Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-29
2004-06-01
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06743917
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds and methods of preparation thereof and, particularly, to silyl camptothecin derivatives or analogs and to methods of preparation of such silyl camptothecin analogs.
BACKGROUND OF THE INVENTION
(20S)-Camptothecin (CPT, see below) and its derivatives are some of the most promising agents for the treatment of solid tumors by chemotherapy. See, for example, Wall, M. E. et al,
J. Ethnopharmacol.,
51, 239 (1996);
Camptothecin: New Anticancer Agents;
Potmesil, M. and Pinedo, H., Eds.; CRC, Boca Raton, Fla. (1995); Bonneterre,
J., Bull. Canc.,
82, 623 (1995); Sinha, D. K.,
Drugs,
49, 11 (1995). This natural alkaloid was first isolated in 1966 from the extract of a Chinese plant,
Camptotheca accuminata,
by Wall. Wall, M. E. et al,
J. Am. Chem. Soc.,
88, 3888 (1966). As depicted below, camptothecin has a fused ring system generally comprising a pyrrolo[3,4-b]quinoline system (rings ABC) fused to a 2-pyridone ring (ring D), which, in turn, is fused to a lactone ring (ring E).
Camptothecin belongs to the family of topoisomerase I poisons. See, for example, Froelich-Ammon, S. J. et al.,
J. Biol. Chem.,
270, 21429 (1995). Research to date strongly suggests that this molecule acts by interfering with the unwinding of supercoiled DNA by the cellular enzyme topoisomerase I, an enzyme which is usually overexpressed in malignant cells. In the highly replicating cancer cells, this triggers a cascade of events leading to apoptosis and programmed death. See Slichenmyer, W. J. et al.,
J. Natl. Cancer Inst.,
85, 271 (1993). Recent advances at the molecular pharmacology level are reviewed in Pommier, Y. et al.,
Proc. Natl. Acad. Sci. USA ,
92, 8861 (1995).
Camptothecin's initial clinical trials were limited by its poor solubility in physiologically compatible media. Moreover, early attempts to form a water-soluble sodium salt of camptothecin by opening the lactone ring with sodium hydroxide resulted in a compound having a poor antitumor activity. It was later reported that the closed lactone-form is an absolute requisite for antitumor activity. See Wani, M. C. et al.,
J. Med. Chem.,
23, 554 (1980). More recently, structure-activity studies have identified analogous compounds with better solubility and better antitumor activity. For example, topotecan (TPT) and irinotecan (IRT) have recently been approved for sale in the United States., while GI-147211C is in late stage clinical trials. These analogs are effective against a variety of refractory solid tumors such as malignant melanoma, stomach, breast, ovarian, lung and colorectal cancers, and seem particularly promising for the treatment of slow-dividing cancer lines. See, for example, Kingsbury, W. D. et al.,
J. Med. Chem.,
34, 98 (1991); Sawada, S. et al.,
Chem. Pharm. Bull.,
39, 1446 (1991); Luzzio, M. J. et al.,
J. Med. Chem.,
38, 395 (1995); Abigerges, D. et al.,
J. Clin. Oncol.,
13, 210 (1995). Furthermore, synergistic or additive effects have been observed in combination therapies with cisplatin, irradiation, or hyperthermia. See Fukuda, M. et al.,
Canc. Res.,
56, 789 (1996); Goldwasser, F. et al.,
Clin. Canc. Res.,
2, 687 (1996); Wang, D. S. et al.,
Biol. Pharm. Bull.,
19, 354 (1996).
Although most research has focused on the development of water-soluble derivatives of camptothecin, new formulations, such as lipid-complexation, liposomal encapsulation, and wet milling technology have recently been developed. Such formulations result in new therapeutic opportunities for poorly water-soluble camptothecins. See Daoud, S. S. et al.,
Anti
-
Cancer Drugs,
6, 83 (1995); Merisko-Liversidge, E. et al.,
Pharm. Res.,
13, 272 (1996); and Pantazis, P.,
Leukemia Res.,
19, 775 (1995). An attractive feature of these formulations is their impact on drug biodistribution. Sugarman and coworkers have recently reported that while free camptothecin achieves the greatest concentration in the pulmonary parenchyma, lipid-complexed camptothecin has the highest concentration in the gastrointestinal tract. These results open new and interesting perspectives for the treatment of colon cancer. See Sugarman, S. M. et al.,
Canc. Chemother. Pharmacol.,
37, 531 (1996). Another interesting aspect of using insoluble camptothecin analogs is that they are usually more active than their water-soluble congeners and seem less likely to create drug-induced resistance, probably because they are not substrates of the p-glycoprotein multi-drug transporter. See Pantazis, P.,
Clin. Canc. Res.,
1, 1235 (1995).
In this context, new camptothecin analogs that combine good to excellent anti-tumor activities with different solubility and biodistribution profiles could play a crucial role in the therapeutic arsenal for the treatment of various types of cancers.
Given the proven beneficial biological activity of camptothecin and analogs thereof, it is desirable to develop additional camptothecin analogs and methods of preparation of camptothecin analogs.
SUMMARY OF THE INVENTION
The present invention provides generally a compound having the following formula (1):
The present invention also provides a method of
synthesizing compounds having the formula (2):
via a 4+1 radical annulation/cyclization wherein the precursor
is reacted with an aryl isonitrile having the formula
R
1
and R
2
are independently the same or different and are preferably hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an acyloxy group, —OC(O)OR
d
, wherein R
d
is an alkyl group, a carbamoyloxy group, a halogen, a hydroxy group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group(—C(O)R
f
wherein R
f
is preferably an alkyl group, an alkoxy group, an amino group or a hydroxy group), an amino group, —SR
c
, wherein, R
c
is hydrogen, an acyl group, an alkyl group, or an aryl group, or R
1
and R
2
together form a group of the formula —O(CH
2
)
n
O— wherein n represents the integer 1 or 2.
R
3
is preferably H, a halogen, a nitro group, an amino group, a hydroxy group, or a cyano group. R
2
and R
3
can also together form a group of the formula —O(CH
2
)
n
O— wherein n represents the integer 1 or 2.
R
4
is preferably H, F, a trialkylsilyl group, a C
1-3
alkyl group, a C
2-3
alkenyl group, a C
2-3
alkynyl group, or a C
1-3
alkoxy group. R
5
is preferably a C
1-10
alkyl group. A preferred alkyl group is an ethyl group. Preferred substituted alkyl groups for R
5
include an allyl group, a propargyl and a benzyl group.
R
6
, R
7
and R
8
preferably are independently (the same or different) a C
1-10
alkyl group, a C
2-10
alkenyl group, a C
2-10
alkynyl group, or an aryl group. A preferred substituted alkyl group for R
6
, R
7
and R
8
is a —(CH
2
)
N
R
9
group, wherein N is an integer within the range of 1 through 10 and R
9
is a hydroxy group, an alkoxy group, an amino group, a halogen atom, a cyano group or a nitro group. Preferred amino groups for R
9
include alkylamino groups and a dialkylamino groups.
R
11
is preferably an alkylene group, an alkenylene or an alkynylene group. R
12
is preferably —CH═CH—CH
2
— or —C≡C—CH
2
—. X is preferably Cl, Br or I. More preferably, X is Br or I. Most preferably, X is Br.
The present invention also provides a compound having the formula (2):
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
11
are as defined prior to this paragraph. The present invention further provides a compound of the above formula wherein one of R
1
, R
2
, R
3
, and R
4
is not H. The present invention still further provides a compound of the above formula wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
11
are as defined prior to this paragraph and wherein R
5
is a methyl group, a C
3-10
alkyl group, an allyl group, a benzyl group or a propargyl group.
The present invention further provides a compound having the following formula (3):
The present invention further provides a compound having the following formula (4):
The t
Bom David
Burke Thomas G.
Curran Dennis P.
Josien Hubert
Bartony & Hare, LLP
Ford John M.
University of Pittsburgh
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