Cytotoxic compounds

Details Cytotoxic compounds Cytotoxic compounds

2002-04-18

2004-05-11

Lambkin, Deborah C (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S448000, C549S062000, C549S065000, C549S066000, C549S070000, C549S071000

Reexamination Certificate

active

06734207

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel compounds that are effective anti-cancer agents and potent inhibitors of tubulin polymerization.
BACKGROUND OF THE INVENTION
Cancer is a major disease that continues as one of the leading causes of death at any age. In the United States alone, it is estimated that more than a half a million Americans will die annually of cancer. Currently, radiotherapy and chemotherapy are two important methods used in the treatment of cancer.
Considerable efforts are underway to develop new chemotherapeutic agents for more potent and specific anti-cancer therapy, presenting effective and efficient cytotoxicity against tumor cells, with minimal interference with normal cell function. Accordingly, there is an urgent need for the development and analysis of novel, effective anti-cancer agents.
Cellular proliferation, for example, in cancer, occurs as a result of cell division, or mitosis. Microtubules play a pivotal role in mitotic spindle assembly and cell division. These cytoskeletal elements are formed by the self-association of the &agr;&bgr; tubulin heterodimers.
Recently, the structure of the &agr;&bgr; tubulin dimer was resolved by electron crystallography of zinc-induced tubulin sheets. According to the reported atomic model, each 46×40×65 Å tubulin monomer is made up of a 205 amino acid N-terminal GTP/GDP binding domain with a Rossman fold topology typical for nucleotide-binding proteins, a 180 amino acid intermediate domain comprised of a mixed &bgr; sheet and five helices which contain the taxol binding site, and a predominantly helical C-terminal domain implicated in binding of microtubule-associated protein (MAP) and motor proteins.
As disclosed in U.S. Pat. No. 6,258,841 B1, tubulin has a binding pocket in a region within the intermediate domain of tubulin, located between the GDP/GTP binding site and the taxol binding site. The approximate dimensions of the binding pocket are 6 Å×22 Å×7 Å. The pocket, referred to as the COBRA binding pocket, has an abundance of leucine residues (7 leucine and 2 isoleucine) providing a highly hydrophobic binding environment. It is characterized by a narrow cavity with elongated dimensions, suitable for accommodating an aliphatic chain of up to about 12 carbons.
Compounds that bind with the COBRA binding pocket can interfere with tubulin polymerization and can provide novel agents for the treatment of cancer.
SUMMARY OF THE INVENTION
The compounds of the invention bind to tubulin causing tubulin depolymerization and inhibiting tubulin polymerization. The tubulin binding compounds of the invention are therapeutically effective to inhibit cellular proliferation, for example, as effective anti-cancer agents. The compounds are cytotoxic against tumor cells such as leukemia cells. The compounds are novel furan, thiophene, thiazole, oxazole, or imidazole derivatives.
One aspect of the invention includes COBRA compounds represented by the general formula I:
where
X is O, S, or NH;
R is a saturated or unsaturated (C
7
to C
15
) hydrocarbon chain;
R
1
is hydrogen, halogen, OH, (C
1
to C
6
) alkoxy, (C
1
to C
6
) acyl, (C
1
to C
6
) ester, or (C
1
to C
6
) carboxylic acid;
Y is OH, SH, CN, halogen, or (C
1
to C
6
) alkoxy; and
pharmaceutically acceptable salts thereof.
In another aspect of the invention, COBRA compounds are provided of the general formula II:
where
X is NH, O, or S;
R is a saturated or unsaturated (C
7
to C
15
) hydrocarbon chain;
R
2
is hydrogen, OH, (C
1
to C
6
) alkoxy, (C
1
to C
6
) alkyl, (C
1
to C
6
)alkenyl, (C
1
to C
6
) alkynyl, (C
3
to C
7
) cycloalkyl, aryl, heteroaryl, halogen, (C
1
to C
6
) acyl, (C
1
to C
6
) ester, or (C
1
to C
6
) carboxylic acid;
Y is OH, SH, CN, halogen, or (C
1
to C
6
) alkoxy; and
pharmaceutically acceptable salts thereof.
In yet another aspect of the invention, the COBRA compound has the general formula III:
where
X is NH, O, or S;
R is a saturated or unsaturated (C
7
to C
15
) hydrocarbon chain;
R
2
is hydrogen, OH, (C
1
to C
6
) alkoxy, (C
1
to C
6
) alkyl, (C
1
to C
6
)alkenyl, (C
1
to C
6
) alkynyl, (C
3
to C
7
) cycloalkyl, aryl, heteroaryl, halogen, (C
1
to C
6
) acyl, (C
1
to C
6
) ester, or (C
1
to C
6
) carboxylic acid;
Y is OH, SH, CN, halo, or (C
1
to C
6
) alkoxy;
and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. As used in this application, the following words or phrases have the meanings specified.
As used herein, “acyl” refers to a group containing a carbon attached to oxygen by a double bond. Acyl groups can be a part of, for example, aldehydes or ketones. Typically, acyl groups include 1 to 15 carbon atoms or 1 to 6 carbon atoms. The carbon atoms can be aliphatic or aromatic. In some embodiments, the acyl group has 1 to 3 carbon atoms or 1 carbon atom.
The term “alkyl” refers to straight or branched hydrocarbon radicals, such as methyl, ethyl, propyl, butyl, pentyl, octyl, isopropyl, tert-butyl, sec-butyl, and the like. Typically, alkyl groups include 1 to 15 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms.
As used herein, “alkythio” comprises a sulfur attached to an alkyl by a single bond. Typically, alkythio groups include 1 to 15 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms.
As used herein, “alkene” and “alkenyl”, includes both branched and straight chain aliphatic hydrocarbon groups that have at least one double bond. Typically, alkene groups include 1 to 15 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms.
The term “alkoxy” refers to an oxygen atom substituted with an alkyl radical as defined above. Typical alkoxy groups include 1 to 15 or 1 to 6 carbon atoms or 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy, iso-propoxy, and the like. Preferable alkoxy groups include methoxy and ethoxy.
As used herein, “alkyne” and “alkynyl” includes both branched and straight chain aliphatic hydrocarbon groups that have at least one triple bond. Typically, alkyne groups include 1 to 15 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms.
As used herein “amine” refers to compounds of the formula NR
a
R
b
and includes primary, secondary, and tertiary amines. R
a
and R
b
are each independently hydrogen, (C
1
to C
6
) alkyl, aryl, heteroaryl, (C
1
to C
6
) acyl, (C
3
to C
7
) cycloalkyl, or R
a
and R
b
taken together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino.
The term “aryl” refers to monovalent unsaturated aromatic carbocyclic radicals having a single ring, such as phenyl, or multiple fused rings, such as naphthyl or anthryl.
As used herein, “aryloxy” comprises an oxygen attached to an aryl by a single bond.
As used herein, “cycloalkyl” includes cyclic alkanes having 3 to 7 carbon atoms.
As used herein, an “ester” comprises a carbon attached to a first oxygen by a double bond and to a second oxygen by a single bond. The second oxygen is also attached to an alkyl group which has 1 to 15 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms.
As used herein, the term “carboxylic acid” comprises a carbon attached to a first oxygen by a double bond and to a second oxygen by a single bond. The second oxygen is also attached a hydrogen atom, i.e. COOH.
As used herein, the terms “halogen” or “halo” refers to fluoride, chloride, bromide, and iodide radicals.
As used herein, “heteroaryl” includes substituted or unsubstituted aromatic hydrocarbon compounds having at least one atom of O, N or S in an aromatic ring. Typical heteroaryl groups include, for example, furan, thiophene, pyrrole, thiazole, oxazole, or imidazole group. Heteroaryl groups can include two aromatic groups fused together such as, for example, benzothiophene, indole, carbazole, quinazoline, quinoline, and purine.
As used herein, the term “thioacyl” refers to a group comprising a carbon atom attached to a sulfu

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