WO1994008973A1

WO1994008973A1 - Azole compound

Info

Publication number: WO1994008973A1
Application number: PCT/JP1993/001509
Authority: WO
Inventors: Tomoyuki Shibata; Yukio Sugimura; Kazuhiko Tanzawa; Masaaki Takahashi; Tomowo Kobayashi; Yoshihiro Mitsuhashi
Original assignee: Sankyo Company, Limited
Priority date: 1992-10-21
Filing date: 1993-10-20
Publication date: 1994-04-28
Also published as: AU5285593A

Abstract

A compound represented by general formula (I), wherein R1 represents imidazolyl, triazolyl or tetrazolyl each of which may be substituted by methyl and/or ethyl. R2 represents naphthyl, phenanthryl or anthryl each of which may be substituted by substituent(s) selected from the following group A: C¿1?-C4 alkyl, C1-C4 alkoxy, C1-C6 acyloxy, aromatic acyloxy, OH, trialkyl, C1-C4 acyl amino, alkoxyalkoxy, alkoxyacyloxy and trialkylsilyloxy; and R?3¿ represents hydrogen, methyl or cyano. This compound has an excellent aromatase inhibitor activity and is useful particularly as a remedy for breast cancer.

Description

Specification

[Title of Invention]

Azole compounds

[Technical field]

The present invention relates to a novel azole compound having excellent aromatase inhibitory activity, a method for producing the same, and a use thereof.

[Background technology]

Conventionally, azo compounds which inhibit aromatase are disclosed in JP-A-61-128688, JP-A-62-2121369 and JP-A-63 — The compounds described in Japanese Patent Publication No. 3167775 are known.

However, these compounds are not satisfactory in the strength of aromatase inhibitory activity.

[Disclosure of the Invention]

The present inventors have studied over many years to develop a novel compound which is superior to the above-mentioned compound having an aromatase inhibitory activity. As a result, the azole compound of the present invention has a strong aromatase inhibitory activity. And completed the present invention. The novel azole compounds having strong aromatase inhibitory activity of the present invention are represented by the general formula (1)

(Wherein, R ¹ may be substituted with a methyl or ethyl group; 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, 1- (1,3,4) ) Triazolyl, 1- (1,2,3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, wherein R ² is a substituent selected from the following group A Represents a naphthyl, phenanthryl or anthryl group which may be substituted with R 3 represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms ′) and a salt thereof.

[Group A] an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, an aromatic acyloxy group, a hydroxyl group, and a carbon atom having 1 to 4 carbon atoms Aliphatic acylamino group, alkoxy substituted alkoxy group, alkoxy substituted aliphatic acyloxy group, trialkylsilyloxy group

The compound (1) of the present invention has at least one asymmetric carbon and has stereoisomers in which the configuration is the R configuration or the S configuration. Included in the invention.

In the formula (1), the relative position of the cyano group on the benzene ring is preferably the P-position or the m-position, and more preferably the P-position.

Preferable examples of the aforementioned R ¹ include 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, and 1-1 (1,2) which may be substituted by methyl. , 3) triazolyl or 2-tetrazolyl groups, most preferably 1-imidazolyl, 5-methyl-1-imidazolyl, 4-imidazolyl, 1-methyl-5-imidazolyl, 1- (1,2,4) ) Triazolyl, 1- (1,2,3) triazolyl or 2-tetrazolyl.

Examples of the above-mentioned alkyl group having 1 to 4 carbon atoms in Group A include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or 1-butyl group. Group. '

Examples of the above-mentioned alkoxy group having 1 to 4 carbon atoms in Group A include methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy and t-butoxy groups, and a methoxy group is preferred. .

Examples of the above-mentioned aliphatic asiloxy group having 1 to 6 carbon atoms in Group A include formyloxy, acetoxy, propionyloxy, butyryloxy, isoptyryloxy, valeryloxy, and bivaloyloxy groups. is there. Examples of the aromatic acyloxy group of the above-mentioned group A include benzoyloxy, naphthylcarbonyloxy, phenanthrylcarbonyloxy, anthrylcarbonyloxy, and those having 1 to 3 substituents on these aromatic rings. Examples of the substituent include an alkyl group such as methyl and ethyl, a halogeno group such as fluorine and chlorine, and an alkoxy group such as methoxy and ethoxy, and preferably unsubstituted benzoyl and 3, 4, 5 — It is a trimethoxybenzoyl group.

Examples of the above-described aliphatic acetylamino group having 1 to 4 carbon atoms in Group A include formylamino, acetylamino, propionylamino, butyrylamino, isoptyrylamino, and bivaloylamino groups, and preferably acetylamino. Examples of the alkoxy-substituted alkoxy group in Group A include methoxy methoxy, 2-methoxy ethoxy, ethoxy methoxy, 2-ethoxy ethoxy, and propoxy methoxy, and the like, preferably methoxy methoxy and 2-methoxy ethoxy. .

Examples of the alkoxy-substituted aliphatic acyloxy group in Group A include methoxyacetoxy, ethoxyacetoxy, and methoxypropionyloxy groups, and are preferably methoxyacetoxy groups.

Examples of the trialkylsilyloxy group in Group A include trimethylsilyloxy, triethylsilyloxy, diisopropylmethylsilyloxy, and 1: 1-butyldimethylsilyloxy, and preferably t-butyl. It is a dimethylsilyloxy group.

Among the above-mentioned group A, preferred are:

A 'group below,

[Α 'group] an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, an alkoxy-substituted alkoxy group, and an alkoxy-substituted aliphatic acyloxy group

More preferred are those in the group A '' below,

[Α 'group] an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, and an alkoxy-substituted aliphatic acylo group Xyl groups-most preferred are those of the group A '''below.

[A * ′ ′ Group] Methyl group, methoxy group, acetooxy group, methoxyacetoxy group Examples of the naphthyl group for R ² include an 11-naphthyl group and a 2-naphthyl group.

Examples of the above-mentioned phenanthryl group for R ² include i-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-1 fenthryl group, and preferably 1-phenanthryl, 2-funanthryl or 9-1thryl group. It is a phenanthryl group, and more preferably, it is a 91-phenanthryl group. The above-mentioned anthryl group for R ^{2 is} a 1-1-anthryl, 2-anthryl or 91-anthryl group, preferably a 2-anthryl or 9-anthryl group, and more preferably a 91-anthryl group.

Among the above-mentioned R ² , preferred are a naphthyl, an unsubstituted 91-anthryl or an unsubstituted 91-phenanthryl group which may be substituted with a substituent selected from the following A '' group,

[Α 'group] alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, aliphatic acyloxy group having 1 to 6 carbon atoms, alkoxy-substituted aliphatic alkoxy group

Specifically, naphthalene-11-yl, naphthalene-1-yl, 6-methoxy-naphthylene-1-yl, 6-ethoxynaphthalene-2-yl, 6-propoxy-naphthalene-1 2 —Yl, 3,5-dimethoxy-1-phthalene-2-yl, 6-cetoxynaphthalene-2-yl, 6-propionyloxynaphthalene-2-yl, 1-methoxynaphthalene-2- 2-yl, 6-butoxy-naphthalene-1-yl, 4-methylnaphthyl-1-yl, 4-ethyl-naphthalene 1-1-yl, 4-butyl-naphthalene-11-yl, 4-methoxy-naphthalene 1-yl, 2,3-dimethoxynaphthalene 1-2-yl, 1,4-dimethoxynaphthalene 1-2-yl, anthracene 9-yl, phenanthrene 9-1yl, 6-acetoxinaphthalene 1 2-yl, 3 and 5-jase Kishi naphthalene one 2-I-le, 1,4-Diacetoxynaphthalene-12-yl and 6-methoxyacetoxynaphthalene-12-yl.

More preferred are naphthyl, unsubstituted phenanthryl and unsubstituted anthryl groups which may be substituted with a substituent selected from the following group A ′ ″ ″.

[Α '' 'group] methyl group, methoxy group, acetoxy group, methoxyacetoxy group

Naphthalene-1-yl, naphthalene-1-yl, 6-methoxy-naphthalene-12-yl, 3,5-dimethoxynaphthyl-1--2-yl, 1,4-dimethoxynaphthalene-1-yl , 6-acetoxynaphthalene-1-yl, 3,5-diacetoxynaphthalene-1-yl, 1,4-diacetoxynaphthalene-1-yl, anthracene 9-1yl, fenanthrene-1 9-yl group (especially, naphthalene-11-yl, naphthalene-12-yl, 6-methoxy-naphthalene-12-yl, 3,5-dimethoxy-1-naphthalene-12-yl, 1, 4-dimethoxynaphthalene-21-yl, 6-methoxyacetoxynaphthalene-12-yl, anthracene-19-yl, phenanthrene-19-yl group).

Examples of the above-mentioned alkyl group having 1 to 4 carbon atoms of R ³ include the same as the above-mentioned alkyl group having 1 to 4 carbon atoms in the group ^III , and preferably a methyl group.

R ^{3 as a} whole is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.

Among the compounds of the present invention, preferred compounds include the following compound groups. 2) General formula (1)

(In the formula, R ¹ may be substituted with a methyl or ethyl group. 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, 1- (1,3,4 ) Triazolyl, 1- (1,2,3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, wherein R ² is naphthyl, phenanthryl or anthryl which may be substituted with a substituent selected from the following group A ': R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms) and a salt thereof.

[Α 'group] an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, an alkoxy-substituted alkoxy group, an alkoxy-substituted aliphatic acyloxy group

3) General formula (1)

(Wherein, R ¹ may be substituted with a methyl or ethyl group, 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl,

1- (1,3,4) triazolyl, 1- (1,2, '3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, and R ² is a substitution selected from the following group A'' A naphthyl, an unsubstituted phenanthryl or an unsubstituted anthryl group which may be substituted with a group, and R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms) and Its salt.

[Α ′ ′ group] an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, and an alkoxy-substituted aliphatic alkoxy group 4) General formula (1

(Wherein, R ¹ may be substituted with a methyl or ethyl group; 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl,

1- (1,3,4) triazolyl, 1- (1,2,3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, and R ² is a substituent selected from the following A '''' group And R ³ represents a hydrogen atom, a methyl or a cyano group, and a salt thereof.

[Α '' 'group] methyl group, methoxy group, acetoxy group, methoxyacetoxy group

5) General formula (1)

(-1;

(Wherein, R ¹ is 1-imidazolyl, 5-methyl ^ 1-imidazolyl, 4-imidazolyl, 1-methyl-5-imidazolyl, 1-1 (1,2,4) triazolyl, 1-1 (1,2,3) Represents a triazolyl or 2-tetrazolyl group, wherein R ² is naphthyl which may be substituted with a substituent selected from the following group A ′ ″ ′, unsubstituted phena S represents a thrill or an unsubstituted anthryl group, and R ³ represents a hydrogen atom) and a salt thereof.

[Group “M”, “Methyl”, “Methoxy”, “Acetoxy”, “Methoxyacetoxy” The compound of the present invention can be converted into a salt when it has a basic group. For example, salts of mineral acids such as hydrochloride, hydrobromide, sulfate, organic sulfonates such as methanesulfonate, benzenesulfonate, acetate, propionate, butyrate And aliphatic carboxylate such as benzoate and the like. Of these salts, preferred are salts of mineral acids (particularly hydrochloric acid) and salts of aliphatic carboxylic acids (particularly acetic acid).

Representative compounds of the present invention are described in the following table, but the compounds of the present invention are not limited to these compounds.

In the table, column CN shows the binding position of Shiano groups for bonding positions location of C ^a on the benzene ring of the following formula, in each group of columns of R ^1, the number of the left end, C ^a and shows the bonding site to the imidazo Ichiru, triazole or tetrazole Ichiru, in each group of columns of R ^2, numbers in the right end indicates C ^a and naphthyl, the binding position of the Fouesnant thrill or anthryl.

In the table below, the meanings of the abbreviations are as follows. Im represents an imidazolyl group, Tri represents a triazolyl group, Tet represents a tetrazolyl group, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Bu represents a butyl group, and Nap h Represents a naphthyl group, Phe represents a phenanthryl group, Ant represents an anthryl group, TBS represents a t-butyldimethylsilyl group, Ac represents an acetyl group, Pre represents a propionyl group, and Ph represents a phenyl group. 345TMeOPh represents a 3,4,5-trimethoxyphenyl group, diMe〇 represents dimethoxy, and MeOEt represents a methoxyethoxy group.

NO. CR ¹ R ² R ³ Y Optical rotation

1 P-I 1-Im Naph-2-H HC1

2 One 4-Im Naph-2-H

3 P-1-Tet Naph-2-H

4 P-1- (1,3,4-Tri) aph-2-H p-I (1, 2, 3-Tri) Naph- 2-H

P-l-Im Naph-1-H — one 4-Im Naph-1-H one 1-Ira phe-9- H HC1 one 2-Tet phe-9- H HC1

P-I 1- (1, 2, 3-Tri) phe-9- H HC1

P-one 1-Tet phe-9- H HC1-one 4-Im phe-9- H one

P-I l-Im Anth-9- H HC1

P-1- (1, 2, 3-Tri) Anth-9- H HC1 I-Im (6-MeO-Naph) -2-H HC1

P-1-Tet (6-MeO-Naph) -2-H HC1

P-l-Im (6-TBSO-Naph) -2-H ―

P-I 2-Tet Naph-1-H ―

P-l-Im (6-HO-Naph) -2-H HC1 m- 1-Ira (6-MeO-Naph) -2-H HC1 m-l-Im (6-EtO-Naph)-2-H HC1 m- l-Im (6-PrO-Naph)-2-H HC1

P-l-Im (3, 6-diMeO-Naph) -2-H HC1

P-l-Im (6-AcO-Naph)-2-HHC1 4-Im (6-MeO-Naph) -2-'H HC1

P-l 5- (l- e-Im) Naph-1-H HC1 l-Im (6-PrcO-Naph)-2-H HC1

P-l-Im (6-PhC00-Naph) -2-H HC1

P-l-Im (6- (345B1e0PhC00) -Naph) -2-H HC1

P-I 1-ΐιιι (6-NaphCOO-Naph) -2-H HC1

P-l-Im (6-MeOAcO-Naph) -2-H HC1 P-l- (1-Me-Im) Naph-2-H HC1 / 6 /: ε 60ε¾ ε 68§ O 6M

C dimension LO DO OO CD O CNi rO dimension ID CD-> OO CD O — (Γ dimension LO CO CC CC CQ CO CQ O dimension dimension dimension dimension dimension dimension dimension dimension dimension dimension lO lO lO lD lD lO LO LO LD LO

61 p-1-Im (6- eO-Naph) -2-Me

62 P-one • (1,2,3-Tri)

G (6-MeO-Naph) -2-H ―

63 P-I 1-Im (6-MeO-Naph)-2-CN HC1

64 One (1,2,4-Tri) Anth-9- H ―

65 One 2-Tet Anth-9- H ―

66 P- (1,2,4-Tri) jNaph-1- H-

67 P (1,2,3-Tri) (3, 5-diMeO-Naph)-2-H-

68 P-one (1,2,4-Tri) Phe-9- H-one

69 1 5-(1- e-Im) Phe-9- H ―

70 P (1,2,4-Tri) Naph-1-Me ―

71 P-one (1,2,3-Tri) Naph-1-H one

72 P mono (1,2,4-Tri) (4-Me-Naph) -1-H ―

73 P (1,2,4-Tri) (6-HO-Naph) -2-H HC1

74 P-1-Tet (6-HO-Naph) -2-H HC1

75 P-1- (1,2,4-Tri) (6-AcO-Naph) -2-H HC1

76 P-1- (5- e-Tet)) (6-AcO-Naph) -2-H HC1

77 P-I (1,2,4-Tri) (6-MeO-Naph) -2-H HC1

78 I (1,2,4-Tri) (6-TBSO-Naph)-2-H HC1

79 1 1-Im Anth-9- H HC1

80 P-1- (5-e-Im) Naph-2-H Particularly preferred compounds include

4- (p-cyano α- (naphthylene-1-yl) benzyl) imidazole (2 (Example 2)), 11- (Ρ-cyano α- (phenylanthylene-1-yl) benzyl) ) Imidazole (8 (Example 5)), 1- (ρ-cyano α- (anthracene-9-yl) benzyl) Imidazole (13 (Example 7)), 1- (ρ-cyano-a- (6 —Methoxynaphthalene-1-yl) benzyl) imidazole (15 (Example 8)), 11- (p-cyano α- (6-Methoxyacetoxynaphthalene) 2- (yl) benzyl) imidazole (31 (Example 14)), 5- (ρ-cyano-a- (2-naphthyl) benzyl) 1-1-methylimigazole (32 (Example 15)) , 1- (p-cyano α- (2-naphthyl) benzyl) 1,1,2,4-triazole (37 (Example 19)), 1- (ρ-cyano α- (3,5-dimension) Xinaphthylene-2-yl) benzyl) -1,2,4-triazole (54 (Example 27)), 11- (ρ-cyano-α- (1,4-dimethoxynaphthalene-1) — Yl) benzyl) 1,1,2,4-triazol (57 (Example 29)), 1-1 (Ρ-cyano-α-methyl-1-α- (6-methoxymethoxyphthalene-2-yl) ) Benzyl) imidazole (61 (Example 32)), 1- (Ρ-cyano α- (anthracene-91-yl) benzyl) 1,1,2,4-triazole (64 (Example) 34)), 1 (Ρ-cyanone cr— (naphthalene-11-yl) benzyl) 1,2,4-triazolyl (66 (Example 35)), 1— (p-cyanone α— (phenanthrene 9-1) 1,2,4-triazole (68 (Example 36)) and 1- (ρ-cyano α-methyl-1 α- (naphthalene-11-yl) benzyl) 1,1,2,4-triazole (68 (Example 36)) 2,4-triazole (70 (Example 37)).

[Process Schedule 1 ']

,twenty one

[Schedule 2]

N

[^ Halla]

9 ΐ

SlO / £ 6df / JDd £ / .680 / ^ 6 ΟΛ \ The compound (1) of the present invention can be produced according to the reaction steps shown in Process Tables 1, 2 and 3.

In the process charts 1, 2, and 3, R ¹ , R ^2, and R ³ have the same meanings as described above, R ^3a represents an alkyl group having 1 to 4 carbon atoms or a cyano group, and R ^2a represents water. R ² represents a naphthyl, phenanthryl or anthryl group substituted with an acid group; Represents a naphthyl, phenanthryl or anthryl group substituted with an aliphatic or aromatic acyloxy or alkoxysiloxy group, and R ⁴ represents a methyl or ethyl group.

Z ¹ represents a hydrogen atom or a halogeno group; Z ² represents a halogeno group; Z ³ is an alkylsulfonyloxy having 1 to 4 carbon atoms which may be substituted with a halogen atom; and 6 to 10 carbon atoms. Represents an arylsulfonyloxy or halogeno group, and Z ⁴ and Z ⁵ represent a halogeno group.

The alkyl sulfates Honiruokishi group are carbon atoms and optionally 1 to four substituted with a halogen atom Z ^3, methanesulfonyl O carboxymethyl, ethanesulfonyl O carboxymethyl, propanesulfonyl O alkoxy, or Bok Riffle O b methanesulfonyl O alkoxy group And a methanesulfonyloxy or trifluoromethanesulfonyl group.

The number 6 to 10 § Li one Le sulfonyl O alkoxy group having a carbon of Z ^3, benzene Suruhoniruokishi, p- toluenesulfonyl O alkoxy, or the like naphthalenesulfonyl Okishi group and the like, preferably, benzenesulfonyl O It is a xy or p-toluenesulfonyloxy group.

Examples of the halogeno group for Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ include a chloro group, a bromo group and a chloride group, and preferably a bromo group for Z ¹ , Z ² and Z ^5. There, the Z ³ is black hole or bromo group, for Z ⁴ are bromo or Yodo group.

Hereinafter, each reaction step will be described in detail.

(First step)

In this step, compound R ² Z ¹ (2) is reacted with a metal reagent in an inert solvent under an inert atmosphere. And converting it into an organometallic compound, and then reacting the compound (3) to obtain an alcohol compound (4).

As the inert atmosphere, a nitrogen atmosphere or an argon atmosphere is suitable.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably selected from ethers such as tetrahydrofuran, dioxane and ether, and aliphatic solvents such as pentane and hexane. Hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, more preferably tetrahydrofuran, ether, hexane or benzene.

Examples of the metal reagent used include alkyllithiums such as n-butyllithium and tert-butyllithium, and alkaline earth metals such as metal magnesium, and preferably n-butyllithium. .

The reaction temperature when converting the compound (2) into an organometallic reagent varies depending on the metal reagent to be used, and is usually 1 to 78 ° C to 100 ° C, preferably -78 to 80 ° C. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 5 minutes to 15 hours, preferably 5 minutes to 5 hours.

The reaction temperature of the reaction between the formed organometallic compound and the compound (3) is -78 ° C to 100 ° C, preferably -78 ° C to 30 ° C, and the reaction time is as follows. Although it varies depending on the reaction temperature and the like, it is usually 5 minutes to 5 hours, preferably 30 minutes to 3 hours.

After completion of the reaction, the target compound is obtained in a conventional manner, for example, by pouring the reaction mixture into water, extracting the mixture with a water-immiscible solvent such as ethyl acetate or methylene chloride, and distilling off the solvent from the extract. The obtained residue is obtained by recrystallization or purification by various types of chromatography.

(2nd step)

In this step, a compound (5) is reacted with a metal reagent in an inert solvent in an inert atmosphere to convert the compound into an organometallic compound, and then the compound (6) is reacted to obtain an alcohol (4). This can be performed in the same manner as in the first step.

(3rd step) This step is a step of reacting compound (4) with a sulfonylating agent or a halogenating agent in an inert solvent in the presence of a base to obtain compound (7).

The inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride or chloroform, or an ester such as ethyl acetate or methyl acetate. And aliphatic hydrocarbons such as pentane and hexane, and nitriles such as acetonitrile, and more preferably, methylene chloride, chloroform and ethyl acetate.

As the base to be used, organic amines such as triethylamine, N, N-dimethylaminopyridine, pyridine, and the like, alkali metal carbonates such as potassium carbonate and calcium carbonate or carbonates of alkaline earth metals are preferable. It is.

Examples of the halogenating agent to be used include thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus tribromide and the like, and preferably, thionyl chloride, thionyl bromide or phosphorus tribromide.

Examples of the sulfonylating agent to be used include sulfonyl halides such as methanesulfonyl chloride and p-toluenesulfonyl chloride, and sulfonic anhydrides such as trifluoromethanesulfonic anhydride.

The reaction temperature is from 110 ° C to 100 ° C, preferably from 0 to 80 ° C. The reaction time varies depending on the compound, the reaction temperature and the like, but is 5 minutes to 15 hours, preferably 30 minutes to 5 hours.

After completion of the reaction, the target compound was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with a water-immiscible solution such as methylene chloride and ethyl acetate, and the extract was washed with water and saturated saline. Thereafter, it is obtained by distilling off the solvent from the extract. The obtained target compound can be used in the next step without purification, or in some cases, can be purified by various types of chromatography.

(4th step)

In this step, the compound (7) is reacted with the azole compound R ¹ H in an inert solvent to convert the sulfonyloxy group or the halogeno group of the compound (7) into an azolyl group (imidazolyl). , Triazolyl or tetrazolyl group) to obtain the compound (1) of the present invention.

The inert solvent used is not particularly limited as long as it does not inhibit the reaction, and is preferably acetonitrile or ethyl acetate.

The reaction temperature is from 10 ° C. to 150 ° C., preferably from 60 ° C. to 100 ° C. The reaction time varies depending on the compound, the reaction temperature, etc., but is usually from 10 minutes to 10 minutes. It is 30 hours, preferably 30 minutes to 15 hours.

After completion of the reaction, the target compound is obtained by a conventional method, for example, by pouring the reaction mixture into water, extracting with a water-immiscible solvent such as methylene chloride or ethyl acetate, and distilling the solvent from the extract to obtain a mixture. It can be obtained by purification by various types of chromatography.

(Fifth step)

This step is a step performed as desired when R ³ is a hydrogen atom.

In this step, the compound (1) is reacted with an alkyl halide or a cyanating agent in an inert atmosphere in an inert solvent in the presence of a base, and the hydrogen atom of R ³ is replaced with an alkyl group or a cyano group. This is a step of obtaining a compound (la).

Examples of the inert atmosphere include a nitrogen atmosphere and an argon atmosphere.

The inert solvent is not particularly limited as long as it does not inhibit the reaction. Examples of the inert solvent include ethers such as tetrahydrofuran, dioxane and ether, and nitriles such as acetate nitrile. And tetrahydrofuran.

As the base to be used, potassium t-butoxide and lithium diisopropylamide are preferable.

The reaction temperature is −78 ° C. to 50 ° C., and the reaction temperature is preferably −178 ° C. to 30 ° C. Examples of the alkyl halide used include methyl iodide, methyl iodide, methyl bromide, and the like. Chill is preferred.

As the cyanating agent used, tosyl cyanide is preferred. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 minute to 30 hours, preferably 5 minutes to 15 hours.

After completion of the reaction, the target compound is obtained by the same treatment as in the fourth step.

(Step 6)

This step is an optional step performed in the case of the imidazolyl group of the R ¹ of compound (7).

This step is a step of reacting compound (7) with 1-trimethylsilylimidazole in the presence of titanium tetrachloride in an inert atmosphere in a chloroform solution to obtain compound (1).

The reaction temperature is from 120 ° C. to 50 ° C., preferably from 110 ° C. to 30 ° C.

The reaction time varies depending on the compound and the reaction temperature, but is usually 1 minute to 30 hours, preferably 5 minutes to 15 hours.

After the completion of the reaction, the target compound is extracted by a conventional method, for example, by pouring the reaction mixture into a saturated aqueous solution of sodium hydrogen carbonate, extracting with a water-immiscible solvent such as chloroform, methylene chloride, ethyl acetate and the like, and distilling off the solvent. The resulting mixture is purified by various chromatographic methods.

(Step 7)

This step is a step of reacting the compound (7) with azolylurea in an inert solvent to obtain an aluminum salt (8).

The inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably acetonitrile or ethyl acetate.

As azolyl perrea to be used, 11- (N, N-dimethylaminocarbonyl) imidazole and 11- (N, N-dimethylaminocarbonyl) -14-methylimidazole are preferred.

The reaction temperature is from 0 ° C to 150 ° C, preferably from 60 ° C to 1 ° C. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 30 minutes to 30 hours, preferably 1 hour to 15 hours. The target compound of this step is used in the eighth step without purification. (8th process)

This step is a step of obtaining a compound (1) by reacting the compound (8) obtained in the seventh step with ammonia in an inert solvent.

The same inert solvent as that used in the seventh step is preferably used.

The reaction temperature is −20 ° C. to 3 (TC, preferably 0 ° C. to 30 ° C. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 minute to 1 hour. Preferably, it is 1 minute to 15 minutes.

(9th step)

In this step, when a trialkylsilyloxy group is present on R ² in compound (1), the trialkylsilyl group is removed as required to obtain a compound having a hydroxyl group. .

In this step, the compound (1) is reacted with an acid in an inert solvent to remove the trialkylsilyloxy group to obtain the compound (lb).

Examples of the inert solvent used include ethers (especially ethers) such as ether and tetrahydrofuran, alcohols such as methanol and ethanol, and water.

As the acid to be used, hydrogen chloride, hydrogen chloride, and hydrogen sodide are preferable.

The reaction temperature is from -10 ° C to 50 ° C, preferably from 0 ° C to 30 ° C. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 5 minutes to 15 hours, preferably 1 hour to 8 hours.

After completion of the reaction, the target compound is obtained by the same treatment as in the sixth step.

(Step 10)

In this step, a hydroxyl group on the compound (lb) is reacted with an acylating agent in an inert solvent in the presence of a base to convert the hydroxyl group into an acyloxy group, thereby obtaining a compound (lc). The inert solvent used is not particularly limited as long as it does not inhibit the reaction. However, halogenated hydrocarbons such as chloroform and methylene chloride are preferred. As the base to be used, triethylamine, N, N-dimethylaminopyridinine is preferred.

Examples of the acylating agent to be used include a desired sulfonic acid anhydride such as acetic anhydride, and a desired alkoxyacyl halide such as methoxyacetyl chloride.

The reaction temperature is −78 to 50 ° C., preferably −10 to 30 ° C. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 5 minutes to 50 hours, preferably 30 minutes to 15 hours.

(Step 1)

This step is an optional step performed when the power of compound (1) is an imidazolyl group.

This step is a step of reacting compound (1) with N, N-dimethylpotassium chloride in an inert solvent in the presence of a base to obtain compound (9).

The inert solvent used is not particularly limited as long as it does not inhibit the reaction, and is preferably acetonitrile.

Examples of the base used, it is preferable Bok Riechiruamin force ^s.

The reaction temperature is from 120 to 100 ° C, preferably from 20 to 80 ° C. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 3 days.

(Step 12)

This step is a step of reacting the compound R ⁴ Z ⁵ (9) with an alkyl halide in an inert solvent to obtain an onium salt (10).

The inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably acetonitrile. The alkyl halide used is preferably methyl iodide.

The reaction temperature is usually from 0 to 150 ° C., preferably from 60 to 100. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually from 30 minutes to 30 hours, preferably from 30 to 30 hours. 1 to 15 hours.

The target compound is used in the thirteenth step without any particular purification.

(13th step)

In this step, the compound (10) obtained in the twelfth step is reacted with ammonia in an inert solvent to obtain a compound (Id).

The same inert solvent as used in the twelfth step can be used as the inert solvent.

The reaction temperature is from 20 to 30 ° C, preferably from 0 to 30 ° C.

The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 minute to 1 hour, preferably 1 to 15 minutes.

After completion of the reaction, the target compound is subjected to the same treatment as in the fourth step.

Examples of the dosage form of the compound (1) of the present invention include oral administration by tablets, capsules, granules, powders, syrups and the like, and parenteral administration by injections and suppositories. These preparations are produced by known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents. The dosage varies depending on symptoms, age, etc., but is 0.1 to 1000 mg / kg body weight per day, preferably 1 to 500 mg / kg body weight per day for normal adults once or several times a day. It can be administered in divided doses.

[The invention's effect]

The compounds of the present invention have excellent pharmacological properties. That is, it is useful as an inhibitor of aromatase activity and an inhibitor of estrogen biosynthesis in mammals, and is also useful as a therapeutic agent for pathological symptoms caused by these.

Specifically, the compounds of the present invention inhibit the metabolic conversion of androgens to estrogens in mammals, and are therefore useful, for example, in treating male breast hypertrophy. Also, the compounds of the present invention are useful in the treatment of estrogens-dependent diseases in women, such as estrogen-dependent breast cancer in women, especially in postmenopausal women, by inhibiting estrogen biosynthesis. is there.

These effects can be demonstrated by in vitro assays or in vivo studies in animals using mammals (eg, guinea pigs, mice, rats, cats, dogs or monkeys).

In vitro inhibition of the aromatase activity of the compound of the present invention can be carried out, for example, by the following method. '

In other words, first, Microsoft! The dog fraction is prepared from the human placenta substantially by the method of Thompson and Siiteri (丄 Biol. Chem. 249, 5364 (1974)). The resulting microsomal preparation is lyophilized and stored at 140 ° C. The test can be proved by a modification of the method of Douglas F. Covey et al. (丄 Biol. Chem. 256, 1076 (1981)). The _Iso value can be determined graphically as the concentration of the test compound at which the aromatization of androstenedione to the estrone is reduced to 50% of the comparative value. In vivo inhibition of aromatic enzyme activity of a compound of the invention, for example, inhibition of estrogen synthesis in rats, is calculated from the ovarian estrogen content in the treated animals as compared to control animals.

The in vivo inhibition of the aromatic enzyme activity of the compound of the present invention can also be evaluated, for example, by the following method. That is, androstenedione (30 mg Zkg administered subcutaneously), alone and with the aromatase inhibitor to be tested (oral or subcutaneous administration), is administered to immature female rats once a day for 4 days. After the fourth dose, the rats are sacrificed, the uterus is removed and weighed. Aromatase inhibition is evaluated by measuring the extent to which uterine hypertrophy induced by androstenedione alone is suppressed by co-administration of an aromatase inhibitor.

The antitumor activity, particularly in the case of estrogens-dependent tumors, has been demonstrated in vivo, for example, in human nude mice (Balb / cA-nu) in human ovarian cancer BG-1 strain (Geisinger, KR). et al., Cancer 63: 280-288 (1989)). The compounds of the present invention, by daily administration of 15 to SO mgZkg or more orally, degrade existing tumors and suppress the development of new tumors.

The compounds of the present invention have excellent estrogen biosynthesis inhibitory effects in mammals, such as, for example, breast cancer (breast carcinoma) in women, endometriosis, premature birth and uterine cancer, as well as breast enlargement in men. Useful for the treatment of estrogen-dependent diseases.

[Best Mode for Carrying Out the Invention]

Hereinafter, the present invention will be described more specifically with reference to Examples, Formulation Examples, and Test Examples (Example 1).

1 — (p—cyanore α— (naphthalene-2-yl) benzyl) imidazole

1 a) p-cyano α- (naphthalene-1-yl) benzyl alcohol η-butyllithium (1.65 M hexane solution, 3 mL), 2-bromonaphthalene (l.OO), and p-cyanobenzaldehyde ( 633 mg) to give p-cyano α- (naphthalene-1-yl) benzyl alcohol (903 mg) in the same manner as in Reference Example 1a.

Marauder (CDCla) 2.2-2.6 (1H, br), 6.04 (1H, s), 7.38 (ΙΗ 'dd, J = l.6, 8.6Hz), 7.47-7.5 4 (2H, m), 7.56 (2H, d, J = 8.6Hz), 7.63 (2H, d, J = 8.6Hz), 7.80-7.89 (4H, m)

1 b) p-cyano-a- (naphthyl-1-yl) benzyl chloride

Using P-cyano a- (naphthalene-1-yl) benzyl alcohol (512 mg) and thionyl chloride (0.5 mL) in the same manner as in Reference Example 1b, column chromatography on silica gel was performed. Purification with ethyl ethyl acetate (5: 1)) gave P-cyano a- (naphthalene-1-yl) benzyl chloride (483 mg).

Listening (CDCla) 6.29 (ΙΗ 's), 7.42 (1H, dd, J = 1.6, 8.0Hz), 7.53 (1H, t, J = 8.0Hz), 7.54 (1H, t, J = 8.0Hz), 7.59 (2H, d, J = 8.0Hz), 7.66 (2H, d, J = 8.0Hz), 7.80-7.89 (4H, m)

1 c) 1- (p-cyano a- (naphthyl-2-yl) benzyl) imidazole hydrochloride

After treatment in the same manner as in Reference Example 7c using P-cyano a- (naphthylene-1-yl) benzyl chloride (1 O Omg) and imidazole (245 mg), a silica gel column was used. Purification by chromatography (ethyl acetate-hexane (4: 1)) afforded 1- (p-cyano a- (naphthylene-1-yl) benzyl) imidazole (75 mg), which was obtained. Dissolve in methanol, add a solution of hydrogen chloride in ether, stir for 5 minutes, and evaporate the solvent under reduced pressure to remove 1- (p-cyano a- Taren-1-yl) benzyl) imidazole hydrochloride was obtained.

Negation _{(CD 3 0D) 7.39 (IH} , s), 7.41 (IH, dd, J = l.7, 8.6Hz), 7.50 (2H, d, J = 8.3Hz), 7.53 -7.61 (2H, m), 7.66 (IH, s), 7.70 (1H, s), 7.74 (1H, s), 7.85 (2H, d, J = 8.3Hz), 7.87 (1H, d, J = 8.6Hz), 7.92 (1H, d , J = 8.6Hz), 7.99 (IH, d, J = 8.6Hz), 8.96 (IH, s)

(Example 2)

41 Dissolve (p-cyano α- (naphthalene-1-yl) benzyl) imidazole titanium tetrachloride (1 IO JUL) in chloroform (3 mL), and in a nitrogen atmosphere at 0 ° C, A solution of trimethylsilylimidazole (150 wL) in chloroform was added (2 mL), and the mixture was stirred at room temperature for 30 minutes. A solution (3 mL) of p-cyano-α- (naphthalen-2-yl) benzyl chloride (56 mg) obtained in Example 1b was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted with methylene chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 4- (Ρ-cyano α- (naphthalene-1-yl) benzyl) imidazole (57 mg).

Listen (CDCls) 5.63 (1H, s), 6.57 (1H, s), 7.26 (IH, s), 7.29 (1H, dd, J = 1.6,8.6Hz), 7.34 (2H, d, J = 8.4 Hz), 7.45 (1H, t, J = 6.8Hz), 7.46 (1H, t, J = 6.8Hz), 7.56 (IH, s), 7.58 (2H, d, J = 8.4Hz), 7.67-7.85 ( 4H, m)

(Example 3)

1- (p-cyano α- (naphthalene-111) benzyl) imidazole 3 a) p-cyano α- (naphthalene-111) benzyl alcohol

The same treatment as in Reference Example 1a was carried out using η-butyllithium (1.65 M hexane solution, 2.56 mL), 1-bromonaphthalene (0.6 mL), and p-cyanobenzaldehyde (566 mg). However, purification was performed by silica gel column chromatography (hexane monoethyl acetate (1: 1)) to obtain p-cyano-α- (naphthalene-11-yl) benzyl alcohol (574 mg).

Thigh (CDCla) 2.50 (1H, d, J = 4.OHz), 6.54 (IH, d, J = 4.OHz), 7.43-7.52 (4H, m), 7.54 (2H, d, J = 8.6Hz) , 7.62 (2H, d, J = 8.6Hz), 7.82-7.93 (2H, m), 8.01 (1H, dd, J = 2.6, 6. OHz 3 b) p-cyano-a- (naphthalene-1-yl) benzyl chloride

P-cyano α- (naphthalene-111) Using benzyl alcohol (545 mg) and thionyl chloride (310 L), in the same manner as in Reference Example lb, P-cyano α- (naphthalene-111) was used. Benzyl chloride (56 lmg) was obtained. Thigh _{(CDC1 3) 6.85 (1H,} s), 7.43-7.55 (4H, m), 7.08 (2Η, d, J = 8.6Hz), 7.65 (2H, d, J = 8.6Hz), 7.88 (lH, d , J = 6.6Hz), 7.91 (lH.dd, J = 3.3, 6.6Hz), 7.96 (1H, dd, J = 3.3, 6.6Hz)

3 c) 1- (p-cyano-α- (naphthalene-11-yl) benzyl) imidazole

After treatment in the same manner as in Reference Example 7c using P-cyano a- (naphthalene-11-yl) benzyl chloride (10 Omg) and imidazole (245 mg), silica gel column chromatography ( Purification with ethyl hexane monoacetate (1: 2)) afforded 111- (p-cyano a- (naphthylene-11-yl) benzyl) imidazole (64 mg).

Thigh _{(CDC1 3) 6.82-6.86 (2H,} m), 7.13 (lH, m), 7.21 (2H, d, J = 8.6Hz), 7.31 (1H, s), 7 .41 (1H, m), 7.42 (1H, t, J = 7.3Hz), 7.48 (IH, dt, J = 1.3, 7.3Hz), 7.54 (IH, dt, J = 1.3, 7.3Hz), 7.68 (2H, d, J = 8.6Hz), 7.75 (1H, dd, J = l.3, 7.3Hz), 7.89-7.96 (2H, m)

(Example 4)

4- (p-cyanol c- (naphthalene-111-yl) benzyl) imidazole titanium tetrachloride (0.2 niL), N-trimethylsilyl midazol (0.27 mL) and p-cyananol obtained in Example 3b The same treatment as in Example 2 was carried out using 1a- (naphthalene-1-yl) benzyl chloride (101 mg). However, purification by silica gel column chromatography (ethyl hexane monoacetate (1: 4)) gave 4- (p-cyano α- (naphthalene-11-yl) benzyl) imidazole (55 mg). .

Negation _{(CDC1 3) 6.28 (1H,} s), 6.46 (IH, br s), 7.04 (IH, d, J = 7.3Hz), 7.31 (2H, d, J = 8. 6Hz), 7.37 (1H, d , J = 8.6Hz), 7.38-7.50 (3H, m), 7.57 (2H, d, J = 8.6Hz), 7.63 (IH, s), 7. / £ 6 € ΙεΓΛ £ 68 / ΟΜ0

〇

■ in eyes

•

P-Cyanol cr-1 (Phenanthrene-1-yl) benzyl) imidazole'hydrochloride (72 mg) was obtained.

麵 (D SO-de) 7.28 (IH, s), 7.52 (2H, d, J = 8.3Hz), 7.63-7.69 (2H, m) ₅ 7.74-7.80 (4H, m), 7.92 (IH, d, J = 8.3Hz), 7.97 (3H, d, J = 8.3Hz), 8.12 (1H, s), 8.89 (IH, d, J = 8.3Hz), 8.97 (lH, d, J = 8.3Hz), 9.00 (lH, s)

(Example 6)

4- (p-cyano α- (phenanthrene-91-yl) benzyl) imidazo-titanium tetrachloride (170 L), N-trimethylsilylimidazole (230 uL) and P- obtained in Example 5b The same treatment as in Example 2 was carried out using cyano-α- (phenanthrene-1-yl) benzyl chloride (1 OO mg). However, column chromatography of silica gel (methylene chloride triethylamine)

(95: 5)) to give 41- (p-cyano α- (phenanthrene-19-yl) benzyl) imidazole (81 mg).

Organ (CDCla) 3.4-4.4 (IH, br), 6.24 (IH, s), 6.47 (1H, s), 7.22 (IH, s), 7.31 (2H, cl, J = 8.3Hz), 7.46-7.72 ( 8H, m), 7.94 (IH, d, J = 8.3Hz), 8.64 (1H, d, J = 8.3Hz), 8.71 (IH, d, J = 8.3Hz)

(Example 7)

1- (p-cyano α- (anthracene-91-yl) benzyl) imidazole • hydrochloride

7 a) p-Cyanaw α- (anthracene-9-yl) benzyl alcohol η-butyllithium (1.65 M hexane solution, 2.4 mL), 9-bromoanthracene (1.0 g), and p-cyanobenzaldehyde (514 mg) And processed in the same manner as in Reference Example la. However, purification was performed by silica gel column chromatography (hexane-ethyl acetate (5: 1)) to obtain P-cyano-α- (anthracene-9-1yl) benzyl alcohol (839 mg).

Noodles _{(CDC1 3) 2.75 (IH,} d, J = 4. OHz), 7.39-7.59 (9H, m), 8.05 (2H, m), 8.27 (2H, m), 8 • 53 (lH, s) 7 b) ρ, —cyanone α— (anthracene-9-yl) benzyl chloride

P-Cyanaw a— (Anthracene 9-1yl) Using benzyl alcohol (20 Omg) and thionyl chloride (O.lmL), as in Reference Example lb, p-Cyanaw a— (Anthracene 9-1yl) ) Benzyl chloride (209 mg) was obtained.麵 (CDCls) 7.45-7.60 (8H, m), 7.72 (IH, s), 8.05-8.10 (4H, m), 8.58 (1H, s)

7 c) 1-(p-cyano a- (anthracene 91-yl) benzyl) imidazol hydrochloride

It was treated in the same manner as in Reference Example 7c using P-cyano a- (anthracene-9-yl) benzyl chloride (10 lmg) and imidazole (21 Omg). However, purification by column chromatography on silica gel (ethyl hexane monoacetate (1: 2)) yielded 11- (p-cyano-a- (anthracene-9-yl) benzyl) imidazole, which was then treated with methanol. In water, add a solution of hydrogen chloride in ether, stir for 5 minutes, and evaporate the solvent under reduced pressure to remove (p-cyano-a- (anthracene-1-yl) benzyl) imidazole. The hydrochloride (12 mg) was obtained.

Thigh _{(CD 3 0D) 7.38 (2H} , d, J = 8.6Hz), 7.51-7.57 (4H, m), 7.68 (2H, d, J = 6.8Hz), 7.78 (2H, d, J = 8.6Hz) , 8.03 (1H, s), 8.05 (1H, s), 8.21 (2H, dd, J = 2.6,6.8Hz), 8.67 (IH, s), 8.84 (lH, s), 8.93 (lH, s)

(Example 8)

1- (p-cyano a- (6-methoxymethoxyphthalene-2-yl) benzyl) imidazole hydrochloride

8 a) p-Cyanaw α- (6-Methoxynaphthal-2-yl) benzyl alcohol η-butyllithium (1.65 M hexane solution, 14 mL), 2-bromo-6-methoxynaphthalene (5.00 g), Using p-cyanobenzaldehyde (2.8 g) and p-cyano-α- (6-methoxynaphthalene-1-yl) benzyl alcohol (4.35 g) in the same manner as in Reference Example la. Was.

Image (CDCla) 2.1-2.7 (IH, br), 3.91 (3H, s), 6.00 (1H, s), 7.11 (IH, d, J = 2.4Hz), 7.17 (IH, dd, J = 2.4 , 8.3Hz), 7.33 (IH, dd, J = 2.0, 8.3Hz), 7.54 (2H, d, J = 8.3Hz), 7.62 (2H, d, J = 8.6Hz), 7.71 (IH, d, J) = 8.3Hz), 7.72 (1H, d, J = 8.3Hz), 7.74 (IH, d, J = 2. OHz) One c, one {(-z one part oto:, ^ [— _ one 9) one σ—, four one d 6 one four ^, one ichi — one} — — d)-T

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60SlO / £ 6df / JOd £ 680/6 OW The same treatment as in Reference Example 1a was performed using butyldimethylsilyloxynaphthalene (794 mg) and p-cyanobenzaldehyde (339 mg). However, after purification by column chromatography on silica gel (ethyl hexane monoacetate (4: 1)), P-cyano α- (6-t-butyldimethylsilyloxynaphthalene-12-yl) benzyl alcohol ( 645 mg).

Difficult (CDC1 ₃ ) 0.24 (6H, s), 1.01 (9H, s), 2.40 (1H, d, J = 3.3Hz), 6.00 (1H, d, J = 3.3Hz), 7.10 (IH, dd, J) = 2.6, 8.6Hz), 7.16 (1H, d, J = 2.6Hz), 7.31 (1H, dd, J = 2.0,8.6Hz), 7.56 (2H, d, J = 8.6Hz), 7.63 (2H, d, J = 8.6Hz), 7.66 (IH, d, J = 8.6Hz), 7.71 (lH, d, J = 8.6Hz), 7.75 (lH, brs)

9 b) p-cyano α- (6-t-butyldimethylsilyloxynaphthalene-1-yl) benzyl chloride

P-cyano a- (6-t-butyldimethylsilyloxynaphthalene-12-yl) Using benzyl alcohol (622 mg) and thionyl chloride (0.21 mL), as in Reference Example lb, p-cyano a— (6-t-Butyldimethylsilyloxy-1-naphthylene-1-yl) benzyl chloride (648 mg) was obtained.

Awake (CDCla) 0.22 (6H, s), 0.99 (9H, s), 6.24 (1H, s), 7.09 (1H, dd, J = 2.6,8.6Hz), 7.16 (IH, d, J = 2.6 Hz), 7 · 34 (1H, dd, J = 2.0, 8.6Hz), 7.56 (2H, d, J = 8.6Hz), 7.63 (2H, d, J = 8.6Hz), 7.66 (1H, d, J = 8.6Hz), 7.68 (IH, d, J = 8.6Hz), 7.70 (IH, br s)

9 c) 1- (p-cyano a- (6-t-butyldimethylsilyloxynaphthalene-1-yl) benzyl) imidazole

It was treated in the same manner as in Reference Example 7c using P-cyano a- (6-t-butyldimethylsiloxynaphthalene-12-yl) benzyl chloride (207 mg) and imidazole (342 mg). However, after purification by silica gel column chromatography (ethyl acetate-cyclohexane (3: 1)), 1- (p-cyano a- (6-t-butyldimethylsilyloxynaphthalene-1-yl) Benzyl) imidazole (113 mg) was obtained.

(CDCla) 0.25 (6H, s), 1.02 (9H, s), 6.69 (IH, s), 6.87 (IH, s), 6.99-7.17 (3H, s), 7.19 (1H, brs), 7.23 ( 2H, d, J = 8.6Hz), 7.39 (IH, br s), 7.46 (1H, s), 7.64 (IH, d, J = 8 .6Hz), 7.68 (1H, d, J = 8.6Hz), 7.71 (2H, d, J = 8.6Hz)

(Example 10)

1- (p-cyano α- (6-hydroxynaphthalen-1-yl) benzyl) imidazole-hydrochloride

1- (ρ-Cyanol α- (6-t-butyldimethylsilyloxynaphthalene-1-yl) benzyl) imidazole (85 mg) was dissolved in ether (lmL), and a solution of hydrogen chloride in ether (1M, 1.9 mL) and methanol (few drops) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride-methanol (1: 1)) and purified by elution with 1- (P-cyano α- (6-hydroxynaphthalene-2-yl) benzyl) imidazole (61 mg). ). This was dissolved in methanol, an ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. Then, the solvent was distilled off under reduced pressure to obtain 1- (p-cyano α- (6-hydroxynaphthylene-1-yl). Benzyl) Imidazole hydrochloride was obtained.

Negation _{(CD 3 0D) 7.11-7.16 (2H} , m), 7.27-7.32 (2H, m), 7. 6 (2H, d, J = 8.6Hz), 7.61 (2H, s), 7.66 (1H, s ), 7.71 (1H, d, J = 8.6Hz), 7.76 (1H, d, J = 8.6Hz), 7.84 (2H, d, J = 8.6Hz), 8.85 (lH, s)

(Example 11)

1- (m-cyano α- (6-methoxynaphthalene-1-yl) benzyl) dimidazole hydrochloride ''

1 1 a) m-Cyanaw α- (6-Methoxynaphthalene-1-yl) benzyl alcohol

Treated in the same manner as in Reference Example 1a using η-butyllithium (1.65 M hexane solution, 1.28 mL), 2-bromo-6-methoxynaphthalene (500 mg), and P-cyanobenzaldehyde (276nig) did. However, purification by silica gel column chromatography (ethyl hexane monoacetate (2: 1)) gave m-cyano- _α- (6-methoxynaphthalene-12-yl) benzyl alcohol (374 mg). . Negation _{(CDC1 3) 2.41 (IH,} d, J = 3.3Hz), 3.92 (3H, s), 5.99 (1H, d, J = 3.3Hz), 7.12 (IH, d, J = 2.6Hz), 7.17 ( IH, dd, J = 2.6, 8.6Hz), 7.34 (1H, dd, J = 2.0, 8.6Hz), 7.43 (1H, t, J = 8. OHz), 7.55 (1H, br d, J = 8. OHz), 7.65 (1H, br d, J = 8. OHz), 7.72 (IH, d, J = 8.6Hz), 7.74 (lH, d, J = 8.6Hz), 7.76 (lH, brs)

1 lb) m- Shiano a-- _ (6 - '1 main Bok carboxymethyl ■ naphthalate ^1, Le ¹ down one ¹ 2 I le ■) Benjiruku b ^ de m- Shiano a- (6- methoxynaphthalene one 2 —Yl) Benzyl alcohol (120 mg) and thionyl chloride (120 uL), and m-cyano a— (6-Methoxynaphthalen-1-yl) benzyl chloride in the same manner as in Reference Example 1b (124 mg) was obtained.

Awake (CDCls) 3.91 (3H, s), 6.24 (1H, s), 7.13 (IH, d, J = 2.6Hz), 7.18 (1H, dd, J = 2.6, 8.6Hz), 7.38 (1H, dd, J = 2.0,8.6Hz), 7.44 (IH, t, J = 8.OHz), 7.57 (IH, d, J = 8.0Hz), 7.6 6-7.75 (5H, m)

1 1 c) 1- (m-cyano a- (6-methoxynaphthalene-1-yl) benzyl) imidazole * hydrochloride

Using m-cyano a- (6-methoxynaphthalene-12-yl) benzyl chloride (112 mg) and imidazole (125 mg), the same treatment as in Reference Example 7c was carried out to obtain 11-m —Cyano-α- (6-methoxynaphthalene-1-yl) benzyl) imidazole was obtained. This was dissolved in methanol, an ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. Then, the solvent was distilled off under reduced pressure to obtain 1- (m-cyano-a- (6-methoxynaphthalene-1-yl). Benzyl) imidazole 'hydrochloride (105 mg) was obtained.

顧_{(D 2 0) 3.94 (3H} , s), 7.17 (IH, s), 7.23 (IH, d, J = 8.6Hz), 7.35 (2H, s), 7.46 (1H, s), 7.58-7.63 ( 5H, m), 7.75 (IH, d, J = 8.6Hz), 7.82 (IH, d, J = 8.6Hz), 7.87 (1H, d, J = 8.6Hz), 8.61 (lH, s)

(Example 12)

—Cyanaw a— (3,6-Dimethoxyxanaphthalene-1-yl) benzyl) Imidazole hydrochloride 12 a) p-cyano a- (3,6-dimethoxynaphthalene-1-yl) benzyl alcohol

Under a nitrogen atmosphere, 2,7-dimethoxynaphthalene (508 mg) was suspended in ether (5 mL), n-butyllithium (1.65 M hexane solution, 1.8 mL) was added, and the mixture was heated under reflux for 1 hour. Cool the reaction mixture to 1-10 ° C and add p-cyanobenzaldehyde

(389 mg) in tetrahydrofuran (5 mL) was added, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl hexane monoacetate (2: 1)) to obtain p-cyano a- (2,7 dimethyl-3-naphthyl) benzyl alcohol (270 mg).

(CDC1 ₃ ) 3.19 (1H, d, J = 5.3Hz), 3.91 (3H, s), 3.93 (3H, s), 6.11 (1H, d, J = 5.3Hz), 7.02 (1H, dd, J) = 2.6, 8.6Hz), 7.05-7.08 (2H, m), 7.53 (2H, d, J = 8.6Hz), 7.55 (1H, s), 7.61 (2H, d, J = 8.6Hz), 7.62 (1H , d, J = 8.6Hz)

12 b) p-cyano a— (3,6-dimethylmethoxyphthalene-2-yl) benzyl chloride

P-Cyanoa- (3,6-dimethoxynaphthylene-1-yl) Using benzyl alcohol (268 mg) and thionyl chloride (O.llmL), as in Reference Example lb, Cyano a- (3,6-dimethoxynaphthalene-1-yl) benzyl chloride (27 lmg) was obtained.

Marauder (CDC1 ₃ ) 3.88 (3H, s), 3.91 (3H, s), 6.59 (1H, s), 7.00-7.05 (3H, m), 7.55 (2H, d, J = 8.6Hz), 7.62 (2H , d, J = 8.6Hz), 7.66 (1H, d, J = 8.6Hz), 7.84 (1H, s),

1 2 c) 1- (p-cyano a- (3,6-dimethylmethoxynaphthalene-2-yl) benzyl) imidazole 'hydrochloride

The same treatment as in Reference Example 7c was performed using P-cyano a- (3,6-dimethoxynaphthalene-1-yl) benzyl chloride (lOOmg) and imidazole (200 mg). However, it is purified by column chromatography on silica gel (hexane monoacetate (1: 4)) to give 1- (P-cyano a- (3,6-dimethoxynaphthalene-1-yl) benzyl) imidazo- (10 lmg). This is meta Dissolved in ethanol, and added with a solution of hydrogen chloride in ether. The mixture was stirred for 5 minutes, and the solvent was distilled off under reduced pressure to obtain a solution of 1- (Ρ-cyano α- (3,6-dimethoxynaphthalene-2-yl) benzyl). ) Imidazole hydrochloride was obtained.

Awake (CDaOD) 3.88 (3H, s), 3.91 (3H, s), 7.01 (1H, dd, J = 2.4, 8.6Hz), 7.24 (1H, d, J = 2.4Hz), 7.28 (IH, s) , 7.35 (IH, s), 7.42 (IH, d, J = 8.6 Hz), 7.43 (1H, s), 7.60 (2H, d, J = 8.6 Hz), 7.65 (IH, s), 7.84 (2H , d, J = 8.6Hz), 8.89 (IH, s)

(Example 13) 1- (p-cyano-α- (6-acetoxynaphthalene-1-yl) benzyl) imidazole-hydrochloride

1- (ρ-cyano-α- (6-hydroxynaphthalene-1-yl) benzyl) imidazole (31 mg) obtained in Example 10 was dissolved in methylene chloride (2 ml), and triethylamine was dissolved. (151) and acetic anhydride (10w1) were added, and after stirring at room temperature for 1 hour, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 11- (p-cyano-α- (6-acetoxynaphthalen-l-yl) benzyl) imidazole (30 mg). This was dissolved in methanol, a solution of hydrogen chloride in ether was added, and the mixture was stirred for 5 minutes.

(6-acetoxynaphthalene-1-yl) benzyl) imidazole 'hydrochloride was obtained. _{NMR (CD 3 0D) 2.3B (} 3H, s), 7.34 (1H, dd, J = 8.8, 2Hz), 7.38 (1H, s

), 7.44 (1H, dd, J = 8.7, 2Hz), 7.49 (2H, d, J = 8.2Hz), 7.6-7.75 (3H, m), 7.76 (1H, s), 7.85 (2H, d, J = 8.2Hz), 7.91 (1H, d, J = 8.8Hz), 7.97 (1H, d, J = 8.7Hz), 8.95 (1H, s)

(Example 14) 1- (p-cyano-a- (6-methoxyacetoxynaphthalene-1-yl) benzyl) imidazole 'hydrochloride

11- (P-cyano-a- (6-hydroxynaphthalene-12-yl) benzyl) imidazole (25 mg) obtained in Example 10 was dissolved in methylene chloride (3 ml), and triethylamine (25AX 1 ), Dimethylaminopyridine (catalytic amount) and methoxyacetyl chloride (201) were added, and the mixture was stirred at room temperature for 2 days. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate: hexane = 4: 1).

1- (p-Cyan-1-α- (6-methoxyacetoxynaphthalene-1-yl) benzyl) imidazole (12 mg) was obtained. This was dissolved in methanol, an ethereal solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. The solvent was distilled off to remove 1- (P-cyano-α- (6-methoxyethoxycetonaphthalene-1-yl). ) Benzyl) imidazole

• obtained the hydrochloride salt.

Thigh _{(CD 3 0D) 3.3K3H, s} ), 4.87 (2H, s), 7.13 (1H, dd, J = 8.6, 2Hz), 7.1 4 (1H, s), 7.26 (1H, s), 7.29 (1H , dd, J = 8.6, 2Hz), 7.oO (2H, d, J = 8.2Hz), 7.60 (2H, broad s), 7.64 (1H, d, J = 2Hz), 7.71 (1H, d , J = 8.6Hz), 7.84 (2H, d, J = 8.2Hz), 8.82 (1H, s)

(Example 15) 5- (p-cyano-α- (naphthalene-2-yl) benzyl) 1-1-methylimidazole.hydrochloride

1 5 a) 4— (p—Cyanol α— (naphthylene-1-yl) benzyl) 1-11 dimethylcarbamoylimidazole

4- (ρ-cyano-α- (naphthalene-2-yl) benzyl) imidazole (275 mg) obtained in Example 2 was dissolved in acetonitrile (3 ml), and triethylamine (1401) and dimethylcarbamoyl were dissolved. Chloride (90) Li1) was added, and the mixture was stirred at room temperature for 60 hours. Ether was added to the reaction solution, and the resulting precipitate was removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give 4- (p-cyano-1α- (naphthalene-1-yl) benzyl) 1) -Dimethylcarbamoylimidazole (215 mg) was obtained.

_{NR (CDC1 3) 3.07 (6H} , s), 5.62 (1H, s), 6.82 (1H, s), 7.34 (1H, dd, J = 8 .6, 2Hz), 7.39 (2H, d, J = 7.9 Hz), 7.43-7.50 (2H, m), 7.58-7.63 (3H, m), 7.72 -7.84 (3H, m), 7.92 (1H, d, J = 2Hz)

1 5 b) 5— (p—Cyaneau α— (Naphthyl-2-yl) benzyl) 1 1— Methyl imidazole hydrochloride

4— (p-Cyan-1-α- (naphthalene-2-yl) benzyl) 1-1-Dimethylcarbamoylimidazole (l O Omg) is dissolved in acetate nitrile (3 ml), and methyl iodide (1 ml) is dissolved. 8 1) was added and the mixture was heated under reflux for 3 hours. After cooling, ammonia gas was blown for 5 minutes. The solvent was distilled off from the reaction solution, the residue was dissolved in ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on silica gel (methylene chloride: methanol = 10: 1), and the residue was purified using 5- (ρ-cyano-1-α- (naphthylene-1--2-yl). ) Benzyl) 1-methylimidazole (70 mg) was obtained. This was dissolved in methanol, an ethereal solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. The solvent was distilled off to give 5- (P-cyano-a- (naphthalene-1-yl) benzyl) -1-methyl. Imidazole 'hydrochloride was obtained. NMR (CD ₃ OD) 3.66 (3H, s), 6.03 (1H, s), 6.94 (lh, s), 7.37 (1H, dd, J = 8.8, 2Hz), 7.48 (2H, d, J = 8.2Hz) ), 7.50-7.54 (2H, m), 7.63 (1H, s), 7.77 (2H, d, J = 8.2Hz), 7.80-7.82 (1H, m), 7.86-7.90 (1H, m), 7.92 (1H, d, J = 8-5Hz), 8.97 (1H, s)

(Example 16) 1- (p-cyano α- (3,7-dimethoxynaphthalene-1-yl) benzyl) imidazole 'hydrochloride

1 6 a) p-cyano α- (3,7-dimethyloxynaphthalene-1-yl) benzyl alcohol ―

Performed using 2,6-dimethoxynaphthalene (1.0 g), n-butyllithium (1.68 M, hexane solution) (3.5 ml) and p-, cyanobenzaldehyde (76.7 mg) Treated as in Example 12a. However, silica gel column chromatography was performed with ethyl acetate: hexane = 1: 1 to obtain P-cyano α- (3,7-dimethylxinaphthalene-1-yl) benzyl alcohol (279 mg).

_{NR (CDC1 3) 3.27 (1H} , d, J = 6Hz), 3.87 (3H, s), 3.88 (3H, s), 6.13 (1H, d, J = 6Hz), 7.07 (1H, d, J = 2Hz ), 7.11 (1H, s), 7.13 (1H, dd, J = 8.6, 2Hz), 7.51-7.57 (3H, m), 7.59-7.66 (3H, m) 16 b) p-cyano-a- (3,7-dimethoxynaphthyl-2-yl) benzyl chloride

P-Cyanoa- (3,7-dimethoxynaphthalen-1-yl) benzyl alcohol (279 mg) and thionyl chloride (0.12 ml) in the same manner as in Example 12b — (3,7-Dimethoxynaphthalene-1-yl) benzyl chloride (293 mg) was obtained.

_{NR (CDC1 3) 3.87 (3H} , s), 3.90 (3H, s), 6.62 (1H, s), 7.08-7.20 (3H, m), 7.53-7.68 (6H, rn)

1 6 c) 1- (p-cyano-1a- (3,7-dimethoxynaphthalene-1-yl) benzyl) imidazole 'hydrochloride

P-Cyanore a— (3,7-Dimethoxyxinaphthalen-1-yl) Using benzyl chloride (96 mg) and imidazole (193 mg), 1- (p— Cyanoa- (3,7-dimethoxynaphthalene-12-yl) benzyl) imidazole 'hydrochloride (92 mg) was obtained.

Visceral _{(CD 3 0D) 3.83 (3H} , s), 3.86 (3H, s), 7.13 (1H, d, J = 2Hz), 7.17 (IH, dd, J = 8.8, 2Hz), 7.28 (1H, s) , 7.39 (1H, s), 7.43 (2H, d, J = 8.2 Hz), 7.46 (1H, s), 7.62 (1H, s), 7.65 (1H, s), 7.75 (1H, d, J = 8.8) Hz), 7.85 (2H, d, J = 8.2Hz), 8.90 (1H, s)

Example 17 1- (p-cyano a- (3,7-dimethoxynaphthalene-1-yl) benzyl) 1,1,2,4-triazolyl hydrochloride

Using p-cyano a- (3,7-dimethoxynaphthalene-2-yl) benzyl chloride (197 mg) and 1,2,4-triazole (403 mg) obtained in Example 16b The same treatment was performed as in Reference Example 1c. However, silica gel column chromatography was performed with ethyl acetate: hexane = 3: 1, and 1- (P-cyano-a- (3,7-dimethyloxynaphthalene-1-yl) benzyl) 1-1,2,2 4 Triazole.hydrochloride (38 mg) was obtained.

_{NMR (CD 3 0D) 3.83 (} 3H, s), 3.85 (3Η, s), 7.10 (IH, d, J = 2Hz), 7.14 (1H, dd, J = 8.8, 2Hz), 7.337 (1H, s) , 7.342 (1H, s), 7.47 (2H, d, J = 8.2Hz), 7.50 ( . Recorded (s 9 · ε) Wei ί · I ^

{(-Z-^^ ^-^ z ^-l) — σ—, / :, one d)-τ (ο 8 Τ

( ^Ζ Η2'6 = Γ 'Ρ' Ηΐ)

ZQ-L '(ω Ήΐ) 9 · Α-8λΖ' ("ί.'Ητ) εΑΊ-99 · '(' 9.8 · = 'Γ' HT) 99'A '(ΖΗ9.8 = Γ

'ρ' 5 · '(s Ήΐ) 6εΑ Α' ("ΐ Ήε) Αε.-οεΆ '(S'HS) 66'S (ηοαα) HWN

ο ¾ (s 6 ε · ε) ^^ c

q T fi ^ (ΐ ^ 99 · τ) ( ^s s · ε) ^-

— Σ—, ー d ΤΓΤ η

^ M ^ ^ y- _Z -^^-^^ A ≠-) — D—, ku, ct (qs χ

(ZH9

= Γ 'P' ΗΤ) 66 · '( ^Ζ ΗΓ6 = Γ' Ρ 'Ηΐ) 68 丄丄' (ΖΗ9.8 = Γ 'Ρ' ΗΙ) ε8 · '(ΖΗ9ΖΗ8 = Γ' Ρ ΉΖ) 39 Α '(·) Ήε) 09-Ζ ^ ΖΑ' ( ^Ζ Η9'8 = Γ 'Ρ LZ'L' ( ^z HZ'6 = r 'Ρ' HT) T £ 'i' ( ^Ζ Η9'8 = Γ 'Ρ Ήΐ) 9 9' ( ^s ' Η8) 98 '(ΖΗ9 · 8 = Γ' Ρ Ήΐ) 28-ε ( ^ε Τ3αθ) ΗΜΜ

°: (S 6-£) ^ — 匚 ^ ^ Λ (-Z- ^ \ ^-(r-I) —:, -d

,, ¾¾ ζ

• z). ^ ^ ^-^ M ^ (s T ') τ

-in 1- 3, (II) ((^^^ 9-T)

(B 8 T m-^-A ^^ (^^ be ((-z-^^ i ^-^^ -ΐ) — one, / :, one d) —i (8 τ Μ)

(s'

Ηΐ) 0Γ6 '(s ΉΤ) .9 · 9 ζ (ζ 8 = Γ' Ρ 'Cold 8ί' (ΖΗ8 · 8 = Γ 'Ρ' Ηΐ) '' (s Ήΐ

Ζ ― 60SlO / £ 6df / JDd £ 680 6 O NMR (CDaOD) 3.69 (3H, s), 7.30 (2H, d, J = 8.3Hz), 7.46 (1H, dd, J = 7.0, 8.0Hz), 7.5K1H, d, J = 9.0Hz, 7.60 ( 1H, dd, J = 7.0, 8.5Hz), 7.6δ (1Η, s), 7.72 (1H, s), 7.76 (2H, d, J = 8.3Hz), 7.96 (1H, d, J = 8.0 Hz), 8.01 (111, s), 8.1 1 (1H, d, J = 8.5Hz), 8.13 (1H, d, J = 9.0Hz), 8.98 (1H, s)

(Example 19) 1- (p-cyano-α- (naphthalene-2-yl) benzyl) -1, 2,4-triazole 'hydrochloride

Using Ρ-cyano-α- (naphthalene-2-yl) benzyl chloride (4.17 g) and 1,2,4-triazole (5.30 g), as in Reference Example 7c Processed. Silica gel column chromatography is performed with ethyl acetate: hexane = 1: 1, and 1- (p-cyano-α- (naphthylene-1-2-yl) benzyl) 1-1,2,4-triazole I got This was dissolved in methanol, an ethereal solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. Then, the solvent was distilled off to obtain 1- (ρ-cyano-α- (naphthalene-2-yl) benzyl) -1-1. , 2,4 Triazole 'hydrochloride (1.89 g).

_{NMR (CD 3 0D) 7.40-7.60 (} 6H, m), 7.78-7.78 (6H, m), 8.71 (IH, s), 9.43 (1

H, s)

(Example 20) 1- (p-cyano α- (6-butoxynaphthalene-1-yl) benzyl) imidazole-hydrochloride

20 a) p-cyano α- (6-butoxynaphthalene 2-yl) benzyl alcohol

Reference Example 7a using η-butyllithium (1.65Μ, hexane solution) (1.2 ml), 2-promo-6-butoxynaphthalene (552 mg) and p-cyanobenzaldehyde (26 Omg). In the same manner as in the above, p-cyano α- (6-butoxynaphthalene-1-yl) benzyl alcohol (336 mg) was obtained.

NR (CDCla) 1.00 (3H, t, J = 7.3Hz), 1.53 (2H, sex, J = 7.3Hz), 1.83 (2H, 'quin, J = 7.3Hz), 2.30-2.50 (IH, br), 4.07 (2H, t, J = 7.3Hz), 6.00 (1H, s), 7.11 (IH, d, J = 2.4Hz), 7.17 (1H, dd, J = 8.9Hz), 7.32 (1H, dd) , J = 1.5, 8.9Hz), 7 • 55 (2H, d, J = 8.3Hz), 7.63 (2H, d, J = 8.3Hz), 7.69 (IH, d, J = 8.9Hz), 7.71 (1H , D, J = 8.9Hz), 7.74 (1H, br s)

20 b) p-cyano a- (6-butoxynaphthalene-2-yl) benzyl chloride

P—Cyanault a— (6-butoxynaphthalene-1-yl) benzyl alcohol

(203 mg) and thionyl chloride (230 1) were used to obtain p-cyano-a- (6-butoxynaphthalene-12-yl) benzyl chloride (228 mg) in the same manner as in Reference Example 22b.

_{NR (CDC1 3) 1.00 (3H} , t, J = 7.3Hz), 1.53 (2H, sex, J = 7.3Hz), 1.83 (2H, quin, J = 7.3Hz), 4.07 (2H, t, J = 7.3 Hz), 6.26 (1H, s), 7.12 (1H, d, J = 2.6Hz),

7.17 (1H, dd, J = 2.6, 8.6Hz), 7.37 (1H, dd, J = 1.5, 8.6Hz), 7.57 (2H, d, J = 8 • 6Hz), 7.64 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.6Hz), 7.72 (1H, brs) 20 c) 1- (p-cyano-1a- (6-butoxynaphthalene-1-2-yl) benzyl) imidazo-1 * Hydrochloride

Using P-cyanore a— (6-butoxynaphthalene-1-yl) benzyl chloride (218 mg) and imidazole (220 mg), 1- (p-cyanore a— (6-Butoxynaphthalene-2-yl) benzyl) imidazole hydrochloride (168 mg) was obtained.

_{NMR (CD 3 0D) 1.0K3H,} t, J = 7.6Hz), 1.55 (2H, sex, J = 7.6Hz), 1.82 (2H, quin, J = 7.6Hz), 4.11 (2H, t, J = 7.6 Hz), 7.19 (1H, dd, J = 2.6, 8.9Hz), 7.28 (1H, d, J = 2.6Hz), 7.33 (1H, s), 7.35 (1H, dd, J = 1.5, 8.9Hz) , 7.47 (2H, d, J = 8.2Hz), 7.649 (1H, d, J = 1.5Hz), 7.652 (1H, s), 7:69 (1H, s), 7.75 (1H, d, J = 8-9Hz), 7.84 (2H, d, J = 8.2Hz), 7.87 (1H, d, J = 8.9Hz), 8.94 (1H, s)

(Example 21) 1- (p-cyano a- (6-methoxyethoxynaphthalene-1-yl) benzyl) imidazole 'hydrochloride

21 a) p-cyano α- (6-methoxyethoxynaphthalene-1-yl) benzyl alcohol

η-Butyllithium (1.65Μ, hexane solution) (0.88 ml), 2-butane 6-methoxyethoxynaphthalene (405 mg) and p-cyanobenz In the same manner as in Reference Example 3a, p-cyano-α- (6-methoxyethoxynaphthalene-12-yl) benzyl alcohol (305 mg) was obtained using 4δ aldehyde (190 mg).

_{NMR (CDC1 3) 2.3-2.5 (1Η} , br), 3.48 (3H, s), 3.82 (2H, t, J = 4.8Hz), 4.2 3 (2H, t, J = 4.8Hz), 6.00 (1H, s), 7.12 (1H, d, J = 2.3 Hz), 7.22 (1H, dd, J = 2.3, 8.9 Hz), 7.32 (1H, dd, J = 1.6, 8.6 Hz), 7.55 (2H, d, J = 8.3Hz), 7.62 (2H, d, J = 8.3Hz), 7.69 (1H, d, J = 8.6Hz), 7.72 (1H, d, J = 8.9Hz), 7.75 (1H, br.s) 2 1 b) p-Cyanoa- (6-methoxyethoxynaphthalene-1-yl) benzyl chloride

Using p-cyano a- (6-methoxyethoxynaphthalene-1-yl) benzyl alcohol (203 mg) and thionyl chloride (230 il) in the same manner as in Reference Example 22b, p-cyano a- (6 —Methoxyethoxynaphthalene-1-yl) benzyl chloride (218 mg) was obtained.

_{NMR (CDC1 3) 3.48 (3H} , s), 3.82 (2H, t, J = 4.6Hz), 4.24 (2H, t, J = 4.6Hz), 6.26 (1H, s), 7.13 (1H, d, J = 2.3Hz), 7.23 (1H, dd, J = 2.3, 8.6Hz), 7.37 (1H, dd, J = 1.6, 8.6Hz), 7.57 (2H, d, J = 9.6Hz), 7.65 (2H, d , J = 8.6Hz), 7.71 (2H, d, J = 8.6Hz), 7.73 (1H, br s)

2 1 c) J ^: (p-cyano-a- (6-methoxyethoxynaphthalene-1-yl) benzyl) imidazole, hydrochloride

Using p-cyano a- (6-methoxyethoxynaphthalene-1-yl) benzyl chloride (208 mg) and imidazole (220 mg) in the same manner as in Reference Example 1c, a— (6-Methoxyethoxynaphthalene-1-yl) benzyl) imidazole hydrochloride (202 mg) was obtained.

Discussions _{(CD 3 0D) 3.45 (3H} , s), 3.81 (2H, t, J = 4.5Hz), 4.2δ (2Η, t, J = 4.5Hz), 7.23 (1H, dd, J = 2.3, 8.9Hz ), 7.32 (2H, s), 7.36 (1H, dd, J = 2.0, 8.6Hz), 7.47 (2H, d, J = 8.3Hz), 7.64-7.66 (2H, m), 7.68-7.70 ( 1H, m), 7.77 (1H, cl, J = 8 • 9Hz), 7.84 (2H, d, J = 8.3Hz), 7.88 (1H, d, J = 8.6Hz), 8.93 (1H, s)

(Example 22) 1- (p-cyano-1-a- 4-methylnaphthalene-11-yl) Benzyl) imidazole hydrochloride

22 a) p-cyano α- (4-methylnaphthalene-1-yl) benzyl alcohol

Reference Example 3a using η-butyllithium (1.65Μ, hexane solution) (1.4 ml), 4-promote 1-methylnaphthalene (350ul) and p-cyanobenzaldehyde (29 Omg) In the same manner as in the above, p-cyano α- (4-methylnaphthalene-11-yl) benzyl alcohol (386 mg) was obtained.

NMR (CDCla) 2.56-2.62 (1Η, br), 2.69 (3H, s), 6.47 (1H, br s), 7.25-7.36 (2H, m), 7.42-7.60 (6H, m), 8.00- 8.06 (2H, m)

22 b) p-cyano a- (4-methylnaphthalene-11-yl) benzyl chloride K

P-Cyanoa- (4-methylnaphthalene-11-yl) Using benzyl alcohol (386 mg) and thionyl chloride (520 il), as in Reference Example 22b, 4-Methylnaphthalene-11-yl) benzyl chloride (384 mg) was obtained.

顧_{(CDC1 3) 2.7K3H, s)} , 6.84 (1H, s), 7.30 (1H, d, J = 7.2Hz), 7.39 (1H, d, J = 7.9Hz), 7.48-7.58 (2H, m) , 7.58 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 7.99 (1H, dd, J = 2.0, 7.9 Hz), 8.07 (1H, dd, J = 2.0, 7.2 Hz)

22 c) 1- (p-cyano a- (4-methylnaphthalene-11-yl) benzyl) imidazole, hydrochloride

Using P-cyano-1a- (4-methylnaphthalene-11-yl) benzyl chloride (384 mg) and imidazole (448 mg), 1- (p-cyano-1a- ( 4-Methylnaphthalene-11-yl) benzyl) imidazole hydrochloride (355 mg) was obtained.

Thigh _{(CD 3 0D) 2 · 74} (3Η, s), 6.88 (1H, d, J = 7.4Hz), 7.38 (1H, d, J = 7.4Hz), 7.43 (2H, d, J = 8.2Hz) , 7.57 (1H, t, J = 7.9Hz), 7.61 (1H, s), 7.63 (1H, t, J = 7.9Hz), 7.69 (1H, s), 7.84 (2H, d, J = 8.2Hz) , 7.92 (1H, d, J = 7.9Hz), 8.00 (1H, s), 8.18 (1H, d, J = 7.9Hz), 8.82 (1H, s) (Example 23) 1- (p-cyano-α- (4-acetoaminonaphthalene-1-yl) ^^ undil) imidazole 'hydrochloride

23 a) p-cyano α- (4-acetaminonaphthalene-11-yl) benzyl alcohol

Reference example using η-butyllithium (1.65Μ, hexane solution) (1.3 ml), 4-bromo-1-acetoaminonaphthalene (270ul) and P-cyanobenzaldehyde (135mg) In the same manner as in 3a, p-cyano-α- (4-acetaminonaphthalene-11-yl) benzyl alcohol (202 mg) was obtained.

_{_{NR (CDC1 3 -CD 3 0D)}} 2.2K3H, s), 6.37 (1H, s), 7.37-7.55 (8H, ra), 7.89- 8.0Κ2Η, m)

23 b) p-cyano α- (4-acetaminonaphthalene-11-yl) benzyl chloride

Using p-cyano α- (4-acetamino naphthalene), benzyl alcohol (63 mg) and thionyl chloride (75 μl) in the same manner as in Reference Example 22b, p-cyano α- (4-Acetaminonaphthyl-1-yl) benzyl chloride (57 mg) was obtained.

_{NMR (CDC1 3) 2.3K3H, br} s), 6.80 (1H, br s), 7.44-7.68 (7H, m), 7.74- 8.04 (4H, m)

23 c) 1- (p-cyano-a- (4-acetoaminonaphthyl) benzyl) imidazole 'hydrochloride'

The same procedure as in Reference Example 1c was carried out using P-cyano-a- (4-acetoaminonaphthalene-11-yl) benzyl chloride (57 mg) and imidazole (60 mg). However, it is purified by silica gel column chromatography (ethyl acetate: methanol 2 19: 1) and purified by eleven (P-cyano-a- (4-acetoaminonaphthalene-1-yl) benzyl) imidazole hydrochloride. The salt (33 mg) was obtained.

NMR (CDsOD) 2.29 (3H, s), 6.99 (1H, d, J = 7.9Hz), 7.44 (1H, d, J = 7.9Hz), 7.46 (1H, s), 7.45-7.72 (5H, m) , 7.85 (2H, d, J = 8.6Hz), 7.95 (1H, dd, J = 2. 0, 7.2Hz), 8.0K1H, s), 8.16 (1H, dd, J = 2.0, 7.2Hz), 8.82 (1H, s)

(Example 24) 1- (p-cyano a- (4-methoxynaphthalene-1-yl) benzyl) imidazole hydrochloride

24 a) p-cyano α- (4-methoxynaphthalene-11-yl) benzyl alcohol

η-Butyllithium (1.60Μ, hexane solution) (1.7 ml), p-bromobenzonitrile (0,49 g) and 4-methoxynaphthalene-11-carboxaldehyde (0.50 g) In the same manner as in Reference Example 7a, p-cyano a- (4-methoxynaphthalene-11-yl) benzyl alcohol (656 mg) was obtained.

_{NMR (CDC1 3) 2.45 (1H} , d, J = 4. OHz), 4.01 (3H, s), 6.44 (1H, d, J = 4.0Hz), 6.76 {1H, d, J = 7.9Hz), 7.33 (1H, d, J = 7.9Hz), 7.44-7.51 (2H, m), 7.53 (2H, d, J = 8.6Hz), 7.6K2H, d, J = 8.6Hz), 7.94-8.01 (1H, m ), 8.30-8.36 (1H, m) 24 b) p-cyano-1a- (4-methoxynaphthalene-11-yl) benzylic P-lide p-cyano-1a- (4-methoxynaphthalene-1 11 ^ T Benzyl alcohol (637 mg) and thionyl chloride (800 w 1) in the same manner as in Reference Example 22b, p-cyano-a- (4-methoxynaphthalene-11-yl) benzyl chloride (651 mg) ).

_{NMR (CDC1 3) 4.0K3H, s} ), 6.76 (1H, d, J = 7.9Hz), 6.79 (1H, s), 7.33 (1H, d, J = 7.9Hz), 7.48-7.57 (2H, m) , 7.60 (2H, d, J = 8.6Hz), 7.65 (2H, d, J = 8.6Hz), 7.91-7.96 (1H, m), 8.31-8.38 (1H, m)

24 c) 1- (p-cyano-1a- (4-methoxynaphthalene-11-yl) benzyl) imidazole * hydrochloride

Using P-cyano-a- (4-methoxymethoxyphthalene) benzyl chloride (152 mg) and imidazole (170 mg), as in Reference Example lc, 1- (p-cyano a- (4-Methoxynaphthalene-11-yl) benzyl) imidazole · hydrochloride (161 mg) was obtained.

_{NR (CD 3 0D) 4.04 (} 3H, s), 6.93 (2H, s), 7.41 (2H, d, J = 8.3Hz), 7.55-7. 62 (3H, m), 7.68 (1H, s), 7.85 (3H, d, J = 8.3 Hz), 7.92 (1H, s), 8.35-8.39 (1H, ra), 8.80 (1H, s)

(Example 25) 1- (p-cyano-α- (4-methoxynaphthalene-1-yl) benzyl) -1,1,2-triazolyl 'hydrochloride

Using と -cyano-α- (4-methoxynaphthalene-1-yl) benzyl chloride (493 mg) and 1,2,4-triazole (533 mg) obtained in Example 24b, as in Reference Example lc I made it. However, purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1) yields 1- (P-cyano-α- (4-methoxynaphthalene-11-yl) benzyl) -1,2, There was obtained 41-triazole (51 mg). This was dissolved in methanol, an ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. Then, the solvent was distilled off to obtain a hydrochloride.

Marauder (CD ₃ OD) 4.03 (3H, s), 6.90 (1H, d, J = 8.3Hz), 7.02 (1H, d, J = 8.3Hz), 7.42 (2H, d, J = 8.4Hz), 7.51 -7.59 (2H, m), 7.81 (2H, d, J = 8.4Hz), 7.83-7.86 (1H, in), 7.94 (1H, s), 8.34-8.37 (1H, m), 8.70 (1H, s), 9.19 (1H, s)

Example 26 1- (p-cyano α- (3,5-dimethyloxynaphthalene-1-yl) benzyl) imidazole'hydrochloride

26 a) p-cyano α- (3,5-dimethyloxynaphthalene-2-yl) benzyl alcohol

η-butyllithium (1.60Μ, hexane solution) (4.2 ml), p-bromobenzonitrile (1.23 g) and 2,8-dimethoxynaphthalene-1-potency lipoxaldehyde (1.45 ml) g) was used to obtain p-cyano-α- (3,5-dimethoxynaphthalene-1-yl) benzyl alcohol (1.43 g) in the same manner as in Reference Example la.

NMR (CDCla) 3.23 (1H, d, J = 6.6Hz), 6.14 (1H, d, J = 6.6Hz), 6.83 (1H, d, J = 7.3Hz), 7.28 (1H, t, J = 7.3Hz) ), 7.35 (1H, d, J = 7.3Hz), 7.53 (2H, d, J = 7.9Hz), 7.56 (1H, s), 7.6K2H, d, J = 7.9Hz), 7.63 (1H, s)

26 b) p-cyano-a- (3,5-dimethoxynaphthalene-1-yl) benzyl chloride OAV6 / o / eJdsloedf-

(Example 28) 1- (1-cyano-1- (1-, 4-dimethyloxynaphthalene-1-yl) benzyl) imidazole.hydrochloride

28 a) p-Cyanophenyl-1,4-dimethoxynaphthalene-12-ylketo n-butyllithium (1.60 M, hexane solution) (4.1 ml), p-bromobenzonitrile (1.19 g) and 1 The same procedure as in Reference Example 7a was carried out using 1,4-dimethoxynaphthalene-1-carboxylic acid (1.61 g). However, purification by column chromatography on silica gel (benzene) gave p-cyanophenyl (1,4-dimethoxynaphthalene-1-yl) -ketone (576 mg).

Thigh _{(CDC1 3) 3.66 (3H,} s), 4.01 (3H, s), 6.83 (1H, s), 7.58-7.66 (2H, m), 7.75 (2H, d, J = 7.9Hz), 7.96 (2H , d, J = 7.9Hz), 8.08-8.14 (1H, m), 8.28-8.35 (1H, m)

28 b) p-cyano a- (1,4-dimethoxynaphthalene-1-yl) benzyl alcohol

P-Cyanophenyl (1,4-dimethoxyxanaphthalene-1-2-le) -ketone (207mg) is dissolved in isopropanol (2ml) -tetrahydrofuran (3ml) and sodium borohydride (248mg) Was added and stirred at room temperature for 40 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain P-cyano-a- (1,4-dimethoxynaphthalene-12-yl) benzyl alcohol (208 mg).

_{NMR (CDC1 3) 2.79 (1H} , d, J = 4.6Hz), 3.86 (3H, s), 3.92 (3H, s), 6.39 (1H, d, J = 4.6Hz), 6.64 (1H, s), 7.48-7.65 (6H, m) "δ.03 (1H, d, J = 7.9Hz), 8.23 (1H, d, J = 7.9Hz)

28 c) p—Cyanaw a— (1,4-Dimethoxyxinaphthyl-2-yl) benzyl chloride

P-cyanone a— (1,4-dimethoxynaphthalene-1-yl) Using benzyl alcohol (207 mg) and thionyl chloride (240 wl), as in Reference Example 22b, p-cyanone a— ( 1,4-Dimethoxynaphthyl-1-yl) benzyl chloride (218 mg) was obtained. _{NMR (CDC1 3) 3.90 (3H} , m), 3.93 (3H, s), 6.64 (1H, s), 6.85 (1H, s), 7.4 8-7.6K6H, m), 8.05 (1H, d, J = 7.9Hz), 8.23 (IH, d, J = 7.9Hz)

28 d) 1- (p-cyanol α- (1,4-dimethoxynaphthyl-2-yl) benzyl) imidazole-hydrochloride

Using P-cyano-a- (1,4-dimethoxynaphthalene-12-yl) benzyl chloride (100 mg) and imidazole (101 mg), 1- (p —Cyanol a— (1,4-dimethoxynaphthalene-2-yl) benzyl) imidazole 'hydrochloride (38 mg) was obtained.

NMR (CDsOD) 3.83 (3H, s), 3.87 (3H, s), 6.46 (IH, s), 7.48 (2H, d, J = 8.3 Hz), 7.57-7.68 (3H, ra), 7.70-7.72 (IH, m), 7.74-7.75 (IH, m), 7.86 (2H, d, J = 8.3Hz), 8.10 (1H, d, J = 8.3Hz), 8.26 (1H, d, J = 8.3Hz) , 9.02 (1H, brs) (Example 29) 1- (p-cyano a- (1,4-dimethoxynaphthalene-1-yl) benzyl) 1,1,2,4-triazole.hydrochloride

P-cyano a- (1,4-dimethylmethoxynaphthalene-2-yl) benzyl chloride (11 Omg) and 1,2,4-triazole (113 mg) obtained in Example 26b And the same as Reference Example lc. However, it is purified by silica gel column chromatography (ethyl acetate: hexane = 4 _: 1), and 1- (p-cyano a- (1,4-dimethoxynaphthalene-12-yl) benzyl) 1-1,2, 4 One triazole (56 mg) was obtained. This was dissolved in methanol, an ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes, and then the solvent was distilled off to obtain a hydrochloride.

_{NMR (CD 3 0D) 3.87 (} 6H, s), 6.68 (1H, s), 7.45 (2H, d, J = 8.3), 7.57 (1H, t, J = 7.8), 7.63 (1H, t, J = 7.8), 7.73 (1H, s), 7.80 (2H, d, J = 8.3), 8.09 (1H, d, J = 7.8), 8.24 (1H, d, J = 7.8), 8.76 (1H, s), 9.60 (1H, s)

(Example 30) (-)-111 (P-cyano a- (anthracene-1-9-yl) benzyl) imidazole

HPLC (hexane: ethanol = 2 :) of 1- (p-cyano-α- (anthracene-91-yl) benzyl) imidazole (18 mg) obtained in Example 7 was performed using Chiral Cell-OC (manufactured by Daicel Chemical Industries, Ltd.). Separate and purify in 1), (1) -1 (P-Cyan.-1α- (Anthracene-91-yl) benzyl) imidazole (5 · Omg) was obtained. [a] _D = -251 ° (c = 0.25, MeOH)

(Example 31) (+) 1-11 (P-cyano α- (anthracene 91-yl) benzyl) imidazole

In Example 30, the compound of Example 30 was eluted with HP LC, and further eluted with hexane: ethanol = 2: 1 to obtain (+) — 1 — (-cyano-one- (anthracene-one-one). Benzyl) imidazole (2.8 mg) was obtained.

[a] _D = + 25Γ (c = 0.14, MeOH)

(Example 32) 1- (p-cyano α-methyl-α- (6-methoxynaphthalene-2-yl) benzyl) imidazole

Under a nitrogen atmosphere, 1- (ρ-cyano-α- (6-methoxynaphthalen-2-yl) benzyl) imidazole (100 mg) obtained in Example 8 was dissolved in tetrahydrofuran (3 ml), and Botashim was added. After adding 1-tert-butoxide (33 mg) and stirring at 0 ° C. for 5 minutes, methyl iodide (20 jul) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: triethylamine = 20: 1) to obtain a residue (P- Cyan-1-α-methyl-1-α- (6-methoxynaphthylene-1-yl) benzyl) midazole was obtained.

_{NMR (CDC1 3) 2.46 (3H} , s), 3.93 (3H, s), 6.84 (1H, br s), 7.10-7.22 (6H, in), 7.25 (1H, br s), 7.38 (1H, br s ), 7.62 (lH, 'd, J = 8.6Hz), 7.66 (2H, d, J = 8.6Hz), 7.75 (1H, d, J = 8.6Hz)

(Example 33) 1- (P, a-disocyanol a- (6-methoxynaphthyl-2-yl) benzyl) imidazole * hydrochloride

11- (P-cyano-a- (6-methoxynaphthalene-12-yl) benzyl) imidazole (100 mg), botacidium-tert-butoxide (33 mg) and tosyl cyanide (54 mg) obtained in Example 8 were added. And used in the same manner as in Example 32. However, silica gel column chromatography (ethyl acetate: ε68 / -0 OAV

Dimension 2

5 δ

(Example 36)] 1- (ρ-Ciano) α- (Fenanslen-1-yl) benzyl) 1,1,2,4-Triazolyl

Reference Example 7c was obtained using p-cyano α- (phenanthrene-19-yl) benzyl chloride (200 mg) and 1,2,4-triazolyl (2 12 mg) obtained in Example 5b. Treated similarly. However, silica gel column chromatography was performed with ethyl acetate: hexane = 2: 1, and 1- ( _P -cyano-a- (phenanthrene-9-yl) benzyl) 1-1,2,4-triazole (84mg)

_{NMR (CDC1 3) 7.15 (1H} , s), 7.26 (2H, d, J = 8.6Hz), 7.5δ-7.64 (3H, m), 7. 68-7.81 (6H, m), 7.90 (1H, s ), 8.12I1H, s), 8.7K1H, d, J = 8.6Hz), 8.79 (1H, d, J = 8.6Hz)

(Example 37) 1- (p-cyano-α-methyl-α- (naphthalene-1-yl) benzyl) 1-1,2,4-triazole

1- (ρ-cyano-α- (naphthalene-11-yl) benzyl) 1,1,2,4-triazolyl (88 mg), botashem-t-butoxide (33 mg) obtained in Example 35 and The same treatment as in Example 32 was carried out using methyl iodide (201). However, silica gel column chromatography was performed with benzene: ethyl acetate = 3: 1, and 1- (p-cyano α-methyl-1-α- (naphthalene-11-yl) benzyl) 1,1,2,4- Liazol (28 mg) was obtained.

_{NR (CDC1 3) 2.64 (3H} , s), 6.80 (1H, d, J = 7.3Hz), 7.21-7.29 (2H, mj, 7. 38-7.47 (4H, m), 7.6o (2H, d, J = 7.9Hz), 7.83 (1H, s), 7.91 (2H, d, J = 8.6Hz),

8.1K1H, s)

(Example 38) 1- (p-cyano a- (4-methylnaphthalene-1-yl) benzyl) -1,2,4-triazole

Using p-cyanoa- (4-methylnaphthalene-1-yl) benzyl chloride (459 mg) and 1,2,4-triazolyl (545 mg) obtained in Example 22b The same treatment as in Reference Example 7c was performed. However, silica gel column chromatography was performed with ethyl acetate: hexane = 2: 1, and 1— (P—Cyanau a—i δ 6

4-Methylnaphthalene-1-yl) benzyl) 1-1,2,4-triazole (264 mg) was obtained.

_{NMR (CDC1 3) 2.72I3H, s} ), 6.8K1H, d, J = 7.3Hz), 7.16I2H, d, J = 8.6Hz), 7.27 (1H, d, J = 7.3Hz), 7.5K1H, t, J = 7.3Hz), 7.57 (111, s), 7.59I1H, t, J = 7.3Hz), 7.68 (2H, d, J = 8.6Hz), 7.79I1H, d, J = 7.3Hz), 7.80 (1H , si, 8.07 (1 H, s), 8.10 (1H, d, J-7.3Hz)

(Example 39) 1- (p-cyano α- (6-t-butyldimethyl-l-reoxy-cinnaphthalene- ^1- yl) benzyl) 1,2,4-triazolyl

Example 9b, P-cyano-1a- (6-t-butyldimethylsilyloxynaphthalene-1-yl) benzyl chloride (0.70 g) and 1,2,4-triazo-1 And treated in the same manner as in Reference Example 7c. However, silica gel column chromatography was performed with ethyl acetate: hexane = 1: 1, and 1- (P-cyano-a- (6-t-butyldimethylsilyloxynaphthalene-1-yl) benzyl) 1 1 , 2,4-Triazole (199 mg) was obtained.

_{NMR (CDC1 3) 0.25 (6H} , s), 1.02 (9Η, s), 6.90 (1Η, s), 7.12 (1Η, dd, J = 8 • 6, 2.0Hz), 7.19-7.27 (4H, m) , 7.66 (1H, d, J = 8.6Hz), 7.68 (2H, d, J-8.6Hz), 7.73 (1H, d, J = 8.6Hz), 8.00 (1H, s), 8.07 (1H, s)

(Example 40) 1- (p-cyano-a- (6-hydroxynaphthalene-1-yl) benzyl) 1,1,2,4-triazol 'hydrochloride

1- (p-cyano-a- (6-hydroxyhydroxyphthalene-2-yl) benzyl chloride (199 mg), ether solution of hydrogen chloride (1 M, 4.2 ml) and methanol (Several drops) and treated in the same manner as in Example 10. However, silica gel column chromatography was carried out with ethyl acetate: hexane = 1: 1, and 1- (p-cyano-a- (6-hi) Droxinaphthalene-12-yl) benzyl) -1,1,2,4-triazolyl hydrochloride (138 mg) was obtained.

Negation _{(CD 3 0D) 7.10-7.14 (2H} , m), 7.34 (1H, dd, J = 2.0, 8.6Hz), 7.36I1H, s), 7.49 (2H, d, J = 8.6Hz), 7.68 (1H , d, J = 2.0Hz), 7.71 (1H, d, J = 8.6Hzi, 7.72 (1H, d, J = 8.6Hz), 7.79 (2H, d, J = 8.6Hz), 8.79 (1H, s), 9.50 (1H, s) δ-cho

(Example 41) 1- (1-cyano-1- (6-acetoxynaphthalene-1-yl ') benzyl) 1-1,2.4-triazol hydrochloride

1- (ρ-cyano-α- (6-hydroxynaphthalene-2-yl) benzyl)-1,2,4-triazole (37 mg), acetic anhydride (122) and triethylamine The same treatment as in Example 13 was carried out using 17ul). However, silica gel column chromatography was performed with ethyl acetate: hexane = 2: 1.

(P-cyano-α- (6-acetoxynaphthalene-12-yl) benzyl) 1,1,2,4-triazole hydrochloride (36 mg) was obtained.

Noodles _{(CD 3 0D) 2.33 (3H} , s), 7.32 (1H, dd, J = 2.0, 8.6Hz), 7.4K1H, s), 7 .47 (1H, dd, J = 2.0, 8.6Hz), 7.50 (2H, d, J = 8.6Hz), 7.64 (1H, d, J-2.0Hz), 7.78-7.81 (3H, m), 7.89 (1H, d, J = 8.6Hz), 7.92 (1H, d, J = 8.6Hz), 8.65 (1H, s), 9.34 (1H, s)

(Example 42) 1- (p-cyano-α- (6-methoxyethoxy-naphthalene-2-) benzyl) 1,1,2,4-triazolyl 'hydrochloride

1- (ρ-cyano-α- (6-hydroxynaphthylene-2-yl) benzyl)-1,2,4-triazol (105mg), methoxyacetyl chloride (74u1), The same treatment as in Example 14 was carried out using triethylamine (1121) and dimethylaminopyridine (catalytic amount). However, silica gel column chromatography was performed with ethyl acetate: hexane = 2: 1, and 1— (p—cyano_α—

(6-Methoxyacetoxynaphthalene-1-yl) benzyl) 1,1,2,4-triazole.hydrochloride (115 mg) was obtained.

N R (DMSO-de) 3.43 (3H, s), 4.40 (2H, s), 7.38 (1Η, dd, J = 2.2, 8.6Hz),

7.42-7.47 (4Η, m), 7.74 (1Η, d, J = 2.2Hz), 7.80I1H, s), 7.8812H, d, J = 8.6H ζ), 7.95 (1Η, d, J = 8.6Hz) , 7.98 (1Η, d, J = 8.6Hz), 8. ΙδίΙΗ, s), 8.75 (1H, s) (Reference example 1)

1 — (p—Cyaneau α— (benzyl quinoline_3—yl) benzyl) Imidazole 2

1) Piano-α- (quinoline-3-yl) benzyl alcohol ^ /

Under a nitrogen atmosphere, η-butyllithium (1.65 M hexane solution, 3 mL) was dissolved in anhydrous tetrahydrofuran (5 mL). — At 78 ° C, a solution of 3-bromoquinoline (l.OOg) in anhydrous tetrahydrofuran (4 mL), and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added a solution of p-cyanobenzaldehyde (630 mg) in anhydrous tetrahydrofuran (4 raL) at 178 ° C, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain P-cyano-α- (quinolin-3-yl) benzyl alcohol (875 mg).

_{NMR (CDC1 3) 3.08 (1H} , s), 6.05 (1H, s) 7.55-7.63 (3H, m), 7.67 (2H, d, J = 8.6Hz), 7 .73 (lH, dt, J = 1.4 , 8.6Hz), 7.86 (lH, dd, J = 1.4,8.6Hz), 8.06 (lH, d, J = 8.6Hz), 8.14 (lH, d, J-2.6Hz), 8.83 (lH, d, (J = 2.6Hz)

1 b) _p cyano α- (quinoline-3-yl) benzyl chloride

Ρ-cyano α- (quinoline-3-yl) benzyl alcohol (26 Omg) was suspended in methylene chloride (3 mL), thionyl chloride (150 uL) was added, and the mixture was stirred at room temperature for 1 hour. . The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain p-cyano-r- (quinolin-13-yl) benzyl chloride (266 mg).

Awakening: _{(CDC1 3) 6.33 (1H,} s), 7.55-7.6δ (3H, m), 7.70 (2H, d, J = 8.6Hz), 7.77 (1H, dt, J = 1.4,8.6Hz), 7.83 ( lH, dd, J = 1.4,8.6Hz), 8.10-8.15 (2H, m), 8.89 (1H, d, J = 2.6Hz)

1 c) 1-(p-cyano α-(quinoline-3-yl) benji kid ') imidazole dihydrochloride

P—Cyaneau a— (quinoline-3-yl) benzyl chloride (55 mg) The residue was dissolved in toluene (5 mL), imidazole (68 mg) was added, and the mixture was heated under reflux overnight. After cooling to room temperature, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1- (p-cyano G- (quinolin-3-yl) benzyl) imidazole (47.3 mg). This was dissolved in methanol, an ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. Then, the solvent was distilled off, and 1- (p-cyano-α- (quinoline-3-yl) benzyl) imidazole · 2HCl The salt (58.3 tng) was obtained.

_{MR (D 2 0) 7.54 (} 2H, d, J = 8.6Hz), 7.61-7.64 (2H, m), 7.66-7.68 (lH, m), 7.93 (2H, d, J = 8.6Hz), 7.94 ( IH, dt, J = 1.4, 8.6Hz), 8.12-8.19 (2H, m), 8.25 (1H, d, J = 8.6Hz), 8.76 (IH, d, J = 2.4Hz), 8.87-8.89 ( IH, m), 9.08 (1H, d, J = 2.4Hz)

(Reference Example 2)

1- (p-cyano-α- (quinoline-3-yl) benzyl) 1-1,2,4-triazol dihydrochloride

The ρ-cyano-α- (quinolin-3-yl) benzyl chloride (61 mg) obtained in Reference Example 1b was dissolved in acetonitrile (6 mU) to give 1,2,4-triazole. (76 mg), and the mixture was heated under reflux overnight, and treated in the same manner as in Reference Example 1c to give 1- (P-cyano α- (quinolin-3-yl) benzyl) -1-i, 2,4-tria. Zol 'dihydrochloride (44 mg) was obtained.

Thigh _{(D 2 0) 7.49 (1H} , d, J = 8.6Hz), 7.65 (IH, s), 7.88 (2H, d, J = 8.6Hz), 8.00 (IH, dt, J = 1.4,8.6Hz) , 8.18-8.31 (3H, m), 8.78 (IH, s), 8.98 (IH, d, J = 2.OHz), 9.11 (lH, d, J = 2.OHz)

(Reference example 3)

1— (p—cyano a- (22thiazolyl ') be> Jill) imidazo1). 2 salt ||

3 a) p-cyano α- (2-thiazolyl) benzyl alcohol

η-butyllithium (1.65M hexane solution, 2.6 mL), thiazole (300 " L) and p-cyanobenzylaldehyde (555 mg) were treated in the same manner as in Reference Example 1a. However, purification by column chromatography on silica gel '.hexane-ethyl acetate (1: 1)) gave p-cyano α- (2-thiazolyl) benzyl alcohol (23 Omg).

_{MR (CDC1 3) 3.96 (1H} , d, J = 4. OHz), 6.13 (1H, d, J = 4.0Hz), 7.34 (lH, d, J = 2.6Hz), 7 .62 (2H, d, J = 8.6Hz), 7.67 (2H, d, J = 8.6Hz), 7.73 (1H, d, J-2.6Hz)

3 b) p-cyano cr— (2-thiazolyl) benzyl chloride

After treating with P-cyano-α- (2-thiazolyl) benzyl alcohol (188 mg) and thionyl chloride (128 L) in the same manner as in Reference Example 1b, column chromatography on silica gel (hexane monoacetic acid) Purification with ethyl (5: 1)) gave -cyano-l- (2-thiazolyl) benzyl chloride (128 mg). Negation _{(CDC1 3) 6.33 (1H,} s), 7.41 (1Η, d, J = 2.6Hz), 7.64 (2H, d, J = 8.6Hz), 7.69 (2H, d, J = 8.6Hz), 7.78 ( (lH, d, J = 2.6Hz)

3 c) 1-ίρ-cyano a— (2-thiazolyl) benzyl) imidazole ′

1- (P-cyano-a-('2) in the same manner as in Reference Example 1c using P-cyano a- (2-thiazolyl) benzyl chloride (6 Omg) and imidazole (87 mg). (Thiathiazolyl) benzyl) imidazole 'dihydrochloride (16 mg) was obtained.

Image _{(D 2 0) 7.43 (2H} , d, J = 8.6Hz), 7.45 (1H, s), 7.47-7.51 (2H, ra), 7.69 (1H, d, J = 3. 3Hz), 7.77 (2H , d, J = 8.6Hz), 7.82 (1H, d, J = 3.3Hz), 8.76 (1H, m)

(Reference Example 4) ''

1- (p-cyano a— (2-thiazolyl) benzyl) —1,2,4-triazole / dihydrochloride

Using 1-p-cyano-a- (2-thiazolyl) benzylclide (66 mg) and 1,2.4-triazol (199 mg) obtained in Reference Example 3b, Reference Example 1c In the same manner, 1- (p-cyano a- (2-thiazoli) penzyl)-丄, 2,4-triazol dihydrochloride (13 mg) was obtained.

Awakening: _{(D 2 0) 7.38 (2H} , d, J = 8.6Hz), 7.40 (1H, s), 7.60 (1H, d, J = 3.3Hz), 7.70 (2H, d, J = 8.6Hz), 7.74 (1H, d, J = 3.3Hz), 8.09 (IH, s), 8.59 (lH's)

(Reference Example 5)

1- (p-cyano α- (isoquinoline-4-yl) benzyl) imidazole zerom tm¾itm

5 a) p-sia-a- (isoquinoline-1-yl) benzyl alcohol n-butyllithium (1.65 M hexane solution, U mL), 4-promoisoquinoline (500 mg), p-cyanobenzaldehyde (3 15 mg) to give p-cyano-α- (isoquinoline-41-yl) benzyl alcohol (17 lmg).

Thigh _{(CDC1 3) 2.94 (lH,} br s), 6.42 (lH, br s), 7.57 (2Η, d, J = 8.6Hz), 7.60-7.70 (4 H, m), 7.99 (2H, t, J = 8.6Hz), 8.53 (lH, s), 9.23 (1H, s)

5 b) p-cyano α- (isoquinoline-1-yl) benzyl chloride 'hydrochloric acid

P-cyano a- (isoquinoline-41-yl) benzyl alcohol (13 Omg) was suspended in methylene chloride (2 mL), and thionyl chloride (75 uL) was added, followed by stirring at room temperature for 2 hours. The resulting precipitate was collected by filtration and washed with hexane to obtain p-cyano a- (isoquinoline-4-yl) benzyl chloride hydrochloride (146 mg). Thigh (CDaOD) 7.37 (1H, s), 7.75 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz), 8.08 (IH, t, J = 8.6Hz), 8.25 (1H, t, J = 8.6Hz), 8.36 ( IH, d, J = 8.6Hz), 8.61 (1H, d, J-8.6Hz), 8.73 (lH, s), 9.87 (lH, s) '

5 c) 1- (p-cyano-a- (isoquinoline-1-yl) -benzy) imidazole dihydrochloride

1- (p-cyano a- (isoquinoline-1-yl) benzyl chloride 'hydrochloride (6 lmg) and imidazole (133 mg) in the same manner as in Reference Example 1c. Isoquinoline-1-yl) benzyl) imidazole dihydrochloride (32 mg) was obtained.

(D ₂ 0) 7.52 (2H, d, J = 8.6Hz), 7.59 (lH, m), 7.66 (lH, m), 7.90 (2H, d, J-8.6Hz), 7.96 (1H, s), 7.96-8.15 (4H, m), 8.49 (1H, d, J = 8.6Hz), 8.75 (lH, m), 9.66 (1H, s) (Reference example 6)

1- (p-cyano-α- (isoquinoline-41-yl) benzyl) 1-1,2,4-triazol · dihydrochloride

Using p-cyano-α- (isoquinolin-1-yl) benzyl chloride 'hydrochloride (58.4 mg) and 1,2,4-triazole (128 mg) obtained in Reference Example 5b In the same manner as in Example lc, 1- (p-cyano-α- (isoquinoline-1-yl) benzyl) -1,2,4-triazol dihydrochloride (46 rag) was obtained.

_{NR (D 2 0) 7.47 (} 2H, d, J = 8.6Hz), 7.86 (2H, d, J = 8.6Hz), 7.98 (1H, s), 8.05-8.15 (3 H, m), 8.17-8.25 (2H, m), 8.58 (1H, d, J = 8.6Hz), 8.66 (lH, s), 9.76 (1H, s)

(Reference Example 7)

1- (P-cyanore α- (2-benzothiazolyl) benzyl) 1-1,2,4-triazole

7 a) Add p-cyano α- (2-benzothiazolyl) benzyl alcohol η-butyllithium (1.65 M hexane solution, 12.8 mL), benzothiazole (2.25 mL), and p-cyanobentaldehyde (2.70 g). And processed in the same manner as in Reference Example 1a. However, purification was performed by silica gel column chromatography (hexane monoethyl acetate (4: 1)) to obtain p-cyano-α- (2-benzothiazolyl) benzyl alcohol (2.16 g).

Image _{(CDC1 3) 3.75 (1H,} d, J = 4. OHz), 6.21 (1H, d, J = 4. OHz), 7.40 (1H, dt, J = l.4, 8.0 Hz), 7.50 (lH , dt, J = l.4, 8. OHz), 7.69 (4H, s), 7.86 (lH, br d, J = 8. OHz), 8.01 (lH.br d, J = 8.0Hz)

7 b) p-cyano-a- (2-benzothiazolyl) benzyl chloride

The same treatment as in Reference Example 1b was performed using P-cyano a- (2-benzothiazolyl) benzyl alcohol (129 mg) and thionyl chloride (70 ii L), followed by silica gel column chromatography (hexane). The residue was purified by ethyl acetate (10: 1)) to obtain p-cyano a- (2-benzothiazolyl) benzyl chloride (47 mg). 6 O / dfAd ε80 / AVocec l

Benzoic acid (72.5 mg) was added, and the mixture was stirred at room temperature for 3 hours. Then, m-chloroperbenzoic acid (7 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into dilute hydrochloric acid and washed with ethyl acetate. The aqueous layer was made basic by adding aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, an ethereal solution of hydrogen chloride was added, the mixture was stirred for 5 minutes, and the resulting white precipitate was collected by filtration to obtain 11- (P-cyano α- (Ν-quinoline quinoline 13). 1-yl) benzyl) imidazole 'hydrochloride (27 mg) was obtained.

Listen (D ₂ 0) 7.44 (1H, s), 7.54 (2H, d, J = 8.6Hz), 7.62 (1H, ra), 7.66 (IH, m), 7.87 (IH, t, J = 8.6Hz) , 7.92 (2H, d, J = 8.6Hz), 8.01-8.09 (3H, m), 8.54 (IH, d, J = 8.6Hz), 8.75 (1 H, m), 8.86 (lH, s)

(Reference Example 10)

1-(1-(4-Cyanophenyl) 1 1-1 (Quinolin 1-3-yl) ethyl) -Midazole dihydrochloride

In a nitrogen atmosphere, 11- (p-cyano α- (quinoline-3-yl) benzyl) imidazole (74 mg) obtained in Reference Example lc was dissolved in tetrahydrofuran (3 mU), and the solution was dissolved in tetrahydrofuran (3 mU). After stirring at room temperature for 5 minutes, methyl iodide (37 JUL) was added, and the mixture was stirred at room temperature for 30 minutes.The reaction solution was poured into water and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (ethyl acetate), and the residue was purified by 1- (111- (4-cyanophenyl) -111 (quinoline-3-yl). ) Ethyl) Imidazole was obtained, dissolved in methylene chloride, an ether solution of hydrogen chloride was added, and the resulting white precipitate was collected by filtration to obtain 1- (1- (4-cyanophenyl) -1- (quinoline). One 3-yl) ethyl) Imidazole 'dihydrochloride (42 mg) was obtained.

Image _{(D 2 0) 2.74 (3H} , s), 7.44 (2H, d, J = 8.6Hz), 7.62 (IH, t, J = 1.5Hz), 7.68 (IH, t, J = 1.5Hz), 7.91 (2H, d, J = 8.6Hz), 7.93 (IH, t, J = 8.OHz), 8.13 (1H, d, J = 8.OHz) '8.14 (IH, t, J = 8.OHz), 8.24 (1H, d, J = 8. OHz), 8.64 (IH, d, J = 2. OHz), 8.82 (1H, t, J = 1.5Hz), 9.00 (lH, d, J = 2.0Hz) 6 δ

(Reference Example 11)

21- (Ρ-cyano α- (quinolin-3-yl) benzyl) tetrazol ρ-cyano-α- (quinolin-1-yl) benzyl chloride obtained in Reference Example 1b (207 mg) and tetrazo And treated with silica gel column chromatography. The fraction eluted with hexane monoacetate (1: 2) was purified by 2- (p —Cyano α- (quinoline-3-yl) benzyl) tetrazol (85 mg) was obtained.

Image _{(CDC1 3): 7.41 (2H} , d, J = 8.6Hz), 7.60 (1H, t, J = 7.3Hz), 7.64 (1H, s), 7.71 (2H, d, J = 8.6Hz), 7.75 -7.86 (2H, m), 8.07 (1H, d, J = 2.6Hz), 8.13 (1H, d, J = 8.6Hz), 8.67 (IH, s), 8.89 (lH, d, J = 2.6Hz)

(Reference Example 12)

11- (p-cyano α- (quinolin-1-yl) benzyl) tetrazole In Reference Example 11, the compound of Reference Example 11 was eluted by silica gel chromatography, and then eluted with ethyl acetate. —Cyano-α— (quinolin-3-yl) benzyl) tetrazole (125 mg) was obtained.

Awakening: _{(CDC1 3): 7.37 (2H} , d, J = 8.6Hz), 7.45 (1H, s), 7.61 (IH, t, J = 8.6Hz), 7.71 (2H, d, J = 8.6Hz), 7.79 (IH, t, J = 8.6Hz), 7.80 (1H, d, J = 8.6Hz), 7.97 (IH, d, J = 2.6Hz), 8.11 (IH, d, J = 8.6Hz), 8.84 (1H , D, J = 2.6Hz), 8.86 (1H, s)

(Reference Example 13)

1- (p-cyano α- (quinolin-3-yl) benzyl) 1-methylimidazole dihydrochloride ''

13 a) 1-Dimethylcarbamyl-1-methylimidazole

2-Methylimidazole (509 mg) was dissolved in acetonitrile (5 mL), dimethylcarbamyl chloride (630iiL) and triethylamine (1.05 mL) were added, and the mixture was stirred at room temperature for 60 hours. The reaction solution was poured into ether, and the generated precipitate was removed by filtration. The filtrate was concentrated, poured into ether, and the generated «was removed by filtration. The solvent was distilled off under reduced pressure to obtain 1-dimethylcarbamyl-2-methylimidazole (95 Orag). Female _{(CDC1 3) 2.48 (3H,} s), 3.03 (6H, s), 6.94 (IH, s), 6.97 (1H, s)

13 b) p-cyano α- (quinoline-3-yl) benzyl bromide

Suspension of ノー -cyano α- (quinolin-3-yl) benzyl alcohol (565 mg) obtained in Reference Example 1a was suspended in ethyl acetate (5 mL), and phosphorus tribromide (75 wL) was added. Heated to reflux. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl hexane monoacetate (1: 1)) to obtain P-cyano α- (quinolin-13-yl) benzylcarbamide (206 mg).

_{NR (CDC1 3) 6.44 (IH} , s), 7.61 (IH, t, J = 8.6Hz), 7.63 (2H, d, J = 8.6Hz), 7.69 (2H, d, J = 8.6Hz), 7.77 ( 1H, dt, J = 1.4, 8.6Hz), 7.82 (1H, dd, J = 1.4, 8.6Hz), 8.12 (1H, d, J = 8.6Hz), 8.13 (1H, d, 3 = 2.6Hz) Hz), 8.95 (1H, d, J = 2.6Hz)

13 c) 1- (p-cyano-1α- (quinoline-3-yl) benzyl-1-2-methylimidazole 'dihydrochloride

Dissolve P-cyano a- (quinoline-3-yl) benzyl bromide (276 mg) in acetonitrile (l〇mU), add 1-dimethylcarbamyl-12-methylimigzo one child (260 mg), and add 1 week After cooling, ammonia gas was blown in, the mixture was stirred for 5 minutes, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on silica gel (ethyl ethyl acetate (9: 1)), and the residue was purified using P-cyano a- (quinoline-3-yl). Benzyl) 1-2-methylimidazole was dissolved in methanol, an ethereal solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. The solvent was distilled off under reduced pressure to obtain 1- (P-cyano a-). (Kinori One 3-I le ') benzyl) one 2-methylimidazo Ichiru • 2 salt | give the § salt (35 mg).

_{NMR (D 2 0) 2.68 (} 3H, si, 7.22 (IH, d, J = 2.0Hz), 7.476 (IH, d, J = 2.4Hz), 7. 79 (2H, d, J = S.6Hz) , 7.55 (IH, s), 7.9 g 7.95 (3H, m), 8.12-8.19 (3H, m), 8.25 (IH, d, J = 8.6 Hz), δ.66 (IH, d, J = 2.0 Hz ), 9.02 (IH, d.j = 2.4Hz) (Reference Example 14)

1- (p-cyano α- (quinoline-3-yl) benzyl) -1-5-methylimidazole dihydrochloride

The same treatment as in Reference Example 7c was carried out using ρ-cyano α- (quinolin-3-yl) benzyl chloride (582 mg) and 4-methylimidazole (857 mg) obtained in Reference Example 1b. However, purification was performed by silica gel column chromatography (ethyl acetate triethylamine (95: 5)) to obtain 11- (p-cyano α- (quinolin-3-yl) benzyl) -15-methylimidazole. Dissolve in methanol, add an ethereal solution of hydrogen chloride, stir for 5 minutes, then distill off the solvent under reduced pressure to obtain 1- (ρ-cyano-1α- (quinoline-13-yl) benzyl) 1-5- Methyl imidazole dihydrochloride (17 mg) was obtained.

Listen (D ₂ 0) 2.26 (3H, s), 7.46 (1H, d, J = 2.4Hz), 7.48 (2H, d, J = 8.6Hz), 7.53 (1H, s), 7.95 (2H, d, J = 8.6Hz), 7.97 (IH, t, J = 8.6Hz), 8.17 (1H, d, J = 8.6Hz), 8.19 (1H, t, J = 8.6Hz), 8.28 (1H, d, J = 8.6Hz), 8.1 (1H, d, J = 2. OHz), 8.71 (1H, d, J = 2. OHz), 9.09 (1H, d, J = 2.4Hz)

(Reference Example 15)

1- (p-cyano α- (quinoline-3-yl) benzyl) 1- 4-methylimidazole dihydrochloride

In Reference Example 14, elution of 11- (Ρ-cyano α- (quinolin-13-yl) benzyl) -15-methylimidazole by silica gel column chromatography was followed by ethyl acetate triethylamine (4: 1). By elution, 11- (Ρ-cyano α- (quinoline-3-yl) benzyl) -14-methylimidazole was obtained. After dissolving in methanol, adding an ether solution of hydrogen chloride and stirring for 5 minutes, the solvent is distilled off under reduced pressure to obtain 1- (1-cyano α- (quinoline-3-yl) benzyl) 1. 4-Methylimidazole dihydrochloride (107 rag) was obtained.

瞧 (D ₂ 0) 2.35 (3H, s), 7.32 (IH, d, J = 2. OHz), 7.54 (2H, d, J = 8.3Hz), 7.57 (IH, s), 7.93 (2H, d , J = 8.3Hz), 8.01 (IH, dt, J = 1.5,6.8Hz), 8.19-8.32 (3H, m), 8.74 (IH, d, J = 2 • OHz), 8.89 (1H, d, J = 2. OHz), 9.12 (1H, d, J = 2. OHz) (Reference Example 16)

1- (p-cyano α- (1,4-benzodioxane-1-6-yl) benzyl) imidazole hydrochloride

16 a) £ —Cyano-α- (1,4-benzodioxane-6-yl) benzyl alcohol

Dissolve η-butyllithium (1.65M hexane solution, 3.4 mL) in tetrahydrofuran (5 mL), and place it under a nitrogen atmosphere. Add p-bromobenzonitrile (1.0 g) at C, stir for 1 hour, add 1,4-benzodioxane-16-carboxaldehyde (903 mg), stir for 1 hour, and add 1. 5 hours. The reaction solution was poured into water and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl hexane monoacetate (1: 2)) to obtain p-cyano α- (1,4-benzodioxane-16-yl) benzyl alcohol (1.14 g). .

Thigh _{(CDC1 3) 2.40 (1H,} d, J = 3.3Hz), 4.23 (4H, s), 5.75 (1H, d, J = 3.3Hz), 6.76-6.87 (3H, m), 7.49 (2H, d , J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz)

16 b) p-cyano α- (1,4-benzodioxane-6-yl) benzyl chloride

P-Cyanore a— (1,4-Benzodioxane-16-yl) Benzyl alcohol (1.115 g) and thionyl chloride (Q.54 mL) were used in the same manner as in Reference Example lb. — (1,4-Benzodioxane-1-6-yl) benzyl chloride (1.144 g) was obtained.

Marauder (CDCla) 4.25 (4H, s), 6.03 (1H, s), 6.79-6.90 (3H, m), 7.53 (2H, d, J = 8.6Hz), 7.64 (2H, d, J = 8.6 Hz)

16 c) 1— (p—Cyanault a— (1,4-benzodioxane-16-yl) benzyl) Imidazole * hydrochloride

The same treatment as in Reference Example 7c was carried out using P-cyano a- (1,4-benzodioxane-1-6- ^ f) benzyl chloride (102 mg) and imidazole (243 mg). However, silica gel column chromatography (hexane monoethyl acetate) (1: 2)) to give 1- (p-cyanol α- (1,4-benzodioxane-16-yl) benzyl) imidazole (92 mg), which was dissolved in methanol and hydrogen chloride was added. After stirring for 5 minutes, the msr.

1- (P-Cyanau α- (1,4-benzodioxane-16-yl) benzyl) imidazole hydrochloride was obtained.

Customer (CDsOD) 4.26 (4H, s), 6.75 (1H, dd, J = 2.0, 8.3Hz), 6.79 (1H, d, J = 2.0Hz), 6.93 (1H, d, J = 8.3Hz), 7.06 (1H, s) „7.39 (2H, d, J = 8.3Hz), 7.58 (lH.m), 7.66 (lH, m), 7.82 (2H, d, J = 8.3Hz), 8.86 (lH, m)

(Reference Example 17)

1- (p-cyano α- (1,4-benzodioxane-1-6-yl) benzyl) 1,1,3,4-triazole

Using 1,2,4-triazole (243 mg) and p-simmer a- (1,4-benzodioxane-16-yl) benzyl chloride (100 mg) obtained in Reference Example 16b The same treatment as in Reference Example 7c was performed. Purification by silica gel column chromatography and elution with hexane monoacetate (1: 4) yielded 11- (p-cyano α- (1,4, benzodioxane-16-yl) benzyl) benzyl. -1,3,4-Triazole (47 mg) was obtained.

Awake (CDCla) 4.28 (4H, s), 6.55 (1H, s), 6.60-6.65 (2H, m), 6.30 (1H, d, J = 9.2Hz), 7.20 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.6Hz), 8.07 (2H, s)

(Reference Example 18)

1- (p-cyano α- (1,4,1-benzodioxane-1-6-yl) benzyl) — 1,2,4-triazole

Purification was performed by silica gel column chromatography in the same manner as in Reference Example 17. From the fraction eluted with hexane monoacetate (1: 4), 1- (ρ-cyano α- (1,4benzodioxane) was purified. 6-yl) Benzyl) After elution of 1,3,4-triazole (47 mg), fractions eluted with ethyl acetate were added to the fraction (p-cyano α- (1,4 benzodioxane). 6-yl) benzyl-1), 2,4-triazole (56 mg) was obtained. NMR (CDCla). 4.26 (4H, s), 6.66-6.70 (3H, m), 6.89 (1H, d, J = 9.2Hz), 7.18 (2H, d, J = 8 OHz), 7.66 (2H, d, J = 8. OHz), 7.97 (1H, s), 8.03 (1H, s)

(Reference example 19)

1- (p-cyano α- (1,2-methylenedioxy-1-phen-4-yl)) midazole hydrochloride

1 9 a) p-cyano-α- (1,2-methylenedioxy-1-phen-4-yl) benzyl alcohol,

Reference Example 1 using η-butyllithium (1.65 M hexane solution, 3 mL), 4-bromo-1,2-methylenedioxybenzene (0.6 mL), and p-cyanobenzaldehyde (658 mg). Treated as in a. However, the product was purified by silica gel column chromatography (ethyl hexane monoacetate (1: 3 ')) to give p-cyano α- (1,2-methylenedioxy-phen-141-yl) benzyl alcohol (93 6 mg) I got

Sat (CDCla) 2.36 (1H, d, J = 3.3Hz), 5.78 (1H, d, J = 3.3Hz), 5.93-5.98 (2H, m), 6.76 7 (1H, d, J = 8. OHz) , 6.773 (1H, d, J = 2.OHz), 6.81 (1H, dd, J = 2.0,8 OHz), 7.50 (2H, d, J = 8.6Hz), 7.62 (2H, d, J = 8.6 Hz)

1 9 b) p-cyano cr-1 (1,2-methylenedioxy-1-phen-4yl) benzyl chloride

Using p-cyanore α- (1,2-methylenedioxy-1-phenyl) benzyl alcohol (926 mg) and thionyl chloride (0.47 mL) in the same manner as in Reference Example 1b, p-cyanol α— ( 1,2-Methylenedioxy-1-phen-4-yl) benzyl chloride (962 mg) was obtained.

NMR (CDC) 5.97 (2H, s), 6.05 (1H, s), 6.74-6.83 (3H, m), 7.54 (2H, d, J = 8.6 Hz), 7.65 (2H, d, J = 8.6 Hz)

1 9 c) 1-(p-cyano α- (1,2-methylenedioxy-1-phen-14-1-benzyl:) benzyl) imidazole 'hydrochloride

Reference Example 7c was prepared using P-cyano-a- (1,2-methylenedioxy-1-phen-141-yl) benzyl chloride (114 mg) and imidazole (286 mg). The same treatment was performed. However, it can be purified by silica gel column chromatography (ethyl hexane monoacetate (1: 3)) and purified by elution with 1- (P-cyano α- (1,2-methylenedioxyphen-14-1yl) benzyl) imidazole ( 107 mg), which was dissolved in methanol. An ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. The solvent was distilled off under reduced pressure to remove 1- (p-cyano α- (1,2-methylenedioxyphene). -4-yl) benzyl) imidazole 'hydrochloride was obtained.

NR (CDaOD) 6.02 (2H, s), 6.76-6.81 (2Η, m), 6.90 (1Η, d, J = 8.ΟΗζ), 7.11 (lH, s), 7.40 (2Η, d, J = 8.0Hz), 7.59 (lH.s), 7.66 (1H, s), 7.82 (2H, d, J = 8.0Hz), 8.88 (1H, s) (Reference Example 20)

4- (p-cyano-α- (1, .4-benzodioxane-1 6- ^ Τ) benzyl) imidazole hydrochloride

To a methylene chloride solution (3 mL) of titanium tetrachloride (180 L) was added a methylene chloride solution (3 mL) of N-trimethylsilylimidazole (240 juL), and the mixture was stirred at room temperature for 30 minutes. A methylene chloride solution (3 mL) of p-cyano α- (1,4-benzodioxane-16-yl) benzyl chloride (10 mg) obtained in the above was added, and the mixture was stirred for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was extracted with 1 N hydrochloric acid, the hydrochloric acid layer was neutralized with a 1 N aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate), and 41- (P-cyano α- (1,4-benzodioxane-1-6-yl) benzyl) imidazole was purified. Obtained. This was dissolved in methanol, an ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. The solvent was distilled off under reduced pressure to obtain 41- (ρ-cyano α- (1,4-benzodioxane-16-yl) benzyl) imidazole 'hydrochloride (61 mg) 麵 (D ₂₀ ) 4.28 (4H, s), 5.65 (1H, s), 6.76 (1H, d, J = 8.2Hz), 6.78 (1H, s), 6.92 (1H, d, J = 8.2Hz), 6.98 (1H, s) ), 7.40 (2H, d, J = 8.2Hz), 7.74 (2H, d, J = 8.2Hz), 8.67 (1H, s) (Reference example 21) 1- (p-cyano α- (5-pyrimidyl) benzyl) 1,1,4-triazole

2 1 a) Ciano-a- (5-pyrimidyl) benzyl alcohol

The same treatment as in Reference Example la was performed using n-butyllithium (1.65 M hexane solution, 3.8 mL), 5-bromopyrimidine (1.0 g), and p-cyanobenzaldehyde (826 mg). However, purification was performed by silica gel column chromatography (hexane monoethyl acetate (1: 2)) to obtain TP-cyano a- (5-pyrimidyl) benzyl alcohol (2 16 mg).

Thigh _{(CDC1 3) 3.01 (1H,} br s), 5.95 (1H, br s), 7.53 (2H, d, J = 8.6Hz), 7.70 (2H, d, J = 8.6Hz), 8.71 (2H, s ), 9.14 (lH, s)

2 1 b) p-cyano ct- (5-pyrimidyl) benzyl chloride

Using P-cyano α- (5-pyrimidyl) benzyl alcohol (48 mg) and thionyl chloride (50 uL) in the same manner as in Example lb, P-cyano α- (5-pyrimidyl) benzyl chloride ( 40 mg).

Awakening: _{(CDC1 3) 6.12 (1H,} s), 7.50 (2H, d, J = 8.6Hz), 7.70 (2H, d, J = 8.6Hz), 8.76 (2H, s), 9.20 (lH, s)

2 1 c) 1- (p-cyano α- (5-pyrimidyl) benzyl) 1,1,2,4-triazole

The same treatment as in Reference Example 7c was carried out using P-cyano a— (5-pyrimidyl) benzyl chloride (51 mg) and 1,2,4-triazole (153 mg), and Cyanol α- (5-pyrimidyl) benzyl) 1,1,2,4-triazole (27 mg) was obtained.

Image (CDCla) 6.78 (1H, s), 7.33 (2H, d, J = 8.6Hz), 7.73 (2H, d, J = 8.6Hz), 8.09 (1H, s), 8.22 (lH, s), 8.66 (2H, s), 9.25 (lH, s)

(Reference Example 22) 1- (p-cyano a- (1,2,3,4-tetrahydronaphthalen-1-yl) benzyl) imidazole 'hydrochloride

22 a) p-cyano α- (1,2,3,4-tetrahydronaphthalene 1-2-benzyl alcohol n-Butyllithium (1.65M, hexane solution) (1.4ml), p-bromobenzonitrile (409mg) and 1,2,3,4-tetrahydronaphthalene-l2-carboxaldehyde (360mg) In the same manner as in Reference Example 7a, p-cyano α- (1,2,3,4-tetrahydronaphthalene-12-yl) benzyl alcohol (380 mg) was obtained.

_{NMR (CDC1 3) 1.38-1.81 (2H} , m), 2.02-2.33 (2Η, m), 2.46-2.98 (4H, m), 4 .63 & 4.69 (total 1H, each dd, J = 3.3, 6.6Hz ), 6.93-7.13 (4H, m), 7.48 & 7.50 (total 2H, each d, J = 7.9Hz), 7.67 (2H, d, J = 7.9Hz)

22 b) _p-cyano-a- (1,2,3,4-tetrahydronaphthalene-1-yl) benzyl chloride '

P-Cyanore a— (1,2,3,4-tetrahydronaphthylene-1-yl) Dissolve benzyl alcohol (102 mg) in ethyl acetate (3 ml) and add thionyl chloride (140 u 1). The mixture was refluxed for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to remove P-cyano a- (1,2,3,4-tetrahydronaphthalene-1-yl) benzyl chloride ( 11 mg).

_{NMR (CDC1 3) 1.36-1.78 (2H} , m), 2.30-2.55 (2Η, m), 2.63-3.20 (3H, m), 4 .75 (d, J = 8.9Hz) & 4.80 (d, J = 7.6Hz) (total 1H), 6.8 & -7.18 (4H, m), 7.52 & 7.58 (total 2H, each d, J = 7.9Hz), 7.69 (2H, d, J = 7.9Hz)

22 c) 1- (p-cyano-α- (1,2,3,4-tetrahydronaphthalene-12-yl) benzyl) imidazole 'hydrochloride'

Using P-cyanoa- (1,2,3,4-tetrahydronaphthalene-12-yl) benzyl chloride (111 mg) and imidazole (134 mg) in the same manner as in Reference Example 7c , 1- (P-Cyanau a- (1,2,3,4-tetrahydronaphthalene-1-yl) benzyl) imidazole was obtained. This was purified by preparative tic (ethyl acetate) to convert 1- (P-cyano-a- (1,2,3,4-tetrahydronaphthalene-1-2-yl) benzyl) imidazole into both isomers. divided. Dissolve each isomer in methanol, add a solution of hydrogen chloride in ether, stir for 5 minutes, q_ Interview ₉ _- Ma, (suio 0 T) ¾ ( Γ /: (Γ -z- ^^ c - ^^^ A ^ -9) - Ku, one a) -τ ^ m ^ \.

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60SlO / e6df / JDd £ 1680 / ^ 6 OAV (Test Example 1)

The aromatase inhibitory activity of the compounds of the present invention can be determined by an improved method of Douglas F. Covey et al. (Journal of Biological Chemistry, 256, 1076-1079, 1981). Proven by. ^{That, 1 uM [19 - 14 C} ] - androstenone - 3.17- dione, O.lm NADPH, and a small amount of dimethyl sulphoxide mediation Si buffer one containing the test I arsenide compound dissolved in de (1 Omm potassium phosphate buffer (HP7.5), 10 Om potassium chloride, ImMethylenediaminetetraacetic acid, 4% propylene glycol) and add 12.5 / 1 g of protein as a microsomal protein prepared from human placenta. The final volume of the solution was adjusted to 0.5 mL, and the mixture was reacted at 37 ° C for 30 minutes. The reaction was stopped by adding 2.5 mL of black-mouthed form, stirred with a vortex mixer for 40 seconds, and centrifuged at 2000 rpm for 5 minutes. The aqueous layer 100 L was added to the scintillation one coater of 3 mL, the results obtained by measuring the count of free H ¹⁴ CO_〇_H by comparing inhibitor and results pair irradiation test tested without adding , conversion percent inhibition to estrone from androstenone dione seek {%) was determined 50% inhibitory concentration (1 _5. value) graphically. I _s of the compounds of the present invention. The values are shown in Table 2.

2 Example _i0 (nM)

1 4.6

3 5.1

5 8.0

7 6.3

8 3.7

10 7.9 As shown in Table 2, the compounds of the present invention have high inhibitory activity against aromatase. W

7 7 shown.

(Formulation example 1) (Hard capsule)

Manufacture unit capsules by filling each of the standard bisected hard gelatin capsules with 100 mg of the compound of Example 27 in powder form, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate After washing, it was dried. (Formulation Example 2) (Tablets)

In a conventional manner, 100 mg of the compound of Example 27, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 rag of starch and 98.8 mg Of lactose.

In addition, the skin was applied as required.

(Formulation Example 3))

1.5 parts by weight of the compound of Example 27 was stirred in 10 parts by volume of propylene glycol, made up to a constant volume with water for injection, and then sterilized to produce.

(Formulation Example 4) (Suspension)

In 5 ml, 100 mg of the micronized compound of Example 27, 100 mg sodium carboxymethylcellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (Japanese Pharmacopoeia) and 0.025 ral Of vanillin.

Claims

-General formula (1)

(Re

(In the formula, R ¹ may be substituted with a methyl or ethyl group. 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, 1-1- (1,3,4 ) Triazolyl, 1- (1 2,3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, wherein R ² is naphthyl which may be substituted with a substituent selected from the following group; A phenanthryl or anthryl group, R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms) and a salt thereof.

[Group A] an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyl group having 1 to 6 carbon atoms, an aromatic acyloxy group, a hydroxyl group, and a carbon number having 1 to 4 Aliphatic acylamino groups, alkoxy-substituted alkoxy groups, alkoxy-substituted aliphatic acyloxy groups, trialkylsilyloxy groups

2 · General formula (1)

(

(Wherein, R ¹ may be substituted with a methyl or ethyl group. 1-imidazolyl, 4-imidazolyl, 5-imidazoli, 1- (1,2,4) triazoli Λ., 1— (1, 3, 4) triazolyl, 1- (1, 2, 3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, wherein R ² is naphthyl which may be substituted with a substituent selected from the following group A ′; A phenanthryl or anthryl group, and R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms) and a salt thereof.

3. General formula (1)

(Wherein R ¹ may be substituted with a methyl or ethyl group, 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl,

1- (1,3,4) triazolyl, 1- (1,2, '3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, and R ² is a substitution selected from the following group A''' A naphthyl group which may be substituted with a group, an unsubstituted phenanthryl or an unsubstituted anthryl group, and R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms) and Its salt.

4. General formula (1

(Re

1-(1,3,4) triazolyl, 1- (1,2,3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, and R ² is a substituent selected from the following A '''' group A substituted naphthyl, an unsubstituted phenanthryl group or an unsubstituted anthryl group, and R ³ represents a hydrogen atom, a methyl or a cyano group) and salts thereof.

[Α '' 'group] methyl group, methoxy group, acetoxy group, methoxyacetoxy group

5. General formula (1)

(Wherein R ¹ is 1-imidazolyl, 5-methyl-11-imidazolyl, 4-imidazolyl, 1-methyl-5-imidazolyl, 1-1 (1,2,4) triazolyl, 1-1 (1,2,3) R ² represents a triazolyl or 2-tetrazolyl group, R ² represents a naphthyl which may be substituted with a substituent selected from the following group A ′ ′ ″, unsubstituted phenanthril or unsubstituted anthryl group, and R ³ represents Represents a hydrogen atom) SI compounds and salts thereof.

[Α '' 'group] methyl group, methoxy group, acetoxy group, methoxyacetoxy group

6. Compound selected from the following compound group.

4- (Icano-1- (naphthalene-1-yl) benzyl) imidazole, 1-(-Icano-1 (2- (phenanthrene-1-9-1) benzyl) imidazole,

1— (Ρ—Cyaneau α— (Anthracene 9-yl) benzyl) Imidazole

1- (ρ-Cyanore α- (6-Methoxynaphthalene-2-yl) benzyl) midazole,

1- (ρ-cyano α- (6-methoxyethoxynaphthalene-1-yl) benzyl) imidazole,

5- (ρ-cyano-α- (2-naphthyl) benzyl) 1-1-methylimidazole,

1- (ρ-Cianeau α- (2-naphthyl) benzyl) — 1, 2, 4-triazole

1- (ρ-cyano-α- (3,5-dimethoxyxinaphthalene-1-yl) benzyl) 1 1,2,4-triazolyl,

1— (ρ—cyanone α— (1,4-dimethoxynaphthalene-1-yl) benzyl) 1 1,2,4-triazolyl, '

1- (ρ-cyano α-methyl-α- (6-methoxymethoxyphthalene 2-yl) benzyl) imidazole,

1- (ρ-cyano α- (anthracene-91-yl) benzyl) 1 1,2,4-triazole,,

1-(ρ—Cyaneau α— (Naphthylene-1-yl) benzyl) 1,1,2,4-triazole,

1— (ρ—Cyaneau α— (Fenansulen-1-yl) benzyl) 1 1, 2, 4 Triazole,

1- (p-cyano α-methyl-1-α- (naphthylene-1-yl) benzyl—1,2,4-triazole

7. An inhibitor of aromatase activity, comprising an effective amount of a pharmaceutically acceptable salt of the compound of claim 1 together with a pharmaceutically acceptable carrier or excipient.

8. An inhibitor of aromatase activity, comprising an effective amount of a pharmacologically acceptable salt of a compound selected from the following compound group together with a pharmaceutically acceptable carrier or excipient.

4- (ρ-cyano α- (naphthalene-2-yl) benzyl) imidazole, 1-1 (ρ-cyano α- (phenanthrene-1-yl) benzyl) imidazole,

1— (ρ—Cyaneau α— (Anthracene-91-yl) benzyl) Imidazole

1- (ρ-Cyanaw α- (6-Methoxy-naphthylene-2-yl) benzyl) midazole,

1-(ρ-Cyanaw-Hi-I (6-Methoxyethoxy-naphthalene-1-yl) benzyl) imidazole,

5- (ρ-cyano-α- (2-naphthyl) benzyl) 1-1-methylimidazole,

1— (ρ—Cyanault α— (2-naphthyl) benzyl) 1,1,4—triazole,

1- (ρ-cyano α- (3,5-dimethoxynaphthalene-1-yl) benzyl) 1-1,2,4-triazole,

1— (ρ—Cyanaw α— (1,4 dimethoxynaphthalene-1-yl) benzyl) — 1, 2, 4—triazole,

1-(ρ-cyano-α-methyl-α- (6-methoxy-2-phthalene-2-yl) Benzyl) imidazole,

1— (P-cyano α——9-1yl) benzyl) 1,1,2,4-triazole,

1-(ρ—Cyaneau α— (Naphthalene 1-yl) 1 1, 2,4-1 Triazole,

1- (ρ-cianeau α- (phenanthrene-1-yl) benzyl) 1-, 1,2-triazole,

1- (ρ-cyano α-methyl-1-α- (naphthalene-11-yl) benzyl) -1-1,2,4-triazole

9. A therapeutic agent for a female estrogen-dependent disease, comprising an effective amount of a pharmacologically acceptable salt of the compound of claim 1 together with a pharmaceutically acceptable carrier or excipient.

10. Treatment of female estrogen-dependent disease, containing an effective amount of a pharmacologically acceptable salt of a compound selected from the following compound group together with a pharmaceutically acceptable carrier or excipient. Agent.

4- (ρ-cyano α- (naphthalene-1-yl) benzyl) imidazole, 1- (ρ-cyano α- (phenanthrene-1-yl) benzyl) imidazole,

1— (ρ—Cyanault α— (Anthracene 9-yl) benzyl) imidazole

1- (ρ-Cyanaw α- (6-Methoxynaphthalene-1-yl) benzyl) midazole,

1- (ρ-Cyanol α- (6-Methoxyacetoxynaphthalene-1-yl) benzyl) imidazole,

5- (ρ-cyano α- (2-naphthyl) benzyl) 1-methylimidazole,

1-(ρ-Cyanau α- (2-naphthyl) benzyl) 1-, 2, 4-triazo Tool,

1- (p-cyano α- (3,5-dimethoxynaphthalene-1-yl) benzyl) 1-1,2,4-triazole,

1— (ρ—Cyanaw α— (1,4-Dimethoxyxinaphthalene-1-yl) benzyl) 1-1,2,4-Triazole,

1- (ρ-Cyanore α-methyl-1-α- (6-methoxynaphthalene-2-yl) benzyl) imidazole,

1— (ρ—cyanone α— (anthracene-9-yl) benzyl) -1,2,4-triazole,

1- (ρ-cyano-α- (naphthylene-1-yl) benzyl) 1,1,2,4-triazole,

1— (ρ—Cyanone α— (Fenansulene 91-yl) benzyl) 1,1,2,4-Triazole,

1- (ρ-cyano-α-methyl-α- (naphthalene-11-yl) benzyl) — 1,2,4-triazolyl

11. A therapeutic agent for breast cancer, comprising an effective amount of a pharmacologically acceptable salt of the compound of claim 1 together with a pharmaceutically acceptable carrier or excipient.

12. A therapeutic agent for breast cancer, comprising an effective amount of a pharmacologically acceptable salt of a compound selected from the following compound group together with a pharmaceutically acceptable carrier or excipient.

4- (ρ-cyano α- (naphthalene-2-yl) benzyl) imidazole, 1- (ρ-cyano α- (phenanthrene-1 9-yl) benzyl) imidazole,

1- (ρ-Cyanault α- (Anthracene-9-yl) benzyl) imidazole

1- (ρ-cyano a- (6-methoxynaphthalene-2-yl) benzyl) midazole, 1- (p-cyano α- (6-methoxyacetoxynaphthalene-1-yl) benzyl) imidazole,

5- (ρ-cyano-α- (2-naphthyl) benzyl) 1-methylimidazole,

1- (ρ-Cyanau α- (2-naphthyl) benzyl) 1-, 2,4-triazole,

1— (ρ—cyano-1α— (3,5-dimethyloxynaphthalene-2-yl) benzyl) 1 1,2,4-triazolyl,

1— (ρ—Cyanaw α— (1,4-dimethoxynaphthalene-1-yl) benzyl) 1-1,2,4-triazolyl,

1- (ρ-cyano-α-methyl-1-α- (6-methoxynaphthalene-2-yl) benzyl) imidazole,

1- (ρ-Cianeau α- (Anthracene-91-yl) benzyl) 1,1,2,4-Tritriazole,

1- (ρ-cyano-α- (naphthalene-11-yl) benzyl) 1,1,2,4-triazole,

1- (ρ-cyano-α- (phenanthrene-91-yl) benzyl) -1,2,4-triazole,

1- (ρ-cyano-α-methyl-α- (naphthalene-11-yl) benzyl)-1,2,4-triazolyl 3.

In an inert solvent, general formula (（)

(In the formula, R ² represents a naphthyl, phenanthryl or anthryl group which may be substituted with a substituent selected from the following group A, and R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms. And Z ³ represents an alkylsulfonyloxy group having 1 to 4 carbon atoms, an arylsulfonyloxy group having 6 to 10 carbon atoms, or a halogeno group which may be substituted with a halogen atom. , Azole compound R ¹ H (R ¹ may be substituted with a methyl or ethyl group. 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, 1- (1 , 3,4) Triazolyl (1, 2,3) represents a triazolyl, 1-tetrazolyl or 2-tetrazolyl group.

(R

(Wherein, R ¹ , R ² and R ³ have the same meanings as described above.).

[Group A] Alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, aliphatic acyloxy group having 1 to 6 carbon atoms, aromatic acyloxy group, hydroxyl group, 1 to 4 carbon atoms Aliphatic acylamino group, alkoxy substituted alkoxy group, alkoxy substituted aliphatic acyloxy group, trialkylsilyloxy group

14.

In an inert atmosphere, in an inert solvent, in the presence of a base, the general formula (1)

S 7

(Wherein R ¹ may be substituted with a methyl or ethyl group, such as 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, 1- (1,3, 4) Triazolyl (1-, 2, 3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, wherein R ² is a naphthyl, funananthryl or anthryl group which may be substituted with a substituent selected from the following group A Wherein R ³ represents a hydrogen atom.) In the compound of formula (I), an alkyl halide R ^3a Z ⁴ (where R ^3a represents an alkyl group having 1 to 4 carbon atoms or a cyano group, and Z ⁴ represents a halogeno group) Or a reaction with a cyanating agent to obtain a compound of the general formula (1a)

(Wherein, R ¹ , R ² and R ^3a have the same meanings as described above.).

Fifteen

General formula (7)

(Wherein, R ² is naphthyl which may be substituted with a substituent selected from the following group A) , A phenanthryl or anthryl group, R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms, and Z ³ represents an alkylsulfonyloxy group having 1 to 4 carbon atoms or 6 to 10 carbon atoms. Represents an arylsulfonyloxy group or a halogeno group. 1) trimethylsilylimidazole is reacted with the compound of formula (1) in the presence of titanium tetrachloride in an inert atmosphere in the presence of titanium tetrachloride.

General formula (1)

(R

(Wherein, R ¹ represents an unsubstituted 5-imidazolyl group, and R ² and R ³ have the same meanings as described above).

(In the formula, R ¹ may be substituted with methyl or ethyl group. 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, 1- (1,3,4 ) Triazolyl 1-1 (1, 2, 3) Triazolyl, 1-tetra Represents a zolyl or 2-tetrazolyl group; R ² represents a naphthyl, phenanthryl or anthryl group substituted by a trialkylsilyloxy group; R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms. Show. ), The trialkylsilyl group is removed to obtain a compound of the general formula (lb)

(Wherein, R ¹ and R ³ have the same meanings as described above, and R ^2a represents a naphthyl, phenanthryl or anthryl group substituted with a hydroxyl group).

17

—General formula (l b)

(Wherein, R ¹ may be substituted with a methyl or ethyl group, such as 1-imidazolyl, 4-imidazolyl, 5-^ — midazolyl, 1- (1,2,4) triazolyl,

1 one (1, 3, 4) Toriazoriru 1 i (1, 2, 3) Toriazoriru, 1-tetra Zoriru or indicates 2-tetrazolyl group, R ^za represents a substituted naphthyl, full Yunansuriru or anthryl group with a hydroxyl group And R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms. ) Is reacted with an acylating agent in an inert solvent in the presence of a base to give a compound of the formula (1c)

(In the formula, R ¹ and R ³ have the same meanings as described above, and R ^2b represents a naphthyl, phenanthryl or anthryl group substituted with an aliphatic or aromatic acyloxy group or an alkoxyacyloxy group. ).

18

In an inert solvent, general formula (10)

(Wherein, R ² represents a naphthyl, phenanthryl or anthryl group which may be substituted with a substituent selected from the following group A, and R ³ represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms. And R ⁴ represents a methyl or ethyl group.) Ammonia is reacted with the compound represented by the general formula (Id)

(Wherein, R ² , R ³ and R ⁴ have the same meanings as described above.).

[Group A] an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, C1-C6 aliphatic acyloxy group, aromatic-acyloxy group, hydroxyl group, C1-C4 aliphatic acylamino group, alkoxy-substituted alkoxy group, alkoxy-substituted aliphatic acyloxy group, trialkylsilyloxy group