JP2520416B2 - ω-[[[5- (substituted benzylthio) thiadiazol-2-yl] thiomethyl] phenoxy] alkylcarboxylic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention relates to a medicine, particularly SRS-A (slow reacting subst).
ω-[[[5- (substituted benzylthio) represented by the following general formula (I), which is useful as an ance of anaphylaxis) antagonist.
Thiadiazol-2-yl] thiomethyl] phenoxy]
It relates to an alkylcarboxylic acid, a lower alkyl ester thereof or a non-toxic salt thereof.

(The symbols in the formulas have the following meanings.

R ¹ is a lower acyl group R ² is a lower alkyl group A is a lower alkylene group R ³ is a hydrogen atom or a lower alkyl group B is a lower alkylene group R ⁴ is a hydrogen atom or a lower alkyl group n is an integer of 1 to 4, where n Is an integer of 2-4, the group -OB-COO
B and R ⁴ in R ⁴ may be different from each other. ) (Prior art) Human allergic asthma and other atopic diseases,
Alternatively, in animal anaphylactic shock, various chemical mediators are released from the lungs and other tissues, contracting smooth muscles such as bronchial muscles and pulmonary blood vessels, and enhancing permeability of cutaneous blood vessels, resulting in damage to the body. It is believed to cause Such scientific mediators include histamine and SRS-A. Histamine plays an important role in anaphylactic shock in guinea pigs, but is a less important chemical messenger in human allergic asthma [Eiser,
Pharmacology and Therapeutics (Phar
m. Ther.), 17, 239-250 (1982)]. On the other hand, there is much evidence to suggest that SRS-A is the most important chemical messenger in human allergic asthma [Bro-cklehurst, Journal of Physiology (J.Physiol.). , 151, 416-435 (1960); Austen and Orange, American Review of Respiratory Diseases (Am.Rev.Resp.Dis.), 12,423-436 (1975); Adams and Liechtenstein (Lichtenstei)
n), Journal of Immunology (J.Immunol.),
122,555-562 (1979)].

The development of drugs for preventing, eliminating or alleviating the symptoms of allergic reactions has been aimed at suppressing the production or release of such chemical mediators or antagonizing their effects. As a drug that suppresses histamine release, disodium cromoglycate (disodium
Cro-moglycate) is well known, and many antihistamines are commercially available as drugs that antagonize histamine. On the other hand, SRS-A was known as a slow-acting and long-lasting chemical mediator, whereas histamine is a fast-acting and short-duration chemical mediator. Recently, Samuel-sson Leukotrienes C ₄ and D ₄ whose structure was determined by
And it has been revealed a mixture of E _4. SRS-
A, namely leukotriens, is a metabolite of polyunsaturated fatty acids (particularly arachidonic acid) by lipoxygenase. In addition to the action as a chemical mediator in the above-mentioned allergic reaction, mucosecretory action, ciliary movement lowering action, coronary blood vessel It has been clarified that there are actions such as a contraction action and a cardiac contraction force reduction action. Therefore, such SRS-
Development of a drug that suppresses the production and release of A or antagonizes their effects is desired.

The present inventors have been searching for a drug that suppresses SRS-A production and release or a drug that antagonizes these effects.
As a result, they found that the above compound (I) strongly antagonized SRS-A, and completed the present invention.

(Means for Solving Problems) The chemical structural characteristics of the compound of the present invention are as follows: in the compound represented by the following formula, a phenyl group represented by the (b) part and a group represented by the (a) part are In addition, 1 to ⁴ -OB-COOR < ⁴ > groups shown in part (c) are bonded.

Next, the meaning of the symbols of the compound of the present invention represented by formula (I) will be further explained.

Examples of the “lower acyl group” for R ¹ include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group,
Examples thereof include a valeryl group, an isovaleryl group, a pivaloyl group, and a hexanoyl group. Further, examples of the “lower alkyl group” of R ² , R ³ and R ⁴ include methyl group, ethyl group, propyl group and isopropyl group. Group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-
Methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1 dimethylbutyl group, 1,2 -Dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1 , 2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1
-Ethyl-2-methylpropyl group, heptyl group, 1-methylhexyl group, 1-ethylpentyl group, 6-methylhexyl group, octyl group, and the like. Further, as "lower alkylene group" of A and B, Is a methylene group, ethylene group (-CH
₂ CH ₂ −), propylene group (−CH ₂ CH ₂ CH ₂ −), butylene group (−CH ₂ CH ₂ CH ₂ CH ₂ −), Is a linear or branched alkylene chain having 1 to 5 carbon atoms.

Next, n is an integer of 1 to 4. This means that the group of the formula -O-B-COO R ⁴ on the phenyl ring is substituted at least one, up to four. When -O-B-COO R ⁴ group is substituted two or more, may be these are groups different Tsu each other.

Although the compound of the present invention has been described above, when R ³ or R ^{4 in the} formula (I) is a hydrogen atom, a free carboxy group is present. Compounds having these free carboxy groups can form salts.

Examples of the salt include salts with inorganic bases such as sodium salt and potassium salt, and salts with organic bases such as ethylamine salt, propylamine salt, diethylamine salt, triethylamine salt, morpholine salt and diethanolamine salt.

The compound of the present invention has optical isomers based on asymmetric carbon atoms. The present invention includes separated isomers and mixtures of each isomer.

(Production Method) The compound (I) of the present invention is produced, for example, by the method represented by the following reaction scheme.

(The symbols in the formulas have the following meanings.

R ¹ , R ² , R ³ , R ⁴ , A, B and n are the same as above.

M is a hydrogen atom or an alkali metal.

X is a halogen atom or the formula Y-SO ₂ O- (showing a wherein Y is a lower alkyl group or an optionally substituted phenyl group.) Sulfonyl group represented by. ) First Production Method The compound (I) of the present invention comprises a substituted benzyl halide or a substituted benzyl sulfonate represented by the general formula (II) and a mercapto-substituted heterocyclic compound represented by the general formula (III) or an alkali metal substitution product thereof. It is manufactured by reacting with.

The reaction is carried out in an approximately equimolar amount of compound (II) and compound (III) or in a slight excess of one of them, and an organic solvent such as dimethylformamide, dimethylsulfoxide, methanol, ethanol, propanol, acetone, methylethylketone, tetrahydrofuran, chloroform, dioxane. Done in.

When a mercapto-substituted heterocyclic compound is used as the compound (III), it is usually carried out in the presence of a base, and as such a base, potassium carbonate, Triton B, potassium hydroxide, sodium hydride and the like are suitable. Further, in order to accelerate the reaction, catalytic amounts of potassium iodide, tetra-n-butylammonium bromide and the like may be added.

The reaction temperature is not particularly limited, but is usually set to room temperature or under heating.

Second Production Method To carry out this method, a mercapto-substituted heterocyclic compound or its alkali metal substitution (IV) is used as a raw material, and this is reacted with a substituted benzyl halide or a substituted benzyl sulfonate (V). This reaction can be performed in substantially the same manner as in the first production method.

Third Production Method In this production method, the objective compound (Ia) having a corresponding free carboxy group by deesterifying the compound (VI) which is an esterified carboxy group of the objective compound (I)
Is what you get. In the deesterification reaction, a method of hydrolyzing in the presence of a base such as sodium carbonate or sodium hydroxide or an acid such as trifluoroacetic acid or hydrochloric acid can be adopted.

The compound of the present invention produced by these various methods is isolated and purified by applying chemical procedures commonly used in this field such as extraction, recrystallization, column chromatography and the like.

(Effect of the Invention) As described above, the compound (I) of the present invention strongly antagonizes SRS-A, and thus various allergic diseases caused by SRS-A (eg, bronchial asthma, allergic rhinitis, urticaria).
It is useful for prevention and treatment of ischemic diseases and inflammation caused by SRS-A and SRS-A.

Next, the SRS-A antagonism of the compound of the present invention will be shown together with the test method.

Anti-SRS-A action method in guinea pig ileum: body weight 500
-700g of Hartley guinea pig was killed by bruising the head. The ileum specimen was aerated with 95% oxygen + 5% carbon dioxide
It was suspended with a tension of 1 g in a Magnus tank containing Tyrode's solution at 37 ° C. The tissue was allowed to equilibrate for 60 minutes. During this period, the Tyrode solution was replaced every 15 minutes, and the tension was adjusted to 1 g each time. Isometric contractions were recorded on a lectic coder via a strain gauge transducer. The ileal contractile response to submaximal concentrations of SRS-A (prepared from guinea pig lung) was measured in the absence of drug, followed by the presence of varying concentrations of drug. The drug incubation time was 20 minutes.

Results: The compounds of the present invention show a strong anti-inflammatory effect in the guinea pig ileum.
It shows SRS-A action, and its IC ₅₀ value (50% inhibitory concentration) is 4.2 × 10 ⁻¹⁰ M for the compound of Example 6 and 1.7 for the compound of Example 7.
It was × 10 ^-10 M.

In addition to the SRS-A antagonism, the compound of the present invention contains SR
It also includes compounds having both SA production and release suppression effects and bronchodilation effects.

Furthermore, the compound of the present invention is also useful as an anti-inflammatory agent and an anti-ulcer agent.

The compound (I) of the present invention is a pharmaceutical composition as it is or in a mixture with a pharmaceutically acceptable carrier or excipient known per se [eg, tablets, capsules, powders, granules, pills,
Ointments, syrups, injections, inhalants, suppositories] can be safely administered orally or parenterally.
The dose varies depending on the administration subject, administration route, symptoms, etc., but is usually 0.1 to 500 mg / day, preferably 1 to 20 / day for adults.
It is 0 mg and is orally or parenterally administered in 2 to 3 divided doses per day.

(Examples) The compounds of the present invention were produced, for example, by the methods shown in the following Examples, but the compounds of the present invention are not limited to these Examples.

In addition, the manufacturing method of the raw material compounds used in the examples will be described in reference examples.

Reference Example 1 (raw material of Example 2) (A) To a mixed solution of 3 g of 2,5-dihydroxybenzaldehyde, 6.5 g of anhydrous potassium carbonate and 10 ml of N, N-dimethylformamide, 7.62 g of ethyl bromoacetate was added under cooling, and the reaction solution was stirred overnight at room temperature. 150 ml of ethyl acetate in the reaction solution
Was added, and the mixture was washed successively with water, a dilute aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 6.5 g of ethyl [(4-ethoxycarbonylmethoxy-2-formyl) phenoxy] acetate. Melting point 58 ° C.

(B) Ethyl [(4-ethoxycarbonylmethoxy-
To a mixed solution of 6.5 g of 2-formyl) phenoxy] acetate, 10 ml of ethyl acetate and 10 ml of ethanol, 1 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 10 minutes. Add 50 ml of ethyl acetate to the reaction mixture, neutralize with 1N hydrochloric acid, and separate. The aqueous layer was extracted with ethyl acetate, the extract was combined with the organic layer, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain ethyl [(4-ethoxycarbonylmethoxy-2-hydroxymethyl) phenoxy] acetate. I got 6.0g. Melting point 58
° C.

(C) Ethyl [(4-ethoxycarbonylmethoxy-
2-Hydroxymethyl) phenoxy] acetate 1.23 g
1 ml of thionyl chloride is added to a solution of 15 ml of benzene and 15 ml of benzene under ice cooling, and the mixture is stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in toluene (50 ml), the toluene solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl [(2-chloromethyl-4-ethoxycarbonylmethoxy) phenoxy] acetate. Obtained 1.22 g.

NMR (CDCl ₃ , TMS internal standard) δ: 1.30 (3H, t), 1.32 (3H, t), 4.28 (2H, q), 4.30 (2
H, q), 4.60 (2H, s), 4.67 (2H, s), 4.72 (2H, s), 6.70
~ 7.08 (3H, m) Reference Example 2 (raw material of Example 3) (A) 2,4-hydroxybenzaldehyde and ethyl
Bromoacetate was used as a starting material and treated in the same manner as in Reference Example 1 (a) to obtain ethyl [(5-ethoxycarbonylmethoxy-2-formyl) phenoxy] acetate.
Melting point 92 ° C.

(B) Ethyl [(5-ethoxycarbonylmethoxy-
2-Formyl) phenoxy] acetate was used as a starting material and treated in the same manner as in Reference Example 1 (b) to obtain ethyl [(5-ethoxycarbonylmethoxy-2-hydroxymethyl) phenoxy] acetate.

NMR (CDCl ₃ , TMS internal standard) δ: 1.30 (6H, t), 4.28 (4H, q), 4.60 (2H, s), 4.64 (2
H, s), 4.68 (2H, s), 6.47 (1H, d), 6.49 (1H, s), 7.21
(1H, d) (c) Ethyl [(5-ethoxycarbonylmethoxy-
2-Hydroxymethyl) phenoxy] acetate was used as a starting material and treated in the same manner as in Reference Example 1 (c) to obtain ethyl [(2-chloromethyl-5-ethoxycarbonylmethoxy) phenoxy] acetate.

NMR (CDCl ₃ , TMS internal standard) δ: 1.30 (6H, t), 4.28 (4H, q), 4.60 (2H, s), 4.68 (2
H, s), 4.70 (2H, s), 6.40 to 6.60 (2H, m), 7.31 (1H, d) Reference Example 3 (raw material of Example 1) (A) Reference example 1 (a) using 3,4-dihydroxybenzaldehyde and ethyl bromoacetate as starting materials
Was treated in the same manner as described above to obtain ethyl [(2-ethoxycarbonylmethoxy-4-formyl) phenoxy] acetate.

NMR (CDCl ₃ , TMS internal standard) δ: 1.30 (3H, t), 1.32 (3H, t), 4.29 (4H, q), 4.78
(2H, s), 4.82 (2H, s), 6.92 (1H, d), 7.38 (1H, d), 7.
48 (1H, dd), 9.84 (1H, s) (b) Ethyl [(2-ethoxycarbonylmethoxy-
4-formyl) phenoxy] acetate was used as a starting material and treated in the same manner as in Reference Example 1 (b) to obtain ethyl [(2-
Ethoxycarbonylmethoxy-4-hydroxymethyl)
Phenoxy] acetate was obtained.

NMR (CDCl ₃ , TMS internal standard) δ: 1.30 (6H, t), 4.26 (4H, q), 4.58 (2H, s), 4.70 (2
H, s), 4.71 (2H, s), 6.70 to 7.0 (3H, m) (c) ethyl [(2-ethoxycarbonylmethoxy-
4-Hydroxymethyl) phenoxy] acetate was used as a starting material and treated in the same manner as in Reference Example 1 (c) to obtain ethyl [(4-chloromethyl-2-ethoxycarbonylmethoxy) phenoxy] acetate. Melting point 62 ° C. Reference Example 4 (raw material of Example 4) (A) Reference example 1 using 2,3,4-trihydroxybenzaldehyde and ethyl bromoacetate as starting materials
The same treatment as in (a) gave ethyl [(2,3-diethoxycarbonylmethoxy-4-formyl) phenoxy] acetate. Melting point 93 ° C. (b) Ethyl [(2,3-diethoxycarbonylmethoxy-4-formyl) phenoxy] acetate was used as a starting material and treated in the same manner as in Reference Example 1 (b) to obtain ethyl [(2,3- Diethoxycarbonylmethoxy-4-hydroxymethyl) phenoxy] acetate was obtained.

NMR (CDCl ₃ , TMS internal standard) δ: 1.2 to 1.4 (9H, m), 4.0 to 4.5 (6H, m), 4.64 (4H,
s), 4.72 (2H, s), 5.04 (2H, s), 6.54 (1H, d), 6.99 (1
H, d) (c) Ethyl [(2,3-diethoxycarbonylmethoxy-4-hydroxymethyl) phenoxy] acetate was used as a starting material and treated in the same manner as in Reference Example 1 (c) to give ethyl [(4- Chloromethyl-2,3-diethoxycarbonylmethoxy) phenoxy] acetate was obtained.

NMR (CDCl ₃ , TMS internal standard) δ: 1.30 (9H, t), 4.0 to 4.5 (6H, m), 4.66 (2H, s), 4.71
(2H, s), 4.76 (2H, s), 4.92 (2H, s), 6.59 (1H, d), 7.
09 (1H, d) Reference Example 5 (raw material compound of Example 5) 600 mg of 2,5-dimercapto-1,3,4-thiadiazole was added to a solution of 160 mg of sodium hydroxide in 1.3 ml of water and 6 ml of methanol. The insoluble matter in this mixture was removed by filtration, and the solution was concentrated to dryness under reduced pressure. A solution of the residue in 4 ml of 2-butanone was obtained in Reference Example 3 (c), ethyl [4-chloromethyl-2.
A solution of 995 mg of-(ethoxycarbonylmethoxy) phenoxy] acetate in 4 ml of 2-butanone was added dropwise over 20 minutes under ice cooling. After stirring the mixture for 2 hours, water and ethyl acetate were added. The ethyl acetate layer was washed successively with water twice and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1.2: 1) and purified with ethyl [4-[[(5-mercapto-1,3,4-thiadiazol-2-yl) thio]. ] Methyl] -2- (ethoxycarbonylmethoxy) phenoxy] acetate (940 mg) was obtained. Melting point 79-81 ° C.

MS m / z; 444 (M ⁺ ) NMR (CDCl ₃ ,) δ: 1.30 (6H, t), 4.23 (2H, s), 4.27 (4H, q), 4.72 (2
H, s), 4.74 (2H, s), 6.8 ~ 7.0 (3H), 11.35 (1H, broa
d) Example 1 340 mg of 2-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] -5-mercapto-1,3,4-thiadiazole and ethyl [4-chloromethyl-2- (ethoxy) obtained in Reference Example 3 Carbonylmethoxy) phenoxy] acetate 350 mg N, N-dimethylformamide 3 ml
390 mg of anhydrous potassium carbonate was added to the solution. The mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate.
The mixture was washed with water twice and saturated brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to give ethyl [[4-
[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] 1,3,4-thiadiazole-2-
430 mg of [yl] thio] methyl] -2-ethoxycarbonylmethoxy] phenoxy] acetate was obtained.

Melting point 104-106 ℃ Elemental analysis value (as C ₂₉ H ₃₄ N ₂ O ₈ S ₃ ) C (%) H (%) N (%) S (%) Theoretical value 54.87 5.40 4.41 15.15 Experimental value 54.74 5.30 4.35 15.28 Implemented Example 2 2-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] -5-mercapto-1,3,4-thiadiazole 0.3 mg N, N-dimethylformamide 5 ml solution in anhydrous potassium carbonate 0.13 mg and reference 0.3 mg of ethyl [(2-chloromethyl-4-ethoxycarbonyl) phenoxy] acetate obtained in Example 1 and N, N-dimethylformamide
Add 1 ml of solution and stir overnight at room temperature. To the reaction mixture is added 30 ml of toluene, washed with dilute aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixed solution of toluene-ethyl acetate (9: 1) to give oily ethyl [[2-[[5-[(4-acetyl-3-hydroxy-2-hydroxy-2- 0.35 mg of propylbenzyl) thio] -1,3,4-thiadiazol-2-yl] thio] methyl] -4-ethoxycarbonylmethoxy] phenoxy] acetate was obtained.

NMR (CDCl ₃ , TMS internal standard) δ: 1.03 (3H, t), 1.30 (6H, t), 1.4 to 1.8 (2H, m), 2.
63 (3H, s), 2.60 to 2.90 (2H, m), 4.28 (4H, q), 4.57 (2
H, s), 4.58 (2H, s), 4.61 (2H, s), 4.65 (2H, s), 6.70
〜7.75 (5H, m), 12.68 (1H, s) Elemental analysis value (as C ₂₉ H ₃₄ N ₂ O ₈ S ₃ ) C (%) H (%) N (%) S (%) Theoretical value 54.87 5.40 4.41 15.15 Experimental value 54.68 5.35 4.37 15.18 Example 3 2-[(4-Acetyl-3-hydroxy-2-propylbenzyl) thio] -5-mercapto-1,3,4-thiadiazole and ethyl [(2-chloromethyl-5-, obtained in Reference Example 2). Ethoxycarbonylmethoxy) phenoxy] acetate was used as the starting material and treated in the same manner as in Example 2 to give ethyl [[2-[[[5-[(4-acetyl-
3-hydroxy-2-propylbenzyl) thio] -1,3,
4-thiadiazol-2-yl] thio] methyl] -5-
Ethoxycarbonylmethoxy] phenoxy] acetate was obtained. Melting point 88-90 ° C Elemental analysis value (as C ₂₉ H ₃₄ N ₂ O ₈ S ₃ ) C (%) H (%) N (%) Theoretical value 54.87 5.40 4.41 Experimental value 54.70 5.32 4.39 Example 4 2-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] -5-mercapto-1,3,4-thiadiazole and ethyl [(4-chloromethyl-2, 3-Diethoxycarbonylmethoxy) phenoxy] acetate was used as a starting material and treated in the same manner as in Example 2 to give oily ethyl [[4-[[[5-[(4-acetyl-3-hydroxy-2-propyl-2-propyl Benzyl) thio]
-1,3,4-thiadiazol-2-yl] thio] methyl-
2,3, -diethoxycarbonylmethoxy] phenoxy] acetate was obtained.

NMR (CDCl ₃ , TMS internal standard) δ: 1.00 (3H, t), 1.10 to 1.40 (9H, m), 1.40 to 1.80 (2H,
m), 2.64 (3H, s), 2.50 ~ 2.84 (2H, m), 4.10 ~ 4.40 (6
H, m), 4.56 (2H, s), 4.66 (2H, s), 4.72 (2H, s), 4.94
(2H, s), 6.51 (1H, d), 6.94 (1H, d), 7.16 (1H, d), 7.
56 (1H, d), 12.69 (1H, s) Elemental analysis value (as C ₃₃ H ₄₀ N ₂ O ₁₁ S ₃ ) C (%) H (%) N (%) theoretical value 53.79 5.47 3.80 experimental value 53.68 5.35 3.69 Example 5 Ethyl [4-[[(5-mercapto-1,3,4-thiadiazol-2-yl) thio] methyl] obtained in Reference Example 5
-2- (ethoxycarbonylmethoxy) phenoxy] acetate 910 mg and 4-chloromethyl-2-hydroxy-
To a solution of 3-propylacetophenone (465 mg) in N, N-dimethylformamide (10 ml) was added anhydrous potassium carbonate (340 mg). After stirring this mixture for 4 hours at room temperature, water and ethyl acetate were added. The ethyl acetate layer was washed successively with water twice and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) and purified with ethyl [[4-[[[5-[(4-acetyl-3
-Hydroxy-2-propylbenzyl) thio] -1,3,4
-Thiadiazol-2-yl] thio] methyl] -2-ethoxycarbonylmethoxy] phenoxy] acetate 1.
20 g were obtained. The physical properties of this product were the same as those obtained in Example 1.

Example 6 Ethyl obtained in Example 1 [[4-[[[5-[(4-
Acetyl-3-hydroxy-2-propylbenzyl) thio] -1,3,4-thiadiazol-2-yl] thio] methyl] -2-ethoxycarbonylmethoxy] phenoxy]
To a solution of 410 mg of acetate in 20 ml of methanol and 10 ml of dioxane, 6 ml of 1.5N sodium hydroxide was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure until the volume became half. The aqueous mixture was washed with ethyl acetate and acidified with 10% hydrochloric acid. The mixture was extracted with ethyl acetate, the ethyl acetate layer was washed twice with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from 2-propanol and [[4-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] -1,3,4-thiadiazol-2-yl] thio. ] 250 mg of [methyl] -2-carboxymethoxy] phenoxy] acetic acid were obtained. Melting point 102
To 105 ° C. Elemental analysis _{(C 25 H 26 N 2 O} 8 as _{S 3) C (%) H} (%) N (%) S (%) Theoretical values 51.89 4.53 4.84 16.62 Found 51.93 4.52 4.87 16.86 Example 7 The ethyl [[2-[[[5-[(4-
Acetyl-3-hydroxy-2-propylbenzyl) thio] -1,3,4-thiadiazol-2-yl] thio] methyl] -4-ethoxycarbonylmethoxy] phenoxy]
The same procedure as in Example 6 was carried out using acetate as a starting material to give [[2-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] -1,3,4-thiadiazole. -2-yl] thio] methyl] -4-carbomethoxy] phenoxy] acetic acid was obtained. Melting point 165 ° C. Elemental analysis value (as C ₂₅ H ₂₆ N ₂ O ₈ S ₃ ) C (%) H (%) N (%) Theoretical value 51.89 4.53 4.84 Experimental value 51.31 4.55 4.66 Example 8 Ethyl [[2-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] -1,3,4-thiadiazol-2-yl] thio] methyl] obtained in Example 3. -5-Ethoxycarbonylmethoxy] phenoxy]
The same procedure as in Example 6 was carried out using acetate as a starting material to give [[2-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] -1,3,4-thiadiazole. -2-yl] thio] methyl] -5-carboxymethoxy] phenoxy] acetic acid was obtained. Mp 111 to 113 ° C. Elemental analysis _{(C 25 H 26 N 2 O} 8 S 3 · 3/5 H 2 as O) C (%) H ( %) N (%) Theoretical values 50.94 4.65 4.75 Found 50.86 4.75 4.71 Example 9 Obtained in Example 4, ethyl [[4-[[[5-[(4-
Example using acetyl-3-hydroxy-2-propylbenzyl) thio] -1,3,4-thiadiazol-2-yl] thio] methyl] -2,3-diethoxycarbonylmethoxy] phenoxy] acetate as a starting material Treat as in 6 to give [[4-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl) thio] -1,3,4-thiadiazol-2-yl] thio] methyl ] -2,3-Dicarboxymethoxy] phenoxy] acetic acid was obtained. Melting point 159
Elemental analysis value (as C ₂₇ H ₂₈ N ₂ O ₁₁ S ₃ ) C (%) H (%) N (%) Theoretical value 49.68 4.32 4.29 Experimental value 49.44 4.38 4.28

Claims (1)

(57) [Claims] 1. A general formula (The symbols in the formulas have the following meanings: R ¹ : lower acyl group R ² : lower alkyl group A: lower alkylene group R ³ : hydrogen atom or lower alkyl group B: lower alkylene group R ⁴ : hydrogen atom or lower Alkyl group n: an integer of 1 to 4, provided that when n is an integer of 2 to ⁴ , B and R ⁴ in the group —O—B—COO R ⁴ can be different from each other. ω-[[[5- (substituted benzylthio) thiadiazol-2-yl] thiomethyl] phenoxy] alkylcarboxylic acid, its lower alkyl ester or its non-toxic salt.