SU820663A3 - Method of preparing substituted 2-vinylchromones or their salts - Google Patents

Description

The invention relates to a method for producing new compounds — substituted 2-vinyl chromones of the formula (T) (D) where R is a hydrogen atom or an alkyl unsubstituted or substituted by a group of the formula -NR 4 R 5 4 B is a hydrogen atom or an alkyl C (R. - alkyl Cr- C4 or alkenyl R is a hydrogen or methyl atom; R "is a forglula group where Rfe and Rf are independently hydrogen or halogen or groups of the formula - (O) where n is an integer equal to O or 1, and Rg is alkyl unsubstituted or 3-substituted by a lower alkoxy group, or their salts. These compounds have antiallergic activity. It is an objective of the invention to obtain new substituted 2-vinylchromones possessing valuable biologically active properties. This goal is achieved by the fact that the compound of formula (H), 0, is used in the preparation of a mixture of the cyclization of j o-hydroxy-05-methoxyacetophenone-O in the presence of acid tl. -CH-R, OH CO-CRi CH-R3, A-de R, R, R, and R are as defined above, cyclized at boiling in the presence of an acid, such as formic or hydrochloric, in an inert solvent such as as aliphatic alcohol, dioxane, tetrahydrofuran, vinegar ustic acid or dimethylformamide, and isolate the desired product in free form or as a salt. The compounds of formula (jf) have anti-allergic activity, which is confirmed by the fact that they are active in passive skin anaphylaxis (PKA) when tested in rats. Thus, they can be used to prevent and in the treatment of bronchial asthma, allergic rhinitis, hay famously, urticaria and dermatoses. . The proposed compounds also possess the properties of highly active anti-allergic agents, also when taken per OS. The table shows the activity values of some compounds in comparison with the activity of 6-carboxy-2-trans-styrylchromone (K 10210), i.e. the most active compound of the vinyl series, with the antiallergic activity of this compound taken as a conventional unit. Antiallergic activity was determined by inhibition of PKA, you-. called ZEU in accordance with the method of Guza J. and Blair-AMJ.H using homocytotropic antibodies grown in rats in accordance with the method of Mota. Test compounds were injected into the organism peros 15 minutes before the introduction of the antibody at the level of 3 or more doses At least 8 animals were used for each dose. The degree of antiallergic activity was calculated in accordance with the method of Filne D.J. a preferred daily dosage of 0.25 to 15 mg / kg, or by inhalation, preferably at a daily dosage of 0.25 to 100 mg, more preferably 0.5 to 25 mg, or when topically applied. The nature of the pharmaceutical compositions, which include the proposed compounds together with pharmaceutically acceptable excipients (carriers) or diluents, depends on the desired method of their administration 3 organism. Such compositions can be prepared by conventional methods using conventional components. For example, compounds (1) can be administered in the form of aqueous or oily solutions or suspensions, aerosols, as well as powders, tablets, pills, gelatin capsules, syrups or creams, lotions for local processing. Thus, for example, for the administration of peros in a preferred embodiment, pharmaceutical compositions that contain compounds (I) should be used in the form of tablets, pills or gelatin capsules, which are in addition to the active substance. include diluents, in particular lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, lubricants, for example silica, talc, stearic acid, stearate magnesium or calcium, or poly, ethylene glycols, binders, in particular starches, gelatin, methylcellulose, carboxymethylcellulose, gum arabic, tragacanth, olivinylpyrrolidone, disintegrating agents such as starches, alic acid, alginates, starch sodium glycol, gassing agents, dyes, sweeteners; macerating agents, in particular lecithin, polysorbates, lauryl sulfates, as well as possible non-toxic and non-selectively inactive substances, which are usually used in pharmaceutical compositions. Said pharmaceutical preparations may be prepared by conventional methods, for example, by mixing, gelatinization, tabletting, sugar-lidding, or film coating methods. For the treatment of allergic asthma, the compounds of formula {) can also be administered by inhalation. For this purpose, suitable compositions may include a suspension or solution of the active component, preferably in the form of a salt, for example in the form of a sodium salt in water, for administration to the body through a disintegrant. Alternatively, such compositions may be a suspension or solution of the active ingredient in a conventional liquefied propellant, in particular in dichlorodifluoromethane or dichlorotetrafluoroethane, for use with a pressurized aerosol dispenser. In the case when the medicament does not dissolve in the propellant, it may be necessary to add a co-solvent, in particular ethanol, dipropylene glycol, isopropyl myristate, and or a surface-active agent to the composition in order to suspend the medicaments in the propellant medium, and B as such surface-active agent You can use any commonly used for this purpose product, such as non-ionic surface-active agents, in particular lecithin. Compounds (I) can also be introduced into the body in the form of powders using an appropriate injection device, in which case particles of fine powders of the active components can be mixed with a diluent material, in particular lactose. Moreover, compounds (I) can also administer by subcutaneous or intravenous injections in the usual way. In addition to oral administration, the compounds (|) can be used in topical preparations, for example in creams, lotions or pastes used for dermatological procedures. To this end, the compositions of the active component can be mixed with conventional oily or emulsifying inert fillers. Example 1. 14 g of methyl 3-butyryl-3-hydroxybenzoate (mp. 54-55c), dissolved in 80 ml of dioxane containing 20 ml of pyridine, are reacted with trans-chinnes oyl chloride at room temperature for 20 hours. The reaction mixture is diluted with water, acidified to pH 4 by adding 23% hydrochloric acid and extracted with ethyl acetate. The separated organic phase is washed with 5% sodium bicarbonate solution and water, and then evaporated to the state. 24 g of the residue obtained is dissolved in 240 ml of methyl ethyl ketone, 62 g of anhydrous potassium carbonate is added and the mixture is stirred vigorously under reflux for 3 hours. After cooling, the mixture is diluted with 250 ml of cyclohexane and filtered. The collected product is dissolved in water and the addition of an excess of 20% citric acid is precipitated. After filtration, washing with water and drying, 17.8 g of crude 1- (2-hydroxy-5-carbomethoxybenzoyl) -1-trans-cinnamoylpropane are obtained, which is taken up in 50 ml of 99% formic acid and heated at reflux. within 20 min. After cooling, the mixture is diluted with ice water and filtered. After crystallization from ethanol, 9.7 g of 6-carbomethoxy-3-ethyl-2-trans styrylchromone are obtained with a mp. 194-195s, which is treated with 190 ml of a 1% solution of potassium hydroxide in 95% ethanol at reflux for 30 minutes. After cooling, the mixture is acidified with 23% hydrochloric acid to pH 4, and the precipitate is filtered, washed with ethanol and water until neutral, resulting in 8.4 g of 6-carboxy-3-ethyl-2-trans-styrylchromone with mp. 282-284 ° C. By analogy with the foregoing and using acceptable intermediate products, the following compounds are obtained:. 6-carboxy-3-propyl-2-trans-styrylchromone, m.p. 270-272 С; 6-carboxy-3-isopropyl-2-trans-styrylchromone, m.p. 271-273®C 6-carboxy-3-butyl-2-trans-styryl chromone, m.p. 261-2t2C; 6-carboxy-3-stil-2-trans- (2-methylstyryl) -chromone, m.p. 270-271®C; 6-carboxy-3-propyl-2-trans- (4-methylstyryl) -chromone, m.p. 266-267 6-carboxy-3-propyl-2-trans- (3-methylstyryl) -chromone, m.p. 246-, 247Сг 6-carboxy-3-propyl-2-trans- (2-ethylstyryl) -chromone, m.p. 232-233 ° C. 6-carboxy-3-propyl-2-trans- (2-methoxystyryl) -chromone, m.p. 263264 0 6-carboxy-3-propyl-2-trans- (2-ethoxystyryl) -chromone, m.p. 270271 ° C; 6-carboxy-3-propyl-2-trans (-3-methoxystyryl) -chromone, m.p., 231232 ° C; 6-carbox 1-3-propyl-2-trans- (2, 5-dimethylstiryl) -chromone, so pl. 263264 ° C; 6-carboxy-3-propyl-2-trans- (2-fluorostiryl) -chromone, m.p. 254-255 ° C; 6-car6oxy-3-propyl-2-trans- (4-fluorostiryl) -chromone, m.p. 295-297 ° C; 6-carboxy-3-ethyl-2-trans- (4-methylstyrene) -chromone, m.p. 305-307 ° C; 6-carboxy-3-ethyl-2-trans- (2-methoxystyryl) -chromone, m.p. 280-281 C; 6-carboxy-3-ethyl-2-trans-C2- (2-ethoxyethoxy) -stililT-chromone, m.p. 225-227C; 6-carboxy-3-ethyl-2-trans - (- (2furyl-5-methyl) -vinylD-chromone, mp. 270-271 ° C; 6-carboxy-3-ethyl-2-trans-I-2thienyl ) -Vinyl-Chromone, so pl. 268700С; 6; -carboxy-3-ethyl-2-trans-p- (2-pyridyl) -vinyl-chromone, m.p. 28386 “C; 6-carboxy-3-propyl-2-trans-p (2-furyl) -vinyl 1-chromone, m.p. 220g 6-car6oxy-3-propyl-2-trans-p (2-thienyl) vinyl 1-chromone, m.p. 244345C; 6-car6oxy-3-propyl-2-trans-p (2-pyridyl) -vinyl-chromone, m.p. 78-280 0; 6-carboxy-3-propyl-2-trans-L (3-pyridyl) -vinyl-chromone, m.p. 08-3090С; 6-carboxy-3-propyl-2-trans-B (2-furyl-5-methyl) -vinyl-Chroon, m.p. 244-247 C; 6-carboxy-3-pro.pil-2-trans- (2-thienyl-5-methyl) -vinylT-hryon, m.p. 254-255 ° C; 6-carboxy-3-propyl-2-trans | (2-pyridyl-6-methyl) -vinyl-Chroon, m.p. 253-255 ° C. Example 2. Similarly to the primer 1 and using acceptable ot-meyl-trans-cinnamoyl chlorides as similar reagents, the following compounds are obtained: 6-carboxy-3-ethyl-2-trans- (oC-methyl styryl) -HEJumon, m.p. 193-194 C; 6-carboxy-3-propyl-2-trans-1Lmethylstilil) -chromone, m.p. 176-178 ° C; 6-carboxy-3-ethyl-2-trans- (ai, 2methylstyryl) -chromone; 6-carboxy-3-propyl-2-trans- (oc, -dimethyl styryl) -chromone, m.p. 173740G. Example 3. 38 g (2-hydroxy-5arbomethoxybenzoyl) -trans-cinnamoylmethane with so pl. 138-140 ° C is obtained by carrying out the process in accordance with Example 1 using 3-acetyl-4-hydroxybenzoate and trans-cinnamoyl chloride as starting reagents, after which the product is dissolved in 400 ml of dioxane and 80 ml of dimethylformamide and reacted with 26 ml of allibromide in the presence of 32.4 g of anhydrous potassium carbonate at 80 ° C with stirring for 20 hours. After cooling, the reaction mixture was diluted with ice-water and acidified with citric acid. The precipitate was filtered and washed with water. After crystallization from a mixture of dichloroethane and ethyl acetate, 23 g of 6-carbomethoxy-3-allyl-2-trans. Styrylchromone are obtained with a mp. 215-217 C, which is treated with 450 ml of a 1% solution of potassium hydroxide in 95% ethanol at reflux for 30 minutes. After cooling, the solution is acidified with 23% hydrochloric acid to pH 4, the precipitate is filtered and washed with ethanol and water until neutral to obtain, thus, 20.2 g of 6-carboco-3-allyl-2-trans-styrylchromone m.p. 270-273 0. During the same experiment using acceptable substituted cinnamoyl chlorides, the following compounds are obtained: b-carboxy-3-allyl-2-trans- (2-methylstyryl) -chromone, m.p. 2G7-269 C. 1. Example 4. 12 g of 6-carboxy-3-propyl-2-trans-styrylchloromone is reacted with 4 ml of thionyl chloride in 80 ml of dichloroethane at the temperature of intense evaporation (refluxed for 2 hours. After cooling the reaction mixture is evaporated to dryness and the reaction is carried out with an excess of anhydrous ethanol at 50 ° C for 1 hour. This mixture is concentrated to a little

Compound

6-Carboxy-3-ethyl-2-trans-styrylchromone

6-Carboxy-3-propyl-2-trans-styrylchromone

6 Carboxy-3-allyl-2-trans-styrylchromo

6-Carboxy-3-propyl-2-trans- (2-methylstyryl) -chromone

b-Carboxy-3-ethoxytrans-styrylchrome

Antiallergic activity (K 10210 1)

9.85

(13,999-29,133)

(19.316-42,308)

27.95

(20,038-47,823) 29.90

(47,174-144,857)

78.48

(13,851-32,890) 20.96 ° residual volume and diluted with one to obtain after filtration 9.6 g of 6-carbethoxy-3-propyl-2trans-styrylchromone with mp. 15456 0. During the course of conducting the same experiments, the following compounds are obtained: 6-carbethoxy-3-propyl-2-trans- (2-methylstyryl) -chromone, m.p. 152153 С; 6-carbethoxy-3-propyl-2-trans-Gr- (2-furyl-5-methyl) -vinylJ-chloron, m.p. 135-1370С. Example 5. 5 g of 6-carboxy-3-propyl-2-trans- (2-methylstyryl) -chromone are reacted at a temperature from 1.25 g of sodium bicarbonate in 25 ml of water, protecting the reaction medium from light to complete dissolving process. When the solution was cooled to 5 ° C, a precipitate was separated, which was then filtered and washed with ice water to obtain 4.4 g of sodium salt of 6-carboxy-3-propyl-2-trans- (2-methylstyryl) -chromone, m.p. . 300 ° C. Example 6. 6.2 g of 3-propyl-2-trans-styrylchromone-6-carbonyl chloride, prepared as described in Example 4, is dissolved in 40 ml of dioxane, and then reacted with 2 ml of 2-diethylaminoethanol in the presence of 1 ml triethylamine at room temperature for 20 hours. The reaction mixture is diluted with water and filtered. The collected product is dissolved in 200 ml of acetone and treated with a stoichiometric amount of concentrated hydrochloric acid. The precipitate thus obtained is filtered, washed with acetone and dissolved in water. After basifying the aqueous solution with potassium carbonate and filtering, 4.5 g of 6-carboxy-3-propyl-2-trans-styrylchromone diethylaminoethyl ester are obtained. 89-91 S.

Compound

Claims (1)

6-Carboxy-3-propyl-2-trans-B- (2-thienyl) -vinyl) -chromo, Claim 1. The method for producing substituted 2-vinyl chromones of formula (J) O CR j CH-R j, where R is a hydrogen atom or alkyl, unsubstituted or substituted by a group of the formula, where R4 and Rj are hydrogen atoms or alkyl alkyl C-C4 or alkenyl C4-C4; hydrogen or methyl; R is a group of the formula where R and independently of d ga is a hydrogen and halogen atom or a group of the formula - (Olp-Rg, g Table continuation Antiallergic Trusteeship active (K 10210 "limits for 1) P 0.95 (14,554-38,654) 23.19 p is an integer equal to, O or 1, and R 8 is alkyl. , unsubstituted or substituted by a lower alkoxy group or their salts, characterized in that the compound (formula (s) -CH-R, NO. CO-CYa "CH-H5 where R, R Rg and Rg have the above values, is cyclized at boiling in the presence of an acid such as formic or hydrochloric, s in an environment of an inert solvent such as aliphatic alcohol, dioxane, tetrahydrofuran, acetic acid or dimethylformamide, and the desired product is obtained in a free form or in the form of salt. examination 1. Elderfield R. Heterocycles EU-Kie compound. M. IL, 1954, T. II, p. 182.