JPH068274B2 - 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 hereafter abbreviated as TxA ₂ ) is produced by the metabolism of arachidonic acid that is widely present in various animal organs (for example, liver, kidney, lung, brain, etc.). It is known that various thrombosis such as peripheral arterial thrombosis, pulmonary embolism, coronary artery occlusion, myocardial infarction, and transient cerebral ischemia are often caused by the platelet aggregation action of TxA _2. Has been. Therefore, 4- (2-benzenesulfonylaminoethyl) phenoxyacetic acid has been reported as a drug that suppresses platelet aggregation based on TxA ₂ [Thrombosis Research,
35, 379-395 (1984)].

(Structure and Effect of the Invention) (However, ^one of R ¹ and R ² is a lower alkyl group, a phenyl group-substituted lower alkyl group or a phenyl group, the other represents a hydrogen atom, R ³ is a halogenophenyl group, a phenyl group or a naphthyl group, R ⁴ is It represents an optionally protected carboxyl group, hydroxyl group or di (lower alkyl) amino group, m represents 0 or 1, and n represents an integer of 0 to 5.
However, when m and n are 0 and R ⁴ is a carboxyl group which may be protected, either ^one of R ¹ and R ² is a phenyl group-substituted lower alkyl group or a phenyl group, or Represents that ³ is a naphthyl group. ) The phenoxyacetic acid derivative or its salt shown by these.

The compound (I) of the present invention and a salt thereof have a more excellent TxA ₂ antagonistic activity as compared with the above-mentioned known compounds, and are useful as a platelet aggregation inhibitor and a prophylactic / therapeutic agent for thrombosis, and in coronary / cerebral blood vessels. It is a pharmaceutical compound useful as a prophylactic / therapeutic agent for smooth muscle spasm and asthma.

As specific examples of the compound of the present invention, ^one of R ¹ and R ² in the general formula (I) is a lower alkyl group, a phenyl group-substituted lower alkyl group or a phenyl group, and R ³ is a fluorine atom or a chlorine atom. A phenyl group or naphthyl group optionally substituted with a halogen atom such as a bromine atom, R ⁴ is a free carboxyl group, a hydroxyl group or a di (lower alkyl) amino group, or a lower alkyl group, a benzyl group, p -Methoxybenzyl group. Examples thereof include compounds having a phenyl group-substituted lower alkyl group which may have a nitro group or a lower alkoxy group on the phenyl group such as p-nitrobenzyl group, or a carboxyl group protected by a benzhydryl group.

In addition, in the specific examples, the compound that is preferable in terms of efficacy is a compound whose alkyl group is a C _1-4 alkyl group, and more preferable compound is that the alkyl group is a methyl group or an ethyl group and the halogen atom is a chlorine atom or bromine. It is a compound of atoms.

The compound (I) of the present invention is 2 based on one asymmetric carbon atom.
Although optical isomers of species may exist, the present invention includes both these isomers and mixtures thereof.

According to the present invention, the target compound (I) has, for example, the general formula: (However, R ¹ , R ² and R ³ have the same meanings as described above.) And a salt thereof and a general formula X ¹ CH ₂ (CONH) _m- (CH ₂ ) _n -R ⁴¹ (III (However, X ¹ represents a reactive residue, R ⁴¹ represents an optionally protected carboxyl group, hydroxyl group or di (lower alkyl) amino group, and m and n have the same meanings as described above.) When R ⁴¹ is a protected carboxyl group by subjecting it to a condensation reaction with a compound represented by, it can be produced by optionally removing the protecting group.

The target compound (I) has the general formula (Wherein Y represents an amino group which may be protected or a reactive residue, and R ¹ , R ² , R ⁴¹ , m and n have the same meanings as described above) or a salt thereof. , R ³ SO ₂ Z (V) (provided that Z is a hydroxyl group or a reactive residue when Y is an amino group which may be protected, and a free amino group when Y is a reactive residue. Represents a group, R ³ has the same meaning as described above), and R ⁴¹ is a protected carboxyl group and / or group Y is a protected amino group. In some cases, the protective group can be removed if desired.

Further, among the target compounds (I), the general formula (However, R ¹ , R ² and R ³ have the same meanings as described above.) (However, R ⁵ represents a lower alkyl group or a hydrogen atom,
R ¹ , R ² and R ³ have the same meaning as described above. ) It can also be produced by subjecting a carboxylic acid compound represented by

Further, among the target compounds (I), the compound of m = 1 is a compound of the carboxylic acid compound (Ia) in which R ⁵ is a hydrogen atom or a reactive derivative at the carboxyl group thereof and a compound of the general formula NH ₂ — (CH ₂ ) _n -R ⁴¹ (VI) (provided that R ⁴¹ and n have the same meanings as described above) by condensation reaction with an amine compound or a salt thereof, and R ⁴¹ is a protected carboxyl group. If desired, the protective group can be removed to prepare the compound.

As the carboxyl group-protecting group in the raw material compounds (III), (IV) and (VI), any protecting group that can be easily removed by ordinary treatment such as hydrolysis, acid treatment or reduction can be used. As such a protecting group, for example, a lower alkyl group, a lower alkyl group substituted with a substituted or unsubstituted phenyl group (eg, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, etc.), benzhydryl group, etc. Is mentioned. Examples of the reactive residue (X ¹ and Y or Z) include a halogen atom, a lower alkylsulfonyloxy group, a substituted or unsubstituted phenylsulfonyloxy group (eg, benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc.). It can be preferably used.

The condensation reaction of the phenol compound (II) or its salt with the compound (III) can be suitably carried out according to a conventional method, for example, in a solvent. As the salt of the phenol compound (II), for example, an alkali metal salt, an alkaline earth metal salt or the like can be used. This reaction is preferably carried out in the presence of a deoxidizing agent, for example, an alkali metal carbonate, an alkali metal hydroxide, an alkali metal bicarbonate, pyridine, or an organic amine such as tri-lower alkylamine. As the solvent, for example, acetone, chloroform, alkanol, methylene chloride, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, or a mixed solvent thereof can be preferably used. This reaction can be suitably carried out at room temperature to under heating.

The condensation reaction of compound (IV) or a salt thereof and sulfonic acid compound (V) can be appropriately carried out in the presence or absence of a deoxidizing agent. As the deoxidizing agent, those mentioned above can be used in the same manner. The reaction can be carried out in a solvent or without solvent, and as such a solvent, ether, benzene, methylene chloride, dioxane, ethanol, methanol, water or a mixed solvent thereof can be appropriately used. Further, when the group Y is an amino group, the compound (IV) can be subjected to the reaction in the form of a salt such as a mineral acid salt or an organic acid salt, and the group Y is a protected amino group or R ^41. When it is a free carboxyl group, it can be used in the reaction in the form of a salt such as an alkali metal salt or an alkaline earth metal salt. Further, when the group Y is a protected amino group, it is preferable to use a lower alkanoyl group or an aryloxycarbonyl group (for example, a benzyloxycarbonyl group) or the like as the protecting group for the amino group. This reaction can be suitably carried out under heating to heating.

The reduction reaction of the carboxylic acid compound (Ia) can be carried out 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,
Tetrahydrofuran is a suitable solvent. This reduction reaction is preferably carried out under cooling to heating.

The condensation reaction of the compound in which R ^{5 of the} carboxylic acid compound (Ia) is a hydrogen atom or the reactive derivative at the carboxyl group thereof and the amine compound (VI) can be carried out according to a conventional method. For example, a free carboxylic acid type compound (I
The condensation reaction between compound (VI) and compound (VI) can be carried out in the presence of a dehydrating agent, and as the dehydrating agent, any conventional one such as carbonyldiimidazole or dicyclohexylcarbodiimide can be used. . On the other hand, the condensation reaction between the reactive derivative at the carboxyl group of the compound (Ia) in which R ⁵ is a hydrogen atom and the compound (VI) can be carried out in the presence or absence of a deoxidizing agent. As the reactive derivative at the carboxyl group of the compound (Ia), for example, corresponding acid halides, mixed acid anhydrides, active esters and the like can be suitably used, and as the deoxidizing agent, the above-mentioned compound (II) can be used. What was illustrated by the condensation reaction can be used. All of these condensation reactions are preferably carried out in a suitable solvent (eg, tetrahydrofuran, methylene chloride) under cooling to heating.

In the product thus obtained, when R ⁴¹ is a protected carboxyl group and / or when the group Y is a protected amino group, the protecting group may be optionally removed. The removal can be carried out by a conventional method such as hydrolysis, solvolysis, acid treatment and reduction.

Since all the above reactions proceed without racemization, if the optically active substance is used as the starting compound (II) or (IV), the desired product (I) can also be obtained as the optically active substance.

The object compound (I) of the present invention or a salt thereof has an excellent TxA ₂ antagonism as described above, and thus is useful as a platelet aggregation inhibitor, for example, cerebral thrombosis, coronary artery thrombosis, pulmonary thrombosis, lung. It can be used for treatment, alleviation and prevention of various thrombosis such as embolism, peripheral vascular embolism and thrombovascular inflammation, embolism and the like. In addition, the objective 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 is 1 is affected by Tx in both oral administration and parenteral administration.
It has an excellent feature that it does not show an A ₂ -like action.

The object compound (I) of the present invention can be used in medicinal use in either a free form or a salt form thereof. When used for pharmaceutical purposes, the salt is preferably a pharmacologically acceptable salt. Examples of such a salt include salts with inorganic or organic bases, for example, alkali metal salts such as sodium salt and potassium salt, calcium salt. , Alkaline earth metal salts such as magnesium salts, heavy metal salts such as zinc salts, ammonium salts, triethylamine salts, pyridine salts, ethanolamine salts, organic amine salts such as basic amino acid salts, and organic acid addition salts such as formate salts, Includes oxalates, methanesulphonates and glucuronates. These salts can be easily obtained by, for example, treating compound (I) with an inorganic or organic base or an organic acid in a suitable solvent.

The target compound (I) or a salt thereof can be administered orally or parenterally, and can be mixed with an excipient suitable for oral or parenteral administration and used as a medicinal material. Further, the medicinal materials may be solid preparations such as tablets, capsules and suppositories, and liquid preparations such as solutions, suspensions and emulsions. When administered parenterally, it can be used in the form of injection.

The starting compounds (II) and (IV) of the present invention are novel compounds, and the starting compound (II) is (However, R ⁶ represents an optionally protected hydroxyl group, Y ¹ represents an optionally protected amino group or a reactive residue, and R ¹ and R ² have the same meanings as described above.). It can be produced by reacting a compound and a sulfonic acid compound (V) under the same conditions as in the condensation reaction of the starting compounds (IV) and (V). Alternatively, in the starting compound (II), a compound in which R ² is a lower alkyl group or a phenyl group and R ¹ is a hydrogen atom has the general formula (Provided that R ⁶ has the same meaning as described above) and a sulfonic acid compound (V) (provided that Z
= Halogen atom) in the presence of an alkali metal carbonate in a solvent, the product is reacted with a lower alkyl or phenyl magnesium halide, and then the product is catalytically reduced in the presence of a palladium carbon catalyst. If necessary, it can be produced by further removing the protective group for the hydroxyl group. On the other hand, the starting compound (IV) is, for example, the compound (VII)
Can be produced by reacting a compound in which R ⁶ is a hydroxyl group with the compound (III) under the same conditions as in the condensation reaction of the starting compounds (II) and (III).

In the present specification, "lower alkyl", "lower alkoxy" and "lower alkanoyl" each have 1 carbon atom.
It represents a straight-chain or branched alkyl having 6 to 6, an alkoxy having 1 to 6 carbons, and an alkanoyl having 1 to 4 carbons.

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 to 20 animals / kg. 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 administration of arachidonic acid until the ambulatory movement was recovered (recovery time: min).
The comparison was made with that of the non-administration group of the sample to which MC was administered. 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) Magnesium 5.83 g was dried in tetrahydrofuran 100.
5 ml of 1,2-dibromoethane, and after stirring at room temperature, 28.3 g of phenyl bromide in 70 ml of tetrahydrofuran.
The solution is added dropwise. Then, a solution of 7.65 g of 2-benzenesulfonylamino-1- (4-benzyloxyphenyl) ethanone in 100 ml of tetrahydrofuran was added dropwise to the mixture while stirring with ice-water cooling, and the mixture was stirred at room temperature. After the reaction, dilute ammonium chloride aqueous solution is added, and then the mixture is extracted with ethyl acetate. After washing and drying the extract, the solvent was distilled off, the residue was purified by silica gel flash column chromatography (solvent: chloroform), and recrystallized from a mixed solution of ethyl acetate-n-hexane to give 2-benzenesulfonylamino-1. -(4-benzyloxyphenyl) -1-
5.37 g of phenylethanol are obtained as colorless crystals.

(2) 4.91 g of this product is used in 100 ml of tetrahydrofuran and 20 ml of water
3.85 g of oxalic acid was added to the solution, and pressurized with hydrogen gas (3.5 atm) in the presence of 3.2 g of 10% palladium on carbon.
Conduct catalytic reduction at 50-60 ℃ for 2.5 days. After the reaction, the catalyst is filtered off and the filtrate is concentrated. Ethyl acetate is added to the residue, washed and dried, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: methanol = 50:
It was purified in 1) and recrystallized from a mixed solution of ethyl acetate-toluene-n-hexane to obtain 3.26 g of 4- (1-phenyl-2-benzenesulfonylaminoethyl) phenol as colorless needle crystals.

M. P. 120-124 ° C (3) Dissolve 3.10 g of this product in 25 ml of acetone, add 1.33 g of potassium carbonate and 1.61 g of ethyl bromoacetate, and stir at room temperature for 2.5 days. Evaporate the solvent,
Water is added, the mixture is extracted with ethyl acetate, washed and dried, and then the solvent is distilled off. The residue was purified by silica gel flash column chromatography (solvent; toluene: ethyl acetate = 20: 1 to 10: 1) to give 1.85 g of ethyl 4- (1-phenyl-2-benzenesulfonylaminoethyl) phenoxyacetate as a colorless oil. Get as a thing.

(4) Dissolve 1.81 g of this product in 16 ml of ethanol, and
6.2 ml of N-sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the aqueous solution of the residue was treated with a nonionic adsorption resin (trade name: Diaion HP-20;
After purification by packed column chromatography, 4 ml of 1N-sodium hydroxide aqueous solution was added again to make a disodium salt and recrystallized from isopropyl alcohol.
1.227 g of (1-phenyl-2-benzenesulfonylaminoethyl) phenoxyacetic acid disodium salt is obtained as colorless needle crystals.

Yield 69% M.I. p. > 320 ° C Example 2 (1) After washing 6 g of 60% sodium hydride with n-hexane, 200 ml of tetrahydrofuran was added, and a solution of 30.7 g of diethyl malonate in 50 ml of tetrahydrofuran was added dropwise under cooling with ice water. Then, after stirring at room temperature for 1 hour, a solution of 4-benzyloxybenzyl chloride (23.4 g) in tetrahydrofuran (50 ml) was added dropwise, and the mixture was heated under reflux for 12 hours. After cooling, 200 ml of ethanol was added, and 22.4 g of potassium hydroxide was added in 100 ml of an aqueous solution,
Heat to reflux for hours. The reaction solution is concentrated, water is added to the residue,
Extract with ethyl acetate. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with chloroform. The chloroform extract was dried, the solvent was distilled off, and the residue was recrystallized from a mixed solution of ethyl acetate-n-hexane to give β- (4-benzyloxyphenyl) -α-phenylpropionic acid (21.7 g) as colorless plate crystals. obtain.

Yield 66% M. p. 133-137 ° C. (2) 3.32 g of this product, 3.3 g of diphenylphosphoryl azide and 1.21 g of triethylamine were added to toluene 4
It is dissolved in 0 ml and heated under reflux for 0.5 hours, then 2.16 g of benzyl alcohol is added, and the mixture is further heated under reflux for 3 hours. After the reaction, ethyl acetate is added, washed and dried, and then the solvent is distilled off. The residue is recrystallized from a mixed solution of ethyl acetate-n-hexane to obtain 3.54 g of N-benzyloxy-2- (4-benzyloxycarbonylphenyl) -1-phenylethylamine as colorless needle crystals.

Yield 81% M. p. 111-112 ℃ (3) 4.37 g of this product in tetrahydrofuran (45 ml)
-Dissolve in a mixed solution of water (5 ml) and conduct catalytic reduction in the presence of 450 mg of 10% palladium-carbon. After 8 hours, 250 mg of 10% palladium-carbon was added, the reaction was continued for 2.5 hours, and the catalyst was removed by filtration. 2 ml of concentrated hydrochloric acid, 5 ml of water and 50 ml of ethanol are added to the filtrate, and the solvent is distilled off. The residue is recrystallized from an ethanol-ether mixed solution to obtain 2.1 g of 4- (2-amino-2-phenylethyl) phenol hydrochloride as colorless needle crystals.

Yield 84% p. 255-256 ° C. (4) 2 g of this product was added to a mixed solution of 70 ml of ethyl acetate and 50 ml of a saturated aqueous solution of sodium hydrogencarbonate, and then 1.69 g of 4-chlorophenylsulfonyl chloride was added to the mixture.
Stir at room temperature for hours. The organic layer is separated and dried,
The solvent is distilled off. The residue was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 4- [2- (4-chlorophenyl)) sulfonylamino-2-phenylethyl] phenol.2.
63 g are obtained as colorless prism crystals.

Yield 85% p. 174-178 ° C. (5) 2.52 g of this product is dissolved in 45 ml of acetone, 1.2 g of methyl bromoacetate and 1.8 g of potassium carbonate are added,
Stir at room temperature for 15 hours. The solvent is distilled off, water is added, and the mixture is extracted with chloroform. The solvent is distilled off, the residue is dissolved in 15 ml of methanol, 5 ml of 10% aqueous sodium hydroxide solution is added, and the mixture is left at room temperature for 15 minutes. The reaction mixture was concentrated, the residue was dissolved in water, and purified by non-ionic adsorption resin (trade name: Diaion HP-20; manufactured by Mitsubishi Kasei) packed column chromatography, followed by isopropyl alcohol-water-
Recrystallization from an ether mixture gives 1.42 g of 4- [2- (4-chlorophenyl) sulfonylamino-2-phenylethyl] phenoxyacetic acid sodium salt as colorless prism crystals.

M. p. 215-218 ° C. Free carboxylic acid: colorless prism crystal M.I. p. 180-181 ° C. (recrystallized from acetone-n-hexane) Examples 3 to 5 Corresponding raw material compounds are treated in the same manner as in Examples 2- (4) and (5) to obtain the compounds shown in Table 2 below.

Example 6 (1) Diisopropylamine (9.11 g) was dissolved in dry tetrahydrofuran (120 ml), and n-butyllithium hexane solution (10 w / v%) (54 ml) was added at -10 to 0 ° C.
Add dropwise over 5 minutes. After stirring for 10 minutes, at the same temperature, 3-
A solution of 12.5 g of (4-methoxyphenyl) propionic acid ethyl ester in 60 ml of tetrahydrofuran is added dropwise over 45 minutes. After stirring for 20 minutes, 1 mL of a solution of 16.4 g of benzyl bromide and 9.24 g of hexamethylphosphoric triamide in 50 ml of tetrahydrofuran at -60 ° C.
Add dropwise over 0 minutes. After stirring at the same temperature for 2 hours, the temperature is returned to room temperature over 1 hour, and the mixture is stirred at room temperature for 1 hour. Under cooling,
Water and 10% hydrochloric acid are added and the mixture is extracted with ethyl acetate. Washing,
After drying and filtering, the solvent is distilled off. Purification by flash column chromatography (solvent; n-hexane: ethyl acetate = 30: 1) gives 2-benzyl-3- (4-methoxyphenyl) propionic acid ethyl ester (9.5 g) as a colorless oil.

(2) Dissolve 9.49 g of this product in 95 ml of ethanol, and
42 ml of a 5% aqueous sodium hydroxide solution is added, the mixture is stirred at room temperature for 1 hour, and then heated under reflux for 1 hour. Evaporate the solvent,
While cooling, 20 ml of concentrated hydrochloric acid was added and the mixture was extracted with ethyl acetate. After drying and filtering, the solvent is distilled off and the residue is recrystallized from n-hexane to give 2-benzyl-3- (4-methoxyphenyl) propionic acid (6.68 g) as colorless needle crystals.

(3) Dissolve 6.61 g of this product in 75 ml of dry toluene,
2.97 g of triethylamine and 8.08 g of diphenylphosphoryl azide were added, and the mixture was kept at room temperature for 20 minutes and then 80%.
Stir for 30 minutes at ° C. The solvent is distilled off, 80 ml of tert-butyl alcohol is added, and the mixture is heated under reflux overnight. The solvent is distilled off, the residue is dissolved in ethyl acetate, washed, dried and filtered, and the solvent is distilled off. The obtained residue is subjected to flash column chromatography (solvent; n-hexane: ethyl acetate = 10: 1).
And then recrystallized from n-hexane to give N- (1-benzyl-4′-methoxyphenethyl) carbamic acid te.
4.83 g of rt-butyl ester are obtained as colorless prism crystals.

(4) 24 ml of 25% hydrobromide acetic acid solution to 4.68 g of this product
After foaming and dissolving, 480 ml of ether was gradually added. The precipitated crystals are collected by filtration and dried to obtain 1.75 g of 1-benzyl-4′-methoxyphenethylamine hydrobromic acid as colorless prism crystals.

(5) To 4.31 g of this product, 50 ml of water, 2.48 g of sodium hydrogen carbonate and 100 ml of ethyl acetate were added, and a solution of 4.40 g of 4-chlorophenylsulfonyl chloride in 50 ml of ethyl acetate was added dropwise to the mixture with vigorous stirring at room temperature. Then stir for 1 hour. The organic layer is separated, washed, dried and filtered, and then the solvent is distilled off to give 2-benzyl-2- (4-
6.14 g of chlorophenyl) sulfonylamino-1- (4-methoxyphenyl) ethane are obtained as a pale yellow oil. Dissolve this in 90 ml of dry methylene chloride,
Cool to -60 ° C. A solution of boron tribromide (7.72 g) in methylene chloride (90 ml) was added dropwise with stirring in an argon stream. The reaction solution is stirred at the same temperature for 20 minutes and then returned to room temperature over 1 hour. After completion of the reaction, water is added under cooling, the organic layer is separated, washed, dried and filtered, and then the solvent is distilled off. The residue was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 4- [2-
4.65 g of benzyl-2- (4-chlorophenyl) sulfonylaminoethyl] phenol is obtained as colorless prism crystals.

Yield 86% Mass (m / e): 401 (M ⁺ ) (6) This product (4.65 g) was treated in the same manner as in Example 2- (4) and (5) to give 4- [2-benzyl-2- (4-). 2.87 g of chlorophenyl) sulfonylaminoethyl] phenoxyacetic acid are obtained as colorless prism crystals.

M. p. 149.5-151 ° C Example 7 775 mg of 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid was dissolved in 10 ml of tetrahydrofuran, and 0.75 ml of borane-1,4-oxathiane complex (7.8M) was dissolved. Is dripped on an ice bath. After stirring at room temperature for 1 hour, methanol is added and the solvent is distilled off. The residue is extracted with ethyl acetate, washed and dried, and then the solvent is distilled off. The crude crystals were recrystallized from toluene to give 2-
632 mg of {4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxy} ethanol are obtained as colorless crystals.

Yield 85% p. 108.5-110.5 ° C Examples 8-9 The products of Reference Examples 3-4 are treated in the same manner as in Example 7 to obtain the compounds shown in Table 3 below.

Example 10 1.34 g of 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid was added to methylene chloride (1
0 ml) -tetrahydrofuran (10 ml) mixed solution,
Add 2 ml of thionyl chloride and heat to reflux for 2 hours. The solvent is distilled off and the residue is dissolved in 10 ml of methylene chloride. The solution was added with N, N-dimethyl-1,2-ethanediamine 3
12 mg and triethylamine 354 mg of methylene chloride 1
Add dropwise to 5 ml solution and stir overnight at room temperature. After the reaction, the solvent is distilled off and the residue is extracted with ethyl acetate. Washing,
After drying, the solvent is distilled off and the residue is converted to oxalate. Recrystallization from a mixed solution of methanol-water-isopropyl alcohol and 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid. (N, N-dimethyl-2-
1.47 g of aminoethyl) amide oxalate are obtained as colorless prism crystals.

Yield 77% p. 154 to 157 ° C. Examples 11 to 18 The products of Examples 3 and Reference Examples 1 to 4 and the corresponding amine compounds are treated in the same manner as in Example 10 to obtain the compounds shown in Table 4 below.

Example 19 1.15 g of 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid was added to methylene chloride (7
ml) -tetrahydrofuran (7 ml) in a dry mixed solvent, added with thionyl chloride (2.2 ml) and heated under reflux for 2 hours. The solvent is distilled off to obtain 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetyl chloride as an ocher oil. A 10 ml solution of this product in tetrahydrofuran and 6 ml of a 0.6N sodium hydroxide aqueous solution were stirred, and at the same time, 6-aminohexanoic acid 7
87 mg of a 0.6N aqueous sodium hydroxide solution (11 ml), ethanol (20 ml) and ether (10 ml) were added dropwise to the homogeneous solution, and the mixture was stirred overnight at room temperature. 50 ml water and 5 ether
0 ml was added and the layers were separated, the aqueous layer was acidified with 10% hydrochloric acid and extracted with ethyl acetate. After washing, drying, filtering, and removing the solvent by distillation, the pale yellow caramel obtained is purified by silica gel column chromatography (solvent; chloroform, then chloroform: methanol = 9: 1) to give 4- [2- (4-chlorophenyl). ) Sulfonylaminopropyl] phenoxyacetic acid
1.50 g of (5-carboxypentyl) amide are obtained as a colorless oil.

100% yield Example 20 900 mg of 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid. (3-methoxycarbonylpropyl) amide was dissolved in 5 ml of methanol to give 1
Add 5 ml of N-sodium hydroxide aqueous solution and add 0.5 at room temperature.
Stir for time. The solvent is evaporated, acidified with 10% hydrochloric acid and extracted with chloroform. After drying, the solvent was distilled off to give 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid. (3-carboxypropyl).
900 mg of amide are obtained as a colorless oil.

100% yield Examples 21 to 26 The products of Examples 11 to 12 and 14 to 17 are treated in the same manner as in Example 20 to obtain the compounds shown in Table 5 below.

Reference Example 1 (1) 1- (4-Benzyloxyphenyl) -2-chloroethanone (78 g) and hexamine (63 g) are dissolved in chloroform and stirred overnight at room temperature. The mixture is concentrated and then refluxed with stirring. After cooling, the precipitated crystals are washed, dried, added to a mixed solution of ethanol and concentrated hydrochloric acid, and refluxed. After cooling, wash and dry the precipitated crystals.
2-Amino-1- (4-benzyloxyphenyl) ethanone 55.
6 g are obtained as colorless crystals.

Yield 67% mp225 ° C (decomposition) (2) Dissolve 1.11 g of this product in a tetrahydrofuran-water mixed solution, and add an aqueous solution of potassium carbonate 1.11 g and a solution of benzenesulfonyl chloride 1.41 g of tetrahydrofuran at 40 ° C at the same time. To do. Then, the mixture is stirred at room temperature and extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off,
The residue was recrystallized from ethyl acetate and 2-benzenesulfonylamino-1- (4-benzyloxyphenyl) ethanone 1.34g
As colorless needles.

Yield 89% mp 148-149 ° C (3) This product was treated in the same manner as in Examples 1- (1) to (4) to give 4- (1-methyl-2-benzenesulfonylaminoethyl).
Phenoxyacetic acid sodium salt is obtained as a colorless powder.

mp 180 ° C or higher Free carboxylic acid: colorless caramel Reference Example 2 (1) 4- (2-aminopropyl) phenol hydrobromide 2.32 g, sodium hydrogencarbonate 4.2 g, water 50
ml, 100 ml of ethyl acetate and 2.11 g of 4-chlorophenylsulfonyl chloride are stirred at room temperature for 3 hours. After the reaction, the ethyl acetate layer was separated, dried and the solvent was distilled off to obtain 3.25 g of 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenol as a brown oil.

100% yield (2) 1.63 g of this product was treated in the same manner as in Example 1- (3) to obtain crude 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid methyl ester.
This is dissolved in 15 ml of methanol, 4 ml of 10% aqueous sodium hydroxide solution is added, and the mixture is left at room temperature for 1 hour. 10%
Acidify with hydrochloric acid, extract with chloroform, dry and evaporate the solvent. The residue was separated and purified by silica gel column chromatography (solvent; chloroform, and then developed with chloroform: methanol = 19: 1) to give 4- [2- (4-
0.96 g of chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid are obtained.

Yield 50% mp132-136 ° C. (recrystallized from chloroform-n-hexane) In addition, (R) -4- (2
-Aminopropyl) phenol hydrobromide was used to carry out the same treatment to obtain (R) -4- [2- (4-
Chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid is obtained.

mp132-133 ° C (recrystallized from ethyl acetate-n-hexane) Reference Example 3 (1) A solution of 19.8 g of 1-amino-2- (4-methoxyphenyl) propane and 84 g of sodium hydrogen carbonate in ethyl acetate-water was cooled, and a solution of 18.8 g of acetyl chloride in ethyl acetate was added dropwise. After the reaction, the ethyl acetate layer was separated, washed and dried, and the solvent was distilled off to give 1-acetylamino-
24.8 g of 2- (4-methoxyphenyl) propane are obtained as an oil.

(2) To a methylene chloride solution of this product, a solution of 69 g of boron tribromide in methylene chloride was added dropwise with cooling and stirring. After reacting under cooling, it is decomposed with water and chloroform is added. Then, the organic layer is separated, washed and dried, and the solvent is distilled off to give 4-
23.1 g of (2-acetylamino-1-methylethyl) phenol are obtained as an oil.

100% yield (3) This product is dissolved in 400 ml of acetone, 19.9 g of methyl bromoacetate and 18 g of potassium carbonate are added, and the mixture is stirred overnight. Further, 7.96 g of methyl bromoacetate and 7.2 g of potassium carbonate are added, and the mixture is stirred for 3 days. After the reaction, the solvent is distilled off, water is added to the residue, and the mixture is extracted with ethyl acetate. After washing and drying, the solvent and excess methyl bromoacetate were removed by distillation.
31.6 g of methyl (2-acetylamino-1-methylethyl) phenoxyacetate is obtained as a yellow oil.

(4) This product is added to 200 ml of 6N hydrochloric acid and heated under reflux for 7.5 hours. After the reaction, the solvent is distilled off, and the residue is crystallized from tetrahydrofuran to obtain 19 g of 4- (2-amino-1-methylethyl) phenoxyacetic acid hydrochloride as a colorless solid.

(5) This product 2.95 g, potassium carbonate 3.65 g, water 3
0 ml and 4-chlorophenylsulfonyl chloride 2.7
1 g of the mixture is stirred at 80 ° C. for 2 hours. 6N after cooling
Adjust the pH to 1 with hydrochloric acid and extract with ethyl acetate. The solvent was distilled off and 4- [2- (4-chlorophenyl) sulfonylamino-1-methylethyl] phenoxyacetic acid 2.53 g
To get

mp118-119.5 ° C. (decomposition, recrystallization from ethyl acetate-n-hexane) Reference Example 4 The corresponding starting material compound was treated in the same manner as in Reference Example 3 to give 4- [2-
(4-Bromophenyl) sulfonylamino-1-methylethyl] phenoxyacetic acid is obtained.

mp131-133 ° C (recrystallized from ethyl acetate-n-hexane)

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shima ▲ ▼ Tamotsu 4-7 Chiyoda, Sakado City, Saitama Prefecture 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, ^one of R ¹ and R ² is a lower alkyl group, a phenyl group-substituted lower alkyl group or a phenyl group, the other represents a hydrogen atom, R ³ is a halogenophenyl group, a phenyl group or a naphthyl group, R ⁴ is It represents an optionally protected carboxyl group, hydroxyl group or di (lower alkyl) amino group, m represents 0 or 1, and n represents an integer of 0 to 5.
However, when m and n are 0 and R ⁴ is a carboxyl group which may be protected, either ^one of R ¹ and R ² is a phenyl group-substituted lower alkyl group or a phenyl group, or R ³ Represents a naphthyl group. ) A phenoxyacetic acid derivative represented by or a pharmacologically acceptable salt thereof. 2. ^One of R ¹ and R ² is a C _1-4 alkyl group, a phenyl group-substituted C _1-4 alkyl group or a phenyl group,
The other represents a hydrogen atom and R ⁴ is a free carboxyl group, a hydroxyl group or a di (C _1-4 alkyl) amino group, or a C _1-4 alkyl group, a nitro group or a C group on the phenyl group.
_1-4 Phenyl group-substituted C which may have alkoxy group
_1-4. A phenoxyacetic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is a carboxyl group protected by an alkyl group or a benzhydryl group. 3. ^One of R ¹ and R ² represents a methyl group, a benzyl group or a phenyl group, the other represents a hydrogen atom, R ³ represents a phenyl group, a chlorophenyl group, a bromophenyl group or a naphthyl group, and R ^4. A phenoxyacetic acid derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein ⁴ is a free carboxyl group, a hydroxyl group or a dimethylamino group, or a carboxyl group protected by a methyl group or an ethyl group. 4. The phenoxyacetic acid derivative according to claim 3, which is 2- {4- [2- (4-bromophenyl) sulfonylamino-1-methylethyl] phenoxy} ethanol, or a pharmaceutically acceptable salt thereof. 5. The phenoxyacetic acid derivative or the pharmaceutically acceptable salt thereof according to claim 3, which is 4- [2- (4-chlorophenyl) sulfonylaminopropyl] phenoxyacetic acid. (2-carboxyethyl) amide. 6. A phenoxyacetic acid derivative or a pharmaceutically acceptable salt thereof according to claim 3, which is 4- [2- (4-chlorophenyl) sulfonylamino-2-phenylethyl] phenoxyacetic acid.