GB2055797A - 2-[(Trimethoxy-phenyl)-cyclopropyl]-chromone derivatives and process for their preparation - Google Patents

Abstract

2-[(Trimethoxy-phenyl)-cyclopropyl]-chromone derivatives of the formula: <IMAGE> and their salts [wherein n is zero or 1; each of the groups R, which may be the same or different, is alkyl of 1 to 4 carbon atoms; R1 is hydrogen or alkyl of 1 to 12 carbon atoms which is unsubstituted or substituted by <IMAGE> in which R3 and R4 are the same or different and each is hydrogen or alkyl of 1 to 6 carbon atoms; and R2 is alkyl of 1 to 4 carbon atoms or alkenyl of 3 to 4 carbon atoms] have valuable anti-allergic, anti-ulcer, and bronchodilator activity, combined with a high therapeutic index. They may be made by reaction of a corresponding 2-[(trimethoxy-phenyl)-ethenyl]-chromone derivative with dimethyl sulphoxonium methylide.

Description

SPECIFICATION 2-[(trimethoxy-phenyl)-cyclopropyl]-chromone derivatives and process for their preparation The present invention relates to substituted chromone derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

The present invention provides novel 2-[(trimethoxy-phenyl)cyclopropyl]chromone derivatives which have the following formula:

wherein n is zero or 1; each of the groups R, which may be the same or different, is alkyl of 1 to 4 carbon atoms; R1 is hydrogen or alkyl of 1 to 12 carbon atoms which is unsubstituted or substituted by

in which R3 and R4 are the same or different and each is hydrogen or alkyl of 1 to 6 carbon atoms; and R2 is alkyl of 1 to 4 carbon atoms or alkenyl of 3 to 4 carbon atoms.

The present invention also provides the pharmaceutically acceptable salts of the compounds of formula (I), and the various possible isomers and their mixtures.

The compounds of the invention are preferably in the trans-configuration, that is the two hydrogen atoms on the a and ss carbon atoms are on the opposite sides with respect to the plane of the cyclopropane ring, but they may also be in the cis-configuration, or a mixture of the cis- and trans-isomers.

The alkyl and alkenyl groups may be branched or straight chain groups. When R1 is an unsubstituted alkyl of 1 to 12 carbon atoms, it preferably contains up to 6 carbon atoms, as in particular, in methyl, ethyl, isopropyl, t-butyl and n-hexyl. When R3 and/or R4 are alkyl of 1 to 6 carbon atoms, the alkyl group is preferably alkyl of 1 to 4 carbon atoms, and in particular, methyl, ethyl, isopropyl ort-butyl. R2 is preferably n-propyl or allyl. Preferably the groups R are the same and are methyl.

Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, Nethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine, ss-phenethylamine, N-benzyl-ss- phenethylamine, and N-benzyl-N,N,-dimethylamine and the other pharmaceutically acceptable organic amines, as well as the salts with inorganic acids, e.g. hydrochloric, hydrobromic and sulphuric acids, and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulphonic and ethanesulphonic acids.

Preferred salts are the sodium and potassium salts of the compounds of formula (I) where R1 is hydrogen, and the hydrochlorides of the basic esters, e.g. the 2-diethylaminoethyl and 2-dimethylamino-ethyl esters. In the compounds of the invention the -COOR1 group is preferably a free or salified carboxy group.

Examples of particularly preferred compounds of the invention are: 6-carboxy-3-propyl-2-trans-[2(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; 6-carboxy-3-propoxy-2-trans-{2-(2,4,5-trimethoxy-phenyl )-cyclopropyl]-chromone; 6-carboxy-3-ethyl-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; 6-carboxy-3-ethoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone;; and 6-ca rboxy-3-a l lyloxy-2-trans-[2-(2,4,5-tri methoxy-phenyl)-cyclopropylj-ch romone and their pharmaceutically acceptable salts, in particularthe sodium salts and the hydrochlorides of the basic esters (e.g. those with 2-diethylamino-ethanol and 2-dimethylamino-ethanol) and the C1-C6 alkyl esters thereof, in particular the methyl, ethyl, isopropyl,t-butyl and n-hexyl esters.

The compounds of the invention may be prepared by reacting a compound of formula (II)

wherein n, R, R1 and R2 are as defined above, with dimethyl sulphoxonium methylide and, if desired, converting a compound of formula (I) so obtained into another compound of formula (I) and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable saltthereofand/or, if desired, converting a salt into a free base or acid.

The reaction of a compound of formula (II) with dimethylsulphoxonium methylide (that is the compound

prepared, e.g., according to the method described in J. Chem. Soc., 1967,2495) is preferably carried out in an inert organic solvent, such as, e.g., dimethylformamide, dimethylsulphoxide, dioxane or a mixture thereof, at a temperature preferably between about 0 C and about 50"C.

A compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods. For example, the compound of formula (I) wherein -COOR1 is an esterified carboxy group, may be converted into a compound of formula (I) wherein -COOR1 is carboxy by hydrolysis, e.g. basic hydrolysis, using, for example, sodium or potassium hydroxide, in a solvent, such as, e.g., water or a lower aliphatic alcohol, and operating at a temperature from room temperature to about 150"C. The same reaction may be also carried out, e.g., by treatment with lithium bromide in dimethylformamide at a temperature higher than 50"C. Also, a compound of formula (I) wherein -COOR1 is a t-butoxycarbonyl group may be converted into a compound of formula (I) wherein -COOR, is carboxy, e.g. by treatment with trifluoroacetic acid either in the absence of a solvent or in the presence of an inert organic solvent, such as, e.g., benzene, toluene, or dioxane, at a temperature from about O"C to about 50"C or also by treatment with, e.g., trimethylsilyliodide in an inert organic solvent, preferablytetrachloromethane, according to the procedure described in J. Am. Chem. Soc. 99,968(1977).

A compound of formula (I) wherein -COOR1 is carboxy may be converted into a compound of formula (I) wherein -COOR1 is an esterified carboxy group as defined above, by conventional methods, for example by reacting an alkali metal salt of the acid with a suitable alkyl halide, in an inert solvent, such as, e.g., acetone, dioxane, dimethylformamide, a hexamethylphosphorotriamide, at a temperature from about OOC to about 1 00'C. Alternatively the esterification of a compound of formula (I) may be effected a) by converting the compound offormula (I) wherein -COOR1 is carboxy into the corresponding halocarbonyl, preferably chlorocarbonyl, derivative, by reaction, e.g., with an acid halide such as oxalyl chloride, thionyl chloride, PC13, PCl5 or POCI3, either in the absence of a solvent or in an inert organic solvent such as, e.g., benzene, toluene, xylene, dioxane, dichloroethane, methylene chloride, ortetrahydrofuran, at a temperature preferably from about 0 C to about 120"C; and then b) reacting the obtained halocarbonyl derivative with an alcohol of formula R1-OH, wherein R1 is as defined above, in an inert solvent such as, e.g. benzene, toluene, xylene, dioxane, dichloroethane, methylene chloride, or tetrahydrofuran, at a temperature varying between about O"C and about 120"C, preferably in the presence of a base, such as e.g., triethylamine or diethylamine.

The optional salification of a compound of formula (I) as well as the conversion of a salt into a free acid or base and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.

The compounds of formula (II), which may be in trans- or in cis-configuration, or be a mixture of the cisand trans-isomers, may be prepared, for example, according to the method described in German Offenlegungsschrift P 27 25 932, corresponding to the Belgian Patent No. 855, 657.

The compounds of the invention have antiallergic activity and are therefore useful in the prevention and treatment of all affections of allergic origin, e.g., bronchial asthma, allergic rhinitis, hay fever, urticaria and dermatosis. The anti-allergic activity of the compounds of the invention is shown, e.g. by the fact that they are active in the rat in the passive cutaneous anaphylaxis (PCA) test of J. Goose and A.M.J.N. Blair (Immunology, 16,749, 1969). An important property of the compounds of the invention is that they exhibit a high level of antiallergic activity when administered orally.

The compounds of the present invention also possess anti-ulcer activity, as demonstrated by the fact that they are active in inhibiting stress-induced ulcers in rats undergoing restraint in a water bath at 250C for 40 minutes, using a modification ofthetechniqueofTakagi K. and Okabe S. (Jap.J. of Pharmac., 1968,19:9).

The compounds of the invention also have bronchodilator activity as shown by the fact that they are active in inhibiting the bronchospasm induced by histamine in guinea-pigs, in the method of Kanzett and Rössler, Arch. Exp. Path. Pharmakol. 71, 195 (1940).

In view of their high therapeutic index, the compounds of the invention can be used safely in medicine.

For example, the approximate acute toxicity (LD 50) of the compound 6-carboxy-3-propyl-2-trans-[2-(2,3,4 trimethoxy-phenyl)-cyclopropyl)-chromone in the mouse, determined by single administration of increasing doses and measured on the seventh day of treatment, is higher than 800 mg/Kg per os. Analogous toxicity data have been found for the other compounds of the invention.

The compounds of the invention may be administered in conventional manner, for instance, orally or parenterally, at a daily dosage preferably of 0.5 to 15 mg/kg, or by inhalation, preferably at a daily dosage of 0.5 to 100 mg, preferably 0.5 to 25 mg, or by topical application, e.g. in a cream containing about 0.5-5 mg, preferably 1-2 mg, of the active principle per 100 mg of cream.

The exact composition of the pharmaceutical compositions of this invention, which contain a compound of this invention in association with a pharmaceutically acceptable carrier or diluent, will, of course, depend upon the desired mode of administration.

Such composition may be formulated in the conventional manner with the usual ingredients. For example, the compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, as aerosols, and as powders, tablets, pills, gelatine capsules, syrups, drops, suppositories, or creams, or lotions for topical use.

Pharmaceutical compositions containing the compounds of this invention for oral administration are preferably tablets, pills, or gelatine capsules which contain the active substance together with diluents, such as, for example, lactose, dextrose, sucrose, mannitol, sorbitol, or cellulose; lubricants, for instance, silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as, for example, starches, gelatine, methylcellulose, carboxymethylcellulose, gum-arabic, tragacanth, polyvinyl pyrrolidone, and disintegrating agents, such as, for instance, lecithin, polysorbates, or laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.Said pharmaceutical preparations may be manufactured in known manner, for example, by mixing, granulating, tabletting, sugar-coating, orfilm-coating processes.

For the treatment of allergic asthma, the compounds of the invention may also be administered by inhalation. For such use, suitable compositions may comprise a suspension or solution of the active ingredient, preferably in the form of a salt, such as the sodium salt, in water, for administration by a conventional nebulizer. Alternatively, the compositions may comprise a suspension or solution of the active ingredient in a conventional liquified propellant, such as dichlorodifluoromethane or dichlorotetrafluoroethane to be administered from a pressurized container, i.e. an aerosol dispenser.When the medicament is not soluble in the propellant, it may be necessary to add a co-solvent, such as ethanol, dipropylene glycol, or isopropyl myristate, and/or a surface-active agent to the composition, in order to suspend the medicament in the propellant medium and the surface-active agent, e.g. lecithin.

The compounds of the invention may also be administered in the form of powders by means of a suitable insufflator device and in this case fine particles of the active ingredient may be mixed with a diluent material such as lactose.

Furthermore, the compounds of this invention may also be administered by intradermal or intravenous injection in the conventional manner.

In addition to internal administration, the compounds of this invention may be used in compositions for topical application, e.g. as creams, lotions or pastes for use in dermatological treatments. For these compositions the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.

The following Examples illustrate the present invention.

Example 1 Trimethyl-sulphoxonium iodide (1.1 g) was reacted with 50% sodium hydride (0.24 g) in dimethylformamide (20 ml) with stirring at room temperature for 1 hour. A solution of 6-carbomethoxy-3-propyl-2-trans [2,4,5-trimethoxy-phenyl)-ethenyl]-chromone, m.p. 18-188"C, (1.7 g) in dimethylformamide (20 ml) was added. The mixture was allowed to react with stirring at room temperature for 6 hours, and was diluted with ice water. The precipitate was filtered off and washed with water until neutral. The 6-carbomethoxy-3-propyl 2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone so obtained (1.2 g; m.p. 136-138"C) was reacted with 1% KOH in 95% ethanol solution (28 ml) at refluxtemperature for 10 minutes.After cooling, the reaction mixture was acidified with HCI. concentrated in vacuo and diluted with ice water. The precipitate was filtered off and crystallized from ethanol, so obtaining 0.5 g of 6-carboxy-3-propyl-2-trans-[2-(2,4,5trimethoxyphenyl)-cyclopropyl]-chromone, m.p. 214-215"C; IR (KBr) : y (C=O) carboxy 1690 cm-'. y (C=O) chromone 1635, 1610 cm-1; NMR (DMSO d6)6: 0.88 (t) (-CH2CH2CH3), 1.76-2.04(m) (CH2-CH2-CH3 and

3.79 (s) (6H, OCH3), 3.85 (s) (3H, OCH3), 6.76 (s) and 6.8 (s) (C3 and C-6 phenyl protons), 7.73 (d) (6-8 chromonyl proton), 8.31 (d.d) (C-7 chromonyl proton),8.66 (C-5 chromonyl proton).

By proceeding analogously the following compounds were prepared: 6-carboxy-3-ethyl-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; 6-carboxy-3-propoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; 6-carboxy-3-ethoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; 6-carboxy-3-allyloxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropylj-chromone; 6-carboxy-3-propyl-2-trans-[2-(2,3,4-trimethoxy-phenyl)-cyclopropyl]-chromone, m.p. 21 5-21 6"C; 6-carboxy-3-propoxy-2-trans-[2-(2,3,4-trimethoxy-phenyl)-cyclopropyl]-chromone, m.p. 162-163"C; 6-carboxy-3-ethoxy-2-trans-[2-(2,3,4-trimethoxy-phenyl)-cyclopropyl]-chromone; and 6-carboxy-3-propyl-2-trans-[2-(3,4,S4rimethoxy-phenyl-cyclopropyl]-chromone, m.p. 200-202'C.

Example 2 Trimethylsulphoxomium iodide (1.95 g) was reacted with 50% sodium hydride (0.42 g) in dimethyl formamide (25 ml) with stirring at room temperature for 2 hours. A solution of 6-tert-butoxycarbonyl-3 ethoxy-2-trans-[2-(3,4,5-trimethoxy-phenyl)-ethenyl]-chromone (3 g) in dimethylformamide (25 ml) was then added. The mixture was allowed to react with stirring at room temperature for 6 hours and was then diluted with ice water and extracted with ethyl acetate. The organic layer was washed with water until neutral and then evaporated to dryness in vacuo.The crude product (2.8 g) was purified through a SiO2 column using benzene as eluant, so obtaining 2.1 g of 6-tert-butoxycarbonyl-3-ethoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)- cyclopropyl]-chromone which was reacted with trimethylsilyl iodide (1 g = 1.2 ml) in C Cl4 (30 ml) under nitrogen, with stirring at room temperature for 4 hours and then at 50"C for 2 hours. After cooling, the reaction mixture was diluted with ethyl ether and extracted with 2% aqueous NaHCO3. The aqueous layer was separated and acidified with 23% aqueous HCI and the precipitate was filtered off and washed with water until neutral.Crystallization from ethanol gave 1.4 g of 6-carboxy-3-ethoxy-2-trans-[2-(2,4,5trimethoxy-phenyl)-cyclopropyl]-chromone, m.p. 212-213"C; IR (KBr); y (C=O) carboxy 1730 cam~', y (C=O) chromone 1620 cm-'; NMR (DMSO d6) 1.26(t) (-OCH2CH3), 1.7-2.0(m)

3.71 (s) (4-OCH3), 3.83 (s) (3 and 5 -OCH3), 4.15 (q) (-OCH2CH3), 6.67 (s) (C-2 and C-6 phenyl protons), 7.75 (d) (C-8 chromonyl proton), 8.33 (d.d) (C-7 chromonyl proton), 8.67 (d) (C-5 chromonyl proton).

By proceeding analogously, the following compounds were prepared: 6-carboxy-3-propoxy-2-trans-[2-(3,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; 6-carboxy-3-ethyl-2-trans-[2-(2,3,4-trimethoxy-phenyl )-cyclopropyl]-chromone; and 6-carboxy-3-allyloxy-2-trans-[2-(2,3,4-trimethoxy-phenyl)-cyclopropyl]-chromone.

Example 3 6-carboxy-3-propoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone (0.7 g) was reacted with ethyl iodide (0.54 g) and an hydros K2CO3 (0.63 g) in dimethylformamide (7 ml) with stirring at room temperature for 6 hours. After dilution with ice water the precipitate was filtered off and crystallized from isopropyl ether-n-hexane so obtaining 0.4 g of 6-carbethoxy-3-propoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)- cyclopropyl]-chromone.

By proceeding analogously, the following compounds were prepared: 6-carbethoxy-3-propyl-2-trans-[2-(2,4,5-trimethoxy-phenyl )-cyclopropylj-chromone; 6-carbethoxy-3-ethoxy-2-trans-[2-(2,4,S-trimethoxy-phenyl)-cyclopropyl]-chromone; and 6-carbethoxy-3-al Iyloxy-2-trans[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone.

Example 4 6-carboxy-3-ethoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl )-cyclopropyl]-chromone (1.5 g) was reacted with SOCI2 (0.6 ml) in dioxane (30 ml) at reflux temperature for 1 hr. The reaction mixture was then evaporated to dryness in vacuo. The residue was dissolved in anhydrous dioxane (30 ml) containing triethylamine (0.5 ml) and reacted with 2-diethylamino-ethanol (1 ml) at room temperature for 24 hours. After dilution with water the precipitate was filtered off, dissolved in ethyl ether (100 ml), and treated with the stoichiometric amount of HCI in ether. The precipitate was filtered off, washed with ethyl ether and dissolved in water. Alkalinization with K2CO3, filtration and crystallization of the residue from isopropyl ether gave 0.7 g of 6-carboxy-3-ethoxy 2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone,2-diethylamino-ethyl ester.

By proceeding analogously, the following compounds were prepared: 6-carboxy-3-propyi-2-trans-[2-(2,4,5-trimethoxy-phenyl )-cyciopropyl ]-chromone, 2-diethylaminoethyl-ester; 6-carboxy-3-ethoxy-24rans-[2-(2,4,S-trimethoxy-phenyl)-cyclopropylj-chromone, 2-diethylaminoethyl-ester; and 6-carboxy-3-allyloxy-2-trans-[2-(2,4,5-tri methoxy-phenyl)-cyclopropyl]-chromone,2-diethylaminoethylester.

Example 5 By proceeding as in Example 4, the 2-dimethyl-aminoethyl-esters of the following compounds were prepared: 6-carboxy-3-propyl-2-trans-[2-(2,4,S-trimethoxy-phenyl)-cyclopropylj-chromone; 6-carboxy-3-propoxy-2-trans-[2-(2,4,S-trimethoxy-phenyl)-cyclopropylj-chromone; 6-carboxy-3-ethoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; and 6-carboxy-3-allyloxy-2-trans-[2-(2,4,S4rimethoxy-phenyl)-cyclopropyll-ch romone.

Example 6 6-carboxy-3-propyl-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone was dissolved by heating in the stoichiometric amount of 2N NaOH. The solution was then concentrated in vacuo and diluted with acetone. The precipitate was filtered off and washed with acetone. 6-Carboxyl-3-propyl-2-trans-[2-(2,4,5- trimethoxy-phenyl)-cyclopropyl]-chromone, sodium salt, m.p. > 300 C, was obtained.

By proceeding analogously, the sodium salts of the following compounds were obtained: 6-carboxy-3-propoxy-2-trans-{2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; 6-carboxy-3-ethoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone; 6-carboxy-3-ethyl-2-trans-[2-(2,4,5-trimethoxy-phenyl )-cyclopropyl]-chromone; and 6-carboxy-3-al Iyloxy-2-trans-[2-(2,4,5-tri methoxy-phenyl)-cyclopropyl]-chromone.

Example 7 Tablets, each weighing 150 mg and containing 50 mg of the active substance are manufactured as follows: Composition (for 10,000 tablets) 6-ca rboxy-3-propyl-2-trans-!2-(2,4,S-tri methoxy phenyl)-cyclopropyl]-chromone 500 g lactose 710 g corn starch 237.5 g talc powder 37.5 g magnesium stearate 15 g The 6-carboxy-3-propyl-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone, lactose and half the corn starch are mixed. The mixture is then forced through a sieve having 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried and comminuted on a sieve having 1.4 mm openings. The remaining starch, talc and magnesium stearate are added, carefully mixed and processed into tablets using punches of 8 mm diameter.

Example 8 Aerosol formulation 6-ca rboxy-3-propyl-2-trans-[2-(2,4,5-trimethoxy- phenyl)-cyclopropyl]-chromone 2 % ethanol 10 % lecithin 0.2 % mixture of dichlorodifluoromethane and dichlorotetrafluoroethane (70:30 mixture) ad 100 %

Claims (14)

1. Acompound oftheformula:

and its pharmaceutically acceptable salts; wherein n is zero or 1; each of the groups R, which may be the same or different, is alkyl of 1 to 4 carbon atoms; R1 is hydrogen or alkyl of 1 to 12 carbon atoms which is unsubstituted or substituted by

in which Rg and R4 are the same or different and each is hydrogen or alkyl of 1 to 6 carbon atoms; and R2 is alkyl of 1 to 4 carbon atoms oralkenyl of 3 to 4 carbon atoms.

2. 6-Carboxy-3-propyl-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone and its pharmaceutically acceptable salts.

3. 6-Carboxy-3-propoxy-2-trans-[2-(2,4,5-trimethoxy-phenyi)-cyclopropyl]-chromone and its pharmaceutically acceptable salts.

4. 6-Carboxy-3-ethyl-2-trans-[2-(2,4,5-trimethoxy-phenyl )-cyclopropyl]-chromone and its pharmaceutically acceptable salts.

5. 6-Carboxy-3-ethoxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-chromone and its pharmaceutically acceptable salts.

6. 6-Carboxy-3-al Iyloxy-2-trans-[2-(2,4,5-trimethoxy-phenyl)-cyclopropyl]-ch romone and its pharmaceutically acceptable salts.

7. The sodium salt of a compound as claimed in any of claims 2 to 6.

8. A basic ester of a compound as claimed in any of claims 2 to 6 or a pharmaceutically acceptable acid addition salt thereof.

9. The hydrochloride of a basic ester as claimed in claim 8.

10. A compound as claimed in claim 8 or 9 wherein the basic ester is the 2-diethylamino-ethanol or the 2-dimethylamino-ethanol ester.

11. A process for the preparation of a compound as claimed in any one of the preceding claims, which comprises reacting a compound offormula:

wherein n, R, R1 and R2 are as defined in claim 1), with dimethylsulphoxonium methylide and, if desired, converting a compound of formula (I) so obtained into another compound of formula (I) and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, converting a salt into a free base or acid.

12. A process as claimed in claim 7, substantially as claimed in any one of the foregoing Examples 1 to 6.

13. A compound as claimed in any of claims 1 to 10 when produced by the process of claim 11 or 12.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or 13 and a pharmaceutically acceptable carrier and/or diluent.