WO1986002927A1

WO1986002927A1 - 1,2,4-thiadiazole derivatives

Info

Publication number: WO1986002927A1
Application number: PCT/JP1985/000617
Authority: WO
Inventors: Daigaku Takiguchi; Saburo Kano
Original assignee: Nippon Soda Co., Ltd.
Priority date: 1984-11-08
Filing date: 1985-11-06
Publication date: 1986-05-22
Also published as: AU5067985A

Abstract

Compounds represented by formula (I), wherein R represents hydrogen, halogen, C1-4 alkyl, trifluoromethyl, phenyl or C1-4 alkoxy, n represents 0,1 or 2, A represents formula (II), wherein X represents halogen or optionally halogen-substituted C1-4 alkyl, m represents 0,1 or 2, B represents CH, N or (III), W represents -O-, formula (IV) wherein r3, r4, r5, r6, r7, and r8 each represents hydrogen, hydroxy or C1-4 alkyl, k and j each represents 1, 2, or 3, l represents 0 or 1, Q represents aryl such as substituted phenyl, substituted pyridyl, etc., E and D each represents CH, N or formula (III) (provided that E and D do not represent N or formula (III) at the same time), and r1 and r2 each represents hydrogen, halogen or C1-4 alkyl, and Y represents O, CH2, S or SO2, provided that symbols $(1,5)$ between positions 1 and 2 and between positions 3 and 4 in the Y-containing tricyclic system each represents a single or double bond have antifungal and antiprotozoan effects against candasis, trichomoniasis, mycosis, etc.

Description

Specification

. 1,2,4-thiadiazol derivative Technical field:

The present invention relates to a novel 1,2,4-thiadiazole derivative having a bactericidal and protozoalicidal action against pathogenic microorganisms such as candidiasis, trichomoniasis, and dermatophytosis, and a method for producing the same. Background art

A compound similar to the compound of the present invention has the general formula

(In the formula, r represents a hydrogen atom, a chlorine atom, a methyl group or a methoxy group.) It is known that the compound represented by the formula has a bactericidal action. [Japanese Patent Publication No. 37-Π997, Japanese Patent Publication No. 38-25382, Pharmaceutical Magazine 88, 1437-49 (1968), etc.]

However, these known compounds showed primary irritation to the skin, and could not be put to practical use as a fungicide. Formula:

〇〉-A compound represented by CF ₃ has been proposed (JP-A-51-61370), but has not yet been put into practical use. -Disclosure of invention:

The present invention has the general formula

R

N -S (0) n one A C I

,

{Wherein, R represents a hydrogen atom, a halogen atom, _1-4 alkyl group, Application Benefits Full Affairs Lome butyl group, a phenyl group or a Ct～ ₄ § alkoxy group, '

n is 0, 1 or 2;

A is a group represented by the formula ^Q , a group represented by the formula, or a group represented by the formula:

Wherein, X is optionally substituted with a halogen atom or a halogen atom (^ _1-4 alkyl group, m is 0, 1 or 2,

O

†

B represents CH, N or N,

W is 〇 N ■ C

kr ⁸ O

I II

— O ~~ e or N— C

^{^{Wherein, r 3, r 4, r}} 5, r 6, r 7 and r ⁸ each represent a hydrogen atom, human Dorokishi group or _{C t} ~ ₄ alkyl groups k and j Waso respectively! : Indicates 2 or 3. )

Represents 0 or 1 and OCH (r ⁹ ) i

^Q is a group represented by Formula 1,

^ -G 0

(Where G is CH, N or N,

r ⁹ may be substituted with a halogen atom, a _4- anolealkyl group, a C 1-4 alkoxy group,

Ten

Wherein S0 ₂ N <(r ¹⁰ and r ¹¹ represents a hydrogen atom or _1-4 alkyl group.) In the depicted Ru group of the formula - S0 ₃ M (M: A Luke Li metal) in represented Ru group, halogen Atom or nitro group, i represents 0, 1 or 2. ) Group represented by the formula

A group represented by the formula (CH ₂ ) h,

(In the formula, h represents 3, 4 or 5.)

C ₃ - ₈ consequent opening alkyl or

A group represented by the formula N

(In the formula, B, n and R have the same meanings as described above.)

0

T

E and D represent CH, N or N, respectively (however, E and D

0.

D is not simultaneously N or N. )

r ¹ and iota · ² are each a hydrogen atom, a halogen atom or an-alkyl group Y represents a 0, CH _2, S or S0 _2.

However, between 1 and 2 and between 3 and 4 in the three-ring system containing Y represents a single bond or a double bond, respectively. ] And a method for producing the same.

BEST MODE FOR CARRYING OUT THE INVENTION

(1) The present invention can be produced according to the following reaction formula. R base

[Π] [I] Oxidizing agent

R N

N S (0) n "-A

, S,

C I]

(In the formula, Hal represents a halogen atom, η represents 1 or 2, and the condensation reaction between the compound represented by the general formula (Π) and the compound represented by the general formula (ΠΙ) is performed in the presence of a base in a solvent. -Between 20'C and 150, preferably between 10'c and 80'c for 10 minutes to several roars.

Examples of the base to be used include alkali metal hydroxides such as sodium hydroxide and sodium hydroxide, sodium hydride, alkali metal hydrides such as hydrogenation sodium, and the like. Usual bases such as alcoholic alcohols such as sodium methylate and tertiary amines such as triethylamine can be mentioned.

The solvent used depends on the type of base, such as ice, alcohols, benzene, tonolenene, xylene, DMF, DMSO, ether, THF, dioxane and HMPA. Solvents can be used.

By oxidizing the compound represented by the general formula [I] ′ as necessary, a compound represented by the general formula [Π] 〃, that is, a compound represented by the general formula [I], wherein n is 1 or 2 is obtained.

As the oxidizing agent, organic peracids such as perbenzoic acid and hydrogen peroxide can be used. The reaction is carried out in a solvent when synthesizing a compound of the general formula [I] wherein T1 is 1 in a solvent. The reaction is performed with 1.2 equivalents or less of the compound represented by

'The compound represented by, 2 ¹ using equivalent or more, to 120 at -20' formula (I) the oxidizing agent when n is combining two compounds in the general formula (I) between the c To carry out the reaction. When n is 1 or 2 ', the solvent used depends on the type of oxidizing agent, such as water, organic acids such as acetic acid, and ketones such as clog form, methylene chloride, and acetate. And the like are appropriately selected.

After completion of the reaction, the desired product can be obtained by performing ordinary post-treatment.

(2) The compound of the general formula [I] wherein ri is 2 can also be directly produced according to the following reaction formula.

+ T0 ₂ S-A

C Π]

R

[I Γ '

(In the formula, T represents an alkali metal atom.)

(3) In the general formula [I], the compound can also be produced according to the following reaction formula depending on the type of the substituent represented by Α.

r ¹⁰

When the groups represented by S0 ₂ N <or formula _{S0 3 M - (a) r} 9 has the formula:,

~-N Xm, ((r "

N ~ S (0) one S0 _Z C £

, B

(b) When r ⁹ is a nitro group:

The structure of the compound obtained in this way was determined from the results of analysis of IR, NMR, MASS, spectrum, and the like.

Next, the present invention will be described in more detail by way of examples.

Example 1 Compound No. 89

After cooling 20 m of ethanol with ice and stirring, add 28% sodium chloride liquid methanol solution 2.9 g (15 min monole), 41 g (phenoxy) thiol nor 3.0 g (14.8 mi) 2.5 g (15 mmol) of 5-bromo-1,2, -thiadiazole and kept under ice-cooling for 30 minutes, then kept at 50'c for 2 hours The reaction product was concentrated to dryness, and the residue was extracted by adding 50 mL of benzene and 30 mL of a 5% aqueous sodium hydroxide solution. The benzene layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and 5-[4-1 (phenoxy) phenylthio]-1,2, 4-thiadiazole 4.0 g (14 mmol, Yield 94%). To 4.0 g (14 mmol) of the obtained compound was added 50 mL of a form of black mouth and 9.lg (37 mmol) of 70% methanol perbenzoic acid, and the mixture was heated and refluxed for 4 hours. The reaction was cooled on ice, 100 ml of 5% sodium hydroxide was added, and the mixture was stirred and separated.The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove chloroform. I left. The obtained crude crystals were recrystallized from n-hexane-toluene (6: 1 ol) to give 51 g ('41 phenoxybenzensulfonyl) -11,2,4-thiadiazole 3.0 g (67% yield). Mp ^{87- 89 'c, H 1 -} MR (100 MHz, CDC 3); 57.2 ~ 8.4ppm (m, 9

H), 9.0 ppm (s, 1H), Mass; m / e 318 (M +) Example 2 Compound No. 91

CH

Mix 2.9 g (15 mmol) of 28% sodium hydroxide solution with 30 m of ethanol, and add 4-[4-1 (trifluormethyl) phenol B) 4.05 g (15 mmol) of benzenethiol was added and stirred, and at room temperature, 2.0 g (15 mmol) of 5—Clonole 3-methyl-1,1,2-, 4-thiadiazole was added. Was. After the exotherm ceased, the mixture was heated and kept at 50 ° C for 1 hour. The reaction product was concentrated under reduced pressure, water and benzene were added to the residue, and the mixture was extracted. The benzene layer was washed with 10% sodium hydroxide and water, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. Chill-1 5-[4-(4-Trifluoromethylphenoxy) phenylthio]-1,2,4-thiadiazole 4.9 g was obtained. Dissolve 3.5 g (9.5 mmol) of this compound in 30 m of chloroform and add 5. lg (purity 80%, 23.8 mmol) of metachloroperbenzoic acid to the mixture under stirring. For 1 hour and then heated and maintained under reflux for 4 hours. The reaction product was cooled, added with 20 g of ice and 20 mL (50 mmol) of a 10% aqueous sodium hydroxide solution, and extracted by shaking. The black hole form layer was separated, washed twice with cold water, dried over anhydrous magnesium sulfate, and the black hole form was distilled off under reduced pressure. 3 — Dachiru 5 — [4 — (4-Trifluoromethyl benzene) benzenesulfonyl] 1, 1, 2, 4 — 3.8 g of thiadiazole crystals were obtained. This was recrystallized from cyclohexane to obtain a purified product. Melting point 80.5-81.5, TLC; silica gel-benzene single spot, H ¹ —NMR; 52

7ppm (s ヽ 3H), 7.2-8.3ppm (m.8H)

Example 3 Compound No. 93

S0 ₃ Na

7.0 g (22 mmol) of the compound obtained in Example 1 was dissolved in 30 m of 1,2-dichloropentane, and 7 g of 25% fuming sulfuric acid was added thereto at 0 ° C with stirring for 0 min. . It was kept on ice for 1 hour, then heated and kept at 15'c for 1 hour. After distilling off 1,2-dichloroethane under reduced pressure, 40 g of ice was added to the obtained tar-like substance, followed by stirring and filtration to obtain a clear aqueous solution. This was cooled on ice and neutralized with a 20% aqueous sodium hydroxide solution. Crystals of sodium salt were deposited. The crystals are separated by filtration, washed with a saturated saline solution, then washed with acetate, dried under reduced pressure, and dried under reduced pressure to give a colorless powder of 4—C 4-(1,2,4-thiadiazole-5-yl) sulfur Ruphonyl] phenoxybenzensulfonate sodium (7.16 g) was obtained. Decomposition point 260 'c or higher. Yield 77.5%. Example 4 Compound No. 94

To 4.2 g (10 mmol) of the compound obtained in Example 3, 4 g of phosphorus oxychloride was added, and the mixture was heated to 75'c and kept for 1 hour and 30 minutes. I left. The residue was diluted with 15 g of dioxan. A mixture of 3 g (50 mmol) of n-proviramine and 30 g of dioxane was cooled on ice, and the diluted solution was gradually added thereto with stirring. After keeping at room temperature for 1 hour and 30 minutes, the mixture was concentrated under reduced pressure, and the obtained residue was extracted by adding water and ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. 5- (4- [4— (Nn-propylsnorefhamayl) phenoxy] benzenesulfonyl] — 1,2,4-thiadiazole 3.

0 g was obtained. This was purified by column chromatography [silica gel, silica gel form-ethyl acetate (9: 1)] to obtain purified crystals. H ¹ -NMR (100 MHz.

_{CDC ί 3); <5 0.8ppm} (.. T, 3H), 1.5p P m (m 2H), 2.9 ppm (t, 210, 7 ~ 8.2ppm (m 8H), 8.7ppm (s, 1

H), Mass; m / e 439 (M ⁺ ) Example 5 Compound No. 95

4.4 g of 97% sulfuric acid was added to 4 g (38.6 mmol) of 61% nitric acid under ice-cooling, and the mixture was cooled to -5 and stirred, and 12.0 g (6.2 mmol) of the compound obtained in Example 1 was added thereto. ) And kept at the same temperature for 30 minutes and then at 25'c for 30 minutes. Ice and ethyl acetate were added to the reaction product, followed by extraction and liquid separation. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crude oil yield 2.3 g. This was purified by column chromatography [Shigeru gel, benzene-ethyl acetate (20: 1)], and purified by 5- [4- (4-troenoxy) benzene]. Sulfonyl] 1,2,4-thiadiazole was obtained. Melting point 119-120 ° C, H ¹ -MR (100 MHz. CDC i ₃ ); δ Ί to 8.3 PP «I (m, 8 Η), 8.65 ppm (s, 1H), Mass; m / e 363 (M + )

Example 6 Compound No. 11

I 4

6- (4—Chronolefoxy) 1 3—Pyridine Chiral 1.7 g (7 mimol) in ethanol 30 m and 28% sodium methylate metabolite Add 1.42 g of sodium chloride solution (7 millimoles of sodium methylate), stir, cool to 0, and add 1.16 g (7 millimoles) of 5-bromo-1,2,4-thiadiazole Was added. twenty five. After holding at c for 1 hour, it was kept at 50'c for .1 hour. '

The reaction mixture was dried I under reduced pressure, and the residue was extracted by adding water and chloroform.The mouth-form phase was washed with water, dried over anhydrous magnesium sulfate, and chloroform was distilled off under reduced pressure. Then, 5 g of C 6-(4 chlorophenoxy) — 3 —pyridylthio] — 1, 2, 4 — 1.8 g of an oil of thiadiazole was obtained.

5 — [6 — (4-chlorophenoxy) 1-3-pyridylthio] 1, 2, 4 — Thiadiazole 1,8 g (6.2 mimol) is dissolved in 50 m of clog form. 0. Add 4.6 g (purity 70%, 18.6 mmol) of methanol perbenzoic acid with cooling to c and stir, keep at 25 for 1 hour, then keep at 40'c for 1 hour and 30 minutes 1 δ

Ivy

The reaction mixture was cooled, and 50 g of water and a 48% aqueous sodium hydroxide solution were added for extraction.2 g of the mixture were extracted, and the clot-form layer was washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure. (B) After distilling off form, 5 — [6 — (4-chlorophenoxy) — 3 — pyridylsulfonyl] 1, 1, 2, 4 —thiadiazol ±.

a HH

1.6 g was obtained. This was recrystallized from benzene-n-hexane (1: 1 vol). _mp 117-119'C Mass; m / e 353 (M +) Example 7 Compound No. 138

1,4 g of 4'-methyl biphenyl 4 -thiol was dissolved in 30 m of ethanol, cooled to 110 ° C, and 1.4 g of 28% sodium methoxide was added. To this was added dropwise 1.3 g of 5-bromo-1,2,4-thiadiazole in 10 m of ethanol. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, and further heated under reflux for 10 minutes. Ethanol was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (benzene-hexane), and 5-(4 'methionolebifueryl 4-dithio) — 1,2,4 — 800 rag of thiadiazole (40% yield). mp97—98 ° C i 6

Example 8 Compound No. 52

5 — (4'-methyl-biphenyl-41-ylthio) 420 g of 1,1,2,4-thiadiazo-1-nore was dissolved in 30 m of holomade and cooled to 10'C. To this was added 380 of metachloroperbenzoic acid with 70% purity. The mixture was stirred for 2 hours. Thereafter, the mixture was roughly stirred at room temperature for 1 hour. The black mouth form layer was washed with a 5% aqueous solution of sodium hydroxide, dried over anhydrous magnesium sulfate, and the black mouth form was distilled off. The residue was purified by silica gel chromatography to obtain 5 — (4'-methyl biphenyl 2- 4-islunoreffininole) — 1,2,4 — thiadiazole 300 Was. (Yield 70%) mp 140-141 Example 9 Compound No. 140

10.7 g of 4-chloronaphthalene-1-thiol was dissolved in 100 mJ2 of ethanol and cooled to 0'C. To this was added llg of 28% sodium methylate. To this, 9.4 g of 5-bromo-1,2,4-thiadiazole dissolved in 30 m of ethanol was dropped. After the completion of the dropwise addition, the mixture was heated under reflux for 30 minutes. Ethanol was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 12 g of 5- (4-chloronaphthyl 1-dithio) —1,2, -hydroxyazole. . (Yield 78%) mp 103-104 'C

Based on the above Examples, Table 1 shows typical examples of the compounds of the present invention produced in the same manner.

O Z6S / 98l) d / d0 / 8f0s 9

m

cm

οε

Dl / df8 / s>

〇

―,

Three

ΰάdr / s / s

§ 8A) -lddf / 8s,

CO

Ο

Re dldr / S / S 9

m

Co

s OM s / 98】 ldf / d80s / _

Bird

oo t-rH

1 in

H

ϋ

Industrial applicability:

The compounds of the present invention are effective against pathogenic microorganisms such as candidiasis, trichomoniasis, dermatophytosis, etc., and exhibit an antibacterial activity superior to known compounds, particularly against candidiasis, and Skin No primary irritation is expected, and development as an antifungal agent is expected.

Some test examples relating to the efficacy of the compound of the present invention and the primary irritancy of the skin are shown.

Test example 1

Using Trichophyton mentagrophytes IFO 6202 as the test bacterium, the antibacterial activity was measured by the agar plate dilution method using a microplate. Was. That is, the test compound was dissolved in DMS0 to prepare a 100-fold solution of the final test concentration, and the mixture was added to the Sabrobe dextrose agar medium heated at 50 to 1: 100 and stirred well. m to My Plate [Fa Icon 3047

(Registered trademark)]. Then, after the addition of 0. 1 m of the test bacterial solution and (about ¹⁰⁶ spores偭No m &) to solidified Saburobu de sugar agar surface, at 27'C

After culturing for 7 days, the minimum inhibitory concentration (MIC ug / mH) was determined. The results are shown in Table 2. • i Compound number MIC β g / m &

11 丄 .25

18 0.625

19 0.625

25 0.625

26 1.25

34 1.25

35 丄 .25

36 丄, 25

37 0.625

38 1.25

39 1.25

50 0.625

51 0.625

52 0.625

54 1.25

59 0.625

60 0.625

61-0.625

63-1.25

73 0.625

78 1.25

90 0.625

91 1.25

99 1.25 Reference compound * 0.625

* Clotory masonole

Test example 2

Using Candida albicans IFO 0579 as a test bacterium, the antibacterial activity was measured by an agar plate dilution method using microplates. That is, the test compound was dissolved in DMS0 to prepare a 100-fold solution of the final test concentration, and the mixture was added to a Sabouraud glucose agar medium heated to 50% in a ratio of 1: 100, and the mixture was stirred well. Then, 1 m of the microplate was used for microplate [Falcon 3047 (registered trademark)].

(Φ15M). Then, after adding 0.1 mt (about 10 ^ft偭 m &) of the test bacterial solution to the surface of the solidified sublobe dough sugar agar medium, culture the cells at 27'c for 7 days to obtain the minimum inhibitory concentration · (MIC μg / m &) was determined.

Table 3 shows the results.

Test example 3

The compounds were applied to Polyethylene glycol ointment (400 60% and 1540 40%) at 1% and 5 10%, applied to New Zealand white heron shaved skin, Draze, JH (J. pharm. Exp. Therap. 82, 377-390, 1944) to determine the primary stimulus rate (PII).

Table 3 shows the results. Table 3

Control compound 1 *

C & (* 37 * -17997)

Control compound 2

CF ₃ (JP 56-61370)

Claims

The scope of the claims

l. General formula (0) n A

{Wherein, R represents a hydrogen atom, a halogen atom, (^ - ₄ alkyl group, Application Benefits Funoreo ii main Chinore group, full et alkenyl group or _1-4 § o †

The alkoxy group is

n is 0, 1 or 2,

A is a group represented by the formula and Q,

Expression-Expression

,

Wherein, X is a halogen atom or a C androgenic ~ which may be substituted with atoms ₄ alkyl group,

m is 0, 1 or 2,

B represents CH, N or N,

W is one 0——, one N—,

k

4.2

r ⁶ r ⁸ 0

0 ■ C Chi or N-C-a, r ⁷

(In the formula, r ³ , r ⁴ , r ⁵ , r ⁶ r ⁷ and r ⁸ each represent a hydrogen atom, a hydroxy group or an alkyl group, and k and j each represent 1, 2 or 3, respectively.)

£ is 0 or 1,

(r ⁹ ) i

Q is a group represented by the formula:

(Where G is CH, N or N,

r ⁹ is optionally substituted with a halogen atom 'good C _t ~ ₄ A Crequi Kure group, Anoreko key sheet group,

_ I 0

Formula S0 ₂ N '<(r ¹⁰ and r ¹¹ are each hydrogen

r represents a 1 I atom or a 44 alkyl group. ) In represented Ru group, wherein one S0 ₃ f1 (M: alkali metal) in represented Ru group, a halogen atom or a double filtrated group, i is represents 0, 1 or 2. ) A group represented by the formula:

A group represented by the formula H "C factory (pH ₂ ) h,

(Equation Φ, h indicates 3, 4 or 5.)

C ₃ - ₈ consequent opening alkyl or A group represented by the formula

(In the formula, B, n and R have the same meanings as described above.)

0

ΐ

Ε and D represent CH, N or N, respectively (however, E and

0

†

And D are not N or N at the same time. )

r ¹ and r ² are each a hydrogen atom, a halogen atom or a C _t ~ * alkyl group Y represents a 0, CH _2, S or S0 _2. However, between 1 and 2 and between 3 and 4 in the three-ring system containing Y represents a single bond or a double bond, respectively. ]] The compound represented by these.

2. General formula al

(Wherein, R represents a hydrogen atom, a halogen atom, C, ~ ₄ alkyl group, Application Benefits Furuorome butyl group, phenyl group or C, and _1-4 § alkoxy group, Hal represents a halogen atom.) It expresses in Compound

General formula

HS (0) n 'one A

(Where n 'is 0 or 2, A represents a group represented by the formula represented by the formula Q, or a group represented by the formula:

Wherein, X is a halogen atom or a halogen atom may be substituted with _1-4 alkyl groups,

Hi is 0, 1 or 2;

B represents CH, N or N,

0

W is one 0—, — ~~ (C)-one

kr ⁸ O

O—— f C) —— or one N—C

(In the formula, r ³ , r ⁴ , r ⁵ , r ⁶ , r ⁷ and r ⁸ each represent a hydrogen atom, a hydroxy group or a 〜4 alkyl group, and k and j each represent 1, 2 or 3 respectively. Show. )

Represents 0 or 1,

Q is a group represented by the formula:

0

†

(Where G is CH, N or N

r ⁹ may be substituted with a halogen atom

Alkyl group, alcohol,

Ten

Formula S0 ₂ N <(r ¹⁰ and r ¹¹ are each hydrogen r ¹¹

Atom or (^ _1-4 alkyl group shown.) In the depicted Ru group, wherein one S0 ₃ M: group you express by (M alkali metal), a halogen atom or a double filtrated group,

i represents 0, 1 or 2. ) A group represented by the formula "0 丄〇]

Λ

A group represented by the formula ((^ H ₂ ) h, wherein h represents 3 ′, 4 or 5)

C ₃ - ₈ consequent opening alkyl or

A group represented by the formula

(In the formula, B, n and R have the same meanings as described above.)

0

†

E and D represent CH, N or N, respectively (however, E and D

0

T

And D are not N or N at the same time. ) r ¹ and r ^z each represent a hydrogen atom, a halogen atom or a C,-, alkyl group; and Υ represents 0, CH ₂ , S or SO ₂ .

However, between 1 and 2 and between 3 and 4 in the three-ring system containing Y represent a single bond or a double bond, respectively. The compound represented by the general formula (0) n'-ACI) characterized by reacting a compound represented by the formula (1) in the presence of a base:

(Wherein, R, n ′ and A have the same meanings as described above.)