WO1999033827A1

WO1999033827A1 - Novel imidazole derivatives

Info

Publication number: WO1999033827A1
Application number: PCT/JP1998/005930
Authority: WO
Inventors: Hiroyuki Sueoka; Jouji Yasuoka; Akira Nishiyama; Masatoshi Kiuchi; Katsuya Yamamoto; Kunio Sugahara
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1997-12-26
Filing date: 1998-12-24
Publication date: 1999-07-08
Also published as: AU1690199A; JP2004067510A

Abstract

Novel imidazole derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof: (wherein R1 is hydrogen, optically substituted alkyl or the like; R2 is hydrogen, optically substituted alkyl or the like; R3 is optically substituted heteroaryl; and R4 is optically substituted cycloalkyl, optically substituted phenyl or the like, provided that when R1 is hydrogen and R2 is phenyl or phenyl substituted with halogeno, lower alkyl or lower alkoxy, R3 is benzothiazolyl or phenyl-substituted benzothiazolyl). The above derivatives and salts exhibit an inhibitory activity against the production of IL-4 and IL-5 form Th2 cells, and are therefore useful as preventive and therapeutic agents for allergic diseases such as atopic dermatitis, bronchial asthma and allergic rhinitis.

Description

Specification

New imidazole derivatives

Technical field

The present invention has an inhibitory effect on the production of interleukin 4 (hereinafter, IL-4) and interleukin 5 (hereinafter, IL-15) from type 2 helper T cells (hereinafter, abbreviated as Th2 cells). The present invention relates to a novel imidazole derivative useful for the prevention and treatment of allergic diseases and a pharmaceutically acceptable salt thereof.

Background art

Helper T cells are classified into Th1 and Th2 based on the difference in the cytokines they produce. Th1 cells produce cytokines such as interleukin 2 (hereinafter, IL-2) and interferon-7 (hereinafter, IFN-7), and mainly regulate cellular immunity. On the other hand, Th2 cells produce cytokines such as IL-4, IL-5, and interleukin 10 (hereinafter, IL-10), and mainly regulate humoral immunity. Immune response is regulated by the balance between Th1 and Th2 cells, and IFN-7 produced by Th1 cells promotes differentiation into Th1 cells and inhibits differentiation into Th2 cells . In addition, IL-4 produced by Th 2 cells promotes differentiation into Th 2 cells and inhibits differentiation into Th 1 cells.

In recent years, it has been clarified that various immune diseases are caused by disruption of the balance of ThlZTh2 cells. It has been reported that Th 2 cells are predominant in allergic diseases and systemic autoimmune diseases, and Th 1 cells are predominant in organ-specific autoimmune diseases.

Among the cytokines produced by Th2 cells, IL-14 has the effect of class switching to immunoglobulin E (IgE) and inducing differentiation into Th2 cells, and IL-5 activates eosinophils. It has effects such as infiltration induction, and it has been suggested that it is particularly deeply involved in the pathogenesis of allergy. In fact, in the alveolar lavage fluid of asthmatics I

Many reports have shown that L-14 and IL-15 levels are high, and that IL-14 and IL-15 mRNA are present in the rash area of patients with atopic dermatitis (Am. J. Respir. Cell Mo 1. Biol., Vol. 12, p. P. 477-487, 1995, J. Immu no., Vol. 158, p. P. 3539 -3544 and J. Exp. Med., Vol. 173, pp. 775-778, 199 1) o

It has also been reported that various allergic reactions are unlikely to occur in mice deficient in the IL-14 or IL-5 gene (Nature, Vol. 362, pp. 245-247, 1). 993 and J. Exp. Med., Vol. 183, pp. 195-201, 1996). In addition, it has been reported that administration of anti-IL-15 antibody strongly suppresses eosinophil infiltration in monkey airway inflammation models and various animal models (Am. J. Respir. Cri t. Care Med., Vol. 152, pp. 467-472, 1995).

Thus, it has been clarified that IL-4 or IL-15 is involved in the development of allergic diseases in animal models of allergic diseases.

Therefore, it is thought that a drug that inhibits the production of IL-4 and IL-5 in allergic patients, improves the bias toward Th2 cells, and suppresses eosinophilic inflammation can be a useful antiallergic drug.

On the other hand, Japanese Patent Publication No. 7-537 16 describes a certain imidazole derivative having anti-inflammatory and analgesic effects, but it inhibits the production of IL_4 and IL-5 from Th2 cells. Nothing is described.

A recently developed sublatast tosilate (IPD-1151T) has a specific inhibitory effect on the production of IL-4 and IL-15 from Th2 cells, and is effective against asthmatic diabetic dermatitis. Clinical results have been reported to be effective (Clinical Medicine, Vol. 8, No. 7, 1992). The inhibitory effect of IPD-1151T on IL-4 and IL_5 production is not very strong, and whether or not it expresses the inhibitory effect of IL-14 and IL-15 production at clinical doses It is not clear.

At present, steroids are widely used as therapeutic agents for allergic diseases and have shown high clinical effects. Steroids produce IL-5 due to their wide-ranging effects. It has an inhibitory effect on biosynthesis, and its inhibitory effect on IL-15 production is considered to be a mechanism for suppressing eosinophilic inflammation. Steroids have a wide range of effects, and their side effects are problematic.

Furthermore, recent studies suggest that immunosuppressants such as cyclosporin A and tacrolimus also inhibit IL-5 production and are effective against eosinophilic inflammation. However, these drugs have side effects on the kidneys and side effects such as immunosuppression and induction of infection by widely inhibiting the production of cytokines such as IL-2 as well as IL-5.

Therefore, at present, drug discovery of a therapeutic drug for allergic diseases, which has a strong antiallergic effect equivalent to that of steroids and has few side effects, is expected.

A compound that has a specific inhibitory effect on IL-14 and IL-15 production can be compared to conventional drugs by improving the bias toward Th2 cells in allergic patients and suppressing eosinophilic inflammation. Atopic dermatitis, bronchial asthma, and allergic drugs with fewer side effects compared to other drugs are expected to be useful for the prevention and treatment of allergic diseases such as rhinitis o

An object of the present invention is to provide a drug that specifically inhibits the production of IL-14 and IL-5, which are deeply involved in the pathogenesis of allergies, among the cytokines produced from Th2 cells. is there.

Disclosure of the invention

The present inventors have conducted intensive studies in view of the above circumstances, and as a result, have found that a novel imidazole compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof are excellent in IL-4 and IL. The present inventors have found that they have an inhibitory effect on the production of 5, and are useful as preventive and therapeutic agents for allergic diseases, thereby completing the present invention.

That is, the present invention is as follows.

(1) General formula (I) (I)

(Wherein, R ¹ represents hydrogen, an optionally substituted alkyl group, an optionally substituted aralkyl group or a morpholinoalkyl group,

R ² is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted quinolyl group Represents an optionally substituted isoquinolyl group, an optionally substituted pyridyl group or an optionally substituted aralkyl group.

R ³ represents an optionally substituted heteroaryl group,

R represents an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted heteroaryl group.

Provided that R ¹ is hydrogen, R ² is a phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group, and R ⁴ is a phenyl group or a halogen atom, When it is a phenyl group substituted with a lower alkyl group or a lower alkoxy group, R ^{3 is a} benzothiazolyl group or a thiazolyl group substituted with a phenyl group. )

Or a pharmaceutically acceptable salt thereof.

(2) General formula (I)

(Wherein, R ¹ is hydrogen, an optionally substituted alkyl group, or an optionally substituted Represents an aralkyl group or a morpholinoalkyl group,

R ³ represents an optionally substituted heteroaryl group,

R ⁴ represents a cycloalkyl group which may be substituted, a phenyl group which may be substituted, a naphthyl group which may be substituted, or a heteroaryl group which may be substituted.

However, when R ¹ is hydrogen and R ² is a phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group, R ⁴ is a phenyl group or a halogen atom. And represents a group other than a phenyl group substituted with a lower alkyl group or a lower alkoxy group. )

Or a pharmaceutically acceptable salt thereof.

(3) R ^{1 in the} general formula (I) represents hydrogen,

R ² is a nitro group, an amino group, a monoalkylamino group, a dialkylamino group, an acylamino group, a dialkylaminoalkylamino group, an acyloxyalkylcarbonylamino group, a dialkylaminoalkoxy group, an acyloxyalkoxy group, It may be substituted with a hydroxyalkoxy group or a lower alkyl group having 1 to 6 carbon atoms, and may contain an oxygen atom.Saturated 5- or 6-membered heteromonocyclic ring containing 1 to 2 nitrogen atoms. A phenyl group substituted by any one of the groups; R ³ represents an optionally substituted heteroaryl group;

The imidazole derivative according to (1), wherein R ⁴ is a phenyl group which may be substituted, or a pharmaceutically acceptable salt thereof.

(4) R ^{1 in the} general formula (I) represents hydrogen,

R ² represents a naphthyl group which may be substituted, R ³ represents a heteroaryl group which may be substituted,

(5) 5-(4-methylphenyl) — 2 — (1-naphthyl) 1 N — (2-thiazolyl) imidazole-1-carboxamide,

5-(4-Methoxyphenyl) 1 2-(4-Ditrophenyl) 1 N-(2-Thiazolyl) imidazole-4-Carboxamide,

5- (4-Methoxyphenyl) -1-2- (4-methylaminophenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide,

2-(4-butylaminophenyl) 1 5 _ (4-methoxyphenyl) 1 N-(2-thiazolyl) imidazo 1-4-

2- (3-dimethylaminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-5-hexylboxamide,

2- (4-butylaminophenyl) -1-5- (4-chlorophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide,

5- (4-chlorophenyl) 1 2- (4-methylaminophenyl) N- (2-thiazolyl) imidazo-l-41-carboxamide,

5- (4-chlorophenyl) 1 2- (4-nitrophenyl) N- (2-thiazolyl) imidazo-l-41-carboxamide,

5- (4-chlorophenyl) 1 2— (4- (1-pyrrolidinyl) phenyl) 1 N

-(2-thiazolyl) imidazo-l-l 4-carboxamide,

5- (4-chlorophenyl) -1-2- (4- (2-dimethylaminoethyloxy) phenyl) — N— (2-thiazolyl) imidazo-l-41-carboxamide,

5- (4-chlorophenyl) 1 2- (4- (3-dimethylaminopropyloxy)

) Phenyl) — N— (2-thiazolyl) imidazoyl 4-carboxamide and

5-(4-Chlorophenyl) 1 2-(4-(2-Hydroxyshetyloxy) Hue Nyl) 1-N- (2-thiazolyl) imidazole-41-carboxamide; the imidazole derivative according to (1) or a pharmacologically acceptable salt thereof.

(6) A pharmaceutical composition comprising a therapeutically effective amount of the imidazole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (5) and a pharmaceutically acceptable additive. .

(7) A selective production inhibitor of interleukin-4 and interleukin-5, comprising the imidazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).

(8) An antiallergic agent containing the imidazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the effect of the compound of Example 1 on an ovalbumin-induced mouse biphasic edema model in Experimental Example 2. Each value represents the mean soil standard error. (The number of cases is 23 to 28). The significance test was performed using Dunnet's multiple comparison. ** indicates that a significant difference from the control was observed at P <0.01.

FIG. 2 shows the effects of the compounds of Examples 79 and 99 on the increase in Eosinophi 1 peroxidase (EPO) activity in the ovalbumin-induced mouse biphasic edema model in Experimental Example 3. It is a graph. Each value represents the standard error of the mean. (The number of cases is 13 to 16). The significance test was performed using Dunnett's multiple comparison. ** indicates that a significant difference from the control was observed at p <0.01.

Detailed description of the invention

The definitions of the substituents of the compound represented by formula (I) of the present invention are as follows. The alkyl group of the `` optionally substituted alkyl group '' of R ¹ and R ² is a linear or branched alkyl group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, Propyl, isopropyl, butyl, isoptyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, o Octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl

Octadecyl group, icosyl group and the like, preferably alkyl having 1 to 6 carbon atoms.

Examples of the substituent of the “optionally substituted alkyl group” include an aralkyloxy group (a benzyl group such as a benzyloxy group, a phenylethoxy group, a phenylpropyloxy group, and a phenylbutoxy group). A hydroxyl group; a lower alkoxy group (indicating an alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group and a butoxy group); A hydroxyalkoxy group (having 1 to 6 carbon atoms such as a hydroxyethoxy group, a hydroxypropyloxy group, a hydroxyisopropyloxy group, a hydroxybutoxy group, a hydroxyisobutoxy group, a hydroxypentyloxy group, etc.) A hydroxyalkoxy group in which a lower alkoxy group is substituted with a hydroxyl group); Coxyalkoxy group (C1-C5 such as methoxymethoxy group, methoxyxetoxy group, methoxyl pyroxy group, ethoxypropyloxy group, propyloxyethoxy group, isopropyloxybutoxy group, butoxyisopropyloxy group, etc. An alkoxyalkoxy group in which a lower alkoxy group of 6 is substituted with an alkoxy group having 1 to 6 carbon atoms); an aminoalkoxy group (an aminoethoxy group, an aminopropyloxy group, an aminoisopropyloxy group, an aminobutoxy group) Monoalkylaminoalkoxy group (methylaminoethoxy group, ethylaminoethoxy group, ethylyl group), monoalkylaminoalkoxy group (methylaminoethoxy group, ethylaminoethoxy group, ethylamino) Minoisobutoxy group, propylaminoethoxy group, iso A monoalkylaminoalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a propylaminobutoxy group is substituted with an alkylamino group having 1 to 6 carbon atoms); a dialkylaminoalkoxy group (dimethylaminoethoxy group, A dialkylaminoalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a tilaminopropyloxy group, a diisopropylaminoethoxy group or a dibutylaminoisopropyloxy group is substituted by an alkylamino group having 1 to 6 carbon atoms); Alkoxy group (Shows a mercaptoalkoxy group in which a mercapto group is substituted with a lower alkoxy group having 1 to 6 carbon atoms such as a mercaptoethoxy group, a mercaptopropyloxy group, a mercaptoisopropyloxy group, and a mercaptobutoxy group); an alkylthioalkoxy group (methylthioethoxy group A lower alkoxy group having 1 to 6 carbon atoms such as a group, ethylthioethoxy group, ethylthiopropyloxy group, propylthioisopropyloxy group or isopropylthiobutoxy group is substituted with an alkylthio group having 1 to 6 carbon atoms. An alkylthioalkoxy group); an acyloxyalkoxy group (acetyloxyethoxy group, propionyloxyethoxy group, isoptyryloxypropyloxy group, acetyloxypropyloxy group, 1 to 6 carbon atoms such as xypropyloxy group A lower alkoxy group having 2 to 6 carbon atoms substituted with an aliphatic alkoxy group, which represents an acyloxy alkoxy group); a cyanoalkoxy group (cyanoethoxy group, cyanopropyloxy group, cyanoisopropyloxy group, A cyanoalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a cyanobutoxy group and a cyanoisobutoxy group is substituted with a cyano group; and a ditroalkoxy group (a ditroethoxy group, a nitropropyloxy group, a nitrobutoxy group, a nitroiso group) A nitroalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a butoxy group is substituted with a nitro group; a haloalkoxy group (a chloromethoxy group, a bromomethoxy group, a fluoromethoxy group, a trifluoromethoxy group, a dichloroethoxy group); , Dibromoethoxy group, pentafluoro mouth ethoxy A haloalkoxy group in which a halogen atom (fluorine, chlorine, bromine, iodine) is substituted on a lower alkoxy group having 1 to 6 carbon atoms such as a propyloxy group, a cyclopropyloxy group or a dichlorobutoxy group; a mercapto group; An alkylthio group whose alkyl part is an alkyl group having 1 to 6 carbon atoms such as an alkylthio group, an ethylthio group, a propylthio group, an isopropylthio group, an isopropylthio group, a butylthio group, and an isobutylthio group); an amino group; a monoalkylamino group (methylamino Dialkylamino group (dimethylamino group, dimethylamino group, dipropylamino group); alkyl group such as dimethylamino group, propylamino group, and butylamino group represents a monoalkylamino group having 1 to 6 carbon atoms. , Diisopropylamino group, dibutylamido A dialkylamino group in which the alkyl moiety such as an amino group is an alkyl group having 1 to 6 carbon atoms); a dialkylaminoalkylamino group (an alkyl group such as a dimethylaminoethylamino group or a dimethylaminopropylamino group). Part represents a dialkylaminoalkylamino group having 1 to 6 carbon atoms); a carbamoyl group; a monoalkyl carbamoyl group (a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, a butylcarbamoyl group) A monoalkyl group having an alkyl moiety of 1 to 6 carbon atoms, such as a monoalkyl group having an alkyl group of 1 to 6; a dialkyl group having a carbamoyl group (dimethylcarbamoyl group, getylcarbamoyl group, dipropylcarbamoyl group, dibutylcarbamoyl group, etc.); Where the alkyl part is an alkyl group having 1 to 6 carbon atoms An acylamino group (indicating an aliphatic acylamino group having 2 to 6 carbon atoms such as an acetylamino group and a propionylamino group and a benzoylamino group); a nitro group; a cyano group; an alkylsulfonyl group (a methylsulfonyl group, An alkyl moiety such as a tylsulfonyl group represents an alkylsulfonyl group having 1 to 6 carbon atoms; an alkylsulfinyl group (an alkyl moiety such as a methylsulfinyl group or an ethylsulfinyl group has 1 to 6 carbon atoms); A sulfamoyl group; a monoalkylsulfamoyl group (an alkyl moiety such as a methylsulfamoyl group or an ethylsulfamoyl group is an alkyl group having 1 to 6 carbon atoms) A monoalkylsulfamoyl group); a dialkylsulfamoyl group ( An alkyl moiety such as a methylsulfamoyl group or a getylsulfamoyl group represents a dialkylsulfamoyl group having an alkyl group having 1 to 6 carbon atoms); a cycloalkyl group (a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, A halogen atom (fluorine, chlorine, bromine, iodine); a carboxyl group; an alkoxycarbonyl group (a methoxycarbonyl group, an ethoxycarbonyl group, a propylo group). An alkoxy group such as a xycarbonyl group or a butoxycarbonyl group represents an alkoxycarbonyl group having 1 to 6 carbon atoms; an acyl group (a carbon atom such as a formyl group, an acetyl group or a propionyl group); Represents an aliphatic acetyl group and a benzoyl group of from 6 to 6); Xy group (indicating an aliphatic acyloxy group having 1 to 6 carbon atoms such as a formyloxy group, an acetyloxy group, a propionyloxy group and a benzoyloxy group), and the like, preferably a hydroxyl group, an amino group, a monoalkylamino group, a dialkylamino group A lower alkoxy group, a halogen atom, an aralkyloxy group and the like.

The “optionally substituted alkyl group” may be substituted by 1 to 3 substituents, which may be the same or different.

The aralkyl group in the “optionally substituted aralkyl group” of R ¹ and R ² is a phenyl group substituted with an alkyl group having 1 to 6 carbon atoms, and is a benzyl group, a phenylethyl group, a phenylpropyl group. And a phenylbutyl group.

Examples of the substituent on the phenyl ring of the “optionally substituted aralkyl group” include lower alkyl groups (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl) An alkyl group having 1 to 6 carbon atoms, such as an isopentyl group, a hexyl group, etc.); a hydroxyalkyl group (a hydroxymethyl group, a hydroxyethyl group, a hydroxylpropyl group, a hydroxyisopropyl group, a hydroxypropyl group) A hydroxyalkyl group in which a lower alkyl group having 1 to 6 carbon atoms such as a hydroxy group, a hydroxylisobutyl group, or a hydroxypentyl group is substituted with a hydroxyl group); an alkoxyalkyl group (a methoxyxyl group, a methoxyl group) Propyl, ethoxypropyl, propyloxethyl, isopropyloxybutyl, An alkoxyalkyl group in which a lower alkyl group having 1 to 6 carbon atoms such as a toxic butyl group is substituted with an alkoxy group having 1 to 6 carbon atoms; an aminoalkyl group (an aminomethyl group, an aminoethyl group, an aminoamino group, an aminopropyl group) Monoalkylaminoalkyl (methylaminomethyl, methylaminoethyl, ethylamino, etc.); an aminoalkyl group in which a lower alkyl group having 1 to 6 carbon atoms such as an aminobutyl group or an aminoisobutyl group is substituted with an amino group. A monoalkylaminoalkyl group in which a lower alkyl group having 1 to 6 carbon atoms such as an ethyl group, an ethylaminoisobutyl group, a propylaminoethyl group, and an isopropylaminobutyl group is substituted by an alkylamino group having 1 to 6 carbon atoms; ); Dialkylaminoalkyl group (dimethylaminomethyl Dialkylamino in which a lower alkyl group having 1 to 6 carbon atoms such as an alkyl group, a dimethylaminoethyl group, a acetylaminopropyl group, a diisopropylaminoethyl group, and a dibutylaminoisopropyl group is substituted with an alkylamino group having 1 to 6 carbon atoms. A mercaptoalkyl group (indicating a mincapalkyl group); a mercaptoalkyl group (indicating a mercaptoalkyl group in which a lower alkyl group having 1 to 6 carbon atoms such as a mercaptomethyl group, a mercaptoethyl group, and a mercaptoisopropyl group is substituted with a mercapto group); Alkylthioalkyl groups (1 to 6 carbon atoms such as methylthiomethyl group, methylthioethyl group, ethylthioethyl group, ethylthiopropyl group, peroxypropylthioisopropyl group, isopropylthiobutyl group, etc.) Represents an alkylthioalkyl group substituted with an alkylthio group of ~ 6) Acyloxyalkyl group (carbon such as acetyloxymethyl group, acetyloxyethyl group, propionyloxymethyl group, propionyloxyshethyl group, isobutyloxymethyl group, acetyloxypropyl group, butyloxypropyl group, etc.) An acyloxyalkyl group in which a lower alkyl group having 1 to 6 carbon atoms is substituted with an aliphatic acylosoxy group having 2 to 6 carbon atoms); an acysiloxy group (acetyloxy cetyl group, acetyloxy propionyl) Group, acetyloxybutyryl group, propionyloxyacetyl group, propionyloxypropionyl group, etc., is substituted by an aliphatic acyl group having 2 to 5 carbon atoms. An alkoxycarbonylalkyl group (a methoxycarbonylmethyl group, an ethoxy group). A lower alkyl group having 1 to 6 carbon atoms such as a cicarbonylmethyl group, a propoxycarbonylmethyl group, a butoxycarbonylmethyl group, a methoxycarbonylethyl group, or a methoxycarbonylpropyl group; An alkoxycarbonylalkyl group substituted with an alkoxycarbonyl group); an acyloxyalkylcarbonylamino group (acetoxymethylcarbonylamino group, acetoxitytylcarbonylamino group, propionyloxymethylcarbonylamino group); An acyloxyalkylcarbonylamino group in which an aliphatic acylamino group having 2 to 6 carbon atoms is substituted with an aliphatic acylylamino group having 2 to 6 carbon atoms such as a mino group and a propionyloxyshethylcarbonylamino group); Cyanoalkyl group (cyanomethyl group, A cyanoethyl group, a cyanopropyl group, a cyanoisopropyl group, a cyanobutyl group, a cyanoalkyl group in which a cyano group is substituted with a lower alkyl group having 1 to 6 carbon atoms such as a cyanoisobutyl group); a nitroalkyl group (nitromethyl group, nitroethyl group) A nitroalkyl group in which a lower alkyl group having 1 to 6 carbon atoms such as a nitropropyl group, a nitropropyl group, a nitroisobutyl group, etc. is substituted by a nitro group); a haloalkyl group (chloromethyl group, bromomethyl group, fluoromethyl group, trifluoromethyl) Halogens (fluorine, chlorine, bromine, iodine) such as chloromethyl, dichloroethyl, dibromoethyl, pentafluoroethyl, chloropropyl, dichlorobutyl, etc. have been substituted with alkyl groups having 1 to 6 carbon atoms. A haloalkyl group); a phenyl group; Alkyl group (indicating an aralkyl group in which a phenyl group such as a benzyl group, a phenylethyl group, a phenylpropyl group, or a phenylbutyl group is substituted with an alkyl group having 1 to 6 carbon atoms); an aralkyl group (a benzyloxy group, a phenylethyl group) A phenyl group such as a ethoxy group, a phenylpropyloxy group, a phenylbutyloxy group, or a chlorobenzyloxy group is substituted with an alkyl group having 1 to 6 carbon atoms, and the phenyl group is a halogen (fluorine). , An aralkyloxy group which may be substituted with chlorine, bromine or iodine); a hydroxyl group; a lower alkoxy group (having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group). An alkoxy group); a hydroxyalkoxy group (a hydroxyethoxy group, a hydroxypropyloxy group, A hydroxyalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a droxyisopropyloxy group, a hydroxybutoxy group, a hydroxyisobutoxy group, or a hydroxypentyloxy group is substituted with a hydroxyl group); Alkoxy groups (lower alkoxy having 1 to 6 carbon atoms such as methoxy methoxy, methoxy ethoxy, methoxy propyl oxy, ethoxy propyl oxy, propyl oxy ethoxy, isopropyl oxy butoxy, butoxy isopropyl oxy, etc. An alkoxyalkoxy group in which a C1-6 alkoxy group is substituted on the group); an aminoalkoxy group (an aminoethoxy group, an aminopropyloxy group, an aminoisopropyloxy group, an aminobutoxy group, an aminoaminobutoxy group) 1 to 6 carbons such as lower al A monoalkylaminoalkoxy group (methylaminoethoxy group, ethylaminoethoxy group, ethylaminoisobutoxy group, propylaminoethoxy group, isopropylaminobutoxy group) A monoalkylaminoalkoxy group having 1 to 6 carbon atoms substituted with a lower alkoxy group having 1 to 6 carbon atoms, such as a monoalkylaminoalkoxy group); a dialkylaminoalkoxy group (dimethylaminoethoxy group, dimethylaminopropyloxy group) A dialkylaminoalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms, such as acetylaminopropyloxy group, diisopropylaminoethoxy group, and dibutylaminoisopropyloxy group, is substituted with an alkylamino group having 1 to 6 carbon atoms) ; Mercaptoalkoxy (Shows a mercaptoalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a mercaptoethoxy group, a mercaptopropyloxy group, a mercaptoisopropyloxy group, a mercaptobutoxy group is substituted with a mercapto group); an alkylthioalkoxy group (methylthioethoxy group) Alkylthioalkyl group in which a lower alkoxy group having 1 to 6 carbon atoms such as a group, ethylthioethoxy group, ethylthiopropyloxy group, propylthioisopropyloxy group, or isopropylthiobutoxy group is substituted with an alkylthio group having 1 to 6 carbon atoms ); Carbon atoms such as an acyloxy alkoxy group (acetyloxy shetoxy group, propionyloxyethoxy group, isoptyryloxypropyloxy group, acetyloxypropyloxy group, and butyryloxypropyloxy group) Number 1 to 6 A lower alkoxy group having 2 to 6 carbon atoms substituted with an aliphatic acyloxy group); a cyanoalkoxy group (cyanoethoxy group, cyanopropyloxy group, cyanoisopropyloxy group); A cyanoalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a cyanobutoxy group or a cyanoisobutoxy group is substituted with a cyano group); a nitroalkoxy group (nitroethoxy group, nitropropyloxy group, A nitroalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a nitrobutoxy group and a nitroisobutoxy group is substituted by a nitro group; a haloalkoxy group (chloromethoxy group, bromomethoxy group, fluoromethoxy group, trifluoromethoxy group) Group, dichloroethoxy group, dibromoethoxy group, penta Carbon number of fluoroethoxy group, chloropropyl group, dichlorobutoxy group, etc.

A haloalkoxy group in which a halogen atom (fluorine, chlorine, bromine, iodine) is substituted for a lower alkoxy group of 1 to 6; a mercapto group; an alkylthio group (methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group) An alkylthio group whose alkyl part is an alkyl group having 1 to 6 carbon atoms, such as an amino group or an isobutylthio group; an amino group; a monoalkylamino group (a methylamino group, an ethylamino group, a propylamino group, a butylamino group, an isopentyl) An alkyl group such as an amino group represents a monoalkylamino group having 1 to 6 carbon atoms); a dialkylamino group (a dimethylamino group, a dimethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, etc.) Is an alkyl group having 1 to 6 carbon atoms. A dialkylamino group); a dialkylaminoalkylamino group (a dialkylaminoalkylamino group in which the alkyl moiety such as a dimethylaminoethylamino group or a dimethylaminopropylamino group is an alkyl group having 1 to 6 carbon atoms) A monoalkyl carbamoyl group (a monoalkyl carbamoyl group, a methyl carbamoyl group, an ethyl carbamoyl group, a propyl carbamoyl group, a butyl carbamoyl group, etc.) wherein the alkyl portion is an alkyl group having 1 to 6 carbon atoms. A dialkyl carbamoyl group (indicating a dialkyl carbamoyl group in which the alkyl moiety such as a dimethylcarbamoyl group, a getylcarbamoyl group, a dipropyl carbamoyl group, a dibutylcarbamoyl group is an alkyl group having 1 to 6 carbon atoms) An acetylamino group (acetylyl) Amino group, propionylamino group, etc., represent an acylamino group and a benzoylamino group in which the acyl moiety is an aliphatic acryl group having 1 to 6 carbon atoms); nitro group; cyano group; alkylsulfonyl group (methylsulfonyl group, ethylsulfonyl) Where the alkyl part of the group is an alkylsulfonyl group having 1 to 6 carbon atoms)

An alkylsulfinyl group (an alkylsulfinyl group in which the alkyl portion is an alkyl group having 1 to 6 carbon atoms, such as a methylsulfinyl group or an ethylsulfinyl group)

An alkylsulfinyloxyalkyl group (methylsulfinyloxymethyl group, methylsulfinyloxyshethyl group, methylsulfinyloxypropyl group, An alkylsulfinyloxyalkyl group in which the alkyl portion is an alkyl group having 1 to 6 carbon atoms, such as an ethylsulfinyloxymethyl group, an ethylsulfinyloxyxethyl group, and an ethylsulfinyloxypropyl group. Monoalkylsulfamoyl group; monoalkylsulfamoyl group in which the alkyl part such as methylsulfamoyl group and ethylsulfamoyl group is an alkyl group having 1 to 6 carbon atoms; Sulfamoyl group (dialkylsulfamoyl group in which the alkyl part such as dimethylsulfamoyl group and acetylsulfamoyl group is an alkyl group having 1 to 6 carbon atoms); cycloalkyl group (cyclopropyl group, cyclobutyl group) Group, cyclopentyl group, cyclohexyl group, etc. A cycloalkylalkyl group (a cycloalkyl in which a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, or a cyclohexylmethyl group is substituted with an alkyl group having 1 to 6 carbon atoms) A halogen atom (indicating fluorine, chlorine, bromine, or iodine); a carboxyl group; an alkoxycarbonyl group (such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, or a butoxycarbonyl group) A moiety represents an alkoxycarbonyl group having 1 to 6 carbon atoms); an acyl group (an aliphatic acyl group having 1 to 6 carbon atoms such as a formyl group, an acetyl group, a propionyl group and a benzoyl group); ); Acyloxy group (formyloxy group, acetyloxy group) And an acyl moiety such as a propionyloxy group represents an aliphatic acyl group having 1 to 6 carbon atoms and an acyloxy group which is a benzoyl group); a lower alkyl group having 1 to 6 carbon atoms (eg, a methyl group) Or an alkyl group such as ethyl, propyl, isopropyl, butyl, isoptyl, tert-butyl, pentyl, isopentyl, and hexyl). A saturated 5- or 6-membered heterocyclic monocyclic group containing 1 to 2 nitrogen atoms (e.g., represents lipidinyl, imidazolidinyl, birazolidinyl, piperidyl, piperazinyl, morpholinyl, morpholino, etc.); To 6 lower alkyl groups (for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group Or a tert-butyl group, a pentyl group, an isopentyl group, or a hexyl group, etc.), which may be substituted with a nitrogen-containing heteromonocyclic alkyl group (the nitrogen-containing heterocyclic ring contains an oxygen atom. A saturated 5- or 6-membered heterocyclic monocyclic group containing 1 to 2 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, birazolidinyl, piperidyl, piperazinyl, morpholinyl, morpholino, etc. Represents a nitrogen-containing heteromonocyclic alkyl group having an alkyl group having 1 to 6 carbon atoms, such as a piperazinylmethyl group, a pyrrolidinylmethyl group, a piperidinomethyl group, a morpholinylmethyl group, and a morpholinomethyl group. And preferably a hydroxyl group, an amino group, a monoalkylamino group, a dialkylamino group, a nitro group, Lower alkyl group, lower alkoxy group, haloalkyl group, halogen atom, aralkyl group, aralkyloxy group optionally substituted by halogen, hydroxyalkyl group, hydroxyalkoxy group, dialkylaminoalkyl group, acyloxyalkyl group, alkoxycarbonylalkyl Group, acyloxyalkylcarbonylamino group, phenyl group, acyloxyalkoxy group, dialkylaminoalkoxy group, acylamino group, alkylsulfinyloxyalkyl group, and may contain an oxygen atom. And a saturated 5- or 6-membered heterocyclic monocyclic group containing one nitrogen atom, a nitrogen-containing heteromonocyclic alkyl group which may be substituted with a lower alkyl group having 1 to 6 carbon atoms, and the like.

The phenyl ring of the "optionally substituted aralkyl group" may be substituted by 1 to 3 substituents, which may be the same or different.

Examples of the substituent of the alkyl portion of the “optionally substituted aralkyl group” include a phenyl group, an aralkyloxy group (a phenyl group such as a benzyloxy group, a phenylethoxy group, a phenylpropyloxy group, a phenylbutoxy group, etc.). A hydroxy group; a lower alkoxy group (indicating an alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group and a butoxy group); A hydroxyalkoxy group (a hydroxyethoxy group, a hydroxypropyloxy group, a hydroxyisopropyloxy group); A hydroxyalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a hydroxy group, a hydroxybutoxy group, a hydroxyisoptoxy group, or a hydroxypentoxy group is substituted with a hydroxyl group); an alkoxyalkoxy group (a methoxymethyl group) Lower alkoxy groups having 1 to 6 carbon atoms such as ethoxy, methoxy, methoxy, methoxypropyloxy, ethoxypropyloxy, propyloxyethoxy, isopropyloxybutoxy, and butoxybuisopropyloxy An alkoxyalkoxy group substituted by an alkoxy group having 1 to 6 carbon atoms); an aminoalkoxy group (aminoethoxy group, aminopropyloxy group, aminoisopropyloxy group, aminobutoxy group, aminoaminobutoxy group) Amino group was substituted with a lower alkoxy group having 1 to 6 carbon atoms, such as An aminoalkoxy group); a monoalkylaminoalkoxy group (a lower alkyl group having 1 to 6 carbon atoms such as a methylaminoethoxy group, an ethylaminoethoxy group, an ethylaminoisobutoxy group, a propylaminoethoxy group, and an isopropylaminobutoxy group) A monoalkylaminoalkoxy group in which an alkoxy group is substituted by an alkylamino group having 1 to 6 carbon atoms); a dialkylaminoalkoxy group (dimethylaminoethoxy group, acetylaminopropyloxy group, diisopropylaminoethoxy group, A dialkylaminoalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as dibutylaminoisopropyloxy group is substituted by an alkylamino group having 1 to 6 carbon atoms); a mercaptoalkoxy group (a mercaptoethoxy group, a mercaptopropyl group) Oxy group, Mercap An alkylthioalkoxy group (e.g., methylthioethoxy group, ethylthioethoxy group, ethylthiopropyl); a lower alkoxy group having 1 to 6 carbon atoms such as isopropyloxy group, mercaptobutoxy group or the like, which is substituted with a mercapto group by a lower alkoxy group; An alkylthioalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms, such as an oxy group, a propylthioisopropyloxy group, or an isopropyl thioptoxy group, is substituted by an alkylthio group having 1 to 6 carbon atoms); Group (C 1-6 lower alkoxy groups such as acetyloxyethoxy group, propionyloxyethoxy group, isobutyryloxypropyloxy group, acetyloxypropyloxy group, 2 ~ 6 aliphatic A siloxy alkoxy group substituted with a siloxy group); a cyano alkoxy group (a cyanoethoxy group, a cyanopropyloxy group, a cyanoisopropyloxy group)

, A cyanooxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a cyanobutoxy group and a cyanoisobutoxy group is substituted with a cyano group); a nitroalkoxy group (nitroethoxy group, nitropropyloxy group, nitrobutoxy group) A nitroalkoxy group in which a lower alkoxy group having 1 to 6 carbon atoms such as a nitroisobutoxy group is substituted with a nitro group); a haloalkoxy group (a chloromethoxy group, a bromomethoxy group, a fluoromethoxy group, a trifluoromethoxy group, A halogen atom (fluorine, chlorine, bromine, iodine) is substituted by a lower alkoxy group having 1 to 6 carbon atoms such as dichloroethoxy group, dibromoethoxy group, pentafluoroethoxy group, chloropropyloxy group, dichlorobutoxy group and the like. Represents a haloalkoxy group); a mercapto group; an alkyl Monoalkyla (an alkylthio group in which the alkyl moiety such as a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, and an isobutylthio group is an alkyl group having 1 to 6 carbon atoms); an amino group; Amino group (a monoalkylamino group in which the alkyl part such as a methylamino group, an ethylamino group, a propylamino group, and a butylamino group is an alkyl group having 1 to 6 carbon atoms); a dialkylamino group (a dimethylamino group, a acetylamino group, a dipropylamino group An alkyl group such as an amino group, a diisopropylamino group or a dibutylamino group represents a dialkylamino group having 1 to 6 carbon atoms; a dialkylaminoalkylamino group (an alkyl such as a dimethylaminoethylamino group or a dimethylaminopropylamino group); Where carbon number is 1-6 Dialkylaminoalkylamino group which is an alkyl group); carbamoyl group; monoalkyl levamoyl group (methylcarbamoyl group, ethylcarbamoyl group, propyllvamoyl group, butylcarbamoyl group, etc., where the alkyl part has 1 to 6 carbon atoms) A monoalkyl carbamoyl group, which is an alkyl group of); a dialkylcarbamoyl group (a dimethylcarbamoyl group, a dimethylcarbamoyl group, a dipropylcarbamoyl group, a dibutylcarbamoyl group, etc.) wherein the alkyl portion is an alkyl group having 1 to 6 carbon atoms. A dialkyl rubamoyl group); an acylamino group (acetyl An aliphatic acylamino group having 2 to 6 carbon atoms and a benzoylamino group such as an amino group and a propionylamino group; a nitro group; a cyano group; an alkylsulfonyl group (an alkyl moiety such as a methylsulfonyl group and an ethylsulfonyl group); An alkylsulfonyl group which is an alkyl group having 1 to 6 carbon atoms); an alkylsulfinyl group (where the alkyl portion such as a methylsulfinyl group or an ethylsulfinyl group is an alkyl group having 1 to 6 carbon atoms) Sulfamoyl group; monoalkylsulfamoyl group (indicating a monoalkylsulfamoyl group in which the alkyl moiety such as a methylsulfamoyl group or an ethylsulfamoyl group is an alkyl group having 1 to 6 carbon atoms) A dialkylsulfamoyl group (dimethylsulfamoyl group, A dialkylsulfamoyl group in which the alkyl part of the alkyl group is an alkyl group having 1 to 6 carbon atoms); a cycloalkyl group (3 to 7 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group) A halogen atom (fluorine, chlorine, bromine, iodine); a carboxyl group; an alkoxycarbonyl group (a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxypropyl group, a butoxycarbonyl group, etc.) An alkoxycarbonyl group which is an alkoxy group having 1 to 6 carbon atoms; and an acyl group (an aliphatic acryl group having 1 to 6 carbon atoms such as a formyl group, an acetyl group, and a pionyl group) and a benzoyl group. Asiloxy group (formyloxy group, acetyloxy group, propionyloxy group, etc.) Preferably represents a hydroxyl group, an amino group, a monoalkylamino group, a dialkylamino group, a nitro group, a lower alkyl group, a lower alkoxy group, a haloalkyl group, or the like. Examples include a halogen atom, an aralkyl group, and an aralkyloxy group.

The substituents on the alkyl portion of the “optionally substituted aralkyl group” may be substituted by 1 to 3 substituents, and the substituents may be the same or different.

The “morpholinoalkyl group” of R ¹ is a morpholino group substituted by an alkyl group having 1 to 6 carbon atoms, and is a morpholinomethyl group, a morpholinoethyl group, It represents a linopropyl group, a morpholinobutyl group and the like.

The cycloalkyl group of the “optionally substituted cycloalkyl group” of R ² and R ⁴ represents a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. .

Further, the substituent of the “optionally substituted cycloalkyl group” has the same meaning as the substituent that can be substituted on the fuunyl ring of the “optionally substituted aralkyl group”.

The cycloalkyl group of the “optionally substituted cycloalkyl group” may be substituted with 1 to 3 substituents, and the substituents may be the same or different.

The heteroaryl group of the "optionally substituted heteroaryl group" for R ³ and R ⁴ includes thiazolyl, thiazolinyl, oxazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzozoxazolyl, and benzozimiyl. Dazolyl, quinolyl, isoquinolyl, etc. Further, the substituent of the “optionally substituted heteroaryl group” has the same meaning as the substituent that can be substituted on the fuunyl ring of the “optionally substituted aralkyl group”.

The heteroaryl group in the “optionally substituted heteroaryl group” may be substituted with one to three substituents, and the substituents may be the same or different.

R ² , R ⁴ "optionally substituted phenyl group", "optionally substituted naphthyl group", R ² "optionally substituted quinolyl group", "optionally substituted isoquinolyl" The substituents of the “group” and the “optionally substituted pyridyl group” are the same as the substituents that can be substituted on the phenyl ring of the “optionally substituted aralkyl group”.

"Optionally substituted phenyl group", "optionally substituted naphthyl group", "optionally substituted quinolyl group", "optionally substituted isoquinolyl group" and "optionally substituted The phenyl group or each hetero ring of the "good pyridyl group" may be substituted by 1 to 3 substituents, and the substituents may be the same or the same. It may be different.

In the proviso, “halogen atom”, “lower alkyl group” and “lower alkoxy group” of R ² and R ⁴ are the “halogen atom which can be substituted on the phenyl ring of the“ optionally substituted aralkyl group ”. "," Lower alkyl group "and" lower alkoxy group ".

Preferred examples of the "optionally substituted heteroaryl group" for R ³ include thiazolyl, thiazolinyl, thiadiazolyl, benzothiazolyl, pyrimidinyl, and imidazolyl. Preferred examples of the substituent that can be substituted on the heteroaryl group include: Examples include lower alkyl groups, alkoxycarbonylalkyl groups, and phenyl groups.

Preferred examples of the "optionally substituted heteroaryl group" for R ⁴ include pyridyl and pyrimidinyl. Preferred examples of the substituent that can be substituted on the heteroaryl group include a lower alkyl group and a lower alkoxyl group Is mentioned.

Preferred examples of the substituent of the “optionally substituted phenyl group” for R ² include a lower alkyl group, an aralkyloxy group optionally substituted with halogen, a hydroxyl group, a lower alkoxy group, an amino group, and a mono group. Contains an alkylamino group, a dialkylamino group, an acylamino group, a nitro group, a halogen atom, an acyloxyalkylcarbonylamino group, a dialkylaminoalkoxy group, an acyloxyalkoxy group, a hydroxyalkoxy group, and an oxygen atom And a saturated 5- or 6-membered heterocyclic monocyclic group containing 1 or 2 nitrogen atoms.

Preferable examples of the substituent of the “naphthyl group which may be substituted” in R ² include a monoalkylamino group, a dialkylamino group, a nitro group, a lower alkyl group and a lower alkoxy group.

Preferred examples of the substituent of the “optionally substituted phenyl group” for R ⁴ include a lower alkyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, an acyloxyalkyl group, a haloalkyl group, a hydroxyl group and a lower alkoxy group. Group, amino group, monoalkylamino group, dialkylamino group, nitro group, halogen atom, al Kylsulfinyloxyalkyl group, a saturated 5- or 6-membered heterocyclic monocyclic group containing 1-2 nitrogen atoms which may contain an oxygen atom, substituted with a lower alkyl group having 1-6 carbon atoms And a nitrogen-containing heteromonocyclic alkyl group which may be substituted.

Pharmaceutically acceptable salts of the compound of the general formula (I) of the present invention include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and acetic acid. Salts with organic acids such as pionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Is mentioned. In addition, salts with metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide, and salts with organic bases such as triethylamine and pyridine can be given. Since the compound of the general formula (I) and the pharmaceutically acceptable salt thereof of the present invention may exist in the form of a hydrate or a solvate, these hydrates or solvates are also included in the present invention. Is included.

Further, when the present compound contains an asymmetric carbon, it can be obtained in the form of a racemic mixture or an optically active substance. When the compound further has at least two asymmetric carbons, it can be obtained as an individual diastereomer or a mixture thereof. can get. The present invention includes these mixtures and individual isomers as well as stereoisomers.

The novel imidazole compound represented by the general formula (I) of the present invention can be produced, for example, by the following method. However, the method for producing the compound of the present invention is not limited to these.

Manufacturing method 1

Ol)

(I)

(Wherein R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described above, Z is a halogen atom such as chlorine or bromine; an azide group; an N-hydroxybenzotriazolyl group; (Ii) trophenyloxy group; p-chlorophenyloxy group; alkoxy group such as methoxy group and ethoxy group; and acyloxy group such as acetyloxy group and bivaloyloxy group.

An isobutyloxycarbonyloxy group; a methoxycarbonyloxy group; an ethoxycarbonyloxy group and the like. )

The compound represented by the general formula (II) is reacted with thionyl chloride, isobutyl carbonate, methyl carbonate, ethyl carbonate, or the like in an inert solvent according to a conventional method to form a reactive intermediate. (III) and then reacting with a compound represented by the general formula (IV) in an inert organic solvent in the presence or absence of a base, preferably in the presence of a base. Can be made (process

1 and 2).

In addition, the compound represented by the general formula (II) may be converted to a compound represented by the general formula (IV) in the presence of a base or by using a suitable condensing agent without converting the compound represented by the general formula (II) into a reactive derivative. Reaction in an inert organic solvent in the absence, preferably in the presence of a base It can also be manufactured by performing the process (Step 3).

The base used in the method of the present invention includes pyridine, picoline, lutidin, collidine, N-methylbiperidine, N-methylpyrrolidine, N-methylmorpholine, N, N-dimethylaminopyridine, triethylamine, diisopropyl Examples include ethylamine, potassium carbonate, sodium carbonate and the like, with preference given to pyridin, N, N-dimethylaminopyridine, triethylamine, diisopropylethylamine and potassium carbonate. The inert organic solvent used in the method of the present invention may be any solvent as long as it does not inhibit the reaction, and is preferably ether, benzene, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform, Examples thereof include methylene chloride, dimethyl sulfoxide, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, pyridine and the like. Particularly preferred are toluene, tetrahydrofuran, dioxane, chloroform, methylene chloride, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, pyridine and the like. The reaction is carried out at a temperature equivalent to the reflux temperature of the solvent used from _30 ° C, preferably from room temperature to a temperature equivalent to the reflux temperature of the solvent used, particularly preferably at a temperature equivalent to the reflux temperature of the solvent used. It is advantageous to carry out. Examples of the condensing agent include N, N'-dicyclohexylcarbodiimide, 1,1-carbonyldimidazole, 1-hydroxybenzotriazol, and 1-hydroxy-17-azabe Benzotriazole, 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4,4,1-dichloro It is preferable to use α-methylbenzhydrol or the like.

Manufacturing method 2

In the general formula (I), the compound having a lower alkoxy group or an aralkyloxy group as a substituent is a compound in which the corresponding substituent of the general formula (I) is a hydroxy group and a corresponding lower alkyl alcohol or phenyl lower group. Reaction of alkyl alcohol in the presence of triphenylphosphine and acetyldicarboxylate Therefore, it can be manufactured.

Manufacturing method 3

In the general formula (I), a compound having a hydroxyl group, a hydroxyalkyl group, an amino group or an aminoalkyl group as a substituent is a compound in which the corresponding substituent of the general formula (I) is an acyloxy group, an acyloxyalkyl group, A compound having an acylamino group or an acylaminoalkyl group can be produced by performing a hydrolysis reaction under basic or acidic conditions.

In the general formula (I), a compound having a hydroxyl group, a hydroxyalkyl group, an amino group, or an aminoalkyl group as a substituent is a compound in which the corresponding substituent of the general formula (I) is a benzyloxy group, a benzyloxyalkyl group, Hydrogenation of a compound that is a benzylamino group or a benzylaminoalkyl group in the presence of a catalyst such as palladium, or reaction with hydrobromic acid in a solvent such as acetic acid, or treatment in thioanisole or trifluoroacetic acid Can also be manufactured.

Manufacturing method 4

In the general formula (I), a compound having an amino group or an aminoalkyl group as a substituent is a compound in which the corresponding substituent in the general formula (I) is a nitro group or a nitroalkyl group, and iron powder. Reduction with an acid such as hydrochloric acid, acetic acid or sulfuric acid, hydrogenation in the presence of a catalyst such as palladium, or heating to reflux in a 6 molar hydrochloric acid solution of tin chloride (II) hexahydrate Can be manufactured.

Manufacturing method 5

In the general formula (I), the compound having a dialkylamino group or a monoalkylamino group as a substituent can be obtained by alkylating a compound of the general formula (I) in which the corresponding substituent is an amino group. Can be obtained. Alkylation methods include alkylation using alkyl halide, alkyl paratoluenesulfonate and the like and, if necessary, bases such as triethylamine, pyridine, carbonated sodium carbonate, sodium carbonate and sodium hydrogencarbonate. Or, formalin, alkyl aldehyde, etc., sodium borohydride, sodium borohydride So-called reductive alkylation by reacting with a metal-hydrogen complex compound such as lime, or catalytic reduction.

The compound of the general formula (II) used as a starting material in the present invention is obtained, for example, by hydrolyzing a compound of the general formula (VII and XI) obtained by the following methods 1 to 4 under alkaline or acidic conditions. It can be manufactured by decomposing. Method 1

R ⁴ — CO

(V)

(VII)

(In the formula of the above step, R ² and R ⁴ have the same meanings as described above, and R ⁵ represents a lower alkyl group.)

—The compound represented by the general formula (VII) can be produced by reacting the compound represented by the general formula (V) with the compound represented by the general formula (VI) (Step 4). As the reaction solvent, for example, toluene, benzene, xylene, pyridine, picolin, dioxane, hexane, petroleum ether, acetonitrile, acetic acid, tetrahydrofuran and the like can be used.

The reaction is carried out at a temperature equivalent to the reflux temperature of the solvent to be used, preferably from room temperature to a temperature equivalent to the reflux temperature of the solvent used, particularly preferably at a temperature equivalent to the reflux temperature of the solvent used. It is.

Method 2

It is represented by the general formula (VIII) reported by Harry H. Wasserman, Tetrahedron Letter, Vol. 33, No. 40, pp. 6003-6006, 1992, etc. The compound represented by the general formula (IX) is added to a compound represented by the general formula (IX) in the presence of an ammonium salt of a lower alkane carboxylate such as ammonium acetate or ammonium formate or an ammonium salt of an inorganic acid such as ammonium carbonate. By reacting in an acidic solution of a lower alkanecarboxylic acid such as propionic acid, the compound represented by the general formula (VII) can be produced (Step 5).

As the reaction solvent, for example, toluene, benzene, xylene, pyridine, picolin, dioxane, hexane, petroleum ether, acetic acid and the like can be used. In addition, the reaction may be performed without a solvent.

The reaction is advantageously carried out from 0 ° C. under the reflux temperature of the solvent used. ⁴ — CO

(V) (Vtf)

-The compound represented by the general formula (V) is represented by the general formula (IX) in the presence of an ammonium salt of a lower alkanecarboxylic acid ammonium salt such as ammonium acetate or ammonium formate, or an inorganic acid ammonium salt such as ammonium carbonate. The compound represented by the general formula (VII) can be produced by reacting with the compound (Step 6) o

As the reaction solvent, for example, acetic acid, toluene, pyridine, ethyl acetate and the like can be used.

The reaction is preferably carried out at a temperature equivalent to the reflux of the solvent used from 0, but it is particularly preferred to carry out the reaction at a temperature equivalent to the reflux of the solvent used.

Method 4

The compound of the general formula (II) in which R ¹ is other than hydrogen can be synthesized by the following O step.

(vn)

(XI) (In the formula of the above step, R ¹ , R ² , and R ⁴ have the same meanings as described above, R ⁵ represents a lower alkyl group, and X represents a halogen atom.)

The compound represented by the general formula (XI) can be obtained by converting the compound represented by the general formula (VII) in the presence or absence of a base such as sodium hydroxide, potassium hydroxide, sodium hydride, and the like. Can be produced by reacting the compound represented by the formula with an inert organic solvent (step 7).

Examples of the inert organic solvent include toluene, tetrahydrofuran, dioxane, chloroform, methylene chloride, N, N-dimethylformamide and the like. The reaction is carried out at a temperature ranging from 130 ° C. to a temperature equivalent to the reflux of the solvent used, preferably from room temperature to a temperature equivalent to the reflux of the solvent used, particularly preferably at a temperature equivalent to the reflux of the solvent used. It is advantageous.

The pharmaceutically acceptable salts of the compounds of the general formula (I) of the present invention include inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (acetic acid, Treated with pionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and conventional methods By doing so, the above-mentioned acid addition salt can be obtained. Oxalate can also be used for the purpose of crystallization of the compound. The corresponding metal salt can be obtained by treating with lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, etc., and the salt with an organic base by treating with triethylamine, pyridine, etc. You can do it. When the obtained crystals of the compound of the present invention are anhydrous, the compound of the present invention can be converted into a hydrate or a solvate by treating the compound with water, an aqueous solvent or another solvent.

The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method or a column chromatography method. When the resulting product is racemic, for example, by fractional recrystallization of a salt with an optically active acid, or By passing through a column filled with a suitable carrier, the desired optically active substance can be separated. Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds and the like. Stereoisomers can be isolated by recrystallization, column chromatography, or the like.

When the novel imidazole derivative of the present invention and a pharmaceutically acceptable salt thereof are used as a medicament, the compound of the present invention is pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, odorant). Pharmaceutical compositions or preparations (tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions) obtained by mixing with pharmaceuticals, emulsifiers, diluents, solubilizers, etc. , Solutions, injections, drops, ointments, pastes, liniments, lotions, blasters, cataplasms, eye drops, eye ointments, suppositories, compresses, inhalants, sprays, aerosols , A liniment, a nasal drop, a cream, a tape, a patch, etc.) can be administered orally or parenterally. The pharmaceutical compositions can be formulated according to the usual methods. For example, excipients (lactose, D-mannitol, starch, crystalline cellulose, etc.), binders (hydroxypropylcellulose, hydroxylpropylmethylcellulose, polyvinylpyrrolidone, etc.), disintegrants (carboxymethylcellulose, carboxymethylcellulose potassium) Etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxylpropyl methylcellulose, sucrose, etc.), base materials (polyethylene glycol, hard fat, etc.) Solubilizers or solubilizers that can constitute aqueous or time-adjustable injections

(Distilled water for injection, physiological saline, propylene glycol, etc.), PH regulators (inorganic acids, organic acids or inorganic bases), and stabilizers are used.

The compound of general formula (I) of the present invention and a pharmaceutically acceptable salt thereof inhibit the production of IL-4 and IL-5 produced from Th2 cells, It is effective as a preventive and therapeutic agent for allergic diseases such as asthma and allergic rhinitis. The dosage of this drug to treated patients can vary depending on the type and extent of the disease, the compound administered, the route of administration, the age, sex, and weight of the patient, but in general, for adults, the daily dose is oral. About 1.0 to 100 Omg for parenteral administration, and about 1.0 to 500 Omg for parenteral administration.

Example

Hereinafter, the present invention will be specifically described with reference to raw material synthesis examples, examples, and experimental examples, but the present invention is not limited to these raw material synthesis examples, examples, and experimental examples.

Raw material synthesis example 1

2-Hydroxyimino 3- (4-methylphenyl) -13-oxopropionic acid ethyl ester 13.7 g 1-Naphthalene nutylamine 11.0 g is dissolved in xylene 133 ml, and The mixture was heated under reflux for 9 hours while draining water using a drainage device. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. Isopropyl alcohol was added to the residue obtained by concentrating the solvent under reduced pressure, and the residue was crystallized and filtered to give 5- (4-methylphenyl) -12- (1-naphthyl) imidazole-4 2.5 g of oxyethyl ester was obtained. Melting point 190-192V

Raw material synthesis example 2

5— (4-Methylphenyl) — 2- (1-Naphthyl) imidazo-l-41-Carboxylic acid ethyl ester 4.5 g was dissolved in 90 ml of ethyl alcohol, and 38 ml of 1 molar sodium hydroxide solution was added. added. The reaction solution was heated under reflux for 12 hours and then concentrated under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the mixture was separated. The aqueous layer was filtered, aqueous citric acid was added to the filtrate, and the precipitated crystals were collected by filtration.

4-Methylphenyl) 2- (1-naphthyl) imidazo-1-yl 4-carboxylic acid

3.3 g were obtained. Melting point 1 65 (decomposition)

Raw material synthesis example 3

To a suspension of 10.0 g of ammonium nitrate and 10 ml of fouling acid, 2.0 g of 3- (4-methylphenyl) -1,2,3-dioxopropionic acid methyl ester was added at room temperature and mixed. After the solution was stirred for 10 minutes, cyclohexanecarbaldehyde 1.6 was added, and the mixture was heated on a water bath at 40 to 50 and stirred for 2 hours. Water was added to the reaction solution, and the solvent was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography, and 2-cyclohexyl-5- (4-methylphenyl) imidazole-4-carboxylic acid methyl ester was obtained. 92 Omg was obtained. Mp 2 1 0-2 1 3 In one NMR 4 0 0 MH z (CDC 1 3, p pm) δ: 1. 2 6 - 2.12 (1H, m), 2.81 (10H, m), 2.38 (3H, s), 383 (3H, s), 7.21 (2H, d), 7 . 79 (2 H, d)

Raw material synthesis example 4

90 Omg of 2-cyclohexyl-5- (4-methylphenyl) imidazole-4-carbonic acid methyl ester is dissolved in 2 Om1 of ethyl alcohol, and 1.1 g of lithium hydroxide hydrate and 1 Om1 of water are added. After heating under reflux for 2.5 hours, the mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the mixture was separated. The aqueous layer was filtered, aqueous citric acid was added to the filtrate, and the precipitated crystals were collected by filtration to obtain 39 Omg of 2-cyclohexyl-5- (4-methylphenyl) imidazo-l-u-l-carboxylic acid. . Melting point 205-206 ¾, ¹ H-NMR 400 MHz (CDC 13, DMSO-D ₆ , p pm) δ: 1.25-2.05 (10 H, m) 2.36 (3H, s), 2 78 (1H, m), 7.20 (2H, d), 7.84 (2H, m)

Raw material synthesis example 5

2.6 g of tert-butyl 3-cyclohexyl-1-hydroxyimino-3-oxopropionate, 2.lg of benzylamine in 50 ml of benzene Dissolve and heat to reflux for 16 hours. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform-ethyl acetate 8: 1) to give 5-cyclohexyl-2-phenylimidazole-1-4 rubonic acid 0.90 g of tert-butyl ester was obtained. Melting point 2 2 2 to 22 3 ° C

Raw material synthesis example 6

2.8 g of tert-butyl 2-hydroxyimino 3- (4-pyridyl) propionic acid and 2.4 g of benzylamine were dissolved in 80 ml of acetonitrile, and reacted in the same manner as in Synthesis Example 5 for starting materials. By the treatment, 1.4 g of tert-butyl ester of 2-phenyl-5- (4-pyridyl) imidazo-1-yl 4-carboxylate was obtained. With a melting point of 205-206

Raw material synthesis example 7

2-Hydroxyimino-3-oxo-3- (3-pyridyl) propionic acid tert-butyl ester 4. Using lg, benzylamine 3.5 g, and acetonitrile 80 ml, react in the same manner as in Raw Material Synthesis Example 5. As a result, 2.2 g of 2-tert-butyl-5- (3-pyridyl) imidazo-l-carboxylic acid tert-butyl ester was obtained. Melting point 196-16-197

Raw material synthesis example 8

2-Hydroxyimino 3-oxo-1- (2-pyridyl) propionic acid tert-butyl ester 6.O g and benzylamine 5.7 g were dissolved in acetonitrile 100 ml and reacted in the same manner as in Raw Material Synthesis Example 5. By the treatment, 1.8 g of 2-tert-butyl-5- (2-pi ') zyl) imidazo-l-ru-butyric acid tert-butyl ester was obtained. Melting point 2 1 1 to 2 1 3

Raw material synthesis example 9

2-Hydroxyimino-3-oxo-3- (2-pyrazinyl) propionic acid tert-butyl ester 4. lg, benzylamine 4. Og was dissolved in 100 ml of acetonitrile and reacted in the same manner as in Synthesis Example 5 By the treatment, 1.0 g of 2-phenyl 5- (2-pyrazinyl) imidazole-4 tert-butyl ribonate was obtained. With melting point 196-16-197

Raw material synthesis example 10

t-BuOOC Dissolve 5.0 g of tert-butyl 2-hydroxyimino-3-oxo-4- (4-pyridyl) propionate and 3.5 g of naphthylmethylamine in 6 ml of toluene, and dissolve The mixture was heated to reflux for 3 hours while draining water using a Stark drainage device. After cooling, the precipitated crystals were collected by filtration and dried to obtain 1.3 g of 2- (1-naphthyl) -5- (4-pyridyl) imidazole-4-4 tert-butyl ribonate. Was. With melting point 18 4 ~ 19 0

Raw material synthesis example 1

Dissolve 3.0 g of tert-butyl 2-hydroxyimino-1,3-oxo-3- (4-pyridyl) propionate and 1.7 g of 4-methoxybenzylamine in 80 ml of toluene, By reacting in the same manner as in Raw Material Synthesis Example 10, 1.4 g of 2- (4-methoxyphenyl) -5- (4-pyridyl) imidazole-4-carboxylic acid tert-butyl ester was obtained. Melting point 2 1 1 ~ 2 1 2¾

Raw material synthesis example 1 2

Dissolve 3.9 g of tert-butyl ester of 2-hydroxy-1-amino-3- 3- (4-pyridyl) propionic acid and 3.0 g of 4-benzyl benzylamine in 80 ml of toluene, and prepare 10 By the same reaction treatment, 1.9 g of 2- (4-chlorophenyl) -5- (4-pyridyl) imidazole-4-carboxylic acid tert-butyl ester was obtained. Melting point 206-207 ° C

Raw material synthesis example 1 3

2-Hydroxyminnow 3-oxo-1- 3- (4-pyridyl) propionic acid tert-butyl ester 3.2 g, 3-methoxybenzylamine 2. lg dissolved in toluene 12 Oml to synthesize raw material The reaction was conducted in the same manner as in Example 10 to obtain 1.4 g of tert-butyl 2- (3-methoxyphenyl) -15- (4-pyridyl) imidazo-l--4-carboxylate. (Melting point 197-199 T)

Raw material synthesis example 1 4

2-Hydroxyimino-3-oxo-3- (4-pyridyl) propionic acid tert-butyl ester 3.0 g, 412-trobenzylamine 2.2 g dissolved in toluene 4 Om 1 The reaction was carried out in the same manner as in Synthesis Example 10 to obtain 0.7 g of tert-butyl 2- (4-nitrophenyl) -5- (4-pyridyl) imidazole-4 ribonate. Mp 2 8 0 or ^{more, I H- NMR 4 0 OMH z} (CDC 13, p pm) δ: 1. 5 8 (9H, s), 7. 9 2 (2 H, d), 8. 1 5 (2 H, d), 8.36 (2 H, d), 8.70 (2 H, d)

Dissolve 3.0 g of tert-butyl 2-hydroxyimino-3-oxo-4- (4-pyridyl) propionate and 2.9 g of 2-chlorophenylpenyldiamine in toluene 8 Om 1 The reaction was carried out in the same manner as in Synthesis Example 10 to obtain 1.3 g of tert-butyl 2- (2-chlorophenyl) -15- (4-pyridyl) imidazolyl-4 monopropanoate. Melting point 2 2 3 to 2 2 4 (decomposition)

Raw material synthesis example 1 6

Dissolve 6.0 g of tert-butyl 2-hydroxyimino 3-oxo-4- (4-pyridyl) propionate and 4.O g of 4-tert-butylphenylbenzylamine in 60 ml of toluene. The mixture was heated under reflux for 3 hours while draining water using a Dinsterk drainage device. After cooling, the precipitated crystals were collected by filtration and dissolved in ethyl acetate. To this was added 3 ml of a 1 molar hydrochloric acid-ether solution, and the precipitated crystals were collected by filtration to give 2- (4-tert-butylphenyl) -15- (4-pyridyl :) imidazo-l-ru-tert-butyl 4-carboxylate. 3.2 g of the hydrochloride of the ester were obtained. ¹ H_NMR 40 OMH z (CD ₃ OD, ppm) δ: 1.37 (9 H, s), 1.63 (9 H, s), 7.58 (2 H, d), 8.02 (2 H, d), 8.76 (2 H, d), 8.85 (2 H, d)

Raw material synthesis example 1 7

2-hydroxyimino 3- (4-methylphenyl) -13-oxopropionic acid ethyl ester 12.8 g and 2-aminomethylnaphthalene 10.3 g should be treated in the same manner as in Raw Material Synthesis Example 1. 5- (4-methylphenyl) -2- (2-naphthyl) imidazo-l- 4-carboxylic acid ethyl ester obtained by the above was dissolved in 0.5 ml of 4.8 g of ethyl alcohol in 10 ml of ethyl alcohol. The reaction was carried out in the same manner as described above to obtain 0.26 g of 5- (4-methylphenyl) 1-2- (2-naphthyl) imidazole-4-carboxylic acid. Melting point 2 27 ° C (decomposition) Raw material synthesis example 18

2-hydroxyimino 3- (4-methylphenyl) -13-oxopropionic acid ethyl ester 16.0 g, 1- (aminomethyl) -14-methoxynaphthalene 15.3 g were the same as in Raw Material Synthesis Example 1. 2- (4-Methoxy-11-naphthyl) -15- (4-methylphenyl) imidazo-ru-41-Carboxylic acid ethyl ester 22.2 g obtained in the reaction By dissolving and reacting in the same manner as in Raw Material Synthesis Example 2, 12.1 g of 2- (4-methoxy-11-naphthyl) -5- (4-methylphenyl) imidazo-l--4-carboxylic acid was obtained. Obtained. Melting point 2 2 6 (decomposition)

Raw material synthesis example 1 9

2-Hydroxyimino-3- (4-methylphenyl) -3-oxopropion 10.5 g of oxyethyl ester and 5.8 g of 4-aminomethyl pyridine were dissolved in 100 ml of xylene, and the reaction was carried out in the same manner as in Raw Material Synthesis Example 1 to give 5- (4-methylphenyl) -12- ( 4-Pyridyl) imidazo-1-yl 4-carboxylic acid ethyl ester 54.2 g was obtained. With a melting point of 18 2 to 18 5

Raw material synthesis example 20

2-Hydroxyimino 3- (4-methylphenyl) -13-oxopropionic acid ethyl ester 10.0 g, 3-aminomethylviridine 5.3 ml were obtained by carrying out a reaction treatment in the same manner as in Synthesis Example 1 of the raw material. 5- (4-Methylphenyl) -2- (3-pyridyl) imidazole-4 monoethyl ester of ribonucleic acid (4.0 g) was dissolved in 10 ml of ethyl alcohol. The reaction was carried out in the same manner as in 2, to obtain 0.39 g of 5- (4-methylphenyl) -2- (3-pyridyl) imidazo-l--4-carboxylic acid. Melting point 140-: I42

Raw material synthesis example 2 1

2-Hydroxyimino-1- (4-methylphenyl) -13-oxopropionic acid ethyl ester 10.6 g and 3-aminomethylquinoline 8.5 g were obtained by the same reaction treatment as in Example 1 of the starting material. 6.7 g of 7.0 g of 5- (4-methylphenyl) -1- (3-quinolyl) imidazo 4-ethyl ribonate was dissolved in 135 ml of ethyl alcohol. Same as 2 After the reaction, 2.5 g of 5- (4-methylphenyl) 1-2- (3-quinolyl) imidazole-4 monocarboxylic acid was obtained. Melting point 2 2 4 (decomposition)

Raw material synthesis example 2 2

Example of raw material synthesis using ammonium acetate 15. Og, acetate 20 ml, 3- (4-methylphenyl) -1,2,3-dioxopropionic acid methyl ester 3. Og, and acetoaldehyde 1.1 g By the same reaction treatment as in 3, 1.6 g of 2-methyl-5- (4-methylphenyl) imidazo-l- 4-carboxylic acid methyl ester was obtained. ^{1 H- NMR 4 0 0 MH z} (CDC 1 3, p pm) δ: 2. 3 6 (3 Η, s), 2. 4 5 (3 H, s), 3. 3 8 (3 H, s ), 7.2 1 (2 H, d), 7.67 (2 H, d)

Raw material synthesis example 2 3

Example of raw material synthesis using ammonium acetate 10.0 g, acetate 10 m1, 3- (4-methylphenyl) -1,2,3-dioxopropionic acid methyl ester 2.O g and heptyl aldehyde 1.7 g 2-Hexyl-5- (4-methylphenyl) imidazoyl-4 obtained by the same reaction treatment as in 3-4.Methylester monoester ruborate 1.2 g was dissolved in ethyl alcohol 20 ml and lithium was dissolved. Hydroxide hydrate (420 mg) and water (10 ml) were added, and the reaction was carried out in the same manner as in Raw Material Synthesis Example 4 to give 2-hexyl-5- (4-methylphenyl) imidazo-l-ru 4 70 Omg of the acid was obtained. Melting point 2 15-2 18 ° C Raw material synthesis example 2 4

Example of raw material synthesis using ammonium acetate 10.0 £, acetic acid 101111, 3- (4-methylphenyl) -methyl 2,2,3-dioxopropionate 2.0 g and decylaldehyde 2.3 g By the same reaction treatment as in 3, 5- (4-methylphenyl) -12-nonylimidazo-l-4u-Rubonic acid methyl ester 80 Omg was obtained. - NMR 40 0 MHz (CDC 1 3, p pm) 5: 0. 8 8 (3 H, s), 1. 2 6 (1 2 H, m), 1. 7 5 (2 H, m), 2 .38 (3H, s), 2.76 (2H, t), 3.84 (3H, s), 7.22 (2H, d), 7.71 (2H, d) )

Raw material synthesis example 25

Starting material synthesis example 3 using ammonium acetate 10.0 g, acetate 15 ml 1, methyl 3- (4-methylphenyl) -1,2,3-dioxopropionate 2.0 g and pivalaldehyde 1.3 g The reaction was carried out in the same manner as in the above to give 2-tert-butyl-5- (4-methylphenyl) imidazo-l-41-methyl ribonate methylester 63 Omg. - NMR 4 0 OMH z (CDC 1 3, p pm) δ: 1. 44 (9 H, s), 2. 40 (3 H, s), 3. 8 3 (3 H, s), 7. 2 1 (2H, d), 7.8 1 (2H, d)

Raw material synthesis example 2 6

Aluminum acetate 1.5 Og, 30 ml of acetic acid, 3- (4-methylphenyl) -methyl 2,3-dioxopropionate 3.Og, 2.9 ml of hydrocinnamaldehyde By reacting in the same manner as in Synthesis Example 3 for starting materials,

1.6 g of (4-methylphenyl) -2- (2-phenylethyl) imidazo-l- 4-carboxylic acid methyl ester was obtained. — NMR 400 MHz (CD C 13, ρ pm) δ: 2.38 (3 Η, s), 3.09 (4 Η, m), 3.81

(3 Η, s), 7.19-7.32 (1 O H, m)

Raw material synthesis example 2 7

2-Hydroxyimino-3- (4-chlorophenyl) -13-oxopropionic acid ethyl ester 10.0 g, 1-aminomethylnaphthalene 7.O g are treated in the same manner as in Synthesis Example 1 of the starting material. 5- (4-chlorophenyl) -1-2- (1-naphthyl) imidazole-4 obtained by dissolving 6.0 g of ethyl ester of ribonucleic acid in 6.0 g of ethyl alcohol dissolved in 120 ml of ethyl alcohol 1 mol sodium hydroxide solution 45 ml

Was. The reaction solution was subjected to a reaction treatment in the same manner as in Raw Material Synthesis Example 2, to obtain 4.1 g of 5- (4-chlorophenyl) -2- (1-naphthyl) imidazo-1-lu-4-carboxylic acid. Melting point 210 ° C (decomposition)

Raw material synthesis example 2 8

2-Hydroxyimino-3- (4-methoxyphenyl) -13-oxopropionic acid ethyl ester 10.0 g, 1-aminomethylnaphthalene 7.5 and 5 g are reacted in the same manner as in Synthesis Example 1. 5- (4-Methoxyphenyl) -2- (1-naphthyl) imidazo-1-yl 4-carboxylate obtained from the above was dissolved 5.0 g of 5.2 g of ethyl ester in 300 ml of ethyl alcohol, 50 ml of a 1 molar sodium hydroxide solution was added, and the reaction was carried out in the same manner as in Raw Material Synthesis Example 2 to obtain 5- (4-methoxyphenyl) —2- (1-naphthyl) imidazole—41 3.9 g of carboxylic acid were obtained. Melting point 1 7 8V (decomposition)

Raw material synthesis example 2 9

10.0 g of ethyl 2-hydroxyimino-3-phenyl-1-oxopropionate and 7.8 g of 1-aminomethylnaphthalene were subjected to a reaction treatment in the same manner as in Raw Material Synthesis Example 1 to obtain "". Of the 6.4 g of 2- (1-naphthyl) -1-5-phenylimidazo-ru-4-carboxylic acid ester obtained, 6.0 g was dissolved in 120 ml of ethyl alcohol, and a 1 molar sodium hydroxide solution 4 5 ml was added thereto, and the reaction was carried out in the same manner as in the synthesis of the original ^ I-synthesis example 2 to obtain 4.1 g of 2- (1-naphthyl) -15-phenylimidazole-4-4 rubonic acid. Melting point 17 2 ° C (decomposition) Raw material synthesis example 30

2-Hydroxyimino 3- (4-trifluoromethylphenyl) 1-3-oxopropionic acid ethyl ester 15.0 g and 1-aminomethylnaphthalene 9.6 g were reacted in the same manner as in Raw Material Synthesis Example 1. Of the 6.4 g of 2-((1-naphthyl) -15- (4-trifluoromethylphenyl) imidazole-4 immobilized ethyl ribonate obtained by the treatment, It was dissolved in 100 ml of ethyl alcohol, and 30 ml of a 1 molar sodium hydroxide solution was added. The reaction was carried out in the same manner as in Synthesis Example 2 of the starting material, whereby 2- (1-naphthyl) -15- (4- (Trifluoromethylphenyl) imidazo-l--4-carboxylic acid (3.4 g) was obtained. Melting point 1 6 6Ϊ (decomposition) Raw material synthesis example 3 1

2-Hydroxyimino 3- (4-fluorophenyl) -13-oxopropionic acid ethyl ester 10.0 g, obtained by reacting 8.3 g of 1-aminomethylnaphthalene in the same manner as in Raw Material Synthesis Example 1. 5— (4-Fluorophenyl) —2— (1-Naphthyl) imidazole—4Ethyl rubrate 3.0 g of 3.3 g was dissolved in 100 ml of ethyl alcohol, and Molar hydroxide 2 Oml of thorium solution was added, and the reaction was carried out in the same manner as in Synthesis Example 2 of raw material to give 2.4 g of 5- (4-fluorophenyl) 1-2- (1-naphthyl) imidazole-41-carboxylic acid I got Melting point 1 7 5 (decomposition)

Raw material synthesis example 3 2

2-Hydroxyiminow 3- (4-nitrophenyl) -13-oxopropionic acid ethyl ester 10.0 g and 1-aminomethylnaphthalene 6.4 g were obtained by carrying out the reaction treatment in the same manner as in Synthesis Example 1. 2 -— (1-naphthyl) —5 -— (412-trophenyl) imidazo-l-u- 4-carboxylate ester 3.0 g of 3.6 g was dissolved in 100 ml of ethyl alcohol, and 1 molar water was added. 20 ml of sodium oxide solution was added, and the reaction was carried out in the same manner as in Raw Material Synthesis Example 2 to give 2- (1-1-naphthyl) -5- (4-nitrophenyl) imidazo-l-ru 4-4 rubonic acid 3.4 g I got Melting point 1 6 1 ^ (decomposition)

Raw material synthesis example 3 3

Reaction reaction of 2-hydroxyimino-13- (4-methylphenyl) -13-oxopropionic acid ethyl ester 50.0 g and 4,12-trobenzylamine 50.0 g in the same manner as in Synthesis Example 1 of the raw material 5- (4-methylphenyl) -1- 2-(4,12-trophenyl) imidazole-4 Dissolved ethyl ester of rubonic acid 58.Og was dissolved in ethyl alcohol 12Om1 and 1M sodium hydroxide solution 30Om1 was added, and raw material synthesis example 2 37.6 g of 5- (4-methylphenyl) 1-2- (412-trophenyl) imidazole-4-carboxylic acid was obtained by the same reaction as described above. Melting point 2 12 ^ (decomposition)

Raw material synthesis example 3 4

2-Hydroxyimino 3- (4-methylphenyl) -13-oxopropionic acid ethyl ester 12.8 g and 2-nitrobenzylamine 8.6 g were obtained by carrying out a reaction treatment in the same manner as in Example 1 of the starting material. 5- (4-Methylphenyl) -1-1 (2-nitrophenyl) imidazo-l-u- 4-carboxylate Ethyl ester 3.0 g of 3.5 g was dissolved in 100 ml of ethyl alcohol, and 1 molar water was added. Sodium oxide solution 2 Om 1 was added, and the reaction was carried out in the same manner as in Raw Material Synthesis Example 2 to give 5- (4-methylphenyl)-2- (2-nitrophenyl) imidazo-l-ru 4-4 rubonic acid 2.4 g I got Melting point 1 4 4 (decomposition)

Raw material synthesis example 3 5

2-Hydroxyimino-3-oxo-1- 3- (4-pyridyl) propionic acid tert-butyl ester and 4-fluorobenzylamine were dissolved in 80 ml of acetonitrile and reacted in the same manner as in Raw Material Synthesis Example 5. By processing, 2— (4 one full (Orphanilyl) — 5-— (4-pyridyl) imidazoyl 4-butyric acid rubonic acid et-butyl ester was obtained.

Raw material synthesis example 3 6

2-Hydroxyimino-3-oxo-1-3- (4-pyridyl) propionic acid tert-butyl ester, 4-methylbenzylamine dissolved in 8 Oml of acetonitrile and treated in the same manner as in Synthesis Example 5 Yields 2- (4-methylphenyl) -5- (4-pyridyl) imidazole-4 tert-butyl ribonate.

Raw material synthesis example 3 7

2-hydroxyimino 3- (4-methoxyphenyl) -13-oxopropionic acid ethyl ester 105.2 g and 4,12-trobenzylamine 76.4 g were prepared in the same manner as in Raw Material Synthesis Example 1. 5- (4-Methoxyphenyl) 1-2- (412-trophenyl) imidazo-l-ul 4-ethyl ethyl ester 55.1 g obtained by the reaction treatment is dissolved in ethyl alcohol, and By adding a molar sodium hydroxide solution and performing a reaction treatment in the same manner as in Raw Material Synthesis Example 2, 5- (4-methoxyphenyl) -12- (4-ditrophenyl) imidazo-l-ru-4 4-Rubonic acid 40. 3 g were obtained. Melting point 205-208 (decomposition)

Raw material synthesis example 3 8

2-hydroxyimino 3-oxo-1- 3- (4-trifluoromethylphenyl)) propionic acid ethyl ester 24.6 g and 4-nitrobenzylamine 14.0 g were prepared in the same manner as in Synthesis Example 1 of the starting material. 9.0 g of 2- (4-nitrophenyl) -15- (4-trifluoromethylphenyl) imidazo-l-41-carbonic acid ethyl ester obtained by the reaction treatment Then, 1 mol of sodium hydroxide solution was added to the mixture, and the mixture was reacted in the same manner as in Raw Material Synthesis Example 2 to give 2- (4-ditrophenyl) -15- (4-trifluoromethylphenyl). (2) Imidazo-I-ru-ru-ruvonic acid 8.2 g was obtained. Melting point 1 7 2— 1 7 4 ¾

(Disassembly)

Raw material synthesis example 3 9

3-6.1 g of 2-hydroxyimino 3-ethyl 3-oxopropionate and 27.9 g of 4,12-trobenzylamine were obtained by a reaction treatment in the same manner as in Synthesis Example 1 of the starting material. 2- (4-212-nitrophenyl) -1-5-phenylimidazole 4-ethyl ether ester 19.2 g of 18.2 g was dissolved in ethyl alcohol, and 1M sodium hydroxide solution was added. The reaction was carried out in the same manner as in Raw Material Synthesis Example 2 to obtain 1-2.8 g of 2- (4-nitrophenyl) -15-phenylimidazo-l-ru-41-rhubonic acid. With melting point of 175--178 (decomposition) Raw material synthesis example 40

2,5-Hydroxyimino 3- (4-nitrotrophenyl) -13-oxopropionate, 4-nitrobenzylamine, 2,5-bis ( 4,12-Trophenyl) Imidazo-l-uyl 4-carboxylate is dissolved in ethyl alcohol, a 1M sodium hydroxide solution is added, and the reaction is carried out in the same manner as in Raw Material Synthesis Example 2 to give 2,5-bis (4 (12-Trophenyl) Imidazo-l-u 4 Obtained rubonic acid.

Raw material synthesis example 4 1

5- (4-chlorophenyl) 2-hydroxyimino 3-oxopropionic acid ethyl ester, 4- (2-chlorophenyl) 5- (4-chlorophenyl) obtained by reacting benzylamine in the same manner as in Synthesis Example 1 of the starting material 1) 2-(4-12-Trophenyl) imidazo-1-4-ethyl ether ester is dissolved in ethyl alcohol, a 1 molar sodium hydroxide solution is added, and the reaction is carried out in the same manner as in Synthesis Example 2 of raw material. , 5- (4-chlorophenyl) 1-2- (4-nitrophenyl) imidazole-4 rubonic acid is obtained.

Raw material synthesis example 4 2

3-3.5- (4-fluorophenyl) -1-hydroxyimino 3-ethyl oxopropionate ester 33.5 g, 4-12 trobenzylamine 23.7 g as raw material The reaction treatment is performed in the same manner as in Synthesis Example 1. 5- (4-Fluorophenyl) —2- (4-nitrophenyl) imidazo-l-ul-ethyl ester 12.1 g obtained by the above method is dissolved in ethyl alcohol, and a 1 molar sodium hydroxide solution is added. By carrying out the reaction treatment in the same manner as in Raw Material Synthesis Example 2, 10.3 g of 5- (4-fluorophenyl) -2- (4-ditrophenyl) imidazo-l-ru-41-ruvonic acid was obtained. Melting point 1 7 3— 1 7 8 (decomposition)

Raw material synthesis example 4 3

2-Hydroxyimino 3- (3-methoxyphenyl) 1-3-oxopropionic acid ethyl ester 84.5 g and 4-nitrobenzylamine 61.4 g are reacted as in Synthesis Example 1. As a result, 39.0 g of 5- (3-methoxyphenyl) 1-2- (4-nitrophenyl) imidazo-l-4u-Ru-rubonate was obtained. With a melting point of 1 9 4—1 9 6 Raw material synthesis example 4 4

5-5.1- (4-Methoxyphenyl) 1-2- (4-nitrophenyl) imidazo-l- 4-ethyl carboxylate 45.1 g was dissolved in ethanol, and a 1 molar sodium hydroxide solution was added. In the same manner, the reaction was carried out to obtain 52.1- (3-methoxyphenyl) -2- (4-trotropinyl) imidazo-l-ru-ru-rubonic acid 42.1 g. Melting point 1 16—1 18 (decomposition)

Raw material synthesis example 4 5

2-Hydroxyimino 3- (4-ethoxyphenyl) -13-oxopropionic acid ethyl ester 84.5 g, 4-nitrobenzylamine 87.1 g The raw material The reaction treatment was performed in the same manner as in Synthesis Example 1. Is 5— (4-ethoxyphenyl) — 2—

(4-Nitrophenyl) imidazo-l-4-ethyl carboxylate 2 8.

1 g was obtained. With a melting point of 2 1 4—2 1 7 Raw material synthesis example 4 6

5- (4-Ethoxyphenyl) — 2- (412-trophenyl) imidazole-4 monoethyl ribonate 27.6 g was dissolved in ethanol, and a 1 molar sodium hydroxide solution was added. By the same reaction treatment, 30.7 g of 5- (4-ethoxyphenyl) 1-2- (4-nitrophenyl) imidazo-l- 4-carboxylic acid was obtained. With a melting point of 1 4 8—1 5 2

Raw material synthesis example 4 7

2-hydroxyimino 3- (4-methoxyphenyl) -13-oxopropionic acid ethyl ester 121.6 g, 3-methyl-4-nitrobenzylamine 105.4 g were prepared in the same manner as in Synthesis Example 1 of the starting material. After the reaction, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography to give 5- (4-methoxyphenyl) -2- (3-methyl-412-trophenyl) imidazo-1-yl 41.5 g of ethyl ester was obtained. Melting point 1 8 7—1 9 1

Raw material synthesis example 4 8

9-g of 5- (4-methoxyphenyl) -1- (3-methyl-4-nitrophenyl) imidazole-4-carboxylate in ethanol, add 2M sodium hydroxide solution and add 2M sodium hydroxide solution The reaction was carried out in the same manner as in 2, to obtain 20.9 g of 5- (4-methoxyphenyl) 1-2- (3-methyl-14-nitrophenyl) imidazo-l--4-carboxylic acid. Melting point 2 2 9—2 3 0

Raw material synthesis example 4 9

3- (4-Dimethylaminophenyl) 1-2-hydroxyimino-13-year-old oxopropionic acid ester 3.8 g and 412-trobenzylamine 2.8 g in the same manner as in raw material synthesis example 1— The reaction treatment yielded 1.8 g of 5- (4-dimethylaminophenyl) 1-2- (4-nitrophenyl) imidazole-4-ethyl carboxylate. Melting point 2 4 0 to 2 4 2 ¾

Raw material synthesis example 50

2-Hydroxyminol 3- (4-isopropoxyphenyl) 1-3-oxopropionic acid ethyl ester 15.0 g and 4-12-trobenzylamine 11.2 g were reacted in the same manner as in Raw Material Synthesis Example 1. By the treatment, 4.2 g of 5- (4-isopropoxyphenyl) -2- (412-trophenyl) imidazo-l-41-ethyl ribonate was obtained.

Raw material synthesis example 5 1

3-3.9 g of tert-butyl ester of 3- (4-acetoxymethylphenyl) -l-hydroxyimino 3-oxopropionic acid and 19.3 g of 4-nitrobenzylamine were used as starting material synthesis examples 1 and 2. By the same reaction treatment, 7.07 g of 5- (4-acetoxymethylphenyl) -2- (4-nitrophenyl) imidazo-l-41-carboxylic acid tert-butyl ester was obtained. Melting point: 178-180 X; (decomposition)

Raw material synthesis example 52

Using 107.8 g of 2-hydroxyimino-3- (4-nitrophenyl) -13-oxopropionic acid ethyl ester and 35.4 g of 4-tert-butylbenzylamine, the raw material synthesis example 10 was used. By the same reaction and treatment, 22.5 g of 2- (4-tert-butylphenyl) -15- (4-nitrophenyl) imidazole-4-ethyl carboxylate was obtained. Melting point 190-191

Raw material synthesis example 5 3

2- (4-tert-butylphenyl) -1-5- (4-ditrophenyl) imidazole-4 monoethyl ester of rubonate 22.5 g, ethyl alcohol 1.21, 1-molar aqueous solution of sodium hydroxide The reaction was carried out in the same manner as in Raw Material Synthesis Example 2 to give 2- (4-tert-butylphenyl) -15- (4-nitrophenyl) imidazo-l-ru-41-Rubonic acid 18.4 g .

Melting point 2 23 ° C (decomposition)

Raw material synthesis example 5 4

Same as in Raw Material Synthesis Example 10 using 2-0.0 g of 2-hydroxyimino-3- (4-methoxyphenyl) ethyl 3-oxopropiosate and 15.0 g of 3-nitrobenzylamine 5— (4-Methoxy キシ) 13.3 g of 2- (3-nitrophenyl) imidazo-1-imidazo-4-carboxylate was obtained. With melting point 208-210

Raw material synthesis example 5 5

5— (4-Methoxyphenyl) —2- (3-nitrophenyl) imidazole—4 ethyl acetate 13.3 g, ethyl alcohol 26.6 m1, 1 molar sodium hydroxide aqueous solution 127 ml The reaction was carried out in the same manner as in Raw Material Synthesis Example 2 to give 9.5 g of 5- (4-methoxyphenyl) -2- (3-ditrophenyl:) imidazole-4 monorubonic acid. Melting point 2 3 4 to 2 3 5 Raw material synthesis example 5 6

5- (4-ethoxyphenyl) obtained by reacting 2-hydroxyimino-1- (4-ethoxyphenyl) -13-oxopropionic acid ethyl ester and 3-nitrobenzylamine in the same manner as in Raw Material Synthesis Example 1. 1) 2- (3-Nitrophenyl) imidazole-4-carboxylic acid ethyl ester is dissolved in ethyl alcohol, a 1 molar aqueous sodium hydroxide solution is added, and the reaction is carried out in the same manner as in Raw Material Synthesis Example 2. (4-Ethoxyphenyl) — 2- (3-diphenyl) imidazole—4 is obtained. Raw material synthesis example 5 7

2-hydroxyimino-3- (3-methoxyphenyl) -13-oxopropionic acid ethyl ester, 3-nitrobenzylamine obtained by reacting in the same manner as in Synthesis Example 1 of raw material 5— (3— Methoxyphenyl) 1 2 — (3-Nitrophenyl) Imidazoyl 4-ethyl ribonate is dissolved in ethyl alcohol, a 1M aqueous sodium hydroxide solution is added, and the reaction is carried out in the same manner as in Raw Material Synthesis Example 2. This gives 5- (3-methoxyphenyl) -12- (3-nitrophenyl) imidazole-4 monorubonic acid.

Raw material synthesis example 5 8

2-Hydroxyimino-3- (4-chlorophenyl) -13-oxopropionic acid ethyl ester, 3-nitrobenzylamine obtained by reacting in the same manner as in Raw Material Synthesis Example 1 5- ( 4- (Methyl phenyl) 2- (3-Nitrophenyl) imidazo-l- (4) Dissolve ethyl ribonate in ethyl alcohol, add 1M aqueous sodium hydroxide solution, and react in the same manner as in Raw Material Synthesis Example 2. This gives 5- (4-chlorophenyl) 1-2- (3-nitrophenyl) midazo-l-4u-rubonic acid. Raw material synthesis example 5 9

5- (4-Fluorophenyl) obtained by reacting 2-hydroxyimino 3- (4-fluorophenyl) ethyl 3-oxopropionate and 3-nitrobenzylamine in the same manner as in Raw Material Synthesis Example 1. 1 2— (3-Nitrophenyl) imidazole-4 Dissolve the ethyl ester of ribonucleic acid in ethyl alcohol, add 1M aqueous sodium hydroxide solution, and react in the same manner as in Raw Material Synthesis Example 2. (4-Fluorophenyl) 1-2- (3-nitrophenyl) imidazole-4 This gives rubonic acid.

Example 1

Dissolve 2.0 g of 5- (4-methylphenyl) 1-2- (1-naphthyl) imidazole-4 obtained from Raw Material Synthesis Example 2 in 35 ml of dioxane, and add 1 M hydrochloric acid-ether solution 2 After adding 5 ml, the mixture was stirred for 30 minutes. 29 ml of thionyl chloride was added to the reaction solution, and the mixture was heated under reflux for 2.5 hours and concentrated under reduced pressure. 50 ml of pyridine and 0.79 g of 2-aminothiazole were added to the residue, and the mixture was heated under reflux for 5 hours, cooled to room temperature, added with a saturated aqueous solution of hydrogencarbonate, and extracted with ethyl acetate. Ethyl acetate After the layer was washed with water, dried and concentrated, ether was added to the obtained residue, and the precipitated crystals were collected by filtration. The resulting crude crystals were recrystallized from ethyl acetate to give 1.2 g of 5- (4-methylphenyl) -l- (1-naphthyl) -N- (2-thiazolyl) imidazo-l-l-l-carboxamide. Obtained. With a melting point of 22 8-2 229

In addition, acid addition salts of hydrochloric acid, methanesulfonic acid, P-toluenesulfonic acid, hydrobromic acid and nitric acid were obtained.

Hydrochloride Melting point 250 ° C (decomposition), — NMR 400 MHz (DMS O-D ₆ , ppm) 5: 2.39 (3 H, s), 7.28 (1 H, d ), 7.33 (2H, d), 7.55 (1H, t), 7.65 (3H, m), 7.84 (2H, d), 7.99 (1 H, d), 8.05 (1 H, d) 8.10 (1 H, d), 8.86 (1 H, d),

Methanesulfonate Melting point 252-254 (decomposition),

p-Toluenesulfonate Melting point 233-2 3 4 ^ (decomposition),

Hydrobromide Melting point 275-227 (decomposition),

Nitrate Melting point 1 69-170 (decomposition)

Example 2

Raw material synthesis example 17 5- (4-Methylphenyl) -1-2- (2-naphthyl) imidazole obtained from 7-1.4-rubric acid 1.4 g, 1 M hydrochloric acid-ether solution 25 m 1, chloride Using 0.56 g of thionyl 20 ml and 2-aminothiazole, the reaction was carried out in the same manner as in Example 1 to give 5- (4-methylphenyl)-2- (2-naphthyl) -N- (2 —Thiazolyl) 0.995 g of imidazoyl 4-carboxamide was obtained. Above melting point 250 — NMR 400 MHz (CDC ₁₈ , ρ Ρ m) δ: 2.44 (3H, s), 7.02 (1H, d), 7.33 (1H, d), 7.55 (2H, t), 7.85 (2H, d) , 7.89 (1H, t), 7.96 (2H, m), 8.21 (1H, d), 8.54 (1H, s)

Example 3

Raw material synthesis example 2- (4-Methoxy-1-naphthyl) -5- (4-methylphenyl) imidazo-l-ru4 4-g rubonic acid 2.0 g, 1 M hydrochloric acid-ether solution 25 m 1 The reaction was carried out in the same manner as in Example 1 by using 0.73 g of 25 ml of thionyl chloride and 0.73 g of 2-aminothiazole, to give 2- (4-methoxy-1-naphthyl) -15- (4-methylphenyl). ) — N— (2-thiazolyl) imidazole—

4. One and two g of carboxamide were obtained. > 250 with melting point — NMR 4

00 MHz (CDC 13, p pm) δ: 2.39 (3Η, s), 4.05 (3 H, S), 7.13 (1H, d), 7.25 (1 H, d), 7 33 (2 H, t), 7.51 (1H, d), 7.60 (1 H, t), 7.68 (1 H, t), 7.

84 (2H, d), 7.92 (1H, d), 8.27 (1H, d), 8.95 (

1H, d)

Example 4

Raw material synthesis example 19 5- (4-methylphenyl) -2- (4-pyridyl) imidazole-4-carboxylic acid obtained by reacting the compound obtained in 9 in the same manner as in Raw material synthesis example 2 1.0 g, 1 mol hydrochloric acid-ether solution (1.3 ml), thionyl chloride (3 ml), and 2-aminothiazol (0.36 g), the reaction was carried out in the same manner as in Example 1 to give 5- (4 1-methylphenyl) 1 2— (4 pyridyl) 1 N—

0.88 g of (2-thiazolyl) imidazole-4-carboxamide was obtained. Melting point 2 5 0 or ^{more, 1 H - NMR 4 0 0} MHz (CDC 1 3, p pm) δ:. 2 4 4 (3 H, s), 7. 04 (1 H, d), 7. 3 3 (2 H, d), 7.48

(1 H, d), 7.77 (2 H, d), 8.05 (2 H, d d), 8.65 (2 H, d d)

Example 5

Raw Material Synthesis Example 5— (4-Methylphenyl) —2- (3-pyridyl) obtained in 20-imidazo-l-ru 4-Rubonic acid 0.39 g, 1-molar hydrochloric acid-ether solution 0.52 ml, The reaction was carried out in the same manner as in Example 1 using 0.15 g of thionyl chloride (4.2 ml) and 2-aminothiazole, to give 5- (4-methylphenyl) -12-

(10-g) of (3-pyridyl), —N— (2-thiazolyl) imidazole-4 was obtained. Mp 2 0 0 ¾ above, 'Η- NMR 4 0 0 MH z (CDC 1 3, p pm) δ:'. 2 42 (3Η, s), 6. 99 (1 Η, d), 7. 3 0 (2Η, d), 7.47 (1Η, d), 7.51 (1Η, t), 7.77 (2Η, d), 8.49 (1Η, m) , 9.1 1 (1 Η, d)

Example 6

Raw material synthesis example 21 5- (4-Methylphenyl)-2- (3-quinolyl) imidazo-l-u4 obtained from 1) 0.5-g sorbic acid, 5.0 ml of 1M hydrochloric acid-ether solution, 5.0 ml, chloride The reaction was carried out in the same manner as in Example 1 using thionyl 7.5 ml and 0.18 g of 2-aminothiazole, to give 5- (4-methylphenyl) — 2- (3-quinolyl) 1 N— ( 2-thiazolyl) imidazo-l 4- 4-carboxamide 0.1

5 g were obtained. Melting point 250 ° C or higher, — NMR 400 MHz (DMSO—D

6, ρ pm) <5: 2.40 (3 Η, s), 7.26 (1 Η, d), 7.36 (2 Η, d), 7.54 (1 Η, d) , 7.69 (1Η, t), 7.82 (2H, m), 9.07 (1Η, s), 9.79 (1H, s), 11.49 (1 H, s), 1 3.50 (1 H, s)

Example 7

39 Omg of 2-cyclohexyl-5- (4-methylphenyl) -imidazoyl 4-carboxylic acid obtained in Raw Material Synthesis Example 4 was suspended in 20 ml of dichloromethane, and 0.2 ml of thionyl chloride was added. N, N-Dimethylformamide (0.1 ml) was added, and the mixture was heated under reflux for 3.5 hours and concentrated under reduced pressure. The residue was dissolved in 20 ml of dichloromethane, and this solution was added dropwise to a solution of 20 mg of 2-aminothiazole in 20 ml of pyridine. , N-dimethylaminopyridine 2 Omg was added, and the mixture was stirred at room temperature for 18 hours. Ethanol and water were added to the reaction solution, and the mixture was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography and crystallized from ethyl acetate-methanol to give 2-cyclohexyl-5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide 27 Omg was obtained. Mp 199~200, ^ -NMR 400 MHz (CD C 1 3, ppm) δ:. 1. 25-2 0 9 (10 Η, m) 2. 39 (3 Η, s), 2. 72 (1 Η , m), 6.94 (1 Η, d), 7.25 (2 Η, d), 7.47 (1), d), 7.68 (2 Η, d), 9.03 (1 Η, d) , brs), 10.6 (1Η, brs)

Example 8

2-Methyl-5- (4-methylphenyl) imidazole-4-carbonic acid 52 Omg obtained by reacting the compound obtained in Raw Material Synthesis Example 22 in the same manner as in Raw Material Synthesis Example 52, thionyl chloride 1. Omethyl and 210 mg of 2-aminothiazol were reacted in the same manner as in Example 1 to give 2-methyl-5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide 3 83 mg I got Melting point 275-276, ^ -MR 400 MHz (CD C 13, ppm) δ ": 1.25-2.09 (10 H, m) 2.39 (3 H, s), 2.72 (1H, m ), 6.94 (1H, d), 7.25 (2H, d), 7.47 (1H, d), 7.68 (2H, d), 9.03 (1H, brs), 10.6 (1 H, brs) Example 9

Raw material synthesis example 23 2-Hexyl-5- (4-methylphenyl) imidazolone 4-carboxylic acid 90 Omg, thionyl chloride 2.Oml, 2-aminothiazole 300 mg obtained in 3-3 The reaction was carried out in the same manner as in Example 1 to obtain 2-hexyl 5- (4-methylphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide 70 Omg. This was used as the hydrochloride to obtain amorphous 2-hexyl-5- (4-methylphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide hydrochloride (325 mg). Mp ^{1 2 4~1 3 0, X H} -NMR 4 0 0 MHz (DMSO - D 6, p pm) δ: 0. 86 (3H, t), 1. 3 0 (6 H, m), 1. 7 7 (2 H, m), 2.37 (3 H, s), 6.93 (2 H, t), 7.25 (1 H, d), 7.34 (2 H, d), 7.5 1 (1 H, d), 7.71 (2 H, d)

Example 10

Raw material synthesis example 24 5- (4-methylphenyl) -2-nonylimidazole-1-4 cal obtained by reacting the compound obtained in 4 in the same manner as in raw material synthesis example 2 The reaction was carried out in the same manner as in Example 1 using 80 Omg of boric acid, 1.Oml of thionyl chloride, 20 mg of N, N-dimethylaminopyridine and 230 mg of 2-aminothiazol, to give 5- (4− Methylphenyl) -1-nonyl-N- (2-thiazolyl) imidazo-41-carboxamide 40 Omg was obtained. This was used as a hydrochloride to obtain amorphous 5- (4-methylphenyl) -2-nonyl-N- (2-thiazolyl) imidazole-41-carboxamide hydrochloride (24 Omg). Melting point

125-128, — NMR 400 MHz (DMSO—D ₆ , ppm) δ: 0.85 (3 H, t), 1.25-1.3 1 (10H, m), 1.78 (2 H, m), 2.39 (3 H, s), 2.88 (2 H, t), 7.25 (1 H, d), 7.34 (2 H, t), 7.52 (1 H, t) d), 7.72 (2 H, d) Example 11

2-tert-butyl-5- (4-methylphenyl) imidazole-4 obtained by reacting the compound obtained in the raw material synthesis example 25 in the same manner as in the raw material synthesis example 2, 500 mg of rubutyric acid, thionyl chloride 0 3 ml, N, N-dimethylaminoviridine 2 Omg, 2-aminothiazole 250 mg, and the reaction treatment in the same manner as in Example 1 to give 2-tert-butyl-5- (4-methylphenyl) One N- (2-thiazolyl) imidazo-l-41-carboxamide 2 10 mg was obtained. Melting point 218, ^lH -NMR 400 MHz (CDC I s, ppm) δ

: 1.42 (9H, s), 2.39 (3H, s), 6.95 (1H, d), 7.

27 (2 H, d), 7.47 (1 H, d), 7.68 (2 H, d), 9.0 1 (

1H, brs), 10.6 (1H, brs) Example 1 2

Raw material synthesis example 26 5- (4-methylphenyl)-2- (2-phenylethyl) imidazol-4 obtained by reacting the compound obtained in 6 in the same manner as in raw material synthesis example 2 The reaction was carried out in the same manner as in Example 1 using 80 Omg of acid, 2.60 ml of thionyl chloride, 20 mg of N, N-dimethylaminopyridine, and 260 mg of 2-aminothiazole to give 5- (4 —Methylphenyl) — 2— (2-phenylethyl) — N— (2-thiazolyl) imidazole—4-carboxamide

63 Omg was obtained. This was used as a hydrochloride to obtain amorphous 5- (4-methylphenyl) -12- (2-phenylethyl) -N- (2-thiazolyl) imidazo-l-4u-carboxamide hydrochloride (265 mg). Mp ^{1 9 8~2 0 1, X H} -NMR 4 0 OMH z (DMS 0-D 6, ppm) δ: 2. 3 9 (3 Η, s)

, 3.16 (4 mm, m), 7.21 (8 H, m), 7.51 (1 H, d), 7.

7 2 (2 H, m)

Example 13

Raw material synthesis example 27 5- (4-chlorophenyl)-2- (1-naphthyl) imidazole-4 obtained from 7-4 3.0-g rubonic acid 1 M solution of 1M hydrochloric acid in 1 ether 15 m

1. Thionyl chloride 2 Om 1,2-aminothiazole 1. By using Og, the same reaction treatment as in Example 1 was carried out to obtain 5- (4-chlorophenyl) -2- (1-naphthyl) -1 N— (2-thiazolyl) imidazole-4-1-carboxamide 1.4

8 g were obtained. Melting point 206-208Τ; hydrochloride: melting point 250 or more;-NMR 400 MHz (DMSO—D ₆ , ppm) δ: 7.30 (1Η, dd), 7. 5 5-7.69 (6 H, m), 7.98-8.11 (5 H, m), 8.9

0 (1 H, d)

Example 14

Raw material synthesis example 2 5- (4-Methoxyphenyl) -2- (1-naphthyl) imidazo-l- 4-carboxylic acid obtained in 8 1.996 g, 1 M hydrochloric acid-ether solution 10 ml, chloride By reacting with thionyl 15 ml and 0.65 g of 2-aminothiazole in the same manner as in Example 1, 5- (4-methoxyphenyl) —2- (1-naphthyl) —N— (2-thiazolyl) 0.25 g of imidazo-l-4-carboxamide was obtained. Melt 1 9 8〜20 0 ¾

Example 15

2- (1-Naphthyl) -1-5-phenylimidazole-4-carboxylic acid obtained in Example 29 of raw material synthesis 3.00 g, 1M hydrochloric acid-ether solution 15m1, thionyl chloride 20ml, 2-aminothiazo 2- (1-naphthyl) -5-phenyl-N- (2-thiazolyl) imidazo-l-41-carboxamide 1 47 g were obtained. With a melting point of 250 or more, Martian R 40 OMHz (DMS O-De, ppm) δ: 7.26 (d, 1H), 7.45-7.71 (7H, m), 7.93- 8.09 (5H, m), 8.97 (1H, d), hydrochloride: melting point 250 or higher, — NMR 40

OMH z (DMSO— D ₆ p pm) δ: 7.30 (lH, d), 7.46— 7.69 (7H, m), 793—8.12 (5H, m), 8.88 (1H, d

)

Example 16

2- (1-Naphthyl) -5- (4-trifluoromethyl phenyl) imidazo-l-carboxylic acid 2.50 g obtained in Example 30 of raw material synthesis, 1-molar hydrochloric acid The reaction was carried out in the same manner as in Example 1 using 15 ml of toluene solution, 20 ml of thionyl chloride, and 1.0 g of 2-aminothiazole to give 2- (1-naphthyl) -15-

0.80 g of (4-trifluoromethylphenyl) -N- (2-thiazolyl) imidazo-l-4-carboxamide was obtained. Mp 222-223 T: hydrochloride: mp 250 or more, — NMR 400 MHz (DMSO—D ₆ , ppm) δ

: 7.30 (1 H, d), 7.55 (1 H, d), 7.61-7.68 (3 H, m), 7.90 (2 H, d), 8.01-8.18 (5H, m), 8.95 (1H, d)

Example 17

Raw material synthesis example 3 5- (4-Fluorophenyl)-2- (1-naphthyl) imidazo-l-u4 obtained from 1) 1.30 g of rubonic acid, 1M hydrochloric acid-ether solution 15 m1, The reaction was carried out in the same manner as in Example 1 using 1.0 g of thionyl chloride (20 m 1, 2-aminothiazole) to give 5- (4-fluorophenyl) —2- (1-naphthyl) 1 N — (2-thiazolyl) imidazole-41-carboxamide 0.80 g was obtained. Mp 2 1 8-220, hydrochloride: mp 2 50 ° C or _{higher, -NMR 400 MHz (DMSO- D 6} , ppm) δ: 7. 2 8 (1 H, d), 7. 3 6 - 7. 40 (2 H, m), 7.55 (1 H, d), 7.61-7.69 (3 H, m), 7.99-8.11 (5 H, m) , 8.9 1 (1 H, d) Example 18

Raw material synthesis example 3 2- (1-naphthyl) —5- (4-ditrophenyl): imidazo-l-4-carboxylic acid 3.0 g obtained in 2, 1-molar hydrochloric acid-ether solution 15m 1, thionyl chloride The reaction was carried out in the same manner as in Example 1 using 1.0 ml of 20 ml and 2-aminothiazole, whereby 2- (1-naphthyl) -5- (4-nitrophenyl) —N— ( 2-thiazolyl) 1.06 g of imidazo-l-41-carboxamide was obtained. Melting point 23 7-2 38 X :, hydrochloride: melting point 250 or more, if! -NM R 400 MHz (DMS O-De, p pm) δ: 7.29 (1 H, d ), 7.55 (1H, d), 7.63-7.68 (3H, m), 8.01—8.12 (3H, m), 8.25 ( 2 H, d), 8.37 (2 H, d), 8.97 (1 H, d)

Example 19

Raw material synthesis example 3 5- (4-Methylphenyl)-2- (4-nitrophenyl) imidazole obtained in 3-4 1-force rubonic acid 15.0 g, 1M hydrochloric acid-ether solution 75m1, Thionyl chloride 5 Using 5.27 g of 0m 1, 2-aminothiazole, The reaction was carried out in the same manner as in Example 1 to give 5- (4-methylphenyl) -12- (412-trophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide 0.86 g I got Mp 2 56-2 58, hydrochloride: mp 2 5 0 than on, - NMR 4 0 OMH z ( DMSO - D 6, p pm) <5: 7. 2 7 (1 H, d), 7. 3 4 (2 H, d), 7.55 (1 H, d), 7.80 (2 H, d), 8.38 (2 H, d), 8.48 (2 H, d)

Example 20

Raw Material Synthesis Example 3 5- (4-Methylphenyl) -1-2- (2-ditrophenyl) imidazole obtained in 4-4. 2-butane rubonic acid 2.20 g, 1 M hydrochloric acid-ether solution 15 m1, chloride The reaction was carried out in the same manner as in Example 1 by using 1.0 g of thionyl 20 m 1 and 2-aminothiazole, whereby 5- (4-methylphenyl) 12- (2-ditrophenyl) —N— (2-thiazolyl) imidazole-4-carboxamide 0.50 g was obtained. Melting point 203-204

Example 2 1

5- (4-Methylphenyl) —2- (4-ditrophenyl) —N— (2-thiazolyl) obtained in Example 19—0.44 g of imidazo-l-uyl 4-carboxamide was suspended in methanol. And ice-cooled. To the suspension was added 10 ml of a solution of 1.0 g of chloride (II) hexahydrate in 6 molar hydrochloric acid, heated under reflux for 2.5 hours, added with water, neutralized with carbonated lime, and treated with acetic acid. Extracted with ethyl. After the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate, 5 ml of a 1 M hydrochloric acid-ether solution was added, and the precipitated crystals were collected by filtration. The resulting crude crystals were recrystallized from methanol to give 2- (4-aminophenyl) -1-5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazo-1-yl 4-carboxamide 0.2 8 g were obtained. Melting point 2 44 ° C (decomposition)

Example 22

(1) 2-Hydroxyimino-1- (4-methylphenyl) -13-oxopropionic acid ethyl ester 44.9 g, 4-benzyloxybenzaldehyde 6 1

.0 g and ammonium acetate (147 g) were added to acetic acid (400 ml), and the mixture was heated under reflux for 17 hours. Then, water (1.51) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate and ether to give 36.9 g of 2- (4-benzyloxyphenyl) -15- (4-methylphenyl) imidazo-1-yl 4-carboxylate Obtained. With a melting point of 16-8-17

(2) 2-(4-benzyloxyphenyl) — 5- (4-methylphenyl) imi 2- (4-Benzyloxyphenyl) -5- (4-methylphenyl) imidazo 41.3 g of rurubic acid was obtained. Melting point 1 6 8 V (decomposition)

(3) A reaction treatment of 7.80 g of 2- (4-benzyloxyphenyl) -1-5- (4-methylphenyl) imidazole-4 monocarboxylic acid was carried out in the same manner as in Example 1. More 2- (4-benzyloxyphenyl) -1-5- (4-methylphenyl) -N-

5.85 g of (2-thiazolyl) imidazole-41-carboxamide was obtained. Mp 207-208. Hydrochloride: melting point 206 (decomposition)

Example 23

Example 22 2- (4-benzyloxyphenyl) -5- (4-methylphenyl) -1- (2-thiazolyl) imidazole-4-1-carboxamide obtained in (3) 5.10 g, 6.4 ml of thioanisol was dissolved in 100 ml of trifluoroacetic acid and stirred for 6 hours. The reaction solution was made alkaline with a 2 molar aqueous sodium hydroxide solution, acidified with aqueous citric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried, and the solvent was distilled off. The obtained residue is purified by silica gel chromatography (hexane: ethyl acetate = 6: 4), and recrystallized from ethyl acetate and hexane to give 2- (4-hydroxyphenyl) -15- (4- 2.33 g of methylphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide was obtained. With melting point 286-192 (decomposition)

Example 2 4

2- (4-Hydroxyphenyl) -1- (4-methylphenyl) -N- (2-thiazolyl) imidazo obtained from Example 23 3. 0.14 g of black benzyl alcohol and 0.26 g of triphenylphosphine were dissolved in 25 ml of tetrahydrofuran, 0.16 ml of dimethyl diazolate was added, and the mixture was stirred for 40 hours. Water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried. The residue obtained by distilling off the solvent is purified by silica gel chromatography (hexane: ethyl acetate = 7: 3), and the resulting residue is converted to the hydrochloride to give 2- (4- ( 4-Chlorophenylmethyloxy) phenyl) -5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide hydrochloride (61 mg) was obtained. With melting point 203-205 (decomposition)

Example 2 5

2- (4-Hydroxyphenyl) obtained in Example 23-3—5- (4-Methylphenyl Phenyl) -N- (2-thiazolyl) imidazole-4-carboxamide 0.52 g, phenethyl alcohol 0.33 ml, triphenylphosphine 0.72 g and azodicarboxylic acid getyl ester 0 4 4m1 was treated in the same manner as in Example 24 to give 5- (4-methylphenyl) 1-2- (4- (2-phenylethyloxy) phenyl) -1-N- (2-thiazolyl) imidazoyl 0.19 g of 4-carboxamide hydrochloride was obtained. Melting point 166-16-17 (decomposition)

Example 26

(1) Dissolve 1.5 g of 5- (4-methylphenyl) -12- (1-naphthyl) imidazole-4-ethyl carboxylate obtained in Raw Material Synthesis Example 1 in 13 ml of N, N-dimethylformamide Then, 0.19 g of 60% sodium hydride was added, and the mixture was stirred for 20 minutes. 0.55 ml of benzyl bromide was added, and the mixture was further stirred for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried. The residue obtained by distilling off the solvent was purified by silica gel chromatography (hexane: ethyl acetate = 8: 2) to give 1-benzyl-5- (4-methylphenyl) —2- (1-naphthyl). ) 0.73 g of imidazo 1-carboxylic acid ethyl ester was obtained.

_{^ -NMR 400 MHz (CDC 1 3} , p pm) δ: 1. 2 7 (3 H, t), 2. 3 9 (3H, s), 4. 3 0 (2H, q), 4. 8 5 (2 H, s), 6.44 (2 H, d), 6.97-7.07 (3 H, m), 7.2 1-7.28 (4 H, m), 7 . 4 1 (1 H, dd), 7.48-7.53 (3 H, m), 7.6 4-7.67 (1 H, m), 7.87-7.92 (2 H, m)

(2) 1 Benzyl 5- (4-methylphenyl) 1-2- (1-naphthyl) imidazoyl-4 4-ethyl ribonate 0.65 g was hydrolyzed in the same manner as in Raw Material Synthesis Example 2. The residue thus obtained was treated in the same manner as in Example 1 to give 1-benzyl-5- (4-methylphenyl) -2- (1-naphthyl) -1-N- (2-thiazolyl) imidazo-1-lu 0.5 lg of carboxamide was obtained. Melting point 231-232, hydrochloride: Melting point 2 27-229 ° C (decomposition)

Example 2 7

(1) 5- (4-Methylphenyl) 1-2- (1-naphthyl) imidazole-4 obtained in Example 1 for raw material synthesis 3.0 g of ethyl ribonate, 0.5 g of methyl iodide Example 26 1-Methyl-4- (4-methylphenyl) -2- (1-naphthyl) imidazole-5-carbonic acid ethyl ester 1.68 g and 1-methyl — 5— (4-Methylphenyl) 1-2- (1-naphthyl) imidazole-4-ethyl carboxylate 1.32 g was obtained.

1 one methyl - 4 one (4 one-methylphenyl) - 2- (1-naphthyl) imidazo Ichiru one 5- force carboxylic acid Echiruesuteru: - NMR 4 0 0 MH z (CD C 1 3, p pm) δ: 1. 2 9 (3 H, t), 2, 39 (3 H, s), 3.69 (3 H, s), 4.32 (2 H, q), 7.2 1 (2 H, d), 7.49—7.59 (

3H, m), 7.64 (1H, d), 7.67-7.71 (3H, m), 7.9 1-7.94 (1 H, m), 7.99 (1 H, d)

1-methyl-5- (4 one-methylphenyl) Single 2- (1-naphthyl) imidazole one 4 Ichiriki carboxylic acid ^{Echiruesuteru: 1 H- NMR 400 MHz (CDC} 1 3, ppm) δ: 1. 28 (3H, t ), 2.44 (3H, s), 3.23 (3H, s), 4.30 (2H, Q), 7.30 (2H, d), 7.38 (2H, d) , 7.48-7.56 (3H, m), 7.62-7.67 (2H, m), 7.89-7.92 (1H, m), 7.96 (1H , D)

(2) 1.60 g of 1-methyl-4- (4-methylphenyl) -2- (1-naphthyl) imidazole-5-carboxylate obtained in (1) was prepared in the same manner as in Synthesis Example 2 of the starting material. The residue obtained by hydrolysis was treated in the same manner as in Example 1 to give 1-methyl-4- (4-methylphenyl) 1-2- (1-naphthyl) -1-N-

(2-thiazolyl) imidazole-5-carboxamide 1.23 g was obtained. Melting point 281-283 X: (decomposition), hydrochloride: melting point 265-266 (decomposition)

Example 27 1.22 g of 1-methyl-5- (4-methylphenyl) -2- (1-naphthyl) imidazole-4-carboxylic acid ethyl ester obtained in (1) was hydrolyzed in the same manner as in Raw Material Synthesis Example 2. The obtained residue was subjected to a reaction treatment in the same manner as in Example 1 to give 1-methyl-15- (4-methylphenyl) -12- (1-naphthyl) -N- (2-thiazolyl) imidazole-4- 0.45 g of carboxamide was obtained. With a melting point of 251-252, Hydrochloride: - NMR 40 0 MHz (DMSO - D 6, p pm) δ: 2. 4 1

(3H, s), 3.29 (3H, s), 7.27 (1H, d), 7.37 (2H

, D), 7.52 (1 H, d), 7.57 (2 h, d), 7.60-7.65 (

2H, m), 7.70 (1H, dd), 7.83 (1H, d), 7.90-7.93 (1H, m), 8.08—8 1 0 (1 H, m), 8.18 (1 H, d) Example 2 9

(1) 5- (4-Methylphenyl) 1-2- (1-naphthyl) imidazole-4-carboxylic acid ethyl ester obtained in Raw Material Synthesis Example 1 3.0 g, 4- (2-chloroethyl) 乇By reacting 1.39 g of ruphorin in the same manner as in Example 26 (1), 4- (4-methylphenyl) 1-1- (2-morpholinoethyl) -12- (1-naphthyl) imidazole-5 —Ethyl carboxylate 2.89 g and 5- (4-Methylphenyl) —1- (2-Morpholinoethyl) -12- (1-naphthyl) imidazo-l-uyl 4-0.7% carboxylic acid ester Was.

4- (4-Methylphenyl) 1-11- (2-morpholinoethyl) 1-2- (1-Naphthyl) imidazo-1-yl 5-Ethyl carboxylate: — NMR 400 MHz (CDC 13, ppm) δ: 1.27 (3H, t), 2.09 (4H, t), 2.39 (3H, s), 2.49 (2H, t), 3.36 (4H, t) t), 4.28 (2 H, t), 4.31 (2 H, q), 7.2 1 (2 H, d), 7.49 -7.58 (3 H, m), 7.64-7.70 (4 H, m), 7.90-7.92 (1 H, m), 7.98 (1 H, d)

5- (4-Methylphenyl) 1-1- (2-morpholinoethyl) 1-2- (1-Naphthyl) imidazole-4Ethyl ribonate: — NMR 400 MHz (CDC 13, Ρpm) δ: 1.2 6 (3Η, t), 1.78 (4Η,, 2.04 (2Η, t), 2.43 (3Η, s), 3.30 (4Η, t), 3.80 (2Η, t), 4.29 (2Η, q), 7.32 (2Η, d), 7.40 (2Η, d), 7.5 1-7 .5 7 (3Η, m), 7.68-7.70 1 (2Η, m), 7.90-7.93 (1Η, m), 7.97 (1Η) , D)

(2) 4-79- (4-Methylphenyl)-2- (1-naphthyl) -imidazo-1-yl 5-carboxylate obtained from (1) 2.79 g of raw material synthesis The residue obtained by hydrolysis in the same manner as in Example 2 was treated in the same manner as in Example 1 to give 4- (4-methylphenyl) 111- (2-morpholinoethyl) 1-2- (1-naphthyl) ) — N— (2-thiazolyl) imidazole-5-carboxamide was obtained. This compound was treated in the same manner as in Example 1 to give 4- (4-methylphenyl) 1-111 (2-morpholinoethyl) —2- (1-naphthyl) —N- (2-thiazolyl) imidazole-5— 0.40 g of carboxamide dihydrochloride was obtained. ¹ H—NMR 400 MHz (DMS O—D ₆ , p pm) δ: 2.35 (3 H, s), 2.92 (2 H, br.s), 3.08 (2 H, b r.s), 3.42 (2 H, b r.s), 3.66 (2 H, b r.s), 3.75 (

2H, br.s), 4.65 (2H, br.s), 7.28—7.30 (3H, m), 7.55-7.78 (7 H, m), 8.09 (1 H, b r.d), 8.1

3—8.15 (1 H, m), 8.28 (1 H, d) Example 30

Example 29 0.71 g of 5- (4-methylphenyl) -1- (2-morpholinoethyl) -1-2- (1-naphthyl) imidazo-1-ru 4-carboxylate obtained in Example (1) was synthesized as a raw material. The residue obtained by the reaction treatment in the same manner as in Example 2 was subjected to the reaction treatment in the same manner as in Example 1 to give 5- (4-methylphenyl) — 1— (2- 乇 ulfolinoethyl) —2— (1-naphthyl) 0.40 g of 1 N- (2-thiazolyl) imidazole 4-carboxamide was obtained. Melting point 226-227, hydrochloride ¹ H-NMR 400 MHz (DMSO-D ₆ , p pm) δ: 2.43 (3Η, s), 2.49 (2Η, br.s), 2. 68 (2Η, br.s), 2.81 (2Η, br.s), 3.48 (2H, br.s), 3.60 (2H, br, s), 4.2 1 (2 H, t), 7.23 (1H, d), 7.40 (2 H, d), 7.48 (1 H, d), 7.6 1-7.69 (4 H, d m), 7.71 (1H, dd), 7.89 (2H, d), 8.08-8.11 (lH, m), 8.19 (1H, d)

Example 31

1.0 g of tert-butyl 5-cyclohexyl-2-phenylimidazole-4-carboxylate obtained in Raw Material Synthesis Example 5 was dissolved in 15 ml of trifluoroacetic acid and stirred at room temperature for 4 days. . The trifluoroacetic acid was distilled off under reduced pressure, and the obtained residue was crystallized from ethyl acetate to obtain 1.4 g of trifluoroacetic acid salt of 2-phenyl-5- (4-cyclohexyl) imidazole-4 monocarboxylic acid. Dioxane (30 ml) and thionyl chloride (1.0 ml) were added, and the mixture was heated under reflux for 0.5 hour. The solvent was distilled off under reduced pressure. To the obtained residue, 40 ml of pyridine and 0.333 g of 2-aminothiazole were added, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. After the organic layer was washed with water and dried, the solvent was distilled off. The obtained residue was dissolved in ethyl acetate, 3 ml of a 1M hydrochloric acid / ether solution was added, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from methanol-ethyl acetate to give 5-cyclohexyl-2-phenyl-N- (2-thiazolyl) imidazole-41-carboxamide dihydrochloride 0.16 g was obtained.

With a melting point of 2 12 to 2 15 (decomposition), — NMR 40 OMH z (CD ₃ OD, p pm) δ: 1.0-2.00, (10 H, m), 3.92 ( 1 H, t), 7.15 (1 H, d), 7.48 (1 H, d), 7.60-7.72 (3 H, m), 8.00 (2 H , dd)

Example 3 2

2-Phenyl-5- (4-pyridyl) imidazole-4 obtained from raw material synthesis example 6 tert-butyl ribonate 3.0 g, trifluoroacetic acid 30 ml 1, thionyl chloride 0.4 ml, Example using 0.43 g of 2-aminothiazole 31 0.1 g of 2-phenyl-5- (4-pyridyl) -N- (2-thiazolyl) imidazole-41-potassium lipoxamide dihydrochloride was obtained by the same reaction treatment as in 1. . Melting point 280 or more, — NMR 40 OMH z (CD ₃ OD, ppm) δ: Ί. 41 (1 H, d), 7.45-7.63 (3 H, m), 7. 7 0 (lH, d), 8.10-8.25 (2H, m), 8.80 (2H, d), 8.94 (2H, d)

Example 3 3

2-Phenyl-5- (3-pyridyl) imidazo-l-4 obtained from raw material synthesis example 7 tert-butyl ribonate 2.2 g, trifluoroacetic acid 30m1, thionyl chloride 18m1, 2 Using 2-aminothiazol (0.6 lg), the reaction was carried out in the same manner as in Example 31 to give 2-phenyl-5- (3-pyridyl) —N—

0.35 g of (2-thiazolyl) imidazole-4 lipoxamide dihydrochloride was obtained. Mp 27 79-28 OX) (decomposition),-NMR 400 MHz (CD 3 OD, ppm) δ: 7.39 (1H, d), 7.55-7.67 (3 H, m), 7.67 (1 H, d), 8.12-8.22 (2 H, m), 8.26 (1 H, dd), 8.95 ( 1 H, d), 9.18 (1 H, dt), 9.16 (1 H, d)

Example 3 4

2-Phenyl-5- (2-pyridyl) imidazo-l-4u-Rubonic acid tert-butyl ester obtained in raw material synthesis example 8 1.2 g, trifluoroacetic acid 30m1, thionyl chloride 0.4m1,2— 2-phenyl-5- (2-pyridyl) -N- (2-thiazolyl) imidazole-4-imidicylboxyl was obtained by subjecting 0.35 g of aminothiazole to the reaction treatment in the same manner as in Example 31. 0.46 g of dehydrochloride was obtained. With a melting point of 283 to 284 (decomposed), — NMR 400 MHz (CD a OD, p pm) δ: 7.22 (1 H, d), 7.38—7.53 (3 H, m), 7.55 (1H, d), 7.82 (1H, t), 7.99-8.10 (2H, m), 8.46 (1H, t), 8 . 7 3 (1 H, d), 8.97 (1 H, d) Example 35

2-Phenyl-5- (2-pyrazinyl) imidazole-4-carboxylic acid tert-butyl ester obtained in Raw Material Synthesis Example 9 0.9 g, trifluorosulfonic acid 30 ml, thionyl chloride 0.2 ml, 2 Using 2-aminothiazol (0.20 g), the reaction treatment was carried out in the same manner as in Example 31 to give 2-phenyl-5- (2-pyrazinyl) -N- (2-thiazolyl) imidazoyl 4-carboxamide hydrochloride 0.10 g of the salt was obtained. Melting point 2 66-2 68 8 (decomposition), — NMR 400 MHz (C D ₃ OD, p pm) δ: 7.40 (1H, d), 7.49—7.62 (3H, m), 7.71 (1H, d), 8.05-8.19 ( 2H, m), 8.76 (1H, d), 8.95 (1H, s) 9.78 (1H, s)

Example 36

2- (1-naphthyl) '-5- (4-pyridyl) imidazole-4-carboxylic acid tert-butyl ester obtained in Raw Material Synthesis Example 10 2.3 g, trifluoroacetic acid 20 m 1, thionyl chloride 0.5 m Using 0.45 g of 1,2-aminothiazole, the reaction was carried out in the same manner as in Example 31 to give 2- (1-naphthyl) -15- (4-pyridyl) -1-N- (2-thiazolyl) imidazo 0.05 g of 1-roux 4-carboxamidoni hydrochloride was obtained. Melting point 217-222 (decomposition), ifi-NMR 400 MHz (CD ₃ OD, ppm) δ: 7.35 (1H, d), 7.55—7.73 (4H, m), 7.97 (1 H, d), 8.03 (1 H, d), 8.13

(1H, d), 8.63 (1H, d), 8.85 (2H, d), 8.95 (2H, d)

Example 37

Raw material synthesis example 11 2- (4-Methoxyphenyl) -5- (4-pyridyl) imidazole-4-carboxylic acid tert-butyl ester obtained in 1 1.3 g, trifluoroacetic acid 2 Om 1, thionyl chloride 1 Using 0.55 g of 5m1 and 2-aminothiazole, the reaction was carried out in the same manner as in Example 31 to give 2- (4-methoxyphenyl) — 5- (4-pyridyl) — N— ( 0.40 g of 2-thiazolyl) imidazole-4-carboxamide hydrochloride was obtained. Melting point 251-253 (decomposition),

^J H-NMR 400 MHz (CD ₃ OD, p pm) 5: 7.09 (2 H, d), 7.2 1 (1 H, d), 7.54 (1 H, d) , 8.09 (2 H, d), 8.80 (2 H, d), 8.85 (2 H, d)

Example 3 8

2- (4-chlorophenyl) -15- (4-pyridyl) imidazole-4-carboxylic acid tert-butyl ester obtained in Raw Material Synthesis Example 12 1.2 g, trifluoroacetic acid, thionyl chloride 2.Oml, 2- Using 0.34 g of the aminothiazole, the reaction was carried out in the same manner as in Example 31 to give 2- (4-chlorophenyl) 1.51- (4-pyridyl) -1-N- (2-thiazolyl) imidazoyl-4 —0.13 g of carboxamide dihydrochloride was obtained. Melting point 270 T) or higher, — NMR 400 MHz (CD ₃ CD ", p pm) δ: 7.42 (1 H, d), 7.60 (2 H, d), 7.71 (1H, d), 8.20 (2H, d), 8.81 (2H, d), 8.94 (2H, d)

Example 3 9

Raw material synthesis example 13 2- (3-Methoxyphenyl) -1- (4-pyridyl) imidazole-4-carboxylic acid tert-butyl ester obtained in 1.3 1.4 g, trifluoroacetic acid 30 m 1 Using 0.5 m 1 of thionyl chloride and 0.34 g of 2-aminothiazole, the reaction treatment was carried out in the same manner as in Example 31 to give 2- (3-methoxyphenyl) — 5 -— (4-pyridyl) 0.27 g of 1 N- (2-thiazolyl) imidazole-41-carboxamide hydrochloride was obtained. Melting point 271-27 ZV (decomposition), 'H-NMR 400 MHz (CDs OD, ppm) δ: 7.09 (1 H, d), 7.22 (1 H, d), 7.47 (1H, t), 7.54 (1H, d), 7.66-7.77 (2H, m), 8.80 (2H, d), 8 . 8 6 (2 H, d) Example 40

Raw material synthesis example 14 2- (4-12-trophenyl) -15- (4-pyridyl) imidazole- ₄ -carboxylic acid tert-butyl ester 0.65 g, trifluoroacetic acid 10m1, The reaction was carried out in the same manner as in Example 31 using 0.54 of thionyl chloride (0.5 ml) and 0.34 g of 2-aminothiazole, whereby 2- (4-nitrophenyl) — 5-— (4-pyridyl) — N — (2-Thiazolyl) imidazole—4-force Lupoxamide dihydrochloride 0.06 g was obtained. Melting point over 280 ° C, — NMR 4 0 0 MHz (DMSO - D 6, p pm) δ: 7. 3 4 (1 H, d), 7. 6 0 (1 H, d), 8. 4 3 (2H, d), 8. 5 5 (2 H, d), (2 H, m), 8.66 (2 H, d), 8.98 (2 H, d)

Example 4 1

5- (4-Methylphenyl) -2-phenylimidazo-l-yl 0.5-g of 4-carboxylic acid and 0.35 g of 2-aminobenzothiazole were reacted in the same manner as in Example 1 to obtain a reaction product. N- (benzothiazole-2-yl) -1- (4-methylphenyl) -2-phenylimidazo-l-41-carboxamide 0.05 g was obtained. Mp 26 9-270

Example 42

5- (4-Methylphenyl) -reaction similar to Example 1 using 0.5 g of 2-phenylimidazoyl 4-monocarboxylic acid and 0.55 g of 2-amino-4-phenylthiazole By treatment, 5- (4-methylphenyl) -1-2-phenyl-1-N— (4-Fuenthithiazol-1-yl) 2-imidazole-41-carboxamide was obtained in an amount of 0.6 g. Melting point 2 7 4 to 2 7 6 ° C

Example 4 3

Starting material synthesis example 15 Using 2- (2-glolophenyl) -5- (4-pyridyl) imidazole-4-carboxylic acid tert-butyl ester obtained in 5 and 2-aminothiazole, in the same manner as in Example 31 The reaction gives 2- (2-chlorophenyl) -5- (4-pyridyl) -N- (2-thiazolyl) imidazole-41-carboxamide as hydrochloride.

Example 4 4

Raw material synthesis example 16 Using 2- (4-tert-butylphenyl) -5- (4-pyridyl) imidazo-1-yl 4-carboxylic acid tert-butyl ester hydrochloride and 2-aminothiazol obtained in 16 Example 31 2- (4-tert-butylphenyl) —5- (4-pyridyl) —N— (2-thiazolyl) imidazole—41-carboxamide as a hydrochloride Can be

Example 4 5

Raw Material Synthesis Example 35 Using 2- (4-fluorophenyl) -15- (4-pyridyl) imidazo-1-yl 4-carboxylic acid tert-butyl ester obtained in 5 and tert-butyl ester and 2-aminothiazole in the same manner as in Example 31 The reaction treatment gives 2_ (4-fluorophenyl) -5- (4-pyridyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide as the hydrochloride.

Example 4 6

Same as Example 31 using 2- (4-methylphenyl) -5- (4-pyridyl) imidazo-l-ru4 4-tert-butyl tert-butyl ester and 2-aminothiazol obtained in raw material synthesis example 36. 2- (4-Methylphenyl) -1-5- (4-pyridyl) -N- (2-thiazolyl) imidazo-l-l- 4-carboxamide is obtained as a salt-acid salt.

Example 4 7

Raw material synthesis example 3 5- (4-Methoxyphenyl) 1-2- (412-Trophenyl) imidazole-4 obtained from Example 7 4.9 g of rubonic acid, 1 M hydrochloric acid-ether solution 30 m 1, 50 ml of thionyl chloride and 1.5 g of 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-methoxyphenyl) 1-2- (4-1 There was obtained 0.93 g of ditrophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide. This was used as a hydrochloride to obtain 0.27 g of 5- (4-methoxyphenyl) —2- (4-nitrophenyl) —N— (2-thiazolyl) imidazo-ru-ru-ruxoxamide hydrochloride. Example 4 8 (decomposition) with a melting point of 2 7 4—2 7 6

5- (4-Methoxyphenyl) 1-2- (4-nitrophenyl) -1-N- (2-thiazolyl) imidazoyl-4-4-ruboxamide obtained in Example 47, 0.52 g, tin chloride (II) The same reaction treatment as in Example 59 was carried out using 1.2 g of 6-hydrate to give 2- (4-aminophenyl) 1-5- (4-methoxyphenyl) 1N 0.17 g of 1- (2-thiazolyl) imidazo-ru-ru-Ichi-l-poxamide was obtained. Melting point 2 5 7— 2 5 8 (decomposition)

Example 4 9

Raw material synthesis example 3 2- (4-nitrophenyl) -5- (4-trifluoromethylphenyl) imidazole obtained in 8-4 4.0 g rubonic acid 4.0 g, 1 molar hydrochloric acid-ether solution 2 Om 1, 1.1 g of thionyl chloride 4 Om 1,2-aminothiazole was treated in the same manner as in Example 1 to give 2- (4-ditrophenyl) 1-5- (4- 2.36 g of (trifluoromethylphenyl) -N- (2-thiazolyl) imidazo-l-u-l 4-carboxamide was obtained. Using this as the hydrochloride, 2-((4-torotropenyl) -15- (4-trifluoromethylphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide hydrochloride 1.65 g was obtained. Melting point 250 ° C or more

'H-NMR 400 MHz (DMSO-D ₆ , pm) δ: 8.48 (2 Η, d), 8.40 (2 Η, d), 8.13 (2 H, d ), 7.90 (2 H, d), 7.56 (1 H, d), 7.28 (1 H, d)

Example 5 0

Example 4 2- (4-nitrophenyl) -5- (4-trifluoromethylphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide obtained in 9 Hydrogenate 0.42 g in methanol using palladium. Then, the catalyst is removed by filtration, and the mixture is concentrated to give 2- (4-aminophenyl) 1.51- (4-trifluoromethylphenyl) -N- (2-thiazolyl) imidazole-4-1. 0.25 g of carboxamide was obtained. With a melting point of 1 7 5—1 7 7

Example 5 1

Raw material synthesis example 39 2- (4-Nitrophenyl) -5-phenylimidazolone obtained in 9-4. The same reaction as in Example 1 was carried out using 1.7 g of 2-aminothiazole to give 2- (4-ditrophenyl) -5-phenyl N- (2-thiazolyl) imidazoyl. Lu 4-carboxamide 3.84 g was obtained. This was used as a hydrochloride to obtain 0.51 g of 2- (4-nitrophenyl) -15-phenyl-N- (2-thiazolyl) imidazole-4-carboxamide hydrochloride. Melting point 250 or more

^ -NMR 400 MHz (DMSO-D ₆ , ppm) δ: 8.49 (2 H, d), 8.49 (2 H, d), 7.89 (2 H, d), 7. 5 5—7.4 8 (4 H, m), 7.27— (1 H, d)

Example 5 2

Example 51 2- (4-212-tropinyl) -1-5-N- (2-thiazolyl) imidazo-1-41-carboxamide obtained in 1-0.52 g, tin (II) 6 water The same reaction treatment as in Example 59 was carried out using 1.2 g of the hydrate to give 2- (4-aminophenyl) -15-phenyl-2-N- (2-thiazolyl) imidazole—4-force 0.17 g of lipoxamide was obtained.

Melting point 2 5 7-2 5 8 (decomposition)

Example 5 3

Example of raw material synthesis Example 2, using 2,5-bis (4-nitrophenyl) imidazole obtained in 40--4 rubonic acid, 1M hydrochloric acid-ether solution, thionyl chloride, and 2-aminothiazole. By performing the reaction treatment in the same manner as in 1, 2,5-bis (412-tropinyl) -N- (2-thiazolyl) imidazole-4-carboxamide is obtained.

Example 5 4

The 2,5-bis (412-trophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in Example 53 is suspended in methanol and cooled with ice. To the suspension was added a 6 molar hydrochloric acid solution of 鍚 (Π) chloride, and the reaction was carried out in the same manner as in Example 48. ) Imidazole-4-carboxamide is obtained.

Example 5 5

Raw material synthesis example 4 Using 5- (4-chlorophenyl) 1-2- (412-trophenyl) imidazole-4 immobilized rubonic acid, 1M hydrochloric acid-ether solution, thionyl chloride, and 2-aminothiazole obtained in 1 By carrying out the reaction treatment in the same manner as in Example 1, 5- (4-chlorophenyl) -2- (4-nitrophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide was obtained. can get.

Example 5 6

Example 55 5- (4-chlorophenyl) -12- (4-nitrophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in 5 is suspended in methanol and cooled with ice. A 6 molar hydrochloric acid solution of tin (II) chloride hexahydrate was added to the suspension solution, and the reaction was carried out in the same manner as in Example 48 to give 2- (4-aminophenyl) -15- (4-chloro (Phenyl) -N- (2-thiazolyl) imidazole-4-potassium lipoxamide is obtained.

Example 5 7

Raw material synthesis example 4 5- (4-fluorophenyl)-2- (4-ditrophenyl) imidazole obtained in 2-4-carboxylic acid, 1M hydrochloric acid-ether solution, thionyl chloride, 2-aminothiazole And treated in the same manner as in Example 1 to obtain 5- (4-fluorophenyl) -2- (4-nitrophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide. Can be

Example 5 8

Example 5 5- (4-Fluorophenyl) 1-2- (412-trifluoro) -lN- (2-thiazolyl) imidazole-41-carboxamide obtained in 7 was converted to methanol. And cool on ice. A 6 molar hydrochloric acid solution of tin chloride (II) hexahydrate was added to the suspension, and the reaction was carried out in the same manner as in Example 48 to give 2- (4-aminophenyl) -5- (4-fluorophenyl) — N- (2-thiazolyl) imidazole-4-carboxamide is obtained.

Example 5 9

Example 18 1.22 g of 2- (1-naphthyl) -5- (4-nitrophenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide obtained in Example 8 was suspended in methanol and iced. Cooled down. To the suspension was added 3 Om 1 of a solution of 3.O g of chloride (II) hexahydrate in 6 mol of hydrochloric acid, and the mixture was heated under reflux for 1.5 hours, and the precipitated white crystals were collected by filtration. The crystals were dissolved in ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium hydrogen carbonate solution and water, and then dried. 1 mol hydrochloric acid monoether was added to the ethyl acetate layer, and the precipitated crystals were collected by filtration. The resulting crude crystals were recrystallized from methanol to give 5- (4-aminophenyl) -2- (1-naphthyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide 0.28 g I got

Melting point of hydrochloride 2 42 (decomposition)

Example 6 0

(1) 3- (4-Acetoxymethylphenyl) 1-2-hydroxyiminot 3-oxopropionic acid tert-butyl ester 19.2 g, 1-naphthylmethylamine 11.3 g By performing the reaction treatment in the same manner as in Synthesis Example 1, 5- (4-a-cetoxymethylphenyl) -12- (1-naphthyl) imidazole-4-butyronic acid tert-butyl ester 10.5 g I got Melting point 16 2 to 16 4 ° C

(2) 5- (4-Acetoxymethylphenyl) -1- (1-naphthyl) imidazo mono-l-carboxylic acid tert-butyl ester (10.5 g) was used in the same manner as in Example 31. The reaction treatment yielded 6.62 g of 5- (4-acetoxymethylphenyl) —2- (1-naphthyl) —N— (2-thiazolyl) imidazo-l-41-carboxamide. Mp 197-199, hydrochloride: mp 22-227 (decomposition)

Example 6 1

Example 6 5- (4-Acetoxymethylphenyl) 1-2- (1-naphthyl) -N- (2-thiazolyl) imidazole-41-carboxamide obtained in (2) 2. 98 g of acetone was dissolved in 250 ml of acetone, and 56 ml of a 0.25 M aqueous sodium hydroxide solution was added under ice cooling, followed by stirring at room temperature for 2 hours. Acetone was distilled off under reduced pressure, acidified with aqueous citric acid solution, and extracted with ethyl sulphate. After washing the ethyl acetate layer with water, the solvent is distilled off, and the resulting residue is recrystallized from ethyl acetate to give 5- (4-hydroxymethylphenyl) —2- (1-naphthyl). —N— (2-thiazolyl) dimidazole-4-carboxamide 2.08 g was obtained. Mp 226-228, hydrochloride: mp 278-281 n (decomposition) Example 6 2

Example 21 2- (4-aminophenyl) -5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazo-l-41-carboxamide 0.1 g obtained in 1 and sodium borohydride 1.5 g of tetrahydrofuran suspension in 3N sulfuric acid 3 m

To a solution of 1 and 37% formaldehyde in 3 ml of tetrahydrofuran was added dropwise under ice cooling. After stirring at room temperature for about 30 minutes, water was added, and the mixture was made alkaline with potassium hydroxide. The aqueous phase was extracted twice with ethyl acetate, and the ethyl acetate layer was washed with saturated saline, dried and concentrated. The resulting white precipitate was recrystallized from ethyl acetate to give 2- (4-dimethylaminophenyl) -1,5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazo-l-ru 4 Omg was obtained. Melting point 2 6 5—

2 6 7 (decomposition)

Example 6 3

0.30 g of 2- (4-aminophenyl) -1-5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide obtained in Example 21 was dissolved in 20 ml of pyridine and acetyl chloride. After 0.8 ml was added dropwise under ice cooling, the mixture was stirred at room temperature for 2 hours. When the reaction mixture was concentrated, white crystals precipitated, which were recrystallized with ethyl acetate to give 2- (4-acetoamidophenyl) -5- (methylphenyl) -N- (2-thiazolyl) imidazo-l-4- 0.17 g of carboxamide was obtained. With a melting point of 269—271

Example 64

Dissolve 0.30 g of 2- (4-aminophenyl) -1- (4-methylphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in Example 21 in 20 ml of pyridine Then, 0.1 ml of acetoxyacetyl chloride was dropped under ice cooling, and the mixture was stirred at room temperature for 4 hours. After concentration, purification was carried out by chromatography on silica gel using a mixture of form / form / ethyl acetate in a 20: 1 ratio as mobile phase. By recrystallization from ethyl acetate, 0.13 g of 4- [5- (4-methylphenyl) -1-41- (2-thiazolylcarbamoyl) imidazo-1-yl-2-yl] phenylcarbamoylmethyl acetate was obtained. . Melting point 250 ° or more ¹ H-NMR 400 MHz (DMS 0- d ₆ > p pm) 5: 13.1 (1H, s), 1 1.2 (1H, s), 10.3 (1 H, s) 8.14 (2H, d), 7.79 (2H, d), 7.71 (2H, d), 7.51 (1H.d), 7.32

(2 H. d), 7.24 (1H, d), 4, 67 (2 H, d), 2.39 (3 H , s), 2.3 (3 H, s)

Example 6 5

5- (4-Methylphenyl) -2- (1-naphthyl) imidazole-4-carboxylic acid obtained in Raw Material Synthesis Example 2 0.5 g, 1 M hydrochloric acid-ether solution 5 m1, Thionyl chloride 1 The same reaction treatment as in Example 1 was carried out using 0.3 g of 0 ml and 2-amino-4-methylthioacetic acid methyl ester to give 2- [5- (4-methylphenyl) 1-2- (1-Naphthyl) imidazole-4-carboxamide] 0.14 g of methyl 4-thiazolylacetic acid was obtained. Melting point 1 4 7—1 4 9 (decomposition)

Example 6 6

Example 5 5- (4-aminophenyl) -2- (1-naphthyl) -N- (thiazolyl) imidazole obtained in Example 9-41-lipoxamide 0.42 g, sodium borohydride 1.5 g, 3N sulfuric acid 3 ml, 37% formaldehyde 3 ml 1 By treating in the same manner as in Example 6, 2, 5- (4-dimethylaminophenyl) 1-2- (1-naphthyl) —N— (2-thiazolyl) imidazo-1-ru 4-carboxamide 0.1 6 g were obtained. Melting point 2 4 2-2 4 3 (decomposition)

Example 6 7

2- (4-aminophenyl) — 5- (4-trifluoromethylphenyl) -N- (2-thiazolyl) imidazo-l-ru 4-potassium lipoxamide 0.2 g, sodium borohydride 1.5 g By treating 3 ml of 3N sulfuric acid and 3 ml of 37% formaldehyde in the same manner as in Example 62, 2- (4-dimethylaminophenyl) 15- (4-trifluoromethylphenol) was obtained. Enyl) -N- (2-thiazolyl) imidazolone 4-carboxamide 0.20 g was obtained. Melting point 260-26 (decomposed), hydrochloride melting point 27-229 (decomposition)

Example 6 8

2- (4-aminophenyl) -1- (4-trifluoro) obtained in Example 50 Methylphenyl) -N- (2-thiazolyl) imidazo-l-u 4-Carboxamide 0.7 g, sodium borohydride 1.5 g, 3N sulfuric acid 3 ml, acetoaldehyde lm 1 treated as in Example 62 As a result, 0.6 g of 2- (4-methylethylaminophenyl) -1-5- (4-trifluoromethylphenyl) -1-N- (2-thiazolyl) imidazo-1-ru-41-carboxamide was obtained. This was used as the hydrochloride to give 2- (4-ethylpyraminophenyl) -1-5- (4-trifluoromethylphenyl) -N- (2-thiazolyl) imidazole- 4-carboxamide hydrochloride. 58 g were obtained. With melting point 25 3-25 5 (decomposition)

Example 6 9

Example 21 2- (4-Aminophenyl) -1-5- (4-methylphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 1 0.3 g, sodium borohydride 0.5 g, 3 ml of 3N sulfuric acid and 0.3 ml of acetoaldehyde were treated in the same manner as in Example 62 to give 2- (4-ethylpyraminophenyl) 1 5— (4— 0.117 g of methylphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide was obtained. Melting point 9 8-9 9 (decomposition)

Example 7 0

Example 48 2- (4-aminophenyl) -5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide obtained in 8 0.5 g, sodium borohydride 1.5 g g, 3N sulfuric acid (3 ml) and 37% formaldehyde (3 ml) were treated in the same manner as in Example 62 to give 2- (4-dimethylaminophenyl) -15- (4-methoxyphenyl) -1-N — (2-thiazolyl) imidazole—4-carboxamide 0.27 g was obtained. By converting this to the hydrochloride,

0.3 g of (4-dimethylaminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-l-41-carboxamide hydrochloride was obtained. Melting point 2

2 8—2 3 0 (decomposition)

Example 7 1

Example 48 2- (4-aminophenyl) -15- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide obtained in 8 1.5 g, sodium borohydride 3.0 g, 6 ml of 3N sulfuric acid and 2 ml of acetoaldehyde were treated in the same manner as in Example 62 to give 2- (4-getylaminophenyl) -5- (4-methoxyphenyl). 0.85 g of 1 N- (2-thiazolyl) imidazole-4 -carboxamide was obtained. By converting this to the hydrochloride, 2- (4-1-ethyl-aminophenyl) -15- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole- 4-carboxamide hydrochloride 0.7 8 g were obtained. Melting point 2 17-220 ° C (decomposition)

Example 7 2

Example 48 2- (4-Aminophenyl) -15- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-1-ru obtained from Example 8 1.0 g of tetrahydrofuran, methanol It was dissolved in a mixed solvent and added to a tetrahydrofuran solution of 0.2 ml of 4N sulfuric acid and 0.2 ml of acetoaldehyde. 0.13 g of sodium borohydride was added to the solution, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and the ethyl acetate phase was washed with saturated saline and dried. After concentration, purification was carried out by chromatography on a silylation gel using a chromate form / ethyl ester mixture in a ratio of 100: 1 as a fluid phase. Then, 1.2 g of 2- (4-ethylaminophenyl) -5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide was obtained. By converting this into the hydrochloride, 0.48 g of 2- (4-ethylaminophenyl) -1- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-141-carboxamide hydrochloride was obtained. Was. Melting point 25 OX! Or more ¹ H-NM R 400 MHz (DMS O—d ₆ , p pm) d: 8.16 (2 H, d), 7.8 1 (2 H, d), 7 . 5 7 (1 H, d), 7.30 (1 H, d), 7.1 1

(2 H, d), 6.97 (2 H, d), 3.85 (3 H, s), 3.21 (2 H, q), 1.22 (3 H, t)

Example 7 3

Example 48 2- (4-aminophenyl) -5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide obtained in 8 1.0 g, sodium borohydride By treating 0.13 g, 0.2 ml of 4N sulfuric acid and 0.2 ml of propyl aldehyde in the same manner as in Example 72, 5- (4-methoxyphenyl) -2- (4-propylamino (Phenyl) —N— (2-thiazolyl) imidazole-41-carboxamide 1. lg was obtained. By converting this to the hydrochloride, 5- (4-methoxyphenyl) -12- (4-propylaminophenyl) -1-N- (2-thiazolyl) imidazo-1-ru 4-dipotoxolamide hydrochloride 0.28 g was obtained. Mp: 250 MHz or higher — NMR 270 MHz (DMS 0—d ₆ , ppm) δ: 8.13 (2 H, d), 7.79 (2 H, d), 7.57 ( 1 H, d), 7.30 (1 H, d), 7.12 (2 H, d), 6.88 (2 H, d), 3.85

(3H, s), 3.15 (2H, t), 2.51 (2H, m), 0.96 (3H, t)

Example 7 4

Example 4 2- (4-aminophenyl) -1-5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 8 1.0 g, sodium borohydride 0.13 g, 0.2 ml of 4N sulfuric acid and 0.3 ml of butyraldehyde were treated in the same manner as in Example 72 to give 2- (4-butylaminophenyl) -1-5- (4-methoxyphenyl). Le) -N- (2-thiazolyl) imidazo-lu-41-carboxamide 1. lg was obtained. By converting this to the hydrochloride,

0.20 g of (4-butylaminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide hydrochloride was obtained. ¹ H—NMR 27 0 MHz (DMS 0—d ₆ , ppm) 5: 8.12 (2 H, d), 7.80 (2 H, d), 7. 5 6 (1 H, d), 7.30

(1 H, d), 7.11 (2 H, d), 6.87 (2 H, d), 3.85 (3 H, s), 3.15 (2 H, t), 1.59 (2 H, m), 1.40 (2 H, m), 0.92 (3 H, t)

Example 7 5

Example 48 2- (4-aminophenyl) -1-5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in 8-0.8 g, sodium borohydride 0.1 3 g, 2.5 N sulfuric acid (0.4 ml) and isopentyl aldehyde (0.3 ml) were treated in the same manner as in Example 72 to obtain 2- (4-sopentylaminophenyl) 1-5- ( 0.3 g of 4- (methoxyphenyl) -N- (2-thiazolyl) imidazo-l-l-loxaxamide was obtained. Melting point 2 3 5— 2 3 9T;

Example 7 6

2- (4-Aminophenyl) -15- (4-methoxyphenyl) -1- (2-thiazolyl) imidazoyl-4-yl lipoxamide obtained in Example 48 2.0 g, sodium borohydride 0.8 g, 4 ml of 3N sulfuric acid and 4 ml of 25% glutaraldehyde were treated in the same manner as in Example 62 to give 5- (4-methoxyphenyl) 1-2- (4-piperidinoff 1.53 g of (denyl) —N— (2-thiazolyl) imidazole—4-carboxamide were obtained. By converting this into a hydrochloride, 5- (4-methoxyphenyl) -12- (4-piperidinophenyl) -1-N- (2-thiazolyl) imidazo-1-ru 4-carboxamide hydrochloride 0.2 5 g were obtained. Above melting point 250-NMR 27 0 MHz (DMS 0-d ₆ , ppm) 5: 8.34 (2 H, d), 7.87 (2 H, d), 7.6 1 (1H, d), 7.33 (1H, d), 7.11 (2H, d), 6.87 (2H, d), 3.85 (3H, s), 3.52 (4H, br), 1.90 (4H, br), 1.67 (2H, br)

Example 7 7

2- (4-tert-Butylphenyl) — 5- (4-Trotropinyl) —N— (2-thiazolyl) imidazole-41-carboxamide 16.3 g is dissolved in a mixed solvent of dioxane and methanol. For hydrogenation. After removal of the catalyst by filtration, concentration and crystallization with ethyl acetate and isopropyl ether, 5- (4-aminophenyl) — 2— (4-tert-butylphenyl) — N— (2— Thiazolyl) imidazo-l-41-carboxamide 7.13 g was obtained. Of these, 1.0 g was converted to the hydrochloride to give 5- (4-aminophenyl) -2- (4-tert-butylphenyl) -N- (2-thiazolyl) imidazo-leu-4-carboxamide hydrochloride 0.48 g was obtained. With melting point of 2700—2272 (decomposition)

Example 7 8

Example 7 2.0 g of 5- (4-aminophenyl) 1-2- (4-tert-butylphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in 7 was dissolved in methanol, and Add 3.6 ml of 7% formaldehyde and ice Under cooling, sodium boron cyanide (3.0 g) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated, and purified by silica gel chromatography using a mixture of ethyl formnoacetate having a ratio of 100: 1 as a fluid phase. After purification, it can be converted to hydrochloric acid to give 2- (4-tert-butylphenyl) -15- (4-dimethylaminophenyl) -N- (2-thiazolyl) imidazo-l 4-carboxamide hydrochloride 0.47 g was obtained. Melting point 2 2 8-2 3 0 (decomposition)

Example 7 9

Example 7 0.5- (4-aminophenyl) 1-2- (4-tert-butylphenyl) -N_ (2-thiazolyl) imidazole-41-carboxamide obtained in 7-0.5 g in triethyl orthoformate was added.晚 After refluxing, the mixture was concentrated. Ethanol and tetrahydrofuran were added thereto, 0.4 g of sodium borohydride was added, and the mixture was heated under reflux for 2 hours. After the reflux, water was added, extraction was performed with ethyl acetate, and the ethyl acetate phase was washed with saturated saline and dried. After drying and concentration, 0.5 g of 2- (4-tert-butylphenyl) -1-5- (4-methylaminophenyl) -1-N- (2-thiazolyl) imidazo-l-u-l 4-carboxamide was obtained. By converting this into a hydrochloride, 2- (4-tert-butylphenyl) -5- (4-methylaminophenyl) -1-N— (2-thiazolyl) imidazole-1-4-carboxamide hydrochloride 0 24 g were obtained. Melting point 2 5 7—2 5 9 ° C (decomposition)

Example 8 0

Raw material synthesis example 4 5- (3-Methoxyphenyl) —2- (4-nitrotrophyl) imidazo-4 obtained from 4-4 5.0 g rubonic acid, 1 M hydrochloric acid / ether solution 20 m 1 By performing the same reaction treatment as in Example 1 using 1.5 g of thionyl chloride, 10 m 1 and 1.5 g of 2-aminothiazole, 5- (3-methoxyphenyl) -2-(41-2 (Trofanil) -N- (2-thiazolyl) imidazo-l-41-carboxamide was obtained. This was used as the hydrochloride to obtain 0.73 g of 5- (3-methoxyphenyl) -2- (4-trotropinyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide hydrochloride. Melting point 2 5 7— 2 6 0 ^ (decomposition)

Example 8 1

Raw material synthesis example 4 5- (4-ethoxyphenyl) 1-2- (4-nitrophenyl) imidazole-4-carboxylic acid obtained in 6 5.0 g, 1 M hydrochloric acid-ether solution 20 m 1, thionyl chloride 10 m 1,2-aminothiazole 1.5 g The same reaction treatment as in Example 1 was carried out to obtain 5- (4-ethoxyphenyl) -1- (412-tropenyl) -N- (2-thiazolyl) imidazole-41-carboxamide. This was used as a hydrochloride to obtain 0.14 g of 5- (4-ethoxyphenyl) -2- (4-nitrophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide hydrochloride. Melting point 2 67-270 ° C (decomposition)

Example 8 2

Raw material synthesis example 3 5- (4-Methoxyphenyl) 1-2- (4-nitrophenyl) imidazo-1-yl obtained from 7 7 1.0 rubonic acid 1.0 g, 1 M hydrochloric acid-ether solution 5 ml, thionyl chloride The same reaction as in Example 1 was carried out using 0.3 ml of 2 ml and 2-amino-4-methylthiazol to give 5- (4-methoxyphenyl) — 2- (4-nitrophenyl). 1) N- (4-Methyl-2-thiazolyl) imidazole-4-carboxamide was obtained. Using this as the hydrochloride salt, 0.31 g of 5- (4-methoxyphenyl) -2- (4-ditrophenyl) -N- (4-methyl-2-thiazolyl) imidazo-l-ru- 4-carboxamide hydrochloride Obtained. Melting point 2 1 0 1 2 1 2 (decomposition)-

Example 8 3

5-g (4-aminophenyl) -2- (4-tert-butylphenyl) -1-N- (2-thiazolyl) imidazo-1-ru obtained from Example Ί7 1.0 g of 4-carboxamide tetrahydrofuran 55 m1 methanol 5 5 m 1 and _{_{_{KH 2 P0 4 - Na 2 H}}} P0 4 buffer (pH 6. 5) 7 was dissolved in 0 m l, under ice-cooling 25% Darutaruarude hydrate aqueous solution 1. 2 2 g, and cyan sodium borohydride 1 After adding 32 g, the mixture was stirred at room temperature for 17 days. Water (100 ml) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the desired 2- (4-tert-butylphenyl) -15- (4-piperidinophenyl) -N- (2-thiazolyl) imidazole-4 —Carboxamide 0.12 g was obtained. Melting point 250-252 (decomposition)

Example 8 4

Raw material synthesis example 5— (4-Methoxyphenyl) obtained in 8—2— (3-methyl — 4-Nitrophenyl) imidazole — 4 0.9 g rubonic acid, 1 mol hydrochloric acid in 1 ether 38 μm, thionyl chloride 48.2 m 1, using 2-aminothiazole 6.56 g By performing the same reaction treatment as in Example 1, 5- (4-methoxyphenyl) —2- (3-methyl-4-nitrophenyl) —N— (2-thiazolyl) imidazole—41 12.5 g of carboxamide was obtained. 1.0 of these

9-g hydrochloride, 5- (4-Methoxyphenyl) 1-2- (3-Methyl-4--2-trophenyl) -N- (2-Thiazolyl) imidazo-l-Ul 4-Carboxamide hydrochloride 0.6 8 g were obtained. Melting point> 250 — NMR 27 0 MHz

(DMS 0- d ₆ ^ p pm) δ: 8.39 (1 H, s), 8.28 (1 H, d), 8.13 (1 H, d), 7.90 ( 1H, d), 7.65 (1H, d), 7.

3 4 (1H, d), 7.09 (1H, d), 5.22 (2H, br), 3.84

(3 H, s), 2.62 (3 H, s)

Example 8 5

Example 8 5- (4-Methoxyphenyl) 1-2- (3-methyl-4-12-trophenyl) obtained in 4: 1-N- (2-thiazolyl) imidazole-4-carboxamide 1.5 was dissolved in 60 ml of 50% aqueous ethanol solution and 50 ml of dioxane, 6 g of iron powder was added, and 0.06 ml of concentrated hydrochloric acid was added under reflux, followed by refluxing for 1 hour. The filtrate was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. Was. 0.79 g of the obtained crystals was dissolved in 24 ml of methanol and 35 ml of dioxane, and 5.85 ml of a 1M hydrochloric acid-ether solution was added, followed by stirring at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the obtained crystals were recrystallized from ethanol to give the desired 2- (4-amino-3-methylphenyl) -15- (4-methoxyphenyl) -1-N-

0.43 g of (2-thiazolyl) imidazole-41-carboxamide hydrochloride was obtained. ¹ H-NMR 270 MHz (DMSO-d ₆ , p pm) δ: 8.13 (1 H, s), 8.06 (1 H, d), 7.8 4 (1 H, d),

7.59 (1 H, d), 7.31 (1 H, d), 7.23 (1 H, d), 7.1

0 (1H, d), 5.50 (4H, br), 3.85 (3H, s), 2.50 (

3 H, s)

Example 8 6

In a solution of 7 ml of tetrahydrofuran, 8.3 ml of 2.5 N sulfuric acid and 7 ml of 37% formalin, stirred under ice-cooling, the 2- (4-amino-3-methylphenyl) -1-5- obtained in Example 85 was obtained. (4 main Tokishifuweniru) Single N-(2-thiazolyl) to give a Imi Dazo one route 4 one Karubokisami de 1. 2 g and tetrahydrofuran 4 5 m 1 pressure and stirred 5 min ^_. After adding 3.5 g of sodium borohydride little by little, the mixture was stirred at room temperature for 2.5 hours. After neutralization with a 5% aqueous potassium carbonate solution, the solvent was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, the solvent is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography to obtain the desired 2- (4-dimethylamino-13-methylphenyl). 5-(4-Methoxyphenyl) -N- (2-thiazolyl) imidazo-l-ruboxamide was obtained. Using this as the hydrochloride, 2- (4-dimethylamino-3-methylphenyl) -15- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-1-ol 4-carboxamide hydrochloride 0. 40 g were obtained. Melting point 2 45-250 ° C (decomposition)

Example 8 7

Raw material synthesis example 49 1.2 g of 5- (4-dimethylaminophenyl) -2- (4-nitronitro) imidazole-4-ethyl carboxylate obtained in 9 was used as raw material synthesis example 2, followed by Example 1. The reaction was carried out in the same manner as described above to obtain 230 mg of 5- (4-dimethylaminophenyl) 1-2- (412-trophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide. Melting point 250 to 25 1 Example 8 8

Raw material synthesis example 5— (4-Isopropoxyphenyl) —2— (4-nitrophenyl) imidazo-4,4-hydroxyethyl ether ester 1.4 g obtained from 50 was synthesized as raw material synthesis example 2. By performing the reaction treatment in the same manner as in Example 1, 5- (4-isopropane) 55-Omg of 2- (4-ditrophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide is obtained. Example 8 9 with a melting point of 26 7 to 27 0

Raw material synthesis example 5— (4-Isopropoxyphenyl) —2- (4-nitrophenyl) imidazole-4 obtained from Example 50 1.4 g of ethyl ribonate was the same as in Raw material synthesis example 2. The resulting carboxylic acid and 2-aminopyrimidine (20 Omg) were treated in the same manner as in Example 1 to give 5- (4-isopropoxyphenyl) -12- (4-nitrophenyl) -N — (2-Pyrimidinyl) imidazo 1-l 4-carboxamide hydrochloride 59 mg was obtained. Above the melting point of 2 7 5 Example 9 0

Example 6 5- (4-Hydroxymethylphenyl) -1-2- (1-naphthyl) -N- (2-thiazolyl) imidazole-41-carboxamide obtained in 1 30 Omg of pyridine was added to 5 m of pyridine. 1 and 5 ml of propionic anhydride were dissolved and left for 12 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The residue obtained by washing, drying and concentrating the ethyl acetate layer with water is recrystallized from ethyl acetate to obtain 2- (1-naphthyl). One 5-O-mg of 5- (4-propionyloxymethylphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide was obtained. Example 9 1 with a melting point of 281-283

Example 6 5- (4-Hydroxymethylphenyl) -1-2- (1-naphthyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 1 1.0 g of tetrahydrofuran 2 It was dissolved in Om1 and 1.24 g of triphenylphosphine and 63 mg of N-chlorosuccinimide were added. After stirring for 15 minutes, 1.24 g of triphenylphosphine and 63 mg of N-chlorosuccinimide were further added, followed by stirring for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The obtained residue was suspended in 3 Om 1 of acetone, 3 ml of a 1 molar hydrochloric acid ether solution was added, and the solvent was distilled off. Ethyl acetate was added to the obtained residue, and the resulting crystals were collected by filtration to give 5- (4-chloromethylphenyl) -2- (1-naphthyl) -1-N- (2-thiazolyl) imidazoyl. _ Carboxamide hydrochloride 58 Omg was obtained. 1 H—NMR 40 OMHz (DMS 0—d ₆ , p pm) S: 4.85 (2H, s), 7.31 (1 H, d), 7.5 6 (1 H, d), 7.58-7.69 (5 H, m), 7.95 (2H, d), 8.01 (1 H, d) 8.05 (1 H, d), 8.11 (1 H, d), 8.90

(1 H, d)

Example 9 2

5.27 g of 5- (4-acetoxymethylphenyl) -2- (4-nitrophenyl) imidazole-4-carboxylic acid tert-butyl ester obtained in Example 5 The reaction was carried out in the same manner as in Example 31 to give 5- (4-acetoxymethylphenyl) -l- (4-nitrophenyl) -lN- (2-thiazolyl) imidazo-l-ru 41-l-l-poxamide 5.75. . With a melting point of 265-266 (decomposed), hydrochloride of 2557-261 (decomposed)

Example 9 3

Example 9 4.9 g of 5- (4-acetoxymethylphenyl) -12- (4-ditropenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide obtained in 2 was carried out. Example 6 5- (4-Hydroxymethylphenyl) -12- (4-nitrophenyl) -N- (2-thiazolyl) imidazole-4-caproloxamate 4. 45 g were obtained. Example 9 4 with a melting point of 2 4 9 to 2 52

Example 9 5- (4-Hydroxymethylphenyl) -2- (4--2-trophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide 2.67 g obtained in 3 was added to tetrahydrofuran 30 It was dissolved in Om1, and 3.33 g of triphenylphosphine and 1.70 g of N-chlorosuccinimide were added. After stirring for 15 minutes, 3.33 g of triphenylphosphine and 1.70 g of N-chlorosuccinimide were further added, followed by stirring for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The obtained residue was recrystallized from ethyl acetate to give 5- (4-chloromethylphenyl) -12- (412-trophenyl) -1N—

2.60 g of (2-thiazolyl) imidazole-4-carboxamide was obtained. Melting point 2 80 or more, 1 H- NMR 4 0 0 MH z (DMSO- d 6, p pm) δ: 4. 85 (2 Η, s), 7. 2 8 (1 H, d), 7. 5 6 (1 H, d), 7.59 (2H, d), 7.90 (2 H, d), 8.40 (2 H, d), 8.48 (2 H, d)

Example 9 5

Example 9 5- (4-Chloromethylphenyl) —2- (4-ditrophenyl) —N— (2-thiazolyl) imidazole-4-carboxamide obtained in 4 700 mg and sodium methanesulfinate (325 mg) were dissolved in dimethylformamide (30 ml), and the mixture was stirred at 80 ° C for 1 hour. The mixture was poured into water (100 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried, and the solvent was distilled off. The obtained residue was suspended in acetone (3 Oml), a 1 M hydrochloric acid ether solution (3 ml) was added, and the solvent was distilled off. The obtained residue was recrystallized from acetone to give 5- (4-methanesulfinyloxymethylphenyl) —2- (4-nitrophenyl) —N— (2-thiazolyl) imidazoyl—41-carboxamide hydrochloride 736 mg were obtained. Melting point 2 7 8 to 2 8 2 V (decomposition)

Example 9 6

Example 9 5- (4-Chloromethylphenyl) —2- (4-nitrophenyl) -1-N— (2-thiazolyl) imidazole—41-carboxamide obtained in 4 900 mg and 1 By reacting 30.9 mg of 1-methylbiperazine in the same manner as in Example 95, 5- (4- (4-methylbiperazine-11-ylmethyl) phenyl) 1-2- (4-nitrophenyl) —N— ( 2-thiazolyl) imidazole-4-carboxamide trihydrochloride 742 2 mg was obtained. Melting point 2 48 to 25 2 (decomposition)

Example 9 7

Example 9 5- (4-Chloromethylphenyl) —2- (412-Trophenyl) —N— (2-Thiazolyl) imidazo-l-uyl 4-carboxamide 900 mg and dimethylamine obtained in 4 By reacting 5 ml of a 50% aqueous solution in the same manner as in Example 95, 5- (4-dimethylaminomethylphenyl) 1-2- (4-nitrophenyl) —N— (2-thiazolyl ) 645 mg of imidazole-4-carboxamide dihydrochloride were obtained. Melting point 2 7 3 to 2 7 QV (decomposition)

Example 9 8

Raw material synthesis example 53 2- (4-tert-butylphenyl) -15- (412-tropenyl) imidazole-4-carboxylic acid obtained in 3 18.4 g, 1 mol hydrochloric acid-ter solution 92 m1, Using 5.8 g of thionyl chloride 11 Oml and 2-aminothiazole, the reaction and treatment were conducted in the same manner as in Example 1 to give 2- (4-tert-butylphenyl) -5- (4-12- 17.3 g of trophenyl) -N- (2-thiazolyl) imidazo-ru-ru-ru-pipoxamide were obtained. Higher than the melting point of hydrochloride 240

^ -NMR 270 MHz (DMSO-d ₆ , p pm) δ: 1.34 (9 H, s), 7.31 (1 H, d), 7.57-7.6 ( 3 H, m), 8.17 (2 H, d), 8.2 1 (2 H, d), 8.37 (2 H, d)

Example 9 9

Example 4 2- (4-aminophenyl) -5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-l-u 4- 4-potassium propyloxamide obtained in 8 to 1.35 g of ethyl ethyl orthoformate 4 Om 1 and 0.5 ml of trifluoroacetic acid were added, and the mixture was heated and refluxed overnight. The reaction solution was concentrated, and 40 ml of tetrahydrofuran and 25 ml of ethyl alcohol were added to the residue, and sodium borohydride was added with stirring. 2 g was added. After stirring at room temperature for 1 hour, the mixture was heated and refluxed for 2 hours. The reaction mixture was extracted with ethyl acetate, dried and concentrated. The resulting crude product was purified by silica gel column chromatography to give 5- (4-methoxyphenyl) 1-2- (4-methylaminophenyl). One N—

0.6 g of (2-thiazolyl) imidazo-l- 4-carboxamide was obtained. Further, when this compound was dissolved in ethyl acetate and ether hydrochloric acid was added, hydrochloride crystals were precipitated. The precipitated crystals are filtered and recrystallized from methyl alcohol to give 5- (4-methoxyphenyl) -12- (4-methylaminophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide hydrochloride Dihydrate 24 Omg was obtained. With a melting point of 1 9 3-1 9 7

Example 1 100

5- (4-Methoxyphenyl) -1-2- (3-ditrophenyl) imidazo-l-u-l 4-Carboxylic acid 11.3 g, 1M hydrochloric acid in 1 ether 5 Om 1, Thionyl chloride 27.2 ml, 2- Using 3.7 g of aminothiazole, the reaction and treatment were carried out in the same manner as in Example 1 to give 5- (4-methoxyphenyl) -12- (3-nitrophenyl) -N- (2-thiazolyl) imidazo 8.9 g of 1-rou 4-carboxamide hydrochloride monohydrate was obtained. With a melting point of 205-207

Example 10 1

5- (4-Methoxyphenyl) 1-2- (3-ditrophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide hydrochloride monohydrate 1. Og to methanol 100 The mixture was suspended in a mixed solvent of m1 and dioxane (100 ml), and 0.5 g of 10% palladium carbon (50% water content) was added, followed by normal pressure catalytic reduction. The reaction mixture was filtered and concentrated, and the resulting crude crystals were recrystallized from methanol to give 2- (3-amino There was obtained 11 Omg of phenyl) -5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazo-lu-41-carboxamide hydrochloride trino2hydrate. Melting point 2 4 5 V (decomposition)

Example 102

2-(3-Aminophenyl) 1-5-(4-Methoxyphenyl) 1 N-(2-thiazolyl) imidazo 1-4- 4-potassium lipoxamide hydrochloride 3 Z dihydrate 1.5 g The residue was dissolved in 40 ml of tetrahydrofuran, 9 ml of 37% formalin, and 9 ml of 3N sulfuric acid, and 4.5 g of sodium borohydride was gradually added thereto with ice cooling. After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate, dried and concentrated. The obtained product was purified by silica gel column chromatography, dissolved in dioxane, added with a hydrochloric acid ester solution, and concentrated under reduced pressure. When the obtained crude crystals were recrystallized from methanol, 2- (3-dimethylaminophenyl) -15- (4-methoxyphenyl) -1-N— (2-thiazolyl) imidazole-4-1-carboxamide dihydrochloride

0.7 g of 3 dihydrate was obtained. Melting point 23 V (decomposition)

Example 1 0 3

Example 1 Using 5- (4-Methoxyphenyl) -1-2- (412-trophenyl) imidazole-4-carboxylic acid, 1M hydrochloric acid-ether solution, thionyl chloride, 2-amino-1,3,4-thiadiazole 5- (4-Methoxyphenyl) -1- (4-nitrophenyl) -1-N— (1,3,4-thiadiazol-2-yl) imidazo-1-ru-4 carboxamide Get. Example 1 0 4

5- (4-Methoxyphenyl) -1-2- (4-nitrophenyl) -1-N— (1,3,4-thiadiazoyl-2-yl) imidazo-1-ru-4 Using one carboxamide, as in Example 85. By reaction and treatment, 2- (4-aminophenyl) -5- (4-methoxyphenyl) —N— (1,3,4-thiadiazoyl-2-yl) imidazoyl—4-carboxamide Get.

Example 1 0 5

2- (4-Aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (1,3,4-thiadiazoyl-2-yl) imidazole-4-carboxamide, as in Example 102 By reaction and treatment, 2- (4-dimethylaminophenyl) —5- (4-methoxyphenyl) —N— (1,3,4-thiadiazol—2-yl) imidazole—41-carboxamide Get.

Example 1 0 6

2- (4-aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (1,3,4-thiadiazole-2-yl) imidazo-1-ru 41-carboxamide was used to prepare Examples 9-9. Similarly, the reaction and treatment yields 5- (4-methoxyphenyl) -12- (4-methylaminophenyl) -1-N— (1,3,4-thiadiazol-l-yl) imidazole- 4—Get the carboxamide.

Example 10 7 "

2- (4-aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (1,3,4-thiadiazoyl-2-yl) imidazo-1-ru 4-carboxamide was used to prepare Example 7 4 By the same reaction and treatment, 2- (4-butylaminophenyl) -1-5- (4-methoxyphenyl) -1-N- (1,3,4-thiadiazoyl-2-yl) Get imidazole-41-carboxamide.

Example 1 0 8

2- (4-12-trophenyl) 15- (4-methoxyphenyl) imidazo-l-ul 4 Reaction with rubonic acid, 1M hydrochloric acid-ether solution, thionyl chloride and 2-aminothiazoline in the same manner as in Example 1. By the treatment, 5- (4-methoxyphenyl) -2- (4-ditrophenyl) -1-N- (2-thiazolinyl) imidazo-leu-4-carboxamide was obtained. 'H—NMR of melting point of hydrochloride over 260¾

2 7 OMH z (DMS O-de, ppm) 5: 3.54 (2Η, t), 3.85 (3Η, s), 4.04 (2Η, t), 7.11 (2Η, d), 7.87 (2 (, d), 8.40 (2Η, d), 8.50 (2Η, d)

Example 1 0 9

5- (4-Methoxyphenyl) 1-2- (4-Ditrophenyl) -N- (2-thiazolinyl) imidazo-l-41 Reaction and treatment in the same manner as in Example 85, using 4-carboxamide Thus, 2- (4-aminophenyl) -15- (4-methoxyphenyl) -N- (2-thiazolinyl) imidazo-l-41-carboxamide is obtained. Example 110

2- (4-aminophenyl) -5- (4-methoxyphenyl) 1-N- (2-thiazolinyl) imidazo-l-l 4-Carboxamide was reacted and treated in the same manner as in Example 102. This gives 2- (4-dimethylaminophenyl) — 5- (4-methoxyphenyl) -N- (2-thiazolinyl) imidazole-4-carboxamide.

Example 1 1 1

2- (4-aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolinyl) imidazole-1-reaction and treatment in the same manner as in Example 99 using 4-carboxamide Thus, 5- (4-methoxyphenyl) 1-2- (4-methylaminophenyl) -N- (2-thiazolinyl) imidazoyl-4-carboxamide is obtained.

Example 1 1 2

The reaction and treatment were carried out in the same manner as in Example 74 by using 2- (4-aminophenyl) -15- (4-methoxyphenyl) -1- (2-thiazolinyl) imidazo-l-4-carboxamide, as in Example 74. 2- (4-Butylaminophenyl) -5- (4-Methoxyphenyl) 1- (2-thiazolinyl) imidazole One-to-one lipoxamide is obtained.

Example 1 1 3

5- (4-Methoxyphenyl) 1-2- (3-nitrophenyl) imidazole '4-carboxylic acid, 1M hydrochloric acid-ether solution, thionyl chloride, 2-amino-1,3,4-thiadiazol The reaction and treatment were carried out in the same manner as in Example 1 to give 5- (4-methoxyphenyl) -12- (3-ditrophenyl) -1-N- (1,3,4-thiadiazol-2) Ill) Obtain imidazo 4-ru-carboxamide. Example 1 1 4

5- (4-Methoxyphenyl) 1 2- (3-nitrophenyl) 1 N— (1,3,4-thiadiazoyl 2-yl) imidazo monoru 4-Carboxamide, as in Example 85 2- (3-aminophenyl) -1-5- (4-methoxyphenyl) -N- (1,3,4-thiadiazoyl-2-yl) imidazo-ru-4-1-carboxami Get Example 1 1 5

Example 10 using 2- (3-aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (1,3,4-thiadiazole-2-yl) imidazo-l 4-carboxamide 2- (3-dimethylaminophenyl) -15- (4-methoxyphenyl) -1-N— (1,3,4-thiadiazol-12-yl) Obtain imidazo-l 4- 4-carboxamide.

Example 1 1 6

2- (3-aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (1,3,4-thiadiazol-2-yl) imidazole-4-carboxamide Example 9 By reacting and treating in the same manner as in 9, 5- (4-methoxyphenyl) -2- (3-methylaminophenyl) -1-N— (1,3,4-thiadiazole-21-yl) imidazo One liter of 4-carboxamide is obtained.

Example 1 1 7

2- (3-aminophenyl) -1-5- (4-methoxyphenyl) -N- (1,3,4-thiadiazol-2-yl) imidazol-4 Using 1-carboxamide, Example 74 By reacting and treating in the same manner as in the above, it is possible to obtain 2- (3-butylamino) -5- (4-mexyloxyphenyl) -1-N- (1,3,4-thiadiazoyl-2-yl) imidazo 1 roux 4 Get 1 carboxamide.

Example 1 1 8

Reaction and treatment in the same manner as in Example 1 using 5- (4-methoxyphenyl) -12- (3-nitrophenyl) imidazo-l--4-carboxylic acid, molar hydrochloric acid-ether solution, thionyl chloride, and 2-aminothiazoline This gives 5- (4-methoxyphenyl) 1-2- (3-ditrophenyl) -N- (2-thiazolinyl) imidazo-leu-4-carboxamide.

Example 1 1 9

5- (4-Methoxyphenyl) _2- (3-Ditrophenyl) -1-N- (2-thiazolinyl) imidazo-l-l 4-Carboxamide, using the same reaction and treatment as in Example 85 Thus, 2- (3-aminophenyl) -1- (4-methoxyphenyl) -N- (2-thiazolinyl) imidazole-41-carboxamide is obtained.

2- (3-Aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolinyl) imida * -Ru 4-Carboxamide is reacted and treated in the same manner as in Example 102. This gives 2- (3-dimethylaminophenyl) -5- (4-methoxyphenyl) -N- (2-thiazolinyl) imidazo-l-41-carboxamide.

Example 1 2 1

2- (3-Aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolinyl) imidazo-1-yl Reaction and treatment in the same manner as in Example 99 using 4-carboxamide Thus, 5- (4-methoxyphenyl) 1-2- (3-methylaminophenyl) -1-N- (2-thiazolinyl) imidazole-4-carboxamide is obtained.

Example 1 2 2

2- (3-aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolinyl) imidazole-4-carboxamide was reacted and treated in the same manner as in Example 74 to obtain -(3-Butylaminophenyl) -1-5- (4-methoxyphenyl) -N- (2-thiazolinyl) imidazo-1-yl 4-carboxamide is obtained.

Example 1 2 3

Using 2- (3-aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-l-4-carboxamide, the reaction and treatment were carried out in the same manner as in Example 99. As a result, 5- (4-methoxyphenyl) —2- (3-methylaminophenyl) -N- (2-thiazolyl) imidazo-l-u-l 4-carboxamide is obtained.

Example 1 2 4

2- (3-Aminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-1-yl 4-carboxamide was reacted and treated in the same manner as in Example 74. , 2- (3-butylaminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-l-u- 4-carboxamide Example 1 25

Example 81 5- (4-Ethoxyphenyl) -1-2- (4-nitrophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 1 was treated in the same manner as in Example 85. The desired 2- (4-aminophenyl) -5- (4-ethoxyphenyl) -1-N- (2-thiazolyl) imidazo-1-ru 4-carboxamide is obtained.

Example 1 2 6

Example 1 2- (4-aminophenyl) -1-5- (4-ethoxyphenyl) -1-N- (2 thiazolyl) imidazo-1-ru 4-carboxamide obtained in Example 25 was treated in the same manner as in Example 102. Thus, the desired 2- (4-dimethylaminophenyl) -5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide is obtained.

Example 1 2 7

Example 1 2- (4-Aminophenyl) -1-5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide obtained in 25 was treated in the same manner as in Example 99. This gives the desired 5- (4-ethoxyphenyl) -2- (4-methylaminophenyl) -N- (2-thiazolyl) imidazole-41-carboxamide.

Example 1 2 8

Example 1 2- (4-Aminophenyl) -1-5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazoyl-4 ___________________________________________ Oxide obtained by Example 25 can be converted into By treatment, the desired 2- (4-butylaminophenyl) -1-5- (4-ethoxyphenyl) _N- (2-thiazolyl) imidazole-4-carboxamide is obtained.

Example 1 2 9

Raw material synthesis example 5— (4-Ethoxyphenyl) -12- (3-nitrophenyl) imidazoyl-4 obtained in Example 6-4 (4-Ethoxyphenyl) 1-2- (3-ditrophenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide is obtained.

Example 1 3 0

Example 12 5- (4-ethoxyphenyl) —2- (3-nitrophenyl) —N— (2-thiazolyl) imidazole-41-carboxamide obtained in Example 9 was prepared in the same manner as in Example 85. The desired 2- (3-aminophenyl) -1-5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide is obtained by the treatment. Example 13

Example 13 2- (3-Aminophenyl) -5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide obtained in 30 was treated in the same manner as in Example 102. This gives the desired 2- (3-dimethylaminophenyl) -5- (4-ethoxyphenyl) —N— (2-thiazolyl) imidazole—41-carboxamide.

Example 1 3 2

Example 13 2- (3-aminophenyl) -5- (4-ethoxyphenyl) -1-N- (2-thiazolyl) imidazo-1-ru obtained from 30 is treated with 4-carboxamide in the same manner as in Example 99. This gives the desired 5- (4-ethoxyethoxy)-2- (3-methylaminophenyl) -N- (2-thiazolyl) imidazole- 4-carboxamide. Example 1 3 3

Example 13 2- (3-aminophenyl) -5- (4-ethoxyphenyl) -1-N- (2-thiazolyl) imidazoyl-4 4-carboxamide obtained in 30 is treated in the same manner as in Example 74. This gives the desired 2- (3-butylaminophenyl) -1-5- (4-ethoxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide.

Example 1 3 4

Raw material synthesis example 57 The 5- (3-methoxyphenyl) 1-2- (3-ditrophenyl) imidazole-4-carboxylic acid obtained in 7 is treated in the same manner as in Example 1 to give the desired 5- (3 —Methoxyphenyl) 1 2— (3-Nitrophenyl) 1 N— (2 —Thiazolyl) imidazo-1-ru 41-carboxamide is obtained.

Example 1 3 5

Example 13 The treatment of 5- (3-methoxyphenyl) 1-2- (3-ditrophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide obtained in 34 in the same manner as in Example 85 This gives the desired 2- (3-aminophenyl) -1-5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-1-yl 4-carboxamide.

Example 1 3 6

Example 13 2- (3-Aminophenyl) -15- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in 35 was treated in the same manner as in Example 102. This gives the desired 2- (3-dimethylaminophenyl) -5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide. Example 1 3 7

Example 13 2— (3-Aminophenyl) -1-5 -— (3-methoxyphenyl) -1-N— (2-thiazolyl) imidazolyl-4_carboxamide obtained in 35 was prepared in the same manner as in Example 99. By treatment, the desired 5- (3-methoxyphenyl) -2- (3-methylaminophenyl) -1-N- (2-thiazolyl) imidazo-1-lu-4-carboxamide is obtained.

Example 1 3 8

Example 13 By treating 2— (3-aminophenyl) -1-5- (3-methoxyphenyl) —N— (2-thiazolyl) imidazole-4—carboxamide obtained in 35 in the same manner as in Example 74, The desired 2- (3-butylaminophenyl) — 5- (3-methoxyphenyl) — N— (2-thiazolyl) imidazole—4-carboxamide is obtained. Example 1 3 9

2- (4-aminophenyl) -1-5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazo-1-yl 4-carboxamide was treated in the same manner as in Example 102 to give 5 — (4-chlorophenyl) -1-2- (4-dimethylaminophenyl) -1-N- (2-thiazolyl) imidazo-l-41 to give carboxamide.

Example 1 4 0

2- (4-Aminophenyl) -1-5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide was treated in the same manner as in Example 99 to give 5- (4-1-1 2- (4-Methylaminophenyl) -1-N- (2-thiazolyl) imidazole-1-carboxamide.

Example 1 4 1

2- (4-aminophenyl) -1-5- (4-chlorophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide was treated in the same manner as in Example 74 to give 2- (4-butylaminophenyl). Nil) one 5— (4-chlorophenyl) one N—

(2-Thiazolyl) imidazole-4-carboxamide is obtained.

Example 1 4 2

2- (4-aminophenyl) -1-5- (4-fluorophenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide was treated in the same manner as in Example 102 to give 2- (4- Dimethylaminophenyl) 1-5- (4-fluorophenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide is obtained. Example 1 4 3

2- (4-Aminophenyl) -1-5- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazo-l-u 4-Carboxamide was treated in the same manner as in Example 9-9 to give 5- (4-1-1 Fluorophenyl) -1- (4-methylaminophenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide is obtained.

Example 1 4 4

2- (4-aminophenyl) -1-5- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide was treated in the same manner as in Example 74 to give 2- (4- Butylaminophenyl) — 5— (4-fluorophenyl) —N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide is obtained.

Example 1 4 5

The 5- (4-chlorophenyl) imidazole-4—carboxylic acid is treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2— (3-Nitrophenyl) — N— (2-Thiazolyl) imidazo-l-41

Example 1 4 6

By treating 5- (4-monophenylphenyl) -1- (3-nitrophenyl) -1-N- (2-thiazolyl) imidazo-l-4-carboxamide in the same manner as in Example 85, 2- (3 —Aminophenyl) 1 5— (4-chlorophenyl) 1N— (2 thiazolyl) imidazole-4 1-carboxamide is obtained.

Example 1 4 7

2- (3-Aminophenyl) -1-5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazo-1-yl 4-carboxamide was treated in the same manner as in Example 102 to give 5- (4-Chlorophenyl) 1-2- (3-Dimethylaminophenyl) -1-N- (2-thiazolyl) imidazole- 4-carboxamide is obtained.

Example 1 4 8

2- (3-Aminophenyl) -1-5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide was treated in the same manner as in Example 99 to give 5- (4 1- (3-Methylaminophenyl) -1-N-1- (2-thiazolyl) imidazo-l-u-l 4-carboxamide is obtained.

Example 1 4 9

By treating 2- (3-aminophenyl) -1-5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide in the same manner as in Example 74, 2- (3- Butylaminophenyl) 5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazo-l-41-carboxamide is obtained.

Example 15

By treating 5- (4-fluorophenyl) -12- (3-nitrophenyl) imidazo-1-yl 4-carboxylic acid in the same manner as in Example 1, 5- (4-fluorophenyl) -12- (3-nitrophenyl) 1N- (2-thiazolyl) imidazole 1-41-carboxamide is obtained.

Example 1 5 1

5- (4-Fluorophenyl) -1- (3-ditrophenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide was treated in the same manner as in Example 85 to give 2- (3-Aminophenyl) -1-5- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazo-l-41-carboxamide is obtained.

Example 1 5 2

The 2- (3-aminophenyl) -1- (4-fluorophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide was treated in the same manner as in Example 102 to give 5- (4 —Fluorophenyl) -1- (3-dimethylaminophenyl) -1-N— (2-thiazolyl) imidazole—4-carboxamide is obtained.

The 2- (3-aminophenyl) -1- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide was treated in the same manner as in Example 99 to give 5- ( 4-Fluorophenyl) -1- (3-methylaminophenyl) -N- (2-thiazolyl) imidazole- 4-carboxamide is obtained.

Example 1 5 4

2- (3-Aminophenyl) -1-5- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide was treated in the same manner as in Example 74 to give 2- (3-butyl (Aminophenyl) -1-5- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazo-l-41-carboxamide is obtained.

Example 1 5 5

1.8 g of 5- (3-methoxyphenyl) —2- (4-nitrophenyl) —N— (2-thiazolyl) imidazole—4-carboxamide obtained in Example 80 was obtained in the same manner as in Example 85. Thus, 1.3 g of the desired 2- (4-aminofuunyl) -5- (3-methoxyphenyl) -1-N- (2-thiazolyl) imidazoyl-41-carboxamide was obtained. Melting point 2 6 2— 2 6 3

Example 1 5 6

Example 15 0.4-g of 2- (4-aminophenyl) -1-5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-1-ru 4-carboxamide obtained in 55 was used as in Example 99. In the same manner, 0.32 g of the desired 5- (3-methoxyphenyl) -2- (4-methylaminophenyl) -1-N- (2-thiazolyl) imidazole-1-carboxamide is obtained. Obtained. Melting point 2 4 8—2 5 1 (hydrochloride) Example 1 5 7

Example 1 0.8 g of 2- (4-aminophenyl) -15- (3-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide obtained in 55 was added to Example 74. The desired 2- (4-butylaminophenyl) -5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-u-l 4-carboxamide can be obtained by treating in the same manner as described above. 8 g were obtained. Melting point 2 28—2 3 IX) (Hydrochloride) Example 15 8

Example 15 2- (4-Aminophenyl) -5- (3-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide obtained in Example 5 was obtained in the same manner as in Example 102. By treatment, the desired 2- (4-dimethylaminophenyl) -1- (3-methoxyphenyl) -N- (2-thiazolyl) imidazole-4-carboxamide is obtained.

Example 1 5 9

5- (4-Methoxyphenyl) —2- (4-nitrophenyl) -1-N— (2-thiazolyl) imidazo-l-u- 4-carboxamide obtained in Example 4 7 2.1 g of dichloromethane 21 OmI And 3 ml of boron tribromide was added thereto, followed by stirring all day and night. The reaction solution was poured into cold water, and the precipitated crystals were collected by filtration. 5- (4-Hydroxyphenyl) -2- (4-trophenyl) -1-N- (2-thiazolyl) imidazo-l-4-carboxamide 1.7 g was obtained.

Mp 2 5 0 or more hydrochloride - NMR 2 7 0 MHz (DMSO- d 6, p pm) δ: 6. 9 0 (2 H, d), 7. 2 8 (1 H, d), 7. 56 (1H, d), 7.75 (2H, d), 8.38 (2H, d), 8.47 (2H, d)

The reaction was carried out in the same manner as in Example 22 using 2-hydroxyimino 3- (4-methoxyphenyl) -ethyl 3-oxopropionate, 4-benzyloxybenzaldehyde, and ammonium acetate to give 2- ( 4—benzylo Xyphenyl) — 5— (4-Methoxyphenyl) imidazole—4 is obtained. 2- (4-benzyloxyphenyl) — 5- (4-methoxyphenyl) imidazole-4 Xyphenyl) -5- (4-Methoxyphenyl) Imidazo-l- 4-carboxylic acid is obtained. 2- (4-Benzyloxyphenyl) -1-5- (4-methoxyphenyl) imidazoyl 4-carboxylic acid was reacted and treated in the same manner as in Example 1 to give 2- (4-benzyloxyphenyl). Phenyl) 1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-l-u- 4-carboxamide is obtained.

Example 16 1

2- (4-Benzyloxyphenyl) -1-5- (4-Methoxyphenyl) -N- (2-thiazolyl) imidazole-4 By reacting 1-carboxamide in the same manner as in Example 23, 2 — (4-Hydroxyphenyl) -5— (4-methoxyphenyl) — N— (2—thiazolyl) imidazole—to obtain 4-butane lipoxamide Example 16 2

2- (4-Hydroxyphenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-l 4- 4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine, gediazocarboxylate The ester was treated with the ester in the same manner as in Example 24 to give 2- (4- (2-dimethylaminoethyloxy) phenyl) -5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo- Roux 4-carboxamide is obtained.

Example 1 6 3

The reaction was carried out in the same manner as in Example 22 using 3- (4-chlorophenyl) -1-hydroxyimino 3-ethylpropionate 3-oxopropionate, 4-benzyloxybenzaldehyde, and ammonium acetate. 4-Benzyloxyphenyl-1-5- (4-chlorophenyl) Imidazo-l-lu4 Ethyl rubonic acid ethyl ester is obtained. 2- (4-Benzyloxyphenyl) —5- (4-chlorophenyl) imidazo-l-uyl 4-butyric ester of ribonate is treated in the same manner as in Raw Material Synthesis Example 2 to give 2- (4-benzylo-phenyl). Xyphenyl) -1-5- (4-chlorophenyl) imidazo-1-yl 4-carboxylic acid is obtained. twenty four- Benzyloxyphenyl) 5- (4-chlorophenyl) imidazo-l- 4-force By reacting rubonic acid in the same manner as in Example 1, 2- (4-benzyloxyphenyl) -5- (4— Chlorophenyl) -N- (2-thiazolyl) imidazo-Ru 4-carboxamide is obtained.

Example 1 6 4

2- (4-Benzyloxyphenyl) -5- (4-chlorophenyl) 1-N- (2-thiazolyl) imidazole-4 Carboxamide was treated in the same manner as in Example 23 to give 5 — (4-Chlorophenyl) -1-2- (4-hydroxyphenyl) -1-N— (2-thiazolyl) imidazo-l-u 4- 4-carboxamide is obtained. Example 1 6 5

5- (4-chlorophenyl) 1-2- (4-hydroxyphenyl) -1- (2-thiazolyl) imidazo-l 4- 4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine, azodicarboxylic acid Using getyl ester, The reaction was carried out in the same manner as in Example 24 to give 5- (4-chlorophenyl) -12- (4- (2-dimethylaminoethyloxy) phenyl) -1-N- (2-thiazolyl) imidazoyl Carboxamide is obtained.

Example 1 6 6

The reaction was carried out in the same manner as in Example 22 using 2- (4-fluorophenyl) -12-hydroxyimino-13-oxopropionic acid ethyl ester, 4-benzyloxybenzaldehyde, and ammonium acetate. — (4-Benzyloxyphenyl) — 5 -— (4-Fluorophenyl) imidazoyl 4-ethyl ether ester By reacting 2- (4-benzyloxyphenyl) -5- (4-fluorophenyl) imidazole-4-ethyl carboxylate in the same manner as in Synthesis Example 2, 2- (4-benzyloxyphenyl) Oxyphenyl) — 5- (4-fluorophenyl) imidazo-l--4-carboxylic acid is obtained. 2- (4-Benzyloxyphenyl) -1- (4-fluorophenyl) imidazo-l 4-carboxylic acid is treated in the same manner as in Example 1 to give 2- (4-benzyloxyphenyl). Nyl) — 5— (4-Fluorophenyl) -N- (2-thiazolyl) imidazo-l-u- 4-carboxamide is obtained.

Example 1 6 7

2- (4-Benzyloxyphenyl) -1- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide was subjected to a reaction treatment in the same manner as in Example 23. Gives 5- (4-fluorophenyl) -1- (4-hydroxyphenyl) -N- (2-thiazolyl) imidazole-41-carboxamide

0

Example 1 6 8

5- (4-fluorophenyl) -2- (4-hydroxyphenyl) mono- (2-thiazolyl) imidazole—4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine, acetyldicarboxylate The reaction was carried out in the same manner as in Example 24 to give 5- (4-fluorophenyl) -12- (4- (2-dimethylaminoethyloxy) phenyl) -1- (2-thiazolyl) imidazo One roux 4-carboxamide is obtained.

Example 1 6 9

2- (4-hydroxyphenyl) -1-5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine, azodicarboxylic acid The reaction was carried out in the same manner as in Example 24 using the tyl ester to give 2- (4- (2-dimethylaminoethyloxy) phenyl) -15- (4-methylphenyl) -N- (2-thiazolyl) This gives 41-carboxamide.

Example 1 7 0

2- (4-hydroxyphenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide, 2-hydroxyethyl acetate, triphenylphosphine, acetyldicarboxylate The reaction was carried out in the same manner as in Example 24 to give 2- (4- (2-acetoxy-shethyloxy) phenyl) -5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole 4—Produces lipoxamide.

Example 1 7 1

2- (4- (2-acetoxitytyloxy) phenyl) — 5— (4-methoxyphenyl) —N— (2-thiazolyl) imidazo-l-u 4-carboxamide with sodium hydroxide Hydrolysis yields 2- (4-(2-hydroxyethyloxy) phenyl) -1-5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-uyl 4-carboxamide.

Example 1 7 2

5- (4-chlorophenyl) 1-2- (4-hydroxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide, 2-hydroxyethyl acetate, triphenylphosphine, azodicarboxylic acid The reaction was carried out in the same manner as in Example 24 using getyl ester to give 2- (4- (2-acetoxyethyloxy) phenyl) -5- (4-chlorophenyl) -1-N- (2-thiazolyl) B) Imidazole-4-carboxamide is obtained.

Example 1 7 3

2- (4- (2-acetoxitytyloxy) phenyl) -5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazole-4 When carboxamide is hydrolyzed with sodium hydroxide, 5 — (4-Chlorophenyl) — 2- (4- (2-Hydroxyethyloxy) phenyl) N- (2-thiazolyl) imidazole— 4-carboxamide.

Example 1 7 4

5- (4-fluorophenyl)-2- (4-hydroxyphenyl) -N- (2-thiazolyl) imidazole- 4-carboxamide, acetic acid 2-hydroxyethyl ester, triphenylphosphine, azodicarboxylic acid getyl ester The reaction was carried out in the same manner as in Example 24 to give 2- (4- (2-acetoxy shetyloxy) phenyl) -1-5- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazole- 4--Carboxamide is obtained.

Example 1 7 5

2- (4-(2-acetoxitytyloxy) phenyl) -1-5- (4-fluorophenyl) -1-N- (2-thiazolyl) imidazo-l-41-Carboxamide hydrolyzed with sodium hydroxide When decomposed, 5- (4-fluorophenyl) — 2- (4- (2-hydroxyethyloxy) phenyl) — N— (2-thiazolyl) imidazo-l-u-l 4-hexylpoxamide is obtained.

Example 1 7 6

Using 2-hydroxyimino 1-3- (4-methoxyphenyl) -13-oxopropionate ethyl ester and 4- (1-pyrrolidinyl) benzylamine, the raw material was reacted in the same manner as in Synthesis Example 1 to give 5- (4-Methoxyphenyl) — 2- (4- (1-Pyrrolidinyl) phenyl) imidazole-4 One-strength ribonate is obtained. 5- (4-Methoxyphenyl) 1-2- (4- (1-pyrrolidinyl) phenyl) imidazole-4 monoethyl ribonate was treated in the same manner as in Synthesis Example 2 of the raw material to give the 5- (4-methyphenyl). Toxiphenyl) — 2— (4--(1-pyrrolidinyl) phenyl) imidazo-l-u-l 4-obtained rubonic acid. 5- (4-Methoxyphenyl) 1-2- (4- (1-pyrrolidinyl) phenyl) imidazo-1-yl 4-carboxylic acid was treated in the same manner as in Example 1 to give 5- (4-methoxyphenyl). 1) 2- (4- (1-pyrrolidinyl) phenyl) 1-N- (2-thiazolyl) imidazo-1-yl 4-carboxamide is obtained.

Example 1 7 7

Using 3- (4-chlorophenyl) 1-2-hydroxyimino 3-ethylpropionate ethyl ester and 4- (1-pyrrolidinyl) benzylamine, the reaction was carried out in the same manner as in Raw Material Synthesis Example 1 to give 5- (4 1-chlorophenyl) 2- (4- (1-Pyrrolidinyl) phenyl) imidazoyl 4-ethyl ether ester is obtained. 5- (4-chlorophenyl) — 2- (4- (1-pyrrolidinyl) phenyl) imidazole — 4-carboxylic acid ester 2- (4- (1-Pyrrolidinyl) phenyl) imidazo-l-u-l 4-obtained rubonic acid. 5- (4-Chlorophenyl) -1-2- (4- (1-pyrrolidinyl) phenyl) imidazo-ru 4 By reacting the monocarboxylic acid in the same manner as in Example 1, 5- (4-chlorophenyl) 1-2- (4- (1-Pyrrolidinyl) phenyl) — N— (2-thiazolyl) imidazo-l-u-l 4-carboxamide is obtained.

Example 1 7 8

Using 3- (4-fluorofluoro) ethyl 2-hydroxyimino 3-oxopropionic acid ethyl ester and 4- (1-pyrrolidinyl) benzylamine, the raw material was treated in the same manner as in Synthesis Example 1 to give 5- (4-fluoro Phenyl) 1- (4- (1-pyrrolidinyl) phenyl) imidazole-4-ethyl carboxylate is obtained. 5- (4-Fluorophenyl) -2- (4- (1-pyrrolidinyl) phenyl) imidazo-l-uyl 4-carboxylate ) — 2— (4- (1-Pyrrolidinyl) phenyl) Imidazo-l- (4-)-Rubonic acid is obtained. 5- (4-Fluorophenyl) -1-2- (4- (1-pyrrolidinyl) phenyl) imidazo-1-yl 4-hydrofuronic acid is treated in the same manner as in Example 1 to give 5- (4-fluorophenyl). 2- (4- (1-Pyrrolidinyl) phenyl) 1-N- (2-Thiazolyl) imidazo-l-l 4-carboxamide is obtained.

Example 1 7 9

2-hydroxyimino-3- (4-methylphenyl) -1-oxopropion The reaction was carried out in the same manner as in Synthesis Example 1 of the starting material using an acid ester and 4- (1-pyrrolidinyl) benzylamine to give 5- (4-methylphenyl) 1-2- (4- (1-pyrrolidinyl) phenyl) imidazo Lou 4 Obtains rutile acid ester. 5- (4-Methylphenyl) -1-2- (4- (1-pyrrolidinyl) phenyl) imidazoyl-4-carboxylic acid ester is treated in the same manner as in Raw Material Synthesis Example 2 to give 5- (4-methylphenyl). 1) 2- (4- (1-Pyrrolidinyl) phenyl) Imidazo-l-ul 4-Rubonic acid is obtained. 5- (4-Methylphenyl) -2- (4- (1-Pyrrolidinyl) phenyl) imidazo-Ru 4-Carboxylic acid is treated in the same manner as in Example 1 to give 5- (4-Methylphenyl) 1-2- (4- (1-pyrrolidinyl) phenyl) 1 N-(2-thiazolyl) imidazo-1-4-carboxamide is obtained.

Example 1 8 0

2- (4-hydroxyphenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenylphosphine, azodicarboxylic acid The reaction was carried out in the same manner as in Example 24 using the tyl ester to give 2- (4- (3-dimethylaminopropyloxy) phenyl) -1-5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazo One liter of 4-carboxamide is obtained.

Example 18 1

5- (4-chlorophenyl) 1-2- (4-hydroxyphenyl) -1-N- (2-thiazolyl) imidazo-l-41-carboxamide, 3-dimethylaminopropanol, triphenylphosphine The reaction was carried out in the same manner as in Example 24 using dimethyl diazolate and azodicarboxylic acid, to give 5- (4-chlorophenyl) 121 (4-1 (3-dimethylaminopropyloxy) phenyl) 1N— (2-thiazolyl) imidazo-l-41-carboxamidoca is obtained.

Example 1 8 2

5- (4-fluorophenyl) 1-2- (4-hydroxyphenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenylphosphine, azodicarbon The reaction was carried out in the same manner as in Example 24 using getyl acid acetic acid to give 5- (4-fluorophenyl) -2- (4- (3-dimethylaminopropyloxy) phenyl) 1 N— (2 —Tizazolyl) Imidazo-l-41-carboxamide is obtained.

Example 1 8 3

2- (4-hydroxyphenyl) -1-5- (4-methylphenyl) -1-N- (2-thiazolyl) imidazo-l-41-carboxamide, 3-dimethylaminopropanol, triphenylphosphine, azodicarboxylic acid The reaction was carried out in the same manner as in Example 24 using getyl ester to give 2- (4- (3-dimethylaminopropyloxy) phenyl) -1-5- (4-methylphenyl) -N- (2-thiazolyl) imidazo- This gives 4-carboxamide.

Hereinafter, the effects of the present invention will be described in detail with reference to experimental examples.

Experimental Example 1 Effects on IL-14 and IL-5 production from mouse Th2 cell line 1. Experimental method

1) Preparation of test substance

The test substance at dimethylsulfoxide id, dissolved so as to 1 Omm, final concentration ^10-5 and diluted with culture land - was 10 ⁷ M.

2) Th2 cell line

D 10. G4.1 was used as the Th2 cell line. D 10. G 4. 1 recognizes the antigen cona 1 b urn in the restricted I- Alpha ^kappa.

3) Medium

Inactivated fetal bovine serum was added to RPMI 1640 medium at 10%, and 2-mercaptoethanol was added to 50 M for use.

4) Preparation of antigen-presenting cells

6- to 12-week-old male C 3H / HeN mice are bled to death and the spleen is aseptically removed. Then, a spleen cell suspension was prepared. Mitomycin C was added to a final concentration of 40 // g / ml and incubated at 37T; for 30 minutes. Thereafter, the spleen cells were washed twice with the medium and used as antigen-presenting cells.

5) Measurement of IL-4 and IL-5 produced from Th2 cell line

2 X 10 the Th 2 cell line per Uweru in 96-well plates ^4, antigen presenting cells ^{lxl 0 5, c ona l bumi} n by adding 100〃G / ml and the test substance, C0 ₂ incubator one 2 Cultured for days. After culturing, 1001 supernatant was collected from each well. The concentrations of IL-4 and IL-5 in the supernatant were measured by a sandwich ELISA method.

2. Result

The effects on IL-14 and IL-15 production are shown in Table 1. Representative compounds included in this patent inhibited IL-4 production at around 1M and IL-5 at an IC50 of around 0.5M.

Table 1 Inhibition of IL-4 and IL-5 production from Th2 clones

I nh i b i t i on

I Cso (M)

I L- 4 I L- 5

Compound of Example 1 0.91 0.33

Compound of Example 47 2.98 0.69

Compound of Example 70 3.77 0.44

Compound of Example 79 0.7 1 0.16 Experimental Example 2 Effect on ovalbumin (OA) -induced mouse biphasic ear edema model 1. Experimental method

1) Preparation of test substance

The test substance was suspended in a 0.5% hydroxypropylmethylcellulose (HPMC) solution so as to be 0.1 ml per 10 g body weight.

2) Experimental procedure

0.5 ml of a physiological saline solution containing 10 ig of 0A and 1 mg of aluminum hydroxide gel was intraperitoneally administered to 7-week-old male BALBZc mice to actively sensitize. On the 14th day after the sensitization, 5 βg of OA was intradermally administered to the auricle to perform antigen challenge. The thickness of the auricle before and after the antigen challenge and at 1 and 24 hours after the antigen challenge was measured with a dial thickness gauge, and the change in the thickness of the auricle was calculated by the following equation.

Increased pinna thickness

== Thickness of the auricle after intradermal administration of antigen -Thickness of auricle before intradermal administration of antigen The test substance was orally administered daily for 3 days from 2 days before the antigen challenge to the day of the antigen challenge.

Result

The effect of the compound of Example 1 on swelling of the pinna during the late phase (24 hours after antigen challenge) is shown in FIG. The compound of Example 1 significantly suppressed the late-stage edema mainly involving T cells and eosinophils at a dose of 1 Omg / kg.

Experimental Example 3 Auricle in OA-induced mouse biphasic ear edema model

Effects on Eo s i noph i l p e r ox i da s e (E PO) activity

1. Experimental method

1) Preparation of test substance

The test substance was used by suspending it in a 0.5% hydroxypropylmethylcellulose (HPMC) solution to a concentration of 0.1 ml per 10 g body weight.

2) Experimental procedure

Contains 10 μg of egg A albumin (OA) and lmg of aluminum hydroxide gel 0.5 ml of physiological saline was intraperitoneally administered to 7-week-old male B ALB-noc mice for active sensitization. On the 14th day, 5 g of OA was intradermally administered to the pinna, and antigen challenge was performed. The test substance was orally administered every day for three days from the day before the antigen challenge to the day of the antigen challenge. The mice were bled to death 12 hours after the antigen challenge, and the pinna was removed. The minced ear tissue was minced and homogenized in 1 ml of 5 OmM Tris-HCl buffer (pH 8.0) containing 0.5% hexadecyltrimethylammonium bromide. The homogenized suspension was centrifuged at 3000 rpm for 15 minutes, and the supernatant was collected. EPO activity in the supernatant was measured using 0-phenylenediamine (OPD) as a substrate. FIG. 2 shows the effects of the compounds of Example 79 and Example 99 on increasing the auricular EP0 activity. The compound of Example 79 was 1 OmgZkg, and the compound of Example 99 significantly inhibited the increase in EP0 activity in the auricle from 3 mg kg.

Experimental Example 4 Mouse 0 A-induced airway inflammation model

1. Experimental method

1) Preparation of test substance

The test substance was suspended in a 0.5% hydroxypropylmethylcellulose (HPMC) solution so as to be 0.1 ml per body weight and used.

2) Experimental procedure

Actively sensitized 7-week-old male BAL B / c mice by intraperitoneal administration of 0.5 ml of saline containing 10 g of OA and lmg of aluminum hydroxide gel on days 1 and 15 did. On day 2 „5, 29 and 33, a physiological saline solution 50/1 containing 1 g of OA was administered into the airway.Bronchoalveolar lavage was performed 2.4 hours after the last airway administration, and bronchoalveolar lavage fluid ( The total leukocyte count in the BALF was measured with an automatic hemocytometer, and a BASF site spin sample was prepared, and after diff-Quick staining, the percentage of eosinophils was calculated by microscopy. The eosinophil count in BALF was calculated from the total leukocyte count and the ratio of eosinophils. The test substance was orally administered every day for 10 days from day 24 to day 33.

Experimental example 50 A induced mouse nasal allergic model

1. Experimental method

1) Preparation of test substance

The test substance was used by suspending it in a 0.5% hydroxypropylmethylcellulose (HPMC) solution so as to be 0.1 ml per 10 g body weight.

2) Experimental procedure

Active sensitization of 7-week-old male BALB / c mice by intraperitoneal administration of 0.5 ml of saline containing OA5 / g and lmg of aluminum hydroxide gel on days 1 and 15 did. Mice were instilled with 20 μl of a 2 mg Zm 1 OA solution every other day for a total of eight times from day 22. After the last nasal instillation on day 36, the number of sneezes for 10 minutes was measured. Also, 24 hours after the last nasal drip, the airway of the mouse was incised under deep anesthesia, a catheter was inserted into the nasal cavity side, and the nasal cavity was washed with 3 ml of a phosphate buffer solution containing 0.5% BSA. The total leukocyte count in the lavage fluid was measured with an automatic hemocytometer. In addition, a site spin specimen of nasal washings was prepared, and after Diff-Quick staining, the ratio of eosinophils was calculated by microscopy. The eosinophil count in BALF was calculated from the total leukocyte count and the ratio of eosinophils.

The test substance was orally administered every day for 8 days from the 29th to 36th days.

Industrial applicability

The compound of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof inhibit the production of IL-4 and IL-5 produced from Th2 cells, and produce atopic dermatitis, bronchial asthma, Effective as a preventive and remedy for allergic diseases such as rhinitis rhinitis

I? Confuse. This application is based on Japanese Patent Application No. 359671 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

1. General formula (I)

R ³ represents an optionally substituted heteroaryl group,

Provided that R ¹ is hydrogen, R ² is a phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group, and R ⁴ is a phenyl group or a halogen atom, a lower alkyl group; When it is a phenyl group substituted with a group or a lower alkoxy group, R ^{3 is a} benzothiazolyl group or a thiazolyl group substituted with a phenyl group. )

Or a pharmaceutically acceptable salt thereof.

2. General formula (I)

(I)

R ³ represents an optionally substituted heteroaryl group,

Or a pharmaceutically acceptable salt thereof.

3 — R ^{1 in the} general formula (I) represents hydrogen,

R ² is a nitro group, an amino group, a monoalkylamino group, a dialkylamino group, an acylamino group, a dialkylaminoalkylamino group, an acyloxyalkylcarbonylamino group, a dialkylaminoalkoxy group, an acyloxyalkoxy group, It may be substituted with a hydroxyalkoxy group or a lower alkyl group having 1 to 6 carbon atoms, and may contain an oxygen atom.Saturated containing 1 to 2 nitrogen atoms 5 or

R ³ represents a heteroaryl group which may be substituted, wherein R represents a substituted or unsubstituted heteroaryl group;

2. The imidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ is a phenyl group which may be substituted.

4. R ^{1 in the} general formula (I) represents hydrogen, R ² represents a naphthyl group which may be substituted,

R ³ represents a heteroaryl group which may be substituted,

5.5- (4-Methylphenyl) — 2 -— (1-naphthyl) — N— (2-thiazolyl) imidazole—41-carboxamide,

5— (4-Methoxyphenyl) 1 2— (4-Trophenyl) 1N— (2-Thiazolyl) imidazo 1-Lu 4-Carboxamide,

5- (4-Methoxyphenyl) 1 2- (4-Methylaminophenyl) N- (2-Thiazolyl) imidazole-1 41-box ruboxamide,

2- (4-butylaminophenyl) -1-5- (4-methoxyphenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide,

2- (3-dimethylaminophenyl) -1-5- (4-methoxyphenyl) -1-N- (2-thiazolyl) imidazo-l-5-potassium

2- (4-butylaminophenyl) -1-5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazo-1-yl 4-carboxamide,

5- (4-chlorophenyl) _2- (4-methylaminophenyl) -N- (2-thiazolyl) imidazole-4-carboxamide,

5- (4-chlorophenyl) -1-2- (4-nitrophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide,

5-(4-(1-pyrrolidinyl) phenyl) 1 N

-(2-thiazolyl) imidazo-l 4- 4-carboxamide,

5- (4-chlorophenyl) 1-2- (4- (2-dimethylaminoethyloxy) phenyl) -N- (2-thiazolyl) imidazo-1-yl 4-carboxamide,

5- (4-chlorophenyl) 1 2— (4- (3-dimethylaminopropyloxy)

) Phenyl) — N_ (2-thiazolyl) imidazoyl 4-carboxamide and 5- (4-chlorophenyl) -1-2- (4-1- (2-hydroxyhydroxy) phenyl) -N- (2-thiazolyl) imidazo-l-4 1-carboxamide Is the imidazole derivative described in the item or its pharmacologically acceptable? So

6. A pharmaceutical composition comprising a therapeutically effective amount of the imidazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and a pharmaceutically acceptable additive.

7. A selective inhibitor of int-leukin 4 and int-leukin 5 containing the imidazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

8. An antiallergic agent containing the imidazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.