JPH0841032A - New azole methylphenyl derivative having aromatase-inhibiting action - Google Patents

Abstract

PURPOSE:To provide a new compound exhibiting an excellent aromatase- inhibiting activity, high in specificity and safety, and useful for preventing and treating estrogen-dependent diseases and as a female birth-controlling agent. CONSTITUTION:The compound of formula I (A is methylene, O, S; D is N, methine; R<1> is halogen, cyano, nitro, etc.; R<2> is group of formula II, etc.,) or its salt, e.g. 6-[4-ch1oro-2-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]-1-methyl-1H- benzotriazole. The compound of formula I is obtained by reacting a benzyl halide derivative or benzyl alcohol derivative of formula III (R<5> is halogen, OH) with an azole compound of formula IV. The compound of formula I is useful for preventing and treating estrogen-dependent cancers such as breast carcinoma, ovarian cancer and corpus uteri cancer, endometritis, hysteromyoma, benign breast diseases, mastitis, birth precox, prostatic hypertrophy, prostatic cancer, precocious puberty, gynecomastiamale sterility, biliary calculus, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel azole methylphenyl derivative, a method for producing the same, an aromatase inhibitor containing the same, and a pharmaceutical composition useful as a preventive and / or therapeutic agent for an estrogen-dependent disease containing the same. It is about things.

[0002]

Aromatase catalyzes the aromatic ring cyclization of the A-ring of the steroid skeleton in a series of steroid biosynthetic pathways initiated by side chain cleavage of cholesterol, namely the conversion of androstenedione to estrone and testosterone. It is a P450-based enzyme that catalyzes the conversion of methionine into estradiol, and is a rate-limiting enzyme in the estrogen biosynthesis system.

Therefore, a compound having an aromatase inhibitory action has an estrogen biosynthesis inhibitory action. Further, when administered to a living body, a decrease in blood estrogen concentration is expected. Therefore, it is considered that estrogen may be applied to various diseases (estrogen-dependent diseases) associated with the onset and exacerbation of pathological conditions.

[0004] Such estrogen-dependent diseases include estrogen-dependent cancers (breast cancer, ovarian cancer, endometrial cancer, etc.), endometriosis, uterine fibroids, benign breast diseases (fibrocystic mastopathy), and mastopathy. , Preterm labor, benign prostatic hyperplasia, prostate cancer, precocious puberty, gynecomastia, and male infertility or cholelithiasis associated with oligospermia.

In the treatment of estrogen-dependent diseases, a method of inhibiting the estrogen action in target cells and a method of lowering the estrogen concentration itself in blood have been considered. As a representative of the former, administration of an estrogen antagonist such as tamoxifen has been performed, but it has not been clinically sufficiently satisfactory.
In addition, as a representative of the latter, the ovary, which is the main estrogen producing organ, is removed by surgical treatment in order to cut off the production of estrogen. However, such a surgical treatment involves a problem of quality of life (QOL) due to the removal of a woman's original functional organ. In postmenopausal female patients, it is difficult to reduce blood estrogen levels by ovariectomy.
This method has limitations and problems in clinical application, such as not being applicable to male patients and being unable to cope with estrogen produced by cancer cells themselves. For these,
As a medical treatment method, an aromatase inhibitor, which is a synthetic inhibitor of estrogen, is expected to have a therapeutic effect on an estrogen-dependent disease, since it can obtain a low estrogen state while maintaining QOL. In addition, it is expected to be applied to estrogen antagonist ineffective cases and postmenopausal female and male patients.

Aminoglutethimide (AG), which has a weak aromatase inhibitory action, is used in part for the treatment of breast cancer. However, since AG has a strong inhibitory effect on cholesterol side chain cleaving enzyme and causes a decrease in glucocorticoids and electrolyte corticoids, which are essential for life support, replacement therapy with these hormones is unavoidable and widely used in clinical settings. Has not arrived.

Further, aromatase inhibitory activity has also been found in imidazole derivatives of miconazole, clotrimazole and ketoconazole, which have been developed and used clinically as antifungal agents (Biochemical Pharmacology).
34 ), 1087-1092, 1985). However, these drugs have not been used as therapeutic agents for estrogen-dependent diseases, probably because sufficient enzyme inhibition specificity has not been obtained.

The aromatase inhibitors reported so far are roughly classified into steroidal and nonsteroidal ones in terms of structure. Steroid aromatase inhibitors include test lactone and 4-hydroxyandrostenedione, but test lactone does not show sufficient therapeutic effect, and these are poorly absorbed orally and have side effects specific to steroids. Is expected and not clinically satisfactory.

On the other hand, focusing attention on non-steroidal aromatase inhibitors, the following reports have been made. JP 61-
Although 12671 describes N-substituted imidazole and triazole compounds, the aromatase inhibitory action of these compounds is weak and the enzyme selectivity is unknown. Substituted bicyclic compounds are described in JP-A-61-2688. CG, one of these compounds
S16949A has been reported to inhibit the aldosterone biosynthesis system, and the enzyme selectivity is not sufficient. JP 63-
Although a benzotriazole derivative is described in Japanese Patent No. 316775, there is no description about the enzyme selectivity of these compounds, and in fact the selectivity is not sufficient. JP-A 1-29
No. 0663 discloses N-substituted imidazole, but it does not describe activity in vivo, and does not disclose pharmacological data on selectivity. However, in reality, the benzyloxy-substituted imidazole has weak activity in vivo. That is, it is unclear whether these prior arts can be clinically used because there is no disclosure of aromatase inhibitory activity in vivo, or even if there is disclosure, the action is weak and the enzyme selectivity is not sufficient.

[0010]

SUMMARY OF THE INVENTION An object of the present invention is to solve at least one of the problems in the prior art as mentioned above. At present, there is a demand for the development of a drug which has a high enzyme selectivity, selectively inhibits only aromatase and does not require supplementation with adrenocortical hormones, etc., and has a sufficient action in vivo. In other words, a small dose surely lowers the level of estrogen in vivo, has no effect on other steroid hormone synthesis systems in the adrenal gland and gonads, has no effect on drug metabolism related to cytochrome P450 in the liver, and has few side effects and safety High drug is desired. The object of the present invention is to provide a high aromatase inhibitor with high enzyme selectivity, to exert a sufficient aromatase inhibitory action in vivo, and also to provide an aromatase inhibitor with high enzyme selectivity, To provide a prophylactic and / or therapeutic agent for estrogen-dependent diseases with few side effects and high safety, to provide an azole methylphenyl derivative useful for those uses, and a method for producing the same, at least one of them To provide more than one.

[0011]

[Means for Solving the Problems] The present inventor selectively inhibits only aromatase among the many P450 enzymes involved in steroid biosynthesis, and has high specificity in animals,
As a result of earnest research to obtain a useful and highly safe non-steroidal inhibitor, it was found that a specific azole methylphenyl derivative and a salt thereof have potent and selective aromatase inhibitory activity, and the present invention was completed. I arrived.

A first aspect of the present invention is represented by the following formula (I)

[0013]

[Chemical formula 26]

(Wherein A represents a methylene group, an oxygen atom or a sulfur atom, D represents a nitrogen atom or a methine group, R ¹ represents a halogen atom, a cyano group, a nitro group, one or more fluorine atoms. A C 1 -C 2 alkoxy group which may be substituted with, a C 1 -C 2 alkyl group which may be substituted with one or two or more fluorine atoms, a C 2 -C 5 straight chain or Represents a branched alkenyl group, a linear or branched alkynyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group or a hydrogen atom, and R ² represents Formula (II)

[0015]

[Chemical 27] Or formula (III)

[0016]

[Chemical 28]

In the formula, E represents a nitrogen atom or a methine group, and R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. )
Is a novel azole methylphenyl derivative compound represented by or a salt thereof.

Preferred combinations of the substituents in the compound represented by the above formula (I) are shown below, but the present invention is not limited thereto.

As the combination of A, R ¹ and R ² , A is preferably an oxygen atom, the substitution position of R ¹ is preferably the 4-position, and R ² is an atomic group represented by the above formula (III). A combination in which the bonding position is the 6th position is preferable.

In addition to this combination, those in which D is a nitrogen atom are preferred.

Further, it is preferable that E is a nitrogen atom and R ³ is a methyl group.

Further, R ¹ is more preferably a halogen atom, a cyano group or a nitro group.

Further, it is more preferable that R ¹ is a vinyl group or an ethynyl group.

The most preferred compounds of the present invention have the formula (IV)

[0025]

[Chemical 29]

(In the formula, R ⁴ is a halogen atom, a cyano group,
Represents a nitro group, vinyl group or ethynyl group. ) Is a compound or a salt thereof.

A second aspect of the present invention is a method for producing the derivative compound (Production Methods 1 to 3).

(Production Method 1) The following formula (IX)

[0029]

Embedded image

(In the formula, A represents a methylene group, an oxygen atom or a sulfur atom, and R ¹ represents a halogen atom, a cyano group, a nitro group, a carbon number which may be substituted with one or more fluorine atoms. 1 to 2 alkoxy group, 1 to 2 carbon atom alkyl group optionally substituted with 2 or more fluorine atoms, 2 to 5 carbon chain straight or branched alkenyl group, carbon number E represents a linear or branched alkynyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group, or a hydrogen atom, and is described in the definition of R ² and R ^2. And R ³ has the same meaning as in the above formula (I), and R ⁵ represents a halogen atom or a hydroxyl group.)
A halogenated benzyl derivative, a benzyl alcohol derivative or a salt thereof represented by the following formula (X)

[0031]

[Chemical 31]

By reacting with an azole compound represented by the formula (wherein D represents a nitrogen atom or a methine group), the following formula (I)

[0033]

Embedded image

(Wherein E and R ³ in the definitions of A, D, R ¹ , R ² and R ² have the same meanings as described above), or a salt thereof. Is the way.

(Production Method 2) The following formula (VII)

[0036]

[Chemical 33]

(In the formula, G represents an oxygen atom or a sulfur atom, R ¹ represents a halogen atom, a cyano group, a nitro group, or 1 or 2 carbon atoms which may be substituted with at least two fluorine atoms. Alkoxy group, an alkyl group having 1 to 2 carbon atoms which may be substituted with one or more fluorine atoms, a straight chain or branched alkenyl group having 2 to 5 carbon atoms, and 2 to 5 carbon atoms. Represents a linear or branched alkynyl group, an alkoxycarbonyl group having 1 or 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group or a hydrogen atom, R ⁵ represents a halogen atom or a hydroxyl group, and R ⁶ represents the following formula: (II)

[0038]

Embedded image Or the following formula (XI)

[0039]

Embedded image

In the formula, R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ) A halogenated benzyl derivative or a benzyl alcohol derivative or a salt thereof represented by the following formula (X)

[0041]

Embedded image

(Wherein D has the same meaning as described above), and reacted with an azole compound represented by the following formula (VII)
I)

[0043]

Embedded image

(In the formula, G represents an oxygen atom or a sulfur atom, D represents a nitrogen atom or a methine group, R ¹ is a halogen atom, a cyano group, a nitro group, or one or more fluorine atoms. 1 to 2 carbon atoms that may be added
An alkoxy group, an alkyl group having 1 to 2 carbon atoms which may be substituted with one or two or more fluorine atoms, a linear or branched alkenyl group having 2 to 5 carbon atoms,
Represents a linear or branched alkynyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group or a hydrogen atom, and R ⁶ represents the following formula (II).

[0045]

[Chemical 38] Or the following formula (XI)

[0046]

[Chemical Formula 39]

In the formula, R ³ has the same meaning as described above. ), An azole methylphenyl derivative represented by the formula (1) or a salt thereof is produced and, if necessary, further subjected to a reduction reaction and then a cyclization reaction.

[0048]

[Chemical 40]

(Wherein E and R ³ in the definitions of G, D, R ¹ , R ² and R ² have the same meanings as described above), or a salt thereof. Is the way.

(Production Method 3) The following formula (VI)

[0051]

Embedded image

(In the formula, G represents an oxygen atom or a sulfur atom, D represents a nitrogen atom or a methine group, R ¹ is a halogen atom, a cyano group, a nitro group, or one or more fluorine atoms. 1 to 2 carbon atoms that may be added
An alkoxy group, an alkyl group having 1 to 2 carbon atoms which may be substituted with one or two or more fluorine atoms, a linear or branched alkenyl group having 2 to 5 carbon atoms,
It represents a linear or branched alkynyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group or a hydrogen atom. ) Azolemethylphenol or an azolemethylthiophenol derivative represented by the formula) or a salt thereof, and a compound represented by the formula R ⁶ X (wherein X represents a halogen atom, R ⁶
Is the following formula (II)

[0053]

Embedded image Or the following formula (XI)

[0054]

[Chemical 43]

In the atomic group represented by the formula, R ³ has the same meaning as described above. ) Is reacted with an aryl halide represented by the following formula (VIII)

[0056]

[Chemical 44]

[0057] producing the azole-methylphenyl derivative or a salt thereof ^{(wherein, G, D, R 1,} R 6 and R ³ described R ⁶ are defining. To represent the same meaning as described above) is represented by Then, if necessary, a reduction reaction and then a cyclization reaction are carried out to obtain the following formula (I) -b.

[0058]

Embedded image

(Wherein E and R ³ in the definitions of G, D, R ¹ , R ² and R ² have the same meanings as described above), or a salt thereof. Is the way.

The third aspect of the present invention is a prophylactic and / or therapeutic agent for an estrogen-dependent disease, which comprises as an active ingredient at least one of the compounds represented by the above formula (I) or salts thereof. is there.

As a combination of A, R ¹ and R ² , A is preferably an oxygen atom, the substitution position of R ¹ is preferably the 4-position of phenol, and R ² is the above formula (III).
It is preferable that the bonding position of the atomic group represented by is 6-position.

In addition to this combination, it is preferable that D is a nitrogen atom.

Further, it is preferable that E is a nitrogen atom and R ³ is a methyl group.

Further, R ¹ is more preferably a halogen atom, a cyano group or a nitro group.

Further, it is more preferable that R ¹ is a vinyl group or an ethynyl group.

The most preferable compound useful as a prophylactic agent and / or therapeutic agent of the present invention is a compound represented by the above formula (IV) (wherein R ⁴ has the same meaning as described above) or a salt thereof. Is.

Further, a fourth aspect of the present invention is an aromatase inhibitor containing as an active ingredient at least one of the compound represented by the above formula (I) or a salt thereof.

In the formula, preferred examples of E and R ³ and most preferred compounds described in the definitions of A, D, R ¹ , R ² and R ² are the same as those in the third embodiment.

The present invention will be described in detail below.

The compound of the present invention is represented by the above formula (I). In the formula, A represents a methylene group, an oxygen atom or a sulfur atom, A excluding the methylene group is represented by G, and an oxygen atom is preferable. D represents a nitrogen atom or a methine group, and a nitrogen atom is preferable. R ¹ is a halogen atom, a cyano group, a nitro group, an alkoxy group having 1 or 2 carbon atoms which may be substituted with 1 or 2 or more fluorine atoms, and 1 or 2 or more fluorine atoms. Optionally an alkyl group having 1 to 2 carbon atoms, a straight chain or branched alkenyl group having 2 to 5 carbon atoms, a straight chain or branched alkynyl group having 2 to 5 carbon atoms, and 1 to 2 carbon atoms Represents an alkoxycarbonyl group, carboxyl group, acetyl group, formyl group or hydrogen atom, chlorine atom, bromine atom, fluorine atom, iodine atom, cyano group, nitro group, methoxy group, trifluoromethoxy group, trifluoromethyl group, ethoxy Carbonyl group, carboxyl group, acetyl group, formyl group or hydrogen atom is preferable, chlorine atom, bromine atom, iodine atom, cyano group, nitto Group, a vinyl group or more preferably an ethynyl group, the substitution position is preferably 4-position or 5-position of phenol, 4-position is more preferable.

R ² is the above formula (II) or formula (III)
The atomic group represented by the formula (III) is preferable. The bonding position of the atomic group represented by the formula (III) is preferably the 5-position or the 6-position, more preferably the 6-position. In the formula, E represents a nitrogen atom or a methine group, R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, preferably a methyl group or an ethyl group. The above bonding position will be described. The bonding position of R ¹ in the formula (I) is represented by the carbon atom to which A is bonded as the 1-position, and is, for example, the 3-position, 4-position, 5-position or 6-position. Since the formula (II) is a naphthyl group, the bonding position is represented by α-position or β-position. The bonding position of formula (III) is R ³
The bonded nitrogen atom of is represented as the 1-position, for example, 4
The 5th, 6th or 7th place.

The compound of the present invention can form a salt with an inorganic acid or an organic acid. Examples of these salts include:
Salts with inorganic acids such as hydrochlorides, sulfates, nitrates, acetates,
Examples thereof include salts with organic acids such as oxalate, P-toluenesulfonate and methanesulfonate. These salts can be obtained by a conventional method, for example, by mixing an equivalent amount of the compound of the present invention with a solution containing a desired acid and collecting the desired salt by filtering or distilling off the solvent.

The most preferred compounds of the present invention have the formula (IV)

[0074]

Embedded image

(In the formula, R ⁴ has the same meaning as described above.)
Or a salt thereof.

More specifically, 6- [4-chloro-2
-(1H-1,2,4-triazol-1-ylmethyl) phenoxy] -1-methyl-1H-benzotriazole (Example 41), 6- [4-bromo-2- (1H-
1,2,4-Triazol-1-ylmethyl) phenoxy] -1-methyl-1H-benzotriazole (Example 43), 1-methyl-6- [4-nitro-2- (1H-
1,2,4-Triazol-1-ylmethyl) phenoxy] -1H-benzotriazole (Example 50) or 4- [6- (1-methyl-1H-benzotriazoyloxy)]-3- (1H-1 , 2,4-triazole-1
-Ylmethyl) benzonitrile (Example 52).

The compound of the present invention represented by the formula (I) can be obtained by the production method shown in the following reaction scheme. The following reaction formula and formula (V) in the description

[0078]

[Chemical 47]

(In the formula, G represents an oxygen atom or a sulfur atom, and R ⁵ represents a halogen atom or an optionally substituted hydroxyl group.), Formula (I), formula (I) -b, formula (I)
I), formula (III), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula ( XIV), formula (X
V) and each compound represented by the formula R ⁶ X, and further R ¹ , R ² , R ³ , R ⁵ , R ⁶ , A, D, E,
The definitions of G and X are the same as above. Formula (I) -b
Is a formula included in formula (I).

The azole methylphenyl derivatives represented by the formula (I) which are the compounds of the present invention and their salts are synthesized by
A compound represented by the formula (V) or a compound represented by the formula (X
II) by reacting the compound represented by the formula (VII) or the formula (IX) or a salt thereof further derivatized with a commercially available azole compound represented by the formula (X) It can be manufactured.

Further, the synthesis of the derivative having a diaryl ether or diaryl thioether bond, which is one of the basic skeletons of the compound of the present invention represented by the formula (I), can be easily produced from a known compound or a commercially available compound. A possible compound represented by the formula (V) or a compound represented by the formula (VI) derived from the compound represented by the formula (V) and an aryl halide derivative represented by R ⁶ X It can be produced by the Ullmann reaction of the following production method or an ether or thioether bond forming reaction utilizing the characteristics of fluorine. Intermediates of formula (XII) can be derived from compounds of formula (XIII) which are either known in the literature or can be readily prepared from commercially available compounds. The reaction formulas showing the outline of the reaction of the present invention and the reaction formula of the intermediate (XII) showing the outline of the reaction of the intermediate of the formula (XII) are shown below.

[0082]

Embedded image

[0083]

[Chemical 49]

The manufacturing method will be described in detail below. <Production Method 1> 1) Step of producing azole methylphenol or azolemethylthiophenol compound represented by formula (VI): A compound represented by formula (V) and a compound represented by formula (X) are reacted as starting materials. By doing so, the compound represented by the formula (VI) can be obtained. That is, when R ^{5 of the} compound represented by the formula (V) is a halogen atom, the reaction can be carried out as follows. That is, a halogenomethyl derivative and an azole such as 1,2,4-triazole or imidazole are combined with an inorganic base such as potassium carbonate, cesium carbonate or calcium carbonate or an organic base such as triethylamine, pyridine or N, N-dialkylaniline, Preferably, cesium carbonate is used as a base, and a solvent is a polar solvent such as acetonitrile or dimethylformamide (DMF), chloroform, a halogenated hydrocarbon solvent represented by methylene chloride, ether, or an ether represented by tetrahydrofuran (THF). Using a system solvent, preferably acetonitrile, as a solvent, the reaction can be carried out at a temperature from room temperature to a temperature at which the reaction mixture is heated to reflux, preferably at a reflux condition temperature, for a time sufficient for the reaction to proceed, specifically for 10 minutes to 3 hours.

Further, among the compounds represented by the formula (V),
When R ⁵ is a hydroxyl group, it is decalin, dimethyl sulfoxide (DMSO), 1,2-dimethoxyethane (DME), dibutyl ether, DMF or 1,3.
-In a suitable high boiling point solvent such as dimethyl-2-imidazolidone (DMI) or without solvent, preferably without solvent, at 120 to 200 ° C, preferably 150 to 160 ° C.
Then, the time for the reaction to proceed sufficiently, specifically 10 minutes to 3
It is also possible to introduce the azole group directly by reacting with 1,2,4-triazole or imidazole over time.

Among the compounds represented by the formula (V) as starting materials, those in which R ⁵ is a halogen atom can be obtained by the method described below.

That is, an optionally substituted orthocresol or orthothiocresol compound (corresponding to a compound in the case where R ^{5 in the} formula (V) is a hydrogen atom)
Is chlorine gas, bromine, copper bromide, N- in the presence or absence of light or a peroxide such as benzoyl peroxide (BPO).
A suitable halogenating agent such as bromosuccinimide (NBS), N-chlorosuccinimide (NCS), trihalogenomethanesulfonyl halogenide or trichlorobromomethane, preferably NBS in the presence of BPO, is used. In a halogenated hydrocarbon solvent, an aromatic hydrocarbon nonpolar solvent such as benzene or toluene, acetic acid or carbon disulfide, preferably a carbon tetrachloride solvent, at room temperature to a temperature at which the reaction mixture is heated under reflux, preferably under reflux. It can be converted to a halogenomethyl derivative for a time at which the reaction proceeds sufficiently at the condition temperature, specifically 1 to 5 hours.

Further, among the compounds represented by the formula (V), R
^{When 5} is a hydroxyl group, hydrogen halides such as hydrogen bromide and hydrogen chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide or phosphorus oxychloride, and other phosphorus halide reagents, thionyl chloride. or thionyl halide reagent thionyl bromide, _{etc., (PhO) 3 P-Br} 2, Ph 3 P-C
A phosphonic acid triester reagent such as Cl ₄ or Ph ₃ P-Br ₂ or a phosphine compound is used, preferably with thionyl halide from under ice cooling to a temperature at which the reaction mixture is heated to reflux, preferably under ice cooling. At room temperature, the time required for the reaction to proceed sufficiently, specifically, from 5 minutes to 2 hours, R ⁵
Can be converted to a halogenomethyl derivative in which is a halogen atom.

2) Formula (VIII) or Formula (I) -b
In general, a compound represented by the formula (VI) obtained as described above and a halogenated aryl represented by the formula R ⁶ X are reacted with each other to produce a diaryl ether or a diaryl thioether compound represented by The diaryl ether or diaryl thioether compound represented by the formula (VIII) can be produced. That is, the compound represented by the formula (VI) and the aryl halide represented by the formula R ⁶ X are treated with an inorganic material such as potassium hydroxide or potassium carbonate in the presence of copper powder or iron powder, preferably copper powder. The reaction may be carried out using a base or an alkali metal reagent such as sodium alkoxide or sodium hydride. In this reaction, iodide and bromide are generally used as the aryl halide, but the reaction easily proceeds even with chloride if the aromatic ring is activated.

I) When R ^{6 in} formula (VIII) (or R ^{2 in} formula (I) -b) is a naphthalene ring, the compound represented by formula (VI) is converted into potassium hydroxide or potassium carbonate. Inorganic bases such as sodium alkoxide,
An alkali metal reagent such as sodium hydride, preferably potassium hydroxide or sodium methoxide, is used to lead to phenoxide or thiophenoxide, and the reaction with bromonaphthalene is performed by using DMF, DMSO, DM.
Formula (VIII) or formula (VIII) by heating in a suitable high boiling solvent such as E, dibutyl ether, xylene, decalin, or DMI, preferably in DMI at 100-200 ° C, preferably 120-150 ° C. A phenoxynaphthalene derivative or a thiophenoxynaphthalene derivative represented by I) can be obtained.

[0091] ii) To synthesize a compound represented by the formula (I) having a benzimidazole ring and a benzotriazole ring R ² is atomic formula (XI) as R ⁶ in the formula R ⁶ X group Can be carried out via a compound represented by the formula (VIII).

That is, a compound represented by the formula (VI) and a compound represented by the formula R ⁶ X having an atomic group represented by the formula (XI) are prepared in the above i) in the presence of copper powder. Using the indicated solvent (preferably DMI) at 100-200 ° C,
Preferably, the compound represented by the formula (VIII) can be synthesized by heating at 120 to 150 ° C. to carry out Ullmann reaction.

Iii) On the other hand, when X is a fluorine atom in the compound represented by the formula R ⁶ X, the following synthetic method can be employed. That is, the reaction of the compound represented by the formula (VI) with the compound represented by the formula R ⁶ X having the atomic group represented by the formula (XI), provided that X is a fluorine atom, that is, fluoronitro With an aniline derivative, an inorganic base such as potassium hydroxide or potassium carbonate or an alkali metal reagent such as normal butyl lithium (n-BuLi), sodium alkoxide or sodium hydride, preferably potassium carbonate as a base, is used as a solvent. As an ether type inert solvent such as dioxane, THF or DME, or a polar solvent such as DMSO, DMF or DMI, preferably using DMF as a solvent, at room temperature to 200 ° C., preferably 70 to 120 ° C. The compound represented by the formula (VIII) can be synthesized by heating at. This method can be carried out under mild reaction conditions if the fluorobenzene derivative is readily available, and is extremely practical because it does not utilize a metal catalyst.

3) Process for producing the compound represented by the formula (I) -b The compound represented by the formula (VIII) thus obtained is further represented by the formula (I) -b as follows. Guided by the compound represented.

Specifically, zinc reduction in acetic acid solvent, reduction with stannic chloride or tin powder in hydrochloric acid, or hydrogenation under Raney nickel or palladium catalyst in a solvent such as alcohol is preferred. Converts the nitro group of the compound represented by formula (VIII) into an amino group by a zinc reduction reaction in an acetic acid solvent at −20 to 100 ° C., preferably under ice-cooling to room temperature. The produced diamino derivative is further passed through a diazo compound by allowing sodium nitrite to act in the presence of a suitable mineral acid such as dilute sulfuric acid or dilute hydrochloric acid at −20 to 100 ° C., preferably under ice-cooling to room temperature, It can lead to a benzotriazole derivative represented by the formula (I) -b. On the other hand, by heating the above diamino derivative under reflux in formic acid, or by using an appropriate reagent such as triethyl orthoformate,
It can be converted into a benzimidazole derivative represented by the formula (I) -b.

<Production Method 2> First, using the compound represented by the formula (V) as a starting material, the reaction with the aryl halide represented by the formula R ⁶ X is described in 2) of <Production method 1>. When carried out according to the method, a diaryl ether or diaryl thioether compound represented by the formula (VII) can be obtained. In this reaction, R ⁵ is preferably a hydroxyl group.

That is, when a naphthalene ring is introduced as R ⁶ , the compound represented by the formula (V) is introduced into phenoxide or thiophenoxide by using potassium hydroxide, sodium methoxide, etc. Law 1>
Can be carried out by a method similar to that shown in the above, that is, an Ullmann reaction using an aryl halide represented by the formula R ⁶ X and copper as a catalyst. When the atomic group represented by the formula (XI) is introduced as R ⁶ , an Ullmann reaction or a reaction utilizing a fluorobenzene derivative is used to form the formula (VI).
Leads to compounds of I).

Then, the compound of the formula (VII)
The compound represented by the formula (VIII) can be synthesized by reacting with the azole compound represented by the formula (X) by the method described in 1) of the production method 1>. The reaction conditions are <
It is the same as the method shown in 1) of manufacturing method 1>.

Thus, when R ⁶ is a naphthyl group (R ² = R ⁶ ), a compound represented by the formula (I) -b in which R ² is a naphthyl group is obtained. Further, in the compound represented by the formula (I) -b, when R ² is benzotriazole or benzimidazole, R ⁶ represented by the formula (VIII).
By the method shown in 3) of <Production Method 1>, the partial nitro group is specifically converted to an amino group by zinc reduction in acetic acid to form a diamino body, and then sodium nitrite is converted to diamino by using diluted sulfuric acid or diluted hydrochloric acid. It can be made to act and lead to a benzotriazole derivative represented by the formula (I) -b via a diazo compound. The diamino compound can be converted into a benzimidazole derivative represented by the formula (I) -b by heating under reflux in formic acid.

<Production Method 3> A compound represented by the formula (VII) obtained by the method described in <Production method 2>, wherein R ⁶ is an atomic group represented by the formula (XI), <Production method> Law 1> 3)
The compound represented by the formula (IX) can be derived by the method described in 1. As a preferable example of this,
The compound represented by the formula (VII) is converted to a diamino compound by zinc reduction in acetic acid, and then, using dilute sulfuric acid or dilute hydrochloric acid, sodium nitrite is allowed to act, and the compound represented by the formula (IX) is expressed via the diazo compound. To a benzotriazole compound. Further, the above-mentioned diamino compound can be converted into a benzimidazole derivative represented by the formula (IX) by heating under reflux in formic acid. When R ⁶ is a naphthyl group, the compound represented by formula (VII) has the formula (I
It is the same as the compound represented by X). In addition, as described below, the compound of formula (IX) can be derived from the intermediate of formula (XII).

The compound represented by the formula (IX) is a compound represented by the formula (I) by reacting with the azole compound represented by the formula (X) by the method described in 1) of <Production Method 1>. Can be synthesized. The reaction conditions are the same as the method described in 1) of <Production method 1>.

<Production Method 4> 1) Production Step of Diarylhalomethane Intermediate Represented by Formula (XII) The organometallic compound represented by formula (XIII) and the formula (XI)
V) by reacting the compound represented by the formula (X
The intermediate represented by V) can be synthesized. Expression (X
The organometallic compound represented by III) can be prepared as follows. Using a bromotoluene derivative as a starting material, manganese dioxide, chromic acid, lead tetraacetate, etc., an appropriate oxidizing agent, preferably acetic anhydride-leading to an aldehyde derivative by chromic acid oxidation in the presence of sulfuric acid, boron, aluminum, silicon, Using metallic hydrogen compounds such as tin,
Preferably, sodium borohydride is used to reduce the aldehyde to give a hydroxymethyl derivative. The hydroxyl group is John Willy and Sons (John Willy
and Sons, published by TW Green and PG Wuts, Protective Groups in Organic Synthesis
active Groups in Organic
Synthesis) 2nd edition, 1991, after protecting with a suitable protecting group, preferably a silyl group, as described in the review article, if metal magnesium is used, an organomagnesium compound, metal lithium, alkyllithium, lithium amide or the like is used, preferably normal. Butyllithium can be used to lead to organolithium compounds. An adjusted organometallic compound, preferably an organomagnesium compound (Grineer's reagent), is used as a solvent, and an ether-based inert solvent such as dioxane, THF, DME, preferably ether is used. The reaction is preferably carried out at room temperature to synthesize the diarylmethanol intermediate (XV).

The hydroxyl group of the compound represented by the formula (XV) is
Using the halogenating agent described in 1) of <Production Method 1>, preferably thionyl halide, at a temperature at which the reaction mixture is heated to reflux from under ice cooling, preferably for a time sufficient for the reaction to proceed under ice cooling, specifically, Specifically, it can be converted to a diarylhalomethane intermediate in 5 minutes to 2 hours.

2) Process for producing diarylmethane compound represented by formula (IX) The halogen at the benzyl position of the diarylhalomethane intermediate represented by formula (XII) is catalytically reduced using Pd, a metal of aluminum or boron. A suitable reducing agent such as a hydrogen complex compound, preferably sodium borohydride, can be used for dehalogenation by reduction using DMSO. The protecting group of the compound of formula (IX) thus obtained has a protective group in organic synthesis (Protective Groups in Org).
anic synthesis), when the protecting group is a silyl group, desilylation may be performed using a fluorine compound such as tetrabutylammonium fluoride, cesium fluoride, potassium fluoride, HF, preferably tetrabutylammonium fluoride. It can be converted into a diarylmethane compound represented by the formula (IX) in which the protecting group is removed (wherein A is a methylene group).

The compound represented by the formula (IX) (wherein A is a methylene group) is reacted with the azole compound represented by the formula (X) by the method described in 1 of <Production Method 1>. The compound represented by formula (I) can be synthesized. The reaction conditions are the same as the method described in 1) of <Production method 1>.

<Manufacturing Method 5> The above <Manufacturing Method 1> to <
In the compound represented by the formula (I) synthesized by Production Method 4>, R ¹ can be variously converted, that is, the substituent on the benzene ring, by the following method. Also,
A substituent can be newly introduced on the benzene ring.

Generally, the compounds of formula (I) are R ¹
Is a hydrogen atom, a halogen atom, an alkyl group optionally substituted with a fluorine atom or an alkoxy group optionally substituted with a fluorine atom, more efficient than <Production Method 1> to <Production Method 4>. Can be synthesized.

On the other hand, a compound in which R ¹ is a cyano group, a nitro group, an alkoxycarbonyl group, a carboxyl group, an acetyl group, a formyl group, an alkenyl group or an alkynyl group is represented by the formula (I) wherein R ¹ is halogen or hydrogen. It is preferred to convert from the compounds represented. A specific example is shown below.

1) Conversion to a cyano group The compound represented by the formula (I) in which R ¹ is a halogen atom is a method of heating at about 250 ° C. with copper cyanide in the absence of a solvent, or a transition metal complex. The halogen atom can be converted to a cyano group by a method of reacting sodium cyanide or potassium cyanide using C as a catalyst. As the transition metal complex, a palladium complex typified by palladium acetate, a nickel complex such as tetrakistriphenylphosphine nickel [Ni (PPh ₃ ) ₄ ] or the like is used. Examples of the solvent when the palladium complex is used as a catalyst include ether solvents such as ether, THF, dioxane or DME, and polar solvents such as DMSO or DMF, and DMF is preferably used as the solvent. As a solvent when the nickel complex is used as a catalyst, ether, THF, dioxane, ether solvent such as DME, or DMSO
Or polar solvent such as DMF or methanol,
An alcohol solvent such as ethanol can be used, and ethanol is preferably used. The reaction temperature is room temperature to 200 ° C.
And preferably 70 to 120 ° C. When the halogen atom of R ¹ is a bromine atom, the transition metal catalyst is preferably palladium acetate, DMF is used as a solvent, and 70 to 1
It is preferable to react potassium cyanide at 20 ° C. Further, the transition metal catalyst when the halogen atom of R ¹ is a chlorine atom is preferably tetrakistriphenylphosphine nickel, and ethanol is used as a solvent.
It is preferred to react potassium cyanide at ~ 120 ° C. In this way, the halogen atom of R ¹ can be converted into a cyano group, that is, a benzonitrile derivative can be obtained.

2) Conversion to formyl group The benzonitrile derivative obtained in 1) was converted into LiAl.
A suitable metal hydrogen complex compound such as H ₄ , DIBAL-H or Red-Al ^™ is used, preferably DIBAL-H.
With ether, THF, dioxane or DM
In an ether solvent such as E or an aromatic hydrocarbon solvent such as benzene or toluene, preferably THF is used as a solvent under cooling with dry ice-acetone (-78).
° C.) at to 100 ° C., preferably by reduction at -78~0 ℃, can be derived as the R ¹ to a formyl group.

3) Conversion to Carboxyl Group or Alkoxycarbonyl Group The benzonitrile derivative obtained in 1) is easily hydrolyzed under suitable alkaline conditions such as sodium hydroxide or potassium hydroxide to convert R ¹ into a carboxyl group. Can be converted. Furthermore, this carboxyl group is sulfuric acid,
A mineral acid such as hydrochloric acid, an organic acid such as an aromatic sulfonic acid, or an esterification reaction involving dehydration using an alcohol in the presence of a Lewis acid such as boron fluoride etherate, or diazomethane, a dialkyl sulfuric acid, an alkyl halide, R ¹ can also be easily derivatized to an alkoxycarbonyl group by O-alkylation reaction using an alkylating agent such as orthoformate, preferably by using dialkyl sulfuric acid in the presence of potassium carbonate in an acetone solvent.

4) Conversion to an alkenyl group The compound represented by the formula (I) in which R ¹ is a halogen atom is a nickel catalyst such as bis (triphenylphosphine) dichloronickel or tetrakistriphenylphosphine palladium [Pd ( PPh ₃ ) ₄ ], (bistriphenylphosphine) palladium chloride [PdCl ₂ (P
Ph ₃ ) ₂ ] or the like is used to carry out a cross-coupling reaction with an organometallic reagent such as an alkenyl magnesium halide, an alkenyl boron compound or an alkenyl tin compound to convert it into a derivative having an alkenyl group in R ^1. be able to. Further, the compound represented by the formula (I) in which R ¹ is a halogen atom is Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , in the presence of an inorganic base such as sodium carbonate or an organic base such as triethylamine. It can be converted into a derivative having an alkenyl group in R ¹ by a Heck reaction of condensation with an alkene using palladium such as palladium acetate as a catalyst.

Further, the alkenyl derivative is R obtained in 2).
A benzaldehyde derivative represented by the formula (I) in which ¹ is a formyl group is subjected to a Wittig reaction or a Wittig-Horner-Emmons (Wittig-Horn).
er-Emmons) reaction. That is, a phosphonium salt or an alkyl phosphite diester, preferably an alkyltriphenylphosphine phosphonium halide, especially methyltriphenylphosphonium bromide is added to an inorganic base such as sodium hydroxide or sodium carbonate or an organic base such as Et ₃ N. , Or n
-BuLi, potassium butoxide (t-BuOK), an alkali metal reagent such as sodium hydride, preferably t-
Using BuOK as a base, ether as a solvent, TH
In an ether type inert solvent such as F, dioxane or DME or a polar solvent such as DMSO, DMF or DMI, preferably using THF, at -78 to 100 ° C.
Preferably, it is converted to a derivative having an alkenyl group in R ¹ by reacting with a benzaldehyde derivative at −78 to 100 ° C., preferably at room temperature after forming phosphorus ylide at room temperature.

5) Conversion to alkynyl group R¹A compound of formula (I) in which is a halogen atom
Is copper acetylene using pyridine or DMF as a solvent.
R by reacting with¹To
Can be converted to derivatives with alkynyl groups
It Also, R¹Is represented by formula (I) in which is a halogen atom
Compound is Pd (PPh₃)_Four, PdCl ₂(PPh
₃)₂, Palladium catalysts such as palladium acetate, preferably
Is sodium hydroxide, carbonic acid in the presence of palladium acetate catalyst
Inorganic bases such as sodium and Et₃An organic base such as N, or
Is n-BuLi, sodium alkoxide, hydrogenated sodium
An alkali metal reagent such as thorium, preferably Et₃N
Used as a base, such as benzene or toluene as a solvent
Aromatic hydrocarbon solvents, ether, THF, dioxa
Ether, an inert solvent such as DME, or DM
In a polar solvent such as SO, DMF, DMI, preferably
Using DMF at room temperature to 200 ° C., preferably 100
Acetylene compounds or their trials at ~ 120 ° C
Kirsilyl derivative or its trialkyltin, al
Killyl-boron substitute, preferably triacetyl of acetylene compound
Alkylsilyl derivatives, especially trimethylsilylacetyl
R by reacting with ren¹Has an alkynyl group
Can be converted into a derivative. In addition,
R due to potassium carbonate¹Trialkylsilyl group
You can also remove.

6) Introduction of an acetyl group Furthermore, the compound represented by the formula (I) in which R ¹ is a hydrogen atom is a Friedel-Crafts reaction, that is, carbon disulfide, nitrobenzene, tetrachloroethane is used as a solvent, or It is also possible to introduce an acetyl group into R ¹ in the absence of a solvent, preferably using carbon disulfide as a solvent, with an acetyl halide such as acetyl chloride in the presence of aluminum chloride.

7) Introduction of nitro group The compound represented by the formula (I) in which R ¹ is a hydrogen atom is a suitable nitrating agent such as concentrated nitric acid, fuming nitric acid, alkyl nitrate, nitrate or nitronium tetrafluoroborate. ,
It is also possible to obtain a compound of formula (I) in which R ¹ is a nitro group, preferably using sodium nitrate in trifluoroacetic acid.

When the compound of the present invention is used as a medicine, it is a pharmaceutically acceptable excipient, binder, lubricant, coloring agent, flavoring agent, disintegrating agent, preservative, isotonic agent, stabilizer, dispersion. Agents, antioxidants, buffers, preservatives, fragrances, suspending agents or emulsifiers, commonly used suitable carriers or solvents,
For example, if necessary, sterilized water, vegetable oil, physiologically acceptable solvent, solubilizing agent and the like can be appropriately combined with the compound of the present invention to give various dosage forms.

Examples of such dosage forms include tablets, capsules, granules, powders, suppositories, vaginal suppositories, syrups, inhalants, external preparations, injections, etc., and oral or parenteral (eg,
It can be administered to a patient by intravenous administration, intraarterial administration, subcutaneous administration, intramuscular administration, rectal administration, vaginal administration, transdermal absorption or transmucosal absorption, etc.).

The dose of the compound of the present invention varies depending on the symptoms, but is usually 0.0001 to 10 per day for an adult.
Within the range of mg / kg, preferably 0.001-1 mg
The dose is preferably in the range of / kg, but can be increased or decreased as appropriate according to the patient's condition and the like.

It is also possible to administer the total amount in a single dose or in 2 to 6 doses orally or parenterally, or to administer continuously such as intravenous drip infusion.

Test Example Next, the pharmacological action of the representative compounds of the present invention will be described.

Experimental Example 1. Rat ovarian aromatase inhibitory action Aromatase inhibitory action is produced by Brodie
Et al. Journal of Steroid Biochemistry
mistry), 7, a female rat ovary microsomal fraction as enzyme preparation was prepared according to the method described in 783,1976, Thompson (Thompson) et al., Journal of the Biological Chemistry (Jo
urinal of the Biological C
Chemistry), 249 , 5364, 1974. That is, 0.1 mg protein / m
1 microsome fraction, 30 nM [1β- ³ H] androstenedione and 0.1 nM-10 nM test compound in 50 mM potassium phosphate buffer (pH 7.
The reaction was started by adding NADPH with a final concentration of 0.2 mM to 4), and after heating at 37 ° C. for 15 minutes, the reaction was stopped by cooling with ice. Then, 5% activated carbon and 0.5% dextran T-70 suspension were added to adsorb the unreacted substrate, and after precipitation by centrifugation, [ ³ H] H was released in the supernatant.
The radioactivity of ₂ O was measured with a liquid scintillation counter. As a control compound, Japanese Patent Application Laid-Open No. 63-316 was developed focusing on the highly specific aromatase inhibitory action.
7-[(4-chlorophenyl)-(1H-1,2,4-triazol-1 which is the compound of Example 20.
-Yl) methyl] -1-methyl-1H-benzotriazole (R76713) and 5- (p-cyanophenyl) which is the compound of Example 1 of JP 61-12688 A.
-5,6,7,8-Tetrahydroimidazo [1,5-
a] Pyridine (CGS16949A) was tested.

In Table 1, the numerical value shown as IC ₅₀ represents the concentration of the test compound required for inhibiting the aromatic ring cyclization reaction of the A ring of androstenedione, that is, the aromatase activity by 50%.

[0124]

[Table 1] Remarkable aromatase inhibitory activity was observed in all the compounds of the present invention.

Experimental Example 2. Blood estrogen lowering effect Blood estrogen lowering effect is
rs) et al., Journal of Steroid Biochemistry.
Biochemistry), 32 , 781, 1989.
Measurement was carried out by partially modifying the method described in. That is, pregnant horse serum gonadotropin (PMS) was added to 3-week-old SD female rats.
G) 200 IU / rat was subcutaneously administered, and 72 hours later, 2
The test compound 0.001 to 0.1 mg / kg dissolved in a 0% propylene glycol aqueous solution was orally administered. Blood was collected 4 hours after the administration of the test drug, the plasma estradiol concentration was quantified by radioimmunoassay (RIA), and the reduction rate (%) relative to the plasma estradiol concentration in the control group was calculated. R7673 and CGS1 as control compounds
6949A was tested. The results are shown in Table 2.

Table 2 Blood estrogen lowering effect ───────────────────────────────── Plasma estradiol lowering rate (%) ────────────────────── Example Drug dose (mg / kg) ────────────────── ──── 0.001 0.01 0.1 ───────────────────────────────── 38 --- -44 41-46 70 70 43-41 69 44---- 23 46-36-48 --30 30 --50-59-52 22 77 791 80---49 R76713 --60 85 CGS16949A 44 81 94 ─────────────────────────────────── −: Not studied Compound Both showed potent blood estrogen lowering effect.

Experimental Example 3. Examination of Effects on Various Steroid Hormone Synthesis Studies on effects on various steroid hormone synthesis are described in Waters et al., Journal of Steroids Biochemistry.
Steroid Biochemistry), 3
2 , the method described in 781, 1989 was partially modified. That is, 0.1 to 10 m of the test compound dissolved in a 20% propylene glycol aqueous solution in 7-week-old male SD rats
Oral administration of g / kg, 3 hours later, intramuscular administration of adrenocorticotropic hormone (ACTH) 25 μg / rat and gonadotropin-releasing hormone (LH-RH) 40 ng / rat, and 1 hour later, blood was collected to obtain plasma aldosterone. , Corticosterone, progesterone, 17α-hydroxyprogesterone and testosterone concentrations were measured by RIA. For each hormone, the blood hormone concentration in the test drug administration group was compared with that in the control group, and the change rate (%) was calculated. As a control compound, R767
13 and CGS16949A 10 mg / k each
The test was conducted by administering up to 1 mg / kg.

The hormones measured are the major steroid hormones synthesized in the adrenal cortex as well as the male and female glands, as well as the end products or major intermediates in the steroid hormone synthesis pathway. Therefore, it is considered that when the drug influences some enzyme in the steroid hormone producing system, the blood hormone concentration changes.

Plasma corticosterone, progesterone and testosterone concentrations were determined by the compounds of Examples 41 and 52 of the present invention as well as R76713 and CGS.
The highest dose of 16949A each was unaffected. In contrast, plasma aldosterone and 17α
-Hydroxyprogesterone concentration was found to change in plasma concentration depending on the test compound. The results are shown in Tables 3 and 4.

Table 3 Plasma aldosterone lowering effect ───────────────────────────────── Plasma aldosterone lowering rate (%) ─ ──────────────────── Example Drug dose (mg / kg) Compound ──────────────────── ── 0.1 13 10 ───────────────────────────────── 41 −−−− NE NE 52 − − −− NE NE R76713 −− −− NE 28 CGS16949A 37 55 −−−− ──────────────────────────────── --- NE: No action ---: Not examined

Table 4 Plasma 17α-hydroxyprogesterone elevation effect ────────────────────────────────── Plasma 17α-hydroxy Progesterone increase rate (%) ──────────────────────── Example Drug dose (mg / kg) Compound ────────── ─────────────── 0.1 13 10 ────────────────────────────── ───── 41 −−−− NE NE 52 −−−− NE NE R76713 −−−− 276 460 CGS 16949A 169 313 −−−− ───────────────── ───────────────── NE: No effect ---: Not examined

The compounds of Examples 41 and 52 of the present invention are 1000 times to 1 times the blood estrogen lowering action amount.
Administration of 10 mg / kg, which corresponds to a 0000-fold dose, did not affect the blood levels of any steroid hormone. On the contrary, R76713 used as a control compound showed an increase in plasma 17α-hydroxyprogesterone concentration of 3 mg / kg or more,
/ Kg, a decrease in plasma aldosterone concentration was observed. On the other hand, in CGS16949A, a decrease in plasma aldosterone concentration and 17α was observed at a dose of 0.1 mg / kg or more.
-The level of hydroxyprogesterone was increased, and the degree of dissociation of the expression dose from the plasma estrogen-lowering amount was 10
It was 0 times or less.

Experimental Example 4. Acute toxicity test The compounds of the present invention were examined for acute toxicity. 9 weeks old Wi
When 10 mg / kg of the compound of Example 52 of the present invention was orally administered to star male rats and observed for 7 days, there were no deaths and no abnormalities in body weight or general symptoms were observed.

From the results of Experimental Examples 1 and 2 described above, it is shown that the compound of the present invention has a remarkable aromatase inhibitory activity in vitro, and surely lowers the blood estrogen level in vivo even when administered in a small amount. It was Therefore,
The compound of the present invention is expected to be a useful aromatase inhibitor.

From the results of Experimental Example 3, the compound of the present invention was confirmed to be R76713 and CGS16949 which are under development as pharmaceuticals.
Compared with A, the target aromatase has a higher selectivity, and estrogen is more specifically reduced in vivo.
Assuming application to patients with estrogen-dependent diseases such as breast cancer that requires long-term drug administration, affecting blood levels of various steroid hormones essential for maintaining homeostasis in the body is a serious side effect. Needless to say, there is a need for a drug that has a risk of being linked and that has a higher specificity for aromatase. From this viewpoint, the substance of the present invention is expected to be a highly safe therapeutic agent with fewer side effects than other compounds under development.

From the results of Experimental Example 4, the compound of the present invention was expected to have low toxicity since no abnormalities were observed when administered to experimental animals.

From the above, the azole methylphenyl derivative of the present invention exhibits an excellent aromatase inhibitory activity in vitro and a remarkable blood estrogen lowering effect in animal experiments using an in vivo experimental animal model in rats. It was revealed that the specificity of aromatase inhibition was high and the safety was high. It has been revealed that the azole methylphenyl derivative of the present invention is excellent in at least one or more of these.

The azole methylphenyl derivative of the present invention can be applied to estrogen-dependent diseases such as estrogen-dependent cancers (breast cancer, ovarian cancer, endometrial cancer, etc.), endometriosis, uterine fibroids, and benign breast diseases (fibrocystic). Mastopathy), mastopathy,
Preterm labor, benign prostatic hyperplasia, prostate cancer, precocious puberty,
It is extremely useful as a prophylactic and / or therapeutic agent for gynecomastia, male infertility or gallstone disease associated with oligospermia. Furthermore, it is useful as a female fertility regulator.

Further, from the results of Experimental Examples 1 to 3, the compound of the present invention has an aromatase inhibitory activity in vitro and in vivo, and is therefore useful as a reagent or an aromatase inhibitor for animals.

[0140]

EXAMPLES Next, examples will be given to explain the present invention in more detail, but the present invention is not limited thereto.

NMR is Geol FX90A (JEOL
FX90A) FT-NMR (* is displayed on the data, manufactured by JEOL Ltd.) or Geor JNM-EX270
(JEOL JNM-EX270) FT-NMR (manufactured by JEOL Ltd.), IR is HORIBA
FT-200 (manufactured by Horiba, Ltd.), melting point is Mettler FP80 or FP90 (both are Mettler Co., Ltd.), and high performance liquid chromatography is Tosoh CCPD (manufactured by Tosoh Corp.).
Or Shimadzu LC-10A (SHIMADZU CORPORATION)
(Manufactured by Shimadzu Corporation).

Example 1 Synthesis of 1- (4-chloro-2-methylphenoxy) naphthalene 4-Chloro-2-methylphenol (10 g) was mixed with powdered KOH (4.6 g) at 150 ° C. for 1 hour. Heated for hours. After cooling to 100 ° C., DMI (50 ml) was added to dissolve the contents, and then 1-bromonaphthalene (1
4.5g) and copper powder (350mg) were added and the mixture was heated at 130 ° C for 3
The mixture was heated and stirred for an hour. The mixture was returned to room temperature, 1N-NaOH was added, and the mixture was extracted with ether. The ether layer is again 1N-NaOH
After washing with water, it was washed twice with water and once with saturated saline.
After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:
The title compound (2 g; 11%) was obtained by purification with ether = 99: 1).

(Example 2) Synthesis of 2- (4-chloro-2-methylphenoxy) naphthalene According to Example 1, 4-chloro-2-methylphenol and 2 were used.
The title compound (9%) was obtained from -bromonaphthalene.

(Example 3) 1- (2-bromomethyl-
Synthesis of 4-chlorophenoxy) naphthalene 1- (4-chloro-2-methylphenoxy) naphthalene (1.8 g) obtained in Example 1 was replaced with carbon tetrachloride (10 ml).
, NBS (1.2 g) and a catalytic amount of benzoyl peroxide were added, and the mixture was refluxed for 2 hours. After returning to room temperature, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ether = 99: 1) to give the title compound (90
0 mg; 39%).

Example 4 2- (2-Bromomethyl-
Synthesis of 4-chlorophenoxy) naphthalene 2- (4-chloro-2) obtained in Example 2 according to Example 3
The title compound was obtained from -methylphenoxy) naphthalene.

Example 5 1- [5-chloro-2-
Synthesis of (1-naphthyloxy) benzyl] -1H-imidazole 1- (2-Bromomethyl-4-chlorophenoxy) naphthalene (400 mg) obtained in Example 3 was dissolved in acetonitrile (20 ml), and imidazole (235 m was added thereto.
g) and cesium carbonate (1.1 g) were added and the mixture was refluxed for 10 minutes. After returning to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 99: 1) to obtain the title compound (270 mg; 70%). This product had a purity of 99.9% according to a purity test by HPLC.

(Examples 6 and 7) According to Example 5, the compounds shown in Table 5 below were synthesized.

[0148]

Example 8 5-Chloro-2-nitro-
Synthesis of N-trifluoroacetylaniline 5-Chloro-2-nitroaniline (25 g) was dissolved in methylene chloride (250 ml) to give pyridine (11.7 g).
To the mixture containing was added trifluoroacetic anhydride (20
(ml) in methylene chloride (50 ml) was added dropwise and the mixture was stirred for 2 hours. Next, water was added to the reaction mixture and the methylene chloride layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (38 g; 98%).

Example 9 5-Chloro-N-methyl-
Synthesis of 2-nitro-N-trifluoroacetylaniline The 5-chloro-2-nitro-N-trifluoroacetylaniline (38 g) obtained in Example 8 was replaced with acetone (300 m).
After dissolution in l), potassium carbonate (19.5 g) was added. Dimethylsulfate (13.4m) was added to this mixture under ice cooling.
1) was added dropwise and the mixture was stirred for 1.5 hours. The insoluble inorganic matter was removed by filtration and washed with ethyl acetate. The solvent was distilled off under reduced pressure, hexane was added to the residue and the mixture was stirred, and then crystals were collected by filtration. The crystals were washed with a mixed solution of ether and hexane to give the title compound (33 g; 83.5%).

Example 10 Synthesis of 5-chloro-N-methyl-2-nitroaniline 5-Chloro-N-methyl-2-nitro-aniline obtained in Example 9
N-trifluoroacetylaniline (30 g) was dissolved in methanol (300 ml), 15% NaOH aqueous solution was added thereto, methanol (50 ml) was further added, and the mixture was stirred for 3 hours. The reaction mixture was poured into 400 ml of water and the precipitate was filtered and washed with water. The precipitate was dissolved in 300 ml of methylene chloride, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (19 g; 96%).

Example 11 Synthesis of 4-bromo-2-hydroxymethylphenol An ether (200 ml) suspension of LiAlH ₄ (5.7 g) was cooled with ice while ether of 5-bromosalicylic acid (21.7 g) was added. The (200 ml) solution was slowly added dropwise. 30
After stirring for 3 minutes at room temperature, the reaction solution was slowly poured into 3N-HCl in which ice was floated and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The oily residue obtained by evaporating the solvent under reduced pressure was crystallized from ether-hexane and collected by filtration to give the title compound (15.5 g;
76.5%).

(Examples 12 to 16) The compounds in Table 6 below were synthesized according to Example 11.

[0154]

(Example 17) 2-hydroxymethyl-
Under ice cooling 4-methoxy ether synthesis LiAlH ₄ (0.75 g) of phenol (50ml) suspension, 5-methoxy salicylaldehyde (5
A solution of g) in ether (20 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. LiAlH ₄ (0.5g)
Was added under ice-cooling, and the mixture was further stirred at room temperature for 30 minutes. Ice was carefully added to the reaction solution, and then 1N HCl and ether were added. The insoluble material was filtered off using Celite ^™ , the ether layer was separated from the filtrate, and the aqueous layer was further extracted with ether. These ether layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude crystals of the residue were washed with ether-hexane and collected by filtration to give the title compound (3.9 g; 77%).

Example 18 2-Hydroxymethyl-
Synthesis of 4- (trifluoromethoxy) phenol According to Example 17, the title compound (2.04 g; 1) was obtained from 5- (trifluoromethoxy) salicylaldehyde (2 g).
00%).

Example 19 4-Chloro-2- (1H
-Synthesis of imidazol-1-ylmethyl) phenol 4-chloro-2-methylphenol (9 g) was dissolved in pyridine (30 ml), and acetic anhydride (7.2 g) was added thereto while cooling with ice.
(ml) was added and the mixture was stirred at room temperature for 2 hours. Next, ether was added to the reaction solution, washed with water three times and once with 1N-HCl, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 2-acetoxy-5-chlorotoluene (11 g; 95%).

This acetoxy derivative (8.75 g) was dissolved in carbon tetrachloride (100 ml), and NBS (9
g) and benzoyl peroxide (30 mg) were added and the mixture was refluxed for 2 hours. After returning to room temperature, the insoluble matter was removed by filtration, the filtrate was washed with a saturated sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. 6 g of 2-acetoxy-5-chlorobenzyl bromide obtained by distilling off the solvent under reduced pressure was taken and dissolved in acetonitrile (100 ml) to obtain imidazole (1.5 g) and cesium carbonate (7.2 g). The mixture was stirred at room temperature for 1 hour. Furthermore, imidazole (1.5
g) was added and the mixture was refluxed for 30 minutes.

After returning the reaction solution to room temperature, it was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent obtained by evaporating the solvent under reduced pressure was dissolved in methanol, and the residue was dissolved in 1N-NaO.
After adding H and stirring at room temperature for 1 hour, methanol was distilled off. Water was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 49: 1), and the crystals obtained were washed with ether to give the title compound (1.45 g; 3
1.5%) was obtained.

Example 20 4-Chloro-2- (1H
Synthesis of -1,2,4-triazol-1-ylmethyl) phenol Method A: The intermediate 2-acetoxy-5 obtained in Example 19
-Chlorobenzyl bromide (6 g) was dissolved in acetonitrile (60 ml), and 1H-1,2,4-triazole (1.15 g) and cesium carbonate (7.5 g) were added thereto.
Was refluxed for 1 hour. Return to room temperature, remove insoluble material,
This insoluble material was washed with ethyl acetate. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure. The residue was neutralized with 1N-HCl and extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 49: 1) to give the title compound (1.5 g; 31.5%). Method B: 4-chloro-2-hydroxymethylphenol (25.3 g) obtained in Example 12 and 1H-1,2,
A mixture of 4-triazole (32.7 g) was stirred at around 160 ° C for 1 hour. The crystals solidified after cooling were recrystallized from ethanol and collected by filtration to give the title compound (31.
7 g; 73%) was obtained.

(Example 21) 2- (1H-1,2,4)
Synthesis of -triazol-1-ylmethyl) phenol 2-hydroxymethylphenol (25.3g) and 1H
A mixture of -1,2,4-triazole (15.5 g) was stirred at around 160 ° C for 1 hour. The crystals solidified after cooling were recrystallized from ethanol and collected by filtration to give the title compound (27 g; 76%).

(Examples 22 to 27) The compounds in Table 7 below were synthesized according to Example 21.

[0163]

Example 28 5- [4-chloro-2-
(1H-imidazol-1-ylmethyl) phenoxy]
Synthesis of -N-methyl-2-nitroaniline 4-chloro-2- (1H-imidazol-1-ylmethyl) phenol (210 mg) obtained in Example 19 and powdered KOH (66 mg) were mixed, and at 130 ° C. Heated and melted. The reaction mixture was dried under reduced pressure, and DMI (1 m
l), 5-chloro-N-methyl-2-obtained in Example 10.
Add nitroaniline (190mg) and a small amount of copper powder 1
Heated at 30 ° C. for 3 hours. After returning to room temperature, water and ethyl acetate were added, the copper powder was filtered off, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 99: 1) to give the title compound (250 mg; 69.5).
%) Was obtained.

(Example 29) 5- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -N-methyl-2-nitroaniline 4-chloro-2- (1H-1,2,4 obtained in Example 20
-Triazol-1-ylmethyl) phenol (840
mg) and powdered KOH (260 mg) were mixed to obtain 150
It was melted by heating at ℃. The reaction mixture was dried under reduced pressure and added to it DMI (4 ml), 5-chloro-N- obtained in Example 10.
Methyl-2-nitroaniline (750 mg) and a small amount of copper powder were added, and the mixture was heated at 130 ° C for 3 hours. Return to room temperature,
Water and ethyl acetate were added, the copper powder was filtered off, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 99: 1) to give the title compound (750
mg; 52%).

Example 30 5- [4-Bromo-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -N-methyl-2-nitroaniline 4-bromo-2- (1H-1,2,4 obtained in Example 22
-Triazol-1-ylmethyl) phenol (11.
4 g) in methanol solution (200 ml) with NaOMe
(2.6 g) was added in portions at room temperature. After stirring for 15 minutes at room temperature, the mixture was concentrated to dryness under reduced pressure. DMI (150m
l), 5-chloro-N-methyl-2-obtained in Example 10.
Nitroaniline (8.4 g) and copper powder (0.3 g) were added, and the mixture was heated at 130 ° C. for 3 hours. After returning to room temperature, water and ethyl acetate were added and the copper powder was filtered off. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 39: 1) to give the title compound (11.4 g; 62.5%).

(Examples 31 to 36) The compounds in Table 8 below were synthesized according to Example 30.

[0168]

(Example 37) 5- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -2-nitroaniline 4-chloro-2- (1H-1,2,4 obtained in Example 20
-Triazol-1-ylmethyl) phenol (25
g) in methanol solution (500 ml) with NaOMe
(7.1 g) was added in portions at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated to dryness under reduced pressure. DMI (500m
l), 5-chloro-2-nitroaniline (20.6 g)
And copper powder (0.76 g) were added, and the mixture was heated at 130 ° C. for 2.5 hours. After returning to room temperature, water and ethyl acetate were added and the copper powder was filtered off. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with methylene chloride to give the title compound (11 g; 27%).

(Example 38) 6- [4-chloro-2-
(1H-imidazol-1-ylmethyl) phenoxy]
Synthesis of -1-methyl-1H-benzotriazole 5- [4-chloro-2- (1H-imidazol-1-ylmethyl) phenoxy] -N-methyl-2-nitroaniline (250 mg) obtained in Example 28 was used. Acetic acid (3 ml)
And zinc dust (250 mg) was added little by little at room temperature. After the addition, ethyl acetate was added to remove the insoluble matter, and a saturated sodium hydrogen carbonate solution was carefully added to the filtrate to separate the layers. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 97: 3) to give 4- [4-chloro-2- (1H-imidazol-1-ylmethyl) phenoxy]-. 2-methylaminoaniline (160 mg;
70%).

This amino compound (140 mg) was added to 6N-HC
1 (1.5 ml), sodium nitrite (60 mg) aqueous solution (0.1 ml) was added thereto under ice cooling,
The temperature was raised to room temperature and stirring was continued for 20 minutes. Then, it was neutralized with a sodium hydrogen carbonate solution under ice cooling and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 4).
9: 1) to give the title compound (76 mg;
52%). This product had a purity of 94.7% in a purity test by HPLC.

Example 39 4- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -1,2-phenylenediamine 5- [4-chloro-2- (1H-1,
2,4-triazol-1-ylmethyl) phenoxy]
2-Nitroaniline (11 g) with acetic acid (100 ml)
And zinc powder (12.5 g) was added little by little under water cooling. After the addition, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and saturated sodium hydrogen carbonate solution was added carefully to make it alkaline. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the residue was chloroform (100 m
1) and ethanol (10 ml) were crystallized, and the precipitated crystals were collected by filtration to give the title compound (4.98 g; 50%).

(Example 40) 5- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -1H-benzotriazole 4- [4-chloro-2- (1H-1,
2,4-triazol-1-ylmethyl) phenoxy]
-1,2-Phenylenediamine (3.2 g) under ice cooling 1
The mixture was dissolved in 0% H ₂ SO ₄ (30 ml), an aqueous solution of sodium nitrite (1.4 g) (3 ml) was added thereto, the temperature was raised to room temperature, and stirring was continued for 2 hours. Then, it was neutralized with a sodium hydrogen carbonate solution and extracted twice with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ether to give the title compound (3 g; 91%). This is H
It had a purity of 99.1% in a purity test by PLC.

(Examples 41 and 42) 6- [4-chloro-2- (1H-1,2,4-triazol-1-ylmethyl) phenoxy] -1-methyl-1H-benzotriazole and 5- [4 -Chloro-2- (1H-1,2,4
-Triazol-1-ylmethyl) phenoxy] -1-
Synthesis of methyl-1H-benzotriazole 5- [4-chloro-2- (1H-1,
2,4-triazol-1-ylmethyl) phenoxy]
Dimethyl sulfuric acid (0.96 ml) was added to a DMF (15 ml) suspension of -1H-benzotriazole (3 g) and potassium carbonate (1.27 g), and the mixture was stirred at room temperature for 2 hours.
Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel flash column chromatography. From the fraction eluted with methylene chloride, 5- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Phenoxy] -2-methyl-2H-benzotriazole (0.67 g; 21%) was obtained. Methylene chloride: methanol = 99: 1 to 49: 1 6-from the elution fraction
The (1-methyl) -1H-benzotriazoyloxy derivative and the 5- (1-methyl) -1H-benzotriazoyloxy derivative were obtained as a mixture. This product was purified again by silica gel flash column chromatography. 6- [4-chloro-2- (1H-1,2,4-triazol-1-ylmethyl) phenoxy] -1-methyl-from the elution portion of ethyl acetate: hexane = 3: 1 to 4: 1.
1H-benzotriazole <Example 41> (0.71
g; 23%) was obtained. This product had a purity of 94.7% in a purity test by HPLC. Also, ethyl acetate:
Hexane = 9: 1 From the eluted portion, 5- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Phenoxy] -1-methyl-1H-benzotriazole <Example 42> (0.44 g; 14%) was obtained. This product had a purity of 99.7% in a purity test by HPLC.

The compound of Example 41 6- [4-chloro-
2- (1H-1,2,4-triazol-1-ylmethyl) phenoxy] -1-methyl-1H-benzotriazole can also be synthesized by the following alternative method.

5- [4-chloro-2-obtained in Example 29
(1H-1,2,4-triazol-1-ylmethyl)
Phenoxy] -N-methyl-2-nitroaniline (72
0 mg) was dissolved in acetic acid (5 ml), and zinc dust (700 mg) was added thereto little by little at room temperature. After the addition, ethyl acetate was added to remove the insoluble matter, and a saturated sodium hydrogen carbonate solution was carefully added to the filtrate to separate the layers. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane: methanol = 80: 20:
4- [4-chloro-2- (1
H-1,2,4-triazol-1-ylmethyl) phenoxy] -2-methylaminoaniline (400 mg; 6
0.5%) was obtained.

This amino compound (280 mg) was cooled with ice to give 10
% H ₂ SO ₄ (5 ml), dissolved in sodium nitrite (120 mg) aqueous solution (0.2 ml),
The temperature was raised to room temperature and stirring was continued for 1 hour. Then, it was neutralized with a sodium hydrogen carbonate solution and extracted twice with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 99: 1 to 9).
8: 2) to give the title compound (200 m
g; 69%).

(Example 43) 6- [4-bromo-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -1-methyl-1H-benzotriazole 5- [4-bromo-2- (1H-1,
2,4-Triazol-1-yl) methyl] phenoxy-N-methyl-2-nitroaniline (11 g) was dissolved in acetic acid (120 ml), and zinc powder (10.
6 g) was added in small portions. After the addition, the mixture was stirred for 5 minutes. Ethyl acetate was added to remove insoluble matter, and the filtrate was concentrated under reduced pressure. A saturated sodium hydrogen carbonate solution was carefully added to the residue to make it alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting crude product of 4- [4-bromo-2- (1H-1,2,4-triazol-1-ylmethyl) phenoxy] -2-methylaminoaniline was iced. It was dissolved in 10% H ₂ SO ₄ (120 ml) under cooling, and sodium nitrite (3.75 g) aqueous solution (20 ml) was added thereto.
After adding, the mixture was warmed to room temperature and stirred for 1 hour.
Then, it was neutralized with a sodium hydrogen carbonate solution and extracted twice with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1-20: 1) to give the title compound (4.55 g; 43%). This is HPLC
It had a purity of 99.2% in the purity test according to.

Example 44 1-Methyl-6- [2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -1H-benzotriazole Method A: According to Example 43, N-methyl-2-nitro-5- [2- (1H-1,2,4-triazole-1-) obtained in Example 31. The title compound (4.18 g; 81%) was obtained from ylmethyl) phenoxy] aniline (5.5 g). This product is 99.7% in purity test by HPLC.
Had a purity of. Method B: 6- [4-bromo-2- (1 obtained in Example 43
H-1,2,4-triazol-1-ylmethyl) phenoxy] -1-methyl-1H-benzotriazole (7
7 mg) was suspended in DMF (1 ml) -MeOH (1 ml), 10% palladium carbon (10 mg) was added thereto, the reaction system was replaced with hydrogen, and the mixture was stirred at room temperature for 7 hours. Ethyl acetate was added, the catalyst was filtered off, the reaction mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ether was added to the residue for crystallization to give pale yellow crystals (53 mg; 87%).

(Examples 45 to 49) According to Example 43, the compounds shown in Table 9 below were synthesized.

[0181]

Example 50 1-Methyl-6- [4-
Nitro-2- (1H-1,2,4-triazole-1-
Synthesis of Ilmethyl) phenoxy] -1H-benzotriazole 1-Methyl-6- [2- (1H-1,
2,4-triazol-1-ylmethyl) phenoxy]
A suspension of -1H-benzotriazole (0.5 g), sodium nitrate (0.28 g) and trifluoroacetic acid (5 ml) was stirred at room temperature for 3 days. Sodium nitrate (0.
28 g) was added, and the mixture was further stirred at room temperature for 1 day. The reaction mixture was neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The pale yellow crude crystals obtained were washed with ethyl acetate and the white crystals obtained were recrystallized from methanol three times to give the title compound (0.15 g; 25%).
I got This product was 98.8 by purity test by HPLC.
It had a purity of%.

Example 51 4- [6- (1-Methyl-1H-benzotriazoyloxy)]-3- (1H-
Synthesis of 1,2,4-triazol-1-ylmethyl) acetophenone 1-Methyl-6- (1H-1,2,4 obtained in Example 44
-Triazol-1-ylmethyl) phenoxy-1H-
Benzotriazole (0.5 g) carbon disulfide (10 m
l) Acetyl chloride (0.7 ml) and then aluminum chloride (0.44 g) were added to the suspension, and the mixture was heated under reflux for 8 hours. Water (20 ml) was added, the reaction mixture was adjusted to pH 8 with saturated sodium hydrogen carbonate solution and extracted with methylene chloride.
The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (ethyl acetate: hexane = 8: 1) to give the title compound (0.13 g; 23%). This is HPLC
It had a purity of 98.3% in the purity test according to.

(Example 52) 4- [6- (1-methyl-1H-benzotriazoyloxy)]-3- (1H-
Synthesis of 1,2,4-triazol-1-ylmethyl) benzonitrile 6- [4-bromo-2- (1H-1,
2,4-triazol-1-ylmethyl) phenoxy]
-1-Methyl-1H-benzotriazole (2.3 g)
Was dissolved in anhydrous DMF (20 ml), and palladium acetate (200 mg) and triphenylphosphine (0.4
7 g), KCN (0.6 g) crushed in a mortar and calcium hydroxide (62 mg) were added, and the mixture was heated with stirring at 100 ° C. for 30 minutes. After returning to room temperature, water was added to the reaction solution, and the mixture was extracted twice with methylene chloride. The organic layers were combined, washed with water three times and saturated brine once, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography (hexane: ethyl acetate = 1: 6).
The title compound (1.8 g; 90%) was obtained by purification with. This product has a purity of 96.3% by HPLC.
Had a purity of.

Example 53 4- [6- (1-Methyl-1H-benzotriazoyloxy)]-3- (1H-
Synthesis of 1,2,4-triazol-1-ylmethyl) benzaldehyde 4- [6- (1-methyl-1H-benzotriazoyloxy)]-3- (1H-1,2,4 obtained in Example 52 −
Triazol-1-ylmethyl) benzonitrile (1.
1.5 g of a suspension of 0 g) of THF (20 ml) at -78 ° C.
Add M DIBAL-H (2.2ml) for 2 hours-78
Stirred at ° C. The mixture was returned to room temperature, water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. Combine the organic layers and mix with water 3
The extract was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate = 1: 6) to give the title compound (0.2 g;
21%) was obtained. This product had a purity of 92.5% in a purity test by HPLC.

(Example 54) 4- [6- (1-methyl-1H-benzotriazoyloxy)]-3- (1H-
Synthesis of 1,2,4-triazol-1-ylmethyl) benzoic acid 4- [6- (1-methyl-1H-benzotriazoyloxy)]-3- (1H-1,2, obtained in Example 52 4-
Triazol-1-ylmethyl) benzonitrile (0.
5 g of 1N-NaOH (5 ml), ethanol (5 m
l) The suspension was heated to reflux for 8 hours. The reaction solution was concentrated under reduced pressure, water (10 ml) was added, and the pH was adjusted to 4 with acetic acid. The precipitated crystals were collected by filtration and washed successively with ethanol and ether to give the title compound (0.48 g; 91%). This product had a purity of 93.3% in a purity test by HPLC.

Example 55 4- [6- (1-Methyl-1H-benzotriazoyloxy)]-3- (1H-
Synthesis of 1,2,4-triazol-1-ylmethyl) benzoic acid ethyl ester 4- [6- (1-methyl-1H-benzotriazoyloxy)]-3- (1H-1, obtained in Example 54 2,4-
Triazol-1-ylmethyl) benzoic acid (0.2
g), potassium carbonate (43 mg) in acetone (5 ml)
Diethyl sulfuric acid (97 mg) was added to the suspension, and the mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, water (10 ml) was added, the mixture was adjusted to pH 9 with saturated sodium hydrogen carbonate and extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel flash column chromatography (methylene chloride: methanol = 99: 1 to 49:
The title compound (0.14 g; 6
5%). This product has a purity test of 9
It had a purity of 9.2%.

(Example 56) 6- [4-ethenyl-2]
Synthesis of-(1H-1,2,4-triazol-1-ylmethyl) phenoxy] -1-methyl-1H-benzotriazole Methyltriphenylphosphonium bromide (1.07g) in anhydrous THF (30ml) suspension. T-BuOK at room temperature
(0.34 g) was added and stirred for 1 hour. The reaction mixture was ice-cooled and the 4- [6- (1-methyl-1H-benzotriazoyloxy)]-3- (1H-obtained in Example 53 was obtained.
A solution of 1,2,4-triazol-1-ylmethyl) benzaldehyde (0.50 g) in methylene chloride (30 ml) was added dropwise. After dropping, the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (100 ml) and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (ethyl acetate: hexane = 9: 1) to give the title compound (0.47 g; 95%). This product had a purity of 100% in a purity test by HPLC.

(Example 57) 6- [2- (1H-1,
2,4-triazol-1-ylmethyl) -4- (trimethylsilylethynyl) phenoxy] -1-methyl-1
Synthesis of H-benzotriazole 6- [4-bromo-2- (1H-1,
2,4-triazol-1-ylmethyl) phenoxy]
-1-Methyl-1H-benzotriazole (0.50
g), palladium acetate (2.9 mg), triphenylphosphine (6.8 mg), triethylamine (2 m
l), D of trimethylsilylacetylene (0.29 g)
The MF (5 ml) solution was heated with stirring at 120 ° C. for 5 hours. The reaction solution was diluted with methylene chloride (50 ml), water,
It was washed successively with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (ethyl acetate: hexane = 1: 1-4: 1) to give the title compound (0.39 g; 75%).

(Example 58) 6- [4-ethynyl-2]
Synthesis of-(1H-1,2,4-triazol-1-ylmethyl) phenoxy] -1-methyl-1H-benzotriazole 6- [2- (1H-1,2,4-triazole obtained in Example 57. To a solution of -1-ylmethyl) -4- (trimethylsilylethynyl) phenoxy] -1-methyl-1H-benzotriazole (0.38 g) in methanol (3 ml) was added potassium carbonate (15 mg), and the mixture was stirred at room temperature for 1.5 hours. It was stirred. The reaction solution was diluted with methylene chloride (30 ml) and washed successively with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude crystals, which were washed with hexane to give the title compound (0.2
5g; 80%) was obtained. This product had a purity of 100% in a purity test by HPLC.

(Example 59) 2-methoxymethoxy-
Synthesis of 5- (trifluoromethyl) benzaldehyde 1. To a solution of 4- (trifluoromethyl) phenylmethoxymethyl ether (5 g) in anhydrous ether (50 ml).
6M n-BuLi (16.7 ml) is slowly added dropwise at room temperature. After stirring at room temperature for 2 hours, DMF (4.13 m
An anhydrous ether solution (20 ml) of 1) was added dropwise over 30 minutes and then stirred for 1 hour. Water was added to the reaction solution and the ether layer was separated. The ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: hexane = 1: 1) to give the title compound (4.49 g; 79%).

(Example 60) 2-methoxymethoxy-
Synthesis of 5- (trifluoromethyl) benzyl alcohol A solution of 2-methoxymethoxy-5- (trifluoromethyl) benzaldehyde (3.3 g) obtained in Example 59 in anhydrous methanol (20 ml) was ice-cooled and NaBH ₄ (0 .5
3 g) was added slowly. After stirring for 15 minutes at room temperature, the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.15 g; 95%) as a colorless oil.

Example 61 2-Hydroxymethyl-
Synthesis of 4- (trifluoromethyl) phenol 10% H ₂ SO ₄ (5 m) was added to a methanol solution (20 ml) of 2-methoxymethoxy-5- (trifluoromethyl) benzyl alcohol (3.15 g) obtained in Example 60.
1) was added and the mixture was heated under reflux for 1 hour. The solvent is distilled off under reduced pressure,
Water was added to the residue and extracted with ether. The ether layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.5 g; 98%).

(Example 62) 2- (1H-1,2,4)
Synthesis of -triazol-1-ylmethyl) -4- (trifluoromethyl) phenol According to Example 21, 2-hydroxymethyl-4- (trifluoromethyl) phenol (2.7 was obtained in Example 61.
g) and 1H-1,2,4-triazole (1.07 g)
Gave the title compound (1.55 g; 45%).

Example 63 N-Methyl-2-nitro-5- [2- (1H-1,2,4-triazole-1-
Synthesis of Ilmethyl) -4- (trifluoromethyl) phenoxy] aniline 2- (1H-1,2,4-triazol-1-ylmethyl) -4- (trifluoromethyl) phenol (1. 0g), 5-fluoro-N-methyl-2
- nitroaniline (700 mg) and K ₂ CO ₃ (0.
57 g) of DMF (10 ml) at 100 ° C. 90
Heated for minutes. The temperature was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 99: 1) to give the title compound (960
mg; 59%).

(Example 64) 6- [2- (1H-1,
Synthesis of 2,4-triazol-1-ylmethyl) -4- (trifluoromethyl) phenoxy] -1-methyl-1H-benzotriazole N-methyl-2-nitro-5- [2- obtained in Example 63
(1H-1,2,4-triazol-1-ylmethyl)
-4- (Trifluoromethyl) phenoxy] aniline (1.0 g) was dissolved in acetic acid (10 ml), and zinc dust (830 mg) was added thereto little by little at room temperature. After the addition, ethyl acetate was added to remove the insoluble matter, and a saturated sodium hydrogen carbonate solution was carefully added to the filtrate to separate the layers. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product 2-methylamino-4-
[2- (1H-1,2,4-triazol-1-ylmethyl) -4- (trifluoromethyl) phenoxy] aniline (920 mg) was obtained.

This amino compound was treated with 10% H ₂ SO under ice cooling.
Dissolve in ₄ (10 ml) and add sodium nitrite (3
After adding 50 mg) aqueous solution (1.0 ml), the temperature was raised to room temperature and stirring was continued for 5 hours. Then, it was neutralized with a sodium hydrogen carbonate solution and extracted twice with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride: methanol = 99: 1 to 98: 2).
The title compound (790 mg; 83
%) Was obtained. This product has a purity test of 9
It had a purity of 9.4%.

Example 65 Synthesis of 5-chloro-N-ethyl-2-nitroaniline A suspension of LiAlH ₄ (0.53 g) in THF (50 ml) was cooled with ice and N-acetyl-5-chloro- A solution of 2-nitroaniline (3 g) in THF (30 ml) was added dropwise over 30 minutes. Then, the mixture was stirred for 1 hour under ice cooling. Ice was carefully added to the reaction solution, ethyl acetate and saturated brine were added, and the insoluble material was filtered off. The ethyl acetate layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to give the title compound (1.14 g; 41%).

(Example 66) 5- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -N-ethyl-2-nitroaniline 4-chloro-2- (1H-1,2,4 obtained in Example 20
-Triazol-1-ylmethyl) phenol (1.4
g) in MeOH solution (30 ml) with NaOMe (0.4
g) was added in portions at room temperature. After stirring for 15 minutes at room temperature, the mixture was concentrated to dryness under reduced pressure. To this, DMI (30 ml), 5-chloro-N-ethyl-2-nitroaniline (1.34 g) obtained in Example 65 and copper powder (42 mg) were added, and 130 ° C was added.
Heated at 3.5 hours. The temperature was returned to room temperature, water and ethyl acetate were added, and the copper powder was filtered off. Wash the organic layer with saturated saline,
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (methylene chloride: methanol = 99: 1) to give the title compound (1.75 g; 70%).

(Example 67) 6- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of Phenoxy] -1-ethyl-1H-benzotriazole 5- [4-chloro-2- (1H-1,
2,4-triazol-1-ylmethyl) phenoxy]
-N-Ethyl-2-nitroaniline (1.7 g) was dissolved in acetic acid (20 ml), and zinc powder (1.42) was added thereto at room temperature.
g) was added little by little and stirred for 5 minutes. Ethyl acetate was added to remove insoluble matter, and the filtrate was concentrated under reduced pressure. A saturated sodium hydrogen carbonate solution was carefully added to the residue to make it alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting crude product of residue 4- [4-chloro-2- (1
H-1,2,4-triazol-1-ylmethyl) phenoxy] -2-ethylaminoaniline was cooled to 10% H under ice cooling.
_After dissolving in ₂ SO ₄ (20 ml) and adding an aqueous solution of sodium nitrite (0.63 g) (3 ml) thereto, the temperature was raised to room temperature and stirring was continued for 1 hour. Then, it was neutralized with a sodium hydrogen carbonate solution and extracted twice with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 99: 1 to 49:
The title compound (1.3 g; 81
%) Was obtained. This product has a purity test of 9
It had a purity of 9.3%.

(Example 68) 6- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenoxy] -1-methylbenzimidazole 4- [4-chloro-2-obtained as intermediate in Example 41
(1H-1,2,4-triazol-1-ylmethyl)
Phenoxy] -2-methylaminoaniline (100 m
Formic acid (1 ml) was added to g) and the mixture was stirred under reflux for 1 hour. The mixture was returned to room temperature, neutralized with saturated sodium hydrogen carbonate, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (95 mg; 92%). This is H
It had a purity of 97.7% in a purity test by PLC.

(Example 69) 5- (4-chloro-2-
Hydroxymethylphenylthio) -N-methyl-2-ni
Synthesis of troaniline 4-chloro-2- (hydroxymethyl) obtained in Example 16
Lu) thiophenol (1.0 g), 5-fluoro-N-
Methyl-2-nitroaniline (1.0 g) and K ₂CO
₃(0.81g) in DMF (20ml) at 90 ° C
And heated for 15 minutes. Return to room temperature, add water, and add ethyl acetate.
It was extracted with. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
Dried with thorium. The solvent was evaporated under reduced pressure and the residue was
Purification by Kagel column chromatography (methylene chloride)
The title compound (1.62 g; 85%) was prepared by
Obtained.

(Example 70) 5- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of phenylthio] -N-methyl-2-nitroaniline 5- (4-chloro-2-hydroxymethylphenylthio) -N-methyl-2-nitroaniline (0.20 g) obtained in Example 69, pyridine ( 0.055 ml) in methylene chloride (3 ml) under ice cooling to thionyl chloride (0.05 ml).
(49 ml) was added, followed by stirring for 15 minutes. Water was added, the mixture was extracted with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 5- [4-chloro-2- (chloromethyl) as a crude product.
Phenylthio] -N-methyl-2-nitroaniline (0.21 g) was obtained. This chloromethyl derivative was dissolved in acetonitrile (3 ml), and cesium carbonate (0.3 g) and 1H-1,2,4-triazole (6
0 mg) was added and the mixture was refluxed for 15 minutes. The mixture was returned to room temperature, the solvent was distilled off, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 19).
The title compound (140 mg; 60%) was obtained by purification with 9: 1 to 99: 1).

(Example 71) 6- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of Phenylthio] -1-methyl-1H-benzotriazole 5- [4-chloro-2- (1H-1,
2,4-Triazol-1-ylmethyl) phenylthio] -N-methyl-2-nitroaniline (0.14 g)
Was dissolved in acetic acid (2 ml), and zinc powder (12 ml) was added at room temperature.
0 mg) was added in small portions. After the addition, ethyl acetate was added to remove the insoluble matter, and a saturated sodium hydrogen carbonate solution was carefully added to the filtrate to separate the layers. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product 4- [4-chloro-2- (1H-1,
2,4-triazol-1-ylmethyl) phenylthio] -2-methylaminoaniline was obtained.

This aniline derivative was treated with 10% H ₂ S under ice cooling.
Dissolve in O ₄ (2 ml) and add sodium nitrite (5
0 mg) aqueous solution (0.5 ml) was added, the temperature was raised to room temperature, and the mixture was stirred for 20 hours as it was. Then, it was neutralized with a sodium hydrogen carbonate solution and extracted twice with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride: methanol = 99: 1 to 98: 2).
By purification with the title compound (55 mg; 41%)
I got This is 100% in purity test by HPLC
Had a purity of.

(Example 72) Synthesis of 2-bromo-5-chlorobenzaldehyde A solution of 2-bromo-5-chlorotoluene (25 g) in acetic anhydride (100 ml) and concentrated sulfuric acid (20 ml) was cooled to -15 ° C. Chromium trioxide (36.5g) acetic anhydride (20
0 ml) solution was added dropwise over 3 hours. After stirring at -5 ° C for 1 hour, the reaction mixture was poured into ice water and extracted with ether. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was ethanol (100 ml), 3N-HCl (20
0 ml) and the mixture was refluxed for 1 hour. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ether. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: methylene chloride = 4: 1) to obtain the title compound (20.5 g; 77%).

Example 73 Synthesis of 2-bromo-5-chlorobenzyl alcohol A solution of 2-bromo-5-chlorobenzaldehyde (20.5 g) obtained in Example 72 in anhydrous methanol (200 ml) was ice-cooled, Sodium borohydride (1.06 g) was gradually added, and the mixture was stirred for 30 minutes. Acetone was added, the solvent was evaporated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (19.5 g; 94%).

Example 74 Synthesis of 2-bromo-5-chloro-3-t-butyldimethylsilyloxymethylbenzene 2-Bromo-5-chlorobenzyl alcohol (10.0 g) obtained in Example 73, imidazole A solution of (3.23 g) in anhydrous DMF (50 ml) was ice-cooled and t-butylchlorodimethylsilane (7.15 g) in anhydrous DMF (10 m).
l) The solution was added dropwise over 20 minutes. After dropping, at room temperature 3
Stir for 0 minutes. The reaction solution was diluted with ether, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: methylene chloride = 4: 1) to obtain the title compound (13.3 g; 88%).

Example 75 α- [2- (t-butyldimethylsilyloxy) methyl-4-chlorophenyl]
Synthesis of 1-methyl-1H-benzotriazole-6-methanol 2-Bromo-5-chloro-obtained in Example 74 was added to a suspension of magnesium (0.84 g) and iodine (a small amount) in anhydrous ether (3 ml). Anhydrous ether of 3-t-butyldimethylsilyloxymethylbenzene (10.3 g) (100 m
l) The solution was gradually added dropwise at room temperature, and the mixture was stirred for 1 hour after the addition. The reaction solution was ice-cooled, and anhydrous THF (100 ml) of 1-methyl-1H-benzotriazole-6-carboxylic acid aldehyde (3.29 g) was added dropwise over 20 minutes. After dropping, the mixture was stirred at room temperature for 30 minutes, ice-cooled again, saturated aqueous ammonium chloride was gradually added, and the ether layer was separated. The ether layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 9: 1) to give the title compound (4.3
1 g; 51%) was obtained.

Example 76 6- [2- (t-butyldimethylsilyloxy) methyl-4-chlorobenzyl]
Synthesis of -1-methyl-1H-benzotriazole α- [2- (t-butyldimethylsiloxy) methyl-4-chlorophenyl] -1-methyl-1 obtained in Example 75
H-benzotriazole-6-methanol (0.50
g), pyridine (0.11 ml) in methylene chloride (5 m
1) The solution was ice-cooled, thionyl chloride (0.10 ml was added, and the mixture was stirred for 30 minutes. The reaction solution was diluted with methylene chloride,
It was washed with water and saturated saline. It was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude 6- [2
-(T-Butyldimethylsiloxy) methyl-α, 4-dichlorobenzyl] -1-methyl-1H-benzotriazole was obtained.

Anhydrous DMSO (5 ml) of the obtained crude product
Sodium borohydride (90 mg) was added to the solution,
The mixture was stirred at room temperature for 2 hours. Sodium borohydride (9
0 mg) was added, and the mixture was stirred at room temperature for 2.5 days. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (methylene chloride) to give the title compound (0.24 g; 50%).

Example 77 5-chloro-2-[(1
Synthesis of -Methyl-1H-benzotriazol-6-yl) methyl] benzyl alcohol 6- [2- (t-butyldimethylsiloxy) methyl-4-chlorobenzyl] -1-methyl-1 obtained in Example 76
H-benzotriazole (0.24 g) in THF (3 m
l) 1.0 M tetrabutylammonium fluoride (1.2 ml) was added to the solution, and the mixture was stirred at room temperature for 30 minutes.
The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 2).
The title compound (0.16 g; 93
%) Was obtained.

Example 78 6- [4-chloro-2-
Synthesis of (chloromethyl) benzyl] -1-methyl-1H-benzotriazole 5-chloro-2-[(1-methyl-1) obtained in Example 77
H-benzotriazol-6-yl) methyl] benzyl alcohol (0.16 g), pyridine (0.05 ml)
The methylene chloride (2 ml) solution of was cooled with ice, thionyl chloride (0.04 ml) was added, and the mixture was stirred for 30 minutes. The title compound (0.12 g; 70%) was obtained by purifying the residue obtained by evaporating the solvent under reduced pressure by silica gel column chromatography (methylene chloride: methanol = 199: 1).
I got

Example 79 6- [4-chloro-2-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of benzyl] -1-methyl-1H-benzotriazole 6- [4-chloro-2- (chloromethyl) benzyl] -1-methyl-1H-benzotriazole (0.11 g), obtained in Example 78, 1H A suspension of -1,2,4-triazole (37 mg) and cesium carbonate (0.18 g) in acetonitrile (2 ml) was heated under reflux for 30 minutes.
The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 9).
9: 1) to give the title compound (63 mg;
52%). This product had a purity of 96.7% in a purity test by HPLC.

(Example 80) 4-[(1-methyl-1)
H-benzotriazol-6-yl) methyl] -3-
(1H-1,2,4-triazol-1-ylmethyl)
Synthesis of benzonitrile 6- [4-chloro-2- (1H-1,
2,4-triazol-1-ylmethyl) benzyl]-
1-methyl-1H-benzotriazole (80 mg),
KCN (46 mg) in anhydrous EtOH (8 ml) was added to tetrakis (triphenylphosphine) nickel (0.3
9 g) was added, and the mixture was stirred in a sealed tube at 90-100 ° C for 10 hours. Ethyl acetate was added to the reaction solution, insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate). The title compound (23 mg; 29%) was obtained by recrystallization from. This product had a purity of 96.5% in a purity test by HPLC.

Physical property data of the compounds of Examples 1 to 80 are shown in Table 10, and structural formulas are shown in Table 11.

[0219]

[Table 2]

[0218]

[Table 3]

[0219]

[Table 4]

[0220]

[Table 5]

[0221]

[Table 6]

[0222]

[Table 7]

[0223]

[Table 8]

[0224]

[Table 9]

[0225]

[Table 10]

[0226]

[Table 11]

[0227]

[Table 12]

[0228]

[Table 13]

[0229]

[Table 14]

[0230]

[Table 15]

[0231]

[Table 16]

[0232]

[Table 17]

Next, formulation examples containing the compound of the present invention will be shown, but the present invention is not limited thereto.

(Formulation Example 1 Tablet) Example Compound 41 2 g Polyethylene glycol 6000 100 g Sodium lauryl sulfate 15 g Corn starch 30 g Lactose 348 g Magnesium stearate 5 g After weighing the above ingredients, respectively, polyethylene glycol 6000 was heated to 70 to 80 ° C. Then, Example Compound 41, sodium lauryl sulfate, corn starch and lactose are added thereto, and the mixture is cooled as it is. The solidified mixture is pulverized by a crusher. The granules are mixed with magnesium stearate and compressed to give tablets having a weight of 250 mg.

(Formulation Example 2 Capsule) Example Compound 43 10 g Lactose 340 g Corn starch 50 g Microcrystalline cellulose 95 g Magnesium stearate 5 g After weighing each of the above components, the four components other than magnesium stearate are uniformly mixed. Add magnesium stearate and mix for a few more minutes. 250m weight of the mixture in a suitable hard capsule with an encapsulator
Fill each g to make a capsule.

(Formulation Example 3 Injection) Example compound 52 1 g Propylene glycol 200 g Sterile distilled water for injection Appropriate amount After weighing the above components, the example compound 52 is dissolved in propylene glycol. Sterile distilled water for injection is added to make the total volume up to 1,000 ml, and after sterilization by filtration, 5 ml each is dispensed into 10 ml ampoules and sealed to obtain an injection.

(Formulation Example 4 Suppository) Example Compound 50 5 g Polyethylene glycol 1500 250 g Polyethylene glycol 4000 250 g Example Compound 50 was sufficiently ground in a mortar to give a fine powder, and then 1 g of each suppository was prepared by a melting method. And

[0238]

Industrial Applicability The azole methylphenyl derivative of the present invention exhibits excellent aromatase inhibitory activity in vitro, and exhibits remarkable blood estrogen lowering effect in animal experiments using an in vivo experimental animal model in rats. It was revealed that the specificity of aromatase inhibition is high and the safety is high. It has been revealed that the azole methylphenyl derivative of the present invention is excellent in at least one or more of these.

Therefore, these azole methylphenyl derivatives are useful for estrogen-dependent diseases such as estrogen-dependent cancers (breast cancer, ovarian cancer, endometrial cancer, etc.), endometriosis, uterine fibroids, benign breast disease, and mastopathy. , Preterm labor, benign prostatic hyperplasia, prostate cancer, precocious puberty, gynecomastia,
It is extremely useful as a prophylactic and / or therapeutic agent for male infertility or cholelithiasis associated with hypospermia. Furthermore, it is useful as a female fertility regulator.

Since the compound of the present invention has an aromatase inhibitory activity in vitro and in vivo, it is useful as a reagent or an aromatase inhibitor for animals.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/695 C07D 233/61 101 249/08 515 526 249/18 501 403/12 233 C12N 9 / 99 // C07F 7/18 T (72) Inventor Manabu Ito 1-7 Yotsuya, Shinjuku-ku, Tokyo Mochida Pharmaceutical Co., Ltd.

Claims (16)

[Claims] 1. The following formula (I): (In the formula, A represents a methylene group, an oxygen atom or a sulfur atom, D represents a nitrogen atom or a methine group, R ¹ is substituted with a halogen atom, a cyano group, a nitro group, or one or more fluorine atoms. 1 to 2 carbon atoms that may be added
An alkoxy group, an alkyl group having 1 to 2 carbon atoms which may be substituted with one or two or more fluorine atoms, a linear or branched alkenyl group having 2 to 5 carbon atoms,
Represents a linear or branched alkynyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group or a hydrogen atom, and R ² is represented by the following formula (II): 2] Or the following formula (III): In the formula, E represents a nitrogen atom or a methine group, and R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ) The compound represented by these, or its salt. 2. A is an oxygen atom and D is a nitrogen atom.
R¹Is at the 4-position, and R is ²Is the formula (III)
The bonding position of the atomic group represented by is 6-position,
1. The compound according to 1, or a salt thereof. 3. The compound according to claim 1 or 2, wherein E is a nitrogen atom and R ³ is a methyl group, or a salt thereof. 4. The compound according to claim 1, wherein R ¹ is a halogen atom, a cyano group or a nitro group, or a salt thereof. 5. The compound according to claim 1, wherein R ¹ is a vinyl group or an ethynyl group, or a salt thereof. 6. A is an oxygen atom and D is a methine group.
R¹Is at the 4-position, and R is ²Is the formula (III)
The bonding position of the atomic group represented by is 6-position,
1. The compound according to 1, or a salt thereof. 7. The following formula (IX): (In the formula, A represents a methylene group, an oxygen atom or a sulfur atom, R ¹ represents a halogen atom, a cyano group, a nitro group, or 1 or 2 carbon atoms which may be substituted with one or more fluorine atoms. Alkoxy group, an alkyl group having 1 to 2 carbon atoms which may be substituted with one or more fluorine atoms, a straight chain or branched alkenyl group having 2 to 5 carbon atoms, and 2 to 5 carbon atoms. Represents a linear or branched alkynyl group, an alkoxycarbonyl group having 1 or 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group or a hydrogen atom, and R ² is represented by the following formula (II): Or the following formula (III): In the formula, E represents a nitrogen atom or a methine group, R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a halogen atom or It represents a hydroxyl group which may be protected. ) Or a salt thereof and the following formula (X): (Wherein D represents a nitrogen atom or a methine group) by reacting with an azole compound represented by the following formula (I): (Wherein E and R ³ described in the definitions of A, D, R ¹ , R ² and R ² have the same meanings as described above), or a method for producing a salt thereof. 8. The following formula (VII): (In the formula, G represents an oxygen atom or a sulfur atom, R ¹ represents a halogen atom, a cyano group, a nitro group, or an alkoxy group having 1 or 2 carbon atoms which may be substituted with one or more fluorine atoms. An alkyl group having 1 or 2 carbon atoms which may be substituted with one or two or more fluorine atoms,
A straight-chain or branched alkenyl group having 2 to 5 carbon atoms, a straight-chain or branched alkynyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group Or a hydrogen atom, R ⁵ represents a halogen atom or an optionally protected hydroxyl group, and R ⁶ represents a compound represented by the following formula (II): Or the following formula (XI): In the formula, R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ) Or a salt thereof and a compound represented by the following formula (X): (Wherein D represents a nitrogen atom or a methine group) is reacted with an azole compound to give a compound represented by the following formula (VIII): (In the formula, D represents a nitrogen atom or a methine group, and G, R
¹ and R ⁶ have the same meanings as described above. ) Or a salt thereof, and if necessary, further subjected to a reduction reaction and then a cyclization reaction to obtain a compound represented by the following formula (I):
-B (Wherein E and R ³ described in the definitions of G, D, R ¹ , R ² and R ² have the same meanings as described above), or a method for producing a salt thereof. 9. The following formula (VI):(In the formula, G represents an oxygen atom or a sulfur atom, and D represents nitrogen.
Represents an elementary atom or a methine group, R¹Is a halogen atom,
Cyano group, nitro group, one or more fluorine atoms
An alkoxy having 1 to 2 carbon atoms which may be substituted with
A group, substituted by one or more fluorine atoms
Also, an alkyl group having 1 or 2 carbon atoms, or 2 or 3 carbon atoms
5 straight or branched chain alkenyl group, no carbon number 2
A straight-chain or branched alkynyl group having 5 carbon atoms
Alkoxycarbonyl group, carboxyl group,
It represents a cetyl group, a formyl group or a hydrogen atom. )
Compound or a salt thereof, and a compound of formula R⁶X (in the formula
X represents a halogen atom, R ⁶Is represented by the following formula (II):Or the following formula (XI):Is an atomic group represented by R in the formula³Is a hydrogen atom or carbon
Represents a straight or branched chain alkyl group of the numbers 1 to 4
You ) With an aryl halide represented by
Formula (VIII):(In the formula, G, D, R¹, R⁶And R⁶Listed in the definition
R³Represents the same meaning as described above. ) Compound
Compound or its salt, and if necessary further reduction
The following formula (I) is obtained by carrying out a reaction and then a cyclization reaction.
-B(In the formula, G, D, R¹, R²And R²Listed in the definition
E and R³Represents the same meaning as described above. )
And a method for producing the salt thereof. 10. The following formula (I): (In the formula, A represents a methylene group, an oxygen atom or a sulfur atom, D represents a nitrogen atom or a methine group, R ¹ is substituted with a halogen atom, a cyano group, a nitro group, or one or more fluorine atoms. 1 to 2 carbon atoms that may be added
An alkoxy group, an alkyl group having 1 to 2 carbon atoms which may be substituted with one or two or more fluorine atoms, a linear or branched alkenyl group having 2 to 5 carbon atoms,
Represents a linear or branched alkynyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group or a hydrogen atom, and R ² is represented by the following formula (II): 21] Or the following formula (III): In the formula, E represents a nitrogen atom or a methine group, and R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ) A prophylactic or therapeutic agent for an estrogen-dependent disease, which comprises, as an active ingredient, at least one selected from the group consisting of the compound represented by the formula) and a pharmaceutically acceptable salt thereof. 11. A is an oxygen atom and D is a nitrogen atom.
R¹Is at the 4-position, and R is ²Is the formula (III)
The bonding position of the atomic group represented by is 6-position,
10. Preventive agent or treatment for estrogen-dependent diseases according to 10.
Agent. 12. The preventive or therapeutic agent for an estrogen-dependent disease according to claim 10, wherein E is a nitrogen atom and R ³ is a methyl group. 13. The preventive or therapeutic agent for an estrogen-dependent disease according to claim 10, wherein R ¹ is a halogen atom, a cyano group or a nitro group. 14. The preventive or therapeutic agent for an estrogen-dependent disease according to claim 10, wherein R ¹ is a vinyl group or an ethynyl group. 15. A is an oxygen atom and D is a methine group.
R¹Is at the 4-position, and R is ²Is the formula (III)
The bonding position of the atomic group represented by is 6-position.
0. Preventive agent or treatment for estrogen-dependent diseases according to 0.
Agent. 16. The following formula (I): (In the formula, A represents a methylene group, an oxygen atom or a sulfur atom, D represents a nitrogen atom or a methine group, R ¹ is substituted with a halogen atom, a cyano group, a nitro group, or one or more fluorine atoms. 1 to 2 carbon atoms that may be added
An alkoxy group, an alkyl group having 1 to 2 carbon atoms which may be substituted with one or two or more fluorine atoms, a linear or branched alkenyl group having 2 to 5 carbon atoms,
Represents a linear or branched alkynyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 2 carbon atoms, a carboxyl group, an acetyl group, a formyl group or a hydrogen atom, and R ² is represented by the following formula (II): 24] Or the following formula (III): In the formula, E represents a nitrogen atom or a methine group, and R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. A) an aromatase inhibitor containing as an active ingredient at least one selected from the group consisting of a compound represented by the formula (1) and salts thereof.