SOTES
Sovemher 1908
12-29
TABLE I BIOLOGICAL ACTIVITIESO F REPRESEKTITIVE BEsZO-1,4-DI.~ZEPINES 7
Compd
p
Ataxiaa
-
Median effective dose, ing /kg ip------. l I o t o r act. hntielec decrease" shock' Antistrychc p
Lethality
16 28 13 ) 280 7-Chloro-2-methylamino-5-phenyl-3H-1 ,Cbenzodiazepine 4-oxide (I)d 7-Chloro-l-methyl-~-phenyl-l,3-dihydro-2H-l,4-benzodia~epin-2-o1ie (II)e 8 9 11 3 >800 (2O)J 1,3-Dihydro-l-methyl-.S-phenyl-7-trifli1oromethoxy-2H-l,4-benzodiaze23 22 20 7 2.58 pin-2-one bisulfate (IXa) 2,3-Dihydro-S-phe~1yl-7-trifluorometho~y-lH-l,4-benzodiazepine (SI) 82 >50 >50 (40)f 8..i 328 1,3-I>ihydro-3-hydroxy-.i-phenyl-i-trifluoromethoxy-2H-l,4-benzodiazepin-2-one (XI-b) >lo0 >bo >30 (0)' 27 >270 ( 0 ) j Determined as described by W. B. Wright, Jr., H. J. Brabander, R. A. Hardy, Jr., and A . C. Osterberg, J . X e d . Chem., 9, 852 (1066). * Determined as described by E. A. Swinyard, W. C. Brown, and L. S. Goodman, J . Pharmacal. Ezptl. Therap., 106, 319 (19.52). Determined by a modification of method of H. h l . Hanson and C. A. Stone in "Animal and Clinical Pharmacological Techniques in Driig Evaluation," Tol. I, J. H. Sodine and P. E . Siegler, Ed., Yearbook Medical Publishers Inc., Chicago, Ill., 1864, p 317. d Librium". e Valium@. Figure in parentheses gives percentage of mice affected at highest test dose. TABLE I1 7-TRIFLUOROYETHOXY-
AXD 7-TFLIFLUOROMETHYLTHIO-~,4-BEKZODIhZEPINESA S D I N T E R M E D I A T E S I N THEIR
Yield, NO.
Compd
YG
Recrystn solvent
Mp, " C
PREP.LR.iTIOS
Forrnula
.1nalyses
VIa VIb \Xa
2-.4mino-~5-trifluoromethoxyberizopheno1ie~ 82 EtOH-HzO 91-92 C~~HIOFBSO? C, HI F, N 2-Amino-5-trifluoromethylt hioben~ophenone~ 100 EtOH-H?O 67-68 CiaHioFaSOY C, H, F, S , S Benzyl (2-benzoyl-4-trifluoromethoxyphenylcar49 C6H6-hexane bamoylmethyl)carbamatec 117-1 19 CiaHigF3N,Oj C, H, F, S VIIIa 1,3-I)ihydro-5-phenyl-i-trifluorornethoxy-2H-l,4benzodiazepin-2-onec 7A l\IeZCO-heuane 157-158 C~OH~IF,X;?O? C, H, F, X VIIIb 1,3-Dihydro-5-phenyl-i-trifluoromethylthi0-2H1,4-benzodiazepin-2-onec 18 hIe2C0-hexane 176-178 C,eHiiFaN,OS C, H, F, N ; Sd IXa lJ3-L)ihydro-l-methyl-S-phenyl-7-trifluoromethoxy-2H-l,4-benzodiazepin-2-onebisulfatee 85 PvlezCO-hexaiie 234-236 CiiHi3F3?$20?.HnSOI C, H, F, K, S 1,3-Dihydro-l-rnethyl-5-phenyl-7-trifluoromethyl- 61 JlezCO-hexane 181-184 C ~ T H ~ ~ F ~ F ~ O S . HC, IXb * SH, O IF, N thio-2H-1,4-benzodiazepin-2-one bisulfatee (gas 1 1,3-Dihydro-.i-phenyl-i-trifluoromethoxy-2H-l ,446 EtzO-petr Xa 187-188 CIGHI~FBN?OS C, H, F, N, S ether benzodiazepine-2-thione' 1,3-Dihydro-l-rnethyl-5-phenyl-i-trifluoromeXh 47 EtnO-petr 175-176 C17HisF3S20S C, H, F, N, S ether0 thoxy-2H-l,4-benzodiazepine-2-thionef 2,3-Dihydro-5-phenyl-i-trifluoromethoxy-lH-1,4- 43 CHzClz-EtzO XI 117-118 CisHi,F,SzO C, H, F, ?; benzodiazepineh 2-l\lethylmercapto-.3-phenyl-7-trifluoromethoxy- 90 l\IeOH-HzO XI1 82-84 CiiH13F3NzOS C, H, N 3H-1,4-benzodiazepine' XI11 2-Methylarnino-5-phenyl-i-trifluoromethoxy-3H- 80 l\lezCO-H20 176-178 CiiHi4F3N10 c, H, F, N 1,4-benzodiazepine' SIT' 1,3-Dihydro-~-phenyl-7-trifluoromethoxy-2K-l,4-87 MeZCO-hexane 197-198 CisHiiFaNzOa H, F, N; C I benzodiazepin-2-one 4-oxide' XVa 3-Acetoxy-lJ3-dihydro-5-phenyl-7-trifluorome71 MezCO-hexane 1.53-155 C18H13F,N204 H, F, S ; C' thoxy-2H-lI4-benzodiazepin-2-one~ XVb 1,3-Dihydro-3-hydroxy-5-phenyl-i-trifluorome79 3lezCO-hexane 201-202 C I ~ H I I F ~ N & C, H, F, ?u' t hoxy-2H-1,4-benzodiazepin-2-onek a LIethod A, ref 6. b Reference 9. c Reference 7. d S: calcd, 9.53; found, 10.02. e L. H. Sternbach and E. Reeder, J . Org. Chem., Reference 12. S. C. Bell, T. S. Sulkowski, C. Gochman, 26, 4936 (1961). f Reference 11. 0 Eluted by hexane-CHzClz (1:9). Referenre 13. C: calcd, 57.15; found, 56.67. and S. J. Childress, J . Org. Chem., 27, 562 (1962). 1 C: calcd, 57.15; found, 56.68.
VIb, this reaction was superior in the 7-trifluoromethoxy series. These results with VI and VI11 suggest a reduced nucleophilicity for the nitrogen functions in the trifluoromethylthio series, an observation qualitatively in accord with the behavior predicted by the substituent constants for the ORF and SRF g r o u p ~ . ~I n view of these synthetic difficulties other 1,4-benzodiazepines were prepared only in the 7-trifluoromethoxy series. Thus, treatment of the 1,4-benzodiazepin-2-ones VIIIa and I X a with P& in pyridinell gave the 2thiones X a and Xb, respectively (Scheme 11). Methylation of X a furnished the 2-methylmercapto derivative XII, which reacted with methylamine to furnish XIII. l1 Reduction of VIIIa with LiA1H4I2 afforded the 2,3(11) G. .1.Archer and L. H. Sternbach, J . 070. Chem., 29, 231 (1964). (12) L. H. Sternhach, E. Reeder, and G. A. Archer, nbtrl., 28, 2456 (1963).
dihydro-lH-l,4-benzodiazepineXI. Finally, oxidation of VIIIa with m-chloroperbenzoic acid gave the S-oxide XIV, which was readily transformed by the Polonovski reaction into the 2-acetoxy derivative XVa and then to the 2-hydroxy derivative XVb. l 3 Pharmacology.-Representative compounds were tested for their ability to induce ataxia, to decrease locomotor activity, and to afford protection against electroshock-induced and strychnine-induced convulsions in mice. The activities of our most interesting compounds are given in Table I ; comparable data for the 7-chloro derivatives I and I1 are included. These limited tests indicate compound IXa to have activity, potency, and acute toxicity similar t o that of the clinically effective compound I. (13) S. C. Bell and S..J. Childress, ibid., 27, 1691 (1962).
c,
H Xa,R = H h, R = CH
(,
H
SI
I
C, H; ST1
II
H
(',
XITI E1
X1V
>;\'a. li.
n = A( K=H
Experimental Section ALelting pc~iritawere detei,mitietl i i i opeii capillary tubes O I L :I Alel-Temp apparatiih aiid are ~iiic(irrecied. Prwedrirea ii>etl t(ir 1 he preparat ioti ( i f iiew compoiiiidh are indicated by the appropriate reference; when c.hr~matogi,;tphy was reqiiired for the isola1 ioii [ i f piire materialb, as confirmed by thin layer chromatography, 1 he details are >-iinimarized. .U c8hromatographywa': c.oiidiirted o t i a syiithetiv magiiesia-.~iIic*a.gel adsorbent, The petroleiim rther itred rva. the fi,ac.tioti boiliiiy at 30-60". 1Yhei.e analyse:we itidicated (iiily t)y synibc~lsof the elemelit;, atialyt ica1 resrilt. were within rt0.4f; of the theoretiral valiies. 3-Phenyl-5-trifluoromethoxyanthranil(Va) w w prepared t i ) . -1 triflriorometh>-l ether'b with I'lieluted with petrolerim ether--C:I1 lIeyC:O-H20) with dificiilty : 20' IlsFaSO!) C, 11, 4. 3-Phenyl-5-trifluoromethylthioanthranil(Vb).---Phenyl t 1.if~l~lif'O~lethpl siilfide (i34.5 g, 0.194 mole) wt-nitrated as dew'ibeti previorisly.li' I )istillation of the criide prodiic,t i2S a ) with :I apinitiiiy-baiid c ~ r l i i r n i igave 4 T " , of R mist lire of 0- aiid p-nitrophenyl trifliiororner hyl siilfitle.. C'i~iideii*atioii( i f L>.:3 g of t hi? tiiistrii'e with PhCII2CX w:i< c,ffec.ted n-ith niethxrirdic. KO€i.L.q The prodiic,t, i-oliireci w i t h ertwi,, K W tli.-solvetl i n pet roleiini ethet,-CIlrC1:! (:3: 1) aiid chrc~ni:~togf'aphetl.The inatwin1 c l i i t ed by pet rolerim ether-CH1Clp to fiirtii.sh 7.:14 y ( X f ~ ;of) )-ellow ( l i z d from lIeO€I-€I?O had rnp 07-!)X". .1 nwl. IC14HsF,NOSI ('! FI, N, S. I he remainiiiy i i e w c~c~niporiiitl~ :ire giveii i i i Table 11. r ,
Acknowledgment.-:\ 1icro:mnlyses i\-erc fiunished :\[I-. I,. 13r:incoiie :md hi:: st,:iff.
clq.yHc?HrlH BuNHCONHS02
0 V
unlibely, yieldq uiider compimihle react ion coiidiiioii. :I iiiono~nlfonjlurea derivative (I7)of very siinilnr st i w ture to 11. We t w :it :i lo+ t o cxplnin the u k r v c d differenceh uiider n hat :ippcws t o be cxl reactioii cottditioii5. Compourid I1 IVRS dtvoid of hypoglycemic activity i t i the guinea pig hut showed a diuretic poteiiry in rat e-sentially fquivaleiit t o that of hydrochlorothi:izi(~(.. but with :t ~oniew\.hat, better Sa IC ratio. ('ompoiind 5' \VAS much less potent than I1 ai n diuretic. agelit. 4
Experimental Section'
Sulfonylureas Having Diuretic Activity
6-Chloro-3,4-dihydro-7-( N-butylcarbamoyl)sulfamyl-2H-l,2,4benzothiadiazine 1,l-Dioxide.-To H soliition of 10 0 g (0.0.LX mole) of R-rhlor1)-.2,4-dihydro-'i-s~ilfamoyl-%H-1,2,4-ben~cithi~/ m e 1,l-dioxide ( I ) 111 34 nil (0.0336 mole) of 1 S SaOH and 34 nil of X e X O at loo, wa\ added :; 32 g (0.0336 mole) of n-biiiyl ( 2 ) F. lioraer in " O r r a n i c Sillfur C~~niporinds." T-ol. I. S . I,b:,i., Pergamon Press Inc., Sen- Y o r k , S . I-.,1861. p 495. ( 3 ) We are indelitrit IO I l r . -1 Maaw and D r . 11. R'alz and tlieir statis. these lahoratories, fiir t l l r luological test rmults. For the diuretic a w a y , t titi procedure of V. 13. \VirAelliaiis, F. T. Hrennan, a n d G . I . S
