May, 1963
ANTICONVULSANT N-SUBSTITUTED BENZENEDISULFONAMIDES
307
Preparation and Anticonvulsant Activity of N- Substituted Benzenedisulfonamides GERALDF. HOLLAND, WILLIAMH. FUNDERBURK,' AXD KEXNETH F. FINGER Medical Research Laboratories, Chas. Pfizer &. Co., Inc., Groton, Connecticut Received December 14, 1962
A series of S-substituted-3- and -4-benzenedisulfonamides (Tables I and 11) have been prepared by the reaction between 3- and 4-sulfamylbenzenesulfonyl chloride and amines, respectively. A number of other synthetic methods were not successful. The anticonvulsant and carbonic anhydrase inhibitory properties of these compounds are listed in Tables 111-VII. Some show greater anticonvulsant activity than either acetazolamide or ethoxzolamide. The N-substituted-4-benzenedisulfonamidesare more potent anticonvulsant agents than the N-substituted-3-benzenedisulfonamides. Within the ~-substituted-4-benzenedisulfonamide series, bulky or polar substituents (R1, Rz)decrease anticonvulsant activity. A correlation between in vivo inhibition of brain carbonic anhydrase and anticonvulsant activity is suggested.
Within the past few years a considerable body of literature has appeared relating to the clinical usefulness of a wide variety of benzene and heterocyclic sulfonamides. Some of these, such as the 1,2,4-benzothiadiazine-1,l-dioxides and l13-benzenedisulfonamides, are potent diuretic Other sulfonamides, such as acetazolamide,g ethoxzolamide,1° dichlorpheiiamide, and methazolamide, I 2 which were originally developed as diuretic agents, are used now either in the treatment of glaucoma or epilepsy. The diuretic, antiglaucoma and anticonvulsant activities of these latter drugs result from their inhibiting the enzyme carbonic a n h y d r a ~ e ~l 3-- I~7 in the renat tubules, ciliary body of the eyela l 9 and braiii,?O21 respectively. The more effective 1,2,4-benzothiadiazine-l,l-dioxideshave largely replaced the carbonic anhydrase inhibitors as diuretic agents. -1 series of S-substituted beiizenedisulfonamides was prepared during the course of a search for prototype sulfonamides. This report is a structure-anticoiivulsaiit activity study of these compounds, inasmuch as their diuretic actixrity has already been shown (1) A. H. Robins Company, lnc.. Richmond. Virginia. ( 2 ) It. M.Taylor and J. G . Topliss. J . .]fed. Pharm. Chem., 5, 312 I1902), and references cited in this paper. (3) P. W. Feit, Acta Chem. Scand.. 16, 297 (1902); E. Schlittler, G . de Stevens, and L. Werner. Angetc. Chem. Intern. Ed. Engl.. 1, 236 (1962). (4) K. H. Beyer and J. E . Baer, "Progress in Drur Research,'' Yol. 11, E. Jucker, E d . , Interscience Publishers, Inc., S e w York. N. Y . , 1900. p. Y. ( 3 ) H . Heller and M. Ginsbura, "Progress in Medicinal Chemistry," Vol. I, G. P. Ellis and G. B. West. E d . , Butterworths, London, 1961, p. 132. ( 0 ) K. H. Beyer and J. E . Baer, Pharmacol. Reu., 13, 517 (1961): S. Y. P'an, A. Scriabine, D. E. hIcKersie, and W. h'f. RIcLarnore, J . Pharmacol. E x p l l . Therap., 128, 122 (1960). (7) A. David and E;. P. Fellows, J . Pharm. and Pharmacol., 12, 05 (1960). (8) B. G. Bomiano, S. Condon, .\I. 'T. Davies, G. B. Jackman. B. G. Overell. V. Petrow, 0. Stephenson. and A. 31. Wild. zbid., 12, 419 (1960). (9) Diamox @. 10) Cardrase @. (11) Daranide @. (1%) Neptazane @. ( 1 3 ) R. 0. Roblin, Jr., and J. W. Clapp, J . A m . Chem. Soc.. 72, 4890
to be qualitatively similar to that of the carbonic anhydrase
Synthesis S-Substituted benzenedisulfonamides were described only recently.??2 3 a Initially, the chlorosulfonation of benzenesulfonamides followed by amination was considered as a possible route to the X-substituted-3benzenedisulfonamides. However, a t elevated temperatures benzenesulfonamides react xvith a large excess of chlorosulfoiiic acid, followed by thioiiyl chloride. to give 3-benzenedisulfonyl chlorides. The lability of the sulfarnyl group to certain acidic reagents is k n o ~ ~ n .These ~ ~ - earlier ~ ~ investigators observed the formation of beiizenesulfoiiyl chlorides when benzenesulfonamides were treated with a slight excess of either chlorosulfonic acid or phosphorus pentachloride. Our results are similar to theirs. However we observe, in addition to the cleavage of the sulfamyl group, ring chlorosulfoiiation when using a large excess of chlorosulfonic acid. Further chlorosulfoiiatioii experiments were carried out employing lower temperatures and using chloroform as a solvent. These are listed below. Under CHI.OROSCLFOXhTIOS ESPERIMESTS W I T H ~-TOLYLSCLFOSAMIDE CHC1, p-CHaCsH$OsSHz ClSOaH __t ~ - C H ~ C B H ~ S O ~ C I 3 hr.
+
N o . of
moles
1 1 1 1
S o . of moles
Tenip.,
4 4 2
61 25 25 26
1
O C .
Yield,
So
84 60 60
Starting material
72, 4893
t h e conditions cleavage of the sulfamyl group without ring chlorosulfonation takes place. It is notmeworthythat at 2 5 O , or even below 25°127the coiiversion of a sulfamyl function t'o a sulfonyl chloride is
(15) R. W. 1-ounn, Iheresidue recrystallized from water, 6.5 g. (697"yield), m.p. 191-192'. 3-Benzenedisulfonyl Chloride from the Reaction of Benzenesulfonamide and Chlorosulfonic Acid at 125".-Chlorosulfonic acid (46.6 g., 0.4 mole) was added dropwise with cooling t o 15.7 g. (0.1 mole) of benzenesulfonamide over a period of 30 min. K h e n the addition was complete the mixture was heated t o 125' for 3 hr., cooled and 14.7 ml. (0.2 mole) of thionyl chloride added. The temperature was then maintained at 80" for another 90 min. After cooling, the mixture was cautiously poured into 400 ml. of cracked ice. 3-Benzenedisulfonyl chloride was col-
lil
j=17
207 f 33 Weak 354 46 215 f 25
Electroshock
21 34
134 65
f3 f4 f IO zk 16
Strychnine*
?;one up to 177 Xone up to 300
6.6 f 0.6 21 i 3 >266 31 f 4 Intern. Pharnzacodyn., 104, 333 (1956). lected by suction filtration and dried in vucr/o, 20 g. (is?; yieldj, m.p. 56-58', The product had an identical infrared spectrum and a purified sample did not depress a mixture melting point with authentic 3-benzenedisulfonyl chloride. A portion of this mat,erial was treated with ammonium hj-droside; melting point, mixture melting point with authentic 3-henzenedisiilfonnniide and comparison of infrared spectra showed this product to be iden tical with 3-benzenedisulfonamide. Under the same conditions 4-tolylsulfonamide gave 4-methyl3-benzenedisulfonl-1 chloride. 4-Tolylsulfonyl Chloride from the Reaction of 4-Tolylsulfonamide and Chlorosulfonic Acid in Chloroform.-To a solution of 4.25 g. (0.02.5 mole) of 4-tolylsulfonamide in 10 ml. of chloroform was added a t 23" 6.5 nil. (0.1 mole) of chlorosulfonic acid. After heating to reflux for 1 hr., the mixture was cooled and diluted with 30 ml. of ethyl acetate and 20 nil. of water. The organic layer was collected, dried and concentrated i n I ' U C U O . There was obtained 4.0 g. (84% yield) of 4-tolylsulfon~-lchloride, m.p. 63-65". The product had an identical spectrum and a purified sample did not depress a mixture melting point with authentic 4-tolylsulfonyl chloride. Small portions were treated with ammonium hydroxide and benzylamine; melting point, mixture melting point with authentic 4-tolylsulfonaniide and N-benz>-l-4tolylsulfonamide, respectively, and comparison of infrared spectra showed the products to be 4-tolylsulfonamide and S-benzyl-4tolylsulfonamide, respectively. The reactions of 4-tolylsulfonamide and chlorosulfonic acid in chloroform at 2.5' nere carried out in the same nianner. Pharmacology. Anticonvulsant Methodology.-The compounds to he tested were finely ground in a mortar with 1 drop of Tween 80 and then suspended in the appropriate amount of deionized water. They were administered to Swiss-Webster male mice weighing li-2.j g. by intraperitoneal injection in volumes of approximately 0.25 ml. Only protection from maximal electroshock seizures, indicated by hind-leg extension, was considered in testing for anticonvu!sant activity.35 The stimulus was alternating current of 50 ma. intensity with a duration of 0.2 sec. applied through corneal electrodes from a Hans Technical Associates Stimulator. This amount of current is approximately 6 times threshold. The electroshock challenge was given in all cases 1 hr. following the administration of the compound. X o animal was shocked more than once. The latency of each seizure was recorded to evaluate the results better. The latency was measured from the beginning of the current to the beginning of hind-leg extension. Tlie dose of compound necessar>- to prevent hind-leg extension in 507;: of the animals (PI&,) and standard deviations were calculated by the method of moving averages employing quantal data.36 The animals were given a minimum of 4 geonietrically spaced doses of the test drug utilizing 5 mice per dose. Since, for this method, it is necessary t,o select the 4 doses ranging from veq- low activity to very high activity man)- more than the minimum of 20 animals were frequently used for earh coinpound. It should be noted that some compounds gave inconsistent results if they were not finely ground before suspending in aqueous solution. Carbonic Anhydrase Inhibition Methodology.-In vitro carbonic anhydrase activity was determined by a modification of the colorimetric method of Philpot and P h i l p ~ t . ~ 'The activitj- was (35) E. A. Swinyard, W. C. Brown, and L. S. Goodman, J . Pharmacol. Exptl. Therap., 106, 319 (1952). ( 3 6 ) W. R. Thompson and C. S.Weil. Biometrics, 8 , 51 (1952). (37) F. J. PhilIJot and J. Philpot, Baochem. J . , SO, 2191 (193Gi.
expressed in teriiis o f enzyme units anti c d i d t t e d from t l i e expression
where I*;.L. represents enzyiiie units, 7 , , the tiriie of tlie uncatuIyzed reaction in sec., and 7’ the tinie of the catalyzed reaction i n sec‘. A11 reactions were curried out in a cold roiim maintained a t ,J zk 1 ”, The inhibitors were preincuhated with the enzyme for 10 rniri. prior to the addition of sul-)strate. This procedure : piw’edi1i-e of Lustig aiid T iiitermediates for the synthesis of +til)stituted 3,l-diliydro ~H-l,’,l-beiizothiadiaziiie-i-~iil fotiai~iide-l.l-diosidrs.’~DtIrillg the coiirso of t , l i i \ work it hcaiiic npparciit that the inpthods r t ~ ~ - ~ r w c v l i n the precediiig paragraph \\-ere iiot adeqaatc f o r tlic coiivenient iyith of cwtaiii m-benzciiedisi~lfoiiamides and it is the purpose of this paper to discus? a 1 1 additional approach whicli w have found to br verv useful in the synthesis of these compounds. The approach in queutioii ir dependent upoii tlir. activating effect of sulfarnoyl groups oTfho and para to a suitable leaving group (halogen or iiitro) iii tlif t)oiizriie iiucleu~’ 4 ‘l’hus iwwtion of 4-amiiio- .7,& dichloro-m-~,eiizenc.disulfoiiaiiiide ( I ) with anmioiii:~ i i i cthanol at 170-180’ for 5 lir. furnished .7-(31i1~ro-4,0diamiiio-7n-br~izciiedisulfoiiaiuid~(11) iii satis1a:toi.t yield. This c*onipouiid (11) also was obtainctl i i i i d ~ i qimilar leactioii roiiditioiis from .~,(i-dichloro-2H-1 - 2 ,iC1
SOL”:! HzNOzS
yJy$
HzNOzS
I
111
CI
CI
\ I ) 0 . 1,ustig and ll. ICatsclier. .Ilonafsii.. 48, 87
ilUSij. (’2) JV, Ijavies and H. G. Poole, J . Chem. Sot.., 1122 (1927). !:I) 1‘. Novello and .J. 31.Sprapur. J . d m Chem. Sor.. 79, 2028 flY.??). 14) I’. C. Norello, C . S. Patent 2.809.1Y4. Oct. 8, 1957. ( R ) TV, .T. Close, 1,. K . S a e t t , L. E. Brads., .T. €I. Short, and 31. \’ernsten, .I. . t n i . Cliem. Soc.. 82, 1132 (1960). 1 6 ) .1. 11. Short a n d C . Birrrnacher, ?hid.. 82, 1133 (1960). (,7j I,. 11. \Verner, A. Halarnandaris. S. Riocs, Jr., L. Dorfinaii. and (;. de
r.
Stevens, ihid., 82, 1161 (1960). (8) H. L. Yale, K. Loaee, and J. Bernstein, Ibid., 83, 2042 (1960). ($1) I?. C . Novello, S. C. Bell, E. I,. .\. .\brains, C. Ziegler, and .T. M. Spritgue, J . O r g . Chem., 2 6 , 965 (1960). 110) C:. T.Holdrere, R. B. Babel, and I,. C . C‘heney, .I. A m . Chem. S o c . . 81, 1807 (1930). ( 1 1 ) (a) 11. A I w r a f . i i i . I ; . 13Cichri~*r,niiil K. \ . u t i I:nister, .I. p r o k t . C h e r n . . I 2 J 162, 237 flK39): (h) 11. Meerwein, (;. 1)ittiiiar. C;. (;ijlln?r. IC. N a f n ? r . 1:. \Imscl:. a u d 0. Steinfort. Chem. Ber., 90, 841 (195i). I 1’2) 1.. Petrow, 0 . Stephenson, and .1.3 f . Wild, J . Pharm. and Phnrmncol.. 1 2 , 70.; (IHAn).
I1
1V
(13) J. G. Topliss. 41.H. Sherlock, I . H. Clarke, 31. C. Daly, I3. I’ettt-rwn. J. Lipski, and N . Fperber, J . O r g . Ciicm.. 26, 3842 (1061j. ( M ) Subsequent t o t l i e
