325
SOTES
hIarch 1969
Rc~, SCHEME I
H -,NH~
2 SnCll
\
I 1. CH,COCH,CH-COOC?H~
I11
I1
T.\nm I1 SUBBTITL-TLD INDOLESCTL HYDRAZIDES
TABLE I ETHYL %,5-1)ISC Deriv of eth>I ~ndole-3-acetate
2,,5-11e2 2,7-lIe2 ?-Ale 2-1 1e-.i-OlIe
USTITUTED INDOLEACETATES
BP, O C (mm)
Yield,
170 ( 5 ) 180 ( 5 ) 135-138 ( 5 ) 180 (6)
58 45 ,5 5 50
%
Formula
CiJL7NOz CiJIi7KO) CISHIJNO? Ci4HiiTOi
RI Yield,
R
R1 H
H
In the present study attempts have been made to inveatignte the structure-activity relationship of these compounds n i t h respect to their ability to inhibit rat liver 1IXO. The various substituted indole derivative< n ere Yynthe4zed hy the route outlined in Schenie I.
Ri CHI
lip, 'Ca
o/c
Formulab
136 70 CliH13?j30 60 CiiH13N30 133 CHJ H H CHJ H CH3 156 70 CizHioKIO H CHI CHI 140 70 C1?Hi:x30 CHIO H CH3 158 70 CuHijX30 a lleltitig points were taken in opeii capillary tubes and are graphically corrected. b All compounds nere analyzed for C, H, N and analyses were found within limits.
Experimental Section Substituted Alkoxy- and Alkylphenylhydrazines (I).-The hydrazines synthesized according to the methods reported earlier6 were o-methyl-, p-methyl-, aiid p-methoxyphenylhydrazine. Ethyl 2,B-Disubstituted Indoleacetates (IL).-Cyclization of siibstitiited phenylhydrazines and ethyl levulinate in 2 -VEtOHHCI was wed. The crude prodiicts'-I0 isolated with Et,O were washed (KaHC03, H,O) and distilled under rediiced presslire (Table I). Substituted Indoleacyl Hydrazides (MI).-The various SLIDstitiited ethyl indoleacetates (0.1 mole) were refluxed wi-h hydrazine hydrate (0.15 mole; 8 0 5 ) in 25 ml of absolute EtOH for 8 hi,. On dktilling excess E t O H the hydrazides which separated out were filtered and recrystallized from appropriate solvents. The hydrazies (Table 11) were characterized by their sharp meltiirg points aiid elemeiital analyses. Substituted Indole Isopropylidenehydrazides (IV).-SiiI)htitnted indole hydrazides (0.2 mole) and 50 ml of l l e z C O or E t C O l I e were refliixed for 13 hr. The reaction mixture wts filtered hot and c.oncenti,ated in UUCZLO. On cooling, the solid mass which separated out was filtered and recrystallized from the appropriate solvent (see Table 111). Substituted Indole N-Isopropylhydrazides (V).-A solution of
CH, CH, 142 .io CIa&S3O H H CH, C2H.j 140 60 CiaHigSaO CHI H CHI CH, CHI 16.5 60 CljHlnSIO CH, H CH, CH, C ~ H J 170 55 Ci,H?iSsO 138 60 Ci;Hi,NoO H CH3 CHa CH3 CHI 50 Ci6H?iN30 H CH, CHa CH, CrH: 168 60 CijHiiiT302 180 CH3O H CH, CH, CII3 1:3.i 30 CisHziNsOr CH3O H CHI CHj CiHj LCIeltiiig points were taken in open capillary tubes and are graphically corrected. 6 All compounds were analyzed for C, H, N and anall-ses \%-erefound within limits.
(61 Ii. G . 13lackie a n d Ti-. H. Perkin. J . Chem. Soc.. 125, 296 (1924). (71 E. V'alton. C. H. Stammer. R.F. Xutt. 9. R. Jenkins, a n d F. It-,Holly, . I . .Wed. Chem., 8 , 204 (1965). ( 8 ) I'. J. Stex-ens and C. F. S u , J . Org. Chem., 27, 500 (1962). '9) 11.It-, I3ullock and S. Fox, J . Am. Chem. So?., 73, 5155 (1951). (10) I:. Slian-, ? b i d . , 77, 4319 (1955).
2 g of a substitilted indole isopropylidenehydrazide (0.01 mole) in 150 ml of absoliite EtOH was hydrogenated with 0.1 g of PtO, a t an initial pressure of 2.8 kgIcm2. The required amount of H2 was absorbed iii 15 hr. The mixture was filtered and the
I Ri
Mp.
R
H
RI
H
Kj
R3
R4
"c"
Yield,
'.;
Formulah
CH, CHI
0
