DE1470260C - 3,5 Dioxopyrazoiidine derivatives and a process for their preparation - Google Patents

Description

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

RH ₂ C- HC

CO - N - QH ₅

-N-QH 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-dioxopyrazolidines characterized by a significantly lower habit and better tolerability.

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 ^ -DiphenyW ^ -dioxo-4- (3'-oxobutyl) with regard to their anti-inflammatory activity ) -pyrazolidine (B) compared. The following table shows the acute toxicity after oral administration to rats (LD ₅₀ ), the percentage inhibition of exudate in experimental pleurisy (pleurisy) after oral administration of a dose of 200 mg / kg rat, the calculated ED ₅₀ in mg / kg and the therapeutic range LD ₅₀ ZED ₅₀ are given.

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
mg / kg rat Inhibition of Effective dose
ED ₅₀ mg / kg Therapeutic breadth Tested substance Exudate at the
exp. Pleurisy rat 450 200 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-QH ₅ H ₂ C

\: O-N-QH ₅ .

with a compound of the general formula

II

R-CH ₂ -NR ₂

Χ ^Θ

III

where R _x 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 - CH, - N

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 acidifying this extract isolated. ,

It is also possible to prepare the starting material of the general formula HI 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

IV R-CH ₂ -N

her, uses an alcoholic solution of an alkali salt of 1,2-diphenyl-3,5-dioxo'pyrazoIidins 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 will go through several hours of refluxing ended. The reaction product is then given as above isolated.

Claims (2)

The following examples explain the invention. Example 1 1,2-Dipnenyl-3,5-dioxo-4- (3'-phenyl-3'-oxo-propyl) -pyrazolidine 23.5 g of dimethylaminopropiophenone hydrochloride are dissolved in 200 ml of absolute methanol and the mixture is stirred the base is released 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 1,2-diphenyl-3,5-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 ° C. Example 2 1,2-Diphenyl-3,5-dioxo-4- (2'-oxo-cyclohexyl-methyl) pyrazolidine , 4 g · 1,2-diphenyl-3,5-dioxopyrazolidine in 200 ml of absolute methanol, in which an equivalent amount of sodium was dissolved. In a solution of 2 - dimethylaminomethyl 1 - cyclohexanone - methosulfate, prepared by dissolving 36.0 g of 2-dimethylaminomethyl-cyclohexanone in 120 ml of absolute methanol and quaternizing at -5 ° C by adding dropwise 29.2 g of dimethyl sulfate in 50 ml Methanol, the solution of the pyrazolidine sodium is poured all at once, the reaction mixture is heated to the boil with stirring and refluxed for 6 to 8 hours. After cooling and filtering, the filtrate is evaporated to dryness and the residue is extracted at 40 ° C with an approximately 3% sodium hydroxide solution. 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 to 143 ° C. B ei s 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 warming 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 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 leaving it to stand for one hour at room temperature - a solution of 25.2 g of 2-diphenyl-3,5-dioxopyrazolidine is added 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, then it is refluxed for 6 to 8 hours. After standing overnight, the precipitated solid is filtered off with suction and the filtrate is evaporated The residue is extracted with 400 ml of an approximately 5% sodium hydroxide solution, the extract is filtered with the addition of decolorizing charcoal and the product is precipitated by acidifying the filtrate with 10% hydrochloric acid, after recrystallization from ethanol or chloroform-cyclohexane the product is obtained in a yield of 17.8 g, mp 152 ° to 153 ° C. Example 4. 1,2-Diphenyl-3,5-dioxo-4- [3 '- (p-chlorophenyl) -3 '-oxo-propyl] -pyrazolidine One dissolves 27.3 g of p-chloro-dimethylamino-propiophenone hydrochloride in 250 ml of absolute methanol and sets the Mannich base free by adding a sodium methylate solution, prepared by dissolving 2.5 g of sodium in 70 ml of absolute methanol. The mixture is stirred for 15 minutes. In the meantime, 25.2 g of 1,2-diphenyl-3,5-dioxo-pyrazolidine are 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. The reaction mixture is heated to the boil and a solution of 13.8 g of dimethyl sulfate in 70 ml of methanol is added dropwise over the course of about 30 minutes. 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 is clarified with decolorizing charcoal and, after filtration, the filtrate is acidified with dilute hydrochloric acid (1: 1), which causes the product to separate out; Yield 24.0g. After recrystallization from chloroform, chloroform-cyclohexane or cyclohexane, it melts at 136 to 137 ° C. ■ Claims ·: 1. 3,5-Dioxopyrazolidine derivatives of the general formula 45 RH ₇ C- HC , CO-NC ₆ H ₅ ^ CO-NC ₆ H ₅ wherein R one optionally in the o-position through a hydroxyl group or in the ρ-position a chlorine atom-substituted 2-phenyl-2-oxoethyl group or a 2-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 , CO-NG ₁ H H, C 6 "5 N - C "H ₅ with a compound of the general formula R - = - CH ₂ - NR Χ ^Θ - III. wherein Ri 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 Χ ^{θ is} an anion of an inorganic acid, in Reacts the presence of a solution of an alkali metal alcoholate in an absolute alkanol with 1 to 4 carbon atoms at the boiling point of the reaction mixture.