NO760297L - - Google Patents

Description

Method of manufacture of

6,11-dihydrodibenzo-thiepin-11-one derivatives.

The present invention relates to new 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one derivatives from one of the following formula groups:

or individual (d)-acid isomers or (1)-acid isomers of formula (B), where R denotes hydrogen, alkyl with from 1 to 12 C atoms, as well as pharmaceutical salts thereof when R denotes hydrogen, or esters and pharmaceutical salts of single isomers of formula B, and processes for their preparation.

The invention also includes compositions, preparations and methods of use for compounds of formula A, B or the (d)-acid isomer of formula B or said esters and pharmaceutical salts of the (d)-acid isomer.

The term "alkyl" includes branched and straight chain hydrocarbons having from 1 to 12 carbon atoms. Typical alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isoamyl, neopentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl, dodecyl and the like.

The term "pharmaceutical salts" refers to salts prepared from pharmaceutically usable and non-toxic bases, including inorganic and organic bases. Salts of inorganic bases can be sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganese(II), aluminium, ferric, manganese(IV) salts and the like. Ammonium, potassium, sodium, calcium and magnesium salts are particularly preferred. Salts of pharmaceutical, organic uggitigé bases include

among others, salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, for example isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine , histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethafflin, choline and caffeine.

The new compounds of formula B and formulas 10, 11, 12 and 14 as shown later exist as pairs of optical isomers (or enantiomorphs), i.e. a (dl) mixture.

When the new compounds according to the invention are used as physiological reagents (such as anti-inflammatory, analgesic and anti-pyretic agents), a preferred subgroup are compounds of formula A and B and the (d)-acid isomer of formula B as well as their esters and pharmaceutical salts.

A further subgroup for substances to be used as medicinal preparations are compounds of formula B and the (d)-acid isomer of formula B and their esters and pharmaceutical salts, and this subgroup can be divided into two further subgroups consisting of ( a) compounds of formula B, i.e. the (dl) compounds and (b) the (d) acid isomer of formula B and esters and pharmaceutical salts thereof. The (1)-acid isomer of formula B and their esters and pharmaceutical salts are useful as intermediates for the preparation of the (dl)-acid of formula B as described more fully later.

Japanese Patent 425/72 (1972) generally describes compounds of formula:

C<l><2>and S

where R , R and R all denote hydrogen atoms or a lower alkyl group (e.g. methyl, ethyl, propyl and isopropyl), X denotes a hydrogen atom, a halogen atom (Cl, Br, J and F) or a lower alkyl group and Y denotes an oxygen atom , -CH0S- or^(where R^denotes a hydrogen atom or, a lower alkyl group)]

or salts thereof, and mentions in particular in example 3 H-oxo-6,11-dihydro-dibenzp-(b.e.)-thiepin-2-yl-acetic acid.

German Specification 24.42.060 (published 1975) generally describes oxepin compounds of formula:

where X is equal to C=O, CHC1, CHBr, CH2 or CHOR^; Y denotes alkyl with from 1 to 4 carbon atoms, alkoxy with from 1 to 4 carbon atoms, halogen or trifluoromethyl; n is a number 0, 1, 2 or 3>

Z represents C00r<5>, CH^OR^, CONR^ or CONHOR^; and R<1>toR^ denotes hydrogen or alkyl with from 1 to 4 C atoms...

Certain oxepin compounds are described, also in Belgian Patent No. 818.O55 (issued November 18, 1974)*

The new compounds according to the present invention, namely substances of formula. oxo-6,11-""dihydrodibenzo [b .e.) thiepin-2-yl-acetic acid and ll-oxo-6,11-dihydro-benzo (b.e.) thi<pi>n-2-yl-propionic acid), judged by the rat's paw carrageenan method, as discussed later.

The new compounds according to the invention are produced

according to the reaction core below:

The diisopropylnitroterephthalate (1) is prepared by

to esterify nitroterephthalic acid (a) with isopropanol, the isopropanol serving both as a reaction agent and solvent, in the presence of hydrogen chloride at between approx. 25°C and the addition of the mixture

backflow temperature, ■ for a period of between approx. /\. Q and 200 hours. Generally, it is preferred to carry out the reaction by reflux

for 48 to 96 hours.

The diisopropylnitroterephthalate (1) is then treated with benzyl mercaptan and sodium hydride in the presence of a suitable organic solvent such as dimethylformamide, dimethylsulfoxide and the like at a temperature between approx. -40°C and 50°C, preferably between approx. -35°C°g 20°C, in periods between approx. one hour and ten hours., preferably between two and three hours, for the preparation of diisopropyl (benzylthio) terephthalate (2)i.

Base hydrolysis of (2) gives the (benzylthio)-tefcephthalic acid (3). This reaction is carried out by treating (2) with base, e.g. potassium hydroxide, sodium hydroxide and the like, in the presence of water and an organic solvent such as methanol, ethanol, propanol and the like, at a temperature between approx. /\. 0°C and the reflux temperature of the reaction mixture, for between 1 and 12 hours. Preferably, the hydrolysis reaction is carried out with aqueous methanolic potassium hydroxide at reflux temperature.

(Benzylthio)-terephthalyl chloride (4) is prepared by treating (3) with thionyl chloride at a temperature of between approx. 25°C and the reflux temperature of the reaction mixture for 1 to 6 hours. Preferably, the reaction takes place at reflux temperature.

The cyclization reaction whereby (4) is converted to 6,11-dihydroctibenzo-(b.e.]-thiepin-11-one-3-carbonyl chloride (5) is carried out by treating (4) with nitromethane and aluminum chloride in the presence of a suitable organic solvent such as methylene chloride, carbon disulfide, o-dichlorobenzene and the like at a temperature between about 15°C and 3^°C>for half an hour to 24 hours, preferably at about 20°C to 25°C and for 4 to 12 hours.The preferred solvent is methylene chloride.

The conversion of (5) to 3-<Ayazoacetyl-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one (6) is effected by treating (5) with diazomethane in an organic solvent such as methylene chloride, ether, carbon tetrachloride and the like , or their mixtures,

at between approx. -20°C and 10°C, for periods of from 15 minutes to 12 hours. Preferably, the reaction takes place at a temperature of between approx. -5°C and 5°C in times of 15: minutes to approx. 60 minutes.

The rearrangement of (6) to methyl-6,11-dihydrodibénzo-

Cb.e.] -thiepin-ll-one-3-acetate (7) occurs by careful mixing

of (6) with methanol at a temperature between 50°C and the mixture's reflux temperature, after which a silver salt such as silver benzoate, dissolved or suspended in a solvent such as methanol or triethylamine, is added in portions. In the same way, other "^- esters are produced which otherwise correspond to (7) by

use the appropriate alkyl alcohol containing 2 to 12 carbon atoms instead of methanol.

Hydrolysis of (7) to 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (8) occurs by heating (7) with a base such as potassium hydroxide, sodium hydroxide, sodium carbonate or the like in the presence of water and an organic solvent such as methanol, ethanol, propanol and the like at a temperature between approx.

0°C and 7°°c>in periods of from 1 to 24 hours. The hydrolysis reaction advantageously takes place with aqueous methanolic potassium hydroxide at 20 to 30°C. In a similar way, the other 3-esters produced above can be hydrolysed to 3-acetic acid (8). The hydrolysis temperature will depend on the particular ester that is hydrolysed and can therefore lie between approximately 0°C and reflux temperature.

Treatment of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-carbonyl chloride (5) with diazoethane in an organic solvent such as ether, methylene chloride, carbon tetrachloride and the like at between -30°C and -10 °C gives 3-(S-diazoporpionyl)-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one (9). It is advantageous to carry out this reaction with ethereal diazoethane at between -25 and -20°C.

The rearrangement of (9) to benzyl(dl)-2-(6,11-dihydro-dibenzd-Cb.e.)-thiepin-11-on-g-yl) propionate (10) occurs by treating (9) with a high-boiling alcohol such as benzyl alcohol in the presence of an organic amine such as collidine, quinoline, diethylaniline and the like at a temperature of approx. 160°C to 190°C for about one minute to one hour, preferably at 170°C to 175°C for about 2 to 30 minutes.

To achieve the production of the free acid, (dl)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-on-3-yl)propionic acid (12) in purer form, (10) first undergoes base hydrolysis as above described for conversion of (7) to (8) [or (2) to (3)3 ,

followed by treatment with dicyclohexylamine to give dicyclohexylammonium-(dl)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-on-3-yl)propionate (11).

The conversion of (11) to (dl)-2-(6,11-dihydrodibenzo-(b.e.j -thiepin-11-on-3-yl)propionic acid (.12) occurs by treating (11) in an organic solvent such as methylene chloride , ether, benzene and the like, with an acid salt or a strong acid, for example, sodium hydrogen sulfate, hydrochloric acid, sulfuric acid and the like at a temperature of about 0°C to ^ 0°C for about a minute to an hour, preferably eved 20°C to 25°C for about one to five minutes.

Alternatively, compounds of formula (12) are prepared as indicated by the following reaction core:

where RT denotes an alkyl group with from 1 to 12 C atoms.

a-methylation of the compounds of formula (13)»esters of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (R' = alkyl ^ y^ i^' ^or'trinnsv:i-s Rf = methyl) to compounds of formula (14) > esters of (dl)-2-(6,11-dihydrodibenzo-(b.e.J - thiepin-11-on-3-yl)propionic acid (RT = alkyl C]_-C] _2> preferably R' = methyl), occurs by treating compounds of formula (13) with an alkali metal hydride, alkali metal amide, alkali metal dialkyl amide, and the like, for example sodium hydride, lithium diisopropyl amide or sodium dimethyl amide, in the presence of a polar aprotic solvent as N,N-dimethylacetamide, dimethylformamide,.hexa-

methyl phosphoric acid triamide (HMPA), dimethyl sulfoxide, sulfolane and the like at a temperature between approx. 10 and 60°C, followed by treatment with methyl halide such as methyl iodide or a dialkyl sulfate such as dimethyl sulfate at between approx. -15 and 60°C for approx. 5 minutes to 1 hour.

The compounds of formula (14) are then hydrolysed to free acids of formula (12) as described earlier for the hydrolysis of compounds of formula (7) to formula (8).

The methods for preparing compounds of formula (13) where R' denotes C 8 -C 14 -alkyl are described in full in the following. The (dl) mixture of (12) is separated into the respective d-isomer, the (12)-(d)-acid isomer and the 1-isomer, the (12)-(1)-acid isomer according to known methods , e.g. the separation methods described in example 12B.

After preparation, the free acids of formula (8), (12), the (12)r(d)-acid isomer and the (12)-(l)-acid isomer can be converted into the corresponding esters and acid addition salts.

The salt derivatives of compounds of formula (8), (12), the (12)-(d)-acid isomer and the (12)-(l)-acid isomer are prepared by

treating these free acids with a suitable amount of pharmaceutically acceptable base. Representative pharmaceutical bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide,

.calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganese (CET) hydroxide, aluminum hydroxide, ferric hydroxide, manganese (IV) hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-?ethylpiperidine, polyamine resins and the like. The reaction is carried out in water, alone or combined with an inert, water-miscible organic solvent at a temperature of approx. 0°C to 100°C, preferably at room temperature. Typical inert and water-miscible organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio between compounds of formula (8), (12), the (12)-(d)-acid isomer and the (12)-(1)-acid isomer and the base used

are chosen so that the right conditions are achieved for the particular situation

salt. For the production of e.g. calcium salts or magnesium salts of compounds of formula (A) and (B), and the individual (d)- and (1)-acid isomers of the latter, one can treat the fUe acid of formula (8), (12) , the (12)-(d)-acid isomer and the (12)-(1)-acid isomer, respectively, with at least half a molar equivalent of pharmaceutical base to produce a neutral salt. When preparing aluminum salts of compounds of formula (A) and

(B) and the individual (d)- and (1)-acid isomers of the latter are used at least one-third molar equivalent of pharmaceutical base if

you want a neutral salt product.

In a preferred method, calcium salts and magnesium salts of compounds of formula (A) and (B), and calcium and magnesium salts of the (d)- and (1)-acid isomer of formula (B) are prepared by treating the corresponding sodium - or potassium salts of compounds of formula (A.) and (B), and sodium or potassium salts of the (d)- and (1)-acid isomer of formula (B) with at least half a molar equivalent of calcium chloride or magnesium chloride , respectively, in aqueous solution, alery or combined with an inert water-miscible organic solvent, at a temperature of between approx. 20°C and 100°C. Preferably, the aluminum alloy of compounds of formula (A) and (B) and the aluminum salt of the (d)- and (1)-acid isomer of formula (B) can be prepared by treating the corresponding free acids of compounds of formula (8), (12), (12)-(d)-isomerene and (12)-(1)-isomer with at least one-third molar equivalent of aluminum alkoxide such as aluminum trietoxide, aluminum tripropoxide and the like in a hydroca. rbdn solvent such as benzene, xylene, cyclohexane and the like at a temperature of approx. 20°C to 115°C. Similar methods can be used for the preparation of salts of inorganic bases which are not sufficiently soluble for simple reaction.

'. Salt production is isolated in a known manner. E.g. the reaction mixture is evaporated to dryness and the salts can be further purified in known ways.

Salt derivatives of compounds of formula (8), (12) and salt derivatives of the 12-(d)-acid isomer and the 12-(1)-acid isomer can be reduced to their respective free acids by acidifying the salts with an acid, preferably an inorganic acid such as hydrochloric acid or sulfuric acid at temperatures between 0°C and 0°C, preferably at room temperature.

Esters of formula (A) and (B) and esters of the (d)-acid isomer and the (1)-acid isomer of formula (B) are prepared by esterifying the corresponding free acids of formula (8), (12 ), the (12)-(d)-acid isomer and the (12)-(1)-acid isomer with an alcohol corresponding to the desired ester, e.g. an alkanol with up to 12 C atoms. This reaction is carried out in the presence of a strong acid such as boron trifluoride, hydrogen chloride, sulfuric acid, p-toluenesulfonic acid and the like. If the alcohol reagent used for the esterification is a liquid at the reaction temperature, the alcohol can be a solvent. Optionally, the reaction can be carried out in an inert, organic solvent which dissolves the free acid of formula (8), (12), the (12)-(d)-acid isomer and the (12)-(1)-acid isomer and the alcohol , for example a hydrocarbon solvent such as hexane, iso-octane, decane, cyclohexane, benzene, toluene, xylene; a halogenated hydrocarbon such as methylene chloride, chloroform, dichloroethane, or an ether such as diethyl ether, dibutyl ether, dioxane, tetrahydrofuran and the like. When the alcohol is solid, the reaction can preferably take place in anhydrous, inert, organic solvent. The reaction is carried out at between 0°C and the reflux temperature of the mixture) preferably with hydrogen chloride and at a temperature between 15°C and 35°c

The product is isolated in a known manner, e.g. by diluting the reaction mixture with water, extracting the reaction mixture with an inert organic solvent which is not miscible with water, for example diethyl ether, benzene, methylene chloride, and the like, combining the extracts, washing the extracts with water to neutrality and evaporation under reduced pressure.

The preferred acid esters of formula (A) and (B) and esters of the (d)-acid isomer and the (1)-acid isomer of formula (B) are ester derivatives prepared from methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol , 2-butyl alcohol, isoamyl alcohol, pentyl alcohol, 2-pentyl alcohol, isopentyl alcohol, hexyl alcohol, 2-hexyl alcohol, isohexyl alcohol, heptyl alcohol, 2-heptyl alcohol, isoheptyl alcohol, octyl alcohol, 2-octyl alcohol, isooctyl alcohol, nonyl alcohol, 2-nonyl alcohol, isononyl alcohol, decyl alcohol , 2-decyl alcohol, isodecyl alcohol, undecyl alcohol, dodecyl alcohol and the like.

Alternatively, esters of formula (A) and (B) and esters of the (d)-acid isomer and the (1)-acid isomer of formula (B) can be prepared by transesterification in a known manner. It is an advantage for the production of esters by transesterification to go from a lower to a higher ester, e.g. from the methyl ester to the isoamyl ester. However, by using a significant excess of lower alcohol, a higher ester can be converted into a lower ester, e.g. by using a large excess of ethanol, the hexyl ester can be transesterified to the ethyl ester.

The (12)-(1)-acid isomer, (1)-2-(6,11-dihydrodibenzo-, (,b.e.)-thiepin-11-on-3-yl)propionic acid and the corresponding esters';, © g of salts, is transferred to (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid (12) by treatment with an excess of a

strong base such as sodium hydroxide, potassium hydroxide, tetramethylammonium hydroxide and the like at a temperature between 60°C and the reflux temperature of the reaction mixture for 4 to 10 hours under an inert atmosphere such as e.g. nitrogen, followed by acidification with a mineral acid such as hydrochloric acid, sulfuric acid and the like. When the above reaction is carried out on the (12)-(1)-acid isomer or its salts, water is a preferred solvent. When the reaction takes place with esters of the (12)-(1)-acid isomerene, the preferred solvents are aqueous alkanols such as aqueous methanol.

Compounds of formula (A) and (B) and the (d)-acid isomer of formula (B) as well as their esters and pharmaceutical salts are useful as anti-inflammatory agents, platelet-clotting inhibitors, fibrinolytic agents and smooth muscle relaxants. Compounds of formulas (A) and (B) and (d)-acid isomers of formula (B) as well as their esters q-g pharmaceutical salts can be used both prophylactically and therapeutically.

Compounds of formula (A) and (B) and the (d)-acid isomer of formula (B) and their esters and pharmaceutical salts have anti-inflammatory, analgesic and antipyretic effects. Consequently, preparations containing the compounds in question are suitable for treating and combating inflammation in e.g. the muscular/skeletal system, joint tissue and other tissues, e.g. in the treatment of inflammatory conditions such as rheumatism, shock, lesions, arthritis, broken bones, post-traumatic conditions and rheumatic fever. In the case where the above conditions are associated with pain and fever in addition to inflammation, the relevant compounds will be suitable for eliminating these conditions at the same time as the inflammation.

Administration of the active compounds of formula (A) and (B) and the (d)-acid isomer of formula (B) as well as their esters and pharmaceutical salts in suitable pharmaceutical preparations can take place in any known way for the treatment of inflammation , pain and fever or to prevent these conditions. One can thus give the compounds orally, parenterally or locally in the form of solid, semi-solid or liquid preparations such as e.g. tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions etc, preferably as dosage units for easy administration of precise doses. The preparations will contain usual pharmaceutical carriers and diluents as well as active compounds of formula (A) or (B) or the (d)-acid isomer of formula (B) or their esters and pharmaceutical salts and in addition other medicinal substances, carriers, diluents etc. .

The preferred route of administration in connection with the above-mentioned conditions is oral daily doses that can be adapted to the condition in question. Generally, a daily dose of 0.05 to 10 mg of active compound of formula (A) or (B) or the (d)-acid isomer of formula (B) or their esters and pharmaceutical salts per kg body weight be suitable. Most conditions can be treated positively with a dosage of around 0.25 to 3 mgPr» kg body weight per day. For such oral use, the pharmaceutical preparation is compounded by incorporation, in common drench agents such as e.g. pharmaceutical grades of mannitol, lactose, starch-magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate<p>g and the like. The preparations can be solutions, suspensions, tablets, pills, capsules, powders, preparations with an extended duration of action and the like.

The active compounds of formula (A) and (B) as well as the (d)-acid isomer of formula (B) and their esters and pharmaceutical salts can be incorporated into suppositories with e.g. poly-poly-

alkylene glycols of the type Kpropylene glycol as a carrier. Liquid pharmaceutical preparations can e.g. produced by dissolving,

disperse etc. an active substance as described above, and various pharmaceutical ingredients in a carrier such as e.g. water, saline, aqueous dextrose, glycerol, ethanol and the like, forming a solution or suspension. If desired, the pharmaceutical preparation can also contain smaller amounts of non-toxic excipients such as wetting agents or emulsifiers, pH buffers and the like, for example riatri<m>acetate, sorbitan monolaurate, triethanolamine oleate etc.

Current methods for producing such dosage units are known and will be obvious to those skilled in the art, see e.g. Remington<T>'s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th ed., I97O. The preparations to be

given will in all cases contain an amount of active substance or substances in pharmaceutically effective amounts to remedy or reverse the particular condition being treated.

The compounds of formula (A) and (B) and the (d)-acid isomer of formula (B) as well as their esters and pharmaceutical salts as described above are also muscle relaxants for smooth muscles of the uterus and are therefore suitable as pregnancy-sustaining agents for pregnant mammals, for the benefit of the mother and/or the fetus, until the pregnancy is medically assumed to

be terminated or the time to be more favorable for the mother and/or the fetus. However, it should be understood that in certain cases, e.g. when fetal expulsion has already begun (i.e. the mother is undergoing uterine contractions, especially towards full term), that administration of the compounds in question may not maintain the pregnancy period for a longer period of time. In such cases, the pregnancy period will probably be extended somewhat, a factor that can be an advantage for the mother and/or for the foetus.

In particular, compounds of formula (A) and (B) can

and the (d)-acid isomer of formula (B) and their esters and pharmaceutical salts, are used as drugs to delay initiation or delay labor. This is to be understood as a delay or postponement of birth caused by giving one of the compounds of formula (A) or (B) or the (d)-acid isomer of formula (B) or their esters and pharmaceutical salts on

a time before uterine contractions have begun. The chosen expression will thus include prevention of abortion during early pregnancy

(ie before the fetus is "viable") as well as delaying premature birth, at a later point in pregnancy when the fetus is presumed to be "viable". In all cases, the preparations will be given as preventive measures, as such administration will be able to prevent childbirth from occurring. The treatment is particularly useful for women with a history of spontaneous abortion, miscarriage or premature birth. Treatment with these preparations is also appropriate when there are clinical indications that. the pregnancy will be able to end before full term and it is otherwise beneficial for the mother and/or the foetus.

In connection with animals, the treatment can be used for

to synchronize the birth of a group of pregnant animals to a time when the birth can be treated more easily.

The condition of the patient, including the time within the postpartum period when the muscle contractions began, the strength and duration of the contractions will affect the results obtained by administering compounds of formula (A) or (B), the (d)-acid isomer of formula (B) or esters or pharmaceutical salts thereof. E.g. the effect can consist of a reduction in the intensity and/or duration of these contractions (birth will in this case be "prolonged"), or the contractions can be stopped completely. In all cases, the effect will be to extend the total delivery time depending on the patient's condition as mentioned, as the effect may be weak or, under suitable conditions, somewhat greater. One can thus give the relevant preparations to prevent sudden abortion, to make the birth easier and/or less painful for the mother or to bring it to take place at a more suitable time and/or place.

In all cases, administration of compounds of formula (A) and (B), (d)-acid isomer of formula (B) and their esters and pharmaceutical salts for the above purposes should be consistent with best medical or veterinary practice to make the benefits for the mother and/or fetus as great as possible. E.g. you should not give preparations so long after full term that the fetus dies in the womb.

The preparation given will in all cases contain an amount of active substance or substances which is enough to delay the entry of; the birth, or postpone the birth if uterine contractions have already begun. In general, a daily dose of from 5 to 250 mg of active substance per kg of body weight in single daily doses or up to 3 or 4 smaller doses will be sufficient. The amount of active substance given will naturally depend on the relative activity level.

The following description will make it easier to understand the invention and carry it out in practice. Where nothing else is stated, the reactions are carried out at room temperature (20°C to 30°C).

EXAMPLE 1

200 g of nitroterephthalic acid (a) was dissolved in 1 liter of isopropanol and the solution was saturated with hydrogen chloride and boiled at reflux for 3 days. (During this time hydrogen chloride was bubbled through the solution at intervals to maintain the concentration.) The reaction solution was cooled and the isopropanol removed by evaporation under reduced pressure to a residue which was dissolved in 500 ml of methylene chloride. The solution was washed with 10% aqueous sodium carbonate and the organic layer was dried over magnesium sulfate whereupon the solvent was removed in vacuo to give 245 g (87" 5 <f°) of diisopropyl nitroterephthalate (1) in the form of an oil:

IR:N)max?: W2, 1350 cm"<1>

NMR: $j^gL3: 1.35 (6H, d), 1.40 (6H, d), 5.24 (1H, 7 lines),

5.27 (1H, 7 lines), 7.71 (1H, d), 8.2.4 (1H, dd), 8.43 ppm (1H, d).

EXAMPLE' 2

5.1 g of sodium hydride was slowly added to a cooled (-20°C) solution of 23.5 ml of benzylmercaptan in 100 ml of dimethylformamide. The solution was cooled to -30°C and 53 g of diisopropylnitroterephthalate (1) in 100 ml of dimethylformamide was added. After one hour at -30°C and two hours at 0°C, the reaction mixture was poured into water, the precipitate was filtered off, washed with water and dried to 77-92% crude diisopropyl(benzylthio)terephthalate (2), of which a sample after recrystallization from pentane melted at 70-71°C•

EXAMPLE V

The crude diisopropyl-(benzylthio)-terephthalate (2) prepared in example 2 was boiled. at reflux with 500 mL meta-

nol, 25 g of potassium hydroxide and 50 ml of water for two hours. The reaction mixture was concentrated to a small volume, cooled, diluted with water and filtered through diatomaceous earth (Celite). The filtrate was acidified with 4-N hydrochloric acid and the precipitate was filtered off and dried at 90-100°C. to yield 45 g (87 <fo) (benzylthio)-terephthalic acid (3) with melting point 299-300°C.

EXAMPLE 4

10 g of (benzylthio)-terephthalic acid (3) was treated with 10 ml of thionyl chloride and the solution boiled at reflux for four

hours. After removing excess thionyl chloride in vacuo,

the resulting residue was slurried in hexane and the solid product was filtered off to give 10.2 g ($92) of (benzylthio)-terephthalyl chloride (4)

with melting point 158°C.

EXAMPLE' 5

10.2 g of (benzylthio)-terephthalyl chloride (4) in 100 ml of methylene chloride was added to a solution of 14.75 g of aluminum chloride in 100 ml of methylene chloride containing 10.51 ml of nitromethane. After five hours at 25°C, 16.5 ml of saturated aqueous sodium chloride were added with vigorous stirring. The inorganic salts that precipitated were filtered off and the filtrate evaporated to dryness, after which the dry evaporation residue was slurried with ether. The ether slurry was filtered to give 7.0 g (70.7%) of 6,11-dihydrodibenzo-[b.e.j'-thiepin-11-one-3-carbonyl chloride (5) m.p. 119-120°C.

EXAMPLE - 6

A solution of 11 g of 6,11-dihydrodibenzo-[b.e.J-thiepin-11-one-3-carbonyl chloride (5) in 100 ml of methylene chloride was slowly added to an excess of diazomethane (prepared from 20 g of N-nitroso-N-methylurea ) in 200 ml ether solution. After two hours

■fefcå the reaction mixture concentrated to approx. 50 ml by evaporation of the solvent followed by cooling. The cooled reaction mixture was filtered to give a residue of 9.5 g (85%) of 3-diazoacetyl-6,11-dihydrodibenzo-[b.e.]-thiepine ion (6) m.p. 153°C with decomposition.

EXAMPLE 7

9»5S 3~diazoacetyl-6,11-dihydrodibenzo-(b.e.}]-thiepin-ll-one (6) was suspended in 500 ml of methanol and the suspension stirred vigorously under reflux. 2 g of silver berizoate suspended in 20 ml of methanol was added in 2 ml portions over 50 minutes The reaction mixture was refluxed for 15 hours,

cooled, and the solvent removed in vacuo and then the mixture was chromatographed on 400 g of silica gel to give 7 g of methyl-6,11-dihydrodibenzo-(b.e.]-thiepin-11-one-3-acetate (7) with a melting point (ether) of 100 -101°C.

By similarly using other alkyl alcohols containing 2 to 12 C atoms instead of methanol in the above process, one obtains, for example: 'ethyl-6,11-dihydrodibenzo-[b.ejj -thiepin-ll-one-3 -acetate, propyl-6,11-dihydrodibenzo-(b.e0 -thiepin-ll-one-3-acetate, isopropyl-6,11-dihydrodibenzo-[b.e.)-thiepin-ll-one-3-acetate., hexyl -6,11-dihydrodibenzo-(b.e.j -thiepin-ll-one-3-acetate, . ,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate and the like.'

EXAMPLE 8

7.0 g of methyl-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate (.7) was stirred with 200 ml of methanol and a solution of 2.0 g of potassium hydroxide in 5 ml of water added. After one hour the solution was clarified by filtration and the filtrate acidified with 3% aqueous hydrochloric acid and diluted with /\. 00 ml of water. The precipitated solid was filtered off, dried in an oven at approx. 80°C and recrystallized from benzene:hexane to 5*6 g of 6,11-dihydro-dibénzo-Cb.e.)-thiepin-11-one-3-acetic acid (8) of melting point . 154-155°C. Acute oral toxicity (LD^Q) equal to II90 mg/kg.

In a similar manner, 6,11-dihydrodibenzo-[b.e.J-thiepin-11-one-3-acetic acid is obtained by replacing methyl 6,11-dihydrodibenzo-[b.e.J-thiepin-11-one-3-acetate and use the other 3-esters prepared in example 7" e.g. ethyl-6,,11-dihydrodibenzo- [b. e.j -thiepin-11-one-3-acetate,

propyl-6,11-dihydrodibenzo-(b.e.)-thiepin-ll-one-3-acetate, isopropyl-6,11-dihydrodibenzo-(b.e.0 -thiepin-ll-one-3-acetate, . rhexyl -6,11-dihydrodibenzo-Cb.e.)-thiepin-11-one-3-acetate,

nonyl-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate,

. dodecyl-6,11-dihydrodibenzo-(b^e.)-thiepin-rII-one-3-acetate

and such.

EXAMPLE 9

A solution of 2.5 g of 6,11-dihydrodibenzo-(b.e.J - thiepin-11-one-3-carbonyl chloride (5) in 30 ml of methylene chloride was added to a solution of diazoethane (prepared from 20 g of N-ethyl-N-nitrosourea ) in 150 ml of ether at -20° C. The reaction mixture

was allowed to warm to room temperature and most of the solvent was evaporated in a stream of nitrogen, -after which the mixture was filtered to give 1.5 g of 3-(oc-diazopropionyl)6,11-dihydrodibenzo-Cb.e.J-tiepin-ll-one (9 ) with melting point 127°C, (decomp.).

EXAMPLE 10

1.1 g of 3-(α_diazopropionyl)-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one (9) suspended in 3 ml of collidine was added to a mixture of 5 ml of benzyl alcohol and 5 ml of collidine at 170-175 C. After 5 minutes, the reaction mixture was cooled and the solvent distilled off in vacuo, followed by chromatography on silica gel to give 1.0 g of benzyl-(dl)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-one) -3-yl)propionate (10), a colorless oil,

IR:Vmax?<1>735, 1640, 1600cm"<1>

NMR: δ CDCl 3 1.50 (3H, d), 3.66 (1H, q), 4.0 (2H, s), 5.07 (2H, s)

™S 7.0-7.6.(6H, m), 8.10 ppm (1H, dd)

MS:388 (M<+>)

EXAMPLE 11'

1.0 g of benzyl-(dl)-2-(6,11-dihydrodibenzo)-(b.é.J-thiepin-11-on-3-yl)propionate (10) in 25 ml of methanol was treated with 0, 3 g of potassium hydroxide in 2 ml of water. After one hour, the reaction mixture was poured into 25 ml of 3N hydrochloric acid and 100 ml of water. The mixture was extracted with ethyl acetate and the organic layer extracted with 10% aqueous sodium carbonate solution. The basic aqueous layer was acidified with 3N hydrochloric acid and the precipitated acid, (dl)-2-(6,11-dihydrodibenzo-(b.e.")-thiepin-11-on-3-yl)-propionic acid, was extracted with ether. The ether layer was evaporated after drying over magnesium sulfate to an oil which was taken up in 5 ml of benzene.The benzene solution was treated with 0.5 g of dicyclo-

hexylamine and the solution set aside for crystallization overnight after which it was dried to 640 mg of dicyclohexylammonium-(dl)-2-(6,11-dihydrodibenzo-Cb.e.}-thiepin-ll-on-3-yl)propionate (11) with melting point l63-l65°C.

EXAMPLE 12

640 mg of dicyclohexylammonium-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin>on-3-yl)propionate (11) was dissolved in 10 ml of methylene chloride and the solution stirred for 15 minutes with an excess of sodium hydrogen sulfate monohydrate (1.0 g). The reaction mixture was filtered and the solvent removed in vacuo. The evaporation residue was extracted with ether. Evaporation of the ether extract gave an oil which on drying under high vacuum (0.1 mm) gave 300 mg of (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-ll-on-3-yl)propionic acid (12 )

like a foam, med

IR: ^max. 3700-2500, 1710, I64O cm"<1>

NMR: 1.47 (3H, d), 3.68 (1H, q), 4.00 (2H, s),

7.'0-8.0 (6H, m), 8.10 ppm (1H, d),

MS: 298 (M<+>)

Dicyclohexylammonium-(dl)-2-(6,11-dihydrodibenzo-(b.ej -thiepin-11-on-3-yl)propionate (11) was prepared in several experiments as described in example 11. The products from these parallel experiments were combined and treated as in Example 12 to a foam which was crystallized from diethyl ether:hexane (2:1) to give (dl)-2-(6,11-dihydrodibenzo-Cb.e.]-thiepin-ll- on-3-yl)propionic acid (12) with melting point 113-115°C, and the same IR7 NMR and MS values

as described above in Example 12.

EXAMPLE 12A

To 4.0 g of sodium hydride (110%) in 600 ml of N,N-dimethylacetamide under a nitrogen atmosphere was added 41 g of methyl-6,11-dihydrodibenzo-(b.e.J-thiepin-ll-one-3-acetate (13, R' = methyl),

and the mixture turned dark red. It was stirred at room temperature overnight, after which 20.0 g of methyl iodide was quickly added.

The prepared reaction mixture, which turned from red to green-blue, was stirred at room temperature for 15-20 minutes, poured into a mixture of 6 liters of saturated sodium chloride solution, 600 ml of water and 2 liters of ethyl acetate while shaking. The layers were separated and the organic layer washed several times with 3 x 300 ml saturated sodium chloride solution. The washing water was successively extracted with 3 x 300 ml of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and evaporated to dryness in vacuo to give 4-6 >0 g of a dark yellow evaporation residue which consisted of methyl-(dl)-2-(6,11-dihydrodibenzo-Cb.e.J -tiepin-ll- on-3-yl)propionate (14, R' = methyl) which was combined with 25.0 g of the substance prepared above under the same alkylation method. The combined evaporation residues (71.0 g) were filtered through a kg of silica gel and eluted with methylene chloride and finally with ethyl acetate:methylene chloride (2:98). The eluted fractions, which by thin-layer chromatography proved to consist essentially of α-methylated product, were combined and evaporated to dryness to 62.0 g of pure light yellow powder in the form of methyl(dl)-2-(6,11-dihydrodibenzo- [b.e.)-thiepin-ll-on-3-yl)propionate (14, R' methyl), Cen sample of methyl-(dl)-2-(6,ll-dihydrodibenzo-fb.e.J-thiepin-ll-one -3-yl)propionate (14, R' = methyl), prepared in the same way, after crystallization from diethyl ether had the following physical constants: Melting point 62.0 - 62.5°C;

IR: Vmax. 3700-2500, 1740, 1640 cnT<1>

NMR: 5^<1>3 1.47 (3H, d), 3.65 (3H, s), 3.68 (1H, q), 4.02

(2H,- s), 7.0-8.0 (6H,.m), 8.21 ppm (1H, d) ,

4

MS: 312 (M<r>)),

which was dissolved in a mixture of 1600 ml of tetrahydrofuran and 800 ml of water. 180 ml of 1N sodium hydroxide was added to the solution and the reaction mixture was stirred for 3 hours, after which the tetrahydrofuran was removed in vacuo and diluted with 3 liters of water. The dilute basic solution was extracted with 2 x 600 mL of ethyl acetate, followed by acidification of the aqueous layer with 2N hydrochloric acid. The acidic aqueous solution was extracted several times with methylene chloride. The methylene chloride extracts were combined, dried over sodium sulfate and evaporated to dryness to a residue which was taken up in 250 ml of diethyl ether and set aside for crystallization. The fine white crystals that formed were filtered, washed with ice-cold diethyl ether and suctioned dry to 40.0 g of (dl)-2-(6,11-dihydrodibenzo-Cb.e.J-thiepin-ll-on-3-yl)propionic acid (12) with melting point equal to 114.5 - H5>5°C

(uncorrected),

IR:^max. 370t)-2500, 1710, 1655 cm"<1>

NMR: 1.47 (3H»3.68 (1H, q), 4.00 (2H, s),

7.0-8.0 (6H, m), 8.12 ppm (1H, d),

MS: 298 (M<+>)

By similarly using other 3'-esters of 6,11-dihydrodibenzo-(Jd .e.J -thiepin-11-one-3-acetic acid, e.g. ethyl-6,11-dihydroaibenzo-Cb.e.J- tiepin-ll-one-3-acetate, propyl-6,11-dihydrodibenz'o-lb.e.) -tiepin-ll-one-3-acetate, isoamyl-6,11-dihydrodibenzo-Cb.e.) - tiepin-ll-one-3-acetate, hexyl-6,11-dihydrodibenzo-(b.eJ -tiepin-ll-one-3-acetate, nonyl-6,11-dihydrodibenzo-Cb.e.)-thiepin-ll -one-3-acetate, dodecyl-6,11-dihydrodibenzo-(b.e.)-thiepin-ll-one-3-acetate and the like, instead of methyl 6,11-dihydrodibenzo-(b.e.}-thiepin-ll- oh-3-acetate gives (dl)-2-6,11-dihydrodibenzo-(b.e.]-thiepin-11-on-3-yl)propionic acid.

EXAMPLE 12B

(a) 5.0 g of (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid (12) was dissolved in 50 ml of benzene which. contained 5 ml of thionyl chloride and 3 drops of dimethylformamide and stirred for 1/2 hour. The reaction mixture was evaporated to an oily residue which was dissolved in 50 ml. dry benzene and re-evaporated to an oily residue which consisted of (dl)-2-(6,11-dihydrodibenzo-(b.e.J -thiepin-11-on-3-yl)propionyl chloride. This oily residue was dissolved in 250 ml of acetonitrile and 10 ml of (1)-1-phenylethylamine and 6.5 ml of triethylamine were added. After stirring for 2 hours, the reaction mixture was added to 750 ml of water and extracted with 400 ml of ethyl acetate. The organic extract produced was washed with 400 ml of 2N hydrochloric acid, dried and evaporated, to a residue which was chromatographed on 400 g of silica gel, eluted with benzene:ethyl acetate (10:1), thereby first preparing 3.36

of the least polar (1)-2-(6,11-dihydrodibenzo-[b.e.)-thiepin-11-on-3-yl)propionyl-(1)-1-phenylethylamide, which after crystallization from ethyl acetate:hexane (1 :2), had a melting point of 162-163°C and (oOD equal to +16.4° (10 mg/ml, chloroform), and then 2.8 g of the more polar (d)-2-(6.11 -dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionyl-(1)-1-phenylethylamide which after recrystallization

from ethyl acetate:hexane (1:2) had a melting point of 170-171°C

°g Cal]3 equal to -1.4° (10 mg/ml, chloroform).

(b) 3.0 g of (d)-2-(6,11-dihydrodibenzo-(b.e.J -thiepin-11-on-3-yl)propionyl-(1)-1-phenylethylamide in 93 ml of concentrated hydrochloric acid and 62 ml acetic acid was heated for 8 hours at 87°C. The mixture was cooled, poured into water and extracted with 250 ml of ethyl acetate. The ethyl acetate extract was washed with water and extracted with 250 ml of 0.5 molar aqueous sodium carbonate. The ethyl acetate solution after extraction from the aqueous sodium carbonate solution was dried and evaporated to give 1.06 g of unchanged phenylethylamide starting material. The aqueous sodium carbonate extract was acidified with 500 ml of 2N hydrochloric acid and extracted with 350 ml of ethyl acetate. The ethyl acetate extract was dried and evaporated to give 1, 34 g of a residue consisting of 2-(6,11-dihydrodibenzo-(b.ej -thiepin-11-on-3-yl)propionic acid. 1.06 g of worked-up phenylethylamide starting material was dissolved in 45 ml of concentrated hydrochloric acid and 30 ml of acetic acid and heated for 14 hours at 85°C and then worked up as described above to 0.86 g evaporation residue of 2-(6,11-dihy drodibenzo-[b.e0 -thiepin-11-on-3-yl)propionic acid which was combined with the 1.34 g prepared earlier. The combined crude compounds (2.2 g) were dissolved in 10 ml of isopropanol and 0.95 g of 1-amphetamine was added. The solution was cooled to -10°C and left for 4 hours and filtered to 2.69 g of residue which was shaken with 100 ml of 2N hydrochloric acid and 100 ml of ethyl acetate.

The separated organic layer was dried over magnesium sulfate

and evaporated to 1.90 g of residue which was dissolved in 9 ml of isopropanol, followed by the addition of 0.86 g of 1-amphetamine. The solution was cooled to -10°C and left for 2 hours and then filtered to 2.53 g of residue which was shaken with 100 ml of 2N hydrochloric acid and 100 ml of ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated to 1.75 g which was dissolved in 7 ml of isopropanol and 0.83 g of 1-amphetamine was added. The solution was cooled to -10°C and set aside for 16 hours, followed by filtration, and then obtained 2.40 g of filtration residue which was shaken with 100 ml of hydrochloric acid and 100 ml of ethyl acetate. The separated organic layers were washed, dried over magnesium sulfate and evaporated to 1.647 g of (d)-2-(6,11-dihydrodibenzo-[b.e0-thiepin-11-on-3-yl)-propionic acid C(12)- (d)-acid isomer], as a gummy for-

bond, with C°0 j) = +37»2° (5<mg>/ml, chloroform),

MR:.<$TMS<l>3 1.48 (3H>d)'3.68 (1H, q), 4.01 (2H, s),

7.0-7.6 (6H, m), 8.15 PPm (1H, d),

MS: 298 (M<+>) 265, 253. (c) 2.64 g of (1)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionyl-( 1)-1-Phenylethylamide was dissolved in 21 ml of acetic acid and 111 ml of acetic anhydride and the solution cooled to 0°C. 9.25 g of sodium nitrite was added in four portions over one hour. The mixture was stirred at 0°C for 5 hours and at room temperature for 17 hours. 250 ml of water and 100 ml of ethyl acetate were added and the mixture stirred vigorously for 1 l/2 hours and diluted with 500 ml of water and extracted with 400 ml of ethyl acetate. The organic layer was washed, dried over magnesium sulfate, evaporated and the residue refluxed for one hour in 50 ml of benzene. The benzene solution was cooled, washed with 100 ml of 0.5 molar aqueous calcium carbonate, dried over magnesium sulfate and evaporated. The residue produced was chromatographed on 100 g of silica gel, eluted with benzene to give 0.75 g of (1)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid-1-phenylethanol ester , like an oil,

NMR: &^ f~ 3 1.29-1.52 3.68 (1H, q) , 4.02 (2.H, s) ,

7.0-7.6 (11H, m), 8.16 ppm (1H, m).

0.74 g of 1-phenylethanol ester was stirred in 10 ml of benzene and 10 ml of trifluoroacetic acid for 2 hours, after which 200 ml of water was added and extracted with 200 ml of ethyl acetate. The organic layer was washed, dried over magnesium sulfate and evaporated to 0.51 g of (1)-2-(6,11-dihydrodibenzo-(b.e0-thiepin-11-on-3-yl)-propionic acid C(12) -(1)-acid isomer) as a gummy compound with (cOD= -37.8° (5 mg/ml, chloroform), and the same NMR and MS data as above for the corresponding (d) compound ( (12)-(d)-acid<->isomer) in part (b) of the example.

EXAMPLE 13

250 mg of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (8) was dissolved in 30 ml of isoamyl alcohol and the solution saturated with hydrogen chloride. After 90 minutes, the excess alcohol was distilled off in vacuo and the residue purified by thin-layer chromatography (silica gel, ethyl acetate:hexane (1:9)) to

171 mg of isoamyl-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate, which after crystallization from methylene chloride/hexane had a melting point of 91-92°C•

In a similar way, other esters such as methyl-, ethyl-, propyl-, isopropyl-, hexyl-, nonyl-, dodecyl-

and similar esters of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (8) by using other and corresponding alcohols instead of isoamyl alcohol.

EXAMPLE' 14-

150 mg of (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid (12) was dissolved in 5 ml of methanol and the solution saturated with hydrogen chloride. After 24 hours, the excess alcohol was distilled off in vacuo and the evaporation residue was purified by chromatography on silica gel (eluent: ethyl acetate: hexane (1:8) which gave 120 mg of methyl-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepine -11-on-3-yl)propionate as an oil with UV:^maxT<2>5°'350.nm (£ 21,200, 295O).

IR:V?max?' W0'l645>1600 cm"<1>,

NMR<:5>^S<1>3 1'4-8 (3H, d) , 3.60 (3", s), 4.0 (2H, s) ,

7.0-7.6 (6H, m), 8.10 ppm (1H, dd).

In a similar way, by using the corresponding (12)-(d)-acid isomer, namely (d)-2-(6,11-dihydrodibenzo-Cb.e0-thiepin-11-bn-3-yl)propionic acid or the corresponding (12)-(1)-acid isomer instead of the (dl)-mixture the methyl ester of (d)-2-(6,11-dihydrodibenzo-[b.e J -thiepin-ll-on-3-yl )propionic acid or the corresponding methyl ester of the (12)-(1)-acid isomer, respectively.

example" 15

300 mg of (dl)-2-(6,11-dihydrodibenzo-(b.e.J -thiepin-11-on-'3-yl)propionic acid (12) was dissolved in 5 ml of isoamyl alcohol and the solution was saturated with hydrogen chloride. After 24 hours, the excess alcohol distilled off in vacuo and the residue purified by chromatography on aluminum oxide to give 350 mg of isoamyl-(dl)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-ll-on-3-yl)propionate as an oil with

UV: Æa?H 245, 350 nm (8 19-700, 2240) ,

HlcLKS •

IR: Vmax? 173°) I65O, 1600 cm"<1>

NMR: δTMS 0.80 (6H'd) 1'45

4.0 (2H, s), .7.0-7.6 (6H, m), 8.1 ppm (1H, dd).

In a similar manner, other esters such as ethyl, propyl, isopropyl, hexyl, nonyl, dodecyl and similar esters of (dl)-2-(6,11-dihydrodibenzo-1b.e.J -thiepine-ll -on-3-yl)propionic acid (12) prepared by using other and similar alcohols instead of isoamyl alcohol.

By similarly using the (12)-(d)-acid isomer, (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)-propionic acid or the corresponding (12)-(l)-acid isomer instead of the (dl) mixture, one obtains with the selected alcohol corresponding esters of (d)-2-(6,11-dihydrodibenzo-(b.e J-thiepin-ll- on-3-yl)-propionic acid or corresponding esters of the (12)-(l)-acid isomer, respectively..

EXAMPLE 16

300 mg of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (8) in 5 ml of methanol was titrated with 1N methanolic potassium hydroxide to a light orange color. The color was destroyed by adding 3 mg of solid 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid. The solvent was evaporated in vacuo and the residue taken up in 2 ml of methanol followed by precipitation with ether to give 335 mg of crude potassium 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate which after crystallization from isopropanol had a m.p. at 206-208°C (decomp.). Other salts were prepared in a similar way, e.g. ammonium and sodium salts of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (8.) by using ammonium hydroxide and sodium hydroxide instead of potassium hydroxide.

EXAMPLE 17

I.50 mg of (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid (12) in 1 ml of methanol was titrated with 1N methanolic potassium hydroxide to light orange color. A small amount of solid (dl)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-on-3-yl)propionic acid was added to decolorize the solution. The solvent was distilled off and 5 ml of toluene was added. prepared toluene solution was evaporated to dryness to a solid which was dried at 100°C in vacuo to give 158 mg of potassium-(dl)-2-(6,11-dihydrodibenzo-(b. e. 3-thiepin-11-one- 3-yl)-propionate which softened at 120° C. and had a melting point of 145-155° C. This solid melted on exposure to moist air and solidified again as 175 mg of dihydrate of potassium-(dl)-2- (6,11-dihydrodibenzo-(b.e;)-thiépin-11-on-3-yl)propionate with melting point 88-90°C•

In a similar way, other salts such as ammonium and sodium salts of (dl)-2-(6,11-dihydrodibenzo-(b.e.3-thiepin-1-or*3-yl)propionic acid (12) were prepared by using e.g. eg ammonium hydroxide and sodium hydroxide instead of potassium hydroxide.

By similarly using the (12)-(d)-acid isomer, (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)-propionic acid or the corresponding (12)-(1)-acid isomer instead of the (dl)-mixture with a suitable hydroxide one obtains potassium, ammonium or sodium salts of (d)-2-(6,11-dihydrodibenzo-(b.e.J -thiepin- 11-on-3-yl)propionic acid or the corresponding salts of the (12)-(1)-acid isomer, respectively.

EXAMPLE 18

300 mg of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (8) was dissolved in an excess of 1N aqueous sodium hydroxide and the solution buffered with 0.3 g of ammonium chloride.

The buffered solution was added to a solution of 200 mg of calcium carbonate in 1N aqueous hydrochloric acid. The precipitate formed was filtered off, washed with water, dimethoxyethane and ether to 180 mg calcium-6.,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate with melting point 220-225°C (decomp.), with a softening point above 205°C.

In a similar way, magnesium 6,11-dihydrodibenzo-(b.e.J -thiepin-11-one-3-acetate) is obtained by using magnesium carbonate instead of calcium carbonate.

EXAMPLE IQ

1-75 mg of (dl)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-on-3-yl)propionic acid (12) in ^ > ml of methanol was titrated with 1N methanolic potassium hydroxide to a light orange color which was removed by adding 3 mg of solid (dl)-2-(6,11-dihydrodibenzo-(b.e."3-thiepin-11-on-3-yl)propionic acid to give a soln.

which contained potassium (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate. A solution of 40 mg of calcium carbonate

dissolved in a minimal amount of 1N hydrochloric acid to dissolve the calcium carbonate was buffered with 100 mg of solid ammonium chloride, followed by 5 ml of water. The calcium solution thus buffered was added to a solution of potassium-(dl)-2-(6,11-dihydrodibenzd-(b.e.)-thiepin-11-on-3-yl)propionate which gave a precipitate. The precipitate was filtered off, washed with water and dried at room temperature to 160 mg of calcium-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate which softened at 150°C and had a melting point of 160-165°C.

Similarly, magnesium-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate was prepared by using magnesium carbonate instead of calcium carbonate.

By similarly using the (12)-(d)-acid isomer, (d)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-on-3-yl)-propionic acid or the corresponding ( 12)r(l)-acid isomer instead of the (dl)-mixture in connection with suitable carbonate, calcium and magnesium salts of (d)-2-(6,11-dihydrodibenzo-(b.e.)-tiepin- 11-on-3-yl)propionic acid or corresponding salts of the (12)-(1)-acid isomer, respectively.

EXAMPLE 20

200 mg of 6,11-dihydrodibenzo-(b.e.J -thiepin-11-one-3-acetic acid (8) in 1 ml of methanol was titrated with 1N methanolic potassium hydroxide to a faint orange color. A small amount of solid 6,11-dihydrodibenzo-(b.e.J -thiepin-ll-one-3-edoic acid was added to decolorize the solution. The solvent was distilled off and the residue dissolved in 5 ml of water. The aqueous solution of potassium 6,11-dihydrodibenzo-(b.eJ-thiepinJ6h-3-acetate became-

added to a solution of 150 mg of cupric nitrate trihydrate in 5 ml of water. The precipitate was collected, washed with water and dried in air to give 200 mg of copper 6,11-dihydrodibenzo-(b.eJ -thiepin-11-one-3-acetate), which sintered at 139-140°C and had a melting point of 155-160°C.

EXAMPLE 21

200 mg of (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid (12) in 1 ml of methanol was titrated with 1N methanolic potassium hydroxide to light orange color. A small amount of solid (dl)-2-(6,11-dihydro-dibenzo-(b.e.)-thiepin-11-one-

3-yl)propionic acid was added to decolorize the solution. The solvent was distilled off and the residue dissolved in 5 ml of water. The prepared aqueous solution of potassium-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate was added to a solution of 150 mg of cupric nitrate trihydrate in 5 ml of water . The precipitate was collected, washed with water and dried in air to give 200 mg of copper-(dl)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-on-3-yl)propionate which sintered at 14-0° C and had a melting point of 160-165° C. :;

In a similar way one got using the (12)-(d)-acid isomer, (d)-2-(6,11-dihyd!dodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid or the corresponding (12 )-(l)-acid isomer instead of the (dl) mixture, a copper salt of (d)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-on-3-yl) propionic acid or the corresponding copper salt of the (12)-(l)-acid isomer, respectively;

EXAMPLE' 22

200 mg of 6,11-dihydrodibenzo-(b.e.J-thiepin-11-one-3-acetic acid (8) in 15 ml of hot benzene was treated with 60 mg of isopropylamine. The solution was allowed to cool at room temperature and the product filtered off, washed with ether and dried to 217 mg of isopropylammonium-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate with melting point equal to 147-148°C.

Other salts were prepared in a similar way, e.g. amine salts such as diethylamine-^ethanolamine-, piperidine-, tromethamine-, choline- and caffeine-salts of 6,11-dihydrodibenzo-(b.e.)-thiepin-ll-one-3-acetic acid (8) by using the above-mentioned amines in instead of isopropylamine.

EXAMPLE 23

193 mg of (dl)-2-(6,11-dihydrodibenzo-(b.e.J-thiepin-11-on-3-yl)propionic acid (12) in 10 ml of benzene was treated with 60 mg of piperidine. The prepared solution was allowed to stand for one hour and the crystalline substance formed was filtered, washed with ether and air-dried to 183 mg of piperidinium-(dl)-2-(6,11-dihydrodibenzo-fb.e.)-thiepin-11-on-3-yl)propionate, of which a sample after recrystallization from benzene had a melting point of 140-141°C.

In the same way, other salts were prepared as amine salts, for example isopropylamine, diethylamine, ethanolamine, tromethamine, choline and caffeine salts of (dl)-2-(6,11-dihydro dibenzo-(b.e.]-thiepin-11- on-3-yl)propionate using the above amines instead of piperidine.

Using the (12)-(d)-acid isomer, (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid or the corresponding (12)- The (l)-acid isomer instead of the (dl)-mixture and the suitable amine gives the corresponding amine salts or the corresponding (12)-(l)-acid isomeric amine salts, respectively.

EXAMPLE 24-

1 g of potassium 6,11-,dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate was dissolved in 50 ml of water and the solution was acidified with 2.0 ml of 3N aqueous hydrochloric acid. The reaction mixture was extracted twice with ethyl acetate (25 mL portions). The extracts were combined, washed with 50 ml of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue recrystallized from benzene to give 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (8);

In a similar manner, other salts such as sodium-., ammonium-, calcium-, amine- and others of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid are converted to 6,11-dihydrodibenzo-(b.e. )-thiepine-ll-one-3-acetic acid.

In a similar way, by using salts such as potassium, sodium, ammonium, calcium, amine and the like of (dl)-2-(6,11-dihydrodibenzo-(b.e.}-thiepin-ll-one) 3-yl)propionic acid, (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid and corresponding (1)-acid isomeric salts, respectively, prepare (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)-propionic acid, (d)-2-(6,11-dihydrodibenzo-(b.e.)- thiepin-11-on-3-yl)-propionic acid and corresponding (1)-acid isomers.

EXAMPLE 25

LI. g of methyl-6,11-dihydrodibenzo-(b.e.J-thiepin-11-one-3-acetate (7) was dissolved in 500 ml of toluene containing 56n-octanol and 0.5 g of p-toluenesulfonic acid. The reaction mixture was heated under a nitrogen atmosphere and a total of 350 ml of toluene was slowly liquid distilled over the course of 5 hours.

cooled and concentrated to approx. 10 ml by evaporation under reduced pressure. The residue was then chromatographed on 200 g of silica gel and eluted with hexane:ethyl acetate (1:8) to give octyl-6,11-dihydrodibenzo-1 b.e. J -thiepin-11-one-3-acetate.

Similarly, other lower esters (e.g., the propyl ester) of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-aeddylic acid were transesterified to higher esters (e.g., the decyl ester)

of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid.

In a similar manner, lower esters (e.g. the methyl ester) of (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid are converted, (d)-2-( 6,11-dihydrodibenzo-(b.e.J-thiepin-1-on-3-yl)propionic acid or the corresponding (1)-acid isomer lower ester of the corresponding higher esters (e.g. the octanyl ester) of' (dl )-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid, (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-one- 3-yl)propionic acid or the corresponding higher ester of the (1)-acid isomer, respectively.

EXAMPLE' 26.

500 mg of dodecyl-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate was refluxed with 250 ml of absolute ethanol containing 10 mg of sodium cyanide for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled and evaporated under reduced pressure to give a residue which was chromatographed on 100 g of silica gel and eluted with hexane:ethyl acetate (1:8) to give ethyl 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3 -acetate.

Similarly, other higher esters (e.g., the nonyl ester) of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid can be transesterified to a lower ester (e.g., the hexyl ester)

of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3^acetic acid.

Similarly, higher esters (e.g., the dodecyl ester) of (dl)-2-(6,11-dihydrodibehzo-(b.e.)-thiepin-11-on-3-yl)propionic acid can be converted to lower esters (e.g. .eg the ethyl ester) of (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid.

EXAMPLE 27 .

0.05 g of (l)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid (the (12)-(l)-acid isomer) was refluxed under nitrogen in 6 ml of water containing 0.07 g of sodium hydroxide for 7 hours. The reaction solution was cooled, acidified with 5 ml of 2N hydrochloric acid and extracted with 15 ml of ethyl acetate. The extract was washed with 15 ml of water, dried with magnesium sulfate and evaporated to 0.04-1 g of (d^-2-(6,11-dihydro-

dibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid (12), a gummy compound, with (aj^ = -0.80 + 1.0° (5 mg/ml chloroform),

NMR: 6™<X>3 1.47 (3H, d), 3.70 (1H, g), 7.0-7.6 (6H, m) ,

8.13 ppm (1H, d),

MS: 298 (M+),' 265, 253.

EXAMPLE 28

The above substances are carefully mixed and pressed

tablets with fracture drills.

EXAMPLE 29

The above substances are carefully mixed and pressed

tablets with fracture drills.

12.5 mg of (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid is used instead of 25 mg of the above

(dl) compound with said composition.

EXAMPLE' 30

The above ingredients are mixed and filled into hard gelatin capsules.

EXAMPLE 31

The above substances are mixed and filled into hard gelatin capsules.

EXAMPLE - 32

The above ingredients are carefully mixed and pressed into tablets with a crushing machine.

EXAMPLE. 33

The above ingredients are mixed and filled onto a hard gelatin capsule No. 1.

EXAMPLE 34-

The above substances are carefully mixed and pressed into tablets with a crushing drill, one tablet being given every 3 to 4 hours.

EXAMPLE' 35

The above substances are carefully mixed and pressed

pills.

EXAMPLE 36

The above substances are mixed and filled into hard gelatin capsules.

12.5 mg of (d.)-2-(6,11-dihydrodibenzo-(b.e.j -thiepin-11-on-3-yl)propionic acid is used instead of 25 mg of (dl) compound of the above composition.

. EXAMPLE 37

The above ingredients are mixed and topped up

hard gelatin capsules.

EXAMPLE 38

The above compounds are mixed and pressed into single tablets.

EXAMPLE 39

The above ingredients are carefully mixed and pressed into tablets with a single breaking drill.

EXAMPLE 4- 0

The above ingredients are carefully mixed and pressed into tablets.

Example 41

The above ingredients are mixed and filled into hard gelatin capsules.

EXAMPLE 42

The above ingredients are mixed and filled into hard gelatin capsules.

EXAMPLE 43

An injection preparation buffered to a pH equal to .8.5 is prepared with the following ingredients:

0.1 g of (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid is used instead of 0.2 g of the above (dl) compound.

EXAMPLE 44

A suppository weighing a total of 2.8 g is prepared from the following mixture: (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid 25 mg

"Witepsol H-15".

(triglycerides of saturated vegetable

fatty acids) the rest

12.5 mg of (d)-2-(6,11-dihydrodibenzo-(>b.e.)-thiepin-11-on-3-yl)propionic acid is used instead of 25 mg of (dl) compound above.

EXAMPLE 45

An oral suspension for pediatric use is prepared from the following ingredients:

0.125 g of (d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-on-3-yl)propionic acid is used instead of 0.25 g of the (dl) compound of the above composition.

EXAMPLES 4- 6- 47

Powder-containing top dressings for veterinary use are produced with the following composition:

0.1 g of (d)-2-(6,11-dihydrodibenzo-(b.e.J -thiepin-11-on-3-yl)propionic acid is used instead of 0.2 g of (dl)-compound in the composition according to example /\ 6.

0.2 g of (d)-2-(6,11-dihydrodibenzo-[b.e.)-thiepin-11-on-3-yl)propionic acid is used instead of 0.4 g of (dl) compound in Example 47*

EXAMPLE" 48

A suppository with a total weight of 2.8 g and the following composition is produced:

• EXAMPLE 49

Several experiments were run which simultaneously assessed the effect of

ta) phenylbutazone,

(b) 6,11-dihydrodibenzo-(.b.e.l-thiepin-11-one-2-acetic acid,

(c) 6,11-dihydrodibenzo-Lb.e.)-oxepin-ll-one-3-acetic acid, and (d) 6,11-dihydrodibenzo-Cb.e.)-thiepin-ll-one-3-acetic acid , with regard to oral anti-inflammatory action by means of carrageenan-iriclusted paw inflammation in the rat, according to the method of Winter' et al., Proceedings of the Society for Experimental Biology and Medicine, Volume III, pages 544-547 (1962) which follows: Compounds and methods -- Female rats with a body weight of 80-90 grams are used. The test compounds are given orally, at time 6 in 1 ml of aqueous carrier medium. After 1 hour, 0.05 Tal 1% solution (in 0.9% NaCl) of the carrageenan is injected into the rat's right hind paw. The injection causes inflammation in the paw. The animals are killed on

hour 4 °g both hind paws are removed and weighed separately. End point: fo increase in paw size calculated as follows:

weight of right paw - weight of left paw^qq

weight of left paw

The obtained data from different experiments that were run for simultaneous and relative evaluation of the compounds were analyzed by standard statistical methods and the following results were obtained:

TABLE I

Oral anti-inflammatory action of the compounds

(b), (c) and (d) relative to phenylbutazone, compound (a).

TABLE II

Oral anti-inflammatory activity of compound (d) compared directly with compound (b).

' TABLE III

Oral anti-inflammatory action of compound (d)

compared directly with compound (c)

EXAMPLE 50

Several simultaneous trials were carried out for the evaluation of

(a) phenylbutazone,

(b) (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-2-yl)-propionic acid, and (c) (dl)-2-(6,11-dihydrodibenzo- fb.e.] -thiepin-11-on-3-yl)-propionic acid,

with regard to oral anti-inflammatory action with carrageenan-induced paw inflammation in rats as described in the previous example.

The following results were obtained from the experiment:

TABLE- I

Oral anti-inflammatory activity of compounds (b) and (c) relative to phenylbutazone, compound (a)

Claims (46)

1. Compounds selected from groups with the following formulas: or the individual (d)-acid isomer or (1)-acid isomer of formula (B), where R represents hydrogen, an alkyl group having from 1 to 12 C atoms or its pharmaceutically acceptable salt when R represents hydrogen, or said esters and pharmaceutical salts of single isomers of formula (B). 2. Compounds selected from groups with formula: or the (d)-acid isomer of formula (B), where R denotes hydrogen, alkyl with from 1 to 12 C atoms or its pharmaceutically usable salt when R denotes hydrogen, or esters and pharmaceutical salts of (d)- the acid isomer of formula (B). 3. Compounds with formula or its (d)-acid isomer where R represents hydrogen, alkyl with from 1 to 12 C atoms or its pharmaceutically usable salt when R represents hydrogen, or said esters and pharmaceutical salts of the (d)-acid isomer. 4. Compounds with formula where R represents hydrogen, alkyl with from 1 to 12 C atoms or their pharmaceutical salts when R represents hydrogen. 5. Compounds with formula where R represents hydrogen, alkyl with from 1 to 12 C atoms or their pharmaceutical salts when R represents hydrogen. 6. Compounds with formula where R represents hydrogen, alkyl with from 1 to 12 C atoms or their pharmaceutical salts when R represents hydrogen. 7« Compounds of formula (A) as stated in claim 1, where R denotes hydrogen, 6,11-dihydrodibenzo-(b.e0-thiepin-11-one-3-acetic acid). 8. Compounds of formula (A) according to claim 1 where R denotes methyl, ethyl ether trimethyl-6,11-dihydrodibenzp^ (b.e.J - thiepin-11-one-3-acetate. 9» Compound of formula (A) as stated in claim 1 where R denotes isoamyl: isoamyl-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate. 10. The sodium salt of a compound of formula (A) as set forth in claim 1: sodium 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate. 11. The potassium salt of a compound of formula (A) as set forth in claim 1: kolammm-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate. 12. The calcium salt of a compound of formula (A) as set forth in claim 1: calcium 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate. 13. The copper salt of a compound of formula (A) as set forth in claim 1: copper 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate. 14« The isopropylammonium salt of a compound of formula (A) as set forth in claim 1: isopropylammonium-6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetate. 15. The compound of formula (B) as stated in claim 1 where R denotes hydrogen: (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid. 16. Compound of formula (B) as stated in claim 1 where R denotes methyl: methyl-(dl)-2-(6,11-dihydrodibenzo-(b.e. J -thiepin-11-on-3-yl)propionate. 17. Compound of formula (B) as stated in claim 1 where R denotes isoamyl: isoamyl-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate. 18. The sodium salt of a compound of formula (B) according to claim 1: sodium (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate. 19. The potassium salt of a compound of formula (B) according to claim 1: potassium-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate. 20. The calcium salt of a compound of formula (B) according to claim 1: calcium-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate. 21. The copper salt of a compound of formula (B) according to claim 1: copper-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate. 22. The piperidinium salt of a compound of formula (B) according to claim 1: piperidinium-(dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionate. 23.. The (d)-isomer of a compound of formula (B) according to claim 1 where R denotes hydrogen: (d)-2-(6,11-dihydrodibenzo- (b . e 0 -thiepin-ll- on-3-yl)propionic acid. 24. The (d)-acid isomer of formula (B) as set forth in claim 1 where R denotes methyl: the methyl ester of (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3 -yl)propionic acid. 25. The (d)-acid isomer of formula (B) as stated in claim 1 where R denotes isoamyl: the isoamyl ester of (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3 -yl)propionic acid. 26. The sodium salt of the (d)-acid isomer of formula (B) as stated in claim 1: the sodium salt of (d)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-one- 3-yl)propionic acid. 27. The potassium salt of the (d)-acid isomer of formula (B) as stated in claim. 1: the potassium salt of (d)-2-(6,11-dihydrodibenzo-(fe.e.)-thiepin-11-on-3-yl)propionic acid. 28. The calcium salt of the (d)-acid isomer of formula (B) as set forth in claim 1: the calcium salt of (d)-2-(6,11-dihydrodibenzo-(b.e.J -thiepin-11-on-3-yl) propionic acid. 29. The copper salt of the (d)-acid isomer of formula (B) as stated in claim 1: the copper salt of (d)-2-(6,11-dihydrodibenzo-(b.e.*)-thiepin-11-one-3 -yl) propionic acid. 30. The piperidinium salt of the (d)-acid isomer of formula (B) as stated in claim 1: the piperidinium salt of (d)-2-(6,11-dihydrodibenzo-(b.e.3-thiepin-11-on-3-yl)propionic acid .. 31. The (1)-isomer with formula (B) according to claim 1 where R denotes hydrogen: (1)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid. 32. Dicyclohexylammonium-(dl)-2-(6,11-dihydrodibenzo-(b.e.3-thiepin-11-on-3-yl)propionate. 33* Preparation for the treatment of inflammation, pain or febrile conditions in mammals essentially consisting of pharmaceutical carriers and a therapeutically effective amount of a compound of the formula: or the (d)-acid isomer of formula (B), where R denotes hydrogen, alkyl with from 1 to 12 C atoms or pharmaceutical salts thereof when R denotes hydrogen, or said esters and pharmaceutical salts of (d)-acid -isomer. 34» Procedure for treating inflammation, pain or fever in mammals which consists in administering a therapeutically effective amount of a compound of the formula: or the (d)-acid isomer of formula (B), where R denotes hydrogen, alkyl with from 1 to 12 C atoms or its pharmaceutical salt when R denotes hydrogen, or said esters and pharmaceutical salts of (d)- the acid isomer. 35. Preparation for administration to pregnant mammals consisting essentially of pharmaceutical carriers and a therapeutically effective amount of a compound of formula: or the (d)-acid isomer of formula (B), where R represents hydrogen, alkyl with from 1 to 12 C atoms or, its pharmaceutically usable salt where R represents hydrogen, or said esters and pharmaceutical salts of (d)- the acid isomer. 36. A method comprising administering to a pregnant mammal a compound selected from the formulas: or the (d)-acid isomer of formula (B), where R denotes hydrogen, alkyl with from 1 to 12 C atoms or its pharmaceutical salt, when R denotes hydrogen, or said esters and pharmaceutical salts of (d)- the acid isomer. 37. Method as stated in claim 36, characterized in that said pregnant mammal is a woman who does not suffer from inflammation, fever or pain and that the compound is given in a therapeutically effective amount which is adapted to delay the onset of labor. 38. Procedure as stated in claim 37" characterized by the fact that the pregnant woman has previously had a spontaneous abortion, miscarriage or premature birth. 39• Method as stated in claim 36, characterized in that the pregnant mammal is a woman who does not suffer from inflammation, fever or labor-related pains, but who undergoes uterine contractions, the compound being given in a therapeutically effective amount adapted to reduce the intensity or the duration of the muscle contractions or stop the uterine contractions completely so that the onset of labor is delayed in relation to the time at which it would otherwise have occurred. 40. Preparation for the treatment of inflammation, pain or fever in mammals, essentially containing pharmaceutical carriers and a therapeutically effective amount of a compound of formula where R denotes hydrogen, alkyl with from 1 to 12 C atoms or its pharmaceutical salt when R denotes hydrogen. 41' A method of treating pain, febrile conditions or inflammation in a mammal, comprising administering a therapeutically effective amount of a compound of formula where R denotes hydrogen, alkyl with from 1 to 12 C atoms or a pharmaceutically usable salt of this compound, when R denotes hydrogen. 42. Preparation for administration to pregnant lactating animals consisting essentially of pharmaceutical carrier media and a therapeutically effective amount of a compound of formula: where R denotes hydrogen, alkyl with from 1 to 12 C atoms or a pharmaceutically usable salt thereof when R denotes hydrogen. 43» Method comprising administering to a pregnant mammal a compound selected from compounds of formula: where R denotes hydrogen, alkyl with from 1 to 12 C atoms or pharmaceutically usable salts thereof when R denotes hydrogen. 44* Method as stated in claim 43" characterized in that the pregnant mammal is a woman who does not suffer from inflammation, pain or fever and that the compound is given to the mother in a therapeutically effective amount adapted to delay the onset of labor. 45* Procedure as specified in claim 44"characterized by the fact that the pregnant woman has had a previous spontaneous abortion, miscarriage or premature birth. 46. Method as stated in claim 45"characterized in that the pregnant mammal is a woman who does not suffer from inflammation, fever or labor-related pains, but who is exposed to uterine muscle contractions, the compound being given in a therapeutically effective amount adapted to reduce intensity or duration of the uterine contractions or stop them completely, so that the birth is postponed in relation to the time at which it would otherwise have occurred. 47* Procedure for the manufacture of. 6,11-dihydrodibenzo- (b.e. J-thiepin-11-one compounds of formula: or the individual (d)-acid isomer or (1)-acid isomer of formula (B), where R represents hydrogen, alkyl with from 1 to 12 C atoms or a pharmaceutical salt thereof, when R represents hydrogen or said esters and pharmaceutical salts of individual isomers of formula (B), comprising one or more of the following steps: (a) treatment of 3-diazoacetyl-6,11-dihydrodibenzo-(b.e.)-thiepin-ll-one in the presence of a C-^-C-^-alkanol to produce the corresponding esters of 6,11-dihydrodibenzo-( b.e.) - tiepin-ll-one-3-acetic acid, (b) hydrolysis of the C 1 -C 4 -alkyl ester of 6,11-dihydrodibenzo-(b.e.)-thiepin-ll-one-3-acetic acid to produce 6,11-dihydrodibenzo-(b.e.)-thiepih-ll- on-3-acetic acid, (c) treating a salt of (dl)-2-(6,11-dihydrodibenzo-Cb.e.)-thiepin-11-on-3-yl)propionic acid' with an acid salt of a strong acid to produce (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin-11-on-3-yl)propionic acid, (d) α-methylation of the C-L-C^rj -alkylester of 6,11- .•: dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid for ferret position, of the C-^-C-^-alkyl ester of (dl)-2-(6,11-dihydrodibenzo-(b.e.)-thiepin- 11-on-3-yl)propionic acid, (e) separation of the (dl)-2-(6,11-dihydrodibenzo-(("b.e.)-thiepin-11-on-3-yl)propionic acid in the (d)-2-(6,11-dihydrodibenzo-(b.e.) ^-thiepin-ll-on-3-yl)propionic acid and (1)-2-(6,11-dihydrodibenzo-(b.e.j -thiepin-ll-on-3-yl)propionic acid, (f) 'esterification of an acid of formula (A) or (B) and individual isomers of the latter to produce corresponding C-^-C-^-alkyl esters, (g) converting an acid of formula (A) or (B) or individual isomers of the latter into pharmaceutically usable salts; (h) racemization of an (l)-isomer of formula (B) to (dl)-2-(6,11-dihydrodibenzo-Cb.e.j -thiepin-11-on-3-yl)-propionic acid, (i) hydrolysis of an ester of formula (A) or (B) or individual isomers of the latter to produce the corresponding free acid; (i) transesterification of a lower ester of formula (A) or (B) or individual isomers of the latter, to produce a higher ester thereof, (k) Transesterification of a higher ester of formula (A) or (B) to produce a lower ester thereof, (1) conversion of salts of formula (A) or (B) or individual isomers of the latter to produce the corresponding free acids, (m) conversion of a. salt of formula (A) or (B) or individual isomers of the latter to another salt by salt exchange.