WO1997015546A1

WO1997015546A1 - Carboxylic acid derivatives and pharmaceutical compositions

Info

Publication number: WO1997015546A1
Application number: PCT/JP1996/003056
Authority: WO
Inventors: Tomiyoshi Aoki; Kenji Kuwabara
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 1995-10-26
Filing date: 1996-10-21
Publication date: 1997-05-01

Abstract

Carboxylic acid derivatives of general formula (1); pharmaceutically acceptable salts thereof; and solvates of these (wherein R?1, R2, R3 and R4¿ are each independently hydrogen, alkyl, halogeno, hydroxy or alkoxy; R?5 and R6¿ are each independently alkyl; R7 is hydrogen or alkyl; -X- is -O- or -S-; Y is hydrogen, alkyl, halogeno, hydroxy or alkoxy, and Z?1 and Z2¿ are each hydrogen, or alternatively Y, Z?1 and Z2¿ are joined together to represent -CH=; -A- is ⊃CH-OH, ⊃C=O, ⊃CH-OR8 or ⊃CH-OCOR9 wherein R8 is alkyl and R9 is alkyl or aryl; and T is alkylene optionally containing a multiple bond or the like). The above compounds are efficacious in preventing and treating arterial sclerosis, ischemic heart diseases, cerebral infarction, post-PTCA restenosis, and so on.

Description

Specification

Potassium rubonic acid derivatives and pharmaceutical compositions

Technical field

The present invention relates to a novel carboxylic acid derivative and a pharmaceutically acceptable salt thereof, and a solvate thereof.

Background technology

Both blood cholesterol (hereinafter abbreviated as TC) and lipoprotein (a) (hereinafter abbreviated as Lp (a)) are considered to be risk factors for arteriosclerosis (Circulation, 42, 625 (1970)) JAMA, 256, 2540 (1986); JAMA, 258, 1183 (1987)).

Regarding TC, it has been confirmed that the incidence of ischemic heart disease decreases by lowering its blood concentration (JAMA, 251, 351 (1984); JAMA, 251, 365 (1984)).

Since Lp (a) is similar in structure to plasminogen, it is thought to be involved in the suppression of fibrin degradation in blood and to inhibit the fibrinolytic system (Fibrinolysis, 5, 135 (1991)). . In addition, it has been reported that Lp (a) promotes the proliferation of vascular smooth muscle cells because it suppresses the activation of TGF-(Transforming Growth Factor β) by suppressing the production of plasman (Science, 260 , 1655 (1993)). From these facts, it is considered that substances that lower the Lp (a) value suppress thrombotic and proliferative vascular stenosis and suppress the onset of ischemic heart disease. In addition, it has been reported that blood Lp (a) levels are independent of other risk factors for ischemic heart disease, including TC values, and are independent risk factors (Clin. Chem., 36, 20). (1990); "Lipoprotein (a)", 151, Scanu A (ed), New York, Academic Press (1990)). In addition, it has been reported that high Lp (a) increases the risk of coronary artery disease in patients with high TC or a major component of low-density lipoprotein cholesterol (Atherosclerosis, 62, 249). (1986)).

Therefore, a compound having both a TC lowering effect and an Lp (a) lowering effect is considered to be more useful as an anti-arteriosclerosis agent.

2,2-Dimethyl-ω-aryloxycarboxylic acid derivative is a lipid in blood

(Cholesterol, triglyceride) are known to have a lowering action (Japanese Patent Publication No. 47-22567, Japanese Patent Application Laid-Open No. 62-207236), but their action strength was not sufficient. Also, the Lp (a) lowering effects of these compounds were not known. Recently, 2,2-dimethyl-5-

(2,5-Xylyloxy) valeric acid (generic name: gemfiprodil) was reported to have an Lp (a) lowering effect (Rinou-kuizaru, Journal of Lipid Research, 36. 1294 (1995)), but TC reduction The effect was not sufficient. That is, a 2,2-dimethyl- _ω -aryloxy carboxylic acid derivative having both excellent TC lowering action and Lp (a) lowering action was not known.

Disclosure of the invention

An object of the present invention is to provide a novel compound which has both a TC lowering action and an Lp (a) lowering action and is more useful as an anti-atherosclerotic agent.

The present invention provides a carboxylic acid derivative represented by the following formula [1] and a pharmaceutically acceptable salt thereof, and a solvate thereof. (a) It has a lowering effect and is useful for treatment and prevention of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis, etc. [1]

In the formula, RR ² , R ³ and R ⁴ are the same or different and represent hydrogen, alkyl, halogen, hydroxy or alkoxy.

R ⁵ and R ⁶ are the same or different and represent alkyl.

R ⁷ represents hydrogen or alkyl.

—X— represents one or one S—.

Y represents hydrogen, alkyl, Nono androgenic and Table arsenide Dorokishi or alkoxy, one or Y Z ¹ and Z ² each represent hydrogen, 2 ¹ and sigma ² becomes one cord CH =.

One A—> CH—ΔH, ≧ C = 0, ＞ CH ₂ ,> CH—OR ⁸ or> CH—OCOR ⁹ Here, R ⁸ represents alkyl, and R ⁹ represents alkyl or aryl.

— T-one (the left hand represents a bond to A. The same applies to the following)

Represents one Q—, one CH ₂ — 0— Q— or one Q—0—

One Q— (the bond on the left represents a bond to the A side, and so on)

①- (CH ₂ ) _n- , ②- (CH ₂ ) _f- CH = CH- (CH ₂ ) _g- or ③- (CH ₂ ) _h- C≡C- (CH ₂ ) j—.

n represents an integer from 1 to 15, and f, g, h, and j each represent an integer from 0 to 13. Here, f + g is 0: 13 is set to an integer, h + j is _c where, R ² is hydroxy an integer of 0 to 13, Y is hydrogen, in one X- is one 0- And Z ¹ and Z ² are hydrogen, one A— is CH ₂ , one T— is — Q—, — Q— is — (CH ₂ ) _n —, and n is 1 to Integer of 8 And

R ² is hydrogen, alkyl or halogen, — X— is — 0—, Z ¹ and Z ² are hydrogen, —A— is CH ₂ , — T— is one Q— Yes, unless Q is — (CH ₂ ) _n — and n is an integer from 1 to 4.

The compound of the present invention is a novel compound not described in the literature.

Examples of the alkyl represented by R 1 to R 9 and γ include linear or branched alkyl groups having 1 to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, i Examples include sobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, and isoheptyl.

R 1 to R 4 and alkoxy represented by γ are straight-chain or branched-chain alkoxy having 1 to 7 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , Isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, n-heptyloxy and isoheptyloxy.

Is a Ariru represented by R ^9, ones having 6 to 10 carbon atoms, e.g., phenyl, 1-naphthyl, 2-naphthyl.

Examples of the halogen represented by R 1 to R ⁴ and γ include fluorine, chlorine, bromine and iodine.

Preferred compounds among the compounds of the present invention are those wherein one A— is> CH ₂ ,> CH—OH or> C = 〇, —X— is —0—, Z ¹ and Z ² are hydrogen, —C— is — Q— and — Q— is — (CH ₂ ) _n — Wherein n is from 6 to 10, and wherein R ⁷ is hydrogen. C More preferred compounds are 1 ^ ¹ to ⁴ and ¥ are hydrogen, alkyl or halogen; R ⁵ and R ⁶ are both methyl, one A— is> CH ₂ ,> CH-OH or> C = 0, one X— is —0—, Z ¹ and Z ² are hydrogen , One T— is one Q—, one Q— is — (CH ₂ ) _n —, n is 6 to 10, and R ⁷ is hydrogen.

Among the compounds of the present invention, particularly preferred compounds include the following compounds.

(1) 10— (4-tert-butylphenoxy-1,2,2-dimethyl-9-hydroxydecanoic acid

(2) 1 1— (4-tert-butylphenoxy—2,2-dimethyl-1-10—hydroxy-decanoic acid

(3) 1 2-(4-tert -Butyl phenoxy 1, 2,2-dimethyl-1 1-hydroxy dodecanoic acid

(4) 13- (4-tert-butylphenoxy-1,2,2-dimethyl-1-12-hydroxytridecanoic acid

(5) 14- (4-tert-butylphenoxy — 2,2-dimethyl-1- 13-hydroxytradecanoic acid

(6) 12- (4-tert-butylphenoxy-2,2-dimethyl-1-11-oxo-dodecanoic acid

(7) 11- (4-Chlorophenoxy) 1,2,2-dimethyl-10-Hydroxydinc decanoic acid

(8) 1 2— (4-chlorophenoxy) 1,2,2-dimethyl 1 1 1 Hydroxy dodecanoic acid

(9) 13— (4-Chlorophenoxy) 1,2,2-dimethyl-12—hydroxy tridecanoic acid

The compound [1] of the present invention can be produced, for example, by the following method.

Production method 1 (When A — >> (: 11〇H and Z ¹ and Z ² are hydrogen)

(2) (3) (101)

[Wherein, Ri, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y and T are as defined above. ]

The compound of the present invention [101] can be produced by reacting a phenol or thiophenol represented by the formula [2] with an epoxide [3].

This reaction is usually carried out using a suitable solvent (for example, a polar solvent such as acetonitrile, N, N-dimethylformamide (DMF), an ether-based solvent such as tetrahydrofuran (THF), getyl ether, chloroform, Halogenated hydrocarbon solvents such as methylene chloride, ester solvents such as methyl acetate and ethyl acetate, hydrocarbon solvents such as benzene, toluene, n-hexane, methanol, ethanol, isopropanol, tert-butyl alcohol Bases (eg, potassium carbonate, sodium carbonate, etc.) in alcoholic solvents such as In the presence of inorganic bases such as sodium hydride, sodium hydroxide, and hydroxylated water, and organic bases such as pyridine, 4-dimethylaminopyridine, and triethylamine), the reaction can be performed at -20 to 150. Although it depends on the type of [2] and [3] and the reaction temperature, usually 30 minutes to 100 hours is appropriate. The dose of the compound [2] is preferably 1 to 2.0 times the molar amount of the compound [3].

Preparation 2 (- A- is> C = 0, Y, if the Zeta ¹ and Zeta ² represents an CH = Te summer together)

[4] [5] [102]

[Wherein, RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X and T have the same meanings as described above. L represents a leaving group such as halogen (eg, chlorine, bromine or iodine) -p-toluenesulfonyloxy, methanesulfonyloxy and the like. ]

The compound [102] of the present invention can be produced by reacting the compound [5] with 0-formylphenol or 0-formylthiophenol represented by the formula [4].

This reaction is usually carried out in a non-protonic solvent (for example, a polar solvent such as acetonitrile-N, N-dimethylformamide (DMF), an ether such as tetrahydrofuran (THF), or getyl ether). Solvents, halogenated hydrocarbon solvents such as chloroform and methylene chloride, ester solvents such as methyl acetate and ethyl acetate, benzene, and toluene. _n- Hexanes and other hydrocarbon solvents or mixed solvents thereof)

(For example, inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, and organic bases such as pyridine, 4-dimethylaminopyridine, and triethylamine Base) in the range of -20 to 150. The reaction time varies depending on the types of the compounds [4] and [5] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the compound [4] to be used is preferably 1 to 1.2 times the molar amount of the compound [5].

Production method 3 (— A— is CH ₂ , Z ¹ and Z ² are hydrogen,

— T— is — Q— and one Q— is (CH ₂ ) _n —

(2) (6) (10 3)

[Wherein, RR ² , R ³ , RR ⁵ , R ⁶ , R ⁷ , X, Y and L are as defined above. m represents an integer of n + 2 (n represents an integer of 1 to 15). That is, m represents an integer of 3 to 17. ]

The compound [103] of the present invention can be produced by reacting the phenol or thiophenol represented by the formula [2] with the compound [6].

This reaction can be carried out in the same manner as in the reaction between compound [4] and compound [5].

Another compound of the present invention can be produced by converting the A moiety of the compound of the present invention in the formula [1], for example, by the method shown below.

(205)

[Wherein, R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , XY, Z〗, Z ² and T have the same meanings as described above. ]

The compound [201] (hydroxy compound) is the case where -A- is> CH-OH in the compound [1] of the present invention.

Compound [2 0 2] (alkoxy form), among the present compounds (1) - A- is> For CH- OR ^8.

Compound [2 0 3] (Ashiruokishi body) is one among the present compounds [1] A- is> CH- is 0 C 0 For R ^9.

Compound [204] (oxo form) is the case where -A-> C = 0 in compound [1] of the present invention. Compound [205] (deoxy form) is the case where —A— is CH ₂ in compound [1] of the present invention.

Compounds obtained by the above production process 1 [1 0 1] is a case where Z ¹ and Z ² are hydrogen in the compound [2 0 1].

Compound obtained in Preparation 2 [1 0 2], among the compounds [2 04] Y, Zeta ¹ and Zeta ² are together a connexion - a case of representing a CH =.

The compound obtained in Preparation 3 [1 03] is Z ¹ and Z ² are hydrogen in the compound [2 0 5], - a T- gar Q-,

— Q— is — (CH ₂ ) _n —.

Therefore, after the compound [101] (hydroxy form) is produced by the production method 1, an alkoxy form, an acyloxy form, an oxo form and a deoxy form can be produced according to the above conversion method. Further, after producing the compound [102] (oxo form) by Production method 2, a hydroxy form, an alkoxy form, an acyl form and a dex form can be produced according to this conversion method.

Hereinafter, the conversion method will be described in detail.

The hydroxy compound represented by the formula [201] is reacted with an alkylating agent (eg, alkyl halide, alkyl p-toluenesulfonate) to form an alkoxy compound represented by the formula [202]. Body can be manufactured.

This reaction is usually carried out in a nonprotonic solvent (eg, acetonitrile, polar solvent such as N, N-dimethylformamide (DMF), tetrahydrofuran (THF), Such as ether solvents, halogenated hydrocarbon solvents such as chloroform and methylene chloride, and acetic acid Ester solvents such as methyl and ethyl acetate, hydrocarbon solvents such as benzene, toluene and _n- hexane, or mixed solvents thereof), base

(For example, inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, pyridine,

4-dimethylaminopyridine, an organic base such as triethylamine) in the presence of -20 to 150. The reaction time varies depending on the type of the compound [201], the type of the alkylating agent, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the alkylating agent used depends on the compound

The molar amount is preferably 1 to 1.2 times the amount of [201].

The hydroxy compound represented by the formula [201] is reacted with an acylating agent (eg, acyl halide, carboxylic anhydride, etc.) to give the compound of formula

An acyloxy compound represented by [203] can be produced. This reaction can be carried out in the same manner as in the reaction of the above-mentioned compound [201] with an alkylating agent.

By oxidizing the hydroxy form of the formula [201], the formula

The oxo form represented by [204] can be produced. Examples of the oxidizing agent include chromium oxide (VI) —sulfuric acid (Jones reagent), pyridinium chromate (PCC), chromium oxide (VI) —pyridin complex, and dichromate monosulfate. it can.

For example, when a dilute sulfuric acid solution of chromium (VI) oxide is used, this reaction can be performed in an acetate solvent at -20 to 30. The reaction time varies depending on the compound [201] and the reaction temperature, but usually 5 minutes to 12 hours is appropriate. The amount of chromium (VI) oxide to be used is preferably 1- to 1.2-fold the molar amount of compound [201]. By reducing the oxo form represented by the formula [204], a hydroxy form represented by the formula [201] can be produced. As the reducing agent, for example, metal hydride complex compounds (sodium borohydride, sodium cyanoborohydride, etc.) can be used. When R ⁷ is alkyl, diborane can be used.

For example, when sodium borohydride is used, the reaction is carried out in a polar solvent (eg, water, methanol, ethanol, isopropanol, N, N-dimethylformamide, dimethyl sulfoxide), -20 to 100 t : Can do it. The reaction time varies depending on the compound [204] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of sodium borohydride to be used is preferably 0.25 to 0.5 times the molar amount of the compound [201].

The oxo form represented by the formula [204] can be reduced to produce the dex form represented by the formula [205]. As the reducing agent, for example, p-tosylhydrazine-metal hydride complex compound (for example, sodium borohydride, sodium cyanoborohydride), zinc-hydrogen chloride gas, hydrazine monoalkali (for example, sodium hydroxide) And potassium hydroxide).

For example, when tosylhydrazine or sodium cyanoborohydride is used, this reaction can be carried out in N, N-dimethylformamide-sulfolane at 80 to 150 in the presence of a tosylate catalyst. The reaction time varies depending on the compound [204] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of sodium borohydride to be used is preferably 0.5 to 1.0 times the molar amount of the compound [204]. When the compound produced by the above method is an ester (R ⁷ is an alkyl), it can be hydrolyzed and converted to a carboxylic acid (R ⁷ is hydrogen) if desired. In the presence of a base such as sodium hydroxide, potassium hydroxide or the like, the reaction can be carried out usually in water, methanol, ethanol or a mixed solvent thereof at 0 to 150 * C, preferably 20 to 100.X. The amount of the alkali to be used is 1-5 mol, preferably 2-3 mol, per 1 mol of the ester.

This hydrolysis reaction is carried out in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, in a suitable solvent (for example, aqueous alcohol such as aqueous methanol or aqueous ethanol, or acetic acid) from room temperature to sot: You can also. The amount of the acid to be used is 0.1 to 10 mol, preferably 0.2 to 3 mol, per 1 mol of the ester.

When the produced compound is a carboxylic acid (R ⁷ is hydrogen), it can be converted to an ester (R ⁷ is alkyl) by esterification, if desired. In this esterification reaction, a large excess of alcohol is used in the presence of an acid such as ρ-toluenesulfonic acid, hydrochloric acid, sulfuric acid or the like, or using a Dean-Stark water separator or the like using benzene or toluene as a solvent. Usually, it is 0 to 150, preferably 20 to 100 ", for example, at the boiling point of the solvent.

In the production of the compound of the present invention, when the raw material has a substituent (for example, hydroxy, carboxy, etc.) which is not desired to react, the raw material is converted to benzyl, acetyl, tert-butyl by a known method in advance. It is generally used in the reaction after protection with toxic carbonyl and the like. After the reaction, known methods such as catalytic reduction, alkali treatment, and acid treatment Can remove the protecting group.

Among the compounds of the present invention, compounds in which A is> CH—OH or compounds in which R ⁵ and R ⁶ are different have optically active isomers due to having an asymmetric carbon. Each optically active isomer and a mixture thereof Are also included in the present invention.

The optically active substance can be obtained from the mixture using liquid chromatography using a column for separating an optically active substance (for example, CH I RALCEL OD, CH I RALCEL OF manufactured by Daicel). The optically active substance in which A— is CH—OH can be produced by the following method according to the method described in W094 / 24117.

Hydrolysis

[201— M] [Wherein, R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y, Z ¹ , Z ² and T are as defined above. R ^{2 0} represents an alkyl of from 1 to 1 0 carbon atoms, R ^{2 1} is haloalkyl (e.g., 2,2,2 Torifuruoroechi Le, 2, 2, 2-trichloromethyl E chill) or alkenyl (e.g., vinyl, isopropenyl Benyl). P and M indicate that these marked carbons are asymmetric carbons which are mirror images of each other. For example, compound [201-P] and compound [201-M] are enantiomers. ]

That is, by reacting compound [201] with compound [50] in the presence of lipase, only one of the optically active forms is selectively acylated to produce compound [51-M]. be able to.

Examples of the compound [50] include alkenyl esters such as vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, isopropenyl propionate, and isopropenyl butyrate; and 2,2,2-trifluoroethyl acetate Active esters such as haloalkyl esters such as 2,2,2-trichloroethyl propionate, 2,2,2-trichloroethyl acetate, and 2,2,2-trichloroethyl propionate may be used. it can.

The solvent to be used depends on the type of the compound [201], and examples thereof include polar solvents such as acetonitrile, N, N-dimethylformamide, and ethers such as tetrahydrofuran, dimethyl ether, diisopropyl ether and the like. Examples include a system solvent, a halogenated hydrocarbon solvent such as chloroform, methylene chloride and the like, and a hydrocarbon solvent such as benzene, toluene and n-hexane. The reaction temperature can be carried out at 20-40 You. The reaction time varies depending on the type of compound [201] and compound [50] and the reaction temperature, but is usually 30 minutes to 24 hours.

The resulting mixture is subjected to column chromatography to obtain an optically active compound.

[201-P] and compound [51-M] can be isolated and purified. In some cases, fractionated crystals can be used for isolation and purification. Compound

By hydrolyzing [51-M] as described above, the compound is obtained.

[2 0 1-M) can be obtained.

The present invention compounds having carboxyl (1) (R ⁷ is hydrogen) can be formed with pharmaceutically acceptable salts by known methods. Examples of the salt include an alkali metal salt such as a sodium salt and a potassium salt and an alkaline earth metal salt such as a potassium salt ₍ e.g., the alkali metal salt of the compound of the present invention has carboxy). The compound of the present invention can be obtained by adding one equivalent of sodium hydroxide or a hydroxylating power, preferably in an alcohol solvent.

The alkaline earth metal salt of the compound of the present invention can be obtained by dissolving the alkali metal salt produced by the above method in water, methanol, ethanol or a mixed solvent thereof and adding one equivalent of calcium chloride or the like. it can.

Solvates (including hydrates) are usually obtained by recrystallizing the compound of the present invention or a salt thereof from a solvent corresponding to the desired solvate or an appropriate mixed solvent containing the corresponding solvent. There are cases. These solvates (including hydrates) are also included in the present invention. For example, the hydrate of the compound of the present invention is obtained by recrystallizing the compound of the present invention from aqueous alcohol. In some cases. The compound of the present invention may be in a polymorphic form. The polymorph is also included in the present invention. The compound of the present invention or a salt thereof can be separated from the above reaction mixture by the usual separation and purification.

+

Manufacturing method, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography

It is isolated and purified by means such as R-chromatography and thin layer chromatography.

Compound [3] used as a starting material for the production of the compound of the present invention can be produced, for example, by the following method.

1)-When the dash is (3-),-Q-is-(CH ₂ ) _n- .

R ⁵ R ⁵

(C¾) _n -L (CH ₂ ) _n -C-C00R ⁷ (8) \ 1

[7]

C3-1]

[Wherein, R ⁵ , R ⁶ , ⁷ L and n are as defined above. The compound [9] can be produced by reacting the compound [7] with the compound [8]. This reaction is usually performed at -80 to 0 in the presence of a strong base (eg, lithium diisopropylamide (LDA), n-butyllithium) in the nonprotonic solvent described in Production Method 2. Can be. The reaction time depends on the type of compound [7] and compound [8] and the reaction temperature. However, usually 30 minutes to 24 hours are appropriate. The amount of compound [8] to be used is preferably 1- to 1.2-fold the molar amount of compound [7].

The compound [3-1] can be produced by reacting the compound [9] with an organic peracid (for example, m-chloroperbenzoic acid, perbenzoic acid, peracetic acid). This reaction is usually carried out in an appropriate solvent (eg, a halogenated hydrocarbon solvent such as chloroform, methylene chloride, etc., or an ether solvent such as tetrahydrofuran (THF) or dimethyl ether). It can be carried out. The reaction time varies depending on the type of the compound [9] and the organic peracid, and the reaction temperature, but is usually 30 minutes to 24 hours. The amount of the organic peracid to be used is preferably 1 to 1.2 equivalents to the compound [9].

Compound [9] can also be produced as follows. iXCE k—L ² + C00R ⁷

[1 0] [7] [1 1]

R ⁵

(CH ₂ ) _n -C-C00R ⁷

R ⁶

[9]

[Wherein, R ⁵ , R ⁶ , R ⁷ and n are as defined above. L ^{1 and} L ² each represent a leaving group such as halogen (eg, chlorine, bromine, iodine), p-toluenesulfonyloxy, methanesulfonyloxy, and k is an integer of n + 2 (n is 1 to 15 Represents an integer.) Represents. That is, k represents an integer of 3 to 17. ] Compound [11] can be produced by reacting compound [7] with compound [10]. This reaction can be carried out in the same manner as in the reaction between compound [7] and compound [8].

The compound [9] can be obtained by heating the compound [11] to -120-250 in hexamethylphosphate triamide (HMPA).

2) — T— is — CH ₂ —〇— Q- and one Q— is one (CH ₂ ) _n-

¾ 口.

= " ^Ll + H0- (C¾) _n -L ² one> ^ = ^ ⁰ " ^(CH 2 ^} n " ^L2

[1 3] [1 2] [1 4]

[1 5]

[3-2]

[Wherein, R ⁵ , R ⁶ , R ⁷ , n, L ¹ and L ² are as defined above. ]

Compound [14] can be produced by reacting compound [12] with compound [13].

This reaction is usually carried out in a nonprotonic solvent described in Production Method 2 with a base. (Eg, sodium hydride, lithium diisopropylamide (LDA), pyridine, triethylamine) at -70 to 100. The reaction time varies depending on the kind of the compound [12] and the compound [13] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of compound [13] to be used is preferably 1- to 1.2-fold the molar amount of compound [12]. Compound [15] can be produced by reacting compound [7] with compound [14]. This reaction can be carried out in the same manner as in the reaction of compound [7] with compound [8]. The compound [3-2] can be produced by reacting the compound [15] with an organic peracid. This reaction can be carried out in the same manner as in the reaction of the above compound [9] with an organic peroxide.

3) — T— is one Q—〇— and — Q— is (CH n one ^ a c

R ⁵ R ⁵

(CH ₂ ) _n -L + H0C-C00R ⁷ (CH ₂ ) _n -0-C-C00R ⁷

R ⁶ R ⁶

(8) (1 6) (1 8)

[3-3]

[Wherein, R ⁵ , R ⁶ , R ⁷ , L and n are as defined above. Compound [18] can be produced by reacting compound [16] with compound [8]. This reaction can be carried out in the same manner as in the reaction between compound [12] and compound [13]. Compound [3-3] can be produced by reacting compound [18] with an organic peracid. This reaction can be carried out in the same manner as in the reaction of the above compound [9] with an organic peroxide. 4) One T and one is Q,

— Q—is one (CH ₂ ) _f -CH = CH- (CH ₂ ) _g — or

― (CH ₂ ) _h -C≡C- (CH ₂ ) j

R ⁵ R ⁵

L ^ C ^ -Q! -L ² + HC-COOR ⁷ ""-L ^ C ^ -Q! -C-COOR ⁷

R ⁶

(1 9) (7) (20)

[

[twenty one〕

(3-4)

[Wherein, R ⁵ , R ⁶ , R ⁷ , L ¹ and L ² are as defined above. — Q ¹ — represents one (CH ₂ ) _f -CH = CH— (CH ₂ ) g— or one (CH ₂ ) _h — C 1 C 1 (CH ₂ ) j—. ί, g, h, j are as defined above. ]

Compound [20] can be produced by reacting compound [7] with compound [19]. This reaction can be carried out in the same manner as in the reaction between compound [7] and compound [8]. By reacting the compound [20] with bis (triptyltin) oxide and silver nitrate in a polar solvent such as DMF at 0-40 :, the hydroxy compound [21] can be produced.

The formyl compound [22] can be produced by oxidizing the hydroxy compound [21]. Examples of the oxidizing agent include pyridinium chromate (PCC), chromium oxide (VI) —pyridine complex, dimethyl sulfoxide (DMSO) —dicyclohexylcarbodiimide (DCC), and the like. For example, when using chromium oxide (VI) -pyridine complex, the reaction can be carried out in a suitable solvent (such as methylene chloride) at 0-25.

The compound [3-4] can be produced by cycloaddition of a methylene unit to the formyl [22]. As the precursor of the methylene unit, monolithium bromochloromethane, trimethyloxosulfonium monohydrogen sodium, and the like can be used. For example, in the case where sodium trimethyloxosulfonium dihydrogen is used, the reaction can be carried out in a suitable solvent (DMSO, THF, etc.) at 20-70.

5) — T—is CH ₂ — 0— Q—

— Q—ga (CH ₂ ) _f -CH = CH- (CH ₂ ) g—or

One (CH ₂ ) h "C≡C- (CH ₂ ) j One case.

(R ¹⁰⁰ ) ₂ CHCH ₂ -L ³

(2 3) (2 5)

[2 6] [3-5]

Wherein R ⁵ , R ⁶ , R ⁷ and Q ¹ are as defined above. R ¹⁰ represents alkyl, and L ³ represents halogen (eg, chlorine, bromine, iodine). ]

The compound [25] can be produced by reacting the compound [23] with a dialkyl haloacetal [24]. As the dialkyl haloacetal, dimethylchloroacetal, methylbutane moisetal, and the like can be used. This reaction can be carried out in the same manner as in the reaction between compound [12] and compound [13] (compound [25] in an alcoholic solvent (such as methanol and ethanol). By treating with acid (dilute hydrochloric acid, dilute sulfuric acid, etc.) at 40, a formyl body [26] can be produced.

The compound [3-5] can be produced by cycloaddition of a methylene unit to the formyl derivative [26]. This reaction is performed by The reaction can be performed in the same manner as in the reaction for cycloaddition of a methylene unit to the product [22].

6) — T— is— Q— 0—

— Q—ga (CH ₂ ) _f -CH = CH- (CH ₂ ) _g — or

One (CH ₂ ) _h — CC one (CH ₂ ) j —

R ⁵ R ⁵

L then CH ^ Q ¹ L ² + H0C-C00R ⁷ ~--(¾-0 then 0-: -C00R ⁷

R ⁶ R ⁶

[1 9] [1 6] [27]

R ⁵ R ⁵

HO-CHn-Q! -OC-COOR ⁷ OHC-Q! -OC-COOR ⁷

R ⁶

(28) (29)

[3-6

[Wherein, R ⁵ R ⁶ , R ⁷ , Q ¹ L ¹ and L ² have the same meanings as described above. ]

Compound [27] can be produced by reacting compound [16] with compound [19]. This reaction can be carried out in the same manner as in the reaction between compound [16] and compound [8].

The compound [27] can be converted to the hydroxy form [28]. This reaction can be carried out in the same manner as the above-mentioned reaction for converting the compound [20] to the compound [21]. The formyl form [29] can be produced by oxidizing the hydroxy form [28]. This reaction can be carried out in the same manner as in the above-mentioned reaction for converting the compound [21] into the compound [22].

The compound [3-6] can be produced by cycloaddition of a methylene unit to the formyl [29]. This reaction can be carried out in the same manner as in the above reaction for cycloaddition of a methylene unit to compound [22].

The compound [5] used as a starting material in the production of the compound of the present invention can be produced, for example, by the following method.

R ⁵ R ⁵ R ⁵

TC-C00R ⁷ -TC-C00R ⁷ TC-C00R ⁷

0 R ⁶ OH 0 R ⁶

[3] [30] [5-1]

[ Five ]

[Wherein, R ⁵ , R ⁶ , R ⁷ , T and L are as defined above. The compound [30] can be produced by reacting the epoxide [3] with lithium chloride in the presence of an acid.

This reaction can be usually performed in the nonprotonic solvent described in Production Method 2 in the presence of an acid (eg, diacid) at -20 to 50. The reaction time varies depending on the type of compound [3] and the reaction temperature, but usually 30 minutes to 48 hours is appropriate. The amount of lithium chloride used is based on Compound [3]. Thus, a molar amount of 1 to 1.2 times is preferable.

Compound [5-1] can be produced by oxidizing compound [30]. This reaction can be carried out in the same manner as in the above-mentioned reaction for converting compound [201] to compound [204].

The compound [5] can be produced by reacting the compound [5-1] with a nucleophile such as lithium bromide, lithium iodide, silver p-toluenesulfonate, silver methanesulfonate or the like. .

This reaction can be usually performed in a nonprotonic solvent described in Production Method 2 at 0 to L00. The reaction time varies depending on the compound [5-1], the type of the nucleophilic reagent, and the reaction temperature, but usually 30 minutes to 48 hours is appropriate. The amount of the nucleophile to be used is preferably 1 to 1.2 times the molar amount of the compound [5-1].

The compound (6) used as a starting material for the production of the compound of the present invention can be produced in the same manner as in the above-mentioned reaction for producing the compound (11) from the compound (10) and the compound (7). it can.

Compound [2], Compound [4], Compound [7], Compound [8], Compound [10], Compound [13], Compound [1] used as a starting material in the production of the compound of the present invention 6], compound [17] and compound [19] are known compounds or can be produced by a method according to a known method, for example, as shown in Reference Examples described later.

The compound of the present invention is effective for treating and preventing hyper-Lp (a) emia or hypercholesterolemia and diseases caused by these. Since the compound of the present invention has both Lp (a) lowering action and TC lowering action, it is expected to be a particularly excellent therapeutic agent for arteriosclerosis as compared with known compounds. Also the book The compound of the present invention also has a blood high specific gravity lipoprotein cholesterol-elevating action (see, for example, the compounds of the present invention (for example, Example 8, Example 10, Example 12-Example 20 and Example 2). 2, Example 24, Example 33, Example 34-Example 48, Example 59, Example 61 The acute toxicity (eg, in male mice) of the compound of Example 1 is greater than the effective dose. From the above, the compound of the present invention and the pharmaceutical composition of the present invention are effective for treating and preventing arteriosclerosis caused by hyperlipidemia. Coronary artery disease including re-occlusion after coronary angioplasty (PTCA; Percutaneous Transluminal Coronary Angioplasty); angina pectoris and ischemic heart disease caused by coronary artery disease; Applicable to the treatment of infarction, thrombus and arteriosclerosis caused by it Rukoto can.

When the compound of the present invention is administered as a medicament, the compound of the present invention contains 0.1 to 99.5%, preferably 0.5 to 90% as it is or in a pharmaceutically acceptable nontoxic and inert carrier. As a composition. Administered to animals, including humans.

As the carrier, one or more solid, semi-solid or liquid diluents, fillers and other auxiliaries for formulation are used. Desirably, the pharmaceutical compositions are administered in dosage unit form. The pharmaceutical composition of the present invention can be administered intravenously. Oral administration, intradermal administration, topical administration (such as transdermal administration), or rectal administration. It is needless to say that the composition is administered in a dosage form suitable for these administration methods. Oral administration is particularly preferred.

The dose of the pharmaceutical composition for treating high Lp (a) emia is determined in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, and the like. Usually, the amount of the active ingredient of the present invention for an adult is in the range of 50 to 600 mg / h, preferably 100 to 300 mg / h, for an adult. In some cases, less is sufficient. Conversely, higher doses may be required. It can also be administered in divided doses two to three times a day.

The composition for treating arteriosclerosis and other prophylactic or therapeutic compositions can be applied using the same dose as described above.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Formulation Examples, and Test Examples of the compound of the present invention.

Reference example 1

1 1-Bromo-2,2-dimethylethyl decanoate

To 12.4 g of ethyl ethyl isobutyrate was added 124 ml of dry tetrahydrofuran, and the mixture was cooled with sodium chloride-ice in an argon stream to keep the internal temperature at 15 to 10 "while maintaining the internal temperature at 15 to 10". 80 ml of a tetrahydrofuran solution of lithium diisopropylamide was added dropwise, and the mixture was stirred at the same temperature for 1 hour, and then 61 g of 1,9-dibutene mononan was added at once, and the internal temperature was reduced to 15 to 1 The mixture was stirred for 1 hour at 0 :, gradually returned to room temperature and stirred for 15 hours. <The reaction solution was poured into ice water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate (the organic layer was washed with brine, The residue was dried over anhydrous magnesium sulfate and concentrated, and the residue was distilled under reduced pressure to obtain 33.2 g of a slightly yellow oily substance.

Boiling point 1 5 5 to 16 6/5 mm Hg

The following compounds were produced in the same manner as in Reference Example 1.

12-Bromo-2,2-dimethylethyl dodecanoate 14-Bromo-2,2-dimethyltetraethyl tetradecanoate

Reference example 2

2,2-Dimethyl-10-ethyl decenoate

Hexamethylphosphoric acid triamide (HMPA) (20.9 g) was added to 25 g of the compound obtained in Reference Example 1, and the mixture was stirred at 190 to I95 for 1 hour. The reaction solution was cooled, poured into ice water, and extracted with n-hexane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue was distilled under reduced pressure to obtain 8.0 g of a pale yellow oil.

Boiling point 107 to 109 9 mm 5 gH g

The following compounds were produced in the same manner as in Reference Example 2.

2,2-dimethyl-1-ethyl 3-tetradecenoate

Reference example 3

Separate production of 2,2-dimethyl-10-ethyldecenoate

To 125 ml of ethyl ethyl isobutyrate was added 120 ml of dry tetrahydrofuran, and while maintaining the internal temperature at 110 to 115 in an argon stream, a solution of 2.0 M lithium diisopropylamide was added. 110 ml of the trahydrofuran solution was added dropwise. After the addition, the mixture was stirred at the same temperature for 1 hour, and then a solution of 9-bromo-1-nonene 3 O gZ tetrahydrofuran (60 ml) was added dropwise at 110 to 0 T. After stirring for 1 hour while cooling with salt-ice, the mixture was gradually returned to room temperature and stirred for 15 hours. The reaction solution was poured into ice water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to obtain 24 g of a slightly yellow oily substance.

Boiling point 13 0 to 13 5 ° C / 17 mmH g The following compounds were produced in the same manner as in Reference Example 3.

2,2-dimethyl-6-ethyl heptenoate

2,2-dimethyl-7-ethyloctenoate

2,2-dimethyl-8-ethyl nonenoate

2,2-dimethyl-9-ethyl decenoate

2,2-dimethyl-1 1-ethyl dodecenoate

2,2-dimethyl-12-ethyl ethyl tridecenoate

Reference example 4

2,2-Dimethyl-10,11-Ethyl epoxide

To 9.2 g of the compound obtained in Reference Example 3, 92 ml of methylene chloride was added to dissolve the mixture, and the mixture was cooled with iced water, and while stirring, 9.44 g of 70% m-chloroperbenzoic acid was added. Stirred at room temperature for 7 hours. The reaction solution was concentrated, n-hexane was added to the residue, insolubles were removed by filtration, and the filtrate was washed four times with a 10% aqueous solution of carbonated lime, washed with water, and dried over anhydrous magnesium sulfate. After concentration, 9.74 g of a colorless oil was obtained. IR cm— ¹ (NaC ¹ ): 2932, 1728, 1474, 1150

The following compounds were produced in the same manner as in Reference Example 4.

2,2-dimethyl-6,7-epoxyheptanoate

2,2-Dimethyl-7,8-Ethyl epoxyoctanoate

2,2-Dimethyl-8,9-Ethyl epoxynonanoate

2,2-Dimethyl-9,10-Ethyl epoxydecanoate

2,2-dimethyl-1-epoxy 1,2-epoxy dodecanoate

2,2-Dimethyl- 1,2,13-Ethoxy tridecanoate 2,2-Dimethyl-13,14-Epoxytetraethyl decadeate Reference example 5

1 2—2,2-Dimethyl-11 1-Hydroxydodenic acid ethyl

Dissolve 27.04 g of 2,2-dimethyl-11,12-epoxydodecanoic acid in 270 ml of dry tetrahydrofuran and, with stirring at room temperature, 6.78 g of anhydrous lithium chloride and 18.01 of acetic acid g was added and stirred at room temperature for 2 days. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue is concentrated to silica gel column chromatography (Co-gel C-200 (registered trademark), n-hexane: ethyl acetate = 2). Purification by 0: 1) gave 23.68 g of a colorless oil.

IR cm— ¹ (NaC ¹ ): 2932, 1728, 1177, 1154

Reference example 6

12 2-Chloro-2,2-dimethyl-11-oxo-dodecanoate Compound 2.2.58 g obtained in Reference Example 5 was dissolved in 560 ml of acetone, and the mixture was stirred under ice-cooling and stirred with a J0nes reagent (chromium oxide). (VI) 26.72 g-Prepared from concentrated sulfuric acid (23 ml) and water (100 ml). 52.2 ml was added dropwise over 1 hour. After the addition, the mixture was stirred at room temperature for 18 hours. Under ice-cooling and stirring, 75 ml of isopropanol was added to decompose excess Jones reagent, and then the reaction solution was poured into ice water and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue is concentrated. The residue is purified by silica gel gel column chromatography (ヮ Ko-gel C1000 (registered trademark), n-hexane: ethyl acetate = Purification by 9: 1) gave 21.37 g of a colorless oil. 1 R em— ¹ (NaC ¹ ): 2934, 1724, 1177, 1152

The following compounds were produced in the same manner as in Reference Example 6.

7-chloro-2,2-dimethyl-6-oxoheptanoate

8-Chloro-2,2-dimethyl-17-ethyl ethyl oxooctanoate Reference Example 7

Aryl 3-bromopropyl-ter.

Add 20 g of 3-bromopropanol to N, N-dimethylformamide

The solution was dissolved in 200 ml, and 8.6 g of 60% sodium hydride was gradually added to the solution under water cooling, followed by stirring at room temperature for 10 minutes. Subsequently, 17.4 g of aryl bromide was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice water, acidified with hydrochloric acid, and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to obtain a pale yellow oil (16.5 g).

100 mm at boiling point 100 mmH g

Reference Example 8

Methyl 2- (9-decenyloxy) -2-methylpropionate

Dissolve 31.4 g of 2-hydroxymethyl 2-methylpropionate in 50 ml of N, N-dimethylformamide, and add 11.1 g of 60% sodium hydride to this solution on ice. The mixture was gradually added under stirring, and stirred at room temperature for 10 minutes. Next, 45 g of 10-promo 1-decene was added, and the mixture was stirred at 90 for 3 hours. The reaction solution was cooled, poured into ice water, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel (ヮ Kogel C-200 (registered trademark), n-hexane: Purification with ethyl acetate = 20: 1) gave 32.1 g of a pale yellow oil. IR cm- ¹ (NaCl): 2857, 1736, 1435, 1144

The following compounds were produced in the same manner as in Reference Example 8.

2-aryloxymethyl 2-methylpropionate

2- (10-Pindecenyloxy) monomethyl 2-propionate Reference Example 9

5-aryloxy-1,2,2-dimethylpentanoate

Using ethyl isobutyrate and the compound obtained in Reference Example 7, a pale yellow oil was obtained in the same manner as in Reference Example 1.

IR cm— ¹ (NaCl): 2934, 1728, 1474, 1146

Reference example 10

5- (2,3-epoxypropoxy) 1,2,2-dimethylethyl pentanate

A pale yellow oil was obtained in the same manner as in Reference Example 4 using the compound obtained in Reference Example 9.

IR cm " ¹ (NaCl): 2994, 1732, 1472, 1146

Reference example 1 1

Methyl 2- (9,10-epoxydecyloxy) -2-methylpropionate

Using the compound obtained in Reference Example 8, a pale yellow oil was obtained in the same manner as in Reference Example 4.

IR cm— ¹ (NaCl): 2930, 1736, 1466, 1144

The following compounds were produced in the same manner as in Reference Example 11.

2- (2,3-epoxypropoxy) monomethyl 2-methylpropionate 2-(10, 1 1 -epoxypandecyloxy) monomethyl 2-methylpropionate

Reference example 1 2

2,2-dimethyl-10-pentadecenoic acid

29.0 g of the compound obtained in Reference Example 3 was dissolved in 290 ml of ethanol, and a solution prepared from 9.68 g of sodium hydroxide and 29 ml of water was added thereto, followed by heating under reflux for 18 hours. . After the reaction solution was concentrated under reduced pressure, ice water was added to the residue, neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ヮ -gel C-200 (registered trademark), n-hexane: ethyl acetate = 10: 1) to give a colorless oil.

25.7 g were obtained.

IR cm— ¹ (NaC ¹ ): 2928, 1701, 1476, 1202

Reference Example 1 3

2,2-dimethyl-10,11-epoxydiandecanoic acid

260 ml of methylene chloride was added to 25.7 g of the compound obtained in Reference Example 12 to dissolve it, and the bath was cooled with ice water, and 25.5 g of peroxybenzoic acid was added with stirring. After the addition, the mixture was stirred for 17 hours. Reaction solution

The extract was washed once with a 10% aqueous sodium hydrogen carbonate solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ヮ Kogel C-200 (registered trademark), n-hexane: ethyl acetate = 30: 1) to obtain 21.7 g of a colorless oil. Obtained.

IR cm- ¹ (NaC1): 2932, 1701, 1476, 1260 Example 1

1 1— (5—t ert—butylbenzofuran-1-yl) 1,2,2-dimethyl-1 1 1-oxodonedecanoate

The compound 21.37 g obtained in Reference Example 6 and 5-tert-butyl-2-hydroxyhydrazine aldehyde 14.99 g were dissolved in dry acetate nitrile 210 m 1. Then, 14.53 g of ground potassium carbonate was added, and the mixture was stirred at 60 for 8 hours. After cooling, the reaction solution was poured into ice water, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue is concentrated on a silica gel column chromatography (Co-gel C1200 (registered trademark), n-hexane: ethyl acetate = 20). : 1) to obtain 24.0 g of a yellow oily substance.

IR cm— ¹ (NaCl): 2934, 1728, 1557, 1273

Example 2

1 1— (5-tert-butyl-benzofuran-1-yl) 1,2,2-dimethyl-1- 1 1-ethylethyldecanoate

The compound (24.0 g) obtained in Example 1 was dissolved in methanol (240 ml), and sodium borohydride (2.11 g) was added thereto under ice-cooling and stirring, followed by stirring at room temperature for 3 hours. The reaction solution was poured into ice water, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 24.9 g of a pale yellow oil.

IR cm— ¹ (NaCl): 2934, 1730, 1475, 1271

Example 3

1 1- (5-tert-Butylbenzofuran-1-yl) 1,2,2-Dimethyl-11-hydroxy-1-decanoic acid The compound obtained in Example 2 (2.30 g) was dissolved in ethanol (230 ml), and a solution prepared from sodium hydroxide (6.41 g) and water (23 ml) was added thereto. The mixture was heated and refluxed for 18 hours. . After the reaction solution was concentrated under reduced pressure, ice water was added to the residue, the mixture was neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated, and the residue is purified by silica gel column chromatography (ヮ -gel C-200 (registered trademark), chromate form) to give a colorless oil. 8 g were obtained.

IR cm— ¹ (NaC ¹ ): 2934, 1700, 1478, 1271

Example 4

1 1- (5-tert-butyl-benzofuran-1-yl) 1,2,2-dimethyl-11 1-sodium hydroxyhydroxydecanoate

The compound 19.Og obtained in Example 3 was dissolved in 190 ml of methanol, and 50 ml of a methanol solution of 1.80 g of sodium hydroxide was added thereto, followed by concentration. Benzene was added to the residue, and the mixture was further concentrated, n-hexane was added, and the crystals were collected by filtration to obtain 18.18 g of white crystals.

Melting point 143 ~: I 47

Elemental analysis (as _{_{C 2 5 H 3 7 N a}} 0 4)

Calculated value (%) 70.73 H: 8.78

Actual value (%) 70.67 H: 8.66

Example 5

6- (5-tert-butyl-benzofuran-1-yl) -1,2,2-dimethyl-6-ethylhexyl hexanoate

A colorless oil was obtained in the same manner as in Examples 1 and 2 using 7-chloro-2,2-dimethyl-6-oxoheptanoate. IR em- ¹ (NaC ¹ ): 2962, 1727, 1477, 1272 Example 6

6- (5-tert-butyl-benzofuran-1-yl) -1,2,2-dimethyl-6-hydroxyhexanoate

Using the compound obtained in Example 5, white crystals were obtained in the same manner as in Examples 3 and 4.

Melting point 194.5-: 196.5 X:

Elemental analysis (as _{_{C 2 oH 2 7 N a 0}} 4 · 1 / 2H 2 0)

Calculated value _{(0/0) 66.10 H:} 7.76

Measured value (%) C: 65.96 H: 7.89

Example 7

7- (5-tert-butyl-benzofuran-1-yl) -1,2,2-dimethyl-7-ethylethylheptoxyheptanoate

A slightly yellow oil was obtained in the same manner as in Examples 1 and 2, using 8-ethyl-2-chloro-2,2-dimethyl-7-oxooctanoate. IR cm— ¹ (NaC ¹ ): 2963, 1728, 1476, 1271

Example 8

7— (5-tert e-Butylbenzofuran-1-yl) 1,2,2-Dimethyl 7-Sodium hydroxyhepnate

Using the compound obtained in Example 7, white crystals were obtained in the same manner as in Examples 3 and 4.

With a melting point of 110

Elemental analysis value (as C ₂ H _{2 9} N a〇 ₄ · 1 / 2H ₂₀ )

Calculated value (%) 66.82 H-.8.01 Actual value (%) 66.55 H: 8.40

Example 9

1 2— (4-tert-butylphenoxy) 1,2,2-dimethyl-1 1-hydroxyethyl dodecanoate

2,2-Dimethyl-11,12-epoxyethyl dodecanoate 18.8 g, p-tert-butylphenol 20.9 g Ground calcium carbonate 19.2 g and acetonitrile 200 ml of the mixture was heated to reflux for 72 hours. The reaction solution was cooled, poured into ice water, and extracted with n-hexane. The extract was washed five times with a 5% aqueous sodium hydroxide solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ヮ -gel C-200 (registered trademark), η-hexane: ethyl acetate = 10: 1) to give 23.0 g of a pale yellow oil. Obtained.

IR cm— ¹ (NaC ¹ ): 2984, 1728, 1514, 1248

Example 10

1 2— (4—t ert—butylphenoxy) one 2,2—dimethyl one

1 1—hydroxy dodecanoic acid

Using 19 g of the compound obtained in Example 9, the reaction was carried out in the same manner as in Example 3. After the reaction solution was concentrated under reduced pressure, ice water was added to the residue, neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from n-hexane to give white crystals.

14.2 g were obtained.

Melting point 6 6-6 8 t

Elemental analysis value (as C ₂₄ H ₄ o〇 ₄ ) Calculated value (%) 73.43 H: i0.27

Actual value (%) 73.02 H: i0.16

Example 1 1

1 3— (4-tert-butylphenoxy) 1,2,2-dimethyl

1 2—ethyl ethyl tridecanoate

2,2-Dimethyl- 1,2,13-epoxytridecanoate 22.5 g, p-tert-butylbutylphenol 35.6 g, ground calcium carbonate 21.8 g and acetonitrile A mixture of 200 ml of the toluene was heated to reflux for 72 hours. The reaction solution was cooled, poured into ice water, and extracted with n-hexane. The extract was washed with a 5% aqueous sodium hydroxide solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Co-gel C-200 (registered trademark), n-hexane: ethyl acetate = 10: 1) to give a pale yellow oil. g was obtained.

IR cm— ¹ (NaC ¹ ): 2930, 1728, 1514, 1248

Example 1 2

1 3— (4-tert-butylphenoxy) 1,2,2-dimethyl-12,2-hydroxytridecanoic acid

Using 25 g of the compound obtained in Example 11, 21.2 g of white crystals were obtained in the same manner as in Example 10.

Melting point 63

Elemental analysis (as _{_{_{C 2 5 H 4 2 0 4}}} )

Calculated value (%) 73.85 H: i0.41

Found C173.72 H: 10.13 PT / 9 3 56

40 Example 13

7— (4-tert-butylphenoxy) mono 2,2-dimethyl 6-—ethyl heptylate

A slightly yellow oil was obtained in the same manner as in Example 9 using 2,2-dimethyl-16,7-epoxyheptanoate.

IR cm— ¹ (NaC ¹ ): 2965, 1728, 1516, 1267

Example 14

7- (4-tert-Butylphenoxy) -12,2-dimethyl-16-hydroxyheptanoic acid The compound obtained in Example 13 was used, and the same results as in Example 10 were obtained.

Melting point 1 15-1 17:

Elemental analysis (as C ₉ H ₃ o0 ₄₎

Calculated value (%) 70.77 H! 9.38

Actual value (%) 70.56 H: 9.27

Example 15

8-(4-tert-butylphenoxy) 1,2,2-dimethyl-7-ethylethyloctanoate

A slightly yellow oil was obtained in the same manner as in Example 9 using 2,2-dimethyl-7,8-epoxyoctanoic acid.

IR cm- ¹ (NaC1): 2965, 1728, 1515, 1266

Example 16

8— (4-tert-butylphenoxy) -1,2,2-dimethyl-17—sodium hydroxytactate Using the compound obtained in Example 15, white crystals were obtained in the same manner as in Examples 3 and 4.

Melting point 18 1-1 83

Elemental analysis (as _{_{C 2 oH 3 1 N a 0}} 4)

Calculated value _{(0/0) 67.02 H:} 8.72

Actual value (%) 66.72 HI8.73

Example 17

9— (4-tert-butylphenoxy) -1,2,2-dimethyl-1-8-ethylethyl hydroxynonanoate

A slightly yellow oily substance was obtained in the same manner as in Example 9 using 2,2-dimethyl-18,9-epoxynonanoate ethyl.

I R cm—〗 (NaCl): 2932, 1728, 1514, 1250

Example 18

9- (4-tert-Butylphenoxy) 1,2,2-Dimethyl-8-Hydroxynonanoic acid

Using the compound obtained in Example 17, white crystals were obtained in the same manner as in Example 10.

With melting point 84-86

Elemental analysis (as C ₂ i H ₃₄ 0 ₄₎

Calculated value (%) 71.96 H: 9.78

Actual value (%) 71.68 H: 9.90

Example 19

1 0— (4-tert-butylphenoxy) 1,2,2-dimethyl-9-hydroxyethyl ethanoate A slightly yellow oil was obtained in the same manner as in Example 9 using 2,2-dimethyl-19,10-ethylepoxydecanoate.

IR cm ~ ¹ (NaC1): 2930, 1562, 1516, 1252

Example 20

1 0— (4—t ert—butylphenoxy) mono 2,2-dimethyl-9-sodium hydroxide

Using the compound obtained in Example 19, white crystals were obtained in the same manner as in Examples 3 and 4.

Melting point 154-155

Elemental analysis (as the _{_{C 2 2 H 3 5 N a}} 0 4)

Calculated value /. ) 68 · 37 H: 9.13

Observed value (%) CI68.01 H: 9.11

Example 2 1

1 4- (4-tert-butylphenoxy) 1,2,2-dimethyl-13-hydroxyethyl ether

A slightly yellow oily substance was obtained in the same manner as in Example 9 using 2,2-dimethyl-13,14-epoxytetradecanoate.

IR cm— ¹ (NaC ¹ ): 2930, 1728, 1513, 1245

Example 22

1 4- (4-tert-butylphenoxy) 1,2,2-dimethyl-1 3 -hydroxytradecanoic acid

Using the compound obtained in Example 21, white crystals were obtained in the same manner as in Example 10.

With a melting point of 56-57 Elemental analysis value (as C _{2 6} H ₄₄ 〇 ₄ )

Calculated value (%) 74.24 HI10.54

Actual value (%) 74.04 H: i0.44

Example 23

1 1 1 (4 1 tert-butylphenoxy) 1 2, 2-dimethyl 1

1 0—ethyl ethyl decanoate

A mixture of 9.6 g of the compound obtained in Reference Example 4, 11.2 g of p-tert-butylphenol, 10.4 g of ground calcium carbonate and 112 ml of N, N-dimethylformamide was added to 1 After stirring at 00 for 24 hours, the reaction solution was cooled, poured into ice water, and extracted with n-hexane. The extract was washed 5 times with a 5% aqueous sodium hydroxide solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ヮ -gel C-1200 (registered trademark), n-hexane: ethyl acetate = 10: 1) to give a pale yellow oil. g was obtained.

IR cm— ¹ (NaC ¹ ): 2934, 1728, 1514, 1248

Example 24

1 1 1 (4-tert-Butylphenoxy) 1,2,2-Dimethyl 10 0-Hydroxydinodecanoic acid

Using 9.23 g of the compound obtained in Example 23, 7.22 g of white crystals were obtained in the same manner as in Example 10.

73.5 to 75.0 t

Elemental analysis (as C _{2 3} H ₃₈ 0 ₄₎

Calculated value (%) 72.98 H 0.12 Actual value (%) 72.81 H: i0.04

Example 2 5

1 2— (4—t e rt—pentylphenoxy) 1,2,2-dimethyl—1 1-hydroxydethyl dodecanoate

A slightly yellowish oil was obtained in the same manner as in Example 9 using 2,2-dimethyl-11,12-epoxydodecanoate ethyl and p-tert-pentylphenol.

IR cm— ¹ (NaCl): 2964, 1728, 1514, 1250

Example 26

1 2— (4-tert-pentylphenoxy) 1,2,2-dimethyl-1

1 1—Sodium hydroxydodecanoate

Using the compound obtained in Example 25, white crystals were obtained in the same manner as in Examples 3 and 4.

Melting point 1 53-: L 55

Elemental analysis (as _{_{C 2 5 H 4 N a 0}} 4)

Calculated value (%) 70.06 H.-9.64

Actual value (%) 69 · 86 Η: 9 · 51

Example 2 7

1 2— (3-tert-butylphenoxy) 1,2,2-dimethyl-1 1-hydroxyethyl dodecanoate

A slightly yellow oil was obtained in the same manner as in Example 9, using 2,2-dimethyl-11,12-epoxyethyl dodecanoate and m-tert-butylphenol.

IR cm— ¹ (NaC ¹ ): 2932, 1730, 1489, 1275 Example 2 8

1 2— (3-tert-butylphenoxy) -1,2,2-dimethyl-1-sodium sodium dodecanoate

Using the compound obtained in Example 27, white crystals were obtained in the same manner as in Examples 3 and 4.

Melting point 102-; at I 04

Elemental analysis (as the C _{2 4} H _{3 9} N A_〇 ₄₎

Calculated value (%) 69.53 H: 9.48

69.34 HI9.32 to actual value (%)

Example 2 9

2,2-Dimethyl 11-Hydroxy 12-Ethyl phenoxydodecanoate

A slightly yellow oil was obtained in the same manner as in Example 9 using 2,2-dimethyl-11,12-epoxyethyl dodecanoate and phenol. IR cm— ¹ (NaCl): 2932, 1728, 1497, 1246

Example 30

2,2-Dimethyl-11-hydroxy-11-phenoxidedodecanoic acid Using the compound obtained in Example 29, white crystals were obtained in the same manner as in Example 10.

Melting point 79 ~ 8 1

Elemental analysis (as C _₂ oH ₃ ₂ 0 ₄₎

Calculated value (%) 71.39 H! 9.59

Measured value (%) C: 71.38 Η: 9 · 50

Example 3 1 1 2-(4-tert-butylphenylthio) -1,2,2-dimethyl-1-

1 1—Ethyl hydroxy dodecanoate

A slightly yellow oil was obtained in the same manner as in Example 9 using 2,2-dimethyl-1-1,1-epoxyethyl dodecanoate and p-tert-butylthiophenol.

IR cm— ¹ (NaC ¹ ): 2932, 1730, 1489, 1152

Example 3 2

1 2-(4-tert-Butylphenylthio) 1,2,2-dimethyl-11 1-Sodium hydroxydodecanoate

Using the compound obtained in Example 31, white crystals were obtained in the same manner as in Examples 3 and 4.

Melting point 99-: L01

Elemental analysis (as _{_{C 24 H 3 9 N a 0}} 3 S)

Calculated value (%) 66.94 H: 9.13

Actual value (%) 66.85 H: 9.20

Example 33

(-) — 1 2— (4—t ert—butylphenoxy) 1,2,2-dimethyl-1 1-hydroxy-dodecanoic acid

Using 12- (4-tert-butylphenoxy) -2,2-dimethyl-11-hydroxydodecanoate obtained in Example 9,

White crystals were obtained in the same manner as in Example 16 described in W094 / 24117. With melting point 6 1 ~ 6 2

Elemental analysis (as C ₂₄ H _₄ 00 ₄₎

Calculated value (./.) At 73.43 H: 10.27 Measured value (%) C: 73.79 H! IO.07

^{[A] D 2 0 = -} 1. 3 5. (c = 1.08, CH ₃ OH)

A mixture of (+) and (-) optically active forms of 12- (4-tert-butylphenoxy) -12 _: 2-dimethyl-11-hydroxydodecanoate was also obtained.

Example 3 4

(+) — 1 2— (4—t e rt—butyl phenoxy) 1,2,2-dimethyl-11-hydroxy-dodecanoic acid

Using a mixture of optically active substances of 12- (4-tert-butylphenoxy) -12,2-dimethyl-11-hydroxydodecanoate of (+) and (-) obtained in Example 33, White crystals were obtained in the same manner as in Example 17 described in W094 / 24117.

With a melting point of 59.5 to 6 1

Elemental analysis (as C _{2 _₄} H ₄ o0 ₄₎

Calculated value (%) 0: 73.43 HI 10.27

Actual value (%) 73.43 H 0.10

[H] _D ²⁰ = 1.42. (C = 1.05, CH ₃ OH)

Example 3 5

(1)-1 1-(4-tert-butyl-phenoxy) 1,2,2-dimethyl-10-hydroxy-decanoic acid

White crystals were obtained in the same manner as in Example 33 using the ethyl 11- (4-tert-butylphenoxy) -12,2-dimethyl-10-hydroxydecanoate obtained in Example 23.

With a melting point of 63.5 to 65.0 Elemental analysis (as C ₂₃ H ₃₈ 0 ₄₎

Calculated value _{(0/0) C 72.98 H} :! 10.12

Measured value (%) C: 73.02 HI10.03

[] D ^{2 0} =-1.24 ° (c = 2.09, CH ₃ OH)

A mixture of (11)-(41-tert-butylphenoxy) -1,2,2-dimethyl-10-ethyl ethyl decanoate of (+) and (-) was also obtained.

Example 3 6

(+)-1 1-(4-tert-butylphenoxy) 1 2.2-Dimethyl-10 -Hydroxydinedecanoic acid

A mixture of the optically active isomers of (+) and (−) of 111- (4-tert-butylphenoxy) -2,2-dimethyl-10-hydroxy-decanoate obtained in Example 35 was used. Used and white in the same manner as in Example 34.

Melting point 64.5-66.0 X:

Elemental analysis (as C ₂₃ H ₃₈ 0 ₄₎

Calculated value _{(0/0) 72.98 H:} 10.12

Found (%) 72.83 H: 9.97

[Hi] _D ²⁰ = 1.20 ° (c = 2.11 CH ₃ OH)

Example 3 7

5-[3- (4-tert-butylphenoxy) -l-hydroxypropoxy] -ethyl 2,2-dimethylpentanoate

Using the compound obtained in Reference Example 10, a pale yellow oily substance was obtained in the same manner as in Example 9. 1 R em- ¹ (N a C 1): 2963, 1701, 1514, 1250

Example 3 8

5— “3— (4—t ert—butyl phenoxy) 1—2-hydroxypropoxy 1—2,2-dimethyl sodium pentanoate

Using the compound obtained in Example 37, white crystals were obtained in the same manner as in Examples 3 and 4.

Melting point 1 52 ~: at I 54

Elemental analysis (as _{_{C 2 oH 3 i N a 0}} 5)

Calculated value (%) 64.15 H: 8.34

Actual value (%) 63.82 H: 8.06

Example 3 9

2-"10— (4-tert-butylphenoxy) -1-9-hydroxysidedecyloxy] —methyl 2-methylpropionate

Using 18.4 g of the compound obtained in Reference Example 11, 17.0 g of a colorless oil was obtained in the same manner as in Example 9.

IR cm— ¹ (NaCl): 2934, 1736, 1514, 1248

Example 40

2— “10— (4-tert-butylphenoxy) -1-9-hydroxysidedecyloxy 1-2-methylpropionic acid

17.0 g of the compound obtained in Example 39 was dissolved in 170 ml of ethanol, and a solution prepared from 3.2 g of sodium hydroxide and 17 ml of water was added thereto, followed by heating for 12 hours. Refluxed. After the reaction solution was concentrated under reduced pressure, ice water was added to the residue, neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated, and the residue is Purification by column chromatography (ヮ Kogel C-200 (registered trademark) n-hexane: ethyl acetate = 2: 1) yielded 14.3 g of white crystals.

Melting point 4 1 ~ 4 2 X:

Elemental analysis value (as C ₂₄ H ₄₀ 〇 ₅ )

Calculated value _{(0/0) 70.55 H:} 9.87

Actual value (%) 70.30 HI9.82

Example 4 1

_2-[1 1-(-4-tert-butylphenoxy)-1-10-hydrogen mouth xyldecyloxy 1-methyl-2-propionate

2-(10,11-epoxypandecyloxy) -12-methylbutane A slightly yellow oil was protected in the same manner as in Example 39 using methyl pionate.

IR cm— ¹ (NaC ¹ ): 2951, 1734, 1515, 1248

Example 4 2

2-d 1 1-d 4-t e rt-butylphenoxy) _-J 0-Hydroxydoxydecyloxy, 1-2-methylpropionic acid

Using the compound obtained in Example 41, white crystals were obtained in the same manner as in Example 40.

With a melting point of 52-53

Elemental analysis (as _{_{_{C 2 5 H 4 2 0 5}}} )

Calculated value (%) 71.05 H: i0.02

Actual value (%) 71.09 H: 10.09

Example 4 3 1 1- (4-tert-butylphenoxy) 1,2,2-dimethylethyl decanoate

Dissolve 11.7 g of p-tert-butylphenol in 100 ml of N, N-dimethylformamide and gradually add 3.43 g of 60% sodium hydride to this solution under ice-cooling. The mixture was stirred at room temperature for 10 minutes. <Next, 25.0 g of ethyl 11-bromo-1,2-dimethyldimethyldecanoate was added, and the mixture was stirred at 90 for 3 hours. The reaction solution was cooled, poured into ice water and acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was silica dim force Ramukuroma Togurafi chromatography (Wa co one gel C one 2 0 0 (R) - _n - hexane: acetic acid Echiru = 1 0: 1) to give an oil 23. 6 g .

IR cm " ¹ (NaCl): 2932, 1730, 1514, 1248

Example 44

1 1— (4-tert-butylphenoxy) 1,2,2-dimethyl undecanoic acid

Dissolve 23.6 g of the compound obtained in Example 4 3 in 200 ml of ethanol, add a solution prepared from 4.8 g of sodium hydroxide and 2 Om1 of water, and heat for 12 hours Refluxed. After the reaction solution was concentrated under reduced pressure, ice water was added to the residue, neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated, and the residue is purified by silica gel column chromatography (ヮ -gel C-200 (registered trademark) _-n -hexane: ethyl acetate = 10: 1). Purification yielded 18.3 g of white crystals. 55-57 "C

Elemental analysis (as C ₂₃ H _{₃ 8} 0 ₃₎

Calculated value (96) 76.20 H: 10.57

Actual value (%) 75.90 HI10.30

Example 4 5

1 2— (41-tert-butylphenoxy 1-2, _2-dimethyldoethyl decanoate

A slightly yellow oil was obtained in the same manner as in Example 43 using 12-promo 2,2-dimethyldodecanoic acid ethyl ester.

IR cm— ¹ (NaCl): 2930, 1730, 1514, 1248

Example 46

1 2— (4—t e rt—butyl phenoxy) 1,2,2-dimethyldodecanoic acid

Using the compound obtained in Example 45, white crystals were obtained in the same manner as in Example 44.

With a melting point of 65-67

Elemental analysis (as C ₂₄ H ₄ o0 ₃₎

Calculated value (%) 76.55 H: 10.71

Actual value (%) 76.48 H: i0.73

Example 4 7

1 1— (4-Chlorophenoxy) 1,2,2-Dimethyl 10 0-Hide

Using the compound obtained in Reference Example 4 and p-chlorophenol, a pale yellow oil was obtained in the same manner as in Example 9. IR em- ¹ (NaCl): 2934, 1727, 1493, 1246

Example 48

1 1— (4-Chlorophenoxy) 1,2,2-Dimethyl 10 0-Hyd

Using the compound obtained in Example 47, white crystals were obtained in the same manner as in Example 10.

Melting point 72-74 X:

Elemental analysis (as _{_{C 1 9 H 2 9 C 1}} 0 4)

Calculated value (%) 63.94 H: 8.19

Actual value (%) 63 · 70 H! 8.15

Example 4 9

2,2-Dimethyl 10 0-Hydroxy 1 1- (4-methylphenoxy)

Using the compound obtained in Reference Example 4 and p-methylphenol, a pale yellow oil was obtained in the same manner as in Example 9.

IR cm— ¹ (NaC ¹ ): 2932, 1728, 1512, 1244

Example 5 0

2,2-Dimethyl 10-Hydroxy 1 1- (4-Methylphenoxy) pentadecanoic acid

Using the compound obtained in Example 49, white color formation was performed in the same manner as in Example 10.

B said.

With a melting point of 8 7-88

Elemental analysis (as C _₂ oH ₃ ₂ 0 ₄₎

Calculated value (%) C: 71.39 H: 9.59 Actual value (%) 71.24 HI9.51

Example 5 1

2,2-Dimethyl 1 2— (2,5-Dimethylphenoxy) 1 1 1 Hydroxyethyl dodecanoate

2,2-Dimethyl-11,12-epoxyethyl dodecanoate

Using 5-dimethylphenol, a pale yellow oil was obtained in the same manner as in Example 9.

IR cm— ¹ (NaC ¹ ): 2930, 1730, 1508, 1267

Example 52

2,2-Dimethyl-1-2- (2,5-dimethylphenoxy) -1-11-1 Sodium hydroxydodecanoate

Using the compound obtained in Example 51, white crystals were obtained in the same manner as in Examples 3 and 4.

Melting point 1 1 1 to 1 1 3

Elemental analysis (as _{_{C 2 2 H 3 5 N a}} 0 4)

Calculated value (%) C: 68.37 H-.9.13

Actual value (%) 68.03 HI8.93

Example 53

1 1- (3,5-di-tert-butyl-1-4-hydroxyphenylthio) 1-2,2-dimethyl-10-hydroxyethyldecanoate The compound obtained in Reference Example 4 and 2,6-di-tert Using -butyl-4-mercaptophenol as in Example 9, a slightly yellow oil was obtained.

IR cm- ¹ (NaC1): 2932, 1726, 1425, 1156 Example 54

1 1 1 (3,5-di-tert-butyl-1-4-hydroxyphenylthio) 1,2,2-dimethyl-10-hydroxy-decanoic acid

To a mixture of 21.7 g of the compound 2 obtained in Reference Example 13, 2,7.2 g of 2,6-di-tert-butyl-4-mercaptophenol and 20 Nm of N, N-dimethylformamide, Under an argon stream, 26.3 g of ground potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ヮ -gel C-200 (registered trademark), n-hexane: ethyl acetate = 10: 1) to obtain 35.0 g of white crystals.

With a melting point of 75-76

Elemental analysis (as C _{2 7} H _{4 6} 〇 ₄ S)

Calculated value _{(0/0) 69 · 48} H: 9.93

Actual value (%) 69.22 H: 9.74

Example 5 5

Di “2—” 3— (4-tert-butylphenoxy) 1-2-hydroxypropoxy 1-2-methylpropionate 1 calcium

25.8 g of 2- (2,3-epoxypropoxy) methyl 2-methylpropionate, 30 g of p-tert-butylphenol, pulverized 28.5 g of lithium carbonate and 250 ml of acetonitrile The mixture was heated at reflux for 72 hours. The reaction solution was cooled, poured into ice water, and extracted with n-hexane. Wash the extract with 5% aqueous sodium hydroxide The extract was washed, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (ヮ co-gel C-200 (registered trademark), black-mouthed form). 6- (4-tert-Butylphenoxymethyl) -1,3,3-dimethyl-1,4-dioxane-12-one) 18.0 was obtained.

IR cm— ¹ (NaC ¹ ): 2935, 1732, 1472, 1146

The obtained compound (18.0 g) was dissolved in ethanol (180 ml), a solution prepared from sodium hydroxide (5.2 g) and water (18 ml) was added thereto, and the mixture was heated under reflux for 5 hours. . After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and 4.1 g of calcium chloride was added under ice cooling to precipitate crystals. The crystals were separated by filtration, washed with water, and dried to obtain 16.8 g of white crystals.

Melting point 16 8-17 1 X:

Elemental analysis value (as C ₃₄ H ₅ o C a 0 _{1 ()} · 2Η ₂₀ )

Calculated value (%) 58.79 Η: 7.84

Actual value (%) 58.72 Η: 7.58

Example 56

1 2— (4—t e r t—butylphenoxy) 1,2,2-dimethyl

1 1-Oxo dodecanoate

33.0 g of the compound obtained in Example 9 was dissolved in 500 ml of acetone, and a J0nes reagent (chromium oxide (VI) 26.72 g, concentrated sulfuric acid 23 m1, water 100 m1) was stirred under ice-cooling and stirring. 50 ml was added dropwise over 1 hour. After the addition, the mixture was stirred at room temperature for 2 hours. Under ice-cooling and stirring, isopropanol (75 ml) was added to decompose excess Jones reagent, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract is washed with water and anhydrous magnesium sulfate After drying in a humidifier, the mixture was concentrated and the residue was purified by column chromatography on silica gel (Co-gel C-200 (registered trademark), n-hexane: ethyl acetate = 15: 1), and colorless. 30.65 g of an oil were obtained.

IR cm— ¹ (NaC ¹ ): 2934, 1726, 1514, 1248

Example 5 7

1 2 (4-tert e-t-butylphenoxy) 1,2,2-dimethyl

1 1-oxo dodecanoic acid

Using 10 g of the compound obtained in Example 10, the reaction was carried out in the same manner as in Example 56. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (ヮ -gel C-200 (registered trademark), n-hexane: ethyl acetate = 6: 1). After purification, the obtained crystals were recrystallized from n-hexane to obtain 8.lg of white crystals.

With a melting point of 53-54

Elemental analysis (as C ₂₄ H ₃₈ 0 ₄₎

Calculated _{(0/0) 73.81 H-} .9.81

Observed value (%) C: 73.81 H: 9.74

Example 58

1 2— (4-Chlorophenoxy) 1,2,2-dimethyl-11-hydroxyethyl dodecanoate

A slightly yellow oil was obtained in the same manner as in Example 9 using 2,2-dimethyl-11,12-epoxyethyl dodecanoate and p-chlorophenol <IR cm— ¹ (Na C 1): 3468 , 2978, 2932, 2855, 1728, 1493, 1285, 1246 Example 5 9

1 2— (4-Chlorophenoxy) 1,2,2-dimethyl-11 1-Hydroxy dodecanoic acid

Using the compound obtained in Example 58, white crystals were obtained in the same manner as in Example 10.

With a melting point of 70.5 to 71.5

Elemental analysis (as _{_{_{C 2 oH 3 i C 10 4}}} )

Calculated value _(0/0) 64.76 HI8.42

Actual value (%) 64.72 H: 8.30

Example 6 0

1 3— (4-Chlorophenoxy) 1,2,2-dimethyl-12-Hethyloxytridecanoate

A slightly yellow oil was obtained in the same manner as in Example 9 using ethyl 2-, 2-dimethyl-12,13-epoxytridecanoate and p-chlorophenol.

I cm- ¹ (NaCl): 3447, 2978, 2930, 2855, 1728, 1493, 1286, 1246

Example 6 1

1 3— (4-Chlorophenoxy) 1,2,2-dimethyl-12-Hydroxytridecanoic acid

Using the compound obtained in Example 60, white crystals were obtained in the same manner as in Example 10.

Melting point 6 2 to 6 3

Elemental analysis value (as C _{2 1} H ₃₃ C 10 ₄ ) Calculated value (%) 65.52 H: 8.64

Actual value (%) 65.52 H! 8.62

Example 6 2

(1)-1 3-4-te butylphenoxy) 1,2,2-dimethyl-1 12 -hydroxytridecanoic acid

Example 13 Using 13- (4-tert-butylbutyloxy) -2- (1,2-dimethyl-12-hydroxytriethyl decanoate) obtained in Example 1. White crystals were obtained in the same manner as in Example 33. .

With a melting point 54-56

Elemental analysis (as _{_{_{C 2 5 H 4 2 0 4}}} )

Calculated value (96) C: 73.85 H: i0.41

Actual value (%) 73.75 H: 10.27

[] D ^{2 5} = — 1.38 ° (c = l.013, CH ₃ OH)

A mixture of optically active forms of (+) and (-) 13- (4-tert-butylpentoxy) -12,2-dimethyl-12-hydroxytridecanoate was also obtained.

Example 6 3

(+) — 1 3— (4—t ert—butylphenoxy) 1,2,2-dimethyl-12-hydroxy-tridecanoic acid

Using a mixture of the optically active forms of (13)-(4-tert-butylphenoxy) -12,2-dimethyl-12-hydroxyethyltridecanoate of (+) and (-) obtained in Example 62 In the same manner as in Example 34, white

Melting point 49-51 Elemental analysis (as _{_{_{C 2 5 H 4 2 0 4}}} )

Calculated value (%) 73.85 H 0.41

Actual value (%) 73.64 H: i0.39

[] D ²⁵ = 10 8 ° (c = l. 0 10, CH ₃ OH) Formulation Example 1

Tablets (oral tablets)

Prescription 1 tablet 180mg

Example 10 Compound 100 mg Lactose 45 mg Corn starch 20 mg Low-substituted hydroxypropylcellulose 9 mg Polyvinyl alcohol (partially saponified) 5 mg Magnesium stearate 1 mg And take it internally.

Formulation Example 2

Tablets (oral tablets)

Prescription 1 tablet 180mg

Example 5 Compound of 7 100 mg Lactose 45 mg Tomato starch 20 mg Low substituted hydroxypropyl cellulose 9 mg Polyvinyl alcohol (partially saponified) 5 mg Magnesium stearate 1 mg And take it internally. The results of pharmacological tests showing the utility of representative examples of the present compound are shown below.

Test example 1

Effect on TC and LD (a)

APF containing 0.1% of the control compound and the compound of the present invention was used in each of the administration groups using 3 to 7 male cynomolgus monkeys (body weight 2 to 9 kg) in each group. Was given to the control group at a rate of 20 g / kg each day for 4 weeks.

As a control compound, gemfiprodil, which has been reported to have an Lp (a) lowering effect in cynomolgus monkeys, was used.

Blood was collected two weeks before the start of dosing, on the first day of dosing, and on the fourth week of dosing. Plasma was prepared by adding 1/10 volume of 3.8% aqueous solution of sodium citrate to blood, and TC and Lp (a) were measured by enzymatic method and ELISA method, respectively. The average of the TC and Lp (a) measured values two weeks before the start of dosing and on the day of starting the dosing was used as the pre-value, and the percentage of each measured value at the fourth week of dosing to the pre-value was calculated. In Experiment 1, the control group was subjected to the Student's t test for the administration group, and in Experiments 2 to 5, the administration group was subjected to the significant difference test by the Dunnet's multiple test for the control group.

Table 1 shows the results. Table 1 Effects on TC and Lp (a) i! K. Rei 物 T¾y 暂例暂 p L p (a) number

,,,

丄 n D D-le 4 87 11 11 100 Sat 5

ノ ^ ノ ι- ¹ ✓ ノ Ai 丄 1 H UQ3 + ェ丄 1 << ^ 5 55 7 **

2 Control 4 84 technicians 3 95 ± 10

Compound of Example 20 4 68 Sat 5 <■) 丄化合物 Compound of Example 24 4 4 62+ 9 * 33 Sat y ** Husband Λ

rt & WI 丄 Lin Ί L mouth 00-ΰ 0 32 Sat 6 **

3 Control 1 4 Sat 4 90 90 3

Example 12 Compound 4 2 4 62 ± 25 23 Sat 2 ** or Example 9 9 k Compound t 7 / fi r +? Π \) 37 g ** Example 5 7 Compound Q r丄 26 Sat

4 J knot D— J 491 ± 4 90 technicians 3

Compound of Example 3 4 4 56 Sat 4 ** 34 Sat A ** Compound of Example 3 3 4 62 4 ** 32 Sat ^ **

5 Control 7 106 persons 15 126 + 7

Example 3 Compound 6 6 80 ± 13 36 Sat 4 ** Example 3 Compound 6 90 ± 15 40 3 **

*: P is 0.05, **: P is 0.01

The excellent TC lowering effect and Lp (a) lowering effect of the compound of the present invention are apparent. In addition, it is clear that the compound of the present invention has the same or more potent Lp (a) lowering action and a stronger TC lowering action than the control compound. Industrial applicability

As described above, the compound of the present invention has an excellent TC lowering action and an Lp (a) lowering action, and is effective for treatment and prevention of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis and the like.

Claims

The scope of the claims

1. A carboxylic acid derivative represented by the following formula [1], a pharmaceutically acceptable salt thereof, or a solvate of any of them. [1]

Wherein represents ^{^{R, R 2, R 3,}} R 4 are the same or different and each is hydrogen, alkyl, halogen, a human Dorokishi or alkoxy.

R ⁵ and R ⁶ are the same or different and represent alkyl.

R ⁷ represents hydrogen or alkyl.

— X— represents — 0— or 1 S—.

Y represents hydrogen, alkyl, halogen, hydroxy or alkoxy, and z ¹ and z ² each represent hydrogen, or Y, taken together, represents 1 CH =.

- A- is> CH- 0H,> C = _{〇,> CH 2,> CH- OR} 8 or represents a> CH- 0C_〇_R ^9. Here, R ⁸ represents alkyl, and R 9 represents alkyl or aryl.

-T- (the left hand represents a bond to A. The same applies to the following)

— Q—, represents one CH ₂ — 0— Q— or one Q— 0—

-Q- (the bond on the left represents a bond to the A side; the same applies hereinafter)

①— (CH ₂ ) _n- , ②— (CH ₂ ) _f -CH = CH- (CH ₂ ) _g —

Or ③- (CH ₂ ) _h — C≡C— (CH ₂ ) j—.

n represents an integer of 1 to 15, and f, g, h, and j each represent an integer of 0 to 13. Here, i + g is an integer from 0 to 13, and h + j is an integer from 0 to 13. Where R ² is hydroxy, Y is hydrogen, one X— is —0—, Z ¹ and Z ² are hydrogen, one A— is CH ₂ , and — T— — Q—, — Q— is — (CH ₂ ) _n —, and n is an integer from 1 to 8, and

R ² is hydrogen, alkyl or halogen, — X— is —0—, Z ¹ and Z ² are hydrogen, — A— is> CH ₂ , — T— is — Q— , — Q— is — (CH ₂ ) _n —, and n is an integer from 1 to 4

2. — A—> CH—〇 H, ＞ C = 0,> CH—OR ⁸ or

The rubonic acid derivative according to claim 1, which is CH—OCOR ⁹ , or a pharmaceutically acceptable salt thereof, or a solvate of any of them.

3. —A—> CH ₂ ,> CH—OH or> C = 0, —X— is —0—, Z ¹ and Z ² are hydrogen, — T—is —Q— _2. The carboxylic acid derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein — Q— is — (CH ₂ ) _n —, n is 6 to: I 0, and R ⁷ is hydrogen. Or a solvate of any of them.

4. —A—> CH—0H or> C = 0, X— is —0—, Z ¹ and Z ² are hydrogen, —T— is —Q— The carboxylic acid derivative according to claim 1, wherein —Q— is — (CH ₂ ) _n —, n is 6 to: I 0, and R ⁷ is hydrogen, or a pharmaceutically acceptable salt thereof, or a salt thereof. Any of the solvates of

Five. ! ^ And and are hydrogen, alkyl or halogen, R ⁵ and R ⁶ are both methyl, — A— is> CH ₂ ,> CH—OH or> C = C, and — X— is —〇 — And Z ¹ and Z ² are hydrogen There, one T one is an Q-, - Q-is - (CH ₂₎ _n -, and 'n is 6-1 0, carboxylic San誘conductor according to claim 1, wherein R ⁷ is hydrogen Or a pharmaceutically acceptable salt thereof or a solvate of any of them.

6.! ^ ~! ^ Is hydrogen, alkyl or halogen, R ⁵ and R ⁶ are both methyl, — A— is> CH—OH or> C = 〇, and — X— is — 0— , Z ¹ and Z ² are hydrogen, — T— is — Q—, — Q— is — (CH ₂ ) _n —, n is 6-10, and R ⁷ is hydrogen 2. The carboxylic acid derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

7. The carboxylic acid derivative according to claim 1, selected from the group consisting of the following compounds (1) to (9), or a pharmaceutically acceptable salt thereof, or a solvate of any of them.

(1) 10- (4-tert e-butylphenoxy—2,2-dimethyl-1-9-hydroxydenoic acid

(2) 1 1— (4-tert-Butylphenoxy 2,2-dimethyl-1 10—Hydroxydinedecanoic acid

(3) 1 2— (4—t ert—butylphenoxy—2,2-dimethyl-1-111-hydroxy dodecanoic acid

(4) 1 3— (4-tert e-tert-butylphenoxy 2, 2-dimethyl-12-hydroxytridecanoic acid

(5) 1 4— (4-tert-butyl-2-oxy-1,2,2-dimethyl-3-13-hydroxytradecanoic acid

(6) 1 2— (4—tert-butyl phenoxy 2,2—dimethyl Chill 1 1-year-old xo dodecanoic acid

(7) 1 1— (4-Chlorophenoxy) 1 2 2 1-Dimethyl 10 Hydroxydiandecanoic acid

(8) 1 2— (4-Chlorophenoxy) 1,2,2-dimethyl-1 1-hydroxy-dodecanoic acid

(9) 13- (4-Chlorophenoxy) 1,2,2-dimethyl-1 12-Hydroxy tridecanoic acid

8. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7 as an active ingredient.

9. A pharmaceutical composition for preventing or treating hypercholesterolemia, comprising at least one compound according to claim 1 as an active ingredient.

10. A pharmaceutical composition for preventing or treating hyper-L p (a) blood, comprising at least one compound according to claim 1 as an active ingredient.

11. A pharmaceutical composition for preventing or treating arteriosclerosis, comprising at least one compound according to claims 1 to 7 as an active ingredient.

12. A pharmaceutical composition for preventing or treating ischemic heart disease, comprising at least one compound according to any one of claims 1 to 7 as an active ingredient.

13. A pharmaceutical composition for preventing or treating cerebral infarction disease, comprising at least one compound according to claims 1 to 7 as an active ingredient.

14. A pharmaceutical composition for preventing or treating restenosis after PTCA surgery, comprising at least one compound according to any one of claims 1 to 7 as an active ingredient.