CS197253B2 - Method of producing novel derivatives of oxyphenyl butazone - Google Patents

Description

The invention relates to a process for the preparation of novel oxyphenylbutazone derivatives of the general formula I

CM

c „h ₉

I / CH oc ^x co

000 ^ 000 N (I) where | n stands for 4 or 5.

Is it known that oxyphenylbutazone and its derivatives of formula II?

where

R 1 represents a straight or branched chain alkyl group or a C 3 -C 7 cycloalkyl group such as butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopentyl or cyclohexyl, furthermore 3-oxobutyl, 3-methyl-2- butenyl, 2-phenylthioethyl, 2-phenylsulfinylethyl or 2-phenylsulfonylethyl are pharmacologically active substances which have a particularly high anti-inflammatory effect. These known oxyphenylbutazone derivatives are preferably used for systemic treatment in inflammation, such as e.g.

However, these known oxyphenylbutazone derivatives have proven to be ineffective in the treatment of joint inflammation, i.e., topical use, in the treatment of inflammatory dermatoses.

It has now been found that the local efficacy of the known oxyphenylbutazone derivatives can be surprisingly substantially enhanced if the oxyphenylbutazone derivatives ζζ-ΝΗ-O (CH _k ) where n is as defined above are condensed with a malonic acid derivative of the formula V

C4H9

C1OC-CH-COCl (V).

The process according to the invention is carried out under the conditions customary for the production of phenylbutazone derivatives from hydrazo compounds.

For example, the bis-hydrazo compounds of formula (IV) may be reacted under normal conditions with malonic acid dichlorides or mixed substituted malonic anhydrides in the presence of basic catalysts such as pyridine, collidine, lutidine, 4-dimethylaminopyridine, sodium or potassium carbonate, or sodium hydroxide. or potassium.

The bis-hydrazo compounds of formula IV used as starting materials can be prepared from a dicarboxylic acid derivative of formula III

XOC (CH 2) n COX, (ΠΙ) where n is as defined above and

X represents, for example, a hydroxyl group or a chlorine atom and a hydrazo compound of the formula VI

3 of formula (II) are converted into their previously unknown derivatives of formula (I).

The invention therefore relates to a process for the preparation of novel oxyphenylbutazone derivatives of the general formula I, wherein n is as defined above, characterized in that the bis-hydrazo compound of the general formula IV

(VI)

The novel oxyphenylbutazone derivatives of the formula I are pharmacologically active substances which, in particular when used topically, are characterized by a high anti-inflammatory effect in dermatoses of inflammatory origin. They differ in this respect from the known oxyphenylbutazone derivatives, which are considerably less effective when applied topically.

The inflammation-inhibiting effect exhibited by the novel oxyphenylbutazone derivatives can be ascertained using the known vasoconstriction assay.

On the backs of the volunteers who undergo the experiment, Stratum corneum decomposes into twenty superimposed strips, creating a marked hyperemia. Inside the strips of the demarcated area, 50 mg ointment containing 0.1% / 0.01% or 0.01% of the test substance or reference substance in the water-oil system is applied to 4 cm ² large patches each. The extent of vasoconstriction was determined at 1.4 and 8 hours after administration.

For the detection of vasoconstriction, a representative inflammatory braking syndrome, the color value of the treated and untreated skin in strips is determined and compared to the color value of normal skin, the color value of normal skin being expressed as 100 and the color value of untreated skin in the strips determined by 0. then slight moderate and high vasoconstriction is between 0 and 100.

7 2 5 3

Vasoconstriction test Table 1 Number Substance Active substance conc.

TI 6α-fluoro-11 (3,21-di-0,1 hydroxy-16α-methyl 1,4-pregnadien-3,20- 0,01

-dione (= fluocortolone)

The results of the vasoconstrictor assay show that the compounds of the invention are substantially more potent than phenylbutazone, and their efficacy is comparable to steroid II, which could not be expected with non-steroids.

The topical inflammatory activity of the novel oxyphenylbutazone derivatives may also be determined by the Tonelli procedure as follows:

Dissolve the test substance in an irritant consisting of 4 parts pyridine, 1 part distilled water, 5 parts ether and 10 parts 4% croton oil ether solution. This test solution impregnates a felt strip, which is attached to the inside of the pin.

8

75 85

65 85 zeta, and the latter with the strip is pressed under gentle pressure for 15 seconds on the right ear of a male rat weighing 100-160 g.

The left ear is not treated and is used for comparison. Three hours after application, the animals are sacrificed and 9 mm ² plates are excised from their ears with a punch. The weight difference between the right and left earplate is a measure of the edema formed.

Control animals are treated equally with the only difference that the irritant solution used does not contain any test substance.

The concentrations of the active substances (ED50) were determined to detect a 50% reduction in edema formation.

C.

Table 2 Edema test

Substance ED50 (mg / ml)

II 6a-fluoro-11 / 3,21-dihydroxy-3,4

-16'-methyl-1,4-pregnadien-3,30-dione (= fluocortolone j

It can be seen from the table that the novel oxyphenylbutazone derivatives have a higher anti-inflammatory effect compared to the structurally analogous known compounds. The anti-inflammatory effect of the novel oxyphenylbutazone derivatives when applied topically is as strong as that of the known anti-inflammatory corticoids.

Thus, within the scope of the invention, non-steroidal compounds have been produced which locally exert an excellent inflammatory inhibitory effect.

Corticosteroids, which have been used in the treatment of skin inflammation so far, have, in addition to local effects, a permanent systemic effect. Therefore, even with topical application, these corticoids can pass into the bloodstream due to inflammatory skin resorption or as a result of skin damage, where they, as hormonally active substances, can in many ways affect bodily functions.

These disadvantages do not occur with the topically active oxyphenylbutazone derivatives according to the invention. In addition, oxyphenybutazone derivatives have the advantage of low toxicity.

The novel compounds are suitable in combination with carriers customary in galenical pharmacy for topical treatment of allergies, contact dermatides, eczema of various kinds, neurodermatides, erythrotiermias, burns, Pruritis vulvae et ani, as well as in the treatment of Rosacea, Erythomatodes cutaneus, Psoriassis and Lichen rubus planus and similar skin diseases.

The preparation of the dosage forms is carried out in the usual way by treating the active substances with appropriate additives to the dosage form of interest, such as solutions, liquid forms, ointments, creams, inhalants or patches. In such formulations, the concentration of active ingredient is dependent on the dosage form. For liquid preparations and ointments, a concentration of active ingredient of from 0.005% to 5% is usually used.

The method according to the invention is illustrated by the following example.

Example

A solution of 1.9 g of butyl malonic acid dichloride and 1.7 ml of pyridine in 20 ml of chloroform is added dropwise at 0 to 5 ° C.

2.5 g of adipic acid di- [4-phenylhydrazophenyl] ester in 200 ml of chloroform. The reaction mixture was allowed to stand at room temperature overnight. It is then washed first with 0.1 N hydrochloric acid solution and then with water and evaporated. The residue was recrystallized from methanol. Yield: 2 g of adipic acid [4- (4-butyl-3,5-dioxo-2-phenyl-pyrazolidinyl) -phenyl] ester, m.p. 128-131 ° C.

Adipic acid bis- (4-phenyl-drazophenyl) ester is prepared as follows:

(a) Dissolve 164 g of polyphosphoric acid ethyl ester in 60 ml of chloroform. To this solution was added a suspension of 14.86 g of adipic acid and 40.0 g of p- (phenylazo) -phenol in 340 ml of chloroform. The reaction mixture is stirred for 4 hours, then 35 g of adipic acid bis- (4-phenylazophenyl) ester is filtered off with suction and recrystallized from ethyl acetate. 30 g of pure material are obtained. Celsius.

b) Adipic acid bis- (4-phenylazo-phenyl) ester in an amount of 5 g was hydrogenated in a mixture of ethyl acetate and pyridine using 10% palladium on carbon catalyst at room temperature and atmospheric pressure in a shaking vessel. After the calculated amount of hydrogen had been bound, the catalyst was separated, the colorless solution was evaporated under nitrogen and the residue was recrystallized from methanol. 3 g of adipic acid bis (4-phenylhydrazophenyl) ester are obtained, m.p. 167-171 ° C.

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of novel oxyphenylbutazone derivatives of the general formula I C 1 H 3 -cyclo-C 1 -o o-c C-O-H-N-O-O-OCH 3 COO-O-N (II) wherein n is 4 or 5, characterized in that the bis-hydrazo compound of formula (IV) is: (C4) wherein C 4 H 9 η has: the above meaning, C1OC — CH — COC1 condenses with a malonic acid derivative of formula V (V) severography, np, plant 7, Most