Taxol enhancer compounds

Details Taxol enhancer compounds Taxol enhancer compounds

2002-07-10

2004-07-13

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S148000, C564S149000, C564S151000

Reexamination Certificate

active

06762204

ABSTRACT:

BACKGROUND OF THE INVENTION
Many new drugs are now available to be used by oncologists in treating patients with cancer. Often, tumors are more responsive to treatment when anti-cancer drugs are administered in combination to the patient than when the same drugs are administered individually and sequentially. One advantage of this approach is that the anti-cancer agents often act synergistically because the tumors cells are attacked simultaneously with agents having multiple modes of action. Thus, it is often possible to achieve more rapid reductions in tumor size by administering these drugs in combination. Another advantage of combination chemotherapy is that tumors are more likely to be eradicated completely and are less likely to develop resistance to the anti-cancer drugs being used to treat the patient.
One serious limitation of combination chemotherapy is that anti-cancer agents generally have severe side effects, even when administered individually. For example, the well known anti-cancer agent taxol causes neutroperia, neuropathy, mucositis, anemia, thrombocytopenia, bradycardia, diarrhea and nausea. Unfortunately, the toxicity of anti-cancer agents is generally additive when the drugs are administered in combination. As result, certain types of anti-cancer drugs are generally not combined. The combined toxic side-effects of those anti-cancer drugs that are administered simultaneously can place severe limitations on the quantities that can be used in combination. Often, it is not possible to use enough of the combination therapy to achieve the desired synergistic effects. Therefore, there is an urgent need for agents which can enhance the desirable tumor attacking properties of anti-cancer agents without further increasing their undesirable side-effects.
SUMMARY OF THE INVENTION
It has now been found that certain bis[thio-hydrazide amide] compounds significantly enhance the anti-cancer activity of taxol. For example, Compound (1) was used in combination with taxol (Paclitaxel) to treat tumors induced in nude mice from the human breast tumor cell line MDA-435. The tumor volume was about five fold less after 24 days of treatment in mice which had been administered 5 mg/kg of taxol and 25 mg/kg of Compound (1) than in mice which had only been administered 5 mg/kg of taxol or in mice which had only been administered 50 mg/kg of Compound (1) (Example 7). These results are shown graphically in FIG.
1
. The structure of Compound (1) is shown below:
It has also been found that these bis[thio-hydrazide amide] compounds have minimal toxic side effects. For example, the mice treated with taxol and Compound (1) showed little if any weight loss over the treatment period (see FIG.
2
). Based on these results, novel compounds which enhance the anti-cancer activity of taxol, pharmaceutical compositions comprising these compounds and methods of treating a subject with cancer are disclosed herein.
One embodiment of the present invention is a compound represented by the Structural Formula (I):
Y is a covalent bond, a phenylene group or a substituted or unsubstituted straight chained hydrocarbyl group. In addition, Y, taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted aromatic group. Preferably, Y is a covalent bond or —C(R
7
R
8
)—.
R
1
is an aliphatic group, a substituted aliphatic group, a non-aromatic heterocyclic group, or a substituted non-aromatic heterocyclic group.
R
2
-R
4
are independently —H, an aliphatic group, a substituted aliphatic group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, an aryl group or a substituted aryl group, or R
1
and R
3
taken together with the carbon and nitrogen atoms to which they are bonded, and/or R
2
and R
4
taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring.
R
5
-R
6
are independently —H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group.
R
7
and R
8
are each independently —H, an aliphatic or substituted aliphatic group, or R
7
is —H and R
8
is a substituted or unsubstituted aryl group, or, R
7
and R
8
, taken together, are a C2-C6 substituted or unsubstituted alkylene group.
Z is ═O or ═S.
In one aspect, R
1
and R
2
in the compound represented by Structural Formula (I) are not both C1-C5 alkyl (preferably not both methyl) when Y is —C(R
7
R
8
)—R
3
and R
4
are both phenyl and R
5
-R
8
are all —H.
Another embodiment of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I). Preferably, the pharmaceutical composition comprises an effective concentration of the compound.
Yet another embodiment of the present invention is a method of treating a subject with cancer. The method comprises administering to the subject an effective amount of taxol or a taxol analog and an effective amount of a compound represented by Structural Formula (I).
The disclosed compounds increase the anti-cancer activity of taxol and taxol analogs. In addition, these compounds have minimal toxic side-effects. Consequently, it is possible to increase the effectiveness of taxol and analogs thereof when used in combination with the disclosed compounds, even when approaching the highest tolerated doses of taxol. Thus, it is expected that combination therapy with the compounds of the present invention will provide improved clinical outcomes for patients with cancers that are being treated with taxol. By co-administering the disclosed compounds with taxol, it is also possible to achieve the same therapeutic effectiveness previously achieved with higher doses of taxol, thereby reducing the side-effects and improving the quality of life for the patient.


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Schwarz et al, CA77:48081, 1972.*
Rupp, Walter, CA76:126992, 1972.*
Chuyguk, V. A. and Nemazanyj A.G., “Mesoionic Methine Dyes from Biquaternary Salts of Dihetarylmethanes—1,2,3,4-Oxa(thia)diazoles and 1,4-Triazoles Derivatives,”Ukr. Khim. Zhurn. 48:520 (1984).
“REMARKS” paper as submitted by applicant's attorney.

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