JPS62207236A - Phenoxyalkanoic acid derivative - Google Patents

Abstract

NEW MATERIAL:A phenoxyalkanoic acid derivative expressed by formula I [R<1> and R<2> are lower alkyl; R<3> is H or lower alkyl; R<4> is H or protecting group of the hydroxyl group; R<5> is H, alkyl, or lower alkoxy; R<6> is H, lower alkyl or lower alkoxy; Z is the formula COOR<7> (R<7> is H or lower alkyl) or formula II (R<8> is H or acyl); n is 1-10] and salt thereof. EXAMPLE:5-(4-tert-Butyldimethylsilyloxy-2,3,5-trimethylphenoxy)-2,2-di methyl pentanoic acid. USE:Useful for treating human hyperlipemia, having improving action on lipid metabolism in blood and capable of exhibiting high antioxidant action on unsaturated fatty acids and esters, e.g. linoleic acid, ethyl linoleate, etc. PREPARATION:A shown in the reaction formulas, a halide compound is reacted with a carbanion and the protecting group of the hydroxyl group is then removed from the resultant product to give a compound expressed by formula Ia, which is further reduced to afford the aimed compound expressed by formula Ib.

Description

[Detailed Description of the Invention] Purpose of the Invention In recent years, lipid peroxide in the body has been considered to be a cause of circulatory system disorders. For this purpose, we conducted extensive research on steric R'dF phenolic compounds, and found that a phenoxyalka/acid derivative having the general formula il+ described below has an effect on improving blood lipid metabolism, leading to the completion of the present invention.

Structure of the Invention The novel phenoxyalka/acid derivatives of the present invention are compounds represented by the general formula and pharmacologically acceptable salts thereof.

In the above formula, R and R are the same or different and represent a lower alkyl group, R represents a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a hydroxyl group, R represents a hydrogen atom, an alkyl group, or represents a lower alkoxy group, R represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group; 2 represents a -COOR group (wherein R represents a hydrogen atom or a lower alkyl group) or a -CH20R group (the formula (wherein, R represents a hydrogen atom or an acyl group), and n represents an integer of 1 to 10.

In the general formula (1), R and R are the same or different and represent a linear or branched alkyl group having 1 to 5 carbon atoms, and R is a hydrogen atom or a linear or branched alkyl group. R represents an alkyl group having 1 to 5 carbon atoms, and R is a hydrogen atom or a protecting group for a hydroxyl group, such as an aliphatic acyl group, an aromatic acyl group, an araliphatic acyl group, an alicyclic acyl group, or a heterocycle having carbons Xa 2 to 6. Indicates an acyl group such as an acyl group, R is a hydrogen atom, a linear or branched chain with 1 carbon number
1 to 10 alkyl groups or linear or branched alkoxy groups having 1 to 5 carbon atoms, R is a hydrogen atom, linear or branched alkyl groups having 1 to 5 carbon atoms, or linear or a branched chain alkoxy group having 1 to 5 carbon atoms; 2 is a group of the formula -COOR (wherein R represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; ) or a -CH20R group (wherein R is a hydrogen atom or a C2-C6 aliphatic acyl group, aromatic acyl group, aromatic aliphatic acyl group, alicyclic acyl group, heterocyclic acyl group, etc.) ) represents an acyl group, and n
represents an integer from 1 to 10.

In the general formula (!), when RjR, R, R and R represent an alkyl group, R,
R, R, R and R are the same or different, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, impentyl, 2-methylbutyl or 1
- C1 to C5 such as ethylpropyl, and when R5 represents an alkyl group, R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te
rt-butyl, pentyl, impentyl, neopentyl, tart-pentyl, hechusyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, heptyl, octyl, 1-methylheptyl, 2-ethyl hechusyl, 1 .1.
3.3-Tetramethylbutyl, nonyl, decyl or λ
Examples include those having 1 to 10 carbon atoms such as T-dimethyloctyl, and when R5 and R represent an alkoxy group, R and R may be the same or different and include methoxy, ethoxy, propoxy, impropoxy, butoxy, imbutoxy, When R4 and R represent an acyl group, R and R8 may be the same or different and include acetyl, propionyl, butyryl, imbutyryl, pivaloyl, hexamethyl, acryloyl, methacryloyl. or an aliphatic acyl group having 2 to 6 carbon atoms which may have an unsaturated bond such as crotonoyl: penzoyl, p-)luoyl, 0-7 disoyl, 4-nitrobenzoyl, 3-fluoropenzoyl, 2
- aromatic acyl groups such as chlorobenzoyl, 4-7 minopenzoyl, 3-dimethylaminobenzoyl, 3,4-dichlorobenzoyl, 1-naphthoyl; phenylacetyl, 4-chlorophenylacetyl, 3-phenylpropionyl or cinnamoyl; An aromatic aliphatic acyl group which may have an unsaturated bond such as a cycloaliphatic acyl group such as dichlorpentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl: or 2-furoyl, 3-thenoyl, 3-pyridinecarbonyl , 4-pyridinecarbonyl and other heterocyclic acyl groups.

When the target compound of the present invention represented by the general formula +11 has an acidic group, the conventional method may be used. Examples of such salts include salts of alkali metals such as sodium and potassium, and salts of alkaline earth metals such as calcium.

Furthermore, suitable compounds for the compound of the present invention (11) include R and R being a linear or branched alkyl group having 1 to 3 carbon atoms, particularly a methyl group;
R and R are a hydrogen atom or a linear or branched chain alkyl group having 1 to 3 carbon atoms, especially a hydrogen atom or a methyl group; is a hydrogen atom; R5 is a straight or branched alkyl group having 1 to 8 carbon atoms, particularly methyl, tart-butyl or 1,1. λ3-tetramethylbutyl group; n is an integer of 2 to 8, especially 3
Mention may be made of compounds in which 22 is an integer of the formula -cH20R (R represents a hydrogen atom, an acetyl group or a benzoyl group), in particular a -cm2on group.

Specific examples of the phenoxyalkanoic acid derivatives of the present invention include compounds having the structural formulas shown below (Table 1 and Table 2).

In addition, in the table below, TMB represents a 1.1.3.3-tetramethylbutyl group.

Table 2 The phenyl sialkanoic acid derivative 11) of the present invention can be produced, for example, by the method shown below.

121' (1a) In the above formula, RjR, R, R,, R and n have the same meanings as defined above, Ra represents a hydrogen atom, and B represents 1 such as methoxyethyl or 1-methoxyethyl. - lower alkoxyalkyl groups, cyclic ether groups such as tetrahydropyranyl, trialkylsilyl groups such as trimethylsilyl, dimethyl-1-butylsilyl, or benzyl;
It represents a hydroxyl protecting group such as an aralkyl group such as p-methoxybenzyl or p-bromobenzyl, X represents a halogen atom such as chlorine, bromine, or iodine, and Y represents an alkali metal atom such as sodium or potassium. show.

In the first step, the carbanion (3) is added to the halide compound (2).
) This is a step in which the target compound (1a) of the present invention is obtained by carrying out a complete reaction and then removing the hydroxyl group-protecting group from the obtained reaction product.

The reaction between the initial halide (2) and carbanion (3) can be carried out according to the method described in Qra, Syn, Vol. 50, p. 58.

That is, it is achieved by reacting a carboxylic acid having the formula (wherein R and R have the same meanings as defined above) with (2) in an inert solvent with a base. Bases used include, for example, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, methyllithium, butyllithium, tart-butyllithium,
Examples include organolithium compounds such as phenyllithium or lithium dialkylamides such as lithium diisopropylamide and lithium dicyclohexylamide. The inert solvent to be used is not particularly limited as long as it does not participate in the reaction, but examples thereof include ether, ethers such as tetrahydrofuran and dioxane, and amides such as dimethylformamide and dimethylacetamide. The temperature of the reaction is 0°C to 80°C, and the time required for the reaction is 1 to 24 hours.

The carbon derivative with a protected phenolic hydroxyl group (in the formula, R, R, R, R, R, B and n have the same meanings as described above) produced by this reaction can be isolated. However, the next deprotection reaction can usually be carried out without isolation.

The unbinding reaction can be carried out in a conventional manner according to the di class of the protecting group, but for example, when the protecting group for a hydroxyl group is a trialkyl-substituted silyl group, it may be carried out by contacting it with water or water containing water. easily achieved by The acids to be contained in this case include, without particular limitation, acids such as formic acid, ceric acid, and oxalic acid, and mineral acids such as hydrochloric acid, hydrochloric acid, and sulfuric acid. In the reaction, if water is used as a solvent, no other solvent is particularly required. When using other solvents, for example, a mixed solvent of water and an organic solvent such as ethers such as tetrahydrofuran and dioxane, and alcohols such as methanol and ethanol is used. The reaction temperature is not particularly limited, but it is usually suitably carried out around room temperature. The time required for the reaction is 30 minutes to 5 hours. It is also achieved by treatment with tetrabutylammonium fluoride in ethers such as tetrahydrofuran, dioxane, or fatty acids such as vinegar.

The phenoxyalkanoic acid conductor (1a) produced by the above reaction is subjected to a conventional esterification method and, if necessary, an acylation method, to obtain the corresponding ester, which is the target compound of the present invention (in the formula: R, R, R, R, R, R and n have the same meanings as described above, and Rb represents a lower alkyl group.

The second step is a step of reducing the phenoxyalkanoic acid derivative (1a) or (1c) to obtain the corresponding alcohol (1b), which is the target compound of the present invention.

This reduction step can be carried out according to a conventional method for converting carboxylic acids into alcohols, and the reducing agent used is, for example, lithium aluminum hydride or bitride (sodium bis[2-methoxyethoxy]aluminum hydride). Metal hydrides such as: The inert solvent used is not particularly limited as long as it does not participate in the reaction, but ethers such as ether, tetrahydrofuran, and dioxane are suitable. The temperature for one reaction is QC to 50°C, and the time required for the reaction is 30 minutes to 3 hours.

Compound (1b) obtained by the reaction of this step can be converted to the corresponding acyl compound (in the formula R, R, R
, R, R and n have the same meanings as described above, and R4
"and R are the same or different and represent the above-mentioned acyl group."

The phenoxyalkanoic acid derivative (1) obtained by the above reaction is isolated and purified by known separation and purification means such as concentration, vacuum concentration, solvent extraction, dissolution, crystallization recrystallization, reprecipitation, chromatography, etc. can do.

The halide compound (2), which is a raw material compound for producing the target compound having the general formula (1) of the present invention, can be produced, for example, by the method shown below.

In the above formula, R, R, R, B, X and n have the same meanings as defined above, and A represents a lower aliphatic acyl group such as acetyl, propionyl, butyryl, isobutyryl, and pivaloyl.

Step A is to react a hydroquinone derivative (4) with a reactive derivative of carboxylic acid to protect the less sterically hindered phenolic hydroxyl group of compound (4) with an acyl group to produce compound (5). This is the process of

The reactive derivatives of carboxylic acids used include, for example, acid halides such as acetyl chloride, butyryl bromide, pivaloyl chloride, or acid anhydrides such as acetic anhydride, propionic anhydride, but preferably pivaloyl chloride. It is an acid chloride such as yl chloride. The inert solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, but aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, dichloromethane, etc. Ethers such as '-thyl, tetrahydrofuran and dioxane can be mentioned.

This acylation reaction is suitably carried out in the presence of a deoxidizing agent according to a conventional method. As a deoxidizing agent, for example, an organic base such as triethylamine or pyridine is preferable, and if an excessive amount of these is used, a solvent may be used. You don't have to. The reaction temperature is usually -10°C to 60°C, preferably around room temperature.

The time required for the reaction is 30 minutes to 48 hours.

Step B is a step of protecting the phenolic hydroxyl group of compound (6) with protecting group B to produce compound (6).

When the protecting group is a 1-lower alkoxyalkyl group, trialkylsilyl group, or aralkyl group, this reaction can be carried out in the presence of a base such as triethylamine, pyridine, imidazole, or sodium hydride, or after a pretreatment. When the protecting group is a 1-lower alkoxyalkyl group (having 2 to 4 carbon atoms) or a cyclic ether group, for example, methanesulfone, p-)luenesulfone, etc. This is achieved by reaction with the corresponding vinyl ether (methyl vinyl ether, dihydrofuran, dihydropyran) in the presence of an acid or an acid such as hydrochloric acid. The solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, but examples include aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene and toluene,
Examples include ethers such as ether, tetrahydrofuran, and dioxane, amides such as dimethylformamide, and sulfoxides such as dimethylsulfoxide, and dimethylformamide is preferred. The reaction temperature and reaction time are the same as those for ordinary reactions for protecting hydroxyl groups, but the reaction is preferably carried out at around room temperature for 10 to 24 hours.

Step C is a step for producing compound (7) by removing the acyl protecting group A of the hydroxyl group of compound (6).

This reaction is achieved by a commonly used basic hydrolysis reaction or solvolysis reaction.

Examples of the base used in the reaction include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and barium hydroxide.

The solvent used is not particularly limited to those used in hydrolysis reactions, such as alcohols such as methanol, ethanol, and isopropyl alcohol, ethers, ethers such as tetrahydrone, dioxane, and dimethoxyethane, and dimethyl sulfoxide. Examples include sulfoxides such as , amides such as dimethylformamide, and mixed solvents of these organic solvents and water. The reaction temperature is usually around room temperature to the reflux temperature of the solvent.

The reaction time varies depending on the reaction temperature, etc., but is usually 1 to 24 hours.

In step D, the phenolic hydroxyl group of compound (7) is alkylated with halide compound (8) to form compound (2).
This is the process of manufacturing.

This reaction can be carried out according to the usual alkylation method, but? etrahedron, volume 30,
This is suitably carried out by the method using a phase transfer catalyst described on page 1379 (1,974). The solvent to be used is usually a mixed solvent of excess halide compound (8) and water, but for example, halogenated hydrocarbons such as dichloromethane and chloroform, or aromatic hydrocarbons such as benzene and toluene. A mixed solvent of an organic solvent such as hydrogen and water can also be used. Examples of the base used in the reaction include alkali metal hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Further, as a phase transfer catalyst to be used, tetrabutylammonium hydrogen sulfate is suitable. The reaction temperature is preferably 10 to 50°C, and the reaction time varies depending on the reaction temperature, etc.
The duration ranges from 0 minutes to 10 hours.

Effect of the invention The target compound of the present invention represented by the general formula (1) is:
Since it has a high antioxidant effect on unsaturated fatty acids and their esters such as linoleic acid and ethyl linoleate, it is expected that it will be able to prevent the oxidation of phospholipids, which have a high proportion of unsaturated fatty acids, in vivo. # nto
chem.

Biophya, Res, Commun, 9'4
．． In the peroxidation inhibition test of rat liver microsomal lipids shown on pages 734-737 (1980), it not only had a strong lipid peroxide lowering effect, but also showed that In tests, this compound shows excellent effects on improving blood lipid metabolism, such as lowering blood peroxide lipids, triglycerides, and cholesterol.

From the results of the above tests, the phenoxyalkanoic acid derivative +11 of the present invention is expected to be useful for treating hyperlipidemia in humans.

Administration methods include oral administration in the form of tablets, capsules, powders, granules, etc., as well as parenteral administration in the form of injections (intravenous, subcutaneous, intramuscular), suppositories, etc. The dosage varies depending on symptoms, age, etc., but when used as a therapeutic agent for hyperlipidemia, for example, 50 to 5 f per day can be administered orally or parenterally to an adult.

EXAMPLES The present invention will be explained in more detail with reference to Examples and Reference Examples below.

Example 1 (a) Diisopropylamine 149.5R9 and tetrahydrofuran 1.5 j! Add 91.5 ~ of 5S% oily sodium hydride to the mixture of /. Then isobutyric acid 124, OI
After adding a solution of Q in tetrahydrofuran (1,5R1) dropwise, the mixture was heated under reflux for 10 minutes in a nitrogen stream. The reaction mixture was cooled to -5 to 0°C, and a 15/7 butyllithium-hexane solution was added dropwise. The mixture was stirred at the same temperature for 15 minutes, and a solution of 30-dimethylsilyloxy-2,3,5-)limethylphenoxy)propyl 430~ in tetrahydrofuran (1p) was added dropwise. Thereafter, the mixture was stirred at 20C for 30 minutes, at 3G-35C for 30 minutes, and then at room temperature overnight. Tetrahydrofuran was distilled off under reduced pressure, and 3 parts of water was added to the residue.
5. Add water and wash the aqueous layer with ether. Hexane and 511 Ll of concentrated hydrochloric acid α are added to the aqueous layer, and the mixture is stirred at room temperature for 1 hour. The organic layer is washed with water and then dried with anhydrous sulfuric acid (IJum).

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent; benzene:ethyl acetate-10:
1) to obtain the target compound.

Melting point: 103-140 Example 1(b) 5-(4-t-butyldimethylsilyloxy-24λ5
-trimethylphenoxy)-2,2-dimethylpentanoic acid 1?61119, tetrabutylammonium fluoride 3
hydrate 364 inches, tetrahydrofuran 1- and acetic acid a
Stir the 2f mixture at room temperature for 3 hours. After the reaction is complete, tetrahydrofuran is distilled off under reduced pressure, and water and ether are added. Separate the organic layer and dry with magnesium sulfate. The powder obtained by distilling off the solvent was recrystallized from a mixed solvent of benzene and hexane to obtain the desired product.

Melting point: 8F-89℃ Example 2 Lithium aluminum hydride 15α7 was added to a mixture of 5-(4-hydro-2.3.5-)-2,2-dimethylpentanoic acid α3t and tetrahydrofuran 5-. Add and stir at room temperature for 2 hours. Pour the reaction solution into ice water, acidify with dilute hydrochloric acid, and extract with benzene. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (eluent: benzene:ethyl acetate-6:1) to obtain the target compound.

Melting point near 8-79°C Compounds of Examples 3 to 6 shown below were obtained in the same manner as in Examples 1 and 2.

1:11 Reference Example 1 Phenoltrimethylhydroquinone 3.5? , dichloromethane 25
2.8 pivaloyl chloride in a mixture of 6 and pyridine
A dichloromethane (2 (111 Ll) solution of 1 was added dropwise,
Leave at room temperature overnight. 4,25-acetic acid and 20 mL of water are added, and the organic layer is separated, further washed with water, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent: benzene:ethyl acetate - 10:1), and further recrystallized from hexane to obtain the target compound in the form of pale yellow prisms.

Melting point: 120-121°C Reference example 2 Otsu 2, λ6-drimethyl-+4-pivaloyloxyphenol 2.7F, dimethylformamide 10g and t-
2.3 f of imidazole is gradually added to a mixture of 1.92 g of butyldimethylchlorosilane, and then left overnight at room temperature. Pour the reaction mixture into a mixture of ice and aqueous ammonia,
Extract with hexane. After washing the extract with water, it is dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent: benzene) to obtain the target compound.

Melting point: 48-490 Reference Example 3 32.6 t of 4-t-butyldimethylsilyloxy-24λ5-trimethyl-1-pivaloyloxybenzene was dissolved in 60-dimethylformamide, and 219 methanol (10Od) of potassium hydroxide was added thereto. The solution is added dropwise under nitrogen atmosphere. After being left at room temperature for 2 days, salt production rR2at,
Ice 300fj? ! Pour into a mixture of 11 parts of water and water and extract with hexane. The organic layer is washed with water and dried with anhydrous sulfuric acid and IJum. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography (eluent: benzene:ethyl acetate-20:1) to obtain the target compound as a pale brown oil.

Rf value of silica gel thin layer chromatography -145 (
Developing solvent; benzene:ethyl acetate - 10:1) Reference example 4 1 Sodium dicarbonate 6.5f, tetrabutylammonium hydrogen sulfate 8.5F, sodium hydroxide &8t and water 10
While vigorously stirring in a nitrogen stream, 4-1-butyldimethylsilyloxy-2,λ5 was added to a mixture consisting of
- A mixture of trimethylphenol 17f and 1,3-dibromopropane 1309 is added dropwise. Then continue stirring at room temperature for 2 hours. After the reaction, the organic layer was separated and
The extract is extracted with 1,3-dibromopropane and dried over anhydrous sodium sulfate. The residue obtained by distilling off 1.3-dibromopropane under reduced pressure was subjected to silica gel column chromatography (eluent: hexane and hexene:benzene - 10:1) to obtain the target compound. 46℃

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 and R^2 are the same or different and represent a lower alkyl group, and R^3 is a hydrogen atom or a lower alkyl group. , R^4 represents a hydrogen atom or a hydroxyl group protecting group, R^5 represents a hydrogen atom, an alkyl group or a lower alkoxy group, R^6 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, Z is the formula -COOR^7 group (
In the formula, R^7 represents a hydrogen atom or a lower alkyl group. ) or the formula -CH_2OR^8 group (in the formula, R^8 represents a hydrogen atom or an acyl group), and n is 1 to 10
indicates an integer. ] A phenoxyalkanoic acid derivative and a pharmacologically acceptable salt thereof.