September 19RS
INSECT CHEMOSTERTLANTR. VI1
the combined filtrates were dried (MgSOd). Removal of the drying agent and solvent left 28.24 g of a yellow liquid. Shortr path distillation gave 2456 g (77.5'5) of 11 (ea. 99% pure by glpc). A single redistillation gave the analytical sample, n% __ 1.4932, bp 7i' (0.005 nim). Anal. (C?H&lN;OP) C, H,-X, P. Isolation of N-Methylformamide from Oxidation Mixtures.I n various oxidations of 1 (Table I ) and in the oxidation of 3 to 6, a low-boiling product was noted in the initial distillations of
96 1
the criide products. The volatile material was identified as N-methylformamide by comparing its ir spectrum with that of the authentic compound.
Acknowledgments.-We thank A h . E. L. Gooden and Dr. John L. Ruth of this Division for the pmr and mass Spectra, respectively.
Insect Cheniosterilants. VII.' Oxidative Degradation of Hexamethylmelamine
The chloroform- and ether-soluble products of the oxidation of hexamei hylmelamine with potassiirm permanganate were identified as methylmelamines and mono- and diformylated methylmelamines. The formyl compounds were also synthesized by formylation of methylmelamine\ wii h formamide o r wit h formyl fliioride.
I n conjuction with our study of the metabolism of hexaniethyliiielaniirie ( H E I I E L ) in male house flies, Sfusca domestzca L., we have investigated the oxidation of this chemosterilant with aqueous potassium permanganate. Our previous experiments with the cheinosterilant HEAIPA (hexamethylphosphoric triamide) showed that this dimethylamino coinpound was demethylated in uwo3 and in vztro' to the corresponding peritaniethyl derivative. The pentamethylphosphoric trianiide is a much less effective sterilant than HERIPA and its further oxidation or deniethylation does not yield active chemosterilants. On the other hand, a gradual demethylation of HEMEL leads to compounds of considerable activity that sonietimes surpasses t h a t of the initial c ~ i n p o u r i d . I~n~ the ~ present study, we have isolated and identified the chloroform-soluble and ether-soluble products of the oxidation of H E J I E L : all were derivatives of s-triazine. The possibility that other s-triazines which were not extracted with chloroform or ether still remained in the mixture cannot be entirely eliininated but the solubility characteristics of most triazines which could be formed by oxidizing H E J I E L do not support it. The mildly exothermic oxidation of H E J I E L with aqueous KAIiiO~was carried out a t room temperature. dlthough the insoluble base was first dissolved in acid, the mixture became basic and heterogeneous as the reaction progressed. The solubility of methylnielamines in water increases with the decreasing number of nieth) 1 groups and the lower methylmelamines had to be extracted with ether from the aqueous phase. Higher methylmelamines and formylnielaniines were extracted with chloroform from the solid phase. The products obtained from a typical reaction are shown in Table I. All possible methylmelamines, with the exception of S*,S2-diniethylmelaniine mere detected aniong the products. About 11% of the initial quantity of 1 WVRSrecovered and about 39Yc of it was converted to ( 1 ) Prelious paper in t h e serie. P H. Terry and .A B Boikovec l l e d C l i e n , 11, 958 (1968) (2) h C Chano \ B DeAIilo C 11 V oods. and 4 B Boikoirc, .I. Eron Entomol , in preqq ( 3 ) S C. Chane, P H T e r n C 11 IVoods, and A B Boihovec, ahzd , 60, 1623 (1967) (4) (a) .i.B. R o i k o i e r and P H Trrr C 9 P a t m t 3 189,.521(l!lRA) [lij 1 13 Buihmer and 1 R I h h I i l o , .I Pi1 C h p n i , 10, 4 5 i ( l Q 6 i ) .
R" \v t SO.
R
N(CHB)? KHCH, SH, SHCH, .iS H 2 6 NHCH, 1 2 3 4
R"
R'
K(CH, 17
N(CH,), S (CH, 12 N(CH3)s ~ ( C H S ) ~ S(CH3)2 K(CHB)? NHCH, NHCH3 N(CH,), NHCH3 NHCH,
Yieldn Mole
%
55
10.ih 7.5' 0.3' 9.5'
10.7 7 9 0.3 11.0
O..ib
0.7
3.1h 1.7c 5.1' 4.1'
t3.8 2.1 7.0 6 1 4.5 :3.2 3.4
7 NH, S HC H, SHCHp 8 NHZ NH2 NHCH, 9 K(CH3)CHO S(CH3)2 N(CHa)2 4 . R h 10 N(CH3)CHO XHCH, N(CH,)% 3.2' 11 Ii(CH3)CHO X(CH3)CHO X(CH,), 3.9' 12 S(CH,)CHO N(CH,)CHO S H C H , Trace' The individiial yields refer to the initial amount of H E I I E L rised in the reaction. They were calciilated from glpc peak areas (CHCL fraction) or estimated by tlc (Et20 fraction). * I n CHCI, extract. I n Et20 extract.
lower methylnielamines. In analogy t o H E J I P A , the oxidation of 1 follows two routes which appear to have n H
.
I
-.\
I
CHO
\
CHa
common intermediate. Xone of the possible methylol intermediates was found in the oxidatiori mixture but some of them have been synthesized previously and were sufficiently stable to be used in confirmatory reactions. Thus, when { [4,6-bis(diniethylamino)-s-triazin-2-yl]niethylaniino 1 methanol4b was oxidized with aqueous permanganate, both expected products 2 and 9 wcrc isoh t ed.
September 190s
P O T E X T I A L i4NTITIJhfOR A G E K T S .
was kept a t - 70" for 1 hr, a t 0" for 1hr, and a t room temperature overnight, the solids were collected by filtration and washed with EtlO. The filtrate and washings were combined and treated in the same manner as described for the preparation of 10. T h e filter cake was washed with H 2 0 and the insoluble solids were combined with the residue from the Et20 filtrate to give 3.13 g of products. Glpc analysis showed that the mixt,ure consisted of 1.67 g (27.9%) of 11 and 1.46 g (27.6c0) of 10. The mixture was stirred in 40 ml of 0.1 S HCL, and the acid-insoluble product was collected by filtration. *4second treatment with acid and recrystallization of the insoliihle product from cyclohexane gave 0.9 g of 11, mp 182.5-184.5". .2nal. (C!,H1&&) C , H, N. B.--A mixtiire of ,iOO mg (2.75 mmoles) of 4 and 3 ml of formamide was heated at 1.80" f o r :3 hr iinder rediiced pressiire (i3t.j mm). The melt was poiired into 20 ml of H 2 0 and 330 mg of insoliible solids was collected by filtration ( 2 1 . 3 5 of 11 by glpc). The solids were triturated with 10 ml of 1 S HC1, and the acidinsoluble product was collected by filtration, washed with HyO, and dried. Recrystallization from cyclohexane gave 106 mg of 11. C.-Oxidation of 336 mg of 9 wit,h aqueous KMnOc and extraction of the solids with CHC1, gave 1.1 mg of 10 and 9.9 mg of 11: rompoiind 2 roiild not be detected among the products.
Potential Antitumor Agents.
Ix
963
N,N'- [6-(Methylamino)-s-triazin-2,4-diyl] bis( N-methylformamide) (12).-A mixture of 7 g (0.042 mole) of 6 and 18 ml of formamide was heated a t 185' for 2 hr. The melt was poured into 40 ml of H20 and the mixture was chilled in an ice bath. The insoluble products were collected by filtration and triturated with 40 ml of 1 AVHC1.I0 The acid-insoluble product was collected by filtration, washed with HzO, and dried. Recrystallization from CC14 gave 0.26 g (3%) of 12, mp 207.5-209'. Anal. (C~HnNfi0,)C, H, X . N- [4,6-Bis(dimethyIamino)-s-triazin-2-y1] formamide was prepared in .)8cc yield from 3 by method B. The prodlict was recrystallized from EtOfT, mp 182.5-184.3O. .-lna/. (CnH,J60)
c, H, s.
Acknowledgments.-We thank 11r. Robert Brouillette for valuable technical assistance and 1Ir. E. L. Gooden for the pnir spectra. (10) The major product of the reaction which was soluble in HC1 was identified as N- [4,6-his(methylamino)-.~-triazin-2-yl]-N-meth~.lformamide~ m p 168-171° (analytical sample). Anal. (CiHnNaO) C. H , K.
IX. Bisquaternary Salts
B. F. C A I S ,G. ~ J. ATWELL, AKD R. N. SEELYE Cancer Chemotherapy Laboratory, Cornwall Geriatric Hoopital, Aitckland, S e w Zealand Received April 11, 1968 The postulate that a close approach to over-all planarity in bisquaternary ammonium heterocycles is essential for maximum activity when tested against the L1210 system has been further investigated. The preparation of L1210 active quaternary salts containing a diphenyl system suggests that complete planarity in this type of molecule is not an essential requirement
In an earlier paper2 we demonstrated that a close approach to over-all planarity of certain quaternary heterocycles was apparently essential for significant activity in the Ll2lO system in mice. Proceeding from this point prepared314active agents whose length exceeded 30 A. This paper details an investigation into these longer molecules in which deliberate attempts have been made to introduce a sinall degree of twist in the central area of the molecules. Using the biphenyl moiety as a central fragment having the desired degree of twist about the pivot bond, activity WRS first found in series I. Here, convincing
allow a clear cut distinction between these two molecules. It is interesting to observe that the relative Rf values for the ethyl and n-propyl quaternary salts of I lie on either side of the figure noted for the optimum meinbers in a series prepared Thus it would appear that, even with the structural changes introduced into I, the R f values can still serve as a reliable guide to the relative hydrophilic-lipophilic balance. A marked contrast exists between the active series I and the completely inactive biphenyl analog I1 reported
"$0 m(=y/ -N
/
H
\
/HCo\
\ /
/
\
hA
I1
activity against the L1210 system could be dewonstrated in the series from methyl through n-butyl quaternary salts (Table I ) . Higher activity was shown by the bis(ethy1 and bis(n-propyl quaternary) salts as compared to the other homologs, but the precision of the test system does not (1) (2) (3) (4)
Author t o whom correspondence should he addressed. G. J. Atwell and B. F. Cain, J . M e d . Chom., 10, 706 (1967). G. J. Atwell and B. F. Cain, { b i d . , 11, 295 (1968). B. F. Cain. G. .I. Atwell, and R . N. Seelye, i h k l . , 11, 300 (1968).
by B e ~ i n e t t . ~Our results so far are now able to resolve this apparent discrepancy. In our lead series, the quaternary salts from S,N'-bis(6-quinolyl)terephthalamide, optimum activity is associated with the bis-nbutyl salt, the higher n-hexyl homolog being inactive. In variant I, where biphenyl replaces phenylene, in our lead series, a lower quaternary salt (ethyl or n-propyl) exhibits maximum activity. The change from phenyl to biphenyl has thus increased the lipophilic character of the resultant series by a factor equivalent to several methylene groups. Thus, if in the active 4',"'-bis(Zimidazolin-Zyl)terephthalanilide6 the imidazoline as (5) L . 1,. Bennett, ,Jr., PTOUT. E r p . Tumor Res., 7, 259 (1965).
