JPH0672867A - Antilipemic agent - Google Patents

Abstract

PURPOSE:To obtain a new compound, having blood serum cholesterol lowering action and useful for preventing and treating hyperlipemia, arteriosclerosis, etc. CONSTITUTION:The objective antilipemic agent comprises a compound of for I [R<1> is (substituted)phenyl, naphthyl, lower alkyl, etc.; R<2> is H or lower alkyl; R<3> to R<6> are H or lower alkyl; R<7> and R<8> are lower alkyl; Alk1 and Alk2 are single direct bond or lower alkylenel e.g. 2-[4-{2-(p-chlorobenzenesulfonylamino) propyl}phenoxy]-2-methylpropionic acid. Furthermore, this compound of formula is obtained by condensing an amine compound of formula II [CO2 is (protected) carboxyl; R<21> is H or lower alkyl] with a sulfonic acid compound of formula III (X<1> is reactive residue or hydroxyl group).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an antilipemic agent.

[0002]

2. Description of the Related Art Hyperlipidemia, in which hyperlipidemia such as serum total cholesterol and serum triglyceride is increased, and especially hypercholesterolemia are considered to be one of the main causes of various adult diseases such as arteriosclerosis. ing.

For the prevention and treatment of such hyperlipidemia, bezafibrate [chemical name: 2- [4- {2- (p-chlorobenzamino) ethyl} phenoxy] -2-methylpropionic acid] and the like can be used. Antilipemic agents are used clinically.

On the other hand, a compound in which a lower alkyl group is substituted on the ethyl group of 4- {2- (benzenesulfonylamino) ethyl} phenoxyacetic acid is known to have a platelet aggregation inhibitory effect. No antilipemic action is known (JP-A 64-62). Further, a compound in which a lower alkyl group is substituted at its acetic acid site is known to have a platelet aggregation-inhibiting action and a lipid-lowering action, but its blood lipid-lowering action has not been said to be sufficient yet (Japanese Patent Laid-Open No. 2000-242242). 54-122250).

[0005]

DISCLOSURE OF THE INVENTION The present invention provides an antilipemic agent comprising a novel phenoxyalkanoic acid compound as an active ingredient, which has an excellent blood lipid lowering action, and particularly a strong serum cholesterol lowering action. is there.

[0006]

The present invention has the general formula [I]

[0007]

[Chemical 2]

[Wherein R ¹ is a substituted or unsubstituted phenyl group, naphthyl group, sulfur-containing or nitrogen-containing 5- or 6-membered heteromonocyclic group or lower alkyl group; R ² is a hydrogen atom or lower alkyl group; R ³ To R ⁶ are any one or two lower alkyl groups, the others are hydrogen atoms; R ⁷ and R ⁸ are both lower alkyl groups; Alk ₁ and Alk _{2 each} represent a single bond or a lower alkylene group. ] A phenoxyalkanoic acid derivative represented by
The present invention relates to an antilipemic agent containing a pharmaceutically acceptable amide or salt thereof as an active ingredient.

The phenoxyalkanoic acid derivative [I], which is the active ingredient of the present invention, is based on the structural characteristic that both lower alkyl groups are present on the ethyl group site and the acetic acid site, and is compared with known compounds of structural approximation. It is a pharmaceutical compound having an even more excellent blood lipid lowering action and useful as a prophylactic and therapeutic agent for hyperlipidemia.

As specific examples of the phenoxyalkanoic acid derivative [I], R ¹ is a phenyl group; a phenyl group substituted with a halogen atom; a phenyl group substituted with a lower alkyl group; a phenyl group substituted with a lower alkoxy group. A phenyl group substituted with a lower alkanoylamino group; a naphthyl group; a 5- or 6-membered sulfur-containing or nitrogen-containing heteromonocyclic group such as a pyridyl group or a thienyl group; or a compound which is a lower alkyl group.

Among them, preferable compounds in view of the medicinal effect are, in the general formula [I], R ¹ is phenyl group; halogenophenyl group; lower alkylphenyl group; lower alkoxyphenyl group or thienyl group, Alk ₁ and Alk _2. The compound which is a single bond is mentioned.

Further, as a more preferable compound in terms of efficacy, in the general formula [I], R ¹ is a halogenophenyl group; a lower alkylphenyl group or a thienyl group, R ² and R ^{4 to} R ⁶ are hydrogen atoms, R ³ , R ⁷ and R ⁸ are lower alkyl groups, and Alk ₁ and Alk ₂ are single bonds.

The phenoxyalkanoic acid derivative [I] can be used for medicinal use in the form of any of a free carboxylic acid, a pharmaceutically acceptable amide and a salt thereof. Specific examples of such amides include unsubstituted amides such as lower alkyl amides, di lower alkyl amides, carboxy lower alkyl amides or di (carboxy lower alkyl) amides, and mono groups in which the alkyl moiety may be substituted with a carboxyl group. -Or di-lower alkyl amide, as a salt, a salt with an inorganic or organic base, for example, an alkali metal salt such as sodium salt and potassium salt, an alkaline earth metal salt such as calcium salt and magnesium salt, and a heavy metal such as zinc salt. Examples thereof include salts, ammonium salts, triethylamine salts, pyridine salts, ethanolamine salts, organic amine salts such as basic amino acid salts.

In the phenoxyalkanoic acid derivative [I] and its pharmaceutically acceptable amide or salt, the lower alkyl group, the lower alkoxy group, the lower alkanoylamino group and the lower alkylene group are those having 1 to 6 carbon atoms. Particularly, those having 1 to 4 carbon atoms are preferable, and examples of the lower alkanoyl group include those having 2 to 6 carbon atoms, and those having 2 to 4 carbon atoms are particularly preferable.

Further, a phenoxyalkanoic acid derivative [I]
When R ³ and R ⁴ , R ⁵ and R ⁶ and / or R ⁷ and R ⁸ substituted on the same carbon atom are different from each other, 2 to 8 isomers may be present. Any of the mixtures is included as a compound which is an active ingredient of the present invention.

The dose of the phenoxyalkanoic acid derivative [I], or a pharmaceutically acceptable amide or salt thereof, varies depending on the administration method, age of the patient, body weight, condition and kind of disease to be treated, but is usually About 0.1-100m per day
g / kg, especially about 0.5 to 10 mg / kg is preferable.

The antilipemic agent of the present invention can be administered orally or parenterally (eg, intravenous, intramuscular, subcutaneous).

The dosage form for oral administration may be solid preparations such as tablets, granules, capsules and powders,
It may be a liquid preparation such as a solution, suspension or emulsion, and can be used as a pharmaceutical preparation together with a pharmaceutical carrier suitable for oral administration. Examples of such pharmaceutical carriers include binders (syrup, gum arabic, gelatin, sorbit,
Tragant, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.) ) Or a wetting agent (sodium lauryl sulfate, etc.) or any other conventional one can be used.

On the other hand, the dosage form for parenteral administration is preferably an injection or drip injection using, for example, distilled water for injection, physiological saline, an aqueous glucose solution or the like.

The phenoxyalkanoic acid derivative [I] which is the active ingredient of the present invention comprises a) the general formula [II]

[0021]

[Chemical 3]

[However, —CO ₂ Y ¹ represents a carboxyl group or a protected carboxyl group, R ²¹ represents a hydrogen atom or a lower alkyl group, and other symbols have the same meanings as described above. ] The amine compound or its salt shown by these, and general formula [I
II]

[0023]

[Chemical 4]

[However, X ¹ represents a reactive residue or a hydroxyl group, and other symbols have the same meanings as described above. ] Or a b) general formula [IV]

[0025]

[Chemical 5]

[However, the symbols have the same meanings as described above. ] The phenol compound or its salt shown by these, and general formula [V]

[0027]

[Chemical 6]

[Wherein X ² is a reactive residue, --CO ₂ Y ²
Represents a carboxyl group or a protected carboxyl group, and other symbols have the same meanings as described above. ] When the acetic acid derivative represented by or a salt thereof is subjected to a condensation reaction, and c) the group —CO ₂ Y ¹ or the group —CO ₂ Y ² is a protected carboxyl group, the protecting group is removed, and d ) When R ²¹ is a hydrogen atom, the product is N-
It can be produced by alkylation.

In the above-mentioned starting compounds [II] and [V], the protecting group (Y ¹ and Y ² ) for the carboxyl group is a protecting group which can be easily removed by a conventional treatment such as hydrolysis, acid treatment or reduction. Can be used.

Condensation reaction of amine compound [II] and sulfonic acid compound [III] and phenol compound [IV]
The condensation reaction of the acid with the acetic acid derivative [V] can be appropriately carried out in the presence or absence of a deoxidizing agent.

Amine compounds [II] and acetic acid compounds [V] in which the groups -CO ₂ Y ¹ and -CO ₂ Y ² are free carboxyl groups, and sulfonic acid compounds [I in which X ¹ is a hydroxyl group [I]
II] and the phenol compound [IV] can be used in the reaction in the form of a salt.

In the product thus obtained, the group --CO
_{When 2} Y ¹ or the group —CO ₂ Y ² is a protected carboxyl group, the removal of the protecting group is carried out by a conventional method such as hydrolysis, acid treatment or reduction depending on the kind of the protecting group. be able to.

When R ²¹ is a hydrogen atom, N-alkylation of the product can be carried out by reacting with a lower alkyl halide in the presence or absence of a deoxidizing agent.

Further, the amide of the free carboxylic acid type phenoxyalkanoic acid derivative [I] thus obtained can be produced by a conventional method.

The starting compound [II] has, for example, the general formula [VI]

[0036]

[Chemical 7]

[However, the symbols have the same meanings as described above. ] The aminophenol compound or its salt shown by these and acetic acid derivative [V] or its salt are made to react in a suitable solvent in presence of a deoxidizing agent, and it can manufacture.

On the other hand, the starting compound [IV] is, for example, a compound represented by the general formula [VII]

[0039]

[Chemical 8]

[However, R ⁹ represents a hydroxyl group or a protected hydroxyl group, and other symbols have the same meanings as described above. ] When an alkylamine compound represented by the formula [1] or a salt thereof is reacted with a sulfonic acid compound [III] or a salt thereof in the presence of a deoxidizing agent in a suitable solvent, R ⁹ is a protected hydroxyl group, the product Can be produced by removing the protecting group from the compound and, if necessary, N-alkylating.

[0041]

[Action]

Experimental Example (Serum cholesterol level lowering effect) Male SD rats (body weight: 120 to 140 g, 5 animals per group) were given 2 W / W% cholesterol and 0.5 W / W sodium cholate.
% Of the feed was freely given for 4 days. Thereafter, the control group was allowed to freely ingest the above feed, and the sample administration group was allowed to freely ingest the sample plus the feed. Three days later, the rat was anesthetized with ether, and the weight was measured and blood was collected from the abdominal aorta. The blood was allowed to stand at room temperature for 1 hour and then centrifuged to obtain serum, from which the amount of serum cholesterol was measured by an enzymatic method [Clinical Chemistry, No. 20.
Vol., P. 470 (1974)]. Based on the results of this experiment, the serum total cholesterol lowering rate of the test compound was determined according to the first formula. The results are shown in Table 1.

[0042]

[Equation 1]

[0043]

[Table 1]

Production Example 1 (1) 2.6 g of 4-{(RS) -2- (benzenesulfonylamino) propyl} phenol, potassium carbonate 1.
38 g and 2-bromo-2-methylpropionic acid ethyl ester 1.95 g are added to acetone 30 ml and refluxed overnight. Furthermore, 1.38 g of potassium carbonate and 1.95 g of 2-bromo-2-methylpropionic acid ethyl ester are added, and the mixture is further refluxed overnight. Then, the inorganic substances are removed by filtration, and the filtrate is concentrated. The residue was dissolved in ethyl acetate, washed with water and dried, and then the solvent was distilled off to give a crude 2- [4-{(R
3.3 g of S) -2- (benzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid ethyl ester are obtained.

(2) This product is dissolved in 30 ml of methanol, 20 ml of 10% aqueous potassium hydroxide solution is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. 5% of this ethyl acetate layer
Extract with an aqueous sodium hydrogen carbonate solution, acidify the extract with concentrated hydrochloric acid and further extract with chloroform. After the extract was dried, the solvent was distilled off to give 2- [4-{(RS) -2-
(Benzenesulfonylamino) propyl} phenoxy]
2.35 g of 2-methylpropionic acid are obtained as a pale yellow oil. Yield: 70% IR ^Nujol ν _max (cm ^-1 ): 1770 (sh.), 1
718 Mass (m / z): 377 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.06 (d., J = 6.4H)
z, 3H), 1.60 (s., 6H).

(3) 5.66 g of this product was added to 17 ml of a 1N aqueous sodium hydroxide solution, and purified with a nonionic adsorption resin (trade name; Diaion HP-20, manufactured by Mitsubishi Kasei) packed column (solvent: water and 50% methanol). Fractions containing the desired product were collected and lyophilized to give 2- [4-
5.09 g of {(RS) -2- (benzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid sodium salt is obtained as a colorless powder. Yield: 85% IR ^Nujol ν _max (cm ⁻¹ ): 1590 Mass (m / z): 422 (M + Na) ⁺ , 400
(M + H) ⁺ NMR (D ₂ O) δ: 1.01 (d., J = 6.4H
z, 3H), 1.52 (s., 6H).

Production Example 2 (1) 2.60 g of 4-{(RS) -2- (benzenesulfonylamino) propyl} phenol, 5-bromo-
2,2-Dimethylpentanoic acid methyl ester 1.84 g
And 3.10 g of potassium carbonate are added to 50 ml of acetone, and the mixture is stirred at room temperature overnight. After refluxing for another 24 hours,
After removing the inorganic substances by filtration and concentrating the filtrate, the residue was dissolved in ethyl acetate, washed with water and dried, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate-n-hexane = 3). : 7), and separated and purified to give 5- [4-{(R
2.02 g of S) -2- (benzenesulfonylamino) propyl} phenoxy] -2,2-dimethylpentanoic acid methyl ester is obtained as an oil. Yield: 62% IR ^Liquid ν _max (cm ⁻¹ ): 1730 Mass (m / z): 433 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.08 (d., J = 6.4)
Hz, 3H), 1.22 (s., 6H), 3.66.
(S., 3H).

(2) 1.98 g of this product 30 m of ethanol
To the 1 solution, 4 ml of 4N sodium hydroxide is added and refluxed for 5 hours. The solvent was distilled off, the residue was dissolved in water, acidified with 10% hydrochloric acid, extracted with ethyl acetate, washed with water and dried, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: chloroform- Ethyl acetate = 7: 3) was used for separation and purification, and 1.57 g of 5- [4-{(RS) -2- (benzenesulfonylamino) propyl} phenoxy] -2,2-dimethylpentanoic acid was obtained as an oil. obtain. Yield: 82% IR ^Liquid ν _max (cm ^-1 ): 1740 (sh.), 1
700 Mass (m / z): 419 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.09 (d., J = 6.4)
Hz, 3H), 1.26 (s., 6H).

(3) This product was treated in the same manner as in Production Example 1- (3) and recrystallized from isopropyl alcohol to give 5-
[4-{(RS) -2- (benzenesulfonylamino)
1.0 g of propyl} phenoxy] -2,2-dimethylpentanoic acid sodium salt is obtained. Yield: 61% P. : 135-136 ° C IR ^Nujol ν _max (cm ^-1 ): 1540 Mass (m / z): 464 (M + Na) ⁺ , 442
(M + H) ⁺ NMR (D ₂ O) δ: 1.13 (s., 6H), 1.1
7 (d., J = 6.6 Hz, 3H).

Production Example 3 (1) 2- [4-{(RS) -2-aminopropyl} phenoxy] -2-methylpropionic acid ethyl ester.
2.0 g of oxalate and 8.0 g of potassium carbonate are added to a mixture of 20 ml of ethyl acetate and 10 ml of water. The mixture was cooled with ice under p-chlorobenzenesulfonyl chloride 1.1.
Add 7 g and stir at room temperature for 1 hour. After completion of the reaction, the ethyl acetate layer is separated, washed and dried, and then the solvent is distilled off. Recrystallize with a mixed solution of ethyl acetate-n-hexane to give 2
2.2 g of-[4-{(RS) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid ethyl ester is obtained as colorless prism crystals.

M. P. : 78-80 ° C (2) To a solution of 15.0 g of this product in 120 ml of ethanol,
Add 40 ml of 3N sodium hydroxide and stir at room temperature for 2 hours. After completion of the reaction, ethanol was distilled off, diluted with water, acidified with hydrochloric acid, extracted with ethyl acetate, washed with water, dried and concentrated to further crystallize by adding n-hexane. , 2- [4-{(RS) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy]-
13.6 g of 2-methylpropionic acid are obtained as colorless prism crystals.

M. P. : 136-137 ° C. IR ^Nujol ν _max (cm ⁻¹ ): 1710 Mass (m / z): 411 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.13 (d., J = 6.5).
Hz, 3H) 1.60 (s., 6H) (3) This product was treated in the same manner as in Production Example 1- (3), and the eluate was lyophilized to give 2- [4-{(RS) -2
-(P-chlorobenzenesulfonylamino) propyl}
Phenoxy] -2-methylpropionic acid sodium salt (1.98 g) was obtained as a colorless powder. Yield: 82% IR ^Nujol ν _max (cm ⁻¹ ): 1590 Mass (m / z): 456 (M + Na) ⁺ , 434
(M + H) ⁺ NMR (DMSO-d ₆ ) δ: 0.87 (d., J =
6.3 Hz, 3H), 1.36 (s., 6H).

Production Example 4 (1) 2.28 g of 2- [4-{(RS) -2-benzenesulfonylaminopropyl} phenoxy] -2-methylpropionic acid ethyl ester, 1.6 g of methyl iodide and potassium fluoride -Aluminum oxide-water mixture 4.
Add 6 g to 10 ml of acetonitrile and stir at room temperature for 1.5 hours. Then, the insoluble matter was filtered off, the filtrate was diluted with ethyl acetate, washed with water and dried, and then the solvent was distilled off.
[4-{(RS) -2- (N-benzenesulfonyl-N
-Methylamino) propyl} phenoxy] -2-methylpropionic acid ethyl ester 2.32 g is obtained as an oil.

IR ^Liquid ν _max (cm ^-1 ): 1730 Mass (m / z): 419 (M ⁺ ) NMR (CDCl ₃ ) δ: 0.93 (d., J = 6.8)
Hz, 3H), 1.25 (t., J = 7.3Hz, 3
H), 1.58 (s., 6H), 2.73 (s., 3)
H), 4.23 (q., J = 7.3 Hz, 2H) (2) 2.22 g of this product was dissolved in 6 ml of ethanol, and a solution of 1 g of sodium hydroxide in 2 ml of water was added thereto at room temperature. Stir for 5 hours. Then, the solution was concentrated, the residue was acidified with 10% hydrochloric acid, extracted with ethyl acetate, washed with water,
Dry and evaporate the solvent to remove 2- [4-{(RS) -2-
(N-benzenesulfonyl-N-methylamino) propyl} phenoxy] -2-methylpropionic acid 2.15 g
As an oil.

IR ^Liquid ν _max (cm ^-1 ): 1740 Mass (m / z): 391 (M ⁺ ) NMR (CDCl ₃ ) δ: 0.94 (d., J = 6.8)
Hz, 3H), 1.58 (s., 6H), 2.74
(S., 3H) (3) 2.15 g of this product was treated in the same manner as in Production Example 1- (3), freeze-dried, and 2- [4-{(RS) -2- (N-
1.5 g of benzenesulfonyl-N-methylamino) propyl} phenoxy] -2-methylpropionic acid sodium salt is obtained as a colorless powder.

IR ^Nujol ν _max (cm ⁻¹ ): 1600 Mass (m / z): 436 (M + Na) ⁺ , 414
(M + H) ⁺ NMR (DMSO-d ₆ ) δ: 0.82 (d., J =
6.8 Hz, 3H), 1.35 (s., 6H), 2.6
7 (s., 3H).

Production Examples 5 to 25 The corresponding raw material compounds are treated in the same manner as in Production Examples 1 to 4 to obtain the compounds shown in Tables 2 to 7 below.

[0058]

[Table 2]

[0059]

[Table 3]

[0060]

[Table 4]

[0061]

[Table 5]

[0062]

[Table 6]

[0063]

[Table 7]

Production Example 26 3.0 g of 2- [4-{(R) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid sodium salt was added to thionyl chloride 20.
Dissolve in ml and stir the solution at room temperature for 2 hours. Excessive thionyl chloride was distilled off from the reaction solution under reduced pressure, and the residue (2- [4-{(R) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid chloride) was removed. It is dissolved in 10 ml of chloroform, and the solution is added dropwise to a mixed solution of 20 ml of 50% dimethylamine aqueous solution and 10 ml of chloroform. The mixture is stirred at room temperature for 2 hours, and the organic layer is separated from the reaction solution. The organic layer is washed with water and dried, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 1: 1) to give N, N-dimethyl-2- [4-{(R) -2- (p.
2.52 g of -chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropanamide are obtained.

Yield: 83% P. : 107 to 108 ° C. (recrystallized from 2-propanol-isopropyl ether mixed solution) IR ^Nujol ν _max (cm ⁻¹ ): 3190, 1625, ¹
580 Mass (m / z): 439 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.10 (d., J = 6.8).
Hz, 3H), 1.62 (s., 6H), 2.60
(D., J = 6.8 Hz, 2H), 2.96 and 3.1.
7 (d., 6H), 3.40-3.60 (m., 1
H), 4.31 (d., J = 7.3 Hz, 1H), 6.
69 (d., 2H), 6.88 (d., 2H), 7.4
2 (d., 2H), 7.68 (d., 2H).

Production Example 27 (1) Prepared from 3.0 g of 2- [4-{(R) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid sodium salt and 20 ml of thionyl chloride. Acid chloride [2- [4-
[(R) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid chloride] and 1.4 g of β-aminopropionic acid methyl ester hydrochloride were mixed with a two-phase solvent system (sodium hydrogen carbonate). Production Example 26 except that the reaction is performed with an aqueous solution and chloroform)
Treated in the same manner as in N-methoxycarbonylethyl-2-
2.92 g of [4-{(R) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropanamide are obtained. Yield: 85%.

IR ^Nujol ν _max (cm ^-1 ): 3400,
3280, 3200, 1730, 1660 Mass (m / z): 497 (M + H) ⁺ NMR (CDCl ₃ ) δ: 1.11 (d., J = 6.3).
Hz, 3H), 1.49 (s., 6H), 2.56
(D., J = 6.3 Hz, 2H), 2.64 (J = 6.
4Hz, 2H), 3.40-3.70 (m., 3H),
3.63 (s., 3H), 4.41 (d., J = 7.8)
Hz, 1H), 6.76 (d., 2H), 6.92
(D., 2H), 7.17 (d., 1H), 7.42
(D., 2H), 7.68 (d., 2H).

(2) A mixture of 2.1 g of this product and 2 ml of a 4N aqueous sodium hydroxide solution and 20 ml of methanol was stirred at room temperature for 2 hours, and then methanol was distilled off from the reaction solution under reduced pressure. The residue is dissolved in 100 ml of water, ethyl acetate is added and the mixture is shaken, and then the aqueous layer is separated. 10% in the water layer
After adding hydrochloric acid, extract with ethyl acetate, wash the extract,
After drying, the solvent was distilled off under reduced pressure to give N-carboxyethyl-2- [4-{(R) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2.
1.95 g of methylpropanamide are obtained.

IR ^Liquid ν _max (cm ^-1 ): 3400,
3280, 1730, 1660 Mass (m / z): 483 (M + H) ⁺ NMR (CDCl ₃ ) δ: 1.03 (d., J = 6.4)
Hz, 3H), 1.56 and 1.58 (d., 6H),
2.40-2.88 (m., 4H), 3.40-3.7
0 (m., 3H), 5.02 (d., J = 7.8Hz,
1H), 6.72 (d., J = 8.8Hz, 2H),
6.96 (d., J = 8.8Hz, 2H), 7.43
(D., J = 8.8 Hz, 2H), 7.70 (d., J
= 8.8 Hz, 2H).

(3) This product was dissolved in 1 ml of a 4N aqueous sodium hydroxide solution, and the solution was treated in the same manner as in Production Example 1- (3) to prepare N-carboxyethyl-2- [4-{(R). −
1.80 g of 2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropanamide sodium salt is obtained. Yield: 85% IR ^Nujol ν _max (cm ^-1 ): 3300, 3280, ¹
660, 1580 Mass (m / z): 527 (M + Na) ⁺ , 505
(M + H) ⁺ NMR (D ₂ O) δ: 1.17 (d., J = 6.8H
z, 3H), 1.47 (s., 6H), 2.42.
(T., J = 7.3 Hz, 2H), 2.51 (dd.,
J = 14.2Hz, 9.3Hz, 1H), 2.72 (d
d. , J = 13.7 Hz, 4.9 Hz, 1H), 3.4
8 (t., J = 7.3 Hz, 2H), 3.40-3.6.
0 (m., 1H), 6.74 (d., J = 8.3 Hz,
2H), 6.97 (d., J = 8.3Hz, 2H),
7.47 (d., J = 8.8Hz, 2H), 7.58
(D., J = 8.8 Hz, 2H).

Production Example 28 (1) From 2- [4-{(R) -2- (p-methylbenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid sodium salt 3.01 g and thionyl chloride 20 ml Prepared acid chloride (2- [4-
{(R) -2- (p-methylbenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid chloride) and 975 mg of γ-aminobutanoic acid methyl ester hydrochloride were prepared in the same manner as in Production Example 27- (1). Treated with N-methoxycarbonylpropyl-2- [4-
2.4 g of {(R) -2- (p-methylbenzenesulfonylamino) propyl} phenoxy] -2-methylpropanamide are obtained. Yield: 85% IR ^Liquid ν _max (cm ^-1 ): 3380, 3280, ¹
740,1660 Mass (m / z): 491 (M + H) ⁺ NMR (CDCl ₃ ) δ: 1.04 (d., J = 6.6).
Hz, 3H), 1.48 (s., 6H), 1.65-
2.05 (m., 2H), 2.33 (t., J = 6.8)
Hz, 2H), 2.42 (s., 3H), 2.56-
2.70 (m., 2H), 3.20-3.60 (m.,
3H), 3.65 (s., 3H), 4.48 (d., J
= 7.5 Hz, 1 H), 6.70-7.00 (br.,
1H), 6.75 (d., J = 8.7Hz, 2H),
6.96 (d., J = 8.7 Hz, 2H), 7.25
(D., J = 9 Hz, 2H), 7.70 (d., J = 9
Hz, 2H).

(2) This product was treated in the same manner as in Production Examples 27- (2) and (3) to give N-carboxypropyl-2.
1.7 g of sodium salt of-[4-{(R) -2- (p-methylbenzenesulfonylamino) propyl} phenoxy] -2-methylpropanamide are obtained. Yield: 86
% IR ^Nujol ν _max (cm ^-1 ): 3300, 3280, ¹
660, 1580 Mass (m / z): 499 (M + Na) ⁺ , 477.
(M + H) ⁺ NMR (D ₂ O) δ: 1.06 (d., J = 6.4H
z, 3H), 1.48 (s., 6H), 1.64-1.
68 (m., 2H), 2.14 (t., J = 7.3H)
z, 2H), 2.40 (s., 3H), 2.44-2.
72 (m., 2H), 3.25 (t., J = 7.3H)
z, 2H), 3.32-3.52 (m., 1H), 6.
75 (d., J = 8.7 Hz, 2H), 6.97
(D., J = 8.7 Hz, 2H), 7.32 (d., J
= 8.8 Hz, 2H), 7.57 (d., J = 8.8H
z, 2H).

Reference Example 1 (1) 4-{(RS) -2-aminopropyl} pheno-
29.76 g of le bromate and 53 g of potassium carbonate are added to a mixed solution of 400 ml of ethyl acetate and 170 ml of water, 21.11 g of carbobenzoxylcolide is added dropwise, and the mixture is stirred at room temperature for 40 minutes. After the reaction, separate the organic layer,
After washing and drying, the solvent was distilled off to give 4-{(RS) -2-
(Carbobenzoxyamino) propyl} phenol 3
7.5 g are obtained as an oil.

(2) 12.20 g of this product, 2-bromo-2
23.5 g of methyl propionic acid ethyl ester and 16.6 g of potassium carbonate were added to 180 ml of acetone,
Reflux for an hour. Further, 11.8 g of 2-bromo-2-methylpropionic acid ethyl ester is added, and the mixture is refluxed for 24 hours. The inorganic substances were removed by filtration, the filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with water and dried, the solvent was distilled off, the residue was dissolved in 150 ml of ethanol, and 10% palladium-carbon 1. Add 7 g and carry out catalytic reduction in hydrogen at atmospheric pressure.

After the reduction, the palladium-carbon was filtered off, the filtrate was concentrated, the residue was dissolved in ethyl acetate and extracted with 10% hydrochloric acid, the hydrochloric acid layer was made alkaline with potassium carbonate and extracted with ethyl acetate. After drying, the solvent was distilled off, and then ethanol was added.
, Oxalic acid 8.0 g and ether were added,
The precipitated crystals were collected by filtration to give 2- [4-{(RS) -2-
Aminopropyl} phenoxy] -2-methylpropionic acid ethyl ester oxalate 11.0 g is obtained as colorless needle crystals. Yield: 71% P. : 115-117 ° C IR ^Nujol ν _max (cm ^-1 ): 1730 Mass (m / z): 265 (M ⁺ ) NMR (DMSO-d ₆ ) δ: 1.06 (d., J =
6.3 Hz, 3H), 1.16 (t., J = 7.3H)
z, 3H), 1.50 (s., 6H).

Reference Example 2 4-{(R) -2-aminopropyl} phenol bromate was treated in the same manner as in Reference Example 1 to give 2- [4-{(R)
2-Aminopropyl} phenoxy] -2-methylpropionic acid ethyl ester oxalate is obtained as colorless needles.

Yield: 84% P. : 125-126 ° C. (Ethanol-ether) [α] _D : −5.87 ° (C = 1.02, CH ₃ OH,
20 ° C).

Reference Example 3 4- (2-methyl-2-aminopropyl) phenol.
Oxalate 3.06 g, 1,2-dichloroethane 40 m
A mixture of 1, benzenesulfonyl chloride 8.48 g and triethylamine 9.69 g is refluxed for 5 hours. The solvent is distilled off, 50 ml of methanol and 50 ml of 10% sodium hydroxide solution are added, and the mixture is refluxed for 40 minutes. The methanol was distilled off, the pH was adjusted to 1 with 6N hydrochloric acid, the mixture was extracted with ethyl acetate, washed with water, washed with a 5% sodium hydrogen carbonate solution, further washed with water, dried and the solvent was distilled off to obtain an oily product. Was purified by silica gel column chromatography (solvent: ether-n-hexane = 3: 2), and ethyl acetate-n-
Recrystallize from a hexane mixture to give 4- {2-methyl-2-
2.0 g of (benzenesulfonylamino) propyl} phenol is obtained as colorless prism crystals. Yield: 55% P. 147-148 ° C Mass (m / z): 305 (M ⁺ ).

Reference Example 4 4.0 g of 4-{(S) -2-aminopropyl} phenol bromate is added to a solution of 10.1 g of sodium hydrogen carbonate in 80 ml of ethyl acetate and 40 ml of water. A solution of 8.2 g of p-chlorobenzenesulfonyl chloride in 20 ml of ethyl acetate was added dropwise to this mixture at 10-20 ° C. with stirring over 10 minutes. The mixture was stirred at room temperature for 2 hours, acidified with 10% hydrochloric acid, and the organic layer was separated.
The aqueous layer is extracted with ethyl acetate, combined with the previously separated organic layer, washed with water and dried, and then the solvent is distilled off under reduced pressure. N-
Crystallized from hexane and recrystallized from a mixed solution of ethyl acetate-n-hexane to give (S) -4- {2- (p-chlorobenzenesulfonylamino) propyl} phenol 9.5 g.
As colorless needles. Yield: 73% P. : 103-105 ° C (ethyl acetate-n-hexane) IR ^Nujol ν _max (cm ^-1 ): 3300 Mass (m / z): 325 (M ⁺ ) [α] _D : + 2.91 ° (C = 1. 03, CHCl ₃ ,
20 ° C).

Reference Example 5 p-Methylbenzenesulfonyl chloride was treated in the same manner as in Reference Example 4 to prepare 4-{(S) -2- (p-methylbenzenesulfonylamino) propyl} phenol as colorless prism crystals. obtain. Yield: 86% P. : 119-120.5 ° C (ethyl acetate-isopropyl ether-n-hexane) [α] _D : -4.71 ° (C = 1.91, CHCl ₃ ,
20 ° C).

Reference Example 6 To a solution of 3.1 g of 4-{(S) -2-aminopropyl} phenol bromate and 3.8 g of triethylamine in 30 ml of tetrahydrofuran was added 2.4 g of 2-thiophenesulfonyl chloride. Stir at room temperature for 3 hours.
The reaction solution was diluted with water, extracted with ethyl acetate, the organic layer was washed with water and dried, and the solvent was evaporated to give 4-{(S) -2- (2
4.09 g of -thienylsulfonylamino) propyl} phenol are obtained as a pale yellow oil (quantitative).

IR ^Liquid ν _max (cm ⁻¹ ): 3430, 3300 Mass (m / z): 297 (M ⁺ ) [α] _D : + 5.76 ° (C = 1.04, CHCl ₃ ,
20 ° C)

[0083]

The phenoxyalkanoic acid derivative [I], which is the active ingredient of the present invention, and its pharmaceutically acceptable amide or salt are more excellent than the known compounds described in JP-A-54-122250. It is a useful pharmaceutical compound having an antilipemic action, particularly a strong serum cholesterol lowering action, and it is useful for hyperlipidemia (for example, hypercholesterolemia), arteriosclerosis (for example, atherosclerosis, Menkeberg). It can be effectively used for the treatment and prevention of arteriosclerosis.

For example, when the effect of lowering serum total cholesterol was examined in rats, 2- [4] which is the active ingredient of the present invention was investigated.
-{(RS) -2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid sodium salt is 2- [4- {2- (benzenesulfonylamino) ethyl} phenoxy] -2- It showed about 3 times more potent serum total cholesterol lowering effect than methylpropionic acid sodium salt.

The phenoxyalkanoic acid derivative [I], which is the active ingredient of the present invention, has low toxicity.
[4-{(RS) -2- (benzenesulfonylamino)
Propyl} phenoxy] -2-methylpropionic acid sodium salt and 2- [4-{(RS) -1,1-dimethyl-2- (benzenesulfonylamino) ethyl} phenoxy] -2-methylpropionic acid sodium salt Even when 2000 mg / kg was orally administered to each male ddY strain mouse, no death was observed within 72 hours.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07C 311/17 7419-4H 311/29 7419-4H 311/46 7419-4H C07D 213/71 333 / 34 (72) Inventor Akio Otani 1-6-35-519 Namiki, Kawaguchi City, Saitama Prefecture

Claims (9)

[Claims] 1. A compound represented by the general formula [I]: [Wherein R ¹ is a substituted or unsubstituted phenyl group, naphthyl group, sulfur-containing or nitrogen-containing 5- or 6-membered heteromonocyclic group or lower alkyl group; R ² is a hydrogen atom or lower alkyl group;
Any one or two of R ^{3 to} R ⁶ is a lower alkyl group,
Others are hydrogen atoms; R ⁷ and R ⁸ are both lower alkyl groups; Al
k ₁ and Alk ₂ represent a single bond or a lower alkylene group. ]
An antilipemic agent comprising a phenoxyalkanoic acid derivative represented by: or a pharmaceutically acceptable amide or salt thereof as an active ingredient. Wherein R ¹ is a phenyl group; a halogenophenyl group; lower alkyl phenyl group; a lower alkoxyphenyl group, lower alkanoylamino phenyl group; a naphthyl group;
The antilipemic agent according to claim 1, which is a pyridyl group; a thienyl group or a lower alkyl group. 3. The antilipemic agent according to claim 2, wherein R ¹ is a phenyl group, a halogenophenyl group, a lower alkylphenyl group, a lower alkoxyphenyl group or a thienyl group. 4. R ¹ is a halogenophenyl group, a lower alkylphenyl group or a thienyl group; R ² and R ^{4 to} R ⁶ are hydrogen atoms; R ³ , R ⁷ and R ⁸ are lower alkyl groups; Alk ₁ and Alk ₂ The antilipemic agent according to claim 3, wherein is a single bond. 5. The antilipemic agent according to claim 1, wherein the pharmaceutically acceptable amide is an unsubstituted amide or a mono- or di-lower alkylamide in which the alkyl moiety may be substituted with a carboxyl group. 6. An antilipemic agent comprising 2- [4- {2- (p-chlorobenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid or a pharmaceutically acceptable salt thereof as an active ingredient. 7. An antilipemic agent comprising 2- [4- {2- (p-methylbenzenesulfonylamino) propyl} phenoxy] -2-methylpropionic acid or a pharmaceutically acceptable salt thereof as an active ingredient. 8. An antilipemic agent comprising 2- [4- {2- (2-thienylsulfonylamino) propyl} phenoxy] -2-methylpropionic acid or a pharmaceutically acceptable salt thereof as an active ingredient. 9. Prevention of hyperlipidemia and / or arteriosclerosis
The antilipemic agent according to claim 1, which is a therapeutic agent.