DE1937241B - 3,5-Dioxopyrazolidine derivatives, processes for their preparation and pharmaceuticals containing these compounds - Google Patents

Description

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

O R

R, -CH = CH-N

I = O

in which R ₁ denotes a hydrogen or halogen atom or a lower alkyl group, R ₂ denotes an alkyl group having 1 to 6 carbon atoms and R ₃ denotes a phenyl group which is optionally substituted in the 4-position by a lower alkoxy group or in the 2,3-position by a methylenedioxy group.

The halogen atom R ₁ includes fluorine, chlorine, bromine and iodine atoms. The alkyl radicals include straight and branched alkyl radicals.

Examples of lower alkyl radicals are the methyl, ethyl, n-propyl, isopropyl, η-butyl and tert-butyl groups. Examples of lower alkoxy radicals are the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy groups. Examples of alkyl radicals R ₂ are the methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-amyl, isoamyl and n-hexyl groups. The n-propyl, η-butyl and n-AmyJ groups are particularly preferred.

The invention further relates to a novel process for the preparation of 3,5-d Dioxopyrazolidinderivate _he general formula I, which is characterized in that either

a) a phenylhydrazone of the general formula R, -CH, -CH = N-NH - "

R ₁ (II)

in which R ₁ and R _{3 have} the above meaning, or b) an N ^ Nj-diacylphenylhydrazine of the general formula

lat, sodium ethylate, potassium ethylate, potassium tert-butylate, Sodium amide or potassium amide condensed at temperatures of 80 to 150 ° C.

As reactive derivatives of malonic acid of the general formula IV, for. B. alkyl esters, Acid halides or mixed acid anhydrides in question. Preferred condensing agents are sodium methylate and sodium ethylate. The reactions are carried out in a solvent such as benzene, toluene, xylene or dioxane. A solvent with a higher boiling point is preferably used, in order to be able to carry out the implementation in a shorter time.

After the reaction has ended, the reaction mixture is worked up in a customary manner by the reaction mixture is acidified with aqueous mineral acid, then extracted with a solvent, evaporated the extract to dryness and the crude 3,5-dioxopyrazolidine z. B. by recrystallization further cleans.

The phenylhydrazones of the general formula II used according to the process are, for. B. through implementation a corresponding carbonyl compound of the general formula

R ₃ - CH ₇ - CH = OV

R ₁ -CH = CH-N

(III)

C = O C = O

R ₂ -HC

, COOH

^ COOH

(IV)

in which R _{3 has} the above meaning with the corresponding phenylhydrazine of the general formula

R ₄ R ₄

in which R ₁ and R _{3 have} the above meaning and R _{4 is} an alkyl radical having 1 to 3 carbon atoms, with a malonic acid of the general formula

in which R _{2 has} the above meaning, or a reactive derivative of such an acid in a solvent and in the presence of at least stoichiometric amounts of sodium methyl-H ₇ N-NH

(VI)

in which R _{1 has} the above meaning, or its salt is prepared.

The N _l5 N ₂ -Diacylphenylhydrazine of the general formula III used as starting materials are obtained by reaction of phenylhydrazones of the general formula II with an aliphatic carboxylic acid having 1 to 4 carbon atoms, or its reactive derivative. In this acylation, the hydrazone double bond is shifted, and a hydrazine derivative of the general formula III is obtained. Examples of reactive derivatives of the aliphatic carboxylic acid are acetic anhydride, propionic anhydride, acetyl chloride and acetyl bromide. Acetic anhydride is particularly preferred.

The acylation is carried out at temperatures between 50 and 140 ⁰ C and preferably in the presence of a small amount of a catalyst such as p-toluenesulfonic acid, hydrochloric acid, boron trifluoride, aluminum chloride or zinc chloride. P-Toluenesulfonic acid is particularly preferred.

The _t phenylhydrazines of the general formula III may be readily isolated, they can be, however, also be brought directly with the malonic acid of the general formula IV or its reactive derivative to implement.

The new 3,5-dioxopyrazolidine derivatives of the general formula I not only have an excellent one anti-inflammatory effect, but also a relatively low toxicity. When administered orally on rats and mice in doses of over 200 mg / kg are no toxic symptoms and occult BlumngsflJobserved. The anti-inflammatory activity of these compounds is much higher than that of

l ^ -Diphenyl ^ S-dioxo ^ -n-butylpyrazolidine. The therapeutic The quotients of the compounds according to the invention are therefore significantly greater than those known Medicinal substances with a similar direction of action.

The results of phannacological investigations on some compounds according to the invention and on 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine are
given in the table below.

connection

1,2-Diphenyl-3,5-dioxo-4-n-butylpyrazolidine

1-Phenyl-2-styryl-4-n-butyl-3,5-dioxopyrazolidine ... 1 - (p-Tolyl) -2-styryl-4-n-butyl-3,5-dioxopyrazolidine. l- (p-Tolyl) -2- (p-methoxystyryl) -4-n-butyl-3,5-dioxo-

pyrazolidine

l- (p-chlorophenyl) -2- (p-methoxystyryl) -4-n-butyl-

3,5-dioxopyrazolidine

l- (p-Tolyl) -2- (2 ', 3'-methylen-dioxystyrylH-n-butyl-

3,5-dioxopyrazolidine

Inhibition of carrageenin

edema on the rat paw,

ED _i0 . po. mg / kg

320
125

75

65

60

120

LD ₅₀ , rat
po, mg / kg

about 600
> 500
> 500

> 500
> 500
> 500

LD ₅₀ / ED ₅ ,

about 1.9
> 4.0
> 6/7

V 7.7
> 8.3
> 4.2

It was also found that these compounds also have a relatively strong analgesic effect, determined according to the method of H a f f η e r, and show antipyretic effect in the pyrogen test.

The examples illustrate the invention.

example 1

3 g of sodium metal are dissolved in 100 ml of anhydrous ethanol. The solution obtained is admixed with 15 g of phenylacetaldehyde phenylhydrazone and a solution of 17 g of diethyl n-amylmalonate in 150 ml of xylene. The mixture is heated for 3 hours at 100 ⁰ C and 14 hours at 140 ° C with stirring. After cooling, the reaction mixture is poured into water while cooling with ice and acidified with hydrochloric acid. The organic solution is separated off and the aqueous solution is extracted with ethyl acetate. The ethyl acetate extract is combined with the organic solution, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue crystallizes on trituration with ethanol. The l-phenyl-2-styryl-4-n-amyl-3,5-dioxopyrazolidine is obtained; M.p. 141 to 142 ° C. After recrystallization from ethanol, 13 g of the product with a melting point of 142 to 143 ° C. are obtained.

Similarly, the corresponding phenylacetaldehyde-phenylhydrazones become the following compounds manufactured:

1 - Phenyl ^ -styryM-n-butyl-S ^ -dioxopyrazolidine,

M.p. 166 ° C;
lp-Tolyl-2-styryl-4-n-butyl-3,5-dioxopyrazole-

idin, m.p. 138-139 ° C;
lp-chlorophenyl-2-styryl-4-n-butyI-3,5-dioxo-

pyrazolidine, mp 147-148 ° C; l-phenyl-2- (p-methoxystyryl) -4-n-butyl-

3,5-dioxopyrazolidine, m.p. 150 to 15PC; l-p-Tolyl-2- (p-methoxystyryl) -4-n-butyl-

3,5-dioxopyrazolidine, mp 133-134 ° C; l-p-chlorophenyl-2- (p-methoxystyryl) -4-n-butyl-3,5-dioxopyrazolidine, F. 127 to 128 ° C.

55

60 Example 12

A solution of 2 g of sodium metal in 100 ml of ethanol is _{mixed with a solution of N ^^ - diacetyl-N 2} -styrylphenylhydrazine in benzene, which has been prepared as indicated below, and 14 g of diethyl n-butylmalonate. 100 ml of xylene are added to the mixture and the mixture is heated to 140 ° C. for 10 hours. Benzene and methanol are distilled off here. After cooling, the reaction mixture is poured into water and acidified. The organic solution is separated off and the aqueous solution is extracted with chloroform. The combined organic solutions are washed with water and dried over sodium sulfate. The residue crystallizes on trituration with ethanol. Yield 7.5 g of 1 - phenyl - 2 - styryl - 4 - η - butyl - 3,5 - dioxopyrazolidine; 166 ° C.

The solution of N ₁ , N ₂ -diacetyl-N ₂ -styryl-phenylhydrazine required as starting material is prepared in the following way:

A mixture of 15 g of phenylacetaldehyde-phenylhydrazone and 0.6 g of p-toluenesulfonic acid in 100 g of acetic anhydride is refluxed for 1 hour. After cooling, the reaction mixture is with 0.3 g of sodium acetate were added and the mixture was evaporated under reduced pressure. The oily residue is in 100 ml of benzene are dissolved, the solution is washed with water and dried over sodium sulfate. This Benzene solution of N ^^ - diacetyl-Nj-styrylphenylhydrazine is used for condensation.

In a manner similar to Example 2, the corresponding Nj ^ -diacetyl-p-phenylhydrazones are converted receive the following connections:

l-phenyl-2-styryl-4-n-butyl-3,5-dioxopyrazolidine,

M.p. 166 ° C;
lp-Tolyl ^ -styryM-n-butyl-S ^ -dioxopyrazole-

idin, m.p. 138-139 ° C;
lp-chlorophenyl ^ -styryM-n-butyl-S ^ -dioxo-

pyrazolidine, mp 147-148 ° C;
l-phenyl-2- (p-methoxystyryl) -4-n-butyl-

3,5-dioxopyrazolidine, mp 150-151 ° C;
1 -p-Tolyl-2- (p-methoxystyryl) -4-n-butyl-

3,5-dioxopyrazolidine, mp 133-134 ° C;

l-p-chlorophenyl-l-ip-methoxystyryl ^ -n-butyl-3,5-dioxopyrazolidine, F. 127 to 128 ° C.

Claims (8)

Patent claims: 1. 3,5-Dioxopyrazolidine derivatives of the general formula R, - CH = CH-N IO == O (I) in which R ₁ denotes a hydrogen or halogen atom or a lower alkyl group, R ₂ denotes an alkyl group having 1 to 6 carbon atoms and R ₃ denotes a phenyl group which is optionally substituted in the 4-position by a lower alkoxy group or in the 2,3-position by a methylenedioxy group. 2.1-Phenyl-2-styryl-4-n-butyl-3,5-dioxopyrazolidine. 3. 1- (p-Tolyl) -2-styryl-4-n-butyl-3,5-dioxopyrazolidine. 4. 1 - (p-Tolyl) -2- (p-methoxystyryl) -4-n-butyl-3,5-dioxopyrazolidine. 5. 1- (p-Chlorophenyi) -2- (p-methoxystyryl) -4-n-butyl-3,5-dioxopyrazolidine. 6. 1- (p-Tolyl) -2- (2 ', 3'-methylenedioxystyryl) -4-n-butyl-3,5-dioxopyrazolidine. 7. A method for the preparation of the compounds according to claim 1, characterized in that one either a) a phenylhydrazone of the general formula R ₃ -CH ₂ -CH = N-NH (II) in which R ₁ and R _{3 have} the meaning given in claim 1, or
b) an N ^^ - diacylphenylhydrazine of the general formula R ₃ -CH = CH-N -N- C = O C = O R ₄ R ₄ (III) in which R ₁ and R _{3 have} the meaning given in claim 1 and R _{4 is} an alkyl radical having 1 to 3 carbon atoms, with a malonic acid of the general formula HC , COOH ^ COOH (IV) in which R _{2 has} the meaning given in claim 1, or a reactive derivative of such an acid in a solvent and in the presence of at least stoichiometric amounts of sodium methylate, sodium ethylate, potassium ethylate, potassium tert-butylate, sodium amide or potassium amide at temperatures of 80 to 150 ⁰ C condensed. 8. Medicament containing a compound according to claim 1 and customary pharmacologically acceptable carriers.