JPH0753716B2 - Imidazol carboxamide derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel and pharmaceutically useful imidazolecarboxamide derivative and an acid addition salt thereof.

[Conventional technology]

Japanese Unexamined Patent Publication (Kokai) No. 57-175172 discloses a non-steroidal anti-inflammatory drug having a structure of imidazolecarboxamide, 5
-Imidazole carboxamides have been described. In addition, Berihite (Berichte), to 92, 550, 1959, 2
An imidazolecarboxamide derivative has been reported, but no reference is made to its pharmacological action.

[Problems to be solved by the invention]

The present inventors focused their attention on these known imidazolecarboxamide skeletons and conducted diligent studies for the purpose of developing a useful anti-inflammatory / analgesic agent.

[Means for solving problems]

As a result, the present inventors have found that the novel imidazolecarboxamide derivative and its acid addition salt have useful anti-inflammatory / analgesic effects, and completed the present invention.

That is, the present invention is a general formula, And an acid addition salt thereof.

[In the above formulas, in ring A and ring B, when ring B is substituted at the 2-position of the imidazole nucleus, ring A and ring B are the same or different and are substituted with halogen, lower alkyl or lower alkoxy. When ring B is substituted at position 5 of the imidazole nucleus, ring A and ring B simultaneously represent phenyl which may be substituted with halogen, lower alkyl or lower alkoxy.

R ¹ and R ² are the same or different and each is hydrogen, lower alkyl, aryl or aralkyl which may have a substituent on the benzene ring, nitrogen-containing heteroaromatic ring, cycloalkyl, formula (In the formula, X and Y are the same or different, and N and CH are
Represents 0, 1, 2, 3 and W represents hydrogen, lower alkyl, phenyl or aralkyl which may have a substituent on the benzene ring. ) Or a group which is bonded to each other to form a heterocycle with an adjacent nitrogen atom. Explaining the symbol of the general formula (I) by definition, halogen is chlorine, bromine, iodine and fluorine, and lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. Etc.
Lower alkoxy is methoxy, ethoxy, propoxy,
In isopropoxy, butoxy, etc., the aryl of aryl optionally having a substituent on the benzene ring is phenyl, naphthyl, etc., and the substituent is halogen, lower alkyl, lower alkoxy, etc., benzene ring The aralkyl of the aralkyl which may have a substituent above is benzyl, phenylethyl, phenylpropyl, phenylbutyl, etc., and the substituent is halogen, lower alkyl, lower alkoxy, etc., a nitrogen-containing heteroaromatic ring As pyridyl (2-pyridyl, 3
-Pyridyl, 4-pyridyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.) and the like, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. And the like, the heterocyclic ring formed by bonding to each other with an adjacent nitrogen atom is pyrrolidinyl, piperidino, piperazinyl, morpholino and the like.

The compound of the general formula (I) of the present invention can be synthesized by the method shown below.

Method 1 This method is applied when ^one of R ¹ and R ¹ in the 2-imidazolecarboxamide derivative of the general formula (I) is hydrogen. (Wherein ring A ′ and ring B ′ represent phenyl simultaneously substituted with halogen, lower alkyl or lower alkoxy) and a compound of the general formula R ⁴ N═C═O (III) , R ⁴ represents lower alkyl, aryl, aralkyl, or cycloalkyl.).

This reaction is a well-known method for synthesizing 2-imidazolecarboxamide derivatives (Berichte, 92 , 550, 195).
According to 9), it is usually carried out under heating in an inert solvent such as nitrobenzene.

Method 2 This method is applied when neither R ¹ nor R ² is hydrogen in the 2-imidazolecarboxamide derivative of the general formula (I), and can be produced by the following two-step reaction.

In the first step, the compound of general formula (II) and the general formula [In the formula, R ⁵ and R ⁶ are the same or different and are lower alkyl, aryl optionally having a substituent on the benzene ring, and a group which is bonded to each other to form a heterocyclic ring with the adjacent nitrogen atom, Hal Represents halogen (chlorine, bromine, iodine, fluorine). ] The carbamic acid halide derivative represented by (In the formula, ring A ′, ring B ′, R ⁵ and R ⁶ have the same meanings as described above.).

The reaction is generally carried out in a solvent such as benzene, toluene, pyridine and chloroform in the presence of a deoxidizing agent such as trialkylamine, sodium acetate, sodium alkoxide and alkali hydroxide.

The second step is a step of rearranging the compound of the general formula (V) to obtain the desired product, and the reaction is carried out in an inert solvent such as nitrobenzene at the boiling temperature.

Method 3 This method is applied to the 2-imidazolecarboxamide derivative of the general formula (I) and can be prepared by the following three-step reaction.

The first step is the general formula (Wherein ring A ′ and ring B ′ have the same meanings as defined above, and R ³ represents lower alkoxymethyl), and the isocyanate derivative of the general formula (III) is reacted to give a compound of the general formula (In the formula, ring A ′, ring B ′, R ³ and R ⁴ have the same meanings as described above.).

The reaction is performed according to the reaction conditions of Method 1.

In the second step, the compound of the general formula (VII) and the general formula R ⁷ -Q (VIII) (in the formula, R ⁷ is lower alkyl, aryl or aralkyl which may have a substituent on the benzene ring, Represents a nitrogen-containing heteroaromatic ring, cycloalkyl, and Q represents a leaving group such as halogen). (In the formula, ring A ′, ring B ′, R ³ , R ⁴ and R ⁷ have the same meanings as described above.).

The reaction is generally carried out in an inert solvent, alkali metal hydride,
It is carried out in the presence of an alkali metal amide or the like.

The third step is R ³ as a protecting group for compounds of general formula (IX)
Is a step of removing .alpha.

Method 4 This method is applied to the 5-imidazolecarboxamide derivative of general formula (I) [In the formula, ring A ′ and ring B ′ are the same or different and each represents phenyl which may be substituted with halogen, lower alkyl or lower alkoxy, and Z is halogen, lower alkoxy, —OCOOR ⁸ (in the formula, R ⁸ Represents a lower alkyl or an aryl which may have a substituent), and a dihydrocyclohexylisourea residue or the like. ] And a compound represented by the general formula [In the formula, R ⁹ and R ¹⁰ are the same or different, and are lower alkyl,
Aryl or aralkyl which may have a substituent on the benzene ring, a nitrogen-containing heteroaromatic ring, cycloalkyl,
formula (In the formula, X, Y, n and W have the same meanings as described above.) Or a group which is bonded to each other to form a heterocycle with an adjacent nitrogen atom. ] It can manufacture by making the compound represented by these react in a suitable solvent, and forming an amide bond.

In the compound (X), when Z is a halogen compound,
First, 2,4-diaryl- which is a precursor of compound (X)
According to a conventional method, a 5-imidazolecarboxylic acid derivative is reacted with thionyl chloride, phosphorus pentachloride and the like to give 2,4-diaryl-5-imidazolecarboxylic acid chloride,
This acid chloride compound or its acid addition salt and the general formula (X
I) with the amine derivative in a suitable solvent such as benzene, toluene or chloroform in the presence of a tertiary amine such as trialkylamine or a base such as alkali carbonate at -10 ° C.
To the boiling point of the solvent used.

In the compound (X), when Z is —OCOOR ⁸ (wherein R ⁸ has the same meaning as described above), first, the compound (X)
The precursor of 2,4-diaryl-5-imidazolecarboxylic acid derivative in an inert solvent in the presence of a tertiary amine and the like, in the general formula Hal-COOR ⁸ (wherein R ⁸ and Hal have the same meanings as described above). It is carried out by reacting with a compound represented by the formula (1) to give a mixed acid anhydride, and further reacting the mixed acid anhydride with an amine derivative of the general formula (XI).

In the case of a compound (X) in which Z is a dicyclohexylisourea residue, first, a 2,4-diaryl-5-imidazolecarboxylic acid derivative which is a precursor of the compound (X) is reacted with carbodiimide. , Further, in a suitable solvent such as tetrahydrofuran, acetonitrile,
It can be produced by reacting with an amine derivative of the general formula (XI).

The compound of the general formula (I) thus obtained is, if desired, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, mandelic acid,
A pharmaceutically acceptable acid addition salt can be obtained by treating with an organic acid such as citric acid, tartaric acid or methanesulfonic acid.

[Operation and effect of the invention]

The novel imidazolecarboxamide derivative of the general formula (I) of the present invention and its acid addition salt have anti-inflammatory action, analgesic action, antipyretic action, PGE ₂ production inhibitory action, SRS production inhibitory action,
It has a pharmacological action such as a platelet aggregation inhibitory action and is useful as an anti-inflammatory / analgesic / antipyretic agent. Also, rheumatism, gout,
It can be used for prevention and treatment of various inflammations in skeletal muscles such as arthritis, joints and other organs, as well as pain, fever and other symptoms associated with inflammation.

When the compound of the present invention is used as a medicine, it is mixed with a pharmacologically acceptable excipient, carrier, diluent and other additives for pharmaceutical preparations, and tablets, granules, powders, capsules and injections are prepared. It can be administered orally or parenterally in the form of agents, ointments and suppositories. The dose may vary depending on the patient's age, body weight, symptoms, etc.
It is usually 50 to 500 mg per day for an adult, and this can be administered once or in several divided doses.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Example 1 4,5-bis (4-methoxyphenyl) imidazole 7.0 g
And phenyl isocyanate 5g to nitrobenzene 50ml
Reflux for 7.5 hours. After the reaction, the mixture was allowed to cool and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-methanol (5: 1) to give 4,5-bis (4-methoxyphenyl) -2-mp having a melting point of 234 to 235 ° C. 4.7 g of imidazolecarboxanilide is obtained as white needle crystals.

Example 2 5.1 g of 4,5-bis (4-chlorophenyl) imidazole was suspended in 100 ml of toluene, and triethylamine 2.3 was added at room temperature.
g and 3.1 g of diethylcarbamic acid chloride are added, and the mixture is refluxed for 6 hours. After the reaction, the residue obtained by washing with water and distilling off the solvent was purified by a column and crystallized from n-hexane to give a melting point of 12
4.0 g of 4,5-bis (4-chlorophenyl) -N, N-diethyl-1-imidazolecarboxamide at 0-122 ° C. are obtained as crystals. Furthermore, this compound was added to nitrobenzene 30
Reflux in ml for 46 hours. After the reaction, the reaction mixture was allowed to cool and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-methanol (1: 1) to give 4,5-bis (4-chlorophenyl) -N, N- having a melting point of 243-245 ° C. 1.5 g of diethyl-2-imidazolecarboxamide are obtained as crystals.

Example 3 24.8 g of 4,5-bis (4-methoxyphenyl) -1-methoxymethylimidazole and phenylisocyanate 1
Reflux 5.5 g in 155 ml nitrobenzene for 7 hours. After the reaction, the product was purified by a column and crystallized from n-hexane to give 21.4 g of 4,5-bis (4-methoxyphenyl) -1-methoxymethyl-2-imidazolecarboxyanilide having a melting point of 104 to 107 ° C. Obtained as. Next, 0.66 g of sodium hydride (60%) was suspended in 15 ml of benzene,
Under reflux, 50 ml of a benzene solution containing 6.7 g of this compound is added dropwise, and the mixture is refluxed for 1 hour. 10 ml of a dimethylformamide solution containing 2.6 g of methyl iodide at room temperature in the reaction mixture.
Is added dropwise, and the mixture is stirred at room temperature for 16 hours. After the reaction, the residue obtained by washing with water and distilling off the solvent is crystallized by adding isopropyl ether. By filtering this off, the melting point
4,5-bis (4-methoxyphenyl) -1 at 131-133 ° C
6.0 g of -methoxymethyl-N-methyl-2-imidazolecarboxanilide are obtained as crystals. This compound
6.0g with ethanol 60ml, concentrated hydrochloric acid 30ml, water 9ml
Reflux for 8.5 hours. After the reaction, it is diluted with water, made alkaline with sodium hydroxide, and extracted with chloroform. After washing with water, ether is added to the residue obtained by distilling off the solvent for crystallization. When this was recrystallized from ethyl acetate-methanol (1: 2), 1.6 g of 4,5-bis (4-methoxyphenyl) -N-methyl-2-imidazolecarboxanilide having a melting point of 186 to 189 ° C was obtained as white needles. Obtained as crystals.

Example 4 (a) 77.5 g of α-oxyimino-4-methoxybenzoylacetic acid ethyl ester and 4-fluorobenzylamine 38.
6 g is dissolved in 2.5 l of xylene and refluxed for 4 hours under draining conditions. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-methanol (2: 1) to give ethyl 2- (4-fluorophenyl) -4- (4-methoxyphenyl) having a melting point of 195-198 ° C. Enyl) -5-imidazole carboxylate 50
g is obtained as pale yellow needle crystals. 15.9 g of this compound is heated and reacted with 5.6 g of sodium hydroxide, 37 ml of water and 9 ml of alcohol at 70 ° C. for 5 hours. After the reaction, the pH was adjusted to 6 with dilute hydrochloric acid, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-methanol (1: 1) to give a melting point of 212-21.
2- (4-fluorophenyl) -4- at 4 ° C (decomposition)
9.5 g of (4-methoxyphenyl) -5-imidazolecarboxylic acid are obtained as white crystals. 2.7 g of this compound was suspended in alcohol, and isopropyl alcohol-hydrochloric acid (20
%), And after concentration, ether was added and the precipitated crystals were collected by filtration to give 2- (4-fluorophenyl) -4- (4
-Methoxyphenyl) -5-imidazolecarboxylic acid
2.9 g of hydrochloride are obtained.

(B) 2- (4-Fluorophenyl) -4- (4-methoxyphenyl) -5-imidazolecarboxylic acid / hydrochloride
5.0 g of benzene was suspended in 70 ml of benzene and dimethylformamide was added.
After adding 5 ml and thionyl chloride 3.4 g, reflux for 3 hours. After cooling, the solid was collected by filtration and washed with benzene to give 2- (4
-Fluorophenyl) -4- (4-methoxyphenyl)
5.3 g of -5-imidazolecarboxylic acid chloride.hydrochloride are obtained. Next, 0.85 g of 2-aminopyridine and 1.8 g of triethylamine are dissolved in 40 ml of acetone, 3.3 g of this compound is added at room temperature, and the mixture is refluxed for 2.5 hours. After the reaction, the mixture is poured into water, extracted with chloroform and washed with water. Crystallization occurs when ether is added to the residue obtained by distilling off the solvent. This was recrystallized from ethyl acetate-methanol (10: 1) to give 2- (4-fluorophenyl) -4-, mp 229-231 ° C.
(4-Methoxyphenyl) -N- (2-pyridyl) -5
0.8 g of imidazolecarboxamide is obtained as white crystals.

Example 5 2- (4-Fluorophenyl) -4- (4-methoxyphenyl) -5-imidazolecarboxylic acid sodium salt
2.1 g of acetone was suspended in triethylamine at 0 ° C.
64 g and ethyl chlorocarbonate 1.4 g are added, and the mixture is stirred at the same temperature for 1 hour. 0.60 g of aniline is added to this and reacted at room temperature for 4 hours. After the reaction, add 10 ml of 1N sodium hydroxide,
Stir at 40 ° C for 1 hour. Crystals precipitated by diluting with water were collected by filtration, washed with water, and recrystallized from ethyl acetate-chloroform-methanol (5: 2: 5) to give a melting point of 2
2- (4-fluorophenyl) -4- (4 at 35 to 237 ° C
1.0 g of -methoxyphenyl) -5-imidazolecarboxyanilide are obtained as white needle crystals.

Example 6 According to the method described in Example 1, 4,5-bis (4-
7.0 g of methoxyphenyl) imidazole and 4.2 g of n-butylisocyanate are refluxed in nitrobenzene for 7 hours.
After the reaction, purify on a column and recrystallize from methanol-isopropyl ether (1: 2) to give a melting point of 150-152 ° C.
4,5-Bis (4-methoxyphenyl) -N- (n-butyl) -2-imidazolecarboxamide is obtained as white crystals.

Example 7 According to the method described in Example 1, 4,5-bis (4-
7.0 g of methoxyphenyl) imidazole and 7.1 g of 1-naphthylisocyanate are refluxed in nitrobenzene for 7 hours. After the reaction, the precipitated crystals were collected by filtration and recrystallized from dimethylformamide-methanol (1: 1) to give a melting point of 240
4,5-bis (4-methoxyphenyl) -N- at ~ 243 ° C
(1-Naphthyl) -2-imidazole ruboxamide is obtained as white crystals.

Example 8 According to the method described in Example 1, 4,5-bis (4-
7.0 g of chlorophenyl) imidazole and 5.6 g of 4-fluorophenylisocyanate are refluxed in nitrobenzene for 7 hours. After the reaction, the precipitated crystals were collected by filtration, and ethyl acetate-
Recrystallized from methanol (1: 1), melting point 264-267 ℃
4,5-Bis (4-chlorophenyl) -N- (4-fluorophenyl) -2-imidazolecarboxamide is obtained as white crystals.

Example 9 According to the method described in Example 1, 4,5-bis (4-
7.0 g of chlorophenyl) imidazole and 5.1 g of cyclohexyl isocyanate are refluxed in nitrobenzene for 46 hours. After the reaction, the product was purified by a column and recrystallized from ethyl acetate-methanol (2: 1) to give 4,5-mp of melting point 281-283 ° C.
Bis (4-chlorophenyl) -N-cyclohexyl-2
-Imidazole carboxamide is obtained as white crystals.

Example 10 According to the method described in Example 2, 4,5-bis (4-
Methoxyphenyl) imidazole 5.0 g toluene 100 ml
2.3 g of triethylamine and 3.1 g of diethylcarbamic acid chloride are added and the mixture is refluxed for 6 hours. After the reaction, the residue obtained by washing with water and distilling off the solvent is purified by a column to obtain 4,5-bis (4-methoxyphenyl) -N, N-diethyl-1-imidazolecarboxamide. The compound is refluxed in nitrobenzene for 42 hours. After the reaction
Purified by column and recrystallized from ethyl acetate-methanol (1: 2), 4,5-bis (4-methoxyphenyl) -N, N-diethyl-2-imidazolecarboxamide with melting point 169-171 ° C is white. Obtained as needle crystals.

Example 11 According to the method described in Example 2, 4,5-bis (4-
Methoxyphenyl) imidazole 5.0 g toluene 100 ml
2.3 g of triethylamine and 4.2 g of diphenylcarbamic acid chloride are added and the mixture is refluxed for 6 hours. After the reaction, by treating in the same manner as in Example 10, the melting point 182
4,5-bis (4-methoxyphenyl) -N, N-
Diphenyl-1-imidazolecarboxamide is obtained as white crystals. This compound in nitrobenzene 46
Reflux for an hour. After the reaction, purification with a column and recrystallization from methanol give 4,5-bis (4-methoxyphenyl) -N, N-diphenyl-2-imidazolecarboxamide as white crystals with a melting point of 191-193 ° C.

Example 12 2- (4-Fluorophenyl) -4- (4-methoxyphenyl) -5 obtained by the method described in Example 4.
-Imidazolecarboxylic acid chloride hydrochloride is suspended in tetrahydrofuran, 28% aqueous ammonia is added and stirred at room temperature for 2 hours. After the reaction, the mixture was poured into water, and the precipitated crystals were collected by filtration and recrystallized from chloroform-methanol (10: 1) to give 2- (4-fluorophenyl) -4- (4-methoxyphenyl) having a melting point of 253-255 ° C. Enyl) -5-imidazolecarboxamide is obtained as white crystals.

Example 13 3.3 g of 2- (4-fluorophenyl) -4- (4-methoxyphenyl) -5-imidazolecarboxylic acid chloride hydrochloride was dissolved in acetone together with 0.9 g of 2-aminothiazole and 1.8 g of triethylamine. React under reflux for 2.5 hours. After the reaction, the reaction mixture was treated in the same manner as in Example 4 and recrystallized from ethyl acetate-methanol (1: 1) to give a melting point of 270.
2- (4-fluorophenyl) -4- (4-
Methoxyphenyl) -N- (2-thiazolyl) -5-imidazolecarboxamide is obtained as white crystals.

Example 14 According to the method described in Example 4, 4-amino-1-
Dissolve 2.9 g of (2-phenylethyl) piperidine and 2.9 g of triethylamine in 70 ml of tetrahydrofuran,
5.3 g of 2- (4-fluorophenyl) -4- (4-methoxyphenyl) -5-imidazolecarboxylic acid chloride hydrochloride was added at 5 ° C, and the mixture was reacted at room temperature for 3 hours. After the reaction, the mixture is poured into water, extracted with chloroform and washed with water. Purification by column, recrystallizing the crystals precipitated by alcohol-hydrochloric acid from methanol-ethanol (1: 1),
2- (4-fluorophenyl) -4-, mp 255-258 ° C
(4-Methoxyphenyl) -N- (1- (2-phenylethyl) -4-piperidyl) -5-imidazolecarboxamide dihydrochloride hemihydrate is obtained as white needle crystals.

Example 15 According to the method described in Example 4, 1.6 g of morpholine and 3.6 g of triethylamine are added to 100 ml of tetrahydrofuran.
Dissolved in 2- (4-fluorophenyl) at -5 to 0 ° C.
6.6 g of -4- (4-methoxyphenyl) -5-imidazolecarboxylic acid chloride / hydrochloride is added, and the mixture is reacted at room temperature for 2 hours. After the reaction, the reaction mixture was poured into water, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-methanol (20: 1).
2- (4-fluorophenyl) -4- (4 at 202-204 ° C
-Methoxyphenyl) -5-morpholinocarbonylimidazole is obtained as white crystals.

Example 16 (a) α-Oxyiminobenzoyl acetic acid ethyl ester
Dissolve 52.3 g and benzylamine 29.5 g in 1.6 l of xylene,
Reflux for 3 hours under draining conditions. After allowing to cool, the precipitated crystals were collected by filtration to obtain 27.5 g of ethyl 2- (4-fluorophenyl) -4-phenyl-5-imidazolecarboxylate having a melting point of 211 to 213 ° C. Then 27.5 g of this compound
12.4 g sodium hydroxide, 69.3 ml water and 1 alcohol
Reflux with 6 ml for 1.5 hours. After the reaction, dilute with water,
The pH is adjusted to 7 with dilute hydrochloric acid and the precipitated crystals are collected by filtration. This was recrystallized from ethyl acetate-methanol (2: 1) to give 2- (4-fluorophenyl) having a melting point of 219 to 221 ° C (decomposition).
21.0 g of -4-phenyl-5-imidazolecarboxylic acid are obtained as white crystals. 21.0 g of this compound was suspended in alcohol, isopropyl alcohol-hydrochloric acid (20%) was added, the mixture was concentrated, isopropyl alcohol-hydrochloric acid was further added, and the precipitated crystals were collected by filtration to give 2- (4-fluorophenyl)- 24.0 g of 4-phenyl-5-imidazolecarboxylic acid hydrochloride are obtained.

(B) According to the method described in Example 4, 2- (4-
24.0 g of fluorophenyl) -4-phenyl-5-imidazolecarboxylic acid hydrochloride is suspended in 200 ml of benzene, 2.6 ml of dimethylformamide and 27.0 g of thionyl chloride are added, and the mixture is refluxed for 25 hours. After the reaction, the solid is filtered to give 2
22.0 g of-(4-fluorophenyl) -4-phenyl-5-imidazolecarboxylic acid chloride.hydrochloride are obtained. Next, 3.0 g of 2- (4-phenyl-1-piperazinyl) ethylamine and 2.9 g of triethylamine were dissolved in 70 ml of tetrahydrofuran, and 4.9 g of this compound was obtained at -5 to 0 ° C.
Is added and reacted at room temperature for 3 hours. After the reaction, it is poured into water, extracted with chloroform and washed with water. The product was purified by a column, and crystals precipitated with alcohol-hydrochloric acid were recrystallized from hydrous ethanol to give 2- (4-
Fluorophenyl) -4-phenyl-N- (2-4-phenyl-1-piperazinyl) ethyl) -5-imidazolecarboxamide dihydrochloride hemihydrate is obtained as white needle crystals.

Example 17 2.3 g of 3-piperidinopropylamine and 3.2 g of triethylamine were dissolved in 70 ml of tetrahydrofuran, and -5 to 0 was obtained.
2- (4) obtained by the method described in Example 162.
-Fluorophenyl) -4-phenyl-5-imidazolecarboxylic acid chloride-hydrochloride (5.4 g) is added, and the mixture is reacted at room temperature for 3 hours. After the reaction, the mixture is poured into water, extracted with chloroform and washed with water. Purified by column and recrystallized from isopropyl ether to give 2- (4-fluorophenyl) -4-phenyl-N- (3- (1-piperidino) propyl) -5-imidazolecarboxamide having a melting point of 141-143 ° C. Are obtained as white crystals.

Example 18 According to the method described in Example 6, 4,5-bis (4-
14.0 g of methylphenyl) imidazole and 8.4 g of butylisocyanate are refluxed in nitrobenzene for 8 hours.
After the reaction, the product was purified by a column and methanol-hexane (1:
When recrystallized from 2), 4,5-bis (4
-Methylphenyl) -N-butyl-2-imidazolecarboxamide is obtained as white crystals.

Example 19 0.9 g of benzylamine and 2.1 g of triethylamine were dissolved in 50 ml of teratohydrofuran, and 2- (4-fluorophenyl) -4-phenyl-5-imidazolecarboxylic acid chloride / hydrochloride 2.9 g was dissolved at 0 to 5 ° C. Is added and reacted at room temperature for 2 hours. After the reaction, pour into water and extract with chloroform,
Wash with water. It was purified by column and recrystallized from ethyl acetate-ether (1: 1) to give 2- (4
-Fluorophenyl) -4-phenyl-N-benzyl-
5-Imidazolecarboxamide can be obtained as white crystals. Example 20 2- (4-Methoxyphenyl) -4- (4-methylphenyl) -5-imidazolecarboxylic acid / hydrochloride 26.0 g was suspended in benzene 200 ml to obtain dimethylformamide. After adding 2.6 ml and 27.0 g of thionyl chloride, reflux for 2.5 hours. After the reaction, the solid is collected by filtration to obtain 2- (4-methoxyphenyl) -4- (4-methylphenyl) -5-imidazolecarboxylic acid chloride / hydrochloride. 2.1 g of 2- (4-methyl-1-piperazinyl) ethylamine and 2.9 g of triethylamine were dissolved in 70 ml of tetrahydrofuran,
2- (4-methoxyphenyl) -4- (4 at -5 to 0 ° C
-Methylphenyl-5-imidazolecarboxylic acid chloride-5.3 g of hydrochloric acid salt is added and reacted at room temperature for 3 hours. After the reaction, the mixture was poured into water, extracted with chloroform, washed with water, and purified with a column to give 2- (4-methoxyphenyl)-
4- (4-Methylphenyl) -N- (2- (4-methyl-1-piperazinyl) ethyl) -5-imidazolecarboxamide is obtained.

Example 21 23.1 g of 2,4-bisphenyl-5-imidazolecarboxylic acid / hydrochloride was suspended in benzene to obtain dimethylformamide.
After adding 2.6 ml and 27.0 g of thionyl chloride, reflux for 2.5 hours. After the reaction, the solid is collected by filtration to obtain 2,4-bisphenyl-5-imidazolecarboxylic acid chloride.hydrochloride. Then 1.0 g of pyrrolidine and 2.
Dissolve 9 g in tetrahydrofuran and at 0 ° C. 2,4-bisphenyl-5-imidazolecarboxylic acid chloride.hydrochloride 4.
Add 8 g and react at room temperature for 3 hours. After the reaction, the mixture is poured into water, extracted with chloroform, washed with water, and then purified on a column to obtain 2,4-bisphenyl-5-pyrrolidinocarbonylimidazole.

Example 22 2- (4-Methylphenyl) -4-phenyl-5-imidazolecarboxylic acid hydrochloride (24.2 g) was suspended in benzene, and 2.6 ml of dimethylformamide and thionyl chloride 27.
After adding 0 g, reflux for 2.5 hours. After the reaction, the solid was collected by filtration to give 2- (4-methylphenyl) -4-phenyl-5.
-Imidazolecarboxylic acid chloride hydrochloride is obtained. Next, 1.2 g of 2-aminooxazole and 2.9 g of triethylamine were dissolved in tetrahydrofuran and the mixture was stirred at 0 ° C. for 2 hours.
5.0 g of-(4-methylphenyl) -4-phenyl-5-imidazolecarboxylic acid chloride hydrochloride is added, and the mixture is reacted at room temperature for 3 hours. After the reaction, the mixture was poured into water, extracted with chloroform, washed with water, and purified with a column to give 2- (4-
Methylphenyl) -4-phenyl-N- (2-oxazolyl) -5-imidazolecarboxamide is obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location // A61K 31/415 AAH 9454-4C 31/42 ACB 9454-4C 31/425 9454-4C 31 / 44 ABE 9454-4C 31/445 AAG 9454-4C 31/495 9454-4C 31/535 9454-4C

Claims (1)

[Claims] 1. A general formula An imidazolecarboxamide derivative represented by and an acid addition salt thereof. [In the above formulas, in ring A and ring B, when ring B is substituted at the 2-position of the imidazole nucleus, ring A and ring B are the same or different and are substituted with halogen, lower alkyl or lower alkoxy. When ring B is substituted at position 5 of the imidazole nucleus, ring A and ring B simultaneously represent phenyl which may be substituted with halogen, lower alkyl or lower alkoxy. R ¹ and R ² are the same or different and each is hydrogen, lower alkyl, aryl or aralkyl which may have a substituent on the benzene ring, nitrogen-containing heteroaromatic ring, cycloalkyl, formula (In the formula, X and Y are the same or different, and N and CH are
Represents 0, 1, 2, 3 and W represents hydrogen, lower alkyl, phenyl or aralkyl which may have a substituent on the benzene ring. ) Or a group which is bonded to each other to form a heterocycle with an adjacent nitrogen atom. ]