DESCRIPTION
PHARMACEUTICAL COMPOSITION FOR TREATMENT AND/OR PREVENTION
OF PULMONARY DISEASE
5
TECHNICAL FIELD
[0001] The present invention relates to a pharmaceutical composition for the treatment
andor prevention of pulmonary disease containing, as an active ingredient thereof, a
novel substituted biaryl compound or a pharmacologically acceptable salt thereof.
10
BACKGROUND ART
[0002] Chronic obstructive pulmonary disease is a disorder composed of a diverse
range of pathological conditions including structural and functional changes in the lungs,
and is characterized by emphysema, chronic bronchitis caused by increased secretion of
15 mucus in the bronchi and irreversible, persistent airway obstruction. This disease is
caused by smoking, gases associated with air pollution or the presence of harmful fine
particles, and leads to inflammation of the bronchi and destruction of alveoli. As a
result, patients present with symptoms such as coughing, expulsion of phlegm or
shortness of breath, and in advanced cases, may progress to respiratory failure due to
20 hypoxemia.
Drugs used for the treatment of chronic obstructive pulmonary disease consist
primarily of anticholinergic drugs, P2 agonists, theophylline preparations and other
bronchodilators, and although other drugs such as expectorants or steroids are also used,
a safe and established therapeutic drug has yet to be found. Thus, there is a desire for
25 a more effective drug for the treatment of chronic obstructive pulmonary disease that is
associated with minimal adverse side effects.
[0003] On the other hand, prostaglandin E2 (hereinafter, abbreviated as "PGE211h) as a
wide variety of physiological activities as a metabolic product in the arachidonic acid
cascade, and acts as an agonist against the four receptors of EP1, EP2, EP3 and EP4.
30 PGE2 is involved in numerous inflammatory reactions, and in addition to having a
prophlogistic effect such as upregulation of vascular permeability, release of various
types of inflammation mediators, induction of inflammatory cells/immune cells and
promotion of vascularization, PGE2 has also been reported to demonstrate an
anti-inflammatory effect mediated by EP2 andor EP4 receptors (see Non-Patent
35 Document 1).
[0004] It has previously been disclosed that a prostanoid-based compound exhibiting
an EP2 antagonistic effect is useful for the prevention andlor treatment of respiratory
diseases including chronic obstructive pulmonary disease (see Patent Document 1). In
addition, non-prostanoid-based compounds exhibiting an EP2 antagonistic effect are
also known (see Patent Documents 2 to 7), and among these, various diseases
5 exemplified as medicinal applications of the compounds described in Patent Documents
2 to 7 include chronic obstructive pulmonary disease.
PRIOR ART DOCUMENTS
Patent Documents
10 [0005] Patent Document 1 : W020061043655
Patent Document 2: W020091113600
Patent Document 3: W020111030868
Patent Document 4: W020111030871
Patent Document 5: W020111030872
15 Patent Document 6: W02011/030873
Patent Document 7: W020111078303
Non-Patent Documents
[0006] Non-Patent Document 1 : British Journal of Pathology, 122, 149 (1 997)
20 SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0007] However, examples of specific pharmacological studies indicating that the
compounds described in the aforementioned Patent Document 2 to 7 have
anti-inflammatory effects and are useful for chronic obstructive pulmonary disease are
25 not described in any of the prior art documents. Moreover, none of the
aforementioned prior art documents describe examples of the sulfonamide compound
according to the present invention having, as a partial structure thereof, a biaryl group in
which a specific substituent is substituted at a specific site.
The inventors of the present invention conducted intensive research for the
30 purpose of providing a pharmaceutical composition that is useful for the treatment
andlor prevention of chronic obstructive pulmonary disease. As a result, since a
compound in which a specific substituent of a specific length is introduced at a specific
site of a terminal aryl group of a sulfonamide compound having a biaryl group has
excellent anti-inflammatory action, such as action that inhibits the production of
35 inflammatory cytokines, it was found to be useful as a therapeutic andlor prophylactic
drug (and preferably as a therapeutic drug) for chronic obstructive pulmonary disease in
particular, thereby leading to completion of the present invention.
The present invention provides a pharmaceutical composition containing, as an
active ingredient thereof, a substituted biaryl compound, or a pharmacologically
acceptable salt thereof, that has an EP2 antagonistic effect and an excellent
5 anti-inflammatory effect, and is useful as a therapeutic drug and/or prophylactic drug
(and preferably as a therapeutic drug) for chronic obstructive pulmonary disease in
particular.
Means for Solving the Problems
10 [0008] The present invention provides the following.
[0009] (1) A pharmaceutical composition for treatment andlor prevention of chronic
obstructive pulmonary disease, comprising a substituted biaryl compound represented
by general formula (I):
15 [0010] 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,
20 pyridin-3-yl group, thiophen-2-yl group or thiophen-3-yl group
or a pharmacologically acceptable salt thereof.
[0011] (2) The pharmaceutical composition described in (I), wherein, in general
formula (I), R' represents a carboxy group or C1-C6 alkoxycarbonyl group.
[OO 121 (3) The pharmaceutical composition described in (I), wherein, in general
25 formula (I), R' represents a carboxy group, ethoxycarbonyl group, isopropoxycarbonyl
group or hexyloxycarbonyl group.
[OO 131 (4) The pharmaceutical composition described in (I), wherein, in general
formula (I),
R' represents a carboxy group, ethoxycarbonyl group, isopropoxycarbonyl
30 group or hexyloxycarbonyl group,
W represents a nitrogen atom or -CH= group,
R~ represents a 1 -propenyl group or 1 -propynyl group, and
Z represents a phenyl group, 3-fluorophenyl group, pyridin-2-yl group,
p yridin-3 - yl group, thiophen-2-yl group or thiophen-3 - yl group.
[OO 141 (5) The pharmaceutical composition described in (I), wherein the substituted
biaryl compound represented by general formula (I) is:
ethyl
(6- {[3 '-(I -propenyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-
ylamino)acetate,
(6- {[3 '-(I -propenyl)biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl)aminomethyl } -
pyridin-2-y1amino)acetic acid,
ethyl
(6- {[3 ' -(1- propynyl)biphenyl-4-ylmethyl]( pyridin-2-ylsulfonyl)aminomethyl}p yridin-2-
pyridin-2-y1amino)acetic acid,
ethyl
(6- {[3' -(I -propynyl)biphenyl-4-ylmethyl]( pyridin-3- ylsulfonyl)aminomethyl} pyridin-2-
ylamino)acetate,
(6- {[3' -(I -propynyl)biphenyl-4-ylmethyl]( pyridin-3 -ylsulfonyl)aminomethyl} -
pyridin-2-y1amino)acetic acid,
(6- [(3 ' -ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl] -
pyridin-2-ylamino} acetic acid,
hexyl (6-[(3 ' -ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethy-l ]
pyridin-2-ylamino } acetate,
(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-]
pyridin-2-ylamino} acetic acid,
(6- {[4-(6-ethoxypyridin-2-yl)benzyl] (pyridin-2-ylsulfony1)aminomethyl) -
p yridin-2-y1amino)acetic acid,
ethyl (6- {[3' -(I -propynyl)biphenyl-4-ylmethyl]( thiophen-2-ylsulfony1)-
aminomethy1)pyridin-2-y1amino)acetic acid,
ethyl (6- {(benzenesulfonyl) [3 ' -(1 -prop ynyl)biphenyl-4-ylmethyl] -
aminomethy1)pyridin-2-ylamino)acetate,
(6- {(benzenesulfonyl)[3'- (I -propynyl)biphenyl-4-ylmethyl]a minomethyl)-
pyridin-2-y1amino)acetic acid,
5 ethyl (6- { [3' - ( 1- propynyl)biphenyl-4-ylmethyl]( thiophen-3- ylsul fony1)-
aminomethy1)pyridin-2-ylamino)acetate,
(6- {[3' -(I -propynyl)biphenyl-4-ylmethyl](t hiophen-3- ylsulfonyl)-
aminomethy1)pyridin-2-y1amino)acetic acid,
(6- {(3- fluorobenzenesulfonyl)[3' -(1- propynyl)biphenyl-4-ylmethyl-]
10 aminomethyl) pyridin-2-y1amino)acetic acid, or
isopropyl
(6- {[3' -(I -propynyl)biphenyl-4-ylmethyl]( pyridin-2-ylsulfonyl)aminomethyl}p yridin-2-
ylamino) acetate.
15 Effect of the Invention
[OO 151 The substituted biaryl compound represented by general formula (I), or the
pharmacologically acceptable salt thereof, of the present invention is effective for
chronic obstructive pulmonary disease due to having an EP2 antagonistic effect and an
excellent anti-inflammatory effect. Thus, a pharmaceutical composition containing the
20 substituted biaryl compound represented by general formula (I), or the
pharmacologically acceptable salt thereof, of the present invention as an active
ingredient thereof is useful as pharmaceuticals, and especially as a therapeutic and/or
prophylactic drug (and preferably as a therapeutic drug) for chronic obstructive
pulmonary disease.
25
MODE FOR CARRYING OUT THE INVENTION
[OO 161 Preferred embodiments of each substituent in the substituted biaryl compound
represented by the aforementioned general formula (I) are indicated below.
[OO 171 The protected or unprotected carboxy group represented by R' of general
30 formula (I) refers to a carboxy group or a carboxy 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-Clz alkyl groups,
such as a methyl group, ethyl group, propyl group, isopropyl group, 1-ethylpropyl group,
butyl group, isobutyl group, sec-butyl group, tert-butyl group, 3,3-dimethylbutyl group,
3 5 pentyl group, isopent yl 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 or dodecyl group; C7-C18 aralkyl groups, such as a benzyl group,
phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group,
phenylhex yl group, phenylhept yl group, phenyloctyl group, phenylnonyl group,
5 phenyldecyl group, phenylundecyl group or phenyldodecyl group; C1-C4 alkyl groups
substituted with a C2-Cs alkanoyloxy group, such as an acetoxymethyl group,
1 -acetoxyethyl group, 1 -acetoxypropyl group, 1 -acetoxybutyl group,
propanoyloxymethyl group, 1-propanoyloxyethyl group, butanoyloxymethyl group,
1 -butanoyloxyethyl group, pivaloyloxymethyl group, 1 -pivaloyloxyethyl group,
10 1 -pivaloyloxypropyl group or 1 -pivaloyloxybutyl group; C '-C4 alkyl groups substituted
with a (C1-C4 alkoxy)carbonyloxy group, such as a methoxycarbonyloxymethyl group,
1 -methoxycarbonyloxyethyl group, ethoxycarbonyloxymethyl group,
1 -ethoxycarbonyloxyethyl group, propoxycarbonyloxymethyl group,
1 -propoxycarbonyloxyethyl group, isopropoxycarbonyloxymethyl group,
1 5 1 -isopropoxycarbonyloxyethyl group, butoxycarbonyloxymethyl group,
1 -but ox ycarbonylox yethyl group, tert-but ox ycarbonylox ymethyl group or
1 -tert-butoxycarbonyloxyethyl group; N,N-dialkylaminocarbonylalkyl groups, such as
an N,N-dimethylaminocarbonylmethyl group or N,N-diethylaminocarbonylmethyl
group; 2-(N,N-dialky1amino)ethyl groups, such as a 2-(N,N-dimethy1amino)ethyl group
20 or 2-(N,N-diethy1amino)ethyl group; C '-C4 alkyl groups substituted with a 5 -membered
or 6-membered saturated heteromonocyclic group containing 1 or 2 hetero atoms
selected from N, 0 and S, such as a 2-(morpholin-4-y1)ethyl group, 2-piperidinoethyl
group or 2-(4-methy1piperidino)ethyl group; and groups that are readily deprotected in
vivo and can be converted to a carboxy group, such as a
25 (5-methyl-2-0x0- 1,3-dioxolen-4-y1)methyl group or
(5-phenyl-2-0x0- 1,3-dioxolen-4-y1)methyl group. The partial structure of the
ester-type protective group is preferably a C1-CI2 alkyl group, C7-C18 aralkyl group,
C1-C2 alkyl group substituted with a C2-C5 alkanoyloxy group, C1-C2 alkyl group
substituted with a (C1-C4 alkoxy)carbonyloxy group,
3 0 N,N-dimethylaminocarbonylmethyl group, 2- (morpholin-4-y1)ethyl group,
(5-methyl-2-0x0- 1,3-dioxolen-4-y1)methyl group or
(5-phenyl-2-0x0- 1,3-dioxolen-4-y1)methyl group. The partial structure of the
ester-type protective group is more preferably a C1-C6 alkyl group, and particularly
preferably an ethyl group, isopropyl group or hexyl group.
35 [0018] 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.
[OO 191 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
5 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.
[0020] 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
10 (I) of the present invention, R2 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-
[0021] 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
15 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 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.
20 [0022] 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, and when the compound has a proton tautomer, such tautomer
is also included in the scope of the present invention.
[0023] Although the compound represented by general formula (I) of the present
25 invention can be converted to a pharmacologically acceptable salt by a conventional
method as necessary, the pharmacologically acceptable salt can be also directly
separated from the reaction mixture as a salt.
[0024] The compound represented by general formula (I) of the present invention is
converted to a pharmacologically acceptable acid addition salt by treating it with an acid.
30 Examples of such a salt include, for example, inorganic acid salts, such as a
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate; and organic
acid salts, such as an acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate,
maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate,
trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate or aspartate.
35 [0025] When R' in the compound represented by 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 a sodium salt, potassium salt, calcium salt or magnesium salt; inorganic
salts, such as an ammonium salt; and organic amine salts, such as a triethylamine salt or
guanidine salt.
5 [0026] For cases where R' of the compound represented by general formula (I) of the
present invention is a carboxy group protected by a protective group, when administered
intravitally (such as in an in vivo test), the compound is easily hydrolyzed by a
biochemical reaction (e.g., esterase or the like) in vivo, and thus can be converted to a
pharmacologically active form in which R' is a carboxy group.
10 [0027] A representative method for producing the compound of the present invention
is indicated below. Note that specific methods for producing each compound of the
present invention are described in detail in Examples to be subsequently described.
[0028]
Compound (a} f R~ 0
O=$..="J~'
Compound (c)
Compound (g)
Compound (f) Compound (h)
15 Wherein R2, W, and Z are as defined in the above, R1' 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,
methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group or
trifluoromethanesulfonyloxy group, and X' represents a chloro group, bromo group, or
20 iodogroup.
[0029] The compound represented by general formula (I) of the present invention can
be obtained by any method of synthetic routes 1 to 5, as a compound (Ia), in which R3 is
a hydrogen atom, for cases where R' is a carboxy group, or as a compound (1'), in
which R3 is a hydrogen atom, for cases where R' is a carboxy group protected by a
protective group.
5 [0030] Synthetic route 1
When X is a hydroxy group in the compound (a), the compound (1') can be
obtained by reacting the compound (a) with the compound (b) in an inert organic
solvent and in the presence of an azo compound-based condensing agent and a
phosphine reagent.
10 The inert organic solvent used is not particularly limited as long as it does not
inhibit the reaction and dissolves the raw materials to a certain degree, and examples
thereof include aromatic hydrocarbons, such as benzene, toluene or xylene; ethers, such
as diethyl ether, tetrahydro furan, 1,4-dioxane or 1,2-dimethoxyethane; amides, such as
N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; nitriles,
15 such as acetonitrile or propionitrile; esters, such as methyl acetate, ethyl acetate, or
isopropyl acetate; and arbitrary mixed solvents thereof, and preferably tetrahydrofuran,
N,N-dimethylformamide and acetonitrile, or a mixed solvent thereof.
Examples of the azo compound-based condensing agent used include diethyl
azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD),
20 N,N,N' ,N' -tetraisopropylazodicarboxamide (TIPA), 1,l '-(azodicarbony1)dipiperidine
(ADDP), N,N,N',N'-tetramethylazodicarboxamide (TMAD) or
1,6-dimethyl-l ,5,7-hexahydro- l,4,6,7-tetrazocine-2,5-dione(D HTD), and preferably
diethylazodicarboxylate (DEAD) or N,N,N',N'-tetramethylazodicarboxamide (TMAD).
A molar amount of the azo compound-based condensing agent used is typically 0.9- to
25 10-fold, and preferably 1 - to 5-fold, based on 1 mole of the compound (b).
Examples of the phosphine reagent used include trimethylphosphine,
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
30 of the compound (b).
A molar amount of the compound (a) used is typically 0.8- to 2-fold, and
preferably 0.9- to 1.5-fold, based on 1 mole of the compound (b).
Although varying depending on the types and amounts used of raw materials,
solvents and the like, the reaction temperature is typically -20°C to 100°C and
35 preferably -5°C to 50°C.
Although varying depending on the reaction temperature and the like, the
reaction time is typically 30 minutes to 48 hours and preferably 1 hour to 24 hours.
[003 11 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
5 compound (a) with the compound (b) in an inert organic solvent and in the presence of a
base.
The inert solvent used is not particularly limited as long as it does not inhibit
the reaction and dissolves the raw materials to a certain degree, and examples of the
inert solvent include ethers, such as tetrahydrofuran, 19-dioxane or
10 1,2-dimethoxyethane; halogenated aliphatic hydrocarbons, such as methylene chloride,
chloroform or 1,2-dichloroethane; nitriles, such as acetonitrile or propionitrile; esters,
such as methyl forrnate, ethyl formate, methyl acetate or ethyl acetate; aromatic
hydrocarbons, such as benzene or toluene; amides, such as N,N-dimethylformamide,
N,N-dimethylacetamide or N-methylpyrrolidone; sulfoxides, such as dimethyl
1 5 sulfoxide; and arbitrary mixed solvents thereof, and preferably tetrahydro furan,
N,N-dimethylformamide, methylene chloride or 1,2-dichloroethane.
Examples of the base used include alkali metal hydrides, such as sodium
hydride or potassium hydride; alkali metal amides, such as lithium amide, sodium
amide, lithium diisopropylamide or lithium bis(trimethylsily1)amide; alkali metal
20 alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide or
potassium tert-butoxide; alkali metal carbonates, such as sodium carbonate or potassium
carbonate; and amines, such as triethylamine, tributylamine, diisopropylethylamine,
pyridine, picoline, 2,6-lutidine or 4-dimethylaminopyridine, and preferably sodium
hydride, potassium carbonate, triethylamine or diisopropylethylamine. However,
25 when the inert solvent used is an ester, nitrile or halogenated aliphatic hydrocarbon, the
base is preferably triethylamine or 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
30 preferably 0.5- to 1.5-fold, based on 1 mole of the compound (b).
Although varying depending on the 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
35 reaction time is typically 10 minutes to 48 hours and preferably 1 hour to 24 hours.
[0032] 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 and in the presence of an azo compound-based condensing agent and phosphine
reagent. This step is performed in accordance with the case where X in the compound
5 (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
10 trifluoromethanesulfonyloxy group, the compound (1') can be obtained by reacting the
compound (c) with the compound (d) in an inert organic solvent and 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
15 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).
[0033] Synthetic route 3
Synthetic route 3-1 is a step for obtaining the compound (f) by reacting the
compound (c) with the compound (e) in an inert organic solvent and in the presence of a
20 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 lf 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).
25 In Synthetic route 3-2, the compound (1') can be obtained by reacting the
compound (f) obtained in Synthetic route 3- 1 with the compound (g) in an inert solvent
in an inert gas atmosphere and 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
30 the reaction and dissolves the raw materials, catalyst, and base (or fluoride) to a certain
degree, and examples thereof include aromatic hydrocarbons, such as benzene or
toluene; ethers, such as tetrahydro furan, 1,2-dimethoxyethane or 1,4-dioxane; alcohols,
such as methanol, ethanol, propanol or isopropanol; esters, such as methyl acetate or
ethyl acetate; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide or
3 5 N-methylpyrrolidone; sulfoxides, such as dimethyl 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 and argon.
Examples of the palladium catalyst used include metal palladiums, such as
palladium-activated carbon or palladium black; organopalladium complexes, such as
5 tetralus(triphenylphosphine)palladium, bis(triphenylphosphine)palladium chloride,
1,l'- bis(diphenylphosphino)f errocene palladium chloride or
tris(dibenzylideneacetone)dipalladium; and, palladium salts, such as palladium chloride
or palladium acetate, and preferably tetralus(triphenylphosphine)palladium or palladium
acetate. A molar amount of palladium used as the catalyst is typically 0.0001- to
10 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, butyl
15 di- 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, butyl di- 1 -adamantylphosphine, triphenylphosphine or
20 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 or potassium acetate; alkali metal carbonates, such as sodium carbonate,
25 potassium carbonate or cesium carbonate; alkali metal phosphates, such as trisodium
phosphate or tripotassium phosphate; alkali metal hydroxides, such as lithium hydroxide,
sodium hydroxide or potassium hydroxide; quaternary ammonium hydroxides, such as
tetramethylammonium hydroxide, tetraethylammonium hydroxide or
tetrabutylammonium hydroxide; and fluorides, such as cesium fluoride,
30 tetramethylammonium fluoride, tetraethylarnrnonium fluoride or tetrabutylammonium
fluoride, and preferably sodium carbonate or tripotassium 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
35 preferably 1 - to 2-fold, based on 1 mole of the compound (g).
Although varying depending on the 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
reaction time is typically 10 minutes to 120 hours and preferably 1 hour to 48 hours.
5 [0034] Synthetic route 4
The compound (1') can be obtained by reacting the compound (h) with the
compound (i) in an inert organic solvent and in the presence or absence of (preferably in
the presence of) a base.
The inert organic solvent used is not particularly limited as long as it does not
10 inhibit the reaction and dissolves the raw materials to a certain degree, and examples
thereof include aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated
aliphatic hydrocarbons, such as methylene chloride, chloroform or 1,2-dichloroethane;
ethers, such as 1 ,4-dioxane, tetrahydro hran, diethyl ether or 1,2-dimethoxyethane;
amides, such as N,N-dimethylformamide, N,N-dimethylacetamide or
15 N-methylpyrrolidone; nitriles, such as acetonitrile or propionitrile, and arbitrary mixed
solvents thereof, and preferably methylene chloride, 1,2-dichloroethane,
N,N-dimethylformamide, acetonitrile or a mixed solvent thereof.
Examples of the base used include organic bases such as triethylamine or
diisopropylethylamine; and inorganic bases such as sodium bicarbonate, potassium
20 bicarbonate, sodium carbonate or potassium carbonate, and preferably triethylamine or
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 (h).
25 Although varying depending on the 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.
30 [0035] Synthetic route 5
When R3 in the compound (1') is a tert-butoxycarbonyl group, the compound
represented by general formula (I), in which R' is a carboxy group protected by the
ester-type protective group, can be obtained by deprotecting the compound (1') by acid
treatment. However, when R" is a tert-butyl group and R3 is a tert-butoxycarbonyl
35 group in the compound (1'), the compound represented by general formula (I), in which
R' is a carboxy group, can be obtained by deprotecting by acid treatment with
hydrochloric acid, trifluoroacetic acid and the like. Similarly, when R3 in the
compound (1') 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') by alkaline
hydrolysis and the like.
5 [0036] For the substituent R ~a, d esired substituent may be introduced at the beginning,
or a desired substituent may be introduced, after having its basic structure produced
according to the method described above, using a commonly used synthesizing method
including oxidation, reduction, alkylation, esterification, amidation, dehydration
reaction, deprotection reaction, hydrolysis, coupling reaction, cyclization reaction
10 andlor a combination thereof.
The starting compound of the compound of the present invention is
commercially available or can be produced according to a production method that is
publicly known by those skilled in the art. The methods for producing the starting
compound and an intermediate compound of the compound of the present invention are
15 described in detail in Reference Examples to be subsequently described.
[0037] The target compound formed in each of the reactions can be obtained from 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
20 immiscible with water is added followed by washing with water, separating the organic
layer containing the target compound, drying 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 and purified by
25 suitably combining conventional methods, such as recrystallization, re-precipitation or
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
phaseheversed phase column chromatography methods using silica gel or alkylated
30 silica gel (and preferably high performance liquid chromatography)).
[0038] The compound represented by general formula (I), or the pharmacologically
acceptable salt thereof, of the present invention can be present as a hydrate or a solvate.
[0039] A pharmaceutical composition containing the substituted biaryl compound
represented by general formula (I), or the pharmacologically acceptable salt thereof, as
35 an active ingredient thereof 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 administration, intrabronchial administration, pulmonary administration,
intracutaneous administration, subcutaneous administration and the like) in the dosage
form, such as a tablet, capsule, powder, syrup, granule, fine granule, pill, suspension,
5 emulsion, percutaneous absorption agent, suppository, ointment, lotion, aerosol, powder
inhalation agent or injection, that is produced by mixing with suitable
pharmacologically acceptable excipients, diluents and the like.
These dosage forms are prepared by commonly known methods using additives
such as excipients, lubricants, binders, disintegrators, emulsifiers, stabilizers, corrigents
1 0 or diluents.
[0040] Examples of the excipients include organic excipients and inorganic excipients.
Examples of the organic excipients include sugar derivatives, such as lactose, sucrose,
glucose, mannitol or sorbitol; starch derivatives, such as corn starch, potato starch,
a-starch or dextrin; cellulose derivatives, such as crystalline cellulose; gum arabic;
15 dextran; and pullulan. Examples of the inorganic excipients include light anhydrous
silicic acid and sulfates such as calcium sulfate.
[0041] Examples of the lubricants include stearic acid; stearic acid metal salts, such as
calcium stearate or magnesium stearate; talc; colloidal silica; waxes, such as beeswax or
spermaceti wax; boric acid; adipic acid; sulfates, such as sodium sulfate; glycol; fbmaric
20 acid; sodium benzoate; D,L-leucine; sodium lauryl sulfate; silicic acids, such as silicic
acid anhydride or silicic acid hydrate; and starch derivatives described above for the
excipients.
[0042] Examples of the binders include hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, polyvinylpyrrolidone, Macrogol and compounds described above for
25 the excipients.
[0043] Examples of the disintegrators include cellulose derivatives, such as lowly
substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl
cellulose or internally crosslinked calcium carboxymethyl cellulose; crosslinked
polyvinylpyrrolidone; and chemically modified starch or cellulose derivatives, such as
30 carboxymethyl starch or sodium carboxymethyl starch.
[0044] Examples of the emulsifiers include colloidal clays, such as bentonite or
Veegum; anionic surfactants, such as sodium lauryl sulfate; cationic surfactants, such as
benzalkonium chloride; and nonionic surfactants, such as polyoxyethylene alkyl ether,
polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.
35 [0045] Examples of the stabilizers include para-hydroxybenzoates, such as
methylparaben or propylparaben; alcohols, such as chlorobutanol, benzyl alcohol, or
phenylethyl alcohol; benzalkonium chloride; phenols, such as phenol or cresol;
thimerosal; acetic anhydride; and sorbic acid.
[0046] Examples of corrigents include sweeteners, such as saccharin sodium or
aspartame; acidulants, such as citric acid, malic acid or tartaric acid; and flavorings,
5 such as menthol, lemon extract or orange extract.
[0047] Examples of diluents include compounds commonly used as diluents, such as
lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropyl cellulose,
microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol,
glycerol, starch, polyvinylpyrrolidone or mixtures thereof.
10 [0048] In addition, suitable additives can be used depending on the dosage form. For
example, when the compound represented by general formula (I), or the
pharmacologically acceptable salt thereof, of the present invention is formed into an
aerosol for transnasal administration or intrabronchial administration,
chlorofluorocarbons (CFCs), such as dichlorodifluoromethane, trichlorofluoromethane
15 or dichlorotetrafluoroethane, or carbon dioxide can be used as a propellant.
[0049] Although the dosage of the active ingredient of the pharmaceutical composition
of the present invention can be varied depending on the conditions such as symptoms,
age or weight of the patient, the dosage for an adult in the case of a single oral
administration has a lower limit of 0.001 mglkg (preferably 0.01 mglkg) and an upper
20 limit of 20 mglkg (preferably 10 mglkg), while the dosage for an adult in the case of a
single parenteral administration has a lower limit of 0.000 1 mglkg (preferably 0.0005
mglkg) and an upper limit of 10 mglkg (preferably 5 mglkg), and these can be
administered 1 to 6 times per day corresponding to symptoms.
25 EXAMPLES
[0050] Although the following provides a more detailed explanation of the present
invention through Examples, Reference Examples, Comparative Examples, Test
Examples and Preparation Examples, the present invention is not limited thereto.
[0051] [Example 11
30 Ethyl
(6- (13 '-( 1 -propenyl')biphenyl-4-ylmethyl~(pyridin-2-ylsulfonylaminomethyl~pyridin-2-
y1amino)acetate
[0052] 320mg (0.913 mmol) ofethyl
(6- [byridin-2-ylsulfonyl)aminomethyl]p~inoa}ce tate obtained according
35 to the same method as Reference Example I-(&, 570 pL (2.3 1 mmol) of
tri-n-butylphosphine and 236 mg (1.37 mmol) of
N,N,N1,N'-tetramethylazodicarboxamidwee re added to 9.4 mL solution of
tetrahydro furan containing 205 mg (0.93 1 mol) of
3'-(1-propeny1)biphenyl-4-ylmethanol obtained in Reference Example 3-(b) followed by
stirring for 5 hours at room temperature. After completion of the reaction, water was
5 added to the reaction solution followed by extracting with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution and dried with
anhydrous magnesium sulfate followed by concentration under reduced pressure. The
residue was subjected to silica gel column chromatography (elution solvent:
n-hexane:ethyl acetate = 2:3 (VN)) and the fractions containing the target product were
10 concentrated under reduced pressure to obtain 5 10 mg of the title compound in the form
of a slightly yellow oil (quantitative).
Mass spectrum (FAB, d z ) : 557 (~++1).
1 H-NMR spectrum (CDC13, 6 ppm): 8.62 (ddd, J = 4.7, 1.8, 1.0 Hz, 1 H), 7.83 (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
15 (m,6H),7.27-7.20(m,1H),6.51(d,J=7.3Hz,1H),6.50-6.42(m,1H),6.38-6.26(m,
lH), 6.23 (d, J = 8.3 Hz, lH), 4.80 (s, 2H), 4.70 (t, J = 5.4 Hz, 0.9H), 4.42 (s, 2H), 4.22
(q, J=7.1 Hz,2H), 3.96(d, J=5.4Hz,2H), 1.91 (dd, J=6.3, 1.5Hz,3H), 1.28 (t, J =
7.1 Hz, 3H).
[0053] [Example 21
20 (6- { r3 ' -( 1 -Propenyl)biphenyl-4-ylmethyll (pyridin-2-ylsulfonyl)aminomethylp
yridin-2-v1amino)acetic acid
[0054] 1.98 mL (1.98 mmol) of 1 mol/L aqueous sodium hydroxide solution was
added to 2.0 mL solution of ethanol containing 220 mg (0.395 mmol) of the ethyl
(6- {[3 '-(I -propenyl)biphenyl-4-ylmethyl] (pyridin-2-ylsulfony1)aminomethyl)pyridin-2-
25 y1amino)acetate obtained in Example 1 followed by stirring for 2.5 hours at room
temperature. After completion of the reaction, water was added to the reaction
solution followed by adjusting the pH to 4.5 with 1 moVL hydrochloric acid. The
precipitated solid was collected by filtration and then dried under reduced pressure to
obtain 146 mg of the title compound in the form of a white solid (yield: 70%).
30 mass spectrum (FAB, d z ) : 529 (~++1).
'H-NMR spectrum (DMSO-d6, 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 (m, 4H),
7.48-7.44 (m, lH), 7.39-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.19 (dd, J = 8.3, 7.2 Hz, lH),
6.61 (brs, 0.8H), 6.52-6.47 (m, lH), 6.44-6.37 (m, lH), 6.33 (d, J = 8.3 Hz, lH), 6.28 (d,
35 J=7.2Hz,lH),4.74(~,2H),4.24(~,2H),3.76(d,J=4.0Hz,2H),1.87(dd,J=6.2,
1.5 Hz, 3H).
[0055] [Example 31
Ethyl
(6- { r3 ' -( 1- propvnyl)biphenyl-4-ylmethyll( pyridin-2-ylsulfonyl)aminomethylj -pyridin-2-
y1amino)acetate
5 [0056] 3 15 mg (0.900 mmol) of ethyl
(6- [(p yridin-2-ylsul fonyl)aminomethyl] p~e obtained according
to the same method as Reference Example 1-(g), 450 pL (1 -82 mmol) of
tri-n-butylphosphine and 3 10 mg (1.80 mmol) of
N,N,N',N'-tetramethylazodicarboxamidew ere added to 4.0 mL solution of
10 tetrahydrofuran containing 200 mg (0.900 mol) of
3'-(1 -propynyl)biphenyl-4-ylmethanol obtained in Reference Example 4-(b) followed by
stirring for 3 hours at room temperature. After completion of the reaction, water was
added to the reaction solution followed by extracting with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution and dried with
15 anhydrous magnesium sulfate followed by concentration under reduced pressure. The
residue was subjected to silica gel column chromatography (elution solvent:
n-hexane:ethyl acetate = 3:2+2:3 (VN)) and the fractions containing the target product
were concentrated under reduced pressure to obtain 483 mg of the title compound in the
forrn of a white foam (yield: 97%).
20 mass spectrum (FAB, d z ) : 555 (~++1).
'H-NMR spectrum (CDC13, F 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 (m, lH), 7.47-7.43
(m, 3H), 7.41-7.31 (m, 5H), 7.23 (dd, J = 8.2, 7.1 Hz, lH), 6.51 (d, J = 7.1 Hz, 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
25 Hz,2H),3.96(d, J=5.4Hz,2H),2.08 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
[0057] [Example41
(6- {[3' -(I -Propynyl)biphenyl-4-ylmethyl(]p yridin-2-ylsulfonyl)aminomethyl}-
pyridin-2-y1amino)acetic acid
[0058] 3.43 mL (3.43 mmol) of 1 mol/L aqueous sodium hydroxide solution was
30 added to 3.0 mL solution of ethanol containing 476 mg (0.858 mmol) of the ethyl
(6- {[3 '-(1 -propynyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyidin-2-
y1amino)acetate obtained in Example 3 followed by stirring for 5 hours at room
temperature. After completion of the reaction, water was added to the reaction
solution and the pH was adjusted to 4.5 with 1 mol/L hydrochloric acid followed by
35 extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous magnesium sulfate followed by
concentration under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent: methylene ch1oride:methanol = 15 : 1 --+ 10: 1 (VN))
and the fractions containing the target product were concentrated under reduced
pressure to obtain 444 mg of the title compound in the form of a white foam (yield:
5 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, 1.8, 1 .O Hz,
lH), 7.95 (ddd, J = 7.8, 7.7, 1.8 Hz, lH), 7.80 (ddd, J = 7.8, 1.0, 1.0 Hz, lH), 7.63-7.56
(m, 5H), 7.43 (dd, J = 7.9, 7.9 Hz, lH), 7.37 (ddd, J = 7.9, 1.7, 0.9 Hz, lH), 7.35-7.32
10 (m, 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).
[0059] [Example 51
Ethyl
1 5 (6- { 13 '-(I -proppyl)biphenyl-4-ylmethyll (pyridin-3-ylsulfony1)aminomethyl)p yridin-2-
y1amino)acetate
[0060] 280 mg (0.800 mmol) of ethyl
( 6 - [ ( p y r i d i n - 3 - y l s u l f o n y l ) a m i n o m e t h y l ] p ~a)c etate obtained according
to the same method as Reference Example 2-(b), 395 pL (1 -60 mmol) of
20 tri-n-butylphosphineand276mg(1.60mmol)of
N,N,N',N1-tetramethylazodicarboxamidwe ere added to 4.0 mL solution of
tetrahydrofuran containing 178 mg (0.800 mol) of
3'-(1 -propynyl)biphenyl-4-ylmethanol obtained in Reference Example 4-(b) followed by
stirring for 3 hours at room temperature. After completion of the reaction, water was
25 added to the reaction solution followed by extracting with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution and dried with
anhydrous magnesium sulfate followed by concentration under reduced pressure. The
residue was subjected to silica gel column chromatography (elution solvent:
n-hexane:ethyl acetate = 3:7+0: 1 (VN)) and the fractions containing the target product
30 were concentrated under reduced pressure to obtain 400 mg of the title compound in the
form of a slightly yellow oil (yield: 90%).
mass spectrum (ESI+, d z ) : 555 (~++1).
1 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 (m, lH), 7.52-7.49 (m, 2H),
35 7.48-7.46(m,lH),7.38-7.35(m,4H),7.32-7.27(m,2H),6.46(d,J=7.0Hz,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 = 7.2
Hz, 2H), 3.87 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H).
[0061] [Example61
(6- f r3 ' -( 1 -Propynyl)biphenyl-4-ylmethyll (pyridin-3 -y1sulfony1)arninomethy1) -
pyridin-2-y1amino)acetic acid
5 [0062] 3.0 mL (3.00 mmol) of 1 mol/L aqueous sodium hydroxide solution was added
to 3.0 mL solution of ethanol containing 395 mg (0.712 mmol) of the ethyl
(6- {[3 ' '- (1- propynyl)biphenyl-4-ylmethyl]( pyridin-3-ylsulfonyl)aminomethyl}p yridin-2-
y1amino)acetate obtained in Example 5 followed by stirring for 16 hours at room
temperature. After completion of the reaction, water was added to the reaction
10 solution and the pH was adjusted to 4.5 with 1 moUL hydrochloric acid followed by
extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous sodium sulfate followed by
concentration under reduced pressure. 10 mL of tert-butyl methyl ether and 0.5 mL of
methanol were added to the residue and the solid that precipitated following sonification
15 was collected by filtration and then dried under reduced pressure to obtain 340 mg of
the title compound in the form of a white solid (yield: 91%).
mass spectrum (ESI', mlz): 527 (~++1).
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),
20 7.47(ddd,J=8.1,4.8,0.6Hz,lH),7.44(dd,J=7.9,7.9Hz,lH),7.39-7.36(m,3H),
7.24 (dd, J = 8.3, 7.1 Hz, lH), 6.78 (t, J = 5.9 Hz, lH), 6.37 (d, J = 8.3 Hz, lH), 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).
[0063] [Example 71
16-r(3' -Ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethy-l ~
25 pyridin-2-ylamino) acetic acid
[0064] 7-(a): tert-Butyl (tert-butoxycarbonyl{6-1(3'-ethoxybiphenyl-4-ylmethyl)
(pyridin-2-ylsulfony1)- aminomethyllpyridin-2-ylamino) acetate
422 mg (0.880 mmol) of tert-butyl
(tert-butoxycarbonyl{6- [(pyridin-2-ylsulfonyl)aminomethyl] p~ } acetate
30 obtained according to the same method as Reference Example 1-(f), 395 pL (1.60
mmol) of tri-n-butylphosphine and 276 mg (1.60 mmol) of
N,N,N1,N'-tetramethylazodicarboxamidwee re added to 4.0 mL solution of
tetrahydrofuran containing 183 mg (0.800 mol) of 3'-ethoxybiphenyl-4-ylmethanol
obtained in Reference Example 5 followed by stirring for 3 hours at room temperature.
35 After completion of the reaction, water was added to the reaction solution followed by
extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous magnesium sulfate followed by
concentration under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent: to1uene:ethyl acetate = 8: 1 -+6: 1 (VIV)) and the
fractions containing the target product were concentrated under reduced pressure to
5 obtain 537 mg of the title compound in the form of a white foam (yield: 98%).
mass spectrum (FAB, d z ) : 689 (~++1).
'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, lH), 7.65 (d, J = 8.3 Hz, lH),
7.48-7.26 (m, 7H), 7.1 1 (ddd, J = 7.9, 1.7, 0.9 Hz, lH), 7.07 (dd, J = 2.3, 1.7 Hz, lH),
10 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, 9H).
[0065] 7-(b): /6-r(3 '-Ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl-~
pyridin-2-ylamino) acetic acid
3.2 mL (19.2 mmol) of 6 mol1L hydrochloric acid and 0.8 mL of water were
15 added to 4.0 mL solution of 1,4-dioxane containing 525 mg (0.762 rnrnol) of the
tert-butyl (tert-butoxycarbonyl{6-[(3'-ethoxybiphenyl-4-ylmethyl)
(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-ylaminoa)c etate obtain in Example 7-(a)
followed by stirring for 3 hours at 70°C. After completion of the reaction, the reaction
solution was concentrated under reduced pressure followed by addition of water,
20 adjusting the pH to 4.4 with 1 mol/L aqueous sodium hydroxide solution and extracting
with ethyl acetate. The organic layer was washed with saturated aqueous sodium
chloride solution and dried with anhydrous magnesium sulfate followed by
concentration under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent: methylene ch1oride:methanol = 15: 1 -+ 10: 1 (VN))
25 and the fractions containing the target product were concentrated under reduced
pressure to obtain 369 mg of the title compound in the form of a white foam (yield:
91%).
mass spectrum (FAB, d z ) : 533 (~++1).
'H-NMR spectrum (DMSO-ds, 6 ppm): 12.41 (brs, 0.4H), 8.64 (ddd, J = 4.6, 1.8, 0.9 Hz,
30 1H),7.95(ddd,J=7.8,7.8,1.8H~,1H),7.80(ddd,J=7.8,1.0,0.9Hz,1H),7.59-7.56
(m, 3H), 7.36 (dd, J = 8.1, 8.1 Hz, lH), 7.33-7.31 (m, 2H), 7.20 (dd, J = 8.2, 7.1 Hz, lH),
7.18 (ddd, J = 8.1, l.8,0.8 Hz, lH), 7.14 (dd, J = 2.3, 1.8 Hz, lH), 6.92 (ddd, J = 8.1,
2.3, 0.8 Hz, lH), 6.75 (t, J = 5.9 Hz, IH), 6.34 (d, J = 8.2 Hz, lH), 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= 5.9 Hz, 2H), 1.35 (t,
35 J = 7.0 Hz, 3H).
[0066] [Example 81
Hexyl (6- r(3 '- ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl~-
pyidin-2-ylamino ) acetate
[0067] 305 mg (0.750 mrnol) of the hexyl
(6-[(pyridin-2-ylsulfonyl)aminomethyl]p~)ac etate obtained in
5 Reference Example 6,280 pL (1.14 mrnol) of tri-n-butylphosphine and 196 mg (1.14
mrnol) of N,N,Nt,N'-tetramethylazodicarboxamidwe ere added to 4.0 mL solution of
tetrahydrofuran containing 17 1 mg (0.750 mol) of 3'-ethoxybiphenyl-4-ylmethanol
obtained in Reference Example 5 followed by stirring for 16 hours at room temperature.
After completion of the reaction, water was added to the reaction solution followed by
10 extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous magnesium sulfate followed by
concentration under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent: n-hexane:ethyl acetate = 3:2-+2:3 (VN)) and the
fractions containing the target product were concentrated under reduced pressure to
15 obtain 429 mg of the title compound in the form of a colorless oil (yield: 93%).
mass spectrum (FAB, d z ) : 6 17 (M++l).
'H-NMR spectrum (CDC13, 6 ppm): 8.6 1 (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 (m, 2H), 7.38 (ddd,
J = 7.7,4.7, 1.1 Hz, lH), 7.35-7.31 (m, 3H), 7.23 (dd, J = 8.4, 7.3 Hz, lH), 7.12 (ddd, J
20 =8.l71.8,1.0Hz,1H),7.08(dd,J=2.4,1.8Hz,1H),6.88(ddd,J=8.l,2.4,1.0Hz,
lH), 6.51 (d, J = 7.3 Hz, lH), 6.23 (d, J = 8.4 Hz, lH), 4.79 (s, 2H), 4.70 (t, J = 5.3 Hz,
lH),4.42(~,2H),4.15(t , J=6.8Hz,2H),4.10(q, J=7.0Hz,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).
25 [0068] [Example 91
f 6-r(3 '- Ethoxybiphenyl-4-ylmethy1)(pyridin-3-ylsulfonyl)aminomethy-l ~
pyridin-2-ylamino) acetic acid
[0069] 9-(a): tert-Butyl (tert-butoxycarbonylf6-~(3'-ethoxybiphenyl-4-ylmethyl)
(pyridin-3- ylsulfonyl~aminomethy11pyridin-2-ylami)n aoc etate
30 422 mg (0.880 mrnol) of tert-butyl
(tert-butoxycarbonyl(6-[(pyridin-3 -ylsulfonyl)aminomethyl]pyridin-2-ylamino}a cetate
obtained according to the same method as Reference Example 2-(a), 395 pL (1.60
mrnol) of tri-n-butylphosphine and 276 mg (1.60 mrnol) of
N,N,N1,N'-tetramethylazodicarboxamidwee re added to 4.0 mL solution of
3 5 tetrahydro furan containing 1 83 mg (0.800 mol) of 3'-ethoxybiphenyl-4-ylmethanol
obtained in Reference Example 5 followed by stirring for 3 hours at room temperature.
After completion of the reaction, water was added to the reaction solution followed by
extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous magnesium sulfate followed by
concentration under reduced pressure. The residue was subjected to silica gel column
5 chromatography (elution solvent: n-hexane:ethyl acetate = 7:3+ 1 : 1 (VN)) and the
fractions containing the target product were concentrated under reduced pressure to
obtain 550 mg of the title compound in the form of a white foam (quantitative).
mass spectrum (FAB, d z ) : 689 ( ~ + + l ) .
'H-NMR spectrum (CDC13, 6 ppm): 8.96 (dd, J = 2.4, 0.7 Hz, lH), 8.71 (dd, J = 4.8, 1.6
10 Hz,1H),7.87(ddd,J=7.9,2.4,1.6Hz,1H),7.71(d,J=8.5Hz,1H),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 = 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 = 7.0 Hz, 2H), 1.52 (s, 9H), 1.45 (t, J = 7.0 Hz, 3H), 1.42 (s,
9H).
15 [0070] 9-(b): (6-r(3 '-Ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl~-
pyridin-2-ylamino ) acetic acid
3.3 mL (20 mmol) of 6 molIL hydrochloric acid and 1 .O mL of water were
added to 4.0 mL solution of 1,Cdioxane containing 540 mg (0.784 mmol) of the
tert-butyl (tert-butoxycarbonyl(6- [(3'-ethoxybiphenyl-4-ylmethyl)(pyridin- -ylsulfonyl)
20 aminomethyllpyridin-2-ylaminoa)c etate obtained in Example 9-(a) followed by stirring
for 2 hours at 70°C. After completion of the reaction, the reaction solution was
concentrated under reduced pressure followed by addition of water, adjusting the pH to
4.4 with 1 molIL aqueous sodium hydroxide solution and extracting with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride solution and
25 dried with anhydrous magnesium sulfate followed by concentration under reduced
pressure. The residue was subjected to silica gel column chromatography (elution
solvent: methylene ch1oride:methanol = 15: 1 3 10: 1 (VN)) and the fractions containing
the target product were concentrated under reduced pressure. 2 mL of ethyl acetate
and 8 mL of n-hexane were added to the concentrate and the precipitated solid was
30 collected by filtration and dried under reduced pressure to obtain 388 mg of the title
compound in the form of a white solid (yield: 93%).
mass spectrum (FAB, d z ) : 533 (M++l).
1 H-NMR spectrum (DMSO-ds, 6 ppm): 12.43 (brs, 0.4H), 8.83 (dd, J = 2.4, 0.7 Hz, lH),
8.72 (dd, J = 4.8, 1.7 Hz, lH), 8.02 (ddd, J = 8.0,2.4, 1.7 Hz, lH), 7.64-7.61 (m, 2H),
35 7.47(ddd,J=8.0,4.8,0.7Hz,lH),7.38-7.34(m,3H),7.24(dd,J=8.3,7.2Hz,lH),
7.20 (ddd, J = 7.8, 1.7, 0.9 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 Hz,
lH), 4.70 (s, 2H), 4.21 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.71 (d, J = 5.9 Hz, 2H), 1.36 (t,
J = 7.0 Hz, 3H).
[0071] [Example 101
5 (6- [(Benzenesulfonyl)(3 ' -ethoxybiphenyl-4-ylmethyl)aminomethyllpyridin-2-
ylamino) acetic acid
[0072] 1 0-(a): tert-Butvl((6-[(benzensulfonyl)(3'-ethoxybiphenyl-4-ylmethyl)-
aminomethyllpyridin-24) tert-butox~carbon~1amino)acetate
178 pL (1.28 mmol) of triethylamine and 98 pL (0.77 mmol) of
10 benzenesulfonyl chloride were added to 1.8 mL solution of methylene chloride
containing 350 mg (0.639 mmol) of tert-butyl (tert-butoxycarbonyl-
{6-[(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-y1a}m ino)acetate obtained
in Reference Example 7(b) while cooling with ice followed by stirring for 1 hour at
room temperature. After completion of the reaction, the reaction solution was
15 subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate
= 4: 1+7:3 (VN)) and the fractions containing the target product were concentrated
under reduced pressure to obtain 392 mg of the title compound in the form of a white
foam (yield: 89%).
mass spectrum (CI, mlz): 688 (M'+l).
20 '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), 7.1 1 (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),
6.86(d, J=7.5 Hz, lH), 4.54 (s,2H),4.39 (s72H),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).
25 [0073] 1 0-(b): (6-[(Benzenesulfonyl!(3 '-ethoxybiphenvl-4-ylmethy1)aminomethyllpyridin-
2-yl ) acetic acid
5.8 mL (76 mmol) of trifluoroacetic acid was added at room temperature to 5.8
mL solution of methylene chloride containing 389 mg (0.566 mmol) of the tert-butyl
( {6- [(benzensulfonyl)(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl] -
30 pyridin-2-yl} tert-butoxycarbony1amino)acetate obtained in Example 10-(a) followed by
allowing to stand undisturbed for 3.5 hours. After completion of the reaction, the
reaction solution was concentrated under reduced pressure followed by addition of
water, adjusting the pH to 4.4 with saturated aqueous sodium bicarbonate solution and 1
mol/L hydrochloric acid, and extracting with ethyl acetate. The organic layer was
35 washed with saturated aqueous sodium chloride solution and dried with anhydrous
sodium sulfate followed by concentration under reduced pressure. 3.9 mL of
diisopropyl ether was added to the concentrate and the precipitated solid was collected
by filtration and dried under reduced pressure to obtain 293 mg of the title compound in
the form of a white solid (yield: 97%).
mass spectrum (FAB, d z ) : 532 (M++l).
5 'H-NMR spectrum (DMSO-d6, 6 ppm): 12.4 1 (brs, 0.8H), 7.74-7.72 (m, 2H), 7.6 1-7.59
(m, 3H), 7.52-7.48 (m, 2H), 7.35 (dd, J = 7.8, 7.8 Hz, lH), 7.31-7.29 (m, 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 Hz, lH),
6.91 (ddd, J = 7.8,2.3,0.9 Hz, lH), 6.76 (t, J = 5.9 Hz, 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 =
10 5.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).
[0074] [Example 111
{6-r(3 '-Ethoxybiphenyl-4-ylmethyl)(thiophen-2-ylsulfonyl)aminomethyl~-
... a . . , . * pyndin-2-ylamino ) acetic acid
[0075] 1 1 -(a): tert-Butyl (tert-butoxycarbonyl~6-[(3'-ethoxybiphenyl-4-ylmethyl)
15 (thiophen-2-ylsulfonyl)aminomethyllpyridin-2-yla)c etate
178 pL (1 -28 mmol) of triethylamine and 0.3 mL solution of methylene
chloride containing 141 mg (0.772 mmol) of 2-thiophenesulfonyl chloride were added
to 1.8 mL solution of methylene chloride containing 350 mg (0.639 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl-]p yridin-2-yl}-
20 amino)acetate obtained in Reference Example 7(b) while cooling with ice followed by
stirring for 1.5 hours at room temperature. After completion of the reaction, the
reaction solution was subjected to silica gel column chromatography (elution solvent:
n-hexane:ethyl acetate = 9: 1+3:2 (VIV)) and the fractions containing the target product
were concentrated under reduced pressure to obtain 376 mg of the title compound in the
25 form of a white foam (yield: 85%).
mass spectrum (CI, d z ) : 694 (M++l).
1 H-NMR spectrum (CDC13, 6 ppm): 7.70 (d, J = 8.5 Hz, lH), 7.54-7.42 (m, 5H), 7.33
(dd, J = 8.0, 7.8 Hz, lH), 7.27-7.23 (m, 2H), 7.12 (ddd, J = 7.7, 1.7, 0.9 Hz, 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 = 7.6 Hz, lH), 6.88
30 (ddd, J=8.0,2.4,0.9Hz, lH),4.56(~,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).
[0076] 1 1 -(b): {6-[(3'-Ethoxybiphenyl-4-ylmethvl)(thiophene-2-ylsu1fonyl)-
aminomethvllpyidin-2-?rl) acetic acid
5.6 mL (73 mmol) of trifluoroacetic acid was added at room temperature to 5.6
35 mL solution of methylene chloride containing 374 mg (0.53 8 mmol) of the tert-butyl
(tert-butoxycarbonyl{6- [(3'-ethoxybiphenyl-4-ylmethyl)
(thiophen-2-ylsulfonyl)aminomethyl]pyridin-21a cetate obtained in Example 11 - (a)
followed by allowing to stand undisturbed for 3.5 hours. After completion of the
reaction, the reaction solution was concentrated under reduced pressure followed by
addition of water, adjusting the pH to 4.4 with saturated aqueous sodium bicarbonate
5 solution and 1 mol/L hydrochloric acid, and extracting with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution and dried with
anhydrous sodium sulfate followed by concentration under reduced pressure. 3.7 mL
of tert-butyl methyl ether was added to the concentrate and the precipitated solid was
collected by filtration and dried under reduced pressure to obtain 272 mg of the title
10 compound in the form of a white solid (yield: 94%).
mass spectrum (FAB, rnlz): 538 (M++l).
'H-NMR spectrum (DMSO-d6, F ppm): 12.42 (brs, 0.7H), 7.91 (dd, J = 5.1, 1.4 Hz, lH),
7.61-7.58 (m, 2H), 7.54 (dd, J = 3.7, 1.4 Hz, lH), 7.35 (dd, J = 7.9, 7.8 Hz, lH),
7.34-7.31 (m, 2H), 7.27 (dd, J = 8.4, 7.2 Hz, lH), 7.19 (ddd, J = 7.8, 1.7, 0.9 Hz, lH),
15 7.15(dd,J=2.3,1.7Hz71H),7.13(dd,J=5.1,3.7Hz,1H),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 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.83 (d, J = 5.8 Hz, 2H), 1.35 (t, J = 7.0
Hz, 3H).
[0077] [Example 121
20 (6- { r4-(6-Ethoxvpyridin-2-y1)benzyll( pyridin-2-ylsulfonyl)aminomethyl-)
pyridin-2-y1amino)acetic acid
[0078] 12-(a): tert-Butyl rtert-butoxycarbonyl(6- -f 14-(6-ethoxvpyridin-2-y1)benzyll
(pyridin-2-ylsulfonyl)aminomethyl)p~idin-2-yl)aminoa1c etate
560 mg (1.17 mmol) of tert-butyl (tert-butoxycarbonyl(6-[(pyridin-2-
25 ylsulfonyl)aminomethyl]pyridin-2-yl} amino)acetate obtained according to the same
method as Reference Example 1-(f), 724 pL (2.90 mmol) of tri-n-butylphosphine and
300 mg (1.74 rnrnol) of N,N,N1,N1-tetramethylazodicarboxamidwe ere added to 11 mL
solution of tetrahydrofuran containing 267 mg (1.16 mol) of
4-(6-ethoxypyridin-2-y1)phenyl methanol obtained in Reference Example 8 followed by
3 0 stirring for 1.5 hours at room temperature. After completion of the reaction, water was
added to the reaction solution followed by extracting with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution and dried with
anhydrous magnesium sulfate followed by concentration under reduced pressure. The
residue was subjected to silica gel column chromatography (elution solvent:
35 n-hexane:ethyl acetate = 3: 1 (VN)) and the fractions containing the target product were
concentrated under reduced pressure to obtain 606 mg of the title compound in the form
of a white foam (yield: 76%).
mass spectrum (CI, mlz): 690 (M++l).
'H-NMR spectrum (CDC13, 6 ppm): 8.60 (ddd, J = 4.7, 1.8, 1.1 Hz, lH), 7.92-7.88 (m,
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
5 =8.5Hz,lH),7.61(dd,J=8.2,7.5Hz,lH),7.45(dd,J=8.3,7.5Hz,lH),7.38(ddd,J
= 7.5, 4.7, 1.3 Hz, lH), 7.34-7.30 (m, 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), 4.48 (q, J = 7.1
Hz, 2H), 4.46 (s, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H).
[0079] 12-(b): (6- { r4-(6-Ethoxypyridin-2-y1)benzyll( pyridin-2-ylsulfony1)-
1 0 aminomethyl 1 pyridin-2-y1amino)acetic acid
8.6 mL (1 12 mmol) of trifluoroacetic acid was added at room temperature to
8.6 mL solution of methylene chloride containing 590 mg (0.855 mmol) of the tert-butyl
[tert-butoxycarbonyl(6- {[4-(6-ethoxypyridin-2-yl)benzyl]
(pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate obtained in Example
15 12-(a) followed by stirring for 6 hours at room temperature. After completion of the
reaction, the reaction solution was concentrated under reduced pressure followed by
addition of water, adjusting the pH to 4.5 with 2 mol1L aqueous sodium hydroxide
solution and dilute hydrochloric acid, and extraction with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution and dried with
20 anhydrous magnesium sulfate followed by concentration under reduced pressure to
obtain 357 mg of the title compound in the form of a white foam (yield: 78%).
mass spectrum (FAB, rnlz): 534 (M++l).
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.59 (brs, 0.5H), 8.67 (d, J = 4.7 Hz, lH),
8.01-7.95 (m, 3H), 7.85 (d, J = 7.7 Hz, lH), 7.76 (dd, J = 8.4, 7.5 Hz, lH), 7.61 (dd, J =
25 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).
[0080] [Example 131
Ethyl (6- { r3 '-(I -propynyl)biphenyl-4-ylmethyll (thiophen-2-ylsulfony1)-
30 aminomethyl t pyridin-2-y1amino)acetate
[008 11 333 mg (1.50 mmol) of 3'-(1-propyny1)biphenyl-4-yl methanol obtained
according to the same method as Reference Example 13, 740 pL (3.00 mmol) of
tri-n-butylphosphine and 5 1 7 mg (3.00 mmol) of
N,N,N',N'-tetramethylazodicarboxamide were added to 8.0 mL solution of
35 tetrahydrofuran containing 533 mg (1.50 mol) of the ethyl
(6- [(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}a cetate obtained in
Reference Example 9-(b) followed by stirring for 7 hours at room temperature. After
completion of the reaction, water was added to the reaction solution followed by
extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous magnesium sulfate followed by
5 concentration under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent: n-hexane:ethyl acetate = 1 :0+1: 1 (VN)) and the
fractions containing the target product were concentrated under reduced pressure to
obtain 806 mg of the title compound in the form of a colorless oil (yield: 96%).
mass spectrum (CI, d z ) : 560 (M++l).
10 'H-NMR spectrum (CDC13, F ppm): 7.60-7.59 (m, lH), 7.5 1 (dd, J = 5.0, 1.3 Hz, lH),
7.48-7.43 (m, 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 (d, J= 5.4 Hz, 2H), 2.07 (s, 3H), 1.27 (t, J= 7.1 Hz, 3H).
[0082] [Example 141
15 (6- f [3 ' -( 1- Propynyl)biphenyl-4-ylmethyll(t hiophen-2-ylsulfony1)-
aminomethy1)pa-idin-2-y1amino)acetic acid
[0083] 6.0 mL (6.0 rnmol) of 1 mol/L aqueous sodium hydroxide solution was added
to 6.0 mL solution of ethanol containing 800 mg (1.43 mrnol) of the ethyl
(6- { [3 ' -(1 -prop ynyl)biphenyl-4-ylmethyl] (thiophen-2-ylsulfony1)-
20 aminomethy1)pyridin-2-y1amino)acetate obtained in Example 13 followed by stirring
for 4 hours at room temperature. After completion of the reaction, water was added to
the reaction solution and the pH was adjusted to 4.5 with 1 mol/L hydrochloric acid
followed by extracting with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate
25 followed by concentration under reduced pressure. The concentrate was dissolved in
10 mL of ethyl acetate and 10 mL of n-hexane was added at 50°C followed by stirring
until the temperature of the solution reached room temperature over the course of 1.5
hours. The precipitated solid was collected by filtration and dried under reduced
pressure to obtain 620 mg of the title compound in the form of a white solid (yield:
30 82%).
mass spectrum (ESI+, d z ) : 532 (M++l).
1 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), 6.80 (t,
35 J=5.8Hz,1H),6.41(d,J=8.3Hz71H),6.35(d,J=7.2Hz,1H),4.59(s,2H),4.18(s,
2H), 3.84 (d, J = 5.8 Hz, 2H), 2.07 (s, 3H).
[0084] [Example 151
Ethyl (6- {(benzenesulfonyl) [3 '-(I -propynyl)biphenyl-4-ylmethyllaminomethyl]
pyridin-2-y1amino)acetate
[0085] 333 mg (1.50 mmol) of 3'-(1 -propynyl)biphenyl-4-yl methanol obtained
5 according to the same method as Reference Example 13, 740 pL (3 .OO 11111101) of
tri-n-butylphosphine and 5 17 mg (3.00 mmol) of
N,N,N1,N1-tetramethylazodicarboxamidwe ere added to 8.0 mL solution of
tetrahydrofuran containing 524 mg (1.50 mol) of the ethyl
{6-[(benzenesulfonyl)aminomethyl]pyridin-2-ylamino}a cetate obtained in Reference
10 Example 10-(b) followed by stirring for 2 hours at room temperature. After
completion of the reaction, water was added to the reaction solution followed by
extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous magnesium sulfate followed by
concentration under reduced pressure. The residue was subjected to silica gel column
15 chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 -+ 1 : 1 (VN)) and the
fractions containing the target product were concentrated under reduced pressure to
obtain 809 mg of the title compound in the form of a colorless oil (yield: 97%).
mass spectrum (CI, mlz): 554 (~++1).
1 H-NMR spectrum (CDC13, 6 ppm): 7.78-7.75 (m, 2H), 7.59-7.58 (m, lH), 7.53-7.40 (m,
20 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 =
5.2 Hz, lH), 4.58 (s, 2H), 4.32 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.90 (d, J = 5.2 Hz, 2H),
2.07 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).
[0086] [Example 161
(6- {(Benzenesulfonyl)[3' -(I -prop)myl)biphenyl-4-ylmethyllaminomethyl]-
25 pyridin-2-y1amino)acetic acid
[0087] 6.0 mL (6.0 mmol) of 1 mol/L aqueous sodium hydroxide solution was added
to 6.0 mL solution of ethanol containing 804 mg (1.45 mmol) of the ethyl
(6- {(benzenesulfonyl)[3'- (1 -propynyl)biphenyl-4-ylmethyllaminomethy1)
pyridin-2-y1amino)acetate obtained in Example 15 followed by stirring
30 for 4 hours at room temperature. After completion of the reaction, water was added to
the reaction solution and the pH was adjusted to 4.5 with 1 mol/L hydrochloric acid
followed by extracting with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate
followed by concentration under reduced pressure. The concentrate was dissolved in
35 10 mL of ethyl acetate, and 10 mL of n-hexane was added at 50°C followed by stirring
until the temperature of the solution reached room temperature over the course of 2
hours. The precipitated solid was collected by filtration and dried under reduced
pressure to obtain 724 mg of the title compound in the form of a white solid (yield:
95%).
mass spectrum (ESI', d z ) : 526 (~++1).
5 'H-NMR spectrum (DMSO-d6, 6 ppm): 12.40 (brs, 0.6H), 7.75-7.72 (m, 2H), 7.63-7.58
(m, 5H), 7.53-7.48 (m, 2H), 7.43 (dd, J = 7.7, 7.7 Hz, lH), 7.37 (ddd, J = 7.7, 1.4, 1.4
Hz, lH), 7.33-7.30 (m, 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, lH), 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).
10 [0088] [Example 171
Ethyl (6- ( r3 ' -( 1- propynyl)biphenyl-4-ylmethyll( thiophen-3- ylsulfonyl)-
aminomethy1)pyridin-2-y1amino)acetate
178 mg (0.800 mmol) of 3'-(1-propyny1)biphenyl-4-yl methanol obtained
according to the same method as Reference Example 13,395 pL (1.60 mmol) of
15 tri-n-butylphosphine and 276 mg (1.60 mmol) of
N,N,N1,N1-tetramethylazodicarboxamiwdeer e added to 4.0 mL solution of
tetrahydrofuran containing 284 mg (0.800 mol) of the ethyl
{6-[(thiophen-3- ylsulfonyl)aminomethyl]pidin-2-lamino}a cetate obtained in
Reference Example 1 1 -(b) followed by stirring for 3 hours at room temperature. After
20 completion of the reaction, water was added to the reaction solution followed by
extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous magnesium sulfate followed by
concentration under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent: n-hexane:ethyl acetate = 4: 1+ 1 : 1 (VN)) and the
25 fractions containing the target product were concentrated under reduced pressure to
obtain 432 mg of the title compound in the form of a colorless syrup (yield: 97%).
mass spectrum (CI, d z ) : 560 (~++1).
1 H-NMR spectrum (CDC13, 6 ppm): 7.80 (dd, J = 3.1, 1.3 Hz, lH), 7.60-7.59 (m, lH),
7.50-7.45 (m, 3H), 7.36-7.28 (m, 6H), 7.17 (dd, J = 5.1, 1.3 Hz, lH), 6.52 (d, J = 7.2 Hz,
30 lH), 6.31 (d, J=8.0Hz, lH),4.80(t, J=5.4Hz, 1H),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).
[0089] [Example 181
(6- ( 13 ' -( 1 -Proppyl)biphenyl-4-ylmethyll (thiophen-3 -ylsulfonyl)-
aminomethyl 1 pyridin-2-y1amino)acetic acid
35 3.5 mL (3.5 mmol) of 1 molIL aqueous sodium hydroxide solution was added
to 3.5 mL solution of ethanol containing 426 mg (0.762 mmol) of the ethyl
(6- {[3' -(I -propynyl)biphenyl-4-ylmethyl]( thiophen-3- y lsulfony1)-
aminomethy1)pyridin-2-y1amino)acetate obtained in Example 17 followed by stirring
for 16 hours at room temperature. After completion of the reaction, water was added
to the reaction solution and the pH was adjusted to 4.4 with 1 mollL hydrochloric acid
5 followed by extracting with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate
followed by concentration under reduced pressure. 5 mL of ethyl acetate and 5 mL of
n-hexane were added to the concentrate followed by heating to 50°C and stirring until
the temperature of the solution reached room temperature over the course of 2 hours.
10 The precipitated solid was collected by filtration and dried under reduced pressure to
obtain 390 mg of the title compound in the form of a white solid (yield: 96%).
mass spectrum (CI, d z ) : 532 ( ~ + + l ) .
1 H-NMR spectrum (DMSO-d6, 6 ppm): 12.46 (brs, 0.6H), 8.14 (dd, J = 3.0, 1.4 Hz, lH),
7.66(dd, J=5.1,3.0Hz, lH), 7.64-7.59(m,4H), 7.45-7.24(m, 6H), 6.81 (t, J=5.5Hz,
15 1H),6.40(d,J=8.2Hz,1H),6.33(d,J=7.0Hz,1H),4.58(s,2H),4.16(s,2H),3.84
(d, J = 5.5 Hz, 2H), 2.07 (s, 3H).
[0090] [Example 191
(6- ((3-Fluorobenzenesulfonyl)~3 ' -( 1 -propynyl)biphenyl-4-ylmethyllaminomethy1)
pyridin-2-y1amino)acetic acid
20 [0091]
19-(a): tert-Butyl [tert-butoxycarbonyl(6- ((3 -fluorobenzenesulfonyl)
13'41- propynyl)biphenyl-4-ylmethylla minomethyl)p yridin-2-y1)aminol acetate
280 pL (2.0 1 mmol) of triethylamine and 150 pL (1.13 mmol) of
3-fluorobenzenesulfonyl chloride were added to 3.5 mL solution of methylene chloride
25 containing 542 mg (1 .OO mmol) of tert-butyl [tert-butoxycarbonyl-
(6- {[3'-(1 -propynyl)biphenyl-4-ylmethyl]aminomethyl)pyridin-2-yl)amino]acetate
obtained in Reference Example 12(c) while cooling with ice followed by stirring for 2
hours at room temperature. After completion of the reaction, water was added to the
reaction solution followed by extracting with methylene chloride. The organic layer
30 was washed with saturated aqueous sodium chloride solution and dried with anhydrous
magnesium sulfate followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl
acetate = 9: 1+7:3 (VN)) and the fractions containing the target product were
concentrated under reduced pressure to obtain 673 mg of the title compound in the form
35 of 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 (m, lH),
7.53-7.32 (m, 9H), 7.27-7.19 (m, 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).
[0092] 19-(b): (6- { (3-Fluorobenzenesulfonyl)~'3- ( 1- propynyl)biphenyl-4-ylmethyll-
5 aminomethyl 1 pyridin-2-y1amino)acetic acid
5.0 mL (20 mmol) of 4 mol/L hydrochloric acid was added to 5.0 mL solution
of tetrahydrofuran containing 595 mg (0.850 mmol) of the tert-butyl
[tert-butoxycarbonyl(6-( (3-fluorobenzensulfony1)[ 3'-(1- propynyl)biphenyl-4-ylmethyl]-
aminomethyl) pyridin-2-yl)amino] acetate obtained in Example 19-(a) followed by
10 stirring for 5 hours at 70°C. After completion of the reaction, the pH was adjusted to
4.5 with 1 mol/L aqueous sodium hydroxide solution followed by extracting with ethyl
acetate. The organic layer was washed with saturated aqueous sodium chloride
solution and dried with anhydrous sodium sulfate followed by concentration under
reduced pressure. 10 mL of ethyl acetate and 5 mL of n-hexane were added to the
15 concentrate followed by heating to 50°C and stirring until the temperature of the
solution reached room temperature over the course of 2 hours. The precipitated solid
was collected by filtration and dried under reduced pressure to obtain 429 mg of the title
compound in the form of a white solid (yield: 93%).
mass spectrum (ESI', mlz): 544 (~++1).
20 1H -NMR spectrum (DMSO-d6, 6 ppm): 12.41 (brs, 0.9H), 7.65-7.60 (m, 4H), 7.58-7.50
(m, 2H), 7.46-7.34 (m, 6H), 7.25 (dd, J = 8.3,7.2 Hz, lH), 6.79 (t, J = 5.7 Hz, 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).
[0093] [Example 201
25 Isopropyl(6- { 13 '-(I -propynyl)biphenyl-4- ylmethyll (pyridin-2-ylsulfony1)-
aminomethy1)pyridin-2-y1amino)acetate
[0094] 640 mg (2.88 mmol) of 3 '-(I -propynyl)biphenyl-4-yl methanol obtained
according to the same method as Reference Example 13, 1.42 mL (5.76 mmol) of
tri-n-butylphosphine and 992 mg (5.76 mmol) of
30 N,N,N1,N'-tetramethylazodicarboxamidwee re added to 15 .0 mL solution of
tetrahydro furan containing 1.05 g (2.88 mol) of the isopropyl
{6-[(pyridin-2-ylsulfonyl)aminomethyl]p~)ac etate obtained in
Reference Example 14 followed by stirring for 3 hours at room temperature. After
completion of the reaction, water was added to the reaction solution followed by
35 extracting with ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried with anhydrous magnesium sulfate followed by
concentration under reduced pressure. The residue was subjected to silica gel column
chromatography (elution solvent: n-hexane:ethyl acetate = 3:2-+2:3 (VN)) and the
fractions containing the target product were concentrated under reduced pressure to
obtain 1.59 g of the title compound in the form of a colorless syrup (yield: 97%).
5 mass spectrum (CI, mlz): 569 (M++l).
1 H-NMR spectrum (CDC13, 6 ppm): 8.62 (ddd, J = 4.7, 1.7, 1.0 Hz, lH), 7.83 (ddd, J =
7.7, 1.0, 1.0 Hz, lH), 7.76 (ddd, J = 7.7, 7.7, 1.7 Hz, lH), 7.60-7.58 (m, lH), 7.47-7.43
(m, 3H), 7.38 (ddd, J = 7.7,4.7, 1.0 Hz, lH), 7.36-7.32 (m, 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),
10 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).
[0095] The compounds used in the examples were synthesized in the manner
described below.
[0096] [Reference Example 11
15 Ethyl {6-~(p~idin-2-ylsulfonyl)aminomethyl]p~idin-2-ylamaicneot)a te
[0097] 1 -(a): tert-Butyl
Jtert-butoxycarbonyl(6-ethoxycarbonylp~idin-2-y1)aminaoc~e tate
300 mL solution of N,N-dimethylformamide containing 8 1.2 g (0.305 mol) of
ethyl 6-tert-butoxycarbonylaminopyridine-2-carboxlate (see W020061074884) were
20 dropped into 362 mL solution of N,N-dimethylformamid containing 15.7 g (0.360
mol) of sodium hydride (55% by weight mineral oil dispersion) over the course of 20
minutes while cooling with ice in an argon atmosphere followed by stirring for 1 hour at
room temperature. Next, 54.0 mL (0.366 mol) of tert-butyl bromoacetate were
dropped in over the course of 10 minutes while cooling with ice followed by
25 additionally stirring for 1 hour at room temperature. After completion of the reaction,
an aqueous solution obtained by dissolving 1.77 g (33.0 mmol) of ammonium chloride
in 300 mL of water was added to the reaction solution followed by extracting with
toluene. The organic layer was washed with saturated aqueous sodium chloride
solution and dried with anhydrous magnesium sulfate followed by concentration under
30 reduced pressure. The residue was subjected to silica gel column chromatography
(elution solvent: n-hexane:ethyl acetate = 9: 1+4: 1 (VN)) and the fractions containing
the target product were concentrated under reduced pressure to obtain 108 g of the title
compound in the form of a pale yellow oil (yield: 93%).
mass spectrum (CI, rnlz): 38 1 (M++l).
35 'H-NMR spectrum (CDC13, 6 ppm): 8.04 (d, J = 7.8 Hz, lH), 7.8 1 (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-Butyl
~tert-butoxycarbonyl(6-hydrox~ethylpyridin-2-yl)amiancoe tate
195 mL solution of ethanol containing 34.6 g (0.3 12 mol) of calcium chloride
5 were dropped into 195 mL solution of ethanol containing 98.8 g (0.260 mol) of the
tert-butyl [ t e r t - b u t o x y c a r b o n y l ( 6 - e t h o x y c a r b o n y l p ~ a c e t a toeb tained in
Reference Example 1-(a) over the course of 20 minutes while cooling with ice. After
completion of dropping, 105 mL (0.3 15 mol) of 3 mol1L sodium
borohydrideltetraethylene glycol dimethyl ether solution were dropped in over the
10 course of 20 minutes at 35OC or lower followed by additionally stirring for 15 minutes
at room temperature. After completion of the reaction, the reaction solution was
dropped into a mixed solution of 17.8 mL of acetic acid and 195 mL of water over the
course of 10 minutes while cooling with ice followed by stirring for 1 hour at room
temperature. Next, 3 15 mL of water was added followed by extracting with toluene.
15 The organic layer was sequentially washed with saturated aqueous sodium bicarbonate
solution, water and saturated aqueous sodium chloride solution and then 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 the
fractions containing the target product were concentrated under reduced pressure to
20 obtain 8 1.1 g of the title compound in the form of a pale yellow oil (yield: 92%).
mass spectrum (CI, mlz): 339 (~++1).
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 (m, lH), 4.68-4.65 (m, 2H), 4.54 (s, 2H), 3.39 (t, J = 5.3 Hz, lH), 1.54 (s,
9H), 1.46 (s, 9H).
25 [0099] 1 -(c): tert-Butyl ~tert-butoxycarbonyl(6-formylp~idin-2-yl)aminoacetate
50 mL solution of methylene chloride containing 10.0 g (29.6 mrnol) of the
tert-butyl [tert-butoxycarbonyl(6-hydroxymethylpyriacetate obtained in
Reference Example 1 -(b) were dropped into 130 mL solution of methylene chloride
containing 12.9 g (30.4 mmol) of Dess-Martin reagent over the course of 20 minutes
30 while cooling with ice in an argon atmosphere. Following completion of dropping, the
reaction solution was stirred for 2 hours at room temperature. After completion of the
reaction, 305 mL of 0.1 % by weight sodium thiosulfate solution was added to the
reaction solution followed by extracting with methylene chloride. The organic layer
was sequentially washed with 0.5 mollL aqueous sodium hydroxide solution and
35 saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate,
and then concentrated under reduced pressure to obtain 9.6 1 g of the title compound in
the form of a pale yellow oil nearly quantitatively.
mass spectrum (EI, d z ) : 336 (M+).
1 H-NMR spectrum (DMSO-d6, 6 ppm): 9.82 (s, 1 H), 8.1 1-7.99 (m, 2H), 7.68 (dd, J =
6.6, 1.5 Hz, lH), 4.58 (s, 2H), 1.48 (s, 9H), 1.42 (s, 9H).
5 [0100] 1-(d): tert-Butyl
~tert-butoxycarbonyl(6-hydroxyiminomethylpidin-2-ylamiancoe tate
0.650 g (9.35 mmol) and 3.5 mL (43 mmol) of pyridine were added to 29 mL
solution of methanol containing 2.88 g (8.56 mmol) of the tert-butyl
[tert-butoxycarbonyl(6-formylpyridin-2-yl)amino]acetate obtained in Reference
10 Example 1-(c) followed by stirring for 1 hour at room temperature. After completion
of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl
acetate was added to the resulting residue followed by sequentially washing with 5% by
weight aqueous potassium hydrogen sulfate, saturated aqueous sodium bicarbonate
solution and saturated aqueous sodium chloride solution, drying with anhydrous
15 magnesium sulfate, and then concentration under reduced pressure. The residue was
subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate
= 3:2 (VIV)) and the fractions containing the target product were concentrated under
reduced pressure to obtain 2.76 g of the title compound in the form of a colorless oil
(yield: 92%).
20 mass spectrum (EI, d z ) : 3 5 1 (M').
1 H-NMR spectrum (CDC13, 6 ppm): 8.06 (s, lH), 7.9 1 (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).
[0101] 1-(e): tert-Butyl
25 ~(6-aminomethvlp~idin-2-~l)tert-butox~carbonylamino~acetate
0.98 g of 10% by weight palladium-activated charcoal (water content: 50% by
weight) was added to 49 mL solution of ethanol containing 2.75 g (7.83 mmol) of the
tert-butyl [tert-butoxycarbonyl(6-hydroxyiminomethylp~idin-2-yl)amino]acetate
obtained in Reference Example 1-(d) followed by stirring for 1 hour at room
30 temperature in a hydrogen atmosphere at 1 atm. After completion of the reaction,
insoluble substances were collected by filtration and the filtrate was concentrated under
reduced pressure to obtain 2.48 g of the title compound in the form of a colorless oil
(yield: 94%).
mass spectrum (CI, d z ) : 338 (M++l).
35 1~-~~~spectrum(CDC13,6ppm):7.68(d,J=8.3Hz,1H),7.58(dd,J=8.3,7.4Hz,
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 1 021 1 -(f) : tert-Butyl
(tert-butoxycarbonyl~6-~(pyridin-2-ylsulfonyl)aminomethyllpyridin-2-aym1]i no)acetate
12 mL solution of methylene chloride containing 1.20 g (3.56 mmol) of the
tert-butyl [(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate obtained in
5 Reference Example 1-(e) and 2.24 mL (16.2 mmol) of triethylamine were added to 14
mL solution of methylene chloride containing 0.640 g (3.60 mmol) of 2-pyridylsulfonyl
chloride followed by stirring for 0.5 hours at room temperature. After completion of
the reaction, a 5% by weight aqueous potassium hydrogen sulfate solution was added to
the reaction solution followed by extracting with methylene chloride. The organic
10 layer was sequentially washed with saturated aqueous sodium bicarbonate solution and
saturated aqueous sodium chloride solution, dried with 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 : 1 (VN)) and the
fractions containing the target product were concentrated under reduced pressure to
15 obtain 1.46 g of the title compound in the form of a white solid (yield: 86%).
mass spectrum (APCI, mlz): 479 (M++l).
'H-NMR spectrum (CDC13, 6 ppm): 8.56 (ddd, J = 4.7, 1.7, 0.9 Hz, lH), 7.97 (ddd, J =
7.8, 1.1, 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, 0.5 Hz,
20 1H),5.86(t,J=5.6Hz,1H),4.48(s,2H),4.36(d,J=5.6Hz,2H),1.53(s,9H),1.45(s,
9H).
[O 1031 1- (g): Ethyl {6-[(pyridin-2-ylsulfony1)aminomethyl~p~naoc)e tate
37.5 mL (75.0 mmol) of 2 mollL hydrogen chloridelethanol solution was added
to 3.59 g (7.50 mmol) of tert-butyl
25 (tert-butox ycarbonyl{6- [(p yridin-2-ylsul fonyl)aminomethyl] p~ } amino)acetate
obtained according to the same method as Reference Example 1-(f) followed by stining
for 3 hours while heating to reflux. After completion of the reaction, water was added
to the reaction solution followed by neutralizing with 1 molIL aqueous sodium
hydroxide solution and extracting with ethyl acetate. The organic layer was washed
30 with saturated aqueous sodium chloride solution, dried with anhydrous magnesium
sulfate and then concentrated under reduced pressure to obtain 2.17 g of the title
compound in the form of a brown oil (yield: 83%).
mass spectrum (CI, rn/z): 35 1 (M++l).
'H-NMR spectrum (DMSO-d6, 6 ppm): 8.71 (ddd, J = 4.8, 1.8, 0.8 Hz, lH), 8.18 (brs,
35 0.1H),8.05(ddd,J=7.8,7.6,1.8Hz,1H),7.91(ddd,J=7.8,1.0,0.8Hz71H),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 (s, 2H),
3.95 (s72H), 1.16(t7 J=7.1 Hz,3H).
[O 1041 [Reference Example 21
Ethyl f 6 - [ ( p y r i d i n - 3 - y l s u l f o n y 1 ) a m i n o m e t h y l l p ~ e
5 [0105] 2-(a): tert-Butyl
(tert-butoxycarbonyl f 6- [(p yridin-3- ylsulfonyl)aminomethyllpydh4-yla mino)acetate
1.45 g of the title compound were obtained in the form of a colorless oil by
performing the reaction and post-treatment in accordance with Reference Example 1 -(f)
with the exception of using 1.20 g (3.56 mmol) of tert-butyl
10 [(6-aminomethylpyridin-2-yl)tert-butoxycarbonylaminoa]c etate obtained according to
the same method as Reference Example 1 -(e) and using 640 mg (3.60 mmol) of
3 -pyridylsulfonyl chloride in place of 2-p yridylsulfonyl chloride (yield: 8 5 %).
mass spectrum (CI, rnlz): 479 (M++l).
1 H-NMR spectrum (CDC13, 6 ppm): 9.06 (d, J = 2.2 Hz, 1 H), 8.7 1 (dd, J = 4.6, 1.5 Hz,
15 1H),8.13-8.08(m,1H),7.68(d,J=8.2Hz,1H),7.52(dd7J=8.2,7.4Hz,1H),
7.38-7.32 (m, 1H), 6.77 (d, J = 7.4 Hz, lH), 5.80 (t, J = 5.1 Hz, lH), 4.40 (s, 2H), 4.24
(d, J = 5.1 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H).
[O 1 061 2-(b) : Ethyl (6-[(pyidin-3 -ylsulfonyl)aminomethyllpyridin-2-ylamino ) acetate
686 mg of the title compound were obtained in the form of a brown oil by
20 performing the reaction and post-treatment in accordance with Reference Example 1-(g)
with the exception of using 1.00 g (2.09 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]p~am ino)acetate
obtained according to the same method as Reference Example 2-(a) in place of
tert-butyl
25 (tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]p~}a mino)acetate,
and using 10.4 mL (20.8 mmol) of 2 mollL hydrogen chloridelethanol solution (yield:
94%).
'H-NMR spectrum (CDC13, 6 ppm): 9.06 (dd, J = 2.3, 0.7 Hz, lH), 8.71 (dd, J = 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
30 (dd,J=8.3,7.3Hz,1H),6.38(d,J=7.3Hz,1H),6.29(d,J=8.3Hz,1H),5.95(t7J=
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 = 5.4Hz7 2H), 1.32 (t, J=7.2Hz7 3H).
[O 1071 [Reference Example 31
3'4 1 -Propenyl)biphenyl-4-ylmethanol
3 5 [O 1081 3 -(a): 3'-(1 -Propenyl)biphenvl-4-ylcarbaldehyde
27.5 mL of toluene and 1.65 mL of water were added to 500 mg (1.91 mmol)
of 3-bromobiphenyl-4-ylcarbaldehyde (see Journal of Organic Chemistry, 68,247
(2003)) followed by the addition of 1.63 g (7.68 mmol) of tripotassium phosphate and
656 mg (7.64 mrnol) of 1-propenylboronic acid and placing the mixture in a nitrogen
gas atmosphere. Moreover, 6.2 mg (0.028 mrnol) of palladium acetate and 20.2 mg
5 (0.0563 mrnol) of butyl di-1 -adamantylphosphine were added followed by stirring for
4.5 hours at 100°C in a nitrogen gas atmosphere. After completion of the reaction,
water was added to the reaction solution followed by extracting with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride solution, dried
with anhydrous magnesium sulfate and then concentrated under reduced pressure. The
10 residue was subjected to silica gel column chromatography (elution solvent:
n-hexane:ethyl acetate = 4: 1 (VN)) and the fractions containing the target product were
concentrated under reduced pressure to obtain 420 mg of the title compound in the form
of a slightly yellow oil (yield: 99%).
mass spectrum (CI, d z ) : 223(~++1).
15 1H -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 (m, lH), 7.41-7.37 (m, 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).
[O 1091 3-(b): 3'-( 1 -Propenvl)biphenvl-4-ylmethanol
35.6 mg (0.941 mmol) of sodium borohydride was added to 4.6 mL solution of
20 ethanol containing 4 17 mg (1.8 8 mrnol) of the
3'-(1 -propenyl)biphenyl-4-ylcarbaldehyde obtained in Reference Example 3-(a) at room
temperature followed by stirring for 45 minutes at the same temperature. After
completion of the reaction, saturated aqueous ammonium chloride solution was added
to the reaction solution followed by extracting with ethyl acetate. The organic layer
25 was washed with saturated aqueous sodium chloride solution, dried with 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 (VN)) and the fractions containing the target product were concentrated under
reduced pressure to obtain 401 mg of the title compound in the form of a white solid
30 (yield: 95%).
mass spectrum (EI, d z ) : 224 (M').
1 H-NMR spectrum (CDC13, 6 ppm): 7.63-7.56 (m, 2H), 7.55-7.52 (m, lH), 7.47-7.29 (m,
5H), 6.47 (dd, J = 15.9, 1.5 Hz, lH), 6.31 (dq, J = 15.9, 6.6 Hz, lH), 4.74 (d, J = 5.7 Hz,
2H), 1.91 (dd, J = 6.6, 1.5 Hz, 3H), 1.70 (t, J = 5.7 Hz, 1H).
3 5 [O 1 101 [Reference Example 41
3'-(1 -Propynyl)biphenyl-4-ylmethanol
[O 1 1 11 4-(a): 3'-(1 -Prop~mvl)biphenyl-4-ylcarbaldehvde
10 mL solution of toluene containing 1.04 g (3.98 mmol) of
3'-bromobiphenyl-4-ylcarbaldehyde were degassed under reduced pressure followed by
substituting with argon gas. Next, 23 1 mg (0.200 mmol) of
5 tetrakis(tripheny1phosphine)palladium and 1.46 mL (4.80 mmol) of
tributyl(1 -propynyl)tin were added followed by stirring for 7 hours at 1 1 O°C in an argon
gas atmosphere. After completion of the reaction, 60 mL of 0.8 mol/L aqueous
potassium fluoride solution was added to the reaction solution followed by extracting
with toluene. The organic layer was washed with saturated aqueous sodium chloride
10 solution, dried with 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 :0+4: 1 (VN))a nd the fractions containing the target
product were concentrated under reduced pressure to obtain 660 mg of the title
compound in the form of a pale yellow solid (yield: 75%).
15 massspectrum(CI,mlz):221(~++1).
1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, lH), 7.97-7.93 (m, 2H), 7.76-7.72 (m,
2H), 7.68-7.67 (m, lH), 7.55-7.52 (m, lH), 7.45-7.37 (m, 2H), 2.08 (s, 3H).
[O 1 121 4-(b): 3'-(1 -Prop~myl)biphenvl-4-ylmethanol
588 mg of the title compound were obtained in the form of a slightly yellowish
20 white solid by performing the reaction and post-treatment in accordance with Reference
Example 3-(b) with the exception of using 723 mg (3.28 mmol) of
3'-(1 -propynyl)biphenyl-4-ylcarbaldehyde obtained according to the same method as
Reference Example 4-(a) in place of 3'-(1 -propenyl)biphenyl-4-ylcarbaldehyde, and
using 62.2 mg (1.64 mmol) of sodium borohydride (yield: 8 1%).
25 mass spectrum (EI, d z ) : 222 (M').
1 H-NMR spectrum (CDC13, 6 ppm): 7.63-7.62 (m, lH), 7.60-7.56 (m, 2H), 7.5 1-7.47 (m,
lH), 7.46-7.42 (m, 2H), 7.38-7.32 (m, 2H), 4.75 (d, J = 6.0 Hz, 2H), 2.07 (s, 3H), 1.68
(t, J = 6.0 Hz, 1H).
[O 1 131 [Reference Example 51
30 3'-Ethoxybiphenyl-4-ylmethanol
15 mL of toluene, 15 mL of ethanol and 4.5 mL (9.0 mmol) of 2 mol/L
aqueous sodium carbonate solution were added to 1.21 g (6.02 mmol) of
3-bromophenetole followed by degassing under reduced pressure and substituting with
argon gas. Next, 1.37 g (9.02 mmol) of 4-(hydroxymethyl)phenylboronic acid and 347
3 5 mg (0.3 00 mmol) of tetralus(triphenylphosphine)palladium were added followed by
stirring for 4 hours at 100°C in an argon gas atmosphere. After completion of the
reaction, the reaction solution was concentrated under reduced pressure and water was
added to the residue followed by extracting with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride solution, dried with anhydrous
magnesium sulfate and then concentrated under reduced pressure. The residue was
5 subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate
= 9: 1+7:3 (VN)) and the fractions containing the target product were concentrated
under reduced pressure to obtain 1.23 g of the title compound in the form of a pale
yellow oil (yield: 90%).
mass spectrum (CI, mlz): 229 (~'+1).
10 'H-NMR spectrum (CDC13, 6 ppm): 7.6 1-7.56 (m, 2H), 7.46-7.4 1 (m, 2H), 7.34 (dd, J =
8.0, 8.0 Hz, lH,), 7.18-7.1 1 (m, 2H), 6.91-6.87 (m, lH), 4.74 (d, J = 5.9 Hz, 2H), 4.10
(q, J = 7.0 Hz, 2H), 1.67 (t, J = 5.9 Hz, IH), 1.45 (t, J = 7.0 Hz, 3H).
[O 1 141 [Reference Example 61
Hexvl (6-~~pyidin-2-ylsulfonyl)aminomethyllp~idin-2-~laamcietnaot)e
15 0.56 mL (10 rnrnol) of concentrated sulfuric acid was added to 6.0 mL solution
of n-hexanol containing 957 mg (2.00 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]p~inoa}c etate
obtained according to the same method as Reference Example 1-(f) followed by stirring
for 8 hours at 100°C. After completion of the reaction, the reaction solution was
20 poured into a saturated aqueous sodium bicarbonate solution followed by extracting
with ethyl acetate. The organic layer was washed with saturated aqueous sodium
chloride solution, dried with 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 : 1 +3:7 (VN)) and the fractions containing
25 the target product were concentrated under reduced pressure to obtain 658 mg of the
title compound in the form of a slightly yellow oil (yield: 8 1%).
'H-NMR spectrum (CDC13, 6 ppm): 8.62 (ddd, J = 4.6, 1.8, 1 .O 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 Hz, lH),
30 6.02(t,J=5.3Hz,lH),4.92(t,J=5.3Hz,lH),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 (m, 2H), 1.39-1.26 (m, 6H), 0.91-0.87 (m,
3H).
[O 1 1 51 [Reference Example 71
tert-Butvl (tert-butoxycarbonvl(6-~(3'-ethoxybiphenyl-4-ylmethyl)-
3 5 aminomethyllpyidin-2-ylamino) acetate
[O 1 161 7-(a): 3'-Ethoxybiphenyl-4-ylcarbaldehvde
4.08 g of the title compound were obtained in the form of a colorless oil by
performing the reaction and post-treatment in accordance with Reference Example 5
with the exception of respectively using 4.20 g (22.7 mmol) of 4-bromobenzaldehyde in
place of 3-bromophenetole and 3.13 g (1 8.9 mmol) of 3-ethoxyhenylboronic acid in
5 place of 4-(hydroxymethy1)phenylboronic acid, and using 28.4 mL (56.8 mmol) of 2
mo1lL aqueous sodium carbonate solution and 2.18 g (1.89 mmol) of
tetrakis(tripheny1phosphine)palladium (yield: 9 5 %) .
mass spectrum (CI, d z ) : 227 (~++1).
1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, lH), 7.97-7.93 (m, 2H), 7.76-7.73 (m,
10 2H),7.38(dd,J=8.1,7.9Hz,1H),7.21(ddd,J=7.9,2.0,0.9Hz,1H),7.16(dd,J=2.3,
2.0 Hz, lH), 6.95 (ddd, J = 8.1,2.3,0.9 Hz, lH), 4.11 (q, J = 6.9 Hz, 2H), 1.46 (t, J =
6.9 Hz, 3H).
[O 1 171 7-(b): tert-Butyl (tert-butoxycarbonyl(6-r(3'-ethoxybiphenyl-4-ylmethyl)-
aminomethyllpyridin-2- yl) amino)acetate
15 2.46 g (10.9 mmol) of the 3'-ethoxybiphenyl-4-ylcarbaldehyde obtained in
Reference Example 7-(a) was added to 12 mL solution of methylene chloride containing
4.02 g (1 1.9 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate obtained according to
the same method as Reference Example 1-(e) followed by stirring for 30 minutes at
20 room temperature. Next, 3.25 g (15.3 mmol) of sodium triacetoxyborohydride was
added while cooling with ice followed by stirring for 3.5 hours at the same temperature.
After completion of the reaction, aqueous sodium bicarbonate solution was added
followed by extracting with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried with anhydrous potassium carbonate,
25 and then concentrated under reduced pressure. The residue was subjected to silica gel
column chromatography (elution solvent: n-hexane:ethyl acetate = 3:2+0: 1 (VN)) and
the fractions containing the target product were concentrated under reduced pressure to
obtain 3.68 g of the title compound in the form of a pale yellow oil (yield: 62%).
mass spectrum (CI, d z ) : 548 (M++l).
30 '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 (m, 2H), 7.43-7.39 (m, 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, l.OHz, lH),4.57(~,2H),4.10(qJ, =7.1 Hz,2H),3.84(~,2H),3.83(s ,
2H), 1.53 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H).
3 5 [O 1 1 81 [Reference Example 81
4-(6-Ethoxypyridin-2-y1)phenylmethanol
284 mg of the title compound were obtained in the form of a white solid by
performing the reaction and post-treatment in accordance with Reference Example 5
with the exception of using 0.49 g (2.4 mmol) of 2-bromo-6-ethoxypyridine (see US
200311 99440) in place of 3-bromophenetole, and using 0.59 g (3.9 mmol) of
5 4-(hydroxymethy1)phenylboronic acid, 1.7 mL (3.4 mmol) of 2 mol1L aqueous sodium
carbonate solution, and 138 mg (0.1 19 mmol) of tetralus(triphenylphosphine)palladium
(yield: 5 1 %).
mass spectrum (CI, d z ) : 230 (M++l).
1 H-NMR spectrum (CDC13, F ppm): 8.05-8.01 (m, 2H), 7.62 (dd, J = 8.2, 7.4 Hz, lH),
10 7.47-7.43(m,2H),7.32(dd,J=7.4,0.6Hz,lH),6.67(dd,J=8.2,0.6Hz,1H),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 91
Ethyl f 6-~(thiophen-2-ylsulfonyl~aminomethyl~pidin-2-yla)m aicneot ate
15 [O 1201 9-(a): tert-Butyl (tert-butoxycarbonylf6-~(thiophen-2-ylsulfonyl)aminomethyl~-
pyridin-2-ylamino ) acetate
1.6 1 g of the title compound were obtained in the form of a white solid by
performing the reaction and post-treatment in accordance with Reference Example 1-(f)
with the exception of using 1.35 g (4.00 mmol) of tert-butyl
20 [(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetatoeb tained according to
the same method as Reference Example 1-(e), and using 73 1 mg (4.00 mmol) of
2-thiophenesulfonyl chloride in place of 2-pyridylsulfonyl chloride (yield: 84%).
mass spectrum (CI, d z ) : 484 (M++l).
1 H-NMR spectrum (CDC13, 6 ppm): 7.71 (d, J = 8.4 Hz, lH), 7.57 (dd, J = 3.8, 1.3 Hz,
25 lH), 7.56 (dd, J=8.4, 7.4Hz, lH),7.50(dd, J=5.0, 1.3 Hz, lH), 7.01 (dd, J=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 f 6 - ~ ( t h i o p h e n - 2 - ~ l s u l f o n ~ l ~ a m i n o m e t h ~ l l ~ )
acetate
30 20 mL (40 mmol) of 2 mollL hydrogen chloridelethanol solution was added to
1.60 g (3.3 1 mmol) of the tert-butyl (tert-butoxycarbonyl{6-[(thiophen-2-ylsulfony1)-
aminomethyllpyridin-2-ylamino)a cetate obtained in Reference Example 9-(a) followed
by stirring for 3 hours while heating to reflux. After completion of the reaction, the
reaction solution was concentrated under reduced pressure and neutralized with
35 saturated aqueous sodium bicarbonate solution followed by extracting with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride solution, dried
with 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 the fractions containing the target product
were concentrated under reduced pressure to obtain 1.10 g of the title compound in the
5 form of a colorless oil (yield: 93%).
mass spectrum (CI, mlz): 356 (M++l).
1 H-NMR spectrum (CDC13, 6 ppm): 7.57 (dd, J = 3.8, 1.3 Hz, lH), 7.5 1 (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,
10 1H),4.26(q,J=7.2Hz,2H),4.18(d,J=4.9Hz,2H),4.06(d,J=5.3Hz,2H),1.32(t,
J = 7.2 Hz, 3H).
[O 1221 [Reference Example 101
Ethyl f 6-~(benzenesulfonyl)aminomethyllpyridin-2-ylamin)o a cetate
[O 1231 10-(a): tert-Butyl
15 ( (6-~(benzenesulfonTvI)aminomethyl~pyridine-te-r1t-)b utoxycarbony1amino)acetate
1.71 g of the title compound were obtained in the form of a slightly beige solid
by performing the reaction and post-treatment in accordance with Reference Example
1 -(f) with the exception of using 1.35 g (4.00 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylaminoa]c etate obtained according to
20 the same method as Reference Example 1-(e) and using 707 mg (4.00 mmol) of
benzenesulfonyl chloride in place of 2-pyridylsulfonyl chloride (yield: 89%).
mass spectrum (CI, d z ) : 478 (M++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,
25 1H),4.41(s,2H),4.19(d,J=5.4Hz,2H),1.53(s,9H),1.46(s,9H).
[O 1241 10 -(b): Ethyl (6-~(benzenesulfonyl)aminomethyllpyridin-2-ylaminaoc)e tate
1.13 g of the title compound were obtained in the form of a white solid by
performing the reaction and post-treatment in accordance with Reference Example 9-(b)
with the exception of using 1.70 g (3.56 mmol) of the tert-butyl
3 0 ( (6- [(benzenesulfony1)aminomethyl]pyridine-2-yl } tert-butoxycarbony1amino)acetate
obtained in Reference Example 10-(a) in place of tert-butyl
(tert-butoxycarbonyl{6-[ (thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-ylaminoa)c etat
e, and 20 mL (40 mmol) of 2 mol1L hydrogen chloridelethanol solution (yield: 91%).
mass spectrum (CI, d z ) : 350 (M++l).
35 'H-NMR spectrum (CDC13, 6 ppm): 7.87-7.84 (m, 2H), 7.53-7.42 (m, 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, 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 = 5.2 Hz, 2H), 1.32 (t, J = 7.2Hz, 3H).
[O 1251 [Reference Example 1 1 ]
Ethyl (6-~(thiophen-3-~lsulfon~l)aminometh~l~~~idin-2a-ce~tlaatem ino)
5 [O 1261 1 1 -(a): tert-Butvl (tert-butoxycarbonyl(6-[(thiophen-3-ylsulfony1)-
aminomethyllpyridine-2-yl) amino)acetate
1.64 g of the title compound were obtained in the form of a slightly yellowish
white solid by performing the reaction and post-treatment in accordance with Reference
Example 1-(f) with the exception of using 1.35 g (4.00 mmol) of tert-butyl
10 [(6-aminomethylpyridin-2-yl)tert-butoxycarbonylaminoa]c etate obtained according to
the same method as Reference Example 1-(e) and using 73 1 mg (4.00 mrnol) of
3-thiophenesulfonyl chloride in place of 2-pyridylsulfonyl chloride (yield: 85%).
mass spectrum (CI, mlz): 484 (M++l).
'H-NMR spectrum (CDC13, 6 ppm): 7.93 (dd, J = 2.9, 1.4 Hz, lH), 7.69 (d, J = 8.3 Hz,
15 1H),7.54(dd,J=8.3,7.4Hz,1H),7.30(dd,J=5.1,2.9Hz,1H),7.28(dd,J=5.1,1.4
Hz, lH), 6.80 (dd, J = 7.4, 0.6 Hz, lH), 5.59 (t, J = 5.4 Hz, lH), 4.43 (s, 2H), 4.23 (d, J
= 5.4 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H).
[O 1 271 1 1 -(b) : Ethyl (6- [(thiophen-3 - ylsulfonyl)aminomethyllpyridin-2-lamino)
acetate
20 The reaction and post-treatment were performed in accordance with Reference
Example 9-(b) with the exception of using 1.63 g (3.37 mmol) of the tert-butyl
(tert-butoxycarbonyl{6-[(thiophen-3-ylsulfonyl)aminomethyl]p~a}m ino)acet
ate obtained in Reference Example 1 1-(a) in place of tert-butyl
(tert-butoxycarbonyl{6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}a cetat
25 e, and using 17.5 mL (35.0 mmol) of 2 molIL hydrogen chloridelethanol solution. The
residue was subjected to silica gel column chromatography (elution solvent:
n-hexane:ethyl acetate = 7:3+ 1 : 1 (VN)) and the fractions containing the target product
were concentrated under reduced pressure. The resulting crude product was
recrystallized with 5 mL of ethyl acetate to obtain 73 1 mg of the title compound in the
30 form of a white solid (yield: 6 1%).
mass spectrum (CI, mlz): 356 (M++l).
1 H-NMR spectrum (CDC13, 6 ppm): 7.93 (dd, J = 3 .O, 1.4 Hz, lH), 7.33-7.28 (m, 3H),
6.40 (dd, J = 7.3,0.6 Hz, lH), 6.32 (dd, J = 8.3, 0.6 Hz, lH), 5.76 (t, J = 5.1 Hz, lH),
4.95 (t, J= 5.4 Hz, lH), 4.27 (q, J=7.2Hz, 2H), 4.13 (d, J= 5.1 Hz, 2H), 4.06 (d, J =
35 5.4 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H).
[O 12 81 [Reference Example 121
tert-Butyl rtert-butoxycarbonyl(6- { r3'-(1 -propynyl)biphenyl-4-ylmethyl]-
aminomethyl) pyridin-2-y1)aminolacetate
[O 1291 12-(a): 1 -Bromo-3-(1 -proppyl)benzene
1.43 g (7.5 1 mmol) of cuprous iodide and 1.45 g (1.25 mmol) of
5 tetrakis(triphenylphosphine)palladium were added to 50 mL solution of toluene
containing 7.07 g (25.0 mmol) of 1 -bromo-3 -iodobenzene followed by degassing under
reduced pressure and substituting with argon gas. Next, 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
mmol) of 1.0 mollL tetrafluoroamrnonium fluorideltetrahydrofuran solution were added
10 followed by stirring for 17 hours at room temperature in an argon gas atmosphere.
After completion of the reaction, water and t-butyl methyl ether were added to the
reaction solution and insoluble substances were collected by filtering through Celite
(trade name). Following separation, the organic layer was dried with anhydrous
magnesium sulfate and then concentrated under reduced pressure. The residue was
15 subjected to silica gel column chromatography (elution solvent: n-hexane) and the
fractions containing the target product were concentrated under reduced pressure to
obtain 4.22 g of the title compound in the form of 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,
20 1.7, 1.0 Hz, lH), 7.31-7.29 (m, lH), 7.14 (dd, J = 8.0, 8.0 Hz, lH), 2.04 (s, 3H).
[0130] 12-(b): 3'-(1-Pro yny1)biphenyl-4-vlcarbaldehyde
3.3 1 g of the title compound were obtained in the form of a pale yellowish
white solid by performing the reaction and post-treatment in accordance with Reference
Example 5 with the exception of respectively using 2.93 g (15.0 mmol) of
25 1-bromo-3-(1 -propynyl)benzene obtained according to the same method as Reference
Example 12-(a) in place of 3-bromophenetole and using 3.37 g (37.5 mmol) of
4-formylphenylboronic acid in place of 4-(hydroxymethy1)phenylboronic acid, and
using 11.3 mL (22.6 mmol) of 2 mollL aqueous sodium carbonate solution and 867 mg
(0.750 mmol) of tetra~s(triphenylphosphine)palladium (quantitative).
30 The NMR spectrum of the compound obtained in the present Reference
Example 12-(b) was the same as the NMR spectrum of the compound obtained in
Reference Example 4-(a).
[O 13 11 12-(c): tert-Butyl [tert-butoxycarbonyl(6- { 13'-(1 -propynyl)biphenyl-
4-ylmethyll aminomethyl lpyridin-2-y1)aminol acetate
35 6.48 g of the title compound was obtained in the form of a pale yellow oil by
performing the reaction and post-treatment in accordance with Reference Example 7-(b)
with the exception of using 5.57 g (16.5 mmol) of tert-butyl
[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate obtained according to
the same method as Reference Example 1 -(e), 3.30 g (1 5.0 mmol) of the
3'-(1 -prop ynyl)biphenyl-4-ylcarbaldehyde obtained in Reference Example 1 2-(b) in
5 place of 3'-ethoxybiphenyl-4-ylcarbaldehyde, and 4.45 g (2 1.0 mmol) of sodium
triacetoxyborohydride (yield: 80%).
mass spectrum (CI, mlz): 542 (~'+1).
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),
10 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), 2.07
(s, 3H), 1.53 (s, 9H), 1.41 (s, 9H).
[O 1321 [Reference Example 131
3'41 -Propynyl)biphenyl-4-ylmethanol
A reaction was performed in accordance with Reference Example 5 with the
15 exception of using 3.90 g (20.0 mrnol) of 1 -bromo-3-(1 -propynyl)benzene obtained
according to the same method as Reference Example 12-(a) in place of
3 -bromophenetole, and using 4.56 g (3 0.0 mmol) of 4-(hydroxymethyl)phenylboronic
acid, 15 mL (30 mmol) of 2 mollL aqueous sodium carbonate solution and 1.16 g (1 .OO
mmol) of tetrakis(triphenylphosphine)palladium. After completion of the reaction,
20 water was added to the reaction solution followed by extracting with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride solution, dried
with 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 the fractions containing the target product
25 were concentrated under reduced pressure. The resulting crude product was stirred for
1 hour in 45 mL of a mixed solvent (ethyl acetate:n-hexane = 1 : 10 (VN)), and the
precipitated solid was collected by filtration and then dried under reduced pressure to
obtain 3.85 g of the title compound in the form of a white solid (yield: 87%).
The NMR spectrum of the compound obtained in the present Reference
30 Example 13 was the same as the NMR spectrum of the compound obtained in
Reference Example 4-(b).
[O 13 31 [Reference Example 141
Isopropyl (6- ~(pyridin-2-ylsulfonvl)aminomethyllpidin-2-ylami)n aoc etate
1.05 g of the title compound were obtained in the form of a white solid by
35 performing the reaction and post-treatment in accordance with Reference Example 9-(b)
with the exception of using 1.44 g (3.0 1 mmol) of tert-butyl
(tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]p~)a cetate
obtained according to the same method as Reference Example 1-(f) in place of tert-butyl
(tert-butoxycarbonyl(6- [(thiophen-2-ylsulfonyl)aminomethyl]p~idin-2-ylaminoa)c etat
e, and using 16.0 mL (32.0 mmol) of 2 mol/L hydrogen chloride/isopropanol solution in
5 place of the 2 mol/L hydrogen chloridelethanol solution (yield: 96%).
mass spectrum (CI, d z ) : 365 (M++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),
10 6.04 (t, J = 5.4 Hz, lH), 5.10 (sep, J = 6.3 Hz, lH), 4.93 (t, J = 5.4 Hz, lH), 4.25 (d, J =
5.4 Hz, 2H), 4.04 (d, J = 5.4 Hz, 2H), 1.28 (d, J = 6.3 Hz, 6H).
[O 1341 [Comparative Example 11
f6-~(3'-Propylbiphenyl-4-ylmethyl)(pyridin-2-yl~~lf0nyl)amin0methy11pyridin-
2-ylamino 1 acetate
15 This compound is the compound of Example Number 754 of W02009/113600.
[O 13 51 1 -(a): 3'-Propylbiphenyl-4-ylcarbaldehyde
1.7 mL of water, 1.63 g (7.68 mmol) of tricalcium phosphate and 675 mg (7.68
mmol) of propylboronic acid were added to 28 mL solution of toluene containing 500
mg (1.9 1 mmol) of 3'-bromobiphenyl-4-ylcarbaldehyde followed by degassing under
20 reduced pressure and substituting with nitrogen gas. Next, 6.2 mg (0.028 mrnol) of
palladium acetate and 20.2 mg (0.0563 mmol) of butyl di- 1 -adamantylphosphine were
added followed by stirring for 3 hours at 100°C in a nitrogen gas atmosphere.
Post-treatment following completion of the reaction was performed in accordance with
Reference Example 5 to obtain 406 mg of the title compound in the form of a pale
25 yellow oil (yield: 86%).
mass spectrum (EI, d z ) : 224 (M').
1 H-NMR spectrum (CDC13, 6 ppm): 10.06 (s, lH), 7.99-7.91 (m, 2H), 7.78-7.73 (m,
2H), 7.51-7.34 (m, 3H), 7.28-7.20 (m, lH), 2.73-2.61 (m, 2H), 1.80-1.62 (m, 2H), 0.98
(t, J = 7.3 Hz, 3H).
30 [O 1361 1 -(b): 3'-Propylbiphenyl-4-ylmethanol
383 mg of the title compound were obtained in the form of a white solid by
performing the reaction and post-treatment in accordance with Reference Example 3-(b)
with the exception of using 400 mg (1.78 mmol) of the
3'-propylbiphenyl-4-ylcarbaldehyde obtained in Comparative Example 1 -(a) in place of
35 3'-(1 -propenyl)biphenyl-4-ylcarbaldehyde, and using 33.7 mg (0.89 1 mmol) of sodium
borohydride (yield: 95%).
mass spectrum (EI, d z ) : 226 (M').
1 H-NMR spectrum (CDC13, 6 ppm): 7.64-7.55 (m, 2H), 7.48-7.30 (m, 5H), 7.2 1-7.13 (m,
lH), 4.74 (d, J = 5.6 Hz, 2H), 2.71-2.59 (m, 2H), 1.77-1.62 (m, 3H), 0.97 (t, J = 7.3 Hz,
3H).
5 [O 1371 1 -(c): tert-Butyl (tert-butoxycarbonyl/6-~(3'-propylbiphenyl-4-ylmethyl)
(pyridin-2-ylsulfonvl)aminomethyllpyridin-2-ya1m) ino)acetate
255 mg of the title compound were obtained by performing the reaction and
post-treatment in accordance with Example 1 with the exception of respectively using
94.6 mg (0.41 8 rnmol) of the 3'-propylbiphenyl-4-ylmethanol obtained in Comparative
10 Examplel-(b)and200mg(0.418mmol)oftert-butyl
(tert-butoxycarbonyl{6-[(pyridin-2-ylsulfonyl)aminomethyl]p~inoa}c etate
obtained according to the same method as Reference Example 1-(f) in place of
3'-(1 -propenyl)biphenyl-4-ylmethanol,a nd using 19 8 pL (0.802 mmol) of
tri-n-butylphosphine and 1 13 mg (0.656 mmol) of
15 N,N,N',N1-tetramethylazodicarboxamid(ey ield: 89%).
1 H-NMR spectrum (CDC13, 6 ppm): 8.62-8.58 (m, lH), 7.85-7.73 (m, 2H), 7.65 (d, J =
8.3 Hz, lH), 7.49-7.23 (m, 9H), 7.20-7.12 (m, lH), 6.92 (d, J = 7.3 Hz, lH), 4.73 (s,
2H), 4.52 (s, 2H), 4.46 (s, 2H), 2.69-2.61 (m, 2H), 1.77-1.6 1 (m, 2H), 1.52 (s, 9H), 1.42
(s, 9H), 0.98 (t, J = 7.3 Hz, 3H).
20 [O 13 81 1 -(d): ~6-~(3'-Propylbiphenyl-4-ylmethyl~(pyridin-2-ylsulfonyl)aminomethyl~-
p yridin-2-ylamino 1 acetate
0.74 mL (9.7 mrnol) of trifluoroacetic acid was added at room temperature to
1.7 mL solution of methylene chloride containing 247 mg (0.360 mmol) of the tert-butyl
(tert-butoxycarbonyl{6-[(3'-propylbiphenyl-4-ylmethyl)(pyridin-
25 2-ylsulfonyl)aminomethyl]pyridin-2-yl} amino)acetate obtained in Comparative
Example 1-(c) followed by stirring for 20 hours at room temperature. After
completion of the reaction, the reaction solution was concentrated under reduced
pressure followed by addition of water and adjusting the pH to 4.5 with 1 molIL
aqueous sodium hydroxide solution and 1 mol/L hydrochloric acid. The precipitated
30 solid was collected by filtration, washed and concentrated under reduced pressure to
obtain 16 1 mg of the title compound in the form of 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 (m, lH), 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),
35 7.57-7.53 (m, 2H), 7.46-7.41 (m, 2H), 7.38-7.34 (m, lH), 7.33-7.30 (m, 2H), 7.25-7.16
(m, 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 (m, 2H), 1.68-1.60 (m, 2H), 0.92 (t, J = 7.3 Hz,
3H).
[0139] [Test Example 11
Measurement of EP2 Receptor Binding Action
5 Measurement of EP2 receptor binding action was performed in accordance
with the method of Abramovitz et al. (Biochimica et Biophysica Acta, 1483,285
(2000)). A test compound dissolved in dimethyl sulfoxide (final concentration: 1.0
(VN)%a)n d [3~]prostaglandiEn2 (NET-428, manufactured by PerlunElmer) (final
concentration: 10 nM) were added to a buffer solution (1 0 mM MES-KOH (pH 6.0), 10
10 mM MgC12, 1 mM EDTA) in which 10 pg of a membrane fraction of HEK293 cells
expressing human EP2 receptor (ES-562-M, manufactured by Euroscreen) was
suspended, and then incubated at 30°C for 60 minutes. The membrane fraction was
collected on glass fiber filter paper (GFIB, manufactured by Whatman) using a cell
harvester (M30R, manufactured by Brandel), and after washing with a buffer solution
15 (10 mM MES-KOH (pH 6.0), 10 mM MgC12), radioactivity was measured with a liquid
scintillation analyzer (2000CA, manufactured by Packard). The concentration of test
compound required to replace 50% of the ['~l~rosta~landEi2n b ound to the receptor
(IC50 value) was calculated using EXSAS (Ver. 7.1.6, manufactured by Arm Systex),
and the inhibition constant (Ki value) was determined using the formula indicated
20 below.
Ki = IC50/ (1 + ([3~]prostaglandinE 2 concentration / Kd))
Furthermore, the dissociation constant (Kd value) was calculated by Scatchard
analysis.
The test results are shown in Table 1.
25 [0140] [Table 11
[O 14 11 In the present test, compounds of the present invention demonstrated superior
EP2 receptor binding action.
[O 1421 [Test Example 21
5 Test of Inhibition of LPS-Induced TNFa Production Using Human Peripheral
Blood Mononuclear Cells
Peripheral blood collected in the presence of heparin from healthy subjects was
diluted two-fold with PBS containing 2 (VN)% FBS. Hemocyte separation solution
(Ficoll PaqueTMm, anufactured by GE Healthcare Science) was added to SepMateTM-50
10 (manufactured by STEMCELL Technologies Inc.) followed by layering the diluted
blood thereon. A peripheral blood mononuclear cell (hereinafter abbreviated as
PBMC) layer was recovered by centrifuging for 10 minutes under conditions of 20°C
and 1200xg. The resulting PBMCs were further centrifuged and washed twice
followed by suspending in RPMI1640 medium containing 1 (V/V)% FBS for use in the
15 following test.
[0143] A test of inhibition of LPS-induced TNFa production was performed by
partially modifying the method of Mary et al. (Journal of Pharmacology and
Experimental Therapeutics, 284,420 (1998)). 185 pL of PBMC suspension prepared
to a final concentration of 5 x lo5 cellslmL was added to a 96-well plate, subsequently
20 10 pL of RPMI1640 medium, containing 1 (VN)% DMSO in which a test compound
was dissolved, was added to each well (DMSO final concentration: 0.05 (VN)%).
RPMI1640 medium containing 1 (VN)% DMSO was similarly added to a well to
which test compounds had not been added. After incubating for 1 hour in a carbon
dioxide gas incubator, 5 pL of RPMI1640 medium containing LPS (L2880-500MG,
25 manufactured by Sigma) was added to each well (LPS final concentration: 100 ngImL).
5 pL of RPMI1640 medium was added to a non-LPS stimulation well. After culturing
for about 18 hours in a carbon dioxide gas incubator, the culture supernatant was
recovered. The recovered culture supernatant was stored at -20°C until measurement
of TNFa content.
5 [0144] A sandwich ELISA kit (Quantikine DTAOOc, manufactured by R&D Systems)
was used to measure TNFa content. The TNFa content of each sample was calculated
from a standard curve of E. coli-derived human recombinant TNFa provided with the
kit. TNFa production inhibition rate at each test compound concentration was
calculated based on a value of 100% for the amount of TNFa produced by LPS in the
10 case of only adding DMSO. The concentration of test compound that inhibited TNFa
production by 50% was calculated as the ICso value (nM) from the relationship between
concentration of the added test compound and TNFa production inhibition rate of the
test compound.
The test results are shown in Table 2.
15 [0145] [Table 21
[O 1461 In the present test, compounds of the present invention demonstrated superior
inhibitory action on production of TNFa.
[O 1471 [Test Example 31
20 Inhibitory Effect on Neutrophil Infiltration of Rat Lung
A test of inhibition of neutrophil infiltration of the rat lung was performed by
partially modifying the method of Spond et al. (Pulmonary Pharmacology and
Therapeutics, 14, 157 (2001)). 25 pL (approx. 4 pglKg) of physiological saline
solution containing LPS (L28 80-500MG, manufactured by Sigma) (concentration: 0.04
25 mg1mL) was administered intratracheally under isoflurane inhalation anesthesia into SD
rats fasted for about 16 hours (males, 7-8 weeks old, body weights: 240 g to 270 g
(average: approx. 250 g), supplied by Charles River Laboratories, Japan). A
Micro sprayerTM(I A- 1C -M, manufactured by PennCentury) was used for intratracheal
administration.
[0148] Dosing solutions of the test compounds were prepared by dissolving the test
5 compounds in a 0.1 moVL or 1 mol/L aqueous sodium hydroxide solution followed by
adding medium and neutralizing (final test compound concentration: 1 mg/mL). PBS
or phosphate buffer solution (20 mM, pH = 7.4) was used for the medium. 25 pL
(approx. 0.1 mg/Kg) of the test compound solution prepared in this manner was
administered intratracheally in the same manner as LPS administration 1 hour prior to
10 administration of LPS. Medium .was administered to a control group. Furthermore, 6
animals were used in the test compound dosing groups and control group, respectively.
[0149] Bronchoalveolar lavage was performed in the manner described below 4 hours
after administration of LPS followed by collection of white blood cells present in the
lungs. The SD rats were anesthetized by intraperitoneal administration of
15 somnopentyl(1 mL/Kg) and then exsanguinated by severing the inferior vena cava.
After exposing the trachea and inserting a mouse feeding needle (manufactured by
Fuchigami Kikai) connected to a disposable syringe (5 mL, manufactured by Terumo),
the trachea was immobilized by ligation. 4 mL of physiological saline solution
containing BSA (final concentration: 1 %) and heparin (final concentration: 1 U/mL)
20 were injected and then immediately collected to obtain bronchoalveolar lavage fluid
(BALF). This procedure was then repeated twice, and after centrifuging the resulting
BALF (420xg, 10 minutes, 4OC), supernatant was removed until the amount of liquid
became 1.5 mL followed by suspending the precipitated cells to obtain a BALF cell
suspension. Measurement of the numbers of white blood cells and neutrophils in the
25 BALF cell suspension was performed according to either (Method 1) or (Method 2)
described below.
[O 1501 (Method 1)
The number of white blood cells present in the BALF suspension was
measured using a multiparameter automated hematology analyzer (KX-2 1,
30 manufactured by Sysmex). Next, the BALF suspension was diluted so that the number
of white blood cells was lo6 cells/mL, and 100 pL of this cell suspension was then
applied to a slide glass to prepare a thin layer smear. Next, after staining the cells
using the Diff-Quik staining kit (Cat. No. 16920, manufactured by Sysmex), the number
of neutrophils present among 300 white blood cells was measured under a light
35 microscope (BH-2, manufactured by Olympus) followed by calculating the ratio of
neutrophils to white blood cells (NR = the number of neutrophils among 300 white
blood cells/300). The inhibition rate of neutrophil infiltration following administration
of a test compound was calculated according to the equation indicated below.
Inhibition rate (%) = 100 - [(WBCc x NRc)/(WBCv x NRv)] x 100
WBCv: Number of white blood cells in BALF cell suspension of control group
5 WBCc: Number of white blood cells in BALF cell suspension of test
compound dosing group
NRv: Ratio of neutrophils to white blood cells of control group
NRc: Ratio of neutrophils to white blood cells of test compound dosing group
[0151] (Method2)
10 The number of neutrophils present in the BALF cell suspension was measured
using a multiparameter automated hematology analyzer (XT-2000iV, manufactured by
Sysmex). The inhibition rate of neutrophil infiltration following administration of a
test compound was calculated according to the equation indicated below.
Inhibition rate (%) = 100 - [(NEUTc)/(NEUTv)] x 100
NEUTv: Number of neutrophils in BALF cell suspension of control group
NEUTc: Number of neutrophils in BALF cell suspension of test compound
dosing group
[O 1521 In the present test, the test compounds of the present invention demonstrated
superior inhibitory action on infiltration of the lungs by neutrophils. For example, the
20 compounds of Examples 4, 14 and 16 inhibited plumonary neutrophil infiltration by
71%, 65% and 66%, respectively.
[O 1531 Representative preparation examples used in the present invention are
indicated below.
(Preparation Example 1) (Hard Capsule)
50 mg of the compound of Example 2 in powdered form, 128.7 mg of lactose,
70 mg of cellulose and 1.3 mg of magnesium stearate are mixed and passed through a
60-mesh sieve followed by placing 250 mg of this powder in a No. 3 gelatin capsule to
obtain a capsule preparation.
[O 1541 (Preparation Example 2) (Tablet)
30 50 mg of the compound of Example 2, 124 mg of lactose, 25 mg of cellulose
and 1 mg of stearic acid are mixed and formed into a tablet with a tablet-malung
machine to obtain a tablet weighing 200 mg per tablet. This tablet can be provided
with a sugar coating as necessary.
3 5 INDUSTRIAL APPLICABILITY
[0155] The substituted biaryl compound represented by general formula (I), or the
pharmacologically acceptable salt thereof, of the present invention is effective for
chronic obstructive pulmonary disease due to having an EP2 antagonistic effect and an
excellent anti-inflammatory effect. Thus, a pharmaceutical composition containing the
substituted biaryl compound represented by general formula (I), or the
5 pharmacologically acceptable salt thereof, of the present invention as an active
ingredient thereof is useful as pharmaceuticals, and especially as a therapeutic and/or
prophylactic drug (and preferably as a therapeutic drug) for chronic obstructive
pulmonary disease.
CLAIMS
1. A pharmaceutical composition for treatment andlor prevention of chronic
obstructive pulmonary disease, comprising a substituted biaryl compound represented
by 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,
pyridin-3-yl group, thiophen-2-yl group or thiophen-3-yl group
or a pharmacological acceptable salt thereof.
2. The pharmaceutical composition according to claim 1, wherein, R' represents a
carboxy group or C1-C6 alkoxycarbonyl group.
3. The pharmaceutical composition according to claim 1, wherein R' represents a
carboxy group, ethoxycarbonyl group, isopropoxycarbonyl group or hexyloxycarbonyl
group.
4. The pharmaceutical composition according to claim 1, wherein
R' represents a 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,
pyridin-3-yl group, thiophen-2-yl group or thiophen-3-yl group.
5. The pharmaceutical composition according to claim 1, wherein the substituted
biaryl compound represented by general formula (I) is:
ethyl
(6- {[3' -(I -propenyl)biphenyl-4-ylmethyl]( pyridin-2-ylsulfonyl)aminomethyl} pyridin-2-
ylamino)acetate,
(6- {[3' -(I -propenyl)biphenyl-4-ylmethyl(]p yridin-2-ylsulfonyl)aminomethyl}-
pyridin-2-y1amino)acetic acid,
ethyl
(6- {[3 ' -(1 -prop ynyl)biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl)aminomethyl } pyridin-2-
ylamino)acetate,
5 (6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl-}
pyridin-2-y1amino)acetic acid,
ethyl
(6-{ [3 ' -(1 -propynyl)biphenyl-4-ylmethyl(]p yridin-3-ylsulfonyl)aminomethyl} pyridin-2-
ylamino)acetate,
10 (6- {[3 '-(1 -propynyl)biphenyl-4-ylmethyl](pyridin-3-ylsulfonyl)aminomethyl} -
pyridin-2-y1amino)acetic acid,
{6-[(3 '- ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl]-
pyridin-2-ylamino}a cetic acid,
hexyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsu1fony1)aminomethy1]-
15 pyridin-2-ylamino}a cetate,
(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,
20 (6-[(3 '- ethoxybiphenyl-4-ylmethyl)(thiophen-2-ylsulfonyl)aminomethyl-]
pyridin-2-ylamino}a cetic acid,
(6-{ [4-(6-ethoxypyridin-2-yl)benzyl]( pyridin-2-ylsulfony1)aminomethyl)-
pyridin-2-y1amino)acetic acid,
ethyl (6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl](thiophen-2-ylsulfonyl)-
25 aminomethy1)pyridin-2-ylamino)acetate,
(6-{ [3 '-(I -propynyl)biphenyl-4-ylmethyl]( thiophen-2-ylsulfony1)-
aminomethy1)pyridin-2-y1amino)acetic acid,
ethyl (6-{ (benzenesulfonyl) [3 '-(I -propynyl)biphenyl-4-ylmethyl-]
aminomethy1)pyridin-2-ylamino)acetate,
30 (6-{ (benzenesulfonyl)[3 '-(I -propynyl)biphenyl-4-ylmethyl]aminomethyl}-
pyridin-2-y1amino)acetic acid,
ethyl (6- {[3 '-(I -propynyl)biphenyl-4-ylmethyl](thiophen-3-ylsulfonyl)-
aminomethy1)pyridin-2-ylamino)acetate,
(6-{ [3 '-(I -propynyl)biphenyl-4-ylmethyl]( thiophen-3- ylsulfonyl)-
3 5 aminomethyl} pyridin-2-y1amino)acetic acid,
(6- ((3-fluorobenzenesulfony1)[3 '-(I -propynyl)biphenyl-4-ylmethyll
aminomethyl}pyridin-2-ylamino)acetic acid, or
isopropyl
(6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate.