\'Ill. 1 0
Neuropharmacological Investigation of N-Benzylsulfamides
X aeries of 35 benzylsiilfamide derivativeb have t)eeii hyiitherized aiiti c o n i p u w l for i~eiuophni.macologic.:ll activity. These cornpornids produced moderate CSS depressniit efiects with n npectriim resembling anticoilvulsants and/or mild traiiyuilizers. Propargyl sitbstitiitioii o i i the amide ilitrogen provided siihstaiices nitli greater activity while halogellatioil of the heiizeiie ring provided a diversity of efiects, depeiiderit oii amide iiit uigeii substitution aiid iiumber aiid/or position of halogen siihstitueiits.
It has been kriown for borne time that alkyl, aryl, or aralkyl derivatives of urea (I) possess anticonvulsant hypnotic, sedative, and depressant activity.' The (*orresponding derivatives of sulfamide (II), the SO? ~
aiialog of urea, have not been evaluated fur this type of activity.2 I n the present work T1-e n.ish to report that the N-benzylsulfamides do posbess central nervoub system activity particularly as anticonvulsants and mild tranquilizer^. The S-benzylsulfamides prepared for this study were obtained by treating sulfamide or dimethylsulfamoyl chloride with a benzylamine (111) i n a11 appropriate
tests.",' Studies of' lethality (followirig intr:ipcritoireal administration) were initially ninde o i i n few selcrtetl c~)nipoundswith tlie tlctermiiiation that :t gcricrnl dositge ruiige of 35-400 mg/kg ip would s:itiFfy coniparisoli of suhst:trices within the series and coniparisoii with standard agents. The level of antic'oiivuls.:irit activity i w s studied i i i niiw, using as indicw t h r : L I J tagonisni to strychnine5and tlie nntagonism to iiinsinial electroshock," with definition of over-all C S S del:~ssaiit activit'y represented hy the barbiturate reinduction test.' Secsondary eviiluatiori cwneisted of in gttioii of selec*tcdcompounds ( ~ i ispinal reflex :w it1 intact c.hloralose-atiestlictized and eth(>r-spin:il cats .x, '3
\\ere adniiiiistered iiitrupcritoiie:illy :uid intravenously iri the (*:itspinal R=ll aninials per dose were used in e:ic*li AllCIT~NIiII+ 11 --+- .IHCIILSIISO>SII?. EtOIl-H 0 of the niouse tests, a r i d three cuts were studied oii encli 111 I\ id in s;ccoiidury tests). Because :dl the s u b were iiisoluhle in H,C> or saliiic, parenteral tr:itioti \vas acconiplished by suspending tlir: c~inip(iuridsi i i L: I ,Oy{, solutiori of c.arboxymetliylccIluI0se. solvent. Pyridine 11-as a satisfactory solvent for preResults of the relative antiuoiivulsaiit ~ t n dIiexoh~rparing 1-benzyl-1-alkylsulfaniides (V) from a secondbit:tl-reinduc.ing activities of the series of t~ciizylsulfary amine arid 11, while a water-ethanol niixt'ure gave amide derivatives :ire sumninrized i i i T:rljles I--I Y . a good yield of the 1-benzylsulfaniides IV from a priSt andtirtl c*onipounds utilized for uiiiip:trisurr \vert mary benzyl amine arid 11. Ilimethylsulfamoyl chloglutethimidc, :~niiiioglutcthiniide, dipheiiylhydaiitoirl, ride reacts with excess primary or secondary benzylmethsuximide, and rnethylpeiitynol (see Ta'ble Y). amine in diethyl et'her or toluene below room temperaAs can be seeii (Tahle I), the parent molecule, benzylture to give 1-benzyl- and l-benzyl-l-alkyl-3,3-disulfmiide ( I ) , provides mild :ttitagonisni to strychniiic niethylsulfamides (VI arid VII). nird moderate ant agoiiisni t I) ninxinial t.lectroshovl~, . I I ~ c ~ ~ ~ s I ~ s ~ ~. ~ ~ I( ~cc II IT ~ ~ N~I ?~ s ~ ~ s ~ c whereas I ~ ~ ) ? no reiriductioii iii slecp following Iicxoharbital u p t o 200 nig,kg. 1-1 \TI niiesthesi:i TKLS cilitaiiicd :it do Addition of nlliyl or :~ll;e~iylor ( L oal1;yl grc.)upsto the Pharmacology.-Preliminary investigations in this S-1positioii provided no reniur1;ahle c1i:tnge i n artivity laboratory 011 the C 9 S effects of S-benzylsulfamide ewept i n the c2:ise of t h e ])1")JJRrgJdentity (4), w h ~ ' r :I( ~ showed this substance t o be a nioderate CKS depressant sigiiificniit inc~rensci t i 1)oteiic.yw:ts ohcrvecl :LS regnrclz; with possible anticoiivulsant :iIic$'or mild tranquilizing h i t h st rycahiiiIie arit:rgo~iisni aiitl reiuducatioii of sleq) I)roperties. On this basis a l q ~ o p r i a t estudies were f i ) I l i ) ~ v i i i ghcsoh:irljit:d aiieat1iesi:i. Iritorestirigly, subinitiated to determine the relative level of activit,y of stitution hy tlie 1)eiizyl g r o u ~ :it ) the S - 1 1iosition (13) it series of 55 benzylsulfaniide derivatives as compared provitletl L; conipound h:i,viug convulsant net-ivity :ui(I to six st:iirdard substances. -111 substancez; were submitted t o :t preliniiiiary screen iii niouse behavior ( H I S . Ira.in i n ''.\niu1:11 alii1 ('linicnl 1 ' l ~ u r i n ; t c o i Lvaliiatiun," J. 11. S u d i n e and 1'. IC. Sirgler, I;d. (a) IC. d. \\heeler i n ".\Iedicinal Cliicaeo, Ill., 1064. 1~1' 36-51, Chemistry," Vol. V I , E. E. Campaiene and \V. t i . IIartiing, Ed., John ! 4 j C . Clien, "SymlJosiuin oil serlativi, a n d IIyi \\'iley a n d Suns, Inc.. New York, N. Y., 1963, pi] 1-215; (1)) .I.Sginks and liams a n d \\-ilkins Company, l3altimore, l l i l , . 195%. I\'. S.\Varing, I'rogr. .Ifei/. Ctiem,, 3, 261 (1963). ( 5 ) 31. .1. OrloR, €1. I,. \\illiam*, anri (', (-'. P ( 2 ) .\fter iiiir work had l)een complrted there appeared in t h e patent litera t i i r c reports tiifit ('r,IIs(C1Ir),NIISO?N11 = 2-5) and C r t l ; C H ~ C l I ~ ! ~ ( ' I I S I I S O ~ N I I : derivatives pmsess a n t i e o n w l s a n t . antianxiety, sedarire, and tranyuilizinp properties: (a) Cilia Ltd., Yoiitli .lfrican P a t e n t 6:3:509-12 ( 1 0 6 3 ) : (1,) J. J . Lafferty a n d 13. Loev, U. S. P a t e n t 3,143,549 (lL4611: C'herii. d b s l ~ . .68, -189 (1865); (c) J. J. Lafferty a n d 13. Lues. U. S.Potcrit ;%.l4i,:%O5 ( l W 6 I ) ; Chcm. . l i i ~ t r . .61, 13243 (lLl6.1) 11) For r c v i e u s un this artivit3 refer
LU
CXS ACTIVEN-BEN~YLSULFAMIDES
July 1967 TABLE I
260 240
SEUHOPH.\K~.ICOLOGIC.~L D.AT.I OK ~-BENZYL-I-R-WLFAUIDES C~H~CH~NSOINH~
637
I H
200
I
R 160
HRC RD50,
NO.
1 2 3 4
R Ild CHSe C?Hj HCEZCCH?' H&=CHCH# Cyclopropyl
EDw, mg/kg ip MES~
mdkg ip
120
238 217 232
>200 248 > 100 2.j 150 138 >100 133 >200
80
sP"
--10
58 117 92 88 117 92 >100 123
92 1.70 163 7 %-car{, 8 i-CsHi 123 283 . . .* 9 H,C=CCH,CH2 1.50 138 88 10 n-CIHu 17.5 92 100 11 i-CIHg 300 163 80 12 Cyclopentyl 13 CcHjCH2 . . .h . . .h 42 14 '2-Norbornyl >300 >300 >300 1.5 n-CloH~ 300 300 >300 SP = strychnine protection. 11ethod of 11.J. Orloff, H . L. Williams, atid C. C. Pfeiffer, Proc. Soc. Erptl. B i d . ,$Zed., 70, 2.54 (1949), was used with ten animals per dose. The ED50 was det,ermined using the Litchfield-Wilcoxon method (J. T. Litchfield and F. Wilcoxon, J . Pharmacol. Ezptl. Therap., 96, 99 (1949)). * 1IES = maximum electroshock. hlethod of J. E. P. Toman, E. A . Swillyard, and L. S. Goodman, J . ,Yeurophysiol., 9, 231 (1946), was used with ten animals per dose. H R = hexobarbital reinduction. llodified method of C. F. Winter, J . Pharmacol. Ezptl. Therap., 94, 7 (l948), was used in which aliimals were administered compound immediately following recovery from hexobarbital anesthesia (70 mg/kg iv) and reinduction of "anesthesia" (loss of righting) was measured from that time. d Compornid did not affect spinal reflexes in the cat a t 100 mg/kg iv. For method, see Table 111, footnote d . e Dose required to produce 3O"i,, depression of spinal reflexes was 125 mg/kg. On spinal reflexes, compoiuid prodiiced facilitation a t low doses and produced 3OC;, depression a t 60 mg/kg. 0 Substaiice produced only facilitation of spinal reflexes a t doses up t,o 100 mg/kg. h Compoiirtd provided no protection from convulsants but, instead, produced convulsions a t 73 mg/kg ip. S o t tested. ,j
6
yet causing reinduction of sleep following hexobarbital a t a dose only slightly greater than that found to be effective with 4. Substitution by methyl groups on S-3 or o n the Q: carbon in the benzylsulfaniide molecule generally decreased the over-all CSS depressant activity and, in the latter instance, tended to produce the opposite eff ect-locomotor stimulation, reversal of hexobarbital anesthesia, and convulsions at toxic doses (see 21 and 21a, Table 11). Phenyl or benzyl substitution on the a carbon provided compounds having the same spectrum of activity as the parent substance, with the phenyl derivative denionstrating significantly greater over-all CNS depressant effects (see 22 and 23, Table 11). Halogen substitution on the benzene ring of the parent molecule provided a diversity of results, depending upon the position and number of substitutions (Table 111). Compounds having three chlorines located in the 2 , 3, and 6 positions (47 and 48) produced maximal effects as regards protection from strychnine convulsions and reinduction following hexobarbital anesthesia, whereas changing these substitutions to the 2, 4, and Yj positions markedly decreased these activities. Increasing or decreasing the number of halogen substituents on the benzene ring tended to decrease the aforementioned pharmacological effects (33, 36, 42-44,
40
200
.-
M
w 160
\ 3
120
80 40
200 160
I
CH,-CSCH BCH,-:H-SO,-NH~
R
120
80 40
Figure 1.-Effect of halogenation on anticonvulsant and hexobarbital reinducing activities of benzylsulfamide (1) and its Tu'methyl (2) and N-propargyl (4) derivatives. The numbers in parentheses refer to compounds found in Tables I-IV. See text for explanation. m, strychnine antagonism; S, maximum electroshock antagonism; m, hexobarbital reinduction.
50, and 51). Of the mono- or dlchlorinated derivatives, compounds having substitution in the 2 or 2,4 positions, respectively, provided the most activity as regards protection from strychnine deaths and reinduction of sleep following hexobarbital (24, 27, 33, and 36). Notably, the replacement of chlorine by fluorine tended to decrease the anticonvulsant activity and provided no significant increase in hexobarbital reinducing activity (compare 31 and 33). An analysis of Table IV shows that cyclization of the nitrogen substituent with the benzene ring results in a marked decrease in over-all activity (compare 54 and 55 with 3 and 23). This is not the case, however, when cyclization is accomplished with the substituent off the Q: carbon and the benzene ring (compare 52 and 53 us. 22). I n the latter respect, the anticonvulsant activity is decreased but the total CKS depressant activity (as measured by reinduction of sleep following hexobarbital) is not altered. Figure 1presents a graphic summary of effects of compounds having the amide nitrogen unsubstituted us. those having a methyl or propargyl substitution. As can he seen, a structure-activity relationship can be
111, I
