US2848448A - Nu1-acyl-nu1-(5-ethyl-1, 3, 4-thiadiazole-2-yl)-sulfanilamides - Google Patents

Description

Patented Aug. 19, 1958 Free N -ACYL-N -(S-ETHYL-1,3,4-THIADIAZOLE-2-YL)- SULFANILAIVIIDES Russell E. Rhodes, Glenside, and Blaine M. Sutton, Philadelphia, Pa., assignors to Smith, Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania N Drawing. Application August 23, 1956 Serial No. 605,706

7 Claims. (Cl. 260-23935) This invention relates to a new class of N -(5-ethyl- 1,3,4-thiadiazole-2-yl)-sulfanilamide derivatives of unusual therapeutic properties.

More particularly, this invention relates to N -acyl- N S-ethyl- 1 ,3,4-thiadiazole-2-yl) -su1fanilamides .represented by the general structural formula:

where I R C 0 represents an alkanoyl group. As a practical matter the N -acyl group must be the acyl portion of a nontoxic acid.

The lower saturated alkanoyl (preferably of from 2 to 6 carbon atoms) derivatives are of particular advantage. The alkyl group (R) is advantageously chosen of low molecular Weight so that the proportion of active N -(5-ethyl-l ,3,4-thiadiazole-2-yl) -sulfanilamide released per dosage unit of drug is high, thereby enabling administration of large amounts of active medicament in a dosage form of convenient size for the patient. In this regard the compound where R represents methyl is the compound of choice.

The compounds of this invention have utility as chemotherapeutic agents, particularly as antibacterial agents active against both Gram negative and Gram positive organisms. Exemplary of such organisms are Micrococcus pyogenes var. aureus, Micrococcus pyogenes var. albus, Streptococcus pyogenes, Diplococcus pneumoniae, Escherichia coli, Aerobacter aerogenes, Proteus vulgaris, and Salmonella typhosa. Further, these compounds have particularly favorable characteristics which make them valuable in medical practice.

N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is excreted rapidly from the body. This necessitates repeated doses of the drug to provide adequate therapeutic effect. The compounds of this invention have been found to give prolonged blood and urine levels of active medicament upon oral administration.

The sulfa family of chemotherapeutic agents is generally accepted to be detoxified in vivo by acetylation on the N atom. These N compounds are inactive biologically. Contrariwise, the synthetic N -acyl derivatives which are the object of this invention are antibacterially active on ingestion and give sustained therapeutic blood levels of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide.

It is readily apparent to one skilled in the art that a drug form that gives prolonged therapeutic blood levels is of great advantage in medical practice. This unexpected property of the compounds of this invention enables the doctor to administer the drug, for example, twice a day rather than at four or six-hour intervals. The great advantage of such a dosage regimen is the security of therapeutic blood levels twenty-four hours a day with two doses. Another important advantage is convenience to the patient. A sustained blood level of active medicament is maintained rather than the peak and valley etfect of the multiple daily administration of current medical practice.

Further, these compounds are quite palatable when compared with the disagreeable taste of the parent compound, N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide. Therefore, the drug may be administered by preparing suitable pharmaceutical forms, such as tablets or suspensions for oral use.

The compounds of this invention are prepared by reacting N -(S-ethyl-l,3,4-thiadiazole-2-yl)-sulfa.nilamide with an acylating agent, preferably an acid anhydride, in the presence of an inorganic or a tertiary organic base such as pyridine, collidine, tributylamine 'or sodium carbonate in .an inert organic solvent for the sulfanilamide such as dimethylformamide, water, acetone or a water-acetone mixture, preferably at relatively low temperatures, for instance from 030 C. It is apparent that the base may be present in equimolar quantities or in excess. In the latter case, the base may serve as the reaction medium as well. Since the N -acyl derivatives in solution tend to rearrange to the N atom under the influence of heat, the use of hot solvents during the preparation of the N -acyl derivatives should be avoided.

The compounds of this invention are also prepared by acylating the N-(S-ethyl-1,3,4-thiadiazole-2-yl)-4-nitrobenzenesulfonamide with an acyl halide or acyl anhydride in an inert organic solvent for the sulfonamide, for example, acetone or dimethylformamide, with conditions which may be more forcing than those described previously, such as at higher temperatures, for example, room temperatures to C. Of course this wider range of reaction conditions, namely using higher temperature and the more reactive acyl halides, are applicable since the possibility of N -acylation is not present. The base may be present in equimolar quantities or in excess. In the latter case the base may serve as the reaction medium as well. The resulting N-acyl-N- (S-ethyl- 1,3 ,4-thiadiazole-2-yD-4-nitrobenzenesulfonamide is reduced under mild reduction conditions to the desired N -acyl-N -(5-ethyl-1,3,4- thiadiazole-Z-yl)-sulfanilamide, for example, by catalytic reduction using Adams catalyst or palladium-on-charcoal in an alcoholic medium, such as in ethanol or methanol at low pressures and temperatures. This method is particularly advantageous where acylation at the N position of, N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is more diflicult due to RC=O in the foregoing structural formula being a particularly bulky group, such as a tertiary butyryl or benzoyl moiety.

Alternatively, the N -acyl compounds of this invention can be prepared from the sodium, potassium or silver salt of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide by reaction with an appropriate acyl halide in an inert organic solvent for the sulfanilamide such as acetone, acetonitrile or dimethylacetamide.

The methods of preparing the compounds of this invention will be readily apparent from the following examples:

Example I A suspension of 113.6 g. of N -(5-ethyl-1,3,4-thiadiazole-2-y1)-sulfanilamide in a mixture of 1 l. of acetone and l 1. of water is stirred with 26 ml. of strong ammonia water until a complete solution is attained. The solution is cooled to ()--10 C. and 51 g. of acetic anhydride is added rapidly dropwise. After thirty minutes in the cold, the desired product crystallizes from solution. The product is separated by filtration, washed with Water and cold ethanol to give white crystals of N -acetyl-N -(5-ethyl- 1,3,4-thiadiazole-2-y])-sulfanilamide; M. P. 220-221 C. after preliminary gathering at 137l38 C. The product may be recrystallized from aqueous acetone if desired.

Example II A suspension of 31.6 g. of the sodium salt of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide (prepared by reacting the sulfonamide with one equivalent of sodium hydroxide solution, evaporating the water by freeze-drying and using the salt at once) in 200 ml. of acetone with 12 ml. of tributylamine is stirred vigorously while 14.0 g. of benzoyl chloride is added dropwise over a two-hour period. The crystalline product is obtained by quenching in water and then Washing the precipitate with water to remove the admixed sodium chloride. The crude product, N -benzoyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)- sulfanilamide, is purified by recrystallization from a benzene dimethylformamide mixture.

Example III A suspension of 32 g. of N-(5-ethyl-1,3,4-thiadiazole- 2yl)-4-nitrobenzenesulfonamide in 150 ml. of pyridine is swirled as 13 g. of pivalyl chloride is added dropwise. After standing at room temperature for twelve hours, the reaction mixture is quenched in a large excess of water. The crude solid, N-trimethylacetyl-N-(S-ethyl- 1,3,4-thiadiazole-2-yl)-4-nitrobenzenesulfonarnide, is then suspended in 200 ml. of ethanol with 5% palladium-oncharcoal and hydrogenated at room temperature and 50 p. s. i. The resulting solution is then filtered. The solid thusly obtained is extracted with acetone. After concentrating the combined alcohol-acetone filtrates by evaporation under reduced pressure, a crystalline solid, N -trimethylacetyl-N -(S-ethyl-l ,3,4-thiadiazole2-yl sulfanilam de, is obtained.

Example IV A suspension of 14.2 g. of N -(5-ethyl-1,3,4-thiadiazole- 2-yl)-sulfanilamide in 50 ml. of acetone is acylated with 6.5 g. of propionic anhydride in dimethylformamide with 6 ml. of pyridine at -5 C. The crystalline product, N -propionyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide, is obtained by quenching the reaction mixture in water and recrystallizing the precipitate from aqueous acetone; M. P. 2l9221 C. after preliminary melting at 9910l C.

Example V A suspension of 26.4 g. of crude oleoyl anhydride (prepared by reacting 29 g. of oleic acid with 15 g. of acetic anhydride and removing the volatiles in vacuo) and 14.2 g. of N -(-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is reacted according to the process of Example I-t0 give N -oleoyl-N (S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide after trituration With isooctane in the cold.

Example VI -butyryl-N 5 -ethyll ,3 ,4-thiadiazole-2-yl) -sulfanilamide is prepared from 14.2 g. of N -(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide and 7.9 g. of butyric anhydride as in Example I to give white crystals; M. P. 219-221 C. after preliminary melting at 120-122 C.

4 Example VII N -phenylacetyl-N -(S-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 28.4 g. of N -(5-ethyll,3,4-thiadiazole-Z-yD-sulfanilamide and 25.4 g. of phenylacetic anhydride as in Example I, but using 4 ml. of pyridine as a base. The crude product is recrystallized from a benzene-dimethylformamide mixture.

Example VIII A solution of 21.4 g. of carbobenzoxyglycyl chloride in dry ethyl ether is added dropwise to a stirred suspension of 31.4 g. of N-(S-ethyl-l,3,4-thiadiaZole-2-yl)-4-nitrobenzenesulfonamide in ml. of dried ethyl acetate with 9 ml. of pyridine. The reaction mixture is concentrated in vacuo and cooled. The resulting precipitate is then separated, washed with water and dried in vacuo.

The crude N-carbobenzoxyglycyl-N-(5-ethyl-l,3,4-thiadiazole-Z-yl)-4-nitrobenzenesulfonamide is suspended in 350 m1. of ethanol and hydrogenated at low pressure and temperature in the presence of palladium black catalyst. The catalyst is separated by filtration. Concentrating the filtrate and cooling yields a white solid, N -glycyl-N -(5-ethyl-l,3,4-thiadiazolc-2-yl)-sulfanilamide by fractional crystallization.

Example IX N -isobutyryl-N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 14.2 g. of N -(5-ethy1-l,3,4- thiadiazole-Z-yl)-sulfanilamide and 7.9 g. of isobutyryl anhydride as in Example I to give white crystals from aqueous acetone, M. P. 21922l C. after preliminary melting at l24125 C.

Example X N -stearoyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 14.2 g. of N -(5-ethyl-l,3,4-thiadiazole-Z-yl)-sulfanilamide and 27.5 g. of crude stcaric anhydride as in Example V to give white crystals from an isooctane-acetone mixture.

Example XI N -caproyl-N -(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 28.4 g. of N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide and 21.4 g. of n-caproyl anhydride as in Example I but using tributyl amine as the basic reactant to give white crystals from aqueous acetone.

What is claimed is:

is a member selected from the group consisting of saturated alkanoyl having from 2 to 6 carbon atoms, benzoyl, oleoyl, phcnylacetyl, glycyl and stearoyl.

2. Compounds in accordance with claim l characterized in that is acetyl.

3. Compounds in accordance with claim 1 characterized in that is propionyl.

4. Compounds in accordance with claim 1 characterized in that is butyryl.

5. Compounds in accordance with claim 1 charactcrized in that RC=O is isobutyryl.

6. Compounds in accordance with claim 1 character- 10 ized in that m -0 is caproyl.

7. Compounds in accordance With claim 1 characterized in that R(J=O is saturated alkanoyl having from 2 to 6 carbon atoms.

References Cited in the file of this patent UNITED STATES PATENTS

Claims (1)

1. COMPOUNDS REPRESENTED BY THE FOLLOWING FORMULA: