CS207643B2 - Method of making the substituted 2-cyclopropylchromones - Google Patents

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

where 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 formula

Re

Z —N \

R 5 wherein each R 6 and R 5 is independently selected from the group consisting of hydrogen or C 1 -C 10 alkyl, or wherein R 6 and R 6 together with the nitrogen atom to which they are attached form N-pyrrolidinyl, piperidine; or morpholine radical,

R @ 2 denotes an alkyl group having 1 to 8 carbon atoms or an alkenyl group having 3 or 4 carbon atoms and

R3 denotes

(a) a furyl, thienyl or pyridyl group optionally substituted by a methyl group; or

b) a group of the general formula

wherein each individual R e and R 7 is independently selected from the group consisting of a ') a hydrogen atom, b') a halogen atom, and c ') a group of the formula - (O) _{nJL -Rs} wherein n1 is zero or 1 and R5 is alkenyl C 3 -C 4 or C 1 -C 6 alkyl, said groups being optionally substituted by at least one C 1 or C 2 alkoxy or hydroxy group.

The present invention also provides a process for the preparation of pharmaceutically acceptable salts and all possible isoimeric 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 N - and δ-carbon atoms of the formula I on the same side with respect to the plane of the cyclopentane ring, the compounds are in the cis-configuration, and vice versa, if on the opposite sides the compounds are in the trans-configuration . Also included within the scope of the invention are mixtures of the cis and trans isomers. 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:

(b) when R3 is a pyridyl group:

(c) if R3 is a furyl or thienyl group:

where

X represents an oxygen or sulfur atom.

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

When R1 represents an unsubstituted alkyl group having 1 to 20 carbon atoms, it is preferably an alkyl group having 1 to 6 carbon atoms and in particular a methyl, ethyl, isopropyl, tert-butyl or hexyl group.

When R1 is C1 -C20 alkyl substituted by C2 -C5 alkanoyloxy, R1 is preferably pivaloyloxymethyl.

When R 1 and / or R 5 is a C 1 -C 10 alkyl group, it is preferably a C 1 -C 4 alkyl group and preferably a methyl, ethyl, isopropyl or tert-butyl group.

Preferably R2 represents an alkyl group having 2 or 3 carbon atoms, in particular an ethyl or propyl group, or an alkenyl group having 3 carbon atoms, in particular an allyl group.

When R3 represents a furyl, thienyl or pyridyl group, it is preferably a 2-furyl, 24-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 5 and R 7 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkoxy, especially methoxy and ethoxy, and C 1 -C 4 alkyl, especially methyl and ethyl.

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

N-ethylpiperldine,

N, N-diethylaminoethylamine,

N-ethylmorpholinera, (3-phenethylamine,

N-benzyl-5S-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 acids and ethanesulfonic acid.

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

Particularly preferred compounds of the invention are those compounds of formula I wherein R1 is a) a hydrogen atom, b) a C1-C6 alkyl group optionally substituted with a formula of the general formula

R4

Z —N \

R 5 wherein R 4 and R 5, which are the same or different, denotes a (C 1 -C 4) alkyl group, (c) 2- (N-pyrrolidinyl) ethyl, (d) pivaloyloxymethyl, n represents zero or 1, R 2 represents an alkyl group having 1 to 4 carbon atoms, in particular an ethyl or propyl group, or an alkenyl group having 3 carbon atoms, especially an allyl group, R3 denotes a (a) phenyl group, optionally substituted with an alkyl group having 1 to 4 carbon atoms, especially methyl or ethyl or C1-C4alkoxy, in particular methoxy or b ', 2-furyl, 2-thienyl or 2-pyridyl, optionally substituted by methyl, as well as pharmaceutically acceptable salts thereof.

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

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

trans-6-carboxy-3-propyl-2- [2-phenylcyclopropyl] chomonone, trans-6-carboxy-3-allyl-2- (2-phenylcyclopropyl) chromium, 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) 1) cyclopropyl] chromone, trans-6-carboxy-3-propyl-2- [2- (3'-methylphenyl) cyclopropyl] chromone, trans-6-carboxy-3-allyl-2- [2- (3'- methylphenyl) cyclopropyl] chromone, trans-6-carboxy-2-propyl-2- [2- (3'-methoxyphenyl) cyclopropyl] chromone, trans-6-carboxy-3-propyl-2- [2- ( 2'-methoxyphenyl] cyclopropyl] chromone, trans-6-carboxy-3-propyl-2- [2- (2'-pyridyl) cyclopropyl] chromone, trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-furyl] cyclopropyl] chromone, trans-6-carboxy-3-ethoxy-2- [2- (5'-methyl-2'-furyl] cyclopropyl] chromone trans-6-carboxy-3-ethyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'- thienyl J cyclopropyl] chromone, trans-6-carboxy-3-ethoxy-2- [2- (5'-methyl-2'-thienyl] cyclopropyl J chromone,

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

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

Trans-6-carboxy-3-proipyl-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 alkyl esters having 1 to 6 carbon atoms, in particular methyl, ethyl, isopropyl, tert-butyl and hexyl esters.

The substituted 2-cyclopropylchromones of the formula I, their pharmaceutically acceptable salts as well as the isomers thereof are prepared according to the invention by cyclizing a compound of the formula II

where

R 1, R 2 and R 3 are as defined above, or a salt thereof, to form a compound of formula I wherein n is zero and the compound of formula I obtained is optionally converted in a known manner into another compound of formula I, and / or or the compound of formula I is converted into the corresponding pharmaceutically acceptable salt, and / or the salt obtained is converted to the free compound, and / or the resulting mixture of isomers is separated into the individual isomers.

The cyclization of the compound of formula (II) is preferably carried out in the presence of an acid catalyst, such as hydrochloric, hydrobromic, sulfuric or formic acid, suitably at a temperature between 20 and 120 ° C. Celsius. The cyclization reaction is conveniently carried out in an inert organic solvent, for example selected from the group consisting of methanol, ethanol, dioxane, tetrahydrofuran, benzene, toluene, acetic acid or a mixture thereof.

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 —COOR 1 represents an esterified carboxyl group may be converted to a compound of formula (I)

COOR 1 denotes a carboxyl group, by hydrolysis, for example, under alkaline conditions with, for example, sodium or potassium hydroxide, in a suitable solvent such as water or a lower aliphatic alcohol at a temperature ranging from room temperature to about 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 substituents are 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 selected e.g. from the group comprising 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 wherein -COOR 1 is a carboxyl group can be converted to a compound of formula I wherein -COCO 1 is an esterified carboxyl group optionally substituted with 2 to 5 carbon alkanoyloxy or a group of formula

R4 /

—N \

R 5 wherein R 4 and R 5 are as defined above, may be converted by conventional means, for example by reaction of an alkali acid salt with a suitable alkyl halide, in an inert solvent such as acetone, dioxane, dimethylformamide or hexamethylphosphoric triamide at a temperature in the range of about 0 to about 100 ° C.

Alternatively, esterification of a compound of formula (I) may be carried out by:

a) converting a compound of formula I in which —COORt is a carboxyl group, to a corresponding halocarbomyl, preferably a chlorocarbonyl derivative, by reaction with, for example, a suitable aeyl halide, e.g. oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride, 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 reacting the obtained halocarbonyl derivative with a suitable alcohol of formula R 1 —OH in which R1 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 cd. 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 base and then crystallizing the mixture of salts. 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) may be prepared in a conventional manner by reacting a compound of formula (IV)

(IV) where

R1 and R2 are as defined above, reacted with a compound of formula V

ZOC-CH2-CH-Rj where

Z represents a bromine, chlorine or iodine atom;

R3 is as defined above, for example, the reaction is carried out in an inert solvent such as benzene, toluene or dioxane at a temperature ranging from 0 to the boiling point of the mixture in the presence of a basic agent such as pyridine or triethylamine as the acid acceptor; the compound of formula VI obtained

TT CH-CH-R \ / ³ (v \) where

R 1, R 2 and R 3 are as defined above, similar to the rearrangement to give a compound of formula II. The rearrangement is preferably carried out in an inert solvent such as pyridine, methyl ethyl ketone, toluene or isopropyl alcohol in the presence of a strong base such as sodium, sodium amide, potassium hydroxide or sodium or potassium carbonate at a temperature ranging from room temperature to the boiling point of the reaction. mixtures.

Compounds of formula (IV) may be prepared, for example, by Frles rearrangement from suitable isomeric phenoxy derivatives, which are known compounds.

The compounds of formula (V) are known compounds and can be prepared by conventional methods.

The compounds produced by the method of the invention have significant antiallergic activity and can therefore be used to prevent and treat 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. Blair [Immunology 16, 749 (1969)]. An important advantage of the compounds of formula I is that they exhibit a high level of antiallergic activity even 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 13456, compared to the generally known antiallergic drug cromoglycic acid disodium salt ( DSCG).

The potency of the substances is expressed in K _B 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 β} DR-1 'where

B denotes the dose of antagonist compound, expressed in mg / kg; DR refers to the dose: 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. 40, 49, 1955).

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 13423 = trans-6-carboxy-3-propyl-2- [2- (2‘-methylphenyl) cyclopropyl] chromone,

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

K 13449 = trans-6-carboxy-3-propyl-2- [2- (3'-methoxyphenyl) cyclopropyl] chromone and K 13456 = trans-6-carboxy-3-propyl-2- [2- (5 ') methyl-2'-furyl) cyclopropyl] chromone.

Compound

Table

Test substance treatment time (min)

Antiallergic efficacy K _B (mg / kg) - per os

K 13423 15 Dec 0.48 K 13262 15 Dec 4.3 K 13449 15 Dec 4,56 K 13456 15 Dec 5.62 cromoglycic acid disodium salt 15 Dec > 200

Antiallergic efficacy was determined by inhibiting immunoglobin E (IgE) mediated anaphylaxis (PCA), according to the method of J. Goos and AMJN Blair (cited 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 value of> 400 mg / kg in rats.

Furthermore, the substituted 2-cyclopropylchromones of formula (I) have significant anti-ulcer activity 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 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 in a test according to the method described by Kanzett and Rossler in Arch. Exp. Path. Pharmakol. 71, 195 (1940).

The substituted 2-cyclopropylchromones of the formula I can be administered by conventional means, for example orally or parenterally, in daily doses of preferably 0.5 to 15 mg / kg, or by inhalation, in 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 depend upon the intended route 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, as well as powders, tablets, pills, gelatin capsules, syrups, drops, suppositories or creams and lotions for topical use.

For oral administration, pharmaceutical preparations containing compounds of the 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, and lubricants. 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 baking agents such as starches, alginic acid, alginates or sodium salt of glycolised starch, with effervescent mixtures, with colorants, with sweeteners, with wetting agents such as lecithin, with polysorbates or with lauryl sulphate, and generally with other non-tolic and pharmacologically inactive excipients. used in the manufacture of dosage forms in the pharmaceutical industry. These 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 containing a suspension or solution of the active ingredient in a conventional liquefied propellant such as dichlorodifluoromethane or dichlorotetrafluoroethane may be used. If the active ingredient is not soluble in the propellant, a solubilizer 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, for example lecithin.

The compounds of formula (I) may also be administered in the form of powders by means of suitable inhalation devices, and for this method of administration, 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 injections.

In addition to internal administration, the compounds of formula (I) may also be administered in the form of preparations for topical application, for example creams, lotions or pastes for use in dermatological treatments. 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 g of methyl 3-valeroyl-4-hydroxybenzoate dissolved in 100 ml of anhydrous benzene and 10 ml of pyridine was reacted at room temperature with trans-2-phenylcyclopropyl-1-carbonyl chloride for 20 hours. The organic solution was washed with dilute hydrochloric acid, 5% sodium bicarbonate solution and water and the solvent was distilled off to dryness under reduced pressure. The oily residue (17 g) was dissolved in 2-butanone (150 ml), anhydrous potassium carbonate (18.6 g) was added and the mixture was heated under reflux for 5 hours with stirring. After cooling, the reaction mixture is poured into ice water, neutralized and extracted with ethyl acetate, the organic phase is separated and the solvent is distilled off under reduced pressure to dryness.

The obtained 15.4 g of crude material was dissolved in 30 ml of 99% formic acid and the solution was heated under reflux for 30 minutes. After cooling, the reaction mixture is poured into ice water, the precipitate formed is filtered off, washed thoroughly with water and recrystallized from ethyl acetate. 6.7 g of trans-6-methoxycarbonyl-3-propyl-2- (2-phenylcyclopropyl) chromene, m.p. 171-173 ° C, are obtained, which are reacted with 1% potassium hydroxide solution in 105 ml of 95% ethanol for 30 minutes. under reflux. After cooling, the reaction mixture was acidified with ^23%! hydrochloric acid, evaporated under reduced pressure and the evaporation of the solution diluted with water. the precipitate is filtered, washed with water and recrystallized from ethyl acetate. There were obtained 5.4 g of trans- 6-carboxy-3-propyl-2- (2-phenylcyclopropyl) chromone, m.p. 195-196 ° C.

In an analogous manner, starting from the appropriate 3-alkanoyl-4-hydroxybenzoates, the following compounds are obtained:

trans-6-carboxy-3-ethyl-2- (2-phenylcyclopropyl) chromon, m.p. 217-218 ° C and trans-6-carboxy-3-butyl-2- (2-phenylcyclopropyl) chromium, temperature mp 198-199 ° C.

Example 2

Following the procedure described in Example 1, starting from the appropriate trans-2-aryl-cyclopropyl-1-carbonyl chlorides, the following compounds can be prepared:

trans-6-carboxy-3-ethyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. 226-228 ° C;

trans-6-carboxy-3-propyl-Z- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. 206-207 ° 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, m.p. 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] chromone, m.p. 158-160 ° C;

trans-6-carboxy-3-methyl-2- [2- (2'-imethylphenyl) cyclopropyl] chromone, m.p. 251-252 ° C;

trans-6-carboxy-3-propyl-2- [2- [2'-ethylphenyl] cyclopropyl] chromone, m.p. 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) cyclopropyl] chromone, m.p. 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) cyclopropyl] chromone, m.p. 180-181 ° C;

trans-6-carboxy-3-propyl-2- [2- (2'-methoxy-3'-ethoxyphenyl) cyclopropyl] chromone, m.p. 205-207 ° C;

trans-6-carboxy-3-propyl-2- [2- (2'-ethoxy-3'-methoxyphenyl) cyclopropyl] chromone, m.p. 219-220 ° C;

trans-6-carboxy-3-allyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. 189-190 ° C;

trans-6-methoxycarbonyl-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone, m.p. 137-138 ° C;

trans-6-methoxycarbonyl-3-propyl-2- [2- (3'-methylphenyl) cyclopropyl] chromone, m.p. 115-117 ° C; and trans-6-methoxycarbonyl-3-propyl-2- [2- ( 125 DEG-127 DEG C. 2 ' -methoxyphenyl) cyclopropyl] chromone.

Example 3

The following compounds were prepared as described in Example 1, using the appropriate trans-2-heteroaryl-cyclopropyl-1-carhonyl chlorides:

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

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

trans-6-carboxy-3-propyl-2- [2- (2H-thienyl) cyclopropyl] chromone, m.p. 196-197 ° C;

trans-6-carbomethoxy-3-propyl-2- [2- (5'-methyl-2'-thienyl] cyclopropyl] chromone, m.p. 151-153 ° C;

trans-6-carbomethoxy-3-propyl-2- (2- (2'-thienyl) cyclopropyl] chromone, m.p. 159-161 ° C;

trans-6-carbomethoxy-3-propyl-2- [2- (2'-pyridyl) cyclopropyl] chromone, m.p. 180-182 ° C; and trans-6-carbomethoxy-3-propyl-2- [2- (2 209 DEG-210 DEG.

Example 4

4.3 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone tert-butyl ester are reacted with 30.2 ml of trifluoroacetic acid at room temperature for 6 hours The trifluoroacetic acid is distilled off under reduced pressure, the residue is diluted with ice water, and the precipitate formed is filtered off and washed with water until neutral, after recrystallization from ethanol, 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-carboxy-3-propyl-2- [2- (3'-methoxyphenyl) cyclopropyl] chromone, m.p. 158-160 ° C; and trans-6-carboxy-3-propyl-2- [2- (2'-methoxyphenyl) cyclopropyl] chromone, m.p. 161-163 ° C.

Example 5 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 '') tert-butyl ester. of methyl-2'-furyl] cyclopropyl] chromone with stirring under nitrogen atmosphere, for 2 hours at room temperature and then for 2 hours at 50 ^° C. After cooling, the reaction mixture is diluted with ethyl ether and the product is shaken into 2% aqueous sodium bicarbonate solution. The aqueous layer was separated, acidified with 23% hydrochloric acid, the precipitate formed was filtered off and washed with water until neutral, and the crude product was recrystallized from isopropyl alcohol to give 2.35 g of trans-6-carboxy-3-propyl-2- [2- { 166 DEG-169 DEG C. 5'-methyl-2'-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 6 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, m.p. 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 7 g of trans-6-carboxy-3-propyl-2- (2- (2'-methylphenyl) cyclopropyl) chromone were reacted in 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 portion was washed with 5% sodium bicarbonate solution and water. carboxy-3-propyl-2- (2'-methylphenyl) cyclopropyl] chromene; IR: v (C = O) 1735 cm ^-1 ester, v (C = O) chromone 1640 om ^first

Example 8

3.6 g trans-6-carboxy-3-propyl-2- [2- (2-207643)

(methylphenyl) cyclopropyl] chromone was treated with 2.7 g of 1-chloro-2-diethylaminoethane and 2.8 g of anhydrous potassium carbonate under stirring for 8 hours in an atmosphere 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. After recrystallization from isopropyl ether, 2.2 g of trans-6-carboxy-3-propyl-2- [2- (2‘-methylphenyl) cyclopropyl] chromimone 2-diethylaminoethyl ester is obtained, m.p. 89-90 ° C.

Example 9 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone were 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. 7.8 g of trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chromone 2-diethylaminoethyl ester of melting point 89-90 ° C are obtained;

IC spectrum: v (C-O) ester 1720 cm -1, v (C = 1 = O ¹ chromium 1640-1610 cm ^-1) .

Example 10

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-propylchrornones:

trans-6-carboxy-3-propyl-2- [2- (2'-methylphenyl) cyclopropyl] chroimone tert-butyl ester, oily liquid; IR spectrum: v (C = O) ester 1710 cm ^-1 ; v (C-O) chromone 1640 cm -1 and trans-6-carboxy-3-propyl-2- [2- (5'-methyl-2'-furyl) cyclopropyl] chromone tert-butyl ester, oily liquid; IR: v (C-O) ester 1720 cm ^-1 , v (C-O) chromone 1645 cm ^-1 .

The following compounds are prepared in an analogous manner:

Trans-6-carboxy-3-propyl-2- (2-phenylcyclopropyl) chromone 2-diethylaminoethyl ester, m.p. 92-94 ° C; and

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

Claims (1)

SUBJECT A process for the preparation of substituted 2-cyclopropylchromones of formula I 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 formula Re Z —N \ R 8 wherein each individual R 6 substituent YNALEZU and R a are independently selected from the group consisting of hydrogen and C 1 -C 10 alkyl, or wherein R 6 and R 6 together with the nitrogen atom to which they are attached form an N-pyrrolidinyl, piperidine or morpholine radical, R @ 2 denotes an alkyl group having 1 to 8 carbon atoms or an alkenyl group having 3 or 4 carbon atoms and R 3 is also a furyl, thienyl or pyridyl group, which may be optionally substituted by a methyl group, or b) a group of the formula wherein each R 6 and R 7 is independently selected from the group consisting of a ') hydrogen, b' j halogen and c ') a group of the formula - (Ojm-R 5, wherein n 1 is zero or 1 and R e represents a C 3 or C 4 alkenyl or C 1 -C 6 alkyl group, said groups being optionally substituted with at least one alkoxy group having 1 or 2 carbon atoms or a hydroxy group, and pharmaceutically acceptable salts and isomers thereof, characterized in that the compound of formula (II) is cyclized with OOC CO-x. CH OH CO 'CH — CH-R, X / ^{3 CH} Z (II) where R 1, R 2 and R 3 are as defined above, or a salt thereof to form a compound of formula I wherein n is zero, and the compound of formula I obtained is optionally converted to 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.