Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-06
2004-03-09
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S014000, C546S048000
Reexamination Certificate
active
06703399
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to halo-alkyl esters of camptothecin and is also directed to compositions including derivatives of halo-alkyl esters of camptothecin in delivery systems, preferably derivatives having low toxicity and side effects. The present invention also relates to the use of these derivatives for cancer or tumor treatment in mammals. The disclosures of all documents referred to in this application are incorporated herein in their entirety by reference.
BACKGROUND OF THE INVENTION
Camptothecin, a cytotoxic alkaloid first isolated from the wood and bark of Camptotheca Acuminata (Nyssaceae) by Wall and his coworkers (
J. Am. Chem. Soc
. 88, 3888, 1966), was shown to have antitumor activity against the mouse leukemia L 1210 system. The structure of camptothecin, an alkaloid which has a commonly occurring indole alkaloid group (Heckendorf et al,
J Org. Chem
. 41, 2045, 1976), is shown below as Formula (X).
This compound (“CPT”) has a pentacyclic ring system with only one asymmetrical center in ring E with a 20(S)-configuration. The pentacyclic ring system includes a pyrrolo [3, 4-b] quinoline moiety (rings A, B and C), a conjugated pyridone (ring D), and a six-membered lactone (ring E) with an &agr;-hydroxyl group. Camptothecin was of great interest from the time of its initial isolation due to its noteworthy activity in the mouse leukemia L 1210 system. Earlier data for the antitumor activity of camptothecin were obtained by employing experimentally transplanted malignancies such as leukemia L 1210 in mice, or Walker 256 tumor in rats (
Chem. Rev
. 23, 385, 1973
, Cancer Treat. Rep
. 60, 1007, 1967). Subsequent clinical studies showed that this compound was not usable as an anticancer agent in vivo due to its high toxicity. Camptothecin itself is insoluble in water. Therefore, camptothecin was evaluated clinically as a water-soluble sodium carboxylate salt in the early times. This form of camptothecin produced severe toxicity and seemed devoid of anticancer activity (Gottlieb et al,
Cancer Chemother. Rep
. 54, 461, 1970, and 56, 103, 1972, Muggia et al,
Cancer Chemother. Rep
. 56, 515, 1972, Moertel et al,
Cancer Chemother. Rep
. 56, 95, 1972, and Schaeppi et al,
Cancer Chemother. Rep
. 5:25, 1974). These results caused the discontinuation of phase II trials. Continued evaluation of this agent showed that the sodium carboxylate salt is only 10% as potent as the native camptothecin with the closed lactone ring intact (Wall et al,
In International Symposium on Biochemistry And Physiology of The Alkaloids, Mothes et al, eds, Academie—Verlag, Berlin
, 77, 1969, Giovanella et al,
Cancer res
. 51, 3052, 1991). In addition, important parameters for antitumor activity in the camptothecin family have been established (Wall et al,
Ann. Rev., Pharmacol. Toxicol
. 17, 117, 1977). These results indicate that an intact lactone ring E and &agr;-hydroxyl group are essential for antitumor activity.
In 1989, Giovanella et al. found that some of the non-water soluble derivatives of camptothecin have high antitumor activity against xenograft of human tumors (Giovanella et al.,
Science
, 246, 1046, 1989). It has also been shown that administration of camptothecin with closed lactone ring is superior to injections of water-soluble carboxylate salt (Giovanella et al,
Cancer Res
., 51, 3052, 1991). These findings further confirmed the importance of the intact lactone ring to biological activity.
Ring opening of 20(S)-camptothecin (“CPT”) leads to much more potent anticancer activity in mice than in humans. In effect, CPT administered intramuscularly (“i.m.”), subcutaneously (“s.c.”), and intrastomach (“i.s.”) has proved to be a very potent anticancer agent against human tumors in mice, i.e., when growing as xenotransplants in nude mice (Giovanella et al, Cancer Res. 51:3052, 1991). However, when tumors were treated with CPT in humans, a lower degree of anticancer activity in humans, than in mice, was exhibited (Stehlim et al., In Camptothecins: New Anticancer Agents, 1995, CRC Press, pp. 59-65).
The same phenomenon was observed with other CPT-derivatives. In mice, 9-nitrocamptothecin (“9NC”) has proven to be 2-3 times more potent than CPT against human tumor xenografts causing the total eradication of all the human malignancies treated (Pantazis et al., Cancer Res. 53:1577, 1993; Pantazis et al., Int. J. Cancer 53:863, 1995).
Pharmacological studies demonstrated that the majority (57%) of the 9NC drug present in the plasma after i.s. administration is in the closed lactone form. Pharmacological studies on the plasma levels of 9NC after oral administration to Phase I clinical trial patients demonstrate that, on average, only ~3% of the drug present is in the closed lactone form.
In perfect agreement with such findings, the clinical responses in this group of patients, although higher than those obtained with CPT are still a far cry below the results obtained in mice (32/32 complete tumor regressions in mice versus 2/32 in humans). Clearly, there is a pressing need for a modification which will slow and delay the lactone ring opening upon its entrance into the blood circulation.
Ring opening is particularly problematic in that camptothecins exist in two distinct forms at physiological pH, i.e., 7 or above, as shown in the following equilibrium equation:
The hydrolysis reaction of the biological active lactone ring of camptothecins with water at higher pH gives the biologically inactive open form. Additionally, the hydrolysis problem with CPT and its analogs is exacerbated in human blood because the predominant blood serum albumin preferentially binds to the carboxylate form, which shifts the lactone/carboxylate equilibrium toward the inactive form (J. Biochem., 212, 285-287, 1993; Biochemistry, 33, 10325-10336, 1994; Biochemistry, 33, 12540-12545, 1994). Accordingly, preserving the lactone ring of the molecule for a sufficient time for the tumor cells to cycle through the S-phase is a major challenge and has been the focus of a considerable amount of research.
A number of attempts have been made to provide derivatives of camptothecin having greater biological activity and enhanced stability. Many of these compounds are the products of modifications on the A, B, and C rings of the molecule, but few of these modifications have enhanced the stability of the lactone ring under physiological conditions. Other approaches have been more successful. For instance, acylating of 20-OH group provides a useful tool for the protection of lactone ring E. Wall et al., U.S. Pat. No. 4,943,579, describes several acylated camptothecin compounds having water solubility, although the lactone may not remain intact under physiological conditions. U.S. Pat. No. 5,968,943 to Cao et al. discloses CPT-derivatives which are effective antitumor agents. Unfortunately, because mammalian physiological conditions break down all known CPT-derivatives, a need still exists for new CPT-derivatives and associated delivering systems for medical purposes.
In particular, there is a continuing need to modify 20(S)-camptothecin to enable the lactone ring to remain intact at normal physiological conditions, while retaining the structural elements, i.e. 20-hydroxyl and lactone ring E, for its antitumor activity. Accordingly, the present invention describes new CPT-derivatives which delay the opening of the lactone ring E, enhancing and prolonging the antitumor activity as compared to the mother analog, CPT.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide halo-alkyl esters of camptothecins which remain intact longer in a mammalian body, particularly in a human body.
It is another object of the present invention to provide new CPT-derivatives which retain the lactone ring E and the 20-hydroxyl group intact, which are important for antitumor or anticancer activity.
It is still another object of the present invention to use these compounds in a liposomal delivery system for living mammals.
Additional objects and advantages of the present inventio
Cao Zhisong
Giovanella Beppino C.
Dentz Bernard
Kilyk & Bowersox P.L.L.C.
The Stehlin Foundation for Cancer Research
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