JPH06183974A - Nephrotoxicity-reducing agent containing dihydropyridine compound - Google Patents

Abstract

PURPOSE:To prepare the subject agent containing a specific dihydropyridine compound (salt) and capable of reducing nephrotoxicity caused by administration of a medicine having immunosuppressive sction, e.g. tricyclo compound without exerting an undesirable influence upon onset of pharmacological action of the medicine. CONSTITUTION:This agent contains a dihydropyridine compound of the formula (R<24> is nitrophenyl; R<25> to R<27> are lower alkyl) [preferably 6-cyano-5- methoxycarboxyl-2-methl-4-(3nitrophenyly)-1,4-dihydropyridine-3-carbox ylic acid isopropyl ester] or its salt. The compound of the formula is usually administered by oral route, preferably in daily amount of 1-500mg. Effective does is perferbly selected in a range of 0.05 to 2 mg/kg body weight of patient.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nephrotoxicity-reducing agent based on a nephrotoxicity-reducing action which is a pharmacological action first discovered for a dihydropyridine compound represented by the following general formula (1).

[0002]

Dihydropyridine compounds (1) used in the present invention

[0003]

[Chemical 3]

[Wherein R ²⁴ is nitrophenyl, R ²⁵ and R ²⁶
And R ²⁷ each are the same or different and mean lower alkyl] is a compound already described in British Patent No. 2,036,722, and with regard to its pharmacological action,
It was found to be useful as a therapeutic agent for angina pectoris or antihypertensive agent based on Ca ²⁺ antagonism, or as an antiarteriosclerotic agent, and a patent application has already been filed by the present applicant (JP-A-61-61). No. 155327). Also, the applicant of the present application has already applied for a patent as a drug exhibiting an effect of improving venous distensibility and an effect of suppressing cardiac hypertrophy, or as a drug having a cerebral nerve cell protective effect (the former is JP-A 1-250320, The latter is disclosed in JP-A-2-62825.
issue).

[0005]

OBJECT OF THE INVENTION The present invention is intended to provide a new nephrotoxicity-reducing agent on the basis of the nephrotoxicity-reducing action which is the first pharmacological action found for the dihydropyridine compound (1).

[0006]

The dihydropyridine compound (1) or a salt thereof has various pharmacological actions as described above, but the nephrotoxicity-reducing action is a completely novel pharmacological action found by the study of the present inventors. It is an action.

This action of reducing renal toxicity is effective against various types of nephrotoxicity caused by these substances, regardless of the causative substances such as foods and drinks, pharmaceuticals or natural toxic substances. It has been confirmed that it can be used therapeutically or prophylactically.
Therefore, the below-mentioned tricyclo compound (2) described below
The description on the reduction of nephrotoxicity based on the above is merely the description of the tricyclo compound (2) as a representative example, and the application of the present invention should not be construed to be limited by this description. . The tricyclo compound (2) taken for representative explanation is represented by the following general formula.

[0008]

[Chemical 4]

(Wherein each adjacent pair of "R ¹ and R ² ", "R ³ and R ⁴ ", "R ⁵ and R ⁶ " is independently a) a) two adjacent hydrogens Represents an atom, or b) forms another bond with the carbon atom to which it is bonded, but in addition R ² may be an alkyl group, R ⁷ is a hydrogen atom, May represent a hydroxy group, a protected hydroxy group, or an alkyloxy group, or may represent together with R ¹ an oxo group,
R ⁸ and R ⁹ are independently a hydrogen atom, a hydroxy group, R ¹⁰ is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, and one or more hydroxy groups. An alkenyl group or an alkyl group substituted by an oxo group, X is an oxo group, (a pair of hydrogen atom and hydroxy group), (a pair of hydrogen atom and hydrogen atom), or a group represented by the formula —CH ₂ O—. Where Y is an oxo group, (a pair of hydrogen atom and hydroxy group), (a pair of hydrogen atom and hydrogen atom), or a formula = NN
R ¹¹ R ¹² or a group represented by ═N—OR ¹³ is represented by R ¹¹
And R ¹² independently represents a hydrogen atom, an alkyl group, an aryl group, or a tosyl group, and R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ ,
R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²² and R ²³ are independently a hydrogen atom or an alkyl group, R ²⁰ and R ²¹ are independently an oxo group, or each independently (R ²⁰ _a , a hydrogen atom) And a pair of (R ²¹ _a , hydrogen atom), R ²⁰ _a and R ²¹ _a are independently a hydroxy group, an alkyloxy group, or a group of the formula —OCH ₂ OCH ₂ CH ₂ OCH _3. Or R ²¹ _a represents _a protected hydroxy group, R ²⁰ _a and R ²¹ _a may together represent an oxygen atom in the epoxide ring, and n is 1, 2 or Represents 3.

In addition to the above meaning, Y, R ¹⁰ and R ²³ together with the carbon atom to which they are attached are a nitrogen atom, a sulfur atom or a nitrogen atom consisting of a saturated or unsaturated 5- or 6-membered ring. Although it may represent a heterocyclic group containing an oxygen atom, the heterocyclic group may be an alkyl group, a hydroxy group, an alkyl group substituted by one or more hydroxy groups, an alkyloxy group, a benzyl group and a formula-
This tricyclo compound (1) or a pharmaceutically acceptable salt thereof may be substituted with one or more groups selected from the group represented by CH ₂ Se (C ₆ H ₅ ). Known (Japanese Patent Laid-Open No. 61-148181, European Patent Publication No. 03
23042), and is expected to be used in various medical fields such as organ transplantation.

Each definition used in the above general formula (2), specific examples thereof, and preferred embodiments thereof will be described in detail below. Unless otherwise specified, the term "lower" used in the description of the symbols used in the above general formula (2) and the description given below has 1 carbon atom.
It means that it is ~ 6 pieces.

Preferred examples of the "alkyl group" include straight chain or branched chain aliphatic hydrocarbon residues, for example, lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl. Groups.

Preferred examples of "alkenyl group" include:
Included are straight or branched chain aliphatic hydrocarbon residues containing one double bond, such as vinyl, propenyl,
Lower alkenyl groups such as butenyl, methylpropenyl, pentenyl, hexenyl and the like can be mentioned.

Preferred examples of "aryl group" include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like.

Preferred in "protected hydroxy group"
Examples of protective groups include methylthiomethyl, ethyl
Thiomethyl, propylthiomethyl, isopropylthiome
Tyl, butylthiomethyl, isobutylthiomethyl, hex
Such as lower alkylthiomethyl groups such as silthiomethyl
1- (lower alkylthio) (lower) alkyl group, further
C as preferred₁ ~ C_Four An alkylthiomethyl group,
Most preferred is a methylthiomethyl group; for example
Trimethylsilyl, triethylsilyl, tributylsilyl
, Tertiary butyl-dimethylsilyl, tri tertiary butyl
Tri (lower) alkylsilyl such as silyl, eg methyl
Ru-diphenylsilyl, ethyl-diphenylsilyl,
Ropyl-diphenylsilyl, tert-butyl-diphenyl
Lower alkyl-diaryl such as silyl etc.
Tri-substituted silyl groups, more preferably tri (C
₁ ~ C_Four ) Alkylsilyl groups and C₁ ~ C_Four Alkyl
Diphenylsilyl group, most preferably tertiary
Cyl-dimethylsilyl group and tertiary butyl-dipheny
Rusilyl group; carboxylic acid, sulfonic acid and carbamine
Acid-derived aliphatic acyl groups, aromatic acyl groups and
And an acyl such as an aliphatic acyl group substituted with an aromatic group
Group; and the like.

Suitable aliphatic acyl groups are carboxy such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl. A lower alkanoyl group optionally having one or more substituents, for example, cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentayl. Noyl, menthyloxyhexanoyl, etc., cyclo (lower) alkoxy (lower) alkanoyl groups optionally having one or more suitable substituents such as lower alkyl, cane Asuruhoniru groups, for example carboxy-methylcarbamoyl, carboxy ethylcarbamoyl, carboxymethyl propylcarbamoyl, carboxymethyl butylcarbamoyl, carboxymethyl pentylcarbamoyl,
Carboxy (lower) alkylcarbamoyl groups such as carboxyhexylcarbamoyl, or for example trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylsilylcarbonylcarbonylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl. Groups such as tri (lower) alkylsilyl (lower) alkoxycarbonyl (lower) alkylcarbamoyl groups, protected carboxy (lower) alkylcarbamoyl groups, etc., or suitable substituents such as protected carboxy, etc. Examples thereof include a lower alkylcarbamoyl group having one or more.

As the aromatic acyl group, for example, benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc., aroyl optionally having one or more suitable substituents such as nitro. A group such as benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.
The arene sulfonyl group which may have one or more groups and the like can be mentioned.

Examples of the aliphatic acyl group substituted with an aromatic group include phenylacetyl, phenylpropionyl, phenylbutyryl and 2-trifluoromethyl-2-.
Such as lower alkoxy and trihalo (lower) alkyl, such as methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenylacetyl, etc. Examples thereof include an ar (lower) alkanoyl group which may have one or more suitable substituents.

Among the above-mentioned acyl groups, more preferable acyl groups are C ₁ -C ₄ alkanoyl groups optionally having carboxy, and cyclo (C ₁ -C ₄ ) alkyl having two (C ₁ -C ₄ ) alkyl in the cycloalkyl moiety. _{5 to} C ₆ ) alkyloxy (C _{1 to} C ₄ ) alkanoyl group, camphorsulfonyl group, carboxy (C _{1 to} C ₄ ) alkylcarbamoyl group, tri (C _{1 to} C ₄ ) alkylsilyl (C _{1 to} C ₄ ).
Alkoxycarbonyl (C ₁ -C ₄ ) alkylcarbamoyl group, benzoyl group optionally having 1 or 2 nitro groups, benzenesulfonyl group having halogen,
Examples thereof include a phenyl (C ₁ -C ₄ ) alkanoyl group having C ₁ -C ₄ alkoxy and trihalo (C ₁ -C ₄ ) alkyl, among which the most preferable ones are acetyl, carboxypropionyl and menthyloxyacetyl. , Camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-
Examples include phenylacetyl.

"A nitrogen atom consisting of a 5- or 6-membered ring,
Preferred examples of the “heterocyclic group containing a sulfur atom or an oxygen atom” include a pyrrolyl group and a tetrahydrofuryl group.

The pharmaceutically acceptable salt of the compound (2) is a non-toxic pharmaceutically acceptable conventional salt, for example, an alkali metal salt such as sodium salt, potassium salt, etc., such as calcium salt, magnesium salt, etc. Alkaline earth metal salts, ammonium salts, salts with inorganic or organic bases such as amine salts such as triethylamine salts, N-benzyl-N-methylamine salts and the like.

In compound (2), there may exist one or more pairs of stereoisomers such as optical isomers and geometrical isomers due to conformers or asymmetric carbon atoms and double bonds. It is known that the conformer or isomer also has the excellent immunosuppressive action as described above.

The most typical compound of the compound (2) is the compound represented by the general formula (2), wherein R ¹ , R ² , R ⁸ , R ²³ = hydrogen R ⁷ , R ⁹ = hydroxy group R ¹⁰ = aryl group R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²² = methyl group R ²⁰ = R ²⁰ _a , H (R ²⁰ _a = methoxy group) R ²¹ = R ²¹ _a , H (R ²¹ _a = Hydroxy group) X, Y = oxygen n = 2 R ³ , R ⁴ = another bond with the carbon atom to which it is attached R ⁵ , R ⁶ = another bond with the carbon atom to which it is attached One bond A compound represented by a solid line and a dotted line = single bond and in a free state was selected. This compound is expected as a particularly excellent immunosuppressive substance, and is referred to as FK506 in the following description.

FK506 is known as a substance having an immunosuppressive action as described above, and its remarkable effect has been clinically confirmed in the field of organ transplantation. For example, heart, liver, kidney, bone marrow, skin, cornea, lung, pancreas, small intestine, muscle,
It is expected to be used for organ transplantation of nerves, extremities, etc., and other medical fields.

Although FK506 has the excellent pharmacological action as described above, it is unavoidable to encounter the problem of side effects, which is a common idea of pharmaceuticals, in actual clinical application.
Nephrotoxicity is considered to be a typical side effect thereof, and the usefulness of the present invention is expected also here.

As the nitrophenyl represented by R ²⁴ in the dihydropyridine compound (1) used as the active ingredient in the nephrotoxicity reducing agent of the present invention, 2-nitrophenyl, 3-nitrophenyl and 4-nitrophenyl are shown. Of these, particularly preferred is 3-nitrophenyl. The lower alkyl for R ²⁵ , R ²⁶ and R ²⁷ includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, hexyl and the like. Include alkyl having 1 to 6 carbons, among which alkyl having 1 to 4 carbons is preferable, isopropyl is the most preferable example of R ²⁵ , and the most preferable example of R ²⁶ and R ²⁷ is Methyl is mentioned. Therefore, in the following description, a compound in which R ²⁴ is 3-nitrophenyl, R ²⁵ is isopropyl, and R ²⁶ and R ²⁷ are each methyl [chemical name: 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate isopropyl, hereinafter referred to as nilvadipine] will be representatively described. However, this description is merely described by taking nilvadipine as a typical example, and the scope of application of the present invention should not be construed in a restrictive manner by this description.

Similar dihydropyridine compounds other than the dihydropyridine compound represented by the above general formula (1) can be expected to have similar nephrotoxicity reducing effects. Examples of such dihydropyridine compounds include amlodipine, benidipine, felodipine, isradipine, lacidipine, Manidipine, Nicardipine,
Examples include nifedipine, nimodipine, nisoldipine, nitrendipine, dalodipine, masnidipine, oxodipine, paronidipine, pranidipine and the like.

Examples of pharmaceutically acceptable salts of the dihydropyridine compound represented by the formula (1) include acetate, trifluoroacetate, maleate, tartrate,
Methane sulfonate, benzene sulfonate, formate,
Organic acid addition salts such as toluene sulfonate; inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; acidity such as aspartate and glutamate A salt with an amino acid;

When FK506 was intramuscularly administered to spontaneously hypertensive rats for 2 weeks, an increase in blood urea nitrogen and serum creatinine and a decrease in creatinine clearance were observed, and these trends were dose-dependent. Then, according to the microscopic findings of the renal tissue of the rat having such a renal disorder, luminal stenosis was observed in the small arteries near the glomerulus. Taken together with these results, it is understood that acute renal toxicity caused by FK506 appears as systemic sphere dysfunction mediated by contraction of renal arterioles.

However, FK50 which causes renal damage in this way
When nilvadipine was co-administered to 6 and follow-up observation of changes in renal function, it was found that all of the above-mentioned renal dysfunction parameters (blood urea nitrogen, serum creatinine, creatinine clearance) were improved. It was also confirmed morphologically that the lumen stenosis of renal arterioles was completely resolved.

As a result of the above, nirvadipine had FK506.
It was confirmed that the drug has a preventive pharmacological action against nephrotoxicity. Moreover, it should be noted that the plasma concentration was sufficiently maintained even when FK506 was administered alone, and
It was confirmed that there was no effect on the immunosuppressive action, which is a characteristic of 06.

As described above, the nilvadipine of the present invention is FK5.
It was confirmed that the drug exerts a preventive effect on the nephrotoxicity caused by 06 without exerting any adverse effect on the expression of the original pharmacological action of FK506, but other drugs, foods and drinks, and natural products It effectively acts on renal toxicity caused by substances and the like, particularly on renal toxicity mediated by narrowing of renal arterioles.

The nephrotoxicity reducing agent of the present invention can be applied to mammals including humans in capsules, microcapsules, tablets, granules, powders, troches, pills, ointments, suppositories, injections, syrups. Orally or parenterally in the form of a conventional pharmaceutical preparation such as

The agent for reducing nephrotoxicity of the present invention is an excipient such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate; for example, cellulose, methyl cellulose, hydroxymethyl cellulose, Binders such as polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose and starch; disintegrants such as starch, carboxymethyl cellulose, hydroxypropyl starch, sodium hydrogen carbonate, calcium phosphate, calcium citrate; magnesium stearate Lubricants such as Aerosil, talc and sodium lauryl sulfate; Flavoring agents such as citric acid, menthol, glycine and orange powder; eg sodium benzoate, sodium bisulfite , Preservatives such as methylparaben, propylparaben; stabilizers such as citric acid, sodium citrate, acetic acid; suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminum stearate; dispersants such as hydroxypropylmethylcellulose; A diluent such as water; for example cocoa butter,
It can be produced by a conventional method using various organic or inorganic carriers commonly used in formulation techniques such as white petrolatum, base waxes such as polyethylene glycol; and the like.

The dose of the dihydropyridine compound (1) depends on the body weight and / or age of the patient, and / or whether the purpose is to prevent the onset of nephrotoxicity or to treat the nephrotoxicity that has already occurred. In the case of a substance that is expected to cause nephrotoxicity and its dose and administration period, in the latter case, it depends on various factors such as the degree of progress of nephrotoxicity and the means of administration. The daily dose is 0.5 to 1000 mg, preferably 1 to 500 mg. Effective single dose is 0.01 ~ / kg of patient's body weight.
It is selected in the range of 20 mg, preferably in the range of 0.05-2 mg.

[0036]

In order to show the usefulness of the dihydropyridine compound (1) or the pharmaceutically acceptable salt thereof used in the nephrotoxicity reducing agent of the present invention, the pharmacological test data of this compound (1) are shown below. .

[ Test compound ] Nilvadipine [ Test method ] (1) Target animal: body weight 254 to 326 g, blood pressure 161 to 208 mmHg
11-week-old spontaneously hypertensive rat [spontaneously hypert
expensive rat: SHR (Charles River Japan) below was used. Rats should be kept in 2-3 cages,
Standard chow diet CA-1 (CLEA Japan, Inc.) was given ad libitum except when collecting urine. As drinking water, tap water containing 2 ppm of free chlorine was freely given.

(2) Drug to be administered FK506 The intramuscular preparation (Fujisawa Pharmaceutical Co., Ltd.) is diluted with physiological saline,
Each dose of FK506 or its placebo preparation was administered at 1 ml / kg once a day for 14 days into rat limb thigh muscle. Nilvadipine (Fujisawa Pharmaceutical Co., Ltd.) was suspended in physiological saline, and each dose was subcutaneously administered twice a day (immediately before administration of FK506 and 4 to 5 hours after that).

(3) Experimental Protocol In all experiments, 7 male SHRs per group were used, and an untreated group and an FK506 placebo administration group were placed in each group. In Experiment 1, 1,2,4 mg / kg of FK506 was investigated in order to investigate the nephrotoxicity profile of FK506 in SHR.
/ Day was administered intramuscularly for 14 days. Experiment 2 was conducted to examine the detoxifying effect of nilvadipine on FK506 nephrotoxicity. In this experiment, FK506 and nilvadipine combination treatment groups were set up. That is, 4 mg / kg of FK506 was intramuscularly administered once a day for 14 days, and the doses of nilvadipine 0.1, 0.5 and
1.0 mg / kg / day was subcutaneously administered twice a day in divided doses.

(4) Urine test After the final administration, the rat was placed in a metabolic cage and urine was collected for 24 hours. No food was provided during urine collection, but water was allowed ad libitum. The urine volume, NAG activity and creatinine volume of the collected urine were measured. The NAG activity and the amount of creatinine were both measured by a colorimetric method (NAG test kit: Shionogi, CRE-EN Kainos kit: Kainos).

(5) On the day after the last administration of biochemistry (after the completion of urine collection), blood was collected from the rat abdominal aorta under anesthesia with ether, and serum creatinine (S-Cr), blood urea nitrogen (BUN) and Na were collected. And K
Was measured by Hitachi 7150 Autoanalyzer. Creatinine clearance (CCr) was calculated from the amount of creatinine in urine from the urinalysis and the level of creatinine in serum. Separately, the FK506 level in whole blood was
It was measured by the EIA method using the FK506 antibody.

(6) To produce antibodies against sheep red blood cells
In order to investigate the immunosuppressive activity of FK506, 2 × 10 ⁹ Sheep Red Blood cells (SRBC) suspended in physiological saline was added to the rat tail vein the day before the first administration of FK506. It was administered from The agglutinating antibody titer was measured by the hemagglutinitakatsui microtechnique using the serum of the preceding paragraph. The antibody titer was represented by the log with the base being 2, which is the maximum dilution factor of the serum that causes SRBC aggregation.

(7) Histopathological Examination Immediately after removing the kidney extracted from the rat after blood collection, 10
% Solution. After embedding in paraffin, 3 μm thick sections were prepared, stained with hematoxylin and eosin, and examined microscopically. (8) Statistical significant difference test The significant difference between the control group and the treatment group is the Student's t.
It was tested by the test method.

[Test Results] (1) Prophylaxis of FK506 nephrotoxicity in spontaneously hypertensive rats
Intramuscular administration of FK506 to Phil SHR is BUN, S-Cr
And showed nephrotoxicity findings characterized by elevated CCr and decreased CCr. That is, all these parameters are FK5
A dose-dependent change of 06, which is a high dose of F
BUN or S-Cr level of K506 4 mg / kg was 2.37 times or 1.76 times that of placebo group, respectively.
Doubled.

The CCr value of this group is 6 for the placebo group.
A very low value of 0% was shown. Apart from this, FK506
Had no effect on urine volume, serum Na, K ^+, and urinary NAG activity, which is an indicator of proximal tubular injury (Table 1).

Histopathologically, basophilization of the renal tubules and luminal stricture of arterioles near the glomerulus were observed in the kidneys of the FK506-treated group, and the frequency of these occurrences depended on the dose of FK506. Increased.

FK506 1, which showed such nephrotoxicity
Plasma concentrations of FK506 in the 2 and 4 mg / kg groups were 16.2,
30.1 and 41.0 ng / ml. Further, in the FK506-treated group, antibody production of SRBC, which is a T cell-dependent antigen, was clearly suppressed (Table 1).

[0048]

[Table 1]

(2) Nitrotoxicity induced by FK506
Effect of luvadipine FK506 4 mg / kg / day showed nephrotoxicity characterized by elevated BUN, S-Cr and decreased CCr, but when nilvadipine 0.1, 0.5 and 1 mg / kg / day were co-administered, Nilvadipine improved renal toxicity in these parameters (Table 2). That is, nilvadipine is FK5
The 06-induced increase in BUN and S-Cr was dose-dependently decreased, and the S-Cr level of 1 mg / kg nilvadipine was almost the same as that of the placebo group.

With the improvement of S-Cr, nilvadipine was converted to C
Cr was increased in a dose-dependent manner, and 1 mg / kg nilvadipine completely restored the decrease in CCr caused by FK506.

Although nilvadipine has been shown to have a diuretic effect in SHR, urine volume also tended to increase in a dose-dependent manner even in the nilvadipine combination group in this test. This result paralleled the increase in CCr by nilvadipine.

On the other hand, FK506 leads to basophilization of renal tubules and luminal narrowing of arterioles in the vicinity of glomeruli, but nilvadipine 0.5 and 1 mg / kg / day hardly showed these findings. In particular, luminal stenosis of arterioles was absent in both groups, and arterioles in all animals in these groups were normal. However, these findings remained in the 0.1 mg / kg / day nilvadipine group.

Considering these results, in particular, FK50
The findings in 6 arterioles and that in the nilvadipine combination group suggest that the decrease in CCr by FK506 was mediated by renal vascular changes.

Also in this experiment, the anti-SRBC antibody titer and the FK506 plasma concentration were measured from the blood of the animals after administration for 14 days. The decrease in anti-SRBC antibody titer due to FK506 is maintained even by the combined use of nilvadipine,
It was confirmed that nilvadipine does not affect the immunosuppressive activity of FK506. Furthermore, the FK506 plasma concentration results showed that nilvadipine did not affect the blood concentration of FK506 (Table 2).

[0055]

[Table 2]

[0056]

【Example】

Example 1 Dihydropyridine compound A 100 g Hydroxypropylmethylcellulose 500 g Dihydropyridine compound A is dissolved in absolute ethanol (5 liters), and hydroxypropylmethylcellulose is added to this solution to prepare a suspension. Then, the organic solvent is removed under reduced pressure to obtain a solid dispersion composition.

Example 2 Dihydropyridine compound A 100 g Hydroxypropylmethylcellulose 500 g Sucrose 9.4 kg Sucrose is added to a suspension of dihydropyridine compound A and hydroxypropylmethylcellulose in absolute ethanol (5 l) and the resulting mixture is stirred.
Then, the organic solvent is removed under reduced pressure to obtain a solid dispersion composition. This composition is made into a fine granule by a conventional method.

Example 3 Dihydropyridine Compound A 100 g Hydroxypropylmethylcellulose 500 g Lactose 6.87 Kg Lower-substituted hydroxypropylcellulose 1.5 kg Magnesium stearate 30 g Dihydropyridine Compound A and hydroxypropylmethylcellulose were suspended in anhydrous ethanol (5 liters) and lactose and Lower substituted hydroxypropyl cellulose is added, the resulting mixture is stirred and then the organic solvent is removed under reduced pressure to give a solid dispersion composition. This composition is made into granules by a conventional method, magnesium stearate is added thereto, and tablets are formed by a conventional method. This tablet contains 2 mg of dihydropyridine compound A in one tablet.

Example 4 Each tablet obtained in Example 3 was treated with hydroxypropylmethylcellulose (5.1 mg), titanium dioxide (1.6 mg), polyethylene glycol 6000 (0.8 mg), talc (0.4 mg),
Film coating with a coating layer of yellow iron oxide (0.1 mg) is carried out by a conventional method to give a film-coated tablet containing 2 mg of dihydropyridine compound A in one tablet.

Claims (3)

[Claims] 1. A compound represented by the general formula (1): [Wherein R ²⁴ is nitrophenyl and R ²⁵ , R ²⁶ and R ²⁷ are the same or different and each is lower alkyl], or a pharmaceutically acceptable salt thereof. Nephrotoxicity reducing agent. 2. The dihydropyridine compound is isopropyl 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate as claimed in claim 1. Nephrotoxicity reducing agent. 3. A compound represented by the general formula (2): (Wherein “R ¹ and R ² ”, “R ³ and R ⁴ ”,
Each adjacent pair of “R ⁵ and R ⁶ ” independently represents a) two adjacent hydrogen atoms, or b) another bond between the carbon atoms to which they are attached. In addition to that, R ² may be an alkyl group, R ⁷ represents a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkyloxy group, or R ¹
May together represent an oxo group, R ⁸ and R ⁹ are independently a hydrogen atom or a hydroxy group, R ¹⁰ is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, An alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group, X is an oxo group, (a hydrogen atom, a hydroxy group), (a hydrogen atom, a hydrogen atom pair) Or a group represented by the formula —CH ₂ O—, Y is an oxo group, (a pair of hydrogen atom and hydroxy group), (a pair of hydrogen atom and hydrogen atom), or a group of the formula ═N—NR ¹¹ R ¹² or In the group represented by N-OR ¹³ , R ¹¹ and R ¹² independently represent a hydrogen atom, an alkyl group, an aryl group, or a tosyl group, and R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ^19, R ²² Hoyo The R ²³ is independently a hydrogen atom or an alkyl group, R ²⁰ and R ²¹ are oxo group independently or each independently, (R ²⁰ _a, hydrogen atom) pairs, and (R ²¹ _a, hydrogen atom) R ²⁰ _a and R ²¹ _a are independently a hydroxy group, an alkyloxy group, or a group of the formula —O.
A group represented by CH ₂ OCH ₂ CH ₂ OCH ₃ , or R ²¹ _a represents _a protected hydroxy group, and further R ²⁰
_a and R ²¹ _a may together represent an oxygen atom in the epoxide ring, and n represents 1, 2 or 3. In addition to the above meanings, Y, R ¹⁰ and R ²³ together with the carbon atom to which they are attached are a nitrogen atom, a sulfur atom or an oxygen atom consisting of a saturated or unsaturated 5- or 6-membered ring. It may represent the heterocyclic group contained, but the heterocyclic group may be an alkyl group, a hydroxy group, an alkyl group substituted by one or more hydroxy groups, an alkyloxy group, a benzyl group and a formula —CH ₂ Se ( C ₆ H ₅ ), which reduces the nephrotoxicity resulting from the use of the tricyclo compound represented by (which may be substituted by one or more groups selected from the group represented by C ₆ H ₅ ) or a pharmaceutically acceptable salt thereof. The nephrotoxicity reducing agent according to claim 1 or 2.