DE2032748B2 - BASIC DERIVATIVES OF L-PHENYL-2- (P-HYDROXYPHENYL) -3,5-DIOXO-4-N-BUTYLPYRAZOLIDINE METHOD OF THEIR MANUFACTURING AND PHARMACEUTICAL PREPARATIONS - Google Patents

Description

- Ν—

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) - methylpyraiolidine.

3. Process for the preparation of the compounds according to Claims 1 and 2, characterized in that that p-hydroxyphenylbutazone with an amino ether of the general formula

X N-CH ₂ -OC ₂ H ₅

in which X has the meaning given in claim 1, 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 1 and customary additives and carriers.

The invention relates to new basic derivatives of l-phenyl-2- (p-hydroxyphenyl) -3.5-dioxo-4-n-butylpyrazolidine (p-Hydroxyphenylbutazone) of the general formula I.

N-

OH

O = C C = O

CHj (CH ₂ J ₃ CH ₂ -NX

(I)

in which X is the direct bond between the carbon

: - atoms of matter or —O,

- N—

CH ₃

or - CH ₂ - and 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-hydroxyphenylbutazone, cannot be produced by the classic Mannich reaction. It was found that the compounds by reacting the p-hydroxyphenylbutazone with an amino ether of the generalities formula

X N —CH, OC, H,

(H)

which is obtained in a known manner can be prepared.

To carry out the process according to the invention, p-Hydroxv phenylbutazone 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, since 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 antipyretic effect, containing a compound according to claim 1 and customary additional and carriers. They are used to treat inflammatory syndromes in humans and animals. The pharmacological examination of the compounds has shown that they have the following properties :

1. Anti-inflammatory properties for the edema on the rat paw caused by Carraghenin was caused, and in the case of erythema, caused by UV rays in guinea pigs was evoked;

2. analgesic properties ([contortion test, where the contortions in the mouse by 2-Phe-

nyl-1,4-benzoquinone were caused; electrical stimulation of the tooth pulp in rabbits; Test according to Randall and Sei it to (Arch. Int. Pharm., 1957, 111, 4, p. 409 418) to the rat]);

3. Antipyretic properties (effect on hyperthermia, which in the rat dead by injection Microbes).

In addition, the compounds (I) are distinguished from that administered in an equimolar dose p-Hydroxyphenylbutazone surprisingly has a faster and more permanent effect.

Furthermore, because of their basicity, they are for the

The stomach is better tolerated than p-hydroxyphenylbutazone

The preferred compound is 1 - phenyl-2- (p-hydro-

xyphenyl) -3,5-dioxo-4-n-butyl-4- (4-methylpiperazino) methylpyrazolidine.

Pharmaceutical preparations with one of the compounds (1) as an active ingredient contain such excipients, which are suitable for the administration of these preparations by the oral, rectal or percutaneous route. These Pharmaceutical preparations may also contain other drug 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.) are used, the unit dose of the active compound between 100 and 500 mg and the daily dose is 500 to 2000 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 experiments with p-hydroxyphenylbutazone, which is recognized as a good agent, show that the compounds according to the invention have about twice as high Ln ₅₀ values with approximately the same effectiveness.

Further comparative tests against the one exhibiting a high anti-inflammatory effect Indomethacin have shown that the compounds according to the invention are less anti-inflammatory are than this, but have a significantly lower toxicity, so that the therapeutic The index of the compounds according to the invention is significantly more favorable than that of indomethacine.

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

example 1

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

To a 100 ml flask was placed a solution of 10 g (0.031 gramol) of p-II-hydroxyphenylbutazone in 45 ml of chloroform. To this solution was added 4.5 g (0.031 gramol) of N-ethoxymethylmorpholine while stirring. The mixture was left to stand at room temperature overnight and the chloroform was 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, the precipitate was centrifuged off and dried in vacuo over phosphoric anhydride. 9.6 g (yield = 73.5%) of 1-phenyl-2- (p-hydroxyphenyl) -3.5-dioxo-4-η-butyl -4-morpholino-methylpyrazolidine were obtained which, after recrystallization in isopropyl alcohol, had a melting point of 191 ^° C.

Analysis for C ₃₄ H ₂₉ N 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-butyl-4- (4-methylpiperazino) methylpyrazolidine

A solution of 9.4 g (0.025 gramol) of p-hydroxyphenylbutazone was added to a 100 ml flask placed in 45 ml of chloroform. The solution was stirred with 4.6 g (0.025 gramol) of 1-ethoxymethyl-4-methylpiperazine offset. The solution was left to stand at room temperature overnight; then the chloroform was placed on a water bath evaporated in vacuo and the residue was triturated in 20 ml of isopropyl alcohol crystallized. The mixture was cooled, the precipitate was centrifuged and vacuumed over Phosphoric anhydride dried. In this way, 8 g (yield = 63.5%) of l-phenyl-2- (p-hydroxyphenyl) -3,5-dioxo-4-n-butyl-4- (4-methylpipera / ino) - methylpyrazolidine obtained, which had a melting point of 155-158 C after recrystallization in isopropyl alcohol.

Analysis for C ₂₅ H ₃₂ N ₄ O ₃ (436):

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

^ B eis ρ ie 1 3

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

A solution of 9.7 g (0.03 gram mol) of p-hydroxyphenylbutazone in 45 ml of chloroform was taken under Stir 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 has a melting point after recrystallization in isopropyl oxide of 146 148 C.

Analysis for C ₂₄ H ₂₉ N ₃ O ₃ (407):

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

Example 4

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

A solution of 6.1 g (0.019 gramol) of p-hydroxyphenylhutazone was added to 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 triturated in 25 ml of isopropyl oxide; the whole 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%)

l-Phenyl-2- (p-hydroxyphenyl; -3,5-dioxo-4-n-buty! - 4-piperidino-methy! pyrazolidine obtained after Recrystallization in 2 ml of methyl alcohol had a melting point of 135.degree.

Analysis for C ₂₅ H ₃₁ N ₃ O ₃ (421):

Calculated ... C 71.26, H 7.36, N 9.97%;
found ... C 7!, 27, H 7.32, NO, () O%.

Claims (1)

Patent claims: 1. Basic derivatives of l-phenyl-2- (p-hydroxy phenyl) -3,5-dioxo-4-n-butylpyrazolidine of the eye my form) CH ₃ (CH ₂ J ₃ CH ₂ -NX in which X is the direct bond between the carbon atoms, - O-,