WO2004033432A1 - Novel pyrazole compounds having antifungal activity - Google Patents

Abstract

A pyrazole compound represented by the following general formula (I) or its salt and a drug containing the same as the active ingredient: (I) wherein R1, R2, R3, R4 and R5 represent each a substituent; and X represents a methine group or a nitrogen atom. The above compound is useful as a preventive or a remedy for mycosis, in particular, deep-seated mycosis caused by deep-seated fungi such as candida and aspergillus and superficial mycosis caused by fungi such as trichophyton.

Description

 Novel virazole compounds with antifungal activity

Technical field

 The present invention relates to virazo / le compounds having high antifungal activity and useful for preventing and treating infectious diseases caused by fungi in mammals. Rice field

Background art

 Mycosis includes superficial mycosis represented by various tinea, vulgaris, psoriasis, cutaneous candidiasis, etc., fungal meningitis, fungal respiratory infections, mycemia, urinary tract mycosis, etc. And mycosis profound. Of these, deep-seated mycosis, such as dysbiosis and aspergillosis, has been increasing in recent years, especially due to the frequent use of cancer chemotherapeutics and immunosuppressants, and a decrease in in vivo immunity due to HIV infection and the like. There is a need for a drug that is effective against these bacteria.

 Conventionally, as a drug effective against Aspergillus and Candida, amphotericin B-diazole compounds such as fluconazole and itraconazole are known, but they are sufficient in terms of antifungal spectrum, pharmacokinetics, resistance and the like. Not satisfactory.

 In addition, azole compounds, which have been studied for many years in this field, have different structures from conventional compounds because of the problems of their effectiveness in severe patients and resistance to long-term use of the same drug. It is desired to develop a compound having excellent antibacterial activity against deep mycosis and excellent safety.

Currently, the development of new and more effective antifungal agents is underway. Antifungal agents having a pyrazole skeleton have been proposed (US Pat. No. 4,751,229, International Publication No. 0 1/2 3 8 5 and International Publication No. 9 8 8 8 9 9 5), satisfactory effective Antifungal activity has not been obtained! / Disclosure of the invention

 Therefore, an object of the present invention is to provide a virazole compound which is highly safe and has an effective antifungal activity against deep mycosis and superficial mycosis.

 The present invention provides the following general formula (I)

(Wherein, R ¹ represents an alkyl group, an alkenyl group, a phenyl group which may have a substituent, a biphenyl group which may have a substituent, or a heteroaromatic group which may have a substituent; R ³ represents a hydrogen atom, an alkyl group, an alkenyl group, a substituted or unsubstituted biphenyl group, or a substituted or unsubstituted heteroaromatic ring group; R ² represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a cyano group, a CH ₂ OH group or a CH ₂ NR ⁶ R ⁷ group ( R ⁶ and R ⁷ represents a) the same or different and each represents a hydrogen atom or a lower alkyl group;. R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, Ashiru group, a lower alkyl group, a cycloalkyl group or Fueniruaru It may have, or R ⁴ and R ⁵ indicates a Le group to form a lower alkylenedioxy O alkoxy group with together such connexion two oxygen atoms; X represents a methine group or a nitrogen atom).

Or a salt thereof.

The present invention also provides a pyrazole compound represented by the general formula (I) or a salt thereof. It is intended to provide a medicine as an active ingredient.

 The present invention also provides a pharmaceutical composition containing the pyrazole compound represented by the general formula (I) or a salt thereof, and a pharmaceutically acceptable carrier.

 The present invention also provides use of the pyrazole compound represented by the general formula (I) or a salt thereof for producing a medicament.

 Further, the present invention provides a method for treating a fungal infection, which comprises administering an effective amount of the pyrazole compound represented by the general formula (I) or a salt thereof. The pyrazole aldehyde compound represented by the general formula (I) of the present invention may be a fungal disease, particularly a deep fungal disease caused by fungi such as Candida and Aspergillus and a superficial fungus caused by fungi such as trichophyton. It is useful as a prophylactic or therapeutic agent for diseases. BEST MODE FOR CARRYING OUT THE INVENTION

In the general formula (I), the alkyl group represented by R ¹ and R ³ is preferably an alkyl group having 1 to 16 carbon atoms, more preferably 1 to 10 carbon atoms, and particularly preferably 1 to 6 carbon atoms. The alkyl group may be linear or branched, and examples thereof include a methyl group, an ethyl group, an isopropyl group, an n-butyl group, an n-hexyl group, and an n-octyl group. The alkenyl group is preferably an alkenyl group having 2 to 16 carbon atoms, more preferably 2 to 10 carbon atoms, and particularly preferably 2 to 6 carbon atoms. The alkenyl group may be linear or branched, and includes, for example, a butyl group, a propenyl group and a pentyl group.

Examples of the substituent on the phenyl group, biphenyl group and heteroaromatic group represented by R ¹ and R ³ include a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitrile group, and a NR. ⁸ R ⁹ group (R ⁸ and R ⁹ may be the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkoxyalkyl group, or R ⁸ and R ⁹ together with a nitrogen atom have a substituent May form a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group or a thiomorpholinyl group.), A halogeno-lower alkyl group, a halogeno-lower alkoxy group, a lower-alkylthio group, an acyl group, a carboxy group Xyl groups, lower alkoxycarbonyl groups, rubamoyl groups, N-lower alkyl rubamoyl groups, N, N-di-lower alkyl rubamoyl groups and the like. These substituents may be on the phenyl, biphenyl or heteroaromatic groups: You may have up to three.

Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. As the lower alkyl group, an alkyl group having 1 to 6 carbon atoms, particularly an alkyl group having 1 to 4 carbon atoms is preferable. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group. Here, the same may be mentioned as the lower alkyl group represented by R ⁸ and R ⁹ . As the lower alkoxy group, an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, is preferred, and specific examples include a methoxy group, an ethoxy group, an isopropyloxy group, and a butoxy group. As the lower alkoxyalkyl group represented by R ⁸ and R ⁹ , a CM alkoxy-C ₆ alkyl group, particularly a C _W alkoxy monoalkyl group, is preferred, and a methoxyethyl group, a methoxypropyl group, an ethoxyshetyl group, and an ethoxypropyl group are preferred. And the like. The ring formed by R ⁸ and R ⁹ together with the nitrogen atom is pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, which includes a lower alkyl group, a phenyl group, and an oxo group. (= 0) etc. may be substituted. — Specific examples of NR ⁸ R ⁹ groups include amino group, dimethylamino group, ethylamino group, methoxypropylamino group, pyrrolidinyl group, 3-oxopyrrolidinyl group, piperidinyl group, piperazinyl group, N-phenylpipe Radinyl group, morpholino group, thiomorpholino group and the like can be mentioned. As the halogeno lower alkyl group, an alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, which is substituted by 1 to 3 halogen atoms is preferable.Specific examples are chloromethyl group, trifluoromethyl group, and chloromethyl group. And a tyl group. As the halogeno lower alkoxy group, an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, which is substituted by 1 to 3 halogen atoms is preferable, and a specific example is a trifluoromethoxy group. A lower alkylthio group and For example, an alkylthio group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, is preferable, and specific examples include a methylthio group, an ethylthio group, and an isopropylthio group. As the acyl group, an alkenyl group having 2 to 6 carbon atoms is preferable, and examples thereof include an acetyl group and a propionyl group. As the lower alkoxycarbonyl group, an alkylcarbonyl group having a total of 2 to 7 carbon atoms is preferable, and specific examples include a methoxycarbonyl group and an ethoxycarbonyl group.

As the heteroaromatic ring group represented by R ¹ and R ³ , a 5-membered ring group, a 6-membered ring group or a 9- to 12-membered ring having 1 to 4 hetero atoms selected from oxygen, nitrogen and sulfur atoms And a condensed ring group of Examples of the five-membered ring include thiophene, furan, pyrrole, thiazole, imidazole, pyrazole, oxazole, triazole and the like. Examples of 6-membered rings include pyridine, pyrimidine, pyrazine, triazine and the like. Examples of the condensed ring include benzothiazole, benzimidazole, benzoxazole and the like.

As the lower alkyl group represented by RR ⁴ , R \ R ⁶ and R ⁷ , an alkyl group having 1 to 6 carbon atoms, particularly an alkyl group having 1 to 4 carbon atoms is preferable, and specifically, a methyl group, an ethyl group, and an n-propyl group Isopropyl group, n-butyl group, tert-butyl group and the like. The lower alkoxy group represented by R ² is preferably an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, and specific examples include a methoxy group, an ethoxy group, an isopropyloxy group and a butoxy group. As the lower alkoxycarbonyl group represented by R ² , an alkanol group having a total of 2 to 7 carbon atoms is preferable, and specific examples include a methoxycarbonyl group and an ethoxycarbonyl group. An CH ₂ NR ^f 'R ⁷ group represented by R ^2, aminomethyl group, dimethyl § amino methyl, Mechirua Minomechiru group, Jefferies chill § amino methyl group, and the like.

As the acyl group represented by R ⁴ and R ⁵ , an alkanoyl group having 2 to 6 carbon atoms is preferable, and examples thereof include an acetyl group and a propionyl group. The cycloalkyl group represented by R ⁴ and R ⁵ is preferably a cycloalkyl group having 3 to 6 carbon atoms, For example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group and the like can be mentioned. The phenylalkyl group represented by R ⁴ and R ^5, phenylene rules CM alkyl Le group is preferred, for example, base Njiru group, phenethyl group, phenylpropyl group and the like. As the lower alkylenedioxy group, an alkylenedioxy group having 1 to 3 carbon atoms is preferable, and examples thereof include a methylenedioxy group and an ethylenedioxy group.

 In addition, the dissociated ion of the pyrazole compound (I) is different depending on the pyrazole derivative (I) on which the pyrazole compound (I) is based, and when the pyrazole compound (I) is basic, hydrochloride, nitrate, Hydrobromide, p-toluenesulfonate, methanesulfonate, fumarate, maleate, malonate, succinate, citrate, tartrate, etc., and pyrazole compounds (I When) is acidic, sodium salts, potassium salts, ammonium salts and the like can be mentioned.

 The pyrazole compound (I) or a salt thereof may exist in the form of hydrates and various solvates, and these hydrates and solvates are also included in the present invention. Further, the pyrazole compound (I) or a salt thereof may have an isomer in some cases, and the present invention includes a mixture of the isomers, an optically active substance, and the like.

As the pyrazole compound represented by the general formula (I) of the present invention, compounds shown in the following Tables 1 to 8 are preferable.

table 1

表 2

Table 2

表 3

Table 3

表 4

Table 4

表 5

Table 5

表 6

Table 6

表 7

Table 7

表 8

Table 8

 Bn: benzyl group, Ph: phenyl group, Me: methyl group, Et: ethyl group, tBu: tertiary butyl group, Ac: acetyl group

* 1: and become R ⁵ gar緖forming a Mechirenjiokishi group together with two oxygen atoms.

The pyrazole compound represented by the general formula (I) of the present invention is obtained, for example, by condensing an aromatic aldehyde (1) and a ketone (2) into an enone (3) as shown below, and converting the enone (3) into hydrazine. It is produced by reacting with (4) to obtain pyrazoline (5) or hydrazone (6), which is then oxidized.

(Wherein, RR ² , R ³ , R ⁴ , R ⁵ and X are the same as described above.)

When R ⁴ and R ^{5 of} the pyrazole compound (I) are a benzyl group or a methyl group, and R ⁴ and R ⁵ are joined together to form an alkylene group, O—R ⁴ and. By the child break the bond one ^{R 5, R 4 == R 5} = pyrazole compound is a hydrogen atom (I) one 1s are manufactured.

^(I) (I) -1

(Wherein, RR ² , R ³ , R ⁴ , R ⁵ and X are the same as described above.)

Further, the pyrazole compound (I) is also produced by adding R ⁴ and R ⁵ to two hydroxyl groups of the pyrazole compound (I).

Enone (3) can be obtained by converting an aromatic aldehyde (1) and a ketone (2) into an alcohol such as methanol or ethanol in sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, potassium hydroxide or potassium hydroxide. Aqueous solution, hydroxide It can be obtained by reacting at room temperature for 10 to 24 hours in the presence of thorium or an aqueous solution thereof, a base such as pyridine, piperidine and pyrrolidine, or an acid such as acetic acid and sulfuric acid. Alternatively, it can be obtained by reacting at room temperature for 10 to 24 hours in the presence of a base such as pyridine, piperidine and pyrrolidine and an acid such as acetic acid.

 Further, the ketone (2) is converted to a Honey-Emmons reagent or a Wittig reagent (for example, J, Org. Chem. 1986, 51 (231,4342. Synthesis 1985 (11), 1048, J. Org. Chem. 1968, 33, The enone (3) can be obtained by heating at room temperature to 100 ° C in the presence of an appropriate base in a solvent such as 3504) and an aromatic aldehyde (1) and dimethylformamide or tetrahydrofuran.

 Here, the aromatic aldehyde (1) and the ketone (2) are commercially available, but may be produced by a known method.

 By refluxing enone (3) and hydrazine (4) in a solvent such as ethanol for 3 to 5 hours, pyrazoline (5) or hydrazone (6) can be obtained. Although hydrazine (4) is commercially available, it is manufactured by the method described in “New Experimental Chemistry Lecture 14” edited by The Chemical Society of Japan, and synthesis and reaction of organic compounds III, p.1573-1585 (1985) or a modified method thereof. You may do it.

 Virazolin (5) or hydrazone (6) is dissolved in a solvent such as toluene, benzene, xylene, or acetic acid, in a solvent such as 2,3-dichloromethane_5,6-dicyano-1,4-benzoquinone (DDQ), chloranil, and superatom. The pyrazole compound (I) is produced by oxidation together with an oxidizing agent such as a divalent iodine compound, preferably by heating at 100 ° C. for 1 to 4 hours.

Further, when R ^{5 of} the pyrazole compound (I) and R ⁵ are both a benzyl group and a methyl group, and R ⁵ is an alkylene group together, boron trifluoride, boron tripromide / methyl sulfide complex, aluminum chloride The reaction is carried out in an appropriate solvent at 0 ° C. to room temperature for 5 to 12 hours to obtain a pyrazole compound (I) in which R ⁴ and R ⁵ of the pyrazole compound (I) are both hydrogen atoms. One is obtained.

 After the above reaction, the pyrazole (I) can be isolated from the final reaction mixture by a conventional method, for example, solvent extraction, recrystallization, column chromatography, or the like.

When R ¹ in the general formula (I) is a phenyl group which may have a substituent, a biphenyl group which may have a substituent, or a heteroaromatic ring group which may have a substituent, It is also produced by the following reaction formula.

(I) -3 (I) One 2 (Wherein, R ^{1 {)} represents a phenyl group, a biphenyl group or a heteroaromatic ring which may have a substituent, wherein the substituent is the same as the substituent of the phenyl group in which R ¹ has a substituent. Y represents a chlorine atom, a bromine atom or an iodine atom, and R ² , R ³ , R ⁴ , R ⁵ and X are as defined above. )

Similarly to the above-mentioned production method, the aromatic aldehyde (1) and the ketone (2) are condensed to obtain an enone (3), which is then reacted with hydrazine, and then oxidized to obtain a pyrazole (7). 7) is subjected to a coupling reaction using copper (for example, J. CH CH. S0C. 2002, 124/7421), followed by separation of positional isomers to obtain pyrazole compound (I) -12. Examples of the ligand used in this coupling reaction include N, Ν'-dimethylethylenediamine, trans- 一, Ν'dimethyl-1,2-cyclohexanediamine, and the like. Powders, copper iodide (CuI), copper chloride (CuCl), Cu (acac) _{2 and the} like, and bases such as potassium phosphate, potassium carbonate, cesium carbonate and the like. In the same manner as in the above-mentioned production method, pyrazole compound (I) wherein R ⁴ and R ^{5 are a} benzyl group, a methyl group, and when R ⁴ and R ⁵ are an alkylene group, O—R ⁴ and By breaking the bond of O—R ⁵ , pyrazole compound (I) 13 in which R ⁴ = R ⁵ == hydrogen atom is obtained, and pyrazole compound (I) —from pyrazole compound (I) 13 — Production of 2 is also possible.

 In the above reaction, the pyrazole compound (I) -2, (I) -13 can be isolated from the final reaction compound by a conventional method, for example, solvent extraction, recrystallization, column chromatography, etc.

 The pyrazole compound (I) or a salt thereof thus obtained has an excellent antibacterial activity against various fungi, as shown in Examples described later, and has a superficial and deep fungal infection to mammals including humans. It is useful as a drug for the prevention and treatment of diseases.

Pharmaceutical compositions containing one or more of the pyrazole compound (I) or a pharmaceutically acceptable salt thereof are usually prepared using carriers, excipients, and additives used in formulation. Tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, vaginals, ointments, creams, gels, patches, etc., orally or parenterally Administered.

 In order to produce a solid preparation, the excipient and, if necessary, a binder, a disintegrant, a bulking agent, a coating agent, a sugar-coating agent, etc. are added to the pyrazole compound (I). Preference is given to granules, capsules, suppositories and the like. When preparing an injection, the pyrazole compound (I) is previously dissolved in an aqueous carrier such as distilled water for injection, dispersed, emulsified, etc. to make a liquid, or a powder for injection for dissolution before use. do it. Administration methods for injections include intravenous administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, and intravenous infusion. To prepare external preparations such as ointments, creams, gels, and liquids, the pyrazole compound (I) is dissolved, dispersed, or emulsified in an aqueous or oily base to prepare an ointment, cream, liquid, or gel. What should I do?

 The dose of the pyrazole compound (I) to a human varies depending on the state of infection and the method of administration. For example, when administered to an adult patient for the purpose of treating Candida infection, oral administration of about 0.01 to 1 : L 0 O mg / kg / day, preferably about 0.1 to 50 mg / kg / day. More preferably, it is about 1-2 Omg / kg / day. Example

 Hereinafter, the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 Production of enone (3)

Enones (3) shown in Tables 9 and 10 were produced. Table 9

表 1 o

Table 1 o

 THP: 2-tetrahydroviranyl group

 Production example (1)

To 0.17 g (1 Oiol) of 4,5-dimethoxy-l-pyridinecarbaldehyde was added 10 OmL of 0.1 mol / L aqueous sodium hydroxide solution, and the mixture was stirred. 1.20 g (1 Ommol) of the compound was added dropwise, and the mixture was stirred at room temperature for 12 hours. After the completion of the reaction, the precipitated crystals were collected by filtration, dried, and 2.38 g of (E) -3 (4,5-dimethoxy-2-pyridinyl) -1-phenyl-2-propene-11-one (2.38 g ( 88.2%).

Production example (2)

 Dissolve 0.64 g (2 benzyl) of 4,5-bis (benzyloxy) 1-2-pyridinecarbaldehyde in 8 ml of methanol, add 0.24 g of acetophenone (2 ol) and add sodium methoxide with stirring. 12 g (2.2 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the precipitated crystals were collected by filtration and dried, and (E) -3- (4,5-dimethoxy-2-bis (benzyloxy) -12-pyridinyl) -11-phenyl-2-propene-1-one 0.56 g (66.7%).

 The enones of Production Examples (6) and (7) were produced in the same manner as in Production Example 2.

Production Example 3

 Getyl 2-oxo-2-phenylphenylphosphonate 0.45 g (1.76 wake 1) was dissolved in 2 mL of tetrahydrofuran (THF), and sodium hydride 0.07 at 0 ° C under an argon stream. g (1.76 mmol) was added and stirred for 10 minutes. Then, a solution of 0.28 g (1.41 liters) of 6-formyl-14-methoxy-3-pyridinyl acetate in 2 mL of THF was added dropwise and stirred at 0 ° C. for 1 hour. After the completion of the reaction, the reaction product was poured into water and extracted with ethyl acetate. After washing with water and a saturated saline solution, the mixture was dried over sodium sulfate, and the solvent was distilled off. The residue was reconstituted with ethyl acetate-hexane to give 4-methoxy-6-[(E) -13-oxo-13-phenyl-1-probenyl] -3-pyridinyl acetate in 0.20 g ( 47.0%).

Production Example 4

4-Hydroxy-5-methoxy-2-pyridinecarbaldehyde 1.39 g (1 Ommol) Acetophenone 1.20 g (1 Ommol) is dissolved in methanol (5 OmL), and the solution is 20% (w / v) sodium hydroxide aqueous solution under Ot. Add 4 OmL and 0 ~ 10 ° C at 4 o'clock While stirring. After completion of the reaction, the reaction solution was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration, dried, and (E) -3- (4-hydroxy-5-methoxy-12-pyridinyl) -11-phenyl-2-propene — 1.63 g (69.1%) of one onion was obtained.

Production Example 5

 0.49 g (2.5 mmol) of 4,5-bis (benzyloxy) -2-pyridinecarbaldehyde, 0.40 g (2.Immol) of ethyl 3-oxo-1-3-phenylpropanoate in benzene After dissolving in 4 mL, piperidine (0.05 mL) and acetic acid (4 mL) were added, and the mixture was refluxed at 120 ° C for 5 hours. After cooling, getyl ether was added, and the mixture was washed successively with lmolZL hydrochloric acid, 5% (w / v) aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1), and ethyl (Z) -2-benzoyl-3- [3,4-bis (benzyloxy) -1-5-methoxy-2-pyridinyl] 0.94 g (77.0%) of -2-propanolate was obtained.

Production Example 8

 3,4 Bis (benzyloxy) benzaldehyde 3.18 g (10 bandol) and 1.2 g (10 bandol) of ethanol in 5 OmL of ethanol, and stirred at room temperature under stirring 0.67 g of potassium hydroxide (12 band) ol) in 15 mL of ethanol was added dropwise and stirred for 20 hours. After completion of the reaction, the reaction product was poured into water, and the precipitated crystals were collected by filtration and dried. (E) —3— [3,4-Bis (benzyloxyphenyl) -11-phenyl-1-2-propene-11 4.02 g (95.6%) of one ounce was obtained.

 In the same manner as in Production Example 8, the enones of Production Examples 9 to 11, 14 to 24, and 59 to 63 were produced. Further, enones of Production Example 13 were produced according to the method described in Production Example 12 and J. Ceni. Soc, Perkin I, 1972, 3001, respectively, according to the method described in US Pat. No. 5,847,225.

Production Example 64

4-bromo-1,2-dimethoxy-benzene 2.17 g (10 bandol), 3, 3 —Diethoxypropene 3.90 g (3 Ommol), palladium acetate 0.067 g (0.3 t ol), tetrabutylammonium acetate 6.0 g (2 Ommol), potassium carbonate 2.1 g ( A mixture of 15 ol), 0.75 g (1 Ommol) of potassium chloride and OmL of DMF4 was stirred at 90 ° C for 13 hours. After completion of the reaction, 2 OmL of 2N hydrochloric acid was added to the reaction product at room temperature, and the mixture was stirred for 10 minutes to hydrolyze the acetate. Ethyl acetate was added for extraction, washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (hexane: ethyl acetate 9: 1) to obtain 0.98 g (51.0%) of (E) —3- (3,4-dimethoxyphenyl) monopropenal as pale yellow crystals. .

Reference example 2

Pyrazolines (5) shown in Tables 11 to 13 were produced.

Table 11

OR ⁵

表 1 2

Table 1 2

表 13

Table 13

製造例 25

Production example 25

 (E) One 3- (4,5-dimethoxy-2-pyridinyl) one-phenyl-2-one propene-1-one 0.81 g (3 mmol), one methyl hydrazine 0.17 g (3.6 parts) ol), 1 OmL of ethanol was added, and the mixture was refluxed for 5 hours. After completion of the reaction, the solvent was distilled off, and the residue was purified by alumina column chromatography (hexane: ethyl acetate 3: 1) to give 4,5-dimethoxy-12- (1-methyl-3-phenyl-4,4). 0.43 g (49.0%) of 5-dihydro-1H-pyrazol-5-yl) pyridine was obtained.

 Production Example 26

(E) -3- [4,5-Bis (benzyloxy) -1-2-pyridinyl]-1-phenyl-2-propen-1-one 0.42 g (1 ol), 1-methylhydrazine 0.14 g (3 Was added to 1 OmL of ethanol and refluxed for 2 hours. After completion of the reaction, the solvent is distilled off, and 4,5-bis (benzyloxy) 1-2- (1-methyl-3-phenyl) 0.25 g of pyridine 4,5-dihydro-1H-pyrazole-5-yl) pyridine

(99.0%).

Production Example 27

 (E) -3- [4,5-Bis (benzyloxy) -1-pyridinyl] — 1-phenyl-2-propene-one 0.42 g (1 ol), 1-phenylhydrazine 0.16 g (1.5 t) was added with 1 OmL of ethanol and refluxed for 2 hours. After the reaction is completed, after cooling, the precipitated crystals are collected by filtration, dried, and 4,5_bis (benzyloxy) 1-2- (1,3-diphenyl-4,5-dihydro-1H-pillazol-5-yl). 0.36 g (69.7%) of pyridine was obtained.

Production Example 32

 (E)-3-[3,4-Bis (benzyloxy) phenyl] 1-1- (4-fluorophenyl)-2-propene 1_one 0.35 g (0.8 t ol), 1-phenyl To 0.13 g (1.2 bandol ol) of luhydrazine, 4 mL of ethanol and 0.2 inL of ethanol saturated with hydrochloric acid were added, and the mixture was refluxed for 4 hours. After cooling, the precipitated crystals were collected by filtration, dissolved in ethyl acetate, and purified by silica gel chromatography (hexane: ethyl acetate 5: 1) to give benzyl 2- (benzyloxy) -4- [3 -— (4 —Fluorophenyl) -1-1-phenyl-4,5-dihydro-1H-pyrazole-15-yl] phenyl ether was obtained in an amount of 0.24 g (55.6%).

Production Example 33

 (E) -3- [3,4-Bis (benzyloxy) phenyl] —1-phenyl-2-propen-1-one 0.84 g (2. Ommol), 1- (4-fluorophenyl) hydrazine To 0.49 g (3.0 mmol) of the hydrochloride, 1 OmL of ethanol was added, and the mixture was refluxed for 2 hours. After completion of the reaction, after cooling, the precipitated crystals were collected by filtration, dried, and treated with benzyl 2-

0.79 g of (benzyloxy) -4- [3-phenyl-1- (4-fluorophenyl) -4,5-dihydro-1H-pyrazol-5-yl] phenyl ether

(74.2) obtained. Production example 41.

 (E) -3-[3,4-Bis (benzyloxy) phenyl] 1-1-phenyl-1-2-propen-1-one 4.20 g (1 Oimol), 2-hydrazinopyridine 1.60 g (15 thighs) ol) was added with 10 OmL of ethanol and refluxed for 12 hours. After completion of the reaction, the mixture was cooled, and the precipitated crystals were collected by filtration, dried, and benzyl 2- (benzyloxy) -14- [3-phenyl-1- (2-pyridinyl) -1,4,5-dihydro-1H-pyrazol. —5—yl] was obtained in an amount of 3.27 g (64.0%).

 Pyrazoline of Preparation Examples 28 to 31 and 34 in the same manner as in Preparation Example 27, Birazolin of Preparation Examples 35 to 40 in the same manner as in Preparation Example 33, and Preparation Examples 42 to 55 and 65 in the same manner as in Preparation Example 41 ~ 73 pyrazolines were each produced.

 Reference Example 3 Production of hydrazone (6)

 The hydrazone (6) shown in Table 14 was produced.

 Table 14

製造例 56

Production Example 56

(E) i 3 [4,5_Bis (benzyloxy) i 2 -pyridinyl] ― 1-f 2 OmL of ethanol was added to 0.84 g (2.0 mmol) of phenyl-2-propene-1-one and 0.49 g (3.0 mmol) of 1- (4-fluorophenyl) hydrazine hydrochloride, and the mixture was refluxed for 2 hours. After the reaction is completed, after cooling, the precipitated crystals are collected by filtration, dried and dried. (E) -3- [4,5_Bis (benzyloxy) _2-pyridinyl] -1-phenyl-2-propene 1-one N — 0.51 g (47.4%) of (4-fluorophenyl) hydrazone was obtained.

Production Example 57

 (E) —4- [3,4-bis (benzyloxy) phenyl] -1-3-butene—2—one 1.59 g (4..4 bandol ol), 2-hydrazinopyridine 0.97 g (8.9 4 OmL of toluene was added to the mixture, and the mixture was refluxed for 4 hours. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 5: 1) to give (E) -4- [3,4-bis (benzyloxy) phenyl] 13. —Butene-1-2-N- (2-pyridinyl) hydrazone was obtained in an amount of 0.68 g (34.3%).

Production Example 58

 (E)-1-[3,4-Bis (benzyloxy) phenyl] 1-Pendecene_3 -one (Preparation Example 13) Bis (benzyloxy) phenyl] -l-pandene_3_one N- (2-pyridinyl) hydrazone was obtained in an amount of 0.33 g (80.5%).

Production example 74

(E) — 3- (3,4-dimethoxyphenyl) 1-propenal 0.13 g (0.68 maraudal 01) was dissolved in ethanol 2 niL, and 2-hydrazinopyridine 0.08 1 g (0.74 A solution of thighol) in 0.5 mL of ethanol was added, and the mixture was stirred at room temperature for 0.5 hour. After completion of the reaction, the precipitated crystals were collected by filtration and dried, and 0.1% of (E)-(3-, 3,4-dimethoxyphenyl) -propenal N- (2-pyridinyl) hydrazone was obtained as yellow crystals. g (62.3%). Reference example 4

 3-(3-Feneru 1H-pyrazole-1%) pyridine

 1.44 g (1 Ommol) of 3-phenylpyrazole, 2.05 g (1 Ommol) of 3-iodopyridine, 0.19 g (1 ol) of cuprous iodide, 1,10-phenol A mixture of 0.18 g (1 ol), 4.24 g (2 Ommol) of tripotassium phosphate and toluene 10 was stirred at 12 under argon stream for 14 hours. After the reaction was completed, water was added to the reaction product, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 2: 1) to give 1.74 g (79.0%) of the title compound.

Reference example 5

 5- [3,4-Bis (benzyloxy) phenyl] _ 3-phenyl-2-H-pyrazole

 (E) —3— [3,4-Bis (benzyloxy) phenyl] 1-1-phenyl 2-propene — 1one 6.37 g (15 mmol), hydrazine monohydrate 0.85 g (15IMO1) A mixture of 6 OmL of ethanol was refluxed for 4 hours. After completion of the reaction, the solvent was distilled off, and 4.14 g (59 imol) of o-chloranil and 6 OmL of toluene were added to the residue, followed by refluxing for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with water, washed with 20% sodium hydroxide, and sequentially with saturated saline, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 5: 1 to 3: 1) to obtain 4.1 g (63.0%) of the title compound.

Example 1 Production of pyrazole compound (I) from pyrazoline (5)

The compounds shown in Tables 15-17 were prepared. Table 15

表 16

Table 16

表 17

Table 17

化合物 1

Compound 1

 Hydrochloric acid 4,5-dimethoxy-1 2_ (1-methyl-3-phenyl-1H-pyrazo-Lu-5-yl) pyridine

 4,5-dimethoxy-2- (1-methyl-3-phenyl-1,4-dihydro-1H-pyrazole-1-yl) pyridine 0.40 g (1.4 marl), DDQ 0.31 g (1. To the mixture was added 1 OmL of toluene, and the mixture was heated at 80 "C for 2 hours. After cooling, ethyl acetate was added, washed with a saturated aqueous solution of sodium hydrogencarbonate, washed with a saturated saline solution, dried over sodium sulfate, and dried. The residue was purified by alumina column chromatography (hexane: ethyl acetate 4: 1) to give 0.26 g (65.0%) of the title compound as an oil.

'H-NMRiCDCls) δ: 4.00 (3Η, s), 4.0Κ3Η, s), 4.22 (3H, s), 6.79 (1H, s), 7.12 (1H, s), 7.29-7.39 (1H, m), 7.41-7.43 (2H, m), 7.83-7.85 (2H, m), 8.22 (1H, s) .Compound 2

 4,5-bis (benzyloxy) -2- (1-methyl-3-phenyl-1H-pyrazol-5-yl) pyridine

 4,5-bis (benzyloxy) -1-2- (1-methyl-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl) pyridine 0.45 g (1.0 bandages 0 1), To 0.34 g (1.5 mmol) of DDQ, 1 OmL of 1,4-dioxane was added, and the mixture was refluxed for 2 hours. After cooling, the insolubles were removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1) to give the title compound as an oil (0.15 g, 32%). 7%).

 'H-NMRiCDCls) 6: 4.13 (3H, s), 5.26 (2H, s), 5.28 (2Η, s), 6.69 (1H, s), 7.15 (1H, s), 7.25-7.50 (13H, m) , 7.8K2H, d, J = 7.3Hz), 8.24 (1H, s).

Compound 4

 4,5-bis (benzyloxy) _2- (1,3-diphenyl-1H-pyrazo-lu-5-yl) pyridine

 The title compound was obtained as an oil from 4,5-bis (benzyloxy) -2- (1,3-diphenyl_4,5-dihydro-1H-pyrazole-5-yl) pyridine in the same manner as compound 2. (99.0%).

 'H-NMRiCDCls) δ: 4.85 (2Η, s), 5.23 (2H, s), 6.65 (1H, s), 7.04 (1H, s), 7.20- 7.48 (18H, m), 7.87 (2H, br d) , J = 7.3Hz), 8.23 (1H, s).

Compound 10

 Benzyl 4-benzyloxy 6- [3-phenyl 1- (2-pyridinyl) 1-1H-pyrazol-5-yl] —3-pyridinyl ether

4,5_Bis (benzyloxy) -1-2- [3-phenyl-2- (2-pyridinyl) -1,4,5-dihydro-1H-pyrazol-5-yl] pyridine 0.10 g (0. Add 1 OmL of toluene to 0.066 g (0.29 t) of DDQ. The mixture was refluxed for 4 hours. After completion of the reaction, the solvent was distilled off.The residue was extracted with ethyl acetate, washed successively with 5% (w / v) aqueous sodium hydroxide solution, water and saturated saline, dried over sodium sulfate, and evaporated. . The residue was purified by gel chromatography (hexane: ethyl acetate 5: 1) to give 0.1 lg (99.0%) of the title compound.

_{• H-NMR (CDC1 3)} δ: 5.10 (2Η, s), 5.21 (2H, s), 6.94 (1Η, s), 7.00 (1H, s), 7.18- 7.21 (1H, in), 7.32-7.45 (13H, m), 7.71-7.73 (lH, ni), 7.78-7.82 (lH, m), 7.91--7.93 (2H, m), 8.11 (1H, s), 8.24-8.25 (1H, m ).

 Melting point: 146-148 ° C

Compound 1 8

 5— [3,4-Bis (benzyloxy) phenyl] —1,3-diphenyl — 1 H-pyrazole

 The title compound was obtained from 5-[3,4-bis (benzyloxy) phenyl] -1,3-diphenyl-1,4,5-dihydro-1H-birazol in the same manner as for compound 10 (85.6 %).

Ή over丽_{R (CDC1 3) δ: 4.90} (2Η, s), 5.15 (2H, s), 6.72 (1Η, s), 6.75-6.90 (3H, m), 7.25-7.47 (18H, m), 7.85 -7.95 (2H, m)-Melting point: 82-83.5 ° C

Compound 2 1

 5- [3,4-bis (benzyloxy) phenyl]-1-phenyl 3- (4-fluorophenyl) 1-1H-pyrazole

 5- [3,4-bis (benzyloxy) phenyl] -1-phenyl 3- (4-fluorophenyl) —4,5-dihydro-1H-pyrazole to give the title compound in the same manner as compound 10 (38.5%).

_{Ή-NMR (CDC1 3) δ} : 4.91 (2Η, s), 5. 16 (2H, s), 6.67 (1H, s), 6.77 (1H, d, J = 2.0 H z), 6.85-6.88 (2H , m), 7.11 (2H, t, J = 8.8 Hz), 7.31-7.39 (13H, m), 7.44 (2H, d, J = 6.8 Hz), 7.84-7.88 (2H, m).

 Melting point: 119-120 ° C

Compound 2 3

 5— [3,4_Bis (benzyloxy) phenyl] — 1— (4-Fluorophenyl) —3_Phenol 1 H-Pyrazole

 5— [3,4-Bis (benzyloxy) phenyl] — 1— (4-Fluorophenyl) 13-phenyl-4,5-dihydro-1H-Virazole in the same manner as compound 10 to give the title compound (83.2%).

Ή-band R (CDC1 ₃ ) δ: 4.99 (2Η, s), 5.17 (2H, s), 6.70 (1Η, s), 6.75-6.85 (2H, m), 6.89 (1H, d, J = 8.3Hz), 7.01 (2H, t, J = 8.3Hz), 7.20-7.48 (15H, m), 7.88 (2H, d, J = 8.3Hz).

 Melting point: 82-84

Compound 2 5

 5- [3,4-bis (benzyloxy) phenyl] 1-1,3_bis (4-fluorophenyl) 1-1H-pyrazole

 5- [3,4-Bis (benzyloxy) phenyl] 1-1,3-bis (4-fluorophenyl) -4,5-dihydro-1H-virazole to give the title compound as an oil in the same manner as for compound 10 (79.0%).

Ή-丽_{R (CDC1 3) (5:} 4.99 (2H, s), 5. 17 (2H, s), 6.65 (1H, s,) 6.75-6.85 (2H, m), 6.89 (1H, d, J = 8.3Hz), 7.0K2H, t, J = 8.8Hz), 7.10 (2H, t, J = 8.8Hz), 7.20-7.48 (12H, m), 7.80-7.87 (2H, m).

Compound 2 7

 4- [3-(2,5-dimethoxyphenyl)-1- (4-fluorophenyl)-1 H-pyrazole-5-]-1,2-benzenediol

4- [3- (2,5-dimethoxyphenyl) 1-11 (4-fluorophenyl) 1,4,5-dihydro-1H-pyrazol-1-yl 5-yl] — 1,2-benzenediol 15 mL of ethanol was added to 0.41 g (1.0 marl ol) and 34 g (1.5 dragon ol) of DDQO. The mixture was refluxed for 2 hours. After cooling, the reaction product was concentrated, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to obtain 0.027 g (6.7%) of the title compound.

_{'H-NM (CDC1 3)} δ: 3.75 (3Η, s), 3.84 (3Η, s), 6.54 (1H, dd, 2.4, 8.3Hz), 6.64 (1 H, d, J = 2.4Hz), 6.7 K1H, d, J = 8.3Hz), 6.87-6.95 (2H, m), 7.06 (1H, d, J = 8.8Hz), 7.26 (2H, t, J = 8.8Hz), 7.33-7.43 (2H, m ), 7.48 (1H, d, J = 3.4Hz), 8.99 (1H, s), 9.10 (1H, s).

 Melting point: 185-186

Compound 2 8

 2— [5— [3,4-bis (benzyloxy)] — 1— (4-fluorophenyl) 1-1H—pyrazol-1-yl 3-pyridine

 2- [5- [3,4-bis (benzyloxy)] — 1- (4-fluorophenyl) —4,5-dihydro-1H-pyrazol-3-yl] title in the same manner as compound 2 from pyridine Compound was obtained as amorphous (9 0.3%)

_{Ή-NMR (CDC1 3) δ} : 4.98 (2Η, s), 5.16 (2H, s), 6.76-6.92 (3Η, m), 7.03 (2Η, t, J = 8.8Hz), 7.09 (1H, s) , 7.20-7.50 (13H, ni), 7.75 (1H, dt, J = l.5, 7.8Hz), 8.06 (1H, brd, J = 7.8Hz), 8.62-8.70 (lH, m).

Compound 30

 5- [3,4_Bis (benzyloxy) phenyl] — 1- (2,4-difluorophenyl) 1 3— (4-Fluorophenyl) 1 1 H-Pyrazol

 5- [3,4-Bis (benzyloxy) phenyl] 1-11 (2,4-difluorophenyl) 1-3- (4-Fluorophenyl) 1,4,5-dihydro-1H Same as compound 10 from 1H-pyrazole The title compound was obtained by the method (87.0%).

_{Ή-NMR (CDC1 3) <} 5: 5.00 (2H, s), 5. 15 (2H, s), 6.68 (1Η, s), 6.78-6.98 (3H, m), 7.11 (2H, t, J = 6.8Hz), 7.13-7.47 (13H, m), 7.82-7.86 (2H, m). Melting point: 109- lire

Compound 32

 5-[3,4-Bis (benzyloxy) phenyl] — 1- (4-trifluoromethoxyphenyl) 1 3 _ (4-fluorophenyl) 1 1 H-pyrazol

 5- [3,4-bis (benzyloxy) phenyl] 1-1- (4-trifluoromethoxyphenyl) -3- (4-fluorophenyl) -1,4,5-dihydro-1H-pyrazole in the same manner as compound 10 The title compound was obtained (86.8%).

Ή over丽_{R (CDC1 3) δ: 4.96} (2H, s), 5.18 (2H, s), 6.66 (1Η, s), 6.67 (. 1H, d, J = 2 OH z), 6.83 (1H, dd , J = 2.0, 8.3Hz), 6.90 (1H, d, J = 8.3Hz), 7.11 (2H, t, J = 8.8Hz), 7.19 (2H, d, J = 8.8Hz), 7.31- 7.40 (10H, m), 7.45 (2H, d, J = 6.8Hz), 7.83-7.87 (2H, m). Melting point: 104-105 ° C

Compound 34

 2-[5— [3,4-bis (benzyloxy)] — 1— (4-trifluoromethyloxyphenyl) _ 1 H-pyrazol-3-yl] pyridine

 (E)-3- [3,4-Bis (benzyloxy) phenyl] 1-1- (2-pyridinyl) 1-2-propen-1-one 0.35 g (0.83 mmol), 1- [4 To 1- (trifluoromethoxy) phenyl] hydrazine hydrochloride (0.29 g, 1.25 marl 01), 5 mL of ethanol was added, and the mixture was refluxed for 8 hours. After completion of the reaction, the solvent was distilled off, and to the residue, 0.28 g (1.24 mmol) of DD Q and 5 mL of toluene were added, and the mixture was refluxed for 24 hours. After completion of the reaction, the solvent was distilled off, the residue was extracted with ethyl acetate, washed with 5% (w / v) aqueous sodium hydroxide solution, water and saturated saline solution in that order, dried over sodium sulfate, and the solvent was distilled off. did. The residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to obtain 0.08 lg (16.5% in two steps) of the title compound.

Ή—band R (CDC1 ₃ ) <5: 4.96 (2H, s), 5.18 (2H, s), 6.82-6.91 (3H, m), 7.11 (1Η, s), 7.19-7.45 (16H, m ), 7.74-7.78 (1H, in), 8.07 (1H, d, J = 8.3Hz), 8.67 (1H, d, J = 4.4Hz). Melting point: 116.5-117.5 ° C

Compound 3 6

 5- [3,4-bis (benzyloxy) phenyl]-1-(4-trifluoromethylphenyl)-3-(4-fluorophenyl) — 1 H-pyrazole

 5- [3,4-Bis (benzyloxy) phenyl] — 1— (4-Trifluoromethylphenyl) _3— (4-Fluorophenyl) 1,4,5-dihydro-1H-Virazole in the same manner as Compound 10 The title compound was obtained (82.1%).

_{^{! H-NMR (CDC1 3)}} δ: 5.00 (2Η, s), 5.19 (2H, s), 6.68 (1H, s), 6.80-6.82 (2H, m), 6.9K1H, d, J = 8.8Hz) , 7.12 (2H, t, J = 8.8Hz), 7.30-7.45 (12H, m), 7.58 (2H, d, J = 8.8Hz), 7.84-7.88 (2H, m).

 Melting point: 122-124 ° C

Compound 3 8

 5-1- [3,4-bis (benzyloxy) phenyl] 1-11 (4-t-butylphenyl) 1-3- (4-fluorophenyl) 1 1 H-pyrazol

 5- [3,4-Bis (benzyloxy) phenyl] — 1- (4-t-butylphenyl) -13- (4-fluorophenyl) -1,4,5-dihydro-1 H-pyrazole in the same manner as compound 10 Afforded the title compound (83.3%).

 • H-NMRiCDCls) δ: 1.32 (9H, s), 4.83 (2H, s), 5.16 (2Η, s), 6.67 (1Η, s), 6.74 (1H, s), 6.90 (2H, s) , 7.10 (2H, t, J = 8.3Hz), 7.26-7.44 (14H, -m), 7.86 (2H, dd, J = 5.4, 8.3Hz).

 Melting point: 112.5-113.5 ° C

Compound 45

 2 -— {5- [3,4-bis (benzyloxy) phenyl] —3-phenyl-2-H-pyrazole-1-yl} pyridine

2-{5-1- [3,4-bis (benzyloxy) phenyl] -3-phenyl-4,5-dihydro-1H-pyrazole-1-yl} Same as compound 10 from pyridine The title compound was obtained in the same manner (56.6%).

_{Ή-NMR (CDC1 3) (} 5: 4.99 (2H, s), 5.17 (2H, s), 6.74 (1Η, s), 6.87-6.91 (3H, s), 7.19-7.22 (lH, ni)) 7.29 -7.48 (13H, m), 7.71-7.75 (1H, HI), 7.91-7.93 (2H, m), 8.3 8-8.39 (lH, m).

 Melting point: 95-95.5 ° C

Compound 47

 2- [5- (3,4-dimethoxyphenyl) _3-phenyl-1-H-pyrazol-1-yl] pyridine

 2- [5- (3,4-dimethoxyphenyl) -l_3-phenyl-l, 5-dihydrol 1H-pyrazol-l-l-yl] The title compound is converted to an oily substance from pyridine in the same manner as for compound 10. (75.0%).

_{Ή-NMR (CDC1 3) δ} : 4.99 (2Η, s), 5.17 (2Η, s), 6.74 (1H, s), 6.87-6.91 (3H, s), 7.19-7.22 (lH, m), 7.29- 7.48 (13H, m), 7.71-7.75 (lH, m), 7.91-7.93 (2H, m), 8.3 8-8.39 (lH, m).

Compound 50

 2- {5- [3,4-bis (benzyloxy) phenyl] —3- (2-methoxyphenyl) 1H-pyrazole-1-yl} pyridine

 2- {5- [3,4-bis (benzyloxy) phenyl] -3- (2-methoxyphenyl) 1,4,5-dihydro-1H-pyrazole-1-yl} The title compound is obtained from pyridine in the same manner as compound 10. (78.0%).

- negation _{R (CDC1 3) δ: 3.92} (3Η, s), 4.99 (2Η, s), 5.17 (2H, s), 6.89 (2H, s), 6.97 (1H, s), 6.98-7.04 (2H, m), 7.18 (1H, dd, J = 5.86, 7.33Hz), 7.25-7.50 (13H, m), 7.69-7.73 (1H, m), 8.09 (1H, dd, J = 2.0, 7.3Hz) , 8.37 (1H, dd, J = l.0, 4.9Hz).

 Melting point: no- lire

Compound 52

2- {5- [3,4-bis (benzyloxy) phenyl] —3— (3-methoxy 1-H-pyrazol-1-yl} pyridine

 2- {5- [3,4-bis (benzyloxy) phenyl] 1-3- (3-methoxyphenyl) 1,4,5-dihydro-1H-pyrazole-1-yl} From pyridine in the same manner as compound 10 (76.0%).

Ή one _{NMR (CDC1 3) δ: 3.87} (3Η, s), 4.99 (2H, s), 5.17 (2Η, s), 6.72 (1H, s), 6.86- 6.91 (4H, m), 7.21 (1H, dd, J = 4.9, 7.3Hz), 7.29-7.49 (14H, m), 7.70-7.75 (lH, m), 8.39 (1H, d, J = 3.9Hz).

 Melting point: 90-92 ° C

Compound 54

 2-{5- [3,4-Bis (benzyloxy) phenyl] -3- (4-methoxyphenyl) 1H-pyrazole-1-yl} pyridine

 2- {5— [3,4-bis (benzyloxy) phenyl] -3--3- (4-methoxyphenyl) 1,4,5-dihydro-1H-pyrazol-1-yl} From pyridine Same as compound 10 The title compound was obtained by the method of (67.0%).

 WMRiCDCla) δ: 3.84 (3Η, s), 4.99 (2H, s), 5.17 (2H, s), 6.66 (1H, s), 6.86-6.96 (5H, m), 7.17-7.46 (12H , m), 7.14-7.19 (lH, m), 7.84 (2H, dd, 1 = 2.0, 6.8Hz), 8.37 (1H, dd, J = l.0, 4.9Hz).

 Melting point: 167-170T:

Compound 56

 2- {5- [3,4-bis (benzyloxy) phenyl] -3- (2-chlorophenyl) 1-1H-pyrazole-1-yl} pyridine

 2— {5 -— [3,4-bis (benzyloxy) phenyl] -13- (2-chlorophenyl) -1,4,5-dihydro-1H-pyrazole-1-yl} A method similar to that for compound 10 from pyridine Afforded the title compound (71.0%).

_{MMR (CDC1 3) (5:} 5.00 (2H, s), 5.17 (2H, s), 6.89 (3Η, brs), 6.95 (1H, s), 7.2 0-7.49 (15H, m), 7.70-7.75 ( lH, m), 7.95 (1H, dd, J = 2.0, 7.3Hz), 8.40 (1H, d, J = 4.4 Hz).

 Melting point: 113-114 ° C

Compound 58

 2- {5- [3,4-bis (benzyloxy) phenyl] -3- (3-chlorophenyl) -1-H-pyrazole-1-yl} pyridine

 2— {5-1- [3,4-bis (benzyloxy) phenyl] —3 -— (3-chlorophenyl) -1,4,5-dihydro-1H-pyrazole-11- {0}} Same as pyridine 10 The title compound was obtained in the same manner as described above (80.0%).

Ή one _{NMR (CDC1 3) <5:} 4.99 (2H, s), 5.17 (2H, s), 6.71 (1H, s), 6.86-6.91 (3H, m), 7.20-7.46 (14H, m), 7.72 -7.79 (2H, m), 7.93 (1H, brs), 8.40 (1H, d, J = 3.9Hz). Melting point: 107-110 ° C

Compound 60

 2- {5- [3,4-bis (benzyloxy) phenyl] -1-3- (4-chloro'phenyl) _ 1H-pyrazole-1-yl} pyridine

 2- {5- [3,4-bis (benzyloxy) phenyl] -3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-1-yl} Method similar to compound 10 from pyridine Afforded the title compound (85.0%).

Ή-丽 R (CDC1 ₃ ) (5: 4.99 (2H, s), 5.17 (2H, s), 6.85-6.91 (3Η, m), 7.20-7.45 (14 Η, ι), 7.70-7.74 (lH, m), 7.85 (2Η, d, J = 8.3Hz), 8.40 (1H, dd, J = 2.0, 4.9Hz).

 Melting point: 123-126:

Compound 62

 2-—5- (3,4-bis (benzyloxy) phenyl) -3- (3-ditrophenyl) -1-H-virazol-1-yl} pyridine

2- {5- [3,4-bis (benzyloxy) phenyl] _3- (3-ditrophenyl) -1,4,5-dihydro-1H-pyrazol-1-yl} From pyridine in the same manner as compound 10. The title compound was obtained (69.0%). 'H-NMRiCDCls) <5: 5.00 (2H, s), 5.18 (2H, s), 6.80 (1H, s), 6.86-6.92 (3H, m), 7.24-7.47 (13H, m), 7.57-7.61 (lH, m), 7.73-7.78 (1H, m), 8.19 (1H, dd, J = 1.5, 8.3 Hz), 8.27 (1H, d, J = 7.8Hz), 8.41 (1H, dd, J = 2.0, 4.9Hz), 8.73 (1H, s).

 Melting point: 113-117 ° C

Compound 64

 2- {5- [3,4-bis (benzyloxy) phenyl] -3- (4-nitrophenyl) -1-H-pyrazol-1-yl} pyridine

 2-{5- [3,4-bis (benzyloxy) phenyl]]-3- (4-nitrophenyl) -4,5-dihydro_1H_birazol-1-yl} Compound from pyridine 10 The title compound was obtained in the same manner as in (83.0%).

_{Ή-NMR (CDC1 3) δ} : 4.99 (2Η, s), 5.18 (2Η, s), 6.81 (1H, s), 6.85-6.92 (3H, m), 7.26-7.45 (12H, m), 7.73- 7.78 (lH, m), 8.07 (2H, d, J = 8.8Hz), 8.28 (2H, d, J = 8.8Hz), 8.43 (1H, dd, J = l.0, 4.9Hz).

 Melting point: 145-148 ° C

Compound 69

 2- [3,5-bis (3,4-dimethoxyphenyl) -1H-pyrazole-1yl] pyridine

 2- [3,5-bis (3,4-dimethoxyphenyl) -1,4,5-dihydro-1H-pyrazole-11-yl] The title compound was obtained as an oil from pyridine in the same manner as for compound 10. (75.9%).

 MMRiCDCls) δ: 3.73 (3H, s), 3.90 (3H, s), 3.93 (3H, s), 3.99 (3H, s), 6.75 (1H, s), 6.79 (1H, d, J = 2.0Hz) , 6.84 (1H, d, J = 8.3Hz), 6.89-6.95 (2H, m), 7.23-7.26 (1H, m), 7.43 (1H, dd, 1 = 2.0, 8.3Hz), 7.49 (1H , d, 1 = 1.8Hz), 7.55 (1H, d, J = 2.OHz), 7.76 (1H, ddd, J = 2.0, 7.8, 7.8Hz), 8.45-8.46 (1H, m).

 Melting point: 119-122. C

Compound 7 1 2- [5- [3,4-bis (benzyloxy)] _ 1- (2-pyridinyl) -1H-pyrazol-3-yl] pyridine

 2— [5— [3,4-Bis (benzyloxy)] ー 1-1 (2-pyridinyl) ―

The title compound was obtained from [4,5-dihydro-1 H-pyrazole-3-yl] pyridine in the same manner as for compound 10 (39.9%).

Ή over丽_{R (CDC1 3) δ: 4.98} (2Η, s), 5. 16 (2Η, s), 6.85-6.91 (3H, m), 7. 13 (1H, s), 7.22-7.45 (13H, m), 7.71-7.76 (2H, m), 8.14 (1H, d, J = 7.8Hz), 8.44 (1H, dd, J = 0.9, 4.3Hz), 8.60 (1H, dd, J = 3.9, 4.9Hz) ).

 Melting point: 122-123 ° C

Compound 7 3

 2- (5_ [3,4_Bis (benzyloxy) phenyl])-3- (4'-Flo [1,1'-Biphenyl] 4-yl) 1H-Pyrazol-l-yl} Pyridine

 2-{5-1 [3,4-bis (benzyloxy) phenyl]-3-(4 '-Flow port [1, 1'-pifenyl] 4-yl) 1,4,5-Dihydro-1H-pyrazole-1 1-yl } The title compound was obtained from pyridine in the same manner as for compound 10 (80.8%).

_{'H-NMR (CDC1 3)} (5:. 5.00 (2H, s), 5. 18 (2H, s), 6.77 (1H, s), 6.88-6.93 (2Η, m), 7.12-7 16 (2H , m), 7.22-7.46 (13H, m), 7.59-7.62 (4H, m), 7.72-7.76 (1H, m), 7.96 (2H, d, J = 8.3Hz), 8.42-8.43 (1H, m).

 Melting point: 118-120 ° C

Compound 7 5

 2— {5- [3,4-Bis (benzyloxy) phenyl] -13— (2-Chenyl) 1-1H—Pyrazol-1-yl} Pyridine

2- {5- [3,4-Bis (benzyloxy) phenyl] -3- (2-Chenyl) -1,4,5-dihydro-1H-pyrazole-1-yl} Compound 1 from pyridine The title compound was obtained in the same manner as in 0 (69.0%).

Ή over丽_{R (CDC1 3) δ: 4.98} (2Η, s), 5.16 (2H, s), 6.63 (1Η, s), 6.84-6.90 (3H, m), 7.06-7.09 (lH, m), 7.18 -7.21 (1H, m), 7.28-7.48 (13H, m), 7.70-7.74 (lH, m), 8.36 (1H, d, J = 4.9Hz).

 Melting point: 124-126 ° C

Compound 7 7

 2- {5— [3,4-bis (benzyloxy) phenyl] —3- (3-cell) -1-H-pyrazole-1-yl} pyridine

 2- {5- [3,4-bis (benzyloxy) phenyl] 13- (3-cell) —4,5-dihydro_1H-pyrazol-1-yl} pyridine in the same manner as compound 10 The title compound was obtained (54.0%).

 'H-NMRiCDCl ^ δ: 4.98 (2Η, s), 5.17 (2H, s), 6.62 (1Η, s), 6.84-6.90 (3H, m), 7.20 (1H, dd, J = 4.9, 7.3Hz) , 7.25-7.45 (12H, m), 7.58 (1H, dd, J = 1.5, 4.9Hz), 7.6 8-7.73 (2H, m), 8.39 (1H, d, J = 3.4Hz).

 Melting point: 110-113t:

Compound 7 9

 2- {5— [3,4-bis (benzyloxy) phenyl] -1-3- (2-pyridinyl) -1H-pyrazol-1-yl}-1,3-benzothiazole

 2- {5-[3,4_Bis (benzyloxy) phenyl] -3- (2-pyridinyl) —4,5-dihydro-1H-pyrazol-1-yl} — from 1,3-benzothiazole The title compound was obtained in the same manner as for Compound 10 (42.0%).

_{Ή-NM (CDC1 3) <} 5: 5.14 (2H, s), 5.24 (2H, s), 6.75 (1Η, s), 6.99 (1H, d, J = 8.3H z), 7. 15 (1H, dd, J = 2.4, 8.3Hz), 7.23-7.50 (16H, m), 7.2K1H, d, J = 7.3Hz), 7.81 (lH, d, J = 6.8Hz), 7.93 (2H, d, J = (8.3Hz).

 Melting point: 142.5-143.

Compound 8 1 1 _Benzyl-5- (3,4-bis-benzyloxy-phenyl) —3-phenyl-1-H-pyrazole

 Benzirel 51- (3,4-bis-benzyloxy-phenyl) -13-phenyl-14,5-dihydro-1H-pyrazole to give the title compound in the same manner as for compound 10 (60.0%) .

_{Ή- NMR (CDC1 3) δ:} 4.93 (2Η, s), 5.19 (2H, s), 5.29 (2H, s), 6.84-6.93 (3H, m), 7.05 (2H, d, J = 6.8Hz) , 7.24-7.46 (16H, m), 7.84 (1H, d, J = 7.3H z).

 Melting point: 120-121 ° C

Compound 8 3

 5- (3,4-bis-benzyloxyphenyl) 1-1- (3-methoxyphenyl) -3-3phenyl-1-H-pyrazole

 5- (3,4-Bis-benzyloxyphenyl) -1- (3-methoxyphenyl) -13-phenyl-4,5-dihydro-1 H-Pyrazol in the same manner as compound 10 Afforded the title compound as a pale yellow oil (63.0%).

Ή-丽 R (CDC1 ₃ ) δ: 3.73 (3Η, s), 4.98 (2H, s), 5.23 (2H, s), 6.74 (1H, s), 6.83-6.97 (3H, m), 7.26-7.51 (17H, m), 7.88-7.90 (2H, m).

Compound 8 5

 5- (3,4-bis-benzyloxyphenyl)-1- (4-methoxyphenyl) 1-3-phenyl 1H-pyrazole '

 5- (3,4-bis-benzyloxyphenyl) -11- (4-methoxyphenyl) -13-phenyl-14,5-dihydro-1H-pyrazole was used to give the title compound in the same manner as compound 10 Obtained as a pale yellow oil (41.0%).

_{Ή-NMR (CDC1 3) δ} : 3.81 (3Η, s), 4.94 (2Η, s), 5. 15 (2H, s), 6.70 (1H, s), 6.81-6.8 8 (5H, m), 7.25 -7.44 (15H, m), 7.89 (2H, dd, J = 0.8, 8.3Hz). Compound 87

 5- (3,4-bis-benzyloxyphenyl) -1-3-phenyl-1- (4-trifluoromethoxyphenyl) -1H-pyrazole

 5-(3,4-bis-benzyloxyphenyl) 1-3-phenyl 1- (4-trifluoromethoxyphenyl) 1,4,5-dihydro-1H-pyrazol In a similar manner to 10, the title compound was obtained as a pale yellow oil (63.0%).

_{Ή-NMR (CDC1 3) δ} : 4.99 (2Η, s), 5.18 (2Η, s), 6.72 (IH, s), 6.80-6.82 (2H, m), 6.91 (IH, d, J = l.3Hz ), 7.28-7.46 (15H, m), 7.57 (2H, d, J-8.3Hz), 7.89 (1H, dd, J = l.0, 8.3Hz).

Compound 89

 2-[5- (3,4-Bis-benzyloxyphenyl) -3-phenyl- 1 H-pyrazole-11-yl] —4-trifluoromethyl-pyrimidine

 2- [5- (3,4-bis-benzyloxyphenyl) -3-phenyl-4,5-dihydro-lH-pyrazole-l-yl] -4-trifluoromethyl-pyrimidine compound The title compound was obtained in the same manner as in 10 (37.0%).

 'H-NMRiCDClg) 6: 5.09 (2H, s), 5.21 (2H, s), 6.77 (IH, s), 6.84-6.93 (3H, in), 7.22-7.47 (14H, m), 7.96 (2H, m), 8.91 (IH, d, J-5.4Hz).

 Melting point: 115-117 ° C

Compound 91

 2— [5— (3,4-bis-benzyloxyphenyl) -1-3- (2,4-difluorophenyl) _ 1 H-pyrazole-1-yl] —pyridine

 2— [5- (3,4-Bis-benzyloxyphenyl) —3 -— (2,4-difluorophenyl) -4,5-dihydro-1H_pyrazol_1-yl] —pyridin The title compound was obtained in the same manner as in Compound 10 (68.0%).

Ή one _{NMR (CDC1 3) δ: 4.99} (2Η, s), 5.17 (2Η, s), 6.83-6.96 (6H, m), 7.21-7.45 (12H, m), 7.71 (IH, dt, J = l .8, 7.8Hz), 8.13 (IH, dd, J = 2.0, 6.8Hz), 8.41 (IH, d, J = 3.4Hz). Melting point: 125-128 ° C

Compound 9 3

 2- [5- (4-benzyloxy-3-methoxyphenyl) -1-3-phenyl 1H-pyrazole-1-yl] pyridine

 2-[5- (4-Benzyloxy-3-methoxyphenyl) -3-phenyl-1,4,5-dihydro-1H-pyrazole-1-yl] The title compound is obtained from 1-pyridine in the same manner as for compound 10 (44.0%).

 'H-NMRiCDClj) <5: 3.72 (3H, s), 5.16 (2H, s), 7.22-7.53 (10H, m), 7.77 (1Η, dt, J = 2.0, 7.8Hz), 7.93 (2H, d , J = 8.8Hz), 8.44 (1H, d, J = 3.0Hz)..

Compound 9 5

 2- [5- (3-benzyloxy-4-methoxyphenyl) -3-phenyl-1H-pyrazol-1-yl] -pyridine

 2- [5- (3-Benzyloxy-1-methoxyphenyl) -3-phenyl-1,4,5-dihydro-1H-pyrazol-1-yl] -pyridine to the title compound in the same manner as compound 10 (83.0%)

Ή-Marauder R (CDC1 ₃ ) <5: 3.87 (3H, s), 4.96 (2H, s), 6.72 (1H, s), 6.81-6.93 (3H, m), 7.16-7.46 (10H, m ), 7.70 (1H, dt, J = 2.0, 7.8Hz), 7.92 (2H, d, J = 8.3Hz), 8.37 (1H, dt, J = l.0, 4.9Hz).

 Melting point: 89-91

Compound 1 0 7

 2- [5- (3,4-bis-benzyloxyphenyl) 1-3- (3-promophenyl) 1 1H-pyrazole-1 1-yl] pyridine

2- [5- (3,4-bis-benzyloxyphenyl) -13- (3-promophenyl) -4,5-dihydro-1H-pyrazole-11-yl] The title compound was obtained in a similar manner (81.0%). ] _{H-NMR (CDC1 3):} 4.99 (2H, s), 5.17 (2H, s), 6.71 (1H, s), 6.91-6.84 (2H, m), 7.21-7.39 (11H,), 7.43-7.52 (3H, m), 7.74 (1H, dt, J = l.9, 8.3 Hz), 7.81-7.84 (1H, m), 8.09 (1H, t, J = l.9Hz), 8.39-8.41 (1H, m).

 Melting point: 127-129 ° C

 Example 2 Production of pyrazole compound (I) from hydrazone (6)

 The compounds shown in Table 18 were produced.

 Table 18

化合物 8

Compound 8

 4,5-bis (benzyloxy) -1-2- [1- (4-fluorophenyl) -3--3-phenyl 1 H-pyrazol-5-yl] pyridine

(E) -3-[4,5-bis (benzyloxy) —2-pyridinyl] -1-phenyl-1-propene 1-one N- (4-fluorophenyl) hydrazone 0.50 g (0.95 ol ol ) And 0.24 g (1.04 t) of DDQ were added with 10 mL of toluene and refluxed for 2 hours. After completion of the reaction, the solvent was distilled off, and the residue was extracted with ethyl acetate, washed successively with a 5% (w / v) aqueous sodium hydroxide solution, water and saturated saline, dried over sodium sulfate, and evaporated. The residue is subjected to force gel chromatography. Purification by sun: ethyl acetate 3: 1) afforded 0.29 g (58.0%) of the title compound.

 MMRiCDCls) δ: 4.99 (2Η, s), 5.22 (2H, s), 6.73 (1H, s), 6.96 (1H, s), 7.04 (1H, t, J = 8.8Hz), 7.25-7.44 (15H, ni), 7.85-7.92 (2H, m), 8.17 (1H, s).

 Melting point: 91-92 ° C

Compound 40

 2-—5— [3,4-bis (benzyloxy) phenyl] —3-methyl—1H-pyrazole—1-yl} pyridine

 (E) 14- [3,4-bis (benzyloxy) phenyl] -13-butene1-2one N- (2-pyridinyl) hydrazone (Preparation Example 57) was obtained in the same manner as for compound 8 to give the title compound. (64.7%).

 MMRiCDClg) δ: 2.37 (3Η, s), 4.97 (2H, s), 5.16 (2Η, s), 6.22 (1Η, s), 6.79-6.81 (2H, m), 6.86-6.88 (1H, s), 7.15-7.18 (1H, m), 7.21-7.38 (9H, m), 7.43-7.45 (2H, m), 7.62-7.67 (lH, m), 8.39-8.40 (1H, m).

 Melting point: 153-154

Compound 42

 2- {5— [3,4-Bis (benzyloxy) phenyl] 13 1-year-old 1-H-pyrazole-1-yl} pyridine

 (E) 11- [3,4_Bis (benzyloxy) phenyl]-1- pendene-13-one N- (2-pyridinyl) hydrazone was obtained in the same manner as compound 8 to give the title compound (90. 0%).

_{Ή-NMR (CDC1 3) <} 5: 0.88 (3H, t, J = 6.8Hz), 1.24-1.41 (8Η, m), 1.67-1.73 (4Η, m), 2.70 (2Η, t, 1 = 1.8Hz ), 4.97 (2Η, s), 5.16 (2Η, s), 6.24 (1Η, s), 6.80-6.81 (2Η, m), 6.86-6.88 (1Η, m), 7.15-7.18 (lH, m), 7.24-7.46 (llH, m), 7.63-7.67 (1Η, πι), 8.38-8.39 (lH, m).

Melting point: 65-66 ° C Compound 9 7

 2- [5-(3,4-dimethoxyphenyl) -1H-pyrazole-1-yl] pyridine

 The title compound was obtained from (E) -3- (3,4-dimethoxyphenyl) -2-propenal N- (2-pyridinyl) hydrazone in the same manner as for Compound 8 (14.2%).

_{Ή-NMR (CDC1 3) δ} : 3.70 (3Η, s), 3.89 (3Η, s), 6.49 (. IH, d, J = 2 OHz), 6.73 (IH, d, J = 2. OHz), 6.81 -6.87 (2H, m), 7.22-7.26 (1H, m), 7.43 (IH, d, J = 8.3Hz), 7.73-7.78 (2H, m), 8.43-8.44 (1H, m).

 Melting point: 84-85 ° C

Example 3 Preparation of 4,5-bis (benzyloxy) -2- (1,3-diphenyl_4-ethoxycarbone-1H-pyrazol-5-yl) pyridine (Compound 12).

 Ethyl (Z) —2—Benzoyl 3 -— [3,4-Bis (benzyloxy) 1-2-pyridinyl] -12-Propenoate 1 · 29 g (2.6, 1) was converted to N, Ν'-dimethylformaldehyde 6 mL was dissolved in 3 niL of acetic acid, 0.5 mL of phenylhydrazine was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate, washed with an aqueous solution of ImolZL sodium hydroxide, water and saturated saline in that order, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (hexane: ethyl acetate 5: 1) to give 1.41 g (93.0) of the title compound as an oil.

_{Ή-NMR (CDC1 3) δ} : 0.99 (3Η, t, J = 7.3Hz) '4.10 (2H, Q, J = 7.3HZ), 5.23 (2H, s), 5.26 (2H, s), 7.27-7.48 (20H, m), 7.57 (IH, s), 8.25 (IH, s).

Example 4 Preparation of pyrazole compound (I) (R ⁴ = R ⁵ = hydrogen atom)

 The compounds shown in Tables 19-22 were prepared.

Table 19

Table 20

化合物 3 6- ( 1ーメチル— 3—フエ二ルー 1 H—ピラゾール— 5—ィル) -3, 4— ピリジンジオール Table 2 1

Compound 3 6- (1-Methyl-3-phenyl-1H-pyrazole-5-yl) -3,4-pyridinepyridine

(クロロフオルム：メタノール 100 : 1) で精 製し表題化合物を 0. 07 g (80. 3%) 得た。 4,5-bis (benzyloxy) -1- (1-methyl-13-phenyl-1H-pyrazole-5-yl) pyridine (compound 2) 0.15 g (0.33, fraction 1) was added to 4 mL of ethanol. And 0.05% of 10% (w / v) palladium on carbon was added, and hydrogenated under 2.0 atm for 2 hours. After completion of the reaction, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was removed.

(Chloroform: methanol 100: 1) to give 0.07 g (80.3%) of the title compound.

'H-NMR (DMS0-d ₆ ) δ: 4.06 (3Η, s), 6.96 (1H, s), 7.03 (1H, brs), 7.30 (1H, t, J = 7.3 Hz), 7.41 (2H, br) t, J = 7.3Hz), 7.77-7.85 (2H, m), 7.96 (1H, brs).

 Melting point: 283-285 ° C

Compound 5

 6- (1,3-diphenyl-1H-pyrazolyl 5-yl) —3,4-pyridindiol

 4,5_Bis (benzyloxy) —2- (1,3-diphenyl 1H-pyrazol-1-yl 5-yl) The title compound was obtained from pyridine (compound 4) in the same manner as for compound 3 (65 . Five %) .

Ή-NMR (DMS0-d ₆ ) (5: 6.60 (1H, brs), 7.16 (1H, s), 7.30-7.50 (8H, m), 7.74 (1Η, brs), 7.87-7.95 (lH, m) .

 Melting point: 277-279

Compound 9

 6- [1- (4-Fluorophenyl) -3-phenyl-1H-pyrazole-5-yl] -1,3,4-pyridinediol

4,5-Bis (benzyloxy) -2- [1- (4-fluorophenyl) -3-phenyl-2-H-pyrazol-5-yl] The title compound was obtained from pyridine (Compound 8) in the same manner as Compound 3. (41.9%). 'H-NMR (DMS0-d ₆ ) δ: 6.68 (1H, brs), 7.17 (1H, s), 7.27 (2H, t, J = 8.8Hz), 7.30-7.44 (3H, m), 7.45 (2H, t, J = 8.8Hz), 7.75 (1H, br s), 7.85-7.95 (2H, m)

 Melting point: 282-284T '

匕

 6-[3-phenyl-1- (2-pyridinyl) — 1 H-pyrazole-5-yl]-3,4-pyridinepyridine

 Benzyl 4- (1-benzyloxy) -6- [3-phenyl-11- (2-pyridinyl) -11H-pyrazole_5_yl] -13-pyridinyl ether (Compound 10) in the same manner as for Compound 3 Afforded the title compound (52.3%).

_{Ή-NMR (CDC1 3) δ} : 6.88 (1H, s), 7.00 (1Η, s), 7.39-7.52 (5H, m), 7.88-7.90 (2 H, m), 7.99-8.03 (1H, m) , 8. 10-8.12 (lH, m), 8.46-8.47 (lH, m), 13.65 (1H, brs). Melting point: 235-237

Compound 1 3

 Ethyl 5-(4,5-dihydroxy-2-pyridinyl)-1,3-diphenyl 1 H-pyrazol-l-carboxylate

 4,5-bis (benzyloxy) 1-2- (1,3-diphenyl-4-ethoxypropyl 1H-pyrazole-5-yl) pyridine (Compound 12) in the same manner as Compound 3 The title compound was obtained (35.0%).

Ή one _{NMR (CDC1 3) δ: 0.89} (3Η, t, J = 7.4Hz), 4.10 (2H,, 3Hz), 7.21-7.42 (10 H, m), 7.46 (1Η, s), 7.54 (1H, s).

 Melting point: 127-129 ° C

Compound 1 9

 4- (1,3-diphenyl-1H-pyrazole-5-yl)-1,2-benzenediol

5- [3,4-Bis (benzyloxy) phenyl] -1,3-diphenyl-1H-pyrazole (Compound 18) to give the title compound in the same manner as for Compound 3. (68.7%).

H—NMR (DMSO-d ₆ ) δ: 6.56 (IH, dd, J = 2.0, 8.3 Hz), 6.67 (IH, d, J = 2. OHz), 6.71 (1 H, d, J = 8.3 Hz) ), 6.95 (1H, s), 7.28-7.49 (8H, m), 7.85-7.94 (2H, m), 8.97 (IH, s), 9.12 (IH, s).

 Melting point: 182-183 ° C

Compound 22

 4- [3- (4_Fluorophenyl) -1-1-phenyl -1H-pyrazole-5-yl]-1,2-benzenediol

 5-[3,4-Bis (benzyloxy) phenyl]-1-phenyl 3- (4 -fluorophenyl) -1H-pyrazole (Compound 21) The title compound was obtained as an amorphous compound in the same manner as Compound 3. (89.1%).

• H-NMR (DMSO- d ₆ ) δ: 6.56 (IH, dd, J = 2.4, 8.3 Hz), 6.68 (IH, d, J = 2.4 Hz), 6.72 (1 H, d, J = 7.8 Hz) , 6.95 (IH, s), 7.24-7.44 (7H, m), 7.92-7.95 (2H, m), 8.99 (IH, s), 9.12 (IH, s).

Compound 24

 4- [1— (4-fluorophenyl) -1-3-phenyl 1H-pyrazol-1-yl] — 1, 2-benzenediol

 5- [3,4-Bis (benzyloxy) phenyl] — 1- (4-fluorophenyl) 13-phenyl 1H-pyrazol (Compound 23) (76.0%).

Ή-NMR (DMSO-d ₆ ) δ: 6.57 (IH, dd, J = 2.0, 8.3 Hz), 6.60-6.78 (2H, m), 6.95 (IH, s), 7.20-7.50 (7H, m), 7.89 (2H, d, J = 7.3Hz), 8.99 (IH, s), 9.13 (IH, s).

 Melting point: 198-200 ° C

Compound 26

4- [1,3_bis (4-fluorophenyl) -1H-pyrazole-5-yl]-1,2 benzenediol The title compound was obtained from 5- [3,4-bis (benzyloxy) phenyl] -1,3-bis (4-fluorophenyl) -1H-pyrazole (compound 25) in the same manner as compound 3 (6 8.1%).

• H-NMR (DMS0 - d 6) <5: 6.57 (1H, dd, J = 2.0, 8.3Hz), 6.67 (1H, d, J = 2.0Hz), 6.73 (1 H, d, J = 7.8Hz ), 6.95 (1H, s), 7.20-7.44 (6H, i), 7.88-7.98 (2H, m), 9.01 (lH.br s), 9.15 (1H, br s).

 Melting point: 193-194

Compound 29

 4- [1- (4-Fluorophenyl) — 3— (2-pyridinyl) — 1H—pyrazol-1-51] 1-1,2-benzenebenzene

 2-[5-[3,4_Bis (benzyloxy)] — 1— (4-fluorophenyl) 1H-pyrazol-3-yl] pyridine (Compound 28) in the same manner as Compound 3 The compound was obtained (51.8%).

Ή— NMR (DMS0-d ₆ ) <5: 6.58 (1H, dd, J = 2.0, 7.8Hz), 6.66 (1H, d, J = 2.0Hz), 6.73 (1H, d, J = 7.8Hz) , 7.00 (1H, s), 7.20-7.45 (5H, m), 7.85 (1H, dt, J = l.5, 7.8Hz), 8.00 (1H, d, J = 7.8Hz), 8.58-8.66 (1H , m), 9.01 (1H, brs), 9.15 (1H, brs).

 Melting point: 128-134

Compound 3 1 '

 4- [1- (2,4-difluorophenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl] 1-1,2-benzenediol

 5— [3,4-bis (benzyloxy) phenyl] —1- (2,4-difluorophenyl) 1-3- (4-fluorophenyl) —1H-pyrazole (Compound 30) The compound was obtained (46.3%).

Ή-NMR (DMS0-d ₆ ) <5: 6.55 (1H, dd, J = 2.4, 8.3Hz), 6.65 (1Η, d, J = 2.4Hz), 6.70 (1H, d, J = 7.8Hz) , 7. OKIE s), 7.23-7.28 (3H, m), 7.40-7.45 (lH, m), 7.63-7.68 (1 H, m), 7.90-7.94 (2H, m), 8.99 (1H, s) , 9.13 (1H, s). Melting point: 193-195 ° C

Compound 33

 4- {3- (4-Fluorophenyl) -1-1- [4- (trifluoromethoxy) phenyl] -1-H-pyrazole-5-yl} —1,2-benzenediol

 5-[3,4-Bis (benzyloxy) phenyl] 1-11 (4-trifluoromethoxyphenyl) -3- (4-fluorophenyl) 1H-pyrazol (Compound 32) In the same manner as for Compound 3 Afforded the title compound (72.2%).

Paper R (DMS0-d ₆ ) (5: 6.57 (1H, dd, 1 = 2.4, 7.8Hz), 6.68 (1Η, d, J = 2.4Hz), 6.74 (1H, d, J = 8.3Hz) ), 6.98 (1H, s), 7.27 (2H, t, J = 8.8Hz), 7.41-7.47 (4H, m), 7.92-7.96 (2H, m), 9.03 (1H, s), 9.17 (1H, s).

 Melting point: 155-156 ° C

Compound 35

 4- {3- (2-pyridinyl) 1-11- [4- (trifluoromethoxy) phenyl] —1H-pyrazole-5-yl} —1,2-benzenediol

 2 -— [5— [3,4-Bis (benzyloxy)] —1— (4-Trifluoromethoxyphenyl) 1H-pyrazol-3-yl] Pyridine (Compound 34) in the same manner as Compound 3 to give the title compound Was obtained as amorphous (86.2%).

Ή-NMR (DMS0-d ₆ ) <5: 6.59 (1H, dd, 1 = 2.0, 8.3Hz), 6.67 (1Η, d, 1 = 2.0Hz), 6.74 (1H, d, J = 8.3Hz) , 7.0K1H, s), 7.34-7.38 (lH, m), 7.43-7.50 (4H, m), 7.86-7.88 (1 H, m), 8.OKIE d, J = 7.8Hz), 8.63 (1H, d, J = 3.9Hz), 9.03 (1H, s), 9.17 (1H, s). Compound 37

 4- {3- (4-fluorophenyl) 1-1- [4- (trifluoromethyl) phenyl] -1H-pyrazole-5-yl} 1-1,2-benzenediol

5- [3,4-Bis (benzyloxy) phenyl] — 1— (4-Trifluoromethyl phenyl) -3- (4-Fluorophenyl) -1H-pyrazole (Compound 36) (64.3%). ¾-NMR (DMS0-d ₆ ) δ: 6.60 (1H, dd, J = 2.0, 7.8Hz), 6.68 (1H, d, J = 2.0Hz), 6.76 (1H, d, J = 8.3Hz), 7.02 (1H, s), 7.28 (2H, t, J = 8.8Hz), 7.56 (2H, d, J = 8.3Hz), 7,80 (2H, d, J = 8.3Hz), 7.94-7.98 ( 2H, m), 9.07 (1H, brs), 9.19 (1H, brs).

 Melting point: 172-173 ° C

Compound 3 9

 4- [1-[4- (tert-butyl) phenyl] _3— (4-fluorophenyl) 1-1H-pyrazol-1-yl 5-yl] -1,2-benzenediol

 5- [3,4-Bis (benzyloxy) phenyl] -1- (4-1: butylylphenyl) -3- (4-fluorophenyl) -1H-pyrazole (compound 38) in the same manner as compound 3 The title compound was obtained (52.0%).

'H-NMR (DMS0-d ₆ ) <5: 1.30 (9H, s), 6.55-6.57 (1H, s), 6.68-6.72 (1H, s), 6.91 (1H, s), 7.23-7.27 (6H , m), 7.43 (2H, d, J = 8.3Hz), 7.90-7.93 (2H, m), 8.97 (1H, br s), 9.12 (1H, br s).

 Melting point: 204-206 ° C

Compound 4 1

 4- [3-Methyl-11- (2-pyridinyl) -1H-pyrazole-5-yl] -1,2-benzenediol

 2- {5- [3,4-Bis (benzyloxy) phenyl] -13-methyl-1H-pyrazole-1-yl} The title compound was obtained from pyridine (Compound 40) in the same manner as for Compound 3 (73.1% ).

Ή-NMR (DMS0-d ₆ ) δ: 2.24 (3Η, s), 6.27 (1H, s), 6.43-6.46 (1H, m), 7.33-7.36 (lH, m), 7.49 (1H, d, J = 8.3Hz), 7.89-7.94 (1H, m), 8.32-8.33 (1H, m), 8.84 (1H, s), 8.96 (1H, s).

 Melting point: 228-231

Compound 43

4- [3—octyl 1— (2-pyridinyl) 1 1 H—pyrazol Ru]-1,2 benzenediol

 2-{5-[3,4-Bis (benzyloxy) phenyl] _ 3 -octyl-1 1-pyrazole-1-yl} The title compound was obtained from pyridine (Compound 42) in the same manner as Compound 3 (5 0.0%).

_{Ή-NMR (CDC1 3) (} 5: 0.88 (3H, t, J = 6.4Hz), 1.27 (8Η, m), 1.61-1.63 (4Η, m), 2.62 (2Η, t, J = 7.8Hz), 6.17 (1H, s), 6.37-6.38 (1H, m), 6.64-6.72 (2H, m), 7.20-7.26 (2H, m), 7.69-7.73 (1H, m), 8.32-8.33 (1H, a ).

 Melting point: 124-125 ° C

Compound 46

 4- [3-phenyl-1- (2-pyridinyl) -1H-pyrazole-5-yl] — 1,2-benzenediol

 2-—5— [3,4-bis (benzyloxy) phenyl] 13-phenyl-2-H-pyrazole-1-yl} The title compound was obtained from pyridine (compound 45) in the same manner as compound 3 (6 2 . Five %) .

Ή-NMR (DMS0-d ₆ ) δ: 6.56 (1H, dd, J = 7.8, 2.OHz), 6.67 (1H, d, J = 2.0Hz), 6.70 (1H, d, J = 8.3Hz) , 6.99 (1H, s), 7.30-7.40 (1H, m), 7.40-7.50 (3H,), 7.62 (1H, d, J = 8.3 Hz), 7.98 (1H, ddd, J = 7.8, 7.8, 2) OHz), 7.90-8.00 (2H, m), 8.41 (1H, dd, 4.9, 1.5Hz), 8.92 (1H, brs), 9.06 (1H, brs).

 Melting point: 212-214 ° C

Compound 5 1

 4- [3- (2-Methoxyphenyl) _1- (2-pyridinyl) -1H-pyrazol-5-yl] 1-1,2-benzenebenzene

 2-—5— [3,4-Bis (benzyloxy) phenyl] —3- (2-methoxyphenyl) —1H—pyrazole-1-yl} The title compound is obtained from pyridine (Compound 50) in the same manner as Compound 3. (63.0%).

Ή-NMR (DMS0-d ₆ ) δ: 3.90 (3Η, s), 5.62 (1H, d, J = 8.3Hz), 6.65-6.69 (2H, m), 6. 91 (1H, s), 7.0K1H, t, J = 7.8Hz), 7.13 (1H ₍ d, J = 8.3Hz), 7.33-7.42 (2H, m), 7.61 (1H, d, J = 7.8Hz) , 7.93-7.99 (2H, m), 8.40 (1H, d, J = 4.9Hz), 8.90 (1H, s), 9.01 (1 H, s).

 Melting point: 206-208 ° C

Compound 53

 4- [3- (3-Methoxyphenyl) 1-11 (2-pyridinyl) 1 1H-virazol-5-yl] —1, 2-benzenediol

 2- {5_ [3,4-bis (benzyloxy) phenyl] -13- (3-methoxyphenyl) 1-1H-pyrazol-1-yl} Pyridine (Compound 52) in the same manner as for Compound 3 to give the title compound (88.0%).

Ή-NMR (DMS0-d ₆ ) δ: 3.82 (3Η, s), 6.54 (1H, dd, J = 2.0, 8.3 Hz), 6.65 (1H, d, J = l.7Hz), 6.68 (1H, d , J = 8.3Hz), 6.92 (1H, dd, J = 2.0, 8.3Hz), 6.99 (1H, s), 7.35 (1H, t, J = 7.8Hz), 7. —7 · 50 (3Η, ηι ), 7.60 (1H, d, J = 7.8Hz), 7.98 (1H, dd, 1 = 2.0, 7.8Hz), 8.40 (1H, td, J = l.0, 4.9Hz), 8.89 (1H, brs ), 9.04 (1H, brs).

 Melting point: 211-214 ° C

Compound 55

 4- [3- (4-Methoxyphenyl) 1-111 (2-pyridinyl) -1H-pyrazole_5-yl] 1-1,2-benzenediol

 2- {5- [3,4-Bis (benzyloxy) phenyl] —3- (4-methoxyphenyl) —1H-pyrazole-1-yl} Pyridine (Compound 54) in the same manner as Compound 3 to give the title compound (77.0%).

Ή-NMR (DMS0-d ₆ ) <5: 3.84 (3H, s), 6.62-6.83 (3H, m), 6.94 (2Η, d, J = 8.3 Hz), 7.20-7.23 (lH, m) , 7.34-7.38 (lH, m), 7.17 (1H, t, J = 6.4Hz), 7.85 (2H, d, J = 8.3Hz), 8.45 (1H, d, J = 3.9Hz).

 Melting point: 205-209

Compound Ί 2 4- [1,3-di (2_pyridinyl) -1H-pyrazole-1-5-yl] 1-1,2-benzenediol

 2 -— [5— [3,4-bis (benzyloxy)] 1-11- (2-pyridinyl) 1-1H-pyrazolyl-3-yl] pyridine (compound 71 1) in the same manner as compound 3 The compound was obtained (20.5%).

'H-NMR (DMS0-d ₆ ) δ: 7.22 (1H, s), 7.49-7.52 (3Η, m), 7.58 (1H, s), 7.84 (1H, t, J = 7.2Hz), 8.00 (1H , dt, J = l.4, 7.8Hz), 8.27 (1H, d, 1 = 1.8Hz), 8.38 (1H, t, J = 7.8Hz), 8.75 (1H, sJ = 4.3Hz), 8.89 ( 1H, d, J = 8.7Hz), 9.65 (1H, d, J = 7.3Hz).

 Melting point:> 300t

Compound 74

 4- [3— (4'-Fluoro [1,1'-biphenyl] -1-4-yl) 1-1H-Pyrazol-5-yl] —1,2-benzenediol

 2- (5- [3,4-Bis (benzyloxy) phenyl] -1-3- (4'-fluoro [1,1'-biphenyl] -4-yl) 1-1H-pyrazol-1-yl} pyridin ( The title compound was obtained from compound 73) in the same manner as for compound 3 (10.8%).

Ή— NMR (DMS0-d ₆ ) (5: 6.56 (1H, dd, J = 7.8, 2.OHz), 6.66 (1Η, d, J = 2.0Hz), 6.68 (1 H, d, J = 8.3Hz) ), 7.04 (1H, s), 7.28-7.32 (2H, m), 7.42-7.45 (1H, m), 7.63 (1H, d, J = 8.3Hz), 7.73-7.79 (4H, m), 7.97- 8.02 (3H, m), 8.41-8.42 (lH, m), 8.91 (1H, br s), 9.06 (1H, br s).

 Melting point: 249-251 ° C

Compound 8 0

 4-1-1 [1- (1,3-benzothiazole-2-yl) -1-3 phenyl -1H-pyrazol-5-yl] -1,2-benzenediol

2— {5- [3,4-bis (benzyloxy) phenyl] —3- (2-pyridinyl) -1-H-pyrazole-1-yl} —1,3-benzothiazole (compound 7 From 9), the title compound was obtained in the same manner as for Compound 3 (84.0%).

Ή-NMR (DMS0-d ₆ ) δ 6.81 (1H, d, J = 8.3 Hz), 6.90 (1H, dd, J = 2.0, 7.8 Hz), 6.99 (1

H, d, J = 2.0Hz), 7.17 (1H, s), 7.41-7.53 (5H, m), 7.74 (1H, d, 1 = 1.8Hz), 7.97 (2H, d, J = 7.3Hz), 8.10 (1H, d, J = 7.8Hz), 9.13 (1H, s), 9.31 (1H, s).

 Melting point: 197-199 ° C

Compound 5 7

 4- [3- (2-chlorophenyl) _ 1- (2-pyridinyl) -1H-pyrazol-l-5-yl]-1,2-benzenediol

1. 39 g (4. 4画 ol) を加え 12時間撹拌し た。 反応終了後、 反応物に水を加え、 飽和炭酸水素ナトリウムで pH約 6. 0と しクロロフオルムで抽出した。 有機層を硫酸ナトリウムで乾燥し、 溶媒留去し た。 残渣をシ力ゲルクロマトグラフィー (クロロフオルム：メタノール 100 ： 1) で精製し、 表題化合物を 0. 038 g (53. 0%) 得た。 2- {5- [3,4-Bis (benzyloxy) phenyl] -13_ (2-cyclophenyl) -1H-pyrazole-1-yl} Pyridine (compound 54) 0.22 g (0.4 mmol) Dissolve in 1 OmL of methylene and add boron tribromide at room temperature-

1. 39 g (4.4 ol) was added and the mixture was stirred for 12 hours. After the completion of the reaction, water was added to the reaction mixture, the pH was adjusted to about 6.0 with saturated sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform: methanol 100: 1) to give 0.038 g (53.0%) of the title compound.

Ή-NMR (DMS0-d ₆ ) δ: 6.51-6.69 (3Η, m), 7.07 (1H, s), 7.31-7.53 (3Η, m), 7.62 (1H, d, J = 7.8Hz), 7.88 ( 1H, d, J = 7.8Hz), 7.95-8.01 (2H, m), 8.41 (1H, d, J = 2.0Hz), 8.91 (1H, brs), 9.06 (1H, brs).

 Melting point: 228-231 ° C

Compound 5 9

 4- [3- (3-chlorophenyl) 1-1- (2-pyridinyl) -1H-pyrazolyl 5-yl] — 1,2-benzenediol

2- {5_ [3,4-bis (benzyloxy) phenyl] -1-3- (3-chlorophenyl) -1-H-pyrazole-1-yl} 'Title from pyridine (compound 58) in the same manner as compound 57 The compound was obtained (25.0%). 'Η-丽 R (DMS0-d ₆ ) δ: 6.54 (IH, d, J = 7.3 Hz), 6.66-6.69 (2H, m), 6.93 (IH, s), 7.43-7.45 (3H, m ), 7.56 (1H, d, J = 5.4Hz), 7.63 (IH, d, J = 7.8Hz), 7.88 (IH, d, J = 4.8Hz), 7.99 (IH, t, J = 7.3Hz) , 8.4K1H, d, J = 2.4Hz), 8.91 (IH, brs), 9.06 (IH, brs). Melting point: 224-227 ° C

Compound 61

 4- [3- (4-phenylphenyl) 1-111 (2-pyridinyl) 1-1H-pyrazol-5-yl] 1,1,2-benzenediol

 2- {5- [3,4-Bis (benzyloxy) phenyl] -13- (4-chlorophenyl) -1H-pyrazole-1-yl} The title compound was obtained from pyridine (Compound 60) in the same manner as for Compound 57. (76.0%).

Ή-NMR (DMS0-d ₆ ) <5: 6.54 (IH, dd, J = 2.0, 8.3 Hz), 6.64 (IH, d, J = 2.0 Hz), 6.68 (1 H, d, J = 8.3 Hz) , 7.OKIE s), 7.43 (IH, dd, J = 4.9, 6.8Hz), 7.50 (2H, d, J = 8.3Hz), 7.60 (IH, d, J = 8.3Hz), 7.93 (2H, d , J = 8.3Hz), 7.98 (td, J = l.5, 7.8Hz), 8.40 (IH, d, J = 3.4Hz), 8.90 (IH, brs), 9.06 (IH, brs).

 Melting point: 235-237 ° C

Compound 63

 4- [3- (3-nitrophenyl) 1 1- (2-pyridinyl) 1 1H-pyrazo-Lu 5 ^^] 1,1,2-benzenediol

 2- (5- [3,4-Bis (benzyloxy) phenyl] -13- (3-nitrophenyl) -1H-pyrazol-1-yl) The title compound is obtained from pyridine (Compound 62) in the same manner as Compound 57. (87.0%).

Ή-NMR (DMS0-d ₆ ) δ: 6.65-6.70 (2Η, m), 7.21 (IH, s), 7.46 (IH, dd, J = 5.4, 7.3Hz), 7.64 (IH, d, J = 7.3Hz), 7.76 (1H, t, J = 8.3Hz), 8.01 (IH, t, J = 7.3Hz), 8.21 (IH, d, J = 7.8Hz), 8.36 (IH, d, J = 7.8Hz) ), 8.44 (IH, d, J = 3.4Hz), 8.69 (IH, bs), 8.92 (1H, brs), 9.09 (IH, brs).

Melting point: 225-227 ° C ' Compound 6 5

 4- [3- (4-nitrophenyl) 1 1- (2-pyridinyl) 1 1H-pyrazol 1-ru 5-yl] 1,1,2-benzenediol

 2- {5- [3,4-bis (benzyloxy) phenyl] -1- (4-nitrophenyl) -1H-pyrazole-1-yl} The title compound is obtained from pyridine (compound 64) in the same manner as compound 57. (54.0%).

Ή-NMR (DMS0-d ₆ ) δ: 6.54 (1H, dd, J = 2.44, 8.3 Hz), 6.65 (1H, d, J = 2.0 Hz), 6.69 (1H, d, J = 8.3 Hz), 7.20 (1H, s), 7.47 (1H, dd, J = 4.9, 7.3Hz), 7.62 (lH, d, J = 7.8Hz), 8.01 (1H, td, J = 2.0, 7.8Hz), 8.19 (2H, d, J = 8.8Hz), 8.31 (2H, d, J = 9.3Hz), 8.44 (1 H, dd, J = l.0, 4.9Hz), 8.95 (1H, brs), 9.10 (1H, brs) .

 Melting point: 197-210 ° C

Compound 6 6

 4- [3- (2-Hydroxyphenyl) 1-1- (2-pyridinyl) 1-1H-pyrazole-5_yl] — 1,2_benzenediol

 2- {5- [3,4-bis (benzyloxy) phenyl] -3- (2-methoxyphenyl) 1-1H-pyrazole-1-yl} pyridine (compound 50) in the same manner as compound 57 The title compound was obtained (%).

Ή-NMR (DMS0-d ₆ ) δ: 3.90 (3Η, s), 5.62 (1Η, d, J = 8.3 Hz), 6.65-6.69 (2H, m), 6.91 (1H, s), 7.0K1H , t, J = 7.8Hz), 7.13 (1H, d, J = 8.3Hz), 7.33-7.42 (2H, m), 7.61 (lH, d, J = 7.8Hz), 7.93-7.99 (2H, m) , 8.40 (1H, d, J = 4.9Hz), 8.90 (1H, s), 9.01 (1 H, s).

 Melting point: 137-140 ° C

Compound 6 7

 4- [3- (3-Hydroxyphenyl) -1- (2-pyridinyl) -1-H-pyrazole-5-yl] — 1,2-benzenediol

2— {5— [3,4-Bis (benzyloxy) phenyl] _ 3 _ (3-methoxy The title compound was obtained (18.0%) from cyphenyl) -1H-pyrazole-1-yl} pyridine (compound 52) in the same manner as for compound 57.

H-band R (丽 S0-d ₆ ) δ: 6.54 (1H, dd, J = 2.0, 8.3 Hz), 6.63 (1H, d, J = 2.0 Hz), 6.67 (1 H, d, J = 8.3 Hz), 6.75 (1H, dd, J = 2.0, 6.8Hz), 6.87 ((1H, s), 7.20-7.24 (1H, πι), 7.3 0-7.32 (2H, fli), 7.4K1H, dd, J = 4.9, 7.3Hz), 7.59 (1H, d, J = 8.3Hz), 7.95-8.00 (1H, m), 8.39 (1H, d, J = 3.4Hz), 8.89 (1H, s), 9.03 (1H , s), 9.39 (1H, s).

 Melting point: 228-232 ° C

Compound 6 8

 4- [3- (4-Hydroxyphenyl) 1-1- (2-pyridinyl) 1-1H-pyrazole-5-yl] -1,1,1-benzenediol

 2- {51- [3,4-bis (benzyloxy) phenyl] -3- (4-methoxyphenyl) -1-H-pyrazole-1-yl} pyridine (compound 54) in the same manner as compound 57 The compound was obtained (10.0%).

Ή one _{NMR (DMS0 - d 6) δ} : 6.52 (1H, dd, J = 2.0, 8.3Hz), 6.62 (1H, d, J = 2.0Hz), 6.67 (1 H, d, J = 8.3Hz), 6.81-6.83 (2H, m), 7.39 (1H, dd, J = 4.9, 7.3Hz), 7.58 (1H, d, J = 7.8Hz), 7.7K1H, d, J = 8.8Hz, 7.94-7.98 (lH, m), 8.37 (1H, d, J = 2.9Hz), 8.87 (1H, s), 9.0K1H, s), 9.49 (1H, s).

 Melting point: 159-159.5

Compound 7 0

 4- [3- (3,4-dihydroxyphenyl) 1-111 (2-pyridinyl) 1-1H-pyrazole-5-yl] 1-1,2-benzenediol

2- [3,5-bis (3,4-dimethoxyphenyl) -1H-pyrazole-1 1-yl] pyridine (compound 67) 0.2 1 g (0.5 ol) and methylene chloride in 5 mL Then, at 0 ° C, 2.5 mL (2.5 tmol) of boron tripromide (1M methylene chloride solution) was added, and the mixture was stirred at 0 ° C for 3 hours at room temperature. After completion of the reaction, the reaction product was poured into ice water, and the precipitated crystals were collected by filtration and washed sequentially with ethyl acetate and ethanol. After purification, the precipitate was dried to obtain 0.14 g (74.6%) of the title compound.

Ή-NMR (DMS0-d ₆ ) <5: 6.52 (IH, dd, J = 2.0, 7.8 Hz), 6.62 (IH, d, J = 2. OHz), 6.67 (1 H, d, J = 8.3 Hz) ), 6.75 (IH, s), 6.78 (IH, d, J = 8.3 Hz), 7.16 (IH, dd, J = 2.0, 8.3 Hz), 7.32 (1H, d, J = 2.OHz), 7.37- 7.41 (IH, m), 7.57 (IH, d, J = 8.3Hz), 7.96 (IH, dd, J = 2.0, 7.8Hz), 8.37-8.38 (lH, m).

 Melting point: 255-260 ° C

Compound 76

 4- [1- (2-Pyridinyl) -3- (2-Chenyl) -1H-pyrazole-5-yl] -1,2-benzenediol

 2— {5— [3,4-Bis (benzyloxy) phenyl] 13— (2-Chenyl) 1-1H—Virazol-1-yl} The title compound was obtained from pyridine (Compound 75) in the same manner as Compound 57. (55.0%).

Ή— NMR (DMS0-d ₆ ) <5: 6.52 (IH, dd, J = 1.95, 8.3 Hz), 6.23 (IH, d, J = 2. OHz), 6.67 (IH, d, J = 8.3) Hz), 6.88 (IH, s), 7.13 (IH, t, J = 4.9 Hz), 7.42 (IH, dd, J = 4.9, 6.8 Hz), 7.51-7.56 (3H, m), 7.97 (IH, td) , J = l.47, 7.33Hz), 8.4K1H, d, J = 3.41H), 8.91 (1H, s), 9.06 (1H, s).

 Melting point: 218-219 ° C

Compound 78

 4-1-1 [2- (pyridinyl) -1-3- (3-Chenyl) —1H-pyrazol-5-^-f1] 1,1,2-benzenediol

 2— {5- [3,4-Bis (benzyloxy) phenyl] —3— (3-Chenyl) 1H-pyrazole-1-yl} The title compound from pyridine (Compound 77) in the same manner as Compound 57 (35.0%).

Ή— NMR spectroscopy SO— d ₆ ) 6: 3.90 (3H, s), 5.62 (IH, d, J = 8.3 Hz), 6.65-6.69 (2H, m), 6.9K1H, s), 7.0K1H, t , J = 7.8Hz), 7.13 (1H, d, J = 8.3Hz), 7.33-7.42 (2H, m), 7.61 (IH, d, J = 7.8Hz), 7.93-7.99 (2H, m), 8.40 (IH, d, J = 4.9Hz), 8.90 (IH, s), 9.01 (1 oz

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 98

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9S8Z10 / C00idf / X3d Compound 88

 4- [3 _phenyl-2-1-1 [4- (trifluoromethoxy) phenyl] 1 1H-pyrazole-5-yl] 1-1,2-benzenediol

 Compound 87 was obtained in the same manner as compound 3 (69.0%).

_{Ή-NMR (CDC1 3) (} 5: 1.72 (2H, bs), 6.62-6.77 (3H, m), 6.70 (IH, s), 7.36-7.47 (5H, m), 7.56 (2H, d, J = 8.8Hz), 7.87 (2H, d, J = 8.3Hz).

 Melting point: Π9-182

Compound 90

 4- [3-phenyl-2-1- [4- (trifluoromethyl) -2-pyrimidinyl] 1 1-pyrazole-5-yl-1,2-benzenediol

 Compound 89 was obtained in the same manner as compound 3 (69.0%).

'H-NMR (DMSO-d ₆ ) <5: 6.56-6.71 (3H, m), 7.09 (IH, s), 7.38-7.49 (3H, m), 7.95 (2H, d, J = 6.8Hz), 8.03 (IH, d, J = 4.9Hz), 8.91 (IH, s), 9.07 (IH, s), 9.21 (IH, d, J = 4.9Hz).

 Melting point: 107-113 ° C

Compound 92

 4- [3- (2,4-difluorophenyl) 1 1- (2-pyridinyl) 1 1H-pyrazole-5-yl] 1,1,2-benzenediol

 Compound 3 was obtained in the same manner as Compound 3 from Compound 91 (38.0%).

• H-NMR (DMS0-d ₆ ) (5: 6.53 (IH, d, J = 7.8 Hz), 6.63 (IH, bs), 6.67 (IH, d, J = 8.3 Hz), 6.81 (IH, d, J = 3.4Hz), 7.16-7.20 (IH, m), 7.33-7.38 (IH, m), 7.43-7.46 (IH, m), 7.61 (IH, d, J = 7.8Hz), 7.97-8.05 (2H, m), 8.42 (IH, s), 8.91 (IH, s), 9.06 (IH, s).

 Melting point: 244-247 ° C

Compound 94

2-Methoxy-1-41- [3-phenyl-1- (2-pyridinyl) -1-H-virazol-5-yl] phenol Compound 93 was obtained in the same manner as compound 3 (64.0%).

'H-NMR (DMS0-d ₆ ) δ: 3.61 (3Η, s), 6.70 (2Η, dd, J = 2.0, 8.3 Hz), 6.80 (IH, d, J = l.5Hz), 7.11 (IH, s), 7.35-7.48 (4H, m), 7.67 (IH, d, J = 7.8Hz), 7.

92 (2H, d, J = 8.8Hz), 8.01 (IH, dt, J = 2.0, 7.8Hz), 8.42 (IH, dd, J = l.5, 4.

9Hz), 9.25 (IH, s).

 Melting point: 117-119 ° C

Compound 96

 2-Methoxy-5- [3-phenyl-11- (2-pyridinyl) 1-1-H-pyrazol-5-yl] phenol

 Compound 95 was obtained in the same manner as Compound 3 (47.0%).

H-NMR (DMS0-d ₆ ) δ: 3.76 (3Η, s), 6.67 (2Η, m), 6.88 (IH, m), 7.05 (IH, s), 7.35-7.47 (4H, in), 7.66 (IH, d, J = 7.8Hz), 7.92 (2H, d, J = 7.3Hz), 8.00 (IH, dt, J = 2.0, 7.8Hz), 8.40 (IH, m), 9.07 (IH, s).

 Melting point: 90-92 ° C

Compound 98

 4- [1-(2-pyridinyl) -1H-pyrazole-5-yl] — 1,2-benzenediol

 Compound 97 was obtained in the same manner as compound 70 (39.5%).

Ή-NMR (DMS0-d ₆ ) δ: 6.45-6.48 (2Η, m), 6.58 (1H, d, J = 2.OHz), 6.65 (IH, d, J = 7, 8Hz), 7.40 (IH , dd, J = 4.9, 7.3Hz), 7.53 (IH, d, J = 7.8Hz), 7.68 (IH, d, J = 2.OHz), 7.96 (IH, dd, J = 2.0, 7.3Hz), 8.37 (IH, dd, J = l.0, 4.9Hz), 8.86 (IH, s), 8.99 (IH, s).

 Melting point: 151-154 ° C

Compound 101

 5- (3,4-dihydroxyphenyl) 1-3-phenyl 1-1 (2-pyridinyl) 1 1H-pyrazole-4 lipoxylic acid

Compound 100 was obtained in the same manner as Compound 3 (69.0%). 'H-NMRiDMSO-de) δ: 6.49 (1H, m), 6.63 (1H, d, J = 8.3Hz), 6.70 (1H, d, J = 2.0Hz), 7.43 (4H, m), 7.51 (1H , d, J = 7.8Hz), 7.70 (2H, dd, J = l.2, 8.3Hz), 7.94 (1H, dt, J = 2.0, 7.8Hz), 8.39 (1H, m), 9.02 (1H , s), 9, 14 (1H, s).

 Melting point: 223-226 ° C

Compound 103

 4- [1-(5_Nitro-1-2-pyridinyl) -3-phenyl-1-H-pyrazol-5-yl-1,2-benzenediol

 Compound 102 was obtained in the same manner as compound 70 (58.0%).

Ή-NMR (DMS0-d ₆ ) δ: 6.63-6.88 (3Η, m), 7.09 (1H, s), 7.38-7.50 (4H, m), 7.80-7.95 (3H, m), 8.74 (2H, dd) , J = 2.9, 8.8Hz), 8.94 (1H, s), 9.12 (2H, d, J = 2.9Hz).

 Melting point: 122-125 ° C

Compound 104

 4- [1- (5-Amino-2-pyridinyl) -1,3-phenyl-1-H-pyrazol-5-^-per] -1,2-benzenediol

 Compound 103 was obtained in the same manner as Compound 3 (34.0%).

Ή- thigh _{R (DMS0- d 6) δ:} . 5.54 (2Η, br), 6.52 (1Η, dd, J = 2.0, 8.3Hz), 6.64-6 67 (. 2H m), 6.87 (1H, s) , 7.02-7.05 (1H, m), 7.12 (1H, d, J = 8.3Hz), 7.3 0-7.33 (1H, m), 7.40-7.43 (2H, m), 7.74 (1H, d, J = 2.5 Hz), 7.85-7.87 (2H, m), 8.86 (1H, s), 9.00 (1H, s).

 Melting point: 134-137 ° C

Compound 1 06

 4- [3-phenyl-2- (1-pyridinyl) -11H-pyrazole-5-yl] ― 1,2-benzenediol

Compound 105 was obtained in the same manner as compound 70 (24.0%). Ή Ichi匪_{R (CDC1 3) δ: 6.58} (IH, dd, J = 2.0, 8.3Hz), 6.68 (IH, d, J = 2.4Hz), 6.74 (IH, d, J = 8.3Hz), 7.01 ( IH, s), 7.36-7.38 (IH, m), 7.43-7.50 (3H, m), 7.76-7.79 (IH, m), 7.91 (2H, d, J = 7.3Hz), 8.54 (IH, s) , 8.55 (IH, s), 9.04 (IH, brs), 9.18 (IH, brs).

 Melting point: 238-241

Compound 108

 4_ [3- (3-Bromophenyl) 1 1_ (2-pyridinyl) 1 1H-pyrazol 1-ru 5-yl] 1 1,2-benzenediol

 The compound was obtained from compound 107 in the same manner as compound 70 (26.0%).

'H-NMR (DMS0-d ₆ ) δ: 6.53 (IH, dd, J = 2.0, 7.8 Hz), 6.63 (IH, d, J = 1.9 Hz), 6.68 (IH, d, J = 7.8 Hz) , 7.1 (IH, s), 7.40-7.46 (2H, m), 7.56 (IH, d, J = 8.3Hz), 7.63 (IH, d, J = 7.8Hz), 7.93 (IH, d, J = 7.8Hz), 7.98-8.02 (IH, m), 8.K1H, s), 8.41 (IH, d, J = 3.9Hz), 9.01 (IH, s), 9.17 (IH, s).

 Melting point: 206-210 ° C

Compound 1 10

 4- [3- (3-Morpholinophenyl)-1- (2-pyridinyl) -1H-pyrazole-5-yl] 1,1,2-benzenediol

 Compound 109 was obtained in the same manner as Compound 3 (72.0%).

 "H-NMRiDMSO-de) δ: 3.17 (4Η, t, J = 4.4Hz), 3.76 (4H, t, J = 4.4Hz), 6.53 (IH, dd, J = l.9, 8.3Hz), 6.63 (IH, d, J = l.9Hz), 6.67 (IH, d, 1 = 1.8Hz), 6.94 (IH, dd, J = l.9, 8.3Hz), 7.03 (IH, s), 7.27 -7.46 (4H, m), 7.61 (IH, d, J = 7.8Hz), 7.99 (IH, dt, J = l.9, 7.8Hz), 8.40-8.41 (1H, m), 8.99 (IH, s ), 9.15 (IH, s).

 Melting point: 206-209

Compound 1 1 3

1,3- [5- (3,4-dihydroxyphenyl) 1-1- (2-pyridinyl) 1-1H-pyrazol-3-yl] phenyl-1-2-pyrrolidinone τ-(-z- ^ \ -i-Nie Ot / :,-'ε) -s] -ε

 6 τ τ om- u: W

'(s' HI) 91 · 6 '( ^s ' Ηΐ) 00 · 6 '( ^ra Ήΐ)-ΪΓ8' (s Ήΐ) 8ΐ '8' (ΖΗ8 'S = ί' ΡΪ 'ΗΙ) 00 "8' ( ΖΗ8 ί 'Ρ' ΗΙ) Ζ6 "ΉΖ) Ζ" Ζ-9Ζ "'ΗΖ) 9 Ή9 · Ή3) ZS -8 S''(s' ΗΙ) 9 I" ¾) 0Z' 9-S9 '9' ( ZHC '8' 0 Ή 'PP' HI) S3 '9: P ( ⁹ P-0S) NH,

 ° (% o 'z 8) ¾¼? ^) Fe |? Ε i¾ ^> Q 9 τ τ% ^> ir-^^-2' T-¾--(— ε— r

—A? i-UZ-Ο ^ 1 Ζ—, (ιΆ-Ζ -A (y- ε—

 L I τ

 Oo62I-9ZI:, • (ω 'HI) ZS--Κ' 8 '(ω ΉΙ) II' ί-Ζί Ί '(sjq' ΗΙ) 99 'L' (· 8 = 1 V Ήΐ) JP · ί ' (ω 'Η9) -ΖΙ' Ζ '(ω' ΗΖ) 10 'Ζ-Ιβ · 9' -Z = f 1 'Ηΐ) 68 · 9' (ω 'ΗΖ) SZ • 9--89 · 9' (s 'HI) Ζ9 "9' (¾0 · Ζ = ί 'Ρ' ΗΙ) 89 · 9 '' Η8) '2-98 Έ: 9 lOOO) 丽-Η 【

 ° (% · ο ζ)-^ ^ m? Ε i # ^ α ^ τ τ

One Ζ— [ni-e-— (4Γ-I-^^ ^ Γ- ^-^) — ε] -3} —

 S I T

 ΟοΙΖΐ-69ΐ: ^ boat

^{• (s Ήΐ) 9Γ6 '(} s ΉΙ) 00 · 6' HI) Z over ^{· 8 '(s' HI)} CI' 8 '(Z HC "8 Ό - ^ f' IP 'HI) 00 -8' HO 0Z '-09' HZ) 9 Ζ_Ζ '( ^s ΉΙ) I O'Z' ΉΖ) 69 '9-29 "9' (ZHC '8' 0 Ζ = ί 'PP' HI) ½9 '( ΖΗ8 9 = ί 'ΗΖ) 16

'e' (ZHS -8 = ί ΈΖ) ι ^ ¹ m ・ = ί 'w. ^) ^ τQ ( ⁹ P-OSM) MN-HI

 ° (% o · L 8)-^ ^ omu ^ ε ^ a ^ z 1 1

9S8ZTO / COOZdf / X3d [H-pyrazol-3-yl] -N, N-dimethylpenzamide It was obtained in the same manner as for compound 3 from compound 118 (97.0%).

'H_NMR (DMS0- d ₆ ) δ: 2.94 (3Η, brs), 3.01 (3H, brs), 6.54 (1H, dd, J = 2.0, 7.8Hz), 6.63-(1H, d, 1 = 2.0 Hz), 6.66 (1H, d, J = 7.8Hz), 7.08 (1H, s), 7.3

7 (1H, d, J = 7.8Hz), 7.43-7.46 (1H, m), 7.50 (1H, t, J = 8.0Hz), 7.63 (1H, d, J = 7.8Hz), 7.91 (1H, s ), 7.96-8.02 (2H, m), 8.40-8.42 (1H, m), 9.00 (1

H, s), 9.16 (1H, s).

 Melting point: 125-128 ° C

Compound 122

 4- [3- (3-Piperidinophenyl)-1-(2-pyridinyl) _ 1 H-Pyrazol-l_5_yl]-1,2-Benzenediol

 Compound 123 was obtained in the same manner as compound 3 (82.0%).

'H-NMR (DMS0-d ₆ ) 6: 1.55-1.57 (2H, m), 1.63-1.64 (4H, m), 3.18-3.21 (4H, m), 6.53 (1H, dd, J = l.9 , 8.3Hz), 6.63 (1H, d, J = 1.9Hz), 6.67 (1H, d, J = 8.3Hz), 6.92 (1H, d, J = 7.8Hz), 7.00 (1H, s), 7.23 -7.30 (2H, m), 7.41-7.4 4 (2H, m), 7.61 (1H, d, J = 7.8Hz), 7.98 (1H, dt, J = l.9, 7.3Hz), 8.40-8.41

(1H, m), 8.97 (1H, s), 9.13 (1H, s).

 Melting point: 135-137 ° C

Compound 124

 4 -— [3-3-[(3-Methoxypropyl) amino] phenyl-11- (2-pyridinyl) _1H-pyrazole_5_yl] 1-1,2-benzenediol Same as compound 3 from compound 121 (67.0%).

H-NMR (DMS0-d ₆ ) δ: 1.79 (2Η, uint, J = 6.4), 3.08-3.12 (2Η, m), 3.25 (3Η, s), 3.43 (2Η, t, J = 6.4Hz) ), 5.65 (1H, bs), 6.51-6.57 (2H, m), 6.61 (1H, d, J = 2.0Hz), 6.67 (1H, d, J = 7.8Hz), 6.87 (1H, s), 7.04 -7.15 (2H, m), 7.40-7.43 (1H, m), 7.59 (1H, d, J = 8.3Hz), 7.99 (1H, dt, J = l.9, 7.8Hz), 8.3 9-8.41 (1H, m), 8.98 (1H, s), 9.12 (1H, s).

 Melting point: 123-126 ° C

Example 5 Production of 6- (1,3-diphenyl_1H-pyrazole-5-yl) -14-methoxy_3-pyridinol Hydrochloride (Compound 6)

 (E) -3- [4-Methoxy-15- (methoxymethoxy) 1-2-pyridinyl] 1-1-phenyl-12-propen-1-one 0.25 g (0.84 t ol) of phenylhydrazine 0.27 g (2.53 thigh 01) and 1 OmL of ethanol were added, and the mixture was refluxed for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 1 OmL of toluene and 0.29 g (1.27 mmol) of DDQ were added to the residue, followed by stirring at 80 ° C for 12 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate and saturated saline in that order, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform: hexane 3: 1). 5 mL of trifluoroacetic acid was added to the obtained compound, and the mixture was stirred at room temperature for 0.5 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, washed successively with saturated sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (chloroform: hexane 3: 1), and converted to a hydrochloride with 4 mol / L hydrochloric acid-ethyl acetate to give 0.074 g (21.1%) of the title compound.

NMR (DMS0-d ₆ ) δ: 3.80 (3Η, s), 7.24 (1Η, s), 7.39-7.50 (9H, m), 7.91-7.93 (2H, m), 8.14 (1H, s), 10.93 (1H, brs).

 Melting point: 164-170 ° C

Example 6 Production of 2- (1,3-diphenyl 1H-pyrazole-5-yl) -1-5-methoxy-4-pyridinol hydrochloride (Compound 7)

2- (1,3-diphenyl 1H-pyrazolyl 5-yl) —5-methoxy—41-[(4-methoxybenzyl) oxy] pyridine 0.20 g (4.3 marl ol) in acetic acid 10 mL was added and the mixture was stirred at 90 ° C for 2 hours. After cooling with ice, neutralize with 1 mol ZL aqueous sodium hydroxide solution, extract with chloroform, dry with sodium sulfate, and evaporate the solvent. Was. The residue was purified by silica gel chromatography (chloroform: methanol 100: 2) to give 6- (1,3-diphenyl-1H-pyrazole-5-yl) _4-methoxy-3-pyridinol. 5 g (98.0%) were obtained. This was converted to a hydrochloride with 4 mol / L hydrochloric acid-ethyl acetate to give 0.086 g (47.3%) of the title compound.

• H-NMR (DMS0-d 6) (5: 3.93 (3H, s), 7.00 (1H, s), 7.39-7.50 (9Η, m), 7.92 (2H, d, J = 8.0Hz), 8.22 ( 1H, s).

 Melting point: 144_148 ° C

Example 7 'Production of 5- [4,5-bis (benzyloxy) 1-2-pyridinyl] _1,3-diphenyl-1H-birazol-4-caproloxylic acid (Compound 14)

 4,5-bis (benzyloxy) -2- (1,3-diphenyl-4 ethoxy ethoxylated 1H-pyrazole-5-yl) 'Similar to compound 3 of Example 4 from pyridine (compound 12) The title compound was obtained by the method (26.0%).

_{Ή-NMR (CDC1 3) (} 5: 5.25 (2H, s), 5.33 (2H, s), 7.20-7.51 (20Η, m), 8.03 (2H, s) mp:. 253- 255 ° C

Example 8 Preparation of 5- (4,5-dihydroxy_2-pyridinyl) 1-1,3-diphenyl-1H-pyrazole-14-hydroxypropyloxylic acid (compound 15) ethyl 5- (4,5 —Dihydroxy-1-pyridinyl) -1,3-diphenyl—1H-pyrazole-4-carboxylate (Compound 13) 0.26 g (0.65 ol) was dissolved in 5 mL of ethanol and 2 molZL 2 mL of aqueous sodium hydroxide solution was added, and the mixture was stirred for 12 hours. After completion of the reaction, the reaction solution was made acidic by adding lmolZL hydrochloric acid, and the precipitated crystals were collected by filtration to give the title compound (0.08 lg, 33.0%).

Ή-NMR (DMSO-d ₆ ) δ: 7.27-7.38 (12H, m), 7.74 (1Η, s), 8.11 (1H, s).

 Melting point: 188-190 ° C

Example 9 6- [3- (3,5-difluoro-1-hydroxyphenyl) —1 _ Preparation of phenyl-1H-birazol-5-yl] — 4-methoxy-13-pyridinol (compound 16)

 2- [3-(3,5-difluoro-1-4-benzyloxyphenyl) 1-phenyl 1 H-birazol-1-5-yl] 1-4-methoxy-5-benzyloxypyridin The title compound was obtained in a similar manner to that of compound 3 of Example 4 (70.0%).

^! H-NMR (DMS0-d ₆ ) δ: 3.72 (3Η, s), 7.03 (1H, s), 7.22 (1H, s), 7.31-7.55 (7H, m), 8.29 (1H, s), 9.66 (1H, s), 10.24 (1H, s).

 Melting point: 143-145 ° C

Example 10 Production of 4- [5- (4,5-dimethoxy-2-pyridinyl) -11-phenyl-2-H-pyrazole_3_yl] -2,6-difluorophenol (Compound 17)

 2- {3- [4- (benzyloxy) -1,3,5-difluorophenyl] -11-phenyl-1H-pyrazolyl-5-yl} -4,5-dimethoxypyridine Same as compound 3 in Example 4 The title compound was obtained by the method (14.0%).

One _{NMR (CDC1 3) (5:} 3.62 (3H, s), 3.98 (3H, s), 6.57 (1H, s), 6.70-6.71 (1H, m), 6.84 (1H, s), 7.34-7.42 ( 7H, m), 8.15 (1H, s).

 Melting point: 220-223 ° C

Example 11 Production of 4- [3- (4-aminophenyl) -1-1-phenyl-1-H-pyrazolyl 5-yl] -1,2-benzenediol (Compound 20)

 Benzyl 2- (benzyloxy) -4- [3- (4-nitrophenyl) -1-1-phenyl-4,5-dihydro-1H-pyrazole-5_yl] phenyl

(Production 31 compounds) The title compound was obtained as amorphous by the same method as compound 3 of example 4 (24.2%).

Ή— NMR—SO—d ₆ ) δ: 519 (2H, br), 6.51-6.70 (6H, m), 7.28—7.41 (5H, m), 7.54 (2H, d, J = 8.3Hz), 8.93 (1H, s), 9.06 (1H, s).

Example 12 2- (acetyloxy) -4-1- [3-phenyl-2- (2-pyri) Preparation of 1H-pyrazole-5-yl] phenylacetate (Compound 49)

 4- [3-phenyl-1- (2-pyridinyl) -1H-pyrazole-5-yl] _1,2-benzenediol (compound 46) was acetylated with acetic anhydride and sodium acetate to give the title compound ( 62.0%).

 'H-NMRiCDCls) δ: 2.26 (3Η, s), 2.30 (3H, s), 6.84 (1Η, s), 7.16-7.26 (4H, m),

7.34-7.38 (lH, m), 7.42-7.46 (2H, m), 7.67-7.69 (1H, m), 7.81 (1H, ddd, 1 = 2.0, 7.

8, 7.8Hz), 7.92-7.94 (2H, m), 8.37-8.38 (1H, m).

 Melting point: 122-125 ° C

 Example 13 Production of pyrazole compound (1) having lower alkylenedioxy group

 The compounds shown in Table 22 were produced.

 Table 22

化合物 44

Compound 44

2— [5— (1,3-benzenebenzene-1-5-yl) -13-year-old 1-H-pyrazole-1-yl] pyridine 4- [3-octyl-1- (2-pyridinyl) -1-H-pyrazole-5-yl] — 1,2-benzenediol (compound 43) 75. Omg (0.2 lmmol) of Ν, Ν'-dimethyl Dissolve in 1 OmL of formamide, and 0.10 g of cesium carbonate

(0.3 Ommol) and 0.04 g (0.3 lmmol) of bromochloroethane were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. The residue was reconstituted with hexane: ethyl acetate (1: 1) to give the title compound as an oil (0.055 g, 7%).

1.0%).

_{Ή- NMR (CDC1 3) δ:} 8.41 (1H, d, J = 4.9Hz), 7.69-7.73 (1H, m), 7.37 (1H, d, 7.8H z), 7.18 (lH, m), 6.70- 6.75 (3H, m), 6.27 (1H, s), 5.97 (2H, s), 2.71 (2Hmt, J = 7.8 Hz), 1.68-1.74 (2H, m), 1.28-1.42 (10H, m), 0.88 (3H, t, J = 6.8Hz).

Compound 48

 2- [5- (1,3-benzenedioxo-1-yl) -1-3-phenyl-1H-pyrazole-1-yl] pyridine

 4- [3-phenyl-1- (2-pyridinyl) -11H-pyrazol-5-yl] 1-1,2-benzenediol (compound 46) in the same manner as compound 44 to give the title compound as an oil (96.6%).

_{Ή-NMR (CDC1 3) δ} : 8.42 (1H, d, J = 4.9Hz), 7.92 (2H, d, J = 7.3Hz), 7.77-7.81 (1H, m), 7.58 (1H, J = 7.3Hz ), 7.37-7.45 (3H, m), 7.22-7.26 (1H, m), 6.77-6.83 (4H, m), 5.98 (2H, s).

Example 14

Compound 99

 2— [5— (3,4-Bis-benzyloxy-phenyl) 14-Iodine 3 —Phenol 1 H-Vilazole-11-yl] -Pyridine

A mixture of 451.64 g (3.0 t ol) of compound, 1.48 g (6.5 awake ol) of N-dosuccinimide, 0.11 mL of HC1 and 12 mL of DMS O was stirred at room temperature for 1 hour. Stirred. After completion of the reaction, the precipitated crystals were collected by filtration, washed successively with water and ethyl hexane monoacetate, and dried to obtain 1.80 g (89.0%) of the title compound.

 'H-NMRiCDCls) δ: 5.09 (2Η, s), 5.18 (2H, s), 6.85-6.97 (3H, m), 7.16 (1H, m), 7.26-7.48 (14H, m), 7.67 (1H, dt, J = l.5, 7.8Hz), 7.92 (2H, dd, J = l, 1, 8.3Hz), 8, 33 (1H, dd, J = l.5, 4.5Hz).

 Melting point: 171-173 ° C

Example 15

Compound 100

 5— (3,4_Bis-benzyloxyphenyl 3-phenyl) —1— (2-pyridinyl) 1-1H-pyrazole—4-carboxylic acid

Compound 99 0. 34 g (0. 5mmol) , P d (OAc) 2 0. 00248 g (0. 0 1 lmmol), PP h 3 0. 0234 g (0. 089mmol), KI 0. 0851 g (0 A mixture of 0.15 g (2.0 t) of Ac OK, 1.5 mL (2.0 t) of Ac OK, and 1.5 mL of DMF was stirred at room temperature for 18 hours under a stream of carbon monoxide. After completion of the reaction, water and diluted hydrochloric acid were added to the reaction product, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1 to 1: 1) to give 0.095 g (34.0%) of the title compound.

Ή one _{NMR (CDC1 3) <5:} 5.06 (2H, s), 5.15 (2H, s), 6.86-6.87 (2H, m), 6.97 (1H, d, J = l.5Hz), 7.19-7.44 ( 15H, m), 7.65 (1H, dt, J = 2.0, 7.8Hz), 7.74-7.77 (2H, m), 8.36-8.37 (1H, m).

 Melting point: 201-203 ° C

Example 16

Compound 102

2- [5— (3,4-bis-benzyloxyphenyl) -1-3-phenyl 1 H—pyrazol-1-yl] —5-nitro-2-pyridine 5- [3,4-bis (benzyloxy) phenyl] 1-3-phenyl 1H-pyrazole 0.216 g (0.5 t ol), cuprous iodide 0.0116 g (0.06 丽ol), 1,10-Fuenanthroline 0.0129 g (0.07 t ol), cesium carbonate 0.36 g (1.1 t ol), 2-bromo-5-ditropyridine 0.115 g (0.56 imol ) And a mixture of 0.5 mL of 1,4-dioxane were stirred at 100 ° C. for 11 hours under an argon stream. After completion of the reaction, insolubles were removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to obtain 0.13 g (46.0%) of the title compound.

 'H-NMRiCDCl ^ δ: 5.12 (2Η, s), 5.24 (2H, s), 6.75 (1Η, s), 6.87-6.97 (3H, m), 7.22-7.50 (13H, m), 7.90-7.94 ( 3H, m), 8.45 (1H, dd, J = 2.5, 8.8 Hz), 8.85 (1H, d, 1 = 2.4Hz).

 Melting point: 139-143 ° C

Example 17

Compound 105

 3-[5- (3,4_dimethyloxyphenyl) -1-3-phenyl-1H-pyrazol-1-yl] pyridine ''

3- (3-phenyl-2-H-pyrazole-1-yl) pyridine 0.1 g (0.5 t ol), 4-bromoveratrol 0.217 g (1 ol), Pd (OA _{c) 2 0. 011 g (0.} 05 Yuzuru ol) BI NAP 0. 031 g ( 0. 05m mol), cesium carbonate 0. 326 g (1 thigh ol), tetra-n- Petit Ruan monitor © beam Buromi de 0. A mixture of 177 g (0.55 ol) and 2.5 mL of DMF was stirred at 130 ° C for 80 hours under an argon stream. After the reaction was completed, water was added to the reaction product, which was extracted with ethyl acetate. The organic layer was washed successively with zK and saturated saline, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 2: 1) to obtain 0.073 g (41.0%) of the title compound. Ή-NMR (CDCI3) δ: 12 (3H, s), 3.90 (3H, s), 6.74 (IH, s), 6.82-6.83 (3H, m), 7.2 6-7.46 (4H, m), 7.74 ( IH, d, J = 8.3Hz), 7.91 (2H, d, J = 7.3Hz), 8.54 (IH, dd, J = l.0, 4.9Hz), 8.68 (IH, d, J = 2.4Hz) .

 Melting point: 138-1401:

Example 18

Compound 109

 4- {3 -— [5- (3,4-bisbenzyloxyphenyl) -1- (pyridine-1-2-yl) —1H-pyrazol-3-yl] phenyl} morpholine

Compound 107 0.75 g (lmmol), morpholine 0.13 mL (1.5 mio 1), Pd ₂ (dba) ₃ 0.093 g (0.1 mmol), BI NAP 0.195 g (0.15 mmol) A mixture of 3 t ol), 0.274 g of NaOt Bu (2.85 t ol) and 5 mL of toluene was stirred at 110 ° C for 12 hours. After completion of the reaction, water was added to the reaction product, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (hexane: ethyl acetate 1: 1) to give the title compound (0.409 g, 67.0%).

 'H-NMRiCDCls) δ: 3.24 (4Η, t, d = 4.4Hz), 3.88 (4H, t, d = 4.4Hz), 4.99 (2H, s), 5.17 (2H, s), 6.71 (IH, s), 6.84-6.92 (4H, m), 7.18-7.22 (IH, m), 7.29-7.70 (14H, m), 7.71-7.75 (IH, m), 8.38-8.39 (IH, m).

 Melting point: 129- 13 C

Compound 1 14

 1- {3-[5- (3,4-bis-benzyloxyphenyl) -1-1-pyridine-2-yl-1H-pyrazol--3-yl] -phenyl} -4-1 Fenirubipera gin

 Obtained in a similar manner to compound 109 (76.2%).

_{Ή-NMR (CDC1 3) δ} : 3.36-3.43 (8Η, m), 5.00 (2H, s), 5.18 (2H, s), 6.73 (IH, s), 6.8 8-6.91 (4H, m), 6.98-7.01 (4H, m), 7.20-7.49 (15H, m), 7.59 (1H, s), 7.72-7.76 (1H, m), 8.39-8.40 (lH, m ).

 Melting point: 61-64 ° C

Compound 121

 2-[5- (3,4-Bisbenzyloxyphenyl) -1-3- (3-piperidine-11-ylofenyl) -pyrazole-1-yl] -pyridine

 Obtained as a pale-yellow oil in the same manner as for Compound 109 (76.0%).

 'H-NMRiCDCls) δ: 1.57-1.61 (2Η, m), 1.70-1.75 (4H, m), 3.22 (4H, t, J = 5.4Hz), 4.99 (2H, s), 5.17 (2H, s), 6.71 (1H, s), 6.86-6.94 (3H, m), 7, 1 8-7.21 (1H, m), 7.26-7.52 (15H, m), 7.73 (1H, dt, J = 2.0, 8.2Hz), 8.36-8.38 (1H, m).

Example 19

Compound 1 1 6

 2- [3-Biphenyl-4f1-5- (3,4-bisbenzyloxyphenyl) -pyrazole-1-yl] -pyridine

Compound 1 0 7 59 6. lmg (1. 00顧ol), phenylene Ruporan acid 1 6 2. 5 mg (1. 3 3 Bian 1), P d (PP h 3) 4 6 9. 5mg (0. 0 6 negation _{ol), 2MN a 2 C0 3} 9mmol, and stirred for 1 8 h toluene 14 mL, a mixture of ethanol 1 mL in 1 0 0 ° C. After the reaction was completed, water was added to the reaction product, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 1: 1) to give 0.363 g (62.0%) of the title compound.

'H-NMRiCDCls) δ 5.00 (2Η, s), 5.17 (2H, s), 6.78 (1Η, s), 6.87-6.92 (3H, m), 7.20-7.22 (1H, m), 7.27-7.51 (15H, m), 7.56-7.59 (1H, m), 7.66- 7.68 (2H, m), 7.74 (1H, dt, J = 2.0, 7.8Hz), 7.88-7.91 (1H, m), 8.14 -8. 15 (1H, m), 8.38-8.40 (1H, m). Melting point: 114-115 ° C

Example 20

Compound 1 11

 2— [5— (3,4-bis-benzyloxyphenyl) -1-3- (3-iodophenyl) 1-1H-pyrazol-1-yl] —pyridine

 Compound 107 0.589 g (limol), cuprous iodide 0.022 g (0.1 1 thigh ol), Na l 0.303 g (2 sol ol), trans-N, N-dimethyl-1- A mixture of 0.0383 g (0.27 mmol) of 2-cyclohexanediamine and 2 mL of 1,4-dioxane was stirred at 110 ° C for 12 hours. After completion of the reaction, water was added to the reaction product, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (form: methanol: 100: 1) to give 0.553 g (87.0%) of the title compound.

_{- NMR (CDC1 3) <5} : 4, 99 (2H, s), 5.17 (2H, s), 6.70 (1H, s), 6.84-6.90 (3H, m), 7.15 (1H, t, J = 8.3 Hz), 7.0-7.24 (1H, m), 7.28-7.39 (9H, m), 7.43-7.45 (2H, m), 7.65-7.68 (1H, m), 7.71-7.75 (1H, m ), 7.84-7.87 (1H, in), 8.30 (1H, t, J = 1.5Hz), 8.39-8.41 (1H, m).

 Melting point: 123-124 ° C

Example 21

Compound 112

 1-3-[5- (3,4-dibenzyloxyphenyl) 1-111 (2-pyridinyl) 1-1H-pyrazil-1-yl 3-phenyl] phenyl 2-pyrrolidinone

Compound 1 1 110.635 g (l ol), 2-pyrrolidinone 0.085 mL (1.1 t ol), Cu I 0.0223 g (0.117 t ol), Trans-N, N-N-dimethyl 1, the 2-cyclopropyl Kisanjiamin 0. 0316 g (0. 22 _{Yuzuru. 1), K 3 P0 4} 0. 447 g (2. Ommol), mixing of 1, 4 one Jiokisan 1 mL The material was stirred at 110 ° C for 12 hours. After completion of the reaction, water was added to the reaction product, which was extracted with ethyl acetate. The organic layer was washed successively with 7K and saturated saline, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 1: 3) to give the title compound (90.0%).

 'H-NMRiCDClj) δ: 2.18 (2Η, Quint J = 7.3Hz), 2.63 (2H, t, J = 7.8Hz), 3.95 (2H, t, J = 7.3Hz), 4.99 (2H, s), 5.17 (2H, s), 6.76 (1H, s), 6.85-6.91 (3H, m), 7.20-7.23 (1H, m), 7.29-7.47 (12H, m), 7.69-7.75 (3H, m), 8.06 (1H, s), 8.38-8.40 (1H, m).

 Melting point: 106-109 ° C

Compound 1 2 0

 4- [5-(3-aminophenyl) 1 2-pyridine-1 2-yl 2H-pyrazol 1-3-yl] 1-benzene-1 1,2-diol

 {3— [5- (3,4-bisbenzyloxyphenyl) 1 1 _pyridine-2-yl 1 H-pyrazol-3-yl] —phenyl 2 Benzyl ester was synthesized and reduced in the same manner as in Compound 3 (55.0%).

Ή— NMR (DMS0-d ₆ ) <5: 5.13 (2H, brs), 6.51-6.56 (2H, m), 6.61 (1Η, d, J = 2.0Hz), 6.67 (1H, d, J = (8.3Hz), 6.81 (1H, s), 7.01-7.09 '(2H, m), 7.16 (1H, t, J = 2.0Hz), 7.40-7.43 (1H, m), 7.59 (1H, d, J = 7.8Hz), 7.98 (1H, dt, J = 2.0, 7.8Hz), 8.38-8.40 (1H, m), 8.99 (1H, s), 9.13- (1H, m).

 'Melting point: 192-194. C

Example 22

Compound 1 1 8

 3-[5- (3,4-Bisbenzyloxyphenyl) — 1-pyridine-1-2-yl 1 H-pyrazole-3-yl] — N, N-dimethylpenzamide

Compound 1 1 1 0. 6 5 6 g (l. 0 3mmol), P d 2 (dba) 3 0. 0 2 A mixture of 58 g (0.028 ol), POC 130.316 g (2.06 sol) and DMF 1 OmL was stirred at 110 ° C for 24 hours under a stream of argon. After completion of the reaction, water was added to the reaction product, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 1: 3) to give 0.418 g (70.0%) of the title compound as a pale yellow oil.

_{Ή- NMR (CDC1 3) δ:} 3.01 (3Η, brs), 3.13 (3H, brs), 4.99 (2H, s), 5.17 (2 H, s), 6.75 (1H, s), 6.85-6.91 (3H , m), 7.20-7.23 (1H, m), 7.27-7.48 (13 H, m), 7.73 (1H, dt, J = 2.0, 8.3 Hz), 7.95-7.98 (2H, m), 8.38-8.40 ( 1H, m).

Example 23

Compound 123

 {3- [5- (3,4-bisbenzyloxyphenyl) 1-11-pyridine-2-yl-1H-pyrazole-3-yl] -1-phenyl} ― (3-methoxypropyl) One amine

Compound 107 1 1 88.9 mg (2.02 bandol), 3-methoxypropylamine 0.3 1 mL (3.0 bandol), cuprous iodide 43.Omg (0.26 mmol), Ν, Ν '- Jefferies chill Sari sill amide 1 57. 8mg (0. 82mmol), K 3 P0 4 855. 2mg (4. 02 thigh ol), 1, 4 one Jiokisan 5.24 hours stirring the mixture OmL at 90 ° C did. After completion of the reaction, water was added to the reaction product, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 1: 1) to obtain 0.519 g (43.0%) of the title compound as a pale yellow oil.

'H-NMRiCDClg) δ: 1.91 (2Η, quintet, J = 6.4Hz), 3.30 (2H, t, J = 6.4Hz), 3.36 (3H, s), 3.52 (2H, t, J = 6. Etc.) , 4.00 (1H, brs), 4.99 (2H, s), 5.17 (2H, s), 6.59-6.69 (1H, m), 6.70 (1H, s), 6.84-6.90 (3H, m), 7.18-7.24 (3H, m), 7.27-7.38 (Ran, m), 7.43 -7.49 (2H, m), 7.70-7.74 (1H, m), 8.36- 8.38 (1H, m).

 Table 23 shows the pyrazole compounds (I) obtained in Examples 14 to 23.

 Table 23

実施例 24 抗真菌活性

Example 24 Antifungal activity

Determination of antifungal activity

 (1) Measurement of in vitro antifungal activity against Candida albicans and krusei The following operation was performed according to NCCLS protocol M27-A.

 Test compound solution: The test compound was dissolved in dimethyl sulfoxide (DMSO) to make a solution of up to 6.4 mg / mL, and diluted with DMSO to prepare a two-fold dilution series. These solutions were added to the test medium at a rate of 1% (v / v).

 Test medium: 10.44 g of RPMI 1640 was dissolved in 90 OmL of distilled water, and dissolved by adding a MOPS buffer (0.165 M). Next, the pH was adjusted to 7.0 with a 5 mol ZL sodium hydroxide aqueous solution, and distilled water was added to make 100 OmL.

 Inoculum: C. albicans AT CC 90028 and C. krusei ATCC 6258 were cultured on Sabouraud dextrose agar medium at 35 ° C for 24 hours, and then subcultured once more under the same conditions. Five colonies were picked and suspended in 5 mL of sterile physiological saline. After adjusting the permeability of the suspension to McFarland O.5, the suspension was diluted 1000-fold with a test medium to obtain an inoculum.

Antifungal activity measurement: Dispense 100 μL of each concentration dilution of the sample in the test medium into each well of a 96-well round bottom microplate, and add 100 μL of the inoculated bacterial solution described above (final bacterial concentration: 0.5 2.52.5 × 10 ³ cells / mL) at 35 ° C. for 48 hours. After the culture was completed, the absorbance at 60 Onm was measured, and the minimum drug concentration that inhibited the growth of the bacteria by 80% or more compared to the control without drug was defined as MIC (ii g / niL).

 (2) Measurement of in vitro antifungal activity against Aspergillus genus and Trichophyton genus The following operation was performed according to NCCLS protocol M38-P.

 Test compound solution and test medium: In accordance with the above-mentioned method for measuring in vitro antifungal activity against C. albicans and C. krusei.

Inoculated spore fluid: Aspergillus ilavus I FM41 935 and A, fumigatus I FM For 40808, after culturing on a potato dextrose agar medium at 27 ° C for 7 days, spores were suspended in sterile saline containing 0.05% (w / v) Tween 80, and a cell strainer (pore size: 70 m) was used. Passed through. This was prepared using a test medium to a concentration of 6.0 × 10 ⁴ conidia / mL. The medium was supplemented with alamar Blue ™ to a final concentration of 10% (w / v). For Trichophyton mentagrophytes IF40769 and T. rubrum IFO6204, a high salt medium (neopeptone 0.1% (w / v), glucose 0.2% (w / v), magnesium sulfate v), potassium dihydrogen phosphate 0.1% (w / v), agar 2.0% (w / v)) at 27 ° C for 14 days, and then sterilized with 0.05% (w / v) Tween 80 suspended spores in physiological saline to prepare this _P having passed through the cell stra INER 2. with 0 x 10 ⁵ conidia / mL test culture areas to a concentration of.

Antifungal activity measurement: Dispense 100 μL of each concentration dilution of the sample in the test medium into each well of a 96-well round bottom microplate, add 100 L of the inoculated spore solution described above, and use Aspergillus fungus at 35 μl. 48 h (final spore ^{concentration: 3. Ox 10 4 conidia / m} L), Trichophyton Shokumakin at 27 ° C 72 h (final spore ^{concentration: 1. Ox 10 5 conidia / m} L) and cultured. After completion of the culture, the absorbance (ref: 600ηπι) of 57 Onm was measured for Aspergillus spp., And visually determined for Trichophyton spp., The growth of the fungus was suppressed by 50% or more compared to the drug-free control. The minimum drug concentration was MIC (/ ig / mL).

Table 24 shows the results of measurement of the antifungal activity MIC (xg / mL) of the compound of the present invention and the control drug. Table 2 4

表中の記号は以下に示す通りである。

The symbols in the table are as shown below.

 C. alb: Candida albicans ATCC 90028

 C. kru: Candida C. krusei ATCC 6258

 A. f la: Aspergi l lus f lavus IFM 41935

 A. fum: Aspergi l lus fumigatus IFM 40808

 T. men: Trichophyton mentagrophytes IFM 40769

 T. rub: Trichophyton rubrum IFO 6204

 FLCZ: Fluconazole

 As is evident from the table, the compounds of the present invention exhibited excellent antibacterial activity against various deep mycosis and the causative bacteria of superficial mycosis. In particular, aspergillus was confirmed to have significantly better antibacterial activity than the control drug fluconazole.

Claims

 The scope of the claims 1 · The following general formula (I)

(Wherein, R ¹ represents an alkyl group, an alkenyl group, a phenyl group which may have a substituent, a biphenyl group which may have a substituent, or a heteroaromatic group which may have a substituent; ³ represents a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group which may have a substituent, a biphenyl group which may have a substituent or a heteroaromatic group which may have a substituent; R ² is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a cyano group, a CH ₂ OH group or a CH ₂ NR ⁶ R ⁷ group (R ⁶ and R ⁷ shows a) the same or different and each represents a hydrogen atom or a lower alkyl group;. R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, Ashiru group, a lower alkyl group, a cycloalkyl group or Fueniruaru Or showing a group or R ⁴ and R ⁵ are taken Ichi緖may form a lower alkylenedioxy O alkoxy group with two oxygen atoms; X represents a methine group or a nitrogen atom). A pyrazole compound represented by or a salt thereof  2. A medicament comprising the pyrazole compound according to claim 1 or a salt thereof as an active ingredient. 3. An antifungal agent comprising the pyrazole compound according to claim 1 or a salt thereof as an active ingredient. 4. A pharmaceutical composition comprising the pyrazole compound according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier. 5. Use of the pyrazole compound or a salt thereof according to claim 1 for the manufacture of a medicament. 6. Use according to claim 5, wherein the medicament is an antifungal agent.  7. A method for treating a fungal infection, which comprises administering an effective amount of the pyrazole compound or a salt thereof according to claim 1.