Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
2002-08-05
2004-07-20
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S418000
Reexamination Certificate
active
06765105
ABSTRACT:
Several scientific publications were published about compounds of antiplasmid effect. There was no mention about antiplasmid effect of hydroxy-benzoic acids up to now in the literature, only some publications dealing with their antibacterial effect appeared in this field (e.g.
Himejima, Masaki; Kubo, Isako, J. Agric.
1991, 39/2, 411-421.)
The importance of compounds of antiplasmid effect consists of their capability to destroy the acquired resistance of bacteria against antibiotics which can often save lives. The effect of bacteria living in the environment to the health seems unimportant for a human being while he or she is healthy. It becomes important only, when he or she gets ill because of a bacterial infection. The major part of these bacterial illnesses can be cured by means of antibiotics, but there is a growing number of infections, that are fatal because of the antibiotic resistance of the disease germ.
The phenomenon of insensibility to the antibiotics, the resistance spreads not only to human pathogenic germs, but also to pathogenic germs of animals and plants as well.
The resistance occurs among both the aerobic and anaerobic bacteria. These strains of bacteria are resistant to a multitude of antibiotics, even to those, which are reserved for the treatment of heavy infections, e.g. aminoglycosides, types of penicillin, cephalosporine and tetracycline,
We set the target to produce one or more compounds with antiplasmid effect. We have found that certain hydroxy-benzoic acid derivatives have antiplasmid effect. There are some specific sorts of bacteria causing often epidemic infections, which are capable to inactivate several antibiotics.
The bacteria can be classified into three groups according to the origin of their resistance to antibiotics
a) resistance pertaining to the species, which is a well-known phenomenon of some species of bacteria to some kinds of antibiotics,
b) resistance, which originates from a mutation, a phenomenon of small probability with regard to a kind of antibiotic, it has a small practical importance by this reason,
c) The most dangerous kind of resistance, the so-called plasmid-coupled infectious resistance is in the focus of interest, which has epidemic growth among the bacteria.
The plasmids are DNA molecules, which have special proliferation mechanism and carry genetic information independently from the chromosomes of bacteria and they are capable to transmit various properties, e.g. resistance to antibiotics, virulence and other ones.
The plasmid of resistance enables the proliferation of bacteria in the presence of an antibiotic and the bacteria can transmit this feature not only to their descendants but even to other bacteria in their environment. Such epidemic spreading of resistance to antibiotics in the bacterial flora of humans and animals is well-known since about 30 years.
The antagonistic effect to replication of plasmids of acridine paints, the ethidium bromide and the sodium dodecil sulphate was discovered by former research works, these compounds are not eligible for medical purposes because of their high toxicity. The recognition, that two well-known medicaments, chloro-promazine and prometazine eliminated the resistance to tetracycline, chloro-amphenicol and sulfonamide at 10 to 30% of bacteria culture
Escherichia coli
in vitro, underlay to the experiments aiming elimination of plasmids. The experiments were done with several well-known, in the literature described strains of bacteria cultures and cell cultures with loss of specific plasmids on specific selective culture media.
The elimination of R-plasmids and F′lac plasmids, as well as inhibition of transmission of R-plasmid transfer were studied.
The more and more extending resistance causes the research work in the field of medicaments to search continuously for new antibiotics and to supply the medicine with them.
The usage of compounds being subject of our application could result not only in a great economic benefit, but a great number of people could be successfully cured, who are actually beyond recovery because of the resistance, provided the in vivo experiments give similar results.
We found three compounds effective from 36 ones which were studied by in vitro experiments for antiplasmid effect. These are the compounds under mark FC-1181, FC-1186 and Sila-439. The compound sila-429 (75%) was compared against three representatively antibiotic resistant strains of bacteria, as follows: the polyresistant
Acinetobacter anitratus
, the resistant to gentamycine
staphylococcus aureus
and the Methycilline resistant
Staphylococcus aureus
strains.
The fact, that 3 compounds from 36 ones proved to be active in the searched effect, should be considered as an outstanding result even at international level.
We performed a preliminary study of toxicology, and established, that the mice inoculated with a dose of 50 mg/kg lived and moved vividly exactly like those in the control group, which were inoculated intraperitoneally with 0.2 ml of physiologic saline solution
We used the usual dose of inoculation i.e. 0.2 ml per 10 g weight. When we augmented the dose ten times to 500 mg/kg, spasms occurred in the 5 inoculated mice in two minutes after the intraperitoneal inoculation and all the five mice died.
It can be supposed on the base of preliminary toxicological experiment that the value LD
50
is 4 to 6 times higher than the effective in vitro dose.
This latter fact should be studied in an institute dealing with toxicology and clinical pharmacology.
The experiments should be completed with examinations for plasmid elimination in an in vivo environment.
The results of experiments and calculations of quantum chemistry in relation to the examined molecules encouraged us to indicate some perspectives to design antiplasmid medicaments on the base of the relationship existing between the biological effects and the structures of molecules.
Certain compounds appeared to be promising on the base of the results of preliminary experiments and calculations. Some representatives of the mentioned groups of compounds were synthesised and examined in laboratory experiments by this reason.
The Hungarian patent specification under No. HU 180,334 (IPC C07C 87/78) describes production of 1,1-biphenyl-2-il-alkyl-amin derivatives.
The U.S. patent specification of U.S. Pat. No. 4,695,631 (IPC C07C 87/24) describes a method for producing enamines or -imines.
Antibiotics are often used to eliminate plasmids or other elements similar to chromosomes from the host cells. Michel, Briand and his fellow workers describe usage of several 4-quinolone derivatives (J. Antimicrob. Chemother., 18, 667-674 /1986/) included cinoxacine and novobiocine with the aim to extirpate various plasmids of resistance to medicaments from the cells of the family Enterobacteriaceae.
A special plasmid development method, a map of plasmid restriction and functions, as well as a flowchart of said method are described for producing somatotropic hormone for cattle in the US document laid open to public inspection of No. 54415/1990.
It can be established on the base of the cited sources of literature that no relevant solution was published, which affects the subject matter of the invention, they cannot be reviewed by his reason.
We tested a multitude of representatives of the group of compounds that we supposed to have antiplasmid effect, as we endeavoured to search for base of following research activity (that should be the target of the invention) to approach our aims in our targeted work but having elements of fundamental research, by means of analysis of the relationship between the chemical structure and biological effect.
We could establish a well recognisable relation to the antiplasmid effect depending on the substituents and functional groups.
We established during our experiments, that the derivatives of benzoic acid and those of benzoic acid imides having the general formula (I)
as new compounds have antiplasmid effect. The general formula (I) is shown in the FIG.
1
.
The substituents of the compound are a
Hegyes Peter
Töröcsik Mihály
Brich Stewart Kolasch & Birch, LLP
Oláh Gabriella
Seaman D. Margaret
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