NO147648B - STAALTAU WITH A PLASTIC OR RUBBER INLET. - Google Patents

Description

Process for the production of therapeutic, in particular analgesic, anti-pyretic, antiphlogistic and muscle relaxant active hitherto unknown pyrido

The present invention relates to

methods for the production of so far

unknown pyrido[2,3-e][l,3]oxazines, with

therapeutic, in particular analgesic, anti-pyretic, antiphlogistic and muscle relaxant effects.

It has surprisingly been found that

oxazine derivatives of the general formula I

in which R, means hydrogen or a

monounsaturated or unsaturated aliphatic

residue with no more than 12 carbon atoms,

which may also contain halogen, hydroxyl, lower alkoxy, lower carboxy,

lower alkylthio, nitrile or lower dialkylamino groups, or means a lower cycloaliphatic, a phenyl, lower phenylalkyl,

lower phenoxyalkyl or a lower phenylalkenyl residue, whereby the aromatic rings

may optionally be substituted with at most

three substituents from the series: lower alkyl groups, lower alkoxy groups, halogen atoms, trifluoromethyl groups, hydroxyl groups, nitro groups and/or amino groups, and

whereby further a saturated aliphatic residue which

is adjacent to the nitrogen atom in the 3-position,

may be substituted with a thenyl-, fu-

ryl-, 5-nitrofuryl-, pyridyl-, piperidinyl- or a piperidinocarbonyl group, a lower dialkylcarbamoyl- or with a lower-alkyl-N-phenyl-carbamoyl group have valuable pharmacological properties, in particular analgesic, antipyretic, antiphlogistic, muscle relaxant , as well as bacteriostatic and fungistatic effects. Furthermore, they exhibit an inhibitory effect on mono-amino oxidase. However, they are also valuable intermediate products, e.g. for the production of further pharmacologically active substances, as well as pest control agents.

The method products according to the present patent show, in standard test trials, a stronger analgesic effect in comparison with the best, previously known compounds with the same indication and similar constitution at toxicities of the same order of magnitude. Certain process products, which are more toxic than the comparison compound, therefore exhibit an at least correspondingly higher analgesic effect.

The antiphlogistic effect, which was determined according to the method for producing formalin peritonitis in rats, is significantly stronger with the process products than it can be achieved with the aforementioned comparison compound at the same dosages.

For the preparation of compounds defined above, a compound with the general formula II is condensed:

in which R has the above meaning, in the presence of an inorganic or organic base, with a compound of the general formula III: where X and Y are the same or different and hydrocarbon residues bonded over oxygen atoms, in particular lower alkoxy or phenoxy residues, or halogen atoms, especially chlorine, or each residue means the group or one reacts a compound of the general formula IV: in which R' means a lower alkyl residue, especially the methyl residue, in the presence of a base with an isocyanate of the general formula V: converts a optionally as intermediate obtained compound of the general formula VI: by heating to a compound of the general formula I, and optionally then transfers an obtained compound of the general formula I, where Rx means a hydrogen atom, to a metal or ammonium salt and reacts this with a reactive ester of a hydroxy compound of the general formula VII:

where R,' has the meaning given for R, except hydrogen.

In method a), the choice of the reaction conditions depends to a large extent on the type of the residues X and Y. If this concerns hydrocarbon residues bound over oxygen atoms, e.g. alkoxy residues, then the condensation is carried out in particular by heating in the presence or absence of a solvent or diluent until the release of a compound of the general formula XH. If at least one of the aforementioned symbols is a halogen atom, the condensation preferably takes place by heating in organic bases, such as e.g. pyridine, quinoline or quinaldine. Other suitable acid binding agents are e.g. aqueous alkali or sodium hydride or lithium amide in anhydrous medium.

A special embodiment of this method consists in allowing a compound of the general formula II to act in aqueous alkali or in the presence of organic bases, in particular quinoline, quinaldine, sym. collidine or 2,6-lutidine, in the presence or absence of a solvent a chlorocarbonic acid derivative of the general formula Illa:

where Y' means a chlorine atom or a methoxy, ethoxy or phenoxy residue. Particularly preferred is reaction of a compound of the general formula II with a chlorocarbonic acid derivative of the general formula IIa in acetonitrile as solvent and using sym. collidine or 2,6-lutidine at room temperature.

As starting compounds with the general formula III should be mentioned in particular: phosgene, chlorocarbonic acid methyl ester, chlorocarbonic acid ethyl ester, chlorocarbonic acid phenyl ester, chlorocarbonic acid benzyl ester, N,N'-carbonyldiimidazole, diethylcarbonate, dimethylcarbonate and diphenylcarbonate.

The starting substances with the general formula II are e.g. by proceeding from optionally substituted 3-hydroxy-pyridine-2-carboxylic acid in a manner known per se obtainable.

A special embodiment of method b) consists in using an isocyanate with the general formula V:

where Rj" means a lower alkyl residue or one optionally with halogen atoms or

lower alkyl residues substituted by phenyl residues, and carry out the reaction in the presence of triethylamine as a base.

The reaction of reactive esters of the general formula VII with metal salts of compounds of the general formula I which have a hydrogen atom in the 3-position, e.g. with sodium, potassium or silver salts of such compounds, is carried out advantageously at temperatures of 0° to approx. 200°, preferably in a suitable inert, organic solvent, e.g. in dimethylformamide or dimethylsulfoxide, at room temperature.

Suitable starting substances with the general formula VII are e.g. alkyl halides, benzyl halides and phenacyl halides with an aromatic ring optionally substituted with halogen atoms, alkyl or alkoxy groups, further e.g. aryl sulfonic acid and alkanesulfonic acid alkyl esters and dialkyl sulfates.

The following examples explain the method according to the invention. The temperatures are indicated in degrees Celsius.

Example 1.

1.38 g of 3-hydroxy-picolinic acid amide and 2.5 ml of quinoline are mixed in a distillation flask and cooled to 0°C. 1.92 ml of ethyl chloroformic acid are added in one portion, and the mixture is heated with stirring to 40-50 °C. The temperature now rises quickly without further heat input to approx. 100°C, the mixture turning into a homogeneous light-brown oil. It is now heated to 200°C within 3 minutes. In doing so, it first turns green and then black. The mixture is cooled to 150° and dissolved in 30 ml at once of added 99 percent ethanol. The dark ethanolic solution is cooled to 0°C and added with a cooled to -10°C mixture of 10 ml each of concentrated hydrochloric acid and water in one portion. From the clear solution obtained, after cooling and if necessary scratching, the crude 3,4-dihydro-2,4 - dioxo- 2 H-pyr ido [ 2,3 - e ] [ 1,3 ] - crystallizes out

oxazine hydrochloride as blue-green powder. It is filtered off after 15 minutes, washed with two portions, each of 5 ml ethanol and dried. The release of the base can take place in one of the following ways: The crude hydrochloride can be transferred to the base by washing with water, until the filtrate runs off neutral. Also solutions of the hydrochloride in 2-n caustic soda and subsequently

Subsequent neutralization with dilute hydrochloric acid leads to the base. This can be recrystallized from boiling water, glacial acetic acid or pyridine and then melts at 280 °C. The compound gives no ferric chloride reaction (in methanol) and with a solution of 2,4-dinitrophenyl-hydrazine in 2-n hydrochloric acid no precipitation.

The same compound 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine can also be prepared by the following ring closure reactions: a) 8.3 g of 3- hydroxypicolinamide is suspended in 50 ml of dry acetonitrile and 8.2 g of sym. collidine and stirred with a solution of 11 g of chloroformic acid phenyl ester in 20 ml of acetonitrile during 20 hours at 40°C. The suspension is evaporated in vacuo at 50°C, the residue is added to 50 ml of water, and the insoluble matter is filtered off. The filtration residue is washed with 50 ml of water and 20 ml each of isopropanol and acetone. The 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine thus precipitated shows a melting point of 276-278°C, the yield is 81 percent. By recrystallization from glacial acetic acid with the addition of coal, a colorless product with a melting point of 280°C is obtained.

b) 3.3 g of N,N'-carbonyl-diimidazole and 1.4 g of 3-hydroxypicolinamide are heated in 40 ml

absolute tetrahydrofuran over 16 hours under reflux to boiling. The reaction mixture is filtered, and the filtrate is evaporated in vacuo. A gray residue remains, which after recrystallization from dioxane with the addition of decolorizing charcoal melts at 280°C. Dividend 46 per cent.

. Example 2.

30 g of 3,4-dihydro-2,4-dioxo-2H-pyrido-[2,3-e][1,3]oxazine are suspended in 80 ml of dimethylformamide. While stirring and cooling with ice, 8.9 g of a 50% suspension of sodium hydride in mineral oil are introduced in portions, so that the temperature does not exceed 15°C. After completion of gas evolution, a solution of 31.4 g of benzyl bromide in 30 ml of dimethylformamide is added during further cooling. After resting for one to two days at room temperature, a sample, diluted with five times the volume of water, shows a pH of 7-8. When this is the case, the total reaction mixture is poured into 500 ml of water. The crystalline precipitated 3-benzyl-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine is filtered off, washed with 50 ml each of water, isopropanol and ether, and is recrystallized from dioxane with the addition of charcoal. Melting point 174°C, yield 75-80 per cent.

Example 3.

From 98.5 g of 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine is prepared with 14.9 g of sodium hydride suspension (50 percent) in 290 ml dimethylformamide, the sodium salt as in example 4. A solution of 103 g of phenacyl chloride in 140 ml of dimethylformamide is added to this solution under ice-cooling. After 6 hours, the reaction mixture is poured into 2500 ml of water. The light beige crystals of 3-phenacyl-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine are filtered off and recrystallized from dioxane while adding charcoal. Melting point 175°C. Dividend 78 per cent.

Example 4.

From 30 g of 3,4-dihydro-2,4-dioxo-2H-pyri-di[2,3-e][1,3]oxazine is prepared with 9 g of sodium hydride suspension (50 percent) in 70 ml of dimethylformamide, the sodium salt as in example 4. Under ice cooling, a solution of 31.2 g of ethyl iodide in 20 ml of dimethylformamide is added, the mixture is allowed to stand for 16 hours at room temperature and then poured into 400 ml of water. The separated crystals of 3-ethyl-3,4-dihydro-2,4-dioxo-2H-pyrido-[2,3-e][1,3]oxazine are filtered off, washed with 50 ml of water and recrystallized from isopropanol. Melting point 150-151 °C. Dividend 30 per cent.

Example 5.

16.4 g of 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine, 27.6 g of anhydrous potassium carbonate and 50 ml of dimethylformamide are stirred while omitting water in a nitrogen atmosphere during one hour at room temperature. 22.4 g of p-methyl-phenacyl bromide, dissolved in 25 ml of dimethylformamide, are then added, whereby a weak exothermic reaction occurs. After one hour, the reaction mixture has turned dark brown.

It is stirred for a further two hours at room temperature and then completely on 500 g of ice. The precipitated 3-(4'-methyl-phenacyl)-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine melts after recrystallization from dioxane ether at 202-203°C.

Example 6.

From 16.4 g of 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine, 4.8 g of sodium hydride suspension (50 percent) and 40 ml of dimethylformamide is prepared as in example 4, the sodium salt, and to this is added a solution of 13.2 g of dimethylsulphate in 20 ml of dimethylformamide. After two days, the mixture is poured into 200 ml of water. 3-methyl-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e]-[1,3]oxazine gradually crystallizes from the solution. Melting point 136°C (from isopropanol). Dividend 45 per cent.

Example 7.

a) A solution of 2.00 g of 3-hydroxy-N-benzylpicolinamide in 3.6 ml of 3.5-n KOH and

0.9 ml of ethyl chloroformate is added to 30 ml of water and shaken for 10 minutes. The precipitated oil is taken up in methylene chloride ether and the organic phase is extracted with 1-n KOH, washed with water, dried and evaporated. The residue gives, after crystallization from isopropanol, colorless crystals, melting point 174°C. (Yield 8 percent) b) 3.6 g ammonium salt of 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine

is suspended in 20 ml of dimethylformamide and 3.6 g of benzyl bromide are added while stirring. After 20 minutes, a homogeneous solution is obtained. This is allowed to stand for 16 hours and then poured into 100 ml of water. Crystalline 3-benzyl-3,4-dihydro-2,4-di-oxo-2H-pyrido[2,3-e] [1,3]oxazine is obtained. Melting point 174°C (dioxane), yield 63 per cent.

Example 8.

From 32.8 g of 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine, the sodium salt is prepared in a similar way as in example 4 and allowed to stand for 28 hours at room temperature with the sodium salt of 32.2 g of 2-bromopropionic acid in 100 ml of dimethylformamide. Then pour in 300 ml of water and treat with animal charcoal. After filtration, the solution is brought to pH 3 with 2-n hydrochloric acid. 3-(2'-carboxyethyl)-3-4-dihydro-2,4-dioxo-2H-pyrido[2,3-e] [1,3]oxazine precipitates out crystalline and shows, recrystallized from isopropanol-dioxane, a melting point of 250° C. Yield 32 per cent.

Example 9.

20 g of p-nitrobenzyl-3,4-hydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine (m.p. 208— 209°) are hydrated in 1000 ml of dioxane over 8 g Pd/carbon at room temperature and atmospheric

Print. After 17 hours and absorption of 3 mol of hydrogen, the hydration comes to a standstill. The catalyst is filtered off and the solution is strongly concentrated in vacuo. The separated crystals are brought back into solution by adding acetone and heating. After cooling, the crystallized 3-(p-aminobenzyl)-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine is filtered off and dried in a high vacuum. Melting point 200-202°C, 78% unconverted.

In an analogous manner, the following amino derivatives are obtained from the corresponding nitrodes: 3-(p-amino-|3-phenylethyl)-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1, 3]oxazine. Melting point 180-186°C, yield 37% 3-(p-amino-phenacyl)-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine. Melting point 230°C, yield 72 per cent.

Example 10.

14 g of 3-(p-aminobenzyl)-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine (compare example 12) are suspended in

a mixture of 16 g of concentrated sulfuric acid and 160 ml of ice water. At -5° to 0°C, inert is added dropwise with stirring for 10 minutes

a solution of 4.2 g of sodium nitrite in 24

ml of water and then stirred for a further 40 minutes at 20°C. The increasingly heterogeneous mixture is poured into 300 ml of boiling water and

heat for 5 minutes until boiling. The solution is filtered from the resulting tar and poured into 200 ml of ice water. The brick-red crystals obtained are treated in dioxane with charcoal. On the ether addition, 3-(p-hydroxybenzyl)-3,4-dihydro-2,4-di-oxo-2H-pyrido[2,3-e][1,3]oxazine crystallizes out little by little. Melting point 215-218°C. Dividend 37 per cent.

In an analogous way, 3-(p-hydroxy-phenacyl)-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine is obtained. Melting point 235— 240° (methanol), yield 13 per cent.

Example 11.

From 39.4 g of 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine and 11.5 g of sodium hydride suspension (50 percent) is prepared in 120 ml the dimethylsulfoxide sodium salt (analogue example 4) and this is allowed to stand with a solution of 40.7 g of chloroacetylpiperidine in 40 ml of dimethylsulfoxide for 16 hours at room temperature. By cooling in ice, the reaction mixture is brought to crystallization. The crystals are filtered off, washed with water and the 3-piperidinocarbonyl-methyl-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e]-[1,3]oxazine is recrystallized from isopropanol-dioxane. Melting point 210°. Dividend 68 per cent.

Example 12.

From 16.4 g of 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine, 4.8 g of sodium hydride suspension (50 pst) and 40 ml of dimethylformamide is prepared , as in example 4, the sodium salt and this is allowed to stand with 16.6 g of isoamyl methanesulfonate for 7 days at room temperature. After dilution with 300 ml of water, little by little 3-isoamyl-3,4-dioxo-2H-pyrido[2,3-e][1,3]-oxazine crystallizes out. It is filtered off and crystallized from acetone with the addition of animal charcoal. Melting point 98-100°C. Dividend 25 per cent.

Example 13.

From 30 g of 3,4-dihydro-2,4-dioxo-2H-pyridor2,3-e][1,3]oxazine, 8.9 g of sodium hydride and 80 ml of dimethylformamide, the sodium salt is prepared as in example 4, and this allowed to stand with 50 g of n-amyl-toluenesulfonate in 25 ml of dimethylformamide for 78 hours at room temperature. By pouring on 500 ml of water, the 3-n-amyl-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine will precipitate out crystalline. It is recrystallized from dioxane, then isopropanol. Melting point 100-102°C. Dividend 53 per cent.

Example 14.

From 16.4 g of 3,4-dihydro-2,4-dioxo-2H-Dyrido[2,3-e][1,3]oxazine and 4.8 g of sodium hydride suspension (50 per cent) in 40 ml. Dimethylformamide is prepared according to example 4, the sodium salt, and this is allowed to stand with 22.2 g of 2-piperidinoethyl chloride for 5 days at room temperature. The reaction mixture is evaporated in vacuo, and the residue is extracted hot with isopropanol. The isopropanol extract is treated with charcoal and concentrated after filtering off the charcoal in a vacuum. The evaporation residue is recrystallized while adding charcoal from isopropanol. 3-(2'-piperidino-ethyl)-3,4-dihydro-2,4-dioxo-2H-pyrido-[2,3-e][1,3]oxazine is thus obtained. Melting point 121-122° C. Yield 29 per cent.

Example 15.

From 18.6 g of 4-chloroacetyl-fuel catechin, the di-(tetrahydropyranyl) ether is prepared according to a known method to protect the OH groups, and the crude product obtained is dissolved in 50 ml of dimethylformamide, reacted with the sodium salt from 14 g of 3, 4-dihydro-2,4-dioxo-2H-pyrido [2,3-e] [ 1,3] - oxazine, 3.7 g sodium hydride suspension

(50 percent) and 40 ml of dimethylformamide. After

standing for 60 hours at room temperature, the reaction mixture is added with each 250 ml of water and dioxane and 100 ml of 1-n hydrochloric acid, and this is allowed to stand for 16 hours. It is then carefully neutralized with 100 ml of sodium hydroxide solution. The precipitated crystals of 3-(3',4'-dihydroxy-benzoylmethyl)-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine are recrystallized from pyridine- ether. Melting point 280°C (decomposition from 260°). Dividend 46 per cent.

Prepared analogously, however by evaporation in vacuum and extraction isolated with isopropanol: 3-(3'-hydroxypropyl)-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3] oxazine. Melting point 150-151°C. Dividend 13 per cent.

3 - (2' -hydroxyethyl) - 3,4 -dihydr o -2,4 -

dioxo-2H-pyrido[2,3-e][1,3]oxazine. Melting point 144-146°C. Dividend 10 per cent.

Example 16.

A suspension of 2.8 g of 3-hydroxy-N-benzylpicolinamide in 8 ml of sym.collidine is added to 2.5 ml of chloroformate ethyl ester. The resulting reaction mixture is heated in an oil bath over 15 minutes to 180°C and is allowed to stand at this temperature for 15 minutes during the simultaneous distillation of volatile components. Water and ether are added to the cooled reaction product, filtered and the residue recrystallized with the addition of animal charcoal from isopropanol methylene chloride; 2 g colorless crystals. Melting point 174°C (yield 64 per cent).

Following the same procedure, the following was produced:

Example 17.

11.8 g of N-methyl-3-hydroxy-picolin-amide are added to 50 ml of dry acetonitrile and

10.9 g sym. collidine while stirring with 7 ml of chloroformic acid methyl ester in 20 ml of acetonitrile. From the initially homogeneous reaction mixture, a little separates

after a bit of a slump. It is stirred for 4-6 hours at 30-40°C and allowed to stand overnight. After evaporation in a vacuum, a residue is left, which is added with 150 ml of water. 3-methyl-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e]-[1,3]oxazine is excreted on standing. Melting point 136°C (from isopropanol). Dividend 50 per cent.

Analogously, the following 3-substituted derivatives of 3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine are obtained: 3-isoamyl: M.p. 98—100° (acetone), yield 31 per cent,

3-benzyl: mp. 174° (dioxane), yield

72 percent,

3-isobutyl: M.p. 131° (isopropanol-acetone), yield 49 per cent,

3-(3'-dimethylaminopropyl): crystallized from the evaporation residue as hydrochloride, m.p. 230° (of methanol). Dividend 46 per cent.

Example 18.

A solution of 9 g of 3-hydroxy-N-phenyl-picolinamide in 25 ml of sym. collidin is added to 8 ml of chloroformic acid ethyl ester, whereby a precipitate forms on heating. The reaction mixture is heated for 15 minutes in an oil bath at 155°C and heated for 15 minutes at 175°C with simultaneous distillation of volatile components. The reaction product is cooled, water and ether are added, filtered and the remaining violet crystals are recrystallized from dioxane with the addition of animal charcoal. Colorless crystals of 3-phenyl-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]oxazine, melting point 279-281 °C, yield 44 percent.

Following the same procedure, the following was produced:

Example 19.

A solution of 2.5 g of 3-hydroxy-picolinic acid methyl ester, 1.8 g of phenyl isocyanate and 6 drops of triethylamine in 20 ml of absolute ether was allowed to stand for 30 hours at room temperature. The solvent is decanted from the separated large crystals, and these are re-dissolved from methylene chloride-ether. Colorless crystals, melting point 72-74°C (yield 58 per cent).

When heated to approx. At 200°C, the product converts during separation from methanol to 3-phenyl-3,4-dihydro-2,4-di-oxo-2H-pyrido[2,3-e] [1,3]oxazine. Melting point 279-281 °C.

Example 20.

A solution of 2.5 g of 3-hydroxy-picolinic acid methyl ester, 1.8 g of phenyl isocyanate and 6 drops of triethylamine in 20 ml of dry acetonitrile was allowed to stand for 30 hours at room temperature. The reaction mixture is evaporated in vacuo and the crystalline residue is digested with ether, filtered and recrystallized from dioxane. Colorless crystals of 3-phenyl-3,4-dihydro-2,4-dioxo-2H-pyrido[2,3-e][1,3]-oxazine, melting point 279-281 °C (yield 45 per cent).

Following the same procedure, the following was produced:

Example 21.

3 g of 3-hydroxy-picolinic acid methyl ester, dissolved in 10 ml of anhydrous acetonitrile, is left closed with 4 g of n-butyl isocyanate and 5 drops of triethylamine for approx. 3 days at room temperature. After evaporation of up-

the solvent in vacuum again becomes a crystalline residue, which melts at 111-112°C. On recrystallization from a little methanol, the melting point of the obtained 3-n-butyl-3,4-dihydro-2,4-dioxo-2H-pyrido-[2,3-e][1,3]oxazm rises to 115°C, dividend 57 per cent.

(cf. example 7, the table).

Claims (1)

Process for the production of therapeutic, in particular analgesic, antipyretic, antiphlogistic and muscle relaxant active, hitherto unknown pyrido[2,3-e]-[l,3]oxazines with the general formula where Rx means hydrogen or a monovalent saturated or unsaturated aliphatic residue with no more than 12 carbon atoms, which may also contain halogen, hydroxyl, lower alkoxy, lower carboxy, lower alkylthio, nitrile or lower dialkylamino groups, or means a lower cycloaliphatic, a phenyl, lower phenylalkyl, lower phenoxyalkyl or a lower phenylalkenyl radical, whereby the aromatic rings may optionally be substituted with a maximum of 3 substituents from the series lower alkyl groups, lower alkoxy groups, halogen atoms, trifluoromethyl groups, hydroxyl groups, nitro groups and/or amino groups, and whereby further a saturated aliphatic radical, which is adjacent to the nitrogen atom in the 3-position, may be substituted with a thenyl, furyl, 5-nitrofuryl, pyridyl, piperidinyl or a piperidium nocarbonyl group, a lower dialkylcarbamoyl or with a lower alkyl-N-phenylcarbamoyl group, characterized in that one reacts in a manner known per se either a) a compound with the general formula optionally in the presence of an inorganic or organic base with a compound of the general formula where X and Y are the same or different and hydrocarbon residues bonded over oxygen atoms, especially lower alkoxy or phenoxy residues, or halogen atoms, especially chlorine, or each residue means the group or b) reacts with a compound of the general formula where R' means a lower alkyl residue, in the presence of a base with an isocyanate of the general formula and converts any compound obtained as an intermediate with the general formula by heating to a compound of the general formula I, and optionally then transfers the compounds of the general formula I obtained by the above-mentioned methods, where Rx means a hydrogen atom, to a metal or ammonium salt, and reacts this with a reactive ester of a hydroxy compound of the general formula where R/ has the meaning specified for Rt with the exception of hydrogen.