JPH07116125B2 - Phenoxyalkylcarboxylic acid derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention has a novel selective phenoxyalkylcarboxylic acid derivative having a strong selective leukotriene antagonism and useful for the prevention and treatment of allergic diseases such as asthma. The intermediate material and the manufacturing method thereof.

[Conventional technology]

Leukotrienes (leukotrienes C ₄ , D ₄ , and E ₄ ), which are metabolites of the 5-lipoxygenase system of arachidonic acid, are considered to be the main causative agents of immediate-type allergic diseases such as bronchial asthma. reacting substance of an
aphylaxis) is a component.

Therefore, drugs that antagonize leukotrienes are expected as useful antiallergic agents, but few drugs are orally effective, and no practical examples have been reported so far.

Further, as a compound having a structure similar to that of the compound of the present invention, there is a description in JP-A-58-189137, but it is a compound having an ether bond and does not have a thioether bond as in the compound of the present invention, but has a structural difference It is a thing. Furthermore, the biological activity of the similar compound is not sufficient, and is not useful as compared with the compound of the present invention.

[Problems to be Solved by the Invention and Means for Solving the Problems]

The present inventors have conducted extensive studies on drugs that antagonize leukotrienes, and as a result, the 6-position acetylphenoxyalkylcarboxylic acid derivative represented by the following general formula [I] has a strong and selective leukotriene antagonism in oral administration. The present invention has been completed and the present invention was completed by further surprisingly finding that the respiratory tract hypersensitivity induced in guinea pigs is significantly suppressed.

[In the formula, R ¹ is a hydrogen atom, a methyl group or an ethyl group, m is an integer of 2 to 5, n is an integer of 3 to 8, X ¹ and X ² are the same or different, and are a sulfur atom, It represents an oxygen atom, a sulfinyl group or a sulfonyl group, but X ¹ and X ² are not oxygen atoms at the same time.] According to the present invention, the compound of the general formula [I] can be produced by the route described below.

(1) The compound of the following general formula [Ia] can be produced by reacting the compound of the general formula [II] with the compound of the general formula [III].

[In the formula, R ² is a methyl group or an ethyl group, m is an integer of 2 to 5, n is an integer of 3 to 8, X ¹ is a sulfur atom, an oxygen atom,
A sulfinyl group or a sulfonyl group, X ³ represents a sulfur atom or an oxygen atom, but X ¹ and X ³ are not oxygen atoms at the same time] The reaction is carried out in an organic solvent such as acetone, methyl ethyl ketone, diethyl ketone or dimethylformamide. ,
The reaction temperature is preferably room temperature to solvent reflux temperature. It is also preferable to add an inorganic base such as potassium carbonate or sodium carbonate, and to add potassium iodide.

[In the formula, R ² and n are as described above, and X ³ represents a sulfur atom or an oxygen atom.] [Wherein, m and X ¹ are as described above, and Y represents a halogen atom] (2) The compound represented by the following general formula [Ib] is the same as the compound of the general formula [IV] in the formula [V]. It can be produced by reacting the compound of

[In the formula, R ² is a methyl group or an ethyl group, m is an integer of 2 to 5, n is an integer of 3 to 8, X ² is a sulfur atom, an oxygen atom,
A sulfinyl group or a sulfonyl group, X ³ represents a sulfur atom or an oxygen atom, but X ² and X ³ are not oxygen atoms at the same time] The reaction is carried out in an organic solvent such as acetone, methyl ethyl ketone, diethyl ketone or dimethylformamide. ,
The reaction temperature is preferably room temperature to solvent reflux temperature. It is also preferable to add an inorganic base such as potassium carbonate or sodium carbonate, and to add potassium iodide.

[In the formula, R ² , X ² n and m are as described above, and Y ¹ represents a halogen atom] [Wherein X ³ is as described above] (3) The compound represented by the following general formula [IIa] is obtained by reacting the compound of the general formula [VI] with the compound of the general formula [VII], It can be produced by removing the protecting group.

[Wherein R ² and n are the same as above] The reaction is preferably carried out in an organic solvent such as acetone, methyl ethyl ketone, diethyl ketone or dimethylformamide at a reaction temperature of from room temperature to a solvent reflux temperature. It is also preferable to add an inorganic base such as potassium carbonate or sodium carbonate, and to add potassium iodide.

In the compound of the general formula [VI], examples of the protecting group for the thiol group include a dimethylaminocarbonyl group and a benzyl group.

[In the formula, R ³ represents a protecting group] Y ² -(CH ₂ ) _n COOR ² [VII] [In the formula, R ² and n are as described above, and Y ² represents a halogen atom] (4 ) The compound represented by the general formula [IIa] is also produced by the following steps. The compound of the general formula [VI] is reacted with the compound of the following general formula [VIII] to give a general formula [IX].

Y ³ -(CH ₂ ) _{n -Y4} [VIII] [wherein n is as described above, and Y ³ and Y ⁴ represent the same or different halogen atoms] [Wherein R ³ , Y ⁴ and n are as described above] The reaction may be carried out in an organic solvent such as acetone, methyl ethyl ketone, diethyl ketone or dimethylformamide at a reaction temperature of room temperature to a solvent reflux temperature. preferable. Then, the compound represented by the general formula [IX] is reacted with sodium cyanide or potassium cyanide to obtain the general formula [IXa].

[Wherein R ³ and n are as described above] The reaction is preferably carried out in an organic solvent such as dimethylsulfoxide or dimethylformamide at a temperature of room temperature to 100°C. Further, the compound represented by the general formula [IXa] is hydrolyzed and then esterified with an alcohol to obtain the general formula [IIa]. The hydrolysis of the nitrile is preferably sodium hydroxide or potassium hydroxide aqueous solution, and the esterification is preferably refluxed in the presence of a catalytic amount of concentrated sulfuric acid in an alcohol.

(5) The compound represented by the following general formula [IVa] can be produced by reacting the compound of general formula [IIa] with the compound of general formula [VIII′].

[Wherein R ² , Y ¹ , m and n are the same as above] Y-(CH ₂ ) _m -Y ¹ [VIII'] [wherein Y, Y ¹ and n are as described above] Reaction Is preferably carried out in an organic solvent such as acetone, methyl ethyl ketone, diethyl ketone or dimethylformamide at a reaction temperature of room temperature to solvent reflux temperature. The presence of an inorganic base such as potassium carbonate or sodium carbonate, and addition of potassium iodide is also preferable.

(6) X ¹ and X in the general formula [III] or [IV], respectively.
A compound in which ² is a sulfinyl group is represented by the following general formula [III
It is produced by oxidizing a compound represented by a] or [IVa].

[In the formula, Y represents a halogen atom, and m represents an integer of 2 to 5] [Wherein R ² , Y, m and n are the same as above] Typically, an equivalent or excess mild oxidizing agent to the compound represented by the general formula [IIIa] or [IVa], for example, m-chloro It is produced by reacting perbenzoic acid, aqueous hydrogen peroxide and the like in a suitable solvent such as methylene chloride and alcohol.

(7) X ¹ and X in the general formula [III] or [IV], respectively.
Compounds in which ² is a sulfinyl group are represented by the general formulas [IIIa], [I
It is produced by reacting the compound represented by Va] with a mild oxidant similar to (6) in a double amount or in excess.

(8) In the general formula [I], R ¹ is a methyl group or an ethyl group, X ¹
Is an oxygen atom or a sulfonyl group and X ² is a sulfinyl group and a compound of the general formula [I] in which R ¹ is a methyl group or an ethyl group, X ¹ is a sulfinyl group and X ² is an oxygen atom or a sulfonyl group, respectively. The following general formula [Ia′],
An equivalent amount or excess (6) of the compound represented by [Ib']
It is produced by reacting a mild oxidizing agent similar to.

[In the formula, R ² represents a methyl group or an ethyl group, m represents an integer of 2 to 5, n represents an integer of 3 to 8, and X ⁴ represents an oxygen atom or a sulfonyl group] [In the formula, R ² represents a methyl group or an ethyl group, m represents an integer of 2 to 5, n represents an integer of 3 to 8, and X ⁴ represents an oxygen atom or a sulfonyl group] (9) General formula [I ] And R ¹ is a methyl group or an ethyl group, X ¹
Is an oxygen atom or a sulfonyl group and X ² is a sulfonyl group, and a compound of the general formula [I] in which R ¹ is a methyl group or an ethyl group, X ¹ is a sulfonyl group and X ² is an oxygen atom or a sulfonyl group, respectively. General formula [Ia'], [Ib']
It is produced by reacting the compound represented by the formula (2) with a 2-fold amount or an excess amount of a mild oxidant similar to (6).

〔Example〕

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

Example 1. 4-[6-acetyl-3-[3-(4-acetyl-3-
Hydroxy-2-propylphenylthio)propoxy]
2-Propylphenoxy]ethyl butyrate Ethyl 4-(6-acetyl-3-hydroxy-2-propylphenoxy]butyrate Ethyl 1.6 g, potassium iodide 0.5 g, potassium carbonate 1.45 g and acetone 30 ml A mixture was heated under reflux with stirring. While (4-(3-bromopropylthio)-2-
A solution prepared by dissolving 1.9 g of hydroxy-3-propylphenyl)ethanone in 10 ml of acetone was added dropwise. After heating and refluxing for 6 hours with stirring, inorganic substances are separated, the liquid is concentrated,
The residue was separated and purified by silica gel column chromatography (benzene:ethyl acetate=9:1) to give 2.1 g of crystals (72.4
%) was obtained. When this crystal is recrystallized from ethanol,
It becomes colorless crystals. Melting point 65-66°C.

Elemental analysis value (%): Calculated value as C ₃₁ H ₄₂ O ₇ S (measured value) C: 66.64 (66.53) H: 7.58 (7.72) Examples 2 to 7 The same as Example 1 and shown in Table 1. The compound was synthesized.

Example 8 4-[6-acetyl-3-[2-(4-acetyl-3-
Hydroxy-2-propylphenylthio)ethoxy]-
2-Propylphenoxy]ethyl butyrate 4-(6-acetyl-3-(2-chloroethoxy)-2
-Propylphenoxy) ethyl butyrate 0.60 g, (2-hydroxy-4-mercapto-3-propylphenyl)ethanone 0.51 g, potassium iodide 0.1 g, potassium carbonate 0.65 g and acetone 40 ml were heated to reflux with stirring for 19 hours. did.
After cooling, the inorganic substances were separated, the liquid was concentrated, and the residue was separated and purified by silica gel column chromatography (benzene:ethyl acetate=15:1 then 9:1) to give 0.73 g (82.8%) of the desired product as a brown oil. Got

Elemental analysis value (%): Calculated value (measured value) as C ₃₀ H ₄₀ O ₇ S C: 66.15 (66.12) H: 7.40 (7.50) Examples 9 and 10 The results are shown in Table 2 in the same manner as in Example 8. The compound was synthesized.

Example 11. Ethyl 4-[6-acetyl-3-mercapto-2-propylphenoxy)butyrate (i) 4-(N,N-dimethylcarbamoylthio)-2
-Hydroxy-3-propylphenyl)ethanone 26.6 g,
A mixture of 92.2 g of ethyl 4-bromobutyrate, 1 g of potassium iodide, 26.1 g of potassium carbonate and 200 ml of acetone was heated to reflux with stirring. 13 g of potassium carbonate was added after 9 hours and 14 hours, respectively, and the mixture was heated under reflux for 29 hours with stirring, then the inorganic substances were passed through and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane and then benzene and finally eluted with benzene:ethyl acetate=9:1) to give 4-(6-acetyl-3-(N,N-dimethylcarbamoylthio) as light brown crystals. 31.5 g (84.2%) of ethyl-2-propylphenoxy)butyrate was obtained.

Melting point 60 to 63°C Elemental analysis value: Calculated value as C ₂₀ H ₂₉ NO ₅ S (actual value) C: 60.74 (60.89) H: 7.39 (7.58) N: 3.54 (3.38) (ii) 4-(6-acetyl Ethyl-3-(N,N-dimethylcarbamoylthio)-2-propylphenoxy)butyrate (10.6 g), potassium hydroxide (4.5 g) and ethanol (100 ml) were mixed and stirred under reflux for 1.5 hours. Ice water and concentrated hydrochloric acid were added (pH 1), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. To the residue was added 30 ml of ethanol and 0.5 ml of concentrated sulfuric acid, and 1.
The mixture was heated and stirred under reflux for 5 hours. Ice water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. 7.8 g (89.7%) of ethyl 4-(6-acetyl-3-mercapto-2-propylphenoxy)butyrate was obtained as a brown oil. ^′ H-NMR(CDCl ₃ ) δ:1.03 (3H,t,J=7Hz,-CH ₂ CH ₂ C
H ₃ ),1.28 (3H,t,J=7Hz,CO ₂ CH ₂ CH ₃ ),1.57 (2H,m,-CH ₂
CH ₂ CH ₃ ),2.12 (2H,m,-OCH ₂ CH ₂ CH ₂ COOEt),2.5 (2H,m,-
CH ₂ CO ₂ Et),2.57 (3H,s,COCH ₃ ),2.6 (2H,m,- CH ₂ CH ₂ C
H ₃ ),3.78 (2H,t,J=6Hz,-O CH ₂ CH ₂ CH ₂ CO ₂ Et),4.16 (2
H,q,J=7Hz, CO ₂ CH ₂ CH ₃ ), 7.10 (1H,d,J=8Hz, Example 12. Ethyl 5-(6-acetyl-3-mercapto-2-propylphenoxy)pentanoate In the same manner as in Example 11, the target product was quantitatively obtained as a brown oil. ^′ H-NMR(CDCl ₃ ) δ:1.03 (3H,t,J=7Hz,-CH ₂ CH ₂ C
H ₃ ),1.27 (3H,t,J=7Hz,-CO ₂ CH ₂ CH ₃ ),1.57 (2H,m,-C
H ₂ CH ₂ CH ₃ ),1.8 (4H,m,-OCH ₂ CH ₂ CH ₂ CH ₂ CO ₂ Et),2.39 (2
H,m, CH ₂ CO ₂ Et),2.57 (3H,s,COCH ₃ ),2.70 (2H,m,- CH ₂ C
H ₂ CH ₃ ),3.75 (2H,m,-O CH ₂ (CH ₂ ) ₃ CO ₂ Et),4.14 (2H,q,J
= 7Hz, CO ₂ CH ₂ CH ₃ ), 7.10 (1H, d, J = 8Hz, Example 13. Ethyl 6-(6-acetyl-3-mercapto-2-propylphenoxy)hexanoate In the same manner as in Example 11, the target product was obtained as a brown oil in a yield of 69.0%. ^′ H-NMR(CDCl ₃ ) δ:1.02 (3H,t,J=7Hz,-CH ₂ CH ₂ C
H ₃ ),1.26 (3H,t,J=7Hz,-CO ₂ CH ₂ CH ₃ ),1.66 (8H,m,-C
H ₂ CH ₂ CH ₃ and -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CO ₂ Et), 2.34 (2H,t,J
=7Hz,- CH ₂ CO ₂ Et),2.57 (3H,s,COCH ₃ ),2.60 (2H,m,- C
_{H 2 CH 2 CH 3),} 3.73 (2H, t, J = 6Hz, -O CH 2 (CH 2) 4 CO 2 Et), 4.
13 (2H,q,J=7Hz, CO ₂ CH ₂ CH ₃ ), 7.10 (1H,d, Example 14. Ethyl 7-(6-acetyl-3-mercapto-2-propylphenoxy)heptanoate (i) (4-(N,N-dimethylcarbamoylthio)-
2-hydroxy-3-propylphenyl)ethanone 5.8
A mixture of 25 g of g,1,6-dibromohexane, 1 g of potassium iodide, 5.7 g of potassium carbonate and 40 ml of acetone was heated and stirred under reflux. 2.9 g of potassium carbonate after 9.5 hours, 20 hours and 3
The mixture was added after 0.5 hours and refluxed for a total of 41 hours. After cooling, the inorganic substances were passed and the solvent was concentrated under reduced pressure. Silica gel column chromatography of the residue (benzene:hexane=1:1)
Then it was purified with benzene:ethyl acetate=9:1) to give 7.3 g (79.7%) of (2-(6-bromohexyloxy)-4-(N,N-dimethylcarbamoylthio) as a brown oil.
-3-Propylphenyl)ethanone was obtained. ^′ H-NMR(CDCl ₃ )δ:0.99(3H,t,J=7Hz,-CH ₂ CH ₂ C
H ₃ ), 1.2 to 1.8 (10H,m,-CH ₂ CH ₂ CH ₃ and -OCH ₂ CH ₂ CH ₂ CH ₂ C
H ₂ CH ₂ Br),2.59 (3H,s,COCH ₃ ),2.70 (2H,m,- CH ₂ CH ₂ C
H ₃ ),3.08 (6H,s,-N( CH ₃ ) ₂ ),3.35 (2H,t,J=6Hz,- CH ₂ B
r), 3.77 (2H,t,J=6Hz, -O CH ₂ (CH ₂ ) ₅ Br), 7.30 (2H,m, (Ii) Sodium cyanide (0.89 g) was added to dimethyl sulfoxide (20 ml) and heated to about 50° C. to obtain (2-(6-bromohexyloxy)-4-(N,N-dimethylcarbamoylthio)-3-propylphenyl. ) A solution of 7.3 g of ethanone dissolved in 40 ml of dimethyl sulfoxide was added dropwise at about 50-60°C with stirring. After reacting at 90° C. for 15 minutes, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (benzene:ethyl acetate=9:1 then 7:3) to give 4.4 g (68.6%) of 7-(6-acetyl-3-(N,N-dimethyl) as a brown oil. Carbamoylthio)-2-propylenoxy)heptanenitrile was obtained. ^′ H-NMR (CDCl ₃ ) δ:0.99 (3H,,J=7Hz,-CH ₂ CH ₂ C
H ₃ ), 1.3 to 2.0 (10H,m,-CH ₂ CH ₂ CH ₃ and -OCH ₂ CH ₂ CH ₂ CH ₂ C
H ₂ CH ₂ CN), 2.36 (2H,m,-OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CN), 2.59
(3H,s,-CO CH ₃ ), around 2.8 (2H,m,- CH ₂ CH ₂ CH ₃ ), 3.08 (6
H,s,( CH ₃ ) ₂ NCOS−), 3.77 (2H,t,J=6Hz,-O CH ₂ CH ₂ CH ₂ CH
₂ CH ₂ CH ₂ CN), 7.32 (2H,s, (Iii) A mixture of 7-(6-acetyl-3-(N,N-dimethylcarbamoylthio)-2-propylphenoxy)heptanenitrile 4.4 g, potassium hydroxide 1.9 g, and ethanol 30 ml was heated and stirred under reflux for 1.5 hours. After that, it was concentrated under reduced pressure.
Ice water and then concentrated hydrochloric acid were added to the residue to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a brown oil (3.7 g). 2.0 g of the brown oil, 2.0 g of potassium hydroxide, 20 m of water
The mixture (1) was heated and stirred under reflux for 3 hours and then concentrated under reduced pressure. Ice water and then concentrated hydrochloric acid were added to the residue to acidify it, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. 0.5 ml of concentrated sulfuric acid and 20 ml of ethanol were added to the residue, and the mixture was further refluxed for 1.5 hours. Ice water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. 1.8 g (78.4%) of ethyl 7-(6-acetyl-3-mercapto-2-propylphenoxy)heptanoate was obtained as a brown oil. ^′ H-NMR(CDCl ₃ ) δ:1.02 (3H,t,J=7Hz,-CH ₂ CH ₂ C
_{H 3), 1.26 (3H,} t, J = 7Hz, -CO 2 CH 2 CH 3), 1.2~2.0 (10H,
m,CH ₂ CH ₂ CH ₃ and -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CO ₂ Et), 2.31 (2
H,m,- CH ₂ CO ₂ Et), 2.57 (3H,s,COCH ₃ ), around 2.6 (2H,m,-
CH ₂ CH ₂ CH ₃ ), 3.72 (2H,t,J=6Hz,- CH ₂ (CH ₂ ) ₅ CO ₂ Et), 4.
12 (2H,q,J=7Hz,-CO ₂ CH ₂ CH ₃ ), 7.01 (1H,d,J=8Hz, Example 15 Ethyl 9-(6-acetyl-3-mercapto-2-propylphenoxy)nonanoate In the same manner as in Example 14, the target product was obtained as a brown oil in a total yield of 67.3%. ^′ H-NMR(CDCl ₃ ) δ:1.03 (3H,t,J=7Hz,-CH ₂ CH ₂ C
_{H 3), 1.26 (3H,} t, J = 7Hz, -CO 2 CH 2 CH 3), 1.2~2.0 (14H,
m,-CH ₂ CH ₂ CH ₃ and -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CO ₂ Et),
2.30 (2H,t,J=7Hz,- CH ₂ CO ₂ Et), 2.58 (3H,s,COCH ₃ ),
Near 2.60 (2H,m,- CH ₂ CH ₂ CH ₃ ), 3.72 (2H,t,J=7Hz,-O CH
₂ (CH ₂ ) ₇ CO ₂ Et), 4.12 (2H,q,J=7Hz, CO ₂ CH ₂ CH ₃ ),7.01
(1H,d,J=8Hz, Example 16 4-[6-acetyl-3-[3-(4-acetyl-3-
Ethyl hydroxy-2-propylphenylthio)propylthio]-2-propylphenoxy]butyrate 2.0 g Ethyl 4-(6-acetyl-3-mercapto-2-propylphenoxy)butyrate, (4-(3-Bromopropylthio)- A mixture of 2.0 g of 2-hydroxy-3-propylphenyl)ethanone, 0.5 g of potassium iodide, 1.7 g of potassium carbonate and 40 ml of acetone was heated and stirred under reflux for 9 hours. After cooling, the inorganic substances were separated, the liquid was concentrated, and the residue was separated and purified by silica gel column chromatography (benzene:ethyl acetate=9:1) to give 1.8 g (50.
8%).

Elemental analysis value (%): Calculated value (measured value) as C ₃₁ H ₄₂ O ₆ S ₂ C:64.78 (64.66) H: 7.36 (7.38) Examples 17 to 22 Shown in Table 3 as in Example 16. Compounds were synthesized.

Example 23 4-[6-acetyl-3-[3-(4-acetyl-3-
Hydroxy-2-propylphenoxy)propylthio]
Ethyl-2-propylphenoxy]butyrate 1.7 g Ethyl 4-(6-acetyl-3-mercapto-2-propylphenoxy)butyrate, (4-(3-Bromopropoxy)-2-hydroxy-3-propylphenyl)ethanone 1.7 A mixture of g, 0.5 g of potassium iodide, 1.45 g of potassium carbonate and 40 ml of acetone was heated and stirred under reflux for 7.5 hours. Ice water and concentrated hydrochloric acid were added, and the mixture was extracted with ethyl acetate. After washing with water, drying over sodium sulfate and concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (benzene:ethyl acetate=9:1) to give 2.08 g (71.0%) of the desired product as pale yellow crystals.
Got Melting point 87-88°C.

Elemental analysis value (%): Calculated value (measured value) as C ₃₁ H ₄₂ O ₇ S C:66.64 (66.85) H: 7.58 (7.56) Example 24 The compounds shown in Table 4 were prepared in the same manner as in Example 23. Synthesized.

Example 31 4-[6-acetyl-3-[3-(4-acetyl-3-
Hydroxy-2-propylphenylsulfinyl)propoxy]-2-propylphenoxy]butyrate ethyl 4-(6-acetyl-3-[3-(4-acetyl-3-]
Hydroxy-2-propylphenylthio)propoxy]
1.2 g of ethyl-2-propylphenoxy]butyrate was dissolved in 40 ml of methylene chloride, and m-chloroperbenzoic acid of 0.
51 g was added, and the mixture was stirred at the same temperature for 2 hours. The organic layer was washed twice with a cooled aqueous solution of potassium carbonate and then with a saturated saline solution,
It was dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (benzene: ethyl acetate = 1:
Purification in 1) gave 0.78 g (63.2%) of the desired product as colorless crystals.

Melting point 74-76°C Elemental analysis value (%): Calculated value (measured value) as C ₃₁ H ₄₂ O ₈ S C:64.78 (64.78) H: 7.37 (7.43) Example 32 4-[6-acetyl-3-3 [3-(4-acetyl-3-
Hydroxy-2-propylphenylsulfonyl)propoxy]-2-propylphenoxy]ethyl butyrate 4-[6-acetyl-3-[3-(4-acetyl-3-]
Hydroxy-2-propylphenylthio)propoxy]
Ethyl-2-propylphenoxy]butyrate (1.3 g) was dissolved in methylene chloride (40 ml), and m-chloroperbenzoic acid (1.
After adding 05g and stirring at the same temperature for 1 hour, it was further stirred at room temperature for 3 hours.
Stir for hours. The organic layer was washed twice with cooled aqueous potassium carbonate solution, then with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (benzene:ethyl acetate=9:1 then 7:3) to obtain 0.97 g (70.6%) of the desired product as colorless crystals.

Melting point 77 to 79° C. Elemental analysis value (%): Calculated value as C ₃₁ H ₄₂ O ₉ S (measured value) C: 63.03 (63.11) H: 7.17 (7.19) Example 33 4-[6-acetyl-3- [3-(4-acetyl-3-
Hydroxy-2-propylphenylthio)propoxy]
2-Propylphenoxy]butyric acid 4-[6-acetyl-3-[3-(4-acetyl-3-]
Hydroxy-2-propylphenylthio)propoxy]
2.1 g of ethyl-2-propylphenoxy]butyrate was dissolved in 10 ml of ethanol, and a solution of 0.26 g of sodium hydroxide in 10 ml of water was added. After heating on a hot water bath for 5 minutes, ice water was added and cooled, hydrochloric acid was added to acidify, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (ethanol:methylene chloride=3:100) to obtain 1.3 g (65.2%) of the desired product as colorless crystals. Melting point 79-81°C.
Elemental analysis value (%): Calculated value (measured value) as C ₂₉ H ₃₈ O ₇ S C:65.64 (65.81) H: 7.22 (7.24) Examples 34 to 64 The results are shown in Table 5 in the same manner as in Example 33. The compound was synthesized.

Example 65 4-[6-acetyl-3-[3-(4-acetyl-3-
Hydroxy-2-propylphenoxy)propylsulfinyl]-2-propylphenoxybutyrate ethyl In the same manner as in Example 31, the target product was obtained as a pale yellow oily substance.
Obtained at 81.0%.

Elemental analysis value (%): Calculated value (measured value) as C ₃₁ H ₄₂ O ₈ S C:64.78 (64.76) H: 7.37 (7.38) Example 66 4-[6-acetyl-3-[3-(4) -Acetyl-3-
Hydroxy-2-propylphenoxy)propylsulfonyl]-2-propylphenoxybutyrate ethyl In the same manner as in Example 31, the target compound was obtained in the form of a pale yellow oily substance.
Obtained at 58.4%.

Elemental analysis value (%): Calculated value (measured value) as C ₃₁ H ₄₂ O ₉ S C: 63.03 (63.14) H: 7.17 (7.19) Example 67 [4-(3-Bromopropylsphinyl]-2- Hydroxy-3-propylphenyl]ethanone The target product was obtained as a pale yellow oil in the same manner as in Example 31.
Obtained in 55.2%.

Mass spectrum m/z: 346 (M ⁺ ), 348 (M ⁺ +2) Example 68 [4-(3-Bromopropylsulfonyl]-2-hydroxy-3-propylphenyl]ethanone Yellow as in Example 32. The target product was obtained as an oil in a yield of 63.4%.

Mass spectrum m/z: 362 (M ⁺ ), 364 (M ⁺ +2) Examples 69 to 71 In the same manner as in Examples 16 and 31, the compounds shown in Table 6 were synthesized.

[Effect of the invention] Example 1. Guinea pig airway constriction inhibition test Male Hartley type guinea pigs with a body weight of about 450 g were anesthetized with pentobarbital sodium 30 mg/kg (intraperitoneal), and changes in airway pressure were detected by the konzet-wrestler. Modified method (Konzett-Rossler; J. Harvey et al., J. Pharmaco
l. Method. 9 , 147-155, 1983). The airway constriction reaction was induced by administering leukotriene D ₄ (3 μg/kg) from a cannula inserted into the left external jugular vein. Prior to leukotriene D ₄ administration, indomethacin and propranolol were intravenously administered to the animals.
The test compound was suspended in a 5% gum arabic solution and orally administered 2 hours before the administration of leukotriene D ₄ . Table 7 shows the experimental results
It was shown to.

The present invention showed a strong leukotriene D ₄ antagonism in the isolated ileum of the guinea pig or the tracheal smooth muscle specimen, and further showed the effect of suppressing airway stenosis at a low dose by oral administration.

As is clear from the above results, the compounds of the present invention are diseases caused by leukotrienes, such as bronchial asthma, eyes,
Nose and gastrointestinal allergic diseases and allergic dermatitis,
It is also useful for treating circulatory disorders and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 319/02 319/14 323/22

Claims (12)

[Claims] 1. A general formula [I] [In the formula, R ¹ is a hydrogen atom, a methyl group or an ethyl group, m is an integer of 2 to 5, n is an integer of 3 to 8, X ¹ and X ² are the same or different, and a sulfur atom, Represents an oxygen atom, a sulfinyl group or a sulfonyl group, but X ¹ and X ² are not oxygen atoms at the same time.] or an alkali salt thereof. 2. A general formula [II] [Wherein, R ² represents a methyl group or an ethyl group, n represents an integer of 3 to 8 and X ³ represents a sulfur atom or an oxygen atom], and a compound represented by the following general formula [III] [In the formula, m is an integer of 2 to 5, Y is a halogen atom, X ¹
Represents a sulfur atom, an oxygen atom, a sulfinyl group, or a sulfonyl group, but when X ³ is an oxygen atom, X ¹ is not an oxygen atom]. Ia] [In the formula, R ² is a methyl group or an ethyl group, m is an integer of 2 to 5, n is an integer of 3 to 8, X ¹ is a sulfur atom, an oxygen atom,
A sulfinyl group or a sulfonyl group, X ³ represents a sulfur atom or an oxygen atom, but X ¹ and X ³ are not oxygen atoms at the same time.]. 3. A general formula [IV] [In the formula, R ² is a methyl group or an ethyl group, Y ¹ is a halogen atom, m is an integer of 2 to 5, n is an integer of 3 to 8, and X ² is a sulfur atom, an oxygen atom, or a sulfinyl group. Or a sulfonyl group] to the compound represented by the following general formula [V] [Wherein, X ³ represents a sulfur atom or an oxygen atom, but when X ² is an oxygen atom, X ³ is not an oxygen atom]. The compound represented by the following general formula [Ib ] [In the formula, R ² is a methyl group or an ethyl group, m is an integer of 2 to 5, n is an integer of 3 to 8, X ² is a sulfur atom, an oxygen atom,
A sulfinyl group or a sulfonyl group, X ³ represents a sulfur atom or an oxygen atom, but X ² and X ³ are not oxygen atoms at the same time.]. 4. General formula [VI] [Wherein R ³ represents a protecting group] and the following general formula [VII] Y ² -(CH ₂ ) _n COOR ² [VII] [wherein R ² represents a methyl group or an ethyl group] , Y ² is a halogen atom, and n is an integer of 3 to 8], and the protecting group is removed after the compound represented by the general formula [IIa]. [Wherein R ² and n are the same as defined above]. 5. A general formula [VI] [Wherein R ³ represents a protecting group] and the following general formula [VIII] Y ³ -(CH ₂ ) _n -Y ₄ [VIII] [wherein Y ³ and Y ⁴ are the same or in phase Different halogen atoms,
n represents an integer of 3 to 8] and a compound represented by the general formula [IX] [Wherein R ³ , Y ⁴ , and n are the same as those defined above] and then cyanated with sodium cyanide or potassium cyanide to give a compound of the general formula [IXa] In addition, after the hydrolysis, the esterification and the protecting group are removed by alcohol, and the general formula [IIa] [Wherein R ² and n are the same as defined above]. 6. A general formula [IIa] [Wherein R ² and n are the same as above] and the following general formula [VIII′] Y—(CH ₂ ) _m —Y ¹ [VIII′] [wherein Y and Y ¹ are the same] Or a different halogen atom, m represents an integer of 2 to 5], a compound represented by the general formula [IVa] [Wherein R ² , Y ¹ , m and n are the same as defined above] 7. A general formula [IVa] [Wherein R ² represents a methyl group or an ethyl group, Y ¹ represents a halogen atom, m represents an integer of 2 to 5, and n represents an integer of 3 to 8]. A method for producing a compound having the general formula [IV], wherein X ² is a sulfinyl group or a sulfonyl group. 8. A general formula [IIIa] [Wherein Y represents a halogen atom and m represents an integer of 2 to 5], and X ¹ is a sulfinyl group or a sulfonyl group in the general formula [III], which is characterized by being oxidized. Method for producing compound. 9. A general formula [Ia′] [Wherein, R ² represents a methyl group or an ethyl group, m represents an integer of 2 to 5, n represents an integer of 3 to 8, and X ⁴ represents an oxygen atom or a sulfonyl group]. In the formula [I], R ₂ is a methyl group or an ethyl group, X ¹ is an oxygen atom or a sulfonyl group, and X ² is a sulfinyl group or a sulfonyl group. 10. A general formula [Ib′] [Wherein, R ² represents a methyl group or an ethyl group, m represents an integer of 2 to 5, n represents an integer of 3 to 8, and X ⁴ represents an oxygen atom or a sulfonyl group]. Wherein R ² is a methyl group or an ethyl group, X ¹ is a sulfinyl group or a sulfonyl group, and X ² is an oxygen atom or a sulfonyl group. 11. General formula [Ia] [In the formula, R ² is a methyl group or an ethyl group, m is an integer of 2 to 5, n is an integer of 3 to 8, X ¹ and X ³ are the same or different, and are a sulfur atom, an oxygen atom, A sulfinyl group or a sulfonyl group, wherein X ¹ and X ³ are not oxygen atoms at the same time] is hydrolyzed, and in the general formula [I], R ¹ is a hydrogen atom. Method for producing compound. 12. General formula [I] [In the formula, R ¹ is a hydrogen atom, a methyl group or an ethyl group, m is an integer of 2 to 5, n is an integer of 3 to 8, X ¹ and X ² are the same or different, and are a sulfur atom, An oxygen atom, a sulfinyl group, or a sulfonyl group, but X ¹ and X ² are not oxygen atoms at the same time] or an antiallergic agent containing at least one compound thereof as an active ingredient.