NO164897B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OXAZOLIDINON DERIVATIVES. - Google Patents

Description

The invention relates to an analogue method for the preparation of therapeutically active oxazolidinone derivatives of general formula Ia

in which Rc- denotes a hydrocarbon residue with two to four carbon-

atoms.

Numerous similar compounds are previously known. So-

thus, for example, pyrrolidone derivatives are described in US patent specification 4 012 495 and oxazolidinone derivatives are described in US patent specification 4 186 129. Based on these patents,

it can be deduced that these compounds are characterized by a central depressant, antidopaminergic, antinociceptive and anticonvulsant activity and furthermore have phosphodiesterase-inhibiting properties

creates .

It has now been found that the compounds of general formula

Ia when administered topically exhibits a strong anti-inflammatory

matory activity.

The analogy method according to the invention is known

characterized by the fact that an amine of general formula

wherein R,, has the above meaning, is condensed with a carbonyl compound of general formula V

wherein X denotes chlorine atoms, lower alkoxy groups or 1-imidazolyl residues.

This series of reactions can, for example, be carried out below

the conditions described in US patent 4,186,129.

The anti-inflammatory activity of the compounds of general formula Ia was determined by the rat ear test according to Tonelli (Endocrinol. TT_, 1965, 625 and Proe. Soc. Exp. Med., 159, 1978, 223): Different concentrations of test substance were dissolved in a 5 volume % ethanolic croton oil solution or dispersed by 5 minute treatment in an ultrasonic bath. Per concentration, 50 µl of this solution and substance-free croton oil solution were applied with a 1 ml tuberculin syringe to both outer ear sides of 10 anesthetized Wistar rats (weight 160 to 200 g). An untreated group served as a control. 15 hours after the treatment, the animals were euthanized by treatment with C02 gas, the ears were cut off and weighed in pairs.

As a measure of the topical anti-inflammatory effect of the test substance, the percentage inhibition of weight gain induced by croton oil was determined. The following table shows the results obtained in this test.

The stated results show that the compounds of general formula Ia when administered topically are significantly more anti-inflammatoryly active than the previously known comparable substances 1 and 2. They almost achieve the intensity of action of highly active corticoids such as hydrocortisone-17-butyrate ( substance 3).

Preparation of the medicinal specialties takes place in the usual way, as the active substance is transferred with suitable additives in the desired administration form, such as e.g. solutions, lotions, ointments, creams or plasters. In the drugs formulated in this way, the active substance concentration depends on the form of administration. For lotions, creams and ointments, an active substance concentration of 0.01% is preferably used

to 10%.

Embodiments concerning the synthesis of oxazolidinone derivatives of general formula Ia

Example 1

3.10 g (15.0 mmol) of 3-allyloxy-4-methoxyacetophenone, 2.18 ml (16.4 mmol) of trimethylsilyl cyanide and 126 mg (0.39 mmol) of zinc iodide were stirred for 5 hours at 100°C and in 14 hours at room temperature under argon. To the reaction mixture was added 4.6 ml of ether, and 0.69 g (18.5 mmol) of 1 lithium aluminum hydride in 13.5 ml of ether was added dropwise. After a stirring time of 1 hour at 40°C bath temperature, 0.7 ml of water, 0.75 ml of 4 N caustic soda and 2.1 ml of water were successively added to the reaction mixture. The solid formed was washed several times with ether, the combined ether phases were dried over sodium sulfate, filtered and evaporated (3.33 g of oil). After further addition of 42 mg of zinc iodide and 0.73 ml of trimethylsilyl cyanide, the mixture was stirred for a further 4 hours at 100°C. The reaction mixture was diluted with 3 ml of ether and was added dropwise to a suspension of 240 mg of lithium aluminum hydride in 6 ml of ether. The mixture was then stirred at 40°C for 30 minutes, after which 0.2 ml of water, 0.26 ml of 4 N caustic soda and 0.8 ml of water were added to the reaction mixture. The solid formed was washed several times with ether, the combined ether phases were dried over sodium sulfate, filtered and evaporated. The oily residue (2.06 g) was stirred in 31 ml of tetrahydrofuran with 2.11 g (12.4 mmol) of carbonyldiimidazole for 20 hours at room temperature. The reaction mixture was evaporated in vacuo, the residue was dissolved in ethyl acetate, the organic solution was washed with 2 N hydrochloric acid and water, was dried over sodium sulfate, filtered and evaporated (1.52 g of oil). Chromatography on silica gel with methylene chloride/ether (1:1) yielded 260 mg of 5-methyl-5-(3-allyloxy-4-methoxyphenyl)-2-oxazolidinone as an oil.

■""H-NMR (CDCl 3 ) : S = 1.75 (s, 2H), 3.63 (s, 2H), 3.83 (s, 3H), 4.55 (pseudo d, 2H), 5 .10-6.23 (m, 4H),

6.80 (pseudo d, 3H).

Example 2

2.84 g (12.9 mmol) of 3-cyclopropylmethoxy-4-methoxyacetophenone, 1.87 ml (14.0 mmo]) of trimethylsilyl cyanide and 109 mg (0.33 mmol) of zinc iodide were stirred for 5 hours at 100° C and for 14 hours at room temperature. After adding 4.5 ml of ether, 0.6 g (15.8 mmol) of lithium aluminum hydride in 12 ml of ether was added dropwise, and the mixture was stirred for 1 hour at 40°C (bath temperature). 0.7 ml of water, 0.75 ml of 4 N caustic soda and 2.1 ml of water were successively added to the reaction mixture. The solid formed was washed several times with ether, the combined ether phases were dried with sodium sulfate, filtered and evaporated in vacuo. The residue (2.31 g of oil) was stirred with 2.21 g (13.0 mmol) of carbonyldiimidazole in 33 ml of tetrahydrofuran for 4 hours at room temperature. The further work-up took place as described in example 1. 558 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-oxazolidinone with m.p. 96 to 97°C.

Example 3

1.63 g (7.8 mmol) of 3-propoxy-4-methoxyacetophenone, 1.1 ml (8.5 mmol) of trimethylsilyl cyanide and 66 mg (0.21 mmol) of zinc iodide were stirred for 4.5 hours at 100°C and for 14 hours at room temperature. To the reaction mixture was added 4.6 ml of ether, and 0.36 g (9.6 mmol) of lithium aluminum hydride in 7 ml of ether was added dropwise. After 1 hour of stirring at 40°C (bath temperature) the reaction mixture was successively added

0.4 ml water, 0.4 ml 4 N caustic soda and 1 ml water. The further implementation took place analogously to example 1, however, in the further addition of reagents, 20 mg of zinc iodide and 0.36 ml of trimethylsilyl cyanide were used respectively. 0.1 ml of water, 0.13 ml of 4 N caustic soda and 0.4 ml of water. For the carbonylation, 1.19 g (7.0 mmol) of carbonyldiimidazole in 17.5 ml of tetrahydrofuran were used. 152 mg of 5-methyl-5-(4-methoxy-3-propoxyphenyl)-2-oxazolidinone were obtained as a crystalline oil. Recrystallization in ethyl acetate gave a melting point of 78°C.

Example 4

3.47 g (15.6 mmol) of 3-butoxy-4-methoxyacetophenone, 2.26 ml (17.0 mmol) of trimethylsilyl cyanide and 131 mg (0.91 mmol) of zinc iodide were stirred for 5 hours at 100°C and in 14 hours at room temperature. After adding 4.6 ml of ether, 0.73 g (19.2 mmol) of lithium aluminum hydride in 14 ml of ether was added dropwise, and the mixture was stirred for 1 hour at 40°C (bath temperature). The further implementation took place analogously to example 2, however, 2.18 g (12.8 mmol) of carbonyldiimidazole in 32.5 ml of tetrahydrofuran were used. 569 mg of 5-methyl-5-(3-butoxy-4-methoxyphenyl)-2-oxa-zolidinone with m.p. 108-109°C (from vinegar).

Example 5

3.01 g (14.5 mmol) 3-isopropyl-4-methoxyacetophenone,

2.1 ml (15.8 mmol) of trimethylsilyl cyanide and 122 mg (0.38 mmol) of zinc iodide were stirred under argon for 5 hours at 100°C and for 14 hours at room temperature. The further execution took place analogously to example 1. 456 mg of 5-methyl-5-(3-isopropoxy-4-methoxyphenyl)-2-oxazolidinone with m.p. 67 to 69.5°C.

Example 6

1.66 g (8.55 mmol) of 3-ethoxy-4-methoxyacetophenone was stirred with 1.24 ml (9.3 mmol) of trimethylsilyl cyanide and 72 mg (0.22 mmol) of zinc iodide for 5 hours at 100° C and for 14 hours at

room temperature and under argon. The reaction mixture was diluted with 2.5 ml of ether and was added dropwise to 0.4 g (10.5 mmol) of lithium aluminum hydride in 8 ml of ether. After a stirring time of 1 hour at 40°C (bath temperature), 0.45 ml of water, 0.45 ml of 4 N caustic soda and 1.1 ml of water were successively added to the reaction mixture. The solid formed was washed several times with ether, and the combined ether phases were dried over sodium sulfate, filtered and evaporated in vacuo. The residue (1.5 g) was stirred in 24 ml of tetrahyrofuran

1.61 g (9.5 mmol) of carbonyldiimidazole for 4 hours at room temperature. The reaction solution was evaporated, the residue was dissolved in ethyl acetate, the organic solution was washed with 2 N hydrochloric acid and water, dried over sodium sulfate, filtered and evaporated (0.8 g of oil). Chromatography on silica gel with methylene chloride/ether (1:1) gave 370 mg of 5-methyl-5-(3-ethoxy-4-methoxy-phenyl)-2-oxazolidinone with m.p. 63 to 65°C.

Example 7

3.7 g (15.7 mmol) of 4-methoxy-3-(3-tetrahydrofuryloxy)-acetophenone, 2.3 ml (17.1 mmol) of trimethylsilyl cyanide and 134 mg (0.40 mmol) of zinc iodide were stirred under argon for 5 hours at 100°C and for 14 hours at room temperature. The further execution took place analogously to example 1. 600 mg of 5-methyl-5-[4-methoxy-3-(3-tetrahydrofuryloxy)-phenyl]-2-oxazolidinone was obtained as a colorless oil.

Example 8

500 mg (1.8 mmol) 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone, 113 mg (2.0 mmol) potassium hydroxide and 0.15 ml (2.2 mmol) methyl iodide were stirred in 4 ml of tetrahydrofuran for 4 hours at room temperature. The reaction mixture was filtered, the filtrate was added to 30 ml of water and was then extracted with acetic acid. The acetate phase was washed with water, dried over sodium sulfate, filtered and evaporated (390 mg yellow oil). By PSC separation with methylene chloride/ether (1:1), 212 mg of 5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3,5-dimethyl-2-oxazolidinone were obtained as an oil.

Example 9

500 mg (2.0 mmol) of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-2-oxazolidinone, 125 mg (2.22 mmol) of potassium hydroxide and 0.167 ml (2.38 mmol) of methyl iodide were stirred in 4 ml of tetrahydrofuran for 4 hours at room temperature. The further operation took place analogously to example 8. 201 mg of 5-(3-ethoxy-4-methoxyphenyl)-3,5-dimethyl-2-oxazolidinone were obtained as an oil.

Example 10

500 mg (2.0 mmol) of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 60 mg (2.5 mmol) of sodium hydride in 14 ml of dimethylformamide for 30 minutes, and after addition of 0.29 ml (3.0 mmol) (bromomethyl)-cyclopropane stirred for 17 hours at room temperature. The reaction mixture was added to 50 ml of water and was then extracted with acetic acid. The acetate phase was washed with water, dried over sodium sulfate, filtered and evaporated (766 mg yellow oil).

Chromatography on silica gel with methylene chloride/ether (1:1) gave 438 mg of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-3-cyclopropylmethyl-2-oxazolidinone as an oil.

Example 11

500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes, and after addition of 0.25 ml (2.7 mmol) isopropyl bromide stirred for 17 hours at room temperature. The further execution took place analogously to example 1. 169 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxy-phenyl)-3-isopropyl-2-oxazolidinone were obtained as an oil.

Example 12

500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes, and after addition of 0.32 ml (2.7 mmol) of benzyl

bromide was stirred for 2 hours at room temperature. The further execution took place analogously to example 10. 348 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-benzyl-2-oxazolidinone were obtained as an oil.

Claims (1)

Analogous process for the preparation of therapeutically active oxazolidinone derivatives of general formula Ia in which R,, denotes a hydrocarbon residue with two to four carbon atoms, characterized in that an amine of general formula in which R,, has the above-mentioned meaning, is condensed with a carbonyl compound of general formula V in which X denotes chlorine atoms, lower alkoxy groups or 1-imidazolyl -remains.