\-01. 11
(350
Synthetic Schistosomicides. IX. N- (Dialkylaminoalky 1) -4-ni troso- 1-naphthylamines
\‘arioiis ~ - ( d i a l k ? - b m i t i o a l k \ . - l ~ - ~ - r i i ~ r o ~ ~ o - l - r i a p h t h ~( 111) l a n i i twere i e ~ prepared by iii1romtic)ti of ihe vortcspoiidirig naphthylamiiies it1 ailhydrous ethanol. These materials undergo facile hydrolytic cleavage 1 0 4iiiti,o~;c)-l-iiaphTholin aqrieoiis media. Several of the riitrosotiaphthylamities (111) were highly active against S’chisfosorria rriansoai i n n i i c c The mo:t promising coniporirid, 1-(;1-[($-11it1.oso-l-riaphthyl)amirio]propyl 1piperidine, also exhibited strong therapeutic effects in rhesiis monkeys.
The potent chemotherapeutic activity of vwriou5 1(dialliylitmitioalliylaini~i~~)-l-naphthylazocompound\ I - 4 and the corresponding 1,l-tiaphthalenediamiries 11” :tg:iin+t iiifectiotis of SCIIistosoma t m / i s o / /i arid Sch istosoiiza japo/iL C I L ~ N iii experiineiit:tl ariimals led us to cotihider the preparation of the tiitroso atlalogs 111. Thew materi:ili tire intermediate i n tlie oxidation pathwa) NH-Y I
-3 R, R?
N=N-Aror I
+-y-NRlb
Het
NH-Y-NR& I
NH,
I1 N--Y--SR,RL
@
NO 111
NOH IV
kwtweeri the arylazo compound.: I a r i d the a r j lamiiie. 11. atid also have the potential t o esi+t i t i the tautomeric quinoid itructure IT, a form poiyibl) iieceshary for biological zictivit). within these *erie5.5.6 111 previoii. -tudie-L-5 the diethylaminoethyl derivatives aniotig type3 I and I1 exhibited optimum activit:., therefore, wc’ undertooh initially the tiitrosatiori of S.S-dieth! l-S’-l-iiaphthyleth: leriediarnirie (Table I).7 Sitrosatiori under standard cotidition1-1,~3-propanediamine7W U ~ then iiiveitigated. .idditioii of a iaturated aqueous wlutioii of wdium iiitrite t o ail ethanol solution of the diamine containing 8 equiv of concentrated HCl at .yo led to rapid separation of green crystals of the h: drochloride salt of S,S-diethyl-S’-(1-riitroso-1tiaphthyl)-1,3-propariediamine (I‘Ib). IsolatioIi wa5 effected b! filtration or, more wtisfactorily, by pouring the reaction mixture into ether. decanting, arid tallizirig the precipitate from 2-propariol. I’ procedure. :iseries of analogs (Tables lI-II*) of general *tructurc I11 \vah prepared. Occa~ionallythe products were iqolated b!. pouring the reaction mixture into cold aqueoub base, rapidly extracting the mixture with ether, und bubblirig HC1 iiito t he tlrieci et her ext rwct s. I-tilizing similar procedures, representative S-(alkyl-. -hydroxyalkyl-, and -nllioxyalkyl)-4-nitroso-l-naphthylamitlei iTable \-) were !s nthesizcd, as well as 1-{3[ (.i.(i,;.X-tetraliydrol-nitro~o- 1-iiaph t h y I)a m i n o ]p r opyl] piperidinc (YII) : i t i d \- /(2-diethylaminoeth\iI)amino 1-6-methos: -.i-tiitro~oc~uitiolitie (ITIII). S-
** NO
V
NO VIa, x = 2 b,x=3
( 1 ) I’reiimis 1)aper: E. F. 1:lslager. 1). B. Vapps. I ) . H , K i i r t L , F, \ \ , Sh(irt. I,. 31. \Verliel, and I). F. \Vortli, d . M e r / . Chem., 9 , 378 (1966). ( 2 ) 1‘. F. ElslaKer, I). B. Capps. I.. AI, \\-erl>el, 11. F. \Vorth. J. E. 3Ieisenhelder, H. Najarian, and P.E. T l i o m p s o n , i b z r i . . 6, 217 (1963). (:O 1;. F. Elslaper, D. B. Capps, D. H. Kiirtz, L. hl. \Verbel, and D. F. \\-orth. bid., 6, 646 (1963). (4) 9. T. Ch’en. I . F. Cli’en, P.C. Kiiri, S. c‘. H u , J . H. Yao, a n d T. H. ('lieu, Yiio Hsueh Hsueh P o o , 15, 30 (1966). ( 5 ) 1.. F, Elslaner. 1).B. Capps, I,. 31. \Verbel, I). E‘. \\-orth, .J. E. hleisenlielder, and P. E. Tliompson. J . J J e d . Chem., 7 , 487 (1964). ( 6 ) 1.:. 1.’. Elslager. I). B. Capps. and I,. 31. \\-erliel, ibid., 7, 668 il964!. 31. \Verl)el, I ) . B. Capps. E. I’. Eislager, \V. Pearlman, F. \I .I. \Veinstein. ami 11. F. \Vortlc, ih(/., 6 , ti37 (106:i).
l l e t h l l-l-riitro~o-~-tiaphth~ lamine (Ix) 11 a s prepared bv the reaction of l-nitroso-‘-Iiaphthol with metht 1amine The assignment of structure I11 for the compouiidi summarized in Tables II--II‘is predicated on their coriversion to the kno~viiY and their uv and nmr spectra Their hvdrol\ tic conversion to Tr confirms the 1.4 18) 0 1‘120)
bihclier
(
1)ietricii
arid t
\\
el87
J
I’ruit
I hem
100, 168
SYXTHETIC SCHISTOSOMICIDES. IX
September 196s
951
T.%nLE I N,N-DI.LLKYL-N '-I-KAPHTHYLALKYLENEDIAYINES~ R3
I
Yield purified,
KR1R2
oc
"a
Purifn solvent
Analyses'j
Ra
R4
H
H
221-224 dec
41
JIeOH
H, S ; Cc
PJOH
H
H
12i-129
68
i-PrOH
C, H, 9
P X H , W
H
H
228 dec
63
AleOH-EtzO
C, H, X
H
H
206 dec
66
EtOH
C, H, S
H
57-39
26
i-Oc t ane
C, H, S
Mp,
CH,
--
XeOH-petr C, H, S , C1 ether b 3-Rromopropylnaphthylamine hydrobromide was pura These compounds were prepared cia method VIIIA described in ref 7. chased from Kaplop Laboratories, Detroit, hlich. Carbon: calcd, 62.76; found, 62.30. 3-Chlo~o-2-hydroxypropyl-l-naphthylamine hydrochloride was prepared according to E. Fourneau, J. Tr6foue1, aiid G. Benoit, Ann. Inst. Pasteur, 44, 719 11930).
OH
243-246
i .)
NO Yield NO.
LIP,
oc
purified, 7c
Purifn solvent
Analyses'5
1
156-15i. 5 dec
73
MeOH
H, N, HzO; Ca
2
1-50dec
30
NeOH
c, H, N, C1; HzOb
3
160-163 dec
19
C, H, N,HzO
4
l.5i-139
68
C, H, N, HZO
1
133-136
46
i-PrOH
C, 11, Ti,H20
6
159-160
20
i-PrOH
C, H, X
7
176 dec
i
MeOH-Et20
H, X ;
8
165 dec
22
EtOII-Et20
C, H, N, GI
9
133-135
16
NeCS
C, H, S
IO
133 dec
38
i-PrOH
H, ?;, Hz0; c"
a C: calcd, 31.73; found, 31.29. HzO: calcd. 4.84: found, 3.86. Base, nip 149-133' dec, from Cs&. C, IS, X. d C : calcd, 53.47; found, 52.87. e C: calcd, 71.74; fourid, 72.18.
orientation in 111, as does the nmr spectra (in deuterioacetone) which indicate the presence of the ring proton ortho to the secondary aromatic amine as a doublet at 6.6, 6.75 ppm shifted upfield from the other aromatic protons. Such a shift is also observed for the ortho proton of the naphthylamines used as starting materials (Table I). The uv spectra of 111 present a
C d
-4nal.
(CI;H~X~O~)
consistent, pH-dependent picture (Figure 1). These curves are in excellent agreement with those of Nethyl-4-nitroso-l-naphthylamine,but in contradistinction to the spectrum of N-nitroso-S-ethylaniline, which has a single peak at 270 mp in methanol and does not shift in either acid or base, and of S-nitroso-Sethyl-1-naphthylamine, which has a peak in methanol
Yol. 11
R, I
NHCH~-&-CH~NR~R~
I
I
valcd, .54.24: foriird, X 3 . T I . Base, m p 1.54-16Io de(. (EtOH). . l n d . C, I T, X. ' S : ralrd. 10.39; ~ I I I I I I ~ , Foiincl valiies are roirertrd for .i.i6'; f320. The ieac.tioii Inistiire \vas filtered, tritiwated with ether, aiid decaiiled. 1 ht, i,rsidual giim was tritrirated a i t h i-I'i,O€f satiuated with gaseoiis I-TCI, and the solid was recrystallized from i-PrOH. '3
(':
!l,~h!),
'j
d
,. I .\ li 1,I.:
a t 2 h l mu with shoulders a t "0 and 290 mp arid i b also independent of change in pH. The refererice compound, S-nitrobo-S-eth? 1-1-naphthylamine, was prepared b? nitrosation of S-ethyl-Iriaphthylamirie with sodium nitrite in aqueous HCl at .) , The reaction mixture was extracted with ether. -0
\.
the solvent wab removed a t room temperature, arid thc residue was subjected t o spectral analysis immediately. Iri addition to the uv data, the absence of S H or OH absorption i i i the ir spectrum confirm:: the 1-riitroqo .tructure. The other isomer, S-ethy1-4-nitroso-lriaphthylainine, w;tb prepared by riitrosatiori iii ethanol
(cf. Experimental Section), and its spectral properties clearly confirm the structure assignment. While it is possible that the N-(dialkylaminoalky1)-S-nitroso-1naphthylamines are formed initially and rearrange to the C-nitroso isomer during work-up, the rapid separation of the hydrochloride salts of the 4-nitroso-1-naphthylamines 111 directly from the reaction mixtures suggests direct C-nitrosation. Blangey9 has postulated nitrosation on carbon when simple 1-naphthylamine derivatives were treated with nitrosyl sulfuric acid. D’Amico arid coworkers’O have also reported the tendency of aromatic amines to nitrosate on nitrogen in aqueous medium and on carbon in alcoholic medium. The nmr spectrum of 3-nitroso-N-ethyl-1-naphthylamine is also of interest. In CC1, it shows tu70 CH3 triplets centered a t 1.0 and 1.27 ppm and two CH, quartets centered a t 3.93 and 4.5 ppm. This observation, which indicates the presence of two steric configurations resulting from restricted rotation about a partial S=S double bond Et
\+
/
It
N=N
\
0-
is in accord with previous observations on other nitrosamines,” arid serves further to confirm the K-nitroso structure of this material. The stability of the nitroso compounds 111 was examined by uv spectroscopy and was found to vary considerably with the nature of the side chain. The most labile compound was K,S-diethyl-S’-4-nitroso1-riaphthylethylenediamine (VIa). This material could be isolated in crude form by direct filtration of an anhydrous reaction mixture, but could be purified by recrystallization only in small amounts and with substantial losses due to its instability. The inherent instability of the dialkylaminoethyl side chain is further illustrated by the failure to obtain any of the desired products from naphthylamines containing a dimethylaminoisopropyl, diisopropylaminoethyl, or al1ylcyclohexylaniinoethyl side chain. A cyclic terminal amine conferred additional stability; for example, 1- { 2- [(4-nitroso-l-naphthyl)amino]ethyl} piperidine (17, Table IV) was converted to T.’ to the extent of 9S70 in 2 hr a t p H 3, but only to the extent of S6yc after 24 hr a t p H 7. I n general, compounds in a hich the side chain interruption was greater than two carbon atoms were more stable. Thus, N,N-diethylS ’-( h i troso- 1-naphthyl)-I ,3-propanediamine (VIb) was converted to 1- to the extent of 42y0 at p H 3 in 2 h r and 86% a t p H 7 in 24 hr. 1-(2,2-Dimethyl3- [(4-1iitrc~~o-l-naphthyl)amino]propyl) piperidine (14, Table 111) :&O showed greater neutral stability, being converted to V only to the extent of 48% after 24 hr at pH 7. 1- (3-[(4-Sitroso-l-naphthyl)amino]propyl] piperidine (6, Table 11) exhibited a similar picture showing excellent 24-hr stability in alkaline methanol, somewhat less stability in acidic methanol, and extremely poor stability in both acidic and basic aqueous systems. The instability of these materials is undoubtedly coniiected nith the presence of a terminal amine in the (9) L Blanpe\, Helv Chzm. A h 21, 1579 (19.38). (10) I I D lrnico. C C. Tung, and L. A Valker, J A m Chem. hoc., 81, i 9 i T (1939) (11) G J kardbstsus aiid K .I. ‘laller, h d . , 86, 4d7d ( l V b 4 ) .
II- 70.2 20
200
250
350
300
h
I
N
~
400
450
500
V
Figure 1.-UV spectra of 1-(3-[ (4-nitroso-1-riaphthy1)aminuJpropy1)piperidine (6): - in MeOK, - - - in LIeOH pliis 1 drop of 5 HCl/cell, - - - - in methanol plris 1 drop of 12 -Y KOH/cell; S-nitroso-N-ethyl-1-naphthylamine in l\leOH -. -; and N-nitroso-N-ethylaniline in &OH --.
side chain. Thus S-ethyl-4-nitroso-l-naphth> laniine (21, Table T’) remained essentially unchanged even after 7 days in neutral, acidic, or basic methanol. It is interesting to note that replacement of naphthalene by quinoline affords a much more stable system. S o difficulty was experienced in the preparation of S- [ (2-diethylaminoeth?l)amino]-6-methoxy- 5-nitrosoquinoline (VIII), and in fact hydrolysis of similar compounds12 requires reflux in methanolic potassium hydroxide. The S-methyl derivative of T’Ia could not be isolated. Its extreme lability resulted in an immediate precipitate of T’ from the reaction mixture, and this was the only isolable product. This is in agreement with results of experiments on N,S-dimethyl- and K,Sdiethyl-I-naphthylamine in which the 4-nitroso derivatives could be isolated only in the crude form and rapidly decomposed to V upon attempted purification. The facile lability of 111provides a simple preparative route to substituted 1,4-nitrosonaphthols. Thus, 6methoxy-4-nitrodo-1-naphthol and 8-chloro-4-nitroso1-naphthol were readily prepared from K,S-diethylK’-(6-methoxy-1-naphthy1)ethylenediamine and S,Ndiethyl-N’-(8-chloro-l-naphthyl)ethylenediamine, respectively. The nitrosonaphth) lamirie derivatives described in the present communicatioii were tested in mice against a Puerto Rican strain of S. 7 n ~ ~ ~ s by o nDr. z ~ Paul ~ ~ E. Thompson and coworkers of these laboratories. Drug. were given in a powdered diet for 14 days or by gavage in 10 ml/kg of aqueow 1% hjdroxyethyl- or carboxymethylcellulose for 5 or 10 days. Drug amounts are expressed as free base. Only the S,S-dialkyl-S’(4-nitroso-1-naphthy1)alkylenediamines(Tables 11-IT) (12) R C Llrlerfield am1 C Ressler i l i d , 72, 4050 ( I q i O ) , descrilie tlie nitrosation u f analogous aminoyuinolines (13) ( a ) For a descrlption of test methods see P E Thompson. J E SIeisenlielder. and H Kajarian, A m .I Z r o p W e d H y y , 11, 31 (1962) (11) D Roui, G. Peru//otti, L \V Dennis, L, 1 BerlJeriaii, I 1 I r e e k , B 1’ rullsr, arid b IiLlier, J .Wed Chem , 10, 8b7 (1YbiJ
to warm to room temperature overnight. Filtration gave a moved in vacuo, and the residue distilled to give 95.4 g (44'/,) of brown solid which was dissolved in aqueous NaOH, filtered, and the product, bp 126-128" (0.2 mm). Anal. (C14HliSO) C, acidified with HCl to give a yellow solid. Recrystallization from H, N. 95% EtOH gave 1.9 g (37%) of product', mp 219-221" dec. N-(2-Ethylbutyl)-l-naphthylamine.-A mixture of 42.9 g (0.3 mole) of 1-naphthylamine and 30.0 g (0.3 mole) of 2-ethyl;Inal. (CllHsN03) C, H, N. 8-Chloro-4-nitroso-l-naphthol.-The reaction of nitrous acid butyraldehyde in 400 ml of CsHO containing 1.0 g of p-toluenewith N,N-diethyl-~'-(8-chloro-l-naphthyl)ethyleriediamine7as sulfonic acid was heated under reflux for 3 hr. HzO was removed above gave 42yc of product as a pale yellow solid, mp >300". with a water take-off head. The mixture was concentrated to .Lnal. (C1,H&lxO,) C, H, N. di,yness and hydrogenated over 0.5 g of PtO? in 250 ml of EtOH 8-[ (2-Diethylaminoethyl)amino]-6-methoxy-5-nitrosoquinoline fur 16 hr at an initial temperature of 25' and a hydrogen pressiire (VIII).-To a solution of 7.4 g (0.027 mole) of 8-[(2-diethylaminoof 3.87 kg/cm2. The catalyst was removed by filtration and the ethyl)amino]-6-methox?-q~iitioline1* in 95% EtOH containing solveiit was removed in vacuo. Distillation of the residue gave 7 ml of concentrated HC1 at 5' was added an aqueous solution of 23.4 g (:MC;) of the product, bp 106-108" (0.09 mm). d n a l . 1.87 g (0.027 mole) of N a S 0 , . The mixture was stirred for (C16HPL?J) C, H, N. several hours, diliited with H20, and made basic with SaOH. The green-brown solid which resulted was removed by filtration, Acknowledgments.-The authors wish to express dried, and recrystallized from CaH6 to give 4.1 g (50%) of the their appreciation t o Dr. Paul E. Thompson and coA n a l . (C~OH??NIOB) product as a yellow solid, mp 135.5-137'. Xvorkers for the antischistosome testing and t o A h . C. H. N. N-(3-Methoxypropyl)-l-naphthylamine.-A mixtrue of 144 g Aririette .A. Phillips for synthesizing several of the (1.0 mole) of 1-naphthol, 93 g (1.06 mole) of 3-methoxypropylcompounds described herein. We also tharik Air. C. E. amine, and 174 g (1.0 mole) (Jf Na&Oa in 600 nil of H20 was Childs arid associates for the microanalyses arid Dr. heated in a bomb for 8 hr at 1.50'. The mixture war removed froni tJ. :\I. Vandenbelt arid Co-\Vorkt?rS for the Spectral t h e bomb, made baric with N ~ O H and , extracted with Studies. ht&. The extracts were dried (Na2S04), the solvent was reI
,
2,2-Dimethyl-3-vinylcyclobutaneaceticAcid, a Fungistatic Agent Derived from Pinene'"
R,I,. SETTISE,'~' J . B. L E J V I YRUTH , ~ ~ : \ I A Y s E , ~ANI) ~ C.; IT;. H E U H I C K ~ ~ Depwtment of Chemistry, T h e I:niversily o,f 111ississippi, Cniwrsity, .If r'ssissippi, al-avul Stores Laboratory, Olustee, Florida, and Southern Utilization Research and Developmenl Division, .lgric~iltural Research Service, c'. S . Department of Agriculture, -Yew Orleans, Louisiana Received February 9, 1968 Piire 2,2-diniel h?-19-vitiylc~clobtit~iieacetic acid was prepared by pyrolysib of piiiolic acid aiid some acyl esters followed by helective epoxidatiori of the ethylideiie homolog which was produced aloiig with the vinyl compound. Tests indicate that 2,2-dimethyl-3-vinylcyclobiitaneaceticacid is comparable to 10-heiidecenoic acid in its fungistatic activity against Aspergillus niger, Aspergillits oryzae, arid rlspergillus f a v u s .
10-Hendecenoic acid and its salt are reported to have unusually good fungistatic action.2 Because both 10heridecenoic acid and a recently described acid, 2,2dimethyl-3-vinylcyclobutaneacetic acidq3 contains a terminal vinyl group it was believed that the latter acid may also be an effective fungistatic agent. Tests on Aspeiyillus niger, Aspergillus oryzae, and Aspergillus flavus suggest that the test material is as fungistatic as 10-hendecenoic acid. Since di-n-hexyl pinate4 and lauryl pinonatej are not fungistats, the fungicidal properties of the vinylcyclobutane derivative must be due to the vinyl group rather than the dimethylcyclobutaiieacetic acid moiety which is present in all three compouiidh. I n additiori to the biological activity the acid has a more pleasant odor than 10-hendecenoic acid. This report covers new information on the synthesis and isolation of the vinylcyclobutaneacetic acid and (1) (a) Presented a t t h e 153rd National Meeting of t h e American Chemical Society, Miami Beach, Fla., April 1967; (b) T h e University of l\lississippi; (c) Naval Stores Laboratory; (d) Agricultural Research Service. (2) K . S. Marklev, " F a t t y Acids, P a r t I, 2nd ed, Interscience Publishers, Inc., Kew York, N. Y . , 1960, p 122. (3) J. D. Park, R . L. Settine, and G . JT. Hedrick, J . Ore. Chem., 27, 902 (1962). (4) S. Berk, H. Ebert. and L. Teitell, r n d . E I L ~ C h. e m . , 49, 1115 (1957). ( 5 ) H. R.Summers. G. \V. Hedrick, F.C. N a r n e , and It. T.Mayne. i 6 i d . , 51, .549 (1Y5Y).
results of fungistatic tests of the acid compared with 10-hendecenoic acid. of pinolic acid, .',%-dimethyl-3-(l-hydroxyethy1)cyclobutaneacetic acid, or its acetate gave R mixture of 2,2-dimethy1-3-vinyl- and ?,%dimethyl+ ethylidenecyclobutaneacetic acids. -4 comparison of this mixture with 10-hendecenoic acid gave somewhat discouraging results.6 In the present work, the ratio of vinyl to ethylidene compounds was considerably less than previously reported. To improve the yield of desired product, the pyrolyses of some esters other than the acetate were investigated (Table I). I'ivalic and 3,3-dimethylhexanoic acid esters gave substantially better yieldh than the other esters. Separation of producti: was effected by selective epoxidation of thr olefin mixture with ni-chloroperbeiizoic acid (JICPA) in ether. The vinyl compound was less readily attacked than the ethylidene derivative and distillation of the partially epoxidized mixture gave dimethylvinylcyclobutaneacetic acid free of the ethylidene derivative. Thoi7 and Trave8 and other workers have given the name cis-dl-pinolic acid to the solid isomer, mp 105" ( 6 ) R. Mayne, unpulAished results, 1Y61. ( 7 ) Le-ran Thoi, ..irin. Chim. ( R u n e ) , 10, 3: (1Y3I) (8) 8. Trave, Chim.I t i d . , 86, YO8 (lY58).
