Synthesis of 4H-chromene derivatives

Details Synthesis of 4H-chromene derivatives Synthesis of 4H-chromene derivatives

2002-02-01

2003-12-09

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S407000, C549S398000

Reexamination Certificate

active

06660871

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the fields of organic chemistry and molecular biology and, more particularly, is directed to a method for synthesizing 4H-chromene derivatives.
BACKGROUND OF THE INVENTION
Bcl-2 and a family of related proteins regulate apoptosis or programmed cell death and are implicated in a number of human diseases such as cancer. Specifically, Bcl-2 can contribute to neoplastic cell expansion by preventing normal cell turnover caused by physiological cell death mechanisms. High levels of Bcl-2 gene expression are found in a wide variety of human cancers and can lead to tumor cell resistance to conventional chemotherapy and radiotherapy. Synthetic peptides that bind to a functional surface pocket of Bcl-2 have in vitro activity for inducing apoptosis in cell-free systems and in HeLa cells. Furthermore, Bcl-2 binding peptides containing a fatty acid as a cell permeable moiety can induce apoptosis in vitro and have in vivo activity in slowing human myeloid leukemia growth in severe combined immunodeficient mice. These studies suggest that peptides or other small molecules targeted to the Bcl-2 surface pocket could have important clinical applications.
The organic compound HA14-1 (FIG.
1
), a 4H-chromene derivative, exhibits binding activity for the surface pocket of Bcl-2 protein (IC
50
=9 &mgr;M) and induces apoptosis of tumor cells. The discovery of this Bcl-2 binding compound provides a promising lead compound for the development of potential anti-cancer agents and prompted the chemical synthesis of a series of HA14-1 analogs in order to study its structure-activity relationship and increase its potency.
While there are currently two methods for the preparation of 4H-chromene derivatives, both methods have limitations. The first method involves the cyclization of salicylaldehyde derivatives with alkyl cyanoacetates in the presence of ammonium acetate at 5-10° C., which produces analogs of HA14-1.
The reaction temperature (5-10° C.) is crucial for obtaining the desired products. If the temperature is just slightly raised to 15° C., the reaction will fail to give the desired product. In another procedure, aluminum oxide (Al
2
O
3
) is used as the catalyst instead of ammonium acetate. However, this procedure is further limited by low yields.
The present invention provides a procedure for the preparation of 4H-chromene derivatives that overcomes the limitations of the current methodology. In one embodiment of the present invention, molecular sieve, more particularly, molecular sieve 3Å, is used as the catalyst. This novel catalyst as disclosed in the present invention, allows the reaction to take place under milder conditions, about 15-300° C., and gives higher yields of 4H-chromene derivatives, about 86%.
DEFINITIONS
In the present invention, “4H-chromene derivatives”, “HA14-1 derivatives” and “HA14-1 analogs” are used interchangeably. They include molecules of the formula:
Within the scope of the present invention, but not being limited thereto, R
1
and R
2
are CH
3
, CH
2
CH
3
, CH
2
CH═CH
2
, CH
2
Br, CF
3
, NH
2
, OH, OCH
3
, CN, NO
2
, Cl, Br, F, COOH or COOCH
3
; and, R
3
is selected from the group consisting of hydrogen, CH
3
, CH
2
CH
3
, CH
2
CH
2
CH
3
, CH
2
CH
2
CH
2
CH
3
, C(CH
3
)
3
, CH
2
Ph or CH
2
CH
2
OCH
3
.
“structure-activity relationship” as used herein, means the relationship between the structure of a peptide or a molecule and its ability to bind to the functional surface pocket of Bcl-2, thus inhibiting the biological activity of Bcl-2 and inducing apoptosis in cancer cells.


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patent: 5659051 (1997-08-01), Higashii et al.
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