DE1088499B - Process for the preparation of therapeutically active 1,2-diaryl-3,5-dioxo-pyrazolidine-4-acetic acids and their salts - Google Patents

Description

Process for the preparation of therapeutically effective 1,2-diaryl-3,5-dioxo-pyrazolidine-4-acetic acids and their salts The invention relates to a process for the preparation of therapeutically effective 1,2-diaryl-3,5-dioxo-pyrazolidine 4-acetic acids and their salts of the general formula wherein Ar and Are are phenyl radicals which can be substituted by low molecular weight alkyl or alkoxy groups or halogen atoms, R a low molecular weight alkyl radical, R, hydrogen or a low molecular weight alkyl radical and R2 is hydrogen or a normal equivalent of a cation.

These compounds are prepared using a metal compound, in particular an alkali metal compound, of a 4-substituted 1,2-diaryl-3,5-dioxopyrazolidine of the general formula or its tautomeric form, in which R, Ar and Are have the meanings given above, with an α-haloalkanecarboxylic acid ester of the general formula where X is a halogen atom and R2 'is a low molecular weight alkyl radical and R1 has the meaning given above, in a manner known per se, then hydrolyzes the ester obtained to the free acid or "a salt thereof and, if desired, leads the free acid in the customary manner a salt with an organic or inorganic base. To carry out the reaction, for example, a 4-substituted 1,2-diaryl-3,5-dioxo-pyrazolidine of the general formula II can be dissolved in an alcoholic solution of an alkali metal alcoholate and then the a- Add the haloalkanecarboxylic acid ester of the general formula III slowly while warming. Instead of alcohols, diethylene glycol diethyl ether, for example, can also be used as a solvent for the alkali metal compound of the dioxo-pyrazolidine alkali metal salt solutions of the acids which can be prepared according to the invention are obtained from d If necessary, the free acids are separated off by acidic acids and, if desired, these are in turn converted into salts with inorganic or organic bases.

As starting materials of the general formula II, for example known 4-substituted 1,2-diaryl-3,5-dioxo-pyrazolidines, such as 4-methyl-, 4-ethyl-, 4-n-propyl-, 4-isopropyl-, 4-n-butyl- and 4-isobutyl-1,2-diphenyl-3,5-dioxo-pyrazolidine, and correspondingly substituted 1,2-bis (p-methyl-phenyl) -, 1,2-bis (p-methoxyphenyl) - and 1,2-bis- (p-chlorophenyl) -3,5-dioxo-pyrazolidines into consideration. For example, you can with the low molecular weight alkyl esters of chloro- or bromoacetic acid, a-chlorine and a-bromopropionic acid and a-chloro and a-bromobutyric acid are reacted.

On the other hand, one can also use a metal compound, in particular an alkali metal compound, of a 4-substituted 1,2-diaryl-3,5-dioxo-pyrazohdine of the general formula in which Arl, Are, R1 and R2 have the meanings given above, in an analogous manner with a halogen compound of the general formula RX V in which X and R have the meanings given above, to convert this to an ester of an acid of the general formula I, this to the free acid or a salt thereof and hydrolyze the free acid, if desired, in a. Transfer salt with an inorganic or organic base.

As has been found, have the inventively producible, new, excellent compounds which are water-soluble but not enolizable in the form of their salts anti-inflammatory, anti-pyretic and analgesic effectiveness.

The aqueous solutions of the alkali salts of the new carboxylic acids possess almost neutral reaction and can be used in the treatment of rheumatic diseases, for example for intramuscular or intravenous injection. However, the acids and salts which can be prepared according to the invention can also be used for oral administration Find rheumatism treatment use.

There are already therapeutically, in particular anti-inflammatory, antipyretic and analgesic 1,2-diaryl-3,5-dioxo-pyrazolidines known which are monosubstituted in the 4-position of the pyrazolidine ring by hydrocarbon radicals, which radicals are optionally interrupted by heteroatoms or by carbonyl groups can be substituted by hydroxyl groups. All of these compounds contain an enolizable keto group and are consequently alkali-soluble. Also described in French Patent 1092 336, disubstituted at the 4-position, but in the 2-position ursubstituierten 1,4-diphenyl-4-alkyl-3,5-dioxo-pyrazolidines having a inAlkalienlöslichmachende enolizable keto group. The pyrazolidine derivatives further described in the 1- and 2-positions and disubstituted in the 4-position, such as 1,2,4-triphenyl-4-methyl-3,5-dioxo-pyrazolidine, are not enolizable and due to the absence of free Carboxyl groups are not capable of forming salts and are therefore not soluble in water, which makes them unusable for therapeutic use in the form of aqueous injection solutions. Carboxylic acids of the 1,2-diaryl-3,5-dioxo-pyrazolidine series disubstituted in the 4-position with non-enolizable keto groups, which compounds in the 4-position contain a water-solubilizing aliphatic radical bearing a free carboxyl group instead of a phenyl group, have not yet been described been.

These carboxylic acids obtained according to the invention are notable for injection as aqueous solutions compared to the known 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine due to a noticeably better anti-inflammatory effectiveness (determined by reducing swelling in the rat paw formalinoedem test) and a significantly lower toxicity. the The following examples are intended to explain the animal position of the new compounds in more detail. Parts therein mean parts by weight; these relate to parts by volume like grams to cubic centimeters.

Example 1 a) In 1600 parts of absolute alcohol are successively 35.5 parts of sodium and 462 parts of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazohdin registered. The mixture is then heated to boiling and 186 parts of ethyl chloroacetate are slowly added at the boiling point dripped in. After 40 hours of refluxing, the mixture is cooled to room temperature, the sodium chloride formed separated off by filtration and the filtrate at reduced Pressure restricted. The residue is extracted with benzene and the benzene extract after shaking thoroughly with 0.5 N sodium hydroxide solution, dried over sodium sulfate. To Distilling off the benzene leaves an oily crude product, from which through 1,2-Diphenyl-3,5-dioxo-4-n-butyl-4-carbethoxymethylpyrazolidine is allowed to crystallize from cyclohexane is obtained in crystals with a melting point of 81 to 82 ° C.

b) To 74 parts of potassium hydroxide in 600 parts of water are 462 parts 1,2-Diphenyl-3,5-dioxo-4-n-butyl-4-carbethoxymethyl pyrazolidine in 600 parts of alcohol admitted. After refluxing for 6 hours, the solvent is reduced in vacuo distilled off, the residue dissolved in 4000 parts of water and the solution with ether shaken. The aqueous solution separated from the ether is treated with animal charcoal and then made Congo sour with hydrochloric acid. The precipitate is made with chloroform extracted, the chloroform solution evaporated and the residue obtained therefrom recrystallized from benzene-cyclohexane, the 1,2-diphenyl-3,5-dioxo-4-n-butyl-4-carboxymethylpyrazolidine from melting point 146 to 148 ° C is obtained.

Example 2 170 parts of 1,2-diphenyl-3,5-dioxo-1-isopropyl-pyra.zolidine are made up of 225 parts by volume of sodium ethylate solution in 225 parts by volume Ethanol and 13.3 parts of sodium, dissolved and at the boiling point within 15 minutes 108 parts of ethyl α-bromopropionate were added dropwise. After 17 hours of cooking the ethanol is distilled off under reflux and the residue between 1N sodium hydroxide solution and ether distributed. The ethereal phase is separated off and the ether is distilled off. The unreacted ethyl α-bromopropionate is removed from the residue with petroleum ether extracted. The remaining substance is dissolved in 500 parts by volume of ethanol and 100 Dissolved parts by volume of water and refluxed with 32 parts of potassium hydroxide for 6 hours cooked. After cooling, the 1,2-diphenyl-3,5-dioxo-4-isopropyl-4- (a-carbethoxyethyl) pyrazolidine is extracted from the alkaline solution with . Ether and evaporate the ether extract. The crude ester is another 12 hours refluxed with 6% alcoholic potassium hydroxide solution and after cooling extracted from the reaction mixture of the unsaponified ester with chloroform. The alkaline The solution is then acidified with 2N hydrochloric acid. The precipitated 1,2-diphenyl-3,5-dioxo-4-isopropyl-4- (a-carboxyethyl) -pyrazohdin After recrystallization from benzene-cyclohexane, it melts 1:10 at 171 ° C.

Example 3 33.8 parts of 1,2-diphenyl-3,5-dioxo-4-carbethoxymethylpyrazolidine (produced by the condensation of hydrazobenzene, sodium and carbethoxymethyl malonic acid diethyl ester in absolute alcohol) are in 330 parts dissolved in absolute toluene and treated with 3.9 parts of sodium amide and heated under reflux for 2 to 3 hours, until no more ammonia escapes. For the boiling mixture of the resulting metal compound 14.0 parts of n-butyl bromide, dissolved in 50 parts of absolute toluene, are then added dropwise. very slowly and reflux for a further 14 hours. Now the mixture is on Cooled room temperature, the sodium bromide formed was separated off by filtration and the solvent is partially evaporated off under reduced pressure. After washing the toluene extract with 0.5 N sodium hydroxide solution is dried over sodium sulfate. To Distilling off the toluene leaves an oily crude product from which through 1,2-Diphenyl-3,5-dioxo-4-n-butyl-4-carbethoxymethylpyrazolidine is allowed to crystallize from cyclohexane is obtained in crystals with a melting point of 81 to 82 ° C.

The saponification of this ester to form 1,2-diphenyl-3,5-dioxo-4-n-butyl-4-carboxymethylpyrazolidine, which melts at 146 to 148 ° C (free acid) is carried out in the same way as indicated in Example 1, b).

Claims (1)

PATENT CLAIM: Process for the preparation of therapeutically effective 1,2-diaryl-3,5-dioxo-pyrazolidine-4-acetic acids and their salts of the general formula wherein Arl and Are phenyl radicals which can be substituted by low molecular weight alkyl or alkoxy groups or halogen atoms, R a low molecular weight alkyl radical, R1 hydrogen or a low molecular weight alkyl radical and R2 hydrogen or a normal equivalent of a cation, characterized in that either a) a metal compound of a 4-substituted 1,2-diaryl-3,5-dioxo-pyrazolidine of the general formula or its tautomeric form, in which Ar, Are and R have the meanings given above, with an α-haloalkanecarboxylic acid ester of the general formula where R1 is as defined above, X is a halogen atom and R2 'is a low molecular weight alkyl radical, reacted in a manner known per se, or b) a metal compound of a 4-substituted 1,2-diaryl-3,5-dioxo-pyrazolidine - the general formula in which Ar, Are, R1 and Rz have the meaning given above, with a halogen compound of the general formula RX V in which R and X have the meaning given above, is reacted by known methods, then the ester obtained according to a) or b) to form the free acid or a salt thereof and, if desired, the free acid is converted into a salt with an organic or inorganic base. A test report was displayed when the registration was announced.