riip 140-142" dec. Recrystallizatiori from EtOH gave an aim- lytical sample, mp 142-144" dec. Anal. (C17H18N20&) C, H, N. 3-Piperonylrhodanine (VIII).--.4 solution of 4.7 g (0.05 mole )

of C1CH2C02H in 5 ml of HzO was treated with 1 g (0.025 mole) of NiiOIl arid sufficient KatCOo t o bring the p l l to T.5. To thii stii,red solution was added, during 80 rniii, 12.2 g (0.05 mole) of \TI. Uuriiig the addition, 15 ml of H2O and 40 ml of DXIF were added to facilitate the solution of the carbamtte salt. The ~ L Y - t,iire was stirred fo r 36 hr arid the resulting solid, nip 144-145" tlec, was collected by filtration aiid washed (H20, EtOH). It wiis slurried in 30 In1 of €LO and acidified with 6 ,Y €IC1 t o pH 2 . The mixture was heated at 80" for 1.5 mill and cooled. 'The yel- I I ) K iolid was collected by filtratiori, washed (MzO), arid drie(1 irr C I L C U O to give ti.: g (>2( J+dd) of prodiict? nip 11i-11%". 1kc.rystallixation frorii aq l i t 0 1 1 gave an:dytic*:illy ~ i t [ r c 1.11 I ,

3-(3,4-Methylenedioxyphenyl)alanine (IX ). -.A iiiirtiii,e of 7 g (U.O:i mole) of IIa aiid t i t i g (0.21 nlolej of L3a(OH)2.81120 i i i ;l50 nil of H20 \vas reflrised l v i t l i stii,riiig fiir 3 chys iiiitil evoliitioii of N I i s had (.eased. The rextioii iriixturt! was cooled t u 20" x i i d

;widified witli concd H,S04 to pi1 1. 'Tlie pptd BaSOr wab filtered :iiid washed with 200 nil uf H20. 'rhe filtrate a i d wvushiiigs were cririihiiied and evaporated co oiie-third of the origiiial volume. I t wis then rieutralized with S I I I O I I . The resulting precipitate LWS collected by filtration arid re illized from 1320 t o give I .I g (22yo) of IX, mp 253-23.1' ti .fi nip 2.50-2.5.5'). tl n u l .

3-(3,4-Jlethylenedioxyphenyl)-2-thiopyruvic Acid @).-A mix- i i i w of 12 g (0.045 mole) of IIId and 100 ml of 4 .V SaOH was i.efliised with stirring for 30 miri. The clew solution was coolrd r:tpidl)- t o 10" and acidified with 100 1111 of rold 4 - \ HC1. A f t PI'

1.; iiiiii the pale yellow precipitat wished with H20, aiid dried, mp 1 lizatioiis from hIeOH gave 4 g (40 riip 208-210' dec.). Anal . (ClaIlbO

Acknowledgment.----The nut 11IJI.S \\ish t o tliaiilc I ) r . Hou-ard W. Bond :itid I>r. Lco for their ititeiwt, :itid l l r s . :\Iargaret 1,. Rouiid:: and I I r . , J ~ l l i i li. Gravat t for t,ho analytical sild inst'runient:d niensuremerits.

11111 117-1111". A d . (CiiIlnSUaSi) c', 11, T.

~(', , ,~rlls04j C, H , S.

(10) R. .\ndreasch. .llo!irLtsii. Chem. , 39, -119 ( l < l l 8 ) .

Studies on the in Vivo Antiviral Efl'ects of Benzothiazole Derivatives against Various

Influenza A2 Strains

SCIG AK~,KFI:LD I<

Virology Deparlnient) lksearch Dt purtnicnt of the K.iBI Group, #-lo.$ 2.5 Stockholm 30, S w e d e n

Received A p r d 28, 1U70

During it11 investigatioii of tht. efl'tlct of v:trious heterocyclic ring systems oii mice iiifrctrcl \ \ i t ti variow iiif lurrizu virlis str:iiii:,, i t 11 : i ~ t 'o t i i ic i that 2-aniiiio- btiiizot tiiazolt,, \\lieii adrnitiittercvl iiitl.al)eritoiit.wllj to t i i iw, gave :L protection to thr aiiiiii:LIt cluittl coinl):irablc to that of :tminoadaniantaiie. structure-activity * t iidy \\.as then uiidertaken to itivestigatc. n-hethcr ( 8 I i t t i i i i structur:tl changes could improve thr :illtiviral ot'fcct of thc comi)ound. rtimarkable sensitivity t o variations in structure was found. Indeed, out of 17 benzothiasoles only the 2-amino- and 2-amino-4-chloro derivatives showed significant protective effect at the dose levels tested.

All 17 compounds \\.ere also tested in in citm systenis using human amnioriic cells iiifected with rhiiio virus :EKMt', ndriio virus :j7 a t i c l l ier~) t .+ hiiiiplvx \ i i u - . l e i protcctive c+fcct s could htb dt~nioii~tratcd n itli :ill>

compound in the concentration lunge of 1-50 bg 1111

Journal of Medicinal Chevzistry, 1370, Vol. 13, S o . 5 1018

Dose nq/animal

(ip) 0 . 1 0 . 3 0 , .i 0 . .i 0 , ,i I . *-, 1 , .j 0 . .-I 0 , *-> 0 . .i 0 . .i 0 . 5

Yo sur- vivors

treated group 30 0

i o 60 .i 0 60 x0 10 60 40 10 90

"0

survivors control group

7 7 i 7

20 7

47 1 :i 87 60 3 3 17

Dose mx/animal

(ip) 0 . 1 0 . :3 0 . .i 0 . 3

0 . 3 0 . .i 0 . 3 0 . .i 0 . 3 0 . *j 0 . 5

yo sur- vivors treated group

2 0 50 90

100

60 2 3 :30

100 60

0 90

%I

stirvibvrs control group

20 20 20 20

8 20 13 87 60 33 l i

Ddse mg/animal

(ip) 1 . 0

1 .0

1 .0 1 . 0 1 .0 1 .0 1 . 0

sur- vivors treated group

70

30

50 90 60 70 i o

Yo survi\ orzl

control group

8

20

1 :% 8 i 60 :3 3

8

2-aminobenzothiazole i t would appear that the antivi- ral effect is not improved by increasing the dose level above 0.; mg per animal.

Acknowledgment.-The author is indebted to S. Gejer, G. Fuchs, E. Holubars, and 31. Brundin for skillful technical a4s t ance and to G. Westin for pre- paration of some of the substances.

H / 2

H l b

Cycloserine Derivatives'

CH.\RLKS IT. STAMMER,^ C. CHANDRASEKHARAX KARTHA, ~ I S H I T H c. CHATURVEDI, B N D JAMES 1). MCKINNEY

Dipurtn~enl of Chenzisiry, Gnivusity of Georgia, Athens, Georgia 30601

Received January 27, 1970

The ki10n-ri3 biological activity of D-cycloserine ( la) , a broad spectrum :mtibiotic, led use to examine de- rivatives of this compound for antimalarial activity.

ANHK

RJ 1

a, R = R = H b. R =aralkyl; R' = H c. R = H; R =aralkyl d. R = R =aralkyl

We have previously4 reported the synthesis of several derivatives of cycloserine having general structures l b (R = 3-hvdrosy-3-chlorobenzyl) and l e (R' = Ph3C). The pathway by which this was done is shown in Scheme I. In this report, several new Schiff bases (2) are described which can be reduced with KaBH4 to

(1 ) Suppoi l w l i i i pari 1j.v ( ' c ~ ~ i L r a , ~ l I).i-49-1!43-A1 L)-2993 from tlie U. S.

(2) To \vlioiu inquiries alioiild be addreiiued. ( 3 ) Francie C. Neuhaus, in "Antibiotics," Vol. I, D. Gottlieb and P. L.

Siiaiv, Ed., Springer-Verlag, Heidelburg, 1967, Chapter 2. (4) (a) C. 11. Stammer and J. D. McKinney, J. Org. Chem., 30, 3436

(IVti:); ( b ) K . .I. Payne and C. H. Stammer, ib id . , 33, 2421 (1968).

. i rmy Medical Hesearch and L)aveloymeut Comlnand.

I R'

3

IC < /XHCHIR"

I R

Id

type lb or alkylated giving 3 which is further hydrolyzed or reduced to IC or Id.

Of greatest chemical interest is the considerable varia- tion in the ease of racemization of Schiff bases 2 as a function of the aldehyde used. Earlier showed that when 5-chlorosalicylaldehyde was employed, the Schiff base was optically quite stable4" in solution but was completely racemized during conversion into its 2-trityl derivative 3, R' = Ph3C, or its 2-lIe de- rivative6 3, R' = Me, These 2-alkylations were carried out in the presence of I<,C03 which apparently cata- lyzed the racemization of the products by abstraction of a proton from the asymmetric ce~i ter .~b Polarimetric measurements 011 a solution of t'he Schiff base Ka salt in diniethoxyethane showed that the rate of race- mization more than doubled after the addition of the alkyl halide. Hydrolysis of both of t'hese Schiff bases gave the racemic 2-alkylated cycloserines in good yield. SaB€14 reductiori of 3-chlorosalicylideIie-D- cycloserine, however, gave4b an optically active de- rivative lb, R = 5-chloro-2-hydroxybenzyl. The 5- nitrosalicylidene Schiff base 2, I1 = 5-nitrosalicyl, had the same optical properties, i . e . , alkylation gave an optically inactive 2-derivative while reduction gave :Ln active N-5-nitro-2-hydroxybeiiz~l-i)-cSclos~ririe.

In ail attempt to syrithesize an optically active 2-tritylcycloserine, the Schiff bwe 2, It" = '-hydroxy-

(3) P1i.D. Thesis of James D. Ncliinney, University of Georgia, Athens, Georgia, 1968.