[FROM TIIE DEPARTMENT OF ORQANIC CHEMISTRY , MEDICALRESEARCH DIVISION, SHARP AND DOHME, INC.]
DERIVATIVES OF SULFATHIAZOLE A. H. LAND, CARL ZIEGLER,
AND
JAMES M. SPRAGUE
Received Mal! 9 , 1946
A number of derivatives of sulfathiazole having alkyl or aryl substituents in the thiazole nucleus have been synthesized and shown to possess antibacterial activity (1). Other properties, however, render this type of derivative unsuitable for chemotherapeutic use. In view of this adverse effect of the alkyl and aryl groups, a study has been made of the properties of sulfathiazole derivatives containing functional substituents in the thiazole ring. The results reported in previous papers (2, 3) have shown that the introduction of a carboxylic acid group reduced tl?e antibacterial activity and also restricted absorption from the intestinal tract following oral administration. Compounds of t h k type may be useful therapeutic agents, particularly where limited absorption is desirable (3, 4). The present paper describes the preparation and properties of sulfathiazole derivatives having a tert.-amino, mercapto, or hydroxyl group on the alkyl substituent of the tliiazole nucleus. Recently me have described methods for the preparation of 2-aminothiazoles with aminoalkyl, alkylmercaptoalkyl, or hydroxymethyl substituents (5, 6 ) . In general, these compounds formed sulfonamides by reaction with a sulfonyl chloride in the presence of pyridine. The solubility characteristics of the sulfonamido-tert.-aminoalkylthiazoles necessitated some modification of the usual isolatiion procedure and the products were handled more satisfactorily as salts. The synthesis of fort.-aminoalkylsulfathiazolesthrough the reaction of N-acetylsulfanilylthiourea with a-bromo-tert.-amino ketone salts was unsatisfactory. Although 1-bromo-4-dimethylamino-2-butanonehydrobromide afforded a very low yield of 2,PI;4-acetylsulfanilamido-4-(2-dimethylaminoethyl)thiazole hydrobromide by this method, no sulfonamide was isolated when several other bromoamino ketone salts were used. This type of synthesis of sulfathiazole derivatives has been employed successfully by Foldi and co-workers (7) with a variet:y of a-halogen carbonyl compounds. The condensation of N-acetylsulfanilyi chloride with 2-amino-4-[2-(1,2,3 ,4tetrah,ydroisoquinolino)ethyllthiazole,2-amino-4-dimethylaminomethylthiazole, 2-amino-4-hydroxymethylthiazoleand bis-(2-amino-4-thiazolylmethyl)disulfide gave only tars or poorly defined amorphous solids. Since the sulfonyl chloi ide condensation with 2-amino-4-hydroxymethylthiazole failed, 2-sulfanilarnido-4-hydroxymethylthiazole was prepared in low yield l3y the methcd of Foldi (7) through the reaction of N-acetylsulfanilylthiourlea with a,?-dichloroacetone follo.vted by hydrolysis of the chloromethyl compound. Sulfapyridine and sulfadiazine derivatives having a free amino group in the heterocyclic nucleus (8, 9 , 10) as well as disulfanilamidopyridine (9) and disulfani lamidopyrimidine (10) have been described. The preparation of anal617
618
LAND, ZIEGLER, AND SPRAGUE
ogous compounds in the thiazole series by the usual procedures would require a diaminothiazole as a starting material. The hydrochloride of one such diamine was obtained by the reaction of chloroacetonitrile and thiourea in hot alcohol solution. The product may be represented as 2,4-diamincthiazole (IT). The reaction probably proceeds through S-cyanomethylisothiourea (I) which has been prepared previously (11) by carrying out the reaction in acetone a t room temperature. The isothiourea readily yielded I1 on warming in alcohol solution. Although the product of these reactions can be formulated as the diamine 11, its chemical properties more nearly agree with those expected of the amineimine 111.' Hydrolysis under mild conditions yielded 2-amino-4-thiazolone (IV). The reaction of the hydrochloride of I1 with either one or two equivalents of K-acetylsulfanilyl chloride in pyridine gave a black amorphous product that TABLE I 2-SULFANILANIDO-R-THIAZOLES XAX. BLOOD CONC! UC./lM) aa.
R
SN'
5400 4-Piperidinomethyl 5398 4 - (2-Dimethylaminoethyl) 5392 4-Dimethylaminomethyl4,5,6,7-tetrahydrobenzo 8462 4-Ibfethylmercaptomethyl 4-Ethylmercaptomethyl 4-Hydroxymethyl 1649 4,5,6,7-Tetrahydr~benzo~ 106 4-Methyld 103 H (Sulfathiazo1e)d ~~
~
I n Vitro6 ANTIBACTERXAL A"lTIES
1.1 2.9
0.10 0.06
2.3 20.5 11.9 8.0 2.2
0.20 0.70 0.50 0.04 0.20
12.6
0.90
18.3
1.00
~
See footnote 3. Maximum blood concentration of drug attained in mice following the oral administration of 1.0 g./kg. The concentration reached the maximum two hours after the dose. e Activity against E . coli expressed as a fraction of the activity of sulfathiazole. d Known compounds used as standards for comparison. a
b
resisted purification. Hydrolysis of this material gave 2-sulfanilamido-4thiazolone (V)which had been prepared (12) previously from 2-amino-4-thiazolone (IV). The antibacterial activities against E. coli in vitro and the blood concentrations following oral administration to mice are summarized in Table I.' The introduction of the hydroxymethyl group or dialkylaminoalkyl groups into sulfathiazole caused a marked reduction in activity when compared with sulfathiazole or sulfamethylthiazole. On the other hand, the introduction of a dimethylaminomethyl group in the 4-position of 2-sulfanilamido-4,5,6,7-tetrahydrobenzothiazole did not alter the activity. The alkylmercaptomethyl 1 Since this work was completed, a German Patent has described t h e preparation of 2,4-diaminothiazole from thiourea and a haloacetonitrile; Ger. P a t . 729,583;cf. Chem. Abstr., 38, 382 (1944). e We are indebted t o the Departments of Bacteriology and Pharmacology of this laboratory for the biological data. (Table I.)
619
DERIVATIVES OF WJLFATRIAZOLE ”2
I
CSCHzCN
II
NH
‘I S-CH HzN-C
I
S-CH2
I
C-NH, ”/
A
H2N-C
I
\N/
11
I11
I 1
I 1
S-CH2
I
I
I
C-NH
S-CHZ
H2N-C I L H~N(T>SO~NHC c=o \N/ NN’
v
O
IV
compounds shewed activities higher than those of the tert.-aminoalkyl derivatives and comparable with the activity of sulfathiazole. The concentration of drug in the blood following oral administration to mice of a single dose reached only very low levels with the amino derivatives, a somewhat higher level with the hydroxymethyl compound, and high levels with the two alkylmercapto derivatives. Again, the presence of the dimethylaminomethyl group in the tetrahydrobenzothiazole compound had little ir.fluence; the parent compound and the substituted derivative gave comparable blood levels. Urinary excretion studies in dogs showed that the low blood concentration of the amino derivatives was due not alone to poor absorption from the gastrointestinal tract but also to rapid renal elimination. Two compounds, 2-sulfanilamido-4-piperidinomethylthiazoleand 2-sulfanilamido-4-dimethylaminomethyl4 5 , 6 j,7-tetrahydrobenzothiazole, were excreted in the urine to the extent of 30-60 % of the administered dose in 72 hours. These values lie between those obtained with succinylsulfathiazole (12-26%), or phthalylsulfathiazole (1216%)) and sulfaguanidine (60%). With the exception of the mercapto derivatives, none of the compounds exhibited any significant therapeutic activity against experimental streptococcal or pneumococcal infection in mice. Some of these compounds and the itermediate 2-aminothiazoles were tested also in avian )
a These tests were carried out by the Survey of Antimalarial Drugs of the National Research Council. The survey number (SN in Table I) identifies the compound in a forthcoming monograph, A Survey of Antimalarial Drugs 1941-1945. The activity and pharmscology will be given in this monograph.
620
LAND, ZIEOLER, AND SPRAOUE: EXPERIMENTAL'
The aminoalkyl-2-aminothiazoles(5, 6) were dissolved in dry pyridine and cooled in an ice-bath while a 10% excess of N-acetylsulfanilyl chloride was added in small portions. The solutions were kept overnight a t room temperature and then distilled i n uacuo at 50-60' to remove most of the pyridine. Since the free bases tended to form oils, the products were converted to crystalline salts by the addition of an ewes9 of aqueous hydrochloric or hydrobromic acid. The acetylsulfanilamido derivatives of the alkylmercaptomethylthiazoles (5) were prepared and isolated in the usual manner (13). Deacetylation to the sulfonamido derivatives was effected by heating the acetyl derivatives for tn-o to four hours on a steam-bath with aqueous sodium hydroxide or hydrochloric acid or by refluxing with alcoholic hydrogen chloride solution. 2-Sulfanilamido-4-piperidinomsthylthiazole.The hydrochloride of the acetyl derivative usually crystallized out of the pyridine solution. Occasionally, however, i t was necessary to concentrate the solution. The hydrochloride was dissolved in cold dilute sodium hydroxide solution and reprecipitated by the addition of an excess of concentrated hydrochloric acid. After recrystallization from dilute alcohol, i t melted at 253-255" dec., yield 40%. Anal. Calc'd for C1&2NaO&.IICl: C1, 8.23. Found: C1, 8.17. The acetyl derivative was hydrolyzed with 3 N hydrochloric acid and the free base was precipitated by neutralizing the solution with sodium hydroxide; yield 85%. An analytical saniple, r1i.p. 209.5-210.5" dec., was prepared by recrystallization from dilute methanol. AmZ. Cslc'd for C I S H P Q S I O LC,S ~51.16; : H, 5.73; N, 15.90. Found: C, Fj0.96; 11, 5.33;S , 15.78. ; ? - ~ u l f a n i l a ? ; ~ i 3 o - 4 - ~ ~ - d i m ~ t h ~ ~ l n r n i n o z t kThe ~ ~ l ~pyridine ~ h i a ~ o l reaction e. mixture was filtered to rexove :I solid tLat 'uas found t o be the hydrochloride of the aminothiazole. The sclid n-as xashed nith a little ethanol and the combined filtrate and washings were concentrated i n vacuo. The residue was diluted with water axd made strongly acid with 48% hydrobromic acid. The hydrobromide separated sloc-ly as a yellow powder. Recrystalliz:ition from water gave light yellow needles, m.p. 230-231' dec., yield 4070. A n d . Calc'd for C1J&0X4Q3&.€IBr: N, 12.47; Br. 17.79. Found: N, 12.39; Br, 17.72. The acetyl derivative was hydrolyzed with 10% sodium hydroxide solution. The hemihydrate of the sulfonamide, 1n.p. 164-165" dec., was obtained in 72% yield after rccrystallization from water. A rapidly cooled water solution of this compound gave crystals, m.p. 179-180", that reverted to the lower-melting form on subsequent crystallization from a don-ly cooling solution. Dehydration zn e'acuo was accompanied by the evolution of dimethylamine and resinification of the residue. Anal. Czlc'J for (C1SHISS*02S2)2.HiO:X, 1G.71. Found: X, 16.79. 2 , p-NitrobenzencsulfonaniirEo-4-dimethyl~minomet~~~l-~,~,6, '7-tetrahydro3enzothiazolewas prepared by addirg one molecular equivalent of p-nitrobenzenesulfonyl chloride to a pyridine solution of the aminothiazole. After standing overnight a t room temperature the reaction mixture was dissolved in dilute sodium hydroxide solution and the hydrochloride of the sulfonamide was precipitated by the addition of an excess of concentrated hydrochloric acid. Recrystallization from very dilute hydrochloric acid gave a 63% yield of bright yellow crystals, m.p. 237-235" dec. N, 12.91; C1, 8.19. Anal. Calc'd for C1~H~~N.IOIS(.HC1: Found: K,12.85; C1, 8.17. 2-Su~anilamido-~-dzmethylamin~m~th~l-~,5,6,7-t~trah~drobenzothiazole. A . The residue obtained after t?ie removal of pyridine was diluted with water and neutralized with sodium hydroxide. The dark oily precipitate slowly changed to a cotton-like mass of crystals. The moist product dissolve3 readily in 6 N hydrochloric acid and a copiolls pre4
All melting points are uncorrected.
DERIVATIVES OF SULFATHIAZOLE
621
cipitate of the crystalline hydrochloride monohydrate of the acetyl derivative separated almost immediately; yield 45%. White crystals, m.p. 226-228' dec., were obtained by crystallization from 95% alcohol. Anal. Calc'd for C:~HZ,N~O,S~.HCI.H,O: N, 12.12; C1, 7.66. Found: N, 12.08; C1, 7.70. The deacetylation was carried out in 6 N hydrochloric acid. The sulfanilamido compound was obtained as a monohydrate, map.156-158" dec., by recrystallization from water. Anal. Calc'd. for C : ~ H Z ~ N ~ O B ~ N, . H ~14.57. O : Found: N,14.37. B. 2,p-Nitrobenzenesulfonamido-4-dimethylaminomethyl-4,5,6,7-tetrahydrobenzothiazole was reduced with iron and 8% acetic acid and the amino compound wm recrystallized from water. The melting point and mixed melting point showed that i t waa identical with the sulfanilamido compound prepared from acetylsulfanilyl chloride. The free base formed complexes with many of the common solvents and the removal of solvent was always accompanied by evolution of dimethylamine. The dihydrochloride, m.p. 214-216' dec., separated as white crystals when a solution of the frets base in methanolic hydrogen chloride solution was diluted with ethyl acetate. The yield, based on the acetyl derivative, was 89%. Anal. Calc'd for C:tH&aO.S2.2HCl: N, 12.75; C1, 16.14. Found: N, 12.62; C1, 16.19. &-Sulfanilamido-~-piperzdznomsthyl-4,6,6,7-tetrahydrobenzlothiazole.The hydrochloride dihydrote of the acetyl derivative was obtained as a crystalline solid by diluting the residue from the pyridine distillation with water and adding an excess of concentrated hydrochloric acid. Recrystallization froin water gave a 57% yield of pale yellow crystals that melted with decomposition a t about 160' in a rapidly heated bath. Anal. Calc'd for C ~ : H Z B N ~ O ~ S Z . H C I C1, . ~ H6.81. ~ O : Found: C1, 6.88. Hydrolysis with 6 N hydrochloric acid gave the sulfanilamido derivative which was precipitated by neutralizing the hydrolysis mixture and purified by recrystallization from a large volume of methanol; yield 5570, The pure compound melted at 189-190" dec. Anal. Calc'd for Ci~H?aN40zSz: C, 56.16;H, 6.45; N, 13.80. Found: C, 55.47; 13, 6.59; N , 13.56. 8-Sulfanilamido-~-methylmercaptomethylthiazole. The crude acetyl derivative was difficult to crystsllize. After most of the pyridine was removed by distillation i n vacuo, the residue was diluted with water and adjusted to pH 5 with sodium hydroxide. Concentration of the resulting solution in vacuo left a gummy residue that solidified slowly. After two reprecipitations from sodium hydroxide solution by acidification with hydrochloric acid the sulfonamide separated in crystalline form. Crystallization from dilute ethanol gave a 70% yield of white product, m.p. 216-218'. Anal. Calc'd for C1311:bNJ0&: N, 11.76. Found: N, 11.67. The acetyl derivative was hydrolyzed with boiling 4 M hydrochloric acid. The sulfanilaniido compound separated as an oil when the mixture was neutralized. It was obtained in crystalline form by dissolving it in boiling alcohol and slowly adding water to the solution; yield 70%. After two recrystallizations from a benzene-alcohol mixture, the melting point was 138-139". Anal. Calc'd for CnH:&O?S3: N, 13.33. Found: N,13.21. &-StZfaniEamido-4-ethylmercaptomethylthiazole.The acetyl derivative was precipitated by acidification of the diluted reaction mixture. Reprecipitation followed by crystallization from ethanol gave a 65% yield of white crystals, m.p. 208-210". The acetyl derivative was deacetylated in boiling 10% alcoholic hydrogen chloride. The hydrochloride of the sulfanilamido compound, which separated on cooling, was decomposed with sodium hydroxide solution and the free base was crystallized from dilute ethanol. A 48% yield of white plates, m.p. 149-150" was obtained. Anal. Calc'd for C:zH:sN30zS3: N, 12.77. Found: N,12.74. &-Sulfanilamido-~-carboxymethylmercaptomethyZlhiazole. 2-Amino-4-carbethoxymethylmercaptomethylthiazole was treated with acetylsulfanilyl chloride in the usual manner.
622
LAND, ZIEGLER, AND SPRAGUE
After removal of the pyridine, the residue was stirred with water until i t solidified. Reprecipklation from sodium hydroxide solution followed by two crystallizations from 30% alcohol gave a 56% yield of white crystals, m.p. 208-210' dec. The solubility of the product in sodium bicarbonate showed that the ester group had been hydrolyzed during the isolation. Anal. Calc'd for ClrH~rN~OaSz: N, 10.47. Found: N, 10.43. The acetyl derivative waa hydrolyzed with 10% sodium hydroxide. The sulfanilamido compound was precipitated by acidification to pH 2 and the product was recrystallized from water three times. A 65% yield of material melting at 158-160' was obtained. Anal. Calc'd for CllHlrNtOISJ: N , 11.70. Found: N, 11.47. The ethyl ester, m.p. 114-115", was prepared by esterification with alcoholic hydrogen chloride followed by recrystallization from dilute alcohol. Anal. Calc'd for CirHirNaO4Sa; N, 10.85. Found: N, 10.77. ~-Sulfanilamido-4-hydroxymethylthiazole. This sulfonamide, m.p. 200-201' dec., waa prepared in 17% yield from N4-acetylsulfanilylthiourea by the method by Foldi. (7). R-Amino-4-imim-R-thiazolinehydrochloride (111).5 A . Chloroacetonitrile (8.5 g., 0.11 mole), thiourea (7.6 g., 0.1 mole), and 60 cc. of alcohol were mixed and warmed under reflux on a steam-bath. The thiourea dissolved rapidly and the exothermic reaction caused the alcohol to boil vigorously. The product separated as a fine white crystalline solid and the filtrate gave a negative test for thiourea with ammoniacal silver nitrate. The yield of hydrochloride was 13.0 g. (86%). It was recrystallized rapidly from water or dilute alcohol solution. Both the crude and recrystallized material gave the same analyses and were unmelted a t 350'. Anal. Cala'd for CIH&lNaS: N, 27.70; C1, 23.39. Found: N, 27.62; C1,23.30. B . A solution of S-cyanomethylisothiourea hydrochloride (11) in alcohol wm refluxed on a steam-bath. After a few minutes, II fine crystalline precipitate of the hydrochloride began t o form. The solid was identical with that obtained under A . Anal. Found: N, 27.54. The addition of saturated aqueous picric acid to a solution of the hydrochloride in water gave a crystalline picrate. This did not melt up to 350". Anal. Calc'd for CaHhNaS*C6HsN$O,:N, 24.40. Found: N, 24.35. Recrystallization of the hydrochloride from hot water containing hydrochlorio acid gave 2-amino-4-thiazolone hydrochloride (IV) which did not melt at 350" and wa9 identical with a sample prepared from thiourea and chloroacetic acid (14). Anal. Calc'd for C3H&lN20S: N , 18.35; C1, 23.24. Found: N, 18.37; C1, 23.43. SUMMARY
Derivatives of sulfathiazole having tert.-aminoalkyl, hydroxymethyl, or alkylmercaptomethyl groups in the thiazole nucleus have been prepared. The effect of these groups upon the antibacterial activity and the absorption following oral administration is discussed. An attempt to prepare 2,4-disulfanilamidothiazole was not successful. GLENOLDEN, PENNA. REFERENCES (1) GANAPATKI, SHIRSAT,AND DELIWALA, Proc. Indian Acad. Sci., 16 A, 126 (1912); JENSEN A N D TRORSTEINGSON, Dansk Tids. Favm., 16, 41 (1941); BACKER A N D DE JONQE, Rec. trav. chim., 60, 495 (1941); NEWBERRY AND VIAUD,British Patent 517,272. 6
This preparation was carried out by Dr. L. W. Kissinger.
DERIVATIVES OF SULFATHIAZOLE
623
(2) SPRAQUE, LINCOLN, A N D ZIEQLER, J . A m . Chem. SOC.,68, 266 (1946). (3) PorH AND Ross, J . Lab. Clin. Med., 30,843 (1945). Proc. SOC.Ezptl. Biol. Med., 68, 116 (1945); WRITE, BELL, (4) HARRISAND FINLAND, BONE,DEMPSEY, A N D LEA, J. Pharmacol., 85, 247 (1946). (5) SPRAGUE, LAND,AND ZIEGLER, J . A m . Chem. SOC.,in press. (6) LAND, SPRAQUE, A N D ZIEQLER, J . A m . Chem. soc., in press. ( 7 ) F ~ L DGERECS, I, DEMJEN,A N D KONIG,U. S. Patent 2,332,906 (1943). DUESEL,AND FRIEDMAN, U. S. Patent 2,202,933; EWINAND PHILLIPS, British (8) TIEIZA, Patent 512,145; ANDERSON, FAITH, MARSON, WINNER,AND ROBLIN, J. A m . Chem.. SOC.,64, 2902 (1942); FOSBINDER A N D WALTER,J. A m . Chem. SOC.,61, 2032, (1939). (9) ROBLIN A N D WINXER, J. Am. Chem. SOC., 62, 1999 (1940). (10) ROBLIN,WINNER,A N D ENGLISH, J . A m . Chem. SOC.,64, 567 (1942). (11) MILLER,SPRAGUE, KISSINGER,AND MCBURNEY, J. A m . Chem. SOC.,62, 2099 (1940) (12) MOOREAND MILLER,J. A m . Chem. SOC., 63,2781 (1941). KISSINGER, AND LINCOLN, J. A m . Chem. Soc., 63, 578, 3028 (1941). (13) SPI~AGUE, (14) SCHMIDT, Arch. Pharm., 268, 229 (1920).
