SU1287745A3 - Method of producing derivatives of quinolones - Google Patents

Abstract

The invention relates to quinoline derivatives, in particular compounds of the general formula CH CH-C-C (0-C-Shg-8 (OH-CH3. Rh 1,. CH CH-C-18 (CH3) -CH where a) R C1 when n 0; b) R 7-SGS. 7-F, 7-Br at n 1; c) R H, 7-CFj, 7-C1, 7-F, 6-F with n 2, which possess antihypertensive activity, and therefore can be used in biology or medicine. In order to reveal the activity among the quinolone derivatives, new IV were obtained. Their synthesis is carried out by the reaction of compound (1), where instead of the group S (0) CH, halogen, hydroxy or adetoxygroup is contained with alkali metal methanesulfinate (get 1, where n 2), or alkali metal methylthiolate (get I, where n 0 ), followed by oxidation of the resulting product with benzoic acid (in an equimolar amount, if in the target I n 1, or dvuhmolnom quantity, if in the target I n 2) and isolation of the target product. Tests 1 show that they have a better antihypertensive effect without side effects than the known tolmesoxide. 1 tab. g (V) iNd 00 h m 42 cl cm

Description

This invention relates to a method for producing quinolone derivatives, new biologically active; compounds that can be used in biology and medicine.

The purpose of the invention is a process for the production of noisy quinolone derivatives with high antihypertensive effect and with no side effects;).

Example 1. (a) A solution of thionyl chloride (9.48 g) in dichloromethane (800 ml) is added to a stirred and refluxed suspension of finely milled 3-hydroxymethyl-1-methyl-4-quinolone (15.01 g ) in dichloromethane (200 ml). The mixture was heated under reflux for another 1.5 h, cooled to room temperature, and filtered to obtain the novel compound 3-chloromethyl-1-methyl-4-quinolone hydrochloride (mp. 178-181 ° C). This compound (12.71 g) was added to a stirred solution of sodium methanethiolate in methanol at 0 ° C (116 mp, containing 0.109 mol of NaSCH) for 5 minutes. The resulting mixture is allowed to warm to room temperature and left overnight. The mixture is then cooled to 0 ° C and water is added to form a solution. The solution is neutralized to pH 7.0 with diluted hydrochloric acid and filtered. Meta

NOL is distilled from the filtrate and the residue

extracted with dichloromethane (3x50 ml) The combined extracts are dried over anhydrous magnesium sulphate and evaporated to give a solid product. The product is purified by high pressure liquid chromatography on silica gel, eluting with 15:85 isopropanol: dichloromethane at a flow rate of 300 ml / min. The same solvent is used to apply the product on silica gel. The described method gives a new 1-methyl-3-methylthiomethyl-4-quinolone (mp. 118-120 ° C).

(B) To a solution of the above-described 1-methyl-2-methylthiomethyl-4-quinolone (4.86 g) in dichloromethane (220 ml) at -20 ° C, add a solution of 3-chlorobenzoic acid (85%, 4, 86 g) in dichloromethane (220 ml) for one hour. The solution is allowed to warm to room temperature and extracted with saturated aqueous sodium bicarbonate.

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The organic phase is dried over anhydrous magnesium sulphate and evaporated to afford a solid. The product is crystallized from acetone to give a novel, 1-methyl-3-methylsulfonyl-1-4-quinolone (mp. 93-95 C).

To a stirred solution of 1-methyl-3-methylthiomethyl-4-quinolone (1.3 g) in dichloromethane (60 ml) at -20 ° C is added a solution of 3-chloro benzene benzoic acid (85%, 2.75). d) in dichloromethane (85 ml) for 20 min. The stirred solution is allowed to warm to room temperature and then stirred for one hour. The solution is extracted with saturated aqueous sodium bicarbonate until liberation of the peracid. The organic phase is dried over anhydrous magnesium sulphate and evaporated to give a solid. This product is crystallized from acetone. to produce a new 1-methyl-3-methyl-sulfanylmethyl-4-quinolone (mp. 203-).

Example 2. To a stirred solution of 1-methyl-3-methylthiomethyl-7-β-trifluoromethyl-4-quinolone (6.5 g) in dichloromethane (150 ml) was added a solution of 3-chloroperbenzoic acid (85%, 4, 2 g) in dichloromethane (90 ml) for 30 minutes. The solution is extracted with all saturated sodium bicarbonate prior to liberation of the peracid. The organic phase is dried over anhydrous magnesium sulphate and evaporated to give a solid, which is then crystallized from ethyl acetate: dichloromethane to give a new 1-methyl-3-methylsulfinylmethyl-7-trifluoromethyl-4-quinolone (mp. 208-) .

Froze To a stirred solution of 1-methyl-3-methylthiomethyl-7-β-trifluoromethyl 4-quinolone (7.8 g) in dichloromethane (150 ml) at room temperature is added a solution of 3-chloroperbenzoic acid (85%, 11.3 g) in dichloromethane (100 cells) for 3 min. After stirring at this temperature for one more hour, the solution is extracted completely; aqueous sodium bicarbonate is added until the peracid is liberated. Ore -: - the organic phase is dissolved over anhydrous magnesium sulfate and evaporated to give a solid product, which is then crystallized from industrial frothy methylated alcohol: dichloromethane to produce a new 1-methyl-3-methylsulfanylmethyl-7-trifluoromethyl-4-hino-5-4-hydroxyquinoline (91.5 g, containing halogen (mp 240-242 C).

Example 4. 7-Chloro-4-hydroxy-3-hydroxymethylquinoline is treated with dimethyl sulfate to obtain a new 7-chloro-1-methyl-3-hydroxymethyl-4-quinolone, mp. 204-206 ° С (from industrial methylated alcohol). The interaction of this product with thionyl chloride gives 7-chloro-3-chloromethyl-1-methyl-4-quinolone hydrochloride (mp. 205-207 ° C), which then reacts with sodium methanethiolate to produce a new 7-chloro 1-methyl-3-methylthiomethyl-4-quinolone, so pl. 163-164 ° C. (from industrial methylated alcohol).

Example 5. The method of Example 2 of 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone is oxidized with 3-chloro-perbenzoic acid to produce the new 7-chloro-1-methyl. -3-methylsulfinyl-methyl-4-quinolone, so pl. 181 ° С (from dichloromethane: petroleum ether, bp 60-80 ° С).

EXAMPLE 6 By the method of Example 2, 7-chloro-1-methyl-3-methylthiomethyl-TIL-4-HINOLON is oxidized with 3-chloro-benzoic acid to give a new 7-chloro-1-methyl-3 -methylsulfonylfO

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a certain amount of 5-fluoro-isomer), aqueous sodium hydroxide (1.0 n. 666 ml) and aqueous formaldehyde (37%, 91.5 ml) are stirred at 35-37 ° C for 5.5 h. one portion of aqueous formaldehyde (37%, 91.5 ml) and stirring are continued for 54 hours. The solid product is collected by filtration, added to water (600 ml) and the mixture acidified to pH 4.0 with concentrated hydrochloric acid. The solid precipitate is collected, washed with water and dried to give 7-fluoro-4-hydroxy-3-hydroxymethylquinoline, m.p. 295-300 ° С (containing some amount of 5-fluoro-isomer). Another portion of the product (mp. 295-300 ° C) is obtained from the alkaline filtrate of the reaction mixture by acidification to pH 4.0 with concentrated hydrochloric acid, after which both portions are combined.

 (B) This combined product is mixed with water (1300 ml), potassium hydroxide (17.3 g) and dimethyl sulfate (35 ml). The mixture was stirred at 25 ° C for 17 hours and then basified with 5N. aqueous caustic potash. The precipitate is collected, washed with water and

Tyl-4-quinolone, so pl. 215-21b ° C (out of 35 crystallized from industrial methanol). , ethylated alcohol to obtain

Example 1. (a) By the method of the new 7-fluoro-3-hydroxymethyl-1-methyl-example 3 6-fluoro-1-methyl-3-methylthio-4-quinolone, (so pl. 219-222 ° С ). Methyl-4-quinolone is oxidized with 3-chlorobenzoic acid to give new 40-6-fluoro-1-methyl-3-methylsulfononylmethyl-4-quinolone, m.p. 200-205 ° С (from industrial methylated alcohol).

(B) The starting material is used for 10 minutes to mix the sodium methanethiolate solution, stirred in the above procedure, by the method of Example 3. 6-fluoro-4-oxyquinoline is reacted with 40% aqueous formaldehyde in an aqueous solution of caustic soda to produce a new 6-fluoro-4-hydroxy-3-hydroxymethylquinoline, m.p. 310-315 ° C. Pro (c) This compound is reacted with thionyl chloride by the method of Example 3 to obtain 3-o-methyl-7-fluoro-1-methyl-4-quinolone, mp 169-171 ° C.

(d) This compound (20.7 g) is added

methanol (from methanethiol (10 ml) and methanolic sodium methoxide (0. 64 M 280 ml) at 10 ° C. The mixture is stirred

50 at 20 ° C for one hour and then poured into water (700 ml). The precipitate is collected and crystallized from industrial methylated alcohol to produce a new 7-fluoro-1-methyl-3-methylduct methylated with dimethyl sulfate to obtain a new b-fluoro-T-methyl-3-oxymethyl-4-quinolone, mp. 209-212 ° C. The interaction of this product with thionyl chloride, and then with methane thiolato sodium, gives a new 6-fluoro 1287745. four

-1-methyl-3-methylthiomethyl-4-quinolone, mp, 114-116 ° C (from industrial methylated alcohol).

Example, (a) A mixture of 7-fluorine -

fO

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a certain amount of 5-fluoro-isomer), aqueous sodium hydroxide (1.0 n. 666 ml) and aqueous formaldehyde (37%, 91.5 ml) are stirred at 35-37 ° C for 5.5 h. one portion of aqueous formaldehyde (37%, 91.5 ml) and stirring are continued for 54 hours. The solid product is collected by filtration, added to water (600 ml) and the mixture acidified to pH 4.0 with concentrated hydrochloric acid. The solid precipitate is collected, washed with water and dried to give 7-fluoro-4-hydroxy-3-hydroxymethylquinoline, m.p. 295-300 ° С (containing some amount of 5-fluoro. Isomer). Another portion of the product (mp. 295-300 ° C) is obtained from the alkaline filtrate of the reaction mixture by acidification to pH 4.0 with concentrated hydrochloric acid, after which both portions are combined.

 (B) This combined product is mixed with water (1300 ml), potassium hydroxide (17.3 g) and dimethyl sulfate (35 ml). The mixture was stirred at 25 ° C for 17 hours and then basified with 5N. aqueous caustic potash. The precipitate is collected, washed with water and

A new 7-fluoro-3-hydroxymethyl-1-methyl-4-quinolone, (mp. 219-222 ° C).

(c) This compound is reacted with thionyl chloride by the method of Example 3 to obtain 3-o-methyl-7-fluoro-1-methyl-4-quinolone, mp 169-171 ° C.

(d) This compound (20.7 g) is added over 10 minutes to a stirred solution of sodium methanethiolate in

methanol (from methanethiol (10 ml) and methanolic sodium methoxide (0, 64 M, 280 ml) at 10 ° C. The mixture is stirred

at 20 ° C for one hour and then poured into water (700 ml). The precipitate is collected and crystallized from industrial methylated alcohol to produce a new 7-fluoro-1-methyl-3-methylthiomethyl-4-quinolone (mp. 167les-c).

(e) This sulfide is oxidized with an equimolar amount of 3-chloro-perbenzoic acid by the method of example 1 to obtain the corresponding new ulfoxide: 7-fluoro-1-methyl-3-methylsufin Il-4-quinolone, m.p. 179-180 C (from industrial methylated alcohol).

(f) The sulfide from (e) is oxidized with the polar equivalents of 3-chloroperbenzoic acid by the method of Example 2 to give the corresponding new sulfone: 7-fluoro-1-methyl-3-methylsulfonylmethyl-4-quinolone, m.p. . 212 - 215 ° С (from industrial methylated alcohol).

PRI me R 9. The following reactions were carried out in Example 8.

(a) 7-Bromo-4-hydroxyquinoline interacts with formaldehyde in aqueous sodium hydroxide to produce a new 7-bromo-4-hydroxy-3-hydroxymethyl quinoline, mp. .

(b) This compound is methylated by boiling water under reflux.

with dimethyl sulfate and potassium carbonate in 2-butanol. The result is a new 7-bromo-3-hydroxymethyl-1- -methyl-4-quinolone, so pl. 300 ° C (from industrial alcohol).

(c) This compound reacts with thionyl chloride in dichloromethane

to produce a new 7-bromo-3-chloromethyl-1-methyl-4-quinolone hydrochloride.

(d) This compound is reacted with sodium methanethiolate in methanol to obtain a crude product, which is purified by column chromatography on silica gel, eluting with dichloromethane: industrial methylated alcohol 9: 1, followed by column chromatography on silica gel with ethyl acetate as eluant. This gives a new 7-bromo-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 168-170 C.

(e) This sulfide is oxidized with an equimolar amount of 3-chloroperbenzoic acid to produce a new 7-bromo-1-methyl-3-methylsulfonylmethyl-4-quinolone, m.p. 243-245 ° С (from industrial methylated alcohol).

Example 10 To a solution of 3-acetoxymethyl-1-methyl-4-quinolone (0.8 g) in acetone (15 ml) was added a solution of sodium methanesulfinate (0.53 g) in water (10 ml). The mixture is refluxed for 24 hours. A further portion of methanesulfur is added.

sodium nitate (0.14 g) and the mixture is refluxed for 4 hours. The acetone is evaporated, leaving a white solid which is recrystallized from industrial methylated alcohol to give 1-methyl-3- -methylsulfonylmethyl-4-kinolona, so pl. 195-197 C.

 Example 11. To a stirred suspension of sodium methanesulfinate (5.0 g) in anhydrous dimethylformamide (70 ml) at room temperature, 3-chloromethyl-1-methyl-4-quinolone hydrochloride chloride (2, 0 g). The mixture is stirred at this temperature for 16 hours and then evaporated to dryness. The residue is treated with water 0 (50 ml), filtered and the filtrate is acidified with aqueous sodium hydroxide, and then extracted with dichloromethane (2 X 50 ml). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to give a new 1-methyl-3-methylsulphonylmethyl-4-quinolone, mp. 201-204 C (from acetone).

Biological tests of the described quinolone derivatives have been carried out. The therapeutic activity of the cannons of the general formula (I) is demonstrated using tests that. include (A) oral administration of 5 compounds in rats of the spontaneously hyper-intrusive line and (B) intraduodenal use of the compounds in rats of the normotensive line.

Tests were conducted as follows.

Test A. Maca rats weighing 180-240 g of the Aoki-Okamoto spontaneously hypertensive line were used. The rats are divided into groups of four and are not fed overnight before use of the test substance. Blood pressure is determined as follows. The rats are placed in a box, the temperature of which was maintained at 50 ° C, and their tails were put out through the holes in the box. After 30 minutes in this box, blood pressure is measured using a pumped cuff wrapped around the base of the tail and an arterial pulsation controlled by a pneumatic pulse sensor. In the cuff create

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pressure, exceeding the estimated blood pressure, after which it is slowly reduced. The pressure in the cuff, at which the arterial pulsation appeared again, is taken as the blood pressure. The rats are removed from the box and each group is administered through the mouth a given dose of the test compound as a solution or suspension in 0.25% aqueous carboxymethyl cellulose. After 1.5 and 5.0 hours after the administration of the substance, the blood pressure is measured. A compound is considered active if it gives a blood pressure drop of 20% or more at any of these time intervals.

Test B, male normal rats (Wistar line) weighing 210-240 g were used. Rats are anesthetized and cannula inserted into the carotid artery.

 At a dose of 90 mg / kg, no side effects were observed as opposed to tolmesoxide, for which serious side effects were observed at doses of 90 mg / kg, as previously indicated.

and 12 duodenal ulcer. Blood pressure is recorded using an electronic sensor connected to the arterial cannula. The test compound is introduced into the 12-perforated. the intestine as a solution or suspension in 0.23% aqueous carboxymethylcellulose. Blood pressure is recorded before giving the drug and 30 minutes after its administration. Results are obtained as mean values of determinations in three rats per dose. Compounds that cause a pronounced decrease in blood pressure of .14% or more within 30 minutes after administration are referred to as active.

The table shows the threshold doses of the activity of the proposed compounds.

The table shows that the proposed compounds were active at a dose of 90 mg / kg and less.

Moreover, the threshold dose of activity for the most active compounds 5 is 10–30 mg / kg, other compounds have a threshold dose of activity that is the same as tolmesoxide 30–90 mg / kg, however, at doses of 90 mg / kg, tolmesoxide has harmful side effects. Significant effects of sedation and lethargy. In some rats, difficulty breathing was observed and they fell into prostration.

The proposed quinolo-5 derivatives are either more active than tolmes oxide, or their activity corresponds to the level of toxicity of tolmesoxide, but they do not cause serious side effects with which Tolmesoxide is treated in doses of 90 mg / kg.

Claims (1)

Invention Formula where p O, 1, 2; if p Oh, chlorine; if p 1, R 7-trifluoromethyl, 7-chloro or 7-bromo; p 2, R is hydrogen, 7-trifluoromethyl, 7-chloro, 7-fluoro, 6-fluoro, characterized in that the compound of the general formula ABOUT SNOX where X, R Shz halogen or acetoxy group; has the indicated meanings. enter into interaction with methanesulfonate CH, an alkali metal, to obtain compounds of the general formula (l), where n 2, or, if X is halogen, is subjected to interaction with methyl thiolate CH alkali metal and, if necessary, followed by oxidation of the obtained method for the preparation of hino-- derivatives - compounds of the general formula (I), where p O is an equimolar amount of chloro-perbenzoic acid to a compound of the general formula (I), where n 1, or a two-molar amount of chloradnad (I) 30 benzoic acid to a compound of the general formula (I), where n 2, c postlone. general formula O, pCH2S (0) t, CH3 Shz blowing the target product. where p O, 1, 2; if p Oh, chlorine; if p 1, R 7-trifluoromethyl, 7-chloro or 7-bromo; p 2, R is hydrogen, 7-trifluoromethyl, 7-chloro, 7-fluoro, 6-fluoro, characterized in that the compound of the general formula ABOUT SNOX X, R Shz halogen or acetoxy group; has the indicated meanings. enter into interaction with methanesulfonate CH, an alkali metal, to obtain compounds of the general formula (l), where n 2, or, if X is halogen, is subjected to interaction with methyl thiolate CH alkali blowing the target product. Compiled by V.Volkov Editor V.Kovtun Tehred I.Popovich Proofreader L.Pilipenko Order 7732/61 Circulation 371 Subscription In NShSHI of the USSR State Committee for Inventions and Discoveries 4/5, Zh-35, Raushsk nab. 113035, Moscow Production and printing company, Uzhgorod, st. Project, 4