WO1993002076A1

WO1993002076A1 - 1,2-dithiolane compound

Info

Publication number: WO1993002076A1
Application number: PCT/JP1991/000957
Authority: WO
Inventors: Yutaka Kanda; Tohru Fukuyama; Hiromitsu Saito; Katsushige Gomi; Kayo Nomura
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 1991-07-18
Filing date: 1991-07-18
Publication date: 1993-02-04

Abstract

A 1,2-dithiolane compound with antibacterial and cell growth inhibitory activities represented by general formula (I), wherein n represents an integer of 0 to 2; R1 represents OR3 (wherein R3 represents hydrogen or lower alkyl), NR4R5 (wherein R?4 and R5¿ may be the same or different from each other and each represents hydrogen, lower alkyl, alicyclic alkyl or benzyl), or α (wherein p represents an integer of 2 to 8); and R2 represents hydrogen or lower alkyl.

Description

Light

1, 2 —Dithiophene compound

Technical field

The present invention relates to 1,2-dithiolane compounds. This compound exhibits antibacterial activity and cell growth inhibitory activity, and is useful as an antibacterial agent and an antitumor agent.

Background technology

DC-107 is a substance produced by a microorganism belonging to the genus Streptomyces.

It is a compound having antibacterial activity against various bacteria and antitumor activity, and having the following structure disclosed in Japanese Patent Application Laid-Open No. H11-112988.

A compound having a 1,2-dithiolane skeleton, which exists as a partial structure of DC-107 and is considered to be essential for the expression of its activity, is expected as an antibacterial or antitumor agent Also, it can be used as a synthetic intermediate of DC-107.

Disclosure of the invention

The present invention provides a compound of the formula (I)

Wherein n is an integer from 0 to 2, R ¹ is OR ³ (where R ³ represents hydrogen or lower alkyl), NR ⁴ R ^S (where R ⁴ and R ⁵ are Identical or different, represents hydrogen, lower alkyl, alicyclic alkyl or benzyl) or N iCH ₂ ) p (where p represents an integer from 2 to 8), and R ² represents hydrogen or 1.2 dithiolane compound [hereinafter, referred to as compound (I)]. The same applies to compounds of other Shikin-ban.]

In the definition of formula (I), lower alkyl is straight-chain or branched alkyl having 18 carbon atoms, such as methyl, ethyl, propyl, isopπ-bir, butyryl, isobutyl, sec-butylyl, ert-butylyl, pentyl, isopentyl, hexyl, heptyl, octyl, etc. are aliphatic alkyls having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclobutyl. Including pentyl, cyclohexyl, cyclooctyl and the like:

Next, the production method of compound (I) will be described =

(Process 1)

(Wherein, R ² has the same meaning as described above, and R ^la represents a group excluding OH in the definition of)

A known method [Helv. Chim. Acta, 50, 798 (196)) or a compound obtained by esterifying or midifying a 4-oxo-12-pentenoic acid (Ha) synthesized according to the method. (D b) is obtained. (Process 2)

(Ha), (llb)

(Wherein, R ¹ and R ² are as defined above)

The compound (IE) is obtained by reacting the compound (（a) or (Πb) with a lithium salt of ethyl vinyl ether prepared from ethyl vinyl ether and t-butyllithium in an inert solvent. The lithium salt of ethyl vinyl ether is used in an amount of 1 to 5 equivalents to the compound (（a) or (Πb). As the inert solvent, tetrahydrofuran, dioxane, ether or the like is used alone or in combination. The reaction is usually performed at 180 to 0, and is completed in 30 minutes to 5 hours.

(Process 3)

(IV)

(Wherein, R ¹ and R ² are as defined above)

Compound (TV) can be obtained by reacting compound (m) with N-butene succinic acid imide (BS) in an inert solvent in the presence of water. NBS is used in an amount of 1 to 10 equivalents to the compound (EI). Water is used in an amount of 1 to 20 equivalents based on compound (II), but a large excess may be used also as a solvent. Inert solvents are acetonitrile, tetrahydrofuran, dioxane, water The reaction, which is used alone or as a mixture, is usually carried out in a range of 120 to 30 I, and is completed in 10 minutes to 3 hours.

(Step 4)

(Wherein, R ¹ and R ² are as defined above)

The compound (V) is obtained by reacting the compound (IV) with hydrogen sulfide in an inert solvent in the presence of a base. As the base, triethylamine 1,8-diazabicyclodecene (DBU), lithium carbonate or the like is used. Usually, 1 to 20 equivalents are used based on compound (IV). As the inert solvent, acetonitrile, tetrahydrofuran, dioxane, toluene, or the like is used alone or as a mixture. The reaction is usually carried out at 0 to 50: and is completed in 1 to 20 hours.

(Process 5)

(Wherein, R ¹ and R ² are as defined above)

Compound (VI) is obtained by reacting compound (V) with isopropyl nitrite in an inert solvent in the presence of a base. Bases include sodium methoxide, sodium hydride, potassium hydroxide, and triet. Chillamine or the like is used, and it is usually used in an amount of 1 to 20 equivalents based on the compound (V). Isoamyl nitrite is usually used in an amount of 1 to 20 equivalents based on compound (V). As the inert solvent, methanol, ethanol, acetonitrile, tetrahydrofuran or the like is used alone or as a mixture. The reaction is usually performed at 0 to 50 t, and is completed within 1 to 10 hours.

(Step 6)

(Wherein, R ¹ and R ² are as defined above, and X represents benzoyl, 2,6-dimethylbenzoyl or vivaloyl)

Reaction of compound (VI) with benzoyl chloride, 2,6-dimethylpentoxy J-Reck or Pinoro-Like mouth in an inert solvent in the presence of a base to give compound (W) Is obtained. As the base, pyridin, potassium t-butoxide, triethylamine or the like is used, and it is usually used in an amount of 1 to 30 equivalents to the compound (W). Benzoyl π-lide, 2,6-dimethylbenzoyl chloride or vino-mouth yl chloride is usually used in an amount of 1 to 30 equivalents to compound (VI). Inert solvents: Macromolecule form, methylene chloride, acetonitrile, tetrahydrofuran, etc. are used alone or in combination. The reaction is usually performed at 0 to 50, and is completed in 10 minutes to 5 hours.

(Process Ί)

(Wherein, tr, R ² and x are as defined above)

The compound (¥) is obtained by reacting the compound (¥) with sodium methethyl sulfide or lithium methyl sulfide in an inert solvent. The sodium sulfide or lithium ethyl sulfide is usually used in an amount of 1 to 30 equivalents to the compound. As the inert solvent, tetrahydrofuran, dioxane, acetonitrile, or the like is used alone or as a mixture. The reaction is usually performed at 0 to 50 t, and is completed in 10 minutes to 5 hours.

(Process 8)

(Wherein, R ¹ and R ² are as defined above)

The compound (I) is reacted with sodium ice sulfide in an inert solvent and subsequently reacted with iodine to obtain a compound (I) in which n is 0 among the compounds (I). The sodium ice sulfide and iodine are usually used in 1 to 30 equivalents to the compound. As the inert solvent, tetrahydrofuran, dioxane, acetonitrile, or the like is used alone or as a mixture. The reaction is usually performed between 0 and 50 t and ends between 10 minutes and 5 hours _:

(Wherein, R ′ and R ² have the same meanings as described above, and m represents 1 or 2.) The compound (la) is reacted with methanolic perbenzoic acid in an inert solvent to give the compound (I Wherein n is 1 and / or 2

(I b) is obtained. Oral metabenzoate is generally used in an amount of 1 to 10 equivalents to the compound (Ia), and in the case of 1 to 2 equivalents, when the compound in which m is 1 is used in excess of 2 equivalents or more, , And m is 2 are formed as main products. As the inert solvent, chloro-D-form, methylene chloride, tetrahydrofuran, dioxane, etc. are used alone or in combination. The reaction is usually carried out at a temperature of 120 to 50, and is completed in a time of 10 minutes to 5 hours.

After completion of the reaction in each step, if necessary, water, an acid, a buffer and the like are added to the reaction solution, and the mixture is extracted with a non-aqueous solvent such as ethyl acetate, chloroform, and ether. The extract is washed with water, saline, etc., dried over anhydrous sodium sulfate, etc., and the residue obtained after evaporating the solvent is purified by silica gel chromatography. Purify by chromatography, high-performance liquid preparative chromatography, recrystallization, etc.

After completion of the reaction in each step, it can be used in the next step without isolation and purification.

Table 1 shows the structures of representative compounds belonging to compound (I) and the compound names. Table 2 shows the structural formulas of the synthetic intermediates of the compounds shown in Table 1 and the compound No. Table 1

, 2 Compound number n R ¹

Table 2

Compound number Structural formula Compound number Rehearsal formula

P

Next, the pharmacological activity of the representative compound (I) will be described with reference to experimental examples.

Experimental example 1 Antibacterial activity against various bacteria

The antibacterial effect is obtained by dissolving 3 g of Bacto Tripton (manufactured by Difco), 3 g of meat extract, 1 g of yeast extract, 1 g of glucose and 16 g of agar in 1 ^ water. The measurement was performed by the agar dilution method using the prepared medium (PH 7). Table 3 shows the antibacterial activity of representative compounds in terms of the minimum inhibitory concentration (MIC).

M I C (g /)

Compound Spring Issue

C A P A

0. 1 8 0. 1 8

CA: Candida albicans ATCC 10231

PA: Pseudomonas aeruginosa Bin H No.1

Experimental Example 2 He La S ₃ cell growth inhibition test

9 6 hole microphone furnace data one plates He S ₃ cells 3 was adjusted to x 1 0 ⁴ pieces Zmi in舍Mu ME M medium 1 0% fetal bovine serum you and 2 mM glutaminase in to each Ueru of Dispensed by 0.1 π¾2 each. After culturing overnight at 37 ° C in a carbon dioxide incubator, 0.05 ml of the test compound appropriately diluted with the medium was added to each well. After culturing the cells for 1 hour in a carbon dioxide incubator, remove the culture supernatant, wash once with phosphate-buffered saline (PBS), and add 0.1 lmfi of fresh medium to each well. In addition, the cells were cultured in a carbon dioxide incubator at 3 C for 72 hours. After removing the culture supernatant, a medium containing 0.02 neutral red was added to each well in 0.1 meli portions, and the cells were cultured in a carbon dioxide incubator at 37 t for 1 hour to stain the cells. After removing the culture supernatant, the cells were washed once with physiological saline, and the dye was extracted with 0.001N hydrochloric acid 30% ethanol. The absorbance at 550 nm of the extract was measured using a micro-mouthed plate reader. By comparing the absorption of untreated cells and cells treated with a known concentration of the drug, the concentration of the drug that inhibits cell growth by 50% was calculated, and this was calculated as IC ₅ . And

IC _{5 for} representative compounds. Are shown in Table 4.

Compound No. IC _5. (UM)

4 3. 4 1 Examples and reference examples of the present invention are shown below. The physicochemical properties shown in the following Examples and Reference Examples were measured using the following instruments =

R JEOL FX-100 (100MHz)

Bull Ichiichi AM-400 (400MHz)

MS Hitachi M-80B

I JASCO IR-810

In addition, as for the gel of gel force, Wako Pure Chemical Industries Co., Ltd.'s Co-Igel® C-200 was used. = In the following Examples and Reference Examples, the usual post-treatment means the following post-reaction treatment- After completion of the reaction in each step, if necessary, add water, an acid, a buffer, etc. to the reaction solution, and extract with a water-insoluble solvent such as ethyl acetate, chloroform, ether. The extract is washed with water, saline, etc., dried over anhydrous sodium sulfate, etc., and the solvent is distilled off.

Example 1 Synthesis of Compound 1

Compound e (35 mg) obtained in Reference Example 5 was dissolved in 1.5 ml of tetrahydrofuran, 20 mg of sodium hydrosulfide was added, and the mixture was stirred at room temperature for 1 hour. A solution of iodine in tetrahydrofuran was added to the reaction mixture. After filtering off the insolubles, the product was purified by thin-layer chromatography to obtain 24 mg of Compound 1 (yield: 5%).

Si -.MS m / z; 334 ( H) - 'HXMR (CDC1 3, 400 Ηζ) δ ppm; 5.64 (br, 1Η), 3.80 (m, 1Η), 2.73 (d, J = 14.3Hz, 1H) , 2.57 (d, J = 14.3Hz, 1H), 1.95— 1.10 (m, 10H), 1.57 (s, 3H), 1.2 (s, 3H)

IR (KBr) cm- ¹ ; 3350, 2940, 2860, 1700, 1630, 1570, 1450, 1360, 1190, 1060, 950, 895, 805

Example 2 Synthesis of Compound 2

To a chloroform solution im 1 of compound 1 (10 mg, 0.033 tnmol) was added 8 mg (? 0, 0.033 mtnol) of benzoic acid at 0, and stirred for 10 minutes. Through After usual work-up, the solvent was distilled off under reduced pressure to give 10 mg of compound 2.

(95% yield). Compound 2 was a 4: 3 mixture of the stereochemistry of sulfoxide.

SI-MS m / z; 320 (+1) ⁺

'HNMRiCDCla, 100 Hz) δ ppm; major isomer 5.9-5.6 (m, 1H), 3.7 (m, 1H), 3.09 (d, J = 15.6Hz, 1H), 2.79 (d, J = 15.6Hz, 1H) , 1.66 (s, 3H), 1.33 (s, 3H), 2.05-1.0 (m, 10H): minor isomer 5.9-5.6 (m, 1H), 3.7 (m, 1H), 2.61 (d, J = 14.9Hz , 1H), 2.25 (d, J = 14.9Hz, 1H), 1.81 (s, 3H), 1.40 (s, 3H), 2.05-1.0 (m, 10H)

IR (Br) cm- ¹ ; 3350, 2940, 2860, 1720, 1640, 1550, 1450, 1380, 1090, 950, 895, 805

Example 3 Synthesis of Compound 3

In the same manner as in Example 1, 13.5 mg (yield: 75%) of compound 3 was obtained from compound j (20 mg). 10 mg of sodium persulfate and iodine.

SI-MS m / z; 290 (M + 1) ⁺

'Eta Jour _{R (CDC1 3, lOOMHz) δ} ppm; 3.70-3.35 (m, 4H), 3.06 (d, J = 15 Hz, 1H), 2.71 (d, J = 15Hz, 1H), 1.75-1.40 (πι , 4H), 1.58 (s, 3H), 1.53 (s, 3H)

Example 4 Synthesis of Compound 4

By a method similar to that in Example 2, 6 mg (yield: 60%) of compound 4 was obtained from compound 3 (9.5 mg, 0.03 mmol) and 8.lmg of methyl peroxybenzoic acid. SI-MS m / z; 307 (+2) ⁺ , 306 (M + 1) '

'HNMRCCDCla, lOOMHz) d ppm; 3.7-3.3 (m, 4H), 3.12 (s, 2H), 1.8-1.4 (m, 6H), 1.68 (s, 3H), l ".37 (s, 3H)

Example 5 Synthesis of Compound 5

In the same manner as in Example 1, 12.7 mg (yield: 64%) of compound 5 was obtained from compound P (22 mg), sodium hydrosulfide 10 mg and iodine.

SI-MS m / z; 276 (Μ ÷ 1) ' _{'HXMR (CDC1 3, 100MHz)} δ ppm; 4.01 (dd, J = 8.5, 5.6Hz, 1H), 3. -3.3 (m, 4H), 2.97 (dd, J = 16, 5.6Hz, Iff), 2.63 (dd, J = 16, 8.5Hz, 1H), 1.75-1.0 (m, 6H), 1.39 (s, 3H)

Example 6 Synthesis of Compound 6

By a method similar to that in Example 2, 3 mg (yield: 23%) of compound 6 was obtained from compound 5 (12 mg) and 15 mg of methanolic perbenzoic acid. Compound 6 was a mixture of about 3: 2 regarding the stereochemistry of sulfoxide. _C SI -MS m / z; 292 (M ÷ l) ^

_{'H. \' R (CDC1 3} , 100MHz) δ ppm; major isomer 4.22 (dd, J = 9.5, 4.6Hz, 1H), 3.7-3.2 (m, 4H), 2.54 (dd, J = 17, 4.6Hz , 1H), I.24 (dd, J = 17, 9.5Hz, 1H), 1.47 (s, 3H), 1.75-1.4 (m, 6H):

minor isomer 3.9-3.0 (m, 6H), i.75-1.4 (m, 6H), 1.61 (s, 3H) Reference Example 1 Synthesis of Compound a

2.5 g (19.omraol) of 4-oxo-13-methylpentenoic acid synthesized by a known method [Helv. Chim. Acta, 50, 798 (1967)] and 2.8 ml (21.5 ml) of isobutyl formate (mmol) in methylene chloride solution (40 ml), triethylamine (3.0 ml, 21.5 mmol) was added thereto. After stirring for 10 minutes, 2.23 ml (19.5 ml) of cyclohexyl: diamine was added, and the mixture was further stirred for 15 minutes. After the usual post-treatment, crystallization was performed from chloroform Z ether Z hexane to obtain 2.a (yield 54%) of compound a.

^ XMRCCDC, 100MHz) o ppm; 6.56 (q, J = l.2Hz, 1H), 5.55 (brs, 1H), 3.80 (m, 1H), 2.34 (s, 3H), 2.15 (d, J = l. 2Hz, 3H), 2.05-1.0 (m, 10H)

Reference Example 2 Synthesis of Compound b

12 ml of t-butyllithium (I.58M pentane solution, 19mtnoI) was added to 40 ml of a solution of 1.82 ml (19 mmol) of ethyl vinyl ether in tetrahydrofuran over a period of 8 t, and the temperature was raised to 0. After cooling to 78, compound a l.0 g (4.8 mmo :; was added. After usual post-treatment, the solvent was distilled off under reduced pressure. After dissolving in 20 ml of cetonitrile, adding 2 ml of water, 850 mg of N-bromoconodiimide was added at 0. After stirring for 10 minutes, ordinary post-treatment was carried out, and purification was performed by siegel gel gel chromatography (hexane Z ethyl acetate = 1/1) to obtain 920 mg of compound b (yield 58%). Was.

'H MRiCDC, 100MHz) δ ppm; 6.08 (q, J = 1.2Hz, 1H), 5.50 (brs, 1H), 4.34 (d, J = 14Hz, 1H), 4.16 (d, J = 14Hz, 1H) , 3.? 8 (m, 1H), 2.01 (d, J = l.2Hz, 1H), 1.56 (s, 3H), 2.0-1.0 (m, 10H)

SI-MS m / z; 334, 332 (÷ 1) ⁺

Reference Example 3 Synthesis of Compound c

Hydrogen sulfide gas was blown into 20 ml of a solution of compound 670 mg (2.02 mniol) in tetrahydrofuran for 5 minutes. 1.5 ml of triethylamine was added, and the mixture was stirred at room temperature for 8 hours. After ordinary post-treatment, purification was carried out by silica gel gel chromatography (ethyl ethyl hexanoacetate = 1Z1) to obtain 440 mg of compound c (yield 77%). Compound c was a di-stereomeric mixture of about 4: 1.

'H RiCDCla, 100MHz) δ ppm; major isomer 5.0 (br, 1H), 3.7 (m, 1H), 3.46 (d, J = 17Hz, 1H), 3.30 (d, J = 17Hz, 1H), 2.88 (d , J = lo Hz, 1H), 2.38 (d, J = 15Hz, 1H), 1.95-1.0 (m, 10H), 1.55 (s, 3H), 1.37 (s, 3H)

Reference Example 4 Synthesis of Compound d

A solution of 440 mg (l.54 mmol) of Compound c, 0.4 ml of isonitrile nitrite and 240 mg of sodium methoxide in 10 ml of methanol was stirred at room temperature for 1.5 hours. Amberlist ® 15 was added, and the mixture was further stirred for 20 minutes. The solid was filtered off, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (chloroform form Z methanol = 9 Z1) to give 356 tng of compound d (yield completion). 4%).

SI-MS m / z; 315 (M ÷ 1) - 'H \: MR (CDC1 3 - CDGOD, 100¾HZ) O ppm; 3.6 (m, 1H), 2.84 (d, J = 15Hz, 1H), 2.52 (d, J = 15Hz, 1H), 1.93-0.90 (m, 10H), 1.47 (s, 3H) 1.0 (s, 3H)

Reference Example 5 Synthesis of Compound e

63 mg (0.2 mmol) of compound d was dissolved in 1 ml of chloroform and 0.2 ml of pyridine, and 0.05 ml of 2,6-dimethylbenzoyl chloride was added at room temperature. After 10 minutes, the usual post-treatment was carried out, and the solvent was distilled off. The residue was dissolved in tetrahydrofuran (1 ml), and sodium tetrahydrofuran prepared from 0.6 ml of ethanethiol and 80 mg of hydrogenated sodium tetrahydrofura was prepared. The solution was added at room temperature. After stirring for 20 minutes, ordinary post-treatment was carried out, followed by purification by thin-layer chromatography (ether / hexane = 1Z4) to obtain 38 mg of compound e (yield 57%).

SI-MS m / z; 334 (M + 1) ⁺

_{'HNMR (CDC1 3, 100MHz)} δ ppm;? 7.25 (br, 1H), 5.60 (br, 1H), 3.80 (m, 1H), 2.92 (d, J = 15Hz, 1H), 2. 7 (q, J = 7.5Hz, 2H), 2.36 (d, J = 15Hz, 1H), 1.56 (s, 3H), 1.9 (s, 3H), 1.23 (t, J = 7.5Hz, 3H), 2.05-1.05 (m, 10H)

Reference Example 6 Synthesis of compound f

According to the same method as in Reference Example 1, 4-oxo-13-methylpentenanoic acid (2.5 mmol), isobutyl chloroformate 2.8 ml (21.5 mmol), triethylamine 3 ml, and pyridine Using 1.95 ml (19.ommol), 4 g of compound f was obtained as a crude product.

• HN 'RiCDC, 100MHz) 6 ppm; 6.82 (q, J = l.2Hz, 1H), 3.7-3.3 (m, 4H), 2.35 (s, 3H), 1.87 (d, J = l.2Hz, 3H) ), 1.7-1.4 (m, 6H) Reference example? Synthesis of compound g

In the same manner as in Reference Example 2, compound f 3.0 g, ethyl vinyl ether 4 ml, t-butyllithium 25 ml (1.58 M pentane solution), X-bromosuccinimide 1.-5 g and Using 2.5 ml of water, 3.32 g (yield? 0%) of compound g was obtained. Jour _{R (CDC1 3, 100MHz) d} PP m; 6.28 (q, J = l.2Hz, 1H), 4.33 (s, 2H), 3.7-3.3 (m, 4H), 1.71 (d, J = l.2Hz , 3H), 1.7- 1.45 (m, 6H), 1.54 (s, 3H)

Reference Example 8 Synthesis of Compound h

By a method similar to that of Reference Example 3, compound g was obtained in an amount of 2.2 g (yield 78%) using 3.3 g of compound g and 3 ml of triethylamine and hydrogen sulfide gas. The compound h is a compound of di-stereomeric mixture of about 3.3: 1 in ¹ ^ 111 ^.

SI-MS m / z; 272 (M + 1) ⁺

• H MRiCDC, 100MHz) δ ppm; major isomer 3.7-3.3 (m, 4H), 3.48 (d, J = 18Hz, 1H), 3.35 (d, J = 18Hz, 1H), 2.81 (s, 2H), 1.7 -1.4 (m, 6H), 1.49 (s, 3H), 1.44 (s, 3H): minor isomer 3.7-3.3 (m, 4H) 3.31 (s, 2H), 2.81 (s, 3H), 1.7-1.4 ( m, 6H), 1.45 (s, 3H), 1.37 (s, 3H)

Reference Example 9 Synthesis of Compound i

In the same manner as in Reference Example 4, compound h 1.6 g, nitrite solution

1. From Oml and 600 mg of sodium methoxide, 0.9 g (yield 51%) of compound i was obtained.

SI-MS m / z; 300 (M + 1) ⁺

_{'H MRiCDCls + CD 3 0D,} 100MHz) δ ppm; 3.7-3.2 (m, 4H), 2.89 (d, J = 17Hz, 1H), 2.72 (d, J = 17Hz, 1H), 1.7-1.3 (m, 6H), 1.41 (s, 3H), 1.37 (s, 3H)

Reference Example 10 Synthesis of Compound j

In the same manner as in Reference Example 5, compound i 62 tng (0.21 mmol), 2,6-dimethylbenzoyl σ-lide 0.05 ml, pyridin 0.2 ml, ethanethiol 0.4 ml and hydride 34 mg (yield 51%) of compound j was obtained from 90 mg of the stream.

SI-MS m / z; 320 (M + 1) ⁺ _{'H \' R (CDC1 3} , 100MHz) d ppm; 3.7-3.3 (m, 4H), 2.84 (s, 2H), 2.75

(q, J = 7.3Hz, 2H), L7-1.4 (m, 4H), 1.57 (s, 3H), 1.47 (s, 3H), 1.21

(t, J = 7.3Hz, 3U)

Reference Example 11 Synthesis of Compound k

According to the same method as in Reference Example 1, 4-oxo-2-pentenoic acid 1.5

From 3 g (13.4 mmol), 1.9 ml (14.8 mmol) of isobutyl chloroformate, 2.06 ml (14.8 mmol) of triethylamine and 1.46 ml (14.8 mtnol) of piperidine, the compound k 1.lg (Yield 45%) was obtained.

'HXMRiCDCh, 100MHz) σ ρρπι; 7.24 (d, J = 15Hz, 1H), 6.95 (d, J = 15Hz, 1H), 3.7-3.4 (m, 4H), 2.34 (s, 3H), 1.75-1.50 ( m, 6H)

Reference Example 12 Synthesis of Compound ^

To a solution of 1.01 g (5.6 mmol) of the compound in 15 ml of tetrahydrofuran was prepared a mixture of 2.7 ml (28 mmol) of ethyl vinyl ether and 20 rol of t-butyllithium (20 M in 1.4 M solution of titanium). Toxivinyllithium solution was added at 17.8. After the temperature was raised to Ot :, ordinary post-treatment was carried out and purified by silica gel column chromatography (ether Z hexane = 4 Z 1) to obtain 841 mg of compound ^ (yield 59%). Was.

• HXMRfCDC, 100MHz) δ ppm; 6.56 (d, J = 15Hz, 1H), 4.26 (d, J = 2.9Hz, 1H), 3.98 (d, J = 2.9Hz, 1H), 3.75 (q, J = 6.8 Hz, 2H), 3.7-3.5 (m, 4H), 2.76 (brs, 1H), 1.7-1.4 (m, 6H), 1.30 (t, J = 6.8Hz, 3H) Reference Example 13 Synthesis of Compound m

Compound 220 mg (0.87 mmol) was dissolved in 10 ml of cetonitrile, 2 ml of water was added, and 154 mg of N-bromosuccinic acid imid was added at 0 t. After ordinary post-treatment, purification was performed by thin-layer chromatography (ether Z hexane == 1 Z 1) to obtain 230 mg of compound m (yield 92%).

• H MRCCDCU, 100MHz) δ ppm; 6.90 (d, J = 15Hz, 1H), 6.65 (d, J = 15Hz, 1H), 4.38 (s, 2H), 3.7-3.4 (m, 4H), 1.58 (s , 3H), 1.7-1.5 (ra, 6H) Reference Example 14 Synthesis of Compound n

In the same manner as in Reference Example 3, compound m 230 mg. Trimethylamine 1 ml and hydrogen sulfide gas were used to obtain compound. As a result, 59 mg (yield: 29%) of a compound 立体, which is a stereoisomer of, and 3 mg (yield: 50%) of a compound n ₂ lG were obtained.

^ NMRCCDC, 400ΜΗζ) δ ppm; n ,: 3.76 (dd, J = 8.4, 5.9 Hz, 1H), 3.6-3.4 (m, 4H), 3.42 (s, 2H), 2.80 (dd, J = 16.7, 8.4 Hz, 1H), 2.72 (dd , J = 16.7, 5.9Hz, 1H), 1.70-1.54 (m, 6H), 1.34 (s, 3H); n 2: 3.56 (t, J = 5.4Hz, 1H), 3.5-3.4 (m, 4H), 3.39 (d, J = 17Hz, 1H), 333 (d, J = 17Hz, 1H), 2.88 (dd, J = 16, 5.4Hz, 1H), 2.66 (dd, J = 16, 5.4 Hz, 1H), 1.7-1.5 (m, 6H), 1.55 (s, 3H)

Reference Example 15 Synthesis of Compound o

In the same manner as in Reference Example 4, Compound T1 ₂ 51 mg (0.2 mmol), nitrite Lee Thor mils 0. lml and Na Application Benefits Umume butoxy de 30mg, the I匕合product o 43tng (75% yield) Obtained.

SI-MS m / z; 287 (M + 1) ⁺

_{'HN R (CDC1 3, 100MHz} ) δ ppm; 4.00 (t, J = 7.2Hz, 1H), 3.65-3.55 (m, 4H), 2.97 (dd, J = 16, 7.2Hz, 1H), 2.87 (dd , J = 16, 7.2Hz, 1H), 1.75-1.45 (m, 6H), 1.37 (s, 3H)

Reference Example 16 Synthesis of Compound p

In the same manner as in Reference Example 5, compound o 30 mg, Viva π-ylchloride 0.05 ml, pyridine 0.1 ml, further ethanethiol 0.2 ml and T1 monobutyllithium 0.2 ml (1.6 l hexane) Solution) to obtain 19 mg of compound p (yield 62%).

SI-MS m / z; 306 (M + 1) ⁺

'H MRCCDC, 100MHz) δ ppm; 3.7-3.5 (m, 5H), 2.96 (dd, J = 16, 5.2Hz, 1H), 2.82 (q, J = 7.5Hz, 2H), 2.70 (dd, J = 16, 4.3Hz, 1H), 2.15 (d, J = llHz, 1H), 1.7-1.45 (m, 6H), 1.53 (s, 3H), 1.24 (t, J = 7.5Hz, 3H)

Claims

Expression

-5-11 blue

of 2

ο

[Wherein, ΙΊ represents an integer of 0 to 2, R ¹ represents OR ³ (where R ³ represents hydrogen or lower alkyl), NR ⁴ R ^S (where R and R ⁵ are the same or Is different and represents hydrogen, lower alkyl, alicyclic alkyl or benzyl) or li (CHgJp, where p is an integer from 2 to 8), and R ² represents hydrogen or lower alkyl. 1,2-dithiolane compound represented by the formula: