Cancer is one of the leading causes of death in the world. According to the World Health Organization, cancer is the third most common cause of death in the world, after heart disease and infectious disease. Cancer is the second most common cause of death (after heart disease) in the developed world. Accordingly, discovery of new and effective treatments for cancer is a high priority for health care researchers.
Cancer is often treated by using chemotherapy to selectively kill or hinder the growth of cancer cells, while having a less deleterious effect on normal cells. Chemotherapeutic agents often kill rapidly dividing cells, such as cancer cells; cells which are dividing less rapidly are affected to a lesser degree. Other agents, such as antibodies attached to toxic agents, have been evaluated for use against cancers. These agents target the cancer cells by making use of a characteristic specific to the cancer, for example, higher-than-normal rates of cell division, or unique antigens expressed on the cancer cell surface.
Various naturally-occurring and synthetic amine-containing compounds have been evaluated for anti-cancer and antiproliferative activity. The following patents and patent applications, all of which are hereby incorporated by reference in their entirety, discuss certain of these compounds: U.S. Pat. Nos. 5,541,230, 5,880,161, and 5,889,061; and International Patent Cooperation Treaty Applications WO 00/66587, WO 98/17624, and WO 95/18091. Other publications which discuss various amine-containing compounds, for a wide variety of applications, include U.S. Pat. No. 3,956,502, to polyamine alcohols as microbicides; U.S. Pat. No. 4,013,507 and U.S. Pat. No. 5,866,016, which relate to the compounds commonly called ionenes; CA 2,231,200, which discusses polyalkylimines as gene transport carriers; EP 889 112, directed to a lubricating oil composition for automatic transmissions; U.S. Pat. No. 4,971,598, directed to reaction products of alkenyl succinimides with ethylenediamine carboxy acids as fuel detergents; U.S. Pat. No. 5,091,576, which discusses anti-neoplastic, anti-viral, or anti-retroviral spermine derivatives, and U.S. Pat. No. 5,393,757, which discusses polyamines and anti-diarrheal and gastrointestinal anti-spasmodic pharmaceutical compositions and methods of treatment; WO 93/04036 and U.S. Pat. No. 5,185,369, directed to synthetic aryl and heteroaryl polyamines as excitatory amino acid neurotransmitter antagonists; U.S. Pat. No. 5,530,092 and U.S. Pat. No. 5,698,662, directed to dendritic macromolecules and the preparation thereof; U.S. Pat. No. 5,750,788, which discusses preparation of amines from compounds having at least three cyano groups; U.S. Pat. No. 5,847,190, to dendritic nitrogen-containing organic compounds; U.S. Pat. No. 6,046,282, to reactive diluents for polyamidoamine epoxy curatives; WO 95/20580, to macrocyclic octaaza compounds; WO 96/38528, directed to betaine esters for the delivery of alcohols; WO 97/07674, WO 98/51660, and WO 99/17802, to ethyleneimine oligomers for selective modification of nucleic acids; WO 00/09634, to diesel fuels comprising hydrocarbyl amines; WO 01/64779, to polyamine polyoxides used as asphalt emulsifiers; WO 01/79329, to oligopolysuccinimides; Bruice TC et al., “A microgonotropen branched decaaza decabutylamine and its DNA and DNA/transcription factor interactions,” Bioorg Med Chem. 5(4):685-92 (1997); Satz AL and Bruice TC, “Recognition in the minor groove of double-stranded DNA by microgonotropens: Acc. Chem. Res. 35(2):86-95 (2002); Kroger N et al., “Species-specific polyamines from diatoms control silica morphology,” Proc. Natl. Acad. Sci. USA 97(26):14133-8 (2000); Bacchi CJ et al., “Novel synthetic polyamines are effective in the treatment of experimental microsporidiosis, an opportunistic AIDS-associated infection,” Antimicrob. Agents Chemother. 46(1):55-61 (2002); and Bacchi CJ et al., “SL-11158, a synthetic oligoamine, inhibits polyamine metabolism of Encephalitozoon cuniculi,” J. Eukaryot. Microbiol. Suppl:92S-94S (2001).
Despite intensive research aimed at finding effective treatments for cancer, is well-known that, while some cancers can be treated with relative success, no effective treatments exist for other cancers. Thus, there is a need for additional pharmaceutical agents to complement the medicinal remedies currently available for treatment of cancer and diseases characterized by uncontrolled cell proliferation.
In addition to treatment of cancer, the oligoamine compounds of the present invention are also useful for treatment of diseases caused by microorganisms such as bacteria, viruses, and parasites. See Bacchi CJ et al., “Novel synthetic polyamines are effective in the treatment of experimental microsporidiosis, an opportunistic AIDS-associated infection,” Antimicrob. Agents Chemother. 46(1):55-61 (2002); and Bacchi CJ et al., “SL-11158, a synthetic oligoamine, inhibits polyamine metabolism of Encephalitozoon cuniculi,” J. Eukaryot. Microbiol. Suppl:92S-94S (2001). Microsporidiosis refers to infections caused by any of the parasitic protists of the phylum Microspora; over 140 genera and 1200 species of microsporidia are known, and at least 14 of these species can cause pathology in humans: Enterocytozoon bieneusi, Encephalitozoon intestinalis (previously known as Septata intestinalis), Encephalitozoon hellem, Encephalitozoon cuniculi, Pleistophora sp., Trachipleistophora hominis, T. anthropophthera, Nosema ocularum, N. algerae, Vittaforma corneae, Microsporidium ceylonensis, M. africanum, Brachiola vesicularum, and B. connori. (See Centers for Disease Control information at World Wide Web URL www.dpd.cdc.gov/dpdx/HTML/Microsporidiosis.htm). Microsporidiosis is most prevalent in immunocompromised hosts, such as patients with AIDS and HIV-related diseases, or transplant recipients on immunosuppressive therapy. Healthy hosts appear to harbor asymptomatic or self-limiting microsporidiosis. Symptoms of microsporidiosis include diarrhea and other gastrointestinal complications, muscle infections, genitourinary infections, respiratory infections, and eye infections.
While pharmaceutical treatments currently exist for microsporidiosis, such as albendazole and metronidazole (Flagyl), not all treatments are effective against every pathogen, and undesirable side effects to specific medicines can occur in certain individuals. Thus, additional medicinal agents are needed to complement the treatments currently available for microsporidiosis and other diseases caused by microbes.