JPH0753380A - Hyperlipidemia treatment agent and hyperuricemia treatment agent - Google Patents

Abstract

(57) [Summary] [Structure] A therapeutic agent for hyperlipidemia and hyperuricemia comprising a pyrimidine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [Chemical 1] (In the formula, R ₁ and R ₂ are each independently a hydrogen atom, a linear or branched lower alkyl group, a substituted or unsubstituted phenyl group or a cyclohexyl group, and R ₃ is a linear or branched chain. Each represents a chain-like lower alkyl group or a lower alkoxy group. In addition, ~ indicates that it includes stereoisomerism.) [Effect] LDL, VLDL, free cholesterol, total cholesterol, and phospholipid levels in blood are significantly increased. HDL while reducing and preventing the oxidation of LDL
It is useful in the treatment of hyperlipidemia by increasing the blood concentration of. or,
It is also useful for treating hyperuricemia by promoting excretion of uric acid contained in blood, reducing blood concentration of uric acid. Furthermore, the drug has no side effect of causing ulcer of digestive system and is suitable for long-term or repeated continuous oral administration.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a drug containing a pyrimidine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, particularly a therapeutic agent for hyperlipidemia and hyperuricemia. Regarding therapeutic agents.

[0002]

2. Description of the Related Art Hyperlipidemia and hyperuricemia are considered to be one of the causative factors of atherosclerosis. Especially in hyperlipidemia, low-density lipoprotein (Low Den
The behavior of cholesterol present in the site Lipoprotein (LDL) has been noted.
That is, LDL has a role of transporting lipids, mainly cholesterol, to various body tissues including blood vessels, but when LDL is present in excess, the LDL is oxidized by 5-lipoxygenase and the like (Proc. . Nat
l. Acad. Sci. 86 , 1046 (198
9)), it is considered that the scavenger cells existing in the endothelium of the artery are taken up by the scavenger receptor. In addition, oxidized LDL is taken up into body tissues earlier than normal LDL that is not oxidized,
It is also reported that it is deposited in the tissue [J. Cli
n. Invest. 77 , 641 (1986)]. In this way, cholesterol accumulates significantly in the arterial wall,
It is believed to cause atherosclerosis.

Further, vascular lesions due to atherosclerosis cause cardiac diseases such as myocardial infarction. The onset of heart disease is directly proportional to the blood level of LDL, while high density lipoprotein (High Density Lipoprot) is used.
ein: HDL) is reported to be inversely proportional [Clin. Chem. 29 , 1890 (198
3)]. Hyperlipidemia is considered to be a risk factor causing atherosclerosis, and its therapeutic agent has already been developed and put into practical use. Conventionally proposed therapeutic agents for hyperlipidemia include clofibrate lipid lowering agent, HMG-C.
There are oA inhibitors, probucol, ACAT inhibitors and the like. However, although each has some effect on cholesterol lowering, each has its drawbacks. For example, the clofibrate lipid lowering agent is
Insufficient cholesterol lowering action and no antioxidant action. The HMG-CoA inhibitor has no antioxidant action and does not sufficiently increase the blood concentration of HDL. Probucol has both a cholesterol-lowering effect and an antioxidant effect, but it also significantly reduces blood levels of HDL. Further, ACAT inhibitors have problems such as lack of antioxidant action and side effects such as indigestion, and have a pharmacological action of lowering the concentration of LDL contained in blood, an antioxidant effect of LDL and None of them completely satisfy the effect of increasing the concentration of HDL contained in blood.

Further, hyperuricemia is not only a risk factor for causing atherosclerosis, but also one of the factors causing the development of hyperlipidemia, gout, diabetes, obesity, hypertension,
It is listed as a risk factor along with heredity.

[0005]

The object of the present invention is to reduce the concentration of LDL contained in blood, and
Is a drug for treating hyperlipidemia or hyperuricemia based on the inhibition of oxidization of erythrocyte, increasing the concentration of HDL, and decreasing the concentration of uric acid contained in blood. It is an object of the present invention to provide a drug having a pharmacological action for preventing the development of atherosclerosis accompanying the treatment of diseases. That is, an object of the present invention is to provide a novel therapeutic agent for hyperlipidemia and a therapeutic agent for hyperuricemia.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a pyrimidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Have a pharmacological action of reducing the concentration of cholesterol contained in blood, and further have a pharmacological action of reducing the concentration of uric acid contained in blood, and complete the present invention. Came to.

[0007]

[Chemical 2] (In the formula, R ₁ and R ₂ are each independently a hydrogen atom, a linear or branched lower alkyl group, a substituted or unsubstituted phenyl group or a cyclohexyl group, and R ₃ is a linear or branched chain. Each represents a chain-like lower alkyl group or a lower alkoxy group. In addition, ~ represents stereoisomerism.)

That is, the present invention provides a drug for treating hyperlipidemia, which comprises a pyrimidine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. is there. Further, the present invention provides a therapeutic agent for hyperuricemia, which comprises a pyrimidine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. is there.

The pyrimidine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof has already been filed by the applicant before (Japanese Patent Application No. 4-271161 and Japanese Patent Application No. 3-1161).
-290538, European Patent Publication 54666
1A1), it was proposed as a novel compound. Further, in these applications, a drug containing the pyrimidine derivative or a salt thereof as an active ingredient,
It has been proposed to be used as an anti-inflammatory therapeutic drug, a respiratory tract disease therapeutic drug, or a cerebrovascular disorder therapeutic drug.

The mechanism of action of lowering blood cholesterol concentration in the present invention is to promote the uptake of LDL, which has a role of transporting lipids mainly containing cholesterol, into the liver, or as a bile acid associated with the metabolism of LDL in the liver. It is thought that the excretion of urine is promoted. Furthermore,
VLDL (Very Low Densit) consumed by the formation of LDL is accompanied by a decrease in the blood concentration of LDL.
It is considered that the blood concentration of y Lipoprotein) is also reduced.

The lower alkyl group of R ₁ , R ₂ and R ₃ of the pyrimidine derivative of the general formula (I) in the present invention is an alkyl group having 1 to 5 carbon atoms, for example, methyl, ethyl, propyl, n-butyl, Examples thereof include sec-butyl, tert-butyl, and pentyl groups. The substituted phenyl group or cyclohexyl group is a phenyl group or cyclohexyl group in which one or more of the above-mentioned lower alkyl group, hydroxyl group or halogen group such as chlorine, bromine or fluorine is substituted on the benzene ring or cyclohexyl ring. Further, as the lower alkoxy group for R ₃ , methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, n-butoxy group, sec-butoxy group, t
carbon number of ert-butoxy group or pentyloxy group etc.
To 5 alkoxy groups can be mentioned.

The pyrimidine derivative of the general formula (I) generally forms a group of compounds substituted by various combinations of the above-mentioned substituents, and specific compounds included in the group include 1-methyl- 3-phenyl-5- (3,5-
Ditert-butyl-4-hydroxybenzylidene)-
Pyrimidine-2,4,6-trione, 1,3-diethyl-5- (3,5-ditert-butyl-4-hydroxybenzylidene) -pyrimidine-2,4,6-trione,
1,3-dicyclohexyl-5- (3,5-ditert
-Butyl-4-hydroxybenzylidene) -pyrimidine-2,4,6-trione, 1-butyl-5- (3,5-
Ditert-butyl-4-hydroxybenzylidene)-
Pyrimidine-2,4,6-trione, 1-cyclohexyl-5- (3,5-ditert-butyl-4-hydroxybenzylidene) -pyrimidine-2,4,6-trione, 1-phenyl-5- (3 , 5-ditert-butyl-4-hydroxybenzylidene) -pyrimidine-2,
4,6-trione, 1,3-ditoluyl-5- (3,5
-Ditert-butyl-4-hydroxybenzylidene)
-Pyrimidine-2,4,6-trione, 3-methyl-1
-Phenyl-5- (3,5-dimethyl-4-hydroxybenzylidene) -pyrimidine-2,4,6-trione,
3-methyl-1-phenyl-5- (3,5-methoxy-
4-hydroxybenzylidene) -pyrimidine-2,4
6-trione, 1-methyl-3- (4-fluorophenyl) -5- (3,5-ditert-butyl-4-hydroxybenzylidene) -pyrimidine-2,4,6-trione, 1-methyl-3 -(4-chlorophenyl) -5-
(3,5-Dimethyl-4-hydroxybenzylidene)-
Pyrimidine-2,4,6-trione etc. can be illustrated.

The pyrimidine derivative represented by the general formula (I) is, for example, a pyrimidine derivative represented by the following general formula (II):

[Chemical 3] (Wherein, R ₁ and R ₂ are used in which R ₁ and R ₂ the same meaning of the general formula (I).) And 4-hydroxybenzaldehyde derivative represented by the following general formula (III)

[Chemical 4] (In the formula, R ₃ has the same meaning as in the general formula (I).) It can be produced by reacting. The reaction is
For example, it can be carried out in a suitable alcohol solvent such as methanol, ethanol or propanol, usually at room temperature or at the reflux temperature of the obtained reaction mixture. The production method of these pyrimidine derivative (II), 4-hydroxybenzaldehyde derivative (III) and pyrimidine derivative is
It has already been described in the aforementioned European patent publication and is known.

In the above reaction, two substituents R ₁ and R _{2 of the} pyrimidine derivative (II) represented by the general formula (II) are used.
Are different from each other, the reaction mixture has the following formula (I
Two stereoisomers of E-form and Z-form represented by -1) and (I-2) can be produced.

[Chemical 5]

[Chemical 6] Further, the pharmacologically acceptable salts in the present invention include hydrochloride, sulfate and the like.

The pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof is mixed with a conventional organic or inorganic carrier or excipient and is used in a solid, semisolid or liquid form. It can be used as a pharmaceutical preparation. These can be used in the form of oral, parenteral or external use. For example, tablets, pellets, capsules, batches,
It may be mixed with conventional non-toxic carriers or excipients for suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carrier or excipient used is not particularly limited. Examples of these include water, glucose, lactose, gum arabic, gelatin and the like.

The dose or effective dose of the compound of the present invention varies depending on the age and symptoms of individual patients, but generally, the active ingredient is appropriately selected within the range of about 0.1 to 500 mg / kg,
It is administered as a daily dose for treating the patient. These can be orally administered once to several times a day or parenterally in the form of intravenous injection, intramuscular injection, intraarterial injection or the like.

[0017]

The pyrimidine derivative of the general formula (I) according to the present invention is a pharmacological agent that lowers the blood concentration of LDL by promoting LDL uptake into the liver or by promoting LDL metabolism in the liver. It is thought to achieve the effect. Further, LDL is oxidatively modified by the inhibitory action of enzyme activity such as lipoxygenase, or the action of suppressing the action of active species or active oxygen species which promotes the oxidation produced by the enzyme, or the accompanying lipid oxidation inhibiting action. It has the effect of suppressing Thereby, atherosclerosis resulting from hyperlipidemia can be prevented. Furthermore, since the pyrimidine derivative has a pharmacological action of promoting excretion of uric acid and reducing the blood concentration of uric acid, it is not only applicable to drug therapy for hyperuricemia but also a risk factor for hyperlipidemia. The reduction of hyperuricemia can also suppress the onset of hyperlipidemia.

Next, a production example of a pyrimidine derivative as an active ingredient of the present invention will be shown as a reference example.

Reference Example 1 (1-Methyl-3-phenyl-5- (3,5-di-tert-butyl-4-hydroxybenzylidene) -pyrimidine-2,4,6-trione) 3,5-ditert- Butyl-4-hydroxybenzaldehyde 1.29 g
(5.5 mmol) and 1.09 g (5 mmo) of 1-methyl-3-phenylpyrimidine-2,4,6-trione.
1) is dissolved in 25 ml of ethanol and heated under reflux for 2 hours. After completion of the reaction, the reaction solution is cooled and the precipitated crystals are collected by filtration. 1.43 g of pale yellow crystals having the following physical properties were obtained. The yield was 66%. Melting point: 156-158 ° C. Molecular weight: M ⁺ 434 ¹ H-NMR (CDCl ₃ ) δ: 8.61 & 8.52
(1H, s), 8.32 & 8.26 (2H, s), 7.
55-7.21 (5H, m), 6.08 & 6.02 (1
H, s), 3.48 (3H, d), 1.47 (18H,
s)

[0019]

Example 1 (Reducing blood concentration of LDL in cholesterol-loaded rabbits) Oral administration of a drug containing the pyrimidine derivative (I) of the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient The effect of reducing the concentration of LDL contained in blood was examined by the following method. The test drug used in this example was prepared by suspending a predetermined dose in a medium using 0.5% CMC-Na solution as a medium.

Japanese white rabbits weighing about 2 kg were randomly divided into 3 groups, each group consisting of 6 individuals. All of the above-mentioned three groups were fed with a feed containing 1% cholesterol, and the test drug was used in the first group and probucol (probuco) was used as a positive control in the second group.
l), and the remaining third group as the reference group, vehicle alone was orally administered once daily for 28 days each. After the 28-day drug administration period had elapsed, blood was collected from the abdominal vena cava of each individual. Serum was prepared from blood collected from each individual by a conventional method, and a blood chemistry test was performed to measure the concentration of lipid contained in the blood collected from each individual. The measured lipids are HDL-cholesterol, LDL, and VL which are present as lipoproteins.
From the measured values of DL, free cholesterol and total cholesterol, and phospholipids, and the individuals constituting each of the above-mentioned three groups, the average value of each group and its standard deviation were determined.

As the pyrimidine derivative (I) to be contained in the test drug as an active ingredient, the pyrimidine derivative (1-methyl-3-phenyl-5-) according to Reference Example 1 above is used.
(3,5-di-tert-butyl-4-hydroxybenzylidene) -pyrimidine-2,4,6-trione: hereinafter referred to as pyrimidine derivative. ) Was used as the dose of 50 mg / kg per dose, and the dose of probucol used as a positive control was also 50 mg / kg per dose, and the average value of the three groups and the standard deviation thereof were shown in Table 1. The following results were obtained. From the results shown in Table 1, the results of administration of the test drug containing the pyrimidine derivative as an active ingredient and the results of administration of probucol known to have an action of lowering the concentration of lipid contained in blood are shown. Comparing these, the lipids contained in blood measured after administration, specifically LDL, VLDL, free cholesterol, and total cholesterol, and the phospholipid concentration (average value) were all effective with the pyrimidine derivative. It can be seen that the value of the drug as an ingredient is lower than that of the drug as an active ingredient of probucol. That is, it is understood that, when the same dose is administered, the test drug has a function comparable to that of the drug containing at least probucol, which reduces the lipid concentration contained in blood. Further, it can be seen that the test drug is remarkably excellent in the effect of reducing the VLDL concentration as compared with the drug containing probucol.

On the other hand, paying attention to the HDL-cholesterol concentration, it has been conventionally known that probucol also significantly lowers the blood concentration of HDL (or HDL-cholesterol). As for the test drug, the HDL-cholesterol concentration (average value) measured after administration was higher than that of the drug containing probucol. Furthermore, 0.5% CMC-N of the medium
Even when compared with the third group (reference group) to which only the a solution was administered, the result that the HDL-cholesterol concentration was increased when the test drug was administered was obtained. That is, it was found that the test drug has an action of increasing the blood concentration of HDL-cholesterol, and in that respect, it contrasts with probucol, which significantly lowers the blood concentration of HDL (or HDL-cholesterol). Target.

[0023]

Example 2 (Uric Acid Excretion Promoting Action) A drug containing the pyrimidine derivative (I) of the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient is orally administered and contained in the blood. The effect of reducing uric acid concentration and the effect of promoting uric acid excretion were investigated by the following methods. The test drug used in this example was prepared by suspending the pyrimidine derivative (I) or a pharmaceutically acceptable salt thereof in a 0.5% CMC-Na solution as a medium. SD rats were randomly divided into two groups of 6 individuals in each group. Of the above two groups, the first group was orally administered with the test drug, and the remaining second group was orally administered only with a 0.5% CMC-Na solution as a vehicle. Was also kept under fasting for 24 hours. Part 2
Urine excreted by each individual was separately accumulated for 4 hours. The amount of uric acid contained in the collected urine was measured. Also, part 2
After 4 hours, blood was collected from each individual. Serum was prepared from the blood collected from each individual in accordance with a conventional method, and a blood chemistry test was performed to measure the concentration of uric acid contained in the blood collected from each individual. The amount of uric acid contained in the measured urine was divided by the body weight of each individual to obtain the amount of uric acid excreted in urine. Further, the average value and the standard deviation of each group were obtained from the values obtained for the individuals constituting each group. The second group is an example in which the dose of the test drug is zero and serves as a reference group.

The pyrimidine derivative (I) to be contained as an active ingredient in the test drug was tested using the above pyrimidine derivative at a dose of 100 mg / kg, and Table 2 shows the average values of the two groups and the standard thereof. The results shown as deviations were obtained. From these results, the amount of uric acid excreted as urine (urine uric acid excretion amount) by administration of the test drug containing the pyrimidine derivative as an active ingredient
It can be seen that the blood concentration of uric acid is reduced. It can be seen that the test drug has an effect of reducing the blood concentration of uric acid and promoting excretion of uric acid. It is also considered that the amount of uric acid excreted as urine was increased, and as a result, the concentration of uric acid remaining in blood was reduced. Furthermore, the action of the test drug to reduce the blood concentration of uric acid is to reduce the amount of uric acid produced by metabolic inhibition, or to localize / accumulate uric acid in blood in specific organs or biological tissues. It is not expected to occur.

[0025]

Example 3 (LDL Antioxidant Action) The ability of the pyrimidine derivative (I) of the general formula (I) or a pharmacologically acceptable salt thereof to inhibit LDL oxidation was examined by the following method.

Blood collected from a healthy human was centrifuged at 3000 rpm for 15 minutes at 4 ° C. to obtain plasma. Further, this plasma was ultracentrifuged to separate and collect the LDL fraction. The concentration of the protein contained in the LDL fraction was determined by the method of Bradford et al. [Anal. Bioch
em. Vol. 72 p. 248-254 (197)
6)] was measured. The protein contained in the LDL fraction was mainly LDL, and the measured protein concentration was regarded as the LDL concentration. This pre-contained L
The test substance was added to a predetermined amount of the LDL fraction for which the concentration of DL was measured, and the antioxidant effect of the test substance was measured by the TBA method. In addition, copper sulfate was used for the oxidation of LDL,
The specific method for measuring the antioxidant action by the TBA method is Ma
O. et al. [J. Med. Chem. vol. 34
p. 298-302 (1991)].

In this example, the test substance was preliminarily DM
A solution dissolved in SO was used. The concentration of the test substance is indicated by the molar concentration in the solution obtained by adding the test substance to the LDL fraction. The amount of DMSO contained in the solution of the test substance to be added is such that the DMSO concentration in the solution obtained by adding it to the LDL fraction is 6.7.
The amount is set to be%. The reference value, that is, the inhibition rate of LDL oxidation is 0%, and the inhibition rate of LDL oxidation is expressed as the inhibition rate, when the equivalent amount of DMSO to distilled water that does not have an antioxidant action on the oxidation of LDL is added instead of DMSO. Table 3 shows the results obtained by measuring the inhibition rate of LDL oxidation using the pyrimidine derivative of the above-mentioned pyrimidine derivatives (I) as a test substance. Table 3 also shows the results of measurement of the inhibition rate of LDL oxidation using probucol as a control substance known to have an LDL oxidation prevention action. In addition, the result when DMSO containing no test substance is added, that is, the result when the concentration of the test substance added is zero is referred to as the test substance DMSO.

From the results shown in Table 3, there is no significant difference between the LDL antioxidant activity of probucol and the LDL antioxidant activity of the pyrimidine derivative.
It can be seen that both have an antioxidant effect. Furthermore, Table 3
From the results shown in, calculation of addition concentration IC ₅₀ of a test substance as a percentage inhibition of 50% of LDL oxidation, IC ₅₀ values of the pyrimidine derivatives are 3.6 × 10 ^-6 M, IC ₅₀ values of probucol Value of 4.6 × 10 ⁻⁶ M. That is, at least the concentration to be added is 0.5 to 5 × 1.
In the range of 0 ^-6 M, the result was that the pyrimidine derivative had a higher LDL antioxidant activity than the probucol.

[0029]

Example 4 (Formulation) 1-Methyl-3-phenyl-5- (3,5-di-tert-butyl-4-hydroxybenzylidene) -pyrimidine-2,4,6-trione obtained in Reference Example 1 Lactose (35 g), hydroxypropyl cellulose (4.5 g) and magnesium stearate (0.5 g) were mixed with 10 g and the mixture was compression-molded by a conventional method to give 200 tablets. This tablet is administered to a patient with hyperlipidemia or hyperuricemia at a predetermined dose depending on the symptom, for example, one tablet several times a day.

[0030]

[Table 1]

[Table 2]

[Table 3]

[0031]

The drug containing the pyrimidine derivative of the general formula (I) or a pharmacologically acceptable salt thereof of the present invention as an active ingredient is excellent in the pharmacological action of lowering the concentration of LDL contained in blood. In addition, since it has the antioxidant effect of the LDL and the effect of increasing the concentration of HDL contained in blood, it can be effectively used for the prevention and treatment of hyperlipidemia. Further, since it has an effect of promoting the excretion of uric acid contained in blood, it can be used for reducing the blood concentration of uric acid and can be used for the prevention and treatment of hyperuricemia. Furthermore, the pyrimidine derivative of the general formula (I) or a pharmacologically acceptable salt thereof contained in the drug as an active ingredient has no side effect of causing an ulcer of the digestive system, and has a long-term or repeated continuation. It is suitable as a therapeutic agent for hyperlipidemia or a therapeutic agent for hyperuricemia, which is used for oral administration.

Claims (2)

[Claims] 1. A therapeutic agent for hyperlipidemia, which comprises a pyrimidine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [Chemical 1] (In the formula, R ₁ and R ₂ are each independently a hydrogen atom, a linear or branched lower alkyl group, a substituted or unsubstituted phenyl group or a cyclohexyl group, and R ₃ is a linear or branched chain. Each represents a chain-like lower alkyl group or a lower alkoxy group. In addition, ~ represents stereoisomerism.) 2. A therapeutic agent for hyperuricemia, which comprises a pyrimidine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.