US3905989A - (Tetrazolyl)thioxanthone-10,10-dioxides - Google Patents

(Tetrazolyl)thioxanthone-10,10-dioxides Download PDF

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US3905989A
US3905989A US361523A US36152373A US3905989A US 3905989 A US3905989 A US 3905989A US 361523 A US361523 A US 361523A US 36152373 A US36152373 A US 36152373A US 3905989 A US3905989 A US 3905989A
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acid
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tetrazolyl
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dioxide
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Harold F Hodson
John Frederick Batchelor
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SmithKline Beecham Corp
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Burroughs Wellcome Co USA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/12—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • 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
    • 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
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings
    • C07D327/08—[b,e]-condensed with two six-membered carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/76—Dibenzothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings

Definitions

  • the above compounds are useful for the relief or prophylaxis of allergic conditions.
  • tricyclic compounds of formula l as defined hereinbelow, are active in mammals and in in vitro mammalian preparations as inhibitors of allergic reactions associated with reaginic antibodies of the kind responsible for asthma in man, and that this effect is attributable to the suppression of the release of anaphylactic mediators.
  • Z is a substituent in the 1-,2-,3-, or 4- position and is carboxyl, S-tetrazolyl, 5(l-alkyl) tetrazolyl, or 5-( 2'alkyl)tetrazolyl in which the alkyl groups have 1 to 6 carbon atoms and are each optionally substituted by a hydroxyl group or a basic or acidic group;
  • Z is hydrogen or a substituent in the 5-,6-, 7-, or 8-position selected from the values of the group Z as defined above or is alkylsulphonyl, alkylsulphinyl, thioalkyl, amino, acylamino, nitro, cyano, halogen preferably chlorine or bromine, acyl, alkyl or alkoxy wherein the alkyl" moiety of each of the acyl, alkyl, alkoxy, thioalkyl, acylamino, alkylsulphinyl and alkylsulphony
  • esters of formula 1 compounds of formula I wherein either of Z and Z is or both are an alkyl carboxylate group, are hereinafter referred to as esters of formula 1.
  • references to amides of formula I shall be construed as references to compounds of formula I wherein one or both of Z and Z is an optionally substituted carboxamide, and references to salts of formula I shall mean salts of formula I wherein one or both of Z and Z is a salt of the acid.
  • Pharmaceutically acceptable salts of compounds of formula I include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth salts such as magnesium and calcium salts, and salts of organic bases, for example, amine salts derived from mono-, di-, or tri-lower alkyl or lower alkanolamines such as triethanolamine and diethylaminoethylamine and salts with heterocyclic amines such as piperidine pyridine, piperazine and morpholine.
  • water soluble salts most preferably those having a solubility in water of at least 1 mg/ml.
  • the carboxylate salt group may be a salt of any pharmaceutically acceptable cation, since the pharmacological activity of the salts is associated. with the anion.
  • Suitable amides include amides derived from primary or secondary, aliphatic amines such as N-alkyl and N,N-dialkyl amines for example diethylamine.
  • Suitable esters include esters derived from alkyl alcohols. The alkyl moieties of the alkyl esters and N-alkyl and N,N- dialkyl carboxamides, preferably each have 1 to 6 carbon atoms, most desirably l to 4 carbon atoms.
  • Each of the alkyl moieties of the esters, alkyltetrazoles and amides is optionally substituted by at least one hydroxy, basic or acidic substituent.
  • Suitable basic substituents include amino groups optionally substituted by one or two alkyl groups and heterocyclic amino groups such as piperidine or morpholine.
  • the esters and amides having basic substituents as well as the amides themselves may be in the form of pharma' ceutically acceptable acid addition salts.
  • Suitable acidic substituents include S-tetrazolyl groups and carboxyl groups, and their pharmaceutically acceptable salts.
  • Z is a substituent in the l-,2-,3- or 4-position and is a car' boxyl group, a carboxylate salt group, an alkyl carboxylate group wherein the alkyl moiety has 1 to 6, preferably l to 4 carbon atoms, a carboxamide group optionally N-substituted by alkyl having 1 to 6, preferably 1 to 4 Carbon atoms, a S-tetrazolyl group, a S-tctrazolyl salt group, a 5-( l-alkyl)tetrazolyl group or a 5-(2- alkyl)tetrazolyl group in which the alkyl groups have 1 to 6 carbon atoms and are each optionally substituted by a basic group;
  • Z is hydrogen or a substituent in the 5-,6-,7-, or 8- position and has the same values as the group Z as defined above or is an alkylsulphonyl group, an alkylsulphinyl group, a thioalkyl group, an amino group, an acylamino group, a nitro group, a cyano group, a halogen atom, an acyl group, an alkyl group or an alkoxy group wherein the alkyl moiety of each of the acyl, alkyl, alk
  • oxy, thioalkyl, acylamino, alkylsulphinyl and alkylsulphonyl groups has 1 to 6 carbon atoms; and Z is carbonyl.
  • Especially preferred sulphone compounds of formula I include tricyclic compound of formula IV wherein Z is as defined in formula I, and Z is selected from a carboxyl group, a carboxylate salt group, an alkyl carboxylate group having 1 to 4 carbon atoms in the alkyl moiety, a carboxamide group optionally N-substituted by an alkyl group having 1 to 4 carbon atoms, a 5- tetrazolyl group and a S-tetrazolyl salt group.
  • Other preferred compounds of formula I include tricyclic compounds of formula V wherein Z is as de fined in formula I, and Z and Z are the same or different and each is selected from a carboxyl group, a carboxylate salt group, an alkyl carboxylate group having 1 to 6 carbon atoms, a carboxamide group optionally N-substituted by an alkyl group having 1 to 6 carbon atoms, a S-tetrazolyl group, and a S-tetrazolyl salt group.
  • Compounds of formula I which show a very high antiallergic activity on oral administration include 3- carboxythioxanthone- 10, l O-dioxide, and 3-( 5- tetrazolyl)thioxanthone-10,10-dioxide, and salts of these compounds, especially alkali metal salts including sodium and potassium salts.
  • Preferred compounds of the present invention also include tricyclic compounds of formula ll wherein Z is a substituent in the 3-position and is carboxyl or tetrazolyl and Z is hydrogen or a substituent in the -,6-,7- or 8-position selected from the values of the group Z as defined above or is nitro, chlorine, bromine, or alkyl having 1 to 6 carbon atoms; and the pharmaceutically acceptable salts of said compounds.
  • Novel thioxanthone-IO, lO-dioxide compounds of the present invention include tricyclic compounds of formula lX wherein Z is a substituent in the l-,2-,3-, or 4-position and is carboxyl, a carboxylate salt group, an alkyl carboxylate group wherein the alkyl moiety has 1 to 6, preferably 1 to 4 carbon atoms, a S-tetrazolyl salt group, 5-( l-alkyl)tetrazolyl or 5-(2-alkyl) tetrazolyl in which the alkyl groups have 1 to 6 carbon atoms and are each optionally substituted by a hydroxyl group or a basic or acidic group; and Z is a hydrogen or a substituent in the 5,-,6-,7-, or 8-position and is alkylsulphonyl, alkylsulphinyl, thioalkyl, amino, acylamino, nitro, cyano, halogen preferably
  • Novel tetrazolyl compounds and their derivatives of the present invention include tricyclic compounds of formula Xl wherein Z is a substituent in the l-,2-,3-, or 4-position and is S-tetrazolyl, a S-tetrazolyl salt group, 5-( l-alkyl) tetrazolyl or 5-(2-alkyl)tetrazolyl in which the alkyl groups have 1 to 6 carbon atoms and are each optionally substituted by a hydroxyl group or a basic or acidic group; Z is a hydrogen or a substituent in the 5-,6-,7-, or 8-position selected from the values of the group Z as defined above or is alkylsulphonyl, alkylsulphinyl, thioalkyl, amino, acylamino, nitro, cyano, halogen preferably chlorine or bromine, acyl, alkyl, or alkoxy wherein the alkyl moiety of each of the acy
  • Novel compounds of the present invention also in clude the solid tricyclic compounds of formula Xll wherein Z is a substituent in the l-,2-,3, or 4-position and is a pharmaceutically acceptable carboxylate salt group, S-tetrazolyl, a S-tetrazolyl salt group, 5-(1- alkyl)tetrazolyl or 5-(2-alkyl)tetrazolyl in which the alkyl groups have 1 to 6 carbon atoms and are each optionally substituted by a hydroxyl group or a basic or acidic group;
  • Z is a hydrogen or a substituent in the 5-,6-,7-, or 8position selected from the values of the group Z defined above or is alkylsulphonyl, alkylsulphinyl, thioalkyl, amino, acylamino, nitro, cyano, halogen preferably chlorine or bromine, acyl, alkyl, or alkoxy wherein the alkyl moiety of the acyl
  • the compounds of formula I may be prepared by known chemical techniques. In general, the methods include cyclisation wherein the central ring is completed by ring closure, hydrolysis, oxidation or reduction of precursors leading to both of the groups Z and Z by a variety of techniques. Examples of the preparation of certain compounds of formula I by these methods are described at the end of this specification. These general synthetic procedures are also applicable in some instances to the preparation of intermediates.
  • the cyclisation preparative methods in general include the formation as the final step of one or both of the bridges of the central ring.
  • compounds of formula Xlll wherein Z, Z and Z are defined in formula (I) may be reacted with chlorosulphonic acid to provide corresponding compounds of formula I, or using chlorosulphonyl compounds of formula XIV wherein Z, and Z and Z are defined in formula I, the corresponding compounds of formula I may be prepared, by ring closure using a Lewis acid, for example aluminium chloride with heat.
  • Preferred protonic acids are polyphosphoric acid (tetraphosphoric acid,) and sulphuric acid.
  • Suitable Lewis acids include aluminium trichloride and boron trifluoride. The reaction is preferably carried out at a temperature from 50 to 300C.
  • oxidation techniques may be used to prepare the compounds of formula (I) by completion of one or both of the bridges of the central ring.
  • the thioxanthone-l(),l0-dioxides (in formula l, Z is carbonyl) may be prepared by oxidation of the corresponding thioxanthene-lO, lO-dioxides (in formula l, Z is methylene), using for example Triton B, pyridine and oxygen.
  • Compounds of formula I may also be prepared by oxidation of the corresponding sulphoxides and sulphides to form the sulphones, using for example hydrogen peroxide and acetic acid.
  • the compounds of formula I may also be prepared by formation of one or both of the groups Z and Z as the final step.
  • these compounds may be prepared by reaction of hydrazoic acid or a salt thereof or nitrous acid with an appropriate compound of formula XVlll wherein Y is a group Z as defined in formula 1 or a tetrazolyl group precursor and Y is a group 2'' as defined in formula (I) or a tetrazolyl group precursor, provided that at least one of Y and Y is a tetrazolyl group precursor.
  • a suitable tetrazolyl group precursor is a group wherein R and R together form a bond (nitrile), R is hydrogen or alkyl and R is alkoxy having I to 6 carbon atoms (imidoester), thioalkyl having 1 to 6 carbon atoms (imidothioester), NI-l NI-I (amidrazone), or amino (amidine) or R is hydroxy and R is amino (amidoxime), or R is alkyl and R is halogen (imidohalide
  • the reaction is preferably carried out in a polar aprotic liquid medium using a salt of hydrazoic acid.
  • a suitable tetrazolyl precursor group is a group wherein R is hydrogen or alkyl and R is -NI-INI-I (amidrazone) or R is hydrogen and R is amino (amidine).
  • R is hydrogen or alkyl and R is -NI-INI-I (amidrazone) or R is hydrogen and R is amino (amidine).
  • tetrazolyl compounds of formula I thus prepared may be isolated as the free acid or as a tetrazolyl salt, and the one converted to the other in known manner and as specifically described below in relation to the carboxylic acids of formula I and their salts.
  • the 5-(1- and 2alkyl)tetra7.olyl compounds of formula I may be made from the corresponding tetrazolyl compounds of formula I or their salts by alkylation.
  • the carboxylic acids of formula I wherein one or both of Z and Z are carbonyl may be prepared by a variety of methods which include as the final step the formation of the carboxyl group. These compounds may be isolated as the free acid, as salts thereof, or converted to amides or esters of formula I, depending upon the nature of the desired products.
  • Y and Y are a carboxyl group precursor, such as a nitrile group, trichloromethyl group or a group COL wherein L is a leaving group, such as a nucleophilic atom or group, for example, a trichloromethyl group, an optionally substituted amino group, a halogen atom or an alkoxy group, when the other is Z or Z as defined in formula I, as appropriate, or is Y as defined above; and Z has the meaning defined in formula I.
  • Hydrolysis is conveniently effected by heating a compound of formula XIX with a base or a dilute aqueous mineral acid optionally with an organic acid. For example, one may use dilute sulphuric acid or dilute hydrochloric acid with acetic acid.
  • esters and amides of formula I may be prepared directly from compounds of formula XIX.
  • reaction of a compound of formula XIX with an appropriate alcohol yields an ester of formula I
  • reaction with ammonia or an appropriate primary or secondary amine yields an amide of formula I.
  • the carboxylic acids of formula land their salts may also be made by oxidation of a compound of formula XX wherein Y is an alkyl group, an acyl group or a group Z as defined in formula I, Z is as defined in formula I, and Y is an alkyl group, an acyl group or a group Z as defined in formula I provided that at least one of Y and Y is an alkyl or acyl group.
  • Oxidation of compounds wherein Y and/or Y are lower alkyl groups may be effected with : such conventional oxidising agents as acid or alkaline aqueous potassium permanganate solution; chromium trioxide, for example, with acetic acid or sulphuric acid; oxygen in the presence of a conventional catalyst such as vanadium, cobalt and manganese salts or oxides; or aqueous solutions of dichromate salts.
  • a conventional oxidising agents as acid or alkaline aqueous potassium permanganate solution
  • chromium trioxide for example, with acetic acid or sulphuric acid
  • oxygen in the presence of a conventional catalyst such as vanadium, cobalt and manganese salts or oxides
  • aqueous solutions of dichromate salts such conventional oxidising agents as acid or alkaline aqueous potassium permanganate solution
  • chromium trioxide for example, with acetic acid or sulphuric acid
  • Oxidation of compounds wherein Y and/or Y are the groups C(:O)R may be effected with such conventional oxidising agents as chromium trioxide, for example, with acetic acid or sulphuric acid; aqueous solutions of salts of hypochlorous and hypobromous acids in the presence of a base; sodium or potassium dichromate with acetic acid; or-nitric acid.
  • oxidising agents as chromium trioxide, for example, with acetic acid or sulphuric acid; aqueous solutions of salts of hypochlorous and hypobromous acids in the presence of a base; sodium or potassium dichromate with acetic acid; or-nitric acid.
  • the compounds of formula I wherein Z is other than hydrogen, alkyl, acyl, carboxyl or a derivative thereof or tetrazolyl or a derivative thereof may also be made by formation of the group Z as the final step.
  • Such compounds are prepared by introducing an alkylsulphonyl group, alkylsulphinyl group, cyano group, halogen amino group, acylamino group, nitro group, cyano group, halogen atom or alkoxy group into an appropriate compound of formula XXII wherein Z and Z are as defined in formula I and Q is hydrogen, a leaving group or a precursor, by known methods.
  • the compounds may be made by reduction of the corresponding nitro compounds which themselves may be made by nitration.
  • the amino compounds may be converted into acylamino compounds by acylation and into the corresponding diazonium compounds of formula XXIII wherein Z and Z" are defined in formula I and W is an anion, for example chloride, bromide or hydrogen sulphate by reaction with nitrous acid.
  • diazonium compounds may be converted by known methods to the alkoxy compounds (by reaction with water and alkylation of the resulting hydroxy compounds); to the halo compounds (by the Sandmeyer reaction using cuprous bromide or chloride; by the Gattermann reation using a copper catalyst to produce bromo or chloro compound where W is the chloride or bromide ion; by the BalzSchiemarin reaction using the fluoroborate diazonium salt to produce the fluoro compounds; or by using an alkali metal iodide to produce the iodo compounds); to the nitrile compounds (by modified Sandmeyer or Gattermann reactions using cuprous cyanide or potassium cyanide and copper powder); to thiols and alkylthio compounds (by the Leuckart synthesis by formation of diazoxanthates or diazothioxanthates from the diazo compounds and alkali metal alkyl xanthates or thioxanthates respectively which are decomposed in faintly
  • compositions of tetrazoles or carboxylic acids of formula I are prepared by any conventional method, for. example by neutralising the corresponding carboxylic acid or tetrazole with an appropriate Bronsted base, or by double decomposition of a salt of an acid or tetrazole of formula I so as to produce the desired salt of an appropriate pharmaceutically acceptable cation.
  • the carboxylic acid or tetrazole may be either the isolated acid or tetrazole, or may be present in solution in the reaction mixture resulting from a preparation of the compound, for example by such a method as described hereinbefore.
  • Suitable Bronsted bases include organic bases such as ethanolamine, and bases containing ammonium, and alkali metal and alkaline earth metal cations.
  • Double decomposition may be effected advantageously in an anion exchange resin wherein a solution of a salt of an acid or tetrazole of formula I is passed through a cation exchange resin, the resin being charged with a pharmaceutically acceptable cation of the suitable base.
  • Double decomposition may also be effected in ordinary solution between a salt of an acid or tetrazole of formula I and a salt of the desired pharmaceutically acceptable cation.
  • pharmaceutically acceptable salts of carboxylic acids of formula I may be prepared by reaction in a polar medium of a compound of formula XXIV wherein R and R" are the same or different and each is selected from a carboxylic group and a group Y as defined hereinbefore in formula XIX. and Z has the meaning in formula I, with an appropriate Bronsted base and, when the Bronsted base does not contain a hydroxyl ion, in the presence of water.
  • appropriate Bronsted bases are alkali and alkaline earth metal oxides and hydroxides for producing corresponding alkali and alkaline earth metal salts of formula I.
  • the reaction is effected with heating.
  • Salts of formula l may be isolated from a reaction medium by any conventional process for the isolation of salts from a solution thereof in a polar medium. Thus the salts may be isolated by precipitation of the salt or by removal of the polar medium.
  • Precipitation of the salt may be effected by mixed solvent crystallisation or by the addition of excess of base or salt thereof so as to produce a concentration of the cation of the salt to be isolated, substantially in excess of the molar ratio thereof in said salt to be isolated.
  • Mixed solvent crystallisation may be effected by addition, to a solution of a salt of formula I in a polar medium, of a second solvent miscible with the solvent already present and in which second solvent the salt of formula I is less soluble than in the solvent already present.
  • Removal of the polar medium may be effected by evaporation, for example. by freeze-drying, or by azeotropic distillation.
  • the salts of formula I are purified prior to incorporation in a pharmaceutical composition.
  • Purification may be effected by any conventional method.
  • a particularly valuable purification process comprises isolation of a crude solid salt of formula I from a reaction mixture wherein said salt has been produced, by any method for the isolation of salts of formula I as described hereinabove; treatment of an aqueous solution of salt with hydrochloric acid; recovery of the corresponding acid of formula I as solid; neutralisation of the acid of formula 1 with Brdnsted base of which base the cation isthe cation of the required salt of formula I; re-
  • a carboxylic acid of formula I may be 10 purified prior to neutralisation, by recrystallisation or by isolation of a N,N-dimethylformamide adduct and subsequently heating the adduct to drive off the N,N-dimethylformamide.
  • Recrystallisation may be effected using a polar organic solvent optionally containl5 ing water, for example, aqueous dimethylformamide,
  • aqueous acetone or acetic acid may be used.
  • Esters and amides of acids of formula l may be prepared by any conventional method including esterification of the acid or acid chloride with an alkyl or aryl alcohol to yield the corresponding alkyl or aryl ester respectively and reaction of the acid or acid chloride with ammonia or an amine to yield the corresponding amide or substituted amide respectively.
  • Compounds of formula I where Z and Z are different and are chosen from acid, ester, amide and salt functions, may
  • the compounds of formula I are useful in the treatment or prophylaxis of mammalian allergic conditions such as asthma and other allergic chest conditions, hay
  • a prophylactic or therapeutic dose of compound of formula I will of course vary with the nature and the severity of the allergic 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 2 g. to 100 mg. per Kg. body weight of a mammal.
  • a suitable dosage is from 5 pg. to 0.5 mg, preferably form 20 pg. to 0.2 mg, for example about 0.1 mg., of a compound of formula l, per Kg. of bodyweight of the patient undergoing treatment, when pulmonary administration as described hereinafter is employed.
  • 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 bodyweight of patient, and in the case where an oral composition is employed a suitable dosage range is about 30mg/Kg. e.g. l to mg. of a compound of formula I per Kg. of bodyweight of a patient, preferably from 10 to 40 mg/Kg.
  • a suitable dose is from 0.5 to 25 mg. of a compound of formula I per patient.
  • 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 ingre transients.
  • 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.
  • compositions of the present invention suitable for oral administration 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 oilin-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 accessory ingredients.
  • the 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 freeflowing 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 50mg. to 500mg. of the active ingredient, and each cachet or capsule contains from 50 to 500 mg. of the active ingredient.
  • a particularly valuable form of a pharmaceutical composition of the present invention, for use in the treatment of allergic asthma is a composition suitable for pulmonary administration via the buccal cavity; although of course conditions other than allergic asthma may also be treated by pulmonary administration of the composition.
  • the composition is such that particles having a diameter of 0.5 to 7,u most preferably 1 to on, containing active ingredient, are delivered into lungs of a patient. This ensures that a maximal amount of active ingredient is administered to the alveolar sacs of the lungs and retained therein thus producing a maximal effect in the patient.
  • Such compositions are most pref erably in the form of dry powders for administration from a powder inhalation device or self-propelling powder-dispensing compositions.
  • the powders of the pulmonary compositions as described hereinabove and hereinbelow comprise particles containing active ingredient of which particles at least 98 percent by weight have a diameter greater than 0.5a and at least 95 percent by number have a diameter less than 7p Most desirably at least 95 percent by weight of the particles have a diameter greater than 1,41. and at least 90 percent by number of the particles have a diameter less than op
  • the compositions in the form of dry powders preferably comprise particles containing the solid active ingredient, the particles having a diameter of 0.5 to 7y. most preferably 1 to 6p. Preferably these compositions inelude a solid diluent in the form of a fine powder.
  • compositions may be conveniently presented in a pierceable capsule of a pharmaceutically acceptable material, for example gelatin.
  • Such compositions may be conveniently prepared by comminution of solid active ingredient optionally with a solid diluent. If desired the resulting powder may be filled into a pierceable capsule of a pharmaceutically acceptable material.
  • These self propelling compositions may be either powderdispensing compositions or compositions dispensing the active ingredient in the form of droplets of a solution or suspension.
  • Self-propelling powder-dispensing compositions preferably comprise dispersed particles of solid active ingredient, having a diameter of0.5 to 7;; most preferably l to 61.1. and a liquid propellant having a boiling point of below 65F at atmospheric pressure.
  • the liquid propellant may be any propellant known to be suitable for medicinal administration and may comprise one or more lower alkyl hydrocarbons, or halogenated lower alkyl hydrocarbons, or mixtures thereof. Chlorinated and fluorinated lower alkyl hydrocarbons are especially preferred propellant.
  • the propellant may constitute 50 to 99.9 percent w/w of the composition whilst the active ingredient may constitute 0.l to 20 percent'w/w, for example, about 2 percent w/w, of the composition.
  • the pharmaceutically acceptable carrier in such selfpropelling compositions may include other constituents in addition to the propellant, in particular a surfactant or a solid diluent or both.
  • Surfactants are desirable in preventing agglomeration of the particles of active ingredient and in maintaining the active ingredient in suspension.
  • Suitable liquid non-ionic surfactants are those having a hydrophilelipophile balance (HLB, see Jour nal of the Society of Cosmetic Chemists Vol. I pp. 3l l326 1949)) of below 10, in particular esters and partial esters of fatty acids with aliphatic polyhydric alcohols, for instance.
  • the liquid nonionic surfactant may constitute up to 20 percent w/w of the composition. though preferably it constitutes below 1 percent w/w of the composition.
  • Suitable solid anionic surfactants include alkali metal, ammonium and amine salts of dialkyl sulphos'uccinate, where the alkyl groups have 4 to 12 carbon atoms, and alkylbenzene sulphonic acid where the alkyl group has 8 to 14 carbon atoms.
  • the solid anionic surfactants may constitute up to 20 percent w/w of the composition, though preferably below 1 percent w/w of the composition.
  • Solid diluents may be advantageously incorporated in such self-propelling compositions where the density of the active ingredient differs substantially from the density of the propellant; also in order to help to maintain the active ingredient in suspension.
  • the solid diluent is in the form of a fine powder, preferably having a particle size of the same order as that of the particles of active ingredients.
  • Suitable solid diluents include sodium choride and sodium sulphate.
  • compositions of the present invention may also be in the form of a self-propelling composition wherein the active ingredient is present in solution.
  • Such selfpropelling compositions may comprise an active ingredient, propellant and co-solvent, and advantageously an antioxidant stabiliser.
  • the propellant is one or more of those already cited above.
  • Co-solvents are chosen for their solubility in the propellant, their ability to dissolve the active ingredient, and for their having the lowest boiling point consistent with these abovementioned properties. Suitable co-solvents are lower alkyl alcohols and ethers and mixtures thereof.
  • the cosolvents may constitute to 40 percent w/w of the composition, though preferably less than percent w/w of the composition.
  • Antioxidant stabilisers may be incorporated in such solution-compositions to inhibit deterioration of the active ingredient and are conveniently alkali metal ascorbates or bisulfites. They are preferably present in an amount of up to 0.25 percent w/w of the composition.
  • Such self-propelling compositions may be prepared by any method known in the art.
  • the active ingredient either as particles as defined hereinbefore in suspension in a suitable liquid or in up to 20 percent w/v solution in an acceptable co-solvent as appropriate, is mixed with any other constituents of a pharmaceutieally acceptable carrier.
  • the resulting mixture is cooled and introduced into a suitable cooled container and propellant is added thereto in liquid form; and the container is sealed.
  • such self-propelling compositions may be prepared by mixing the active ingredient either in particles as hereinbefore defined or in 2 to 20 percent w/v alcohol or aqueous solution as appropriate, together with the remaining constituents of the pharmaccutically acceptable carrier other than propellant; introducing the resulting mixture, optionally with some propellant, into a suitable container; sealing the container; and injecting propellant under pressure into the container at ambient temperature through a valve which comprises a part of the container and is used to control release of the composition from it.
  • the container is purged by removing air from it at a convenient stage in the preparation of the selfpropelling composition.
  • a suitable container for a self-propelling composition is one provided with a manually operable valve and being constructed of aluminium, stainless steel or reinforced glass.
  • the valve should of course be one having the desired spray characteristic, that is, the spray issuing from the valve should have the characteristics of particle size as hereinbefore defined.
  • the valve is of the metered type, that is a valve of the type which delivers a fixed amount of composition on the occasion of each operation of the valve, for example, about 50 or l00 microlitres of composition in each delivery.
  • compositions of the present invention may also be in the form of aqueous or dilute alcoholic solution, optionally a sterile solution, of the active ingredient for use in a nebuliser or atomiser, wherein an accelerated air stream is used to produce a fine mist consisting of small droplets of the solution.
  • Such compositions usually contain a flavouring agent such as saccharin sodium and a volatile oil.
  • a buffering agent such as sodium phosphate; an antioxidant such as sodium metabisulfite; and a surface active agent may also be included in such a composition.
  • such a composition should contain a preservative such as methylhydroxybenzoate.
  • compositions of the present invention suitable for parenteral administration conveniently comprise sterile aqueous solutions of the active ingredient, which solutions are preferably isotonic with blood of a patient under treatment. These are preferably administered intra-venously, although administration may also be effected by means of subcutaneous or intra-muscular injection.
  • Such compositions may be conveniently prepared by dissolving solid active ingredient in water to produce an aqueous solution, and rendering said solution sterile and isotonic with human blood.
  • compositions of the present invention suitable for topical use include compositions suitable for administration to the skin, eyes, nose and mouth.
  • compositions for use on the skin include lotions and creams comprising liquid or semi-solid emulsions, ei ther oil-in-water or water-in-oil, which preferably contain from 0.2 to 5 w/v of the active ingredient.
  • Ointments comprising 0.2 to 5 percent w/v of the active ingredient dissolved or dispersed in a semi-solid basis may also be used for topical administration to the skin.
  • the semi-solid basis contains liquid or semi-solid hydrocarbons, animal fat, wool alcohol or a macrogol, possibly with an emulsifying agent.
  • the creams and ointments should contain a preservative such as methyl hydroxybenzoate.
  • compositions for administration to the eye include eye drops comprising the active ingredient in aqueous or oily solution, preferably at a concentration of 0.2 to 5 percent w/v.
  • Such solutions are desirably fungistatic and bacteriostatic and are preferably prepared sterilev
  • Compositions for administration to the eye also include eye ointments which preferably comprise the same concentration of active ingredient, conveniently in the form of a salt, either dissolved in one of the ingredients of the semi-solid basis of the ointment or as a finely divided suspension therein.
  • compositions suitable for administration to the nose include powder, self-propelling and spray compositions similar to those already described under compositions suitable for pulmonary administration but having when dispersed, a somewhat larger particle size of the order of 10 to 200 microns.
  • this effect may be achieved by choice of a valve having the desired spray characteristic i.e. being capable of producing a spray having the desired particle size or by incorporating the medicament as a suspended powder of controlled particle size.
  • Other compositions suitable for nasal administration include a coarse powder having a particle size of 20 to 500 microns which is administered in the manner in which snuff is taken i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Another composition suitable for nasal administration is nasal drops comprising 02 to 5 percent w/v of the active ingredient in aqueous or oily solution.
  • compositions suitable for topical administration in the mouth include lozenges comprising 10 to mg. of the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; and pastilles comprising 10 to 100mg. of the active ingredient in an inert basis such as gelatin and glycerin; or sucrose and acacia.
  • bronehodilators suitable for inclusion in the hereinbefore described compositions, especially in the case of those compositions intended for use in the treatment of allergic asthma.
  • Any bronchodilator may be used in such a composition although particularly suitable bronchodilators are isoprenaline, adrenaline, orciprenaline,isoethanine and physiologically acceptable acid addition salts thereof, especially isoprenaline sulphate.
  • the bronehodilator is present in the compositionin an amount of 0.1 to 50 percent w/w of the weight of active ingredient present.
  • compositions comprising a compound of formula I as defined hereinabove in asso ciation with a pharmaceutically acceptable carrier therefor.
  • compositions comprising a compound of formula I as defined hereinabove as an active ingredient, by any conventional method, including admixture of the ingredients.
  • a method of treatment or prophylaxis of mammalian allergic conditions comprising administration of a therapeutic or prophylactic dose respectively, of a compound of formula I as defined hereinabove.
  • Diphenyl sulphone-2,5dicarboxylic acid (156.8 g.) was stirred withtetraphosphoric acid (ca.3,300 g.) and phosphorus pentoxide (ca.330 g.) at 220 to 230C for 20 minutes, cooled, and poured onto ice-water with stirring. The precipitated solid was filtered off under suction, washed well with water and dried at 100C. The total product was recrystallised from aqueous dimethyl formamide, filtered at the boil. The product separated as beige crystals. These were first dried at 100C, then under vacuum at ca.
  • Preparation dioxide A mixture of thioxanthone-3-carboxylic acid (0.120 g), acetic acid (6.0 m1) and 30 percent hydrogen peroxide (0.12 ml) was boiled under reflux for 15 hr. filtered while hot, and allowed to cool. The product crystallised out slowly. It was filtered off and dried at 110C, m.p. 285-287C.
  • tricarboxylic acid 2,4,4-Trimethyldiphenyl sulphone (32.0g.) was heated with 35 percent nitric acid (200 ml.) in an autoclave to 175C over 1.5 hr. This temperature was main tained for a further 075 hr. After cooling the solid product was filtered off, washed with water, recrystallised from aqueous dimethylformamide, and driedat 1 C, giving diphenyl sulphone-2,4.4tricarboxylic acid m.pt. 352-353C with decomposition.
  • Diphenyl sulphone-2,4,4-tricarboxylic acid (8.50g.) was heated with polyphos phoric acid 127g.) at 290C for 0.5 hr. with stirring. The dark syrup was cooled and decomposed with water overnight. The dark solid product was filtered off and recrystallised twice from dimethylformamide to give 2,7-dicarboxythioxanthone- 10,10-dioxide, m.pt. 372375C with decomposition.
  • the acid 109g) was boiled with thionyl chloride (ca. 10 ml) for 1 hr. and the excess thionyl chloride was evaporated off.
  • the residual acid chloride was recrystallised from toluene, then hydrolysed by boiling with excess sodium hydroxide. Acidification gave the acid, which was recrystallised from acetic acid and dried at 156C. in vacuo, m.p. 276284C. pure by thin layer chromatography.
  • EXAMPLE 4 7- Ethyl3-( S-tetrazolyl )thioxanthonel 0. 1 0 dioxide
  • 3-Cyano-7-cthylthioxanthone 7Ethylthioxanthone-3-carboxylic acid (607g) was boiled under reflux in thionyl chloride (40ml) containing dimethylformamide 1 drop). The thionyl chloride was distilled off and the residual acid chloride treated with 0.880 ammonia 140 ml). The mixture was boiled for 20 minutes. cooled, and the amide filtered off and dried. To a solution of the amide in dimethylformamide ml) cooled to 30C.
  • EXAMPLE 7 4-Carhoxythioxanthone-l0,10-dioxide
  • Cupric o-chlorobenzoate o-Chlorobenzoic acid 31 .3g was dissolved in a solution of sodium hydroxide (8.0g) in water (250 ml) and the warmed solution filtered and treated with a solution of cupric sulphate pentahydrate (25.0g) in water (200 ml). The precipitated blue-green solid was filtered off, washed with water, and dried to give cupric chlorobenzoate, m.p. 259C, with decomposition.
  • Cupric complex of thiosalicylic acid Thiosalicylic acid (30.8g) was added to a solution of sodium hydroxide 16.0g) in water (300 ml) and to the resulting solution was added a solution of cupric sulphate pentahydrate (50.0g) in water (30 ml). The precipitated black complex was filtered off, washed with water and ethanol, and dried.
  • C. Diphenyl sulphide 2,2'-dicarboxylic acid A mixture of cupric o-chlorobenzoate (282g), thiosalicyclic acid cupric complex (32.4g) and dimethylformamide (450 ml) was boiled under reflux for 2 hr.
  • the dull green precipitate was filtered from the cooled mixture and allowed to stand overnight in 2N. hydrochloric acid (200 ml). The product was filtered off, washed with water, and heated with normal sodium hydroxide solution (400 ml). A black residue was filtered off and the filtrate acidified to precipitate diphenyl sulphide 2.2-dicarhoxylic acid which was filtered off. washed with water and dried, m.p. 232-234C. A sample recrystallised from acetic acid had m.p. 236C.
  • EXAMPLE 8 4-(S-Tetrazolyl)thioxanthone- 10, 1 O-dioxide
  • 4-Cyanothioxanthone-10,10-dioxide 4-Carboxythioxanthonel 0, l O-dioxide (2. g) wa boiled with thionyl chloride ml) containing 1 drop of dimethylformamide for 10 min., cooled and evaporated. The residual acid chloride was treated with 0.880 ammonia (30 ml.) and warmed on a steam bath for 10 min. The solid amide (1.75g) was filtered off and dried (m.p. 252254C).
  • p-Chlorophenylsulphonylterephthalic acid p-Chlorophenylthioterephthalic acid (2.0g), acetic acid (20 ml) and 30 percent hydrogen peroxide (2.0 ml) were boiled together under reflux for 30 min. Further peroxide (2.0 ml) was added and boiling continued for a further 30 min. The solution was partially evaporated, diluted with water, and the precipitated pchlorophenylsulphonylterephthalic acid filtered off and recrystallised from aqueous acetic acid m.p. 270272C. D.
  • 2-(p-Chlorophenylthio-4-(S-tetrazolyl)benzonitrile p-Chlorophenylthioterephthalonitrile (328g), sodium azide (0.78g), ammonium chloride (0.65g) and dimethylformamide (30 ml) were heated together on the steam bath for 16 hr. The mixture was cooled and poured into dilute hydrochloric acid. The oil which precipitated and solidified slowly was dissolved in sodium bicarbonate solution and the solution extracted with chloroform to remove unchanged starting material.
  • the warm solution was acidified with hydrochloric acid and the precipitated 2-( p-chlorophenylthio )-4-( tctrazolyl)benzoic acid filtered off, washed with water and dried, decomposes at 245C.
  • EXAMPLE l6 3-Carboxy-7-methoxyhioxanthone'l0,10-dioxide
  • p-Methoxyphenylthioterephthalonitrile Sodium (4.66g) was dissolved in methanol ml) and p-methoxythiophenol (28.3g, prepared by the method used for p-ethylthiophenol) was added. The solution was evaporated to dryness and the residue dissolved in dimethylsulphoxide (200 ml). Nitroterephthalonitrile (349g) was added, and the resulting solution heated on the steam-bath for 1 hr.

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4012517A (en) * 1975-01-24 1977-03-15 Burroughs Wellcome Co. Compositions and treatment
US4012516A (en) * 1975-01-24 1977-03-15 Burroughs Wellcome Co. Pharmacologically active compositions
US4221800A (en) * 1977-12-23 1980-09-09 Miles Laboratories, Inc. Cycloalkenochromone
US4237160A (en) * 1979-11-27 1980-12-02 Merck Sharp & Dohme (I.A.) Corp. 3-Hydroxymethyldibenzo[b,f]thiepins as prostaglandin antagonists
US4377579A (en) * 1981-12-03 1983-03-22 Minnesota Mining And Manufacturing Company N-(Tetrazol-5-yl)phenazine-1-carboxamides
US4394515A (en) * 1978-06-23 1983-07-19 Merck & Co., Inc. 10,11-Dihydro-11-oxodibenzo[b,f]thiepin compounds
US4432986A (en) * 1979-06-18 1984-02-21 Riker Laboratories, Inc. Tetrazoles bonded to certain polycyclic aromatic systems and anti-allergic use thereof
EP0150891A1 (en) * 1984-01-05 1985-08-07 The Wellcome Foundation Limited Tricyclic compounds, processes for their preparation, compositions containing such compounds and their use in medicine
US4535171A (en) * 1982-11-18 1985-08-13 Merck Frosst Canada, Inc. Dibenzo[b,f]thiepin-3-carboxaldehydes as prostaglandin antagonists
US4536507A (en) * 1977-07-26 1985-08-20 Merck & Co., Inc. Prostaglandin antagonists
US4616032A (en) * 1984-01-05 1986-10-07 Burroughs Wellcome Co. Use of nitrogen heterocyclic compounds

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH628343A5 (en) * 1977-03-24 1982-02-26 Sandoz Ag Process for preparing thioxanthones
FR2419282A1 (fr) * 1978-03-09 1979-10-05 Labaz Nouveau derive de benzonitrile, son procede de preparation et son application
CH640849A5 (de) * 1979-05-18 1984-01-31 Ciba Geigy Ag Thioxanthoncarbonsaeureester, -thioester und -amide.
NL8005946A (nl) * 1979-11-02 1981-06-01 Hoffmann La Roche Middelen tegen vetzucht en verhoogde vetspiegel.
US4731363A (en) * 1979-12-26 1988-03-15 Hoffmann-La Roche Inc. Thromboxane synthase inhibitors as insulin lowering agents and antiobesity agents
US4500540A (en) * 1979-12-26 1985-02-19 Hoffmann-La Roche Inc. Thromboxane synthase inhibitors as insulin lowering agents and antionbesity agents
JPS5716821A (en) * 1980-07-04 1982-01-28 Yoshitomi Pharmaceut Ind Ltd Remedy for disease due to immunological dysfunction

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US3096343A (en) * 1960-07-20 1963-07-02 Du Pont Method for isolating aromatic carboxylic acids
US3597420A (en) * 1969-02-17 1971-08-03 Sterling Drug Inc Tertiary-amino-lower-alkoxy-9-benzylidene-xanthenes and thioxanthenes
US3642997A (en) * 1969-06-25 1972-02-15 Merck & Co Inc Tricyclic carboxylic acids in the treatment of inflammation
US3706768A (en) * 1969-11-27 1972-12-19 Allen & Hanburys Ltd Xanthone derivatives

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US3096343A (en) * 1960-07-20 1963-07-02 Du Pont Method for isolating aromatic carboxylic acids
US3597420A (en) * 1969-02-17 1971-08-03 Sterling Drug Inc Tertiary-amino-lower-alkoxy-9-benzylidene-xanthenes and thioxanthenes
US3642997A (en) * 1969-06-25 1972-02-15 Merck & Co Inc Tricyclic carboxylic acids in the treatment of inflammation
US3706768A (en) * 1969-11-27 1972-12-19 Allen & Hanburys Ltd Xanthone derivatives

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4012517A (en) * 1975-01-24 1977-03-15 Burroughs Wellcome Co. Compositions and treatment
US4012516A (en) * 1975-01-24 1977-03-15 Burroughs Wellcome Co. Pharmacologically active compositions
US4536507A (en) * 1977-07-26 1985-08-20 Merck & Co., Inc. Prostaglandin antagonists
US4221800A (en) * 1977-12-23 1980-09-09 Miles Laboratories, Inc. Cycloalkenochromone
US4394515A (en) * 1978-06-23 1983-07-19 Merck & Co., Inc. 10,11-Dihydro-11-oxodibenzo[b,f]thiepin compounds
US4432986A (en) * 1979-06-18 1984-02-21 Riker Laboratories, Inc. Tetrazoles bonded to certain polycyclic aromatic systems and anti-allergic use thereof
US4237160A (en) * 1979-11-27 1980-12-02 Merck Sharp & Dohme (I.A.) Corp. 3-Hydroxymethyldibenzo[b,f]thiepins as prostaglandin antagonists
US4377579A (en) * 1981-12-03 1983-03-22 Minnesota Mining And Manufacturing Company N-(Tetrazol-5-yl)phenazine-1-carboxamides
US4535171A (en) * 1982-11-18 1985-08-13 Merck Frosst Canada, Inc. Dibenzo[b,f]thiepin-3-carboxaldehydes as prostaglandin antagonists
EP0150891A1 (en) * 1984-01-05 1985-08-07 The Wellcome Foundation Limited Tricyclic compounds, processes for their preparation, compositions containing such compounds and their use in medicine
US4616032A (en) * 1984-01-05 1986-10-07 Burroughs Wellcome Co. Use of nitrogen heterocyclic compounds

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GB1447031A (en) 1976-08-25
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CH616423A5 (enrdf_load_stackoverflow) 1980-03-31
IL42311A0 (en) 1973-07-30
AR210245A1 (es) 1977-07-15
IE37646B1 (en) 1977-09-14
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CA1024987A (en) 1978-01-24
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IL50000A0 (en) 1976-09-30
IL50000A (en) 1978-03-10
DE2325300A1 (de) 1973-12-20
NL7306958A (enrdf_load_stackoverflow) 1973-11-21
IL42311A (en) 1978-03-10
AR209311A1 (es) 1977-04-15
JPS4948657A (enrdf_load_stackoverflow) 1974-05-11
FR2185407B1 (enrdf_load_stackoverflow) 1977-08-19
AU5595973A (en) 1974-11-21
FR2300088B1 (enrdf_load_stackoverflow) 1980-04-25
DD108539A5 (enrdf_load_stackoverflow) 1974-09-20
ATA435573A (de) 1976-08-15
ES414888A1 (es) 1976-06-01
IE37645B1 (en) 1977-09-14
IE37645L (en) 1973-11-19
AR206633A1 (es) 1976-08-06
LU67622A1 (enrdf_load_stackoverflow) 1973-11-23
FR2293198B1 (enrdf_load_stackoverflow) 1979-06-29
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