NOTES
March 1966 Acknowledgments.-The authors are indebted to Dr. Peter Lim for the infrared interpretations and to his staff for the spectral data and paper chromatography. The authors also thank Dr. Lois Durham of Stanford 'C'nirersity for some of the nmr interpretations.
TABLEI SCREENING DATAIN THE WALKERC.~RCIXOS.ARCOYI 256 (SUBCUTISEOUS) SSSTEM
Compd
Compounds Derived from L-Threitol 1,4-Bismethanesulfonate PETERIT, FEIT Leo Pharmaceutzcnl Products, Ballerup, Denmark Receiwtl September 18, 1965
I n continuation of the synthesis of the 1,a-bisniethaiiesulforiates of the stereoisomeric butaiietetraols arid related cornpouridS,l arid for reasons already discussed' we prepared the following derivatives of L-threitol 1,4bismethane.ulforiate (I) with the purpose of obtaining substances for investigation as anticancer agents, and of getting further information about the structureactivity relationship of this type of alkylating agents : di-2,3-0-carbethosy-L-threitol l,~-bismethaiiesulforiate (11), the 2,3-cyclic carbonate of I (111) [L-4,5-bisiiiethylsulforiyloxyniethyl-l,3-dioxolaiio1ie-(2) 1, arid the 2,3-rgclic sulfite of I (IT) (L-4,5-bisniethylsulfonglosyniethyl-l,3,2-dioxathiolarie2-oxide). The coinCHLOSOICH~ I CH-OR I
RO-YH CHzOSOzCH3 I,R=H II,R=CO~CZHS
"'7
C Ha0 S02CH3
'0
CH20S02CH3 111, x = co
IV, x =so
pounds were obtained by reaction of I with ethyl chloroformate, phosgene, and thioriyl chloride, respectively. Screening by the Cancer Chemotherapy National Servire Center, Xational Institutes of Health, has revealed no significant diff erence in antineoplastic activity betweeti these derivativer and that of I,2 as far as the Kalker carcinosarcoma 256 System is concerned. Moreover, in the KB cell culture system the EDja determined for I1 is more than ten times as high as that of I, 111, and IV. summary of the test data is presented in Tables I and 11. L\
Experimental Section3
Di-2,3-O-carbethoxy-~-threitol 1,4-Bismethanesulfonate(II).-
To a so1ut)ioii of L-threitol 1,4-bismethanesulfonate (10 g) in pyridine (50 ml), ethyl chloroformate (8 ml) was added dropwise while stirring at 0 to 5'. The mixture was stirred for additional 30 min, kept in a refrigerator for 40 lir, and then poured into 4 N HC1 (100 ml) while cooling. The separated oil was extracted with chloroform, the organic layer was washed several times with water, and after drying (3IgSO4) the solvent was removed by evaporation in ~acuo. The residue was triturated with diethyl ether, and the resulting cryst,alliIie material (12.7 g) was recrystallized from benzene-diethyl ether (decolorizing carbon) The analytically pure yielding I1 (10.2 g) with nip 55-61". (1) P. \Y.Feit, J . .\led. Chern., ?, 14 (1964). (2) F. R . K h i t e , Cancer Chrmotherapv R e p f . , 24, 95 (1962). 13) Analyses were by G. Cornali and W. Egger of these laboratories. lleltinp points u-ere taken in open glass ?apillaries and rounded off t o half degrees. using a Hershberg apparatus with thermometers subdivided in 0 . l o . Technical assistance mas b y T h . Rolle.
241
Daily dose, mg/kgQ
Ifean tUmOT weight test/ control, Survivors
c /O b
EDsc.' mg/kg/day
I1
200 616 0 100 616 6 120 95 50 6/6 --( 3 616 25 I11 200 6/6 0 100 616 47 130 50 6/6 70 '25 616 92 I\' 200 6/6 0 100 616 17 130 50 616 48 25 616 105 Administered ip once daily, days 1 through 5 postinocnlation. b Sacrificed and evaluated 10 days postinoculation. c The dose that, inhibits growth to 10% of control growth.
SCREEXIXG D.AT.IIN
T-IBLE I1 K B CELLCULTURE SYSTEN
THE
EDsc,' Compd
irg/
ml
Slopeb
IC
5.0 -0.43 11 -0.56 3.6 -0.28 I1 >I00 I11 7.2 -0.54 I\' 9 .s -0.55 The dose that inhibits growth to 50% of control growth. b Change of response for each 1 log change of dose. Tested a t different days. compound was reached by filtration of a solution of crude I1 in benzene through aluminum oxide (anionotropic, activity grade I), evaporating the filtrate in U U C I I O , aiid triturating the residue with a small amount of benzene, affording crystallization, followed by recrystallization from chloroform-diethyl ether, nip 62-64" (shrinking at S o )[ ,C Y ] * ~ D-9.5" ( c 2 , acetone). Anal. Calcd for ClaHU20&: C, 34.1%; H, 5.25; S, 15.18. Found: C, 34.17; H, 5.31; S,15.15. ~-4,5-Bismethylsulfonyloxymethyl-l,3-dioxolanone-(2) (III).To a solution of L-threitol 1,4-bisniethanesulfonate (10 g) in pyridine (40 ml), a solution of phosgeue (4.5 g) in diethyl ether (20 nil) was added dropwise while stirring at 0 to 5'. The reaction mixture was kept in a refrigerator for 70 hr and then poured into a mixture of 4 .V HC1 (100 nil) and ice. The solid (10.5 g) m-hich separated was filtered off aiid recrystallized from acetonediethyl ether ( 7 5 ml each) (decolorizing carbon), yielding crude 111 (7.9 g) with mp 123-125". The analytically pure and colorless I11 was obtained by filtration of a warm solution of the crude material in acetone through aluminium oxide (anionotropic, activity grade I), and precipitation by adding diethyl ether to the filtrate, followed by recrystallization from a small amount, of acetone, mp 126-127", [ a I z a D -62.6" ( c 2, acetone). Anal. Calcd for C,HI2O9S2: S, 27.63; H, 3.95; S, 21.07. Found: C, 27.82; H, 4.19; S, 21.01. ~-4,5-Bismethylsulfonyloxymethyl-l,3,2-dioxathiolane 2-Oxide (IV).-A suspension of L-threitol 1,4-bismethanesulfonate (IO g) in SOCle (25 ml) was refluxed for 45 min. Bfter cooling, the obtained solution xas evaporated to dryness in zlucuo. The oily residue was treated with benzene ( 2 5 ml), and the evaporation was repeated. The crystalline residue was dissolved in ethyl acetate (200 ml); the solution was washed twice with water, dried (31gS04), and evaporated in z'acuo to yield IT (11.5 g) with mp 97.5-99". The crude material was recrystallized from ethyl acetate (50 ml) and redissolved in Tvarm ethyl acetate (75 ml); the warm solution was diluted with diethyl ether (50 ml) and chilled after filtration over decolorizing carbon removing turbidity, mp 98.5-loo", [ a l Z o D -105.5' ( c 2, acetone).
.Irrcrl
Found
C a l d for CCH120&. C', 2 2 . 2 2 . H, XZ3, d, 29 65. C, 22.30: H, 3.80; S,29.70.
Acknowledgment.-The author i- indebted to thcb C:tiicer Chemotherapy Xatioiial Service Center, ?;ational Institutes of Health, Bethestla 14, JIarylaiid. foi the screeriirig of the coiiipouiid- aiid for iiiakiiig th(1 results avnilahle.
Synthesis of Grisan and Coumaran-3-one Derivatives with Potential Insect-Repellent Properties'
111 developing btructurul deiigiis for conipountl\vhic.h would prove effective a- sy+temically admiiiiztwed in-ect repellent-, we -ought to (,omhilie withiii :I niriglc iriolecule ( I ) :I compoiiciit l , r n a k L 81, , 662 (1960). (PI I-'. .1. Rotti, J r . , and €1. I
