Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-01
2003-09-02
Solola, Taofiq (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S455000, C549S027000, C549S280000, C549S391000
Reexamination Certificate
active
06613797
ABSTRACT:
BACKGROUND
Protozoan parasites cause diseases such as malaria, trypanosomiasis, Chagas' disease, leishmaniasis, giardiasis, and amoebiasis. These and other parasitic diseases historically have occurred in tropical and sub-tropical areas where they cause widespread suffering of human populations. Although they receive little attention in the Western world, protozoan diseases affect more people worldwide than diseases brought on by any other biological cause (Heyneman, 1988).
Today, malaria remains the most destructive single infectious disease in the developing world. It is responsible for more human death, energy loss, more debilitation, more loss of work capacity, and more economic damage than any other human ailment facing the world today (Heyneman, 1988). The World Health Organization estimates that 1 to 2 million deaths are caused by malaria each year in Africa alone; most of these are children under the age of five (World Health Organization, 1991). In addition, over 300 million people worldwide are believed to be chronically infected, and each year nearly one third of these individuals will suffer acute manifestations of the disease.
Today, the pathologic capacity of protozoa is being increasingly demonstrated in the Western world among AIDS (Acquired Immunodeficiency Syndrome) victims. AIDS depletes the immune system of affected individuals. This allows opportunistic agents to infect AIDS patients, which agents otherwise would be defeated by an active immune system. Several protozoa have proved especially opportunistically infectious in AIDS patients, including
Cryptosporidium parvum, Entamoeba histolytica, Giardia lamblia, Pneumocystis carinii
(which may be a fungal or protozoal pathogen), and
Toxoplasmosis gondii.
Despite the prevalence and significance of protozoan infections, therapy for these diseases is generally poor or in need of improvement. Many chemotherapeutic agents used to treat protozoan infections are non-specific cytotoxins that are highly toxic and cause severe side effects in patients. However, these drugs are used because there are no better alternatives. For example, giardiasis and amoebiasis are treated using metronidazole (a nitroimidazole), but the mutagenic potential of this drug (Campbell, 1986) and its adverse interaction with alcohol are problematic. For trypanosomiasis and leishmaniasis standard therapies (suramin, melarsoprol, and pentavalent antimonials) are dangerously toxic, occasionally fatal, and often ineffective (Mebrahtu, 1989; Grogl et al., 1992). Other drugs are becoming ineffective due to emerging resistance. In the case of malaria, effective therapy previously has been provided by chloroquine but its efficacy is now threatened by the rapid emergence of drug resistant strains of
Plasmodium falciparum
, the causative agent for the most severe, often fatal, form of the disease (Cowman, 1990). Other protozoal infections such as cryptosporidiosis or Chagas' disease have no proven curative agent.
New therapeutic agents have been developed to treat protozoan infections. For example, Winter et al., U.S. Pat. No. 5,977,077, which is incorporated herein by reference, describes certain xanthone analogs which have sub-10 &mgr;M IC
50
s (some having sub-1&mgr;M IC
50
s), against Plasmodium and Leishmania. Despite these new xanthone analogs useful for treating infectious diseases, particularly protozoan diseases, there still is a need for new agents with comparable or better activities and reduced undesirable attributes, such as toxicity. A diverse array of therapeutic agents also is desireable to prevent or reduce the development of drug-resistant protozoan strains.
SUMMARY
The present invention concerns new compounds which are useful, amongst other things, as antiparasitic agents. Methods for using these new compounds and certain known compounds as anti-parasitic agents are described. These antiparasitic agents form complexes with heme and with porphyrins with superior affinity and are therefore useful in a variety of other applications. The invention also is directed to compounds with broad-spectrum anti-microbial activity.
As a result of studies aimed at developing new anti-parasitic agents, the present inventors have discovered that xanthones and a wide range of xanthone derivatives and structurally related compounds, as represented by Formula X below, have potent anti-parasitic activity. The compounds have broad-spectrum anti-microbial activity, including anti-fungal activity against
Candida albicans
and
Aspergillus fumigatus
, and may possess antiviral activity as well.
Formula X
With reference to Formula X, A is oxygen, substituted antimony (stibium), sulfur or N-R' where R′ is H, OH, alkyl, haloalkyl, aryl or haloaryl. Examples of substituted antimony groups include antimonial oxides and antimony substituted with hydroxy, chlorine, alkyl and aryl groups (e.g. SbCl, SbCl
3
, SbOH, Sb(O)(OH)). R
1
-R
8
are independently selected from the group consisting of H, OH, halogen, aryl, arylamine, alkyl, alkene, substituted alkyl (such as alkylamine, alkylthio, haloalkyl, and substituted alkyls having two or more of such substituents), alkoxy, particularly lower alkoxy, such as methoxy, substituted alkoxy (such as alkoxylamine, cycloaminoalkoxy, dialkylaminoalkoxy, such as diethylaminoethoxy, haloalkoxy, and alkoxy groups having two or more of such substituents) amino, ester, ether, nitro groups and O-linked and C-linked carbohydrates. Alkyl and alkoxyl groups often include 10 or fewer carbon atoms in a straight or branched chain, and are referred to as “lower” alkyl or alkoxy groups. Y is selected from the group consisting of NO, NOH, C═O, CH—OH, S═O, and SO
2
.
Compounds having Y=carbonyl further satisfy Formula X1, where A and R
1
-R
8
are as stated above with reference to Formula X.
Formula X1
Certain Formula X1 compounds are compounds which also satisfy Formula X2:
Formula X2:
With reference to Formula X2, A is oxygen or sulfur, and R
1
-R
6
are independently selected from the group consisting of H, OH, halogen, aryl, arylamine, alkyl, alkene, substituted alkyl (such as alkylamine, alkylthio, haloalkyl, and substituted alkyls having two or more of such substituents), alkoxy, substituted alkoxy (such as alkoxyamine, alkoxythio, haloalkoxy, and alkoxy groups having two or more of such substituents) amino, ester, ether, nitro groups and O-linked and C-linked carbohydrates. Particular compounds satisfying Formula X2 have R
1
and R
6
selected from the group consisting of H, —OH, OR, whre R typically is lower alkyl, such as OCH
3
, and halogen. R
2
-R
5
preferably are selected from the group consisting of side chains linked to the aromatic rings by a carbonyl or thiocarbonyl (i.e., C═O or C═S, respectively), a methylene group (i.e., CH
2
), oxygen, nitrogen or sulfur, and which further have a positively charged group on the terminal end of the linker. Such side chains are represented by Formula X3.
Formula X3:
With reference to Formula X3, “A” is carbon, generally a methylene group, a carbonyl, amido, O, S, or N; “n” ranges from 1 to 10, preferably 2 to 8, and even more preferably from about 3 to 7 both branched chains or linear chains; and “P” is a group positively charged at physiological pH, such as amines, amidines, guanidines, cycloalkylamines, such as dicyclopropyl amine, or cycloalkylimines, such as pyrrolidine. “n” is selected to provide a chain length so that “P” preferably can interact with negatively charged groups, such as the propionate groups of heme. Compounds having superior biological activity against Plasmodium and Leishmania have been made using alkoxy amines, such as those represented by Formula X4.
Formula X4:
With reference to Formula X4, “n” ranges from about 1 to 10, preferably 2 to 8, and even more preferably from about 3 to 7, including both branched chains and linear chains, and “R” typically is selected from the group of hydrogen and alkyl or cyclo-alkyl groups, preferably lower alkyl groups, such as ethyl groups. Moreover, the R groups of Formula X4
Hinrichs David J.
Riscoe Michael K.
Winter Rolf W.
Interlab Inc.
Solola Taofiq
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