The present invention is directed to a process for the synthesis of xcex2-lapachone (Beta-lapachone) and lapachol, the xcex2-lapachone (Beta-lapachone) intermediate, which are important agents in cancer chemotherapy.
Over 1.22 million new cancer cases will be diagnosed in the U.S. in the year 2001 alone. With more than 563,000 deaths annually, cancer is the second leading cause of death behind heart disease (UBS Warburg xe2x80x9cDisease Dynamics: The Cancer Marketxe2x80x9d, Nov. 8, 2000). Surgery and radiotherapy may be curative if the disease is found early, but current drug therapies for metastatic disease are mostly palliative and seldom offer a long-term cure. Even with the new chemotherapies entering the market, improvement in patient survival is measured in months rather than in years, and the need continues for new drugs effective both in combination with existing agents as first line therapy and as second and third line therapies in treatment of resistant tumors.
As a single agent, xcex2-lapachone has demonstrated significant antineoplastic activity against human cancer cell lines at concentrations typically in the range of 1-10 xcexcM (IC50). Cytotoxicity has been demonstrated in transformed cell lines derived from patients with promyelocytic leukemia (Planchon et al., Cancer Res., 55 (1996) 3706), prostate (Li, C. J., et al., Cancer Res., 55 (1995) 3712), malignant glioma (Weller, M. et al., Int. J. Cancer, 73 (1997) 707), hepatoma (Lai, C. C., et al., Histol Histopathol, 13 (1998) 8), colon (Huang, L., et al., Mol Med, 5, (1999) 711), breast (Wuertzberger, S. M., et al., Cancer Res., 58 (1998) 1876), ovarian (Li, C. J. et al., Proc. Natl. Acad. Sci. USA, 96(23) (1999) 13369-74), pancreatic (Li, Y., et al., Mol Med, 6 (2000) 1008; Li, Y. Z., Mol Med, 5 (1999) 232), and multiple myeloma cell lines, including drug-resistant lines (Li, Y., Mol Med, 6 (2000) 1008). No cytotoxic effects were observed on normal fresh or proliferating human PBMC (Li, Y., Mol Med, 6 (2000) 1008).
xcex2-lapachone has been shown to be a DNA repair inhibitor that sensitizes cells to DNA-damaging agents including radiation (Boothman, D. A. et al., Cancer Res, 47 (1987) 5361; Boorstein, R. J., et al., Biochem. Biophys. Commun., 117 (1983) 30). xcex2-lapachone has also been shown to disrupt DNA replication, causing cell-cycle delays in G1 and/or S phase, inducing either apoptotic or necrotic cell death in a wide variety of human carcinoma cell lines without DNA damage and independent of p53 status (Li, Y. Z. et al (1999); Huang, L. et al.). Topoisomerase I is an enzyme that unwinds the DNA that makes up the chromosomes. The chromosomes must be unwound in order for the cell to use the genetic information to synthesize proteins; xcex2-lapachone keeps the chromosomes wound tight, so that the cell cannot make proteins. As a result, the cell stops growing. Because cancer cells are constantly replicating and circumvent many mechanisms that restrict replication in normal cells, they are more vulnerable to topoisomerase inhibition than are normal cells.
xcex2-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione), a quinone, is derived from lapachol (a naphthoquinone) which can be isolated from the lapacho tree (Tabebuia avellanedae), a member of the catalpa family (Bignoniaceae). Lapachol and xcex2-lapachone have the following chemical structures: 
It is, however, both difficult and time consuming to obtain the necessary large-scale quantities of xcex2-lapachone naturally from the lapacho tree. Although the lapacho tree is nowhere near as rare as the Pacific yew tree, from which paclitaxel (Taxol(copyright)) is derived, ensuring a sufficient quality and supply of xcex2-lapachone from natural sources can be problematic. Numerous methods are known in the art for synthesizing xcex2-lapachone. Two related known methods for producing lapachol, an intermediate from which xcex2-lapachone may be synthesized are illustrated in Scheme 1. 
Method (1) is described in Schaffner-Sabba, K., et al., xcex2-Lapachone: Synthesis of Derivatives and Activities in Tumor Models, J Med. Chem., 27, (1984) 990-994, and is known as the potassium salt method. Method (2) is described in Sun, J. S. et al., A Preparative Synthesis of Lapachol and Related Naphthoquinones, Tetrahedron Letters, 39 (1998) 8221-8224), and is know as the lithium salt method. Both of these methods require the formation of a metal salt. Amaral, A., et al., in The Total Synthesis of xcex2-lapachone, J. Heterocyclic Chem., 29 (1992) 1457-1460, describes the synthesis of xcex2-lapachone xcex1-naphthol in eight steps and results in an overall yield of only 23%. Additionally, in U.S. Pat. No. 5,763,625, lapachol is first converted into 3-bromolapachone, which is then converted in a two-step sequence into 3-hydroxy-xcex2-lapachone.
These known methods, however, typically provide the product in low yield, require tedious procedures or use explosive chemicals in the synthesis. Accordingly, there is a need for a process for synthesizing xcex2-lapachone and its derivatives which is safe and simple and which produces xcex2-lapachone and its intermediates, analogs and derivatives in high yield and excellent quality.
The present invention is directed generally to a process for the synthesis of xcex2-lapachone and its intermediate, lapachol. More specifically, the invention is directed to process for synthesizing xcex2-lapachone and its intermediates, derivatives and analogs, by a safe and simple process and which produces xcex2-lapachone in high yield and high quality.
The process of the present invention teaches a novel method for the synthesis of the xcex2-lapachone intermediate, lapachol. Lapachol is then quantitatively converted to xcex2-lapachone and purified. Unlike the reported methods in which a metal (lithium or potassium) salt of 2-hydroxy-1,4-naphtoquinone was prepared in situ by addition of lithium hydride or separately by addition of potassium hydroxide to the quinone solution as the first step and then reacting the metal salt with bromide compound to form lapachol, the process of the present invention eliminates this first step and commences directly with 2-hydroxy-1,4-naphthoquinone to react with 1-bromo-3-methyl-2-butene in the presence of sodium iodide and a weak base such as triethylamine, pyridine, trimethylamine, N,N-diisopropylethylamine, 2,6-lutidine, preferably triethylamine or pyridine, most preferably triethylamine, to form lapachol, a xcex2-lapachone intermediate from which xcex2-lapachone is subsequently synthesized.
The above description sets forth rather broadly the more important features of the present invention in order that the detailed description thereof that follows may be understood, and in order that the present contributions to the art may be better appreciated. Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the accompanying drawings. It is to be understood, however, that the drawings are designed solely for the purposes of illustration and not as a definition of the limits of the invention, for which reference should be made to the appended claims.