3-HYDROXYMETHYLDIBENZO(B,F)THIEPINS AND DIBENZO(B,F)THIEPIN-3-CARBOXALDEHYDES AS PROSTAGLANDIN ANTAGONISTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS

Abstract: A compound of the formula: or an ester or acetal thereof, wherein n is an integer from 1 to 4; z is thio, sulfinyl, or sulfonyl; R¹ and/or R² is hydrogen, halogen including chloro, bromo, fluoro and iodo, amino, C₁ to C₄ alkyl, C₁ to C₄ alkanoyl, hydroxyl, C₁ to C₄ alkoxy, thiol, C₁ to C₄ alkylthio, C₁ to C₄ alkylsulfinyl, C₁ to C₄ alkylsulfonyl, trifluoromethyl, trifluoromethylthio, cyano, nitro, and C₁ to C₄ alkyl or dialkylamino, aralkyl including benzyl and phenethyl, hydroxyalkyl as CH₃CHOH; and the dotted line indicates either an olefinic bond or saturation at the 10-, 11-position, is prepared and employed in the treatment and control of allergic conditions such as allergic asthma.

Description: TITLE OF THE INVENTION 3-Hydroxymethyldibenzo(b,f)thiepins and dibenzo(b,f)thiepin-3-carboxaldehydes as Prostaglandin Antagonists, process for their preparation and pharmaceutical compositions. SUMMARY OF THE INVENTION This invention relates to prostaglandin antagonists useful in treating a variety of conditions, such as allergic asthma where excessive contractile activity of prostaglandins and prostaglandin biosynthetic intermediates occur. These prostaglandin antagonists are 3-hydroxymethyldibenzo[b,f]thiepins having the structural formula: or wherein EMI1.1 n is an integer of from 1-4 Z is thio, sulfinyl, or sulfonyl; R1 and/or R2 is hydrogen, halogen including chloro, bromo, fluoro and iodo, amino, C1 to C4 alkyl, C1 to C4 alkanoyl, hydroxyl, C1 to C4 alkoxy, thiol, C1 to C4 alkylthio, C1 to C4 alkylsulfinyl, C1 to C4 alkylsulf onyl, trifluoromethyl, trifluoromethylthio, cyano, nitro, and C1 to C4 alkyl or dialkylamino, aralkyl including benzyl and phenethyl, hydroxyalkyl as CH3CHOH; and the dotted line indicates either an olefinic bond or sat uration at the 10-, ll-position. As used herein, the term halogen (or halo) includes chlorine, bromine, iodine, and fluorine. Unless otherwise specifically stated, the terms loweralkyl and loweralkoxy include straight and branched chain alkyl and alkoxy groups having 1 to 4 carbon atoms in the alkyl or alkoxy moiety such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, and isobutoxy. The term loweralkanoyl includes straight or branched chain alkanoyl groups having 1 to 4 carbon atoms in the alkanoyl moiety such as, for example, formyl, acetyl, propanoyl, and isobutyryl. The terms aralkyl includes straight or branched chain alkyl radicals having one of the hydrogens replaced by a phenyl or substituted phenyl group including phenyl, halophenyl such as chloro, bromo, iodo, and fluorophenyl, nitrophenyl, aminophenyl, hydroxyphenyl, loweralkylphenyl, and the like. These dbenzolb,f]thiepin derivatives antagonize the actions of contractile prostaglandins, such as PGF2 PGG2, PGHz, and TXA2 The use of agents which act as prostaglandin antagonists offers new approaches to therapy in a number of disease states. For example, certain prostaglandins, such as pGF2, PGG, and PGH2, are potent contractants of bronchial muscle. Indeed human asthmatics have been shown to be especially sensitive to the bronchial constricting action of PGF In addition to the involvement of contractile prostaglandins in chronic obstructive lung disease (or asthma), prostaglandins are known to play a role in other allergic conditions, as well as inflammation, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature abortion, and dismenorrhea. In addition to the prostaglandin antagonist actions, the dibenzo[b,f]thiepins of this invention are antagonists of slow reacting substance of anaphylaxis (SRS-A). This contractile substance is released in the lung tissue in allergic asthma, and antagonism of its actions contributes to alleviation of this disease. The dibenzotb,f]thiepins of formula I of this invention are prepared according to the following general reaction scheme: EMI3.1 where R1, R2, Z, and n are as defined above; and A is COOH or a loweralkyl ester thereof. As shown in the above reaction scheme, an appropriately substituted dibenzo [b,f) thiepin-3-carboxylic acid of a loweralkyl ester thereof is reduced to the correspondingly substituted 3-hydroxymethyldibenzo[b,f]thiepin by treatment with an alkali metal aluminum hydride, preferably lithium aluminum hydride or borane. Either reagent is effective in reducing a carboxy or a carbalkoxy substituent to the corresponding hydroxymethyl substituent but borane is preferred for the reduction of the carboxyl function in a dibenzothiepin-3-carboxylic acid, 5,5-dioxide. The reduction is conducted in a solvent which is inert under the reaction conditions and may be either a volatile or non-volatile ether. Ethyl ether or other loweralkyl ethers are satisfactory and tetrahydrofuran is a commonly preferred solvent. The reducing reagent, either lithium aluminum hydride or borane, is employed in a slight excess over the stoichiometric amount needed in order to insure completeness of reaction. The reduction reaction is maintained at a temperature between 0 and 100 C. or the reflux temperature of the solvent. Most acids and esters are reduced relatively completely at room temperature (250C.) and in a relatively short time (approximately 1 hour) and therefore the reduction is usually conducted by stirring the acid or ester for a period of from 30 minutes to 12 hours at a temperature of from 100 to -400C. Following the completion of the reaction1 the product is isolated by the addition of water and extraction into ether. The ether extract is evaporated to obtain the residual product which is recrystallized from an appropriate solvent. Products which may be obtained directly by reduction of the appropriate acid are 3-hydroxymethyldibenzo Fb, f] thiepin and 3-hydroxymethyldibenzotb,f3thiepin 5,5dioxide or derivatives bearing R1 and R2 substituents which are resistant to the reducing effect of lithium aluminum hydride or borane. Ordinarily the 3-hydroxymethyl dibenzo[b,f]thiepMn 5-oxide or R1,R2 derivatives thereof are prepared by oxidation of the corresponding 3-hydroxy methyldibenzotb,fJthiepin with organic peroxides such as peroxy acids like m-chloroperbenzoic acid. The oxidation can be carried further, if an additional equivalent of acid is employed, to produce the corresponding dibenzo [b,f)thiepin-5,5-dioxides. It will be apparent to one skilled in the art that variations in these preparative schemes will allow one to prepare a variety of substituted 3-hydroxymethyldibenzo[b,f]thiepin,as well as the corresponding thiepin-5-oxides and the thiepin-5,5-dioxides. For example, 8-amino-3-hydroxymethyldibenzo[b,f]- thiepin is prepared by reduction of the correspondingly substituted acid or by catalytic hydrogenation of 3 hydroxymethyl-8-nitrodibenzo[b,f]thiepin. The dibenzo[b,f]thiepins of formula Ia of this invention are prepared according to the following general reaction scheme: EMI5.1 wherein R11 R2, and Z are as defined above. As shown in the above reaction scheme, an appropriately substituted 3-cyano-dibenzo[b,f]thiepin is reduced and hydrolyzed to the correspondingly substituted dibenzo [b,f]thiepin-3-carboxaldehyde in the presence of a metal containing reducing agent in accordance with the following procedures. In one method of effecting the conversion of the 3-cyano substituent to a 3-carboxaldehyde substituent, the 3-cyano-dibenzo[b,f]thiepin is treated in dry ether with hydrogen chloride gas and anhydrous stannous chloride at a temperature of 0-500C., but preferably between 0-10"C. Solvents for the reaction are ethers or other inert anhydrous solvents which do not contain an active hydrogen and which will dissolve the reactants. The intermediate which first forms is the imino chloride salt of the amine which is reduced by the action of stannous chloride to the intermediate tin halide complex. This intermediate aldiminium stannic chlorite complex is then hydrolyzed to produce the desired dibenzo[b,f]thiepin-3--carboxaldehyde. In order to isolate the aldehyde from the tin complex, it is sometimes necessary to utilize a chromatographic procedure and/or a second hydrolytic step fusing an aqueous alcohol solution. In an alternate procedure for converting 3-cyano dibenzo Cb,f] thiepins to dibenzo (b,f] thiepin-3-carboxalde- hydes and the corresponding 10,11-dihydro compounds, the selected cyano compound is treated with from 1-5 parts by weight of Raney alloy (50% Ni/50% Al) in aqueous formic acid. The mixture is stirred at temperatures from OOC. to reflux temperature, but preferably at the reflux temperature for a period of from 1-24 hours. When the reduction and hydrolysis is complete, the product is recovered by removal of the alloy by filtration while hot, and extraction of the product from the filtrate, followed by crystallization from ethyl acetate. In a further alternate procedure for the preparation of dibenzo[b,f]thiepin-3-carboxaldehydes or the corresponding 10,11-dihydro derivative, the selected 3-cyanodibenzo[b,f]thiepin or the 10,11-dihydro -derivative employed as starting material is reduced to the corresponding aldehyde by selective reduction with sodium hypophosphite and Raney nickel in aqueous acid (preferably aqueous acetic acid or mixtures containing pyridine in aqueous acetic acid). The reaction is preferably conducted at 250C., although the temperature may be maintained at from 0-1000C. to moderate the speed of reaction and/or to increase the yield of product obtained. The product is readily recovered from the reaction mixture after removal of the Raney nickel catalyst by filtration, followed by washing with ethyl acetate to extract any occluded product. The combined filtrate and washings containing the product are then extracted with a mixture of ethyl acetate and ether and the product obtained as a solid residue by evaporation of the solvents from product-containing extract. In a further alternate procedure for preparing dibenzo[b,f]thiepin-3-carboxaldehydes, the corresponding 10,11-dihydro-3-hydroxymethyldibenzo[b,f]thiepin, or a 10,11-dihydro compound is oxidized by means of pyridinium chlorochromate in an inert solvent such as dichloromethane, at a temperature between OOC. and reflux temperature, but preferably at room temperature, for a period of 1-24 hours. When oxidation is complete, the mixture is filtered through a bed of Florisil and then washed through with the solvent. Evaporation of the filtrate affords the dibenzo[b,f]thiepin3-carboxyaldehyde which may be purified by chromatography and/or recrystallization as may be appropriate. A further alternate procedure is employed when the starting material contains a reducible substituent such as a nitro group. In such instances, the substituted e.g., 8-nitro-dibenzo[b,f]thiepin-3-carboxylic acid chloride is reduced with lithium tri-tert-butoxy-aluminum hydride in tetrahydrofuran at -780C. Products which may be obtained directly by reduction of the appropriate nitrile are dibenzo[b,f]thiepin3-carboxaldehyde and dibenzo[b,f]thiepin-3-carboxaldehyde 5,5-dioxide or derivatives bearing R1 and R2 substituents which are resistant to the reducing effect of the reaction conditions employed. Ordinarily the dibenzo[b,f]thiepin 5-oxide or R1,R2 derivatives thereof are prepared by oxidation of the corresponding dibenzo[b,f]thiepin with organic peroxides such as peroxy acids like m-chloroperbenzoic acid. The oxidation can be carried further, if an additional equivalent of acid is employed, to produce the corresponding dibenzo (b,fi thiepin-5, 5-dioxides. It will be apparent to one skilled in the art that variations in these preparative schemes will allow one to prepare a variety of substituted dibenzo [b, f) thiepin-3-carboxalde- hydes, as well as the corresponding thiepin-5-oxides and the thiepin-5,5-dioxides. PREPARATION OF STARTING MATERIALS As described in greater detail in United States Application Serial No. 917,212 filed June 23, 197 & an appropriately substituted mercaptobenzoic acid II is reacted with m-dibromobenzene III (R3 = Br) to obtain the O-(3-bromophenylthio)benzoic acid IV. Or alternatively, an appropriately substituted o-bromobenzoic acid II (R2 = Br) is reacted with m-bromobenzethiol III (R = SH) to & ve IV: EMI8.1 where R1 or R2 are each selected from hydrogen, nitro, amino, C1 to C4 alkanoyl, hydroxyl, C1 to C4 alkoxy, C1 to C4 alkylsulfinyl, C1 to C4 alkylsulfonyl, and C1 to C4 alkyl, trifluoromethyl, and trifluoromethylthio. R2 and R3 are different and alternatively are thiol and bromo. Generally, the sulfide-forming reaction is carried out according to the methods described by Jilek et al., MONATSH. CHEM. 96, 200 (1965); Protiva et al., Czechoslovakian Patent 121,337, CHEM. ABSTRACTS 68: 105, 247t (1968); and U.S. Patent 3,711,489; and by other procedures well known in the art. The resulting o-(3-bromophenylthio)benzoic acid (IV) is reduced to the alcohol, brominated, and the bromo replaced with cyano. The cyano derivative is then hydrolyzed to the carboxylic acid V. EMI9.1 The carboxylic acid V is transformed into the 3-bromo-ll oxo-l0,11-dihydrodibenzo[b,f]thiepin by first conversion to the acid halide with thionyl or phosphoryl halide followed by Friedel-Crafts cyclization with a Lewis acid such as aluminum chloride to give VI. Reduction of the ketone VI with alkali metal borohydrides to the alcohol VII, followed by heating in an appropriate solvent such as toluene with catalytic amounts of a mineral acid, such as sulfuric acid or toluenesulfonic acid provides the 3bromodibenzo[b,f]thiepin VIII. EMI9.2 The 3-bromo derivative VIII is then converted to the 3-nitrile IX by reaction with cuprous cyanide in a high boiling polar solvent such as dimethylformamide, Nmethylpyrrolidone, and the like. EMI10.1 The 3-cyano derivative IX may be hydrolyzed with aqueous mineral acid or base to give the dibenzo [b,f]thiepin-3-carboxylic acid X. Alternatively, the cyano intermediate IX may be oxidized with organic peroxides such as peroxy acids, for example, m-chloroperbenzoic acid and the like, in a stepwise fashion to the corresponding sulfoxide XI and sulfone XII, controlling the molar ratio of oxidant to reductant. This determines the oxidation level of the sulfur. For example, a 1:1 molar ratio results largely in the production of sulfoxide XI. In contrast, a 2:3 molar excess of oxidant results in a yield predominantly comprising the sulfone XII. EMI10.2 Hydrolysis of XI and XII using aqueous mineral acid or alkali provides the corresponding carboxylic acid XIII and XIV. EMI10.3 Compounds of type I where the 10,11-double bond is saturated are prepared from intermediates VII, by displacement of the hydroxy using PBr3, and reduction of the resulting 3,11-dibromide XV by NaBH4 in a solvent such as sulfolane to yield the 3-bromo-l0,11-dihydro derivative XVI. EMI11.1 The bromine in XVI can be displaced by cuprous cyanide in a high-boiling polar solvent such as dimethylformamide, and the resulting 3-nitrile XVII hydrolyzed with aqueous mineral acid or base to give the 10,11-di hydrodibenzo [b,f]thiepin-3-carboxylic acid XVIII. EMI11.2 Compound XVII can be oxidized with one equivalent of an organic peroxide, such as m-chloroperbenzoic acid, to yield the sulfoxide XIX which can then be hydrolyzed with mineral acid or base to the carboxylic acid XX. Compound XVII may also be oxidized with two equivalents of the oxidizing agent to afford the corresponding sulfone XXI, which on hydrolysis gives the acid XXII. EMI11.3 EMI12.1 Substituent R1 in I (R2=H) can also be introduced by modification of the nitro group in IX or XVII (R1=NO2, R2=H) by known procedures. For example, XXIII can be reduced with stannous chloride in acidic medium, hydrochloric acid, and the like, to yield XXIV which canbe hydrolyzed with mineral acids or bases to XXV. EMI12.2 Alternatively, XXIII may be oxidized with peroxides, for example, m-chloroperbenzoic acid to yield XXVI which can be reduced to XXVII and then hydrolyzed with mineral acids or bases to XXVIII. EMI12.3 Intermediate XXIV can be reacted with sodium nitrite in mineral acid to the diazonium salt XXIX, where X is a mineral acid counter ion, for example, ci, HSO4 , BF4 , and the like, which on reaction with CuCl and CuC12 yields intermediate XXX which can be hydrolyzed to the acid XXXI. Intermediate XXX may also be oxidized to the sulfone derivative XXXII, then followed by a hydrolysis to the carboxylic acid XXXIII. EMI13.1 Derivative XXIX can be hydrolyzed with a solution of sulfuric acid 10 to 50% in strength at temperatures ranging from 0 to 900C. to yield XXXIV. XXIX may also be reacted with potassium thioxanthate at temperatures from 400 to 700C. followed by basic hydrolysis to yield the thiol acid XXXV. EMI13.2 EMI14.1 Compound XXVII can be transformed in the usual manner to the diazonium salt XXXVI, which can be reacted as described above to yield compounds XXXVII and XXXVIII. EMI14.2 Compounds XXXIV, XXXV, XXXVII, and XXXVIII can be reacted with alkyl halides RS in which is a loweralkyl C1 to C4, benzyl, and X is a leaving group such as C1, Br, I, and CH3 --#-- SO3, in the presence of bases such as alkali carbonate, hydroxides, and the like, in solvents such as dimethylformamide, at temperatures ranging from 300 to 1600C. to yield XXXIX, XL, XLI, and XLII, respectively. EMI14.3 EMI15.1 Compound XL can in a controlled oxidation with peroxides such as hydrogen peroxide or organic peroxy acids such as m-chloroperbenzoic acid, yield compound XLIII. XLII may be oxidized with one equivalent of organic peroxides such as m-chloroperbenzoic acid or with hydrogen peroxide in hydroxylic solvents such as alcohols, organic acids such as acetic acid, at temperatures below 300C., to yield XLIV. Compounds XL, XLII, and XLIV may also be oxidized with excess organic peroxides such as m-chloroperbenzoic acid at room temperature, or with peroxides such as hydrogen peroxide in acidic medium such as acetic acid at temperatures between 800 and 1000C. to yield XLV. EMI15.2 EMI16.1 Specific introduction of substituents in position 8 in I can also be achieved as follows. For example, XVII (R1= R2=H) can react with alkanoyl halide RCOX or alkanoic anhydride RCOOCOR in which R is a loweralkyl C1 to C4 and X is chloro or bromo, under Freidel-Crafts conditions, to yield the 8-substituted acyl derivative XLVI; the 10,11bridge may be brominated with a brominating agent such as N-bromosuccinimide, and treatment with a base such as DBN can generate the 10,11-unsaturated derivative XLVII. EMI16.2 Both XLVI and XLVII can be hydrolyzed with mineral acid or base to the corresponding acids XLVI II and XLIX. EMI17.1 XLVII can be oxidized with oxidizing agents such as mchloro perbenzoic acid stepwise to yield sulfoxide L and sulfone LI which are hydrolyzed under acidic or basic conditions to afford acids LII and LIII respectively. EMI17.2 Compound XLIX can be reacted with hydroxylamide hydrochloride with presence of base to yield oxime LIV which on a Beckman rearrangement, yields the acylamino compound LV which upon hydrolysis yields amino acid LVI. EMI18.1 Compound LV can be oxidized with hydrogen peroxide in acetic acid stepwise to yield the corresponding sulfoxide LVII and sulfone LVIII which upon hydrolysis afford the acids LIX and LV. EMI18.2 Compounds LVI, LIX, and LX can be treated in various Sandmeyer reactions as described earlier to yield I substituted in the 8 position. Compound XLIX (R = CH3), when treated with sodium hypochlorite and base at temperatures from 0 to 700C. for half an hour, yield the diacid XLI. When the process is carried for two days under the same conditions, XLII is obtained. EMI19.1 Compounds XLIX, LII, and LIII can be reduced with sodium borohydride to afford the corresponding alcohols, XLIII, LXIV, and LXV. EMI19.2 The higher homologs of Compound X hereinabove are prepared, starting with the appropriately substituted 3-carboxylic acid, through reduction, bromination, cyanization, and oxidation, to afford the corresponding 3-acetic acid derivative. Quite obviously, the described reduction, bromination, cyanization, and oxidation sequence can be repeated, employing the 3-acetic acid derivative as starting material, in order to obtain the corresponding propionic acid derivative which, in turn, can be employed as starting material for preparing the corresponding butyric acid derivative. In this manner, any desired 3-loweralkanoic acid derivative is readily prepared. Corresponding sulfinyl or sulfdnyl derivatives are prepared by the oxidation techniques previously described. Compounds of type IA where the 10,11 double bond is saturated are prepared from intermediate V in which the 3-bromo is converted to a cyano derivative XVIIA. EMI20.1 The compound XVIIA is reduced by conventional methods, e.g., Wolff-Kishner, to compound XXII. EMI21.1 Substituent R in IA can also be introduced by modification of the nitro group in IX (R = NO2) by known procedures. For example, XXXIIIA can be reduced with stannous chloride in acidic medium, hydrochloric acid, and the like, to yield XXXIVA which can be hydrolyzed with mineral acids or bases to XXXV. EMI21.2 Alternatively, XXXIIIA may be oxidized with peroxides, for example, m-chloroperbenzoic acid to yield XXXVIA which can be reduced to XXXVI IA and then hydrolyzed with mineral acids or bases to XXXVIIIA. EMI21.3 Intermediate XXXIVA can be reacted with sodium nitrite in mineral acid to the diazonium -s-alt XXXIXA, where X is a mineral acid counter ion, for example, C1 , HSO4 BF4 , and the like, which on reaction with CuC1 and Curl2 yields intermediate XLA which can be hydrolyzed to the acid XLIA. Intermediate XLA may also be oxidized to the sulfone derivative. EMI22.1 Compound XXXVI IA can be transformed in the usual manner to the diazonium salt XLVA. EMI22.2 The 3-hydroxymethyldibenzo[b,flthiepin and the 10,11-dihydro compounds which may be used as intermediates for the preparation of the aldehydecompounds may be made by reduction of the corresponding dibenzo[b,f]thiepin-3-carboxylic acids or esters as described in detail in United States Application Serial No. 917,212, filed June 23, 1978. EMI23.1 These alcohols may be oxidized to the sulfinyl or sulfonyl oxidation levels by a peroxy acid, for example m-chloroperbenzoic acid or the like, in a stepwise fashion. EXAMPLE 1 3-Hydroxymethyl-lO, ll-dihydrodibenzo [b, f) thiepin Dissolve 7.5 gm. of l0,11-dihydrodibenzo [b,f]- thiepin-3-carboxylic acid in 140 ml. of tetrahydrofuran. With stirring, add 90 ml. of 1N diborane in tetrahydrofuran. Stir at room temperature for 2 hours and dilute the reaction mixture with water. Extract into ether, and evaporate the ether extract to dryness. Stir the residue with hexane and filter to obtain the title-product (m.p., 82-840C.). EXAMPLE 2 3-Hydroxymethyl-lO ,ll-dihydrodibenzo [b, f ] thiepin- 5-oxide Dissolve 2 gm. of 3-hydroxymethyl-l0, ll-dihydro- dibenzo[b,f]thiepin in 200 ml. of methylene chloride at room temperature. Add 1.7 gm. of m-chloroperbenzoic acid. Stir at room temperature for 2 hours. Add 4 gm. of calcium hydroxide and 50 ml. of methylene chloride. Continue stirring for 15 minutes. Filter through celite evaporate the filtrate to dryness. Crystallize the residue from toluene to obtain the title product (m.p., 144-1460C.). EXAMPLE 3 3-Hydroxymethyl-10,ll-dihydrodibenzo [b,f] thiepin-5,5-di- oxide Repeat the process of Example 6, substituting an equivalent quantity of 10,11-dihydrodibenzolb,f]thiepin- 3-carboxylic acid-5,5-dioxide for the dibenzoLb,fithíepin- 3-carboxylic acid-5,5-dioxide, to obtain the title product (m.p., 128-1300C,). EXAMPLE 4 3-Hydroxymethyldibenzo[b,f]thiepin Repeat the process of Example 1, substituting an equivalent quantity of dibenzotb,f]thiepin-3-carboxylic acid for the l0,ll-dihydrodibenzo [b,f]thiepin-3-carboxylic acid, to obtain the title product (m.p., lll-1120C.). EXAMPLE 5 3-Hydroxymethyldibenzo[b,f]thiepin-5-oxide Repeat the process of Example 2, substituting an equivalent quantity of 3-hydroxymethyldibenzo[b,f]thiepin for the 3-hydroxymethyl-10,11-dihydrobenzo[b,f]- thiepin, to obtain the title product (m.p., 146-1480C.). EXAMPLE 6 3-Hydroxymethyldibenzo[b,f]thiepin-5,5-dioxide Mix 2.8 gm. of dibenzo[b,fithiepin-3-carboxylic acid-5,5-dioxide, 50 ml. of tetrahydrofuran, and 30 ml. of 1N diborane in tetrahydrofuran. Stir at room temperature for 1 hour. Dilute the reaction mixture with water, and extract into ether. Evaporate the ether extract to dryness. Stir the residue in ether, and evaporate to dryness to obtain the title product (m.p., 156-1580C.). EXAMPLE 7 3-Hydroxymethyl-8-nitro, dibenzo [b,f] thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-nitrodibenzo[b,f]thiepin-3carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin3-carboxylic acid, to obtain the title product. EXAMPLE 8 3-Hydroxymethyl-8-nitro-dibenzotb,f]thiepin-5-oxide Repeat the process of Example 2, substituting an equivalent quantity of 3-hydroxymethyl-8-nitro-dibenzo [b,f]thiepin for the 3-hydroxymethyl-l0,1l-dihydrodibenzo- [b,fithiepin, to obtain the title product. EXAMPLE 9 3-Hydroxymethyl-8-nitro-dibenzo [b, f] thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-nitrodibenzo[b,f]thiepin-3carboxylic acid 5,5-dioxide for the dibenzolb,f]thiepin- 3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 10 8-Amino-3-hydroxymethyl-dibenzo[b,f]thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-aminodibenzo tb, f] thiepin-3- carboxylic acid for the 10,l1-dihydrodibenzo[b,f]thiepin- 3-carboxylic acid, to obtain the title product. EXAMPLE 11 8-Amino-3-hydroxymethyl-dibenzo[b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-amino-dibenzo[b,f]thiepin-3carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3- carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 12 8-Chloro-3-hydroxymethyl-dibenzo[b,f]thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-chlorodibenzo[b,f]thiepin-3carboxylic acid for the 10,11-dihydro-dibenzo[b, f] thiepin3-carboxylic acid, to obtain the title product. EXAMPLE 13 8-Chloro-3-hydroxymethyl-dibenzo [b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-chloro-dibenzo[b,f]thiepin-3carboxylic acid 5,5-dioxide for the dibenzolb,f]thiepin-3- carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 14 8-Hydroxy-3-hydroxymethyl-dibenzo[b,f]thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-hydroxy-dibenzo[b,f]thiepin3-carboxylic acid for the 10,11-dihydro-dibenzolb,f]thiepin3-carboxylic acid, to obtain the title product. EXAMPLE 15 8-Hydroxy-3-hydroxymethyl-dibenzo[b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-hydroxy-dibenzo[b,f]thiepin3-carboxylic acid 5,5-dioxide for the dibenzotb,f]thiepin- 3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 16 3-Hydroxymethyl- 8-mercapto-dibenzo [b, fj thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-mercaptodibenzo[b,f]thiepin3-carboxylic acid for the 10.11-dihydro-dibenzo[b,f]- thiepin-3-carboxylic acid, to obtain the title product. EXAMPLE 17 3-Hydroxymethyl-8-mercapto-10 ,ll-dihydrodibenzo [b,f]- thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-mercapto-10,11-dihydrodibenzo [b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo [b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 18 3-Hydroxymethyl-8-methoxy-dibenzo Ib, fj thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-methoxy-dibenzo[b,fJthiepin- 3-carboxylic acid for the 10,11-dihydrodibenzoSb,f]thiepin- 3-carboxylic acid, to obtain the title product. EXAMPLE 19 3-Hydroxymethyl-8-methoxy-dibenzo[b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-methoxy-dibenzolb,f]thiepin- 3-carboxylic acid 5,5-dioxide for the dibenzotb,f]thiepin- 3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 20 3-Hydroxymethyl-8-methylthio-dibenzo [b, fithiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-methylthiodibenzo[b,f]thiepin3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin3-carboxylic acid, to obtain the title product. EXAMPLE 21 3-Hydroxymethyl-8-methylthio-dibenzo [b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-methylthiodibenzo [b, f] thiepin- 3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 22 3-Hydroxymethyl-8-methylsulfinyl-dibenzo[b,f]thiepin 5,5dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-methylsulfinyldibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo [b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 23 3-Hydroxymethyl-8-methylsulfinyl-dibenzo [b,f]thiepin 5-oxide Repeat the process of Example 2, substituting an equivalent quantity of 3-hydroxymethyl-8-methylthiodi benzotb,f]thiepin for the l0,ll-dihydrodibenzo [b, f]thiepin, to obtain the title product. EXAMPLE 24 3-Hydroxymethyl-8-methylsulfonyl-dibenzotb,f]thiepin 5,5dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-methylsulfonyldibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo [b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 25 8-Acetyl-3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-acetyl-l0,11-dihydrodibenzo [b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product. EXAMPLE 26 8-Acetyl-3-hydroxymethyl-10,11-dihydrOdibenzo[b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-acetyl-l0,11-dihydrodibenzo Lb,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo lb,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 27 3,8-Dihydroxymethyl-10,11-dihydrodibenzofb,f]thiepin Repeat the process of Example I, substituting an equivalent quantity of 8-hydroxymethyl-l0,ll-dihydro- dibenzolb,f]thiepin-3-carboxylic acid for the 10,11-di hydrodibenzotb,f]thiepin-3-carboxylic acid, to obtain the title product. EXAMPLE 28 3,8-Dihydroxymethyl-10,ll-dihydrodibenzo [b, fithiepin 5,5dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-hydroxymethyl-10,11-dihydro- dibenzotb,fJthiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product. EXAMPLE 29 3(2-Hydroxyethyl)-11-oxo-1O,11-dihydrodibenzo[b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of l0.11-dihydro-ll-oxodibenzo- [b,f]thiepin-3-acetic acid 5,5-dioxide for the dibenzo fb,fthiepin-3-carboxylic acid, to obtain the title product. EXAMPLE 30 8-Fluoro-3-hydroxymethyl-l0 ,1l-dihydrodibenzo fb,fi thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-fluoro-l0,11-dihydrodibenzo [b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodi benzo[b,flthiepin-3-carboxylic acid, to obtain the title product (m.p., 80-810C.). EXAMPLE 31 8-Fluoro-3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin 5-oxide Repeat the process of Example 2, substituting an equivalent quantity of 8-fluoro-3-hydroxymethyl-l0,11dihydrodibenzo[b,f]thiepin for the 3-hydroxymethyldibenzo [b,f]thiepin, to obtain the title product (m.p. 181-1830C.). EXAMPLE 32 8-Fluoro-3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-fluoro-l0,11-dihydrodibenzo [b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product (m.p., 116-118"C.). EXAMPLE 33 8-Fluoro-3-hydroxymethyl-dibenzo [b, f] thiepin Repeat the process of Example 1, substituting an equivalent quantity of 8-fluorodibenzo[b,f]thiepin-3carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin- 3-carboxylic acid, to obtain the title product (m.p., 123-125"C.). EXAMPLE 34 8-Fluoro-3-hydroxymethyl-dibenzoLb,f]thiepin 5-oxide Repeat the process of Example 2, substituting an equivalent quantity of 8-f luoro-3-hydroxymethyldibenzo- [b,f]thiepin for the 3-hydroxymethyldibenzo ib, f thiepin to obtain the title product (m.p., 161-1630C.). EXAMPLE 35 8-Fluoro-3-hydroxymethyl-dibenzo[b,f]thiepin 5,5-dioxide Repeat the process of Example 6, substituting an equivalent quantity of 8-fluorodibenzofb,fithiepin-3- carboxylic acid 5,5-dioxide for the dibenzotb,f]thiepin- 3-carboxylic acid 5,5-dioxide, to obtain the title product (m.p., 131-133 C.). EXAMPLE 36 Dibenzotb,f]thiepin-3-carboxaldehyde 5,5-dioxide Mix 267 mg. (1 mmole) 3-cyano-dibenzotb,f]thiepin 5,5-dioxide with Raney alloy (500 mg.) and a mixture of 4 ml. formic acid and 1 ml. water at the reflux temperature. After 3 hours, add 200 mg. additional Raney alloy and heat for one hour to obtain complete reduction. Filter the reaction mixture while hot to remove the alloy, and wash with ethyl acetate to remove any occluded solvent. Wash the organic layer containing the product with water and with saturated sodium chloride solution. Separate the organic layer containing the product to produce a residue of a pale yellow oil, which crystallizes in a small volume of ethyl acetate, m.p. 167-1710C. EXAMPLE 37 Dibenzo [b, f] thiepin-3-carboxaldehyde 5,5-dioxide Mix 267 mg. (1 mmole) of 3-cyano-dibenzo[b,f] thiepin 5,5-dioxide, 10 ml. pyridine, 5 ml. acetic acid, and 5 ml. water. Add 0.5 g. sodium hypophosphite and approximately 0.1 g. Raney nickel. Stir at 250C. for 24 hours and then at 45-50 C. for 2 hours. Filter the reaction mixture to remove the catalyst and wash any product from the catalyst using 10 ml. ethyl acetate. Add 10 ml. 6N hydrochloric acid and separate the organic layer containing the product. Evaporate the organic layer to obtain a solid residue comprising the title product, m.p., 175-177"C. Swishing with methanol and drying the residue gives product melting at 177-1780C. EXAMPLE 38 Dibenzo ib, f] thiepin-3-carboxaldehyde Saturate a suspension of anhydrous stannous chloride (378 mg; 2 mmole) in 7.5 ml. dry ether with hydrogen chloride at a temperature of 0-50C., and add 235 mg. (1 mmole) of 3-cyano-dibenzo[b,f]thiepin. Stir for one hour at OOC. and allow to warm to room temperature (250C.). Continue stirring at room temperature for approximately 48 hours. Add 5 ml. of water and 1 ml. 2N hydrochloric acid, and extract with a mixture of 5 ml. ether and 5 ml. ethyl acetate. When the hydrolysis of the chloro stannate is complete, evidenced by the disappearance of solids from the solution, separate the organic layer containing the product, wash with water/sodium chloride solution, and after drying, evaporate the solution to produce a dark oil which solidifies when triturated with hexane. The title product is obtained when the above solid material is crystallized from acetonitrile, m.p. 114.5-115.5 C. EXAMPLE 39 Dibenzo [b,f]thiepin-3-carboxaldehyde 5-oxide Dissolve 512 mg. (2 mmole) of 3-hydroxymethyldibenzo[b,f]thiepin 5-oxide in 50 ml. of methylene chloride and add 648 mg. (3 mmole) of pyridinium chlorochromate. Stir at room temperature for 1.5 hours and then filter the mix through a bed of Florisil. Wash the Florisil with dichloromethane; and to the combined filtrate, add 4 g. of silica gel. Evaporate the suspension to dryness, and place the solid on top of a column of 50 g. of silica and elute the title compound with a 1:9 mixture of ethyl acetate and toluene. The compound has a m.p. of 188-1900C. EXAMPLE 40 10,11-Dihydro-dibenzoib,f]thiepin-3-carboxaldehyde Mix 4.74 g. (20 mmole) of 3-cyano-l0,ll-dihydro- dibenzolb,fZthiepin with 7.56 g. (40 mmole) anhydrous stannous chloride and 150 ml. ether saturated with anhydrous hydrogen chloride. Stir the mixture at 250C. for approximately 50 hours to produce a crystalline solid suspended in the reaction mixture. Shake the crystalline solid with 200 ml. ice water, and extract with 150 ml. ethyl acetate using methanol to dissolve any residual lumpy yellow solid. Separate the ethyl acetate layer containing the product, and after washing with water/saturated chloride solution and drying, the ethyl acetate is removed by evaporation to produce as a residue an amber-colored oil, which cystallizes overnight. Distill the crystalline residue under reduced pressure at 1450C. at 0.04 mm. The distilled product crystallizes, m.p. 55.5-56.50C. EXAMPLE 41 l0,ll-dihydro-dibenzo [b,f]thiepin-3-carboxaldehyde 5-oxide Mix 2.84 g. (11.83 mmole) of 10,11-dihydro-di benzo[b,f)thiepin-3-carboxaldehyde with 90 ml. methylene chloride at OOC. Add 2.3 g. (11.33 mmoles) of 85% mchloroperbenzoic acid, followed by the addition of 100 ml. methylene chloride. Stir for 2 hours, and then add 4.6 g. calcium hydroxide to the resulting clear solution at room temperature. After stirring the suspension for 15 minutes, filter to remove the inorganic solid, and evaporate the filtrate containing the dissolved product to dryness, producing as a residue a dry solid comprising the title product. Purify by recrystallization from acetonitrile, m.p. 158.5-1600C. EXAMPLE 42 10,11-Dihydro-dibenzotb,f]thiepin-3-carboxaldehyde 5,5dioxide Repeat the procedure of Example 39, substituting an equivalent amount of 10,11-dihydro-3-hydroxymethyl- dibenzotb,f]thiepin 5,5-dioxide in place of 3-hydroxy methyldibenzo[b,f]thiepin 5-oxide to obtain the title compound, m.p., 135-136eC. EXAMPLE 43 8-Fluoro-dibenzo [b, f] thiepin-3-carboxaldehyde Dissolve 568 mg. (2.2 mmole) of 2-fluoro-7 hydroxymethyldibenzo[b,fjthiepin in 30 ml. of methylene chloride and add 647 mg. of 98% pyridinium chlorochromate. Stir the mixture and follow the reaction by thin layer chromatography (Merck silica gel F254 with 5% ethyl acetate in toluene). When complete, filter the mixture through a bed of Florisil, and wash through with methylene chloride. Evaporate the filtrate to obtain a brown solid (600 mg.). Purify the crude product by chromatography on silica gel using toluene as solvent to obtain the title compound as a yellow solid, m.p., 137-1390C. EXAMPLE 44 8-Fluoro-dibenzo Ib,f]thiepin-3-carboxaldehyde 5-oxide Repeat the procedure of Example 39, substituting an equivalent amount of 3-hydroxymethyl-8-fluorodibenzo [b,f]thiepin 5-oxide in place of the 3-hydroxymethyldi benzo[b,f]thiepin 5-oxide to obtain the title compound, m.p., 212-2140C. EXAMPLE 45 8-Fluoro-dibenzotb,f]thiepin-3-carboxaldehyde 5,5-dioxide Repeat the procedure of Example 39, substituting an equivalent amount of 3-hydroxymethyl-8-fluorodibenzo [b,f]thiepin 5,5-dioxide in place of 3-hydroxymethyldi benzotb,f]thiepin 5-oxide to obtain the title compound, m.p., 200-2020C. EXAMPLE 46 8-Fluoro-lotll-dihydrodibenzotbtfJthiepin-3-carboxaldehyde Proceeding as in Example 39, but starting with 0.5 g. (1.9 mmole) of 8-fluoro-3-hydroxymethyl-l0,11-di- hydrodibenzojb,f]thiepin, there is obtained 0.42 g. (84%) of 8-fluoro-3-formyl-10,11-dihydrodibenzotb,f]thiepin, m.p., 78-790C. EXAMPLE 47 8-Fluoro-1O,11-dihydrodibenzo[b,f]thiepin-3-carboxaldehyde 5-oxide Proceeding as in Example 39, but starting with 0.5 g. (1.8 mmole) of 8-fluoro-3-hydroxymethyl-10,11-di- hydrodibenzo[b,f]thiepin 5-oxide, there is obtained 0.38 g. (77%) of 8-fluoro-3-formyl-10,11-dihydrodibenzo- [b,f]thiepin 5-oxide, m.p., 188-1890C. EXAMPLE 48 8-Fluoro-10,11-dihydrodibenzo[b,f]thiepin-3-carboxaldehyde 5,5-dioxide Proceeding as in Example 39, but starting with 0.5 g. (1.7 mmole) of 8-fluoro-3-hydroxymethyl-10,ll-di- hydrodibenzo[b,f]thiepin 5,5-dioxide, there is obtained 0.43 g. (87%) of 8-fluoro-3-formyl-10,11-dihydrodibenzo- [b,f]thiepin 5,5-dioxide, m.p., 155-1560C. EXAMPLE 49 8-Aminodibenzo[b,f]thiepin-3-carboxaldehyde 5,5-dioxide Repeat the procedure of Example 38, substituting an equivalent quantity of 8-amino-3-cyanodibenzo[b,f]thi- epin 5,5-dioxide in place of 3-cyanodibenzo[b,f]thiepin 5,5-dioxide to obtain the title product. EXAMPLE 50 8-Chlorodibenzotb,f]thiepin-3-carboxaldehyde Repeat the procedure of Example 38, substituting an equivalent quantity of 8-chloro-3-cyano-dibenzo[b,f]thiepin for the 3-cyano-dibenzo[b,f]thiepin to obtain the title product. EXAMPLE 51 8-Chlorodibenzo[b,f]thiepin-3-carboxaldehyde 5-oxide and 5, 5-dioxide Repeat the procedure of Example 41, substituting an equivalent quantity of 8-chlorodibenzotb,f]thiepin-3- carboxaldehyde in place of the 10 ,ll-dihydrodibenzo [b,f]- thiepin-3-carboxaldehyde to obtain the title 5-oxide compound. Repeat the above procedure using twice the equivalent amount of m-chloroperbenzoic acid to obtain the corresponding 5,5-dioxide. EXAMPLE 52 8-Hydroxydibenzo [b, f] thiepin-3-carboxaldehyde Repeat the procedure of Example 37, substituting an equivalent quantity of 3-cyano-8-hydroxydibenzo[b,fi- thiepin in place of the 3-cyano-dibenzo[b,f]thiepin 5,5dioxide to obtain the title compound. EXAMPLE 53 8-Hydroxydibenzotb,f]thiepin-3-carboxaldehyde 5,5-dioxide Repeat the procedure of Example 37 using an equivalent amount of 3-cyano-8-hydroxydibenzotb,f]thiepin 5,5-dioxide in place of 3-cyano-dibenzo[b,fithiepin 5,5dioxide to obtain the title compound. EXAMPLE 54 8-Methylthiodibenzo[b,f]thiepin-3-carboxaldehyde Repeat the procedure of Example 38, substituting 3-cyano-8-methylthio-dibenzo[b,f]thiepin in place of 3cyano-dibenzo[b,f]thiepin to obtain the title product. EXAMPLE 55 8-Methylsulfinyldibenzo [b, f thiepin-3-carboxaldehyde Repeat the procedure of Example 41 using an equivalent amount of 8-methylthiodibenzo[b,f]thiepin-3- carboxaldehyde in place of 10,11-dihydrodibenzo[b,f]thi- epin-3-carboxaldehyde to obtain the title product. EXAMPLE 56 8-Methylthiodibenzo [b,f]thiepin-3-carboxaldehyde 5-oxide Dissolve 8-methylthiodibenzo [b,f]thiepin-3- carboxaldehyde (5 mmole) in methylene chloride (100 ml.); and while cooling the solution in an ice-bath, add a 1 M solution of 90t nitric acid in methylene chloride (5 ml.). Monitor the reaction mixture by tlc after 30 minutes, and add the nitric acid solution in small increments until starting material has disappeared. Treat the reaction mixture with sodium bicarbonate solution to remove acidic substances. Dry the organic solution, evaporate to dryness, and purify the title product by column chromatography on silica gel using 1:4 ethyl acetate/toluene for elution. EXAMPLE 57 8-Methylsulfinyldibenzo [b ,f] thiepin-3-carboxaldehyde 5oxide ¯¯¯¯¯¯¯¯¯¯¯¯¯ Repeat the procedure of Example 56 usinq 3 to 5 equivalents of 1 M nitric acid in methylene chloride in place of sliqhtly more than one equivalent to obtain the title compound. EXAMPLE 58 8-Methylthiodibenzo fb, f] thiepin-3-carboxaldehyde 5,5-dioxide React 8-methylthiodibenzo [b,f] thiepin-3-carb- oxylic acid 5,5-dioxide with excess thionyl chloride under reflux until conversion to the acid chloride is complete. Distill off excess thionyl chloride under vacuum and remove the last traces by adding benzene to the residue and evaporating under vacuum. Dissolve the crude 8-methylthiodibenzo [b, fi - thiepin-3-carboxylic acid chloride 5,5-dioxide in glyme, and with stirring under dry nitrogen, add a filtered solution of 1.1 equivalents of lithium tri-tertiary butoxyaluminum hydride in glyme dropwise with cooling (ice-bath) Stir the mixture for 1 hour after the addition is complete and pour into ice-cold dilute hydrochloric acid. Isolate the crude title compound by extraction with chloroform and purify the compound by column chromatography on silica gel using toluene as the solvent. EXAMPLE 59 8-Methylsulfinyldibenzo[b,f]thiepin-3-carboxaldehyde 5,5dioxide Repeat the procedure of Example 41, substituting an equivalent quantity of 8-methylthiodibenzo[b,f]thiepin3-carboxaldehyde 5,5-dioxide in place of 10,11-dihydrodi benzo[b,f]thiepin-3-carboxaldehyde to obtain the title product. EXAMPLE 60 8-Methylsulfonyldibenzoib,fZthiepin-3-carboxaldehyde Repeat the procedure of Example 58, substituting 8-methylsulfonyldibenzolb,f]thiepin-3-carboxylic acid in place of 8-methylthiodibenzo ib, f) thiepin-3-carboxylic acid 5,5-dioxide to obtain the title product. EXAMPLE 60 8-Nitrodibenzo [b, f] thiepin-3-carboxaldehyde Heat a mixture of 8-nitrodibenzolb,f]thiepin-3- carboxylic acid and excess thionyl chloride under reflux until conversion to the acid chloride is complete. Evaporate excess thionyl chloride under vacuum and remove traces of thionyl chloride from the product by treating the residue with benzene and evaporating again under vacuum. Stir a mixture of the crude 8-nitrodibenzo[b,f]thiepin-3-carboxylic acid chloride in dry tetrahydrofuran at -780C. under nitrogen, and add dropwise a filtered solution of 1.1 equivalents of lithium tri-tertiarybutoxyaluminum hydride in tetrahydrofuran. Stir the mixture for 30 minutes at -78 C. and allow to warm to ambient temperature. Add the mixture to ice-cold dilute hydrochloric acid, and isolate the product by extraction with chloroform. Purify the title compound by chromatography on silica gel using a mixture of ethyl acetate and toluene for elution. EXAMPLE 61 8-Nitrodibenzo [b,f]thiepin-3-carboxaldehyde 5-oxide and 5, 5-dioxide Repeat the procedure of Example 41, substituting 8-nitrodibenzotb,f]thiepin-3-carboxaldehyde in place of 10, ll-dihydrodibenzo [b, f] thiepin-3-carboxaldehyde to obtain the title 5-oxide compound. Repeat the above procedure using twice the equivalent amount of m-chloroperbenzoic acid to obtain the corresponding 5,5-dioxide. EXAMPLE 62 8-Methoxydibenzoib,f]thiepin-3-carboxaldehyde Repeat the procedure of Example 39, substituting an equivalent quantity of 3-hydroxymethyl-8-methoxydi benzoib,f]thiepin for the 3-hydroxymethyldibenzo [b,f]- thiepin to obtain the title product. EXAMPLE 63 8-Methoxydibenzo [b,f]thiepin-3-carboxaldehyde 5-oxide Repeat the procedure of Example 41, substituting an equivalent quantity of 8-methoxydibenzo[b,f]thiepin-3- carboxaldehyde in place of the 10, ll-dihydrodibenzo [b,f]- thiepin-3-carboxaldehyde to obtain the title 5-oxide compound. Repeat the above procedure using twice the equivalent amount of m-chloroperbenzoic acid to obtain the corresponding 5,5-dioxide. The compounds of formula I and IA wherein Z is defined as sulfinyl are capable of existing as optical isomers because of the tetrahedral structure of the sulfoxide substituent. Thus, the sulfoxide disclosed in the Examples are racemic mixtures of D and L isomers which may be resolved by known procedures into their enantiomers. Each of the enantiomorphic isomers may exhibit variation in biological potency. Thus, the compounds of Examples 2, 5, 8, 11, 23, 32, 35, 39, 41, 44, 47, 56, 57 and the 5-oxide compounds prepared in 51, 61 and 63 may be resolved by conventional procedures into their D and L enantiomorphs.

Claims: WHAT IS CLAIMED IS: 1. A compound of the formula: EMI43.1 or an ester or acetal thereof, wherein n is an integer from 1 to 4; z is thio, sulfinyl, or sulfonyl; RÚ and/or Rê is hydrogen, halogen including chloro, bromo, fluoro and iodo, amino, C1 to C4 alkyl, C1 to C4 alkanoyl, hydroxyl, C1 to C4 alkoxy, thiol, C1 to C4 alkylthio, C1 to C4 alkylsulfinyl, C1 to C4 alkylsulf onyl, trifluoromethyl, trifluoromethylthio, cyano, nitro, and C1 to C4 alkyl or dialkylamino, aralkyl including benzyl and phenethyl, hydroxyalkyl as CH3CHOH; and the dotted line indicates either an olefinic bond or sat uration at the 10-, ll-position. 2. A compound according to Claim 1 where Z is thio. 3. A compound according to Claim 1 where the dotted line indicates an olefinic bond. 4. A compound according to Claim 1 where the dotted line indicates saturation. 5. A compound according to Claim 1 selected from 3-hydroxymethyldibenzo[b,f]thiepin, 3-hydroxymethyldibenzo[b,f]thiepin-5-oxide, 3-hydroxymethyldibenzo[b,f] thiepin-5,5-dioxide, 8-fluoro-3-hydroxymethyldibenzo[b,f] thiepin, 8-fluoro-3-hydroxymethyldibenzo[b,f]thiepin-5-oxide, 8-fluoro-3-hydroxymethyldibenzo[b,f]thiepin-5,5-dioxide, 3-hydroxymethyl-1O,11-dihydrodibenzo[b,f]thiepin, 3-hydroxy methyl-l0,11-dihydrodibenzo [b,f]thiepin-5-oxide, 3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin-5,5-dioxide, 8-fluoro 3-hydroxymethyl-10,11-dihydrodibenzotb,f]thiepin, 8-fluoro- 3-hydroxymethyl-1O,11-dihydrodibenzo[b,f]thiepin-5-oxide, 8-fluoro-3-hydroxymethyl-10,11-dihydrodibenzo[btf]thiepin- 5,5-dioxide, dibenzo [b,f] thiepin-3-carboxaldehyde, dibenzo[b,f] thiepin-3-carboxaldehyde 5-oxide, dibenzotb,f]thiepin-3- carboxaldehyde 5,5-dioxide, 8-fluoro-dibenzo[b,f]thiepin-3- carboxaldehyde, 8-fluoro-dibenzo[b,f]thiepin-3-carboxaldehyde 5-oxide, 8-fluoro-dibenzolb,f]thiepin-3-carboxaldehyde 5,5 dioxide, 10,11-dihydrodibenzolb,f]thiepin-3-carboxaldehyde, 10,11-dihydrodibenzo[b,f]thiepin-3-carboxaldehyde 5-oxide, 10,11-dihydrodibenzo[b,f]thiepin-3-carboxaldehyde 5,5dioxide, 8-chloro-dibenzo[b,f]thiepin-3-carboxaldehyde, 8-chloro-dibenzo[b,f]thiepin-3-carboxaldehyde 5-oxide, 8-chloro-dibenzo[b,f]thiepin-3-carboxaldehyde 5,5-dioxide, 8-hydroxydibenzo[b,f]thiepin-3-carboxaldehyde, 8-hydroxy dibenzo[b,f]thiepin-3-carboxaldehyde 5,5-dioxide, 8-fluoro 10,11-dihydrodibenzo[b,f]thiepin-3-carboxaldehyde, 8-fluoro10,11-dihydrodibenzo[b,f]thiepin-3-carboxaldehyde 5-oxide, 8-fluoro-10,11-dihydrodibenzolb,f]thiepin-3-carboxaldehyde 5,5-dioxide, 8-methoxydibenzo [b,f] thiepin-3-carboxaldehyde, 8-methoxydibenzo[b,f]thiepin-3-carboxaldehyde 5-oxide, 8-methoxydibenzo [b, f] thiepin-3-carboxaldehyde 5,5-dioxide, 8-methylthiodibenzotb,f]thiepin-3-carboxaldehyde, 8-methyl thiodibenzo[b,f]thiepin-3-carboxaldehyde 5-oxide, 8-methyl thiodibenzo[b,f]thiepin-3-carboxaldehyde 5,5-dioxide, 8-methylsulfinyldibenzo[b,f]thiepin-3-carboxaldehyde, 8-methylsulfinyldibenzo[b,f]thiepin-3-carboxaldehyde 5oxide, 8-methylsulfinyldibenzo[b,f] thiepin-3-carboxaldehyde 5,5-dioxide, 8-methylsulfonyldibenzo[b,f]thiepin-3-carbox- aldehyde, 8-methylsulfonyldibenzo fb, f thiepin-3-carbox- aldehyde 5-oxide, 8-methylsulfonyldibenzo[b,f]thiepin- 3-carboxaldehyde 5,5-dioxide, 8-nitrodibenzo[b,f]thiepin- 3-carboxaldehyde, 8-nitrodibenzo [b, f] thiepin-3-carboxaldehyde 5-oxide, and 8-nitrodibenzotb,fJthiepin-3-carboxaldehyde 5,5-dioxide. 6. A process for preparing a compound of the formula: EMI45.1 wherein n is an integer from 1 to 4; Z is thio, sulfinyl, or sulfonyl; R1 and/or R2 is hydrogen, halogen including chloro, bromo fluoro and iodo, amino, C1 to C4 alkyl, C1 to C4 alkanoyl, hydroxyl, C1 to C4 alkoxy, thiol, C1 to C4 alkylthio, C1 to C4 alkylsulfinyl, C1 to C4 alkylsul fonyl, trifluoromethyl, trifluoromethylthio, cyano, nitro, and C1 to C4 alkyl or dialkylamino, aralkyl including benzyl and phenethyl, hydroxyalkyl as CH3CHOH: and the dotted line indicates either an olefinic bond or saturation at the 10-, ll-position; which comprises reducing a compound of the formula: EMI46.1 with an alkali metal aluminum hydride or borane to convert the COOH substituent into a hydroxymethyl substituent. 7. A process for preparing a compound of the formula: EMI46.2 or an ester or acetal thereof, wherein Z is thio, sulfinyl, or sulfonyl; R1 and/or R2 is hydrogen, halogen including chloro, bromo fluoro and iodo, amino, C1 to C4 alkyl, C1 to C4 alkanoyl, hydroxyl, C1 to C4 alkoxy, thiol, C1 to C4 alkylthio, C1 to C4 alkylsulfinyl, C1 to C4 alkylsul fonyl, trifluoromethyl, trifluoromethylthio, cyano, nitro, and C1 to C4 alkyl or dialkylamino, aralkyl including benzyl and phenethyl, hydroxyalkyl as CH3CHOH; and the dotted line indicates either an olefinic bond or saturation at the 10-, ll-position; which comprises reducing a compound of the formula: EMI46.3 with a metal containing reducing agent, followed by hydrolysis. 8. A composition for treating undesirable contractile activity of prostaglandins consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula: EMI47.1 or an ester or acetal thereof, wherein n is an integer from 1 to 4; Z is thio, sulfinyl, or sulfonyl; R1 and/or R2 is hydrogen, halogen including chloro, bromo fluoro and iodo, amino, C1 to C4 alkyl, C1 to C4 alkanoyl, hydroxyl, C1 to C4 alkoxy, thiol, C1 to C4 alkylthio, C1 to C4 alkylsulfinyl, C1 to C4 alkylsul fonyl, trifluoromethyl, trifluoromethylthio, cyano, nitro, and C1 to C4 alkyl or dialkylamino, aralkyl including benzyl and phenethyl, hydroxyalkyl as CH3CHOH. and the dotted line indicates either an olefinic bond or saturation at the 10-, ll-position.

Inventors: HAMEL, PIERRE A., ROKACH, JOSHUA A.
Applicants: MERCK SHARP & DOHME (I.A.) CORP.
Application year: 1980
Main classification: C07D337
IPC codes: C07D337