J. M. SPRAGUE, R. M. LINCOLN AND CARLZIEGLER
266 [CONlRIBUTION FROM
THE
DEPARTMENT O F ORGANIC
CHFiMISTRY,
MEDICAL &SEARCH DIVISION,SHARP
VoI. 68 AND
DOHME,
INC.]
Carboxy Derivatives of Sulfonamidothiazoles BY JAMES M. SPRAGUE, ROBERTM. LINCOLN AND CARLZIEGLER
A number of N4-carboxyacyl derivatives' of the sulfa drugs have been found to be active antibacterial agents in the intestinal tract.2 N4-pcarboxypropionyl and Na-o-carboxybenzoylsulfathiazole have proved particularly u ~ e f u l . ~ Further study of agents of this type led to the preparation of carhoxy derivatives of sulfathiazole in
amide residue free. These compounds are largely carboxy or carboxymethyl derivatives4 and are recorded in Table I together with intermediate compounds obtained in the syntheses. Related sulfonamide compounds are given in Table I1 and additional compounds are described in the experimental part.
TABLE I DERIVATIVES O F SULFATHIAZOLE, ~-SULFANILAMIDO-(R)-THIAZOLE M. P., (uncor.)
R
OC."
Formula
Max. -Percentage compositionNitrogen, % Chlorine, % c0nc.b Calcd. Found Calcd. Found mg./100 cc.
In vitroC antibact. ratio
4-Cartoxyd 238-242 1/1800 13.96 . . . ... 1.9 Hydrochloride 200 .... 12.71 10.55 10.25 .. 192-193 7.8 4-Carbethoxy 12.99 . . . 1/ 5 ... 176-178 N4-Acetyl, 4-carbethoxy 11.34 . . . .... ... .. 210-2 15 1/25O 14.01 5-Carboxy' 2.7 , . . ... 217 Hydrochloride .... 12.45 10.55 10.52 .. 201-203 .... 5-Carbethoxy 12.50 ... ... .. 225-227 .... N*-Acetyl, 5-carbethoxy' .. 11.50 . . . ... 190-2OOi 1/30 4-Metliyl-5-carbo~y~~~~~ 13.32 . . . 8.t; ... 230-233 .... 12.20 10.14 10.03 Hydrochloride .. 1/8900 162-163 .. 4-Carboxymethyl hydrochloride 11.87 10.14 9.61 1 1 .... N4-Acrty1, 4-carbetho~ymethyl'~~ 168-16gk .. 11.05 238-244 2.5 1!3400 4-Methyl-5-carboxymethyl 12.70 ... ... .... 234-238 Hydrochlioride .. 11.46 9.75 9.74 1/90 4-Methyl-5-carbethoxymethyl' 183-184 4.4 11.67 . . . ... "-Ace tyl,4-methyl-5-carbethoxy201-202 .. .... methyl' CisHieOsNaSa 10.58 10.63 1 248-252 CiiHsOeNaS2 12.25 12.25 . . . ... 1 .:3'n 1/4500 4,5-Dicarboxy 155-156 1/1200 4,s-Dicarbethoxy 11.8 CisHi,OeN& 10.52 10.46 ... ... X1-Acety1, 4,5-dicarbethoxy 187-189 .... ... C ~ ~ H I ~ O ~ S 9.52 ~ S Z 9.55 ... . . . 1/400 184-1 86" CizHiiOfN& 11.75 11.74 ... 4.7 4-Carboxymei hyl-5-carboxy ... .... 184-1 85 Ci2Hiz0~S&C1 10.66 10.42 9.05 9.17 Hydrochloride ... N4-Acetyl, 4-carbethoxymethyl-5.... 245-246 ... carbethoxy .. 1/1400 302-305 6-Carboxybenzo .... 262-263 6-Carbethoxybenzo Most of the carboxy compounds and hydrochlorides melt with decomposition; the exact temperature varies with the condition of heating. * Maximum blood level attained in mice following oral administration. Unless otherwise designated, the dose was 2.5 g./kg. The maximum level was reached in all cases two hours after administration. Bloodlevels for standard drugs were: sulfathiazole (1.0 g./kg.) 18.3 ; sulfaguanidine (1.0 g./kg.) 4.8; succinylsulfathiazole Activity against E. coli expressed as a fraction of the activity of sulfathiazole. The activities of (2.5 g.,'kg.) 3.5. standard drugs were: sulfathiazole 1.0; sulfaguanidine 1/52; succinylsulfathiazole 1/5500. Backer and de Jonge, Rec. trr.v. chim., 60, 495 (1941). E Harris and Finland, Proc. SOG. Exptl. BioE. Med., 58, 116 (1945). Ganapathi, DeliJensen and Thorsteinsson, wala and Shit-sat, Proc. Indian Acad. Sci., 16A, 126 (194)Z. g British Patent 517,272. Daitsk Tids. Furm., 15, 41 (1941). A sample of 2-sulfanilamido-4-methylthiazole formed by decarboxylation melted Obtained as monohydrate on recrystallization from a t 235-237". i Anal. for C2Hb0, calcd.: 11.7. Found: 11.23. dilute alcohol; m. p. 130-135O. Anal. for C2Hs0, calcd.: 11.32. Found: 101.16. Dose 4.0 g./kg. A sample of 2-sulfariilamido-4-methylthiazole formed by decarboxylatton melted a t 236-237 .
'
'
'
which a carboxy group is part of the thiazole portion thus leaving the amino group of the sulfanil(1) Moore and Miller, THISJOURNAL, 64, 1572 (1942). (2) Poth, Knotts, Lee and Inui, Arch. Surg.. 44,287 (1942); Poth and Rosi, Tex. X p t . B i d . Med., 1, 345 (1943) (3) Poth and Knotts, Arch. Surg., 44, 208 (1942); Poth, Ter. Slate J. ,!-fed., 39,369 (1943); Poth and Ross, J. Lab. Clin. M e d . , 29, 785 ( l 9 i t ) .
Most of the compounds were prepared through the reaction of the ethyl ester of the appropriate 2-aminothiazole carboxylic acid with N-acetylsulfanilyl chloride or p-nitrobenzenesulfonyl chlo(4) Some of these compounds or derivatives have been reported in foreign literature. References are given in the footnotes to the tables. No biological data have appeared previously.
Feb., 1946
CARBOXY DERIVATIVES OF SULFONAMIDOTHIAZOLES
267
TABLE I1 SULFONAMIDOTHIAZOLES
thiourea limits the usefulness of this method. Foldi, et a1.,6have recently described this method for the preparation of sulfathiazole derivatives M. P., Z-Sulfonamido-( )'C.,= Nitrogen, % including a carboxy compound by the use of ethyl thiazole uncor. Formula Calcd. Found a-chloroacetoacetate. Z-Benzenesulfonamido-( )-thiazoles The various sulfonamido-carboxythiazoles 9.01 4-Carbethoxy 124-125 C ~ H I Z O ~ N Z S8.97 Z (Tables I and 11) exhibit marked differences in 4-Carboxy 264-265 CioHaOiNzSz 9.85 9.74 stability and ease of decarboxylation depending 4-Methyl-5-carbethoxy 186-187 CiaH1404NzSI 8.59 8.55 4-Methyl-5-carboxy 209-210 CiiHioO~NzSz 9.40 9.39 upon the position of the carboxy group. In an effort to correlate this property with pharma2-p-Nitrobenzenesulfonamido-()-thiazoles cological and bacteriological results, quantitative 4-Carbethoxy 162-164 CizHiiOahTaSz 11.76 11.65 4-Carboxy 268-270 CioH7ObNaSz 12.76 12.72 decarboxylations were carried out in quinoline. 4-Methyl-5-carbethoxyA carboxy group attached directly to the thiazole Ci4Hi606NaSz 10.90 10.86 methyl 184-185 nucleus a t the 5-position was very labile; carbon 9.76 CisHisOsNaSi 9.78 4,s-Dicarbethoxy 129-130 dioxide was evolved readily a t temperatures as CiiHiOsNaSz 10.74' 10.66 4,6-DicarboxyC 210-220 250-255 low as 80' and the product was isolated and identified. However, a carboxy group in the 42.m-Nitrr,benzenesulfonamido-()-thiazoles position was relatively stable; evolution of carbon 4-Carbethoxy 123-127 CizHiiOsNaSz 11.76 11.63 dioxide occurred only when the temperature was 4-Carboxy 278-281 CioHiO6NaSz 12.76 12.77 4-Methyl-5-carbethoxyraised to 210-225' and no identifiable product CuKi&OsNaSz 10.90 10.66 methyl 171-172 could be isolated. The 2-amino- and 2-methylCiaHisOsNaSz 9.78 9.71 4,5-Dicarbethoxy 115-116 monocarboxythiazoles, which were included for CiiHiOaNaSz 10.74d 10.73 4,5-DicarboxyJ 190-196' comparison, behaved similarly. 2-Sulfonamidoa Most of the carboxy compounds melt with vigorous effervescence. The temperature a t which this occurs de- 4,5-dicarboxythiazoles, as well as the 2-amino pends largely on experimental conditions such as rate of and 2-methyl analogs, lost only the 5-carboxy heating. Many show multiple melting points due to group ; the corresponding 4-monocarboxy comhydrate formation or decarboxylation. * Monohydrate. pound was identified as the product.0 Conditions c Very soluble in hot water (5.0 g. per 30 cc.) crystallized in heavy block crystals; solubility much less in dilute necessary for further evolution of carbon dioxide hydrochloric acid and on crystallization gives hair-like resulted in complete decomposition. needles. Decarboxylates a t 228-230" to give the 4When the substituent group in the thiazole monocarboxy compound together with some 2-#-nitro- nucleus was carboxymethyl, the order of stability benzenesulfonamidothiazole; m. p. 254-256 '. Mono; was reversed. A 5-carboxymethyl group was hydrate. e Efferwsces 190-195 ", solidifies around 200 and remelts with effervescence 265-275 . Some samples relatively more stable than a 4carboxymethyl when heated rapidly effervesced or sintered slightly around group; a higher temperature was required to 160-165 '. Solubility similar to #-nitro compound. bring about decarboxylation and the evolution Heating t o 200-208 caused evolution of carbon dioxide and gave the 4-monocarboxy compound which melted with of carbon dioxide was incomplete. 2-Sulfanilamido-4-carboxymethyl-5-carboxythiazole readily effervescence a t 2713-280". underwent complete decarboxylation a t PO-100' ride in pyridine solution. Hydrolysis of the prod- to give 2-sulfanilamido-4-methylthiazole. uct of this reaction, or reduction and hydrolysis At the time these studies were initiated, the in the case of the nitro compounds, gave the results that were reported in the literature on the desired carboxy compounds. An alternative pro- decarboxylation of thiazolecarboxylic acids were cedure proved useful in some cases. This pro- conflict in^.^ All of our results are in accord with cedure is represented by the following scheme for recent work8 on other compounds and, in contrast the preparation of 2-sulfanilamido-4,5-dicarboxy- with the earlier reports, show that the substituent thiazole. in the 2-position of the thiazole ring does not inS CHCI-COzC2H5 fluence the relative lability of the carboxy I! I CHsCONH-- C>-SOzh-H-C 4- CO-COzCzHs + group in the 4- or 5-position. I Experimental9 f
r-
CH,CO~-H--()-SO,~-HC~
NHz S-C-COzCzHq I ll ,C-CO~C~H~ + N COZH
All of the 2-aminothiazoles that were used as inter; mediates in this work have been described in the iit-
( 5 ) Foldi, Gerecs, Demjen, and Konlg, U. S. Patent 2.332.906 (1943). (6) Roubleff, A m . , 259, 275 (1890), was unable to isolate any definite product from the decarboxylation of 2-amino-4,jH2N-C)SOZ~H-~ COzH dicarboxythiazole. (7) Koubleff, ibid., 269, 253 (1890); Erlenmeyer and Meyer\r\: burg, H e h . Chim. Acta, 20, 204 (1937); German Patent 658,363 N-Acetvlsulfanilvlthiourea condensed smoothlv ( C . A . , 32, 4727 (1938)); Schoberl and Stock, B e y . . 73,1240 (1940). , . ( 8 ) Schoberl and Stock. ;bid., 73, 1240 (1940); Erlenmeyer and in pyr&ne wit6 halogenated keto esters. TLe Morel, H e h . Chim.A c k 25, 1073 (1942); Erlenmeyer, Ruchmann thiazole thus formed was isolated in a high state and Schenkel, ibid., 27, 1432 (1914); Huntress and Pfister, THIS
I,
of purity and in excellent yields. However, the relative inaccessibility of the N-acetylsulfanilyl-
66, 2167 (1943). (9) AU melting points are uncorrected.
268
J. M. SPRAGUE, R. M. LINCOLN AND CARLZIEGLER
Vol. 68
erature except 2-amino-4-carbethoxymethyl-5-carbethoxy- The yields of all of the other sulfonamidothiazoles listed thiazole. The preparation of this compound and an im- in Tables I and I1 were 75% or more. proved preparation of 2-amino-4-carbethoxythiazole from B. This compound was also prepared in excellent yield commercial pyruvic acid are described below. and in high purity from N-acetylsulfanilylthiourea and Z-Amino-4-carbethoxymethyl-S-carbethoxythiazole.- ethyl ethoxalylchloroacetate. The thiourea derivative One-tenth mole of sulfuryl chloride (13.5 9.) was added was prepared essentially as described by Foldi.6 slowly to 20.2 g. (0.1 mole) of ethyl acetonedicarboxylate. Ethyl ethoxalylchloroacetate (2.23 g., 0.01 mole) was The reaction mixture was stirred and cooled cluring the added t o 2.7 g. (0.01 mole) of acetylsulfanilylthiourea dissolved in 10 cc. of dry pyridine. After the exothermic addition and finally heated on a steam-bath under reduced pressure until there was no further evolution of gases. reaction had taken place, the mixture was warmed gently The crude chloroester was added to a suspension of 7.6 g. on a steam-bath for a few minutes and then was diluted (0.1 mole) of thiourea in 50 cc. of alcohol and the mixture with an equal volume of alcohol. On acidification with was heated to refluxing for thirty minutes. The alcoholic hydrochloric acid and dilution with water, 4.0 g. (91G/o)of solution was poured into 200-300 cc. of cold water, and the light yellow crystalline product separated (m. p. 183-18600). aqueous mixture made alkaline by the addition of sodium After crystallization from alcohol it melted a t 187-189 . carbonate. The 2-amino-4-carbethoxymethyl-5-carbeth- 2-Sulfanilamido-4,5-dicarboxythiazole.-The acetyl deoxythiazole was removed by filtration and dried. The rivative was dissolved in 10% sodium hydroxide solution yield was 21.6 g., 84Cj,. This melted a t 122’, resolidified (5 cc. per g,) and the solution was heated for one hour on a and remelted a t 127-128 . After recrystallization from steam-bath. An equal volume of water was added and the benzene it yelted a t 122-123 ’, resolidified and remelted hot solution was neutralized with concentrated hydroat 129-130 . Keither drying nor fusion changed the chloric acid. After treatment with “Norit” decolorizing charcoal, the hot solution was made strongly acid. The melting point. behavior. A n d Calcd. for C I O H I ~ O ~ J ~NS, : 10.83, CsH50, precipitated product was washed with water and alcohol before drying; yield 87%, m. p. 239” with effervescence. 34.89. F0un.d: N, 10.78, C2HrO. 34.67. Since this substance is very insoluble in water and organic 2-Amino-4-carbethoxythiazole.~~-To 440 g. (2 moles) of solvents, it was purified by dissolving in sodium bicara 40%) aqueous commercial solution of pyruvic acid that bonate solution, treating with “Darco” decolorizing was heated to 70’ and stirred, 352 g. (2.2 moles) of bro- carbon and reprecipitating from the hot solution by acidimine was added during a period of two and one-half hours. fication. This process was repeated several times from Heating was continued for thirty minutes or until the bro- dilute solutions. The product melted a t 251’ with efmine had disappeared. To this solution was added slowly fervescence. This dicarboxy compound is insoluble in with cooling and stirring 200 g. (2.67 moles) of finely pow- acids and does not form a hydrochloride. The other dered thiourea. After standing overnight the hydro- sulfanilamidothiazole compounds in Table I were soluble bromide of 2-amino-4-carboxythiazole had separated and in dilute hydrochloric acid and precipitated crystalline was removed by filtration, washed with acetone and dried. hydrochlorides when excess acid was added to a concenThe yield of crude hydrobromide was 418 g. (calcd. 380 trated solution. In these cases the carboxy compounds g.). This was suspended in 1400 cc. of anhydrous ethanol were isolated after alkaline hydrolysis by careful acidificacontaining 11.0 cc. of concentrated sulfuric acid and the tion to congo red. The addition of excess acid precipisuspension was refluxed for forty-four hours. Nine tated the hydrochloride. They were purified by recrystalhundred cc. of alcohol was removed under diminished lization from dilute alcohol. pressure and 700 cc. of water was added t o the residue. 2-Sulfanilamido-4,5-dicarbethoxythiazole was obtained The turbid solution that resulted was filtered and the by refluxing the hT-acetyl derivative with 2.5 N hydrofiltrate was made alkaline with sodium bicarbonate. The chloric acid in 50y0 alcohol until solution %-ascomplete white crystalline solid which separated was collected on a and, after dilution with water and chilling, precipitating Buchner funnel and washed with water. After drying, the the product with sodium bicarbonate. The mono-carproduct weighed 193 g., m. p. 174.5-175.5”, and the yield, bethosy derivatives were prepared in a similar manner or by calculated from the pyruvic acid, was 56%. the esterification of the corresponding acid using sulfuric Sulfonamidothiazo1es.-The condensation of the sul- acid in dry ethanol. The esters were purified by crystallifonyl chlorides with the 2-aminothiazoles was carried out zation from alcohol or alcohol and water. in pyridine by a modification of the usual procedure. AtDecarboxylations.-One to two millimoles of the cartempts to use the 2-aminothiazole carboxylic acids in boxy compound and 3-5 cc. of purified synthetic quinoline aqueous alkali were unsuccessful under conditions that were placed in an alkoxy1apparatus. The mixture was imwere satisfactory for aminobenzene and aminopyridine mersed in an oil-bath and heated slowly. A rapid stream carboxylic and sulfonic acids.” The following procedure of carbon dioxide-free nitrogen was used to carry the using 2-arnin~~-4,5-dicarbethoxythiazole illustrates condi- evolved carbon dioxide into standard barium hydroxide. tions that gave good results in all cases. The lowest temperature a t which precipitation of barium 2-N~-Acetylsulfanilamido-4,5-dicarbethoxythiazole.-A. carbonate appeared was observed and the heating then To n solution (of 12.2 g. of 2-amino-4,5-dicarbethoxythiazole continued above this temperature. The extent of dein 20 cc. of dry pyridine, 13.0 g. (10% excess) of acetyl- carboxylation was determined by titration of the barium sulfanilyl chloride was added slowly with stirring. The hydroxide with standard acid at various intervals. The solution was allowed to stand at room temperature for six- products of the decarboxylation were isolated from these teen hours. Heating of the reaction mixture caused exces- runs or from larger runs which were carried out for the sive darkening and the production of a large amount of purpose in the same manner. tar. Ten cc. of alcohol was added and the solution diluted 2.-( p-Nitrobenzenesulfonylimino)-3-methyl-2,3-dihydrowith 2056 hydrochloric acid until it was strongly acid to 4-carboxythiazole.-To 3.3 g. (0.01 mole) of the 2-(p-nitrocongo red. The brown crystalline product was removed benzenesulfonamido)-4-carboxythiazolesuspended in 25 by filtration and washed with dilute acid and water. The cc. of water, sunicient 20y0 sodium hydroxide was added yield, after drying, was 11.15 g. or 50%; in. p. 181-184’. to dissolve the solid and then a two-fold excess of sodium After crystallization from dilute alcohol, the melting hydroxide added. With vigorous stirring, 1.5 g. (0.012 mole) of dimethyl sulfate was added dropwise over a period point was 187-189”. Unreacted 2-amino-4,5-dicarbethoxythiazole was re- of fifteen minutes, maintaining strong alkaline conditions covered from the acid filtrate by additiori of sodium by addition of more 20% sodium hydroxide as necessary. Stirring was continued for an additional fifteen minutes, hydroxide until strongly alkaline. after which a small amount of insoluble material was removed. Acidification caused the precigitation of about (10) bteude, A m . , 261, 20 (1801). (11) Crossley Northey and Hultquist, THIS JOURNAL, 60, 2217 3 g. of crude material melting at 237-240 . Recrystallization from dilute alcohol gave 1.4 g. (40yo) of product, (1938): Ewins, f I ol., U. S . Patent 2,259,222 (1941), 2,275,354 (1942), m. p. 255.5256’ with effervescence. 2,335,221 (1943); Kolloff, TXISJOURNAL, 60, 050 (1938).
Feb., 1946
CARBOXY DERIVATIVES OF SULFONAMIDOTHIAZOLES
269
Anal. Calcd. for C1iHeOsN&: N, 12.24, neut. equiv., 343.3. Found: N, 12.25, neut. equiv. 344.6, (phenolphthalein indicator). No attempt was made t o locate deiinitely the methyl group in this compound or any of the compounds that were derived from it. The structure is assigned through analogy with the results obtained when sulfathiazole and related compounds are methylated under similar conditions.12
tion to mice (Table I) and t o degsl' indicate that the introduction of a carboxy group into the heterocyclic nucleus of sulfathiazole greatly reduces the absorption from the gastrointestinal tract. The antibacterial activity, as measured in vitro (Table I), is reduced t o a fraction of the activity of sulfathiazole and is comparable t o the activity of the N4-carboxyacyl derivatives, although in these latter compounds the amino group is blocked. In spite of this lowered in vitro antibacterial activity, many of the com2-Sulfanilylimino-3-methyl-2,3-dihydro4carboxythia- pounds have shown a marked activity in lowering the number of coliform bacteria in the intestinal tracts of rats zo1e.-Two and one-half grams of 2-(p-nitrobenzenesulfonylimino)-3-methyl-2,3-dihydro4-carboxythiazole was and dogs. The 4,5-dicarboxy compound was particularly suspended in 50 cc. of alcohol and 90 cc. of 0.057 N sodium interesting because of the low blood and urine levels and hydroxide was added. One gram of moist Raney nickel the lack of toxicity. Although no exact correlation of the biological results was added to the solution and hydrogenation carried out a t low pressure. Absorption of hydrogen ceased when the with the ease of decarboxylation to the highly active theoretical amount had been taken up. The catalyst was and readily absorbable sulfathiazole or sulfamethylfiltered off, the filtrate concentrated t o half its volume, and thiazole can be made, the most labile compounds gave the product precipitated by neutralization; yield 1.8 g. slightly higher blood levels and exhibited greater anti(82%) of crude product, m. p. 230-231 with effervescence. bacterial activity. The extreme ease with which the 4Recrystallizationofrom dilute alcohol raised the melting methyl-5-carboxy compound undergoes decarboxylation undoubtedly accounts for the high blood level and relapoint t o 235-236 . high activity of this compound. The instability Anal. Calcd. for CllH110~N&: N, 13.41. Found: tively makes difficult the preparation of material completely free N, 13.39. of sulfamethylthiazole and also probably results in the 2-( N-p-Carboxypropionylsulfanilimido)-3-methyl-2,3-diformation of sulfamethylthiazole during the tests. Of the hydro-4-carboxythiazole.-Three and one-tenth grams two dicarboxy derivatives, the greater lability of the 4(0.01 mole) of 2-sulfanilimido-3-methyl-2,3-dihydro-4-car-carboxymethyl-5-carboxy compound results in a higher boxythiazole and 1 g. of succinic anhydride were heated activity and greater absorption than is the case for the 4,5under reflux for twenty minutes in 20 cc. of dioxane. dicarboxy derivative. The very low activity of the 4Soon after all the solid had dissolved the product began to carboxymethyl compound, which is also very easily decarcrystallize. The suspension was chilled and filtered. The boxylated, is unexpected. Reyield was 3.5 g. (877,) of product, m. p. 185-188'. On oral administration to mice with experimental strepcrystallization from ethanol gave an alcoholate which when tococcal or pneumococcal infections, none of these sulfadried for four hours at 140O in vacuo gave a product melting nilamido-carboxythiazoles showed therapeutic activity; a t 208-210' with effervescence. the esters were slightly active against the streptococcal Anal. Calcd. for CljHljO7N&: N, 10.16. Found: infections. 10.14.
Summary 2-(N-Acetylsulfanilylimino)-2,3-dihydro-3,4-dimethyl-Scarbethoxymethylthiazole was prepared by dissolving 4 g. (0.01 mole) of 2-N-acetylsulfanilamido4-methyl-5-car- Derivatives of sulfathiazole having carboxy or bethoxymethylthiazole in dilute sodium hydroxide solution carboxymethyl groups in the thiazole nucleus and adding 1.5 g. (0.012 mole) of dimethyl sulfate dropwise have been prepared. with stirring while chilling the reaction mixture in an iceThe carboxy derivatives showed a much lower bath. The product precipitated fro: solution. The yield was 2.0 g. (.joo/o); m. p. 190-194 Recrystalliza- antibacterial activity than sulfathiazole when tested in vitro. Certain of the compounds gave tionofrom 70% alcohol yielded a product melting at 202203 . low blood levels following oral administration to Anal. Calcd. for C17Hz10&N&: N, 10.21. Found: animals and exhibited marked antibacterial 10.14. activity in the intestinal tracts. Hydrolysis of this product in dilute sodium hydroxide Decarboxylation studies showed that a carboxy did not give a well defined product. group in the 5-position or a carboxymethyl group Biological Data's in the 4-position of the thiazole ring is very labile. The blood concentrations following the oral administra- A 4carboxy or a 5-carboxymethyl group is rela-
.
(12) Druey, Helu. Chim. Acta, 24, 226 (1941); Hartman and Druey, i b i d . , 24, 536 (1941); Jensen, rbid., 24, 1249 (1941); Jensen and Thorsteinsson, Dansk T i d s . Farm., 16, 41 (1941); Shepherd, JOURNAL, 64, 2532 (1942). Bratton and Blanchard, THIS (13) We are indebted to the Departments of Bacteriology and Pharmacology of there Laboratories and t o Dr. E. J. Poth, University of Texas Medical Branch, Galveston, Texas, for these data.
tively stable. Substituents in the 2-position do not influence the relative lability of a 4- or 5carboxy group. GLENOLDEN, PA.
RECEIVEDNOVEMBER17, 1945
(14) Poth and Ross, J. Lab. Clin. Mcd., SO, 843 (1945).
