IL43709A - Dioxo benzodipyran-di-carboxamido tetrazole derivatives their production and pharmaceutical compositions containing them - Google Patents

Description

45709/3 jmR o* *3un ntnpn †iis»* £©¾mti¾r©s» ¾¾^JP production and pharmaceutical compositions containing tnem 0. 41835 43709/2 This invention relates to new benzodipyran carboxamido tetrazole compounds.

According to our invention we provide a compound (to called a compound I) in which two chains of formula XX, in which, each pair of Rg and may be the same or different, and Rg and are the same or different and are hydrogen, alkyl CI to 6, al'kenyl C2 to 6, phenyl or phenyl- (alkyl CI to 6) , are attached respectively to two pairs of ortho positions on a benzene nucleus, and pharmaceutically acceptable derivatives thereof. >bre specifically we provide compounds of formula Ix, in which one adjacent pair of P, 0, R and T present a chain of formula XX and th remainder of Q, R and T represent hydronen or an alkoxy group, d RQ and R, n have the same meaning as above.

According to our invention we also provide a process for the production of a compound of the formula Ix, or a pharmaceutically acceptable derivative thereof, which comprises (a) producing a compound of f rmula Ix in which both R10 9rouPs are hydrogen by removing both R.. groups from a compound of formula II, in which Pa, Qa, Ra and Ta have the same significances as P, Q, R and T above, save that an adjacent pair of Pa, Qa, Ra and Ta represent a chain of formula XXb, Rg is as defined above, and R^ represents a group which may be replaced by hydrogen, (b) producing a compound of formula Ix in which each Rg group is hydrogen, by (i) removing both Rj^ groups from a compound of formula VI, in which Pb, Qb, Rb and Tb have the same significances as P, in which is as defined above, and ¾2 rePresents a group which may be replaced by hydrogen, f.ii) cyclising a compound of formula Till, in which Pg, Qg, Rg and Tg have the same significances as P, Q, R and T above, save that an adjacent pair of Pg, Qg, Rg and Tg represent a chain of formula XXe, I NR, 0 10 I XXe -COCH= OCONH-ON, in which RJQ is as defined above, (c) producing a compound of formula Ix in which Rg and are as defined above save that Rg must be hydrogen when RJQ is hydrogen, by reacting a compound of formula III, 43709/2 in which Pc, Qc, Rc and Tc have the same significances as P, Q, R and T above, save that an adjacent pair of Pc, Qc, Rc and Tc represent a chain -C0CH-C(C0OIi)-O-, or an acid halide, an ester or a mixed anhydride of a compound of formula III, with a compound of formula IV, in which R In process (a) and process (b) the group R^ may be, for example, an aralkyl, e.g. a benzyl, E-methoxybenzyl, triphenyl-methyl or diphenylmethyl group; an aroylalkyl, e.g. a phenacyl group; an acyl, e.g. acetyl group; an amino group; or a group -(0112)20, where 0 is an electron withdrawing group, for example a nitrile, a carboxylic ester, e.g. of a lower alkanol, or an acyl group, e.g. an acetyl group.

When represents an aralkyl group the group may be removed either using a hydrogen halide, e.g. HBr, in acetic acid or by catalytic hydrogenation using, for example, a palladium catalyst in a solvent which is inert under the reaction conditions, e.g. acetic acid, or by using sodium in liquid ammonia.

When represents an acyl group, the group may be removed under basic conditions with, for example, sodium hydroxide.

When represents a group -CHgCHgG the group may be removed under basic conditions with, for example, sodium hydroxide.

When Rj^ represents an amino group, the group may be removed by reductive de-amination with, for example, hypophosphorous acid, stannous chloride or sodium in liquid ammonia.

Process (b)(i) may be carried out under the same conditions as specified above for process (a).

R12 ^e Ε00 Rli as described above, but should not of course be the same as Process (b)(ii) may be carried out under basic conditions, e.g. by treating the compound VIII with a mild base such as sodium bicarbonate. Alternatively the cyclisation may be effected at an elevated temperature, for example of from 50 to 150°C, preferably in a solvent which is inert under the reaction conditions, e.g. dimethylformamide.

In process (c) the anhydride is preferably a mixed anhydride of such a type that it will cleave preferentially, to give the desired benzodipyran - or naphthodipyran- carboxamidotetrazole, as the major product when reacted with a compound of formula IV.

Examples of suitable acids from which the mixed anhydride may be derived are sulphonic acids e.g. benzene sulphonic acid, sterically hindered carboxylic acids, e.g. pivalic, isovaleric, diethylacetic or triphenylacetic acid, and alkoxy formic acids, e.g. a lower alkoxy formic acid such as ethoxy or isobutoxy formic acid. When an acid halide is used it may conveniently be an acid chloride. The reaction is preferably carried out under anhydrous conditions in a solvent which will not react with either S "XT the compound of formula IV or the mixed anhydride or acid halide, e.g. pyridine or dimethylformamide. However when the reaction is carried out in a non-basic solvent, e.g. dimethylformamide, an adequate proportion of an acid acceptor, e.g. triethylamine, should also preferably be present. The reaction is preferably carried out at a temperature of from about -15° to +20°C. When an ester is used we prefer to use a lower alkoxy ester and to carry out the reaction in a solvent which is inert under the reaction conditions, e.g. glacial acetic acid, at a temperature of from about 100 to 200°C. When a compound III itself is used the reaction may be carried out by heating the compound III and the compound of formula IV in a solvent which is inert under the reaction conditions, e.g. dimethylacetamide, at a temperature of from 100 to 200°C. Alternatively the reaction may be carried out in the present of a condensation agent, e.g. Ν,Ν'-carbonyl-dii idazole or dicyclohexyl carbodiimide, in an aprotic solvent, e.g. dimethylformamide, at a temperature of from about 10 to 40°C.

In process (d) the cyclisation may be carried out by heating or under basic or neutral conditions. It is, however, preferred to carry out the cyclisation in the presence of an acid, e.g. hydrochloric acid, and in a solvent which is inert under the reaction conditions, e.g. ethanol or dimethylacetamide. The reaction may be carried out at a temperature of from 20 to 150°C.

In process (e) the dehydrogenation may be carried out using a mild oxidising agent, e.g. selenium dioxide or chloranil.

Alternatively the dehydrogenation may be carried out indirectly by halogenation followed by dehydrohalogenation, for example by treatment with N-bromosuccinimide or pyridinium bromide perbromide to yield the 3-bromo derivative, which is subsequently dehydrobrominated. The reaction may be carried out in a solvent which is inert under the reaction conditions, e.g. a halogenated hydrocarbon such as chloroform, xylene or glacial acetic acid. The reaction may be carried out at a temperature of from about 20° to 150°C.

The compounds I may be recovered from the reaction mixture using conventional techniques.

The compounds II may be made by reaction of a compound III, or an acid halide, ester or a mixed anhydride thereof with a compound of formula V, RgNhI _c _N _Rii v N ,N in which g and j^ are as defined above. The reaction may be carried out under the conditions set out for process (c) above. The acid halides, esters and the mixed anhydrides of the compounds III, the compounds iUthemselves, and the compounds of formula IV and V are either known or may be made by methods known for the manufacture of similar known compounds.

The compounds VI may be made by reacting a compound (to be 1° called a coinpound VII) , in which two chains of formula XXg, I 0 -COCH=C-CONH — C — — 2 XXg' N N \ > in which is as defined above, are attached to two pairs of ortho positions on a benzene or naphthalene nucleus, with a compound R^^ l in which Hal- represents a halogen atom and is as defined above. The reaction may be carried out by reacting the compound I VI I with sodium hydride in hexamethylphosphoramide as solvent, and then ' adding the compound ^,jHal, e.g. methyl iodide with stirring at room temperature. Alternatively, when is methyl .the compound VI I may be reacted with diazomethane in a solvent such as (li ethylf orriamide .

The compounds XVII may be made in a manner analogous to the process described above fi>r making compounds VI.

The compounds VII may be made from compounds III by processes analogous to process ( c) above .

The compounds VIII may be made by reacting an acid halide of a compound III with a compound of formula IX, -.Mr- in which is as defined above. The reaction may be carried out in a suitable solvent which is inert under the reaction conditions and in the presence of an acid acceptor, e.g. triethylamine in dimethylacetamide. Alternatively the reaction may be carried out in a basic solvent, e.g. pyridine.

Compounds XII in which Y is -OH may be made by reacting a compound (to be called a compound XIV) in which two pairs of groups -OH and -COCH3 are attached to two pairs of ortho positions on a benzene or nophthalono nucleus, with a compound of formula XV, RxOOCCDRg-^C—N—R10 XV N N in which Rg and are as defined above, and Rx is an alkyl CI to 6 group. The reaction may be carried out under conditions conventional for a Claisen condensation.

Compounds XII in which Y is an -OH group may also be prepared by the action of mild alkali on a compound I. Compounds XII in which Y is a group -L]L2 may be made by the action of an amine HNLjL2 on a compound I.

Compounds XIII may be made by selective hydrogenation of a compound I or by a method analogous to process (c) above using a compound (to be called a compound XVI) in which two chains -(XX^Ol(CQOH)-O- are attached to two pairs of ortho positions on a benzene nucleus, or an acid halide, an ester or a mixed anhydride thereof.

Compounds XIV and XVI and compounds of formula XV are either known or may be made from known compounds using techniques known per se.

Some of the groups P, Q, R, T may be affected by the reaction conditions described above. Where necessary or desirable therefore the reaction may be carried out using protected derivatives of the reagents.

The processes described above may produce the compound Ix or a derivative thereof. It is also within the scope of this invention to treat any derivative so produced to liberate the free compound Ix, or to convert derivative into another. Suitable derivatives include salts and notably water-soluble salts. Salts which may be mentioned include salts with inorganic alkalis, such as the alkali-metal and alkaline-earth metal salts e.g. the potassium, lithium and calcium salts and, notably the sodium salt. Other salts include salts with organic bases,' e.g. bases containing both nitrogen and oxygen atoms. Specifically there may be mentioned salts with alkanolamines, e.g. tri- and di-ethanol amine; hydroxyalkyl-alkylamines, e.g. tri-(hydroxymethyl) methylamino ; 5 or 6 membered nitrogen containing heterocyclic rings,' e.g. morpholine; and N-alkylajnino substituted sugars, e.g. N-methylglucamine.

- XT According to our invention we also provide a process for the production of a pharmaceutically acceptable salt of a compound I which comprises treating a compound I or a salt thereof, with a compound containing an available pharmaceutically acceptable cation, e.g. a base, or with an appropriate salt using a metathetical process.

The compounds I, and pharmaceutically acceptable derivatives thereof, are useful because they possess pharmacological activity in animals; in particular they are useful because they inhibit the release and/or action of pharmacological mediators which result from the in vivo combination of certain types of antibody and specific antigen, e.g. the combination of reaginic antibody with specific antigen. (See Example A below) .

In man, both subjective and objective changes which result from the inhalation of specific antigen by sensitised subjects are inhibited by prior administration of the new compounds.

Thus the new compounds are indicated for use in the treatment of asthma, e.g. allergic asthma. The new compounds are also indicated for use in the treatment of so-called 'intrinsic' asthma (in which no sensitivity to extrinsic antigen can be demonstrated) . The new compounds are also indicated for use in the treatment of other conditions in which antigen-antibody reactions are responsible for disease, for example, hay fever; certain eye conditions, e.g. trachoma; urticaria; and gastrointestinal allergy, especially in children, e.g. milk allergy.

For the above mentioned uses the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered at a dosage of from 0.1 to 50 mg per kg of animal body weight in the test set out in Example A. For man the total daily dosage is in the range of from about 1 mg to 3,500 mg which may be administered in divided doses from 1 to 6 times a day or in sustained release form. Thus dosage forms suitable for administration (by inhalation or oesophageally) comprise from about 0.17 mg to 600 mg of the compound admixed with a solid or liquid pharmaceutically acceptable diluent or carrier.

According to our invention we also provide a pharmaceutical composition comprising (preferably a minor proportion of) a compound I, or a pharmaceutically acceptable derivative thereof, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are:- for tablets and dragees; lactose, starch, talc or stearic acid; for capsules, tartaric acid or lactose; for suppositories and ointments, natural or hardened oils or waxes; for inhalation compositions, coarse lactose. For use in inhalation (and other) compositions the compounds I, or the pharmaceutically acceptable derivative thereof, preferably has a fine particle size of from 0.01 to 10 microns and may if desired be used in combination with a bronchodilator, e.g. isoprenaline.

The compound of fine particle size may be made, for example by grinding or milling. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, sweettming and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form. Compositions for inhalation may also comprise a solution, e.g. iin aqueous solution, of the compound Ix or the pharmaceutically acceptable derivative thereof; or may comprise a mixture of the compound with a liquifyable gas, under pressure, the mixture being put up in a container having a valve adapted to dispense a metered dose.

Those of P, Q, R and T which do not form a chain of formula XX are preferably hydrogen, or lower alkoxy.

We prefer those compounds in which each pair of groups Rg and R1Q are the same. We also prefer Rg and R1Q to be different and to be hydrogen; lower alkyl, e.g. methyl; or phenyl-lower alkyl, e.g. benzyl. Another value of R, and R10 which may be mentioned is allyl. We prefer one of each pair of Rg and R^Q to be hydrogen.

As a specific group of compounds we provide compounds of formula In in which formula Rg and R1Q is as defined above, and Pa and Qa represent hydrogen or alkoxy.

The carboxamido tetrazole groups in compounds Ix in which each Rg group is hydrogen may also exist in the following tautomeric forms, — N -C=N C N — N R. 10 N =N / -C0 =C N H and in the compounds Ix in which each R10 group is hydrogen, in the following tautomeric form, In this specification and in the claims the term 'lower' is used to indicate that the group contains from.l to 6 carbon atoms.

The invention is illustrated, nut in no way limited by the foll wing Examples.

EXAMPLE 1 5-Methoxy-4 ,10-dioxo-4H,lQH-benzo/1 ,2-b : 3 , -h dipyran-2 ,8-cli- N-nv3thyl-N-(tetrazol-5-yl)7 carboxamide. (a) 5- ethoxy-4 ,10- ioxo-4H,l011-benzo/j ,2-b :3,4-hj/Mipyran-2 ,8-di pyridine (20 ml) was added 5-methylamino-] -benzyltetrazole (1.2 gm) in small portions. The mixture was stirred for 2 hours at room temperature, evaporated to dryness in vacuo and the solid residue was washed well with water. The solid was crystallised from ethanol giving 5-methoxy-4,10-dioxo- 4H,10H-benzo/l ,2-b:3,4-b'/dipyran-2,8-di-/N-methyl-N-(1- benzyltetrazol-5-yl/carboxamide as pale yellow needles (0.5 gm) mp 150°C Spectral Characteristics The nmr spectrum in deuterochloroform was consistant with the assigned structure, (b) 5-Methoxy-4t10-dioxo-4H,10H-benzoZ?,2-b:3,4-b^dipyran-2 ,8- di/N-methyl-N-(tetrazol-5-yl)7carboxamide. (i) To a soultion of the dibenzyl product of step (a) (0.2 gm) in. glacial acetic acid (30 ml) containing concentrated hydrochloric acid (5 drops), was added 5¾ Pd/C catalyst (0.1 gm). The mixture was hydrogenated at 60°C with a starting pressure of 45 psi for 24 hours.

The catalyst was removed by filtration and the solvent was evaporated in vacuo. The residue wa washed well with ether and dried giving the required de-benzylated a idotetrazole (0.1 gm). (ii) A solution of the dibenzyl product of step (a) (0.2 gm) in 2 hydrogen bromide/acetic acid (5 ml) was stirred at room temperature for 16 hours. The reaction was quenched with IS 21/A 130 ήί water (30 ml) and the solid was filtered and dried to give the required debenzylated amidotetrazole (0.1 gm).

EXAMPLE 2 5-Methoxy-4,10-dioxo-4H,10H-benzo I,2-b:5,4-bl/dipyran-2 ,8-di-(N-(1-methyltetrazol-5-yl)carboxamide (a) 5-Methoxy-4,10-dioxo-4H,lOH-benzo/l,2-b:3,4-b'Jdipyran- 2,8-di-(N-(1-methyltetrazol-5-yl))carboxamide 5-ffethoxy-4 ,10-dioxo-4H,lC«-benzo/l,2-b:3,4-b|7dipyran-2 ,8- dicarbonyl chloride (jafll.4g) and 5-amino-l-methyltetrazole (7.2g) were mutually dissolved in dry pyridine and the mixture was stirred overnight at 21°C. The solid produced was filtered off, washed with pyridine and sucked dry. This material was triturated with acidified water, filtered off and washed with water, acetone and ether. The solid was dried in vacuo (13.Og), mp 253-258°C. Crystallisation from dimethysulphoxide-water afforded pure 5-methoxy-4,10-dioxo- 4H,10H-benzol,2-b:3,4-b'7dipyran-2 ,8-di-(N-(1-methyltetrazol- 5-yl))-carboxamide, which was refluxed in acetone (150 ml) for 3 hours, filtered off and finally dried at 100°C and O.Oljnm pressure for 24 hours (8.6g), mp 267-268.5°C decomp.

Analysis: Found: C, 45.8; II, 3.2; N, 28.1% Spectral Confirmation The nmr spectrum is hexadeuterodimethylsulphoxide displayed a six proton, singlet resonance at 5.98 "f for the two -.23 - 2.0 N-methyl groups, a three proton, singlet at 5.91 ^ for the 5-methoxy group and three, one proton, singlet resonances at 3.05, 2.97 and 2.80ffor the 3,9 and 6-protons. 5-Methoxy-4,i0-dioxo-4H,1OH-benzo/T,2-b:3,4-bl7dipyran-2 ,8-di-(N-(l-methyltetrazol-5-yl))carboxamide disodium salt. 5-Methoxy-4 ,10-dioxo-4H,10H-benzoZl,2-b: 3,4-b dipyran-2 ,8-di-(N-(l-methyltetrazol-5-yl))carboxamide (7.Qg) and sodium bicarbonate (2.381g) were heated in water (350 ml) at 100°C until complete solution was obtained. The resulting hot solution was filtered and the filtrate was evaporated to dryness in vacuo. The solid residue was triturated with ethanol, filtered off and washed with ethanol and ether. The desired product, 5-methoxy-4,10-dioxo-4H,10H-benzo^I,2-b 3,4-b!7dipyran-2,8-di-(N-(1-methyltetrazol-5-yl))carboxamide disodium salt was obtained as a pale yellow solid after drying in vacuo at 95°C for 24 hours (6.0g).

Analysis: Found: C, 39.7; H, 3.1; N 24.5¾ C19H12N10°7 ^a2 6*6°δ water content requires: C, 39.6; Spectral Confirmation The nmr spectrum in deuterium oxide displayed three, singlet resonances at 6.38, 6.25 and 6.18 for the two N-methyl groups and the 5-methoxy group; and also three, one proton singlets at 3.21, 3.15 and 3.02tfor the 3,9 and 6-protons.

- EXAMPLE 3 5-Methoxy-4^O-dioxo^H.lOH-benzo/1,2-b:3,4-b' dipyran-2 ,8-di-/N-(1-methyltetrazol-5-yl]7carboxamide. (a) To a suspension of 5-methoxy-4,10-dioxo-4H,10H-benzo/I,2-b: 3,4-b dipyran-2,8-dicarbonyl chloride (1.0 gm) in dry di- methylacetamide (20 ml) was added 5-methylaminotetrazole (0.6 gm). This mixture was stirred at room temperature while triethylamine (0.8 ml) was added dropwise after which stirring was continued for 18 hours. The mixture was poured into water (200 ml) and the precipitated solid (0.7 g) was filtered, washed well with hot ethanol and dried. The infra red spectrum of this solid showed a strong band at 2160 cm indicating that the ring opened form (the imino-azide) of the required amidotetrazole had been formed. (b) The solid from part (a) (0.6 gm) was dissolved in saturated aqueous sodium bicarbonate (10 ml) and the solution was heated at 100°C for one hour. The precipitated solid was removed by filtration, washed well with water and dried giving 5-methoxy-4,10-dioxo-4H,10H-benzol,2-b :3,4-bl7dipyran-2 ^e- di-/R-(l-methyltetrazol-5-yl)7carboxamide (0.5 gm) as an off- white solid, m.p. 266-8°C.

Spectral Confirmation The infra red spectrum was superimposable upon that of an authentic sample of this compound (see Example 1). The nuclear magnetic resonance spectra of the two samples in hexadeutero^ 2 - 2fr - dimethylsulphoxide were also identical.

EXAMPLE 4 5-Methoxy-4 t10-dioxo-4H,10H-benzo/l,2-b:3,4-bl7dipyran-2 ,8-di-/ft-(1-benzyltetrazol-5-yl7carboxamide 5-Methoxy-4,10-dioxo-4H,10H-benzoI,2-b:3,4-bl7dipyran-2 ,8-dicarbonyl chloride (10 g) and 5-amino-l-benzyltetrazole (11.7g) were mutually dissolved in N,N-dimethylacetamide (200 ml).

Triethylamine (12.2 ml) was added and the mixture was stirred at 21°C for 18 hours. The mixture was cooled to 0°C and the triethylammonium chloride was filtered off. The filtrate was evaporated to dryness in vacuo to give a red oil. The latter was triturated with dilute hydrochloric acid to afford a white solid. This was filtered off washed with dilute hydrochloric acid, water and finally dried in vacuo. The solid was heated with 10% aqueous sodium bicarbonate solution, filtered off, washed with water, acetone, ether and dried in vacuo to give 5-methoxy-4,10-dioxo-4H,10H-benzo/i,2-b:3 ,4-bl7dipyran-2 ,8-di-/ft-(1-benzyltetrazol-5-ylJ7carboxamide (lOg) as a cream powder, mp 250°C (decomposes without melting) .

Analysis Found : C, 56.0; II, 3.5; N, 21¾ ci3H22Nio°7 Rec^ires : c» 57·5; H> 3*5; N> 21*5 Spectral Confirmation The nmr spectrum in hexadeuterodimethylsulphoxide revealed a three proton, singlet at S.QS't'for the 5-methoxy group; two, two- Ί3 proton, singlets at 4.36 and 4.27¾'for the benzylic methylene groups; three, one proton, singlets at 3.05 , 3.00 and 2.80 f for the 3, 9 and 6-protons and a ten proton, singlet at 2.63 Ύ for the aromatic protons of the benzylic groups. The infra red spectrum displayed intense bands at 3250 (NH str.) cm- , 1655 (4-oxo) cnf and 1590 (aromatic C-C str.) cm"1.

EXAMPLE 5 S- ethoxy^^O-dioxo^H.lOH-benzoZi^-b : 3>4-b'7dipyran-2,8-di-/N-(tetrazol-5-yl)7carboxamide (a) 5-Methoxy-4,10-dioxo-4H,10H-benzo/i,2-b : 5,4-bfJdipyran-2,8- dicarbonyl chloride 5-Niethoxy-4,10-dioxo-4H,10H-benzo/I,2-b : 3,4-b'7dipyran-2,8- dicarboxylic acid (28.0gm) and thionyl chloride (22.4gm) were heated it reflux in dichloroethane (800 ml) containing dimethylformamide (16 drops) for 16 hours. The mixture was cooled and filtered giving white needles of the di-acid chloride, 25.0gm. , m.p. 242-3°C (d).

Analysis: · found: C, 48.9; H, 1.651 C15H6C1207 requires: C, 48.8; H, 1.6% Spectra 1 Confirmation The mol cular weight was shown to be 368 by mass spectrometry.

The i.r. spectrum displayed carbonyl bands at 1760 cm 1 and 1650 cm 1 due to the acid chloride and 4-oxo groups respectively. The n. r. spectrum in deuterochloroform showed three singlets at 2.8~> (H3 and Hg), 3.IT (1¾) and 5.93 f (0CH3) . 2 Purther confirmation of the structure of the acid chloride was obtained by preparatio and characterisation of the bis anilide. (b 5-Methoxy-4.10-dioxo-4Ht10H-benzoT¾2-b : 3,4-bl7dipyran-2,8- di-/N-(tetrazol-5-yl7carboxamide To a stirred mixture of 5-methoxy-4,10-dioxo-4H,10H-benzo/l,2- 1b : 3,4-bl7dipyran-2,8-dicarbonyl chloride (24.0gm.) and anhydrous 5-aminotetrazole (30.0gm.) in dimethylacetamide (200 ml) was added triethylamine (40ml.) . Iiranediate solution occurrd and the mixture was heated at 100°C for 1\. hours after ^hich time precipitation was complete. The mixture was filtered and the residue was washed with hot dimethyl- acetairide and dried under vacuum at 80°C giving 5-methoxy-4, 10-dio Analysis: Found C, 42.0; H, 2.8; N, 29.0% C17H1010°7 with ,1¾ wter requires: C, 42.0; H, 2.6; , 28.8V Spectral Confirmation The i.r. spectrum showed -NH bands from 3500 - 3260 cm amide ,:arbonyl bands at 1720 and 1705 cm ad a strong band at 1660 cm due to the 4-oxo groups. The n.m.r. spectrum in hexadeuterodimcthyl sulphoxide revealed four singlet peaks at 2.95, 3.12, 3.22 and 6.05 that at highest field being due to the methoxyl group. The NH protons gave broad low field signals, (c) 5-Methoxy-4,10-dioxo-4H.10H-benzo^>2-b : 3,4-b dipyran-2,8- di- -(tetrazol-.5-yll7carboxaniide, sodium salt Water (40Qmlr) was added to an intimate mixture of 5-methoxy-4,10-dioxo-4H,10H-benzol,2-b : 3,4-bl7dipyran- 2,8-di- l¾-(tetrazol-5-yl)7 carboxamide (10.25gm.) and sodium bicarbonate (3.70gm.). The solution obtained was cooled in ice and excess ethanol was added causing precipitation of the disodium salt. The solid was filtered and crystallised from a mixture of water and ethanol giving 5-methoxy-4,10- dioxo-4H,10H-benzo l,2-b : 3,4-b7dipyran-2,8-di/ -(tetrazol- disodium salt trihydrate as a yellow solid, lO.Ogm.

Analysis: Found: C, 36.3; H, 2.5; N, 24.7% C17H8N1()Ma207.3H20 requires: C, 36.3; H, 2.45; N, 24.9% Spectral Confirmation The i.r. spectrum showed a broad band at 1700 cm"" due to the amide carbonyls and a similar band at 1660 cm"* due to the 4-oxo carbonyls. The n.m.r. spectrum in hexadeuterodi- methylsulphoxide showed four singlets at 2.65, 3.1, 3.22 and 6.05 ''. That at highest field was due to the methoxyl group.

EXAMPLE 6 5- etJioxy-4,10-dioxo-4H,10H-benzoZI,2-b : 3,4-b!_7dipyran-2,8-di-/R-(tetrazol-5-y37carboxamide, di-triethanolamine salt.

A suspension of 5-methoxy-4,10-dioxo-4H,10H-benzoZl,2-b : 3,4-bI7dip)Tran-2,8-di-/5l-(tetrazol-5-yl7carboxamide (2.S gm) in water (30 ml) was stirred while a solution of triethanolamine (1.60 gm) in water (20 ml) was added. The mixture was heated, to effect complete reaction, filtered and the filtrate was freeze-dried giving the required salt as a yellow powder (3.2 gm, 78%) mp 150-2°C (d).

Analysis: Found: C, 44.58; H, 5.63; N, 21.681 ¾9¾0N12°13 ^Φ*1"68 2«H¾ water content C, 44.58; H, 5.4; N, 21.5%.

'Spectral Confirmation The infra-red spectrum showed bands due to the amide carbonyl at 1700 cm" and the pyrone carbonyl at 1650 cm"*.

The nmr spectrum in hexadeuterodimethylsulphoxide displayed singlets at 2.76, 3.07, 3.2 and 6,0 in the ratio 1:1:1:3 and two triplets at 6.3 and 6.85 due to the methylene groups of the triethanolamine residue.

EXAMPLE 7 5-Methoxy-4qO-dioxo-4H,10H-benzoZI.2-b : 3t4-b7dipyran-2,8-di-iffl-(tetrazol-5-yl)7carboxamide,di-(N-methylglucamine salt) .

To a stirred suspension of 5-methoxy-4,10-dioxo-4H,10H-benzo/l,2-b : 3,4-b'7dipyran-2,8-di-ZN-(tetrazol-5-yl)7- carboxamide (2.5 gm) in water (30 ml) was added a solution of N-methylglucamine (2.095 gm) in water(20 ml). The mixture was heated to effect complete reaction, and was then filtered.

The filtrate was freeze-dried giving the requiredsalt as a yellow powder (4.0 gm, 85%) , mp 140-2°C, (d).

Analysis: Found: C, 43.0; H, 5.3; N, 19.031 ¾¾4Nl2°l7 ^^i1^5 with water content C, 43.0; H, 5.2; N, 19.4¾.

Spectral Confirmation The infra-red spectrum was very broad in the region 3500-2000 cm" (NH and OH stretch) , The amide carbonyls occurred at 1700 cm""1 and the pyrone carbonyls at 1650 cm' . The nmr spectrum in hexadeuterodimethylsulphoxide displayed singlets at 2.6, 3.06, 3.2 and 6.0"Cin the ratio 1:1:1:3. The multiplet at 6.3 - 7.Vtwas due to the protons of the sugar residue.

EXAMPLE 8 5-Methoxy-4,10-dioxo-4H,10II-benzoZI,2-b : 3,4-b7dipyran^2,8-di- R-(tetrazol-5-yl)7carboxamide, calcium salt.

To an intimate mixture of 5-methoxy-4,10-dioxo-4H,10H-benzo !ZI,2-b : 3,4-bl7dipyran-2,8-di-^N-(tetrazol-5-yl)7carboxamide '(10.0 gm) and sodium hydrogen carbonate (3.60 gm) was added water (200 ml). he mixture was heated and stirred until reaction was complete. The mixture was filtered.

A solution of calcium nitrate (3.52 gm) in water (10 ml) was added to the filtrate with stirring at room temperature. After -Sf 2,8 the addition the mixture was cooled in ice and filtered. The solid so obtained was washed well with ethanol and dried in vacuo at 90°C giving the calcium salt as a yellow powder (10.4 gm) , mp > 250°C.

Analysis: Found: C, 32.2; H, 3.2; N, 22.5% C17HgCaN100^ requires with 20.4! water C, 32.2; H, 3.5; N, 22.5!.

Spectral Confirmation The in'ra-red spectrum was consistent with the required structure having the amide carbonyl band at 1690 cm~ . The nmr spectrum in hexadeuterodimethylsulphoxide showed four singlets at 2.7, 3.09, 3.11 and 6.0"£ln the ratio 1:1:1:3.

EXAMPLE 9 5-Methoxy-4,10-dioxo-4H,10H-benzo/I,2-b : 3,4-b^dipyran-2,3-di- N-(tetrazol-5-yl7carboxamide dilithium salt.

To a stirred suspension of 5-methoxy-4,10-dioxo-4H,10H-benzo I,2-b : 3,4-bl7dipyTan-2 j8-di-^J-(tetrazol-5-yll7carboxamide (1.00 gm) in water (40 ml) was added a solution of lithium hydroxide monohydrate (0.18 gm) in water (10 ml). The solution was filtered and freeze dried giving the dilithium salt as a yellow powder (0.95 gm), mp >250°C.

Analysis: Found: C, 37.4; II, 2.8; M, 25.5! Cj Hgl^N-^O.-, requires with 12.21 water content C, 37.5; H, 2.85; N, 25.7%. - .'33'- Spectral Confirmation The nmr spectrum in hexadeuterodimethylsulphoxide displayed four singlets at 2.65, 3.05, 3.18 and 6.0'^ n the ratio 1:1:1:3. The infra-red spectrum of the salt was consistent with the required structure having the amide carbonyl band at 1690 cm and other bands due to the 4-oxo groups and aromatic ring.

EXAMPLE 10 N- tetrazol-5-yl) carboxamide dipotassium salt.

To an intimate mixture of 5-methoxy-4,10-dioxo-4H,10H-henzo /I,2-b : 3,4-bl7dipyran-2,8-di-N-(tetrazol-5-yl7carboxamide (7.00 gm) and potassium hydrogen carbonate (3.00 gm) was added water (350 ml) and the mixture was heated to effect solution.

The solution was filtered and cooled. Addition of acetone gave the required dipotassium salt as a yellow solid (4.5 gm), mp > 250°C.

Analysis: Found: C, 33.3; 11, 2.6; N, 22.8% witn 11·5% water C, 33.3; II, 2.6; N, 22.85%.

Spectral Confirmation The nmr spectrum in hexadeuterodimethylsulphoxide showed four singlets at 2.62, 3.08, 3.2 and 6.0 i the ratio 1:1:1:3. The infra-red spectrum was very much broadened having the amide carbonyl band at 1690 cm ll A 1 2 - 30 - EXAMPLE 11 5-Methoxy-4 ,10-dioxo-4H,10H-benzo/i,2-b : 3,4-b'Jdipyran-2 ,8-di-/N- (tetra¾ol-5-yl /carbpxamide di-tris- (hydroxymeth l) methylamine salt.

Tris-(hydroxymethyl)methylamine (2.6 g; 0.02146 mole) and 5-methoxy-4,10-dioxo-4H,10H-benzo/l,2-b : 3,4-b!7dipyran-2,8-di- N-(Tetrazol-5-yl^7carboxamide (5 g; 0.01073 mole) were heated in water (100 ml) until complete dissolution was obtained. The solution was filtered and the filtrate was freeze-dried to give the desired salt, which was dried in vacuo (7.0 g), mp 160-175° decomp.

Analysis: Found: C, 39.9; H, 4.9; , 22.05°. ^25¾2^12¾3 ^^i1"65 witn 5-8% water content C, 39.9; H, 4.9; N, 22.3% Spectral Confirmation The infra-red spectrum displayed peaks at 1700 (amide I) on" , 1650 (4-oxo) ατ ^ and 1600 cm EXAMPLE 12 5-Methoxy-4 0-dioxo-4H,10H-benzo l ,2-b : 5>4-hl7dipyran-2 ,8-di- N-(tetra2ol-5-yl 7carboxamide di-morpholine salt.

Morpholine (1.87g; 0.02146 mole) was added to a suspension of 5-methoxy-4,10-dioxo-4I!,iai-benzo/l,2-b : ,4-b 7dipyran-2 ,8-di-^'-(tetrazol-5-yl)7carboxamide (5.0g; 0.nif)73 mole) in water (50 ml). The mixture was heated until all the material had dissolved. The resulting solution was filtered and the filtrate - 3tf - was freeze dried. The desired salt so obtained was dried in vacuo at 70°C (5.9g), mp 231°C decomp.

Analysis: Found: C, 44.0; H, 5.1; N, 24.4% C25H28N12°9* 4H2° recluires: c» ·°ί H» 5·°ί N» 24.6%.

Spectral Confirmation The infra red spectrum displayed peaks at 1700 (amide I) cm 1650 (4-oxo) cm and 1600 (aromatic) cm EXAMPLE 13 5-Methoxy-4,10-dioxo-4H,10H-benzo/i,2-b : 3>4-h7dipyraii-2,8-di- M-(tetrazol-5-ylX7carboxamide diethanolamine salt.

Ethanolamine (1.2 ml; 0.0286 mole) was added to a suspension of 5-methoxy-4,10-dioxo-4H,10H-benzo i,2-b : 3,4-b!/dipyran-2,8-di-Zft-(tetrazol-5-yl)7carboxamide (5g; 0.01073 mole) in water (75 ml) . The mixture was heated until all the material had dissolved. The resulting solution was freeze dried. The desired salt so obtained was dried, washed with ether and re-dried in vacuo (5.2g) mp 182¾decomp.

Analysis: Found: C, 41.4; H, 4.7; N, 27.9% ¾1¾4^12¾ requires with 3.51 water content C, 41.3; H, 4.5; , 27.5%.

Spectral Confirmation The infra-red spectrum displayed peaks at 1700 (amide T) cm"1, 1650 (4-oxo) cm-1 and 1600 cm"1. - 3$- EXAMPLE 14 5-Methoxy-4 ,30-dioxo-4H,10H-benzo/l ,2-b : 3 ,4-h'7dipyran-2.8-di/N^(tetrazol-5-yl)7carboxamide .

A suspension of 3,5^1hydroxy-2,4-di(3-N-(tetrazol-5-yl) carboxamidQ7-l,3-dioxopropyl)anisole (l.Ogm) in a solution of dimethylacetamide (10 ml) , and concentrated hydrochloric acid (1 ml) was heated under gentle reflux for 1 hour. The mixture was filtered and the residue washed with hot dimethylacetamide and dried under vacuum at 80°C giving 5-methoxy-4 ,10-dioxo-41',10H-benzol, 2-b : 3,4-b7dipyTan-2,8-di N-(tetrazol-5-yll7carboxamide as a buff solid mp 300°G.

EXAMPLE 15 5-Methoxy-4,10-dioxo-4H,10H-henzo i,2-b : 5,4-b^dipyran-2,8-di/N-(tetrazol-5-yl)7carboxamide A mixture of 5-methoxy-4,10-dioxo-2,3,8,9-tetrahydro-4H,10H-benzol,2-b : 3,4-V7dipyran-2 ,8-di/N-(tetrazol-5-ylX7carboxamide (0.1 gm), pyridinium bromide perbromide (0.2 gm) and glacial acetic acid (115 ml) was stirred at ambient temperature for 18 hours. The mixture was then evaporated in vacuo, and the residue was washed with water and dried giving 5-methoxy-4 ,10-dioxo-4IJ,10II-benzo-/i ,2-b : 3,4-bl7dipyran-2,8-di -(tetrazol-S-yll7carboxamide as a buff solid mp ^ 300°C.

EXAMPLE 16 The following compounds may be made by the process of Example 2 using appropriate starting materials. - 43709/2 C ,I0-DiQxo-5-isiethoxy-4H,ΙΟΗ-benzo(1,2-bi3, -b* )dipyran-2,8-di~ [H- (l-allyltetrazol-5-yl) ]carboxamide. ,6-Dioxo-4H,6H-benzo(1,2-b«5r4-b* )dipyran-2,8-di- [N- (tetrazol- -yl)3carboxamide. -¾tetbOKy-4,6-dio o-4H,6H-benzo(1,2-bs5,4- * )dipyran-2,8-di-[N-(tetrazol-5-yl) }carboxamide. 43709/2 ^ φ -MB hoxy-4,6-dioxo-10~ ropyl-4H,6H-benzo(1,2-bs5,4-b* )dipyran- .8-di-[N- (tetrazol-5-yl) ]carboxamide.

-Me boxy-4,10-dioxo-6-propyl-4H,10H-benzo(1,2-b:3,4-b* )dipyran- #8-di-(H- (tetrazol-5-yi) ]carboxamide. .9-Dioxo-4H,9B-benzo(1,2-bx4,5b* )dipyran-2,7-di[N-(tetrazol- -yl)Icarboxamide. .10-Dioxo-5-ethoxy-4H,10H-benzo(l,2-b:3f -b* )dipyran-2#8-di-[13- TSKAWSm 17 ¾-Methoanr-4.10-diogo-4H.lOH-benzo(1.2-bs .4-»b» )<¾ipyran-2.8-di-El tetrazol-S-vl)Icarboxamide To a solution of 5*→a®thoxy-4f10-dtoxo-4It10H-ben-Bo(l,2-b: 3,4-b' )dlpyran-2#8-di (5-carbonylimino~l,4-dibenzyItetrazol3i») (0.2 go) in glacial acetic acid (30 ml) containing concentrated hydrochloric acid (5 drops) was added 5% palladium on carbon catalyst (0.1 gm). The mixture was hydrogenated at 60° with a starting pressure of 45 P.S.I, for 24 hours* The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was washed well with ether and dried giving the title compound as a buff solid, 21.P. >300°. mwrn a 5*Ι^ο¾ν«4.10-»άίοχο«4Η.10Η>οοη2θ(ΐ. ^¾ .4-b* )dlpyran^2.8«dl~ [H-(tetrazol-5-vl)learboxamlde A solution of 5Haethoxy- »10«-dioxo--4H,10E-benzo(lf2-b: 3»4-V )dipyran-2,8^i~(S-guaijylazldo) carboxamide (0.6 gm) in saturated aqueous sodium bicarbonate (10 ml) was heated at 100 degrees for one hour. After cooling, the solution was acidified with dilute hydrochloric acid. The resulting precipitate was removed by filtration, washed well with water and dried giving the title compound as a buff solid, M.P. >300°.

Example A The procedure set out below may be used to assess the effectiveness of a compound in inhibiting the release of the pharmacological mediators of anaphylaxis.

In this test, the effectiveness of the compounds in inhibiting the passive cutaneous anaphylactic reaction in rats is assessed. It has been proved that this form of test gives reliable qualitative indications of the ability of the compounds under test to inhibit antibody-antigen reactions in man.

In this test method Charles River France/Fisons bred rats (male or female) having a body weight of from 100 to 150 gms are infected subcutaneously at weekly intervals with . brasiliensis larvae in doses increasing from about 2000 larvae per animal to 12000 larvae per animal in order to establish the infection.

After 8 weeks the rats are bled by heart puncture and 15-20 mis. of blood collected from each animal. The blood samples are then centrifuged at 3500 rpm. for 30 minutes in order to remove the blood cells from the blood plasma. The serum is collected and used to provide a serum containing N. brasiliensis antibody. A pilot sensitivity test is carried out to determine the least quantity of serum required to give a skin weal in control animals in the test described below of 2 cm diameter. It has been found that optimum sensitivity of rats in the body weight range 100-130 gms is obtained using a serum diluted with eight parts of physiological saline solution. This diluted solution is called antibody serum Λ. -3^ - The antigen to react with the antibody in serum Λ is prepared by removing N. brasiliensis worms from the gut of the infested rats, centrifuging the homogenate and collecting the supernatent liquor. This liquor is diluted with saline to give a protein content of 1 mg/ml and is known as solution B.

Charles River France/Fisons bred rats in the body weight range 100 to 130 gms are sensitised by intradermal injection of 0.1 mis of serum A into the right flank. Sensitivity is allowed to develop for 24 hours and the rats are then injected intravenously with 1 ml/100 gms body weight of a mixture of solution B (0.25 mis), Evans Blue dye solution (0.25 mis) and the solution of the compound under test (0.5 mis varying percentages of active matter) . Insoluble compounds are administered as a separate intraperitoneal injection 5 minutes before intravenous administration of solution B and Evans Blue dye. For each percentage level of active matter in the solution under test five rats are injected. Five rats are used as controls in each test. The dosages of the compound under test are selected so as to give a range of inhibition values.

Thirty minutes after injection of solution B the rats are killed and the skins removed and reversed. The intensity of the anaphylactic reaction is assessed by comparing the size of the characteristic blue weal produced by spread of the Evans Blue dye from the sensitisation site, with the size of the weal in the control animals. The size of the weal is rated as 0 (no weal 3 32 -Mr - detected, i.e. 1001 inhibition) to 4 (no difference in size of weal, i.e. no inhibition) and the percentage inhibition for each dose level calculated as:- (control group score - treated group score) x 100 % inhibition = Control group score The percentage inhibitions for the various dose levels are plotted graphically for each compound. From these graphs the dosage required to achieve a 501 inhibition of the anaphylactic reaction (ID5Q) may be determined.

The compounds are also evaluated in the above manner using intestinal and gastric administration of the compound.

-AT - Si

Claims (14)

1. 4/A/9 3709^2 What we Claim is 1. A process for the production of a benzodipyran carboxamido tetrazole compound of formula Ix, in which one or more adacent pair of P, Q, R and T represent chain of in which each pair of Rg and may be the same or different, and Rg and Rjg are the same or different and are hydrogen, alkyl C 1 to 6, alkenyl C 2 to 6, phenyl, or phenyl-(alkyl C 1 to 6) , and the remainder of P, Q, R and T represent hydrogen or an alkoxy group, and pharmaceutically acceptable salts thereof, which comprises (a) producing a compound of formula Ix in which both groups are hydrogen by removing both ^ groups from a compound of formula II, 15/A/9 in which Pa, Qa, Ra and Ta have the same significances as P, Q, R and T above, save that an adjacent pair of Pa, Qa, Ra and Ta represent a chain of formula XXb, Rg is as defined above, and Rj^ represents a group which may be replaced by hydrogen, (b) producing a compound of formula Ix in which each Rg group is hydrogen, by (i) removing both Rj^ groups from a compound of formula VI, in which Pb, Qb, Rb and Tb have the same significances as P, Q, R and T above, save that an adjacent pair of Pb, Qb, Rb and Tb represent a chain of formula XXd, 16/A/9 in whic is as defined above, and ¾2 rePresents a group which my be replaced by hydrogen, (ii) cyclising a compound of formula VIII, in which Pg, Qg, Rg and Tg have the same significances as P, Q, R and T above, save that an adjacent pair of Pg, Qg, Rg and Tg represent a chain of formula XXe, in which is as defined above, (c) producing a compound of formula Ix in which Rg and are as defined above save that Rg must be hydrogen when is hydrogen, by reacting a compound of formula III, 17/A 9 43709- in which Pc, Qc, Rc and Tc have the same significances as P, Q, R and T above, save that an adjacent pair of Pc, Qc, Rc and Tc represent a chain -C0CH-C(C00H)-0-, or an acid halide, an ester or a mixed anhydride of a compound of formula III, with a compound of formula TV, in which Rg and (d) cyclising a compound of formula XII, in which Pd, Qd, Rd and Td have the same significances as P, Q, R and T above, save that an adacent pair of Pd, Qd, Rd and Td may represent a pair of groups and A^, and and A2 represent the groups -OH and in which Rg and R^0 are as defined above, and 18/A/9 3709-Λ Υ is an -OH group or a group -NLjI^ in which and I^, which are the same or different are each hydrogen, phenyl, lower alkyl, or together form a saturated or unsaturated 4 or 5 membered alkylene chain, (e) selective dehydrogenation of a confound of formula XIII, in which Pe, Qe, Re and Te have the same significances as P, Q, R and T above, save that an adjacent pair of Pe, Qe, Re and Te may represent a chain of formula XXf, in which Rg and R^Q are as defined above, or (f) producing a compound of formula Ix in which all groups Rg and RJQ are hydrogen, by removing all groups R^ from a compound of formula XVII, 19/A/9 in which Pf, Qf, f and Tf have the same significances as P, Q, R and T above, save that an adjacent pair of Pf, Qf, Rf and Tf represent a chain of formula XXi, in which R^ is as defined above, and where desired or necessary converting the compound of formula I to a pharmaceutically acceptable derivative thereof, or vice versa.

2. A process according to part (a) of Claim 1, wherein is an aralkyl, aroylaltyl, acyl, or amino group, or a group -(O^^G where G is an electron withdrawing group.

3. A process according to part (b)(i) of Claim 1, wherein Rj^ is a group R^ as defined in Claim 1 or Claim 2.

4. A process aecording to part (b)(ii) of Claim 1, wherein the cyclisation is carried out under basic conditions or at an elevated temperature.

5. A process according to part (c) of Claim 1, wherein the mixed 20/A/9 anhydride is derived from a sulphonic acid, a sterically hindered carboxylic acid or an alkoxy formic acid.

6. A process according to part (c) of Claim 1, wherein the acid halide is an acid chloride.

7. A process according to part (c) of Claim 1 or to Claims 5 or 6, wherein the reaction is carried out in a solvent which will not react with either thecompound of formula IV or the mixed anhydride or acid halide.

8. A process according to part (d) of Claim 1, wherein the cyclisation is carried out in the presence of an acid and in a solvent which is inert under the reaction conditions.

9. A process according to part (e) of Claim 1, wherein the dehydrogenation is carried out using a mild oxidising agent or by halogenation followed by dehydrohalogenation.

10. A process for the production of a pharmaceutically acceptable salt of a compound of formula I, as defined in Claim 1, which comprises treating a compound of formula I or a salt thereof, with a compound containing an available pharmaceutically acceptable cation.

11. A process according to Claim 10, which comprises treating a compound of formula I with a base, or with an appropriate salt using a metathetical process.

12. A process according to any one of the preceding claims, wherein each pair of groups Rg and are the same.

13. A process according to any one of the preceding claims, 4*r 21/A 9 wherein Rg and R^ are different, one being lower alkyl and the other being phenyl-lower alkyl,

14. A process according to any one of the preceding claims substantially as hereinbefore described, IS. A process according to any one of the preceding claims substantially as hereinbefore described in any one of Examples 1 to 17. 16. A compound of formula Ix,or a pharmaceutically acceptable salt thereof, whenever made by a process according to any one of the preceding claims. 17. A compound of formula I*as defined in Claim 1, or a pharmaceutically acceptable salt thereof. 18. A compound according to Claim 17, wherein each pair of groups, Rg and R^Q> are the same.-19. A compound according to either of Claims 17 or 18, wherein Rg and RJQ are different and are hydrogen, lower alkyl or phenyl-lower alkyl. 20. A compound according to any one of Claims 17 to 19, wherein Rg and RlQ are different and are hydrogen, methyl or benzyl. 21. A compound according to any one of Claims 17 to 20, wherein one of Rg and JQ in each pair of Rg and is hydrogen. 22. A compound of formula In, 43709/3 in which and RlQ are as defined in any one of Claims 18 to 21, Pa and Qa represent hydrogen or an alkoxy group. 25. 5-Methoxy-4,10-dioxo-4H,lOH-benzo/J"1,2-b:3,4-b'_7dipyran-2,8- diJ"N methyl-N-(tetrazol-5-yl)7 carboxamide. 24. 5-Methoxy-4,10-dioxo-4H,10H-benzo£l,2-b:3,4-b'_7dipyran-2,8- di N-(1-methyltetrazol-5-yl) _7carboxamide. 25. 5-Methoxy-4,10-dioxo-4H,10H-benzo£"l,2-b:3,4-b'_7dipyran-2,8- di N-(l-benzyltetrazol-5-yl)J7carboxamide. 26. 5-Methoxy-4,10-dioxo-4H,10H-benzo/ l,2-b:3,4-b' /dipyran-2,8- di/ N-(tetrazol-5-yl) /carboxamide. 27. A phannaceutically acceptable salt of a compound according to any one of Claims 17 to 26. 28. A triethanolan&ne, N-methylglucamine, calcium, lithium, potassium, tris-(hydroxymethyl)methylamine, morpholine or ethanolamine salt of a compound according to any one of Claims 17 to 26. 29. A sodium salt of a compound according to any one of Claims 17 to 26. 23/A/9 30. A compound according to any one of Claims 17 to 29 having a particle size of from 0.01 to 10 microns. 31. A pharmaceutical composition comprising a compound according to any one of Claims 17 to 30, as active ingredient, in admixture with a solid or liquid pharmaceutically acceptable diluent or carrier. 32. A composition according to Claim 31 comprising from 0.17 mg to 600 mg of the active ingredient in unit dosage form.