JPH068275B2 - Phenoxyacetic acid derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel phenoxyacetic acid derivative or a salt thereof having an excellent inhibitory effect on platelet aggregation.

(Prior Art) Thromboxane A ₂ (Thromboxan A ₂ , hereinafter referred to as TxA ₂ ) is produced by the metabolism of arachidonic acid, which is widely present in various animal organs (eg, liver, kidney, lung, brain, etc.). However, TxA ₂ often causes thrombosis such as peripheral arterial thrombosis, pulmonary embolism, coronary artery occlusion, myocardial infarction, and transient cerebral ischemia due to its platelet aggregation action. Are known. Therefore, 4- (2-benzenesulfonylaminoethyl) phenoxyacetic acid has been reported as a drug that suppresses platelet aggregation based on TxA ₂ [Thrombosis Research, Vol. 35, 379-].
395 (1984)].

(Structure and Effect of the Invention) The present invention relates to a novel phenoxyacetic acid derivative represented by the following general formula or a salt thereof.

(However, R ¹ , R ² , R ³ , R ⁴ and R ⁷ are a hydrogen atom or a lower alkyl group, R ⁵ is a phenyl group or a halogenophenyl group, R ⁶ is a carboxyl group or hydroxyl group which may be protected, ring A Is a phenylene group having 1 to 2 substituents selected from a halogen atom and a nitro group, m is 0 or 1, n is an integer of 0 to 5, m and n are 0 and R ⁶ is protected. When it is a carboxyl group which may be present, R ¹ , R ² , R ³ and R ⁴ are all hydrogen atoms.) The object compound (I) of the present invention or a salt thereof is It is a pharmaceutical compound having a more excellent TxA ₂ antagonistic action and useful as a platelet aggregation inhibitor and a prophylactic / therapeutic agent for thrombosis, and a prophylactic / therapeutic agent for smooth muscle spasm such as coronary and cerebral blood vessels and asthma.

Specific examples of the object compound of the present invention include, in the general formula (I), R ^{1 to} R ⁴ and R ⁷ are a hydrogen atom or a lower alkyl group,
R ⁵ is a phenyl group or a halogenophenyl group, R ⁶ is a free carboxyl group or a hydroxyl group, or a lower alkyl group optionally substituted with a phenyl group which may have a nitro group or a lower alkoxy group (for example, A lower alkyl group, a phenyl lower alkyl group, a lower alkoxy group-substituted phenyl lower alkyl group, a nitro group-substituted phenyl lower alkyl group, etc.) or a benzhydryl group-protected carboxyl group, and ring A is selected from a halogen atom and a nitro group. The compound is a phenylene group having 1 to 2 substituents.

Among them, the compound having preferable drug efficacy is a compound in which R ⁵ is a phenyl group or a halogenophenyl group, and R ⁶ is a carboxyl group, a lower alkoxycarbonyl group or a hydroxyl group.

In the above specific examples and preferred compounds, the lower alkyl group includes any alkyl group having 1 to 6 carbon atoms, but the more preferable compound in terms of efficacy is that the lower alkyl group is an alkyl group having 1 to 4 carbon atoms. It is a compound. Further, preferred examples of the halogen atom include a fluorine atom and a chlorine atom.

The compound (I) of the present invention includes all stereoisomers, optical isomers and mixtures thereof based on 1 to 3 asymmetric carbon atoms.

According to the present invention, the target compound (I) has the general formula (A) (However, the symbols have the same meanings as described above.) And a phenol compound represented by the general formula (Provided that R ⁶¹ is an optionally protected carboxyl group or hydroxyl group, X is a reactive residue, and R ⁷ , m and n have the same meanings as described above.) , Or (B) general formula (Wherein Y represents an amino group which may be protected or a reactive residue, and other symbols have the same meanings as described above), and a phenoxyacetic acid compound represented by the general formula R ⁵ SO ₂ Z (V (However, Z represents a hydroxyl group or a reactive residue when Y is an optionally protected amino group, and represents an amino group when Y is a reactive residue, and R ⁵ has the same meaning as above. With a sulfonic acid compound represented by
If desired, it can be prepared by removing the protecting group from the product.

Among the target compounds (I), compounds in which ring A has a nitro group-substituted phenylene group are (However, the symbols have the same meanings as described above.) When phenoxyacetic acid compound represented by is nitrated, and R ⁶¹ is a protected carboxyl group, the protecting group may be further removed, if desired. You can also

In the target compound (I), the compound of m = 1 is a compound represented by the general formula: (However, R ¹¹ , R ²¹ , R ³¹ , and R ⁴¹ represent a hydrogen atom or a lower alkyl group, and R ⁵ and ring A have the same meanings as described above.) In the phenoxyacetic acid compound or the carboxyl group thereof. And a general formula (However, the symbols have the same meaning as described above.) When R ⁶¹ is a protected carboxyl group, the compound is produced by removing the protecting group, if desired, by subjecting it to a condensation reaction with an amine compound represented by You can also

Furthermore, the general formula of the target compound (I) (However, the symbols have the same meaning as described above.) The compound represented by can also be produced by reducing the phenoxyacetic acid compound (VII) by a conventional method.

As the protective group for the carboxyl group in the raw material compounds (III), (IV), (VI) and (VIII), any protective group which can be removed by a conventional method such as hydrolysis, acid treatment or reduction is used. Examples of such a protecting group include a lower alkyl group, a substituted or unsubstituted phenyl lower alkyl group (benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, etc.), and a benzhydryl group. In addition, as the reactive residue (X and Y or Z), for example, a halogen atom, a lower alkylsulfonyloxy group, a substituted or unsubstituted phenylsulfonyloxy group (benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc.) is preferable. Can be used for.

The condensation reaction between the phenol compound (II) and the compound (III) and the condensation reaction between the phenoxyacetic acid compound (IV) and the sulfonic acid compound (V) are carried out according to a conventional method, for example, in the presence or absence of a deoxidizing agent. It can be carried out. As the deoxidizer, for example, alkali metal carbonate, alkali metal hydroxide,
Alkali metal bicarbonate or organic amines such as pyridine and triethylamine can be preferably used. When Y of the phenoxyacetic acid compound (IV) is a protected amino group, it is preferable to use a lower alkanoyl group, an aryloxycarbonyl group (benzyloxycarbonyl group or the like) or the like as the amino group protecting group. The reaction can be appropriately carried out in a solvent or without a solvent, and as the solvent, for example, acetone, alkanol, methylene chloride, tetrahydrofuran, ethyl acetate, water or a mixed solvent thereof can be preferably used. This reaction suitably proceeds at room temperature to under heating.

The nitration reaction of the phenoxyacetic acid compound (VI) can be carried out by a conventional method in a solvent or without a solvent, for example, treatment with concentrated nitric acid and acetic acid or nitric acid and sulfuric acid, etc., and acetic anhydride or the like is preferably used as a solvent. You can All of the above reactions suitably proceed at room temperature.

The condensation reaction of the phenoxyacetic acid compound (VII) or its reactive derivative at the carboxyl group with the amine compound (VIII) can be carried out according to a conventional method for peptide synthesis. For example, the condensation reaction between the free carboxylic acid type compound (VII) and the amine compound (VIII) can be carried out in the presence of a dehydrating agent, and examples of the dehydrating agent include carbonyldiimidazole, dicyclohexylcarbodiimide and the like. Can be used. On the other hand, reactive derivative of phenoxyacetic acid compound (VII) and amine compound (V
The condensation reaction with III) can be carried out in the presence or absence of a deoxidizing agent. Corresponding acid halides, mixed acid anhydrides, active esters and the like can be preferably used as the reactive derivative, and any of those exemplified in the condensation reaction can be suitably used as the deoxidizing agent. Suitable solvents include, for example, methylene chloride, tetrahydrofuran, ethyl acetate, methanol, ethanol, dioxane or a mixed solvent thereof, and this reaction can be suitably carried out under cooling to room temperature.

The reduction reaction of the phenoxyacetic acid compound (VII) can be carried out according to a conventional method by treating with a reducing agent in a solvent. As the reducing agent, any conventional one such as borane / 1,4-oxathiane complex can be used, and suitable solvents include tetrahydrofuran, dioxane and the like. This reduction reaction is preferably carried out under cooling to heating.

When the group R ⁶¹ in the product thus obtained is a protected carboxyl group and / or the group Y is a protected amino group, the protecting group can be removed by, for example, hydrolysis, solvolysis or acid treatment. , Reduction, etc. can be appropriately carried out.

In the above reaction, starting compounds (II) to (VIII)
Any of them can be used in the reaction in a free form or in the form of a salt thereof. For example, starting compounds (II), (VII), and R
Raw material compound (III) in which ⁶¹ is a free carboxyl group,
(IV), (VI) and (VIII) are alkali metal salts or alkaline earth metal salts, and the starting compounds (IV), (V) and amine compounds (VIII) in which Y or Z is an amino group are organic. It can be used in the reaction as an acid or an inorganic acid addition salt.

Further, since all the above reactions proceed without racemization, the objective compound (I) can be obtained as an optically active substance if it has an optically active substance as a raw material compound.

The thus-obtained object compound (I) of the present invention has an excellent TxA ₂ antagonism as described above, and thus is useful as a platelet aggregation inhibitor, for example, cerebral thrombosis, coronary thrombosis, cerebral thrombosis, pulmonary embolism. It can be used for the treatment, alleviation and prevention of various thrombosis such as illness, peripheral vascular embolism and thrombovascular inflammation, embolism and the like. Further, the target compound (I) or a salt thereof can also be used for the treatment / alleviation and prevention of myocardial ischemia, unstable angina, coronary artery spasm, cerebral vasospasm after subarachnoid hemorrhage, cerebral hemorrhage, asthma and the like. Further, among the conventionally known TxA ₂ antagonists, while exhibiting excellent TxA ₂ antagonistic action, they also exhibit transient TxA ₂ -like action, such as platelet aggregation-inducing action, bronchoconstrictor action, vasoconstrictor action and the like. Although there are some side effects, among the target compounds (I), the compound in which m = 1 is particularly excellent in that it does not show the TxA ₂ -like action in both oral administration and parenteral administration. .

The object compound (I) of the present invention can be used for medicinal use in either a free form or a salt form thereof. When used for pharmaceutical use, the salt is preferably a pharmacologically acceptable salt. Specific examples of such a salt include, for example, alkali metal salts such as sodium salt and potassium salt, calcium salt, magnesium salt and the like. Examples thereof include heavy metal salts such as alkaline earth metal salts and zinc salts, ammonium salts, triethylamine salts, pyridine salts, ethanolamine salts, salts with inorganic or organic bases such as basic amino acid salts.

The object compound (I) of the present invention or a salt thereof can be administered orally or parenterally, and can be used as a pharmaceutical preparation by mixing with an excipient suitable for oral or parenteral administration. The pharmaceutical preparation may be a solid preparation such as a tablet or a granule capsule, or a liquid preparation such as a solution, a suspension or an emulsion. When administered parenterally, it can be used in the form of injection.

The starting compounds (II), (IV), (VI) and the phenoxyacetic acid compound (VII) of the present invention are novel compounds, and the starting compound (II) is (However, R ⁸ represents an optionally protected hydroxyl group, R ¹ ,
R ² , R ³ , R ⁴ and ring A have the same meaning as described above. ) And a sulfonyl halide compound represented by the general formula R ⁵ SO ₂ X ² (X) (wherein R ⁵ has the same meaning as described above and X ² represents a halogen atom). And, if desired, can be produced by removing the protecting group. Alternatively, in the starting compound (II), one of R ² and R ⁴ is a lower alkyl group, the other is a hydrogen atom, and R ¹ and
The compound in which R ³ is a hydrogen atom has the general formula (However, the symbols have the same meanings as above.) After the condensation reaction of the compound and the sulfonyl halide compound (X), the compound is reacted with a lower alkyl magnesium halide, and the compound is further catalytically reduced. If
It can also be produced by removing the protective group for the hydroxyl group. The raw material compound (IV) has, for example, the general formula (However, the symbols have the same meanings as described above.) The compound (III) can be produced by condensation reaction with the compound (III). On the other hand, the starting compound (VI) are formula (II), of (IV) or from the corresponding starting compounds Ring A is an unsubstituted phenylene group in (VII), also phenoxyacetic acid compound (VII), R ¹ ~ A compound in which at least one of R ⁴ is a lower alkyl group is a starting compound (II) or (I
Any of V) can be produced according to the method of the present invention.

Experimental example Arachidonic acid-induced pulmonary embolism inhibitory effect (in vivo) Overnight fasted mouse (ddy strain, male, 5 weeks old, group 8)
The test sample (suspended or dissolved in equimolar sodium hydrogen carbonate and 0.25% carboxymethylcellulose solution) was orally administered (20 ml / kg) to each mouse. After 3 hours, arachidonic acid (125 mg / 2.
5 ml 1% NaHCO ₃ solution + 7.5 ml 0.9% saline / kg) was administered into the tail vein to induce pulmonary embolism. The efficacy of the test compound was measured by measuring the time from the arachidonic acid administration until the ambulatory movement was recovered (recovery time: min), and comparing it with that of the test sample non-administration group in which 0.25% CMC was administered instead of the test sample. . The arachidonic acid-induced pulmonary embolism-suppressing action of the test compound was represented by a dose that reduced the recovery time by 15% or more as compared with the group not administered with the test sample. The results are shown in Table 1.

Example 1 (1) 4- (2-aminoethyl) -2-fluorophenoxyacetic acid methyl ester hydrochloride 1 g was added to ethyl acetate 30 ml,
To a solution of potassium carbonate (1.58 g) in water (15 ml) was added dropwise at room temperature a solution of 4-chlorophenylsulfonyl chloride (0.78 g) in ethyl acetate (15 ml), and the mixture was stirred for 2 hours. The ethyl acetate layer is separated, washed and dried. Evaporate the solvent,
The residue was recrystallized from a mixed solution of ethyl acetate-isopropyl ether-n-hexane to give 1.39 g of 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxyacetic acid methyl ester as colorless prism crystals (M. p.102-103 ° C).

(2) To a solution of 1.33 g of this product in 10 ml of methanol was added 5 ml of 1N sodium hydroxide, and the mixture was stirred at room temperature for 30 minutes. After distilling off methanol, the mixture was acidified with 10% hydrochloric acid, extracted with ethyl acetate, dried and evaporated to remove the solvent.
Recrystallization from a hexane mixture gives 1.25 g of 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxyacetic acid as colorless prism crystals.

M. p. 137-138 ° C IRν ^Nujol _Max (cm ^-1 ): 3300,1710 NMR (CDC1 ₃ -DMS0-d ₆ ): 2.70 (t, J = 7Hz, 2H), 3.08 (q, J = 7H
z, 2H), 4.62 (S, 2H), 6.65 (t, J = 6Hz, 1H, -N H- ), 6.7 ~ 6.9 (m,
3H), 7.45 (d, J = 9Hz, 2H), 7.75 (d, J = 9Hz, 2H), Mass (m / e): 387 (M ⁺ ) Na salt: mp215-217 ° C The raw material compounds are treated in the same manner as in Example 1 to obtain the compounds shown in Table 2 below.

Example 5 A solution of 4-76- (2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxyacetic acid in tetrahydrofuran was dissolved in a tetrahydrofuran solution under an argon stream under ice-cooling stirring.
1 ml of 7.8 M borane-1,4-oxathian complex is added, and the mixture is stirred at room temperature for 2 hours. 20 ml of methanol
Is added dropwise under ice-cooling stirring, and after stirring for 20 minutes, the solvent is distilled off. The residue was purified by silica gel column chromatography [solvent; methanol-chloroform] and recrystallized from a mixed solution of ethyl acetate-isopropyl ether-n-hexane to give 2- {4- [2- (4-chlorophenylsulfonylamino) ethyl]-. 687 mg of 2-fluorophenoxy} ethanol are obtained as colorless prism crystals.

M. p. 80.5 to 82.5 ° C Example 6 (1) 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxyacetic acid 2.03 g
To 20 ml of methylene chloride and 20 ml of tetrahydrofuran was added 3.8 ml of thionyl chloride, and the mixture was stirred for 2 hours. Then the solvent is distilled off. The residue was dissolved in 20 ml of methylene chloride, 1.32 g of glycine methyl ester hydrochloride, 1.77 g of sodium hydrogen carbonate, 30 ml of methylene chloride and 3 parts of water.
The mixture is added dropwise to a 0 ml mixture under ice-water cooling. After stirring the compound as it is for 3 hours, the methylene chloride layer is separated, washed and dried. The solvent was distilled off, and the residue was subjected to silica gel column chromatography [solvent: chloroform methanol (40:
1)] and N- {4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxymethylcarbonyl} glycine methyl ester 1.9.
7 g are obtained as caramel.

Mass (m / e): 458 (M ⁺ ) (2) To a solution of 623 mg of this product in 8 ml of methanol was added 2.8 ml of 1N sodium hydroxide aqueous solution, and the mixture was left standing at room temperature for 3 hours. After the reaction, acidify with 10% hydrochloric acid, extract with ethyl acetate, and dry. The solvent was distilled off, and the residue was recrystallized from a mixed solution of tetrahydrofuran-isopropyl ether-n-hexane to give N- {4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxymethylcarbonyl} glycine 560 mg. Is obtained as colorless prism crystals.

M. p. 186.5-187.5 ° C Mass (m / e): 444 (M ⁺ ) Na salt: M.I. p. 216 to 217 ° C. Examples 7 to 17 (1) The corresponding starting material compounds are treated in the same manner as in Example 6- (1) to obtain the compounds shown in Table 3 below.

(2) The product of (1) above is treated in the same manner as in Example 6- (2) to obtain the compounds shown in Table 4 below.

Example 18 To 970 mg of 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxyacetic acid, 5 ml of anhydrous methylene chloride, 5 ml of anhydrous tetrahydrofuran and 1.8 ml of thionyl chloride were added, and the mixture was refluxed for 1 hour. After the reaction, the solvent is distilled off and the residue is azeotropically distilled with tetrahydrofuran. The obtained product and 0.5N sodium hydroxide solution were combined with 305 mg of ε-aminocaproic acid 0.5N sodium hydroxide 4.7.
ml, 5 ml of diethyl ether and 20 ml of ethanol were added dropwise under stirring with ice cooling, and the mixture was stirred overnight at room temperature. Diethyl ether and water are added and the layers are separated. The aqueous layer is acidified, extracted with ethyl acetate, washed, dried and filtered. The solvent was distilled off from the filtrate, and the resulting pale yellow caramel was purified by silica gel column chromatography to obtain N- {4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxymethylcarbonyl}-. 620 mg of ε-aminocaproic acid are obtained as an almost colorless oil.

Mass (m / e): 500 (M ⁺ ) Example 19 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxyacetic acid was treated as in Example 18 to give N- {4-. [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxymethylcarbonyl} alanine is obtained.

M. p. 174 ~ 175.5 ℃ Example 20 5 g of 4- [2- (benzenesulfonylamino) ethyl] phenoxyacetic acid was added to 30 ml of acetic anhydride, and 3 ml of a concentrated nitric acid-acetic acid (1: 2) mixture was added dropwise under stirring with ice-water cooling. The mixture is reacted at room temperature for 4 hours, poured into a dilute hydrochloric acid-ice mixed solution, extracted with ethyl acetate, and dried. The solvent was evaporated, the residue was purified by silica gel column chromatography (solvent; chloroform ethanol = 60: 1), and recrystallized from a mixed solution of ethyl acetate-n-hexane to give 4- [2- (benzenesulfonylamino) ethyl. ] 3.70 g of 2-nitrophenoxyacetic acid is obtained as colorless needle crystals.

M. p. 135-136 ° C Mass (m / e): 380 (M ⁺ ) Na salt: mp 93 to 100 ° C. Example 21 4- [2- (benzenesulfonylamino) ethyl] -2
80% of 2.18 g of sodium nitrophenoxyacetate
10% palladium-carbon 0.4 in 50 ml methanol solution
4 g is added, and catalytic reduction is performed under normal temperature pressure for 3 hours. After completion of the reaction, the catalyst is filtered off and the filtrate is concentrated. The residue is recrystallized from a mixed solution of isopropyl ether and water to obtain 1.94 g of sodium 4- [2- (benzenesulfonylamino) ethyl] -2-aminophenoxyacetate as pale yellow scaly crystals.

M. p. 111 ~ 115 ℃ (decomposition) Mass (m / e): 395 (M + Na), 372 (M + 1) Reference Example 1 (1) 3-Fluoro-4-methoxybenzaldehyde 9.
Reflux a mixture of 8 g, benzene, nitromethane, n-butylamine, and acetic acid. The reaction solution is extracted with toluene,
The extract is concentrated and recrystallized from acetic acid ester-n-hexane to obtain 10 g of β-nitro-3-fluoro-4-methoxystyrene.

(2) A solution of 10 g of this product in tetrahydrofuran is dropped into a suspension of lithium aluminum hydride and refluxed. After the reducing agent was decomposed by filtration and concentrated, hydrochloric acid was added to the residue and recrystallized from isopropanol-isopropyl ether to obtain 6.6 g of 3-fluoro-4-methoxyphenethylamine hydrochloride. Then 47% of the free amine obtained from 6.1 g of this product
After refluxing in an aqueous solution of hydrogen bromide, the solvent is distilled off and recrystallized from the same solvent as above to obtain 5.1 g of 3-fluoro-4-hydroxyphenethylamine hydrobromide.

M. p. 223.5-226.5 ° C (decomposition) (3) To 5 g of an ethyl acetate-potassium carbonate aqueous solution of this product, a benzyloxycarbonyl chloride solution is added dropwise under ice-water cooling. After stirring at room temperature, the organic layer is separated and the solvent is distilled off.
The residue is recrystallized from isopropyl ether-n-hexane to obtain 2-fluoro-4-benzyloxycarbonylaminoethylphenol (5.2 g).

(4) Add potassium carbonate and methyl bromoacetate to an acetone solution of 5.2 g of this product, and reflux. After the reaction, the solvent was distilled off, and after washing, ethyl acetate-isopropyl ether-n-
Recrystallize from hexane. The obtained 2-fluoro-4-
Of 6.4 g of benzyloxycarbonylaminoethylphenoxyacetic acid methyl ester, 5.4 g is catalytically reduced in methanol in the presence of palladium-carbon. After filtering off the catalyst, the filtrate is treated with methanol-hydrochloric acid and concentrated. The residue was recrystallized from methanol-ether to give 2-fluoro-
3.7 g of 4-aminoethylphenoxyacetic acid methyl ester hydrochloride is obtained as colorless prism crystals.

M. p. 126.5-128.5 ° C. Reference Example 2 (1) Potassium carbonate and benzyl chloride are added to a solution of 4-hydroxy-3,5-difluorobenzaldehyde (20 g) in dimethylsulfoxide, and the mixture is reacted at room temperature. Water is added to the reaction solution and the mixture is extracted with ethyl acetate. The solvent was distilled off from the extract, and the residue was purified with a silica gel column to give 4-benzyloxy-3,5-difluorobenzaldehyde 1
7.4 g are obtained.

(2) This product is treated in the same manner as in Reference Examples 1- (1) to (4) below to give 4- (2-aminoethyl) -2,6-difluorophenoxyacetic acid methyl ester hydrochloride.

Reference Example 3 (1) A tetrahydrofuran solution of 3-fluoro-4-methoxyacetophenone (1.7 g) was added to a mixed solution of a sodium hydride tetrahydrofuran solution and a phosphonoacetate triethyl solution, and the mixture was reacted at room temperature. Water was added to the reaction solution, the organic layer was separated, the solvent was evaporated, and the residue was purified with a silica gel column to give 1.5 g of 3- (3-fluoro-4-methoxyphenyl) isocrotonic acid ethyl ester. .

(2) A catalytic solution of 1.4 g of this product in the presence of palladium-carbon is catalytically reduced, and the catalyst is removed by filtration. After the filtrate is concentrated, methanol and aqueous sodium hydroxide solution are added to the residue and the mixture is stirred. Then, the solvent is distilled off and the residue is extracted with ethyl acetate under hydrochloric acid. The solvent was distilled off from the extract, the residue was purified by a silica gel column, and recrystallized from n-hexane to obtain 1 g of 3- (3-fluoro-4-methoxyphenyl) butyric acid.

(3) 1 g of this product, a toluene solution of triethylamine and diphenylphosphoryl azide are reacted at room temperature under reflux. Benzyl alcohol was added to the reaction solution, refluxed, ethyl acetate was added thereto, and the solvent was distilled off to obtain 1.5 g of 1-benzyloxycarbonylamino-2- (3-fluoro-4-methoxyphenyl) propane. . Treat the acetic acid solution of this product with a 25% hydrogen bromide-acetic acid solution according to a conventional method,
By adding ether and collecting the precipitated crystals by filtration, 1-amino-2
1.1 g of-(3-fluoro-4-methoxyphenyl) propane hydrobromide are obtained.

(4) To 1.1 g of this product, a solution of benzenesulfonyl chloride in methylene chloride was added dropwise to a mixed solution of sodium hydrogencarbonate-methylene chloride-water, and the mixture was stirred at room temperature. After the reaction, the methylene chloride layer is separated and the solvent is distilled off. The residue was purified by silica gel column and recrystallized from isopropyl ether-methanol to give 1-benzenesulfonylamino-2-
(3-Fluoro-4-methoxyphenyl) propane 1 g
To get

(5) Boron tribromide was added dropwise to 1 g of a methylene chloride solution of this product under cooling, and the mixture was stirred at room temperature. After the reaction, add water and extract with chloroform. The solvent is distilled off from the extract. 0.8 g of potassium carbonate and 0.7 g of methyl bromoacetate are added to the acetone solution of the residue, and after the reaction, the solvent is distilled off. The residue is added with water, extracted with ethyl acetate, the solvent is distilled off from the extract, and the resulting residue is treated with an aqueous sodium hydroxide solution. After the reaction, the solvent is distilled off, and the mixture is extracted with ethyl acetate under acidic conditions.
The solvent was distilled off and the residue was purified by silica gel column to give 2
0.9 g of -fluoro-4- (1-methyl-2-benzenesulfonylaminoethyl) phenoxyacetic acid is obtained.

Mass (m / e): 367 (M ⁺ ) Reference Example 4 The corresponding starting material compound is treated in the same manner as in Reference Example 3 to obtain 2-fluoro-4- [1-methyl-2- (4-chlorophenylsulfonylamino) ethyl] phenoxyacetic acid.

M. p. 106.5 to 108.5 ° C Reference Example 5 (1) To a tetrahydrofuran suspension of 2.7 g of lithium aluminum hydride, a tetrahydrofuran solution of 8.2 g of 1- (4-benzyloxy-3-fluorophenyl) -2-nitropropene was added dropwise. The reaction is carried out at room temperature and then under reflux. After decomposing lithium aluminum hydride, it is filtered off,
After treatment with hydrochloric acid-methanol, the solvent was distilled off to give 1- (4-
6.2 g of benzyloxy-3-fluorophenyl) -2-aminopropane hydrochloride are obtained.

(2) 2.5 g of this product is treated in the same manner as in Reference Examples 3- (3) and (4) to obtain 1.8 g of 2-fluoro-4- (2-benzenesulfonylaminopropyl) phenoxyacetic acid.

M. p. 148 to 150 ° C Reference Example 6 The corresponding starting material compound is treated in the same manner as in Reference Example 5 to obtain 2-fluoro-4- [2- (4-chlorophenylsulfonylamino) propyl] phenoxyacetic acid.

M. p. 130.5-132.5 ° C

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shima saki ▼ Ho 4-7 Chiyoda, Sakado, Saitama Wakabadai housing complex 28-1103 (56) References JP-A-54-122250 (JP, A) JP-A-62 -238259 (JP, A) JP-A-62-155250 (JP, A)

Claims (6)

[Claims] 1. A general formula (However, R ¹ , R ² , R ³ , R ⁴ and R ⁷ are hydrogen atoms or lower alkyl groups, R ⁵ is a phenyl group or a halogenophenyl group, R ⁶ is an optionally protected carboxyl group or hydroxyl group, ring A
Is a phenylene group having 1 to 2 substituents selected from a halogen atom and a nitro group, m is 0 or 1, and n is 0 to 5
When m and n are 0 and R ⁶ is an optionally protected carboxyl group, R ¹ , R ² , R ³ and R ⁴
Are both hydrogen atoms. ) A phenoxyacetic acid derivative represented by or a pharmacologically acceptable salt thereof. 2. A carboxyl protected by a lower alkyl group or a benzhydryl group which may be substituted with a phenyl group which may have a nitro group or a lower alkoxy group, wherein R ⁶ is a free carboxyl group or a hydroxyl group. The compound according to claim 1, wherein ring A is a phenylene group having 1 to 2 substituents selected from a fluorine atom and a nitro group. 3. R ⁵ is a phenyl group or a chlorophenyl group, R ⁶
The compound according to claim 2, wherein is a free carboxyl group, a lower alkoxycarbonyl group or a hydroxyl group. 4. The compound according to claim 3, which is 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2,6-difluorophenoxyacetic acid. 5. N- {4- [2- (4-chlorophenylsulfonylamino) ethyl] -2,6-difluorophenoxymethylcarbonyl} -β-alanine.
The described compound. 6. The compound according to claim 3, which is N- {4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-fluorophenoxymethylcarbonyl} -ε-aminocaproic acid.