JPH0820578A - Antifungal agent and its production - Google Patents

Abstract

PURPOSE:To obtain an antifungal agent, having excellent effects even on patients with weakened immunological functions and high safety and useful for treating dermatomycosis, visceral mycosis, etc. CONSTITUTION:Thus compound of formula I (R<1> and R<2> are each a halogen or H; R<3> is H or a lower alkyl; 5 and m are each O or 1; A is N or CH; W is an aromatic ring or its condensed ring which may have one or more substituent groups or hetero-atoms such as N, S and O; X is a (substituted)alkanediyl, a (substituted)alkenedilyl, etc.; Y is S, >SO, >SO2, etc.; Z is H, halogen, lower alkyl, etc., except when W is thiazole ring; R<3> is methyl and A is H when r and m are each 0] or its acid addition salt, e.g. a compound of formula II. The compound of formula I is obtained by reacting a compound of formula III with a compound of formula TV (Hal is Br or Cl).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an antifungal agent. More specifically, the present invention relates to an antifungal agent effective for treating dermatomycosis, visceral mycosis and the like. More specifically, the present invention relates to a compound containing a nitrogen-containing 5-membered heterocycle or a condensed ring system thereof, which is useful as an antifungal agent, and an acid addition salt thereof. The present invention also relates to a method for producing such a compound and an acid addition salt thereof, and a pharmaceutical composition comprising the compound and a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art In the field of antifungal agents, for example, amphoterin B has been used for the treatment of deep-seated mycoses, but recently, azole synthetic antifungal agents have been developed. I arrived. However, even with these azole-based drugs, the emergence of an even more excellent antifungal agent has been earnestly desired in terms of its effect in patients with weakened immune functions.

As a synthetic antifungal agent of azole type, for example, JP-A-57-70885 discloses a triazole compound. Further, JP-A-60-224689 discloses a (1,2,4-triazol-1-yl) -methyl-carbinol derivative.

[0004]

DISCLOSURE OF THE INVENTION The present invention is intended to provide an antifungal agent having a superior effect and a higher safety than conventional antifungal agents.

[0005]

As a result of earnest research, the inventors of the present invention have found that the formula (I)

[0006]

Embedded image

[Wherein R ¹ and R ² represent the same or different halogen atoms or hydrogen atoms, R ³ represents a hydrogen atom or a lower alkyl group, and r and m may be the same or different. Or 1, A means N or CH, W may have one or more substituents, and 1 is a heteroatom selected from N, S and O.
The above means an aromatic ring or a condensed ring thereof which may have, X may have one or more substituents, and N,
An aromatic ring optionally having one or more heteroatoms selected from S and O, an alkanediyl group optionally having one or more substituents, and optionally one or more substituents. It means an alkenediyl group or an alkynediyl group which may have one or more substituents, and Y represents the formula —S—,>SO,>
_{SO 2,> C = S,} > C = O, -O -,> N-R 6,>
C = N-OR ⁶ or (CH _{2) j} - (wherein the R ⁶ is a hydrogen atom or a lower alkyl group, and j is an integer of 1 to 4) refers to a group represented by, Z Is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group,
Hydroxyl group, thiol group, nitro group, cyano group, lower alkanoyl group, phenyl group optionally having one or more substituents, phenoxy group optionally having one or more substituents,
An imidazolyl group which may have one or more substituents, 1
Triazolyl group optionally having the above substituents, tetrazolyl group optionally having one or more substituents or 1
The above means an amino group which may have a substituent.
However, when r = m = 0, W is a thiazole ring,
Except when R ³ is a methyl group and Z is a hydrogen atom. ]

The present invention has been completed by finding that the compound represented by or an acid addition salt thereof has excellent antifungal properties.

The compounds of this invention can be made by a variety of synthetic routes, some of which are exemplified below.

Route I formula:

[0011]

[Chemical 33]

A compound of formula (A, R ¹ , R ² and R ³ are as defined above) and a formula:

[0013]

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(Wherein Hal is Br or Cl, X,
Y, Z, r and m are as defined above) by reacting with a compound of formula:

[0015]

Embedded image

(In the formula, W is a substituted thiazole group, and A, R ¹ , R ² , R ³ , X, Y, Z and r
And m are as defined above).

Route II formula:

[0018]

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A compound of formula (A, R ¹ and R ² are as defined above) and a formula:

[0020]

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By reacting with a compound of the formula (wherein D is a group consisting of a substituted or unsubstituted nitrogen-containing 5-membered heterocycle or a condensed ring thereof, and Z is H or CH ₃ ). formula:

[0022]

[Chemical 38]

(Wherein W is a substituted or unsubstituted nitrogen-containing 5-membered heterocycle or a condensed ring thereof, and A, R
¹ , R ² , R ³ , X, Y, Z, r and m are as defined above).

Route III formula:

[0025]

[Chemical Formula 39]

A compound of formula (A, R ¹ and R ² are as defined above) and a formula:

[0027]

[Chemical 40]

By reacting with a compound represented by the formula (wherein R ³ , X, Y, Z, r and m are as defined above):

[0029]

Embedded image

Where W is substituted or unsubstituted 5
A heterocyclic ring or a condensed ring thereof, A,
R ¹ , R ² , R ³ , X, Y, Z, r and m are as defined above).

Route IV formula:

[0032]

Embedded image

(Wherein R ¹ , R ² , R ³ , W, X, Y,
Z, r and m are as defined above) with a compound of formula: by reaction with metachloroperbenzoic acid followed by 1,2,4-triazole sodium salt or 1,3-imidazole sodium salt.

[0034]

[Chemical 43]

(Wherein A, R ¹ , R ² , R ³ , W, X,
Y, Z, r and m are as defined above).

As the acid of the acid addition salt of the compound of the present invention,
Conventional inorganic acids such as hydrochloric acid, sulfuric acid and the like as well as organic acids such as acetic acid, citric acid and the like can be used. Preferred acids are hydrochloric acid and acetic acid.

Examples of the solvent that can be used in the present invention include:
Lower alcohols such as methanol, ethanol, propanol, butanol, polyalcohols such as ethylene glycol, acetone, methyl ethyl ketone, diethyl ketone, ketones such as cyclohexanone, diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, 1 , Ethers such as 2-dimethoxyethane, nitriles such as acetonitrile and propionitrile, esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and diethyl phthalate, dichloromethane, chloroform, carbon tetrachloride, 1, Halogenated hydrocarbons such as 2-dichloroethane, trichloroethylene, tetrachloroethylene,
Benzene, toluene, xylene, monochlorobenzene,
Aromatic compounds such as nitrobenzene, indene, pyridine, quinoline, collidine, phenol, hydrocarbons such as pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum benzine, petroleum ether, ethanolamine, diethylamine, triethylamine,
Amine such as pyrrolidine, piperidine, piperazine, morpholine, aniline, dimethylaniline, benzylamine, toluidine, formamide, N-methylpyrrolidone, N, N-dimethylimidazolone, N, N-dimethylacetamide, N, N-dimethylformamide Amides such as, hexamethylphosphoric triamide, phosphoric amides such as hexamethylphosphite triamide, organic acids such as formic acid, acetic acid, difluoroacetic acid, trifluoroacetic acid, chloroacetic acid, sulfoxides such as dimethyl sulfoxide, disulfide One or more mixed solvents such as carbon sulfides such as carbon, water, and other commonly used solvents can be mentioned, and the mixing ratio thereof is not particularly limited.

Regarding the compound according to the present invention or an acid addition salt thereof, the following can be exemplified as pharmaceutically acceptable salts thereof.

That is, examples of the inorganic salt include alkali metal salts such as sodium salt and potassium salt; ammonium salt; tetraethylammonium salt; quaternary ammonium salt such as betaine salt; alkaline earth salts such as calcium salt and magnesium salt. Metal salt; Hydrochloride; Hydrobromide,
Examples thereof include inorganic acid salts such as hydroiodide, sulfate, carbonate, and bicarbonate.

The organic salts include, for example, organic carboxylates such as acetate, maleate, lactate and tartrate; methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, Taurine salt,
Organic sulfonates such as benzene sulfonate and toluene sulfonate, arginine salt, lysine salt, serine salt,
Amino acid salts such as aspartate, glutamate and glycine salts; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine Examples thereof include salts, triethanolamine salts, tris (hydroxymethylamino) methane salts, amine salts such as phenethylbenzylamine salts, and the like.

EXAMPLES Next, the present invention will be described more specifically with reference to production examples, examples and experimental examples. However, the present invention is not limited to these production examples and experimental examples.

Production Example 1 Production of Raw Material 1 (2S, 3R) -3- (2,4-difluorophenyl) -3
-Hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl) butyronitrile

Structural formula

[Chemical 44]

Optically active (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4
-Triazol-1-yl) methyloxirane 5 g (2
To a solution prepared by dissolving 0.0 mmol) in 40 ml of toluene was added 80 ml of diethyl aluminum cyanide (1.0 M toluene solution) under a nitrogen atmosphere, and the mixture was heated at 50 ° C. for 12 hours. Water (10 ml) and 1N-HCl (120 ml) were sequentially added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. After filtering through a Florisil pad, the mixture was extracted with ethyl acetate, and the organic layer was washed 4 times with a liquid mixture of water and saturated saline at a ratio of 1: 1 and finally with saturated saline. After evaporating the solvent under reduced pressure, the residue was washed with diisopropyl ether to give an optically active (2S, 3R) -3-
(2,4-difluorophenyl) -3-hydroxy-2-
Obtained 3.15 g of methyl-4- (1H-1,2,4-triazol-1-yl) butyronitrile (56.6%). The physical properties of this product are shown below.

Mp: 181-282 ° C. NMR: δ solvent (CDCl ₃ ) 1.17 (3H, d, J = 7.2Hz) 3.29 (1H, q, J = 7.2Hz) 4.82 (1H, d, J =
14.0Hz) 4.97 (1H, d, J = 14.0Hz) 5.44 (1H, d, J = 0.8Hz) 6.74-6.82 (2
H, m) 7.39-7.46 (1H, m) 7.83 (1H, s) 7.84 (1H, s) MS: MH ⁺ = 279

Production Example 2 Production of Raw Material 1 by Alternative Method Ytterbium Chloride Hexahydrate 388 mg (1 mmol)
Was left under reduced pressure at 120 ° C. for 6 hours. It was suspended in 10 ml of tetrahydrofuran under a nitrogen atmosphere and cooled to -78 ° C. 1.9 ml of n-butyllithium (1.63M hexane solution) was added dropwise thereto, and the mixture was stirred at room temperature for 5 minutes, and then-
Cooled to 78 ° C. 0.8 ml of trimethylsilyl cyanide was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 10 minutes, then at room temperature for 5 minutes, and cooled to -78 ° C. Optically active (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazole-1
A solution of 128 mg (0.5 mmol) of -yl) methyloxirane dissolved in 1 ml of tetrahydrofuran was added dropwise, and the temperature was naturally raised to room temperature. Add saturated ammonium chloride solution,
It was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. After evaporating the solvent under reduced pressure, the residue was recrystallized from diethyl ether to give an optically active (2S, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4-.
81 mg of (1H-1,2,4-triazol-1-yl) butyronitrile were obtained (58.2%).

Production Example 3 Production of Raw Material 2 2- (2,4-difluorophenyl) -3-thioamide-
1- (1H-1,2,4-triazol-1-yl) -2-
Butanol production

Structural formula

Embedded image

Raw material 3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4- (1H-1,2,4-triazole-1) of the raw material 1 obtained in Production Example 1 or 2 - yl) H ₂ O 14m in butyronitrile (14 g)
l, O, O-diethyl dithiophosphate (73 ml) was added and
Heated to reflux for 0 minutes. Bring the reaction mixture to room temperature and add H ₂ O.
The mixture was extracted with AcOEt, the AcOEt layer was washed with H ₂ O and saturated aqueous NaCl solution, dried over MgSO ₄ , and the solvent was evaporated. The resulting residue was purified by silica gel chromatography Hula fee _{(SiO 2 300g CH 2 Cl 2} , then 1% MeOH in CH ₂ Cl ₂ solution and then 2% MeOH in CH ₂ Cl ₂ solution and then in CH ₂ Cl ₂ 3% MeOH solution) After purification with CH ₂ Cl ₂ -IP
Recrystallization from E gave the desired product (8.1 g). In addition, the optically active substance of the raw material 1 is used instead of the racemic body of the raw material 1,
Similarly, the optically active raw material 2 can be obtained.

The physical properties of this product are shown below.

Mp: 164-167 ° C. NMR: δ solvent (CDCl ₃ ) 1.11 (3H, d, J = 7.1Hz) 3.69-3.72 (1H, m) 4.55 (1H, d, J = 14.
3Hz) 5.08 (1H, d, J = 14.3Hz) 6.71-6.80 (2H, m) 7.42-7.48 (1H,
m) 7.80 (1H, brs) 7.94 (1H, s) 8.41 (1H, brs) MS: MH ⁺ = 313

Production Example 4 Production of Raw Material 3 Production of 2-bromo-4'-cyanoacetophenone

Structural formula

Embedded image

4'-Cyanoacetophenone (10 g) was added to C
It was dissolved in 100 ml of HCl ₃ and 1 ml of 48% HBr was added. A solution of Br ₂ (3.7 ml) in CHCl ₃ (10 ml) was added dropwise thereto at room temperature. After stirring at room temperature for 2 hours, H ₂ O saturated NaHCO ₃ aqueous solution was added to the reaction solution for neutralization. Wash the CHCl ₃ layer with H ₂ O saturated NaCl,
After drying MgSO _4, CHCl ₃ was distilled off. AcOET-
Recrystallization from nHex gave the desired product (3.49 g).
The physical properties of this product are shown below.

Mp: 82-84 ° C. NMR: δ solvent (CDCl ₃ ) 4.44 (2H, s) 7.81-7.84 (2H, m) 8.09 (1H, d, J = 8Hz) 8.23 (1
(H, d, J = 8Hz)

Production Example 5 Production of Raw Material 4 Production of 2-Ethyl-6-chlorobenzothiazole

Structural formula

[Chemical 47]

2-Amino-5-chlorothiophenol (2.618 g) was dissolved in N-methylpyrrolidone (6 ml) and propionyl chloride (1.57 ml) was added to give 130.
Heat at 1.5 ° C. for 1.5 hours. Ethyl acetate and aqueous sodium hydrogen carbonate were added to the reaction mixture to separate it, and the organic layer was washed with water, dried and concentrated. The residue was purified with a silica gel column (hexane: ethyl acetate = 2)
0: 1) to give 2-ethyl-6-chlorobenzothiazole (2.3 g). The physical properties of this product are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.47 (3H, t, J = 7.4Hz) 3.14 (2H, q, J = 7.4Hz) 7.40 (1H, dd, J
= 2.0Hz, 8.8Hz) 7.81 (1H, d, J = 2.0Hz) 7.86 (1H, d, J = 8.8Hz)

Production Example 6 2-Ethyl-6- (1,2,3-triazol-2-yl)
Benzothiazole production

Structural formula

Embedded image

1H-1,2,3 triazole (10.0 g) was dissolved in dimethylformamide (280 ml) and 60% mineral oil dispersed sodium hydride (5.79 g) was added portionwise over 10 minutes. Then 4-fluoronitrobenzene (18.6 g) in dimethylformamide (40 ml)
Was added dropwise at room temperature, and the mixture was heated with stirring at 50 ° C. for 9 hours. The reaction mixture was poured into 400 ml of saturated ammonium chloride aqueous solution and 200 ml of water was added. This is ethyl acetate (400 ml
The mixture was extracted with x1, 200 ml x 2), the ethyl acetate layer was washed with water, then with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column (hexane-ethyl acetate = 2: 1 → 1: 1) to give 4- (1,2,3-triazol-2-yl) -nitrobenzene (11.5 g). was gotten.

4- (1,2,3-triazol-2-yl)
-Nitrobenzene (5.75 g) was dissolved in 300 ml of ethanol, 10% palladium-carbon (0.58 g) and hydrazine hydrate (15.0 g) were added, and the mixture was heated under reflux for 5 hours.
The reaction mixture was cooled at room temperature and filtered through Celite. The filtrate was once concentrated under reduced pressure, 500 ml of water was added, and ethyl acetate (2
It was extracted with 00 ml, 100 ml × 2). Wash the organic layer with water,
After washing with saturated saline and drying over anhydrous magnesium sulfate,
Concentration under reduced pressure gave 4- (1,2,3-triazol-2-yl) -aniline (5.0 g). This product was used in the next reaction without purification.

4- (1,2,3-triazol-1-yl) -aniline (5.0 g) obtained in the previous reaction was dissolved in 55 ml of acetic acid and ammonium thiocyanate (6.0 g) was added.
The mixture was stirred under ice cooling. A solution of bromine (1.62 ml) in 20 ml of acetic acid was added dropwise thereto over 30 minutes. Then, it heated up to room temperature and stirred at room temperature for 4 hours.

The reaction mixture was ice-cooled and concentrated aqueous ammonia was added dropwise to adjust the pH to 6. The resulting precipitate was collected by filtration, washed with water, then with cold ethanol, and dried under reduced pressure to give 2-amino-6- (1,2,3-triazol-2-yl) benzothiazole (5.6 g). was gotten.

2-Amino-6- (1,2,3-triazol-2-yl) benzothiazole (2.8 g) was dissolved in N, N-dimethylformamide (60 ml) and isoamyl nitrite (8.66 ml) was added. ) Was added and the mixture was heated with stirring at 65 ° C. for 20 minutes. The reaction mixture was poured into 100 ml of water and extracted with ethyl acetate (100 ml × 3). The organic layer was washed with water, then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (dichloromethane) to give 6- (1,2,3-triazol-2-yl) benzothiazole (1.1 g).

6- (1,2,3-triazol-2-yl)
Benzothiazole (1.1 g) was suspended in ethanol (90 ml), hydrazine and 12 ml of monohydrate were added, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, 20 ml of water was added, and the pH was adjusted to about 7 with acetic acid. Extracted 3 times with ethyl acetate, washed the organic layer with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-amino-5- (1,2,3-triazol-2-yl). -Thiophenol (2.3 g) was obtained. This product was used in the next reaction without purification.

2-Amino-5- (1,2,3-triazol-2-yl) -thiophenol (2.3 g) was dissolved in N-methylpyrrolidone (8 ml) and propionyl chloride (0.472 ml) was added. In addition, the mixture was heated and stirred at 70 ° C. for 5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified with a silica gel column (hexane-ethyl acetate 4: 1 → 1: 1) to give the desired product 2-ethyl-6- (1,2,3-triazole). -2
-Yl) benzothiazole (940 mg) was obtained. The physical properties of this product are shown below.

State: Solid NMR: δ Solvent (DMSO-d ₆ ) 1.49 (3H, t, J = 7.7Hz) 3.17 (2H, q, J = 7.7Hz) 7.83 (2H, s)
8.03 (1H, d, J = 8.80Hz) 8.20 (1H, dd, J = 8.8,3.2Hz) 8.55 (1H, d, J = 8.8Hz)

Example 1 Structural formula

[Chemical 49]

Preparation of the compound of

2- (2,4-difluorophenyl) -3-thioamido-1- (1H-1,2,4-triazol-1-yl)
2-Butanol (raw material 2) (156 mg), EtOH (2 ml)
The solution was dissolved in, and 2-bromo-4'-cyanoacetophenone (raw material 3) (224 mg) was added, and the mixture was heated under reflux for 1 hour. The reaction solution was neutralized with Sat.NaHCO ₃ aqueous solution and extracted with AcOEt, H ₂ O. saturated Na.
After washing with an aqueous Cl solution and drying with MgSO _4, AcOEt was distilled off. The residue was chromatographed on silica gel (SiO ₂ 20 g, CH ₂ Cl ₂ ,
It was then purified with 1% MeOH solution in CH ₂ Cl ₂ ) and crystallized with IPE to give the desired product (109 mg). The physical properties of this compound are shown below.

Mp: 196-197 ° C. NMR: δ solvent (CDCl ₃ ) 1.23 (3H, d, J = 8.0Hz) 4.09 (1H, q, J = 8.0Hz) 4.26 (1H, d, J =
14.3Hz) 4.92 (1H, d, J = 14.3Hz) 5.74 (1H, s) 6.78-6.85 (2H, m) 7.4
8-7.54 (1H, m) 7.64 (1H, s) 7.69 (1H, s) 7.75 (1H, d, J = 8.1Hz) 7.85 (1H,
s) 8.03 (1H, d, J = 8.1Hz) MS: MH ⁺ = 438

Example 2 Structural formula

[0075]

Embedded image

Production of a compound represented by:

By a procedure similar to that described in Example 1, but using 2-bromo-4'-methylthioacetophenone in place of 2-bromo-4'-cyanoacetophenone, the desired product was obtained. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.23 (3H, d, J = 7.2Hz) 2.54 (3H, s) 4.05 (1H, q, J = 7.2Hz)
4.28 (1H, d, J = 14.4Hz) 4.88 (1H, d, J = 14.4Hz) 6.13 (1H, s) 6.75-6.85 (2H, m) 7.3
3 (2H, br-d, J = 8.4Hz) 7.42 (1H, s) 7.46-7.54 (1H, m) 7.66 (1H, s) 7.82 (2H, br-
d, J = 8.4Hz) 7.92 (1H, s) MS: MH ⁺ = 459

Example 3 Structural formula

[0080]

[Chemical 51]

Production of a compound represented by:

By a procedure similar to that described in Example 1, but using 2-bromo-2 ', 4'-difluoroacetophenone in place of 2-bromo-4'-cyanoacetophenone, the desired product was obtained. It was The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.23 (3H, d, J = 7.1Hz) 4.07 (1H, q, J = 7.1Hz) 4.26 (1H, d, J =
14.4Hz) 4.89 (1H, d, J = 14.4Hz) 5.93 (1H, s) 6.77-6.83 (2H, m) 6.9
2-6.98 (1H, m) 7.00-7.05 (1H, m) 7.47-7.54 (1H, m) 7.67 (1H, s) 7.68 (1
H, s) 7.88 (1H, s) 8.13-8.19 (1H, m) MS: MH ⁺ = 449

Example 4 Structural formula

[0085]

Embedded image

Production of a compound represented by:

By a procedure similar to that described in Example 1, but using 2-bromo-4'-methylacetophenone in place of 2-bromo-4'-cyanoacetophenone, the desired product was obtained. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.23 (3H, d, J = 7.1Hz) 2.41 (3H, s) 4.04 (1H, d, J = 7.1Hz)
4.28 (1H, d, J = 14.3Hz) 4.88 (1H, d, J = 14.3Hz) 6.24 (1H, s) 6.76-6.84 (1H, s) 7.2
7 (2H, d, J = 8.3Hz) 7.40 (1H, s) 7.47-7.53 (1H, m) 7.65 (1H, s) 7.80 (2H, d, J =
8.3Hz) 7.94 (1H, s) MS: MH ⁺ = 427

Example 5 Structural formula

[0090]

Embedded image

Preparation of compounds represented by:

By a procedure similar to that described in Example 1, but using 2-bromo-4'-methoxyacetophenone in place of 2-bromo-4'-cyanoacetophenone, the desired product was obtained. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.23 (3H, d, J = 7.1Hz) 3.88 (3H, s) 4.04 (1H, q, J = 7.1Hz)
4.28 (1H, d, J = 14.3Hz) 4.87 (1H, d, J = 14.3Hz) 6.24 (1H, s) 6.76-6.84 (2H, m) 7.0
0 (2H, d, J = 8.2Hz) 7.32 (1H, s) 7.47-7.53 (1H, m) 7.65 (1H, s) 7.84 (2H, d, J =
8.2Hz) 7.94 (1H, s) MS: MH ⁺ = 443

Example 6 Structural formula

[0095]

[Chemical 54] A compound represented by:

By a procedure similar to that described in Example 1, but using 2-bromo-4'-nitroacetophenone in place of 2-bromo-4'-cyanoacetophenone, the desired product was obtained. The physical properties of this compound are shown below.

Mp: 180-182 ° C. NMR: δ solvent (CDCl ₃ ) 1.25 (3H, d, J = 7.1Hz) 4.11 (1H, d, J = 7.1Hz) 4.27 (1H, d, J =
14.2Hz) 4.94 (1H, d, J = 14.2Hz) 5.70 (1H, s) 6.79-6.85 (2H, m) 7.4
3-7.55 (1H, m) 7.70 (1H, s) 7.71 (1H, s) 7.85 (1H, s) 8.08 (2H, d, J = 9.0H
z) 8.32 (2H, d, J = 9.0Hz) MS: MH ⁺ = 458

Example 7 Structural formula

[0099]

[Chemical 55]

Production of compound represented by:

60% sodium hydride (1.570 g) and DMF (30 ml)
5 g of 4-fluorothiophenol in the solution suspended in
Was added and the mixture was stirred at room temperature for 5 minutes. Thereto was added 4'-fluoroacetophenone (4.9 g), and the mixture was stirred at 80 ° C for 3.5 hr. Water was added and the mixture was extracted with ethyl acetate, washed with water and then with saturated saline, and the solvent was evaporated under reduced pressure to give 4-
Fluoro-4'-acetylphenyl sulfide 10.008 g
I got

From this, the structural formula was obtained by the same procedure as described in Production Example 4.

[0103]

[Chemical 56]

An intermediate compound represented by the following formula was prepared and was used in place of 2-bromo-4'-cyanoacetophenone to obtain the desired product by a procedure similar to that described in Example 1. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.22 (3H, d, J = 7.0Hz) 4.05 (1H, q, J = 7.0Hz) 4.26 (1H, d, J =
14.6Hz) 4.88 (1H, d, J = 14.6Hz) 6.04 (1H, s) 6.76-6.85 (2H, m) 7.07 (2H, br-dd, J = 8.4,8.4Hz) 7.32 (2H, br-d , J = 8.4Hz)
7.44 (1H, br-s) 7.44 (2H, br-dd, J = 8.4,8.4Hz) 7.45-7.54 (1H, m) 7.66 (1
H, s) 7.82 (2H, br-d, J = 8.4Hz) 7.89 (1H, s) MS: MH ⁺ = 539

Example 8 Structural formula

[0108]

[Chemical 57]

Production of a compound represented by:

400 mg of the compound of Example 1 was dissolved in 4 ml of N-methylpyrrolidone, NaN ₃ 123 mg, Et ₃ N.HCl 260 mg
, And heat the oil bath at an external temperature of 100 ° C for 6.5 hours and then add NaN ₃ 3
1 mg and Et ₃ N.HCL 65 mg were added and reacted at 90 ° C for 20 hours.
CH ₂ Cl ₂ was added to the reaction solution, the salt was filtered off, and the reaction solution was evaporated. When EtOH, acetone, H ₂ O and 1N HCl were added to the residue and left to stand, a solid was precipitated. The target product is 390m when filtered.
g obtained. The physical properties of this compound are shown below.

Mp: 166-169 ° C. NMR: δ solvent (DMSO-d ⁶ ) 1.14 (3H, d, J = 7.3Hz) 4.11 (1H, q, J = 7.3Hz) 4.37 (1H, d, J =
14.6Hz) 4.87 (1H, d, J = 14.6Hz) 6.08 (1H, s) 6.91-6.96 (1H, m) 7.1
8-7.25 (1H, m) 7.27-7.34 (1H, m) 7.62 (1H, s) 8.11 (2H, d, J = 8.5Hz) 8.20
(2H, d, J = 8.5Hz) 8.22 (1H, s) 8.29 (1H, s) MS: MH ⁺ = 481

Example 9 Structural formula

[0113]

Embedded image

Production of a compound represented by:

800 mg of the compound of Example 1 are suspended in H ₂ O (4 ml) and of the formula:

[0116]

Embedded image

2.6 ml (16.479 mmol) of the compound represented by the above was added and the mixture was heated under reflux for 30 minutes. H ₂ O was added to the reaction solution, and AcOEt was extracted, washed with H ₂ O.saturated NaCl and dried over MgSO ₄ , and then AcOEt was distilled off. The obtained residue was dissolved in 10 ml of acetone without purification and CH
0.45 ml of ₃ I was added, and the mixture was stirred at 40 ° C for 40 minutes. In the reaction solution
H ₂ O was added and AcOEt was extracted H ₂ O. Saturated NaCl washes were dried over MgSO ₄ , and then
AcOEt was distilled off. The resulting residue was not purified and EtOH 10 ml
220 mg of NH ₂ NHCHO, 0.26 ml of Et ₃ N and 1 drop of H ₂ SO ₄ were added, and the mixture was heated under reflux for 1 hour. H ₂ O was added to the reaction solution, and Ac
OEt extraction H ₂ O. Saturated NaCl washes were dried over MgSO _{4, and} AcOEt was distilled off. The obtained residue is subjected to column chromatography (SiO ₂ 5
0 g, CH ₂ Cl ₂ , then 1% MeOH solution in CH ₂ Cl ₂ , then CH ₂ C
(2% MeOH solution in l ₂ ) to give 369 mg of the desired product. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.24 (3H, d, J = 7.1Hz) 4.08 (1H, q, J = 7.1Hz) 4.34 (1H, d, J =
14.4Hz) 4.91 (1H, d, J = 14.4Hz) 6.15 (1H, s) 6.79-6.85 (1H, s) 7.5
2-7.56 (2H, m) 7.69 (1H, s) 7.97-7.99 (3H, m) 8.14 (2H, d, J = 8.2Hz) 8.25
(1H, s) MS: MH ⁺ = 480

Example 10 Structural formula

[0120]

Embedded image

Preparation of a compound of formula:

250 mg of the compound of Example 8 was dissolved in 3 ml of DMF, 174 mg of CsCO ₃ was added, and the mixture was heated at an outer temperature of an oil bath of 60 ° C. for 30 minutes to CH 2.
₃ I 0.05 ml was added, and the mixture was stirred at room temperature for 30 minutes. H ₂ O in the reaction solution
Was added and extracted with AcOEt and washed with saturated aqueous NaCl solution, MgSO 4.
₄ After drying, AcOEt was distilled off. The residue obtained was subjected to column chromatography (30 g SiO ₂ , CH ₂ Cl ₂ , then 1 in CH ₂ Cl _2).
% MeOH solution, then 2% MeOH in CH ₂ Cl ₂ ) to give 125 mg of desired product. The physical properties of this compound are shown below.

Mp: 191-193 ° C. NMR: δ solvent (CDCl ₃ ) 1.25 (3H, d, J = 7.0Hz) 4.09 (1H, q, J = 7.0Hz) 4.29 (1H, d, J =
14Hz) 4.33 (3H, s) 4.92 (1H, d, J = 14Hz) 6.01 (1H, s) 6.77-6.85 (2H, m) 7.49-
7.55 (1H, m) 7.58 (1H, s) 7.67 (1H, s) 7.91 (1H, s) 8.04 (2H, d, J = 8.2Hz) 8.24 (2H, d,
J = 8.2Hz) MS: MH ⁺ = 495

Example 11 Structural formula

[0125]

[Chemical formula 61]

Production of a compound represented by:

200 mg of the compound of Example 9 was dissolved in 5 ml of acetone, 60.6 mg of K ₂ CO ₃ 0.03 ml of CH ₃ I was added, and the mixture was stirred at room temperature for 19 hours. H ₂ O was added to the reaction mixture and extracted with AcOEt to saturate H ₂ O.
After washing with NaCl and drying with MgSO _4, AcOEt was distilled off. The obtained residue was purified by column chromatography _{(SiO 2 40g, CH 2 Cl} 2, then in CH ₂ Cl ₂ 0.5% MeOH solution, then 1% MeOH in CH ₂ Cl ₂
The solution was purified to obtain 142 mg of the desired product. The physical properties of this product are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.13 (1H, d, J = 6.0Hz) 1.25 (2H, d, J = 7.1Hz) 4.01-4.13 (4
H, m) 4.27 (2 / 3H, d, J = 14Hz) 4.29 (1 / 3H, d, J = 14Hz) 4.91 (1H, d,
J = 14Hz) 5.45 (1 / 3H, s) 6.08 (2 / 3H, s) 6.70-6.84 (2H, m) 7.50-7.55 (2H, m) 7.67-
7.68 (4 / 3H, m) 7.79-7.81 (2 / 3H, m)) 7.93 (1H, s) 7.96 (1H, s) 7.98 (1H,
s) 8.10 (1H, s) 8.19 (2H, d, H = 8.4Hz)

Example 12 Structural formula

[0130]

Embedded image

Production of the derivative represented by:

138 mg of the compound of Example 2 was mixed with chloroform 3
215 mg of metachloroperbenzoic acid was added to the solution dissolved in ml, and the mixture was stirred at room temperature. After disappearance of the raw materials, water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with 50% saturated aqueous sodium hydrogen carbonate solution, water, and saturated saline. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from dichloromethane-diisopropyl ether to obtain 98.5 mg of the desired product. The physical properties of this product are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.24 (3H, d, J = 7.2Hz) 3.09 (3H, s) 4.09 (1H, q, J = 7.2Hz)
4.27 (1H, d, J = 14.4Hz) 4.91 (1H, d, J = 14.4Hz) 5.78 (1H, s) 6.78-6.85 (2H, m) 7.4
7-7.55 (1H, m) 7.67 (1H, s) 7.69 (1H, s) 7.87 (1H, s) 8.02 (2H, br-d, J = 8.
4Hz) 8.10 (2H, br-d, J = 8.4Hz) MS: MH ⁺ = 491

Example 13 Structural formula

[0135]

[Chemical formula 63]

Preparation of derivatives of.

The target product was prepared from the compound of Example 7 by the same procedure as in Example 12. The physical properties of this product are shown below.

Mp: Solid NMR: δ Solvent (CDCl ₃ ) 1.22 (3H, d, J = 7.2Hz) 4.07 (1H, q, J = 7.2Hz) 4.23 (1H, d, J =
14.4Hz) 4.90 (1H, d, J = 14.4Hz) 5.73 (1H, s) 6.77-6.84 (2H, m) 7.20 (2H, br-dd, J = 8.4,8.4Hz) 7.46-7.53 (1H, m ) 7.63 (1
H, s) 7.68 (1H, s) 7.83 (1H, s) 7.97-8.07 (6H, m) MS: MH ⁺ = 571

Example 14 Structural formula

[0140]

[Chemical 64]

[0141]

Embedded image

And

[0143]

[Chemical formula 66]

Production of each derivative represented by:

By the same procedure as in Example 1, except that the 4-cyano-phenyl moiety in the starting material 3 was replaced with each pyridyl group having a different bonding position, each compound I, II and III of this example was obtained. The physical properties of these compounds are shown below.

(I) mp: 149-151 ° C. NMR: δ solvent (DMSO-d ⁶ ) 1.13 (3H, d, J = 7.1Hz) 4.07 (1H, q, J = 7.1Hz) 4.36 (1H, d, J =
14.3Hz) 4.86 (1H, d, J = 14.3Hz) 6.07 (1H, s) 6.91-6.96 (1H, m) 7.1
8-7.24 (1H, m) 7.27-7.36 (2H, m) 7.61 (1H, s) 7.88 (1H, t, J = 8Hz) 8.11 (1
H, d, J = 8Hz) 8.22 (1H, s) 8.28 (1H, s) 8.60-8.62 (1H, m) MS: MH ⁺ = 414

(II) mp: 148-149 ° C NMR: δ solvent (CDCl ₃ ) 1.24 (3H, d, J = 7.1Hz) 4.09 (1H, q, J = 7.1Hz) 4.27 (1H, d, J =
14.3Hz) 4.92 (1H, d, J = 14.3Hz) 5.84 (1H, brs) 6.77-6.85 (2H, m) 7.40 (1H, ddd, J = 7.8,4.9,0.92Hz) 7.48-7.56 (1H, m ) 7.58
(1H, s) 7.68 (1H, s) 7.88 (1H, s) 8.21 (1H, ddd, J = 7.8,2.2,1.6Hz) 8.61 (1H, dd, J = 4.8,1.6Hz) 9.15 (1H, dd , J = 2.2,0.92Hz) MS: MH ⁺ = 414

(III) State: Solid NMR: δ Solvent (CDCl ₃ ) 1.24 (3H × 4/5, d, J = 7.1Hz) 1.68 (3H × 1/5, d, J = 6.2Hz) 4.08-4.15 (1H, m) 4.25 (4 / 5H, q, J = 14.5Hz) 4.73 (1 / 5H, d,
J = 13.9Hz) 4.92 (1 / 5H, d, J = 13.9Hz) 4.95 (4 / 5H, d, J = 14.5Hz) 5.77 (4 /
5H, brs) 5.88 (1 / 5H, brs) 6.49-6.55 (1 / 5H, m) 6.66-6.72 (1 / 5H, m) 6.76-6.85 (1H, m) 7.07-7.14 (4 / 5H, m) 7.26 (1 / 5H, s) 7.44 (1 / 5H, s) 7.47-7.55 (4 / 5H, m) 7.61-7.64 (1 / 5H, m) 7.69 (4 / 5H, s) 7.73 (4 / 5H, s) 7.78-7.81 (4 / 5H, m) 7.87 (4
/ 5H, s) 8.03 (1 / 5H, s) 8.64-8.66 (4 / 5H, m) 8.69-8.72 (1 / 5H, m) MS: MH ⁺ = 414

Example 15 Structural formula

[0150]

Embedded image

Production of a compound represented by:

700 mg of the compound (I) of Example 14 was added to AcOEt 7
ml and THF (5 ml), mCPBA (500 mg) was added and the mixture was stirred at room temperature for 1 hr, and mCPBA (227 mg, 0.882 mmol) was further added and the mixture was stirred for 1 hr. Aqueous sodium sulfite solution was added to the reaction solution, stirred for 5 minutes, and extracted with AcOEt.
The aqueous solution of NaHCO ₃ was washed with an aqueous solution of H ₂ O.NaCl, dried over MgSO ₄ , and the solvent was distilled off. The residue was crystallized from CH ₂ Cl ₂ -IPE and N-
510 mg of oxide intermediate was obtained. 5 ml of this CH ₂ Cl ₂
Dissolve in and add 0.49 ml of TMS-CN at room temperature, and after 5 minutes, Me ₂ NCOCl
0.34 ml was added and the mixture was heated under reflux for 1.5 hours. Furthermore TMS-CN 0.2
5 ml and Me ₂ NCOCl 0.17 ml were added and the mixture was heated under reflux for 2.5 hours. Aqueous NaHCO ₃ solution was added to the reaction solution, extracted with AcOEt, washed with an aqueous solution of saturated H ₂ O.NaCl, dried over MgSO _{4, and the} solvent was distilled off. The residue obtained is chromatographed on silica (SiO ₂ 40 g, CH _2
2 Cl _2, then 1% MeOH in CH ₂ Cl ₂ solution and then in CH ₂ Cl ₂ 2
% MeOH solution) to obtain 198 mg of the desired product. The physical properties of this compound are shown below.

Mp: 197-200 ° C. NMR: δ Solvent (DMSO-d ⁶ ) 1.14 (3H, d, J = 7.0Hz) 4.07-4.11 (1H, m) 4.47 (1H, q, J = 14.
3Hz) 4.84 (1H, d, J = 14.3Hz) 6.10 (1H, s) 6.91-6.96 (1H, m) 7.18-7.22 (1H, m) 7.23-7.33 (1H, m) 7.61 (1H, s) 7.98 (1
H, d, J = 7.7Hz) 8.14 (1H, t, J = 7.7Hz) 8.21 (1H, s) 8.40 (1H, d, J = 7.7Hz)
8.44 (1H, s) MS: MH ⁺ = 439

Example 16 Structural formula

[0155]

[Chemical 68]

Compound (I) represented by

[0157]

[Chemical 69]

Production of compound (II) represented by:

2- (2,4-Difluorophenyl) -3-thioamido-1- (1H-1,2,4-triazol-1-yl)
1.6 g of butan-2-ol was dissolved in 16 ml of EtOH, 0.71 ml of ethyl bromopyruvate was added, and the mixture was heated under reflux for 5 hours. The reaction solution was returned to room temperature, neutralized with saturated NaHCO ₃ , extracted with AcOEt, H ₂
After washing with O. saturated NaCl and drying with MgSO _{4, the} solvent was distilled off. The residue was purified by column chromatography _{(SiO 2 150g, CH 2 Cl} 2, then 1% MeOH in CH ₂ Cl ₂ solution and then 2% MeOH in CH ₂ Cl ₂ solution) to give 2- (2,4-difluorophenyl) -3
-(4-Ethoxycarbonylthiazol-2-yl)-
1- (1H-1,2,4-triazol-1-yl) butane-2
-435 mg of all was obtained. 1.9 g of this is 20 ml of THF
The solution was dissolved in and the 5.1 ml of 1M DIBAL toluene solution was slowly added at -78 ° C. 40 minutes later 1M DIBAL toluene solution 2.3
ml was added at the same temperature. After 1 hour, the reaction was cooled to -78 ° C with NH ₄ Cl.
After adding an aqueous solution and returning to room temperature, adding H ₂ O and extracting with AcOEt, H ₂ O
After washing with water and drying over MgSO ₄ , the solvent was distilled off to give 2- (2,4-difluorophenyl) -3- (4-formylthiazole-
9-89 mg of 2-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol was obtained as a crude product.

60% NaH (109 mg) was added to 5 ml of THF under ice cooling, and a solution of (Et ₂ O) ₂ P (= O) CH ₂ CN (0.44 ml) dissolved in 5 ml of THF was added dropwise. After stirring for 1 hour, 989 mg of the above product was added to THF.
A solution dissolved in 10 ml was added slowly. After stirring at room temperature for 30 minutes, H ₂ O was added to the reaction solution, and AcOEt was extracted, washed with H ₂ O.saturated NaCl, dried over MgSO _{4, and} then AcOEt was distilled off. The obtained residue was purified by silica gel chromatography (SiO ₂ 60g, CHCl _3, then 1% MeOH solution CHCl _3, then in CHCl ₃ 2% MeOH solution) Compound I as the first eluate to furnish obtained 115 mg, the 220 mg of geometric isomer compound II was obtained as 2 eluates. The physical properties of these compounds are shown below.

I state: solid mp: 175-177 ° C. NMR: δ solvent (CDCl ₃ ) 1.19 (3H, d, J = 7.1Hz) 4.02 (1H, q, J = 7.1Hz) 4.16 (1H, d, J =
14.3Hz) 4.91 (1H, d, J = 14.3Hz) 5.47 (1H, s) 6.33 (1H, d, J = 16.0Hz)
6.77-6.84 (2H, m) 7.33 (1H, d, J = 16.0Hz) 7.46 (1H, s) 7.47-7.51 (1H, m) 7.7
2 (1H, s) 7.82 (1H, s) MS: MH ⁺ = 388

II state: solid NMR: δ solvent (CDCl ₃ ) 1.20 (3H, d, J = 7.0Hz) 4.05 (1H, q, J = 7.0Hz) 4.45 (1H, d, J =
14.0Hz) 4.89 (1H, d, J = 14.0Hz) 5.56 (1H, d, J = 11.9Hz) 5.78 (1H, s)
6.75-6.82 (2H, m) 7.17 (1H, d, J = 11.9Hz) 7.50-7.59 (1H, m) 7.60 (1H, s) 7.7
5 (1H, s) 8.10 (1H, s) MS: MH ⁺ = 388

Example 17 Structural formula

[0164]

Embedded image

Production of a compound represented by:

According to the procedure of Example 1, except that 2- (2,4-
Difluorophenyl) -3-thioamido-1- (1H-1,
2- (2,4-difluorophenyl) -3-thioamido-1- (1H-1,2,4-triazo-1-yl) instead of 2,4-triazol-1-yl) butan-2-ol Propane-2
-Ool was used to obtain the desired product. The physical properties of this compound are shown below.

Mp: 148-149 ° C. NMR: δ solvent (CDCl ₃ ) 3.38 (1H, d, J = 15.2Hz) 3.87 (1H, d, J = 15.2Hz) 4.65 (1H, d,
J = 14.0Hz) 4.71 (1H, d, J = 14.0Hz) 5.97 (1H, s) 6.70-6.76 (1H, m) 6.7
7-6.83 (1H, m) 7.42 (1H, s) 7.47-7.41 (1H, m) 7.69-7.72 (2H, m) 7.86 (1
H, s) 7.86-7.90 (2H, m) 8.18 (1H, s) MS: MH ⁺ = 424

Example 18 Structural formula

[0169]

Embedded image

Production of a compound represented by: The procedure of Example 17 was followed, but using 2-bromo-4'-fluoroacetophenone instead of 2-bromo-4'-cyanoacetophenone to give the desired compound. The physical properties of this product are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 3.34 (1H, d, J = 15.4Hz) 3.84 (1H, d, J = 15.4Hz) 4.62 (1H, d,
J = 14.0Hz) 4.71 (1H, d, J = 14.0Hz) 6.25 (1H, s) 6.82-6.69 (2H, m) 7.1
3-7.08 (2H, m) 7.17 (1H, s) 7.47-7.40 (1H, m) 7.76-7.72 (2H, m) 7.85 (1
H, s) 8.21 (1H, s) MS: MH ⁺ = 417

Example 19 Structural formula

[0173]

Embedded image

Preparation of compound I represented by: and its diastereomer, compound II.

Normal butyllithium (1.6 M hexane solution; 313 ml) was added dropwise to diisopropylamine (840 μl) in 15 ml of tetrahydrofuran at -65 ° C., then the temperature was raised to 4 ° C. and the reaction was carried out for 15 minutes to obtain lithium diisopropylamide. A solution was prepared. 2-Ethyl-6-chloro-benzothiazole (988 mg) prepared by Preparation Example 5 after cooling to -63 ° C
In tetrahydrofuran (10 ml), followed by 1- (1H-1,
2,4-triazol-1-yl) -2 ', 4'-difluoroacetophenone (1.227 g) in tetrahydrofuran
(12 ml) was sequentially added dropwise at an internal temperature of -60 ° C or lower. After reacting for 15 minutes, the temperature was raised to 0 ° C., an aqueous solution of ammonium chloride was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, dried and dried under reduced pressure. The residue was purified by silica gel column (dichloromethane: methanol = 100: 1), and the obtained diastereomer mixture was further applied to a silica gel column (dichloromethane: ethyl acetate: 10: 1 → 5: 1) to give a low polarity fraction. Compound I: 442 mg and its diastereomer, highly polar fraction Compound II: 66 mg. The physical properties of each of these compounds are shown below.

Imp: 187 ° C. NMR: δ Solvent (CDCl ₃ ) 1.25 (3H, d, J = 7.0Hz) 4.09 (1H, q, J = 7.0Hz) 4.27 (1H, d, J =
14.4Hz) 4.93 (1H, d, J = 14.4Hz) 5.80 (1H, s) 6.85-6.78 (2H, m) 7.48 (1H, dd, J = 8.8Hz, 2.4Hz) 7.49-7.55 (1H, m) 7.67 (1H,
s) 7.87 (1H, s) 7.90 (1H, d, J = 2.4Hz) 7.94 (1H, d, J = 8.8Hz) MS: MH ⁺ = 421

II mp: 127-130 ° C. NMR: δ solvent (CDCl ₃ ) 1.68 (3H, d, J = 6.8Hz) 4.13 (1H, q, J = 6.8Hz) 4.71 (1H, d, J =
14Hz) 4.94 (1H, d, J = 14Hz) 5.87 (1H, s) 6.46-6.50 (1H, m) 6.43-
6.69 (1H, m) 7.09-7.16 (1H, m) 7.38 (1H, dd, J = 2.0Hz, 8.8Hz) 7.69 (1H,
s) 7.72 (1H, d, J = 2.0Hz) 7.80 (1H, d, J = 8.8Hz) 8.04 (1H, s) MS: MH ⁺ = 421

Example 20 Structural formula

[0179]

Embedded image

Physical properties of the compound represented by:

A mixture of 2-ethyl-6-cyanobenzothiazole (1.78 g), sodium azide (1.22 g), triethylamine hydrochloride (2.59 g) was heated in 30 ml of N-methylpyrrolidone at 100 ° C. for 3 hours. . After cooling to room temperature,
150 ml of water was added, the pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried, the solvent was distilled off under reduced pressure, and the remaining solvent was azeotropically distilled with toluene to give 2-ethyl-6- (tetrazol-5-yl).
Benzothiazole (1.86 g) was obtained. This was dissolved in dimethylformamide (20 ml) and cesium carbonate (3.06 g) was added.
Was added and heated at 80 ° C. for 1.5 hours. Then, 1.17 ml of iodomethane was added under ice cooling, the temperature was returned to room temperature, and the mixture was stirred for 7 hours. Water and ethyl acetate were added for liquid separation, and the organic layer was washed with water and dried.
The residue was purified by silica gel column (hexane: ethyl acetate = 4: 1) to obtain 2-ethyl-6- (2-methyl-tetrazol-5-yl) benzothiazole (930 mg). Using this produced compound, a target compound was obtained in the same manner as in Example 19. The physical properties of this compound are shown below.

Mp: 184-185 ° C. NMR: δ solvent (CDCl ₃ ) 1.28 (3H, d, J = 7.2Hz) 4.13 (1H, q, J = 7.2Hz) 4.31 (1H, d, J =
14.2Hz) 4.44 (3H, s) 4.96 (1H, d, J = 14.2Hz) 5.89 (1H, s) 6.78-6.86 (2H, m) 7.5
0-7.58 (1H, m) 7.67 (1H, s) 7.89 (1H, s) 8.13 (1H, dd, J = 0.4Hz, 8.8Hz) 8.30 (1H, dd, J = 1.6Hz, 8.8Hz) 8.74 ( 1H, dd, J = 0.4Hz, 1.6H
z)

Example 21 Structural formula

[0184]

[Chemical 74]

Physical properties of the compound represented by:

The target compound was prepared in the same manner as in Example 19, but using 2-ethyl-6-fluoro-benzothiazole instead of 2-ethyl-6-chloro-benzothiazole. The physical properties of this compound are shown below.

Mp: 151-153 ° C NMR: δ solvent (CDCl ₃ ) 1.25 (3H, d, J = 7.1Hz) 4.08 (1H, q, J = 7.1Hz) 4.28 (1H, d, J =
14.4Hz) 4.93 (1H, d, J = 14.4Hz) 5.83 ((1H, s) 6.77-6.85 (2H, m) 7.
23-7.29 (1H, m) 7.49-7.56 (1H, m) 7.58-7.62 (1H, m) 7.67 (1H, s) 7.87 (1
H, s) 7.96-8.00 (1H, m) MS: MH ⁺ = 405

Example 22 Structural formula

[0189]

[Chemical 75]

Physical properties of the compound represented by:

The target compound was prepared as in Example 19, but using 2-ethyl-6-cyano-benzothiazole instead of 2-ethyl-6-chloro-benzothiazole. The physical properties of this compound are shown below.

Mp: 186-188 ° C NMR: δ solvent (CDCl ₃ ) 1.27 (3H, d, J = 7.2Hz) 4.16 (1H, q, J = 7.2Hz) 4.24 (1H, d, J =
14.0Hz) 4.96 (1H, d, J = 14.0Hz) 5.67 (1H, s) 6.79-6.86 (2H, m) 7.4
9-7.56 (1H, m) 7.69 (1H, s) 7.77 (1H, dd, J = 1.6Hz, 8.4Hz) 7.83 (1H, s) 8.
11 (1H, d, J = 8.4Hz) 8.27 (1H, d, J = 1.6Hz) MS: MH ⁺ = 412

Example 23 Structural formula

[0194]

[Chemical 76]

Preparation of compounds of:

The compound (506 mg) obtained in Example 22 was suspended in methanol (10 ml), and 1N aqueous sodium hydroxide solution (0.37 ml, 30% aqueous hydrogen peroxide (0.42 ml)) was added successively. The mixture was stirred for 2 hours at room temperature, water and ethyl acetate were added thereto for extraction, the organic layer was washed with water, dried and then evaporated. Silica gel column (dichloromethane: methanol = 50: 1 → 20:
The product was purified in 1) to obtain the target compound (311 mg). The physical properties of this compound are shown below.

Mp: 112-117 ° C. NMR: δ solvent (CDCl ₃ ) 1.25 (3H, d, J = 7.0Hz) 4.13 (1H, q, J = 7.0Hz) 4.29 (1H, d, J =
14.4Hz) 4.94 (1H, d, J = 14.4Hz) 5.82 (1H, s) 5.60-6.25 (2H, br) 6.78-6.86 (2H, m) 7.50-7.56 (1H, m) 7.67 (1H, s) 7.87 (1
H, s) 7.90 (1H, dd, J = 1.6Hz, 8.4Hz) 8.08 (1H, dd, J = 0.6Hz, 8.4H
z) 8.48 (1H, dd, J = 0.6Hz, 1.6Hz) MS: MH ⁺ = 430

Example 24 Structural formula

[0199]

Embedded image

Preparation of a compound of:

The compound obtained in Example 22 (507 mg) and 1 drop of triethylamine were added to dimethylformamide (5 ml).
Was dissolved in water, hydrogen sulfide gas was saturated at room temperature, and the mixture was allowed to stand at room temperature for 6 hours. The reaction mixture was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with water, dried, and purified with a concentrated silica gel column (eluting solvent: dichloromethane: methanol = 50: 1). The target compound (538 mg) was obtained. The physical properties of this compound are shown below.

Mp: 157-160 ° C. NMR: δ solvent (CDCl ₃ ) 1.23 (3H, d, J = 7.2Hz) 4.13 (1H, q, J = 7.2Hz) 4.27 (1H, d, J =
14.0Hz) 4.94 (1H, d, J = 14.0Hz) 5.81 (1H, s) 6.78-6.85 (2H, m) 7.2
4-7.30 (1H, br-s) 7.39-7.56 (1H, m) 7.67 (1H, s) 7.66-7.72 (1H, brs) 7.86
(1H, s) 7.95 (1H, dd, J = 2.0Hz, 8.8Hz) 8.02 (1H, d, J = 8.8Hz) 8.59
(1H, d, J = 2.0Hz) MS: MH ⁺ = 446

Example 25 Structural formula

[0204]

Embedded image

Compound represented by (diastereomer
Preparation of 1: 1 mixture).

Compound obtained according to example 24 (2.67 g)
Suspended in 130 ml of acetone, added 1.12 ml of iodomethane
The mixture was heated under reflux at 40 ° C for 8 hours. Structural formula:

[0207]

Embedded image

An intermediate compound represented by: was obtained. This intermediate compound (584 mg) was dissolved in ethanol (5.8 ml), aminodiethyl acetal (174 μl) was added, and the mixture was heated under reflux for 5 hours.
Then, 6N hydrochloric acid (5 ml) was added, and the mixture was heated under reflux for 1 hr.
The reaction mixture was partitioned between sodium bicarbonate water and ethyl acetate, and the organic layer was washed with water, dried and dried. Purify the residue on a silica gel column (dichloromethane: methanol 100: 1 to 10: 1).
The target compound was obtained as a 1: 1 mixture of diastereomers.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.27 (3H, d, J = 7.2Hz) 1.73 (3H, d, J = 7.2Hz) 4.10 (1H, q, J =
7.2Hz) 4.15 (1H, q, J = 7.2Hz) 4.32 (1H, d, J = 14.0Hz) 4.73 (1H, d, J
= 14.0H) 4.94 (1H, d, J = 14.0Hz) 4.95 (1H, d, J = 14.0Hz) 5.92 (1H, s)
5.98 (1H, s) 6.44-6.50 (1H, m) 6.63-6.70 (1H, m) 6.77-6.84 (2H, m) 7.
12-7.17 (1H, m) 7.17 (1H, br-s) 7.22 (1H, br-s) 7.50-7.57 (1H, m) 7.66 (1
H, s) 7.69 (1H, s) 7.84 (1H, dd, J = 1.6Hz, 8.4Hz) 7.89 (1H, s) 7.91 (1H, d, J =
8.4Hz) 7.93 (H, dd, J = 1.6Hz, 8.4Hz) 8.05 (1H, d, J = 8.4Hz) 8.06 (1
H, s) 8.27 (1H, d, J = 1.6Hz) 8.46 (1H, d, J = 1.6Hz)

Example 26 Structural formula

[0211]

Embedded image

Production of a compound represented by:

The intermediate compound (1.17 g) in Example 25 was dissolved in ethanol (12 ml), and formylhydrazine (24
0 mg), triethylamine (250 μl) and 1 drop of concentrated sulfuric acid were sequentially added, and the mixture was reacted at room temperature for 40 minutes and then heated under reflux for 1.5 hours. After cooling, ethyl acetate and water were added for extraction, the organic layer was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain the target compound (742 mg). . The physical properties of this compound are shown below.

Mp: 138-140 ° C. NMR: δ solvent (CDCl ₃ ) 1.27 (3H, d, J = 7.2Hz) 4.13 (1H, q, J = 7.2Hz) 4.33 (1H, d, J =
14.2Hz) 4.95 (1H, d, J = 14.2Hz) 5.96 (1H, s) 6.78-6.86 (2H, m) 7.5
1-7.57 (1H, m) 7.67 (1H, s) 7.91 (1H, s) 8.10 (1H, d, J = 8.4Hz) 8.25 (1H,
d, J = 8.4Hz) 8.32 (1H, s) 8.69 (1H, s) MS: MH ⁺ = 472

Example 27 Structural formula

[0216]

[Chemical 81]

Production of a compound represented by:

The compound (264 mg) obtained in Example 24 and bromoacetaldehyde dimethyl acetal (390 μl),
One drop of concentrated sulfuric acid was heated to reflux in ethanol (2.5 ml) for 1 hour. Bromoacetaldehyde dimethyl acetal
(390 μl) was added and the mixture was heated under reflux for an additional 1 hour. The reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed with water and dried, and the solvent was evaporated. Hexane was added to the residue, and the precipitate was collected by filtration to obtain the target compound (180 mg). The physical properties of this compound are shown below.

Mp: 153-158 ° C NMR: δ solvent (CDCl ₃ ) 1.28 (3H, d, J = 7.2Hz) 4.12 (1H, q, J = 7.2Hz) 4.31 (1H, d, J =
14.2Hz) 4.96 (1H, d, J = 14.2Hz) 5.89 (1H, s) 6.78-6.25 (2H, m) 7.4
0 (1H, d, J = 3.4Hz) 7.66 (1H, s) 7.89 (1H, s) 7.92 (1H, d, J = 3.4Hz) 8.09 (1H, s
d, J = 0.4Hz) 8.10 (1H, d, J = 1.6Hz) 8.57 (1H, dd, J = 0.4Hz, 1.6Hz) MS: MH ⁺ = 470

Example 28 Structural formula A

[0221]

[Chemical formula 82]

And structural formula B

[0223]

[Chemical 83]

Production of each compound represented by:

The compound (453 mg) obtained in Example 26 was dissolved in acetone (4.5 ml), and potassium carbonate powder (138 mg) was added.
And iodomethane (62 μl) were added, and the mixture was stirred overnight at room temperature. The mixture was extracted with ethyl acetate-water, the organic layer was washed with water, dried and evaporated under reduced pressure. The residue was purified by a silica gel column (dichloromethane: methanol = 50: 1 → 30: 1) and then separated and purified by an ODS column (methanol: water = 60: 40 → 65: 35) to obtain a compound of structural formula A (192 mg) And a compound of structural formula B (52 mg) was obtained. The physical properties of these compounds are shown below.

Amp: 180-190 ° C. NMR: δ solvent (CDCl ₃ ) 1.27 (3H, d, J = 7.0Hz) 4.01 (3H, s) 4.11 (1H, q, J = 7.0Hz)
4.32 (1H, d, J = 14.0Hz) 4.94 (1H, d, J = 14.0Hz) 5.99 (1H, s) 6.77-6.86 (2H, m) 7.5
0-7.57 (1H, s) 7.65 (1H, s) 7.91 (1H, s) 8.08 (1H, d, J = 8.4Hz) 8.10 (1H,
s) 8.27 (1H, dd, J = 8.4Hz, 1,6Hz) 8.67 (1H, d, J = 1.6Hz) MS: MH ⁺ = 454

B mp: 196-197 ° C. NMR: δ solvent (CDCl ₃ ) 1.29 (3H, d, J = 7.2Hz) 4.07 (3H, s) 4.15 (1H, q, J = 7.2Hz)
4.30 (1H, d, J = 14.2Hz) 4.97 (1H, d, J = 14.2Hz) 5.82 (1H, s) 6.79-6.86 (2H, m) 7.5
0-7.58 (1H, m) 7.68 (1H, s) 7.82 (1H, dd, J = 1.8Hz, 8.4Hz) 7.87 (1H, s)
7.99 (1H, s) 8.16 (1H, d, J = 8.4Hz) 8.281H, d, J = 1.8Hz)

Example 29 Structural formula

[0229]

[Chemical 84]

Production of a compound represented by:

Instead of 2-ethyl-6-chlorobenzothiazole, 2-ethyl-6- (1,2,3-triazol-2-yl) benzothiazole (529 mg) of raw material 5 prepared according to Preparation Example 6 was used. ) Was used to obtain the target compound (120 mg) by the procedure described in Example 19. The physical properties of this compound are shown below.

State: Oily NMR: δ Solvent (CDCl ₃ ) 1.29 (3H, d, J = 7.1Hz) 4.12 (1H, q, J = 7.1Hz) 4.32 (1H, d, J =
14.2Hz) 4.97 (1H, d, J = 14.2Hz) 5.87 (1H, brs) 6.79-6.83 (2H, m)
7.50-7.58 (1H, m) 7.67 (1H, s) 7.87 (2H, s) 7.89 (1H, s) 8.12 (1H, d, J = 9.0H
z) 8.30 (1H, dd, J = 8.8,2.2Hz) 8.65 (1H, d, J = 2.2Hz)

Example 30 Structural formula

[0234]

Embedded image

Preparation of a compound of the formula (1: 1 mixture of diastereomers).

By a procedure similar to that in Production Example 6, 2-ethyl-
6-Methoxycarbonylbenzothiazole was produced and dissolved in 1 ml of diethyl ether, and methylmagnesium iodide (2.0 M diethyl ether solution was added thereto).
1.2 ml) was added at 0 ° C. After stirring at room temperature for 1 hour, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, and the solvent was distilled off under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain (2-methyl-2-
(2-Ethylbenzothiazol-6-yl) ethanol) (138 mg) was obtained. This is used in place of 2-ethyl-6-chlorobenzothiazole by the procedure described in Example 19, but using twice the amount of n-butyllithium as the target compound (1: 1 mixture of diastereomers. ) Got. The physical properties of this compound are shown below.

Mp state: solid NMR: δ solvent (CDCl ₃ ) 1.25 (1.5H, d, J = 7.2Hz) 1.60 (3H, s) 1.67 (3H, s) 1.80 (1.
5H, d, J = 8.4Hz) 4.05-4.17 (1H, m) 4.27 (0.5H, d, J = 14.4Hz) 4.71 (0.5H, d,
J = 14.0Hz) 4.90-4.95 (1H, n) 6.02 (0.5H, s) 6.13 (0.5H, d, J = 1.6Hz)
6.44-6.51 (0.5H, m) 6.63-6.70 (0.5Hm) 6.63-6.70 (0.5H, m) 6.76-6.85 (1H,
m) 7.10-7.17 (0.5H, m) 7.50-7.56 (1H, m) 7.61-7.65 (0.5H, m) 7.64 (0.5H, s) 7.6
6 (0.5H, s) 7.84 (0.5H, d, J = 8.8Hz) 7.89 (0.5H, s) 7.91 (0.5HdJ = 1.
6Hz) 8.00 (0.5H, d, J = 8.8Hz) 8.06 (0.5H, s) 8.10 (0.5H, d, J = 1.
6Hz) MS: MH ⁺ = 445

Example 31 Structural formula

[0239]

[Chemical 86]

Preparation of a compound of the formula (1: 1 mixture of diastereomers).

2-Ethyl-6-methoxycarbonylbenzothiazole (699 mg) used in Example 30 was dissolved in a mixed solvent (20 ml) of water-methanol 1: 1 and 1N-NaOH aqueous solution (8 ml) was added for 4.5 hours. Heated to reflux. there
8 ml of 1N-HCl and then sodium chloride were added, and the mixture was extracted with ethyl acetate. After washing with saturated saline, the solvent was distilled off under reduced pressure to obtain 6-carboxy-2-ethylbenzothiazole (642 mg).
This product (1.957 g) was purified without purification with xylene (50 m
l), 2-amino-2-methyl-1-
Propanol (6 ml) was added and the mixture was heated under reflux using a Dean-Stark tube for 3 days. The reaction mixture was distilled under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography to give the structural formula

[0242]

[Chemical 87]

The intermediate compound of was obtained. Using this intermediate compound, the target compound was obtained by the same procedure as in Example 19.
The physical properties of this compound are shown below.

Mp state: solid NMR: δ solvent CDCl ₃ 1.27 (1.5H, d, J = 6.8Hz) 1.38 (3H, s) 1.42 (3H, s) 1.70 (1.
5H, d, J = 6.8Hz) 4.08-4.18 (1H, m) 4.12 (1H, s) 4.18 (1H, s) 4.29 (0.5H, d,
J = 14.4Hz) 4.74 (0.5H, d, J = 14Hz) 4.94 (0.5H, d, J = 14.4Hz) 4.95 (0.5
H, d, J = 14 Hz) 5.90 (0.5H, s) 5.94 (0.5H, d, J = 1.6Hz) 6.43-6.49 (0.5H,
m) 6.62-6.69 (0.5H, m) 6.77-6.85 (1H, m) 7.07-7.14 (0.5H,
m) 7.49-7.57 (0.5H, m) 7.66 (0.5H, s) 7.68 (0.5H, s) 7.89 (0.5H, d, J = 8.4Hz) 7.8
9 (0.5H, s) 8.00 (0., 5H, dd, J = 1.6 8.4Hz) 8.03 (0.5H, d, J = 8.4Hz) 8.
05 (0.5H, s) 8.10 (0.5H, dd, J = 1.6,8.4Hz) 8.35 (0.5H, d, J = 1.6Hz) 8.5
3 (0.5H, d, J = 1.6Hz) MS: MH ⁺ = 484

Example 32 Structural formula

[0246]

Embedded image

Production of compound (I) represented by: and compound (II) which is a diastereomer thereof.

2-Ethyl-6-methylthiobenzothiazole was produced by a procedure similar to that described in Production Example 6, and was used to produce a diastereomeric mixture of the target compound by a procedure similar to that in Example 19. Then, the compound (I) and its diastereomer, the compound (II), were separated by silica gel chromatography.

(I) State: Solid NMR: δ Solvent CDCl ₃ 1.24 (3H, d, J = 7.0Hz) 2.57 (3H, s) 4.06 (1H, q, J = 7.0Hz)
4.27 (1H, d, J = 14.2Hz) 4.92 (1H, d, J = 14.2Hz) 5.93 (1H, s) 6.76-6.84 (2H, m) 7.4
2 (1H, dd, J = 2.0,8.4Hz) 7.47-7.55 (1H, m) 7.65 (1H, s) 7.76 (1H, d, J = 2.0) 7.88 (1
H, s) 7.92 (1H, d, J = 8.4Hz) MS: MH ⁺ = 433

(II) State: Solid NMR: δ Solvent CDCl ₃ 1.24 (3H, d, J = 7.0Hz) 2.57 (3H, s) 4.06 (1H, q, J = 7.0Hz) 4.27 (1H, d, J = 14.2Hz) 4.92 (1H, d, J = 14.2Hz) 5.93 (1H, s) 6.76-6.84 (2H, m) 7.42 (1H, dd, J = 2.0,8.4Hz) 7.47-7.55
(1H, m) 7.65 (1H, s) 7.76 (1H, d, J = 2.0) 7.88 (1H, s) 7.92 (1H, d, J
= 8.4Hz) MS: MH ⁺ = 433

Example 33 Structural formula

[0251]

[Chemical 89]

Production of compound (I) represented by and compound (II) which is a diastereomer thereof.

From the compound obtained in Example 32 or its diastereomer, the above-mentioned compound (I) and its diastereomer, compound (II), were obtained by the same procedure as described in Example 12. . The physical properties of these compounds are shown below.

(I) State: Solid NMR: δ Solvent CDCl ₃ 1.29 (3H, d, J = 7.2Hz) 3.13 (3H, s) 4.18 (1H, q, J = 7.2Hz)
4.24 (1H, d, J-14.12Hz) 4.98 (1H, d, J = 14.2Hz) 5.68 (1H, s) 6.79-6.86 (2H, m) 7.4
9-7.56 (1H, m) 7.70 (1H, s) 7.84 (1H, s) 8.06 (1H, dd, J = 2.0,8.8Hz) 8.19
(1H, d, J = 8.8Hz) 8.58 (1H, d, J = 2.0Hz) MS: MH ⁺ = 465

(II) State: Solid NMR: δ Solvent CDCl ₃ 1.71 (3H, d, J = 6.8Hz) 3.08 (3H, s) 4.22 (1H, q, J = 6.8Hz) 4.73 (1H, d, J = 14.0Hz) 4.98 (1H, d, J = 14.0) 5.72 (1H, s)
6.47-6.54 (1H, m) 6.64-6.71 (1H, m) 7.12-7.19 (1H, m), 7.72 (1H, s) 7.96 (1
H, dd, J = 1.7,8.8Hz) 8.02 (1H, s) 8.04 (1H, d, J = 8.8Hz) 8.41 (1H, brd, J = 1.7Hz) MS: MH ⁺ = 465

Example 34 Structural formula

[0257]

[Chemical 90]

Production of a compound of formula:

2-Ethyl-6-chlorobenzothiazole was replaced by 2-ethyl-6- (4-fluorophenylthio) benzothiazole prepared by a procedure similar to that described in Preparation 6. The target product was produced by a procedure similar to the procedure described in Example 19. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent CDCl ₃ 1.24 (3H, d, J = 7.2Hz) 4.07 (1H, q, J = 7.2Hz) 4.26 (1H, d, J =
14.4Hz) 4.92 (1H, d, J = 14.4Hz) 5.84 (1H, s) 6.76-6.84 (2H, m) 7.06 (2H, br-dd, J = 8.6,8.6Hz) 7.39-7.44 (3H, m ) 7.47-7.
55 (1H, m) 7.66 (1H, s) 7.77 (1H, d, J = 1.6Hz) 7.86 (1H, s) 7.93 (1H,
dJ = 8.8Hz) MS: MH ⁺ = 513

Example 35 Structural formula

[0262]

Embedded image

Compound (I) represented by

Structural formula

[0265]

Embedded image

Production of compound (II) represented by:

A mixture of the above compounds was prepared from the compound prepared in Example 34 by a procedure similar to that described in Example 12, and the mixture was separated by silica gel chromatography to prepare each of the above compounds. The physical properties of these compounds are shown below.

(I) State: Solid NMR: δ Solvent (CDCl ₃ ) 1.27 (3H, d, J = 7.2Hz) 4.22 (1H, d, J = 14.4Hz) 4.63 (1H, q, J
= 7.2Hz) 5.11 (1H, d, J = 14.4Hz) 6.56 (1H, brs) 6.76-6.87 (2H, m) 7.23 (2H, br-dd, J = 8.4,8.4Hz) 7.46-7.54 (1H, m) 7.68 (1H,
s) 7.92 (1H, s) 7.99-8.04 (2H, m) 8.12 (1H, dd, J = 1.6,8.4Hz) 8.32 (1H, d,
J = 8.4Hz) 8.51 (1H, br-d, J = 1.6Hz) MS: MH ⁺ = 561

(II) State: Solid NMR: δ Solvent CDCl ₃ 1.26 (3H, d, J-7.2Hz) 4.14 (1H, q, J = 7.2Hz) 4.19 (1H, d, J =
14.4Hz) 4.94 (1H, d, J = 14.4Hz) 5.64 (1H, s) 6.78-6.85 (2H, m) 7.20 (2H, br-dd, J = 8.6,8.6Hz) 7.47-7.54 (1H, m ) 7.68 (1
H, s) 7.81 (1H, s) 7.98-8.03 (3H, m) 8.12 (1H, d, J = 8.8Hz) 8.58
(1H, d, J = 2.0Hz) MS: MH ⁺ = 545

Example 36 Structural formula

[0271]

Embedded image

Preparation of a compound of:

By a procedure similar to that described in Example 19, but using 2-ethyl-4-chloro-benzothiazole instead of 2-ethyl-6-chloro-benzothiazole, the desired product was prepared. The physical properties of this compound are shown below.

State: Oily NMR: δ Solvent CDCl ₃ 1.26 (3H, d, J = 8.0Hz) 4.19 (1H, q, J = 8.0Hz) 4.34 (1H, d, J =
15.2Hz) 4.96 (1H, d, J = 15.2Hz) 5.92 (1H, brs) 6.78-6.84 (2H, m)
7.34-7.40 (1H, m) 7.50-7.58 (2H, m) 7.68 (1H, s) 7.78-7.58 (2H, m) 7.68 (1
H, s) 7.78-7.85 (1H, m) 7.92 (1H, s)

Example 37 Structural formula

[0276]

Embedded image

Production of a compound represented by:

A similar procedure to that described in Example 22 was used, but using 2-ethyl-4-cyano-benzothiazole instead of 2-ethyl-6-cyano-benzothiazole to give the desired product. The physical properties of this compound are shown below.

State: Oily NMR: δ Solvent CDCl ₃ 1.26 (3H, d, J = 7.1Hz) 4.15 (1H, q, J = 7.1Hz) 4.22 (1H, d, J =
14.2Hz) 4.98 (1H, d, J = 14.2Hz) 5.63 (1H, brs) 6.78-6.86 (2H, m) 7.48-7.56 (1H, m) 7.67 (1H, dd, J = 8.2,1.5Hz) 7.70 (1H, s)
7.84 (1H, s) 8.03 (1H, d, J = 8.2Hz) 8.33 (1H, d, J = 1.5Hz)

Example 38 Structural formula

[0281]

Embedded image

Production of a compound represented by:

2-Ethyl-6-chloro-7-azabenzothiazole (3.16 g) and sodium thiomethoxide (1.67 g)
g) was reacted in N-methylpyrrolidone (9 ml) at 90 ° C. for 1 hour. After cooling, water and ethyl acetate were added for liquid separation, the organic layer was washed with water and dried, and the solvent was evaporated. The residue was purified by silica gel column (hexane: ethyl acetate: 10: 1) to obtain the intermediate compound 2-ethyl-6-thiomethoxy-7-azabenzothiazole (2.25 g). Using this intermediate compound, the target product was produced by the same procedure as in Example 19. The physical properties of this compound are shown below.

Mp: 185-186 ° C. NMR: δ solvent (CDCl ₃ ) 1.25 (3H, d, J = 7.2Hz) 2.65 (3H, s) 4.03 (1H, q, J = 7.2Hz)
4.30 (1H, d, J = 14.2Hz) 4.94 (1H, d, J = 14.2Hz) 5.75 (1H, s) 6.77-6.85 (2H, m) 7.3
1 (1H, d, J = 8.4Hz) 7.48-7.55 (1H, m) 7.68 (1H, s) 7.86 (1H, s) 8.02 (1H, d, J =
(8.4Hz)

Example 39 Structural formula

[0286]

[Chemical 96]

Production of a compound represented by:

The compound (400 mg) obtained in Example 38 was dissolved in dichloromethane (4 ml), metachloroperbenzoic acid (476 mg) was added, and the mixture was stirred for 1.5 hours at room temperature. It was washed successively with water and heavy water containing dichloromethane and dried, and the solvent was distilled off to obtain the desired product (452 mg). The physical properties of this compound are shown below.

Mp: 211-214 ° C. NMR: δ solvent (CDCl ₃ ) 1.30 (3H, d, J = 7.0Hz) 3.32 (3H, s) 4.14 (1H, q, J = 7.0Hz)
4.23 (1H, d, J = 14.4Hz) 5.01 (1H, d, J = 14.4Hz) 5.59 (1H, s) 6.80-6.86 (2H, m) 7.4
8-7.56 (1H, m) 7.72 (1H, s) 7.82 (1H, s) 8.25 (1H, d, J = 8.4Hz) 8.47 (1H,
d, J = 8.4Hz) MS: M ⁺ = 466

Example 40 Structural formula

[0291]

Embedded image

Production of a compound represented by:

By a procedure similar to that described in Example 38, but using 2-ethyl-6-chloro- as the intermediate compound.
The desired product was obtained using 7-azabenzothiazole. The physical properties of this compound are shown below.

Mp: 177-178 ° C. NMR: δ solvent (CDCl ₃ ) 1.27 (3H, d, J = 7.2Hz) 4.07 (1H, d, J = 7.2Hz) 4.27 (1H, d J =
14.0Hz) 4.96 (1H, d, J = 14.0Hz) 5.63 (1H, s) 6.78-6.85 (2H, m) 7.4
7 (1H, d, J = 8.4Hz) 7.48-7.55 (1H, m) 7.70 (1H, s) 7.83 (1H, s) 8.19 (1H, d, J =
(8.4Hz)

Example 41 Structural formula

[0296]

Embedded image

Production of a compound represented by: 2-ethyl-7
− Azabenzothiazole (2.95 g) was added to dichloromethane (30 m
It was melted in l) and metachloroperbenzoic acid (4.7 g) was added at room temperature. After 3.5 hours, metachloroperbenzoic acid (2.3 g) was further added. After completion of the reaction, the mixture was treated with an aqueous sodium sulfite solution under ice cooling. Dilute with dichloromethane, wash the organic layer successively with sodium bicarbonate water, water, and brine and dry.
-Ethyl-7-azabenzothiazole-7-oxide
(2.69g) was obtained. This was added to dichloromethane (27 ml), and dimethylaminocarbamoyl chloride (4.16 g) trimethylsilyl cyanide (5.69 ml) triethylamine (6.3 m
l) were sequentially added, and trimethylsilyl cyanide (2.5 ml) and dimethylaminocarbamoyl chloride (2.5 ml) reacted at room temperature for 8 hours were added. After reacting for 2 days at room temperature, heavy soda water was added and stirred for 1 hour. It was extracted with ethyl acetate, the organic layer was washed with water, dried and evaporated. After purification with a silica gel column (eluted with dichloromethane: methanol: 200: 1), recrystallization was carried out with dichloromethane-isopropyl ether to give 2-ethyl-6-cyano-7-azabenzothiazole (1.37 g). A procedure similar to that of Example 19 was used, except that the above compound was used in place of 2-ethyl-6-chlorobenzothiazole to obtain the desired product. The physical properties of this compound are shown below.

Mp: 170-173 ° C. NMR: δ solvent (CDCl ₃ ) 1.30 (3H, d, J = 7.0Hz) 4.13 (1H, qd, J = 7.0Hz, 0.8Hz) 4.25
(1H, d, J = 14.0Hz) 4.98 (1H, d, J = 14.0Hz) 5.59 (1H, d, J = 0.8Hz) 5.59 (1H, d, J
= 0.8Hz) 6.79-6.86 (2H, m) 7.49-7.56 (1H, m) 7.72 (1H, s) 7.81 (1
H, s) 7.84 (1H, d, J = 8.4Hz) 8.35 (1H, d, J = 8.4Hz) MS: MH ⁺ = 413

Example 42 Structural formula

[0300]

Embedded image

Production of a compound represented by:

The target product was prepared from the compound prepared in Example 41 by a procedure similar to that described in Example 24. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.30 (3H, d, J = 7.2Hz) 4.12 (1H, q, J = 7.2Hz) 4.28 (1H, d, J-
14.4Hz) 5.00 (1H, d, J = 14.4Hz) 5.65 (1H, s) 6.80-6.87 (2H, m) 7.4
9-7.56 (1H, m) 7.70 (1H, s) 7.70-7.76 (1H, brs) 7.80 (1H, s) 8.33 (1H, d,
J = 8.8Hz) 8.91 (1H, d, J = 8.8Hz) 9.32-8.38 (1H, br-s)

Example 43 Structural formula

[0305]

[Chemical 100]

Production of a compound represented by:

By a procedure similar to that described in Example 40, except that 1- (1H-1,2,4-triazol-1-yl)-
1- (1H- instead of 2 ', 4'-difluoroacetophenone
1,2,4-triazol-1-yl) -2'-chloroacetophenone was used to obtain the desired product. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 1.22 (3H, d, J = 7.2Hz) 4.22 (1H, d, J = 14.4Hz) 4.67 (1H, q, J
= 7.2Hz) 5.55 (1H, s) 5.60 (1H, d, J = 14.4Hz) 7.18-7.22 (2H, m) 7.34-7.38 (1H,
m) 7.46 (1H, d, J = 8.8Hz) 7.68 (1H, s) 7.69-7.73 (1H, s) 7.81
(1H, s) 8.20 (1H, d, J = 8.8Hz)

Example 44 Structural formula

[0310]

[Chemical 101]

Production of a compound represented by:

A procedure similar to that described in Example 19 was used, but using 2-methyl-6-chlorobenzothiazole instead of 2-ethyl-6-chlorobenzothiazole to obtain the desired product. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 3.43 (1H, d, J = 15.2Hz) 3.88 (1H, d, J = 15.2Hz) 4.65 (1H, d,
J = 14.2Hz) 4.70 (1H, d, J = 14.2Hz) 6.03 (1H, s) 6.69-6.74 (1H, m) 6.7
6-6.81 (1H, m) 7.40 (1H, dd, J = 8.8Hz, 2.0Hz) 7.42-7.50 (1H, m) 7.75 (1H.
dd, J = 2.0Hz) 7.82 (1H, d, J = 8.8Hz) 7.85 (1H, s) 8.18 (1H, s)

Example 45 Structural formula

[0315]

Embedded image

Production of a compound represented by:

By a procedure similar to that described in Example 44, but substituting 2-methyl-6-cyanobenzothiazole for 2-methyl-6-chlorobenzothiazole, the desired product was obtained. The physical properties of this compound are shown below.

Mp: 176-178 ° C. NMR: δ solvent CDCl ₃ 3.52 (1H, d, J = 15.4Hz) 3.95 (1H, d, J = 15.4Hz) 4.69 (2H, s)
5.87 (1H, s) 6.71-6.82 (2H, m) 7.51-7.45 (1H, m) 7.69 (1H, dd, J = 1.6H
z, 8.6Hz) 7.86 (1H, s) 7.99 (1H, dd, J = 0.4Hz, 8.6Hz) 8.13 (1H, dd, J =
0.4Hz, 1.6Hz) 8.15 (1H, s)

Example 46 Structural formula

[0320]

Embedded image

Production of a compound represented by:

By a procedure similar to that described in Example 40, but substituting 2-methyl-6-chloro-7-azabenzothiazole with 2-methyl-6-chloro-7-azabenzothiazole. I got the object. The physical properties of this compound are shown below.

Mp: 145-147 ° C. (MeOH) NMR: δ solvent (CDCl ₃ ) 3.47 (1H, d, J = 15.2Hz) 3.90 (1H, d, J = 15.2Hz) 4.69 (2H, s)
5.76 (1H, s) 6.70-6.83 (2H, m) 7.39 (1H, d, J = 8.4Hz) 7.42-7.49 (1H, m)
7.86 (1H, s) 8.08 (1H, d, J = 8.4Hz) 8.13 (1H, z)

Example 47 Structural formula

[0325]

[Chemical 104]

Production of a compound represented by:

3-nitro-4-chloropyridine hydrochloride (2
038mg) dissolved in ethanol (42ml), sodium hydrosulfide
(2148 mg) was added, and the mixture was stirred at room temperature for 40 minutes. An aqueous solution of sodium hydrosulfite (6.67 g) was added to this reaction mixture, and the mixture was heated with stirring at 80 ° C. for 12 hours. After the insoluble matter was filtered off, the solution was concentrated. This was dissolved in methanol-water, sprinkled on silica gel and dried under reduced pressure (chloroform-methanol 5: 1 → 1: 1) to elute,
3-Amino-4-mercaptopyridine (892 mg) was obtained. 7 ml of ethyl acetate and 4Å of molecular sieves were added thereto, and the mixture was heated under reflux for 20 minutes in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, dissolved in methanol and adsorbed on silica gel. This was eluted with chloroform-methanol = 50: 1 to give 2-methyl-5-azabenzothiazole 59.
0 mg was obtained. A procedure similar to that described in Example 44 was used, except that 2-methyl-5-azabenzothiazole was used in place of 2-methyl-6-chlorobenzothiazole to obtain the desired product. The physical properties of this compound are shown below.

Mp: 137-138 ° C. NMR: δ solvent (CD ₃ OD) 3.69 (1H, d, J = 14.8HZ) 4.08 (1H, d, J = 14.8HZ) 4.77 (1H, d,
J = 14.4HZ) 4.87 (1H, d, J = 14.4HZ) 6.71-6.84 (1H, m) 6.92-7.04 (1H,
m) 7.32-7.46 (1H, m) 7.83 (1H, s) 7.97 (1H, d, J = 5.2Hz) 8.37 (1H, d, J = 5.2Hz) 8.37 (1H, s) 9.06 (1H, s)

Example 48 Structural formula

[0330]

Embedded image

Production of a compound represented by:

Sodium azide (2301 mg) was dissolved in dimethyl sulfoxide (60 ml), 2-bromo-4'-thiomethylacetophenone (3000 mg) was added thereto, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into 200 ml of ice water, extracted with ethyl acetate (200 ml × 5), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane → hexane-ethyl acetate 8: 1). Then, 2-azido-4'-thiomethylacetophenone (215
5 mg) was obtained. Diisopropylamine (1.75 ml) and n -butyllithium 1.6M in 47 ml tetrahydrofuran
After cooling the lithium diisopropylamine solution generated from the hexane solution (7.8 ml) under ice-cooling to -78 ° C, 2-azido-4'-thiomethylacetophenone (2155 m
A tetrahydrofuran solution (19 ml) of g) was added dropwise over 5 minutes, and the mixture was stirred at -78 ° C for 1 hour. Next, propionyl chloride (1.81 ml) was added dropwise, and the mixture was allowed to stand at -78 ° C for 10 minutes,
The temperature was raised to room temperature as it was and stirred at room temperature for 10 minutes. The reaction mixture was poured into ice water, extracted with ether (300 ml × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The obtained oily substance was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 10: 1) to give 2-azido-1- (4′-thiomethylphenyl) vinylpropionate (1.98 g). It was This was dissolved in cyclohexane (38 ml), phosphite was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour and then at 90 ° C for 20 hours.
The mixture was heated and stirred for an hour. The reaction mixture was directly purified by silica gel column chromatography (hexane → hexane: ethyl acetate 30: 1) to give 2-ethyl-5- (4-thiomethylphenyl) oxazole (630 mg). This was used in place of 2-ethyl-6-chloro-benzothiazole to give the desired product by a procedure similar to that described in Example 19. The physical properties of this compound are shown below.

State: Oily NMR: δ Solvent (CDCl ₃ ) 1.55 (3H, d, J = 8.0Hz) 2.50 (3H, s) 3.88 (1H, q, J = 8.0Hz)
4.69 (1H, d, J = 13.3Hz) 4.98 (1H, d, J = 13.3Hz) 5.56 (1H, brs) 6.60-6.72 (2H, m)
7.20-7.26 (2H, m) 7.22-7.34 (1H, m) 7.27 (1H, s) 7.33-7.38 (2H, m) 7.70 (1
H, s) 8.30 (1H, s)

Example 49 Structural formula

[0335]

[Chemical formula 106]

Preparation of a compound of:

The product of Example 48 (77 mg) was added to dichloromethane.
Dissolve it in (6.0 ml) and cool it under ice-cooling with metachloroperbenzoic acid (156
mg) was added and the temperature was raised to room temperature, followed by stirring for 1 hour. A saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, and 10 ml of dichloromethane was added to separate the layers. The aqueous layer was further extracted with dichloromethane (10 ml × 2), the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oily matter was subjected to silica gel column chromatography (hexane-
Ethyl acetate 4: 1 → dichloromethane-methanol 10:
Purification by 1) gave the target compound (54 mg). The physical properties of this compound are shown below.

State: Oily NMR: δ Solvent (CDCl ₃ ) 1.60 (3H, d, J = 7.2Hz) 3.07 (3H, s) 3.91 (1H, q, J = 7.1Hz)
4.71 (1H, d, J = 14.1Hz) 5.00 (1H, d, J = 14.1Hz) 5.40-5.50 (1H, brs) 6.62-6.72 (2
H, m) 7.26-7.33 (1H, m) 7.31 (1H, s) 7.60-7.64 (2H, m) 7.73 (1H, s) 7.92-7.97 (2
H, m) 8.05 (1H, s) MS: m / e FAB 475 (MH ⁺ )

Example 50 Structural formula

[0340]

[Chemical formula 107]

Production of compound represented by: and diastereomer thereof.

A solution of 2-ethyl-4-cyano-5-trimethylsilylthiazole (1.58 g) in 10 ml of tetrahydrofuran was prepared from 20 ml of a solution of lithium diisopropylamide in tetrahydrofuran (1.40 ml of diisopropylamine and 3.2 ml of butyllithium (1.6M hexane solution)). ) To -65 ° C
It was dripped at. Then 10 ml of (1H-1,2,4-triazol-1-yl) -2,4-difluorophenylacetophenone
The tetrahydrofuran solution was added dropwise at -65 ° C. After stirring for 1.5 hours, an aqueous solution of ammonium chloride was added, and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and dried, and the solvent was distilled off. The residue was dissolved in 20 ml of tetrahydrofuran, 20 ml of a tetrahydrofuran solution (1.0 M) of tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature for 1 hour. After separating the mixture between ethyl acetate and water, the organic layer was washed with water, dried, and concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 200: 1) to obtain a single diastereomeric compound (I) (464 m
g) got. The other diastereomer and (1H-1,2,4-
The fraction containing triazol-1-yl) -2,4-difluoroacetophenone was treated with sodium borohydride in methanol and then subjected to silica gel column separation to obtain 564 mg of the other diastereomer compound (II). The physical properties of these compounds are shown below.

(I) mp: 198-205 ° C. NMR: δ solvent (CDCl ₃ ) 1.20 (3H, d, J = 7.1Hz) 4.06 (1H, q, J = 14.4Hz) 4.08 (1H, q, J
= 7.1Hz) 4.96 (1H, d, J = 14.4Hz) 5.41 (1H, s) 6.77-6.83 (2H, m) 7.4
2-7.49 (1H, m) 7.75 (1H, s) 7.80 (1H, s) 8.05 (1H, s) MS: MH ⁺ = 362

(II) mp: 191-194 ° C. NMR: δ solvent (CDCl ₃ ) 1.61 (3H, d, J = 7.1Hz) 4.08 (1H, q, J = 7.1Hz) 4.66 (1H, d, J =
14.0Hz) 4.98 (1H, d, J = 14.0Hz) 5.37 (1H, s) 6.58-6.70 (2H, m) 7.1
2-7.18 (1H, m) 7.75 (1H, s) 7.79 (1H, s) 7.97 (1H, s) MS: MH ⁺ = 362

Example 51 Structural formula

[0346]

[Chemical 108]

Production of a compound represented by:

150 mg of the compound prepared according to Example 50 is dissolved in 2 ml of N-methyl-pyrrolidone and NaN ₃ 54 mg, Et
115 mg of ₃ N HCl was added, and the mixture was heated at an oil bath outer temperature of 100 ° C. for 5 hours. Water was added to the reaction solution and extracted three times with AcOEt, and water and saturated Na were added.
After washing with Cl water and drying with MgSO _4, AcOEt was distilled off. To the residue was added ₂ ml of acetone, 4 ml of EtOH and 10 ml of H ₂ O, and the pH was adjusted with 1N HCl aqueous solution.
When it was adjusted to 3 and left to stand, a solid was precipitated. The crystals were collected by filtration and washed with IPE to obtain 82 mg of the desired product. The physical properties of this compound are shown below.

State: Solid NMR: δ (DMSO-d ⁶ ) 1.13 (3H, d, J = 7.0Hz) 4.11-4.14 (1H, m) 4.34 (1H, d, J = 14.
2Hz) 4.80 (1H, d, J = 14.2Hz) 6.16 (1H, s) 6.93-6.98 (1H, m) 7.18-7.24 (1H, m) 7.28-7.33 (1H, m) 7.61 (1H, s) 8.22 (1
H, s) 8.45 (1H, br-s) MS: MH ⁺ = 405

Example 52 Structural formula

[0351]

[Chemical 109]

Production of a compound represented by:

80 mg of the compound obtained according to Example 51 was added to DMF
The mixture was dissolved in 1 ml, 65 mg of CsCO ₃ was added, the mixture was heated at an oil bath external temperature of 60 ° C. for 30 minutes, 0.03 ml of CH ₃ I was further added, and the mixture was stirred at room temperature for 30 minutes.
H ₂ O was added to the reaction solution, extracted with AcOEt, washed with an aqueous solution of H ₂ O and NaCl, dried over MgSO _{4, and} AcOEt was distilled off. The obtained residue was subjected to column chromatography (SiO ₂ 20 g, CH ₂ Cl ₂ , then CH ₂
1% MeOH solution ₂ Cl _2, the desired product is purified in CH ₂ Cl _{2 2%} MeOH solution) was obtained 58 mg. The physical properties of this compound are shown below.

State: Solid NMR: δ (CDCl ₃ ) 1.22 (0.9H, d, J = 7.1Hz) 1.25 (2.1H, d, J = 7.1Hz) 4.08-4.2
1 (2H, m) 4.45 (0.9H, s) 4.49 (2.1H, s) 4.95 (0.7H, d, J = 14.2Hz) 5.00 (0.3H, d, J = 14.8Hz) 5.40 (0.7H, s ) 5.53 (0.3H, s) 6.76-6.84 (2H, m) 7.45-7.52 (1H, m) 7.72 (0.3H, s) 7.75
(0.7H, s) 7.78 (0.7H, s) 7.81 (0.3H, s) 8.14 (0.3H, s) 8.35 (0.7H,
s) MS: MH ⁺ = 419

Example 53 Structural formula

[0356]

[Chemical 110]

Production of compound (I) represented by: and compound (II) of its diastereomer.

By a procedure similar to that described in Example 50, but replacing 2-ethyl-4-cyano-5-trimethylsilylthiazole with 2-ethyl-4- (4'-fluorophenyl) -5-trimethylsilylthiazole. Was used to obtain the desired product. The physical properties of these compounds are shown below.

(I) mp: 122-124 ° C. NMR: δ solvent (CDCl ₃ ) 1.67 (3H, d, J = 7.0Hz) 4.09 (1H, q, J = 7.0Hz) 4.73 (1H, d, J = 1
3.8Hz) 4.93 (1H, d, J = 13.8Hz) 6.14 (1H, d, J = 1.7Hz) 6.48-6.54 (1
H, m) 6.66-6.73 (1H, m) 7.06-7.12 (3H, m) 7.67 (1H, s) 7.71-7.
74 (2H, m) 8.05 (1H, s)

(II) mp: 87-89 ° C. NMR: δ solvent (CDCl ₃ ) 1.23 (3H, d, J = 7.1Hz) 4.06 (1H, q, J = 7.1Hz) 4.28 (1H, d, J =
14.4Hz) 4.89 (1H, d, J = 14.4Hz) 6.04 (1H, s) 6.77-6.85 (2H, m) 7.1
3-7.17 (1H, m) 7.41 (1H, s) 7.47-7.55 (1H, m) 7.67 (1H, s) 7.85-7.92 (2
H, m) 7.90 (1H, s)

Example 54 Structural formula

[0362]

[Chemical 111]

Production of compound (I) represented by: and compound (II) of its diastereomer.

By a procedure similar to that described in Example 50, but replacing 2-ethyl-4-cyano-5-trimethylsilylthiazole with 2-ethyl-4- (4'-chlorophenyl) -5-trimethylsilylthiazole. Used to obtain each desired product. The physical properties of these compounds are shown below.

(I) mp: 132-133 ° C. NMR: δ solvent (CDCl ₃ ) 1.67 (3H, d, J = 7.0Hz) 4.10 (1H, q, J = 7.0Hz) 4.73 (1H, d, J =
13.9Hz) 4.93 (1H, d, J = 13.9Hz) 6.09 (1H, s) 6.46-6.55 (2H, m) 7.6
5-6.73 (1H, m) 7.05-7.13 (1H, m) 7.17 (1H, s) 7.35-7.40 (2H, m) 7.65-7.
70 (2H, m) 8.04 (1H, s)

(II) mp: 162-164 ° C. NMR: δ solvent (CDCl ₃ ) 1.23 (3H, d, J = 7.1Hz) 4.06 (1H, q, J = 7.1Hz) 4.27 (1H, d, J =
14.4Hz) 4.89 (1H, d, J = 14.4Hz) 5.97 (1H, s) 6.76-6.85 (2H, m) 7.4
0-7.55 (4H, m) 7.67 (1H, s) 7.72-7.77 (2H, m) 7.89 (1H, s)

Example 55 Structural formula

[0368]

[Chemical 112]

Production of a compound represented by:

By a procedure similar to that described in Example 50, but replacing 2-ethyl-4-cyano-5-trimethylsilylthiazole with 2-methyl-4-cyano-5-.
The desired product was obtained using trimethylsilylthiazole.
The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 3.44 (1H, d, J = 15.0Hz) 3.81 (1H, d, J = 15.0Hz) 4.58 (1H, d,
J = 14.2Hz) 4.74 (1H, d, J = 14.2Hz) 5.48 (1H, s) 6.74-6.82 (2H, m) 7.4
0-7.46 (1H, m) 7.85 (1H, s) 7.87 (1H, s) 8.07 (1H, s) MS: MH ⁺ = 348

Example 56 Structural formula

[0373]

[Chemical 113]

Production of a compound represented by:

By a procedure similar to that described in Example 50, but replacing 2-ethyl-4-cyano-5-trimethylsilylthiazole with 2-methyl-4- (4'-chlorophenyl) -5-trimethylsilylthiazole. Used to obtain the desired product. The physical properties of this compound are shown below.

State: Solid NMR: δ Solvent (CDCl ₃ ) 3.34 (1H, d, J = 15.3Hz) 3.85 (1H, d, J = 15.3Hz) 4.62 (1H, d,
J = 14.2Hz) 4.71 (1H, d, J = 14.2Hz) 6.21 (1H, s) 6.69-6.83 (2H, m) 7.2
7 (1H, s) 7.36-7.46 (3H, m) 7.68-7.73 (2H, m) 7.85 (1H, s) 8.20 (1
H, s)

Example 57 Structural formula

[0378]

[Chemical 114]

Production of a compound represented by:

To a suspension of AlCl ₃ (5.88 g) in CH ₂ Cl ₂ (50 ml) was added difluorobenzene (5.77 g), then 2- (4-cyanophenyl) acetyl chloride (5.28 g) in CH ₂ Cl _{2. 2} (30 ml) solution was added dropwise. After heating under reflux for 6 hours, ice water was added and the product extracted with CHCl ₃ was subjected to column chromatography (Si
O ₂ ) and eluted with CH ₂ Cl ₂ -hexane (1: 1) to give compound 4- (2- (2,4-difluorophenyl) -2-
Oxo) ethylbenzonitrile (2.45 g) was obtained.

50% of this compound (1.2 g) in EtOH (12 ml)
Add NaOH (0.67g), then add MeI (0.46ml) dropwise,
Stir at room temperature for 4 hours. The residue obtained by adding ethyl acetate and washing with water and then distilling off the organic layer was purified by column chromatography (SiO ₂ , hexane-CH ₂ Cl ₂ = 3: 1 → 1: 1) to give compound 4- ( 2- (2,4-difluorophenyl) -1-methyl-2-oxo) ethylbenzonitrile
Obtained 0.5 g.

A 1.0 M TMSCH ₂ MgCl ether solution (3.9 ml) was cooled to −78 °, and the above compound (0.5 g) was ether (5 ml).
After the solution was dropped, the temperature was raised to 0 ° C. and the mixture was stirred for 10 minutes.
A saturated aqueous ammonium chloride solution was added, the mixture was extracted with AcOEt, the organic layer was dried, CH ₂ Cl ₂ (10 ml) and BF ₃ -OEt ₂ (0.24 ml) were added at 0 °, and the mixture was stirred at the same temperature for 1.5 hr. . AcOEt
Was added, and the mixture was washed with an aqueous NaHCO ₃ solution and saturated brine, the solvent was evaporated, and the resulting residue was subjected to column chromatography (SiO ₂ ,
Purified with hexane-CH ₂ Cl ₂ 3: 1 → 1: 1) to give compound 4- (2- (2,4-difluorophenyl) -1-methyl-
2-Propenylbenzonitrile (0.2g) was obtained.

This compound (200 mg) was mixed with chloroform (4 m
l) To the solution was added metachloroperbenzoic acid (490 mg) under ice cooling, and the mixture was left overnight. The reaction solution was washed with diluted Na ₂ CO ₃ and then with water, then the organic layer was distilled off, and 5 ml of DMF was added to the resulting residue.
This was mixed with 1,2,4-triazole (272 mg) and 60% NaH (141
mg) was added to a solution of 1,2,4-triazole sodium salt in DMF (3 ml). After reacting at 90 ° C for 2 hours, ethyl acetate was added, the mixture was washed with water and the solvent was distilled off, and the resulting residue was subjected to column chromatography (SiO ₂ , hexane-ethyl acetate 1: 1 → 1: 2). Then, 50 mg of the target compound was obtained. The physical properties of this compound are shown below.

Mp: 208-209 ° C. NMR: δ solvent (CDCl ₃ ) 1.13 (3H, t, J = 7.1Hz) 3.38 (1H, q, J = 7.1Hz) 3.79 (1H, d, J =
14.5Hz) 4.79 (1H, d, J = 14.5Hz) 4.98 (1H, d, J = 1.5Hz) 6.74-6.81 (2
H, m) 7.44-7.51 (1H, m) 7.64 (2H, dJ = 8.4Hz) 7.67 (2H, d, J = 8.4Hz) 7.72 (1H, s) 7.
75 (1H, s)

Example 58 Structural Formula A

[0386]

[Chemical 115]

A compound of formula B

[0388]

[Chemical formula 116]

Preparation of a compound of:

I) The compound of Example 57 (625 mg) was treated with N, N-
Dissolved in dimethylformamide (2 ml) and NaN ₃ (345 mg)
And Et ₃ N.HCl (731 mg) at 100 ° for 7 hours. The insoluble material was filtered off, the solvent was distilled off under reduced pressure, a small amount of ethanol was added to the residue, water was added, pH was adjusted to 2 with HCl, and the precipitated solid was collected by filtration and washed with water. Dried. Yield 539 mg.

Ii) The above solid (514 mg) was dissolved in N, N-dimethylformamide (5 ml) and Cs ₂ CO ₃ (422 mg) and Me were added.
I (0.089 ml) was added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added, the organic layer was washed 3 times with water, the solvent was evaporated, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ → CH ₂ Cl ₂ : Et).
Purification with OAc 4: 1) gave a compound of structural formula A (333 mg) and a compound of structural formula B (93 mg). The physical properties of these compounds are shown below.

Amp: 216-218 ° C. NMR: δ Solvent (CDCl ₃ ) 1.17 (3H, t, J = 7.0Hz) 3.39 (1H, q, J = 7.0Hz) 3.89 (1H, d, J =
14.3Hz) 4.41 (3H, s) 4.83 (1H, d, J = 14.3Hz) 4.83 (1H, d, J = 1.5Hz) 6.74-6.81 (2H, m) 7.44-7.54 (1H, m) 7.64 (2H , d, J = 8.4Hz)
7.71 (1H, s) 7.75 (1H, s) 8.14 (2H, d, J = 8.4Hz)

B mp: 169-171 ° C. NMR: δ solvent (CDCl ₃ ) 1.17 (3H, d, J = 7.1Hz) 3.42 (1H, q, J = 7.1Hz) 3.88 (1H, d, J =
14.1Hz) 4.22 (3H, s) 4.83 (1H, d, J = 14.1Hz) 4.95 (1H, d, J = 1.5Hz) 6.75-6.82 (2H, m) 7.44-7.55 (1H, m) 7.70-7.78 (6H, m)

Example 59 Structural formula

[0393]

[Chemical 117]

Production of compound A represented by and compound B of its diastereomer.

A procedure similar to that described in Example 57 is used except that 2- (4- (1,2,3-triazol-2-yl) is used instead of 2- (4cyanophenyl) acetyl chloride.
The desired product was obtained using phenyl) acetyl chloride.
The physical properties of these compounds are shown below.

Amp: 198-199 ° C. NMR: δ Solvent (CDCl ₃ ) 1.16 (3H, d, J = 7.1Hz) 3.39 (1H, q, J = 7.1Hz) 3.89 (1H, d, J =
14.1Hz) 4.83 (1H, d, J = 14.1Hz) 4.85 (1H, s) 6.72-6.80 (2H, m) 7.4
4-7.55 (1H, m) 7.64 (2H, d, J = 8.6Hz) 7.72 (1H, s) 7.76 (1H, s) 7.83 (2H,
s) 8.08 (2H, d, J = 8.6Hz)

B state: solid NMR: δ solvent (CDCl ₃ ) 1.58 (3H, d, J = 7.0Hz) 3.46 (1H, q, J = 7.0Hz) 4.67 (1H, d, J =
13.9Hz) 4.85 (1H, d, J = 1.3Hz) 5.03 (1H, d, J = 13.9Hz) 6.42-6.48 (1
H, m) 6.61-6.67 (1H, m) 6.93-6.99 (1H, m) 7.14 (2H, brd, J = 8.6H
z) 7.75 (2H, s) 7.76 (1H, s) 7.80 (2H, brd, J = 8.6Hz) 7.86 (1H, s)

Experimental Example A group of 5 ICR mice each was infected with Candida albicans MCY8622 strain (2 × 10 ⁶ cfu / mouse) via the tail vein. After 1 hour, mouse 1kg
Therefore, 2.5 mg or 10 mg of the compound shown in Table 1 was orally administered. Observe for 7 days, calculate the average number of survival days,
It was used as an index of antifungal activity in vivo.

[0399]

[Table 1]

[Table 2]

[Table 3]

[Table 4] It constitutes Table 1.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] August 10, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 5

[Correction method] Change

[Correction content]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 6

[Correction method] Change

[Correction content]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 403/10 249 413/06 249 413/10 249 417/06 249 417/14 213 249 513/04 343 (72) Inventor Akihiko Tsuruoka 3-19-1-2-203 Azuma, Tsukuba-shi, Ibaraki (72) Inventor Satoshi Tsukada 9-7 Inari-mae, Inari-mae, Tsukuba-shi, Ibaraki 406 (72) Inventor Yanagisawa 2-23-5 Amakubo, Tsukuba City, Ibaraki Prefecture Maison Gakuen 302 (72) Inventor Itoyozawa 527-63 Kamihirooka, Tsukuba City, Ibaraki Prefecture

Claims (12)

[Claims] 1. A compound represented by the general formula (1): [Wherein R ¹ and R ² represent the same or different halogen atoms or hydrogen atoms, R ³ represents a hydrogen atom or a lower alkyl group, and r and m may be the same or different and each represents 0 or 1; Means, A means N or CH, W may have one or more substituents, and N,
S and O means an aromatic ring which may have one or more heteroatoms selected from S and O or a condensed ring thereof, X may have one or more substituents, and N, S and O An aromatic ring that may have one or more heteroatoms selected from among, an alkanediyl group that may have one or more substituents, an alkenediyl group that may have one or more substituents, or It means an alkynediyl group optionally having one or more substituents, and Y is a formula —S—,>SO,> SO ₂ ,> C.
= S,> C = O, -O -,> N-R 6,> C = N-OR
⁶ or (CH ₂ ) _j- (wherein R ⁶ represents a hydrogen atom or a lower alkyl group, and j represents an integer of 1 to 4)
Means a group represented by, Z is a hydrogen atom, a halogen atom,
Lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, hydroxyl group, thiol group, nitro group, cyano group, lower alkanoyl group, 1
The phenyl group optionally having the above substituents, the phenoxy group optionally having one or more substituents, the imidazolyl group optionally having one or more substituents, and the one or more substituents It means a triazolyl group which may have one, a tetrazolyl group which may have one or more substituents, or an amino group which may have one or more substituents. However, r =
Except when m = 0, W is a thiazole ring, R ³ is a methyl group, and Z is a hydrogen atom. ] The compound or its acid addition salt represented by these. 2. The compound represented by the general formula (1) according to claim 1, wherein W is a compound represented by the following formula: (In the formula, Q means S, O, and = CH ₂ , and T is = CH-,
= N- or = N ⁺ -O ^- means, Ring E has the formula N, S, and optionally having one or more heteroatoms selected from the group consisting of O means also aromatic ring) in Means a group selected from the group consisting of the groups shown, each X being of the formula: (Wherein, U is = CH -, = N-or = N ⁺ -O ^- means, R ⁴ and R ⁵ are the same or different, represents a hydrogen atom or a lower alkyl group, respectively, n represents 0 or 1)
A group selected from the group consisting of groups represented by
Are the respective formulas: (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group,
j represents an integer of 1 to 4), and Z is of the formula: [Wherein V represents ═CH—, ═N— or> N ⁺ —O ⁻ , R ′ represents a lower alkyl group, R ⁷ and R ⁸ are the same or different, and each represents a hydrogen atom or a lower alkyl group. represents a group R ⁹ is halogen, -CN, 1,2,3-triazolyl, 1,2,4-triazolyl group, -S (O) _n R ¹⁰ and -N- (R ¹⁰⁾ ₂ (wherein , R ¹⁰ is a hydrogen atom or a lower alkyl group, and n is 0 or 1), and R ¹⁰ is a group selected from the group consisting of The compound or an acid addition salt thereof. 3. Of the groups represented by claim 2, The groups represented by are respectively represented by the formula: The compound of claim 2 or an acid addition salt thereof, which is a group selected from the group represented by: 4. Each has a structural formula: [Chemical 9] [Chemical 10] [Chemical 11] [Chemical 12] [Chemical 13] Embedded image [Chemical 15] Embedded image [Chemical 17] Embedded image [Chemical 19] Or a acid addition salt thereof. 5. An optically active (2R, 3S) -2- (2,2
4-difluorophenyl) -3-methyl-2- (1H-
1,2,4-triazol-1-yl) methyloxirane and diethylaluminium cyanide are reacted to give an optically active (2R, 3S) -3- (2,4)
-Difluorophenyl) -3-hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl)
Method for producing butyronitrile. 6. An optically active (2R, 3S) -2- (2,2
4-difluorophenyl) -3-methyl-2- (1H-
1,2,4-triazol-1-yl) methyloxirane and ytterbium cyanide are reacted, which is optically active (2R, 3S) -3- (2,4-difluorophenyl) -3-hydroxy -2-methyl-4-
A method for producing (1H-1,2,4-triazol-1-yl) butyronitrile. 7. The formula: embedded image (Wherein A, R ¹ , R ² and R ³ are as defined in claim 1) and a compound of the formula: (In the formula, Hal is Br or Cl, and X, Y, Z, r
And m are as defined in claim 1) and are reacted with a compound of formula: (In the formula, W is a substituted thiazole ring, A,
R ¹ , R ² , R ³ , X, Y, Z, r and m are as defined above) or a method for producing an acid addition salt thereof. 8. The formula: A compound represented by the formula: wherein A, R ¹ and R ² are as defined in claim 1; (Wherein D is a group consisting of a substituted or unsubstituted nitrogen-containing 5-membered heterocycle or a condensed ring thereof, and Z is H or CH ₃ ). The formula: (In the formula, A, R ¹ , R ² , R ³ , X, Y, Z, r and m
Is as defined in claim 1 and W is a group consisting of a substituted or unsubstituted nitrogen-containing 5-membered heterocycle or a condensed ring thereof, or a method for producing an acid addition salt thereof. 9. The formula: embedded image And a compound of the formula: By reacting with a compound represented by the formula: wherein R ³ , X, Y, Z, r and m are as defined in claim 1. (In the formula, W is a group consisting of a substituted or unsubstituted hetero ring or a condensed ring thereof, and A, R ¹ , R ² , R ³ ,
X, Y, Z, r and m are as defined above)
A method for producing a compound represented by or an acid addition salt thereof. 10. The formula: embedded image (In the formula, R ¹ , R ² , R ³ , W, X, Y, Z, r and m
Is as defined in claim 1) and a compound represented by the formula: metachloroperbenzoic acid and then 1,2,4-triazole sodium salt or 1,3-imidazole sodium salt. [Chemical 30] (Wherein A, R ¹ , R ² , R ³ , W, X, Y, Z, r and m are as defined above) or a method for producing an acid addition salt thereof. 11. A compound represented by the general formula (1): [Wherein R ¹ and R ² represent the same or different halogen atoms or hydrogen atoms, R ³ represents a hydrogen atom or a lower alkyl group, and r and m may be the same or different and each represents 0 or 1; Means, A means N or CH, W may have one or more substituents, and N,
S and O means an aromatic ring which may have one or more heteroatoms selected from S and O or a condensed ring thereof, X may have one or more substituents, and N, S and O An aromatic ring that may have one or more heteroatoms selected from among, an alkanediyl group that may have one or more substituents, an alkenediyl group that may have one or more substituents, or It means an alkynediyl group optionally having one or more substituents, and Y is a formula —S—,>SO,> SO ₂ ,> C.
= S,> C = O, -O -,> N-R 6,> C = N-OR
⁶ or (CH ₂ ) _j- (wherein R ⁶ represents a hydrogen atom or a lower alkyl group, and j represents an integer of 1 to 4)
Means a group represented by, Z is a hydrogen atom, a halogen atom,
Lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, hydroxyl group, thiol group, nitro group, cyano group, lower alkanoyl group, 1
The phenyl group optionally having the above substituents, the phenoxy group optionally having one or more substituents, the imidazolyl group optionally having one or more substituents, and the one or more substituents It means a triazolyl group which may have one, a tetrazolyl group which may have one or more substituents, or an amino group which may have one or more substituents. However, r =
Except when m = 0, W is a thiazole ring, R ³ is a methyl group, and Z is a hydrogen atom. ] The pharmaceutical composition which consists of the compound or its acid addition salt represented by these, and a pharmaceutically acceptable salt. 12. The pharmaceutical composition according to claim 11, which is an antifungal agent.