JPS6348268B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to quinolone compounds with therapeutic activity, therapeutic compositions containing said quinolones, and methods for producing said quinolones. The present invention is based on the general formula (wherein n is 0, 1 or 2, R ₁ is methyl, and a) when n is 0, R ₃
is 7-chloro, or b) when n is 1, R ₃ is 7-chloro, 7-bromo or 7
-trifluoromethyl, or c) when n is 2, R ₃ is hydrogen, 7-chloro, 7-
fluoro, 7-trifluoromethyl, 7-methyl or 6-fluoro). The inventors have found that compounds of the general formula have effective antihypertensive activity. This compound lowers blood pressure when administered to hypertensive mammals. Accordingly, the present invention also provides therapeutic compositions comprising a quinolone of the general formula together with a pharmaceutically acceptable carrier. As used herein, the term "active compound" refers to quinolone compounds of the general formula. For therapeutic use, the active compounds can be administered orally, rectally or parenterally, preferably orally. Thus, the therapeutic compositions of the invention may take the form of any known pharmaceutical composition for oral, rectal or parenteral administration. Pharmaceutically acceptable carriers suitable for use in such compositions are known in the pharmaceutical art. The composition of the invention is 0.1
Suitably they contain from % to 90% by weight of active compound. Compositions of the invention are generally manufactured in unit dosage form. Compositions for oral administration are preferred compositions of the invention and are in known pharmaceutical forms for such administration, such as tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are those known in the pharmaceutical industry. The tablet contains the active compound,
It may be prepared by mixing with an inert diluent such as calcium phosphate in the presence of a disintegrant, eg corn starch, and a lubricant, eg magnesium stearate, and then tableting this mixture by known methods. If desired, such tablets may be coated by known methods, such as using cellulose acetate phthalate. For example, hard or soft gelatin capsules containing the active compound with or without added excipients can be manufactured by conventional means and, if desired, by known methods. An enteric skin may be provided. The enteric-coated compositions of the invention may be advantageous depending on the type of active compound. Tablets and capsules each may suitably contain from 5 mg to 500 mg of active compound. Other compositions for oral administration include aqueous suspensions of the active compound in an aqueous medium in the presence of a non-toxic suspending agent, such as sodium carboxymethyl cellulose, and a suitable vegetable oil, such as peanut oil. There are oily suspensions containing the compounds of the invention. Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, such as suppositories based on cocoa butter or polyethylene glycol. Compositions of the invention suitable for parenteral administration are in known pharmaceutical forms for such administration, such as sterile suspensions in aqueous and oily vehicles or sterile solutions in suitable solvents. In some formulations, it is advantageous to use the compounds of the invention in the form of particles of very small size, such as those obtained by fluid energy milling. In the compositions of the invention, the active compounds may, if desired, be combined with other compatible pharmaceutically active ingredients. The therapeutic activity of compounds of the general formula is demonstrated by tests on standard laboratory animals. Such tests include, for example, oral administration of the compound to a strain of idiopathically hypertensive rats. Compounds of the general formula where n is 0 or 2 have the general formula (wherein R ₁ and R ₃ are as defined above and X is a suitable leaving group, e.g. chloro or acetoxy) can be combined with the methanethiolate anion CH ₃ S or methanesulfur It can be produced by reacting with the nate anion CH ₃ SO ₂ . Reaction with methanethiolate anions gives compounds where n is 0, and reaction with methanesulfinate anions gives compounds where n is 2. Each anion is suitably provided by a suitable alkali metal salt, such as the sodium salt. This reaction is carried out in a manner conventional for such reactions. The compounds of the general formula are new and can be prepared by methods known in the art for similar compounds. Compounds of the general formula where n is 1 can be prepared by oxidation of the corresponding compounds where n is 0. Similarly, compounds of the general formula where n is 2 can be prepared by oxidation of the corresponding compounds where n is 0 or 1.
These oxidations can be carried out using conventional methods for such reactions, for example using organic peracids as oxidizing agents. Compounds of the general formula where n is 2 may also have the general formula (wherein R ₁ and R ₃ are as defined above, A is an anion, and Z is a suitable leaving group,
For example, it can be prepared by hydrolysis of a quinolinium salt (methoxy or chloro). Hydrolysis can be carried out by reacting a compound of the general formula with water under neutral, acidic or basic conditions depending on the type of leaving group. The compound with the general formula is new, and the compound with the general formula
It can be produced by alkylation of quinoline. That is, the anion A is suitably derived from an alkylating agent, such as a halogen anion or a methyl sulfate anion. Compounds of the general formula where n is 2 may also have the general formula (wherein R ₁ and R ₃ are as defined above) It can also be produced by thermal rearrangement of a compound. This rearrangement can be carried out by heating a compound of general formula V to an elevated temperature above the melting point of the compound, optionally in the presence of an inert organic liquid which may be a solvent for the compound. The compound of general formula is new. This compound is obtained from the corresponding 4-chloro-3-chloromethylquinoline by reaction with sodium methanesulfinate, followed by reaction with sodium alkoxide NaOR ₁ . It can be produced by obtaining a compound by Compounds of the general formula where n is 1 or 2,
general formula (where n is 1 or 2 and R ₃ is as defined above). This reaction can be carried out by reacting the compound with an alkylating agent, such as dimethyl sulfate or methyl iodide, in a manner conventional for such reactions. The compound of general formula is new. The compound of the general formula where n is 2 is the general formula can be prepared by reaction with formaldehyde and sodium methanesulfinate in the presence of a tertiary amine such as triethylamine. Compounds of the general formula where n is 1 can be prepared by oxidation of the corresponding compounds where n is 0. The latter compound can be prepared by reacting a compound of the general formula with formaldehyde and sodium methanethiolate in the presence of a tertiary amine, such as triethylamine. Those skilled in the art will appreciate that in compounds of the general formula defined above, where n is 1, the CH ₃ SO-- group contains a chiral center at the sulfur atom. That is, such compounds exist in two enantiomeric forms. The present invention includes both enantiomers and racemic mixtures thereof. As mentioned above, the therapeutic activity of quinolones of the general formula is demonstrated by a study involving oral administration of this compound to (A) a strain of idiopathically hypertensive rats. This test was conducted in the following manner. Test A Female rats of the Aoki-Okamoto strain of idiopathically hypertensive rats with a weight range of 180 g to 240 g were used. 1
Groups of 4 rats were fasted overnight prior to administration of test compound. Blood pressure was measured by the following method. Rats were placed in a box maintained at 38°C with their tails sticking out of the hole in the box. After 30 minutes in the box, blood pressure was measured using an inflatable cuff placed around the base of the tail, and arterial pulse was monitored by an air pulse transducer.
A pressure greater than the expected blood pressure was applied to the cuff and then this pressure was gradually reduced. The pressure in the cuff that reproduced the arterial pulse was defined as blood pressure. The rats were removed from the box and each group was orally dosed with the prescribed dose of test compound as a solution or suspension in 0.25% carboxymethyl cellulose aqueous solution. In addition to predose readings, blood pressure was measured at 1.5 and 5.0 hours postdose. A compound was rated active if it produced a 20% or more reduction in blood pressure during any of these time intervals. The compound was initially tested at a dose of 90mg/Kg.
If active at this dose, a dose of 30 mg/Kg was further tested. If active at this dose, further testing was conducted at a dose of 10 mg/Kg. In this manner, the "threshold" dose at which the test compound is active in this test was determined. 90mg/
A compound that is active at a dose of Kg but inactive at a dose of 30 mg/Kg was evaluated to have an active threshold dose of 30-90 mg/Kg. Similarly, a compound that is active at a dose of 30 mg/Kg but inactive at a dose of 10 mg/Kg was evaluated to have an active threshold dose of 10-30 mg/Kg. The results obtained are shown in the table below.

TABLE All compounds shown in Table 1 above were initially tested in duplicate in Test A at an oral dose of 90 mg/Kg (4 animals/test). Compound 7
In one test with 100%, one of the animals died, but no mortality occurred in other cases. This one death is not more than the normal mortality seen in control rats not receiving the test compound under the test conditions used. The present invention provides a method for lowering blood pressure in a hypertensive mammal, which comprises administering a quinolone compound as defined herein by the general formula.
Administration may be enteral or parenteral, with enteral administration, especially oral administration being preferred. Appropriate doses for the treatment of hypertension in humans and other mammals are administered in single or divided doses and generally range from 0.1 mg/Kg/day to 100 mg/Kg/day.
Kg/day, more usually from 0.5 mg/Kg/day to 75 mg/Kg/day, especially from 1 mg/Kg/day to 50 mg/Kg/day. Suitably unit dosage forms contain from 1 mg to 500 mg, especially from 5 mg to 500 mg of active compound. The invention is illustrated by the following non-limiting examples in which parts and percentages are by weight and the composition of the mixed solvent is given by volume. The novel compounds were identified by one or more of the following spectroscopic techniques: nuclear magnetic resonance (H ¹ or C ¹³ ), infrared and mass spectrometry. Additionally, the example products had satisfactory elemental analysis values. Melting points are given in degrees Celsius. Example 1 (a) Refluxing of a solution of thionyl chloride (9.48 g) in dichloromethane (800 ml) and triturated 3-hydroxymethyl-1-methyl-4-quinolone (15.01 g) in dichloromethane (200 ml) for 4 hours. added to the suspension. The mixture was boiled under reflux for a further 1.5 hours, cooled to room temperature and then filtered to give the new compound 3-
Chloromethyl-1-methyl-4-quinolone hydrochloride was obtained. This compound (12.71g) in 5 minutes
A stirred solution of sodium methanethiolate (0.109 mol) in methanol at 0°
116 ml) containing NaSCH ₃ ). The resulting mixture was allowed to warm to room temperature and kept overnight. The mixture was cooled to 0°C and then water was added to form a solution. This solution was neutralized to pH 7.0 with dilute hydrochloric acid and then filtered. The methanol was distilled off from the filtrate and the residue was then extracted with dichloromethane (3 x 50ml). The combined extracts were dried over anhydrous magnesium sulfate and then evaporated to give a solid product. The product was purified by high pressure liquid chromatography on silica gel, eluting with isopropanol:dichloromethane 15:85 at a flow rate of 300 ml per minute. This product was applied to silica gel using the same solvent. By this operation, the melting point
A new 1-methyl-3-methylthiomethyl-4-quinolone with an angle of 118° to 120° was obtained. (b) To a stirred solution of 1-methyl-3-methylthiomethyl-4-quinolone (1.3 g) in dichloromethane (60 ml) at −20° for 20 minutes, add 3-chloroperbenzoin in dichloromethane (85 ml). A solution of acid (85%, 2.75g) was added. The stirred solution was allowed to warm to room temperature, then for an additional 1
Stir for hours. The solution was extracted with saturated aqueous sodium bicarbonate until free of peracid. The organic phase was dried over anhydrous magnesium sulphate and then evaporated to give a solid product. This product was crystallized from acetone and had a melting point of 203°.
A new 1-methyl-3-methylsulfonylmethyl-4-quinolone with an angle of up to 205° was obtained. Example 2 (a) 3-chloromethyl-1-methyl-7-trifluoromethyl-4-quinolone hydrochloride (4.7g)
was added over 5 minutes to a stirred solution of sodium methanethiolate in methanol (16 ml containing 0.039 mol NaSMe) at 0°. The resulting mixture was warmed to room temperature, then water (100ml)
poured into. The resulting precipitate was collected, dried and then crystallized from dichloromethane:petroleum ether (boiling point 60° to 80°) to form a novel 1-methyl-3-methylthiomethyl-7- with a melting point of 182° to 184°. Trifluoromethyl-4-quinolone was obtained. (b) The starting materials for the above preparation were prepared as follows. A mixture of 4-hydroxy-7-trifluoromethylquinoline (30.0 g), 40% formaldehyde aqueous solution (36 ml) and 1M sodium hydroxide aqueous solution (250 ml) was stirred at 40° to 50° for 8 hours. The solid product was collected and dried to yield a novel 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline with a melting point of 302° to 304°. dimethyl sulfate (24.4 g) for 5 minutes;
4-Hydroxy-3 in a mixture of water (50 ml) and tetrahydrofuran (50 ml) at room temperature.
-Hydroxymethyl-7-trifluoromethylquinoline (23.6g) and potassium hydroxide (16.3g) were added to a stirred solution. After stirring for an additional 3 hours at this temperature, the solid product was collected. The filtrate was dichloromethane (3
×200ml). The combined extracts were dried over anhydrous magnesium sulfate and then evaporated to give a second crop of solids. The combined solids were purified by high pressure liquid chromatography on silica gel using isopropanol:dichloromethane.
Purification was carried out by elution using 10:90 at a flow rate of 200 ml per minute. The product was applied to silica gel using the same solvent. By this operation, from the melting point of 172°
Novel 3-hydroxymethyl-1- up to 175°
Methyl-7-trifluoromethyl-4-quinolone was obtained. A solution of thionyl chloride (2.32 g) in dichloromethane (100 ml) was prepared by pulverizing 3-hydroxymethyl-1-methyl-7-trifluoromethyl-4- in dichloromethane (200 ml) for 1.5 hours.
Added to a refluxing suspension of the quinolone (5.0 g). The solution was boiled under reflux for an additional 0.5 h and then evaporated to dryness under reduced pressure to obtain a novel 3-chloromethyl-1-
Methyl-7-trifluoromethyl-4-quinolone hydrochloride was obtained. (c) To a stirred solution of -methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone (6.5 g) in dichloromethane (150 ml) at −10° for 30 minutes, A solution of 3-chloroperbenzoic acid (85%, 4.2 g) was added. The solution was extracted with saturated aqueous sodium bicarbonate until free of peracid. The organic phase was dried over anhydrous magnesium sulfate and then evaporated to give a solid product. This product was crystallized from ethyl acetate:dichloromethane to give a novel 1-methyl-3-methylsulfinylmethyl-7-trifluoromethyl-
4-quinolone was obtained. Example 3 1 in dichloromethane (150 ml) at room temperature
-To a stirred solution of methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone (7.8 g) was added dichloromethane (100 ml) over 3 minutes.
of 3-chloroperbenzoic acid (85%, 11.3 g) in the solution. After stirring for an additional hour at this temperature, the solution was extracted with saturated aqueous sodium bicarbonate until free of peracid. The organic phase was dried over anhydrous magnesium sulfate, then a solid product was obtained. This product was crystallized from industrial denatured spirit: dichloromethane to yield a novel 1-methyl-3-methylsulfonylmethyl-7-trifluoromethyl-4-quinolone with a melting point of 240° to 242°. Example 4 In a manner analogous to that described in Example 2, 7-chloro-4-hydroxy-3-hydroxymethylquinoline was treated with dimethyl sulfate to produce novel 7-chloro- 1-methyl-3
-Hydroxymethyl-4-quinolone was obtained (from industrial denatured spirit). This product was treated with thionyl chloride to produce 7-chloro-3 with a melting point of 205° to 207°.
-Chloromethyl-1-methyl-4-quinolone is obtained, which is reacted with sodium methanethiolate to produce a novel 7-chloro-1-methyl-3-methylthiomethyl-4- with a melting point of 163° to 164°. Quinolones were obtained (from industrial denatured spirits). Example 5 In a similar manner as described in Example 2, 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone was oxidized with 3-chloroperbenzoic acid,
Novel 7-chloro-1- with melting point from 180° to 181°
Methyl-3-methylsulfinylmethyl-4-quinolone [dichloromethane: petroleum ether (boiling point
from 60° to 80°). Example 6 In a manner analogous to that described in Example 3, 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone was oxidized with 3-chloroperbenzoic acid to give a melting point of 215° to 216°. A new 7-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone was obtained (from ethanol). Example 7 (a) In a similar manner as described in Example 3, 6-fluoro-1-methyl-3-methylthiomethyl-4
-A new 6-fluoro-1-methyl-3-methylsulfonylmethyl-4-quinolone with a melting point of 200° to 205° is obtained by oxidizing quinolone with 3-chloroperbenzoic acid (from industrial denatured spirit) Obtained. (b) The starting materials for the above preparation were prepared in a manner similar to that described in Example 2. 6-Fluoro-4-hydroxyquinoline is reacted with a 40% formaldehyde aqueous solution in a sodium hydroxide aqueous solution, and the melting point is 310°.
A new 6-fluoro-4-hydroxy-3-hydroxymethylquinoline with an angle of up to 315° was obtained. This product was methylated with dimethyl sulfate to give a novel 6-fluoro-1-methyl-3-hydroxymethyl-4- with a melting point of 209° to 212°.
Quinolone was obtained. Reaction of this product with thionyl chloride and then with sodium methanethiolate gives novel 6-fluoro-1-methyl-3-methylthiomethyl-4-quinolones ( obtained from industrial denatured spirits). (c) This sulfide is oxidized in a manner analogous to that described in Example 2 with a molar amount of 3-chloroperbenzoic acid in dichloromethane at -20° to -30° to give a melting point of 154° to 156°. The corresponding new sulfoxide 6-fluoro-1-methyl-3-methylsulfinylmethyl-4-quinolone was obtained (from industrial denatured spirit). Example 8 (a) 7-fluoro-4-hydroxyquinoline (91.5 g, contains some 5-fluoro isomer),
A mixture of aqueous sodium hydroxide (1.0N, 666ml) and formaldehyde (37%, 91.5ml) was stirred at 35° to 37° for 5.5 hours.
Additionally, 1 part formaldehyde aqueous solution (37%,
91.5 ml) was added and stirring continued for 64 hours. The solid product was collected by filtration and dissolved in water (600
ml) and the mixture was then acidified to pH 4.0 with concentrated hydrochloric acid. Collect this solid residue and
After washing with water and then drying, a new 7-fluoro-4-hydroxy-3 with a melting point of 295° to 300°
-Hydroxymethylquinoline (containing some 5-fluoro isomer) was obtained. Further melting point
The product between 295° and 300° is soaked with concentrated hydrochloric acid.
The alkaline filtrate of the reaction mixture was obtained by acidification to PH4.0 and then combined with the initial product. (b) This combined product was combined with water (1300 ml), potassium hydroxide (17.3 g) and dimethyl sulfate (35 g).
ml). Hold this mixture at 25° for 17
Stir for an hour and then basify with 5N aqueous potassium hydroxide. The residue was collected, washed with water, dried, and then crystallized from industrial denatured spirits to determine the melting point.
New compound 7-fluoro from 219° to 222°
3-Hydroxymethyl-1-methyl-4-quinolone was obtained. (c) This compound is reacted with thionyl chloride in a manner analogous to that described in Example 2 to give a melting point of from 169° to
3-chloromethyl-7-fluoro- up to 171°
1-Methyl-4-quinolone was obtained. (d) This compound (20.7 g) was added to a stirred solution of sodium methanethiolate [from methanethiol (10 ml) and methanolic sodium methoxide (0.64 M, 280 ml)] in methanol at 10° for 10 minutes. Added. this mixture
Stir at 20° for 1 hour, then add water (700ml)
injected into. This precipitate was collected and then crystallized from industrial denatured spirits to obtain a new compound, 7-fluoro-1-methyl-3-methylthiomethyl-4-quinolone, with a melting point of 167° to 169°. (e) Oxidation of this sulfide with an equimolar amount of 3-chloroperbenzoic acid in a manner analogous to that described in Example 1 gives the corresponding new 7-fluoro-1 sulfoxide with a melting point of 179° to 180°. -Methyl-3
-Methylsulfinylmethyl-4-quinolone was obtained (from industrial denatured spirit). (f) Oxidation of the sulfide from (d) with 2 molar equivalents of 3-chloroperbenzoic acid in a manner analogous to that described in Example 1 to give the corresponding new sulfones with melting points of 212° to 215°. 7-Fluoro-1-methyl-3-methylsulfonylmethyl-4-quinolone was obtained (from industrial denatured spirits). Example 9 (a) A solution of 7-methyl-4-hydroxyquinoline (2.63 g) in water (55 ml) with aqueous formaldehyde (37%, 3.5 ml), sodium methanesulfinate (6.39 g) and triethylamine (4 ml). was added. The mixture was heated on a steam bath with stirring for 60 hours, cooled to room temperature, and
It was then filtered. The solid residue was washed with water and then dried to obtain a new compound 4 with a melting point of 285° to 290°.
-Hydroxy-7-methyl-3-methylsulfonylmethylquinoline was obtained. (b) This product (3.0 g) was dissolved in aqueous potassium hydroxide solution (22 ml, containing 1.91 g KOH).
Dimethyl sulfate (1.7ml) was added and the mixture was then stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, washed with water, dried, and then crystallized from industrial denatured spirits. The product was washed with diethyl ether to give a melting point of
A new compound of 1,7-dimethyl-3-methylsulfonylmethyl-4-quinolone with an angle of 193° to 195° was obtained. Example 10 The following reaction was carried out in a manner similar to that described in Example 8. (a) By reacting 7-bromo-4-hydroxyquinoline with formaldehyde in an aqueous sodium hydroxide solution, a new compound 7- with a melting point higher than 300° is produced.
Bromo-4-hydroxy-3-hydroxymethylquinoline was obtained. (b) This compound was methylated by boiling under reflux with dimethyl sulfate and potassium carbonate in 2-butanone. New compound 7-bromo-3-hydroxymethyl- with a melting point higher than 300°
1-Methyl-4-quinolone was obtained (from industrial denatured spirit). (c) This compound was reacted with thionyl chloride in dichloromethane to form a new compound 7-bromo-3-
Chloromethyl-1-methyl-4-quinolone hydrochloride was obtained. (d) Reacting this compound with sodium methanethiolate in methanol to obtain the crude product, which was eluted by column chromatography on silica gel with dichloromethane:technical denatured spirits 9:1. and then purified by column chromatography on silica gel eluting with ethyl acetate. As a result, a new compound 7- with a melting point of 168° to 170°
Bromo-1-methyl-3-methylthiomethyl-
4-quinolone was obtained. (e) This sulfide is oxidized with an equimolar amount of 3-chloroperbenzoic acid to produce a new sulfoxide 7-bromo-1-methyl-3 with a melting point of 204° to 207°.
-Methylsulfinylmethyl-4-quinolone was obtained (from isopropanol). (f) Oxidation of the sulfide from (d) with 2 molar equivalents of 3-chloroperbenzoic acid to produce novel sulfones 7-bromo-1-methyl- with melting points from 243° to 245°.
3-Methylsulfonylmethyl-4-quinolone was obtained (from industrial denatured spirits). Example 11 (a) 4-Chloro-3-chloromethylquinoline (14.2g) was added to a stirred suspension of sodium methanesulfinate (7.3g) in dimethylformamide (150ml) at room temperature. The mixture was stirred at room temperature for 14 hours,
Then, the mixture was stirred at 95° to 100° for 0.5 hour. The solvent was evaporated to 1/2 volume and then water was added to the residue. The resulting solid product was collected and then dissolved in dichloromethane. The solution was dried, filtered through charcoal, and then evaporated. The resulting solid was triturated in petroleum ether to obtain a new compound, 4-chloro-3-methylsulfonylmethylquinoline, with a melting point of 202° to 204°. (b) This compound (2.5 g) was added to methanolic sodium methoxide (from 0.25 g sodium and 50 ml methanol) and the mixture was then boiled under reflux for 2 hours. Further sodium methoxide (from 0.25 g of sodium and 5 ml of methanol) was added and the mixture was then boiled under reflux for 4 hours. Let this mixture cool overnight,
It was then diluted with 100ml of water. This solid residue is collected and then dried to a melting point of 151°
A new 4-methoxy-3-methylsulfonylmethylquinoline with an angle of up to 154° was obtained. (c) Place the above compound (1.0 g) in an oil bath.
It was heated to 160° (oil temperature) for 1 hour. After cooling to room temperature,
The product was dissolved in boiling methanol.
The hot solution was filtered through charcoal and then allowed to cool. This gave the crystalline product 1-methyl-3-methylsulfonylmethyl-4-quinolone with a melting point of 200° to 201°. Example 12 (a) 4-chloro- in dichloromethane (300 ml)
Dimethyl sulfate (12.54 g) was added to a stirred solution of 3-methylsulfonylmethyl-4-quinoline (5.0 g). The solution was stirred at room temperature for 4 days and then evaporated to 1/2 volume. The resulting mixture was cooled overnight to 0° to 5° and then filtered to a melting point of 194° to 197° (decomposition).
A new compound 4-chloro-1-methyl-3-methylsulfonylmethylquinolinium methylsulfate was obtained. (b) This compound (1.0 g) was dissolved in 10% aqueous sodium bicarbonate solution (75 ml) and the solution was then kept at room temperature for 45 minutes. The product was isolated by extraction with dichloromethane and then recrystallization from methanol to yield 1-methyl-3-methylsulfonylmethyl-4-quinolone with a melting point of 202° to 204°. Example 13 3-acetoxymethyl in acetone (15 ml)
A solution of 1-methyl-4-quinolone (0.8g) was added to a solution of sodium methanesulfinate (0.53g) in water (10ml). The mixture was boiled under reflux for 24 hours. Further sodium methanesulfinate (0.14g) was added and the mixture was then boiled under reflux for 4 hours. The acetone is evaporated from the mixture and a white solid is separated which is recrystallized from industrial denatured spirit to give 1-methyl-3-methylsulfonylmethyl-, melting point 201° to 203°.
4-quinolone was obtained. Example 14 3-Chloromethyl-1-methyl-4-quinolone hydrochloride (2.0 g) was added in portions over 1 minute to a stirred suspension of sodium methanesulfinate (5.0 g) in anhydrous dimethylformamide (70 ml) at room temperature. added to the suspension. The mixture was stirred at this temperature for 16 hours and then evaporated to dryness. Water (50ml) with residue
The filtrate was made basic with an aqueous sodium hydroxide solution, and then dichloromethane (2
×50ml). The combined extracts were dried over anhydrous magnesium sulfate and then evaporated to yield the new 1-methyl-3-methylsulfonylmethyl-4-quinolone (from acetone) with a melting point of 201° to 204°. Example 15 (a) 4-hydroxyquinoline (2.9 g), sodium methanesulfinate (8.16 g), 40% formaldehyde aqueous solution (4.5 ml) and water (70 ml)
The mixture was stirred at 95° to 100° for 24 hours. Add a larger amount of formaldehyde aqueous solution (5 ml) and then stir the mixture from 95° to
Stirring was continued for an additional 24 hours at up to 100°. The mixture is cooled and then filtered to a melting point of 280°.
New 4-hydroxy-3-methylsulfonylmethylquinolines (from industrial denatured spirit: water) of up to 282° were obtained. (b) Dimethyl sulfate (3.0 ml) was added to a stirred solution of 4-hydroxy-3-methylsulfonylmethylquinoline (1.9 g) and potassium hydroxide (1.4 g) in 5° water (20 ml). . The mixture was stirred at room temperature for 4 hours and then filtered to yield a new 1-methyl-3-methylsulfonylmethyl-4-quinolone with a melting point of 204° to 205°. Example 16 In the manufacture of capsules, equal weight parts of a mixture of 1-methyl-3-methylsulfonylmethyl-4-quinolone and calcium phosphate were encapsulated in hard gelatin capsules. Each capsule contained 10 mg of active ingredient. Example 17 In the manufacture of tablets, the following mixture was dry granulated and then compressed in a tablet machine to obtain tablets containing 10 mg of active ingredient. Parts by Weight Active Compounds 10 Lactose 5 Calcium Phosphate 5 Corn Starch 5 Example 18 In the manufacture of capsules, a mixture of equal parts by weight of 7-chloro-1-methyl-3-methylsulfinylmethyl-4-quinolone and calcium phosphate is added to hard gelatin. Enclosed in a capsule. Each capsule contained 10 mg of active ingredient. Example 19 In the manufacture of capsules, equal parts by weight of a mixture of 7-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone and calcium phosphate were encapsulated in hard gelatin capsules. Each capsule contained 10 mg of active ingredient. Example 20 Tablets were manufactured from the following ingredients: Parts by Weight Active Compound 10.0 Lactose 78.5 Polyvinylpyrrolidone 5.0 Corn Starch 15.0 Magnesium Stearate 1.5 The active compound, lactose and some starch are mixed and then granulated using a solution of polyvinylpyrrolidone in ethanol. The granulate is mixed with magnesium stearate and the remaining starch and the mixture is then compressed in a tablet machine to obtain tablets containing 10 mg of active ingredient. Example 21 Tablets each containing 10 mg of 7-ethyl-1-methyl-3-methylsulfonylmethyl-4-quinolone are prepared by the method of Example 20. The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in 1:1 ethanol:dichloromethane. Example 22 In the manufacture of suppositories, 15 parts by weight of the active compound are
1300 parts by weight of triglyceride suppository base;
This mixture is then formed into suppositories, each containing 15 mg of active compound. Example 23 Tablets are prepared as described in Example 20 using one of the quinolones listed below as active compound. (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]

1 The following formula (), However, in the formula, R ₁ and R ₂ each represent a group selected from the group consisting of a hydrogen atom, a lower alkyl group, a phenyl group which may have a substituent, and _a benzyl group; One of R ₂ is a hydrogen atom and the other is a group other than a hydrogen atom, and the α- or β-substituted-γ-phenylthio-γ-butyrolactones represented by the following are oxidized with methachloroperbenzoic acid. The following formula () is characterized in that the γ-phenylsulfinyl compound is dephenylsulfinylated with pyridine,

Claims (1)

(b) A quinolone compound according to claim 1, wherein n is 1 and R ₃ is 7-chloro or 7-trifluoromethyl or 7-bromo. 4 1-Methyl-3-methylsulfonylmethyl-
The quinolone compound according to claim 1, which is a 4-quinolone. 5. The quinolone compound according to claim 1, which is 7-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone. 6. The quinolone compound according to claim 1, which is 7-fluoro-1-methyl-3-methylsulfonylmethyl-4-quinolone. 7 Claim 1, which is 1,7-dimethyl-3-methylsulfonylmethyl-4-quinolone
Quinolone compounds described in Section. 8 General formula (wherein n is 0 or 2, R ₁ is methyl, and a) when n is 0, R ₃ is 7
-chloro, or c) when n is 2, R ₃ is hydrogen, 7-chloro, 7-fluoro, 7
- trifluoromethyl, 7-methyl or 6-fluoro), the method comprises:
general formula A manufacturing method characterized by reacting a compound of the formula (wherein R ₁ and R ₃ have the above-mentioned meanings and x is a leaving group) with a methanethiolate anion or a methanesulfinate anion. . 9 General formula (wherein n represents 1 or 2, R ₁ is methyl, and b) when n is 1, R ₃
is 7-chloro, 7-bromo or 7-trifluoromethyl, or c) when n is 2, R ₃ is hydrogen, 7-chloro, 7-fluoro, 7
- trifluoromethyl, 7-methyl or 6-fluoro), the method comprises:
general formula (In the formula, n is 0 or 1, and when n is 0, R ₃ is 7-chloro, 7-bromo or 7
-trifluoromethyl, or when n is 1, R ₃ is hydrogen, 7-chloro, 7-fluoro, 7-trifluoromethyl, 7-methyl or 6-fluoro, and R ₁ is A method for producing a quinolone compound having the above meaning. 10 General formula (In the formula, n represents 2, R ₁ is methyl,
and R ₃ is hydrogen, 7-chloro, 7-fluoro,
7-trifluoromethyl, 7-methyl or 6-
A method for producing a quinolone compound represented by
general formula (wherein R ₁ and R ₃ have the meanings given above, Z is a leaving group and A is an anion)
A manufacturing method characterized by hydrolyzing a quinolinium salt compound. 11 General formula (In the formula, n represents 2, R ₁ is methyl,
and R ₃ is hydrogen, 7-chloro, 7-fluoro,
7-trifluoromethyl, 7-methyl or 6-
A method for producing a quinolone compound represented by
general formula (In the formula, R ₁ and R ₃ have the above-mentioned meanings.) A manufacturing method characterized by subjecting a compound of the following formula to thermal rearrangement. 12 General formula (wherein n represents 1 or 2, R ₁ is methyl, and b) when n is 1, R ₃ is 7-chloro, 7-bromo or 7-trifluoromethyl, or c ) When n is 2, R ₃ is hydrogen, 7-chloro, 7-fluoro, 7
- trifluoromethyl, 7-methyl or 6-fluoro), the method comprises:
general formula (In the formula, n and R ₃ have the above-mentioned meanings.) A production method characterized by alkylating the compound represented by the following formula with dimethyl sulfate or methyl iodide.