1050
Notes
Journal of Medicinal Chemistry, 1973, Vol. 16, No. 9
Table 111 R
COzEt
R,OCH,
Compd 81 82 83 84
85 86 87 88 89 90 91 92 93 94 95 96 97
98 99
100 101 la lb IC
Weight ratio Yield purified, (day 5/day O)b R, R, % Mp,"C Formulau 0.01% 0.001% 23 293.5 C,,H,,NO, 1.18 Me Et Me i-Bu 17 248 C,,H,,NO, 1.17 Me n-C,H15 27 +300 C,,H,,NO, 1.25 Me n-CaH17 25 230 C,,H,,NO, 1.25 29 231 C,,H,,NO, 1.17 CHZC 6H 5 Me i-Bu Cl,H,,N05 1.24 Et 17 246 C,,HZ9NO, 1.20 n-C 3 Et 31 222 C,,H,,NO, 1.24 1.23 n-C,H,, Et 47 227 C,,H,,NO, 1.26 1.23 nGH17 Et 31 226 C,,H,,NO, 1.22 n-C9H19 Et 12 225 Cz6H,,NOS 1.21 n-CllH23 Et 31 222 CH2CH,C6H, C,,H,,NO, Et 1.25 56 229 n-Pr n-Bu C,,HZ7NO5 1.19 33 227 C,,H,,NO, n-C,H, 5 1.20 n-Bu 28 217 32 215 C,,H3,N05 1.20 n-CsH17 n-Bu 25 213 C,,H3,N05 1.17 n-Bu n.C9H19 32 221 Et C,,H,,NO, 1.18 n-C,H,, C,,H,,NO, 1.18 CHzC6HS 27 219 n-C,H,, C,,H,,NO, 1.30 n-C,,H,, Et 31 217 CZsH,,NO, 1.19 n-Pr n-C,,HZI 43 213 C,,H,,NO, 1.20 n-C,Hl, n-CloHzl 23 205 Decoquinate (ethyl 6-n-decyloxy-7-ethoxy-4-hydroxy-3-quinoline- 1.24 carboxylate) Nequinate (methyl 7-benzyloxy-6-n-butyI-4-hydroxy-3-quinoline- 1.24 1.19 carboxylate) Amquinate (methyl 7-diethylamino-4-hydroxy-6-n-propyl-31.22 quinolinecarboxylate)
Oocyst count (day 7Ic 0.01% 0.001% 1;l;O;O 1;l 1;l:l;l 1;1;1;1 2;2;2;2 0;O;O 3;2;2 1;2;1;2 1;2;2 2;2 1 ; l ; l ; l 1;1;3;3 0:O;l;l 0;0;2;2 0;O;O;O 0;O;l;l 1;l;O;O 0;0;2;2 1 ; l ; l ; l 1;1;1;1 1;1;2;2 1;1;2;2 1;1;1;1 1;1;2;2 1;l;l;l 1;1;2;2 0;O;l;l 1 ; l ; l ; l 0;O;l;l 1;1;2;2 1;2;2;2 1:l 1 ; l ; l ; l 1;1;1;1 1 ; l ; l ; l 1;1;1;1 3;3 2;1 2;2;1;1 1 ;1;1 ;1 0;o;o;o 0;O;l;l
Fecal score (day 5)d 0.01% 0.001% 1;1;1;1 3;3 2;1;2;3 0;l;l;l 2;2;3;2 1:1;1;1 2;2:1;3 2;2;1;2 1;l;l;O 1;2 1 ; l ; l ; l 3;2;3;3 1;O;l;l 1;1;1;1 0;l;l;l 1;1;2;1 1;l;O;O 1;1;3;3 1;1;1;2 1;1;1;1 0;0;2;1 2:1;1;2 1;2;1;1 1;1;2;1 2;l;l;l 2;2:1;1 0;1;1;0 1;1;1;3 1 ; l ; l ; l 1;1;1;1 1;3;1;1 3;3 1;2;0;1 1;1;2;3 1;l:l;l 0;O:l;l 3;l 3;3 2;1;1;2 1 ;I ;2;2 1;O;l;l 1:l:I;O
0;O;l;O
0;1;2;1
0;1;1;0
0;0:2:1
0;l;l;l
1:1;3;l
0;O;l;O
1;2:3:1
aAll compounds were analyzed for C, H, and N. Compound 97, C: -0.54; 99, C: -0.64; 100, C: +0.47. bRefer to chemotherapy. '0, no oocysts in feces; 1, 0-5 X l o 4 oocyst/g of feces; 2, 5 X 104-1 X lo5 oocyst/g of feces; 3 , 105-2 X lo5 oocyst/g of feces; 4, more than 2 X l o 5 oocyst/g of feces. GO, normal feces; 1, soft to normal feces; 2, fluid droppings with some mucous casts; 3, slimy, greyish, mucoid diarrhea.
E t O ~ C O z E t Table IV. Chemotherapeutical Results of n-C ,HISOCH, Mean weight ratio
Eimeria strain Acervulinaa Brunetti
Tenella'
Treatment Simultaneous Prophylactic Simultaneous Prophylactic Simultaneous Prophylactic
Noninfected chicks 1.33 1.60 1.42 1.65 1.34 1.78
Infected chicks 1.04 1.16 1.14 1.14 1.19 1.33
Infected chicks treated with 0.01% of 88 1.24 1.40 1.53 1.79
Infected chicks treated with 0.001% of 88 1.23 1.50 1.42 1.66 1.51 1.74
Infected chicks treated with 0.001% of l b 1.19 1.50 1.41 1.62 1.49 1.72
aResults of the 5th day. bResults of the 6th day. CResults of the 7th day. filtered and triturated with Me,CO for 1 hr. The precipitate was collected and dried in vacuo to give 5.5 g (47%) of 88, mp 227". Anal. (C,zH,,NO,) C, H, N.
Acknowledgment. The authors are indebted to Mr. F. Sels for the C, H, and N analyses and to Mr. P. Demoen for the other analyses. The work described in this publication is part of a program supported by a grant from the Instituut tot Aanmoediging van het Wetenschappelijk Onderzoek in Nijverheid en Landbouw (IWONL). References (1) C. F. Spencer, A. Engle, Chia-NienYu, R. C. Finch, E. S. Watson, F. F. Ebetino, and C. A. Johnson, J. Med. Chem., 9, 934 (1966). (2) R. A. Bowie, J. P. Cavins, M. S. Grant, A. Hayes, W. G. M. Jones, and J . F. Ryley, Nature (London), 214, 1349 (1967). (3) S. J. Ball, M. Davies, J. N. Hodgson, J. M. S. Lucas, E. W.
Parnell, B. W. Sharp, and D. Warburton, Chem. Ind. (London), 56 (1968). (4) R. H. Mizzoni, F. Goble, E. Konopka, J . Gelzer, J . Szanto. D. C. Maplesden, J. E. Brown, J. Boxer, G. Zaunius, J. B . Ziegler. and G. de Stevens,J. Med. Chem., 13,870 (1970).
Synthesis and Antiviral Activity of
Homologs of Noformycin Guy D. Diana,* Urano J . Salvador, Ethel S. Zalay, and Francis Pancic Sterling- Winthrop Research Institute, Rensselaer, New York 12144. Received February 28, 19 73
In the past two decades, several papers have appeared on the antiviral activity of noformycin'-' (1) obtained from a culture of Nocardia formica. Among the viruses reportedly
Journal ofMedicinal Chemistry, 1973, VoJ. 16, No. 9
Notes
1
susceptible to this compound were swine influenza and sk poliomyelitis. In our laboratories, noformycin has also exhibited in vitro activity against equine rhinovirus, human rhinovirus type 2 , and parainfluenza type 3. In view of its broad spectrum of activity, we became interested in preparing homologs in the hope of retaining activity and lowering toxicity. Ueda, et al.,8 reported on the synthesis of compounds possessing the amidinoethyl carboxamide side chain, with compounds 2 and 3 in their series being the most active.
a
NH
-
NH c N H c H , c H ,/Ic ~ H ,
/I
C H 3 ~ c N H C H 2 c H 2 C N H 2
I/
II
0
0
3
2
However, no biological data have been published. Our intention was to make slight modifications of the noformycin structure. We recently developed a synthesis of noformycin? which lends itself to the preparation of homologs of type 8. (CH,), O
