Fluorinated quinolones as antimitotic and antitumor agents

Details Fluorinated quinolones as antimitotic and antitumor agents Fluorinated quinolones as antimitotic and antitumor agents

2000-09-25

2003-05-27

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S314000, C546S153000, C546S155000

Reexamination Certificate

active

06569870

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns quinolone derivatives, pharmaceutical formulations containing the same, and methods of use thereof as antimitotic and antitumor agents, particularly for the treatment of tumors such as breast cancer and ovarian cancer.
BACKGROUND OF THE INVENTION
Microtubules are one of the most important subcellular targets for the development of anticancer chemotherapeutic compounds. Vinca alkaloids and taxoids are well-known examples of antimitotic agents that are widely used clinically to treat different cancers (E. Rowinsky et al.,
Pharmacol
. &
Ther
. 1992, 52, 35-84; J. Verweij et al.,
Ann. Oncol
. 1994, 5, 495-505). Colchicine (
FIG. 1
) is another well-known agent that inhibits microtubule assembly (S. Hastie,
Pharm
. &
Ther
. 1991, 51, 377-401; S. Hastie,
Pharm
. &
Ther
. 1991, 51, 377-401). Although colchicine has limited utility for cancer therapy, the drug has been an important tool in studies of microtubule structure and function. The vinca alkaloids, taxoids, and colchicine each interact with tubulin by a unique mechanism, probably involving distinct binding sites on the protein.
The synthesis and biological evaluation of a series of 2-phenyl-4-quinolones as antimitotic and antitumor agents has been reported (S. Kuo et al.,
J. Med. Chem
. 1993, 36, 1146-1156; L. Li et al.,
J. Med. Chem
. 1994, 37, 1126-1135; L. Li et al.,
J. Med. Chem
. 1994, 37, 3400-3407). The compounds were evaluated in the National Cancer Institute's 60 human tumor cell line (HTCL) in vitro screen and in a tubulin polymerization inhibition assay. Most compounds showed cytotoxicity in the HTCL screen, with GI
50
values in the low micromolar to nanomolar concentration range. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization. SAR studies led to the discovery of 2′-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (Compound 1;
FIG. 1
) (L. Li et al.,
J. Med. Chem
. 1994, 37, 1126-1135), which showed cytotoxicity with an average log G1
50
value of −6.47 (log concentration which reduced cell growth by 50%) in the HTCL screen. Compound 1 was also an inhibitor of tubulin polymerization, with an IC
50
value of 0.85 &mgr;M. Compound 1 also demonstrated good in vivo activity against the OVCAR-3 ovarian cell line, prolonging the life span of mice bearing the tumor by 130%.
Accordingly, an object of the present invention is to develop additional compounds that can be used as antimitotic agents, antitumor agents, or both.
SUMMARY OF THE INVENTION
A first aspect of the present invention is, accordingly, a compound according to Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
R
1
is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H);
R
2
is is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H);
R
3
is is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H);
R
4
is is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H);
R
5
is is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H); and
n is 0, 1, 2, 3 or 4 (it being understood that, when n is 0, then all positions are substituted by H).
Preferably F is substituted on the phenyl group at the ortho position, or multi-F substituted at the ortho and other positions, as in a compound of the structure:
or a pharmaceutically acceptable salt thereof.
A second aspect of the present invention is a pharmaceutical formulation comprising or consisting essentially of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier (e.g., an aqueous carrier).
A third aspect of the present invention is a method for treating a tumor comprising administering to a subject in need of such treatment a treatment effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A fourth aspect of the present invention is a method of inhibiting cellular mitosis, comprising: contacting a cell with a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cellular mitosis.
A fifth aspect of the present invention is a compound according to Formula II, or a pharmaceutically acceptable salt thereof:
wherein:
R
1
is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, halo, amino, and heterocyclic rings;
R
2
is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, halo, and amino (preferably H or loweralkyl; most preferably H);
R
3
is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, halo, and amino (preferably H or loweralkyl; most preferably H); and
R
4
is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, halo, and amino (preferably H or loweralkyl; most preferably H).
Preferably F is substituted on the phenyl group at the ortho position, or multi-F substituted on the phenyl group at the ortho and other positions, as in a compound of the structure:
or a pharmaceutically acceptable salt thereof.
A sixth aspect of the present invention is a pharmaceutical formulation comprising or consisting essentially of a compound according to Formula II, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier (e.g., an aqueous carrier).
A seventh aspect of the present invention is a method for treating a tumor comprising administering to a subject in need of such treatment a treatment effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof.
An eighth aspect of the present invention is a method of inhibiting cellular mitosis, comprising: contacting a cell with a compound of Formula II, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cellular mitosis.
The foregoing and other objects and aspects of the present invention are explained in detail in the drawings herein and the specification set forth below.


REFERENCES:
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Zhang, Shun-Xiang, et al.,Antitumor Agents. 199. Three-Dimensional Quantitative Structure-Activity Relationship Study of the Colchicine Binding Site Ligands Using Comparative Molecular Field Analysis, J. Med. Chem.,vol. 43, pp. 167-176 (2000).
Zia, Yi, et al.,Antitumor Agents. 211. Fluorinated 2-Phenyl-4-quinolone Derivaties as Antimitotic Antitumor Agents, J. Med. Chem.,vol. 44, pp. 3932-3936 (2001).
Kaye, Perry T., et al., Abstract,Mass spectrometric analysis of 2-phenyl-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones and their tetrazolo[1,5-d]derivatives,J. Chem. Res., Synop,vol. 62, No. 3, pp. 367-82 (1994).

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