Antimalarial analogs of artemisinin

Polyoxoheterocyclic tetracycles related to the Chinese antimalarial natural product qinghaosu (artemisinin) are disclosed. These materials have a ##STR1## core structure with an oxygen (carbonyl or alkyl ether) at position 12 and in some cases one or two alkyl or aralkyl substituents at position 11. These materials have antimalarial properties.

CROSS-REFERENCE TO RELATED APPLICATIONS 
This application is related to three prior applications each made by 
coinventor Mitchell Avery and colleagues and each commonly owned with the 
present application. The prior applications are: 
U.S. Ser. No. 943,555 filed Dec. 18, 1986; now abandoned; 
U.S. Ser. No. 108,138 filed Oct. 13, 1987; now abandoned; 
and U.S. Ser. No. 108,145 filed Oct. 13, 1987, now abandoned. 
BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention is in the field of organic chemistry. More particularly, it 
relates to methods for the synthesis of oxygen-containing heterocyclic 
organic compounds, materials formed by these methods, and intermediates 
generated in the methods. In one application, this method is used to 
prepare analogs of the antimalarial agent known as qinghaosu ("QHS") or 
artemisinin. 
2. Description of Related Art 
The three prior applications noted above all related generally to the same 
project which is dealt with herein. The present application covers recent 
advances over the work covered by these earlier applications. 
This invention relies on ozonolysis of vinylsilanes to give rise to 
polyoxaheterocyclic compounds. A reference of which we are aware which 
involves ozonolysis of a vinylsilane is that of George Buchi et al., 
Journal of the American Chemical Society, Vol 100, 294 (1978). Another 
reference of interest is by R. Ireland et al., Journal of the American 
Chemical Society, Vol 106:3668, (1984), which relates to silylation. 
We also call to the Examiner's attention the publications of some of this 
related work appearing at M. Avery et al., Tet Lett, Vol 28:(40), 4629, 
(1987). 
Other art of interest to the present invention relates to the ancient 
antimalarial natural product known as qinghaosu. The antimalarial 
qinghaosu has been used in China in the form of crude plant products since 
at least 168 B.C. Over the last twenty years, there has been an extensive 
interest in this material. This has led to an elucidation of its structure 
as 
##STR2## 
The chemical name artemisinin has been applied to the material. This name 
will be used in this application to identify the material. 
The carbons in the artemisinin structure have been numbered as set forth 
above. When reference is made to a particular location in a compound of 
this general type, it will, whenever possible, be based on the numbering 
system noted in this structure. For example, the carbon atoms bridged by 
the peroxide bridge will always be identified as the "4" and "6" carbons, 
irrespective of the fact that this invention can involve materials having 
different bridge-length structures in which these carbons would otherwise 
be properly numbered. 
References to artemisinin and to certain of its derivatives include the May 
31, 1985 review article by Daniel L. Klayman appearing in Science, Vol 
228, 1049 (1985); and the article appearing in the Chinese Medial Journal, 
Vol 92, No. 12, 811 (1979). Two syntheses of artemisinin have been 
reported in the literature by Wei-Shan Zhou, Pure and Applied Chemistry, 
Vol 58(5), 817 (1986); and by G. Shmid et al. Journal of the American 
Chemical Society, Vol 105, 624 (1983). Neither of these synthese employs 
ozonolysis or the unsaturated bicyclic ketones as set forth herein. 
In this specification we will at times refer to the following journal 
articles by way of the following footnotes: 
Literature Cited 
1. a. J. Katsuhara. J. Org. Chem., 32, 797 (1967). b. D. Caine, K. Procter, 
and R. Cassell. J. Org. Chem., 49, 2647 (1984). 
2. W. Oppolzer and M. Petrzilka. Helv. Chim. Acta, 61, 2755 (1978). 
3. J. Stowell, D. Keith, and B. King. Org. Synthesis, 62, 140 (1984). 
4. Brossi, A., Venugopalan, B. Dominguez Gerpe, L., Yeh, H. J. C., 
Flippin-Anderson, J. L., Buchs, P., Luo, X. D., Milhous, W., and Peters, 
W. J. Med. Chem. 31, 645 (1988). 
5. Francotte, E., and Lohmann, D. Helv. Chim. Acta 70, 1569 (1987). 
6. Lee, R. A., McAndrews, C., Patel, K. M., and Reusch, W. Tetrahedron 
Lett. 965 (1973). 
7. Primary reference: L. Rosch and G. Altman. J. Organomet. Chem., 195, 47 
(1980). It should be noted that this procedure has failed to work in our 
hands, as well as others: see B. Trost, J. Yoshida, and M. Lautens. J. 
Amer. Chem. Soc., 105, 4494 (1983). However, a procedure which works is 
provided in the experimental. The reagent can be titrated as described or 
by reaction with peperonal: L. Rosch, G. Altman, and W. Otto. Angew. Chem. 
Int. Ed. Engl., 20 581 (1981). 
8. Desjardins, R. E., Canfield, C. J., Haynes, D. E., and Chulay, J. D. 
Antimicrob. Agents Chemother, 16, 710-718 (1979). 
9. Milhous, W. K., Weatherly, N. F., Bowdre, J. H., and Desjardins, R. E. 
Antimicrob. Agents Chemother. 27, 525-530 (1979). 
10. W. Roush and W. Walts. J. Amer. Chem. Soc., 106, 721 (1984). 
11. Claus, R. E., and Schreiber, S. L. Org. Syn. 64, 150 (1985). 
12. U.S. patent application Nos.: 1. 10814 (10/13/87); 2. 108138 
(10/13/87); 3. 943555 (12/18/86). 
13. Y. Imakura, T. Yokoi, T. Yamagishi, J. Koyama, H. Hu, D. R. McPhail, A. 
T. McPhail, and K.-H. Lee. J. Chem. Soc. Chem. Commun. 372 (1988). 
14. T. F. Bates, and R. D. Thomas. J. Org. Chem., 54, 1784 (1989). 
The interest in antimalarial materials which are improved in terms of 
activity, strain selectivity and/or ease of production has prompted this 
continued research effort. The present invention is the result of this 
effort. 
STATEMENT OF THE INVENTION 
In one aspect, the present invention provides yet additional antimalarial 
analogs of artemisinin. These analogs are listed in Table 1. In Table 1, 
the new analogs are assigned numeric identification which are then used in 
the later description of the analogs' preparation and biological 
properties. 
TABLE 1 
__________________________________________________________________________ 
Identifica- 
Identification tion Code 
Code for for Biologi- 
Analog Synthesis cal Results 
__________________________________________________________________________ 
##STR3## 14 R = CH.sub.3 2800 
wherein R is an alkyl 
of 1 to 10 carbons, or 
an aralkyl of 7 to 9 
atoms. 
##STR4## 15 4584 
##STR5## 16 16a R = CH.sub.3 16b R = CH.sub.2 CH.sub.2 CH.sub.3 
6c R = CH.sub.2 Ph 16d R = CH.sub.2 CO.sub.2 .sub.-tBu 
6e R = CH.sub.2 CO.sub.2 H 16f R = CH.sub.2 CH.sub.2 
N(CH.sub.3).sub.2 
4585 
wherein R is a 
lower (1-4 carbon) 
alkyl such as methyl, 
ethyl or propyl; an 
aralkyl of 7 to 9 
carbons; a 1-4 carbon 
carboxylic acid; a 
1-4 carbon alkyl 
ester of a 1-4 carbon 
carboxylic acid; or a 
dialkyl (1-4 carbon 
each) amino 1-4 carbon 
alkyl. 
##STR6## 17 4586 
##STR7## 18 4595 
##STR8## 19 4588 
##STR9## 20 4598 
##STR10## 21 -- 
##STR11## 89 R = -n propyl 108 R = -n hexyl 109 R = -n 
tetradecyl 110 R = .sub.-i propyl 111 R = CH.sub.2 
CH.sub.2 CH.sub.2 Ph 112 R = .sub.-i amyl 120 R = 
CH.sub.2 Ph 4599 
wherein R is a 1-20 
carbon linear or 
branched alkyl or 
a 7 to 12 carbon 
aralkyl. 
##STR12## 90 R = n-propyl 4600 
wherein R is as 
set forth immediately 
above. 
##STR13## 22 4580 
##STR14## 23 4589 
##STR15## 24 4582 
##STR16## 25 4593 
##STR17## 26 4590 
##STR18## 27 
##STR19## 28 
##STR20## 29 4591 
##STR21## 30 4592 
##STR22## 31 4594 
##STR23## 32 4596 
##STR24## 33 4597 
##STR25## 52 
##STR26## 116 
wherein R is hydrogen 
lower alkyl of 1 to 4 
carbon, especially 
methyl. 
##STR27## 93 R = CH.sub.3 94 R = CH.sub.2 CH.sub.3 96 R = 
OCH.sub.2 Ph 
wherein R is a 1 to 4 
carbon alkyl, a 7 to 9 
carbon aralkyl, or a 
7 to 9 carbon aralkyloxy. 
##STR28## 97 
##STR29## 118 
__________________________________________________________________________ 
In an additional aspect, the present invention provides an improved 
simplified synthetic route to artemisinin and its analogs. The improved 
process, which is shown schematically in Scheme I, has as key steps: 
a) reacting 
##STR30## 
with tris (trialkylsilyl) aluminum etherate followed by acetic anhydride 
to yield 
##STR31## 
b) treating 9 with lithium dialkylamine to yield 
##STR32## 
c) subjecting 10 to dianion alkylation with alkyl iodide of the formula 
R.sup.* I, wherein R.sup.* is a lower alkyl of from 1 to 4 carbons, 
optionally including a 14C atom to yield 
##STR33## 
d) subjecting 11 to ozonolysis followed by acidification to yield 
##STR34## 
In an additional aspect, this invention provides antimalarial compositions 
based on the new compounds it enables.