CS207642B2 - Method of making the substituted 2-cyclopropylchromones - Google Patents

Abstract

The invention relates to a process for the production of new ones substituted 2-cyclopropylchromones of formula (I) in which n is zero or 1, R 1 represents a hydrogen atom or an alkyl group with 1 to 20 carbon atoms optionally substituted with alkanoyloxy having 2 to 5 carbon atoms or a general group formula Rl FROM —N \ T R5 wherein each individual R 4 substituent

Description

(54) A method for producing substituted 2-cyclopropylchromones

The invention relates to a process for the preparation of the novel substituted 2-cyclopropylchromones of the formula I

wherein n is zero or 1,

R 1 represents a hydrogen atom or a C 1 -C 20 alkyl group optionally substituted by a C 2 -C 5 alkanoyloxy group or a general formula

Rl

Z —N \

R 5 wherein each of R 1 and R 5 is independently selected from hydrogen or C 1 -C 10 alkyl, or wherein R 1 and R 5 together with the nitrogen atom to which they are attached form an N-pyrrolidinyl radical,

R 2 represents a C 1 -C 8 alkyl group or a C 3 or C 4 alkenyl group, and

R3 also represents a furyl, thienyl or pyridyl group, optionally substituted by a methyl group, or bj is a group of the general formula

R _? wherein each of each of R a and R 7 is independently selected from the group consisting of a'j hydrogen, b 'is halogen, and c'j is a group of formula - (O) n 1 -R 5 wherein R 1 is zero or 1 and R 6 is alkyl (C 1 -C 6) optionally substituted with (C 1 -C 12) alkoxy;

d‘j is C 3 or C 4 alkenyloxy.

The present invention also provides a process for the preparation of pharmaceutically acceptable salts and all possible isomers of the compounds of formula (I) and mixtures thereof.

The compounds of the invention may be in either the cis- or trans-configuration. When both hydrogen atoms are bonded to the α- and β-carbon atoms of formula I on the same side with respect to the plane of the cyclopentane ring, the compounds are in the cis configuration, and conversely, if they are on the opposite sides, the compounds are in the trans configuration . Mixtures of cis and trans isomers are also included within the scope of the invention. Preferably, the compounds of formula I are in the trans configuration.

Conventional numbering is used to denote the place of substitution in R 3 as shown in the following examples: (a) when R 3 is a phenyl group:

bj when Es is a pyridyl group:

cj when Ro is a furyl or thienyl group

wherein X represents an oxygen or sulfur atom.

The alkyl, alkenyl, alkoxy and alkanoyloxy groups may have a branched or straight running carbon chain.

When the substituent R 1 represents an unsubstituted C 1 -C 20 alkyl group, it is preferably an C 1 -C 6 alkyl group, in particular a methyl, ethyl, isopropyl, tert-butyl or hexyl group.

When R 1 represents a C 1 -C 20 alkyl group substituted with C 2 -C 5 alkanoyloxy, R 1 is preferably a pivaloyloxymethyl group.

When Ict and / or R8 is C1 -C10 alkyl, it is preferably C1 -C4 alkyl, preferably methyl, ethyl, isopropyl or tert-butyl.

Preferably R 2 represents an alkyl group having 2 to 3 carbon atoms, in particular an alkyl or propyl group, or an alkenyl group having 3 carbon atoms, in particular an allyl group.

When R3 represents a furyl, thlenyl or pyridyl group, it is preferably a 2-furyl, 2-thienyl or 2-pyridyl group.

When R 5 represents an alkyl group having 1 to 6 carbon atoms, it is preferably a methyl, ethyl or isopropyl group.

The radicals R e and R 7 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkoxy, in particular methoxy and ethoxy, and C 1 -C 4 alkyl, in particular methyl and ethyl.

Examples of pharmaceutically acceptable salts are either salts with inorganic bases such as sodium, potassium, calcium and aluminum hydroxides or salts with organic bases such as lysine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di- (2-ethylhexyl) amine , piperidiin,

N-ethylpiperidine,

N, N-diethylaminoethylamine,

N-ethylmorpholine, β-phenethylamine,

N-benzyl- N -phenethylamine,

N-benzyl-N, N-dimethylamine and other suitable organic amines, as well as salts with inorganic acids such as hydrochloric, hydrobromic and sulfuric acids and with organic acids such as citric, tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfone.

Preferred salts of the compounds of formula I are sodium and potassium salts, as well as hydrochlorides of basic esters, for example diethylaminoethyl and dimethylaminoethyl ester.

Particularly preferred compounds of the invention are those compounds of formula I wherein R 1 is a "] hydrogen, b") an alkyl group having 1 to 6 carbon atoms, optionally substituted with a group of formula

R4 /

- N \

R 5 in which the substituents R 1 and R 5, which may be the same or different, denote a C 1 -C 4 alkyl group, a C 2 - (N-pyrrolidinyl) ethyl group, a d ') pivaloyloxymethyl group, n is zero or 1, R2 denotes a (C1-C4) alkyl group, in particular an ethyl or C2-C4 alkenyl group, or a 3-alkenyl alkenyl group, in particular an allyl group, R3 denotes a (a ') phenyl group, optionally substituted by a C1-C4 alkyl group, in particular methyl or ethyl, or C 1 -C 4 alkoxy, in particular methoxy, or b 2 -furyl, 2-thienyl or 2-pyridyl, which may optionally be substituted by methyl, and also their pharmaceutically acceptable salts .

In preferred compounds of formula I, -COOR 1 is preferably a free or salt-converted carboxyl group.

Examples of particularly preferred compounds of formula I include the following specific compounds:

trans-6-carboxy-3-propyl-2- (2-phenylcyclopropyl) chromone, trans-6-carboxy-3-allyl-2- (2-phenylcyclopropyl) chromone, trans-6-carboxy-3-ethoxy-2- (2-phenylcyclopropyl) chromone, trans-6-carboxy-3-butoxy-2- (2-phenylcyclopropyl) chromone, trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl)] cyclopropyl] chromone, trans-6-carboxy-3-allyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, trans-6-carboxy-3-ethoxy-2- [2- (2'- methylphenyl) cyclopropyl] chromone, trans-6-carboxy-3-propyl-2- [2- (3'-methylphenyl) cyclopropyl] chromone, trans-6-carboxy-3-allyl-2- [2- (3 ') methylmethylphenyl) cyclopropyl] chromone, trans-6-carboxy-2-propyl-2- [2- (3'-methoxyphenyl) cyclopropyl] chromone, trans-6-carboxy-3-propyl-2- [2- (2 1-Methoxyphenyl] cyclopropyl] chromone, trans-6-carboxy-3-propyl-2- [2- (2'-pyridyl) cyclopropyl] chromone, trans-6-carboxy-3-propyl 1-2- [2- (5'-methyl-2'-furyl) cyclopropyl] chromone, trans-6-carboxy-3-ethoxy-2- [2- (5'-methyl-2'-furyl) cyclopropyl] chromone, trans- 6-Carb'-3-ethyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, trans-6-carboxy-3-propyl 1-2- [2- (5'-methyl 1-2) trans-6-carboxy-3-ethoxy-2- (1'-thlenyl) cyclopropyl] chromone 2- (5‘-Methyl-2‘-thienyl) cyclopropyl 1 chromone.

Trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone 2-diethylaminoethyl ester,

2-diethylaminoethyl ester trans-6-carboxy-3-propyl-2- [2- (5‘-methyl-2‘-furyl) cyclopropyl] chromone,

Trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-thienyl) cyclopropyl] chromone 2-diethylaminoethyl ester, as well as pharmaceutically acceptable salts thereof, especially sodium salts and hydrochlorides of basic esters (e.g. esters) with 2-diethylaminoethanol and 2-dimethylaminoethanol and their C 1 -C 6 alkyl esters, especially methyl, ethyl, isopropyl, tert-butyl and hexyl esters.

The substituted 2-cyclopropylchromones of formula (I), their pharmaceutically acceptable salts as well as the isomers thereof are prepared according to the invention by producing a compound of the formula (II) in a compound of the general formula (II).

wherein n, R 1, R 2 and R 5 are as defined above, or in the salts thereof, form a cyclopropane ring, and the compound of formula I obtained is optionally converted in a manner known per se into another compound of formula I, and / or converted to the appropriate pharmaceutically acceptable salt, and / or the obtained salt is converted to the free compound, and / or the resulting mixture of isomers is separated into individual isomers.

The cyclopropane ring formation is preferably carried out by reacting a compound of formula II with dimethylsulfoxonium methylide (prepared, for example, by the method described in J. Chem. Soc., 1967, 2495) in an inert organic solvent such as dimethylformamide, dimethylsulfoxide, dioxane or mixtures thereof, preferably at a temperature. in the range of about 0 to about 50 ° C.

As noted above, the compound of formula (I) obtained may optionally be converted in a known manner into another compound of formula (I). For example, a compound of formula (I) in which - CODR 1 represents an esterified carboxylic acid group may be converted into a compound of formula (I)

COOR 1 denotes a carboxyl group, by hydrolysis, for example, under alkaline conditions, by treatment with, for example, sodium or potassium hydroxide, in a suitable solvent such as water or a lower aliphatic alcohol at 150 ° C; the same hydrolysis can also be carried out, for example, by treatment with lithium bromide in dimethylformamide at a temperature above 50 ° C.

A compound of formula I wherein the —COOR 1 substituent is a t-butoxycarbonyl group can be converted to a compound of formula I wherein the —COOR 1 represents a carboxyl group, for example by treatment with trifluoroacetic acid, either in the absence of solvent or in an inert organic solvent, e.g. benzene, toluene or dioxane, at a temperature in the range of about 0 to about 50 ° C, or also by treatment with, for example, trimethylsilyl iodide in an inert organic solvent, preferably in carbon tetrachloride, as described in J. Am. Chem. Soc. 99, 968 (1977).

A compound of formula I in which —COOR1 represents a carboxyl group can be converted to a compound of formula I in which —COORi represents an esterified carboxyl group, for example an alkoxycarbonyl group, optionally substituted with 2 to 5 carbon alkanoyloxy or a group of formula

Rd /

—N \

R 5 in which R 6 and R 8 are as defined above, by conventional means, for example by reacting an alkali acid salt with a suitable alkyl halide, in an inert solvent such as acetone, dioxane, dimethylformamide or hexamethylphosphoric triamide at a temperature ranging from about 0 to about 100 ° C.

Alternatively, esterification of a compound of formula I may be accomplished by a) converting a compound of formula I wherein -COOR 1 represents a carboxyl group to the corresponding halocarbonyl, preferably chlorocarbonyl, derivative by reaction with, for example, a suitable acyl halide such as oxalyl chloride, thionyl chloride, phosphorus pentachloride or phosphorus oxychloride, either in the absence of solvents or in an inert organic solvent such as benzene, toluene, xylene, dioxane, dichloromethane, methylene chloride or tetrahydrofuran, preferably at a temperature in the range of about 0 to about 120 ° C, and then b) reacting the obtained halocarbonyl derivative with a suitable alcohol of the formula R 1 -OH, wherein R 1 is as defined above, in an inert organic solvent such as benzene, toluene, xylene, dioxane, dichloromethane, methylene chloride or tetrahydrofuran, at a temperature in the range of about 0 to about 120 ° C, preferably in the presence of a base such as triethylamine or diethylamine.

Also, if desired, the conversion of the compounds of the formula I into salts as well as the conversion of salts into the free compounds and the separation of the mixture of isomers into the individual isomers can be carried out by conventional methods.

For example, the separation of a mixture of optical antipodes into individual antipodes can be carried out by converting said mixture into a mixture of salts with an optically active throw, and the mixture of salts is then fractionated crystallized. Also, the separation of the mixture of geometric cis and trans isomers can be carried out, for example, by fractional crystallization.

Compounds of formula II can be prepared for example as described in German laid-Offenlegungsschrift 2 725,932th corresponding to the Belgian patent no ¹ 855 657th

The compounds produced by the process of the invention show significant antiallergic activity and can therefore be used for prevention. and treating all diseases of allergic origin, such as bronchial asthma, allergic rhinitis, hay fever, urticaria and dermatosis. The antiallergic activity of the compounds of the invention results, for example, from being effective in a passive skin anaphylaxis (PCAj) test in rats according to the invention.

J. Goose and A.M.J. Blaira [Immunology 16, 749 (1969)] A significant advantage of the compounds of formula I is that they exhibit a high level of antiallergic activity 1 after oral administration.

The following table shows the efficacy values found in the PCA test in rats following oral administration of a number of compounds of Formula I under numbers K 13423, K 13262, K 13449, K 134456, compared to the generally known anti-allergic drug cromoglycine disodium salt (DSCG). ).

The potency of the substances is expressed in Ku values, which are defined as doses of active compound capable of reducing the activity of the serum used to induce sensitivity to one half:

_K __ B___ ^Kl! DR — 1 'where

B = dose of the antagonist compound, expressed in mg / kg,

DR = dose ratio: anti-logarithm of the difference between the logarithmic functions of an effective dose of serum with and without antagonist (see J. H. Gaddum et al., Exp. Physiol. 1955, 40, p. 49).

K _B values were chosen in the efficacy evaluation because they are not dose-dependent or concentration of the reagent used to induce sensitivity. The lower the K _B value, the higher the antiallergic activity of the test substance.

In the following table, the codes used represent the following compounds of formula I:

K 13262 = trans-6-carboxy-3-propyl-2- (2-phenylcyclopropyl) chromone,

K 13449 = trans-6-carboxy-3-propyl-2- [2- (3'-methoxyphenyl) cyclopropyl] chromone,

K 13456 =

K 13423 = trans-6-carboxy-3-propyl-2- [2- (5‘-methyl-2‘-furyl) cyclopropyl] chromone.

trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone,

Table

Compound Pre - treatment time Antiallergic efficacy of test substance K _B (mg / kg - per os

K 13423 15 ‘ K 13262 15 ‘ K 13449 15 ‘ K 13456 15 ‘ disodium cromoglycinic acid salt 15 ‘

0.48

4.3

4,56

5.62> 200

The antiallergic efficacy was determined by inhibiting anaphylaxis (immunoglobulin E (IgE) mediated PCAj, according to the method of J. Goos and AMJN Blair (see above), using the body's own antibodies raised in rats by the method described by I. Mota in Immunology 7, 681 (1964).

Test compounds were administered orally (p.o.), 15 minutes prior to antigen administration; at least six rats were used to test each dose.

For selected compounds of formula (I), an acute seven-day acute toxicity following oral administration of the compounds was estimated. For example, the compound designated K 13262 showed an LD 50 of> 400 mg / kg in rats.

Furthermore, the substituted 2-cyclopropylchromones of formula (I) have significant anti-ulcer efficacy as evidenced by the fact that they inhibit the formation of stress-induced ulcers in rats that have been subjected to a forced water bath at 25 ° C for 40 minutes; said working technique is a modification of the method they have described

K. Takagi and S. Okabe in Jap. J. of Pharmac., 19, 9 (1968).

The compounds of formula (I) are also potent bronchodilators, as shown by inhibiting histamine-induced bronchial spasms in guinea pigs according to the method described by Kanzett and Rossler in Arch. Exp. Path. Pharmakol. 71, 195 (1940).

The substituted 2-cyclopropylchromones of formula (I) may be administered by conventional means, for example orally or parenterally, at daily doses of preferably 0.5 to 15 mg / kg, or by inhalation, at daily doses of 0.5 to 100 mg, preferably 0.5 to 25 mg. or locally, for example in the form of a cream containing about 0.5 to 5 mg, preferably 1 to 2 mg, of active ingredient per 100 mg of cream. The nature of the pharmaceutical compositions containing the compounds of formula I together with pharmaceutically acceptable carriers or diluents will of course depend on the intended mode of administration.

The pharmaceutical preparations may be formulated in conventional manner using conventional additives. The compounds of the invention may be administered, for example, in the form of aqueous or oily solutions or suspensions, aerosols, powders, tablets, pills, gelatin capsules, syrups, drops, suppositories, or creams and lotions for topical use.

For oral administration, pharmaceutical preparations containing the compounds of formula I are preferably used in the form of tablets, pills or gelatin capsules which contain the active ingredient in admixture with diluents, such as lactose, glucose, sucrose, mannitol, sorbitol or cellulose; glidants such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols, or also in admixture with a binder such as starches, gelatin, methylcellulose, acacia, tragacanth or polyvinylpyrrolidone; with leavening agents such as starches, alginic acid, alginates or sodium glycollated starch; with effervescent mixtures; with dye; with sweeteners; wetting agents such as lecithin, polysorbates or lauryl sulfate; and generally with other non-toxic and pharmacologically inactive excipients used in the manufacture of dosage forms in the pharmaceutical industry. Said pharmaceutical preparations can be prepared by known methods, for example by mixing, granulating, tabletting, sugar-coating or film-coating of other substances.

In the treatment of allergic asthma, the compounds of formula I may also be administered by inhalation. Formulations which contain a suspension or solution of the active ingredient, preferably in the form of a salt, such as a sodium salt, in water may be used for such administration using conventional inhalation devices. Alternatively, for application from pressurized containers, for example aerosol dispensers, formulations may be used which contain a suspension or solution of the active ingredient in a conventional liquefied propellant, such as dichlorodifluoromethane or dichlorotetrafluoroethane. When the active ingredient is not soluble in the propellant, a cosolvent such as ethanol, dipropylene glycol, isopropyl myristate and / or a surfactant may be added to the active ingredient to suspend the active ingredient; suitable surfactants may be any of those commonly used for this purpose, such as nonionic surfactants such as lecithin.

The compounds of formula (I) may also be administered in the form of powders by means of suitable inhalation devices, and for this application the active ingredient sprayed into fine particles is mixed with a suitable solid diluent, such as lactose.

The compounds of formula (I) may further be administered by conventional means in the form of intradermal or intravenous injection.

In addition to internal administration, the compounds of formula (I) may also be administered in the form of preparations for topical application, for example in the form of creams, lotions or pastes for use in dermatological treatment. Suitable formulations for this kind of use can be prepared by mixing the active ingredient with conventional oily or emulsifying excipients.

The process according to the invention is explained in more detail in the following non-limiting examples.

Example 1

A suspension of 0.86 g of 50% sodium hydride in 40 ml of dimethylformamide is treated with 3.96 g of trimethylsulfoxonium iodide (see J. Chem. Soc. 1967, 2495) with stirring at room temperature for 1 hour, and then a solution of 5 g of trans-6 is added. -methoxycarbonyl-3-propyl-2- (2'-methylstyryl) chromone in 50 ml of dimethylformamide and stirred for an additional 90 minutes at room temperature. The reaction mixture was diluted with ice water, and the product was stirred at room temperature for 90 minutes. The reaction was washed with 5% sodium bicarbonate solution and water until neutral and the solvent was distilled off under reduced pressure. The residue is recrystallized from methanol to give 2.4 g of trans-6-methoxycarbonyl-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. Celsius. The ester obtained is heated to reflux with 1% potassium hydroxide solution in 40 ml of 95% ethanol for 30 minutes. After cooling, the reaction mixture was acidified with 23% hydrochloric acid, ethanol was distilled off under reduced pressure, and the evaporated mixture was diluted with water. The precipitate formed is filtered off, washed with water until neutral and recrystallized from methanol. 1.8 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. Celsius. Infrared spectrum: v (C = O) acid 1710, 1690 cm ^-1 , v (C = O) chromium 1645 cm ^-1 .

The following compounds are prepared in an analogous manner:

trans-6-carboxy-3-propyl-2- (2-phenylcyclopropyl) chromone, m.p. 195-196 ° C, trans-6-carboxy-3-propyl-2- [2- (3'-methylphenyl) cyclopropyl] chromone m.p. 177-178 ° C, trans-6-carboxy-3-propyl-2- [2- (4'-methylphenyl] cyclopropyl] chromone, mp 215-216 ° C, trans-6-carboxy-3 -propyl-2- [2- (2'-methoxyphenyl) cyclopropyl] chromone, m.p. 161-163 ° C, trans-6-carboxy-3-propyl-2- [2- (3'-methoxyphenyl) cyclopropyl] chromium, m.p. 158-160 ° C, trans-6-carboxy-3-propyl-2- [2- (2'-ethylphenyl] cyclopropyl] chromone, mp 211-212 ° C, trans-6-carboxy-3 propyl-2- [2- (3'-ethoxyphenyl) cyclopropyl] chromone, m.p. 208-209 ° C, trans-6-carboxy-3-propyl-2- [2- (2 ', 5'-dimethylphenyl) 161-163 ° C, trans-6-carboxy-3-propyl-2- [2- (2 ', 3'-dimethoxyphenyl) cyclopropyl] chromone, m.p. 184-186 ° C, trans -6-carboxy-3-propyl-2- [2- (2 ', 5'-dimethoxyphenyl) l) cyclopropyl] chromone, m.p. 180-181 ° C; trans-6-carboxy-3-propyl-2- [2- (2'-methoxy-3'-ethoxyphenyl) cyclopropyl] chromone, m.p. 207 ° C, trans-6-carboxy-3-propyl-2- [2- (2'-ethoxy-3'-methoxyphenyl (cyclopropyl) chromone, mp 219-220 ° C, trans-6-carboxy-3 -allyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. 189-190 ° C, trans-6-carboxy-3-ethyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, temperature melting 2 ^! Mp 26-228 ° C, trans-6-methoxycarbonyl-3-propyl-2- (2- (3'-methylphenyl) cyclopropyl] chromone, m.p. 115-117 ° C, trans-6-methoxycarbonyl-3-propyl-2 [2- (2'-Methoxyphenyl) cyclopropyl] chromone, m.p. 125-127 ° C, trans-6-carboxy-3-ethyl-2- (2-phenylcyclopropyl) chromone, m.p. 217-218 ° C. trans-6-carboxy-3-butyl-2- (2-phenylcyclopropyl) chromone, m.p. 193-199 ° C, trans-6-carboxy-3-methyl-2- [2- (2'-methyl) 1-phenyl) cyclopropyl] chromone, m.p. 251-252 ° C.

Example 2

A suspension of 0.62 g of 50% sodium hydride in 30 ml of dimethylformamide was treated with

2.86 g of trimethylsulfoxonium iodide with stirring at room temperature for 2 hours, then a solution of 3.52 g of trans-6-methoxycarbonyl-3-propyl-2- [2- (5'-methyl-2'-furyl] vinyl] is added. The reaction mixture was diluted with ice water, acidified with 2N hydrochloric acid and shaken with ethyl acetate, and the organic extract was washed with 5% sodium bicarbonate solution and water until neutral and the solvent was removed. After distillation under reduced pressure, the residue is obtained after recrystallization from methanol

2.2 g of trans-6-methoxycarbonyl-3-propyl-2- (2- (5'-methyl-2'-furyl) cyclopropyl) chromone, m.p. 138-139 [deg.] C. The ester obtained is heated with 1%. The reaction mixture was acidified with 10% potassium dihydrogen phosphate solution, the ethanol was distilled off under reduced pressure, and the evaporated mixture was diluted with water, and the precipitate was filtered off, washed with water and the aq. Recrystallization from isopropanol gave 1.5 g of trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-furyl) cyclopropyl] chromone, m.p. 166-169 ° C.

The following compounds are prepared in an analogous manner:

trans-6-methoxycarbonyl-3-propyl-2- (2- (5'-methyl-2'-thienyl) cyclopropyl] chromone, m.p. 151-153 ° C, trans-6-carboxy-3-propyl-2- [2- (5'-Methyl-2'-thienyl 1-cyclopropyl 1-chromone, m.p. 179-181 ° C, trans-6-methoxycarbonyl-3-propyl-2- (2- (2'-thienyl) cyclopropyl] chromone) mp 159-161 ° C, trans-6-carboxy-3-propyl-2- [2- (2'-thienyl) cyclopropyl] chromone, mp 196-197 ° C, trans-6-methoxycarbonyl-3- propyl 2- [2- (2'-pyridyl) cyclopropyl] chromone, m.p. 180-182 ° C; and trans-6-carboxy-3-propyl-2- [2- (2'-pyridyl) cyclopropyl] chromone, mp 209-210 ° C.

Example 3

A suspension of 0.62 g of 50% sodium hydride in 50 ml of dimethylformamide is treated with 2.86 g of trimethylsulfoxonium iodide with stirring at room temperature for 1 hour, then a solution of 3.7 g of 6-carboxy-3-propyl-2- [sodium] salt is added. Of 2'-methylstyryl chromone in 50 ml of dimethylformamide and the mixture is stirred for another 18 hours at room temperature. The reaction mixture was diluted with ice water, acidified with 23% hydrochloric acid, and the precipitate formed was filtered off and washed with water until neutral. Recrystallization of the crude product from methanol gave 1.85 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. 206-207 ° C.

The following compounds are prepared in an analogous manner:

trans-6-carboxy-3-propyl-2- [2- (3'-methylphenyl) cyclopropyl] chromone, m.p. 177-178 ° C, trans-6-carboxy-3-propyl-2- [2- (2 161-163 ° C; and trans-6-carboxy-3-propyl-2- [2- (3'-methoxyphenyl) cyclopropyl] chromone, m.p. 158-160 ° C.

Example 4

The following compounds were prepared as described in Example 3:

trans-6-carboxy-3-propyl-2- [2- (5'-methyl-3'-furyl) cyclopropyl] chromone, m.p. 166-169 ° C and trans-6-carboxy-3-propyl-2 - [2- (5'-Methyl-2'-thienyl] cyclopropyl] chromone, m.p. 179-181 ° C.

Example 5

The following compounds were prepared as described in Examples 1 and 2 using the appropriate tert-butyl esters of 2-substituted trans-6-carboxy-3-propylchromones:

trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone tert-butyl ester, oily liquid; IC spectrum: v (C = O) ester 1710 cm ^-1 ; v (C =) chromone 1640 cm ^-1 and trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-furyl) cyclopropyl] chromone tert-butyl ester, oily liquid; IR spectrum :

v (C = O) ester 1720 cm -1, v (C = O) chromon 1645 om ^-1 .

Example 6

4.3 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone tert-butyl ester are reacted with 30.2 g of trifluoroacetic acid at room temperature for 6 hours . The trifluoroacetic acid was distilled off under reduced pressure, the residue was diluted with ice water and the precipitate formed was filtered off and washed with water until neutral. Recrystallization of the product from ethanol gave 3.2 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. 206-207 ° C.

The following compounds are prepared in an analogous manner:

trans-6-carbonyloxy-3-propyl-2- [2- (3'-methoxyphenyl) cyclopropyl] chromone, m.p. 158-160 ° C and tris-6-carboxy-3-propyl 1- 2- [2- (2'-Methoxyphenyl) cyclopropyl] chromone, m.p. 161-163 ° C.

EXAMPLE 7 g, i.e. 1.42 ml of trimethylsilyl iodide in 50 ml of carbon tetrachloride, is reacted with 4.25 g of trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-) tert-butyl ester. furyl cyclopropyl jchromone with stirring under a nitrogen atmosphere, 2 hours at room temperature and then 2 hours at 50 DEG C. After cooling, the reaction mixture was diluted with ethyl ether and the product was shaken into a 2% aqueous sodium bicarbonate solution. The precipitate formed is filtered off and washed with water until neutral.The crude product, after recrystallization from isopropyl alcohol, yields 2.35 g of trans-6-carboxy-3-propyl-2- [2- (3'-methyl-2-) 166-169 ° C; (furyl) cyclopropyl] chromone.

The following compound is obtained in an analogous manner:

trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-thienyl) cyclopropyl] chromone, m.p. 179-181 ° C.

Example 8

The following compounds were prepared as described in Examples 1, 3, 5 and 6 using the appropriate trans-6-carboxy- and trans-6-alkoxycarbonyl-3-alkoxy-2-styrylchromones:

trans-6-carboxy-3-ethoxy-2- (2-phenylcyclopropyl) chromone, m.p. 178-180 ° C, trans-6-carboxy-3-butoxy-2- (2-phenylcyclopropyl) chromone, melting point 138-139 ° C, trans-6-carboxy-3-ethoxy-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. 207-208 ° C, trans-6-carboxy-3-ethoxy-2 - [2- (3'-Methylphenyl) cyclopropyl] chromone, m.p. 114-115 ° C, tris-6-carboxy-3-ethoxy-2- [2- (4'-methylphenyl) cyclopropyl] chromone, mp 206-207 ° C, trans-6-carboxy-3-ethoxy-2- [2- (3'-methoxyphenyl) cyclopropyl] chromone, mp 181-182 ° C, and trans-6-carboxy-3- ethoxy-2- [2- (2'-methoxyphenyl) cyclopropyl] chromone, m.p. 175-177 ° C.

Example 9

Following the procedures described in Examples 2, 4, 5 and 7, using the appropriate trans-6-carboxy- and trans-6-alkoxycarbonyl-3-alkoxy-2- (2-heteroarylvinyl) chromones, the following compounds were prepared:

trans-6-carboxy-3-ethoxy-2- [2- (5'-methyl-2'-furyl) cyclopropyl] chromene, m.p. 145-146 ° C, trans-6-carboxy-3-ethoxy-2 - [2- (5'-Methyl-2'-thienyl) cyclopropyl] chromone, m.p. 190-193 ° C and trans-6-carboxy-3-ethoxy-2- [2- (5'-pyridyl) cyclopropyl] m.p. 248-250 ° C.

Example 10 g of trans-6-carboxy-3-propyl-2- [2- (2‘-methylphenyl) cyclopropyl] chromone was reacted with 5.4 g of ethyl iodide in the presence of

6.3 g of anhydrous potassium carbonate in an environment of 70 ml of dimethylformamide with stirring for 4 hours. The reaction mixture is diluted with ice water, the precipitate formed is filtered off and recrystallized from isopropyl ether. 7.8 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone ethyl ester of melting point 118 DEG-120 DEG C. are obtained.

The following compound was prepared in an analogous manner:

trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-furyl) cyclopropyl] chromone ethyl ester, m.p. 76-78 ° C.

Example 11 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone was treated with 5 ml of chloromethyl pivalate and 2 ml of triethylamine in 40 ml of dimethylformamide with heating at 70 ° C for 2 hours. After cooling, the reaction mixture was diluted with ice water, the solution was shaken with ethyl acetate, and the organic layer was washed with 5% sodium bicarbonate solution and water. The solvent was distilled off under reduced pressure and the residue was recrystallized from isopropyl ether. There were obtained 3.85 g of trans-pivaloyloxymethyl ester of 6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl -chromone, IR: v (C = Oj ester 1735 cm ^1, v (C = Oj chromon 1640 cm ^-1 .

Example 12

3.6 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone are treated with 2.7 g of 1-chloro-2-diethylaminoethane and 2.8 g of anhydrous potassium carbonate, stirring for 8 hours in an environment of 40 ml of dimethylformamide at 20 ° C. The reaction mixture is diluted with water, the precipitate is filtered off and washed with water until neutral. Recrystallization from isopropyl ether yields

2.2 g of trans-6-carboxy-3-propyl-2- [2- (2‘-methylphenyl) cyclopropyl] chromone 2-diethylaminoethyl ester, m.p. 9-90 ° C.

Example 13 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone was treated with 6 ml of thionyl chloride in 120 ml of dioxane for 3 hours at room temperature. The volatiles were distilled off under reduced pressure, the residue was dissolved in 80 ml of dioxane, 2 ml of triethylamine was added, followed by 4 ml of 2 diethylaminoethanol, and the mixture was allowed to react at room temperature for 20 hours. The reaction mixture is diluted with water, the precipitate formed is filtered off, dissolved in 100 ml of ethyl ether and a stoichiometric amount of a solution of hydrogen chloride in ether is added to the solution. The precipitate formed is filtered off, washed with ether and dissolved in water. The solution was basified with potassium carbonate and the precipitated product was filtered off. There was obtained 7.8 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone 2-dieithylaminoethyl ester, m.p. 89-90 ° C; IR: v (C = O) ] ester 1720 cm ^-1 , in (C = O) chromium 1640-1610 cm ^-1 .

Example 14

0.5 g of 50% sodium hydride in 30 ml of dimethylformamide was treated with 2.3 g of trimethylsulfoxonium iodide with stirring at room temperature for 1 hour, and then a solution of 3.5 g of trans-6-carboxy-3-propyl-2 2-dimethylaminomethyl ester was added. of styrylchromone in 20 ml of dimethylformamide and the mixture was allowed to react at room temperature with stirring for 90 minutes. The reaction mixture was diluted with water, the solution was shaken with ethyl acetate, the organic portion was washed with water, and the solvent was distilled off under reduced pressure. The residue (2.9 g) was purified by column chromatography on silica gel (eluent: benzene / ethyl acetate / triethylamine 90: 10: 0.2). 1.7 g of trans-6-carboxy-3-propyl-2- (2-phenylcyclopropyl) chromone 2-diethylaminoethyl ester of melting point 92 DEG-94 DEG C. are obtained.

The following compound was prepared in an analogous manner:

Trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone 2-diethylaminoethyl ester, m.p. 89-90 ° C.

Example 15

1.1 g of trimethylsulfoxonium iodide are treated with 0.24 g of 50% sodium hydride in 20 ml of dimethylformamide with stirring at room temperature for 1 hour, and then a solution of 1.55 g of trans-8-carbomethoxy-3-ethoxy-2-12- is added. (2 ', ^3! £ dimethoxy-phenyl ethenyl j 1 chromene, mp 179-181 ° C, in 20 mL of dimethylformamide. the mixture was reacted with stirring at room temperature for 6 hours and then diluted with ice defect. the precipitate was filtered and washed with water until it has a neutral reaction. 1.1 g of the thus obtained trans-6-carbomethoxy-3-ethoxy-2- [2- (2 ', 3'-dimethoxyphenyl j cyclopropyl] chromone, m.p. 115-117 ^C. C was allowed The reaction mixture was then cooled and acidified with 37% hydrochloric acid, evaporated under reduced pressure and diluted with ice water, and the precipitate was filtered off and crystallized from isopropanol. with 0.6 g lrans-6-carbo xy-3-ethoxy-2- (2- (2 ', 3'-dimethoxyphenyl) cyclopropyl) chromone, m.p. 166-168 ° C;

Company ID (nujolj:

v (C = O) acid 1730 cm ^-1 v (C-O) chromium 1645, 1610 cm ^-1

NMR (DMSO d6):

1.23 (t) (—OCH 2 CH 3)

1.58-2.10 (mj-cw - Chi-)

2.65 (IU and 2.97 (111)

3.76 (S) (—OCH3)

3.86 (S) _(OCH3)

4.14 (q) (-OCH 2 CH 3)

6.66-7.20 (m) (phenyl protons)

7.82 (d) (C-8 chromonyl proton)

8.34 (d, d) (C-7 chromonyl proton) 8.70 (d) (C-5 chromonyl proton).

The following compounds are prepared in an analogous manner:

trans-6-carboxy-3-propoxy-2- [2- (2 ', 3'-dimethoxyphenyl) cyclopropyl] chromone, m.p. 164-165 ° C;

trans-6-carboxy-3-ethoxy-2- [2- (2'-methoxy-3'-ethoxyphenyl) cyclopropyl] chromone, m.p. 203-204 ° C; trans-6-carboxy-3-ethoxy-2- [2- (2 ', 5'-dimethoxyphenyl) cyclopropyl] chromone, m.p. 190-192 ° C, trans-6-carboxy-3-propoxy-2- [ (2'-ethoxy-5'-methoxyphenyl) cyclopropyl) chromone, m.p. 156-157 ° C, trans-6-carboxy-3-ethoxy-2- [2- (2 ', 5'-dimethyl) cyclopropyl] chromone, mp 187-188 ° C, trans-6-carboxy-3-propoxy-2- [2- (2 ', 5'-dimethylphenyl) cyclopropyl) chromone, mp 160-161 ° C,

NMR (DMSO-d6) <5:

0.94 (t) (—OCI-12CH2CH3)

1.71 (inter alia)

OCH 2 —CH 2 CH 3)

1.83 (m) \ /

2.32 (S) (6 p, —CH 3)

2.4-2.9 (m) - (CW - - CH -) \

4.08 (t) (—OCH2CH2CH3)

7.05 (m) (phenyl protons)

7.77 (d) (C-8 chromonyl proton)

8.32 (d, d) (C-7 chromonyl proton)

8.72 (d) (C-5 chromonyl proton), trans-6-carboxy-3-propoxy-2- [2- (2 ', 5'-dimethoxyphenyl) cyclopropyl] chromone, m.p. 164-165 ° C ,

NMR (DMSO-d 6) δ:

0.91 (t) (—OCH 2 CH 2 CH 3)

1.69 (m) (—OCH 2 CH 2 CH 3)

1.89 (m)

(-CH-CH-) \ /

2.6-3.05 (m) (-Cu-CW-J \ / _CH

3.80 (S) (6µ, —OCII3)

4.05 (m) (—OCH 2 CH 2 CH 3)

6.7—7.06 (m) (phenyl protons)

7.73 (d) (C-8 chromonyl proton)

8.30 (d, d) (C-7 chromonyl proton)

8.72 (d) (C-5 chromonyl proton) trans-6-carboxy-3-ethoxy-2- [2- (3'-ethoxyphenyl) cyclopropyl) chromone, m.p. 169-171 ° C, trs 6-carboxy-3-ethoxy-2- [2- (4'-methoxyphenyl) cyclopropyl] chromone, m.p. 220-221 ° C, trans-6-carboxy-3-propoxy-2- [2- (2 178-180 ° C, trans-6-carboxy-3-propoxy-2- [2- (3 '-, methylphemyl) cyclopropyl] chromone, m.p. 162-163 ° C; trans-6-carboxy-3-propoxy-2- [2- (4'-methylphenyl) cyclopropyl] chromone, m.p. = 193-193 ° C, trans-6-carboxy-3-propoxy-2- [2] - (2'-methoxyphenyl) cyclopropyl] chromone, pulse ¹ Speed point 154 DEG-156 DEG C. trans-6-carboxy-3-propoxy-2- [2- (3'-methoxyphenyl) cyclopropyl-1] chromone, temperature 159 DEG-162 DEG C., trans-6-carboxy-3-methoxy-2- (2-phenylcyclopropyl) chromium, m.p.

182 DEG C., trans-6-carboxy-3-propoxy-2- (2-phenylcyclopropyl) chromone, m.p. Celsius, trans-6-carboxy-3-allyloxy-2- (2-phenylcyclopropyl) chromone, m.p. 156-157 ° C.

Example 1 a d .16

Following the procedure of Example 15 starting from appropriately substituted trans-6-carboimethoxy-3-propyl-2- (phenylethenyl) chromones, the following compounds were prepared:

tris-6-carboxy-3-propyl-2- [2- (4'-methoxyphenyl) cyclopropyl] chromone, m.p. 209-210 ° C, trans-6-carboxy-3-propyl-2- [2- ( 2'-ethoxyphenyl) cyclopropyl] chromon, m.p. 185-187 ° C, trans-6-carboxy-3-propyl-2- [2- (2'-ethoxy-5'-methoxyphenyl) cyclopropyl] 164-167 ° C, trans-6-carboxy-3-propyl-2- [2- (3 ', 5'-dimethoxyphenyl) cyclopropyl] chromone, melting point 162-163 ° C, trans-6- carboxy-3-propyl-2- 2- (2 ', 4'-dimethoxyphenyl) cyclopropyl] chromone, m.p. 233-234 ° C, trans-6-carboxy-3-propyl-2- [2- (2', 3'-diethoxyphenyl) cyclopropyl] chromone mp 180-182 ° C.

Example 17

3.46 g of trimethylsulfoximium iodide are treated with 0.76 g (50%) of sodium hydride in 50 ml of dimethylformamide with stirring at room temperature for 2 hours. A solution of 3.8 g of trans-6-carboxymethoxy-3-propyl-2- [2- (6'-methyl-2'-pyridyl) ethenyl] chromone, m.p. 161-164 ° C, in 50 ml of dimethylformamide is then added. . The mixture was allowed to react with stirring at room temperature for 6 hours and then diluted with ice water. The precipitate was extracted with ethyl acetate and the solution was evaporated to dryness under reduced pressure. 3.9 g of trans-6-carboxymethoxy-3-propyl-2- [2- (6'-methyl-2'-pyridyl) cyclopropyl) chromene are obtained, which is reacted with 67.6 ml of 1% hydroxide solution. of potassium in 95 ° / o ^! ethanol at reflux for 10 minutes. After cooling, the reaction mixture was diluted with ice water, neutralized with sodium hydrogen phosphate, the precipitate was filtered off and washed with water until neutral. Crystallization from 2-butanone gave 1.4 g of trans-6-carboxy-3-propyl-2- [2- (6'-methyl-2'-pyridyl) -cyclopropyl] -chromone, m.p. 216-217 ° C.

IR (KBrj:

v (C-O) acid 1710 cm ^-1 v (C-O) chroimon, 1640, 1620 cm ¹

NMR (DMSO-d 6) δ:

0.82 (ie (—CH2CH2CH3)

1.44 (mi (—CH 2 CH 2 CH 3))

1.85 (inter alia)

2.47 (sj (-—CH 3) 2.40-3.04 (m) ^X CH ₍ ,

7.07-7.78 (m) (pyridyl protons)

7.69 (d) (C-8 chromonyl proton)

8.28 (d, d) (C-7 chromonyl proton)

8.64 (d) (C-5 chromonyl proton) .If the procedure is analogous, the following compounds are produced:

trans-6-carboxy-3-ethoxy-2- [2- (6'-methyl-2'-pyridyl) cyclopropyl] chromone, m.p. 229-230 ° C, tris-6-carboxy-3- propoxy-2- [2- (6'-methyl-2'-pyridyl) cyclopropyl] chromone, m.p. 199-200 ° C, trans-6-carboxy-3-allyloxy-2- [2- (6'- methyl 2'-pyridyl) cyclopropyl] chromone, m.p. 180-181; ^and C, trans-6-carboxy-3-ethyl-2- [2- (6'-methyl-2'-pyridyl) cyclopropyl] chromone, m.p. mp 291-292 ° C, trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-pyridyl) cyclopropyl] chromone, mp 206-207 ° C, trans-6-carboxy-3 ethoxy-2- [2- (5'-methyl-2 ^I-pyridyl) cyclopropyl] cliromon, mp 207-208 ° C, trans-6-carboxy-3-propoxy-2- [2- (5'- methyl 2'-pyridyl) cyclopropyl] chromone, m.p. 201-202 ° C,

NMR (DMSO-d 6) δ:

0.84 (t) (—OCH 2 CH 2 CH 3)

1.60 (m) (—OCH 2 CH 2 CH 3)

1.88 (m) -CH-CH3]

2.30 (S) (- CH 3) 2.95 (m) \ /

CH 2

4.00 (mj (—OCH 2 CH 2 CH 3))

7.41 (d) (G-3 pyridyl proton)

7.61 (d, d] (C-4 pyridyl proton)

7.73 (d) (C-8 chromonyl proton)

8.30 (d, d) (C-7 chromonyl proton)

8.42 (d) (C-6 pyridyl proton)

8.66 (d) (C-5 chromonyl proton), trams-6-carboxy-3-propyl-2- [2- (4'-methyl-2'-pyridyl) cyclopropyl] chromium, m.p. 229-232 ° C, trans-6-carboxy-3-propoxy-2- [2- (2'-pyridyl) cyclopropyl] chromone, m.p. 200-201 ° C, trans-6-carboxy-3-propoxy-2- [2- (5'-methyl-2'-furyl) cyclopropyl] chromone, m.p. 146-147 ° C.

lote the room for 6 hours. The mixture was diluted with ice water, the precipitate was filtered off and crystallized from n-hexane. Yield 0.4 g of trans-6-carbethoxy-3-propyl-2- (2- (6‘-methyl-2‘-pyridyl) cyclopropyl) chromone, m.p. 95-97 ° C.

Example 19

1.3 g of trans-6-carboxy-3-propyl-2- [2- (6'-methyl-2 '-, pyridyl) cyclopropyl) chromone are reacted with 0.6 ml SOCl 2 in 30 ml dioxane at reflux temperature. flow for 1 hour. The reaction mixture was then evaporated to dryness under reduced pressure. The residue is then dissolved in 30 ml of anhydrous dioxane containing 0.5 ml of triethylamine and treated with 1 ml of 2-ethylaminoethanol at room temperature for 24 hours. After dilution with water, the precipitate was extracted with ethyl acetate and the solution was evaporated to dryness under reduced pressure. The residue was purified on a silica gel column with a mixture of benzene and ethyl acetate as eluent. 0.4 g of trans-6-carboxy-3-propyl-2- [2- (6'-methyl-2'-pyridyl) cyclopropyl] chromone 2-diethylaminomethyl ester was obtained as an oil.

NMR (CDCl 3) δ:

0.90 (t) (-CII 2 CH 2 Cl 2)

1.10 (t) • N

1.55 (m) (—CH 2 CH 2 Cl 2)

1.87 (inter alia)

I-CW- cw-J \ /

2.52 (s) (—CH3) 2.71 (qj

Z / -W (-N

Example 18

2.50—2.90 (ia

0.6 g of trans-6-carboxy-3-propyl-2 - ['2- (6'-methyl-2'-pyridyl) cyclopropyl] chromone was not reacted with 0.54 g of ethyl iodide and 0.63 g of anhydrous potassium carbonate in 7 ml dimethylformamide with stirring at room temperature ⁽ CH 2 CH 7 - CH CH -)

A 5

CH 2

2.95 (t)

Z (—OCH2CH2N) \

4.49 (t)

Z (-OCH 2 CH 2 N) \

6.96-7.64 (m) (pyridyl protons)

7.47 (d) (C-8 chromoinyl proton) 8.32 (d, d] (C-7 chromonyl proton)

8.93 (d) (C-5 chromonyl proton).

Example 20

Dissolve 1.6 g of trans-6-carboxy-3-propyl-2- [2- (6--methyl-2‘-pyridyl) cyclopropyl] chromene in a stoichiometric amount of 2 N sodium hydroxide. The solution was then evaporated under reduced pressure and diluted with acetone. The precipitate was filtered off and washed with acetone. There was obtained trans-6-carboxy-3-propyl-2- [2- (6--methyl-2yl-pyridyl) cyclopropyl] chromene sodium salt, m.p. &gt; 300 ° C.

Claims (2)

SUBJECT A process for the preparation of substituted 2-cyclopropylchromones of the formula I n is zero or 1, R1 represents a hydrogen atom or a C1-C20 alkyl group optionally substituted by a C2-C5 alkanoyloxy group or a group of the formula R4 Z ~ N \ R 5 wherein each of R 4 and R 5 is independently selected from the group consisting of hydrogen and C 1 -C 10 alkyl, or wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an N-pyrrolidinyl radical. R 2 represents a C 1 -C 8 alkyl group or a C 3 or C 4 alkenyl group; R3 also represents a furyl, thienyl or pyridyl group, which may be optionally substituted by a methyl group, or bj is a group of the general formula Wherein each individual R 6 and R 7 is independently selected from the group consisting of a'j hydrogen b ') halogen and c'j - (O) _nl —Re wherein n1 is zero or 1 and R6 is alkyl C 1 -C 6 optionally substituted by C 1 -C 12 alkoxy and C 3 or C 4 alkenyloxy, and pharmaceutically acceptable salts and isomers thereof, characterized in that in a compound of formula (II): n, R 1, R 2 and R 3 are as defined above, or in salts thereof, by treatment with dimethylsulfoxonium methylide to form a cyclopropane ring, and the compound of formula I obtained is optionally converted to another compound of formula I, and / or a pharmaceutically acceptable salt, and / or converting the obtained salt into the free compound, and / or separating the mixture of isomers into the individual isomers. 2. The process of claim 1 wherein the reaction is carried out in an inert organic solvent selected from the group consisting of dimethylformamide, dimethyl sulfoxide, dioxane and mixtures thereof at a temperature between 0 and 50 ° C.