DE1271717B - 2-phenyl-3- (p-amino-benzenesulfonamido) -5-ethyl-pyrazole, its metal salts, its N-carbalkoxy derivatives and its N-lower alkanoyl derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

German class:

Number:
File number:
Registration date:
Display day:

C07d

A61k

12p-8/01

30 h-2/36

P 12 71 717.8-44 (C 29274)

March 1, 1963

4th July 1968

The invention relates to the new 2-phenyl-3- (p-amino-benzenesulfonamido) -5-ethyl-pyrazole the formula

2-phenyl-3- (p-amino-benzenesulfonamido) -5-ethyl-pyrazole, its metal salts, its Nj-carbalkoxy derivatives and its Nj-lower alkanoyl derivatives

H ₂ N-

■ SO, - NH

C ₂ H ₅

as well as its metal salts and its N _r acyl derivatives.

Metal salts to be mentioned are in particular those with alkali, alkaline earth or earth metals, such as sodium, Potassium, calcium, magnesium or aluminum.

N _r acyl derivatives are carbalkoxy radicals, such as the carbethoxy radical, or lower alkanoyl radicals, such as the propionyl, butyryl, valeryl or caproyl radical. However, the acyl radical is primarily the acetyl radical.

The new sulfonamide, its metal salts and its ^ -acyl derivatives have good chemotherapeutic properties Properties with a long duration of action. For example, they instruct in the event of experimental infection Animals such as B. in mice infected with streptococci, a very good healing effect. they are superior to similar known compounds in terms of their effect. They show a long lasting Blood levels. The compound has a significantly longer residence time in the organism than the known 2 - phenyl - 3 - (ρ - amino - benzenesulfonamido) - pyrazole and is, for example, against Staph. aureus 10 essential more effective than the said comparison compound. They can therefore be used pharmacologically or as a remedy or prophylactic agents are used in humans and animals. But they are also available as additives too Suitable for animal feed and can be used as intermediates for the manufacture of other valuable products Chemotherapy drugs are used.

The new compound and its metal salts are obtained by methods known per se. In particular one proceeds in such a way that one creates a compound of the formula

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr.-Ing. Dr. jur. F. Redies, Dr. rer. nat. B. Redies, Dr. rer. nat. D. Turk

and Dipl.-Ing. Ch. Gille, patent attorneys, "5 4000 Düsseldorf-Benrath 3,

Erich-Ollenhauer-Str. 7th Named as inventor: Dr. Paul Schmidt, Therwil (Switzerland)

Claimed priority: Switzerland of March 7, 1962 (2729), dated January 21, 1963 (662)

or a dihydro derivative thereof with a compound of the formula

Z-SO ₂

converts, where X is a hydrogen atom or a residue that can be replaced by hydrogen, Y and Z are residues that can be split off during the reaction, leaving behind the imino group - NH - contained in them, and Z _{1 represents} the amino group or a residue that can be converted into one, or compounds of the formula

with phenylhydrazine or its salts, and in the compounds obtained, in any order, a radical Z ₁ that can be converted into the amino group is converted into one and / or a radical X that can be replaced by hydrogen is replaced by hydrogen and / or obtained dihydropyrazole compounds are oxidized to pyrazole compounds and / or obtained

809 561/564

Cleaves BiS-PZ ₁ -benzenesulfonyl compounds to give the monop-Zi-benzenesulfonyl compounds and / or, if desired, Nj-acylated compounds obtained. These reactions take place in a manner known per se with the groups known from sulfonamide chemistry. So you can z. B. condense a pZ ^ benzenesulfonic acid halide, especially the chloride, with 3-amino-2-phenyl-4-X-5-ethyl-pyrazole or its dihydro derivative, where R, X and Z _{1 have} the meaning given above and where the usual condensing agents, e.g. B. aqueous alkalis, such as alkali metal carbonates, but especially tertiary organic bases such as aminopyrazole itself or pyridine, picoline, lutidine, collidine, lower trialkylamines such as trimethyl or triethylamine, or Ν, Ν'-tetraalkyldiaminoalkanes, such as. B. N, N ^/ -Tetramethyl-w, a> ^/ -diaminohexane, and optionally the usual diluents such as benzene, toluene, methylene chloride, chloroform, methyl ethyl ketone, acetone, dioxane, nitrobenzene and the like. Depending on the reaction conditions, such as condensing agents, reaction temperature, diluent or the use of an excess of sulfonic acid halide, bis-p-Zj -benzenesulfonyl compounds can be obtained as by-products or mainly, which can be obtained in a manner known per se before or after the possibly necessary stages of Conversion of Z ₁ into the amino group, the removal of the radical X or the oxidation, or optionally converting at the same time into the mono-p-Zi-benzenesulfonyl compounds. So the bis-compounds z. B. by hydrolysis or aminolysis, optionally simultaneously with any hydrolysis of the radical Z ₁ , converted into the mono-compounds.

When carrying out the second variant of the process using propionylacetyl sulfonamides, these are expediently reacted with a small excess of the hydrazine compound. The preferred reaction ^{temperatures are between 0 °} C. and room temperature (ice cooling). The free phenylhydrazine and its reactive derivatives (e.g. hydrazones, acylhydrazines, semicarbazide, azines and the quaternary ammonium compounds obtained by reacting diket or aldazines with reactive alkyl esters) can be used as the hydrazine component. In the latter case, the ring closure takes place with elimination of the radical on the hydrazine group (ie the aldehyde or the ketone, for example, is released). The reaction can e.g. B. be carried out with all common acidic condensing agents; she succeeds z. B. already when using the hydrazine hydrochloride or sulfates. If the free hydrazines are used as starting materials (that is, the ring closure takes place with elimination of water), the yields obtained are considerably increased if an acidic condensation agent is used which is capable of binding the water formed; A mixture of phosphoric acid and phosphorus pentoxide has proven particularly advantageous. However, other condensation agents suitable for carrying out condensation reactions in an anhydrous medium can also be used, such as strong hydroscopic acids or Lewis acids. The only prerequisite for the good feasibility of the reaction is that the acidic condensation agents have sufficient solubility for both reactants or that they can be obtained by adding a suitable inert solvent.

The mentioned, possible conversions of the radicals X and Z ₁ into hydrogen or the amino group and the oxidation of dihydropyrazole compounds take place in a manner known per se.

In addition to the amino group, the radical Z ₁ is advantageously a radical which is customary in sulfonamide chemistry and which can be converted into the amino group, especially a radical which can be converted into the amino group by reduction or hydrolysis. B. acylamino groups, especially aliphatic acylamino groups such as carbalkoxyamino groups, e.g. B. the carbethoxyamino group, alkanoylamino groups such as the propionyl, butyryl or caproylamino group, but especially the acetylamino group, dihalophosphorylamino groups, e.g. B. the dichlorophosphorylamino group, or methylideneamino groups, such as. B. alkylidene or benzylidene amino groups, especially the isopropylidene or benzylidene amino group. So you can also use the starting materials of the formula

SO, Z

use where R is the acyl radical of a dibasic acid, especially carbonic acid, or z. Belly represents an alkanedicarboxylic acid and Z has the meaning given at the beginning, and especially halogen represents.

A radical that can be converted into the amino group by reduction is, for example, one by hydrogenolysis cleavable acylamino group, such as the carbobenzoxyamino group or the nitro group, or an azo group, such as an aryl, especially phenylazo group, in the latter case especially a compound the formula

SO, Z

is used as starting material, in which Z has the meaning given at the beginning and above all Means halogen.

The hydrolysis, aminolysis or reduction of the groups mentioned are known per se Way done.

Compounds with a substituent X which can be replaced by hydrogen are preferably chosen those as starting materials which have a free or esterified carboxyl group. According to the procedure obtained p-Zjt-benzenesulfonamido-pyrazole is then, optionally after previous hydrolysis, decarboxylated.

The oxidation, which may be necessary, can be carried out in a conventional manner, for. B. using oxidizing agents, such as organic peracids, bromine, iron (HI) salts, or especially also with hydrogen peroxide, expediently in counter

wart of the iron salts mentioned or of iodine or an iodide, advantageously in acidic solution, e.g. Am Formic or acetic acid. However, if the reaction proceeds via a hydrolysis into the end product As an intermediate product, the oxidation occurs with the usual saponification without any particular one Addition of oxidizing agents.

A particularly advantageous process is that p-acetylamino-benzenesulphonyl chloride with 2-ph.enyl-3-amino-5-ethyl-pyrazole converts and hydrolyzes the condensation product.

The N ₁ acylation is carried out in a customary manner using N ^ acylating agents. These are mainly acid anhydrides or halides, such as chlorides. The reaction is expediently carried out in the presence of basic agents such as inorganic or organic bases, e.g. B. alkali carbonates or tertiary amines, such as pyridine, picoline, lutidine, collidine, trimethylamine, triethylamine, tributylamine or 1,6 - bis ■■ dimethylamine - hexane, and in the presence of inert diluents, especially organic solvents such as dioxane, benzene, toluene, halogenated hydrocarbons, e.g. B. methylene chloride or chloroform, dimethylformamide, lower aliphatic ketones such as acetone or methyl ethyl ketone, or optionally the basic agent itself, such as. B. pyridine, or mixtures thereof, such as especially pyridine-acetone performed. It is advantageous to work in a medium that is as water-free as possible. If an acid halide is used, a metal salt of the sulfonamide, e.g. B. an alkali salt or better the silver salt, use, whereby the addition of basic agents recommended above is unnecessary. Your additional use, e.g. B. as a diluent, but nothing stands in the way.

In the N ₁ acylation of associations in which Z _{1 is} the amino group, e.g. B. of 3- (p-aminobenzenesulfonamido) -2-phenyl-5-ethyl-pyrazole, care must be taken that the reaction is carried out under mild conditions and using approximately equimolecular amounts of the reactants in order to avoid that N ₁ , N ₄ bis-acyl compounds or, by Acyiwanderang, N ₄ acyl compounds are formed. Advantageously, therefore, carried out at low temperature, for example below 40 ° C, such as 10-30 ⁰ C, and in anhydrous medium. When using the acid halides, it is advisable to start from the metal salts of the sulfonamides, such as the silver salt.

If the acyl radical is introduced into the ^ nitrogen atom of a compound in which Z ₁ does not represent the amino group, it is preferred to start from compounds in which Z _{1 is} a group which can be converted into the amino group by reduction. This is then reduced in a manner known per se, expediently while avoiding hydrolyzing conditions and higher temperatures, in order to avoid cleavage or rearrangement of the Nj-acyl radical at the N ₄ nitrogen atom. Particularly suitable is the reduction with hydrogen in the presence of catalysts, e.g. B. noble metal catalysts, such as palladium on carbon.

But you can also start from a compound in which Z _{1 is} a radical convertible into the amino group by hydrolysis under mild conditions, such as. B. an Arylmethyiidenarninogruppe, z. B. a benzylidene amino group. _{After the N 1} acylation, the arylmethylidene group can then be saponified under mild conditions without the N _x acyl group being split off in the process.

Let go of the new amino-benzenesulfonamides win salts in the usual way, such. B. by reacting with bases, especially with therapeutic usable bases, such as hydroxides of alkali, alkaline earth or earth metals, e.g. B. sodium, potassium or Calcium hydroxides, or organic bases.

The salts of the sulfonamide compounds can also be used to purify the sulfonamide compounds obtained serve by converting the sulfonamide compounds into the salts, separating them and in turn liberates the sulfonamide compounds from the salts.

The starting materials are known or can be prepared by methods known per se.

One can also use a compound obtainable as an intermediate at any stage of the process go out and complete the missing stages; can also be a starting material among the Reaction conditions are only formed or used as a salt. You can also, for example prepare the 2-phenyl-3-amino-5-ethyl-pyrazole or its dihydro derivative in a known manner and without isolation with a p-Zi-benzenesulfonic acid halide realize.

The new compounds can be used as remedies, e.g. B. in the form of pharmaceutical preparations, use find which the active material mixed with one for enteral, parenteral or topical Application of suitable pharmaceutical, organic or inorganic, solid or liquid carrier material contain. For oral use, they contain a large amount of the new sulfonamide compounds of over 0.1 g per dosage unit, expediently between 0.25 and 3 g.

The new active compounds can also be used in veterinary medicine in the form of veterinary preparations or can also be used as additives in animal feed. The invention therefore relates to also these veterinary medicines or animal feeds or animal feed additives, which contain the new sulfonamides of the specified type in a mixture with the usual carrier materials.

The invention is described in more detail in the examples below. The temperatures are in Celsius degrees indicated.

example 1

10.8 g of 96% p-acetylamino-benzenesulfonic acid chloride are introduced into a solution of 8 g of 2-phenyl-3-amino-5-ethylpyrazole in 40 cm ^{J of anhydrous pyridine over a period of 10 minutes.} After the reaction has subsided, the mixture is heated to an internal temperature of 90 to 95 ° for a further hour. The reaction solution is then poured into 400 cm ^{3 of} 2 η-hydrochloric acid, after which the sulfonamide precipitates and, after filtering off, is saponified in the following manner: The crude product, consisting of a mixture of 3- (p-acetylaminobenzenesulfonamide) - 2 - phenyl - 5 - ethyl - pyrazole and bis - (ρ - acetylamino - benzenesuifony 1) - 3 - amino - 2 - phenyl-5-ethyl-pyrazole, are taken up in 150 cm ^{3 of} 2N sodium hydroxide solution and refluxed for 2 hours. The solution is clarified with activated charcoal and the filtrate is adjusted to pH 6 with 6η hydrochloric acid, after which a precipitate separates out, which soon solidifies in crystalline form. After recrystallization from alcohol one obtains

2 - phenyl - 3 - (ρ - amino - benzenesulfonamido) - 5 - ethylpyrazole the formula

Comparative experiments

Η, Ν-

■ SO ₂ NH

in white crystals from mp 214 to 215 °.
Example 2

To a solution of 17 g of 2-phenyl-3- (p-aminobenzenesulfonamido) -5-ethyl-pyrazole in 50 cm ^{3 of} acetone and 10 cm ^{3 of} pyridine, 4.8 cm ^{3 of} acetic anhydride are added over 5 minutes with stirring. The mixture is stirred for 5 hours and the mixture is left to stand for 10 hours. ^{300 cm 3 of} 3% strength aqueous ammonia and ice are then added with stirring, after which an oily product precipitates. This is mixed with 200 cm ^{3 of} water and left to stand at room temperature, the oil formed gradually crystallizing. The precipitated product is filtered off with suction, crystallized from alcohol and the Nj-acetyl derivative of 2-phenyl-3- (p-amino-benzenesulfonamido) -5-ethyl-pyrazole of the formula is obtained

C ₂ H ₅ 2-phenyl-3- (p-amino-benzenesulfonamido) -5-ethylpyrazole (I) was treated with the well-known 2-phenyl-3- (p-amino-benzenesulfonamido) pyrazole ( II) compared:

1. Concentration in the blood

Investigations on the concentration in the blood were carried out on dogs and rabbits oral administration of 100 mg / kg of preparations I and II. The time course of the blood concentrations was determined according to the determination method of B r a 11 ο η and M a r s h a 11 (modification of D r u e y and Osterheld) and is given in the following tables. These were the corresponding products of the blood concentration values are determined over a period of 48 hours (= BKZ product).

Table 1

Blood concentrations in the dog after 100 mg / kg, p. O.

SO ₂ -N

COCH

35

40

in white crystals from F. 189 to 19Γ.
Example 3

In an ice bath, 78 cm ^{3 of} anhydrous phosphoric acid are mixed with 21.2 g of phenylhydrazine. As soon as everything has dissolved, 31.2 g of N ¹ - (propionyl - acetyl) - N ⁴ - (acetyl - amino) - benzenesulfonamide are added with stirring. The mixture is stirred for 1 hour at 10 °, 17.3 g of phosphorus pentoxide are added while cooling with ice and the mixture is stirred for a further 3 hours at 10 °. By adding 400 cm ^{3 of} water, the 2-phenyl-3-p-acetylamino-benzenesulfonamido-5-ethyl-pyrazole precipitates. It is taken up in 4 η sodium hydroxide solution, the solution refluxed for 2 hours, then clarified with animal charcoal, filtered and the filtrate adjusted to pH 6 with 6N hydrochloric acid, after which a precipitate separates out, which soon solidifies in crystalline form. After recrystallization from alcohol, 2-phenyl-3- (p-amino-benzenesulfonamido) -5-ethyl-pyrazol of the formula is obtained

Time (hours) Blood concentration values (mg%) I. II 5.7 1 3.4 9.9 3 7.5 10.7 6th 5.7 10.5 9 3.2 9.8 12th 2.4 8.3 24 1.4 4.6 36 0.5 4.3 48 0.3 3KZ product 346 (mg% / hour) 94

Table 2

Blood concentration in rabbits after 100 mg / kg, p. O.

H ₂ N-

SO ₂ NH

C ₂ H ₅

Time (hours) Blood concentration values (mg%) I. II 3.2 1 4.2 7.5 3 5.8 12.1 6th 6.9 12.6 9 6.2 12th 12th 5 10.8 24 4.3 10.8 36 3 6.9 48 2.4 BKZ product 500 (mg% / hour) 199

in white crystals from mp 214 to 215 °.

60 If we consider the experiments on dogs, it follows that for the same single dose of 100 mg / kg, both preparations show a relatively rapid rise and a delayed fall in blood concentrations. However, preparation I reaches higher blood concentrations than II: e.g. on dogs,

> 10mg% in 6 hours, for preparation I and only 5.7 mg% for II. There is also a significantly faster one Decrease in the concentrations of II. After 6 hours, the blood concentration of preparation I is about twice higher than that of II; after 36 and 48 hours it is ~ 9 times and ~ 14 times higher than that of II. Corresponding to this course, the BKZ product of II is only about a third of that from I.

Table 2 shows that very similar conditions exist in rabbits. The superiority von I is also shown in the chemotherapeutic experiment.

2. Chemotherapeutic effect '5

With staph. aureus 10 infected mice were administered a suspension of I po immediately after infection. On the 5th day after infection, the survival rate and thus the ED _{50 were} determined (see Table 3):

25th

10

summary

1. I has a significantly longer residence time in the organism than II.

2. I is also in the chemotherapeutic experiment of the mouse against staphylococcal infection the II clearly superior.

Claims (1)

Claim: 2 - phenyl - 3 - (ρ - amino - benzenesulfonamido) -5-ethyl-pyrazole the formula C ₂ H ₅ SO, - NH aureus K) Tabel 3 II I. 330 85 Staph. and its metal salts, its N _r carbalkoxy derivatives and its N _r lower alkanoyl derivatives. Documents considered: German Patent No. 952 809; French Patent No. 1,255,331; U.S. Patent No. 2,980,669.