Aromatic esters of camptothecins and methods to treat cancers

Details Aromatic esters of camptothecins and methods to treat cancers Aromatic esters of camptothecins and methods to treat cancers

2000-12-22

2002-06-18

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S051000

Reexamination Certificate

active

06407239

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to aromatic esters of camptothecins.
BACKGROUND OF THE INVENTION
Camptothecin, a natural product originally found in China, but now grown in many countries, was isolated and purified by Wall and his coworkers in 1966 (J. Am. Chem. Soc. 88, 3888, 1966). This compound was initially tested against the mouse leukemia L 1210 system and showed good activity. Since it proved to be a potent anticancer in animal models, camptothecin was quickly tested in human clinical trials. At this time, unfortunately, anticancer activity was not found; instead, severe toxicity was observed for those patients who participated in the trials (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). Trials were accordingly discontinued. The reason for the failure of the early trial was later found to be an incorrect drug formulation selected. Camptothecin is insoluble in water itself. In order to use the drug for i.v. administration, camptothecin was converted to its sodium form (CPT sodium carboxylate). This form although water-soluble, is practically devoid of anticancer activity, and quite toxic. For example, a careful evaluation of these agents in animal models made by Wani et al revealed that the sodium salt is only 10-20% as potent as the parent camptothecin (J. Med. Chem. 23, 554, 1980). In addition, important parameters for anticancer activity in the camptothecin series have now been established (Wall et al., Ann. Rev. Pharmacol. Toxicol. 17, 117, 1977). The intact lactone form with an &agr;-hydroxyl group at the position 20 of the molecule is believed to be essential for antitumor activity.
Keeping the molecule as an intact lactone form is the key for success of the treatment. In the laboratory, camptothecin and its derivatives have shown a promising activity against a wide spectrum of human tumors grown in xenografts in nude mice (Giovanella et al., Cancer Res. 51, 3052, 1991, and Natelson et al., Annals N.Y. Acad. Sci. 803, 224, 1996), but much less activity was observed in human clinical trials. This difference in antitumor activity has been associated with the finding that the hydrolysis of lactone to carboxylate of the molecule is much faster in human plasma than in mouse. For example, about 50% of 9-nitrocamptothecin is present as lactone form in mice plasma, but only 5% of the molecule can be found as the lactone form in human plasma. The lactone camptothecin molecule is not stable in human. More studies on the stability of camptothecin derivatives in human serum have been conducted by Burke et al. (Annals N.Y. Acad. Sci. 803, 29. 1996).
Clearly, there is a need to obtain a camptothecin compound that keeps the molecule as an intact lactone when it is in circulation in the body. In other words, a camptothecin product having longer biological life span is wanted. A number of attempts have been made to obtain protected camptothecin derivatives, but none of the compounds has been disclosed to significantly increase the biological life span. U.S. Pat. No. 4,943,579 relates to the preparation of several water-soluble camptothecin esters by the esterification of camptothecin with amino acids as acylating reagents at the 20 position. U.S. Pat. No. 5,646,159 relates to the esterification of 10,11-dioxymethylenecamptothecin with amino acid derivatives as acylating reagents at the position 20 to provide several water-soluble compounds. These two patents use the same acylating reagents (amino acids) for the esterification reaction, and the products are water-soluble, thus they are not related to water-insoluble camptothecin esters and are not within the scope of the present invention. U.S. Pat. No. 5,731,316 discloses esterification of camptothecins with various different acylating reagents rather than amino acids to provide a wide range water-insoluble ester compounds of camptothecins. The compounds disclosed in this invention significantly increase the biological life span while maintaining the inherent antitumor activity and lowering the toxicity. However, the previous patent did not use any aromatic functionality for the esterification reaction. The present invention relates, for the first time, to making aromatic esters of camptothecins.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide new camptothecin compounds which are active against various types of tumors and are non-toxic.
It is a further object of the present invention to provide aromatic esters of camptothecins.
It is another object of the present invention to provide the prodrugs of camptothecins. These prodrugs can regenerate to the parent active camptothecin compounds by an enzymatic hydrolysis after in vivo administration.
It is still another objection of the present invention to provide the methodology of preparing the above-described aromatic esters of camptothecins.
It is still a further object of the present invention to provide an improved treatment for certain types of cancers.
Additional objects and advantages of the present invention will be set forth in part in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. The objects and advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
To achieve the objects and in accordance with the purpose of the present invention, as embodied and broadly described herein, the present invention relates to a compound of formula (I).
The present invention also relates to a method for treating malignant tumors or cancer in a mammal and comprises administering an effective amount of a composition containing one or more of the compounds of formula (I) depicted above.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel camptothecin derivatives. These camptothecin derivatives are preferably water-insoluble aromatic camptothecin esters. The aromatic camptothecin esters preferably have the formula (I):
In this formula, the various R groups represent substituents on one of the rings of the structure above. In particular, R
1
represent H, NO
2
, NH
2
, N
3
, a halogen (e.g., F, Cl, Br, I), carboxyl (COOH), a C
1-16
alkyl group, C
1-16
alkylenyl group, a C
3-8
cycloalkyl group, a C
1-8
alkoxyl group, an aroxyl group, CN, SO
3
H, a C
1-8
halogenated alkyl group, (CH
2
)
n
NR
2
7
(where R
7
is H, or a C
1-8
alkyl group, n is an integer of from 1 to about 8), hydroxyl, SH, SR
8
(where R
8
is a C
1-8
alkyl group, or a phenyl group, or a substituted phenyl group), a carbonyl group, (e.g., COR
9
, where R
9
is a C
1-8
alkyl group, or a phenyl group, or a substituted phenyl group), a SiR
3
10
(where R
10
is a C
1-4
alkyl group). The R
1
group is respectively positioned at the 9, or 10, or 11, or 12 position of ring A. R
1
can also be a disubstituted 10, 11-O—(CH
2
)
y
—O— group (where y is an integer of from 1 to 3). X represents H, a C
1-8
alkyl group, a C
1-8
alkenyl group, a C
1-8
alkoxyl group, an aroxyl group, a SiR
3
11
group (where R
11
is a C
1-4
alkyl group), or CH
2
NZY where Z and Y are, independently, H, C
1-4
alkyl, or a C
1-4
halogenated alkyl group. R
2
, R
3
, R
4
, R
5
, and R
6
are, independently, H(s), C
1-12
alkyl group(s), C
1-12
alkenyl group(s), COOH(s), SO
3
H(s), CN(s), CF
3
(s), CCl
3
(s), CH
2
F(s), CH
2
Cl(s), CHF
2
(s), CHCl
2
(s), OH(s), OR
12
(s) (where R
12
is a C
1-8
alkyl group, or a C
1-8
alkenyl group, or an aromatic group), N
3
, NO
2
(s), NR
2
13
(s) (where R
13
is H, or C
1-4
alkyl group), carbonyl group (s), halogen(s).
More preferred aromatic camptothecin esters of the present invention are as follows, wherein:
R
2
= R
3
= R
4
= R
5
= R
6
= H;
R
2
= R
3
= R
5
= R
6
= H, R
4
=

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