CS228544B2 - Method of production of new quinolones - Google Patents

Description

The invention relates to novel quinolone derivatives having therapeutic efficacy as antihypertensive agents.

The present invention provides a process for the preparation of the novel quinolones of the formula I

where n is 1 or 2,

R1 is methyl or ethyl; and

R 3 represents a hydrogen atom, a methyl group, a methylthio group or a halogen atom.

R1 is preferably methyl. The halogen atom R 3 is preferably a chlorine, bromine or fluorine atom, especially chlorine or fluorine.

The compounds of formula I have been found to exhibit valuable antihypertensive activity. These compounds lower blood pressure when administered to hypertensive mammals.

In accordance with the invention, the compounds of formula (I) above are prepared by alkylating a compound of formula (II)

OH (O) _n CH ₆ wherein n is 1 or 2 a

R3 is as defined above.

This alkylation may be accomplished by reacting a compound of Formula II with an alkylating agent, for example, a dialkyl sulfate or an alkyl iodide, in a manner customary for such reactions.

The compounds of formula (II) are novel.

Those compounds of formula II wherein n is 2 can be prepared by reacting a compound of formula II

III

µm with formaldehyde and sodium methanesulfinate in the presence of a tertiary amine, for example triethylamine.

Those compounds of formula II wherein m is 1 may be prepared by oxidizing the corresponding compounds wherein n is 0. The latter may be prepared by reacting a compound of the above formula III with formaldehyde and sodium methanethiolate in the presence of a tertiary amine, for example triethylamine.

It will be understood that the compounds of formula (I) in which n has the value 1 have, in the CH3SO- group, a chirality center at the sulfur atom. Thus, such compounds may exist in two enantiomeric forms. The invention encompasses both enantiomers and a racemic mixture thereof.

The therapeutic efficacy of the quinolones of formula (I) has been demonstrated by tests (i.e., by oral administration of test substances of the spontaneousHiypertensive strain and (B) by intraduodenal administration of test substances of the normotensive rat strain.

These tests are performed as follows.

Test A

Female rats weighing 780-240 g, a strain of spontaneously hypertensive rats (Aoki-Okamoto), are used for the test. Prior to administration of the test substance, rats, divided into groups of four animals, were fasted overnight. Blood pressure is determined as follows. The rats are placed in a 38 ° C cage so that their tails protrude through the cage openings. The rats are kept in these cages for 30 minutes, after which their blood pressure is measured using an inflatable cuff placed around the base of their tail, the pulse of the artery being monitored by a pneumatic pulse transducer. The cuff is inflated with a pressure higher than the expected blood pressure, whereupon the cuff pressure gradually decreases. The cuff pressure at which arterial pulsation reappears is considered to be blood pressure. The rats are removed from the cage and each group is orally administered a dose of the test compound as a solution or suspension in 0.25% aqueous carboxymethylcellulose. In addition to measurements before administration of the test substance, blood pressure is measured at 1.5 and 5.0 hours after administration. A test substance is considered to be effective if a blood pressure reduction of 20% or more is detected at any of these times.

Test B

Male normotensive rats (Wistar strain) weighing 210-240 g are used for the test. Rats are anesthetized and cannulas are inserted into their carotid and duodenum. Blood pressure is recorded electronically using a pressure transducer connected to the carotid cannula. The test compound is applied to the duodenum as a solution or suspension in 0.25% aqueous carboxymethylcellulose.

Blood pressure is recorded before and 30 minutes after administration of the test substance. As a result, the mean of the values found in the three rats used to test each dose of drug was taken. Compounds that cause a marked decrease in blood pressure (14% or greater within 30 minutes after administration of the test substance) associated with test substance administration are reported to be effective.

The compounds listed in Table 1 below are active in Test A at a dose of 90 mg / kg or less, and are preferred compounds of the invention.

Table 1

O

CH, compound

R3

H

7-C1

7-CH3

The compounds listed in the following Table 2 are not active in Test A at 90 mg / kg, but are active in Test B at 90 mg / kg.

Table 2

Rt n Rs compound

CH3

C2H5

CHs

CH3

7-SCH3

H

H

8-CH3

Compounds 4 and 5 are particularly effective in Test B and are preferred compounds of the compounds listed in Table 2.

For therapeutic application, the novel quinolones of the invention are administered in conventional dosage forms, such as tablets, apsle, suppositories, and sterile injectables. These may be administered enterally or parenterally. Enteral administration, especially oral administration, is preferred. A suitable dose, for the treatment of hypertension in mammals, including humans, is generally in the range of 0.1 to 100 milligrams / kg / day, preferably 0.5 to 70 mg / / kg / day, and especially 1 to 50 mg. / kg / day, wherein the total dose is administered in single or multiple doses. Suitably, the unit dosage forms contain from 1 to 50 mg, in particular from 5 to 500 mg, of active ingredient.

The invention is illustrated by the following non-limiting examples. In these examples, all parts and percentages are by weight unless otherwise specified, parts and percentages by weight, and solvent mixtures are characterized by bulk composition. The novel compounds of the invention were characterized by one or more of the following spectroscopic techniques: nuclear magnetic resonance (H ¹ or C ¹³ ), infrared spectroscopy and mass spectroscopy. The products described in the examples have satisfactory elemental analyzes.

EXAMPLE 1 (a) To a solution of 2.63 g of 7-methyl-4-hydroxyquinoline in 55 ml of water is added 3.5 ml of 37% aqueous formaldehyde, 6.39 g of sodium methanesulfinate and 4 ml of triethylamine. The mixture was heated on a steam bath with stirring for 60 hours, then cooled to room temperature and filtered. The solid material was washed with water and dried to give new 4-hydroxy-7-methyl-3-methylsulfonylmethylquinoline, m.p. 285-290 ° C.

(b) 3.0 g of this product was dissolved in 22 ml of aqueous potassium hydroxide (1.91 g of potassium hydroxide), 1.7 ml of dimethyl sulfate was added and the mixture was stirred at room temperature for 16 hours. The precipitated solid product is filtered off, washed with water, dried and crystallized from denatured alcohol. The resulting product was washed with diethyl ether to give the new 1,7-dimethyl-3-methylsulfonylmethyl-4-quinolone, m.p. 193-195 ° C.

Example 2 (aj Mixture of 4.2 g of 4-hydroxy-7-methylthioquinoline, 8.2 g of sodium methanesulfinate, 9.0 ml of 37% aqueous formaldehyde, 2.85 ml of triethylamine, 130 ml of denatured alcohol and 50 ml of water for 96 hours The reaction mixture was cooled to room temperature, filtered, and the filter residue was washed with hot denatured alcohol to give the new 4-hydroxy-3-methylsulfonylmethyl-7-methylthio-4-quinolone m.p. C.

(bj This methyl compound is dimethyl sulfate in 50% (v / v) aqueous tetrahydrofuran at 20 ° C to give the new 1-methyl-3-methylsulfonylmethyl-7-methylthio-4-quinolone melting after crystallization from denatured alcohol at Mp 243-245 ° C.

EXAMPLE 3 (aj) To a suspension of 10.0 g of 4-hydroxy-8-methylquinoline in 8.8 ml of triethylamine and 15 ml of denatured alcohol, 10.4 ml of methanethiol and then 14.2 ml of methanol are added under stirring at 0-5 ° C. ml 40% aqueous

2283 44 formaldehyde. 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 is added, while maintaining the temperature below 10 ° C, 14.2 ml of 40% aqueous formaldehyde, the resulting solution is added to the above reaction mixture, the resulting mixture is stirred The mixture was refluxed for 20 hours and then allowed to cool overnight. The precipitated crystalline material was filtered off to give the new 4-hydroxy-8-methyl-3-methylthiomethylquinoline, m.p. 226-228 ° C.

(b) A solution of 4.0 g of 85% 3-chloroperbenzoic acid in 100 ml of dichloromethane was added dropwise with stirring to a solution of 2.0 g of this compound in 80 ml of dichloromethane. The resulting solid precipitate was filtered off, washed with diethyl ether and dried to give the new 4-hydroxy-8-methyl-3-methylsulfonylmethylquinoline melting at 274-276 ° C with decomposition.

(c) To a suspension of 1.92 g of this sulfone and 2.11 g of potassium carbonate in 100 mL of 2-butanol was added 1.08 mL of dimethyl sulfate. The reaction mixture was heated under reflux for 16 hours, filtered while hot and the filtrate allowed to cool. New 1,8-dimethyl-3-methylsulfonylmethyl-4-quinolone is obtained as crystals of m.p. 244-246 ° C.

Example 4

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 was added 2.93 g of ethyl iodide with stirring. The reaction mixture was refluxed for 24 hours, then the solvent was evaporated, the residue was diluted with 200 ml of water, allowed to stand overnight, then filtered and the filtrate evaporated to dryness. The white solid residue was purified by high pressure liquid chromatography on silica gel eluting with ethyl acetate: isopropanol (9: 1) as the eluent (flow rate 200 ml / min) to give new 1-ethyl-3-methylsulfonylmethyl-4-quinolone of melting point. Mp 162-164 ° C.

Example 5 (a) By analogy to Example 3, 4-hydroxyquinoline is reacted with 40% aqueous formaldehyde and methanthiol in the presence of triethylamine. New 4-hydroxy-3-methylthiomethylquinoline melting after crystallization from isopropanol at 196-197 ° C is obtained.

(b) To a suspension of 4.4 g of 4-hydroxy-3-methylthiomethylquinoline in 200 ml of dichloromethane at 0-5 ° C was added dropwise a solution of 3.92 g of 85% 3-chloroperbenzoic acid in 100 ml of dichloromethane dropwise with stirring. To the resulting solution was added 500 mL of diethyl ether, the precipitated new 4-hydroxy-3-methylsulfinylmethylquinoline was collected and used for the next reaction without further purification.

(c) To a solution of 4.4 g of 4-hydroxy-3-methylsulfinylmethylquinoline and 1.68 g of potassium hydroxide in 20 ml of water was added 2.52 g of dimethyl sulfate at 0-5 degrees Celsius. The reaction solution was stirred at room temperature for 30 minutes and then neutralized with 5 N aqueous hydrochloric acid. The resulting sticky material afforded a solid product after trituration with denatured alcohol, which was purified by high pressure liquid chromatography on silica gel using isopropanol / dichloromethane (95: 5) as eluent (flow rate 200 mL / min). New 1-methyl-3-methylsulfinylmethyl-4-quinolone is obtained, m.p. 94-96 ° C.

Example 6 (a) A mixture of 2.9 g of 4-hydroxyquinoline, 8.16 g of sodium methanesulfinate, 4.5 ml of 40% aqueous formaldehyde and 70 ml of water is stirred at 95-100 ° C for 24 hours, then a further 5 ml of formaldehyde solution and the resulting mixture was stirred at 95-100 ° C for a further 24 hours. After cooling the reaction mixture and filtration, a new 4-hydroxy-3-methylsulfonylmethylquinoline melting after crystallization from a mixture of denatured alcohol and water at 280-282 ° C is obtained.

(b) To a solution of 1.9 g of 4-hydroxy-3-methylsulfonylmethylquinoline and 1.4 g of potassium hydroxide in 200 ml of water was added 3.0 ml of dimethyl sulfate at 5 ° C with stirring. The reaction mixture was stirred at room temperature for 4 hours, then filtered to give the new 1-methyl-3-methylsulfonylmethyl-4-quinolone melting after crystallization from acetone at 204-205 ° C.

Example 7

In analogy to Example 6, 7-chloro-4-hydroxy-3-methylsulfonylmethylquinoline is methylated with dimethyl sulfate in aqueous potassium hydroxide to give 7-chloro-1-methyl-3-methylsulfonylmethyl-4-quinolone melting after crystallization from ethanol at 215-216 Deň: 32 ° C.

Claims (2)

A process for the preparation of novel quinolones of the general formula I in which n is 1 or 2, R1 is methyl or ethyl; and R @ 3 represents a hydrogen atom, a methyl group, a methylthioscycline or a halogen atom, characterized in that the compound of the formula II in which n is 1 or 2 is alkylated and R @ 3 is as defined above. 2. The process of claim 1, wherein 4-hydroxy-3-methylsulfonylmethylquinoline is reacted with dimethyl sulfate to give 1-methyl-3-methylsulfonylmethyl-4-quinolone.