)larch 190s
RISQU.%TERXA4RYAKTITKJVOR
solution; t,hey could be extracted with Claiien's alkali.20 This was not attempted with IVd. 5 6,7,8-Tetrahydro-5-( p-hydroxybenzyl)-2-naphtholDiacetate (VIIIe). General Method for VIIIa-h and Va-d.-To a 10-g sample of VIIe dissolved in 170 ml of pyridine in a stoppered 500nil flask w-as added, dropwise with swirling, 40 ml of Ac20. This solution was swirled for 10 min at room temperature and allowed to st,and overnight'. H20 (50 ml) was added dropwise to the swirled solution over a 15-min period with slight cooling iu ail ice bath. Further dilut,ion gave an oil that was extracted (Et,O). The ether extract, was washed (5% HC1, H,O, 5% Sa?CO,, FTzO). After drying (?\IgSO,), the solvent was removed a t reduced pressure to leave an oil which crystallized from benzene-hexane t o give 12.4 g of whit'e crystals, mp 89-92', vmax 1745 cm-'. I n the preparation of VIIIg, benzoyl chloride was substituted for Ac20 and work-up was via CHCla extraction. This prodiict, 5,6,7,8-tetrahydro-~-(p-hydroxybenzyl)-2-naphtholdibenzoate, showed vmax 1725 em-'. 6-Acetoxy-l-tetralone.-Demethylation of 6-methoxy-1-tetralone by the method described for the preparation of IVd and VIIc (including separat'ion from neutral material by extraction of the product from ether with 10% aqueous S a O H ) provided a crude pink solid: mp 127-135" (lit,.2' mp 121.0-121.5'); vmax 3580, 3250 (broad), 1658 cm-1. This solid resisted purification. I t was acetylated by the method described for the preparation of VIIIe to give a 56% yield (from 6-methoxy-1-tetralone) of 6acetoxy-1-tetralone as a colorless oil: bp 126-143" (0.16-0.17 mm) [lit.?' 152-154' (1 m m ) ] : vmal 1675, 1754 cm-l. A4ttempted crystallization failed; lit.21 mp 62.5', polymorph mp 42". 5-(p-Benzyloxybenzyl)-7,8-dihydro-2-naphtholAcetate and 5-(p-Benzyloxybenzylidene)-5,6,7,8-tetrahydro-2-naphtholAcetate (IIIh).-The Grignard reagent (56 mmoles), prepared from p-benzyloxybenzyl chloride in the manner described above for IIIf, was added over a period of 1 hr and 10 mill to a sohition of 10 g (49 mmoles) of 6-acetoxy-1-tetralone in 100 ml of dry THF cooled in an ice-salt bath. The mixture was allowed to come to room temperature overnight with st,irring under Sa. At this point a negative Gilmari test22 was obtained. Work-up with ice and aqueous NH4C1 gave about 23 g of an oil. An ir spectriim indicated the presence of some 6-acetoxy-1-tetralone. The oil was diswlved in 500 ml of toliiene with 20 mg of p-toluenesiilfonic (20) L. F. Fieser. "Experiments in Organic Chemistry," D. C. H e a t h and Co., Boston, Rlass.. 1957, p 310. (21) S. N. Ananchenko, V. Ye. Limanor, V. N . Leonoi-, V. X. Rzheznikov, and I. V. Torgov, Tetrahedron, 18, 1355 (1962). (22) J. Cason and H . Rapoport, "Laboratory Text in Organic Chemistr>-," 2nd ed. Prentice-Hall, Inc., Englewood Cliffs, N . J., 1962, p 469.
Potential Antitumor Agents.
AGEXTS
29.5
acid and the solution was heated iinder reflux (Dean-Stark t,rap)for 1 hr. The toluene was removed at' rediiced pressure and replaced with ether. This solution was washed with h'aHCOs and water, dried, and evaporated in vacuo to give about 20 g of a dark oil which could not be crystallized. This oil was dissolved in 100 ml of 95yo E t O H coiitaiiiiiig 5.5 g of KOH and this solut,ion was heated under reflux for 1 hr, poured into HzO (500 ml), and extracted (EtZO) (an emulsion reqiiired that the mixture be centrifuged to effect separation of the layers). The ether extract was then extracted with Claisen's alkali,20 washed well with water, and dried (IIgSO4). Removal of the solvent a t reduced presslire left 7 g of a semisolid j-elloworange residue. The nmr and ir spectra of this material siiggert that it is a mixture of benzyl p-tolyl ether and possibly p-benzyloxybenzyl alcohol. Work-up of the aqueous KOH solution by acidification with lo%, HCl and ether extraction yielded 3.8 g of a dark red oil that partially solidified on standing but which could not' be purified. Any 6-hydroxy-1-tetralone would be expec.t.ed t o be in this residue. The Claisen's alkali extract upon similar work-up gave 5 g of a yellow-red oil that could not be induced to crystallize. Acetylation of this oil by the method described for the preparation of VIIIe provided 2.87 g of I I I h which separated from benzenehexane as a near white powder, mp 83-92', vmax 1748 cm-'. 6-Methoxy-l-(p-methoxybenzyl)naphthalene(IX).-An intimate mixture of 2 g of I I I e and 548 mg of sublimed sulfur was heated under S2a t 205-210' for 5 hr. The mixture was cooled, taken up in ether, and filtered with slight suction. The filtrate wan dried (MgS04) and the solvent was removed in VQCZIO. The residue was decolorized with charcoal in EtOH giving, after two recrystallizations, 666 mg (34c;C)of white crystals: mp 97100"; 331 m p ( E %io), 316 (1960), 296 (6160), 277 (7520), 231 (56,400). The nmr spectriim has a CH, singlet a t 258 cps.
Anal. (C19H1802) C, H. 5-(p-Hydroxybenzyl)-2-naphthol( X ) was prepared from I X by the pyridine hydrochloride method described for the preparation of U I e . A 405, yield of X was obtained as a near-white solid from ?\Ie2CO-H20; mp 191-194' (after drying in vacuo to remove acetone). Anal. (C17H1402)C, H. 5-(p-Hydroxybenzyl)-2-naphtholDiacetate (XI).-Acetylation of X in the manner described for the preparation of VIIIe gave a n 81% yield of XI as fine pale yellow CI hexane; mp 119.~-120.5", umax 1753 cm-'. Anal. (CZ1Hl~O4) C, H.
Acknowledgment.-The
authors are indebted to Drs.
R. E. Mauer, A. I. Cohen, and R. Oslapas for biological data and wish t o thank Dr. Paul Kurath for helpful advice.
VI.
Bisquaternary Salts
G. J. ATWELLAXII B. F. Cars1 Cancer Chemotherapy Laboratory, Cornwall Geriatric Hospital, ilucklanrl, S e w Zenlanrl Received Julg 12, 1967 Investigations of the structure-activity relationship5 of a series of hisqiiaternary ammonium heterocycles against the L1210 leukemia system are described.
I n an attempt to delineate further the features essential for experimental antileukemic activity in this area the quaternary salts represented by I were prepared. These differed from our parent series, the quaternary salts of K,K'-(6-quinolyl)terephthalamide, in the reversal of an amide function. This series (I) covering a range of lipophilic - hydrophilic properties had no active members. Previous work2 had shown an enhancement of experi(1) Author t o whom inquiries should b e addressed. (2) P a r t V : G. J. ht\vell and T3. F. Cain, J . M e d . Chem., 10, 706 (196i)
mental antileukemic effectiveness when intercharge separation mas increased by a variety of means, provided R
I
-
Substituent
ii-(p-Seti~yloxycarbonylben~:iinidc,)&(p-Carboxybeiizamido)F-(p-~lethoxycarbonylpheiiylcarbani(~Sl i6-(p-Carboxyphenylcarbamoj1)O-(p-PITitropheIiyIcnrbam~i? 1)C , - ( p - ~ ~ ~ n ~ n o ~ ) h r n ~ ~ c1-a r h n ~ i c ~ y l
Yi~l~rtitiient,
:~-[p-~p-?;itrokerieitmido)pfiei~)-l] 3- [p-(p-8minobenzamido)phen~-l] .?-(p-Beiizyloxycarboi~ylbellz:tmi(i~J~:{-( p-CarboxyberizamidcJ):$-(p-?;itrobenzamido):I-ip-Amiiiohenzaniido)4-( p-Nitrobemamido)4-(p-Amiriobenzamido)):(-(p-~~ethoxycarboiiyIbeIlz"ido :',-(p-C:arboxybenaamido):',-ip-~Iethox~carbo~iylphen~-l~~art~aiiic )>-I)3-(p-C:arboxyphenylcarbamoyl):I-( p-Nitropheiiylcarbanioy1)3-(p--~niiiiophenylcarbanioSij-
the 1i~)ophilic-hydrophilic hl:nicc W : L ~maintained i l l the correct range. Extension of thc intercharge hep:ir:ition in another manner, by the introductioii of an additional p-aminobenzoate unit into the Iiarent series, led to type I1 compounds. Due t o the balance of lipophilic-hydrophilic propertie. of the benzenoid ring and the amide group, the physical properties of the resultant molecule still lie within the allowable partition rm1ge.l The effectiveness of the iiicreaied charge separation seen in the peak member of serieb I1 (that with R = C2HS)which had greater activity against the L1210 eiii than any member of the parent S,N'-(6quinolyl)terephthalamide series. On the other hand reverqal of one of the existing amide functions in type I1 (to give t > p e 111) afforded only wealily activc compounds, while reversal of t w j :u"e3 functions resulted irt t he completely i1i:ictiw series IT'.3 Further increase in intercharge separations
14
\I
1)romptetl :in eu:iiiiiri:ttiori of thc acj 1aminoI)jridiiiei 111 place of the more difficultly accessible phenylpyridinen. While the iwmeric 2- :md ~-acylaniiriopyridincSCI" (VI1 and JTIII)were inactive, the 3-substituted c1eriv:tt i n + (IY) were markedly active. In contrast t o the ~ . \ I C ( I Q Z I ( . i ~ C " h H Q C " \ H ~ /
\
R'
VI1
R'
\--I
111
by intercalation of an additional p-aminobenzoate unit t o give V abolished activity. However, inactivity of this compound could be due t o extreme insolubility in aqueous media. Also inactive was series VI in ivhicli the previously described2 3-phenylpyridine system way extended by intercalation of a p-aminobenzoate unit. It was suggested in our earlier paperZ that a close approach t o over-all planarity could be a requirement for high activity in these quaternary salts. This ( 3 ) l'lie stereochemical implications of tbeqe results \vi11 be olnIxjmt,ed ~ ~ i o fully r e in R later paper.
' R
\
N
R
N,S'-(6-quinolyl)terephthalamide series the 3-acylaminopyridine (X) with similar intercharge separation is completely inactive. It is interesting that the intercharge separation in X corresponds t o that in the very active 4',4"-(di-2-imidazolinyl)terephtha~anilide described by Hirt and Berchtold4 (19.5-20 A, variations being due t o the various conformations possible about the amide functions). However, the hybrid species XI and XI1 contain very active members. Using a p-carboxycinnamoyl function in place of a (4) R. Hirt and
R. 13elclltold, Ezperzentta, 17, 418 (1961).
terephthaloyl group, a means of increasing charge separation described in an earlier paper has given rise to the further highly active series XI11 and XIV.
/
K
XI11
R/
R'
R ' XIV
I11
IS
SI
299 TABLE 11. (Continued) R
Compd
XI1
SI11
Dose, mg/kg/day
CHI
CI-I,
cwcm
XIV
CH3
CZIL
CH,(CH,),
CII~(CII,),
1; 10 6.7 4 4 3 0 2 0 100 67 44 30 20 100 67 44 30 20 13 50 33 22 15 10 6.7 130 100 67 44 29 20 30 33 22 15 10 60 40 27 18 12 22 15 10
\Vt change
Surrirori
-5.3
1
+0.6 -0.7 $1.1 +1.7 $3.1 -2.5 -0.2 +0.3 +0.6 +1.1 -3.0 -0.8 +O. 1
6 6 G
+0.3 +0.6 -0.8 -4.5 -2.8 -0.8 +0.2 +0.6 f1.0 -2.4 -0.9 -0.3 $0.1 +0.4 f1.2 -2.2 -1.2 $0.8 +1.9 +2.8 -3.0 -1.8 -0.9 -0.2 +o 9 -3.7 -1.9
It is apparent from the range of compounds described, covering a relatively wide spread of intercharge separations, that there is a considerably greater allowable flexibility in structure consonant with high activity in these quaternary salts than in the bisimidazolines so far described.5 Experimental Section Analyses by Dr. A. D. Campbell of the Microchemical Laboratory, University of Otago, Otago, S e w Zealand. Where analyses are indicated by symbols of the elements only, analytical results obtained for those elements were within 1t0.47, of the theoretical values. Melt,ing points have been determined on an Electrothermal melting point apparatus with the makers-supplied, stem-connected thermometer and with a P"/min heating rate from 20" below the melting point. Symmetrical bisbases were prepared by the acylation method.2 Insolribility of some of the amine components, for example, 3(p-aniinobeiizamido)pyridirie in toluene, made a change of solveut, neressary. IXet hq-leiie glycol dimel hyl ether proved siircessfiil in siich ~ n s e s . ( 5 ) (a) R. Hirt, Chemotherapy of Cancer, Proceedings of a n International Symposium, Lugano, 1964, P. .I. Plattner, Ed., Elsevier Publishing Co., New York, S . Y.. 1984, g 228; J. H. Durchenal, i b z d . , p 2 3 3 ; (b) L . Lee Benriett, Jr.. Prom. Ezptl. Tumor Rea., 7 , 259 (1966).
6
6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 5 6 6 6 6 6 6 6 6 6 6 4 6 6 6 6 2 6 6
---.\v s u r r i r a l , daysTreated Cbntrol
11.9 27.3 23.9 17.2 14.6 13.2 20.8 22.2 19.6 15.8 13.9 10.2 21.0 26.2 22.5 16.4 12.2 8.8 24.4 25.8 22.1 18.1 13.4 14.4 19.4 19.2 18.0 16.6 13.6 17.0 16.6 16.8 15.8 14.0 7.3 13.3 16.6 15.5 13.7
9.7 9.Y 9.7 9.7 9.7 Y.7 10.8 10.8 10.8 10.8 10.8 9.8 9.8 9.8 9.8 9.8 9.8 9.5 9.5 9.5 9.7 9.7 9.7 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9 9.9
13.9 11.6
9.8 9.8
T/ c
'/o
123 276 247 178 151 136: 194 205 182 146 129 214 267 230 168 124 257 271 228 187 138 146 196 189 182 168 135 168 164 170 160 139 1.i.j 168 156 13!)
142
For the preparatiou of the unsymmetrical biubases, stepwi,se synthesis was iiecessa For the addition of a p-aminobenzoate iiiiit, it was highly de ble to acylate methyl p-aminobeilzoate, since the methyl p-acylaminobenzoates obtained were readily soluble in organic media, highly crystalline, and thus readily purified in contrast to the p-acylaminobenzoic acids which were very insoluble, microcrystalline, and extremely difficult to purify. Pure p-acylaminobenzoic acids were readily obtainable from the esters by mild alkaline hydrolysis (vide infra). Rather than use protected amino functions as in peptide syntheses, a nitro group was used as a precursor of an amino group. The reduction of the nitro function was carried out with finely divided Fe in aqueous solvents. This reduction proceeded very smoothly giving high yields of aromat,ic amine with no detectable reduction of heterocyclic components. The met,hod evolved was to suspend or dissolve the nitro compound in a convenient volume of 60% aqueous E t O H (or aqueous DAIF if the nitro compound is very insoluble) and add Fe powder (150 g/mole of nitro group) t,hen 20 ml/mole of a starter containing 32.5 g of FeC13 in 100 ml of HSO. On warming, an exothermic reaction usiially took place (violent, wit,h greater than molar qiiaiilities). When reaction abated, the heterogeneous mixture was refliised vigorously iinl il the iiiitial orange color of the iiilerrnediale oxides diatigetl i o that of h h c k Fes04: rediictiorr was the11 complete. Couceiitraled NI1,OII was then added (0.3 nil/ml of FeC13 start"-). The d u t i o i i was filtered hot, the iron oxide mixture was washed well with a suitable solvent, and the filtrate was processed for the aroriiatic ainiiie. In the reduction
