JP2002234839A - Prophylactic or therapeutic agent for arteriosclerosis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new prophylactic or a new therapeutic agent for arteriosclerosis having clinically sufficient effects. SOLUTION: This prophylactic or therapeutic agent for the arteriosclerosis comprises a compound represented by general formula (I) (wherein, R1 denotes hydrogen atom, an acyl group or an arylalkoxycarbonyl group; R2 and R4, together with oxygen atom, form a dihydrofuran ring; R3 denotes hydrogen atom; and R5 and R6 may each be the same or different and denote each a linear or a branched chain pentyl group, hexyl group, heptyl group or octyl group, except that R1 and R6 are simultaneously n-pentyl group), its possible optically active substance or a pharmaceutically acceptable salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a prophylactic / therapeutic agent for arteriosclerosis or xanthomatosis.
The present invention relates to a prophylactic / therapeutic agent for arteriosclerosis or xanthomatosis comprising a 6-di-t-butylphenol derivative as an active ingredient.

[0002]

2. Description of the Related Art It is known that oxidative degeneration of low-density lipoprotein (LDL) is important as one of the causes in the development and progression of arteriosclerosis and xanthomatosis (Steinberg, D., et al.). Parthasarathy, S., Carew, TE,
Khoo, JC & Witztum, JL Beyond Cholesterol; M
odifications of low-density lipoprotein that incre
ase its atherogenicity. N. Engl. J. Med. 320; 915-
924, 1989). However, it has become clear that probucol, an antioxidant, has no therapeutic effect on arteriosclerosis in clinical trials (Walldius,
G., Erikson, U., Olsson, A., Bergstrand, L., Hadel
l, K., Johansson, J., Kaijser, L., Lassvik, C., Mo
lgaard, J., Nilsson, S., Elinder, LS, Stenport,
G. & Holme, I. The effect of probucol on femoral
atherosclerosis: the Probucol Quantitative Regress
ion Swedish Trial (PQRST). Am. J. Cardiol. 84, 875
-883, 1994).

[0003] Regarding the treatment of arteriosclerosis, it has been reported that an HMGCoA reductase inhibitor which is a therapeutic agent for hyperlipidemia suppresses the progress of arteriosclerosis (Scandinavian Simvastatin Survival Study Group Ra).
ndomised trial of cholesterollowering in 4444 pati
ents with coronary heart disease: the Scandinavian
Simvastatin Survival Study (4S). Lancet 344, 1383-
1389, 1994.). However, treatment with a therapeutic agent for hyperlipidemia is limited to hyperlipidemic patients and is not effective for arteriosclerosis in familial hyperlipidemia patients. It is considered that the therapeutic agent for hyperlipidemia reduces the amount of LDL that undergoes oxidative degeneration by reducing LDL, and as a result, exhibits an anti-atherosclerotic effect. On the other hand, antioxidants capable of directly preventing the oxidation of LDL are expected as preventive / therapeutic agents for arteriosclerosis. However, drugs having a clinically sufficient effect including the above-mentioned probucol have not yet been found. It has not been done yet.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel agent for preventing or treating arteriosclerosis having a clinically sufficient effect.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies with the aim of solving the problems, and as a result, general formula (1):

[0006]

Embedded image

[0007] (wherein, R ¹ represents a hydrogen atom, an acyl group or an arylalkoxy group,, R ² is a lower alkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ^4, R ⁵ and R ⁶ may be the same or different, and represent a hydrogen atom, an alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, or an alkynyl optionally having a substituent. Represents an aryl group which may have a substituent, an aryl group which may have a substituent, or an arylalkyl group which may have a substituent, or R ² and R ⁴ together with an oxygen atom represent a furan ring or a dihydro A furan ring may be formed and R ⁵ and R ^{6 taken} together form a cycloalkyl group, or one or more optional methylenes on the ring of the cycloalkyl group, with an oxygen, sulfur, or alkyl-substituted nitrogen atom. Replaced Or a heterocyclic group.
However, when R ² and R ⁴ together with an oxygen atom form a furan ring, R ⁶ is not present. The present inventors have found that the compound represented by the formula (1) has a strong arteriosclerosis inhibitory action on a rabbit arteriosclerosis model and a mouse arteriosclerosis model, and a strong xanthomas inhibitory action on a mouse xanthomas model.

The compound represented by the general formula (1) is disclosed in JP-A-6-206842, and is useful as a therapeutic agent for arteriosclerosis, myocardial infarction and the like. As described as being an effective antioxidant for ischemic organ damage such as myocardial infarction and stroke, data on the antioxidant effect is disclosed, but there are no test examples in animal models.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of R ¹ of the compound represented by the general formula (1), the acyl group has 1 to 10 carbon atoms.
Are preferred, and specific examples include an acetyl group, a formyl group, a propionyl group, and a benzoyl group. The arylalkoxycarbonyl group is preferably an arylalkoxycarbonyl group having 7 to 11 carbon atoms, specifically, a benzyloxycarbonyl group. R ¹ is preferably a hydrogen atom or an acyl group, and more preferably a hydrogen atom. When R ¹ is an acyl group, an acetyl group is preferred. The lower alkyl group for R ² and R ³ represents a linear or branched alkyl group having 1 to 6 carbon atoms,
Examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, and a t-butyl group. R ³ is preferably a hydrogen atom.

The alkyl group of R ⁴ , R ⁵ and R ⁶ is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, for example, a methyl group, Ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, t-butyl group, pentyl group, i-amyl group, hexyl group, heptyl group, octyl group, nonyl group, and decyl Group. The alkenyl group is preferably a linear or branched alkenyl group having 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, for example, a vinyl group, an allyl group, a butenyl group,
Pentenyl, geranyl, and farnesyl groups. The alkynyl group is a linear or branched alkynyl group having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, and includes, for example, an ethynyl group, a propynyl group, and a butynyl group. The aryl group has 6 carbon atoms.
To 20, more preferably a group having 6 to 10 carbon atoms, such as phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl, and phenanthryl. The arylalkyl group means a monovalent substituent in which an alkyl group is substituted with an aromatic hydrocarbon, and is preferably an arylalkyl group having 7 to 20, preferably 7 to 11 carbon atoms, such as benzyl group and phenethyl. Group.

The alkyl group, alkenyl group, alkynyl group, aryl group and arylalkyl group of R ⁴ , R ⁵ and R ⁶ include a halogen atom, a lower alkyl group, a lower alkoxy group and an aryl group having 6 to 10 carbon atoms. It may be substituted by one or more groups such as an oxy group, a hydroxyl group, an amino group, a nitro group, and a trifluoromethyl group. Specific halogen atoms include chlorine, bromine,
Iodine and fluorine; and lower alkyl groups include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, and t-butyl group, and alkoxy group. Are methoxy, ethoxy, n-propoxy, i-propoxy, n-
Butoxy, s-butoxy, and t-butoxy groups, and aryloxy groups include phenoxy group, 3,5-di-tert-butyl-4-hydroxy-2-hydroxy.
Examples include a methylphenoxy group and a naphthoxy group.

Preferably, R ² and R ⁴ form a furan ring or a dihydrofuran ring together with an oxygen atom, and a benzofuran ring or a dihydrobenzofuran ring together with a benzene ring of the general formula (1). Is formed. It is particularly preferred that R ² and R ⁴ together with the oxygen atom form a dihydrobenzofuran ring. R
^{When 2} and R ⁴ together with the oxygen atom form a furan ring, R ⁶ is absent. The cycloalkyl group formed by R ⁵ and R ⁶ is preferably a cycloalkyl group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Can be One or more optional methylenes on the ring of the cycloalkyl group is
Examples of the heterocyclic group substituted by an oxygen atom, a sulfur atom, or an alkyl-substituted nitrogen atom having 1 to 6 carbon atoms include a tetrahydrothiopyranyl group, an N-methylpiperidyl group, and a tetrahydropyranyl group. A heterocyclic group substituted with an oxygen atom is preferred, and a tetrahydropyranyl group is particularly preferred.

The general formula (1) having the above substituents
Among the compounds of the formula (1), particularly preferred compounds are 4,6
-Di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran,
6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran, 4,6-di-t-
Butyl-2,2-diethyl-5-hydroxy-2,3-
Dihydrobenzofuran, 4,6-di-t-butyl-2,
2-di-n-propyl-5-hydroxy-2,3-dihydrobenzofuran,

4,6-di-t-butyl-2,2-di-n
-Butyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-
Octylbenzofuran, 4,6-di-t-butyl-5-
Hydroxy-2-octyl-2,3-dihydrobenzofuran, 2,4,6-tri-t-butyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2- Di-i-propyl-5-hydroxy-
2,3-dihydrobenzofuran,

4,6-di-tert-butyl-2,2-diphenyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-tert-butyl-2,2-dibenzyl-5
-Hydroxy-2,3-dihydrobenzofuran, 4,6
-Di-tert-butyl-2-chloromethyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1 ' -Cyclopentane, 4,6-di-t
-Butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cyclohexane,

4,6-di-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1'-
Cycloheptane, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-
1'-cyclooctane, 4,6-di-t-butyl-5-
Hydroxy-2,3-dihydrobenzofuran-2-spiro-4'-tetrahydropyran, 5-hydroxy-4,
6-di-t-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxybenzofuran,

4,6-di-tert-butyl-5-hydroxy-2-methylbenzofuran, 2,4,6-tri-tert-butyl-5-hydroxybenzofuran, 2,6-di-tert-butyl
Butyl-3-methyl-4-propyloxyphenol,
4-allyloxy-2,6-di-t-butyl-3-methylphenol, 1,3-bis (3,5-di-t-butyl-4-hydroxy-2-methylphenoxy) propane,

4,6-di-t-butyl-2,2-di-n
-Pentyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-n-octyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di -T-butyl-2,2-di-n-heptyl-5-hydroxy-2,3-dihydrobenzofuran,
4,6-di-t-butyl-2,2-di-n-hexyl-
5-hydroxy-2,3-dihydrobenzofuran, 2,
2-di-i-amyl-4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran,

4,6-di-tert-butyl-5-hydroxy-2-methyl-2- (4,8,12-trimethyltrideca-3 (E), 7 (E), 11-trienyl) -2 , 3
-Dihydrobenzofuran, 4,6-di-t-butyl-5
-Hydroxy-2-methyl-2- (4 ', 8', 12 '
-Trimethyltridecyl) -2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-
(5-hydroxy-4-methyl-3 (E) -pentenyl) -2-methyl-2,3-dihydrobenzofuran.

The compound represented by the general formula (1) used in the present invention can be synthesized, for example, according to the method described in JP-A-6-206842. The prophylactic / therapeutic agent for arteriosclerosis or xanthomatosis according to the present invention comprises various drugs comprising a compound represented by the general formula (1) as an active ingredient and a physiologically harmless solid or liquid pharmaceutical carrier. It can be used as a composition. This pharmaceutical composition is prepared and used in various formulations depending on the administration method. Formulation forms include tablets, granules, pills, capsules, solutions, syrups, suspensions, emulsions and injections. As the pharmaceutical carrier, commonly used excipients, binders, disintegrants, lubricants, coating agents, dissolution aids, emulsifiers, suspending agents, stabilizers or solvents can be used.

The compound represented by the general formula (1) of the present invention and the above-mentioned pharmaceutical composition can be used for oral administration, parenteral administration such as intravenous injection, sustained release administration by sustained release preparation or catheter for local administration. It can be used by local administration such as. Further, according to the present invention, the actual dose of the compound represented by the general formula (1) required for prevention or treatment of arteriosclerosis or xanthomatosis depends on the age of the patient, the severity of the symptoms, Depending on the route, etc., the generally accepted effective daily dose for an adult is, for example, 1 to 1000 mg,
Preferably it is 100-300 mg. Such doses may be given once a day to patients in need of prevention or treatment.
It is preferable to administer the drug in three divided doses.

[0022]

EXAMPLES The present invention will be further described below with reference to examples, but the present invention is not limited to these examples.

Example 1: 4,6-di-t-butyl-2,
2-Di-n-pentyl-5-hydroxy-2,3-dihydrobenzofuran The title compound was synthesized by the method described in JP-A-6-206842.

Test Example 1: Action on in vivo atherosclerosis model (1) In order to evaluate the action on the in vivo atherosclerosis model, Watanabe Heritable Hyperlipidemic (WHH) was used.
L) The arteriosclerosis inhibitory effect of the compound of Example 1 on rabbits was examined. Specifically, W consisting of 5 birds per group
After acclimatizing 4 groups of HHL rabbits (Kbl: male, 2-3 months old) for 1 week, 3 of them were 1% probucol, 0.2% and 0.5% of the compound of Example 1 respectively. Was fed by restricted feeding (40 g / kg) once a day for 6 months. The other group was fed a normal diet containing neither probucol nor the compound of Example 1 and served as a control group. For the measurement of atherosclerotic lesions, after the administration of the compound for 6 months, the collected aortic sample was opened, a photograph of the inner surface was created, and the aorta was divided into three consecutive parts (arch, chest, and abdomen). At each site, the area of white fat deposition, which is an arteriosclerotic lesion, and the entire area were measured by image analysis. The measurement results were evaluated by the ratio (percent) of the area of fat deposition to the total area of the entire arch and aorta. The number of individuals used for evaluation was 4 or 5 in each group. Table 1 shows the results of only the most advanced breast region of the atherosclerotic lesion and the results of the entire aorta.

[0025]

[Table 1]

As shown in Table 1, the compound of Example 1 exhibited a strong inhibitory effect on arteriosclerosis in WHHL rabbits. Moreover, its arteriosclerosis inhibitory effect was equivalent to probucol even at a half dose of probucol.

Test Example 2: Effect on in vivo atherosclerosis model (2) In order to evaluate the effect on the in vivo atherosclerosis model, the arteriosclerosis inhibitory effect of the compound of Example 1 on LDL receptor deficient mice was examined. Specifically, 5 to 10 LDL receptor deficient mice (C
(SK: male / female, 6-week-old) After acclimatizing 4 groups for 1 week, 2 of them were each a high fat diet containing 0.5% probucol and the compound of Example 1 (cholesterol content: 1.25) %) For 13 weeks. 2 remaining
One of the groups was similarly fed a high-fat diet containing neither probucol nor the compound of Example 1 and used as a control group, while the other group contained neither probucol nor the compound of Example 1. A normal diet containing no and not high fat was similarly given.

The measurement of atherosclerotic lesions is based on the administration of the compound for 1
After 3 weeks, the cross section of the collected aortic arch sample was stained with Sudan IV, and the area of the atherosclerotic lesion was measured by image analysis under a light microscope. The average value of the area of the atherosclerotic lesion site was calculated for each of the stained arch aortic sections. The number of individuals used for evaluation was 5 in the female normal diet group and 7 to 9 in the other groups. Table 2 shows the results of atherosclerotic lesion area.

[0029]

[Table 2]

As shown in Table 2, the compound of Example 1 exhibited a strong inhibitory effect on arteriosclerosis in LDL receptor-deficient mice. In addition, its arteriosclerosis inhibitory effect,
It was not found in the antioxidant probucol.

Test Example 3: Effect on in vivo atherosclerosis model (3) In order to evaluate the effect on the in vivo atherosclerosis model, an LDL receptor / apolipoprotein E double hetero-deficient (LDL receptor ApoE hetero-deficient) mouse was used. The arteriosclerosis inhibitory effect of the compound of Example 1 was studied.
Specifically, 5 to 10 LDL receptor ApoE hetero-deficient mice per group (CSK: female, 6 weeks old) 4
After acclimatizing the groups for one week, two of the groups were allowed to freely take a high fat diet (cholesterol content: 1.25%) containing 0.5% probucol and the compound of Example 1 for 6 months. . One of the remaining two groups was similarly fed a high fat diet containing neither probucol nor the compound of Example 1 and used as a control group,
Another group was similarly fed a normal diet not containing either probucol or the compound of Example 1 and not high in fat.

For the measurement of atherosclerotic lesions, administration of the compound
After months, the cross section of the collected aortic arch sample was stained with Sudan IV, and the area of the atherosclerotic lesion was measured by image analysis under a light microscope. For the stained aortic sections, the average value of the area of the atherosclerotic lesion site was calculated for each individual. The number of individuals used for the evaluation was 2 in the normal diet group, and 5 to 6 in the other groups. Table 3 shows the results of atherosclerotic lesion area.

[0033]

[Table 3]

As shown in Table 3, the compound of Example 1 showed a strong inhibitory effect on arteriosclerosis exhibited by LDL receptor ApoE hetero-deficient mice. Also, its arteriosclerosis inhibitory effect was not observed with probucol, an antioxidant.

Test Example 4: Effect on in vivo xanthoma model In order to evaluate the effect on the in vivo xanthoma model, the inhibitory effect of the compound of Example 1 on LDL receptor deficient mice was examined. Specifically, 5 to 10 LDL receptor deficient mice (CSK:
(Female / female, 6-week old) After acclimatizing 4 groups for 1 week, 2 of them were high fat diets containing cholesterol (0.5%) and the compound of Example 1 (cholesterol content: 1.25%). For 13 weeks. One of the remaining two groups was similarly fed a high-fat diet containing neither probucol nor the compound of Example 1 and used as a control group, while the other group contained probucol and the compound of Example 1. A normal diet containing none and not high fat was similarly given.

The measurement of xanthomas was performed by scoring the appearance after 13 weeks of administration of the compound. The xanthomas score was calculated as the total score of xanthomas of both forelimbs and of the eyelids. The number of individuals used for the evaluation was 5 in the female normal diet group, and 7 to 9 in the other groups. Table 4 shows the results of the xanthoma score.

[0037]

[Table 4]

As shown in Table 4, the compound of Example 1 showed a strong inhibitory effect on the xanthomas of LDL receptor-deficient mice. In addition, its suppressive effect on xanthomas was not observed with probucol, an antioxidant.

[0039]

EFFECT OF THE INVENTION The preventive / therapeutic agent for arteriosclerosis, xanthomatosis, neuropathy and cataract associated with xanthomatosis according to the present invention, which comprises a 2,6-di-t-butylphenol derivative as an active ingredient, WHHL rabbit, LDL receptor deficient mouse, L
Since it has a strong arteriosclerosis inhibitory effect on arteriosclerosis exhibited by DL receptor ApoE hetero-deficient mice, and has a strong inhibitory effect on xanthomas in LDL receptor-deficient mice, the arteriosclerosis, xanthomatosis, yellow It is useful for the prevention or treatment of neurosis and cataract associated with neoplasia.

────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] December 28, 2001 (2001.12.
28)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image (Wherein, R ¹ represents a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ⁴ together with an oxygen atom form a dihydrofuran ring; and R ³ represents a hydrogen atom. And R ⁵ and R ⁶ may be the same or different and represent a linear or branched pentyl, hexyl, heptyl or octyl group, provided that R ⁵ and R ⁶ are compound, an optically active form thereof, or a pharmaceutical agent for preventing or treating atherosclerosis containing a salt thereof as an active ingredient to be acceptable as possible represented by.) except the case of n- pentyl group.

Embedded image (Wherein, R ¹ represents a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ⁴ together with an oxygen atom form a dihydrofuran ring; and R ³ represents a hydrogen atom. And R ⁵ and R ⁶ may be the same or different and represent a linear or branched pentyl, hexyl, heptyl or octyl group, provided that R ⁵ and R ⁶ are or an optically active form thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, which is an agent for preventing and / or treating xanthomatosis.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0024

[Correction method] Change

[Correction contents]

Test Example 1: Effect on In Vivo Atherosclerosis Model (1) In order to evaluate the effect on the in vivo atherosclerosis model, Watanabe Heritable Hyperlipidemic (WHH)
L) was examined atherosclerosis inhibiting effect of the compound of Example 1 against rabbit. Specifically, after 4 groups of 5 WHHL rabbits (Kbl: male, 2-3 months old) consisting of 5 birds per group were acclimated for 1 week, 1 group of 1% probucol and 0.2% , And 0.5% of the compound of Example 1 were fed on a restricted diet (40 g / kg) once daily for 6 months. The other group was fed a normal diet containing neither probucol nor the compound of Example 1 and served as a control group. For the measurement of atherosclerotic lesions, after the administration of the compound for 6 months, the collected aortic sample was opened, a photograph of the inner surface was created, and the aorta was divided into three consecutive parts (arch, chest, and abdomen). At each site, the area of white fat deposition, which is an arteriosclerotic lesion, and the entire area were measured by image analysis. The measurement result is the ratio of the area of fat deposition to the total area (percent) of the entire bow and aorta.
Was evaluated. The number of individuals used for evaluation was 4 birds or 5
It was a feather. Table 1 shows the results of only the most advanced breast region of the atherosclerotic lesion and the results of the entire aorta.

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0027

[Correction method] Change

[Correction contents]

[0027] Test Example 2: effect on in vivo atherosclerosis model (2) to evaluate the effects on In vivo atherosclerosis model, consider atherosclerosis inhibiting effect of the compound of Example 1 on LDL receptor-deficient mice did. In particular,
After acclimatizing 4 groups of LDL receptor-deficient mice (CSK: male / female, 6 weeks old) consisting of 5 to 10 mice per group for 1 week, two of them were treated with 0.5% probucol and Example A high-fat diet (cholesterol content: 1.25%) containing one compound was freely taken for 13 weeks.
One of the remaining two groups was similarly fed a high-fat diet containing neither probucol nor the compound of Example 1 and used as a control group, while the other group contained probucol and the compound of Example 1. A normal diet containing none and not high fat was similarly given.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0031

[Correction method] Change

[Correction contents]

Test Example 3: Effect on in vivo atherosclerosis model (3) In order to evaluate the effect on the in vivo atherosclerosis model, LDL receptor / apolipoprotein E double hetero-deficient (LDL receptor ApoE hetero-deficient) mice It was examined atherosclerosis inhibiting effect of the compound of example 1. Specifically, LDL consisting of 5 to 10 animals per group
After 4 groups of the receptor ApoE hetero-deficient mice (CSK: female, 6-week-old) were acclimated for 1 week, two of the groups were each fed with a high-fat diet containing 0.5% probucol and the compound of Example 1 ( (Cholesterol content: 1.25%)) for 6 months. One of the remaining two groups was similarly fed a high-fat diet containing neither probucol nor the compound of Example 1 and used as a control group, while the other group contained probucol and the compound of Example 1. A normal diet containing none and not high fat was similarly given.

Claims (12)

[Claims] 1. General formula (1): (Wherein, R ¹ represents a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ⁴ together with an oxygen atom form a dihydrofuran ring; and R ³ represents a hydrogen atom. And R ⁵ and R ⁶ may be the same or different and represent a linear or branched pentyl, hexyl, heptyl or octyl group, provided that R ⁵ and R ⁶ are a prophylactic / therapeutic agent for arteriosclerosis, comprising as an active ingredient a compound represented by the following formula (except when it is an n-pentyl group), a possible optically active form thereof, or a pharmaceutically acceptable salt thereof. 2. R ¹ is a hydrogen atom, an acyl group having 1 to 10 carbon atoms, or an arylalkoxy group having 7 to 1 carbon atoms.
2. Represents one arylalkoxycarbonyl group.
The preventive / therapeutic agent for arteriosclerosis described in the above. 3. The preventive / therapeutic agent for arteriosclerosis according to claim 2, wherein R ¹ represents a hydrogen atom. 4. A 4,6-di-t-butyl-2,2-di-.
n-hexyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-n-heptyl-
5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-n-octyl-
5-hydroxy-2,3-dihydrobenzofuran, 2,2-di-i-amyl-4,6-di-t-butyl-5
The preventive / therapeutic agent for arteriosclerosis according to claim 3, which comprises, as an active ingredient, a compound selected from the group consisting of -hydroxy-2,3-dihydrobenzofuran and a pharmaceutically acceptable salt thereof. 5. A method according to claim 1, wherein the 4,6-di-t-butyl-2,2-di-
n-octyl-5-hydroxy-2,3-dihydrobenzofuran, 2,2-di-i-amyl-4,6-di-t-butyl-5
The preventive / therapeutic agent for arteriosclerosis according to claim 4, comprising a compound selected from the group consisting of -hydroxy-2,3-dihydrobenzofuran and a pharmaceutically acceptable salt thereof as an active ingredient. 6. The atherosclerosis is selected from the group consisting of coronary atherosclerosis, cerebral atherosclerosis, renal atherosclerosis, obstructive atherosclerosis, diabetic atherosclerosis and juvenile atherosclerosis. The agent for preventing or treating arteriosclerosis according to any one of claims 1 to 5. 7. A compound of the general formula (1): (Wherein, R ¹ represents a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ⁴ together with an oxygen atom form a dihydrofuran ring; and R ³ represents a hydrogen atom. And R ⁵ and R ⁶ may be the same or different and represent a linear or branched pentyl, hexyl, heptyl or octyl group, provided that R ⁵ and R ⁶ are or an optically active form thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, which is an agent for preventing and / or treating xanthomatosis. 8. R ¹ is a hydrogen atom, an acyl group having 1 to 10 carbon atoms, or an arylalkoxy group having 7 to 1 carbon atoms.
8. Represents one arylalkoxycarbonyl group.
The preventive / therapeutic agent for xanthomatosis described in the above. 9. The preventive / therapeutic agent for xanthomatosis according to claim 8, wherein R ¹ represents a hydrogen atom. 10. A mixture of 4,6-di-t-butyl-2,2-di-n-hexyl-5-hydroxy-2,3-dihydrobenzofuran and 4,6-di-t-butyl-2,2- Di-n-heptyl-
5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-n-octyl-
5-hydroxy-2,3-dihydrobenzofuran, 2,2-di-i-amyl-4,6-di-t-butyl-5
The preventive / therapeutic agent for xanthomatosis according to claim 9, which comprises, as an active ingredient, a compound selected from the group consisting of -hydroxy-2,3-dihydrobenzofuran and a pharmaceutically acceptable salt thereof. (11) 4,6-di-t-butyl-2,2-di-n-octyl-5-hydroxy-2,3-dihydrobenzofuran, 2,2-di-i-amyl-4,6- Di-t-butyl-5
The preventive / therapeutic agent for xanthomatosis according to claim 10, which comprises, as an active ingredient, a compound selected from the group consisting of -hydroxy-2,3-dihydrobenzofuran and a pharmaceutically acceptable salt thereof. 12. The preventive / therapeutic agent for xanthomatosis according to any one of claims 7 to 11, wherein the xanthomatosis is accompanied by neurosis or cataract.