IL43160A - 2-(1h-tetrazol-5-yl)-fluorenone xanthenone and acridone derivatives their preparation and pharmaceutical compositions containing them - Google Patents

Description

43160/2 l a^naaop ,†i:n,i«iVB-( &-5- iT*snBB-!B )-2 n acin 2-(IH-Ietra2ol-5-yl)"-fl oranone, xanthenone and acridozie derivatives^ their preparation and pharma.ce tieal compositions containing them TEE /EHCOHB FOUNDATION LIMITED C. 4X292 43160/2 The invention relates to tricyclic compounds havin^^ their adaptation for medicinal use.

It has been found that 2- (lH-Tetrazol-5-yl) - , fluorenone, xanthenone, and acridone derivatives, of "formula~I def ned" hereinbelow are active' in"mammaIs 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. at least one of Z and Z is a 5-(1-R) tetrazolyl or a 5-(2-R)tetrazolyl group wherein R is hydrogen or .alkyl having 1 to 6 carbon atoms, and the other is selected from carboxy, alkoxycarbonyl, carboxamxdo optionally substituted by one or two alkyl groups, 5- (1-R) tetrazolyl and 5-(2-R)tet-razolyl where R is as defined above; 3 Z represents a bond or is oxygen, or a group NR^ wherein ^ is hydrogen or alkyl having 1 to 4 carbon atoms; and 43160/2 when Z represents a bond or is NR as defined, 2 3 is also selected from hydrogen, nitro, halogen preferably chlorine or bromine, alkyl or alkoxy wherein the "alkyl" moiety of each of the alkyl and alkoxy groups has 1 to 6 carbon atoms; and salts of said compounds.

The compounds of formula I include 2-Z1, 7-Z2-f1uorenones, 2-Z1,6-Z2-xanthones , 2-Z1,6-Z2- 1 2 acridones and 2-Z , 7-Z -H-alkylacridones in which 1 2 compounds at least one of Z and Z is 5-tetrazolyl and the other is selected from 5-tetrazolyl and caboxy, alkoxycarbonyl, carboxamxdo optionally substituted by one or two alkyl groups and salts of said compounds.

The alkyl moieties of the alkoxy carbonyl groups of of the mono- or dialkylcarboxami.de groups, have 1 to 6 carbon atoms.

The inhibition- activity of the compounds 'of formula I has been demonstrated (a) in tests using the response of pass-i-v -GUtaneous-anaphyJLax.Ls_{PCA test) in v;hich is measured the skin reaction produced as the result of interaction between specific antigen injected intravenously and cell-fixed reaginic a antibody previously injected into the skin of/mammal (see for example Z. Ovary: Fedn. Proc. Am. Soc. exp. Biol. 2A , 94 (1965)), (b) by measurement of the amount of histamine released after antigen ' challenge of peritoneal mast cells from actively sensitised rats (see for example", 1. Acta Pharmacol, et T0XXCO~1T" 30, supp. 1 (1971), 2. Thorax, 27/1, 38 (1972), and (c) , by measurement of the histamine released from human chopped lung tissue passively sensitised in vitro with reaginic antibody when challenged with the homologous antigen (Br. Med. J. 3,272 (1968)). The activity of acids of formula I has been demostrated as desc ib - here^mabove^s-ii¾g--soiutions— of the carboxylate anion.

For the sake of conveJie^ce,_ compounds of formula I 1 2 _ wherein either of Z and Z is~an alkoxycarbonyl~gfoup, shall hereinafter be referred to as "esters" of formula I. Similarly references to "amides" of formula I shall be construed as references to compounds of formula I wherein one of Z1 and Z2 is an optionally mono- or dialkyl substituted carboxamide, and references to "salts" of formula I shall mean compounds of formula I wherein one or 1 2 both—of—Z~~and-Z—■» F—r-f>rbr y1 ntr nr tctrazolyl rait group Pharmaceutically acceptable salts of formula I include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth salts such as magnesium and calcium salts, triethanolamine and diethylami noeth Inline salts, and piperazine and morpholine salts. Especially valuable water soluble salts of formula I most preferably those having a solubility in v/ater of at le t 1 mg/ml.

The anti-allergic activity of the salts of formula I lies in the anion and the nature of the. cation docs not contribute to the activity, but for medicinal purposes the cation must of course be pharmaceutically acceptable .

Pharmaceutically acceptable cations in compounds of formula ' I " include hydrogen, ammonium, alkali metal cations such as sodium and potassium, alkaline earth metal cations such as calcium and magnesium and organic base cations for example, alkylammonium cations of such alkyla ines as triethanolamine and diethylaminoethvlamine, piperazinium and morpholinium cations.

Suitable substituted carboxamide groups include N-alkyl and Ν, -dialkyl substituted carboxamide groups wherein the alkyl moiety is an ' alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

Preparation of compounds of formula I may be effected by any method known in the art of preparing them and compounds of analogous chemical structure. In general the compounds 1 2 of formula I wherein one of Z . and Z is a enroot/late as defined above derivative (for example an amide, ester or s'al , are prepared by suitable treatment of the corresponding acid. However, in certain circumstances it is possible to prepare such derivativ without prior isolation of the carboxylic acid, either by the choice of suitable reactants or by forming the desired derivative in a reaction mixture of the acid, without first isolating the acid. j Methods for the preparation of compounds I and salts of formula/are described hereinbelo , but it will be understood that in some instances the methods may be adopted to yield the corresponding esters. or amides of formula • 1. Hydrolysis of a compound of formula If herein / ' is a carboxyl group precursor, such as a £ ts.i & group, trichloror.ethyl-~group or a group COL1 wherein L1 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; and the other •of Y and Y is .the group Z or Z. , as appropriate,- -as-defined in formula I; /and Z has the meaning defined in -formula I. Hydrolysis is conveniently effected by heating a compound of formula II with a dilute aqueous alkali, or with a dilute aqueous one may use dilute sulfuric acid, dilute hydrochloric acid with acetic acid, or dilute aqueous sodium hydroxide solution Hydrolysis with aqueous alkali will yield inter al ia an aqueous solution of a ^d-icarboxylave salt but if it is desired to collect the maximum ariount of .carboxylic acid, then the reaction mixture should be acidified when hydrolysis is completed to precipitate the acid. On the other hand if the desired end-product is the carboxylase salt, then following hydrolysis,, the cation of the desired salt may be added to precipitate the desired salt by the common ion effect without prior isolation of the corresponding acid.

By means of nucleophilic substitution reactions analogous to hydrolysis, for example, alc h.olysis and ammonolysis, compounds of formula I other than the carboxylic acid may be prepared directly from compounds of formula II', Thus reaction of a compound of formula II with an appropriate alcohol yields an ester of formula I, and reaction with ammonia or an appropriate primary or secondary amine yields an amide of formula I. 2. Cyclisation of a compound of formula III wherein Z , Z. and Z have the meaning defined -in formula I andQ is a hydroxy 1, alkoxy or an optionally substituted amino group, a halogen atom, or a RCO„ group , a -ROC0 aroup or a R " RS03 group wherein^is alkyl or aryl. Cyclisation may be effected by heating a compound of formula IIX at an elevated . tteemmppeerraattuurree,, ffoorr eexxaammppllee uupp ttoo aabboouutt 330000 CC«« PPrreeffeerraabbllyy hheeaattiinngg iiss ccaarrrriieedd oouutt iinn tthhee pprreesseennccee ooff aa LLeevv//iiss aacciidd uunnddeerr aannhhyyddrroouuss ccoonnddiittiioonnss oorr aa pprroottoonniicc aacciidd,, ooppttiioonnaallllyy iinn tthhee pprreesseennccee ooff aa nnoonn--ppoollaarr ssoollvveenntt.. PPrreeffeerrrreedd LLeewwiiss aacciiddss iinncclluuddee bboorroonn ttrriifflluuoorriiddee aanndd aalluummiinniiuumm ttrriicchhlloorriiddee aanndd pprreeffeerrrreedd pprroottoonniicc aacciiddss iinncclluuddee ssuullpphhuurriicc,, hhyyddrroocchhlloorriicc aanndd ppoollyypphhoosspphhoorriicc aacciiddss J. 2 2 I Iff,, hhoowweevveerr,, ZZ iiss aa ccaarrbbooxxyyllaattee ssuubbssttiittuueenntt iinn tthhee 55--ppoossiittiioonn ooff tthhee nnaasscceenntt ccoommppoouunndd ooff ffoorrmmuullaa II,, rreeaaccttiioonn ccoonnddiittiioonnss aanndd//oorr tthhee ggrroouupp QQ mmuusstt bbee cchhoosseenn ssoo aass ttoo aavvooiidd rreeaaccttiioonn ooff tthhee ggrroouupp 2 Z The intermediate compounds -of-formula'- IV iay be prepared by the reaction of a suitable monohydric phenol compound of formula v/herein X is a cyano >or a carbalkoxy* group, with a suitable activated mono-nitrcphenyl compound of formula ' VI cyano wherein X2 and X are each a v&^ziL&. or carbalkoxy gro so as to produce a diphenyl ether 6f formula VII 1 2 3 wherein X , X and X have the same meaning as above. The reaction is effected in a dipolar aprotic solvent such as dimethyl sulfoxide, dimethyl acetamide, N-methyl-2-pyrrolidone sulfolane, hexamethylphosphoramide, dimethyl forma ide and acetonitrile , at an elevated temperature of from 50 to 1S0°C preferably from 100 to 120°C. In the case of compounds of formula VII wherein the groups X 1 and X3 are the same 1 2 as groups Z and Z as previously defined and v/herein the 2 group X is the same as the group C(:0)Q as defined in formula IV ,no further reaction prior to cyclisation is required.

In the case of other compounds of formula VII , for example, 1 2 *? those wherein one or more of the group X , X and X is a cyano ft-i-fe-jf-i-l-e- group , the said other compounds are hydrolysed so as to yield a compound of formula IV wherein Q is a hydroxyl group or an amino group. Hydrolysis is conveniently effected by heating a compound of formula VII v/ith dilute aqueous mineral acid optionally in the presence of an organic acid, or with dilute aqueous alkali. 3. Oxidation of a compound of formula VIII wherein one of W and W is a lower alkyl group or a group C(:0)R wherein R. is an optionally substituted lower alkyl group having 1 to Ί carbon atoms, or is OH, and the other of v 1 and is ? or Z^, as appropriate, as defined in formula I; andΪ'Ρ is as defined in formula I. Oxidation of compounds wherein 1 and/or VJ2 are lower alkyl groups may be effected with such conventional oxidising agents as acid or alkaline aqueous potassium permanganate solution; chromium trioxide, for example, v/ith acetic acid or sulphuric acid; oxygen in the presence of a conventional catalyst such as lead, cobalt and manganese salts, for example, lead acetate; or aqueous solutions of sodium dichromate. 1 2 / is \ Oxidation of compounds wherein W or W the groups C(:0)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; These oxidation procedures are advantageously effected with heating wherein Z and Z have the meaning defined hereinbefore in 3 3 formula I, Y is a group Z as defined hereinbefore in formul 4 " I and Y is of formula IX wherein Z and Z have the meaning defined hereinbefore in 6 7 formula I,. X is a group CH and X is a nitrogen atom.

Oxidation of compounds of formula IXa and IXb may be effected .with such conventional oxidising agents as nitric acid; aqueous solutio of hypochlorous and hypobromous acids in the presence of base chromium trioxide, for example with acetic acid or with sulphuric acid; or aqueous solutions of sodium dichromate. 4 Oxidation of compounds of formula IXa wherein Y is a 3 methylene group and Y is a bond, oxygen or NR wherein R is alkyl having 1 to 4 carbon atoms, ., may also be effected with such convention .oxidising agents as oxygen in the presence of triton B in pyr dine solution; or oxygen in the presence of potassium t-butoxide in the presence of t-butanol and dimethylsulphoxide.

Compounds analogous to the compounds of formula IXa or I 1 2 1 2 wherein either of Z and Z is replaced by a group W or , as appropriate, as defined in formula VIII, may also be oxidi so as to produce carboxylic acids or salts of formula I.

Oxidation in the case of such compounds may be effected with such conventional oxidising agents as chromium trioxide, for . . wherein of , ^ compounds ' / ncithcr/W and V.' * is al yl, oxidation may also be effected with such conventional oxidising agents as aqueous solutions of salts of hypobromous or hypochlorous acids in the presence of a base; or nitric acid. Advantageously any of the hereinbefore described oxidation procedures wherein aqueous solutions of sodium dichrornate are employed, are carried out at an elevated temperature in a sealed container. Oxidation 1 2 of the groups V?" and W' in such a case is preferably . effected at a temperature of from 200 to 2 0°C. Oxidation of the xanthone nucleus in such a case is preferably effected at a temperature of from 240° to 260°C. Oxidation of the tricyclic anthracene; 9 , 10-dialkyl anthracene or t anthrone nucleus in such a case is desirably effected at a temperature of from 250° to 260°C. 5.. Cyclisation of a compound of formula( x) wherein Z * and Z have the meaning defined hereinbefore in formula I and Z4 is a hydroxy1 group or a group NHR wherein RJ is hydrogen or alkyl having 1 to 4 carbon atoms and X is a leaving group, for example, a halogen for example chJorine; hydroxy!; D-toluencsulphonyloxy; nitro; or u i hinate.. Cyclisation may be effected by heating a compound of formula (x)wherein X is other than ni Lro .at an elev ed temperature up to about 120 C, in the presence of an alkaline hydroxide such as sodium hydroxide and optionally in the presence of a polar solvent such as water or aqueous ethanol. Where X is a nitro group cyclisation may be advantageously effected in a dipolar aprotic solv.ent such as dimethyl sulfoxide, dimethyl acetamide, -rnethy1-2-pyrrolidone,, sulfolane, hexamethyl-phosphoramide, dimethyl formamide and acetonitrile, at an elevated temperature of from 50 to 150°C preferably from 100 to 120 C.

Alternatively a compound of formula (x ) wherein one of Z1- and Z2 is replaced by a carbox l . : :— group precursor Y1 as defined, hereinbefore, and X is other than nitro, may be simultaneously cyclised and hydrolysed. Such a reaction may be effected by heating such a compound of formula ( ) at an elevated temperature, up to about 120°C in the presence of an alkaline hydroxide such as sodium hydroxide and optionally in the presence of a polar solvent such as water or aqueous -ethanol.

The intermediate compounds of formula(X) may be prepared by a Friedel Crafts reaction between a compound of formula XI wherein Hal is a halogen atom and X and Z have the meaning given in formulaeCx) and Ί respectively, with a compound formula XH wherein Z has the same meaning as in formula(x)» The reaction is effected in the presence of a Lev/is acid such as aluminum chloride, optionally . in the presence of a polar solvent such as nitrobenzene at an elevated temperatur. preferably from 50°C up to the reflux temperature of the reaction mixture.

. Alternatively the intermediate compounds of formula (x) wherein Z^ is a hydrox 1 group may be prepared by heating the appropriate compound of formula wherein Z ,7, and X are as defined in formula ( ^ , the presence of a Lev/is acid such as aluminum chloride, optionally in the presence of a non-polar solvent such as nitrobenzene or tetrachloroethane, at an elevated temperature from 50°Cu to the reflux temperature of the reaction mixture. Under such conditions compounds of formulaxui rearrange to the corresponding compounds of formulaCxl- N-alkyl acridone esters of formula I may also be prepared by alkylation of corresponding acridone compounds ^ of formula I. Alkylation may be effected by any convent.! onal " process for alkylation of secondary amino groups, for example, 5 by reaction v/ith a group RX wherein K is alkyl having 1 to 6 5 carbon atoms and X is a leaving group such as a halogen atom, in the presence of a strong base. Suitable bases are sodamide and sodium hydride. Desirably alkylation is effected in the presence of a solvent which includes dimethyl sulphoxide xylene, or liquid ammonia. · .

The compounds of formula I may also be prepared by formation of a 5-tetrazolyl group as the final step. Thus in formula I wherein one or both of Z 1 and Z2 are tetrazolyl or (1-alkyl )tetrazolyl groups, these compounds may be 5 prepared by reaction of hydrazoic acid or a salt thereof or hitrous acid v/ith an appropriate compound of formula XIV wherein I is a group Z as defined in formula I or a tetrazolyl group precursor and Y 8 is a group Z2 as defined in formula 10 (I) or a tetrazolyl group precursor, provided that at least one of is a tetrazolyl group precursor.

When hydrazoic acid or a salt thereof is used, a suitable 15 and R is slkoxy having 1 to 6 carbon atoms ( imidoester) , thioalkyl having 1 to 6 carbon atoms (imidothioester) , -NH -NHg (amidrazone ) , or amino (amidine) or R „3 i,s hydroxy and R^ is amino (amidoxime), qr R^ is alkyl and *" is 5.9.75 for halogen (imidohalide) . In the case of amidoximes and underlined * nitriles, only tetrazolyl compounds may be produced and in mea ifinings the case of imidohalides only alkyltetrazolyl compounds may 1C be produced. The reaction is preferably carried out in a polar aprotic liquid medium using a salt of hydrazoic acid.

When nitrous acid is used, a suitable tetrazolyl precursor group is a group ^- The 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 carborylic acids of formula I and their salts.

The an 2- alkyl)tetrazolyl compounds of formula I may be made from the corresponding tetrazolyl compounds of formula I or their salts by alkylation. 43160/2 Salts of formula I may be isolated from a reaction medium by any conventional process for the isolation of salts from a solution thereof in a polar medium.

Desirably the salts of formula I are purified prior to incorporation in a pharmaceutical composition by any conventional method.

Esters and amides of acids of formula I may be prepared by any conventional method including esteri-fication of the acid or acid chloride with an allcyl alcohol to yield the corresponding alkyl ester respective-ly and reaction of the acid or acid chloride with ammonia amine or a mono- or dialkyl/to yield the corresponding amide or alkyl substituted amide respectively. Compounds 1 2 of formula I where Z and Z are different and are chosen from acid, alkyl ester, amide (optionally mono- or dialkyl-substituted) and salt functions, may be prepared by the above methods, and by partial hydrolysis, where appropriate.

A The compounds of formula I are useful in the treat-ment or prophylaxis of mammalian allergic conditions such as asthma and other allergic chest conditions, hay fever (allergic rhinitis), conjunctivitis, urticaria and eczema. In particular they are of value in reaginic mediated Type I hypersensitivity asthma ('extrinsic asthma') and the so-called 'intrinsic asthma' in which no sensitivity to extrinsic antigen can be shown.

The magnitude of a prophylactic or therapeutic dose of compound of formula I will of course vary with the nature J of 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 v/ithin the range of 2 μg. to 100 mg. per Kg. body weight of a mammal In the case of an allergic condition as defined hereinbefore, for example, allergic asthma, a suitable dosage is from 20 g. to 0".5 mg., for example about 0.1 to 0.5 mg., of a compound of formula I, per Kg. of bodyweight of the patient undergoing treatment, when pulmonary administration as described hereinafter is employed. In the case where a composition for intravenous administration 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 from 1 to 50 mg. of a compound of formula I per Kg. of bodyweight of a patient, preferably from 10 to 40 g/Kg.

In the case where a composition for nasal and ocular administration is employed, for example, in the treatment of allergic rhinitis, a suitable dose is from 0.5 to 25 mg.

The pharmaceutical 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.

Pharmaceutical 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 solution or a suspension in an aqueous liquid, a nonaqueous 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 accessory ingredients Desirably, each discrete unit contains from 50 mg. to 500 mg. of the active ingredient* A valuable form of a pharmaceutical composition of the present invention, for use in the treatment of allergic asthma, is one suitab3e for pulmonary administration via the buccal cavity. Preferably the composition is such that particles having a diameter of 0.5 to 7μ, most preferably 1 to 6μ, containing active ingredient, are delivered into lungs of a patient. Such compositions are conveniently in the form of dry pov/ders for administration from a pov/der inhalation device or self-propelling powder-dispensing containers} preferably the pov/ders comprise particles containing active ingredient of v/hich particles at least 98% by weight have a diameter greater than 0.5μ and at least 95% by number have a diameter less than 7μ. Most desirably at least 95% by v/eight and at least 90% of the particles have a diameter greater than Ιμ/by number of the particles have a diameter less than 6μ.

The compositions in the form of dry pov/ders preferably include a solid fine powder diluent and are conveniently pre- of sented in a pierceable capsule, for example/gelatin.

Self-propelling compositions of the invention may be either powder-dispensing compositions or compositions dispensing the active ingredient in the form of droplets of a solution or suspension. Self-propelling powder-dispensing compositions in- o elude a liquid propellant having a boiling point of below C5 F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% w/w of the composition whilst the active ingredient may constitute 0.1 to 20% w/w, for example, about 2% w/w, of the composition. The carrier in such compositions may include other constituents, in particular a liquid non-ionic or solid anionic surfactant, or a solid diluent (preferably having a particle size of the same order as of the particles of active ingredient) or both. The sur-factant may constitute up to 20% w/w, though preferably it constitutes below 1% w/w of the composition.

Self-propelling composition wherein the active ingredient is present in solution comprise an active ingredient, propellant and co-solvent, and advantageously an antioxidant stabiliser. The co-solvents may constitute 5 to 40% w/w of the composition, though preferably less than 20% w/w of the composition.

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.

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.

Pharmaceutical composition 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, either oil-in-water or water-in-oil , and ointment, preferably containing from 0.2 to 5% w/v of the active ingredient. Desirably 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 and ointments, preferably containing 0.2 to 5% w/v of the active ingredient. The eye drops are desirably fungistatic and bacteriostatic and are preferably prepared sterile.

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. 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 0.2 to 5% w/v of the active ingredient in aqueous or oily solution.

Compositions suitable for topical administration in the mouth include lozenges comprising 10 to 100 mg. of the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising 10 to 100 mg. of the active ingredient in an inert base such as gelatin and glycerin; or sucrose and acacia.

Other therapeutic ingredients suitable for inclusion in the hereinbefore described compositions, especially in the case of those compositions intended for use in the treatment of allergic asthma, include bronchodilators such as isoprenaline , adrenaline, orciprenaline , isoethanine and physiologically acceptable acid addition salts thereof, especially isoprenaline sulphate. Conveniently the bronchodilator is present in an amount of 0.1 to 50%,w/w of the weight of active ingredient Included within the scope of the present invention, but in no way limited thereto, are the following specific features : 1. A compound of formula I as defined hereinabove, where novel. 2. The synthesis of compounds of formula I as defined hereinabove, by any method known in the art for preparing them and compounds of analogous chemical structure. 3. Pharmaceutical compositions comprising a- compound of formula I as defined hereinabove in association with a pharmaceutically acceptable carrier therefor. 4. The preparation of pharmaceutical compositons comprising a compound of formula I as defined hereinabove as an active ingredient, by any conventional method, including admixture of the ingredients.

Set forth belov; are examples of this invention. 1 ¾.

Example jf: 5- (7~Propoxycarbonyl-2-fluorenone) tetrazole ' U a) Dipropyl fluorenone-2 ,7-dicarboxylate (m.p. 146.5 to 148°C.) was prepared from fluorenone-2 , 7-dicarboxylic acid by esterification with propanol in the presence of sulphuric acid. This diester was hydrolysed to the 7-propoxycarbonylfluorenone-2-carboxylic acid (m.p. 250 - 252°C.) using sodium hydroxide in the presence of propanol. This half-ester was treated with thionyl chloride to provide the corresponding acid chloride, and the latter converted to the corresponding amide (m.p. 278 - 279° by treatment with aqueous ammonia. b) 7-Propoxycarbonylfluorenone-2-carboxamide (3.8g.) was dissolved in dimethylformamide (50 ml.) with warming and the soluti was then stirred and cooled to L25°C. Thionyl chloride (7.55 ml was added dropwise over 10 minutes and the mixture was allowed t warm to 0°C, left at this temperature for 60 hours, and then treated with an ice water mixture. The pale yellow solid was filtered, washed with water and dried in vacuo to give 7-propoxycarbonylfluorenone-2-carbonitrile, m. pt. 198-199°C ,c) A portion (2g.) of this nitrile, sodium azide (450 mg.) and ammonium chloride (400 mg. ) in dimethylformamide (20 ml.) were heated to 100°C. , with stirring, for 18 hours. The mixture was cooled, poured into water (200 ml.) and made just acid with 2 hydrochloric acid. "The gelatinous precipitate was filtered, washed with water, and redissolved in aqueous sodium bicarbonate the solution was filtered and then acidified with 2 hydrochlori acid. The resulting solid was filtered, dissolved in 2 aqueous ammonia, reprecipitated with hydrochloric acid and then filtered washed with water and dried in vacuo to give 5- (7-propoxycarbony 2-fluorenone) tetrazole , m.pt. 227-228°C. (decomp.) · Preparation of 2 , 7~Dicyano luorenone ^ A mixture of 2 , 7-dibromofluorenone (14.92 g) and cuprous cyanide (9,35 g) in dimethyiformamide (40 ml) was heated to reflux for 5 hours. The hot mixture was added to a solution of ferric chloride (38. g) in water (57 ml) and concentrated hydrochloric acid (9.5 ml). The mixture was heated on a steam bath for 2 hours, filtered, treated again with a similar aqueous acidic solution of ferric chloride and then filtered, washed well with water and dried in vacuo to give 2 , 7-dicyanofluorenone as a yellow solid m.p. above 300°C.

B. Preparation of 2 , 7-Di (5-tetrazolyl ) luorenone A mixture of 2 , 7~dicyanofluorenone (4.6 g) sodium azide (2.62 g) and ammonium chloride (2.6 g) in dimethylfor amide (25 ml) was stirred and heated to 100°C for 10 hours. The mixture was cooled, treated with an excess of 2N Hydrochloric acid and the solid v/as filtered, washed with v/ater, dried in vacuo and recrystallised from a mixture of dimethylformamide and water. This product was dissolved in an excess of 0.1N aqueous sodium hydroxide, the solution was filtered and acidified with hydrochloric acid. The resulting precipitate v/as filtered, washed with water and _dried in vacuo to give 2 , 7-di-(5~ tetrazolyl) fluorenone, m.p. above 300°C.

Example? : Preparation of 2 ,6-Di- (5-tetrazolyl) xanthone -^ 2 , 6-Dicyanoxanthone (alternative Nomenclature 9-oxaxanthene -2 , 6-dicarbonitrile) , prepared (a) by application of the Sandmeyer process to 2 , 6-diaminoxanthone , or (b) by dehydration of xanthone-2 , 6-dicarboxamide with thionyl chloride in dimethyl formamide at -65°C., was heated in dimethyl formamide with sodium azide (1 part) and ammonium chloride (1 part) at 115°C. for 24 hours. On addition of water and dilute by hydrochloric acid there was obtained 2 , 6-di- (5-tetrazolyl ) xanthone , m.p. >400°, which was insoluble in most organic solvents but which dissolved readily in dilute sodium bicarbonate solution.

Example^ : Preparation of 2 , 6-Di-(5-tetrazolyl) acridone 2,6-Diamino acridone was converted by the Sandmeyer diazotisation process into acridone-2 , 6-dicarbonitrile , m.p. >350°C. To a suspension of sodium azide (0.52g.) and ammonium chloride (0.43g.) in dry dimethyl formamide (10 ml.) was added 0.98g. of the dicarbonitrile after 8 hours heating at 100°C.

The reaction mixture was poured into dilute hydrochloric acid containing ice and the precipitate recovered. Crystallisation from dimethyl formamide gave 2 , 6-di- (5-tetrazolyl) acridone , m.p. >400°C.

By a similar process to Example £, 10-methyl acridone-2 , 7- dicarbonitrile gave lO-methyl-2 ,7-di~ (5-tetrazolyl) acridone , m.p. >400°C.

The dicarbonitrile intermediate was prepared from 2,7-diamino-N-methyl acridone by the Sandmeyer reaction. 6 Example - 5-(7-Butyl luorenoBe-2)-tetrazole A mixture of 7-butylfluorenone-2-carboxylic acid (800 mg), thionyl chloride (5 ml) and dimethylfomamide (2 drops) was heated to reflux for two hours and then evaporated under o reduced pressure. The residue was cooled to 0 C. and treated with .880 aqueous ammonia; the resulting mixture was stirred at room temperature for one hour, then at 100°C, for 15 minutes, and was then cooled and filtered to give 7-butylfluorenone-2-carboxamide,m*p.185- 90°C.

The above amide (650 mg) was dissolved in dimethylformamide (11 ml) and the solution was cooled to -20°C, stirred, and treated dropwise v/ith thionyl chloride (1.5 ml). After stirring for a further 30 minutes at ~20oC< the solution was allowed to attain room temperature over 1 hour and was then poured into ice-water (50 ml). The resulting amorphous product was extracted into chloroform and the chloroform solution was washed well with water, dried over anhydrous sodium sulphate and evaporated. The residual amorphous nitrile was dissolved in dimethylformamide (10 ml), treated v/ith sodium azide (200 mg) and ammonium chloride (180 mg) and heated to 110°C, with stirring, for 20 hours. The mixture was poured into water (50 ml), acidified with hydrochloric acid, and the solid was filtered, washed with water and dried. Recrystallisation from ethanol gave pure 5-(7-butylfluorenon3-2)-tetrazole, m„p. 233- 34°C, (decomp.). -50 7 Example - 5-( 7-B oroo luorenone-2)-tetrazole A mixture of 7-hromofluorenone-2-carboxylic acid (850 mg thionyl chloride ( 5 ml) and dimethylformamide ( 2 drops) was heated to reflux for 4- hours end then evaporated under / reduced pressure7! The residue was cooled bo 0°C. and treated with aqueous ammonia; the mixture was stirred at room temperature for 16 hours and at 100°C for 30 minutes and was then cooled and filtered to give 7- romofluorenone-2-carboxamide , m.p. 270-27zt-°C.

This amide ( 700 rng) was dissolved in hot dimethyl-formamide ( 11 ml) and the solution was cooled to -20°C, stirred, and treated dropwise with thionyl chloride ( 1 .5 ml); a yellow solid began to separate during the addition. The mixture was stirred for a further hour at -20°C, then for 3 hours at room temperature, and then poured onto ice-water ( 50 ml). The yellow solid was filtered, washed well with water and dried to give 7- romofluorenone-2-carbonitrile , m.p. 205-2100C. This nitrile ( 500 mg) in dimethyIformamide ( 10 ml) was treated with sodium azide ( 200 mg) and ammonium chloride (180 mg) and the mixture was stirred and heated to 110°C.for 20 hours. The mixture was then poured into water ( 50 ml), acidified with hydrochloric acid, and the yellow solid was filtered, washed with water and dried to give 5- ( 7-hromofluorenone -2)-tetrazole , m.p. 290-295°0Λ (decomp. ) . £xacr,]? 8 - 3'reo.srnti n of 2,6-".^ -( -tetraaolyl jacridono disodium salt 2,6-Di-( 5-tetrazolyl)acridone (0.2 g) was suspended in water (10 nil) 3nd treated with Ώ aqueous sodium hydroxide solution (1.2 ml). The mixture was evaporated to 5 ml and ethanol added to crystallise out the disodium salt which was dried under phosphorus pentoxide. The salt did not melt at 4-70°C and was hygroscopic.

Example , 9 " : Preparation"of 2- ( 5-tetrazo.1 yl')fluorenone, sodium salt A mixture of 2-cyanofluorenone__( 3 · 68. g. ) sodium azide (1.3 S» ) an(* ammonium chloride (1.17 g^ ) in dime thylformamide (10 ml.) was stirred' and heated to 100° for 10 hrs. The tota reaction mixture was acidified with 2N-hydrochloric acid and the resultant solid was filtered, washed well with water and dried in a vacuum desiccator to give crude (5-(9_oxo-2-fluorenyl )-tetrazole , mp. 271-272°. The crude tetrazole was- converted to a solutioh of the sodium salt for biological testing: a sample (500 mg. ) was treated with 0. l -sodiuro hydroxide (20 ml.) and water ( 0 ml.) and the mixture was stirred at room temperature for 2 hr. , treated with a further amount ( 100 mg. ) of crude tetrazole. stirred again for 2 hr. and then filtered to give a yellow solution containing l8.1 mg./ml. of the sodium salt of 2*- (5-te trazolyl fluorenone.

Example 10 : Preparation of 7-Nitro-2- ( 5-tetrazolvl )fluorenone • ' 1 7-Nitr'o-9-oxo-2- luorenecarbonyl chloride ( 6 g. ) asi c added to 2N aqueous ammonia ( 150 ml.) and the mixture was stirred at room temperature for 3 1"" · The total solid was filtered, washed well wit¾ water, dried and recrystallised from dimethylformamide to give crude 7_Nitro-9-oxo-2-fluorene carboxamide m.p. ~^s* 300° .

This amide ( 1 . 12 mg. ) was dissolved in dimethylformami ( 100 ml.) and the solution was cooled to -5° and thionyl chloride ( 2. 8 ml.) was added dropwise with stirring and stirring was then continued for 2-J hr. at 0°~. The reaction mixture was poured onto a mixture of ice and water and the resultant yellow solid was filtered, washed with water, dried and recrystallised three times from a mixture of dimethylformamide and ethanol to give 2-cyano-7-nitro-9-oxofluorene, m.p. _> 300° .

A mixture of this nitrile ( 200 mg.) sodium azide ( 57 · 2 mg. ) and ammonium chloride ( 5 1. 4 mg. ) in dimethyl-formamide ( 2 ml.) was stirred and heated to 123° for 17 hr. The cooled solution was poured into a mixture of ice and 2N hydrochloric acid and the resultant yellow solid was filtered, washed with water and redissolved in hot 2 aqueous ammonia solution. The solution was filtered, cooled and acidified with hydrochloric acid, th give a yellow solid which was filtered, washed with water and dried. Two recrystallisations from dimethylformamide gave 7-nitro-2-( 5-tet^azolyl )-fluorene-9-one , m.p. 276-277° .

Example A - Po der Capsules for Inha3.at i on 2,6-Di-(5-te razolyl)acridone disodium salt · (0.5-7,0 ym powder) 4 mg Lactose (30-90 m powder) 46.0 mg The powders were mixed until homogeneous and filled into suitably sized hard gelatin capsules, 50 mg of mixture per capsule.

Example B - Injection Solution 2,6-Di-(5-tetrazolyl)acridone mg disodium salt Water for Injections B.P. to 1.0 ml .The disodium salt was dissolved in half of the Water and then made up to volume and sterilised by filtration:' The resulting solution was distributed into ampoules under aseptic conditions . j Example C - Inhalation Aerosol 2 ,6-Di-(5-tetrazolyi)acridone (0.5 - 7.0 μπ powder) 200 mg Sorbitan Trioleate 100 mg Saccharin Sodium (0.5 - 7.0 pm powder) 5 mg Menthol ' 2 mg Trichlorofluoromethane 4.5 g Dichlorodifluoro ethane to 10.0 ml The Sorbitan Trioleate and Menthol v/ere dissolved in the Trichlorofluoromethane. The Saccharin Sodium and the diacid ' were dispersed in the mixture -which was then transferred to a suitable aerosol canister and the Dichlorofluoromethane injected through the valve system. This composition provides &. mg..of Acid in each 100 ui. dose.

Example D - Powder Capsules for Inhalation 2,7-Di- (5-tetrazolyl)fluorenone . (0.5-7.0 μπι powder) 4mg Lactose (30-90 μπι powder) 46.0mg The powders were mixed until homogeneous and filled into suitably sized hard gelatin capsules, 50mg of mixture per capsule.

Example E - Inhalation Aerosol 2, 7-Di- (5-tetrazolyl )fluorenone (0.5 - 7.0 μπι powder) 200mg Sorbitan Trioleate 100mg Saccharin Sodium (0.5 - 7o0 μπι powder) · 5mg Menthol 2mg Trichlorofluoromethane 4.5 g Dichlorodifluoromethane to 10.0ml The Sorbitan Trioleate and Menthol were dissolved in the Trichlorofluoromethaneo The Saccharin Sodium' and diacid were dispersed in the mixture which was then transferred to a suitable aerosol canister and the Dichlorofluoromethane. injected through the valve system. This composition provides 2mg of Acid in each 100μ1. dose. 43160/2.

Claims (20)

1. Tricyclic compounds of the general formula wherein at least one of Z and Z is a 5- (1-R) tetrazolyl or a 5- (2-R) tetrazolyl group in which R is hydrogen or alkyl having 1 to 6 carbon atoms, and the other is selected from carboxy; alkoxy carbonyl, carboxamido optionally substituted by one or two alkyl groups, 5- (1-R) tetrazolyl and 5- (2-R) tetrazolyl where R is as defined above; 3 Z represents a bond or is oxygen, or a group ^ wherein R"^ is hydrogen or alkyl having 1 to 4 carbon atoms; and 3 1 2 when Z represents a bond or is NR as defined, Z may also be hydrogen, nitro, halogen preferably chlorine or bromine, alkyl or alkoxy wherein the "alkyl" mdety of each of the alkyl or alkoxy groups has 1 to 6 carbon atoms ; . and salts of such compounds. 43160/2

2. A compound as claimed in Claim 1 wherein at least one 1 2 of Z and Z is a 5- (1-R) tetrazolyl or a 5- (2-R) tetrazolyl group v;herein R is hydrogen or alkyl having 1 to 6 carbon atoms, and the other is selected from carboxy, alkoxy carbonyl, carboxamido optionally substituted by one or two alkyl groups, 3 5- (1-R) tetrazolyl and 5- (2-R) tetrazolyl as defined; Z is 3 as defined in Claim 1; and when Z represents a bond or is ΈΕΓ as defined, S may also be hydrogen, nitro, chlorine or bromine, alkyl or alkoxy wherein the "alkyl" moiety of each of the alkyl, and alkoxy groups has 1 to 6 carbon atoms; and salts of such compounds.

3. A compound as claimed in Claim 1 or 2 wherei at least 1 2 one of 2 and Z is 5-tetrazolyl and the other is selected from 5-tetrazolyl and carboxy, alkoxy carbonyl, carboxamido optionally substituted by one or two alkyl groups, o salts of said compounds. 3

4. A compound as claimed in Claim 1 or 2 wherein 2 represents a bond or is the grpup HR1 in which R1 is alkyl 2 of 1 to 4 carbon atoms, and Z is hydrogen or is a substituent as defined hereinabove in the 7 - position. \ 3

5. A compound as claimed in Claim 1 o 2 wherein Z is 2 oxygen, or -NH-, and Z is hydrogen or a substituent as defined in the 6 - position. 43160/2

6. A compound as claimed in Claim 4 or 5 wherein at 1 2 least one of Z and Z is 5-tetrazolyl and the other is selected from 5-tetra2olyl and caboxy, alkoxy carbonyl, carboxamido optionally substituted by one or two alkyl groups, or salts of said compounds.

7. 2, 7~Di- (5-tetrazolyl)!fluorenone and salts thereof.

8. 2,6~Di- (5-tetrazolyl) aeridone and salts: theasa& .

9. „ A pharmaceutical composition suitable for use in the treatment of allergic conditions comprising a tricyclic compound as defined in any of Claims 1 to 8 in association with a pharmaceutically acceptable carrier therefor.

10. A composition as claimed in Claim 9 in the form of a powder suitable for pulrtonary administration by inhalation.

11. A composition as claimed in Claim 9 comprising a self-propelling,aerosol composition in a sealed container suitable for dispensing t&e- com o ^ ^s a .powder, solution- or suspension in a form suitable for pulmonary administration.

12. A composition as claimed in Claim 9 in the form of discrete units each containing a predetermined : amount of the compound.

13. A composition as claimed in Claim 12 wherein the units are selected from tablets, capsules, lozenges and suppositories 43160/2

14. A method for making a pharmaceutical composition as claimed in claim 9 ^comprising admixture of the compound with the carrier.

15. # A method for preparing a compound as claimed in any of claims l to 8 wherein one :-a) oxidises with an appropriate oxidising agent a compound of the formula wherein Y is an alkyl group, an acyl group, a carboxyl 1 5 group or a group Z as defined hereinabove ; Y is a group 7i as defined hereinabove or a methylene group and Y is a methylene group or a carbonyl group, and Y is an alkyl group, an acyl group, a 2 carboxyl group o a^group Z as defined hereinabove 1 2 provided that when Y is the same as Z and Y is the 2 4 same as Z , Y is not a carbonyl group; b) when one of Z1 and Z2 is carboxyl, hydrolyses a compound of the formula 43160/2 wherein one of and Y is a carboxyl group precursor and 1 2 the other is Z or Z as appropriate, with an aqueous alkali or aqueous mineral acid optionally in the presence of an organic acid; c) heats a compound of formula wherein Z and Z each have the same meaning as above; J has the same meaning as above"and Q is a leaving group, optionally in the presence of a Lewis acid or a protonic acid; d)*when Z^ is oxygen or NR as defined above, one cyclises a compound of the formula wherein Z and Z have" the same meaning as before, X is a leaving group and Z^ is hydrox 1 or NHI^ as defined above, by heating in the presence of a solvent ; or e) one reacts a compound of the formula ' 43160/2 wherein Ί? is as defined hereinabove, Y is a group Z as defined hereinabove or a tetrazolyl group 8 2 precursor and Y is a group Z as defined hereinabove or a tetrazolyl group precursor, provided ^fchat at least one of 7 o Y' and Y is a tetrazolyl group precursor, with hydrazoic acid or a salt thereof or with nitrous acid, as appropriate; (f) one oxidises with an appropriate oxidising agent a compound of formula , 4 . cajrboxyl wherein X is an alkyl group, an acyl group, a edboxyi-group or a group Z1 as defined hereinabove, X6 is a group CH and X7 is a nitrogen atom; and X5 is an alkyl group, an acyl group, a carboxyl group or a group Z as defined hereinabove. to provide a compound as claimed in any one of claims 1 to 8, and where a salt, amide or ester, or alkyltetrazolyl derivative of said compounds is required, one optionally converts the product of a said reaction to the desired salt ester, or amide or (1- or 2-alkyl)tetrazolyl compound of formula I. j t 43160/2

16. A method as claimed in claim 15(e) characterised in that when one carries out the reaction with hydrazoic acid or a salt thereof the tetrazolyl group precursor is a group -C=N * Λ · ¾ •A '3 wherein Ir and R together form a bond, is h hydrogen or alkyl and R is alkoxy having 1 to 6 carbon atoms, thioalkyl having 1 to 6 carbon atoms, -NH-iE^ or amino, or R^ is hydroxy and R is amino, or is alkyl and R is halogen.

17. A method as claimed in claim 15(e) characterised in that when one carries out the reaction with nitrous acid -C= N the tetrazolyl group precursor is a group wherein R R * ¾ R^ is hydrogen or alkyl and R is - H-NIL, or R^ is hydrogen and R is amino.

18. A tricyclic compound as claimed in Claim 1 whenever prepared by the methods set forth in Claims 15 to 17.

19. A method for preparing a tricyclic compound as defined in Claim 1 substantially as hereinbefore described, with particular reference to the Examples .

20. A method for preparing a pharmaceutical composition of a tricyclic compound as defined in Claim 1 substantially as hereinbefore described, with particular reference to the Examples .