Journal of Medicinal Chemistry, 1971, Vol. 14, No. 6 549
NOTES H2O was added t o ppt 4.4 g of 11. Other compds in Table I1 were obtained by this method. 2-(~-Methyl-a-hydroxybenzyl)benzoxazole(9).-A soln of 10 (2.65 g) in anhyd Et20 (50 ml) was dropped slowly into a soln of MeMgBr (1.36 g) in 50 ml of anhyd Et20 with stirring and cooling. After 6 hr a t room temp 30 ml of H20 and 1 ml of concd HC1 were added, and the org layer sepd, was washed with H20, and dried (JIgSO,). After evapn of the solvent, 1.6 g of white solid (9) was collected. 2-(a-Methyl-a-hydroxybenzyl)-5-chlorobenzoxaeole (LO)was obtained in the same way (Table I).
COCH,R
oqx7 H
1, R = H 2,R=Br 3, R = NBu2
Acknowledgments.-The authors wish to thank J. Sorge and K. Young for carrying out the antiviral experiments. The financial assistance of the SRIInstitute Research and Development Program is acknowledged for the antiviral studies.
3- and 4-Carbazole Dialkylaminocarbinols as Potential A n t i m a l a r i a l Agents
4
COOH
CQO
The important role of quinolinemethanol compounds in malaria chemotherapy has prompted the investigation of other heteroaryl carbinols for antimalarial activity. Accordingly we have synthesized 3- and 4(a-hydroxy-P-dibutylaminoethy1)carbazoleand tested the compounds for their antimalarial action against Plasmodium berghi in mice. Unfortunately neither compound showed significant activity in this test system, as shown in Table I. TABLE I
_____ Antimalarial Compd
40
610
4 0.3 0.3 0.5 8 0.2 0.4 0.8 a Increase in survival time (days) of treated mice beyond that of untreated controls after single sc dosages 13 days postinfection). Average survival time of untreated controls was 7.0 f 0.5 days. The infecting organism was P . berghei.
The synthesis of the 3 isomer began with 3-acetylcarbazole 1 followed by bromination and reaction of the bromo ketone 2 with BuJXH. Reduction of the amino ketone 3 with NaBH4 readily afforded the amino alcohol 4. The acid chloride of carbazole-4-carboxy1ic acid 5 was treated with CHZN, to give the chloromethyl ketone 6. A similar displacement with But" and reduction yielded 8. Experimental Section Compounds followed by empirical formulas only were analyzed for C, H, N with values within f0.47, of theoretical. 3-Bromoacetylcarbazole @).-A mixt of 10.7 g (0.029 mole) of PhMe& +.3Br-, 6.0 g (0.029 mole) of 3-acetylcarbaxole1 (I), and 100 ml of T H F was stirred a t room temp for 5 hr, then evapd in vacuo. The residue was thoroughly washed with H20 and Et20 to yield 7.1 g (86%); mp 158-159"; anal. sample, mp 160162" (CsH,). Anal. (ClaHloBrNO): Br. (1) E. Meizner, J . Amer. Chem. Soc., 57, 2327 (1935).
H
5
6,R=C1 7, R = NBu, CH(OH)CH,NBu,
oqo I
H
Received January 22, 1971
bioassay resulta----Dose, mg/kg-------160 320
@
H
VERNON H. BROWN, MOSSOOR KEYANPOUR-RAD, AND JOSEPH I. DEGRAW*
Lzfe Sciences Research, Stanford Research Institute, Menlo Park, California 94025
YOCHZR
I
8
3-Dibutylaminoacetylcarbazole (3).--A mixt of 7.4 g of 2, 40 ml of n-BuzNH, and 150 ml of MeOH was refluxed 3 hr and evapd in vacuo, finally at 1 mm. The residue was treated with 200 ml of H20, acidified to pH 1-2 with concd HC1, and washed with 200 ml of EtOAc. The acid phase containing much insol, oily HC1 salt of the product was alkalized with 10% XaOH to pH 10-11. The oily ppt was extd into 200 ml of E t 2 0 which was washed with HgO, dried (MgSO;), and evapd to leave 4.4 g of syrup. After two pentane washes the syrup was dried at 1 mm to leave 4.0 g which solidified. A portion was recrystd for anal., mp 106-112" (pentane-CsHs). Anal. (C22H28NzO): C, calcd 78.5; found 78.0. 3-(a-Hydroxy-p-di-n-butylamino)ethylcarbazole(4).--,4 mixt of 4.0 g of 3, 1.5 g of SaBH,, and 150 ml of EtOH was warmed into s o h and stirred for 20 hr a t room temp. The solvent was evapd in t'acuo and the residue was partitioned between E t 2 0 and H2O. The Et20 was dried (MgsO4) and evapd to leave 2.7 g of gum, which was extd with three 90-ml portions of boiling pentane. The ext was gassed with HC1. The hygroscopic salt was collected and triturated Tyith 10 ml of Me2C0 and the white cryst were collected (1.10 g, 23170), mp 165-168". Anal. ( ( 2 2 2 HJTzO HC1). 4-C hloroace tylcarbazole (6 ).-The mixt of te trahydrocarbazole-5- and -7-carboxylic acids2 was readily sepd as the Me esters by silica gel chromatography. Dehydrogenation of the 5 isomer followed by saponification afforded 4-carboxycarhazole (4j.3 A s o h of the acid chloride (from 3.16 g of acid and 1.1 ml of SOCl2 in 50 ml of CsHs) in 40 ml of CHzC12 v a s added dropwise to 45 mmoles of CH2X2 in 150 nil of Et20 at 0-5". After 1 hr at 0-3" the soln was gassed with HCI for 20 min arid evapd in vacuo (2.52 g). Chromatography on silica gel gave 2.07 g (57170), mp 158160.t5". -4nal. (ClrHloCINO). 4-Dibutylaminoacetylcarbazole (7).--h mixt of 1.47 g of 6 and 20 ml of B I I ~ K H was stirred at 35-10' for 15 hr. 4 work-up similar to that for the 3 isomer gave an orange syrup (1.0 g, 497,), which slowly crystd; recryiitd, mp 196-204' (EtOH). Elemental anal. and bands at 3.9-4.2 M in the i r indicated a carO)~' bonate salt. Anal. ( C ~ U H Z , N ZH2C03. 4-(~-Hydroxy-~-di-n-butylamino)ethylcarbazole Picrate ( 8 ) . -The ketone 7 was rediiced with NaBH4 in EtOH as above to yield a yellow syrup (367,). The picrate, mp 1i4-179", \vas obtained from EtOH-H20. Anal. (C2sH33NjOa). (2) W ,RI. Collar and S . G. Plant, J. Chem. Soc., 808 (1926). (3) P. H. Carter, S. G . Plant, and M . Tomlinson, z b t d . , 2210 (1957).
NOTES
550 Journal of Medicinal Chemistry, 1971, Vol. 14, S o . 6
work was supported by the
TABLE I
TJ. S. Army Medical Research and Development Com-
Acknowledgment.-This
ACTIVITY OF
mand under Contract 30. DADA 17-67-C-7129. This is Contribution Kumber 890 from the Army Research Program on Malaria. --.
Antimalarial Agents. 7. Compounds Related to 4,4’-Bis(aminopheny1) Sulfone’ IT..IS C. POPOFF,* G O P ~1%. L SISGHAL, \ E ~ DA L L ~ R N. E N G L ~ Pennwalt Corporatzon, Kzng of Prussia, Pennsylvania
19406
4,4’-Bis(acetamidophenyl)sulfone (I) and its loner homolog (11) are highly active2 against Plasmodium berghei in mice. Since they are less toxic2 than 4,4’bis(aminophenl1) sulfone [4,4’-diamino(diphenyl sulfone), DDS, 1111, it was of interest to investigate the antimalarial activity of some other DDS-related compounds in which one or both S H ?groups of I11 were replaced by ?;SO, S H O H , S H S H ? , XO?, etc. Our study also included structures containing the moieties S, SO, SOLCH*,and SOzS instead of the SO2 bridge, as v ell as a pyridine analog of DDS. The N-sulfinylamines XI1 [mp 149-152”, from P h H , 627, yield, Anal. (CI2HBX2O;S~) : C , H, N ] and XXIII [mp 126-128’ from 1 . 1 petr ether-PhJIe, 86% yield, A??al. (C12H9NSL03). X ] \$ere slnthesixed from the corresponding amines by the method for 4,4’-bis(sulfinylaminophenyl) sulfone (IT.’)described in the Experimental Section, which includes the preparation of the remaining new compounds. The testingIc nas carried out by n method described p r e v i o u s l ~and ~ the detailed data are listed in Tables I-IV. S o n e of the compounds reported here was more active than I in the mice test. Replacement of one of the KH2 groups of D D S (111) with H or C1 resulted in total loss of antiplabmodial activity (XXII-XXVII) but not of toxicity (XXII). The oxidation of one K H L to KO?, however, did not render the resulting structures completely iiiactir’e provided that the second KHZ of 111 N L L Snot disubstituted as in the inactive VII, XIV, XVII, and XX. The activity of the sydnones XVIII arid XIX, and of the N-sulfinyl itructure XII, in nhich the second S H ? is disubstituted, can be explained by the relative ease of hydrolj of the sydnonyl and S-bulfin>I moieties to S H K H , (XIII) and S H ? (XI), re-pectively The relative activity of the pairs I-VIII, I-IX, J7-XI, and VIII-IX leads to the speculation that :I p o 4 b l e metabolism of the 5 0 2 group t o KH?, rather than the reverqe, could be part of the mode of action of lied Chrm , 13, 1002 (19i0) (13) this study \\as supijorted ti> U s IrmL Medical Researclr and De\elopment Command This 13 C ontrihution S o 889 from the i r m l Research Program on JIalaria, (1) the Lompounds uere tested b \ Dr L Rane of the Unilersitv of Miami, E lorida (d) anal! ses are indicated I)\ ‘5 inhols of t h e elements smce ana1, tical results olxained for t l m e elements uere nithin & 0 47, of the theoretical \sluef 2 j 1 est data -iiriplied t i \ I)r Icing Poon of \\ alter Reed i r m s Institure for Re-earcii ( < ) T S Ostlene I’ I3 Russell and I Rane J lied Chem 10, 4 3 1 (1‘4tji)
R’
IIIa IV
R‘ R’ ;CHI KH?
VIIId
IS* Se
Recewed January 12, 1871
1) ‘ a ) Part 6, J
I“ IIQ \-* VIC VIIC
SIf SI1 XIIIC SIVC SVC SVIC SYIIC SVIIIC S I S C
IS SSI ISIIQ s sI1I SSIV SSV SXVI SSVII SSVIIl
---Structure-----
R
No.
9 cures or (CIsTh) a t m g j k g
SHAc SHCOJi u II?
nl
sso
KO1 NHOH
20 (10.4)
(0.2) (8.3) 60’
K m0
SH!
“.\e SH> N.30
KO?
KO2 SO? SO? SO? SO. SO?
.10
10
(8.2) (6.6)
sHS 1 x 3
10 1001
(13.9) (0.2) 13 1) (2 0 ) (0 2 ) (35) 153) 105) (Li) (13)’ 10.8)
ii.icCHK02Et SHCHzCOXEt N(NOjCH?CO?II SIICIIzCOzH
Y ( R ” = 11) I - ( K ” = Hr) S ( . l c ) C H (hle)COzE t S 1%C H (XIe j COgE t
NO2 SO? SO? SO? 11 H tI I[ (‘I C‘I SO2
100 100 40 20 100 20 (0 2) 80 60 6ok
(11.8)
NH O H NHXH? S (NO)C H C O X ” KHAc
NH?
160
40 20 20 (8 0 )
R‘
SH?
(0.2) (7 7 ) (7 3 ) (0 2) 90 40
(07) ($4.7)
YtR” = H j SrN0jCN?CO,~l j’1R” = I f )
9) 105)
f-11) (12) (O.!)) ( O i )
( 1 A) (0 7 )
( 0 7) (1 5)
Y-CO
foi)
1oiJ
&-SO ?u’ lICH?COIEt
1
IO
640
100 60m 20m m m 40’“ (0 6 ) 80 100 40“‘ 100
GO”’ n (0 2) 80 40
m 60 80 !1.9) 80 (t4j”l (18) 11 11 (1.Y) fil
7) (().I, Khovalko, Zh. Obsch. lihim., 31,3483 (10611: Chem. .4bstr., 57, 971% (1962). f C. Bere and S. Smile.;, .I. Cheni. Soc., 2359 (1924). B. I:. Baker and .\I. V. Qiierry, Pee J . Org. Chem., 15, 413 (1950): See footnote h of Table I. Table IV for toxicity data. j 2 O C ; riires at, 320 nig,’kg. lL
