DE1049384B - Process for the preparation of a therapeutically active aminobenzenesulfonamide and its salts - Google Patents

Description

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S-ifr S f
GERMAN

FEDERAL REPUBLIC OF GERMANY

KL. 12 ρ ^

INTERNAT. KL. C 07 d

PATENT OFFICE

EDITORIAL 1 049384

C 14763 IVb / 12p

REGISTRATION DATE: APRIL 3O, 1957.

NOTICE

DE-REGISTRATION ■ '..

AND ISSUE OF THE

EDITORIAL: 29 J A NU A R 1 9 5 9

The invention relates to a process for the preparation of 3- ( _P -amino-benzenesulfonamido) -2-phenyl-pyrazole of the formula - ^ - ^

-SO ₂ NH

Method of manufacture

a therapeutically effective one

Aminobenzenesulfonaniids and its salts

H ₉ N-

and its salts, such as B. the alkali and alkaline earth metal salts, especially sodium.

This new compound possesses at experimental. Infection in animals such as B. in mice infected with streptococci , a surprisingly good healing effect. It can therefore preferably be used as a remedy for infectious diseases such. B ^ _S ^ "epJokokkeninfektiq-nen. Find use. Compared to known, comparable aminobenzenesulfonamides, the new compound has surprisingly better chemotherapeutic properties half of that of the known 3 - (p -amino-benzenesulfonamido) -2-phenyl-5-methylpyrazole. Furthermore, the new compound Jm_ Gut shows a better antibacterial effect than the above-mentioned 5-methyl compound and is this also with regard to the urine disinfectant Superior effect.

The new aminobenzenesulionamidopyrazole can win by methods known per se for the preparation of p-Amino.benzolsulfonamiden. The procedure consists in using compounds of the formula

SO ₅ -HaI 40

45

with compounds of the formula

H ₂ N

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority: Switzerland of May 7, 1956, February 21 and April 5, 1957

or their dihydro derivatives, where R is the Dr. Jean Druey, Riehen,

and Dr. Paul Schmidt, Therwil (Switzerland),

have been named as inventors

Amino group or a substituent which can be converted into it, JR ₁ denotes hydrogen or a radical which can be replaced by hydrogen and Hal denotes a halogen atom, and in the compounds obtained any substituent R which can be converted into the amino group is converted into the amino group vindf. or a hydrogen-replaceable substituent R _{1 is} replaced by hydrogen and / or in compounds obtained which are substituted by two benzenesulfonyl radicals one of them is replaced by hydrogen and, if appropriate, dihydropyrazole compounds obtained at any stage of the process are oxidized to pyrazole compounds. For example, a benzenesulfonic acid halide, in particular the chloride, which has a substituent which can be converted into the amino group in the p-position, with a 3-ammo-2-phenyl-pyrazole which is unsubstituted or has a substituent which can be replaced by hydrogen, or let its dihydro derivative react. The implementation according to the process is advantageously carried out in the presence of diluents and condensation agents. A substituent which can be converted into the amino group is e.g. B. one which by hydrolysis like an acylamino-

1 04S384

group, ζ. B. the Acetylarriinor'jOder ^ Carbäthoxyaminogruppe, by reduction like a nitro or azo group or by treatment with ammonia, like a halogen atom in.die.Arninpgruppe can be converted; these conversions are carried out in the usual way. Compounds with a substituent R _{1 which} can be replaced by hydrogen are preferably selected from those starting materials which have a free or esterified carboxyl group. The Ver-

,,. · ■ 'One. Brings ·· then! the reaction solution on ice, provides with concentrated sodium hydroxide to p _H 8, moves with chloroform from the chloroform and distilled residue. The 3-amino-2-phenyl-pyrazole passes over at a pressure of 0.1.5 rhm and a temperature of 142 to 144 ° C and solidifies in crystalline form in the receiver; F. 42 to 44 ° C. ,

The same end product is obtained if the benzenesulfonyl chloride mentioned is mixed with the 3-amino-2-

>: aminobenzenesulfonamido phenyl-4-carbethoxypyrazole obtained according to the method is reacted, the pyrazole obtained is then hydrolyzed and decarboxylated, if appropriate after the previous compound. hydrolysis, decarboxylated. The possibly
Possible oxidation ^r can 'ih ^: ' in the usual way, e.g. More colorful

Use of O: _

salts, hydrogen peroxide and the like. However, the reaction proceeds through hydrolysis intermediate product to be converted into the end product, oxidation occurs in the usual way Saponification without special addition of oxidizing agents.

■ Let go of the new aminobenzenesulfonamides win salts in the usual way, such. B. by reaction with bases such as alkali or alkaline earth metal hydroxides or organic bases. The sodium salt

The 3- (p-amino-benzenesulfonamido) -2-phenyl-pyrazole obtained can be converted into its sodium salt in the usual way. ^l

B e i s ρ i e 1.2-

/• The starting materials are known or summarized win by methods known per se;

The invention is further described in the examples below. ^:

Example 1 In. a solution of 15.9 g of 3'-aminor2-phenyl-pyrazole

A solution of 6.44 g of 3-aminio-2-phenyl-dihydropyrazole in 50 cm ^{3 of} pyridine is admixed with 23.8 g of p-acetylamino-benzenesulphonic acid chloride within 10 minutes. The temperature rises to about. 65 ° C. After the exothermic reaction has subsided, the mixture is heated to 95 ° C. (internal temperature) for one hour and the reaction solution is then brought to 500 cm ^{3 of} 2N salt

of the new sulfonamide has a 10% aqueous solution of hydric acid and a little ice. A precipitate separates out and the very low pH value of 8 is noticed. that is sucked off. He ejithält_B.is, - (p-acet ylamine o-

ben zolsulfony l ) -3-amino-2-phenyI-dihydro-pvrazö l J-

The crude product thus obtained is direct. with 360 cm ³ were added 2.5 η-sodium hydroxide solution, and the suspension obtained is 30 for 2 hours, boiled, mixed with i "■■ animal charcoal and filtered. It then sets the filtrate with 5 η-hydrochloric acid to p _H 5 to 6, after which a crystalline precipitate separates out, which is filtered off with suction and recrystallized from alcohol. It is, spin 60 cm ^{3 of} anhydrous pyridine within 35 3- (p-Amino-benzölstilfonamido) -2-phenyl-pyrazole er about 25 minutes 29 g of p- Carbethoxyamino-benzene. This product corresponds to its melting point, sulphonic acid chloride entered. After the ultraviolet and infrared spectrum has subsided with the compound obtained in the reaction, the mixture is heated to an internal temperature of 90 to 95 ° C for 1 hour. It is poured then the reaction The 3-amino-2-phe-

solution to 300 cm ³ 2 ^ hydrochloric acid, sucked from the 40 nyl-dihydro'-pyrazole is prepared in the following way; deposited precipitate and crystallizes out. 16.1 g of N - (/ 3-cyanoethyl) -N'-phe.nylhydrazine. Pyrazole is produced in white) with. 200 cm ³ 8 η of alcoholic ßen crystals with a melting point of 175 to 176 ° C were obtained. . Hydrochloric acid added. It falls immediately, a white low

The latter is added to 250 .rcm ³ 2 η sodium hydroxide solution. One then stirs for an hour. taken and heated for one hour at the boiling- .. room temperature and heated for another 2 hours for the water bath. After cooling down, the precipitated acid is poured into pu; 6 to 7, sucks off the precipitated, hygroscopic precipitate; sucked off. The precipitate crystallizes from the 75% hydrochloride obtained in this way and is ethyl alcohol in 70 cm ^{3 of} water. The thus obtained 3- (p-Ammo-benzene-50 dissolves, and the solution is made strongly sulfonamido) -2-phenyl ~ pyrazole crystallized in white under ice-cooling, whereupon a white precipitate crystals and shows a ^; F. from 177 to 178 ° C.
- The 3-amino-2-phenyl-pyra'zol 'used as starting material can be used on the following. Paths made
will ^:: -.

"17 parts by weight of Ethoxymethylehcyanessigsäureäthylester are dissolved in 100 parts by volume of ethyl alcohol. The solution is then slowly mixed with a solution of 10.8 parts by weight of phenylhydrazine in

50 parts by volume of ethyl alcohol are added. To complete 60 in 600 cm ^{3 of} anhydrous pyridine .werderii within strengthening. After the reaction, 267 g of 96% p-acetylamino are heated to the boil for 2 hours for about 30 minutes Is crystallized for 1 hour at 90 to 95 ° C. with the addition of benzene. Heated by internal recrystalline temperature. The reaction is then poured from ethyl acetate with the addition of animal charcoal onto 31 2 N hydrochloric acid , whereby the sulfone is obtained '·. S-Ami'nö ^ -phenyl ^ -carbethoxy-pyrazol amide precipitates out in a greasy form' · After decanting off white crystals from 99 to 101 ° C follows saponified:

^ j A solution vori'2 g / 3-Amino-2 ^J phenyr-4-carbäth- The crude product, consisting of a mixture of

Oxy-pyrazole in 2O.cni ³ 75 "/ oig'er ^" sulfuric acid is heated 3 - ^ (p -acetylamino-benzo ^. for. 6 hours in a bath of 150 ° C. 7ί_Έ2 ^ 1ΡΓί ^ ' Ήί ~ Ϊ9Ϊ ⁰ ~ 'θ äus "Ätharioi) ^ nd to ^£ (p ^J ace-

55

fails, which is sucked off. The resulting S-amino ^ -phenyl-dihydro-pyrazol melts nach'dem recrystallization from isopropyl ether at 106-107 ⁰ C. ';

B e i s ρ i e 1 j 3 In a solution of 159g3-amino-2-phenyl7pyrazole

tylamino-benzenesulfonyl) -3-id 3 25 Nl

is taken up in 3 1 2.5 η sodium hydroxide solution and refluxed for 2 ¹ 11 hours. The solution is clarified with animal charcoal and the filtrate is adjusted to p ^ 6 with 6η-hydrochloric acid, after which a precipitate separates out, which soon solidifies in crystalline form. It is recrystallized from 1200 cm ^{3 of} alcohol with the addition of animal charcoal. This gives 3- (p-amino-benzenesulfonamido) -2-phenyl-pyrazole in white crystals which, according to the mixed melting point and ultraviolet spectrum, corresponds to the product obtained in Example 1.

Claims (1)

Claim: Process for the preparation of a therapeutically active aminobenzenesulfonamide and its Salts, characterized in that compounds of the formula SO ₉ -HaI with compounds of the formula C ₆ H ₅ or their dihydro derivatives, where R is the amino group or a substituent which can be converted into it, R _{1 is} hydrogen or a radical which can be replaced by hydrogen and Hal is a halogen atom, converts any substituent R which may be present and which can be converted into the amino group into the amino group in the compounds obtained and / or possibly one through. Substituents R _{1 which can be} replaced by hydrogen are replaced by hydrogen and / or in compounds obtained which are substituted by two benzenesulfonyl radicals, one of them is replaced by hydrogen and, if appropriate, dihydropyrazole compounds obtained at any stage of the process are oxidized to pyrazole compounds and, if appropriate, the 3- (p-aminobenzenesulfonamido) -2- obtained phenyl-pyrazole converted into its salts.