JPH0418021A - Agent of lowering serum uric acid - Google Patents

Abstract

PURPOSE:To obtain an excellent agent of lowering serum uric acid useful for treating cardiovascular disorder, gastric disorder, etc., resulting from gout or hyperuricemia as a basic disease, having lowering action on uric acid, containing a p-aminophenol derivative as an active ingredient. CONSTITUTION:An agent of lowering serum uric acid containing at least one selected from a p-aminophenol derivative shown by the formula [R<1> is lower alkyl; R<2> and R<3> are H, lower alkyl or both are bonded to form -(CH2)4- or -CH=CH-CH=CH-; alpha is aromatic heterocyclic 5-membered or 6-membered group containing 1-3 hetero atoms selected from N, O and S, pyrazine-N-oxide ring group, pyridazine-N-oxide ring group, pyrimidine-N-oxide ring group and these groups may contain lower alkyl group, etc., as substituent group] and a slat thereof as an active ingredient. When used, the agent can be used in the dosage form of injection or suppository besides oral administration of tablet, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a new serum uric acid lowering agent that has a medicinal effect of lowering the amount of uric acid in serum.

Prior Art Uric acid (2,6,8-)lioxypurine) is a type of colorless powder crystalline purine derivative found in urinary stones.
It is in the form of free uric acid or uric acid salts as an end product of purines in the body - approximately 0% during the day and night. It is discharged in an amount of 5 to 0.8 g.

The upper limit of normal serum uric acid level is approximately 6 μ/dl for men and approximately 5 μ/dl for women.
．． However, when uric acid is overproduced due to an inborn abnormality of purine metabolism, when cell breakdown is accelerated due to leukemia, malignant tumor, etc., or when ATP consumption increases due to extreme exercise, stress, etc. In cases where the uric acid concentration in serum increases due to endocrine disorders, uric acid excretion disorders, etc., the above upper limit is exceeded and hyperuricemia, as typified by gout, develops.

As therapeutic agents for hyperuricemia, pharmaceuticals such as allopurinol, sulfinpyrazone, probenecid, and benzpromalone have been developed and commercially available.

However, these therapeutic agents for hyperuricemia are still unsatisfactory in their serum uric acid lowering effects, and there is a demand in the art for new agents to replace them.

Problems to be Solved by the Invention An object of the present invention is to provide a new serum uric acid lowering agent for the treatment of hyperuricemia that meets the needs of the above-mentioned industry.

The present inventors have conducted intensive research for the above purpose, and as a result, p-aminophenol derivatives, which the present inventors have previously researched and developed as an active ingredient for anti-inflammatory agents and lipoxygenase inhibitors [see JP-A-64-25756] ] has been found to have an extremely excellent serum uric acid lowering effect that meets the above objectives, and has now completed the present invention.

Means for solving the problems, that is, the present invention is based on the general formula [wherein R1 represents a lower alkyl group]. R' and R3 each represent a hydrogen atom or a lower alkyl group, or both are bonded to form a group -(CIl+) or a group -C11.CII
-CII•CI+- is shown. α is an aromatic hetero 5- or 6-membered ring group containing 1 to 3 petro atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, pyrazine-N-oxide ring group, pyridazine-N-oxide ring group, or pyrimidine -N-oxide ring group, and each prefecture is a substituent selected from a lower alkyl group, a halogen atom, a phenyl group, a lower alkoxycarbonyl group, an amino group, a lower alkoxy group, and a hydroxy lower alkyl group. It may have up to 3 pieces. ] The present invention relates to a serum uric acid lowering agent characterized by containing as an active ingredient at least one selected from p-aminophenol derivatives and salts thereof represented by the following.

The serum uric acid-lowering agent of the present invention can be used for the treatment of gout, cardiovascular disorders with hyperuricemia as the underlying disease, renal disorders, etc., based on its unique uric acid-lowering effect, thereby achieving the desired and excellent results. Can have therapeutic effects.

The active ingredient compounds of the serum uric acid lowering agent of the present invention are all known [see Japanese Patent Application Laid-Open No. 64-25756].

Preferred examples of the above active ingredient compounds include the following.

General formula [In the formula, R1 is the same as above, R2 represents a lower alkyl group, α' represents a pyrazine ring group or a pyrazine-N-oxide ring group, and each prefecture has a lower alkyl group as a substituent. , a halogen atom, a phenyl group, a lower alkoxycarbonyl group, an amino group, a lower alkoxy group, and a hydroxy lower alkyl group. A p-aminophenol derivative represented by J and its salt.

Among the above, in particular, the general 2 [wherein R1 and R2 are the same as above, α'' represents a pyrazine ring group, and the core layer has a lower alkyl group, a halogen atom, a phenyl group, a lower alkoxycarbonyl group as a substituent, It may have 1 to 3 groups selected from an amino group, a lower alkoxy group, and a hydroxy lower alkyl group.

Preferred are p-aminophenol derivatives represented by the following formula and salts thereof, and 2,6-terl-butyl-4-pyrazinylaminophenol and salts thereof are optimal.

The salts of the p-aminophenol derivatives represented by the above formulas include pharmaceutically acceptable acid addition salts obtained by adding an appropriate acidic compound to each of these derivatives. Examples of acidic compounds that can form acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and acetic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, Examples include organic acids such as benzenesulfonic acid. The above-mentioned salts also include pharmaceutically acceptable basic compound salts of the above-mentioned derivatives. Examples of the group include alkali metal salts such as lithium salts, sodium salts, potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and other metal salts such as copper salts. All of the reactions for forming these isosteric salts can be carried out according to conventional methods.

The serum uric acid lowering agent of the present invention is used in the form of a simple pharmaceutical preparation. The pharmaceutical preparation is prepared using commonly used additives such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants. Various forms can be selected as appropriate for this pharmaceutical preparation, and representative examples include tablets, gunpowder, powders, solutions, suspensions, emulsions, granules, capsules, halves, and injections (liquids, suspensions, etc.). (cloudy agents, etc.), ointments, etc. When molding into tablet form, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, potassium phosphate, and silicic acid, water, ethanol, and propylene chloride are used as carriers. Tools, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, carboxymethyl starch sodium, carboxymethyl cellulose calcium,
Disintegrants such as low-substituted hydroxypropyl cellulose, dry starch, sodium alginate, agar powder, laminaran powder, surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, white sugar, stearin, cocoa butter , disintegration inhibitors such as hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin,
Adsorbents such as bentonite and colloidal silicic acid, and lubricants such as purified talc, stearate, and polyethylene glycol can be used.

Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets, etc. When molding into the form of gunpowder, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc, powdered gum arabic, powdered tragacanth, etc. are used as carriers.
Binders such as gelatin and ethanol, and disintegrants such as laminaran and agar can be used. When molding into a half-open form, use of a carrier such as polyethylene glycol,
Cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used. Capsules can be prepared by mixing the p-aminophenol derivative and/or its salt as an active ingredient with the various carriers listed above and filling the mixture into hard gelatin capsules, soft gelatin capsules, etc. according to a conventional method. Injectables are preferably sterilized and isotonic with blood, and when molded into injectable forms such as solutions, emulsions, and suspensions, diluents such as water, ethyl alcohol, propylene glycol, and ethoxylated isostearyl are used. Alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, etc. can be used. In this case, sufficient amounts of salt, glucose, glycerin, etc. to prepare an isotonic solution may be included in the pharmaceutical preparation, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You may.

Furthermore, the pharmaceutical preparation of the present invention may contain coloring agents, preservatives, fragrances, flavoring agents, sweeteners, etc. and other pharmaceuticals as required.

When molding into a paste, cream or gel form, for example, white petrolatum, paraffin, glycerin, cellulose derivatives, carboxyvinyl polymer, polyethylene glycol, silicone, hentonite, etc. can be used as a diluent.

The amount of the active ingredient compound 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 it is usually 1 to 70% by weight based on the total composition.

There are no particular restrictions on the method of administering the pharmaceutical preparation of the present invention, and it can be administered in a manner appropriate to various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, gunpowders, solutions, suspensions, emulsions, granules, capsules, etc. are administered orally. Injections are administered intravenously alone or mixed with conventional replacement fluids such as glucose and amino acids, and if necessary, administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. If it is partially opened, it is administered rectally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but usually the amount of the active ingredient compound is about 0.0% per kg of body weight per 1 hour.
．． The amount is preferably 1 to 100 μl, and the preparation can be administered in 2 to 4 divided doses per day.

EXAMPLES In order to explain the present invention in more detail, formulation examples of the serum uric acid lowering agent of the present invention will be given as examples, and then pharmacological test examples will be given.

Example 1 2.6-sheet tcrt-butyl-4-pyrazinylaminophenol 250g crystalline cellulose (Japanese Pharmacopoeia crystal) 30g cornstarch (Japanese Pharmacopoeia crystal) 17g talc (Japanese Pharmacopoeia crystal)
2g magnesium stearate
1g (Japanese Pharmacopoeia) Total amount 300
g 2,6-terl-butyl-4 as active ingredient
- Pyrazinylaminophenol, 25 per capsule
Hard gelatin capsules (1000 pieces) containing 0■
Prepared according to the above recipe.

That is, each component was finely powdered, thoroughly mixed to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having desired dimensions to prepare capsules of the present invention.

Example 2 2.6-C+crt-butyl-4-pyrazinylaminophenol 100g crystalline cellulose ([Avicel pl1 101'', manufactured by Asahi Kasei ■) 40g cornstarch 30g non-tearic magnesium amount
172g Hydroxypropyl methylcellulose ("TC-5", 8g manufactured by Shin-Etsu Chemical Co., Ltd.) Polyethylene glycol 6000 2.4g Pigment 0.6g Titanium dioxide 4.0g Wood, 8
5, −, − rule” Total amount 100
g2.6-G1e "1-Butyl-4-pyrazinylaminophenol, crystalline cellulose, cornstarch, and magnesium stearate are mixed and then tableted with a sugar coating R8+nm kineter, and the resulting tablets are mixed with TC-5, polyethylene Film coated tablets of the present invention (1000 tablets) having the above composition were prepared by coating with a film coating agent consisting of glycol 6[100, pigment, titanium dioxide and water].

Example 3 2.6-See! Capsules were prepared in the same manner as in Example 1 using erl-butyl-1[(5-hydroxymethyl-2-pyrazinyl)aminocophenol as the active ingredient.

Example 4 Capsules were prepared in the same manner as in Example 1 using 2-N-(3,5-dierl-butyl-4-hydroxyphenyl)aminopyrazine-N-oxide as the active ingredient.

Example 5 Film-coated tablets were prepared in the same manner as in Example 2 using 2.6-di-1ert-butyl-4-[(6-medoxy-2-pyrazinyl)aminocophenol as the active ingredient.

Example 6 Film-coated tablets were prepared in the same manner as in Example 2 using 2.6-di-1erl-butyl-4-[(5-methoxycarbonyl-2-pyrazinyl)aminocophenol as the active ingredient. .

Example 7 2.6-di-1erl-butyl-4-[(6-chloro-
Film-coated tablets were prepared in the same manner as in Example 2 using 2-pyrazinyl)aminocophenol as the active ingredient.

Pharmacological test I "Serum uric acid level measurement test" Tablets containing 100 μl of 2,6-di-1ert-butyl-4-pyrazinylaminophenol (obtained in Example 2) were administered once to 4 healthy subjects. One tablet was administered twice a day (15 times, experimental group), and two healthy subjects were administered tablets (prepared in the same manner as in Example 2) that did not contain the above-mentioned active ingredient compound ( A double-blind clinical trial was conducted over 8 days (placebo group).

In addition, the tablets prepared in Example 2 above were administered to 6 healthy subjects every day for 12 days (23 times of administration).

Furthermore, the tablets prepared in Example 2 above were administered to 5 healthy subjects every day for 14 days (27 doses).

During the experimental period, each subject's serum uric acid concentration was measured every predetermined day.

Results obtained for the experimental group and the placebo group for the above 8 hours (
The average values of subjects in each group are shown in FIG.

In addition, the results obtained for the 128-year experimental group (same as above) were
As shown in the figure.

Furthermore, the results obtained for the 14-day experimental group (values for each subject in each group) are shown in FIG.

In each figure, the vertical axis represents serum uric acid concentration (mg/dl).
The horizontal axis indicates the number of days that have passed (days, where PRE indicates the day before the start of the experiment). In addition, (1) in Figure 1 indicates the experimental group, (
2) shows the placebo group, in FIG. 3, (1) and (2) show the placebo group subjects, and (3) to (5) show the experimental group subjects, respectively. Further, in each figure, the area between two broken lines indicates the normal serum uric acid concentration range.

From FIGS. 1 to 3 above, it is clear that the p-aminophenol derivative used as an active ingredient in the present invention exhibits excellent medicinal effects as a serum uric acid lowering agent.

[Brief explanation of drawings]

Figures 1, 2, and 3 are graphs showing the results of measuring serum uric acid concentrations over time in subjects with or without administering the preparation of the present invention according to Pharmacology Test Example I of the present invention. . (That's all) ~=C- Continuation of 100 Kano

Claims (1)

[Claims] [1] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents a lower alkyl group. R^2 and R^
3 each represents a hydrogen atom or a lower alkyl group, or both are bonded to form a group -(CH_2)_4- or a group -CH=
Indicates CH-CH=CH-. α is an aromatic hetero 5- or 6-membered ring group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, pyrazine-N-oxide ring group, pyridazine-N-oxide ring group, or pyrimidine -N-oxide ring group, and each of these groups is a substituent selected from a lower alkyl group, a halogen atom, a phenyl group, a lower alkoxycarbonyl group, an amino group, a lower alkoxy group, and a hydroxy lower alkyl group. It may have up to 3 pieces. ] A serum uric acid lowering agent characterized by containing as an active ingredient at least one selected from p-aminophenol derivatives and salts thereof represented by the following. [2] The active ingredient has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is the same as above, R^2 represents a lower alkyl group, and α' is a pyrazine ring group or pyrazine- Indicates an N-oxide ring group, and each of these groups is a substituent selected from a lower alkyl group, a halogen atom, a phenyl group, a lower alkoxycarbonyl group, an amino group, a lower alkoxy group, and a hydroxy lower alkyl group. It may have three pieces. ] The serum uric acid lowering agent according to claim [1], which is selected from p-aminophenol derivatives and salts thereof represented by the following. [3] The active ingredient has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same as above, α'' represents a pyrazine ring group, and this group is It may have 1 to 3 groups selected from a lower alkyl group, a halogen atom, a phenyl group, a lower alkoxycarbonyl group, an amino group, a lower alkoxy group, and a hydroxy lower alkyl group. The serum uric acid lowering agent according to claim [1], which is selected from phenol derivatives and salts thereof. [4] Selected from 2,6-di-tert-butyl-4-pyrazinylaminophenol and salts thereof. Claim [
The serum uric acid lowering agent according to [1].