DE2032748C3 - Basic derivatives of I-phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-butylpyrazolidine. Process for their manufacture and pharmaceutical preparations - Google Patents

Description

O = C

CH ₃ (CH ₂ ) /

OH

C = O

CH ₂ -NX

in which X is the direct bond between the carbon atoms, - O-,

- N—

CH ₃

or —CH ₂ - means, as well as their addition salts with pharmaceutically acceptable mineral and organic acids.

2. 1 - Phenyl - 2 - ρ - hydroxyphenyl - 3,5 - dioxo-4 - η - butyl - 4 - (4 - methylpiperazino) - methylpyrazolidine.

3. Process for the preparation of the compounds according to Claims I and 2, characterized in that that p-hydroxyphenylbutazone with an amino ether of the general formula

X N-CH ₂ -OC ₂ H,

wherein X has the meaning given in claim I, and, if appropriate, converts the ones obtained Compounds with mineral or organic acids in a manner known per se, preferably in an anhydrous medium, converted into the addition salts.

4. Pharmaceutical preparations with anti-inflammatory, analgesic and antipyretic Effect containing a compound according to claim I and customary additives and carriers.

Of

O = C

-N

/ V

Atoms of matter or - O -,

- Ν

CH ₃

_oc | _er _ CH ₁ - means as well as their addition salts with pharmaceutically acceptable mineral and organic acids.

The invention also relates to a process for the preparation of the compounds (I). Let this probably as a result of the action of formaldehyde on the phenolic function of p-hydroxynhenylbutazone, do not produce through the classic Mannich reaction. It was found that the ' bonds by reacting the p-hydroxyphenylbutazone with an amino ether of the general formula

(H)

X N-CH ₂ OC ₂ H ₅

The invention relates to new basic derivatives of - phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-butylpyrazolidine (p-Hydroxyphenylbutazone) of the general formula I.

OH obtained in a known manner can be produced.

To carry out the process according to the invention, p-hydroxyphenylbutazone is either without Intermediate medium or in an inert organic solvent such as chloroform at room temperature implemented with the amino ether. In this way, the compounds (I) are produced in the pure state, because the phenol function of p-hydroxyphenylbutazone Surprisingly did not react with the amino ether.

The mineral or organic salts of this new compound (I) are made by customary processes prepared for the preparation of these salts, preferably working in an anhydrous medium.

In addition, the invention relates to pharmaceutical preparations with anti-inflammatory, analgesic and antipyrelic effect, containing a compound according to claim 1 and customary additional and carriers. You will be treated for

inflammatory syndromes used in humans and animals. The pharmacological study of the compounds has shown that they have the following properties:

1. anti-inflammatory properties

borrowed from the edema on the rat paw caused by carraghenin and the Erythema caused by UV rays in guinea pigs;

2. Analgesic properties ([Konlorsionstest, where contortions in mice caused by 2-phenyl-1,4-benzoquinone electrical stimulation of the tooth pulp in rabbits; Test according to Randall and SeIt to (Aich. Int. Pharm., 1957, 111, 4, pp. 409-418)

the rat ·;]);

C = O 3. antipyretic properties (effect on hyper-

\ / thermie, which is dead in the rat by injection

C '' microbes).

/ \ / ~~ \ In addition, the connections (I)

CH ₃ (CH ₂ J ₃ CH ₂ —NX () ₅ versus exercise ¹ that administered in an equimolar dose

\ I p-Hydroxyphenylbutazon in a surprising way

; through a faster and more lasting effect.

in which X is the direct bond between the coals. Furthermore, because of their basicity, they are for the

The stomach is better tolerated than the p-hydroxyphenylbutazone.

The preferred compound is I-phenyl-2- (p-hydroxyphynyl) -3,5-dioxo-4-n-butyl-4- (4-methylpipcrazino) methylpyrazolidine.

Pharmaceutical preparations with one of the compounds (I) as active ingredient contain such excipients, which are suitable for the administration of these preparations by oral, reclal or percutaneous route. This Pharmaceutical preparations may also contain other medicinal substances with which the compounds (I) are therapeutically acceptable.

For administration by the oral route, the pharmaceutical forms suitable for this route are (Tablets, dragees, capsules, etc.), with the unit dose of the active compound between 100 and 500 mg and the daily dose is 500 to 200C mg per 24 hours.

For administration by the rectal route, suppositories containing 100 to 500 mg of active ingredient are used, 1 to 2 suppositories are prescribed every 24 hours.

For administration by the percutaneous route, ointments are used that contain 2 to 10% of active ingredient, 2 to 3 applications per day are appropriate.

The new basic substituted l-phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-butylpyrazolidines are compared to the known agents with anti-inflammatory, analgesic and antipyretic effects (Indomethacin; Oxyphenylbutazon) less toxic with good effectiveness.

Comparative tests with p-hydroxyphenylbutazone, which is recognized as a good agent, show that the compounds according to the invention have about twice as high LD ₅₀ values with approximately the same effectiveness.

Further comparative tests against the one exhibiting a high anti-inflammatory effect Indomethacin have shown that the invention Compounds, while less anti-inflammatory than this, are considerably less Have toxicity, so that the therapeutic index of the compounds of the invention is essential is cheaper than that of indomethacin.

The following examples serve to illustrate the invention. The temperatures are in Degrees Celsius.

example 1

I - Phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-buty! -4-morpholino-methylpyrazolidine

In a 100 ml KoI A solution of 10 g (0.031 gramol) of p-hydroxyphenylbutazone was produced placed in 45 ml of chloroform. This solution was added with stirring with 4.5 g (0.031 gramol) N-ethoxymethylmorpholine added. The mixture was left to stand at room temperature overnight the chloroform then evaporated on a water bath in vacuo. The residue crystallized in 50 ml of isopropyl alcohol. The mixture was cooled for a few hours and the precipitate was centrifuged off and dried in vacuo over phosphoric anhydride. 9.6 g (yield = 73.5%) 1-phenyl-2- (p-hydroxyphenyl) -3.5-dioxo-4-n-butyl-4-morpholino-methylpyrazolidine obtained, which after recrystallization in isopropyl alcohol had a melting point of 19! "C.

Analysis for C ₂₄ H ₂ CjN ₃ O ₄ (423):

Calculated ... C 68.15, H 6.86, N 9.93%;
found ... C 68.10, H 6.88, N 9.90%.

Example 2

1 - Phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-bulyl-4- (4-methylpiperazino) methylpyrazolidine

A solution of 9.4 g (0.025 gramol) of p-hydroxyphenylbutazone in 45 ml was added to a 100 ml flask. Introduced chloroform. 4.6 g (0.025 gram mol) of 1-ethoxymethyl-4-methylpiperazine were added to the solution with stirring. The solution was left to stand at room temperature overnight; the chloroform was then evaporated on a water bath in vacuo and the residue was crystallized by trituration in 20 ml of isopropyl alcohol. The mixture was cooled, the precipitate was centrifuged off and dried in vacuo over phosphoric anhydride. In this way, 8 g (yield = 63.5%) of 1-phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-butyI-4- (4-methylpiperazino) methylpyrazolidine were obtained after recrystallization from isopropyl alcohol had a melting point of 155- 158 ⁰ C.

Analysis for C ₂₅ H ₃₂ N ₄ O., (436):

Calculated ... C 68.80, H 7.34, N 12.84%;
Found ... C 68.78, H 7.43, N 12.98%.

Example 3

1-phenyl-2- (p-hydroxyphenyi) -3,5-dioxo-4-n-butyl-4-pyrrolidino-methylpyrazolidine

A solution of 9.7 g (0.03 gramol) p-hydroxyphenylbutazone in 45 ml of chloroform was stirred with 3.9 g (0.03 gram mol) of N-ethoxymethylpyrrolidine offset. The chloroform was evaporated in vacuo on a water bath and the brownish viscous residue took a few hours Vacuum dried. It was then triturated in 20 ml of isopropyl alcohol until it crystallized. The solution was cooled for one night, the precipitate was centrifuged off and in vacuo dried over phosphoric anhydride. In this way, 2.2 g (yield == 18%) of 1-phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-butyl-4-pyrrolidino-methylpyrazolidine were obtained obtained, which had a melting point of 146 148 C after recrystallization in isopropyl oxide.

Analysis for C ₂₄ H ₂₉ N ₁ Oj (407):

Calculated ... C 70.75, H 7.13, N 10.32%;
found ... C 70.61, H 7.31, N 10.30%.

B e i s ρ i e 1 4

1-phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-butyl-4-piperidino-methylpyrazolidine

A solution of 6.1 g (0.019 gram!) Of p-hydroxyphenyibutazone was placed in a 100 ml flask placed in 25 ml of chloroform. This solution was added with stirring with 2.7 g (0.019 gramol) N-ethoxymethylpiperidine added. The mixture

was left to stand at room temperature for 3 days; the chloroform was then evaporated on a water bath in vacuo and the residue was triturated in 25 ml of isopropyl oxide; the entire mixture was frozen for several days. The compound crystallized, was centrifuged off and dried over phosphoric anhydride in vacuo.
In this way 1.6 g (yield = 20%) 1-phenyl-2- (p-hydroxy phcny!) -3,5-dioxo-4-n-butyl-4-pipericlino-methylpyrazolidine were obtained, which after recrystallization had a melting point of Π5 C in 2 ml of methyl alcohol.

Analysis for C ₂₅ H ₁ , N, O., (421):

Calculated ... C 71.26. H 7.36. N 9.97%: found .. C 71.27, H 7.32. N! 0, (X)%.

Claims (1)

.'1 Claims: 1. Basic derivatives of l-phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-butylpyrazolidine the general formula -N-