JPH05279255A - Uric acid excretion enhancer - Google Patents

Abstract

(57) [Summary] [Structure] General formula [Chemical formula 1] [In the formula, R ₁ , R ₂ and R ₃ are the same or different, R ₄ is a hydrogen atom, R ₅ is nitro, alkyl halide or cyano, X is a group represented by vinylene or azomethine, A is alkylene, B is _{-N (R 6) (R 7} ) or ## STR2 ## (R ₆ and R ₇ are the same or different and each is alkyl, aralkyl or aryl, R ₈ and Ar are aryl, and n is 1.) and the dihydropyridine derivative or acid addition salt thereof is used as an active ingredient. Uric acid excretion enhancer. Action / Effect The uric acid excretion enhancer of the present invention reduces blood uric acid level by promoting excretion of uric acid into urine. Therefore, it is useful as a uric acid excretion enhancer for the prevention / treatment of hyperuricemia, hyperuricuria, gout, gouty arthritis and the like. Further, it is also useful for the prevention / treatment of nephritis and various renal disorders due to hyperuricemia.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a uric acid excretion enhancer containing a dihydropyridine derivative having a specific structure described below or an acid addition salt thereof as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Uric acid is usually filtered by the glomerulus and a considerable part thereof is reabsorbed by the renal tubule. Generally, a uric acid excretion enhancer is a drug that promotes excretion of uric acid into urine by suppressing the reabsorption of uric acid in the renal tubules. This makes it possible to eliminate the accumulation of uric acid in the body due to abnormal uric acid metabolism or uric acid excretion and to control the amount of uric acid in the body.

Hyperuricemia, gout, gouty arthritis, renal disorders and the like are known as diseases caused by the accumulation of uric acid in the body. Generally, if the blood uric acid level is maintained at 5 to 7 mg / dl,
Acute attacks of gout become milder, the nodules shrink, and renal damage due to renal retention of uric acid improves. For this purpose
A drug capable of controlling the blood uric acid level is desired, and for this purpose, a uric acid excretion enhancer which has a mild action and a long-lasting effect and which can be continuously used for a long period with few side effects is required.

By the way, dihydropyridine derivative (I)
Has a calcium channel antagonism and is already known to be useful as an antihypertensive agent, a peripheral and cerebral vasodilator, and a therapeutic agent for coronary arteries (a therapeutic agent for angina) (JP-A-63-63). 225356).

The present inventors have conducted various researches on this dihydropyridine derivative (I). As a result, the compound was further identified as a cerebral blood flow increasing agent (JP-A-2-62824) and a therapeutic agent for vasospasm (JP-A-2-62). -180826) and a cardiotonic drug (Japanese Patent Application No. 2-166093).

[0006] Further, as a result of intensive studies by the present inventors, the dihydropyridine derivative (I) has an unexpected action different from the above-mentioned action that has been found so far, that is, a uric acid excretion promoting action. It was also found to be useful as a uric acid excretion enhancer.

[0007] An object of the present invention is to provide a uric acid excretion enhancer which is palliative, persistent and has less side effects.

[0008]

DISCLOSURE OF THE INVENTION The present inventors have known that the dihydropyridine derivative having the following specific structure is known to be useful as an antihypertensive agent, a peripheral and cerebral vasodilator, a therapeutic agent for coronary arteries ( I) or its acid addition salt is
The present invention has been completed by finding that it has a stronger uric acid excretion promoting action in addition to the known action.

The uric acid excretion enhancer of the present invention has an active ingredient of the general formula:

[0010]

[Chemical 3]

[Wherein R ₁ , R ₂ and R ₃ are the same or different and are alkyl, cycloalkyl or alkoxyalkyl, and R ₄ and R ₅ are the same or different and are a hydrogen atom, halogen, nitro or halogenated alkyl, Alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio (provided that R ₄ and R ₅ are not hydrogen atoms at the same time), and X is a group represented by vinylene or azomethine. , A is alkylene, B is —N (R ₆ ) (R ₇ ), or

[0012]

[Chemical 4]

(R ₆ , R ₇ and R ₈ are the same or different and each is a hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl, Ar is aryl or pyridyl, and n is 0 or an integer of 1 or 2, respectively. Represents a group represented by])], and a dihydropyridine derivative represented by [hereinafter, referred to as dihydropyridine derivative (I)]
And acid addition salts thereof (usually, pharmacologically acceptable acid addition salts).

The dihydropyridine derivative (I) and its acid addition salt used in the present invention are particularly effective and highly safe because they have a particularly mild action expression and a long duration and their toxicity is extremely low. It has a great feature in that.

In the general formula (I), the alkyl represented by R ₁ , R ₂ and R ₃ may be linear or branched, and lower alkyl having 1 to 6 carbon atoms is particularly preferable, for example, methyl or ethyl. , Propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like, among which those having 1 to 4 carbon atoms are preferable. These alkyl may further have a lower cycloalkyl having 3 to 6 carbon atoms (for example, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, etc.) at the terminal.

The cycloalkyl represented by R ₁ , R ₂ and R ₃ is preferably lower cycloalkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. As the alkoxyalkyl represented by R ₁ , R ₂ and R ₃ , those having a total of 3 to 7 carbon atoms are preferable, and examples thereof include methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl and the like can be mentioned.

The substituents represented by R ₄ and R ₅ may be the same or different and may be substituted at any position on the ring, but especially at the 2-position with respect to the bonding position with the dihydropyridine ring. Or / and those at the 3rd position are preferred. As halogen in R ₄ and R ₅ , fluorine is used,
Each atom of chlorine, bromine and iodine is mentioned, a fluorine atom or a chlorine atom is particularly preferable, and as the alkyl or cycloalkyl, those exemplified as R _{1 to} R ₃ are preferable. The alkoxy and alkylthio are preferably those having a lower alkyl having 1 to 3 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy and methylthio, ethylthio, propylthio, isopropylthio. Examples of the alkoxycarbonyl include those having 2 to 4 carbon atoms such as methoxycarbonyl and ethoxycarbonyl. The halogen of the halide is also the same as above, and an alkyl halide is one in which some hydrogen atoms are halogenated [(CF ₃ ) ₂ CH
CH ₂ —, CF ₃ CH ₂ —, etc.], and all hydrogen atoms thereof are halogenated (trifluoromethyl etc.).
Further, the halogenated alkoxy may be one in which some hydrogen atoms are halogenated or all of the hydrogen atoms may be halogenated. The alkyl halide and the alkoxy halide each have 1 to 6, preferably 1 to 4 carbon atoms. As alkyl in alkylsulfonyl and alkylsulfinyl, R ₁ to
Examples of R ₃ include those having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms).

R ₄ is preferably cyano or an alkyl halide (particularly trifluoromethyl), and R ₅ is preferably a hydrogen atom.

R₆, R₇And R₈Archi indicated by
And R and cycloalkyl are as described above. ₁~ R₃Illustrated by
There are some. As aralkyl, benzyl,
α-phenylethyl, β-phenylethyl, γ-phenyl
Phenyl C such as rupropyl_1-3Alkyl is a
Examples of reels include phenyl and naphthyl.
These aromatic rings have the same or different substituents at arbitrary positions.
You may have. Examples of substituents on these aromatic rings
Is, for example, R_FourAnd R_FiveExamples of
You can As pyridyl, 2-pyridyl and 3-pyridy
And 4-pyridyl, which are the above-mentioned R_Four, R_Five
It may have a substituent exemplified as.

The alkylene represented by A is preferably a linear or branched one having 2 to 4 carbon atoms, specifically, ethylene, trimethylene, tetramethylene and 1,2-
Dimethyl ethylene and the like can be mentioned.

Examples of the aryl and pyridyl represented by Ar include those exemplified above for R ₆ , R ₇ and R ₈ and may have the same substituents. It is the 4-position substituent of dihydropyridine

[0022]

[Chemical 5]

As the ring represented by, when X is vinylene (-CH = CH-), a benzene ring is used, and azomethine (-C
H = N-) means pyridine respectively, and these may be bonded to the 4-position of dihydropyridine at any position thereof.

The substituents R ₄ and R ₅ are 4 of dihydropyridine.
It may be substituted at any of the ortho, meta, and para positions with respect to the carbon atom bonded to the position, preferably the ortho position or /
And substituted at the meta position.

Specific examples of the dihydropyridine derivative (I) and its acid addition salt include the compounds shown in Table 1 below and their acid addition salts.

[0026]

[Table 1]

The dihydropyridine derivative (I) and its acid addition salt are more preferably 2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl.
2,6-dimethyl-4- (3-nitrophenyl) -1,
4-dihydropyridine-3,5-dicarboxylate,
2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,6-dimethyl-4- (4-cyano-2-pyridyl) -1,4-dihydropyridine-
Examples include 3,5-dicarboxylate and acid addition salts thereof.

The dihydropyridine derivative (I) can be produced by subjecting an arbitrary portion and a remaining portion constituting the dihydropyridine derivative (I) to a method known per se, particularly a dehydration ring closure reaction.

Specifically, JP-A-63-107975, JP-A-63-112560 and JP-A-63-2.
25356, JP-A-58-201765,
JP-A-63-99042, JP-A-63-1523
It is manufactured using the manufacturing method described in Japanese Patent Application Laid-Open No. 51-260064.

The dihydropyridine derivative (I) thus produced can be collected in an arbitrary purity by appropriately using known separation and purification means such as concentration, extraction, chromatography, reprecipitation and recrystallization.

Since the dihydropyridine derivative (I) has a basic group, it can be converted into an acid addition salt by a known means. The salt is not particularly limited as long as it is pharmacologically acceptable, for example, a salt with an inorganic acid (hydrochloride, hydrobromide, phosphate, sulfate, etc.), a salt with an organic acid. (Acetate, succinate, maleate, fumarate, malate, tartrate) and the like.

[0032]

[Effects] The dihydropyridine derivative (I) and its acid addition salt, which are the active ingredients of the present invention, have extremely low toxicity and exhibit a mild effect in mammals (eg, mouse, rat, rabbit, dog, cat, human, etc.). A uric acid excretion promoting action with a long duration is observed.

Therefore, the dihydropyridine derivative (I) or its acid addition salt is useful for prevention and treatment of hyperuricemia, hyperuricuria, gout and the like. In addition, nephritis or nephropathy due to hyperuricemia (hyperuricemia nephropathy), that is, hyperuricemia-induced acute renal failure (acute uric acid nephropathy), hyperuric acid nephropathy (gouty kidney, chronic gouty It is also useful for the prevention and treatment of nephropathy, chronic interstitial nephritis, familial hyperuric acid nephropathy, etc. Therefore, it is also effective against various symptoms of these diseases, such as gouty nodules, gout attacks, gouty arthritis, and uric acid stones.

Its mechanism of action is to prevent reabsorption of uric acid from renal tubules and promote its excretion in urine. In the case of gout, it is considered to be effective in lowering blood uric acid and reducing uric acid deposited in joints.

When the dihydropyridine derivative (I) and its acid addition salt are used as the above-mentioned pharmaceuticals, pharmacologically acceptable additives (eg carrier, excipient, diluent, etc.)
Etc., and the like, can be orally or parenterally administered as a pharmaceutical composition in the form of powder, granules, tablets, capsules, syrups, injections, etc. An effective amount of dihydropyridine derivative (I) and its acid addition salt is incorporated in the above-mentioned preparation. The dose varies depending on the administration route, symptoms, patient weight or age, etc.
0.05-20 mg / kg body weight / day, especially 0.1-4 mg / kg
It is desirable to administer the body weight / day in divided doses of one to several times a day.

In the case of intravenous administration, 0.1-30
It is desirable to administer 0 μg / kg body weight / day, particularly 5 to 100 μg / kg body weight / day, divided into one to several times a day.

[0037]

[Experimental Examples / Examples / Reference Examples] Hereinafter, the present invention will be described in more detail with reference to Experimental Examples, Examples, and Reference Examples, but these Experimental Examples / Examples do not limit the present invention. Regarding ¹ H-NMR measurement, CDCl ₃ was used unless otherwise specified.

Experimental Example 1 The LD ₅₀ was determined using male mice of 10 to 11 weeks of age and a weight of 14 to 16 g (3 to 5 mice per group). The results were at least> 1100 mg / kg body weight and most compounds> 1400 mg / kg body weight.

Therefore, the dihydropyridine derivative and its acid addition salt used in the present invention have significantly higher acute toxicity values and higher safety than known compounds.

Experimental Example 2 The change in the uric acid concentration in the body when the dihydropyridine derivative (I) or its acid addition salt was orally administered to healthy adult males was examined. That is, the uric acid concentration in blood before and after administration of the compound was compared.

Test drug: Compound 2 (Reference Example) described below was formulated according to the description in Example 4, filled in a hard gelatin capsule, and prepared as a capsule.

Method: The following test was carried out by 3 to 6 persons per group. Study I (1 to 7): Seven test groups were prepared, and different doses of the test drug (0.25 to 16 mg) were administered once during fasting fasting, and the effects depending on the dose during fasting were compared. did. The test I-1 was carried out by one group of three people, and I-2 to 7 were carried out by one group of five people. Study II (1, 2): 16 mg of test drug by fasting fasting (II-1) and after eating (II-2) by weekly crossover method
Was administered once, and the effects of diet were observed. In addition,
The test was conducted by 6 people per group. Test III (1 to 4): 4 test groups (5 per group) were prepared, and different amounts of the test drug (4 to 32 mg) were administered once after meal, and the effect depends on the dose after meal. Were compared. Test IV: After the meal, 8 mg of the test drug was repeatedly administered for 7 days. The test was conducted by 6 people per group.

Blood was collected from the vein before administration of the test drug and one day after the administration, and the concentration of uric acid in the blood was measured using an enzymatic method. In the case of Study IV, blood was collected and measured the day after the final administration day.

The results are shown in Table 2. Each value is the average value of each group.

[0045]

[Table 2]

Experimental Example 3 The blood uric acid concentration before and after the administration of the test drug was measured in healthy adult male patients (who have a slightly high blood pressure tendency). A comparison was made between the case where the test drug was administered once after meal (8 mg) (test I) and the case where the test drug was repeatedly administered for 6 days (test II).

Blood was collected from the vein before administration of the test drug and one day after administration, and the concentration of uric acid in the blood was measured using an enzymatic method.

The results are shown in Table 3. Each value is the average value of each group.

[0049]

[Table 3]

Experimental Example 4 Uric acid and creatinine excretion in urine In Tests I and II carried out in Experimental Example 3 above, uric acid and creatinine concentrations in urine before and after administration of the test drug were measured, respectively. Examine the amount of uric acid and creatinine excreted,
The effect of the drug was investigated.

FIG. 1 shows the change in the amount of uric acid excreted in urine.

From the results shown in FIG. 1, a significant increase in the excretion amount of uric acid was observed after the administration of the dihydropyridine derivative of the present invention or its acid addition salt. On the other hand, as shown in FIG. 2, the creatinine excretion amount slightly increased, but no significant difference was observed. From this, it is suggested that the reason why the blood concentration of uric acid decreases after administration of the drug is not the inhibition of uric acid synthesis but the increase of uric acid excretion. That is, the drug is positioned as a uric acid excretion enhancer.

Reference Example 2- [p- (4-benzhydrylpiperazino) phenyl] ethylmethyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-di Synthesis of carboxylate (compound 1) and its hydrochloride salt (compound 2):

In a 100 ml round-bottomed flask, 3-nitrobenzaldehyde (1.144 g, 7.57 mmol) and acetoacetic acid [p- (4-benzhydrylpiperazino) phenyl] were added.
Ethyl (3.464 g, 7.59 mmol) and methyl 3-
Add aminocrotonate (873mg, 7.58mmol),
Isopropanol (12 ml) was added, a Dimroth condenser was attached, and the mixture was heated under reflux for 16 hours. The reaction solvent was distilled off under reduced pressure, and the residue was obtained by column chromatography [silica gel, chloroform: methanol (45: 1)] and column chromatography [silica gel, ethyl acetate: n-hexane (2: 3)]. Crude product
Purification by high performance liquid chromatography gave 2.503 g of the title compound 1 (yield 48%).

IR ν _max ^KBr cm ⁻¹ : 1680, 1520 ¹ H-NMR δ: 8.06 (1H, t, J = 2Hz), 7.97 (1H, ddd,
J = 8; 2; 1Hz), 7.1-7.6 (12H), 7.03 (2H, d, J = 8.6H
z), 6.80 (2H, d, J = 8.6Hz), 6.02 (1H, s), 5.07 (1H,
s), 4.26 (1H, s), 4.22 (2H, t, J = 7Hz), 3.64 (3H,
s), 3.15 (4H, dd, J = 5; 4.7Hz), 2.81 (2H, t, J = 7H
z), 2.55 (4H, dd, J = 5; 4.7Hz), 2.33, 2.28 (3H, s respectively)

This compound 1 (2.124 g, 3.16 mm
ol) was placed in a 200 ml eggplant flask and a septum rubber was attached. Methylene chloride (100 ml) was added to the flask, the contents were dissolved, and the mixture was stirred at room temperature for 30 minutes while introducing hydrogen chloride gas. The precipitated crystals were collected by filtration to give the title compound 2 (2.22 g).

IR ν _max ^KBr cm ⁻¹ : 2450, 1680, 1525,
1350. ¹ H-NMR δ: 13.72 (1H, brs), 8.05-7.9 (6H), 7.
82, 7.26 (4H, A ₂ B ₂・ q, J = 8.6Hz), 7.6-7.3 (8H), 6.
28 (1H, s), 5.2-5.05 (2H), 5.01 (2H, s), 4.27 (2H,
t, J = 6.5Hz), 4.3-4.1 (2H), 3.66 (3H, s), 3.65-3.4
5 (4H), 2.95 (2H, t, J = 6.5Hz), 2.36, 2.33 (3H, s respectively).

Example 1: Tablet (1) Compound 2 10 g (2) Fine granules for direct compression No. 209 (manufactured by Fuji Chemical Co., Ltd.) 110 g Magnesium aluminometasilicate 20% Corn starch 30% Lactose 50% (3) Crystalline cellulose 60g (4) CMC calcium 18g (5) Magnesium stearate 2g

(1), (3) and (4) are all 10
Pass through a 0 mesh screen. Each of (1), (3), (4) and (2) is dried to reduce the water content to a constant value, and then mixed in the above weight ratio using a mixer. (5) was added to the mixed powder which was made uniform in quality and mixed for a short time (30 seconds), and the mixed powder was tabletted to give 200 mg tablets.

If desired, the tablets may be coated with a gastric-soluble film coating agent (for example, polyvinyl acetal diethylaminoacetate) or an edible coloring agent which is usually used.

Example 2: Capsule (1) Compound 2 50 g (2) Lactose 930 g (3) Magnesium stearate 20 g The above ingredients were weighed and mixed uniformly, and a hard gelatin capsule was filled with 200 mg each. did.

Example 3: Injection (1) Compound 2 5 mg (2) Glucose 100 mg (3) Physiological saline 10 ml The above mixed solution was filtered through a membrane filter and then sterilized again, and the filtrate was sterilized. The mixture was dispensed into a vial, filled with nitrogen gas, and then sealed to give an intravenous injection.

Example 4 20.1 g of Compound 2 was mixed with unsaturated fatty acid monoglyceride (“Exel O-95R” manufactured by Kao Corporation) and polyoxyethylene sorbitan monooleate (“TO-10” manufactured by Nikko Chemical Co., Ltd.).
M ”) (1: 1) (650 g), dissolved at 40 ° C. and stirred to obtain a non-micelle type solution. 600 g of the solution thus obtained was mixed with 370 g of magnesium aluminometasilicate (“Neucillin US ₂ ” manufactured by Fuji Chemical Industry Co., Ltd.) with a stirring granulator. Furthermore, croscarmellose sodium A
30 g of the mold was mixed and stirred, and 250 ml of purified water was added for granulation. Then, dry at 40 ℃ for 17 hours in a ventilation dryer,
Sieve through 42-200 mesh, capsule filling fine particles 550
g was prepared.

[Brief description of drawings]

FIG. 1 is a graph showing changes in uric acid excretion in urine and effects thereof by administration of the dihydropyridine derivative of the present invention or an acid addition salt thereof.

FIG. 2 is a graph showing changes in the amount of creatinine excreted in urine by administration of the dihydropyridine derivative of the present invention or an acid addition salt thereof.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location // (C07D 401/04 211: 00 9165-4C 213: 00) 6701-4C

Claims (2)

[Claims] 1. A general formula: [Wherein R ₁ , R ₂ and R ₃ are the same or different and are alkyl, cycloalkyl or alkoxyalkyl,
R ₄ and R ₅ are the same or different and each represents a hydrogen atom, halogen, nitro, halogenated alkyl, alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio (provided that R ₄ And R ₅ are not simultaneously hydrogen atoms), X is a group represented by vinylene or azomethine, A is alkylene,
B is _{-N (R 6) (R 7} ) or ## STR2 ## (R ₆ , R ₇ and R ₈ are the same or different and each is a hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl, Ar is aryl or pyridyl,
n represents a group represented by 0 or an integer of 1 or 2, respectively)], and a uric acid excretion enhancer comprising a dihydropyridine derivative represented by the formula [3] or an acid addition salt thereof as an active ingredient. 2. R ₁ , R ₂ and R ₃ are the same or different alkyl, R ₄ is a hydrogen atom, R ₅ is nitro, halogenated alkyl or cyano, and R ₆ and R ₇ are the same or different alkyl and aralkyl. Or aryl, R ₈
Is aryl, Ar is aryl, and n is 1. The uric acid excretion enhancer according to claim 1.