JP3519943B2 - Prevention and treatment of arteriosclerosis - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a prophylactic / therapeutic agent for arteriosclerosis or xanthomatosis, more specifically 2,
The present invention relates to a prophylactic / therapeutic agent for arteriosclerosis or xanthomatosis, which comprises 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 one of the important factors in the development and progression of arteriosclerosis and xanthomatosis (Steinberg, D., 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, the fact that the antioxidant probucol has no therapeutic effect on arteriosclerosis in clinical trials has been clarified (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).

Regarding the treatment of arteriosclerosis, it has been reported so far that a HMGCoA reductase inhibitor, which is a therapeutic agent for hyperlipidemia, suppresses the progression of arteriosclerosis (Scandinavian Simvastatin Survival Study Group Ra.
ndomised trial of cholesterol lowering in 4444 pati
ents with coronary heart disease: the Scandinavian
Simvastatin Survival Study (4S). Lancet 344, 1383-
1389, 1994.). However, the treatment with a therapeutic agent for hyperlipidemia is limited to hyperlipidemia patients, and is not effective for arteriosclerosis of familial hyperlipidemia patients. It is considered that the therapeutic agent for hyperlipidemia reduces the amount of LDL that undergoes oxidative degeneration by decreasing LDL, and as a result, exhibits anti-atherogenic effects. On the other hand, although antioxidants that can directly prevent the oxidation of LDL are expected as prophylactic / therapeutic agents for arteriosclerosis, a drug having a clinically sufficient effect including the above-mentioned probucol has not yet been found. The current situation is that it has not been done.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel prophylactic / therapeutic agent for arteriosclerosis, which has a clinically sufficient effect.

[0005]

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

[0006]

[Chemical 3]

(Wherein R ¹ represents a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group, R ² represents 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 each is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl which may have a substituent. Represents a group, an optionally substituted aryl group, or an optionally substituted arylalkyl group, or R ² and R ⁴ together with an oxygen atom form a furan ring or dihydro group. A furan ring may be formed, and R ⁵ and R ⁶ are taken together to form a cycloalkyl group, or one or more optional methylenes on the ring of the cycloalkyl group are oxygen, sulfur or alkyl-substituted nitrogen atoms. Replaced A heterocyclic group may be formed.
However, R ⁶ does not exist when R ² and R ⁴ together with the oxygen atom form a furan ring. The present invention has been completed by finding that the compound represented by (4) has a strong arteriosclerosis inhibitory action on a rabbit arteriosclerosis model and a mouse arteriosclerosis model, and a strong xanthoma inhibitory action on a mouse xanthoma 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, etc. Although data on antioxidant activity are disclosed as described as being effective antioxidants for ischemic organ damage such as myocardial infarction and stroke, there is no test example 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.
Is preferred, and specific examples thereof include an acetyl group, a formyl group, a propionyl group, and a benzoyl group. The arylalkoxycarbonyl group is preferably an arylalkoxycarbonyl group having an arylalkoxy group having 7 to 11 carbon atoms, and specific examples thereof include a benzyloxycarbonyl group. R ¹ is preferably a hydrogen atom or an acyl group, 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 is a linear or branched alkyl group having 1 to 6 carbon atoms,
Examples thereof include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, and t-butyl group. R ³ is preferably a hydrogen atom.

The alkyl group for 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, such as 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 group is raised. The alkenyl group is preferably a linear or branched alkenyl group having 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, and examples thereof include a vinyl group, an allyl group and a butenyl group.
Examples include a pentenyl group, a geranyl group, and a farnesyl group. The alkynyl group represents a linear or branched alkynyl group having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, and examples thereof include an ethynyl group, a propynyl group, and a butynyl group. An aryl group has 6 carbon atoms
-20, more preferably a group having 6 to 10 carbon atoms, and examples thereof include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. 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 carbon atoms, preferably 7 to 11 carbon atoms, for example, a benzyl group and a phenethyl group. The group is raised.

The alkyl group, alkenyl group, alkynyl group, aryl group and arylalkyl group of R ⁴ , R ⁵ and R ⁶ are 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 with 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,
Examples thereof include iodine and fluorine. Examples of the lower alkyl group 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, and an alkoxy group. Are, for example, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-
Examples thereof include butoxy group, s-butoxy group, and t-butoxy group, and aryloxy groups include phenoxy group, 3,5-di-t-butyl-4-hydroxy-2-.
Examples thereof include a methylphenoxy group and a naphthoxy group.

Preferably, R ² and R ⁴ together with an oxygen atom form a furan ring or a dihydrofuran ring, and each together with a benzene ring of the general formula (1) include a benzofuran ring and a dihydrobenzofuran ring. Will be formed. It is especially preferred that R ² and R ⁴ together with the oxygen atom form a dihydrobenzofuran ring. R
^{If 2} and R ⁴ form a furan ring together with the oxygen atom R ⁶ is absent. The cycloalkyl group formed by R ⁵ and R ⁶ is preferably a cycloalkyl group having a carbon number of 3 to 8, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. To be One or more optional methylenes on the ring of the cycloalkyl group
Examples of the heterocyclic group substituted with 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 preferable, and a tetrahydropyranyl group is particularly preferable.

The general formula (1) having the above substituents
Of these compounds, 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, 4,
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-t-butyl-2,2-diphenyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-dibenzyl-5
-Hydroxy-2,3-dihydrobenzofuran, 4,6
-Di-t-butyl-2-chloromethyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-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-t-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-t-butyl-5-hydroxy-2-methylbenzofuran, 2,4,6-tri-t-butyl-5-hydroxybenzofuran, 2,6-di-t-
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-t-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 of the present invention comprises various pharmaceuticals prepared by mixing a physiologically harmless solid or liquid pharmaceutical carrier with the compound represented by the general formula (1) as an active ingredient. It can be used as a composition. This pharmaceutical composition is prepared and used in various dosage forms depending on the administration method. Examples of the dosage form include tablets, granules, pills, capsules, solutions, syrups, suspensions, emulsions and injections. As a pharmaceutical carrier, a commonly used excipient, binder, disintegrant, lubricant, coating agent, solubilizing agent, emulsifier, suspending agent, stabilizer or solvent can be used.

The compound represented by the general formula (1) of the present invention and the above-mentioned pharmaceutical composition are administered by oral administration, parenteral administration such as intravenous injection, sustained-release administration by sustained-release preparation or local administration catheter. It can be used by local administration such as. In addition, according to the present invention, the actual dose of the compound represented by the general formula (1) required for the prevention or treatment of arteriosclerosis or xanthomatosis depends on the age of the patient, the severity of symptoms, and the administration. Depending on the route and the like, the generally accepted effective daily dose is, for example, 1 to 1000 mg for an adult,
It is preferably 100 to 300 mg. Such doses once a day for patients in need of prophylaxis or treatment
It is preferable to administer in 3 divided doses.

[0022]

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

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

Test Example 1: Action on arteriosclerosis model in vivo (1) In order to evaluate the action on arteriosclerosis model in vivo, Watanabe Heritable Hyperlipidemic (WHH)
L) Inhibition of atherosclerosis by the compound of Example 1 in rabbits
The control effect was examined. Specifically, 4 groups of WHHL rabbits (Kbl: male, 2-3 months old) each consisting of 5 birds were acclimated for 1 week, and then 1% of probucol and 0.2% were added to each of the 3 groups. , And 0.5% of the compound of Example 1 was fed a normal rearing diet once a day for 6 months in a restricted diet (40 g / kg). The remaining one group was similarly fed with a normal rearing food containing neither probucol nor the compound of Example 1 and used as a control group. The arteriosclerotic lesion was measured by administering the compound for 6 months, opening the collected aortic sample to prepare a photograph of the inner surface, and dividing the aorta into three continuous sites (arch, chest, abdomen), The area of white fat deposits and the total area, which are arteriosclerotic lesions, were measured for each site by image analysis. The measurement result is the ratio of the fat deposition area to the total area (percentage) for the entire arch and aorta.
It was evaluated by. The number of individuals used for evaluation was 4 or 5 per group.
It was a feather. Table 1 shows the results of only the chest region where the arteriosclerotic lesion is most advanced and the results of the entire aorta.

[0025]

[Table 1]

As shown in Table 1, the compound of Example 1 showed a strong inhibitory effect on arteriosclerosis of WHHL rabbits. Further, its anti-atherosclerotic effect was equivalent to that of probucol even at a dose of 1/2 of probucol.

Test Example 2: Action on in vivo arteriosclerosis model (2) In order to evaluate the action on in vivo arteriosclerosis model, the atherosclerotic inhibitory effect of the compound of Example 1 on LDL receptor deficient mice was examined. did. In particular,
After acclimating 4 groups of LDL receptor-deficient mice (CSK: male / female, 6-week-old) consisting of 5 to 10 mice per group for 1 week, 0.5% of probucol and Example were applied to each of the 2 groups. A high-fat diet (cholesterol content 1.25%) containing the compound 1 was freely taken for 13 weeks.
One of the remaining two groups was similarly given a high-fat diet containing neither probucol nor the compound of Example 1 to serve as a control group, and the other group was given probucol and the compound of Example 1 as a control group. A normal diet containing neither of them and not high fat was similarly fed.

For the measurement of arteriosclerotic lesions, the administration of the compound was 1
After 3 weeks, the cross section of the collected aortic arch sample was stained with Sudan IV, and the area of the arteriosclerotic lesion site was measured by image analysis under an optical microscope. The average value of the area of the arteriosclerotic lesion site of the stained arch aortic section was calculated for each individual. The number of individuals used for evaluation was 5 in the female normal diet group and 7 to 9 in the other groups. The results of arteriosclerotic lesion area are shown in Table 2.

[0029]

[Table 2]

As shown in Table 2, the compound of Example 1 showed a strong inhibitory effect on arteriosclerosis exhibited by LDL receptor-deficient mice. Also, its arteriosclerosis suppressing effect is
It was not found in probucol, an antioxidant.

Test Example 3: Action on arteriosclerosis model in vivo (3) In order to evaluate the action on arteriosclerosis model in vivo, LDL receptor / apolipoprotein E double hetero deficiency (LDL receptor ApoE hetero deficiency) mice were tested. The inhibitory effect of the compound of Example 1 on atherosclerosis was examined. Specifically, LDL consisting of 5 to 10 animals per group
After acclimation of 4 groups of receptor ApoE hetero-deficient mice (CSK: female, 6 weeks old) for 1 week, 2 groups of them each contained 0.5% probucol and the compound of Example 1 (high fat diet). Cholesterol content 1.25%) was freely taken for 6 months. One of the remaining two groups was similarly given a high-fat diet containing neither probucol nor the compound of Example 1 to serve as a control group, and the other group was given probucol and the compound of Example 1 as a control group. A normal diet containing neither of them and not high fat was similarly fed.

For the measurement of arteriosclerotic lesions, the compound was administered 6 times.
After a period of one month, a cross section of the collected aortic arch sample was stained with Sudan IV, and the area of the atherosclerotic lesion site was measured by image analysis under an optical microscope. The average value of the area of the arteriosclerotic lesion site of the stained aortic slice was calculated for each individual. The number of individuals used for evaluation was 2 in the normal diet group and 5 to 6 in the other groups. The results of arteriosclerotic lesion area are shown in Table 3.

[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. In addition, its arteriosclerosis-suppressing effect was not observed with the antioxidant probucol.

Test Example 4: Action on in vivo xanthoma model In order to evaluate the action on an in vivo xanthoma model, the xanthoma inhibitory effect of the compound of Example 1 on LDL receptor deficient mice was examined. Specifically, 5 to 10 LDL receptor-deficient mice per group (CSK:
After acclimation of 4 groups (male / female, 6 weeks old) for 1 week, 2 groups of them each contained 0.5% probucol and the compound of Example 1 high fat diet (cholesterol content 1.25%) Was freely taken for 13 weeks. One of the remaining two groups was similarly given a high-fat diet containing neither probucol nor the compound of Example 1 to serve as a control group, and the other group was given probucol and the compound of Example 1 as a control group. A normal diet containing neither of them and not high fat was similarly fed.

The measurement of xanthoma was carried out by scoring the appearance after the compound was administered for 13 weeks. The xanthoma score was calculated as a total score by scoring xanthomas of both forelimbs and lids. The number of individuals used for evaluation was 5 in the female normal diet group and 7 to 9 in the other groups. The results of the xanthoma score are shown in Table 4.

[0037]

[Table 4]

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

[0039]

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

Claims (2)

(57) [Claims] 1. 4,6-Di-t-butyl-2,2-di-n
-A prophylactic / therapeutic agent for xanthomatosis containing pentyl-5-hydroxy-2,3-dihydrobenzofuran or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The preventive / therapeutic agent for xanthomatosis according to claim 1, wherein the xanthomatosis is accompanied by neurosis or cataract.