JPH05301817A - Eliminant for uric acid - Google Patents

Abstract

PURPOSE:To obtain a new eliminant for uric acid, comprising a specific pyrazolotriazine derivative or its salt as an active ingredient, having excellent eliminant action on uric acid in addition to inhibiting action on synthesis of uric acid and especially effective in treating hyperuricemia. CONSTITUTION:The objective eliminant for uric acid comprises at least one selected from a pyrazolotriazine derivative expressed by formula I [R<1> is H or OH; R<2> is H, lower alkyl or lower alkoxy; n is 0,1 or 2] and its salt as an active ingredient. This eliminant has excellent eliminant action. A compound expressed by formula II [R<1> is OH or OH; R<2> is lower alkoxy; n' is 1] in the compound expressed by formula I, e.g. 4-hydroxy-8-(3-methoxy-4- phenylsulfinylphenyl)pyrazolo[1,5-a]-1, 3, 5-triazine is especially preferred. Furthermore, the compound expressed by formula I even in the form of a hydrate having water of crystallization can be utilized.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel uric acid excretion enhancer, more specifically to the above-mentioned uric acid excretion enhancer containing a pyrazolotriazine derivative or a salt thereof as an active ingredient.

[0002]

Uric acid is a major product of human metabolism of purine derivatives such as nucleic acids. Normal plasma (plasma) concentrations of uric acid are close to the solubility limit above which crystal precipitation occurs in various tissues in the human body, leading to the pathology known as gout and gouty arthritis. Tend to be brought. And high blood uric acid levels (hyperuricemia) can result from dietary absorption of purine derivatives and can also occur in many disease states. As the latter diseases, for example, pneumonia, blood diseases accompanied by abundant conversion (metabolism) of purine nucleotides (for example, bone marrow leukemia, dysplasia, malignant anemia, etc.), diabetes, kidney disease and the like are known. In addition, hyperuricemia may also occur after cytotoxic chemotherapy or radiotherapy of neoplasms, after the administration of pyrazinamide, various potent drugs that adversely affect liver function, and as a result of excessive biosynthesis due to genetic defects. It is known that this can happen.

To date, a large number of compounds that can reduce blood uric acid concentration have been reported, and typical examples thereof include drugs such as probenecid, benzbromarone, and sulfinpyrazone that excrete uric acid, and uric acid. Drugs such as allopurinol, which has a synthetic inhibitory action, can be mentioned, but all of them have room for improvement in their therapeutic effects.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a uric acid excretion enhancer containing, as an active ingredient, a novel compound which has not been known so far, in place of various conventionally known drugs.

As a result of intensive studies conducted by the present inventors, a compound capable of exhibiting an excellent uric acid excretion promoting action which meets the above-mentioned object was found in a series of pyrazolotriazine derivatives previously studied and developed by the present inventors. It was found that they existed, and the present invention was completed here.

[0006]

That is, the present invention is based on the general formula (1)

[0007]

[Chemical 3]

[Wherein R ¹ is a hydrogen atom or a hydroxyl group, and R ^{2 is}
Is a hydrogen atom, a lower alkyl group or a lower alkoxy group,
n represents 0, 1 or 2. ] A uric acid excretion enhancer comprising at least one selected from a pyrazolotriazine derivative represented by the following formula and a salt thereof as an active ingredient.

In the above general formula (1) representing the compound used as an active ingredient in the drug of the present invention, the lower alkyl group defined is a methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl or hexyl group. Etc. can be illustrated. As a lower alkoxy group,
Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy and hexyloxy groups.

The active ingredient of the uric acid excretion enhancer of the present invention may be a salt of the pyrazolotriazine derivative represented by the general formula (1), that is, a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt include alkali metal salts obtained by reacting the compound of the general formula (1) with an alkali such as sodium hydroxide and potassium hydroxide, calcium salts, aluminum salts and the like. .. Although the compound of the general formula (1) has optical isomers, the active ingredient of the uric acid excretion enhancer of the present invention may be an optical isomer of the compound of the general formula (1). It may be a racemate which is a mixture of isomers. Further, the compound of the general formula (1) may be present in the form of a hydrate having water of crystallization, and in the drug of the present invention,
The compound of the general formula (1) in the form of a hydrate having such water of crystallization can also be used as an active ingredient.

Among the compounds of the above-mentioned general formula (1) used as the active ingredient in the uric acid excretion enhancer of the present invention, particularly preferable compounds are represented by the following general formula (2).

[0012]

[Chemical 4]

[Wherein R ¹ is the same as defined above, R ² is a lower alkoxy group, and n'is 1]. The following compounds can be given as specific examples of the compound belonging to the general formula (2) and other preferable compounds.

4-hydroxy-8- (3-methoxy-
4-phenylsulfinylphenyl) pyrazolo [1,5
-A] -1,3,5-triazine. 2,4-dihydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a]
-1,3,5-Triazine * 4-hydroxy-8- (4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine * 4-hydroxy-8- (3-methyl-) 4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1,3
5-triazine 4-hydroxy-8- (3-methoxy-4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1,
3,5-Triazine The compound represented by the general formula (1) is a known compound previously developed by the present inventors and described in JP-A-64-79184. The publication describes that a series of compounds including the compound of the general formula (1) has a uric acid synthesis inhibitory action, but there is no description that they have a uric acid excretion promoting action, and The fact that the compound of formula (1) has an excellent uric acid excretion promoting action was first discovered by the present inventors. Therefore, the compound of the general formula (1) has both the uric acid synthesis inhibitory action described in the above publication and the uric acid excretion promoting action of the present invention. Hyperuricemia includes hypersynthesis type, excretion reducing type, and mixed type thereof. Generally, it is said that a synthesis inhibitor is more effective for hypersynthesis type patients and an excretion enhancer is more effective for low excretion type patients. There is. From this point, it is particularly effective to have both effects in the treatment of hyperuricemia.

The uric acid excretion enhancer of the present invention is used in the form of a general pharmaceutical preparation containing, as an active ingredient, at least one selected from the compound represented by the general formula (1) and a salt thereof. The preparation is prepared using diluents and excipients such as fillers, fillers, binders, humectants, disintegrants, surfactants and lubricants which are usually used. Various forms can be selected as this pharmaceutical preparation, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules,
Examples thereof include suppositories and injections (solutions, suspensions, etc.). In the case of molding into tablets, those conventionally known in this field can be widely used as carriers, and examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder , Laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, humectants such as starch, starch, lactose, kaolin, pentonite, colloidal silicic acid, etc. Adsorbents, purified talc, stearates, sucrose fatty acid esters, lubricants such as polyethylene glycol. Further, the tablet may be a tablet which is coated with a usual coating, for example, a sugar coating, gelatin, an encapsulated tablet, an enteric coated tablet, a film coated tablet, a double tablet and a multilayer tablet. In the case of molding in the form of pills, those conventionally known in this field as carriers can be widely used, and examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc. Gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, disintegrating agents such as laminaran and agar are included. In the case of molding in the form of suppositories, conventionally known carriers such as polyethylene glycol, esters of higher alcohols, gelatin, semisynthetic glycerides and the like can be used. When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood, and when formed into the form of isotonic solution, emulsion and suspension, they are diluted. As the agent, various agents commonly used in this field can be used. Examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. In this case, a sufficient amount of salt to prepare an isotonic solution, glucose, glycerin and the like may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc., If necessary, coloring materials, preservatives, fragrances, flavoring materials,
A sweetener and the like and other pharmaceuticals may be included in the therapeutic agent. When molding into a paste, cream or gel, white petrolatum, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicone, bentonite, etc. can be used as a diluent.

The amount of the compound represented by the general formula (1) and / or its salt to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected from a wide range, but usually 1 in the total composition. It is preferable that the content is about 70% by weight.

The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and various preparation forms, patient age, sex and other conditions,
It can be determined according to the degree of disease and the like. Tablets, pills,
Solutions, suspensions, emulsions, granules and capsules are administered orally. In addition, the injection is administered alone or mixed with an ordinary replenisher such as glucose or amino acid, and then intravenously administered. Further, if necessary, it is intramuscularly, intradermally, subcutaneously or intraperitoneally administered. Suppositories are administered rectally.

The dosage of the uric acid excretion enhancer of the present invention is as follows:
The amount of the active ingredient compound is usually about 1 to 100 mg per 1 kg of body weight per day, preferably 1 to 20 though it is appropriately selected depending on the age, sex and other conditions of the patient, the degree of disease and the like.
It is preferable to set the dosage in the range of about mg, and the dosage is 2 to 4 per day.
It can also be administered in divided doses.

[0019]

EXAMPLES In order to explain the present invention in more detail, formulation examples of the pharmaceutical preparation of the present invention will be given below, and then pharmacological test examples conducted on the active ingredient compound of the present invention will be given.

[0020]

[Formulation Example 1] Tablet 4-hydroxy-8- (3-methoxy-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,3,5
-To 1000 g of triazine, 600 g of L-HPC (low-substituted hydroxypropylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.), 280 g of lactose and 100 g of TC-5 (hydroxypropyl methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) were added and mixed, and then 750 g of water was added. And granulate with stirring. After drying this granulated product, 20 g of magnesium stearate is added, and the mixture is tableted with a 10 mmφ punch to obtain tablets.

The composition per tablet is as follows.

4-hydroxy-8- (3-methoxy-phenylsulfinylphenyl) pyrazolo [1,5, a] -1,3,5-triazine 100 mg L-HPC 60 mg lactose 28 mg TC-5 10 mg magnesium stearate 2 mg 200 mg

[0023]

[Formulation Example 2] Capsule 2,4-dihydroxy-8- (3-methoxy-phenylsulfinylphenyl) pyrazolo [1,5, a] -1,
L-HPC (low-substituted hydroxypropylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) 600 in 2000 g of 3,5-triazine
g, lactose 250 g, corn starch 120 g and aerosil (light anhydrous silicic acid, manufactured by Nippon Aerosil Co., Ltd.) 1
Add 0 g and mix. 20 g of magnesium stearate was added to this mixed powder, and the mixture was filled in No. 2 capsule to obtain a capsule.

The composition per capsule is as follows.

2,4-Dihydroxy-8- (3-methoxy-phenylsulfinylphenyl) pyrazolo [1,5, a] -1,3,5-triazine 200 mg L-HPC 60 mg lactose 25 mg corn starch 12 mg Aerosil 1 mg stearic acid Magnesium 2mg 300mg

[0026]

[Formulation Example 3] Fine granules 4-hydroxy-8- (4-phenylsulfinylphenyl) pyrazolo [1,5, a] -1,3,5-triazine 800 g to azehil (crystalline cellulose, manufactured by Asahi Kasei Kogyo Co., Ltd.) 400 g , Corn starch 380g and lactose 324
g in a fluid bed granulator and mixed. Then, 5% T
1600 g of an aqueous solution of C-5 (hydroxypropyl methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) is sprayed, granulated, and then dried. 16 g of Aerosil (light anhydrous silicic acid, manufactured by Nippon Aerosil Co., Ltd.) is added to this granulated product to obtain a powder.

The composition per 1 g of the fine granules is as follows.

4-Hydroxy-8- (4-phenylsulfinylphenyl) pyrazolo [1,5, a] -1,3,5-triazine 400 mg Azecel 200 mg Corn starch 190 mg Lactose 162 mg TC-5 40 mg Aerosil 8 mg 1000 mg

[0029]

[Pharmacological Test Example 1] This test was carried out at Shinpukai Maruyama Hospital in Hamamatsu City as follows for the purpose of examining the safety, pharmacokinetics and serum uric acid lowering effect of the active ingredient compound of the present invention in humans. (Clinical Phase I study).

In this test, the serum uric acid-lowering effect was
When examined using parameters such as serum uric acid, urinary uric acid, serum creatinine, and urinary creatinine, the compound of the present invention used as a test compound in a single-dose test, namely 4-hydroxy-8- (3-methoxy) -Phenylsulfinylphenyl) pyrazolo [1,5-a]-
The uric acid excretion promoting action of 1,3,5-triazine was found.

The single-dose test was carried out by using the above test compound in 4 groups of 8 test subjects [100 mg (n = 5),
200 mg (n = 6), 400 mg (n = 6) and placebo administration (n = 7)] It was a 3rd period crossover test. The results are shown in Figure 1.

In the figure, the horizontal axis is the time after drug administration (hr)
The vertical axis shows the amount of uric acid excretion (mg / hr), and each value is ME
Represented by AN ± SD, ** is p <0.01 and * is p <
0.05 (all are significant difference test by Dunnett's method for placebo group).

As shown in FIG. 1, the excretion of uric acid per hour was compared between the drug administration group and the placebo group, and the excretion amount of uric acid was 10 to 20 mg / hr in the 200 mg and 400 mg administration groups 2 to 4 hours after administration. , A temporary increase was recognized. On the other hand, no difference was observed in the amount of creatine excreted.

[0034]

[Pharmacological Test Example 2] This test was conducted using 2,4-dihydroxy-8- (3-methoxy-phenylsulfinylphenyl) pyrazolo [1,5-a] as the active ingredient compound of the present invention.
-1,3,5-triazine (hereinafter referred to as "Compound A")
Was dissolved in polyethylene glycol 400 (PEG400) to prepare 0.75% and 3% respectively,
As a control, the above solvent (PEG400) was administered by using a plastic syringe at a volume of 2 ml / kg as described below.

That is, the Wistar rats (weighing from 264 to 31) were divided into groups so that their weights were almost uniform.
4 g) subcutaneously on the back of the neck, each of the above solution and solvent is administered, and 30 mg / physiological saline is further added to increase the urine output.
kg was gavaged to each rat. After forced urination, it was transferred to a metabolic cage and urine was collected for 4 hours under free water intake. Blood was collected from the orbital vein at the intermediate point (2 hours) of the above urine collection. At the end of the above urine collection, forced urine was further discharged, and the urine adhering to the cage was washed out with 2.5 ml of distilled water.

The weight and specific gravity of the urine obtained by the above operation were measured and then stored frozen. Immediately after the blood was collected, the blood was coagulated under ice-cooling, serum was separated by a cooling centrifuge, and then frozen. The uric acid concentrations in serum and urine were measured using high performance liquid chromatography.

The results are shown in Table 1 below.

[0038]

[Table 1]

The data in the table are shown by the average value and the standard deviation, and each group has 7 cases. In the table, ** is p <0.01 (Dunnett's vs. control solvent group)
Method).

From Table 1 above, a significant difference was observed between the control group and the group of the present invention, which shows that the active ingredient compound of the present invention exhibits an excellent uric acid excretion promoting action.

[Brief description of drawings]

FIG. 1 is a graph showing the amount of uric acid excreted by administration of the active ingredient compound of the present invention according to Pharmacological Test Example 1.

Claims (5)

[Claims] 1. A general formula: [Wherein R ¹ represents a hydrogen atom or a hydroxyl group, R ² represents a hydrogen atom,
A lower alkyl group or a lower alkoxy group is shown, and n is 0, 1 or 2. ] A uric acid excretion enhancer comprising as an active ingredient at least one selected from the pyrazolotriazine derivatives represented by the following and salts thereof. 2. A general formula: [Wherein R ¹ is the same as above, R ² is a lower alkoxy group,
n'represents 1. ] The uric acid excretion enhancer according to claim 1, which comprises at least one selected from the pyrazolotriazine derivatives represented by the following and salts thereof as an active ingredient. 3. The uric acid excretion enhancer according to claim 1, which comprises at least one selected from the following compounds and salts thereof as an active ingredient. 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-Triazine-2,4-dihydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a]
-1,3,5-Triazine * 4-hydroxy-8- (4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1,3,5-triazine * 4-hydroxy-8- (3-methyl-) 4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1,3
5-triazine 4-hydroxy-8- (3-methoxy-4-phenylsulfonylphenyl) pyrazolo [1,5-a] -1,
3,5-triazine 4. The uric acid excretion enhancer according to claim 3, wherein the active ingredient is at least one selected from the following compounds and salts thereof. 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,
3,5-Triazine-2,4-dihydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a]
-1,3,5-triazine 5. The uric acid excretion enhancer according to claim 4, wherein the active ingredient is a hydrate.