so1
PROXIMAL" HTDRAZINO DERIVATIVES OF ~-CHLOROQUISOLIKE
September 1969
and the analogy with other known cases of attack a t the quinoline N15816 support the assignment of propiolate addition to the tautomeric quinoline ring S-H. Two trans-vinyl proton resoiiances from the propiolate portion ( J = 14 Hz) could be ob-
Antimalarials.
served a t 4.79 and 7 . i 2 ppm in the nmr. These not only rule out the possibility that the compound is a stable charge-transfer entity but also support the conclusion that KH to triple bond addition had occurred.
4-“Proximal” Hydrazino Derivatives of 7-Chloroquinoline TAR.4
SISGH,ROBERT G. STEIX,BKD JOHSH. BIEL
Research Laboratories, Alclrich Chemical Company, Inc., Milwaukee, Wisconsin 63210 Received March 7 , 1969 Sixteen “proximal” hydrazino derivatives of 7-chloroquinoline of the general structure I11 have been prepared and tested as antimalarials. Three of these have shown curative activity without toxic deaths up to doses of 640 mg,/kg sc.
In our earlier workl~ with drugs bearing a hydrazine moiety, as in a-methylphenethylhydrazine (I), it was found that, in contrast to the parent amines, drug resisCH ,
I
YHCHCH?CH,CH,K(C,H,)-
had to be changed once or twice to complete the hydrogenation. For the preparation of 11-16, the hydrazino-sidechain amines were first prepared and then put on 4,7-dichloroquinoline according to the sequence of reactions outlined in Scheme I.
D c ~ , I ~ ~ ~ ~ ~ 2
SCHEME
HJ(CH,),P;(R),
c1 I
I1
8:
J c1
TV
HCOC,H, or
1
RiNH(CM,)nN(R),
R?NH(CHJ,N(R)?
-
VI
LAH
v
tCH,CO)IO
HSO,
-
-
R?
I
LA H
ONh’(CH,),N(R), VI1
R> H,NN(CH,), 1N( R),
4.7-dichloroquinoline
111
tame did not develop to the corresponding hydrazines, thereby affording a long duration of action without decrease in efficacy on repeated administration. On this basis, it was considered worthwhile to incorporate a hydrazine moiety in the chloroquine (11) side chain in the hope of obtaining antimalarial drugs which would be effective in chloroquine-resistant malarial strains of Plusmoclaum falcipai um. Accordingly, we prepared the “proximal” hydrazino derivatives of chloroquine represented by the generic structure 111 where Rl is H, CH3, arid CIHj; R?ii dialkylaminoalLj 1, and R1 and R2 being the bame p u t of a hydrazone derivative as in compounds 2, 3, 5, 7, 9, arid 10 (Table I). The key intermediate for the preparation of 2-10 was 7-chloro-4hydrazinoquinoline (1) which was obtained according to the procedure of Surrey and C ~ t l e r . The ~ hydrazones were prepared by the reaction of 4-hydrazinoquinoline with appropriate aldehyde or the diethyl acetal of the aldehyde in the conventional manner. The hydrazines 4, 6, and 8 were obtained by catalytic (I’t) hydrogenation of the corresponding hydrazones in Et011 :it room temperature arid atmospheric pressure. Because of the premature poisoning of the catalyst, it (1) J. H. Biel, 1. E. Drukker, T F. Mitchell, E. P . Sprengeler, P . 4. Vuhfer A C. Connai and \ Horita, J Amer Chem. Soe , 81, 2805 (1959) ( 2 ) J 11. Biel .I Horita and \ !I Druhker in “Psschopharmacological k e n t s , ” To1 I , M Gordon Ed , Academic Press, K e w York, X Y., 1964, P 366 (3) A R. SurreJ and R Cutler, J AmW. Chem Soc., 68, 2570 (1946).
VI11
R,
1-
n = 2-4 R = CHJ, CLHj
IX R, = HCO, CH,CO R? CHJ, CZH5
For 13, the side chain could also be prepared by the alkylation of methylhydrazine with dimethylaminopropyl chloride according to the procedure of Elslager, et aL4 Biological Activity.-The compounds were tested for their antimalarial activity against Plusmodiunz beryhei in mice. The screening was carried out by Dr. L. Rane of the University of Miami, Miami, Fla. The screening procedure is described by T. S. Osdene, et a1.j Compound 1 was toxic. It I d e d one animal at 40 rng/kg and all five at 160 mg. Compounds 6-10 were inactive. Compounds 2-5 were slightly active, showing an increase in mean survival time of about 7.4 days. (4) E. F. Elslager. E. A. Weinstein, and D . F. IVortli, J . .\led. C l i e m . , 7, 493 (1964). (5) T. S. Osdene, P . B. Russell, and L.Rane, %bid., 10, 431 (1967)
2:;\ 240
'I'h(1 i r - u l t 5 for the compound, 11-16 are giveii in Tublc, I 1 ('ompound 15, which 1- a11 S i;,o>tere of chlorocluiiie is toxic at 320 aiid 640 mg killing two and five mice, reipectively. Thi- toxicity i, similar t o chlorocluiiic but leas severe. Tlie curative activity of t h e compoiuids 11-13 i;, noteworth> :L-they produced 110 toxic clr:tth- (Y ('11 :It the mnximum (low of (i40 mg I\g -c.
Experimental Section N-( 2-Dimethylaminoethyl j-N-methylnitrosoamine (VII, R = CHa, I I = 2, Rz = CH3).---A soliition of N-(2-dimeth?-lnmiiior,thyl)-iY-nieth?-l:iriiiine (50.0g, 0.3 mol)! concentrated I ~ , S O I (80.0 g, 0.8 mol), aiid 400 ml of IT& was cooled t o 0". solution of iYa?J02 (12.0 g, 0.6 mol) in H,O was added dropwise over n pei,iod of 2 hr. The mistiire was left to staind for 2 hr and the11 c,ciiic.eritrated to tli,yiies.*. The residue was dissolved in a miniI n i i m amount of HrO, cooled, and basified with KOH pellets. The protliict was estracted with Et2()(three 200-mlportions), the I
