WO1993002031A1

WO1993002031A1 - Alkylphenol derivative

Info

Publication number: WO1993002031A1
Application number: PCT/JP1992/000942
Authority: WO
Inventors: Shuji Jinno
Original assignee: Nippon Suisan Kaisha, Ltd.
Priority date: 1991-07-24
Filing date: 1992-07-24
Publication date: 1993-02-04

Abstract

An alkylphenol derivative wherein the alkyl group has 8 to 23 carbon atoms, which may be further substituted with hydroxy, alkoxy and halogen, and which is excellent in an antioxidant activity and inhibition of lipid peroxide.

Description

Description Alkyl alkyl derivative Technical field

The present invention relates to an alkylphenol derivative. More specifically, the present invention relates to an alkylphenol derivative having an antioxidant action and a lipid peroxide inhibitory action useful for medical products and the like.

Background art

Hitherto, phenols having an antioxidant action have been known, and have been used in the chemical industry and the like. Attention has been paid to this antioxidant effect, and it has been considered to apply it to medical products, etc., but at present it has not been established as a leading drug at present. is there

On the other hand, it has been clarified that lipid peroxide in the living body affects arteriosclerotic diseases and also aging, and suppresses the oxidation mechanism in the living body. Expectations are increasing for peroxidized lipid inhibitors that can do this. In such a situation, the use of phenol derivatives has been studied, but as described above, they are useful as medical products. A phenol derivative capable of exerting a sufficient active action has not yet been found.

The present invention has been made in view of the above circumstances, and provides a new phenol derivative that can be applied to antioxidants, lipid peroxide inhibitors, and the like. It is intended to do so.

Disclosure of the invention

The present invention solves the above-mentioned problem by using the following formula (1)

(In the formula, R ₅ is H, a hydroxyl group or an alkynole group having 8 to 23 carbon atoms, and at least one of R i to R ₅ is a group having 8 to 23 carbon atoms. An alkyl phenyl derivative represented by the following formula:

This phenolic phenol derivative has at least one alkyl group having 8 to 23 carbon atoms as a substituent of the benzene ring. Is one of its major features.

Examples of the alkyl group having 8 to 23 carbon atoms in the above formula (1) include a straight-chain or branched-chain alkyl group.

These phenol derivatives can be produced, for example, by the following method. That is, first, the substituted hydroxybenzenes aldehyde is reacted with a phosphonium salt having 7 to 22 carbon atoms prepared by a known method.

The reaction is carried out in an inert solvent (for example, N, N-dimethylformamide, dimethylphenol foxide, tetrahydrofuran, The presence of basic compounds (eg, sodium hydrate, potassium carbonate, sodium hydroxide, etc.) in the presence or absence of dioxane The reaction can be carried out under ice cooling or at the reflux temperature of the solvent used. Conditions such as the solvent, basic compound, and reaction temperature can be appropriately selected in accordance with the substituted hydroxybenzaldehyde to be used. To 23 alkenyl-substituted phenolic compounds can be prepared by known methods, for example, using an inert solvent (for example, methanol, ethanol, hexane, acetate). Hydrogenation in the presence of a catalyst (eg, platinum dioxide, paradigm carbon, etc.) The compound of formula (1) of the present invention can be produced. The hydroxyl group may be introduced into the benzene ring in advance of the above-mentioned method, or may be a halogen group or an alkoxy group. May be introduced into a benzene ring, and after performing the above-mentioned reaction, a substitution reaction with a hydroxyl group may be carried out.

The reaction time varies depending on the starting material, the type of reaction solvent and the amount used, and the reaction is terminated with the disappearance of the starting material due to thin-layer silica gel chromatography. It can be done.

The formula of the present invention obtained by these appropriate methods

The compound (1) can be purified by recrystallization, adsorption chromatography, or the like.

Further, the present invention provides the following formula (2)

(2)

(X in the formula represents an alkyl group having 8 to 23 carbon atoms,

R 6, R 7, R 8 and R 9 are a halogen atom, a hydroxyl group or a phenol group, and at least one of R ₆ to R ₉ is It shows a alkoxy group. The present invention provides an alkyl phenol derivative represented by the formula:

The alkylphenol derivative represented by the formula (2) has at least one alkoxy group as a substituent and has a carbon atom at the 2-position. Its major feature is that it has an alkyl group of Formulas 8 to 23.

The alkoxy group in the above formula (2) is not particularly limited in the number of carbon atoms, but is more specifically a straight chain having 1 to 0.5 carbon atoms. And a branched lower alkyl group. Examples of the halogen atom include chlorine, bromine, and an atom such as an alkyl group having 8 to 23 carbon atoms, and a straight-chain or branched-chain alkyl group. An example is shown below.

This phenol derivative can be produced by the same method as that for the compound of the above formula (1).

The phenolic alkoxy group may be formed in advance on the benzene ring prior to the above-mentioned method, or may be formed in advance with a halogeno substituent. Is introduced into a benzene ring, and after performing the above-mentioned reaction, a known alkali metal alcohol is reacted in the presence of coligin, Cu 1, or the like. Method (J. Chem. By using Soc. (C), 312, 1969), it is also possible to convert a norogen group into an alkoxy group.

The reaction time varies depending on the starting material, the type of the reaction solvent, and the amount used, and therefore, the disappearance of the starting material due to thin-layer silica gel chromatography, etc. The end of the reaction can be reached.

The compound of the general formula (2) of the present invention obtained by these appropriate methods can be purified by recrystallization, adsorbed column chromatography, etc. You can do it.

Further, the present invention provides the following formula (3)

(Y and Z in the formula are 1-1, an alkoxy group or a hydroxyl group, and at least one of them represents an alkoxy group. , R, ₀ , R !! and R! ₂ are H, alkoxy group or It is an alkyl group having 8 to 23 carbon atoms, and at least one of R _1D to R ₁₂ is an alkyl group having 8 to 23 carbon atoms. The present invention provides an alkylphenol derivative represented by the formula:

The alkylphenol derivative represented by this formula (3) has an anoreoxy group at the 2-, 6- or 6-position, and has 3, 4, and Is characterized by having an alkyl group with 8 to 23 carbon atoms at the 5-position.

The alkoxy group in the above formula (3) is not particularly limited in the number of carbon atoms, but is more specifically a straight-chain or branched chain having 1 to 5 carbon atoms. The lower alkoxy group of the chain is exemplified. In addition, a linear or branched alkyl group having 8 to 23 carbon atoms is also exemplified.

These phenol derivatives can be produced by a method similar to that for the compound of the formula (2).

For example, the compound of the present invention represented by the above formulas (1), (2) and (3) produced by the above-mentioned method has an excellent lipid peroxide inhibitory action, It is also low toxic. Therefore, the compound of the present invention is useful as a therapeutic drug for various diseases considered to be associated with lipid peroxide in vivo, for example, arteriosclerosis, liver disease, etc. It is.

For use as a medicament, the compounds of this invention are commonly used. Various dosage forms, for example, powders Granules, tablets, dragees, ampules, capsules, etc., subcutaneous, intramuscular or intravenous injections , Suppositories, etc.

For this purpose, conventional additives such as bulking agents, binders, disintegrants, pH regulators, solubilizers, and the like can be used.

The dosage for the treated patient will vary depending on the patient's age, disease type and condition, etc., but it is usually 10 to 500 mg per day for adults 1 to several times. Can be administered separately.

Next, the results of the lipid peroxide inhibition test of the compound of the present invention are shown.

Test Example 1 [Lipid peroxide inhibition test of the compound of the formula (1)] The sample was diluted with phosphate buffer and dissolved in 0.85 ml of the diluted solution in dimethyl sulfoxide 100 [11] (with the compound of the present invention and a comparative drug). Then, t-butyl hydroperoxide was added, and the mixture was incubated at 37 ° C for 30 minutes.

Malondialdehyde, a decomposition product of the generated lipid peroxide The de amount quantified Ri by the thio carbonochloridate le bi tools acid method to calculate the maximum Ma B emission Jiarude arsenide de amount of 5 0% inhibition analyte concentration (IC ₅ 0), compared drugs der The ratio of the runo protocol to the IC ₅₀ was determined. The results are shown in Tables 1 and 2.

¾ 1 a - (. N o ) preparative co full error b Lumpur specimen of compound IC ₅ alpha Z test compound

I 5 0

4 へプタタププ

0. 1 <

(Compound 1-1)

3 First Hep Desole Pole

0. 2 9

(Compound 1-2)

2 Heptadeno-Pinole Knoll

2.01

(Compounds 1-3)

4 First heptare series 2 — Hidden

Mouth Kimono Nozore 1.8 4

(Compounds 1-4)

2 First step 5 — Hidden

Roxifenol 1.4.4 4

(Compounds 1-5)

3 — Hepta de Siroux 2 — Hidden

Roxifenonore 4.6.9

(Compounds 1-6)

a-Tocopherolone sample compound I C5. Sample compound

I re 50

2,,,, ■>.

, 3 — N-Hirokin — 5 —

Hepta Desno-Role Knoll 1.4.3

(Compound 1-7)

table

L 1 '\ Nog 7 "

Mouth knives 2. 4 1

(Compound 18) 2;

3, 5 — dihydroquinone 2 —

Heptadecylvinyl

(Compounds 1-9)

2, 4 page Hydroxy 1 3 —

Hepta-de-sinole vinyl 2.2 1

(Compound 110) Test Example 2 [Lipid peroxide inhibition test of compound of formula (2)] 赤 Erythrocyte membrane ghosts collected from herons and having a protein mass of 1-2. mg Z ml, diluted with phosphate buffer, and dissolved in 0.85 ml of the diluted solution in dimethyl sulfoxide 1001 (this invention). And α-tocopherolone as a comparison drug, and t-butylhydrono. — Add oxide and incubate at 37 ° C for 30 minutes.

The amount of malonaldehyde, which is a decomposition product of the produced lipid peroxide, was determined by the Thiobarbituric acid method, and the maximum malonaldehyde was determined. The concentration (IC ₅₀ ) of the subject that suppressed the amount of dialyzate by 5% was calculated, and the ratio to the IC50 of << one-tocopherol (a comparison drug) was determined.

Table 3 shows the results.

The activity was similarly evaluated for ₂ — _{C n} H _{2 n + 1} — 4 — methoxyphenol (n _{= 8} to 19). The results of its n value and activity (alpha - DOO co off We b Lumpur IC ₅ .z trial DOO

! The attached drawing shows the correlation with C5 o).

Table 3 Sample a-Tocopherol I (: ^ Sample! C ₅₀

2-octyl 4-methoxif

0.73

Enol (Compound 2-1)

2 1 heptadecyl 1—method

Cifenol 1.04

(Compound 2-2)

2—Hep evening decyl 1—Metoki

Siphonol 2.25

(Compound 2-3)

3, 5—Dimethoxy 2—Hep

Tadecylphenol 2.3.3

(Compounds 2-4)

3-Promo 2-Heptadecyl

— 6—Methoxy phenol 0.0 1

(Compound 2-5)

2, 4—dipromo 6—hepta

Tesylphenol 0.3 3

(Compound 2-6)

2—Ethoxy 6—Heptadec

Norefanol 0.9 2

(Compound 2-7)

3, 6—Dimethoxy 2—Hep

Tadecylphenol 2.4.9

(Compound 2-8)

3—Promote 2—Heptadecyl

1 6—Methoxy phenol 0.9 8

(Compounds 2-8) Test Example 3 [Lipid peroxide inhibition test of compound of formula (3)] ゥ Erythrocyte membrane ghosts collected and prepared from egrets were adjusted to have a protein mass of 1 to 2.5 mg / ml. The sample was diluted with phosphate buffer and dissolved in 0.85 ml of the diluted solution of dimethylsulfoxide 100β1 (the compound of the present invention and a control reagent). Phenol, and then t-butylhydroxide peroxide, 37. Incubated with C for 30 minutes.

The amount of malondialdehyde, which is a decomposition product of the generated lipid peroxide, was quantified by the tiobarbituric acid method, and the concentration of the analyte that suppressed the maximum amount of malondialdehyde by 50% (IC ₅ 0) was calculated to determine the ratio of the comparison drug der Ru Do one preparative co full We b over IC ₅₀ of Le.

Table 4 shows the results.

Table 4

BRIEF DESCRIPTION OF THE FIGURES

The drawing shows the correlation between the alkyl chain structure and the activity of the compound of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, examples will be shown, and the alkylphenol derivative of the present invention will be described in more detail.

Example 1

Add 0.63 g of sodium hydrogenated to dimethyl alcohol

14 ml was added, and the mixture was stirred at 60 ° C for 2 hours. 1-Bromohexa dissolved in 5 ml of dimethylsulfoxide Decane, triphenylphosphine, and strength, 7.5 g of phosporium salt, were added, and the mixture was stirred at room temperature for 30 minutes. After stirring, 1.0 g of 4-hydroxybenzyl aldehyde was added, and the mixture was stirred at 50 ° C. for 16 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The extract layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent; hexane: ethyl acetate = 10: 1), and the resulting residue was purified with 1 O mi of vinegar. It was dissolved in ethyl acetate, a small amount of platinum dioxide was added, and the mixture was stirred under a hydrogen stream for 4 hours. After the reaction, the reaction mixture is filtered, the filtrate is distilled off under reduced pressure, and the residue is purified by silica gel chromatography chromatography (developing solvent; hexane: ethyl acetate = 10: 1). Purify and add 1.23 g of 41 heptadecinophenol (compound 1-1)

1 Protected o

H ¹ -NMRCCDC ")

δ (p p m)

0.8-1.0 (3 H, m, CH 3), 1.2-1.8 C 3 0 H, m,

(C H 2) 15) 2.53 (2 H, t, J = 7.4 Hz, P h

-C H 2) 4.60 (1 H, s, 0 H)

6.9-7.1 (4 H, m, Ar-H)

Examples 2 to 6

The following compounds were obtained in the same manner as in Example 1. — Heptadecylphenol (Compounds 1 and 2)

H ¹ one NMRCDC ")

δ (ρ ρ m)

0.8- 1.0 (3 H, m, CH 3), 1.2-1.8 (3 0 H, m (CH 2) i 5), 2.55 (2 H, t, J = 7.3 H z, P h one CH 2), 4.68 (1 H, s, OH)

6.6-7.2 (4 H, m, Ar — H)

— Heptadecylphenol (compounds 1-3)

H ¹ NMR (CDC 13)

δ (ρ p m)

0.8- 1.0 (3 H, m, CH ₃ ), 1.2-1.8 (3 OH, m

(CH2) ₁₅ ), 2.60 (2H, t, J = 7.4Hz, Ph-CH2), 4.66 (1H, s, 0 days)

6.7- 7.2 (4 H, m, Ar-H)

1-dep-tinol-phenol (2-compound 14-hydroxyl)

H ¹ -NMR (CDC 13)

δ (ρ ρ m)

0.8- 1.0 (3 H, m, C Η 3) '1.2-1.8 (3 0 Η, m (C Η 2) 1 5), 2.49 (2 Η, t, J = 7.3 H z, P h one C Eta 4.99 (1 Η, s OH)

5.12 (1H, s, 0H), 6.6-6.9 (3H, m, Ar Day)

Violence 2 — Hepta de Sinore 1 5 — Hydroxy feno — Zole

^{_{H I - NMR (CDC 1 3}} )

δ (ρ ρ m)

0.8-1.0 (3Η, m, CH ₃ ), 1.2-1.8 (30H, m, (CH 2) is), 2.50 (2H, t, J = 7.1Hz, Ph-CH 2), 4.59 (1 H, s, 0 days)

4.66 (1H, s, day), 6.3-6.5 (2H, m, Ar-H)

6.94 (1 H, d, J = 9.0 H _z , A r -day)

φ 3 heptadecyl 1 2 — Hydroxy-Pinnole (compounds 16)

H ¹ — NMRCCDC ")

δ (p p m)

0.8-1.0 (3 H, m, CH 3), 1.2-1.8 (3 0 H, m, (CH 2) 15), 2.60 (2 H, t, J = 7.3 H z, P h one CH 2), 5.17 (1 H, s, 0 H)

5.17 (1 H, s, OH), 6.6-6.8 (3 H, m, A r —

H)

Example 7

Hydrogen 0: 6 3 g in sodium dimethyl 14 ml was added, and the mixture was stirred at 60 ° C for 2 hours. 1-Bromohexadecane and triphenylphosphine dissolved in 5 ml of dimethyl sulfoxide, and the resulting phoshonium salt 7.5 g was added and the mixture was stirred at room temperature for 30 minutes. After stirring, add 1.0 g of silanealdehyde, and stir at 50 ° C for 16 hours.After the reaction, add water and extract with ethyl acetate.The extract layer is washed with water and saturated saline. After drying, the solvent was distilled off under reduced pressure. This residue was purified with silica gel chromatography (developing solvent; hexane: ethyl acetate = 5: 1), and the resulting residue was purified to 1 Oml. Was dissolved in ethyl acetate, a small amount of platinum dioxide was added, and the mixture was stirred under a hydrogen stream for 4 hours. After the reaction, the mixture is filtered, the filtrate is distilled off under reduced pressure, and the residue is purified by silica gel chromatography chromatography (developing solvent; hexane: ethyl acetate = 5: 1). The residue was purified to give 1.32 g of 2,6-dimethoxy-1-heptadecylphenol.

0.5 g of this was dissolved in 9 ml of methylene chloride, cooled to 120 ° C, and 5.5 ml of 1N tribromomoblanno methylene chloride solution was added. The mixture was stirred at 120 ° C. for 30 minutes, and further stirred at room temperature for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extracted layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. Gel chromatography chromatography (developing solvent; Purified by oxane: ethyl acetate = 2: 1), 2,3—dihydroxy-5-heptadecylphenol (compound 1—7) 0.38 g.

H '-N M R C C D C l a)

δ (p p m)

0.8 - 1 · 0 (3 Η , m, CH 3), 1.2 - 1.8 (3 0 H, m, (CH 2) is), 2.44 (2 H, t, J = 7.0 H z, P h - CH 2 ), 4.9-5.1 (3H, br, 0 days), 6.2-6.3 (2H, m, Ar—days)

Mass spectrometry

364 (M ⁺ ), 139 (Base)

Example 8 1 0

The following compounds were obtained in the same manner as in Example 7.

• 2—Hepta desinole 1 4—Hydroxypino-no-nore 1

^{_{H 1 - NMR (CDC 1 3}} )

δ (p p m)

0.8 -1.0 (3 Η, m, C Η 3), 1.2 1.8 (3 0 H, m, (C Η 2) i 5), 2.41 (2 Η, t J = 6.8 Η ζ, Ρ h - C Η a ), 6.3-6.7 (3 Η, m A r —day),

8.36 (1Η, s, 0Η), 8.43 (1Ηs, 0H) mass spectrometry

348 CM +), 123 (Base), 57

OH 123 57

I

CH2-C12H2A + CAH9

OH Hata 3, 5 — The Hydroxy 1 2 — Hep Evening Design

(Compounds 1-9)

H ¹ NMR (CDC 1 a)

δ (p p m)

0.8 - 1.0 (3 H, m , CH 3), 1.2 - 1.8 (3 0 H, m, (CH z) is), 2. 52 (2 H, t, J = 7.0 H z,

P h CH ₂ ), 4.60 (1H, s _; 0 days), 4.71 (2Hs, OH, 5.9-6.0 (2H, mAr-H)

Mass spectrometry

364 (M ⁺ ), 139 (Base)

• 2, 4 — Dihydroxy 3 — Hepta-decylamine

(Compound 1-10)

H ¹ NMR (CDC 13)

δ (p p m)

.8 -1.0 C 3 H, m, C H_ ₃ ), 1.2 — 1.8 (30 H, _{m, (CH 2) i 5} ), 2.63 (2 H, t, J = 7.0 H z,

P h -CH ₂ ), 4.39 (1 H, s, 0 days), 4.60 (1 H s, 0 days), 5.31 (1 H, s, 0 days), 6.41 (1 H, d

J = 8.5 Hz,

6.58 (1 H, d, J = 8.5 H

Mass spectrometry

364 (M +), 139 (Base)

139

CH2 + C15H33 Example 1 1

14 ml of dimethinoles norrefoxide was added to 0.63 g of sodium hydrogen chloride, and the mixture was stirred at 60 ° C. for 2 hours. To this was added 1 g of 1-bromoheptane and triphosphorin phosphine dissolved in 5 ml of dimethyl sulfoxide, and 7.5 g of phoshondium salt, which is a force, was added. The mixture was stirred at room temperature for 30 minutes. After stirring, 1.0 g of 2-hydroxy-5-methoxybenzene aldehyde was added, and the mixture was stirred at 5 G ° C for 16 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography chromatography (developing solvent; hexane: ethyl acetate = 5: 1), and the resulting residue was purified to 1 Om 1 Was dissolved in ethyl acetate, a small amount of platinum dioxide was added, and the mixture was stirred under a hydrogen stream for 4 hours. After the reaction, the reaction mixture is filtered, the filtrate is distilled off under reduced pressure, and the residue is purified by silica gel chromatography chromatography (developing solvent; hexane: ethyl acetate = 5: 1). Then, 0.72 g of the following 2 — octyl 4 — methoxyphenol (compound 2 — 1) was obtained. 123 137

C7H15

0CH3 mass spectrometry

236 ( ⁺ ), 137 (Base), 123

^{_{H 1 - NMR (CDC 1 3}} )

δ p p m

0.8 -1.0 (3 H, m, CH 3), 1.2 - 1.8 (3 0 H, m, (CH 2) 6), 2.57 (2 H, t, J = 7.4 H z, P h - CH 2), 3.75 (3 H, s, 0 CH 3),

4.47 (1H, s, OH), 6.6-6.8 (3H, m, Ar once)

Examples 12 to 17

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

Reference 2 —Hepta desinole 1 5 —Methoxy phenol (compound

twenty two )

^{_{H 1 - NMR (CDC 1 3}} )

δ (ppm) 0.8- 1.0 (3 H, m, CH 3), 1, 2 - 1.8 (3 0 H, m, (CH 2) 15), 2.52 (2 H, t, J = 7.3 H z, P h - CH 2 ), 3.75 (3 H, s , 0 CH 3),

4.85 (1H, s, OH), 6.3-6.5 (2H, m, Ar once)

7.00 (1 H, d, J = 7.7 H z, A r —day)

Reference 2 — Hepta de Siroux 4 — Methoxy phenol (compound)

twenty three )

H ¹ — NMRCCDC ")

δ (p p m)

0 · 8 -1.0 (3 H, m, CH ₃ ), 1.2 — 1.8 (30 H, m, (CH 2) is), 2.57 (2 H, t, J = 1.4 Hz, P h-CH 2 ), 3.75 C 3 H, s, 0 CH ₃ ),

4.37 (1H, s, 0 days), 6.6-6.7 (3H, m, Ar-1H)

• 3, 5 — Dimethyoxy 2 — Heptadecylphenol (Compounds 2-4)

H ¹ — NMRCCDC ")

δ (ρ p m)

0.8 - 1.0 (3 Η, m , CH 3), 1.2 - 1.8 (3 0 H, m, (CH 2) is), 2.53 (2 H, t, J = 7.3 H z, P h - CH 2), 3.70 (3 H, s, 0 CH 3), 3.74 (3 H, s, OCH 3), 5.29 (1 H, s, 0 Dan) 6.00 (1 H, d, J = 2.3 H z, A r - Dan), 6.08 (1 H, d , J = 2.3 H z, A r -day)

• 3 — Bromo 2 — heptadine 6 — methoxyphenol (compound 2 — 5)

^{_{H 1 - NMR (CDC 1 3}} )

δ (p p m)

0.8 -1.0 (3 Η, m, C Η 3), 1.2 - 1.8 (3 0 Η, m, (C Η 2) 1 5), 2.69 (2 Η, t, J = 7.4 Η ζ, Ρ h - C Η 2), 3.86 (3 Η , s, Ο C Η 3),

5.75 (1 Η, s, 0 days), 6.58 (1 Η, d, J = 8.8 Η ,, Ar — day), 7.04 (1 Η, d, J = 8.8 Hz,

A r —day)

• 2, 4 — Jib mouth mode 6 — Heptadecylphenol (Dragon compound 2-6)

Η ¹ — NMR (CDC 1 a)

δ (p p m)

0.8 -1.0 (3 H, m, C Η 3), 1.2 - 1.8 (3 0 Η, m, (C Η 2) 15), 2.53 (2 Η, t, J = 7.4 Η ζ, Ρ h - C Η 2), 5.49 (3Η, s, 0 days), 7.18 (1Η, s, 0CΗ3), 5.36 (1Η, s, OH), 6.28 (1Ηd, J = 2.3 Hz, A r — H), 7.42 (1 H, d, J = 2.3 H z, A r -day)

2 — Ethoxy 6 — Heptadecyl sulfone (compound 2-7)

H ¹ -NMR (CDC 13)

δ (p p m)

0.8 -1.0 (3 H, m, CH 3), 1.2 - 1.8 (3 0 H, m, (CH 2)), 1.44 (3 H, t, J = 7.0 H z, 0 CH 2 CH 3), 2.63 (2 H, t, J = 7.4 H z, P h - CH 2), 4.10 (2 H, q, J = 7.0 H z, 0 CH 2 CH a), 5.34 (1 H, s, OH)

6.6-6.8 (3H, m, Ar, H)

Example 18

0.41 g of the compound produced in Example 11 was added to 3.2 ml of 2.5N sodium methylate, and 4.5 ml of iodine was added to 4.5 ml of colidin. 0.20 g of copper was added and the mixture was heated and refluxed for 16 hours. After the reaction, the reaction mixture was filtered, the filtrate was acidified with 1N hydrochloric acid, extracted with ethyl acetate, the extracted layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography chromatography (developing solvent; hexane: ethyl acetate = 10: 1) to give 3,6-dimethoxy. — 2 — Hepta decinole compound (compound 2 — 8)

0.26 g was obtained. ^{_{H 1 - NMR (CDC 1 3}} )

δ (ρ p m)

0.8 -1.0 (3 H, m, CH 3), 1.2 - 1.8 (3 0 H, m, (CH 2) is), 2.64 (2 H, t, 3 = 1. 2 H z,

P h-CH ₂ ), 3.75 (3 H, s, OCH ₃ ),

3.82 (3 H, s, 0 CH 3), 5.68 (1 H, s, 0 H)

6.31 (1 H, d, J = 8.9 Hz, A r —day), 6.63 (1

H, d, J = 8.9 Hz A r H)

Example 19

In the same manner as in Example 18, the following compound was obtained from Compound 2-6.

4 — Bromo 2 — Heptadecyl 6 — Methoxyphenol (Compound 2 — 9)

^{_{H 1 - NMR (CDC 1 3}} )

δ (p p m

0.8 -1.0 (3 H, m, CH 3), 1.2 - 1.8 (3 OH, m, (CH a) is), 2.59 (2 H, t, J = 7.4 H z, P h - CH 2), 3.86 (3 H, s, 0 CH 3),

5.56 (1H, s, 0 days), 6.7-6.9 (2H, m, Ar — days)

Example 20 to 29

The following compounds were obtained in the same manner as in Example 11. Association 2 — Nonisole 4 — Methoxyphonone (Compounds 2 — 10)

^{_{H 1 - NMR (CDC 1 3}} )

δ (p p m)

0.8 -1.0 (3 Η, m, C Η 3), 1.2 1.8 (1 4 Η, m, (C Η 2) 7), 2.57 (2 Η, t J = 7.4 Η ζ,

Ρ h C Η ₂ ), 3.75 (3 Η, s, 0 C Η ₃ )

4.36 (1Η, s, 0 days), 6.6-6.8 (3Ηm Ar-day)

Mass spectrometry

250 (Μ ⁺ ), 137, 57 (Base)

Naina 2 — Decilou 4 Methoxylon (Compound 2 — 1 1)

H ¹ -NMR (CDC 13)

δ (p p m)

0.8 -1.0 (3 H, m, CH 3), 1.2 one 1.8 (1 6 H, m, (CH 2) 8), 2.57 (2 H, t, J = 7.4 _Hz

P h-CH 2), 3.75 (3 H, s, 0 CH ₃ ),

4.38 (1H, s, day), 6.6-6.8 (3H, m, ArH)

Mass spectrometry

264 (M +), 137, 123

鲁 2 — P-decyl- 1-methoxybenzene (compound 2-1 2)

Η ¹ NMR (CDC 13)

δ (p p m)

0.8 -1.0 (3 H, m, CH 3), 1.2 - 1.8 (1 8 H, m, (CH 2) 9), 2.57 (2 H, t, J = 7.4 H z, P h - CH 2), 3.75 (3 H, s, 0 CH 3),

4.44 (1 H, s, OH), 6.6-6.8 (3 H, m, Ar — H) Mass spectrometry

278 (M ⁺ , Base), 137, 123, 57

Two

• 2 — Dodecinolone 4 — Methoxyphosphonolone (Compounds 2-13)

H ¹ — NMR (CDC ls)

δ (p p m)

0.8 -1.0 (3 Η, m, C Η 3), 1.2 - 1.8 (2 0 Η, m, (C Η 2) 10), 2.57 (2 Η, t, J = 7.4 H z, Ρ - C Η 2 ), 3.75 (3 3, s, OCH ₃ )

4.71 (1 Η, s, 0 days), 6.6-6.8 (3 Η, m A r-Η)

Mass spectrometry

292 (Μ ⁺ ), 137 (Base), 123

ε-

'(+ w) οοε

¾ honors c

(Η

J V III H ε) 8 · 9-9 · 9 (Ή "0 s' Η I) S

( ^ε Η 30 's' He) 91 'e' ( ² H 3 qd

^{'Z H' L = £ '} H 2) AS · 2' C 11 (3 H 3) ui 'HZ 2) 8 Ί 2 Ί' (8 H 0 'ω' HS) 0 · Bok 8 - 0

(ui d d) p

( ^ε Ι θ α θ) Ή ^ Η- _Ι Η

(H-

Z i ^) (See-ί ^ Λ — ― ^ 4 _ 2

Hi 600 / Z6df / JOd ΐε0Ζ0 / £ 6 OAV • 2—Tetradecyl 4 methoxyphenol (compound

2-1 5)

^{_{H 1 - NMR (CDC 1 3}} )

δ (p p m)

0.8 -1.0 (3 Η, m, C Η 3), 1.2 - 1.8 (2 4 Η, m, (C Η 2) 1 2), 2.57 (2 Η, t, J = 7.3 H z,

Ρ h C Η 2) 3.75 (3 Η, s, 0 C Η 3),

.37 (1st, s. 0II), 6.6-6.8 (3rd, mAr-day)

Mass spectrometry

320 (M +), 137 (Base), 123, 57

Association 2 — Pentadecinole 4 — Methoxypinoline (Compound 2-16)

^{_{H 1 - NMR (CDC 1 3}} )

0 (ppm) 0.8 -1.0 (3 H, m, CH 3), 1.2 - 1.8 (2 6 H m, (CH 2) i 3), 2.57 (2 H, t, J = 7.3 H z

P h-CH 2), 3.75 (3 H, s, 〇 CH ₃ ),

4.3-4.5 (1 H, b r, O H), 6.6-6.8 (3 H, m A r —day) Mass spectrometry

334 (M ⁺ , Base), 137O, 123, 57

Five

0CH3

• 2 — hexadecyl 4 — methoxyphenol (compound 2-17)

^{_{H 1 - NMR (CDC 1 3}} )

(5 p p m

0.8 - 1.0 (3 H, m , CH 3), 1.2 - 1.8 (2 8 H, m, (CH a) 1 4), 2.57 (2 H, t, J = 7.4 I z, P h - CH 2) , 3.75 (3 H, s, 0 C II ₃ ),

.34 (1 H, s, O H.), 6. G-6.8 (3 H, m, Ar-H) Mass analysis

348 (M +) 137 (Bas) 123, 57

Attack 9 1 year old ladder 4 — methyanphenol (compound

2-1 8)

^{_{H 1 - NMR (CDC 1 3}} )

δ (p P m)

ϋ · 8 - 1.0 (3 Η , m, CH a), 1.2 - 1.8 (3 2 II, m, (CH 2) ie), 2.57 (2 H, t, J = 7.3 H z,

P h-CH 2), 3.75 (3 H, s, 0 CH ₃ ),

4.37 (1H, s, OH), 6.6-6.8 (3H, mAr-H)

Mass spectrometry

376 (M +, Base), 137, 123, 57

鲁₂ — Nonadenosine 4 methoxide (compound 2

-1 9)

^{_{H 1 - NMR (CDC 1 3}} )

δ (p p m)

0.8 -1.0 (3 Η, m, C Η 3), 1.2 - 1.8 (3 4 Η, m, (C Η ζ) 1 7), 2.55 (2 Η, t, J = 7.4 Η ζ,

Ρ h-C Η 2), 3.73 (3 Η, s, 0 C Η ₃ ),

4.43 (1Η, s, 0 days), 6.6-6.8 (3Η, m A r days)

Mass spectrometry

390 (M ⁺ ), 137 (Base)

137

CH2 + C18H37

Example 30

To 0.63 g of sodium hydrogen chloride was added 14 ml of dimethinoles noreoxy chloride, and the mixture was stirred at 60 ° C for 2 hours. In addition to this, 11-bromohexadecane and tri-phenylene phosphine dissolved in 5 ml of dimethylsulfoxide were combined with a phosphine. 7.5 g of sodium chloride was added and the mixture was stirred at room temperature for 30 minutes. After the stirring, 1.0 g of 4-hydroxy-3-methoxybenzene was added, and the mixture was stirred at 50 ° C for 16 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extracted layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. This residue was purified by silica gel chromatography chromatography (developing solvent; hexane: ethyl acetate = 10: 1), and the resulting residue was purified in 1 Oml. Was dissolved in ethyl acetate, and a small amount of platinum dioxide was added thereto, followed by stirring under a hydrogen stream for 4 hours. After the reaction, the mixture is filtered, the filtrate is distilled off under reduced pressure, and the residue is purified with silica gel chromatography (developing solvent; hexane: ethyl acetate = 10: 1). Further purification was performed to obtain 1.19 g of 4-peptidylcinole-2-methoxyphenol (compound 3-1).

H ¹ NMR (CDC 13)

δ ρ p m)

0.8 -1.0 (3 H, m, CH 3), 1.2 - 1.8 (3 0 H, m, (CH 2) 1 5), 2.53 (2 H, t, J = 7.3 H z, P h-CH 2), 3.87 (3 H, s, 0 CH ₃ ),

5.43 (1H, s, 0 days), 6.6-6.9 (3H, m, Ar days)

Example 3 1 to 3 3

The following compounds were obtained from the corresponding starting materials in the same manner as in Example 30.

• 5—Heptadecinole 1—Methoxy phenol (Compound 3-2)

^{_{H 1 - NMR (CDC 1 3}} )

δ (p p m)

0.8-1.0 (3 Η, m, CH 3), 1.2 - 1.8 (3 0 H, m, (CH 2) 15), 2.51 (2 H, t, J = 7.4 H z, P h - CH z), 3.86 (3 H, s, OCH ₃ ),

5.53 (1 H, s, O H), 6.5 — 6.8 (3 H, m, Ar

-Dan)

• 2, 6 — Dimetoxin 4

(Compound 3 — 3)

^{_{H 1 - NMR (CDC 1 3}} )

δ (p p m)

0.8 -1.0 (3 Η, m, C Η 3), 1.2 - 1.8 (3 0 Η, m, (C Η 2) is), 2.53 (2 Η, t, J = 7.4 Η ζ, Ρ h - C Η 2), 3.87 (3 Η, s, 0 C Η 3), 3.87 (3 H, s, 0 CH 3), 5.34 (1 H, s, OH) 6.4 (2 H, m, A r - Dan)

• 2, 3 — Dimethoxy 5 — Heptadecylphenol (compounds 3-4)

H ¹ -NMRCCDC ")

δ (p p m)

0.8 - 1.0 (3 H, m , CH 3), 1.2 - 1.8 (3 0 H, m, (CH 2) i 5), 2.50 (2 H, t, J = 7.3 H z,

P h CH 2) 3.85 (3 H, s, 0 CH ₃ ),

3.86 (3 H, s, 0 CH 3), 5.36 (1 H, s, 0 H) 6.28 (1 H, d, J = 1.6 H z, A r - Dan), 6.43 (1 H, d , J = 1.6 H z, A r -day)

Example 3 4

To 0.63 g of hydrogenated sodium was added 14 ml of dimethinolesulfoxide, and the mixture was stirred at 60 ° C for 2 hours. to this

11-Bromohexadecane and triphenylenosulfin dissolved in 5 m1 of dimethinoles-rufoxide, and a phosporium salt that provides power 7. 5 g was added and the mixture was stirred at room temperature for 30 minutes. After the stirring, 1.0 g of syringanolaldehyde was added, and the mixture was stirred at 50 ° C for 16 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The extract layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. This residue is used for silica gel chromatography. Purification by filtration (developing solvent; hexane: ethyl acetate = 5: 1), the resulting residue was dissolved in 10 ml of ethyl acetate, and a small amount of carbon dioxide was added. The gold was charged and stirred under a stream of hydrogen for 4 hours. After the reaction, the reaction mixture is filtered, the filtrate is distilled off under reduced pressure, and the residue is purified by silica gel chromatography (developing solvent; hexane: ethyl acetate = 5: 1). And purified to give 1.32 g of 2,6-dimethoxy41-heptadecylfuninol.

Dissolve 0.4 g of this in 5 ml of methylene chloride, cool to -20 ° C, and add a 1N solution of tribor at the moborane Z methylene chloride solution. 2.2 ml was added, and the mixture was stirred at 120 ° C. for 30 minutes, and further stirred at room temperature for 3 hours. Then, the solvent is distilled off under reduced pressure, water is added, extracted with ethyl acetate, the extracted layer is washed with water and saturated saline, dried, and the solvent is distilled off under reduced pressure. Was purified by silica gel chromatography (developing solvent; hexane: ethyl acetate = 5: 1) to give 5-heptacinol 2. 0.34 g of 1-hydroxy-1-phenol (compound 315) was obtained.

H ¹ -NMR (CDC 13)

δ (P P m)

0.8 -1.0 (3H, m, CH), 1.2 -1.8 (30H, m, (CH2_) 15), 2.49 (2H, t, J = 7.4Hz,

P h-CH 2), 3.86 (3 H, s, 0 CH 3), 5.19 (1 H, s. 0 days)

5. 21 (1 H, s, 0 days)

6.29 (1 H, d, J = 1.8 Hz

C17H35

6.42 (1 H, d, J = 1.8 H

C17H35 Mass analysis

378 (M ⁺ ) 153 (Base), 57

153 57 Industrial availability

According to the present invention, as described in detail above, a novel alkyl phenol derivative that can be applied to a drug having an antioxidant action, a lipid peroxide inhibitory action, and the like is provided.

It is useful as a therapeutic agent for various diseases in which lipid peroxide in vivo is considered to be involved, for example, arteriosclerotic diseases, liver diseases and the like.

Claims

Sought

1. The following formula (1)

(In the formula, RR ₅ is H, a hydroxyl group or an anoalkyl group having 8 to 23 carbon atoms, and at least one of R i to R _{5 is} a group having 8 to 23 carbon atoms. Alkenyl phenol derivative represented by the following formula:

2. The following equation (2)

(X in the formula represents an alkyl group having 8 to 23 carbon atoms. ₁₆ , R 7, R 8 and R ₉ are H, a halogen atom, a hydroxyl group or a phenol group, and at least one of R ₆ to R 9 The first shows an ano-reoxy group. An alkylphenol derivative represented by).

3. The following equation (3)

(Y and Z in the formula are H, phenolic or hydroxy, and at least one of them represents an alkoxy group; !., R!, your good beauty R! ₂ is, H, § Norre breath shea based on or is Tsu der a alkyl group having 8 to 2 3 carbon, R _{₁ D} ~ R ₁ ₂ of rather small One of them represents an alkyl group having 8 to 23 carbon atoms.)) An alkylphenol derivative represented by the following formula:

4. An antioxidant comprising the compound of claim 1.

5. An antioxidant comprising the compound of claim 2.

6. An antioxidant comprising the compound of claim 3.

7. A lipid peroxide inhibitor comprising the compound of claim 1. 5 ^

5) A lipid peroxide inhibitor comprising the compound of claim 2; and a lipid peroxide inhibitor comprising the compound of claim 3.