Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-16
2002-01-01
Weddington, Kevin E. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S457000
Reexamination Certificate
active
06335363
ABSTRACT:
The invention relates to the use of inhibitors of the KQT1 channel for treating diseases caused by helminths and ectoparasites and for controlling such phytopathogenic pests.
Parasitoses are widespread, and they cause a wide spectrum of pathological effects in man and animals, from slight physiological disturbances to severe, even deadly diseases. Today, many intensively researched diseases caused by parasites are known, threatening the health and the life of man and its domestic and useful animals.
Worldwide, with an increasing tendency, millions of people are diagnosed with an impaired immune system. This group of people is massively attacked by opportunistic parasites such that every year, there are millions of casualties. In the age of long-distance travel, exotic parasites can be encountered even in non-Third-World countries which usually have a high standard of hygiene. The reason for this is an ever-increasing trend for walking and adventure holidays under local hygiene conditions and that the feeling of safety when at home has resulted in a loss of the awareness/knowledge of hygiene risks.
Not only the protection of human health but also animal welfare demands the cure for, and, if possible, the prevention of, suffering and pain caused by parasitoses. Economics are important in particular in husbandry of useful animals, where, owing to unfavorable housing and feeding conditions for animals (for example in the case of certain forms of large-scale livestock farming), parasitic diseases contributing to a reduced performance of a quantitative (quantity of meat, number of eggs, racing ability) or qualitative (quality of meat and wool) kind predominantly occur. The huge damage caused by parasitoses in man and animals make their control desirable, if not essential, in the interests of health and economy.
The use of chemical substances which are toxicologically acceptable in the host (man, animal) and known for their effectiveness against individual parasites or relatively large groups of parasites are still of paramount importance in the control of parasites.
According to their activity spectrum, these substances are differentiated into anthelmintics, which act against helminths, antiprotozoic agents, which act against protozoa, insecticides, which act against insects, acaricides, which act against mites (acaria); the last two groups are also summarized under the name ectoparasiticides.
The increase in resistance to drugs, promoted by the long-term and intensive use in particular in modern large-scale livestock farming, or the occurrence of sometimes strong side-effects, in particular in the case of lengthy medication of people which, in the context of increasing globalization, have to work in tropic and subtropic regions for a relatively long time, and the high costs associated with the prophylaxis/therapy involving certain chemotherapeutics means that the search for other cost-efficient substance classes which have a different mechanism of action and are better tolerated is a must.
In the context of the invention, it was realized that inhibitors of the KQT1 channel represent a novel way of destroying helminths and ectoparasites. The present invention thus relates to the use of blockers of the cellular KQT1 channel, which is present in helminths and ectoparasites, for preparing a medicament for the treatment of vertebrates and humans infested by helminths or ectoparasites. These KQT1 blockers are used as medicaments on their own or in combination with other medicaments and therapeutic measures.
The treatment of a subject for infestation of helminths or ectoparasites may include treatment for the prevention of such infestation. For example, a subject initially suffering from infestation will presumably return to being a “healthy host” upon successful treatment. Additional treatment would thereafter be preventative in nature, and any period of time without such an infestation would be therapeutically useful. The ideal would be a treatment leading to permanent prevention, but the continued treatment of an individual no longer showing symptoms would be prevention.
Surprisingly, it has been found that inhibitors of the I
KS
channel are able to block the KQT1 channel in a potent manner. Thus, inhibitors of the I
KS
channel, with their blocking action on the KQT1 channel, are suitable for preparing a medicament for the treatment of diseases caused by helminths and ectoparasites.
The inhibitors of the I
KS
channel are active compounds which have become the focus of attention only during the last 10 years. In the meantime, numerous applications for this class of active compounds have been described, such as their use as medicaments for the treatment of cardiac arrhythmias, the therapy of ulcers by inhibiting secretion of gastric acid, the therapy of diarrhea, the treatment of Menière's disease, etc. Of particular importance for the therapeutic use of I
KS
blockers is their antiarrhythmic action.
The antiarrhythmic action of the I
KS
channel blockers is based on a prolongation of the plateau phase of heart cells, in particular under conditions of sympathicus stimulation. Delay of repolarization is recognized as an antiarrhythmic principle of the so-called class III antiarrhythmics for terminating malignant cardiac arrhythmias.
According to the surprising realization that the action of I
KS
inhibitors as KQT1 blockers adversely affects the viability of the helminths and ectoparasites, the invention relates to the use of the I
KS
channel blockers included in the claims of the patents below as useful therapeutics for treating infestations of man and vertebrates by helminths and ectoparasites and the resulting diseases; and also to the preparation of a crop protection composition for controlling phytopathogenic arthropods, molluscs and nematodes.
Compounds suitable for the use according to the invention include the following:
1) a chromane of the formula I, or an isomer thereof, or a physiologically acceptable salt of any of the foregoing:
where
(1) and R(2) are the same or different, and each is hydrogen, C
p
F
2p+1
, alkyl having 1, 2, 3, 4, 5, or 6 C atoms, or phenyl,
where any of the foregoing is unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF
3
, methyl, methoxy, sulfamoyl, methylsulfonylamino, and methylsulfonyl, and
p is 1, 2, or 3,
or
R(1) and R(2) together form an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms,
R(3) is R(9)—C
n
H
2n
[NR(11)]
m
—, where
R(9) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7, or 8 C atoms,
n is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10,
m is zero or 1,
R(11) is hydrogen or alkyl having 1, 2, 3, 4, 5, or 6 C atoms, or
R(11) together with R(9) form an alkylene group having 1, 2, 3, 4, 5, 6, 7, or 8 C atoms,
where a CH
2
group of the group C
n
H
2n
is optionally replaced by —O—, —SO
q
— or —NR(10)—,
q is zero, 1 or 2,
R(10) is hydrogen, methyl, or ethyl,
R(4) is R(12)—C
r
H
2r
, where
R(12) is hydrogen, cycloalkyl having 3, 4, 5, 6, 7, or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, C
p
F
2p+1
, pyridyl, thienyl, imidazolyl or phenyl,
any of the foregoing being unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF
3
, methyl, methoxy, sulfamoyl, methylsulfonyl, or methylsulfonylamino;
r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20,
where a CH
2
group of the group C
r
H
2r
is optionally replaced by —O—, —HC═CH—, —C≡C—, —CO—, —CO—O—, —SO
q
— or —NR(10)—,
q is zero, 1, or 2,
R(10) is hydrogen, methyl or ethyl,
R(5), R(6), R(7) and R(8) are the same or different and each is hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3, or 4 C atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 C atoms, —CN, —CF
3
, —C
2
F
5
, —C
3
F
7
, —N
3
, —NO
2
, —CONR(13)R(14), —COOR(15), R(16)—C
s
H
2s
—Y— or phenyl,
where any of the foregoing is unsubstituted or substituted by 1 or 2 substituents selected from F, Cl, Br, I, CF
3
, methyl, methoxy, sulfamoyl, and methylsulfonyl,
R(13) and R(14) are the s
Gerlach Uwe
Hofmann Joachim
Lang Hans Jochen
Wei Aguan
Aventis Pharma Deutschland GmbH
Finnegan, Henderson Farabow, Garrett and Dunner L.L.P.
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