JPH03135917A - Uric acid evacuant - Google Patents

Abstract

PURPOSE:To provide an uric acid evacuant having reduced adverse effects and effective for treating purine dysbolism diseases such as gout by containing a thiolactam-N-acetic acid derivative. CONSTITUTION:The objective agent contains a compound of the formula (R<1> and R<2> are H, halogen, lower alkyl, etc.; R<3> is H or methyl; R<4> is carboxyl; X is O or S), e.g. 3,4-dihydroxy-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-acetic acid. The compound of the formula can be generally administered together with various medically acceptable preparation compositions. The agent is administered in a dose of e.g. 10-2500 mg, preperably 25-900 mg, a day in one- three portions.

Description

[Detailed Description of the Invention] The present invention relates to a uric acid excretion agent containing a thiolactam-N-acetic acid derivative, which is effective for the treatment of purine metabolism disorders such as hyperuricemia and gout. .

BACKGROUND OF THE INVENTION Various drugs have been developed to date for use in diseases such as hyperuricemia and gout caused by purine metabolism disorders.

For example, gout attack treatment agents such as colchicine, indomethacin, and naproxen; uric acid excretion agents such as probenecid, benzpromarone, sulfinpyrazone, and fucolor;
Uric acid synthesis inhibitors such as allopurinol and urine alkaline agents such as sodium bicarbonate are used.

In recent years, quinazoline derivatives (Japanese Patent Application Laid-Open No. 1-1569
20) and 3-(4-bromo-2-fluorobenzyl)-
It has also been reported that 4-oxo-3H-phthalazin-1-yl acetic acid (JP-A-1-216931) can be used as a uric acid excretor or a therapeutic agent for reducing blood uric acid concentration.

Problems to be Solved by the Invention When the conventionally used drugs mentioned above are used, side effects such as gastrointestinal disorders, hypersensitivity, decreased white blood cells, and rash are observed.

Furthermore, quinazoline derivatives and 3-(4-bromo-2fluorobenzyl)-4-oxo-38-phthalazine-yl acetic acid have not yet been put to practical use.

Therefore, the current situation is that the treatment of diseases associated with such an excess of uric acid, especially those of early onset cases and critically ill patients with complications, has not yet been resolved.

It has been desired to develop a drug that can effectively treat diseases exhibiting these symptoms and has fewer side effects.

Means for Solving the Problems The present inventors discovered for the first time that thiolactam-N-acetic acid derivatives lower blood uric acid levels in healthy individuals, and based on this knowledge, they completed the present invention.

That is, the present invention relates to the general formula (1) [In formula (1), R1 and R'' are each the same or different and are hydrogen, halogen, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, a phenylalkyloxy group,
R3 represents hydrogen or a methyl group, R1 represents a carboxyl group which may be esterified, and X represents an oxygen atom or a sulfur atom. ] The present invention relates to a uric acid excretion agent comprising a compound represented by the following.

Compound (1) used in the present invention is a known compound,
It has aldose reductase inhibitory activity and platelet aggregation inhibitory activity. Further, compound (1) can be produced by a known method (Japanese Patent Application Laid-Open No. 107970/1983).

However, it was not known at all that compound (1) had a uric acid excretion effect.

Examples of R1 and R1 in compound (1) include hydrogen, halogen, lower alkyl group, cycloalkyl group, lower alkoxy group, phenylalkyl group, and trifluoromethyl group.

The halogen shown here includes, for example, fluorine, chlorine, bromine, and iodine, and among them, fluorine is preferred.

The lower alkyl group is linear or branched and has 1 carbon number.
~6 is preferred. For example, methyl group, ethyl group,
Propyl group, isopropyl group, butyl group, isobutyl group I 5ec-butyl group, Lert-butyl group, pentyl group, impentyl group, neopentyl group, tert-
Examples include hentyl group, hexyl group, isohexyl group, and the like.

The cycloalkyl group preferably has 3 to 7 carbon atoms. For example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group.

Examples include cyclohebutyl group.

Examples of the lower alkyl group include those in which the aforementioned lower alkyl group and an oxygen atom are bonded.

The phenylalkyloxy group preferably has 7 to 9 carbon atoms. For example, benzyloxy group.

l-phenylethoxy group, 2-phenylethoxy group.

Examples include l-7enylpropyloxy group, 2-phenylpropyloxy group, and 3-phenylpropyloxy group. These may have a substituent on the benzene ring. Such substituents include halogens such as fluorine, chlorine, bromine, and iodine, lower alkyl groups such as methyl, ethyl, propyl, and isopropyl, methoxy,
Ethoxy group Propoxy group 1 Examples include lower alkoxy groups such as isopropoxy group, methylenedioxy group, and trifluoromethyl group. Furthermore, 1 to 3 of these substituents may be substituted at any position on the benzene ring (,
If two items are abnormally substituted, they may be the same or different.

R1 and R'' expressed in this way may be substituted at any position on the benzene ring in compound (1) formula. Among them, the 6th, 7th and 8th positions are preferred. Particularly R1 and R1 When either one of them is an alkyl group or a cycloalkyl group, it is preferable that these are substituted at the 8-position.

In compound (1), R3 is hydrogen or a methyl group.

R4 is a carboxyl group or an esterified carboxyl group.

Examples of the esterified carboxy group shown here include alkoxycarbonyl groups having 2 to 6 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, and imbutoxycarbonyl group. , aryloxycarbonyl group having 7 to 9 carbon atoms such as phenoxycarbonyl group, and 8 carbon atoms such as penzyloxycarbonyl group
-10 aralkyloxycarbonyl groups, and the like.

Among the compounds (]), salts of compounds in which R4 is represented by a carboxyl group are also included in the compounds used in the present invention. In particular, pharmacologically acceptable salts include, for example, alkali metal salts (eg, sodium salts).

potassium salts, etc.), alkaline earth metal salts (eg, carunium salts, etc.), and aluminum salts.

Furthermore, the compound represented by general formula (1) or a salt thereof has an asymmetric carbon atom. Therefore, they can exist as enantiomers or diastereomers and can be resolved into pure isomers if necessary. The separation of these diastereomers and racemic compounds is disclosed in JP-A No. 63-1079.
It can be carried out by the method described in No. 70.

The uric acid excretion agent of the present invention can be effectively used particularly for humans and animals having purine metabolism functions similar to humans.

The present uric acid excretor is effective in alleviating hyperuricemia and treating gout, which is closely related to it. Furthermore, it is possible to improve various symptoms associated with renal disorders, hypertension, arteriosclerosis, obesity, hyperlipidemia, diabetes, and the like.

The thiolactam-N-acetic acid derivative, which is the active ingredient of the present invention, is generally administered together with various pharmaceutically acceptable formulations.

That is, it can be mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, granules, tablets, capsules,
It can be administered orally or parenterally in the form of an injection.

The dosage of the uric acid excretor of the present invention varies depending on the administration route, symptoms, patient's age, body weight, etc., but for example, the active ingredient is 3,4-dihydro-2,8-diisopropyl-3-thioxo- 2H-1,4-benzoxazine-
When using 4-acetic acid (hereinafter referred to as compound A), the amount is within the range of 10 to 25001119 per day, preferably 2
It is desirable to divide the dose into 1 to 3 doses per day within the range of 5 to 900119 doses.

By using the uric acid excretion agent of the present invention, it is possible to effectively treat purine metabolism disorders such as gout with few side effects.

EXAMPLE 1 AND TEST 1 The fact that the thiolactam-N-acetic acid derivative used in the present invention exhibits excellent uric acid excretor action and low toxicity will be explained below using examples and test examples.

[Example] A product was prepared according to the following recipe, and granulated and tableted in a conventional manner. The obtained tablets were film-coated using methylcellulose, titanium oxide, and yellow iron sesquioxide, and the film-coated tablets were applied to the test.

Prescription 1 > 25. Tablet containing On Compound A 25.0g + 9 lactose
184. ld cornstarch
62. Omy human axy 1G birsert λ
8.0 @ 9 λ Thearic acid 7 g
8.0 mg1, 0 m9 Magnesium stearate <Formulation 3> Loo, om9 containing tablet compound Δ
100. Om? lactose
86.5mg cornstarch 55.0I+
+9E Do ■Kimbu 0 Bill Seltos
7.0 m9 Magnesium Stearate
1, 5 m9〈Prescription 4〉
Control Lactose 201.011+9 Cornstarch 60.0mg Human+] 4 Knob II [
n-λ 8.0 m
9λ 7gnenium thearate
1, 0 mg [Test Example 1] Blood uric acid lowering effect The compound was administered to 24 human subjects (healthy adult male volunteers) for 25 to 25 minutes.
A tablet containing 200119 (see Examples) was administered orally once, and the amount of uric acid in the blood was measured 6 hours and 24 hours later.

The results are shown in Table 1. Compound A significantly lowered blood uric acid levels at doses of 25m9 or higher.

Table 1 [Experimental Example 2] Blood uric acid lowering effect (continuous administration) Compound A200m9-containing tablets (
(see Examples) was administered three times a day for eight consecutive days, and changes in the amount of uric acid per meter were examined during the administration period and one week after discontinuation.

The results are shown in Table 2. A decrease in the amount of uric acid per 1 m due to the uric acid excretion effect was observed during the continuous administration period.

Table 2 Next, a tablet containing Compound A200m9 (see Examples) was administered, and the subjects were made to drink roomc water in the same manner, and the amount of uric acid in the urine was measured for 2 hours.

The results are shown in Table 3 as uric acid excretion amount and uric acid clearance per minute. Compound Δ enhanced uric acid excretion into the urine.

Table 3 [Test Example 3 Kouric Acid Excretion Effect (Human) Three human volunteers (healthy adult volunteers) were made to drink 100 mff of water and the amount of uric acid in the urine was measured for 2 hours.

[Test Example 4] Uric acid excretion effect (rats) Sprague-Dawley rats (male, 5-7 weeks old, 5-11 rats) were fasted for 18 hours and subjected to experiments.

Compounds A, B, C and D were each suspended in 5% aqueous gum arabic solution and administered at 1 OOm9/kg ffi
(5mc/9 in) and at the same time 20% in physiological saline.
m12/kg was orally loaded.

Urine was collected for 6 hours after administration of Compound A, and the amount of uric acid in the urine was measured.

As a control, the same dose of physiological saline was administered.

The results are shown in Table 4. Compounds A-D were found to significantly promote urinary excretion of uric acid and lower blood uric acid levels.

Table 4 Compound Number of tests Uric acid level control 11 1.146A
6 1.497 B 5 1.333 C51,503 D 5 1.867 Mean f SD (n=5~l1)-:p<
0.01. *+w: p<0.001 (non-aired CIl, COO11 excretion amount (m9) ± 0.205 ± 0.248- ± 0.422- ± 0.254 self ± 0.291-- t-tesL) The following is the margin> CIl, C0OH Compound C: Animal Mouse Rat Table 5 L D so (a+9/9) 880 830 Compound D: [-Test Example 5] Acute toxicity Group 1 5 male ICR mice (4 weeks old) and W i s
Various doses of Compound A suspended in a 5% gum arabic aqueous solution were orally administered to t a r rats (5 weeks old), followed by observation for 14 days. This facility was opened and water was available ad libitum.

The 50% lethality ffi (Los. value) of this compound is shown in Table 5.
It was as follows.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are each the same or different and represent hydrogen, halogen, lower alkyl group, cycloalkyl group, lower alkoxy group , a phenylalkyloxy group or a trifluoromethyl group, R^3 represents hydrogen or a methyl group, R^1 represents a carboxyl group which may be esterified, and X represents an oxygen atom or a sulfur atom. ] A uric acid excretor comprising a compound represented by: