US2462963A

US2462963A - Derivatives of rho-aminobenzenesulfonamides and process of making same

Info

Publication number: US2462963A
Application number: US496838A
Authority: US
Inventors: Hartmann Max; Druey Jean
Original assignee: CIBA PHARMACEUTIEAL PRODUCTS I
Current assignee: CIBA PHARMACEUTIEAL PRODUCTS I; CIBA PHARMACEUTIEAL PRODUCTS Inc
Priority date: 1943-04-14
Filing date: 1943-07-30
Publication date: 1949-03-01
Anticipated expiration: 1966-03-01

Description

rled out in such a way that the p-aminobenzenesulphonamides, in particular the 2- (p-aminobenmemo Mar. 1, 1949 UNITED STATES, PATENT orrlca aim,

DERIVATIVES F p-AMINOB FONAMIDES AND PROCESS OF MAKING SAME Ma: Hartmann and Jean Druey. Biehen, Switaorland, 'asaignors to Clba Pharmaceutical Prodgets Ino., Summit, N. 1., a corporation of New erse! No Drawing. Application July so, 1m, sci-m No. 496.838. in Switzerland April 14, ms

2 Claims. (Cl. 260-2395) 2 act with slyoxyiic acid salts, for example with sodium glyoxylate in water. if necessary adding a solvent which is miscible with water, e. g. alcohol. The reaction can also be carried out in the presence of organic solvents, particularly it glyoxylic acid or its esters are used. The compounds obtained in the form; of the free. carboxylic acids. esters, etc. can be converted in a known manner into any water-soluble salt e. g. the sodium, ammonium or calcium salt.

The constitution of the new compounds can not be exactly determined. The analytical results give the following probable formulae:

n-zm-sm-Qraon-ooon a-mn-sm-Q-mr-zn-ooon v I I H a-nn-soQmr-on-mrQswNn-a coon wherein R represents a polyheteroatomic, heterocyclic radical. The salts may contain, in addition, crystal solvents.

The compounds obtained by the present process dissolve readily in water in the form of their salts. The neutral solutions which can be prepared from the salts are therefore particularly suitable for parenteral administration and have the same activity as the parent p-aminobenzenesulphonamides, the latter being presumably reformed in the body.

The appended claims are directed to the preierred form 01. the invention, involving the reaction between sodium glyoxylate and 2-(paminobenzenesulphonamido)-thiazole, and the resulting product.

The suggestion has already been made that chemotherapeuticaily active p-aminobenzenesulphonamides which are only slightly soluble in water should be made water-soluble by the introduction into the amino group of radical 5 containing a salt-forming group. The previous processes or this kind had the disadvantage of being diflicult to carry out, or of giving compounds which are considerably less'active on parenteral administration than the unsubstituted amines. These water-soluble derivatives arepresumably not decomposed rapidly enough, with the result that the parent amines are not able to exert their full eflect. g

It has now been found that derivatives of p-aminobenzenesulphonamides which are watersoluble and at the same time parenterally active can be obtained in a satisfactory way if chemotherapeutically active p-aminobenzenesuiphonamides which are substituted in the sulphonamide 2 group by a polyheteroatomic, heterocyclic radical are caused to react with salts of glyoxylic acid, with this free acid or with compounds convertible into glyoxylic acid or into its salts and, if necessary. converting the compounds obtained into water-soluble salts of the corresponding carboxylic acids.

Amongst the p-aminobenzenesulphonamides mentioned as parent products, Z-(p-aminobenzenesulphonamido) -thiazole is particularly suitan able. Other compounds, which are substituted in the sulphonamide group by a polyheteroatomic, heterocyclic radical containing sulphur in the ring, can also be used e. g. Z-(p-aminobenzenesulphonamido) -4,5-dihydrothiazole or 2- (p aminobenzenesulphonamido) thiodiazoles such as 2 (p-aminobenzenesulphonamido) 5 ethyl-thiodiazole. It is also possible to start from p-amlnobenzenesulphonamido-pyrimidines e. g. fi-(p-aminobenzenesulphonamido) -2,4-di- 4o methyl-pyrimidine or from p-aminobenzenesulphonamido-pyrazines.

Particularly suitable salts of glyoxylic acid are the alkali salts, but the alkaline earth or ammonium salts or the salts with organic bases can also be used for thereaction. As compounds convertible into glyoxylic acid or its salts may be ne r pl s'lyoxylic. acid esters. rates out in the form oi a white powder. It is glyoxylic acid ester hemiacetals, thioglyoxylic filtered ofl by t washed with alcohol and acid, diacetoxy-acetic acid, 'dihalo-acetic acids, ether and dried at 100 C. etc. The corresponding calcium salt can. be ob- The reaction should be advantageously cartained from this compound by reaction with cal-- cium chloride; it is less soluble in cold water than the sodium compound. but fairly soluble zenesizlphonamidobthiazole, are caused to reinwarm water. i

Example 1 12.5 gm. of sodium glyoxylate are dissolved in com. or water and the solution heated to about 80 C. 25 gm. of 2-(p-aminobenzenesulphonamido)-thiazole are then introduced, stirring continually, and are dissolved completely within a short time. Any impurities can be filtered oil.

tinually. when the condensation product sepa- The solution is poured into alcohol, stirring con- 3 Example 2 W I llgmf'of 75 per cent g'lyoxylic acid are dis solved in 80 com." of water andneutralized with Example 3 7.2 gm. of 2-(p-aminobenzenesulphonamido)- thiazole are added to 60 com. of hot absolute alcohol containing 6.2 gm. of 68 per cent glyoxylic acid, a clear solution being obtained after a short time. After cooling, the condensation product is precipitated with ether, filtered off by suction and dried. It is a somewhat yellowish powder which dissolves easily in sodium bicarbonate.

The new compound does not have any real melting point. On heatingit turns dark above 170 C. and decomposition starts at 210-220 C., with frothing. v

In the same way a condensation product, which dissolves readily in bacarbonate to give a clear solution, can be obtained from G-(p-aminobenzenesulphonamido)-2,4-dimethyipyrimidine and glyoxylic acid.

Example 4 25 gm. of 2-(p-aminobenzenesulphonamido)- thlazole are dissolved in 250 com. of hot glacial acetic acid and a warm solution of 15 gm. of glyoiwlic acid ethyl-ester hemi-acetal in 150 com. of glacial acetic acid added. On cooling, a yellowish sticky substance soon begins to separate out, rapidly becoming solid on further cooling. The yield is about 28 gm. The new compound does not melt below 300 0.; above 150 C. it gets darker and darker.

To saponify the ester group, 6 gm. of the substance are dissolved in 30 com. of 2N NaOH and allowed to stand for 20 hours at 20 C. The solution is then neutralized by the addition of 20 com. of 2N HCl and separated from the precipitated amorphous substances. 0n precipitation with alcohol, a compound is obtained, whose properties agree with those of the sodium salt described in Example 1.

What we claim is:

1. A process for the manufacture of a derivative of a para-aminobenzenesulplionamide, comprising treating 2-(para-aminobenzenesulphonamido) thiazole with sodium glyoxylate in a solvent medium whereby the para-amino group of the 2 (para-aminobenzenesulphonamido) thiazole reacts with the aldehyde group of the sodium glyoxylate.

2. The compound obtained by a process consisting in treating 2-(para-aminobenzenesulphonamido) -thiazole with sodium glyoxylate in a solvent medium whereby the para-amino group of the 2-(para-aminobenzenesulphonamidc) -thiazole reacts with the aldehyde group of the sodium glyoxylate.

JEAN DRUEY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name OTHER REFERENCES Chemical Reviews, vol. 27, pages 107-109 and 127-129 (1940).