DE2606312A1 - NEW 6,11-DIHYDRODIBENZO-THIEPIN-11-ONE AND METHOD FOR MANUFACTURING IT - Google Patents

Description

New 6,11-dihydrodibenzo- ^ hiepin-i1-one and procedure for their ..first llu

The present invention relates to new 6,11-dihydrodibenzo- / j3.e._7-thiepin-11-ones of the following formulas: O Q

(dl)

HCO ₂ R

or to the single (d) acid isomer or (l) acid isomer Formula (B), in which R is hydrogen or an alkyl group with 1-12 carbon atoms; it relates further to them pharmaceutically acceptable salts when R is hydrogen, or the esters and pharmaceutically acceptable salts of each Isomers of the formula B and on 'v / learn how to prepare them Links.

S0983S / 1043

The present invention further comprises preparations and methods for using the compounds of the formulas (A), (B) or des (d) -acid isomer of formula (B) or the esters and pharmaceutically acceptable salts of the (d) -acid isomer.

The term "alkyl" refers to straight chain and straight chain Hydrocarbons with 1-12 carbon atoms. Typical Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isoamyl, neopentyl, isopentyl, hexyl, octyl, nonyl, Isodecyl, 6-methyldecyl, dodecyl, etc.

The term, "pharmaceutically acceptable salts' · ¹ refers to from pharmaceutically acceptable, non-toxic bases including inorganic and organic bases salts prepared. The derived from inorganic bases salts include the sodium, potassium, lithium, ammonium, calcium -, magnesium, ferrous, zinc, copper, manganese, aluminum, ferric, manganese salts, etc. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from organic, non-toxic bases include those of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-dimethylaminoethane-ol -Diethylaminoethanol, tronrethamine, - lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, Ethylenediamine, glucosamine, i-isthylglucamine, theobronine, purines, piperazine, piperidine, fJ-ethylpiperidine, polyamine resins, etc. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine,

609835/1043

Ethanolamine, piperidine, tromethamine, choline and caffeine.

The new compounds of formula (B) and the formulas shown below (10), (11), (12) and (14) exist as pairs of optical isomers (or enantiomorphs), i.e. as a (dl) mixture. However, the present invention includes each optical isomer as well as their (dl) mixtures.

The new compounds according to the invention are intended to be used for determination a physiological response (e.g. anti-inflammatory, analgesic or antipyretic effectiveness) bzuj. as a medicine are used, then a preferred subgroup is that of the compounds of formulas (A) and (B) and the (d) acidic nucleus of formula (B) and their esters and pharmaceutically acceptable salts.

Another subgroup for the compounds to be used as medicaments are those of the formula (B) and the (d) acid isomer of formula (B) and its esters and pharmaceutically acceptable salts, whereby this subgroup is divided into two further subgroups from (a) the compounds of the formula (B), i.e. the (dl) compounds, and (b) the (d) -acid isomer of formula (B) and its esters and pharmaceutically acceptable salts. The (l) acid isomer of formula (B) and its esters and pharmaceutically acceptable salts are suitable as intermediates for the preparation the (dl) -acid of the formula (B) in the manner described in more detail below.

Japanese Patent Publication 425/72 dated 7.1.72 describes general compounds of the formula:

609835/1043

260R312

COOR '

(in each of R, R ₉ and R each represent a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl and isopropyl, X is a hydrogen atom, a halon atom such as Cl, Br, 3 and F, or a lower alkyl group Is alkyl group and Y is an oxygen atom, -CH ₉ S- or N, where R. is hydrogen or

represents a lower alkyl group) or its salt; in example 3, in particular, the 11-oxo-6,11-dihydrodibenzo- ^ b.e._7_ thiepin-2-yl-acetic acid mentioned.

The German DLS 24 42 060 generally describes oxepine compounds the formula:

in u / elcher X stands for C = O ", CKCl, CHBr, CH ₃ or CHOR; Y stands for an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, halogen or trifluoromethyl; η is an integer with one Value from O to 3; Z stands for COOR ⁵ , CH ₂ OR ⁵ , C0-NR ⁵ ₂ or CONHOR ⁵ J and R ¹ to R ^{5 are} hydrogen or an alkyl group with 1-4 carbon atoms.

Certain oxepine compounds are also in Belgian PS 818 055 described.

The new compounds of the invention, namely those of formulas (A) and (B) and the (d) acid isomer of formula (B)

609835/1043

and its esters and pharmaceutically acceptable salts have im
Same as the next known compounds of the Japanese patent, namely H-Oxo-6,11 -dihydrodibenzo-Zb. e ^ -thiepin-2-ylpropionic acid in the carrageenin rattan paw determination (which is used in the Japanese patent specification), as shown below, a significantly superior anti-inflammatory
Effectiveness.

The novel compounds of the present invention can be made according to the following Reaction scheme can be prepared:

CO ₂ H

(a)

^V NO.

CO ₂ CH (Me) ₂ (1)

SCH ₂ C ₆ H ₅

(2)

OCl

OCl

SCH ^ C-H,

d. OO

i SCH ₂ C ₆ H ₅

(5)

S03835 / 10-43

(5)

(S)

COCHN,

(6)

(8) (7)

COC = N, -

(9) (dl)

HCO ₂ CH ₂ C ₆ H ₅

in·

(10)

(11)

609835/1043

26QR312

(10)

(dl) I O

(di) IO | Io

HCO ₂ H

(12)

several stages to

separation υοη

(12) - (D-acid isomer

(12) "- (d) -aureisor; ier.es

60983S / 1043

26Q6312

Diisopropyl nitroterephthalate (1) is produced by esterification of nitroterephthalic acid (a) with isopropanol (which serves as a reactant and solvent) in the presence of hydrogen chloride at a temperature of about 25 ° C. up to reflux temperature the reaction mixture for about 48-200 hours. Usually the reaction is preferably carried out at reflux for about 48-96 hours.

Then, the Diisopropylnitroterephthalat (i) with sodium hydride in the presence Benzyimercaptan and is of a suitable organic solvent, such as dimethylformamide, Dimetnylsulfoxid, etc. at a temperature of about ⁰ -4o C. to about 5O ⁰ C., preferably about -35 C. to about 20 C, for case = »1-1G hours, preferably about 2-3 hours, treated to form diisopropyl (benzylthio) terephthalate (2).

The basic hydrolysis of the compound (2) gives (benzylthio) terephthalic acid (3). This reaction is carried out by treating (2) with a base such as potassium hydroxide, sodium hydroxide, etc. in Presence of water and an organic solvent such as methanol, ethanol, propanol, etc., at around 40 C. to the reflux temperature the reaction mixture for about 1-12 hours. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at reflux temperature.

The (BenzylthioJ-tered-thalylchlorid (4) is obtained by treating (3) with thionyl chloride at about 25 ⁰ C. to the reflux temperature of the reaction mixture for about 1-6 hours. This reaction is preferably carried out at reflux temperature.

609835/1043

260B3 1 2

The cyclization reaction to convert (4) into 6,11-dihydrodibenzo- / be7-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, etc. , at a temperature of about ¹ '; -35 ° C. for about 1 / 2-24 hours, preferably at about 2D -2 ° C, for about 4-12 hours. The preferred solvent is ethylene chloride.

The conversion of (5) into 3-diazoacetyl-6,11-dihydrodibenzo- / b'.e ./- thiepin-11-one (6) is carried out by treating (5) with diazotene in an organic solvent such as methylene chloride, Ether, carbon tetrachloride, etc. or mixtures thereof, at a temperature of about -2.O ⁰ C. to about IOC. for about 15 minutes to about 12 hours. This reaction is preferably performed at etiua -5 ⁰ C. to about 5 ⁰ C. for about 15-60 minutes.

The rearrangement of (6) in methyl-6,1i-dihydrodibenzo-Zb. eJ thiepin-11-one-3-acetate (7) is carried out by intimately mixing (δ) with methanol at about 50.degree. up to the reflux temperature of the mixture and subsequent batchwise addition of a silver salt dissolved or suspended in a solvent such as methanol or triethylamine, such as silver benzoate. Other 3-esters corresponding to compound (7) are obtained if the corresponding alkyl alcohol is used instead of methanol 2-12 carbon atoms used.

609835/1043

260B312

The hydrolysis of (7) in 6,11-dihydrodibenzo - /. B.e.7-thiepin-11 one-3-acetic acid (8) is done by treating (7) with a base, such as potassium or sodium hydroxide or sodium carbonate, etc., in the presence of water and an organic solvent such as methanol, ethanol, propanol, etc. , at about 0-70 C. for about 1-24 hours. This hydrolysis is preferably carried out using of aqueous methanolic potassium hydroxide at about 20-30 ° C. Similarly, the other 3-esters obtained above are hydrolyzed to 3-acetic acid (8). The hydrolysis temperature depends from the special, too hydrated ester and can thus between stwa 0 ° C. lie up to the reflux temperature.

Treatment of 6, 1 i-dihydrodibenzo- ^ b. e «_7-thiepin-11-one - 3-carbonyl chloride (5) with diazoethane in an organic solvent, for example ether, methylene chloride, carbon tetrachloride, etc., at a temperature of about -30 ° C. to about -10 ° C. delivers the 3- (o "i-Diazopropionyl) -6,11-dihydrodibenzo / be_7-thiepin-11-one (9) This reaction is preferably with ethereal diazoethane at a temperature of- about -25 ⁰ C. to about - 20 ° C. Carried out »

The rearrangement of (9) into benzyl (dl) -2- (6,11-dihydrodibenzo- / b ".e._7-thiepin-11-on-3-yl) propionate (10) is done by treating (9) with a high boiling alcohol such as benzyl alcohol in the presence an organic amine such as collidine, quinoline, diethylaniline, etc., at a temperature of about 160-190 ° C. for about 1 minute to 1 hour, preferably at about 170-175 ° C. for about 2-30 minutes.

To support the production of the free acid, such as (dl) -2- (6,11-dihydrodibenza- ^ b.e.J7-thiepin-11-on-3-yl) -prop ionic acid (12)

809835/1043

260R312

- 11 -

in a purer form, the compound (10) first becomes a basic one Subjected to hydrolysis, ujie them above to convert (7) into (8) / or (2) was described in (3) _7, whereupon dicyclohexylamine treated to dicyclohexylammonium- (dl) -2- (6,11-dihydrodibenzo- / b ". e./-thiepin-11 -on-3-yl) propionate (11).

The conversion of (11) to (dl) -2- (6,11-dihydrodibenzo - ^ / bi.e./-thiepin-11-on-3-yl) -propionic acid (12) is carried out by treating (11) in an organic solvent such as methylene chloride, Ether, benzene, etc., with an acid salt or a strong acid such as sodium hydrogen sulfate, hydrochloric acid, sulfuric acid, etc., at about 0-50 ° C for about 1 minute to 1 hour, preferably at about 20-25 ° C. for about 1-5 minutes.

The compounds of the formula (12) can also be prepared according to the following

Reaction scheme can be prepared: O

> (dl) I O

(13)

(14)

(dl) O

CHCO ₂ H CH ₃

where R 'represents an alkyl group having 1-12 carbon atoms.

609835/1043

The <^ - methylation of the compounds won formula (13), namely the ester of 6,11-dihydrodibenzo- / be ^ / - thiepin-11-one-3-acetic acid (R ¹ I = C ;. alkyl, preferably methyl) to obtain the compounds of formula (14), namely the esters of (dl) -2- (6,11-dihydrodibenzo- / beJ / -thiepin-11-on-3-yl) propionic acid (R '= C, " A] tyl, preferably methyl), is carried out by treating the compounds of the formula (13) with an alkali metal hydride, alkali metal amide, alkali metal dialkyl amide, etc., such as sodium hydride, lithium diisopropyl amide or sodium dimethyl amide, in the presence of a polar, non-protic solvent, u / ie N, N- Dimethylacetamide, dimethyl formamide, hexamethylphosphoric triamide (HMPA), dimethylsulfoxide, sulfolane, etc., at about 10-6G ⁰ C. and subsequent treatment with a methyl halide, uiie diethyl iodide, or a dialkyl sulfate, uiie dimethyl sulfate, at about -15 ° C. to etuia 6Q ⁰ C. for etuja 5 minutes to about 1 hour.

Then the compounds of formula (14) to the free acids of formula (12) according to the above for hydrolysis of the compound of Formula (7) is hydrolyzed in the method described in Formula (8).

Processes for the preparation of the compounds of formula (13,) in which R ^{1 is} C alkyl are described below.

The (dl) mixture obtained from (12) is made by known methods, e.g. Separation procedure described in Example 12B below, in their corresponding d-isomer, (12) - (d) -acid isomer, and 1-isomer. (i2) - (l) -3 acid isomer, separated.

609835/1043

After their preparation, the free acids of the formulas (B), (12), (i2) - (d) -acid isomer and (12) - (l) -acid isomer, in their corresponding esters and acid addition salts are converted.

The salt derivatives of the compounds of formula (8), (12), (i2) - (d) acid isomer and (12) - (l) acid isomers are prepared by treating these free acids with an appropriate amount of a pharmaceutically acceptable base. Pharmaceutically acceptable Bases are e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, Ferric hydroxide, zinc hydroxide, copper hydroxide, manganohydroxide, Aluminum hydroxide, ferric hydroxide, manganese hydroxide, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-Dimethyla ^ iinoäthanol, 2-Diethy laminoäthanol, Tromethainin, Lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, Betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, Purines, piperazine, piperidine, IM-ethylpiperidine, polyamine hearts, etc. The reaction takes place in water alone or in combination with an inert, water-miscible organic solvent at approx O-1DG C, preferably at room temperature. Typical inert, Water-miscible organic solvents include methanol, ethanol, Isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratios of the compounds of formula (8), (12), (I2) ~ (d) acid isomer and (12- (l) acid isomer to the used Bases are selected to give the desired ratio for any particular salt. For example, for the production of the Calcium or magnesium salts of the compounds of formula (A) and (B) and of the individual (d) and (l) acid isomers of the latter the free acids of the formulas (8), (12), (i2) - (d) -3 acid isomer

609835/10 * 3

and (12) - (1) acid isomer with at least one-half molar equivalent of the pharmaceutically acceptable base to form one neutral salt treated u / earth. In the manufacture of aluminum salts of the compounds of formula (A) and (8) and the individual (d) and (l) acid isomers of the latter is at least one One third molar equivalent of the pharmaceutically acceptable base used when a neutral salt is desired as the product.

In the preferred process, the calcium and magnesium salts of the compounds of formula (A) and (B) and the calcium and magnesium salts of the (d) and (I) acid isomers of formula (B) can be prepared by using the corresponding sodium or potassium salts of the compounds of formula (A) and (B) and the sodium or potassium salts of (d) and (l) acid isomers of formula (B) with at least half a molar equivalent of calcium or magnesium chloride in an aqueous solution treated alone or in combination with an inert, u / water-miscible organic solvent at 20-100 C. The aluminum salt of the compounds of formula (A) and (B) and the aluminum salt of the (d) and (l) acid isomers of formula (B) can be prepared by adding the corresponding free acids of the compounds of formula (8), (12), (12) - (d) -isomer and (1 2) - (l) -isomer it with at least one third molar equivalent of an aluminum alkoxide, such as aluminum triethoxide, aluminum tripropoxide, etc., in a hydrocarbon solvent, such as benzene, xylene, cyclohexane, etc., at a temperature of 2O ⁰ C to about 115 ° C. treated. Similar methods can be used to prepare salts of inorganic bases which are not sufficiently soluble to react easily.

609835/1043

- 15 - 260631?

The salt products are isolated in the usual 'orphan'. This is how they are Reaction mixtures, e.g. evaporated to dryness, and the salts can be further purified by conventional methods.

The salt derivatives of the compounds of formulas (8) and (12) and the salt derivatives of the 12 (d) acid isomer and 12 (l) acid isomerpn can be made by acidifying the salts with an acid, preferably an inorganic acid such as hydrochloric acid, sulfuric acid, etc., at about 0-30 C., preferably at room temperature, in their corresponding free acids are converted.

The esters of the formula (A) and (B) and the esters of the (d) acid isomer and (l) -acid isomers of formula (B) are prepared by esterifying the corresponding free acids of formula (θ), (12), (12) - (d) -Äureisornerem and (12) - (l) -Äureisomers with a Alcohol reagent corresponding to the desired ester, e.g. an alkanol with up to 12 carbon atoms. This reaction takes place in Presence of a strong acid such as boron trifluoride, hydrogen chloride, Sulfuric acid, p-toluenesulfonic acid, etc .. If that's in the Esterification used alcohol reagent is a liquid at the reaction temperature, this can be the reaction solvent. Optionally, the reaction can be carried out in an inert organic solvent in which the free acids of formula (8), (12), (i2) - (d) -acid isomer and (12) - (l) -acid isomer ■ and the alcohol reagent are soluble, like a hydrocarbon solvent e.g., hexane, isooctane, decane, cyclohexane, benzene, toluene, xylene; a halogenated hydrocarbon solvent, such as methylene chloride, chloroform, dichloroethane; or an ethereal

609835/1043

260R312

solvents such as diethyl ether, ibutyl ether, ioxane, tetrahydrofuran usuj. If the alcohol reagent is a solid, done the reaction is preferably carried out in a non-aqueous, liquid, inert organic solvent. The reaction is between etiua 0 C. to the reflux temperature of the reaction mixture, preferably using hydrogen chloride at a temperature carried out from 15 to about 35 C.

The product is processed in a conventional manner, for example diluting the reaction mixture with water, extracting the resulting aqueous mixture with a water-immiscible, inert organic solvent such as diethyl ether, benzene, methylene chloride, etc. combine the extracts, washing them with water until neutral and then evaporating them under reduced pressure to be isolated.

The preferred acid esters of formula (A) and (B) and the esters of the (d) acid isomer and (l) acid isomer of formula (3) are those ester derivatives made 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, monyl alcohol, 2-nonyl alcohol, isononyl alcohol, Decyl alcohol, 2-decyl alcohol, isodecyl alcohol, undecyl alcohol, Dodecyl alcohol, etc. are produced.

The esters of Fornel (A) and (B) and the esters of the (d) acid isomer and (I) -acid isomers of formula (B) can also be prepared by known uresterification methods. In the preparation of

809835/1043

the ester by transesterification is preferably of a lower one

gone out and
Ester / unesterified to a higher ester, e.g. from methyl ester to isoamyl ester. By using a substantial excess of a lower alcohol, for example, a higher ester can be transesterified into a lower ester; for example, by using a substantial excess of ethanol, the hexyl ester is transesterified into the ethyl ester.

The (i2) - (l) -Smureisomere, the (l) -2- (6,11-Dihydrodibenzo- ^ be .] - thiepin-11-on-3-yl) -prap: .onic acid and the corresponding esters and Salts thereof are obtained by treatment with excess strong base, such as sodium, potassium or tetramethylammonium dihydroxide, etc., at a temperature of about 60 ° C. up to the reflux temperature

for

the reaction mixture / about 4-10 hours under an inert atmosphere, such as nitrogen, and subsequent acidification with a mineral acid, such as hydrochloric acid, sulfuric acid, etc. into the (di) -2- (6,11-dihydrodibenzo- ^ b. e _o _ / ~ thiepin-11-on-3-yl) propionic acid (12) converted. When the above reaction occurs on the (12) - (1) acid isomer or its salts, water is preferred as the solvent. If the reaction takes place on the esters of the (12) - (l) -Ssureisorneren, then the preferred solvent is an aqueous alkanal, z.3. aqueous methanol.

The compounds of formulas (a) and (B) and the (d) acid isomer of formula (B) and its esters and pharmaceutically acceptable salts are useful as anti-inflammatory agents, antiplatelet inhibitors, fibrinolytic agents and smooth muscle relaxants can be used both prophylactically and therapeutically.

^V 60983S / 1043

2 6 O R 31 2

The compounds of formula (Α) and (B), the (d) acid isomer of formula (B) and its esters and pharmaceutically acceptable salts show anti-inflammatory, analgesic and antipyretic Properties. Therefore, the preparations containing these compounds are useful for treating and relieving inflammation, e.g.

those in the muscular bone system, the bone angel nion,

round and other tissues, such as rheumatism, bruises, crack /, arthritis, Bone fractures, post-traumatic conditions and gout. In cases and / or the above disorders pain and itching in connection with inflammation, the compounds according to the invention are suitable for alleviating these conditions and inflammation.

Administration of an active compound of formula (A) and (B) and the (d) -acid isomer of formula (B) and the esters and pharmaceutically acceptable salts thereof in a corresponding one pharmaceutical preparation can be administered via the usual jjjsjsai for means for the treatment of inflammation, pain or itching or their prophylaxis, i.e. e.g. orally, parenterally or locally in the form of solid, semi-solid or liquid preparations, e.g. as tablets, suppositories, pills, capsules, Powders, liquids, suspensions, creams, lotions, ointments, etc., preferably in one for easy administration of precise doses suitable dosage form. The preparations include a usual one pharmaceutical carrier or an excipient and an active compound of formula (A) or (B) or the (d) -acid isomer of Formula (B) and its esters and pharmaceutically acceptable salts; you can also use other medical and pharmaceutical agents,

609835/1043

- 19 porters, aids usui. include.

The preferred mode of administration for the above diseases is orally using appropriate daily doses which may be adjusted according to the degree of the disease. Usually a daily dose of 0.05-10 mg of active compound will be used of formula (A) and (B) and the (d) -5 acid isomer of formula (B) and its esters and pharmaceutically acceptable salts used per kg of body weight. Most diseases respond to treatment with doses around 0.25-3 mg per kg of body weight per day. For such oral administration, a pharmaceutically acceptable, non-toxic preparation is made by incorporation any of the excipients normally used, such as pharmaceuticals Mannitol, lactose, starch, magnesium stearate, sodium saccharin, Talc, cellulose, glucose, sucrose, magnesium carbonate etc., produced. These preparations can take the form of solutions, suspensions, tablets, pills, capsules, powders, depot formulations etc. accept.

The active compound of formula (A) and (B) and the (d) acid isomer of the formula (B) and the esters and pharmaceutically acceptable salts thereof can, for example, using polyalkylene glycols, such as polypropylene glycol, formulated as a carrier in suppositories will. Know liquid, pharmaceutically administrable preparations z «B. by dissolving, dispersing, etc. an active compound according to in the manner described above and an optional pharmaceutical adjuvant in a carrier, such as water, saline, aqueous Dextrose, glycerin, ethanol, etc. can be made to form a solution or suspension. If necessary, this can be administered

809836/1043

_2o _? 6 η 6 312

Reaching pharmaceutical preparation also small amounts of non-toxic Auxiliary substances, including wetting agents or emulsifiers, pH buffering agents usu /., e.g. sodium acetate, sorbitan monolaurate, triethanolamine oleate usu /. , contain.

The actual manufacturing processes for these dosage forms are known or obvious to the person skilled in the art; see e.g. Remingtons "Pharmaceutical Sciences", Mack Publishing Comp., Easton, Pa., 14th Ed. (1970). Contains the preparation to be administered in any case the active connection (s) in one to ameliorate or remedy the particular disease to be treated pharmaceutically effective amount according to the information provided.

The compounds of formulas (A) and (B) and the acidic acid (d) of Formula (B) but the esters and pharmaceutically acceptable salts thereof are also agents for relaxing smooth utsrins Musculature and therefore suitable for a scholarship to be maintained by the mother and / or fetus until their termination from a medical point of view as cheap or cheaper considered and / or considered for mother and / or fetus. It goes without saying it is possible that in certain cases, e.g. when childbirth has already begun (i.e. the mother uterine contractions, in particular at almost full strength, shows) the administration of the compounds of the invention the security cannot be maintained for an indefinite period of time. In these cases it will take place whose pregnancy etu / as "prolongs", u / as favorable for Can be mother and / or fetus.

The compounds of formula (a) and (B), the (d) acid isomer of formula (B) and the esters and pharmaceutically acceptable

609835/1043

₂₁ _ 260R312

Salts of the same are used in particular as an agent for delaying the onset of labor. The label "to delay The onset of labor "should be achieved by administering the above compounds at any time before the onset of uterine muscle contractions delays in labor. Thus, the prevention of an abortion in the early stages of pregnancy, i.e. before the fetus shows life, as well as the delay of a premature birth, where "premature birth" refers to the Onset of preterm labor in a later stage of pregnancy, when the fetus shows life, is related. In any case the agents are administered as prophylaxis to prevent the onset of childbirth. This administration is particularly useful to treat women with previous spontaneous abortions, miscarriages, or premature births, i.e., births before the full timeframe. Administration is also appropriate where there are clinical signs that the pregnancy could be terminated ahead of time.

This treatment can also be used in animals to synchronize the births of a group of pregnant animals to about the same time or about the desired time and / or place where the births can be more easily managed.

The term "delivery delay" means that by administration of the compounds of formula (A) and (B) and the (d) acid isomer of formula (B) as well as the esters and pharmaceutical acceptable salts of the same delayed parturition after the onset of uterine muscle contractions. The patient's condition

609835/1043

finally the time within pregnancy at the beginning of the Contractions, their severity and the duration they have already taken affect those achieved by administering the above-mentioned compounds Results. The effect can be, for example, in the reduced intensity and / or duration of the contractions u / ird) '' »which consist in the complete cessation of labor. In in either case, however, the pregnancy is prolonged, albeit Depending on the patient's condition, the effect may be slight or, under appropriate circumstances, a little stronger. The administration can prevent spontaneous abortion, a for the buttery easier and / or less painful birth or the occurrence of the birth at a better time and / or Effect place.

In all cases the administration of the compounds of formula (A) and (B) and the (d) acid isomer of formula (B) as well of the esters and pharmaceutically acceptable salts thereof for the stated purposes of the best and / or recognized medicinal products or veterinary practice to produce the most beneficial effects for the mother and fetus. The administration e.g. should not be continued through the full pregnancy so long that the fetus dies in the uterus.

When carrying out the method according to the invention, a therapeutically effective amount of a compound of formula (a) and (B) or of the (d) acid isomer of formula (B) and the esters and pharmaceutically acceptable salts thereof or one of these compounds containing pharmaceutical preparations for pregnant women

609835/1043

or administered to the pregnant animal in the usual, recognized manner. The compound can zeutschen individually or in combination with one or more of the above-mentioned compounds or other pharm Means, carriers, auxiliaries usui, administered, and ziuar can compounds or preparations orally, parenterally in the form administered from solid, semi-solid, or liquid dosage forms will. Administration is usually with one of the pharmaceutically active compound and one or more preparation containing pharmaceutical carriers or auxiliaries.

The pharmaceutical preparation to be administered can be in the form of oral tablets, vaginal or uterine tablets or suppositories, Pills, capsules, liquid solutions, suspensions, etc., preferably in one for easy administration of the exact Can have a suitable shape. Common, non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, Starch, magnesium stearate, sodium saccharin, talc, cellulose, Glucose, sucrose, magnesium carbonate, etc., As mentioned, the active compound with polyalkylene glycols, such as propylene glycol, can be formulated as carriers for suppositories. Liquid, pharmaceutically administrable preparations can, for example, by dissolving, dispersing usuj., an active compound described above and optional pharmaceutical excipients in a carrier such as water, saline, aqueous dextrose, glycerin, ethanol, etc., to form a solution or suspension. Possibly the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances, such as wetting agents

S09835MG43

agents and emulsifiers, pH buffering agents, etc., e.g. sodium acetate, Sorbitan monolaurate, triethanolamine oleate, etc. contain. the Production of such dosage forms is known or the Skilled in the art obviously; See, for example, Remingston's "Pharmaceutical Sciences ", Mack Publishing Comp., Easton, Pa., 14th Ed., (1970). The preparation or formulation to be administered contains in any case the active compound (s) in a delayed manner the beginning of labor or to postpone labor after the onset of labor. Usually a daily one is done Dose from 5 to about 250 mg of active compound per kg of body weight administered, the administration as a single daily dose or up to three or four times in regular doses throughout the day. Of course, the administered one depends Amount of active compound on its relative potency away.

The following examples illustrate the present invention, without restricting them. If necessary, the examples have been used to make additional material for later examples repeated; and unless otherwise specified, the reactions were run at room temperature (i.e. 20-30 ° C.).

Example 1_

200 g of nitroterephthalic acid (a) was dissolved in 1 1 of isopropanol and this solution was saturated with hydrogen chloride and for 3 days Heated to reflux. During this time it became hydrogen chloride occasionally passed into the solution to maintain its concentration. Then the reaction solution was cooled and obtained after evaporation of the isopropanol under reduced pressure

609835/1043

- 25 - 260R312

a residue which was dissolved in 500 ecm of methylene chloride. The resulting solution was washed with 10% aqueous sodium carbonate, and the resulting organic layer was dried over magnesium sulfate. Removal of the solvent in vacuo gave a yield of 245 g (87.4 %) of diisopropyl nitroterephthalate (1) as an oil.

IRY ^CHC1 3 1724, 1542, 1350 cm " ¹
Max

iMMR ^ ^CDC1 3 1.35 (6H, d), 1.40 (6H, d), 5.24 (1H, 7 lines), 5.27

TMS
(1 H ₁ 7 lines), -7.71 (1H, d), 8.24 (1H, dd), 8.43 ppm (1H, d).

Example 2

5.1 g of sodium hydride were slowly added to a solution, cooled to -20.degree. C., of 23.5 ecm benzyl mercaptan in 100 ecm dimethylformamide. The resulting solution was cooled to -30 ° C., then 53 g of diisopropylnitroterephthalate (1) in 100 ecm of dimethylformamide were added. After an hour at -30 c. and for 2 hours at 0 ° C., the reaction mixture was poured into water, the precipitate was filtered off, washed with water and dried and yielded 77-92 , ί crude diisopropyl (benzylthio) terephthalate (2); This sample showed after recrystallization from a F. Penban of 70-71 ⁰ C.
Example 3

The crude diisopropyl (benzylthio) terephthalate (2) obtained in Example 2 was refluxed with 500 ecm of Rethanoi, 25 g of potassium hydroxide and 50 ecm of water for 2 hours. The reaction mixture was then concentrated to a small volume, cooled, diluted with water and filtered through diatomaceous earth (Celite). Jas filtrate thus obtained was acidified with 4N hydrochloric acid and the precipitate formed was filtered off in an oven at 90-100 C. ^D

609835/1043

- Zo -

dried; 45 g (ß7 %) of (benzylthio) terephthalic acid (3) with a F. of 299-300 C. were obtained in this way.

Example 4

10 g of (benzylthio) terephthalic acid (3) were treated with 10 ecm of thionyl chloride and the reaction mixture was refluxed for 4 hours. After removing the excess thionyl chloride in vacuo, the residue obtained is slurried with hexane and the solid product is filtered off. This gave 10.2 g (92 %) of (benzylthio) terephthalyl chloride (4) with a mp of 158 c.

Example 5

10.2 g of (benzylthio) terephthalyl chloride (4) in 100 ecm of methylene chloride was added to a solution of 14.75 g of aluminum chloride in 100 ecm of methylene chloride with 10.51 ecm of nitromethane. Wax for 5 hours at 25 ⁰ C. u / ere 16.5 cc of saturated aqueous sodium chloride added under vigorous stirring. The precipitated inorganic salts were filtered off and the filtrate was evaporated to dryness to a solid residue, which was slurried with ether. The ether suspension was filtered and yielded 7.0 g (70.7 / o) 6,11-dihydrodibenza - / "be_ / ~ -thiepin-11-one-3-carbonyl chloride (5) with a mp of 119-12O ° C.

Example 6

A solution of 11 g of 6,11-dihydrodibenzo- / b.e._7-thiepin-11-one-3-carbonyl chloride (5) in 100 ecm of methylene chloride slowly turned into excess diazomethane (made from 20 g of N-nitroso-N-methylurea) added in 200 ecm ether solution. After 2 hours, the reaction mixture was purified by distilling off the solvent concentrated to about 50 ecm. ". After cooling, the reaction mixture filtered and gave a residue of 9.5 g

609835/1043

260R312

(85 %) 3-Diazoacetyl-6,11-dihydrodibenzo- / beJ ⁷ -thiepin-11-one (6) with a F. of 153 C. u.zers.

Example 7

9.5 g of 3-diazoacetyl-6,11-dihydrodibenzo- / beJ7-thiepin-11-one (6) were suspended in 500 ecm of methanol and the suspension was heated to reflux with vigorous stirring. Within 50 minutes, 2 g of silver benzoate (suspended in 20 ecm of methanol) were added in proportions of 2 ecm. The reaction mixture was refluxed for 15 hours, cooled and the solvent was pumped off. After chromatography of the residue on 400 g of silica gel, 7 g of methyl 6,11-dihydrodibenzo- / bs _t 7-thiepin-11-one-3-acetate (7) with a temperature (ether) of 10-101 ° C. were obtained .

Other than methanol were used in this example Alkyl alcohols with 2-12 carbon atoms used then received one the following connections:

Ät hy 1-6,11 -dihydrodibenzd- / b.ej_7-thiepin-11-one-3-acetate Propy1-6,1i-dihydrodibenzo-Zb.r ./-thiepin-11-one-3-acetate isopropyl-6 , 11-dihydrodibenzo- / be _^ 7-thiepin-11-on-3-acetate hexyl-6,1 i-dihydrodibenzo-ZB.e._7-thiep in-11-on-3-acetate Nony1-6,11- dihydrodibenzo- ^ b. β J- thiepin-11-one-3-acetate Do decy 1-6,11 -dihydrodibenzo-Zb. & * J- thiep in-11-on-3-acetate etc.

Example 8

7.0 g methyl-6,11-dihydrodibenzo- / b.e._7-thiepin-11-one-3-acetate (7) were stirred with 200 ecm of methanol, and it became a solution 2.0 g of potassium hydroxide in 5 ecm of water were added. After one hour the solution cleared by filtration and the filtrate with Acidified 3iM aqueous hydrochloric acid and diluted with 400 ecm of water.

609835 / 10U

- 28 - 260R312

The precipitated solid was filtered off, etu / a ⁰ C. dried and recrystallized from benzene / hexane in an oven at 8O; this gave 5.6 g of 6,11-dihydrodibenzo-Zb. e ._ / - thiepin-11-one-3-acetic acid (8) with a F. of 154-155 ⁰ C. Acute oral toxicity _Q ) 1190 mg / kg.

If instead of Kethyl-ö, 11-dihydrodibenzo- / b.e ^ 7-thiepin-11-one-3-acetate using the other 3-esters of Example 7, e.g.

Ethyl-6,11-dihydrodibenzo- / be_7-thiepin-11-one-3-acetate Propyl - 6,11-dihydrodibenzo- / be _i / -thiepin-11-one-3-acetate Isoprcpy 1-6.1 i -dihydrodibenzo-ZB.eJ ^ -thiepin-11-one-3-acetate hexyl-6,11 -dihydrodibenzo-ZE. eJ- thiepin-11-an-3-acetate Nony 1-6,11-üihydrodibenzo- / Ti. e./-thiepin-1i-on-3-acetab Dodecy 1-6,11 -dihydrodibenzo- / TD.e ./- thiepin-11-on-3-acetate usu ;.

Example 9

A solution of 2.5 g of 6,11 -uihydrodibep.zo- _i / ¹ b .ey-thiepin-11-one-3-carbonyl chloride (5) in 30 ecm of methylene chloride was converted into a solution of diazoethane (prepared from 20 g of N -Ethyl-N-nitrosourea) - added in 150 ecm of ether at -2O ⁰ C. The reaction mixture was allowed to warm to room temperature and most of the solvent was blown away with a stream of nitrogen. After filtration there was obtained 1.5 g of 3- (oH) iazopropionyl) -6,11-dihydrorjibenzo- / be_7-thiepin-11-one (9) having a melting point of 127 ⁰ C. with decomposition.
Example 1_D

1.1 g of 3 - (<3 (-: iazapropionyl) -6,11-dihydro dibenzo- / b.e ./-thiepin-1 1-one (5) was suspended in 3 ecm collicin and made into a mixture from 5 ecm benzyl alcohol and 5 ecm collidine, heated to 170-175 ° C.

809835/1043

- 29 - 260R31?

held and added. After 5 minutes the reaction mixture was cooled and the solvents were distilled off in vacuo. After chromatography of the residue on silica gel, 1.0 g of benzyl (dl) -2- (6,11-dihydrodibenzo ~ / b. E. / - thiepin-11-on-3-yl) propionate was obtained (10) as a colorless oil.

IR V ^CHC1 3 1735, 1640, 1600 cm " ¹
Max

^CDC1

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

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

MS: 388 (M ⁺ ).

Example IJ _-

1.0 g of benzyl (dl) -2- (6,11-dihydrodibenzo- / be_ / - thiepin-11 -on-3-yl) propionate (10) in 25 ecm of methanol was mixed with 0.3 g of potassium hydroxide in Treated 2 ecm 'of water. After one hour, the reaction mixture was poured into 25 ecm 3N hydrochloric acid and 100 ecm water. The resulting mixture was extracted with ethyl acetate and the organic layer was then extracted with 10% aqueous sodium carbonate solution. The basic aqueous layer was acidified with 3N hydrochloric acid and the precipitated (dl) -2- (6,11-dihydrodibenzo- / bey "-thiepin-11-one-3-yl) propionic acid was extracted with ether. The ether layer was extracted after drying Evaporated over magnesium sulfate to give an oil which was taken up in 5 ecm of benzene. The benzene solution was treated with 0.5 g of dicyclohexylamine and the solution allowed to crystallize over [Jacht. After drying, 640 mg of dicyclohexylammonium- (dl) -2- were obtained. (6,11-dihydrodibenzo- / bey-thiepin-11-on-3-yl) propionate (11) with a mp of 163-165 ° C.

609835/10 ^ 3

Example 1_2

640 mg of dicyclohexylammonium (dl) -2- (6,11-dihydrodibenzene- ^ b. EJ- thiepin-11-on-3-yl) propionate (11) were dissolved in 10 ecm of methylene chloride and the solution with excess p-sodium hydrogen sulfate monohydrate (1.0 g) stirred. The reaction mixture was filtered and the solvent removed in vacuo. The residue was extracted with ether. Evaporation of the ether extract gave an oil which, after drying under high vacuum (0.1 mm), 300 mg (dl) -2- (6,11 -dihydrodibenzo- / b \ e, J- thiepin-11-one-3- yl) propionic acid (12) provided as a foam ..

_IRV KBr 37Q ₀ _25Q0 1710, 1640 cm " ¹
Max ''

NMR S ^CDCl 3 1.47 (3H, d), 3.68 (1H, q), 4.00 (2H, s), 7.0-8.0

TMS
(6H, m), 81.0 ppm (1H, d);

MS: 298 (M ⁺ ).

Dicyclohexylammonium (dl) -2- (6,11-dihydrodibenzo-/ be / -thiepin-11-on-3-yl) -prapionate (11) was obtained in several experiments according to the procedure of Example 11. The products thus obtained were combined and treated according to Example 12; the result was a foam which was recrystallized from 2: 1 ether: hexane and (dl) -2- (6,11-dihydr od ib en zo- / be _jL / -th iep in-11-on-3-yl ) propionic acid (12) with a mp of 113-115 ° C. and provided the IR, WMR and MS data mentioned in Example 12.

Example 1 2A

To 4.0 g of matrium hydride (100 %) in 600 ecm I \ l, f \ i-dimethylacetamide, 41 g of methyl-6,11-dihydroaibenzo- / be / -thiepin-11-one-3-acetate ( 13; R '= riethyl) was added, a deep red color developing _o The mixture was

609835/1043

Stirred overnight at room temperature, then 20.0 g of methyl iodide were quickly added. The resulting reaction mixture, changed from red to green-blue, was stirred for 15-20 minutes at room temperature and poured into a mixture of 6 liters of saturated sodium chloride solution, 600 ecm of water and 2 liters of ethyl acetate and shaken with it. The layers are left to separate and the organic layer is washed one after the other three times with 300 ecm of saturated sodium chloride solution each time. The saturated sodium chloride wash materials were successively extracted three times with 300 ecm of ethyl acetate each time. The ethyl acetate extracts were combined, dried over sodium sulfate and evaporated to dryness in vacuo; 46.0 g of a dark yellow residue were obtained from methyl (dl) -2- (6,11 -dihydrodibenzo - ^ 'b. ej ^ -thiepin-11-on-3-yl) propionate (14; R' = Methyl) combined with 25.0 g of a similar material previously obtained by the same alkylation procedure. The combined residues (71.0 g) were percolated over 1 kg of silica gel, then eluted with methylene chloride and finally with 2:98 ethyl acetate-methylene chloride. The eluted fractions, which, according to thin-layer chromatography, predominantly showed the presence of the o ^ -methylated product, were combined and evaporated to dryness and yielded 62.0 g of a pale yellow powder of methyl- (dl) -2- (6,11-dihydrodibenzo- /be_7-.thiepin-11-on-3-yl) propionate (14; R '= methyl), which was dissolved in a mixture of 1600 ecm tetrahydrofuran and 800 ecm water. / A sample of methyl (dl) -2- (6,11-dihydrodibenzo- / be _ / - thiepin-11-on-3-yl) propionate (14; R '= methyl), obtained after the same experience , after recrystallization from diethyl ether had the following physical constants: F. from 62.0 to 62.5 ⁰ C .;

609835M043

_ 32 -

_{IR /} KBr ₃₇₀₀ _ _{250Q 174G 1640 cm} -1. _NHR S ^ h 1.47 (3H, d),

ΓΠ3Χ ι ι id

3.65 (3H, s), 3.68 (1H, q), 4.02 (2H ₁ sj, 7.0-8.0 (6H ₁ m), 8.21

ppm (1H, d); MS: 312 (M ⁺ ) ._7 The resulting solution was
180 ecm of 1N sodium hydroxide are added, the reaction mixture is 3
Stirred for hours, then the tetrahydrofuran was removed in vacuo and it was diluted with 3 liters of water. The diluted green solution was extracted twice with 600 ecm of ethyl acetate each time, whereupon the aqueous layer was acidified with 2N hydrochloric acid. The acidified aqueous solution was extracted a few times with methylene chloride, the ethylene chloride extracts were combined, dried over sodium sulfate and evaporated to dryness; the received
The residue was taken up in 250 ecm of diethyl ether and allowed to crystallize. The fine white crystals formed were
filtered off, washed with ice-cold diethyl ether and sucked dry; 40.0 g of (dl) -2- (6, 11 -dihydrodibenzo- /!}. e ^ 7 ~ thiepin-11-on-3-yl) -propionic acid (12) with a F. of 114 were obtained, 5-115, 114.5 to 115.5 ⁰ C (uncorrected).

3700-2500, 1710, 1655 cm " ¹ .

^ 3 ¹ 3 1.47 (3H, d), 3.68 (1H, q), 4.00 (2H, s), 7.0-8.0 (6H, m), 8.12 ppm (1H , d);
MS: 298 (M ⁺ ).

Instead of methyl-6,11-dihydrodibenzo- / b.e .J7-thiepin-11-οπ-3-acetate other 3-esters of 6,11-dihydrodibenzo-Zb. e ._ / - thiepin-11-one-3-acetic acid used, e.g.

Ethyl-6,11-dihydrodibenzo-be _; _7-thiepin-11-Qn-3-acetate
Propyl-6,11 -d ih yd ro d iben zo - / 'b. ^ .J- thiepin-11-on-3-ac e tat
Isoamyl-6,11-dihydrodibenzo-be J- thiepin-11-an-3-acetate
Hexyl-6,11-dihydrodibenzo / bo & J- thiepin-11-οπ-3-acetate

609835/1043

_ 33 - 2 B O R 3 1 2

l \ lonyl-6,11-dihydrodibenzo- / be _l / -thiepin-11-an-3-acetate Dodecy 1-6,11-dihydrodibenzo- / JT.e »7-th iepin-1 1-on-3- acetate usuj.

then (dl) -2- (6,1I-dihydrodibenzo-Zb.e / 7-thiepin-i1 on-3-yl) prop ionic acid.

Example 1_2B_

(a) 5.0 g (dl) -2- (6,11-dihydrodibenzo- / be _i y-thiepin-11-on-3-yl) propionic acid (12) in 50 ecm benzene, the 5 ecm thionyl chloride and contained 3 drops of dimethylformamide, dissolved and stirred for 1.5 hours. The reaction mixture was evaporated to an oily residue which was dissolved in 50 ml of dry benzene and evaporated again; in this way an oily residue was obtained from (dl) -2- (6,11-dihydrodibenzo- _; / be _i 7-thiepin-11-on-3-yl) propionyl chloride. This was dissolved in 250 ecm acetonitrile, and 10 ecm (l) -1-phenylethylamine and 6.5 ecm triethylamine were added. After stirring for 2 hours, the reaction mixture was added to 750 ecm of water and extracted with 400 ecm of ethyl acetate. The organic extract obtained in this way was washed with 400 ecm of 2N hydrochloric acid, dried and evaporated to give a residue which was chromatographed on 400 g of silica gel while eluting with 1 m: 1 benzene: ethyl acetate; so one obtained first 3.3 g of the less polar (l) -2- (6, .11 -dihydrodibenzo- ^ bey -thiepin-11-on-3-yl) -propionyl- (l) -1- phenylethylamide, which after recrystallization from 1: 2 ethyl acetate: hexane had a F. of 162-163 C. and L ^ -J ⁷ Q +16.4 (10 mg / ecm, chloroform); secondly, tr.an received 2.8 g of the more polar (d) -2- (6, 11 -dihydrodibenzo-Zb ". e Γ / - thiepin-11-on-3-yl) -propionyl- (l) -1 -phenyläthylamids, which after recrystallization from 1: 2 ethyl acetate: hexane an F. of

609835/1043

- 34 170-171 ° C. and / x 7 _D ~ ¹ »4 ° (10 mg / ccm, chloroform).

(b) 3.0 g of (d) -2- (6,11-dihydrodibenzo- / be ^ 7-thiepin-11-on-3-yl) -propionyl- (l) -1-phenylethylamide in 93 ecm conc. Hydrochloric acid and 62 ecm acetic acid were heated to 87 ° C. for 8 hours. The mixture was cooled, poured into water and extracted with 250 ecm ethyl acetate. The ethyl acetate extract was washed with water and extracted with 250 ecm of 0.5 molar aqueous sodium carbonate. The ethyl acetate solution remaining after the aqueous sodium carbonate extraction was dried and evaporated and yielded 1.06 g of unchanged phenylethylamide starting material. The aqueous sodium carbonate extract was acidified with 500 ecm 2N hydrochloric acid and extracted with 350 ecm ethyl acetate. The ethyl acetate extract was dried and evaporated to give 1.34 g of a residue comprising 2 - (6,11-dihydro dibenzo- [ i.e., e7 ~ thiepin-11-on-3-yl) propionic acid. 1.06 g of the recovered starting material were concentrated in 45 ecm. Dissolved hydrochloric acid and 30 ecm of acetic acid and heated to 85 ° C. for 14 hours. After working up in the above manner, 0.86 g of a residue comprising 2- (6,11-dihydrodibenzo- / be_7-thiepin-11-on-3-yl) propionic acid was obtained which combined with the 1.34 g obtained above became. The combined acid residue (2.2 g) was dissolved in 10 cc of isopropanol, and there was added 0.95 g (j ^ -amphetamine The solution was cooled to -1O ⁰ C., stand for 4 hours and filtered;. Was thus obtained 2.69 g of a residue was shaken with 100 ecm 2N hydrochloric acid and 100 ecm ethyl acetate. The separated organic layer was dried over magnesium sulfate and evaporated to give 7.90 g of a residue,

809835/1043

260R312

which was dissolved in 9 ecm of isopropanol, whereupon 0.86 g / lA-amphetamine was added. The solution was cooled to -10 ° C. and left to stand for 2 hours. After filtration, 2.53 g of a residue were obtained, which was shaken with 100 ecm 2N hydrochloric acid and 100 ecm ethyl acetate. The organic layer was separated, and evaporated over magnesium sulfate and getrooYiet afforded 1.80 g of a residue which was dissolved in 8 cc of isopropanol, after which 0.86 g (IV-Amp net admitted on in. The solution was -1O ⁰ C. cooled, left to stand for 2 hours, filtered and yielded 2.46 g of a residue which was shaken with 100 ecm 2N hydrochloric acid and 100 ecm ethyl acetate The organic layer was separated, dried over magnesium sulfate and evaporated to yield 1.75 g Its residue, which was dissolved in 7 ecm of isopropanol, whereupon 0.83 g of (^ l} -amphetamine were added. The solution was cooled to -10 ° C., left to stand for 16 hours, filtered and yielded 2.40 g of a residue, which was shaken with 100 ecm hydrochloric acid and 100 ecm ethyl acetate. The separated organic layer was washed, dried over magnesium sulfate and evaporated to give 1.647 g of (d) -2- (6,11-dihydrodibenzo- / be ./-thiepin-11- on-3-yl) propionic acid / Ji 2) - (d) Sä ureisomeresy as gum with £ ~ <\ J ^ + 37.2 ° (5 mg / ccm, chloroform) NMR E ^ ¹ J 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 (l) -2- (6,11-dihydrodibenzo- / be_7-thiepin-11-on-3-yl) -propionyi- (l) -1-phenylethylamide were in 21 ecm acetic acid and 111 ecm acetic anhydride and the solution to ^{0 0} C.

609835 / 10A3

? 6ÜR312

cooled down. 9.25 g of sodium nitrite were added in 4 portions over the course of one hour. The mixture was stirred at QC for 5 hours and then at room temperature for 17 hours. 250 ecm of water and 100 ecm of ethyl acetate were added and the mixture was stirred vigorously for 1.5 hours. Then it was diluted with 500 ecm of water and extracted with 400 ecm of ethyl acetate. The organic extract was washed, dried over magnesium sulfate and evaporated, and the residue obtained was refluxed in 50 ecm benzene for 1 hour. The benzene solution was cooled, washed with 100 ecm of 0.5 molar aqueous potassium carbonate, dried over magnesium sulfate and evaporated. The residue obtained in this way was chromatographed on 100 g of silica gel while eluting with benzene and yielded 0.75 g (l) -2- (6.1 ". -Dihydrodibenzo-zi). e./-thiepin-11-on-3-yl) -propionic acid 1-phenyl ethanol ester as an oil.

g _{3 1> 29} _ _{1> 52}

7.6 (11H, m), 8.16 ppm (1H, m). 0.74 g of the 1-phenylethanol ester were then stirred with 10 ecm benzene and 10 ecm trifluoroacetic acid for 2 hours. After adding 200 ecm of water, the mixture was extracted with 200 ecm of ethyl acetate. The organic extract was washed, dried over magnesium sulfate and evaporated to give 0.51 g (l) -2- (6,11-dihydrodibenzo- / be _i 7-thiepin-11-on-3-yl) propionic acid / XiZ) - (l) -Aic isomer7 as gum with jTcKjn -37.8 ° (5 mg / ccm., chloroform) and the in part (b) of this example for the corresponding (d) -compound / Ji 2) - (d) - Acid isomers7 mentioned NMR and MS data.

609835/1043

37-26-31?

Example 1J5

250 mg of 6,11-dihydrodibenzo- / be_7-thiepin-11-αη-3-acetic acid (8) were dissolved in 30 ecm of isoamyl alcohol and the solution was saturated with hydrogen chloride. After 90 minutes, the excess alcohol was distilled off in vacuo and the residue was purified by preparative thin-layer chromatography (iesεlsäuregel; 1: 9 ethyl acetate: hexane); there was prepared 171 mg of Isoamyl-6,11-dihydrodibenzo / b.ej ^ thiepin-i1-on-3-acetate, which had a F. of 91-92 ⁰ C. after recrystallization from methylene chloride / hexane.

Instead of isoamyl alcohol, another alcohol such as methyl, ethyl, propyl, isopropyl, hexyl, monyl, dodecyl alcohol was used used, then one received others in a similar orphan Esters, such as the methyl, ethyl, propyl, isopropyl, hexyl, nonyl, dodecyl esters, etc. of the 6, 11-dihydrodibenzo- ^ b. e ^ _7 ~ thiepin-11-one-3-acetic acid (8th).

Example 1_4

150 mg (dl) -2- (6, 11 -dihydrodibenzo-Zb. E ._ / - thiepin-1 1 -on-3-yl) propionic acid (12) were dissolved in 5 ecm of methanol and the solution was saturated with hydrogen chloride. After 24 hours the excess became Alcohol is distilled off under vacuum, and the residue is chromatographed on silica gel (eluent: 1: 8 ethyl acetate: hexane) purified. So you got 120mg methyl- (dl) 2- (6,11-dihydrodibenzo- / b.e.J-thiepin-11-on-3-yl) propionate as Oil.

UV λ j ^ ° * ^at 250, 350 nm (ε 21 200, 2950)

IR ν ^CHlj1 3 1740, 1645, 1600 cm " ¹
nax

609835/1043

NHR / jfi3 3 1 | 48 (3Η, d), 3.60 (3Η, s), 4.0 (2H ₁ s), 7.0-7.6 (6H, m), 8.10 ppm (1H , dd).

Instead of the (dl) mixture, the (12) - (d) acid isomer, namely (d) -2- (6,11-dihydrodibenzo- / b.e.7-thiepin-11-on-3-yl) propionic acid or the corresponding (12) - (1) acid isomer is used, then the methyl ester of (d *) -2- (6,11-dihydrodibenzo-£ b.e._7-thiepin-11 was obtained -on-3-yl) propionic acid or the corresponding methyl ester of the (12) - (l) acid isomer.

Example Ij?

300 mg (dl) -2- (6,11-dihydrodib & nzo- / b.e ./-thiepin-11-on-3-yl) -propionic acid (12) were dissolved in 5 ccrr, isoamyl alcohol and the Solution saturated with hydrogen chloride. iMay_h 24 hours became the excess alcohol is distilled off in vacuo and the residue is purified by chromatography on alumina; so received 350 mg of isoamyl (dl) -2- (6, 11 -dihyrirodibenzo- ^ b. e.y'-thiepin-11-on-3-yl) propionate than oil.

UU ^^ a ^ ^GH 245, 250 nm (£ 19 700, 2240)

~ ¹

IR ^ max ^{13 1750} » ¹⁶⁵⁰ ' ^{16DQ crn}

NMR </ ^ 3 3 0.80 (6H, d), 1.45 (6H, d + m), 3.70 (2H, mn), 4.0 (2H, s), 7.0-7.6 (6H, m), 8.1 ppm (1H, dd).

If other alcohols were used instead of isoamyl alcohol, e.g. ethyl, propyl, isopropyl, hexyl, Fionyl, docecyl alcohol etc., then the other esters were obtained, e.g. ethyl, propyl, isopropyl, hexyl , fionyl, dodecyl esters etc. of (dl) -2- (6,11 -Dihy dro dib enzo- ^ be J- thiep in -H-on-3-yl) -prop ionic acid (12).

609835/1043

By using the (12) - (d) acid isomer, namely (d) -2- (6,11-dihydrodibenzo- / 5'.e _; _7'-thiepin-11-on-3-yl) propionic acid, or of the corresponding (12) - (l) acid isomer instead of the (dl) mixture with the corresponding alcohol, the isoamyl, ethyl, propyl, isopropyl, hexyl, nonyl, doecyl ester, etc. were obtained ) -2- (6,11-dihydrodibenzo- / b.e_ _; 7-thiepin-11 - er, - 3-yl) propionic acid or the corresponding esters of the (12) - (l) acid isomers.

Example 1_6

300 mg 6, 1i-dihydrodibenzo - ^ / b. e ^ 7-thiepin-11-one-3-acetic acid (8) in 5 ecm methanol were titrated to a pale orange color with 1N methanolic potassium hydroxide. The color was made to disappear by adding 3 mg of solid 6,11-dihydrodibenzo- ^ be / 7-thiepin-11-one-3-acetic acid. The solvent was evaporated off in vacuo and the residue was taken up in 2 ecm of methanol and then precipitated with ether. Thus there was obtained 335 mg of crude potassium-6,11-dihydrodibenzo / be / 7-thiepin-11-one-3-acetate, which after recrystallization from isopropanol, a F. of 206-208 ⁰ C. (with decomposition ") would have.

Z. D

By using uon / ammonium and sodium hydroxide instead of Other salts, such as the ammonium and potassium hydroxide

Sodium salt, the 6,11 -dihydrodibenzo- / b ~. e ^ -thiepin-i 1-on-3-acetic acid (8).
Example T7

150 mg (dl) -2- (6, 11 -dihydrodibenzo- / b ~. E ^ -thiepin-i 1 -on-3-yl) -propionic acid (12) in 1 ecm of methanol were mixed with 1N methanolic Potassium hydroxide titrated to a pale orange color. A small amount of solid (dl) -2- (6,11 -Qihydrodibenzo-

609835/1043

/ Jb. e ^ J-thiepin-i 1-on-3-yl) -propionic acid- added to decolorize the solution. The solvent was stripped off and 5 ecm of toluene was added. The toluene solution thus obtained was evaporated to dryness, and yielded a solid which after drying at 1OG ⁰ C. under vacuum 150 mg of potassium (dl) -2- (6,11-dihydrodibenzo / jD.e _i / thiepin-1 ¹ - n °-3-yl) propionate with a softening point of 12O ⁰ C. and F. of 145-155 ° C. delivered. This solid melted after exposure to moist air and resolidified to give 175 mg of the dihydrate of potassium- (dl) -2- (6,11-dihydrcdibenzo / be _i 7-thiepin-11-cn-3 -yl) -propionate with an F. of 68-90 C.

Instead of potassium hydroxide, it was replaced by another hydroxide, such as Ammonium or sodium hydroxide, used, then one obtained the ammonium or sodium salt of (dl) -2- (6,11-dihydrodibenzo- ^ / b.e ^ -thiepin-i 1-on-3-yl) -propionic acid (12).

By using the (12) - (d) acid isomer, namely (d) -2- (6,11-dihydrodibenzo - / _ b. E ^ -thiepin-i 1-on-3-yl) propionic acid, or the corresponding (12) - (l) -Acid isomers instead of the (dl) mixture with the corresponding hydroxide, the potassium, ammonium and sodium salt of (d) -2- (6,11-dihydrodibenzo-Zb. & J- thiepin- 11-on-5-yl) propionic acid or the corresponding salts of the (12) - (l) acid isomer.

Example 1 1_8,

300 mg 6,11 -dihydrodibenzo- ^ b ". EjJT-thiepin-11-one-3-acetic acid (8) were dissolved in excess 1 IM aqueous sodium hydroxide and the solution obtained was buffered with 0.3 g of ammonium chloride. the

609835/1043

₄₁ _ 2BQR31 2

buffered solution became a solution of 200 ng calciui ticarbohat added in 1N aqueous hydrochloric acid. The formed bodice It was filtered off, washed successively with water, dimethoxyethane and ether and yielded 180 mg calcium-6,11-dihydrodibenzo- / b.e.7-thiepin-5.11-one-3-acetate with an average temperature of 220-225 ° C. (and dec.); Softening> 205 ° C.

By using magnesium carbonate instead of calcium carbonate Magnesium-6,11-dihydrodibenzo- / b "was obtained in a similar manner. ej7-thiepin-11-on-3-acetate.

Example 1 £

175 mg (dl) -2- (6,11-dihydrodibenzo- / b ~ .e _: j- ^tn i. ^E pi- ⁿ - ' ¹ 1 -αη-3-yl) -propionic acid (12) in 5 ecm methanol 'Jurde is titrated with 1M methanolic potassium hydroxide to a pale orange color. whereupon the color was removed by adding 3 mg of solid (dl) -2- (6,11-dihydro dibenzo- ^ ET. e_ / 7-thiepin-11-on-3-yl) propionic acid. The resulting solution contained potassium (dl) -2- (6,11-aihydrodibenzo- ^ be ^ -thiepin-i 1-on-3-yl) propionate. A solution of 40 mg calcium carbonate in the minimum amount of 1N hydrochloric acid required for the solution was buffered with 100 mg solid ammonium chloride, then 5 ecm water was added. The buffered calcium solution thus obtained was then added to the solution of potassium (dl) -2- (6,11-dihydrodibenzo- / b * .e _i 7-thiepin-11-on-3-yl) propionate, whereby a bodice formed which was collected, washed with water and dried at room temperature. 160 mg of calcium (dl) -2- (6, 11 -dihydrod ibenzo- ^ b ". Ejthiepin-11-on-3-yl) propionate with a softening point of 150 ° C. and a melting point of 16Q-165 ° C.

609835/1043

By using magnesium carbonate instead of calcium carbonate the magnesium (dl) -2- (6,11-dihydrodibenza- / b) was obtained in a similar manner. e.y-thiepin-11-on-3-yl) propionate.

Instead of the (dl) mixture, the (i2) - (d) -spir isomer, namely (d) -2- (6,1 l-dihydradibenzo- ^ be ^ jZ-thiepii.-i 1 -on-3-yl ) propionic acid or the corresponding (12) - (l) acid isomer used with the corresponding carbonate, then the calcium and magnesium salt of (d) -2- (6,11 -dihydrodibenzo- / b * .e_ _; 7-thiepin-11-on-3-yl) propionic acid or the corresponding salts of the (12) - (1) acid isomers.

Example 20

200 mg 6.11 -DihydΓodibeπzo- _Jί / be _; 7-thiepin-11-one-J-esipsic acid (8) in 1 ecm of methanol was titrated with 1fJ of methanolic potassium hydroxide to a pale orange color. Iuurde for decolorizing the solution, a small f-ienge solid 6,11-dihydrodibenzo / H ". B ^ j thiepin-11-one-3-acetic acid was added. The solvent iuurde stripped and the residue dissolved in 5 cc of water. The so- The resulting aqueous solution of potassium 6,11-d_ihydrodibenzo- ^ be _i 7-thiepin-11-one-3-acetate was added to a solution of 150 mg of cupric nitrate trihydrate in 5 cm of water. The precipitate formed was collected, washed with water and Air-dried and yielded 20 mg of copper-6,11-dihydrodibenzo- ^ b ".e ^ J-thiepin-11-one-3-acetate with a sintering point of 139-140 ° C. and one F. from 155-16O ⁰ C.

609835/1043

Example 2I ₁

200 mg (dl) -2- (6,11-dihydrodibenzo-Zb *. EJ-thiepin-1 1 -οπ-3-yl) propionic acid (12) in 1 ecm methanol and 1N methanolic
Potassium hydroxide titrated to a pale orange color. To decolorize the solution, a small amount of solid (dl) -2- (6, 1 i-dihydrodibenzo - ^ / be_7-thiepin-1 1 -on-3-yl) propionic acid was added. The solvent was stripped off and the residue was dissolved in 5 ecm of water. The aqueous solution of potassium hydroxide (di) -2- (6,1 i-dihydrodibenzo- ^ F.ejy-thiepin-H-on-3-yl) propionate thus obtained became a solution of 150 mg of cupric nitrate trihydrate in 5 ecm
Water added. The precipitate formed was collected, washed with water and air-dried, and yielded 200 mg of copper (dl) -2- (6,11-dihydrodibenzo - / _ b.ey-thiepin-11-on-3-yl) propionate with a sintering point from 140 C. and a F. from 160-165 C.

Instead of the (dl) mixture, the (12) - (d) -5 acid isomer, namely (d) -2, (6,11-dihydrodibenzo- / be / 7-thiepin-11-on-3-yl) -propionic acid , or the corresponding (12) - (l) acid isomer is used, then the copper salt of (d) -2- (6,11-dihydrodibenzo- / be ^ T-thiepin-i1-on-3-yl) - propionic acid or the equivalent
Copper salt of the (12) - (1) acid isomer.

Example 22_

200 mg 6, Ί 1 -dihydrodibenzo-Zb.e ^ -thiepin-i 1 -απ-3-acetic acid (8) in 15 ecm hot benzene was treated with 60 mg isopropylamine. The solution was allowed to cool to room temperature and the product filtered off, washed with ether and dried. So

609835/1043

217 mg of isopropylammonium-6,11-dihydrodibenzo-Zb were obtained. thiepin-11-on-3-acetate with an F. of 147-148 C.

By using the appropriate amines instead of isopropylamine other salts, e.g. amine salts, such as those of diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine, of 6,11-dihydrodibenzo- / b.e._7-thiepin-11-on-3-ylacetic acid (8) manufactured.

Example 23_

193 mg (dl) -2- (6, 11 -dihydro dibenzo - / ^) ". E ^ J-thiepin-i 1 -on-3-yl) propionic acid (12) in 10 ecm benzene were treated with 6U mg piperidine The solution obtained was left to stand for 1 hour and the crystalline material formed was filtered off, washed with ether and air-dried; in this way 183 mg of PipBridiniun- (dl) -2- (6,11 -dihydro dibenzo- / ", e ^ were obtained -thiepin-i 1-on-3-yl) propionate. The sample had after recrystallization from benzene a F. of 140-141 ⁰ C.

By using appropriate amines instead of piperidine other salts such as amine salts such as isopropylamine were obtained amine, diethylamine, ethanolamine, tromethamine, choline and caffeine, des (dl) -2- (6,11-dihydrodibenzo - / _ 'b. e ^ -thiepin-i 1-on-3-yl) propionates.

Instead of the (dl) mixture, the (12) - (d) acid isomer, namely (d) -2- (6,11-dihydro dibenzo-Js ". e ^ -th iepin-11-on-3-yl) propionic acid, or the corresponding (12) - (l) acid isomer is used with the corresponding amine, then the amine salts were obtained, e.g. from piperidine, isopropylamine, diethylamine, ethanolamine,

609835/1043

₄₅ ■ _ 2 6 η β 31 2

Tromethamine, choline and caffeine, the (d) -2- (6,11-dihydrodibenzo- / beJ-thiepin-11-on-3-yl) propionic acid or the corresponding (i2) - (l) -acid isomer amine salts.
Example 24

I g Kaliurπ-6,11-dihydΓodibenzo - /. Be _i 7-thiepin-11-one-3-acetate was in 50 ccn. Dissolved water and acidified the solution with 20 ecm 3 N aqueous hydrochloric acid. The reaction mixture was extracted twice with 25 ecm ethyl acetate each time and the extracts were combined, washed with 50 ecm water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from benzene. This gave 6,11-dihydrodibenzo- ^ bey-thiepin-11-one-3-acetic acid (8).

In a similar way other salts, e.g. sodium, ammonium, Calcium or amines etc., the 6,11 -dihydrodibenzo - ^ / b. e.7-thiepin-11-on-3-acetic acid in 6,11-dihydrodibenzo -, / F.e.7-thiepin-11-one-3-acetic acid converted.

By using e.g. the potassium, sodium, ammonium, calcium, Amine salts etc. of (dl) -2- (6,11 -dihydrodibenzo- / b ~. E ^ -thiepin-

I1 -on-3-yl) propionic acid, the (d) -2- (6 _t 11-dihydrodibenzo- ^ b ". E ^ / - thiepin-11-on-3-yl) propionic acid and the corresponding ( l) Acid isomer salts were obtained (dl) -2- (6, 11 -dihydrodibenzo- /!). e Γ / - thiepin-11-on-3-yl) -propionic acid, (d) -2- (6.1I -Dihydrodibenzo- / be ^ -thiepin-i1-on-3-yl) propionic acid or the corresponding (l) acid isomer.

809835/1043

Example 2_5

1 g of diethyl-6,11-dihydrodibenzo- / b ~ .e _l 7- ^t hiepin-11-one-3-acetate (7) was dissolved in 500 ecm of toluene, the 5 g of n-octanol and 0.5 g of p- Toluenesulfonic acid contained dissolved. The reaction mixture was heated in a nitrogen atmosphere, and a total of 350 ecm of toluene was slowly distilled off over the course of 5 hours. The reaction mixture was cooled and concentrated by evaporation under reduced pressure to about 10 cm. The residue was then chromatographed on 200 g of silica gel while eluting with 1: 8 hexane: ethyl acetate and yielded octyl-6,11-dihydrodibenzo- /ß.e^J-bhiepin-i 1-on-3-acetate.

In a similar way, other πϊβ ^ Γίςε Zster, e.g. the propyl ester, the 6,11 -D ihydrodibenzo - ^ / be7- th ie pin-11 -one-3-acetic acid to higher esters, e.g. the decyl ester, the 6, 11-dihydrodibenzo- £ be // thiepin-11-one-3-acetic acid are transesterified.

Similarly, lower esters, e.g. the methyl ester, the (dl) -2- (6,11-dihydrodibenzo- / b ~ .e / 7-thiepin-i 1-on-3-yl) -p ropionic acid, (d) -2- (6,11-dihydro dibenzo- / b. e_./-thiepin-11 on-3-yl) -prapionic acid or the corresponding lower esters of the corresponding (l) -acid isomer into higher esters, e.g. the octanyl ester, the (dl) -2- (6,11-dihydrodibenzo-/ b. ej_7 ~ thiepin-11-on-3-yl) propionic acid, of (d) -2- (6,1 i-dihydrodibenzo - ^ / b.e ^ y-thiepin-11-on-3-yl) propionic acid or the (l) -acid isomer.

Example 26

500 mg dodecyl-6,11 -riihydrodibenzo- / b ". 8 ^ 7-thiepin-i 1 -αη-3-acetate were with 250 ccn abs. Ethanol containing 10 mg sodium cyanide, Reflux for 16 hours in a nitrogen atmosphere

S09835 / 1043

26ÜB312

- 47 -

heated. The reaction mixture was cooled and under reduced The pressure was evaporated to give a residue which was deposited on 100 g of silica gel while eluting with 1: 8 hexane: ethyl acetate was chromatographed. This gave ethyl 6,11-dihydrodibenzo - ^ / i. e ^ -thiepin-i 1-on-3-acstat.

In a similar way, other higher esters, e.g. the nonyl ester, the 6,11-dihydrodibenzo- / j3.e _l 7-thiepin-11-one-3-acetic acid can be converted ^into lower esters, e.g. the hexyl ester, the 6,11-dihydrodibenzo- / b, e _i y ^r -thiepin-11-one-3-acetic acid can be transesterified.

The higher esters, e.g. the dodecyl ester, the (dl) -2- (6, Ί1-dihydro dibenzo - / _ b .e ./-thiepin-11-on-3-yl) propionic acid were used in similarly into lower esters, e.g. the ethyl ester, of (dl) -2- (6,11 -dihydrodibenzo-Zb ". e ^ Z-thiepin-H -οη-3-yl) propionic acid umgeujadnelt.

Example 27

0.05 g of (l) -2- (6 _T 11-dihydrodibenzo- / be _l 7-thiepin-11-on-3-yl) propionic acid ^ Ji2) - (l) -5 acid isomer7 were dissolved in 6 ecm of water under nitrogen containing 0.07 g of sodium hydroxide, heated to reflux for 7 hours. The reaction solution was cooled, acidified with 5 ecm 2N hydrochloric acid and extracted with 15 ecm ethyl acetate. The extract was washed with 15 cc of water, dried and evaporated with magnesium sulfate and afforded 0.041 g _v id].) - 2- (6,11 -Dihydrodibenzo- / b "e ^ 7-thiepin-11 -one 3-yl) Propionic acid (12) as a gum with a LdiJ ^ -0.80 + 1.0 ° (5mg / ccm, chloroform) NMR S CD _{3 1) 47 (3H)}

8.13 ppm (1H, d)

MS: 298 (F ₁ ⁺ ) 26 5, 253.

609835/1043

Example 28

The following ingredients have been mixed thoroughly and made into individual, notched tablets' pressed:

Amount in mg per tablet,

6,11-dihydrodibenzo-£ b. e, j -thiepin-

11-on-3-acetic acid 150

Cornstarch 40

Sucrose 200

Example 29

The following ingredients were intimately mixed and made into individual, notched tablets pressed:

Amount per tablet; mg

(el) -2- (6,11 -Dihydrodiben za- / jö _a e J-

thiep in-ΙΙ-οπ-3-yl) propionic acid 25

Corn starch 100

Lactose 393

Magnesium stearate 2

Instead of 25 mg of the (dl) compound in the above preparation, 12.5 mg of (d) -2- (6,11 -dihydrodibenzo- ^ b ". E« 7-thiepin-1 ¹ -οπ-3- yl) propionic acid is used.

Example 30

The following ingredients should be mixed and packed into a hard shell Gelatin capsule introduced:

Amount per capsule; mg

Potassium-6,11-dihydrodibenzo / be J- thiepin-11-one-3-acetate 150

Lactose "190

example y \ _

The following ingredients were mixed and placed in a hard shell Gelatin capsule introduced:

609835/1043

Amount per capsule; mg

Ca lc ium-6, 11 -dihydro dibenzo ^ / b. e .J- ^ ^ q

thiepin-ii-on-3-acetate

Lactose 182

Magnesium stearate 8

Example 32

The following ingredients were intimately mixed and made into individual, notched tablets pressed:

Amount per tablet; mg

Isopropylammonium-6,11-dihydro-

dibenzo-ZE.e ^ -thiepin-i 1 -on-3- 150

acetate

Cornstarch! 00

Lactose 370

Magnesium stearate 2

Example 3_3

The following ingredients were mixed and placed in a hard

shell Wr. 1 gelatin capsule inserted:

Amount per capsule; mg

Methyl-6,1 i-dihydrodibenzo-Z ^ b ". Ej-

thiepin-11-on-3-acetate 25

Lactose 225

Example 34

The above ingredients are thoroughly mixed and separated into notched tablets processed, one tablet at a time 3-4 hours was administered:

Amount per tablet; mg

6.11 - Dihydro dibenzo- ^ b.e ^ -th iep in-

11-on-3-acetic acid 150

Sucrose 245

Example 3_5

The following ingredients were intimately mixed and made into individual, notched tablets pressed:

809835/1043

Amount per tablet; mg

Isoainy_l-6,11-dihydrodibenzo- / J3.e.y-thiepin-11-one-3-acetate 200

Corn starch 100

Lactose 368

Magnesium stearate 2

Example 36

The following ingredients were mixed and placed in a hard

shell gelatin capsule introduced:

Amount per capsule; mg

(dl) -2- (6,11-dihydrodibenzo-

/ b. e _! _7-thiepin-11-on-3-yl) -

propionic acid 25

Lactose 225

Dextrose 10

instead of 25 mg of the (dl) -V <=! r bond in the above preparation / 12.5 mg (d) -2- (6,11 -dihydrodibenzo-Zb. Ej ^ -thi epin-11 -on-3-yl) -

propionic acid used.

Example 37

The following ingredients were mixed and placed in a hard

shell gelatin capsule introduced:

Amount per capsule; mg

Methyl-6,11-dihydro dibenzo / F. ej-

thiepin-11-on-3-acetate 1 150

Lactose ~ 99

Example 38

The following ingredients were mixed and used individually

Compressed tablets:

Amount per tablet; mg

Isoarny ^ l-6, 11-cihydrodibenzo-

/b.e.y-thiepin-11 -one-3-acetate 200

Lactose 1J5

nagnesiuin stearate 5

80983S / 1043

_ si - 260R312

Example 39

The following ingredients were mixed thoroughly and added

individual, notched tablets compressed:

Amount per tablet; mg

Calcium-6,11 -dihydrodibenzo- ^ b. ε _7_

thiepin-11-on-3-acetate ~ 150

Corn starch (paste) 50

Magnesium stearate 0.8

Lactose to 500

Example 4 £

The following ingredients were mixed intimately and pressed into individual, notched tablets:

Amount per tablet; mg

Potassium-6,11-dihydrodibenzo- / b.e ._ / thiepin-H-one-3-acetate '125

Corn starch »" 38

Magnesium stearate 0.76

Polyvinyl pyrrolidone 17

Lactose to 380

Example 41_

The following ingredients were mixed and placed in a hard

shell gelatin capsule introduced:

Amount per capsule; mg

Isopropν! Ammonium-6,11-dihydrodi-

benzo- / be ₁ y-thiepin-11-one-3-acetate 250

Corn starch "38

Lactose to 380

Example 42

The following ingredients were mixed and placed into hard-shelled

Gelatin capsules introduced:.,,.

Kenqe per capsule; mg

Isoamyl-6,11-dihydrodibenzo- / b'.e _i 7-

thispin-11-on-3-acetate 300

Lactose 72

Magnesium stearate 8

609835/10 ^ 3

. 52-26QR312

Example 43

It became an injectable, buffered to pH 8.5 Preparation of the following composition made:

(dl) -2- (6,11-dihydrodibenzo- / b \ e _i 7-

thiepin-11-on-3-yl) propionic acid 0.2 g

Buffer (0.4 M solution) 2 ecm

KOH (1N) 8.6 cm

Water (sterile) to 20 ecm

Instead of 0.2 g of the (dl) compound of the above preparation were also 0.1 g (d) -2- (6,11-dihydrodibenzo- ^ b.e ^ Z-thiepin-i 1-on-3-yl) propionic acid used.

Example 44

A suppository totaling 2.8 g was made with the following Composition made:

(dl) -2- (6,11-dihydrodibenzo- ^ E.e ./-

thiepin-11-on-3-yl) propionic acid 25 mg

"Witepsol H-15" (triglycerides saturated Fatty acids; Commercial product from Riches-Nelson Inc., New / York) Rest

Instead of 25 mg of the (dl) binding of the above preparation

even _

were / 12.5 mg (d) -2- (6,11-dihydrodibenzo-Zb. e «7-thiepin-1 1-on-3-yl) propionic acid used.

Example 45_

It was made using an oral suspension for pediatric medicine made of the following composition:

(dl) -2- (6,11-dihydrodibenzo- / b.e._7-thiepin-11-on-3-yl) propionic acid 0.25 g

Fumaric acid 0.5 g

Sodium chloride 2.0 g

Rethyl paraben 0.1 g

granulated sugar 25.5 g

Sorbitol (70-; jige solution) 12.85 g "Veegun K" (Uanderbilt Co.) 1.0 g

• B03835 / 10-43

Aroma center 0.035 ecm

Dye °> ^{5 m} 9

least. Water to 100 ecm

Instead of 0.25 g of the (dl) compound in the above preparation, / 0.125 g (d) -2- (6,11-dihydrodibenzo- / be _L 7- ^tn i ^B P ⁱⁿ - ^{/ I1} - ^on - ^{: 5} -yl) propionic acid is used.

Example 46 and 47

There were powdered preparations for topical application manufactured in veterinary medicine with the following composition:

Example 46 example

(dl) -2- (6,11-dihydrodibenzo- / b ~. ^

thiepin-11-on-3-yl) propionic acid 0.2 g 0.4 g

Sucrose 5.7g 3.7g

Polyvinylpyrrolidone 0.3 g 0.3 g

Instead of 0.2 g of the (dl) compound of the preparation of Example even

46 can / 0.1 g (d) -2- (6,11-dihydrodibenzo-Zb. E ^ -thiepin-i 1-on-

3-yl) propionic acid can be used.

Instead of 0.4 g of the (dl) compound of the preparation of Example even __

47 were / 0.2 g of (d) -2- (6,1I-dihydrodibenzo-Zb.eo / -thiepin-11-on-3-yl) propionic acid used.

Example 48

A suppository totaling 2.8 g was made with the following Composition made:

6.11 -Dihydrodibenzo-Zb ". E.J-thiepin-

11-on-3-acetic acid ~ 275 mg

»Witepsol H-15" rest

Example 49

Various tests for the simultaneous evaluation of

809835/10 ^ 3

(a) phenylbutazone

(b) 6,11-dihydrodibenzü- / b ~. e J- thiepin-11-one-2-acetic acid

(c) 6,11-dihydrodibenzo-£ b.et7-oxepin-11-one-3-acetic acid and

(d) 6,11-dihydrodibenza- / b ~ .ey ^r -thiepin-11-one-3-acetic acid

performed on anti-inflammatory effect; the carrageenin-induced inflammation test of a rat paw according to the method of fe / inter et al "Proceedings of the Society for Experimental Biology and Medicine" Vol. 111, pages 544-47 (1962) was used. Female rats weighing 80-9D g were used. The test materials were administered orally at 0 hour by gavage in 1 cc aqueous vehicle. At hour 1 0.05 ecm of a 1% solution (in 0.9% NaCl) carrageenin was injected into the right hind paw. This injection causes the paw to become inflamed. The rats were slaughtered at hour 4, then both hind paws were removed and weighed separately. Endpoint: % increase in paw, calculated as follows:

Weight d. right paw - weight d. left paw ^ _n -, threaded left paw

The from different, at the same time to evaluate the connections The data obtained from the tests carried out were analyzed according to standard statistical methods, with the analysis results were as follows:

609835/1043

- PP -

Tabel

Drale anti-inflammatory effectiveness of the compounds (b), (c) and (d) compared to phenylbutazone

(Compound a)

Compound anti-inflammatory VJirksarr.k.

(a) phenylbutazone

(b) 6,11-dihydrodibenzo- / b _# e _i 7- g thiepin-11-one-2-acetic acid '

(c) 6,11-dihydrodibenzo / be _t 7-

oxepin-11-one-3-acetic acid

(d) 6,11-Dihydrodibenzo / be ₄ 7-

thiepin-11-one-3-acetic acid

Tabel

Oral anti-inflammatory effectiveness against binding (d) compared to compound (b)

(b) ejii-DiHyZ j

thiepin-11- ^r ~ n-2-eFSetic acid "

(d) 6,11-dihydrodibenzo- _i 7-thiepin-11-one-J-acetic acid

Tabel

Oral anti-inflammatory activity of compound (d) compared to compound (c)

(c) 6,11-dihydrodibenzo-Zb.ejv ⁷

oxepin-11-one-3-acetic acid

(d) 6,11-dihydrodibenzo- _/ /b".e _t 7-

thiepin-11-one-3-acetic acid 3,4

Example 50

Example 49 was used to evaluate

(a) phenylbutazone

(b) (dl) -2- (6,11-dihydrodibenzo- / F.e.j7-thiepin-11-on-2-yl) -propic acid and

(c) (dl) -2- (6,11-dihydrodibenzo-^ B.e ^ -thiepin-11-one-3-yI) -propionic acid

repeated, the results were as follows:

609835/1043

- 56 Table 1

Oral anti-inflammatory activity of the compounds (b) and (c) compared to phenylbutazone (l / erb, aj

Compound anti-inflammatory agents.

(a) Phenylbutazone 1

(b) (dl) -2- (6,11-dihydrodibenzo- / b.e.j7-

thiepin-11-on-2-yl) propionic acid 1, 3

(c) (dl) -2- (6,11-dihydrodibenzo- £ b '. eJ-

t hiep in-11-on-3-yl) propionic acid 130

Table 2

Oral anti-inflammatory activity of compound (c) in direct comparison to (b)

(b) (di) -2- (6,11-dihydradibenzo- / b.e._7-thiepin-11-on-2-yl) propionic acid 1

(c) (dl) -2- (6,11-dihydrodibenzo-/ b.c ^ '-thiepin-11-on-3-yl) -propionic acid 64

609835/1043

Claims (1)

- 57
Patent claims e 260R312 Connections of the formulas: (dl) H ₂ CO ₂ R HCO ₂ R or the single (d) acid isomer or (I) acid isomer of the formula (B), in which R is hydrogen, or a C, alkyl group, or a pharmaceutically acceptable salt thereof, when R is hydrogen, or the Esters and pharmaceutically acceptable salts of each of the Isci.eren ^H er formula (B). 2, - compounds of the formulas: (dl) O HCO ^ R or the (d) acid isomer of the formula (B), where R is hydrogen or a C alkyl group, or a pharmaceutically acceptable one Salt of the same, if R stands for hydrogen, or the Esters and pharmaceutically acceptable salts of the (d) acid isomer of formula (B). 3.- Compounds of the formula: 609835 / 10-43 (dl) O CHCO ₂ R CH ₃ (B) or (d) -Stlureisomere thereof, wherein R ₁ is hydrogen or an allyl group ₁₇ C, or a pharmaceutically acceptable salt thereof, when R is Viasserstoff or dia esters and pharmaceutically acceptable salts of the (d) -Säureisomcren. 4.- compounds of the formula: CHCO ₂ R CH ₃ in which R stands for hydrogen or a C _{1 ΛΟ} alkyl group, or their pharmaceutically acceptable salts when R stands for hydrogen. 5.- compounds of the formula: CHCO ₂ R in which R stands for hydrogen or a C alkyl group, or their pharmaceutically acceptable salts, where R is hydrogen stands. 609835/1043 6, - compounds of the formula: CH ₂ CO ₂ R (A) in which R stands for hydrogen or a C.. "alkyl group, or a pharmaceutically acceptable salt thereof when R is hydrogen. 7.- The l / erbigung of formula (A), claim 1, in which R is for Is hydrogen, namely 6,11-Oihydrodibenzo- ^ b.e ./-thiepin-11-on-3-ess igic acid. 8.- The Veroverbinding won formula (Α), claim 1, in which R is for Methyl, namely methyl-6,11-dihydrodibenzo- ^ b.e. ^ - thiepin-11-one-3-acetate. 9.- The compound of formula (A), claim 1, in which R is Isoamyl, namely isoamyl-6,11-dihydrodibenzo-Zb.e.7-thiepin- ■ H-on-3-acetate. 10.- The sodium salt of the compound of formula (A), claim 1, namely Na trium- 6,11 -dihydrodibenzo - / _ b. e ._ / - thiepin-11-on-3-acetate. 11.- The salt of the compound of formula (A), claim 1, namely Kai ium-6,11 -dihydrodibenzo- / b ~. e ^ y-thiepin-11-one-3-acetate. 12.- The calcium salt of the compound of formula (A), claim 1, namely Ca lc ium-6,11 -dihydrodibenZO - / ^. eJ- thiepin-11-one-3-acetate. 609835/1043 26063Ί2 13, - The copper salt of the compound of 'formula (A), claim 1, namely copper-6,11-dihydrodibenzo / B.ei / -thiepin-11-one-3-acetate. 14, - The isopropylammonium salt of the compound of formula (A), Claim 1, namely isopropylammonium-6, 11 -dihydro dibenzo- / b. e./"-thiepin-ii-on-3-acetate. 15.- The compound of formula (B), claim 1, in which R is hydrogen, namely (dl) -2- (6,11-dihydrodibenzo- ^ b. & .J- thiepin-11-one-3- yl) propionic acid. 16.- The compound of formula (B), AnsDruch 1, Jn luelchsr R stands for methyl, namely flethyJ - (dl) -2- (6,11 -dihycrodibenzo-ZF. E J- thiepin-11-one-3- yl) propionate. 17.- -ie compound of formula (B), claim 1, is wherein R is ^F or Isoanyl, namely Isoamy l- (dl) -2- (6, 11 -dihydrodibenzo - / _ b e thiepin-11-one.. -3-yl) propionate. 18, - The sodium salt of the compound of formula (3), claim A, namely sodium (dl) -2- (6,11 -dihydrodibenzo-Zb ". E_j _ / '- thiepin-11 on-3-yl) propionate . 19, - The potassium salt Ger compound of formula (3), claim 1, namely potassium (dl) -2- (6,11-dihydro dibenzo ~ / b \ e ^ y-thiepin-11-on-3-yl) propionate. 20, - gas calcium salt of the compound of formula (8), claim 1, namely calcium (dl) -2- (6,11 -dihyarodibenzo-Zb ". e ^ y-thiepin-11 on-3-yl) propionate. 21.- The copper salt of the compound of formula (B), claim 1, namely copper- (dl) -2- (6, 11 -dihydrodibenzo- / b ~. E ^ J-thiepin-i 1 on-3-yl) -propionate, 609835/1043 260 R 31 2 22.- The piperidinium salt of the compound of formula (B), claim 1, namely piperidinium- (dl) -2- (6,11 -dihydrodibenzo- ^ b ". & J- thiepin-11-on-3-yl) propionate . ■ 23, - The (d) -isomeric compound of the formula (B) of claim 1, in which R stands for hydrogen, namely (d) -2- (6,11-üihydrodibenzo- / tT. e._7-thiepin-11 -on-3-yl) propionic acid. 24.- The (d) -acid isomer compound of formula (B) of claim 1, in which each R is Kethyl, namely the mathyl ester of (d) -2- (6,11 -dihydrodibenzo - ^ _ b.e _i 7-thiepin -11-on-3-yl) -prop ionic acid. 25.- The (d) acid isomer compound of the formula (ü) of claim 1, in which R stands for isoamyl, namely the isoamyl ester of (d) -2- (6,11 -dihydrodibenzo- ^. Ζ _% j -thiepin- 11-on-3-yl) propionic acid. 26, - The sodium salt of the (d) acid isonic compound of the formula (Q) according to claim 1, namely the sodium salt of (d) -2- (6,11-dihydrodibenzo - / _ b. S _l 7-thiepin-11-one- 3-yl) propionic acid. 27.- The potassium salt of the (d) acid isomer compound of the formula (3) of claim 1, namely the potassium salt of (d) -2- (6,11-dihydrodibenzo- / b ". Β ± j -thiepin-11-one -3-yl) propionic acid. 28.- The calcium salt of the (d) -üÄureisorrieruerbverbindungen of formula ( u) of claim 1, namely the calcium salt dsr (d) -2- (6,11-dihydrodibenzo- / be _i 7-thiepin-11-one-3- yl) propionic acid. 29, - The copper salt of the (d) acid isomer compound of the formula (B) of claim 1, namely the copper salt of (d) -2- (6,11-üihydronzo- ^ b.e ^ '- thiepin-i 1-on-3-yl) propionic acid. 609835/1043 3G, - The piperidinium salt of the (d) acid isomer compound uon formula (B), claim 1, namely the piperidinium salt of (d) -2- (6,11-dihydrodibenzo- ^ b. & \ J -thiepin-11- on-3-yl) propionic acid. 31.- The (l) -isomeric compound of formula (B) of claim 1, in which R is hydrogen, namely (l) -2- (6,11-dihydrodibenzo - ^ / b. E ^ y-thiepin- 11-on-3-yl) propionic acid. 32.- Dicyclohexylammonium- (cl) -2- (6,11-cihydrodibBnzo- _i / b *. E // ~ thiepin-11-on-3-yl) propionate. 33.- Medicinal products for humans or mammals, containing a Compound according to claim 1 to 3? .. 34. Medicines to treat uc inflammation, pain or pruritus consisting of or containing essentially a pharmaceutically acceptable, non-toxic excipient and a therapeutically effective amount of a compound of the formulas: Q (dl) CHCO ₂ R or of the (d) - acid isomer of the formula (B), where R is hydrogen or a C alkyl group, or one pharmaceutical acceptable salt thereof, and if R stands for hydrogen, or the esters and pharmaceutically acceptable salts of the (d) acid isomer. 609835/1043 26Q63T2 35.- Medicines for use by pregnant women, mainly consisting of or containing a pharmaceutically acceptable, non-toxic excipient and a therapeutically effective one Amount of a compound of the formulas: Cdi) O CH ₂ CO ₃ R CHCO ₂ R CH. or of the (d) -acid isomer of the formula (B), where R is hydrogen or a C alkyl group, or a pharmaceutically acceptable salt thereof, if * ■] is hydrogen, or an ester and pharmaceutically acceptable salt of (d) - Acid isomers. 36.- Medicament according to claim 34, consisting essentially of or containing a pharmaceutically acceptable, non-toxic Excipient and a therapeutically effective amount of a compound of the formula: (A) in which R is hydrogen or a C ₁ -C alkyl group, or a pharmaceutically acceptable salt thereof when R is hydrogen. 609835/1043 37.- Medicament according to claim 35, "consisting essentially of of or containing a pharmaceutically acceptable, non-toxic excipient and a therapeutically effective amount a compound of the formula: (A) in which R stands for hydrogen or a C. "alkyl group, or a pharmaceutically acceptable ingredient thereof when R stands for hydrogen. 38.- V / experienced for the production of 6, 11 -Dihydrodibenzo-Zb. e .j thiepin-11-cn ~ compounds of the formulas: (dl) 'CHCO ₂ R CH ₃ or of the individual (d) acid isomer or (l) acid isomer of the formula (B) in which R is hydrogen or a C _{1 Λη} alkyl group, or a pharmaceutically acceptable salt thereof when R is hydrogen, or of the esters and pharmaceutically acceptable salts of the individual isomers of Formsl (B), characterized in that one (a) 3-Diazoacetyl-6,11-dihydrodibenzo-Zb.e ^ -thiepin-i1-one in the presence of a Ζ._ _Λ alkanol to form the corresponding esters of 6,11-Cihydrodibenzo - / ^. eJ'-thiepin -H-one-3-acetic acid treated; 609835/1043 2608312 (b) a C. _? Alkyl esters of 6,11-dihydrodibenzo-be / thiepir _l -11-one-3-acetic acid hydrolyzed to 6,11-dihydrodibenzo-Zb.eJ-thiepin-11 one-3-acetic acid; (c) a salt of (dl) -2- (6,11-dihydrodibenzo-Zb.e ./-thiepin-11-on-3-yl) propionic acid with an acidic salt or a strong acid to form the (dl) -2- (6, 11 -dihydrodibenzo-Zb. e._7-thiepin-11-on-3-yl) propionic acid treated; (d) the C alkyl esters of 6,11 -dihydrodibenzo- / b ~. e ^ j-thiepin- 11-one-3-acetic acid to form the ^c -] _ ₁₂ ^A1! <yl ^{ester of} (dl) -2- (6,11-dihydΓodibenzo- / be7-thiepin-1Ί-on-3-yl) propionic acid is methylated; (e) dis (dl; -2- (6,11-dihydrodibenzo- / 5'.e _i 7-thiepin-11-on-3-yl) propionic acid z-ir formation of (d) -2 ~ (6 , 11 -Dihydrodibenzo- / b.e_ _; _7-thiepin-1l-on-3-yl) -proρionic acid and (l) -2- (6,11-dihydrodibenzo- / b, e J- th iep in-11- on-3-yl) propionic acid separates; (f) an acid of the formulas (A) and (B) or the individual isomers the latter is esterified to form the corresponding C._ alkyl esters ; (g) an acid of the formulas (A) and (B) or the individual isomers converting the latter to a pharmaceutically acceptable salt; (h) a (l) -isomeric compound of the formula (3) is racernized to (dl) -2- (6,11-dihydradibenzo- / be _i 7-thiepin-11-on-3-yl) propionic acid; (i) an ester of the form in (A) and (B) or the individual isomers hydrolyzing the latter to form the corresponding free acid; 609835/1043 - THU - (j) a lower ester of the formulas (A) and (B) or the individual Isomers of the latter unesterified to form higher esters; (k) transesterifying a higher ester of formulas (A) and (B) to form a lower ester thereof; (l) The salts of formula (A) and (B) and the individual isomers the latter converts to the corresponding free acid; and or (m) a salt of formula (A) and (3) or the individual isomers the latter converts it into another salt by exchanging salt. The patent attorney: 609835/1043