JP2006036792A - Prophylactic drug or therapeutic drug for diabetic complication - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a prophylactic drug or a therapeutic drug for diabetic complication which has an excellent inhibitory action on any of nephropathy, hyperlipemia, and hypertension of NIDDM model rats. <P>SOLUTION: The prophylactic drug or the therapeutic drug for diabetic hyperlipemia comprises an imidazolecarboxylic acid of the formula (wherein R<SP>1</SP>is a 1-4C alkyl group; R<SP>2</SP>and R<SP>3</SP>are each H or a 1-4C alkyl group; R<SP>4</SP>are H or a 1-4C alkyl group; R<SP>5</SP>is H; and R<SP>6</SP>is COOH or a tetrazol-5-yl group), its pharmacologically acceptable salt or its pharmacologically acceptable ester as an active ingredient. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a preventive or therapeutic agent for diabetic complications containing imidazole carboxylic acids, pharmacologically acceptable salts or pharmacologically acceptable esters thereof as active ingredients, or imidazole carboxylic acids, pharmacologically acceptable The present invention relates to a renal disease preventive or therapeutic agent containing a salt or a pharmacologically acceptable ester thereof as an active ingredient.

With the westernization of eating habits and the aging of the population, cardiovascular diseases such as hypertension and heart disease,
The number of patients with metabolic diseases such as diabetes and hyperlipidemia continues to increase. In particular, obesity, diabetes [especially non-insulin dependent diabetes mellitus (NIDDM)], syndrome X (Syndrome X) [Diabitis, 37
Volumes 1595 to 1607 (1988): Diabetes, 37 , 1595-1607 (1988)] is an increasing problem. In such patients, the risk of developing coronary artery disease is very high, and useful preventive or therapeutic means have been sought. In Syndrome X, the pathological condition includes insulin dysfunction, that is, insulin resistance [Diabetrodia, Vol. 21, pp. 165 to 171 (1981): Diabetologia, 21
, 165-171 (1981)], and the usefulness of insulin sensitizers such as troglitazone and pioglitazone, which are being developed in recent years, is expected. However, considering the diversity of patients, it is unlikely that an insulin sensitizer alone can treat all of Syndrome X and other diabetic complications, and another means is needed to effectively treat diabetic complications. Is done. In addition, when a diabetic patient has nephropathy, hypertension and hyperlipidemia worsen due to kidney damage, and the prognosis of the patient further worsens. Therefore, prevention and treatment of nephropathy are particularly important among diabetic complications.

Effectiveness of angiotensin converting enzyme (ACE) inhibitor, which has been used as an antihypertensive agent, for diabetic nephropathy in recent years [New England Journal of Medicine, Vol. 313, pp. 1617 to 1620 (1985) Year): New. Eng. J. Med., 313 ,
1617-1620 (1985)] has been clarified, but this drug is also considered to improve insulin resistance, and its mechanism is thought to enhance the kinin system [hypertension. 23, 450-455 (1992): Hypertension,
23 , 450-455 (1992)]. In addition, angiotensi II receptor antagonist, the same renin-angiotensive inhibitor, can be expected to have a renal protective effect. In fact, losartan inhibits nephropathy in insulin-dependent diabetes mellitus (IDDM) rats induced by streptozotocin. [Journal of American Society of Nephrology, Volume 4, pages 40-49 (1993)
: J. Am. Soc. Nephrol., 4 , 40-49 (1993)]. Angiotensi II receptor antagonists that do not have a kinin potentiating action have few side effects such as dry cough, but there is a debate over whether to improve insulin resistance. NIDDM has low renin activity in blood and kidney tissues [Journal of American Society of Nephrology, Vol. 4, pp. 1354 to 1361 (1993): J. Am. Soc .
Nephrol., 4 , 1354-1361 (1993)], Angiotensiveness for NIDDM complications
The effectiveness of II receptor antagonists is not always clear. In fact, spontaneous NIDDM
Angiotensin in obese Zucker rats, model animals
Losartan, an II antagonist, has an antihypertensive effect, but has decreased urinary protein and blood lipids (
It has also been reported that no decrease in cholesterol, triglyceride, etc. is observed [Journal of American Society of Nephrology, Vol. 6, pp. 1295 to 1299 (1995): Am. Soc. Nephrol., 6 ,
1295-1299 (1995)].

On the other hand, renal diseases such as IgA nephropathy [Berger's disease], membranous nephropathy, proliferative glomerulonephritis, sclerosing glomerulonephritis, focal glomerulosclerosis, microscopic As for glomerulonephritis classified into disease types such as change type nephrotic syndrome, the onset mechanism and the development mechanism have not been clarified to date for any of these disease types. For example, IgA nephropathy, the most common type of glomerulonephritis, occurs when IgA-based immune complexes are deposited on the glomeruli and eventually undergo various processes. [American Journal of Kidney
Disdies, Vol. 12, 388-392 (1988): Am. J. Kid. Dis.,
12 , 388-392 (1988), Clinical Nephrology, 38, 245-253.
(1992): Clin. Nephrol., 38 , 245-253 (1992)]. However, IgA
Antigens that stimulate antibody production are still unclear, and the mechanism of nephritis progression after immune complex deposition includes complement activation, leukocyte infiltration, production of growth factors for various cytokines, production of active oxygen, Although involvement of blood coagulation abnormalities has been suggested, details are not clear [Yogo Rin, Vol. 45, pp. 228 to 233 (1996)].

As therapeutic agents for glomerulonephritis and the like, immunosuppressive agents, antiplatelet agents, anticoagulants and the like are currently used mainly for corticosteroids. However, corticosteroids and immunosuppressive drugs have problems in long-term administration because of their side effects, and the effectiveness of each drug is not high because the effects are divided. In fact, the number of kidney disease patients who undergo artificial dialysis continues to increase in Japan.
40% have glomerulonephritis.

Recently, it has been suggested that angiotensin converting enzyme (ACE) inhibitors, among other antihypertensive agents, have a renal protective effect [American Journal of Hypertension, Vol. 10 (Part 2), p. 53S. To page 58S (1995): Am. J.
Hypertens., 10 (Pt.2), 53S-58S (1995)]. However, at present, the only usefulness is the use of ACE inhibitors for diabetic nephritis [New England Journal of Medicine, Vol. 329, pp. 1456 to 1462]
(1993): New. Eng. J. Med., 329 , 1456-1462 (1993)]. Renal protection mechanisms of ACE inhibitors include a decrease in intraglomerular pressure [hyperfilation
(hyperfiltration) correction and suppression of stromal cell proliferation and fibrosis, etc. [New England Journal of Medicine, No. 307
Volumes 652 to 659 (1982): New. Eng. J. Med., 307 , 652-659
(1982), Achievements of International Medicine, Volume 153,
1749 to 1759 (1993): Arch. Intern. Med., 153 , 1749-1759 (1993)
]]. There have been reports on the usefulness of ACE inhibitors in patients with glomerulonephritis who have IgA nephropathy [Contribution to nephrology, Vol. 90, Vol.
161 to 165 (1991): Contrib. Nephrol., 90 , 161-165 (1991)].
However, how it is effective for patients without hypertension is a future issue. In addition, except for some ACE inhibitors that have been developed so far, the excretion route is the kidney, and in that respect, administration to patients with renal disease is forced to be careful.

In addition, angiotensin II antagonists that have been developed recently are expected to have a nephroprotective effect, but their effectiveness against renal diseases, particularly glomerulonephritis, is not clear. For example, in the model of membranous nephropathy [Heymann nephritis], enalapril, an ACE inhibitor, has a clear proteinuria inhibitory effect, whereas losartan, an angiotensin II antagonist, has no proteinuria inhibitory effect. [American Journal of Physology, Volume 263, pages F311 to F318]
(1992): Am. J. Physiol., 263 , F311-F318 (1992)].

The present inventors have conducted various studies in view of the importance of prevention and treatment of diabetic complications, particularly nephropathy, hyperlipidemia and hypertension associated with NIDDM. As a result, specific angiotensin II receptor antagonists have been obtained. The drug has an excellent inhibitory effect on all of nephropathy, hyperlipidemia and hypertension in NIDDM model rats, has few side effects, diabetic complications, especially nephropathy, hyperlipidemia and As a result, it has been found to be a prophylactic or therapeutic drug for 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, specific angiotensin II receptor antagonists have been artificially created in rats. It has been found that it has an excellent inhibitory effect on glomerulonephritis, has few side effects, and is a preventive or therapeutic agent for renal diseases, particularly glomerulonephritis.

The present invention relates to a prophylactic or therapeutic agent for diabetic complications containing a specific angiotensin II receptor antagonist as an active ingredient, or a prophylactic or renal drug containing a specific angiotensin II receptor antagonist as an active ingredient or Provide therapeutic drugs.

The imidazole carboxylic acids that are active ingredients of the present invention are:
General formula

Have

In the above formula,
R ¹ represents a C ₁ -C ₄ alkyl group,
R ² and R ³ are the same or different and each represents a hydrogen atom or a C ₁ -C ₄ alkyl group,
R ⁴ represents a hydrogen atom or a C ₁ -C ₄ alkyl group,
R ⁵ represents a hydrogen atom,
R ⁶ represents a carboxy group or a tetrazol-5-yl group.

_{^{R 1, R 2, C 1}} -C 4 alkyl group of R ³ and R ⁴ are, for example, methyl, obtained is ethyl, propyl, isopropyl, butyl, isobutyl group, the R ¹ C ₁ -
The C ₄ alkyl group is preferably an ethyl, propyl or butyl group, more preferably a propyl or butyl group, particularly preferably a propyl group, R ² ,
The C ₁ -C ₄ alkyl group of R ³ and R ⁴ is preferably a methyl or ethyl group, and particularly preferably a methyl group.

The ester 殘 group (R ⁵ a) of the pharmacologically acceptable ester of compound (I) is, for example, the above-mentioned C ₁ -C ₄ alkyl group, C ₂ -C ₅ alkanoyloxymethyl or 1- (C ₂ -C). ₅ alkanoyloxy) ethyl group (said C ₂ -C ₅ alkanoyl moiety, eg, acetyl, propionyl, butyryl, isobutyryl, valeryl,
It can be isovaleryl or pivaloyl, preferably acetyl or pivaloyl, and particularly preferably pivaloyl. ), C ₁ -C ₄ alkoxycarbonyloxymethyl or 1- (C ₁ -C ₄ alkoxycarbonyloxy) ethyl group (the C ₁ -C ₄ alkoxy moiety is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, It can be isobutoxy, preferably methoxy, ethoxy, propoxy or isopropoxy, particularly preferably ethoxy or isopropoxy), (5-methyl-2-oxo-1,3-dioxolen-4 -Yl) methyl group, (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group, preferably methyl group, ethyl group, acetoxymethyl group, 1- (Acetoxy) ethyl group, pivaloyloxymethyl group, 1-
(Pivaloyloxy) ethyl group, methoxycarbonyloxymethyl group, 1- (methoxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 1-
(Ethoxycarbonyloxy) ethyl group, propoxycarbonyloxymethyl group, 1- (propoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2-oxo -1,3-dioxolen-4-yl) methyl group or phthalidyl group, particularly preferably pivaloyloxymethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, isopropoxycarbonyl Oxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5
-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group, most preferably pivaloyloxymethyl group or (5-methyl-2
-Oxo-1,3-dioxolen-4-yl) methyl group. Further, an ester of a carboxy group at the 5-position of the imidazole ring is preferable.

The compound (I) of the present invention can be converted into a 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,
Salts with bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and salts with organic bases such as guanidine, triethylamine and dicyclohexylamine. Is given.

Furthermore, when an asymmetric carbon atom is present in the molecule of compound (I), racemates and optically active substances are included, and hydrates of compound (I) or salts thereof are also included.

In addition, compound (I) is preferably
(1) A compound in which R ¹ is an ethyl group, a propyl group or a butyl group,
(2) a compound in which R ¹ is a propyl group or a butyl group,
(3) a compound wherein R ¹ is a propyl group,
(4) A compound in which R ² and R ³ are the same or different and are a hydrogen atom or a methyl group,
(5) A compound in which R ² and R ³ are the same and are a methyl group,
(6) A compound in which R ⁴ is a hydrogen atom or a methyl group,
(7) A compound in which R ⁴ is a hydrogen atom,
(8) R ⁵ is a hydrogen atom or a group having the formula R ⁵ a (wherein R ⁵ a is a methyl group, an ethyl group, an acetoxymethyl group, a 1- (acetoxy) ethyl group, a pivaloyloxymethyl group, 1- (pivaloyloxy) ethyl group, methoxycarbonyloxymethyl group, 1- (methoxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, propoxycarbonyloxymethyl group, 1- (propoxy) A carbonyloxy) ethyl group, an isopropoxycarbonyloxymethyl group, a 1- (isopropoxycarbonyloxy) ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or a phthalidyl group. A compound that is
(9) R ⁵ is a hydrogen atom or a group having the formula R ⁵ a (wherein R ⁵ a is a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1- (ethoxycarbonyloxy) ethyl group, isopropoxy A compound that is a carbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group);
(10) R ⁵ is a group having the formula R ⁵ a (wherein R ⁵ a is a pivaloyloxymethyl group or a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group A compound that is
(11) Examples include compounds in which R ⁶ is a tetrazol-5-yl group. It should be noted that between groups showing the same group, the preferred degree increases as the group number increases (for example, (1) is more preferable between R ¹ groups, and (2) is even more (3) is particularly preferred.)

Further, R ¹ is selected from the group consisting of (1)-(3), R ² and R ³ are selected from the group consisting of (4)-(5), and from the group consisting of (6)-(7). Select R ⁴ and
A compound obtained by selecting R ⁵ from the group consisting of (8)-(10) and combining them or combining these with R ^{6 of} (11) is also suitable, and examples thereof include the following. .
(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,
R ⁵ is a hydrogen atom or a group having the formula R ⁵ a (wherein R ⁵ a is a methyl group, an ethyl group, an acetoxymethyl group, a 1- (acetoxy) ethyl group, a pivaloyloxymethyl group, 1- ( Pivaloyloxy) ethyl group, methoxycarbonyloxymethyl group,
1- (methoxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, propoxycarbonyloxymethyl group, 1- (propoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1 -(Isopropoxycarbonyloxy) ethyl group, (
5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group. A compound that 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,
R ⁵ is a hydrogen atom or a group having the formula R ⁵ a (wherein R ⁵ a is a pivaloyloxymethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl) Group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group).
A compound wherein R ⁶ is a tetrazol-5-yl group,
(14) R ¹ is a propyl group,
R ² and R ³ are the same and are methyl groups;
R ⁴ is a hydrogen atom,
R ⁵ is a group having the formula R ⁵ a (wherein R ⁵ a is a pivaloyloxymethyl group or (
5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group.
) And
A compound wherein R ⁶ is a tetrazol-5-yl group.

Specific examples of suitable compounds in formula (I) include the compounds shown in the following Table 1.

(Table 1)
──────────────────────────────────
Compound R ¹ R ² R ³ R ⁴ R ⁵ R ⁶
Number (No.)
──────────────────────────────────
1 Et Me Me HH CO ₂ H
2 Et Me Me H Pom CO ₂ H
3 Et Me Me H Mod CO ₂ H
4 Et Me Me HH Tz
5 Et Me Me H Pom Tz
6 Et Me Me H Mod Tz
7 Pr HHHH CO ₂ H
8 Pr HHH Pom CO ₂ H
9 Pr HHH Mod CO ₂ H
10 Pr HHHH Tz
11 Pr HHH Pom Tz
12 Pr HHH Mod Tz
13 Pr H Me HH CO ₂ H
14 Pr H Me H Pom CO ₂ H
15 Pr H Me H Mod CO ₂ H
16 Pr H Me HH Tz
17 Pr H Me H Pom Tz
18 Pr H Me H Mod Tz
19 Pr Me Me HH CO ₂ H
20 Pr Me Me H Me CO ₂ H
21 Pr Me Me H Et CO ₂ H
22 Pr Me Me H Pom CO ₂ H
23 Pr Me Me H CH ₂ OCO ₂ Et CO ₂ H
24 Pr Me Me H CH (Me) OCO ₂ Et CO ₂ H
25 Pr Me Me H CH ₂ OCO ₂ Pr ⁱ CO ₂ H
26 Pr Me Me H CH (Me) OCO ₂ Pr ⁱ CO ₂ H
27 Pr Me Me H Mod CO ₂ H
28 Pr Me Me H Phth CO ₂ H
29 Pr Me Me HH Tz
30 Pr Me Me H Me Tz
31 Pr Me Me H Et Tz
32 Pr Me Me H Pom Tz
33 Pr Me Me H CH ₂ OCO ₂ Et Tz
34 Pr Me Me H CH (Me) OCO ₂ Et Tz
35 Pr Me Me H CH ₂ OCO ₂ Pr ⁱ Tz
36 Pr Me Me H CH (Me) OCO ₂ Pr ⁱ Tz
37 Pr Me Me H Mod Tz
38 Pr Me Me H Phth Tz
39 Pr Me Me Me H CO ₂ H
40 Pr Me Me Me Pom CO ₂ H
41 Pr Me Me Me Mod CO ₂ H
42 Pr Me Me Me H Tz
43 Pr Me Me Me Pom Tz
44 Pr Me Me Me Mod Tz
45 Bu HHHH CO ₂ H
46 Bu HHH Pom CO ₂ H
47 Bu HHH Mod CO ₂ H
48 Bu HHHH Tz
49 Bu HHH Pom Tz
50 Bu HHH Mod Tz
51 Bu H Me HH CO ₂ H
52 Bu H Me H Pom CO ₂ H
53 Bu H Me H Mod CO ₂ H
54 Bu H Me HH Tz
55 Bu H Me H Pom Tz
56 Bu H Me H Mod Tz
57 Bu Me Me HH CO ₂ H
58 Bu Me Me H Pom CO ₂ H
59 Bu Me Me H CH ₂ OCO ₂ Et CO ₂ H
60 Bu Me Me H CH (Me) OCO ₂ Et CO ₂ H
61 Bu Me Me H CH ₂ OCO ₂ Pr ⁱ CO ₂ H
62 Bu Me Me H CH (Me) OCO ₂ Pr ⁱ CO ₂ H
63 Bu Me Me H Mod CO ₂ H
64 Bu Me Me H Phth CO ₂ H
65 Bu Me Me HH Tz
66 Bu Me Me H Me Tz
67 Bu Me Me H Et Tz
68 Bu Me Me H Pom Tz
69 Bu Me Me H CH ₂ OCO ₂ Et Tz
70 Bu Me Me H CH (Me) OCO ₂ Et Tz
71 Bu Me Me H CH ₂ OCO ₂ Pr ⁱ Tz
72 Bu Me Me H CH (Me) OCO ₂ Pr ⁱ Tz
73 Bu Me Me H Mod Tz
74 Bu Me Me H Phth Tz
75 Bu Me Me Me H CO ₂ H
76 Bu Me Me Me Pom CO ₂ H
77 Bu Me Me Me Mod CO 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-oxo-1,3-dioxolen-4-yl) methyl group
Phth: phthalidyl group
Pom: Pivaloyloxymethyl group
Pr: Propyl group
Pr ⁱ : Isopropyl group
Tz: tetrazol-5-yl group.

In the above table, preferably, Exemplified Compound No. 2, 3, 4, 5, 6
, 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, 11, 12,
14, 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, 11,
12, 14, 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,
Exemplified Compound No. 11: Pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 12: (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4-hydroxymethyl-2-propyl-1- [4- [2
-(Tetrazol-5-yl) phenyl] phenyl] methylimidazole-5
Carboxylate,
Exemplified Compound No. 17: Pivaloyloxymethyl 4- (1-hydroxyethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 18: (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxyethyl) -2-propyl-1- [
4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 32: Pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-
Yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 33: Ethoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 34: 1- (ethoxycarbonyloxy) ethyl 4-
(1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 35: Isopropoxycarbonyloxymethyl 4- (
1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 36: 1- (Isopropoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2
-(Tetrazol-5-yl) phenyl] phenyl] methylimidazole-5
Carboxylate,
Exemplified Compound No. 37: (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazole- 5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 68: Pivaloyloxymethyl 2-butyl-4- (1
-Hydroxy-1-methylethyl) -1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 69: Ethoxycarbonyloxymethyl 2-butyl-
4- (1-hydroxy-1-methylethyl) -1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 70: 1- (ethoxycarbonyloxy) ethyl 2-
Butyl-4- (1-hydroxy-1-methylethyl) -1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Exemplified Compound No. 71: Isopropoxycarbonyloxymethyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate ,
Exemplified Compound No. 72: 1- (Isopropoxycarbonyloxy) ethyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- [4- [2-
(Tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate and Exemplified Compound No. 73: (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- [4- [2- (tetrazole- 5-yl) phenyl] phenyl] methylimidazole-5-carboxylate compound,
Most preferably
Exemplified Compound No. 32: Pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-
Yl) phenyl] phenyl] methylimidazole-5-carboxylate and Exemplified Compound No. 37: (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazole- 5-yl) phenyl] phenyl] methylimidazole-5-carboxylate.

The compound having the above general formula (I), the pharmacologically acceptable salt thereof or the pharmacologically acceptable ester thereof, which is the active ingredient of the present invention, is a nephropathy in a NIDDM model rat,
A prophylactic or therapeutic agent for diabetic complications, especially nephropathy, hyperlipidemia and / or hypertension, which has excellent inhibitory effects on both hyperlipidemia and hypertension and few side effects. (Especially useful as a therapeutic agent).

In addition, the compound having the above general formula (I), the pharmacologically acceptable salt thereof, or the pharmacologically acceptable ester thereof, which is an active ingredient of the present invention, has an excellent nephritis inhibitory action and the like, and has low toxicity. , Kidney disease, especially IgA nephropathy [Berscher
(Berger's disease), prophylactic or therapeutic agent for glomerulonephritis such as membranous nephropathy, proliferative glomerulonephritis, sclerosing glomerulonephritis, focal glomerulosclerosis, minimal change nephrotic syndrome, etc. (
In particular, it is useful as a therapeutic agent).

The compound (I), its pharmacologically acceptable salt or its pharmacologically acceptable ester, which is the active ingredient of the present invention, is known (for example, JP-A No. 5-78328) or a known method ( For example, it can be easily produced according to JP-A-5-78328.

The compound (I), its pharmacologically acceptable salt or its pharmacologically acceptable ester, which is an active ingredient of the present invention, has an excellent NIDDM complication-inhibiting action and weak toxicity. It is useful as a preventive or therapeutic agent for nephropathy, hyperlipidemia, hypertension and the like associated with NIDDM.

In addition, since the compound (I), a pharmacologically acceptable salt thereof 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 low toxicity, , IgA nephropathy [Berger's disease], membranous nephropathy, proliferative glomerulonephritis, sclerosing glomerulonephritis, focal glomerulosclerosis, minimal change nephrotic syndrome, etc. It is useful as a prophylactic or therapeutic agent for glomerulonephritis such as type.

When the compound (I), a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, which is the active ingredient of the present invention, is used as a therapeutic or prophylactic agent for the above-mentioned diseases, itself or an appropriate pharmacological agent Orally mixed with excipients, diluents, etc. and administered orally by tablets, capsules, granules, powders, syrups, etc. or parenterally (particularly orally) by injections, etc. Can do.

These preparations are made of excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose , Low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate Silicate derivatives such as: Phosphate derivatives such as calcium phosphate; Carbonate derivatives such as calcium carbonate; Sulfate derivatives such as calcium sulfate Body, etc.), binders (for example, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; Magrogol etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone Such as chemically modified starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; lux such as veegum and gay wax) Boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; carboxylic acid sodium salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; Salt; silicic anhydride, Silicic acids such as silicic acid hydrate; starch derivatives in the above-mentioned excipients, stabilizers (for example, paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol) Alcohols; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.], flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), dilution Agent, solvent for injection (eg, water, ethanol, glycerin, etc.)
It is produced by a known method using additives such as The amount used varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg (preferably 10 mg) per dose,
An upper limit of 1000 mg (preferably 500 mg), in the case of intravenous administration, a lower limit of 0.5 mg (preferably 5 mg) per dose, an upper limit of 500 mg (preferably 250 mg)
) Is preferably administered to adults 1 to 6 times daily depending on symptoms.

Examples and formulation examples will be shown below to explain the present invention in more detail. However, the scope of the present invention is not limited to these examples.

Example 1
Antihypertensive, lipid-lowering, and proteinuria-suppressing effects in diabetic rats Zucker Diabetic Fatty, a spontaneous NIDDM model
(Zucker Diabetic Fatty: ZDF) Rats were fed with a test compound for 19 weeks from 12 to 31 weeks of age (the concentration of the test compound in the feed was 0.001% or 0.01%)
It is. ) The control group received a feed containing no drug. In addition, as a normal animal group, Lean rats of the same week age were used, and this rat was also given a feed containing no drug.

The following measurements were performed at 30 to 31 weeks of age. That is, systolic blood pressure was measured by the Tail-Cuff method without anesthesia. In addition, 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. Furthermore, blood glucose level is measured by glucose oxidase method, and lipids in plasma (total cholesterol, triglycerides and non-ester free fatty acids) are automatically analyzed (
Hitachi 7250 type, manufactured by Hitachi, Ltd.). Statistical significance was tested by Dunnett's multiple comparison test and a risk factor (P) <0.05 was considered significant. Table 2 shows the results of measurement of systolic blood pressure and protein concentration in urine. Blood glucose levels and plasma lipids (total cholesterol, triglycerides and non-ester free fatty acids)
Table 3 shows the measurement results.
(Table 2)
──────────────────────────────────
Experiment Test compound Dose Animal Weight Systolic blood pressure Urinary protein excretion Number (%) Number (g) (mmHg) (mg / day / 100g body weight)
──────────────────────────────────
1 Exemplified compound number 0.001 ^*) 9 471 ± 15 142 ± 4 65.0 ± 6.2 ^**)
37 compounds
2 Illustrative compound number 0.01 ^*) 10 468 ± 16 121 ± 3 ^**) 22.9 ± 4.2 ^**)
37 compounds ---------------------------------
Control group 0 10 482 ± 19 150 ± 4 92.1 ± 7.2
Normal group 0 10 446 ± 15 123 ± 3 ^**) 3.2 ± 0.5 ^**)
──────────────────────────────────
*) Concentration of test compound in the feed.
**) Significantly different from the control group (P <0.05).

(Table 3)
──────────────────────────────────
Experiment Blood glucose level Total cholesterol Triglyceride Free fatty acid Number (mg / dl) (mg / dl) (mg / dl) (mEq / l)
──────────────────────────────────
1 521 ± 22 212 ± 15 ^**) 460 ± 81 ^**) 1.37 ± 0.12 ^**)
2 526 ± 23 135 ± 9 ^**) 240 ± 27 ^**) 1.16 ± 0.07 ^**)
---------------------------------
Control group 501 ± 27 277 ± 14 907 ± 118 1.84 ± 0.12
Normal group 161 ± 3 ^**) 94 ± 3 ^**) 79 ± 7 ^**) 1.00 ± 0.08 ^**)
──────────────────────────────────
**) Significantly different from the control group (P <0.05).

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 the hypertension, the increase in urinary protein excretion and the lipid content in plasma are possessed by the NIDDM model rats. The increase is remarkably suppressed.

Example 2
Inhibitory effect of nephritis in rats The method of T. Yamamoto & CB Wilson [Kidney
International, 32, 514-525 (1987):
Kid. Int., 32 , 514-525 (1987)], a glomerulonephritis model was prepared by one-tail intravenous injection of anti-rat Thy-1.1 monoclonal antibody to 7-week-old Wistar Kyoto rats.

The test compound was suspended in a 0.5% aqueous carboxymethylcellulose solution (CMC solution) and orally administered at 10 mg / kg / day until the end of the experiment after nephritis was induced.

On the 7th day after nephritis induction, urinary protein and albumin were measured using the pyrogallol red-molybdenum complex method and Elisa method (ELISA), and the degree of glomerulosclerosis was measured. The degree of glomerular sclerosis was measured by staining renal cortical paraffin sections with PAM (Pic: Periodic Acid-Methenamine silver) and then observing 50 glomeruli per animal with a microscope, and Rage et al. (L. Raiji et.al. ) [Kidney International, Vol. 26, pages 137 to 143 (1984): 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 trabecular stiffness index.
(Table 4)
──────────────────────────────────
Experiment Test compound Animal Urinary protein excretion Urinary albumin excretion Number Number (mg / day / 100g body weight) (μg / day / 100g body weight)
──────────────────────────────────
1 Exemplified compound number 7 2.4 ± 0.2 744 ± 112
37 compounds ---------------------------------
Control group 7 ^*) 6.0 ± 1.1 3960 ± 796
Normal group 7 1.6 ± 0.1 159 ± 13
──────────────────────────────────
*) A solvent (CMC solution) was administered.
(Table 5)
──────────────────────────────────
Experiment Test compound Animal Robe hardening index Number Number ───────────────────────────────────
1 Exemplified compound number 7 236.9 ± 13.1
37 compounds ---------------------------------
Control group 7 ^*) 296.6 ± 9.3
Normal group 7 96.0 ± 8.3
──────────────────────────────────
*) A solvent (CMC solution) was administered.

As can be seen from the above results, the compound which is an active ingredient of the present invention remarkably suppresses increases in urinary protein excretion and urinary albumin excretion, and significantly improves rosacea hardening.

Formulation Example 1
Capsules Compound of Exemplified Compound No. 37 50.0 mg
Lactose 128.7
Corn starch 70.0
Magnesium stearate 1.3
250 mg
After the powder of the above formulation is mixed and passed through a 60 mesh sieve, this powder is put into a 250 mg No. 3 gelatin capsule to form a capsule.

Formulation Example 2
Tablet Compound of Exemplified Compound No. 37 50.0 mg
Lactose 124.0
Corn starch 25.0
Magnesium stearate 1.0
200 mg
The powder of the said prescription is mixed and tableted with a tableting machine to make one tablet of 200 mg.

This tablet can be sugar-coated if necessary.

Claims (26)

General formula

(Wherein R ¹ represents a C ₁ -C ₄ alkyl group,
R ² and R ³ are the same or different and each represents a hydrogen atom or a C ₁ -C ₄ alkyl group,
R ⁴ represents a hydrogen atom or a C ₁ -C ₄ alkyl group,
R ⁵ represents a hydrogen atom,
R ⁶ represents a carboxy group or a tetrazol-5-yl group. )
A preventive or therapeutic agent for diabetic hyperlipidemia, which contains, as an active ingredient, an imidazolecarboxylic acid having a pharmaceutically acceptable salt thereof, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof. The active ingredient is
The preventive or therapeutic agent for diabetic hyperlipidemia according to claim 1, wherein R ¹ is an imidazolecarboxylic acid, a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, wherein ethyl group, propyl group or butyl group. The active ingredient is
The preventive or therapeutic agent for diabetic hyperlipidemia according to claim 1, which is an imidazolecarboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, wherein R ¹ is a propyl group or a butyl group. The active ingredient is
The preventive or therapeutic agent for diabetic hyperlipidemia according to claim 1, wherein R ¹ is an imidazole carboxylic acid having a propyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof. The active ingredient is
The diabetic high fat according to claims 1 to 4, wherein R ² and R ³ are the same or different and each is an imidazolecarboxylic acid, a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, which is a hydrogen atom or a methyl group. Antiseptic or therapeutic agent. The active ingredient is
R ² and R ³ are the same, imidazole carboxylic acids are methyl groups, a pharmacologically acceptable salt thereof or a pharmacologically acceptable diabetic hyperlipidemia preventive agent of claims 1 to 4 is an ester or Therapeutic drugs. The active ingredient is
Imidazole carboxylic acids R ⁴ is a hydrogen atom or a methyl group, diabetic hyperlipidemia preventive or therapeutic agent of claims 1 to 6 which is a pharmacologically acceptable salt or its pharmacologically acceptable esters. The active ingredient is
Imidazole carboxylic acids R ⁴ is a hydrogen atom, diabetic hyperlipidemia preventive or therapeutic agent of claims 1 to 6 which is a pharmacologically acceptable salt or its pharmacologically acceptable esters. The active ingredient is
The ester group of a pharmacologically acceptable ester is a methyl group, an ethyl group, an acetoxymethyl group, a 1- (acetoxy) ethyl group, a pivaloyloxymethyl group, a 1- (pivaloyloxy) ethyl group, or a methoxycarbonyloxymethyl group. 1- (methoxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, propoxycarbonyloxymethyl group, 1- (propoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (Isopropoxycarbonyloxy) ethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group is used for prevention of diabetic hyperlipidemia according to claims 1 to 8 Drug or therapeutic agent. The active ingredient is
Ester groups of pharmacologically acceptable esters are pivaloyloxymethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) The prophylactic or therapeutic agent for diabetic hyperlipidemia according to claim 1, which is an ethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group. The active ingredient is
9. The diabetic property according to claim 1, wherein the ester group of the pharmacologically acceptable ester is a pivaloyloxymethyl group or a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group. Hyperlipidemia preventive or therapeutic agent. The active ingredient is
The preventive or therapeutic agent for diabetic hyperlipidemia according to any one of claims 1 to 11, wherein R ⁶ is an imidazolecarboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, wherein R ⁶ is a tetrazol-5-yl group. The active ingredient is
Pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
(5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4-hydroxymethyl-2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole -5-carboxylate,
Pivaloyloxymethyl 4- (1-hydroxyethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
(5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxyethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] Phenyl] methylimidazole-5-carboxylate,
Pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Ethoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
1- (Ethoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxy rate,
Isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
1- (Isopropoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5 Carboxylate,
(5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5- Yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Pivaloyloxymethyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Ethoxycarbonyloxymethyl 2-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-carboxy rate,
Isopropoxycarbonyloxymethyl 2-butyl-4- (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-yl) phenyl] phenyl] methylimidazole-5 Carboxylate and (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- [4- [2- (tetrazole The diabetic of claim 1, which is an imidazolecarboxylic acid selected from the group consisting of -5-yl) phenyl] phenyl] methylimidazole-5-carboxylate, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof. Hyperlipidemia preventive or therapeutic agent. General formula

(Wherein R ¹ represents a C ₁ -C ₄ alkyl group,
R ² and R ³ are the same or different and each represents a hydrogen atom or a C ₁ -C ₄ alkyl group,
R ⁴ represents a hydrogen atom or a C ₁ -C ₄ alkyl group,
R ⁵ represents a hydrogen atom,
R ⁶ represents a carboxy group or a tetrazol-5-yl group. )
A prophylactic or therapeutic agent for glomerulonephritis containing imidazolecarboxylic acids having a pharmaceutically acceptable salt, pharmacologically acceptable salt thereof or pharmacologically acceptable ester thereof as an active ingredient. The active ingredient is
The remedy for glomerulonephritis according to claim 14, wherein R ¹ is an imidazolecarboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, which is an ethyl group, a propyl group or a butyl group. The active ingredient is
The preventive or therapeutic agent for glomerulonephritis according to claim 14, which is an imidazolecarboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, wherein R ¹ is a propyl group or a butyl group. The active ingredient is
The prophylactic or therapeutic agent for glomerulonephritis according to claim 14, which is an imidazolecarboxylic acid wherein R ¹ is a propyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof. The active ingredient is
The glomerulonephritis prevention according to any one of claims 14 to 17, wherein R ² and R ³ are the same or different and each is an imidazolecarboxylic acid which is a hydrogen atom or a methyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof. Medicine or treatment. The active ingredient is
The prophylactic or therapeutic agent for glomerulonephritis according to any one of claims 14 to 17, wherein R ² and R ³ are the same and are imidazolecarboxylic acids which are methyl groups, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof. The active ingredient is
Imidazole carboxylic acids R ⁴ is a hydrogen atom or a methyl group, glomerulonephritis prophylactic or therapeutic agent according to claim 14 or 19 which is a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester. The active ingredient is
Imidazole carboxylic acids R ⁴ is a hydrogen atom, glomerulonephritis prophylactic or therapeutic agent according to claim 14 or 19 which is a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester. The active ingredient is
The ester group of a pharmacologically acceptable ester is a methyl group, an ethyl group, an acetoxymethyl group, a 1- (acetoxy) ethyl group, a pivaloyloxymethyl group, a 1- (pivaloyloxy) ethyl group, or a methoxycarbonyloxymethyl group. 1- (methoxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, propoxycarbonyloxymethyl group, 1- (propoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, The prophylactic or therapeutic agent for glomerulonephritis according to claims 14 to 21, which is 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group. medicine. The active ingredient is
Ester groups of pharmacologically acceptable esters are pivaloyloxymethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) The prophylactic or therapeutic agent for glomerulonephritis according to any one of claims 14 to 21, which is an ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or a phthalidyl group. The active ingredient is
The glomerulus according to any one of claims 14 to 21, wherein the ester group of the pharmacologically acceptable ester is a pivaloyloxymethyl group or a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group. Nephritis preventive or therapeutic agent. The active ingredient is
Imidazole carboxylic acids R ⁶ is tetrazol-5-yl group, a pharmacologically acceptable salt thereof or glomerulonephritis prophylactic or therapeutic agent according to claim 14 or 24 which is a pharmacologically acceptable ester. The active ingredient is
Pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
(5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4-hydroxymethyl-2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole -5-carboxylate,
Pivaloyloxymethyl 4- (1-hydroxyethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
(5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxyethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] Phenyl] methylimidazole-5-carboxylate,
Pivaloyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Ethoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
1- (Ethoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxy rate,
Isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
1- (Isopropoxycarbonyloxy) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5 Carboxylate,
(5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [4- [2- (tetrazol-5- Yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Pivaloyloxymethyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
Ethoxycarbonyloxymethyl 2-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-carboxy rate,
Isopropoxycarbonyloxymethyl 2-butyl-4- (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-yl) phenyl] phenyl] methylimidazole-5 Carboxylate and (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 2-butyl-4- (1-hydroxy-1-methylethyl) -1- [4- [2- (tetrazole The glomerulus according to claim 14, which is an imidazolecarboxylic acid selected from the group consisting of -5-yl) phenyl] phenyl] methylimidazole-5-carboxylate, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof. Nephritis preventive or therapeutic agent.