Synthesis of taxol enhancers

Details Synthesis of taxol enhancers Synthesis of taxol enhancers

2002-07-10

2004-11-30

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

06825235

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, and methods for synthesizing such agents.
SUMMARY OF THE INVENTION
It has been reported in the co-pending U.S. Provisional Applications entitled TAXOL ENHANCER COMPOUNDS, filed Jul. 10, 2001, (Application No. 60/304,252), TAXOL ENHANCER COMPOUNDS, filed Mar. 6, 2002 (Application No. 60/361,946) and TAXOL ENHANCER COMPOUNDS, filed Mar. 6, 2002 (Application No. 60/361,936) that certain bis[thio-hydrazide amide] compounds significantly enhance the anti-cancer activity of taxol and analogs of taxol. The entire teachings of these applications are incorporated herein by reference. Disclosed herein are methods of preparing these taxol enhancing compounds.
One embodiment of the present invention is a method of preparing a thiohydrazide product compound from a hydrazide starting compound. The hydrazide starting compound is represented by Structural Formula (I):
The thiohydrazide product compound is represented by Structural Formula (II):
In Structural Formulas (I)-(II), R
1
and R
2
are independently an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or R
1
and R
2
, 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. When R
2
is an aryl group or a substituted aryl group, then R
5
is a hydrazine protecting group; and when R
2
is an aliphatic or substituted aliphatic group, then R
5
is —H or a hydrazine protecting group. R
10
is —H or a substituted or unsubstituted alkyl group (preferably —H or an unsubstituted alkyl group, more preferably —H or methyl). The method comprises the step of reacting the starting compound with a thionylating reagent.
Another embodiment of the present invention is a method of preparing a product compound represented by Structural Formula (III):
The method comprises the step of reacting Z—C(O)—Y—(CO)—Z or HO—C(O)—Y—(CO)—OH and a carboxylic acid activating agent with the thiohydrazide represented by Structural Formula (II), wherein R
5
is —H.
R
1
, R
2
and R
10
Structural Formula (III) are as described for Structural Formulas (I)-(II).
Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group. Preferably, Y is a covalent bond, —C(R
7
R
8
)—, —CH
2
CH
2
-, trans-(CH═CH)—, cis-(CH═CH)—, —(CC)— or a 1,4-phenylene group. More preferably, Y is a covalent bond or —C(R
7
R
8
)—.
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.
Each Z is a leaving group.
Another embodiment of the present invention is a method of preparing a product compound represented by Structural Formula (III) from a hydrazide starting compound represented by Structural Formula (I). The hydrazide starting compound is thionylated to form a thiohydrazide represented by Structural Formula (II), as described above. If R
5
is —H, then Z—C(O)—Y—(CO)—Z or HO—C(O)—Y—(CO)—OH and a carboxylic acid activating agent is reacted with the thiohydrazide represented by Structural Formula (II) to form the product compound represented by Structural Formula (III), as described above. If R
5
is a hydrazine protecting group, the hydrazine protecting group is first removed before reacting with Z—C(O)—Y—(CO)—Z. Z and Y are as described above.


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