1116 Journal of Medicinal Chemistry, 1971, Vol. 14, N o , 11
TABLE I NEW SCHIFF BASESOF SALICYLALDEHYDE
OH
R'
R2
Formulaa
Mp,
O C
C=N i t r e t c h cm-1
Yield. 'i;
E! hanil, nni
62.3-63. .i h l ..i 1617 "7'' 2-CF3 H CirHioNOFz ')-" 4-CH3 H CirHioN0F1 104..5-103. .i 4 1622 -(.> 3-CF3 6-C1 CI~HDNOC~FB 91-93 $7 1610 27.5 4-CN H CirHioNzO 118-121 (i!) lGl.i 2SO 4-NHCOCH3 H CijHirNzOz 162-164 (i 1 161.5 270 .)-2-COCH3 H CijHi3NOz 164-166 ti0 101.; -*i.) All compds were analyzed for N. b In KBr pellets, The ir spectra of 131 aromatic Schiff lja.;es exhibit ahorptioii a t ltil~5--1(i3!1 cm-' in solid KBr and 1618-1645 cm-1 in CHC13. AI. Nakamura, K. Komatsu, Y. Gondo, K. Ohta, and Y. Ueda, Choii. Phartri. Ili/ii., 15, 585 (1967).
that Schiff bases with electron-wit hdrawing substituents generally hydrolyze more slowly than the unsubstituted compound at pH 7.0. These Schiff bases have been tested in the L1210 lymphoid leukemia of mice6 by the Cancer Chemotherapy National Service Center with the results shown in Table 11. Unfortunately none of these compounds have significant activity ( T / C greater than 1.25) in this tumor system. The increased stabilities of these compounds do not improve their activities in L1210 mouse leukemia. TABLE I1 I~ATE OFSHYDROLYSIS AND ANTITUMOR ACT1VITII:S
Experimental Section Synthesis of Compounds.--Each ci)nipd viis 1)ivpd l)y i ~ v f l i i ~ i i i ~ equimolar quantities of salicylaldehyde aiitl the aromatic, timilie iii ahs EtOIT. The cry.tal< which ftrrmed O I I c.ooliiig wert' sc~ptl and recrystd. Each compd was aiialyzrd for S and sent t i , tiit: C C Y S C for testing. Rates of Reaction.-~~S:triil,le;;w e i ~u.eighed, di,.wlved i i i :L few drops of EtOI-I, aiid the11 qiiickly tlild a i t i n i t , %miwith ii large vol of aq hiiffer (prepd from 0.01 J I KlllPOa nird :idjiihtcd to pH 7.0 with 0.01 JI NaOIT s o h ) in order to make R yo111appriix l o v 4JI. The uv spectriim x a s then recorded for a ,.:imple of t h i h soln held a t 25' as sooii :M possible and a t intervals of ,>-IO n i i i i for 2-3 hr. The wavelength showing the greatest chango ~ I I absorbance was selected arid the absorbances at, varioiis lirncs recorded. The a,bsorhances Tvere used to determine the AI'.). :1na!. ( C I ~ H , I N O ) 13. 2-Hydroxy-lO-chloro-llH-indeno[l,2-b] quinoline (13) was p r q d from 9 i n 927; yield as described for 12. Recrvstn of 13.iIBr from 1)lIE' give pure material: nip >320" subl." Anal. (Cl6IIloC1NO~HBr) C, 1%. 6 8.2-6.8 (m, 8
WHt
OR
Anal.
I
HO
HN
1
OH
CH
~
CHNH?
I
e,
Acknowledgment.-The author wishes to express his appreciation to Dr. H. B. Wood, Drug Development Branch, Sational Cancer Institute, for his interest in this n-orl; :md for making the screening data available.
Gentamicin Antibiotics. 4.' Some Condensation Products of Gentamicin Cp with -4roniatic and Aliphatic Aldehydes'
h,R=H
procedure described previously for the related antibiotic ka~iamycin.~ Gentamicin C' reacted readily with BzH in EtOH on gentle heating to givr a colorless, crystalline benzylidene derivative. Microanal. of this material indicated that 5 aldehyde groups-not 4 as expected-had been incorporated into the molecule. Low-resolution mass spectronietry of this compound surprisingly gavc a strong molecular ion at mle 903 consistent with condensation of 5 aldehyde residues with elimination of 5 moles of H'O. The recent determination of the L-arabino absolute stereochemistry for garosamineSa" (Ib) enables this result to be interpreted in terms of the formation of the novel oxazolidine (11). This was subm,/e 319 CH
grntnmic.ins are a family of broad-spectrum antibiotic#:, bcblonging t o the aminoglycoside group. The isolation,? biological properties,"-d and chromatographic soparationja of the gentamicins have been publishcd and a reccnt communication6 from our laboratory 11a5 dcscribcd the gross structurcs of the components of t h e geritaniiciri C complex. One member of the complex, geritaniicin C? wab shown t o possess structure Ia. In common uitli thc othcr gcntaniicins, Ia is not absorbed to any great extent when given orally in man and, givm parmtc~rally,it is r:Lpidl> escreted in tlie urine requiring rc.lativcly frcquent dosing in order to maintain dfcct ~vcablood l ( v c ~ l ~It . scemed reasonable that a lipophilic. tlorivativcx of thc antibiotic, from n-hich the parcnt compound roultl bc rcgcnerated z n VZL'O, might provide oral absorIition or longer duration of action when given parc>ntcwlly. Such a derivativc could be formed by condc~n~ation of tho primary nniino groups with aldehydes. a 'I'li(h
/
I
/
/
qHN=CHPh
,/
ti "**H
In
c248
HC'H%O
Ph
I1
stantiated by the appearancp in the mass spectrum of intense pealis at m/e 319 (cleaved purpurosamine fragment) and m/e 248 (cleaved garosamine fragment). Formation of the oxazolidine was confirmed by rxamination of the IH nmr spectrum (60 MHz, CDCI,) which contained a 1-proton singlet a t 6 5.0 corresponding to tlie benzylic proton of the oxazolidine system and indicating further that oxnzolidine formation proceds stereospecifically. .I Fujii, li hlaeda and I1 Uineia\\a J A n t h o l , 21, 340 (1968) (8) (a) D J Cooper .\I D 'xudis, R D Guthrie and .S 11 Prior J Ckem Soc C 960 (1971) \I))\T hle,er 711 Reckendorf and I., Blschof. Tetruhedron Lett 2373 (19iO) (7)
