U.S. patent application number 10/434164 was filed with the patent office on 2004-02-19 for use of compounds comprising a nitrogen-oxygen heterocycle.
Invention is credited to Jomaa, Hassan.
Application Number | 20040033994 10/434164 |
Document ID | / |
Family ID | 7906777 |
Filed Date | 2004-02-19 |
United States Patent
Application |
20040033994 |
Kind Code |
A1 |
Jomaa, Hassan |
February 19, 2004 |
Use of compounds comprising a nitrogen-oxygen heterocycle
Abstract
Die invention relates to the use of compounds of the general
formula (I) 1 wherein Y is a C.sub.1-3-alkenylene group, wherein B
is selected from the group, which consists of C.sub.1-26-alkenylene
groups, wherein one C-atom is replaced by an oxygen atom and one
C-atom is replaced by a sulphur atom or two C-atoms may be replaced
by a S-heterocycle, and wherein X represents the organo phosphorous
group 2 or the amino group 3 for inhibition of the
1-deoxy-D-xylulose-5-phosphate-(DOXP)-metabolic pathway, use
thereof as a herbicide and for the preparation of a pharmaceutical
preparation as well as a method for the therapeutic and
prophylactic treatment of infections in humans and animals, caused
by viruses, bacteria, fungi and parasites.
Inventors: |
Jomaa, Hassan; (Giessen,
DE) |
Correspondence
Address: |
HARNESS, DICKEY & PIERCE, P.L.C.
P.O. BOX 8910
RESTON
VA
20195
US
|
Family ID: |
7906777 |
Appl. No.: |
10/434164 |
Filed: |
May 9, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10434164 |
May 9, 2003 |
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09980611 |
Nov 2, 2001 |
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09980611 |
Nov 2, 2001 |
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PCT/EP00/03959 |
May 3, 2000 |
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Current U.S.
Class: |
514/90 ;
514/92 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 1/04 20180101; Y02A 50/475 20180101; A61P 1/16 20180101; A61P
33/00 20180101; A61P 27/02 20180101; A61P 31/10 20180101; Y02A
50/30 20180101; A61P 37/00 20180101; A61P 1/02 20180101; A61K
31/5355 20130101; A61P 3/10 20180101; Y02A 50/463 20180101; A61P
17/00 20180101; A61K 31/42 20130101; A61K 31/675 20130101; A61K
45/06 20130101; A61P 29/00 20180101; A61K 31/535 20130101; A61P
9/10 20180101; A61P 35/00 20180101; A61P 7/00 20180101; A61P 15/00
20180101; A61P 31/00 20180101; Y02A 50/479 20180101; A61P 31/12
20180101; A61K 31/4439 20130101; A61P 31/04 20180101 |
Class at
Publication: |
514/90 ;
514/92 |
International
Class: |
A61K 031/675 |
Foreign Application Data
Date |
Code |
Application Number |
May 3, 1999 |
DE |
19920247.8 |
Claims
1. Use of compounds of the general formula (I) 24wherein Y is a
C.sub.1-3-alkenylene group, which is substituted by the
substituents R.sub.1 and R.sub.2 and optionally by the substituents
R.sub.3 to R6, wherein R.sub.1 to R8 are the same or different and
are selected from the group, which consists of hydrogen, hydroxy,
halogen, substituted and unsubstituted alkyl groups, substituted
and unsubstituted cycloalkyl-(C.sub.0-26)-alkyl groups, substituted
and unsubstituted cycloalkoxy-(C.sub.0-26)-alkyl groups,
substituted and unsubstituted alkoxy (C.sub.0-26)-alkyl groups,
substituted and unsubstituted amino groups and substituted,
unsubstituted thio-(C.sub.0-26)-alkyl groups, substituted and
insubstituted Sulfonyl-(C.sub.0-26)-alkyl groups, substituted and
unsubstituted suinMyl-(C.sub.0-26)-alkyl groups and substituted or
unsubstituted acyl radicals, wherein each alkyl radical, each
alkoxy radical and each acyl radical branched or unbranched and
each alkyl radical, each alkoxy radical and each cycloalkyl group
may be saturated or unsaturated having one or more double or triple
bonds and one or two carbon atoms of the cycloalkyl groups may be
replaced by nitrogen, oxygen or sulphur atoms and R.sub.13 and
R.sub.14 are defmed like R.sub.1 to R.sub.8 or together form an oxo
group, wherein X represents the organo phosphorous group 25wherein
R.sub.9 and R.sub.10 are the same or different and are selected
from the group, which consists of hydrogen, substituted and
unsubstituted (C.sub.1-26)-alkyl groups, substituted and
unsubstituted Hydroxy-(C.sub.1-26)-alkyl groups, substituted and
unsubstituted cycloalkyl-(C.sub.0-26)-alkyl groups, substituted and
unsubstituted acyl, halogen, OX.sub.9 or OX.sub.10, wherein each
alkyl radical, each alkoxy radical and each acyl radical branched
or unbranched and each alkyl radical, each alkoxy radical and each
cycloalkyl group may be saturated or unsaturated having one or more
double or triple bonds and one or two carbon atoms of the
cycloalkyl groups may be replaced by nitrogen, oxygen or sulphur
atoms, wherein X.sub.9 or X.sub.10 may be identical or different
and are selected from the group, which consists of hydrogen,
substituted and unsubstituted (C.sub.1-26)-alkyl groups,
substituted and unsubstituted hydroxy-(C.sub.1-26)-alkyl groups,
substituted and unsubstituted cycloalkyl-(C.sub.0-26)-alkyl groups,
substituted and unsubstituted acyl silyl, a cation of an organic
and inorganic base, in particular of a metal of main group I, II or
III of the periodic system, ammonium, substituted ammonium and
amnmonium compounds which are derived from ethylenediamine or amino
acids, wherein each alkyl radical, each alkoxy radical and each
acyl radical branched or unbranched and each alkyl radical, each
alkoxy radical and each cycloalkyl group saturated or may be
unsaturated having one or more double or triple bonds and one or
two carbon atoms of the cycloalkyl groups may be replaced by
nitrogen, oxygen or sulphur atoms, or wherein X represents the
amino group 26wherein R.sub.11 and R.sub.12 are the same or
different and are selected from the group, which consists of
hydrogen, substituted and unsubstituted alkyl groups, substituted
and unsubstituted cycloalkyl-(C.sub.0-26)-alkyl groups, substituted
and unsubstituted cycloalkoxy-(C.sub.0-26)-alkyl groups,
substituted and unsubstituted alkoxy (C.sub.0-26)-alkyl groups and
substituted or unsubstituted acyl radicals, wherein each alkyl
radical, each alkoxy radical and each acyl radical branched or
unbranched and each alkyl radical, each alkoxy radical and each
cycloalkyl group may be saturated or unsaturated with one or more
double or triple bonds and one or two carbon atoms of the
cycloalkyl groups may be replaced by nitrogen, oxygen or sulphur
atoms, wherein B is selected from the group, which consists of
substituted and unsubstituted C.sub.1-26-alkenylene groups, wherein
one C-atom may be replaced by an oxygen atom and one C-atom may be
replaced by a sulphur atom or two C-atoms may be replaced by a
S-heterocycle and wherein each alkylene radical may be branched or
unbranched and may be saturated or unsaturated with one or more
double or triple bonds and may be substituted with one or more
hydroxy groups, halogen groups or oxo groups, or their
pharmaceutically acceptable salts, esters and salts of the esters
for the inhibition of the
1-deoxy-D-xylulose-5-phosphate-(DOXP)-metabolic pathway.
2. Use according to claim 1, characterised in that and R.sub.13 and
R.sub.14 together form an oxo group in .alpha.-position to the
nitrogen atom.
3. Use according to claim 1 or claim 2, characterised in that Y
represents a methylene group, which preferably is substituted with
two methyl groups.
4. Use according to one of the preceding claims, characterised in
that B represents ether group (II) --A.sub.1--O--A.sub.2--
(II)wherein A.sub.1 is absent or is a (C.sub.1-9)-alkylene radical,
and A.sub.2 is absent or is selected from the group, which consists
of (C.sub.1-9)-alkylene radicals, a sulphur atom and a
(C.sub.3-8)-heterocycle, which comprises at least one sulphur
atom.
5. Use according to claim 4, characterised in that A.sub.1 and
A.sub.2 each represent a methylene group.
6. Use according to one of claims 1 to 3, characterised in that B
represents keto group (III) 27wherein A.sub.3 and A.sub.4, out of
which one or both may be absent, are the same or different, are
selected from the group, which consists of (C.sub.1-9)-alkylene
radicals, wherein all the (C.sub.1-9)-alkylene radicals may be
branched or unbranched, may comprise one or more double bonds or
may be substituted with a hydroxyl group or a halogen group.
7. Use according to claim 6, characterised in that A.sub.3 is
absent and A.sub.4 represents a methylene or an ethylene group.
8. Use according to one of claims 1 to 2, characterised in that B
represents a 2-hydroxypropylene group.
9. Use according to claim 1, characterised in that the compound is
selected from the group, which consists of 28293031323334
10. Use according to claim 9, characterised in that the compound is
selected from the group, which consists of 35
11. Use of an active substance defined according to one of claims 1
to 10 for the preparation of a pharmaceutical preparation for the
treatment of infectious processes in humans and animals, caused by
viruses, bacteria, fungi or parasites.
12. Use of an active ingredient defined according to one of claims
1 to 10 as a herbicide.
13. Use according to claim 11 for the preparation of a
pharmaceutical preparation for the treatment of infections, caused
by bacteria, which are selected from the group, which consists of
bacteria of the family Propionibacteriaceae, in particular the
genus Propiomibacterium, in particular species Propionibacterium
acnes, bacteria of the family Actinomycetaceae, in particular the
genus Actinomyces, bacteria of the genus Corynebacterium, in
particular the species Corynebacterium diphteriae and
Corynebacterium pseudotuberculosis, bacteria of the family
Mycobacteriaceae, the genus Mycobacterium, in particular the
species Mycobacterium leprae, Mycobacterium tuberculosis,
Mycobacterium bovis and Mycobacterium avium, bacteria of the family
Chlamydiaceae, in particular the species Chlamydia trachomatis and
Chlamydia psittaci, bacteria of the genus Listeria, in particular
the species Listeria monocytogenes, bacteria of the species
Erysipelthrix rhusiopathiae, bacteria of the genus Clostridium,
bacteria of the genus Yersinia, of the species Yersinia pestis,
Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia
ruckeri, bacteria of the family Mycoplasmataceae, of the genera
Mycoplasma and Ureaplasma, in particular the species Mycoplasma
pneumoniae, bacteria of the genus Brucella, bacteria of the genus
Bordetella, bacteria of the family Neisseriaceae, in particular of
the genera Neisseria and Moraxella, in particular the species
Neisseria meningitides, Neisseria gonorrlhoeae and Moraxella bovis,
bacteria of the family Vibrionaceae, in particular of the genera
Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular
the species Vibrio cholerae, Vibrio anguillarum and Aeromonas
salmonicidas, bacteria of the genus Camnpylobacter, in particular
the species Campylobacter jejuni, Campylobacter coli and
Carnpylobacter fetus, bacteria of the genus Helicobacter, in
particular the species Helicobacter pylori, bacteria of the
families Spirochaetaceae and Leptospiraceae, in particular the
genera Treponema, Borrelia and Leptospira, in particular Borrelia
burgdorferi, bacteria of the genus Actinobacillus, bacteria of the
family Legionellaceae, the genus Legionella, bacteria of the family
Rickettsiaceae and family Bartonellaceae, bacteria of the genera
Nocardia and Rhodococcus, bacteria of the genus Dermatophilus,
bacteria of the family Pseudomonadaceae, in particular the genera
Pseudomonas and Xanthomonas, bacteria of the family
Enterobacteriaceae, in particular the genera Escherichia,
Klebsiella, Proteus, Providencia, Salmonella, Serratia and
Shigella, bacteria of the family Pasteurellaceae, in particular the
genus Haemophilus, bacteria of the family Micrococcaceae, in
particular the genera Micrococcus and Staphylococcus, bacteria of
the family Streptococcaceae, in particular the genera Streptococcus
and Enterococcus and bacteria of the family Bacillaceae, in
particular the genera Bacillus and Clostridium, and in the
eradication of Helicobacter in ulcers of the gastrointestinal
tract.
14. Use according to claim 1 I for the preparation of a
pharmaceutical preparation for the treatment of infections caused
by viruses, which are selected from the group, which consists of
viruses of the genus Parvoviridae, in particular parvoviruses,
dependoviruses, densoviruses, Adenoviridae, in particular
adenoviruses, mastadenoviruses, aviadenoviruses viruses of the
genus Papovaviridae, in particular papovaviruscs, in particular
papillomaviruses (`wart" viruses), polyomaviruses, in particular JC
virus, BK virus and miopapovaviruses, viruses of the genus
Herpesviridae, in particular herpes simplex viruses,
varicella-zoster viruses, human cytomegalovirus, Epstein-Barr
viruses, human herpesvirus 6, human herpesvirus 7, human
herpesvirus 8, viruses of the genus Poxiviridae, in particular
poxviruses, orthopoxviruses, parapoxviruses, molluscum contagiosum
virus, aviviruses, capriviruses, leporipoxviruses, primarily
hepatotropic viruses, in particular hepatitisviruses, such as
hepatitis A viruses, hepatitis B viruses, hepatitis C viruses,
hepatitis D viruses, hepatitis E viruses, hepatitis F viruses,
hepatitis G viruses, hepadnaviruses, in particular all
hepatitisviruses, such as hepatitis B virus, hepatitis D viruses,
viruses of the genus Picornaviridae, in particular picomaviruses,
all enteroviruses, all polioviruses, all coxsackieviruses, all
echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses,
viruses of the genus Calciviridae, in particular hepatitis E
viruses, viruses of the genus Reoviridae, orbiviruses, rotaviruses,
viruses of the genus Togaviridae, in particular togaviruses,
alphaviruses, rubiviruses, pestiviruses, rubellavirus, viruses of
the genus Flaviviridae, in particular flaviviruses, FSME virus,
hepatitis C virus, viruses of the genus Orthomyxoviridae, in
particular influenza viruses, viruses of the genus Paramyxoviridae,
in particular pararnyxoviruses, morbillivirus, pneumovirus, measles
virus, mumps virus, viruses of the genus Rhabdoviridae, in
particular rhabdoviruses, rabies virus, lyssavirus, vascular
stomatitisvirus, viruses of the genus Coronaviridae, in particular
coronaviruscs, viruses of the genus Bunyaviridae, in particular
bunyaviruscs, nairovirus, phlebovirus, uukuvirus, hantavirus,
hantaan virus, viruses of the genus Arenaviridae, in particular
arenaviruscs, lymphocytic choriomeningitis virus, viruses of the
genus Retroviridae, in particular retroviruses, all HTL viruses,
human T-cell leukaemia virus, oncomaviruses, spumaviruses,
lentiviruses, all HI viruses, viruses of the genus Filoviridae, in
particular Marburg and Ebola virus, slow viruses, prions,
oncoviruses and leukaemia viruses.
15. Use according to claim 11 for the preparation of a
pharmaceutical preparation for the prophylaxis and treatment of
infections caused by unicellular parasites, namely the causative
organisms of malaria and sleeping sickness and of Chagas' disease,
toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis,
pneurnocystosis, balantidiasis, cryptosporidiosis, sarcocytosis,
acanthamoebosis, naeglerosis, coecidiosis, giardiasis and
lambliasis.
16. Method for the treatment of infectious diseases, caused by
bacteria, fungi or parasites, in which a therapeutically active
amount of a compound defined according to claims 1 to 10 compound
is administered to a patient who is taken ill with an infection
caused by bacteria, fungi or parasites.
Description
[0001] This invention relates to the use of compounds comprising a
nitrogen-oxygen heterocycle as an active ingredient and the salts,
esters and salts of the esters thereof and for the therapeutic and
prophylactic treatment of infections in humans and animals, caused
by viruses, bacteria, fungi and parasites, as well as the
corresponding treatment and the thereof as a herbicide.
[0002] In U.S. Pat. No. 4,209,512 phosphono acid derivatives
comprising a nitrogen-oxygen heterocycle are disclosed as
insecticides and acaricides.
[0003] It has now been found, surprisingly, that compounds
according to claim 1 comprising a nitrogen-oxygen heterocycle may
be used as an active ingredient for treatment of the above stated
infections and as a herbicides. It has been shown by experiments,
that the effect of the compounds is based on an inhibition of the
1-deoxy-D-xylulose-5-phosphate- -(DOXP) metabolic pathway, which
can be proved in inicro-organisms and plants, but not for human
beings. Accordingly, the compounds according to the present
invention show an anti-infectious effect against viruses, bacteria,
fungi, uni- and multicellular parasites and as herbicides. Further
developments of the invention are defined by the subclaims.
[0004] Compounds used according to the present invention correspond
to the general formula (I): 4
[0005] in which Y is a C.sub.1-3 alkenylene group, substituted with
the substituents R.sub.1 and R.sub.2 and optionally with the
substituents R.sub.3 to R6,
[0006] in which R.sub.1 to R.sub.8 are the same or different and
are selected from the group, which consists of hydrogen, hydroxy,
halogen, substituted and unsubstituted alkyl groups, substituted
and unsubstituted cycloalkyl (C.sub.0-26)-alkyl groups, substituted
and unsubstituted cycloalkoxy (C.sub.0-26) alkyl groups,
substituted and unsubstituted alkoxy (C.sub.0-26)-alkyl groups,
substituted and unsub- stituted amino groups and substituted,
unsubstituted thio (C.sub.0-26)-alkyl groups, substituted and
unsubstituted sulfonyl-(C.sub.0-26)-alkyl groups, substituted and
unsubstituted sulfinyl-(C.sub.0-26)-alkyl groups and substituted or
unsubstituierten acyl radicals, in which each alkyl radical, each
alkoxy radical and each acyl radical branched or unbranched and
each alkyl radical, each alkoxy radical and each cycloalkyl group
may be saturated or unsaturated having one or more double or triple
bonds and one or two carbon atoms of the cycloalkyl groups may be
replaced by nitrogen, oxygen or sulphur atoms and
[0007] R.sub.13 and R.sub.14 are defined like R.sub.1 to R8 or
together form an oxo group,
[0008] wherein X is the organo phosphorous group 5
[0009] in which R.sub.9 and R.sub.10 are the same or different and
are selected from the group, which consists of hydrogen,
substituted and unsubstituted (C.sub.1-26)-alkyl groups,
substituted and unsubstituted hydroxy-(C.sub.1-26)-alkyl groups,
substituted and unsubstituted cycloalkyl-(C.sub.0-26)-alkyl groups,
substituted and unsubstituted acyl, halogen, OX.sub.9 or OX.sub.10,
in which each alkyl radical, each alkoxy radical and each acyl
radical branched or linear and each alkyl radical, each alkoxy
radical and each cycloalkyl group saturated or may be unsaturated
having one or more double or triple bonds and one or two carbon
atoms of cycloalkyl groups may be replaced by nitrogen, oxygen or
sulphur atoms, wherein X.sub.9 or X.sub.10 may be the same or
different and are selected from the group, which consists of
hydrogen, substituted and unsubstituted (C.sub.1-26)-alkyl groups,
substituted and unsubstituted hydroxy-(C.sub.1-26)-alkyl groups,
substituted and unsubstituted cycloalkyl-(C.sub.0-26)-alkyl groups,
substituted and unsubstituted acyl, silyl, a cation of an organic
and inorganic base, in particular of a metal of main group I, II or
III of the periodic system, ammonium, substituted ammonium and
ammonium compounds which are derived from ethylenediamine or amino
acids, wherein each alkyl radical, each alkoxy radical and each
acyl radical branched or unbranched and each alkyl radical, each
alkoxy radical and each cycloalkyl group may be saturated or
unsaturated having one or more double or triple bonds and one or
two carbon atoms of the cycloalkyl groups may be replaced by
nitrogen, oxygen or sulphur atoms,
[0010] or wherein X represents amino group 6
[0011] wherein R.sub.11 and R.sub.12 are the same or different and
are selected from the group, which consists of hydrogen,
substituted and unsubstituted alkyl groups, substituted and
unsubstituted cycloalkyl-(C.sub.0-26)-alkyl groups, substituted and
unsubstituted cycloalkoxy-(C.sub.0-26)-alkyl groups, substituted
and unsubstituted alkoxy (C.sub.0-26)-alkyl groups and substituted
or unsubstituted acyl radicals, wherein each alkyl radical, each
alkoxy radical and each acyl radical branched or unbranched and
each alkyl radical, each alkoxy radical and each cycloalkyl group
may be saturated or unsaturated having one or more double or triple
bonds and one or two carbon atoms of the cycloalkyl groups may be
substituted by nitrogen, oxygen or sulphur atoms,
[0012] wherein B is selected from the group, which consists of
substituted and unsubstituted C.sub.1-26-alkenylene groups, in
which one C-atom may be replaced by an oxygen atom and one C atom
my be replaced by a sulphur atom or two C-atoms may be replaced by
a S-heterocycle and wherein each alkenylene radical may be branched
or unbranched and may be saturated or unsaturated having one or
more double or triple bonds and may be saturated with one or more
hydroxy groups, halogen groups or oxo groups.
[0013] Preferably R.sub.13 and R.sub.14 together form an oxo group
in .alpha.-Position to the nitrogen atom.
[0014] Y preferably represents a methylene group, which is
particularly preferably substituted with two methyl groups.
[0015] Compounds, in which B represents ether group (II)
--A.sub.1--O--A.sub.2-- (II)
[0016] are advantageous, wherein A.sub.1 is absent or is a
(C.sub.1-9)-alkylene radical,
[0017] and A.sub.2 is absent or selected from the group, which
consists of (C.sub.1-9)-alkylene radicals, a sulphur atom and a
(C.sub.3-8)-heterocycle, which comprises at least one sulphur atom.
It is especially preferred that A.sub.1 and A.sub.2 each represent
a methylene group.
[0018] Also compounds, in which B represents a keto group (III)
7
[0019] are advantageous, wherein A.sub.3 and A.sub.4, out of which
one or both may be absent, are the same or different, may be
selected from the group, which consists of (C.sub.1-9)-alkylene
radicals, wherein all the (C.sub.1-9)-alkylene radicals may be
branched or unbranched, may have one ore more double bonds or may
be substituted with a hydroxyl group or a halogen group. It is
particularly preferred that A.sub.3 is absent and A.sub.4
represents a methylene or an ethylene group.
[0020] Preferably B furthermore is a 2-hydroxypropylene group.
[0021] R.sub.9 and R.sub.10 preferably represent OX.sub.9 and
OX.sub.10, wherein X.sub.9 and X.sub.10 are the same or different
10 and are selected from the group, which consists of a metal of
the first, second or third main group of the periodic system, in
particular sodium and potassium, and methyl, ethyl.
[0022] Examples for individual compounds are listed in the
following: 891011121314
[0023] The following compounds are in particular preferred: 15
[0024] Special features of the above defmitions and suitable
examples thereof are stated below:
[0025] "Acyl" is a substituent which originates from an acid, such
as from an organic carboxylic acid, carbonic acid, carbamic acid or
the thioacid or imidic acid corresponding to the individual
above-stated acids, or from an organic sulfonic acid, wherein these
acids may in each case comprise aliphatic, aromatic and/or
heterocyclic groups in the molecule, as well as carbamoyl or
carbamimidoyl.
[0026] Suitable examples of these acyl groups are stated below.
[0027] Aliphatic acyl groups are deemed to comprise acyl radicals
originating from an aliphatic acid, such groups including the
following:
[0028] alkanoyl (for example formyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl etc.);
[0029] alkenoyl (for example acryloyl, methacryloyl, crotonoyl
etc.); alkylthioalkanoyl (for example methylthioacetyl,
ethylthioacetyl etc.); alkanesulfonyl (for example mesyl,
ethanesulfonyl, propanesulfonyl etc.); alkoxycarbonyl (for example
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl etc.);
alkylcarbamoyl (for example methylcarbamoyl etc.);
(N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.);
alkylcarbamimidoyl (for example methylcarbamimidoyl etc.);
oxalo;
[0030] alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl
etc.).
[0031] In the above examples of aliphatic acyl groups, the
aliphatic hydrocarbon moiety, in particular the alkyl group or
alkane radical, may optionally comprise one or more suitable
substituents, such as amino, halogen (for example fluorine,
chlorine, bromine etc.), hydroxy, hydroxy-imino, carboxy, alkoxy
(for example methoxy, ethoxy,propoxy etc.), alkoxycarbonyl,
acylamino (for example benzyloxycarbonylamino etc.), acyloxy (for
example acetoxy, benzyloxy etc.) and the like; preferred aliphatic
acyl radicals having such substituents which may be mentioned are
alkanoyls substituted, for example, with amino, carboxy, amino and
carboxy, halogen, acylamino or the like.
[0032] Aromatic acyl radicals are deemed to comprise those acyl
radical which originate from an acid with a substituted or
unsubstituted aryl group, wherein the aryl group may comprise
phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are
stated below:
[0033] aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl,
phthaloyl etc); aralkanoyl (for example phenylacetyl etc);
aralkenoyl (for example cinnamoyl etc.); aryloxyalkanoyl (for
example phenoxyacetyl etc.); arylthioalkanoyl (for example
phenylthioacetyl etc.); arylaminoalkanoyl (for example
N-phenylglycyl etc.); arenesulfonyl (for example benzenesulfonyl,
tosyl or toluenesulfonyl, naphthalenesulfonyl etc); aryloxycarbonyl
(for example phenoxycarbonyl, naphthyloxycarbonyl etc.);
aralkoxycarbonyl (for example benzyloxycarbonyl etc.);
arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl
etc.); arylglyoxyloyl (for example phenylglyoxyloyl etc.).
[0034] In the above examples of acyl radicals, the aromatic
hydrocarbon moiety (in particular the aryl radical) and/or the
aliphatic hydrocarbon moiety (in particular the alkane radical) may
optionally comprise one or more suitable substituents, such as
those which have already been stated as suitable substituents for
the alkyl group or the alkane radical. Aromatic acyl radicals
having particular substituents which may in particular be mentioned
and constitute examples of preferred aromatic acyl radicals are
aroyl substituted with halogen and hydroxy or with halogen and
acyloxy, and aralkanoyl substituted with hydroxy, hydroxyimino,
dihaloalkanoyloxyimino, together with arylthiocarbamoyl (for
example phenylthiocarbamoyl etc.); arylcarbamimidoyl (for example
phenylcarbamimidoyl etc.).
[0035] A heterocyclic acyl radical is taken to mean an acyl radical
which originates from an acid with a heterocyclic group; these
include:
[0036] heterocyclic carbonyl, in which the heterocyclic radical is
an aromatic or aliphatic 5- to 6-membered heterocycle with at least
one heteroatom from the group comprising nitrogen, oxygen and
sulphur (for example thiophenyl, furoyl, pyrrolocarbonyl,
nicotinoyl etc.);
[0037] alkanoyl heterocycle, in which the heterocyclic radical is
5- to 6-membered and comprises at least one heteroatom from the
group comprising nitrogen, oxygen and sulphur (for example
thiophenylacetyl, furylacetyl, imidazolylpropionyl,
tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc)
and the like.
[0038] In the above examples of heterocyclic acyl radicals, the
heterocycle and/or the aliphatic hydrocarbon moiety may optionally
comprise one or more suitable substituents, such as those as have
been stated to be suitable for alkyl and alkane groups.
[0039] "Alkyl", unless defined otherwise, is a straight- or
branched-chain alkyl radical having up to 26 carbon atoms, such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl,
pentyl, bexyl and the like. It may be substituted e.g. by hydroxy,
amino, halogen (e.g. fluorine, bromine, chlorine), oxo radicals and
alkoxy radicals, such as methoxy, ethoxy radicals.
[0040] "Alkoxy radicals", unless defmed otherwise, is a straight-
or branched-chain alkyl radical having up to 26 carbon atoms, such
as methoxy, ethoxy radicals etc.. It may be substituted e.g. by
hydroxy, amino, halogen, oxo groups and, alkoxy radicals, such as
methoxy, ethoxy radicals.
[0041] "Alkoxy-(C.sub.0-26)-alkyl" groups are alkoxy radicals,
which can also be bonded to the basic structure via an alkyl
radical. The alkyl and alkoxy groups are as defined above.
[0042] "Cycloalkyl-(C.sub.0-26)-alkyl radicals are cyclic compounds
having 3 to 8 carbon atoms, unless defined otherwise, which are
bonded to the basic structure directly or via an alkylene radical.
The alkylene radical can be branched, unbranched and saturated or
unsaturated having double bonds. Possible substituents of the
cycloalkyl radical are, inter alia, alkoxy radicals, alkyl
radicals, hydroxyl radicals, halogen radicals, amino radicals, oxo
radicals. The cycloalkyl groups can also be aromatic with the
corresponding number of double bonds, i.e. aryl-(C.sub.0-26)-alkyl
radicals (e.g. phenyl, pyridyl, naphtbyl etc). The aromatic cyclic
compounds in particular can furthermore contain substituents, such
as nitro groups and CF.sub.3 and phenyl radicals.
[0043] "Cycloalkoxy-(C.sub.0-26)-alkyl radicals are cyclic
compounds having 3 to 8 carbon atoms, unless defined otherwise,
which are bonded to the basic structure via an oxygen directly or
via an alkylene radical. The alkylene radical can be branched,
unbranched and saturated or unsaturated with double bonds. Possible
substituents of the cycloalkyl radical are, inter alia, alkoxy
radicals, (including alkylenedioxy radicals, such as
methylenedioxy), alkyl radicals, hydroxyl radicals, halogen
radicals, amino radicals, oxo radicals. The cycloalkyl groups can
also be polycyclic radicals and aromatic with the corresponding
number of double bonds (e.g. phenoxy, pyridoxy, naphthoxy etc). The
aromatic cyclic compounds in particular can furthermore contain
substituents, such as nitro groups and CF.sub.3 and phenyl
radicals.
[0044] "Amino radicals" can be substituted, for example by the
alkyl radicals or cycloalkyl-(C.sub.0-26)-alkyl radicals as defined
above.
[0045] "Amino-(C.sub.0-26)-alkyl groups" are amino radicals, which
can also be bonded to the basic structure via an alkyl radical.
Alkyl and amino groups are defined as above.
[0046] "Silyl radicals" may be substituted for example with the
above defined alkyl radicals or cycloalkyl (C.sub.0-26)-alkyl
radicals.
[0047] "Tluo-(C.sub.0-26)-alkyl groups",
"Sulfonyl-(C.sub.0-26)-alkyl groups" and
"Sulfinyl-(C.sub.0-26)-alkyl groups" may be substituted for example
with the above defined alkyl radicals or cycloalkyl-(C.sub.0-26)--
alkyl radicals. The (C.sub.0-26)-alkyl groups are linear or
branched alkylene radicals, such as methylene, ethylene, propylene,
isopropylene, butylene, isobutylene, tert.-butylene, pentylene,
hexylene and the like. they may comprise double or triple bonds and
may be substituted for example with hydroxy, amino, halogen (e.g.
fluorine, bromine, chlorine), oxo radicals and alkoxy radicals,
such as methoxy, ethoxy radicals.
[0048] The radicals X.sub.9 and X.sub.10 may preferably be selected
such that esters are formed on the phosphino group. Suitable
examples of such esters of the formula (I) include alkyl esters
(for example methyl esters, ethyl esters, propyl esters, isopropyl
esters, butyl esters, isobutyl esters, hexyl esters etc.); aralkyl
esters (benzyl esters, phenylethyl esters, benzhydryl esters,
trityl esters etc.); aryl esters (for example phenyl esters, tolyl
esters, naphthyl esters etc.); aroylalkyl esters (for example
phenacyl esters etc); and silyl esters (for example of
trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl,
dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl,
dialkoxydihalosilyl, trialkoxyhalosilyl etc) and the like.
[0049] In the above ester, the alkane and/or arene moiety may
optionally comprise at least one suitable substituenit, such as
halogen, alkoxy, hydroxy, nitro or the like.
[0050] X.sub.9 and X.sub.10 are preferably a metal of main group I,
II or III of the periodic system, ammonium, substituted ammonium or
ammonium compounds which are derived from ethylenediamine or amino
acids. In other words, the salt compounds of the organophosphorus
compounds are formed with organic or inorganic bases (for example
sodium salt, potassium salt, calcium salt, aluminium salt, amonium
salt, magnesium salt, triethylamine salt, ethanolamine salt,
dicyclohexylaamine salt, ethylenediamine salt,
N,N'-dibenzylethylenediamine salt etc) as are salts with amino
acids (for example arginine salt, aspartic acid salt, glutamic acid
salt etc.) and the like.
[0051] The compounds of the formula (I) according to the invention
permit the occurrence of spatial isomers, for example for double
bond-containing or chiral groups R.sub.1 to R.sub.4, A.sub.1 to
A.sub.4. The use according to the invention of the compounds
includes all spatial isomers, both as pure substances and in the
form of mixtures thereof.
[0052] The compounds are in particular suitable for the therapeutic
and prophylactic treatment of human and animal infections which are
caused by viruses, bacteria, uni- and multicellular parasites and
fungi.
[0053] The compounds are active against unicellular parasites
(protozoa), in particular against the causative organisms of
malaria and sleeping sickness and of Chagas' disease,
toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis,
pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis,
acanthamoebosis, naeglerosis, coccidiosis, giardiasis and
lambliasis.
[0054] They are accordingly in particular suitable for the
prophylactic treatment of malaria and of sleeping siclmness and of
Chagas' disease, of toxoplasmosis, amoebic dysentery, leishmaniases
trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis,
sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis
and lambliasis.
[0055] The active substances according to the invention may in
particular be used against the following bacteria:
[0056] bacteria of the family Propionibacteriaceae, in particular
of the genus Propionibacterium, in particular the species
Propionibacteriuni acnes bacteria of the family Actinomycetaceae,
in particular of the genus Actinomiiyces, bacteria of the genus
Corynebacteriurn, in particular the species Corynebacteriuni
diphtheriae and Corynebacterium pseudotuberculosis, bacteria of the
family Mycobacteriaceae, of the genus Mycobacterium, in particular
the species Mycobacteriuni leprae, Mycobacteriun tuberculosis,
Mycobacterium bovis and Mycobacterium avium, bacteria of the family
Chlamydiaceae, in particular the species Chlanmydia trachomatis and
Chlanmydia psittaci, bacteria of the genus Listeria, in particular
the species Listeria monocylogenes, bacteria of the species
Erysipelthrix rhusiopathiae, bacteria of the genus Clostridiuim,
bacteria of the genus Yersinia, the species Yersinia pestis,
Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia
ruckeri, bacteria of the family Mycoplasmataceae, of the genera
Mycoplasma and Ureaplasma, in particular the species Mycoplasma
pneunioniae, bacteria of the genus Brucella, bacteria of the genus
Bordetella, bacteria of the genus Campylobacter, in particular the
species Canipylobacterjejuni, Canipylobacter coli and Campylobacer
fetus, bacteria of the genus Helicobacter, in particular the
species Helicobacter pylori, bacteria of the families
Spirochaetaceae and Leptospiraceae, in particular the genera
Treponema, Borrelia and Leptospira, in particular Borrelia
burgdorferi,
[0057] bacteria of the genus Actiinobacillus, bacteria of the
family Legionellaceae, of the genus Legionella, bacteria of the
family Rickettsiaceae and the family Bartonellaceae, bacteria of
the genera Nocardia and Rhodococcus and bacteria of the genus
Dermatophilus.
[0058] Organophosphorus compounds and the derivatives thereof are
consequently suitable for treating diphtheria, acne vulgaris,
listerioses, swine erysipelas in animals, gas gangrene in humans
and animals, malignant oedema in humans and animals, tuberculosis
ini humans and animals, leprosy and further mycobacterioses in
humans and animals, paratuberculosis in animals, plague,
mesenterial lymphadenitis and pseudotuberculosis in humans and
animals, cholera, legionnaires' disease, borreliosis in humans and
animals, leptospiroses in humans and animals, syphilis,
Cainpylobacter enteritis infections in humans and animals,
Moraxella keratoconjunctivitis and serositis in animals,
brucellosis of animals and humans, anthrax in humans and animals,
actinomycosis in humans and animals, streptotrichoses,
psittacosis/ortnithosis in animals, Q fever, ehrlichiosis.
[0059] Use is furthermore effective in the eradication of
Helicobacter in ulcers of the gastrointestinal tract.
[0060] Combinations with another antibiotic may also be used to
treat the above-stated diseases. Iso- niazid, rifampicin,
ethambutol, pyrazinamide, streptomycin, protionamide and dapsone
are in particular suitable for combination preparations with other
anti-infective agents for the treat- ment of tuberculosis.
[0061] The active substances according to the invention are
furthermore usable in infections with the following viruses:
[0062] Parvoviridae: parvo viruses, dependo viruses, densoviruses,
Adenoviridae: adeno viruses, mastadeno viruses, aviadeno viruses,
Papovaviridae: papovaviruses, in particular papillomaviruses
("wart" viruses), polyomaviruses, in particular JC virus, BK virus
and miopapovaviruses, Herpesviridae: all herpesviruses, in
particular herpes simplex viruses, varicellazoster viruses, human
cytomegalovirus, Epstein-Barr viruses, all human herpesviruses,
human herpesvirus 6, human herpesvirus 7, human herpesvirus 8,
Poxiviridae: poxviruses, orthopoxviruses, parapoxviruses, molluscum
contagiosurn virus, aviviruses, capriviruses, leporipoxviruses, all
primarily hepatotropic viruses, hepatitisviruses: hepatitis A
viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D
viruses, hepatitis E viruses, hepatitis F viruses, hepatitis G
viruses, Hepadnaviruses: all hepatitisviruses, hepatitis B virus,
hepatitis D viruses, Picornaviridae: picornaviruses, all entero
viruses, all polioviruses, all coxsackie-viruses, all echoviruses,
all rhinoviruses, hepatitis A virus, aphthoviruses,
Calciviridae'.hepatitis E viruses, Reoviridae: reoviruses,
orbiviruses, rotaviruses, Togqviridae: togaviruses, alphaviruses,
rubiviruses, pestiviruses, rubellavirus, Flaviviridae:
flaviviruses, FSME virus, hepatitis C virus, Orthoniyxoviridae: all
influenza viruses, Paramnyxoviridae: paramyxo viruses,
morbillivirus, pneumo virus, measles virus, mumps virus,
Rhabdoviridae'.rhobdo viruses, rabies virus, lyssavirus, vascular
stomatitisvirus, Coronaviridae: coronaviruses, Bunyaviridae:
bunyaviruses, nairo virus, phlebo virus, uukuvirus, hantavirus,
hantaan virus, Arenaviridae: arenaviruses, lymphocytic
choriomeningitis virus, Retroviridae: retro viruses, all HTL
viruses, human T-cell leukaemia virus, oncornaviruses,
spumaviruses, lentiviruses, all HI viruses, Filoviridae: Marburg
and Ebola virus, slow-virus infections, prions, onco viruses and
leukaemia viruses.
[0063] The organophosphorus compounds used according to the
invention are consequently suitable for combating the following
viral infections:
[0064] eradication of papillomaviruses to prevent tumours, in
particular tumours of the reproductive organs caused by
papillomaviruses in humans, eradication of JC viruses and BK
viruses, eradication of herpesviruses, eradication of human
herpesvirus 8 to treat Kaposi's sarcoma, eradication of
cytomegaloviruses before transplantations, eradication of
Epstein-Barr viruses before transplantation and to prevent tumours
associated with Epstein-Barr viruses, eradication of hepatitis
viruses to treat chronic liver disease and to prevent liver tumours
and cirrhosis of the liver, eradication of coxsackieviruses in
cardiomyopathy, eradication of coxsackieviruses in diabetes
mellitus patients, eradication of immunodeficiency viruses in
humans and animals, treatment of accompanying infections in AIDS
patients, treatment of respiratory tract inflammation of viral
causation (laryngeal papilloma, hyperplasia, rhinitis, pharyngitis,
bronchitis, pneumonia), of the sensory organs
(keratoconjunctivitis), of the nervous system (poliomyelitis,
meningoencephalitis, encephalitis, subacute sclerosing
panencephalitis, SSPE, progressive multifocal leukoencephalopathy,
lymphocytic choriomeningitis), of the gastrointestinal tract
(stomatitis, gingivostomatitis, oesophagitis, gastritis,
gastroenteritis, diarrhoea), of the liver and gall system
(hepatitis, cholangitis, hepatocellular carcinoma), of the
lymphatic tissue (mononucleosis, lymphadenitis), of the
haemopoietic system, of the reproductive organs (mumps orchitis),
of the skin (warts, dermatitis, herpes labialis, herpes febrilis,
herpes zoster, shingles), of the mucous membranes (papillomas,
conjunctival papillomas, hyperplasia, dysplasia), of the
cardiovascular system (arteriitis, myocarditis, endocarditis,
pericarditis), of the kidney/urinary system, of the reproductive
organs (anogenital lesions, warts, genital warts, sharp condylomas,
dysplasia, papillomas, cervical dysplasia, condyloma acuminatum,
epidermodysplasia verruciformis), of the locomotory organs
(myositis, myalgia), treatment of foot-and-mouth disease in
cloven-hoofed animals, of Colorado tick fever, Dengue syndrome, of
haemorrhagic fever, of early summer meningoencephalitis (FSME) and
of yellow fever.
[0065] The compounds according to the invention, which generally
include for this purpose pharmaceutically acceptable salts, amides,
esters, a salt of such an ester or also compounds which, on
administration, provide the compounds used according to the
invention as metabolites or breakdown products, also called
"prodrugs", may be formulated for administration in any suitable
mamier analogous to known agents having an anti-infective action
(mixed with a non-toxic, pharmaceutically acceptable
excipient).
[0066] Pharmaceutically acceptable salts of the compounds include
salts which the compounds of the formulae (I) used according to the
invention form in their protonated form as an ammonium salt of
inorganic or organic acids, such as hydrochloric acid, sulphuric
acid, citric acid, maleic acid, fumaric acid, tartaric acid,
p-toluenesulfonic acid.
[0067] The salts, such as sodium salt, potassium salt, calcium
salt, ammonium salt, ethanolamine salt, triethylamine salt,
dicyclohexyl amine salt and salts of an amino acid such as arginine
salt, aspartic acid salt, glutamic acid salt, are also particularly
pharmaceutically suitable.
[0068] The activity of the substances is determined using a test
system. This system is based upon in vitro measurement of the
inhibition of growth of bacteria, parasites, viruses, fungi or
plants. Test methods known to the person skilled in the art are in
part used for this purpose.
[0069] For example, antimalarial activity is determined by
measuring the inhibition of the growth of malaria parasites in
blood cultures.
[0070] Antibacterial activity is determined on the basis of
measuring the inhibition of bacterial growth on nutrient media and
in liquid cultures. Antiviral activity is determined on the basis
of the formation of viral elements in cell cultures. Fungicidal
activity is determined on the basis of measuring the inhibition of
fungal growth on nutrient media and in liquid cultures
[0071] Some of the micro-organisms which are to be investigated may
only be investigated in animal models. In this case, we will then
use the appropriate models.
[0072] Substances which exhibit activity in in vitro measurement
systems are then further investigated in in vivo models. The
antiparasitic, antiviral, fungicidal or antibacterial activity is
further evaluated in the appropriate animal models.
[0073] The pharmaceutically active agents may be prepared in dosage
units in the form of pharmaceutical preparations. This means that
the preparation is in the form of individual components, for
example tablets, coated tablets, capsules, pills, suppositories and
ampoules, the active substance content of which corresponds to a
fraction or multiple of an individual dose. The dosage units may
contain, for example 1, 2, 3 or 4 individual doses or {fraction
(1/2, 1/3)} or {fraction (1/4)} of an individual dose. An
individual dose preferably contains the quantity of active
substance which is administered at one time and usually corresponds
to a whole, half, third or quarter of a daily dose.
[0074] Non-toxic, inert, pharmaceutically suitable excipients
should be taken to mean solid, semisolid or liquid diluents,
fillers and formulation auxiliaries of all kinds.
[0075] Preferred pharmaceutical preparations which may be mentioned
are tablets, coated tablets, capsules, pills, granules,
suppositories, solutions, suspensions and emulsions, pastes,
ointments, gels, creams, lotions, powders and sprays. Tablets,
coated tablets, capsules, pills and granules may contains the
active substances together with conventional excipients, such as
(a) fillers and extenders, for example starches, lactose, cane
sugar, glucose, mannitol and silica, (b) binders, for example
carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone,
(c) humectants, for example glycerol, (d) suspending agents, for
example agar-agar, calcium carbonate and sodium carbonate, (e)
dissolution retardants, for example paraffin and (f) resorption
accelerators, for example quaternary ammonium compounds, (g)
wetting agents, for example acetyl alcohol, glycerol monostearate,
(h) adsorbents, for example kaolin and bentonite and (i)
lubricants, for example talcum, calcium and magnesium stearate and
solid polyethylene glycols or mixtures of the substances stated in
(a) to (i).
[0076] The tablets, coated tablets, capsules, pills and granules
may be provided with conventional coatings and shells optionally
containing opacifying agents and may also he composed such that
they release the active substances only with a delay or preferably
in a particular part of the intestinal tract, wherein polymeric
substances and waxes may, for example, be used as the matrices.
[0077] The active substance or substances, optionally together with
one or more of the above-stated excipients, may also be present in
microencapsulated form.
[0078] In addition to the active substance or substances,
suppositories may contain conventional water-soluble or
water-insoluble excipients, for example polyethylene glycols, fats,
for example cocoa butter and higher esters (for example C.sub.14
alcohol with C.sub.16 fatty acid) or mixtures of these
substances.
[0079] In addition to the active substance or substances,
ointments, pastes, creams and gels may contain conventional
excipients, for example animal and vegetable fats, waxes,
paraffins, starch, gum tragacanth, cellulose derivatives,
polyethylene glycols, silicones, bentonites, silica, talcum and
zinc oxide or mixtures of these substances.
[0080] In addition to the active substance or substances, powders
and sprays may contain conventional excipients, for example
lactose, talcum, silica, aluminium hydroxide, calcium silicate and
polyamide powder or mixtures of these substances. Sprays may
additionally contain conventional propellants, for example
chlorofluorocarbons.
[0081] In addition to the active substance or substances, solutions
and emulsions may contain conventional excipients, such as
solvents, solubilising agents and emulsifiers, for example water,
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol, dimethylformamide, oils, in particular cottonseed oil,
peanut oil, corn oil, olive oil, castor oil and sesame oil,
glycerol, glycerol formal, tetrahydroflurfuryl alcohol,
polyethylene glycols and sorbitan fatty acid esters or mixtures of
these substances.
[0082] For parenteral administration, the solutions and emulsions
may also be present in sterile, isotonic form.
[0083] In addition to the active substance or substances,
suspensions may contain conventional excipients, such as liquid
diluents, for example water, ethyl alcohol, propylene glycol,
suspending agents, for example ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminium metahydroxide, bentonite, agar-agar and gum
tragacanth or mixtures of these substances.
[0084] The stated formulations may also contain colorants,
preservatives and odour- or flavour-enhancing additives, for
example peppermint oil and eucalyptus oil, and sweeteners, for
example saccharin.
[0085] The active substances of the formulae (I) should preferably
be present in the pharmaceutical preparations listed above in a
concentration of approx. 0.1 to 99.5 wt. %, preferably from approx.
0.5 to 95 wt. %, of the complete mixture.
[0086] Apart from the compounds of the formulae (I), the
pharmaceutical preparations may also contain further pharmaceutical
active substances.
[0087] The compounds may be used together with hitherto described
substances having antibacterial, antiviral, antimycotic and
antiparasitic properties. Such substances in particular include
compounds which have already been used in therapeutic applications
or are still used. Substances which are suitable for this purpose
are in particular those listed in the Red List or in Simon/Stille,
Antibiokia-Therapie in Klinik und Praxis, 9th edition, 1998,
Schattauer Verlag, or on the Internet at
bttp://www.customs.treas.gov/imp-exp/rulings/harmoniz/hrm 1
29.html. The derivatives may in particular be present with
penicillins, benzylpenicillin (penicillin G), phenoxypenicillins,
isoxazolylpenicillins, aminopenicillins, ampicillin, amoxicillin,
bacam- picillin, carboxypenicillin, ticarcillin, temocillin,
acylaminopenicillins, azlocillin, mezlocillin, piperacillin,
atialcilliri mecillinam, cephalosporins, cefazolin group,
cefuroxime group, cefoxitin group, cefoxitin, cefotetan,
cefinetazole, latamoxef, flomoxef, cefotaxime group, cefozidime,
ceftazidime group, ceflazidime, cefpirome, cefepime, conventional
cephalosporins, cefsulodin, cefoperazone, oral cephalosporins of
the cephalexin group, loracarbef, cefprozil, new broad-spectrum
oral cephalosporins, cefixime, cefpodoxime-proxetil,
cefttroxime-axetil, cefetamet, cefotiam-hexetil, cefdinir,
ceftibuten, other .beta.-lactam antibiotics, carbapenem,
imipenem/cilastatin, meropenem, biapenem, aztreonam,
.beta.-lactamase inhibitors, clavulanic acid/amoxicillin,
clavulanic acid/ticarcillin, sulbactam/ampicillin,
tazobactam/piperacillin, tetracyclines, oxytetracycline,
rolitetracycline, doxycycline, minocycline, chloramphenicol,
aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin,
spectinomycin, macrolides, erythromycin, clarithromycin,
roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin,
lincosamnides, clindamycin, fusidic acid, glycopeptide antibiotics,
vancomycin, teicoplanin, pristinamycin derivatives, fosfomycin,
antimicrobial folic acid antagonists, sulfonamides, co-trimoxazole,
trimethoprim, other diaminopyrimidine-sulfonamide combinations,
nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors
(quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin,
enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118,
nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin,
rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin,
prothionamide, terizidone, dapsone, clofazimine, topical
antibiotics, bacitracin, tyrothricin, polymyxins, neomycin,
kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir,
ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine,
stavudine, ribavirin, idoxuridine, trifluridine, foscamet,
amantadine, interferons, tibol derivatives, proteinase inhibitors,
antimycotics, polyenes, amphotericin B, nystatin, natamycin,
azoles, azoles for septic therapy, miconazole, ketoconazole,
itraconazole, fluconazole, UK- 109.496, azoles for topical use,
clotrimazole, econazole, isoconazole, oxiconazole, bifonazole,
flucytosine, griseofulvin, ciclopirox olamine, tolnafnate,
naftifine, terbinafine, amorolfine, anthraquinones, betulinic acid,
semianthraquinones, xanthones, naphthoquinones, arylamino alcohols,
quinine, quinidines, mefloquine, halofantrine, chloroquine,
amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine,
dapsone, sulfonamides, sulfadoxine, sulfalenes, trimethoprim,
proguanil, chiorproguanil, diaminopyrirnidines, pyrimethamine,
primaquine, aminoquinolines, WR 238,605, tetracycline, doxycycline,
clindamycin, norfloxacin, ciprofloxacin, ofloxacin, artemisinin,
dihydroartemisinin, 10b artemether, arteether, atresunate,
atovaquone, suramin, melarsoprol, nifurtimox, stibogluconate
sodium, pentamidine, amphotericin B, metronidazole, clioquinol,
mebendazole, niclosamide, praziquantel, pyrantel, tiabenzazole,
diethylcarbamazine, ivermectin, bithionol, oxamniquine,
metrifonate, piperazine, embonate.
[0088] The compounds according to the present invention may
furthermore be present in the pharmaceutical preparations in
combination with sulfonamide, sulfadoxine, artemisinin, atovaquone,
quinine, chloroquine, hydroxychioroquine, mefloquine, halofantrine,
pyrimethamine, armesin, tetracyclines, doxycycline, proguanil,
metronidazole, praziquantel, niclosamide, mebendazole, pyrantel,
tiabendazole, diethylcarbazine, piperazine, pyrivinium,
metrifonate, oxamniquine, bithionol or suramin or two or more of
these substances.
[0089] The above-stated pharmaceutical preparations are produced in
the conventional manner using known methods, for example by mixing
the active substance or substances with the excipient or
excipients.
[0090] The stated preparations may be administered to humans and
animals orally, rectally, parenterally (intravenously,
intramuscularly, subcutaneously), intracistemally, intravaginally,
intraperitoneally, topically (powders, ointments, drops) and for
the treatment of infections in cavities, body cavities. Suitable
preparations which may be considered are solutions for injections,
solutions and suspensions for oral therapy, gels, infusion
formulations, emulsions, ointments or drops. Topical treatment may
be performed using ophthalmological and dermatological
formulations, silver and other salts, ear drops, eye ointments,
powders or solutions. Administration to animals may also be
achieved via the feed or drinking water in suitable formulations.
Gels, pulverulent formulations, powders, tablets,
controlled-release tablets, premixes, concentrates, granules,
pellets, tablets, boli, capsules, aerosols, sprays, inhalation
formulations may also be used in humans and animals. The compounds
used according to the invention may also be incorporated into other
supports, such as for example plastics (plastic chains for topical
treatment), collagen or bone cement.
[0091] It has in general proved advantageous in both human and
veterinary medicine to administer the active substances of the
formulae (I) in total quantities of approx. 0.05 to approx. 600,
preferably of 0.5 to 200 mg/kg body weight per 24 hours, optionally
in the form of two or more individual doses in order to achieve the
desired results. An individual dose preferably contains the active
substance or substances in quantities of approx. 1 to approx. 200,
in particular of 1 to 60 mg/kg body weight. It may, however, be
necessary to deviate from the stated dosages, in particular as a
function of the nature and body weight of the patient to be
treated, the nature and severity of the disease, the nature of the
preparations and the route of administration of the drug and the
period of time over which administration is performed. In some
cases, it may be sufficient to use less than the above-stated
quantity of active substance, while in other cases more than the
above-stated quantity of active substance must be used. The person
skilled in the art will use his/her skill to determine the optimum
dosage and route of administration required in each particular
case.
[0092] The compounds according to the invention may be given to
animals in conventional concentrations and preparations together
with feed or feed preparations or with drinking water.
[0093] The compounds according to the invention also show an
excellent herbicidal activity.
[0094] A person skilled in the art knows the methods of preparation
for example from U.S. Pat. No. 4,405,357.
[0095] The activity of the compounds is determined using a test
system. This system is based upon in vitro measurement of growth of
parasites, bacteria, viruses and fungi.
[0096] For example, antimalarial activity is determined by
measuring the inhibition of the growth of malaria parasites in
blood cultures. Antibacterial activity is determined on the basis
of measuring the inhibition of bacterial growth on nutrient media
and in liquid cultures. Antiviral activity is determined on the
basis of the formation of viral elements in cell cultures.
[0097] Some of the micro-organisms which are to be investigated may
be only investigated in animal models. In this case, the
appropriate models will then be used.
[0098] Substances which exhibit activity in in vitro measurement
systems are then further investigated in in vivo models.
Antiparasitic, antiviral, fungicidal or antibacterial activity is
further evaluated in the appropriate animal models.
[0099] Screening for herbicidal activity is determined by means of
algal systems and measurement of isoprene emissions from plants
under standard conditions.
[0100] The activity of some compounds according to the invention is
described below with the help of examples:
EXAMPLES CONCERNING THE ACTIVITY
[0101] Experiments show that the action of the compounds is based
on inhibition of the 1-deoxy-D-xylulose 5-phosphate(DOXP)metabolic
pathway, which can be detected in micro-organisms and plants, but
not for human beings. The following example accordingly shows the
action of the compounds according to the invention on DOXP
reductoisomerase.
EXAMPLE 1
[0102] DOXP reductoisomerase of Escherichia coli was expressed as a
recombinant protein in E. coli. The activity of DOXP
reductoisomerase has been determined in a batch, which comprised
100 mM tris-HCl (pH=7.5), 1 mM MnCl.sub.2, 0.3 mM NADPH and 1 mM
DOXP. The oxidation of NADPH was measured here in a
spectrophotometer at 365 nm. For carrying out the inhibition
studies the activity of the DOXP reductoisomerase in presence of
the compounds 1 to 8 listed on page 9 in various concentrations
between 0.1 and 100 .mu.mol 1.sup.-1 has been measured. The
concentration at which the enzyme is inhibited to half the maximum
extent (IC.sub.50) was determined from the measurement values. The
results, i.e. the IC.sub.50- Werte are listed in table 1.
EXAMPLE 2
[0103] The antimalaria activity of the compounds listed on page 9
was determined on in vitro cultures of the malaria pathogen
Plasmodiun falciparum. The depressions of a 96-well microtitre
plate were charged with in each case 200 .mu.l of an asynchroneous
Plasmodium falciparum culture at a parasitaemia of 0.4% and
haematokrit of 2%. A serial dilution series of the compounds in
triple steps between concentrations of 100 to 0.14 .mu.mol 1.sup.-1
was then prepared. The plates were incubated at 37.degree. C., 3%
CO.sub.2 and 5% O.sub.2 over a period of 48 hours. 30 .mu.l medium
supplemented with 27 .mu.Ci ml.sup.31 1 [.sup.3H]-hypoxanthine were
then added to each well. After incubation for 24 hours the
parasites were harvested by filtration on a glass fibre filter and
the radioactivity which had been incorporated was measured. The
inhibition of the growth of parasites was measured as the
percentage inhibition of the incorporation of tritium. Inhibition
of the growth of the parasites has been determined as percentage
inhibition of incorporation of tritium based on a comparison
without the substance. The half-maximum inhibitory concentration
(IC50) of the substance was determined by extrapolation of the
values. The results, i.e. the IC50-Werte, are listed in table
1.
EXAMPLE 3
[0104] The antibacterial activity of the compounds stated on page 9
was determined. The roman numerals refer to the particularly
preferred compounds stated on pages to.
[0105] A dilution series comprising the concentrations 500, 100,
50, 10 and 0 .mu.mol 1.sup.-1 of the individual compounds in LB
medium is introduced into 5 culture microtubes in a volume of 0.5
ml. The tubes were inoculated with 10 .mu.l of an overnight culture
of E. coli K12 and shaken overnight at 37.degree. C. The growth of
the bacteria was assessed on the basis of the turbidity of the
medium. The minimum concentration causing inhibition of bacterial
growth was determined (minimum inhibition concentration MIC)
[0106] The antibacterial activity of P. aeruginosa was determined
in the same manner. The results are listed in table I.
1 TABLE I IC50 (nM) of DOXP reducto- compound No. isomerase from
Helicobacter pilori 1 22 2 110 3 125 4 78 5 100 6 130 7 18 8 24
IC50(nM) of malaria culture (Plas- compound No. modium falciparum)
1 800 2 1200 3 1700 4 9200 5 1200 6 1600 7 400 8 700 MIC(nM) of
bacteria culture (Pseu- compound No. domonas aeruginosa) 1 500 2
1600 3 2200 4 7000 5 2200 6 2500 7 9000 8 7300
[0107] The herbicidal activity of the compounds according to the
present invention is described be- low:
EXAMPLE 4
[0108] The determination of herbicidal activity is performed
according to standard procedure. Again the compounds listed on page
9 are tested.
2 Compound: 1 16 Hydro Vorauflauf Gramm/ Hektar Reis Lepidium
Echinochloa Solanum 1000 50% 40% 80% 0% Erde Vorauflauf Gramm/ Zea
Beta Alopecurus Avena Cyperus Setaria Hektar mays vulgaris
myosuroides fatua esculentus viridis 500 0% 30% 50% 0% 0% 0% Gramm/
Abutilon Amaranthus Galium Sinapis Xanthium Hektar theophrasti
retroflexus aperine arvensis strumarium 500 0% 0% 0% 40% 0% Erde
Nachauflauf Gramm/ Zea Beta Alopecurus Avena Cyperus Setaria Hektar
mays vulgaris myosuroides fatua esculentus viridis 500 80% 70% 50%
50% 0% 95% Gramm/ Abutilon Amaranthus Galium Sinapis Xanthium
Hektar theophrasti retroflexus aperine arvensis strumarium 500 40%
0% 90% 95% 60% Compound: 2 17 Hydro Vorauflauf Gramm/ Hektar Reis
Lepidium Echinochloa Solanum 1000 0% 0% 0% 0% Erde Vorauflauf
Gramm/ Zea Beta Alopecurus Avena Cyperus Setaria Hektar mays
vulgaris myosuroides fatua esculentus viridis 500 0% 0% 0% 0% 0% 0%
Gramm/ Abutilon Amaranthus Galium Sinapis Xanthium Hektar
theophrasti retroflexus aperine arvensis strumarium Erde
Nachauflauf Gramm/ Zea Beta Alopecurus Avena Cyperus Setaria Hektar
mays vulgaris myosuroides fatua esculentus viridis 500 0% 0% 0% 30%
0% 90% Gramm/ Abutilon Amaranthus Galium Sinapis Xanthium Hektar
theophrasti retroflexus aperine arvensis strumarium 500 0% 0% 0%
30% 50% Compound: 3 18 Hydro Vorauflauf Gramm/ Hektar Reis Lepidium
Echinochloa Solanum 4000 40% 30% 40% 0% Erde Vorauflauf Gramm/ Zea
Beta Alopecurus Avena Cyperus Setaria Hektar mays vulgaris
myosuroides fatua esculentus viridis 2000 0% 30% 60% 0% 0% 0%
Gramm/ Abutilon Amaranthus Galium Sinapis Xanthium Hektar
theophrasti retroflexus aperine arvensis strumarium 2000 0% 0% 0%
30% 0% Erde Nachauflauf Gramm/ Zea Beta Alopecurus Avena Cyperus
Setaria Hektar mays vulgaris myosuroides fatua esculentus viridis
2000 70% 90% 60% 50% 0% 70% Gramm/ Abutilon Amaranthus Galium
Sinapis Xanthium Hektar theophrasti retroflexus aperine arvensis
strumarium 2000 60% 60% 40% 70% 60% Compound: 4 19 Hydro Vorauflauf
Gramm/ Hektar Reis Lepidium Echinochloa Solanum 4000 30% 30% 70%
30% Erde Vorauflauf Gramm/ Zea Beta Alopecurus Avena Cyperus
Setaria Hektar mays vulgaris myosuroides fatua esculentus viridis
2000 30% 60% 0% 60% 0% 0% Gramm/ Abutilon Amaranthus Galium Sinapis
Xanthium Hektar theophrasti retroflexus aperine arvensis strumarium
2000 0% 0% 0% 70% 0% Erde Nachauflauf Gramm/ Zea Beta Alopecurus
Avena Cyperus Setaria Hektar mays vulgaris myosuroides fatua
esculentus viridis 2000 70% 50% 70% 40% 0% 90% Gramm/ Abutilon
Amaranthus Galium Sinapis Xanthium Hektar theophrasti retroflexus
aperine arvensis strumarium 2000 50% 40% 70% 60% 90% Compound: 5 20
Hydro Vorauflauf Gramm/ Hektar Reis Lepidium Echinochloa Solanum
4000 40% 40% 60% 0% Erde Vorauflauf Gramm/ Zea Beta Alopecurus
Avena Cyperus Setaria Hektar mays vulgaris myosuroides fatua
esculentus viridis 2000 0% 30% 60% 0% 0% 0% Gramm/ Abutilon
Amaranthus Galium Sinapis Xanthium Hektar theophrasti retroflexus
aperine arvensis strumarium 2000 0% 0% 0% 50% 0% Erde Nachauflauf
Gramm/ Zea Beta Alopecurus Avena Cyperus Setaria Hektar mays
vulgaris myosuroides fatua esculentus viridis 2000 80% 40% 80% 40%
0% 95% Gramm/ Abutilon Amaranthus Galium Sinapis Xanthium Hektar
theophrasti retroflexus aperine arvensis strumarium 2000 40% 30%
70% 90% 60% Compound: 6 21 Hydro Vorauflauf Gramm/ Hektar Reis
Lepidium Echinochloa Solanum 4000 40% 30% 50% 0% Erde Vorauflauf
Gramm/ Zea Beta Alopecurus Avena Cyperus Setaria Hektar mays
vulgaris myosuroides fatua esculentus viridis 2000 0% 60% 70% 0% 0%
0% Gramm/ Abutilon Amaranthus Galium Sinapis Xanthium Hektar
theophrasti retroflexus aperine arvensis strumarium 2000 0% 0% 0%
30% 0% Erde Nachauflauf Gramm/ Zea Beta Alopecurus Avena Cyperus
Setaria Hektar mays vulgaris myosuroides fatua esculentus viridis
2000 70% 40% 40% 60% 0% 70% Gramm/ Abutilon Amaranthus Galium
Sinapis Xanthium Hektar theophrasti retroflexus aperine arvensis
strumarium 2000 60% 70% 80% 60% 60% Compound: 7 22 Hydro Vorauflauf
Gramm/ Hektar Reis Lepidium Echinochloa Solanum 4000 30% 0% 40% 30%
Erde Vorauflauf Gramm/ Zea Beta Alopecurus Avena Cyperus Setaria
Hektar mays vulgaris myosuroides fatua esculentus viridis 2000 30%
70% 30% 30% 0% 0% Gramm/ Abutilon Amaranthus Galium Sinapis
Xanthium Hektar theophrasti retroflexus aperine arvensis strumarium
2000 0% 20% 0% 30% 0% Erde Nachauflauf Gramm/ Zea Beta Alopecurus
Avena Cyperus Setaria Hektar mays vulgaris myosuroides fatua
esculentus viridis 2000 70% 70% 80% 80% 0% 90% Gramm/ Abutilon
Amaranthus Galium Sinapis Xanthium Hektar theophrasti retroflexus
aperine arvensis strumarium 2000 50% 50% 95% 80% 90% Compound: 8 23
Hydro Vorauflauf Gramm/ Hektar Reis Lepidium Echinochloa Solanum
2000 0% 30% 40% 30% Erde Vorauflauf Gramm/ Zea Beta Alopecurus
Avena Cyperus Setaria Hektar mays vulgaris myosuroides fatua
esculentus viridis 1000 30% 30% 30% 30% 0% 0% Gramm/ Abutilon
Amaranthus Galium Sinapis Xanthium Hektar theophrasti retroflexus
aperine arvensis strumarium 1000 0% 20% 0% 30% 0% Erde Nachauflauf
Gramm/ Zea Beta Alopecurus Avena Cyperus Setaria Hektar mays
vulgaris myosuroides fatua esculentus viridis 1000 70% 40% 70% 80%
0% 90% Gramm/ Abutilon Amaranthus Galium Sinapis Xanthium Hektar
theophrasti retroflexus aperine arvensis strumarium 1000 50% 50%
70% 90% 90%
* * * * *