Antitumor dibenzofluorene derivatives

Details Antitumor dibenzofluorene derivatives Antitumor dibenzofluorene derivatives

2002-01-14

2002-11-12

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06479662

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to compounds having antitumor activity. The invention also relates to pharmaceutical compositions that contain one or more of those compounds, methods of using the compounds to inhibit tumor growth in mammals, and methods of preparing the compounds.
Many thousands of people are diagnosed with cancer each year, and although great advances have been made in cancer therapy, the existing treatments are not successful in many cases. Among the problems with existing therapies are (1) anticancer drugs administered to patients often have toxic effects on non-cancerous cells in the patient's body, (2) cancerous cells whose growth can be inhibited by certain drugs sometimes become resistant to those drugs, and (3) some cancers cannot be effectively treated with a single drug, and sometimes not even with a combination of different anticancer drugs. A long-standing need exists for new anticancer drugs that have one or more of the following characteristics: (1) ability to inhibit the growth of cancerous cells. (2) acceptable levels of toxicity to non-cancerous cells, (3) effectiveness against cancerous cells that are resistant to other drugs, and (4) a different mechanism of action than existing drugs, so that when the new drug is used in combination with an existing drug, the likelihood of the cancer cells developing cross-resistance is reduced.
SUMMARY OF THE INVENTION
The present invention concerns compounds having a formula selected from the group consisting of
or salts thereof. In the above formulas, at least one of R
1
-R
13
in formula (I) or at least one of R
1
-R
12
in formula (II) is —R
14
Z. R
14
is a substituted amino or amido group preferably having from 1-12 carbon atoms. Z is a substituted or unsubstituted heterocyclic group preferably having from 1-12 carbon atoms. The remainder of R
1
-R
13
in formula (I) or R
1
-R
12
in formula (II) are independently selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted amino or amido groups preferably having from 1-12 carbon atoms, and alkyl groups preferably having from 1-12 carbon atoms.
As mentioned above, salts of the compounds (I) and (II) are part of the present invention. Examples of suitable salts include but are not limited to the hydrochloride, iodide, and methane sulfonate salts.
In one embodiment of the invention where the compound has formula I, R
11
is —R
14
Z, and R
1
-R
10
and R
12
-R
13
are independently hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted amino or amido having from 1-12 carbon atoms, or alkyl having 1-12 carbon atoms
In another embodiment of the invention where the compound has formula II, R
11
is —R
14
Z, and R
1
-R
10
and R
12
are independently hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted amino or amido having from 1-12 carbon atoms, or alkyl having 1-12 carbon atoms.
R
14
preferably has the formula —NHR
15
—, where R
15
is a substituted or unsubstituted aliphatic group having from 2-6 carbon atoms. R
15
preferably is selected from the group consisting of —CO(CH
2
)
n
CO—, —(CH
2
)
m
—, and —CO(CH
2
)
q
CHCH(CH
2
)
r
CO—, where n, m, q, and r are independently a number from 0-6. In one preferred embodiment of the invention, n is from 1-4, m is from 2-6, q is from 0-2, and r is from 0-2. Z preferably is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, hydroxyethyl piperazinyl, aminoethyl piperazinyl, and aminomethyldihydroxy piperidinyl.
Another aspect of the present invention is pharmaceutical compositions that comprise a compound as described above and a pharmaceutically acceptable carrier. Yet another aspect of the present invention is a method of inhibiting the growth of tumor cells, in which a tumor-inhibitory amount of a compound as described above is administered to a mammal.
Another aspect of the present invention is a method of synthesizing a cyclic hydrocarbon and keto compound. The method comprises the step of reacting a cyclic hydrocarbon compound that comprises at least two rings with a metal bismuthate in the presence of an acid. The metal bismuthate can be for example an alkali metal bismuthate such as sodium bismuthate. As another example, it can be zinc bismuthate. In certain embodiments of this method, the acid can be an organic acid such as acetic acid or a mineral acid such as sulfuric acid. Optionally the reaction can take place in the presence of an organic solvent, such as acetone. The cyclic hydrocarbon reactant preferably comprises from 10-50 carbon atoms.
The compounds and compositions of the present invention are useful in cancer therapy, either by themselves or in combination with other antitumor chemotherapy or radiation therapy.


REFERENCES:
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