2342 [CONTRIBUTION FROM THE
ROGERADAMS,P. H. LONGA N D A. J, JOHANSON NOYES CHEMICAL LABORATORY, UNIVERSITY MEDICAL SCHOOL]
OF ILLINOIS, AND JOHNS
Vol. 61 HOPKINS UNIVERSITY
Sulfanilamide Derivatives. I BY ROGERADAMS,P. H. LONGAND A. J. JOHANSON' The intensive study of sulfanilamide derivatives during the past few years has been with the objective of discovering compounds of higher activity, lower toxicity and more advantageous physical properties. The work described in this communication involved especially the preparation of a variety of p-acylamidobenzenesulfonalkanolamides and p-aminobenzenesulfonalkanolamides in order to determine, (1) the effect of the alkanolamine, ( 2 ) the effect of the acyl radical, and (3) the effect of changes in water solubility on the toxicity and antistreptococcal activity of the molecules. A few of these compounds have been described by other investigator9 since the initiation of the research but they are included in order to show the general comparisons. The description of certain simple amidesl3 morpholides and double ring compounds is also included. The compounds were prepared by condensation of the proper substituted p-aminobenzenesulfonyl chloride (Table I) and an alkanolamine, ammonia, morpholine, or p-aminobenzenesulfonalkanolamide, according to the eguation
ally lower though not so in all instances. The toxicity, however, was greatly reduced so that in many of these compounds the therapeutic ratio was more favorable than in sulfanilamide. As the acyl group increased in size, the water solubility decreased and the antistreptococcal activity was less. The toxicity, however, remained very low except in the isobutyryl derivative. Several compounds in the series of acylamidobenzenesulfonrnorpholides showed slight to moderate activity and materially reduced water solubility. Carbethoxyaminob en zenesulf onalk anolamides were similar in solubility, effectiveness and toxicity to the lower acyl derivatives. The p-acylamidobenzenesulfonamideswere less effective than sulfanilamide with the valeryl derivative somewhat more effective than the propionyl. The substituted benzenesulfonanilide derivatives were all ineffective. A few compounds in which an alkyl or a benzyl group was substituted for one of the hydrogens in the amino group of an aminobenzenesulfonalkanolamide showed properties not very dissimilar RNHC6HSOzCl 4-NHzCHzCHOHR + RNHCeHSOaNHCHaCHOHR to those of the analogous unsubstituted amino The individual compounds are listed in Tables compound. Several 4 - methoxy - 3 - aminobenzenesulfon11-x. amides and the analogous alkanolamides showed The following general statements can be made essentially no antistreptococcal activity. concerning these various compounds : The various compounds were also tested for (a) The aminobenzenesulfonalkanolamides are antimeningococcal activity. There appeared to more soluble in water than sulfanilamide. The be no correlation with antistreptococcal activity. antistreptococcal activity of these compounds is On the other hand, a large number of the comfrom slight to moderate but lower in every inpounds possessed antimeningococcal activity equistance than that of sulfanilamide. The least valent to that of sulfanilamide. Since the toxicity activity is found in the 2,3-dihydroxypropylamine of most of these compounds was much less than derivative. The therapeutic ratio is more favorthat of sulfanilamide, the therapeutic ratio in able in many of the derivatives than in sulfanilrespect to antimeningococcal activity of the new amide. compounds is much more favorable than in sulf(b) The acylamidobenzenesulfonalkanolamides anilamide. were less soluble in water than the unacylated These preliminary toxicity, antistreptococcal analogs. The antistreptococcal activity was usuand antimeningococcal tests were carried out in ( 1 ) An abstract of a thesis submitted in partial fulfilment of the Johns Hopkins University Medical School by requirements for the degree of Doctor of Philosophy in chemistry, 1938. Dr. P. H. Long. In the tables, ++++ is the (2) Kharasch and Reinmuth, U. S. Patent 2,097,414. equivalence in activity to sulfanilamide. (3) Miller, Rock and Moore, THIS JOURNAL, 81, 1198 (1939).
SULFANILAMIDE DERIVATIVES
Sept., 1939
2343
TABLE I SUBSTITUTED ~-AMINOBENZENESULPONYL CHLORIDES Sulfonyl chloride
M. p., 'C.
Formula
b-ProDionamidobenzenep-n-Butyramidobenzenep-Isobutyramidobenzenep-n-valeramidobenzenep-Isovaleramidobenzenep-MethylacetamidobenzenepEthylacetamidobenzenep-Carbethoxyamidobenzene4-Methoxy-3-acetamidobenzene-
113 120-121 131-132 115-116 120-121 136-137 142-143 103 149
C9HioOsNSCl CioHiz03NSCl CioHizOsNSCl CiiHi40sNSCl CiiHi40aNSCl GHioOaNSCl CioHizOaNSCl GHio04NSCl
No.
1 2 3
4 5 6
7 8 9
*
Experimental Substituted (p)-Aminobenzenesulfonyl Chlorides.-pAcetamidobenzenesulfonyl chloride was prepared by the method of Stewart.' A series of p-acylamidobenzenesulfonyl chlorides (Table I) was synthesized in essentially the same manner, by the reaction of chlorosulfonic acid with the appropriate anilide. I n each case, 1 mole of the anilide was added to 5 moles of chlorosulfonic acid a t 10-20" with stirring. The reactions were, with the exception of numbers 6 and 7, allowed t o proceed, with stirring, from one to five hours a t room temperature followed by a final period of from one to five hours at 50-60'. In the cases of numbers 6 and 7 the mixtures gradually were heated to 80' and the reactions continued a t that temperature for three hours. p-Carbethoxyaminobenzenesulfonyl chloride was prepared by adding 1 mole of phenylurethan to 5 moles of chlorosulfonic acid and stirring for five hours a t room temperature followed by heating a t 60' for one hour. I n no case was hydrogen chloride evolution as extensive as with p-acetamidobenzenesulfonyl chloride. Most of the sulfonyl chlorides tended to separate when poured into the ice-water mixture, as sticky gummy masses, light tan in color. After standing from fifteen minutes to one hour, these masses solidified and could be atered. In most cases the solidification could be hastened by transferring the gum to a fresh ice-water mixture, and stirring and kneading. 4-Methoxy-3-acetamidobenzenesulfonylchloride5 was prepared in the same manner as the p-acetamidobenzenesulfonyl chloride except that the mixture was stirred a t room temperature for twenty hours and then poured into the ice-water mixture. The crude, moist sulfonyl chlorides were used directly in the condensation reactions. Small portions were purified for characterization by recrystallization from benzene and were obtained as small white crystals. I n contrast to Stewart's acetyl compound, these sulfonyl chlorides were all fomd to be very soluble in hot benzene. Although no exact determinations were made on a pure basis, the yields, excepting in the cases of numbers 6 and 7 in Table I, appeared t o be about the same as with the acetyl compound. The yields of numbers 6 and 7 were not more than 15 to 20% of theoretical. (4) Stewart, J . Chcm. SOC.,121, 2558 (1922); "Org. Syntheses," Coll. Vol. I. p. 8. ( 5 ) German patent 573,193 (1931); Friedlacndcr, 19, (I), 699 (1934).
Nitrogen analyses, yo Calcd. Found
5.66 5.35 5.35 5.08 5.08 5.66 5.35 5.32
5.89 5.53 5.53 5.32 5.22 5.81 5.39 5.39
Condensation of the Substituted pAminobenzenesu1fonyl Chlorides with Amino Compounds.--The substituted p-aminobenzenesulfonyl chlorides were condensed with the various amino compounds using molar portions of each and one of the following as a condensing agent to take up hydrogen chloride: (1) a n additional mole of the amine (plus a small excess t o neutralize hydrochloric and sulfuric acids not removed from the crude sulfonyl chloride in the washing process); (2) potassium hydroxide in 10 to 20% aqueous solution, in sufficient quantity t o maintain alkalinity throughout the reaction (about 1.5 moles) ; (3) an excess (3 or 4 moles) of pyridine; (4) in the case of the unsubstituted sulfonamides a large excess of concentrated aqueous ammonia. For the preparation of p-acetamidobenzenesulfon-(8hydroxyethy1)-amide and p-acetamidobenzenesulfon-di(P-hydroxyethy1)-amide and all the morpholides, method 1 was found satisfactory. Method 3 was most satisfactory for the substituted benzenesulfonanilide derivatives. All the other compounds were prepared using method 2. General Procedure.-The amino compound and the condensing agent were placed in an open beaker. To the mixture was added, with stirring, a quantity of the crude damp benzenesulfonyl chloride derivative estimated to contain the desired amount of pure substance. Heat usually was evolved, but the temperature of the mixture was held below 45' by means of an ice-bath. In some cases the sulfonyl chloride dissolved t o form a clear yellow solution. In others, as the sulfonyl chloride dissolved, the product separated immediately in solid form or as a heavy dark oil. The mixture was heated about thirty minutes a t 70-80 ', cooled t o room temperature and neutralized with concentrated hydrochloric acid t o brilliant yellow as indicator. At this point, the product if not already in suspension in solid form or present as an oily layer in the bottom of the beaker, usually separated, either in crystalline form or as a n oil which upon cooling and standing eventually solidified. Evaporation to small volume, cooling and standing caused separation in cases where precipitation did not occur directly when the mixture was neutralized. The products were usually recrystallized from water or aqueous ethanol of various dilutions. I n almost every case one or more treatments with norite was necessary t o remove color. Hydrolysis of Acetamidobenzenesulfonamides.-The compounds shown in Tables V and VI were prepared by acid hydrolysis of the corresponding acetamido compounds. The acetamido compound (1 mole) was added to dilute
ROGERADAMS,P. H.LONGAND A. J. JOHANSON
23.14
hydrochloric acid (4-6 N ) containing a t least 1.4 moles of the acid. The mixture was heated under reflux for two to If the material did not dissolve five hours a t 70-80'. completely on heating, a small quantity of ethanol was added to bring about solution. After completion of the hydrolysis, the solution was cooled and neutralized to lit-
Vol.
(jl
mus with solid sodium carbonate. In nearly every case the amine separated as a heavy oil, which after stirring, cooling and standing became solid. Purification was effected by recrystallization from water or dilute ethanol. Treatment with norite to remove color was necessary in most cases.
TABLE I1 ~ A CLAMIDOBENZENESULFONAMIDES" Y Compounds 1, 2, 3 and 4 have been described recently by Miller, Rock and Moore.3 The melting points reported differed considerably froni those given here. Compound 4 has also been described in French Patent 820,546: C. A . , 32, 2958 (1938). No.
Acyl group
M. p.. ' C .
Antistrep. activity
Anfimenmg. activity
++ +++ + ++++ ++++ +++
Formula
Nitrogen analyses, % Calcd. Found
lb CHJCHZCO 226.5-227.5 CsHizOsNzS 12.28 12.23 2" CHsCHzCHzCO 236-237 CioHirOsNzS 11.57 11.61 3d (CH8)zCHCO 248-249 * CioHirOsNzS 11.57 11.18 4" CHsCHzCHzCH2CO 209-210 CiiHieOsNzS 10.94 10.95 White microcrystalline powders very slightly soluble in water. Yields varied from 53 to 86%. * Recrystallized from 25% ethanol. Recrystallized from a mixture of acetone and 95% ethanol. Recrystallized from an acetonewater mixture. < Recrystallized from 50% ethanol.
'
TABLE 111 P-ACBTAMIDOBENZENESULFON ALKANOLAMIDES" No.
M. p., " C .
Alkanolamine
1 2' 3 4"
NHzCHzCHzOH NH(CH2CHzOH)z NHzCHzCHzCHzOH NHeCHzCHOHCHs
150-151 158-159 133.5-135 166-1 67
5
NH&HzCOH(CH3)z
185-187
6 7
NH2CHzCHOHCHzOH NH(CHs)CHz(CHOH)aCHzOH HO H
132-133 87-91
Antistrep. activity
Antimening. activity
++++ + + + 0 ++ 0 0 0
i
0 0
0
*
Formula
C~OHUOINPS CtzHiaO4NzS CiiHie04NzS CiiHisO4NzS CizHieOiNzS CiiHt&.NzS Ci6Hz40aNzS
Nitrogen analyses, % Calcd. Found
10.81 9.27 10.30 10.30 C, 50.35 H, 6.29 9.72 7.14
10.86 9.53 10.45 10.61 51.01 6.44 10.07 6.93
218 0 0 CI~HZOO~NZS 8.97 8.88 " > B H z H2N Hz Hz White crystalline powders of varying solubility in water. With the exception of number 8, all recrystallized from water. Number 8 from dilute ethanol. Yields from 50 to 75%. Kolloff, TRISJOURNAL, 60, 950 (1938). U. S. Patent 2,097,414, Oct. 26 (1977).
8
'
TABLE IV
P-ACYLAMIDOBENZBNESULFONALKANOLAMIDES' No.
Acyl group
Alkanolamine
M. p., OC.
Antistrep. activity
Antimening. activity
+++ +++ + + ++ ++++ ++ + +++ ++++ ++++ +++
Nitrogen ' analyses, % Calcd. Found
1 CHsCHzCO 0 9.79 NHzCHzCHOHCHs 148 2 9.33 CHaCHzCO NHzCHzCOH(CHs)z 172-173.5 3 CHsCHzCHzCO 0 9.79 NHzCHZCHzOH 139 4 114-1 15 8.48 CHiCHzCHzCO NH (CHzCHzOH) 0 9.33 5 CHsCHzCHzCO 127-128 0 NHzCHeCHOHCHs += 6 CHsCHzCHzCO 8.91 NHzCHzCOH (CHs)z 166 7 9.79 (CHs)zCHCO 116.5 NHzCHzCHzOH * 9.33 144 8 (CHJ zCHCO NH2CHzCHOHCHa * (CHs)2CHCO 9 8.91 173 NHzCH2COH(CHs)z zk 10 CHs(CHz)sCO 8.92 121.5 NHzCHzCHOHCHi =t 11 CHs(CHdsC0 8.54 NHzCHzCOH(CH3)z 136-136.5 12 (CHs)zCHCHzCO 0 8.54 0 NHzCHzCOH(CHs)z 146-147 a White microcrystalline powders, slightly soluble in water. Recrystallized from 25 to 50y0 aqueous ethanol. ranged from 30 to 60'%.
+
9.87 9.45 9.79 8.44 9.65 8.80 9.68 9.23 9.10 8.89 8.56 8.6:3
Yields
SULFANILAMIDE DERIVATIVES
Sept., 1989
2345
TABLE V
p -AMINOBENZENESULFONALKANOLAMIDES" hI. p.. 'C.
Alkanolamine
No
Antistrep. activity
Antimening. activity
Formula
+++ ++++ ++++ ++++ ++++
++ ++ +
Nitrogen analyses, 3 '% Calcd. Found
NH2CHzCHzOH 13.16 95-97 CsHizOsNzS 12.98 NH(CHzCHz0H)z CioHi604NzS 10.77 10.52 * 109-1 10 1233-124 NHzCHzCHzCHzOH * 12.18 CgHinOaNzS 12.18 4 NHzCHZCHOHCHB' 12.20 115-116 CgHirOsNS 12.18 5 NHzCH&OH(CH& 102-103 11.69 0 CloHisOaNzS 11.48 6 NHzCHzCHOHCHzOH 102-104 11.39 11.11 0 GHirO4NzS Hz Hz 7 ">C>Hz 141-142 0 0 CizHiaOaNzS 10.36 10.22 H2N /\ HZ OH H " White crystalline powders soluble in water, number 7 only slightly. Yields varied from 48 t o 67%. Recrystallized froin water with the exception of number 7, which was recrystallized from 20% aqueous ethanol. Cf.Kolloff. 1 2" 3
TABLE VI
ALKYL- AND ~ARALKYLAMINOBENZENESULFONALKANOLAMIDES~ Alkyl or aralkyl group
No.
Antistrep. activity
X.Z. p . , "C.
Alkanolamine
Formula
Nitrogen analyses, % Calcd. Found
CHs NHzCHzCHOHCHa 90-91 .. CioHi60&"S 11.48 11.40 C2H6(COCHa) NHzCHzCOH(CHa)z 134 .. CiiH~04NzS 8.92 8.81 CZH6 NHzCHzCOH(CHa)z 131.5 0 CnHz003NzS 10.29 10.36 CHzCaHa NHzCHzCHzOH 115-1 16 & C16His03NzS 9.15 9.05 White crystalline solids slightly soluble in water. Yields varied from 35 to 60%. All were recrystallized from water except number 4 for which benzene containing 5% methanol was used. 1 2 3 4
TABLE VI1 Amidr
NO.
SUBSTITUTED P-CARBETHOXYAMINOBENZENESUI,PONAMIDP,S" Antistrep. Antimcning. M. p., ' C . activity activity Formula
+
++++ ++ ++ +
Nitrogen analyses. % Calcd. Found
1i6 CIIHIBO&~S 9.72 9.65 192 * ClzH1s06NzS 9.27 9.26 3" 157-158 0 CiaHisOaNzS 8.91 8.89 4c a" 24 1-242 COHIZO~NZS 11.48 11.58 " White microcrystalline solids, very slightly soluble in water. Estimated yields varied from 50 to 86%. " Recrystallized from 60% ethanol. Recrystallized from hot water. Recrystallized from 50% ethanol. ' Recrystallized from acetone and water (1:l). TABLE VI11 p-ACYLAMIDOBLCNZENESUI.FONMORPHOLIDES AND ~-AMINOBENZENESUI,FONMORPHOLIDE"
KHzCHzCHzOH NHzCHzCHOHCHa NH(CHzCHJz0
lh
2'
No.
Acyl group
1 2 3 4
CHsCO CHjCHzCO CHsCHzCHzCO (CHs)zCHCO
+
M. p . , OC.
Antistrep. activity
+ + +
Antimening. activity
165-166 189-190 191-193 147 f 5 H 217 i " White crystalline solids usually as small glistening plates. 82%. Recrystallized from 20 to 50% ethanol.
++ + ++
Formula
CizH1s04NzS CiaHisO4NzS CirHzo04NzS i Ci4Hzo04NzS * CioHirOsNzS Very slightly soluble in water.
Nitrogen analyses, yo Calcd. ' Found
9.86 9.77 9.40 9.49 8.97 8.75 8.97 8.93 11.57 11.51 Yields varied from 50 to
TABLE IX SUBSTITUTED BENLENESULFONANILIDE DERIVATIVES:~ RNHCEH~SOZNHC~HISO~NHR' R
No.
1
CHaCO
2 3
H
R'
Antistrep. Antimening. M. p.. "C. activity activity
Formula
Nitrogen analyses, % Calcd. Found
CHzCHOHCHa 127-128 0 0 CirHziOsNsSi 9.88 9.58 CHzCHOHCHa 123-125 0 Ci6HioOsNaS1 10.97 11.00 CHaCO CHsCOH(CHs)p 213 0 0 CisHaOeNaS2 9.52 9.46 4 H CHzCOH(CHs)z 184-185 * CisHz106NaS 10.52 10.74 5 GHaOCO CHzCHOHCHa 175-177 0 CisHzzO~NaSz 9.19 8.99 ' White microcrystalline powders very slightly soluble in water. Yields varied from 60 to 77%. Recrystallized from 30 to 60% ethanol.
++++ + + ++ ++++
2346
ROGERADAMS,P. H. LONGAND ALLENEJEANES
Vol. 61
TABLE X DERIVATIVES OF 4-METHOXY-3-AMINOBENZENESULFONAMIDE:5 CHsOC>SOnNHR‘ RHN No.
R
RJ
M. p.. ‘C.
AntiAnfistrep. mening. activity activity
Nitrogen analyses, % Calcd. Found
Formula
1 CHsCO H 0 225.5 * CJLz04NzS 11.47 11.34 2 CHBCO CHzCHaOH 152-153 0 0 CIIHIBO~NZS 9.72 9.85 3 CHaCO CHaCHOHCHs 146-147 0 0 CizH1806NaS 9.27 9.36 4 CHaCO CHzCOH(CHa)z 125 0 =t CisHzo06NzS 8.86 9.09 5 H H 142-142.5 0 0 C7HioOaNaS 13.86 13.53 6 H CHzCHOHCHa 102 0 0 CioHisOaNzS 10.77 10.90 ’ Usually small glistening white crystals. Yields varied from 60 to 84%. Slightly soluble in water. Recrystallized from water, excepting number 4 which was recrystallized from dilute ethanol.
Summary A variety of 9-acylamidobenzenesulfonamides, p-acylamidobenzenesuIfonalkanolamides,p-aminobenzenesulfonalkanolamides, p-alkyl- and paralkylaminobenzenesulfonalkanolamides, p-carbethoxyaminobenzenesulfonamides, p-acylamidobenzenesulfonmorpholides, p-aminobenzenesd-
fonanilides and derivatives of 4-methoxy-3aminobenzenesulfonamide have been prepared. All show less antistreptococcal activity than sulfanilamide but practically all are much less toxic. The antimeningococcal activity of many is equivalent to that found in sulfanilamide.
fonmorpholide, p-acyl- and p-aminobenzenesul-
URBANA, ILLINOIS
[CONTRIBUTION FROM
THE
RECEIVED JUNE 16, 1939
NOYESCHEMICAL LABORATORY, UNIVERSITY OF ILLINOIS, AND MEDICAL SCHOOL]
Sulfanilamide Derivatives. BY
JOHNS
HOPKINSUNIVERSITY
II
ROGERADAMS,P. H. LONG AND ALLENEJEANES’
In the previous paper2 it was demonstrated that the acyl groups in acylamidobenzenesulfonalkanolamides greatly reduced the toxicity of the molecule. The antistreptococcal activity was generally lower than that of sulfanilamide but the therapeutic ratio in many instances was more favorable. Consequently, a variety of other substituted acyl substituents has been introduced either directly or indirectly into the molecule. The compounds studied are shown below.
RNHSO,~NHCO(CH,),CONHC>S where x = 1, 2 or 3 and R = -CHzCHaOH or -CHzCHOHCHs / c o - c ~ N ~ a RNHSO~CI)N, CHz-CO where R = H or -CH&H20H -CH,CHOHCHa
R’NHC>SO~NHR
where R = -CH&HOHCHs and R’ = HOOC(CHz)zC& CzH~OOC(CH~)&!+ CH~CHOACCOwhere R = --CHzCHzOH and R’ = HOCH~CHzNHCO(CHz)zCOCHaOCHzCOwhere R = H and R’ = NHgCO(CHz)zCO-
I I1 I11
IV V
(1) The authors are indebted to The Chrmical Foundation for
grants which made possible the work described in this communication. (2) Adams, Long and Johanson, T H I SJ O U H N A L . 81, 2342 (193Y),
~ H R
or
R=NC~)SO~NHR~
where R’ = -CH2CHOHCHa and NH-CO R = >CC \S--C!!HCHa where R’ = H and /CO-CHI
R VI
VI1 VI11
CH~~HOACCOCHaCHOHC&
\c-s
IX
X
XI
I
II
” All the compounds were prepared either (1) by introduction of the sulfonyl chloride grouping into
