JP2000044568A - Intermediate for dibenzoxepin and dibenzothiepine derivatives having physiological action - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new dibenzoxepin derivative and a new dibenzothiepine derivative useful as intermediates for producing dibenzoxepin derivatives and dibenzothiepine derivatives, respectively, having physiological actions such as sedative action, analgesic action, anti-inflammatory action, antiestrogen action, antioxidative action, cerebral function-improving action and bronchodilation action. SOLUTION: A compound of the formula (X is O or S; R1-R5 are each H, an alkyl, an aryl or the like; R6 is H or a protecting group), for example, 9- methoxy-6,7-methylenedioxy-10,11-dihydrodibenzo[b,f]oxepin-10-one. The compound of the formula is obtained by reacting a phenylacetic acid derivative in the presence of the mixture of >=1 equivalent of an acid anhydride (for example, trifluoroacetic anhydride) with a Lewis acid (for example, boron trifluoride.ether complex) at a low temperature, preferably at <=0 deg.C. The phenolic hydroxyl group of the compound of the formula is selectively protected by reacting the hydroxyl group with a mixture comprising a base (for example, potassium butoxide) and a protecting reagent at an extremely low temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate for producing a dibenzo [b, f] oxepin derivative or a dibenzo [b, f] thiepin derivative having a physiological action. The invention further relates to a method for synthesizing said intermediate.

[0002]

2. Description of the Related Art Compounds having a dibenzo [b, f] oxepin skeleton or a dibenzo [b, f] thiepin skeleton have a sedative effect (JP-A-47-35439, JP-A-47-11).
753), analgesic effect (Journal of Hete)
rocyclic Chemistry 23,265
(1985)), anti-inflammatory effect (Chemistry a
nd Pharmaceutical Bulleti
n 36, 3462 (1988)), anticonvulsant action (JP-A-50-160288), antiestrogenic action (Jou
rnal of Medicinal Chemist
ry 26, 1131 (1983)), antioxidant action (Japanese Patent Laid-Open No. 5-153990, International Patent Application No. 96/100)
21), improving brain function (International Patent Application No. 96/25)
927), and has a wide range of pharmacological activities such as bronchodilator effect (Japanese Patent Application No. 8-7904), and a method for efficiently supplying these compounds in large amounts is desired.

In general, an intramolecular cyclization of a phenoxyphenylacetic acid derivative or a phenylthiophenylacetic acid derivative is used for the synthesis of dibenzo [b, f] oxepin or dibenzo [b, f] thiepin. Heretofore, this reaction has been achieved under strongly acidic conditions, such as in polyphosphoric acid or methanesulfonic acid. In particular, when polyphosphoric acid is used, it must be performed at a temperature of about 120 ° C., and cannot be used for a substrate that is unstable to heat. When methanesulfonic acid was used, the reaction proceeded at room temperature, but it took three days or more to complete the reaction. Dibenzo [b, f] oxepin or dibenzo [b, f]
In the case of protecting the phenolic hydroxyl group of thiepin, under general conditions for introducing a protecting group, not only protection of the phenolic hydroxyl group but also enolization of the carbonyl group will occur.

[0004]

SUMMARY OF THE INVENTION The present invention provides an intermediate which is effective for the synthesis of dibenzo [b, f] oxepin or dibenzo [b, f] thiepin having a physiological action, and the efficiency of the intermediate. It is an object to provide an efficient manufacturing method. Hereinafter, the present invention will be described in detail.

[0005]

According to the present invention, there is provided a compound represented by the general formula (1):

Embedded image (Where X is an oxygen atom or a sulfur atom, R1 to R5 are hydrogen, an alkyl group, an aryl group, a halogen, a lower alkoxyl group, an amino group, an N-lower acylamino group, a hydroxyl group, a thiol group, a lower alkylthio group, and R6 is The main feature is a dibenzo [b, f] oxepin and dibenzo [b, f] thiepine derivative represented by hydrogen or any substituent selected from protecting groups commonly used in organic synthetic chemistry.

The above-mentioned dibenzo [b, f] oxepin and dibenzo [b, f] thiepin derivatives are preferably obtained by cyclizing a phenylacetic acid derivative at a low temperature in the presence of a mixture of an acid anhydride and a Lewis acid. It is a cyclized form. There is a problem that the above-described intramolecular cyclization reaction using an acid cannot be applied to a substrate having an acid-labile functional group. Thus, the present inventors have conducted intensive studies to solve this problem, and as a result, using a phenylacetic acid derivative as a substrate, in the presence of trifluoroacetic anhydride and a catalytic amount or more of boron trifluoride / ether complex. It has been found that under mild conditions in which the reaction is carried out at a low temperature, a desired compound having a dibenzo [b, f] oxepin skeleton and a dibenzo [b, f] thiepine skeleton can be obtained in a short time and in a high yield.

The above-mentioned dibenzo [b, f] oxepin and dibenzo [b, f] thiepin derivatives have the general formula (1)
In the case where R 6 is hydrogen, it may be one in which a protecting group is selectively introduced. That is, the above dibenzo [b,
The f] oxepin and dibenzo [b, f] thiepine derivatives include those obtained by selectively introducing a protecting group into a phenolic hydroxyl group having a carbonyl group on a 7-membered ring and an intramolecular hydrogen bond. Regarding the selective protection of the phenolic hydroxyl group, an intermediate in which only the phenolic hydroxyl group was protected was obtained by reacting the previously obtained compound with acetyl chloride at a very low temperature in the presence of potassium butoxide.
It has been found that this intermediate can be converted into a dibenzo [b, f] oxepin having a physiological action through enol etherification and deprotection by a conventional method.

Further, the above-mentioned dibenzo [b, f] oxepin and dibenzo [b, f] thiepin derivatives are intermediates for producing dibenzo [b, f] oxepin and dibenzo [b, f] thiepin derivatives having physiological effects. Body. The dibenzo [b, f] oxepin and dibenzo [b, f] thiepine derivatives having physiological action refer to those described in the section of the prior art.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The starting materials for the dibenzo [b, f] oxepin and dibenzo [b, f] thiepine derivatives (hereinafter sometimes abbreviated as "compound 1") represented by the above general formula (1) are as follows. It is commercially available or can be easily obtained according to, for example, the method described in the Examples or in accordance with the method, and is obtained in a high yield by reacting a mixture comprising at least one equivalent of an acid anhydride and a Lewis acid at a low temperature. Is obtained. The acid anhydride in the above-mentioned production method is not particularly limited as long as the reaction proceeds, but trifluoroacetic anhydride can be preferably exemplified. The Lewis acid in the above production method is not particularly limited as long as it promotes the reaction, but preferably a boron trifluoride / ether complex can be exemplified. The reaction temperature in the above-mentioned production method is not particularly limited as long as the reaction proceeds, but the reaction may preferably be performed at 0 ° C. or lower.

In the selective protection of the phenolic hydroxyl group of compound 1, a compound in which the phenolic hydroxyl group is selectively protected can be obtained in high yield by reacting a mixture comprising a base and a protecting reagent at an extremely low temperature. The base in the above-mentioned production method is not particularly limited as long as it allows the reaction to proceed, but preferably, potassium butoxide can be exemplified. The protective group in the above production method is not particularly limited as long as it promotes the reaction, and examples thereof include a lower alkyl group, a lower alkylcarbonyl group, and a substituted silyl group. The reaction temperature in the above production method is not particularly limited as long as the reaction proceeds, but is preferably -78 to-
Performing the reaction at 20 ° C. can be exemplified. Compound 1 in the above production method can be isolated and purified by subjecting it to a purification method commonly used in synthetic organic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, and the like. . From the compound 1 thus obtained, a dibenzo [b, f] oxepin derivative and a dibenzo [b, f] thiepin derivative having antioxidant activity can be synthesized through, for example, enol etherification and deprotection. Hereinafter, examples of the present invention will be described.

[0011]

EXAMPLES The present invention will be described with reference to examples. The example is an embodiment and does not limit the present invention.

Example 1 9-methoxy-6,7-methylenedioxy-10,11-dihydrodibenzo [b,
f] Synthesis of oxepin-10-one Step 1 Synthesis of methyl 3-benzyloxy-4,5-methylenedioxybenzoate

An anhydrous dimethylformamide (7.5 mL) solution containing methyl 3-hydroxy-4,5-methylenedioxybenzoate (20.17 g) was added to sodium hydride (4.94 g, 60% mineral oil dispersion, 123 .36
mmol) and dimethylformamide (20 mL) at 0 ° C. and stirred. Benzyl bromide (14.67 mL) was added to this mixture at 0 ° C., and the mixture was further reacted at room temperature for 1.5 hours. The reaction solution was diluted with ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from benzene-cyclohexane to give the title compound (20.23 g, 68%). The melting point of this compound is 78.
2-80.4 ° C.

Step 2 Synthesis of 3-benzyloxy-4,5-methylenedioxybenzyl alcohol Methyl 3-benzyloxy-4,5-methylenedioxybenzoate (24.03 g) was added to anhydrous tetrahydrofuran (50 m
L) and lithium aluminum hydride (3.15)
g) and a mixture of anhydrous ether (30 mL) at 0 ° C. and stirred for 1 hour. 90% aqueous methanol was added to the reaction mixture, followed by saturated aqueous ammonium chloride. The resulting precipitate was filtered off and washed well with ethyl acetate. After separating the organic layer, it was washed with water and saturated saline, dried and concentrated. The residue was subjected to silica gel column chromatography (hexane:
The residue was purified by ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (23.1).
4 g, 90%). The melting point of this compound is 61.8-63.
2 ° C.

Step 3 Synthesis of 3-benzyloxy-4,5-methylenedioxybenzaldehyde 3-benzyloxy-4,5-methylenedioxybenzyl alcohol (23.10 g) was added to dichloroethane (15 m
L) and manganese oxide (23.0 g) was added thereto.
Ultrasound was irradiated for a time. After filtering the reaction mixture, the precipitate was thoroughly washed, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
Purification in 1) and recrystallization from benzene-hexane gave the title compound (21.67 g, 95%). The melting point of this compound was 64.0-65.5 ° C.

Step 4 Synthesis of 3-benzyloxy-4,5-methylenedioxyphenol 3-benzyloxy-4,5-methylenedioxybenzoaldehyde (21.66 g) and disodium hydrogenphosphate (21.7 g) were added to dichloromethane. (90mL) plus 0
Stirred at ° C. There, m-chloroperbenzoic acid (19.2)
7g) was added in several portions and stirred at room temperature for 1 hour. The mixture was further refluxed overnight. The reaction mixture was added to ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and recrystallized from ethyl acetate-hexane to obtain the title compound (18.58 g,
90%). The melting point of this compound is 70.4-71.1 ° C.

Step 5 Synthesis of 1-benzyloxy-5-methoxy-2,3-methylenedioxybenzene 3-benzyloxy-4,5-methylenedioxyphenol (12.4 g), potassium carbonate (12.4 g), anhydrous A mixture of acetone (80 mL) and methyl iodide (6.2 mL) was refluxed under an argon atmosphere for 2 days. After filtration, the reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as an oil (12.14 g, 9).
3%). 1H-NMR (400 MHz, C
The peaks due to DC13) were as follows. δ 3.70 (s, 3H), 5.17 (s, 2H), 5.
90 (s, 2H), 6.12 (d, 1H, J = 2H
z), 6.18 (d, 1H, J = 2 Hz), 7.31 −
7.44 (m, 5H).

Step 6 Synthesis of 5-methoxy-2,3-methylenedioxyphenol 1-benzyloxy-5-methoxy-2,3-methylenedioxybenzene (14.30 g) was added to ethyl acetate (70 m
L), 10% Pd-C (715 mg) was added, and the mixture was stirred at room temperature overnight and hydrogenated. The reaction mixture was filtered and concentrated to give the title compound (9.03 g, 97%). The melting point of this compound was 46.7-48.7 ° C.

Step 7 Synthesis of 2- (5-methoxy-2,3-methylenedioxyphenoxy) benzoic acid 5-methoxy-2,3-methylenedioxyphenol (5.0 g), 2-bromobenzoic acid (6 .57 g) and potassium carbonate (7.40 g) were added with 1-methyl-2-pyrrolidone (35 mL) and benzene (25 mL), and the mixture was equipped with a Dean-Stark water separator and heated under reflux for 1 hour. After distilling off benzene, powdered copper (472 mg) and copper iodide (1.42 g) were added, and the mixture was stirred at 120 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and dilute hydrochloric acid, and the organic layer was diluted with water,
Washed sequentially with saturated saline. The organic layer was separated, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to obtain the title compound (6.42 g, 77%). The melting point of this compound was 159.7-160.8 ° C.

Step 8 Synthesis of 2- (5-methoxy-2,3-methylenedioxyphenoxy) benzyl alcohol Tetrahydrofuran of 2- (5-methoxy-2,3-methylenedioxyphenoxy) benzoic acid (6.42 g) Sodium borohydride (0.93 g) was added to the (50 mL) solution at 0 ° C. and stirred for 15 minutes. To this, boron trifluoride / ether complex (3.4 mL) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as an oil (5.79 g,
95%). 1H-NMR of this compound (400 MHz,
The peaks due to CDCl3) were as follows. δ 3.70 (s, 3H), 4.80 (s, 2H), 5.
91 (s, 2H), 6.09 (d, 1H, J = 2H
z), 6.34 (d, 1H, J = 2 Hz), 6.88
(M, 1H), 7.11 (m, 1H), 7.24 (m, 1H)
1H), 7.43 (m, 1H).

Step 9 Synthesis of 2- (5-methoxy-2,3-methylenedioxyphenoxy) benzyl bromide 2- (5-methoxy-2,3-methylenedioxyphenoxy) benzyl alcohol (5.64 g) in dichloromethane (25 mL) Phosphorus tribromide (0.72 m
L) was added and stirred for 30 minutes. The reaction solution was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane: ethyl acetate =
5: 1) and recrystallized from ethyl acetate-hexane to give the title compound (5.24 g, 76).
%). The melting point of this compound was 108.3-109.8 ° C.

Step 10 2- (5-methoxy-2,3-
Synthesis of methylenedioxyphenoxy) benzylnitrile Sodium cyanide (1.10 g) was added to a solution of 2- (5-methoxy-2,3-methylenedioxyphenoxy) benzylbromide (5.10 g) in dimethylsulfoxide (14 mL).
11 g) and stirred at 80 ° C. for 1 hour. The reaction solution was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated.
The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) and recrystallized from ethyl acetate-hexane to give the title compound (3.91 g,
91%). The melting point of this compound was 89.0-90.3 ° C.

Step 11 2- (5-methoxy-2,3-
Synthesis of methylenedioxyphenoxy) phenoxyacetic acid A solution of 2- (5-methoxy-2,3-methylenedioxyphenoxy) benzylnitrile (3.80 g) in ethanol (11 mL) and tetrahydrofuran (5 mL) was added.
0N aqueous sodium hydroxide solution (6.7 mL) was added,
Stirred at 110 ° C. overnight. The reaction solution was diluted with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel chromatography (hexane: ethyl acetate = 1: 1).
Purification in 1) and recrystallization from ethyl acetate-hexane gave the title compound (3.80 g, 94%). The melting point of this compound was 125.0-126.9 ° C.

Step 12 9-methoxy-6,7-methylenedioxy-10,11-dihydrodibenzo [b, f]
Synthesis of oxepin-10-one (compound 2)

[0025]

Embedded image

To a solution of 2- (5-methoxy-2,3-methylenedioxyphenoxy) phenoxyacetic acid (2.50 g) in dichloromethane (25 mL) was added trifluoroacetic anhydride (1.75 mL), and the mixture was stirred at room temperature for 1 hour. . To this, add boron trifluoride-ether complex (0.51 mL) at 0 ° C.
And stirred for 15 minutes. The reaction solution was diluted with water, neutralized with a sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 2), and recrystallized from ethyl acetate-hexane to obtain the title compound (1.82 g, 77%). 1H-NMR of this compound
The peak due to (400 MHz, CDCl3) was as follows. δ 3.82 (s, 3H), 4.02 (s, 2H), 6.
09 (s, 2H), 6.39 (s, 1H), 7.19
(M, 1H), 7.27-7.30 (m, 3H).

Comparative Example 1 2- (5-methoxy-2,3)
-Methylenedioxyphenoxy) phenoxyacetic acid (10
0 mg) was added with methanesulfonic acid (1 mL) or polyphosphoric acid (1 mL), and the mixture was stirred for 1 hour.

Comparative Example 2 2- (5-methoxy-2,3
-Methylenedioxyphenoxy) phenoxyacetic acid (10
(0 mg) in dichloromethane (2.0 mL) was added with trifluoroacetic anhydride (0.07 mL), and the mixture was stirred at room temperature for 1 hour. A catalytic amount of boron trifluoride / ether complex (2.6 μL) was added thereto, and the mixture was stirred at room temperature for 5 hours.
Raw material and quinone-like yellow substance were observed,
Methoxy-6,7-methylenedioxy-10,11-dihydrodibenzo [b, f] oxepin-10-one was present in trace amounts.

Example 2 9-hydroxy-6,7-methylenedioxy-10,11-dihydrodibenzo [b,
f] Synthesis of oxepin-10-one (compound 3)

[0030]

Embedded image

The compound 2 obtained in Example 1 (2.0
To a solution of g) in dichloromethane (20 mL) was added a solution of boron tribromide / methyl sulfide complex (3.3 g) in dichloromethane (10 mL) at 0 ° C., and the mixture was stirred for 10 minutes. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1), and recrystallized from ethyl acetate-hexane to give the title compound as pale yellow crystals (1.64 g, 86%). 1H of this compound
-The peaks by NMR (400 MHz, CDCl3) were as follows. δ 4.09 (s, 2H), 6.0
6 (s, 2H), 6.27 (s, 1H), 7.20
(M, 1H), 7.26-7.31 (m, 3H), 1
3.19 (s, 1H).

Example 3 9-acetoxy-6,7-methylenedioxy-10,11-dihydrodibenzo [b,
f] Synthesis of oxepin-10-one (compound 4)

[0033]

Embedded image

The compound 3 obtained in Example 2 (500
mg of potassium butoxide (218 mg) in tetrahydrofuran (10 mL).
(0 mL) solution at 0 ° C. and stirred for 10 minutes. The solution was cooled to -78 ° C and acetyl chloride (138 μL)
Was added and stirred at -20 ° C for 15 minutes. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane: ethyl acetate =
2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (470 mg, 81
%). 1H-NMR (400 MHz, CD
The peaks due to Cl3) were as follows. δ 3.11 (s, 3H), 4.00 (s, 2H), 6.
16 (s, 2H), 6.43 (s, 1H), 7.18-
7.28 (m, 4H).

Comparative Example 3 Triethylamine (100 μL) and acetic anhydride (100 μL) were added to a dichloromethane (2 mL) solution of the compound 3 (65 mg) obtained in Example 2 above.
L) and 4-dimethylaminopyridine (3 mg) were added, and the mixture was stirred for 10 minutes. After the reaction solution was distilled off, the residue was subjected to silica gel chromatography (hexane: ethyl acetate =
2: 1), the reaction product was 1,11-
Diacetoxy-3,4-methylenedioxydibenzo [b, f] oxepin (84 mg, 99%).
The melting point of this compound was 158.3-160.1 ° C.

Example 4 Synthesis of 1-hydroxy-3,4-methylenedioxy-11-methoxydibenzo [b, f] oxepin (compound 5)

[0037]

Embedded image

Compound 4 obtained in Example 3 (300
mg) in methanol (30 mL), trimethyl orthoformate (2.1 mL) and ( ₊ ) _- 10 _- camphorsulfonic acid (23 mg) were added, and the mixture was stirred at 80 ° C for 2 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. Methanol (30
mL) and saturated aqueous sodium hydrogen carbonate solution (2.0 m
L) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (JP-A-5-15399).
Compound (0) was obtained (208 mg, 76%).
The melting point of this compound was 149.8-151.1 ° C.

[0039]

According to the present invention, a sedative action, an analgesic action,
Dibenzo [b, f] useful as a compound having a wide range of pharmacological activities such as anti-inflammatory, anticonvulsant, antiestrogenic, antioxidant, cerebral function improving and bronchodilator effects
Intermediates of oxepin and dibenzo [b, f] thiepin compounds can be provided.

Claims (4)

[Claims] 1. A compound of the general formula (1) (Where X is an oxygen atom or a sulfur atom, R1 to R5
Is hydrogen, an alkyl group, an aryl group, a halogen, a lower alkoxyl group, an amino group, an N-lower acylamino group, a hydroxyl group, a thiol group, a lower alkylthio group, and R6 is selected from hydrogen and a protecting group commonly used in organic synthetic chemistry. Dibenzo [b, f] oxepin and dibenzo [b, f] thiepine derivatives represented by the following formula: 2. The dibenzo [b, f] oxepin and dibenzo [b, f] cyclized product obtained by reacting a phenylacetic acid derivative at a low temperature in the presence of a mixture of an acid anhydride and a Lewis acid. ] Thiepin derivatives. 3. The dibenzo [b, f] oxepin and dibenzo [b, f] thiepine derivatives according to claim 1 or 2, wherein a protecting group is selectively introduced when R6 is hydrogen in the general formula (1). 4. The dibenzo [b, f] oxepin according to claim 1, 2 or 3, which is an intermediate for producing dibenzo [b, f] oxepin and dibenzo [b, f] thiepin derivatives having physiological action. Dibenzo [b, f] thiepine derivatives.