WO2000078758A1 - Novel imidazole derivatives - Google Patents

Abstract

Novel imidazole derivatives represented by general formula (I); pharmacologically acceptable salts thereof; and drug compositions containing the derivatives or the salts [wherein R1 is optionally substituted phenyl or heteroaryl; and R2 is phenyl substituted with one or two members which may be the same or different from each other and are selected from the group consisting of cyano, substituted alkyl, optionally substituted six- or seven-membered saturated heteromonocycle groups which each contain one or two nitrogen atoms and may additionally contain O or S, spiro-ring groups each composed of two optionally substituted six- or seven-membered saturated heteromonocycles which each contain one to three nitrogen atoms, are the same or different from each other, and may additionally contain O or S, and groups represented by the general formula (II) -(O-(CH2)1)m-O-(CH2)nCH3 (wherein l and m are each an integer of 1 to 4; n is an integer of 0 to 3; and the alkyl chain moiety may be substituted)]. These compounds exhibit inhibitory activities against the production of IL-4 and IL-5 by Th2 cells and are thus useful as preventive and/or therapeutic drugs for allergic diseases.

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-5) from evening eve 2 helper T cells (hereinafter abbreviated as Th2 cells). The present invention relates to a novel imidazole derivative and a pharmaceutically acceptable salt thereof which are useful for the prevention and treatment of allergic diseases.

 Background art

 Helper T cells are classified into Th1 and Th2, depending on the difference in the cytokine they produce. Th1 cells produce cytokins such as inulin-leukin 2 (hereinafter, IL_2) and interferon-I (hereafter, IFN-α) and mainly regulate cell-mediated immunity. On the other hand, Th2 cells produce cytokines such as IL-14, IL-5, and IL-1 leukin 10 (hereinafter IL-10), and mainly regulate humoral immunity. The immune response is regulated by the balance between Th1 and Th2 cells, and IFN-y produced by Th1 cells promotes differentiation into Th1 cells and inhibits differentiation into Th2 cells . In addition, IL-4 produced by Th2 cells promotes differentiation into Th2 cells and inhibits differentiation into Th1 cells.

 In recent years, it has been revealed that various immune diseases are caused by the disruption of the Th1 / Th2 cell balance. 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 immunological diseases.

Among the cytokines produced by Th2 cells, IL-4 acts on immunoglobulin E (IgE) such as class switching and differentiation into Th2 cells, and IL-5 acts on eosinophils. It has been suggested that it is deeply involved in the pathogenesis of allergies in particular. In fact, high levels of IL-4 and IL-15 were shown in bronchoalveolar lavage fluid of asthmatic patients, and mRNAs of IL-4 and IL-5 were found in the rash of patients with arthritis dermatitis. Are reported to exist (Am. J. Respir. Cell MoI. Biol., Vol. 12, pp. 477-487, 1995, J. Immunol., Vol. 158, p. p. 3539-3544 and J. Exp. Med., Vol. 173, p. 775-778, 1991).

 In addition, it has been reported that various allergic reactions are unlikely to occur in mice deficient in the IL-4 or IL-15 genes (Nature, Vol. 362, pp. 245-247, 1 993 and J. Ep. Med., Vol. 183, .195-201, 19996). In addition, it has been reported that administration of anti-IL-15 antibody strongly suppresses eosinophil infiltration in various animal models including airway inflammation models in monkeys (Am. J. Respir. rit. Care Med., Vol. 152,. 467-472, 1995).

 Thus, it has been clarified that IL-14 or IL-5 is involved in the development of allergic disease in animal models of allergic disease.

 Therefore, 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 may 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 inhibits the production of IL-4 and IL-5 from Th2 cells. No effect is described.

 A recently developed subratose tosylate (IPD-115T) has an inhibitory effect on the specific production of IL-14 and IL-5 from Th2 cells, Clinical results have been reported to be effective against inflammation (Clinical Medicine, Vol. 8, No. 7, 19992). However, the inhibitory effect of IFD-1 11 1 on 11 ^ -4 and 11 ^ -5 is not so strong, and it shows the inhibitory effect of IL-14 and IL-5 production in clinical fi It is not clear if they do.

At present, steroids are widely used as therapeutic agents for allergic diseases and have shown high clinical effects. Steroids produce IL-5 in a wide range of actions It has Pfl harmful effects, and its inhibitory effect on IL-15 production is considered to be a mechanism of eosinophilic inflammation suppression.

 However, side effects of steroids are problematic due to their wide-ranging effects. In addition, recent studies suggest that immunosuppressants such as cyclosporin A and evening limus 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-12 as well as IL-5. .

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

 Compounds that have a specific inhibitory effect on the production of IL-14 and IL-5 can improve the bias toward Th2 cells in allergic patients and suppress eosinophilic inflammation, and It is expected to be a useful drug for the prevention and treatment of allergic diseases such as atherosclerotic dermatitis, bronchial asthma, and allergic flare, which have relatively few side effects.

 The purpose 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 allergic diseases, 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-mentioned pathological conditions. As a result, the novel imidazole compound represented by the following general formula (I) and a pharmaceutically acceptable salt thereof have excellent IL-4 and IL The present inventors have found that they have a production inhibitory activity of 5, and are useful as preventive and therapeutic agents for allergic diseases, and have completed the present invention.

 That is, the present invention is as follows.

(1) General formula (I)

(Wherein, R ¹ represents an optionally substituted phenyl group or an optionally substituted heteroaryl group,

R ² is a cyano group, a substituted alkyl group, a substituted or unsubstituted oxygen atom or a saturated 6 or 7 ring heterocycle containing 1 or 2 nitrogen atoms, which may contain a sulfur atom; A monocyclic group, which may be substituted or may contain an oxygen atom or may contain a sulfur atom, may be the same or different and may contain 1 to 3 nitrogen atoms, and two saturated 6 or 7 members Subiro ring group consisting of a ring heteromonocycle, and formula (II)

-(0-(CH ₂ ) 1) _m -〇-1 (CH ₂ ) _n CH ₃ (II)

 (Wherein 1, m is an integer of 1 to 4, n is an integer of 0 to 3, and the alkyl chain part may be substituted.) The same or different groups selected from the group consisting of Represents a phenyl group substituted by one or two groups. ) Or a pharmaceutically acceptable salt thereof (hereinafter also referred to as compound (I)).

(2) In the general formula (I), R ¹ is an optionally substituted phenyl or an optionally substituted heteroaryl group,

R ² is a cyano group, a substituted alkyl group, a saturated 6 or 7 H ring heteromonocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom, And formula (II)

-(0-(CH ₂ ) 1) _m -〇-(CH ₂ ) _n CH ₃ (Π)

(Wherein 1, m is an integer of 1 to 4, n is an integer of 0 to 3, and the alkyl chain part may be substituted.) The same or different groups selected from the group consisting of The imidazole derivative according to the above (1), which is a phenyl group substituted by one or two groups, or a pharmaceutically acceptable salt thereof.

(3) —In the general formula (I), R ¹ is a phenyl group substituted by one group selected from the group consisting of a halogen atom and a methyl group, and R ² is an ft-substituted alkyl group, A saturated 6 or 7 m-ring heteromonocyclic group containing 1 or 2 nitrogen atoms, which may contain an oxygen atom or a sulfur atom, and a compound of the formula (III)

-0- (CH ₂ ) 1-0- (CH ₂ ) _n CH ₃ (III)

 (Where 1 is an integer of 1 to 4, n is an integer of 0 to 3, and the alkyl chain portion may be substituted.) By one group selected from the group consisting of The imidazole derivative according to the above (1), which is a substituted phenyl group, or a pharmaceutically acceptable salt thereof.

(4) In the general formula (I), R ¹ is a phenyl group substituted by one group selected from the group consisting of a halogen atom and a methyl group, and R ² is a trifluoromethyl group, a morpholino group, and a morpholinomethyl group. , 41- (dimethylaminomethyl) bipyridine-1-yl group, and formula (III)

-0- (CH ₂ ) 1-0- (CH ₂ ) _n CH ₃ (III)

 Wherein 1 is an integer of 1 to 4 and n is an integer of 0 to 3. The above-mentioned (1) is a phenyl group substituted by one group selected from the group consisting of groups represented by d) The imidazole 'derivative described in d or a pharmaceutically acceptable salt thereof.

(5) In the general formula (I), R ¹ is a phenyl group substituted by one group selected from the group consisting of a halogen atom and a methyl group, and R ² may be a masked oxygen atom or A phenyl group substituted by a spiro ring group consisting of two saturated 6- or 7-membered ring complexes which may be the same or different and may contain 1 to 3 nitrogen atoms which may contain a sulfur atom Or the pharmaceutically acceptable salt thereof according to the above (1).

(6) 5- (4-chlorophenyl) -1-2- (4-morpholinophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide, 5- (4-fluorophenyl) -1-2- (4-morpholinofinyl) -1-N— (2-thiazolyl) imidazo-l-41-carboxamide,

 5- (4-chlorophenyl) 1-2- [4-1 (morpholinomethyl) phenyl] 1 N-1 (2-thiazolyl) imidazole-4-carboxamide,

 5-(4- (2-methylethoxy) phenyl)

-N- (2-thiazolyl) imidazole-4-carboxamide,

 5- (4-fluorophenyl) -1-2- (4-1- (2-methoxyphenyl) phenyl)

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

 5- (4-methylphenyl) -1-N- (2-thiazolyl) -1-2- (4-trimethylfuromethylphenyl) imidazole-41-carboxamide,

 5- (4-fluorophenyl) -1-N- (2-thiazolyl) -1-2- (4-trifluoromethylphenyl) imidazole-4-carboxamide,

 5- (4-chlorophenyl) -N- (2-thiazolyl) -1- (4-trifluoromethylphenyl) imidazole- 4 _carboxamide and

 5- (4-phenylphenyl) -1-2- (4- [4- (dimethylaminomethyl) bilyzin-1-yl] phenyl] -N- (2-thiazolyl) imidazole-4 lipoxamide

The imigzol derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (4), which is selected from the group consisting of:

 (7) 5— (4-methyl phenyl) 1 2— [4- (4-methyl-1-oxa 1,4,9—diazasbiro [5,5] indecan 1-9-1) phenyl) — N— (2— (Thiazolyl) imidazole-41-carboxamide, the imidazole derivative according to the above (1) or (5) or a pharmacologically acceptable salt thereof.

 (8) A therapeutically effective amount of the imidazole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (7) above and a pharmaceutically acceptable additive! Composition.

(9) The imidazole derivative or the imidazole derivative according to any one of (1) to (7) above An interleukin 4 and an interleukin 5 selective production inhibitor containing a commercially acceptable salt.

 (10) An antiallergic agent comprising the imidazole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (7).

 (11) The antiallergic agent according to the above (10), which is used in combination with a steroid agent.

 BRIEF DESCRIPTION OF THE FIGURES

 Figure 1 shows the auricular region of the compound in Examples 1 and 16 in the late phase (24 hours after antigen challenge) in the ovalbumin (OA) -induced mouse biphasic ear edema model of Experimental Example 2. It is the figure which showed the effect | action with respect to a thigh. Each value represents the standard error (meaning 12 to 16). The significance test was performed using Dunnet's multiple comparison. * Indicates P <0.5 and P <0.01 indicates a significant difference from the control.

 FIG. 2 shows the effect of Example 1 on the number of eosinophils in BALF in the mouse OA-induced airway inflammation model of Experimental Example 3. Each value represents the mean ± standard error. (The number of cases is 9-10). The significance test was performed using a t-test. * Indicates that a significant difference from the control was observed at P <0.5.

 FIG. 3 shows I 义 I showing the effect on the swelling of the pinna in the late phase (24 hours after antigen challenge) of the 0A-induced mouse biphasic ear edema model of Surprising Example 5. ■ indicates the hydrocortisone butyrate-applied group, Hata indicates the combination group of hydrocortisone butyrate (applied) and the compound of Example 16 (10 mg / kg, oral administration), and indicates the group applied betamethasone valerate. Each value represents the mean soil standard error. (The number of cases is 6-12). The significant difference test was performed using a two-way analysis of variance (vs. each group). # Indicates P <0.05 and ## indicates P <0.01, indicating that a significant difference was observed between groups.

 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 substituent of the “phenyl group which may be substituted” of R ¹ includes a halogen atom (fluorine, chlorine, bromine, iodine); a lower alkyl group (methyl group, ethyl group, propyl group, Represents an IS chain or a branched alkyl group having 1 to 6 carbon atoms such as an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a hexyl group; a haloalkyl group ( Halogen (fluorine, chlorine, bromine, iodine) such as chloromethyl group, bromomethyl group, fluoromethyl group, trifluoromethyl group, dichloroethyl group, dibromoethyl group, pentafluoroethyl group, chloropropyl group, dichlorobutyl group, etc. Or a haloalkyl group which is H-substituted into a branched alkyl group having 1 to 6 carbon atoms); a hydroxyalkyl group (a hydroxymethyl group, a hydroxyxethyl group, a hydroxypropyl group, a hydroxyisopropyl group, a hydroxybutyl group) , Hydroxyisobutyl, hydroxypentyl, etc. Represents a hydroxyalkyl group in which a hydroxyl group is substituted on a branched lower alkyl group having 1 to 6 carbon atoms); and the like, and is preferably a halogen atom- (a fluorine atom, a chlorine atom-, a santan atom atom, Iodine atom), lower alkyl group and the like.

 The “optionally substituted phenyl group” may be substituted by one or two substituents, which may be the same or different.

The substituent of the "optionally substituted heteroaryl group" for R ¹ has the same meaning as the substituent of the "optionally substituted phenyl group", and is substituted by one or two substituents. And the substituents may be the same or different. Preferred substitutions include a lower alkyl group, a halogen atom (a fluorine atom, a chlorine atom, a nitrogen atom, an iodine atom) and the like.

 The term "heteroaryl" of the "optionally substituted heteroaryl group" means pyridine or thiophene.

As a substituent of the phenyl group in R ² , `` a saturated 6- or 7-membered heterocyclic ring containing 1 or 2 nitrogen atoms which may be substituted and which may contain an oxygen atom or a sulfur atom The substituent of the “unit group” may be a lower alkyl group (such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a hexyl group). A chain or branched alkyl group having 1 to 6, preferably 1 to 4 carbon atoms); a haloalkyl group (chloromethyl group, Halogen (fluorine, chlorine, bromine, iodine) such as lomomethyl group, fluoromethyl group, trifluoromethyl group, dichloroethyl group, dibromoethyl group, penfluorofluorethyl group, chlorobutyl building group, dichlorobutyl group, etc., is linear or branched. A hydroxyalkyl group (a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxyisopropyl group, a hydroxybutyl group, a hydroxyalkyl group). A hydroxyalkyl group in which a linear or branched lower alkyl group such as a hydroxyisobutyl group or a hydroxypentyl group having 1 to 6, preferably 1 to 4 carbon atoms is substituted with a hydroxyl group; A monoalkylamino group (methylamino group, ethylamino group, propylamino group A alkyl group such as a butylamino group represents a linear or branched monoalkylamino group having 1 to 6 carbon atoms, which is a monoalkylamino group; a dialkylamino group (a dimethylamino group, a cetylamino grave, a dibutyl amino group, a diisopropyl group) An alkyl group such as an amino group or a dibutylamino group represents a linear or branched dialkylamino group having 1 to 6 alkyl groups.); Saturated 5-, 6-, or 7-membered cyclic monocyclic group containing 1 to 2 nitrogen atoms (substituted straight-chain or branched lower alkyl having 1 to 4 carbon atoms) Groups such as pyrrolidine, morpholine, thiomorpholine, piperidine, biperazine, homobiradizine, homobiperidine, methylbiperidine, dimethylbiberidine. An aminoalkyl group (an aminoalkyl group in which the alkyl portion such as an aminomethyl group, an aminoethyl group, an aminobutyl group, or an aminobutyl group is a linear or branched alkyl group having 1 to 6 carbon atoms) ); Monoalkylaminoalkyl tomb (alkyl group on nitrogen such as methylaminomethyl group, methylaminoethyl group, methylaminopropyl group, methylaminoethyl group, etc. is linear or branched and has 1 to 6 carbon atoms) A monoalkylaminoalkyl group having a methylene chain length of 1 to 6; a dialkylaminoalkyl group (dimethylaminomethyl¾, dimethylaminoethyl group, getylaminomethyl group, diprovir Alkyl on nitrogen such as aminomethyl group, diisopropyl aminomethyl group, dimethylaminopropyl group Part represents a dialkylaminoalkyl group having a straight-chain or branched alkyl group having 1 to 6 carbon atoms and a methylene chain length of 1 to 6); an acyloxyalkyl group (acetyl) Acetyloxy tomb, propionyloxy group, etc., such as oxymethyl group, acetyloxyxyl group, propionyloxymethyl group, propionyloxyxyl group, benzoyloxymethyl group, benzoyloxyxethyl group, etc. A chain or branched alkyl group substituted by an aliphatic acylosoxy group or a benzoyloxy group having 2 to 6 carbon atoms, wherein the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. Represents a siloxyalkyl group).

 "A saturated 6- or 7-membered heteromonocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom" is one or four substituents. And the substituents may be the same or different.

 Preferred substituents include a lower alkyl group, a hydroxyalkyl group, a saturated alkyl group containing one or two nitrogen atoms which may be substituted or may contain an oxygen atom or a sulfur atom. And a 6- or 7-membered heterocyclic monocyclic group, a dialkylaminoalkyl group, an acyloxyalkyl group and the like.

 Contains an oxygen or sulfur atom in the `` saturated 6- or 7-membered heterocyclic monocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom '' Saturated 6- or 7-membered double-stranded monocyclic ring containing 1 to 2 nitrogen atoms may be morpholine, bipyridine, biperazine, homobiberazine, homobiperidine, thiomorpholine, etc. Is shown. Preferred are morpholine and viridine.

The alkyl group of the “g-substituted alkyl group” as a substituent of the phenyl group in R ² is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group And isopropyl, butyl, isobutyl, tert-butyl, ventil, isopentyl, hexyl, isohexyl and the like, preferably an alkyl group having 1 to 3 carbon atoms. Examples of the substituent of the “substituted alkyl group” include a halogen atom (fluorine, chlorine, bromine, and iodine); a hydroxyl group; and a straight-chain or branched carbon atom such as an acyloxy group (acetyloxy group, propionyloxy group). Lower alkoxy group (linear or branched carbon number such as methoxy group, ethoxy, propyloxy group, isopropyloxy group, butoxy group, etc.), which represents 2 to 6 aliphatic acyloxy and benzoyloxy groups; 1 to 6 alkoxy groups); haloalkoxy groups (chloromethoxy group, bromomethoxy group, fluoromethoxy group, trifluoromethoxy group, dichloroethoxy group, dibromoethoxy group, penoxyfluorethoxy group, chloropropyloxy group, dichloromethoxy group) Straight-chain or branched lower alcohol having 1 to 6 carbon atoms such as butoxy group Xyl group represents a haloalkoxy group in which a halogen atom (fluorine, chlorine, bromine, iodine) is substituted; alkylthio group (methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, etc.) Straight-chain or branched-chain alkylthio group having 1 to 6 carbon atoms; alkylamino group; amino group; monoalkylamino group (alkyl such as methylamino group, ethylamino group, propylamino group, butylamino group, etc.) A monoalkylamino group having a straight or branched chain alkyl group having 1 to 6 carbon atoms; a dialkylamino group (dimethylamino group, ethylamino group, dipropylamino group, diisopropylamino group) The alkyl moiety such as a dibutylamino group is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. A dialkylamino group which is a alkyl group); a saturated 6- or 7-ring heteromonocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom (Substituents are as defined above, and represent morpholino group, 4-methylpiperidino group, 4-dimethylaminobiperidine-11-yl, etc.); acylamino group (acetylamino group, propionylamino group, etc.) A straight-chain or branched-chain aliphatic acylamino group having 2 to 6 carbon atoms and a benzoylamino group; a carboxyl group; an alkoxycarbonyl group (a methoxycarbonyl group, an ethoxycarbonyl group, a proviroxycarbonyl group, Alkoxycarbonyl wherein the alkoxy moiety such as a butoxycarbonyl group is a linear or branched alkoxy group having 1 to 6 carbon atoms A phthalimidalkyl group (indicating a phthalimidalkyl group in which the alkyl moiety such as a fluorimidethyl group or a phthalimidopropyl group is a straight-chain or branched alkyl having 1 to 6 carbon atoms), etc. And preferably a halogen atom, a hydroxyl group, a lower alkoxy group, an acyloxy group, an amino group, a dialkylamino group, and 1 to 2 which may be substituted and may contain an oxygen atom or a sulfur atom And a saturated 6- or 7-membered heterocyclic monocyclic group containing a nitrogen atom, a fluorinated ethyl group and the like, and more preferably a halogen atom, a hydroxyl group and a lower alkoxy group.

 A “substituted alkyl group” may be substituted with one to three substituents, which may be different or different.

 Preferred “substituted alkyl groups” include trifluoromethyl, morpholinomethyl, aminomethyl, dimethylaminomethyl, dimethylaminoethyl, hydroxymethyl, hydroxyethyl and the like.

As the substituent of the phenyl group in R ^2, the substituent of the alkyl chain portion of the group represented by the formula (II) or the formula (III) includes a substituent of “substituted alkyl group” and a lower alkyl group (methyl group). Straight- or branched-chain alkyl groups having 1 to 6 carbon atoms such as, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, isopentyl, hexyl, etc. Is shown). The alkyl chain portion may be substituted by one or two substituents, and the substituents may be the same or different.

 The carbon number of the alkoxy moiety of the group represented by the formulas (II) and (II I) is an integer of 1 to 4, and the group represented by the formulas (II) and (III) is 2-methoxy. Ethoxy groups,

2-ethoxyethoxy, 2-isopropoxyhetoxy, 4-methoxybutoxy, 2- (2,2,2-trifluoroethoxy) ethoxy, 3-methoxy ethoxy, 2- (2- Morpholinoethoxy) ethoxy group, 2- (2-hydroxyethoxy) ethoxy group, 2— (2-methoxyethoxy) ethoxy group, 2- (2

—Ethoxyethoxy) ethoxy group, 3— (2-methoxyethoxy) propoxy group,

3- (2-hydroxyethoxy) propoxy group, 3- (3-methoxypropoxy) Propoxy, 2- (2-dimethylaminoethoxy) ethoxy, 2- (3-dimethylaminopropoxy) ethoxy, 2- (2- (2-methoxyethoxy) ethoxy) ethoxy, 2- (2- (2-hydroxyethoxy) ethoxy) ethoxy, 2- (2- (2-ethoxyethoxy) ethoxy) ethoxy, 3- (2-

(2-methoxyethoxy) ethoxy) propoxy, 3- (2- (2-hydroxyethoxy) ethoxy) propoxy, 2- (2- (2-dimethylaminoethoxy) ethoxy) ethoxy, etc.

 As the group represented by the formula (II) and the formula (III), preferably, a 2-methoxyethoxy group, a 2-ethoxyethoxy group, a 2-isopropoxyethoxy group, a 4-methoxybutoxy group, a 3-methoxybutoxy group, Examples include a methoxypropoxy group, a 2- (2-methoxyethoxy) ethoxy group, and a 2- (2- (2-methoxyethoxy) ethoxydiethoxy) ethoxy group, and more preferably a 2-methoxyethoxy group.

As a substituent of the Fuweniru group in R ² "Substituted was well oxygen atom or may have a sulfur atom and from 1 may be three nitrogen atoms of the same or different and have two or containing containing The spiro ring of the “saturated 6- or 7-membered heterocyclic monocyclic spiro ring group” includes 4,8- (or 4,9-1) diazasbiro [5,5] indene, 1,4,9-1 (or 1,4,8-) Triazaspiro [5,5] indecan, 1- (2—, 3—, or 5—) Oxa-1,4,8 diazaspiro [5,5] indecan, 1— (2—, 3 —, Or 5—) Oxa-1,4,9-Diazaspiro [5,5] indecane, 1-1 (2—, 3—, or 41) Thia 5,9, Diazaspiro [5,5] indecan, 1-11 (2—, 3—, or 5—) Chia 4,9—Diazabiro [5, 5] The number of nitrogen atoms contained in the single ring constituting the spiro ring is preferably 1 or 2.

 The spiro ring group may be substituted by one or two substituents, and the substituents may be the same or different.

Examples of the substituent include lower alkyl (methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, A linear or branched alkyl group having 1 to 6 carbon atoms such as a pentyl group and a hexyl group), oxo and the like, and preferably methyl and oxo.

 "Spiro consisting of two saturated 6 or 7 K-ring heteromonocycles, which may be substituted and which may contain an oxygen atom or a sulfur atom and which may be the same or different and contain 1 to 3 nitrogen atoms Preferred examples of the "ring" include 4-methyl-1-oxa-1,4,9-diazsubiro [5,5] indecan, 1-oxa-4,9-diazsubiro [5,5] indecan, 1-oxa-3-oxo 1,4,9 diazaspiro [5,5] indecan, 2,3-dioxo-1,4,9-triazaspiro [5,5] indecan, 1,4-dimethyl-1,4,9-triazaspiro [5,5] indecan 1,4,9-triazaspiro [5,5] pandecane, 4-methyl-1-oxa-1,4,8-diazaspone [5,5] pandecane, 4-oxo-1-chia-5,9-diazaspiro [5 , 5] ゥ decane, 4-methyl-1,4-diazane 4,9-dazaspiro [5,5] And more preferably 4-methyl-11-year-old 1,4-diazaspiro [5,5] indene, 1-oxa-1,4,9-diazaspiro [5,5] indene, and the like. The pharmaceutically acceptable salts of compound (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, propionic acid, Salts with organic acids such as 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 Can be Also, salts with dehydrates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide, and salts with organic bases such as triethylamine and pyridine may be mentioned. I can do it.

Furthermore, when the compound (I) of the present invention or a pharmaceutically acceptable salt thereof contains an asymmetric carbon cable, it can be obtained in the form of a racemic mixture or an optically active substance. Can be separated into each optically active substance. When the compound (I) of the present invention or a pharmacologically acceptable salt thereof further has an additional asymmetric carbon atom, the compound may be used as a diastereomer mixture or as a single substance. — Can also exist as diastereomers, and these can also be separated from each other by the ί-method known per se. In addition, the compound (I) of the present invention or a salt thereof which is refreshingly acceptable can exhibit polymorphism, and can exist as more than one tautomer. It can also exist as a solvate (eg, ketone solvate, hydrate, etc.). Therefore, the present invention includes any of the above-mentioned isomers, optical isomers, polymorphs, tautomers, solvates, and any mixtures thereof.

 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

(Formula in the above process,! ^ ¹ , R is as defined above, Z is a halogen atom such as chlorine or bromine; azide group; N-hydroxybenzotriazolyl group; p-ditrophenyl Ethoxy group; p-chloro phenyloxy group; alkoxy group such as methoxy group, ethoxy group; acetyl group such as acetyloxy group, bivaloyloxy group; isobutyloxycarbonyloxy group; methoxycarbonyloxy group; ethoxycarponyl And a hydroxy group. )

 The compound represented by the general formula (IV) is reacted with thionyl chloride, isobutyl carbonate, methyl carbonate, ethyl carbonate, or the like in an inert solvent according to a conventional method, thereby obtaining a reaction during the reaction. The compound (I) is produced by reacting with 2-aminothiazole in the presence or absence of a salt tomb, preferably in the presence of a base, in an inert organic solvent after conversion into the compound (V). (Steps 1 and 2).

 In addition, the compound represented by the general formula (IV) can be converted into a reactive derivative thereof without using a suitable condensing agent or the like in the presence or absence of 2-aminothiazole and a base. The compound (I) can also be produced by reacting in an inert solvent, preferably in the presence of a base (step 3).

 The base used in the method of the present invention includes pyridine, picoline, lutidin, collidine, N-methylbiveridine, N-methylbiopenidine, N-methylmorpholine, N, N-dimethylaminoviridine, triethylamine And diisoprovirethylamine, potassium carbonate, sodium carbonate and the like, and preferred are viridin, 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 react, and is preferably ether, benzene, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform, Examples 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 ranging from −30 ° C. to a temperature corresponding to the reflux of the solvent used, preferably from room temperature to a temperature corresponding to the reflux of the solvent used, particularly preferably at a temperature corresponding to the reflux of the solvent used. Is advantageous.

 The reaction is carried out for 1 to 30 hours, preferably for 1 to 3 hours.

 Examples of the condensing agent include N, N'-dicyclohexylcarpoimide, 2-chloro-1,3-dimethylimidazolinium chloride, 1,1-carbonyldiimidazole, and 1-hydroxyl. Benzotriazole, 1-hydroxy-7-azabenzotriazole, 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloride, benzotriazoyl-1-yloxytris (dimethylamino) phosphonium It is preferable to use hexafluorophosphate, 4,4, dichloro-1-methylbenzhydrol or the like.

Manufacturing method 2

 In the general formula (I), a compound having a lower alkoxy group or an aralkyloxy group as a substituent may be a compound having a hydroxy group corresponding to the lower alkyl alcohol or phenylene compound corresponding to the general formula (I). Alternatively, it can be produced by reacting a lower alkyl alcohol in the presence of triphenylphosphine and acetyl dicarboxylate.

Manufacturing method 3

 In the compound having a hydroxyl group, a hydroxyalkyl group, an amino group or an aminoalkyl group as the substituent in the general formula (I), the corresponding substituent of the general formula (I) may be an acyloxy group or an acyloxyalkyl group. A compound which is 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 penzyloxy group, a benzyloxyalkyl group, A compound that is a benzylamino group or a benzylaminoalkyl group is hydrogenated in the presence of a catalyst such as palladium. It can also be prepared by adding, reacting with hydrobromic acid in a solvent such as acetic acid, or treating in thiodisole and trifluoroacetic acid.

Manufacturing method 4

 In the general formula (I), a compound having an amino group or an aminoalkyl group as a substituent may be a compound in which the corresponding substituent of the general formula (I) is a nitro group or a nitroalkyl group. Reduction with an acid such as 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 (II) chloride hexahydrate Can be manufactured. It can also be produced by reducing a compound of the general formula (I) in which the corresponding substituent is a cyano group or an amide group using a reducing agent such as lithium aluminum hydride.

Manufacturing method 5

 In the general formula (I), a compound having a dialkylamino group or a monoalkylamino group as a substituent can be obtained by alkylating a compound in which the corresponding substituent of the general formula (I) is an amino group. Can also be obtained. The alkylation is carried out by using an alkyl halide, an alkyl paratoluenesulfonate or the like and, if necessary, a base such as triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate or the like. The method includes, for example, so-called reductive alkylation or the like, in which formalin or an alkyl aldehyde is allowed to react with a metal hydride complex compound such as sodium borohydride or sodium borohydride, or is subjected to catalytic reduction.

 The compound of the general formula (IV) used as a starting material in the present invention is obtained, for example, by converting the compound of the general formula (VIII) obtained by the following methods 1 to 3 under alkaline or acidic conditions. It can be produced by hydrolysis.

Method 1

 (VI) (VIII)

(In the above step, formula, I ¹ and R ² have the same meanings as described above, and R ³ represents a lower alkyl group.)

 By reacting the compound represented by the general formula (VI) with the compound represented by the general formula (VII), the compound of the general formula (VIII) can be produced (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 ranging from −30 ° 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 reaction is carried out for 1 to 30 hours, preferably for 10 to 15 hours.

Method 2

 (IX) (VIII)

(In the above formula, R i and R ² have the same meanings as described above, and R ³ represents a lower alkyl group.)

Harry H. Wasserman, Tet ahe dr on Letter, Vol. 33, No. 40, pp. 6003- 6006, 1992), etc., when the compound represented by the general formula (IX) is an ammonium salt of a lower alkane carboxylic acid ammonium salt such as ammonium acetate or ammonium formate or an ammonium salt of an inorganic acid such as ammonium carbonate. The compound represented by the general formula (VIII) is produced by reacting the compound represented by the general formula (X) with an acidic solution of lower carboxylic acid of formic acid, acetic acid, and propionic acid II. (Step 5).

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

_C Reaction of 'interest carried out at the reflux temperature of a solvent used from 0 ° C is from 1 to 30 hours, preferably for 12 to 15 hours.

Method 3

 (VI) (VIII)

(In the formula of the above step, R ¹ R ² has the same meaning as described above, and R ³ is ⁷ J; a lower alkyl group.)

 -A compound represented by the general formula (X) in the presence of an ammonium salt of a lower alkane carboxylate ammonium such as ammonium acetate or ammonium formate or an ammonium salt of an inorganic acid such as ammonium carbonate. By reacting with, the compound represented by the general formula (VI II) can be produced (Step 6).

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

The reaction is o. It is preferable to carry out at a temperature equivalent to the reflux of the solvent used from c. However, it is particularly preferable to carry out the reaction at a temperature corresponding to the reflux of the solvent used. The reaction is carried out for 1 to 30 hours, preferably for 12 to 15 hours.

 The pharmaceutically acceptable salts of compound (I) of the present invention include inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (acetic acid, propionic acid, succinic acid, etc.). 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.) It can be the above-mentioned acid addition salt. 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 can be treated with an organic base by treating with triethylamine, pyridine, etc. Can also be used as a salt. Further, 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, a hydrated 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 and a column chromatography method. When the resulting product is a racemic form, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid or by passing through a column packed with an optically active carrier. Can be done. 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 a recrystallization method, a column chromatography method, 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 converted into a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, Pharmaceutical compositions or preparations obtained by mixing with emulsifiers, diluents, solubilizing agents, etc. (tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions, Solutions, injections, drops, ointments, tablets Starches, liniments, lotions, blasters, cataplasms, eye drops, ointments, suppositories, compresses, inhalants, sprays, aerosols, liniments, nasal drops, creams , Tapes, patches, etc.) can be administered orally or parenterally. The pharmaceutical composition can be formulated according to a usual method. For example, excipients (lactose, D-mannitol, starch, crystalline cellulose, etc.), binders (hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylidolidone, etc.), disintegrants (carboxymethylcellulose, carboxymethyl Lubricants (magnesium stearate, talc, etc.), coating agents (hydroxylpropyl methylcellulose, sucrose, etc.), bases (polyethylene glycol, hard fat, etc.) If the formulation component is an injection, a solubilizer or solubilizing agent that can constitute an aqueous or ready-to-use injection (such as swallow water for injection, saline, propylene glycol, etc.), and pH adjustment Pharmaceutical ingredients such as agents (inorganic acids, organic acids or inorganic bases) and stabilizers are used.

 The compound of the present invention represented by the general formula (I) and a pharmaceutically acceptable salt thereof inhibit the production of IL-14 and IL-15 produced from Th2 cells, and It is effective in preventing and / or treating allergic diseases such as bronchial asthma and allergic rhinitis.

 The dose of Compound (I) to the treated patient may vary depending on the type and degree of the disease, the compound to be administered, the administration route, the age, sex, and weight of the patient, etc., but in general, the daily dose for adults is The dose is about 1.0 to 100 mg for perro-dose and about 1.0 to 500 mg for parenteral administration.

Further, the compound (I) or a pharmaceutically acceptable salt thereof according to the present invention can be used in a preparation containing a conventionally used steroid (hydrocortisone butyrate, dexamethasone acetate, methylprednisolone acetate, etc.) (preferably, for external use) When used together with an anti-allergic agent, a stronger anti-allergic effect can be brought about, and the effect of preventing or treating allergies or exerting a therapeutic effect can be more effectively exerted. By utilizing the combined effect, it is possible to reduce the amount of a steroid agent. 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

77.2 g of N-phenylmorpholine was dissolved in 150 ml of DMF, and 67.1 ml of phosphorus oxychloride was added dropwise in an ice bath. After the dropwise addition, the mixture was stirred at 60 ° C for 22 hours, ice water was added little by little under an ice bath, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Isopropyl ether was added to the remaining droplets, and the precipitated crystals were collected by filtration to obtain 70.7 g of a target 4-morpholino benzaldehyde. 55-55 ° C.

Raw material synthesis example 2

3- (4-chlorophenyl) 1-2-hydr π-ximinino-13-oxopropionate ethyl ester 200 g, 4-morpholinobenzaldehyde 244.4 g and ammonium acetate 603 g After heating and refluxing in acetic acid for 15 hours, the solvent was distilled off under reduced pressure. Dissolve the residue in 2 L of chloroform and neutralize with saturated aqueous sodium hydrogen carbonate Extracted with loroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain crude crystals from ethyl acetate. The crude crystals were subjected to silica gel column chromatography to obtain 78 g of the desired 5- (4-chlorophenyl) -12- (4-morpholinophenyl) imidazole-4 monoethyl ribonate. Melting point 2 Raw material synthesis example 3

5-(4-chlorophenyl) -2- (4-morpholinophenyl) imidazole — 4 solution 53.7 g of ethyl ribonate in 540 ml of ethanol and 217 ml of 3N aqueous sodium hydroxide solution After heating under reflux for 5 hours, the mixture was concentrated under reduced pressure, 100 ml of water was added, and the mixture was washed with toluene. The aqueous layer was neutralized with a 10% aqueous solution of citric acid, and the precipitated crystals were collected by filtration. The desired 5- (4-chlorofuninyl) -2- (4-morpholinophenyl) imidazole-one-one-one-one ruponic acid 49 4 g were obtained. 205 ° C (decomposes).

Raw material synthesis example 4

原料合成例 2 と同様にして 3— （ 4—フルオロフェニル） — 2—ヒ ドロキシィ ミノ一 3—ォキソプロビオン酸ェチルエステル 2 0. 8 g、 4一モルホリノベン ズアルデヒ ド 2 5 gおよび酢酸アンモニゥム 6 7 gより 5— （ 4—フルオロフ ェニル） 一 2— ( 4—モルホリノフエニル） イ ミダゾ一ルー 4—カルボン酸ェチ ルエステル 8. 6 gを得た。 融点 1 9 3°C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-fluorophenyl) -2-hydroxyethyl-3-oxopropionate ethyl ester 20.8 g, 25-morpholinobenzaldehyde 25 g and ammonium acetate 67 g 8.6 g of 5- (4-fluorophenyl) -12- (4-morpholinophenyl) imidazo-l- 4-carboxylic acid ethyl ester was obtained. Melting point 193 ° C.

¹ H-NMR 270 MHz (DMS O—d _fi , p pm) 6: 9.89 (1 H, s), 7.84-7.98 (4 H, m), 6.9 3-7.13 (4 H, m), 4.34 (2 H, q), 3.87 (4H, t), 3.25 (4H, t), 1.33 (3H, t) Raw material synthesis example 5

原料合成例 3と同様にして 5— （4一フルオロフェニル） 一 2— （4一モルホ リノフエニル） イ ミダゾ一ル一 4一力ルボン酸ェチルエステル 8. 6 gから 5 一 （4一フルオロフェニル） 一 2— （ 4—モルホリノフエニル） イ ミダゾールー 4一力ルボン酸 8. 0 gを得た。

In the same manner as in Raw Material Synthesis Example 5, 5- (4-monofluorophenyl) -1- (4-morpholinophenyl) imidazole-41-ethyl ribonate ester 8.6 g to 5- (4-fluorophenyl) -1 8.0 g of 2- (4-morpholinophenyl) imidazole-4 rubonic acid was obtained.

¹ H-NMR 270 MHz (DMS O—d _fi , p pm) (5: 12.8 (1 H, s), 6.99—8.04 (9 H, m), 3. 7 5 (4 H, t), 3.20 (4 H, t) Raw material synthesis example 6

原料合成例 1と同様にして 4ーメチル一 1一フエ二ルビべラジン 16. 5 gか ら目的の 4— ( 4—メチルビペラジン一 1—ィル） ペンズアルデヒ ド 12. 6 gを得た。 融点 50°C。

In the same manner as in Raw Material Synthesis Example 1, 12.6 g of the desired 4- (4-methylbiperazine-11-yl) benzoaldehyde was obtained from 16.5 g of 4-methyl-11-phenylbiverazine. Melting point 50 ° C.

Raw material synthesis example 7

原料合成例 2と同様にして 3— （4—クロ口フエニル） 一 2—ヒドロキシイミ ノー 3—ォキソプロピオン酸ェチルエステル 6. 4 g、 4一 （4—メチルビべ ラジン一 1一ィル）ベンズアルデヒ ド 7.7 gおよび酢酸アンモニゥム 1 9. 4 gから 5— （4—クロ口フエニル） 一2— 〔4— ( 4—メチルビペラジン一 1 —ィル） フエニル〕 イ ミダゾールー 4 _カルボン酸ェチルエステル 3. 7 gを 得た。 融点 190— 192°C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyimino 3-oxopropionate ethyl ester 6.4 g, 4- (4-methylbiberazine-111) benzaldehyde 7.7 g and ammonium acetate 19.4 g from 5- (4-chlorophenyl) 1-2- [4- (4-methylbiperazine-1 1-yl) phenyl] imidazole-4-ethyl carboxylate 3.7 g Was obtained. 190-192 ° C.

Raw material synthesis example 8

原料合成例 3と同様にして 5— (4-クロロフヱニル） 一 2— C4 - (4ーメ チルビペラジン一 1—ィル） フエニル〕 イ ミダゾ一ルー 4—カルボン酸ェチルェ ステル 3. 7 gから 5— ( 4—クロ口フエニル） 一 2— 〔4一 （4—メチルビ ペラジン一 1—ィル） フエニル〕 イミダゾ一ル一 4一力ルボン酸 3. 5 gを得 た。 融点 2 1 4— 2 1 8°C (分解)。

In the same manner as in Raw Material Synthesis Example 3, 5- (4-chlorophenyl) 1-2-C4-(4- Cylbiperazine-1-yl) phenyl] imidazolu-l 4-carboxylate 3.7-g to 5- (4-chlorophenyl) 1-2- [4- (4-methylbiperazine-1-yl) Phenyl] 3.5 g of imidazole-monorubic acid was obtained. Melting point 2 14—2 18 ° C (decomposition).

Raw material synthesis example 9

45.5 g of benzonitrile, 45.5 g of 4-methylhomobidazine, and 28 g of acetic acid potassium were heated in DMS O for 15 hours. After heating, the reaction solution was poured into 1 L of water, and the precipitated crystals were collected by filtration to obtain 34.6 g of target 4- (4-methylhomobiazine) -11-benzonitrile. Melting point 82-84. C.

Raw material synthesis example 10

15 g of 4- (4-methylhomopirazine-11-yl) benzonitrile was dissolved in 25 ml of formic acid, and 15.5 g of Raney nickel was added, followed by heating under reflux for 2.5 hours. After the reaction, the catalyst was separated by filtration and concentrated under reduced pressure. The residue was neutralized with a saturated aqueous solution of potassium carbonate, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 16.1 g of the desired 4- (4-methylhomobiazine 11-yl) benzaldehyde as an oil.

^{1 H-NMR 2 7 0 MH} z (CD C 1 3, pm) 5: 9. 7 1 (1 H, s), 7. 7 1 (2 H, d), 6. 7 1 (2 H, d ), 3.48-3.65 (4 H, m), 2. 66-2.73 (2H, m), 2.52-2.57 (2H, m), 2-37 (3H, s), 1.97-2.06 (2H, m)

Raw material synthesis example 1 1

原料合成例 2と同様にして 3— (4—クロ口フエニル） 一 2—ヒ ドロキシイ ミ ノ一 3—ォキソプロビオン酸ェチルエステル 10. 5 g、 4 - (4—メチルホ モピペラジン一 1—ィル） ベンズアルデヒド 1 6. 2 gおよび酢酸アンモニゥ ム 3 1. 7 gから 5— (4—クロ口フエニル） 一 2— 〔4— (4—メチルホモ ビぺラジン一 1—ィル） フエニル〕 イミダゾ一ル一 4—カルボン酸ェチルエステ ル 5. 3 gを得た。 融点 205— 207°C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyimino-3-oxoethyl ether ester 10.5 g, 4- (4-methylhomopiperazine-11-yl) benzaldehyde 1 6.2 g and ammonium acetate 31.7 g to 5— (4-chlorophenyl) -1-2— [4- (4-methylhomo-pyrazine-1—yl) phenyl] imidazole 1— 5.3 g of ethyl carboxylate were obtained. 205-207 ° C.

Raw material synthesis example 12

原料合成例 3と同様にして 5— （4—クロ口フエニル） 一 2— 〔4一 （4ーメ チルホモピぺラジン一 1—ィル） フエニル〕 イミダゾ一ソレー 4—カルボン酸ェチ ルエステル 5. 3 gから 5— (4—クロ口フエニル） 一 2— 〔4一 （4—メチ ルホモピペラジン一 1一ィル） フエニル〕 イ ミダゾ一ル— 4—カルポン酸 5. 0 gを得た。 融点 177 - 180 "C (分解)。

5- (4-chlorophenyl) 1-2- [4- (4-methylhomopirazine-11-yl) phenyl] imidazo monosole 4-carboxylate 5. 3 g to 5— (4-chlorophenyl) 1 2— [4 1 L-homopiperazine-111) phenyl] imidazole-4-carponic acid (5.0 g) was obtained. 177-180 "C (decomposition).

原料台成例 9と同様にして 4—フルォ口べンゾニトリル 20 g、 4一メチル ピぺリジン 1 6. 4 gから目的の 4一 （ 4—メチルビペリジン一 1—ィル） ベ ンゾニトリル 24. 5 gを得た。 融点 53°C。 Raw material synthesis example 13

In the same manner as in Example 9 of raw material composition, 20 g of 4-fluorobenzonitrile and 16.4 g of 4-methylpiperidine were converted to 24.5 g of the desired 4- (4-methylbiperidine-11-yl) benzonitrile. I got 53 ° C.

原料合成例 1 0と同様にして 4— ( 4—メチルビペリジン一 1一ィル） ペン V 二トリル 1 5 gから目的の 4一 （ 4—メチルビペリジン一 1一ィル） ベンズァ ルデヒドを油状物として 1 3. 8 gを得、 精製することなく次の原料合成例 1 5に用いた。 Raw material synthesis example 14

Raw material synthesis example In the same manner as in Example 10, 4- (4-methylbiperidine-11-yl) pen V nitrile 15 g of the desired 4- (4-methylbiperidine-11-yl) benzaldehyde was converted into an oily substance from 15 g. 3.8 g was obtained and used for the next raw material synthesis example 15 without purification.

Raw material synthesis example 1 5

原料合成例 2と同様にして 3— （4ークロロフ Iニル） 一 2—ヒ ドロキシイミ ノー 3—ォキソプロビオン酸ェチルエステル 8. 7 g、 原料合成例 14にて得 られた未精製の 4一 （4—メチルビペリジン一 1一ィル） ベンズアルデヒド 1 3. 9 gおよび酢酸アンモニゥム 52. 6 gから 5— (4—クロ口フエニル） - 2 - 〔4— ( 4ーメチルビペリジン一 1—ィル） フエニル〕 ィミダゾ一ルー 4 一力ルボン酸ェチルエステル 4. 9 gを得た。 融点 188— 190。C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) n-2-hydroxyiminor 3-oxopropionate ethyl ester 8.7 g, unpurified 4- (4-methylbiperidine) obtained in Raw Material Synthesis Example 14 1-11) Benzaldehyde 13.9 g and ammonium acetate 52.6 g from 5- (4-chlorophenyl) -2- (4- (4-methylbiperidine-11-phenyl) phenyl) 4.9 g of imidazo 1-ruthyl rubonic acid ethyl ester was obtained. Melting point 188-190. C.

Raw material synthesis example 16

原料合成例 3と同様にして 5— （4一クロ口フ エニル） 一 2— 〔4— (4—メ チルビペリジン一 1—ィル） フエニル〕 イミダゾール一 4一力ルボン酸ェチルェ ステル 4. 9 gから 5— (4—クロ口フ エニル） 一 2— 〔4— (4ーメチルビ ペリジン一 1—ィル） フエニル〕 イミダゾ一ルー 4一力ルボン酸 4. 6 gを得 た。 融点 188— 192°C (分解)。

In the same manner as in Raw Material Synthesis Example 5, 5- (4-chlorophenyl) 1-2- [4- (4-methylbiperidine-11-yl) phenyl] imidazole-14-ethyl rubonate 4.9 g From this, 4.6 g of 5- (4-chlorophenyl) -1-2- [4- (4-methylbiperidin-1-yl) phenyl] imidazo-ru-ru-rubonic acid was obtained. 188-192 ° C (decomposition).

原料合成例 9と同様にして 4一フルォ口べンゾニトリル 23 g、 4 , 4ージ メチルビべリジン塩酸塩 28. 5 gから目的の 4— (4, 4—ジメチルビペリ ジン— 1一ィル）ベンゾニトリル 34 · 7 gを得た。 融点 1 1 5— 1 17°C。 原料合成例 18

原料合成例 1◦と同様にして 4一 (4 , 4—ジメチルビペリジン一 1 _ィル） ベンゾニ卜リル 18 gから目的の 4— ( 4， 4—ジメチルビペリジン一 1ーィ ル） ベンズアルデヒドを油状物として 13. l gを得た。 融点 48°C。 原料合成例 19 Raw material synthesis example 1

In the same manner as in Raw Material Synthesis Example 9, the desired 4- (4,4-dimethylbiperidin-11-yl) benzoate was obtained from 23 g of 4-fluorobenzobenzonitrile and 28.5 g of 4,4-dimethylbiveridine hydrochloride. 34 · 7 g of nitrile were obtained. Melting point 1 15—117 ° C. Raw material synthesis example 18

Raw material synthesis example In the same manner as in 1 °, the desired 4- (4,4-dimethylbiperidine-1-yl) was obtained from 18 g of 4- (4,4-dimethylbiperidine-11-yl) benzonitrile. 13.1 lg of benzaldehyde was obtained as an oil. Melting point 48 ° C. Raw material synthesis example 19

原料合成例 2と同様にして 3— (4—クロロフヱニル） 一2—ヒ ドロキシイミ ノー 3—ォキソプロビオン酸ェチルエステル 10. 3 g、 4— (4， 4ージメ チルビペリジン一 1一ィル） ベンズアルデヒ ド 1 3. l gおよび酢酸アンモニ ゥム 3 1 gから 5— （4—クロ口フエニル） 一 2— 〔4— ( 4 , 4—ジメチル ビぺリジン一 1一ィル） フエニル〕 イミダゾール一 4一力ルボン酸ェチルエステ ル 5. 6 gを得た。 融点 205°C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyiminor 3-oxopropionic acid ester 10.3 g, 4- (4,4-dimethylbiperidine-11-yl) benzaldehyde 13. lg and ammonium acetate 3 1 g to 5— (4-chlorophenyl) 1 2— [4— (4,4-dimethylbipyridine) 1-phenyl) imidazole 5.6 g were obtained. Melting point 205 ° C.

Raw material synthesis example 20

原料合成例 3と同様にして 5— (4—クロ口フエニル） 一 2— 〔4— (4, 4 一ジメチルビペリジン一 1—ィル） フエニル〕 イ ミダゾールー 4—カルボン酸ェ チルエステル 5. 6 gから 5 _ (4—クロ口フエニル） 一 2— 〔4一 （4， 4 —ジメチルピペリジン一 1—ィル）フエニル〕ィミダゾ一ルー 4—カルボン酸 5 4 gを得た。 融点 188— 192°C (分解）。

5- (4-chlorophenyl) 1-2- [4- (4,4-dimethylbiperidine-11-yl) phenyl] imidazole-4-carboxylic acid ethyl ester in the same manner as in Raw Material Synthesis Example 3. From 6 g, 54 g of 5_ (4-chlorophenyl) 1-2- [4- (4,4-dimethylpiperidine-11-yl) phenyl] imidazo-1- 4-carboxylic acid was obtained. 188-192 ° C (decomposition).

原料合成例 9と同様にして 4一フルォ口べンゾニトリル 27 g：、 4一 (ジメ チルアミノメチル） ビべリジン 32 gから 的の 4一 〔4一 （ジメチルァミノ メチル） ピぺリジン一 1一ィル〕ベンゾニ卜リル 35. 5 gを得た。 融点 8 4一 86。C。 Raw material synthesis example 21

In the same manner as in Raw Material Synthesis Example 9, 27 g of 4-fluorobenzonitrile and 41 g of 4- (dimethylaminomethyl) biveridine are obtained from 32 g of 4- (dimethylaminomethyl) piperidine. 35.5 g of benzonitrile. Melting point 841-86. C.

原料合成例 10と同様にして 4— 〔4一 （ジメチルアミノメチル） ピぺリジン 1—ィル〕 ベンゾニトリル 35. 5 gから目的の 4一 〔4— (ジメチルアミ ノメチル） ビぺリジン一 1—ィル〕 ベンズアルデヒ ドを油状物として 34 gを 得た。 Raw material synthesis example 22

In the same manner as in Raw Material Synthesis Example 10, 4- [4- (dimethylaminomethyl) piperidine 1-yl] benzonitrile was obtained from 35.5 g of the desired 4- [4- (dimethylamino) Nomethyl) bipyridine-1-yl] benzaldehyde was obtained as an oil to obtain 34 g.

Raw material synthesis example 23

原料合成例 2と同様にして 3— (4—クロ口フエニル） — 2—ヒ ドロキシイ ミ ノー 3 _ォキソブロビオン酸ェチルエステル 22 g、 4— 〔4— (ジメチルァ ミノメチル） ピペリジン一 1—ィル〕 ペンズアルデヒ ド 34 gおよび酢酸アンモ ニゥム 6 6. 5 gから 5— (4—クロ口フエニル） 一 2— {4— 〔4一 （ジメ チルアミノメチル） ビペリジン一 1—ィル〕 フェニル } ィ ミダゾ一ル一 4—カル ボン酸ェチルエステル 7. 2 gを得た。 融点 203— 204°C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) -2-hydroxyhydroxy 3-ethyl oxobrobionate 22 g, 4- [4- (dimethylaminomethyl) piperidine-1-yl] penzaldehyde 34 g and ammonium acetate 66.5 g to 5— (4-chlorophenyl) 1-2— {4 -— (1- (dimethylaminomethyl) biperidine-1-yl) phenyl} midazinyl 7.2 g of 4-ethyl carboxylate were obtained. 203-204 ° C.

Raw material synthesis example 24

原料合成例 3と同様にして 5— (4—クロ口フエニル） 一 2— {4—〔4— (ジ メチルァミノメチル） ビぺリジン一 1—ィル〕 フエ二ル} ィ ミダゾ一ルー 4一力 ルボン酸ェチルエステル 7. 2 gから 5— (4—クロ口フエニル） 一 2— {4 - 〔4— (ジメチルアミノメチル） ビべリジン一 1—ィル〕 フエ二ル} ィ ミダゾ ルー 4—カルボン酸 6. 2 gを得た。 融点 243— 2 4 5°C (分解)。

5- (4-chlorophenyl) 1-2- {4- [4- (dimethylaminomethyl) biperidine-11-yl] phenyl} -midazolu-Ru in the same manner as in Raw Material Synthesis Example 3 4Ethyl rubonic acid ester 7.2 g to 5— (4-chlorophenyl) 1 2— {4- [4- (Dimethylaminomethyl) biveridine-1-yl] phenyl-2-midazole 4-carboxylic acid (6.2 g) was obtained. Melting point 243—245 ° C (decomposition).

Raw material synthesis example 25

In the same manner as in Synthesis Example 9, the desired 4- (3,5-dimethylmorpholine-1-yl) benzonitrile was obtained from 44.2 g of benzonitrile, 4-fluorene benzonitrile and 23 g of 3,5-dimethylmorpholine. 34.8 g were obtained. Mp 75-78. C.

Raw material synthesis example 26

原料合成例 1 0と同様にして 4— ( 3 , 5—ジメチルモルホリン一 4一ィル） ベンゾニトリル 3 4. 8 gから H的の 4— ( 3 , 5—ジメチルモルホリン一 4 —ィル） ベンズアルデヒドを油状物として 3 2. 9 gを得た。

Raw material synthesis example 4— (3,5-dimethylmorpholine-14-yl) benzonitrile from 34.8 g of 4-((3,5-dimethylmorpholine-14-yl)) 32.9 g of benzaldehyde was obtained as an oil.

1 H-NMR 270 MHz (CD C 1 pm) δ 9.78 (1 H, s), 7.73-7.78 (2H, m), 6.89-6. 9 3 (2H, m) ヽ 3-6 3 -3.81 (4H, m), 2.52-2.62 (2H, m), 1.27 (6H, dd ) Example of raw material synthesis 2 7

原料合成例 2と同様にして 3— (4—クロ口フエニル） 一 2—ヒ ドロキシイミ ノー 3—ォキソプロビオン酸ェチルエステル 2 5. 5 g、 4— ( 3, 5—ジメ チルモルホリン一 4—ィル） ベンズアルデヒ ド 32. 8 gおよび酢酸アンモニ ゥム 77 gから 5— （4一クロ口フエニル） 一 2— 〔4一 （3 , 5—ジメチル モルホリン一 4一ィル） フエニル〕 イミダゾ一ルー 4一力ルボン酸ェチルエステ ル 4. 3 gを得た。 融点 178— 180て。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) -12-hydroxyiminor 3-oxopropionic acid ethyl ester 25.5 g, 4- (3,5-dimethylmorpholine-14-yl) From 32.8 g of benzaldehyde and 77 g of ammonium acetate 5- (4- (4-chlorophenyl)) 2- (4- (3,5-dimethylmorpholine-1 4-yl) phenyl) imidazo-l-ru 4.3 g of ethyl ester rubonate were obtained. Melting point 178-180.

Raw material synthesis example 28

原料合成例 3と同様にして 5— (4—クロ口フエニル） 一2— 〔4一 （3， 5 ージメチルモルホリン一 4—ィル） フエニル〕 イミダゾールー 4—カルボン酸ェ チルエステル 5. 5 gから 5— (4—クロ口フエニル） 一 2— 〔4一 （3 , 5 —ジメチルモルホリン一 4一ィル）フェニル〕ィミダゾ一ル一 4—カルボン酸 5 gを得た。 融点 1 75°C (分解）。

Starting from 5.5 g of 5- (4-chlorophenyl) 1-2- [4-1 (3,5-dimethylmorpholine-14-phenyl) phenyl] imidazole-4-carboxylic acid ester in the same manner as in Raw Material Synthesis Example 3 There were obtained 5 g of 5- (4-chlorophenyl) 1-2- [4-1 (3,5-dimethylmorpholine-14-yl) phenyl] imidazole-14-carboxylic acid. Melting point 1 75 ° C (decomposition).

原料合成例 9と同様にして 4一フルォ口べンゾニトリル 39 g、 4一ジメチ ルアミノビペリジン 41 から目的の4_ 〔4一 （ジメチルァミノ） ビベリジ ン— 1—ィル〕 ベンゾニトリルを油状物質として 14 g得た。 Raw material synthesis example 29

In the same manner as in Raw Material Synthesis Example 9, 39 g of 4-fluorene benzonitrile and 41- [41- (dimethylamino) biberidin-1-yl] benzonitrile as an oily substance were obtained from 41-dimethylaminobiperidine 41 as an oil. 14 g were obtained.

1 H-NMR 270MHz (CDC 1 3, p pm) (5: 7. 46 (2 H, d), 6. 85 (2H, d), 3. 89 - 3. 84 (2 H, m), 2 88-2.87 (2H, m), 2.30 (6H, s), 1.95-1.80 (2H, m), 1.70-1.42 (2H, m)

Raw material synthesis example 30

原料合成例 10と同様にして 4一 〔4— (ジメチルァミノ） ビぺリジン一 1— ィル〕 ペンゾニトリル 14 gから目的の 4 _ 〔4— (ジメチルアミノ） ピペリ ジン一 1—ィル〕 ベンズアルデヒドを油状物として 8. 3 gを得た。

In the same manner as in Raw Material Synthesis Example 10, the desired 4_ [4- (dimethylamino) piperidin-1-yl] benzaldehyde was obtained from 14 g of 4- [4- (dimethylamino) bipyridine-1-yl] benzonitrile. 8.3 g were obtained as an oil.

1 H-NMR 270 MHz (CDC 1 _: (.pm) d: 9.75 (1 H, s), 7.72 (2 H, d), 6.90 (2 H, d), 3.98—3 87 (2H, m), 2.96-2.97 (2H, m), 2.30 (6H, s), 1.95-1.90 (2H, m), 1.64 -1.49 (2 H, m)

Raw material synthesis example 31

原料合成例 2と同様にして 3— (4—クロ口フエニル） 一 2—ヒ ドロキシイ ミ ノー 3—ォキソプロピオン酸ェチルエステル 6. 0 g、 4 - 〔4一 （ジメチル ァミノ） ビぺリジン一 1一ィル〕 ベンズアルデヒ ド 8. 3 gおよび酢酸アンモ ニゥム 18. O gから 5— （4一クロ口フエニル） _ 2— {4— 〔4— (ジメチ ルアミノ） ビペリジン一 1—ィル〕フエ二ル}ィ ミダゾ一ル一 4—カルボン酸ェチ ルエステル 2. 5 gを得た。 融点 173— 174°C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxymino-3-oxopropionate ethyl ester 6.0 g, 4- [4- (dimethylamino) bipyridine-1 8.3 g of benzaldehyde and ammonium acetate 18. From Og, 5— (4-chlorophenyl) _ 2— {4— [4— (dimethylamino) biperidine-11-yl] phenyl 2.5 g of methyl 4-methylcarboxylic acid ester were obtained. 173-174 ° C.

Raw material synthesis example 32

原料合成例 3と同様にして 5— (4—クロロフヱニル） 一 2— {4— 〔4— (ジ メチルアミノ） ビベリジン一 1—ィル〕 フェニル }ィ ミダゾ一ル一 4—カルボン酸 ェチルエステル 2. 5 gから 5—（4—クロ口フエニル）一 2— {4—〔4— (ジ メチルアミノ） ピべリジン一 1—ィル〕 フェニル }ィ ミダゾールー 4—カルポン酸 1. 7 gを得た。 融点 210— 2 13°C (分解)。

5- (4-chlorophenyl) -12- {4- (4- (dimethylamino) biveridine-11-yl] phenyl} dimidazole-14-carboxylic acid ethyl ester in the same manner as in Raw Material Synthesis Example 3. 2. From 5 g, 1.7 g of 5- (4-chlorophenyl) -2- (4- [4- (dimethylamino) piberidine-1-yl] phenyl} imidazole-4-carponic acid was obtained. . Melting point 210-213 ° C (decomposition).

Raw material synthesis example 33

原料合成例 2と同様にして 3— （4—メチルフエニル） 一 2—ヒ ドロキシイミ ノー 3—ォキソプロビオン酸ェチルエステル 1 22 g、 4一トリフルォロメチ ルベンズアルデヒド 136 gおよび酢酸アンモニゥム 400 gから 5— (4 —メチルフエニル） 一 2— ( 4 _ トリフルォロメチルフエニル） イミダゾ一ル— 4一力ルボン酸ェチルエステル 43.7 gを得た。 融点 1 63— 1 64^DC。 原料合成例 34

In the same manner as in Raw Material Synthesis Example 2, 3- (4-methylphenyl) 1-2-hydroxyimino 3-oxopropionic acid ethyl ester 122 g, 4-trifluoromethylbenzaldehyde 136 g and ammonium acetate 400 g to 5- (4-methylphenyl) 13.7— (4_Trifluoromethylphenyl) imidazole-4ethyl ether ester 43.7 g was obtained. Mp 1 63- 1 64 ^D C. Raw material synthesis example 34

原料合成例 3と同様にして 5 _ (4—メチルフエニル） 一 2— （4一トリフル ォロメチルフエニル） イミダゾ一ルー 4一力ルボン酸ェチルエステル 43. 7 gから 5— (4—メチルフエニル） 一 2— ( 4— トリフルォロメチルフエニル） イミダゾ一ルー 4—カルボン酸 38. 0 gを得た。 融点 2 18 - 2 19 °C (分解)。

In the same manner as in Raw Material Synthesis Example 5, 5 _ (4-methylphenyl) 1 2-(4-trifluoromethylphenyl) imidazo 1-4 4-ethyl rubonate ethyl ester 43.7 g to 5-(4-methylphenyl) 1 There were obtained 38.0 g of 2- (4-trifluoromethylphenyl) imidazoyl 4-carboxylic acid. Mp 2 18-219 ° C (decomposition).

Raw material synthesis example 35

原料合成例 2と同様にして 3— (4—フルオロフ工ニル） 一 2—ヒ ドロキシィ ミノー 3—ォキソプロピオン酸ェチルエステル 1 5. 0 g、 4—トリフルォロ メチルベンズアルデヒド 1 6. 3 gおよび酢酸アンモニゥム 48. 4 から 5— （4—フルオロフェニル） 一 2— （ 4一 トリフルォロメチルフエニル） イミ ダゾール一 4—カルボン酸ェチルエステル 1 2. 0 gを得た。 融点 1 8 5 — 188。C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-fluorophenyl) 1-2-hydroxyminnow 3-oxopropionic acid ethyl ester 15.0 g, 4-trifluoromethylbenzaldehyde 16.3 g and ammonium acetate 48 4 to 5— (4-Fluorophenyl) 1-2- (4-1trifluoromethylphenyl) imidazole-14-carboxylic acid ethyl ester 12.0 g was obtained. Melting point 1 85-188. C.

Raw material synthesis example 36

原料合成例 3と同様にして 5— (4—フルオロフェニル） 一 2— （4一トリフ ルォロメチルフエニル） イミダゾ一ル— 4—カルボン酸ェチルエステル 1 1. 0 gから 5— （4—フルオロフェニル） 一 2— （ 4一トリフルォロメチルフエ二 ル） イ ミダゾ一ルー 4一力ルボン酸 1 0. 0 gを得た。 融点 1 5 9— 1 6 o。c (分解）。

In the same manner as in Raw Material Synthesis Example 3, 5- (4-fluorophenyl) 1-2- (4-trifluoromethylphenyl) imidazole-4-carboxylic acid ethyl ester 11.0 g to 5- (4-fluorophenyl) 10.0 g of phenyl) 1-2- (4-trifluoromethylphenyl) imidazo-l-ruthenic acid were obtained. Mp 159-16 o. c (decomposition).

Example of raw material synthesis 37

原料合成例 2と同様にして 3— (4—クロ口フエニル） 一2—ヒドロキシイミ ノ一 3 _ォキソプロビオン酸ェチルエステル 1 5. 0 g、 4—トリフルォロメ チルベンズアルデヒド 15. 3 gおよび酢酸アンモニゥム 45. l gから 5 - (4—クロ口フエニル） 一 2— ( 4—トリフルォロメチルフエニル） イミダゾ —ルー 4一力ルボン酸ェチルエステル 9. 7 gを得た。 融点 17 1— 17 3°C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyimino-3_oxopropionic acid ethyl ester 15.0 g, 4-trifluoromethylbenzaldehyde 15.3 g and ammonium acetate 45.lg From this, 9.7 g of 5- (4-chlorophenyl) -1-2- (4-trifluoromethylphenyl) imidazo-leu 4-ethyl ruvonate was obtained. Mp 171-173 ° C.

Raw material synthesis example 38

原料合成例 3と同様にして 5— (4—クロ口フエニル） 一2— (4—トリフル ォロメチルフエニル） イミダゾ一ルー 4—カルボン酸ェチルエステル 9. 0 g から 5— (4—クロ口フエニル） 一 2— ( 4—トリフルォロメチルフエニル） ィ ミダゾ一ルー 4—カルボン酸 8. 9 gを得た。 融点 1 78— 1 80°0 (分 解)。

In the same manner as in Raw Material Synthesis Example 5, 5- (4-chlorophenyl) 1-2- (4-trifluoromethylphenyl) imidazo-1-yl 4-carboxylate ethyl ester 9.0 g to 5- (4-chlorophenyl) 8.9 g of phenyl) 1-2- (4-trifluoromethylphenyl) dimidazole-1-carboxylic acid was obtained. Mp 1 78-1 80 ° 0 (decomposition).

Raw material synthesis example 39

原料合成例 2と同様にして 3— (4—クロロフヱニル） — 2—ヒ ドロキシイミ ノー 3—ォキソプロピオン酸ェチルエステル 1 0. 0 g、 4—シァノベンズァ ルデヒド 7. 7 gおよび酢酸アンモニゥム 30. 8 gから 5— (4—クロ口 フエニル） ー 2— （4一シァノフエニル） イ ミダゾ一ルー 4—カルボン酸ェチル エステル 3. 6 gを得た。 融点 235— 237°C。

In the same manner as in Raw Material Synthesis Example 2, from 3- (4-chlorophenyl) -2-hydroxyimino 3-oxopropionic acid ethyl ester 10.0 g, 7.7 g of 4-cyanobenzaldehyde and 30.8 g of ammonium acetate 3.6 g of 5- (4-chlorophenyl) -2- (4-cyanophenyl) imidazo-l- 4-ethyl carboxylate was obtained. 235-237 ° C.

Raw material synthesis example 40

原料合成例 3と同様にして 5— (4—クロ口フエニル） 一 2— (4—シァノフ ェニル） イミダゾ一ルー 4—カルボン酸ェチルエステル 3. 0 gから 5— （4 一クロ口フエニル） 一 2— (4—シァノフエニル） イ ミダゾール _ 4—カルボン 酸 3. 1 gを得た。 融点 1 87— 1 88°C (分解）。

5- (4-chlorophenyl) 1-2- (4-cyanophenyl) imidazo-1-yl 4-carboxylate ethyl ester from 3.0 g to 5— (4-chlorophenyl) 1-2 in the same manner as in Raw Material Synthesis Example 3 — (4-Cyanophenyl) imidazole_4-carboxylic acid 3.1 g was obtained. Melting point 1 87-1 88 ° C (decomposition).

原料合成例 2と同様にして 3— (4—フルオロフェニル） 一 2—ヒドロキシィ ミノー 3—ォキソプロピオン酸ェチルエステル 1 5. 0 g、 4一シァノベンズ アルデヒ ド 12. 3 gおよび酢酸アンモニゥム 48. 4 gから 5— (4—フ ルオロフェニル） 一 2— (4—シァノフエニル） イ ミダゾール一 4一力ルボン酸 ェチルエステル 3. l gを得た。 融点 208— 2 1 1°C。 Raw material synthesis example 4 1

In the same manner as in Raw Material Synthesis Example 2, 3- (4-fluorophenyl) -1-hydroxyminoh 3-oxopropionic acid ethyl ester 15.0 g, 4-cyanobenzaldehyde 12.3 g and ammonium acetate 48.4 From 5-g, 5- (4-fluorophenyl) 1-2- (4-cyanophenyl) imidazole-14-ethyl ribonate 3.lg was obtained. Melting point 208—2 11 ° C.

Raw material synthesis example 42

原料合成例 3と同様にして 5— (4—フルオロフヱニル） 一 2— (4—シァノ フェニル）ィ ミダゾ一ル— 4一力ルボン酸ェチルエステル 3. 0 gから 2—（ 4 —シァノフエニル） _ 5— （4一フルオロフェニル） イ ミダゾールー 4一カルボ ン酸 2. l gを得た。 融点 193— 194°C (分解）。

In the same manner as in Raw Material Synthesis Example 3, 5- (4-fluorophenyl) 1-2- (4-cyanophenyl) imidazole-4 monoethyl ester of rubonic acid 3.0 g to 2- (4-cyanophenyl) _5— (4-Monofluorophenyl) imidazole-4-carbonic acid 2.lg was obtained. Melting point 193-194 ° C (decomposition).

Raw material synthesis example 43

原料合成例 2と同様にして 2—ヒ ドロキシイミノー 3—ォキソ一 3—フエニル プロビオン酸ェチルエステル 2. 5 g、 4—トリフルォロメチルベンズアルデ ヒ ド 9. 5 gおよび酢酸アンモニゥム 28. 2 gから 5—フエニル _ 2— (4 一トリフルォロメチルフェニル） ィ ミグゾールー 4—カルボン酉変ェチルエステル 3. 6 gを得た。 融点 173— 174°C。

In the same manner as in Raw Material Synthesis Example 2, 2.5 g of 2-hydroxyimino 3-oxo-3-phenylphenylpropionate 2.5 g of 9.5 g of 4-trifluoromethylbenzaldehyde and 28.2 g of ammonium acetate were used. —Phenyl — 2— (4-trifluoromethylphenyl) imiguzol-4-carbone Toriethyl ester 3.6 g was obtained. 173-174 ° C.

Raw material synthesis example 44

原料合成例 3と同様にして 5—フエ二ルー 2— (4—トリフルォロメチルフェ ニル） イ ミダゾールー 4一力ルボン酸ェチルエステル 3. 5 gから 5—フエ二 ル— 2—（4一ト リフルォロメチルフェニル）ィ ミダゾ一ルー 4一力ルボン酸 3. l gを得た。 融点 209— 2 10°C (分解)。

In the same manner as in Raw Material Synthesis Example 3, 5-phenyl 2- (4-trifluoromethylphenyl) imidazole-4 monoethyl rubonate 3.5 g to 5-phenyl-2- (4-tol (Rifluoromethylphenyl) imidazo-l-ru-rubonic acid 3. lg was obtained. Melting point 209—2 10 ° C (decomposition).

Raw material synthesis example 45

原料合成例 2と同様にして 3— (4—ブロモフエニル） — 2—ヒドロキシイミ ノー 3—ォキソブロピオン酸ェチルエステル 1 0. 0 g、 4— トリフルォロメ チルベンズアルデヒド 8. 7 gおよび酢酸アンモニゥム 2 5. 6 gから 5— ( 4一ブロモフエニル） 一 2— （ 4一 トリフルォロメチルフエニル） ィミダゾ一 ルー 4—カルボン酸ェチルエステル 4.2 gを得た。 融点 1 67— 1 68°C, 原料合成例 46

In the same manner as in Raw Material Synthesis Example 2, 3- (4-bromophenyl) -2-hydroxyimino 3-oxopropionic acid ethyl ester 10.0 g, 4-trifluoromethyl benzaldehyde 8.7 g and ammonium acetate 25.6 g 4.2 g of 5- (4-bromophenyl) 1-2- (4-1trifluoromethylphenyl) imidazo-l-carboxylic acid ester was obtained. Melting point 1 67— 1 68 ° C, Raw material synthesis example 46

原料合成例 3と同様にして 5— (4—ブロモフエニル） — 2— (4— ト リフル ォロメチルフエニル） イミダゾールー 4—カルボン酸ェチルエステル 4. 0 g から 5— （4一プロモフエニル） 一 2— （ 4— ト リフルォロメチルフエニル） ィ ミダゾ一ルー 4—カルボン酸 3. 7 gを得た。 融点 1 7 9— 1 80 （分 解)。

5- (4-Bromophenyl)-2- (4-trifluoromethylphenyl) imidazole-4-carboxylic acid ethyl ester from 4.0 g to 5- (4-promophenyl) 1 2— (4-Trifluoromethylphenyl) midazolone 4-carboxylic acid (3.7 g) was obtained. Melting point 179-180.

Raw material synthesis example 47

Dissolve 300 g of 4-hydroxybenzaldehyde and 279 g of 2-chloroethyl methyl ether in 3 L of DMF, and add 408 g of potassium carbonate. The mixture was heated and stirred with C for 16 hours. After the reaction, the reaction mixture was poured into water and the released oil was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous sodium hydroxide solution and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After drying, the mixture was concentrated under reduced pressure to obtain 212 g of oily 4- (2-methoxetoxy) benzaldehyde.

1 H-NMR 270 MHz (CD C 1 pm) δ 9.87 (1 H, s), 7.82 (2 H, d), 7.02 (2 H, d) ヽ 4.18 (2 H, m), 3.77 (2 H, m), 3.44 (3H, s)

Raw material synthesis example 48

原料合成例 2と同様にして 3— (4—クロ口フエニル） 一2—ヒ ドロキシイ ミ ノー 3—ォキソプロピオン酸ェチルエステル 1 5 0 g、 4一 （2—メ 卜キシェ 卜キシ） ベンズアルデヒ ド 1 6 5 gおよび酢酸アンモニゥム 44 7 gから 5 一 （4一クロ口フエニル） 一 2— 〔4— ( 2—メ トキシェトキシ） フエニル〕 ィ ミダゾ一ルー 4—カルボン酸ェチルエステル 6 2. l gを得た。 融点 1 5 7 - 158 °C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyiminor 3-oxopropionate ethyl ester 150 g, 4- (2-methoxyethoxy) benzaldehyde 1 From 65 g and 447 g of ammonium acetate, 51- (4-chloro-2-phenyl) 1-2- [4- (2-methoxetoxy) phenyl] -imidazo-1-yl 4-carboxylate ethyl ester 62.lg was obtained. Melting point 1 5 7-158 ° C.

Raw material synthesis example 49

原料合成例 3と同様にして 5— (4—クロロフヱニル） 一 2— 〔4— (2—メ トキシェトキシ） フエニル〕 イミダゾ一ル一 4—カルボン酸ェチルエステル 6 2 gから 5— (4—クロロフェニル） 一 2— 〔4一 （2—メ 卜キシェ卜キシ） フ ェニル〕 イミダゾールー 4一力ルボン酸 52 gを得た。 融点 142— 14 3°C (分解)。

5- (4-chlorophenyl) -1-2- (4- (2-methoxetoxy) phenyl) imidazole-1-ethyl carboxylate 62 From 6 g of 5- (4-chlorophenyl) -1 2- (4- (2-methoxyphenyl) phenyl) imidazole-4 52 g of rubonic acid were obtained. 142-143 ° C (decomposition).

Raw material synthesis example 50

原料合成例 45と同様にして 4—ヒ ドロキシベンズアルデヒド 10 g、 2— (2—クロ口エトキシ）ェチルメチルエーテル 9. O g、炭酸カリウム 13. 5 gから油状の 4一 〔2— ( 2—メ トキシェトキシ） ェトキシ〕 ベンズアルデヒ ド 10 gを得た。

In the same manner as in Raw Material Synthesis Example 45, 10-g of 4-hydroxybenzaldehyde, 9.O g of 2- (2-chloroethoxyethoxy) ethyl methyl ether, and 13.5 g of potassium carbonate were used to obtain oily 4- [2- ( 2-Methoxyxetoxy) 10 g of benzaldehyde was obtained.

^{1 H-NMR 270MH z (CD} C 1, s p pm) (5: 9. 88 (1 H, s), 7. 82 (2 H, d), 7. 0 1 (2 H, d)ヽ. 4.22 (2H, t), 3.89 (2H, t), 3.54-3.78 (7H, m)

Raw material synthesis example 51

原料合成例 2と同様にして 3— (4—クロロフヱニル） 一 2—ヒドロキシイ ミ ノー 3—ォキソプロビオン酸ェチルエステル 8. 8 g、 4一 〔2— （2—メ 卜 キシエトキシ） エトキシ〕 ベンズアルデヒ ド 10. 2 gおよび酢酸アンモニゥ ム 26. 6 gから 5— (4—クロ口フエニル） 一 2— {4— 〔2— （2—メ ト キシエトキシ） エトキシ〕 フエ二ル} イミダゾール一 4一力ルボン酸ェチルエス テル 2. 3 gを得た。 融点 132— 133°C。

3- (4-chlorophenyl) -1-hydroxyimino 3-oxopropionic acid ethyl ester 8.8 g, 4- [2- (2-methoxyethoxy) ethoxy] benzaldehyde 10. 2 g and ammonium acetate 26.6 g from 5— (4-chlorophenyl) 1-2— {4— [2- (2-methoxyethoxy) ethoxy] phenyl} imidazole-14 2.3 g of ter were obtained. 132-133 ° C.

Raw material synthesis example 52

原料合成例 3と同様にして 5— (4—クロロフヱニル）— 2— {4—〔2— （2 メ トキシェ卜キシ） ェトキシ〕 フェニル } ィミダゾ一ル一 4一力ルボン酸ェチ ルエステル 2. O gから 5— （4一クロ口フエニル） 一 2— {4— 〔2— （2 —メ トキシェトキシ）ェトキシ〕フエ二ル}ィミダゾ一ルー 4一力ルポン酸 1. 3 gを得た。 融点 1 42— 1 43°C (分解）。

5- (4-chlorophenyl) -2- (4- (2- (2methoxyethoxy) ethoxy) phenyl) Ester 2-Og to give 5- (4-chlorophenyl) -1-2- {4- (2- (2-methoxyethoxy) ethoxy] phenyi} imidazo-l-ru 4 1.3 g ruponic acid Was. Melting point 142-143 ° C (decomposition).

Raw material synthesis example 53

原料合成例 4 5と同様にして 4ーヒ ドロキジペンズアルデヒド 1 3. 9 g、 2—クロ口ェチルイソプロビルエーテル 1 4 g、 炭酸カリウム 1 5. 8 gか ら 4一 （2—イソプロポキシエトキシ） ベンズアルデヒド 8. 3 gを得た。

In the same manner as in Raw Material Synthesis Example 45, 13.9 g of 4-hydroxydipenzazaldehyde, 14 g of 2-chloroethylisopropyl ether, and 15.8 g of potassium carbonate were converted to 4- (2-isopropane). Propoxyethoxy) 8.3 g of benzaldehyde was obtained.

1 H-NMR 270 MHz (CD C 1: ppm) δ: 9.88 (1H, s), 7-82 (2H, d), 7.02 (2H, d ), 4.19 (2H, t), 3.80 (2H, t), 3.62-3.82 (1H, m), 1.20 (6H, d)

Raw material synthesis example 54

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) -12-hydroxyimino-3-oxopropionate ethyl ester 6.3 g, 4- (2-isopropoate) Xyethoxy) benzaldehyde 8.3 g and ammonium acetate 20.5 g to 5- (4-chlorophenyl) -1-2- [4- (2-isopropoxyethoxy) phenyl] imidazole-4-carbone 3.58 g of acid ethyl ester were obtained. Mp 1 55-158 ° C.

Raw material synthesis example 55

Raw material synthesis example 5— (4-chlorophenyl) -12- [4- (2-isopropoxyethoxy) phenyl] imidazole-1-ethylcarboxylate from 3.58 g 5- (4-chlorophenyl) 1-2- [4- (2-isopropoxyethoxy) phenyl] imidazole-4 monorubonic acid 3.24 g was obtained. 180 ° C (decomposition).

Raw material synthesis example 56

原料合成例 45と同様にして 4—ヒ ドロキシベンズアルデヒ ド 24 ' 4 g 2—クロ口ェチルェチルエーテル 2 1. 7 g、 炭酸カリウム 28 gから 4 (2—エトキシエトキシ） ベンズアルデヒド 12. 4gを得た。

In the same manner as in Raw Material Synthesis Example 45, 4-hydroxybenzaldehyde 24 '4 g 2-cloethyl ethyl ether 21.7 g, potassium carbonate 28 g to 4 (2-ethoxyethoxy) 12.4 g of benzaldehyde was obtained.

1 H-NMR 270MHz (CD C 1 3, p pm) <5: 9. 88 (1 H, s), 7 83 (2 H, d), 7. 03 (2H, d)ヽ4.2 1 ( 2H, t), 3.82 (2H.t), 3.57-3.65 (2H, q), 1.25 (6H, t)

Raw material synthesis example 57

原料合成例 2と同様にして 3— （4—クロ口フエニル） 一2—ヒドロキシイミ ノ— 3—ォキソプロビオン酸ェチルエステル 10. 9 g、 4一 （2—エトキシ エトキシ） ベンズアルデヒ ド 12. 4 gおよび酢酸アンモニゥム 33 から 5— （4一クロ口フエニル） 一 2— 〔4— (2—エ トキシエトキシ） フエニル〕 イミダゾ一ルー 4一力ルボン酸ェチルエステル 5. 2 gを得た。 融点 15 0 - 152。C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) -1-hydroxyimino-3-oxopropionate ethyl ester 10.9 g, 4- (2-ethoxyethoxy) benzaldehyde 12.4 g and acetic acid From the ammonia 33, 5.2 g of 5- (4-chlorophenyl) 1-2- [4- (2-ethoxyethoxy) phenyl] imidazo-l-4u-ethyl ribonate was obtained. 150-152. C.

Raw material synthesis example 58

原料合成例 3と同様にして 5 _ (4—クロ口フエニル） 一 2— 〔4一 （2—ェ トキシェトキシ）フエニル〕ィ ミダゾ一ルー 4一力ルボン酸ェチルエステル 5. 2 gから 5— （4一クロ口フエニル） 一 2— 〔4一 （2—エトキシエトキシ） フ ェニル〕 イ ミダゾールー 4一力ルボン酸 5. O gを得た。 融点 145— 1 50°C (分解)。

In the same manner as in Raw Material Synthesis Example 3, 5 _ (4-chlorophenyl) 1 2- Toxitytoxy) phenyl] midazole 4-ethyl ether ester 5.2 g to 5— (4-chlorophenyl) 1-2— [4-1 (2-ethoxyethoxy) phenyl] imidazole-4 iron rubonic acid 5. O g was obtained. Melting point 145-150 ° C (decomposition).

Raw material synthesis example 59

原料合成例 45と同様にして 4ーヒ ドロキシベンズアルデヒ ド 16. 8 g、 2—〔2— ( 2—クロ口エ トキシ）エトキシ〕ェチル メチル ェ一テル 25. 24 g、 炭酸力リウム 1 9 から 4— { 2 - 〔2— (2—メ トキシェ トキシ） エトキシ〕 エトキシ } べンズアルデヒ ド 18. 7 gを得た。

In the same manner as in Raw Material Synthesis Example 45, 16.8 g of 4-hydroxybenzaldehyde, 25.24 g of 2- [2- (2-chloroethoxy) ethoxy] ethyl methyl ether, 25.24 g of potassium carbonate 1 From 9 to 4— {2- (2- (2-methoxyethoxy) ethoxy] ethoxy} benzaldehyde 18.7 g was obtained.

1 H-NMR 270 MHz (CD C 1 ppm) (5: 9.88 (1H, s), 7.83 (2H, d), 7.02 (2H, d), 4.22 (2 H, t), 3.89 (2 H, t), 3.54-3.78 (11 H, m)

Raw material synthesis example 60

原料合成例 2と同様にして 3— (4—クロ口フエニル） 一 2—ヒ ドロキシィ ミ ノー 3—ォキソプロビオン酸ェチルエステル 1 0. 5 g、 4 - { 2 - 2 - ( 2 ーメ トキシェトキシ） エトキシ〕 エトキシ } べンズアルデヒ ド 1 8. 7 gおよ び酢酸アンモニゥム 3 1. 6 gから 5— （4一クロ口フエニル） 一 2— (4— {2— 〔2— ( 2—メ トキシェトキシ） ェトキシ〕 ェトキシ} フェニル） イ ミダ ゾ一ルー 4—カルボン酸ェチルエステル 6. 3 gを得た。 融点 90°C。

3- (4-chlorophenyl) 1-2-hydroxymino-3-oxopropionic acid ethyl ester 10.5 g, 4- (2-2- (2-methoxyethoxy) ethoxy) in the same manner as in Raw Material Synthesis Example 2 Ethoxy} Benzaldehyde 18.7 g and ammonium acetate 31.6 g from 5— (4-chlorophenyl) 1-2— (4— {2— [2- (2-methoxyethoxy) ethoxy] Ethoxy) phenyl) imidazo-l-u-l 4-carboxylate ethyl ester 6.3 g was obtained. Melting point 90 ° C.

Raw material synthesis example 6 1

原料合成例 3と同様にして 5— （4一クロ口フエニル） 一 2— (4— {2— 〔2 • ( 2—メ トキシェ卜キシ） ェトキシ〕 ェ トキシ} フエニル） ィ ミダゾ一ルー 4 カルボン酸ェチルエステル 6. 3 gから 5— （4一クロ口フエニル） 一 2— (4 - {2 - 〔2— (2—メ 卜キシエトキシ） エトキシ〕 エトキシ } フエニル） イミダゾ一ルー 4—カルボン酸 5. 7 gを得た。

In the same manner as in Raw Material Synthesis Example 3, 5- (4-chlorophenyl) 1-2- (4- {2- (2 • (2-methoxyethoxy) ethoxy] ethoxy} phenyl) -imidazo-l-carbone Ethyl ester from 6.3 g to 5— (4-chlorophenyl) 1 2— (4- {2- [2- (2-Methoxyethoxy) ethoxy] ethoxy} phenyl) Imidazo-l--4-carboxylic acid 5.7 g was obtained.

^{1 H-NMR 270MH z (CD} C 1 3 pm.) Δ 10. 7 - 1 1. 4 (2 Η, br), 7. 80 - 7. 98 (4 H, m)ヽ7.1 2 -7 .39 (2H, m), 6, 70 (2H, br), 3.24-3.92 (15H, m)

Raw material synthesis example 62

原料合成例 45と同様にして 4ーヒドロキシベンズアルデヒド 14. 4 g、 3—クロロブ口ビルメチルエーテル 1 2. 8 g、 炭酸カリウム 1 6. 3 g力 ら 4一 （3—メ トキシプロボキシ） ベンズアルデヒド 4. 79 gを得た。

In the same manner as in Raw Material Synthesis Example 45, 14.4 g of 4-hydroxybenzaldehyde, 12.8 g of 3-chlorobutane bil methyl ether, 16.3 g of potassium carbonate, etc. 4- (3-methoxypropoxy) benzaldehyde 4. 79 g were obtained.

1 H-NMR 270 MHz (CDC 1 3, ppm) 5: 9. 88 (1 H, s), 7. 83 (2H, d), 7. 0 1 (2 H, d), 4. 1 5 ( 2H, t), 3.56 (2H, t), 3.36 (3H, s), 2.08 (2H, dt)

Raw material synthesis example 63

原料合成例 2と同様にして 3— (4—クロ口フエニル） 一 2—ヒドロキシイミ ノー 3—ォキソブロピオン酸ェチルエステル 4. 2 g、 4— (3—メ 卜キシプ ロポキシ） ベンズアルデヒ ド 4. 79 gおよび酢酸アンモニゥム 12. 7 g から目的の 5— （4一クロ口フエニル） 一 2— 〔4— (3—メ 卜キシプロポキシ） フエニル〕 イミダゾ一ルー 4 _カルボン酸ェチルエステル 2 gを得た。 融点 179— 180。C。

3- (4-chlorophenyl) 1-2-hydroxyimi in the same manner as in Raw Material Synthesis Example 2 No 3-oxopropionic acid ethyl ester 4.2 g, 4- (3-methoxypropoxy) benzaldehyde 4.79 g and ammonium acetate 12.7 g were converted to the desired 5- (4-chlorophenyl) 1-2- [ 4- (3-Methoxypropoxy) phenyl] 2 g of imidazoyl 4-carboxylate ethyl ester was obtained. Melting point 179-180. C.

Raw material synthesis example 64

In the same manner as in Raw Material Synthesis Example 5, 5- (4-chlorophenyl) 1-2- [4- (3-methoxypropoxy) phenyl] -midazo-l-4 mono-ethyl ribonate 2 g to 5- (4 1.87 g of 4- (3-methoxypropoxy) phenyl imidazole-4-carboxylic acid were obtained. 135-140 ° C (decomposition).

原料合成例 9と同様にして 4—フルォロベンゾニトリル 50 g、 へキサメチ レンイ ミン 39. 6 gから 的の 4— (ホモビべリジン一 1—ィル） ベンゾニ トリル 24. 5 gを得た。 融点 62。C。 原料合成例 66

原料合成例 1 0と同様にして 4— (ホモビべリジン一 1一ィル） ベンゾニトリ ル 54 gから 的の 4一 （ホモピぺリジン一 1一ィル） ベンズアルデヒドを油 状物として 45 gを得、 精製することなく次の原料合成例 67に用いた。 Example of raw material synthesis 65

In the same manner as in Raw Material Synthesis Example 9, 50 g of 4-fluorobenzonitrile and 39.6 g of hexamethylenimine were used to obtain 24.5 g of the target 4- (homobiberidine-11-yl) benzonitrile. . Melting point 62. C. Raw material synthesis example 66

In the same manner as in Raw Material Synthesis Example 10, 45 g of target 4- (homopiperidine-11-yl) benzaldehyde was obtained as an oil from 54 g of 4- (homobiberidine-11-yl) benzonitrile as an oil. This was used in the next raw material synthesis example 67 without purification.

Example of raw material synthesis 67

原料合成例 2と同様にして 3— （4—クロ口フエニル） 一 2—ヒ ドロキシイ ミ ノー 3—ォキソプロビオン酸ェチルエステル 37. 7 g、 原料合成例 64にて 得られた未精製の 4一 （ホモビぺリジン一 1—ィル） ベンズアルデヒ ド 45. 0 gおよび酢酸アンモニゥム 1 13. 6 gから 5— （4一クロ口フエニル） 一 2— 〔4一 （ホモピぺリジン一 1一ィル） フエニル〕 イミダゾールー 4一カルボ ン酸ェチルエステル 9. 5 gを得た。 融点 203— 204°C。

In the same manner as in Raw Material Synthesis Example 2, 37.7 g of 3- (4-chlorophenyl) 1-2-hydroxymino 3-ethyl ethyl oxopropionate were obtained. From 15.0 g of benzaldehyde to 15.0 g of benzaldehyde and from 13.6 g of ammonium acetate, 5— (4-phenylphenyl) 1-2— [4-1 (homopiridine-11-yl) phenyl] 9.5 g of imidazole-4-ethyl carbonate was obtained. 203-204 ° C.

Raw material synthesis example 68

原料合成例 3と同様にして 5 _ (4—クロロフヱニル） — 2— 〔4一 （ホモピ ペリジン— 1 -ィル） フヱニル〕 イミダゾ一ル— 4 -カルボン酸ェチルエステル 9. 0 gから 5— （4—クロ口フエニル） 一 2— 〔4— (ホモビぺリジンー 1一 ィル） フエニル〕 イミダゾ一ル— 4—カルボン酸 2. 5 gを得た。 融点 2 08。C (分解)。

In the same manner as in Raw Material Synthesis Example 5, 5_ (4-chlorophenyl) —2- [4-1 (homopiperidine-1-yl) phenyl] imidazoyl-4-carboxylate ethyl ester 9.0 g to 5— (4 —Cross-mouth phenyl) 1-2— [4- (Homobiridine-11-yl) phenyl] imidazole-4-carboxylic acid 2.5 g was obtained. Melting point 208. C (decomposition).

Raw material synthesis example 69

原料合成例 2と同様にして 3— （4—フルオロフェニル） 一 2—ヒ ドロキシィ ミノー 3—ォキソプロビオン酸ェチルエステル、 原料合成例 6 にて得られた 精製の 4— (ホモビぺリジン一 1—ィル） ベンズアルデヒドおよび酢酸アンモニ ゥムから 5— (4—フルオロフェニル） 一 2— 〔4_ (ホモビぺリジン一 1ーィ ル） フエニル〕 イミダゾ一ル一 4一力ルボン酸ェチルエステルが得られる。

3- (4-Fluorophenyl) 1-2-hydroxyminoh 3-oxopropionic acid ethyl ester in the same manner as in Raw Material Synthesis Example 2, the purified 4- (homobidiridine-11-yl) obtained in Raw Material Synthesis Example 6. ) Benzaldehyde and ammonium acetate give 5- (4-fluorophenyl) 1-2- [4_ (homobidiridine-11-yl) phenyl] imidazole-14-ethyl ethyl ester.

Raw material synthesis example 70

原料合成例 3と同様にして 5 _ (4—フルオロフェニル） 一 2— 〔4— (ホモ ピぺリジン一 1—ィル） フエニル〕 イミダゾールー 4—カルボン酸ェチルエステ ルから 5— (4—フルオロフェニル） _ 2— 〔4— (ホモビぺリジン一 1—ィル） フェニル〕 ィミダゾール— 4一力ルボン酸が得られる。

In the same manner as in Raw Material Synthesis Example 3, 5_ (4-fluorophenyl) 1-2- [4- (homopyridin-1-1-yl) phenyl] imidazole-4-carboxylate is converted to 5- (4-fluorophenyl) ) _ 2— [4- (homobidiridine-1-yl) phenyl] imidazole—4 is obtained.

Raw material synthesis example 71

原料合成例 2と同様にして 3— （ 5—メチルチオフェン一 2—ィル） — 2— ヒドロキシイミノー 3—ォキソプロピオン酸ェチルエステル 1 5. 3 g、 4— トリフルォロメチルベンズアルデヒ ド 1 8. 5 gおよび酢酸アンモニゥム 4 8. 9 から 5— （ 5—メチルチオフェン一 2—ィル） ー 2— （4一トリフル ォロメチルフエニル） イミダゾ'一ルー 4—カルボン酸ェチルエステル 3. 3 g を得た。 融点 176_ 177°C。

3- (5-Methylthiophene-2-yl) —2-hydroxyimino 3-oxopropionic acid ethyl ester 15.3 g, 4-trifluoromethylbenzaldehyde 1 in the same manner as in Raw Material Synthesis Example 2 8.5 g and ammonium acetate 4 8.9 to 5— (5-methylthiophene-2-yl) -2- (4-trifluoromethylphenyl) imidazo'-l-ru-4-carboxylate 3.3 g. Melting point 176_177 ° C.

Raw material synthesis example 72

原料合成例 3と同様にして 5 _ ( 5—メチルチオフェン— 2—ィル）— 2—（4 —トリフルォロメチルフエニル） ィミダゾールー 4一力ルボン酸ェチルエステル 4 . O gから 5— （ 5—メチルチオフェン一 2—ィル） 一 2— （4一トリフルォ ロメチルフエニル）イミダゾ一ル— 4—カルボン酸 2 . 6 gを得た。 融点 1 5 4 °C (分解)。

5_ (5-Methylthiophene-2-yl) -2- (4-trifluoromethylphenyl) imidazole-4 One-pot ethyl rubnate 4.Og to 5— (5 2.6 g of —methylthiophene-2-yl) -12- (4-trifluoromethylphenyl) imidazole-4-carboxylic acid was obtained. Melting point: 154 ° C (decomposition).

Raw material synthesis example 7 3

3_ (5-Methylthiophene-12-yl) -12-hydroxyimino-3-oxopropionate in the same manner as in Synthesis Example 2 of the raw material, 41-morpholinobenzaldehyde obtained in Synthesis Example 1 Ammonium acetate gives 5 _ (5-methylthiophene-2-yl) — 2- (41-morpholinophenyl) imidazole-4 monoethyl ribonate.

Example of raw material synthesis 7 4

5- (5-Methylthiophen-2-yl) -2- (4-morpholinophenyl) imidazole-4 5- (5-methylthiophen-1-2-) 1) 2- (4-morpholinophenyl) imidazolu-l 4-carponic acid is obtained.

Raw material synthesis example 7 5

原料合成例 2と同様にして 3— （ 5—メチルチオフヱン一 2 —ィル） 一 2—ヒ ドロキシィミノ— 3—ォキソプロピオン酸ェチルエステル、 原料合成例 4 7で得 られた 4 - ( 2—メ トキシェトキシ） ベンズアルデヒ ドおよび酢酸アンモニゥム から 2— 〔4一 （ 2—メ トキシェトキシ） フェニル〕 一 5— （ 5—メチルチオフ ェンー 2 -ィル） ィミダゾール— 4一力ルボン酸ェチルエステルが得られる。

3- (5-Methylthiophenone-12-yl) -12-hydroxyimino-3-ethyl oxopropionate in the same manner as in Raw Material Synthesis Example 2, 4- (2-Methoxyxethoxy) ) Benzaldehyde and ammonium acetate give 2- [4- (2-methoxetoxy) phenyl] -15- (5-methylthiophen-2-yl) imidazole-4 ethyl ethyl ribonate.

Raw material synthesis example 6

2- [4- (2-Methoxyethoxy) phenyl] -15- (5-Methylthiophene-2-yl) imidazole-1-4 [4- (2-Methoxyethoxy) phenyl] -1-5- (5-Methylthiophene-2-yl) imidazo-l-u-4-carbonic acid is obtained.

Raw material synthesis example 77

6.8 g of 2-N- (4-bromophenyl) -N, N-dimethylethylamine was heated and refluxed with magnesium for 1 hour to prepare a Grignard reagent, and then reacted with DMF. 4.2 g of 2-dimethylaminoethyl) benzaldehyde was obtained as an oily substance.

¹ H-NMR 270 MHz (CD C 1 ppm) δ: 9.87 (1 H, s), 7.82 (2H, d), 7.02 (2H, d), 4.18 (2 H , M), 3.77 (2 H, m), 3.44 (3 H, s)

Raw material synthesis example 78

原料合成例 2と同様にして 3— （4—クロ口フエニル） 一 2—ヒ ドロキシイ ミ ノー 3—ォキソプロピオン酸ェチルエステル 4. 0 g、 4— ( 2—ジメチルァ ミノェチル） ベンズアルデヒ ド 4. 2 gおよび酢酸アンモニゥム 1 2. 0 g から 5— （4一クロ口フエニル） 一 2— 〔4一 （ 2—ジメチルアミノエチル） フ ェニル〕 イ ミダゾ一ルー 4—カルボン酸ェチルエステル 0. 6 gを得た。 融点 128 - 1 29。C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) -12-hydroxymino-3-oxopropionate ethyl ester 4.0 g, 4- (2-dimethylaminominethyl) benzaldehyde 4.2 g From ammonium acetate and 12.0 g, 0.6 g of 5- (4-chlorophenyl) 1-2- [4- (2-dimethylaminoethyl) phenyl] imidazo-1-yl 4-carboxylate was obtained. . 128-129. C.

Raw material synthesis example 79

原料合成例 3と同様にして 5— （4—クロ口フエニル） 一 2— 〔4— (2—ジ メチルアミノエチル） フエニル〕 イ ミダゾール一 4—カルボン酸ェチルエステル から 5— (4—クロ口フエニル） 一 2— 〔4一 （ 2—ジメチルアミノエチル） フ ェニル〕 ィミダゾ一ルー 4一力ルボン酸が得られる。

In the same manner as in Raw Material Synthesis Example 5, 5- (4-chlorophenyl) 1-2- [4- (2-dimethylaminoethyl) phenyl] imidazole-1 4-carboxylic acid ethyl ester is converted to 5- (4-chlorophenyl). 1) 2- [4- (2-Dimethylaminoethyl) phenyl] imidazo-l-ul 4 is obtained.

原料合成例 4 7と同様にして 4—ヒ ドロキシベンズアルデヒ ド、 4—クロロブ チルメチルエーテル、 炭酸力リウムから 4一 （ 4—メ トキシブトキシ） ベンズァ ルデヒ ドが得られる。 Raw material synthesis example 80

In the same manner as in Raw Material Synthesis Example 47, 4- (4-methoxybutoxy) benzaldehyde can be obtained from 4-hydroxybenzaldehyde, 4-chlorobutylmethyl ether, and lithium carbonate.

Raw material synthesis example 8 1

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyiminor 3-oxoethyl propionate, 4- (4-methoxybutoxy) pentanealdehyde and ammonium acetate — (4-Methyl phenyl) 1 2 -— (4- (4-Methoxybutoxy) phenyl) imidazole-4 Ethyl ribonate is obtained.

Raw material synthesis example 8 2

In the same manner as in Raw Material Synthesis Example 5, 5- (4-chlorophenyl) 1-2— [4- (4-methoxybutoxy) phenyl] imidazole-4— (4-chlorophenyl) 1-2 — [4 -— (4-Methoxybutoxy) phenyl] ミ Midazo-l-luu 4 is obtained.

Raw material synthesis example 83

原料合成例 10と同様にして 4一 （ 4—モルホリノビペリジン一 1—ィル） ベ ンゾニト リル 23. 1 gから 0的の 4一 （ 4一モルホリノピペリジン一 ：！.一ィ ル） ベンズアルデヒ ド 2 1 gを得た。 融点 130°C。 In the same manner as in Raw Material Synthesis Example 9, 4-fluorobenzonitryl 11.9 g and 4-morpholinobiperidine 16.7 g were converted to S-like 4- (4-morpholinobiperidine-1 _Yl) Benzonitrile 23. lg was obtained. 123-128 ° C. Raw material synthesis example 84

In the same manner as in Raw Material Synthesis Example 10, forty-one (4-morpholinopiperidine-1-yl) benzonitrile is used. B) 21 g of benzaldehyde was obtained. 130 ° C.

Raw material synthesis example 85

原料合成例 2と同様にして 3— （4—クロ口フエニル） 一 2—ヒ ドロキシイ ミ ノ一 3—ォキソプロピオン酸ェチルエステル 6. 2 g、 4一 （4一モルホリノ ビぺリジン一 1—ィル） ベンズアルデヒ ド 1 0 gおよび酢酸アンモニゥム 1 8. 7 gから目的の 5— (4—クロ口フエニル） 一 2— 〔4— (4—モルホリノ ビペリジン一 1一ィル） フエニル〕 ィミダゾ一ルー 4—カルボン酸ェチルエステ ル 6. 2 gを得た。 融点 228— 23 1°C。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyimi-no-3-oxopropionate ethyl ester 6.2 g, 4- (4-morpholino bipyridine-1) Le) Benzaldehyde (10 g) and ammonium acetate (18.7 g) were converted to the desired 5- (4-chlorophenyl) -1-2- [4- (4-morpholino-biperidine-1-11) phenyl) imidazo-l-4 —6.2 g of ethyl carboxylate was obtained. Melting point 228—231 ° C.

Raw material synthesis example 86

原料合成例 3と同様にして 5— （4—クロロフヱニル） — 2— 〔4一 （4ーモ ルホリノビペリジン一 1一ィル） フエニル〕 イ ミダゾ一ル一 4—カルボン ェチ ルエステル 6. 2 gから 5— （4—クロ口フエニル） 一 2— 〔4— (4—モル ホリノビペリジン一 1—ィル） フエニル〕 イ ミダゾ一ル一 4一力ルボン酸 5. 6 gを得た。 融点 1 8 0— 1 8 5 °C (分解) _c

5- (4-Chlorophenyl) —2- (4-1- (4-morpholinobiperidine-11-yl) phenyl) -imidazole-1-4-carboxyethyl ester 6 in the same manner as in Raw Material Synthesis Example 3 From 2 g to 5— (4-chlorophenyl) 1 2— [4— (4-Morolinobiperidine 1-yl) phenyl] imidazole 1 4 1-Rubonic acid 5. 6 g were obtained. Melting point 180-185 ° C (decomposition) _c

Raw material synthesis example 8 7

原料合成例 2と同様にして 3— （4—フルオロフェニル） 一 2—ヒ ドロキシィ ミノ一 3—ォキソプロピオン酸ェチルエステル、 4一 （ 4—モルホリノビベリジ ンー 1—ィル） ベンズアルデヒ ドおよび酢酸アンモニゥムから 5— （ 4—フルォ 口フエニル） 一 2— 〔4一 （ 4一モルホリノビペリジン一 1 一ィル） フエニル〕 ィミダゾ一ルー 4一力ルボン酸ェチルエステルが得られる。

3- (4-fluorophenyl) -12-hydroxymino-3-oxopropionic acid ethyl ester, 4- (4-morpholinovivedin-1-yl) benzaldehyde and acetic acid in the same manner as in Raw Material Synthesis Example 2 From ammonium, 5- (4-fluorophenyl) -1- (4- (4-morpholinobiperidin-11-yl) phenyl) -imidazo-1-yl 4-ethyl rubonate is obtained.

Raw material synthesis example 8 8

原料合成例 3と同様にして 5— ( 4—フルオロフヱニル） ー 2— 〔4一 （4— モルホリノビべリジン一 1 —ィル） フェニル〕 ィ ミダゾールー 4一力ルボン酸ェ チルエステルから 5— ( 4—フルオロフェニル） 一 2— 〔4一 （4—モルホリノ ビべリジン— 1—ィル） フエニル〕 イミダゾ一ル一 4一力ルボン酸が得られる。 原料合成例 8 9

原料合成例 2と同様にして 3— (4—フルオロフェニル） 一 2—ヒドロキシィ ミノ— 3—ォキソプロビオン酸ェチルエステル 1 5. 0 g、 原料合成例 47で 得られた 4一 （ 2—メ トキシェトキシ） ペンズアルデヒ ド 1 6. 9 gおよび酢 酸アンモニゥム 48. 3 gから 5— (4—フルオロフェニル） _ 2—〔4一 （ 2 —メ トキシェトキシ） フエニル〕 イ ミダゾ一ル一 4—カルボン酸ェチルエステル 7. 2 を得た。 融点 183— 184 °C。

In the same manner as in Raw Material Synthesis Example 3, 5- (4-fluorophenyl) -2- [4-1- (4-morpholinoviveridine-1-yl) phenyl] midazole-4 4-hydrofuronic acid ethyl ester 5- (4- Fluorophenyl) 1- [4- (4-morpholino-beveridine-1-yl) phenyl] imidazole-l-41-carboxylic acid is obtained. Raw material synthesis example 8 9

3- (4-fluorophenyl) -1-hydroxyimino-3-oxopropionic acid ethyl ester 15.0 g in the same manner as in Raw Material Synthesis Example 2; 4- (2-methoxhetoxy) obtained in Raw Material Synthesis Example 47 Penzaldehyde 16.9 g and ammonium acetate acetate 48.3 g from 5- (4-fluorophenyl) _2- [4- (2-methoxyethoxy) phenyl] imidazole-1-ethyl carboxylate 7. I got 2. 183-184 ° C.

Raw material synthesis example 90

原料合成例 3と同様にして 5— （4—フルオロフェニル） 一 2— 〔4— ( 2 - メ トキシェ卜キシ）フエニル〕ィミダゾ一ルー 4一力ルボン酸ェチルエステル 7 2 gから 5— （4—フルオロフェニル） 一 2— 〔4— (2—メ 卜キシエトキシ） フヱニル〕 イミダゾ一ルー 4一力ルボン酸 5. l gを得た。 融点 138— 140。C。

In the same manner as in Raw Material Synthesis Example 5, 5- (4-fluorophenyl) 1-2- [4- (2-methoxyethoxy) phenyl] imidazo-l-4u-Ethyl rubonate 72 2 g to 5- (4- Fluorophenyl) 1-2- [4- (2-Methoxyethoxy) phenyl] Imidazo-l-41-rubic acid 5. Ig was obtained. Melting point 138-140. C.

原料合成例 1と同様にして N _フヱニルチオモルホリン、 ォキシ塩化リンから 4— (チオモルホリン- 4—ィル） ベンズアルデヒドが得られる。 Raw material synthesis example 91

In the same manner as in Raw Material Synthesis Example 1, 4- (thiomorpholin-4-yl) benzaldehyde can be obtained from N-phenylthiomorpholine and phosphorus oxychloride.

Raw material synthesis example 9 2

原料合成例 2と同様にして 3— ( 4—クロ口フエニル） — 2—ヒドロキシイミ ノー 3—ォキソプロビオン酸ェチルエステル、 4一（チオモルホリン一 4一ィル） ベンズアルデヒドおよび酢酸アンモニゥムから 5— ( 4—クロ口フエニル） 一 2 — 〔4— (チオモルホリン一 4一ィル） フエニル〕 ィミダゾール一 4一力ルボン 酸ェチルエステルが得られる。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) -2-hydroxyimino 3-oxopropionic acid ethyl ester, 4- (thiomorpholine-141-yl) benzaldehyde and ammonium acetate 5- (4- 2- (4- (thiomorpholine-41-yl) phenyl) -imidazole-1.4-ethyl ribonate ester is obtained.

Raw material synthesis example 9 3

原料合成例 3と同様にして 5— (4—クロ口フエニル） —2— 〔4— (チォモ ルホリン— 4—ィル） フエニル〕 イミダゾール— 4一力ルボン酸ェチルエステル から 5— (4—クロ口フエニル） 一 2— 〔4— (チオモルホリン一 4一ィル） フ ェニル〕 イミダゾ一ル—4—カルボン酸が得られる。

In the same manner as in Raw Material Synthesis Example 3, 5- (4-chlorophenyl) -2- (4- (thiomphophorin-4-yl) phenyl) imidazole-4 Phenyl) 1- 2- [4- (thiomorpholine 4- yl) phenyl] imidazole-4-carboxylic acid is obtained.

Raw material synthesis example 94

20.46 g of 4- (aminomethyl) benzoic acid was dissolved in 100 ml of ethyl acetate, 100 ml of a 3N aqueous sodium hydroxide solution was added, and 14 ml of acetic anhydride was added at 5 to 7 ° C. The reaction solution was stirred at room temperature for 1 hour, made acidic with 10% hydrochloric acid, and extracted with ethyl acetate: ethanol (10: 1) (100 ml × 5). The extract was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 27.2 g of a pale yellow solid. The obtained solid was crystallized from ethyl acetate: ethanol (1: 1,500 ml) to give 16.7 g of the desired 4-acetoamidomethylbenzoic acid as white crystals. Melting point 200~202 ^D C.

Raw material synthesis example 95

4-Acetamidomethylbenzoic acid 4.0 was dissolved in 100 ml of 0.5% hydrogen chloride-methanol solution. The reaction solution was stirred at 4 ° C. for 3.5 hours, poured into 300 ml of ice water, and extracted with ethyl acetate (100 ml × 4). Extract Was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 4.3 g of a pale yellow solid. The obtained solid was crystallized with 5 Oml of ethyl acetate to obtain 3.2 g of the target methyl 4-acetamidomethylbenzoate as pale yellowish white product. Mp 110-111 ° C.

Raw material synthesis example 96

水素化リチウムアルミニウム 5 70mgの THF 80ml懸濁液に 4—ァ セトアミ ドメチル安息香酸メチル 3. 1 :の丁11？ 20ml溶液を氷冷下加 えた。 この反応液を室温で 1. 5時間撹拌した後飽和硫酸ナトリウム水 7ml を 10°Cで加え、 室温で 1時間撹拌した。 沈殿物を濾別し溶媒を留去して、 的 の N— ( 4—ヒドロキシメチルフエニルメチル） ァセトアミ ド 2. 8 gを 色 固体として得た。

Lithium aluminum hydride 5 To a suspension of 70 mg of THF in 80 ml of THF 4-acetamide methyl benzoate 3.1: A 20 ml solution was added under ice cooling. After stirring the reaction solution at room temperature for 1.5 hours, 7 ml of a saturated aqueous sodium sulfate solution was added at 10 ° C, and the mixture was stirred at room temperature for 1 hour. The precipitate was separated by filtration and the solvent was distilled off to obtain 2.8 g of the target N- (4-hydroxymethylphenylmethyl) acetamide as a color solid.

'H-NMR 270 MHz (DMS 0-d ₆ , ppm) δ: 1.86 (3H, s), 4.22 (2 H, d), 4.46 (2H, s), 5.13 (1H, br.s), 7.19 (2H, d), 7.25 (2H, d) ヽ 8.30 (1H, m)

Raw material synthesis example 97

0.73 ml of thionyl chloride was added to a solution of 1.5 g of N- (4-hydroxymethylphenylmethyl) acetamide in 50 ml of chloroform, and the mixture was heated under reflux for 1 hour. did. The residue obtained by distilling off the solvent was crystallized from ethyl acetate to obtain 1.8 g of the desired N- (4-chloromethylphenylmethyl) acetamide as pale yellow crystals. . Mp 116-118 ° C.

Raw material synthesis example 98

Dissolve 19.7 g of N- (4-chloromethylphenylmethyl) acetamide and 10.5 ml of morpholine in 90 ml of DMF, add 13.8 g of potassium ^^ acid, and add 60 g for 3 hours. Stirred for 20 minutes. Toluene was added to the residue obtained by evaporating the solvent, and the insoluble solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 27 g of an oil. The obtained oil is dissolved in 150 ml of ethyl acetate, ice-cold F 14% hydrogen chloride-ethanol solution is added, and the precipitated crystals are collected by filtration to obtain the desired N- (4-morpholinomethylphenylmethyl) hydrochloride. 28.4 g of acetate amide were obtained. Melting point 60 ° C. Raw material synthesis example 99

塩酸 N— ( 4—モルホリ ノメチルフェニルメチル） ァセ トアミ ド 28. 4 g を 4N塩酸 1 14 mlに溶かし、 3時間 1 5分加熱還流した。 溶媒を留去して 酢酸ェチルより結晶を濾取した。 得られた結品を水 40mlに溶解させ、 酸 力リウムを飽和するまで加え、 クロ口ホルムにて抽出した。 無水硫酸ナ卜リゥム で乾燥後、 溶媒を減圧濃縮することにより 的の 4— (モルホリノメチル） フエ ニルメチルァミン 1 7. 4 gを得た。 融点 47— 49°C。

28.4 g of N- (4-morpholinomethylphenylmethyl) acetamide hydrochloride was dissolved in 114 ml of 4N hydrochloric acid, and the mixture was refluxed for 3 hours and 15 minutes. Evaporate the solvent The crystals were collected by filtration from ethyl acetate. The obtained product was dissolved in 40 ml of water, and potassium hydroxide was added until the solution was saturated, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to obtain 17.4 g of target 4- (morpholinomethyl) phenylmethylamine. 47-49 ° C.

Raw material synthesis example 100

4.Dissolve 8 g of mono (morpholinomethyl) phenylmethylamine and 8.26 g of 3- (4-chlorophenyl) 1-2-hydroxyimino-13-oxopropionate in 120 ml of pyridine, The mixture was refluxed for 2 hours. The solvent was reduced and concentrated, and the resulting residue was subjected to silica gel column chromatography to obtain the desired 5- (4-chlorophenyl) 1-2- [4- (morpholinomethyl) phenyl] imidazole_4-carboxylate ester 8 46 g were obtained. Mp 1 83-185. C.

Raw material synthesis example 101

5- (4-Chlorophenyl) —2— [4- (morpholinomethyl) phenyl] imidazo-l-ul 4-Ethyl rubonate ester 8.8.4 g to 5 -— (4-chloro-mouth) There was obtained 7.6 g of (phenyl) -1- [4- (morpholinomethyl) phenyl] imidazole-4-butanoic acid. Melting point 1 75-180 ° C

(Disassembly)

原料合成例 9と同様にして 4—フルォロベンゾニ 卜 リル、 4一 （4—メチルビ ペラジン一 1—ィル） ビぺリジンから目的の 4— 〔4— ( 4ーメチルビペラジン — 1一ィル） ピペリジン一 1 一ィル〕 ベンゾニ卜 リルが得られる。 Raw material synthesis example 102

In the same manner as in Raw Material Synthesis Example 9, 4-fluorobenzonitrile and 4- (4-methylbiperazine-11-yl) were converted from the desired 4- (4- (4-methylbiperazine-11-yl) ) Piperidine-111] benzonitrile is obtained.

原料合成例 1 0と同様にして 4 _ 〔4一 （4—メチルビべラジン一 1 一ィル） ピペリジン一 1—ィル〕 ベンゾニトリルから目的の 4— 〔4一 ( 4—メチルピぺ ラジン一 1一ィル） ピペリジン一 1—ィル〕 ベンズアルデヒ ドが得られる。 Raw material synthesis example 103

In the same manner as in Raw Material Synthesis Example 10, the 4- (4- (4-methylbiverazine-1-1yl) piperidine-1-yl) was converted from benzonitrile to the desired 4- (4- (4-methylpiperazine-1). 1-yl) piperidine-1 1-yl] benzaldehyde is obtained.

原料合成例 2と同様にして 3— (4—クロ口フエニル） 一 2—ヒ ドロキシイ ミ ノ一 3—ォキソプロビオン酸ェチルエステル、 4一 〔4一 （4—メチルビペラジ ン一 1一ィル） ピペリジン一 1一ィル〕 ベンズアルデヒ ドおよび酢酸アンモニゥ ムから 5— （4一クロ口フエニル） 一 2— { 4 - 〔4— (4—メチルビペラジン — 1一ィル） ビぺリジン一 1—ィル〕 フヱニル} イ ミダゾ一ルー 4一力ルボン酸 ェチルエステルが得られる。 Raw material synthesis example 104

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) 1-2-hydroxyimino-3-oxoethyl ester, 4- [4- (4-methylbiperazin-1-yl) piperidine-1 1 5- (4-phenylphenyl) 1-2- {4-(4- (4-methylbiperazine-111) bibenzyl-1- (1-yl) phenyl) from benzaldehyde and ammonium acetate Imidazo 1-fluoroethyl ester is obtained.

Raw material synthesis example 105

原料合成例 3と同様にして 5— (4—クロロフヱニル） 一 2—{4一 〔4— (4 —メチルピペラジン一 1—ィル） ビベリジン一 1—ィル〕 フエ二ル}ィ ミダゾ一ル - 4—カルボン酸ェチルエステルから 5 _(4—クロロフェニル）一 2— { 4—〔4 一 （4—メチルビペラジン一 1—ィル） ピペリジン一 1—ィル〕 フエ二ル}ィミダ ゾールー 4—カルボン酸が得られる。

5- (4-chlorophenyl) -1-2- (4- [4- (4-methylpiperazine-11-yl) viberidine-11-yl] phenyl} midazole in the same manner as in Raw Material Synthesis Example 3. -4- (4-chlorophenyl) -2- (4- (4- (4-methylbiperazine-11-yl) piperidine-11-yl) phenyl} imidazole-4-carboxylic acid from 4-carboxylic acid ethyl ester Is obtained.

原料合成例 7 7と同様にして N— 〔2— ( 4—ブロモフエニル） ェチル〕 モル ホリン、 マグネシウムおよび D M Fから目的の 4— ( 2—モルホリノエチル） ベ ンズアルデヒドが得られる。 Raw material synthesis example 106

N- [2- (4-Bromophenyl) ethyl] morpholine, magnesium and DMF give the desired 4- (2-morpholinoethyl) benzaldehyde in the same manner as in Synthesis Example 7 of Starting Materials.

Raw material synthesis example 107

原料合成例 2と问様にして 3— （4一クロ口フエニル） 一 2—ヒ ドロキシイミ ノ一 3—ォキソプロビオン酸ェチルエステル、 4一 （2—モルホリノエチル） ベ ンズアルデヒドおよび酢酸アンモニゥムから 5— ( 4—クロ口フエニル） 一 2— 〔4一 （2 —モルホリノエチル） フエニル〕 イミダゾールー 4—カルボン酸ェチ ルエステルが得られる。

In the same manner as in Raw Material Synthesis Example 2, 3- (4-chlorophenyl) -12-hydroxyimino-3-oxopropylionate, 4- (2-morpholinoethyl) benzaldehyde and ammonium acetate were converted to 5- (4 —Cross phenyl) 1 2— [4-1 (2-morpholinoethyl) phenyl] Imidazole-4-carboxylic acid ethyl ester is obtained.

Raw material synthesis example 1 0 8

原料合成例 3と同様にして 5 _ (4—クロ口フエニル） 一 2— 〔4一 （2—モ ルホリノエチル） フエニル〕 イ ミダゾ一ルー 4—カルボン酸ェチルエステルから 5— (4—クロ口フエニル） 一 2— 〔4一 （2—モルホリノエチル） フエニル〕 ィ ミダゾ一ルー 4一力ルボン酸が得られる。

In the same manner as in Raw Material Synthesis Example 5, 5_ (4-chlorophenyl) 1-2- [4- (2-morpholinoethyl) phenyl] imidazolu-l 4-carboxylic ethyl ester to 5- (4-chlorophenyl) 1 2-[[4-1 (2-morpholinoethyl) phenyl]]-midazo-l-u-l-l-l-Rubonic acid is obtained.

Raw material synthesis example 109

N— (4-chloromethylphenylmethyl) acetamide 20. Og and 9.9 g of dimethylamine hydrochloride are dissolved in 19 ml of acetonitrile, and 28 g of potassium carbonate is further added. Heated to reflux. After filtering off the insoluble solid, the solvent was distilled off to obtain 28.4 g of the desired N- [4- (dimethylaminomethyl) phenylmethyl] acetamide as an oily substance.

¹ H-NMR 2 70 MHz (CD C 1. pm) δ: 1.99 (3H, s), 2.02 (3H, s), 4.36 (2H, s), 4 6 6 (2H, s), 7.37 (2H, d), 7.47 (2H, d)

Raw material synthesis example 1 10

N- [4-1 (dimethylaminomethyl) phenylmethyl] acetamide 22 g Was dissolved in 100 ml of 4N hydrochloric acid, and the mixture was heated under reflux for 3 hours and 40 minutes. The solvent was distilled off, and the crystals were collected by filtration from ethyl acetate. The obtained crystals were dissolved in 4 Oml of water, potassium carbonate was added until saturation, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to obtain 11.7 g of the desired 4- (dimethylaminomethyl) phenylmethylamine. Mp 38-39. C

Raw material synthesis example 1 1 1

4-(Dimethylaminomethyl) phenylmethylamine 11.7 g and 3- (4-chlorophenyl) 1-2-hydroxyimino 3-oxopropionic acid ethyl ester 1 5.lg are dissolved in 220 ml of pyridine. The mixture was heated under reflux for 12 hours. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to give the desired 5- (4-chlorophenyl) 1-2- [4-1 (dimethylaminomethyl) phenyl] imidazole-4-carboxylic acid ester 9 .0 g were obtained. Melting point 175-175 ° C.

Raw material synthesis example 1 1 2

原料合成例 3と问様にして 5— (4—クロ口フエニル） 一2— C4 - (ジメチ ルアミノメチル）フエニル〕ィ ミダゾール— 4一力ルボン酸ェチルエステル 9. 0 gから 5— （4一クロ口フエニル） 一 2— 〔4一 （ジメチルアミノメチル） フ ェニル〕 イ ミダゾールー 4一力ルボン酸 8. 3 gを得た。 融点 1 17— 1 18。C„

Synthesis of Raw Material Example 3 5- (4-chlorophenyl) 1-2-C4- (dimethylaminomethyl) phenyl] imidazole-4 monoethyl ester of rubonic acid 9.0 g to 5— (4 8.3 g of phenyl) 1-2- [4- (dimethylaminomethyl) phenyl] imidazole-4 rubonic acid were obtained. Mp 117-118. C „

Raw material synthesis example 1 13

4- (Hydroxymethyl) phenylmethylamine and 3- (4-chlorophenyl) 1-2-hydroxymino-13-oxopropionic acid tert-butylester are dissolved in pyridine, and raw material synthesis example 1 11 By treating in the same manner as in 1, the desired 5- (4-chlorophenyl) 1-2- (4-hydroxymethylphenyl) imigazoru-4 is obtained. Can be

Raw material synthesis example 1 14

5— (4—クロ口フエニル） 一 2— ( 4—ヒドロキシメチルフエニル） イミダ ゾ一ル—4—カルボン酸 t e r t—ブチルエステルをピリジンに溶解させ、 無 水酢酸を反応させることにより、 目的の 2— （4ーァセトキシメチルフエニル） 一 5— (4—クロ口フエニル） ィミダゾ一ルー 4—カルボン酸 t e r t—ブチ ルエステルが得られる。

5- (4-Methyl phenyl) 1-2- (4-hydroxymethylphenyl) imidazole-4-carboxylic acid tert-butyl ester is dissolved in pyridine and reacted with anhydrous acetic acid to obtain the desired compound. 2- (4-acetoxymethylphenyl) -1-5- (4-chlorophenyl) imidazo-1-yl 4-carboxylic acid tert-butyl ester is obtained.

Raw material synthesis example 1 15

By dissolving 2- (4-acetoxymethylphenyl) -1-5- (4-chlorophenyl) imidazole-4-carboxylic acid tert-butyl ester in trifluoroacetic acid and stirring at room temperature, The desired 2- (4-acetoxymethylphenyl) -5- (4-chlorophenyl) imidazole-4-carboxylic acid is obtained.

Raw material synthesis example 116

4- (2-Hydroxitytyl) phenylmethylamine and 3- (4-phenylphenyl) 1-2-hydroxyimimino 3-oxopropionic acid tert-butyl Is dissolved in pyridine and treated in the same manner as in Raw Material Synthesis Example 1 1 1 to give the desired 5- (4-chlorophenyl) 2- [4-1 (2-hydroxyxethyl) phenyl] —The carboxylic acid tert-butyl ester is obtained.

Raw material synthesis example 1 17

原料合成例 1 14と同様にして、 5—（4一クロ口フエニル） 一 2—〔4 _ ( 2 ーヒドロキシェチル） フエニル〕 イ ミダゾ一ルー 4—カルボン酸 t e r t—ブ チルエステルから、 □的の 2— 〔4— ( 2—ァセ 卜キシェチル） フエニル〕 一 5 - ( 4—クロ口フエニル） ィミダリールー 4—カルボン酸 t e r t -ブチルェ ステルが得られる。

In the same manner as in Raw Material Synthesis Example 14, from 5- (4-chlorophenyl) 1-2- [4- (2-hydroxyethyl) phenyl] imidazo-l- 4-carboxylic acid tert-butyl ester, 2- [4- (2-acetoxityl) phenyl] -1-5- (4-chlorophenyl) imidalyl 4-carboxylic acid tert-butyl ester is obtained.

Raw material synthesis example 1 18

Raw Material Synthesis Example 1 2- [4- (2-acetoxyl) phenyl] -5- (4-chlorophenyl) imidazole-4 From 2-ester [4- (2-acetoxityl) phenyl]

(4-phenyl phenyl) -midazo-l--4-carboxylic acid is obtained.

Raw material synthesis example 1 1 9

原料合成例 9と同様にして 4—フルォロベンゾ ト リル、 1一 （ 2—ヒ ドロキ シェチル） ピぺラジンから目的の 4— 〔4— ( 2 ヒ ドロキシェチル） ピペラジ ンー 1—ィル〕 ベンゾニ卜リルが得られる。

In the same manner as in Raw Material Synthesis Example 9, 4-fluorobenzotolyl and the desired 4- (4- (2hydroxyshethyl) piperazin-1-yl) benzonitrile were obtained from 11- (2-hydroxyshethyl) piperazine. can get.

Raw material synthesis example 1 2 0

4 - a [4- (2-arsenide de port Kishechiru) piperidines Rajin one 1 one I le] Benzonito Lil Ri by the reducing by L i A 1 Η _4, ϋ manner of 4- [4 one (2 —Hydroxityl) bidazine-1—yl] phenylmethylamine is obtained.

Raw material synthesis example 1 2 1

4— 〔4— ( 2—ヒ ドロキシェチル） ピぺラジン一 1 _ィル〕 フエニルメチル ァミンおよび 3— ( 4—クロ口フエニル） 一 2 —ヒ ドロキシィ ミノ一 3—ォキソ プロビオン酸 t e r t —ブチルエステルをピリジンに溶解し、 原料合成例 1 1 1と同様に処理することにより、 的の 5— （4—クロ口フエニル） 一 2— { 4 一 〔4一 （ 2—ヒ ドロキシェチル） ビペラジン _ 1 一ィル〕 フェニル } ィ ミダゾ —ル—4—カルボン酸 t e r t—ブチルエステルが得られる。

4- (4- (2-Hydroxitytyl) pidazine-1-yl) phenylmethylamine and 3- (4-chlorophenyl) 1-2-hydroxyhydroxymino-3-oxopropionic acid tert-butyl ester in pyridine , And treated in the same manner as in Raw Material Synthesis Example 1 1 1 to obtain the target 5- (4-chlorophenyl) 1-2- {4-1 (4-1- (2-hydroxyxethyl) biperazine_1-yl Phenyl} imidazole-4-carboxylic acid tert-butyl ester is obtained.

Raw material synthesis example 1 2 2

原料合成例 1 1 4と同様にして 5— （4一クロ口フヱニル） 一 2— { 4— 〔4 一 （2—ヒ ドロキシェチル） ビべラジン一 1—ィル〕 フエ二ル} イ ミダゾールー 4一力ルボン酸 t e r t—プチルエステルから 2— { 4 - 〔4— ( 2—ァセ ト キシェチル） ピぺラジン一 1 一ィル〕 フエ二ル} — 5— （4—クロ口フエニル） ィミダゾールー 4一力ルボン酸 t e r t—ブチルエステルが得られる。

Example of raw material synthesis 1 1 5— (4-chlorophenyl) 12— {4 -— (4- (2-hydroxyshethyl) biverazine-11-yl] phenyl} imidazole-4 2-R 4- (4- (2-acetoxyshethyl) piperazine-1 1-yl) phenyl from tert-butyl ester of one-strength rubonic acid} —5— (4-chlorophenyl) imidazole-4 One-part tert-butyl rubonic acid is obtained.

Raw material synthesis example 1 2 3

原料合成例 1 1 5と同様にして 2— {4— 〔4— (2—ァセトキシェチル） ビ ペラジン一 1—ィル〕 フエ二ル} - 5 - (4一クロ口フエニル） イ ミダゾ一ルー 4一力ルボン酸 t e r t—ブチルエステルから 2 - {4 - 〔4— (2—ァセトキ シェチル） ビぺラジン一 1—ィル〕 フエ二ル} — 5— (4—クロ口フエニル） ィ ミダゾ一ルー 4一力ルボン酸が得られる。

Example of raw material synthesis 1 1 2 Same as in 5 2- {4- (4- (2-acetoxitytyl) biperazine-1 1-yl] phenyl}-5-(4-chlorophenyl) imidazo 1-4 1-Rubonic acid tert-butyl ester to 2- {4- [4- (2-acetoxy-shethyl) biradin-1-yl] phenyl} — 5— (4-chlorophenyl) midazolu 4 One-strength rubonic acid is obtained.

原料 ^成例 9と同様にして 4—フルォ口べンゾニトリル 1 0 g、 4—メチ ル一 1—ォキサ一4， 9一ジァザスビロ [ 5 , 5〗ゥンデカン 1 5. 7 gから 的の 4一 （4—メチルー 1—ォキサー 4， 9—ジァザスピロ [5, 5]ゥンデカン — 9—ィル） ベンゾニトリル 9. 7 gを得た。 融点 105— 109°C。 Raw material synthesis example 124

Ingredients ^ In the same manner as in Example 9, 4-fluorene benzonitrile 10 g, 4-methyl-11-oxa-4,9,1 diazasbylo [5,5-dedecane 15.7 g to 4 4-Methyl-1-oxer 4,9-dazaspiro [5,5] indecan-9-yl) benzonitrile 9.7 g was obtained. 105-109 ° C.

Raw material synthesis example 125

リチウムアルミニウムハイ ドライ ド 2 gを THF 40mlに懸濁させ、 氷冷下 4― (4ーメチル一 1—ォキサー 4, 9—ジァザスビロ [5， 5]ゥンデ力 ン一 9一ィル）ベンゾニ卜リル 1 2 の丁11 100 m 1溶液を滴下した。 室温で 2時間 40分攪袢後、氷冷下少しずつ飽和硫酸ナトリウム水溶液を加え、 析出した固形物を濾別しクロ口ホルムで洗浄した。 クロロホルム層を無水硫酸 ナトリウムで乾燥後、 溶媒を減圧留去することにより目的の 4— (4—メチル — 1—ォキサ一 4， 9 -ジァザスピロ [5, 5]ゥンデカン一 9一ィル） フェニル メチルアミン 1 3 gを得、精製することなく次の原料合成例 1 26に用いた, 原料合成例 126

Lithium aluminum hydride (2 g) is suspended in THF (40 ml), and cooled under ice-cooling. A solution of 100 ml of 2 11 was added dropwise. After stirring at room temperature for 2 hours and 40 minutes, a saturated aqueous sodium sulfate solution was added little by little under ice-cooling, and the precipitated solid was separated by filtration and washed with a black hole form. After drying the chloroform layer with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure to obtain the desired 4- (4-methyl-1-oxa-1,4,9-diazaspiro [5,5] indecan-1-yl) phenyl Methylamine (13 g) was obtained and used without purification in the following Raw Material Synthesis Example 126.

原料合成例 1 2 5で得られた未精製の 4一 ( 4ーメチルー 1—ォキサ— 4， 9ージァザスピロ [5 , 5]ゥンデカン一 9—ィル） フエニルメチルァミン 1 3 gと 3— (4—クロ口フエニル） 一 2—ヒ ドロキシィミノ一 3—ォキソプロビ オン酸ェチルエステル 1 0. 9 gをビリジン 1 30 m 1に溶かし 1 7時間 加熱還流した。 反応後溶媒を減圧留去し、 シリカゲルカラムクロマトグラフィ —に付すことにより目的の 5— （4—クロ口フエニル） 一 2— 〔4— (4ーメ チル一 1—ォキサ一 4， 9一ジァザスビロ [ 5， 5]ゥンデカン一 9—ィル） フエ ニル〕イミダゾールー 4一力ルボン酸ェチルエステル 6. 5 7 gを得た。 融 点 235— 236°C。

Raw Material Synthesis Example 1 Unpurified 4- (4-methyl-1-oxa-4,9diazaspiro [5,5] pandecane-1-9-yl) obtained in 25 25 phenylmethylamine 13 g and 3— ( 4-Chlorophenyl) 1-Hydroxyimino-13-oxopropionic acid ethyl ester (10.9 g) was dissolved in viridine (130 ml) and heated under reflux for 17 hours. After the reaction, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography to give the desired 5- (4-chlorophenyl) 1-2- [4- (4-methyl-11-oxa-1,4,9-diazasbylo [ [5,5] Pindecane-9-yl) phenyl] imidazole-4. Melting point 235-236 ° C.

Raw material synthesis example 127

原料合成例 3と同様にして 5— (4—クロ口フエニル） 一 2— 〔4— ( 4 メチルー 1一ォキサ一 4 , 9ージァザスピロ [5, 5]ゥンデカン一 9—ィル） フ ェニル〕 イミダゾ一ルー 4—カルボン酸ェチルエステル 6. 57 gから 5— (4—クロ口フエニル） 一2— 〔4一 （ 4—メチルー 1一ォキサ一 4 , 9ージ ァザスピロ [5， 5]ゥンデカン— 9—ィル） フエニル〕 ィミダゾ一ルー 4一カル ボン酸 5 gを得た。 融点 190— 195°C (分解)。

In the same manner as in Raw Material Synthesis Example 5, 5- (4-chlorophenyl) 1 2— [4— (4 Methyl-1 oxa-1,4,9 diazaspiro [5,5] indane-1 9-yl) phenyl] Imidazo-l-uyl 4-carboxylate 6.57 g to 5- (4-chlorophenyl) 1-2- [ 4- (4-Methyl-11-oxa-1,4,9-diazaspiro [5,5] indene-9-yl) phenyl] imidazo-l-41-carboxylic acid 5 g was obtained. 190-195 ° C (decomposition).

荚 Example 1

原料合成例 3で得られた 5— （4一クロ口フエニル） — 2— (4—モルホリノ フエニル）イ ミダゾール一 4 _カルボン酸 49.4 gをテ トラヒ ドロフラン 1 000mlに懸濁し、 2 N塩化水素—エーテル溶液 1 54mlを加えた後、 3 0分間攪拌した。愁濁溶液へ: DM F 1 5 mlと塩化チォニル 94mlを加え、 2時間加熱還流後、 減圧濃縮した。 残渣へピリジン 1500ml、 2—ァミノ チアゾ一ル 1 2. 9 gを加え 1時間 45分加熱還流した。 反応後溶媒を減圧濃 縮し、 飽和重曹水にて屮和したのち、 クロ口ホルムにて抽出した。 有機層を無水 硫酸マグネシウムにて乾燥し、 減圧濃縮後残渣をシリカゲルカラムクロマトグラ フィ一に付し、 得られた粗結晶をテトラヒ ドロフランより再結晶することにより

49.4 g of 5- (4-chlorophenyl) imidazole-14-carboxylic acid obtained in Synthesis Example 3 of the starting material in 41,000 g of tetrahydrofuran was suspended in 1,000 ml of tetrahydrofuran, and 2N hydrogen chloride— After adding 154 ml of an ether solution, the mixture was stirred for 30 minutes. To the turbid solution: 15 ml of DMF and 94 ml of thionyl chloride were added, and the mixture was heated under reflux for 2 hours and concentrated under reduced pressure. 1500 ml of pyridine and 12.9 g of 2-aminothiazol were added to the residue, and the mixture was heated under reflux for 1 hour and 45 minutes. After the reaction, the solvent was concentrated under reduced pressure, and the residue was extracted with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was applied to silica gel column chromatography, and the obtained crude crystals were recrystallized from tetrahydrofuran.

There were obtained 21.8 g of 5- (4-chlorophenyl) -12_ (4-morpholinophenyl) -1-N- (2-thiazolyl) imidazole-41-carboxamide. Melting point 2

Over 60 ° C.

¹ H-NMR 270 MHz (DMS O—d or pm) δ: 12.98 (1Η, s), 11.26 (1Η, s), 8.03 (2 d, d), 7.94 (2Η, d), 7. 54-7.6 1 (3H, m), 7.26 (1H, d), 7.05 (2H, d), 3.76 (4H, t), 3.21 (4H, t)

In addition, an acid addition salt of hydrochloric acid was obtained. Monohydrochloride Melting point 255-258 "C

¹ H-NMR 270 MHz (DMS O-d _fi , p pm) 5: 8.60-10.6

0 (2 H, br), 8.20 (2 H, d) ヽ 7.92 (2 H, d), 7.58- 7.

63 (3H, m), 7.31 (1H, d), 7.15 (2H, d), 3.77 (4H, t), 3.31 (4H, t)

Example 2

実施例 1と同様にして原料合成例 5で得られた 5— （4—フルオロフェニル） — 2— （ 4—モルホリノフエニル） イ ミダゾ一ルー 4—カルボン酸 1. 2 g、 1 N塩化水素—エーテル溶液 7. 8ml、 DMF 0. 3ml、 塩化チォニル 2. 4 m 1、 2—ァミノチアゾール 0. 33 gから 5— (4—フルオロフェニ ル） — 2— (4—モルホリノフエニル） 一 N— (2—チアゾリル） イ ミダゾ一ル 一 4一カルボキサミ ド 0. 17 gを得た。 融点 25 CTC以上-。

5- (4-fluorophenyl) -2- (4-morpholinophenyl) imidazo-l-u 4-carboxylic acid obtained in the same manner as in Example 1 but obtained in Raw Material Synthesis Example 5 1.2 g, 1 N hydrogen chloride — 7.8 ml of ether solution, 0.3 ml of DMF, 2.4 ml of thionyl chloride, 0.33 g of 2-aminothiazole from 5- (4-fluorophenyl) — 2- (4-morpholinophenyl) 0.17 g of N- (2-thiazolyl) imidazole-41-carboxamide was obtained. Melting point 25 CTC or more.

1 H-NMR 270 MHz (DMS O—d ₆ヽ pm) δ: 12.96 (1Η, s), 11.19 (1 H, s), 7.93-8.55 (4H , M), 7.54 (1H, d) ゝ 7.37 (1H, t), 7.26 (1H, d), 7.06 (2H, d), 3.76 (4H , T), 3.22 (4H, t)

Example 3

原料合成例 8で得られた 5— (4—クロ口フエニル） 一 2— 〔4— (4—メチ ルビペラジン一 1一ィル） フェニル〕 ィミダゾ一ルー 4一力ルボン酸 2 g、 1 N塩化水素一エーテル溶液 1 8. l ml、 DMF 0. 3ml、 塩化チォニル 3. 7ml、 2—ァミノチアゾ一ル 0. 5 0 gを用いて、 実施例 1と同様に反 応処理することにより 5— (4—クロ口フエニル） 一 2— 〔4— (4—メチルビ ペラジン一 1一ィル） フエニル〕 一 N— ( 2—チアゾリル） イミダゾ一ルー 4一 カルボキサミ ド 0. 59 gを得た。 融点 250°C以上。

5- (4-chlorophenyl) -1-2- (4- (4-methylbiperazine-111) phenyl) obtained in Raw Material Synthesis Example 8 A reaction was carried out in the same manner as in Example 1 using 18.1 ml of hydrogen monoether solution, 0.3 ml of DMF, 3.7 ml of thionyl chloride, and 0.50 g of 2-aminothiazole, to give 5- ( 4-59- (4-Methylbiperazine-11-yl) phenyl] -1-N- (2-thiazolyl) imidazo-1-ru 41-carboxamide 0.55 g was obtained. Melting point 250 ° C or more.

1 H-NMR 270 MHz (D ₂₀ , p pm) δ 7.93-8.01 (4Η, m), 7.53-7.59 (3H, m), 7.26 ( 1 H, d), 7.04 (2 H, d), 3.23 -3.33 (4 H, br) ヽ 2.44-2.50 (4 H, br), 2.23 (3H, s)

Example 4

原料合成例 1 2で得られた 5— （4—クロ口フエニル） 一2— 〔4一 （4—メ チルホモビべラジン一 1 _ィル） フエニル〕 イミダゾール一 4一力ルボン酸 2 g、 1 N塩化水^一エーテル溶液 1 7. 5 m l、 DMF 0. 3m l、 塩化チ 才ニル 3. 5 5m l , 2—ァミノチアゾール 0. 4 9 gを実施例 1と同様に反 応処理することにより 5— （ 4一クロ口フエニル） 一 2— 〔4— (4ーメチルホ モピペラジン一 1一ィル） フエニル〕 一 N— （ 2—チアゾリル） イ ミダゾ一ルー 4—カルボキサミ ド 0. 47 gを得た。 融点 2 2 5— 2 3 0°C (分解）。 実施例 5

Raw material synthesis example 1 5— (4-chlorophenyl) 1- (4- (4-methylhomobiverazine-1-yl) phenyl) obtained in 2 2 g, 17.5 ml of 1N aqueous chloride / ether solution, 0.3 ml of DMF, 3.5 ml of thienyl chloride, 0.49 g of 2-aminothiazole in the same manner as in Example 1. 5- (4-methylphenyl) -1- (4- (4-methylphomopiperazine) -phenyl) -1-N- (2-thiazolyl) imidazo-1-ru 4-carboxamide 0. 47 g were obtained. Melting point 2 25—230 ° C (decomposition). Example 5

原料合成例 1 6で得られた 5— （ 4—クロロフヱニル） 一2— 〔4一 （4—メ チルビペリジン一 1一ィル） フヱニル〕 イ ミダゾールー 4—カルボン酸 2. 2 g、 1 N塩化水^—エーテル溶液 1 3. 9 m l、 DMF 0. 3 m l、 塩化チ ォニル 4. l ml、 2—ァミノチアゾ一ル 0. 5 6 gを実施例 1と同様に反 応処理することにより、 5— （4一クロ口フエニル） - 2 - 〔4一 （ 4一メチル ピぺリジン一 1一ィル） フエニル〕 一 N— （ 2—チアゾリル） イ ミダゾ一ルー 4 —カルボキサミ ド 1. 04 gを得た。 融点 2 5 0°C以上。

Raw material synthesis example 16 5- (4-chlorophenyl) 1-2- [4- (4-methylbiperidine-11-yl) phenyl] imidazole-4-carboxylic acid obtained in 16 2.2 g, 1N chloride water Reaction of 13.9 ml of ^ -ether solution, 0.3 ml of DMF, 4. l ml of thionyl chloride and 0.56 g of 2-aminothiazole was carried out in the same manner as in Example 1 to give 5- (4-phenyl phenyl) -2-[4- (4-methylpiperidine-1-11) phenyl] -1-N- (2-thiazolyl) imidazolu-l 4- 4-carboxamide 1.04 g was obtained. Was. Melting point 250 ° C or higher.

1 H-NMR 2 7 0MH z (DMS O- d f;, p pm) δ 1 2. 9 3 (1 Η, s), 1 1. 1 9 (1 Η, s), 7. 9 3 - 8 0 0 (4 H, m), 7.5 3-7.66 (3 H, m) ヽ 7.26 (1 H, d) ヽ 7.0 2 (2 H, d), 3. 8 1 (2H, d), 2.73 (2Hs dd) ヽ 1.49-1.72 (3H, m), 1.1-1.22 (2H, m), 0.94 (3H, d)

Example 6

原料合成例 20で得られた 5— (4—クロ口フエニル） 一 2— 〔4一 （4， 4 —ジメチルピペリジン一 1—ィル）フヱニル〕ィ ミダゾ一ルー 4—カルボン酸 2 g、 1 N塩化水素—エーテル溶液 1 1. 7ml、 DMF 0. 7ml, 塩化チォ ニル 3. 6ml、 2—ァミノチアゾ一ル 0. 49 gを実施例 1と同様に反応処 理することにより 5— (4—クロ口フエニル） 一 2— 〔4一 （4, 4ージメチル ピぺリジン一 1一ィル） フエニル〕 一 N— (2—チアゾリル） イ ミダゾールー 4 一カルボキサミ ド 0. 63 gを得た。 融点 150— 154°C。

5- (4-chlorophenyl) 1-2- [4- (4,4-dimethylpiperidine-11-yl) phenyl] midazo-1-ru 4-carboxylic acid obtained in Synthesis Example 20 of raw material 2 g, 1 N hydrogen chloride-ether solution 11.7 ml, DMF 0.7 ml, thionyl chloride 3.6 ml, 2-aminothiazole 0.49 g were treated in the same manner as in Example 1 to give 5- (4- 0.63 g of (2- (4,4-dimethylpiperidine-11-yl) phenyl) -1-N- (2-thiazolyl) imidazole-4-1-carboxamide was obtained. 150-154 ° C.

Example 7

原料合成例 24で得られた 5— (4—クロ口フエニル） — 2— {4—〔4 _ (ジ メチルァミノメチル） ビぺリジン一 1—ィル〕 フェニル } ィ ミダゾ一ル一 4—力 ルボン酸 4 · 7 g、 1 N塩化水素—エーテル溶液 38. 5ml、 DMF 1. 4ml、 塩化チォニル 7. 8ml、 2—ァミノチアゾ一ル 1 · 07 gを実施 例 1と同様に反応処理することにより 5— （4—クロ口フエニル） ー 2— {4— 〔4— (ジメチルアミノメチル） ビべリジン一 1一ィル〕 フエ二ル} -N- ( 2 一チアゾリル） イミダゾ一ルー 4一カルボキサミ ド 1. 08 gを得た, 融点 246— 248。C。

5- (4-Cross-terminal phenyl) obtained in raw material synthesis example 24—2- {4- [4_ (dimethylaminomethyl) biperidin-1-yl] phenyl} midazol-1 4 4.8 g of rubonic acid, 38.5 ml of 1N hydrogen chloride-ether solution, 1.4 ml of DMF, 7.8 ml of thionyl chloride, and 1.07 g of 2-aminothiazole are treated in the same manner as in Example 1. 5— (4-chlorophenyl) —2— {4— [4- (dimethylaminomethyl) biveridine-1-yl] phenyl} -N- (2 (Ithiazolyl) imidazo-l-41-carboxamide 1.08 g was obtained, mp 246-248. C.

Further, an acid addition salt of fumaric acid was obtained.

 1 fumarate Melting point 235-240 ° C (decomposition).

Example 8

原料合成例 28で得られた 5— （4ークロロフヱニル） 一 2— 〔4— (3， 5 ージメチルモルホリンー 4—ィル）フエニル〕ィ ミダゾール一 4—カルボン酸 3 g、 1 N塩化水素—エーテル溶液 8. 7 m I DMF 0. 6ml、 塩化チォ ニル 5. 3ml、 2—ァミノチアゾール 0. 73 gを実施例 1と同様に反応 処理することにより、 5— （4—クロ口フエニル） 一 2— 〔4一 （ 3， 5—ジメ チルモルホリン一 4—ィル） フエニル〕 —N— ( 2—チアゾリル） イ ミダゾ一ル 一 4_カルボキサミ ド 0. 8 gを得た。 融点 250 C以上。

5- (4-chlorophenyl) 1-2- [4- (3,5-dimethylmorpholine-4-yl) phenyl] imidazole obtained in raw material synthesis example 28 4-carboxylic acid 3 g, 1 N hydrogen chloride— The ether solution 8.7 m I DMF 0.6 ml, thionyl chloride 5.3 ml, 2-aminothiazole 0.73 g was treated in the same manner as in Example 1 to give 5- (4-chlorophenyl). There was obtained 0.8 g of 1 2-([4- (3,5-dimethylmorpholine-14-yl) phenyl]]-N- (2-thiazolyl) imidazole-14-carboxamide. Melting point 250 C or more.

1 H-NMR 270MH z (DMSO - d B, p pm) δ: 12. 96 (1 Η, s)ヽ1 1. 23 (1 H, s ), 8. 0 1 (2 H, d)ヽ7 .94 (2H, d), 7.58 (2H, d), 7.54 (1H, d), 7.26 (2H, d) ヽ 7.55 (2H, d) ヽ 3 67-3.74 (4H, m), 2.32 (2H, t), 1.18 (6H, d)

In addition, monohydrochloride was obtained by adding hydrochloric acid. 233-238 (decomposition).

Example 9

原料合成例 42で得られた 2— (4—シァノフヱニル） 一 5— (4—フルォロ フエニル） イミグゾ一ルー 4一力ルボン酸 2. ◦ g、 I N塩化水素一エーテル 溶液 8. 5ml、 DMF 0. 2m l、 塩化チォニル 3. 2ml、 2—アミ ノチアゾ一ル 0. 7 gを実施例 1と同様に反応処理することにより、 2— （4 一シァノフエニル） ー 5— （4一フルオロフェニル） 一 N— ( 2—チアゾリル） イミダゾールー 4一カルボキサミ ドを得た。 塩酸を加えることにより、 塩酸の酸 付加塩を 0. 5 g得た。 1塩酸塩 融点 2 50°C以上。

2- (4-Cyanophenyl) -15- (4-fluorophenyl) imigzo-l-4 obtained from Example 42 of raw material immobilization-rubic acid 2.◦g, IN hydrogen chloride-ether solution 8.5 ml, DMF 0. 2 ml, thionyl chloride 3.2 ml and 2-aminothiazole 0.7 g were reacted in the same manner as in Example 1 to give 2- (4-cyanophenyl) -5- (4-fluorophenyl) 1 N — (2-Thiazolyl) imidazole-41-carboxamide was obtained. By adding hydrochloric acid, 0.5 g of an acid addition salt of hydrochloric acid was obtained. 1 Hydrochloride Melting point 2 50 ° C or higher.

1 H-NMR 270MH z (DMS_〇- _{d 6, p pm) 6:} 8. 46 (2 H, d)ヽ8. 02- 7. 9 7 (5 H , m), 7. 6 6 (1 H , D), 7.37-7.34 (4 H, m)

Example 10

原料合成例 40で得られた 5— (4—クロ口フエニル） 一 2— （4ーシァノフ ェニル） イミダゾール— 4一力ルボン酸 3. 0 g、 I N塩化水素一エーテル溶 液 1 2ml、 DMF 0. 3ml, 塩化チォニル 1 0ml、 2—ァミノチア ゾ一ル 0. 9 gを実施例 1と同様に反応処理することにより、 5— （4一クロ 口フエニル） 一2— (4—シァノフエニル） 一 N— ( 2—チアゾリル） イミダゾ —ルー 4一カルボキサミ ド 0. 7 gを得た。 さらに塩酸を加えることにより塩 酸の酸付加塩を得た。 1塩酸塩 融点 250°C以上。

5- (4-chlorophenyl) 1-2- (4-cyanophenyl) imidazole obtained in Example 40 of raw material imidazole-4 3.0 g of rubonic acid, IN Hydrogen chloride monoether solution The reaction of 2 ml of the solution, 0.3 ml of DMF, 0.3 ml of thionyl chloride, and 0.9 g of 2-aminothiazole was carried out in the same manner as in Example 1 to give 5- (4-monophenyl) 1-2 ( 0.7 g of 4-cyanophenyl) -N- (2-thiazolyl) imidazo-ru-41-carboxamide was obtained. Further, hydrochloric acid was added to obtain an acid addition salt of hydrochloric acid. 1 Hydrochloride Melting point 250 ° C or higher.

¹ H-NMR 2 70 MHz (DMS O—, p pm) (5: 8.45 (2 H, d), 7.98 (2 H, d), 7.97 (2 H, d), 7. 6 5 (1H, d), 7.58 (2H, d)

Example 1 1

原料合成例 44で得られた 5—フエ二ルー 2 _ ( 4—ト リフルォロメチルフエ ニル） イミダゾールー 4—カルボン酸 2. 5 ：、 1 N塩化水素一エーテル溶液 1 2ml、 DMF 0. 3 ml, 塩化チォニル 5. 5ml、 2—ァミノチアゾ —ル 0. 7 gを実施例 1と同様に反応処理することにより、 5—フヱニル— N - (2—チアゾリル） 一 2— （ 4—トリフルォロメチルフエニル） イミダゾ一ル —4一カルボキサミ ド 0. 3 gを得た。 さらに塩酸を加えることにより塩酸の 酸付加塩を得た。 1塩酸塩 融点 250°C以上。

5-phenyl-2- (4-trifluoromethylphenyl) imidazole-4-carboxylic acid 2.5 obtained in Raw Material Synthesis Example 44, 1N hydrogen chloride / ether solution 12 ml, DMF 0.3 ml, 5.5 ml of thionyl chloride and 0.7 g of 2-aminothiazole were reacted in the same manner as in Example 1 to give 5-phenyl-N- (2-thiazolyl) 1-2- (4-trifluorofluoride). Methylphenyl) imidazole-4-carboxamide 0.3 g was obtained. Further, hydrochloric acid was added to obtain an acid addition salt of hydrochloric acid. 1 Hydrochloride Melting point 250 ° C or higher.

¹ H-NMR 270 MHz (DMS〇—dpm) δ: 8.47 (2H, d), 7.93-7.90 (4H, m), 7.64 (1H, d)ヽ 7.5 3 (2H, d), 7.34 (1H, d)

Example 1 2

原料合成例 36で得られた 5— （ 4—フルオロフヱニル） 一 2— (4—卜リフ ルォロメチルフエニル） イ ミダゾ一ル一 4一力ルボン酸 3. 0 gを塩化メチレ ン 6 Omlに懸濁させた。 懸濁溶液に 2—ァミノチアゾ一ル 0. 9 g、 トリ ェチルァミン 2. 4 mlを加えた。 2—クロ口一 1 , 3—ジメチルイミダゾリ ニゥムクロライ ド 2. l gを塩化メチレン 2 0m 1に溶解させた溶液を氷冷 下で滴下した後、 室温で 2時間攪拌した。 反応後、 飽和重曹水を加え、 機層を 酢酸ェチルにて抽出した。 有機層を乾燥後、 残渣をシリカゲルクロマトグラフィ 一に付し、 5— （4—フルオロフェニル） 一 N— （2—チアゾリル） 一 2— （4 一トリフルォロメチルフエニル） イミダゾールー 4 _カルボキサミ ドを得た。 さ らに塩酸を加えることにより塩酸の酸付加塩 1. 2 gを得た。 1塩酸塩 融 点 250 °C以上。

Raw material synthesis example 5— (4-Fluorophenyl) -12- (4-trifluoromethylphenyl) imidazole-1-4 rubonic acid 3.0 g in 6 mL of methylene chloride Suspended. 0.9 g of 2-aminothiazole and 2.4 ml of triethylamine were added to the suspension solution. A solution of 2.lg of 1,2-dimethylimidazolinium chloride in 20 ml of methylene chloride was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, saturated aqueous sodium hydrogen carbonate was added, and the organic layer was extracted with ethyl acetate. After drying the organic layer, the residue was subjected to silica gel chromatography to give 5- (4-fluorophenyl) -1-N- (2-thiazolyl) -12- (4-trifluoromethylphenyl) imidazole-4_carboxamide. Obtained. Further, hydrochloric acid was added to obtain 1.2 g of an acid addition salt of hydrochloric acid. 1 Hydrochloride Melting point 250 ° C or more.

 'H-NMR 270 MHz (DMS O-d or p pm) δ: 8.48 (2H, d), 8.03-7.98 (4H, m), 7.67 (1H, d) , 7.4 1-7.34 (3 H, m)

Example 13

原料合成例 38で得られた 5— （ 4—クロ口フエニル） 一 2— ( 4—トリフル ォロメチルフエニル） イミダゾ一ル一 4—カルボン酸 3. 0 g、 2—アミノチ ァゾ一ル 0. 8 g、 トリェチルァミン 2. 3ml、 2—クロ口一 1 , 3—ジ メチルイ ミダゾリニゥムクロライ ド 2. 2 gを実施例 1 2と同様に反応処理す ることにより 5— (4—クロ口フエニル） 一 N— (2—チアゾリル） 一 2— (4 一卜りフルォロメチルフエニル） イミダゾ一ルー 4—カルボキサミ ドを得た。 さ らに塩酸を加えることにより塩酸の酸付加塩を ◦. 3 g得た。

5- (4-chlorophenyl) 1-2- (4-trifluoromethylphenyl) imidazole-1-carboxylic acid 3.0 g, 2-aminothiazole obtained in Raw Material Synthesis Example 38 0.8 g, 2.3 ml of triethylamine, 2.2 g of 2-chloro-1,3-dimethylimidazolinium chloride were treated in the same manner as in Example 12 to give 5- (4- N- (2-thiazolyl) -12- (4-fluoromethylphenyl) imidazo-1-yl 4-carboxamide was obtained. Further, hydrochloric acid was added to obtain 3 g of an acid addition salt of hydrochloric acid.

 1 Hydrochloride Melting point 250 ° C or more.

¹ H-NMR 270 MHz (DMS O_d ₆ , p pm) δ: 8.47 (2 H, d), 7.99-7.88 (4 H, m), 7.65-7.55 (3 H, m), 7.34 (1H, d)

Example 14

原料合成例 46で得られた 5— （4一ブロモフエニル） 一 2— (4— トリフル ォロメチルフエニル） イミダゾールー 4一力ルボン酸 3. 0 g、 1 N塩化水素 一エーテル溶液 1 5 ml、 DMF 0. 3 m l、 塩化チォニル 5. 3ml、 2—ァミノチアゾール 0. 7 gを実施例 1と同様に反応処理することにより 5 一 （4—ブロモフエニル） 一 N— ( 2—チアゾリル） 一 2— (4—卜リフルォロ メチルフエニル） イミダゾールー 4—カルボキサミ ドを得た。 さらに塩酸を加え ることにより塩酸の酸付加塩 0. 4 gを得た。 1塩酸塩 融点 2 5 6— 2 5 7°C。

5- (4-bromophenyl) 1-2- (4-trifluoromethylphenyl) imidazole obtained in Example 46 of raw material imidazole-4 rubonic acid 3.0 g, 1 N hydrogen chloride By reacting 15 ml of a monoether solution, 0.3 ml of DMF, 5.3 ml of thionyl chloride and 0.7 g of 2-aminothiazole in the same manner as in Example 1, 5 (4-bromophenyl) 1 N— (2-thiazolyl) -1-2- (4-trifluoromethylphenyl) imidazole-4-carboxamide was obtained. Further, hydrochloric acid was added to obtain 0.4 g of an acid addition salt of hydrochloric acid. Monohydrochloride Melting point 25 56—25 7 ° C.

Example 15

原料合成例 3 4で得られた 5— （ 4—メチルフエニル） 一 2— （4— トリフル ォロメチルフエニル） イミダゾ一ル— 4—カルボン酸 2. 0 g、 1 N塩化水素 一エーテル溶液 1 2 ml、 DMF 0. 2 ml、 塩化チォニル 2. 9 m l , 2—ァミノチアゾール ◦ . 6 gを実施例 1 と同様に反応処理することにより 5 一 （4一メチルフエニル） 一 N— ( 2—チアゾリル） 一 2 _ ( 4—トリフルォロ メチルフエニル） イミダゾ一ルー 4一カルボキサミ ドを得た。 さらに塩酸を加え ることにより塩酸の酸付加塩 0. 4 gを得た。 1塩酸塩 融点 2 5 CTC以 上。

Raw material synthesis example 3 5- (4-methylphenyl) 1-2- (4-trifluoromethylphenyl) imidazole-4-carboxylic acid obtained in 4 2.0 g, 1 N hydrogen chloride monoether solution 1 2 ml, 0.2 ml of DMF, 2.9 ml of thionyl chloride and 6 g of 2-aminothiazole were reacted in the same manner as in Example 1 to give 5- (4-methylphenyl) -1-N— (2- Thiazolyl) 1-2_ (4-trifluoromethylphenyl) imidazo-l-41-carboxamide was obtained. Further, hydrochloric acid was added to obtain 0.4 g of an acid addition salt of hydrochloric acid. 1 Hydrochloride Melting point 25 CTC or more.

¹ H-NMR 270 MHz (DMS O _ d _fi , p pm) δ 8.47 (2 H, d), 7.90 (2 H, d), 7.82 (2 H, d ), 7.64 (1H, d), 7.35-7.32 (3H, m), 2.40 (3H, s)

Example 16

原料合成例 49で得られた 5— （4—クロ口フエニル） 一 2— 〔4— (2—メ トキシエトキシ） フヱニル〕 イミダソ'一ル一 4—カルボン酸 45. 5 g、 I N 塩化水素一エーテル溶液 13 Om 1、 触媒量の DMF、 塩化チォニル 70m 1、 2—ァミノチアゾール 12 gを実施例 1と同様に反応処理することにより 5— （ 4一クロ口フエニル） 一 2— 〔4— ( 2—メ トキシェトキシ） フエニル〕 一 N— (2—チアゾリル） イミダゾールー 4一カルボキサミ ドを 30· 2 た。 融点 147— 148 C。

5- (4-chlorophenyl) 1-2- [4- (2-methoxyethoxy) phenyl] imidazo'-1-yl 4-carboxylic acid obtained in raw material synthesis example 49 45.5 g, IN hydrogen chloride By reacting the ether solution 13 Om 1, a catalytic amount of DMF, thionyl chloride 70 m 1, and 2-aminothiazole 12 g in the same manner as in Example 1, 5— (4-cyclophenyl) 1-2— (2-Methoxyxetoxy) phenyl] 1 N- (2-thiazolyl) imidazole-41-carboxamide was used. 147-148C.

Further addition of hydrochloric acid gave 31. O g of an acid addition salt of hydrochloric acid.

Monohydrochloride mp 238-240 ° C.

Example 17

原料合成例 52で得られた 5— (4—クロ口フエニル）一 2— {4—〔2— (2 —メ トキシェトキシ）ェ卜キシ〕フエ二ル}ィ ミダゾ一ル一 4一力ルボン酸 1 · 3 g、 1 N塩化水素一エーテル溶液 4. 5ml、 DMF 0. 1ml、 塩化チ ォニル 1 · 6ml、 2—ァミノチアゾ一ル 12 gを実施例 1と同様に反応処 理することにより 5— (4—クロ口フエニル） 一 2— {4 - 〔2— (2—メ 卜キ シェ卜キシ） エトキシ〕 フエ二ル} -N- (2—チアゾリル） イミダゾ一ルー 4 —カルボキサミ ドを得た。さらに塩酸を加えることにより塩酸の酸付加塩を 0. 4 g得た。 1塩酸塩 融点 205— 206°C。

5- (4-chlorophenyl) -2- (4- (2- (2-methoxyethoxy) ethoxy) phenyI) midazol-14 obtained from raw material synthesis example 52 1.3 g, 1 N hydrogen chloride-ether solution 4.5 ml, DMF 0.1 ml, titanium chloride 1-6 ml of 2-onaminothiazol and 12 g of 2-aminothiazol were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2- {4- [2- (2-methacrylic acid). [Ethoxy] phenyl] -N- (2-thiazolyl) imidazo-l-u-l 4-carboxamide was obtained. Further addition of hydrochloric acid gave 0.4 g of an acid addition salt of hydrochloric acid. Monohydrochloride Melting point 205-206 ° C.

Example 18

原料合成例 6 1で得られた 5— (4—クロ口フエニル） 一 2—（4一 {2—〔2 - (2—メ トキシェトキシ） エトキシ〕 ェ 卜キシ} フエニル） ィ ミダゾ一ルー 4 一力ルボン酸 3. 5 g、 2 N塩化水素—エーテル溶液 4. 56ml、 DMF 0. 6 ml、 塩化チォニル 5. 5ml、 2—ァミノチアゾ一ル 0. 76 gを 実施例 1と同様に反応処理することにより 5—（4一クロ口フエニル）一 2—（ 4 一 {2— 〔2— （2—メ トキシエトキシ） エトキシ〕 エトキシ } フエニル） 一 N 一 （ 2—チアゾリル）イミダゾールー 4—カルボキサミ ド 1. 3 gを得た。 融 点 120— 122 °C。

Raw material synthesis example 6 5- (4-chlorophenyl) -1-2- (4- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy] phenyl) obtained in 1) The reaction treatment was carried out in the same manner as in Example 1 by adding 3.5 g of carboxylic acid, 4.56 ml of a 2N hydrogen chloride-ether solution, 0.6 ml of DMF, 5.5 ml of thionyl chloride and 0.76 g of 2-aminothiazole. It is possible to obtain 5- (4-chlorophenyl) 1-2- (4-1 {2- [2- (2-methoxyethoxy) ethoxy] ethoxy] phenyl) -1-N-1 (2-thiazolyl) imidazole-4-carboxamide 1 3 g were obtained. Melting point 120-122 ° C.

Furthermore, monohydrochloride was obtained by adding hydrochloric acid. Melting point 75-80 ° C;

Example 19

原料合成例 58で得られた 5— (4—クロ口フエニル） — 2— 〔4— (2—ェ トキシエトキシ） フエニル〕 イミダゾ一ルー 4—カルボン酸 3 g、 2 N塩化水 素一エーテル溶液 4. 7ml、 DMF 0. 6ml, 塩化チォニル 5. 6m 1、 2—ァミノチアゾール 0. 78 gを実施例 1と同様に反応処理することに より 5— （4—クロ口フエニル） 一 2— 〔4— (2—エトキシエトキシ） フエ二 ル〕 — N— （ 2—チアゾリル） イミダゾール— 4一カルボキサミ ドを 0. 94 g得た。 融点 1 15て。

Raw material synthesis example 5- (4-chlorophenyl) -5- (4- (2-ethoxyethoxy) phenyl) imidazo-l- 4-carboxylic acid 3 g, 2N hydrogen chloride-monoether solution obtained in 58 4.7 ml, 0.6 ml of DMF, 0.6 ml of thionyl chloride, 5.6 ml of 0.78 g of 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2- [4- (2-ethoxyethoxy) phenyl] —N— (2-thiazolyl) imidazole—0.94 g of 4-carboxamide was obtained. Melting point 1 15

Further addition of hydrochloric acid gave the monohydrochloride. Melting point 195-200. C.

Example 20

原料合成例 55で得られた 5— (4—クロ口フエニル） — 2— 〔4一 （2—ィ ソプロポキシエトキシ） フエニル〕 イミダゾールー 4一力ルボン酸 2 g、 2 N 塩化水素—エーテル溶液 3ml、 DMF 0. 4ml, 塩化チォニル 3. 6 4ml、 2—ァミノチアゾール 0. 5 gを実施例 1と同様に反応処理すること により 5— （4一クロ口フエニル） 一 2—〔4— (2—イソブロポキシエトキシ） フエニル〕 一N— (2—チアゾリル） イミダゾ一ルー 4—カルボキサミ ド 0 62 gを得た。 融点 12 1— 125°C。

5- (4-cyclopentylphenyl) —2- (4- (2-dipropoxyethoxy) phenyl) imidazole obtained in Example 55 of raw material imidazole-4 2 g of rubutonic acid, 2 N hydrogen chloride—ether solution 3 ml , DMF (0.4 ml), thionyl chloride (3.64 ml), and 2-aminothiazole (0.5 g) were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2- [4- ( 2-isopropoxyethoxy) [Phenyl] 1-N- (2-thiazolyl) imidazo-l-4-carboxamide 0 62 g was obtained. Mp 121-125 ° C.

Further addition of hydrochloric acid gave the monohydrochloride. Melting point 195-198 ° C.

Example 21

原料合成例 64で得られた 5— (4—クロ口フエニル） 一 2— 〔4— (3—メ 卜キシブロポキシ） フエニル〕 イ ミダゾ一ルー 4—カルボン酸 1. 87 g、 2 N塩化水素一エーテル溶液 2.9ml、DMF 0.2 ml、塩化チォニル 3. 53ml、 2—ァミノチアゾール 0. 48 gを実施例 1と同様に反応処理するこ とにより 5— （4一クロ口フエニル） 一2— 〔4一 （ 3—メ トキシプロポキシ） フエニル〕 一 N— (2—チアゾリル） イ ミダゾ一ルー 4—カルボキサミ ド 0. 84 gを得た。 融点 173— 177°C。

5- (4-chlorophenyl) -1- 2- (4- (3-methoxypropoxy) phenyl) imidazo-1-yl 4-carboxylic acid obtained in Synthesis Example 64 1.87 g, 2N hydrogen chloride 2.9 ml of an ether solution, 0.2 ml of DMF, 3.53 ml of thionyl chloride and 0.48 g of 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2- [ 4- (3-Methoxypropoxy) phenyl] -N- (2-thiazolyl) imidazo-l-u 4-84-carboxamide 0.84 g was obtained. 173-177 ° C.

Furthermore, monohydrochloride was obtained by adding hydrochloric acid. Melting point 230-234. Example 22

原料合成例 68で得られた 5— （4ークロロフェニル） 一 2— 〔4一 （ホモビ ペリジン一 1—ィル） フエニル〕 イミダゾ一ルー 4—カルボン酸 2. 0 g、 1 N塩化水素一エーテル溶液 10ml、 DMF 0. 2 m 1、塩化チォニル 2. 5ml、 2—ァミノチアゾール 0. 5 gを実施例 1と同様に反応処理すること により 5— (4—クロ口フエニル） 一 2 - 〔4- (ホモピべリジン一 1一ィル） フェニル〕 — N— （ 2一チアゾリル） ィ ミダゾ一ルー 4一カルボキサミ ド 0. 47 gを得た。 融点 246— 247 °C

5- (4-Chlorophenyl) 1-2- [4- (homobiperidine-11-yl) phenyl] obtained in Example 68 of raw material imidazo-1-ru 4-carboxylic acid 2.0 g, 1 N hydrogen chloride monoether A solution of 10 ml of the solution, 0.2 ml of DMF, 2.5 ml of thionyl chloride, and 0.5 g of 2-aminothiazole was treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2- [ 4- (Homopiberidine-11-yl) phenyl] —N— (2-thiazolyl) -midazo-l-41-carboxamide 0.47 g was obtained. 246-247 ° C

Example 23

原料合成例 70で得られる 5— （4一フルオロフヱニル） 一 2— 〔4— (ホモ ピぺリジン— 1一ィル） フエニル〕 イ ミダゾ一ル— 4一力ルボン酸、 2N塩化水 素—エーテル溶液、 DMF、 塩化チォニル、 2—ァミノチアゾールを実施例 1と 同様に反応処理することにより 5— (4—フルオロフェニル） 一 2— 〔4一 （ホ モビペリジン一 1一ィル） フエニル〕 一 N— (2—チア Vリル） イミダゾール一 4一カルボキサミ ドが得られる。

Raw material synthesis example 5- (4-Fluorophenyl) 1-2- [4- (homopyridine-11-yl) phenyl] imidazoyl obtained from 70 70% rubonic acid, 2N hydrogen chloride-ether The solution, DMF, thionyl chloride, and 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-fluorophenyl) 1-2- [4- (phomobiperidine-11-yl) phenyl] 1- N- (2-Thia V-ril) imidazole-141 carboxamide is obtained.

Example 24

原料合成例 72で得られた 5—（ 5—メチルチオフェン一 2—ィル）一 2—（4 —トリフル才ロメチルフエニル） イ ミダゾ一ルー 4—カルボン酸 1. 0 g、 2 —ァミノチアゾ一ル 0. 3 g、 卜リエチルァミン 0. 8ml、 2—クロロー 1， 3—ジメチルイミダゾリゥムクロライ ド 0. 7 gを実施例 1 3と问様に反応 処理することにより 5— （ 5—メチルチオフェン一 2—ィル） 一N— ( 2—チア ゾリル） 一 2— （4一トリフルォロメチルフエニル） イミダゾ一ル一4—力ルポ キサミ ド 0. 4 gを得た。 融点 235— 237°C。

5- (5-Methylthiophen-12-yl) -12- (4-trimethyl romethylphenyl) imidazo-l- 4-carboxylic acid 1.0 g, 2-aminothiazol 0 obtained in Example 72 of raw material synthesis 3 g, 0.8 ml of triethylamine and 0.7 g of 2-chloro-1,3-dimethylimidazorim chloride were treated in the same manner as in Example 13 to give 5- (5-methylthiophene-1 2 —Yl) 1N— (2-thiazolyl) 1-2— (4-trifluoromethylphenyl) imidazole-14-potoxamine 0.4 g was obtained. 235-237 ° C.

Example 25

原料合成例 74で得られる 5—（ 5—メチルチオフェン一 2—ィル）一 2—（ 4 一モルホリノフエニル） イ ミダゾ一ル— 4—カルボン酸、 2 N塩化水素—ェ一テ ル溶液、 DMF、 塩化チォニル、 2—ァミノチアゾールを突施例 1と同様に反応 処理することにより 5— ( 5—メチルチオフェン一 2—ィル） 一 2— (4—モル ホリノフエニル） 一 N— ( 2—チアゾリル） イミダゾールー 4—カルボキサミ ド が得られる。 実施例 26

5- (5-Methylthiophene-2-yl) -12- (4-morpholinophenyl) imidazole-4-carboxylic acid, 2N hydrogen chloride-ether solution obtained in Raw Material Synthesis Example 74 , DMF, thionyl chloride and 2-aminothiazole were subjected to a reaction treatment in the same manner as in Example 1 to give 5- (5-methylthiophene-2-yl) -12- (4-morpholinophenyl) -1N- ( 2-thiazolyl) imidazole-4-carboxamide is obtained. Example 26

原料合成例 7 6で得られる 2— 〔4— ( 2—メ トキシェトキシ） フヱニル〕 一 5— （ 5—メチルチオフェン一 2—ィル） イミダゾール一 4一力ルボン酸、 2 N 塩化水素一エーテル溶液、 DMF、 塩化チォニル、 2—ァミノチアゾールを実施 例 1と同様に反応処理することにより 2— 〔4一 （ 2—メ トキシェトキシ） フエ ニル〕 一 5— （ 5—メチルチオフェン一 2—ィル） 一 N— （2—チアゾリル） ィ ミダゾ一ルー 4—カルボキサミ ドが得られる。

Raw material synthesis example 7 2- [4- (2-Methoxyxethoxy) phenyl] 1-5- (5-methylthiophene-2-yl) obtained in 6-Imidazole-14-Rubonic acid, 2N Hydrogen chloride-ether solution , DMF, thionyl chloride, and 2-aminothiazole were treated in the same manner as in Example 1 to give 2- [4- (2-methoxhetoxy) phenyl] -1- (5-methylthiophene-12-yl). 1) N- (2-thiazolyl) -midazo-l-l 4-carboxamide is obtained.

Example 27

原料合成例 7 9で得られる 5— (4—クロ口フエニル） 一 2— 〔4— (2—ジ メチルアミノエチル） フエニル〕 イ ミグゾール— 4—カルボン酸、 2 N塩化水素 一エーテル溶液、 DMF、 塩化チォニル、 2—ァミノチアゾールを実施例 1と同 様に反応処理することにより 5— （4—クロ口フエニル） 一 2— 〔4一 （2—ジ メチルアミノエチル） フエニル〕 一 N— ( 2—チアゾリル） イミダゾールー 4— カルボキサミ ドが得られる。

Raw Material Synthesis Example 7 5- (4-Clo-Methylphenyl) 1-2- [4- (2-Dimethylaminoethyl) phenyl] imigsol-4-carboxylic acid, 2N Hydrogen chloride monoether solution obtained in 9-9, DMF , Thionyl chloride, and 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) -12- [4- (2-dimethylaminoethyl) phenyl] -1N- (2-thiazolyl) imidazole-4 Carboxamide is obtained.

Example 28

5- (4-chlorophenyl) 1-2- [4- (4-methoxybutoxy) phenyl] imidazole-4-carboxylic acid, 2 N hydrogen chloride-ether solution obtained in Raw Material Synthesis Example 82, DMF , Thionyl chloride and 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2- [4- (4-methoxybutoxy) phenyl] -1N- (2 —Thiazolyl) Imidazo-l-41-carboxamide is obtained.

Example 29

原料合成例 86で得られた 5— （4一クロロフヱニル） 一 2— 〔4一 （4ーモ ルホリノビぺリジン一 1一ィル）フエニル〕ィ ミダゾ一ルー 4一力ルボン酸 1 · 66 g、 2 N塩化水素—エーテル溶液 6. 4ml、 DMF 0. 3ml、 塩化 チ才ニル 2. 59ml, 2—ァミノチアゾール 0. 36 gを実施例 1と同様 に反応処理することにより目的の 5— （4一クロ口フエニル） 一2— 〔4— (4 一モルホリノビペリジン一 1一ィル） フエニル〕 一 N— （2—チアゾリル） イ ミ ダゾールー 4一カルボキサミ ド 0.46 gを得た。 融点 165— 170°C。 実施例 30

5- (4-Chlorophenyl) -1- (4- (4-morpholinovidine) -l-phenyl) -midazo-l-u4 obtained from Example 86 of raw material synthesis 6.4 ml of 2 N hydrogen chloride-ether solution, 0.3 ml of DMF, chloride 2.59 ml of 2-aminothiazole and 0.36 g of 2-aminothiazole were treated in the same manner as in Example 1 to give the desired 5- (4-chlorophenyl) 1-2- [4- (4-morpholinobine). Peridine (11-yl) phenyl) -N- (2-thiazolyl) imidazole-41-carboxamide 0.46 g was obtained. Melting point 165-170 ° C. Example 30

原料合成例 88で得られる 5— (4—フルオロフヱニル） —2— 〔4一 (4- モルホリノビベリジン一 1—ィル） フエニル〕 ィ ミダゾールー 4一力ルボン酸、 2 N塩化水素一エーテル溶液、 DMF、 塩化チォニル、 2—ァミノチアゾ一ルを 実施例 1と同様に反応処理することにより 5— （4一フルオロフェニル） ー 2— 〔4一 （4—モルホリノピぺリジン一 1—ィル） フエニル〕 一 N— （2—チアゾ リル） イミダゾ一ルー 4一カルボキサミ ドが得られる。

5- (4-Fluorophenyl) -2- (4- (4-morpholinoviveridine-1-yl) phenyl) imidazole obtained in Example 88 of raw material synthesis 4-Ribonic acid, 2N hydrogen chloride monoether solution , DMF, thionyl chloride, and 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-fluorophenyl) -2- [4- (4-morpholinopiperidine-11-yl) phenyl. 1-N- (2-thiazolyl) imidazo-1-41-carboxamide is obtained.

Example 31

原料合成例 32で得られた 5— (4—クロロフヱニル） 一 2— {4— 〔4一 （ジ メチルァミノ）ビぺリジン一 1一ィル〕フエ二ル}ィミダゾールー 4—カルボン酸、 2 N塩化水素一エーテル溶液、 D M F、 塩化チォニル、 2—ァミノチアゾールを 実施例 1と同様に反応処理することにより 5 _ ( 4—クロ口フエニル）一 2— { 4 — 〔4— (ジメチルアミノ） ビぺリジン一 1—ィル〕 フエ二ル}— N— ( 2—チア ゾリル） イミダゾ一ルー 4一カルボキサミ ドが得られる。

5- (4-chlorophenyl) 1-2- {4— [4-1- Methylamino) bipyridine-1-yl] phenyl} imidazole-4-carboxylic acid, 2N hydrogen chloride monoether solution, DMF, thionyl chloride, and 2-aminothiazole are treated in the same manner as in Example 1. To give 5 _ (4-cyclophenyl) -2- (4— [4- (dimethylamino) bipyridine-1-yl) phenyl} —N— (2-thiazolyl) imidazo Carboxamide is obtained.

Example 3 2

原料合成例 9 0で得られた 5— （4一フルオロフヱニル） 一 2— 〔4— ( 2— メ トキシエトキシ） フエニル〕 イミダヅ一ルー 4—カルボン酸、 2 N塩化水素一 エーテル溶液、 D M F、 塩化チォニル、 2—ァミノチアゾールを実施例 1と同様 に反応処理することにより 5— （4一フルオロフェニル） 一 2— 〔4一 （2—メ トキシェトキシ） フエニル〕 一 N— ( 2—チアゾリル） イミダゾ一ルー 4—カル ボキサミ ドが得られる。

Raw material synthesis example 5- (4-Fluorophenyl) 1-2- [4- (2-methoxyethoxy) phenyl] imida-1-ru 4-carboxylic acid, 2N hydrogen chloride-ether solution, DMF, chloride obtained in 90 Thionyl and 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-fluorophenyl) 1-2- [4-1 (2-methoxetoxy) phenyl] -1-N- (2-thiazolyl) imidazo One roux 4-carboxamide is obtained.

Example 3 3

原料合成例 93で得られる 5— (4—クロ口フエニル） — 2— 〔4- (チォモ ルホリン一 4—ィル） フエニル〕 イミダゾールー 4一力ルボン酸、 2 N塩化水^ 一エーテル溶液、 DMF、 塩化チォニル、 2—ァミノチアゾ一ルを実施例 1と同 様に反応処理することにより 5— (4—クロ口フエニル） 一 N— (2—チアゾリ ル） 一 2— 〔4— (チオモルホリン一 4—ィル） フェニル〕 ィ ミダゾ一ルー 4一 カルボキサミ ドが得られる。

5- (4-chlorophenyl)-2- (4- (thiomoφholin-4-yl) phenyl) obtained in Example 93 of raw material synthesis imidazole-4 immobilized rubonic acid, 2N aqueous solution of hydrochloric acid in monoether, DMF , Thionyl chloride and 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) -1N- (2-thiazolyl) 1-2- [4- (thiomorpholine 4-yl) phenyl] midazolu-41-carboxamide is obtained.

Example 34

原料合成例 1 0 1で得られた 5— (4—クロ口フエニル） 一 2— 〔4— (モル ホリノメチル） フエニル〕 イミダゾ一ルー 4—カルボン酸 2. 5 g、 2N塩化 水素—エーテル溶液 7. 5ml、 DMF 0. 3ml、 塩化チォニル 4. 6 ml、 2—ァミノチアゾ一ル ◦ . 6 3 gを実施例 1と同様に反応処理すること により 5— (4—クロ口フエニル） 一 2— 〔4一 （モルホリノメチル） フェニル〕 一 N— ( 2—チアゾリル） イミダゾール— 4 _カルボキサミ ド 1. 87 gを捋 た。 融点 253— 255-C

Raw material synthesis example 5- (4-chlorophenyl) 1-2- [4- (morpholinomethyl) phenyl] imidazo-l- carboxylic acid 2.5g obtained in 101 and 2N hydrogen chloride-ether solution 7 5 ml, 0.3 ml of DMF, 4.6 ml of thionyl chloride, and 2-aminothiazole 6.3 g were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2— [ 4- (Morpholinomethyl) phenyl] -1-N- (2-thiazolyl) imidazole-4_carboxamide 1.87 g was obtained. Melting point 253-255-C

Furthermore, dihydrochloride was obtained by adding hydrochloric acid. Melting point 260 or less.

1 H-NMR 270MH z (DMSO- d 6, ppm) δ: 1 1. 6 9 (. 1 Η, br s)ヽ8. 34 (2 H, d)ゝ7. 98 (2 H, d) , 7.82 (2H, d), 7.59-7.62 (3H, m), 7.32 (1H, d), 4.40 (2H, br.s) , 3.83—3.97 (4H, m), 3.14-3.28 (4H, m)

Example 35

原料合成例 1 05で得られる 5— (4—クロ口フエニル） — 2— {4 - 〔4 - ( 4ーメチルビべラジン一 1一ィル） ピベリジン一 1—ィル〕 フエ二ル} イ ミダ ゾ一ル— 4—カルボン酸、 2 N塩化水素—ェ一テル溶液、 DMF、塩化チォニル、 2—アミノチアゾ一ルを実施例 1と同様に反応処理することにより 5— (4—夕 ロロフエニル） 一 2— {4— 〔4一 （ 4ーメチルビペラジン一 1一ィル） ビペリ ジン一 1—ィル〕 フエ二ル} — N— （ 2—チアゾリル） イミダゾールー 4一カル ボキサミ ドが得られる。

Raw material synthesis example 105— (4-chlorophenyl) obtained in 05—2— {4- [4- (4-methylbiverazine-1-yl) piberidine-1-1-yl] phenyl} imida By reacting sol-4-carboxylic acid, 2N hydrogen chloride-ether solution, DMF, thionyl chloride, and 2-aminothiazole in the same manner as in Example 1, 5- (4-chlorophenol) was obtained. 2 -— {4 -— [4- (4-methylbiperazine-11-yl) biperidin-1-1-yl] phenyl} — N— (2-thiazolyl) imidazole-41-carboxamide .

Example 36

原料合成例 1 08で得られる 5— (4—クロ口フエニル） 一 2— 〔4— ( 2— モルホリノエチル） フエニル〕 イミダゾ一ル— 4一力ルボン酸、 2N塩化水素一 エーテル溶液、 DMF、 塩化チォニル、 2—ァミノチアゾ一ルを実施例 1と同様 に反応処理することにより 5— （4—クロロフヱニル） — 2— 〔4一 （ 2—モル ホリノエチル） フエニル〕 一 N— ( 2—チアゾリル） イミダゾ一ルー 4—カルボ キサミ ドが得られる,

Raw material synthesis example 5- (4-chlorophenyl) 1-2- [4- (2-morpholinoethyl) phenyl] obtained in 08 Imidazole-1-4 rubonic acid, 2N hydrogen chloride-ether solution, DMF, By reacting thionyl chloride and 2-aminothiazole in the same manner as in Example 1, 5- (4-chlorophenyl) —2- [4-1 (2-morpholinoethyl) phenyl] 1 N— (2-thiazolyl) imidazo One roux 4—Carbo Kisamide is obtained,

Example 37

原料合成例 1 12で得られた 5— （4—クロロフヱニル） 一 2— 〔4— (ジメ チルアミノメチル） フエニル〕 イ ミダゾ一ルー 4—カルボン酸 2. 0 g、 2 N 塩化水素一エーテル溶液 10ml、 DMF 0. 2ml、 塩化チォニル 2. 7ml, 2—ァミノチアゾール 0. 6 gを実施例 1と同様に反応処理すること により 5— （4—クロ口フエニル） 一2— 〔4— (ジメチルアミノメチル） フエ ニル〕 一 N— ( 2—チアゾリル） イ ミダゾ一ル— 4一カルボキサミ ド 0. 4g を得た。 融点 143— 145 。

Raw material synthesis example 1 5- (4-chlorophenyl) 1-2- [4- (dimethylaminomethyl) phenyl] imidazo-l- 4-carboxylic acid 2.0 g, 2 N hydrogen chloride-ether solution obtained in 12 10-ml, 0.2 ml of DMF, 2.7 ml of thionyl chloride and 0.6 g of 2-aminothiazole were treated in the same manner as in Example 1 to give 5- (4-chlorophenyl) 1-2— [4- ( [Dimethylaminomethyl) phenyl] -N- (2-thiazolyl) imidazole-41-carboxamide 0.4 g was obtained. 143-145.

Example 38

実施例 10で得られた 5— (4—クロ口フエニル） 一 2— （4—シァノフエ. ル） 一 Ν— ( 2—チアゾリル） ィ ミダゾールー 4一力ルポキサミ ドを、 L i A Η₄にて還元することにより、 2— (4—ァミノメチルフエニル） 一5— (4 クロ口フエニル） 一 N— （2—チアゾリル） イミダゾ一ルー 4—カルポキサミ ド が得られる。

The resulting 5- (4-black port phenyl) Single 2- (4-Shianofue. Le) Single Nyu- (2-thiazolyl) I Midazoru 4 Ichiriki Rupokisami de with Example 10 at L i A Eta ₄ By reduction, 2- (4-aminomethylphenyl) -1-5- (4 N- (2-thiazolyl) imidazo-l-4-carpoxamide is obtained.

Example 3 9

原料合成例 1 1 5で得られる 2—（4—ァセ 卜キシメチルフヱニル）一 5—（4 一クロ口フエニル） イミグゾ一ル一 4 -カルボン酸、 2 N塩化水素—エーテル溶 液、 D M F、 塩化チォニル、 2—ァミノチアゾ一ルを実施例 1と同様に反応処 ¾ することにより 2— （ 4—ァセ卜キシメチルフエニル） 一 5— （4—クロ口フエ 二ル）一 N—（ 2—チアゾリル）ィミダゾ一ル一 4—カルボキサミ ドが得られる。 実施例 4 0

Raw material synthesis example 1 2- (4-Acetoxymethylphenyl) -15- (4-chlorophenyl) imigzol-14-carboxylic acid, 2N hydrogen chloride-ether solution obtained in 15 , DMF, thionyl chloride, and 2-aminothiazole were reacted in the same manner as in Example 1 to give 2- (4-acetoxymethylphenyl) -15- (4-chlorophenyl) one. N- (2-thiazolyl) imidazole-14-carboxamide is obtained. Example 40

実施例 3 9で得られる 2— ( 4 —ァセトキシメチルフエニル） 一 5— ( 4—ク ロロフエニル） 一 N— （ 2—チアゾリル） イミダゾ一ルー 4 —カルボキサミ ドを 水酸化ナトリウム水溶液で加水分解することにより、 目的の 5— ( 4—クロロフ ェニル） 一 2— ( 4—ヒドロキシメチルフエニル） 一 N— ( 2—チアゾリル） ィ ミダゾ一ルー 4一カルボキサミ ドが得られる,

Example 3 2- (4-Acetoxymethylphenyl) -1-5- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazo-1-ru obtained from Example 9 4-Carboxamide was hydrolyzed with an aqueous sodium hydroxide solution. By decomposition, the desired 5- (4-chlorophenyl) -12- (4-hydroxymethylphenyl) -1-N- (2-thiazolyl) Midazolu-41-carboxamide is obtained,

Example 4 1

Raw material synthesis example 1 2- (4- (2-acetoxitytyl) phenyl) obtained in 1-8-5- (4-chlorophenyl) imidazole-4 mono-rubonic acid, 2N hydrogen chloride-ether solution, DMF, thionyl chloride , 2-Aminothiazol was subjected to a reaction treatment in the same manner as in Example 1 to give 2- [4- (2-acetoxityl) phenyl] 5-1 (4-chlorophenyl) -1-N- (2-thiazolyl) Imidazole-4_carboxamide is obtained.

Example 4 2

実施例 4 0と同様にして実施例 4 1で得られる 2— 〔4一 （ 2—ァセ 卜キシェ チル） フエニル〕 一 5— （4—クロ口フ エニル） 一N— （2—チアゾリル） イミ ダゾ一ル一 4一カルボキサミ ドから、 目的の 5— （4一クロ口フエニル） 一 2— 〔4— (2—ヒ ドロキシェチル） フエニル〕 一N— ( 2—チアゾリル） イミダゾ 一ルー 4一カルボキサミ ドが得られる。

2- [4-1- (2-acetoxyl) phenyl] -15- (4-chlorophenyl) 1N- (2-thiazolyl) obtained in Example 41 in the same manner as in Example 40 From the imidazole 4-carboxamide, the desired 5- (4-chlorophenyl) 1-2 [4- (2-Hydroxityl) phenyl] 1-N- (2-thiazolyl) imidazo 1-ru 41-carboxamide is obtained.

Example 43

5- (4-cyclopentyl) phenyl 2- (4- (2-hydroxishethyl) phenyl) -1-N- (2-thiazolyl) imidazo-1-ru obtained in Example 42 4-carboxamide, phthalimid, By subjecting it to Mitsunobu reaction using getyl azodicarboxylate and triphenylphosphine, the desired 5- (4-phenylphenyl) -2--2- {4- (2- (phthalimidyl) ethyl) 1) N- (2-thiazolyl) imidazo-l-4-carboxamide is obtained.

Example 44

実施例 43で得られる 5— （4一クロ口フエニル） 一 2— {4— 〔2— (フタ ルイミ ド— 1一ィル） ェチル〕 フェニル } -N- ( 2一チア、 Jリル） ィ ミダゾ一 ル一4一カルボキサミ ドをヒ ドラジン 1水和物にて反応させることにより 的の 2 - 〔4— ( 2—アミノエチル） フエニル〕 一 5— （4一クロ口フエニル） 一 N 一 （2—チアゾリル） イミダゾ一ルー 4一カルボキサミ ドが得られる。

5- (4-chlorophenyl) 1-2- {4- (2- (phthalimid-11-yl) ethyl] phenyl) obtained in Example 43} -N- (21-thia, J-yl) Midazo By reacting 4-carboxamide with hydrazine monohydrate, 2- [4- (2-aminoethyl) phenyl] -15- (4-chlorophenyl) -1-N- (2- Thiazolyl) Imidazoyl 4-carboxamide is obtained.

Example 45

原料合成例 1 23で得られる 2— {4一 〔4一 （ 2—ァセトキシェチル） ビぺ ラジン一 1—ィル〕 フエ二ル} — 5— (4—クロ口フエニル） イ ミダゾールー 4 一力ルボン酸、 2 N塩化水素—エーテル溶液、 DMF、 塩化チォニル、 2—アミ ノチアゾ一ルを実施例 1と同様に反応処埋することにより 2— {4— 〔4一 （ 2 —ァセトキシェチル） ビぺラジン一 1一ィル〕 フエ二ル} 一 5— (4—クロロフ ェニル） 一 N— （2—チアゾリル） イミダゾ一ル— 4—カルボキサミ ドが得られ る。

Raw material synthesis example 1 2- {4-([1- (2-acetoxicetyl) biazine-1-yl] phenyl] obtained in 23} —5- (4-chlorophenyl) imidazole-4 An acid, 2N hydrogen chloride-ether solution, DMF, thionyl chloride, and 2-aminothiazole were reacted and treated in the same manner as in Example 1 to give 2- {4- [4-1- (2-acetoxicetyl) biazine. 11-yl] phenyl} 1- (4-chlorophenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide.

Example 46

突施例 40と同様にして、 実施例 4 5で得られる 2— {4— 〔4— ( 2—ァセ トキシェチル） ビぺラジン一 1一ィル〕 フエ二ル} - 5 - ( 4—クロ口フエニル） 一 N— ( 2—チアゾリル）イミダゾ一ルー 4一力ルポキサミ ドから目的の 5— ( 4 —クロ口フエニル） 一 2— {4— 〔4— (2—ヒ ドロキシェチル） ビぺラジン一 1一ィル〕 フエ二ル} -N- (2—チアゾリル） イミダゾール— 4—カルボキサ ミ ドが得られる。

In the same manner as in the projection 40, 2— {4— [4— (2-base Tokishetil) Biradizin-1 11] Phenyl}-5-(4-chlorophenyl) 1-N- (2-thiazolyl) imidazo 1-ru 4 Methyl phenyl) 1—2— {4— [4— (2-Hydroxyshetyl) biperazine—11-yl] phenyl} -N- (2-Thiazolyl) imidazole—4-Carboxamide.

Example 47

In the same manner as in Example 1, 5- (4-chlorophenyl) 1-2- [4- (4-methyl-1-oxa-1,4,9diazaspiro [5,5]) obtained in Starting Material Synthesis Example 127 Didecane-1 9-yl) phenyl] imidazole-4-carboxylic acid 4,65 g, 2N hydrogen chloride monoether solution 17.3 ml, DMF 0.62 ml, thionyl chloride 7.3 ml, 2-aminothiazole lg to 5 — (4-Cross-phenyl) 1 2 _ [4- (4-Methyl-1-oxa 4,9-diazaspiro [5,5] pandecane-1 9-yl) phenyl) -1-N— (2-thiazolyl) imidazole-1 1.6 g of 4-carboxamide was obtained. Melting point 205—2 10 ° C.

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

Experimental Example 1 Effect on IL-4 and IL-15 production from mouse Th2 cell line 1. Experimental method

1) Preparation of test substance

The test substance was dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) at 1 Ommo 1 / Dissolved so that L, and to a final concentration of 10-5 one 10- 7 _{MO L} Bruno L and diluted with RPMI 1640 medium (Nacalai Tesque Inc.).

 2) Th2 cell line

D 10. G4.1 (from ATCC) was used as the Th2 cell line. D 10.G 4.1 recognizes cona 1 bum in as an antigen in I 一^κ restriction.

3) Medium

 Inactivated fetal bovine serum (Gibco BRL) was added to RPMI 1640 medium at 10%, and 2-mercaptophenol (Wako Pure Chemical Industries, Ltd.) was added to 50〃mol ZL. .

 4) Preparation of antigen-presenting cells

 A 6-12 week old male C3H / HeN mouse (Nippon Charls River Co., Ltd.) was bled to death and the spleen was aseptically removed to prepare a spleen cell suspension. Mitomycin C (Sigma) was added to a final concentration of 40 g / mL and incubated at 37 ° C 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

96-well plates (Sumitomo base one Cry preparative Co.) in 1 Uweru per Th 2 cell line 2 X 10 ^4, lxl 0 ⁵ antigen-presenting cells, c ona lbumin (S i gma Co., L ot 67H 7 145) Was added to 100 g Zml and a test substance, and cultured in a CO ₂ incubator (SANYO) for 2 days. After the culture, 10 pieces of the upper blanches were collected from each well. The concentrations of IL-14 and IL-15 in the supernatant were determined by sandwich ELISA (anti-mouse IL-14 antibody, anti-mouse IL-4 antibody, anti-mouse IL-4 antibody, biotin-labeled anti-mouse IL-5 antibody, anti-mouse IL-5 antibody, biotin-labeled anti-mouse IL-5 antibody). And POD-labeled streptavidin were purchased from Pharmingen, and Peroxidase Coloring Kit 0 was purchased from Sumitomo Beicrypt Co., Ltd.).

2. $ π = Κ

The effects on IL-14 and IL-15 production are shown in Table 1. Covered by this patent Representative compounds inhibited by IL one 4, IL- 5 production of 1 Λίπιο 1ZL before and after the IC ₅ o.

 table 1

Inhibitory effect on IL-14 and IL-5 production from Th2 clones

I n h i b 1 t i o n

 I C s o (/ i m o 1 / L)

 I shi 4 I L-5 Example 1 0.46 0.49

 Example 2 0.94 0.96

 Example 1 0.6 0.5 3 1.62

 Example 1 2 1.1.5 0.87

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 used by suspending it in a 0.5% hydroxypropylmethylcellulose (HPMC) solution so as to be 0.1 mL per 10 g of body weight.

 2) Experiential procedure

OA (ova lbumi n, Sigma, Lot 37 H70 10) 10 g and aluminum hydroxide gel (L-S'L, Lot 74502 22) lmg physiological saline (( (Otsuka Pharmaceutical Factory) 0.5 mL was intraperitoneally administered to a 7-week-old male BALB mouse (l-Challus Riva Co., Ltd.) for active sensitization. On the 14th day after sensitization, OA5 was intradermally administered to the auricle area to perform antigen challenge. The thickness of the pinna at 1 and 24 hours before and after antigen challenge is measured with a dial thickness gauge (Peacock, G-1A). The change in the thickness of the pinna was calculated by the following equation.

 Increased pinna thickness

 = (Thickness of the pinna after intradermal injection) ― (Thickness of the pinna before intradermal administration) The test substance was used twice for three days from two days before the antigen challenge to the day of the antigen challenge. H 絰 Π was administered. (Dose of 0.3mg / kg, lmg / kg, 3mgZkg for each test substance)

 2. Result

 FIG. 1 shows the effects of the compounds of Examples 1 and 16 on swelling of the pinna in the late phase (24 hours after antigen challenge). Each value represents the average soil standard error (the number of examples is 12 to 16). The significance test was performed using the multiple comparison of the dangling.

 * Indicates that P <0.5 and P <0.01 indicates a significant difference from the control. In Example 1 at a dose of 1 mgZkg or more, and in Example 16 at a dose of 3 mg / kg, late-phase edema mainly involving T cells and eosinophils was significantly suppressed.

Experimental Example 3 Mouse OA-induced airway inflammation model

 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 of rest.

 2) Experimental procedure

Seven-week-old male B ALBZc mice were actively sensitized on the 1st and 15th days by intraperitoneal administration of 0.5 mL of saline containing 10 μg of OA and 1 mg of aluminum hydroxide gel. On days 25, 29, and 33, 5 μL of a physiological saline solution containing OA l〃g was administered into the respiratory tract. 24 hours after the last intratracheal administration, bronchoalveolar lavage was performed, and bronchoalveolar lavage fluid (BALF) was collected. The total white blood cell count in BALF was measured with an automatic blood cell counter (Nihon Kohden Kogyo Co., Ltd.). In addition, BALF cytosbin (Shandon, Cytospin3) specimens were prepared, stained with Diff-Quick (International Reagents Co., Ltd.), and the eosinophil ratio was calculated by microscopy. . Total white blood cell count The number of eosinophils in BALF was calculated from the ratio of eosinophils and eosinophils.

The test substance was orally administered every day for 10 EI from day 24 to day 33.

 "· ¥ b

 The effect of Example 1 on the number of eosinophils in BALF is shown in FIG. Each value represents the standard error of the mean. (The number of cases is 9-10). The significance test was performed using the t-test.

 * Indicates that a significant difference from the control was observed at P <0.5. In Example 1, at 3 mg / k, the number of eosinophils having a B ALF width was significantly inhibited.

Experimental Example 4 OA-induced mouse nasal allergy model

 1. Experimental method

 1) Preparation of test substance

 The test substance was used in a 0.5% hydroxypropyl methylcellulose (HPMC) solution in a turbid state so as to be 0.1 mL per 10 g body weight.

 2) Experimental procedure

 Seven-week-old male B ALBZc mice were actively sensitized on day 1 and day 15 by intraperitoneal administration of 0.5 mL of saline containing 5 g of OA and 1 mg of aluminum hydroxide gel. From 22, mice were instilled with 20 mL of 2 mg ZmL OA solution every other day for a total of eight times. After the last nasal drip on day 36, the number of sneezes for 10 minutes was measured. Also, 24 hours after the last nasal instillation, the airway of the mouse was incised under deep anesthesia, a catheter was inserted into the subcutaneous space side, and 0.5% BSA (bovi ne se rum al bumi n, Wako Pure Chemical Industries, Ltd.) The nasal cavity was washed with 3 mL of a phosphate buffer solution. The total leukocyte count in the lavage fluid was measured with an automatic hemocytometer. In addition, a site spin specimen of the nasal washing was prepared, and after Diff-Quick staining, the ratio of eosinophils was determined by microscopy. From the total β blood cell count and the ratio of eosinophils, the number of eosinophils in the nasal washings was calculated. The test substance was orally administered for 8 consecutive days from the 29th to the 36th day.

Experimental Example 5 Effect of combination with topical steroid agent

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. Hydrate Butyrate Oral cortisone (medium class steroid topical drug, Sigma, Lot 40H0863) and betamethasone valerate (strong class steroid topical drug, Sigma, L ot 9 3 H 0330) is 50% ethanol (Wako Pure Chemical Co., Ltd.) so that each becomes 0.0 1 0g / 10 h.0.0 3 ig / 10 j 0.1 g g 10ZL. The drug was dissolved in the solution.

 2) Experimental procedure

 • An A-induced mouse biphasic ear edema model was prepared in the same manner as in Experimental Example 2 and R1. The test substance was administered orally (dose 10 mg / kg) once a day for 3 times from the day before the antigen challenge to the day of the antigen challenge. The topical steroid preparation was applied to the auricle area 1 bl at a time, once a day for 3 days.

 The group to which only the solvent of each test substance was administered was set as a positive control group, and the group to which only a physiological saline solution was challenged instead of the antigen solution containing OA was set as a negative control group.

ώ. 5l

 Fig. 3 shows the effect of ffl on the auricular swelling in the late phase (24 hours after antigen challenge). Each value represents the standard error of the mean. (The number of cases is 6 to 12). The significance test was performed using a two-way analysis of variance.

 ## indicates that a significant difference was observed between the groups at P <0.01. Addition of the compound of Example 16 (drug administration) to the application of hydrocortisone butyrate (extramedicine steroid steroid of the medium class) was observed, and its efficacy was demonstrated by betazone yuzonate (stro). ng class steroid topical drug) It was almost the same as single application. References

 1) L i f e S c i., 64: P L 139-PL 144, 1 999

 2) J n. J. Pharmaco., 75: 129-1 34, 1 997

3) Allergy, 45: 1 127—1 132, 1 996 4) Proceedings of the Society of Otolaryngology, 99: 454-463, 1996.

 The imidazole derivative 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, allergic rhinitis and the like. It is effective for prevention and treatment of allergic diseases.

 The present invention is based on Japanese Patent Application No. 1-74074 and Japanese Patent Application No. 2000-045165 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims  1. General formula (I)

(Wherein, R 1 represents an optionally substituted phenyl group or an optionally substituted heteroaryl group, R ² is a cyano group, a substituted alkyl group, a substituted or unsaturated 6 or 7 ring heterocyclic monocyclic group containing 1 or 2 nitrogen atoms which may contain an oxygen atom or a sulfur atom, May be substituted and may contain an oxygen or sulfur atom, may be the same or different and may contain 1 to 3 nitrogen atoms. A cyclic group, and formula (II) -(0- (CH ₂ ) 1) _m -0- (CH ₂ ) _n CH ₃ (ID  (Wherein 1, m is an integer of 1 to 4, n is an integer of 0 to 3, and the alkyl chain part may be substituted.) The same or different groups selected from the group consisting of Represents a phenyl group substituted by one or two groups. ) Or a pharmaceutically acceptable salt thereof. 2. —In the general formula (I), R ¹ is an optionally substituted phenyl group or an optionally substituted heteroaryl group, R ² represents a cyano group, a substituted alkyl group, a saturated 6- or 7-membered heterocyclic monocyclic group containing 1 or 2 nitrogen atoms which may be substituted and may contain an oxygen atom or a sulfur atom, And formula (II) One (0— (CH ₂ ) 1) _m -O- (CH ₂ ) _n CH ₃ (II) (Wherein 1, m is an integer of 1 to 4, n is an integer of 0 to 3, and the alkyl chain part may be substituted.) The same or different groups selected from the group consisting of 2. The imidazole derivative according to claim 1, which is a phenyl group substituted by one or two groups, or a pharmaceutically acceptable salt thereof. 3. —In the general formula (I), R ¹ is a phenyl group substituted by one group selected from the group consisting of a halogen atom and a methyl group, and R ² is a substituted alkyl group or a substituted phenyl group. May contain oxygen or sulfur atom from 1 A saturated 6- or 7-membered heterocyclic group containing two nitrogen atoms, and a compound of the formula (III) — 0- (CH ₂ ) 1-0- (CH ₂ ) _n CH ₃ (III)  (Where 1 is an integer of 1 to 4, n is an integer of 0 to 3, and the alkyl chain portion may be substituted.) By one group selected from the group consisting of 2. The imidazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is a substituted phenyl group. 4. —In the general formula (I), R ¹ is a phenyl group substituted by lflfil selected from the group consisting of a halogen atom and a methyl group, and R ² is a trifluoromethyl group, a morpholino group, and a morpholinomethyl group. , 41- (dimethylaminomethyl) biveridine-1-yl group, and formula (III) 1 0-(CH ₂ ) 1-0- (CH ₂ ) n ^c H 3 (III)  Wherein 1 is an integer of 1 to 4 and n is an integer of 0 to 3. A phenyl group substituted by one group selected from the group consisting of groups represented by the following claims. The imidazole derivative or the pharmaceutically acceptable salt thereof described in the item 1 of the dance. 5. —In the general formula (I), ¹ is a phenyl group substituted by one group selected from the group consisting of a halogen atom and a methyl group, and R ² may be substituted and may be an oxygen atom or Optionally substituted with 1 to 3 nitrogen atoms, which may be the same or different, and substituted by two saturated 6- or 7-membered heteromonocyclic subiro ring groups 2. The imidazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 6. 5- (4-chlorophenyl) -1-2- (4-morpholinophenyl) -N- (2-thiazolyl) imidazole-41-carboxamide,  5- (4-fluorophenyl) -1-2- (4-morpholinophenyl) -N- (2-thiazolyl) imidazo-l-41-carboxamide,  5- (4-chlorophenyl) 1 2- [4- (morpholinomethyl) phenyl] 1 N-1 (2-thiazolyl) imidazo-l-41-carboxamide,  5— (4-chlorophenyl) 1 2— [4-1 (2-methoxyethoxy) phenyl] -N- (2-thiazolyl) imidazole 4-carboxamide,  5- (4-fluorophenyl) -1-2- (4-1- (2-methoxyphenyl) phenyl) -1-N- (2-thiazolyl) imidazole-4-carboxamide,  5- (4-Methylphenyl) -1-N- (2-Thiazolyl) 1-2- (4-Trifluoromethylphenyl) imidazo-l-41-carboxamide,  5- (4-fluorophenyl) -1-N— (2-thiazolyl) 1-2— (4-trifluoromethylphenyl) imidazole-1-carboxamide,  5- (4-chlorophenyl) -N- (2-thiazolyl) -1- (4-trifluoromethylphenyl) imidazole-41-carboxamide and  5- (4-chlorophenyl) -1-2- (4- [4- (dimethylaminomethyl) biberidine-1-yl] phenyl] -1-N— (2-thiazolyl) imidazo-l-u 4- 4-box ruboxamide The imidazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is selected from the group consisting of:  7.5— (4-chlorophenyl) 1 2 -— [4- (4-methyl-1-oxa 4,9-diazaspiro [5,5-decane-1 9-yl) phenyl] —N— (2-thiazolyl 6.) The imidazole derivative or the pharmaceutically acceptable salt thereof according to claim 1 or 5, which is imidazole-4-carboxamide. 8. A medicament comprising a therapeutically effective amount of the imidazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 and a pharmaceutically acceptable additive. Drug composition.  9. Selective inhibition of induichileukin 4 and induichileukin 5 containing the imidazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 Agent.  10. An anti-allergic agent comprising the imidazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.  11. The anti-allergic agent according to claim 10 for use in combination with a steroid agent.