Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1998-05-27
2003-08-05
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S327000, C568S331000, C568S337000, C514S679000
Reexamination Certificate
active
06603046
ABSTRACT:
The present invention relates to the use of a particular class of aromatic compounds, in particular bis-aromatic &agr;,&bgr;-unsaturated ketones, most of which are novel compounds, for the treatment or prophylaxis of a number of serious conditions caused by microorganisms or parasites, in particular protozoa such as Leishmania, Plasmodia, and Coccidia such as Eimeria, and intracellular bacteria, including Legionella and Mycobacteria. The invention also relates to the novel bis-aromatic &agr;,&bgr;-unsaturated ketones and methods of preparing them, as well as to pharmaceutical and antiparasitic compositions. Furthermore, the invention also relates to a method for treatment or prophylaxis of diseases caused by microorganisms or parasites.
Parasitic diseases, among these malaria and leishmaniasis, are, on a world basis, among the most important diseases. The most effective known drugs against the diseases have many side effects for which reason it is not possible to maintain the treatment or prophylaxis of specific diseases for years.
Recently, the development of resistance against the available drugs against particularly malaria and leishmania parasites has been reported.
Especially malaria and leishmaniasis remain serious diseases despite the efforts to control the diseases and reduce their prevalence by vector eradication and drug treatment.
More than 12 million people in the world are inflicted by leishmaniasis. There are more than 400,000 new cases and 100,000 deaths each year but as many as 350 million people are at risk of infection (WHO,1990). The annual incidence of clinical leishmaniasis is estimated to exceed 2,000,000 cases in some 80 countries. It is one of the 7 important tropical diseases included in the TDR program.
Leishmaniasis are characterized by a broad spectrum of clinical manifestations depending on the strain of the parasite and the host immune response. The parasites infect macrophages and multiply inside these cells. The first step in the Leishmania/macrophage interactions is the binding of the parasite to the macrophage followed by uptake of the parasite. Integrity and fluidity of the host cell membrane is essential for this interaction. Certain parasite surface antigens such as membrane glycoprotein (Gp63) and lipophosphoglycan (LPG) as well as a number of macrophage surface receptors are also important in binding and uptake of the parasite by macrophages.
Various species of the protozoan parasite Leishmania cause a broad spectrum of diseases ranging from the cutaneous healing skin lesions caused by
L. major
to a fatal visceral form of the disease called kala azar caused by
L. donovani
(Manson-Bahr, 1987). Leishmaniases are widespread in many parts of the world with highest prevalence in Africa, Asia, and Latin America (WHO, 1989). Recently an increasing number of AIDS patients are becoming infected with Leishmania (Brenguer, 1989; Flegg 1990).
Therapy of patients with leishmaniasis still poses a serious problem. Most of the available antileishmanial drugs exhibit considerable toxicity and there are reports of large scale clinical resistance to the conventional antimonial drugs. No effective, safe, and nontoxic antileishmanial drug is available at present.
There are also reports of large scale clinical drug resistance in visceral leishmaniasis. (TDR News No. 34, 1990)
Malaria, another parasitic disease, is also a serious health problem. Human malaria is caused by four species of the protozoan genus, Plasmodium. The species
Plasmodium falciparum
is the most dangerous, causing acute severe infections that are often fatal, especially in young children and immigrants entering endemic areas. The life cycle of
P. falciparum
includes different stages; in the first stage, the sporozoite stage, the parasite is brought into the blood stream by the Anopheles mosquito. The sporozoites are carried in the blood stream to the liver where they invade the hepatocytes and develop into merozoites in the course of 5-7 days. Merozoites released from infected cells start a new cycle by invading the erythrocytes. It is the invasion of the erythrocyte which gives rise to the clinical disease. In the erythrocyte, the parasite shows an asexual multiplication which involve a maturation of the parasite through different parasite stages, the ring, the trophozoite and the schizont stage (the stage that undergoes nuclear division). When the schizont-infected erythrocyte bursts, new merozoites are released. Some merozoites, however, differentiate into gametocytes (microgametocytes and macrogametocytes), the sexual form of the parasite. Contrary to the asexual infected erythrocytes, these sexual parasite stages are able to continue the life cycle when the infected cells, the erythrocytes, are ingested by mosquitoes during a blood meal. By fertilization in the mosquito gut, the gametocytes develop into a mobile ookinete stage. The ookinete pass through the epithe and matures into a oocyst. In the oocyst, the new sporozoites develop. These sporozoites are released and move to the salivary gland, and are then ready to be injected into a new host. The parasites are haploid in most of the life cycle as they perform a meiotic cell division shortly after fertilization. The Anopheles mosquito is the primary vector of malaria, but the disease can be seen after blood transfusion, i.v. injection of medicaments and after transfer from an infected mother to the newborn child through the placenta.
Each year, several hundreds of millions of human beings are affected by the parasitic disease malaria. The treatment and prophylaxis of malaria has been difficult because the available drugs exhibit severe side effects, and furthermore, the Plasmodia are showing increasing resistance towards the drugs (Ann (WHO) 1990).
Coccidial protozoa such as
Eimeria tenella
are some of the most important parasites causing disease in poultry resulting in significant economic loss. There are problems with resistance development against some of the available anticoccidial drugs used in prophylaxis and treatment of these diseases, for which reason there is a need for development of new anticoccidial drugs.
Also, Babesia species cause devastating damage to cattle in many parts of the world, and there is a need for the development of safe, effective and inexpensive drugs to control these diseases.
Thus, there is a great need for effective drugs against parasitic diseases, especially for drugs exhibiting none or only less severe side effects.
According to the present invention, it has been found that a class of aromatic compounds, said class comprising compounds containing an alkylating site, show a remarkable capability of effectively suppressing the growth of parasitic protozoa and intracellular bacteria, which compounds at the same time can be so chosen that they are tolerable to animal cells such as human cells. This valuable selective activity of such alkylating aromatic compounds seems to be based on their capability of interfering with oxygen metabolism in the parasites by destroying their mitochondria, at concentrations at which the compounds, while thus being harmful to the microorganisms, do not affect the mitochondria of the animal cells.
Without being limited to any particular theory, it is believed that the capability of the compounds to alkylate nucleophilic groups in biomolecules, as evidenced by their capability of alkylating the thiol group of N-acetyl-L-cysteine, is of importance for the antimicrobial effect.
In accordance with this, the present invention, in its broadest aspect, relates to the use of an aromatic compound which contains an alkylating site, and which is capable of alkylating the thiol group in N-acetyl-L-cysteine at physiological pH, for the preparation of a pharmaceutical composition or a medicated feed, food or drinking water for the treatment or prophylaxis of a disease caused by a microorganism or a parasite in an animal, including a vertebrate, such as a bird, a fish or a mammal, including a human, the microorganism or parasite being selected from
parasitic protozoa, in parti
Christensen Søren Brøgger
Kharazmi Arsalan
Ming Chen
Theander Thor Grundtvig
Corless Peter F.
Edwards & Angell LLP
Lica Pharmaceuticals A/S
O'Day Christine C.
Richter Johann
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