803
SOTES
November, 1963
TABLEI 7-Oxabicyclo [ 2 . 2 .I]heptane-2,3-dicarboximides
X
R'
1. Hydrogen 2. Hydrogen 3. Hydrogen 4. Hydrogen 5. Methyl 6. Methyl 7. Methyl 8 Methyl 9. Ethyl 10. E t h l l 11. Propyl 12. Butyl" 13. Amylb 14. Hexyl' 15. Heptyld 16. Octyl" 17. Xoriyl' 18 Decyl8 19. 2-Hydroxjethyl 20. 3-Methoxypropylh 21. 3-Iwpropoxypropyl' 22. Benzyl 23. 4-Methosyphenyl 24. Hornover:itr> 1 25. 2-Pyridyl 26. 4-Carboayphenyl
1LI.g.,
H H H
185 160-161 lil-li2°
CH,3 H H" H CH, H
205-20b 1 35
Hydrogen Calcd. Found
Carbon Calcd. 1;ound
oc
6.66 6.08 6.65 6.54 7.34 6.54 7.39 7.09 7.78 7.88 8.23 8.57 9.02 8.91 0.28 9.15 ll.51 9.48 6 . 2 0 6.13
5.34 5.96
- --
H
15H-160
H
52-5:3
60,23 60.45
7.16 7.24
5.85 5.73
H
1 14-115
62.90 63.01 70.05 70.02
7.92 7.80 5.88 6.00
5.24 5.37 5.44 5.29
H
180-190 106-107 162-163
65.92 6.5.95 65.24 65.24 63.92 63.W
5.53
H H H
265-266
62.71 62.58
4.56 4.73
H
H H H H
H H H
54-56 10s 128 3 165-166 95-98 78-70 80-81 66-67 30-31 66-67 33-34 41-42
H
Oxygen Calcd. Found
8.38 8.63 7.73 i . 1 0 7.73 7.57 7.18 6.99 7 . 7 3 7.83 7.18 7.09 7.18 7.41 6.69 6.66 7.18 7.2s 6.69 6.78 6.69 6.76 6.27 6.44 5.90 6.15 5 , 5 7 5.66 5.28 5.30 5.01 4.98 4.77 4.83 4.56 4.*55 6.63 6.52
5.43 6.12 6.12 6.71 6.12 6.71 6.71 7.23 6.71 7.23 7.23 7.6s 8.07 8.42 8.74
57.60 59,65 59.46 61.61 -59.56 61.54 61.48 63.14 63.02 61.52 61.65 63.14 63.25 63.14 63.05 64.55 64.44 65.80 65.98 66.90 67.18 67.89 67.73 68.78 68.78 6 9 59 69.65 70.32 70.40 36.86 57.04
H
57.48 59.66 59.66 01.52 59.66 61.52 61.52
Xi t I'ogen Found Calcd.
6.12
28.72 28.69 26.49 26.38 26.49 26.72 26.49 26.63
24. *59 24.65
22.94 22.94 21.50 20.23 19.10 18.10 17.18 16.36 15.61
23.13 22.90 21.62 20.33 lCJ.26
18.09 17.40 16.48 15.50
5.71 5.13 5 ,30 4.23 4.37 6 . U 6.24 4.95 5.00 11.47 11.56 4.88 4.51
Related Imides and Isoindolines n
z _ _ ~ _ Analyses, _ %------------A
X
Z
Empirical formula
Carbon Calcd. Found
Hydrogen Calcd. Found
Nitrogen Calcd. Found
3-Methpl-3,6-epoxycyclohexane-1,2- Ethyl 72.88 72.93 10.56 10.85 7.73 8.02" CIIHI&O~ 2H C?aH43SO?' 76.34 76.38 11.48 11.71 3 , 7 1 3.99 0 Octadecyl Cyclohexane-1 >282.44 83.60 13.55 13.65 4.01 Cz*Ha.iKLn 4.20' Cyclohexane-1,POctadecyl 2H 1.01 1.13 36.16 36.12 4.68 4.82' 0 CsH3ClJO:" J14,5,6-tetrachlorophenyl-1,2Methyl a B.p. 115-125' (0.3mm.). B.p. 130-140" (0.3 mm.). B.p. 137-145"(0.2mm.). B.p. 153-160"(0.2mm.). e B.p. 155-165' (0.3 mm.). B.p. 163-170"(0.3 mm.). BB.p.166-176' (0.3 mm.). B.p. 130-133" (0.2mm.). B.p. 144-154" (0.2 mm.). 71,2Dimethyl, from Cantharidin. B.p. 86-87" (3.5-4nim.). B.p. 188-194" (0.2.3 mm). B.p. 164-166" (0.25mm.). N.p. 208rndo-cis configuration. All others, exo-cis configuration. 1' Hydrochloride, m.p. 139-14O0. d n a l . Calcd. for C11H&1?;0: 210'. C1, 16.28. Found: C1, 16.19. Methiodide, m.p. 120-121". Anal. Calcd. for CI?HJXO: I, 39.26. Found: I, 38.90. Hydrochloride, m.p. 1x4-185'. Anal. Calcd. for CZ4H,,ClX: C1, 9.18. Found: C1, 9.09. Methiodide, n1.p. 221-222". -Anal. Calcd. for CzjHjoIS: I, 25.82. Found: I, 26.09. Allyliodide, n1.p. 172-173". A n a l . Calcd. for Cz;HgJX: I, 24.52. Found: I, 24.68. Butiodide, ni. p. 199-202'. Anal. Calcd. for C2811561S:I, 23.78. Found: I, 28.XT. Ihdeciodide, m.p. 231-232". Anal. Calcd. for C3&8IS: I, 20.54. Found: I, 20.47. -4nai. Calcd.: C1, 47.44. Found: C1, 47.20.
'
'O
O
5-180 and Ch-755 except the methyl imide of ring system 4. The dimethylhydrazine imides (Table 11) were inactive. Compounds which passed one 01' more stages j i i the secluential screening procedure against 5-180 or Ca-7.55 ti^ listed i l l Table 111, togcther with values for a felv
"near misses" of closely related structural types, for comparison. In general the methyl, butyl (or hexyl), and decyl derivatives were tested and activity was discmwed i i i the loiiger alkyl rhaiiis, primarily the quateri i a i y salts, cwept i i i the caw of ring 7 in which little diffcrcuc*ct)etwcwll liaw a i d c l u a t c ~ ~ a rconfiguratiori y
804
.\ccoidiiigly, ail oc.tadec.yl dei 11 ati\.e \\ as made aiid a group of cjuateiiiaiy salts piepared from it. Toxicity wa5 iiicreased, as npected, aiid activity decreased. A11 possible peimutatioiis of the dialkglnmiiioalkyl aiid heterocyclic alkyl side ctiaiiis aiid ring bystems were uot studied as this would in\-ol\e thouhaiids of compouiids. I-€o\veiei , I cpresei1tatii.e membci s studicd iwealed acti\ i t s agaiiist S-180 and Ca-755 i i i the 131s-quateriiary salts of tlir Ion e1 dialkyl (methyl. et 1iyl)amiiioalkyl ( n = 2 d ) 1~011idolii1e~.The basic. ,stiuctui.eb (ab hydiochloiide~)appaieiitly. oil the bash of limitctl data, uiidergo a icversal n-itli the longer I?' gi'ouph aiid / i values >3, :LC. t li(1 dietliylamniohexyl deiivativc of riiig 2 is moip acti1.t. thaii i t 3 t)is-cjuatri~ i a i yi o i i . The morplioliiiopiopyl del i\-atii.ea were t hc most acti! e of the side ehaiiih stutiictl \ \ a s hec'ti.
a Tj(' limiting vnlues for ttie threr stages of the secjuentinl :iii:ilysis for synthetirs itre 2 0 5:i; O . l ! ) : O . O i . 13lanks in t h e w c , i i l u i i m s represent negative data while those in the IC13 colurnii rrprrsent no screening ci:it:i :i\vdiihlc~.
, Y
1 lie tissue culture data permit i i o Coiiclusioiis exrcpt that compounds within the basic structure studied are capable of producing giowtli iiihibitioii at T
