JPH08245590A - Sulfonamide derivative and medicinal preparation containing the same - Google Patents

Abstract

PURPOSE: To obtain an unknown sulfonamide derivative which is useful as an antithrombotic and an antiallergic due to its thromboxane A2 synthesis inhibitory action, thromboxane A2 and prostaglandin H antagonistic action and antiplatelet coagulation action. CONSTITUTION: This sulfonamide derivative is represented by formula I [X is H, hydroxyl, a halogen, nitro; Z is the formula: -O-(CH2 )m -CH (m is an integer of 0-4), -N(R<1> )-(CH2 )m -CH- (R<1> is H, a lower alkyl, phenyl); R is the formula: -(CH2 )n -COOR<2> (n is an integer of 0-4; R<2> is a lower alkyl, H) ], for example, 3-(4- 1-(4-chlorobenzene-sulfonamidemethyl)-4-[(3-pyridyl)amino]butyl}phenyl) propionic acid. For example, when a compound of formula II (m is an integer of 1-3) is used as a starting substance, a compound of formula III (R<1> is an alkoxycarbonyl; R<2> is methyl, ethyl) is obtained as a compound of formula I and the product is hydrolyzed to give another compound of formula I.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel sulfonamide derivative, a thromboxane A ₂ synthesis inhibitor containing the same, a thromboxane A ₂ antagonist, a prostaglandin H ₂ antagonist, an antithrombotic agent and an antiallergic agent. It is related to agents.

[0002]

2. Description of the Related Art Thrombosis such as myocardial infarction and cerebral infarction has been increasing in recent years, and it has been strongly desired to develop an antithrombotic drug that effectively prevents the thrombosis. The cause of these diseases is thromboxane A ₂ (TX), which is a strong platelet aggregating substance produced by cells such as platelets.
A ₂ ) plays an important role, and it is known that inhibiting this action is an effective means for preventing thrombus formation. Also, for allergies and asthma, TXA ₂
And chemical mediators such as leukotriene D ₄ (LTD ₄ ) are involved as smooth muscle contractile substances.
Suppressing the action of ₂ is one of the effective means for treating late-onset asthma.

[0003] For these reasons, synthetic inhibitors and TXA ₂ antagonists such as inhibiting the production of TXA ₂ are already known, all of which contain the problem. For example, Dazoxiben, Ozagrell
Since a biosynthesis inhibitor such as el) inhibits thromboxane synthase, it conversely accumulates prostaglandin H ₂ (PGH ₂ ) which is a substrate of this enzyme. PGH
₂ itself has a platelet aggregation action and a smooth muscle contraction action like TXA _2, and prostaglandins such as PGE ₂ produced from PGH ₂ also have a similar action. Therefore, despite inhibiting the production of TXA ₂ , it produces platelet aggregates and smooth muscle contractile substances instead of them, which is considered to be the reason for reducing the effect of the actual drug by half. On the other hand, since TXA ₂ antagonists such as S-145 and Daltroban antagonize the TXA ₂ receptor, when the amount of TXA ₂ produced is small, it shows an effective inhibitory effect by antagonizing this.
_{If 2} is overproduced, its effectiveness is diminished. Therefore, in such a case, it becomes necessary to inhibit the production itself of TXA ₂ .

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
₍₂₎ An object of the present invention is to provide a drug having a TXA ₂ and PGH ₂ antagonistic action as well as a synthetic inhibitory action.

[0005]

The present inventors have SUMMARY OF THE INVENTION synthesizes a novel sulfonamide derivative, a result of examining their pharmacological activity intensive, certain derivatives are TXA ₂ and PGH ₂ antagonists with TXA ₂ synthesis inhibition It has been found to have an action. The present invention is as follows.

(1) A sulfonamide derivative represented by the general formula (I) and its optical isomers and pharmaceutically acceptable salts thereof.

[0007]

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(In the formula I, X is a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, a trifluoromethyl group,
A lower alkyl group or a lower alkoxy group, Z is the formula _{-O- (CH 2) m -CH -} , - N (R 1) - (CH 2) m -C
^{H -, - C (R 1} ) = CH-CH =, - C (R 1) = CH-C
H ₂ — or —C (R ¹ ) — (CH ₂ ) _m —CH—, and R
The formula ^{_{- (CH 2) n -COOR 2}} , -O- (CH 2) n -COO
R ² or a lower alkoxy group is shown. n and m each independently represent an integer of 0 to 4, R ¹ represents a hydrogen atom, a lower alkyl group or a phenyl group, and R ²
Means a lower alkyl group or a hydrogen atom. )

(2) A thromboxane A ₂ synthesis inhibitor containing the sulfonamide derivative described in (1) above. (3) A thromboxane A ₂ antagonist containing the sulfonamide derivative according to (1) above.

(4) A prostaglandin H ₂ antagonist containing the sulfonamide derivative according to (1) above. (5) An antithrombotic agent containing the sulfonamide derivative according to (1) above. (6) An antiallergic agent containing the sulfonamide derivative according to (1).

The sulfonamide derivative of the present invention is TXA ₂
It also has a synthetic inhibitory effect and a TXA ₂ antagonistic effect. Therefore, while the production of TXA ₂ is suppressed and the production of its precursor PGH ₂ is increased, it simultaneously antagonizes the PGH ₂ receptor and the TXA ₂ receptor, so that both effects can be inhibited. Therefore, the sulfonamide derivative of the present invention is useful as a therapeutic or prophylactic drug for various TXA ₂ pathological conditions such as thrombosis and allergies.

In the general formula (I), X is a hydrogen atom, a halogen atom (preferably a chlorine atom or a fluorine atom), a lower alkyl group (preferably a methyl group, an ethyl group, a propyl group or an isopropyl group). ),
Lower alkoxy group (preferably toxy group or ethoxy group), hydroxy group, nitro group, cyano group,
Alternatively, it represents a trifluoromethyl group. Z is -O- (C
H _{2) m} -CH- _(m is an integer of 0 to 4, preferably 3 or ^{4), - N (R 1} ) - (CH 2) m
-CH- (R ¹ represents a hydrogen atom, a lower alkyl group or a phenyl group, preferably a hydrogen atom or a methyl group, and m represents an integer of 0 to 4, preferably 3 or 4. Yes), -C (R ¹ ) = CH-C
H = (R ¹ represents a hydrogen atom, a lower alkyl group or a phenyl group, preferably a hydrogen atom or a phenyl group), —C (R ¹ ) ═CH—CH ₂ — (R ¹ is
A hydrogen atom, a lower alkyl group or a phenyl group is meant, preferably a hydrogen atom or a phenyl group)
Or ^{-C (R 1) - (CH} 2) m -CH- (R 1 is a hydrogen atom, means a lower alkyl group or a phenyl group,
It is preferably a hydrogen atom or a methyl group, m is an integer of 0 to 4, preferably 3 or 4, and R is — (CH ₂ ) _n —COOR ² (n is 1 to 4). Is preferably 2 and R ² is a hydrogen atom or a lower alkyl group, preferably a hydrogen atom), —O— (CH ₂ ) _n —COOR ² (n
Means an integer from 1 to 4, but is preferably 1,
R2 means a hydrogen atom or a lower alkyl group,
It is preferably a hydrogen atom) or a lower alkoxy group (preferably a methoxy group or an ethoxy group).

The sulfonamide derivative of the present invention may be a pharmaceutically acceptable salt thereof. Examples of such salts include salts with alkali metals such as sodium and potassium, alkali salts such as calcium and magnesium. Salts with earth metals, salts with organic bases such as ammonium, triethylamine, tromethamine, dicyclohexylamine, salts with organic acids such as acetic acid, tartaric acid, methanesulfonic acid, toluenesulfonic acid, inorganics such as hydrochloric acid, sulfuric acid, nitric acid Salt with acid,
Alternatively, salts with amino acids such as arginine, lysine and aspartic acid are included. The sulfonamide derivative of the present invention may be an optical isomer.

In the general formula (I), X is a chlorine atom and Z
There formula ^{-N (R 1) - (CH} 2) m -CH- ( wherein, R ¹ represents a hydrogen atom, a lower alkyl group or an alkoxycarbonyl group, m is an integer from 1 3), R is the formula - (CH _{2) 2} -
The sulfonamide derivative of the present invention represented by COOR ² (wherein R ² represents a lower alkyl group or a hydrogen atom) is synthesized by the following method.

Compounds of general formula (II) (wherein m is 1
To an integer of 3) are halogenated with a halogenating agent and the amine moiety is protected to give a compound of the general formula (III) (formula III
Wherein R ¹ represents an alkoxycarbonyl group or a lower alkyl group, X represents a halogen atom, and m represents an integer of 1 to 3).

[0016]

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[0017]

[Chemical 4]

Next, the compound of the general formula (III) is reacted with p- (cyanomethyl) benzaldehyde dimethyl acetal in the presence of a base, and the obtained acetal derivative is treated with an acid to give the general formula (IV). (In the formula IV, R ¹ represents an alkoxycarbonyl group or a lower alkyl group, m
Represents an integer of 1 to 3).

[0019]

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Next, the Horner-witt of the compound of the general formula (IV) and alkyl dimethylphosphonoacetate in the presence of a base.
ig reaction is carried out, and in the general formula (V) (in the formula V, R ¹ represents an alkoxycarbonyl group or a lower alkyl group, R ² represents a methyl group or an ethyl group, and m represents an integer of 1 to 3). The compound represented is obtained.

[0021]

[Chemical 6]

Next, the compound of the general formula (V) is partially catalytically reduced to obtain a propionic acid ester derivative, and then the cyano group is catalytically reduced to give a compound of the general formula (VI) (in the formula VI, R ¹ is an alkoxycarbonyl group). Or a lower alkyl group, R ²
Represents a methyl group or an ethyl group, and m represents an integer of 1 to 3).

[0023]

[Chemical 7]

Next, by reacting the compound of the general formula (VI) with p-chlorobenzenesulfonyl chloride, in the general formula (I) sulfonamide derivative, X is a chlorine atom,
Z is the formula ^{-N (R 1) - (CH} 2) m -CH- ( wherein, R ¹ represents a lower alkyl group or an alkoxycarbonyl group, m is an integer from 1 3), R is formula - (CH ₂ ) ₂ -COOR ²
(Wherein R ² represents a lower alkyl group or a hydrogen atom), and is represented by general formula (VII) (wherein R ¹ represents an alkoxycarbonyl group or a lower alkyl group, and R ² represents a methyl group or an ethyl group. And m is an integer of 1 to 3), and the sulfonamide derivative of the present invention can be obtained. Further, this compound can be hydrolyzed according to a conventional method to obtain another compound represented by the general formula (I).

[0025]

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In the general formula (I) of the present invention, X
Is a chlorine atom, and Z is a formula —O— (CH ₂ ) _m —CH— (in the formula, m
Represents an integer of 2 to 4), R is formula - (CH _{2) 2} -COO
The sulfonamide derivative of the present invention represented by R ² (wherein R ² represents a lower alkyl group or a hydrogen atom) is synthesized by the following method.

General formula (VIII) (wherein m is 2 to 4)
Of the compound) is reacted with p- (cyanomethyl) benzaldehyde dimethyl acetal in the presence of a base and then acid-treated to give a compound of the general formula (IX) (wherein m is 2
To an integer of 4) is obtained.

[0028]

[Chemical 9]

[0029]

[Chemical 10]

Then, the compound of general formula (IX) is reacted with alkyl dimethylphosphonoacetate in the presence of a base to give general formula (X) (in the formula X, R ¹ represents a methyl group or an ethyl group, and m is A compound represented by the formula (indicating an integer of 2 to 4) is obtained.

[0031]

[Chemical 11]

Next, the compound of the general formula (X) is partially catalytically reduced to obtain a propionic acid ester derivative, and then the cyano group is catalytically reduced to give a compound of the general formula (XI) (in the formula XI, R ¹ is a methyl group or An ethyl group and m represents an integer of 2 to 4).

[0033]

[Chemical 12]

Next, the compound of the general formula (XI) is reacted with p-chlorobenzenesulfonyl chloride in the presence of a base, and in the general formula (I), X is a chlorine atom and Z is a formula -O.
In (CH _{2) 2} -COOR ² (wherein, R ² is a lower alkyl _{group) - - (CH 2) m} -CH- ( wherein, m represents an integer of 2 to 4), R is formula There is a general formula (XII) (in formula XII,
R ¹ represents a methyl group or an ethyl group, and m represents an integer of 2 to 4) to obtain the sulfonamide derivative of the present invention. Further, according to a conventional method, this compound can be hydrolyzed to obtain another compound represented by the general formula (I).

[0035]

[Chemical 13]

In the general formula (I) of the present invention, X
Is a chlorine atom, Z is of the formula -C (R ¹ ) = CH-CH =, -C (R
¹ ) = CH—CH ₂ — or —CH (R ¹ ) —CH ₂ —CH ₂
-(In the formula, R ¹ represents a hydrogen atom, a phenyl group or a methyl group), and R represents the formula-(CH ₂ ) _2- COOR ² (R ²
Represents a lower alkyl group or a hydrogen atom), and the sulfonamide derivative of the present invention is synthesized by the following method.

In the presence of a base, the compound of the general formula (XIII) (in the formula XIII,
R ¹ represents a hydrogen atom, a phenyl group or a methyl group)
By conducting Horner-wittig reaction between the compound of formula ( ¹ ) and alkyl dimethylphosphonoacetate or diethyl cyanomethylphosphonate, the compound of general formula (XIV) (in formula XIV, R ¹ represents a lower alkoxycarbonyl group or a nitrile group, and R ² represents a hydrogen atom). , A phenyl group or a methyl group).

[0038]

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[0039]

[Chemical 15]

Next, the compound of the general formula (XIV) is converted to an aldehyde using a reducing agent, and then reacted with p- (cyanomethyl) cinnamic acid ester to give the compound of the general formula (XV) (in the formula XV, R ¹
It is ^{-C (R 3) = CH-} CH =, - C (R 3) = CH-CH 2
- or _{^{-CH (R 3) -CH 2 -CH}} 2 - ( provided that, R ³
Represents a hydrogen atom, a phenyl group or a methyl group), and R ₂ represents a lower alkyl group).

[0041]

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Next, the compound of the general formula (XV) is partially catalytically reduced, and the cyano group of the obtained compound is catalytically reduced to give a compound of the general formula (XVI) (in the formula XVI, R ¹ is —C (R ³ )). = CH-CH
^{=, - C (R 3)} = CH-CH 2 - or -CH (R ³⁾ -
A compound represented by CH ₂ —CH ₂ — (wherein R ³ represents a hydrogen atom, a phenyl group or a methyl group) and R ₂ represents a lower alkyl group) is obtained.

[0043]

[Chemical 17]

Then, the compound of the general formula (XVI) and p-chloro
Reaction with lobenzenesulfonyl chloride to give a compound of the general formula
In (I), X is a chlorine atom and Z is a formula-C (R¹) = C
H-CH =, -C (R¹) = CH-CH₂-Or-CH
(R¹) -CH₂-CH₂-(In the formula, R¹Is a hydrogen atom, pheny
Group or a methyl group), and R is of the formula-(C
H₂) ₂-COOR²(R²Is a lower alkyl group)
There is a general formula (XVII) (in the formula XVII, R¹Is -C (R³) = C
H-CH =, -C (R³) = CH-CH₂-Or-CH
(R³) -CH₂-CH₂-(However, R³Is a hydrogen atom,
Represents a nyl group or a methyl group), and R₂Is a lower class
A sulfonamide of the present invention represented by
Derivatives can be obtained. In addition, this
The compound is hydrolyzed to give another compound represented by the general formula (I).
You can get a compound.

[0045]

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Examples of the solvent, base and reduction catalyst that can be used in the present invention are as follows. The solvent is selected from, for example, 1,4-dioxane, ethyl acetate, methanol, ethanol, acetone, methylene chloride, chloroform, N, N-dimethylformamide, tetrahydrofuran, etc., and is used as appropriate, alone or mixed according to the reaction method or purification method. Can be used below. As the base, for example, sodium hydroxide, sodium alkoxide, triethylamine and the like can be appropriately selected and used.
Examples of the reducing catalyst include Raney nickel and Raney cobalt.

The sulfonamide derivative of the present invention is a thromboxane A ₂ antagonist, a prostaglandin H ₂ antagonist,
It is used as a thromboxane A ₂ synthesis inhibitor and a prophylactic agent effective against diseases caused by thromboxane A ₂ , such as an antithrombotic agent and an antiallergic agent. The dose is from 10 to 600 mg, preferably from 1 to 200 mg, and can be administered in 1 to 3 divided doses as needed depending on the symptoms. The administration method can be any form suitable for administration, and oral administration is particularly preferable, but intravenous injection is also possible.

The sulfonamide derivative of the present invention is used as an active ingredient or one of the active ingredients, alone or in combination with a pharmaceutical carrier, according to a known formulation technique such as tablets, powders, capsules,
Granules, syrups, solutions, suspensions, injections, eye drops,
Alternatively, it may have any formulation suitable for administration of suppositories and the like. Specific formulation carriers include starches,
Excipients such as sucrose, lactose, methyl cellulose, carboxymethyl cellulose, crystalline cellulose, sodium alginate, calcium hydrogen phosphate, magnesium aluminometasilicate, silicic acid anhydride, and synthetic aluminum silicate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Binders such as gelatin and polyvinylpyrrolidone, carboxymethylcellulose calcium, disintegrating agents such as crosslinked sodium carboxymethylcellulose and crosslinked polyvinylpyrrolidone, lubricants such as magnesium stearate and talc, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate , Coating agents such as methacrylic acid and methyl methacrylate copolymers, polyethylene glycol, etc. Desolvation aid, sodium lauryl sulfate, lecithin, sorbitan monooleate, polyoxyethylene cetyl ether, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil and emulsifiers such as glyceryl monostearate, chelating agents such as EDTA, buffering agents, Moisturizers, preservatives, cocoa butter and witebsol W
Examples include bases such as 35.

[0049]

EXAMPLES The present invention will now be described more specifically by showing Examples and Test Examples, but the present invention is not limited to these. (Example 1) Synthesis of 3- (4- {1- (4-chlorobenzenesulfonamidomethyl) -4-[(3-pyridyl) amino] butyl} phenyl) propionic acid i) Under ice-cooling, 3- Thionyl chloride (5.9 ml) was added to a chloroform solution of [(3-pyridyl) amino] propanol (3.11 g), and the mixture was stirred at room temperature for 1 hour.
The mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ether. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-chloro-1-[(3-pyridyl) amino] propane (3.60 g) as a crude composition product.

Ii) Under ice cooling, 4-chloro-1-
A solution of [(3-pyridyl) amino] propane (3.60 g) in N, N-dimethylformamide was gently mixed with 1.7 M butyllithium-hexane solution (13.1 ml) and ethyl chlorocarbonate (2.9 ml). added. After stirring at room temperature for 8 hours, saturated saline was added and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
1) 3-Chloro-1- [ethoxycarbonyl (3-pyridyl) amino] propane (1.96 g) was obtained from the eluted fraction.

Iii) Diisopropylamine (0.98
The tetrahydrofuran solution of g) was cooled to -50 ° C,
1.7 M butyllithium-hexane solution (5.66 ml)
After stirring for 10 minutes, 4- (cyanomethyl) benzaldehyde dimethyl acetal (1.85 g) in tetrahydrofuran, hexamethylphosphoric acid triamide (8.40 ml) and 1-chloro-3- [ethoxycarbonyl (3-pyridyl) Amino] propane (1.9
6 g) of tetrahydrofuran solution were added respectively, and -5
After stirring at 0 ° C. for 1 hour, the mixture was further stirred at room temperature for 11 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, ethyl acetate-
From the elution fraction of hexane (2: 1), 4- {1-cyano-4
-[Ethoxycarbonyl (3-pyridyl) amino] butyl} benzaldehyde dimethyl acetal (2.04
g) was obtained.

Iv) 4- {1-Cyano-4- [ethoxycarbonyl (3-pyridyl) amino] butyl} benzaldehyde To a solution of dimethyl acetal (2.04 g) in methanol was added 6N hydrochloric acid (4 ml), and the mixture was brought to room temperature. 18
After stirring for an hour, the reaction solution was concentrated. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 4- {1-cyano-4- [ethoxycarbonyl (3-pyridyl) amino]
Butyl} benzaldehyde (1.53 g) was obtained.

V) Methyl dimethylphosphonoacetate (0.81 ml) was gently added to a solution of 60% sodium hydride (0.20 g) in N, N-dimethylformamide under ice cooling.
After stirring for 0 minutes, a solution of 4- {1-cyano-4- [ethoxycarbonyl (3-pyridyl) amino] butyl} benzaldehyde (1.46 g) in N, N-dimethylformamide was added dropwise at room temperature for 10 hours. Allowed to stir. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 4- {4- {1-cyano-4- [ethoxycarbonyl (3 Methyl -pyridyl) amino] butyl} cinnamate (1.59 g) was obtained.

Vi) Methyl 4- {4- {1-cyano-4- [ethoxycarbonyl (3-pyridyl) amino] butyl} cinnamate (1.59 g) in 1,4-dioxane was added with 10% palladium-. Carbon (0.32 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 36 hours. The reaction solution was filtered under reduced pressure and the solvent was distilled off under reduced pressure to give 3- (4- {1-cyano-4-
Methyl [ethoxycarbonyl (3-pyridyl) amino] butyl} phenyl) propionate (1.61 g) was obtained.

Vii) 3- (4- {1-cyano-4-
Raney nickel (1.6) was added to saturated ammoniacal methanol of methyl [ethoxycarbonyl (3-pyridyl) amino] butyl} phenyl) propionate (1.61 g).
g) is added and the autoclave is operated at room temperature under 15 atm
After catalytic reduction for an hour, the reaction solution was filtered under reduced pressure. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 3- (4) was obtained from the fraction eluted with chloroform-methanol-aqueous ammonia (100: 10: 1).
-{1-aminomethyl-4- [ethoxycarbonyl (3
Methyl -pyridyl) amino] butyl} phenyl) propionate (0.88 g) was obtained.

Viii) 3- (4- {1-aminomethyl-
A solution of methyl 4- [ethoxycarbonyl (3-pyridyl) amino] butyl} phenyl) propionate (0.88 g) in methylene chloride was treated with triethylamine (0.33 ml) and p-chlorobenzenesulfonyl chloride (0.44 ml).
9 g) was added, and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction solution, extraction was performed with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and extracted with a chloroform-methanol (100: 1) elution fraction to give 3
Methyl-(4- {1- (4-chlorobenzenesulfonamidomethyl) -4- [ethoxycarbonyl (3-pyridyl) amino] butyl} phenyl) propionate (1.2
0 g) was obtained.

Ix) Ethylene glycol solution of methyl 3- (4- {1- (4-chlorobenzenesulfonamidomethyl) -4- [ethoxycarbonyl (3-pyridyl) amino] butyl} phenyl) propionate (1.20 g) 2N aqueous sodium hydroxide solution (0.3 ml) was added to and the mixture was stirred at 100 ° C. overnight. Water was added to the reaction solution and washed with ethyl acetate. The aqueous layer was made weakly acidic with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3- (4- {1- (4-chlorobenzenesulfonamidomethyl) -4-[(3-pyridyl) amino] butyl} phenyl) propionic acid (0.08 g) as a colorless amorphous substance. It was The spectroscopic data for this support the following structural formula (XVIII).

¹ H NMR (CDCl ₃ ) δ = 1.38-
1.58 (2H, m), 1.72-1.81 (1H, m),
2.63-2.68 (1H, m), 2.68-2.68 (1
H, m), 2.70 (2H, t, J = 6.78Hz), 2.84
-3.03 (3H, m), 2.97 (2H, t, J = 6.78)
Hz), 3.24-3.28 (1H, m), 6.80-6.8
4 (1H, m), 6.94 (2H, d, J = 8.06Hz),
7.03-7.08 (1H, m), 7.18 (2H, d, J =
8.06Hz), 7.33-7.36 (1H, m), 7.41
-7.46 (2H, m), 7.65-7.69 (2H,
m), 7.81-7.84 (1H, m) IR (KBr Disk) cm ^-1 : 3600-3000,
1718, 1330, 1162

[0059]

[Chemical 19]

Example 2 Synthesis of 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4- (3-pyridyloxy) butyl] phenyl} propionic acid i) 3-hydroxypyridine (15. Bromochloropropane (49.66 g) and anhydrous potassium carbonate (43.54 g) were added to an acetone solution of 00 g) and the mixture was heated under reflux for 4 hours. After cooling, the reaction solution was filtered under reduced pressure and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography, and 1-chloro-3- (3-pyridyloxy) propane (8.46 g) was obtained from the fraction eluted with ethyl acetate-hexane (2: 3).

Ii) Diisopropylamine (1.22)
The tetrahydrofuran solution of g) was cooled to -50 ° C,
After adding 1.7 M butyl lithium-hexane solution (7.8 ml) and stirring for 5 minutes, 4- (cyanomethyl) benzaldehyde dimethyl acetal (1.93 g) in N, N was added.
-Dimethylformamide solution, hexamethylphosphoric acid triamide (9.2 ml) and 1-chloro-3- (3-pyridyloxy) propane (8.46 g) in N, N-dimethylformamide solution were added respectively, and at -50 ° C. After stirring for 1 hour, the mixture was further stirred at room temperature overnight. Water was added to the reaction solution and extracted with ethyl acetate, the organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1:
1) 4- [1-cyano-4- (3-pyridyloxy) butyl] benzaldehyde dimethyl acetal (1.10 g) was obtained from the eluted fraction.

Iii) 4- [1-Cyano-4- (3-pyridyloxy) butyl] benzaldehyde To a methanol solution of dimethyl acetal (1.10 g) was added 6N hydrochloric acid (2.2 ml), and the mixture was stirred at room temperature for 4 hours. After stirring for an hour, the reaction solution was concentrated. A saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 4- [1-cyano-4- (3-pyridyloxy) butyl] benzaldehyde (0.94 g).

Iv) Methyl dimethylphosphonoacetate (0.60 ml) was gently added to a solution of 60% sodium hydride (0.20 g) in N, N-dimethylformamide under ice cooling, and the mixture was stirred for 10 minutes. [1-Cyano-4- (3-
Pyridyloxy) butyl] benzaldehyde (0.94
The N, N-dimethylformamide solution of g) was added dropwise, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 4- [1-cyano-4- (3-pyridyloxy) butyl was obtained from the ethyl acetate-hexane (2: 1) elution fraction. ] Methyl cinnamate (0.74 g) was obtained.

V) A solution of methyl 4- [1-cyano-4- (3-pyridyloxy) butyl] cinnamate (0.74 g) in 1,4-dioxane was added with 10% palladium-carbon (0.74 g).
22 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere.
The reaction solution was filtered under reduced pressure and the solvent was distilled off under reduced pressure to give 3- {4-
Methyl [1-cyano-4- (3-pyridyloxy) butyl] phenyl} propionate (0.79 g) was obtained.

Vi) 3- {4- [1-cyano-4- (3
Raney nickel (0.79 g) was added to saturated ammoniacal methanol of methyl-pyridyloxy) butyl] phenyl} propionate (0.79 g), and the mixture was catalytically reduced in an autoclave at room temperature and 10 atm for 2 days, and then the reaction solution was depressurized. Filtered. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 3- {4- [1-aminomethyl-4] was extracted from the fraction eluted with chloroform-methanol-aqueous ammonia (100: 10: 1). -(3-
Methyl pyridyloxy) butyl] phenyl} propionate (0.11 g) was obtained.

Vii) 3- {4- [1-aminomethyl-
Triethylamine (0.33 ml) and P-chlorobenzenesulfonyl chloride (0.46 g) were added to a methylene chloride solution of methyl 4- (3-pyridyloxy) butyl] phenyl} propionate (0.11 g), and the mixture was stirred at room temperature overnight. did. Water was added to the reaction solution and extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and chloroform-methanol (10
0: 2) From the eluted fraction, methyl 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4- (3-pyridyloxy) butyl] phenyl} propionate (0.
11 g) was obtained.

Viii) Methyl 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4- (3-pyridyloxy) butyl] phenyl} propionate (0.1
2N aqueous sodium hydroxide solution (0.17 ml) was added to a methanol solution of 1 g), and the mixture was stirred at 50 ° C. for 4 hours.
The reaction solution was concentrated, water was added to the residue and the mixture was washed with ethyl acetate. The aqueous layer was made weakly acidic with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 3- {4-
[1- (4-chlorobenzenesulfonamidomethyl)-
4- (3-Pyridyloxy) butyl] phenyl} propionic acid (0.10 g) was obtained as a colorless amorphous.
The spectroscopic data for this support the following structural formula (XIX).

¹ H NMR (CDCl ₃ ) δ = 1.56-
1.72 (3H, m), 1.83-1.94 (1H, m),
2.62 (1H, t, J = 7.70Hz), 2.68-2.77
(1H, m), 2.92 (1H, t, J = 7.70Hz), 2.
97-3.04 (1H, m), 3.18-3.24 (1H,
m), 3.86-3.91 (2H, m), 6.98-7.0.
2 (2H, m), 7.12-7.16 (2H, m), 7.1
6-7.20 (1H, m), 7.22-7.28 (1H,
m), 7.43-7.47 (2H, m), 7.67-7.7
1 (2H, m), 8.04-8.07 (2H, m) IR (KBr Disk) cm ^-1 : 3600-3200,
1710, 1326, 1100

[0069]

Embedded image

Example 3 Synthesis of 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -5- (3-pyridyloxy) pentyl] phenyl} propionic acid The bromochloropropane was replaced by bromochlorobutane. Except for the above, the same operation as in Example 2 is performed and 3- {4- [1-
(4-chlorobenzenesulfonamidomethyl) -5-
(3-Pyridyloxy) pentyl] phenyl} propionic acid was obtained. The spectroscopic data for this support the following structural formula (XX).

¹ H NMR (CDCl ₃ ) δ = 1.10-
1.31 (2H, m), 1.52-1.75 (4H, m),
2.61-2.70 (3H, m), 2.93-3.01 (3
H, m), 3.24-3.29 (1H, m), 3.89-
3.93 (2H, m), 4.46 (1H, brS), 6.9
2-6.94 (2H, m), 7.13-7.26 (3H,
m), 7.42-7.46 (2H, m), 7.65-7.6
9 (2H, m), 8.11-8.60 (2H, m), 7.4
3-7.47 (2H, m) IR (KBr Disk) cm ^-1 : 3000-3600,
1718, 1340, 1163

[0072]

[Chemical 21]

Example 4 Synthesis of 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -3- (3-pyridyloxy) propyl] phenyl} propionic acid The bromochloropropane was replaced by bromochloroethane. Otherwise, the same operation as in Example 2 is performed and 3- {4- [1-
(4-chlorobenzenesulfonamidomethyl) -3-
(3-Pyridyloxy) propyl] phenyl} propionic acid was obtained. Its spectroscopic data support the following structural formula (XXI).

¹ H NMR (CDCl ₃ ) δ = 1.86-
1.97 (1H, m), 2.13-2.23 (1H, m),
2.66 (2H, t, J = 7.7Hz), 2.93 (2H, t,
J = 7.7 Hz), 2.90-3.02 (1H, m), 3.0
9 (1H, dd, J = 9.0, 12.4Hz), 3.32 (1
H, dd, J = 5.7, 12.4 Hz), 3.71-3.80
(1H, m), 3.82-3.91 (1H, m), 6.95
(2H, d, J = 8.1Hz), 7.13 (2H, d, J = 8.
1Hz), 7.09-7.14 (1H, m), 7.21 (1
H, dd, J = 4.6, 8.4 Hz), 7.44 (2H, d, J =
8.5Hz), 7.69 (2H, d, J = 8.5Hz), 8.04
(1H, d, J = 2.7Hz), 8.15 (1H, d, J = 4.
6 Hz) IR (KBr Disk) cm ^-1 : 3400-2800,
2930, 1722, 1582, 1282, 1164
1100

[0075]

[Chemical formula 22]

Example 5 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4-phenyl-4- (3-pyridyl) butadienyl] phenyl} propionic acid, and 3- {4-
[1- (4-chlorobenzenesulfonamidomethyl)-
4-phenyl-4- (3-pyridyl) -3-butenyl]
Synthesis of phenyl} propionic acid i) Under a nitrogen atmosphere, sodium metal (1.26 g) was washed with hexane and added to absolute ethanol (200 ml),
Ethoxide. Ethyl diethylphosphonoacetate (11.73 g) was added thereto, 3-benzoylpyridine (6.00 g) was further added, and the mixture was refluxed for 6 hours. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and Z / of ethyl 3-phenyl-3- (3-pyridyl) acrylate was extracted from the fraction eluted with methylene chloride.
An E-form mixture (7.78 g) was obtained.

Ii) Under nitrogen atmosphere, ethyl 3- [3-phenyl-3- (3-pyridyl)] acrylate (2.00
g) was dissolved in toluene (40 ml), and a 1.51 M toluene solution of diisobutylaluminum hydride (13.2 ml) was added dropwise at -78 ° C, and after 6 hours, further 5.26 m was added.
After 2 hours, another 2.63 ml was added, and the mixture was stirred at -78 ° C for another 2 hours. After dropwise addition of methanol, a Rochelle salt aqueous solution was added, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and the fraction eluted with methanol-methylene chloride (5:95) was used as 3- [3-phenyl-3-
(3-Pyridyl)] allyl alcohol (1.20 g) was obtained.

Iii) 3- [3-phenyl-3- (3-
Pyridyl)] allyl alcohol (1.20 g) in chloroform (50 ml) solution of active manganese dioxide (1.94).
g) was added and stirred for 18 hours, and active manganese dioxide (1.94 g) was further added and stirred for 2.5 hours. The reaction mixture was filtered under reduced pressure, and the solvent was evaporated under reduced pressure from the filtrate to give 3-phenyl-3- (3-pyridyl) acrolein (1.13 g).

Iv) Sodium methoxide (0.58)
To a solution of g) in methanol (30 ml) was added methyl p- (cyanomethyl) cinnamate (1.09 g), followed by addition of 3-
Phenyl-3- (3-pyridyl) acrolein (1.1
3 g) was added and stirred for 5 minutes. The precipitated crystals were collected by filtration to give EE / EZ / of methyl 4- [1-cyano-4-phenyl-4- (3-pyridyl) butadienyl] cinnamate.
A ZE / ZZ body mixture (1.85 g) was obtained.

V) 10% palladium-carbon (0.40)
g) in the presence of 4- [1-cyano-4-phenyl-4-
A solution of methyl (3-pyridyl) -1,3-butadienyl] cinnamate (1.00 g) in acetone (50 ml) was catalytically reduced at room temperature and atmospheric pressure for 15 hours, the reaction mixture was filtered under reduced pressure, and the solvent was distilled off from the filtrate under reduced pressure. I left. The resulting compound was dissolved in ethyl acetate-saturated ammoniacal methanol (1: 1) (60 ml) without purification and Raney nickel (ald
In the presence of rich (W-2 equivalent) (0.5 g), the mixture was subjected to catalytic reduction in an autoclave at room temperature and 15 atm for 23 hours, the reaction mixture was filtered under reduced pressure, and the solvent was distilled off under reduced pressure from the filtrate. To a solution of the obtained compound and triethylamine (0.60 g) in methylene chloride (10 ml) without purification, p.
-Chlorobenzenesulfonyl chloride (0.60 g) was added, and the mixture was stirred for 63.5 hours. Saturated saline was added and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 3- {4- [1- (4-chlorobenzenesulfonamidomethyl)) was collected from the methanol-methylene chloride (1:99) elution fraction. -4-phenyl-4- (3-pyridyl)-
Methyl 1,3-butadienyl] phenyl} propionate (0.11 g) and 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4-phenyl-4-
Methyl (3-pyridyl) -3-butenyl] phenyl} propionate (0.20 g) was obtained.

Vi) 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4-phenyl-4- (3
Methyl (-pyridyl) -1,3-butadienyl] phenyl} propionate (0.11 g) was dissolved in methanol (5 ml), 2N aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at 50 ° C for 30 min. . Concentrate the solvent under reduced pressure,
The mixture was neutralized with 2N hydrochloric acid and then extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, 3- {4- [1- (4-
Chlorobenzenesulfonamidomethyl) -4-phenyl-4- (3-pyridyl) -1,3-butadienyl] phenyl} propionic acid (0.11 g) was added as a pale yellow amorphous EE / EZ / ZZ body. Obtained as a mixture. Its spectroscopic data supports the following structural formula (XXII).

¹ H NMR (CDCl ₃ ) δ = 2.56-
2.76 (2H, m), 2.88-3.04 (2H, m),
4.30 (1H, br s), 5.10 (1H, br s),
6.22-6.38 (1H, m), 6.90-7.90 (1
6H, m), 8.40-8.64 (2H, m) IR (film) cm ^-1 : 3400-2800, 1716,1
480, 1336, 1164, 1100

[0083]

[Chemical formula 23]

Vii) 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4-phenyl-4-
Methyl (3-pyridyl) -3-butenyl] phenyl} propionate (0.25 g) was dissolved in methanol (10 ml), 2N aqueous sodium hydroxide solution (2.0 ml) was added, and the mixture was stirred at 50 ° C. for 30 min. . Concentrate the solvent under reduced pressure, and
The mixture was neutralized with normal hydrochloric acid and then extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4-phenyl-
4- (3-Pyridyl) -3-butenyl] phenyl} propionic acid (0.25 g) was obtained as a charcoal yellow amorphous E, Z mixture. Its spectroscopic data supports the following structural formula (XXIII).

[0085]

[Chemical formula 24]

¹ H NMR (CDCl ₃ ) δ = 2.20-
4.40 (9H, m), 5.56-6.10 (1H, m),
6.70-7.80 (16H, m), 8.20-8.60
(2H, m)

Example 6 Synthesis of 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4-phenyl-4- (3-pyridyl) butyl] phenyl} propionic acid i) Under nitrogen atmosphere Sodium (0.69 g) is washed with hexane and added to absolute ethanol (100 ml) to give an ethoxide. Diethyl cyanomethylphosphonate (5.32 g) was added thereto, 3-benzoylpyridine (5.00 g) was further added, and the mixture was refluxed for 24 hours. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (4:
1) 3-Phenyl- (3-pyridyl) acrylonitrile (2.44 g of Z-form / 1.98 g of E-form) was obtained from the eluted fraction.

Ii) A solution of 3-phenyl-3- (3-pyridyl) acrylonitrile (2.51 g of Z-form) and sodium borohydride (1.00 g) in ethanol (50 ml) was heated under reflux for 71 hours and further hydrogenated. 1.51 g of sodium boron was added, and the mixture was refluxed for 8 hours. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 3- [3-phenyl-3 was extracted from a fraction eluted with methanol-methylene chloride (5:95).
-(3-Pyridyl)] propionitrile (2.22 g)
I got

Iii) Under a nitrogen atmosphere, 3- [3-phenyl-3- (3-pyridyl)] propionitrile (2.2
2 g) was dissolved in toluene (20 ml), a 1.0 M toluene solution of diisobutylaluminum hydride (12.7 ml) was added dropwise at -78 ° C, and the mixture was stirred for 30 minutes. 0 ° C
Then, after adding 2N sodium hydroxide aqueous solution dropwise, 2N hydrochloric acid was added to make the liquid acid and the aqueous layer was extracted with ethyl acetate, while the aqueous layer was made alkaline with 2N sodium hydroxide aqueous solution and extracted with ethyl acetate. It was extracted, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and the fraction eluted with methanol-methylene chloride (5:95) was treated with 3- [3-phenyl-3- (3-pyridyl)] pro. Pioaldehyde (0.67g) was obtained.

Iv) Sodium methoxide (0.22)
To a solution of g) in methanol (10 ml) was added a solution of methyl p- (cyanomethyl) cinnamate (0.41 g) in methanol (10 ml), and then 3- [3-phenyl-3-
(3-Pyridyl)] propioaldehyde (0.43 g)
Methanol (3 ml) solution was added dropwise and stirred for 1 hour.
2N hydrochloric acid was added and the aqueous layer was extracted with ethyl acetate, while
The aqueous layer was made alkaline with 2N aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and the eluate from methanol-methylene chloride (5:95) gave 4
-[1-Cyano-4-phenyl-4- (3-pyridyl)
Butenyl] E / Z mixture of methyl cinnamate (0.21
g) was obtained.

V) 4- [1-cyano-4-phenyl-
Methyl 4- (3-pyridyl) butenyl] cinnamate (0.
21 g) was dissolved in methanol (10 ml) and subjected to catalytic reduction at room temperature and atmospheric pressure for 5 hours in the presence of 10% palladium-carbon (0.09 g). The reaction mixture was filtered under reduced pressure, and the solvent was evaporated under reduced pressure from the filtrate to give methyl 3- {4- [1-cyano-4-phenyl-4- (3-pyridyl) butyl] phenyl} propionate. The compound was dissolved in saturated ammoniacal methanol (20 ml) and Raney nickel (aldrich
After reacting for 17 hours at room temperature and 13.5 atm in an autoclave in the presence of (W-2 equivalent) (0.1 g), the reaction mixture was filtered. The solvent was distilled off from the filtrate under reduced pressure, and 3- {4
Methyl-[1-aminomethyl-4-phenyl-4- (3-pyridyl) butyl] phenyl} propionate (0.1
3 g) of a diastereomeric mixture was obtained.

Vi) 3- {4- [1-aminomethyl-4]
-Phenyl-4- (3-pyridyl) butyl] phenyl}
To a solution of methyl propionate (128 mg) and triethylamine (32 mg) in methylene chloride (10 ml) was added P-chlorobenzenesulfonyl chloride (67 mg) and 5
Stir for minutes. Saturated saline was added and the mixture was extracted with methanol-methylene chloride (5:95). The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and the fraction eluted with methanol-methylene chloride (5:95) was used as 3- {4- [1- (4-chlorobenzenesulfonamidomethyl). Methyl -4-phenyl-4- (3-pyridyl) butyl] phenyl} propionate (120
mg) as a mixture of diastereomers.

Vii) 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4-phenyl-4-
Methyl (3-pyridyl) butyl] phenyl} propionate (120 mg) was dissolved in methanol (5 ml), 2N aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at 70 ° C for 30 min. The solvent was concentrated under reduced pressure, neutralized with 2N hydrochloric acid, extracted with methanol-methylene chloride (5:95), the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 3- {4 from the fraction eluted with methanol-methylene chloride (5:95).
-[1- (4-chlorobenzenesulfonamidomethyl)
-4-Phenyl-4- (3-pyridyl) butyl] phenyl} propionic acid (69 mg) was obtained as a white amorphous diastereomeric mixture. Its spectroscopic data supports the following structural formula (XXIV).

¹ H NMR (CDCl ₃ ) δ = 1.28-
1.50 (1H, m), 1.50-1.70 (1H, m),
1.70-1.98 (2H, m), 2.55-2.76 (3
H, m), 2.82-3.03 (3H, m), 3.09-3.
21 (1H, m), 3.72-3.85 (1H, m), 4.
78 (1H, brs), 6.84-6.91 (2H,
m), 7.00-7.28 (11H, m), 7.36-7.
46 (2H, m), 7.59-7.64 (2H, m), 1
0.22 (1H, br s) IR (film) cm ^-1 : 3400-2400, 2935, ¹
718, 1340, 1164, 1100

[0095]

[Chemical 25]

Example 7 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4- (3-pyridyl) pentyl] phenyl}
Synthesis of propionic acid i) Under nitrogen atmosphere, 60% sodium hydride in mineral oil (1.32 g) was washed with hexane, suspended in N, N-dimethylformamide (20 ml), and ethyl dimethylphosphonoacetate was added at 0 ° C. A solution of (6.74 g) of N, N-dimethylformamide (5 ml) was added dropwise, and the mixture was stirred for 10 minutes. 3-
A solution of acetylpyridine (3.64 g) in N, N-dimethylformamide (5 ml) was added, and the mixture was stirred at room temperature for 13.5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed thoroughly with water, further washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 3- (3
-Pyridyl) crotonate ethyl (3.41g) E / Z
Obtained as a mixture.

Ii) Ethyl 3- (3-pyridyl) crotonate (3.41 g) was dissolved in toluene (30 ml), and-
1M-DIBAL toluene solution (39.2 ml) at 78 ° C
Was added, and the mixture was stirred for 14 hours while gradually raising the temperature to room temperature. 2N aqueous sodium hydroxide solution was added dropwise to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel chromatography to obtain a fraction eluted with methanol-methylene chloride (95: 5). Then, 3- (3-pyridyl) -2-butenol (3.41 g) was obtained as an E / Z mixture.

Iii) 3- (3-pyridyl) -2-butenol (1.80 g) and active manganese dioxide (6.3).
A solution of 8 g) in chloroform (100 ml) was heated at reflux for 30 minutes. The reaction solution was filtered under reduced pressure, and the solvent was distilled off from the filtrate under reduced pressure. The obtained residue was subjected to silica gel chromatography, and 3- (3-pyridyl) crotonaldehyde (1.06 g) was obtained as an E / Z mixture from a fraction eluted with methanol-methylene chloride (95: 5).

Iv) Sodium methoxide (0.78)
To a solution of g) in methanol was added a solution of methyl 4- (cyanomethyl) cinnamate (1.45 g) in methanol (1.45 g), and after stirring for 30 minutes, 3- (3-pyridyl) crotonaldehyde (1.06 g) was added. ) In methanol (10 ml) was added. The precipitated crystals were collected by filtration to give EE / EZ / of methyl 4- [1-cyano-4- (3-pyridyl) -1,3-pentadienyl] cinnamate (1.38 g).
A ZE / ZZ mixture was obtained.

V) 10% palladium-carbon (1.00
g) in the presence of 4- [1-cyano-4- (3-pyridyl)
-1,3-Pentadienyl] methyl cinnamate (1.38
A solution of g) in 1.4-dioxane (400 ml) was hydrogenated at ambient temperature and pressure for 43 hours. The reaction solution is filtered under reduced pressure,
When the solvent was distilled off from the filtrate under reduced pressure, 4- [1-cyano-4-
(3-Pyridyl) pentyl] methyl cinnamate (1.37
A diastereomeric mixture of g) was obtained.

Vi) In the presence of Raney nickel (0.5 g), a solution of methyl 4- [1-cyano-4- (3-pyridyl) pentyl] cinnamate (1.37 g) in saturated ammoniacal methanol (30 ml) was autoclaved. Medium, room temperature 1
Hydrogenation was carried out at 5 atmospheres for 16 hours. The reaction solution was filtered under reduced pressure, and the solvent was distilled off from the filtrate under reduced pressure. The obtained residue was subjected to silica gel chromatography, and 3- {4-[(1-aminomethyl) -4- (3-pyridyl) pentyl was extracted from the fraction eluted with aqueous ammonia-methanol-chloroform (1: 10: 100). ] Methyl phenyl} propionate (1.02 g) was obtained.

Vii) Methyl 3- {4-[(1-aminomethyl) -4- (3-pyridyl) pentyl] phenyl} propionate (1.02 g), chlorobenzenesulfonyl chloride (0.64 g) and triethylamine (0 A solution of 0.31 g) in methylene chloride (40 ml) was stirred at room temperature for 25 minutes. After water was added to the reaction mixture and the organic layer was separated, the aqueous layer was extracted with methylene chloride, the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography, and methanol-methylene chloride (9
5: 5) From the eluted fraction, 3- {4- [1- (4-chlorobenzenesulfonamidomethyl) -4- (3-pyridyl)
Pentyl] phenyl} methyl propionate (1.14
g) was obtained.

Viii) A solution of methyl 3- {4- [1- (chlorobenzenesulfonamidomethyl) -4- (3-pyridyl) pentyl] phenyl} propionate (1.14 g) in methanol (20 ml) with 2N water. An aqueous solution of sodium oxide (5 ml) was added and the mixture was heated under reflux for 40 minutes. The reaction mixture was neutralized with 2N hydrochloric acid, the solvent was evaporated under reduced pressure, and the aqueous layer was extracted with methanol-methylene chloride (95: 5). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3- {4- [1-
(Chlorobenzenesulfonamidomethyl) -4- (3-
Pyridyl) pentyl] phenyl} propionic acid (1.0
5 g) of a diastereomeric mixture was obtained as a colorless oil. The spectroscopic data of this product is the following structural formula (XXV)
I support.

¹ H NMR (CDCl ₃ ) δ = 1.16-
1.67 (7H, m), 2.58-2.71 (4H, m),
2.86-2.98 (3H, m), 3.08-3.17 (1
H, m), 5.10 (1H, br s), 6.08-6.92
(2H, m), 7.07-7.14 (2H, m), 7.31
-7.44 (3H, m), 7.52-7.69 (3H,
m), 8.20-8.28 (1H, br s), 8.40-
8.46 (1H, br s) IR (KBr Disk) cm ⁻¹ : 3600-2400,
1720, 1594, 1328, 1164, 1100

[0105]

[Chemical 26] (Insert the formula XXV on the separate sheet when applying)

Test Example 1 Inhibitory Effect on Platelet Aggregation After collecting blood from human forearm with 1/10 volume 3.8% sodium citrate, the blood was centrifuged to obtain platelet-rich plasma (PR
P: Platelet count 2 × 10 ⁵ / μl) is obtained. The PRP2
00 μl and Tris buffered saline (25 mM Tris-
HCl, 130 mM NaCl, 10 mM CaCl ₂ , p
24 μl of H7.4 (hereinafter abbreviated as TBS) was placed in a cuvette, set in an aggregometer, and heated at 37 ° C. for 2 minutes to prepare DMSO of the sulfonamide derivative of the present invention.
After adding 1 μl of (dimetyl sulfoxide) solution and incubating for 3 minutes, it is a stable derivative of PGG ₂ / H ₂ and has a strong platelet aggregation-inducing action U-46619 (Cayman Chemical Company).
p.), and platelet aggregation was measured with an aggregometer (Hematracer VI: Nikko Bioscience Co., Ltd.). Table 1 shows the 50% inhibitory concentration on the platelet aggregation caused by U-46619 (320 nM).

[0107]

[Table 1] (Insert Table 1 on the separate sheet when applying)

As shown in Table 1, the sulfonamide derivative of the present invention showed remarkable antiplatelet aggregation activity. The 50% inhibitory concentration in Table 1 means that when the sulfonamide derivative according to the present invention is not introduced, the platelet aggregating ability is 100%, and the introduction of the sulfonamide derivative reduces the platelet aggregating ability to 50%. It means the sulfonamide derivative solution concentration required for inhibition.

Test Example 2 Thromboxane Synthase Inhibitory Action After collecting blood from human forearm with 1/10 volume 3.8% sodium citrate, the blood was centrifuged to obtain platelet-rich plasma (PR
P: Platelet count 2 × 10 ⁵ / μl) is obtained. The PRP2
00 μl and 24 μl of TBS were placed in a cuvette, set in an aggregometer and heated at 37 ° C. for 2 minutes, 1 ml of the DMSO solution of the sulfonamide derivative of the present invention was added and incubated for 3 minutes, and then 20 U / ml thrombin solution was added. It caused platelet aggregation. The plasma after aggregation was separated, ethyl acetate was added, and the generated thromboxane B ₂ was extracted and quantified by the RIA method (using a kit manufactured by Amersham). Table 2 shows the results.

[0110]

[Table 2]

As shown in Table 2, the sulfonamide derivative of the present invention exhibited an excellent thromboxane synthase inhibitory action.

(Acute toxicity) Using an ICR male mouse (5 weeks old), an acute toxicity test by oral administration was conducted.
Both LD ₅₀ values of the sulfonamide derivatives of the present invention 3
It was 00 mg / kg or more, and high safety was confirmed.

[0113]

INDUSTRIAL APPLICABILITY The present invention provides a novel sulfonamide derivative. INDUSTRIAL APPLICABILITY The novel sulfonamide derivative of the present invention has an antiplatelet aggregation action, a thromboxane A ₂ and prostaglandin H ₂ antagonistic action, and a thromboxane A ₂ synthesis inhibitory action, and therefore is a preventive agent for diseases caused by thromboxane A _2. And is effective as a therapeutic drug.
Particularly, it is effective as an antithrombotic agent and an antiallergic agent.

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Claims (6)

[Claims] 1. A sulfonamide derivative represented by the general formula (I). Embedded image (In the formula I, X represents a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, a trifluoromethyl group, a lower alkyl group or a lower alkoxy group, and Z represents a formula —O— (C
_{H 2) m -CH -, -} N (R 1) - (CH 2) m -CH -, - C
^{(R 1) = CH-CH} =, - C (R 1) = CH-CH 2 - or ^{-C (R 1) - (CH} 2) shows the _m -CH-, R is the formula - (C
H _{²⁾ n} -COOR _2, shows a -O- (CH _{²⁾ n} -COOR ₂ or a lower alkoxy group. n and m each independently represent an integer of 0 to 4, R ¹ represents a hydrogen atom, a lower alkyl group or a phenyl group, and R ² represents a lower alkyl group or a hydrogen atom. ) 2. A thromboxane A ₂ synthesis inhibitor containing the sulfonamide derivative according to claim 1. 3. A thromboxane A ₂ antagonist containing the sulfonamide derivative according to claim 1. 4. A prostaglandin H ₂ antagonist containing the sulfonamide derivative according to claim 1. 5. An antithrombotic agent containing the sulfonamide derivative according to claim 1. 6. An antiallergic agent containing the sulfonamide derivative according to claim 1.