WO1998034922A1 - Prophylactic or therapeutic agent for diabetic complication - Google Patents

Abstract

A composition comprising as the active ingredient an imidazolecarboxylic acid compound represented by general formula (1) (wherein R1 represents an alkyl group; R?2 and R3¿ represent each a hydrogen atom or an alkyl group; R4 represents a hydrogen atom or an alkyl group; R5 represents a hydrogen atom; and R6 represents a carboxyl or tetrazol-5-yl group), possesses an excellent inhibitory activity against nephropathy of an NIDDM model rat and is useful as a prophylactic or therapeutic agent for diabetic complication.

Description

Prophylactic or therapeutic drug for diabetic complications [Technical field]

 The present invention relates to a composition for preventing or treating diabetic complications, comprising an imidazole carboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof as an active ingredient; Use of imidazole carboxylic acids, pharmacologically acceptable salts or pharmaceutically acceptable esters thereof, or imidazole carboxylic acids, pharmacologically acceptable salts thereof, for producing a composition for therapy A method for preventing or treating diabetic complications by administering an effective amount of a pharmacologically acceptable ester to a warm-blooded animal, or an imidazole carboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient A composition for the prevention or treatment of renal disease, comprising Use of imidazole carboxylic acids, pharmacologically acceptable salts or pharmacologically acceptable esters thereof, or imidazole carboxylic acids, pharmacologically acceptable salts thereof, or pharmacologically acceptable esters thereof for the production of products And administering to a warm-blooded animal an effective amount of

[Technical background]

 With the westernization of the diet and the aging of the population, the number of patients with cardiovascular diseases such as hypertension and heart disease, and metabolic diseases such as diabetes and hyperlipidemia are steadily increasing. Especially obesity

, Diabetes [particularly, non-insulin-dependent diabetes mellitus (NIDDM)], Syndrome X (Syndrome X), which simultaneously complicates hypertension and hyperlipidemia [Diaby Taste, Vol. 37, pp. 1595 to 1607] (1988): Diabetes, 37, 1595-1607 (1988)] is an increasing number of patients. In such patients, they develop coronary artery disease The risk of infection is very high and useful preventive or therapeutic measures have been sought. In Syndrome X, insulin dysfunction, that is, insulin resistance [Diabetologia, Vol. 21, pp. 165 to 171 (1981): Diabetologia, 21, 165-171 (1981)] is included in the disease state. It is very active, and the usefulness of insulin sensitizers such as troglitazone and pioglitazone, which are being developed in recent years, is expected. However, given the diversity of patients, it is unlikely that insulin sensitizers alone can treat Syndrome X and all other diabetic complications, and there are other ways to treat diabetic complications effectively. Needed. When diabetic patients have nephropathy, hypertension and hyperlipidemia worsen due to renal impairment, and the prognosis of patients further worsens. Therefore, prevention and treatment of nephropathy among diabetic complications are particularly important. Effectiveness of angiotensin-converting enzyme (ACE) inhibitors, which have recently been used as antihypertensive agents, for diabetic nephropathy [New England Journal ■ Saibu Medicine, Vol. 313, pp. 1617 to 1617 1620 (1985): New. Eng. J. Med., 313, 1617-1620 (1985)], but it is said that this drug also improves insulin resistance. The mechanism is considered to be a kinin-type potentiator [Hypertension, Vol. 23, pp. 450-455 (1992): Hypertension, 23-450-455 (1992)]. Angiotensin II receptor antagonist, which is the same renin 'angiotensin system inhibitor, can also be expected to have a renal protective effect. In fact, streptozotocin-induced insulin-dependent diabetes mellitus (IDDM) rats. In Japan, oral sultan has been reported to inhibit nephropathy [Journal · 'American' Society 才 Sai Beneflorology-1, Vol. 4, pp. 40-49 (1993) Am. So Nephrol., 4, 40-49 (1993)]. Kinin type II Angiotensin II receptor antagonists without strong action have little side effects such as dry cough, but there is controversy over whether to improve insulin resistance. In NIDDM, renin activity in blood and renal tissue is low [Journal 'Saibu' American 'Society · Saibu' Nephrology 1 ', Vol. 4, pp. 1354 to 1361 (1993):丄 Am. Soc Nephrol., 4, 1354-1361 (1993)], NIDDM complications

 The efficacy of II receptor antagonists is not always clear. In fact, in the obese Zucker rat of a spontaneous NIDDMM model animal,

It has also been reported that oral sultan, an II antagonist, has a hypotensive effect, but no decrease in urine protein or blood lipids (cholesterol, triglyceride, etc.) is observed. · American 'Society 1 · Ob' Nephrology, Vol. 6, pp. 1295 to 1299 (1995): {Am. Soc Nephrol., 6, 1295-1299 (1995)].

 On the other hand, renal diseases, for example, eye disease (IgA) nephropathy [Berber disease], membranous nephropathy, proliferative glomerulonephritis, sclerosing glomerulonephritis, focal glomerulosclerosis However, the pathogenesis and progression mechanism of glomerulonephritis classified as a type such as minimal change nephrotic syndrome has not been elucidated to date. Taking the case of IgA nephropathy, which is considered to be the most common type of glomerulonephritis as an example, IgA-based immune complexes develop in the glomeruli of the kidney and develop through various processes, eventually becoming glomerular. It is thought to progress to hardening [American Journal, Kidney-Disease, Vol. 12, pp. 388-392 (1988): Am. J. Kid. Dis., 12, 388-392 (1988), Clinical-Nephrology, 38, 245-253 (1992): Clin. Nephrol., 38, 245-253 (1992)]. The antigen that stimulates IgA antibody production in this disease is still unknown, and the mechanism of progression of nephritis after immune complex deposition is described in terms of complement activation, leukocyte infiltration, It has been suggested that increased production of growth factors, production of active oxygen, abnormal blood coagulation, etc. are involved, but details are not clear [Sogo Ringo, Vol. 45, pp. 228-233 (19%)] .

At present, immunosuppressants, antiplatelet drugs, anticoagulants, etc., mainly for adrenocortical steroids, are used as therapeutic agents for glomerulonephritis and the like. However, corticosteroids and immunosuppressants have problems with long-term administration because of side effects. However, the effect is divided, and the effective rate is not high. In fact, in Japan, the number of kidney disease patients undergoing dialysis is on the rise, but about 40% of the causes are glomerulonephritis.

Recently, among the antihypertensive agent, in particular Angi old tensin converting enzyme (ACE) has been suggested that there ^s a force renoprotective work in inhibitor [Amerikan 'journal O blanking. Hyper Ten Chillon, Vol. 10 (Part 2 ), Pages 53S to 58S (1995): Am. J.

 Hypertens., 10 (Pt. 2), 53S-58S (1995)]. However, at present the only established utility is the use of ACE inhibitors for diabetic nephritis [New 'Ingrand' Journal of Obd 'Medicine, Vol. 329, pp. 1456 to 1462. page

(1993): New. Eng. J. Med., 329, 1456-1462 (1993)]. The renal protection mechanisms of ACE inhibitors include lowering glomerular pressure [hyperfiltration

(Hyperfiltration) and the suppression of proliferation and fibrosis of stromal cells [New 'England' Journal. Saibu Medicine, Vol. 307, pp. 652 to 659 ( 1982): ew. Eng. J. Med., 307, 652-659 (1982), Achieves 'ob' International Medicine, Volume 153, pp. 1749 to 1759 (1993): Arch. Intern Med., 153, 1749-1759 (1993) .The efficacy of ACE inhibitors has been reported in patients with IgA nephropathy among glomerulonephritis [Contribution-Tow'Nephrology 1] 90, pp. 161 to 165 (1991): Contrib. Nephrol., 90, 161-165 (1991)] How effective is it in patients with high blood pressure and without hypertension? The excretion route of the ACE inhibitor, which has been developed so far, It must be administered with caution to patients with renal disease, and the recently developed Angiotensin II antagonist is expected to have renal protection. In particular, its efficacy against glomerulonephritis is not clear, for example, in a model of membranous nephropathy [Heymann nephritis], an ACE inhibitor, Lil, has a clear proteinuria-suppressing effect, but Tensin II antagonist It has been reported that oral sultan, a drug, has no proteinuria-suppressing action. [American Journal of Physiology, Vol. 263, pp. F311 to F318 (1992): Am. J. Physiol., 263, F311-F318 (1992)].

[Disclosure of the Invention]

 The present inventors have conducted various studies in view of the importance of prevention and treatment of diabetic complications, especially nephropathy, hyperlipidemia and hypertension associated with NIDDM, and as a result, have found that a specific angiotensin II Receptor antagonists have an excellent inhibitory effect on nephropathy, hyperlipidemia and hypertension in NIDDM model rats, have few side effects, and have diabetic complications, especially nephropathy, It has been found to be a prophylactic or therapeutic agent for hyperlipidemia and / or hypertension.

In addition, the present inventors have conducted various studies in view of the importance of prevention and treatment of renal diseases, particularly glomerulonephritis, and as a result, a specific angiotensin II receptor antagonist has been It has an excellent inhibitory effect on glomerulonephritis, which has been specifically produced, and has few side effects, and has been found to be a prophylactic or therapeutic agent for renal diseases, particularly glomerulonephritis. The present invention relates to a composition for preventing or treating diabetic complications comprising an imidazole carboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient, and a composition for preventing diabetic complications. Alternatively, use of imidazole carboxylic acids, pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof, or imidazole carboxylic acids, pharmaceutically acceptable salts thereof, or a pharmaceutically acceptable salt thereof for producing a therapeutic composition. A method for preventing or treating diabetic complications by administering an effective amount of a pharmacologically acceptable ester to a warm-blooded animal, or an imidazole carboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient A composition for the prevention or treatment of renal disease, comprising Imidazole carboxylic acids for the production of goods, the use of a pharmacologically acceptable Ru salt or its pharmacologically acceptable esters, or imidazole carboxylic Or a pharmacologically acceptable salt thereof or a pharmacologically effective salt thereof is administered to a warm-blooded animal.

 The imidazole carboxylic acids which are the active ingredients of the present invention include:

 General formula

を有する。

Having.

 In the above formula,

R ¹ represents a d-C ₄ alkyl group,

R ² and R ³ are the same or different and each represent a hydrogen atom or a -C ₄ alkyl group;

R ⁴ represents a hydrogen atom or a C, -C ₄ alkyl group,

R ⁵ represents a hydrogen atom,

R ⁶ represents a carboxy group or a tetrazol-5-yl group.

The C, 1 C ₄ alkyl group of FT, R ² , R ³ and R ⁴ can be, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, and the d-C ₄ alkyl group of FT is It is preferably an ethyl, propyl or butyl group, more preferably a propyl or butyl group, particularly preferably a propyl group, and the d-alkyl group of R ² , R ³ and R ⁴ is Preferably, it is a methyl or ethyl group, and particularly preferably, a methyl group.

The ester residue (R ⁵ a) of the pharmacologically acceptable ester of compound (I) is, for example, The above d—C ₄ alkyl group, C ₂ —C ₅ alkanoyloxymethyl or 1— (C ₂ -C ₃ alkanoyloxy) ethyl group (the C ₂ —C ₅ alkanoyl moiety is, for example, It may be acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, vivaloyl, preferably acetyl or vivaloyl.

Particularly preferred is Vivaloyl. ), D -c ₄ alkoxycarbonyl Nirusaiki Shimechiru or 1 one (d - c ₄ alkoxycarbonyl old alkoxy) Echiru group (wherein d - c ₄ alkoxy moiety, for example, methoxy, ethoxy, Purobokishi, iso Purobokishi, butoxy , Isobutoxy, preferably methoxy, ethoxy, propoxy or isopropoxy, particularly preferably ethoxy or isopropoxy.), (5-methyl-2-oxo-1, 3-dioxolen-14 Methyl), a methyl group, (5-phenyl-2-oxo-1,3-dioxolen-4-yl), a methyl group or a phthalidyl group, preferably a methyl group, an ethyl group, an acetyloxymethyl group, 1- (Acetoxy) ethyl group, Bivaloyloxymethyl group, 1—

(Bivaloyloxy) ethyl group, methoxycarbonyloxymethyl group, 11 (methoxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 11

(Ethoxycarbonyloxy) ethyl group, propoxycarbonyloxymethyl group, 1- (propoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl) Methyl 2- or 1,3-dioxolen-4-yl) a methyl group or a phthalidyl group, particularly preferably a bivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, Ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-1-2-oxo-1,3-di-isoquinone-4-yl) ) A methyl group or a phthalidyl group, most preferably a bivaloyl xymethyl group or a (5-methyl-2-oxo1-1, 3-dioxolen-4-yl) It is a methyl group. Further, esters of the carboxy group at the 5-position of the imidazole ring are preferred. The compound (I) of the present invention can be converted into the corresponding pharmacologically acceptable salt by treating with an acid or a base according to a conventional method, if desired. Examples of such acid addition salts include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as maleic acid, fumaric acid, tartaric acid, and citric acid. Examples of the salt with a base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and organic bases such as guanidine, triethylamine and dicyclohexylamine. Salt.

 Furthermore, when an asymmetric carbon is present in the molecule of the compound (I), the compound includes racemates and optically active compounds, and also includes hydrates of the compound (I) or a salt thereof. Compound (I) is preferably

(1) a compound wherein R ¹ is an ethyl group, a propyl group or a butyl group,

(2) a compound wherein R ¹ is a propyl group or a butyl group,

(3) a compound wherein R ¹ is a propyl group,

(4) R ² and R ^{3 are} the same or different and are a hydrogen atom or a methyl group

(5) a compound wherein R ² and R ³ are the same and are a methyl group,

(6) a compound wherein R ⁴ is a hydrogen atom or a methyl group,

(7) a compound wherein R ⁴ is a hydrogen atom,

(8) group (wherein the R ⁵ is a hydrogen atom or the formula R ^s a, R ⁵ a is a methyl group, E Ji group, § Se Bok Kishimechiru group, 1 i (§ Se Bok carboxymethyl) Echiru group, Bivaloyl xymethyl group, 1— (Bivaloyl xy) ethyl group, methoxycarbonyloxymethyl group, 11- (methoxycarbonyl oxy) ethyl group, ethoxycarbonyl xymethyl group, 1— (ethoxycarbonyl) Ethoxy group, propoxycarbonyloxymethyl group, 11- (propoxycarbonyloxymethyl) ethyl group, isopropoxycarbonyloxymethyl group, 11- (isopropoxycarbonyloxy) ethyl group , (5-methyl-2-yl-1,3-dioxolen-1-yl) A methyl group or a phthalidyl group. A compound which is

(9) group (wherein the R ⁵ is a hydrogen atom or the formula R ⁵ a, R ⁵ a is pivaloyl ingenuity Shimechiru group, an ethoxycarbonyl old Kishimechiru group, 1- (ethoxycarbonyl old carboxymethyl) Echiru group, isopropoxy It is a carbonyl group, a dimethyl group, a (isopropoxycarbonyl) ethyl group, a (5-methyl-2-chloro-1,3-dioxolen-4-yl) methyl group or a phthalidyl group. A compound,

(1 0) group (wherein the R ⁵ has the formula R ^s a, R ⁵ a is Viva Roy Ruo carboxymethyl group or a (5-methyl-one 2-year old Kiso one 1, 3-di old Kisoren one 4- A) a compound which is a methyl group.

(11) Compound wherein R ^{6 is a} tetrazol-5-yl group

Can be given. It should be noted that, between groups indicating the same group, the degree of the preference increases as the group number increases (for example, among R ¹ groups, (1) is more preferred, (2); ^ It is even more preferred, indicating that (3) is particularly preferred.)

Also, (1) R ¹ is selected from the group consisting of (3), R ² and R ³ are selected from the group consisting of (4)-(5), and (6)-(7) force> Choose R ⁴ from the group,

(8) — (10) Compounds obtained by selecting R ⁵ from the group consisting of force and combining these or by combining these with R ⁶ of (11) are also suitable. Are given.

(12) R ¹ is an ethyl group, a propyl group or a butyl group,

R ² and R ^{3 are} the same or different and are a hydrogen atom or a methyl group,

R ⁴ is a hydrogen atom or a methyl group,

Group (wherein the R ⁵ is a hydrogen atom or the formula R ⁵ a, R ⁵ a is a methyl group, Echiru group, Asetokishimechiru group, 1 i (§ Se Bok carboxymethyl) Echiru group, pivaloyl old Kishimechiru group, 1 i ( Bivaloyl) ethyl group, methoxycarbonyloxymethyl group, 1- (Methoxycarbonyl) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyl) ethyl, propoxycarbonyl-methyl, 1- (propoxycarbonyl) ethyl, iso- Propoxycarbonyl, a methyl group, 11- (isopropoxycarbonyl) ethyl group, (5-methyl-2-cyclo-1,3-dioxolen-4-yl) methyl group or phthalidyl group. A compound which is

(13) R ¹ is a propyl group or a butyl group,

R ² and R ³ are the same and are methyl groups,

R ⁴ is a hydrogen atom,

Group (wherein the R ⁵ is a hydrogen atom or the formula R ⁵ a, R ⁵ a is pivaloyl old Kishime butyl group, an ethoxycarbonyl old Kishimechiru group, 1 i (ethoxycarbonyl O carboxymethyl) Echiru group, isopropoxycarbonyl old Kishimechiru A 1- (isopropoxycarbonyl) ethyl group, a (5-methyl-2-oxo-1,3, -dioxolen-4-yl) methyl group or a phthalidyl group.

A compound wherein R ^{6 is a} tetrazolyl 5-yl group,

(14) R ¹ is a propyl group,

R ² and R ^{3 are} the same, a methyl group,

R ⁴ is a hydrogen atom,

Group (wherein the R ⁵ has the formula R ⁵ a, R ⁵ a is a pivaloyl old Kishimechiru group or (5-methyl-one 2-year old Kiso one 1, 3-di old Kisoren one 4-I) methyl group )

A compound wherein R ⁶ is a tetrazole-5-yl group.

i ] Wn n 3 As the suitable compound in the general formula (I), the compounds shown in the following Table 1 can be specifically exemplified.

i] Wn n 3

Rider H thing R H H R R R

(o.) t Me Me HH ϋ ₂ 11

2 Et Me Me H Pom C0 ₂ H

3 Et Me Me H Mod C0 ₂ H

4 Et Me Me H H Tz

5 Et Me Me H Pom Tz

6 Et Me Me H Mod Tz

7 Pr HHHH C0 ₂ H

8 Pr HHH Pom C0 ₂ H

9 Pr HHH Mod C0 ₂ H

10 Pr H H H H Tz

11 Pr H H H Pom Tz

12 Pr H H H Mod Tz

13 Pr H Me HH C0 ₂ H

14 Pr H Me H Pom C0 ₂ H Pr H Me H Mod C0 ₂ H

Pr H Me H H Tz

Pr H Me H Pom Tz

Pr H Me H Mod Tz

Pr Me Me HH C0 ₂ H

Pr Me Me H Me C0 ₂ H

Pr Me Me H Et C0 ₂ H

Pr Me Me H Pom C0 ₂ H

Pr Me Me H CH ₂ 0C0 ₂ Et C0 ₂ H

Pr Me Me H CH (Me) 0C0 ₂ Et C0 ₂ H

Pr Me Me H CHaOCOaPr ¹ C0 _z H

Pr Me Me H CH (Me) 0C0 ₂ Pr 'C0 _Z H

Pr Me Me H Mod C0 ₂ H

Pr Me Me H Phth C0 ₂ H

Pr Me Me H H Tz

Pr Me Me H Me Tz

Pr Me Me H Et Tz

Pr Me Me H Pom Tz

Pr Me Me H CH ₂ 0C0 ₂ Et Tz

Pr Me Me H CH (Me) 0C0 ₂ Et Tz

Pr Me Me H CH ₂ 0C0 ₂ Pr ⁱ Tz

Pr Me Me H CH (Me) OCO aPr ¹ Tz

Pr Me Me H Mod Tz

Pr Me Me H Phth Tz

Pr Me Me Me H C0 ₂ H

Pr Me Me Me Pom C0 ₂ H z 9H H 99 zi HH 59

H ^s 03 d H ne ^ 9

H ^s OD \ H £ 9

H ² 00, 0.0 (3W) HO H Z9

H ^z 00; Jc [ ^z OOO ^s HD H 19

H ^z 00 ¾ ² 000 (9 ^) HD H 09

H ^s 03 H 69

H ² 00 mod H 8S

H ^a 00 HH A5

 z ェ mod H H 5S zi H H H S

H ²⁰⁰ PON HH ng 85

H ^z 00 mod HH ng 23

H ²⁰⁰ HHH Tig IS

 H H H ng OS

H H H 6 ^ z H H H H H 8 ^

H ^ff 00 HHH LV

H ² 0. mod HHH 9 ^

H ²⁰⁰ HHHH

 z 丄 pow-^ d

 mod d

 H d ZV

3W · ¾ f / I3c [OAV 67 Bu Me Me H Et Tz

 68 Bu Me Me H Pom Tz

 69 Bu Me Me H ClLOCOpEt Tz

70 Bu Me Me H CH (Me) 0C0 _? Et Tz

71 Bu Me Me H CH _? 0C0 Pr ^l Tz

 72 Bu Me Me H CH (Me) OCO Pr 'Tz

 73 Bu Me Me H Mod Tz

 74 Bu Me Me H Phth Tz

75 Bu Me Me Me H C0 ₂ H

76 Bu Me Me Me Pom C0 ₂ H

77 Bu Me Me Me Mod C0 ₂ H

 78 Bu Me Me Me H Tz

 79 Bu Me Me Me Pom Tz

 80 Bu Me Me Me Mod Tz In the above table, abbreviations indicate the following groups.

 Bu: butyl group

Et: ethyl group

Me: methyl group

 Mod (5-methyl-2-year-old oxo-1 3-di-yearly xolen-4-yl) methyl group

 Phth: phthalidyl group

 Pom: Vivaloyl oxymethyl group

 Pr: propyl group

^Pr;: Isopuropiru based on

 Tz: Tetrazol-5-yl group.

In the above table, preferably, the exemplified compound number No. , 7,8,9,10,11,12,13,14,15,16,17,18,19,22,23,24,25,26,27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 , 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 79 and 80,

 More preferably, Exemplified Compound No. 5, 6, 8, 9, 10, 10, 11, 12, 14, 15, 15, 16, 17, 18, 19, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,

62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 and 74,

 Even more preferably, Exemplified Compound No. 5, 6, 8, 9, 10, 10, 11, 12, 14, 15, 15, 17, 18, 22, 23, 24, 25, 26 , 27, 29, 32, 33, 34, 35, 36, 37, 38, 49, 50, 55, 56, 58,

63, 65, 68, 69, 70, 71, 72, 73 and 74, particularly preferably

 Illustrative Compound No. 11 1: Bivaloyl oxymethyl 4-hydroxymethyl — 2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazoyl 5-carboxyle Uru,

 Illustrative compound number No. 12: (5-Methyl-2-oxo-1,3-dihexolen-4-yl) methyl 4-hydroxymethyl-1-propyl-1- 1- [4-[2-1] (Tetrazole-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,

Illustrative compound number No. 17: Bivaloyl dimethyl 4- (1-hydroxyethyl) 1-2-propyl-1- 1- "4-" 2- (tetrazol-5-yl) [Phenyl] methylimidazole-5-carboxylate, Exemplified Compound No. 18: (5-Methyl_2-year-old 1,3-di-year-old solen-41-yl) methyl 41- (1- (Hydroxityl) —2-propyl—1-1 [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazolone 5-5-carboxylate,

 Illustrative Compound No. 32: Bivaloyl xymethyl 4- (1-hydroxy-1-methylethyl) -12-propyl-11- [4- [2- (Tetrazol-5-yl) phenyl] phenyl] methylimidazole 5-Carboxylate, Exemplified Compound No. 33: Ethoxycarbonyl 4-methyl (4-hydroxy-1-methylethyl) 4- (1-hydroxy-1-methylethyl) 4- [1- [2- (tetrazolyl 5-) Phenyl) phenyl] methylimidazole-5-carboxylate,

 Illustrative Compound No. 34: 1- (Ethoxycarbonyl) ethyl 4- (1-Hydroxy-1-methylethyl) —2-Propyl-1- (4- [2- (Tetrazoyl-5-yl) ) Phenyl] phenyl] methylimidazole-5-carboxylate,

 Illustrative Compound No. 35: Isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -1-2-propyl-1- [4-1- [2- (tetrazol-5-yl) phenyl] phenyl] Methylimidazole-5-carboxylate,

 Illustrative Compound No. 36: 1- (Isopropoxycarbonyl) ethyl 4- (1-hydroxy-1-methylethyl) -1-2-propyl-11- [4-—2

-(Tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,

Illustrative Compound No. 37: (5-Methyl-2-oxo-1,3, -dioxylene-41-yl) methyl 4- (1-hydroxy-11-methylethyl) -12-pro Pill-1-1 [4-1-1 [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,

Exemplified Compound No. 68 _: Bivaloyloxymethyl 2-butyl-4-1 (1-hydroxy-1-methylethyl) 1-1- [4- [2- (Tetrazol-5-yl) phenyl] phenyl] methylimidazole— 5-carboxylate, Exemplified Compound No. 69: ethokinecarbonyloxymethyl 2-butyl-4- (1-hydroxy-1-methylethyl) — 1- [4- [2- (tetrazol-5-yl) phenyl] phenyl ] Methyl imidazole-5-carboxylate Exemplified Compound No. 70: 1- (Ethoxycarbonyl) ethyl 2-butyl-4- (1-hydroxy-1-methylethyl) — 1— [4— [2-( Tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,

Illustrative Compound No. 71 _: Isopropoxycarbonyl 2-methyl 4-butyl (1-hydroxy-1-methylethyl) — 1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] Methyl imidazole-5-carboxylate,

 Illustrative Compound No. 72: 1- (Isopropoxycarbonyl) ethyl 2-butyl-4- (1-hydroxy-1-methylethyl) —1-1 [4-1] [2- (tetrazol-5-yl) [Phenyl] phenyl] methylimidazole-5-force lipoxylate and

 Illustrative Compound No. 73: (5-Methyl-2-oxo-1,3-diethyl oxylene-4-yl) Methyl 2-butyl-4- (1-hydroxy-1-methylethyl)

) — 1— [4— [2— (tetrazol-5-yl) phenyl] phenyl] methyl imidazole-5 _carboxylate

Is a compound of Most preferably,

 Exemplified Compound No. 32: Bivaloyloquinemethyl 4-(. 1-hydroxy-1-methylethyl) -2-propyl-11- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylyl Mitazol-5-carboxylate and Exemplified Compound No. 37: (5-Methyl-2-oxiso 1,3-Dioxolen-4-yl) Methyl 4- (1-hydroxy 1 —Methylethyl) —2—Propyl— 1— [4— [2— (Tetrazol-5_yl) phenyl] phenyl] methylimidazole-5-carboxylate

Is a compound of

 The compound (I), a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, which is the active ingredient of the present invention, is known (for example, JP-A-5-78328) or a known method. (For example, JP-A-5-78328). The compound (I), a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, which is an active ingredient of the present invention, has an excellent inhibitory action on NIDDM complications and low toxicity, so that diabetic complications, especially It is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for nephropathy, hyperlipidemia, and hypertension or hypertension associated with NIDDM.

 The compound (I), a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, which is an active ingredient of the present invention, has an excellent nephritis inhibitory action and the like, and has a low toxicity. Di-Ai (IgA) nephropathy [Berger's disease], Spherical nephropathy, reproductive glomerulonephritis, sclerosing glomerulonephritis, focal glomerulosclerosis, minimal change nephrotic syndrome, etc. It is useful as a prophylactic or therapeutic agent (especially a therapeutic agent) for glomerulonephritis such as a disease type.

[Industrial applicability]

When the compound (I) which is an active ingredient of the present invention, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof is used as a therapeutic or prophylactic agent for the above-mentioned diseases, As such or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., orally with tablets, capsules, granules, powders or syrups, or parenterally with injections, etc. In particular, it can be administered orally.

These preparations contain excipients (eg, lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; corn starch, potato starch, α-starch, dextrin, carboxymethyl starch). Starch derivatives; crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally cross-linked carboxymethylcellulose sodium; gum arabic; dextran; Silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; calcium sulfate Sulphate derivatives such as Pum), binders (for example, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; magrogol and the like); disintegrants (for example, the above-mentioned excipients; croscarmellose sodium); Chemically modified starch such as sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc., lubricants (eg, talc; stearic acid; calcium stearate, metal stearate such as magnesium stearate; colloid) Dosilica; luxes such as veegum, gay mouth; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate such as sodium benzoate; sodium sulfate and the like. Sulfates; leucine; sodium lauryl sulfate, lauryl sulfate Lauryl sulfates such as magnesium; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, para-xylbenzoic acid such as methylparaben and propylparaben) Esters; Alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; Benzal conidium; Phenols such as phenol and cresol; Thimerosal; Acetic acid; sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, sour agents, flavors, etc.), diluents, solvents for injections (eg, water, ethanol, glycerin, etc.). And manufactured by a well-known method. The dosage varies depending on symptoms, age, etc.In the case of oral administration, the lower limit is lrng (preferably 10 mg) and the upper limit is 10 O Omg (preferably 500 mg) intravenously. In the case of, the lower limit of 0.5 mg (preferably 5 mg) and the upper limit of 500 mg (preferably 250 mg) can be administered to an adult 1 to 6 times per day depending on the symptoms. desirable.

[Best Mode for Carrying Out the Invention]

 Hereinafter, the present invention will be described in more detail by way of Examples and Preparation Examples, but the scope of the present invention is not limited thereto.

 (Example 1)

 Antihypertensive, lipid-lowering and proteinuria-suppressing effects in diabetic rats

 Zucker Diabetic Fatty (ZDF) rat, a spontaneous NI DDM model, was administered a test compound in a diet for 12 weeks from the age of 12 weeks to 31 weeks (in addition to the The concentration of the test compound is 0.001% or 0.01%.) The control group received a diet containing no drug. As a normal animal group, Lean rats of the same age were used, and the rats were also fed a drug-free diet.

The following measurements were performed at the age of 30 to 31 weeks of age. That is, the systolic blood pressure was measured by the Til-Cuff method under asthma. Urine was collected for 24 hours using a metabolic cage, and the protein concentration in the urine was measured by the pyrogallol red-molybdenum complex method. In addition, blood glucose is measured by the glucose oxidase method, and plasma lipids (total cholesterol, triglyceride and non-ester free fatty acids) are measured by an automatic analyzer (Hitachi 7250, manufactured by Hitachi, Ltd.). did. Statistical significance was tested by Dunnett's multiple comparison test, and a significance level (P) less than 0.05 was considered significant. did. Table 2 shows the measurement results of systolic blood pressure and protein concentration in urine, and Table 3 shows the measurement results of blood glucose level and plasma lipids (total cholesterol, triglyceride and nonester free fatty acids).

[Table 2] Experiment Test compound dose Animal weight 4S systolic blood pressure Urinary protein excretion

 (%) Number (g) (ramHg) (mg / day / lOOg body weight)

1 Exemplified compound number 0.00Γ) 9 471 ± 15 142 ± 4 65.0 ± 6.2 **) 37 compounds

 2 Exemplified compound number 0.0Γ) 10 468 ± 16 121 ± 3 **) 22.9 ± 4.2 **)

3? Compound Control group 10 482 ± 19 150 ± 4 92.1 ± 7.2 Normal group 10 446 ± 15 123 ± 3 ") SJiO.S *"

*) Concentration of test compound in feed.

**) There is a significant difference (P <0.05) compared to the control group.

[Table 3] Blood sugar level Total cholesterol Triglyceride Free fatty acid (mg / dl) (mg / dl) (mg / dl) (mEq / 1)

521 ± 22 212 ± 15 '') 460 soil 8Γ *)

 526 ± 23 135 Sat 9 ") 240 + 27 **, 1.16 ± 0.07 **) Control group 501 ± 27 277 ± 14 907 ± 118 1.84 ± 0.12 Normal group 161 Sat 3 **) 94 Sat 3 **) 79 Sat 7 ** '1.00 ± 0.08 **)

**) There is a significant difference (P <0.05) compared to the control group.

 As can be seen from the above results, the compound which is the active ingredient of the present invention does not affect the body weight and blood glucose level, but has high blood pressure, increased excretion of urinary protein and increased plasma Significantly suppress the increase in lipids.

 (Example 2)

 Suppression of nephritis by rat

 T. Yamamoto & CB Wilson's method [Kidney-Inta-National, Vol. 32, pp. 514-525 (1 987): Kid. Int., 32, 514-525 ( 1987)], a glomerulonephritis model was prepared by once intravenously injecting an anti-rat Thy-1.1 monoclonal antibody into a 7-week-old Wistar Kyoto rat.

The test compound was suspended in a 0.5% carboxymethylcellulose aqueous solution (CMC solution) and administered orally at 10 _mg / kg / day after the nephritis was induced until the end of the experiment. On the 7th day after inducing nephritis, urinary protein and α-reactive protein were analyzed using the pyrogallol red 'molybdenum complex method and the ELISA (Enzyme-Linked Immunosorbent Assay). Bumin was measured and the degree of glomerular sclerosis was measured. To measure the degree of glomerular sclerosis, renal cortical paraffin sections were stained with PAM (Periodic Acid-Methenamine silver), and then 50 glomeruli per animal were observed under a microscope, and Raiji et al. [Kidou 21 'International, Vol. 26, pp. 137-143 (1988): Kid. Int., 26, 137-143 (1984)]. Table 4 shows the results of urinary protein excretion and urinary albumin excretion, and Table 5 shows the results of the ovule sclerosis index.

[Table 4] Experiment Test compound Animal Urinary protein excretion Urinary albumin excretion Number (mg / day / 100g body weight) (g / day / 100g body weight)

1 Exemplified compound number 2.4 ± 0.2 744 ± 112

 37 compounds Control group 6.0, 6.0 ± 1.1 3960 ± 7% Normal group 7 1.6 ± 0.1 159 soil 13

*) The solvent (CMC solution) was administered. [Table 5] Experiment Test compound Animal

 number

1 Exemplary compound number 7 236.9 ± 13.1

 37 compounds Control group 7 * '296.6 Sat 9.3

 Normal group 7 96.0 Sat 8.3

*) The solvent (CMC solution) was administered.

 As can be seen from the above results, the compound that is the active ingredient of the present invention significantly suppresses the increase in urinary protein excretion and urinary albumin excretion, and significantly improves ovule hardening.

 (Formulation Example 1)

 —: Cell agent

 Compound of Exemplified Compound No. 37 50.0 mg

 Lactose 128.7

 Starch sorghum starch 70.0

 Magnesium stearate 1.3

 250 mg

 After mixing the powder of the above formulation and passing through a 60 mesh sieve, the powder is placed in a 25 Omg No. 3 gelatin capsule to form a capsule.

(Formulation Example 2) Compound of Exemplified Compound No. 37 50.0 mg Sucrose 124.0

 Corn starch 25.0

 Magnesium stearate 1.0

 200 mg

 The powder of the above formulation is mixed and tableted with a tableting machine to make a tablet of 200 mg per tablet.

 The tablets can be sugar-coated as needed.

Claims

Claims General formula

(In the formula, R ¹ represents a d-C ₄ alkyl group, R ² and R ³ are the same or different and each represent a hydrogen atom or a d-C ₄ alkyl group; R ⁴ represents a hydrogen atom or a d-C ₄ alkyl group, R ⁵ represents a hydrogen atom, R ⁶ represents a carboxy group or a tetrazol-5-yl group. )  A composition for the prevention or treatment of diabetic complications, comprising, as an active ingredient, an imidazolecarboxylic acid having the formula (I), a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.  2. The active ingredient is 2. The composition according to claim ¹ , wherein R ¹ is an imidazole carboxylic acid, a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, wherein R ¹ is an ethyl group, a propyl group or a butyl group.  3. The active ingredient is 2. The composition according to claim ^{1, wherein} R1 is an imidazolecarboxylic acid, wherein R1 is a propyl group or a butyl group, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. 4. The active ingredient is 3. The composition according to claim ^{1, wherein} R ¹ is a propyl group, an imidazole carboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. 5. The active ingredient is Claims 1 to 4 wherein R ² and R ^{3 are} the same or different and are a hydrogen atom or a methyl group, imidazolecarboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. Composition. 6. The active ingredient is The composition according to any one of claims 1 to 4, wherein R ² and R ^{3 are} the same and are a methyl group, imidazole carboxylic acid, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof. 7-the active ingredient is 7. The composition according to claim 1, wherein R ⁴ is a hydrogen atom or a methyl group, imitazole carboxylic acids, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof.  8. The active ingredient is 7. The composition according to claim 1, which is an imidazole carboxylic acid wherein R ⁴ is a hydrogen atom, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.  9. The active ingredient is Group (wherein the R ⁵ is a hydrogen atom or the formula R ⁵ a, R ⁵ a is a methyl group, Echiru group, Asetokishimechiru group, 1 i (Asetokishi) Echiru group, Viva Roy Ruo carboxymethyl group, 1 i (pivaloyl Ethyoxy group, methoxycarbonyl xymethyl group, 1- (methoxycarbonyloxy) ethyl group, ethoxy carbonyl xymethyl group, 1- (ethoxy carbonyl xydi) ethyl group, propoxycarponyloxymethyl group, 1— (Propoxycarbonyl) ethyl group, isopropoxy It is a bonyloxymethyl group, a 1- (isopropoxycarbonyloxy) ethyl group, a (5-methyl-2-oxo1-1,3-dioxolen-4-yl) methyl group or a phthalidyl group. 9. The composition according to claim 1, which is an imidazole carboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.  1 0. The active ingredient is Group (wherein the R ⁵ is a hydrogen atom or the formula R ⁵ a, R ⁵ a is pivaloyl old Kishime methyl group, an ethoxycarbonyl O carboxymethyl group, 1 i (ethoxycarbonyl O carboxymethyl) Echiru group, isoproterenol ball alkoxycarbonyl An imidazo group which is a methoxymethyl group, a 1- (isopropoxycarbonyloxy) ethyl group, a (5-methyl-2-year-old 1,3-di-oxolen-4-yl) methyl group or a phthalidyl group. 9. The composition according to claim 1, which is a monocarboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. 1 1. Group (wherein R ⁵ is of the formula R ⁵ a, R ⁵ a is pivaloyl talent Kishimechiru group or (5-methyl-one 2-year old Kiso one 1, 3-Jiokisoren one 4-I) methyl 9. The composition according to claim 1, which is an imidazole carboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.  1 2. The active ingredient is 12. The composition according to claim 1, wherein R ⁶ is an imidazole carboxylic acid having a tetrazol-5-yl group, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.  1 3. The active ingredient is  Bivaloyl xymethyl 4-hydroxymethyl-2-propyl-1_ [4- [2- (tetrazol-5_yl) phenyl] phenyl] methylimidazole-5-carboxylate, (5-Methyl- 2-isolated 1, 3-Di-isolated 4-yl) Methyl 4- Hydroxymethyl-2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,  Bivaloyl xymethyl 4- (1-hydroxyethyl) -2-propyl-1 -— [4-1 [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,  (5-methyl-2- (1,3-dioxylene-1-4)) methyl 4- (1-hydroxyethyl) —2-propyl-1- (4- [2-(tetrazole-5-) Phenyl) phenyl] methylimidazole-5-carboxylate, bivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-11- [1- [2- (tetrazol-5-yl) Phenyl] phenyl] methylimidazoyl 5-carboxylate,  Ethoxycarbonyloxymethyl 4- (1-hydroxy-1-1-methylethyl) —2-propyl-11- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazoyl 5-carboxylate,  1- (Ethoxycarbonyl) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazo One roux 5-carboxylate,  Isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-1-methylethyl) —2-propyl-1-111 [4 -— [2- (tetrazo-1-yl-5-phenyl) phenyl] phenyl] methylimidazole-5— Carboxylates,  1- (Isopropoxycarbonyloxy) ethyl 4- (1-Hydroxy-1-methylethyl) 1-2-propyl-1 1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5- Carboxylate,  (5-methyl-1-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-1-methylethyl) 1-2-propyl-1- [4-1- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carbo Xylate,  Bivaloyloxymethyl 2-butyl-1- (1-hydroxy-1-1-methylethyl) 1-1-1 [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazo-1-yl 5-carboxylate,  Ethoxycarbonyl 2-methyl-butyl 4- (1-hydroxy-1-methylethyl) — 1— [4-—2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,  1- (Ethoxycarbonyloxy) ethyl 2-butyl-4- (1-hydroxy-1-methylethyl) — 1- [4— [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5— Carboxylates,  Isopropoxycarbonyloxymethyl 2-butyl-4- (1-hydroxy-11-methylethyl) — 1- [4- [2- (tetrazo-1-yl-5-phenyl) phenyl] phenyl] methylimidazole-5-carboxy Rate,  1- (Isopropoxycarbonyl) ethyl 2-butyl-4-1- (1-hydroxy-1-methylethyl) 1-1-1 [4-1 [2- (tetrazo-1-yl-5-yl) phenyl] phenyl] methylimidazoleー 5-carboxylate and  (5-Methyl-l-l-l-l-l-l-l-l-l-l-l-l-l-l-l-l-l-yl) Methyl 2-l-butyl-l-l-l- (l-hydroxy-l-methylethyl)-1- [4- [2--(tetrazol-5 —Yl) phenyl! Phenyl) methylimidazole— imidazolecarboxylic acids selected from the group consisting of 5-carboxylates, pharmacologically acceptable salts thereof, and pharmacologically acceptable esters thereof. Composition.  14. The composition according to any one of claims 1 to 13, wherein the diabetic complication is nephropathy, hyperlipidemia or hypertension. 15. General formula

(Wherein, R ¹ represents a C, mono-C ₄ alkyl group, R ² and R ³ are the same or different and each represent a hydrogen atom or a C ₄ alkyl group; R ⁴ represents a hydrogen atom or a C, -C ₄ alkyl group, R ⁵ represents a hydrogen atom, R ⁶ represents a carboxy group or a tetrazol-5-yl group. )  A composition for preventing or treating renal disease, comprising as an active ingredient an imidazole carboxylic acid having the formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof.  16. The active ingredient is R ¹ is Echiru group, imidazo one Rukarubon acids propyl group or a butyl group, a pharmacologically acceptable salt or range囲第15 of the composition according to a pharmacologically acceptable ester.  17. The active ingredient is 16. The composition according to claim 15, wherein R ¹ is an imidazole carboxylic acid having a propyl group or a butyl group, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof.  18. The active ingredient is 16. The composition according to claim 15, wherein R ¹ is a propyl group, an imidazole carboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. 1 9. The active ingredient is R ² and R ³ were the same or different, imidazole Rukarubon acids is a hydrogen atom or a methyl group, to the first 5 wherein the range of a pharmacologically acceptable claimed salts or ester le that is pharmacologically acceptable first 18. The composition of clause 8. 20. The active ingredient is Claims 15 to 18 wherein R ² and R ^{3 are} the same, a methyl group, which is imidazole carboxylic acid, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof. Composition. 2 1. The active ingredient is Imidazole carboxylic acids R ⁴ is a hydrogen atom or a methyl group, a pharmacologically permissible salt or first 5 Ko乃optimum second 0 term in the composition claims a pharmacologically acceptable ester. 2 2. The active ingredient is Imidazole carboxylic acids R ⁴ is a hydrogen atom, a pharmacologically acceptable Shiowaka properly first paragraph 5 or the composition of the second 0 term claims a pharmacologically acceptable ester.  2 3. The active ingredient is Group (wherein the R ⁵ is a hydrogen atom or the formula R ⁵ a, R ⁵ a is a methyl group, Echiru group, § Se Bok Kishimechiru group, 1- (Asetokishi) Echiru group, Viva Roy Ruo carboxymethyl group, 1 1- (bivaloyloxy) ethyl group, methoxycarbonyloxymethyl group, 1- (methoxycarbonyloxy) ethyl group, ethoxycarbonyl-l-oxymethyl group, 1-l- (ethoxycarbonylloxy) ethyl group, propoxycarbonylloxy Methyl group, 1- (propoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl1-2-oxo-1,3-dioxolene) 4-yl) a methyl group or a phthalidyl group.)) Or a pharmacologically acceptable salt thereof. Or the composition according to claim 15, which is a pharmacologically acceptable ester thereof.  2 4. The active ingredient is Group (wherein the R ⁵ is a hydrogen atom or the formula R ⁵ a, R ⁵ a is pivaloyl old Kishime butyl group, an ethoxycarbonyl old Kishimechiru group, 1- (ethoxycarbonyl old carboxymethyl) Echiru group, isopropoxycarbonyl old Kishimechiru An imidazole carboxy group which is a 1- (isopropoxycarbonylcarbonyl) ethyl group, a (5-methyl-2-alkyl-1,3-dioxolen-4-yl) methyl group or a phthalidyl group. The composition according to any one of claims 15 to 22, which is an acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. . 2 5 group (wherein the R ⁵ has the formula R ⁵ a, R ⁵ a is pivaloyl talent Kishimechiru group or (5-methyl-one 2-year old Kiso - 1, 3-di old Kisoren - 4- I le The composition according to any one of claims 15 to 22, wherein the composition is an imidazole carboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. 2 6. The active ingredient is The composition according to any one of claims 15 to 25, wherein R ⁶ is an imidazolecarboxylic acid having a tetrazol-5-yl group, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. . 2 7. The active ingredient is  Bivaloyloxymethyl 4-hydroxymethyl _2-propyl-1 _ [4-1  [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,  (5-Methyl _ 2-1,4-dioxolene 4 f) Methyl 4 _ hydroxymethyl-2-propyl _ 1 [4-[2-(tetrazol-5-^ T) phenyl ] Phenyl] methylimidazole-5-carboxylate, 4— (1-hydroxyethyl) —2-propyl— 1 -[4 -— [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,  (5-Methyl-1-2-Kiso-1,3-Di-Kiso-Len-4-yl) Methyl 4- (1-Hydroxityl) — 2-Propyl—1 _ [4-1- [2-(Tetrazol— 5- (yl) phenyl] phenyl] methylimidazo-1-yl 5-carboxylate, bivaloyl xymethyl 4- (1-hydroxy-1-methylethyl) 1-2-propyryl-1— [4--1- [2- (tetrazol-5— Phenyl) phenyl] methylimidazole-5-carboxylate,  Ethoxycarbonyl 4-methyl (4-hydroxy-1-methylethyl) 2- (1-propyl) -1- [4- [2- (tetrazol-1-yl) phenyl] phenyl] methylimidazole-5-carboxylate ,  1— (Ethoxycarbonyl) ethyl 4 -— (1-Hydroxy-1-methylethyl) —2_propyl—1-1 [4-1- [2- (Tetrazol-5— ^ fur) phenyl] phenyl] methylimidazole-5 —Carboxylate,  Isopropoxycarbonyl xymethyl 4- (1-hydroxy-1-methylethyl) 1-2-propyl-11- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxy Rate,  1- (Isobroboxycarbonyl) ethyl 4- (1-Hydroxy-1- 1-methylethyl) -2-propyl-1- [4- [2- (Tetrazol-5- ^ Tl) phenyl] phenyl ] Methylimidazoyl 5-carboxylate,  (5 _ methyl _ 2 -oxo 1, 3-dioxylene 1-4 -yl) methyl 4-1 (1-hydroxyl-1-methylethyl)-2-propyl 1-1 [4-[2-( Trazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate, Bivaloyl xymethyl 2-butyl-41- (1-hydroxy-1-methylethyl) — 1— “4-—2- (tetrazol-5-yl) phenyl] phenyl] me Tilimidazole-5-carboxylate,  Ethoxycarbonyl 2-methyl-butyl 4- (1-hydroxy-1-methylethyl) — 1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,  1- (Ethoxycarbonyl) ethyl 2-butyl-4— (1-hydroxy-1-methylethyl) — 1— [4-—2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole — 5—Carboxylates,  Isopropoxycarbonyloxymethyl 2-butyl-41- (1-hydroxy-1-methylethyl) — 1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole_5-carboxylate,  1- (Isopropoxycarbonyloxy) ethyl 2-butyl-4- (1-hydroxy-1-methylethyl) — 1- [4- [2- (tetrazol-5- ^ re) phenyl] phenyl] methyl Imidazo mono-5-carboxylate and  (5-Methyl-2-yl-1,4-dioxolen-4-yl) Methyl-2-butyl-4 _ (1-hydroxy-1-1-methylethyl) — 1— [4— [2— (tetrazol— 5_yl) [phenyl] phenyl] methylimidazole-5-carboxylates, imidazolecarboxylic acids selected from the group consisting of pharmaceutically acceptable salts, and pharmacologically acceptable esters thereof. The composition of 28. The composition according to paragraphs 15 through 27, wherein the kidney disease is glomerulonephritis.