3 mL of methylene chloride were added under ice cooling and then stirred for 1.5
hours at room temperature. After the completion of the reaction, the reaction solution
was subjected to silica gel column chromatography (elution solvent; n-hexane:ethyl
35 acetate = 9: 1 -+ 3:2 (VIV)), and fractions containing the target product were
concentrated under reduced pressure to afford 376 mg of the title compound as a white
foam. (Yield: 85%)
Mass spectrum (CI, mlz): 694 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 7.70 (d, J = 8.5 Hz, lH), 7.54-7.42 (my
5H), 7.33 (dd, J = 8.0,7.8 Hz, lH), 7.27-7.23 (my 2H), 7.12 (ddd, J = 7.7, 1.7,0.9 Hz,
5 lH), 7.08 (dd, J=2.4, 1.7 Hz, lH), 7.02 (dd, J = 5.1,3.7 Hz, lH), 6.92 (d, J=7.6HzY
lH), 6.88 (ddd, J = 8.0,2.4, 0.9 Hz, lH), 4.56 (s, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 4.10 (q,
J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H)
[0077] 1 1-(b): {6-~(3'-Ethoxybiphenyl-4-vlmethvl)(thiophen-2-vlsulfonvl)aminomethyllpvridin-
2-ylamino) acetic acid
10 To a solution of 374 mg (0.538 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(3'-ethoxybiphenyl-4-ylmethyl)(thiophen-2-ylsulfony1)-
aminomethyllpyridin-2-y1)amino)acetate obtained in Example 1 1-(a) in 5.6 mL of
methylene chloride, 5.6 mL (73 mmol) of trifluoroacetic acid was added at room
temperature and allowed to stand undisturbed for 3.5 hours. After the completion of
15 the reaction, the reaction solution was concentrated under reduced pressure, followed by
addition of water. Then pH of the solution was adjusted to 4.4 using saturated aqueous
sodium bicarbonate solution and 1 mol/L hydrochloric acid, followed by extraction with
ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate, and then concentrated under reduced
20 pressure. To the concentrated product was added 3.7 mL of tert-butyl methyl ether,
and the precipitated solid was collected by filtration, followed by drying under reduced
pressure to afford 272 mg of the title compound as a white solid. (Yield: 94%)
Mass spectrum (FAB, rnlz): 538 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.42 (brs, 0.7H), 7.91 (dd, J = 5.1, 1.4
25 Hz,1H),7.61-7.58(m,2H),7.54(dd,J=3.7,1.4Hz,1H),7.35(dd,J=7.9,7.8Hz,
lH), 7.34-7.31 (my 2H), 7.27 (dd, J = 8.4,7.2 Hz, lH), 7.19 (ddd, J = 7.8, 1.7,0.9 Hz,
lH), 7.15 (dd, J =2.3, 1.7 Hz, lH), 7.13 (dd, J = 5.1, 3.7 Hz, lH), 6.91 (ddd, J = 7.9,2.3,
0.9 Hz, lH), 6.79 (t, J = 5.8 Hz, lH), 6.41 (d, J = 8.4 Hz, lH), 6.35 (d, J = 7.2 Hz, lH),
4.58 (s,2H),4.17(~,2H),4.10(qJ, =7.0HzY2H)3, .83 (d, J=5.8HzY2H),1 .35 (t, J =
30 7.0 Hz, 3H)
[0078] Example 12
J6- ~~4-(6-Ethoxy~vridin-2-yl)benz(yplvlr idin-2-ylsulfony1)aminomethyl)-
pyridin-2-y1amino)acetic acid
[0079] 12-(a): tert-Butyl rtert-butoxycarbonyl(6- { r4-(6-ethox~pyridin-2-yl)benzvll-
35 Jpvridin-2-ylsulfonyl)aminomethvllp vridin-2-y1)aminol acetate
To a solution of 267 mg (1.16 mmol) of
4-(6-ethoxypyridin-2-y1)phenylmethanol obtained in Reference Example 8 in 1 1 mL of
tetrahydrofuran, 560 mg (1.17 mmol) of tert-butyl (tert-butoxycarbonyl-
{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyd&2-yl) amino)acetate obtained in the
same manner as in Reference Example 1-(f), 724 pL (2.90 mmol) of
5 tri-n-butylphosphine, and 300 mg (1.74 mmol) of
N,N,N',N'-tetramethylazodicarboxamide were added and stirred for 1.5 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution, followed by extraction with ethyl acetate. The organic layer was washed
with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
10 sulfate, and then concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography (elution solvent; n-hexane:ethyl acetate = 3: 1 (VIV)),
and fractions containing the target product were concentrated under reduced pressure to
afford 606 mg of the title compound as a white foam. (Yield: 76%)
Mass spectrum (CI, d z ) : 690 (M++l)
15 'H-NMR spectrum (CDC13, 6 ppm): 8.60 (ddd, J = 4.7, 1.8, 1.1 Hz, lH),
7.92-7.88 (my 2H), 7.82 (ddd, J = 7.7, 1.3, 1.1 Hz, lH), 7.76 (ddd, J = 7.7,7.5, 1.8 Hz,
lH), 7.65 (d, J = 8.5 Hz, lH), 7.61 (dd, J = 8.2, 7.5 Hz, lH), 7.45 (dd, J = 8.3,7.5 Hz,
lH), 7.38 (ddd, J = 7.5,4.7, 1.3 Hz, lH), 7.34-7.30 (my 2H), 7.28 (dd, J = 7.5,0.6 Hz,
lH), 6.90 (d, J = 7.5 Hz, lH), 6.66 (dd, J = 8.3, 0.6 Hz, lH), 4.76 (s, 2H), 4.49 (s, 2H),
20 4.48(q,J=7.1Hz,2H),4.46(s,2H),1.52(s,9H),1.44(t,J=7.1Hz,3H),1.42(s,9H)
[0080] 12-(b): (6- I~4-(6-Ethox~widin-2-yl)benz~ll(p~din-2-ylsulfonyl)aminomethy1)
pwidin-2-y1amino)acetic acid
To a solution of 590 mg (0.855 mmol) of tert-butyl
[tert-butoxycarbonyl(6- {[4-(6-ethoxypyridin-2-yl)benzyl] (pyridin-2-ylsulfony1)-
25 aminomethy1)pyridin-2-yl)amino]acetate obtained in Example 12-(a) in 8.6 mL of
methylene chloride, 8.6 mL (1 12 mmol) of trifluoroacetic acid was added at room
temperature and stirred for 6 hours at room temperature. After the completion of the
reaction, the reaction solution was concentrated under reduced pressure, followed by
addition of water. Then pH of the solution was adjusted to 4.5 with 2 mol/L aqueous
30 sodium hydroxide solution and dilute hydrochloric acid, followed by extraction with
ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced
pressure to afford 357 mg of the title compound as white foam. (Yield: 78%)
Mass spectrum (FAB, mlz): 534 (Mf+l)
35 'H-NMR spectrum (DMSO-d6, 6 ppm): 12.59 (brs, 0.5H), 8.67 (d, J = 4.7 Hz,
IH), 8.01-7.95 (my 3H), 7.85 (d, J = 7.7 Hz, lH), 7.76 (dd, J = 8.4,7.5 Hz, lH), 7.61 (dd,
J = 7.2,4.7 Hz, lH), 7.50 (d, J = 7.5 Hz, lH), 7.36-7.27 (m, 3H), 6.75 (d, J = 8.4 Hz,
lH), 6.44 (s, lH), 6.37 (s, lH), 4.72 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.33 (s, 2H), 3.87
(s, 2H), 1.37 (t, J = 7.1 Hz, 3H)
[0081] Example 13
5 Ethyl (6- { r3 '41 -~ro~wl)biphenvl-4-~lmethvll(thiophen-2-vlsulfonyl)-
aminomethyllpyridin-2-y1amino)acetate
[0082] To a solution of 533 mg (1.50 mmol) of ethyl
{6-[(thiophen-2-ylsulfonyl)aminomethyl]pidin-2-ylamino) acetate obtained in
Reference Example 9-(b) in 8.0 mL of tetrahydrofuran, 333 mg (1.50 mmol) of
10 3'-(1-propyny1)biphenyl-4-ylmethanol obtained in the same manner as in Reference
Example 13,740 yL (3.00 mmol) of tri-n-butylphosphine, and 517 mg (3.00 mmol) of
N,N,NY,N'-tetramethylazodicarboxamidwe ere added and stirred for 7 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution, followed by extraction with ethyl acetate. The organic layer was washed
15 with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The.residue was subjected to
silica gel column chromatography (elution solvent; n-hexane:ethyl acetate = 1:O + 1: 1
(VIV)), and fractions containing the target product were concentrated under reduced
pressure to afford 806 mg of the title compound as a colorless oil. (Yield: 96%)
20 Mass spectrum (CI, rnlz): 560 ( ~ + + l )
'H-NMR spectrum (CDC13, 6 ppm): 7.60-7.59 (my lH), 7.51 (dd, J = 5.0, 1.3
Hz, lH), 7.48-7.43 (my 4H), 7.36-7.27 (m, 5H), 7.01 (dd, J = 5.0, 3.8 Hz, lH), 6.54 (d, J
= 6.9 Hz, lH), 6.29 (d, J = 8.0 Hz, lH), 4.78 (t, J = 5.4 Hz, lH), 4.60 (s, 2H), 4.33 (s,
2H),4.21 (q, J=7.1 Hz,2H),3.99(dYJ = ~ . ~ H Z , ~ H ) , ~ . O ~1(.S27,(~tYHJ =)7,. 1 Hz,
25 3H)
[0083] Example 14
(6- {[3'-(1 -Pro~vnyl)biphenyl-4-ylmethvll(thiophen-2-ylsulfonyl)-
aminomethvllpvridin-2-y1amino)acetic acid
[0084] To a solution of 800 mg (1.43 mmol) of ethyl
30 (6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl](thiophen-2-ylsulfonyl)aminomethyl)pyridin-
2-y1amino)acetate obtained in Example 13 in 6.0 mL of ethanol, 6.0 mL (6.0 mmol) of 1
mol/L aqueous sodium hydroxide solution was added and stirred for 4 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution. Then pH of the solution was adjusted to 4.5 with 1 mol/L hydrochloric acid,
35 followed by extraction with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The concentrated product was dissolved in
10 mL of ethyl acetate, followed by addition of 10 mL of n-hexane at 50°C, and then
the solution was cooled to room temperature for 1.5 hours with stirring. The
precipitated solid was collected by filtration and then dried under reduced pressure to
5 afford 620 mg of the title compound as a white solid. (Yield: 82%)
Mass spectrum (ESI', d z ) : 532 ( ~ + + l )
'H-NMR spectrum (DMSO-d6, 6 ppm): 12.39 (brs, 0.9H), 7.91 (dd, J = 5.0, 1.3
Hz, lH), 7.64-7.59 (m, 4H), 7.54 (dd, J = 3.8, 1.3 Hz, lH), 7.43 (dd, J = 7.7,7.7 Hz,
lH), 7.38-7.32 (m, 3H), 7.26 (dd, J = 8.3,7.2 Hz, lH), 7.13 (dd, J = 5.0, 3.8 Hz, lH),
10 6.80(t,J=5.8Hz,1H),6.41(d,J=8.3Hz,1H),6.35(d,J=7.2Hz,1H),4.59(s,2H),
4.18 (s,2H),3.84(d, J=5.8Hz,2H),2.07(~3, H)
[0085] Example 15
Ethyl (6- {(benzenesulfonyl)r3'-( 1 -propynyl)biphenvl-4-ylmethyllaminomethy1)
pwidin-2-y1amino)acetate
15 [0086] To a solution of 524 mg (1.50 mmol) of ethyl
{6-[(benzenesulfonyl)aminomethyl]pyridin-2-ylamino) acetate obtained in Reference
Example 10-(b) in 8.0 mL of tetrahydrofuran, 333 mg (1.50 rnmol) of
3'-(1-propyny1)biphenyl-4-ylmethanol obtained in the same manner as in Reference
Example 13,740 pL (3.00 mmol) of tri-n-butylphosphine, and 517 mg (3.00 mmol) of
20 N,N,N',N'-tetrarnethylazodicarboxamide were added and stirred for 2 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution, followed by extraction with ethyl acetate. The organic layer was washed
with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue was subjected to
25 silica gel column chromatography (elution solvent; n-hexane:ethyl acetate = 3: 1 + 1 : 1
(VN)), and fractions containing the target product were concentrated under reduced
pressure to afford 809 mg of the title compound as a colorless oil. (Yield: 97%)
Mass spectrum (CI, d z ) : 554 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 7.78-7.75 (m, 2H), 7.59-7.58 (m, lH),
30 7.53-7.40 (m, 6H), 7.37-7.25 (m, 5H), 6.48 (d, J = 7.0 Hz, lH), 6.27 (d, J = 8.0 Hz, lH),
4.74(t, J=5.2Hz, 1H),4.58 (s,2H),4.32(s,2H),4.21 (q, J=7.2Hz,2H),3.90(d, J =
5.2 Hz, 2H), 2.07 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H)
[0087] Example 16
16- {(Benzenesulfonvl)r3'-(1 -propyny1~biphenyl-4-ylmethyl1aminomethy-l )
35 pvridin-2-v1amino)acetic acid
[0088] To a solution of 804 mg (1.45 rnmol) of ethyl
(6- {(benzenesulfonyl)[3'-(1 -propynyl)biphenyl-4-ylmethyl]aminomethyl)pyridin-2-
y1amino)acetate obtained in Example 15 in 6.0 rnL of ethanol, 6.0 mL (6.0 mmol) of 1
mol/L aqueous sodium hydroxide solution was added and stirred for 4 hours at room
temperature. After the completion of the reaction, water was added to the reaction
5 solution. Then pH of the solution was adjusted to 4.5 with 1 mollL hydrochloric acid,
followed by extraction with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The concentrated product was dissolved in
10 mL of ethyl acetate, followed by addition of 10 mL of n-hexane at 50°C, and then
10 the solution was cooled to room temperature for 2 hours with stirring. The precipitated
solid was collected by filtration and then dried under reduced pressure to afford 724 mg
of the title compound as a white solid. (Yield: 95%)
Mass spectrum (ESI', d z ) : 526 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.40 (brs, 0.6H), 7.75-7.72 (my 2H),
15 7.63-7.58 (my 5H), 7.53-7.48 (m, 2H), 7.43 (dd, J = 7.7,7.7 Hz, lH), 7.38-7.35 (my lH),
7.33-7.30 (my 2H), 7.23 (dd, J = 8.3,7.2 Hz, lH), 6.75 (t, J = 5.6 Hz, lH), 6.37 (d, J =
8.3 Hz, IH), 6.29 (d, J = 7.2 Hz, lH), 4.59 (s, 2H), 4.17 (s, 2H), 3.77 (d, J = 5.6 Hz, 2H),
2.07 (s, 3H)
[0089] Example 17
20 Ethyl (6- { r3'-( 1 -~ro~vnyl)biphen~l-4-ylmethyll(thiophen-3-vlsulfonyl)-
aminomethy1)pvridin-2-y1amino)acetate
To a solution of 284 mg (0.800 mmol) of ethyl
(6- [(thiophen-3- ylsulfonyl)aminomethyl]pyridin-2-ylamino)a cetate obtained in
Reference Example 11-(b) in 4.0 mL of tetrahydrofuran, 178 mg (0.800 mmol) of
25 3'-(1-propyny1)biphenyl-4-ylmethanol obtained in the same manner as in Reference
Example 13,395 pL (1.60 rnrnol) of tri-n-butylphosphine, and 276 mg (1.60 mmol) of
N,N,N',NY-tetramethylazodicarboxamidwe ere added and stirred for 3 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution, followed by extraction with ethyl acetate. The organic layer was washed
30 with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography (elution solvent; n-hexane:ethyl acetate = 4: 1 -+ 1 : 1
(VIV)), and fractions containing the target product were concentrated under reduced
pressure to afford 432 mg of the title compound as a colorless syrup. (Yield: 97%)
35 Mass spectrum (CI, d z ) : 560 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 7.80 (dd, J = 3.1, 1.3 Hz, lH), 7.60-7.59
(my lH), 7.50-7.45 (my 3H), 7.36-7.28 (m, 6H), 7.17 (dd, J = 5.1, 1.3 Hz, lH), 6.52 (d, J
= 7.2 Hz, lH), 6.31 (d, J = 8.0 Hz, lH), 4.80 (t, J = 5.4 Hz, lH), 4.61 (s, 2H), 4.32 (s,
2H), 4.21 (q, J = 7.2 Hz, 2H), 3.99 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.27 (t, J = 7.2 Hz,
3H)
5 [0090] Example 18
(6- { r3 '41 -Propvnvl~biphenvl-4-ylmethyll(thiophen-3-ylsulfonyl)-
aminomethy1)pwidin-2-v1amino)acetic acid
To a solution of 426 mg (0.762 mmol) of ethyl
(6- {[3' -(I -propynyl)biphenyl-4-ylmethyl(]t hiophen-3-ylsulfonyl)aminomethyl)p yridin-
10 2-y1amino)acetate obtained in Example 17 in 3.5 mL of ethanol, 3.5 mL (3.5 mmol) of 1
molIL aqueous sodium hydroxide solution was added and stirred for 16 hours at room
temperature. After the completion of the reaction, water was added to the reaction
solution. Then pH of the solution was adjusted to 4.4 with 1 mol/L hydrochloric acid,
followed by extraction with ethyl acetate. The organic layer was washed with
15 saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. To the concentrated product were added 5
mL of ethyl acetate and 5 mL of n-hexane and heated to 50°C, and then the solution was
cooled to room temperature for 2 hours with stirring. The precipitated solid was
collected by filtration and then dried under reduced pressure to afford 390 mg of the
20 title compound as a white solid. (Yield: 96%)
Mass spectrum (CI, mlz): 532 ( ~ + + l )
1 H-NMR spectrum (DMSO-ds, F ppm): 12.46 (brsi 0.6H), 8.14 (dd, J = 3.0, 1.4
Hz, 1H),7.66(ddYJ =5.1,3.0Hz7l H),7.64-7.59(rn,4H),7.45-7.24(m,6H),6.(8t,1 J
= 5.5 Hz, lH), 6.40 (d, J = 8.2 Hz, lH), 6.33 (d, J = 7.0 Hz, lH), 4.58 (s, 2H), 4.16 (s,
25 2H),3.84(d,J=5.5Hz72H),2.O7(s,3H)
[0091] Example 19
16- 1(3-Fluorobenzenesulfonvl~'~-(3 1 - propvnvl)biphenvl-4-ylmethvllaminomethv1)
pyridin-2-y1amino)acetic acid
[0092] 19-(a): tert-Butvl rtert-butoxvcarbonvl(6- {(3-fluorobenzenesu1fonyl)-
30 J3'-(1-~ro~vnvl)biphenyl-4-y1methvllaminomethvl)pvridin-2-yl)aminolacetate
To a solution of 542 mg (1 .OO mmol) of tert-butyl
[tert-butoxycarbonyl(6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl] aminomethy1)pyridin-2-
yl)amino]acetate obtained in Reference Example 12-(c) in 3.5 mL of methylene
chloride, 280 pL (2.01 mmol) of triethylamine and 150 pL (1.13 mmol) of
35 3-fluorobenzenesulfonyl chloride were added under ice cooling and stirred for 2 hours
at room temperature. After the completion of the reaction, water was added to the
reaction solution, followed by extraction with methylene chloride. The organic layer
was washed with saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (elution solvent; n-hexane:ethyl acetate
5 = 9: 1 + 7:3 (VIV)), and fi-actions containing the target product were concentrated under
reduced pressure to afford 673 mg of the title compound as a white foam. (Yield:
96%)
Mass spectrum (CI, d z ) : 700 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 7.70 (d, J = 8.1 Hz, lH), 7.59-7.58 (my
10 lH), 7.53-7.32 (my 9H), 7.27-7.19 (my 3H), 6.87 (d, J = 7.3 Hz, lH), 4.57 (s, 2H), 4.39
(s, 2H), 4.37 (s, 2H), 2.08 (s, 3H), 1.52 (s, 9H), 1.42 (s, 9H)
[0093] 19-(b): /6- {(3-Fluorobenzenesulfonyl)~3 '-(1 -propvnyl)biphenyl-4-ylmethyllaminomethyl
pvridin-2-y1amino)acetic acid
To a solution of 595 mg (0.850 mmol) of tert-butyl
15 [tert-butoxycarbonyl(6- ((3-fluorobenzenesulfony1)[3 '-(I -propynyl)biphenyl-4-
ylmethyl]aminomethyl)pyridin-2-y1)aminolacetate obtained in Example 19-(a) in 5.0
mL of tetrahydrofuran, 5.0 mL (20 mrnol) of 4 mol/L hydrochloric acid was added, and
stirred at 70°C for 5 hours. After the completion of the reaction, pH of the solution
was adjusted to 4.5 with 1 mol/L aqueous sodium hydroxide solution, followed by
20 extraction with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated
under reduced pressure. To the concentrated product were added 10 mL of ethyl
acetate and 5 mL of n-hexane and heated to 50°C, and then the solution was cooled to
room temperature for 2 hours with stirring. The precipitated solid was collected by
25 filtration and then dried under reduced pressure to afford 429 mg of the title compound
as a white solid. (Yield: 93%)
Mass spectrum (ESI', d z ) : 544 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.41 (brs, 0.9H), 7.65-7.60 (my 4H),
7.58-7.50 (my 2H), 7.46-7.34 (my 6H), 7.25 (dd, J = 8.3,7.2 Hz, lH), 6.79 (t, J = 5.7 Hz,
30 lH), 6.38 (d, J = 8.3 Hz, lH), 6.32 (d, J = 7.2 Hz, lH), 4.67 (s, 2H), 4.19 (s, 2H), 3.74
(d, J = 5.7 Hz, 2H), 2.07 (s, 3H)
[0094] Example 20
Isopropyl(6- { r3 '-( 1- prop~nyl)biphenyl-4-ylmethyl(lp yridin-2-ylsulfony1)-
aminomethy1)pvridin-2-y1amino)acetate
35 [0095] To a solution of 1.05 g (2.88 mmol) of isopropyl
{6-[(pyridin-2-ylsulfonyl)aminomethyl]p~ino)acetateo btained in
Reference Example 14 in 15.0 mL of tetrahydrofuran, 640 mg (2.88 mmol) of
3'-(1-propyny1)biphenyl-4-ylmethanol obtained in the same manner as in Reference
Example 13, 1.42 mL (5.76 mmol) of tri-n-butylphosphine, and 992 mg (5.76 mmol) of
N,N,Ny,N'-tetramethylazodicarboxamidwee re added and stirred for 3 hours at room
5 temperature. After the completion of the reaction, water was added to the reaction
solution, followed by extraction with ethyl acetate. The organic layer was washed
with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography (elution solvent; n-hexane:ethyl acetate = 3:2 + 2:3
10 (VN)), and fractions containing the target product were concentrated under reduced
pressure to afford 1.59 g of the title compound as a colorless syrup. (Yield: 97%)
Mass spectrum (CI, rnlz): 569 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 8.62 (ddd, J = 4.7, 1.7, 1 .O Hz, lH), 7.83
(ddd, J = 7.7, 1.0, 1.0 Hz, IH), 7.76 (ddd, J = 7.7,7.7, 1.7 Hz, lH), 7.60-7.58 (my lH),
15 7.47-7.43 (my 3H), 7.38 (ddd, J = 7.7,4.7, 1.0 Hz, lH), 7.36-7.32 (my 4H), 7.23 (dd, J =
8.2, 7.3 Hz, lH), 6.50 (d, J = 7.3 Hz, lH), 6.22 (d, J = 8.2 Hz, lH), 5.09 (sep, J = 6.3 Hz,
lH), 4.79 (s, 2H), 4.70 (t, J = 5.3 Hz, lH), 4.42 (s, 2H), 3.92 (d, J = 5.3 Hz, 2H), 2.08 (s,
3H), 1.26 (d, J = 6.3 Hz, 6H)
The compounds used in Examples were synthesized as described below.
20 [0096] Reference Example 1
Ethyl ~6-~~~vridin-2-vlsulfonyl)aminomethyllp~din-2-ylamino~acetate
COO971 1-(a): tert-Butvl ~tert-butoxycarbonyl(6-ethoxycarbonylp~idin-2-yl)-
amino1 acetate
To a solution of 15.7 g (0.360 mol) of sodium hydride (55 wt.% mineral oil
25 dispersion) in 362 mL of N,N-dimethylformamide, a solution of 8 1.2 g (0.305 mol) of
6-tert-butoxycarbonylamino-pyridine-2-carboxylic acid ethyl ester (see
W020061074884) in 300 mL of N,N-dimethylformamide was added dropwise for 20
minutes under ice cooling in an argon atmosphere, and stirred for 1 hour at room
temperature. Thereafter, 54.0 mL (0.366 mol) of tert-butyl bromoacetate was added
30 dropwise for 10 minutes under ice cooling, and further stirred for 1 hour at room
temperature. After the completion of the reaction, an aqueous solution in which 1.77 g
(33.0 mmol) of ammonium chloride and 300 mL of water were dissolved was added to
the reaction solution, followed by extraction with toluene. The organic layer was
washed with saturated aqueous sodium chloride solution, dried over anhydrous
35 magnesium sulfate, and then concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (elution solvent; n-hexane:ethyl acetate
= 9: 1 -+ 4: 1 (VN)), and fractions containing the target product were concentrated under
reduced pressure to afford 108 g of the title compound as a pale yellow oil. (Yield:
93%)
Mass spectrum (CI, mlz): 38 1 ( ~ + + 1 )
5 'H-NMR spectrum (CDC13, 6 ppm): 8.04 (d, J = 7.8 Hz, lH), 7.81 (dd, J = 7.6,
1.5 Hz, lH), 7.76 (dd, J = 7.8, 7.6 Hz, lH), 4.67 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.52
(s, 9H), 1.45 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H)
[0098] 1-(b): tert-Butvl ~tert-butoxvcarbonvl(6-hvdroxymethv1pyridin-2-vl~-
amino1 acetate
10 To a solution of 98.8 g (0.260 mol) of tert-butyl
[tert-butoxycarbonyl(6-ethoxycarbonylpyridin-2-yl)amino]acetateo btained in
Reference Example 1-(a) in 195 mL of ethanol, a solution of 34.6 g (0.312 mol) of
calcium chloride in 195 mL of ethanol was added dropwise for 20 minutes under ice
cooling. After the completion of dropwise addition, 105 mL (0.3 15 mol) of 3 mol1L
15 sodium borohydrideltetraethylene glycol dimethyl ether solution was added dropwise
for 20 minutes at 35OC or lower, and then further stirred for 15 minutes at room
temperature. After the completion of the reaction, the reaction solution was added
dropwise to a mixed solution of 17.8 mL of acetic acid and 195 mL of water for 10
minutes under ice cooling, and stirred for 1 hour at room temperature. Thereafter, 3 15
20 mL of water was added to the solution, followed by extraction with toluene. The
organic layer was sequentially washed with saturated aqueous sodium bicarbonate
solution, water, and then saturated aqueous sodium chloride solution, and concentrated
under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent; n-hexane:ethyl acetate = 4: 1 + 3:2 (VN)), and
25 fractions containing the target product were concentrated under reduced pressure to
afford 8 1.1 g of the title compound as a pale yellow oil. (Yield: 92%)
Mass spectrum (CI, d z ) : 339 ( ~ + + l )
1 H-NMR spectrum (CDC13, 6 ppm): 7.74 (d, J = 8.2 Hz, lH), 7.63 (dd, J = 8.2,
7.4 Hz, lH), 6.93-6.98 (my lH), 4.68-4.65 (m, 2H), 4.54 (s, 2H), 3.39 (t, J = 5.3 Hz, lH),
30 1.54 (s, 9H), 1.46 (s, 9H)
[0099] 1-(c): tert-Butvl [tert-butox~carbonvl(6-fomvlpyridin-2-vl)aminolacetate
To a solution of 12.9 g (30.4 mmol) of the Dess-Martin reagent in 130 mL of
methylene chloride, a solution of 10.0 g (29.6 mmol) of tert-butyl
[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetateo btained in Reference
35 Example 1-(b) in 50 mL of methylene chloride was added dropwise for 20 minutes
under ice cooling in an argon atmosphere. After the completion of the dropwise
addition, the solution was stirred for 2 hours at room temperature. After the
completion of the reaction, 305 mL of 0.1 wt.% aqueous sodium thiosulfate solution
was added to the reaction solution, followed by extraction with methylene chloride.
The organic layer was sequentially washed with 0.5 mol/L aqueous sodium hydroxide
5 solution and saturated aqueous sodium chloride solution, and then dried over anhydrous
magnesium sulfate. Thereafter, by concentrating under reduced pressure, 9.61 g of the
title compound was obtained substantially quantitatively as a slightly yellow oil.
Mass spectrum (EI, mlz): 336 (M')
1 H-NMR spectrum (DMSO-d6, S ppm): 9.82 (s, lH), 8.1 1-7.99 (m, 2H), 7.68
10 (dd, J = 6.6, 1.5 Hz, lH), 4.58 (s, 2H), 1.48 (s, 9H), 1.42 (s, 9H)
[O 1001 1 -(d): tert-Butyl ~tert-butoxycarbonyl(6-hydrox~minomethylp~idin-2-yl)-
amino] acetate
To a solution of 2.88 g (8.56 mmol) of tert-butyl
[tert-butoxycarbonyl(6-fomylpyridin-2-yl)amino]acetate obtained in Reference
15 Example 1 -(c) in 29 mL of methanol, 0.650 g (9.35 mmol) of hydroxylammonium
chloride and 3.5 mL (43 mmol) of pyridine were added and stirred for 1 hour at room
temperature. After the completion of the reaction, the reaction solution was
concentrated under reduced pressure. To the obtained residue, ethyl acetate was added,
and the residue was sequentially washed with a 5 wt.% aqueous potassium hydrogen
20 sulfate solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous
sodium chloride solution. Then, the residue was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was subjected to silica
gel column chromatography (elution solvent; n-hexane:ethyl acetate = 3:2 (VN)), and
fractions containing the target product were concentrated under reduced pressure to
25 afford 2.76 g of the title compound as a colorless oil. (Yield: 92%)
Mass spectrum (EI, d z ) : 35 1 (M')
1 H-NMR spectrum (CDC13, S ppm): 8.06 (s, lH), 7.91 (s, lH), 7.85 (d, J = 8.2
Hz, lH), 7.65 (dd, J = 8.2, 7.6 Hz, lH), 7.47 (dd, J = 7.6,0.7 Hz, lH), 4.59 (s, 2H), 1.53
(s, 9H), 1.45 (s, 9H)
30 [O 10 11 1 -(e): tert-Butyl r(6-aminomethylpyridin-2-y1)tert-but ox^-
amino1 acetate
To a solution of 2.75 g (7.83 mmol) of tert-butyl
[tert-butoxycarbonyl(6-hydroxyiminomethylpdin-2-yl)amino]acetate obtained in
Reference Example 1 -(d) in 49 mL of ethanol, 0.98 g of 10 wt.% palladium-activated
35 carbon (containing 50 wt.% of water) was added and stirred for 1 hour at room
temperature in a hydrogen atmosphere at 1 atm. After the completion of the reaction,
insoluble substances were filtered off. The filtrate was then concentrated under
reduced pressure to afford 2.48 g of the title compound as a colorless oil. (Yield:
94%)
Mass spectrum (CI, mlz): 338 (M++l)
5 1 H-NMR spectrum (CDC13, 6 ppm): 7.68 (d, J = 8.3 Hz, lH), 7.58 (dd, J = 8.3,
7.4 Hz, lH), 6.91 (d, J = 7.4 Hz, lH), 4.57 (s, 2H), 3.85 (s, 2H), 1.53 (s, 9H), 1.46 (s,
9H)
[O 1021 1 -(f): tert-Butyl (tert-butoxvcarbonyl{6-~~pyridin-2-ylsulfonvl)aminometh~llpyridin-
2-vl) amino)acetate
10 To a solution of 0.640 g (3.60 mmol) of 2-pyridylsulfonyl chloride in 14 mL of
methylene chloride, a solution of 1.20 g (3.56 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbony1amino]acetateo btained in Reference
Example 1-(e) and 2.24 mL (16.2 mmol) of triethylamine in 12 mL methylene chloride
was added and stirred for 0.5 hours at room temperature. After the completion of the
15 reaction, a 5 wt.% aqueous potassium hydrogen sulfate solution was added to the
reaction solution, followed by extraction with methylene chloride. The organic layer
was sequentially washed with saturated aqueous sodium bicarbonate solution and
saturated aqueous sodium chloride solution. Then, the residue was dried over
anhydrous magnesium sulfate and concentrated under reduced pressure. The residue
20 was subjected to silica gel column chromatography (elution solvent; n-hexane:ethyl
acetate = 1 : 1 (VIV)), and fractions containing the target product were concentrated
under reduced pressure to afford 1.46 g of the title compound as a white solid. (Yield:
86%)
Mass spectrum (APCI, rnlz): 479 (M++l)
25 'H-NMR spectrum (CDC13, 6 ppm): 8.56 (ddd, J = 4.7, 1.7, 0.9 Hz, lH), 7.97
(ddd, J = 7.8, l.l,0.9 Hz, lH), 7.84 (ddd, J = 7.8,7.7, 1.7 Hz, lH), 7.68 (d, J = 8.4 Hz,
lH), 7.52 (dd, J = 8.4,7.4 Hz, lH), 7.40 (ddd, J = 7.7,4.7, 1.1 Hz, lH), 6.84 (dd, J = 7.4,
0.5HzY lH),5.86(t, J=5.6HzY 1H),4.48(sy2H),4.36(d, J=5.6HzY2H), 1.53 (s,9H),
1.45 (s, 9H)
30 [O 1031 1- (g): Ethyl {6-~(pyridin-2-ylsulfonyl~aminomethyllpyridin-2-ylamiancoe)ta te
To 3.59 g (7.50 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl) amino)acetate
obtained in the same manner as in Reference Example 1-(f), 37.5 mL (75.0 mmol) of 2
molIL hydrogen chloridelethanol solution was added and heated to reflux for 3 hours
35 with stirring. After the completion of the reaction, water was added to the reaction
solution, and the reaction solution was neutralized with 1 mollL aqueous sodium
hydroxide solution, followed by extraction with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure to afford 2.17 g of the
title compound as a brown oil. (Yield: 83%)
5 Mass spectrum (CI, mlz): 35 1 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6,6 ppm): 8.71 (ddd, J = 4.8, 1.8, 0.8 Hz, lH),
8.18 (brs, O.lH), 8.05 (ddd, J = 7.8, 7.6, 1.8 Hz, lH), 7.91 (ddd, J = 7.8, 1.0,0.8 Hz, lH),
7.64 (ddd, J = 7.6,4.6, 1.0 Hz, lH), 7.33 (dd, J = 8.1, 7.2 Hz, lH), 6.86 (t, J = 6.1 Hz,
0.2H), 6.52 (d, J = 7.2 Hz, lH), 6.39 (d, J = 8.1 Hz, lH), 4.08 (q, J = 7.1 Hz, 2H), 4.01
10 (~,2H),3.95(~,2H),1.16(t,J=7.1Hz,3H)
[O 1041 Reference Example 2
Ethvl ~6-~~~yridin-3-~lsulfonvl)aminomethvllpwidin-2-valcaemtaitneo ~
[O 1051 2-(a): tert-Butvl (tert-butoxvcarbonvl{6-~(pyridin-3-vlsulfon~l~aminomethvllpyridin-
2-vl) amino)acetate
15 The reaction and post-treatment were performed in accordance with Reference
Example 1-(f) except for using 1.20 g (3.56 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate obtained in the same
manner as in Reference Example 1-(e), and using 640 mg (3.60 mmol) of
3-pyridylsulfonyl chloride in place of 2-pyridylsulfonyl chloride, to afford 1.45 g of the
20 title compound as a colorless oil. (Yield: 85%)
Mass spectrum (CI, rnlz): 479 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 9.06 (d, J = 2.2 Hz, lH), 8.71 (dd, J = 4.6,
1.5 Hz, lH), 8.13-8.08 (m, lH), 7.68 (d, J = 8.2 Hz, lH), 7.52 (dd, J = 8.2, 7.4 Hz, lH),
7.38-7.32 (m, lH), 6.77 (d, J = 7.4 Hz, lH), 5.80 (t, J = 5.1 Hz, lH), 4.40 (s, 2H), 4.24
25 (d, J = 5.1 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H)
[0 1061 2-(b): Ethyl {6-[(pyridin-3-ylsulfony1)aminomethvllp~inoa)c etate
The reaction and post-treatment were performed in accordance with Reference
Example 1-(g) except for using 1 .OO g (2.09 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]p~a}m ino)acetate
30 obtained in the same manner as in Reference Example 2-(a) in place of tert-butyl
(tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl} amino)acetate,
and using 10.4 mL (20.8 mmol) of 2 mol1L hydrogen chloridelethanol solution, to
afford 686 mg of the title compound as a brown oil. (Yield: 94%)
'H-NMR spectrum (CDC13, 6 ppm): 9.06 (dd, J = 2.3,0.7 Hz, lH), 8.71 (dd, J
35 = 4.9, 1.6 Hz, lH), 8.09 (ddd, J = 8.0,2.3, 1.6 Hz, lH), 7.35 (ddd, J = 8.0,4.9,0.7 Hz,
lH), 7.28 (dd, J = 8.3,7.3 Hz, lH), 6.38 (d, J = 7.3 Hz, lH), 6.29 (d, J = 8.3 Hz, lH),
5.95 (t, J = 5.4 Hz, lH), 4.96 (t, J = 5.4 Hz, lH), 4.27 (q, J = 7.2 Hz, 2H), 4.14 (d, J =
5.4 Hz, 2H), 4.03 (d, J = 5 .4HzY2 H), 1.32 (t, J = 7.2HzY3 H)
[O107] Reference Example 3
3 '-(I -Propenyl)biphenyl-4-ylmethanol
5 [O 1081 3-(a): 3'-(1-Propeny1)biphenyl-4-ylcarbaldehvde
To 500 mg (1.91 mmol) of 3'-bromobiphenyl-4-ylcarbaldehyde (see Journal of
Organic Chemistry, 68,247 (2003)), 27.5 mL of toluene and 1.65 mL of water were
added, and then 1.63 g (7.68 mmol) of tripotassium phosphate and 656 mg (7.64 mmol)
of 1 -propenylboronic acid were added. Thereafter, the mixture was placed in a
10 nitrogen gas atmosphere. Furthermore, 6.2 mg (0.028 mmol) of palladium acetate and
20.2 mg (0.0563 mmol) of butyldi-1-adamantylphosphine were added and stirred for 4.5
hours at 100°C in a nitrogen gas atmosphere. After the completion of the reaction,
water was added to the reaction solution, followed by extraction with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride solution, dned
15 over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (elution solvent;
n-hexane:ethyl acetate = 4: 1 (VN)), and fractions containing the target product were
concentrated under reduced pressure to afford 420 mg of the title compound as a
slightly yellow oil. (Yield: 99%)
20 Mass spectrum (CI, mlz): 223 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, lH), 7.98-7.92 (m, 2H),
7.79-7.72 (m, 2H), 7.59-7.55 (m, lH), 7.49-7.42 (my lH), 7.41-7.37 (my 2H), 6.48 (dd, J
= 15.9, 1.5 Hz, lH), 6.33 (dq, J = 15.9,6.3 Hz, lH), 1.92 (dd, J = 6.3, 1.5 Hz, 3H)
[0 1091 3-(b): 3'41 -Propenyl)biphenyl-4-ylmethanol
25 To a solution of 4 17 mg (1.88 mmol) of
3'-(1 -propenyl)biphenyl-4-ylcarbaldehyde obtained in Reference Example 3-(a) in 4.6
mL of ethanol, 35.6 mg (0.941 mmol) of sodium borohydride was added at room
temperature and stirred for 45 minutes at the same temperature. After the completion
of the reaction, saturated aqueous ammonium chloride solution was added to the
30 reaction solution, followed by extraction with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (elution solvent; n-hexane:ethyl acetate
= 7:3 (ViV)), and fractions containing the target product were concentrated under
35 reduced pressure to afford 40 1 mg of the title compound as a white solid. (Yield:
95%)
Mass spectrum (EI, d z ) : 224 (M')
1 H-NMR spectrum (CDC13, 6 ppm): 7.63-7.56 (my 2H), 7.55-7.52 (my lH),
7.47-7.29 (my5 H), 6.47 (dd, J = 15.9, 1.5 Hz, lH), 6.31 (dq, J = 15.9,6.6 Hz, lH), 4.74
(d, J= 5.7HzY2 H), 1.91 (dd, J=6.6, 1.5 Hz, 3H), 1.70 (t, J=5.7HzY1 H)
5 [O 1 1 01 Reference Example 4
3 '-( 1 -Proppyl)biphenyl-4-ylmethanol
[O 1 1 11 4-(a): 3 '-( 1 -Proppyl)biphenyl-4-vlcarbaldehyde
A solution of 1.04 g (3.98 mmol) of 3'-bromobiphenyl-4-ylcarbaldehyde in 10
mL of toluene was degassed under reduced pressure and then substituted with argon gas.
10 Thereafter, 23 1 mg (0.200 mrnol) of tetrakis(tripheny1phosphine)palladium and 1.46
mL (4.80 mmol) of tributyl(1-propyny1)tin were added and stirred for 7 hours at 1 10°C
in an argon gas atmosphere. After the completion of the reaction, 60 mL of 0.8 mol/L
aqueous potassium fluoride solution was added to the reaction solution, followed by
extraction with toluene. The organic layer was washed with saturated aqueous sodium
15 chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under
reduced pressure. The residue was subjected to silica gel column chromatography
(elution solvent; n-hexane:ethyl acetate = 1:O + 4: 1 (VIV)), and firactions containing
the target product were concentrated under reduced pressure to afford 660 mg of the
title compound as a pale yellow solid. (Yield: 75%)
20 Mass spectrum (CI, d z ) : 221 (~'+1)
1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, lH), 7.97-7.93 (my 2H),
7.76-7.72 (my 2H), 7.68-7.67 (m, lH), 7.55-7.52 (my lH), 7.45-7.37 (my 2H), 2.08 (s,
3H)
[O 1 121 4-(b): 3'41 -Propynyl)biphenyl-4-ylmethanol
25 The reaction and post-treatment were performed in accordance with Reference
Example 3-(b) except for using 723 mg (3.28 mmol) of
3'-(1-propyny1)biphenyl-4-ylcarbaldehyde obtained in the same manner as in Reference
Example 4-(a) in place of 3'-(1-propeny1)biphenyl-4-ylcarbaldehyde, and using 62.2 mg
(1.64 mmol) of sodium borohydride, to afford 588 mg of the title compound as a pale
30 yellowish white solid. (Yield: 8 1%)
Mass spectrum (EI, d z ) : 222 (M')
1 H-NMR spectrum (CDC13, 6 ppm): 7.63-7.62 (my 1 H), 7.60-7.56 (my 2H),
7.51-7.47 (my lH), 7.46-7.42 (my 2H), 7.38-7.32 (my 2H), 4.75 (d, J = 6.0 Hz, 2H), 2.07
(s, 3H), 1.68 (t, J = 6.0 Hz, 1H)
3 5 [O 1 131 Reference Example 5
3 '-Ethoxvbiphenyl-4-ylmethanol
To 1.2 1 g (6.02 mmol) of 3-bromophenetole were added 15 mL of toluene, 15
mL of ethanol, and 4.5 mL (9.0 mmol) of 2 mol/L aqueous sodium carbonate solution,
degassed under reduced pressure, and then substituted with argon gas. Thereafter,
1.37 g (9.02 mmol) of 4-(hydroxymethy1)phenylboronic acid and 347 mg (0.300 mmol)
5 of tetrakis(tripheny1phosphine)palladium were added and stirred for 4 hours at 1 00°C in
an argon gas atmosphere. After the completion of the reaction, the reaction solution
was concentrated under reduced pressure. Thereafter, water was added to the residue,
followed by extraction with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate,
10 and then concentrated under reduced pressure. The residue was subjected to silica gel
column chromatography (elution solvent; n-hexane:ethyl acetate = 9: 1 + 7:3 (VN)),
and fractions containing the target product were concentrated under reduced pressure to
afford 1.23 g of the title compound as a pale yellow oil. (Yield: 90%)
Mass spectrum (CI, mlz): 229 ( ~ + + 1 )
15 1 H-NMR spectrum (CDC13, 6 ppm): 7.61-7.56 (my 2H), 7.46-7.41 (my 2H),
7.34 (dd, J = 8.0, 8.0 Hz, lH,), 7.18-7.1 1 (m, 2H), 6.91-6.87 (my lH), 4.74 (d, J = 5.9
Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.67 (t, J = 5.9 Hz, lH), 1.45 (t, J = 7.0 Hz, 3H)
[O 1 141 Reference Example 6
Hexyl ~6-~(pvidin-2-ylsulfonyl~aminomethyllp~idin-2-ylamino)acetate
20 To a solution of 957 mg (2.00 mmol) of text-butyl
(tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]pydh2-yl} amino)acetate
obtained in the same manner as in Reference Example 1-(f) in 6.0 mL of n-hexanol,
0.56 mL (10 mmol) of concentrated sulfuric acid was added and stirred for 8 hours at
100°C. After the completion of the reaction, the reaction solution was poured into
25 saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl
acetate. The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was subjected to silica gel column chromatography (elution
solvent; n-hexane:ethyl acetate = 1:l + 3:7 (VN)), and fractions containing the target
30 product were concentrated under reduced pressure to afford 658 mg of the title
compound as a slightly yellow oil. (Yield: 8 1 %)
'H-NMR spectrum (CDC13, 6 ppm): 8.62 (ddd, J = 4.6, 1.8, 1.0 Hz, lH), 7.97
(ddd, J = 7.7, 1.2, 1.0 Hz, lH), 7.84 (ddd, J = 7.7, 7.7, 1.8 Hz, lH), 7.41 (ddd, J = 7.7,
4.6, 1.2 Hz, lH), 7.29 (dd, J = 8.4,7.4 Hz, lH), 6.44 (d, J = 7.4 Hz, lH), 6.28 (d, J = 8.4
35 Hz,1H),6.02(t,J=5.3Hz,1H),4.92(t,J=5.3Hz,1H),4.25(d,J=5.3Hz,2H),4.18
(t, J = 6.7 Hz, 2H), 4.08 (d, J = 5.3 Hz, 2H), 1.71-1.61 (my 2H), 1.39-1.26 (my 6H),
0.91-0.87 (my 3H)
[O 1 151 Reference Example 7
tert-Butyl (tert-butoxycarbonyl16-~(3'-ethoxybiphenyl-4-ylmethyl~aminomethyllpyridine-
2-vl) amino)acetate
5 [O 1 1 61 7-(a): 3 '-Ethoxybiphenyl-4-ylcarbaldehyde
The reaction and post-treatment were performed in accordance with Reference
Example 5 except for using 4.20 g (22.7 mmol) of 4-bromobenzaldehyde in place of
3-bromophenetole, using 3.13 g (1 8.9 mmol) of 3-ethoxyphenylboronic acid in place of
4-(hydroxymethy1)phenylboronic acid, and using 28.4 mL (56.8 mmol) of 2 mol/L
10 aqueous sodium carbonate solution and 2.18 g (1.89 mmol) of
tetrakis(triphenylphosphine)palladium, to afford 4.08 g of the title compound as a
colorless oil. (Yield: 95%)
Mass spectrum (CI, d z ) : 227 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, lH), 7.97-7.93 (my 2H),
15 7.76-7.73 (my 2H), 7.38 (dd, J = 8.1, 7.9 Hz, lH), 7.21 (ddd, J = 7.9,2.0,0.9 Hz, lH),
7.16 (dd, J = 2.3,2.0 Hz, lH), 6.95 (ddd, J = 8.1,2.3,0.9 Hz, lH), 4.1 1 (q, J = 6.9 Hz,
2H), 1.46 (t, J = 6.9 Hz, 3H)
[0117] 7-(b): tert-Butyl (tert-butoxycarbonyl~6-~(3'-ethoxybiphenyl-4-ylmethyl)-
aminomethyllpyridin-2-yl) amino)acetate
20 To a solution of 4.02 g (1 1.9 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate obtained in the same
manner as in Reference Example 1-(e) in 12 mL of methylene chloride, 2.46 g (10.9
mmol) of 3'-ethoxybiphenyl-4-ylcarbaldehyde obtained in Reference Example 7-(a)
was added and stirred for 30 minutes at room temperature. Thereafter, 3.25 g (15.3
25 mmol) of sodium triacetoxyborohydride was added under ice cooling and stirred for 3.5
hours at the same temperature. After the completion of the reaction, an aqueous
sodium bicarbonate solution was added to the reaction solution, followed by extraction
with ethyl acetate. The organic layer was washed with saturated aqueous sodium
chloride solution, dried over anhydrous potassium carbonate, and then concentrated
30 under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent; n-hexane:ethyl acetate = 3:2 + 0: 1 (VN)), and
fractions containing the target product were concentrated under reduced pressure to
afford 3.68 g of the title compound as a pale yellow oil. (Yield: 62%)
Mass spectrum (CI, d z ) : 548 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 7.69 (d, J = 8.2 Hz, lH), 7.59 (dd, J = 8.2,
7.3 Hz, lH), 7.57-7.53 (my 2H), 7.43-7.39 (my 2H), 7.33 (dd, J = 7.9, 7.7 Hz, lH), 7.16
(ddd, J = 7.7, 1.7,0.9 Hz, lH), 7.12 (dd, J = 2.3, 1.7 Hz, lH), 6.97 (d, J = 7.3 Hz, lH),
6.87 (ddd, J = 7.9,2.3, 1.0 Hz, lH), 4.57 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H),
3.83 (s, 2H), 1.53 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H)
[O 1 1 81 Reference Example 8
5 4-(6-Ethoxypvridin-2-y1)phenylmethanol
The reaction and post-treatment were performed in accordance with Reference
Example 5 except for using 0.49 g (2.4 mmol) of 2-bromo-6-ethoxypyridine (see
US20031199440) in place of 3-bromophenetole, and using 0.59 g (3.9 mmol) of
4-(hydroxymethyl)phenylboronic acid, 1.7 mL (3.4 mmol) of 2 mol/L aqueous sodium
10 carbonate solution, and 138 mg (0.1 19 mmol) of tetrakis(triphenylphosphine)palladium,
to afford 284 mg of the title compound as a white solid. (Yield: 5 1%)
Mass spectrum (CI, d z ) : 230 (M++1)
'H-NMR spectrum (CDC13, 6 ppm): 8.05-8.01 (m, 2H), 7.62 (dd, J = 8.2, 7.4
Hz, lH), 7.47-7.43 (m, 2H), 7.32 (dd, J = 7.4, 0.6 Hz, lH), 6.67 (dd, J = 8.2, 0.6 Hz,
15 lH), 4.75 (d, J = 6.0 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 1.67 (t, J = 6.0 Hz, lH), 1.44 (t, J
= 7.1 Hz, 3H)
[O 1 191 Reference Example 9
Ethyl ~6-~(thiophen-2-ylsulfonyl)aminomethyllp~idin-2-ylamiancoe)ta te
[O 1201 9-(a): tert-Butyl (tert-butoxycarbonyl~6-~(thiophen-2-ylsulfonyl~-
20 aminomethyllpvridin-2-yl) amino)acetate
The reaction and post-treatment were performed in accordance with Reference
Example 1-(f) except for using 1.35 g (4.00 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetateo btained in the same
manner as in Reference Example 1-(e), and using 73 1 mg (4.00 mmol) of
25 2-thiophenesulfonyl chloride in place of 2-pyridylsulfonyl chloride, to afford 1.61 g of
the title compound as a white solid. (Yield: 84%)
Mass spectrum (CI, d z ) : 484 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 7.71 (d, J = 8.4 Hz, lH), 7.57 (dd, J = 3.8,
1.3 Hz, lH), 7.56 (dd, J = 8.4, 7.4 Hz, lH), 7.50 (dd, J = 5.0, 1.3 Hz, lH), 7.01 (dd, J =
30 5.0,3.8 Hz, lH), 6.83 (d, J = 7.4 Hz, lH), 5.67 (t, J = 5.3 Hz, lH), 4.45 (s, 2H), 4.27 (d,
J = 5.3 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H)
[O 12 11 9-(b): Ethyl {6-[(thiophen-2-ylsulfony1)aminomethyllpvridin-
2-ylamino) acetate
To 1.60 g (3.3 1 mmol) of tert-butyl (tert-butoxycarbonyl(6-[(thiophen-2-yl-
35 sulfonyl)aminomethyl]pyridin-2-yl} amino)acetate obtained in Reference Example 9-(a),
20 mL (40 mmol) of 2 mol1L hydrogen chloridelethanol solution was added and heated
to reflux with stirring for 3 hours. After the completion of the reaction, the reaction
solution was concentrated under reduced pressure and was neutralized using saturated
aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride solution, dried over
5 anhydrous magnesium sulfate, and then concentrated under reduced pressure. The
residue was subjected to silica gel column chromatography (elution solvent;
n-hexane:ethyl acetate = 7:3 + 1: 1 (VN))a,n d fractions containing the target product
were concentrated under reduced pressure to afford 1.10 g of the title compound as a
colorless oil. (Yield: 93%)
10 Mass spectrum (CI, d z ) : 356 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 7.57 (dd, J = 3.8, 1.3 Hz, lH), 7.51 (dd, J
= 5.0, 1.3 Hz, lH), 7.32 (dd, J = 8.3,7.3 Hz, lH), 7.01 (dd, J = 5.0,3.8 Hz, lH), 6.44
(dd, J = 7.3,0.6 Hz, lH), 6.32 (dd, J = 8.3, 0.6 Hz, lH), 5.86 (t, J = 4.9 Hz, lH), 4.96 (t,
J = 5.3 Hz, lH), 4.26 (q, J = 7.2 Hz, 2H), 4.18 (d, J = 4.9 Hz, 2H), 4.06 (d, J = 5.3 Hz,
15 2H), 1.32 (t, J = 7.2 Hz, 3H)
[0 1221 Reference Example 10
Ethyl 16-~(benzenesulfonvl~aminomethvllp~idin-2-ylamaicneot)a te
[O 1231 10-(a): tert-Butyl ( 16-~(benzenesulfony1)aminomethyllpyridin-2-yl-)
tert-butoxycarbony1amino)acetate
20 The reaction and post-treatment were performed in accordance with Reference
Example 1-(f) except for using 1.35 g (4.00 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetateo btained in the same
manner as in Reference Example 1-(e), and using 707 mg (4.00 mrnol) of
benzenesulfonyl chloride in place of 2-pyridylsulfonyl chloride, to afford 1.7 1 g of the
25 title compound as a slightly beige solid. (Yield: 89%)
Mass spectrum (CI, mlz): 478 ( ~ + + l )
1 H-NMR spectrum (CDC13, 6 ppm): 7.86-7.83 (m, 2H), 7.67 (d, J = 8.4 Hz,
lH), 7.53-7.48 (m, 2H), 7.45-7.41 (m, 2H), 6.78 (dd, J = 7.4, 0.6 Hz, lH), 5.56 (t, J =
5.4 Hz, lH), 4.41 (s, 2H), 4.19 (d, J = 5.4 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H)
30 [O 1241 10 -(b): Ethyl ~6-~~benzenesulfonyl)aminomethyllpyridin-2-ylamiancoet)a te
The reaction and post-treatment were performed in accordance with Reference
Example 9-(b) except for using 1.70 g (3.56 mmol) of tert-butyl
((6-[(benzenesulfonyl)aminomethyl]pyridin-2-yl} tert-butoxycarbony1amino)acetate
obtained in Reference Example 10-(a) in place of tert-butyl
35 (tert-butoxycarbonyl{6-[(thiophen-2-ylsulfonyl)aminomethyl]pyri} amino)acetat
e, and using 20 mL (40 mmol) of 2 mol1L hydrogen chloridelethanol solution, to afford
1.13 g of the title compound as a white solid. (Yield: 9 1 %)
Mass spectrum (CI, d z ) : 350 ( ~ + + l )
1 H-NMR spectrum (CDC13, 6 ppm): 7.87-7.84 (my 2H), 7.53-7.42 (my 3H),
7.28 (dd, J = 8.3,7.3 Hz, lH), 6.39 (dd, J = 7.3, 0.6 Hz, lH), 6.30 (dd, J = 8.3,0.6 Hz,
5 lH), 5.73 (t, J = 4.9 Hz, lH), 4.92 (t, J = 5.2 Hz, lH), 4.26 (q, J = 7.2 Hz, 2H), 4.09 (d, J
=4.9 Hz, 2H), 4.04 (d, J = 5.2Hz7 2H), 1.32 (t, J = 7.2 Hz, 3H)
[O 1251 Reference Example 1 1
Ethyl i6-~(thiophen-3-ylsulfonyl)aminomethyllp~idin-2-ylamino)acetate
[O 1261 1 1 -(a): tert-Butyl (tert-butoxycarbonyli6-[(thiophen-3-ylsulfony1)-
10 aminomethyllpvridin-2-ylla mino)acetate
The reaction and post-treatment were performed in accordance with Reference
Example 1 -(f) except for using 1.35 g (4.00 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate obtained in the same
manner as in Reference Example 1-(e), and using 73 1 mg (4.00 mmol) of
15 3-thiophenesulfonyl chloride in place of 2-pyridylsulfonyl chloride, to afford 1.64 g of
the title compound as a pale yellowish white solid. (Yield: 85%)
Mass spectrum (CI, d z ) : 484 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 7.93 (dd, J = 2.9, 1.4 Hz, lH), 7.69 (d, J =
8.3 Hz, lH), 7.54 (dd, J = 8.3, 7.4 Hz, lH), 7.30 (dd, J = 5.1,2.9 Hz, lH), 7.28 (dd, J =
20 5.1,1.4Hz,1H),6.80(dd,J=7.4,0.6Hz,1H),5.59(t,J=5.4Hz,1H),4.43(s,2H),
4.23 (d, J = 5.4 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H)
[O 1271 1 1 -(b): Ethyl i6-~(thiophen-3-ylsulfonyl)aminomethyllpvridin-2-ylamino)
acetate
The reaction and post-treatment were performed in accordance with Reference
25 Example 9-(b) except for using 1.63 g (3.37 mmol) of tert-butyl
(tert-butoxycarbonyl(6-[(thiophen-3 -ylsulfonyl)aminomethyl]pyridin-2-yl}a mino)acetat
e obtained in Reference Example 1 1-(a) in place of tert-butyl
(tert-butoxycarbonyl{6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-yl} amino)acetat
e, and using 17.5 mL (35.0 mmol) of 2 mol/L hydrogen chloridelethanol solution. The
30 residue was subjected to silica gel column chromatography (elution solvent;
n-hexane:ethyl acetate = 7:3 + 1:1 (VN))a, nd fractions containing the target product
were concentrated under reduced pressure. The obtained crude material was
recrystallized from 5 mL of ethyl acetate to afford 73 1 mg of the title compound as a
white solid. (Yield: 61%)
35 Mass spectrum (CI, d z ) : 356 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 7.93 (dd, J = 3.0, 1.4 Hz, lH), 7.33-7.28
(my3H),6.40(dd,J =7.3,0.6HzY1 H),6.32(ddYJ =8.3,0.6HzYl H),5.76(t, J=5.1 Hz,
IH), 4.95 (t, J = 5.4 Hz, IH), 4.27 (q, J = 7.2 Hz, 2H), 4.13 (d, J = 5.1 Hz, 2H), 4.06 (d,
J = 5.4 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H)
[O 1281 Reference Example 12
5 tert-Butyl rtert-butox~carbonyl(6{- [ 3'-( 1- prop~nyl)biphenyl-4-ylmethyllaminomethvlj
pyridin-2-~1)aminoal cetate
[O 1291 12-(a): 1 -Bromo-341 -propynyl)benzene
To a solution of 7.07 g (25.0 mmol) of 1-bromo-3-iodobenzene in 50 mL of
toluene were added 1.43 g (7.5 1 mrnol) of copper(1) iodide and 1.45 g (1.25 mmol) of
10 tetrakis(triphenylphosphine)palladium, degassed under reduced pressure, and then
substituted with argon gas. Thereafter, 2.8 1 g (25.0 mmol) of
1-trimethylsilyl-1-propyne,1 1.5 mL (82.5 mmol) of triethylamine, and 25.0 mL (25.0
rnrnol) of 1 mollL tetrafluoroammonium fluorideltetrahydrofuran solution were added
and stirred for 17 hours at room temperature in an argon gas atmosphere. After the
15 completion of the reaction, water and t-butyl methyl ether were added to the reaction
solution, and insoluble substances were filtered off through Celite (trade name). The
organic layer after separation was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent; n-hexane), and fractions containing the target product
20 were concentrated under reduced pressure to afford 4.22 g of the title compound as a
colorless oil. (Yield: 86%)
Mass spectrum (CI, mlz): 195, 197 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 7.53 (dd, J = 1.7, 1.7 Hz, lH), 7.39 (ddd, J
= 8.0, 1.7, 1.0 Hz, lH), 7.31-7.29 (my lH), 7.14 (dd, J = 8.0, 8.0 Hz, lH), 2.04 (s, 3H)
25 [O 1301 12-(b): 3'-(1-Propyny1)biphenyl-4-ylcarbaldehyde
The reaction and post-treatment were performed in accordance with Reference
Example 5 except for using 2.93 g (1 5.0 mmol) of 1-bromo-3-(1-propyny1)benzene
obtained in the same manner as in Reference Example 12-(a) in place of
3-bromophenetole, using 3.37 g (37.5 mmol) of 4-forrnylphenylboronic acid in place of
30 4-(hydroxymethy1)phenylboronic acid, and using 1 1.3 mL (22.6 mmol) of 2 mol1L
aqueous sodium carbonate solution and 867 mg (0.750 mmol) of
tetrakis(triphenylphosphine)palladium, to afford 3.3 1 g of the title compound as a pale
yellowish white solid. (Quantitative)
The NMR spectrum for the compound obtained in this Reference Example
35 12-(b) was identical to the NMR spectrum for the compound obtained in Reference
Example 4-(a).
[O 13 11 12-(c): tert-Butyl rtert-butoxycarbonyl(6- { r3'-(1 -propynyl)biphenyl-4-ylmethyl1
aminomethyl )pvridin-2-y1)aminol acetate
The reaction and post-treatment were performed in accordance with Reference
Example 7-(b) except for using 5.57 g (1 6.5 mmol) of tert-butyl
5 [(6-aminomethylpyridin-2-yl)tert-butoxycbonylamino]acetate obtained in the same
manner as in Reference Example 1-(e), using 3.30 g (15.0 mmol) of
3'-(1-propyny1)biphenyl-4-ylcarbaldehyde obtained in Reference Example 12-(b) in
place of 3'-ethoxybiphenyl-4-ylcarbaldehyde, and using 4.45 g (21.0 mmol) of sodium
triacetoxyborohydride, to afford 6.48 g of the title compound as a pale yellow oil.
10 (Yield: 80%)
Mass spectrum (CI, mlz): 542 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 7.70 (d, J = 8.2 Hz, lH), 7.63-7.62 (m,
lH), 7.59 (dd, J = 8.2,7.4 Hz, lH), 7.55-7.52 (m, 2H), 7.50-7.47 (m, lH), 7.43-7.40 (m,
2H), 7.37-7.32 (m, 2H), 6.97 (d, J = 7.4 Hz, lH), 4.57 (s, 2H), 3.85 (s, 2H), 3.83 (s, 2H),
15 2.07(~,3H),l.53(~,9H),1.41(~,9H)
[O 1321 Reference Example 13
3 '-( 1 -Propynyl)biphenyl-4-ylmethanol
The reaction was performed in accordance with Reference Example 5 except
for using 3.90 g (20.0 mmol) of 1-bromo-3-(1-propyny1)benzene obtained in the same
20 manner as in Reference Example 12-(a) in place of 3-bromophenetole, and using 4.56 g
(30.0 mmol) of 4-(hydroxymethy1)phenylboronic acid, 15 mL (30 mmol) of 2 mol/L
aqueous sodium carbonate solution, and 1.16 g (1 .OO mmol) of
tetrakis(tripheny1phosphine)palladium. After the completion of the reaction, water
was added to the reaction solution, followed by extraction with ethyl acetate. The
25 organic layer was washed with saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then concentrated under reduced pressure. The
residue was subjected to silica gel column chromatography (elution solvent;
n-hexane:ethyl acetate = 4: 1 + 1 : 1 (VN)), and fractions containing the target product
were concentrated under reduced pressure. The obtained crude material was stirred in
30 45 mL of mixed solvent (ethyl acetate:n-hexane = 1 : 10 (VN)) for 1 hour. The
precipitated solid was collected by filtration and then dried under reduced pressure to
afford 3.85 g of the title compound as a white solid. (Yield: 87%)
The NMR spectrum for the compound obtained in this Reference Example 13
was identical to the NMR spectrum for the compound obtained in Reference Example
35 4-(b).
[O 1 3 31 Reference Example 14
Isopropyl {6-~(pyridin-2-ylsulfonyl)aminomethyllpvridin-2-ylaminaoc)e tate
The reaction and post-treatment were performed in accordance with Reference
Example 9-(b) except for using 1.44 g (3.01 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(pyidin-2-ylsulfonyl)aminomethyl]pyridin-2-yla)m ino)acetate
5 obtained in the same manner as in Reference Example 1-(f) in place of tert-butyl
(tert-butoxycarbonyl{6-[(thiophen-2-ylsulfonyl)aminomethyl]pyidin-2-yl)a mino)acetat
e, and using 16.0 mL (32.0 mmol) of 2 mol1L hydrogen chloridelisopropanol solution in
place of 2 mol/L hydrogen chloridelethanol solution, to afford 1.05 g of the title
compound as a white solid. (Yield: 96%)
10 Mass spectrum (CI, mlz): 365 ( ~ + + l )
'H-NMR spectrum (CDC13, 6 ppm): 8.63 (ddd, J = 4.7, 1.7, 1.0 Hz, lH), 7.97
(ddd, J = 7.7, 1.0, 1.0 Hz, lH), 7.84 (ddd, J = 7.7,7.7, 1.7 Hz, lH), 7.41 (ddd, J = 7.7,
4.7, 1.0 Hz, lH), 7.29 (dd, J = 8.2,7.3 Hz, lH), 6.44 (d, J = 7.3 Hz, lH), 6.28 (d, J = 8.2
Hz, lH), 6.04 (t, J = 5.4 Hz, lH), 5.10 (sep, J = 6.3 Hz, lH), 4.93 (t, J = 5.4 Hz, lH),
15 4.25(d,J=5.4Hz,2H),4.04(d,J=5.4Hz,2H),1.28(d,J=6.3Hz,6H)
[0 1341 Comparative Example 1
~6-T(Biphenvl-4-vlmethyl)(pwidin-2-ylsulfonyl)aminomethyllpyridin-2-
ylamino] acetic acid
This compound is the compound described in Example 17 of W02009/113600
20 (Example Number 538).
[O 1351 Comparative Example 2
{6-T(Biphenyl-4-ylmethyl)(pyidin-3-ylsulfonyl~aminomethvllpvridin-2-
ylamino) acetic acid
This compound is the compound described in Example 6 of W020091113600
25 (Example Number 546).
[O 1361 Comparative Example 3
{6-~(4'-Fluorobiphenyl-4-vlmethyl)(pyridin-3-ylsulfonyl)aminomethvllpyridin-
2-ylamino] acetic acid
This compound is the compound described in Example 9 of W020091113600
30 (Example Number 605).
[O 1371 Comparative Example 4
{6-~(4'-Chlorobiphenyl-4-y1methy1)(p~din-3-y1~u1fon~1)aminomethy11-
p yridin-2-ylamino ) acetic acid
This compound is the compound described in Example 10 of W02009/113600
35 (ExampleNumber681).
[O 13 81 Comparative Example 5
pyridin-2-y1amino)acetic acid
This compound is the compound described in Example 22 of W02009/113600
(Example Number 1446).
5 [O 1391 Comparative Example 6
{6-[(3 '-Methylbi~henyl-4-ylmethyl~(pyridin-2-~lsulfonyl)aminomethyllpyridin-
2-ylamino) acetic acid
This compound is the compound of Example Number 740 described in
W02009/113600.
10 [O 1401 6-(a): 3'-Methylbiphenyl-4-ylmethanol
The reaction and post-treatment were performed in accordance with Reference
Example 5 except for using 1.71 g (10.0 mmol) of 3-bromotoluene in place of
3-bromophenetole, and using 2.28 g (1 5.0 mmol) of 4-(hydroxymethy1)phenylboronic
acid, 7.5 mL (15 mmol) of 2 mol/L aqueous sodium carbonate solution, and 580 mg
15 (0.500 mmol) of tetrakis(triphenylphosphine)palladium, to afford 1.74 g of the title
compound as a pale white yellow solid. (Yield: 88%)
Mass spectrum (EI, d z ) : 198 (M')
1 H-NMR spectrum (CDC13, 6 ppm): 7.60-7.57 (m, 2H), 7.45-7.38 (m, 4H),
7.35-7.31 (m, lH), 7.18-7.15 (m, IH), 4.74 (d, J = 6.0 Hz, 2H), 2.42 (s, 3H), 1.66 (t, J =
20 6.0Hz,lH)
[O 14 11 6-(b): tert-Butyl (tert-butoxycarbonyl{6-[(3 '-methylbiphenyl-4-ylmethv1)-
(pyridin-2-~lsulfonyl~aminomethyllpyridina-m2i1n o)acetate
The reaction and post-treatment were performed in accordance with Example 1
except for using 403 mg (0.841 mmol) of tert-butyl
25 (tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]p~a}m ino)acetate
obtained in the same manner as in Reference Example 1-(f) and 159 mg (0.800 mmol)
of 3'-methylbiphenyl-4-ylmethanol obtained in Comparative Example 6-(a) in place of
3'-(1-propeny1)biphenyl-4-ylmethanol, and using 395 pL (1.60 mmol) of
tri-n-butylphosphine and 277 mg (1.60 mmol) of
30 N,N,N',N'-tetramethylazodicarboxamide, to afford 480 mg of the title compound as a
white foam. (Yield: 9 1 %)
Mass spectrum (ESI', d z ) : 659 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 8.60 (ddd, J = 4.8, 1.7, 0.9 Hz, lH), 7.82
(ddd, J = 7.7, 1.2, 0.9 Hz, lH), 7.77 (ddd, J = 7.7, 7.6, 1.7 Hz, lH), 7.65 (d, J = 7.8 Hz,
35 lH), 7.47-7.42 (m, 3H), 7.38 (ddd, J = 7.6,4.8, 1.2 Hz, lH), 7.35-7.27 (m, 5H),
7.17-7.14 (m, lH), 6.92 (d, J = 7.4 Hz, lH), 4.74 (s, 2H), 4.51 (s, 2H), 4.46 (s, 2H), 2.42
(s, 3H), 1.52 (s, 9H), 1.43 (s, 9H)
[O 1421 6-(c): {6-[(3 '-Methylbiphenyl-4-ylmeth~1~(pyridin-2-ylsulfonyl)-
arninomethyllpyridin-2-ylamino1 a cetic acid
To a solution of 477 mg (0.724 mmol) of tert-butyl
5 (tert-butoxycarbonyl(6-[(3 '-methylbiphenyl-4-ylmethyl)(pyidin-2-ylsulfonyl)-
aminomethyllpyridin-2-yl) amino)acetate obtained in Comparative Example 6-(b) in 10
mL of methylene chloride, 2.8 mL (37 mmol) of trifluoroacetic acid was added at room
temperature and stirred for 16 hours. After the completion of the reaction, the reaction
solution was concentrated under reduced pressure. Thereafter, water was added to the
10 reaction solution, and pH of the solution was adjusted to 4.5 with 1 mol/L aqueous
sodium hydroxide solution, followed by extraction with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate, and then concentrated under reduced
pressure. The residue was subjected to silica gel column chromatography (elution
solvent; ethyl acetate:methanol = 1:O + 3: 1 (VN)), and fractions containing the target
15 product were concentrated under reduced pressure to afford 364 mg of the title
compound as a white foam. (Quantitative)
Mass spectrum (ESI', mlz): 503 ( ~ + + 1 )
'H-NMR spectrum (DMSO-d6, 6 ppm): 12.41 (brs, 0.9H), 8.64 (ddd, J = 4.7,
1.7, 1.0 Hz, lH), 7.95 (ddd, J = 7.7, 7.7, 1.7 Hz, lH), 7.82-7.79 (my lH), 7.60-7.53 (my
20 3H), 7.45-7.41 (my 2H), 7.36-7.30 (my 3H), 7.23-7.17 (my 2H), 6.78 (brs, lH), 6.35 (d, J
= 8.2 Hz, lH), 6.30 (d, J = 7.0 Hz, lH), 4.73 (s, 2H), 4.25 (s, 2H), 3.84 (s, 2H), 2.38 (s,
3H)
[O 1431 Comparative Example 7
{6-[(3 '-Ethylbiphenyl-4-ylmethyl)(p~din-2-ylsulfonyl)aminomethyllpyridin-
25 2-ylaminot acetic acid
This compound is the compound of Example Number 75 1 described in
W02009/113600.
[O 1441 7-(a): 3 '-Ethylbiphenyl-4-ylcarbaldehyde
To a solution of 380 mg (1.43 mmol) of 3'-bromobiphenyl-4-ylcarbaldehyde in
30 21 mL of toluene were added 1.2 mL of water, 1.22 g (5.75 mmol) of tripotassium
phosphate, and 423 mg (5.72 mmol) of ethyl boronic acid, degassed under reduced
pressure, and then substituted with nitrogen gas. Thereafter, 4.6 mg (0.020 mmol) of
palladium acetate and 15.1 mg (0.042 1 mmol) of butyl-di- 1 -adamantylphosphine were
added and stirred for 3 hours at 100°C in a nitrogen gas atmosphere. The
35 post-treatment after the completion of the reaction was performed in accordance with
Reference Example 5 to substantially quantitatively afford 325 mg of the title
compound as a brown oil.
1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, lH), 7.99-7.91 (my 2H),
7.79-7.72 (m, 2H), 7.49-7.35 (my 3H), 7.29-7.22 (my lH), 2.74 (q, J = 7.6 Hz, 2H), 1.30
(t, J = 7.6 Hz, 3H)
5 [O 1451 7-(b): 3'-Ethylbiphenyl-4-vlmethanol
The reaction and post-treatment were performed in accordance with Reference
Example 3-(b) except for using 320 mg (equivalent to 1.43 mmol of pure content) of
3'-ethylbiphenyl-4-ylcarbaldehyde obtained in Comparative Example 7-(a) in place of
3'-(1-propeny1)biphenyl-4-ylcarbaldehyde, and using 28.7 mg (0.759 mmol) of sodium
10 borohydride, to substantially quantitatively afford 3 17 mg of the title compound as a
colorless oil.
'H-NMR spectrum (CDC13, 6 ppm): 7.63-7.56 (my 2H), 7.49-7.3 1 (my 5H),
7.23-7.16 (my lH), 4.74 (s, 2H), 2.72 (q, J = 7.6 Hz, 2H), 1.70 (brs, 0.8H), 1.29 (t, J =
7.6 Hz, 3H)
15 [O 1461 7-(c): tert-Butyl (tert-butoxvcarbonyl{6-~(3'-ethvlbiphenyl-4-vlmethyl)-
[pvidin-2-ylsulfony1)aminomethvllpyridin-2-y1a)m ino)acetate
The reaction and post-treatment were performed in accordance with Example 1
except for using 200 mg (0.41 8 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yla)m ino)acetate
20 obtained in the same manner as in Reference Example 1-(f) and 88.7 mg (0.418 mmol)
of 3'-ethylbiphenyl-4-ylmethanol obtained in Comparative Example 7-(b) in place of
3'-(1-propeny1)biphenyl-4-ylmethanol, and using 198 pL (0.802 mmol) of
tri-n-butylphosphine and 113 mg (0.656 mmol) of
N,N,N',N'-tetramethylazodicarboxamide, to afford 253 mg of the title compound as a
25 white syrup. (Yield: 90%)
Mass spectrum (FAB, rnlz): 673 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 8.63-8.58 (m, lH), 7.85-7.73 (my 2H),
7.65 (d, J = 8.5 Hz, lH), 7.50-7.25 (my 9H), 7.22-7.15 (my lH), 6.92 (d, J = 7.3 Hz, lH),
4.74 (s, 2H), 4.52 (s, 2H), 4.46 (s, 2H), 2.72 (q, J = 7.7 Hz, 2H), 1.52 (s, 9H), 1.43 (s,
30 9H), 1.29 (t, J = 7.7 Hz, 3H)
[0147] 7-(d): {6-~(3'-Ethylbiphenyl-4-ylmethy1~(pvridin-2-ylsulfonyl)-
aminomethyllpvridin-2-ylamino)a cetic acid
To a solution of 243 mg (0.36 1 mmol) of tert-butyl
(tert-butoxycarbonyl(6- [(3'-ethylbiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)-
35 aminomethyllpyridin-2-y1)amino)acetate obtained in Comparative Example 7-(c) in 3.6
mL of methylene chloride, 3.6 mL (47 mmol) of trifluoroacetic acid was added at room
temperature and stirred at room temperature for 2.5 hours. After the completion of the
reaction, the reaction solution was concentrated under reduced pressure. Thereafter,
water was added to the reaction solution, and pH of the solution was adjusted to 4.5
with 1 mollL aqueous sodium hydroxide solution and 1 mol/L hydrochloric acid. The
5 precipitated solid was collected by filtration, washed with water, and then concentrated
under reduced pressure to afford 158 mg of the title compound as a white solid.
(Yield: 85%)
Mass spectrum (FAB, d z ) : 5 17 ( ~ + + l )
'H-NMR spectrum (DMSO-d6, 6 ppm): 12.41 (brs, 0.8H), 8.67-8.61 (m, lH),
10 7.98-7.92 (m, lH), 7.83-7.78 (m, lH), 7.60-7.56 (my lH), 7.57-7.54 (my 2H), 7.47-7.42
(my 2H), 7.38-7.34 (my lH), 7.34-7.30 (m, 2H), 7.24-7.18 (my 2H), 6.77 (brs, 0.8H),
6.36 (d, J = 8.1 Hz, IH), 6.30 (d, J = 7.0 Hz, lH), 4.73 (s, 2H), 4.25 (s, 2H), 3.84 (s, 2H),
2.67 (q, J = 7.7 Hz, 2H), 1.23 (t, J = 7.7 Hz, 3H)
[O 1481 Comparative Example 8
15 {6-~(3~-Propylbiphenyl-4-ylmethy1)(pyridin-2-yl~~1fony1)aminomethy1~-
pyridin-2-ylamino) acetic acid
This compound is the compound of Example Number 754 described in
W02009/113600.
[O 1491 8-(a): 3 '-Propylbiphenyl-4-ylcarbaldehyde
20 To a solution of 500 mg (1.91 mmol) of 3'-bromobiphenyl-4-ylcarbaldehyde in
28 mL of toluene were added 1.7 mL of water, 1.63 g (7.68 mmol) of tripotassium
phosphate, and 675 mg (7.68 mmol) of propylboronic acid, degassed under reduced
pressure, and then substituted with nitrogen gas. Thereafter, 6.2 mg (0.028 mmol) of
palladium acetate and 20.2 mg (0.0563 mmol) of butyl-di-1-adamantylphosphinew ere
25 added and stirred for 3 hours at 100°C in a nitrogen gas atmosphere. The
post-treatment after the completion of the reaction was performed in accordance with
Reference Example 5 to afford 406 mg of the title compound as a pale yellow oil.
(Yield: 86%)
Mass spectrum (EI, d z ) : 224 (M')
30 1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, 1 H), 7.99-7.9 1 (m, 2H),
7.78-7.73 (my 2H), 7.51-7.34 (my 3H), 7.28-7.20 (m, lH), 2.73-2.61 (my 2H), 1.80-1.62
(my 2H), 0.98 (t, J = 7.3 Hz, 3H)
[O 1501 8-(b): 3 '-Propylbiphenyl-4-ylmethanol
The reaction and post-treatment were performed in accordance with Reference
35 Example 3-(b) except for using 400 mg (1.78 mmol) of
3'-propylbiphenyl-4-ylcarbaldehyde obtained in Comparative Example 8-(a) in place of
3'-(1-propeny1)biphenyl-4-ylcarbaldehyde, and using 33.7 mg (0.891 mmol) of sodium
borohydride, to afford 383 mg of the title compound as a white solid. (Yield: 95%)
Mass spectrum (EI, d z ) : 226 (M+)
1 H-NMR spectrum (CDC13, 6 ppm): 7.64-7.55 (my 2H), 7.48-7.30 (my 5H),
5 7.21-7.13 (my lH), 4.74 (d, J = 5.6 Hz, 2H), 2.71-2.59 (my 2H), 1.77-1.62 (m, 3H), 0.97
(t, J = 7.3 Hz, 3H)
[O 15 11 8-(c): tert-Butvl (tert-butoxvcarbon~l{6-T(3'-propylbiphenyl-4-ylmethyl)-
~pyridin-2-~lsulfonyl~aminomethvllpyridin-2a-mvlin) o)acetate
The reaction and post-treatment were performed in accordance with Example 1
10 except for using 200 mg (0.418 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]p~a}m ino)acetate
obtained in the same manner as in Reference Example 1-(f) and 94.6 mg (0.418 mmol)
of 3'-propylbiphenyl-4-ylmethanol obtained in Comparative Example 8-(b) in place of
3 '-(I -propenyl)biphenyl-4-ylmethanol, and using 198 pL (0.802 mmol) of
15 tri-n-butylphosphine and 113 mg (0.656 mmol) of
N,N,NY,N'-tetramethylazodicarboxamidet,o afford 255 mg of the title compound.
(Yield: 89%)
Mass spectrum (FAB, d z ) : 687 ( ~ + + l )
1 H-NMR spectrum (CDC13, 6 ppm): 8.62-8.58 (m, lH), 7.85-7.73 (my 2H),
20 7.65(d,J=8.3Hz,1H),7.49-7.23(m,9H),7.20-7.12(m,1H),6.92(d,J=7.3Hz,1H),
4.73 (s, 2H), 4.52 (s, 2H), 4.46 (s, 2H), 2.69-2.61 (my 2H), 1.77-1.61 (my 2H), 1.52 (s,
9H), 1.42 (s, 9H), 0.98 (t, J = 7.3 Hz, 3H)
[O 1521 8-(d): {6-~(3'-Propylbiphenvl-4-ylmethy1)(pvridin-2-ylsulfonyl)aminomethyl~-
pvridin-2-vlamino 1 acetic acid
25 The reaction and post-treatment were performed in accordance with
Comparative Example 7-(d) except for using 247 mg (0.360 mmol) of tert-butyl
(tert-butoxycarbonyl(6-[(3 '-propylbiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)-
aminomethyllpyridin-2-y1)amino)acetate obtained in Comparative Example 8-(c) in
place of tert-butyl (tert-butoxycarbonyl{6-[(3'-ethylbiphenyl-4-ylmethyl)-
30 (pyridin-2-ylsulfonyl)aminomethyl]pyridin-2a)m ino)acetate, and using 0.74 mL (9.7
mmol) of trifluoroacetic acid, to afford 161 mg of the title compound as a white solid.
(Yield: 84%)
Mass spectrum (FAB, d z ) : 53 1 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.42 (brs, 0.8H), 8.66-8.63 (my lH),
35 7.95 (ddd, J = 7.7, 7.6, 1.5 Hz, lH), 7.83-7.79 (m, lH), 7.58 (ddd, J = 7.6,4.7,0.8 Hz,
lH), 7.57-7.53 (m, 2H), 7.46-7.41 (m, 2H), 7.38-7.34 (my lH), 7.33-7.30 (my 2H),
7.25-7.16 (my 2H), 6.78 (brs, 0.8H), 6.36 (d, J = 8.1 Hz, lH), 6.30 (d, J = 7.0 Hz, lH),
4.73 (s, 2H), 4.26 (s, 2H), 3.84 (s, 2H), 2.65-2.60 (my 2H), 1.68-1.60 (my 2H), 0.92 (t, J
= 7.3 Hz, 3H)
[O 1531 Comparative Example 9
5 (6- { 13 '41- Buten~l)bi~henvl-4-ylmeth~ll(pwidin-2-ylsulfonyl~aminome- thyl~
pwidin-2-y1amino)acetic acid
[0 1541 9-(a): 3 '41 -Butenyl)biphenyl-4-ylcarbaldehyde
The reaction and post-treatment were performed in accordance with Reference
Example 5 except for using 445 mg (2.1 1 mmol) of 1-bromo-3-(1 -butenyl)benzene (see
10 W020081124848) in place of 3-bromophenetole, using 497 mg (3.31 mmol) of
4-formylphenylboronic acid in place of 4-(hydroxymethy1)phenylboronic acid, and
using 1.5 mL (3.0 mmol) of 2 mol1L aqueous sodium carbonate solution and 120 mg
(0.104 mmol) of tetrakis(triphenylphosphine)palladium, to afford 489 mg of the title
compound as a colorless oil. (Yield: 98%)
Mass spectrum (CI, d z ) : 237 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, lH), 8.00-7.92 (my 2H),
7.80-7.73 (my 2H), 7.61-7.57 (my lH), 7.53-7.37 (my 3H), 6.50-6.30 (my 2H), 2.33-2.21
(my 2H), 1.12 (t, J = 7.4 Hz, 3H)
[O 1551 9-(b): 3 '-( 1 -Butenyl)biphenyl-4-vlmethanol
20 The reaction and post-treatment were performed in accordance with Reference
Example 3-(b) except for using 480 mg (2.03 mmol) of
3'-(1-buteny1)biphenyl-4-ylcarbaldehyde obtained in Comparative Example 9-(a) in
place of 3'-(1-propeny1)biphenyl-4-ylcarbaldehyde, and using 38.5 mg (1.02 mmol) of
sodium borohydride, to afford 465 mg of the title compound as a white solid. (Yield:
25 96%)
Mass spectrum (EI, d z ) : 238 (M+)
1 H-NMR spectrum (CDC13,6 ppm): 7.64-7.57 (my 2H), 7.57-7.54 (my 1 H),
7.48-7.30 (my 5H), 6.50-6.26 (m, 2H), 4.75 (d, J = 5.9 Hz, 2H), 2.33-2.19 (my 2H), 1.66
(t, J = 5.9 Hz, lH), 1.11 (t, J = 7.4 Hz, 3H)
30 [O 1561 9-(c): Ethyl (6- { r3'-(1 -butenyl)biphenvl-4-ylmethyll(pvridin-2-ylsulfonyl)-
aminomethvl lpwidin-2-~lamino)acetate
The reaction and post-treatment were performed in accordance with Example 1
except for using 200 mg (0.571 mmol) of ethyl
{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-y1amin0)acetate obtained in the same
35 manner as in Reference Example 1-(g) and 136 mg (0.571 mmol) of
3'-(1 -butenyl)biphenyl-4-ylmethanol obtained in Comparative Example 9-(b) in place
of 3'-(1 -propenyl)biphenyl-4-ylmethanol, and using 270 pL (1.09 mmol) of
tri-n-butylphosphine and 154 mg (0.894 mmol) of
N,N,N7,N'-tetramethylazodicarboxamide, to afford 188 mg of the title compound as a
colorless oil. (Yield: 58%)
5 'H-NMR spectrum (CDC13, 6 pprn): 8.62 (ddd, J = 4.6, 1.7, 0.9 Hz, lH), 7.83
(ddd, J = 7.7, 1.0, 0.9 Hz, lH), 7.75 (ddd, J = 7.7, 7.6, 1.7 Hz, lH), 7.53-7.50 (my lH),
7.50-7.45 (my 2H), 7.40-7.32 (my 6H), 7.23 (dd, J = 8.3, 7.3 Hz, lH), 6.51 (d, J = 7.3 Hz,
lH), 6.49-6.27 (my 2H), 6.23 (d, J = 8.3 Hz, lH), 4.80 (s, 2H), 4.70 (t, J = 5.4 Hz, IH),
4.42(s,2H),4.22(qYJ =7.1 Hzy2H),3.96(d,J =5.4Hz,2H),2.32-2.20(m,2H), 1.28
10 (t,J=7.lHz,3H),l.ll(t,J=7.4Hz,3H)
[O 1571 9-(d): (6- { [3'-( 1 -Butenyl)biphen~l-4-ylmethyll(pyridin-2-ylsulfonyl)-
aminomethyl pyridin-2-y1amino)acetic acid
The reaction and post-treatment were performed in accordance with Example 2
except for using 180 mg (0.3 15 mmol) of ethyl
15 (6- {[3 '-(I -butenyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl)pyridin-2-
y1amino)acetate obtained in Comparative Example 9-(c) in place of ethyl
(6- {[3' -(I -propenyl)biphenyl-4-ylmethyl]( pyridin-2-ylsulfony1)aminomethyl)p yridin-2-
ylamino)acetate, and using 1.58 mL (1.58 mmol) of 1 mol/L aqueous sodium hydroxide
solution, to afford 134 mg of the title compound as a white solid. (Yield: 78%)
20 Mass spectrum (FAB, d z ) : 543 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.52 (brs, 0.6H), 8.69-8.65 (my lH),
8.03-7.95 (my lH), 7.89-7.81 (my lH), 7.65-7.53 (my 4H), 7.46-7.43 (my lH), 7.40-7.38
(my 2H), 7.36-7.22 (my 3H), 6.60-6.21 (my 4H), 4.70 (s, 2H), 4.33 (s, 2H), 3.89 (s, 2H),
2.26-2.20 (my 2H), 1.08 (t, J = 7.5 Hz, 3H)
25 [O 1581 Comparative Example 10
16- { T3 7-~2-Propen~l~biphenyl-4-~1me(tphyyrlidli n-2-~lsulfonyl)aminomethy-l ~
pyridin-2-~1amino)acetic acid
[O 1591 10-(a): 3 '-(2-Propeny1)biphenyl-4-ylmethanol
To a mixed solution of 2.11 g (8.00 rnmol) of 3'-bromobiphenyl-4-ylmethanol
30 (see W02001/070753) in 80 mL of toluenelethano1 = 1: 1 (V/V) were added 8.0 mL (16
mmol) of 2 mol/L aqueous sodium carbonate solution and 2.24 mL (12.0 mmol) of
allylboronic acid pinacol ester, degassed under reduced pressure, and then substituted
with argon gas. Thereafter, 462 mg (0.400 mmol) of
tetralus(tripheny1phosphine)palladium was added and stirred for 9 hours at 1 OO°C in an
35 argon gas atmosphere. Furthermore, 1.50 mL (8.00 mmol) of allylboronic acid pinacol
ester and 925 mg (0.800 mmol) of tetrakis(tripheny1phosphine)palladium were added
and stirred for 5 hours at the same temperature. After the completion of the reaction,
water was added to the reaction solution, followed by extraction with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride solution, dried
over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
5 The residue was subjected to silica gel column chromatography (elution solvent;
n-hexane:ethyl acetate = 4: 1 + 3:2 (VN))a, nd fractions containing the target product
were concentrated under reduced pressure to afford 1.1 1 g of the title compound as a
pale brown solid. (Yield: 62%)
Mass spectrum (EI, d z ) : 224 (M')
10 1 H-NMR spectrum (CDCl3,6 ppm): 7.61-7.57 (my 2H), 7.45-7.34 (my 5H),
7.20-7.17 (my lH), 6.08-5.95 (m, lH), 5.17-5.07 (my 2H), 4.74 (d, J = 4.4 Hz, 2H), 3.46
(d, J = 6.8 Hz, 2H), 1.66 (t, J = 4.4 Hz, 1H)
[O 1601 10-(b): Ethyl (6- {[3 '-(2-propen~l)biphenyl-4-ylmethyll~pyridin-2-y1~~lf0n~l)-
aminomethyl tpyridin-2-y1amino)acetate
15 The reaction and post-treatment were performed in accordance with Example 1
except for using 33 1 mg (0.945 mmol) of ethyl
{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-ylaminoa)c etate obtained in the same
manner as in Reference Example 1 -(g) and 202 mg (0.900 mmol) of
3'-(2-propeny1)biphenyl-4-ylmethanol obtained in Comparative Example 10-(a) in place
20 of 3'-(1-propeny1)biphenyl-4-ylmethanol, and using 450 pL (1.82 mmol) of
tri-n-butylphosphine and 3 10 mg (1.80 mmol) of
N,N,N',N'-tetramethylazodicarboxamide, to afford 478 mg of the title compound as a
colorless oil. (Yield: 95%)
Mass spectrum (FAB, d z ) : 557 ( ~ + + l )
25 1 H-NMR spectrum (CDCl3,6 ppm): 8.6 1 (ddd, J = 4.8, 1.8, 1.1 Hz, 1 H), 7.82
(ddd, J = 7.7, 1.3, 1.1 Hz, lH), 7.75 (ddd, J = 7.7, 7.5, 1.8 Hz, lH), 7.48-7.44 (my 2H),
7.42-7.33 (my 6H), 7.23 (dd, J = 8.2, 7.3 Hz, lH), 7.20-7.16 (my lH), 6.51 (d, J = 7.3 Hz,
lH), 6.23 (d, J = 8.2 Hz, lH), 6.08-5.95 (my lH), 5.17-5.15 (my lH), 5.13-5.08 (my lH),
4.80 (sY2H),4.69(t , J=5.3 Hz, 1H),4.42 (sy2H),4.22(q,J =7.1 Hz,2H), 3.96(dYJ =
30 5.3Hz,2H),3.46(d,J=6.6Hz,2H),1.28(t,J=7.1Hz,3H)
[O 16 11 1 0-(c): (6- ~~3'-(2-Propen~l)bi~henyl-4-ylmethyll(pyridin-2-ylsulfonyl)-
aminomethyltpyridin-2-y1amino)acetic acid
The reaction and post-treatment were performed in accordance with Example 4
except for using 473 mg (0.849 mmol) of ethyl
35 (6- {[3'-(2-propenyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfony1)aminomethyl)pyridin-2-
y1amino)acetate obtained in Comparative Example 10-(b) in place of ethyl
(6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-
ylamino)acetate, and using 3.40 mL (3.40 mmol) of 1 mol/L aqueous sodium hydroxide
solution, to afford 409 mg of the title compound as a white foam. (Yield: 91%)
Mass spectrum (FAB, d z ) : 529 ( ~ + + 1 )
5 'H-NMR spectrum (DMSO-d6, 6 ppm): 12.44 (brs, 0.5H), 8.64 (ddd, J = 4.8,
1.8, 1.0 Hz, IH), 7.95 (ddd, J = 7.8, 7.8, 1.8 Hz, lH), 7.80 (ddd, J = 7.8, 1.0, 1.0 Hz,
lH), 7.58 (ddd, J = 7.8,4.8, 1.0 Hz, lH), 7.56-7.53 (m, 2H), 7.48-7.44 (my 2H), 7.39 (dd,
J = 7.7, 7.7 Hz, lH), 7.33-7.31 (my 2H), 7.20 (dd, J = 8.4, 7.2 Hz, 2H), 6.75 (t, J = 5.7
Hz, lH), 6.34 (d, J = 8.4 Hz, lH), 6.29 (d, J = 7.2 Hz, lH), 6.06-5.97 (my lH), 5.15-5.11
10 (m,1H),5.09-5.06(m,1H),4.74(s,2H),4.24(s,2H),3.82(d,J=5.7Hz,2H),3.44(d,
J = 7.0 Hz, 2H)
[O 1621 Comparative Example 1 1
~6-~~3'-Methoxvbiphenvl-4-v1meth~1~(pyridin-2-y1su1fonv1~aminomethv11-
pyridin-2-vlamino) acetic acid
15 This compound is the compound of Example Number 797 described in
W02009/113600.
[O 1631 1 1 -(a): tert-Butyl (tert-butoxvcarbonvl i6-r(4-iodobenzvl)(pyridin-2-~1-
sulfonvl)aminomethvl1pyridin-2-yl)a mino)acetate
To a solution of 1.50 g (3.14 mmol) of tert-butyl
20 (tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yla}m ino)acetate
obtained in the same manner as in Reference Example 1-(f) in 9 mL of acetonitrile, 8.57
g (6.20 mmol) of potassium carbonate and 1.1 g (3.7 mmol) of 4-iodobenzyl bromide
were added and stirred for 1 hour at room temperature and then for 1 hour at 50°C.
Then, 0.47 g (1.6 mmol) of 4-iodobenzyl bromide was further added and stirred for 2
25 hours at 50°C. After the completion of the reaction, water was added to the reaction
solution, followed by extraction with ethyl acetate. The organic layer was washed
with saturated aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The obtained residue was
subjected to silica gel column chromatography (elution solvent; n-hexane:ethyl acetate
30 = 3: 1 + 1: 1 (VN)), and fractions containing the target product were concentrated under
reduced pressure to afford 2.04 g of the title compound as a white foam. (Yield: 94%)
Mass spectrum (CI, d z ) : 695 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 8.59 (ddd, J = 4.7, 1.8, 1.0 Hz, lH),
7.82-7.74 (m, 2H), 7.66 (d, J = 8.3 Hz, lH), 7.58-7.53 (m, 2H), 7.44 (dd, J = 8.3, 7.5 Hz,
35 lH), 7.42-7.37 (my lH), 7.02-6.97 (my 2H), 6.87 (d, J = 7.5 Hz, lH), 4.65 (s, 2H), 4.44
(s, 2H), 4.43 (s, 2H), 1.53 (s, 9H), 1.42 (s, 9H)
[0 1641 1 1 -(b): tert-Butvl (tert-butoxycarbonyl{6-r(3 '-methoxvbiphenyl-4-ylmethy1)-
~pyridin-2-ylsulfonvl)aminomethyllpwidin-2-ya1m) ino)acetate
The reaction and post-treatment were performed in accordance with Reference
Example 5 except for using 400 mg (0.577 mmol) of tert-butyl
5 (tert-butoxycarbonyl{6-[(4-iodobenzyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-
yl) amino)acetate obtained in Comparative Example 1 1 -(a) in place of
3-bromophenetole, using 134 mg (0.879 mmol) of 3-methoxyphenylboronic acid in
place of 4-(hydroxymethy1)phenylboronic acid, and using 1.3 mL (2.6 mmol) of 2
mol/L aqueous sodium carbonate solution and 67 mg (0.058 mmol) of
10 tetrakis(triphenylphosphine)palladium, to afford 3 15 mg of the title compound as a
white foam. (Yield: 8 1 %)
Mass spectrum (CI, d z ) : 675 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 8.60 (ddd, J = 4.7, 1.8, 1.1 Hz, lH), 7.82
(ddd, J = 7.7, 1.1, 1.1 Hz, lH), 7.77 (ddd, J = 7.7,7.7, 1.8 Hz, lH), 7.65 (d, J = 8.3 Hz,
15 1H),7.47-7.27(m,7H),7.14-7.11(m,1H),7.08-7.06(m,1H),6.92-6.87(m,2H),4.74
(s, 2H), 4.5 1 (s, 2H), 4.46 (s, 2H), 3.87 (s, 3H), 1.52 (s, 9H), 1.42 (s, 9H)
[O 1651 1 1 -(c): {6-r(3 '-Meth0xvbiphen~1-4-v1methy1)(pyridin-2-y1su1f0ny1)-
aminomethvllpyridin-2-ylamino)a cetic acid
To a solution of 3 12 mg (0.462 mmol) of tert-butyl
20 (tert-butoxycarbonyl(6-[(3 '-methoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfony1)-
aminomethyllpyridin-2-yl) amino)acetate obtained in Comparative Example 1 1-(b) in
3.7 mL of methylene chloride, 3.7 mL (48 mmol) of trifluoroacetic acid was added at
room temperature and allowed to stand undisturbed for 4 hours. After the completion
of the reaction, the reaction solution was concentrated under reduced pressure.
25 Thereafter, water was added to the reaction solution, and pH of the solution was
adjusted to 4.4 with saturated aqueous sodium bicarbonate solution and 1 mol/L
hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure to afford 257 mg of the title
30 compound as a white foam. (Quantitative)
Mass spectrum (FAB, d z ) : 519 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.41 (brs, 0.9H), 8.64 (ddd, J = 4.8,
1.8, 1.0 Hz, lH), 7.95 (ddd, J = 7.8, 7.8, 1.8 Hz, lH), 7.80 (ddd, J = 7.8, 1.0, 1.0 Hz,
lH), 7.59-7.56 (m, 3H), 7.37 (dd, J = 8.0, 8.0 Hz, lH), 7.34-7.31 (m, 2H), 7.21-7.18 (m,
35 2H),7.15(dd7J=2.0,2.0Hz,1H),6.93(ddd,J=8.0,2.0,1.1Hz,1H),6.77(brs,1H),
6.35 (d, J = 8.1 Hz, lH), 6.29 (d, J = 7.0 Hz, lH), 4.74 (s, 2H), 4.24 (s, 2H), 3.84 (s, 2H),
3.82 (s, 3H)
[0 1661 Comparative Example 12
{6-~(3'-Propoxybiphenyl-4-vlmethy1)(pyridin-2-y1su1fony1~aminomethy11-
pyridin-2-ylamino 1 acetic acid
5 This compound is the compound of Example Number 803 described in
WO2009/113600.
[O 1671 12-(a): tert-Butyl (tert-butoxycarbonvl{6-r(3 '-propoxybiphenvl-4-ylmethy1)-
(pyridin-2-vlsulfony1)aminomethyllpyridin-2-y1a)m ino)acetate
The reaction and post-treatment were performed in accordance with Reference
10 Example 5 except for using 401 mg (0.577 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(4-iodobenzyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-
y1)amino)acetate obtained in Comparative Example 1 1-(a) in place of
3-bromophenetole, using 156 mg (0.868 mmol) of 3-propoxyphenylboronic acid in
place of 4-(hydroxymethy1)phenylboronic acid, and using 1.3 mL (2.6 mmol) of 2
15 mol/L aqueous sodium carbonate solution and 67 mg (0.058 mmol) of
tetrakis(triphenylphosphine)palladium, to afford 332 mg of the title compound as a
white foam. (Yield: 82%)
Mass spectrum (CI, mlz): 703 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 8.60 (ddd, J = 4.7, 1.8, 1.0 Hz, lH), 7.82
20 (ddd,J=7.7,1.O,l.OHz,1H),7.76(ddd,J=7.7,7.7,1.8Hz,1H),7.65(d,J=8.3Hz,
lH), 7.48-7.26 (my 7H), 7.12-7.07 (my 2H), 6.93-6.86 (my 2H), 4.73 (s, 2H), 4.5 1 (s, 2H),
4.46 (s, 2H), 3.98 (t, J = 6.6 Hz, 2H), 1.90-1.78 (my 2H), 1.52 (s, 9H), 1.42 (s, 9H), 1.06
(t, J = 7.4 Hz, 3H)
[O 1681 12-(b): {6-~(3'-Propoxvbiphenyl-4-ylmethv1)(pyridin-2-y1~~lfony1)-
25 aminomethyllpyridin-2-ylamino 1 acetic acid
To a solution of 328 mg (0.466 mmol) of tert-butyl
(tert-butoxycarbonyl(6-[(3 '-propoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)-
aminomethyllpyridin-2-yl) amino)acetate obtained in Comparative Example 12-(a) in
4.7 mL of methylene chloride, 4.7 mL (61 mmol) of trifluoroacetic acid was added at
30 room temperature and allowed to stand undisturbed for 5 hours. After the completion
of the reaction, the reaction solution was concentrated under reduced pressure.
Thereafter, water was added to the reaction solution, and pH of the solution was
adjusted to 4.4 with saturated aqueous sodium bicarbonate solution and 1 mol/L
hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was
35 washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography (elution solvent; ethyl acetate:acetic acid = 100: 1
(VN)), and fractions containing the target product were concentrated under reduced
pressure to afford 158 mg of the title compound as a white foam. (Yield: 62%)
Mass spectrum (FAB, d z ) : 547 ( ~ + + 1 )
5 1 H-NMR spectrum (DMSO-d6,S ppm): 12.34 (brs, 0.7H), 8.64 (ddd, J = 4.7,
1.8, 1.0 Hz, lH), 7.95 (ddd, J = 7.7, 7.7, 1.8 Hz, lH), 7.80 (ddd, J = 7.7, 1.0, 1.0 Hz,
lH), 7.59-7.56 (my 3H), 7.35 (dd, J = 8.1, 8.0 Hz, lH), 7.33-7.31 (m, 2H), 7.21-7.17 (my
2H), 7.14 (dd, J = 2.1,2.0 Hz, lH), 6.92 (ddd, J = 8.1,2.1, 1.1 Hz, lH), 6.75 (t, J = 5.9
Hz, lH), 6.34 (d, J = 8.4 Hz, lH), 6.28 (d, J = 7.3 Hz, lH), 4.74 (s, 2H), 4.24 (s, 2H),
10 4.00(t,J=6.4Hz,2H),3.82(d,J=5.9Hz,2H),1.79-1.72(m,2H),1.00(t,J=7.4Hz,
3H)
[0 1691 Comparative Example 13
{6-~(2'-Ethoxvbiphenvl-4-y1meth~1~(pyridin-2-v1su1fony1)minomethy11pyridin-2-
ylamino) acetic acid
15 [0 1701 13-(a): tert-Butvl ( ~6-~(4-bromobenzvl)(pvridin-2-vlsulfonvl)aminomethyl~-
pvridin-2-vl) tert-butoxvcarbonv1amino)acetate
The reaction and post-treatment were performed in accordance with
Comparative Example 1 1 -(a) except for using 787 mg (3.15 mmol) of 4-bromobenzyl
bromide in place of 4-iodobenzyl bromide, and using 1.44 g (3.00 mmol) of tert-butyl
20 (tert-butoxycarbonyl{6-[(pyridin-2-ylsulfony1)aminomethyl]pyridin-2-yl) amino)acetate
obtained in the same manner as in Reference Example 1-(f) and 830 mg (6.00 mmol) of
potassium carbonate, to afford 1.77 g of the title compound as a slightly yellow oil.
(Yield: 91%)
Mass spectrum (FAB, d z ) : 647,649 ( ~ + + 1 )
25 'H-NMR spectrum (CDC13,S ppm): 8.59 (ddd, J = 4.8, 1.8, 1.0 Hz, lH),
7.83-7.75 (m, 2H), 7.65 (d, J = 8.5 Hz, lH), 7.47-7.33 (my 4H), 7.15-7.10 (my 2H), 6.87
(d, J = 6.8 Hz, lH), 4.66 (s, 2H), 4.44 (s, 2H), 4.43 (s, 2H), 1.52 (s, 9H), 1.42 (s, 9H)
[O 17 11 13-(b): tert-Butvl (tert-butoxvcarbonvl{6-~(2'-ethoxybiphenvl-4-ylmethyl)-
~~yridin-2-vlsulfonvl)aminomethvllpyridin-2-avmli)n o)acetate
3 0 The reaction and post-treatment were performed in accordance with Reference
Example 5 except for using 5 18 mg (0.800 mmol) of tert-butyl
({6-[(4-bromobenzyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl) tertbutoxycarbony1amino)
acetate obtained in Comparative Example 13-(a) in place of
3-bromophenetole, using 199 mg (1.20 mmol) of 2-ethoxyphenylboronic acid in place
35 of 4-(hydroxymethy1)phenylboronic acid, and using 0.60 mL (1.2 mmol) of 2 mol/L
aqueous sodium carbonate solution and 46.2 mg (0.0400 mmol) of
tetrakis(triphenylphosphine)palladium, to afford 548 mg of the title compound as a
slightly yellowish white foam. (Yield: 99%)
Mass spectrum (FAB, d z ) : 689 ( ~ + + 1 )
1 H-NMR spectrum (CDC13, 6 ppm): 8.60 (ddd, J = 4.7, 1.8, 1.0 Hz, lH),
5 7.83-7.73 (my2 H), 7.65 (d, J = 8.8 Hz, lH), 7.48-7.41 (my3 H), 7.37 (ddd, J = 7.3,4.7,
1.4 Hz, lH), 7.31-7.23 (my 4H), 7.03-6.91 (my 3H), 4.74 (s, 2H), 4.53 (s, 2H), 4.46 (s,
2H), 4.03 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.43 (s, 9H), 1.35 (t, J = 7.0 Hz, 3H)
[O 1721 13-(c): {6-[(2' -Ethoxybiphenyl-4-ylmethy1~(pvridin-2-y1~~1fon~1~-
aminomethyllpvridin-2-ylamino ) acetic acid
10 The reaction and post-treatment were performed in accordance with Example
7-(b) except for using 541 mg (0.785 mmol) of tert-butyl (tert-butoxycarbonyl-
(6-[(2' -ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl]-
pyridin-2-yl} amino)acetate obtained in Comparative Example 13-(b) in place of
tert-butyl (tert-butoxycarbonyl{6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-yl-
15 sulfonyl)aminomethyl]pyridin-2-yl} amino)acetate, and using 3.3 mL (20 mmol) of 6
mol/L hydrochloric acid and 1 .O mL of water, to afford 4 13 mg of the title compound as
a slightly yellowish white foam. (Yield: 99%)
Mass spectrum (FAB, d z ) : 533 ( ~ + + 1 )
'H-NMR spectrum (DMSO-d6, 6 ppm): 12.42 (brs, 0.6H), 8.64 (ddd, J = 4.8,
20 1.8, 1.0 Hz, lH), 7.94 (ddd, J = 7.7, 7.7, 1.8 Hz, lH), 7.79 (ddd, J = 7.7, 1.0, 1.0 Hz,
lH), 7.57 (ddd, J = 7.7,4.8, 1.0 Hz, lH), 7.44-7.41 (my 2H), 7.33-7.26 (my 4H), 7.20 (dd,
J = 8.4, 7.2 Hz, lH), 7.09-7.07 (my lH), 7.01 (ddd, J = 7.5, 7.5, 1.1 Hz, lH), 6.75 (t, J =
5.6 Hz, lH), 6.34 (d, J = 8.4 Hz, lH), 6.29 (d, J = 7.2 Hz, lH), 4.74 (s, 2H), 4.26 (s, 2H),
4.04 (q, J = 7.0 Hz, 2H), 3.82 (d, J = 5.6 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H)
25 [O 1731 Comparative Example 14
{6-~(4'-Ethoxybiphenyl-4-y1methy1)(pvridin-2-y1~u1f0ny1)amin0methy11-
pvridin-2-ylamino) acetic acid
[O174] 14-(a): tert-Butvl (tert-butoxvcarbonyl{6-~(4'-ethoxvbiphen~l-4-ylmethyl)-
(pwidin-2-ylsulfonyl)aminomethyllpwidin-21a mino)acetate
3 0 The reaction and post-treatment were performed in accordance with Reference
Example 5 except for using 389 mg (0.600 mmol) of tert-butyl
({6-[(4-bromobenzyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl) tert-butoxycarbo
ny1amino)acetate obtained in the same manner as in Comparative Example 13-(a) in
place of 3-bromophenetole, using 150 mg (0.900 mmol) of 4-ethoxyphenylboronic acid
35 in place of 4-(hydroxyrnethy1)phenylboronic acid, and using 0.45 mL (0.90 mmol) of 2
mol/L aqueous sodium carbonate solution and 34.7 mg (0.0300 mmol) of
tetrakis(triphenylphosphine)palladium, to afford 395 mg of the title compound as a
slightly yellowish white foam. (Yield: 96%)
Mass spectrum (FAB, d z ) : 689 ( ~ + + 1 )
1 H-NMR spectrum (CDCl3,6 ppm): 8.60 (ddd, J = 4.6, 1.7, 1.0 Hz, lH), 7.82
5 (ddd, J = 7.7, 1.0, 1.0 Hz, lH), 7.76 (ddd, J = 7.7,7.6, 1.7 Hz, lH), 7.65 (d, J = 8.1 Hz,
lH), 7.49-7.36 (m, 6H), 7.27-7.24 (m, 2H), 6.97-6.90 (m, 3H), 4.72 (s, 2H), 4.51 (s, 2H),
4.46 (s, 2H), 4.08 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H)
[O 1751 14-(b): l6-~(4'-Ethoxybiphenvl-4-vlmethy1)(p~din-2-yl~~1fony1~-
aminomethyllpvridin-2-ylamino ) acetic acid
10 The reaction and post-treatment were performed in accordance with Example
7-(b) except for using 390 mg (0.566 mmol) of tert-butyl (tert-butoxycarbonyl-
{6-[(4'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl-)
amino)acetate obtained in Comparative Example 14-(a) in place of tert-butyl
(tert-butoxycarbonyl(6-[(3 '-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)-
15 aminomethyllpyridin-2-yl) amino)acetate, and using 2.35 mL (14.1 mmol) of 6 mol/L
hydrochloric acid and 0.65 mL of water, to afford 296 mg of the title compound as a
slightly yellowish white foam. (Yield: 98%)
Mass spectrum (FAB, d z ) : 533 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6,S ppm): 12.42 (brs, 0.8H), 8.63 (ddd, J = 4.8,
20 1.8, 0.9 Hz, lH), 7.94 (ddd, J = 7.8, 7.8, 1.8 Hz, lH), 7.79 (ddd, J = 7.8,0.9,0.9 Hz,
lH), 7.59-7.55 (m, 3H), 7.52-7.50 (m, 2H), 7.30-7.28 (m, 2H), 7.19 (dd, J = 8.4, 7.1 Hz,
IH), 7.01-6.98 (m, 2H), 6.75 (t, J = 5.8 Hz, lH), 6.34 (d, J = 8.4 Hz, lH), 6.28 (d, J =
7.1Hz,1H),4.72(s,2H),4.23(s,2H),4.06(q,J=7.0Hz,2H),3.82(d,J=5.8Hz,2H),
1.35 (t, J = 7.0 Hz, 3H)
25 [O 1761 Comparative Example 15
/6- l r4-(2-Ethoxwyridin-4-y1)benzyll (pyridin-2-y1~~1f0nyl)aminometh-~ 1)
pyridin-2-v1amino)acetic acid
[O 1771 15-(a): 4-(2-Ethoxwyridin-4-y1)phenylmethanol
The reaction and post-treatment were performed in accordance with Reference
30 Example 5 except for using 0.55 g (2.7 mmol) of 4-bromo-2-ethoxypyridine (see
Tetrahedron Letters, 5 1, 304 1 (20 10)) in place of 3-bromophenetole, and using 0.66 g
(4.3 mmol) of 4-(hydroxymethy1)phenylboronic acid, 1.9 mL (3.8 rnmol) of 2 mol/L
aqueous sodium carbonate solution, and 154 mg (0.133 mmol) of
tetrakis(triphenylphosphine)palladium, to afford 250 mg of the title compound as a
35 yellow oil. (Yield: 40%)
Mass spectrum (CI, d z ) : 230 ( ~ + + 1 )
'H-NMR spectrum (CDC13, 6 ppm): 8.19 (dd, J = 5.4,0.7 Hz, lH), 7.64-7.60
(mY2H),7.49-7.45( my2H),7.09(dd,J =5.4, 1.5 Hz, lH), 6.94(ddYJ = 1.5, 0.7HzYl H),
4.76 (d, J = 5.2 Hz, 2H), 4.40 (q, J = 7.0 Hz, 2H), 1.79 (t, J = 5.2 Hz, 0.9H), 1.43 (t, J =
7.0 Hz, 3H)
5 [O 1781 15-(b): tert-Butyl rtert-butoxvcarbonvl(6- { r4-(2-ethoxypyridin-4-~1)-
benzvll (pyridin-2-vlsulfonyl)aminomethvlp~y ridin-2-y1)aminolacetate
The reaction and post-treatment were performed in accordance with Example 1
except for using 505 mg (1.06 mmol) of tert-butyl (tert-butoxycarbonyl-
{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl)amino)acetate obtained in the
10 same manner as in Reference Example 1 -(f) and 242 mg (1.06 mmol) of
4-(2-ethoxypyridin-4-y1)phenylmethanol obtained in Comparative Example 15-(a) in
place of 3'-(1 -propenyl)biphenyl-4-ylmethanol, and using 662 pL (2.65 mmol) of
tri-n-butylphosphine and 273 mg (1.59 mmol) of
N,N,NY,N'-tetramethylazodicarboxamidet,o afford 0.49 g of the title compound as a
15 white foam. (Yield: 67%)
Mass spectrum (CI, mlz): 690 (Mf+l)
'H-NMR spectrum (CDC13, 6 ppm): 8.60 (ddd, J = 4.8, 1.7, 1.0 Hz, lH), 8.18
(dd, J = 5.4,0.7 Hz, lH), 7.83 (ddd, J = 7.7, 1.1, 1.0 Hz, lH), 7.77 (ddd, J = 7.7, 7.5, 1.7
Hz, lH), 7.65 (d, J = 8.3 Hz, lH), 7.49-7.45 (my 2H), 7.44 (dd, J = 8.3, 7.3 Hz, lH),
20 7.39(ddd,J=7.5,4.8,1.1Hz,1H),7.35-7.31(m72H),7.04(dd,J=5.4,1.5Hz,1H),
6.92-6.88 (m,2H),4.76(~,2H),4.50(~,2H),4.44(~,2H)(q,,4 J.=471. 1 Hz,2H), 1.52
(s, 9H), 1.43 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H)
[0 1791 15-(c): 16- { ~4-~2-Ethox~vridin-4-vl)benzvll(pvridin-2-vlsulfon~l~-
aminomethy1)pyridin-2-v1amino)acetic acid
25 To a solution of 0.47 g (0.68 mmol) of tert-butyl
[tert-butoxycarbonyl(6- {[4-(2-ethoxypyridin-4-yl)benzyl](pyridin-2-ylsulfonyl)-
aminomethy1)pyridin-2-y1)aminolacetate obtained in Comparative Example 15-(b) in
6.8 mL of methylene chloride, 6.8 mL (89 mmol) of trifluoroacetic acid was added at
room temperature and stirred for 6.5 hours. After the completion of the reaction, the
30 reaction solution was concentrated under reduced pressure. Thereafter, water was
added to the reaction solution, and pH of the solution was adjusted to 4.5 with 2 mollL
aqueous sodium hydroxide solution and 0.1 mol1L hydrochloric acid, followed by
extraction with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate, and then
35 concentrated under reduced pressure to afford 293 mg of the title compound. (Yield:
81%)
Mass spectrum (FAB, d z ) : 534 ( ~ + + 1 )
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.52 (brs, 0.7H), 8.66 (dd, J = 4.7, 1.7
Hz, lH),8.20(dd, J=5.5,0.7Hz, 1H),7.98 (dd, J=7.7,7.7Hz, 1H),7.83 (d, J=7.4
Hz, lH), 7.69-7.66 (m, 2H), 7.61 (dd, J = 7.7,4.7 Hz, lH), 7.37-7.35 (my 2H), 7.28 (brs,
5 1H),7.26(dd,J=5.5,1.5Hz,1H),7.04(dd,J=1.5,0.7Hz,lH),6.42(s,1H),6.35(s,
IH), 4.73 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.32 (s, 2H), 3.86 (s, 2H), 1.34 (t, J = 7.1 Hz,
3H)
[O 1801 Comparative Example 16
J6- l T2'-( 1- Pro~ynvl)biphenyl-4-ylmethyl(lp yridin-2-ylsulfonyl)aminometh~-l ~
10 pyridin-2-y1amino)acetic acid
[O 18 11 16-(a): 1 -Bromo-2-(1 -propynyl)benzene
The reaction and post-treatment were performed in accordance with Reference
Example 12-(a) except for using 7.07 g (25.0 mmol) of 1-bromo-2-iodobenzene in place
of 1-bromo-3-iodobenzene, and using 1.43 g (7.5 1 mmol) of copper(1) iodide, 1.45 g
15 (1.25 mmol) of tetrakis(triphenylphosphine)palladium, 2.8 1 g (25.0 mmol) of

CLAIMS
A substituted biaryl compound of general formula (I):
wherein,
R' represents a protected or unprotected carboxy group,
W represents a nitrogen atom or -CH= group,
R2 represents an ethoxy group, 1-propenyl group, or 1-propynyl group, and
Z represents a phenyl group, 3-fluorophenyl group, pyridin-2-yl group,
10 pyridin-3-yl group, thiophen-2-yl group, or thiophen-3-yl group;
or a pharmacologically acceptable salt thereof.
2. The substituted biaryl compound according to claim 1, wherein R' represents a
carboxy group or C1-C6 alkoxycarbonyl group,
or pharmacologically acceptable salt thereof.
15 3. The substituted biaryl compound according to claim 1, wherein R' represents a
carboxy group, ethoxycarbonyl group, isopropoxycarbonyl group, or hexyloxycarbonyl
group,
or pharmacologically acceptable salt thereof.
4. The substituted biaryl compound according to claim 1, wherein R' represents a
20 carboxy group, ethoxycarbonyl group, isopropoxycarbonyl group, or hexyloxycarbonyl
group,
W represents a nitrogen atom or -CH= group,
R2 represents a 1-propenyl group or 1 -propynyl group, and
Z represents a phenyl group, 3-fluorophenyl group, pyridin-2-yl group,
25 pyridin-3-yl group, thiophen-2-yl group, or thiophen-3-yl group,
or pharmacologically acceptable salt thereof.
5. The substituted biaryl compound according to claim 1, wherein the substituted
biaryl compound is
ethyl (6- {[3 '-(I -propenyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)-
30 aminomethy1)pyridin-2-ylarnino)acetate,
(6- {[3 '-(I -propenyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl} -
pyridin-2-y1amino)acetic acid,
ethyl (6- {[3'-(1 -propynyl)biphenyl-4-ylmethyll(pyny1)-
aminomethyl) pyridin-2-ylamino)acetate,
(6- {[3 '-(1 -propynyl)biphenyl-4-ylmethyl](pyridin-2-y1~~1fony1)amin0methyl- )
5 pyridin-2-y1amino)acetic acid,
ethyl (6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](pyridin-3-ylsulfonyl)-
aminomethy1)pyridin-2-ylamino)acetate,
(6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](pyridin-3-ylsulfonyl)aminomethyl) -
pyridin-2-y1amino)acetic acid,
10 (6-[(3 '-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl-]
pyridin-2-ylamino)a cetic acid,
hexyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsu1fony1)minomethy1]-
pyridin-2-ylamino)a cetate,
(6-[(3 '-ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl-]
15 pyridin-2-ylamino)a cetic acid,
(6- [(benzenesulfonyl)(3 '-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-
ylamino) acetic acid,
{6-[(3'-ethoxybiphenyl-4-ylmethyl)(thiophen-2-ylsulfonyl)aminomethyl] -
pyridin-2-ylamino)a cetic acid,
20 (6-{ [4-(6-ethoxypyridin-2-yl)benzyl]( pyridin-2-ylsulfonyl)aminomethyl)-
pyridin-2-y1amino)acetic acid,
ethyl (6-{[ 3 '- ( 1- propynyl)biphenyl-4-ylmethyl(]t hiophen-2-ylsulfony1)-
aminomethyl) pyridin-2-ylamino)acetate,
(6-{ [3 '-(I -propynyl)biphenyl-4-ylmethyl](t hiophen-2-ylsulfony1)-
25 aminomethy1)pyridin-2-y1amino)acetic acid,
ethyl (6- {(benzenesulfonyl)[3 '-(I -propynyl)biphenyl-4-ylmethyllaminomethy1)
pyridin-2-ylamino)acetate,
(6-{ (benzenesulfonyl)[3 '-(1 -propynyl)biphenyl-4-ylmethyl]aminomethyl)-
pyridin-2-y1amino)acetic acid,
30 ethyl (6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](thiophen-3-ylsulfonyl)-
aminomethy1)pyridin-2-ylamino)acetate,
(6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](thiophen-3-ylsulfonyl)-
aminomethy1)pyridin-2-y1amino)acetic acid,
(6-( (3 -fluorobenzenesulfonyl)[ 3 '-(I -propynyl)biphenyl-4-ylmethyl-]
35 aminomethy1)pyridin-2-y1amino)acetic acid, or
isopropyl(6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl](py)-
aminomethyl }pyridin-2-ylamino)acetate,
or pharmacologically acceptable salt thereof.
6. A pharmaceutical composition comprising the substituted biaryl compound
according to any one of claims 1 to 5, or a pharmacologically acceptable salt thereof, as
5 an active ingredient.
7. The pharmaceutical composition according to claim 6, for prophylaxis or
treatment of interstitial pneumonia and/or pulmonary fibrosis.