EP0000978B1 - 7- oder 8-substituierte 10,11-Dihydro-11-oxodibenzo (b,f) thiepinderivate, ihre Herstellung und ihre pharmazeutischen Zusammensetzungen - Google Patents

7- oder 8-substituierte 10,11-Dihydro-11-oxodibenzo (b,f) thiepinderivate, ihre Herstellung und ihre pharmazeutischen Zusammensetzungen Download PDF

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Publication number
EP0000978B1
EP0000978B1 EP78300184A EP78300184A EP0000978B1 EP 0000978 B1 EP0000978 B1 EP 0000978B1 EP 78300184 A EP78300184 A EP 78300184A EP 78300184 A EP78300184 A EP 78300184A EP 0000978 B1 EP0000978 B1 EP 0000978B1
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Prior art keywords
acid
thiepin
dihydro
oxodibenzo
compound
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French (fr)
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EP0000978A1 (de
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Joshua Rokach
Clarence Stanley Rooney
Edward Jethro Cragoe
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D337/14—[b,f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups

Definitions

  • Prostaglandin antagonists are useful in treating a variety of conditions, such as allergic asthma where excessive contractile activity of prostaglandins and prostaglandin biosynthetic intermediates occur.
  • the prostaglandin antagonists of the present invention are 7- and 8-substituted-10,11-dihydro-11-oxodibenzo[b,f]thiepins having the structural formula: in which n is 0 or an integer from 1 to 4; Z is thio, sulfinyl, or sulfonyl; R is in the 7-position or the 8- position 2 and is hydrogen, chlorine, bromine, fluorine, iodine, amino, C 1-4 alkyl, C 1-4 alkanoyl, hydroxyl, C 1-4 alkoxy, mercapto, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, trifluoromethyl
  • halogen includes chlorine, bromine, iodine and fluorine.
  • loweralkyl and lower alkoxy include straight and branched chain alkyl and alkoxy groups having 1 to 4 carbon atoms in the alkyl or alkoxy moiety such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy and isobutoxy.
  • loweralkanoyl includes straight or branched chain alkanoyl groups having 1 to 4 carbon atoms in the alkanoyl moiety such as, for example, formyl, acetyl, propanoyl, butyryl and isobutyryl.
  • dibenzo[b,f]thiepin derivatives antagonize the actions of contractile prostaglandins, such as PGF 2 , PGG z and PGH z and TXA z .
  • the use of agents which act as prostaglandin antagonists offers new approaches to therapy in a number of disease states.
  • certain prostaglandins such as PGF 2a , PGG z and PGH 2
  • PGF 2a , PGG z and PGH 2 are potent contractants of bronchial muscle.
  • human asthmatics have been shown to be especially sensitive to the bronchial constricting action of PGF 2a .
  • prostaglandins are known to play a role in other allergic conditions, as well as inflammation, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature abortion, and dismenorrhea.
  • the dibenzo[b,f]thiepins of this invention are antagonists of slow reacting substance of anaphylaxis (SRS-A). This contractile substance is released in the lung tissue in allergic asthma, and antagonism of its actions contributes to alleviation of this disease.
  • SRS-A slow reacting substance of anaphylaxis
  • the dibenzo[b,f]thiepins of this invention are prepared according to the following general reaction scheme.
  • the sulfide-forming reaction is carried out according to the methods described by Jilek et al., Monatsh. Chem. 96, 200 (1965), Protiva et al, Czech. Patent 121,337 C.A. 68 (105, 247t, 1968) and U.S.P. 3,711,489, and by other procedures well known in the art.
  • the carboxylic acid V is transformed into the 3-bromo-11-oxo-10,11-dihydrodibenzo[b,f]thiepin by first conversion to the acid halide with thionyl or phosphoryl halide followed by Friedel-Crafts cyclization with a Lewis acid such as aluminum chloride to give VI. Reduction of the ketone VI with alkali metal borohydrides, followed by heating with catalytic amounts of a mineral acid, such as sulfuric acid or toluenesulfonic acid provides the 3-bromodibenzo[b,f]thiepin VII.
  • a mineral acid such as sulfuric acid or toluenesulfonic acid
  • the 3-bromo derivative VII is then converted to the 3-nitrile VIII by reaction with cuprous cyanide in a high boiling polar solvent such as dimethylformamide, N-methylpyrrolidone and the like.
  • the 3-cyano derivative VIII may be hydrolyzed with aqueous mineral acid or base to give the dibenzo[b,f]thiepin-3-carboxylic acid IX.
  • the 3-cyano compound VIII may also be reacted with azide ion at reflux in an inert solvent such as dimethylformamide, hexamethylphosphorictriamide and the like for 1/4 to 18 hours to give the tetrazole derivative X.
  • the cyano intermediate VIII may be oxidized with organic peroxides such as peroxy acids, for example, m-chloroperbenzoic acid and the like, in a stepwise fashion to the corresponding sulfoxide XI and sulfone XII, controlling the molar ratio of oxidant to reductant.
  • organic peroxides such as peroxy acids, for example, m-chloroperbenzoic acid and the like
  • ester XIX is reduced by conventional methods, e.g. Wolff-Kishner, to compound XXII or better by reduction with NaBH 4 to XX followed by PBr 3 reaction to XXI, then reduction with NaBH 4 in solvent such as sulfolane to XXII.
  • Compound XXII may be hydrolyzed with aqueous mineral acid or base to give the 10,11-dihydro[b,f]thiepin-3-carboxylic acid XXIII.
  • Compound XXII may also be oxidized with one equivalent of organic peroxides, such as peroxy acids, for example, m-chloroperbenzoic acid and the like, to yield the sulfoxide XXIV, which can then be hydrolyzed with mineral acid or base to provide the carboxylic acid XXV.
  • the acid XXIII may be oxidized with excess organic peroxides such as hydrogen peroxide in acidic solvents such as acetic acid at temperatures ranging from 0°-100°C. to yield compound XXVI.
  • Compound VI may be reacted with phosphorus tribromide followed by reduction with NaBH 4 in solvents, such as sulfolane, and reaction with cuprous cyanide in high boiling polar solvents, such as dimethylformamide, N-methylpyrrolidone and the like, to yield XXVII.
  • solvents such as sulfolane
  • cuprous cyanide in high boiling polar solvents, such as dimethylformamide, N-methylpyrrolidone and the like
  • the 3-cyano derivative XXVII may be reacted with azide ion at reflux in an inert solvent such as dimethylformamide or in THF with the addition of Lewis acid, such as AlCl 3 , to yield the tetrazole derivative XXVIII.
  • Compound XXVII can also be oxidized with excess peroxy acid, such as m-chloroperbenzoic acid followed by the tetrazole forming reaction to yield XXIX.
  • Tetrazole XXVIII may be oxidized with peroxides such as hydrogen peroxide in acidic medium, such as acetic acid, to yield compound XXX.
  • XVII may also be oxidized with one equivalent of organic peroxide, such as peroxy acids, for example, m-chloroperbenzoic acid followed by mineral acid or base hydrolysis to yield XXXI.
  • organic peroxide such as peroxy acids, for example, m-chloroperbenzoic acid followed by mineral acid or base hydrolysis to yield XXXI.
  • XVII can also be reacted with azide ion at reflux in an inert solvent such as dimethylformamide or in THF with the addition of a Lewis acid such as AICI 3 to yield the tetrazole XXXII.
  • XXXIII can be reduced with stannous chloride in acidic medium, hydrochloric acid and the like, to yield XXXIV which can be hydrolyzed with mineral acids or bases to XXXV.
  • XXXIII may be oxidized with peroxides, for example, m-chloroperbenzoic acid to yield XXXVI which can be reduced to XXXVII and then hydrolyzed with mineral acids or bases to XXXVIII.
  • peroxides for example, m-chloroperbenzoic acid
  • Intermediate XXXIV can be reacted with sodium nitrite in mineral acid to the diazonium salt XXXIX, where X is a mineral acid counter ion, for example, Cl - , HSO 4 - , BF 4 - and the like, which on reaction with CuCl and CuCl 2 yields intermediate XL which can be hydrolyzed to the acid XLI.
  • Intermediate XL may also be oxidized to the sulfone derivative, then followed by a hydrolysis to the carboxylic acid XLII.
  • Derivative XXXIX can be hydrolyzed with a solution of sulfuric acid 10 to 50% in strength at temperatures ranging from 0°-90°C. to yield XLIII.
  • XXXIX may also be reacted with potassium thioxanthate at temperatures from 40°-70°C. followed by basic hydrolysis to yield the thiol acid XLIV.
  • Compound XXXVII can be transformed in the usual manner to the diazonium salt XLV.
  • XLV can be reacted as described above to yield compounds XLVJ and XLVII.
  • Compound XLIX can in a controlled oxidation with peroxides such as hydrogen peroxide or organic peroxy acids such as m-chloroperbenzoic acid, yield compound LII.
  • LI may be oxidized with one equivalent of organic peroxides such as m-chloroperbenzoic acid or with hydrogen peroxide in hydroxylic solvents such as alcohols, organic acids such as acetic acid, at temperatures below 30°C., to yield LIII.
  • Compounds XLIX, LI and LIII may also be oxidized with excess organic peroxides such as m-chloroperbenzoic acid at room temperature, or with peroxides such as hydrogen peroxide in acidic medium such as acetic acid at temperatures between 80° and 100°C. to yield LIV.
  • RCOX alkanoyl halide
  • RCOOCOR alkanoic anhydride
  • R is a lower alkyl C 1 to C 4
  • X is chloro or bromo
  • LV can be oxidized with oxidizing agents such as in-chloro perbenzoic acid stepwise to yield sulfoxide LVII and sulfone LVIII which are hydrolyzed under acidic or basic conditions to afford acids LIX and LX respectively.
  • oxidizing agents such as in-chloro perbenzoic acid stepwise to yield sulfoxide LVII and sulfone LVIII which are hydrolyzed under acidic or basic conditions to afford acids LIX and LX respectively.
  • Compound LVI can be reacted with hydroxylamine hydro chloride with presence of base to yield oxime LXI which on a Beckman rearrangement, yields the acylamino compound LXII which upon hydrolysis yields amino acid LXIII.
  • Compound LXII can be oxidized with hydrogen peroxide in acetic acid stepwise to yield the corresponding sulfoxide LXIV and sulfone LXV which upon hydrolysis afford the acids LXVI and LXVII.
  • nitrile, XVII can be substituted for the nitrile starting material, XXVII, in the foregoing reaction sequences in order to prepare correspondingly substituted 10,11-dihydro-11-oxodibenzo[b,f]thiepins.
  • the 3-carboxylic acid derivatives of this invention serve as valuable intermediates in the preparation of other variously substituted thiepins of formula I.
  • the resulting 3-halocarbonyl 10,11-dihydro-11-oxodibenz[b,f][1,4]thiepin i.e., the 3-chlorocarbonyl compound of formula LXXIII then may be treated with various well-known reagents to form desired ester and amide derivatives. These reactions are illustrated in the following reaction scheme wherein R is as previously defined, it being understood that they are equally applicable to the 3-carboxylic acids of formula IX or XXIII.
  • the chlorocarbonyl compound of formula LXXIII may be treated:
  • the corresponding 11-oxide or 11,11-dioxide 3-carboxylic acid may be substituted for starting material XVIII in the foregoing reaction sequence.
  • the product esters and amides obtained in the foregoing reaction sequence may be oxidized by the techniques already described to obtain the corresponding sulfinyl or sulfonyl derivatives.
  • the aldehyde product then is converted into the corresponding 3-(2-aminoacetonitrile) by treatment with sodium cyanide in an alcoholic solvent saturated with ammonia and in the presence of ammonium chloride and ammonium hydroxide.
  • the reaction usually is conducted at room temperature and requires from 8 to 16 hours for completion.
  • the aminoacetonitrile so produced is treated with concentrated hydrochloric acid at room temperature for 20 to 45 minutes in order to obtain the corresponding 3-(2-aminoacetamide) which then is treated with sulfur monochloride in dimethylformamide to obtain the desired 10,11-dihydro-11-oxo-dibenzo[b,f]-thiepin-3-(3-hydroxy-1,2,5-thiadiazol-4-yl) of formula LXXXIV.
  • This reaction sequence is illustrated in the following diagram.
  • novel thiepins of this invention wherein the substituent at the 3-position is 4-hydroxy-A3 - pyrroline-3-yl-2,5-dione are prepared from the appropriately substituted 3-carboxylic acid by reducing the acid to the corresponding alcohol with borane in tetrahydrofuran.
  • the reaction conveniently is carried out at room temperature under an inert atmosphere and usually requires 2 to 4 hours for completion.
  • the alcohol then is brominated with phosphorus tribromide and the bromomethyl compound so produced is treated with sodium cyanide to form the correspondiong 3-cyanomethyl derivative.
  • These reactions may be carried out at room temperature and usually require from 1 to 3 hours for completion.
  • the cyanomethyl intermediate then is hydrolyzed to the corresponding acetic acid which is treated with thionyl chloride followed by ammonia to form the corresponding 3-acetamide derivative by techniques already described.
  • the acetamide then is treated with diethyloxalate in dimethylformamide in the presence of potassium t-butoxide to form the desired dibenzo[b,f]thiepin-3-(4-hydroxy-A3 - pyrrolin-3-yl-2,5-dione), LXXXV.
  • This reaction sequence is illustrated in the diagram following.
  • Steps A-D leads also to the preparation of those thiepins of this invention wherein the substituent at the 3-position is a loweralkanoic acid (i.e., compounds of formula I wherein A is n is an integer between 1 and 4 and R 2 is hydroxy).
  • Steps A-D as described above, starting with the appropriately substituted 3-carboxylic acid, through reduction, bromination, cyanization and oxidation, affords the corresponding 3-acetic acid derivative.
  • any desired 3-loweralkanoic acid derivative of the instant invention readily is prepared.
  • Corresponding sulfinyl or sulfonyl derivatives are prepared by the oxidation techniques previously described.
  • 3-cyanoloweralkyl intermediates obtained from Steps A-C in the reaction sequence described above also serve as intermediates in the preparation of other therapeutically active thiepins of formula I.
  • an appropriately substituted 3-cyanomethyl-1 0,11 -oxodibenzo[b,flthie- pin may be treated with sodium azide and ammonia by techniques previously described to form the corresponding 3-(1 H-tetrazol-5-ylmethyl)-10,1 1-dihydro-1 1-oxodibenzo[b,f]thiepin and the product, if desired, can be oxidized to form the corresponding sulfinyl or sulfonyl derivative.
  • pharmaceutically acceptable salts of the novel thiepins also are included within the scope of this invention.
  • pharmaceutically acceptable salts is intended to include salts derived from pharmaceutically acceptable non-toxic acids and bases such as, for example, ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, salts of organic bases such as amine salts derived from mono-, di and tri- loweralkyl or loweralkanoyl amines such as trimethylamine, dimethylamine and triethanolamine, salts derived from heterocyclic amines such as piperidine, pyridine, piperazine and morpholine, and salts derived from pharmaceuticaly acceptable acids such as hydrochloric acid, sulfuric acid, tartaric acid and propionic acid.
  • pharmaceutically acceptable non-toxic acids and bases such as, for example, ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, salts
  • a mixture consisting of 179 g. m-dibromobenzene (0.758 mole); 46.6 g. thiosalicyclic acid (0.303 mole); 25.9 g cuprous oxide (0.181 mole); 212 cc. quinoline; and 24 cc. pyridine is mechanically stirred and heated in an oil bath at 200°C. to 210°C. for three hours. The internal temperature remains constant at 145°C.
  • the reaction mixture is then poured into 1500 cc. of 5N aqueous HCI.
  • the oily solid is filtered; then dissolved in 750 cc. 1N aqueous NaOH solution; this solution is filtered through celite, then extracted three times with ether.
  • the aqueous fraction is acidified with concentrated HCI and the resulting grayish solid filtered, washed well with water and dried.
  • the crude yield obtained is 65 g. (69.4%). It is used as such in the next step.
  • the organic phase contains the crude alcohol which is chromatographed on a column of silica gel (1 kg.); elution is done with a mixture of 20% ethyl acetate in benzene. Pure 2-(3-bromophenylthio)-3-nitrobenzyl alcohol (50.03 g.) is obtained as a yellow oil (82.8% yield).
  • the oily acid chloride is dissolved in 400 cc. 1,2-dichloroethane and 22.4 g. aluminum chloride (10% excess) is added in portions. The reaction is slightly exothermic but no cooling is necessary. The reaction is permitted to go for 40 minutes then the mixture is poured onto ice. The organic fraction is collected and the aqueous fraction extracted three times with chloroform. Combined organics are washed with water, dried over sodium sulfate and stripped to dryness. The solid residue is triturated in ether and filtered, then triturated in methanol and filtered. The yield of crude product is 34.8 g. (74.8%).
  • N-loweralkylamine for example, ethylamine, propylamine, isopropylamine or butylamine
  • a N,N-diloweralkylamine for example, dimethylamine, diethylamine, dipropylamine or dibutylamine, for the methylamine
  • Reflux 1.0 g of 10,11-dihydro-11-oxodibenzo[b,f]thiepin-3-carboxy)ic acid in 15 cc of thionyl chloride for 30 minutes. Strip the reaction mixture to dryness and dissolve the residue in 25 cc of methylene chloride. Add a solution of 1.0 g of 2-imino-3-methylthiazolidine in 10 cc of methylene chloride. Stir at room temperature for 30 minutes and add water. Continue stirring for 10 minutes. Separate the organic phase, wash it with water and dry it overnight over sodium sulfate. Strip to dryness. Stir and triturate the residue in ether, then in methanol. Chromatograph the resulting solid over silica gel, eluting with 20% ethylacetate in benzene. Strip to dryness to obtain the title product.
  • N,N-diloweralkylaminoloweralkanol for example, diethylethanolamine, 3-N,N-dimethylaminopropan-1-ol or 4-N,N-diethylaminobutan-1-ol, for the N,N-dimethylethanolamine, there is obtained the corresponding N,N-diloweralkylaminoloweralkyl ester.
  • N,N-diloweralkylaminoloweralkanol for example, diethylethanolamine, 3-N,N-dimethylaminopropan-1-ol or 4-N,N-diethylaminobutan-1-ol
  • the compounds of formula I are useful in the treatment or prophylaxis of mammalian disease conditions where excessive undesirable contractile activity of prostaglandins, such as PGF Za , or prostaglandin biosynthetic intermediates contribute.
  • These conditions include asthma, inflammatory states such as arthritis, allergy, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature abortion and dismenorrhea.
  • they are of value in reaginic mediated asthma (extrinsic asthma).
  • a prophylactic or therapeutic dose of compound of formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of formula I and its route of administration. In general, the dose range lies within the range of 0.2 mg to 100 mg. per kg. body weight of a mammal.
  • compositions of the present invention comprise a compound of formula I as an active ingredient, and may also contain pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • the compositions include compositions suitable for oral, rectal, opthalmic, pulmonary, nasal, dermal, topical or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • a suitable dosage range is from 0.2 to 10 mg. (preferably 1 to 5 mg.) of a compound of formula I per kg. of body weight per day and in the case where an oral composition is employed a suitable dosage range is about, e.g., 1 to 50 mg. of a compound of formula I per kg. of body weight per day, preferably from 10 to 40 mg./kg.
  • compositions of the present invention suitable for oral administration and by inhalation in the case of asthma therapy may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from 50 mg. to 500 mg. of the active ingredient and each cachet or capsule contains from 50 mg. to 500 mg. of the active ingredient.
  • the instant invention has been described in the foregoing specification in terms of the use of the novel thiepin disclosed herein in the treatment and control of human and warm-blooded animal disease conditions characterized by excessive undesirable contractile activity of prostaglandins and prostaglandin biosynthetic intermediates, and particularly of asthma, it will be recognized by those skilled in the art that, in addition to the involvement of contractile prostaglandins in chronic obstructive lung disease (e.g., asthma), prostaglandins play a role in other allergic conditions as well as in inflammation, diarrhea, hypertension, angina, cerebral spasm, premature abortion and dismenorrhea.
  • the thiepins of this invention are potent TXA z biosynthesis inhibitors, inhibiting platelate aggregation, and can be useful in diseases such as atherosclerosis, variant anginal and myocardial infarction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Claims (9)

1. Verbindung der Formel:
Figure imgb0055
in welcher bedeuten: n 0 oder eine Zahl von 1 bis 4; Z Thio, Sulfinyl oder Sulfonyl; R, welches sich in der 7-Stellung oder 8-Stellung befindet, Wasserstoff, Chlor, Brom, Fluor, Jod, Amino, C1-4 Alkyl, C1-4 Alkanoyl, Hydroxyl, C1-4 Alkoxy, Mercapto, C1-4-Alkylthio, C1-4-Alkylsulfinyl, C1-4 Alkylsulfonyl, Trifluoromethyl, Trifluoromethylthio, Cyano, Carboxy, Nitro, C1-4-Alkylamino oder Di-(C1-4-alkyl)-amino; A 5-Tetrazolyl, 3-Hydroxy-1,2,5-thiadiazol-4-yl, 4-Hydroxy-2,5-dioxo-Δ3-pyrrolin-3-yl oder
Figure imgb0056
wobei R2 bedeutet: Hydroxy, C1-4-Alkoxy, N,N-Di(C1-4-alkyl)-amino-(C1-4 Alkoxyl, C1-4-Hydroxyalkoxy, Carboxy(C1-4-alkoxy), Amino, C1-4 Alkylamino, Di-(C1-4-alkyl)amino, C1-4-Alkylsulfonylamino, Carboxy-(C1-4-alkyl)amino, Carbamoyl-(C1-4-alkyl)-amino oder 2-Imino-3-methylthiazolidin, mit der Massgabe, dass R2 nicht Wasserstoff ist, wenn n 0, R Wasserstoff und Z Thio bedeuten; und deren pharmazeutisch annehmbare Salze.
2. Verbindung nach Anspruch 1, in welcher n 0 und A 5-Tetrazolyl bedeuten.
3. Verbindung nach Anspruch 1, in welcher n 1, 2, 3 oder 4 und A Carboxy bedeuten.
4. Verbindung nach irgendeinem der Ansprüche 1 bis 3, in welcher R Chloro bedeutet.
5. Verbindung nach irgendeinem der Ansprüche 1 bis 3, in welcher R Bromo bedeutet.
6. 10,11 -Dihydro-11 -oxodibenzo[b,f]thiepin-3-carbonsäure-5-oxid.
7. 10,11-Dihydro-11-oxo-3-(5-tetrazolyl)-dibenzo[b,f]thiepin.
8. Verfahren zur Herstellung einer Verbindung der Formel:
Figure imgb0057
in welcher n, Z und R wie in Anspruch 1 definiert sind und A° 5-Tetrazolyl oder Carboxy bedeutet, welches die Schritte umfasst: Hydrolysieren einer Verbindung der Formel:
Figure imgb0058
mit einer Säure oder einer Base, um die Carboxylverbindung zu bilden, oder Umsetzen der genannten Verbindung mit einem Azidion, um die 5-Tetrazolylverbindung zu bilden.
9. Zusammensetzung zur Behandlung unerwünschter Kontraktionswirksamkeit von Prostaglandin, umfassend eine therapeutisch wirksame Menge einer Verbindung nach irgendeinem der Ansprüche 1 bis 7.
EP78300184A 1977-07-26 1978-07-21 7- oder 8-substituierte 10,11-Dihydro-11-oxodibenzo (b,f) thiepinderivate, ihre Herstellung und ihre pharmazeutischen Zusammensetzungen Expired EP0000978B1 (de)

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US81920077A 1977-07-26 1977-07-26
US91721178A 1978-06-23 1978-06-23
US917211 1978-06-23
US819200 1992-01-10

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JP (1) JPS5444692A (de)
DE (1) DE2862028D1 (de)
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JPS54122284A (en) * 1978-02-17 1979-09-21 Dainippon Pharmaceut Co Ltd Dibenzb,foxepin derivative
FI801638A (fi) * 1979-06-01 1980-12-02 Merck & Co Inc Prostaglandinantagonister
DE3068250D1 (en) * 1979-11-27 1984-07-19 Merck Sharp & Dohme 3-hydroxymethyldibenzo(b,f)thiepins and dibenzo(b,f)thiepin-3-carboxaldehydes as prostaglandin antagonists, process for their preparation and pharmaceutical compositions
US4535171A (en) * 1982-11-18 1985-08-13 Merck Frosst Canada, Inc. Dibenzo[b,f]thiepin-3-carboxaldehydes as prostaglandin antagonists
US4558037A (en) * 1984-06-04 1985-12-10 Merck & Co., Inc. Cardiovascular composition

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FI258574A (de) * 1973-09-13 1975-03-14 Sandoz Ag
US4205170A (en) * 1976-12-03 1980-05-27 Nippon Chemiphar Company, Limited Propionic acid derivatives

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IT7850376A0 (it) 1978-07-19

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