JPH1029979A - New pyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new pyridine derivative having excellent endothelin-1 antagonistic activity, and useful as a therapeutic agent for hypertension, Raynaud disease, myocardial infarction, stenocardia, cerebral infarction, diabetes, endotoxin shock, acute renal insufficiency, etc. SOLUTION: This new pyridine derivative (or medicinally permissible salt thereof) is shown by formula I (R<1> to R<5> are each H, a halogen, OH, amino, nitro, a lower alkyl, lower alkoxy, lower alkenyl, etc.; R<6> is an acidic functional group; R<7> to R<11> are each H, a halogen, OH, amino, nitro, a lower alkyl, lower alkoxy, etc.; R<12> is H, a halogen, OH, amino, nitro, a lower alkyl, etc.; X is O, S, etc.; Y is O, S, etc.; Z is H, OH, carboxyl, etc.; (m) is 0 or 1; (n) is an integer of 0-3) (e.g. a compound of formula II). The compound of formula I is synthesized as the starting process of reaction between the corresponding unsaturated ketone and cyanoacetamide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel pyridine derivatives and to the use of pyridine derivatives as pharmaceuticals. Hypertension, Raynaud's disease, myocardial infarction, angina,
Cerebral infarction, cerebral vasospasm, arteriosclerosis, coronary artery restenosis, bronchial asthma, gastric ulcer, acute liver failure, diabetes, prostatic hypertrophy, endoxin shock, multiple organ failure, disseminated intravascular coagulation, acute renal failure, cyclosporine-induced kidney The involvement of endothelin in pathological conditions such as disorders has been shown, and the compounds of the present invention exhibit an antagonistic action on the endothelin, whereby they can be used as therapeutics for the above-mentioned diseases.

[0002]

2. Description of the Related Art Endothelin (ET) is a polypeptide consisting of 21 amino acids produced from vascular endothelial cells, and is an in vivo factor having a strong vasoconstrictive action and a sustained and strong pressor action. Endothelin has three types of endothelins (ET
-1, ET-2, ET-3) are known to exist, among which endothelin-1 has the strongest and long-lasting action among known vasoconstrictor factors. Clinically, essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes, coronary vasospasm, cerebral vasospasm, renal failure,
In cases such as arteriosclerosis and restenosis after PTCA (percutaneous coronary angioplasty), a significant increase in blood endothelin concentration has been observed. Therefore, an antagonist capable of inhibiting the binding of endothelin to an endothelin receptor is strongly desired.

A number of peptidic or non-peptidic compounds having an antagonistic action on endothelin receptor have been disclosed (for example, EP 05105).
26A1, WO 930879 A1), none of which has been used as an actual drug.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel endothelin antagonist having excellent activity.

[0005]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have synthesized various derivatives and examined their endothelin antagonism. They have found that they have antagonistic activity, and have completed the present invention. That is, the present invention is a pyridine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, and an endothelin antagonist containing them as an active ingredient.

[0006]

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[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ may be the same or different, and any two may be combined to form a ring; atom,
Hydroxyl group, amino group, nitro group, lower alkyl group, lower alkoxy group, lower alkenyl group, lower alkylamino group, lower alkylthio group, lower alkanoyl group, hydroxy lower alkyl group, hydroxy lower alkoxy group, hydroxy lower alkenyl group, halogeno lower Alkyl group,
Represents a halogeno lower alkoxy group, a halogeno lower alkenyl group, an aryl lower alkoxy group, or an aroyl group, R ⁶ represents an acidic functional group, and R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ and R ¹¹ may be the same or different, and any two of them may combine to form a ring, and include a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a lower alkyl group, and a lower alkoxy group. Group, lower alkenyl group, lower alkylamino group, lower alkylthio group, lower alkanoyl group, hydroxy lower alkyl group, hydroxy lower alkoxy group, hydroxy lower alkenyl group, halogeno lower alkyl group, halogeno lower alkoxy group, halogeno lower alkenyl group, aryl Represents a lower alkoxy group or an aroyl group, R ¹² is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a lower alkyl group,
Lower alkoxy group, lower alkenyl group, lower alkylamino group, lower alkylthio group, lower alkanoyl group, hydroxy lower alkyl group, hydroxy lower alkoxy group, hydroxy lower alkenyl group, halogeno lower alkyl group, halogeno lower alkoxy group, halogeno lower alkenyl group , An aryl lower alkoxy group, an aroyl group, an aryl group, a heteroaryl group, or a heterocyclylcarbonyl group. X is the following formula (2)-
(5)

[0008]

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(However, R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different and each represents a hydrogen atom or a lower alkyl group.) Y is any of the following formulas (6) to (9) Represent

[0010]

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(However, R ¹⁶ , R ¹⁷ , and R ¹⁸ may be the same or different and each represents a hydrogen atom or a lower alkyl group.) Z is a hydrogen atom, a hydroxyl group, a carboxyl group, a lower alkoxy group. Carbonyl group, aryloxycarbonyl group, heteroaryloxycarbonyl group, alkylcarbamoyl group, arylcarbamoyl group, heteroarylcarbamoyl group, amino group, alkylamino group, arylamino group, heteroarylamino group, acylamino group or the following formula (10 ) To (15).

[0012]

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(However, R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ ,
^{R 24, R 25, R 26} , R 27, and R ²⁸ may be the same or different and each represents any of a hydrogen atom, a lower alkyl group, an aryl group, a heteroaryl group, Here, R ¹⁹ And R ²⁰ , R ²¹ and R ²² , R ²¹ and R ²³ , R ²²
And R ²³ or R ²⁵ and R ²⁶ may combine to form a ring. M) represents an integer of 0 or 1, and n represents an integer of 0 to 3. ]

The halogen atom in the present invention is fluorine,
Chlorine, bromine, iodine, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, a lower alkylamino group,
In the lower alkylthio group, the lower alkanoyl group, the hydroxy lower alkyl group, the hydroxy lower alkoxy group, the hydroxy lower alkenyl group, the halogeno lower alkyl group, the halogeno lower alkoxy group, the halogeno lower alkenyl group, and the aryl lower alkoxy group, lower is the number of carbon atoms. Represents a group of 1 to 6. The alkyl group as a component of the alkyl group, the alkoxy group, the alkenyl group, the alkylamino group, the alkylthio group, and the alkanoyl group may be linear or branched. Furthermore, the alkyl group mentioned here may be specifically exemplified by a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a secondary and a tertiary butyl group, and the like. The aryl group in the aryl lower alkoxy group is phenyl or a substituted phenyl group, and halogen, alkyl, and alkoxy are particularly considered as the substituent. Specific examples include a benzyloxy group and the like. Specific examples of the aroyl group include a benzoyl group and a pyridylcarbonyl group.

Specific examples of the acidic functional group in the present invention include a carboxyl group, SO ₃ H, PO ₃ H ₂ , tetrazol-5-yl group, sulfonamide group, 2-oxo-3H-1, 2,3,5-oxathiadiazole-4-
Examples thereof include, but are not limited to, an yl group and a 5-oxo-4H-1,2,4-oxadiazol-3-yl group. Further, the heteroaryl group refers to a monocyclic or polycyclic 5- and 6-membered heteroaromatic group having nitrogen, oxygen or sulfur as a hetero atom, specifically, a pyridyl group, Examples include a pyrimidyl group, a furanyl group, a thienyl group, and a quinolyl group.

In the compound of the present invention represented by the general formula (1), R ⁶ is a carboxyl group or a tetrazol-5-yl group, m = n = 1, and Y is the above-mentioned general formula (9) A pyridine derivative or a pharmaceutically acceptable salt thereof, wherein R ¹⁷ and R ¹⁸ are both hydrogen atoms, has high activity.

The pyridine derivative of the present invention can be produced by the following steps.

[0018]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and X are the same as described above. )

That is, by treating an unsaturated ketone (16) and cyanoacetamide in an oxygen stream, for example, in the presence of a base such as potassium t-butoxide, the pyridone (1) is obtained.
7) can be obtained. When the obtained pyridone is treated with a chlorinating agent such as phosphorus oxychloride, for example, 2
A chloropyridine ring (18) can be constructed. Further, the compound (20) can be obtained by treating the obtained 2-chloropyridine ring (18) and, for example, phenol (19) in the presence of a base such as sodium hydride.
For example, when R ⁶ is a tetrazol-5-yl group, the cyano group of (20) is heated in, for example, tributyltin azide and toluene to obtain a compound represented by the general formula (1) of the present invention. A pyridine derivative (21) in which m = n = 0 and Z is a hydrogen atom can be produced.

Unsaturated ketones (16) used as starting materials can be produced by a method as shown in the following scheme if they are not known. For example, the aryl aldehyde (22) and methyl ketone (23) can be produced by using an appropriate base and aldol-type condensation.

[0022]

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Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same as above.

As for the synthesis of a derivative having a substituent at the 5-position of the pyridine ring, for example, pyridone (17) obtained as an intermediate in the above reaction is halogenated with N-bromosuccinimide (hereinafter abbreviated as NBS) or the like. When treated with the agent,
As shown in the following formula, the 5-position of the pyridone ring is easily halogenated, and the pyridine ring (24) can be constructed by the same steps as described above.

[0025]

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When a reaction such as Heck reaction is performed on the obtained pyridine ring (24), various substituents can be introduced at the 5-position of the pyridine ring as shown in the following formula. Thereafter, the desired derivative can be obtained by appropriately converting the substituent. Then, the compound (1) of the present invention can be obtained by converting a cyano group into an acidic group in the same manner as described above.

[0027]

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The compound of the present invention represented by the general formula (1) and a salt thereof thus produced can be obtained by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, and inversion. It can be isolated and purified by dissolution, chromatography and the like.

The salt of the compound of the present invention may be in any form as long as it is pharmaceutically acceptable. Examples thereof include salts with organic amines such as salts, aluminum salts, zinc salts, morpholine and piperidine, and salts with basic amino acids such as arginine and lysine.

The compound of the present invention or a salt thereof may be administered as it is or as various pharmaceutical compositions. The dosage form of such a pharmaceutical composition may be, for example, a tablet, sprinkle, pill, granule, capsule, suppository, solution, dragee, or depot, using common formulation auxiliaries. It can be manufactured according to the usual method. For example, tablets may be prepared by converting the pyridine derivative, which is the active ingredient of the present invention, into a known auxiliary substance, such as lactose, an inert diluent such as calcium carbonate or calcium phosphate, a binder such as acacia, corn starch or gelatin, alginic acid, corn starch, or corn starch. It is obtained by mixing with a leavening agent such as gelatinized starch, a sweetening agent such as sucrose, lactose or saccharin, a flavoring agent such as peppermint, reddish oil or cherry, a lubricating agent such as magnesium stearate, talc or carboxymethylcellulose. .

Endothelin antagonists containing the compound of the present invention or a salt thereof as an active ingredient include hypertension, Raynaud's disease, myocardial infarction, angina, cerebral infarction, cerebral vasospasm, arteriosclerosis, coronary artery restenosis, bronchial asthma, Gastric ulcer, acute liver failure, diabetes,
It can be used as a therapeutic agent for prostatic hypertrophy, endoxin shock, multiple organ failure, disseminated intravascular coagulation, acute renal failure, and cyclosporine-induced renal damage.

The dose used for the above purpose is determined depending on the intended therapeutic effect, administration method, treatment period, age, body weight, etc., and is usually administered by the oral or parenteral route per adult day. The amount is 1 μg to 5 g for oral administration and 0.01 μg to 1 for parenteral administration.
Use g.

[0033]

The present invention will be described in detail with reference to the following examples. These are preferred embodiments of the present invention and are not limited to these examples.

Example 1 Synthesis of 6-butyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) 1- (4-methoxyphenyl) -3-oxo-1
Synthesis of Heptanol Under argon atmosphere, 10 ml of a 1 M hexane solution of lithium bistrimethylsilylamide is added to 20 ml of tetrahydrofuran (hereinafter abbreviated as THF) at -70 ° C. 2-
Hexanone 1.23 ml (10.0 mmol) in THF
10 ml solution is added dropwise and stirred for 10 minutes. After adding 1.20 ml (9.9 mmol) of p-anisaldehyde and stirring for 30 minutes, 1N hydrochloric acid is added to terminate the reaction. Extract with ethyl acetate and wash with saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 4 to 1: 3) to give the title compound. Yield: 1.50 g, Yield: 63.5% MS (ESI, m / z) 259.2 (M + Na) H-NMR (CDCl3): 0.90 (3H, t), 1.29 (2H, sex), 1.55 ( Two
H, quint), 2.45 (2H, t), 2.79 (1H, d), 2.80 (1H,
d), 3.22 (1H, d), 3.80 (3H, s), 5.10 (1H, m), 6.86
(2H, d), 7.30 (2H, d)

2) 1- (4-methoxyphenyl) -1-
Synthesis of hepten-3-one 1.50 g (6.4 mmol) of 1- (4-methoxyphenyl) -3-oxo-1-heptanol was added to toluene 1
The mixture was dissolved in 00 ml, and anhydrous magnesium sulfate (3.0 g) was added. After cooling, the mixture is filtered and the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 5) to give the title compound. Yield: 1.50 g, yield: quantitative MS (ESI, m / z) 219 (MH +) H-NMR (CDCl3): 0.90 (3H, t), 1.38 (2H, sex), 1.68
(2H, quint), 2.62 (2H, t), 3.82 (3H, s), 6.62 (1H,
d), 6.90 (2H, d), 7.55 (2H, d), 7.56 (1H, d)

3) 6-butyl-3-cyano-4- (4-
Synthesis of 1- (4-methoxyphenyl) -1-hepten-3-one 1.20 g (5.5 mmol), 510 mg (6.1 mmol) of cyanoacetamide, 2.50 g of potassium t-butoxy A solution of (22.3 mmol) in 12 ml of dimethylsulfoxide (hereinafter abbreviated as DMSO) is stirred at room temperature for 2 hours under an oxygen atmosphere. The reaction solution generates heat and turns black.
The reaction is stopped with 1N hydrochloric acid and extracted with ethyl acetate. The extract is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1), and the obtained crystals were washed with ethyl acetate: hexane 1: 1 to give the title compound. Yield: 340 mg, yield: 21.9% MS (FAB, m / z) 283 (MH +) H-NMR (CDCl3): 0.99 (3H, t), 1.45 (2H, sex), 1.72
(2H, quint), 2.70 (2H, t), 3.86 (3H, s), 6.25 (1H,
s), 7.04 (2H, d), 7.85 (2H, d)

4) 6-butyl-3-cyano-4- (4-
Synthesis of methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 6-butyl-3-cyano-4- (4-methoxyphenyl) -2-pyridone 240 mg (0.85 mmol) was added to phosphorus oxychloride Dissolve in 5 ml and stir at 80 ° C. overnight.
The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 5 ml of dimethylethylformamide (hereinafter abbreviated as DMF), and 130 mg of sesamol (0.94 mmol) was separately added.
l), a solution of phenoxide ion prepared from 70 mg of sodium hydride (60% oil dispersion, 1.8 mmol) in 5 ml of DMF and added under an argon atmosphere.
Stir for hours. Ice water is added to stop the reaction, and the mixture is extracted with ethyl acetate. The extract is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 4) to give the title compound (50 mg, 14.6).
%). Separately, 140 mg is obtained as a difficult-to-separate mixture with sesamol. Yield: 50 mg, Yield: 14.6% MS (FAB, m / z) 403 (MH +) H-NMR (CDCl3): 0.88 (3H, t), 1.30 (2H, sex), 1.61
(2H, quint), 2.65 (2H, t), 3.88 (3H, s), 6.01 (2H,
s), 6.67 (1H, dd), 6.75 (1H, d), 6.81 (1H, d), 6.95
(1H, s), 7.04 (2H, d), 7.62 (2H, d)

5) Synthesis of 6-butyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6-butyl-3-cyano-4- (4 -Methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine (60 mg, 0.15 mmol) was dissolved in benzene, and 0.5 ml (0.5 mmo) of a 1 M solution of diisobutylaluminum hydride in hexane was added at room temperature under an argon atmosphere.
1) is added dropwise. Stir at room temperature for 30 minutes and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 1 hour, and the insoluble matter is filtered using celite. The filtrate was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to give 6-butyl-4- (4-
Methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde was obtained. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 52 mg MS (FAB, m / z) 406 (MH +) H-NMR (CDCl3): 0.88 (3H, t), 1.30 (2H, sex) 1.60 (2H, quint), 2.63 (2H, t), 3.88 (3H, s), 6.02
(2H, s), 6.63 (1H, dd), 6.73 (1H, d), 6.79 (1H,
s), 6.82 (1H, d), 6.98 (2H, d), 7.34 (2H, d), 10.24
(1H, s)

6) Synthesis of 6-butyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6-butyl-4- (4-methoxyphenyl) ) -2-
52 mg of (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde was added to 0.8 ml of methylene chloride,
Dissolve in 0.4 ml of water, and at 0 ° C., 0.1 m (0.94 mmol) of 2-methyl-2-butene, 20 mg of amidosulfuric acid
(0.21 mmol), 50 mg sodium chlorite
(0.44 mmol) is added and the mixture is returned to room temperature and stirred for 10 minutes. Extract with ethyl acetate, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The obtained residue is subjected to silica gel thin layer chromatography (chloroform: methanol).
9: 1) to give the title compound. Yield: 17 mg, Yield: 26.9% MS (FAB, m / z): 422 (MH +) H-NMR (CDCl3): 0.88 (3H, t), 1.30 (2H, sex), 1.59
(2H, quint), 2.62 (2H, t), 3.81 (3H, s), 5.97 (2H,
s), 6.61 (1H, dd), 6.72 (1H, d), 6.75 (1H, d), 6.85
(1H, s), 6.93 (2H, d), 7.41 (2H, d)

Example 2 Synthesis of 6-butyl-4- (3,4-methylenedioxyphenyl) -2- (4-methoxyphenoxy) pyridine-3-carboxylic acid 1) 1- (3,4-Methylenedioxy) Oxyphenyl) -1
Synthesis of 1-ml of a 1M hexane solution of lithium bistrimethylsilylamide in an argon atmosphere at -70 ° C in THF
Add to 20 ml. 1.23 ml of 2-hexanone (1
(0.0 mmol) in 10 ml of THF is added dropwise and stirred for 40 minutes. Piperonal 1.50ml (10.0mm
ol) and stirred for 1 hour, and then water was added to stop the reaction. Extract with ethyl acetate and wash with saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1) to give 1- (3,4-methylenedioxyphenyl) -3-oxo-1-heptanol as a mixture with piperonal. The obtained alcohol is dissolved in 20 ml of toluene, 4 g of anhydrous magnesium sulfate is added, and the mixture is stirred at 110 ° C. overnight. The insolubles were filtered and the solvent was distilled off under reduced pressure. The obtained crystals were washed with ethyl acetate: hexane 1: 3 to obtain the title compound. Yield: 1.00 g, yield: 43.1% MS (ESI, m / z) 233 (MH +) H-NMR (CDCl3): 0.90 (3H, t), 1.38 (2H, sex), 1.66
(2H, quint), 2.62 (2H, t), 6.01 (2H, s), 6.58 (1H,
d), 6.83 (1H, d), 7.05 (2H, m), 7.48 (1H, d)

2) 6-butyl-3-cyano-4- (3,
Synthesis of 4-methylenedioxyphenyl) -2-pyridone Cyanoacetamide 360m at room temperature under argon atmosphere
g (4.3 mmol), potassium tert-butoxide 480 m
g (4.3 mmol) in 10 ml of DMSO
1.0 g (4.3 mmol) of (3,4-methylenedioxyphenyl) -1-hepten-3-one is added and stirred for 20 minutes. 1.45 g of potassium t-butoxide (12.
9 mmol) and bubbling oxygen for 1 minute. After stirring for 1 hour in an oxygen atmosphere, water and 1N hydrochloric acid are added under ice cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 850 mg, 66.7% MS (FAB, m / z) 297 (MH +) H-NMR (CDCl3): 0.98 (3H, t), 1.45 (2H, sex), 1.73
(2H, quint), 2.70 (2H, t), 6.06 (2H, s), 6.26 (1H,
s), 6.92 (1H, d), 7.10 (1H, d), 7.18 (1H, dd)

3) 6-butyl-3-cyano-4- (3,
Synthesis of 4-methylenedioxyphenyl) -2- (4-methoxyphenyloxy) pyridine 6-butyl-3-cyano-4- (3,4-methylenedioxyphenyl) -2-pyridone 850 mg (2.9 m
mol) dissolved in 6 ml of phosphorus oxychloride and stirred at 90 ° C. overnight. The residue obtained by distilling off phosphorus oxychloride under reduced pressure was dissolved in 10 ml of DMF, and 4-methoxyphenol 3 was separately added.
60 mg (2.9 mmol), sodium hydride 140
mg (60% oil dispersion, 3.5mmo
l) The solution was added to a solution of phenoxide ion prepared in 1) in 5 ml of DMF, and stirred for 1.5 hours under an argon atmosphere. The solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to give the title compound. Yield: 760 mg, yield: 65.1% MS (ESI, m / z) 403 (MH +) H-NMR (CDCl3): 0.85 (3H, t), 1.30 (2H, sex), 1.58
(2H, quint), 2.63 (2H, t), 3.85 (3H, s), 6.06 (2H,
s), 6.78 (1H, s), 6.90 (4H, m), 7.15 (3H, m)

4) 6-butyl-4- (3,4-methylenedioxyphenyl) -2- (4-methoxyphenoxy)
Synthesis of pyridine-3-aldehyde 6-butyl-3-cyano-4- (3,4-methylenedioxyphenyl) -2- (4-methoxyphenoxy) pyridine 760 mg (1.9 mmol) in benzene 20 ml
And 5.0 ml of a 1 M solution of diisobutylaluminum hydride in hexane (5.0 mmol) at room temperature under an argon atmosphere.
1) is added dropwise. Stir at room temperature for 2.5 hours and stop the reaction with methanol and water. The mixture is stirred at room temperature for 30 minutes, and the insoluble matter is filtered using Celite. The filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to obtain the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 520 mg MS (FAB, m / z) 406 (MH +)

5) 6-butyl-4- (3,4-methylenedioxyphenyl) -2- (4-methoxyphenoxy)
Synthesis of pyridine-3-carboxylic acid 6-butyl-4- (3,4-methylenedioxyphenyl) -2- (4-methoxyphenoxy) pyridine-3-
520 mg of aldehyde was added to 8 ml of methylene chloride and 4 ml of water.
Dissolved at 0 ° C. in 0.2 m 2-methyl-2-butene
(1.9 mmol), 760 mg of amidosulfuric acid (7.8 m
mol), 520 mg of sodium chlorite (4.5 mm
ol) and the mixture is returned to room temperature and stirred for 30 minutes. The mixture is extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (chloroform: methanol 50: 1) to give the title compound. Yield: 180 mg, Yield: 32.9% MS (FAB, m / z) 422 (MH +) H-NMR (CDCl3): 0.83 (3H, t), 1.25 (2H, sex), 1.55
(2H, quint), 2.58 (2H, t), 3.79 (3H, s), 5.90 (2H,
s), 6.65-7.05 (8H, m)

Example 3 Synthesis of 6-butyl-4- (4-methoxyphenyl) -2- (4-methoxyphenyloxy) pyridine-3-carboxylic acid 1) 6-butyl-3-cyano-4- (4 Synthesis of 6-butyl-3-cyano-4- (4-methoxyphenyl) -2-pyridone 1.0 g (3.5 mmol) in 10 ml of phosphorus oxychloride Stir overnight.
The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound. This was used for the following reaction without purification. Yield: 1.00 g MS (FAB, m / z) 301 (MH +) H-NMR (CDCl3): 0.95 (3H, t), 1.45 (2H, sex), 1.75
(2H, quint), 2.85 (2H, t), 3.88 (3H, s), 7.05 (2H,
d), 7.20 (1H, s), 7.58 (2H, d)

2) 6-butyl-3-cyano-4- (4-
Synthesis of methoxyphenyl) -2- (4-methoxyphenyloxy) pyridine 130 mg (0.94 mmol) of sesamol, 70 mg of sodium hydride (60% oil dispersion,
D) of phenoxide ion prepared from 1.8 mmol)
6-butyl-3-cyano-4- (4-
(Methoxyphenyl) -2-chloropyridine (500 mg) is dissolved in DMF (10 ml), and the mixture is stirred under an argon atmosphere for 2 hours. The solvent is distilled off under reduced pressure, the residue is dissolved in ether, and washed with water, 1N sodium hydroxide solution and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to give the title compound. Yield: 420 mg, Yield: 6-butyl-3-cyano-4
From-(4-methoxyphenyl) -2-pyridone 61.
8% MS (FAB, m / z) 389 (MH +) H-NMR (CDCl3): 0.85 (3H, t), 1.30 (2H, sex), 1.59
(2H, quint), 2.65 (2H, t), 3.84 (3H, s), 3.88 (3
H, s), 6.92 (2H, d), 6.92 (1H, s), 7.04 (2H, d), 7.
14 (2H, d), 7.61 (2H, d)

3) Synthesis of 6-butyl-4- (4-methoxyphenyl) -2- (4-methoxyphenyloxy) pyridine-3-aldehyde 6-butyl-3-cyano-4- (4-methoxyphenyl) -2- (4-methoxyphenyloxy) pyridine 2
00 mg (0.51 mmol) is dissolved in 5 ml of benzene, and 1.5 ml (1.5 mmol) of a 1M solution of diisobutylaluminum hydride in hexane is added dropwise at room temperature under an argon atmosphere. Stir at room temperature for 2 hours and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 1 hour, and the insoluble matter is filtered using celite. The filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to obtain the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 190 mg MS (FAB, m / z) 392 (MH +)

4) Synthesis of 6-butyl-4- (4-methoxyphenyl) -2- (4-methoxyphenyloxy) pyridine-3-carboxylic acid 6-butyl-4- (4-methoxyphenyl) -2-carboxylic acid (4
-Methoxyphenyloxy) pyridine-3-aldehyde 190 mg was dissolved in methylene chloride 2 ml and water 1 ml,
At 0 ° C., 0.3 m of 2-methyl-2-butene (2.8 mmol)
l), 70 mg (0.72 mmol) of amidosulfuric acid and 200 mg (1.8 mmol) of sodium chlorite are added, and the mixture is returned to room temperature and stirred for 30 minutes. The mixture is extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform: methanol 9: 9).
1) to give the title compound. Yield: 85 mg, Yield: 6-butyl-3-cyano-4-
40.9% MS (ESI, m / z) 408 (MH +) H-NMR (CDCl3) from (4-methoxyphenyl) -2- (4-methoxyphenyloxy) pyridine: 0.82 (3H, t), 1.25 ( 2H, sex), 1.50
(2H, quint), 2.52 (2H, t), 3.60 (3H, s), 3.75 (3H,
d), 6.70 (4H, m), 6.90 (2H, m), 7.35 (3
H, m)

Example 4 4- (4-methoxyphenyl)
-2- (3,4-methylenedioxyphenoxy) -6-
Synthesis of pentylpyridine-3-carboxylic acid 1) Synthesis of 1- (4-methoxyphenyl) -3-oxooctanol -7 was added to 40 ml of THF and 24 ml (24.0 mmol) of 1M lithium bistrimethylsilylamide in THF solution.
At 8 ° C, 2.8 ml (20.1 mmol) of hept-2-one dissolved in 20 ml of THF was added dropwise over 30 minutes. 10 minutes after completion of the dropwise addition, 2.45 m of p-anisaldehyde
1 (20.1 mmol) was added and the mixture was stirred at -78 ° C for 1.5 hours. The reaction was stopped with 15 ml of 2N hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 2.99 g (11.9 mmol), yield: 59.
4% H-NMR (CDCl3): 0.86-0.91 (3H, t), 1.21-1.
35 (4H, m), 1.53-1.64 (2H, m), 2.39-2.46 (2H, t), 2.72-
2.90 (2H, m), 3.23-3.25 (2H, d), 3.80 (3H, s), 5.07-5.14
(1H, m), 6.86-6.90 (2H, d), 7.26-7.30 (2H, d)

2) 1- (4-methoxyphenyl) -1-
Synthesis of octen-3-one 1- (4-methoxyphenyl)-in 80 ml of toluene
2.06 g of 3-oxooctanol (8.23 mmol
l) and anhydrous magnesium sulfate 4.07 g (33.8 mm
ol) was refluxed for 3 hours. After filtration and washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 1.69 g (7.27 mmol), Yield: 88.
3% MS (ESI, m / z) 233 (MH +) H-NMR (CDCl3): 0.88-0.93 (3H, t), 1.28-1.40 (2H, m), 1.
63-1.74 (2H, m), 2.60-2.66 (2H, t), 3.84 (3H, s), 6.60-
6.66 (1H, d), 6.89-6.93 (2H, d), 7.47-7.55 (3H, m)

3) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-pentyl-2-pyridone 506 mg of cyanoacetamide in 10 ml of DMSO.
(6.02 mmol) to 669 m of potassium t-butoxide
g (5.96 mmol) and then 1- (4-methoxyphenyl) -1-octene-3- dissolved in 5 ml of DMSO.
Add 1.40 g (6.01 mmol) of ON and add 20 at room temperature.
Stirred for minutes. 2.13 g of potassium t-butoxide (1
After adding 9.0 mmol), oxygen gas was bubbled for 1 minute, and the mixture was further stirred at room temperature under an atmospheric oxygen atmosphere for 1 hour.
2N Hydrochloric acid was added, and the precipitated crystals were collected by filtration, washed with water and hexane, and dried under reduced pressure to obtain the title compound. Yield: 1.42 g (4.79 mmol), yield: 79.
7% MS (ESI, m / z) 297 (MH +) H-NMR (CDCl3): 0.89-0.94 (3H, t), 1.37-1.42 (4H, m), 1.
71-1.83 (2H, m), 2.68-2.73 (2H, t), 3.88 (3H, s), 6.26 (1
H, s), 7.00-7.03 (2H, d), 7.60-7.63 (2H, d)

4) 2-chloro-3-cyano-4- (4-
Synthesis of (methoxyphenyl) -6-pentylpyridine 3-cyano-4- (4-methoxyphenyl) -6-pentyl-2-pyridone was added to 1.27 g (4.29 mmol) of phosphorus oxychloride in 15 ml and N, N-dimethylaniline. Add 0.55 ml (4.34 mmol) and add 4 at 100 ° C.
Heated for hours. After distilling off phosphorus oxychloride, water was added thereto, and the mixture was extracted with ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used for the next reaction without purification. Yield: 1.27 g (4.03 mmol), yield: 93.
9% MS (ESI, m / z) 315 (MH +) H-NMR (CDCl3): 0.87-0.94 (3H, t), 1.32-1.41 (4H, m), 1.
70-1.83 (2H, m), 2.80-2.86 (2H, t), 3.88 (3H, s), 7.02-
7.06 (2H, d), 7.18 (1H, s), 7.55-7.58 (2H, d)

5) 3-cyano-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy)
Synthesis of -6-pentylpyridine Sesamol 322 mg (2.33 m
mol) and 120 mg of 60% sodium hydride (3.0
mmol) and stirred at room temperature for 15 minutes. 705 mg (2.24 mmol) of 2-chloro-3-cyano-4- (4-methoxyphenyl) -6-pentylpyridine was added to DM
The resultant was dissolved in F1 ml and added dropwise, followed by stirring at room temperature for 4 hours. After distilling off DMF under reduced pressure, 1N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 0.62 g (1.49 mmol), yield: 66.
5% MS (FAB, m / z) 417 (MH +) H-NMR (CDCl3): 0.83-0.89 (3H, t), 1.22-1.34 (4H, m), 1.
56-1.68 (2H, m), 2.62-2.68 (2H, t), 3.88 (3H, s), 6.01 (2
H, s), 6.62-6.82 (3H, m), 6.93 (1H, s), 7.02-7.05 (2H,
d), 7.59-7.62 (2H, d)

6) 4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenoxy) -6-pentylpyridine-3-aldehyde 3-cyano-4- (4-methoxyphenyl) -2-
210 mg (0.50 mmol) of (3,4-methylenedioxyphenoxy) -6-pentylpyridine are dissolved in 5 ml of benzene, and 1.5 ml (1.5 mmol) of a 1M solution of diisobutylaluminum hydride in hexane is added at room temperature for 3 hours at room temperature. Stirred. 0.2 ml of methanol, 1 m of water
was added and stirred for 20 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 176 mg (0.42 mmol), yield: 83.
2% H-NMR (CDCl3): 0.82-0.90 (3H, t), 1.22-1.33 (4H, m), 1.
56-1.67 (2H, m), 2.56-2.67 (2H, m), 3.87 (3H, s), 6.00 (2
H, s), 6.63-6.84 (4H, m), 6.97-7.00 (2H, d), 7.30-7.33
(2H, d), 10.24 (1H, s, CHO)

7) 4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenoxy) -6-pentylpyridine-3-carboxylic acid 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) in 2 ml of methylene chloride and 1 ml of water 169 m of -6-pentylpyridine-3-aldehyde
g (0.43 mmol) in an ice bath, 0.3 ml (2.83 mmol) of 2-methyl-2-butene, 100 g of amidosulfuric acid
mg (1.03 mmol), sodium chlorite 205
mg (2.27 mmol) was added and the mixture was stirred at room temperature for 20 minutes. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (chloroform: methanol 9: 9).
Purification in 1) gave the title compound. Yield: 76 mg (0.17 mmol), yield: 43.1
% MS (ESI, m / z) 436 (MH +) H-NMR (CDCl3), 0.80-0.86 (3H, t), 1.23-1.32 (4H, m), 1.
45-1.60 (2H, m), 2.49-2.55 (2H, t), 3.55 (3H, s), 5.85 (2
H, s), 6.36-6.71 (6H, m), 7.27-7.34 (2H, m)

Example 5 4- (4-methoxyphenyl)
-2- (3,4-Methylenedioxyphenyl) -6-pentylpyridine-3-carboxylic acid 1) 3-cyano-4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenyl) -6-pentylpyridine 2-chloro-3-cyano-4- (4-methoxyphenyl) -6-pentylpyridine 547 mg (1.74 mm
ol), 5 ml of DME and 62 mg (0.05 mmol) of tetrakis (triphenylphosphine) palladium were added, and the mixture was stirred at room temperature for 30 minutes. 314 mg of 3,4-methylenedioxyphenylboric acid suspended in 3 ml of DME
(1.89 mmol), 2.5 ml of a 2M aqueous solution of sodium carbonate was added, and the mixture was refluxed for 7.5 hours. Water and ether were added, the mixture was filtered through celite, the filtrate was extracted with ether, and the organic layer was washed with a 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane: ethyl acetate 6:
Purification in 1) gave the title compound. Yield: 659 mg (1.65 mmol), yield: 94.
6% MS (FAB, m / z) 401 (MH +) H-NMR (CDCl3): 0.89-0.95 (3H, t), 1.35-1.43 (4H, m), 1.
75-1.86 (2H, m), 2.86-2.94 (2H, m), 3.88 (3H, s), 6.04 (2
H, s), 6.92-6.95 (1H, d), 7.03-7.06 (2H, d), 7.17 (1H,
s), 7.37-7.48 (2H, m), 7.57-7.60 (2H,
d)

2) 4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenyl) -6-pentylpyridine-3-aldehyde 3-cyano-4- (4-methoxyphenyl) -2-
289 mg (0.72 mmol) of (3,4-methylenedioxyphenyl) -6-pentylpyridine was added to benzene 7
disodium diisobutylaluminum 1 at room temperature
2.2 ml (2.2 mmol) of M hexane solution was added, and the mixture was stirred at room temperature for 3 hours. 0.3 ml of methanol, 1.5 of water
ml was added and stirred for 20 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 148 mg (0.37 mmol), yield: 50.
9% MS (ESI, m / z) 404 (MH +) H-NMR (CDCl3): 0.88-0.96 (3H, t), 1.32-1.44 (4H, m), 1.
74-1.87 (2H, m), 2.86-2.91 (2H, m), 3.87 (3H, s), 6.03 (2
H, s), 6.87-7.00 (4H, m), 7.09-7.14 (2H, m), 7.29-7.36
(2H, m), 9.95 (1H, s)

3) 4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenyl) -6-pentylpyridine-3-carboxylic acid 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyl) in 2 ml of methylene chloride and 1 ml of water
144 mg of -6-pentylpyridine-3-aldehyde
(0.36 mmol), 0.3 ml (2.83 mmol) of 2-methyl-2-butene in an ice bath, 100 m of amidosulfuric acid
g (1.03 mmol), sodium chlorite 206 m
g (2.28 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (chloroform: methanol 50:
Purification in 1) gave the title compound. Yield: 108 mg (0.26 mmol), yield: 72.
1% MS (ESI, m / z) 420 (MH +) H-NMR (CDCl3): 0.88-0.94 (3H, t), 1.32-1.43 (4H, m), 1.
72-1.85 (2H, m), 2.82-2.88 (2H, t), 3.85 (3H, s), 5.99 (2
H, s), 6.80-6.83 (1H, d), 6.93-6.96 (2H, d), 7.08 (1H,
s), 7.09-7.17 (2H, m), 7.36-7.39 (2H, d)

Example 6 4- (4-methoxyphenyl)
-2- (3,4-methylenedioxyphenoxy) -6-
Synthesis of propylpyridine-3-carboxylic acid 1) Synthesis of 1- (4-methoxyphenyl) -3-oxohexanol THF 30 ml, lithium bistrimethylsilylamide 1M-THF solution 18 ml at -78 ° C THF 15 ml
1.60 ml of pentan-2-one (15.1) dissolved in
mmol) was added dropwise over 15 minutes. 10 minutes after the end of dropping
-Anisaldehyde 1.80 ml (14.8 mmol)
Was added and stirred at -78 ° C for 1.5 hours. 2N hydrochloric acid 15
The reaction was quenched with ml, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane: ethyl acetate 6:
Purification in 1) gave the title compound. Yield: 2.40 g (10.8 mmol) Yield: 73.0
% H-NMR (CDCl3): 0.89-0.94 (3H, t), 1.58-1.68 (2H, m), 2.
38-2.43 (2H, t), 2.71-2.85 (2H, m), 3.23-3.24 (1H, d),
3.80 (3H, s), 5.08-5.15 (1H, m), 6.86-6.89 (2H, d), 7.26
-7.29 (2H, d)

2) 1- (4-methoxyphenyl) -1-
Synthesis of hexen-3-one 1- (4-methoxyphenyl)-in 70 ml of toluene
2.40 g of 3-oxohexanol (10.8 mmol
l) and 3.98 g (33.1 mm) of anhydrous magnesium sulfate
ol) was refluxed for 2 hours. After filtration and washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The residue was used for the next reaction without purification. Yield: 2.19 g (10.7 mmol), yield: 99.
1% MS (ESI, m / z) 205 (MH +) H-NMR (CDCl3): 0.95-1.01 (3H, t), 1.64-1.78 (2H, m), 2.
59-2.65 (2H, t), 3.84 (3H, s), 6.60-6.66 (1H, d), 6.90-
6.93 (2H, d), 7.49-7.54 (3H, m)

3) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-propyl-2-pyridone 905 mg of cyanoacetamide in 20 ml of DMSO
(10.8 mmol) to potassium t-butoxide 1.20
1 g (10.7 mmol) and then 1- (4-methoxyphenyl) -1-hexene-3 dissolved in 5 ml of DMSO.
-One (1.88 g, 10.7 mmol) was added at room temperature.
Stirred for 0 minutes. 3.71 g of potassium t-butoxide (3
After adding 3.1 mmol), oxygen gas was bubbled for 2 minutes, and the mixture was further stirred for 1 hour at room temperature under a normal pressure oxygen atmosphere.
2N Hydrochloric acid was added, and the precipitated crystals were collected by filtration, washed with water and hexane, and dried under reduced pressure to obtain the title compound. Yield: 1.80 g (6.71 mmol), yield: 62.
7% MS (ESI, m / z) 269 (MH +) H-NMR (CDCl3): 1.01-1.07 (3H, t), 1.77-1.85 (2H, m), 2.
67-2.73 (2H, t), 3.88 (3H, s), 6.26 (1H, s), 7.00-7.03 (2
H, d), 7.60-7.63 (2H, d)

4) 2-chloro-3-cyano-4- (4-
Synthesis of methoxyphenyl) -6-propylpyridine To 1.78 g (6.63 mmol) of 3-cyano-4- (4-methoxyphenyl) -6-propyl-2-pyridone were added 30 ml of phosphorus oxychloride and N, N-dimethylaniline. Add 0.90 ml (7.10 mmol) and add 2 at 100 ° C.
Heated for hours. After distilling off phosphorus oxychloride, water was added thereto, and the mixture was extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was used for the next reaction without purification. Yield: 1.59 g (5.55 mmol), yield: 83.
8% MS (ESI, m / z) 287 (MH +) H-NMR (CDCl3): 0.97-1.03 (3H, t), 1.73-1.87 (2H, m), 2.
79-2.84 (2H, t), 3.88 (3H, s), 7.02-7.05 (2H, d), 7.55-
7.58 (2H, d)

5) 3-cyano-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy)
Synthesis of -6-propylpyridine In 15 ml of DMF, 440 mg of sesamol (3.18 m
mol) and 60 mg of sodium hydride (160 mg, 4.0%).
mmol) and stirred at room temperature for 15 minutes. 875 mg (3.05 mmol) of 2-chloro-3-cyano-4- (4-methoxyphenyl) -6-propylpyridine was added to DM
F3ml was dissolved and added dropwise, and the mixture was stirred at room temperature for 2 hours. After distilling off DMF under reduced pressure, 1N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 872 mg (2.24 mmol), yield: 70.
6% MS (FAB, m / z) 389 (MH +) H-NMR (CDCl3): 0.88-0.94 (3H, t), 1.58-1.72 (2H, m), 2.
61-2.66 (2H, t), 3.88 (3H, s), 6.01 (2H, s), 6.62-6.82 (3
H, s), 6.93 (1H, s), 7.02-7.05 (2H, d), 7.60-7.63 (2H, d)

6) 4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenoxy) -6-propylpyridine-3-aldehyde 3-cyano-4- (4-methoxyphenyl) -2-
389 mg (1.00 mmol) of (3,4-methylenedioxyphenoxy) -6-propylpyridine were dissolved in 10 ml of benzene, and 3.0 ml (3.0 mmol) of a 1M solution of diisobutylaluminum hydride in hexane was added at room temperature, followed by 2 hours at room temperature. Stirred. 0.4 ml of methanol, water 2
ml was added and stirred for 20 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 8: 1) to give the title compound. Yield: 279 mg (0.71 mmol), yield: 71.
3% H-NMR (CDCl3): 0.88-0.94 (3H, t), 1.60-1.72 (2H, m), 2.
60-2.65 (2H, t), 3.87 (3H, s), 6.00 (2H, s), 6.61-6.84 (4
H, m), 6.97-7.00 (2H, d), 7.30-7.33 (2H, d) 10.20 (1H, s, C
HO)

7) 4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenoxy) -6-propylpyridine-3-carboxylic acid 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) in 4 ml of methylene chloride and 2 ml of water 274 m of -6-propylpyridine-3-aldehyde
g (0.70 mmol), 0.6 ml (5.66 mmol) of 2-methyl-2-butene in an ice bath, 210 g of amidosulfuric acid
mg (2.16 mmol), sodium chlorite 480
mg (5.31 mmol) was added and the mixture was stirred at room temperature for 20 minutes. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (chloroform: methanol 30:
Purification in 1) gave the title compound. Yield: 191 mg (0.47 mmol), yield: 66.
8% MS (ESI, m / z) 408 (MH +) H-NMR (CDCl3): 0.83-0.88 (3H, t), 1.50-1.63 (2H, m), 2.
48-2.55 (2H, t), 3.60 (3H, s), 5.89 (2H, s), 6.40-6.45 (1
H, m), 6.52-6.59 (2H, m), 6.66-6.73 (3H, m), 7.30-7.33
(2H, d)

Example 7 1) Synthesis of 1- (3,4-dimethoxyphenyl) -3-oxo-1-heptanol 1.12 g of potassium t-butoxide was added to 2.5 ml of 2-hexanone at -70 ° C. under an argon atmosphere. (20.3mm
ol), 1.66 g of veraformaldehyde (10.0 m
mol) in 20 ml of THF and stirred for 1 hour.
The reaction is stopped by adding 1N hydrochloric acid. Extract with ethyl acetate and wash with saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1:
2) to give the title compound. Yield: 1.10 g, Yield: 41.3% MS (ESI, m / z) 249 (MH + -H 2 O) H-NMR (CDCl 3): 0.90 (3H, t), 1.30 (2H, m), 1.59 ( Two
H, m), 2.42 (2H, t), 2.82 (2H, m), 3.30 (3H, s), 3.
87 (3H, s), 5.12 1H, m), 6.82-6.86 (2H, m), 6.94
(1H, d)

2) 1- (3,4-dimethoxyphenyl)
Synthesis of -1-hepten-3-one 1- (3,4-dimethoxyphenyl) -3-oxo-
1.10 g (4.1 mmol) of 1-heptanol is dissolved in 20 ml of toluene, 2.0 g of anhydrous magnesium sulfate is added, and the mixture is stirred at 100 ° C. overnight. After cooling, the mixture is filtered and the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 2) to give the title compound. Yield: 530 mg, Yield: 52.1% MS (ESI, m / z) 249 (MH +) H-NMR (CDCl3): 0.95 (3H, t), 1.39 (2H, sex), 1.68
(2H, quint), 2.66 (2H, t), 3.92 (3H, s), 3.92 (3
H, s), 6.62 (1H, d), 6.88 (1H, d), 7.08 (1H, d), 7.
13 (1H, d), 7.50 (1H, d)

3) 6-butyl-3-cyano-4- (3,
Synthesis of 4-dimethoxyphenyl) -2-pyridone Cyanoacetamide 180m at room temperature under argon atmosphere
g (2.14 mmol), potassium t-butoxide 240
mg (2.14 mmol) in 5 ml of DMSO
(3,4-dimethoxyphenyl) -1-heptene-3
530 mg (2.13 mmol) of DMSO10
Add ml and stir for 20 minutes. potassium t-butoxide 7
20 mg (6.42 mmol) is added and oxygen is bubbled for 1 minute. After stirring for 1.5 hours in an oxygen atmosphere, the mixture is added with 1N hydrochloric acid under ice-cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 280 mg, Yield: 42.1% MS (ESI, m / z) 313 (MH +) H-NMR (CDCl3): 0.98 (3H, t), 1.43 (2H, sex), 1.75
(2H, quint), 2.72 (2H, t), 3.94 (3H, s), 3.95 (3H,
s), 6.26 (1H, s), 6.98 (1H, d), 7.20-7.30 (2H, m)

4) 6-butyl-3-cyano-4- (3,
Synthesis of 4-dimethoxyphenyl) -2-chloropyridine 6-butyl-3-cyano-4- (3,4-dimethoxyphenyl) -2-pyridone 280 mg (0.9 mmol)
Is dissolved in 5 ml of phosphorus oxychloride and stirred at 90 ° C. overnight. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 6-butyl-3-cyano-4- (3,4-dimethoxyphenyl)-
2-Chloropyridine was obtained. This was used for the following reaction without purification. Yield: 280 mg MS (ESI, m / z) 331 (MH +) H-NMR (CDCl3): 0.96 (3H, t), 1.42 (2H, sex), 1.75
(2H, quint), 2.84 (2H, t), 3.95 (3H, s), 3.96 (3H,
s), 7.00 (1H, s), 7.14 (1H, d), 7.19 (1H, dd), 7.2
0 (1H, s)

5) 6-butyl-3-cyano-4- (3,
Synthesis of 4-dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 130 mg (0.94 mmol) of sesamol, 70 mg of sodium hydride (60% oil dispersion,
D) of phenoxide ion prepared from 1.8 mmol)
6-butyl-3-cyano-4- (3,
4-dimethoxyphenyl) -2-chloropyridine 280
mg was dissolved in 10 ml of DMF, and the mixture was stirred for 1 hour under an argon atmosphere. The solvent is distilled off under reduced pressure, the residue is dissolved in ether, and washed with water, 1N sodium hydroxide solution and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 2) to give the title compound. Yield: 230 mg, Yield: 6-butyl-3-cyano-4
59.1% MS (ESI, m / z) 433 (MH +) H-NMR (CDCl3) from-(3,4-dimethoxyphenyl) -2-pyridone: 0.88 (3H, t), 1.32 (2H, m) , 1.62 (2
H, m), 2.68 (2H, t), 3.95 (3H, s), 3.97 (3H, s),
6.02 (2H, s), 6.65 (1H, dd), 6.20 (2H, m), 6.80 (1
H, d), 6.94 (1H, s), 7.00 (1H, s)

6) Synthesis of 6-butyl-4- (3,4-dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6-butyl-3-cyano-4-aldehyde 230 mg (0.53 mmol) of (3,4-dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine are dissolved in 5 ml of benzene, and 1.6 ml of a 1M solution of diisobutylaluminum hydride in hexane at room temperature under an argon atmosphere.
(1.6 mmol) are added dropwise. Stir at room temperature for 1 hour and terminate the reaction with methanol and water. Stir at room temperature for 30 minutes,
The insolubles are filtered using celite. The filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 2) to obtain the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 140 mg MS (ESI, m / z) 437 (MH +) H-NMR (CDCl3): 0.88 (3H, t), 1.32 (2H, sex), 1.62
(2H, quint), 2.66 (2H, t), 3.91 (3H, s), 3.94 (3H,
s), 6.00 (2H, s), 6.63 (1H, dd), 6.73 (1H, d), 6.8
0 (1H, d), 6.85 (1H, s), 6.88 (1H, br), 6.94 (1H,
d), 6.94 (1H, s), 10.22 (1H, s)

7) Synthesis of 6-butyl-4- (3,4-dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 4-dimethoxyphenyl) -2
140 mg of-(3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde was added to 2 ml of methylene chloride,
Dissolve in 1 ml of water, and add 2-methyl-2-butene at 0 ° C.
2 ml (1.9 mmol), amidosulfuric acid 50 mg (0.
5 mmol), 130 mg of sodium chlorite (1.1 mg)
mmol) and the mixture is returned to room temperature and stirred for 1 hour. The mixture is extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform:
Methanol 9: 1) to give the title compound. Yield: 70 mg, yield: 6-butyl-3-cyano-4-
29.3% MS (ESI, m / z) 452 (MH +) H-NMR (CDCl 3): 0.86 (3H , t), 1.28 (2H, m), 1.56 (2
H, quint), 2.58 (2H, t), 3.70 (3H, s), 3.73 (3H,
s), 5.95 (2H, s), 6.46 (1H, br d), 6.57 (2H, m), 6.
68 (1H, m), 6.76 (1H, br s), 6.97 (1H, br s), 6.98
(1H, br d)

Example 8 6-butyl-4- (3,4,5
Synthesis of -trimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) 1- (3,4,5-trimethoxyphenyl) -3
Synthesis of -oxo-1-heptanol Under argon atmosphere, at -70 ° C, 1.12 g of potassium t-butoxide was added to 2.5 ml of 2-hexanone (20.3 mm
ol), 3,4,5-Trimethoxybenzaldehyde (1.96 g, 10.0 mmol) was added to a THF (20 ml) solution, and the mixture was stirred for 2 hours. The reaction is stopped by adding 1N hydrochloric acid. Extract with ethyl acetate and wash with saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1) to give the title compound. Yield: 950 mg, Yield: 32.1% MS (ESI, m / z) 389 (M + Na +) H-NMR (CDCl3): 0.90 (3H, t), 1.30 (2H, sex), 1.58
(2H, quint), 2.43 (2H, t), 2.80 (2H, m), 3.34 (1H,
d), 3.33 (3H, s), 3.34 (6H, s), 5.11 (1H, dt), 6.5
9 (2H, s)

2) Synthesis of 1- (3,4,5-trimethoxyphenyl) -1-hepten-3-one 950 mg of 1- (3,4,5-trimethoxyphenyl) -3-oxo-1-heptanol (3.2 mmol) was dissolved in 20 ml of toluene, and p-toluenesulfonic acid 30 was dissolved.
mg and stirred at 90 ° C. for 10 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 2) to obtain the title compound. Yield: 580 mg, yield: 65.1% MS (ESI, m / z) 279 (MH +) H-NMR (CDCl3): 0.96 (3H, t), 1.39 (2H, sex), 1.68
(2H, quint), 2.67 (2H, t), 3.89 (3H, s), 3.90 (6H,
s), 6.64 (1H, d), 6.78 (2H, s), 7.47 (1H, d)

3) 6-butyl-3-cyano-4- (3,
Synthesis of 4,5-trimethoxyphenyl) -2-pyridone Cyanoacetamide 180m at room temperature under argon atmosphere
g (2.14 mmol), potassium t-butoxide 240
mg (2.14 mmol) in 5 ml of DMSO
580 mg (2.1 mmol) of (3,4,5-trimethoxyphenyl) -1-hepten-3-one in DMSO1
Add 5 ml and stir for 20 minutes. 720 mg (6.4 mmol) of potassium t-butoxide are added, and oxygen is bubbled for 1 minute. After stirring for 1.5 hours in an oxygen atmosphere, the mixture is added with 1N hydrochloric acid under ice-cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 330 mg, Yield: 45.9% MS (ESI, m / z) 343 (MH +) H-NMR (CDCl3): 1.00 (3H, t), 1.47 (2H, sex), 1.77
(2H, quint), 2.74 (2H, t), 3.93 (3H, s), 3.93 (6H,
s), 6.28 (1H, s), 6.85 (2H, s)

4) 6-butyl-3-cyano-4- (3,
Synthesis of 4,5-trimethoxyphenyl) -2-chloropyridine 320 mg of 6-butyl-3-cyano-4- (3,4,5-trimethoxyphenyl) -2-pyridone (0.9 mm
ol) in 5 ml of phosphorus oxychloride and stir at 100 ° C. overnight. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound. This was used for the following reaction without purification. Yield: 360 mg MS (ESI, m / z) 361 (MH +) H-NMR (CDCl3): 0.96 (3H, t), 1.43 (2H, sex), 1.76
(2H, quint), 2.86 (2H, t), 3.93 (3H, s), 3.93 (6H,
s), 6.80 (2H, s), 7.22 (1H, s)

5) 6-butyl-3-cyano-4- (3,
Synthesis of 4,5-trimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 130 mg (0.94 mmol) of sesamol, 70 mg of sodium hydride (60% oil dispersion,
D) of phenoxide ion prepared from 1.8 mmol)
6-butyl-3-cyano-4- (3,
4-dimethoxyphenyl) -2-chloropyridine 360
mg was dissolved in 10 ml of DMF, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. The solvent is distilled off under reduced pressure, the residue is dissolved in ether, and washed with water, 1N sodium hydroxide solution and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 2) to give the title compound. Yield: 160 mg, yield: 6-butyl-3-cyano-4
-(3,4,5-trimethoxyphenyl) -2-pyridone 37.2% MS (ESI, m / z) 463 (MH +) H-NMR (CDCl3): 0.89 (3H, t), 1.32 (2H , sex), 1.61
(2H, quint), 2.68 (2H, t), 3.893 (3H, s), 3.94 (6
H, s), 6.02 (2H, s), 6.67 (1H, dd), 6.74 (1H, d),
6.82 (1H, d), 6.85 (2H, s), 6.95 (1H, s)

6) Synthesis of 6-butyl-4- (3,4,5-trimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6-butyl-3-cyano 160 mg (0.35 mmol) of -4- (3,4,5-trimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine
Was dissolved in 5 ml of benzene, and a 1 M solution of diisobutylaluminum hydride in hexane was added at room temperature under an argon atmosphere at room temperature.
1 (1.0 mmol) is added dropwise. Stir at room temperature for 1 hour and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 1 hour, and the insoluble matter is filtered using celite. The filtrate was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1) to give the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 60 mg MS (ESI, m / z) 466 (MH +)

7) Synthesis of 6-butyl-4- (3,4,5-trimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid Dissolve 60 mg of (3,4,5-trimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde in 2 ml of methylene chloride and 1 ml of water, and add 2-methyl-2 at 0 ° C. 0.1 ml (0.94 mmol) of butene, 20 amidosulfuric acid
mg (0.21 mmol), 50 m of sodium chlorite
g (0.44 mmol) was added and the mixture was returned to room temperature and stirred for 1 hour. The mixture is extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (ethyl acetate: hexane 1: 1) to give the title compound. Yield: 38 mg, Yield: 6-butyl-3-cyano-4-
(3,4,5-trimethoxyphenyl) -2- (3,4
-Methylenedioxyphenyloxy) pyridine from 2
2.5% MS (ESI, m / z) 482 (MH +) H-NMR (CDCl3): 0.88 (3H, t), 1.31 (2H, m), 1.60 (2
H, quint), 2.65 (2H, t), 3.83 (6H, s), 3.86 (3H,
s), 5.99 (2H, s), 6.61 (1H, dd), 6.69 (3H, m), 6.7
6 (1H, d), 6.86 (1H, s)

Example 9 Synthesis of 6-isobutyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) 1- (4-methoxyphenyl) -5-methyl-1-
Synthesis of hexen-3-one Under an argon atmosphere, at -70 ° C, 4.0 g (35.6 mmol) of potassium t-butoxide was added to 4.1 ml (32.8 mmol) of methyl isobutyl ketone and 2.0 ml of p-anisaldehyde (16. 4 mmol) of THF 20 ml
Add to the solution, bring to -20 ° C and stir for 1 hour. The reaction is stopped by adding 1N hydrochloric acid. Extract with ethyl acetate and wash with saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to give the title compound. Yield: 480 mg, yield: 13.4% MS (ESI, m / z) 219 (MH +) H-NMR (CDCl3): 0.98 (6H, d), 2.23 (1H, m), 2.52 (2
H, d), 3.84 (3H, s), 6.63 (1H, d), 6.91 (2H, d),
7.50 (2H, d), 7.50 (1H, d)

2) 6-isobutyl-3-cyano-4-
Synthesis of (4-methoxyphenyl) -2-pyridone Cyanoacetamide 190m at room temperature under argon atmosphere
g (2.3 mmol), potassium t-butoxide 250 m
g (2.2 mmol) in 5 ml of DMSO was added to 1- (4
-Methoxyphenyl) -5-methyl-1-hexene-3
-580 mg (2.1 mmol) of DMSO 15m
Add 1 and stir for 20 minutes. potassium t-butoxide75
Add 0 mg (6.7 mmol) and bubble oxygen for 1 minute. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice-cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 400 mg, Yield: 64.4% MS (ESI, m / z) 283 (MH +) H-NMR (CDCl3): 1.03 (6H, d), 2.12 (1H, m), 2.56 (2
H, d), 3.88 (3H, s), 6.24 (1H, s), 7.50 (2H, d),
7.63 (2H, d)

3) 6-isobutyl-3-cyano-4-
Synthesis of (4-methoxyphenyl) -2-chloropyridine 400 mg (1.4 mmol) of 6-isobutyl-3-cyano-4- (4-methoxyphenyl) -2-pyridone was dissolved in 5 ml of phosphorus oxychloride and the solution was heated at 90 ° C. Stir overnight.
The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound. This was used for the following reaction without purification. Yield: 420 mg MS (ESI, m / z) 301 (MH +) H-NMR (CDCl3): 0.97 (6H, d), 2.17 (1H, m), 2.70 (2
H, d), 3.88 (3H, s), 7.04 (2H, d), 7.15 (1H, s),
7.57 (2H, d)

4) 6-isobutyl-3-cyano-4-
Synthesis of (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 200 mg (1.4 mmol) of sesamol, 120 mg of sodium hydride (60% oil dispersion,
3.0 mmol) of phenoxide ion prepared from
6-isobutyl-3-cyano-4- was added to a 5 ml MF solution.
(4-methoxyphenyl) -2-chloropyridine 420
mg was dissolved in 10 ml of DMF, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The solvent is distilled off under reduced pressure, the residue is dissolved in ether, and washed with water, 1N sodium hydroxide solution and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 2) to give the title compound. Yield: 390 mg, Yield: 6 from 6-isobutyl-3-cyano-4- (4-methoxyphenyl) -2-pyridone
8.2% MS (FAB, m / z) 402 (MH +) H-NMR (CDCl3): 0.88 (6H, d), 2.01 (1H, m), 2.53 (2
H, d), 3.88 (3H, s), 6.01 (2H, s), 6.66 (1H, dd),
6.74 (1H, d), 6.81 (1H, d), 6.90 (1H, s), 7.40 (2
H, d), 7.61 (2H, d)

5) Synthesis of 6-isobutyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6-isobutyl-3-cyano-4- (4 390 mg (1.0 mmol) of -methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine are dissolved in 5 ml of benzene, and 3.0 ml of a 1M solution of diisobutylaluminum hydride in hexane (3.0 ml) at room temperature under an argon atmosphere.
mmol) is added dropwise. Stir at room temperature for 1 hour and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 1 hour, and the insoluble matter is filtered using celite. The filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 2: 5) to give the title compound.
It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 400 mg MS (FAB, m / z) 405 (M +)

6) Synthesis of 6-isobutyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6-isobutyl-4- (4-methoxyphenyl) ) -2-
400 mg of (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde was dissolved in 2 ml of methylene chloride and 1 ml of water, and 0.6 ml of 2-methyl-2-butene was added at 0 ° C.
3 ml (5.9 mmol), 143 mg of amidosulfuric acid
(5.9 mmol), 400 mg sodium chlorite
(1.5 mmol) was added and the mixture was returned to room temperature and stirred for 30 minutes. The mixture is extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (chloroform: methanol 9: 1), and further subjected to silica gel thin layer chromatography (ethyl acetate: hexane).
Purification by 1: 1) gave the title compound. Yield: 120 mg, Yield: 28.5% MS (ESI, m / z) from 6-isobutyl-3-cyano-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine ) 422 (MH +) H-NMR (CDCl3): 0.88 (6H, d), 1.98 (1H, m), 2.52 (2
H, m), 3.83 (3H, s), 5.98 (2H, s), 6.61 (1H, dd),
6.71 (1H, d), 6.76 (1H, d), 6.82 (1H, s), 6.94 (2
H, d), 7.41 (2H, d)

Example 10 Synthesis of 4- (4-methoxyphenyl) -2- (2-naphthoxy) -6-propylpyridine-3-carboxylic acid 1) 3-Cyano-4- (4-methoxyphenyl) -2 −
Synthesis of (2-naphthoxy) -6-propylpyridine 122 mg (0.85
mmol) to 50 mg (1.2%) of 60% sodium hydride.
5 mmol) and stirred at room temperature for 15 minutes. 2-chloro-3-cyano-4- (4-methoxyphenyl) -6
201 mg (0.70 mmol) of propylpyridine was added to D
It was dissolved in 2 ml of MF and added dropwise, followed by stirring at room temperature for 2 hours.
After distilling off DMF under reduced pressure, 1N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-chloroform = 1: 2) to obtain the title compound. Yield: 124 mg (0.31 mmol), yield: 37.
1% MS (ESI, m / z) 395 (MH +) H-NMR (CDCl3): 0.85-0.90 (3H, t), 1.56-1.68 (2H, m), 2.
58-2.63 (2H, t), 3.89 (3H, s), 6.97 (1H, s), 7.04-7.07 (2
H, d), 7.35-7.39 (1H, m), 7.44-7.53 (2H, m), 7.62-7.70
(3H, m), 7.80-7.90 (3H, m)

2) 4- (4-methoxyphenyl) -2-
Synthesis of (2-naphthoxy) -6-propylpyridine-3-aldehyde 3-cyano-4- (4-methoxyphenyl) -2- (2
-Naphthoxy) -6-propylpyridine 118 mg
(1.00 mmol) was dissolved in 7 ml of benzene, and a 1 M solution of diisobutylaluminum hydride in hexane was added at room temperature.
95 ml (0.95 mmol) was added and the mixture was stirred at room temperature for 2 hours. 1.0 ml of methanol and 3 ml of water were added and stirred for 20 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 98 mg (0.25 mmol), yield: 83.3
% H-NMR (CDCl3): 0.85-0.90 (3H, t), 1.54-1.68 (2H, m), 2.
53-2.63 (2H, m), 3.88 (3H, s), 6.58-7.02 (3H, m), 7.26
7.88 (9H, m), 10.31 (1H, s)

3) 4- (4-methoxyphenyl) -2-
Synthesis of (2-naphthoxy) -6-propylpyridine-3-carboxylic acid 4- (4-methoxyphenyl) -2- (2-naphthoxy) -6-propylpyridine- in 1.8 ml of methylene chloride and 0.9 ml of water 98 mg of 3-aldehyde (0.25 mm
ol) in an ice bath 0.21 ml of 2-methyl-2-butene
(1.98 mmol), amidosulfuric acid 70 mg (0.72
mmol), 141 mg of sodium chlorite (1.56
mmol) and stirred at room temperature for 30 minutes. Add water,
The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol 50: 1) to obtain the title compound. Yield: 71 mg (0.17 mmol), yield: 68.7
% MS (ESI, m / z) 414 (MH +) H-NMR (CDCl3): 0.85-0.90 (3H, t), 1.55-1.70 (2H, m), 2.
56-2.61 (2H, t), 3.81 (3H, s), 6.91-6.98 (3H, m), 7.28-
7.60 (6H, m), 7.71-7.87 (3H, m)

Example 11 Synthesis of 6-ethyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine-3-carboxylic acid 1) 1- (4-methoxyphenyl)- Synthesis of 3-oxopentanol THF (30 ml), lithium bistrimethylsilylamide 1M-THF solution (17 ml) at −78 ° C. in THF (15 ml)
1.35 ml (15.1 mmol) of 2-butanone dissolved in
l) was added dropwise over 10 minutes. 20 minutes after the completion of the dropwise addition, 1.80 ml (14.8 mmol) of p-anisaldehyde was added, and the mixture was stirred for 1 hour while gradually raising the temperature from -78 ° C to -30 ° C. The reaction was stopped with 15 ml of 2N hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 6: 1) to give the title compound. Yield: 1.90 g (9.12 mmol), Yield: 61.
6% H-NMR (CDCl3): 1.04-1.09 (3H, t), 2.41-2.50 (2H, qua),
2.78-2.85 (2H, m), 3.21-3.22 (1H, d), 3.80 (3H, s), 5.08
-5.15 (1H, m), 6.87-6.90 (2H, d), 7.27-7.30 (2H, d)

2) 1- (4-methoxyphenyl) -1-
Synthesis of penten-3-one 1- (4-methoxyphenyl)-in 60 ml of toluene
1.90 g of 3-oxopentanol (9.12 mmol
l) and 3.73 g (31.0 mm) of anhydrous magnesium sulfate
ol) was refluxed overnight. After filtration and washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The residue was used for the next reaction without purification. Yield: 1.67 g (8.78 mmol), yield: 96.
3% MS (ESI, m / z) 191 (MH +) H-NMR (CDCl3): 1.14-1.19 (3H, t), 2.64-2.72 (2H, qua),
3.84 (3H, s), 6.61-6.66 (1H, d), 6.90-6.93 (2H, d), 7.48
-7.51 (2H, d), 7.50-7.55 (1H, m)

3) 3-cyano-6-ethyl-4- (4-
Synthesis of methoxyphenyl) -2-pyridone 743 mg of cyanoacetamide in 20 ml of DMSO
(8.84 mmol) in 992 m of potassium t-butoxide
g (8.84 mmol) and then 1- (4-methoxyphenyl) -1-pentene-3- dissolved in 5 ml of DMSO.
1.67 g (8.78 mmol) was added and the mixture was added at room temperature for 30 minutes.
Stirred for minutes. 2.98 g of potassium t-butoxide (2
(6.6 mmol) was added, oxygen gas was bubbled for 1 minute, and the mixture was further stirred at room temperature under a normal pressure oxygen atmosphere for 2 hours.
2N Hydrochloric acid was added, and the precipitated crystals were collected by filtration, washed with water and hexane, and dried under reduced pressure to obtain the title compound. Yield: 1.24 g (4.88 mmol), yield: 55.
6% MS (ESI, m / z) 255 (MH +) H-NMR (CDCl3): 1.35-1.40 (3H, t), 2.74-2.83 (2H, qua),
3.88 (3H, s), 6.28 (1H, s), 7.00-7.03 (2H, d), 7.59-7.62
(2H, d)

4) Synthesis of 2-chloro-3-cyano-6-ethyl-4- (4-methoxyphenyl) pyridine 3-cyano-6-ethyl-4- (4-methoxyphenyl) -2-pyridone To 22 g (4.80 mmol), 22 ml of phosphorus oxychloride and 0.61 ml (4.81 mmol) of N, N-dimethylaniline were added, and the mixture was heated at 100 ° C. for 2.5 hours. After distilling off phosphorus oxychloride, water was added thereto, and the mixture was extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was used for the next reaction without purification. Yield: 795 mg (2.91 mmol), yield: 60.
6% MS (ESI, m / z) 273 (MH +) H-NMR (CDCl3): 1.32-1.37 (3H, t), 2.84-2.92 (2H, qua),
3.88 (3H, s, MeO), 7.03-7.06 (2H, d), 7.20 (1H, s), 7.55-
7.58 (2H, d)

5) 3-cyano-6-ethyl-4- (4-
Synthesis of methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 221 mg of sesamol (1.60 mm) in 7 ml of DMF
ol) to 80 mg of 60% sodium hydride (2.0 mm
ol) and stirred at room temperature for 10 minutes. 2-chloro-3
-Cyano-6-ethyl-4- (4-methoxyphenyl)
Pyridine (408 mg, 1.50 mmol) in DMF (5 m)
The resulting mixture was added dropwise to the mixture and stirred at room temperature for 2 hours. After distilling off DMF under reduced pressure, 1N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 400 mg (1.07 mmol), yield: 71.
2% MS (ESI, m / z) 375 (MH +) H-NMR (CDCl3): 1.17-1.22 (3H, t), 2.65-2.75 (2H, qua),
3.88 (3H, s), 6.01 (2H, s, OCH2O), 6.63-6.83 (3H, m), 6.9
4 (1H, s), 7.02-7.05 (2H, d), 7.59-7.62 (2
H, d)

6) 6-ethyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy)
Synthesis of pyridine-3-aldehyde 3-cyano-6-ethyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 393 mg (1.05 mmol) was added to benzene 10
disodium diisobutylaluminum 1 at room temperature
3.15 ml (3.15 mmol) of a M hexane solution was added, and the mixture was stirred at room temperature for 2 hours. 1 ml of methanol, 3 ml of water
Was added and stirred for 20 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 6: 1) to give the title compound. Yield: 84 mg (0.22 mmol), Yield: 21.1
% H-NMR (CDCl3): 1.17-1.22 (3H, t), 2.64-2.
72 (2H, qua), 3.87 (3H, s, MeO), 6.00 (2H, s), 6.62-6.82
(3H, m), 6.84 (1H, s), 6.97-7.00 (2H, d), 7.30-7.33 (2H,
d), 10.24 (1H, s, CHO)

7) 6-ethyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy)
Synthesis of pyridine-3-carboxylic acid 6-ethyl- in 1.8 ml of methylene chloride, 0.9 ml of water
4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine-3-aldehyde 84
mg (0.22 mmol) of 0.21 ml (1.98 mmol) of 2-methyl-2-butene in an ice bath,
0 mg (0.72 mmol), sodium chlorite 14
0 mg (1.55 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (chloroform: methanol 9: 9).
Purification in 1) gave the title compound. Yield: 56 mg (0.14 mmol), yield: 63.5
% MS (ESI, m / z) 394 (MH +) H-NMR (CDCl3): 1.08-1.13 (3H, t), 2.51-2.61 (2H, qua),
3.60 (3H, s, MeO), 5.87 (2H, s), 6.38-6.59 (3H, m), 6.62
6.65 (2H, d), 6.70 (1H, s), 7.27-7.30 (2H,
d)

Example 12 Synthesis of 6-propyl-4- (4-isopropyloxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) Synthesis of 4-isopropyloxybenzaldehyde 5.0 g of 4-hydroxybenzaldehyde (44.6 m
mol), 6.0 g of potassium carbonate (55.0 mmol)
l), 6.0 ml of isopropyl bromide (63.9 mm
ol), a mixture of 80 ml of DMF is stirred at 50 ° C. overnight. Dilute with ethyl acetate and filter the insolubles. The solvent is distilled off under reduced pressure, and the residue is dissolved in ether. After washing with 1N sodium hydroxide solution, water and saturated saline, drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound. Yield: 6.12 g, yield: 83.6%

2) Synthesis of 1- (4-isopropyloxyphenyl) -3-oxo-1-hexanol In an argon atmosphere, 22 ml of a 1M hexane solution of lithium bistrimethylsilylamide was added to THF10 at -70 ° C.
Add to ml. 2.1 ml of 2-heptanone (19.8 m
mol) in 10 ml of THF, and the mixture is stirred for 10 minutes. 1.64 g of 4-hydroxybenzaldehyde (1
(0.0 mmol) and stirred for 1 hour, and then 1N hydrochloric acid was added to terminate the reaction. Extract with ethyl acetate and wash with saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to give the title compound. Yield: 1.40 g, yield: 55.9%

3) Synthesis of 1- (4-isopropyloxyphenyl) -1-hexen-3-one 1.40 g (5.6 mmol) of 1- (4-isopropyloxyphenyl) -3-oxo-1-hexanol Dissolved in 30 ml of toluene and dried over anhydrous magnesium sulfate 4.0
g and 30 mg of p-toluenesulfonic acid.
Stir for hours. The residue obtained by filtration and evaporation of the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 4) to give the title compound. Yield: 1.09 g, 83.4% MS (ESI, m / z) 233 (MH +) H-NMR (CDCl3): 0.95 (3H, t), 1.35 (6H, d), 1.71 (2
H, sex), 2.62 (2H, t), 4.59 (1H, m), 6.62 (1H,
d), 6.88 (2H, d), 7.47 (2H, d), 7.51 (1H, d)

4) 6-propyl-3-cyano-4- (4
Synthesis of -Isopropyloxyphenyl) -2-pyridone Cyanoacetamide 400m at room temperature under argon atmosphere
g (4.8 mmol), potassium t-butoxide 530 m
g (4.7 mmol) in 10 ml of DMSO
(4-isopropyloxyphenyl) -5-methyl-1
-Hexen-3-one (1.09 g, 4.7 mmol) in 20 ml of DMSO is added, and the mixture is stirred for 15 minutes. 1.58 g (14.1 mmol) of potassium t-butoxide is added, and oxygen is bubbled for 1 minute. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice-cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 910 mg, 65.3% MS (ESI, m / z) 297 (MH +) H-NMR (CDCl3): 1.04 (3H, t), 1.38 (6H, d), 2.00 (2
H, sex), 2.68 (2H, t), 4.63 (1H, m), 6.25 (1H,
s), 6.98 (2H, d), 7.59 (2H, d)

5) 6-propyl-3-cyano-4- (4
Synthesis of -isopropyloxyphenyl) -2-chloropyridine 910 mg (3.1 mm) of 6-propyl-3-cyano-4- (4-isopropyloxyphenyl) -2-pyridone
ol) in 6 ml of phosphorus oxychloride and stir at 90 ° C. overnight. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound. This was used for the following reaction without purification. Yield: 1.10 g MS (ESI, m / z) 315 (MH +) H-NMR (CDCl3): 1.00 (3H, t), 1.38 (6H, d), 1.70 (2
H, sex), 2.72 (2H, t), 4.64 (1H, m), 7.01 (2H,
d), 7.18 (1H, s), 7.55 (2H, d)

6) 6-propyl-3-cyano-4- (4
Synthesis of -isopropyloxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine sesamol 290 mg (2.1 mmol), sodium hydride 170 mg (60% oil dispersion,
D) of phenoxide ion prepared from 4.2 mmol)
6-propyl-3-cyano-4- (4
-Isopropyloxyphenyl) -2-chloropyridine (620 mg) is dissolved in DMF (10 ml), and the mixture is stirred under an argon atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ether.
Wash with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate: hexane)
1: 4) to give the title compound. Yield: 110 mg, yield: 6-propyl-3-cyano-
15.3% from 4- (4-isopropyloxyphenyl) -2-pyridone MS (ESI, m / z) 417 (MH +) H-NMR (CDCl3): 0.90 (3H, t), 1.38 (6H, d) , 2.24 (2
H, sex), 2.62 (2H, t), 4.63 (1H, m), 6.01 (2H,
s), 6.66 (1H, dd), 6.74 (1H, d), 6.80 (1H, d), 6.9
2 (1H, s), 7.00 (2H, d), 7.59 (2H, d)

7) Synthesis of 6-propyl-4- (4-isopropyloxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6-propyl-3-cyano-4- ( 110 mg (0.26 mmol) of 4-isopropyloxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine
Was dissolved in 5 ml of benzene, and a 1 M solution of diisobutylaluminum hydride in hexane was added at room temperature under an argon atmosphere at room temperature.
1 (1.0 mmol) is added dropwise. Stir at room temperature for 1 hour and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 1 hour, and the insoluble matter is filtered using celite. The filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 4) to obtain the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 80 mg MS (ESI, m / z) 420 (MH +)

8) Synthesis of 6-propyl-4- (4-isopropyloxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6-propyl-4- (4-isopropyl) Dissolve 80 mg of (oxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde in 2 ml of methylene chloride and 1 ml of water and, at 0 ° C., 0.12 ml of 2-methyl-2-butene (1,2). 1 mmol), amidosulfuric acid 30
mg (0.31 mmol), sodium chlorite 80m
g (0.70 mmol) was added and the mixture was returned to room temperature and stirred for 20 minutes. The mixture is extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
The obtained residue was subjected to silica gel thin layer chromatography (ethyl acetate: hexane 1: 1) to give the title compound. Yield: 13 mg, yield: 6-propyl-3-cyano-4
-(4-isopropyloxyphenyl) -2- (3,4
-Methylenedioxyphenyloxy) pyridine
1.5% MS (ESI, m / z) 436 (MH +) H-NMR (CDCl3): 0.88 (3H, t), 1.34 (6H, d), 1.64 (2
H, sex), 2.60 (2H, t), 4.55 (1H, m), 5.97 (2H,
s), 6.61 (1H, dd), 6.73 (1H, d), 6.75 (1H, d), 6.8
4 (1H, s), 6.88 (2H, d), 7.38 (2H, d)

Example 13 Synthesis of 4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 1) 1- (4-methoxyphenyl) -1-butenyl-3
Synthesis of -one Acetonyltriphenylphosphonium chloride 3.9
1 g (11.0 mmol) was dissolved in THF (30 ml) and 440 mg of 60% sodium hydride (11.0 mm
ol) at 0 ° C. After returning to room temperature and stirring for 1 hour, 1 g of P-p-anisaldehyde (7.34 mmol
l) was added and stirred overnight. Water was added to the reaction solution, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a crude product of yellow-brown crystals. This was purified on silica gel using hexane / ethyl acetate (5: 1) to give the title compound. Yield: 1,15 g, Yield: 59% MS (ESI. M / z) 177 (MH +) H-NMR (CDCl3): 2.36 (3H, s), 3.85 (3H, s), 6.61 (1
H, d), 6.92 (2H, d), 7.45-7.51 (3H, m)

2) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-methyl-2-pyridone 604 mg of α-cyanoacetamide (7.18 mmol)
l) was dissolved in 30 ml of DMSO, and under an argon atmosphere,
733 mg of potassium t-butoxide (6.53 mmol
1), 1- (4-methoxyphenyl) -1-butenyl-
1.15 g (6.53 mmol) of 3-one was sequentially added at room temperature, and the mixture was stirred for 15 minutes. After confirming the disappearance of the raw materials by TLC, 2.20 g of potassium t-butoxide (19.
6 mmol) was added, oxygen was bubbled for 1 minute, and the mixture was stirred under an oxygen atmosphere for 1 hour. Add 3N hydrochloric acid to the reaction solution
After 0 ml was added and the mixture was stirred for 1 hour, an ocher crystal substance was deposited. The crystalline material was filtered off with suction, washed successively with water and a hexane / ethyl acetate (1: 1) mixture and dried overnight at 100 ° C. to give the title compound. Yield: 990 mg, yield: 67% H-NMR (CD3OD): 2.65 (3H, s), 3.87 (3H, s), 6.39
(1H, s), 7.06 (2H, d), 7.63 (2H, d)

3) 2-Chloro-3-cyano-4- (4-
Synthesis of methoxyphenyl) -6-methylpyridine To 990 mg (4.38 mmol) of 3-cyano-4- (4-methoxyphenyl) -6-methyl-2-pyridone was added 10 ml of phosphorus oxychloride, and the mixture was heated at 120 ° C for 12 hours. Stirred. Thereafter, phosphorus oxychloride was distilled off under reduced pressure,
The residue is added to ethyl acetate, and washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound. Yield: 900 mg, 79% MS (ESI. M / z) 259 (MH +) H-NMR (CDCl3): 2.63 (3H, s), 3.88 (3H, s), 7.06 (2
H, d), 7.04 (1H, s), 7.56 (2H, d)

4) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine Under an argon atmosphere, 400 mg of sesamol (2.90 m
mol) was dissolved in 10 ml of DMF, 116 mg (2.90 mmol) of 60% sodium hydride was added at 0 ° C., and the mixture was stirred for 1 hour. Thereafter, 500 mg (1.93 mmol) of 2-chloro-3-cyano-4- (4-methoxyphenyl) -6-methyl-pyridine was added, and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was poured into water, the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent hexane: ethyl acetate 3: 1). To give the title compound. Yield: 260 mg, Yield: 37% MS (ESI. M / z) 361 (MH +) H-NMR (CDCl3): 2.44 (3H, s), 3.88 (3H, s), 6.01 (2
H, s), 6.62 to 6.74 (3H, m), 6.81 (1H, d), 6.95 (1H,
s), 7.03 (2H, d), 7.60 (2H, d)

5) 4- (4-methoxyphenyl) -6
Methyl-2- (3,4-methylenedioxyphenoxy)
Synthesis of -pyridine-3-aldehyde 3-cyano-4- (4-methoxyphenyl) -6-methyl-2-in methylene chloride 10 ml under argon atmosphere
(3,4-methylenedioxyphenoxy) -pyridine 2
60 mg (0.722 mmol) was dissolved, 2.16 ml of a 1M solution of diisobutylaluminum hydride in hexane was added at 0 ° C., and the mixture was stirred at room temperature overnight. Then 1 ml of water
After stirring for 1 hour, the mixture was filtered through celite and the residue was washed with ethyl acetate. The solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: hexane: ethyl acetate 5: 1) to obtain the title compound. Yield: 190 mg, yield: 72% MS (ESI. M / z) 364 (MH +) H-NMR (CDCl3): 2.42 (3H, s), 3.87 (3H, s), 6.00 (2
H, s), 6.61-6.85 (3H, m), 6.98 (2H, d), 7.30 (2H,
d), 10.2 (1H, s)

6) 4- (4-methoxyphenyl) -6
Methyl-2- (3,4-methylenedioxyphenoxy)
Synthesis of -pyridine-3-carboxylic acid 4- (4-methoxyphenyl) -6-methyl-2-
(3,4-methylenedioxyphenoxy) -pyridine-
Dissolve 190 mg (0.523 mmol) of 3-aldehyde in 5 ml of water and 10 ml of methylene chloride, and cool under ice-cooling.
213 mg (3.03 mmol) of methyl-butene, 76 mg (0.785 mmol) of amidosulfuric acid and 165 mg (1.83 mmol) of sodium chlorite were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 45 mg, Yield: 23% MS (ESI. M / z) 380 (MH +) H-NMR (CDCl3): 2.37 (3H, s), 3.77 (3H, s), 5.95 (2
H, s), 6.55-6.73 (3H, m), 6.85 (3H, t), 7.38 (2H,
d)

Example 14 Synthesis of 4- (4-methoxyphenyl) -2- (1-naphthoxy) -6-propylpyridine-3-carboxylic acid 1) 3-Cyano-4- (4-methoxyphenyl) -2
Synthesis of-(1-Naphthoxy) -6-propylpyridine 123 mg of 1-naphthol (0.85
mmol) to 50 mg (1.2%) of 60% sodium hydride.
5 mmol) and stirred at room temperature for 15 minutes. 2-chloro-3-cyano-4- (4-methoxyphenyl) -6
Propyl pyridine 202 mg (0.70 mmol)
It was dissolved in 2 ml of MF and added dropwise, followed by stirring at room temperature for 2 hours.
After distilling off DMF under reduced pressure, 1N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-chloroform = 1: 2) to obtain the title compound. Yield: 193 mg (0.49 mmol), yield: 69.
6% MS (ESI, m / z) 395 (MH +) H-NMR (CDCl3): 0.85-0.90 (3H, t), 1.45-1.55 (2H, m), 2.
48-2.56 (2H, m), 3.90 (3H, s), 6.94 (1H, s), 7.05-7.08 (2
H, d), 7.26-7.53 (7H, m), 7.65-7.68 (2H, d)

2) 4- (4-methoxyphenyl) -2-
Synthesis of (1-naphthoxy) -6-propylpyridine-3-carboxylic acid 3-cyano-4- (4-methoxyphenyl) -2- (1
-Naphthoxy) -6-propylpyridine 193 mg
(0.49 mmol) was dissolved in 5 ml of benzene.
50 ml (1.50 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 1.0 ml of methanol and 3 ml of water were added and stirred for 20 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 6: 1) to give the corresponding pyridine aldehyde. This was dissolved in 2 ml of methylene chloride and 1 ml of water, and 0.22 ml of 2-methyl-2-butene (2.08 m
mol), amidosulfuric acid 90 mg (0.93 mmol),
160 mg (1.77 mmol) of sodium chlorite was added, and the mixture was stirred at room temperature for 40 minutes. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol 30: 1) to obtain the title compound. Yield: 25 mg (0.06 mmol), yield: 12.2
% MS (ESI, m / z) 414 (MH +) H-NMR (CDCl3): 0.73-0.78 (3H, t), 1.38-1.54 (2H, m), 2.
42-2.48 (2H, t), 3.59 (3H, s), 6.70-6.79 (3H, m), 7.14-
7.43 (6H, m), 7.60-7.63 (1H, d), 7.77-7.80 (1H, d), 7.99
-8.02 (1H, d)

Example 15 Synthesis of 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine-3-carboxylic acid 1) 3-Cyano-4- (4-methoxyphenyl)- 2-
Synthesis of pyridone 1.75 g of cyanoacetamide in 40 ml of DMSO
(20.8 mmol) to 2.35 potassium t-butoxide.
g (20.9 mmol) and then 3.37 g of 4-methoxycinnamic aldehyde dissolved in 10 ml of DMSO (20.
8 mmol) and stirred at room temperature for 30 minutes. After addition of 7.05 g (62.8 mmol) of potassium t-butoxide, oxygen gas was bubbled for 2 minutes, and the mixture was further stirred for 2 hours at room temperature under a normal pressure oxygen atmosphere. 2N Hydrochloric acid was added, and the precipitated crystals were collected by filtration, washed with water and hexane, and dried under reduced pressure to obtain the title compound. Yield: 3.58 g (15.8 mmol), yield: 76.
0% MS (ESI, m / z) 227 (MH +) H-NMR (CDCl3 + CD3OD): 3.89 (3H, s, MeO), 6.43-6.46 (1H,
d), 7.02-7.05 (2H, d), 7.53-7.55 (1H, d), 7.61-7.64 (2
H, d)

2) 2-chloro-3-cyano-4- (4-
Synthesis of methoxyphenyl) pyridine To 3.50 g (15.5 mmol) of 3-cyano-4- (4-methoxyphenyl) -2-pyridone was added 60 ml of phosphorus oxychloride and 2.05 ml of N, N-dimethylaniline (1
6.2 mmol) and heated at 100 ° C. for 1.5 hours. After distilling off phosphorus oxychloride, water was added and extracted with ether.
The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was used for the next reaction without purification. Yield: 2.46 g (10.0 mmol), yield: 64.
8% MS (ESI, m / z) 245 (MH +) H-NMR (CDCl3): 3.89 (3H, s, MeO), 7.04-7.07 (2H, d), 7.3
5-7.37 (1H, d), 7.57-7.60 (2H, d), 8.51-8.53
(1H, d)

3) 3-cyano-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy)
Synthesis of pyridine Sesamol 298 mg (2.16 m
mol) and 60 mg of sodium hydride (100 mg, 2.5 mg).
0 mmol) and stirred at room temperature for 20 minutes. 489 mg (2.0 mmol) of 2-chloro-3-cyano-4- (4-methoxyphenyl) pyridine was dissolved in 2 ml of DMF and added dropwise, followed by stirring at room temperature for 5.5 hours. DM under reduced pressure
After evaporating F, 2N hydrochloric acid was added, and the precipitated crystals were filtered, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound. Yield: 406 mg (1.17 mmol), yield: 58.
6% MS (FAB, m / z) 347 (MH +) H-NMR (CDCl3): 3.89 (3H, s, MeO), 6.02 (2H, s), 6.65-6.8
6 (3H, m), 7.03-7.12 (3H, m), 7.62-7.65 (2H, d), 8.25-8.
26 (1H, d)

4) 4- (4-methoxyphenyl) -2-
(3,4-methylenedioxyphenoxy) pyridine-3
Synthesis of carboxylic acid 3-cyano-4- (4-methoxyphenyl) -2-
(3,4-methylenedioxyphenoxy) pyridine 20
5 mg (0.59 mmol) was dissolved in 15 ml of methylene chloride, and 1.8 ml (1.8 mmol) of a 1 M solution of diisobutylaluminum hydride in hexane was added at room temperature.
Stirred for hours. 0.5 ml of methanol and 1 ml of water were added and stirred for 20 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of methylene chloride and 5 ml of water, and 0.45 ml of 2-methyl-2-butene (4.25 m
mol), 190 mg of amidosulfuric acid (1.96 mmol)
l), 350 mg (3.87 mmol) of sodium chlorite
l) was added and the mixture was stirred at room temperature for 30 minutes. Water was added, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were washed with chloroform to obtain the title compound. Yield: 98 mg (0.27 mmol), yield: 45.4
% MS (ESI, m / z) 366 (MH +) H-NMR (DMSO-d6): 3.82 (3H, s, MeO), 6.06 (2H, s), 6.56-
6.60 (1H, m), 6.78-6.79 (1H, d), 6.90-6.93 (1H, d), 7.06
-7.09 (2H, d), 7.17-7.19 (1H, d), 7.48-7.51 (2H, d), 8.1
4-8.16 (1H, d)

Example 16 6-ethyl-2- (3,4-
Synthesis of dimethoxyphenoxy) -4- (4-methoxyphenyl) pyridine-3-carboxylic acid 1) 3-cyano-6-ethyl-2- (3,4-dimethoxyphenoxy) -4- (4-methoxyphenyl) pyridine Synthesis of 3,4-dimethoxyphenol 157 in 5 ml of DMF
mg (1.02 mmol) to 60% sodium hydride 6
0 mg (1.5 mmol) was added and the mixture was stirred at room temperature for 10 minutes. 2-chloro-3-cyano-6-ethyl-4- (4-
Methoxyphenyl) pyridine 191 mg (0.70 mm
ol) was dissolved in 3 ml of DMF and added dropwise, followed by stirring at room temperature for 11 hours. After distilling off DMF under reduced pressure, 1N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to obtain the title compound. Yield: 176 mg (0.45 mmol), yield: 64.
3% MS (ESI, m / z) 391 (MH +) H-NMR (CDCl3): 1.17-1.22 (3H, t), 2.65-2.73 (2H, qua),
3.87 (3H, s), 3.88 (3H, s), 3.91 (3H, s), 6.78-6.90 (3H,
m), 6.95 (1H, m), 7.03-7.06 (2H, d), 7.60-7.63 (2H, d)

2) Synthesis of 6-ethyl-2- (3,4-dimethoxyphenoxy) -4- (4-methoxyphenyl) pyridine-3-aldehyde 3-cyano-6-ethyl-2- (3,4- Dimethoxyphenoxy) -4- (4-methoxyphenyl) pyridine 1
75 mg (0.45 mmol) was dissolved in 8 ml of benzene, and 1.35 ml (1.35 mmol) of a 1M solution of diisobutylaluminum hydride in hexane was added at room temperature.
Stirred for hours. 1 ml of methanol and 2 ml of water were added and 15
Stirred for minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 86 mg (0.22 mmol), Yield: 48.4
% H-NMR (CDCl3): 1.16-1.22 (3H, t), 2.64-2.72 (2H, qua),
3.87 (3H, s), 3.88 (3H, s), 3.91 (3H, s), 6.73-6.90 (4H,
m), 6.98-7.01 (2H, d), 7.31-7.34 (2H, d), 10.26 (1H, s, C
HO)

3) Synthesis of 6-ethyl-2- (3,4-dimethoxyphenoxy) -4- (4-methoxyphenyl) pyridine-3-carboxylic acid 6 ml of methylene chloride in 1 ml of water
(3,4-dimethoxyphenoxy) -4- (4-methoxyphenyl) pyridine-3-aldehyde 110 mg
(0.28 mmol), 0.22 ml (2.08 mmol) of 2-methyl-2-butene in an ice bath, 80 m of amidosulfuric acid
g (0.82 mmol), sodium chlorite 160 m
g (1.77 mmol) was added and the mixture was stirred at room temperature for 4 hours.
Water was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol 9: 1) to give the title compound. Yield: 17 mg (0.04 mmol), yield: 20.2
% MS (ESI, m / z) 410 (MH +) H-NMR (CDCl3): 1.09-1.14 (3H, t), 2.52-2.60 (2H, qua),
3.60 (3H, s), 3.62 (3H, s), 3.80 (3H, s), 6.52-6.80 (6H,
m), 7.32-7.35 (2H, d)

Example 17 Synthesis of 6-ethyl-4- (4-methoxyphenyl) -2-phenoxypyridine-3-carboxylic acid 1) 3-Cyano-6-ethyl-4- (4-methoxyphenyl) -2 Synthesis of phenoxypyridine 82 mg (0.87 mmol) of phenol in 5 ml of DMF
l) to 55 mg of 60% sodium hydride (1.38 mm
ol) and stirred at room temperature for 15 minutes. 2-chloro-3
-Cyano-6-ethyl-4- (4-methoxyphenyl)
171 mg (0.63 mmol) of pyridine in 3 m of DMF
1 and added dropwise, and stirred at room temperature overnight. D under reduced pressure
After evaporating MF, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 6: 1) to give the title compound. Yield: 74 mg (0.22 mmol), yield: 35.8
% MS (ESI, m / z) 331 (MH +) H-NMR (CDCl3): 1.16-1.21 (3H, t), 2.65-2.72 (2H, qua),
3.88 (3H, s), 6.95 (1H, s), 7.03-7.06 (2H, d), 7.20-7.28
(3H, m), 7.38-7.44 (2H, m), 7.61-7.64 (2H, d)

2) Synthesis of 6-ethyl-4- (4-methoxyphenyl) -2-phenoxypyridine-3-carboxylic acid 3-cyano-6-ethyl-4- (4-methoxyphenyl) -2-phenoxypyridine 74mg (0.22mm
was dissolved in 5 ml of benzene, and 0.7 ml (0.7 ml) of a 1M solution of diisobutylaluminum hydride in hexane at room temperature.
mmol) and stirred at room temperature for 2 hours. 0.5 ml of methanol and 1 ml of water were added and stirred for 15 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was methylene chloride 3m
1, dissolved in 1 ml of water, 0.2 ml (1.89 mmol) of 2-methyl-2-butene in an ice bath, 75 mg of amidosulfuric acid
(0.77 mmol), 151 mg of sodium chlorite
(1.67 mmol) and the mixture was stirred at room temperature for 40 minutes.
Water was added, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel chromatography of the residue (chloroform: methanol 9: 1)
And the title compound was obtained. Yield: 32 mg (0.09 mmol), yield: 40.9
% MS (ESI, m / z) 350 (MH +) H-NMR (CDCl3): 1.09-1.14 (3H, t), 2.52-2.63 (2H, qua),
3.62 (3H, s), 6.68-6.77 (3H, m), 6.97-7.06 (3H, m), 7.13
-7.22 (2H, m), 7.33-7.36 (2H, d)

Example 18 6-methyl-4- (3,5-
Synthesis of dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) Synthesis of 1- (3,5-dimethoxyphenyl) -1-buten-3-one 3,5 1.0 g of dimethoxybenzaldehyde (6.0
mmol), 2.6 g (7.3 mmol) of acetonyltriphenylphosphonium chloride, 500 mg (7.3 mmol) of sodium ethoxide and 10 m of ethanol.
and stirred for 1.5 hours at room temperature under an argon atmosphere. Ethanol is distilled off under reduced pressure, and the obtained residue is extracted with ethyl acetate. Wash with water and saturated saline, and dry over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3 to 1: 1) to obtain the title compound. Yield: 1.00 g, yield: 80.0% MS (ESI, m / z) 207 (MH +) H-NMR (CDCl3): 2.38 (3H, s), 3.82 (6H, s), 6.52 (1
H, m), 6.66 (2H, m), 6.65 (1H, d), 7.42 (1H, d)

2) 6-methyl-3-cyano-4- (3,
Synthesis of 5-dimethoxyphenyl) -2-pyridone at room temperature under argon atmosphere.
g (4.9 mmol), potassium tert-butoxide 550 m
g (4.9 mmol) in 5 ml of DMSO
(3,5-Dimethoxyphenyl) -1-buten-3-one 1.0 g (4.8 mmol) of DMSO (10 ml) is added, and the mixture is stirred for 15 minutes. 1.63 g of potassium t-butoxide
(13.3 mmol) and bubbling oxygen for 1 minute. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 960 mg, yield: 74.0% MS (ESI, m / z) 271 (MH +) H-NMR (CDCl3): 2.50 (3H, s), 3.84 (6H, s), 6.28 (1
H, s), 6.58 (1H, s), 6.71 (2H, s)

3) 6-methyl-3-cyano-4- (3,
Synthesis of 5-dimethoxyphenyl) -2-chloropyridine 960 mg (3.6 mmol) of 6-methyl-3-cyano-4- (3,5-dimethoxyphenyl) -2-pyridone
Is dissolved in 10 ml of phosphorus oxychloride and stirred at 100 ° C. overnight. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound. This was used for the following reaction without purification. Yield: 860 mg MS (ESI, m / z) 289 (MH +) H-NMR (CDCl3): 2.65 (3H, s), 3.85 (6H, s), 6.60 (1
H, t), 6.68 (2H, d), 7.23 (1H, s)

4) 6-methyl-3-cyano-4- (3,
Synthesis of 5-dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine Sesamol 490 mg (3.5 mmol), sodium hydride 280 mg (60% oil dispersion,
7.0 mmol) of phenoxide ion prepared from
6-methyl-3-cyano-4- was added to a 10 ml MF solution.
860 mg of (3,5-dimethoxyphenyl) -2-chloropyridine is dissolved in 10 ml of DMF, and the mixture is stirred for 1 hour at room temperature under an argon atmosphere. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, and washed with water and saturated saline.
After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.
The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to give the title compound. Yield: 70 mg, yield: 6-methyl-3-cyano-4-
4 from (3,5-dimethoxyphenyl) -2-pyridone
9.8% MS (ESI, m / z) 391 (MH +) H-NMR (CDCl3): 2.45 (3H, s), 3.86 (6H, s), 6.02 (2
H, s), 6.59 (1H, t), 6.67 (1H, dd), 6.74 (3H, m),
6.82 (1H, d), 6.97 (1H, s)

5) Synthesis of 6-methyl-4- (3,5-dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6-methyl-3-cyano-4- 70 mg (0.18 mmol) of (3,5-dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine is dissolved in 10 ml of benzene, and 0.55 ml of a 1M solution of diisobutylaluminum hydride in hexane at room temperature under an argon atmosphere.
(0.55 mmol) is added dropwise. Stir at room temperature for 2 hours and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 1 hour, and the insoluble matter is filtered using celite. The filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to obtain the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 60mg

6) Synthesis of 6-methyl-4- (3,5-dimethoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 5-dimethoxyphenyl) -2
Dissolve 60 mg of-(3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde in 2 ml of methylene chloride and 1 ml of water, and add 0.1 g of 2-methyl-2-butene at 0 ° C.
ml (0.94 mmol), 20 mg of amidosulfuric acid (0.
21 mmol), 60 mg of sodium chlorite (0.5 mg)
2 mmol) and the mixture is returned to room temperature and stirred for 30 minutes. Extract with ethyl acetate, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (ethyl acetate: hexane 1: 1) to give the title compound. Yield: 6 mg, yield: 6-methyl-3-cyano-4-
8.1% MS (ESI, m / z) 410 (MH +) H-NMR (CDCl3): 2.41 (3H , s), 3.77 (6H, s), 5.98 (2
H, s), 6.48 (1H, br), 6.58-6.62 (3H, m), 6.70 (1H,
m), 6.76 (1H, d), 7.89 (1H, s)

Example 19 6-methyl-4- (4- (2
-Benzyloxyethoxy) -3-methoxyphenyl)
Synthesis of -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) Synthesis of 4- (2-hydroxyethoxy) -3-methoxybenzaldehyde 1.52 g (10.0 mmol) of vanillin, ethylene 0.7 ml (10.5 mmol) of carbonate and 1.38 g (10.0 mmol) of potassium carbonate in 10 ml of DMF
The solution is stirred at 90 ° C. for 2 days under an argon atmosphere. The DMF is distilled off under reduced pressure, the residue is dissolved in chloroform, and the insoluble matter is filtered using Celite. The crystals obtained by evaporating the solvent under reduced pressure were washed with ethyl acetate: hexane 1: 1 to obtain the title compound. Yield: 1.17 g, 59.6% MS (ESI, m / z) 197 (MH +) H-NMR (CDCl3): 2.35 (1H, br), 3.93 (3H, s), 4.06 (2
H, br t), 4.24 (2H, t), 7.11 (1H, d), 7.43-7.47 (3
H, m), 9.85 (1H, s)

2) 4- (2-benzyloxyethoxy)
Synthesis of -3-methoxybenzaldehyde 1.17 g (6.0 mmol) of 4- (2-hydroxyethoxy) -3-methoxybenzaldehyde was added to DMF10
290 mg of sodium hydride (60% oil dispersion, 7.degree. C.) at 0.degree. C. under an argon atmosphere.
3 mmol), 0.85 ml of benzyl bromide (7.1 mm
ol) and stirred for 20 minutes. The solvent is distilled off under reduced pressure, and water is added. Extract with ethyl acetate and wash with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound. Yield: 1.56 g, 90.8% MS (ESI, m / z) 287 (MH +) H-NMR (CDCl3): 3.90 (2H, m), 3.93 (3H, s), 4.29 (2
H, t), 4.64 (2H, s), 7.01 (1H, d), 7.25-7.36 (5H,
m), 7.40-7.45 (2H, m), 9.85 (1H, s)

3) Synthesis of 4- (4- (2-benzyloxyethoxy) -3-methoxyphenyl) -1-buten-3-one 1.56 g of 4- (2-benzyloxyethoxy) -3-methoxybenzaldehyde (5.4 mmol), acetonyltriphenylphosphonium chloride 2.32 g
(6.5 mmol), 450 mg of sodium ethoxide
(6.6 mmol) was dissolved in 10 ml of ethanol, and the mixture was stirred at room temperature under an argon atmosphere for 2 days. Ethanol is distilled off under reduced pressure, and the obtained residue is extracted with ethyl acetate.
Wash with water and saturated saline, and dry over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1).
2) The title compound was obtained. Yield: 1.30 g, Yield: 73.8% MS (ESI, m / z) 327 (MH +) H-NMR (CDCl3): 2.37 (3H, s), 3.85-3.90 (2H, m), 3.9
0 (3H, s), 4.25 (2H, t), 4.64 (2H, s), 6.60 (1H,
d), 6.91 (1H, d), 7.08 (1H, s), 7.09 (1H, dd), 7.2
5-7.38 (5H, m), 7.45 (1H, d)

4) 6-methyl-3-cyano-4- (4-
Synthesis of (2-benzyloxyethoxy) -3-methoxyphenyl) -2-pyridone Cyanoacetamide 340 m at room temperature under argon atmosphere
g (4.0 mmol), potassium t-butoxide 450 m
g (4.0 mmol) in 5 ml of DMSO
1.30 g of ((2-benzyloxyethoxy) -3-methoxyphenyl) -1-buten-3-one (4.0 mm
ol) of DMSO (10 ml) and stirred for 15 minutes. t
Add 1.35 g (12.0 mmol) of potassium butoxide and bubble oxygen for 1 minute. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 1.25 g, 80.0% MS (ESI, m / z) 391 (MH +) H-NMR (CDCl3): 2.48 (3H, s), 3.86-4.00 (2H, m), 3.9
4 (3H, s), 4.28 (2H, t), 4.65 (2H, s), 6.28 (1H,
s), 7.00 (1H, d), 7.20 (1H, m), 7.20-7.40 (6H, m)

5) 6-methyl-3-cyano-4- (4-
Synthesis of (2-benzyloxyethoxy) -3-methoxyphenyl) -2-chloropyridine 6-methyl-3-cyano-4- (4- (2-benzyloxyethoxy) -3-methoxyphenyl) -2-pyridone 1.25 g (3.2 mmol) of phosphorus oxychloride 10
Dissolve in 100 ml and stir at 100 ° C. for 5 hours. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound. This was used for the following reaction without purification. Yield: 870 mg MS (ESI, m / z) 409 (MH +) H-NMR (CDCl3): 2.64 (3H, s), 3.94 (3H, s), 3.80-4.0
0 (2H, m), 4.28 (2H, t), 4.66 (2H, s), 7.03 (1H,
d), 7.10-7.40 (8H, m)

6) 6-methyl-3-cyano-4- (4-
Synthesis of (2-benzyloxyethoxy) -3-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine Sesamol 440 mg (3.2 mmol), sodium hydride 250 mg (60% oil dispersion,
D) of phenoxide ion prepared from 6.2 mmol)
6-methyl-3-cyano-4- (4
870 mg of-(2-benzyloxyethoxy) -3-methoxyphenyl) -2-chloropyridine is added to 10 m of DMF.
and stirred for 2 hours at room temperature under an argon atmosphere. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
Wash with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate: hexane)
1: 1) to give the title compound. Yield: 260 mg, Yield: 6-methyl-3-cyano-4
-(4- (2-Benzyloxyethoxy) -3-methoxyphenyl) -2-pyridone 15.9% MS (ESI, m / z) 511 (MH +) H-NMR (CDCl3): 2.45 (3H, s) ), 3.90 (2H, t), 3.95 (3
H, s), 4.28 (2H, t), 4.65 (2H, s), 6.02 (2H, s),
6.67 (1H, dd), 6.74 (1H, d), 6.82 (1H, d), 6.96 (1
H, s), 7.05 (1H, d), 7.19 (1H, dd), 7.20 (1H, d),
7.28-7.40 (5H, m)

7) 6-methyl-4- (4- (2-benzyloxyethoxy) -3-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6-methyl-3-cyano-4- (4- (2-benzyloxyethoxy) -3-methoxyphenyl) -2- (3,
4-Methylenedioxyphenyloxy) pyridine 260
mg (0.51 mmol) is dissolved in 3 ml of benzene, and 1.5 ml (1.5 mmol) of a 1 M solution of diisobutylaluminum hydride in hexane is added dropwise at room temperature under an argon atmosphere. Stir at room temperature for 2 hours and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 30 minutes, and the insoluble matter is filtered using Celite. The filtrate was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1) to give the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 160 mg MS (ESI, m / z) 514 (MH +)

8) 6-methyl-4- (4- (2-benzyloxyethoxy) -3-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6-methyl-4- (4- (2-benzyloxyethoxy) -3-methoxyphenyl) -2- (3,4-methylene 160 mg of dioxyphenyloxy) pyridine-3-aldehyde was dissolved in 2 ml of methylene chloride and 1 ml of water,
At 0 ° C., 0.23 ml of 2-methyl-2-butene (2.2 m
mol), 45 mg (0.46 mmol) of amidosulfuric acid,
125 mg (1.1 mmol) of sodium chlorite is added and the mixture is returned to room temperature and stirred for 1 hour. Extract with ethyl acetate, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure.
The obtained residue was subjected to silica gel thin layer chromatography (ethyl acetate: hexane 1: 1) to give the title compound. Yield: 105 mg, Yield: 6-methyl-3-cyano-4
38.9% MS (ESI, m / z) 530 (MH +) H from-(4- (2-benzyloxyethoxy) -3-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine -NMR (CDCl3): 2.40 (3H, s), 3.80 (3H, s), 3.80-3.9
0 (2H, m), 4.18 (2H, br t), 4.62 (2H, s), 5.98 (2H,
s), 6.62 (1H, dd), 6.72 (1H, d), 6.76 (1H, d), 6.
88 (1H, s), 6.90-6.94 (1H, m), 6.98-7.02 (2H, s),
7.20-7.40 (5H, m)

Example 20 6-methyl-4- (4- (2
-Hydroxyethoxy) -3-methoxyphenyl) -2
Synthesis of-(3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6-methyl-4- (4- (2-benzyloxyethoxy) -3-methoxyphenyl) -2- (3,4- Dissolve 80 mg (0.15 mmol) of methylenedioxyphenyloxy) pyridine-3-carboxylic acid in ethanol
50 mg of 0% palladium carbon is added, and the mixture is stirred overnight at room temperature and 1 atm under a hydrogen atmosphere. The catalyst is removed using celite, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (chloroform: methanol 9: 1).
(Twice development) to give the title compound. Yield: 20 mg, yield: 30.1% MS (ESI, m / z) 440 (MH +) H-NMR (CDCl3): 2.38 (3H, s), 3.46 (1H, s), 3.62 (3
H, s), 3.98 (2H, br), 4.14 (2H, br), 5.95 (2H, br)
s), 6.62 (1H, dd), 6.70 (1H, d), 6.73 (1H, d), 6.8
6 (1H, s), 6.92 (1H, d), 7.02 (2H, m)

Example 21 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -2- (3
Synthesis of 4-methylenedioxyphenoxy) -6-methylpyridine-3-carboxylic acid 1) Synthesis of 2- (2-benzyloxyethoxy) -4-methoxybenzaldehyde 3.83 g of 2-benzyloxyethanol in 100 ml of methylene chloride (25.2 mmol), 3.9 ml (50.4 mmol) of methanesulfonic acid chloride, and 7.7 ml (55.2 mmol) of triethylamine at room temperature.
Stirred overnight. 2N Hydrochloric acid was added, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 5 ml of DMF and 2-hydroxy-4-methoxybenzaldehyde 3.1 in 50 ml of DMF.
0 g (20.4 mmol) and 60% sodium hydride 8
88 mg (22.2 mmol) were added to the solution stirred at room temperature for 20 minutes. After stirring at room temperature overnight, the mixture was heated and stirred at 80 ° C. for 4 hours. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 3.86 g (13.5 mmol), yield: 66.
2% H-NMR (CDCl3): 3.84 (3H, s), 3.86-3.90 (2H, m), 4.22-4.
26 (2H, m), 4.63 (2H, s), 6.44-6.58 (2H, m), 7.26-7.39 (5
H, m), 7.81-7.84 (1H, d), 10.34-10.35 (1H, d)

2) Synthesis of 1- (2- (2-benzyloxyethoxy) -4-methoxy) phenyl-1-buten-3-one Acetonyltriphenylphosphonium chloride 6.2
5 g (17.6 mmol), sodium ethoxide
20 g (17.6 mmol) and 2- (2-benzyloxyethoxy) -4-methoxybenzaldehyde 3.86
g (13.5 mmol) in 140 ml of ethanol
Refluxed for days. After distilling off ethanol under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 3.70 g (11.3 mmol), yield: 83.
9% MS (ESI, m / z) 327 (MH +) H-NMR (CDCl3): 2.31 (3H, s), 3.81 (3H, s), 3.88-3.92 (2
H, m), 4.20-4.24 (2H, m), 4.65 (2H, s), 6.47-6.56 (2H,
m), 6.68-6.73 (1H, d), 7.26-7.39 (5H, m), 7.47-7.50 (1
H, d), 7.81-7.86 (1H, d)

3) Synthesis of 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-6-methyl-2-pyridone 953 mg of cyanoacetamide in 20 ml of DMSO
(11.3 mmol) to potassium t-butoxide 1.27
g (11.3 mmol) and then 1- (2- (2-benzyloxyethoxy) -4-) dissolved in 10 ml of DMSO.
3.70 g of methoxy) phenyl-1-buten-3-one
(11.3 mmol) was added and stirred at room temperature for 30 minutes.
3.90 g (34.8 mmol) of potassium t-butoxide
Was added, oxygen gas was bubbled for 2 minutes, and the mixture was further stirred at room temperature under an atmosphere of normal pressure oxygen for 3 hours. 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Yield: 4.05 g (10.4 mmol);
0% MS (ESI, m / z) 391 (MH +) H-NMR (CDCl3): 2.62 (3H, s), 3.75 to 3.90 (5H, m), 4.21-4.
25 (2H, m), 4.56 (2H, s), 6.44-6.68 (3H, m), 7.24-7.42 (6
H, m)

4) Synthesis of 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -2-chloro-3-cyano-6-methylpyridine
Phosphorus oxychloride was added to 4.05 g (10.4 mmol) of (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-6-methyl-2-pyridone.
ml, N, N-dimethylaniline 1.3 ml (10.3
mmol) and heated at 100 ° C. for 2 hours. After distilling off phosphorus oxychloride, water was added, and the mixture was extracted with ether and ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate,
The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used for the next reaction without purification. Yield: 3.02 g (7.38 mmol), yield: 71.
0% MS (ESI, m / z) 409 (MH +) H-NMR (CDCl3): 2.55 (3H, s), 3.76-3.88 (5H, m), 4.20-4.
24 (2H, m), 4.52 (2H, s), 6.59-6.79 (3H, m), 7.19-7.40 (6
H, m)

5) 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-2-
Synthesis of (3,4-methylenedioxyphenoxy) -6-methylpyridine 1.14 g (8.25 m) of sesamol in 30 ml of DMF
mol) to 280 mg (7.0 mg) of 60% sodium hydride.
mmol) and stirred at room temperature for 15 minutes. 4- (2-
3.02 g (7.38 mmol) of (2-benzyloxyethoxy) -4-methoxyphenyl) -2-chloro-3-cyano-6-methylpyridine was dissolved in 20 ml of DMF, added dropwise, and stirred at room temperature for 7 hours. 250 mg (6.25 mmol) of 60% sodium hydride was added, and the mixture was further stirred for 2 hours. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound. Yield: 546 mg (1.07 mmol), yield: 14.
5% MS (ESI, m / z) 511 (MH +) H-NMR (CDCl3): 2.38 (3H, s), 3.84 (3H, s), 3.81-3.87 (2
H, m), 4.22-4.26 (2H, m), 4.54 (2H, s), 6.00 (2H, s), 6.5
8-6.64 (3H, m), 6.70-6.72 (1H, d), 6.77-6.80 (1H, d), 6.
96 (1H, s), 7.23-7.30 (6H, m)

6) 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) -6-methylpyridine-3-
Synthesis of aldehyde 540 mg of 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-2- (3,4-methylenedioxyphenoxy) -6-methylpyridine
(1.06 mmol) was dissolved in 10 ml of benzene, and 3.2 ml (3.2 mmol) of a 1 M solution of diisobutylaluminum hydride in hexane was added at room temperature, followed by stirring at room temperature for 2.5 hours. 1 ml of methanol and 2 ml of water were added and stirred for 15 minutes. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to obtain the title compound. Yield: 242 mg (0.47 mmol), yield: 44.
5% H-NMR (CDCl3): 2.39 (3H, s), 3.69-3.72 (2H, t), 3.83 (3
H, s), 4.09-4.13 (2H, m), 4.49 (2H, s), 5.99 (2H, s), 6.5
3-6.62 (3H, m), 6.67-6.68 (1H, d), 6.75-6.78 (1H, d), 6.
81 (1H, s), 7.13-7.16 (1H, d), 7.21-7.32 (5H, m), 10.18
(1H, s)

7) 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) -6-methylpyridine-3-
Synthesis of carboxylic acid 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -2-in 4 ml of methylene chloride and 2 ml of water
238 mg of (3,4-methylenedioxyphenoxy) -6-methylpyridine-3-aldehyde (0.46 mmol
1) 0.45 ml of 2-methyl-2-butene in an ice bath
(4.25 mmol), 150 mg (1.5 mg) of amidosulfuric acid
4 mmol), 300 mg of sodium chlorite (3.3
2 mmol) and stirred at room temperature for 30 minutes. Water was added, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol 25: 1) to give the title compound. Yield: 202 mg (0.38 mmol), yield: 82.
3% MS (ESI, m / z) 530 (MH +) H-NMR (CDCl3): 2.38 (3H, s), 3.70-3.73 (2H, t), 3.78 (3
H, s), 4.07-4.09 (2H, t), 4.52 (2H, s), 5.96 (2H, s), 6.4
7-6.57 (3H, m), 6.63-6.64 (1H, d), 6.70-6.73 (1H, d), 6.
83 (1H, s), 7.17-7.30 (6H, m)

Example 22 4- (2- (2-hydroxyethoxy) -4-methoxyphenyl) -2- (3,4-
Methylenedioxyphenoxy) -6-methylpyridine-
Synthesis of 3-carboxylic acid 4- (2- (2-benzyloxyethoxy) -4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) -6-methylpyridine-3-carboxylic acid 178
mg (0.34 mmol) was stirred in the presence of 10% Pd-C in 10 ml of methanol at room temperature under an atmosphere of hydrogen at normal pressure overnight. The title compound was obtained after usual work-up. Yield: 112 mg (0.26 mmol), yield: 76.
1% MS (ESI, m / z) 440 (MH +) H-NMR (CDCl3 + CD3OD): 2.40 (3H, s), 3.36 to 3.39 (2H, m),
3.84 (3H, s), 4.01-4.07 (2H, m), 5.97 (2H, s), 6.48-6.64
(3H, m), 6.70 (1H, s), 6.76-6.79 (1H, d), 6.82-6.83 (1H,
d), 7.19-7.22 (1H, d)

Example 23 6- (2-furyl) -4-
(4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) Synthesis of 2- (3- (4-methoxyphenyl) -2-propenoyl) furan 2-acetyl 1.10 g (10.0 mmol) of furan,
1.22 ml of p-anisaldehyde (10.0 mmol
10 ml of a 1N sodium hydroxide solution is added to a solution of 1) in 20 ml of THF, and the mixture is stirred at room temperature for 2 days. After extraction with ethyl acetate, washing with water, 1N hydrochloric acid and saturated saline, drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3). The title compound was obtained. Yield: 1.10 g, Yield: 48.2% MS (ESI, m / z) 229 (MH +) H-NMR (CDCl3): 3.86 (3H, s), 6.58 (1H, dd), 7.31-7.
34 (2H, m), 7.61 (2H, d), 7.64 (1H, m), 7.85 (1H,
d)

2) 3-cyano-6- (2-furyl) -4
Synthesis of-(4-methoxyphenyl) -2-pyridone Cyanoacetamide 410m at room temperature under argon atmosphere
g (4.9 mmol), potassium tert-butoxide 540 m
g (4.8 mmol) in 5 ml of DMSO was added to 2- (3
-(4-methoxyphenyl) -2-propenyl) furan 1.10 g (4.8 mmol) of DMSO in 15 ml
And stir for 15 minutes. potassium t-butoxide 1.6
Add 2 g (14.4 mmol) and bubble oxygen for 1 minute. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 1.18 g, yield: 84.1% MS (ESI, m / z) 311 (MH +) H-NMR (CDCl3): 3.89 (3H, s), 6.69 (1H, m), 6.83 (1
H, s), 7.06 (2H, d), 7.55-7.72 (4H, m)

3) 6- (2-furyl) -3-cyano-4
Synthesis of-(4-methoxyphenyl) -2-chloropyridine 1.18 g (4.0 mmol) of 3-cyano-6- (2-furyl) -4- (4-methoxyphenyl) -2-pyridone
l) is dissolved in 10 ml of phosphorus oxychloride and stirred at 90 ° C. overnight. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The crystals obtained by evaporating the solvent under reduced pressure were washed with ethyl acetate to obtain the title compound. This was used for the following reaction without further purification. Yield: 720 mg MS (ESI, m / z) 311 (MH +) H-NMR (CDCl3): 3.89 (3H, s), 6.61 (1H, dd), 7.06 (2
H, d), 7.31 (1H, dd), 7.61 (1H, m), 7.63 (2H, d),
7.68 (1H, s)

4) 6- (2-furyl) -3-cyano-4
Synthesis of-(4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine Sesamol 320 mg (2.3 mmol), sodium hydride 190 mg (60% oil dispersion,
4.8 mmol) of phenoxide ion prepared from
6- (2-furyl) -3-cyano-
720 mg of 4-((2-benzyloxyethoxy) -3-methoxyphenyl) -2-chloropyridine is added, and the mixture is stirred at room temperature for 30 minutes under an argon atmosphere. The solvent is distilled off under reduced pressure, the residue is dissolved in chloroform, and washed with water and saturated saline. The crystals obtained by drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure were washed with ethyl acetate to obtain the title compound. Yield: 340 mg, Yield: 17.2% MS (ESI, m / z) 413 (MH +) H- from 3-cyano-6- (2-furyl) -4- (4-methoxyphenyl) -2-pyridone. NMR (CDCl3): 3.89 (3H, s), 6.03 (2H, s), 6.58 (1
H, dd), 6.72 (1H, dd), 6.81 (1H, d), 6.83 (1H,
d), 6.92 (1H, d), 7.06 (2H, d), 7.47 (1H, s), 7.52
(1H, m), 7.68 (2H, d)

5) Synthesis of 6- (2-furyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6- (2-furyl)- 340 mg (0.82 mmol) of 3-cyano-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine is dissolved in 10 ml of methylene chloride and diisobutylaluminum hydride 1M is added at room temperature under an argon atmosphere. Hexane solution 2.5
ml (2.5 mmol) are added dropwise. Stir at room temperature for 1 hour and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 30 minutes, and the insoluble matter is filtered using Celite. The filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol 100: 1) to obtain the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 180 mg MS (ESI, m / z) 416 (MH +)

6) Synthesis of 6- (2-furyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6- (2-furyl) -4- (4-methoxyphenyl)-
180 mg of 2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde was added to 4 m of methylene chloride.
l, dissolved in 2 ml of water, 0.3 ml (2.8 mmol) of 2-methyl-2-butene at 0 ° C., 60 mg of amidosulfuric acid
(0.62 mmol), 170 mg of sodium chlorite
(1.5 mmol) was added and the mixture was returned to room temperature and stirred for 1 hour. Extract with methylene chloride, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The obtained residue is subjected to silica gel thin layer chromatography (ethyl acetate: hexane 1: 1:
(12 developments) to give the title compound. Yield: 50 mg, Yield: 27.0 from 6- (2-furyl) -3-cyano-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine
% MS (ESI, m / z) 432 (MH +) H-NMR (CDCl3): 3.81 (3H, s), 5.99 (2H, s), 6.45 (1
H, dd), 6.67 (1H, dd), 6.76 (1H, d), 6.78 (1H,
s), 6.83 (1H, d), 6.94 (2H, d), 7.38 (1H, s), 7.46
(2H, d), 7.47 (1H, m)

Example 24 Synthesis of 5-bromo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 1) 5-Bromo- Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-methyl-2-pyridone 1 g of 3-cyano-4- (4-methoxyphenyl) -6-methyl-2-pyridone (4. 42m
mol) was dissolved in 10 ml of carbon tetrachloride, and NBS 1.5
7 g (8.84 mmol), AIBN 1.45 g (8.8.
84 mmol) and stirred at 100 ° C. for 12 hours. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual yellow crystals were recrystallized from chloroform and hexane to give the title compound. Yield: 370 mg, Yield: 26% MS (ESI. M / z) 319 (MH +) H-NMR (CDCl3): 2.65 (3H, s), 3.88 (3H, s), 7.03 (2
H, d), 7.32 (2H, d)

2) Synthesis of 5-bromo-2-chloro-3-cyano-4- (4-methoxyphenyl) -6-methyl-pyridine 5-bromo-3-cyano-4- (4-methoxyphenyl)- 370 mg of 6-methyl-2-pyridone (1.16
(mmol), and the mixture was stirred at 120 ° C for 24 hours. Thereafter, phosphorus oxychloride is distilled off under reduced pressure, the residue is added to ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound. Yield: 380 mg, yield: 97% MS (ESI. M / z) 338 (MH +) H-NMR (CDCl3): 2.66 (3H, s), 3.88 (3H, s), 7.02-7.
05 (2H, m), 7.27-7.30 (2H, m)

3) 5-Bromo-3-cyano-4- (4-
Synthesis of methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine Under an argon atmosphere, 187 mg of sesamol (1.36 m
mol) was dissolved in 10 ml of DMF, and 54 mg (1.36 mmol) of 60% sodium hydride was added at 0 ° C.
Stir for 1 hour. This is followed by 5-bromo-2-chloro-3
-Cyano-4- (4-methoxyphenyl) -6-methyl-pyridine (380 mg, 1.13 mmol) was added, and 8
The mixture was stirred at 0 ° C for 12 hours. The reaction solution was poured into water, the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent hexane: ethyl acetate 3: 1). To give the title compound. Yield: 200 mg, yield: 40% MS (ESI. M / z) 439 (MH +) H-NMR (CDCl3): 2.60 (3H, s), 3.88 (3H, s), 6.02 (2
H, s), 6.62 to 6.73 (3H, m), 6.81 (1H, d), 7.04 (2H,
d), 7.33 (2H, d)

4) Synthesis of 5-bromo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde In 10 ml of methylene chloride under an argon atmosphere , 5-bromo-3-cyano-4- (4-methoxyphenyl) -6
Methyl-2- (3,4-methylenedioxyphenoxy)
-200 mg (0.455 mmol) of pyridine was dissolved, 2.78 ml of a 1 M solution of diisobutylaluminum hydride in hexane was added at 0 ° C, and the mixture was stirred at room temperature overnight.
Thereafter, 1 ml of water was added and the mixture was stirred for 1 hour, filtered through celite, and the residue was washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give a crude product of the title compound. Due to difficulty in purification, the following reaction was performed without purification. Yield: 80 mg, yield: 40%

5) Synthesis of 5-bromo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 5-bromo-4- ( 4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde 80 mg (0.181 mmol
l) was dissolved in 5 ml of water and 10 ml of methylene chloride, and 76 mg (1.09 mmol) of 2-methyl-butene was added under ice-cooling.
l), 26 mg (0.272 mmol) of amidosulfuric acid and 57 mg (0.634 mmol) of sodium chlorite were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 14 mg, Yield: 17% MS (ESI.m / z) 458 (MH +) H-NMR (CDCl3): 2.53 (3H, s), 3.78 (3H, s), 5.97 (2
H, s), 6.55-6.75 (3H, m), 6.88 (2H, d), 7.17 (2H,
d)

Example 25 6-methyl-4- (3- (2
-Benzyloxyethoxy) -5-methoxyphenyl)
Synthesis of 2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) Synthesis of methyl 3-hydroxy-5-methoxybenzoate 5.5 g of methyl 3,5-dihydroxybenzoate (32.
7 mmol), 2.2 ml of methyl iodide (35.3 mm
ol) and 4.5 g (32.6 mmol) of potassium carbonate in 30 ml of DMF are stirred at room temperature overnight. DMF is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, and the insoluble matter is filtered. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to obtain 2.23 g (37.4%) of the title compound. At this time, 1.88 g of methyl 3,5-dimethoxybenzoate is also obtained. Yield: 2.23 g, Yield: 37.4% H-NMR (CDCl3): 3.82 (3H, s), 3.91 (3H, s), 4.90-5.3
0 (1H, br), 6.62 (1H, m), 7.15 (1H, m), 7.18 (1H,
m)

2) Synthesis of 3- (2-benzyloxy) -5-methoxybenzyl alcohol 1.0 g of methyl 3-hydroxy-5-methoxybenzoate
(5.5 mmol) is dissolved in 10 ml of DMF, 250 mg of sodium hydride (60% oil dispersion, 6.3 mmol) and 1.9 g (8.3 mmol) of 2-benzyloxyethyl methanesulfonate are added, and the mixture is stirred overnight. DMF was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with 1N sodium hydroxide, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3- (2-benzyl) 2.23 g of methyl oxy) -5-methoxybenzoate were obtained. This is used for the following reaction without purification. 3- (2-benzyloxy) -5
2.23 g of methyl methoxybenzoate was dissolved in 20 ml of THF, and 300 mg of lithium aluminum hydride was added at 0 ° C.
(7.9 mmol) was added and the mixture was returned to room temperature and stirred overnight.
The reaction was stopped by adding saturated aqueous ammonia at 0 ° C., and the mixture was filtered using Celite. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1) to obtain the title compound. Yield: 1.41 g, Yield: 88.9% MS (ESI, m / z) 311 (M + Na) H-NMR (CDCl3): 3.78 (3H, s), 3.82 (2H, dd), 4.15 ( Two
H, dd), 4.60 (2H, m), 4.63 (2H, s), 6.42 (1H, t),
6.53 (2H, m), 7.25-7.40 (5H, m)

3) Synthesis of 3- (2-benzyloxy) -5-methoxybenzaldehyde 1.41 g (4.9 mmol) of 3- (2-benzyloxy) -5-methoxybenzyl alcohol was dissolved in 10 ml of chloroform. 2.0 g of manganese dioxide are added and stirred for 2 days. Further add 2.0 g of activated manganese dioxide, stir overnight, and filter using celite. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 2) to obtain the title compound. Yield: 1.04 g, Yield: 74.1% MS (ESI, m / z) 309 (M + Na) H-NMR (CDCl3): 3.84 (3H, s), 3.85 (2H, m), 4.20 ( Two
H, m), 4.64 (2H, s), 6.75 (1H, t), 7.02 (2H, m),
7.25-7.40 (5H, m), 9.90 (1H, s)

4) Synthesis of 1- (3- (2-benzyloxyethoxy) -5-methoxyphenyl) -1-buten-3-one 1.04 g of 3- (2-benzyloxy) -5-methoxybenzaldehyde ( 3.6 mmol), 1.55 g of acetonyltriphenylphosphonium chloride (4.4 m
mol), 0.3 g of sodium ethoxide (4.4 mm
ol) in 20 ml of ethanol and reflux under heating for 5 hours. The ethanol is distilled off under reduced pressure and extracted with ethyl acetate. After washing with water, 1N hydrochloric acid and saturated saline, drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1) to obtain the title compound. Yield: 1.0 g, Yield: quantitative MS (ESI, m / z) 349 (M + Na) H-NMR (CDCl3): 2.37 (3H, s), 3.80 (3H, s), 3.83 (2
H, dd), 4.16 (2H, dd), 4.64 (2H, s), 6.55 (1H,
t), 6.65 (1H, d), 6.67-6.72 (2H, m), 7.26-7.36 (5H,
m), 7.40 (1H, d)

5) 6-methyl-3-cyano-4- (3-
Synthesis of (2-benzyloxyethoxy) -5-methoxyphenyl) -2-pyridone Cyanoacetamide 580m at room temperature under argon atmosphere
g (6.9 mmol), potassium tert-butoxide 780 m
g (6.2 mmol) in DMSO (5 ml) was added to 4- (3
-(2-benzyloxyethoxy) -5-methoxyphenyl) -1-buten-3-one 1.0 g (3.6 mmol)
l) 10 ml of DMSO is added and stirred for 15 minutes. t-
2.32 g (20.7 mmol) of potassium butoxide is added and oxygen is bubbled for 1 minute. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice cooling, and the precipitated viscous substance is removed by decantation. After dissolving in ethyl acetate and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained substance was washed with ethyl acetate: hexane 1: 1 to obtain the title compound. This compound is used for the following reaction without further purification. Yield: 940 mg, Yield: 66.9% MS (ESI, m / z) 413 (M + Na) H-NMR (CDCl3): 2.49 (3H, s), 3.83 (3H, s), 3.84 (2
H, m), 4.20 (2H, m), 4.62 (2H, s), 6.24 (1H, s),
6.62 (1H, m), 6.72 (2H, m), 7.25-7.40 (5H, m)

6) 6-methyl-3-cyano-4- (3-
Synthesis of (2-benzyloxyethoxy) -5-methoxyphenyl) -2-chloropyridine 6-methyl-3-cyano-4- (3- (2-benzyloxyethoxy) -5-methoxyphenyl) -2-pyridone 940 mg (2.4 mmol) of phosphorus oxychloride 10
Dissolve in the solution and stir at 90 ° C overnight. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in chloroform. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound. This was used for the following reaction without purification. Yield: 1.0 g MS (ESI, m / z) 431 (M + Na) H-NMR (CDCl3): 2.62 (3H, s), 3.82 (3H, s), 3.85 (2
H, m), 4.20 (2H, m), 4.64 (2H, s), 6.62 (1H, m),
6.70 (2H, m), 7.22 (1H, s), 7.25-7.40 (5H, m)

7) 6-methyl-3-cyano-4- (3-
Synthesis of (2-benzyloxyethoxy) -5-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 330 mg (2.4 mmol) of sesamol, 190 mg of sodium hydride (60% oil dispersion,
D) of phenoxide ion prepared from 4.7 mmol)
6-Methyl-3-cyano-4- (3-
1.0 g of (2-benzyloxyethoxy) -5-methoxyphenyl) -2-chloropyridine is dissolved in 15 ml of DMF, and the mixture is stirred at room temperature for 30 minutes under an argon atmosphere. The solvent is distilled off under reduced pressure, the residue is dissolved in chloroform, and washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate: hexane)
1: 2) to give the title compound. This contains impurities which are difficult to separate, but is used for the following reaction without further purification. Yield: 530 mg MS (ESI, m / z) 533 (M + Na)

8) 6-methyl-4- (3- (2-benzyloxyethoxy) -5-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 6-methyl-3-cyano-4- (3- (2-benzyloxyethoxy) -5-methoxyphenyl) -2- (3,
4-Methylenedioxyphenyloxy) pyridine 530
mg (1.0 mmol) is dissolved in 10 ml of benzene, and 4.0 ml (4.0 mmol) of a 1 M solution of diisobutylaluminum hydride in hexane is added dropwise at room temperature under an argon atmosphere. Stir at room temperature for 2 hours and terminate the reaction with methanol and water. The mixture is stirred at room temperature for 30 minutes, and the insoluble matter is filtered using Celite. The filtrate was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1) to give the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 280 mg MS (ESI, m / z) 536 (M + Na) H-NMR (CDCl3), 2.41 (3H, s), 3.80 (3H, s), 3.83 (2
H, m), 4.18 (2H, m), 4.64 (2H, s), 6.02 (2H, s),
6.48 (2H, m), 6.57 (1H, m), 6.63 (1H, dd), 6.72 (1
H, d), 6.80 (1H, d), 6.85 (1H, s), 7.20-7.40 (5H,
m), 10.19 (1H, s)

9) 6-methyl-4- (3- (2-benzyloxyethoxy) -5-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6-methyl-4- (3- (2-benzyloxyethoxy) -5-methoxyphenyl) -2- (3,4-methylene 280 mg of dioxyphenyloxy) pyridine-3-aldehyde was dissolved in 4 ml of methylene chloride and 2 ml of water,
At 0 ° C, 0.40 ml of 2-methyl-2-butene (3.8 m
mol), 80 mg (0.82 mmol) of amidosulfuric acid,
After adding 220 mg (1.9 mmol) of sodium chlorite, the mixture is returned to room temperature and stirred for 1 hour. Extract with methylene chloride, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (developed twice with ethyl acetate: hexane 1: 1) to give the title compound. Yield: 140 mg, Yield: 6-methyl-3-cyano-4
11.0% from-(3- (2-benzyloxyethoxy) -5-methoxyphenyl) -2-pyridone MS (ESI, m / z) 530 (MH +) H-NMR (CDCl3): 2.38 (3H, s) ), 3.74 (5H, m), 4.08 (2
H, m), 4.57 (2H, s), 5.95 (2H, s), 6.47 (1H, m),
6.54-6.76 (4H, m), 6.85 (1H, s), 6.90-6.94 (1H,
m), 7.25-7.40 (5H, m)

Example 26 6-methyl-4- (3- (2
-Hydroxyethoxy) -5-methoxyphenyl) -2
Synthesis of-(3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6-methyl-4- (3- (2-benzyloxyethoxy) -5-methoxyphenyl) -2- (3,4- 120 mg (0.23 mmol) of methylenedioxyphenyloxy) pyridine-3-carboxylic acid is dissolved in 5 ml of ethanol, 50 mg of 10% palladium on carbon is added, and the mixture is stirred under a hydrogen atmosphere at room temperature and 1 atm overnight. The catalyst is removed using celite, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel thin layer chromatography (chloroform: methanol).
10: 1 four times) to give the title compound (). Yield: 30 mg, Yield: 29.7% MS (ESI, m / z) 440 (MH +) H-NMR (CDCl3): 2.40 (3H, s), 3.77 (3H, s), 3.90 (2
H, m), 4.05 (2H, m), 5.97 (2H, s), 6.49 (1H, m),
6.57-6.77 (5H, m), 6.87 (1H, s)

Example 27 4- [3- (2-hydroxyethoxy) -4-methoxy-phenyl] -6-methyl-
Synthesis of 2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 1) Synthesis of 3-benzyloxyethoxy-4-methoxy-benzaldehyde 2 g (13.1 mmol) of isovanillin under an argon atmosphere
1) was dissolved in 20 ml of DMF, 632 mg (15.8 mmol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 3.64 g (15.8 mmol) of benzylsulfonic acid benzyloxyethyl ester was added at room temperature, and the mixture was stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
To give the title compound. Yield: 3.45 g, yield: 92% MS (ESI.m / z) 287 (MH +) H-NMR (CDCl3): 3.87 (2H, t), 3.93 (3H, s), 4.26 (2
H, t), 4.64 (2H, s), 6.96 (1H, s), 7.24-7.47 (7H,
m), 9.82 (1H, s)

2) 1- (3-benzyloxyethoxy-)
Synthesis of 4-methoxy-phenyl) -1-butenyl-3-one acetonyltriphenylphosphonium chloride 3.7
3 g (10.5 mmol) of ethanol (20 ml)
Sodium ethoxide 715mg (10.5m
mol) was added at 0 ° C. After returning to room temperature and stirring for 1 hour, 2.00 g (6.99 mmol) of 3-benzyloxyethoxy-4-methoxy-benzaldehyde was added, and the mixture was stirred overnight. The solvent was distilled off from the reaction solution under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This was purified on silica gel using hexane / ethyl acetate (3: 1) to give the title compound. Yield: 1.72 g, Yield: 75% MS (ESI.m / z) 327 (MH +) H-NMR (CDCl3): 2.34 (3H, s), 3.86-3.90 (5H, m), 4.24 (2
H, t), 4.64 (2H, s), 6.56 (1H, d), 6.88 (1H d), 7.12-7.4
6 (8H, m)

3) 4- (3-benzyloxyethoxy-)
4-methoxy-phenyl) -3-cyano-6-methyl-
Synthesis of 2-pyridone α-cyanoacetamide 486 mg (5.78 mmol)
l) in 20 ml of DMSO, and
590 mg of potassium t-butoxide (5.26 mmol
l), 1.72 g of 1- (3-benzyloxyethoxy-4-methoxy-phenyl) -1-butenyl-3-one
(5.26 mmol) was sequentially added at room temperature, and the mixture was stirred for 15 minutes. After confirming the disappearance of the raw materials by TLC, 1.77 g (15.8 mmol) of potassium t-butoxide was added, oxygen was bubbled for 1 minute, and the mixture was stirred under an oxygen atmosphere for 1 hour. When 20 ml of 3N hydrochloric acid was added to the reaction solution and stirred for 1 hour, a yellow-brown crystalline substance was deposited. The crystals were filtered off with suction, washed successively with a mixture of water and hexane / ethyl acetate (1: 1) and dried at 100 ° C. overnight to give the title compound. Yield: 1.62 g, yield: 79% MS (ESI.m / z) 391 (MH +) H-NMR (CDCl3): 2.47 (3H, s), 3.88-3.92 (5H, m), 4.27-
4.29 (2H, m), 4.64 (2H s), 6.23 (1H, s), 6.95-6.98 (1H,
m), 7.22-7.35 (8H, m)

4) 4- (3-benzyloxyethoxy-)
4-methoxy-phenyl) -2-chloro-3-cyano-
Synthesis of 6-methyl-pyridine 4- (3-benzyloxyethoxy-4-methoxy-phenyl) -3-cyano-6-methyl-2-pyridone
10 ml of phosphorus oxychloride in 62 g (4.15 mmol)
Was added and stirred at 100 ° C. for 4 hours. Thereafter, phosphorus oxychloride is distilled off under reduced pressure, the residue is added to ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound. Yield: 1.66 g, 98% MS (FAB. M / z) 409 (MH +) H-NMR (CDCl3): 2.61 (3H, s), 3.88-3.93 (5H, m), 4.
28-4.32 (2H, t), 4.64 (2H, s), 7.00 (1H, d), 7.17-
7.35 (8H, m)

5) 4- (3-benzyloxyethoxy-
4-methoxy-phenyl) -3-cyano-6-methyl-
Synthesis of 2- (3,4-methylenedioxyphenoxy) -pyridine Under an argon atmosphere, 459 mg of sesamol (3.32 m
mol) was dissolved in 10 ml of DMF, 133 mg (3.32 mmol) of 60% sodium hydride was added at 0 ° C., and the mixture was stirred for 1 hour. This is followed by 4- (3-benzyloxyethoxy-4-methoxy-phenyl) -2-chloro-
1.13 g of 3-cyano-6-methyl-pyridine (2.7
6 mmol) and stirred at 80 ° C. for 24 hours. The reaction solution was poured into water, the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent: hexane:
Ethyl acetate (3: 1) gave the title compound. Yield: 200 mg, Yield: 14% MS (ESI.m / z) 511 (MH +) H-NMR (CDCl3): 2.42 (3H, s), 3.89-3.93 (5H, m), 4.
31 (2H, t), 4.65 (2H, s), 6.01 (2H, s), 6.64-7.01
(5H, m), 7.23-7.36 (7H, m)

6) 4- (3-benzyloxyethoxy-)
4-methoxy-phenyl) -6-methyl-2- (3,4
Synthesis of 4- (3) -methylenedioxyphenoxy) -pyridine-3-aldehyde in 10 ml of methylene chloride under an argon atmosphere
-Benzyloxyethoxy-4-methoxy-phenyl)
-3-cyano-6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine 200 mg (0.392
mmol), and 1.18 ml of a 1M hexane solution of diisobutylaluminum hydride was added at 0 ° C., followed by stirring at room temperature overnight. Thereafter, 1 ml of water was added and the mixture was stirred for 1 hour, filtered through celite, and the residue was washed with ethyl acetate.
The solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: chloroform) to obtain the title compound. Yield: 160 mg, 79% MS (ESI.m / z) 514 (MH +) H-NMR (CDCl3): 2.40 (3H, s), 3.86-3.92 (5H, m), 4.25
(2H, t), 4.64 (1H, s), 5.99 (2H, s), 6.61-6.96 (7H,
m), 7.25-7.38 (5H, m), 10.2 (1H, s)

7) 4- [3- (2-Hydroxyethoxy) -4-methoxy-phenyl] -6-methyl-2-
(3,4-methylenedioxyphenoxy) -pyridine-
Synthesis of 3-carboxylic acid 4- (3-benzyloxyethoxy-4-methoxy-phenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde 160 mg
(0.312 mmol) in 5 ml of water, 10 methylene chloride
dissolved in ice-cold water, and ice-cooled, 2-methyl-butene 131 mg
(1.87 mmol), amidosulfuric acid 45 mg (0.46 mmol)
8 mmol), 99 mg of sodium chlorite (1.09
mmol) and stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent hexane: ethyl acetate 1: 1) to give the title compound. Yield: 20 mg, Yield: 15% MS (ESI.m / z) 440 (MH +) H-NMR (CDCl3): 3.70 (5H, br s), 4.03 (2H, br s),
5.94 (2H, s), 6.53-6.70 (3H, m), 6.82-7.13 (4H, m)

Example 28 4- (2-benzyloxyethoxy-5-methoxy-phenyl) -6-methyl-2-
(3,4-methylenedioxyphenoxy) -pyridine-
Synthesis of 3-carboxylic acid 1) Synthesis of 2-benzyloxyethoxy-5-methoxy-benzaldehyde Under an argon atmosphere, 2 g (13.1 mmol) of 2-hydroxy-5-methoxybenzaldehyde was added to 20 m of DMF.
and 632 mg of 60% sodium hydride (1
(5.8 mmol) and stirred at room temperature for 1 hour. Thereafter, methanesulfonic acid benzyloxyethyl ester3.
64 g (15.8 mmol) was added at room temperature,
For 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent: hexane: ethyl acetate 3: 1) to give the title. The compound was obtained. Yield: 3.41 g, yield: 91% MS (ESI.m / z) 287 (MH +) H-NMR (CDCl3): 3.80 (3H, s), 3.85 (2H, t), 4.23 (2
H, t), 4.62 (2H, s), 6.94-7.13 (2H, m), 7.26-7.36
(6H, m), 10.5 (1H, s)

2) 1- (2-benzyloxyethoxy-)
Synthesis of 5-methoxy-phenyl) -1-butenyl-3-one acetonyltriphenylphosphonium chloride 6.3
5 g (11.9 mmol) of ethanol (30 ml)
Sodium ethoxide 1.21g (17.9m
mol) was added at 0 ° C. After returning to room temperature and stirring for 1 hour, 3.41 g (11.9 mmol) of 2-benzyloxyethoxy-5-methoxy-benzaldehyde was added, and the mixture was stirred overnight. The solvent was distilled off from the reaction solution under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This was purified on silica gel using hexane / ethyl acetate (3: 1) to give the title compound. Yield: 3.53 g, yield: 91% H-NMR (CDCl3): 2.28 (3H, s), 3.73 (3H, s), 3.79-3.
82 (2H, m), 4.11-4.14 (2H, m), 4.58 (2H, d), 6.69-
6.86 (3H, m), 7.04-7.10 (1H, m), 7.24-7.35 (5H, m
m), 7.75 (1H, d)

3) 4- (2-benzyloxyethoxy-)
5-methoxy-phenyl) -3-cyano-6-methyl-
Synthesis of 2-pyridone α-cyanoacetamide 999 mg (11.9 mmol)
l) in 20 ml of DMSO, and
1.21 g (10.8 mmol) of potassium t-butoxide
l), 3.53 g of 1- (2-benzyloxyethoxy-5-methoxy-phenyl) -1-butenyl-3-one
(10.8 mmol) were sequentially added at room temperature, and the mixture was stirred for 15 minutes. After confirming the disappearance of the raw materials by TLC, 3.64 g (32.4 mmol) of potassium t-butoxide was added, oxygen was bubbled for 1 minute, and the mixture was stirred under an oxygen atmosphere for 1 hour. When 20 ml of 3N hydrochloric acid was added to the reaction solution and stirred for 1 hour, a yellow-brown crystalline substance was deposited. The crystals were filtered off with suction, washed successively with a mixture of water and hexane / ethyl acetate (1: 1) and dried at 100 ° C. overnight to give the title compound. Yield: 4.00 g, yield: 94% MS (ESI.m / z) 391 (MH +) H-NMR (CDCl3): 2.36 (3H, s), 3.78-3.81 (5H, m), 4.
17 (2H, t), 4.54 (2H, s), 6.27 (1H, s), 6.85-6.97
(3H, m), 7.25-7.34 (6H, m)

4) 4- (2-benzyloxyethoxy-)
5-methoxy-phenyl) -2-chloro-3-cyano-
Synthesis of 6-methyl-pyridine 4- (2-benzyloxyethoxy-5-methoxy-phenyl) -3-cyano-6-methyl-2-pyridone
10 g of phosphorus oxychloride in 27 g (3.25 mmol)
Was added and stirred at 100 ° C. for 12 hours. Thereafter, phosphorus oxychloride is distilled off under reduced pressure, the residue is added to ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound. Yield: 1.07 g, 81% MS (ESI.m / z) 409 (MH +) H-NMR (CDCl3): 2.57 (3H, s), 3.74-3.81 (5H, m), 4.
18 (2H, t), 4.44 (2H, s), 6.80-7.38 (9H, m)

5) 4- (2-benzyloxyethoxy-)
5-methoxy-phenyl) -3-cyano-6-methyl-
Synthesis of 2- (3,4-methylenedioxyphenoxy) -pyridine Under an argon atmosphere, 459 mg of sesamol (3.32 m
mol) was dissolved in 10 ml of DMF, 133 mg (3.32 mmol) of 60% sodium hydride was added at 0 ° C., and the mixture was stirred for 1 hour. This is followed by 4- (2-benzyloxyethoxy-5-methoxy-phenyl) -2-chloro-
1.13 g of 3-cyano-6-methyl-pyridine (2.7
6 mmol) and stirred at 80 ° C. for 2 hours. The reaction solution was poured into water, the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent hexane: ethyl acetate 3: 1). To give the title compound. Yield: 640 mg, yield: 48% H-NMR (CDCl3): 2.39 (3H, s), 3.78-3.81 (5H, m), 4.
19 (2H, t), 4.52 (2H, s), 6.00 (2H, s), 6.60-6.86
(4H, m), 6.96-6.99 (3H, m), 7.24-7.29 (5H, m)

6) 4- (2-benzyloxyethoxy-)
5-methoxy-phenyl) -6-methyl-2- (3,4
Synthesis of 4- (2) -methylenedioxyphenoxy) -pyridine-3-aldehyde in 10 ml of methylene chloride under an argon atmosphere
-Benzyloxyethoxy-5-methoxy-phenyl)
300 mg (0.588) of -3-cyano-6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine
mmol), and 1.76 ml of a 1M solution of diisobutylaluminum hydride in hexane was added at 0 ° C., followed by stirring at room temperature overnight. Thereafter, 1 ml of water was added and the mixture was stirred for 1 hour, filtered through celite, and the residue was washed with ethyl acetate. The solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: chloroform) to obtain the title compound. Yield: 110 mg, yield: 36% MS (ESI.m / z) 514 (MH +) H-NMR (CDCl3): 2.40 (3H, s), 3.67 (2H, t), 3.80 (3
H, s), 4.06 (2H, t), 4.48 (2H, s), 5.99 (2H, s),
6.55-6.91 (7H, m), 7.22-7.30 (5H, m)

7) 4- (2-benzyloxyethoxy-)
5-methoxy-phenyl) -6-methyl-2- (3,4
Synthesis of -methylenedioxyphenoxy) -pyridine-3-carboxylic acid 4- (2-benzyloxyethoxy-5-methoxy-phenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine- 210 mg of 3-aldehyde
(0.409 mmol) in 5 ml of water, 10 methylene chloride
172 mg of 2-methyl-butene under ice-cooling.
(2.45 mmol), amidosulfuric acid 60 mg (0.61 mmol)
4 mmol) and 129 mg of sodium chlorite (1.4 mg).
3 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 90 mg, Yield: 42% MS (ESI.m / z) 530 (MH +) H-NMR (CDCl3): 2.39 (3H, s), 3.67 (2H, t), 3.76 (3
H, s), 4.02 (2H, t), 4.51 (2H, s), 5.96 (2H, s),
6.53-6.85 (7H, m), 7.02-7.29 (5H,
m)

Example 29 4- [2- (2-hydroxyethoxy) -5-methoxy-phenyl] -6-methyl-
Synthesis of 2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 4- (2-benzyloxyethoxy-5-methoxy-phenyl) -6-methyl-2- (3,4-methylenedi (Oxyphenoxy) -pyridine-3-carboxylic acid 70 mg
(0.132 mmol) in 5 ml of ethanol,
A catalytic amount of 10% palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 18 hours. After the reaction solution was filtered and washed with ethanol, the filtrate was evaporated under reduced pressure.
The obtained residue was recrystallized from chloroform and hexane to give the title compound. Yield: 50 mg, yield: 86% MS (ESI. M / z) 440 (MH +) H-NMR (CD3OD): 2.34 (3H, s), 3.69-3.72 (5H, m), 3.
93 (2H, t), 5.92 (2H, s), 6.51-6.98 (7H, m)

Example 30 3-cyano-4- (2- (3
-Chloropropyloxy) -4-methoxyphenyl)-
Synthesis of 6-methylpyridine-3-carboxylic acid 1) 2- (3-benzyloxypropyloxy) -4-
Synthesis of methoxybenzaldehyde 2-hydroxy-4-methoxybenzaldehyde 1.5
2 g (10.0 mmol) is dissolved in 10 ml of DMF,
500 mg of sodium hydride (60% oil dispersion, 12.5 mmol), 2.7 g of 3-benzyloxypropyl methanesulfonate (11.1 mmol)
1) and stirred at 60 ° C. for 6 hours. DMF is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, washed with 1N sodium hydroxide, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Ethyl acetate: hexane 1: 4) to give the title compound. Yield: 1.13 g, yield: 37.6% MS (ESI, m / z) 301 (MH +) H-NMR (CDCl3): 2.17 (2H, quint), 3.67 (2H, t), 3.85
(3H, s), 4.18 (2H, t), 4.52 (2H, s), 6.46 (1H,
d), 6.54 (1H, dd), 7.25-7.38 (5H, m), 7.80 (1H,
d), 10.26 (1H, s)

2) 1- (2- (3-benzyloxypropyloxy) -4-methoxyphenyl) -1-butene-
Synthesis of 3-one 1.13 g (3.8 mmol) of 2- (3-benzyloxypropyloxy) -4-methoxybenzaldehyde,
Acetonyltriphenylphosphonium chloride 1.6
g (4.5 mmol), sodium ethoxide 0.31
g (4.6 mmol) is dissolved in 30 ml of ethanol and heated under reflux overnight. Ethanol is distilled off under reduced pressure, dissolved in ethyl acetate, insoluble matter is filtered, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:
Hexane 1: 3) to give the title compound. Yield: 1.07 g, 82.7% MS (ESI, m / z) 341 (MH +) H-NMR (CDCl3): 2.15 (2H, quint), 2.30 (3H, s), 3.68
(2H, t), 3.83 (3H, s), 4.15 (2H, t), 4.53 (2H,
s), 6.47 (1H, d), 6.52 (1H, dd), 6.66 (1H, d), 7.2
5-7.35 (5H, m), 7.48 (1H, d), 7.76 (1H, d)

3) 3-Cyano-4- (2- (3-chloropropyloxy) -4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenyloxy) pyridine Cyanoacetamide 270m at room temperature under argon atmosphere
g (3.2 mmol), 350 m potassium t-butoxide
g (3.1 mmol) in 5 ml of DMSO was added to 1- (2
1.07 g of-(3-benzyloxypropyloxy) -4-methoxyphenyl) -1-buten-3-one (3.
(1 mmol) in 15 ml of DMSO and stirred for 15 minutes. 1.06 g (9.4 mmol) of potassium t-butoxide
Add l) and bubble oxygen for 1 minute. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice cooling, and the precipitated viscous substance is removed by decantation. After dissolving in ethyl acetate and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is dissolved in 10 ml of phosphorus oxychloride and stirred at 100 ° C. overnight. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is extracted with chloroform. The extract is washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was dissolved in DMF, and 430 mg of sesamol was separately added.
(3.1 mmol), 250 mg of sodium hydride (6
(0% oil dispersion, 6.2 mmol) to a DMF solution of phenoxide ion, and the mixture is stirred at room temperature for 4 hours under an argon atmosphere. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to give the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 90 mg, Yield: 6.4% from 1- (2- (3-benzyloxypropyloxy) -4-methoxyphenyl) -1-buten-3-one

4) Synthesis of 3-cyano-4- (2- (3-chloropropyloxy) -4-methoxyphenyl) -6-methylpyridine-3-aldehyde 3-cyano-4- (2- (3- Chloropropyloxy)
-4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 90 mg (0.21 m
mol) was dissolved in 5 ml of benzene, and 1.0 ml (1.0 mmol) of a 1M solution of diisobutylaluminum hydride in hexane was added dropwise at room temperature under an argon atmosphere. Stir at room temperature for 3 hours and stop the reaction with methanol and water. The mixture is stirred at room temperature for 1 hour, and the insoluble matter is filtered using celite. The filtrate was evaporated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3 then 1: 2) to give the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 30 mg MS (ESI, m / z) 456 (MH +) H-NMR (CDCl3): 2.31 (2H, quint), 2.42 (3H, s), 3.53
(2H, t), 3.86 (3H, s), 4.08 (2H, t), 6.00 (2H, t)
s), 6.54-6.64 (3H, m), 6.72 (1H, d), 6.79-6.81 (2
H, m), 7.14 (1H, d), 10.16 (1H, s)

5) Synthesis of 3-cyano-4- (2- (3-chloropropyloxy) -4-methoxyphenyl) -6-methylpyridine-3-carboxylic acid 3-cyano-4- (2- (3 -Chloropropyloxy)
-4-methoxyphenyl) -6-methylpyridine-3-
30 mg of aldehyde was dissolved in 2 ml of methylene chloride and 1 ml of water, and 0.05 ml of 2-methyl-2-butene was added at 0 ° C.
(0.47 mmol), amidosulfuric acid 10 mg (0.10
mmol), 30 mg of sodium chlorite (0.26 m
mol), and the mixture is returned to room temperature and stirred for 2 hours. Extract with methylene chloride, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (developed twice with ethyl acetate: hexane 1: 1) to give the title compound (). Yield: 12 mg, Yield: 3-cyano-4- (2- (3-
Chloropropyloxy) -4-methoxyphenyl) -2
12.1% MS (ESI, m / z) 472 (MH +) H-NMR (CDCl3): 2.42 (2H, quint), 2.41 (3H, s) from-(3,4-methylenedioxyphenyloxy) pyridine , 3.54
(2H, t), 3.83 (3H, s), 4.04 (2H, t), 5.99 (2H,
s), 6.50 (1H, d), 6.55 (1H, dd), 6.62 (1H, dd), 6.
71 (1H, d), 6.78 (1H, d), 6.84 (1H, s), 7.16 (1H,
d)

Example 31 4- (3-benzyloxypropoxy-4-methoxy-phenyl) -6-methyl-2
Synthesis of-(3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 1) Synthesis of 3-benzyloxypropoxy-4-methoxy-benzaldehyde 2 g (13.1 mmol) of isovanillin under an argon atmosphere
1) was dissolved in 20 ml of DMF, 632 mg (15.8 mmol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 3.64 g (15.8 mmol) of benzylsulfonic acid methanesulfonate was added at room temperature, and the mixture was stirred at 80 ° C. for 6 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography (eluent: hexane: ethyl acetate 5: 1).
To give the title compound. Yield: 3.45 g, yield: 88% MS (ESI.m / z) 301 (MH +) H-NMR (CDCl3): 2.17 (2H, quint), 3.68 (2H, t), 3.9
3-3.97 (3H, m), 4.21 (2H, t), 4.53 (2H, s), 6.95-6.
98 (1H, m), 7.26-7.46 (7H, m), 9.84 (1H, s)

2) Synthesis of 1- (3-benzyloxypropoxy-4-methoxy-phenyl) -1-butenyl-3-one Acetonyltriphenylphosphonium chloride 5.1
8 g (14.6 mmol) of ethanol (30 ml)
Sodium ethoxide 994mg (14.6m
mol) was added at 0 ° C. After returning to room temperature and stirring for 1 hour, 3-benzyloxypropoxy-4-methoxy-
3.45 g (9.72 mmol) of benzaldehyde was added and stirred overnight. The solvent was distilled off from the reaction solution under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This was purified on silica gel using hexane / ethyl acetate (5: 1) to give the title compound. Yield: 2.28 g, 69% MS (ESI.m / z) 363 (M + Na +) H-NMR (CDCl3): 2.16 (2H, quint), 2.35 (3H, s), 3.6
9 (2H, t), 3.88 (3H, s), 4.18 (2H, t), 4.53 (2H, t)
s), 6.59 (1H, d), 6.87 (1H, d), 7.11-7.33 (5H,
m), 7.44 (1H, d)

3) Synthesis of 4- (3-benzyloxypropoxy-4-methoxy-phenyl) -3-cyano-6-methyl-2-pyridone 620 mg of α-cyanoacetamide (7.37 mmol)
l) in 20 ml of DMSO, and
752 mg (6.70 mmol) of potassium t-butoxide
l), 2.28 g of 1- (3-benzyloxypropoxy-4-methoxy-phenyl) -1-butenyl-3-one
(6.70 mmol) was sequentially added at room temperature, and the mixture was stirred for 15 minutes. After confirming the disappearance of the raw materials by TLC, 2.26 g (20.1 mmol) of potassium t-butoxide was added, oxygen was bubbled for 1 minute, and the mixture was stirred under an oxygen atmosphere for 1 hour. When 20 ml of 3N hydrochloric acid was added to the reaction solution and stirred for 1 hour, a yellow-brown crystalline substance was deposited. The crystals were filtered off with suction, washed successively with a mixture of water and hexane / ethyl acetate (1: 1) and dried at 100 ° C. overnight to give the title compound. Yield: 2.13 g, 79% MS (ESI.m / z) 427 (M + Na +) H-NMR (CDCl3): 2.18 (2H, quint), 2.48 (3H, s), 3.7
0 (2H, t), 3.91 (3H, s), 4.22 (2H, t), 4.53 (2H, t)
s), 6.26 (1H, s), 6.96 (1H, d), 7.18-7.32 (8H, m)

4) Synthesis of 4- (3-benzyloxypropoxy-4-methoxy-phenyl) -2-chloro-3-cyano-6-methyl-pyridine 4- (3-benzyloxypropoxy-4-methoxy-pyridine)
Phenyl) -3-cyano-6-methyl-2-pyridone
2.13 g (5.27 mmol) of phosphorus oxychloride 10
Then, the mixture was stirred at 100 ° C. for 5 hours. Thereafter, phosphorus oxychloride is distilled off under reduced pressure, the residue is added to ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order.
After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound. Yield: 2.05 g, 92% MS (ESI.m / z) 445 (M + Na +) H-NMR (CDCl3): 2.18 (2H, quint), 2.62 (3H, s), 3.7
0 (2H, t), 3.91 (3H, s), 4.23 (2H, t), 4.52 (2H, t)
s), 6.97-7.32 (9H, m)

5) Synthesis of 4- (3-benzyloxypropoxy-4-methoxy-phenyl) -3-cyano-6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine Sesamol under argon atmosphere 936 mg (6.78 m
mol) was dissolved in 10 ml of DMF, 271 mg (6.78 mmol) of 60% sodium hydride was added at 0 ° C, and the mixture was stirred for 1 hour. Thereafter, 2.39 g of 4- (3-benzyloxypropoxy-4-methoxy-phenyl) -2-chloro-3-cyano-6-methyl-pyridine (5.
65 mmol) and stirred at 80 ° C. for 12 hours.
The reaction solution was poured into water, the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent hexane: ethyl acetate 3: 1). To give the title compound. Yield: 1.24 g, yield: 42% MS (ESI.m / z) 547 (M + Na +) H-NMR (CDCl3): 2.19 (2H, quint), 2.43 (3H, s), 3.7
1 (2H, t), 3.91 (3H, s), 4.24 (2H, t), 4.53 (2H, t)
s), 6.01 (2H, s), 6.64-7.00 (5H, m), 7.18-7.32 (7
H, m)

6) 4- (3-benzyloxypropoxy-4-methoxy-phenyl) -6-methyl-2- (3,
Synthesis of 4-methylenedioxyphenoxy) -pyridine-3-aldehyde In an argon atmosphere, 4- (3
Benzyloxypropoxy-4-methoxy-phenyl) -3-cyano-6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine 550 mg (1.0 mg)
5mmol), and 3.15 ml of a 1M solution of diisobutylaluminum hydride in hexane was added at 0 ° C, followed by stirring at room temperature for 1 hour. Thereafter, 1 ml of water was added and the mixture was stirred for 1 hour, filtered through celite, and the residue was washed with ethyl acetate. The solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: chloroform) to obtain the title compound. Yield: 550 mg, yield: 99% MS (ESI.m / z) 550 (M + Na +) H-NMR (CDCl3): 2.14-2.20 (2H, m), 2.41 (3H, d), 3.
67-3.72 (2H, m), 3.89 (3H, d), 4.15-4.24 (2H, m),
4.52 (2H, d), 5.98 (2H, d), 6.60-6.99 (7H, m), 7.19
-7.32 (5H, m), 10.2 (1H, s)

7) 4- (3-benzyloxypropoxy-4-methoxy-phenyl) -6-methyl-2- (3,
Synthesis of 4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 4- (3-benzyloxypropoxy-4-methoxy-
Phenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde 550 m
g (1.04 mmol) in 5 ml of water and 10 ml of methylene chloride.
The mixture was dissolved in ice-cold water and cooled under ice-cooling, 439 mg of 2-methyl-butene.
(6.26 mmol), 151 mg of amidosulfuric acid (1.5 mg)
6 mmol), 329 mg of sodium chlorite (3.6
4 mmol) and stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 268 mg, Yield: 47% MS (ESI.m / z) 544 (MH +) H-NMR (CDCl3): 2.07 (2H, quint), 2.37 (3H, s), 3.6
3 (2H, t), 3.78 (3H, s), 4.14 (2H, t), 4.49 (2H, t)
s), 5.94 (2H, s), 6.53-7.10 (7H, m), 7.24-7.29 (5
H, m)

Example 32 Synthesis of 4- [3- (2-hydroxypropoxy) -4-methoxy-phenyl] -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 4- (3-benzyloxypropoxy-4-methoxy-
Phenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 130 m
g (0.239 mmol) was dissolved in 5 ml of ethanol and 2 ml of chloroform, a catalytic amount of 10% palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 5 hours. After the reaction solution was filtered and washed with ethanol, the filtrate was evaporated under reduced pressure. The obtained residue was recrystallized from chloroform and hexane to give the title compound. Yield: 60 mg, Yield: 55% MS (ESI.m / z) 454 (MH +) H-NMR (CDCl3): 2.04 (2H, t), 2.41 (3H, s), 3.84-3.
88 (5H, m), 4.23 (2H, t), 5.98 (2H, s), 6.60-7.15
(7H, m)

Example 33 4- (2-benzyloxypropoxy-5-methoxy-phenyl) -6-methyl-2
Synthesis of-(3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 1) Synthesis of 2-benzyloxypropoxy-5-methoxy-benzaldehyde Under an argon atmosphere, 2.00 g of 2-hydroxy-5-methoxybenzaldehyde ( 13.1 mmol) in DMF
Dissolve in 20 ml, 632 mg of 60% sodium hydride
(15.8 mmol) and the mixture was stirred at room temperature for 1 hour.
Thereafter, 3.86 g (15.8 mmol) of benzylsulfonic acid methanesulfonate was added at room temperature to give 8
Stirred at 0 ° C. for 8 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent hexane: ethyl acetate 10: 1),
The title compound was obtained. Yield: 1.97 g, 50% H-NMR (CDCl3): 2.12 (2H, quint), 3.67 (2H, t), 3.8
0 (3H, s), 4.15 (2H, t), 4.52 (2H, s), 6.93-7.32 (8
H, m), 10.4 (1H, s)

2) Synthesis of 1- (2-benzyloxypropoxy-5-methoxy-phenyl) -1-butenyl-3-one Acetonyltriphenylphosphonium chloride 3.4
9 g (9.84 mmol) of ethanol (30 ml)
Sodium ethoxide 670mg (9.84m
mol) was added at 0 ° C. After returning to room temperature and stirring for 1 hour, 2-benzyloxypropoxy-5-methoxy-
1.97 g (6.56 mmol) of benzaldehyde was added and stirred overnight. The solvent was distilled off from the reaction solution under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This was purified on silica gel using hexane / ethyl acetate (3: 1) to give the title compound. Yield: 1.82 g, yield: 82% MS (ESI. M / z) 363 (M + Na +) H-NMR (CDCl3): 2.13 (2H, quint), 2.32 (3H, s), 3.6
9 (2H, t), 3.79 (3H, s), 4.12 (2H, t), 4.53 (2H,
s), 6.69 (1H, d), 6.85-6.94 (2H, m), 7.07 (1H,
d), 7.24-7.32 (5H, m), 7.82 (1H, d)

3) Synthesis of 4- (2-benzyloxypropoxy-5-methoxy-phenyl) -3-cyano-6-methyl-2-pyridone 495 mg (589 mmol) of α-cyanoacetamide
Was dissolved in 20 ml of DMSO, and t-
600 g (5.35 mmol) of potassium butoxy, 1-
1.82 g of (2-benzyloxypropoxy-5-methoxy-phenyl) -1-butenyl-3-one (5.35
(mmol) at room temperature and stirred for 15 minutes.
After confirming the disappearance of the raw materials by TLC, 1.80 g (16.1 mmol) of potassium t-butoxide was added, and oxygen was added to 1%.
The mixture was bubbled for 1 minute and stirred for 1 hour under an oxygen atmosphere. When 20 ml of 3N hydrochloric acid was added to the reaction solution and stirred for 1 hour, a yellow-brown crystalline substance was deposited. The crystals were filtered off with suction, washed successively with a mixture of water and hexane / ethyl acetate (1: 1) and dried at 100 ° C. overnight to give the title compound. Yield: 1.73 g, 80% MS (ESI.m / z) 427 (M + Na +) H-NMR (CDCl3): 2.04 (2H, quint), 2.40 (3H, s), 3.5
7 (2H, t), 3.80 (3H, s), 4.10 (2H, t), 4.49 (2H, t)
s), 6.18 (1H, s), 6.82-6.96 (2H, m), 7.25-7.31 (7
H, m)

4) Synthesis of 4- (2-benzyloxypropoxy-5-methoxy-phenyl) -2-chloro-3-cyano-6-methyl-pyridine 4- (2-benzyloxypropoxy-5-methoxy-pyridine)
Phosphorous oxychloride was added to 1.73 g (4.28 mmol) of phenyl) -3-cyano-6-methyl-2-pyridone.
Then, the mixture was stirred at 100 ° C. for 5 hours. Thereafter, phosphorus oxychloride is distilled off under reduced pressure, the residue is added to ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order.
After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound. Yield: 1.36 g, yield: 75% MS (ESI.m / z) 445 (M + Na +) H-NMR (CDCl3): 2.01 (2H, quint), 2.60 (3H, s), 3.5
3 (2H, t), 3.80 (3H, s), 4.10 (2H, t), 4.48 (2H, t)
s), 6.79-7.32 (9H, m)

5) Synthesis of 4- (2-benzyloxypropoxy-5-methoxy-phenyl) -3-cyano-6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine Sesamol under argon atmosphere 533mg (3.86m
mol) was dissolved in 10 ml of DMF, 154 mg (3.86 mmol) of 60% sodium hydride was added at 0 ° C., and the mixture was stirred for 1 hour. This was followed by 1.36 g of 4- (2-benzyloxypropoxy-5-methoxy-phenyl) -2-chloro-3-cyano-6-methyl-pyridine (3.
22 mmol) and stirred at 80 ° C. for 12 hours.
The reaction solution was poured into water, the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent hexane: ethyl acetate 3: 1). To give the title compound. Yield: 550 mg, yield: 33% MS (ESI.m / z) 547 (M + Na +) H-NMR (CDCl3): 2.03 (2H, quint), 2.41 (3H, s), 3.5
6 (2H, t), 3.80 (3H, s), 4.11 (2H, t), 4.48 (2H, t)
s), 5.99 (2H, s), 6.63-6.97 (7H, m), 7.22-7.31 (5
H, m)

6) 4- (2-benzyloxypropoxy-5-methoxy-phenyl) -6-methyl-2- (3,
Synthesis of 4-methylenedioxyphenoxy) -pyridine-3-aldehyde In an argon atmosphere, 4- (2
Benzyloxypropoxy-5-methoxy-phenyl) -3-cyano-6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine 550 mg (1.0 mg)
5 mmol) was dissolved, and 3.15 ml of a 1M solution of diisobutylaluminum hydride in hexane was added at 0 ° C., followed by stirring at room temperature overnight. After adding 1 ml of water and stirring for 1 hour,
After filtration through celite, the residue was washed with ethyl acetate. The solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: chloroform) to obtain the title compound. Yield: 430 mg, Yield: 78% MS (ESI.m / z) 550 (M + Na +) H-NMR (CDCl3): 2.03 (2H, quint), 2.41 (3H, s), 3.5
6 (2H, t), 3.80 (3H, s), 4.11 (2H, t), 4.48 (2H, t)
s), 5.99 (2H, s), 6.63-6.97 (7H, m), 7.25-7.31 (5
H, m), 10.2 (1H, s)

7) 4- (2-benzyloxypropoxy-5-methoxy-phenyl) -6-methyl-2- (3,
Synthesis of 4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 4- (2-benzyloxypropoxy-5-methoxy-
Phenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde 430 m
g (0.815 mmol) in 5 ml of water, methylene chloride 1
0 ml, and cooled under ice-cooling, 343 m 2-methyl-butene
g (4.89 mmol), 118 mg of amidosulfuric acid (1.
22 mmol), 258 mg of sodium chlorite (2.
85 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 34 mg, Yield: 8% MS (ESI.m / z) 544 (MH +) H-NMR (CDCl3): 1.90 (2H, quint), 2.35 (3H, quin)
t), 3.44 (2H, t), 3.71 (3H, s), 3.93 (2H, t), 4.39
(2H, s), 5.94 (2H, s), 6.55-6.83 (7H, m), 7.22-7.2
8 (5H, m)

Example 34 Synthesis of 4- [2- (2-hydroxypropoxy) -5-methoxy-phenyl] -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 4- (2-benzyloxypropoxy-5-methoxy-
26 mg of phenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid
(0.0478 mmol) was dissolved in 5 ml of ethanol, a catalytic amount of 10% palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 48 hours. After the reaction solution was filtered and washed with ethanol, the filtrate was evaporated under reduced pressure. The obtained residue was recrystallized from chloroform and hexane to give the title compound. Yield: 18 mg, Yield: 83% MS (ESI.m / z) 454 (MH +) H-NMR (CDCl3): 1.88 (2H, br s), 2.41 (3H, s), 3.65
(2H, br s), 3.78 (3H, s), 4.01 (2H, br s), 5.98
(2H, s), 6.61-6.87 (7H, m)

Example 35 6- (2- (5-Methylfuryl))-4- (4-methoxyphenyl) -2- (3,4
Synthesis of -methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) Synthesis of 2- (3- (4-methoxyphenyl) -2-propenoyl) -5-methylfuran 2-acetyl-5-methylfuran 48 g (20.0
mmol), 2.43 ml of p-anisaldehyde (2
(0.0 mmol) in THF (50 ml) is added with 1N sodium hydroxide solution (20 ml) and stirred at room temperature for 4 days.
After extraction with ethyl acetate, washing with water, 1N hydrochloric acid and saturated saline, drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 5, then 1: 1). ) To give the title compound. Yield: 2.45 g, 50.5% MS (ESI, m / z) 243 (MH +) H-NMR (CDCl3): 2.44 (3H, s), 3.85 (3H, s), 6.21 (1
H, dd), 6.93 (2H, d), 7.23 (1H, d), 7.25 (1H, d),
7.60 (2H, d), 7.83 (1H, d)

2) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6- (2- (5-methylfuryl)) pyridone Cyanoacetamide (850 m) at room temperature under an argon atmosphere.
g (10.1 mmol), potassium t-butoxide 1.1
3 g (10.1 mmol) of DMSO in 10 ml
2.45 g of (-(3- (4-methoxyphenyl) -2-propenoyl) -5-methylfuran (10.1 mmol
1) 20 ml of DMSO is added and stirred for 15 minutes. t-
3.40 g (30.3 mmol) of potassium butoxide is added and oxygen is bubbled for 1 minute. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 2.66 g, yield: 86.0% MS (ESI, m / z) 282 (MH +) H-NMR (CDCl3): 2.44 (3H, s), 3.89 (3H, s), 6.25 (1
H, s), 6.74 (1H, s), 7.04 (2H, d), 7.67-7.70 (3H,
m)

3) 2-chloro-3-cyano-4- (4-
Synthesis of methoxyphenyl) -6- (2- (5-methylfuryl)) pyridine 3-cyano-4- (4-methoxyphenyl) -6- (5
-Methylfuryl) pyridone 2.66 g (8.7 mmo
1) is dissolved in 15 ml of phosphorus oxychloride and stirred at 90 ° C. overnight. The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The crystals obtained by evaporating the solvent under reduced pressure were washed with ethyl acetate to obtain the title compound. This was used for the following reaction without further purification. Yield: 2.60 g H-NMR (CDCl3): 2.42 (3H, s), 3.90 (3H, s), 6.21 (1
H, d), 7.05 (2H, d), 7.22 (1H, d), 7.60 (1H, s),
7.684 (2H, d)

4) 3-Cyano-4- (4-methoxyphenyl) -6- (2- (5-methylfuryl))-2-
Synthesis of (3,4-methylenedioxyphenyloxy) pyridine 1.20 g (8.7 mmol) of sesamol, 700 mg of sodium hydride (60% oil dispersion, 1
7.5 mmol) of phenoxide ion prepared from
2-chloro-3-cyano-4- (4
2.60 g of -methoxyphenyl) -6- (2- (5-methylfuryl)) pyridine are added, and the mixture is stirred at room temperature for 1 hour under an argon atmosphere. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, and washed with water and saturated saline. The residue obtained by drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure is subjected to silica gel column chromatography (ethyl acetate:
The crystals obtained by hexane 1: 3) were further washed with ethyl acetate: hexane 1: 1 to give the title compound. Yield: 750 mg, Yield: 20.2% from 3-cyano-4- (4-methoxyphenyl) -6- (5-methylfuryl) pyridone MS (ESI, m / z) 427 (MH +) H-NMR ( CDCl3): 2.37 (3H, s), 3.89 (3H, s), 6.03 (2
H, s), 6.10 (1H, d), 6.72 (1H, dd), 6.80-84 (3H,
m), 7.06 (2H, d), 7.39 (1H, s), 7.68 (2H, d)

5) 6- (2- (5-methylfuryl))-
Synthesis of 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 3-cyano-4- (4-methoxyphenyl) -6- (2
-(5-methylfuryl))-2- (3,4-methylenedioxyphenyloxy) pyridine 300 mg (0.7 m
mol) was dissolved in 10 ml of benzene, and 2.8 ml (2.8 mmol) of a 1 M solution of diisobutylaluminum hydride in hexane was added dropwise at room temperature under an argon atmosphere. 2 at room temperature
Stir for an hour and terminate the reaction with methanol and water. 3 at room temperature
After stirring for 0 minutes, the insoluble matter is filtered using Celite. The filtrate was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to give the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 90mg

6) 6- (2- (5-methylfuryl))-
Synthesis of 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6- (2- (5-methylfuryl))-4- (4-methoxyphenyl) ) -2- (3,4-Methylenedioxyphenyloxy) pyridine-3-aldehyde (90 mg) was dissolved in methylene chloride (2 ml) and water (1 ml).
0.2 ml (1.9 mmol) of 2-butene, 30 mg (0.31 mmol) of amidosulfuric acid, sodium chlorite 9
0 mg (0.78 mmol) was added, and the mixture was returned to room temperature and stirred for 1 hour. Extract with methylene chloride, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (ethyl acetate: hexane 1: 1) to give the title compound. Yield: 13 mg, yield: 3-cyano-4- (4-methoxyphenyl) -6- (2- (5-methylfuryl))-2
4.2% MS (ESI, m / z) 446 (MH +) H-NMR (CDCl3) from-(3,4-methylenedioxyphenyloxy) pyridine: 2.35 (3H, s), 3.85 (3H, s) , 6.00 (2
H, s), 6.05 (1H, dd), 6.69 (1H, dd), 6.75 (1H,
d), 6.79 (1H, d), 6.80 (1H, d), 6.97 (2H, d), 7.34
(1H, s), 7.48 (2H, d)

Example 36 6- (2-thiophenyl)-
Synthesis of 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) Synthesis of 2- (3- (4-methoxyphenyl) -2-propenoyl) thiophene Synthesis 2-acetylthiophene 2.5 g (19.8 mmol)
l), p-anisaldehyde 2.43 ml (20.0 m
mol) in 50 ml of THF, 20 ml of a 1N sodium hydroxide solution is added, and the mixture is stirred at room temperature for 4 days. After extraction with ethyl acetate, washing with water, 1N hydrochloric acid and saturated saline, drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3). The title compound was obtained. Yield: 2.76 g, 57.1% MS (ESI, m / z) 245 (MH +) H-NMR (CDCl3): 3.86 (3H, s), 6.94 (2H, d), 7.18 (1
H, dd), 7.31 (1H, d), 7.60 (2H, d), 7.66 (1H, d
d), 7.83 (1H, d), 7.85 (1H, m)

2) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6- (2-thiophenyl) pyridone Cyanoacetamide (950 m) at room temperature under an argon atmosphere.
g (11.3 mmol), potassium t-butoxide 1.2
7 g (11.3 mmol) of DMSO in 10 ml
2.76 g (11.3 mmol) of-(3- (4-methoxyphenyl) -2-propenoyl) thiophene in DM
Add 20 ml of SO and stir for 15 minutes. 3.80 g (33.9 mmol) of potassium t-butoxide are added, and oxygen is bubbled for 1 minute. After stirring for 1 hour in an oxygen atmosphere,
1N hydrochloric acid is added under ice cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 3.87 g, yield: quantitative MS (ESI, m / z) 309 (MH +)

3) 2-chloro-3-cyano-4- (4-
Synthesis of methoxyphenyl) -6- (2-thiophenyl) pyridine 3.87 g (12.6 mmol) of 3-cyano-4- (4-methoxyphenyl) -6-thiophenylpyridone was dissolved in 15 ml of phosphorus oxychloride and the temperature was 70 ° C. And stir overnight.
The phosphorus oxychloride is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate. The crystals obtained by evaporating the solvent under reduced pressure were washed with ethyl acetate to obtain the title compound. This was used for the following reaction without further purification. Yield: 2.21 g MS (ESI, m / z) 284 (MH +) H-NMR (CDCl3): 3.89 (3H, s), 6.96 (2H, d), 7.17 (1
H, dd), 7.56 (1H, dd), 7.58 (1H, s), 7.61 (2H,
d), 7.77 (1H, dd)

4) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6- (2-thiophenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 940 mg (6.8 mmol) of sesamol, 540 mg of sodium hydride (60% oil dispersion, 1
D) of phenoxide ion prepared from 3.5 mmol)
2-chloro-3-cyano-4- (4
-Methoxyphenyl) -6- (2-thiophenyl) pyridine (2.21 g) dissolved in DMF (20 ml) was added, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with water and ethyl acetate to obtain the title compound. Yield: 1.82 g, Yield: 37.6 from 2- (3- (4-methoxyphenyl) -2-propenoyl) thiophene
% MS (ESI, m / z) 331 (M + Na) H-NMR (CDCl3): 3.90 (3H, s), 6.04 (2H, s), 6.75 (1
H, dd), 6.84 (1H, d), 6.86 (1H, d), 7.05-7.10 (3H,
m), 7.37 (1H, s), 7.42 (1H, dd), 7.60 (1H, dd),
7.66 (2H, d)

5) 6- (2-thiophenyl) -4- (4
Synthesis of -methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 3-cyano-4- (4-methoxyphenyl) -6- (2
-Thiophenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 860 mg (2.0 mmol)
Was dissolved in 20 ml of benzene, and a 1M solution of diisobutylaluminum hydride in hexane 8.0 at room temperature under an argon atmosphere.
ml (8.0 mmol) are added dropwise. Stir at room temperature for 2 hours and terminate the reaction with methanol and water. Stir at room temperature for 30 minutes, add 1N hydrochloric acid, extract with methylene chloride, and dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to obtain the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 40 mg MS (ESI, m / z) 432 (MH +) H-NMR (CDCl3): 3.88 (3H, s), 6.03 (2H, s), 6.72 (1
H, dd), 6.82 (1H, d), 6.84 (1H, d), 7.02 (2H, d),
7.06 (1H, dd), 7.27 (1H, s), 7.36 (2H, d), 7.40 (1
H, dd), 7.57 (1H, dd), 10.25 (1H, s)

6) 6- (2-thiophenyl) -4- (4
Synthesis of -methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6- (2-thiophenyl) -4- (4-methoxyphenyl) -2- (3,4- Methylenedioxyphenyloxy) pyridine-3-aldehyde (40 mg) was dissolved in methylene chloride (2 ml) and water (1 ml), and 0.1 ml (0.9 mmol) of 2-methyl-2-butene was added at 0 ° C.
g (0.21 mmol), 40 mg of sodium chlorite
(0.56 mmol) was added and the mixture was returned to room temperature and stirred for 30 minutes. Extract with methylene chloride, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The obtained residue is subjected to silica gel thin layer chromatography (ethyl acetate: hexane).
1: 1) to give the title compound. Yield: 40 mg, Yield: 3-cyano-4- (4-methoxyphenyl) -6- (2-thiophenyl) -2- (3,
4.5% MS (ESI, m / z) 448 (MH +) H-NMR (CDCl3) from 4-methylenedioxyphenyloxy) pyridine: 3.79 (3H, s), 5.98 (2H, s), 6.68 (1
H, br), 6.74-6.82 (2H, m), 6.90-6.98 (2H, m), 7.04
(1H, dd), 7.28 (1H, m), 7.34 (1H, br d), 7.40-7.4
8 (2H, m), 7.50 (1H, d)

Example 37 Synthesis of 5-iodo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 1) 3-Cyano- Synthesis of 5-iodo-4- (4-methoxyphenyl) -6-methyl-2-pyridone 1 g of 3-cyano-4- (4-methoxyphenyl) -6-methyl-2-pyridone under an argon atmosphere (4. 42m
mol) was dissolved in 10 ml of acetonitrile, and 1.99 g of N-iodosuccinimide (hereinafter abbreviated as NIS) was dissolved.
(8.84 mmol), and the mixture was stirred at 100 ° C. for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue crystal was recrystallized from chloroform and hexane to give the title compound. Yield: 940 mg, yield: 48% MS (ESI.m / z) 389 (M + Na +) H-NMR (CDCl3): 2.73 (3H, s), 3.88 (3H, s), 7.02 (2
H, d), 7.23 (2H, d)

2) Synthesis of 2-chloro-3-cyano-5-iodo-4- (4-methoxyphenyl) -6-methyl-pyridine 3-cyano-5-iodo-4- (4-methoxyphenyl)- 940 mg of 6-methyl-2-pyridone (2.57
mmol), add 30 ml of phosphorus oxychloride, and add
For 4 hours. Thereafter, phosphorus oxychloride is distilled off under reduced pressure, the residue is added to ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound. Yield: 730 mg, Yield: 74% H-NMR (CDCl3): 2.90 (3H, s), 3.88 (3H, s), 7.0
3 (2H, d), 7.19 (2H, d)

3) 3-Cyano-5-iodo-4- (4-
Synthesis of methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine Under an argon atmosphere, 313 mg of sesamol (1.89 m
mol) was dissolved in 20 ml of DMF, and 91 mg (2.27 mmol) of 60% sodium hydride was added at 0 ° C.
Stir for 1 hour. This is followed by 2-chloro-3-cyano-5
-Iodo-4- (4-methoxyphenyl) -6-methyl-pyridine (730 mg, 1.89 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into water, the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (eluent hexane: ethyl acetate 3: 1). To give the title compound. Yield: 400 mg, Yield: 44% MS (ESI.m / z) 487 (MH +) H-NMR (CDCl3): 2.71 (3H, s), 3.88 (3H, s), 6.02 (2
H, s), 6.63-6.82 (3H, m), 7.04 (2H, d), 7.24 (2H,
d)

4) Synthesis of 5-iodo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde In 3 ml of methylene chloride under an argon atmosphere , 5-Iodo-3-cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy)-
Dissolve 183 mg (0.376 mmol) of pyridine,
Diisobutylaluminum hydride 1M hexane solution
13 ml was added at 0 ° C., and the mixture was stirred at room temperature overnight. Thereafter, 1 ml of water was added and the mixture was stirred for 1 hour, filtered through celite, and the residue was washed with ethyl acetate. The solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: chloroform) to obtain the title compound. Yield: 170 mg, yield: 92% MS (ESI.m / z) 490 (MH +) H-NMR (CDCl3): 2.70 (3H, s), 3.88 (3H, s), 6.02 (2
H, s), 6.63-6.82 (3H, m), 7.03 (2H, d), 7.24 (2H,
d), 9.91 (1H, s)

5) Synthesis of 5-iodo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 5-iodo-4- ( 170 mg (0.347 mmol of 4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde
l) was dissolved in 5 ml of water and 10 ml of methylene chloride, and 146 mg (2.08 mmol) of 2-methyl-butene was added under ice-cooling.
l), 51 mg (0.521 mmol) of amidosulfuric acid and 110 mg (1.21 mmol) of sodium chlorite were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 10 mg, Yield: 6% MS (ESI.m / z) 506 (MH +) H-NMR (CDCl3): 2.66 (3H, s), 3.83 (3H, s), 5.99 (2
H, s), 6.58-6.78 (3H, m), 6.92 (2H, d), 7.14 (2H,
d)

Example 38 5- (3-hydroxy-1-)
Propenyl) -4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy)-
Synthesis of pyridine-3-carboxylic acid 1) Ethyl 3- [3-cyano-4-methoxyphenyl-6-methyl-2- (3,4-methylenedioxyphenoxy-pyridin-5-yl] -2-propenoate Synthesis of ester 520 mg (1.07 mmol) of 3-cyano-5-iodo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine
Was dissolved in DMF (5 ml), and ethyl acrylate (134 mg) was dissolved.
(1.34 mmol), 212 mg of Pd (OAc)
(0.0535 mmol), triphenylphosphine 2
8 mg (0.107 mmol), triethylamine 5 m
was added and stirred at 100 ° C. for 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent hexane: ethyl acetate 5: 1) to give the title compound. Yield: 340 mg, yield: 69% MS (ESI.m / z) 459 (MH +) H-NMR (CDCl3): 1.25 (3H, t), 2.53 (3H, s), 3.87 (3
H, s), 4.17 (2H, q), 5.81 (1H, d), 6.01 (2H, s),
6.65-6.83 (3H, m), 7.13 (2H, d), 7.27 (2H, d), 7.42
(1H, d)

2) 5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -6-methyl-2
Synthesis of-(3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde In an argon atmosphere, 3- [3
-Cyano-4-methoxyphenyl-6-methyl-2-
(3,4-methylenedioxyphenoxy-pyridine-5
-Yl] -2-propenoic acid ethyl ester 340 mg
(0.742 mmol) was dissolved, 5.19 ml of a 1M solution of diisobutylaluminum hydride in hexane was added at 0 ° C., and the mixture was stirred at room temperature overnight. After adding 1 ml of water and stirring for 1 hour, the mixture was filtered through celite and the residue was washed with ethyl acetate. The solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: hexane: ethyl acetate 5: 1) to obtain the title compound. Yield: 120 mg, Yield: 39% MS (ESI.m / z) 420 (MH +) H-NMR (CDCl3): 2.46 (3H, s), 3.86 (3H, s), 4.09 (2
H, br s), 5.58-5.68 (1H, m), 6.01 (2H, s), 6.16-6.2
9 (1H, m), 6.62-7.26 (7H, m), 9.99 (1H, s)

3) 5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -6-methyl-2
-(3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid combined 5- (3-hydroxy-1-propenyl) -4- (4-
Dissolve 120 mg (0.286 mmol) of methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-aldehyde in 5 ml of water and 10 ml of methylene chloride. Butene 120mg (1.72mmol), Amidosulfuric acid 42mg
(0.429 mmol), sodium chlorite 90.5
mg (1.00 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with chloroform,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 42 mg, yield: 34% MS (ESI.m / z) 436 (MH +) H-NMR (CDCl3): 2.41 (3H, s), 3.79 (3H, s), 5.58 (1
H, dt), 5.97 (2H, s), 6.21 (1H, d), 6.59-6.88 (5H,
m), 7.11-7.14 (2H, m)

Example 39 Synthesis of 6-phenyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 1) 3- (4-methoxyphenyl) -1-oxo-1-
Synthesis of phenyl-2-propene 50 mg of sodium was added to a solution of 2.4 g (20.0 mmol) of acetophenone and 2.43 ml (20.0 mmol) of p-anisaldehyde in 20 ml of methanol, and the mixture was stirred at room temperature for 2 days. The methanol was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, 1N hydrochloric acid and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (ethyl acetate:
Hexane 1: 3) to give the title compound. Yield: 3.0 g, Yield: 62.9% MS (ESI, m / z) 239 (MH +) H-NMR (CDCl3): 3.85 (3H, s), 6.94 (2H, d), 7.40 (1
H, d), 7.45-7.60 (5H, m), 7.78 (1H, d), 8.01 (2H,
m)

2) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-phenylpyridone Cyanoacetamide 1.06 at room temperature under an argon atmosphere.
g (12.6 mmol), potassium t-butoxide 1.4
1 g (12.6 mmol) in 10 ml of DMSO
3.00 g (12.6 mmol) of-(4-methoxyphenyl) -1-oxo-1-phenyl-2-propene D
Add 20 ml of MSO solution and stir for 20 minutes. 4.24 g (37.8 mmol) of potassium t-butoxide was added, and 1
Bubble oxygen for minutes. After stirring for 1 hour in an oxygen atmosphere, 1N hydrochloric acid is added under ice cooling, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 3.12 g, 81.9% MS (ESI, m / z) 303 (MH +) H-NMR (CDCl3): 3.84 (3H, s), 6.60-7.10 (5H, m), 7.4
0-7.90 (5H, m)

3) 2-chloro-3-cyano-4- (4-
Synthesis of (methoxyphenyl) -6-phenylpyridine 1.32 g (4.4 mmol) of 3-cyano-4- (4-methoxyphenyl) -6-phenylpyridone is dissolved in 20 ml of phosphorus oxychloride and stirred at 100 ° C. overnight. . The crystals obtained by evaporating phosphorus oxychloride under reduced pressure were washed with ethyl acetate to obtain the title compound. This was used for the following reaction without further purification. Yield: 770 mg MS (ESI, m / z) 321 (MH +) H-NMR (CDCl3): 3.90 (3H, s), 7.08 (2H, d), 7.52 (3
H, m), 7.63 (2H, d), 7.76 (1H, s), 8.06-8.10 (2H,
m)

4) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-phenyl-2- (3,4-methylenedioxyphenyloxy) pyridine Sesamol 330 mg (2.4 mmol), sodium hydride 200 mg (60% oil dispersion,
5.0 mmol) of phenoxide ion prepared from
2-chloro-3-cyano-4- (4
-Methoxyphenyl) -6-phenylpyridine 770 m
g, and stirred at room temperature for 2 hours under an argon atmosphere. The solvent is distilled off under reduced pressure, the obtained residue is extracted with ethyl acetate, washed with water and saturated saline, and the solvent is distilled off under reduced pressure. The obtained crystals were washed with ethyl acetate: hexane 1: 3 to give the title compound. Yield: 780 mg, Yield: 42.0% from 3-cyano-4- (4-methoxyphenyl) -6-phenylpyridone H-NMR (CDCl3): 3.90 (3H, s), 6.04 (2H, s), 6.75 (1
H, dd), 6.83 (1H, d), 6.85 (1H, d), 7.08 (2H, d),
7.42 (3H, m), 7.54 (1H, s), 7.68 (2H, d), 7.88 (2
H, m)

5) Synthesis of 6-phenyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde 3-cyano-4- (4-methoxyphenyl) 100 mg (0.24 mmol) of -6-phenyl-2- (3,4-methylenedioxyphenyloxy) pyridine is dissolved in methylene chloride, and 1.0 ml of a 1M solution of diisobutylaluminum hydride in hexane (1. 0
mmol) is added dropwise. After returning to room temperature and stirring overnight, the reaction is stopped with methanol and water. The mixture was stirred at room temperature for 30 minutes, filtered using Celite, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:
Hexane 1: 1) to give the title compound. It contains impurities which are difficult to separate, but is used in the following reaction without further purification. Yield: 60 mg MS (ESI, m / z) 58 (M + MeOH)

6) Synthesis of 6-phenyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine-3-carboxylic acid 6-phenyl-4- (4-methoxyphenyl) ) -2-
(3,4-methylenedioxyphenyloxy) pyridine-3-aldehyde (60 mg) was treated with methylene chloride (4 ml) and water (2).
dissolved in 0 ml at 0 ° C.
1 (0.9 mmol), amidosulfuric acid 20 mg (0.21
mmol), 50 mg of sodium chlorite (0.70 m
mol), and the mixture is returned to room temperature and stirred for 20 minutes. Extract with methylene chloride, dry over anhydrous magnesium sulfate and evaporate the solvent under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (developed twice with ethyl acetate: hexane 1: 1) to give the title compound. Yield: 15 mg, Yield: 14.2% MS (ESI, m / z) from 3-cyano-4- (4-methoxyphenyl) -6-phenyl-2- (3,4-methylenedioxyphenyloxy) pyridine ) 442 (MH +) H-NMR (CDCl3): 3.83 (3H, s), 6.00 (2H, s), 6.70 (1
H, m), 6.80 (2H, m), 6.97 (2H, br d), 7.34-7.42 (3
H, m), 7.44-7.52 (3H, m), 7.84-7.90 (2H, m)

Example 40 5- (3-hydroxy-1-)
Synthesis of propyl) -4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 5- (3-hydroxy-1-propenyl) -4 − (4-
Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 10 mg (0.0230 mmol) in ethanol 5 ml
, And a catalytic amount of 10% palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 1 hour. After the reaction solution was filtered and washed with ethanol, the filtrate was evaporated under reduced pressure. The obtained residue was recrystallized from chloroform and hexane to give the title compound. Yield: 8 mg, Yield: 78% MS (ESI.m / z) 438 (MH +) 1H-NMR (CDCl3): 1.50-1.59 (2H, m), 2.45-2.52 (5H,
m), 3.45 (2H, t), 3.83 (3H, s), 5.98 (2H, s), 6.60
-6.78 (3H, m), 6.93 (2H, d), 7.17 (2H, d)

Example 41 3- (5-tetrazoyl)-
Synthesis of 4- (4-methoxyphenyl) -6- (2-thiophenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 3-cyano-4- (4-methoxyphenyl) -6- (2
-Thiophenyl) -2- (3,4-methylenedioxyphenyloxy) pyridine 100 mg (0.23 mmol
l) was dissolved in 10 ml of toluene, and sodium azide 10
Tri-n-butyltin azide prepared from 0 mg (1.5 mmol) and 0.27 ml (1.0 mmol) of tri-n-butyltin chloride is added, and the mixture is heated under reflux overnight. 1N hydrochloric acid is added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with methylene chloride to obtain the title compound. Yield: 20 mg, Yield: 18.4% MS (ESI, m / z) 472 (MH +) H-NMR (DMSO-d6): 3.76 (3H, s), 6.63 (1H, dd), 6.86
(1H, dd), 6.88-6.96 (3H, m), 7.13-7.20 (3H, m), 7.6
6 (1H, d), 7.79 (1H, s), 7.95 (1H, d)

Example 42 3- [3-carboxyl-4
-Methoxyphenyl-6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridin-5-yl] -2
Synthesis of ethyl propene acid 5-iodo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -pyridine-3-carboxylic acid 40 mg (0.0419 mmol)
1) was dissolved in DMF (3 ml), and ethyl acrylate (12 m) was dissolved.
g (0.119 mmol), Pd (OAc) 20.88
9 mg (0.00396 mmol), 2.1 mg (0.00792 mmol) of triphenylphosphine and 3 ml of triethylamine were added, and the mixture was stirred at 100 ° C. for 3 days. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 20 mg, Yield: 53% MS (ESI.m / z) 478 (MH +) 1H-NMR (CDCl3): 1.24 (3H, t), 2.48 (3H, s), 3.79
(3H, s), 4.15 (2H, q), 5.76 (1H, d), 5.99 (2H,
s), 6.59-7.14 (7H, m), 7.41 (2H, d)

Example 43 5- (3-hydroxy-1-)
Propenyl) -4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) -3
Synthesis of-(5-tetrazoyl) pyridine 1) 1- (4-methoxyphenyl) -1-butene-3-
Synthesis of ON 50 ml (411 mmol) of p-anisaldehyde is dissolved in 300 ml of acetone, 50 ml of 1N sodium hydroxide solution is added, and the mixture is stirred at room temperature overnight. The crystals from which acetone was distilled off under reduced pressure were washed with water and ethanol to give the title compound. Yield: 57.4 g, 79.3% MS (ESI, m / z) 177 (MH +) H-NMR (DMSO-d6): 2.36 (3H, s), 3.85 (3H, s), 6.72
(1H, d), 6.93 (2H, d), 7.48 (1H, d), 7.50 (2H, d)

2) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-methylpyridone Cyanoacetamide 27.4 at room temperature under an argon atmosphere.
g (326 mmol), potassium t-butoxide 36.6
g (326 mmol) in DMSO 600 ml solution
(4-methoxyphenyl) -1-buten-3-one 5
Add 7.42 g (326 mmol) and stir for 15 minutes. 110 g (980 mmol) of potassium t-butoxide
And bubbling oxygen for 1 minute. After stirring for 1 hour in an oxygen atmosphere, the mixture is poured into ice water, concentrated hydrochloric acid and water are added, and the precipitated crystals are collected by filtration. After washing with water and drying under reduced pressure, the title compound was obtained. This compound is used for the following reaction without purification. Yield: 58.5 g, yield: 74.7% MS (ESI, m / z) 241 (MH +) H-NMR (CDCl3): 2.50 (3H, s), 3.88 (3H, s), 6.28 (1
H, s), 7.01 (2H, d), 7.60 (2H, d)

3) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-methyl-5-iodo-2-pyridone 3-cyano-4- (4-methoxyphenyl) -6-methylpyridone 86 g (32.7 mmol) is dissolved in 100 ml of acetonitrile, 14.7 g (65.3 mmol) of N-iodosuccinimide is added, and the mixture is heated under reflux overnight. After cooling, the precipitate was collected by filtration and washed with ethyl acetate to give the title compound. Yield: 8.42 g, 70.3% MS (ESI, m / z) 367 (MH +) H-NMR (DMSO-d6): 2.53 (3H, s), 3.88 (3H, s), 7.07
(2H, d), 7.22 (2H, d)

4) 2-Chloro-3-cyano-4- (4-
Synthesis of methoxyphenyl) -6-methyl-5-iodopyridine 3-cyano-4- (4-methoxyphenyl) -6-methyl-5-iodo-2-pyridone 8.42 g (23.0 m
mol) in 100 ml of phosphorus oxychloride
And stir overnight. The crystals obtained by evaporating phosphorus oxychloride under reduced pressure were washed with ethyl acetate to obtain the title compound. This was used for the following reaction without further purification. Yield: 6.76 g, 76.5% H-NMR (CDCl3): 2.90 (3H, s), 3.88 (3H, s), 7.03 (2
H, d), 7.24 (2H, d)

5) Synthesis of 3-cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) -5-iodopyridine 2.56 g (18.5 mmol) of sesamol , 890 mg of sodium hydride (60% oil dispersion,
22.3 mmol) was added to a 50 ml solution of phenoxide ion in DMF to give 2-chloro-3-cyano-4-.
7.12 g (18.5 mmol) of (4-methoxyphenyl) -6-methyl-5-iodopyridine was added at 0 ° C,
The mixture is returned to room temperature under an argon atmosphere and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with water and ethyl acetate to obtain 6.47 g of the title compound. The washed solution was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 3) to obtain a further 0.72 g. Yield: 7.19 g, 79.9% MS (ESI, m / z) 487 (MH +) H-NMR (CDCl3): 2.71 (3H, s), 3.89 (3H, s), 6.65 (1
H, dd), 6.72 (1H, d), 6.81 (1H, d), 7.04 (2H, d),
7.24 (2H, d)

6) 3-cyano-5- (2-ethoxycarbonylethenyl) -4- (4-methoxyphenyl) -6
-Methyl-2- (3,4-methylenedioxyphenyl)
Synthesis of pyridine 3-cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) -5
2.0 g (4.1 mmol) of iodopyridine, 10 ml (92 mmol) of methyl acrylate, 3.0 ml (13 mmol) of tri-n-butylamine, palladium acetate 2
0 mg (0.09 mmol) is dissolved in DMF (20 ml) and refluxed by heating at 150 ° C. for 10 hours. Filter the insolubles,
Evaporate the solvent under reduced pressure and extract with ethyl acetate. The crystals were washed with 1N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with ethyl acetate and hexane to give the title compound. Yield: 1.90 g, Yield: quantitative MS (ESI, m / z) 459 (MH +) H-NMR (CDCl3): 1.26 (3H, t), 2.53 (3H, s), 3.87 (3
H, s), 4.18 (2H, q), 5.81 (1H, d), 6.03 (2H, s),
6.67 (1H, dd), 6.75 (1H, d), 6.82 (1H, d), 7.02 (2
H, d), 7.26 (2H, d), 7.43 (1H, d)

7) 3-cyano-5- (3-hydroxy-
1-propenyl) -4- (4-methoxyphenyl) -6
-Methyl-2- (3,4-methylenedioxyphenyl)
Synthesis of pyridine 3-cyano-5- (2-ethoxycarbonylethenyl)
-4- (4-methoxyphenyl) -6-methyl-2-
(3,4-methylenedioxyphenyl) pyridine 1.5
7 g (3.4 mmol) was dissolved in 20 ml of methylene chloride and 13.7 ml (13.7 mm
ol). Stir at -78 degrees for 1 hour and stop the reaction with methanol and water. Stir at room temperature for 2 hours and filter using celite. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 1) to obtain the title compound. Yield: 1.17 g, yield: 82.6% MS (ESI, m / z) 417 (MH +) H-NMR (CDCl3): 2.47 (3H, s), 3.86 (3H, s), 4.11 (2
H, m), 5.64 (1H, dt), 6.02 (2H, s), 6.28 (1H, d
t), 6.67 (1H, dd), 6.75 (1H, d), 6.81 (1H, d), 6.9
8 (2H, d), 7.26 (2H, d)

8) 5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -6-methyl-2
-(3,4-methylenedioxyphenyl) -3- (5-
Synthesis of tetrazoyl) pyridine 3-cyano-5- (3-hydroxy-1-propenyl)
-4- (4-methoxyphenyl) -6-methyl-2-
(3,4-methylenedioxyphenyl) pyridine 300
mg (0.72 mmol) was dissolved in 10 ml of toluene, 300 mg (4.6 mmol) of sodium azide, and 0.81 ml (3.0 mmol) of tri-n-butyltin chloride.
And the mixture is heated under reflux overnight. Add 1N hydrochloric acid, extract with ethyl acetate,
Dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with methylene chloride to obtain the title compound. Yield: 200 mg, Yield: 60.5% MS (ESI, m / z) 460 (MH +) HRMS (FAB) 460.1599 (C24H22N5O5 460.1621) H-NMR (DMSO-d6): 2.45 (3H, s), 3.71 ( 3H, s), 3.88
(2H, m), 4.73 (1H, m), 5.63 (1H, dt), 6.05 (2H, m
s), 6.20 (1H, dt), 6.53 (1H, dd), 6.75 (1H, d), 6.
81 (2H, d), 6.89 (1H, d), 6.93 (2H, d)

Example 44 3- (2- (3,4-Methylenedioxyphenyloxy) -3- (5-tetrazoyl) -4- (4-methoxyphenyl) -6-methylpyridin-5-yl) prope Synthesis of Neuacacid morpholinamide 1) 3-Cyano-5- (2-carboxyethenyl) -4
-(4-methoxyphenyl) -6-methyl-2- (3,
Synthesis of 4-methylenedioxyphenyl) pyridine 3-cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) -5
720 mg (1.5 mmol) of iodopyridine, 1.0 ml (14.7 mmol) of acrylic acid, 5.0 ml (21 mmol) of tri-n-butylamine, and 10 mg (0.04 mmol) of palladium acetate are dissolved in 10 ml of DMF, and the mixture is dissolved at 150 ° C. for 2 hours. Heat to reflux. Filter the insolubles,
The solvent is distilled off under reduced pressure, and the mixture is extracted with ethyl acetate. The crystals were washed with 1N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with ethyl acetate and hexane to give the title compound. Yield: 450 mg, yield: 70.6% MS (ESI, m / z) 431 (MH +) H-NMR (DMSO-d6): 2.45 (3H, s), 3.75 (3H, s), 5.82
(1H, d), 6.10 (2H, s), 6.72 (1H, dd), 6.96 (1H,
s), 6.98 (1H, d), 7.12 (2H, d), 7.26 (1H, d), 7.34
(2H, d)

2) 3- (2- (3,4-methylenedioxyphenyloxy) -3-cyano-4- (4-methoxyphenyl) -6-methylpyridin-5-yl) propenoic acid morpholinamide Synthesis of 3-cyano-5- (2-carboxyethenyl) -4-
(4-methoxyphenyl) -6-methyl-2- (3,4
-Methylenedioxyphenyl) pyridine 100mg
(0.23 mmol), morpholine 0.1 ml (1.1
mmol) in 5 ml of methylene chloride, and
mg (0.52 mmol), dimethylaminopyridine 5
mg and stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate, washed with 1N sodium hydroxide, 1N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound. This compound is used for the following reaction without further purification. Yield: 120 mg, Yield: quantitative MS (ESI, m / z) 500 (MH +) H-NMR (CDCl3): 2.51 (3H, s), 2.96-3.04 (2H, m), 3.4
0-3.50 (2H, m), 3.54-3.68 (4H, m), 3.85 (3H, s),
5.91 (1H, d), 6.03 (2H, s), 6.66 (1H, dd), 6.74 (1
H, d), 6.82 (1H, d), 7.01 (2H, d), 7.26 (2H, d),
7.46 (1H, d)

3) 3- (2- (3,4-Methylenedioxyphenyloxy) -3- (5-tetrazoyl) -4-
(4-methoxyphenyl) -6-methylpyridine-5
Synthesis of yl) propenoic acid morpholinamide 3- (2- (3,4-methylenedioxyphenyloxy) -3-cyano-4- (4-methoxyphenyl) -6
-Methylpyridin-5-yl) propenoic acid
Dissolve 120 mg (0.24 mmol) of morpholinamide in 5 ml of toluene and add 100 mg of sodium azide.
(1.5 mmol), tri-n-butyltin chloride 0.2
Tri-n-azide prepared from 7 ml (1.0 mmol)
Add butyltin and heat to reflux overnight. A 4N hydrochloric acid-dioxane solution was added, and the obtained crystals were washed with ethyl acetate to give the title compound. Yield: 70 mg, Yield: 53.8% MS (ESI, m / z) 543 (MH +) HRMS (FAB) 543.2004 (C28H27N6O6 543.1992 M
H +) H-NMR (DMSO-d6): 2.48 (3H, s), 3.16-3.27 (2H, m),
3.36-3.60 (6H, m), 3.72 (3H, s), 6.07 (2H, s), 6.3
4 (1H, d), 6.55 (1H, dd), 6.77 (1H, d), 6.86 (2H,
d), 6.92 (1H, d), 6.97 (2H, d), 7.22 (1H, d)

Example 45 4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) -5- (3- (2-pyridyloxy) -1-propenyl) -3 Synthesis of-(5-tetrazolyl) pyridine 1) Synthesis of 2-allyloxypyridine 0.96 g of 2-hydroxypyridine in 20 ml of DMF
(10.1 mmol) in 60% sodium hydride 0.4
4 g (11.0 mmol), 2.6 ml of allyl bromide (3
0.0 mmol) was stirred at room temperature for 4 hours. D under reduced pressure
After evaporating MF, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol 50: 1) to obtain the title compound. Yield: 1.12 g (8.26 mmol), yield: 81.
9% H-NMR (CDCl3): 4.55-4.60 (2H, m), 5.14-5.29 (2H, m), 5.
89-6.03 (1H, m), 6.15-6.20 (1H, t), 6.57-6.60 (1H, d),
7.22-7.36 (2H, m)

2) 3-cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) -5- (3- (2-pyridyloxy) -1-
Synthesis of propenyl) pyridine 284 mg (0.58 m) of 3-cyano-5-iodo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) pyridine in 6 ml of DMF
mol), 121 mg of 2-allyloxypyridine (0.
89 mmol), 15 mg of palladium acetate (0.07 m
mol) and 0.42 ml of tributylamine (1.76 m
mol) was heated and stirred at 150 ° C. for 3.5 hours. After evaporating DMF under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol 100: 1) to give the title compound. Yield: 212 mg (0.43 mmol), yield: 73.
5% MS (ESI, m / z) 494 (MH +) H-NMR (CDCl3): 2.43 (3H, s, Me), 3.86 (3H, s, MeO), 4.50-
4.52 (2H, d), 5.52-5.62 (1H, dt), 6.02 (2H, s), 6.04-6.1
0 (1H, dt), 6.21-6.27 (1H, d), 6.51-6.55 (1H, d), 6.63
6.83 (3H, m), 6.86-6.90 (1H, m), 6.92-6.95 (2H, d), 7.18
-7.21 (2H, d), 7.28-7.32 (1H, m)

3) 3-Cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) -5- (3- (2-pyridyloxy) -1-
Synthesis of propenyl) pyridine 215 mg (3.31 mmol) of sodium azide and 0.54 ml (1.99 mmol) of tributyltin chloride were stirred in 10 ml of water in an ice bath for 4 hours. After extraction with methylene chloride, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue, 15 ml of toluene and 3-cyano-4- (4
-Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenyl) -5- (3- (2-pyridyloxy) -1-propenyl) pyridine 212 mg (0.
43 mmol) and refluxed for 4 days. 2 room temperature
Hydrochloric acid and then ethyl acetate were added. The precipitate was filtered, washed with ethyl acetate and dried to give the title compound. Yield: 127 mg (0.24 mmol), yield: 55.
2% MS (ESI, m / z) 537 (MH +) H-NMR (DMSO-d6): 2.40 (3H, s, Me), 3.70 (3H, s, MeO), 4.4
4-4.47 (2H, d), 5.51-5.61 (1H, dt), 6.05 (2H, s), 6.06-
6.13 (1H, dt), 6.20-6.33 (2H, m), 6.51-6.55 (1H, m), 6.7
1-6.91 (6H, m), 7.24-7.28 (1H, m), 7.31-7.38 (1H, m)

Example 46 3- (2- (3,4-Methylenedioxyphenyloxy) -3- (5-tetrazoyl) -4- (4-methoxyphenyl) -6-methylpyridin-5-yl) propa Synthesis of Neuacacid morpholinamide 3- (2- (3,4-methylenedioxyphenyloxy) -3- (5-tetrazoyl) -4- (4-methoxyphenyl) -6-methylpyridin-5-yl) 30 mg of propenoic acid morpholinamide (0.06m
mol) was dissolved in 10 ml of DMF, 10 mg of 10% palladium on carbon was added, and the mixture was stirred overnight at a hydrogen pressure of 4 kg / m2 at room temperature. The solvent is removed under reduced pressure by removing the catalyst using celite. The residue is extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained crystals were washed with ethyl acetate: hexane 1: 1 to give the title compound. Yield: 20 mg, yield: 66.8% MS (ESI, m / z) 545 (MH +) HRMS (FAB) 545.2139 (C28H27N6O6 545.2149 M
H +) H-NMR (DMSO-d6): 2.22-2.32 (2H, m), 2.45 (3H, s),
2.58-2.68 (2H, m), 3.02-3.08 (2H, m), 3.24-3.38 (4
H, m), 3.42-3.50 (2H, m), 3.73 (3H, s), 6.05 (2H,
s), 6.51 (1H, dd), 6.72 (1H, d), 6.83-6.92 (3H,
m), 7.04 (2H, d)

Example 47 3- [4- (4-Methoxyphenyl) -6-methyl-pyridine-2-carbamic acid
2- (3,4-methylenedioxyphenoxy) -3-
Synthesis of (1H-tetrazol-5-yl) pyridin-5-yl] -2-propylene ester 81 mg (0.654 mmol) of picolinic acid was dissolved in 5 ml of toluene, and 198 m of diphenylphosphoryl azide was obtained.
g (0.718 mmol), triethylamine 73 mg
(0.718 mmol), and the mixture was stirred at 80 ° C. for 2 hours. Then 5- (3-hydroxy-1-propenyl)
-4- (4-methoxyphenyl) -6-methyl-2-
(3,4-methylenedioxyphenoxy) -3- (1H
-Tetrazol-5-yl) -pyridine 100 mg
(0.218 mmol) at 80 ° C. and an additional 12
Stirred for hours. After completion of the reaction, 1N hydrochloric acid was added to the reaction solution for 2 hours.
After stirring for 30 minutes, water was added to the reaction solution,
After extraction with ethyl acetate and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 60 mg, Yield: 48% MS (ESI.m / z) 580 (MH +) 1H-H-NMR (DMSO-d6): 2.45 (3H, s), 3.61 (3H, s), 4.5
6 (2H, d), 5.66 (2H, dt), 6.05 (2H, s), 6.40 (1H,
d), 6.52-7.06 (7H, m), 7.74-7.77 (2H, m), 8.24 (1
H, d)

Example 48 Furan-2-carbamic acid
3- [4- (4-methoxyphenyl) -6-methyl-2
-(3,4-methylenedioxyphenoxy) -3- (1
H-tetrazol-5-yl) pyridin-5-yl]-
Synthesis of 2-propylene ester 146 mg (1.31 mmol) of 2-furancarboxylic acid
Was dissolved in 5 ml of toluene, and 419 mg (1.52 mmol) of diphenylphosphoryl azide and 154 mg (1.52 mmol) of triethylamine were added.
Stirred for hours. Then, 5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3-
(1H-tetrazol-5-yl) -pyridine 200 m
g (0.435 mmol) at 80 ° C.
Stir for 8 hours. After completion of the reaction, 2 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 160 mg, Yield: 65% MS (ESI.m / z) 569 (MH +) 1H-NMR (CDCl3): 2.49 (3H, s), 3.69 (3H, s), 4.57
(2H, d), 5.65 (1H, dt), 5.96 (3H, br s), 6.34-7.14
(10H, m)

Example 49 Furan-2-ylcarboxylic acid 3- [4- (4-methoxyphenyl) -6-methyl-
2- (3,4-methylenedioxyphenoxy) -3-
Synthesis of (1H-tetrazol-5-yl) pyridin-5-yl "-2-propylene ester 5- (3-hydroxy-1-propenyl) -4- (4-
Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) -pyridine 100 mg (0.218 mmol)
l) was dissolved in 5 ml of pyridine, 43 mg (0.326 mmol) of 2-furoyl chloride was added at room temperature, and the mixture was stirred for 4 hours. The reaction solution was added with 3 ml of 1N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to column chromatography (eluent: chloroform: methanol 9:
Purification in 1) gave the title compound. Yield: 70 mg, Yield: 59% MS (ESI.m / z) 554 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.66 (3H, s), 4.70
(2H, d), 5.60 (1H, dt), 5.92 (2H, s), 6.32-7.54
(11H, m)

Example 50 3- (2- (3,4-Methylenedioxyphenyloxy) -3- (5-tetrazoyl) -4- (4-methoxyphenyl) -6-methylpyridin-5-yl) propane Synthesis of Neuacacid anilinamide 1) 3- (2- (3,4-Methylenedioxyphenyloxy) -3-cyano-4- (4-methoxyphenyl)-
Synthesis of 6-methylpyridin-5-yl) propenoic acid anilinamide 3-cyano-5- (2-carboxyethenyl) -4-
(4-methoxyphenyl) -6-methyl-2- (3,4
-Methylenedioxyphenyl) pyridine 90 mg (0.
21 mmol), aniline 0.1 g (1.0 mmol)
Was dissolved in 5 ml of methylene chloride, and 80 mg of WSC (0.4 mg) was dissolved.
2 mmol) and stir at room temperature for 3 hours. The mixture was extracted with ethyl acetate, washed with 1N sodium hydroxide, 1N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound. This compound is used for the following reaction without further purification. Yield: 40 mg, Yield: 37.7% MS (ESI, m / Z) 506 (MH +) H-NMR (CDCl3): 2.52 (3H, s), 3.86 (3H, s), 5.79 (1
H, d), 6.02 (2H, s), 6.66 (1H, dd), 6.74 (1H, d),
6.82 (1H, d), 7.00 (2H, d), 7.50 (1H, m), 7.54 (1
H, d)

2) 3- (2- (3,4-methylenedioxyphenyloxy) -3- (5-tetrazoyl) -4-
(4-methoxyphenyl) -6-methylpyridine-5
Synthesis of yl) propenoic acid anilinamide 3- (2- (3,4-methylenedioxyphenyloxy) -3-cyano-4- (4-methoxyphenyl) -6
-Methylpyridin-5-yl) propenoic acid
Anifolinamide (40 mg) was dissolved in toluene (10 ml), sodium azide (100 mg, 1.5 mmol),
0.27 ml of tri-n-butyltin chloride (1.0 mmol
l) Add tri-n-butyltin azide prepared from 1) and add 3
Heat to reflux for days. Add 4N dioxane hydrochloride solution,
The obtained crystals were washed with ethyl acetate to give the title compound. Yield: 35 mg, Yield: 80.1% MS (ESI, m / z) 549 (MH +) H-NMR (DMSO-d6): 2.55 (3H, s), 3.73 (3H, s), 6.07
(2H, s), 6.36 (1H, d), 6.58 (1H, dd), 6.80-7.10 (8
H, m), 7.20-7.38 (3H, m), 7.62 (2H, d), 10.12 (1H,
br)

Example 51 5- [3- (pyrimidine-2)
Synthesis of-(yloxy) -1-propenyl] -4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) -pyridine Under an argon atmosphere, 5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -6-methyl-
2- (3,4-methylenedioxyphenoxy) -3-
(1H-tetrazol-5-yl) -pyridine 60 mg
(0.131 mmol) was dissolved in 5 ml of DMF.
% Sodium hydride (11 mg, 0.261 mmol) was added at room temperature, and the mixture was stirred for 1 hour. Thereafter, 30 mg (0.261 mmol) of 2-chloropyrimidine was added at room temperature, and the mixture was stirred at 80 ° C. for 12 hours. Saturated saline was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 60 mg, Yield: 87% MS (ESI.m / z) 538 (MH +) 1H-NMR (CDCl3): 2.39 (3H, s), 3.69 (3H, s), 4.78
(2H, d), 5.62 (1H, dt), 5.93 (2H, s), 6.26-6.98 (9
H, m), 8.46 (2H, d)

Example 52 4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -5- (3- (2-quinolyloxy) -1-
Synthesis of propenyl) -3- (5-tetrazolyl) pyridine 1) Synthesis of 2-allyloxyquinoline 3.08 g of 2-hydroxyquinoline in 40 ml of DMF
(21.2 mmol) in 60% sodium hydride 0.9
0 g (22.5 mmol), allyl bromide 10 ml (11
6 mmol) was stirred overnight at room temperature. After evaporating DMF under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel chromatography of the residue (hexane: ethyl acetate 4: 1)
And the title compound was obtained. Yield: 3.13 g (16.9 mmol), yield: 79.
7% H-NMR (CDCl3): 4.94 to 4.98 (2H, m), 5.06-5.26 (2H, m), 5.
91-6.04 (1H, m), 6.73 (1H, d), 7.22 (1H, t), 7.33 (1H,
d), 7.50-7.59 (2H, m), 7.70 (1H, d)

2) 3-Cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -5- (3- (2-quinolyloxy) -1
Synthesis of -propenyl) pyridine 285 mg (0.59) of 3-cyano-5-iodo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) pyridine in 6 ml of DMF
mmol), 163 mg of 2-allyloxyquinoline
(0.88 mmol), 17 mg of palladium acetate (0.
07 mmol) and 0.42 ml of tributylamine (1.
(76 mmol) was heated and stirred at 150 ° C. for 4 hours. After distilling off DMF under reduced pressure, 1N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane:
Purification with ethyl acetate (2: 1) gave the title compound. Yield: 240 mg (0.44 mmol), yield: 75.
5% MS (ESI, m / z) 544 (MH +) H-NMR (CDCl3): 2.40 (3H, s, Me), 3.80 (3H, s, MeO), 4.89
(2H, d), 5.59 (1H, dt), 6.00 (2H, s), 6.14 (1H, d), 6.61
6.81 (6H, m), 7.02-7.09 (3H, m), 6.63-6.83 (3H, m), 7.19
-7.27 (1H, m), 7.47 (1H, t), 7.56 (1H, d), 7.66 (1H, d)

3) 4- (4-methoxyphenyl) -6
Methyl-2- (3,4-methylenedioxyphenoxy)
Synthesis of -5- (3- (2-quinolyloxy) -1-propenyl) -3- (5-tetrazolyl) pyridine 408 mg (6.28 mmol) of sodium azide and 1.0 ml (3.69 mmol) of tributyltin chloride were added to 20 ml of water. The mixture was stirred for 4 hours under a medium ice bath. After extraction with methylene chloride, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added 5 ml of toluene, 3-cyano-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -5- (3- (2-quinolyloxy) -1-propenyl). 235 mg of pyridine (0.4 mg
3 mmol) and refluxed overnight. At room temperature, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate,
Dry to obtain the title compound. Yield: 158 mg (0.27 mmol), yield: 62.
3% MS (ESI, m / z) 587 (MH +) H-NMR (DMSO-d6): 2.39 (3H, s, Me), 3.64 (3H, s, MeO), 4.8
4 (2H, d), 5.58 (1H, dt), 6.04 (2H, s), 6.10 (1H, d), 6.43
-6.56 (4H, m), 6.66-6.74 (3H, m), 6.88 (1H, d), 7.22-7.2
8 (2H, m), 7.48-7.55 (1H, m), 7.66-7.71 (1H, m), 7.86 (1
H, d)

Example 53 Cyclohexanecarboxylic acid
3- [4-methoxyphenyl-6-methyl-2- (3,
Synthesis of 4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) pyridin-5-yl "-2-propylene ester 5- (3-hydroxy-1-propenyl) -4- (4-
Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) -pyridine 100 mg (0.218 mmol)
l) was dissolved in 5 ml of pyridine, 48 mg (0.326 mmol) of cyclohexanecarbonyl chloride was added at room temperature, and the mixture was stirred for 12 hours. Add 1N hydrochloric acid to the reaction solution
The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 40 mg, Yield: 32% MS (ESI.m / z) 570 (MH +) 1H-NMR (CDCl3): 1.23-2.30 (11H, m), 2.48 (3H, s),
3.76 (3H, s), 4.51 (2H, d), 5.59 (1H, dt), 5.97 (2
H, s), 6.25 (1H, d), 6.53-6.96 (7H, m)

Example 54 5- (3-hydroxy-1-)
Synthesis of propenyl) -4- (4-methoxyphenyl) -6-methyl-2- (2-chloro-4,5-methylenedioxyphenoxy) -3- (5-tetrazoyl) pyridine Performed in the same manner as in Example 43. Was. MS (ESI, m / z) 494 (MH +) H-NMR (DMSO-d6): 2.16 (3H, s), 3.45 (3H, s), 3.62 (2H,
m), 5.37 (1H, dt), 5.86 (2H, s), 5.94 (1H, d), 6.55 (2H,
d), 6.68 (2H, d), 6.71 (1H, s), 6.88 (1H, s)

Example 55 4-morpholinecarboxylic acid
3- [4- (4-methoxyphenyl) -6-methyl-2
-(3,4-methylenedioxyphenoxy) -3- (1
H-tetrazol-5-yl) pyridin-5-yl "-
Synthesis of 2-propylene ester 5- (3-hydroxy-1-propenyl) -4- (4-
Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) -pyridine 200 mg (0.435 mmol)
l) was dissolved in 5 ml of pyridine, 98 mg (0.653 mmol) of 4-morpholinecarbonyl chloride was added at room temperature, and the mixture was stirred for 48 hours. 3m of 1N hydrochloric acid in the reaction solution
l, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 124 mg, Yield: 51% MS (ESI.m / z) 573 (MH +) 1H-NMR (CDCl3): 2.47 (3H, s), 3.24-3.76 (11H, m),
4.09 (2H, d), 5.66 (1H, dt), 6.00 (2H, s), 6.27 (1
H, d), 6.47-7.07 (7H, m)

Example 56 3- (2- (3,4-Methylenedioxyphenyloxy) -3- (5-tetrazoyl) -4- (4-methoxyphenyl) -6-methylpyridin-5-yl) propane Synthesis of Neuacacid dibutylamide The same procedure was performed as in Example 44. MS (ESI, m / z) 585 (MH +) H-NMR (DMSO-d6): 0.85 (6H, t), 1.08-1.44 (8H, m), 2.48
(3H, s), 3.00 (2H, m), 3.22 (2H, m), 3.71 (3H, s), 6.06 (2
H, s), 6.22 (1H, d), 6.55 (1H, dd), 6.72 (1H, d), 6.84 (2
H, d), 6.91 (1H, d), 6.97 (2H, d), 7.28 (1H, d)

Example 57 3- (2- (3,4-Methylenedioxyphenyloxy) -3- (5-tetrazoyl) -4- (4-methoxyphenyl) -6-methylpyridin-5-yl) prope Neuk Acid 3,4,5-
Synthesis of trimethoxyanilinamide It was carried out in the same manner as in Example 44. MS (ESI, m / z) 639 (MH +) H-NMR (DMSO-d6): 2.55 (3H, s), 3.61 (3H, s), 3.73 (6H,
s), 3.74 (3H, s), 6.07 (2H, s), 6.34 (1H, d), 6.58 (1H, d
d), 6.80-7.02 (8H, m), 7.24 (1H, d)

Example 58 4- (4-Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -5- (3- (6-phenyl-3-pyridazyloxy) -1-propenyl Synthesis of) -3- (5-tetrazolyl) pyridine 5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -6-methyl-2 in 5 ml of DMF
-(3,4-methylenedioxyphenoxy) -3- (5
-Tetrazoyl) pyridine 58 mg (0.13 mmol
l) to 40 mg of 60% sodium hydride (1.0 mmo
l), 3-chloro-6-phenylpyridazine 40 mg
(0.21 mmol) was heated at 80 ° C. for 3 hours. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol 9: 1) to give the title compound. Yield: 32 mg (0.05 mmol), yield: 41.3
% MS (ESI, m / z) 614 (MH +) H-NMR (CDCl3): 2.47 (3H, s, Me), 3.68 (3H, s, MeO), 4.92
(2H, d), 5.76 (1H, dt), 5.97 (2H, s), 6.35-6.95 (8H, m),
7.00 (1H, d), 7.46-7.53 (3H, m), 7.80 (1H, d), 7.93-7.99
(2H, m)

Example 59 3- [4-Methoxyphenyl-6-methyl-2-pyridin-2-ylcarboxylic acid
(3,4-methylenedioxyphenoxy) -3- (1H
-Tetrazol-5-yl) pyridin-5-yl "-2
Synthesis of propylene ester 5- (3-hydroxy-1-propenyl) -4- (4-
Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) -pyridine 200 mg (0.435 mmol)
l) was dissolved in 5 ml of pyridine, and 116 mg of pyridine-2-carbonyl chloride hydrochloride (0.65
3 mmol) at room temperature and stirred for 48 hours. 3N hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate.
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 30 mg, Yield: 13% MS (ESI.m / z) 565 (MH +) 1H-NMR (CDCl3): 2.40 (3H, s), 3.60 (3H, s), 4.76
(2H, d), 5.57 (1H, dt), 5.94 (2H, s), 6.33-6.88 (8
H, m), 7.48-8.03 (3H, m), 8.67 (1H, d)

Example 60 4-butoxybenzoic acid 3-
[4-methoxyphenyl-6-methyl-2- (3,4-
Synthesis of methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) pyridin-5-yl "-2-propylene ester 5- (3-hydroxy-1-propenyl) -4- (4-
Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) -pyridine 200 mg (0.435 mmol)
l) was dissolved in 5 ml of pyridine, 139 mg (0.653 mmol) of 4-butoxybenzoyl chloride was added at room temperature, and the mixture was stirred for 24 hours. Add 1N hydrochloric acid to the reaction solution
The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 120 mg, Yield: 43% MS (ESI.m / z) 636 (MH +) 1H-NMR (CDCl3): 0.99 (3H, t), 1.50 (2H, sext), 1.7
9 (2H, quint), 2.48 (3H, s), 3.68 (3H, s), 4.01 (2
H, t), 4.71 (2H, d), 5.67 (1H, dt), 5.96 (2H, s),
5.96-6.93 (10H, m), 7.84 (2H, d)

Example 61 5- [3- (5-bromopyridine-2-yloxy) -1-propenyl] -4- (4-
Synthesis of methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) -pyridine 5- (3-hydroxy-1-propenyl) under an argon atmosphere ) -4- (4-Methoxyphenyl) -6-methyl-
2- (3,4-methylenedioxyphenoxy) -3-
(1H-tetrazol-5-yl) -pyridine 200 m
g (0.435 mmol) in 10 ml of DMF,
52 mg (1.31 mmol) of 60% sodium hydride
Was added at room temperature and stirred for 1 hour. Thereafter, 309 mg (1.31 mmol) of 2,5-dibromopyridine was added at room temperature, and the mixture was stirred at 80 ° C. for 12 hours. 1 in the reaction solution
After adding 3 ml of normal hydrochloric acid, the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 80 mg, 30% MS (ESI.m / z) 616 (MH +) 1H-NMR (CDCl3): 2.43 (3H, s), 3.69 (3H, s), 4.69
(2H, d), 5.66 (1H, dt), 5.90 (2H, s), 6.26-6.81 (9
H, m), 7.60 (1H, q), 8.07 (1H, d)

Example 62 3,4,5-Trimethoxyphenyl-1-carbamic acid 3- [4-methoxyphenyl-6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H- Synthesis of tetrazol-5-yl) pyridin-5-yl] -2-propylene ester 278 mg of 3,4,5-trimethoxybenzoic acid (1.3 mg)
1 mmol) was dissolved in 5 ml of toluene, and 418 mg (1.52 mmol) of diphenylphosphoryl azide and 154 mg (1.52 mmol) of triethylamine were added.
The mixture was stirred at 80 ° C for 2 hours. Then 5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl)
200 mg (0.435 mmol) of -6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) -pyridine was added at 80 ° C, and the mixture was further stirred for 12 hours. After completion of the reaction, 2 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform: methanol 9: 1) to give the title compound. Yield: 120 mg, Yield: 41% MS (ESI.m / z) 669 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.67 (3H, s), 3.79
(9H, s), 4.55 (2H, d), 5.56 (1H, dt), 5.95 (2H,
s), 6.25-6.87 (10H, m)

Example 63 4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -5- (3-pyrazyloxy-1-propenyl) -3- (1H-tetrazole Synthesis of -5-yl) pyridine In 5 ml of DMF, 227 mg of the compound of Example 43 (0.
49 mmol) to 90 mg of 60% sodium hydride
(2.25 mmol), 0.05 ml of chloropyrazine
(0.56 mmol) was heated at 100 ° C. for 3 hours. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried under reduced pressure to obtain the title compound. Yield 110 mg (0.21 mmol) Yield
4% MS (ESI, m / z) 538 (MH +) 1H-NMR (CDCl3): 2.49 (3H, s), 3.76 (3H, s), 4.79
(2H, d), 5.77-5.79 (1H, m), 5.98 (2H, s), 6.37 (1
H, d), 6.50-6.77 (5H, m), 6.90 (2H, d), 7.99-8.17
(3H, m)

Example 64 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy)-
5- (3-hydroxy-1-propenyl) -3- (1H
Synthesis of -tetrazol-5-yl) pyridine 1) Synthesis of 3-cyano-5-iodo-4- (4-methoxyphenyl) -2-pyridone In 430 ml of acetonitrile, 3-cyano-4- (4-
13.38 g of (methoxyphenyl) -2-pyridone (5
9.1 mmol) to 13.4 N-iodosuccinimide.
5 g (59.8 mmol) was added, and the mixture was heated under reflux for 8.5 hours. After cooling, the crystals were filtered, washed with acetonitrile, and dried under reduced pressure to obtain the title compound. Yield 12.35 g (35.1 mmol) Yield 5
9.4% 1H-NMR (DMSO-d6): 3.83 (3H, s), 7.08 (2H, d), 7.28
(2H, d), 8.20 (1H, s

2) Synthesis of 2-chloro-3-cyano-5-iodo-4- (4-methoxyphenyl) pyridine 3-cyano-5-iodo-4- (4-methoxyphenyl) -2-pyridone 35 g (35.1 mmol)
To the mixture was added 200 ml of phosphorus oxychloride, and the mixture was heated at 100 ° C. overnight. After distilling off phosphorus oxychloride, water was added and the crystals were filtered,
Washing with water, hexane, hexane-ethyl acetate (1: 1) and drying under reduced pressure gave the title compound. . Yield 12.00 g (32.4 mmol) Yield 9
2.3% MS (ESI, m / z) 371 (MH +) 1H-NMR (CDCl3): 3.89 (3H, s), 7.05 (2H, d), 7.27
(2H, d), 8.94 (1H, s)

3) 3-Cyano-5-iodo-4- (4-
Synthesis of methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 4.71 g (34.1) of sesamol in 150 ml of DMF
mmol), 1.37 g of 60% sodium hydride (3
4.3 mmol), 2-chloro-3-cyano-5-iodo-4- (4-methoxyphenyl) pyridine 12.00
g (32.4 mmol) was stirred at room temperature for 4 hours. After evaporating DMF under reduced pressure, the crystals were washed with water, hexane, hexane-ethyl acetate (1: 1) and dried under reduced pressure to obtain the title compound. . Yield 14.52 g (30.8 mmol) Yield 9
4.9% MS (ESI, m / z) 473 (MH +) 1H-NMR (CDCl3): 3.89 (3H,
s), 6.02 (2H, s), 6.63-
6.85 (3H, m), 7.05 (2H,
d), 7.32 (2H, d), 8.65 (1
H, s)

4) 3-Cyano-5- (2-ethoxycarbonylethenyl) -4- (4-methoxyphenyl) -2
Synthesis of-(3,4-methylenedioxyphenoxy) pyridine 3-cyano-5-iodo-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 443 mg (0.94 mmol) 8 ml of DMF
And dissolved in 15 mg of palladium acetate (0.07 mmol
1) and 1 ml (9.23 mmol) of ethyl acrylate,
1 ml (7.21 mmol) of triethylamine in 100
The mixture was heated and stirred at ℃ overnight. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to obtain the title compound. Yield 320 mg (0.72 mmol) Yield
6% MS (ESI, m / z) 445 (MH +) 1H-NMR (CDCl3): 1.28 (3H, t), 3.90 (3H, s), 4.20 (2
H, qua), 6.03 (2H, s), 6.29 (1H, d), 6.65-6.87 (3
H, m), 7.07 (2H, d), 7.33 (2H, d), 7.43 (1H, d),
8.52 (1H, s)

5) 3-cyano-5- (3-hydroxy-
1-propenyl) -4- (4-methoxyphenyl) -2
Synthesis of-(3,4-methylenedioxyphenoxy) pyridine 3-cyano-5- (2-ethoxycarbonylethenyl)
234 mg of 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine (0.5 mg)
3 mmol) was dissolved in 8 ml of methylene chloride, cooled to -78 ° C, and 1.1 ml (1.1 mmol) of a 1M hexane solution of diisobutylaluminum hydride was added over 8 minutes. 1
After stirring for 20 minutes, 0.5 ml (0.5 mmol) of a 1M hexane solution of diisobutylaluminum hydride was further added over 5 minutes. After stirring for one hour, 0.5 ml of a 1 M diisobutylaluminum hexane solution (0.5 m
mol) was added over 5 minutes. After 20 minutes, methanol 0.1.
8 ml and 0.8 ml of water were added. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1) to give the title compound. Yield 150 mg (0.37 mmol) Yield 70.
3% MS (ESI, m / z) 403 (MH +) 1H-NMR (CDCl3): 3.89 (3H, s), 4.22 (2H, d), 6.02
(2H, s), 6.20 (1H, dt), 6.35 (1H, d), 6.65-6.86 (3
H, m), 7.04 (2H, d), 7.33 (2H, d), 8.43 (1H, s)

6) 4- (4-methoxyphenyl) -2-
(3,4-methylenedioxyphenoxy) -5- (3-
Synthesis of hydroxy-1-propenyl) -3- (1H-tetrazol-5-yl) pyridine Tributyltin azide prepared from 436 mg (6.71 mmol) of sodium azide and 1.0 ml (3.69 mmol) of tributyltin chloride and 3-butyltin Cyano-5- (3
145 mg (0.36 mmol) of -hydroxy-1-propenyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine was heated in 5 ml of toluene at 110 ° C for 2 days. At room temperature, 2N hydrochloric acid was added, and the crystals were filtered and washed with chloroform. The obtained crystals were purified by silica gel chromatography (chloroform-methanol = 9: 1), and further purified by TLC (chloroform-methanol = 9: 1) to obtain the title compound. Yield 8.5 mg (0.02 mmol) Yield 5.3
% MS (ESI, m / z) 446 (MH +) 1H-NMR (DMSO-d6): 3.74 (3H, s), 4.00 (2H, m), 6.05
(2H, s), 6.19 (1H, d), 6.36 (1H, dt), 6.51-7.07 (7
H, m), 7.33 (2H, d), 8.57 (1H, s)

Example 65 5- (3-hydroxy-2-
Methylenepropyl) -4- (4-methoxyphenyl)-
2- (3,4-methylenedioxyphenyl) -3- (1
Synthesis of H-tetrazol-5-yl) pyridine 1) Synthesis of 5-methylene-2-phenyl- [1,3] dioxane 2.65 g (30.1 mmol) of 2-methylene-1,3-propanediol in 60 ml of benzene ) And benzaldehyde (3.05 ml, 30.0 mmol) in benzene 6
The mixture was refluxed overnight while removing water in 0 ml. After distilling off benzene under reduced pressure, ethyl acetate was added, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound. Yield 4.65 g (26.4 mmol) Yield
0% 1H-NMR (CDCl3): 4.52 (4H, s), 5.00 (2H, s), 5.62 (1
H, s), 7.32-7.52 (5H, m)

2) 3-cyano-5- (2-formyl-2)
-Propenyl) -4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenoxy) pyridine 491 mg (1.01 mmol) of 3-cyano-5-iodo-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine DMF10m
and 25 mg (0.11 mmol) of palladium acetate
l), 1.70 g (9.65 mmol) of 5-methylene-2-phenyl- [1,3] dioxane and 1 ml (7.21 mmol) of triethylamine were heated and stirred at 100 ° C. overnight. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to obtain the title compound. Yield 392 mg (0.91 mmol) Yield 90.
5% MS (ESI, m / z) 429 (MH +) 1H-NMR (CDCl3): 2.31 (3H, s), 3.40 (2H, m), 3.84 (3
H, s), 5.74 (1H, t), 6.02 (2H, s), 6.04 (1H, t), 6.
66-6.83 (3H, m), 6.96 (2H, d), 7.15 (2H, d), 9.55
(1H, s, CHO)

3) 3-cyano-5- (3-hydroxy-
Synthesis of 2-methylenepropyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyl) pyridine 3-cyano-5- (2-formyl-2-propenyl)-
392 mg of 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine (0.91
mmol), ethanol 10ml, methanol 10m
1, 10 ml of THF was added, and after ice bath, 130 mg (3.44 mmol) of sodium borohydride was added. After stirring for 2 hours, 2N hydrochloric acid was added to stop the reaction, the reaction solvent was distilled off under reduced pressure, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used for the next reaction without purification. Yield 402 mg (0.94 mmol) Crude yield 10
0% MS (ESI, m / z) 431 (MH +) 1H-NMR (CDCl3): 2.39 (3H, s), 3.16 (2H, s), 3.86 (3
H, s), 3.98 (2H, s), 4.45 (1H, s), 5.12 (1H, s), 6.
02 (2H, s), 6.65-6.84 (3H, m), 6.98 (2H, d), 7.24
(2H, d)

4) 5- (3-hydroxy-2-methylenepropyl) -4- (4-methoxyphenyl) -2-
(3,4-methylenedioxyphenyl) -3- (1H-
Synthesis of tetrazol-5-yl) pyridine Tributyltin azide prepared from 698 mg (10.7 mmol) of sodium azide and 1.5 ml (5.53 mmol) of tributyltin chloride and 3-cyano-5- (3
395 mg (0.86 mmol) of -hydroxy-2-methylenepropyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenyl) pyridine were heated in 5 ml of toluene at 120 ° C for 2 days. 2N at room temperature
Hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel chromatography of the residue (chloroform-methanol = 9: 1)
And the title compound was obtained. Yield 53 mg (0.11 mmol) Yield 12.8
% MS (ESI, m / z) 474 (MH +) 1H-NMR (CDCl3): 2.33 (3H, s), 3.05 (2H, s), 3.71 (3
H, s), 3.74 (2H, s), 4.31 (1H, s), 4.85 (1H, brd),
5.03 (1H, s), 6.04 (2H, s), 6.50-6.96 (7H, m)

Example 66 6-Ethyl-5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy)-
Synthesis of 3- (1H-tetrazol-5-yl) pyridine 1) 3-cyano-6-ethyl-5-iodo-4- (4-
Synthesis of methoxyphenyl) -2-pyridone 3-cyano-6-ethyl-4- (4-methoxyphenyl) -2-pyridone 7.0 in 250 ml of acetonitrile.
7.20 g (36.4 mmol) of N-iodosuccinimide was added to 7 g (27.8 mmol), and the mixture was heated under reflux overnight. Acetonitrile was distilled off under reduced pressure, and the residue was washed with hexane and acetonitrile and dried under reduced pressure to obtain the title compound. Yield 5.30 g (13.9 mmol) Yield 50.
1% MS (ESI, m / z) 381 (MH +)

2) Synthesis of 2-chloro-3-cyano-6-ethyl-5-iodo-4- (4-methoxyphenyl) pyridine 3-cyano-6-ethyl-5-iodo-4- (4-methoxy) 5.30 g of phenyl) -2-pyridone (13.9 m
mol), and add 70 ml of phosphorus oxychloride at 100 ° C.
Heated overnight. After the phosphorus oxychloride was distilled off, the residue was subjected to silica gel chromatography (chloroform-hexane = 4:
Purification in 1) gave the title compound. Yield 4.81 g (12.1 mmol) Yield
6% MS (ESI, m / z) 399 (MH +) 1H-NMR (CDCl3): 1.34 (3H, t), 3.14 (2H, qua), 3.88
(3H, s), 7.03 (2H, d), 7.19 (2H, d)

3) Synthesis of 3-cyano-6-ethyl-5-iodo-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 1.86 g (13) of sesamol in 70 ml of DMF .5m
mol), 0.57 g of 60% sodium hydride (14.
3 mmol), 2-chloro-3-cyano-6-ethyl-
4.81 g (12.1 mmol) of 5-iodo-4- (4-methoxyphenyl) pyridine was stirred at room temperature for 5 hours. After evaporating DMF under reduced pressure, water was added, and the mixture was filtered, washed with water and hexane, and dried under reduced pressure to obtain the title compound. Yield 6.36 g (12.7 mmol) Yield
1% MS (ESI, m / z) 501 (MH +) 1H-NMR (CDCl3): 1.13 (3H, t), 2.95 (2H, m), 3.88 (3
H, s), 6.02 (2H, s), 6.64-6.83 (3H, m), 7.03 (2H,
d), 7.24 (2H, d)

4) Synthesis of 3-cyano-5- (2-ethoxycarbonylethenyl) -6-ethyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 6.35 g (12.7 mmol) of cyano-6-ethyl-5-iodo-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine was added to D
Dissolved in 100 ml of MF, 128 mg of palladium acetate
(0.57 mmol) and 10 ml of ethyl acrylate (9
2.3 mmol), 10 ml of triethylamine (72.
(1 mmol) was heated and stirred at 100 ° C. for 5 days. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to obtain the title compound. Yield 3.69 g (7.80 mmol) Yield
4% MS (ESI, m / z) 473 (MH +) 1H-NMR (CDCl3): 1.14 (3H, t), 1.25 (3H, t), 2.80 (2
H, qua), 3.87 (3H, s), 4.17 (2H, qua), 5.74 (1H,
d), 6.02 (2H, s), 6.66-6.83 (3H, m), 6.70 (2H, d),
7.25 (2H, d), 7.44 (1H, d)

5) 3-Cyano-6-ethyl-5- (3-
Synthesis of hydroxy-1-propenyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 3-cyano-5- (2-ethoxycarbonylethenyl)
-6-ethyl-4- (4-methoxyphenyl) -2-
(3,4-methylenedioxyphenoxy) pyridine3.
68 g (7.79 mmol) was dissolved in 90 ml of methylene chloride, cooled to -78 ° C, and then 16.0 ml (16.0 mmol) of a 1M hexane solution of diisobutylaluminum hydride.
Was added over 55 minutes. The mixture was stirred at the same temperature, and 1.5 hours, 3.5 hours, and 4.5 hours after the completion of the dropwise addition. Further, a 1 M hexane solution of diisobutylaluminum hydride was added.
8.0 ml (18.0 mmol) were added over 10 minutes each. After stirring at -78 ° C for 1 hour, methanol 2.0m
1 and 2 ml of water. The precipitate was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound. Yield 3.14 g (7.29 mmol) Yield
6% MS (ESI, m / z) 431 (MH +) 1H-NMR (CDCl3): 1.12 (3H, t), 2.77 (2H, qua), 3.86
(3H, s), 4.09 (2H, m), 5.58 (1H, dt), 6.01 (2H,
s), 6.29 (1H, dt), 6.66-6.82 (3H, m), 6.98 (2H,
d), 7.24 (2H, d)

6) 6-ethyl-5- (3-hydroxy-
1-propenyl) -4- (4-methoxyphenyl) -2
-(3,4-methylenedioxyphenoxy) -3- (1
Synthesis of H-tetrazol-5-yl) pyridine Tributyltin azide prepared from 737 mg (11.3 mmol) of sodium azide and 1.5 ml (5.53 mmol) of tributyltin chloride and 3-cyano-6-ethyl-5- (3 -Hydroxy-1-propenyl) -4-
440 mg of (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine (1.02 mm
ol) was heated in 5 ml of toluene at 120 ° C. for 3 days.
2N Hydrochloric acid was added at room temperature, followed by filtration. The crystals were washed with toluene and ethyl acetate, and dried under reduced pressure to obtain the title compound. Yield 258 mg (0.55 mmol) Yield 53.
3% MS (ESI, m / z) 474 (MH +) 1H-NMR (DMSO-d6): 1.09 (3H, t), 2.77 (2H, qua), 3.
71 (3H, s), 3.87 (2H, t), 5.55 (1H, dt), 6.05 (2H,
s), 6.24 (1H, dt), 6.54 (1H, dd), 6.76-6.96 (6H,
m)

Example 67 6-butyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) -5- (3-hydroxy-1-propenyl)-
Synthesis of 3- (1H-tetrazol-5-yl) pyridine 1) 6-butyl-3-cyano-5-iodo-4- (4-
Synthesis of methoxyphenyl) -2-pyridone 6-butyl-3-cyano-4- (4-methoxyphenyl) -2-pyridone 7.4 in 250 ml of acetonitrile.
8.13 g (36.1 mmol) of N-iodosuccinimide was added to 0 g (26.2 mmol), and the mixture was heated under reflux overnight. Acetonitrile was distilled off under reduced pressure, and the residue was washed with hexane and acetonitrile and dried under reduced pressure to obtain the title compound. Yield 5.23 g (12.8 mmol) Yield
9% MS (ESI, m / z) 409 (MH +)

2) Synthesis of 6-butyl-2-chloro-3-cyano-5-iodo-4- (4-methoxyphenyl) pyridine 6-butyl-3-cyano-5-iodo-4- (4-methoxy) 5.23 g (12.8 m) of phenyl) -2-pyridone
mol) and add 70 ml of phosphorus oxychloride
Heated for hours. After phosphorus oxychloride was distilled off, hexane and water were added, and the crystals were filtered, washed with water, and dried under reduced pressure to obtain the title compound. Yield 2.40 g (5.63 mmol) Yield
0% MS (ESI, m / z) 427 (MH +)

3) 6-Butyl-3-cyano-5- (2-
Synthesis of ethoxycarbonylethenyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 1.76 g (12.7 m) of sesamol in 70 ml of DMF
mol), 0.52 g of 60% sodium hydride (13.
0 mmol), 6-butyl-2-chloro-3-cyano-
4.85 g (11.4 mmol) of 5-iodo-4- (4-methoxyphenyl) pyridine was stirred at room temperature for 6 hours. After evaporating DMF under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in DMF (70 ml), palladium acetate (150 mg, 0.67 mmol) and ethyl acrylate (1).
0 ml (92.3 mmol), triethylamine 10 m
1 (72.1 mmol) was heated and stirred at 120 ° C. overnight. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1) to obtain the title compound. Yield 4.64 g (9.27 mmol) Yield 73.
0% MS (ESI, m / z) 501 (MH +) 1H-NMR (CDCl3): 0.85 (3H, t), 1.22-1.32 (5H, m), 1.
52-1.62 (2H, m), 2.76 (2H, t), 3.87 (3H, s), 4.08-
4.20 (2H, m), 5.70 (1H, d), 6.02 (2H, s), 6.64-6.83
(3H, m), 7.00 (2H, d), 7.24 (2H, d), 7.45 (1H, d)

4) 6-butyl-3-cyano-5- (3-
Synthesis of hydroxy-1-propenyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 6-butyl-3-cyano-5- (2-ethoxycarbonylethenyl)- 4- (4-methoxyphenyl) -2-
(3,4-methylenedioxyphenoxy) pyridine4.
64 g (9.27 mmol) of methylene chloride in 100 ml
And cooled to -78 ° C, and then 18.0 ml of a 1M solution of diisobutylaluminum hydride in hexane (18.0 mmo).
l) was added over 50 minutes. After stirring for 40 minutes, further diisobutylaluminum hydride 1M hexane solution 10.0m
1 (10.0 mmol) was added over 25 minutes. -78 ° C
After stirring for 2 hours, methanol (2.0 ml) and water (2 ml) were added. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane-ethyl acetate =
1: 1) to give the title compound. Yield 2.86 g (6.23 mmol) Yield 67.
2% MS (ESI, m / z) 459 (MH +) 1H-NMR (CDCl3): 0.85 (3H, t), 1.22-1.33 (2H, m), 1.
50-1.62 (2H, m), 2.73 (2H, t), 3.86 (3H, s), 4.09
(2H, t), 5.55 (1H, dt), 6.01 (2H, s), 6.29 (1H, d),
6.64-6.83 (3H, m), 6.97 (2H, d), 7.24 (2H, d)

5) 6-butyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy)
-5- (3-hydroxy-1-propenyl) -3- (1
Synthesis of H-tetrazol-5-yl) pyridine Tributyltin azide prepared from 756 mg (11.6 mmol) of sodium azide and 1.5 ml (5.53 mmol) of tributyltin chloride and 6-butyl-3-cyano-5- (3 -Hydroxy-1-propenyl) -4-
569 mg of (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine (1.24 mm
ol) was heated in 5 ml of toluene at 120 ° C. for 4 days.
At room temperature, 2N hydrochloric acid was added, the crystals were filtered, washed with toluene and then with ethyl acetate-hexane (1: 3), and dried under reduced pressure to obtain the title compound. Yield 514 mg (1.03 mmol) Yield
1% MS (ESI, m / z) 502 (MH +) 1H-NMR (DMSO-d6): 0.82 (3H, t), 1.22-1.33 (2H, m),
1.48-1.62 (2H, m), 2.75 (2H, t), 3.71 (3H, s), 3.8
6 (2H, m), 4.72 (1H, t), 5.53 (1H, dt), 6.04 (2H,
s), 6.23 (1H, dt), 6.53 (1H, dd), 6.73-6.95 (6H,
m)

Example 68 6-ethyl-5- (3- (2
-Methoxyacetyl) amino-1-propenyl) -4-
(4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazole-5
Synthesis of yl) pyridine 1) 5- (3-chloro-1-propenyl) -3-cyano-6-ethyl-4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenoxy) pyridine 3-cyano-6-ethyl-5- (3-chloro-1-propenyl) -4- (4-methoxyphenyl) -2- (3
4-methylenedioxyphenoxy) pyridine 2.06 g
(4.78 mmol) was dissolved in 50 ml of chloroform, and 3.0 ml (41.3 mmol) of thionyl chloride was dissolved in an ice bath.
Was added dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1) to give the title compound. Yield 2.11 g (4.70 mmol) Yield
3% MS (ESI, m / z) 449 (MH +) 1H-NMR (CDCl3): 1.13 (3H, t), 2.76 (2H, qua), 3.87
(3H, s), 4.00 (2H, d), 5.54-5.64 (1H, m), 6.02 (2
H, s), 6.33 (1H, d), 6.65-6.83 (3H, m), 6.99 (2H,
d), 7.25 (2H, d)

2) N- (tert-butoxycarbonyl) -N- (3- (3-cyano-6-ethyl-4- (4
Synthesis of diethyl -methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridin-5-yl) -2-propenyl) phosphoramidate Diethyl N- (tert-butoxycarbonyl) phosphoramidate in 50 ml of benzene. 30 g (9.08
mmol) in 0.36 g of 60% sodium hydride (9.
After addition of 5- (3-chloro-1-propenyl) -3-cyano-6 dissolved in 40 ml of benzene.
-Ethyl-4- (4-methoxyphenyl) -2- (3,
4-methylenedioxyphenoxy) pyridine 2.11 g
(4.70 mmol) was added dropwise. Then, 0.28 g of tetrabutylammonium bromide was added, and the mixture was heated under reflux overnight.
After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1) to obtain the title compound. Yield 2.97 g (4.46 mmol) Yield 94.
9% MS (ESI, m / z) 666 (MH +) 1H-NMR (CDCl3): 1.13 (3H, t), 1.23-1.33 (6H, m), 1.
45 (9H, s), 2.76 (2H, qua), 3.85 (3H, s), 3.98-4.1
3 (6H, m), 5.46-5.58 (1H, m), 6.01 (2H, s), 6.28
(1H, d), 6.65-6.82 (3H, m), 6.97 (2H, d), 7.25 (2
H, d)

3) 5- (3-amino-1-propenyl)
Synthesis of -3-cyano-6-ethyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine N- (tert-butoxycarbonyl) -N- (3-
2.97 g of diethyl (3-cyano-6-ethyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridin-5-yl) -2-propenyl) phosphoramidate (4. To 46 mmol) was added a 36 wt% hydrogen chloride-ethanol solution in an ice bath. After stirring for 9 hours, the mixture was concentrated under reduced pressure. The mixture was made alkaline with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Yield 1.80 g (4.20 mmol) Yield 94.
2% MS (ESI, m / z) 430 (MH +) 1H-NMR (CDCl3): 1.12 (3H, t), 2.76 (2H, qua), 3.25
(2H, d), 3.86 (3H, s), 5.48-5.58 (1H, m), 6.01 (2
H, s), 6.15 (1H, d), 6.66-6.82 (3H, m), 6.97 (2H,
d), 7.25 (2H, d)

4) 3-Cyano-6-ethyl-5- (3-
(2-methoxyacetyl) amino-1-propenyl)-
Synthesis of 4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine 5- (3-amino-1-propenyl) -3-cyano-6
-Ethyl-4- (4-methoxyphenyl) -2- (3,
4-methylenedioxyphenoxy) pyridine 559 mg
(1.30 mmol) was dissolved in 5 ml of pyridine, and 0.15 ml (1.64 mmol) of methoxyacetyl chloride was dissolved.
l) was added dropwise. After stirring at room temperature for 3.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol = 100: 1) to obtain the title compound. Yield 512 mg (1.02 mmol) Yield 78.
5% MS (ESI, m / z) 502 (MH +) 1H-NMR (CDCl3): 1.11 (3H, t), 2.73 (2H, qua), 3.39
(3H, s), 3.83 (2H, s), 3.84-3.89 (2H, m), 3.87 (3
H, s), 5.40 (1H, dt), 6.01 (2H, s), 6.22 (1H, dt),
6.66-6.82 (3H, m), 6.98 (2H, d), 7.23 (2H, d)

5) 6-ethyl-5- (3- (2-methoxyacetyl) amino-1-propenyl) -4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) -3 Synthesis of-(1H-tetrazol-5-yl) pyridine Tributyltin azide prepared from 758 mg (11.7 mmol) of sodium azide and 1.5 ml (5.53 mmol) of tributyltin chloride, and 3-cyano-6-ethyl-5- (3- (2-methoxyacetyl) amino-1-
Propenyl) -4- (4-methoxyphenyl) -2-
(3,4-methylenedioxyphenoxy) pyridine 50
8 mg (1.01 mmol) in 10 ml of toluene
Heat at 20 ° C. for 3 days. 2N Hydrochloric acid was added at room temperature, and the crystals were filtered, washed with toluene and then with ethyl acetate, and dried under reduced pressure to obtain the title compound. Yield 110 mg (0.20 mmol) Yield 20.
0% MS (ESI, m / z) 545 (MH +) 1H-NMR (DMSO-d6): 1.06 (3H, t), 2.72 (2H, qua), 3.
24 (3H, s), 3.64 (2H, t), 3.70 (2H, s), 3.71 (3H,
s), 5.42 (1H, dt), 6.05 (2H, s), 6.16 (1H, dt), 6.5
0-6.96 (7H, m), 7.75 (1H, t)

Example 69 5- (3-hydroxy-1-)
Propenyl) -4- (2,4-dimethoxyphenyl)-
Synthesis of 6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) pyridine 1) 4- (2,4-dimethoxyphenyl) -3-butene-2- Synthesis of 2,4-dimethoxybenzaldehyde 20.8 g (12
To 5.2 mmol), 150 ml of acetone and 25 ml of a 1N aqueous sodium hydroxide solution were added, followed by stirring at room temperature overnight. After concentration under reduced pressure, the crystals were filtered, washed with water, and dried under reduced pressure to obtain the title compound. Yield 25.2 g (122.2 mmol) Yield 9
7.6% 1H-NMR (DMSO-d6): 2.27 (3H, s), 3.82 (3H, s), 3.87
(3H, s), 6.58-6.65 (2H, m), 6.75 (1H, d), 7.63-7.7
5 (2H, m)

2) Synthesis of 3-cyano-4- (2,4-dimethoxyphenyl) -6-methyl-2-pyridone 10.2 g of cyanoacetamide in 250 ml of DMSO
(122 mmol) 13.7 g of potassium t-butoxide
(122 mmol), 25.2 g of 4- (2,4-dimethoxyphenyl) -3-buten-2-one (122 mmol)
l) was added and the mixture was stirred at room temperature for 15 minutes. After adding 41.0 g (367 mmol) of potassium t-butoxide, oxygen gas was bubbled for 1 minute, and the mixture was further stirred at room temperature under an atmosphere of normal pressure oxygen for 1 hour. 2N Hydrochloric acid was added and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound. Yield 12.9 g (47.7 mmol) Yield 39.
1% 1H-NMR (DMSO-d6): 2.27 (3H, s), 3.79 (3H, s), 3.83
(3H, s), 6.18 (1H, s), 6.63-6.73 (2H, m), 7.22 (1
H, d)

3) 3-cyano-5-iodo-4- (2,
Synthesis of 4-dimethoxyphenyl) -6-methyl-2-pyridone 3-cyano-4- (2,4) in 50 ml of acetonitrile
3.48 g (15.5 mmol) of N-iodosuccinimide was added to 3.10 g (12.9 mmol) of -dimethoxyphenyl) -6-methyl-2-pyridone, and the mixture was heated under reflux for 3 hours. Further, N-iodosuccinimide 1.1
0 g (4.89 mmol) was added, and the mixture was heated under reflux for 1.5 hours. Acetonitrile was distilled off under reduced pressure, and the residue was washed with hexane and acetonitrile and dried under reduced pressure to obtain the title compound. Yield 1.40 g (3.83 mmol) Yield 29.
7%

4) Synthesis of 2-chloro-3-cyano-5-iodo-4- (2,4-dimethoxyphenyl) -6-methylpyridine 3-cyano-5-iodo-4- (2,4-dimethoxy 5.10 g of phenyl) -6-methyl-2-pyridone (1
3.9 mmol), add 50 ml of phosphorus oxychloride and add 10
The mixture was heated and stirred at 0 ° C. overnight. After phosphorus oxychloride was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Yield 3.00 g (7.25 mmol) Yield 52.
2%

5) 3-Cyano-5-iodo-4- (2,
4-dimethoxyphenyl) -6-methyl-2- (3,4
Synthesis of -methylenedioxyphenoxy) pyridine In 30 ml of DMF, 1.0 g of sesamol (7.20 mm
ol) to 0.40 g (10.0%) of 60% sodium hydride.
mmol). 2-chloro-3-cyano-4-
3.00 g (7.20 mmol) of (2,4-dimethoxyphenyl) -6-methylpyridine was added, and the mixture was stirred at room temperature for 3 hours. After evaporating DMF under reduced pressure, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1) to obtain the title compound. Yield 1.80 g (3.49 mmol) Yield 48.
4% 1H-NMR (CDCl3): 2.70 (3H, s), 3.82 (3H, s), 3.88 (3
H, s), 6.02 (2H, s), 6.57-6.83 (5H, m), 7.04 (1H,
d)

6) Synthesis of 3-cyano-5- (2-ethoxycarbonylethenyl) -4- (2,4-dimethoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) pyridine 2.0 g (3.87 mmol) of 3-cyano-5-iodo-4- (2,4-dimethoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) pyridine
Was dissolved in DMF (80 ml), and palladium acetate (43 mg) was dissolved.
(0.19 mmol) and 8.4 ml of ethyl acrylate
(77.4 mmol), 10.8 ml of triethylamine
(77.4 mmol) was heated and stirred at 100 ° C. for 4 days. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1) to obtain the title compound. Yield 796 mg (1.63 mmol) Yield 42.
1% 1H-NMR (CDCl3): 1.25 (3H, t), 2.51 (3H, s), 3.78 (3
H, s), 3.87 (3H, s), 4.17 (2H, qua), 5.75 (1H, d),
6.02 (2H, s), 6.53-6.83 (5H, m), 7.03 (1H, d), 7.4
5 (1H, d)

7) 3-cyano-5- (3-hydroxy-
Synthesis of 1-propenyl) -4- (2,4-dimethoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) pyridine 3-cyano-5- (2-ethoxycarbonylethenyl)
-4- (2,4-dimethoxyphenyl) -6-methyl-
796 mg (1.63 mmol) of 2- (3,4-methylenedioxyphenoxy) pyridine was stirred in 20 ml of 1N aqueous sodium hydroxide solution and 10 ml of THF overnight.
The mixture was extracted with dichloromethane, washed with 1N hydrochloric acid, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. TH in the residue
F5 ml, triethylamine 0.34 ml (2.45 m
mol), and after cooling with ice, 0.23 ml of ethyl chloroformate was added.
(2.45 mmol) was added dropwise. After stirring for 20 minutes, 154 mg (4.08 mmol) of sodium borohydride
Was added and stirred for 1 hour. The mixture was extracted with dichloromethane, washed with 1N hydrochloric acid and a saturated aqueous solution of sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane-ethyl acetate =
1: 1) to give the title compound. Yield 326 mg (0.73 mmol) Yield
8% 1H-NMR (CDCl3): 2.46 (3H, s), 3.80 (3H, s), 3.86 (3
H, s), 4.07 (2H, t), 5.59 (1H, dt), 6.01 (2H, s),
6.08 (1H, d), 6.53-6.85 (5H, m), 7.03 (1H, d)

8) 5- (3-Hydroxy-1-propenyl) -4- (2,4-dimethoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -3
Synthesis of-(1H-tetrazol-5-yl) pyridine Tributyltin azide prepared from 285 mg (4.39 mmol) of sodium azide and 0.79 ml (2.92 mmol) of tributyltin chloride and 3-cyano-5
(3-hydroxy-1-propenyl) -4- (2,4-
326 mg of dimethoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) pyridine (0.
73 mmol) was heated at reflux for 5 days in 5 ml of toluene. After cooling, 4N hydrochloric acid-dioxane was added, the mixture was filtered, the crystals were washed with toluene, and purified by silica gel chromatography (chloroform-methanol = 9: 1). Further recrystallization (chloroform-ethyl acetate-hexane) gave the title compound. Yield 180 mg (0.37 mmol) Yield 50.
4% MS (ESI, m / z) 490 (MH +) 1H-NMR (DMSO-d6): 2.42 (3H, s), 3.56 (3H, s), 3.73
(3H, s), 3.85 (2H, t), 4.69 (1H, t), 5.57 (1H, dt),
6.05 (2H, s), 6.19 (1H, d), 6.40-6.92 (6H, m)

Example 70 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -5
Synthesis of (3-hydroxy-1-propenyl) -3- (1H-tetrazol-5-yl) pyridine 1) 4- (3- (2-benzyloxyethoxy) -4-
Synthesis of methoxyphenyl) -3-cyano-5-iodo-6-methyl-2-pyridone 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-6 in 250 ml of acetonitrile. 4.60 g of methyl-2-pyridone (11.8
mmol) in 4.06 g of N-iodosuccinimide (1
8.0 mmol) and heated to reflux overnight. And N
4.78 g of iodosuccinimide (21.2 mmol
l) was added and the mixture was heated under reflux overnight. Acetonitrile was distilled off under reduced pressure, and the residue was washed with hexane and acetonitrile and dried under reduced pressure to obtain the title compound. Yield 4.90 g (9.49 mmol) Yield
4% MS (ESI, m / z) 517 (MH +)

2) Synthesis of 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -2-chloro-3-cyano-5-iodo-6-methylpyridine To 4.90 g (9.49 mmol) of benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-5-iodo-6-methyl-2-pyridone were added 50 ml of phosphorus oxychloride and 1.5 ml of N, N-dimethylaniline.
ml (11.9 mmol) and heated at 110 ° C. for 2.5 hours. After phosphorus oxychloride was distilled off, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1) to obtain the title compound. Yield 1.64 g (3.06 mmol) Yield 32.
2% MS (ESI, m / z) 534 (MH +) 1H-NMR (CDCl3): 2.89 (3H, s), 3.87 (2H, t), 3.94 (3
H, s), 4.25 (2H, t), 4.64 (2H, s), 6.78-7.01 (3H,
m), 7.24-7.39 (5H, m)

3) 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-5-iodo-6-methyl-2- (3,4-methylenedioxyphenoxy) pyridine Synthesis 469 mg of sesamol (3.40 m) in 12 ml of DMF
mol), 145 mg (3.6%) of 60% sodium hydride.
3 mmol), 1.64 g of 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -2-chloro-3-cyano-5-iodo-6-methylpyridine (3.
06 mmol) was stirred at room temperature for 4.5 hours. After distilling off DMF under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane-ethyl acetate =
3: 1) to give the title compound. Yield 1.10 g (1.73 mmol) Yield
7% MS (ESI, m / z) 659 (M + Na +) 1H-NMR (CDCl3): 2.70 (3H, s), 3.88 (2H, t), 3.94 (3
H, s), 4.27 (2H, t), 4.65 (2H, s), 6.62-03 (2H, s),
6.21 (1H, d), 6.64-6.84 (3H, m), 6.86-7.00 (3H,
m), 7.25-7.39 (5H, m), 7.43 (1H, d)

4) 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-5
(2-ethoxycarbonylethenyl) -6-methyl-2
Synthesis of-(3,4-methylenedioxyphenoxy) pyridine 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-5-iodo-6-methyl-2- (3, 644 mg (1.01 mmol) of 4-methylenedioxyphenoxy) pyridine was dissolved in 10 ml of DMF, and 43 mg (0.19 mmol) of palladium acetate was dissolved.
And 1 ml (9.23 mmol) of ethyl acrylate and 1 ml (7.21 mmol) of triethylamine were heated and stirred at 100 ° C. overnight. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to obtain the title compound. Yield 553 mg (0.91 mmol) Yield 90.
0% MS (ESI, m / z) 609 (MH +) 1H-NMR (CDCl3): 1.24 (3H, t), 2.52 (3H, s), 3.86 (2
H, t), 3.93 (3H, s), 4.18 (2H, qua), 4.21 (2H,
t), 4.63 (2H, s), 5.79 (1H, d), 6.03 (2H, s), 6.21
(1H, d), 6.64-6.84 (3H, m), 6.86-7.00 (3H, m), 7.
25-7.39 (5H, m), 7.43 (1H, d)

5) 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-6-methyl-2- (3,4-methylenedioxyphenoxy)-
5- (3-hydroxy-1-propenyl) pyridine 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-5- (2-ethoxycarbonylethenyl) -6-methyl- 449 mg of 2- (3,4-methylenedioxyphenoxy) pyridine (0.74
mmol) was dissolved in 10 ml of methylene chloride, cooled to -78 ° C, and 1.5 ml (1.5 mmol) of a 1 M solution of diisobutylaluminum hydride in hexane was added over 10 minutes.
The mixture was stirred at the same temperature, and 1.5 hours and 3 hours after the completion of the dropwise addition, a total of 3.0 ml (3.0 mmol) of a 1M solution of diisobutylaluminum hydride in hexane was added.
Added at 0 minutes. After stirring at -78 ° C for 1 hour, 1.0 ml of methanol and 1 ml of water were added. The precipitate was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to obtain the title compound. Yield 385 mg (0.68 mmol) Yield
2% MS (ESI, m / z) 567 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.87 (2H, t), 3.92
(3H, s), 4.05 (2H, t), 4.23 (2H, t), 4.63 (2H, s),
5.61 (1H, dt), 6.01 (2H, s), 6.21 (1H, d), 6.64-6.
83 (3H, m), 6.89-6.97 (3H, m), 7.23-7.37 (5H, m)

6) 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -6-methyl-2-
(3,4-methylenedioxyphenoxy) -5- (3-
Synthesis of hydroxy-1-propenyl) -3- (1H-tetrazol-5-yl) pyridine 1.12 g (3.37 mmol) of tributyltin azide
And 4- (3- (2-benzyloxyethoxy) -4-methoxyphenyl) -3-cyano-6-methyl-2-
(3,4-methylenedioxyphenoxy) -5- (3-
380 mg of (hydroxy-1-propenyl) pyridine
(0.67 mmol) was heated in 5 ml of toluene at 140 ° C. overnight. At room temperature, 4N hydrochloric acid-dioxane was added, followed by filtration. The crystals were washed with toluene and purified by silica gel chromatography (chloroform-methanol = 30: 1) to obtain the title compound. Yield 195 mg (0.32 mmol) Yield
8% MS (ESI, m / z) 610 (MH +) 1H-NMR (DMSO-d6): 2.45 (3H, s), 3.70 (2H, brd), 3.
72 (3H, s), 3.90 (2H, t), 3.97 (2H, brd), 4.55 (2
H, s), 4.74 (1H, t), 5.67 (1H, dt), 6.05 (2H, s),
6.23 (1H, d), 6.48-6.76 (3H, m), 6.81-6.92 (3H,
m), 7.23-7.38 (5H, m)

Example 71 5- (3-hydroxy-1-)
Propenyl) -4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy)-
3- (2,5-dihydro-5-oxo-4H-1,2,2
Synthesis of 4-oxadiazol-3-yl) pyridine 1) N-hydroxy-5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenoxy) -6-methylnicotinamidine Hydroxyamine hydrochloride 3.03 g (43.6 mmol)
l) to 25 ml of DMSO and 6.1 ml of triethylamine
(44.0 mmol), and the precipitated precipitate was filtered and T
Washed with HF. After the THF of the filtrate was distilled off under reduced pressure, 3-cyano-5- (3-hydroxy-1-propenyl) -4-.
(4-methoxyphenyl) -6-methyl-2- (3,4
-Methylenedioxyphenoxy) pyridine 2.51 g
(6.03 mmol) and heated at 70 ° C. for 4 days.
After cooling, water was added, and the precipitated crystals were filtered and washed with ethyl acetate to give the title compound as a mixture of amides. Yield 1.56 g (3.76 mmol) Yield 6
2.4% MS (ESI, m / z) 450 (MH +) 1H-NMR (DMS0-d6): 2.36 (3H, s), 3.77 (3H, s), 3.86
(2H, d), 4.67 (1H, t), 5.54 (1H, m), 6.05 (2H, s),
6.12 (1H, d), 6.53-7.18 (7H, m)

2) 5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -6-methyl-2
-(3,4-methylenedioxyphenoxy) -3-
(2,5-dihydro-5-oxo-4H-1,2,4-
Synthesis of oxadiazol-3-yl) pyridine N-hydroxy-5- (3-hydroxy-1-propenyl) -4- (4-methoxyphenyl) -2- (3,4-
Methylenedioxyphenoxy) -6-methylnicotinamidine (455 mg, 1.01 mmol) in DMF 20m
1, pyridine 0.5 ml and phenyl chloroformate 0.26
ml (2.07 mmol) was added and the mixture was stirred at room temperature overnight.
After distilling off DMF under reduced pressure, 2N hydrochloric acid was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1). This compound was heated and stirred at 140 ° C. overnight in 20 ml of xylene and then concentrated under reduced pressure. A 1 M potassium hydroxide-methanol solution was added to the residue, and the mixture was stirred at room temperature for 2 hours. Add 2N hydrochloric acid and concentrate under reduced pressure.
The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol = 100: 1) to obtain the title compound. Yield 98 mg (0.21 mmol) Yield 61.9
% MS (ESI, m / z) 476 (MH +) 1H-NMR (CDCl3): 2.46 (3H, s), 3.44 (1H, t), 3.81 (3
H, s), 4.07 (2H, d), 5.55-5.66 (1H, m), 5.99 (2H,
s), 6.20 (1H, d), 6.55-6.82 (3H, m), 6.84-6.93 (3
H, m), 7.01-7.08 (2H, m)

Example 72 4- (4-Trifluoromethoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -5- (3-hydroxy-1-propenyl) -3- (1H Synthesis of -tetrazol-5-yl) pyridine It was synthesized in the same manner as in Example 43. MS (ESI, m / z) 514 (MH +) 1H-NMR (DMSO-d6): 2.48 (3H, s), 3.85 (2H, d), 5.54
(1H, dt), 6.05 (2H, s), 6.21 (1H, d), 6.52-6.95 (3
H, m), 7.10-7.32 (4H, m)

Example 73: Pyridine-2-carboxylic acid
(3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5
Synthesis of-(1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide 1) 5- (3-chloro-1-propenyl) -3-cyano-6-methyl-4- (4 -Methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxyphenoxy) pyridine 3-cyano-6-methyl-5- (3-hydroxy-1-
Propenyl) -4- (4-methoxyphenyl) -2-
(3,4-methylenedioxyphenoxy) pyridine 9.
20 g (22.1 mmol) in dichloromethane 100 m
and 2.5 ml of thionyl chloride (34.2) in an ice bath.
mmol) was added dropwise. After stirring at the same temperature for 20 minutes, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1) to give the title compound. Yield 9.39 g (21.6 mmol) Yield
7% MS (ESI, m / z) 435 (MH +) 1H-NMR (CDCl3): 2.46 (3 / 2H, s), 2.59 (3 / 2H, s), 3.86
(3 / 2H, s), 3.89 (3 / 2H, s), 4.05 (2 / 2H, d) 5.15-5.
30 (1H, m), 5.58-5.70 (1H, m), 6.02 (2H, s), 6.30
(1 / 2H, d), 6.64 (1H, dd), 6.75 (1H, d), 6.83 (1H,
d), 6.95-7.10 (2H, m), 7.15-7.30 (2H, m), 7.38 (1/2
H, dd)

2) N- (tert-Butoxycarbonyl) -N- (3- (3-cyano-6-methyl-4- (4
Synthesis of diethyl -methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridin-5-yl) -2-propenyl) phospholoamidate 5- (3-chloro-1-propenyl) -3-cyano-6
-Methyl-4- (4-methoxyphenyl) -2- (3,
9.39 g of 4-methylenedioxyphenoxy) pyridine
(21.6 mmol) was dissolved in 100 ml of benzene,
6.56 g (25.9 mmol) of diethyl N- (tert-butoxycarbonyl) phosphoramidate, 0.7 g (2.2 mmol) of tetrabutylammonium bromide, 6
After adding 1.04 g (26 mmol) of 0% sodium hydride, the mixture was heated and refluxed overnight. After cooling, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (hexane-ethyl acetate = 1: 1).
To 1: 3) to give the title compound. Yield 9.12 g (14.0 mmol) Yield
8% MS (ESI, m / z) 652 (MH +) 1H-NMR (CDCl3): 1.30 (6H, t), 1.47 (9H, s), 2.46 (3
H, s), 3.85 (3H, s), 4.10 (6H, m), 5.56 (1H, dt),
6.01 (2H, s), 6.25 (1H, d), 6.66 (1H, dd), 6.74 (1
H, d), 6.80 (1H, d), 6.97 (2H, d), 7.25 (2H, d)

3) 5- (3-amino-1-propenyl)
Synthesis of -3-cyano-6-methyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridine N- (tert-butoxycarbonyl) -N- (3-
9.12 g of diethyl (3-cyano-6-methyl-4- (4-methoxyphenyl) -2- (3,4-methylenedioxyphenoxy) pyridin-5-yl) -2-propenyl) phosphoramidate (14. 0 mmol) was added with a 36 wt% hydrogen chloride-ethanol solution in an ice bath. After returning to room temperature and stirring for 9 hours, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration and washed with ethyl acetate to give the title compound. Yield 4.77 g (10.4 mmol) Yield 74.
3% 1H-NMR (DMSO-d6): 2.44 (3
H, s), 3.40 (2H, br), 3.8
2 (3H, s), 5.60 (1H, dt),
6.10 (2H, s), 6.39 (1H,
d), 6.72 (1H, dd), 6.96
(2H, m), 7.06 (2H, d), 7.3
6 (2H, d), 8.08 (3H, br)

4) Pyridine-2-carboxylic acid (3-
(6- (3,4-methylenedioxyphenyloxy)-
Synthesis of 4- (4-methoxyphenyl) -2-methyl-5-cyanopyridin-3-yl) -allyl) -amide 5- (3-amino-1-propenyl) -3-cyano-6
-Methyl-4- (4-methoxyphenyl) -2- (3,
480 mg of 4-methylenedioxyphenoxy) pyridine
(1.16 mmol) was dissolved in 10 ml of dichloromethane, and 220 mg of pyridine-2-carbonyl chloride hydrochloride was dissolved.
(1.24 mmol), 0.5 ml of triethylamine
(3.59 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and extracted with ethyl acetate. 1N hydrochloric acid,
The extract was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1 to 2: 1) to obtain the title compound. Yield 160 mg (0.31 mmol) Yield 22.
4% MS (ESI, m / z) 521 (MH +) 1H-NMR (CDCl3): 2.47 (3H, s), 3.78 (3H, s), 4.05 (2
H, t), 5.78 (1H, dt), 6.02 (2H, s), 6.28 (1H, d),
6.67 (1H, dd), 6.75 (1H, d), 6.81 (1H, d), 6.94 (2
H, d), 7.25 (2H, d), 7.46 (1H, m), 7.86 (1H, dt),
7.95 (1H, br), 8.18 (1H, d), 8.56 (1H, d)

5) Pyridine-2-carboxylic acid (3-
(6- (3,4-methylenedioxyphenyloxy)-
4- (4-methoxyphenyl) -2-methyl-5- (1
Synthesis of H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide 1,0 ml of tributyltin chloride, sodium azide 36
Tributyltin azide and pyridine
2-carboxylic acid (3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl)
160 mg (0.31 mmol) of 2-methyl-5-cyanopyridin-3-yl) -allyl) -amide were refluxed with heating in toluene for 2 days. After allowing to cool, 4N dioxane hydrochloride was added, the mixture was stirred at room temperature for 30 minutes, and the precipitate was collected by filtration and washed with toluene and ethyl acetate. Yield 150 mg (0.27 mmol) Yield
9% MS (ESI, m / z) 564 (MH +) 1H-NMR (DMSO-d6): 2.44 (3H, s), 3.58 (3H, s), 3.85
(2H, t), 5.61 (1H, dt), 6.05 (2H, s), 6.20 (1H,
d), 6.53 (1H, dd), 6.68 (2H, d), 6.48 (1H, d), 6.79
(2H, d), 7.69 (1H, m), 7.98 (2H, m), 8.62 (1H,
d), 8.75 (1H, t)

Example 74 (3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl) -pyridine Synthesis of -3-yl) -allyl) -benzamide 1) (3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5-cyanopyridine- Synthesis of 3-yl) -allyl) -benzamide pyridine-2-carboxylic acid (3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- This was carried out according to the synthesis of cyanopyridin-3-yl) -allyl) -amide. Yield 56.9% MS (ESI, m / z) 520 (MH +) 1H-NMR (CDCl3): 2.46 (3H, s), 3.75 (3H, s), 4.03 (2
H, t), 5.52 (1H, dt), 5.66 (1H, dd), 5.86 (1H, b
r), 6.01 (2H, s), 6.29 (1H, d), 6.74 (1H, d), 6.81
(1H, d), 6.95 (2H, d), 7.24 (2H, d), 7.40-7.55 (3
H, m), 7.64 (2H, m)

2) (3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl)
Synthesis of -2-methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -benzamide pyridinecarboxylic acid (3- (6- (3,4-methylenedioxyphenyloxy)) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl)
-Pyridin-3-yl) -allyl) -amide. Yield 30.7% MS (ESI, m / z) 563 (MH +) 1H-NMR (DMSO-d6): 2.46 (3H, s), 3.60 (3H, s), 3.84
(2H, t), 5.72 (1H, dt), 6.05 (2H, s), 6.20 (1H, d
d), 6.70-6.75 (3H, m), 6.86-6.96 (3H, m), 7.40-7.56
(3H, m), 7.79 (2H, d), 8.50 (1H, t)

Example 75 3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl) -pyridin- Synthesis of 3-yl) -allyl)-(2-methoxy) acetamide 1) 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-
Synthesis of 5-cyanopyridin-3-yl) -allyl)-(2-methoxy) acetamide pyridinecarboxylic acid (3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5-cyanopyridin-3-yl)-
Allyl) -amide was synthesized. Yield Quantitative MS (ESI, m / z) 488 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.38 (3H, s), 3.82 (2
H, s), 3.87 (3H, s), 3.85 (2H, m), 5.46 (1H, dt),
6.01 (2H, s), 6.18 (1H, d), 6.40 (1H, br), 6.66 (1
H, dd), 6.74 (1H, d), 6.81 (1H, d), 6.98 (2H, d),
7.24 (2H, d)

2) 3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl)-
Synthesis of 2-methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl)-(2-methoxy) acetamide pyridinecarboxylic acid (3- (6- (3,4-methylenedi) Oxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl)
-Pyridin-3-yl) -allyl) -amide. Yield 52.6% MS (ESI, m / z) 531 (MH +) 1H-NMR (DMSO-d6): 2.43 (3H, s), 3.23 (3H, s), 3.66
(2H, t), 3.71 (2H, s), 3.72 (2H, s), 5.52 (1H, d
t), 6.05 (2H, s), 6.11 (1H, d), 6.52 (1H, dt), 6.7
5 (1H, d), 6.80 (2H, d), 6.86-6.94 (3H, m), 7.78
(1H, brt)

Example 76 3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl) -pyridin- Synthesis of 3-yl) -allyl) -4-methoxybenz-amide 1) 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-
Synthesis of 5-cyanopyridin-3-yl) -allyl) -4-methoxybenzamide pyridine-2-carboxylic acid 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-Methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide was synthesized. Yield 54.8% MS (ESI, m / z) 550 (MH +) 1H-NMR (CDCl3): 2.46 (3H, s), 3.78 (3H, s), 3.86 (3
H, s), 4.02 (2H, t), 5.52 (1H, dt), 5.72 (1H, br),
6.02 (2H, s), 6.28 (1H, d), 6.66 (1H, dd), 6.74 (1
H, d), 6.81 (1H, d), 6.90-6.98 (4H, m), 7.25 (2H,
d), 7.62 (2H, d)

2) 3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl)-
Synthesis of 2-methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -4-methoxybenz-amide pyridine-2-carboxylic acid 3- (6- (3,4- Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide was synthesized. . Yield 54.5% MS (ESI, m / z) 593 (MH +) 1H-NMR (DMSO-d6): 2.45 (3H, s), 3.62 (3H, s), 3.80
(3H, s), 3.82 (2H, m), 5.62 (1H, dt), 6.05 (2H,
s), 6.18 (1H, d), 6.54 (1H, d), 6.70-6.78 (3H, m),
6.86-7.00 (5H, m), 7.73 (2H, d), 8.36 (1H, br)

Example 77 3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl) -pyridin- Synthesis of 3-yl) -allyl) -2-methoxybenzamide 1) 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-
Synthesis of 5-cyanopyridin-3-yl) -allyl) -2-methoxybenzamide pyridine-2-carboxylic acid 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-Methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide was synthesized. Yield 79.6% MS (ESI, m / z) 550 (MH +) 1H-NMR (CDCl3): 2.47 (3H, s), 3.72 (3H, s), 3.89 (3
H, s), 4.10 (2H, m), 5.62 (1H, dt), 6.01 (2H, s),
6.25 (1H, d), 6.66 (1H, dd), 6.74 (1H, d), 6.81 (1
H, d), 6.90 (2H, d), 6.96 (1H, d), 7.09 (1H, t),
7.25 (2H, d), 7.45 (1H, m), 7.75 (1H, br), 8.16 (1
H, dd)

2) 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl)-
Synthesis of 2-methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -2-methoxybenz-amide pyridine-2-carboxylic acid 3- (6- (3,4- Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide was synthesized. . Yield 60.0% MS (ESI, m / z) 593 (MH +) 1H-NMR (DMSO-d6): 2.46 (3H, s), 3.60 (3H, s), 3.81
(3H, s), 3.88 (2H, m), 5.62 (1H, dt), 6.05 (2H,
s), 6.20 (1H, d), 6.50 (1H, dd), 6.70-6.76 (3H, m),
6.88-6.94 (3H, m), 7.00 (1H, t), 7.10 (1H, d), 7.
44 (1H, t), 7.63 (1H, dd), 8.14 (1H, brt)

Example 78 Furan-2-carboxylic acid 3
-(6- (3,4-methylenedioxyphenyloxy)
-4- (4-methoxyphenyl) -2-methyl-5-
(1H-tetrazo-5-yl) -pyridin-3-yl)
Synthesis of -allyl) -amide 1) Furan-2-carboxylic acid 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5-cyanopyridine- Synthesis of 3-yl) -allyl) -amide pyridine-2-carboxylic acid 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- ( This was performed according to the synthesis of 1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide. Yield 87.2% MS (ESI, m / z) 510 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.81 (3H, s), 3.98 (2
H, t), 5.50 (1H, dt), 6.02 (2H, s), 6.13 (1H, br),
6.25 (1H, d), 6.52 (1H, dd), 6.66 (1H, dd), 6.74
(1H, d), 6.81 (1H, d), 6.96 (2H, d), 7.09 (1H, d),
7.24 (2H, d), 7.45 (1H, m)

2) Furan-2-carboxylic acid 3- (6-)
(3,4-methylenedioxyphenyloxy) -4-
(4-methoxyphenyl) -2-methyl-5- (1H-
Synthesis of tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide pyridine-2-carboxylic acid 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) ) -2-Methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide. Yield 43.8% MS (ESI, m / z) 553 (MH +) 1H-NMR (DMSO-d6): 2.44 (3H, s), 3.65 (3H, s), 3.78
(2H, t), 5.59 (1H, dt), 6.05 (2H, s), 6.18 (1H,
d), 6.52 (1H, dd), 6.59 (1H, dd), 6.74 (3H, m), 6.8
8-6.94 (3H, m), 7.03 (1H, d), 7.79 (1H, m), 8.37
(1H, brt)

Example 79 3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl) -pyridin- Synthesis of 3-yl) -allyl) -3-methoxybenzamide 1) 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-
Synthesis of 5-cyanopyridin-3-yl) -allyl) -2-methoxybenzamide pyridine-2-carboxylic acid 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-Methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide was synthesized. Yield 80.9% MS (ESI, m / z) 550 (MH +) 1H-NMR (CDCl3): 2.46 (3H, s), 3.75 (3H, s), 3.85 (3
H, s), 4.03 (2H, t), 5.54 (1H, dt), 6.02 (2H, s),
6.28 (1H, d), 6.56 (1H, dd), 6.74 (1H, d), 6.81 (1
H, d), 6.94 (2H, d), 7.05 (1H, dd), 7.11 (1H, d),
7.24 (2H, d), 7.29 (1H, m), 7.33 (1H, t)

2) 3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl)-
Synthesis of 2-methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -3-methoxybenz-amide pyridine-2-carboxylic acid 3- (6- (3,4- Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl) -pyridin-3-yl) -allyl) -amide was synthesized. . Yield 17.5% MS (ESI, m / z) 593 (MH +) 1H-NMR (DMSO-d6): 2.45 (3H, s), 3.60 (3H, s), 3.79
(3H, s), 3.82 (2H, t), 5.60 (1H, dt), 6.05 (2H.,
s), 6.19 (1H, d), 6.54 (1H, dd), 6.70-6.76 (3H, m),
6.86-6.94 (3H, m), 7.07 (1H, m), 7.30-7.38 (3H,
m), 8.50 (1H, t)

Example 80 1- (3- (6- (3,4-
Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5
Synthesis of -yl) -pyridin-3-yl) -allyl) -pyrrolidine-2,5-dione 1) 1- (3- (6- (3,4-methylenedioxyphenyloxy) -4- (4- Synthesis of methoxyphenyl) -2-methyl-5-cyanopyridin-3-yl) -allyl) -pyrrolidine-2,5-dione 5- (3-chloro-1-propenyl) -3-cyano-6
-Methyl-4- (4-methoxyphenyl) -2- (3,
530 mg of 4-methylenedioxyphenoxy) pyridine
(1.2 mmol) was dissolved in 10 ml of THF, 240 mg (2.42 mmol) of succinimide, 100 mg (2.5 mmol) of 60% sodium hydride, and 80 mg (0.25 mmol) of tetrabutylammonium bromide were added. Stir overnight. Add water and extract with ethyl acetate. After washing with saturated saline and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane 1: 2 to ethyl acetate only) to obtain the title compound. Yield 380 mg (0.76 mmol) Yield 63.
7% MS (ESI, m / z) 498 (MH +) 1H-NMR (CDCl3): 2.42 (3H, s), 2.61 (4H, s), 3.87
(3H, s), 4.05 (2H, d), 5.30 (1H, dt), 6.01 (2H,
s), 6.27 (1H, d), 6.65 (1H, dd), 6.74 (1H, d), 6.8
1 (1H, d), 6.95 (2H, d), 7.18 (2H, d)

2) 1- (3- (6- (3,4-Methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-yl)
-Pyridin-3-yl) -allyl) -pyrrolidine-2,
Synthesis of 5-dione pyridinecarboxylic acid (3- (6- (3,4-methylenedioxyphenyloxy) -4- (4-methoxyphenyl) -2-methyl-5-cyanopyridin-3-yl)-
Allyl) -amide was synthesized. Yield 17.0% MS (ESI, m / z) 541 (MH +) 1H-NMR (DMSO-d6): 2.39 (3H, s), 2.54 (4H, s), 3.73
(3H, s), 3.90 (2H, d), 5.32 (1H, dt), 6.05 (2H,
s), 6.19 (1H, d), 6.53 (1H, dd), 6.76 (1H,), 6.76-
6.92 (5H, m)

Example 81 1- (3- (6- (3,4-
Methylenedioxyphenyloxy) -4- (4methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-
Synthesis of yl) -pyridin-3-yl) -3-pyridin-2-yl-urea 1- (3- (6- (3,4-methylenedioxyphenyloxy) -4- (4methoxyphenyl) -2 -Methyl-
5- (1H-tetrazo-5-yl) -pyridin-3-yl-allylamine 50 mg (0.11 mmol), pyridine-2-ylcarbamic acid phenyl ester 30 m
g (0.14 mmol) are refluxed with heating at 100 ° C. in dioxane. After cooling, the solvent was distilled off under reduced pressure.
LC (0.1% TFA water: acetonitrile 95: 5 to 20:80) gave the title compound. Yield 20 mg (0.03 mmol) Yield 31.4
% MS (ESI, m / z) 579 (MH +) 1H-NMR (DMSO-d6): 2.45 (3H, s), 3.61 (3H, s), 3.78
(2H, t), 5.61 (1H, dt), 6.04 (2H, s), 6.20 (1H,
d), 6.52 (1H, dd), 6.72 (3H, m), 6.80 (3H, m), 7.26
(1H, d), 7.70 (1H, brt), 8.10 (1H, d), 8.22 (1H,
d), 9.33 (1H, br)

Example 82 1- (3- (6- (3,4-
Methylenedioxyphenyloxy) -4- (4methoxyphenyl) -2-methyl-5- (1H-tetrazo-5-
Yl) -pyridin-3-yl) -3-thiazol-2-
Synthesis of il-urea 1- (3- (6- (3,4-methylenedioxyphenyloxy) -4- (4methoxyphenyl) -2-methyl-
It carried out according to synthesis of 5- (1H-tetrazo-5-yl) -pyridin-3-yl) -3-pyridin-2-yl-urea. Yield 62.2% MS (ESI, m / z) 521 (MH +) 1H-NMR (DMSO-d6): 2.43 (3H, s), 3.63 (3H, s), 3.72
(2H, m), 5.58 (1H, dt), 6.05 (2H, s), 6.18 (1H,
d), 6.54 (1H, dd), 6.62 (1H, br), 6.73-6.80 (2H,
m), 6.86-6.94 (4H, m), 7.02 (1H, d), 7.25 (1H, d),
7.30 (1H, d)

Example 83 5- (3-hydroxy-1-)
Propenyl) -4- (3,5-dimethoxyphenyl)-
Synthesis of 6-methyl-2- (3,4-methylenedioxyphenoxy) -3- (1H-tetrazol-5-yl) pyridine 420 mg (6.5 mmol) of sodium azide and 0.9 ml (3.25 mmol) of tributyltin chloride )) And 3-cyano-5- (3-
290 mg (0.65 m) of hydroxy-1-propenyl) -4- (3,5-dimethoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) pyridine
mol) was heated under reflux for 3 days. After cooling, 4N hydrochloric acid-dioxane was added and the mixture was filtered.
And purified by silica gel chromatography (chloroform-methanol = 9: 1). Further purification by HPLC yielded the title compound. Yield 55 mg (0.37 mmol) Yield 17.3
% MS (ESI, m / z) 490 (MH +) 1H-NMR (DMSO-d6): 2.45 (3H, s), 3.65 (6H, s), 3.92
(2H, brd), 5.71 (1H, dt), 6.05 (2H, s), 6.16 (2H,
d), 6.25 (1H, d), 6.36 (1H, t), 6.53 (1H, dd), 6.7
5 (1H, d), 6.89 (1H, d)

Example 84 4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxyphenoxy) -5- (3- (6-bromopyridin-2-yloxy) -1- Synthesis of propenyl) -3- (1H-tetrazol-5-yl) pyridine 226 mg (0.4 mg) of the compound of Example 43 in 5 ml of DMF
9 mmol) and 90 mg of 60% sodium hydride (2.
25 mmol), 241 mg of 2,6-dibromopyridine
(1.02 mmol) was heated at 100 ° C. for 3 hours. After distilling off DMF under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol = 50: 1) to obtain the title compound. Yield 234 mg (0.38 mmol) Yield 77.
6% MS (ESI, m / z) 617 (MH +) 1H-NMR (CDCl3): 2.49 (3H, s), 3.77 (3H, s), 4.75 (2
H, d), 5.66-5.76 (1H, d), 5.98 (2H, s), 6.36 (1H,
d), 6.52-6.80 (5H, m), 6.92 (2H, d), 7.04 (1H, d),
7.39 (1H, t)

Example 85 5-Nitro-pyridine-2-
Yl 3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy)-
5- (1H-tetrazol-5-yl) -pyridine-3
Synthesis of -yl] -2-propenyl ether 3- [4- (4-methoxyphenyl) -2-methyl-6
-(3,4-methylenedioxy-phenoxy) -5-
(1H-tetrazol-5-yl) -pyridin-3-yl] -prop-2-en-1-ol 200 mg (0.
435 mmol), 35 mg of 60% sodium hydride
177 mg (0.870 mmol) of 2-bromo-5-nitropyridine was added at 0 ° C to a 5 ml solution of the alkoxide ion in DMF prepared from (0.870 mmol), and the mixture was stirred at 80 ° C under an argon atmosphere for 24 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (chloroform-methanol = 9: 1).
And the title compound was obtained. Yield 35 mg (0.0602 mmol) Yield 14
% MS (ESI, m / z) 582 (MH +) 1H-NMR (CDCl3): 2.49 (2H, s), 3.73 (3H, s), 4.90 (2
H, d), 5.73 (1H, dt), 5.98 (2H, s), 6.48 (1H, d),
6.52 (1H, d), 6.63-6.75 (5H, m), 6.89 (2H, d), 8.33
(1H, dd), 8.96 (1H, d)

Example 86 2,4-Difluorophenyl-carbamic acid 3- [4- (4-methoxyphenyl)
Synthesis of 2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-5-yl] -2-propylene ester 2,4-difluorobenzoate 228 mg of acid (1.44 mm
ol) was dissolved in 5 ml of toluene, and 195 mg (1.58 mmol) of diphenylphosphoryl azide and 160 mg (1.58 mmol) of triethylamine were added.
For 2 hours. Thereafter, 3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazole-5-
Yl) -pyridin-3-yl] -prop-2-ene-1
200 mg (0.480 mmol) of -ol was added at 80 ° C., and the mixture was further stirred for 12 hours. After completion of the reaction, 2 ml of 3N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (chloroform-methanol = 9:
Purification in 1) gave the title compound. Yield 250 mg (0.407 mmol) Yield 48
% MS (ESI, m / z) 615 (MH +) 1H-NMR (CDCl3): 2.43 (3H, s), 3.62 (3H, s), 4.55 (2
H, d), 5.54 (1H, dt), 5.89 (2H, s), 6.26-6.51 (3H,
m), 6.60-6.65 (3H, m), 6.79-6.86 (3H, m), 7.88 (1H,
br s)

Example 87 3- [4- (4-Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridine- Synthesis of 3-yl] -propanol 3- [4- (4-methoxyphenyl) -2-methyl-6
-(3,4-methylenedioxy-phenoxy) -5-
(1H-tetrazol-5-yl) -pyridin-3-yl] -prop-2-en-1-ol 100 mg (0.
218 mmol) was dissolved in 10 ml of ethyl acetate, and 10
% Palladium carbon was added in a catalytic amount, and the mixture was stirred overnight at room temperature under normal pressure of hydrogen. The catalyst was removed using celite, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform 100%) to obtain the title compound. Yield 90 mg (0.195 mmol) Yield 89% MS (ESI, m / z) 462 (MH +) 1H-NMR (CD3OD): 1.50-1.62 (2H, m), 2.48-2.58 (5H,
m), 3.37 (2H, t), 3.76 (3H, s), 5.95 (2H, s), 6.45
-6.61 (2H, m), 6.75 (1H, d), 6.85 (2H, d), 7.02 (2
H, d)

Example 88 4- (4-Methoxyphenyl) -6-methyl-2- (3,4-methylenedioxy-phenoxy) -5-propyl-3- (1H-tetrazol-5-yl) -pyridine 3- [4- (4-methoxyphenyl) -2-methyl-6
-(3,4-methylenedioxy-phenoxy) -5-
160 mg of (1H-tetrazol-5-yl) -pyridin-3-yl] -prop-2-en-1-ol (0.
348 mmol) was dissolved in 10 ml of a methanol-chloroform solution (5: 1), a catalytic amount of palladium chloride was added, and the mixture was stirred overnight at room temperature under hydrogen normal pressure. The catalyst was removed using celite, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform 100%) to obtain the title compound. Yield 120 mg (0.269 mmol) Yield 77
% MS (ESI, m / z) 446 (MH +) 1H-NMR (DMSO-d6): 0.72 (3
H, t), 1.24-1.35 (2H, m),
2.33-2.39 (2H, m), 2.43
(3H, s), 3.73 (3H, s), 6.
04 (2H, s), 6.49-6.53 (1
H, m), 6.72-6.73 (1H, m),
6.84-6.90 (3H, m), 6.99
(2H, d)

Example 89 3- [2-furan-2-yl-4- (4-methoxyphenyl) -6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl ) -Pyridin-3-yl] -prop-2-
Synthesis of en-1-ol 1) 3-cyano-6-furan-2-yl-5-iodo-
Synthesis of 4- (4-methoxyphenyl) -2-pyridone 3-cyano-6-furan-2-yl-4- (4-methoxyphenyl) -2-pyridone 2.00 g (6.84 mm
ol) was dissolved in 50 ml of acetonitrile, 3.08 g (13.7 mmol) of N-iodosuccinimide was added, and the mixture was refluxed overnight. After cooling, the precipitate was collected by filtration and washed with ethyl acetate to give the title compound. Yield 1.57 g (3.75 mmol) Yield 55% MS (ESI, m / z) 419 (MH +) 1H-NMR (DMSO-d6): 0.72 (3H, t), 1.24-1.35 (2H, m),
2.33-2.39 (2H, m), 2.43 (3H, s), 3.73 (3H, s), 6.0
4 (2H, s), 6.49-7.01 (7H, m)

2) Synthesis of 2-chloro-3-cyano-6-furan-2-yl-5-iodo-4- (4-methoxyphenyl) -pyridine 3-cyano-6-furan-2-yl-5 -Iodine-4-
1.57 g of (4-methoxyphenyl) -2-pyridone
(3.75 mmol) was dissolved in 30 ml of phosphorus oxychloride and stirred at 100 ° C. overnight. The crystals obtained by evaporating phosphorus oxychloride under reduced pressure were washed with ethyl acetate to obtain the title compound. This was used for the following reaction without further purification. Yield 800 g (1.88 mmol) Yield 50% MS (ESI, m / z) 437 (MH +) 1H-NMR (CDCl3): 3.89 (3H, s), 6.62-6.63 (1H, m), 7.
04-7.31 (5H, m), 7.67-7.70 (1H, m)

3) 3-cyano-6-furan-2-yl-
5-Iodo-4- (4-methoxyphenyl) -2-
Synthesis of (3,4-methylenedioxy-phenoxy) -pyridine
Chloro-3-cyano-6-furan-2-yl-5-iodo-4- (4-methoxyphenyl) -pyridine 2.23
g (5.25 mmol) was added at 0 ° C., and the mixture was returned to room temperature under an argon atmosphere and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained crystals were purified by silica gel column chromatography (hexane-ethyl acetate = 3: 1) to obtain the title compound. Yield 2.14 g (3.98 mmol) Yield 60% 1H-NMR (CDCl3): 3.89 (3H, t), 6.03 (2H, s), 6.52 (1
H, dd), 6.70-6.85 (3H, m), 7.59 (1H, q)

4) 3- [5-Cyano-2-furan-2-
Yl-4- (4-methoxyphenyl) -6- (3,4-
Synthesis of methylenedioxy-phenoxy) -pyridin-3-yl] -acrylic acid ethyl ester 3-cyano-6-furan-2-yl-5-iodo-4-
2.14 g of (4-methoxyphenyl) -2- (3,4-methylenedioxy-phenoxy) -pyridine (3.98
mmol), 598 mg of ethyl acrylate (5.98 m
mol), 403 mg of triethylamine (3.98 mm
ol), 89 mg of palladium acetate (0.398 mmol)
1) was dissolved in DMF (20 ml) and heated under reflux at 150 ° C. for 5 hours. After filtering the insoluble matter, the solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with 3N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were purified by silica gel column chromatography (hexane-ethyl acetate = 3: 1) to give the title compound. Yield 500 mg (0.979 mmol) Yield 25
% MS (ESI, m / z) 511 (MH +) 1H-NMR (CDCl3): 1.24 (3H,
t), 3.87 (3H, s), 4.15 (2
H, q), 5.45 (3H, m), 6.03
(2H, s), 6.47-6.49 (1H,
m), 6.71-6.92 (4H, m), 6.
97 (2H, d), 7.25 (1H, d),
7.55 (1H, s), 7.88 (1H,
d)

5) 3- [5-cyano-2-furan-2-
Yl-4- (4-methoxyphenyl) -6- (3,4-
Synthesis of methylenedioxy-phenoxy) -pyridin-3-yl] -prop-2-en-1-ol 3- [5-cyano-2-furan-2-yl-4- (4-
Methoxyphenyl) -6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -acrylic acid
500 mg (0.979 mmol) of ethyl ester was dissolved in 20 ml of methylene chloride, and 1.96 ml (1.96 mmol) of a 1M solution of diisobutylaluminum hydride in hexane was added dropwise at −60 ° C. in an argon atmosphere. -60
And the reaction was stopped with methanol and water.
The mixture was stirred at room temperature for 2 hours and filtered using Celite. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate = 3: 1) to obtain the title compound. Yield 120 mg (0.256 mmol) Yield 26
% MS (ESI, m / z) 469 (MH +) 1H-NMR (CDCl3): 3.86 (3H, s), 4.04 (2H, br d), 5.37
(1H, dt), 6.03 (2H, s), 6.45-6.47 (1H, m), 6.69-7.
00 (7H, m), 7.25 (2H, d), 7.52 (1H, s),

6) 3- [2-furan-2-yl-4-
(4-methoxyphenyl) -6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazole-5
-Yl) -pyridin-3-yl] -prop-2-ene-
Synthesis of 1-ol 3- [5-cyano-2-furan-2-yl-4- (4-
Methoxyphenyl) -6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -prop-2-
Dissolve 150 mg (0.320 mmol) of ene-1-ol in 10 ml of toluene and 125 mg of sodium azide
(1.92 mmol), tri-n-butyltin chloride 41
Triazide prepared from 7 mg (1.28 mmol)
n-Butyltin was added and heated under reflux overnight. 1N Hydrochloric acid was added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were purified by silica gel column chromatography (chloroform-methanol = 100: 1 to 30: 1) to obtain the title compound. Yield 35 mg (0.0684 mmol) Yield 21
% MS (ESI, m / z) 512 (MH +) 1H-NMR (CDCl3): 3.72 (3H, s), 3.80 (2H, br), 5.28
(1H, dt), 6.06 (2H, s), 6.45-6.63 (3H, m), 6.80-6.
99 (7H, m), 7.82-7.83 (1H, m)

Example 90 5- [3- (5-bromopyridine-2-yloxy) -propyl] -4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxy-phenoxy ) -3- (1H-Tetrazole-5
Synthesis of -yl) -pyridine 3- [4- (4-methoxyphenyl) -2-methyl-6
-(3,4-methylenedioxy-phenoxy) -5-
(1H-tetrazol-5-yl) -pyridin-3-yl] -propanol 120 mg (0.260 mmol
l), 31 mg of 60% sodium hydride (0.780 m
mol) from DMF 5m
185 mg of 2,5-dibromopyridine (0.7 mg)
80 mmol) at 0 ° C. and 100
Stirred at C for 24 hours. After completion of the reaction, the reaction was stopped with 3N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol = 100: 1) to obtain the title compound. Yield 80 mg (0.130 mmol) Yield 50% MS (ESI, m / z) 617 (MH +) 1H-NMR (CD3OD): 1.75-1.85 (2H, m), 2.49 (3H, s), 2.
65-2.70 (2H, m), 3.74 (3H, s), 4.09 (2H, t), 5.95
(2H, s), 6.46-6.61 (3H, m), 6.73-6.77 (3H, m), 6.97
(2H, d), 7.67-8.10 (2H, m)

Example 91 N- (2-hydroxy-ethyl) -4- (4-methoxyphenyl) -2-methyl-
6- (3,4-methylenedioxy-phenoxy) -5
Synthesis of (1H-tetrazol-5-yl) -nicotinamide 1) N- (2-hydroxy-ethyl) -5-cyano-4
-(4-methoxyphenyl) -2-methyl-6- (3,
Synthesis of 4-methylenedioxy-phenoxy) -nicotinamide 3-cyano-5-iodo-4- (4-methoxyphenyl) -6-methyl-2- (3,4-methylenedioxy-
Phenoxy) -pyridine 1.00 g (2.06 mmol
l), 629 mg of 2-aminoethanol (10.3 mm
ol), 1.04 g of triethylamine (10.3 mmol)
1) palladium acetate 46 mg (0.206 mmol)
Was dissolved in 10 ml of DMF, and carbon
For 24 hours. After standing to cool, insoluble matter was filtered,
The solvent was distilled off under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with 3N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals are subjected to silica gel column chromatography (chloroform 100
%) To give the title compound. Yield 570 mg (1.27 mmol) Yield 62% MS (ESI, m / z) 448 (MH +) 1H-NMR (CDCl3): 2.42 (3H, s), 3.10-3.38 (4H, m), 3.
83 (3H, s), 5.99 (2H, s), 6.30 (2H, s), 6.30 (1H,
br), 6.58-6.80 (3H, m), 6.98 (2H, d), 7.37 (2H, d)

2) N- (2-hydroxy-ethyl) -4
-(4-methoxyphenyl) -2-methyl-6- (3,
Synthesis of 4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -nicotinamide N- (2-hydroxy-ethyl) -5-cyano-4-
(4-methoxyphenyl) -2-methyl-6- (3,4
-Methylenedioxy-phenoxy) -nicotinamide (570 mg, 1.27 mmol) was dissolved in toluene (10 ml), and sodium azide (495 mg, 7.62 mmol) was dissolved.
l), 1.66 mg of tri-n-butyltin chloride (5.0
9 mmol), and refluxed with heating for 24 hours. After completion of the reaction, 1N hydrochloric acid,
Ethyl acetate was added, and the precipitated crystals were filtered and washed with ethyl acetate. The obtained crystals are subjected to silica gel column chromatography (chloroform-methanol = 100: 1 to 1).
0: 1) to give the title compound. Yield 155 mg (0.316 mmol) Yield 25
% MS (ESI, m / z) 491 (MH +) 1H-NMR (CD3OD): 2.44 (3H, s), 3.18-3.32 (4H, m), 3.
74 (3H, s), 5.96 (2H, s), 6.50-6.79 (5H, m), 7.08
(2H, d)

Example 92 {3- [4- (4-Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazole-5
Synthesis of yl) -pyridin-3-yl] -allyl} -acetamide 1) {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-
Synthesis of phenoxy) -pyridin-3-yl] -allyl} -acetamide 3- [5-cyano-4- (4-methoxyphenyl) -2
-Methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -prop-2-
180 mg (0.433 mmol) of ene-1-amine was dissolved in 10 ml of THF, and 88 mg of triethylamine was dissolved.
(0.867 mmol), 66 mg of acetic anhydride (0.65
0 mmol) and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane-
Purification with ethyl acetate = 1: 1) gave the title compound. Yield 130 mg (0.284 mmol) Yield 66
% MS (ESI, m / z) 458 (MH +) 1H-NMR (CDCl3): 1.91 (3H, s), 2.44 (3H, s), 3.80 (2
H, t), 3.86 (3H, s), 5.31 (1H, br), 5.42 (1H, br),
6.01 (2H, s), 6.16 (1H, d), 6.63-6.82 (3H, m), 6.9
9 (2H, d), 7.23 (2H, d)

2) {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-
Phenoxy) -5- (1H-tetrazol-5-yl)
Synthesis of -pyridin-3-yl] -allyl} -acetamide {3- [5-cyano-4- (4-methoxyphenyl)-
130 mg (0.284 mmol) of 2-methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -acetamide was added to 10 m of toluene.
1 mg of sodium azide (1.70 mm
ol), 370 mg of tri-n-butyltin chloride (1.1
4 mmol), and refluxed with heating for 2 days. After completion of the reaction, 1N hydrochloric acid and ethyl acetate were added, and the precipitated crystals were filtered and washed with a hexane-ethyl acetate solution (1: 1). The obtained crystals were purified by silica gel column chromatography (chloroform-methanol = 100: 1 to 50: 1) to give the title compound. Yield 60 mg (0.120 mmol) Yield 42% MS (ESI, m / z) 501 (MH +) 1H-NMR (CD3OD): 1.85 (3H, s), 2.48 (3H, s), 3.73 (2
H, d), 3.75 (3H, s), 5.51 (1H, dt), 5.96 (2H, s) 6.2
2 (1H, d), 6.50 (1H, dd), 6.62 (1H, d), 6.75-6.83
(3H, m), 6.94 (2H, d)

Example 93 3- [4- (4-Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridine- 3-yl] -prop-2-ene-1-
Synthesis of amine 3- [5-cyano-4- (4-methoxyphenyl) -2
-Methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -prop-2-
1.44 g (3.47 mmol) of ene-1-amine was dissolved in 10 ml of toluene, and 4.60 g (13.9 mmol) of tri-n-butyltin azide was added.
Heat to reflux for days. 3 ml of 10% hydrochloric acid-ethanol solution
Was added to stop the reaction, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the obtained residue was subjected to reversed-phase high-performance liquid chromatography using octadodecyl (ODS) group chemically bonded silica gel as a filler to give trifluoroacetic acid in an amount of 0.1%. The mixture was eluted with a mixed solvent of (v / v) water-acetonitrile, and the target compound fraction was lyophilized to give the title compound. Yield 1.04 g (2.27 mmol) Yield 65% MS (ESI, m / z) 459 (MH +) 1H-NMR (CD3OD): 2.53 (3H, s), 3.50 (2H, d), 3.76 (3
H, s), 5.60 (1H, dt), 5.97 (2H, s), 6.50-6.64 (3H,
m), 6.77-6.86 (3H, m), 6.97 (2H, d)

Example 94 1- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazole-
Synthesis of 5-yl) -pyridin-3-yl] -allyl} -urea 1) 1- {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4- Synthesis of methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -urea 3- [5-cyano-4- (4-methoxyphenyl) -2
-Methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -prop-2-
200 mg (3.47 mmol) of ene-1-amine was dissolved in 10 ml of glacial acetic acid-water (1: 2) solution, and 63 mg (0.963 mmol) of sodium cyanate was added, followed by stirring at room temperature for 1 hour. The insolubles were removed by filtration, and the filtrate was evaporated under reduced pressure. Recrystallize the obtained crystals (recrystallization solvent:
Purification by ethyl acetate-hexane) gave the title compound. Yield 130 mg (0.284 mmol) Yield 59
% MS (ESI, m / z) 458 (MH +) 1H-NMR (CDCl3): 2.43 (3H, s), 3.78 (2H, t), 3.85 (3
H, s), 5.41 (1H, dt), 5.51 (1H, br), 6.00 (2H, s),
6.15 (1H, d), 6.63-6.81 (3H, m), 6.97 (2H, d), 7.
22 (2H, d)

2) 1- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl)- Synthesis of pyridin-3-yl] -allyl} -urea 1- {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-
Phenoxy) -pyridin-3-yl] -allyl} -urea 130 mg (0.284 mmol) in toluene 10 m
1 mg of sodium azide (1.70 mm
ol), 369 mg of tri-n-butyltin chloride (1.1
3 mmol), and the mixture was refluxed under heating for 2 days. After completion of the reaction, 1N hydrochloric acid and ethyl acetate were added, and the precipitated crystals were filtered. The obtained crystals were washed with a hexane-ethyl acetate solution (1: 1) to obtain the title compound. Yield 130 mg (0.259 mmol) Yield 91
% MS (ESI, m / z) 501 (MH +) 1H-NMR (DMSO-d6): 2.44 (3H, s), 3.60 (2H, t), 3.72
(3H, s), 5.48 (1H, dt), 6.05 (2H, s), 6.11 (1H, d)
6.53 (1H, dd), 6.75-6.93 (6H, m), 7.85 (1H, br t)

Example 95 2-amino-N- {3- [4
-(4-methoxyphenyl) -2-methyl-6- (3,
Synthesis of 4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -acetamide hydrochloride 1) 2- [N- (t-butoxycarbonyl)] -Amino-
N- {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-
Synthesis of phenoxy) -pyridin-3-yl] -allyl} -acetamide 3- [5-cyano-4- (4-methoxyphenyl) -2
-Methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -prop-2-
220 g (0.530 mmol) of ene-1-amine, N
-(T-butoxycarbonyl) -glycine 186 mg
(1.06 mmol) was dissolved in 10 ml of methylene chloride, 186 mg (1.06 mmol) of WSC was added, and the mixture was stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform 100%) to obtain the title compound. Yield 220 mg (0.384 mmol) Yield 72
% MS (ESI, m / z) 573 (MH +) 1H-NMR (CDCl3): 1.45 (9H, s), 2.43 (3H, s), 3.20 (2
H, d), 3.82 (2H, t), 3.88 (3H, s), 5.40 (1H, dt) 6.
01 (2H, s), 6.17 (1H, d), 6.64-6.82 (3H, m), 6.99
(2H, d), 7.23 (2H, d)

2) 2-amino-N- {3- [4- (4-
Synthesis of methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -acetamide hydrochloride 2 -[N- (t-butoxycarbonyl)]-amino-N-
{3- [5-cyano-4- (4-methoxyphenyl)-
2-methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -acetamide 220 mg (0.384 mmol) in toluene 10 m
and dissolved in sodium azide 150 mg (2.30 mm
ol), 500 mg of tri-n-butyltin chloride (1.5
4 mmol), and refluxed with heating for 1 day. After completion of the reaction, the toluene layer was removed, and 5 ml of 4N hydrochloric acid-dioxane was added, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate. The obtained crystals were purified by recrystallization (recrystallization solvent: methanol-ethyl acetate) to obtain the title compound. Yield 95 mg (0.184 mmol) Yield 48% MS (ESI, m / z) 516 (MH +) 1H-NMR (CD3OD): 2.48 (3H, s), 3.61 (2H, s), 3.76 (3
H, s), 3.80 (2H, d), 5.52 (1H, dt), 5.96 (2H, s),
6.29 (1H, d), 6.49-6.85 (5H, m), 6.95 (2H, d)

Example 96 DL-pyroglutamic acid
{3- [4- (4-methoxyphenyl) -2-methyl-
6- (3,4-methylenedioxy-phenoxy) -5
Synthesis of (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide 1) DL-pyroglutamic acid {3- [5-cyano-4]
-(4-methoxyphenyl) -2-methyl-6- (3,
4-Methylenedioxy-phenoxy) -pyridine-3-
Synthesis of yl] -allyl} -amide 3- [5-cyano-4- (4-methoxyphenyl) -2
-Methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -prop-2-
300 g (0.722 mmol) of ene-1-amine, D
140 mg (1.08 mmol) of L-pyroglutamic acid
Was dissolved in 10 ml of methylene chloride, and 277 mg of WSC was dissolved.
(1.44 mmol) and the mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform 100%).
And the title compound was obtained. Yield 260 mg (0.494 mmol) Yield 68
% MS (ESI, m / z) 527 (MH +) 1H-NMR (CDCl3): 2.00-2.10 (1H, m), 2.30 (1H, t), 2.
44 (3H, s), 3.75-4.10 (7H, m), 5.38 (1H, dt), 6.02
(2H, s), 6.05-6.22 (2H, m), 6.64-6.82 (3H, m), 6.
99 (2H, d), 7.23 (2H, d)

2) DL-pyroglutamic acid ｛3- [4
-(4-methoxyphenyl) -2-methyl-6- (3,
Synthesis of 4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4-]
(4-methoxyphenyl) -2-methyl-6- (3,4
-Methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide 260 mg (0.494 mmol
l) was dissolved in 10 ml of toluene, and sodium azide 19 was dissolved.
Tri-n-butyltin azide prepared from 3 mg (2.96 mmol) and 643 mg (1.98 mmol) of tri-n-butyltin chloride was added, and the mixture was heated under reflux for 3 days. After completion of the reaction, 3N hydrochloric acid and ethyl acetate were added, and the precipitated crystals were filtered. The obtained crystals were purified by recrystallization (recrystallization solvent: methanol-ethyl acetate) to obtain the title compound. Yield 120 mg (0.211 mmol) Yield 43
% MS (ESI, m / z) 570 (MH +) 1H-NMR (DMSO-d6): 2.04-2.15 (2H, m), 2.44 (3H, s),
3.61-3.93 (7H, m), 5.54 (1H, dt), 6.05-6.14 (3H,
m), 6.51 (1H, d), 6.75-6.90 (5H, m), 7.72 (1H, s),
8.03 (1H, br s)

Example 97 Pyrazine-2-carboxylic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5
-(1H-tetrazol-5-yl) -pyridin-3-
Synthesis of yl] -allyl} -amide 1) pyrazine-2-carboxylic acid {3- [5-cyano-
4- (4-methoxyphenyl) -2-methyl-6-
Synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) -2 of Example] -Methyl-6-
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 522 (MH +) 1H-NMR (CDCl3): 2.46 (3H, s), 3.75 (3H, s), 4.03-4.
08 (2H, br), 5.54 (1H, dt), 6.00 (2H, s), 6.27 (1
H, d), 6.62-6.81 (3H, m), 6.91 (2H, d), 7.23 (2H,
d), 7.71 (1H, br), 8.52 (1H, s), 8.75 (1H, s), 9.3
6 (1H, s)

2) pyrazine-2-carboxylic acid {3-
[4- (4-methoxyphenyl) -2-methyl-6-
(3,4-methylenedioxy-phenoxy) -5- (1
H-tetrazol-5-yl) -pyridin-3-yl]
Synthesis of -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
According to the synthesis of methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide. Synthesized. MS (ESI, m / z) 565 (MH +) 1H-NMR (CDCl3): 2.49 (3H, s), 3.58 (3H, s), 4.00 (2
H, br), 5.62 (1H, dt), 5.96 (2H, s), 6.31 (1H, d),
6.48-6.90 (7H, m), 8.65 (1H, t), 8.77 (1H, d), 8.
80 (1H, br), 9.17 (1H, s)

Example 98 N- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazole-
Synthesis of 5-yl) -pyridin-3-yl] -allyl-2-hydroxy-acetamide 1) Synthesis of o-methoxymethyl-ethyl glycolate 3.0 g (28.8 mmol) of ethyl glycolate, di-isopropyl- 7.44 g of ethylamine (57.6 m
mol) was dissolved in methylene chloride and stirred at room temperature for 1 hour. Under ice cooling, 3.48 g of methoxymethyl chloride
(43.2 mmol), and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform 10
0%) to give the title compound. Yield 3.35 g (22.6 mmol) Yield 79% MS (ESI, m / z) 171 (MH +) 1H-NMR (CDCl3): 1.29 (3H, t), 3.41 (3H, s), 4.16 (2
H, s), 4.23 (2H, q), 4.71 (2H, s)

2) Synthesis of o-methoxymethyl-glycolic acid 3.35 g of o-methoxymethyl-ethyl glycolate
(22.6 mmol) dissolved in 50 ml of ethanol,
10 ml of 3N sodium hydroxide aqueous solution (30.0 mm
ol) and stirred for 4 days. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound. Yield 850 mg (7.08 mmol) Yield 31% 1H-NMR (CDCl3): 3.42 (3H, s), 4.24 (2H, s), 4.73 (2
H, s)

3) N- {3- [5-cyano-4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl]-
Synthesis of allyl {-2-methoxymethyl-acetamide 3- [5-cyano-4- (4-methoxyphenyl) -2
-Methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -prop-2-
565 g (1.36 mmol) of ene-1-amine, o-
245 mg of methoxymethyl-glycolic acid (2.04 m
mol) was dissolved in 10 ml of methylene chloride, and
1 mg (2.72 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform 10
0%) to give the title compound. Yield 540 mg (1.04 mmol) Yield 76% MS (ESI, m / z) 518 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.35 (3H, s), 3.86-3.
88 (5H, m), 3.98 (2H, s), 4.62 (2H, s), 5.48 (1H,
dt), 6.00 (2H, s), 6.18 (1H, d), 6.50 (1H, br), 6.6
3-6.81 (3H, m), 6.98 (2H, d), 7.24 (2H, d)

4) N- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl)- Synthesis of pyridin-3-yl] -allyl} -2-hydroxy-acetamide N- {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy) −
Phenoxy) -pyridin-3-yl] -allyl {-2-
540 mg of methoxymethyl-acetamide (1.04 m
mol) was dissolved in 10 ml of toluene, and tri-n-butyltin azide prepared from 406 mg (6.24 mmol) of sodium azide and 1.36 mg (4.17 mmol) of tri-n-butyltin chloride was added, and the mixture was heated under reflux for 2 days. After completion of the reaction, 30% hydrochloric acid-ethanol was added, and the mixture was further stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol = 50: 1 to 9: 1) to obtain the title compound. Yield 80 mg (0.155 mmol) Yield 15% MS (ESI, m / z) 570 (MH +) 1H-NMR (CD3OD): 2.48 (3H,
s), 3.76 (3H, s), 3.80 (2
H, t), 3.89 (2H, s), 5.53
(1H, dt), 5.96 (2H, s),
6.25 (1H, d), 6.48-6.96
(7H, m)

Example 99 Pyridine-3-carboxylic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5
-(1H-tetrazol-5-yl) -pyridin-3-
Synthesis of yl] -allyl} -amide 1) Pyridine-3-carboxylic acid {3- [5-cyano-
4- (4-methoxyphenyl) -2-methyl-6-
Synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) -2 of Example] -Methyl-6-
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 521 (MH +) 1H-NMR (CDCl3): 2.44 (3H, s), 3.74 (3H, s), 4.01 (2
H, t), 5.51 (1H, dt), 6.00 (2H, s), 6.27 (1H, br)
, 6.62-6.93 (5H, m), 7.22 (2H, d), 7.36 (1H, q),
7.99 (1H, dt), 8.71 (1H, d), 8.86 (1H, d)

2) Pyridine-3-carboxylic acid {3-
[4- (4-methoxyphenyl) -2-methyl-6-
(3,4-methylenedioxy-phenoxy) -5- (1
H-tetrazol-5-yl) -pyridin-3-yl]
Synthesis of -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
According to the synthesis of methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide. Synthesized. MS (ESI, m / z) 564 (MH +) 1H-NMR (CD3OD): 2.55 (3H, s), 3.60 (3H, s), 4.02 (2
H, br), 5.69 (1H, brd), 5.95 (2H, s), 6.34 (1H,
d), 6.49-6.95 (7H, m), 8.25 (1H, br), 8.95 (1H, br)
d), 9.06 (1H, br), 9.23 (1H, s)

Example 100 6-Hydroxy-pyridine-3-carboxylic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-
Phenoxy) -5- (1H-tetrazol-5-yl)
-Pyridin-3-yl] -allyl} -amide 1) 6-Hydroxy-pyridine-3-carboxylic acid {3
-[5-cyano-4- (4-methoxyphenyl) -2-
Synthesis of methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxy) of Example Phenyl) -2-methyl-6-
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 537 (MH +) 1H-NMR (CD3OD): 2.44 (3H, s), 3.75 (3H, s), 3.88 (2
H, br), 5.58 (1H, dt), 6.00 (2H, s), 6.24 (1H, d),
6.50-6.95 (6H, m), 7.23 (2H, d), 7.83-7.94 (2H,
m), 8.35 (1H, br)

2) 6-hydroxy-pyridine-3-carboxylic acid {3- [4- (4-methoxyphenyl) -2-
Synthesis of methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid of Example 3 − [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 580 (MH +) 1H-NMR (DMSO-d6): 2.45 (3H, s), 3.63 (3H, s), 3.77
(2H, br), 5.57 (1H, dt), 6.05 (2H, s), 6.15 (1H,
d), 6.32 (1H, d), 6.52 (1H, dd), 6.70-6.90 (6H, m),
7.74-7.89 (2H, m), 8.27 (1H, br t)

Example 101 1- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -Pyridin-3-yl] -allyl} -3-
Synthesis of pyridin-3-yl-urea 1) 1- {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -pyridine- 3-yl] -allyl｝ -3
Synthesis of -Pyridin-3-yl-urea 356 mg (2.89 mmol) of nicotinic acid was dissolved in 5 ml of toluene, and 927 m of diphenylphosphoryl azide was dissolved.
g (3.37 mmol), 341 mg of triethylamine
(3.37 mmol) was added and the mixture was stirred at 80 ° C. for 2 hours. Then 3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -prop-2-ene -1-amine 400 g (0.963 mm
ol) at 80 ° C. and further stirred for 12 hours. After completion of the reaction, 2 ml of 3N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (chloroform-
Purification by methanol = 20: 1 to 10: 1) gave the title compound. Yield 390 mg (0.728 mmol) Yield 76
% MS (ESI, m / z) 536 (MH +) 1H-NMR (DMSO-d6): 2.41 (3H, s), 3.68 (2H, t), 3.73
(3H, s), 5.58 (1H, dt), 6.09 (2H, s), 6.17 (1H,
d), 6.34 (1H, br), 6.69 (1H, q), 6.93-7.33 (6H,
m), 7.86 (1H, br d), 8.11 (1H, br d), 8.51 (1H, br
d), 8.64 (1H, s)

2) 1- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl)- Synthesis of pyridin-3-yl] -allyl-3-pyridin-3-yl-urea 1- {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4 -Methylenedioxy-
[Phenoxy) -pyridin-3-yl] -allyl} -3-
200 mg of pyridin-3-yl-urea (0.373 m
mol) was dissolved in 10 ml of toluene, and tri-n-butyltin azide prepared from 145 mg (2.24 mmol) of sodium azide and 486 mg (1.49 mmol) of tri-n-butyltin chloride was added thereto, and the mixture was refluxed for 2 days.
After completion of the reaction, 30% hydrochloric acid-ethanol was added, and the mixture was further stirred at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the obtained residue was subjected to reversed-phase high-performance liquid chromatography using octadodecyl (ODS) group chemically bonded silica gel as a filler to give trifluoroacetic acid in an amount of 0.1%. The mixture was eluted with a mixed solvent of (v / v) water-acetonitrile, and the target compound fraction was lyophilized to give the title compound. Yield 1.04 g (2.27 mmol) Yield 19.
4% MS (ESI, m / z) 579 (MH +) 1H-NMR (CD3OD): 2.50 (3H, s), 3.60 (3H, s), 3.80 (2
H, d), 5.63 (1H, dt), 5.96 (2H, s), 6.27 (1H, d),
6.48-6.95 (7H, m), 7.87 (1H, q), 8.20 (1H, d), 8.37
(1H, d), 9.13 (1H, s)

Example 102 Pyridine-4-carboxylic acid {3- [4- (4-methoxyphenyl) -2-methyl-
6- (3,4-methylenedioxy-phenoxy) -5
Synthesis of (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide 1) Pyridin-4-carboxylic acid {3- [5-cyano-
4- (4-methoxyphenyl) -2-methyl-6-
Synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) -2 of Example] -Methyl-6-
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 521 (MH +) 1H-NMR (CDCl3): 2.44 (3H,
s), 3.73 (3H, s), 4.00 (2
H, t), 5.49 (1H, dt), 6.0
1 (2H, s), 6.27 (1H, br)
5. d), 6.62-6.81 (3H, m),
91 (2H, d), 7, 22 (2H, d),
7.48 (2H, d), 8.71 (2H, d)
d)

2) Pyridine-4-carboxylic acid {3-
[4- (4-methoxyphenyl) -2-methyl-6-
(3,4-methylenedioxy-phenoxy) -5- (1
H-tetrazol-5-yl) -pyridin-3-yl]
Synthesis of -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
According to the synthesis of methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide. Synthesized. MS (ESI, m / z) 564 (MH +) 1H-NMR (CD3OD): 2.50 (3H, s), 3.61 (3H, s), 4.00 (2
H, br), 5.65 (1H, br), 5.96 (2H, s), 6.30-6.95 (8
H, m), 8.12 (2H, br), 8.92 (2H, br)

Example 103 2,6-Dimethoxy-pyridine-3-carboxylic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5 Synthesis of-(1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide 1) 2,6-dimethoxy-pyridine-3-carboxylic acid
{3- [5-cyano-4- (4-methoxyphenyl)-
Synthesis of 2-methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4 -Methoxyphenyl) -2-methyl-6-
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 581 (MH +) 1H-NMR (CDCl3): 2.47 (3H, s), 3.74 (3H, s), 3.97 (3
H, s), 4.03 (5H, br), 5.61 (1H, dt), 6.00 (2H, s),
6.22 (1H, d), 6.44 (1H, d), 6.64-6.82 (3H, m), 6.
90 (2H, d), 7.24 (2H, d), 7.64 (1H, brt), 8.37 (1
H, d)

2) 2,6-dimethoxy-pyridine-3-
Carboxylic acid {3- [4- (4-methoxyphenyl)-
Synthesis of 2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Example DL-pyroglutamic acid 3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 624 (MH +) 1H-NMR (CD3OD): 2.50 (3H, s), 3.56 (3H, s), 3.98 (5
H, br s), 4.03 (3H, s), 5.66 (1H, dt), 5.96 (2H,
s), 6.29 (1H, d), 6.43-6.52 (2H, m), 6.62-6.78 (4
H, m), 6.90 (2H, d), 8.17 (1H, d)

Example 104 2-Methylbenzoic acid {3-
[4- (4-methoxyphenyl) -2-methyl-6-
(3,4-methylenedioxy-phenoxy) -5- (1
H-tetrazol-5-yl) -pyridin-3-yl]
Synthesis of -allyl} -amide 1) 2-Methylbenzoic acid {3- [5-cyano-4-
(4-methoxyphenyl) -2-methyl-6- (3,4
Synthesis of -Methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6 of Example −
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 534 (MH +) 1H-NMR (CDCl3): 2.37 (3H, s), 2.46 (3H, s), 3.74 (3
H, s), 4.00 (2H, t), 5.55 (1H, dt), 5.70 (1H, br),
6.00 (2H, s), 6.26 (1H, d), 6.64-6.81 (3H, m), 6.9
4 (2H, d), 7.16-7.35 (6H, m)

2) 2-Methylbenzoic acid {3- [4-
(4-methoxyphenyl) -2-methyl-6- (3,4
Synthesis of -methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 577 (MH +) 1H-NMR (CD3OD): 2.31 (3H, s), 2.52 (3H, s), 3.67 (3
H, s), 3.93 (2H, brd), 5.68 (1H, dt), 5.96 (2H,
s), 6.32 (1H, d), 6.48-6.63 (2H, m), 6.75-6.79 (3
H, m), 6.96 (2H, d), 7.10-7.31 (4H, m)

Example 105 2-Fluorobenzoic acid ｛3
-[4- (4-methoxyphenyl) -2-methyl-6-
(3,4-methylenedioxy-phenoxy) -5- (1
H-tetrazol-5-yl) -pyridin-3-yl]
Synthesis of -allyl} -amide 1) 2-Fluorobenzoic acid {3- [5-cyano-4-
(4-methoxyphenyl) -2-methyl-6- (3,4
Synthesis of -Methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6 of Example −
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 538 (MH +) 1H-NMR (CDCl3): 2.46 (3H, s), 3.74 (3H, s), 4.05 (2
H, t), 5.56 (1H, dt), 6.00 (2H, s), 6.27 (1H, d),
6.58-6.81 (4H, m), 6.92 (2H, d), 7.11 (1H, dd), 7.2
2-7.29 (3H, m), 7.42-7.52 (1H, m), 8.04 (1H, td)

2) 2-Fluorobenzoic acid {3- [4-
(4-methoxyphenyl) -2-methyl-6- (3,4
Synthesis of -methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 581 (MH +) 1H-NMR (CD3OD): 2.51 (3H, s), 3.62 (3H, s), 3.95 (2
H, d), 5.65 (1H, dt), 5.96 (2H, s), 6.33 (1H, s),
6.49-6.78 (5H, m), 6.93 (2H, d), 7.14-7.28 (2H, m),
7.50-7.64 (2H, m)

Example 106 2-trifluoromethylbenzoic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy)
-5- (1H-tetrazol-5-yl) -pyridine-
Synthesis of 3-yl] -allyl} -amide 1) 2-trifluoromethylbenzoic acid {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6
Synthesis of-(3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl)-of Example] 2-methyl-6
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 588 (MH +) 1H-NMR (CDCl3): 2.47 (3H, s), 3.77 (3H, s), 4.01 (2
H, t), 5.56 (1H, dt), 5.67 (1H, br), 6.01 (2H, s),
6.26 (1H, d), 6.64-6.82 (3H, m), 6.94 (2H, d), 7.
24 (2H, d), 7.36-7.71 (4H, m)

2) 2-trifluoromethylbenzoic acid
{3- [4- (4-methoxyphenyl) -2-methyl-
6- (3,4-methylenedioxy-phenoxy) -5
Synthesis of (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 631 (MH +) 1H-NMR (CD3OD): 2.52 (3H, s), 3.69 (3H, s), 3.93 (2
H, d), 5.68 (1H, dt), 5.96 (2H, s), 6.33 (1H, d),
6.49-6.63 (2H, m), 6.75-6.81 (3H, m), 6.98 (2H, d),
7.24-7.27 (1H, m), 7.60-7.88 (3H, m)

Example 107 3-trifluoromethylbenzoic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy)
-5- (1H-tetrazol-5-yl) -pyridine-
Synthesis of 3-yl] -allyl} -amide 1) 3-trifluoromethylbenzoic acid {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6
Synthesis of-(3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl)-of Example] 2-methyl-6
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 588 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.71 (3H, s), 4.02 (2
H, t), 5.51 (1H, dt), 6.01 (2H, s), 6.09 (1H, br),
6.28 (1H, d), 6.63-6.81 (3H, m), 6.90 (2H, d), 7.
22 (2H, d), 7.57 (1H, t), 7.78 (1H, q), 7.96 (1H,
s)

2) 3-trifluoromethylbenzoic acid
{3- [4- (4-methoxyphenyl) -2-methyl-
6- (3,4-methylenedioxy-phenoxy) -5
Synthesis of (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 631 (MH +) 1H-NMR (CD3OD): 2.49 (3H,
s), 3.52 (3H, s), 3.95 (2
H, br), 5.64 (1H, dt), 5.
96 (2H, s), 6.30 (1H, d),
6.47-6.92 (7H, m), 7.62-
8.04 (4H, m), 8.70 (1H, b
r)

Example 108 2,5-Difluorobenzoic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5]
-(1H-tetrazol-5-yl) -pyridin-3-
Synthesis of yl] -allyl} -amide 1) 2,5-difluorobenzoic acid {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6-
Synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) -2 of Example] -Methyl-6-
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 556 (MH +) 1H-NMR (CDCl3): 2.46 (3H, s), 3.76 (3H, s), 4.04 (2
H, br), 5.54 (1H, dt), 6.00 (2H, s), 6.25 (1H, d),
6.64-6.81 (3H, m), 6.92 (2H, d), 7.10-7.26 (4H,
m), 7.70-7.76 (1H, m)

2) 2,5-difluorobenzoic acid {3-
[4- (4-methoxyphenyl) -2-methyl-6-
(3,4-methylenedioxy-phenoxy) -5- (1
H-tetrazol-5-yl) -pyridin-3-yl]
Synthesis of -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 599 (MH +) 1H-NMR (CDCl3): 2.50 (3H, s), 3.66 (3H, s), 4.02 (2
H, br), 5.55 (1H, dt), 5.97 (2H, s), 6.27 (1H, d),
6.51-6.78 (5H, m), 6.92 (2H, d), 6.95-7.19 (2H,
m), 7.67 (1H, br)

Example 109 4-trifluoromethoxybenzoic acid {3- [4- (4-methoxyphenyl) -2-
Synthesis of methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide 1) 4-trifluoromethoxybenzoic acid ｛3- [5-
Cyano-4- (4-methoxyphenyl) -2-methyl-
Synthesis of 6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) of Example] -2-methyl-6-
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 604 (MH +) 1H-NMR (CDCl3): 2.46 (3H, s), 3.75 (3H, s), 4.02 (2
H, t), 5.49 (1H, dt), 5.80 (1H, br), 6.02 (1H, d),
6.29 (1H, d), 6.64-6.82 (3H, m), 6.94 (2H, d), 7.
23-7.29 (4H, m), 7.68 (2H, d)

2) 4-trifluoromethoxybenzoic acid
{3- [4- (4-methoxyphenyl) -2-methyl-
6- (3,4-methylenedioxy-phenoxy) -5
Synthesis of (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 647 (MH +) 1H-NMR (CDCl3): 2.50 (3H, s), 3.62 (3H, s), 3.98 (2
H, br d), 5.55 (1H, dt), 5.96 (2H, s), 6.28 (1H,
d), 6.51-6.76 (5H, m), 6.92 (2H, d), 7.26 (2H, d),
7.72 (2H, d)

Example 110 4-trifluoromethylbenzoic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy)
-5- (1H-tetrazol-5-yl) -pyridine-
Synthesis of 3-yl] -allyl} -amide 1) 4-trifluoromethylbenzoic acid {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6
Synthesis of-(3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl)-of Example] 2-methyl-6
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 588 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.72 (3H, s), 4.03 (2
H, t), 5.50 (1H, dt), 5.90 (1H, br), 6.01 (2H, s),
6.29 (1H, d), 6.63-6.82 (3H, m), 6.92 (2H, d), 7.23
(2H, d), 7.72 (4H, q)

2) 4-trifluoromethylbenzoic acid
{3- [4- (4-methoxyphenyl) -2-methyl-
6- (3,4-methylenedioxy-phenoxy) -5
Synthesis of (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 631 (MH +) 1H-NMR (DMSO-d6): 2.46 (3H, s), 3.55 (3H, s), 3.85
(2H, br), 5.64 (1H, dt), 6.05 (2H, s), 6.20 (1H,
d), 6.51-6.90 (7H, m), 7.86 (4H, q), 8.74 (1H, br)

Example 111 3-Fluorobenzoic acid ｛3
-[4- (4-methoxyphenyl) -2-methyl-6-
(3,4-methylenedioxy-phenoxy) -5- (1
H-tetrazol-5-yl) -pyridin-3-yl]
Synthesis of -allyl} -amide 1) 3-Fluorobenzoic acid {3- [5-cyano-4-
(4-methoxyphenyl) -2-methyl-6- (3,4
Synthesis of -Methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6 of Example −
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 538 (MH +) 1H-NMR (CDCl3): 2.44 (3H, s), 3.74 (3H, s), 4.00 (2
H, t), 5.50 (1H, dt), 6.01 (2H, s), 6.26 (1H, d),
6.63-6.81 (3H, m), 6.92 (2H, d), 7.15-7,28 (3H, m),
7.36-7.41 (3H, m)

2) 3-Fluorobenzoic acid {3- [4-
(4-methoxyphenyl) -2-methyl-6- (3,4
Synthesis of -methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 581 (MH +) 1H-NMR (DMSO-d6): 2.46 (3H, s), 3.60 (3H, s), 3.85
(2H, t), 5.63 (1H, dt), 6.05 (2H, s), 6.20 (1H,
d), 6.54 (1H, dd), 6.71-6.76 (3H, m), 6.88-6.93 (3
H, m), 7.36-7.52 (4H, m), 8.62 (1H, br t)

Example 112 2-Methyl-pyridine-3
-Carboxylic acid {3- [4- (4-methoxyphenyl)-]
Synthesis of 2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide 1) 2-Methyl-pyridine -3-carboxylic acid ｛3-
[5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy)
Synthesis of -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6-methyl-6
It was synthesized according to the synthesis of (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 535 (MH +) 1H-NMR (CDCl3): 2.47 (3H, s), 2.60 (3H, s), 3.76 (3
H, s), 4.02 (2H, t), 5.54 (1H, dt), 5.63 (1H, br),
6.02 (2H, s), 6.13 (1H, d), 6.64-6.82 (3H, m), 6.94
(2H, d), 7.14 (1H, dd), 7,24 (2H, d), 8.55 (1H, d
d)

2) 2-Methyl-pyridine-3-carboxylic acid {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy)-
5- (1H-tetrazol-5-yl) -pyridine-3
Synthesis of -yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. MS (ESI, m / z) 578 (MH +) 1H-NMR (CD3OD): 2.52 (3H, s), 2.67 (3H, s), 3.68 (3
H, s), 3.99 (2H, br), 5.69 (1H, dt), 5.97 (2H, s),
6.34 (1H, d), 6.49-6.64 (2H, m), 6.76-6.80 (3H,
m), 6.97 (2H, d), 7.69 (1H, t), 8.04 (1H, d), 8.65
(1H, d)

Example 113 N- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) Synthesis of -pyridin-3-yl] -allyl} -oxalamide ethyl ester 3- [4- (4-methoxyphenyl) -2-methyl-6
-(3,4-methylenedioxy-phenoxy) -5-
(1H-tetrazol-5-yl) -pyridin-3-yl] -prop-2-en-1-amine 73.0 mg.
(0.159 mmol) was dissolved in methylene chloride, and chloroglyoxylic acid ethyl ester 33.0 mg (0.23 mmol) was dissolved.
39 mmol) and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was washed with water and acetonitrile to obtain the title compound. MS (ESI, m / z) 559 (MH +) 1H-NMR (DMSO-d6): 1.26 (3H, t), 2.43 (3H, s), 3.69
(5H, br), 4.21 (2H, q), 5.49 (1H, dt), 6.05 (2H,
s), 6.16 (1H, d), 6.53 (1H, q), 6.75-6.80 (3H, m),
6.88-6.91 (3H, m), 8.93 (1H, br t)

Example 114 1- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -Pyridin-3-yl] -allyl} -3-
Synthesis of phenyl-thiourea 3- [4- (4-methoxyphenyl) -2-methyl-6
-(3,4-methylenedioxy-phenoxy) -5-
(1H-tetrazol-5-yl) -pyridin-3-yl] -prop-2-en-1-amine 54.0 mg.
(0.118 mmol) was dissolved in dioxane, and 19.0 mg (0.141 mmol) of phenylisothiocyanate was dissolved.
l) was added and the mixture was stirred at 100 ° C for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform-methanol = 100: 1 to 10: 1) to obtain the title compound. MS (ESI, m / z) 594 (MH +) 1H-NMR (CD3OD): 2.51 (3H, s), 3.70 (3H, s), 4.17 (2
H, br d), 5.65 (1H, dt), 5.96 (2H, s), 6.25 (1H,
d), 6.48-6.63 (2H, m), 6.75-6.81 (3H, m), 6.97 (2
H, d), 7.17-7.22 (3H, m), 7.32-7.37 (2H, m)

Example 115 1- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -Pyridin-3-yl] -allyl} -3-
Synthesis of pyridin-4-yl-urea 3- [4- (4-methoxyphenyl) -2-methyl-6
-(3,4-methylenedioxy-phenoxy) -5-
(1H-tetrazol-5-yl) -pyridin-3-yl] -prop-2-en-1-amine 150 mg (0.
327 mmol) was dissolved in dioxane, and pyridine-4-
Carbamic acid phenyl ester 105 mg (0.49
1 mmol) and stirred at 100 ° C. for 24 hours.
The solvent was distilled off under reduced pressure, and the obtained residue was subjected to reversed-phase high-performance liquid chromatography using octadodecyl (ODS) group chemically bonded silica gel as a filler, containing 0.1% of trifluoroacetic acid. (V / v) The mixture was eluted with a mixed solvent of water-acetonitrile, and the target compound was lyophilized to give the title compound. Yield 85 mg (0.147 mmol) Yield 45% MS (ESI, m / z) 579 (MH +) 1H-NMR (CD3OD): 2.50 (3H, s), 3.62 (3H, s), 3.81 (2
H, d), 5.62 (1H, dt), 5.97 (2H, s), 6.28 (1H, d),
6.48-6.63 (2H, m), 6.71-6.79 (3H, m), 6.94 (2H, d),
7.89 (2H, d), 8.45 (2H, d)

Example 116 1- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -Pyridin-3-yl] -allyl} -3-
Synthesis of pyrazin-2-yl-urea 60.9 mg of pyrazine-2-carboxylic acid (0.491 m
mol) was dissolved in 10 ml of toluene, 72.5 mg (0.589 mmol) of diphenylphosphoryl azide and 59.6 mg (0.589 mmol) of triethylamine were added, and the mixture was stirred at 80 ° C. for 2 hours. Then 3- [4-
(4-methoxyphenyl) -2-methyl-6- (3,4
-Methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -prop-2-en-1-amine 150 mg (0.327 mmol
1) was added at 80 ° C., and the mixture was further stirred for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to reversed-phase high-performance liquid chromatography using octadodecyl (ODS) group chemically bonded silica gel as a packing material. % Of (v / v) mixed solvent of water-acetonitrile, and the target compound was lyophilized to obtain the title compound. Yield 32 mg (0.0552 mmol) Yield 17
% MS (ESI, m / z) 580 (MH +) 1H-NMR (CD3OD): 2.50 (3H, s), 3.59 (3H, s), 3.89 (2
H, br), 5.62 (1H, dt), 5.96 (2H, s), 6.25-6.93 (8
H, m), 8.13 (2H, d), 8.50 (1H, s)

Example 117 N- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -Pyridin-3-yl] -allyl} -2-
Synthesis of trichloro-acetamide 1) N- {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -Allyl｝ -2
Synthesis of 3-trichloro-acetamide 3- [5-cyano-4- (4-methoxyphenyl) -2
-Methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -prop-2-
200 g (0.481 mmol) of ene-1-amine was dissolved in 10 ml of dioxane, and hexachloroacetone 19 was dissolved.
1 mg (0.722 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane-
Purification by ethyl acetate (3: 1) gave the title compound. Yield 240 mg (0.428 mmol) Yield 8
9.0% MS (ESI, m / z) 560 (MH +) 1H-NMR (CDCl3): 2.44 (3H, s), 3.85 (3H, s), 3.92 (2
H, br), 5.46 (1H, dt), 6.01 (2H, s), 6.29 (1H, d),
6.59-6.82 (4H, m), 6.97 (2H, d), 7.23 (2H, d),

2) N- {3- [4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl)- Synthesis of pyridin-3-yl] -allyl} -2-trichloro-acetamide N- {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy) −
Phenoxy) -pyridin-3-yl] -allyl {-2-
240 mg of trichloro-acetamide (0.428 mm
ol) with 568 mg of tri-n-butyltin azide (1.
(71 mmol) and refluxed under heating for 2 days. After completion of the reaction, 4N hydrochloric acid-dioxane and ethyl acetate were added, and the precipitated crystals were filtered. The obtained crystals were subjected to silica gel column chromatography (chloroform-methanol = 20:
Purification in 1) gave the title compound. Yield 160 mg (0.265 mmol) Yield 6
2.0% MS (ESI, m / z) 603 (MH +) 1H-NMR (CD3OD): 2.49 (3H, s), 3.75 (3H, s), 3.86 (2
H, d), 5.58 (1H, dt), 5.96 (1H, s), 6.28 (1H, d),
6.48-6.63 (2H, m), 6.75-6.81 (3H, m), 6.93 (2H, d)

Example 118 5-Bromofuran-2-carboxylic acid {3- [4- (4-methoxyphenyl) -2]
Synthesis of -methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide 1) 5-bromo-furan- 2-carboxylic acid ｛3- [5
Synthesis of -cyano-4- (4-methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid of the example {3- [5-cyano-4- (4-methoxyphenyl) -2-methyl-6-
(3,4-Methylenedioxy-phenoxy) -pyridin-3-yl] -allyl} -amide. MS (ESI, m / z) 590 (MH +) 1H-NMR (CDCl3): 2.45 (3H, s), 3.81 (3H, s), 3.96 (2
H, t), 5.49 (1H, dt), 6.00 (2H, s), 6.17-6.28 (2
H, m), 6.45 (1H, d), 6.64-6.82 (3H, m), 6.94-7.05
(3H, m), 7.23 (1H, dt)

2) 5-bromofuran-2-carboxylic acid
{3- [4- (4-methoxyphenyl) -2-methyl-
6- (3,4-methylenedioxy-phenoxy) -5
Synthesis of (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide DL-pyroglutamic acid {3- [4- (4-
Methoxyphenyl) -2-methyl-6- (3,4-methylenedioxy-phenoxy) -5- (1H-tetrazol-5-yl) -pyridin-3-yl] -allyl} -amide Synthesized. 1H-NMR (CD3OD): 2.49 (3H, s), 3.66 (3H, s), 3.85
(2H, br d), 5.55 (1H, dt), 5.96 (2H, s), 6.28 (1H,
d), 6.48-6.62 (3H, m), 6.70 (2H, d), 6.76 (1H, d),
6.91 (2H, dt), 7.02 (1H, d)

The compounds synthesized above are shown in the following table.

[0395]

[Table 1]

[0396]

[Table 2]

[0397]

[Table 3]

[0398]

[Table 4]

[0399]

[Table 5]

[0400]

[Table 6]

[0401]

[Table 7]

[0402]

[Table 8]

[0403]

[Table 9]

[0404]

[Table 10]

[0405]

[Table 11]

[0406]

[Table 12]

[0407]

[Table 13]

[0408]

[Table 14]

[0409]

[Table 15]

The inhibitory activity of the compounds of the present invention on endothelin receptors can be demonstrated using the following test procedure.

(Test Example) Endothelin-1 antagonistic activity Endothelin-1 antagonistic activity was determined by activating the radioligand with [12
5I] endothelin-1 and the inhibitory activity of the pyridine derivative was measured by a receptor binding reaction using porcine ventricular fascia as a receptor.

1) Method for Preparing Porcine Ventricular Fascia The pig heart immediately after sacrifice was purchased, and only the ventricle was taken out.
After removing the surface blood vessel portion and the like, cut finely, buffer A
(20 mM NaHCO3, 0.1 mM PMSF, 1
mM EDTA) and homogenized three times with a homogenizer. Centrifuge the homogenate (1000g × 10m
in, 4 ° C.), and the precipitate was centrifuged again to obtain a supernatant. Further centrifuge (35,000 g)
× 20 min, 4 ° C.) to obtain a precipitate. This precipitate was washed with buffer B (50 mM Tris / HCl (pH 7.4),
0.1 mM phenylmethanesulfonyl fluoride (hereinafter abbreviated as PMSF) and 1 mM ethylenediaminetetraacetic acid (hereinafter abbreviated as EDTA) were added, homogenized with a homogenizer, and then centrifuged (35,000 g × 20 min, 4 μm).
° C) to obtain a precipitate. The precipitate was added with buffer B, homogenized again, and diluted and dispensed with buffer B to 0.2 g / 2 ml. This was frozen and stored at −80 ° C. until use as a membrane fraction containing the receptor.

2) Receptor binding reaction [125I] endothelin-1 (specific activity 81.4 TBq / mmol, concentration 2870 KBq /
200 μl) of the receptor membrane fraction 20
0 μl and 200 μl of each sample (buffer C (50 mM tris (hydroxymethyl) aminomethane (hereinafter abbreviated as Tris) / HCl (pH 7.4), 0.1 mM PMS
F, 1 mM EDTA, 0.1% bovine serum albumin (hereinafter abbreviated as BSA)) and 37
Stirred at 90 ° C. for 90 minutes. G / FB for cell harvester
A glass filter was set, and the reaction was terminated by washing the protein captured on the glass filter with a harvester three times with ice-cold buffer C. The amount of isotope remaining on the filter was measured for γ-ray with a γ-counter for a measurement time of 1 minute. The amount of non-specific binding was 0.1.
The measurement was performed using 1 μM of non-radioactive endothelin-1.

The inhibitory activities of the pyridine derivatives thus measured are shown in Table 1. The pIC50 value was determined based on the specific binding of [125I] endothelin-1 in the absence of the compound as a control, and the specific binding amount in the presence of the compound was 50%.
Shown as the negative logarithmic value of the concentration required to reduce.

[0415]

[Table 16]

As is clear from Table 16, the novel pyridine derivatives exhibited excellent endothelin-1 antagonistic activity.

[0417]

【The invention's effect】

The novel pyridine derivative of the present invention exhibited excellent endothelin-1 antagonistic activity. Therefore, the novel pyridine derivative of the present invention is hypertensive, Raynaud's disease, myocardial infarction, angina, cerebral infarction, cerebral vasospasm, arteriosclerosis, coronary restenosis, bronchial asthma, gastric ulcer, acute liver failure, diabetes, prostatic hypertrophy,
It can be used as a therapeutic drug for endoxin shock, multiple organ failure, disseminated intravascular coagulation, acute renal failure, cyclosporine-induced renal damage, and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/44 ADD A61K 31/44 ADD ADP ADP AED AED 31/47 ABU 31/47 ABU 31/505 ABN 31/505 ABN 31/535 ABX 31/535 ABX C07D 405/04 213 C07D 405/04 213 405/12 213 405/12 213 405/14 213 405/14 213 409/14 213 409/14 213 413/14 213 413/14 213 417/14 213 417/14 213 (72) Inventor Hirohisa Uchida 1-1, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Ajinomoto Co., Inc.

Claims (5)

[Claims] 1. A pyridine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof. Embedded image [Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ may be the same or different, and any two may be combined to form a ring, and include a hydrogen atom, a halogen atom, a hydroxyl group , Amino group, nitro group, lower alkyl group, lower alkoxy group,
Lower alkenyl group, lower alkylamino group, lower alkylthio group, lower alkanoyl group, hydroxy lower alkyl group, hydroxy lower alkoxy group, hydroxy lower alkenyl group, halogeno lower alkyl group, halogeno lower alkoxy group, halogeno lower alkenyl group, aryl lower alkoxy group, or represents one of the aroyl group, R ⁶
Represents an acidic functional group, and R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be the same or different, and any two may be bonded to form a ring; Atom, hydroxyl group, amino group, nitro group, lower alkyl group, lower alkoxy group, lower alkenyl group, lower alkylamino group, lower alkylthio group, lower alkanoyl group, hydroxy lower alkyl group, hydroxy lower alkoxy group,
Represents a hydroxy lower alkenyl group, a halogeno lower alkyl group, a halogeno lower alkoxy group, a halogeno lower alkenyl group, an aryl lower alkoxy group, or an aroyl group, and R ¹² represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group. A lower alkyl group, a lower alkoxy group, a lower alkenyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a hydroxy lower alkenyl group, a halogeno lower alkyl group, and a halogeno lower alkoxy group , A halogeno lower alkenyl group, an aryl lower alkoxy group, an aroyl group, an aryl group, a heteroaryl group, or a heterocyclylcarbonyl group. X represents any of the following formulas (2) to (5); (However, R ¹³ , R ¹⁴ , and R ¹⁵ may be the same or different and each represents a hydrogen atom or a lower alkyl group.) Y represents any of the following formulas (6) to (9); Chemical formula 3] (However, R ¹⁶ , R ¹⁷ and R ¹⁸ may be the same or different and each represents a hydrogen atom or a lower alkyl group.) Z is a hydrogen atom, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, Aryloxycarbonyl group, heteroaryloxycarbonyl group, alkylcarbamoyl group, arylcarbamoyl group, heteroarylcarbamoyl group, amino group, alkylamino group, arylamino group, heteroarylamino group, acylamino group or the following formulas (10) to ( 15). Embedded image (However, R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ ,
R ²⁶ , R ²⁷ , and R ²⁸ may be the same or different and each represents a hydrogen atom, a lower alkyl group, an aryl group, or a heteroaryl group, where R ^19, R ²⁰ , and R ²¹ And R ²² , R ²¹ and R ²³ , R ²² and R ²³ , or R ²⁵ and R ²⁶ may combine to form a ring. M) represents an integer of 0 or 1, and n represents an integer of 0 to 3. ] 2. The acidic functional group of R ⁶ is a carboxyl group, S
_{O 3 H, PO 3 H 2} , tetrazol-5-yl group, a sulfonamido group, 2-oxo-3H-1,2,3,5- oxathiadiazol-4-yl group, or a 5-oxo -4H
The pyridine derivative according to claim 1, which is any of a -1,2,4-oxadiazol-3-yl group, or a pharmaceutically acceptable salt thereof. 3. The pyridine derivative according to claim 1, wherein the acidic functional group of R ⁶ is a carboxyl group or a tetrazol-5-yl group, or a pharmaceutically acceptable salt thereof. 4. The pyridine derivative or the pharmaceutically acceptable salt thereof according to claim 3, wherein m = n = 1, Y is represented by the formula (9), and R ¹⁷ and R ¹⁸ are both hydrogen atoms. . 5. An endothelin antagonist comprising the pyridine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.