KOTES
September 1966
775
TABLE I DERIVATIVES OF TETRAHYDROQUII~OLIKE A N D TETR.IHYDROISOQUINOLINE
T e t r a h l dro
x
basea
Q Q Q
e
CN C02C2H,
T
CS
Bp (mm) or mp, O C
----
'Iield
%
-
-Calcd, %-
H
C
5
20.08 4.62 10.93 20.08 4.62 10.93
74 62 5 30 6.98 C02C2H, 67 31 70 29 6,29 CS COzC2Hj 74 62 5.30 I-OQ CN CY 6.98 i6oQ COzC>H, CO2CzHj 67 31 isoQ CY COZC~H, 70 29 6.2Y Q = 1,2,3,4-tetrahydroqiiinohne, isoQ = 1,2,3,4-tetrahydroisoquinoline. 159-160 210 ( 1 5) 114-115 122-123 210 (1 1) 108-110
66 51 91 76 50 95
,----Found, C
I;--
74.81 67.13 69.93 74.73 67.26 70.39
n
s
5 32 7.02 6 . .iS 522 6.92 6.B1
21). 16 4.74 10.94 20.1s 4 64 10.S6
TABLE I1 L)ERIV.iTIVES O F
TETRAHYDROQ~ISOXALISE
CH=C,
/x Y
I
I R Yield,
R
Y
S
hfp, o c
CS
CS 178-17gn C02C2H, 121-122' H CK C02C2Ha Ollb H COzCzH, CH=C(CO~CZH,), CO2C>H, COGH, 116-1lic COCHXCH2Cl CY CN 140-142 CN C02ClHj 129-130d COCH2CH2C1 Recrystallized from methanol. b Purified by chromatography. = C02C2Hs by chromatography. d Recryytallued from ethanol. H
Q
R
7c----
-----Calcd,
-----
Found,
N C 49 68.56 4.80 26.66 68.35 ita 65.32 5.88 16.35 64.80 18 63.15 6.62 9.21 63.32 50 60.75 6.37 5.90 60.63 in 59,90 4.36 18.63 59.79 82 58.87 5,23 12.12 58.88 Recrystallized from ethanol after separation C
H
--
--
H
c7c-----
N
4.72 5 73 6.75 6 51
26.94 16.54 9.11 5.79 4.39 115.65 5.OS 12.00 from R = H , S = 'I'
TIBLE I11 An ~ I S E O P L I S T I C A C T I O SO~F
---lis cell ciiltiiree---EDsa, pg 'ml Slope
yo (T, C) dose,
m g hg-----------
LE^ ape DAJ Other i.wQ CK C?; 3 . 4 x 10' -0.8 91/200 58/400 95/200 iwQ CS C02C2Hj 7 . 9 X 10' -0.4 90/200 71/200 91/100 :3s/lOQ id2 COpC2Hj C02C2Hs 3 . 9 x 10' -0,s 1O%/100 60/100 lO9/50 Q CN CY 111.0 x IO' 90/4n0 79/400 120/200 142/208 97/200 127/200,h 76/23)' CS C02C2Hj 2 . 6 X 10' -1.1 -93/200 i n/200, I 93/200k Q C02C2Hi C02C2Hj a D a t a from Cancer Chemotherapy Sational Service Center. * isoQ = tetrahydroisoquinoline, Q = tetrahydroquinoline. EDjo = dose that inhibits 50% of control growth. Slope = difference in rewlt for a tenfold difference in dose. d L1210 lymphoid leukemia. e P1798 lymphosarcoma. Dunning leukemia (ascites). HS1 human sarcoma (rat, egg). Friend virus leukemia (solid). ' Cystadenocarcinoma of the liver. 1 Lewk lung carcinoma. Sarcoma 180. Baseb
S
I'
u
11). That these compounds were I1 and not some structure bridged between the nitrogens was demonstrated by the appearance of an S-H stretching vibration in the infrared and by the fact that they reacted with 3-chloropropionyl chloride to give I1 (R = COCH2CH2C1). I n the reaction of diethyl ethoxymethylenemalonate (I, X = Y = CO,C,Hj) and 1,2,3,4-tetrahydroquinoxaline a product could not be isolated by the ordinary means of purification used in this series.
When the reaction was run under more severe conditions and the resulting syrup chromatographed, I1 (R = H; X = Y = C02CzHb) and I11 were obtained. The antineoplastic screening results for the conipounds prepared are included in Tables 111 and IV. It can be seen that no outstanding activity is possessed by any of these compounds. It is of interest to note, however, that the two 3-chloropropionyl groups are apparently not necessary for the activity of
-I (i 1
‘
CH=C,
1,4- b i b ( 3 - chloropropionyl) - 1,2,3,4-tetrahydroyuinoxaagainst KB cell culture +ice I1 (R = COCHZCHZCl) is also active against this system.
liiic’”
Experimental Sections p,p-Disubstituted N-Vinyltetrahydroquinolines and -isoquinolines.-A solution of 0.05 mole of 1,2,3,4-tetrahydroquinoline or 1,2,3,4-tetrahydroisoquinolirieand 0.05 mole of the ethoxyinethylene compound (I)6in 125 nil of methanol was refluxed for I hr :rnd cwncentrated 2‘71 ~ ~ ( ‘ u oSolids . were rerrystallized from nieih:iiiol and oils were distilled i o give thr compounds listed in Tnblc I. 1-(P,p-Disubstituted vingl)-1,2,3,4-tetrahydroquinoxaline and 1,4-Bis( p,p-dicarbethoxyviny1)-1,2,3,4-tetrahydroquinoxa1ine.--.is described above 0.05 mole of 1,2,3,4-tetrahydroquinosalineaiid 0.1 mole of the ethoxymethylene compound (I) gave the compouiids of the type I1 as indicated iu Table 11. I n the case of cliet Iiyl ethosymethyleiiemal~n~i~e t wr) products were obtaiiied : ~ t i t ls e p r a t e d on acid-washed alumiir~i. I-(pJ-Disubstituted vinyl)-4-(3-chloropropionyl)-1,2,3,4-tetrahydroquinoxa1ine.--To :t :olut,ii)ii of I1 ( R = H ; S = C S : 1- = CY or COPC2€16) i n 123 nil ( i f mihytlrous chloroform :it 0” \vas added tiropniie, with cvinstniii -tirriiig, a colution of 0.05 niolc ( i f :S-chloropropioiiyl chloridr i n 20 nil of anhydrous CHC1,j. 1 h c mixture nns refluxed for ze il Iioriw, filtered, mid voiriittxtcd in m c u o to give, t ~ o n i p i i i i i i c l - 1vhic.h are iiicludrd i i i l l l l r . 11. - 7
(:arcinostatic Sulfonic Acid Esters of Butyneand Butane-l,i-diols’””’
Receiwd January 23, 1966
The synthesis arid evaluation of the anticancer propert’ies of substitut,ed benzenesulfonate est,ers of 1,4-butanediol and 1,4-butynediol was undertaken siiioe est’ersof alkariesulfonic acids2 have been found to il) (a) This work was supported b y Research Grant CA-06140 from t h e National Cancer Institute, Public Health Service. (bj Reported in part before the Medicinal Chemistry Division, 149th National Meeting, American
