HU184968B - Process for preparing quinolone derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of a quinolone derivative of the formula I wherein n is 0, 1 or 2, R is lower alkyl and R 1 is hydrogen, lower alkyl, methoxy, methylthio, halogen or trifluoro. methyl. The compounds of Formula I have a valuable antihypertensive effect and are therefore useful as pharmaceutical active ingredients. 184968 -1-

Description

The present invention relates to novel quinolone derivatives of the formula I and to antihypertensive pharmaceutical compositions containing them.

1-Alkyl-4-quinolones substituted at the 3-position with methylthio, methylsulfinyl and methylsulfonyl are described in J. Org. Chem. 33, 67 (1968); Chim. Therap. 1973, (1) 46-48 and J. Week. Chem., 15, 113-1166 (1978). U.S. Patent No. 3,772,301 describes 1-methyl-4-methylsulfinylmethyl-2-quinolones.

In the formula I, R is a lower alkyl group,

R _{3 is} hydrogen, lower alkyl, methoxy, methylthio, halogen or trifluoromethyl, and n is 0, 1 or 2.

The term "lower alkyl" refers to a straight or branched C 1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. Preferably R 1 is methyl. When R _{3 is} halogen, this halogen is preferably chlorine, bromine or fluorine, especially chlorine or fluorine.

Compounds of formula I have been found to have a valuable antihypertensive effect when administered to hypertensive mammals to lower blood pressure.

The therapeutic effect of the compounds of the formula I was demonstrated by experiments in laboratory animals. Such experiments included, for example, the compounds being administered spontaneously to rats of the hypertensive rat orally or intraduodenally to normal hypertensive rats.

Compounds of formula I wherein n is 0 or 2 may be prepared by reacting a compound of formula II wherein R 1 and R _{3 are} as defined above and X is a suitable leaving group such as chlorine, acetoxy, or - N (alkyl) _{3 is} reacted with a methane thiolate anion (CH ₃ S ®) or a methanesulfinate anion (CH ₃ S ® O ₂ ). The reaction with the methane thiolate anion provides compounds of the formula where n is 0, while the reaction with the methanesulfinate anion gives compounds of the formula where n is 2. Each anion is conveniently used in the form of the corresponding alkali metal salt, such as the sodium salt. . The reaction is carried out in the usual manner for such reactions. The compounds of formula II are novel and can be prepared from methods known in the art for the preparation of similar compounds.

Compounds of formula I wherein n is 1 may be prepared by oxidation of the corresponding compounds of formula I wherein n is 0. Similarly, compounds of formula I wherein n is 2 may be prepared. suitable for the oxidation of compounds of the formula I in which n is 0 or 1. These oxidations may be carried out in the conventional manner for such reactions, for example using organic peracid as the oxidizing agent.

Compounds of formula I wherein n is 2 may also be prepared by hydrolysis of a quinolinium salt of formula III wherein R ₁ and R _{3 are} as defined above, A R is an anion and

Z is a suitable leaving group such as -OR (such as -OCH 3), -SR, -halogen (chlorine or bromine), -NH ₂ , -NHR, -N (R) ₂ , RSO ₂ -, RSO- or ArSO ₂ a group such as p-toluenesulfonyl, wherein R is lower alkyl and Ar is aryl. Hydrolysis may be accomplished by reacting the compound of formula ΠΙ with water, depending on the nature of the leaving group, under neutral, acidic or basic conditions.

Compounds of formula III may be prepared by alkylation of novel compounds and quinolines of formula IV. Thus, the anion A® is preferably an anion derived from an alkylating agent, such as a halide or methylsulfate anion.

Compounds of formula I wherein n is 2 may also be prepared by thermal rearrangement of compounds of formula V wherein R ₁ and R _{3 are} as defined above. The rearrangement can be accomplished by heating the compound of formula V above, optionally in the presence of an inert organic liquid which may be a solvent of the compound of formula V.

The compounds of formula V are novel. Appropriate

They can be prepared from 4-chloro-3-chloromethyl-quinolines by reaction with sodium methanesulfinate to give the corresponding 4-chloro-3-methylsulfonylmethyl-quinoline, which is reacted with sodium alkylate (NaOR3). for compounds of formula V.

Compounds of formula I wherein n is 1 or 2 may also be prepared by alkylation of compounds of formula VI wherein n is 1 or 2 and R _{3 is} as defined above. The reaction may be carried out by reacting a compound of formula VI with an alkylating agent such as a dialkyl sulfate or alkyl iodide in the usual manner.

The compounds of formula VI are novel.

Compounds of formula VI wherein n is 2 may be prepared by reacting a compound of formula VII with formaldehyde and sodium methanesulfinate in the presence of a tertiary amine such as triethylamine.

Compounds of formula VI wherein n is 1 may be prepared by oxidation of corresponding compounds of formula VI wherein n is 0. The latter compounds may be prepared by reacting a compound of formula VII with a tertiary amine such as triethyl. in the presence of -amine with formaldehyde and sodium methane thiolate.

One of ordinary skill in the art will recognize that in compounds of formula I wherein n is 1, the CH ₃ SO group contains a chiral center on the sulfur atom. Thus, such compounds exist in two enantiomeric forms. The invention encompasses both enantiomers and racemic mixtures thereof.

As mentioned above, the therapeutic effect of the compounds of formula I was demonstrated in experiments in which A) the compounds were spontaneously administered to rats of high blood pressure and B) intraduodenally to members of normal blood pressure. These experiments were performed as follows.

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Experiment A)

Female rats of the Aoki-Okamoto strain, spontaneously hypertensive, weighing 180-240 g, were used for the experiment. Prior to administration of the test compound, groups of 4 to 4 rats were fasted overnight. Blood pressure was measured as follows. The rats were placed in a box at 38 ° C with their tails pulled out through the wells of the box. After 30 minutes in the box, blood pressure was measured by placing an inflatable cuff at the base of the tail and observing the arterial artery with a pneumatic pulse converter. Higher than expected blood pressure was measured on the cuff and this pressure decreased slowly. Blood pressure was defined as the pressure on the cuff at which the arterial artery reappeared. The rats were removed from the box and each group was orally dosed with the test compound in the form of a solution or suspension in 0.25% aqueous carboxymethylcellulose. In addition to the pre-administration reading, blood pressure was measured at 1.5 and 5.0 hours after administration. A compound is said to be effective when it reduces blood pressure by at least 20% at one of the time intervals.

Experiment B)

Male rats of the Wistar strain, weighing 210-240 g and having normal blood pressure, were used for the experiment. The rats were anesthetized and cannulated in the carotid artery and duodenum. Blood pressure was electronically recorded using a pressure transducer attached to a cannula inserted into the carotid artery. The test compound was added to the duodenum as a solution or suspension in 0.25% aqueous carboxymethylcellulose. Blood pressure was recorded before administration and 30 minutes later. The results are the mean values of 3 to 3 rats at each dose. Compounds that produced a reduction in blood pressure of at least 14% over a 30 minute period after administration were declared effective.

The compounds listed in Table I were effective in Experiment A at doses of 90 mg / kg or less, being preferred compounds of the present invention.

Table I

Compounds of formula I wherein R 1 is methyl

Serial number of compound n rj First 2 H Second 0 7-C1 Third 1 7-C1 4th 2 7-C1 5th 1 7-CF 6th 2 7-CF ₃ 7th 2 7-F 8th 2 6-F 9th 2 7-CH 10th 1 7-Br

II. The compounds listed in Table II were not active in Experiment A at 90 mg / kg, but were effective in Experiment B at 90 mg / kg.

II. spreadsheet

Compounds of formula I

Serial number of compound R _t n 11th -CHj 2 8-OCH3 12th -CHj 1 6-F 13th -CHj 2 7 SCHj 14th -CHj 1 7 < ₂ Η ₅ 15th -CHj 2 7-C ₂ H ₅ 16th -CHj 1 8-C1 17th -CHj 0 7-Br 18th -CHj 2 7-Br 19th -CHj 2 7-tC ₄ H ₉ 20th -C ₂ Hj 2 H 21st -CHj 0 H 22nd -CHj 1 H 23rd -CHj 0 7-CF 24th -CHj 0 6-OCH 25th -CHj 2 6-OCH 26th -CHj 0 7-OCH 27th -CHj 1 7-OCH 28th -CHj 2 7-OCH 29th -CHj 0 8-OCH3 30th -CHj 1 8-OCH 31st -CHj 0 7-F 32nd -CHj 1 7-F 33rd -CHj 1 8-F 34th CH, 2 8-F 35th -CHj 0 6-CH 36th -CHj 1 6-CH 37th -CHj 2 6-CH 38th -CHj 2 8-CH 39th CH, 0 6-C1 40th -CHj 1 6-C1 41st -CHj 2 6-C1 42nd -CHj 0 8-Cl 43rd CH, 2 8-C1 44th -CHj 0 7-tC ₄ H, 45th CH, 1 7-tC ₄ H ₉ 46th nC ₃ H ₇ 2 H

In Experiment B, steps 10-20. compounds of formula II were particularly effective; The compounds listed in Table II are preferred.

The novel quinolones may be used in the form of conventional formulations such as tablets, capsules, suppositories and sterile injectable formulations. Administration can be by enteral or parenteral administration, preferably enteral, especially oral. The dosage for the treatment of hypertension in mammals is generally 0.1 to 100 mg / kg, in particular 0.5 to 75 mg / kg, preferably 1 to 50 mg / kg per day, in single or divided doses. Dosage units will generally contain from 1 to 500 mg of active ingredient, particularly from 5 to 500 mg.

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The invention is illustrated by the following non-limiting examples. The novel compounds were characterized by one or more of the following spectroscopic techniques: NMR (H ¹ or C ¹³ ), infrared or mass spectra. In addition, the results of elementary analysis of the products were satisfactory.

Example 1

(a) To a stirred suspension of 15.01 g of finely ground 3-hydroxymethyl-1-methyl-4-quinolone in 200 ml of dichloromethane was added 9.48 g of thionyl chloride in 800 ml of dichloromethane over 4 hours. solution. The reaction mixture was refluxed for a further 1.5 hours, then cooled to room temperature and filtered. This gave the new 3-chloromethyl-1-methyl-4-quinolone hydrochloride (16.2 g), m.p. 178-181 ° C. This compound (12.71 g) was added at 0 ° C over 5 minutes with stirring in 116 ml of methanolic solution of sodium methane thiolate (NaSCH ₃ ) (0.109 mol). The resulting mixture was allowed to warm to room temperature and allowed to stand overnight. It is then cooled to 0 ° C and water is added to make a solution. The solution was adjusted to pH 7.0 with dilute hydrochloric acid and filtered. Methanol was distilled off from the filtrate and the residue was extracted three times with 50 ml of dichloromethane each time. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to give a solid. This was purified by high performance liquid chromatography over silica gel eluting with 15:85 isopropanol / dichloromethane at a flow rate of 300 mL / min. The same solvent was used to apply the product to silica gel to give the new 1-methyl-3-methylthiomethyl-4-quinolone, m.p. 118-120 ° C. Yield 7.0 g.

b) To a solution of the above 1-methyl-3-methylthiomethyl-4-quinolone (4.86 g) in dichloromethane (220 mL) is added 4.86 g of 3-chloroperbenzoic acid per hour at -20 ° C. (85%) in dichloromethane (220 mL). The solution was allowed to warm to room temperature and extracted with a saturated aqueous sodium bicarbonate solution until free from peracids. The organic phase is then dried over anhydrous magnesium carbonate and evaporated to give a solid. This was crystallized from acetone. This gives the new 1-methyl-3-methylsulfinylmethyl-4-quinolone, m.p. 93-95 ° C. Yield 1.5 g.

Example 2

To a solution of 1.3 g of 1-methyl-3-methylthiomethyl-4-quinolone in 60 ml of dichloromethane was added 2.75 g of 3-chloroperbenzoic acid (85%) at -20 ° C with stirring for 20 minutes. 85 ml of dichloromethane. The solution was allowed to warm to room temperature with stirring and stirred for an additional hour. The solution was extracted with a saturated aqueous sodium bicarbonate solution until free from peracids. The organic phase was then dried over magnesium sulfate and evaporated to give a solid. This is crystallized from acetone to give the new 1-methyl-3-methylsulfonylmethyl-4-quinolone, m.p. 203-205 ° C. Yield: 0.5 g.

Example 3 To a stirred solution of α-16 mL of methanolic sodium methane thiolate (NaSCH ₃ ) (0.039 mol) at 0 ° C was added 4.7 g of 3-chloromethyl-1-methyl-7- trifluoromethyl-4-quinolone hydrochloride.

The resulting mixture was allowed to warm to room temperature and then poured into 100 ml of water. The resulting precipitate was collected, dried and crystallized from dichloromethane / petroleum ether (b.p. 60-80 ° C). This gives a new 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone, m.p. 182-184 ° C. Yield 2.3 g.

b) The starting material used in the above process is prepared as follows.

A mixture of 30.0 g of 4-hydroxy-7-trifluoromethyl-quinoline, 36 ml of 40% aqueous formaldehyde and 250 ml of aqueous sodium hydroxide was stirred at 40-50 ° C for 8 hours. The solid product was collected and dried to give the new 4-hydroxy-3-hydroxymethyl-7-trifluoromethyl-quinoline, m.p. 302-304 ° C. Yield 23.6 g.

To a solution of 23.6 g of 4-hydroxy-3-hydroxymethyl-7-trifluoromethyl-quinoline and 16.3 g of potassium hydroxide in 50 ml of water and 50 ml of tetrahydrofuran is added with stirring at room temperature for 24 minutes 24.4 g of dimethyl sulfate. After stirring at this temperature for a further 3 hours, the solid product was collected by filtration. The filtrate was extracted three times with 200 ml of dichloromethane each. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to give an additional solid. The solids were combined and purified by high performance liquid chromatography on silica gel; eluting with 10: 90 isopropanol / dichloromethane at a flow rate of 200 mL / min. The same solvent is used to apply the product to silica gel. This gives the new 3-hydroxymethyl-1-methyl-7-trifluoromethyl-4-quinolone, m.p. 172-175 ° C. Yield: 10.7 g.

To a suspension of 5.0 g of finely ground 3-hydroxymethyl-1-methyl-7-trifluoromethyl-4-quinolone refluxed in 200 ml of dichloromethane was added 2.32 g of thionyl chloride over 1.5 hours. 100 ml of dichloromethane. The solution is refluxed for another half hour and then concentrated to dryness under reduced pressure. This gives the new 3-chloromethyl-1-methyl-7-trifluoromethyl-4-quinolone hydrochloride, m.p. 182-189 ° C. Yield: 5.7 g.

Example 4

To a solution of 6.5 g of 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone in 150 ml of dichloromethane is added at -10 ° C with stirring for 30 minutes.

A solution of 4.2 g of 3-chloroperbenzoic acid (85%) in 90 ml of dichloromethane was added. The solution was extracted with a saturated aqueous sodium bicarbonate solution until free of peracid. The organic layer was then dried over anhydrous magnesium sulfate and evaporated to give a solid. This was crystallized from a mixture of methyl acetate and dichloromethane. This gives the new 1-methyl-3-methylsulfinylmethyl-7-trifluoromethyl-4-quinolone, m.p. 208-210 ° C. Yield: 2.2 g.

Example 5

To a solution of 7.8 g of 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone in 150 ml of dichloromethane was added with stirring at room temperature for 3 minutes.

11.3 g of 3-chloroperbenzoic acid (85%) in 100 ml of dichloromethane. The reaction mixture was stirred for an additional hour at this temperature and the solution was extracted with a saturated aqueous sodium bicarbonate solution until free from acid. The organic layer was then dried over anhydrous magnesium sulfate and evaporated to give a solid. This was crystallized from a mixture of denatured alcohol and dichloromethane to give the new 1-methyl-3-methylsulfonylmethyl-7-trifluoromethyl-4-quinolone, m.p. 240-242 ° C. Yield: 1.7 g.

Example 6

7-Chloro-4-hydroxy-3-hydroxymethylquinoline (4.9 g) was treated with dimethyl sulfate as described in Example 3 to give the new 7-chloro-1-methyl-3-hydroxymethyl-4. a quinolone is obtained, m.p. 204-206 ° C (crystallized from denatured alcohol). Yield 2.5 g. This product (2.0 g) is treated with thionyl chloride to give 7-chloro-3-chloromethyl-1-methyl-4-quinolone hydrochloride, m.p. 205-207 ° C (yield 1.9 g) and (1.5 g) with sodium methane thiolate. This gives the new 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 163-164 ° C (crystallized from denatured alcohol). Yield 1.2 g.

Example 7

7-Chloro-1-methyl-3-methylthiomethyl-4-quinolone (1.0 g)

Oxidation with 3-chloroperbenzoic acid as described in Example 4 gave the new 7-chloro-1-methyl-3-methylsulfinylmethyl-4-quinolone, m.p. 180-181 ° C (dichloromethane and petroleum ether). b.p. 60-80 ° C). Yield 0.6 g.

Example 8

7-Chloro-1-methyl-3-methylthiomethyl-4-quinolone (1.0 g) was

By oxidation with 3-chloroperbenzoic acid, as described in Example 5, a new 7-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone is obtained, m.p. 215-216 ° C (crystallized from ethanol). Yield 0.8 g.

Example 9

a) 6-Fluoro-1-methyl-3-methylthiomethyl-4-quinolone is oxidized with 3-chloroperbenzoic acid as described in Example 5 to prepare the new 6-fluoro-1-methyl-3-methylsulfonyl. -methyl-4-quinolone, m.p. 200-205 ° C (crystallized from denatured alcohol). Yield 1.5 g.

b) The starting material used in the above process was prepared as described in Example 3.

6-Fluoro-4-hydroxyquinoline (92.4 g) in aqueous sodium hydroxide solution is reacted with 40% aqueous formaldehyde solution to give the new 6-fluoro-4-hydroxy-3-hydroxymethylquinoline. m.p. 310-315 ° C; yield 72.5 g. This product (13.7 g) is methylated with dimethyl sulfate to give the new 6-fluoro-1-methyl-3-hydroxymethyl-4-quinolone, m.p. 209-212 ° C; yield 12.5 g. This product (39.5 g) is reacted with thionyl chloride followed by sodium methane thiolate to give the new 6-fluoro-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 114-116. ° C (crystallized from denatured alcohol). Yield 4.0 g.

c) This sulfide is oxidized as described in Example 4 with a molar amount of 3-chloroperbenzoic acid in dichloromethane at -20 ° C to -30 ° C to give the new sulfoxide, 6-fluoro-1-methyl 3-methylsulfinyl-methyl-4-quinolone is obtained, m.p. 154-156 ° C (crystallized from denatured alcohol). Yield 0.7 g.

Example 10

(a) 91.5 g containing a small amount of 5-fluoro isomer

A mixture of 7-fluoro-4-hydroxyquinoline, 666 ml of aqueous sodium hydroxide solution and 91.5 ml of 37% aqueous formaldehyde solution was stirred at 35-37 ° C for 5.5 hours. A further 91.5 ml of a 37% aqueous formaldehyde solution was then added and stirring continued for 64 hours. The solid was collected by filtration, added to water (600 mL) and acidified to pH 4 with concentrated hydrochloric acid. The solid residue was collected, washed with water and dried to give the new 7-fluoro-4-hydroxy-3-hydroxymethylquinoline, m.p. 295-300 ° C (containing a small amount of 5-fluoro isomer). Yield 27.4 g. Further product was obtained from the alkaline filtrate of the reaction mixture, m.p. 295-300 ° C, by acidification to pH 4 with concentrated hydrochloric acid. This additional amount is combined with the first product.

(b) The combined product (59.0 g) was mixed with water (1300 ml), potassium hydroxide (17.3 g) and dimethyl sulfate (35 ml), stirred at 25 ° C for 17 hours and then made basic with 5N aqueous potassium hydroxide. The residue was collected, washed with water, dried and crystallized from denatured alcohol. This gives the new 7-fluoro-3-hydroxymethyl-1-methyl-4-quinolone, m.p. 219-222 ° C. Yield 40.8 g.

c) This compound (20.0 g) was treated with thionyl chloride as in Example 3 to give 3-chloromethyl-7-fluoro-1-methyl-4-quinolone, m.p. 169-171 ° C. Yield 20.8 g.

d) This compound (20.7 g) is added at 10 [deg.] C. with stirring over 10 minutes to 10 ml of methane thiol and 280 ml of 0.64 M sodium methoxide in methanol. The mixture was stirred for 1 hour at 20 ° C and then poured into 700 ml of water. The precipitate was collected and crystallized from denatured alcohol. This gives the new 7-fluoro-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 167-169 ° C. Yield 9.4 g.

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e) This sulfide (2.0 g) was oxidized as in Example 1 with an equimolar amount of 3-chloroperbenzoic acid to give the new sulfoxide, 7-fluoro-1-methyl-3-methylsulfinylmethyl-4. 179-180 ° C (crystallized from denatured alcohol). Yield 0.7 g.

f) The sulfide (2.0 g) obtained in step D) was oxidized as described in Example 2 with 2 molar equivalents of 3-chloroperbenzoic acid to give the corresponding new sulfone, 7-fluoro-1-methyl-3-methylsulfonylmethyl 4-quinolone is obtained, m.p. 212-215 ° C (crystallized from denatured alcohol). Yield 1.4 g.

Example 11

a) To a solution of 7-methyl-4-hydroxyquinoline (2.63 g) in water (55 ml) were added 3.5 ml of 37% aqueous formaldehyde solution, 6.39 g of sodium methanesulfinate and 4 ml of triethylamine. The mixture was heated on a steam bath for 60 hours with stirring, then cooled to room temperature and filtered. The solid residue was washed with water and dried to give the new 4-hydroxy-7-methyl-3-methylsulfonylmethylquinoline, m.p. 285-290 ° C. Yield 3.4 g.

b) This product (3.0 g) is dissolved in 22 ml of an aqueous potassium hydroxide solution containing 1.91 g of potassium hydroxide. Dimethyl sulfate (1.7 mL) was added and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, washed with water, dried and crystallized from denatured alcohol. The product was washed with diethyl ether to give the new 1,7-dimethyl-3-methylsulfonylmethyl-4-quinolone, m.p. 193-195 ° C. Yield: 1.0 g.

Example 12 i

Following the procedure described in Example 10, the following reactions were carried out.

a) 4-Hydroxy-6-methoxyquinoline (7.4 g) was treated with formaldehyde in aqueous sodium hydroxide solution (initially at 40-50 ° C and then kept at 60 ° C for 18 hours). a new 4-hydroxy-3-hydroxymethyl-6-methoxyquinoline is obtained, m.p. 327-334 ° C. Yield: 7.1 g.

b) This compound (1.64 g) is mixed with 80 ml of 2-butanone, 2.2 g of anhydrous potassium carbonate and 1.01 g of dimethylsulfate and refluxed for 3 hours. The hot mixture was filtered and the filtrate was cooled. This gave the new 3-hydroxymethyl-6-methoxy-1-methyl-4-quinolone (1.5 g), m.p. 194-197 ° C.

c) This compound (8.8 g) is treated with thionyl chloride in dichloromethane to give the new 3-chloromethyl-6-methoxy-1-methyl-4-quinolone hydrochloride, m.p. 204-206 ° C. C (dec.). Yield: 10.1 g.

d) This compound (10.0 g) is added in portions to 60 ml of a 0.12 molar solution of sodium methane thiolate in methanol with stirring at 0-5 ° C. The mixture was stirred at room temperature for one hour and then poured into ice water. The precipitate was filtered off and the filtrate was extracted four times with dichloromethane. The combined extracts were dried and evaporated. The residue is crystallized from isopropanol to give the new 6-methoxy-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 122-123 ° C. Yield: 2.2 g.

e) This sulfide is 2 molar equivalents in dichloromethane

Oxidation with 3-chloroperbenzoic acid gives the new 6-methoxy-1-methyl-3-methylsulfonylmethyl-4-quinolone, m.p. 264-267 ° C (crystallized from 2-ethoxyethanol). Yield 1.2 g.

Example 13

Following the procedure described in Example 12, the following reactions were carried out.

a) 4-Hydroxy-7-methoxy-quinoline (7.4 g) is reacted with formaldehyde in aqueous sodium hydroxide solution (initially at 40-50 ° C and then kept at 60 ° C for 18 hours). This gives the new 4-hydroxy-3-hydroxymethyl-7-methoxyquinoline, m.p. 291-297 ° C. Yield 7.0 g.

b (This compound (4.0 g) is methylated with dimethyl sulfate in aqueous potassium hydroxide solution at 5-10 ° C to give the new 3-hydroxymethyl-7-methoxy-1-methyl-4-quinpline. mp 164-166 ° C (crystallized from denatured alcohol) Yield: 1.7 g.

c) This compound (4.4 g) is treated with thionyl chloride in dichloromethane to give the new 3-chloromethyl-7-methoxy-1-melyl-4-quinolinone hydrochloride, m.p. C (dec.). Yield: 4.1 g.

d. This compound (3.9 g) was triturated with sodium methane thiolate at 0-5 ° C in methanol. EZU ^r on the mixture at room temperature was poured into ice water and the precipitate was filtered off and the filtrate was extracted four times with dichloromethane metánral. The combined extracts were dried and evaporated. The residue was purified by high pressure liquid chromatography on silica gel eluting with dichloromethane: isopropanol (95: 5) at a flow rate of 250 mL / min.

This gives the new 7-methoxy-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 135-136 ° C. Yield 0.9 g.

ej This sulfide (2.5 g) is oxidized in dichloromethane with an equimolar amount of 3-chloroperbenzoic acid to give the corresponding sulfoxide as a contaminated product. This was purified by high performance liquid chromatography over silica gel (eluent: dichloromethane / denatured alcohol 90: 10, 200 mL / min). This gives the new sulfoxide, 7-methoxy-1-methyl-3-methylsulfinylmethyl-4-quinolone, m.p. 171-174 ° C. Yield: 0.5 g.

f) The sulfide (2.5 g) obtained in step D) is oxidized in dichloromethane with 2 molar equivalents of 3-chloroperbenzoic acid to give the new sulfone, 7-methoxy-1-methyl-3-methylsulfonylmethyl-4 quinolone, m.p. 248-249 ° C (crystallized from 2-ethoxyethanol). Yield: 2.0 g.

Example 14

Following the procedure described in Example 10, the following reactions were carried out.

a) 4-Hydroxy-8-methoxyquinoline (26.1 g) is reacted with formaldehyde in aqueous sodium hydroxide solution to give

-6184968 A new 4-hydroxy-3-hydroxymethyl-8-methoxyquinoline is obtained, m.p. 350 ° C. Yield:

11.2 g. ¹

b) This compound (10.0 g) is methylated in dimethyl sulfate (10.0 g) in aqueous potassium hydroxide to give the new 3-hydroxymethyl-1-methyl-8-methoxy-4-quinolone, m.p. 162 -167 ° C. Yield:

4.6 g.

c) This compound (5.5 g) is treated with thionyl chloride in dichloromethane to give the new 3-chloromethyl-8-methoxy-1-methyl-4-quinolone hydrochloride, m.p. 184-186 ° C. dec). Yield 6.4 g.

d) This compound (6.4 g) is treated with sodium methane thiolate in methanol at 0-5 ° C to give

8-Methoxy-1-methyl-3-methyl-thiomethyl-4-quinolone is obtained, m.p. 143-145 ° C. Yield 3.8 g.

e) This sulfide (5.0 g) is oxidized in dichloromethane with an equimolar amount of 3-chloroperbenzoic acid to give the corresponding new sulfoxide, 8-methoxy-1-methyl-3-methylsulfinylmethyl-4-quinolone 162-164 ° C (crystallized from ethyl acetate followed by 10: 4 ethyl acetate: dichloromethane). Yield: 1.6 g.

f) The sulfide (5.0 g) obtained in step d) is oxidized in dichloromethane with two molar equivalents of 3-chloroperbenzoic acid to give the corresponding new sulfone, 8-methoxy-1-methyl-3-methylsulfonylmethyl-4. -quinolone, m.p. 193-195 ° C (crystallized from denatured alcohol). Yield 2.4 g.

Example 15

Following the procedure described in Example 10, the following reactions were carried out.

a) 8-Eluoro-4-hydroxyquinoline (20.0 g) is treated with formaldehyde in aqueous sodium hydroxide to give the new 8-fluoro-4-hydroxy-3-hydroxymethylquinoline, m.p. 176-178. ° C (crystallized from dichloromethane). Yield 13.6 g.

b) This compound (2.0 g) is methylated with dimethyl sulfate in aqueous sodium hydroxide at 20 ° C to give the new 8-fluoro-3-hydroxymethyl-1-methyl-4-quinolone, m.p. Mp 206-210 ° C. Yield: 1.7 g.

c) This compound (20.1 g) is treated with thionyl chloride in dichloromethane to give the new 3-chloromethyl-8-fluoro-1-methyl-4-quinolone.0,11 HCl, m.p. 230 233 ° C. Yield 21.2 g.

d) This compound (20.6 g) was treated with sodium methane thiolate in methanol at 0 ° C to give

8-Fluoro-1-methyl-3-methylthiomethyl-4-quinolone is obtained, m.p. 165-167 ° C (crystallized from denatured alcohol). Yield 8.3 g.

e) This sulfide (2.0 g) is oxidized in dichloromethane with an equimolar amount of 3-chloroperbenzoic acid to give the corresponding new sulfoxide, 8-fluoro-1-methyl-3-methylsulfinylmethyl-4-quinolone 170-172 ° C (crystallized from denatured alcohol). Yield 0.8 g.

f) The sulfide (2.0 g) obtained in step d) is oxidized in dichloromethane with 2 molar equivalents of 3-chloroperbenzoic acid to give the corresponding new sulfone, 8-fluoro-1-methyl-3-methylsulfonylmethyl-4. m.p. 236-238 ° C. Yield: 1.8 g.

Example 16

a) 4.2 g 4-hydroxy-7-methylthioquinoline, 8.2 g sodium methanesulfinate, 9.0 ml 37% aqueous formaldehyde solution, 2.85 ml triethylamine, 130 g. A mixture of 50 ml of denatured alcohol and 50 ml of water was heated under reflux for 96 hours. The mixture was then cooled to room temperature and filtered. The residue was washed with hot denatured alcohol to give the new 4-hydroxy-3-methylsulfonylmethyl-7-methylthioquinoline, m.p. 290-292 ° C. Yield 2.6 g.

b) This compound (1.5 g) is methylated in 50% aqueous tetrahydrofuran at 20 ° C with dimethyl sulfate. This gives the new 1-methyl-3-methylsulfonylmethyl-7-methylthio-4-quinolone, m.p. 243-245 ° C (crystallized from denatured alcohol). Yield 0.8 g.

Example 17

Following the procedure described in Example 10, the following reactions were carried out.

a) 4-Hydroxy-6-methylquinoline (7.4 g) was treated with formaldehyde in aqueous sodium hydroxide solution at 40-45 ° C for 60 hours to give the new 4-hydroxy-3-hydroxymethyl 6-methylquinoline (2.7 g) is obtained, m.p. 188-189 ° C (dec.).

b) Methylation of this compound (30.0 g) in aqueous potassium hydroxide solution at room temperature with dimethyl sulfate gave the new 3-hydroxymethyl-1,6-dimethyl-4-quinolone, m.p. 171-173 ° C. crystallized from a mixture of denatured alcohol and ethyl acetate). Yield: 11.5 g.

c) This compound (5.0 g) is treated with thionyl chloride in dichloromethane to give the new 3-chloromethyl-1,6-dimethyl-4-quinolone hydrochloride, m.p. 215-224 ° C. Yield 6.1 g.

dj This compound (6.0 g) is reacted with sodium methane thiolate in methanol at 0-5 ° C. The reaction mixture was poured into water, the solid was boiled with denatured alcohol, cooled and filtered. The filtrate was concentrated to give the new 1,6-dimethyl-3-methylthiomethyl-4-quinolone, m.p. 142-143 ° C. Yield 1.5 g.

e) This sulfide (3.3 g) is reacted with an equimolar amount of 3-chloroperbenzoic acid to give the corresponding new sulfoxide, 1,6-dimethyl-3-methylsulfinylmethyl-4-quinolone, m.p. 177-179 ° C. (crystallized from ethyl acetate). Yield: 0.5 g.

f) Oxidation of the sulfide obtained in step d) (1.7 g) with 2 molar equivalents of 3-chloroperbenzoic acid to the corresponding new sulfone, 1,6-dimethyl-3-methylsulfonylmethyl-4-quinolone (1.3 g). m.p. 252-255 ° C (crystallized from denatured alcohol).

Example 18

(a) To a suspension of 10.0 g of 4-hydroxy-8-methylquinoline in 8.8 ml of triethylamine and 15 ml of denatured alcohol at 0-5 ° C is added 10.4 ml of methanethiol, followed by 14.2 ml. ml of 40% aqueous formaldehyde solution are added. The mixture was heated to reflux for 30 hours with stirring. To a solution of 8.8 ml of triethylamine and 10.4 ml of methanethiol in 15 ml of ethanol are added dropwise with stirring

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14.2 ml of a 40% aqueous formaldehyde solution while maintaining the temperature below 10 ° C. The resulting solution was added to the above reaction mixture and the mixture was heated under reflux for 20 hours. The mixture was allowed to cool overnight and the resulting crystalline solid was collected by filtration. The new 4-hydroxy-8-methyl-3-methylthiomethylquinoline is obtained, m.p. 226-228 ° C. Yield 7.3 g.

b) To a solution of 2.0 g of the compound obtained in 80 ml of dichloromethane is added dropwise a solution of 4.0 g of 85% 3-chloroperbenzoic acid in 100 ml of dichloromethane. The solid precipitate was collected by filtration, washed with diethyl ether and dried. This gives the new 4-hydroxy-8-methyl-3-methylsulfonylmethyl-quinoline, m.p. 274-276 ° C (dec). Yield: 2.0 g.

c) To a suspension of 1.92 g of the resulting sulfone and 2.11 g of potassium carbonate in 100 ml of 2-butanol is added 1.08 ml of dimethyl sulfate. The mixture was refluxed for 16 hours and filtered hot. Allowing the filtrate to cool affords the new 1,8-dimethyl-3-methylsulfonylmethyl-quinolone in crystalline form, m.p. 244-246 ° C. Yield 0.4 g.

Example 19

a) The new intermediate, 7-ethyl-4-hydroxyquinoline, was prepared as follows.

A mixture of 3-ethylaniline (121 g) and diethyl ethoxymethylenemalonate (250 g) was stirred in a steam bath at 95-100 ° C for 1 hour, at which time the evolution of ethyl alcohol ceased. The mixture was then cooled to -60 ° C and the solid was triturated with petroleum ether (b.p. 40-60 ° C). The solid was decanted from the solid and warmed to room temperature to give the novel diethyl (3-ethylanilino) methylene malonate as an oil. Yield 300 g.

A solution of this oil (50 g) in diphenyl ether (90 ml) was added to 420 ml of diphenyl ether refluxed at 60-80 ° C for 30 minutes. The mixture was refluxed for an additional 30 minutes and then allowed to cool to room temperature. The mixture was then diluted with an equal volume of petroleum ether (boiling point 60-80 ° C), the tan solid was collected, washed with additional petroleum ether and dried to give the new ethyl 7-ethyl-4-hydroxyquinoline-3-carboxylate. mp 257-260 ° C. Yield 28.6 g.

A mixture of ethyl 7-ethyl-4-hydroxyquinoline-3-carboxylate (15 g) and 5M aqueous sodium hydroxide was heated to reflux with stirring. After all solids had dissolved, the solution was refluxed for an additional 30 minutes, cooled and acidified to pH 4.0 with 30 mL glacial acetic acid. The solid is collected, washed with water until the wash is neutral and dried. The new 7-ethyl-4-hydroxyquinoline-3-carboxylic acid is obtained, m.p. 175-178 ° C.

To 1.64 L of boiling diphenyl ether is added portionwise 70-min of 7-ethyl-4-hydroxyquinoline-3-carboxylic acid. The mixture was cooled to room temperature with stirring, and an equal volume of light petroleum (b.p. 60-80 ° C) was added. The brown solid was collected and crystallized from water. The new 7-ethyl-4-hydroxyquinoline is obtained, m.p. 148-152 ° C. Yield: 10.6 g.

Following the procedure described in Example 10, the following reactions were carried out.

b) 7-Ethyl-4-hydroxyquinoline (40.0 g) in aqueous sodium hydroxide was treated with 40% aqueous formaldehyde to give the new 7-ethyl-4-hydroxy-3-hydroxymethylquinoline. mp 180-182 ° C. Yield 42.3 g.

c) This compound (10.0 g) is methylated with dimethyl sulfate to give the new 7-ethyl-1-methyl-3-hydroxymethyl-4-quinolone (4.4 g), m.p. 147-148.5 C (crystallized from ethyl acetate).

d) This compound (3.0 g) is reacted with thionyl chloride to give 3-chloromethyl-7-ethyl-1-methyl-4-quinolone, m.p. 136.5-148 ° C (dec). Yield 3.3 g.

e) This compound (3.2 g) is reacted with sodium methane thiolate to give the new 7-ethyl-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 104-106 ° C (denatured) crystallized from alcohol). Yield 0.7 g.

f) This sulfide (3.0 g) is oxidized with an equimolar amount of 3-chloroperbenzoic acid to give the new sulfoxide, 7-ethyl-1-methyl-3-methylsulfinylmethyl-4-quinolone, m.p. 146 DEG C. (crystallized from ethyl acetate). Yield 0.9 g.

g) The sulfide (3.0 g) obtained in step e) is oxidized with 2 molar equivalents of 3-chloroperbenzoic acid to give the new sulfone, 7-ethyl-1-methyl-3-methylsulfonylmethyl-4-quinolone, 172-174 ° C (crystallized from denatured alcohol). Yield 2.8 g.

Example 20

Following the procedure described in Example 10, the following reactions were carried out.

a) 6-Chloro-4-hydroxy-quinoline (18.0 g) was treated with formaldehyde in aqueous sodium hydroxide solution at 55 ° C for 24 hours to give the new 6-chloro-4-hydroxy-3-hydroxy. methyl quinoline (15.4 g) was obtained, m.p.

b) This compound (25.2 g) in aqueous potassium hydroxide solution was stirred at room temperature with dimethyl sulfate to give methyl 6-chloro-3 to give the new 6-chloro-3-hydroxymethyl-1-methyl-4-quinolone, m.p. C (crystallized from a mixture of denatured alcohol and water). Yield: 10.5 g.

c) This compound (10.5 g) is reacted with thionyl chloride to give the new 6-chloro-3-chloromethyl-1-methyl-4-quinolone hydrochloride.

d) This compound is reacted with sodium methane thiolate in methanol and the crude product is purified by high performance liquid chromatography on silica gel eluting with dichloromethane: isopropanol (90:10) at a flow rate of 250 ml / min. The new 6-chloro-1-methyl-3-methylthiomethyl-4-quinolone is obtained, m.p. 148-150 ° C. Yield:

6.6 g.

e) Oxidation of this sulfide (2.0 g) with an equimolar amount of 3-chloroperbenzoic acid gives the new sulfoxide, 6-chloro-1-methyl-3-methylsulfinylmethyl-4-quinolone, m.p. 217-219 '. C. Yield 1.5 g.

f) Oxidation of the sulfide obtained in Step D (2.0 g) with 2 molar equivalents of 3-chloroperbenzoic acid to yield the new sulfone

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6-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone is obtained, m.p. 237-239 ° C (crystallized from ethyl acetate). Yield 1.3 g.

Example 21

Following the procedure described in Example 10, the following reactions were carried out.

a) 8-Chloro-4-hydroxyquinoline (37.8 g) is treated with formaldehyde in aqueous sodium hydroxide solution to give the new 8-chloro-4-hydroxy-3-hydroxymethylquinoline, m.p. 300 ° C. (crystallized from methanol). Yield 33.6 g.

b) This compound (12.6 g) is methylated in 2-butanone by refluxing with dimethyl sulfate and potassium carbonate. The new 8-chloro-3-hydroxymethyl-1-methyl-4-quinolone was obtained, m.p. 182-184 ° C (crystallized from methanol / water). Yield: 6.8 g.

c) This compound (8.0 g) is treated with thionyl chloride in dichloromethane to give the new 8-chloro-3-chloromethyl-1-methyl-4-quinolone hydrochloride. Yield 8.2 g.

d) This compound (8.2 g) is reacted with sodium methane thiolate in methanol to give the new 8-chloro-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 146-148 ° C. crystallized from ethyl acetate). Yield: 5.8 g.

e) This sulfide (2.0 g) is oxidized with an equimolar amount of 3-chloroperbenzoic acid to give the new sulfoxide, 8-chloro-1-methyl-3-methylsulfinylmethyl-4-quinolone, m.p. 158 ° C (crystallized from ethyl acetate). Yield 1.2 g.

f) The sulfide (2.0 g) obtained in step d) is oxidized with 2 molar equivalents of 3-chloroperbenzoic acid to give the new sulfone, 8-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone (1 g). 6 g), m.p. 225-227 ° C (crystallized from denatured alcohol).

Example 22

Following the procedure described in Example 10, the following reactions were carried out.

a) 7-Bromo-4-hydroxy-quinoline (33.6 g) is treated with formaldehyde in aqueous sodium hydroxide to give the new 7-bromo-4-hydroxy-3-hydroxymethylquinoline, m.p. 300 ° C. above. Yield 35.5 g.

b) This compound (25.4 g) was methylated in 2-butanone at reflux with dimethyl sulfate and potassium carbonate to give the new 7-bromo-3-hydroxymethyl-1-methyl-4-quinolone, m.p. Above 300 ° C (crystallized from denatured alcohol). Yield 16.6 g.

c) This compound (16.5 g) is treated with thionyl chloride in dichloromethane to give the new 7-bromo-3-chloromethyl-1-methyl-4-quinolone hydrochloride.

d) This compound is reacted with sodium methane thiolate in methanol and the crude product is purified by chromatography on a silica gel column, eluting with dichloromethane / denatured alcohol 9: 1, then re-chromatographed on silica gel eluting with ethyl acetate. The new 7-bromo-1-methyl-3-methylthiomethyl-4-quinolone is obtained, m.p. 168-170 ° C. Yield 4.3 g.

e) This sulfide (2.4 g) is oxidized with an equimolar amount of 3-chloroperbenzoic acid to give the new sulfoxide, 10a-7-bromo-1-methyl-3-methylsulfinylmethyl-4-quinolone (1.5 g).

g), m.p. 204-207 ° C (crystallized from isopropanol).

f) Oxidation of the sulfide obtained in step d) (2.4 g) with 2 molar equivalents of 3-chloroperbenzoic acid to give the new sulfone

7-Bromo-1-methyl-3-methylsulfonylmethyl-4-quinolone (2.0 g) is obtained, m.p. 243-245 ° C (crystallized from denatured alcohol).

Example 23

Following the procedure described in Example 10, the following reactions were carried out.

a) 7-tert-Butyl-4-hydroxyquinoline (30.2 g) is reacted with formaldehyde in aqueous sodium hydroxide to give the new 7-tert-butyl-3-hydroxymethyl-4-hydroxyquinolone, m.p.> 300 ° C. Yield 32.6 g.

b) This compound (25.4 g) was methylated in 2-butanone at reflux with dimethyl sulfate and potassium carbonate to give the new 7-tert-butyl-3-hydroxymethyl-1-methyl-4-quinolone. 19.6 g, m.p. 46-149 ° C (crystallized from toluene petroleum ether [bp 60-80 ° C]).

c) This compound (17.2 g) is reacted with thionyl chloride to give the corresponding new 3-chloromethyl compound. This compound is reacted with sodium methane thiolate in methanol and the product is purified by silica gel column chromatography. Elution with ethyl acetate gave the new 7-tert-butyl-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 114-116 ° C. Yield 3.5 g.

d) This sulfide (2.2 g) is oxidized with an equimolar amount of 3-chloroperbenzoic acid to give the new sulfoxide, 7-tert-butyl-1-methyl-3-methylsulfinylmethyl-4-quinolone (1, M.p. 166-168 ° C (crystallized from ethyl acetate).

e) Oxidation of the sulfide obtained in step c) (2.2 g) with 2 molar equivalents of 3-chloroperbenzoic acid to the corresponding new sulfone, 7-tert-butyl-1-methyl-3-methylsulfonylmethyl-4-quinolone ( 1.5 g) m.p. 216-218 ° C (crystallized from ethyl acetate).

The starting material of Step a) is prepared as follows.

A mixture of 67.6 g of 3-tert-butylaniline and diethyl ethoxymethylenemalonate was heated in a water bath for 3 hours and the ethanol formed was collected by distillation. The resulting yellow oil was dissolved in 200 ml of diphenyl ether and added at 800-260 ° C over a period of 0.5 hours with stirring into 800 ml of diphenyl ether and the resulting ethanol was collected by distillation. The mixture was stirred at 250-260 ° C for 0.5 h, then allowed to cool to room temperature and diluted with an equal volume of light petroleum (b.p. 60-80 ° C). The precipitate was collected by filtration to give the new ethyl 7-tert-butyl-4-hydroxyquinoline-3-carboxylate, m.p. 279-281 ° C. Yield: 94.3 g.

This compound (92.0 g) was refluxed for 3 hours with 900 ml of 10% w / v aqueous potassium hydroxide solution, cooled and acidified with concentrated hydrochloric acid. The precipitate was collected, washed with water and dried to give the new 7-tert-butyl-4-hydroxyquinoline-3-carboxylic acid, m.p. 271 ° C (dec). Yield 49.5 g.

This compound (75 g) is decarboxylated so that

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At 260 ° C, it was added to 850 ml of diphenyl ether over 0.5 hour. After a further 1.0 hour at 260 ° C, the mixture was cooled to room temperature and diluted with an equal volume of light petroleum (b.p. 80-100 ° C). The precipitate was collected, dried and recrystallized from a mixture of denatured alcohol and water. This gives the new 7-tert-butyl-4-hydroxyquinoline, m.p. 207-209 ° C. Yield: 42.8 g.

Example 24

To a mixture of 1.93 g of 4-hydroxy-3-methylsulfonylmethylquinoline, 2.3 g of anhydrous potassium carbonate and 80 ml of 2-butanone is added 2.93 g of ethyl iodide. The mixture was refluxed for 24 hours and the solvent was evaporated. The mixture was diluted with water (200 mL) and allowed to stand overnight. The mixture is filtered and the filtrate is evaporated to dryness. A white solid is obtained which is purified by high performance liquid chromatography on silica gel. Elution was carried out with a 9: 1 mixture of ethyl acetate and isopropanol at a flow rate of 200 ml / min. This gave the new 1-ethyl-3-methylsulfonylmethyl-4-quinolone, m.p. 162-164 ° C. Yield: 0.5 g.

Example 25

a) A mixture of 5.0 g of 4-hydroxy-3-hydroxymethylquinoline, 1.6 g of anhydrous potassium carbonate, 2.6 ml of propyl bromide and 500 ml of 2-butanone is heated under reflux for 18 hours. . An additional 2 mL of propyl bromide was added and the mixture was refluxed for 23 hours. The solvent was evaporated and the residue was treated with 100 ml of water and basified with 5N aqueous sodium hydroxide solution. The solution is then extracted four times with 100 ml of dichloromethane each time, the extract is dried and evaporated to give an oily substance. This was triturated with petroleum ether, ethyl acetate and denatured alcohol 12: 1: 1 to give the new 3-hydroxymethyl-1-propyl-4-quinolone, m.p. 88-91 ° C. Yield:

2.6 g.

This compound was successively converted to the following novel compounds as described in Example 10:

b) 3-chloromethyl-1-propyl-4-quinolone, m.p. 125-127 ° C; yield 7.9 g from 7.7 g;

c) isolating 3-methylthiomethyl-1-propyl-4-quinolone as an oily substance; yield 6.2 g from 7.4 g;

d) 3-methylsulfonylmethyl-1-propyl-4-quinolone, m.p. 144-146 ° C (crystallized from denatured alcohol); yield 3.3 g from 5.1 g.

Example 26

(a) To a suspension of 7.3 g of sodium methanesulfinate in 150 ml of dimethylformamide is added 14.2 g of 4-chloro-3-chloromethyl-quinoline at room temperature with stirring. The mixture was stirred for 14 hours at room temperature and then for 0.5 hours at 95-100 ° C. The mixture was then concentrated in half and water was added to the residue. The resulting solid product was collected and dissolved in dichloromethane. The solution is dried, filtered from activated carbon and evaporated. The resulting solid was triturated with petroleum ether to give the new 4-chloro-3-methylsulfonylmethyl-quinoline, m.p. 202-204 ° C. Yield 9.0 g.

b) This compound (2.5 g) was added to a solution of sodium methoxide in 0.25 g of sodium and 50 ml of methanol and refluxed for 2 hours. An additional 0.25 g of sodium methylate (5 ml) and methanol (5 ml) were added and refluxed for another 4 hours. Allow to cool overnight and dilute with 100 ml of water. The solid residue was collected and dried to give the new 4-methoxy-3-methylsulfonylmethyl-quinoline, m.p. 151-154 ° C. Yield: 2.1 g.

c) The above compound (1.0 g) was heated in an oil bath at 160 ° C for 1 hour. After cooling to room temperature, the product is dissolved in boiling methanol. The hot solution was filtered through charcoal and allowed to cool. Crystalline 1-methyl-3-methylsulfonylmethyl-4-quinolone is obtained, m.p. 200-201 ° C. Yield 0.3 g.

Example 27

a) To a solution of 5.0 g of 4-chloro-3-methylsulfonylmethyl-4-quinoline in 300 ml of dichloromethane is added 12.54 g of dimethyl sulfate. The solution was stirred at room temperature for 4 days and then concentrated in half. The resulting mixture was kept at 0-5 ° C overnight and filtered to give the new 4-chloro-1-irethyl-3-methylsulfonylmethyl-quinolinium-methylsulfate, m.p. 194-197 ° C (dec.). ). Yield: 5.8 g.

b) This compound (1.0 g) was dissolved in 75 ml of 10% aqueous sodium bicarbonate solution and kept at room temperature for 45 minutes. The product is extracted with dichloromethane and recrystallized from methanol. This gives 1-methyl-3-methylsulfonylmethyl-4-quinolone, m.p. 202-204 ° C. Yield 0.3 g.

Example 28

To a solution of 3-acetoxymethyl-1-methyl-4-quinone (0.8 g) in acetone (15 mL) was added a solution of sodium methanesulfinate (0.53 g) in water (10 mL). The mixture was refluxed for 24 hours. An additional 0.14 g of sodium methanesulfinate was added and the mixture was refluxed for 4 hours. The mixture was evaporated to give a white solid, which was recrystallized from denatured alcohol to give 1-methyl-3-methylsulfonylmethyl-4-quinolone, m.p. 195-197 ° C. Yield 0.3 g.

Example 29

To a suspension of 5.0 g of sodium methanesulphinate in 70 ml of anhydrous dimethylformamide is stirred at room temperature for 1 minute in portions.

-10184968 2.0 g of 3-chloromethyl-1-methyl-4-quinolone hydrochloride are added. The mixture was stirred at this temperature for 16 hours and then evaporated to dryness. The residue was triturated with water (50 mL), filtered, the filtrate basified with aqueous sodium hydroxide solution and extracted with dichloromethane (2 x 50 mL). The combined extracts were dried over anhydrous magnesium sulfate and evaporated. This gave the new 1-methyl-3-methylsulfonylmethyl-4-quinolone (1.2 g), m.p. 201-204 ° C (crystallized from acetone).

Example 30

a) 4-Hydroxyquinoline (14.5 g) was reacted with 40% aqueous formaldehyde solution and methanethiol in the presence of triethylamine as in Example 18 to give the new 4-hydroxy-3-methylthio of methylquinoline, m.p. 196-197 ° C (crystallized from isopropanol). Yield 5.3 g.

(b) To a suspension of 4.4 g of 4-hydroxy-3-methylthiomethyl-quinoline in 200 ml of dichloromethane is added dropwise at 0-5 ° C with stirring.

A solution of 3.92 g of 85% 3-chloroperbenzoic acid in 100 ml of dichloromethane. Diethyl ether (500 mL) was added to the resulting solution, and the precipitated new 4-hydroxy-3-methylsulfinylmethylquinoline was collected and used without further purification.

c) 4.4 g of 4-hydroxy-3-methylsulfinylmethyl-quinoline;

To a solution of 1.68 g of potassium hydroxide in 20 ml of water at 0-5 ° C is added 2.52 g of dimethyl sulfate with stirring. The solution was stirred at room temperature for 30 minutes and then neutralized with 5N aqueous hydrochloric acid. The resulting sticky solid is triturated with denatured spirit to give a solid. This was purified by high performance liquid chromatography on silica gel eluting with 95: 5 isopropanol / dichloromethane at 200 mL / min. This gave the new 1-methyl-3-methylsulfinylmethyl-4-quinolone, m.p. 94-96 ° C. Yield 2.5 g.

Example 31

(a) A mixture of 2.9 g of 4-hydroxyquinoline, 8.16 g of sodium methanesulphinate, 4.5 ml of 40% aqueous formaldehyde and 70 ml of water is stirred at 95-100 ° C for 24 hours. A further 5 ml of formaldehyde solution was added and the mixture was cooled and filtered to give the new 4-hydroxy-3-methylsulfonylmethyl-quinoline (1.2 g), m.p. 280-282 ° C (denatured). crystallized from a mixture of alcohol and water).

b) 1.9 g of 4-hydroxy-3-methylsulfonylmethyl-quinoline;

To a solution of 1.4 g of potassium hydroxide in 20 ml of water was added 3.0 ml of dimethyl sulphate at 5 ° C with stirring. The mixture was stirred for 4 hours at room temperature and then filtered to give the new 1-methyl-3-methylsulfonylmethyl-4-quinolone, m.p. 204-205 ° C (crystallized from acetone). Yield 1.5 g.

The following examples illustrate the preparation of pharmaceutical compositions.

Example 32

To prepare capsules, equal amounts of 1-methyl-3-methylsulfonylmethyl-4-quinolone and calcium phosphate are filled into hard gelatin capsules, each containing 10 mg of the active ingredient.

Example 33

To prepare tablets, the following mixture is dry-granulated and compressed into tablets containing 10 mg of active ingredient on a tabletting machine:

active ingredient 10 parts by weight, lactose 5 parts by weight, calcium phosphate 5 parts by weight, corn starch 5 parts by weight.

Example 34

To prepare capsules, equal amounts of 7-chloro-1-methyl-3-methylsulfinylmethyl-4-quinolone and calcium phosphate are filled into hard gelatine capsules, each containing 10 mg of the active ingredient.

Example 35

To prepare capsules, equal amounts of 7-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone and calcium phosphate are filled into hard gelatin capsules, each containing 10 mg of the active ingredient.

Example 36

Tablets are prepared from the following ingredients:

active ingredient 10.0 parts by weight, lactose 78.5 parts by weight, polyvinylpyrrolidone 5.0 parts by weight, corn starch 15.0 parts by weight, magnesium stearate 1.5 parts by weight.

The active ingredient, lactose and a portion of the starch are mixed and granulated with an ethanolic solution of polyvinylpyrrolidone. The granular product is mixed with the magnesium stearate and the starch residue and compressed into tablets containing 10 mg of active ingredient on a tabletting machine.

Example 37 Tablets containing 7-ethyl-1-methyl-3-methylsulfonyl-methyl-4-quinolone (mg) were prepared as described in Example 36. The tablets are coated as usual with a 1: 1 mixture of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol / dichloromethane.

-1 123

Example 38

To prepare suppositories, 15 parts by weight of the active ingredient are added to 1300 parts by weight of triglyceride suppository base and 15 mg of the active ingredient are prepared as suppositories.

Example 39

Tablets were prepared as described in Example 36, using one of the following quinolones as active ingredient:

a) 1-methyl-3-methylsulfonylmethyl-4-quinolone,

b) 7-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone;

c) 7-fluoro-1-methyl-3-methylsulfonylmethyl-4-quinolone,

d) 1,7-dimethyl-3-methylsulfonylmethyl-4-quinolone.

Claims (4)

Patent claims A process for the preparation of quinolone derivatives of formula I wherein n is 0, 1 or 2, R 1 is lower alkyl and R _{3 is} hydrogen, lower alkyl, methoxy, methylthio, halogen or trifluoromethyl - a) for the preparation of compounds of the formula Γ in which n is 0 or 2, a compound of the formula II in which X represents a leaving group, preferably a halogen atom or an acetoxy group, with CH ₃ S®-methylthiolate anion or CH ₃ S ° O ₂ - reacting with a methanesulfinate anion, or b) hydrolyzing a quinolinium salt of formula III wherein Z represents a leaving group, preferably a halogen atom and A® an anion, to prepare compounds of formula I wherein n is 2; or c) thermally rearranging a compound of formula V to produce compounds of formula I wherein n is 2; or d) alkylating a compound of formula VI wherein n is 1 or 2 to produce compounds of formula I wherein n is 1 or 2; optionally oxidizing a resulting compound of formula I wherein n is 0 to a compound of formula I wherein n is 1 or 2. (Preferred 25 January 1981) 2. A process for the preparation of quinolone derivatives of the formula I wherein n is 0, 1 or 2, R 1 is lower alkyl and R _{3 is} hydrogen, lower alkyl, methoxy, methylthio, halogen or trifluoromethyl - Characterized in that a compound of formula II, wherein R 1 and R _{3 are} a leaving group X, preferably a halogen atom or an acetoxy group, is CH ₃ S ⁹ -methylthiolate anion and, if desired, the resulting compound of formula I , Wherein n is 0 is oxidized. (Priority: 1980. IX. 26.) 3. The process according to any one of claims 1 to 3, wherein 1-methyl-3-methylsulfonylmethyl-4-quinolone is used. 30 characterized in that appropriate starting materials are used. (Priority: 25/25/1981) 4. A process for the preparation of a pharmaceutical composition comprising an active ingredient of the formula I in which n, R ₁ and R _{3 are} as defined in claim 1, characterized in that the compounds of the general formula I obtained by the method of claim 1 are and / or other excipients, to form a medicament. (Priority: 25/25/1981)