JPH11269071A - Preventing and therapeutic agent for glomerular disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject therapeutic agent capable of remarkably restraining the proliferation of mesangium cells by including a specific indole derivative. SOLUTION: This agent comprises, as an active ingredient, e.g. an imidazole derivative of formula I [any one of A and B is a group of formula II (R<1> is e.g. H or a halogen; and R<2> and R<3> are each e.g. H, a halogen or lower alkyl) and the other is e.g. a tetrazolyl], e.g. (E)-N-(2-hydroxyethyl)-5(4)-(3,4,5- trimethoxycinnamoylamino) imidazole-4(5)-carboxamide. A compound of formula I is obtained by pref. reacting a compound of formula II (R<10> is e.g. H or a halogen) with an amine compound of the formula H2 N-R<5> (R<5> is e.g. a tetrazolyl), and the agent is pref. orally administrated in the dose of 0.1 to 1,000 mg/day/adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition useful as an agent for preventing and treating glomerular diseases.

[0002] More specifically, the present invention relates to a compound represented by the general formula:

[0003]

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In the formula, one of A and B is a general formula

[0005]

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(Wherein R ¹ is a hydrogen atom, a halogen atom,
A hydroxyl group, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group, an aralkyloxy group, a lower acyl group, a mono- or di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group, wherein R ² and R ³ are the same or different; And a group represented by a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group or an aralkyloxy group), and the other is a group represented by the general formula -CONHR ^{4 wherein} R ⁴ is General formula-(CH ₂ ) _n -R (wherein R is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and n
Is an integer of 2 to 6) or a tetrazolyl group]), or a pharmacologically acceptable salt thereof as an active ingredient. The present invention relates to an agent for preventing and treating glomerular diseases.

[0007] The glomerular diseases include various glomerular diseases in which the expansion of the mesangial region caused by the proliferation of mesangial cells is involved as one of the causes of the glomerular diseases, for example, glomerulonephritis, diabetic nephropathy. And glomerulosclerosis.

[0008]

2. Description of the Related Art The mesangial region, which is one of the basic structures of glomeruli, is composed of mesangial cells and mesangial substrates. This menthagium region is responsible for various functions such as supporting tissue for maintaining the glomerular looping structure and physiological regulation of glomerular function.

In various glomerular diseases such as glomerulonephritis and diabetic nephropathy, mesangial cell proliferation and extracellular matrix hyperplasia have been observed. For example, the onset and progression of glomerulonephritis Proliferation plays the most important role, and glomerulosclerosis is thought to be largely related to mesangial cell proliferation and extracellular matrix accumulation.

At present, such diseases include antiplatelet agents,
Anticoagulants, anti-radiation solvents, corticosteroids and the like have been used, but their effects are not always satisfactory.
Therefore, development of a novel drug showing an excellent effect on the glomerular disease is greatly desired.

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel agent for preventing and treating glomerular diseases which suppresses the proliferation of mesangial cells.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have conducted intensive studies to find a compound having an inhibitory effect on the growth of mesangial cells. As a result, a certain imidazole derivative represented by the above general formula (I) was found to be mesangial. The present inventors have found that they have an effect of remarkably suppressing cell proliferation, and have found that they are extremely useful as agents for preventing and treating glomerular diseases, and have accomplished the present invention.

That is, the present invention provides a compound represented by the general formula

[0014]

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[A or B in the formula is one of the general formula

[0016]

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[Wherein R ¹ is a hydrogen atom, a halogen atom,
A hydroxyl group, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group, an aralkyloxy group, a lower acyl group, a mono- or di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group, wherein R ² and R ³ are the same or different; And a group represented by a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group or an aralkyloxy group), and the other is a group represented by the general formula -CONHR ^{4 wherein} R ⁴ is General formula-(CH ₂ ) _n -R (wherein R is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and n
Is an integer of 2 to 6) or a tetrazolyl group]), or a pharmacologically acceptable salt thereof as an active ingredient. The present invention relates to an agent for preventing and treating glomerular diseases.

Here, in the compound represented by the general formula (I), a lower alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group. A linear or branched alkyl group having 1 to 6 carbon atoms such as a butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and a hexyl group. , Propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert
-1 to 1 carbon atoms such as pentyloxy group and hexyloxy group
6 refers to a straight-chain or branched alkoxy group, and an aralkyloxy group refers to the lower alkoxy group substituted with an aromatic hydrocarbon group such as a phenyl group or a naphthyl group, and a cycloalkylalkoxy group refers to 3 The above-mentioned lower alkoxy group substituted by a cyclic alkyl group having 7 to 7 members.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a lower acyl group means a linear or branched alkyl group having 2 to 7 carbon atoms such as an acetyl group, a propionyl group and a butyryl group. Means an alkylcarbonyl group. The mono- or di-lower alkyl-substituted amino group refers to an amino group mono-substituted with the lower alkyl group or an amino group di-substituted with the same or different lower alkyl group.

The imidazole derivative represented by the above general formula (I) can be prepared in vitro using mesangial cells.
Showed a remarkable activity of inhibiting the growth of mesangial cells in the test for inhibiting the growth of mesangial cells.

As described above, the imidazole derivative represented by the general formula (I) has an excellent growth inhibitory effect on mesangial cells and is a very useful compound as an agent for preventing and treating glomerular diseases. is there. Therefore,
By using the imidazole derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, it is possible to produce a pharmaceutical composition useful as an agent for preventing and treating glomerular diseases. it can.

The compound represented by the general formula (I) is, for example,

[0022]

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(Wherein R ¹⁰ is a hydrogen atom, a halogen atom, a hydroxyl group having a protecting group, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group, an aralkyloxy group, a lower acyl group, or a mono-lower alkyl group having a protecting group. A substituted amino group, a di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group, wherein R ² and R ³ have the same meanings as described above), and a compound represented by the general formula:

H ₂ N—R ⁵ (III)

[Wherein R ⁵ is a group represented by the general formula-(CH ₂ ) _n -R
⁰ (wherein R ⁰ is a hydroxyl group having a protecting group, an amino group having a protecting group, a mono-lower alkylamino group or a di-lower alkylamino group having a protecting group, and n has the same meaning as described above). Is a group or a tetrazolyl group) is reacted in an inert solvent,
If necessary, it can be produced by removing a protecting group according to a conventional method.

The compound represented by the general formula (II) used as a raw material in the production method is represented by the general formula:

[0027]

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(Wherein R ² , R ³ and R ¹⁰ have the same meanings as described above) or a reactive functional derivative such as an acid halide or an active ester thereof;
General formula

[0029]

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(Wherein one of P and Q in the formula is an amino group and the other is a lower alkoxycarbonyl group) with an aminoimidazole derivative in an inert solvent in the presence of a base or In the absence, the reaction in the presence or absence of a dehydrating agent or a condensing agent, hydrolyze the ester group to convert to a carboxyl group, the general formula

[0031]

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[In the formula, one of Y and Z is a general formula.

[0033]

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Wherein R ² , R ³ and R ¹⁰ have the same meaning as described above, and the other is a carboxyl group. , In an inert solvent in the presence of a dehydrating agent such as acetic anhydride or a condensing agent, or by dehydrating and cyclizing under heating.

The compound represented by the general formula (III) used as a starting material in the above-mentioned production method can be purchased as a commercial product, or can be produced by a known method described in a literature or a method similar thereto.

The compound represented by the general formula (IV) used in the production method can be purchased as a commercial product, or can be produced by a known method described in a literature or a method similar thereto.

The compound represented by the general formula (V) used in the above production method can be produced by a known method described in the literature or a method similar thereto (J. Chem. Soc., 1071 to 1074). Page (1949), J. Chem. Soc. Perkin.
Trans. I, pages 2310-2315 (198
0 years) etc.).

The imidazole derivative represented by the general formula (I) can be converted into a pharmacologically acceptable salt by a conventional method. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. Acid addition salts with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, sodium And salts with inorganic bases such as salts and potassium salts.

The compounds represented by formula (I) include hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.

The compound represented by the general formula (I) includes:
Since it has an unsaturated bond, there are two geometric isomers. In the present invention, any of a cis-form (Z-form) compound and a trans-form (E-form) compound may be used. In the present invention, the trans form (E form) is preferred.

Among the compounds represented by the above general formula (I), compounds having an asymmetric carbon atom have two optical isomers of R configuration and S configuration. May be used, or a mixture of these optical isomers may be used.

When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms are used depending on the usage. Such dosage forms include, for example, powders, granules, fine granules,
Examples include dry syrups, tablets, capsules and injections.

[0043] These pharmaceutical compositions can be prepared by using appropriate excipients, disintegrants,
Binders, lubricants, diluents, buffers, tonicity agents, preservatives,
It can be produced by appropriately mixing, diluting or dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method.

As the powder, for example, an appropriate excipient, a lubricant and the like may be added to the imidazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, if necessary. Mix to form a powder.

Tablets may be prepared, for example, by adding an appropriate excipient, disintegrant, binder, lubricating agent to the imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof. Tablets are made by adding tablets, etc., according to a conventional method. The tablets may be coated, if necessary, to give film-coated tablets, sugar-coated tablets and the like.

Capsules are prepared, for example, by the above-mentioned general formula (I)
In an imidazole derivative represented by the or a pharmacologically acceptable salt thereof, if necessary, a suitable excipient, a lubricant and the like are added and mixed well, and then filled in a suitable capsule to form a capsule. I do. In addition, it may be filled after granules or fine particles are formed by a conventional method.

When the pharmaceutical composition of the present invention is used for actual treatment, the dose of the active ingredient, the imidazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, depends on the patient. The weight, age, sex, degree of disease, etc. are appropriately determined, but in the case of oral administration, it is generally in the range of 0.1 to 1000 mg per adult per day, and in the case of parenteral administration, it is generally 0.01 to 300 mg per adult per day. Can be appropriately administered once or divided into several times.

The dose of the active ingredient, the imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, depends on the type of disease to be treated, the symptoms of the patient, and the therapeutic effect. Depending on the difference, it can be increased or decreased as appropriate.

[0049]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited to these contents.

Reference Example 1 (E) -3,4,5-Trimethoxycinnamic acid chloride 3,4,5-Trimethoxycinnamic acid (10.0 g) and thionyl chloride (6.1 ml) in toluene (100 m
l) Add N, N-dimethylformamide (0.1m
l) was added and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and hexane was added to the residue.
(E) -3,4,5-Trimethoxycinnamic acid chloride (10.3 g) was obtained.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 3.911 (s, 3H), 3.917
(S, 3H), 3.918 (s, 3H), 6.55
(D, J = 15.4 Hz, 1H), 6.80 (s, 2
H), 7.76 (d, J = 15.4 Hz, 1H)

Reference Example 2 Tert-butyl hydroxyiminocyanoacetate Water (50 ml), sodium nitrite (11.0 g) and acetic acid (8.58 ml) were sequentially added to tert-butyl cyanoacetate (15.0 g) under ice cooling. The mixture was stirred at room temperature for 16 hours. Concentrated hydrochloric acid (21.0 ml) was added to the reaction solution, and the precipitate was collected by filtration and washed with water to obtain tert-butyl hydroxyiminocyanoacetate (12.4 g).

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.59 (s, 9H), 11.93 (b
rs, 1H)

REFERENCE EXAMPLE 3 Aluminum foil (190 mg) was added to a solution of mercuric chloride (76 mg) in water (7.6 ml), and the mixture was stirred at room temperature for 1 minute. After removing the solvent and washing the aluminum amalgam with water, methanol and diethyl ether sequentially, a diethyl ether (5.5 ml) solution of tert-butyl hydroxyiminocyanoacetate (1.0 g) in diethyl ether (4 ml) under an argon atmosphere was used. And water (0.4m
l) was added sequentially. After stirring at 40 ° C. for 30 minutes, the insolubles were filtered through celite, and a solution of oxalic acid (256 mg) in ethanol (1 ml) was added to the filtrate. After allowing to stand at 4 ° C. for 1 hour, the precipitate was collected by filtration and 2-aminocyanoacetic acid te
rt-Butyl 1/2 oxalate (596.6 mg) was obtained.

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 1.46 (s, 9H), 4.75
(S, 1H), 5.0-7.5 (br, 3H)

Reference Example 4 Tert-butyl 5 (4) -aminoimidazole-4 (5) -carboxylate A suspension of tert-butyl 2-aminocyanoacetate 1/2 oxalate (500 mg) in methylene chloride (5 ml) was prepared. Neutralized with saturated aqueous sodium bicarbonate. After extraction with methylene chloride and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform (8 ml) and ethanol (6 ml), formamidine acetate (374 mg) was added, and the mixture was heated under reflux for 3 hours under an argon atmosphere. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with water and dried over anhydrous magnesium sulfate.
(4) -aminoimidazole-4 (5) -carboxylic acid t
tert-Butyl (324.8 mg) was obtained.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.58 (s, 9H), 4.77 (br
s, 2H), 7.32 (s, 1H), 10.3-11.
6 (br, 1H)

Reference Example 5 (E) -5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylic acid t
tert-butyl (E) -3,4,5-trimethoxycinnamic acid chloride (454 mg) and 5 (4) -aminoimidazole-
Tert-Butyl 4 (5) -carboxylate (324 mg)
Was dissolved in pyridine (10 ml) and stirred at 120 ° C. for 1.5 hours. After pyridine was distilled off under reduced pressure, water was added and the precipitate was collected by filtration to give (E) -5 (4)-(3,4,5).
-Trimethoxycinnamoylamino) imidazole-4
(5) -tert-butyl carboxylate (396.5 m
g) was obtained.

¹ H-NMR (CDCl ₃ , 400 MH
z) δ ppm: 1.65 (s, 9H), 3.90 (s,
3H), 3.93 (s, 6H), 6.53 (d, J = 1
5.5 Hz, 1H), 6.80 (s, 2H), 7.39
(S, 1H), 7.70 (d, J = 15.5 Hz, 1
H), 9.78 (s, 1H), 11.56 (s, 1H)

Reference Example 6 (E) -5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylic acid (E) -5 (4)-(3,4 , 5-Trimethoxycinnamoylamino) imidazole-4 (5) -carboxylic acid t
tert-butyl (254 mg) was added to 2N hydrochloric acid (40 m
1) and stirred at 50 ° C. for 22 hours. After the precipitate was collected by filtration, washed sequentially with water and diethyl ether,
(E) -5 (4)-(3,4,5-Trimethoxycinnamoylamino) imidazole-4 (5) -carboxylic acid (209.2 mg) was obtained.

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 3.70 (s, 3H), 3.84
(S, 6H), 7.04 (s, 2H), 7.12 (d,
J = 15.6 Hz, 1H), 7.45-7.65 (m,
2H), 9.90 (s, 1H), 12.0-13.7
(Br, 1H)

Reference Example 7 (E) -5- (3,4,5-Trimethoxystyryl) imidazo [4,5-d] [1,3] oxazin-7-one (E) -5 (4)- Acetic anhydride (81.5 μl) was added to a solution of (3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylic acid (100 mg) in pyridine (5 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1)
To give (E) -5- (3,4,5-trimethoxystyryl) imidazo [4,5-d] [1,3] oxazin-7-one (75 mg).

¹ H-NMR (DMSO-d ₆ , 400M
Hz) δ ppm: 3.70 (s, 3H), 3.84
(S, 6H), 7.04 (d, J = 16.1 Hz, 1
H), 7.16 (s, 2H), 7.70 (d, J = 1
6.1 Hz, 1H), 8.22 (brs, 1H), 1
2.7-14.6 (br, 1H)

Example 1 (E) -N- (2-hydroxyethyl) -5 (4)-
(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide (compound 1) (E) -5- (3,4,5-trimethoxystyryl) imidazo [4,5-d] To a solution of [1,3] oxazin-7-one (50 mg) in pyridine (1 ml) was added 2-aminoethanol (73.3 μl), and the mixture was stirred at room temperature for 20 hours. After the solvent was distilled off under reduced pressure, the residue was washed successively with water and diethyl ether to give (E) -N- (2-hydroxyethyl) -5 (4)-(3,4,5-trimethoxycinna (Moylamino) imidazole-4 (5) -carboxamide (40.3 mg) was obtained.

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 3.25-3.4 (m, 2H);
45-3.6 (m, 2H), 3.70 (s, 3H),
3.85 (s, 6H), 4.77 (t, J = 5.3H)
z, 1H), 7.10 (s, 2H), 7.22 (d, J
= 15.5 Hz, 1H), 7.37 (s, 1H), 7.
57 (d, J = 15.5 Hz, 1H), 7.80-7.
95 (m, 1H), 10.32 (brs, 1H), 1
2.5-12.8 (br, 1H)

Example 2 (E) -N- (2-dimethylaminoethyl) -5 (4)
-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide (compound 2) (E) -5- (3,4,5-trimethoxystyryl) imidazo [4,5-d N, N- was added to a solution of [1,3] oxazin-7-one (23.7 mg) in pyridine (5 ml).
Dimethylethylenediamine (63.2 μl) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether, and the obtained crystals were collected by filtration to give (E) -N- (2-dimethylaminoethyl) -5.
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide (18.
9 mg).

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 2.17 (s, 6H), 2.39
(T, J = 6.7 Hz, 2H), 3.2-3.45
(M, 2H), 3.70 (s, 3H), 3.85 (s,
6H), 7.10 (s, 2H), 7.23 (d, J = 1
5.5 Hz, 1H), 7.36 (s, 1H), 7.58
(D, J = 15.5 Hz, 1H), 7.75-7.9
(M, 1H), 10.31 (s, 1H), 12.67
(S, 1H)

Example 3 (E) -N- (1H-tetrazol-5-yl) -5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide (compound 3) (E) -5- (3,4,5-trimethoxystyryl) imidazo [4 To a solution of 5-d] [1,3] oxazin-7-one (100 mg) in pyridine (2 ml) was added 5-amino-1H-tetrazole (130 mg), and the mixture was heated at 100 ° C.
For 17 hours. After the precipitate was collected by filtration, the precipitate was washed successively with water, diethyl ether and methanol to give (E) -N
-(1H-tetrazol-5-yl) -5 (4)-
(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide (60.4 mg)
I got

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 3.71 (s, 3H), 3.84
(S, 6H), 7.06 (s, 2H), 7.14 (d,
J = 15.3 Hz, 1H), 7.5-7.75 (m, 2
H), 10.27 (s, 1H), 11.2-12.2
(Br, 1H), 12.99 (s, 1H), 15.6-
16.6 (br, 1H)

Example 4 (E) -N- (1H-tetrazol-5-yl) -5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide potassium salt (compound 4) (E) -N- (1H-tetrazol-5-yl) -5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide (36.
To a solution of 4 mg) in methanol (5 ml) was added potassium carbonate (12.1 mg), and the mixture was stirred until the reaction mixture became homogeneous. After distilling off the solvent under reduced pressure, the residue was washed with methanol to give (E) -N- (1H-tetrazol-5-yl) -5 (4)-(3,4,5-trimethoxycinnamoyl. Amino) imidazole-4 (5) -carboxamide potassium salt (39.8 mg) was obtained.

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 3.69 (s, 3H), 3.84
(S, 6H), 6.5-7.4 (m, 4H), 7.57
(D, J = 15.7 Hz, 1H), 11.7-12.9.
(Br, 1H)

Example 5 (E) -N- (2-dimethylaminoethyl) -5 (4)
-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide dihydrochloride (compound 5) (E) -N- (2-dimethylaminoethyl) -5 (4)
To a solution of (3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide (30 mg) in methanol (5 ml) was added a saturated hydrogen chloride gas methanol solution until the solution became acidic. The solvent was distilled off. The residue was washed with diethyl ether to give (E)-
N- (2-dimethylaminoethyl) -5 (4)-(3
4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide dihydrochloride (28.2 m
g) was obtained.

¹ H-NMR (DMSO-d ₆ , 400 M
Hz) δ ppm: 2.81 (s, 3H), 2.82
(S, 3H), 3.2-3.35 (m, 2H), 3.5
5-3.7 (m, 2H), 3.71 (s, 3H), 3.
85 (s, 6H), 7.08 (s, 2H), 7.22
(D, J = 15.5 Hz, 1H), 7.61 (d, J =
15.5 Hz, 1H), 7.75-8.0 (br, 1
H), 8.5-8.7 (br, 1H), 9.9-10.
2 (br, 1H), 10.4-10.55 (br, 1
H)

Example 6 Test for confirming the inhibitory action of cultured renal glomerular mesangial cells on cultured renocytes of cultured rat renal glomerular mesangial cells were suspended in RPMI 1640 medium containing 15% fetal bovine serum, and 20,000 cells per square centimeter were placed in a 96-well multi-well culture dish. After the cells were cultured at a cell density of 0.1% and cultured to a cell density to form a monolayer on a culture dish, the culture solution was mixed with 0.5% fetal bovine serum-containing RPMI1.
The growth of the cells was stopped during the rest period by replacing the medium with 640 medium and culturing for another 2 days.

Subsequently, 0.5% containing 2 nM platelet-derived growth factor BB dimer (PDGF-BB) and a test compound
Change to RPMI1640 medium containing fetal calf serum,
It was added ³ H-Thymidine of 25μCi / well, was incorporated into DNA fraction in subsequent 24 hours ³
The radioactivity of H-Thymidine was measured. The difference in the amount of radioactivity uptake between the control group containing no test compound and the unstimulated group (a group to which RPMI1640 medium containing neither PDGF-BB nor the test compound was added) was defined as a stimulation value of 100%. The addition concentration of the test compound that suppresses to 50% was calculated from the measured value, and the 50% inhibition concentration (IC
₅₀ value).

The following Table 1 shows the IC ₅₀ values (μ
M).

[0077]

[Table 1]

Example 7 Acute Toxicity Test A group of 4 to 5 male ICR mice was fasted for 4 hours and suspended in an aqueous solution of 5% ethanol-10% gum arabic (E) -N- (2-hydroxyethyl). ) -5 (4)
-(3,4,5-Trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide was administered orally at a dose of 300 or 1000 mg / kg. as a result,
Twenty-four hours after administration, no death was observed in any of the administration groups.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Kiyoshi Kasai 1164-9 Toyoshina, Toyoshina-cho, Minamiazumi-gun, Nagano Prefecture Maruyama Mansion 305

Claims (2)

[Claims] 1. A compound of the general formula Wherein one of A and B in the formula is a general formula: (Wherein R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group, an aralkyloxy group, a lower acyl group, a mono- or di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group. R ² and R ³ may be the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group or an aralkyloxy group),
The other is ^{R 4} in the general formula -CONHR ⁴ wherein the general formula -
(CH ₂ ) _n -R (wherein R is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and n is 2-6
Which is an integer of) or a tetrazolyl group], or a pharmacologically acceptable salt thereof as an active ingredient. And a prophylactic and therapeutic agent for glomerular diseases. 2. A compound of the general formula Wherein ^one of A ¹ and B ¹ is a general formula: Wherein R ^1a is a lower alkoxy group, R ^2a and R ^3a may be the same or different and each is a hydrogen atom or a lower alkoxy group, and the other is a group represented by the general formula —CONHR ⁴ [wherein R ⁴ is a group represented by the general formula-(CH
₂ ) _n- R (wherein R is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and n is an integer of 2 to 6) or a tetrazolyl group Or a pharmacologically acceptable salt thereof as an active ingredient.