WO2006107059A1 - Medicine for renal perfusion disorder - Google Patents

Abstract

A pharmaceutical that is useful for the prevention and/or treatment of renal impairments, such as nephritis and renal insufficiency. There is provided a medicine for renal perfusion disorder characterized by containing, as an active ingredient, any of dihydropyridine compounds of the general formula: (1) [wherein R1 and R2, identical with or different from each other, represent a hydrogen atom, nitro or a chlorine atom; R3 represents a hydrogen atom, a chlorine atom or a fluorine atom; and n is an integer of 6 to 8] or an optical isomer thereof.

Description

 Meisho's book for renal perfusion disorder

• Technical field ': ·············: The present invention is an organ disorder containing a dihydropyridine compound having an antagonistic action of calcium nocalmodulin (Ca ²⁺ / CaM) as an active ingredient, especially For the prevention and / or treatment of fl dysfunction such as nephritis and renal failure. Vegetables and; ': It relates to drugs for dialysis complications. ';': '' Background technology · ·, ■ ·

'Vasodilators are used for the treatment of hypertension including renal hypertension, essential hypertension and angina pectoris, etc. depending on their action selectivity. • There are no indications for the prevention and treatment of disability and dialysis complications; '' ·: '.

'' Currently sold by dihydr Ppyridines 'calcium antagonists, eg, .Fuji.pin,.; Ϋ: Torevibizi .. ^ Canorespi, 2. / Levazipine., Nidipine, am'

.. ': · Mouth' Ji ° ',' Sat Ho: Jihi. And tezenil: 'Dipine: Dou ,.' 'Has potent vasodilatory action with carminum antagonism as a pharmacological mechanism of action. These strength lucium antagonists have been developed and widely used for hypertension and angina, etc., based on vascular action selectivity and organ selectivity.

'Nika に お developed in Japan. Was first marketed as a cerebral circulation metabolism-improving drug (19: 8.1) and then as a hypotensive drug (1982). Antihypertensive (J ^: dirubadipine: (, ΐ 9 ^{8 9} 'released) .. is an improvement of cerebral circulation metabolism by adding indications. Koyoru's second circulatory cycle in 1999. Re-generation of ffe .. The indications for ritual fc oi 変 changed to essential hyperemia. It was changed. In this way, commercially available dihydride pyrimidine-based calcium antagonists are drugs for the prevention and treatment of brain 'stroke, cerebral infarction, brain float JS', and / or various types of drugs. '"·''Kidneydisorders,' dialysis complications. Treatment of sickness associated with illness:: as a drug for prevention .: floor ffl not approved. ■ ... '·:;.. · ····: · ·'..

'.:,. W study of commercially available calcium antagonists for kidney injury fc. 1999), Tatsuo Saruta: Cardiology Vol. 37 379-383 (.1 ⁹ 9 ⁵ ) Satoshi Yamada et al. :: Therapeutics Vol, ³ 2 20 ^{2 2} 10. ( _: 1 " ⁸ ), ^ Rujipi Vol.52 561—568 (2000), Yue W. et-al., Hypertension Resear ch Vol. 24 429-436 (2001)), Ehonidipine (Yokoyanja T. et al,. Journal _: 'of Cardiovascular Pharmacology Vol.19 851-856 (1992)., Shudo C. et al., General Pharmacology Vol.25 1451 -1458. (1994)), Nitoren Dipin (Journal of Cardiovascular Pharmacology Vol.9 S57-S59 (1987). (2004);), etc., however, That prevention methods, 'Hoyo

. Or treatment, 'and: at doses that have little effect on blood pressure. .. against kidney disease such as nephritis and all renal nephropathy and pathological conditions such as fracture complications' :: Ru ^: Di .: The Rn pyridine proposal is not known. ': ······.':.:. ·: ....: · .:

In recent years, there has been an excessive production of radiant power / reactivity, such as reactive oxygen species, nitric oxide (NO) '. For example, carbonyl stressor, major organs, for example, '.brain,': Koma, .. gastrointestinal tract.:-· Onset and progression of various pathologies in kidney, etc., tissue protein degeneration and dysfunction Yo ... It is clear that fc is involved, such as death. .. .. Ichi ': Dihydr: The research on the antioxidant ability of pyrinic calcium antagonists

.Zimmerman JJ- '· e't' al,-., Bi'ocheinical Pharmacology Vol.38 3601 ÷ -36 10 (1989), Janero DR et al., Biochemical Pharmacology Vol. 38 434 4-4348 (1989), Ro jstaczer. N. et al., Biochemical Pharmacology Vol. 51 141-150 (1989), Mak IT et al. , Circulation Research Vol. 70 10 99-1103 (1992), Lupo E. et al., Biochemical and Biophygical Research Communications Vol. 203 1803-1808 (1994), Sugawara H. et al, Hype rtension Research Vol. 19 223 -228 (1998), Mason RP et al., Journa 1 of Molecular and Cellular Cardiology Vol. 31 275-281 (1999), Yao K. et al., Biological Pharmaceutical Bulletin Vol. 23 766-769 (2000), Cominacini L. et al., Biochemical and Biophygical Research Communications Vol. 302 679-684 (2003)) are known. For example, Matucci R. et al., The British Journal of Pharmacology Vol. 122 1353-1360 (1997), which measured the antioxidant activity of dihydropyridine calcium antagonists using electron spin resonance (ESR). Fujii H. et al., Magnetic Resonance in Medicine Vol. 42 691-674 (1999).

The antioxidant activity of known dihydropyridine calcium antagonists measured using ESR is based on the calcium antagonism of each drug (Yousif FB et al., The Canadian Journal of Physiology and Pharmacology Vol. 64 27 3- 283 (1986), Mason M. et al., The Journal of Pharmacology and Experimental Therapeutics Vol. 275 1157-1166 (1995)). Currently, in the sales of dihydropyridine calcium antagonists, the prevention of kidney diseases such as renal diseases such as nephritis and renal failure, dialysis complications, etc. Or no drug is known to be effective for treatment. Disclosure of the Invention '' In recent years, with the progress of research in basic medicine, various radicals such as reactive oxygen species, nitric oxide (NO) and metabolism of these in vivo are .. Warabeyo to the maintenance of 'also has (^ all roles; not ^a,': t> to the time over剩産produced a field Ordinance,酵化stress to the tissue Oh ^:: Rui work Te carbonyl stress and Les' · For example: Involvement in organ disorders such as: onset and development of various pathologies in major organs such as: sputum, 'heart, gastrointestinal tract, kidney, etc., tissue protein degeneration and dysfunction and cell death Oxidative stress is also known to occur in organ transplants, i.e. only imaginary disorders that occur in the explanted organ. In other words, ¾r such as ischemia-reperfusion injury caused by blood reopening after organ transplantation can be mentioned.

、 腎血管血栓症など） 、 尿細管 ·間質性疾患 （腎盂腎炎、 間質性腎炎） 、 全身疾患に伴う腎疾患 （糖尿病性腎症、 アミロイドドーシス、 痛風腎、 肝 疾患に伴う腎障害、 溶血性尿毒症症候群、 紫斑病性腎炎、 膠原病に伴う腎 障害） 、 腎不全 （急性腎不全、 慢性腎不全） などがある。 また、 透析療法 の合併症として低血圧、 発癌、 易感染症或いは動脈硬化症などがある。 こ の'ような腎臓障害における進展予防法および根本的な治療法の早期の開発 が求められている。 本発明者らは、 上記期待に答えるためカルシウム/ /カルモジュリン拮抗 作用を有する薬物による臓器障害の抑制および治療を目標として鋭意研究 を行った結果、 一般式 （1 ) で表されるジヒドロピリジン系化合物が腎臓 機能障害に対し、 血圧に影響が少ない投与量において、 すぐれた抑制効果 を示し、 且つ、 抗ラジカル作用などを有することを見出し、 本発明を完成 するに至った。 即ち、 本発明は、 下記一般式 （1 )

, Renal vascular thrombosis, etc.) tubule / interstitial disease (pyelonephritis, interstitial nephritis), kidney disease associated with systemic disease (diabetic nephropathy, amyloidosis, gout kidney, kidney disorder associated with liver disease, Hemolytic uremic syndrome, purpura nephritis, renal disorder associated with collagen disease), renal failure (acute renal failure, chronic renal failure). Other complications of dialysis include hypotension, carcinogenesis, infectious disease, or arteriosclerosis. There is a need for early development of preventive and fundamental treatments for such kidney disorders. In order to meet the above expectations, the present inventors have conducted extensive research aimed at suppressing and treating organ damage by a drug having a calcium // calmodulin antagonism. As a result, a dihydropyridine compound represented by the general formula (1) is obtained. The present inventors have found that an excellent inhibitory effect is exhibited at a dose with little effect on blood pressure against renal dysfunction, and that it has an anti-radical action and the like, and the present invention has been completed. That is, the present invention provides the following general formula (1)

[Wherein and R ₂ are the same or different and each represents a hydrogen atom, a nitro group or a chlorine atom, R ₃ represents a hydrogen atom, a chlorine atom or a fluorine atom, and n represents an integer of 6 to 8. ] The medicine for renal dysfunction characterized by containing the dihydropyridine compound shown by these, or those optical isomers as an active ingredient. The present invention provides an effective amount of the dihydropyridine compound represented by the general formula (1) or an optical isomer thereof to a subject such as a patient. Also provided is a treatment for renal dysfunction and acupuncture or prophylaxis characterized by administration to a patient. Effect of the invention .. '. +. □ · + ···.; + ::. ···· :: + ·.: ..'. '.; ..

 : A virazole structure is bound to the steal side chain represented by the general formula Ci) of the present invention: 'The di-bidropiri dizyi' compound is the result of an experiment using a renal reperfusion model.ラ ジ カ ル At a dose that has little effect on blood pressure, it has both excellent inhibitory effect and diuretic action on renal damage caused by renal ischemia. . generated 啤寄 a 'that:.. by the, is, of antioxidant capacity at the time of tissue damage.:.:.,' a drop ... 'to suppress. · '

'Best Mode for Carrying Out the Invention.

 Hereinafter, the present invention will be described in detail.

In the present invention, ^^: preferred in (1) and R '. 'Are' combination example of the Rj are _two:. Toro group R ₂ 'is a hydrogen atom,' is '. R ₂ is chlorine atom in atom, 1 ^ and' hydrogen R ₂ is exemplified chlorine atom I can't wait. .. Suitable R ₃

.Irihara ^: Child, '.Ning Element ^: Can Fuse Fluoro Atom' can be ... R ₁ and + 'Chlorine Atom: Can be expected to be longer lasting than other: . η · is experimental. For renal pelvic disorder: ········ against radical scavenging action Characteristic power> ⁶ · is preferred. '. ..'.

In this effort, the general formula (1 asymmetric dihydropyridine compound is

 , 1, 4-The Dorohi. Jin Li 3 5— ^ Literature widely used for the synthesis of ester

'· 會 己 ¾ Method,: Substituted benzylidene acetate methyl acetate and aminocrotonic acid:

 It can be synthesized according to the method [Drugs οΐ the Future 'Vol.14: (3). 206-210 (1909)] using a conductor. .

: The:,:: ^ General _^;:.....: ^(1:>: represented by .. ¾ compound: JP 6 3 2 3 1 9: .3 No. · .. ■ · In the report, blood vessel ^: dilated 5S action, carnumum ^ ¾ 'action, blood pressure lowering action is known as compound + thing ^ part is known as Ri' is a ditro group, .. 'R: and'; · "; An outline of the pharmacological properties of a compound in which R ₃ is a hydrogen atom and n is 6 is described in Drugs of the Future Vol.14 206-210 (1989) as CV— 1 59, It is suggested to be useful as. In addition, the novel action and effect of CV-1 59 is disclosed in Japanese Patent No. 3365732 as a therapeutic agent for brain reperfusion, but there is no mention of prevention or Z or treatment of ischemic organ failure, especially kidney damage. It has not been. Examples of suitable compounds of the present invention are shown below, but they can be appropriately selected from these according to the purpose.

 1) 1,4-Dihydro-2,6_dimethyl-4 (3-diphenyl) — 3-methoxycarbonyl pyridine 1-Carboxylic acid 6- (5-phenyl-3-virazolyloxy) 'hexyl ester (C (Referred to as V-159)

2) 1,4-Dihydro-1,2,6-Dimethylol 4- (3-Nitrophenyl) 1-3-Methoxycarbonylpyridine _ 5-Strong rubonic acid 6- (5-Phenol 3-bisazolyloxy) Heptyl ester

 3) 1,4-dihydro 2,6 _dimethinore 4 1 (3-Nitrofeninore) 1 3-methyoxycarbonyl bilidine 1-5-strength rubonic acid 6- (5-phenoyl 3-virazolyloxy) o Cutyl ester

 4) 1,4-Dihydro-1,2,6-Dimethyl 41 (3-Nitrophenenyl) — 3-Methoxycarbonylpyridine 5—Strong rubonic acid 6— (5-Orthofunoleolophenyl-3-pyrazoli / Reoxy) Hexinore Estenore

 5) 1,4-Dihydro-2,6-Dimethyl 4 _ (3-Nitrophenol) One 3-Methoxycarbo pyridine One 5-Strength rubonic acid 6- (5-Ortho-oral-Fue-Fe-3-1 Birazoli Norexy) Hexinore Estenore

6) 1,4-Dihydro-2,6-Dimethyl-1,4- (2,3-Dichlorophenyl) — 3-Methoxycarbopyridine, 1—Strong rubonic acid 6— (5-Phenolole, 3-Villazoli / Reoxy) Hexyl Estenole The dihydropyridine compound represented by the general formula (1) of the present invention is a known product. Depending on the technology, tablets, granules, powders, 'hard capsules, emma / resillons, softness' pushells, lipid dome spheres, liposomes, or suppositories can be used. ■ Oral administration method; sublingual administration method, suppository ■

'From any non-acupuncture administration, τ can be thrown according to the purpose. The present invention compounds':: In the event Ordinance formulating ¾, excipients fe Ji and agent administration state, binders ,, lubricants + -:. '&Agents,' collapse ^壤剤:,: coating 'Agent, · ^: coloring agent, buffering agent, moisturizing agent, H adjusting agent, solubilizing agent', solvent, sea surface active agent, buffering agent, stabilizer, tonicity agent, surfactant, preservative, It can be appropriately selected from charged ribosome carriers, water-soluble or water-dispersing polymer compounds, etc., and used as a pharmaceutical composition: . Prevention Further ί or Osamu of the present _invention,: Ryoyo formulation '. Hitoshi ij type mixing according to,'混舍, Ryoneri, granulation, tabletting molding, co ^ I '' - 'ing, It can be prepared by a known and commonly used formulation method such as dissolution, emulsification, high-frequency heating, high-pressure steam heating, sterilization, and centrifugation.

Specific formulation carriers include starches, sucrose, lactose, and crystallization cell ports.

• Sole, Canolepo. Xymethylenoses / relose, 'D—mannitoniore, methinolecellulose •, sodium alginate, hydroxy ”^ methylellesulose,' Keic anhydride, '' Li 'hydrogen carbonate Λ, Synthetic aluminum silicate and Alumina, takey acid • Magnesium acid Λ Which excipient, 'Hydroxy pill Pelcel Rose, Hydroxy Cypro, G. Luluzeros, Gelatin, .. tf Lidon, Carbo '.. ;; Kischi: Lucer: Mouth, One Scalum,' Bridged ¾ Lu ^: Po, Ki 'Mechi: Russell Mouth: N Disintegrating agents such as poly-Buylpyrrolidone, Hydroxypropyl Nore ^: Chi / Rese / Lose Loose Acetate Succinate, Cenorelose Acetate Fuda Les Nito, Methyl Acrylic Acid Copolymer, Meta Atanol Moleic Acid Polymer

A water-soluble ice-ice dispersible polymer compound of poly-primary titanium, fine talc and stearic acid, lubricants of magnesium, calcium stearate, etc. .: ^ Tano / Reamine, Do: Lisaminomethane, Cholesterol

: 酵 Fermentation: Vum. Carbonic acid. Dissolving aids such as sodium carbonate, water for injections, etc.: Luluco: Lu: Pro 'Pyreneglygo', sesame oil, corn oil, etc. of.. ^'soluble:.: Les ^ Chi emissions · ■ ·. (full ^ off:.. a ^ le i Li Shi)', Phosphor lysophosphatidic acid,: O '. Fat, fatidino glycerin mouthwater, phosphatidyzorethanolamine, phosphatidylinositol, polyoxyethylene cetyl ether, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, sonolebitan mono Emulsifiers such as reate and glycerin monotearate, bases such as witebuzole and cocoa butter, L-cystine, glutathione, ascorbic acid, sodium asconolevate, 2-asconolevinate, dalcoside, asconolevinate 2,6 _Dibutyrate, ascorbic acid 2-phosphate magnesium salt, ascorbic acid 2,6-dipalmitate, ascorbic acid 2,6-dilauryl ester, ascorbic acid 2 monosulfate, tocopherol, Fulluric acid, Nanocarbons such as arginine salt of erulic acid, purple root extract, ethyl ammonobenzoate, dibu force hydrochloride, diphenhydramine hydrochloride, cetride, sodium cromoglycate, cetirizine hydrochloride, medical activated carbon, titanium oxide, iron oxide, and fullerene oxide , L-arginine, L-carnosine, urea, etc.

The dose of the compound of the present invention varies depending on the route of administration, the type and extent of the pathological condition to be treated, the age and sex of the patient, the body weight, the sensitivity to the administered drug, the timing of administration and the interval of administration, but is usually about an adult per day. 1 pg to 4 O mg, preferably about 1 pg to 2 mg in the intravenous administration method. In the subcutaneous administration method, it is preferably about 2 pg to 4 mg. In the oral administration method, it is preferably about 0.1 to 50 mg. In the case of a suppository, it is preferably about 0.1 to 2 O mg. Examples of a pharmaceutical composition suitable for an orally administered preparation with high bioavailability include a readily soluble solid dispersion comprising the compound of the present invention and the polymer compound. In order to clarify the effect of a drug in a renal insufficiency on the dihydropyridine compound represented by the general formula (1) and having a pyrazole structure bonded to an ester side chain, the present inventors have developed a renal reperfusion model. Experimented with 'As a result, in particular, as shown in the examples below, 1,4-dibidrow 2,6-dimethyl 4- (3-nitrophenyl) _ 3-methoxycarbonylpyridine:.:; -... · ·: 'Nu 5—Strengthen rubonic acid 6— (5—Fe-l 3—hi. Zori.Noroxy) Hex. :: .Lu: Stell (CV-1 5 -9) Compound, but blood No effect on the dose ...;: In the given dose, it is based on renal guidance. Renal ¾ Excellent inhibitory effect against diuresis and diuresis: Combined with: and under the imaginary ife By inhibiting the generation of radical species generated inside the kidney, it is particularly excellent in the action of suppressing the decrease in antioxidant capacity at the time of tissue damage.

製） を用い、 tail- cuff 法により収縮期圧、 拡張期圧および心拍数を、 上 記の S h a m群、 虚血再灌流実験の開始実験前およぴ虚血性急性腎不全モ デル実験終了後の翌日に測定した。 表 1に示すように血圧には殆んど影響 を与えなかった。

), Tail-cuff method for systolic pressure, diastolic pressure and heart rate before the start of the ischemic reperfusion experiment and the ischemic acute renal failure model experiment. Measurements were made the next day after. As shown in Table 1, blood pressure was hardly affected.

 (2) Urine volume and urinalysis: In each group, urine is measured for urine accumulation, occult blood, and protein is tested, followed by protein quantification, Na, K, C1, Ca, Pi (inorganic phosphorus), NAG (N-acetyl j3-D glucosaminidase), C r (Creachun), C cr

(Creatinine clearance) UN (urea nitrogen) and UA (uric acid) were examined in the usual way. Table 1 shows the measured values that showed a difference between the untreated group and the ARF group.

 (3) Blood test: Heparin blood was collected from the abdominal aorta immediately after the end of the ischemic acute renal failure model experiment in Pharmacological Experiment 1. The blood was centrifuged, and the resulting plasma was divided into 2 minutes, and one was examined for plasma total protein, Na, K, Cl, Ca, Pi, Cr, UN, and UA. Table 1 shows the measured values that showed differences between the untreated group and the ARF group. Table 1 shows the evaluation results of drugs for various test items in rats with ischemic acute renal failure. In the table, Sys represents systolic pressure, Dias represents diastolic pressure, and F ENa (fractional excretion of sodium). Compound CV-1 59 of the present invention markedly improved the deterioration of serum Cr, serum UN, C cr and FE Na, which are indicators of kidney damage, at doses with little effect on blood pressure.

Table 1 Animals (number) Blood pressure (匪 Hg) Serum C r Serum UN C cr FE Na

 Sys / Dias (mg / d.l) (mg / dl) (ml / mi n) ()

Sham group (4) 101 171 0.02 Shi 0.07 15.8 Sat 3.3 1.17 ± 0.35 0.13 ± 0.02

ARF (-) group (6) 102 170 1.98 Sat 1.14 72.2 Sat 22.4 0.14 Sat 0.17 2.57 ± 3.58

ARFW group (6) 98 171 0.73 ± 0.31 36.7 Sat 14.8 0.37 ± 0.25 0.38 Sat 0.29 Example 2 '''...

Measurement of antioxidant capacity of kidney tissue by X-band ESR (Evaluation of anti-radical action) ''. Example: After completion of phlebotomy and reperfusion experiment: E: SR blood sample was collected. ：： 7 crawling ² 0 ~ 3 Om'l cold physiological saline 7 irrigation: After removing blood, remove right kidney

Then, 'a part of the left kidney's upper pole was cut off and weighed', and then 'stored in' Luarin 'as a specimen for pathologic tissue examination. 'The balance of the left ¹¹ was weighed and then frozen and stored in nitrogen. Then homogenize in 10 volumes of homogenized solution (5 Omm Mo 1 phosphate buffer, pH 7.4 containing 0.25 _{m 0} l sucrose), and then centrifuge. Mitochondria i minutes and terrestrial gauges: the test department. The measurement results are shown in ¾ 2 “(kidney sparoxide deciduous” inhibition rate (%) :) and Table 3 (kidney hydroxy: / radical scavenging activity inhibition rate (■%)).

上記の各 E S R測定の結果から本発明の化合物である CV— 1 5 9は、 抗ラジカル作用を有し、 臓器障害の進展と增悪を防止する優れた効果が認 められた。 実施例 3 ' '.' [Experiment 2] '.. ^: ...' .. ':,:'.. '■:.':. ·. '.,' ..: '. Evaluation of antioxidant capacity in ischemic sudden kidney model with kidney in vivo 'ES: R device' (manufactured by JEOL Ltd.):. In the renal ischemia-reperfusion experiment, at 1 o'clock 'after left 申.' Heart ^:: ru it oxidative capacity. Spicitura ^ pill 3-carbamoyl proxyl: '. (. 3 :: C¾): use ^ Te ίη ivo method by ^the:... Ri 'was rated Les.. Ie weight. 5 Using SD male rats around 0 g, creating an ischemic acute renal failure model (ARF), adding 45 minutes of ischemia-reperfusion injury, then administering 3 CP intravenously in the left kidney 3 The decay rate constant of CP (k:-/ min) was compared with that of the ARF drug administration group in the non-ARF drug administration group. The drug was administered intraperitoneally 1 hour before the start of the renal ischemia reperfusion experiment. Table 4 shows the measurement results. Table 4

From the above ESR measurement results, it was confirmed that CV-1 59, which is a compound of the present invention, has an antiradical action and an excellent effect of preventing the progression and deterioration of organ damage. Example 3 ''

Simultaneous measurement of NOZ oxygen concentration in the renal cortex:

For NO and oxygen measurements, a nitric oxide measuring device (MODEL NO-502: manufactured by Eikogaku Kagaku) and NO electrode, an oxygen partial pressure measuring device (MODEL P02-150D) and an oxygen electrode were used. That is, in each group of animals, a NO electrode and an oxygen electrode were inserted into the cortex of the left kidney exposed on the back, and the counter electrode was mounted in the incised skin and measured. In the sham group in which ischemia / reperfusion injury was not performed, the NO / oxygen concentration was measured at the time of sham surgery and 16 hours after that in the non-drug-administered control group and the drug-administered group. The results are shown in Table 5. In the ischemia reperfusion experiment group, ARF (1) and ARF (+) were compared, and the measured values are shown in Table 6. The groups that underwent ischemia-reperfusion injury were treated with NOZ oxygen in the renal cortex before ischemic experiment, at the time of resumption of blood flow after 45 minutes of renal ischemia and immediately after resumption of blood flow 16 hours later, respectively. The change in partial pressure was measured. Table 5 shows the measurement results of NO / oxygen partial pressure. In the table, the unit of oxygen partial pressure (P02) is expressed in mmHg, and NO is the current value. Displayed by p A (picoampere).

1 4.- Table.-5;

14.-

産業上の利用可能性

Industrial applicability

 As described above in detail, the dihydropyridine compound represented by the general formula (1) according to the present invention is useful for renal diseases such as renal failure, nephritis, and dialysis complications that occur due to degeneration disorder of kidney tissue. It is extremely useful as a new active compound for use in the treatment and prevention of ischemia and ischemic reperfusion injury prevention during Z or kidney transplantation.

Claims

'[Wherein, Ri and Shaku ₂ are the same or different and represent a hydrogen atom, a nitro group or a chlorine .. atom], R represents a hydrogen atom, a chlorine atom or a fluorine atom, and n is 6 to Represents 8 canonicals. : A drug for renal perfusion injury comprising a dihydropyridine compound represented by!. Or an optical isomer thereof as an active ingredient 2 .. .1, ···, 4'-Dro 2, 6_dimethyl-. 4 1 (3—: Trophe; .. 2 '):.: 厂 3 ^ 卜. .. Rubonirubiriji down .5 one: carbonitrile phosphate 6- (5-off: -: -: - - ^Le:.... .3; - throat shear Ruokishi). to Gishiru ^ Sutenore: containing as an active ingredient You _: Drugs for renal failure that make every thing ^^. · '' 3: '1 4 dihydro-2, 6-dimethyl 4 (3-2 trophies.: Les) 1 3-mex. 5 E ^'-; -. Le one-3-Birazoriruokishi) hexyl ester as an active ingredient and to be contained as. —Nitrophe ';:'-(

Nilu 3-Viazolyloxy) A dialysis complication drug characterized by containing hexyl ester as an active ingredient.