Hexacyclic camptothecin analogues, and process for preparing the

Details Hexacyclic camptothecin analogues, and process for preparing the Hexacyclic camptothecin analogues, and process for preparing the

1997-09-10

1999-11-23

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546 41, A61K 31435, C07D49122, C07D49822, C07D51322

Patent

active

059901209

DESCRIPTION:

BRIEF SUMMARY
The present application is a 371 of PCT/EP95/05752, filed Dec. 17, 1996.
The present invention relates to new hexacyclic camptothecin analogues possessing antitumor activity, to a process for preparing the same, and to pharmaceutical compositions containing them.
It is well known in the art that camptothecin and some of its analogues display potent antitumor activity by inhibition of topoisomerase I, an enzyme involved in some important cellular functions and in cellular growth (see for instance Wani et al., J. Med. Chem., 1987, 30, 1774; Hsiang et al., Cancer Res., 1989, 49, 4385; Cancer Res., 1989, 49, 1465). Anticancer activity of camptothecin both in vitro and in vivo are significantly greater for the lactone versus the carboxylate form (as disclosed for instance by W. J. Slichenmyer, et al., in "The Current Status of Camptothecin Analogues as Antitumor Agents", J. Natl. Cancer Inst., 1993, 85, 271-291, and the references cited therein), since a closed .alpha.-hydroxy lactone ring is an important structural requirement for both passive diffusion of drug into cancer cells, as well as for a successful drug interaction with the pharmacological target. It has been recently reported that, in the presence of biologically relevant levels of human albumin, the biologically active form of camptothecin has a very short half-life (about 12 min), and 2 hours after drug addition to human plasma, more than 99% of the drug has converted to camptothecin carboxylate, the biologically inactive and potentially toxic form of the drug (see Burke, G. T., and Mi, Z. "The Structural Basis of Camptothecin Interactions with Human Serum Albumin: Impact on Drug Stability", J. Med. Chem., 1994, 37, 40-46). Therefore, a need is felt of finding new camptothecin derivatives having high intrinsic potency and which can gain stability in the presence of serum albumine.
M. C. Wani et al. report in J. Med. Chem., 1986, 29, 2358-2363, that monosubstitution by NH.sub.2 or OH at positions 9, 10, or 11 in ring A of camptothecin yields compounds with antileukemic activity much higher than the parent compound camptothecin. On the contrary, disubstitution in ring A greatly reduces activity. Particularly, compounds with substituents at both positions 9 and 10 demonstrate a marked drop in activity and/or potency, probably due to steric interaction.
The Applicant has now surprisingly found that certain hexacyclic camptothecin analogues as defined hereinunder, having a five-membered aza-heterocycle fused to ring A of camptothecin at positions 9 and 10, possess high antitumor activity.
The present invention therefore provides a hexacyclic camptothecin analogue of formula (Ia) ##STR1## wherein: R.sub.1 is selected from: -C.sub.6 alkyl; independently: C.sub.1 -C.sub.6 alkyl; a C.sub.3 -C.sub.7 cycloalkyl; an optionally substituted phenyl; a C.sub.1 -C.sub.6 alkanoyl; an optionally substituted benzoyl; an optionally substituted C.sub.1 -C.sub.6 alkoxycarbonyl; or a benzoyloxycarbonyl; or R.sub.3 and R.sub.4, combined together with the nitrogen atom to which they are linked, form a 3-7 membered, saturated or unsaturated, optionally substituted, hetero-monocyclic ring; C.sub.1 -C.sub.6 alkyl such as a phenyl C.sub.1 -C.sub.6 alkyl; a C.sub.3 -C.sub.7 cycloalkyl; an optionally substituted phenyl; a C.sub.1 -C.sub.6 alkanoyl; an optionally substituted benzoyl; an optionally substituted C.sub.1 -C.sub.6 alkoxycarbonyl; or a benzoyloxycarbonyl; and C.sub.1 -C.sub.6 alkyl such as a phenyl C.sub.1 -C.sub.6 alkyl; a C.sub.3 -C.sub.7 cycloalkyl; an optionally substituted phenyl; a C.sub.3 -C.sub.7 alkanoyl; an optionally substituted benzoyl; an optionally substituted C.sub.1 -C.sub.6 alkoxycarbonyl; or a benzoyloxycarbonyl; phenyl C.sub.1 -C.sub.6 alkyl; and substituted C.sub.1 -C.sub.6 alkyl such as a phenyl C.sub.1 -C.sub.6 alkyl; a C.sub.3 -C.sub.7 cycloalkyl; an optionally substituted phenyl; a C.sub.1 -C.sub.6 alkanoyl; an optionally substituted benzoyl; an optionally substituted C.sub.1 -C.sub.6 alkoxycarbonyl; a benzoyloxycarbonyl; an optionally substitute

REFERENCES:
patent: 4981968 (1991-01-01), Wall et al.
patent: 5614628 (1997-03-01), Cabri et al.
patent: 5648534 (1997-07-01), Igarashi et al.
patent: 5670500 (1997-09-01), Berges et al.

Affiliated with

Also associated with

Rating

Hexacyclic camptothecin analogues, and process for preparing the does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Hexacyclic camptothecin analogues, and process for preparing the, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hexacyclic camptothecin analogues, and process for preparing the will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1222209