DE1470260B - 3,5-Dioxopyrazolidine derivatives and a process for their preparation - Google Patents

Description

The invention relates to 3,5-dioxopyrazolidine derivatives of the general formula ■

RH ₇ C- HC

CO-N- C ₆ H ₅

- N - C ₆ H ₅

wherein R is optionally in the o-position by a Hydroxy group or 2-phenyl-2-oxoethyl group substituted in the p-position by a chlorine atom or means a 2-oxo-cyclohexyl group.

These compounds have anti-inflammatory and analgesic effects and stand out compared to known 4-alkyl-1,2-diphenyl-3,5-dioxopyrazolidine.n characterized by a significantly lower habit and better tolerability.

With regard to their anti-inflammatory activity, the substances according to the invention were compared with the known substances 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine (A) and _{1,2-diphenyl-3)} 5-d.ioxo-4 - (3'-oxobutyl) pyrazolidine (B) compared. The table below shows the acute toxicity when administered orally to rats (LD ₅₀ ), the percentage inhibition of exudate in experimental pleurisy (pleurisy) when administered orally at a dose of 200 mg / kg rat, the calculated ED ₅₀ in mg / kg and the therapeutic range LO ₅₀ ZEO ₅₀ .

The table shows that the therapeutic range of all substances according to the invention is better than that of known substances; that obtainable according to Example 1 shows the best therapeutic range Connection on.

acute toxicity Inhibition of Effective dose Therapeutic breadth Green substance mg / kg rat Exudate at the ED ₅₀ mg / kg LD ₅₀ ZED ₅₀ 450 exp. Pleurisy rat
200 mg / kg 333 1.35 A. ■■ '■■■; - '' ■ ·. ' 720 30% • 357 2.02 ^B ■ '■': · ■■■. 10,000 28% 370 27.0 Substance according to example 1 2,500 27% 385 -6.5 Substance according to example 2 2,800 26% 323: ■■ 8.68 Substance according to example 3 800 31% 300 2.64. Substance according to example 4 33%

The compounds of general formula I are prepared by being known per se Way 1,2-diphenyl-3,5-dioxopyrazolidine of the formula

CO-N-C ₆ H ₅

H, C

^ CO-NC ₆ H ₅ . with a compound of the general formula

R-CH ₂ -NR ₂

III

wherein R ₁ and R _{2 are} alkyl radicals with 1 to 4 carbon atoms, which with the nitrogen atom can form a heterocyclic ring optionally bearing further heteroatoms, R _{3 is} an alkyl radical with 1 to 4 carbon atoms or an aralkyl radical and X ^{e is} an anion of an inorganic acid, in the presence of a solution of an alkali metal alcoholate in an absolute alkanol having 1 to 4 carbon atoms at the boiling point of the reaction mixture.

The starting materials of the general formula III are prepared from a corresponding ketone the Mannich base of the general formula

, R ₁

R - CH ₂ - N

IV

here that one z. B. with the help of an alkyl halide or dialkyl sulfate, in particular methyl iodide or dimethyl sulfate, for the compound of the general formula III quaternized.

To "carry out the method according to the invention if mixed at room temperature, a solution of an alkali salt of 1,2-diphenyl-3,5-dioxo-.

pyrazolidines of the formula II with the freshly prepared quaternary salt of the general formula III and terminates the reaction by refluxing the reaction mixture for several hours. The reaction product is then in the usual way, for. B. by evaporating the reaction mixture to dryness, Extraction of the residue with an aqueous alkali metal hydroxyl solution and acidification of this extract isolated. ,;

It is also possible to prepare the starting material of the general formula III only in the reaction mixture. In this case, a suitable alkali metal alcoholate solution is first prepared from an alcoholic alkali metal alcoholate solution Salt the Mannich free base of the general formula

, R ₁

R-CH ₅ -N

\ i

her, uses an alcoholic solution of an alkali salt of 1,2-diphenyl-3,5-dioxopyrazolidine of the formula II to, the reaction mixture is heated to the boil, whereupon the boiling mixture is mixed with an alcoholic Solution of the quaternizing agent, e.g. B.

Dimethyl sulfate, added. The reaction is terminated by refluxing for several hours. The The reaction product is then isolated as indicated above.

Claims (2)

The following examples illustrate the invention. B is ρ ie 1 1 1,2-Diphenyl-3,5-dioxo-4- (3'-phenyl-3'-oxo-propyl) -pyrazolidine Dissolve 23.5 g of dimethylaminopropipphenone hydrochloride in 200 ml of absolute methanol, and while stirring, the base is set free by adding a solution of 2.5 g of sodium in 70 ml of absolute methanol. In the meantime, 25.2 g of 1,2-diphenyl-3,5-dioxopyrazolidine are dissolved in a solution of 2.5 g of sodium in 170 ml of methanol. The resulting hot clear solution of the l ^ -DiphenyWjS-dioxopyrazolidine sodium is poured into the free Mannich base and the reaction solution is heated to the boil. A solution of 13.8 g of dimethyl sulfate in 70 ml of absolute methanol is added dropwise to the boiling reaction mixture over the course of 0.5 hours, with thorough stirring. The reaction mixture is boiled for a further 6 to 8 hours while stirring. It is cooled, filtered and evaporated to dryness. The residue is extracted with 500 ml of an approximately 2% strength sodium hydroxide solution at 60 to 70 ° C. After cooling, it is filtered with decolorizing charcoal, and the clear filtrate is acidified with 10% hydrochloric acid, whereby the desired product separates out. The yield of the crude product is 22.7 g. After recrystallization from ethanol or from chloroform-cyclohexane, the compound melts at 172 to 173.degree. .Example 2 leave at room temperature - a solution of. 25.2 g of 1,2-diphenyl-3,5-dioxopyrazolidine in 170 ml of absolute methanol, in which an 'equivalent amount of sodium was dissolved. The mixture is stirred for 1 hour at room temperature and then refluxed for 6 to 8 hours. After standing overnight, the solid matter which has separated out is suctioned off and the filtrate is evaporated to dryness. The residue is extracted with 400 ml of an approximately 5% strength sodium hydroxide solution, the extract is filtered with the addition of decolorizing charcoal and the product is precipitated by acidifying the filtrate with 10% strength hydrochloric acid. After recrystallization from ethanol or chloroform-cyclohexane, the product is obtained in a yield of 17.8 g; F. 152 to 153 ° C. ■ ■ ■ / Bei s pie I 4 20 1,2-Diphenyl-3,5-dioxo-4- [3 '- (p-chlorophenyl> 3'-oxo-propyl] -pyrazolidine Pyrazolidine Dissolve 40.4 g of 1,2-diphenyl-3,5-dioxopyrazolidine in 200 ml of absolute methanol, in which an equivalent amount of sodium was dissolved , 0 g of 2-dimethylaminomethyl-cyclohexanone in 120 ml of absolute methanol and quaternizing at -50C by adding dropwise 29.2 g of dimethyl sulfate in 50 ml of methanol, the solution of pyrazolidine sodium is poured all at once, the reaction mixture is heated to the boil with stirring and boiled 6 After cooling and filtering, the filtrate is evaporated to dryness and the residue is extracted with an approximately 3% sodium hydroxide solution at 40 ° C. The extract is worked up as in Example 1. The yield of the crude product is 46.0 g. After recrystallization from chloroform - cyclohexane or ethanol, the product melts at 142 up to 143 ° C. B eis ρ ie I 3 J, 2-biphenyl-3,5-dioxo-4- [3 '- (o-hydroxyphenyl) -3 -oxo-propyl] -pyrazolidine A solution of o-hydroxy- dimethylaminopropiophenone methosulfate - prepared by dissolving .25.3 g of o-hydroxydimethylaminopropiophenone hydrochloride with moderate heating in 170 ml of absolute methanol, adding a solution of 2.5 g of sodium in 50 ml of methanol, cooling the mixture to 00C, adding a solution of 13.8. g of dimethyl sulfate 6S in 50 ml of absolute methanol while maintaining a temperature of at most 2 "C, then stirring for half an hour at 2 ° C and standing for one hour - 27.3 g of p-chloro-dimethylamino-propiophenone hydrochloride are dissolved in 250 ml of absolute methanol and The Mannich base is released by adding a sodium methylate solution, prepared by dissolving 2.5 g of sodium in 70 ml of absolute methanol, stirring for 15 minutes, meanwhile 25.2 g of 2-diphenyl-3,5-dioxo-pyrazolidine is dissolved in a solution of 2.5 g of sodium in 170 ml of absolute methanol, and this solution is poured all at once into the Mannich base solution 70 ml of methanol are added. The reaction mixture is stirred and refluxed for 7 hours. After cooling and filtering, the filtrate is evaporated to dryness. The residue is extracted with about 3 to 5% sodium hydroxide solution. The alkaline extract g is clarified with decolorizing charcoal and, after filtration, the filtrate is acidified with dilute hydrochloric acid (1: 1), whereby the product separates out; Yield 24.0g. After recrystallization from chloroform, chloroform-cyclohexane or cyclohexane, it melts at 136-1370C. • Patent claims ·: 1. 3,5-Dioxopyrazolidine derivatives of the general Formula; R-H, C-HC CO-NC ₆ H ₅ -N-QH ₅ wherein R one optionally in the o-position through a hydroxyl group or 2-phenyl-2-oxoethyl group substituted in ρ-position by a chlorine atom or is an i-oxo-cyclohexyl group. , 2. Process for the preparation of the compounds according to claim 1, characterized in that 1,2-diphenyl-3,5-dioxopyrazolidine is used in a manner known per se the formula H ₂ C CO-N-QH ₅ - N - C ₆ H ₅ with a compound of the general formula R-CH ₂ -NR ₂ X © where R ₁ and R _{2 are} alkyl radicals with 1 to 4 carbon atoms, which with the nitrogen atom can form a heterocyclic ring optionally bearing further heteroatoms, R _{3 is} an alkyl radical with 1 to 4 carbon atoms or an aralkyl radical and X © is an anion of an inorganic acid, in the presence of a solution of an alkali metal alcoholate in an absolute alkanol having 1 to 4 carbon atoms at the boiling point of the reaction mixture. _: ■; ■ .: '