COMPOSES ORGANOPHOSPHORES ET LEUR UTILISATION

PHOSPHORORGANIC COMPOUNDS AND THE USE THEREOF

Abrégé français

L'invention concerne des composés organophosphorés de formule générale (I), dans laquelle A représente propylène, 2-oxopropylène ou 3-oxopropylène. L'invention concerne également leur utilisation pour le traitement thérapeutique et prophylactique, chez l'homme et les animaux, d'infections dues à des virus, bactéries, champignons et parasites, ainsi que leur utilisation comme fongicide, bactéricide et herbicide pour des végétaux.

Abrégé anglais

The invention concerns the use of phosphororganic compounds of general formula
(I), wherein A represents propylene, 2-oxopropylene or 3-oxopropylene. The
invention also concerns the use of said compounds for therapeutic and
prophylactic treatment of infections in humans and animals caused by virus,
bacteria, fungi and parasites and to their use as fungicides, bactericides and
herbicides.

Revendications

-33-
1. Organophosphorus compounds of general formula (I)
<IMG>
in which A represents propylene, 2-oxopropylene or 3-oxopropylene,
in which R1 is selected from the group consisting of hydrogen, substituted and
unsub-
stituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and
unsubsti-
tuted alkenyl, substituted and unsubstituted alkinyl, substituted and
unsubstituted aryl,
substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl,
substi-
tuted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic
residue,
halogen and OX1,
wherein X1 is selected from the group consisting of hydrogen, substituted and
unsub-
stituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and
unsubsti-
tuted alkenyl, substituted and unsubstituted alkinyl, substituted and
unsubstituted aryl,
substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl,
substi-
tuted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic
residue and
in which R2 and R3 are the same or different and are selected from the group
consisting
of hydrogen, substituted and unsubstituted alkyl, substituted and
unsubstituted hy-
droxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted
acyl, sub-
stituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl,
substituted
and unsubstituted alkinyl, substituted and unsubstituted cycloalkyl,
substituted and un-
substituted heterocyclic residue, halogen, OX2 or OX3,
wherein X2 or X3 may be the same or different and are selected from the group,
con-
sisting of hydrogen, substituted and unsubstituted alkyl, substituted and
unsubstituted
hydroxyalkyl, substituted and unsubstituted aryl, substituted and
unsubstituted aralkyl,
substituted and unsubstituted alkenyl, substituted and unsubstituted alkinyl,
substituted
and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic
residue, a si-
lyl, a cation of an organic and inorganic base, in particular a metal of the
first, second,
or third main group of the periodic system, ammonium, substituted ammonium and
ammonium compounds, which derive from ethylene diamine or amino acid,
and their pharmaceutically acceptable salts, esters and amides and salts of
the esters
with the exception of N-hydroxy-4-phosphonobutyric acid amide and the salts
thereof.
2. Compounds according to claim 1, characterized in that R1 is selected from
the group
consisting of a hydrogen residue, a methyl residue, an ethyl residue and a
phenyl resi-
due.

-34-
3. Compounds according to claim 1 or claim 2, characterized in that R2 and R3
are the
same or different and are selected from the group consisting of a methyl
residue, an
ethyl residue, OX2 and OX3.
4. Compounds according to claim 2, characterized in that X2 and X3 are the
same or dif-
ferent and are selected from the group consisting of sodium, a methyl residue,
an ethyl
residue and a phenyl residue.
5. Compounds according to claim 1, characterized in that they are selected
from the group
consisting of
N-hydroxy-N-methyl-4-phosphonobutyric acid amide monosodium salt,
N-hydroxy-N-phenyl-4-phosphonobutyric acid amide monosodium salt,
N-hydroxy-N-(2-hydroxyethyl)-4-phosphonobutyric acid amide monosodium salt,
N-(1-carboxypropyl)-N-hydroxy-4-phosphonobutyric acid amide monosodium salt,
N-hydroxy-N-(4-imidazolyl)-4-phosphonobutyric acid amide monosodium salt,
N-ethyl-N-hydroxy-4-ethylphosphonobutyric acid amide monosodium salt,
N-benzyl-N-hydroxy-4-ethylphosphonobutyric acid amide monosodium salt,
N-allyle-N-hydroxy-4-ethylphosphonobutyric acid amide monosodium salt,
N-hydroxy-N-(3-(3-phenylpropionyl)-4-ethylphosphonobutyric acid amide monoso-
dium salt,
N-(4-fluorobenzyl)-N-hydroxy-4-ethylphosphono-butyric acid amide monosodium
salt,
N-hydroxy-N-n-propyl-4-diethylphosphonobutyric acid amide,
N-hydroxy-N-ortho-tolyl-4-diethyl-phosphonobutyric acid amide,
N-but-3-inyl-N-hydroxy-4-diethylphosphonobutyric acid amide,
N-(1-carboxy-2-methyl-propyl)-N-hydroxy-4-diethylphosphonobutyric acid amide,
N-hydroxy-N-(2-{4-hydroxy-indol-3-yl)-ethyl)-4-diethyl-phosphonobutyric acid
amide,
N-hydroxy-N-isopropyl-4-dimethyl-phosphinoxido-butyric acid amide,
N-meta-ethylbenzyl-N-hydroxy-4-dimethyl-phosphinoxido-butyric acid amide,
N-cyclohex-2-enyl-N-hydroxy-4-dimethyl-phosphinoxido-butyric acid amide,
N-(1-carboxy-2-methyl-butyl)-N-hydroxy-4-dimethylphosphinoxidobutyric acid
amide,
N-carbamoyl-N-hydroxy-4-dimethylphosphinoxidobutyric acid amide,
N-n-butyl-N-hydroxy-4-(P-methyl-phosphinato)-butyric acid amide,
N-hydroxy-N-(para-isopropylbenzyl)-4-(P-methyl-phosphinato)-butyric acid
amide,
N-hydroxy-N-(4,4,4-trifluorbutyl)-4-(P-methyl-phosphinato)-butyric acid amide,
N-carboxymethyl-N-hydroxy-4-(P-methyl-phosphinato)-butyric acid amide,
N-ethoxycarbonyl-N-hydroxy-4-(P-methyl-phosphinato)-butyric acid amide,
N-isobutyl-N-hydroxy-4-oxo-4-phosphono-butyric acid amide monosodium salt,
N-ortho-chlorophenyl-N-hydroxy-4-oxo-4-phosphono-butyric acid amide monosodium
salt,

-35-
N-cyclohexyl-N-hydroxy-4-oxo-4-phosphono-butyric acid amide monosodium salt,
N-(1-carboxyethyl)-N-hydroxy-4-oxo-4-phosphonobutyric acid amide monosodium
salt,
N-hydroxy-N-(2-(N-hydroxy-carbamoyl)-ethyl)-4-oxo-4-phosphono-butyric acid
amide
monosodium salt,
N-tert-butyl-N-hydroxy-4-ethylphosphono-4-oxo-butyric acid amide monosodium
salt,
N-para-nitrophenyl-N-hydroxy-4-ethyl-phosphono-4-oxo-butyric acid amide monoso-
dium salt,
N-(4-oxocyclohexyl)-N-hydroxy-4-ethyl-phosphono-4-oxo-butyric acid amide
monoso-
dium salt,
N-(1-carboxy-1-methyl-ethyl)-N-hydroxy-4-ethyl-phosphono-4-oxo-butyric acid
amide
monosodium salt,
N-(3-chloro-2,2-dimethyl-propyl)-N-hydroxy-4-ethylphosphono-4-oxo-butyric acid
amide monosodium salt,
N-hydroxy-N-n-pentyl-4-diethyl-phosphono-4-oxo-butyric acid amide,
N-hydroxy-N-(3-acetyl-4-methoxy-phenyl)-4-diethyl-phosphono-4-oxo-butyric acid
amide,
N-hydroxy-N-(3-methylcyclohexyl)-4-diethylphosphono-4-oxo-butyric acid amide,
N-(5-amino-1-carboxy-pentyl)-N-hydroxy-4-diethyl-phosphono-4-oxo-butyric acid
amide,
N-hydroxy-N-(3-(N-morpholino)propyl)-4-diethyl-phosphono-4-oxo-butyric acid
amide,
N-hydroxy-N-isobutyl-4-dimethyl-phosphono-4-oxo-butyric acid amide,
N-beta-naphthyl-N-hydroxy-4-dimethyl-phosphinoxido-4-oxo-butyric acid amide,
N-(4-hydroxymethyl-2-phenyl-1,3-dioxan-4-yl)-N-hydroxy-4-dimethyl-
phosphinoxido-
4-oxo-butyric acid amide,
N-(1-carboxy-3-methyl-butyl)-N-hydroxy-4-dimethyl-phosphinoxido-4-oxo-butyric
acid amide,
N-(2-furyl)-N-hydroxy-4-dimethylphosphinoxido-4-oxo-butyric acid amide,
N-(3-methyl-pentyl)-N-hydroxy-4-(P-methyl-phosphinato)-4-oxo-butyric acid
amide,
N-hydroxy-N-(meta-pyridyl)-4-(P-methyl-phosphinato)-4-oxo-butyric acid amide,
N-hydroxy-N-(1-cyano-cyclohexyl)-4-(P-methyl-phosphinato)-4-oxo-butyric acid
amide,
N-(1-carboxy-pentyl)-N-hydroxy-4-(P-methyl-phosphinato)-4-oxo-butyric acid
amide,
N-(N-phenyl-carbamoyl)-N-hydroxy-4-(P-methyl-phosphinato)-4-oxo-butyric acid
amide,

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N-hydroxy-N-n-octyl-3-oxo-4-phosphonobutyric acid amide monosodium salt,
N-hydroxy-N-(2-indolyl)-3-oxo-4-phosphonobutyric acid amide monosodium salt,
N-hydroxy-N-dec-9-enyl-3-oxo-4-phosphono-butyric acid amide monosodium salt,
N-(1-carboxy-3-methylthio-propyl)-N-hydroxy-3-oxo-4-phosphonobutyric acid
amide
monosodium salt,
N-hydroxy-N-(2,2,2-trichlorethyl)-3-oxo-4-phosphono-butyric acid amide
monosodium
salt,
N-decyl-N-hydroxy-3-oxo-4-ethylphosphono-butyric acid amide monosodium salt,
N-(2-fluorenyl)-N-hydroxy-3-oxo-4-ethylphosphono-butyric acid amide monosodium
salt,
N-(1-adamantyl)-N-hydroxy-3-oxo-4-ethyl-phosphono-butyric acid amide
monosodium
salt,
N-(1,4-dioxane-2-yl)-N-hydroxy-3-oxo-4-ethylphosphonobutyric acid amide mono-
sodium salt,
N-(N-(2,4-dimethyl-phenyl)-carbamoyl)-N-hydroxy-3-oxo-4-ethylphosphono-butyric
acid amide-monosodium salt,
N-(3-methyl-hex-2-yl)-N-hydroxy-3-oxo-4-diethylphosphono-butyric acid amide,
N-meta-Tolyl-N-hydroxy-3-oxo-4-diethylphosphono-butyric acid amide,
N-(3-acetylaminopropyl)-N-hydroxy-3-oxo-4-diethylphosphono-butyric acid amide,
N-(2-pyrrolidone-4-yl)-N-hydroxy-3-oxo-4-diethylphosphono-butyric acid amide,
N-(2-(methylsulfoxido)-ethyl)-N-hydroxy-3-oxo-4-diethylphosphonobutyric acid
am-
ide,
N-dodecyl-N-hydroxy-3-oxo-4-dimethylphosphinoxido-butyric acid amide,
N-papa-hydroxyphenyl-N-hydroxy-3-oxo-4-dimethylphosphinoxido-butyric acid
amide,
N-(2-propionylethyl)-N-hydroxy-3-oxo-4-dimethylphosphinoxido-butyric acid
amide,
N-(1-carboxy-2-(3,4-dihydroxyphenyl)-ethyl)-N-hydroxy-3-oxo-4-dimethyl-phos-
phinoxido-butyric acid amide,
N-(3-phosphonopropyl)-N-hydroxy-3-oxo-4-dimethylphosphinoxido-butyric acid
amide
monosodium salt,
N-(3-ethyl-4-methyl-pentyl)-N-hydroxy-3-oxo-4-(P-methyl-phosphinato)-butyric
acid
amide,
N-(3-hydroxy-3-phenyl-propyl)-N-hydroxy-3-oxo-4-(P-methyl-phosphinato)-butyric
acid amide,
N-(2-(2-methoxy-ethoxy)-ethyl)-N-hydroxy-3-oxo-4-(P-methyl-phosphinato)-
butyric
acid amide,
N-(4-imidazolyl-methyl)-N-hydroxy-3-oxo-4-(P-methyl-phosphinato)-butyric acid
am-
ide,

-37-
N-(2-(7-(2-(N,N-diethylamino)-ethoxy)-fluoren-9-on-2-yloxy)-ethyl)-N-hydroxy-3-
oxo-4-(P-methyl-phosphinato)-butyric acid amide,
N-hydroxy-4-phosphono-butyric acid amide monosodium salt,
N-hydroxy-4-(P-methyl-phosphinato)-butyric acid amide monosodium salt,
N-hydroxy-N-methyl-3-oxo-4-(P-methyl-phosphinato)-butyric acid amide
monosodium
salt,
N-hydroxy-3-oxo-4-(P-methyl-phosphinato)-butyric acid amide-monosodium salt,
N-hydroxy-N-methyl-3-oxo-4-phosphono-butyric acid amide-monosodium salt,
N-hydroxy-3-oxo-4-phosphono-butyric acid amide-monosodium salt,
N-hydroxy-4-diphenylphosphono-butyric acid amide,
N-hydroxy-N-phenyl-4-diphenylphosphono-butyric acid amide,
N-hydroxy-N-benzyl-4-phosphono-butyric acid amide monosodium salt,
N-hydroxy-N-benzyl-3-oxo-4-dimethylphosphonobutyric acid amide,
N-hydroxy-4-(diethylphosphono)-butyric acid amide,
N-hydroxy-N-methyl-4-(diethylphosphono)-butyric acid amide,
N-hydroxy-4-phosphono-N-hydroxybutyric acid amide,
N-hydroxy-N-methyl-4-phosphono-butyric acid amide,
N-hydroxy-3-oxo-4-(diethylphosphono)-butyric acid amide),
N-hydroxy-N-methyl-3-oxo-4-(diethylphosphono)-butyric acid amide,
N-hydroxy-3-oxo-4-phosphono-butyric acid amide),
N-hydroxy-N-methyl-3-oxo-4-phosphono-butyric acid amide),
N-hydroxy-3-oxo-4-phosphonobutyric acid amide,
N-hydroxy-N-methyl-3-oxo-4-phosphonobutyric acid amide,
N-hydroxy-4-oxo-4-(P-methyl-phosphonato) butyric acid amide,
N-hydroxy-4-ethylphosphonobutyric acid amide.

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6. Compounds according to one of the preceding claims characterized in that
they are se-
lected from the group consisting of N-hydroxy-4-phosphonobutyric acid amide
mono-
sodium salt and N-hydroxy-N-methyl-4-phosphonobutyric acid amide monosodium
salt.
7. Pharmaceutical preparation, characterized by
an effective content of an at least one organophosphorus compound according to
one of
claims 1 to 6 together with a pharmaceutically acceptable excipient.
8. Pharmaceutical preparation according to claim 7, characterized by
at least one further pharmaceutical active ingredient.
9. Pharmaceutical preparation according to one of claims 7 or 8, characterized
by

-39-
one or more ingredients out of the group which consists of sulfonamide,
sulfadoxin,
artemisinin, atovaquon, chinin, chloroquine, hydroxychloroquin, mefloquin,
halofantrin,
pyrimethamine, armesin, tetracycline, doxycyclin, proguanil, metronidazol,
praziquan-
til, niclosamide, mebendazol, pyrantel, tiabendazole, diethylcarbazin,
piperazin, pyrivi-
num, metrifonate, oxamniquin, bithionol and suramin.
10. Use of organophosphorus Compounds according to one of claims 1 to 6 for
the treat-
ment of infectious processes in humans and animals caused by viruses,
bacteria, fungi
or parasites and as a fungicide, bactericide or herbicide in plants.
11. Use according to claim 10 for the treatment of infections caused by
bacteria, viruses,
fungi or uni- or multi-cellular parasites.
12. Use according to claim 10 for the treatment of infections caused by
bacteria selected
from the group consisting of bacteria which are selected from the group
consisting of
Bacteria of the family Propionibacteriaceae, in particular the genus
Propionibacterium,
in particular the species Propionibacterium acnes; bacteria of the family
Actinomyceta-
ceae, in particular the genus Actinomyces; bacteria of the genus
Corynebacterium, in
particular the species Corynebacterium diphteriae and Corynebacterium
pseudotuber-
culosis; bacteria of the family Mycobacteriaceae, the genus Mycobacterium, in
particu-
lar 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 Liste-
ria, in particular the species Listeria monocytogenes; bacteria of the species
Ery-
sipelthrix rhusiopathiae; bacteria of the genus Clostridium; bacteria of the
genus Yer-
sinia, the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia
enterocolitica
and Yersinia ruckeri; bacteria of the family Mycoplasmataceae, the genus
Mycoplasma
and Ureapiasma, in particular the species Mycoplasma pneumoniae; bacteria of
the ge-
nus Brucella; bacteria of the genus Bordetella; bacteria of the family
Neiseriaceae, in
particular the genuses Neisseria and Moraxella, in particular the species
Neisseria
meningitides, Neisseria gonorrhoeae and Moraxella bovis; bacteria of the
family Vi-
brionaceae, in particular the genuses Vibrio, Aeromonas, Plesiomonas and
Photobacte-
rium, in particular the species Vibrio cholerae, Vibrio anguillarum and
Aeromonas sal-
monicidas; bacteria of the genus Campylobacter, in particular the species
Campylobac-
ter jejuni, Campylobacter coli and Campylobacter fetus; bacteria of the genus
Helico-
bacter, in particular the species Helicobacter pylori; bacteria of the
families Spirochae-
taceae and the Leptospiraceae, in particular the genus Treponema, Borrelia and
Lepto-
spira, in particular Borrelia burgdorferi; bacteria of the genus
Actinobaeillus; bacteria of

-40-
the family Legionellaceae, the genus Legionella; bacteria of the family
Rickettsiaceae
and family Bartonellaceae; bacteria of the genus Nocardia and Rhodococcus;
bacteria of
the genus Dermatophilus; bacteria of the family Pseudomonadaceae, in
particular the
genuses Pseudomonas and Xanthomonas; bacteria of the family
Enterobacteriaceae, in
particular the genuses Escherichia, Klebsiella, Proteus, Providencia,
Salmonella, Serra-
tia and Shigella; bacteria of the family Pasteurellaceae, in particular the
genus Haemo-
philus; bacteria of the family Micrococcaceae, in particular the genus
Micrococcus and
Staphylococcus; bacteria of the family Streptococcaceae, in particular the
genus Strep-
tococcus and Enterococcus and bacteria of the family Bacillaceae, in
particular the ge-
nus bacillus and clostridium, and in the helicobacter eradication therapy of
ulcers of the
gastro-intestinal tract.
13. Use according to claim 10 for the treatment of infections caused by
viruses selected
from the group consisting of viruses of the parvoviridae, in particular parvo
viruses, de-
pendo viruses, denso viruses, viruses of the genus adenoviridae, in particular
adeno vi-
ruses, mastadeno viruses, aviadeno viruses, viruses of the genus
papovaviridae, in par-
ticular papova viruses, in particular papilloma viruses (so called wart
viruses), polyoma
viruses, in particular JC-virus, BK-virus, and miopapova viruses, viruses of
the genus
herpes viridae, in particular herpes simplex viruses, the varizella-zoster
viruses, human
cytomegalo virus, Epstein-Barr viruses, human herpes virus 6, human herpes
virus 7;
human herpes virus 8, viruses of the genus poxviridae, in particular pox
viruses, ortho-
pox, parapox, molluscum contagiosum virus, avipox viruses, capripox viruses,
lepori-
pox viruses, primary hepatotropic viruses, in particular hepatitis viruses,
such as hepati-
tis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses,
hepatitis E vi-
ruses, hepatitis F viruses, hepatitis G viruses, hepadna viruses, in
particular all hepatitis
viruses, such as hepatitis B virus, hepatitis D viruses, viruses of the genus
picornaviri-
dae, in particular picorna viruses, all entero viruses, all polio viruses, all
coxsackie vi-
ruses, all echo viruses, all rhino viruses, hepatitis A virus, aphtho viruses,
viruses of the
genus Calciviridae, in particular hepatitis E viruses, viruses of the genus
Reoviridae, in
particular reo viruses, orbi viruses, rots viruses, viruses of the genus
togaviridae, in par-
ticular toga viruses, alpha viruses, rubi viruses, pesti viruses, rubella
virus, viruses of
the genus flaviviridae, in particular flavi viruses, FSME virus, hepatitis C
virus, viruses
of the genus orthomyxoviridae, in particular influenza viruses, viruses of the
genus
Paramyxoviridae, in particular paramyxo viruses, morbilli virus, pneumo virus,
measles
virus, mumps virus, viruses of the genus rhabdoviridae, in particular rhabdo
viruses, ra-
bies virus, lyssa virus, viscula stomatitis virus, viruses of the genus corona
viridae, in
particular corona viruses, viruses of the genus bunyaviridae, in particular
bunya viruses,
nairo virus, phlebo virus, uuku virus, hanta virus, viruses of the genus
arenaviridae, in

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particular arenaviruses, lymphocytic choriomeningitis virus, viruses of the
genus retro-
viridae, in particular retro viruses, all HTL viruses, human T-cell leukaemia
virus, on-
corna viruses, spuma viruses, lenti viruses, all HI-viruses, viruses of the
genus filoviri-
dae, in particular Marburg and Ebola virus, Slow viruses, prions, onko viruses
and leu-
kemia viruses.
14. Use according to claim 10 for the prophylactics and treatment of
infections caused by
unicellular parasites, namely pathogens of malaria, the sleeping sickness, the
Chagas'
disease, the toxoplasmosis, amoebic dysentery, leishmaniasis; trichomoniasis,
pnema-
cystosis, balantidiosis, cryptosporidiosis, sarcocystosis, acanthamebiasis,
naegleriasis,
coccidiosis, giardiasis and lambliosis.
15. Method for therapeutic and prophylactic treatment of infectious diseases
caused by
bacteria, fungi or parasites wherein a therapeutically effective amount of a
compound
according to one of claims 1 to 6 is administered to a person being taken ill
with an in-
fection caused by bacteria, fungi or parasites.
16. Method for combating undesired plant growth, characterized in that useful
plants or
their area under cultivation are treated with an active amount of a compound
according
to one of claims 1 to 6 or with an agent containing such a derivative.

Description

WO01/60829 original PCT/EP0001313
_1_
Org_anophosphorus compounds and the use thereof
The invention concerns organophosphorus compounds and their salts, esters, and
amides as
well as their use for the therapeutic and prophylactic treatment of infections
in humans and
animals, caused by viruses, bacteria, fungi and parasites, and the use thereof
as a fungicide,
bactericide and herbicide in plants. According to the invention the
organophosphorus com-
pounds include phosphinoyl derivatives, phosphinic acid derivatives and
phosphoric acid
derivatives.
There is a serious need for the provision of preparations to enhance the
treatment of humans
and animals and the protection of plants, which preparations not only possess
a strong effi-
cacy but in contrast to other pharmaceutical compositions and plant protective
agents, show
reduced side effects and lower environmental impact and therefore represent a
lower risk to
health for humans.
The object of the present invention therefore is to provide a substance, which
can be univer-
sally used in infections by viruses, bacteria, fungi and parasites in humans
and animals and as
2o a fungicide, bactericide and herbicide in plants and fulfils the conditions
given above.
This object is achieved in a completely surprising manner by the group of
substances defined
in claim 1. This group of substances demonstrates- an anti-infectious effect
against viruses,
bacteria, fungi, unicellular and multicellular parasites as well as a
fungicidal and herbicidal
effect in plants.
The organophosphorus compounds according to the present invention correspond
to general
formula (I):
Rl' 0 10 .
N-C-A-P-R2 (I)
/ I
HO R3
in which A represents propylene, 2-oxopropylene or 3-oxopropylene,
in which RI is selected from the group consisting of hydrogen, substituted and
unsubstituted
alkyl, substituted and unsubstituted hydroxyalkyl, substituted and
unsubstituted alkenyl, sub-
stituted and unsubstituted a.lkinyl, substituted and unsubstituted aryl,
substituted and unsub-
stituted acyl, substituted and unsubstituted cycloalkyl, substituted and
unsubstituted aralkyl,
CA 02399947 2002-08-12

CA 02399947 2002-08-12
W 001/60829 amended PCT/EP0001313
-2-
[substituted and unsubstituted] heterocyclic residue, halogen and OX1,
wherein Xl is selected from the group consisting of hydrogen, substituted and
unsubstituted
alkyl, substituted and unsubstituted hydroxyalkyl, substituted and
unsubstituted alkenyl, sub-
s stituted and unsubstituted alkinyl, substituted and unsubstituted aryl,
substituted and unsub-
stituted acyl, substituted and unsubstituted cycloalkyl, substituted and
unsubstituted aralkyl,
substituted and unsubstituted heterocyclic residue and
in which R2 and R3 are the same or different and are selected from the group
consisting of
hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted
hydxoxyalkyl,
1 o substituted and unsubstituted aryl, substituted and unsubstituted acyl,
substituted and unsub-
stituted aralkyl, substituted and unsubstituted alkenyl, substituted and
unsubstituted alkinyl,
substituted and unsubstituted cycloalkyl, substituted and unsubstituted
heterocyclic residue,
halogen, OX2 or OX3,
wherein X2 or X3 may be the same or different and are selected from the group
consisting of
15 hydrogen, substituted and unsubstituted alkyl, substituted and
unsubstituted hydroxyalkyl,
substituted and unsubstituted aryl, substituted and unsubstituted aralkyl,
substituted and un-
substituted alkenyl, substituted and unsubstituted alkinyl, substituted and
unsubstituted cyclo-
allcyl, substituted and unsubstituted heterocyclic residue, a silyl, a cation
of an organic and
inorganic base, in particular a metal of the first, second, or third main
group of the periodic
20 system, ammonium, substituted ammonium and ammonium compounds, which derive
from
ethylene diamine or amino acid,
and their pharmaceutically acceptable salts, esters and amides and salts of
the esters with the
exception of N-hydroxy-4-phosphonobutyric acid amide and the salts thereof.
25 Preferably Rl is selected from the group consisting of a hydrogen residue,
a methyl residue,
an ethyl residue and a phenyl residue.
Furthermore R2 and R3 are preferred being the same or different and being
selected from the
group consisting of a methyl residue, an ethyl residue, OX2 and OX3, wherein
X2 and X3 es-
3o pecially preferably are selected from the group, consisting of sodium, a
methyl residue, a
ethyl residue and a phenyl residue.
Special features of the above definitions and suitable examples thereof are
given below:

CA 02399947 2002-08-12
-2a-
"Acyl" ist ein Substituent, der von einer Sauce stammt, wie von einer
organischen Carbonsau-
re, Kohlensaure, Carbaminsaure oiler der den einzelnen vorstehenden Sauren
entsprechenden
Thiosaure oiler Imidsaure, oiler von einer organischen Sulfonsaure, wobei
diese Sauren je
"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 indi-
go vidually present acids ~or from an organic sulfonic acid, wherein in each
case these acids
[comprise aliphatic, aromatic and/or heterocyclic groups in the molecule as
well as carbamoyl
or carbamimidoyl.]

WO01/60829 origin:al PCT/EPOOOI313
-3-
Suitable examples of these acyl groups were given below.
Acyl residues originating from aliphatic acid are designated as aliphatic acyl
groups and in-
clude:
alkanoyl (for example formyl,, acetyl, propionyl, butyryl, isobutyryl,
valeryl, isovaleryl, piva-
loyl etc.);
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,
isopro-
to poxycarbonyl, butoxycarbonyl, isobutoxycarbonyl etc.);
alkylcarbamoyl (for example methylcarbamoyl etc.);
(N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.);
alkylcarbamimidoyl (for example methylcarbamimidoyl etc.);
axalo;
15 alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).
In the above examples of aliphatic aryl 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-
2o imino, carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.);
alkoxycarbonyl, acyla-
mino (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.
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:
aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);
3o aralkanoyl (for example phenylacetyl etc.);
aralkenoyl (for example cinnamoyl elc.);
aryloxyalkanoyl (for example phenoxyacetyl etc.);
arylthioalkanoyl (fox example phenylthioacetyl etc.);
arylaminoalkanoyl (for example N-phenylglycyl etc.);
arenesulfonyl (for example benzenesulfonyl, tosyl or toluenesulfonyl,
naphthalenesulfonyl
etc.);
aryloxycarbonyl (fox example phenoxycarbonyl, naphthyloxycarbonyl etc.);
aralkoxycarbonyl (for example benzyloxycarbonyl etc.);
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
-4-
arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.);
arylglyoxyloyl (for example phenylglyoxyloyl etc.).
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 amyl substituted with halogen and
hydroxy or with
to halogen and acyloxy, and aralkanoyl substituted with hydroxy, hydroxyimino,
dihaloalka-
noyloxyimino, together with
arylthiocarbamoyl (for example phenylthiocarbamoyl etc.);
arylcarbamimidoyl (for example phenylcarbamimidoyl etc.).
A heterocyclic acyl radical is taken to mean an acyl radical which originates
from an acid
with a heterocyclic group; these include:
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, oxy-
2o gen and sulphur (for example thiophenyl, furoyl, pyrrolocarbonyl,
nicotinoyl etc.);
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)-
2s 2-methoxyiminoacetyl etc.) and the like.
In the above examples of heterocyclic acyl radicals, the heterocycle and/or
the aliphatic hy-
drocarbon moiety may optionally comprise one or more suitable substituents,
such as those as
have been stated to be suitable for alkyl and alkane groups.
"Alkyl" 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, hexyl
and the like.
"Hydroxyalkyl" is a straight- or branched-chain alkyl radical having up to 26
carbon atoms,
which at least comprises one hydroxy group, preferably one or two hydroxy
groups.
"Alkenyl" includes straight- or branched-chain alkenyl groups with up to 26
carbon atoms, for
example vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-
methylpropenyl, 2-
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
-5-
methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl.
"Alkinyl" includes straight- or branched-chain alkinyl radicals having up to
26 carbon atoms.
Cycloalkyl preferably represents an optionally substituted C3_~-cycloalkyl;
possible substitu-
ents are e.g. alkyl, alkenyl, alkinyl, alkoxy (for example methoxy, ethoxy
etc.), halogen (for
example fluorine, chlorine, bromine etc.), vitro and the like:
Aryl is an aromatic hydrocarbon radical such as phenyl, naphthyl etc., which
may optionally
to contain one or more suitable substituents such as alkoxy (for example
methoxy, ethoxy etc.),
halogen (for example fluorine, chlorine, bromine etc.), vitro and the like.
"Aralkyl" includes mono-, di-, triphenylalkyls such as benzyl, phenethyl,
benzhydryl, trityl
and the like, wherein the aromatic part may optionally contain one or more
suitable substitu-
t5 ents such as alkoxy (for example methoxy, ethoxy etc.), halogen (for
example fluorine, chlo-
rive, bromine etc.), vitro and the like.
The radicals X2 and X3 may also be selected such, that esters form on the
phosphono group or
the phosphino group. Suitable examples of such esters according to formula (I)
are generally
2o suitable mono and diesters, for example alkylesters (for example
methylester, ethylester, pro-
pylester, isopropylester, butylester, isobutylester, hexylester etc.);
aralkyl ester (benzyl ester, phenethyl ester, benzohydryl ester, trityl ester
etc.);
aryl ester (for example phenyl ester, toluyl ester, naphthyl ester etc.);
aroylalkyl ester (for ex-
ample phenacyl ester etc.); and silylester (for example of
trialkylhalogensilyl, dialkyldihalo-
25 gensilyl, alkyltrihalogensilyl, dialkylarylhalogensilyl,
trialkoxyhalogensilyl, dialkylaralkyl-
halogensilyl, dialkoxydihalogensilyl, trialkoxyhalogensilyl etc.) and the
like.
With the above ester the alkane and/or arene part may optionally contain at
least one suitable
substituent such as halogen, alkoxy, hydroxy, vitro or the like.
As described above methyl, ethyl and phenyl esters are especially preferred.
Further, XZ and X3 may be a metal of the first, second, or third main group of
the periodic
system, ammonium, substituted ammonium, or ammonium compounds, which derive
from
ethylene diamine or amino acids. In other words the salt compounds of the
phosphorous or-
ganic compounds with organic or inorganic bases (for example sodium salt,
potassium salt,
calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine
salt, ethanola-
mine salt, dicyclohexylamine salt, ethylenediamine salt, N,N'-dibenzylethylene
diamine salt
CA 02399947 2002-08-12

CA 02399947 2002-08-12
-6-
etc.) as well as salts with amino acids (for example arginine salt, a.spartic
acid salt, glutamic
acid salt etc.) and the like are formed. The sodium salt is preferred.
The compounds according to the invention in accordance with formula (I) may be
present in
their protonized form as an ammonium salt of organic or inorganic acids, such
as hydrochlo-
ric acid, hydrobromic acid, sulfur acid, nitric acid, methanesulfonic acid, p-
toluene sulfonic
acid, acetic acid, lactic acid, malefic acid, fumaric acid, oxalic acid,
tartaric acid, benzoic acid,
etc..
The compounds according to the invention in accordance with formula (I) permit
the emer-
gence of spatial isomers for groups containing double bonds or chiral groups
Rl, R2, R3, Xl,
X2, X3 or A. The use of the compounds according to the invention includes all
spatial isomers
both as pure substances and in form of their mixtures.
In the following the preferred compounds are listed:
N-hydroxy-N- o , a
methyl-4-phosphono- ~ P~ OH
2o butyric acid amide ~ ONa
monosodium salt OH
N-hydroxy-N- / o 0
phenyl-4-phosphono- ~ ~ . P' OH
butyric acid amide ~ oi~a
monosodium salt off
N-hydroxy-N- 0 0
(2-hydroxyethyl)- HO~ P~ OH
3o 4-phosphono- ~ a~a
butyric acid amide
monosodium salt

WO01/60829 original PCT/EP0001313
N-(1-carboxypropyl)-
N-hydroxy-4-phosphono- 0 OH 0 0
butyric acid amide ~. P~ OH
s monosodium salt N ONa
OH
N-hydroxy-N- ~ N 0 ~ I I
(4-imidazolyl)-4- HN
phosphonobutyric acid
to amide monosodium salt OH
N-ethyl-N-hydroxy-4-
ethylphosphono butyric ~ ~ ~Et
N ONa
acid amide monosodium salt o ff
is
N-benzyl-N-hydroxy-4- p 0
ethylphosphono butyric acid ~ Ip
amide monosodium salt ~ oEt
~ ~ ~ ONa
OH
20 N-allyle-N-hydroxy
p 0
4-ethylphosphono-
butyric acid amide ~ ~ II
monosodium salt ~N P~ OEt
I ONa
OH
2s N-hydroxy-N-(3-
(3-phenylpropionyl)-
4-ethylphosphonobutyric p1
acid amide monosodium salt ~ oEt
ONa
0
3o N-(4-fluorobenzyl)-N- o
hydroxy-4-ethylphosphono- IPA oEt
butyric acid amide mono- I ~ \N ONa
sodium salt / OH
F
3s N-hydroxy-N-h-propyl- 0
hos hono-
4-liethylp p ~N ~ oEt
butyric acid amide oEt
OH
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
-g_
r
0 0
N-hydroxy-N- ~ ~ P~''~OEt
ortho-tolyl-4-diethyl- j OEt
phosphonobutyric acid amide OH
0
N-but-3-inyl-N-hydroxy-
4-diethylphosphono- j oEtEt
butyric acid amide OH
N-(1-carboxy-2-methyl- 0 OH
O O
to propyl)-N-hydroxy-4- II
diethylphosphono- ~ N P~ oEt
OH
butyric acid amid OEt
H
N-hydroxy-N-(2-{4-hydroxy- N~,
O O
15 indol-3-yl)-ethyl)-4-diethyl- ~ ~ ,~ iP1
phosphonobutyric acid amide ~ ~ ~E Et ,
OH
OH
N-hydroxy-N-
isopropyl-4-dimethyl- O O
2o phosphinoxido-. I (P
butyric acid amide
~OH
N-meta-ethylbenzyl- O
O
N-hydroxy-4-dimethyl- I I
25 phosphinoxido-
I
butyric acid amide ~ off
N-cyclohex-2-enyl- O
O
N-hydroxy-4-dimethyl- ~
3o phosphinoxido- N \
butyric acid amide off
N-( 1-carboxy-2-methyl- o OH
O O
butyl) N-hydroxy-4- Pt 1
35 dimethylphosphinoxido- ~ 'N \
butyric acid amide OH
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
-9-
0
N-carbamoyl-N-hydroxy- O 0
I I
4-dimethylphosphinoxido- ~ P
H.,N' -N
butyric acid amide
OH
O
N-h-butyl-N-hydroxy-4- O
II
(P-methyl-phosphinato)-
' c acid amide ~ ~ P\ off
butyri OH
1 o N-hydroxy-N-(para-
0
isopropylbenzyl)-4- 0
N P\ OH
(P-methyl-phosphinato)-
butyric acid amide I / o ff
15 N-hydroxy-N-
(4,4,4-trifluorobutyl)-4- O
I I
(P-methyl-phosphinato)- P~ OH
butyric acid amide F C~~N
~. . off
2o N-carboxymethyl N-
0
hydroxy-4-(P-methyl- - 0 OH
phosphinato)- IPA off
N
butyric acid amide
off
25 N-ethoxycarbonyl- 0 0
II
N-hydroxy-4- p~ off
(P-methyl-phosphinato)- /~'0 N
butyric acid amide OH
3o N-isobutyl-N-hydroxy- O 0
4-oxo-4- hos hono- IPA OH
p p N ~ ~ ONa
butyric acid amide mono- ~ I p
OH
sodium salt
35 N-ortho-chlorphenyl-N- /' I O 0
drox -4-oxo-4- hosphono- ' ~ IPA OH
hY Y p ~N v ~ ONa
butyric acid amide
CI OH 0
monosodium salt
CA 02399947 2002-08-12

W001/60829 original PCT/EP0001313
-10-
N-cyclohexyl-N-hydroxy-
4-oxo-4-phosphono- 0 O
butyric acid amide ~ ' P~ OH
monosodium salt ~ V ~ ONa
OH O
N-(1-carboxyethyl)-
N-hydroxy-4-oxo-4- 0 OH 0 O
phosphonobutyric acid
OH
amide monosodium salt ~ oNa
OH 0
N-hydroxy-N-(2-(N-hydroxy-
carbamoyl)-ethyl)-4-oxo-4- ~ 0 0
phosphono butyric acid amide HN~N P~ OH
I ONa
monosodium salt OH OH O
N-tert.-butyl-N-hydroxy- O Q
4-ethylphosphono- ~ p~ oEt
4-oxo-butyric acid amide ~ j1 v ~ ONa
off o
monosodium salt
ZO
OzN
N para-nitrophenyl-N- ~ ( 0 0
hydroxy-4-ethyl-phosphono- \ N P~ oEt
4-oxo-butyric acid amide ONa
OH 0
monosodium salt
O
N-(4-oxocyclohexyl)-N- O 0
hydroxy-4-ethyl-phosphono- ~'-OEt
4-oxo-butyric acid amide OH O ONa
monosodium salt
0 OH
N-(1-carboxy-1-methyl- 0 0
ethyl)-N-hydroxy-4-ethyl- P~ OEt
ONa
phosphono-4-oxo-butyric acid off
amide monosodium salt
N-(3-chloro-2,2-dimethylpropyl)- , . O
N ~ OEt
N-hydroxy-4-ethyiphosphono ~ \~ ONa
-4-oxo-butyric acid amide monosodium salt ~~ OH 0
CA 02399947 2002-08-12

W001160829 originnl PCT/EP0001313
-11-
N-hydroxy-N-n-pentyl-
o O
I I
4-diethylphosphono-4-
oxobutyric acid amide N P~ oEt
OEt
OH 0
N-hydroxy-N-(3-acetyl-
4-methoxy-phenyl)-4- O
o O
diethyl-phosphono-4-
oxo-butyric acid amide O ~ N ~ P QE Et
OH 0
1 o N-hydroxy-N-
(3-methylcyclohexyl) ~ o O
4-diethylphosphono- ~ N P~ OEt
4-oxo-butyric acid amide off o OEt
15 N-(5-amino-1-carboxy- O OH
pentyl)-N-hydroxy-4-
o Ii
diethyl-phosphono-4- N ~~ oEt
oxo-butyric acid amide o ff o oEt
NH-
2o N-hydroxy-N-(3- o O
(N-morpholino)propyl)-
~N'~N P~ OEt
4-diethyl-phosphono- I oEt
4-oxo-butyric acid amide o J OH O
O o
25 N-hydroxy-N-
isobutyl-4-dimethyl- N IP ~'
phosphono-4-oxo- OH O
butyric acid amide
3o N-beta-naphthyl- / / I O lol
N-hydroxy-4-dimethyl-
N
phosphinoxido-4-oxo- OH o
butyric acid amide
HO
35 N-(4-hydroxymethyl-2-phenyl- O O o
1,3-dioxane-4-yl)-N-hydroxy- -~ N ,
4-dimethylphosphinoxido- O
off o
4-oxo-butyric acid amide
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
- 12-
N-(1-carboxy-3-methyl- O OH
butyl)-N-hydroxy-4-
dimethyl-phosphinoxido- \ N
4-oxo-butyric acid amide off O
N-(2-furyl)-N-hydroxy-
0 (O ~
4-dimethylphosphinoxido-4=
oxo butyric acid amide
OH O
to N-(3-methyl-pentyl)-
N-hydroxy-4-(P-methyl- 0
phosphinato)-4-oxo- N P~ OH
butyric acid amide OH 0
15 N-hydroxy-N-(meta- / p O
pyridyl)-4-(P-methyl- N~ Ip pH
N
phosphinato)-4-oxo-
butyric acid amide off o
cN o
2o N-hydroxy-N-(1-cyano-
cyclohexyl)-4-(P-methyl- N p~ OH
phosphinato)-4-oxo- ~ OH 0
butyric acid amide
0 off o
0
25 N-(1-carboxy-pentyl)-
N-hydroxy-4-(P-methyl- N ~ off
phosphinato)-4-oxo- OH o
butyric acid amide
/ ~ ~0 0
3o N-(N-phenyl-carbamoyl)-
N' _N ~ OH
N-hydroxy-4-(P-methyl- H
phosphinato)-4-oxo- OH
butyric acid amide
0 O
35 N-hydroxy-N-h-octyl-3- ~~ off
oxo-4-phosphono-butyric N oNa
acid amide monosodium salt OH
CA 02399947 2002-08-12

W001/60829 original PCT/EP0001313
-13-
N-hydroxy-N-(2-indolyl)- -- 0 0 0
3-oxo-4-phosphonobutyric
acid amide monosodium salt N N P ONa
ON
N-hydroxy-N-dec-9-enyl
3-oxo-4-phosphono- 0 0 0
butyric acid amide / N p 0Na
monosodium salt
1o N-(1-carboxy-3-methyl-
O OHO O
thiopropyl)-N-hydroxy-
3-oxo-4-phosphono butyric ~ P~ OH
N
acid amide monosodium salt S ~ oNa
ON
15 N-hydroxy-N-(2,2,2-trichlor-
ethyl)-3-oxo-4-phosphono- O 0 0
P~ OH
butyric acid amide Ct3C N ONa
monosodium salt OH
2o N-decyl-N-hydroxy- 0 0 D
3-oxo-4-ethylphosphono ~ wN P~ oEt
butyric acid amide . ~ o ff ONa
monosodium salt '
25 N-(2-fluorenyl)-N- ., ~ / ~ . ~ o O
hydroxy-3-oxo-4-cthyl- ~, ~~ oEt
phosphonobutyric acid ~ ONa
amide monosodium salt OH
3 o N-( 1-adamantyl)- 0 0
N-hydroxy-3-oxo-4-ethyl- N p ONa t
phosphono-butyric acid OH
amide monosodiumsalt
p 0~ O
3s N-(1,4-dioxan-2-yl)- O N~.~/~~ OEt
ONa
N-hydroxy-3-oxo-4-
ethylphosphonobutyric 0
acid amide monosodium salt
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
- 14-
N-(N-(2,4-dimethyl-phenyl)-
carbamoyl)-N-hydroxy-3-oxo- /~ O 0 O O
4-ethylphosphonobutyric acid
amide monosodium salt ~ H N ~ OEt
OH ONa
N-(3-methyl-hex-2-yl)-
0 0 0
N-hydroxy-3-oxo-4-
II
diethylphosphono-
OEt
butyric acid amide OEt
OH
N-meta-tolyl-N-hydroxy- ~ O 0 II
3-oxo-4-diethyl
phosphonobutyric acid amide \ N P of Et
OH
N-(3-acetylaminopropyl)-
N-hydroxy-3-oxo-4- O O O o
diethylphosphono- ~N/~/~N ply OEt
butyric acid amide H oEt
OH
2o N-(2-Pyrrolidon-4-yl)-
N-hydroxy-3-oxo-4- O O O j II
diethylphosphono- ~H~N p~ OEt
butyric acid amide IOH OEt
N-(2-(methylsulfoxido)-
II o 0 0
ethyl)-N-hydroxy-3-oxo-
4-diethylphosphono- ~ ~N P ~E Et
I
butyric acid amide OH
3o N-dodecyl-N-hydroxy- 0 O O
3-oxo-4-dimethyl p
N
phosphinoxido- I
butyric acid amide OH
HO
N para-hydroxyphenyl- ~ 0 O 0
I I
N-hydroxy-3-oxo-4- '~ ~ N P
dimethylphosphinoxido- I
butyric acid amide OH
CA 02399947 2002-08-12

W001160829 original PCT/EP0001313
-15-
N-(2-propionylethyl)- O 0
N-hydroxy-3-oxo-4- 0~/~,
N
dimethylphosphinoxido- ~ off
0
butyric acid amide
HO O OH
N-(1-carboxy-2-(3,4- 0 O ~I
dihydroxyphenyl)-ethyl)-
HO 'N
N-hydroxy-3-oxo-4-dimethyl- off
to phosphinoxido-butyric acid amide
O 0 0
N-(3-phosphonopropyl)- Hp ~ f II
P
N-hydroxy-3-oxo-4-dimethyl- II~ I
phosphinoxido-butyric acid amide O OH
15 monosodium salt
N-(3-ethyl-4-methyl-pentyl)- 0 O II
N-hydroxy-3-oxo-4- N P~ OH
(P-methyl-phosphinato)- ~ off
2o butyric acid amide
N-(3-hydroxy-3-phenyl- ' - OH 0 0 0
ro yl)-N-hydroxy-3-oxo- I N IPA OH
P P
4-(P-methyl-phosphinato)- ~ off
25 butyric acid amide
O 0 0
N-(2-(2-methoxy-ethoxy)- P~ off
ethyl)-N-hydroxy-3-oxo- ~0~0
4-(P-methyl-phosphinato)- OH
3o butyric acid amide
II
N-(4-imidazolyl-methyl)- N N P~ OH
N-hydroxy-3-oxo-4-
(P-methyl-phosphinato)- N OH
H
35 butyric acid amide
CA 02399947 2002-08-12

CA 02399947 2002-08-12
I6
o ! 0 0 0
p\ OH
OH
o
,....-,
N-(2-(7-(2-(N,N-diethylamino)-ethoxy)-fluorene-9-on-2-yloxy)-ethyl)-N-hydroxy-
3-oxo-4-
(P-methyl-phosphinato)-butyric acid amide.
Further preferred compounds are listed in the examples.
The compound N-hydroxy-N-methyl-4-phosphonobutyric acid amide monosodium salt
is
especially preferred.
The phosphorous organic compounds are in particular suited for the therapeutic
and prophy-
lactic treatment of infections in humans and animals caused by viruses,
bacteria, unicellular
and multicellular parasites and fungi. According to the invention unicellular
parasites are
protozoa according to the narrow definition of parasitology.
2o The compounds are effective against unicellular parasites (protozoa), in
parkicular against
pathogens of malaria and the sleeping sickness as well as Chagas' disease,
toxoplasmosis,
amoebic dysentery, leishmaniasis, trichomoniasis, sarcocystosis,
acanthamebiasis, naegleria-
sis, coccidiosis, giardiasis and Iambliosis.
Therefore, they are particularly suitable as malaria prophylactics and as
prophylactics of
sleeping sickness as well as the Chagas' disease, toxoplasmosis, amoebic
dysentery, Ieishma-
niasis, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiasis,
sarcocystosis, acan-
thamebiasis, naegleriasis, coccidiosis, giardiasis and lambliosis.
3o The active agents according to the invention may in particular be used
against the following
bacteria:
Bacteria of the family Propionibacteriaceae, in particular the genus
Propionibacterium, in
particular the 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

WO01/60829 origi~tal PCT/EP0001313
-17-
leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium
avium; bacte-
ria of the family Chlamydiaceae, in particular the species Chlamydia
trachomatis and Chla-
mydia psittaci; bacteria of the genus Listeria, in particular the species
Listeria monocytoge-
nes; bacteria of the species Erysipelthrix rhusiopathiae; bacteria of the
genus Clostridium;
bacteria of the genus Yersinia, the species Yersinia pestis, Yersinia
pseudotuberculosis, Yer-
sinia enterocolitica and Yersinia ruckeri; bacteria of the family
Mycoplasmataceae, the genus
Mycoplasma and Ureaplasma, in particulax the species Mycoplasma pneumoniae;
bacteria of
the genus Brucella; bacteria of the genus Bordetella; bacteria of the family
Neiseriaceae, in
particular the genuses Neisseria and Moraxella, in particular the species
Neisseria meningiti-
des, Neisseria gonorrhoeae and Moraxella bovis; bacteria of the family
Vibrionaceae, in par-
ticular the genuses Vibrio, Aeromonas, Plesiomonas and Photobacterium, in
particular the
species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas;
bacteria of the
genus Campylobacter, in particular the species Campylobacter jejuni,
Campylobacter coli and
Campylobacter fetus; bacteria of the genus Helicobacter, in particular the
species Helicobac-
ter pylori; bacteria of the families Spirochaetaceae and the Leptospiraceae,
in particular the
genus 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 genus
Nocardia and Rho-
dococcus; bacteria of the genus Dermatophilus; bacteria of the family
Pseudomonadaceae, in
2o particular the genuses Pseudomonas and Xanthomonas; bacteria of the family
Enterobacteria-
ceae, in particular the genuses Escherichia; Klebsiella, Proteus, Providencia,
Salmonella, Ser-
ratia and Shigella; bacteria of the family Pasteurellaceae, in particular the
genus Haemophilus;
bacteria of the family Micrococcaceae, in particular the genus Micrococcus and
Staphylococ-
cus; bacteria of the family Streptococcaceae, in particular the genus
Streptococcus and Ente-
rococcus and bacteria of the family Bacillaceae, in particular the genus
bacillus and clostrid-
gum.
Therefore the phosphorous organic compounds are suitable for treatment of
diphtheria, acne
vulgaris, listeriosis, erysipelas in animals, gas gangrene in humans and in
animals, diseases in
3o hlunans and animals caused by clostridium septicum, tuberculosis in humans
and animals,
leprosy, and further mycobacteriosis in humans and animals, paratuberculosis
in animals,
pestis, mesenterial lymphadenitis and pseudotuberkulosis in humans and
animals, cholera,
legionnaires disease, borrelioses in humans and animals, leptospiroses in
humans and animals,
syphilis, campylobacter enteritides in humans and animals, moraxella
keratoconjunctivitis and
serositis in animals, brucelloses in animals and in humans, anthrax in humans
and animals,
actinomycosis in humans and animals, streptotrichosis, psittakosis/ornithosis
in animals, Q-
fever, ehrlichiosis.
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WO01/60829 original PCT/EP0001313
-18-
Further, the use is advantageous in helicobacter eradication therapy of ulcera
of the gastroin-
testinal tract.
Further combinations with an additional antibiotic may also be used for
treatment of the
above mentioned diseases. As combined preparations with other antiinfective
agents in par-
ticular isoniazide, rifarnpicin, ethambutol; pyrazinamide, streptomycin,
protionamide and
dapsone are suitable for the treatment of tuberculosis
The active agents according to the present invention may furthermore be used
in particular in
to infections with following viruses:
Parvoviridae: parvo viruses, dependo viruses, Denso viruses; Adenoviridae:
adeno viruses,
mastadeno viruses, aviadeno viruses; Papovaviridae: papova viruses, in
particular papilloma
viruses (so called wart viruses), Polyoma viruses, in particular JC virus, BK
virus, and miopa-
pova viruses; herpes viruses: all herpes viruses, in particular herpes simplex
viruses, the
i5 varizella-zoster viruses, human cytomegalo virus, Epstein-Barr viruses, all
human herpes vi-
ruses, human herpes virus 6, human herpes virus 7, human herpes virus 8;
Poxviridae: pox
viruses, orthopox, parapox, molluscum contagiosum virus, avipox viruses,
capripox viruses,
leporipox viruses; all primary hepatotropic viruses, Hepatitis viruses:
hepatitis A viruses, . '
hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E
viruses, hepatitis F vi-
2o ruses, hepatitis G viruses; Hepadna viruses: all hepatitis viruses,
hepatitis B virus, hepatitis D
viruses; Picornaviridae: picorna viruses, all entero viruses, all polio
viruses, alI coxsackie vi-
ruses, all echo viruses, all rhino viruses, hepatitis A virus, aphtho viruses;
Calciviridae: hepa-
titis E viruses; Reoviridae: reo viruses, orbi viruses, rots viruses;
Togaviridae: toga viruses,
alpha viruses, rubi viruses, pesti viruses, rubella virus; Flaviviridae: flavi
viruses, ESME vi-
25 rus, hepatitis-C-Virus; Orthomyxoviridae: all influenza viruses;
Paramyxoviridae: paramyxo
viruses, morbilli virus, pneumo virus, measles virus, mumps virus;
Rhabdoviridae: rhabdo
viruses, rabies virus, lyssa virus, viscula stomatitis virus; Corona. viridae:
corona viruses;
Bunyaviridae: bunya viruses, nairo virus, phlebo virus, uuku virus, hanta
virus; Arenaviridae:
arena viruses, lymphocytic choriomeningitis-virus; Retroviridae: retro
viruses, all HTL vi-
3o ruses, human T-cell leukaemia virus, oncorna viruses, spuma viruses, lenti
viruses, all HI-
viruses; Filoviridae: Marburg and Ebola virus; Slow-virus-infections, priors;
Onco viruses,
leukemia viruses.
The phosphororganic compounds according to the invention are therefore
suitable for fighting
35 the following viral infections:
Eradication of papilloma viruses to prevent tumors, in particular tumors in
the sexual organs
caused by papilloma viruses in humans, eradication of JC viruses and BK
viruses, eradication
of herpes viruses, eradication of human herpes viruses 8 for the treatment of
Kaposi' s sar-
CA 02399947 2002-08-12

W001/60829 original PCTlEP0001313
- 19-
coma, eradication of cytomegalo viruses before transplants, eradication of
Eppstein-Barr vi-
ruses before transplants and to prevent tumors associated with Eppstein-Barr
viruses, eradica-
tion of hepatitis viruses for the treatment of chronic liver diseases and for
the prevention of
tumors of the liver and cirrhosis of the liver, eradication of coxsackie
viruses patients with
cardiomyopathy, eradication of coxsackie viruses in diabetes mellitus
patients, eradication of
immune system debilitating viruses in humans and animals, treatment of
secondary infections
in AIDS-patients, treatment of inflammations of viral origin of the
respiratory tract (larynx
papillomas, hyberplasias, rhinitis, pharyngitis, bronchitis, pneumonias), of
the sensory organs
(Keratoconjunctivitis), of the nervous system (poliomyelitis,
meningoenzephalitis, encephali-
to tis, subacute sklerosing panencephalitis SSPE, progressive multifocal
leukoencephalopathie,
lymphocytic choriomeningitis), of the gastro-intestinal tract (stomatitis,
gingivostomatitis,
oesophagitis, gastritis, gastroenteritis, diarrhoea-causing diseases), the
liver and the gall blad-
der system (hepatitis, cholangitis, hepatocellular carcinoma), of the
lymphatic tissue (mono-
nucleosis, Iymphadenitis), of the haematopoetic system, of the sexual organs
(mumpsorchitis),
of the skin (warts, dermatitis, herpes labialis, heat rush, herpes zoster,
shingles), of the mu-
cons membranes (papillomas, conjunctiva papillomas, hyperplasias, dysplasias),
of the
heart/blood vessel system (arteriitis, myocarditis, endocarditis,
pericarditis), the kid-
ney/urinary tract systems, of the sexual organs (anogenital lesions, warts,
genital warts, acute
condylomas, displasias, papillomas, cervix dysplasias, condylomata acuminata,
epidermodys-
2o plasia verruci formis), of the organs of motion (myositis, myalgien),
treatment of foot and
mouth diseases in cloven-hoofed animals, of Colorado tick fever; of Dengue-
syndrome, of
haemorrhagic fever, of early summer meningoencephalitis (FSME) and of yellow
fever.
The described compounds, i.e. the phosphorous organic compounds according to
formula (I)-
and esters and amides thereof formed on the phosphono group or the phosphino
group as well
as salts thereof show a strong cytotoxic efficacy against bacteria, fungi,
viruses, unicellular
and multicellular parasites. Therefore the compounds according to the
invention are usable in
the treatment of infectious diseases caused by viruses, bacteria, parasites,
and fungi in humans
and animals. The compounds also are suited for use in prophylactics of
diseases due to vi-
3o ruses, bacteria, parasites; and fungi, in particular in prophylactics of
malaria and in prophy-
Iactics of the sleeping sickness.
The phosphorous organic compounds according to the invention which generally
include
pharmaceutically acceptable salts, amides, esters, a salt of such an esters or
else compounds
which upon application provide the compounds use according to the invention
metabolic
products or decomposition products, also called "prodrugs" may all be prepared
for admini-
stration Like known anti-infectious agents in any suitable manner (mixed with
non-toxic
pharmaceutically acceptable carriers).
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WO01/60829 original PCT/EP0001313
-20-
Pharmaceutically acceptable salts of the aminohydrophosphonic acid derivative
include salts,
which form the compounds of formula (I) in their protonised form as an
ammonium salt of
inorganic or organic acids, such as hydrochloric acid, sulfur acid, citric
acid, malefic acid, fu-
maric acid, tartaric acid, p-toluene sulfonic acid.
Salts which are formed by suitable selection of X2 and X3 are especially
suited, such as so-
dium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt,
triethylamine salt,
dicyclohexylamine salt and salts of amino acid such as arginine salt, aspartic
acid salt, glu-
tamic acid salt.
The pharmaceutically effective preparations may be prepared in the form of
pharmaceutical
preparations in dispensing units. This means that the preparations can be
present in the form
of individual parts, for example tablets, dragees, capsules, pills,
suppositories and ampoules,
the active ingredient content of which corresponds to a fraction or a multiple
of a single dose.
The dispensing units can, for example, contain 1, 2, or 4 single doses or i/2,
1/3 or 1/4 of a sin-
gle dose. A single dose preferably contains the quantity of active ingredient
which is admin-
istered during one application and which usually corresponds to a whole, a
half or third of a.
quarter of a daily dose.
Non-toxic, inert pharmaceutically suitable carriers are understood to mean
solid, semi-solid or
liquid diluents, fillers and formulation auxiliary agents of all kinds.
Tablets, dragees, capsules, pills, granules, suppositories, solutions,
suspensions and emul-
sions, pastes, ointments, gels, creams, lotions, powders and sprays axe
mentioned as preferred
pharmaceutical preparations. Tablets, dragees, capsules, pills and granules
may contain in
addition to the conventional excipients the active ingredient, such as (a)
fillers and diluents,
for example starches, lactose, cane sugar, glucose, mannitol and silicic acid,
(b) binders, for
example carboxymethylcellulosis, alginate, gelatine, polyvinylpyrrolidone, (c)
moisture-
3o retaining agents, for example glycerol, (d) dispersing agents, for example
agar-agar, calcium
carbonate and sodium carbonate, (e) solution retarders, for example paraffin
and (f) resorption
accelerators, for example quaternary ammonium compounds, (g) wetting agents,
for example
cetyl alcohol, glycerol monostearate, (h) adsorption agents, e.g. kaolin and
betonite and (i)
lubricants, for example talcum, calcium and magnesium stearate and solid
polyethylene gly-
col or mixtures of the substances listed under (a) to (i).
The tablets, dragees, capsules, pills and granules may be provided with the
conventional
coatings and casings optionally comprising opaquing agents and may also be put
together so
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
-21 -
that they release the active ingredient or active ingredients only or
preferably in a specific part
of the intestinal optionally with sustain release, wherein polymer substances
and waxes for
example may be used as embedding compounds.
The active ingredient or the active ingredients may optionally also be present
in microencap-
sulated form with one or more of the above mentioned excipients.
In addition to the active ingredient or the active ingredients suppositories
may also contain the
conventional water soluble or water insoluble excipients, for example
polyethylene glycols,
1 o fats, for example cacoa fat and higher esters (for example C 14- alcohol
with C 16-fatty acid) or
mixtures of these substances.
In addition to the active ingredients ointments, pastes, creams and gels may
contain the con-
ventional excipients, for example animal and vegetable fats, waxes, paraffins,
starch, traga-
15 canth, cellulose derivative, polyethylene glycols, silicones, bentonites,
silicic acid, talcum and
zinc oxide or mixtures of these substances.
In addition to the active ingredients powders and sprays may contain the
conventional excipi-
ents, for example lactose, talcum, silicic acid, aluminium hydroxide, calcium
silicate and
2o polyamide powder or mixtures of these substances. Sprays may additionally
contain the con-
ventional blowing agents, for example chlorofluorohydrocarbons.
In addition to the active ingredients solutions and emulsions may contain the
conventional
excipients such as solvents, solubilisers and emulgators, for example water,
ethyl alcohol,
25 isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propyle-
neglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular cotton
seed oil, peanut
oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol
formal, tetrahydrofurfuryl
alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of
these substances.
3o The solutions and emulsions may also be present in sterile and blood
isotonic form for paren-
teral application.
In addition to the active ingredients suspensions may contain conventional
excipients such as
liquid diluents, for example water, ethyl alcohol, propylene glycol,
suspending agents, for
35 example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters, micro-
crystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and
tragacanth or mix-
tures of these substances.
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
-22-
The above-mentioned formulations can also contain dyes, preservatives and
odour and flavour
improving additives, for example peppermint oil and eucalyptus oil and
sweeteners, for ex-
ample saccharine.
The active agents of formula (I) should be present in the above listed
pharmaceutical prepara-
tions preferably in a concentration of approximately 0.1 to 99.5 % by weight,
preferably of
approximately 0.5 to 95 % by weight of the total mixture.
In addition to the compounds of formula (I) the pharmaceutical preparations
may also contain
1o further pharmaceutical agents.
Furthermore the phosphorous organic compounds may be present in the
pharmaceutical
preparations in combination with sulfonamide, sulfadoxin, artemisinin,
atovaquon, chinin,
chloroquine, hydroxychloroquine, mefloquin, halofantrin, pyrimethamine,
armesin, tetracy-
15 cline, doxycyclin, proguanil, metronidazol, praziquantil, niclosamide,
mebendazol, pyrantel,
tiabendazole, diethylcarbazin, piperazin, pyrivinum, metrifonate, oxamniquin,
bithionol or
suramin or several of these substances.
The above listed pharmaceutical preparations are produced in the conventional
manner by
2o known methods, for example by mixing the active ingredient or active
ingredients with the
excipient or excipients.
The above-mentioned preparations can be used in humans and animals either
orally, rectally,
parentally, (intravenously, intramuscularly, subcutaneously),
intracisternally, intravaginally,
25 intraperitoneally, topically (powder, ointment, drops) and for the
treatment of infections in
cavities, orifices. Suitable preparations axe injection solutions, solutions
and suspensions for
oral treatment, gels, infusions, emulsions, ointments or drops.
Ophthalmological and derma-
togical formulations, silver and other salts, eardrops, eye ointments, powders
or solutions can
be used for topical treatment. With animals the absorption can occur via the
food or drinking
3o water in suitable formulations. Furthermore gels, powders, tablets, sustain
release tablets,
premixes, concentrates, granules, pellets, tablets, boli, capsules, aerosoles,
sprays, inhalers
can be used with humans and animals. The compounds according to the invention
can fur-
thermore be incorporated into other carrier materials such as, for example,
plastic materials
(plastic chains for topical treatment), collagen or bone cement.
In general it has proved advantageous both in human and veterinary medicine to
administer
the active ingredient or ingredients of formula (I) in total quantities of
approximately 0.05 to
approximately 600, preferably 0.5 to 200 mg/kg body weight per 24 hours,
optionally in the
CA 02399947 2002-08-12

WO01l60829 original PCT/EP0001313
- 23 -
form of several individual doses in order to achieve the desired results. An
individual dose
contains the active ingredient or ingredients preferably in quantities of
approximately 1 to
approximately 200, in particular 1 to 60 mg/kg body weight. It may, however,
be necessary to
deviate from the above-mentioned dosages and this is dependent on the nature
and the body
weight of the patient to be treated, the nature and the severity of the
disease, the nature and
the method and the application of the pharmaceutical compositions as well as
the time scale
or interval within the administration takes place.
Thus in some cases it may be su~cient to get by with less than the above
mentioned quantity
to of active ingredient, whilst in other cases the above-stated quantity of
active ingredient must
be exceeded. The person skilled in the art may determine the optimum dosage
and method of
application of the active ingredient in each case by virtue of his expert
experience.
The compounds according to the invention may be administered in animals in the
conven-
15 tional concentrations and preparations together with the feed or feed
preparations or the
drinking water.
Furthermore compounds according to the invention may be excellently used as
bactericides,
fungicides and herbicides in plants. The compounds according to the invention
especially
2o show good herbicidal activity. Consequently the invention also concerns a
method for con-
trolling undesired plant growth in cultivation of useful plants, wherein their
area under culti-
vation is treated with an active amount of a compound according to the
invention of formula
(I) or an agent containing such a derivative.
25 The activity of substances is determined in a test system. This system is
based on the meas-
uring of the inhibition of growth of bacteria, parasites, viruses, fungi or
plants in vitro. To this
end, test procedures are used, some of which are known to the person skilled
in the .art. To
determine the anti-malaria activity, for example, the inhibition of the growth
of malaria para-
sites in blood cultures is determined. The determining of the anti-bacterial
activity, fox exam-
3o ple is based on the measurement of the inhibition of the growth of bacteria
on culture media
and in liquid cultures. The determining of the anti-viral activity is based on
the inhibition of
the formation of viral elements in cell cultures. The determining of
fungicidal activity is based
on the inhibition of the growth of fungi on culture media and in liquid
cultures. Some of the
micro-organism which should be investigated can only be investigated in animal
models. In
35 this case we will use the corresponding model.
Substances which demonstrate an efficacy in the in vitro measuring system will
be further
investigated in in vivo models. The anti-parasitic, antiviral or fungicide
activity will be further
CA 02399947 2002-08-12

CA 02399947 2002-08-12
-24-
evaluated in the appropriate animal model.
The screening of herbicidal activity is determined by algae systems and
measurement of the
isoprene emission of plants at standard conditions.
Principally a person skilled in the art knows which way of synthesis for
preparing the sub-
stances according to the invention he has to choose. In the following some
ways of synthesis
1 o for compounds of the invention are given by example.
Example 1
N-Hvdroxy-4-(diethvlnhosphonol-butyric acid amide (la)
2.52 g (10 mmol) of 4-phosphonobutyric acid triethyl ester are dissolved in 20
ml of water-
~5 free methanol. A solution of 11 mmol of hydroxylamine in water-free
methanol (filtered from
765 mg (11 mmol) of hydroxylamine hydrochloride and 253 mg (11 mmol) of sodium
in
methanol) is added dropwise at 0°C. 10 mmol of sodium methanolate (from
230 mg (10
mmol) of sodium) in water-free methanol are added to the resulting mixture at
0°C. It is
stirred at room temperature over night. Subsequently, the mixture is filtered,
the residue on
2o the filter is taken up in little water, HCl is added until weak acid
reaction is observed and is
allowed to stand over a period of three weeks. N-hydroxy-4-(diethylphosphono}-
butyric acid
amide (la) is obtained as colorless crystals and in riloderate yield.
Example 2
25 N-Hvdroxx-N-methyl-4-(dieth~phosphonol-butyric acid amide (2a)
In a procedure corresponding to example 1, wherein N-methylhydroxylamine is
used instead
of hydroxylamine N-hydroxy-N-methyl-4-(diethylphosphono)-butyric acid amide
(2a) is ob-
tained as colorless crystals and in moderate yield.

CA 02399947 2002-08-12
-25-
Example 4
N-Hvdroxy-N-meth~phosphonobutyric acid amide {2b)
3.06 g (20 mmol) trixnethylbromsilan are added dropwise to a solution of 5
mmol of N-
s hydroxy-N-methyl-4-(diethylphosphono)-butyric acid amide (2a) in 50 ml of
dry acetonitrile
cooled to 0°C. It is stirred at room temperature for 3 hours.
Subsequently, the solvent is
stripped out in vacuum and the residue is taken up in 20 ml of iced water. The
mixture is
stirred for 1 hour at room temperature and is extracted twice with 20 ml of
ether, respectively.
A pH value of 4.5 is adjusted with 2 M NaOH. Subsequently, water is stripped
out under vac-
lo uum at 50°C maximum in a Rotavapor rotary evaporator. The solid
residue is crystallized
from methanol/ethyl acetate. N-hydroxy-N-methyl-4-phosphonobutyric acid amide
(2b) is
obtained in the form of colorless crystals and in medium yield.
Example 5
15 4-!Diethyl phosphono -~ ~-hvdroxvacetoacetic acid amide (3a! (or N-h~xv-3-
oxo-4-
ldieth,~Tlphosphono,Ltvric acid amide!
2.78 g (1 Ommol) of 4-diethyl phosphonomethyl-2,2-dimethyl-1,3-dioxene-4-one
(prepared
according to Org. Synth. Coll. Vol. VIII, 192-196) is introduced in a pressure
vessel. A solu-
tion of 11 mmol hydroxylamine (filtered from 765 mg (11 mmol) hydroxylamine
hydrochlo-
2o ride and 253 mg (11 mmol) sodium in methanol) in water-free methanol is
added dropwise at
0°C. 10 mmol of sodium methanolate {from 230 mg (10 mmol) of sodium in
water-free
methanol) is added to the resulting mixture at 0°C. The vessel is
closed and the mixture is
heated to 60-70°C over a period of 2 hours. After cooling the produced
precipitate is filtered.
The residue on the filter is taken up in little water, HCl is added until weak
acid reaction and
25 allowed to stand in a refrigerator over night. 4-(Diethyl phosphono)-N-
hydroxyacetoacetic
acid amide (3a) is obtained in the form of colorless crystals and in moderate
yield.
Example 6
~Dieth, l~~nhosphonol-N-h~droxy N-methXlacetoacetic acid amide f4a~or N-
hvdroxy-N-
30 methyl-3-oxo-4.-ldieth~phosphonoy-butyric acid amide)
According to the procedure corresponding to example 5 wherein N-
methylhydroxylamine
instead of hydroxylamine is used 4-(diethyl phosphono)-N-hydroxy-N-
methylacetessig acid
amide (4a) is obtained as colorless crystals and at moderate yield.

CA 02399947 2002-08-12
-25a-
Example 7
N-H~v-4-phosnhonoacetoacetic acid amide l3bl for N-h~v-3-oxo-4-phosphono-
butyric acid amidel
3.06 g (20 mmol) trimethyl bromosilane is added to a solution of 1.27 g (5
mmol) of 4-
(Diethylphosphono)-N-hydroxy acetoacetic acid amide (3a) in 50 ml dry
acetonitrile cooled
to 0°C. It is stirred at room temperature for 3 hours. Then the solvent
is stripped off in vac-
uum and the residue is taken up in 20 ml of iced water. The mixture is stirred
at room tem-
perature for 1 hour and extracted twice with 20 ml ether respectively. A pH
value of 4.5 is
1o adjusted with 2 M NaOH. Then water is stripped out under vacuum at
50°C maximum in a
Rotavapor rotary evaporator. The solid residue is crystallized from
methanol/ethyl acetate. N-

CA 02399947 2002-08-12
-26-
hydroxy-4-phosphonoacetoacetic acid amide (3b) is obtained in the form of a
colorless pow-
der at good yield.
Example 8
N-Hvdroxy-N-methyl-4-phosphonoacetoacetic acid amide (4bl~or N-hvdroxv-N-
methyl-3-
oxo-4-phosphonobutyric acid amidel
According to a procedure corresponding to example 7 starting from 4-
(diethylphosphono)-N-
hydroxy-N-methylacetoacetic acid amide (4a) N-hydroxy-N-methyl-4-
phosphonoacetoacetic
1 o acid amide (4b) is obtained in the form of colorless crystals and in
medium yield.
In the following the activities of different compounds according to the
invention compounds
are stated as examples:
The following substances have been tested:
15 substance 2: N-hydroxy-N-methyl-4-phosphonobutyric acid amide monosodium
salt
substance 3: N-hydroxy-N-phenyl-4-phosphonobutyric acid amide monosodium salt
substance 4: N-hydroxy-4-(P-methyl-phosphinato)butyric acid amide monosodium
salt
substance 5: N-hydroxy-N-methyl-3-oxo-4-(P-methyl-phosphinato)butyric acid
amide mono-
sodium salt
2o substance 6: N-hydroxy-3-oxo-4-(P-methyl-phosphinato)butyric acid amide
monosodium salt
substance 7: N-hydroxy-N-methyl-3-oxo-4-phosphonobutyric acid amide monosodium
salt
substance $: N-hydroxy-3-oxo-4-phosphonobutyric acid amide monosodium salt
substance 9: N-hydroxy-4-diphenyl phosphonobutyric acid amide
substance 10: N-hydroxy-N-phenyl-4-diphenyl phosphonobutyric acid amide
25 substance 11: N-hydroxy-N-benzyl-4-phosphonobutyric acid amide monosodium
salt
substance 12: N-hydroxy-N-benzyl-3-oxo-4-dimethyl phosphonobutyric acid amide
Experiments show that the activity of the compounds in bacteria, parasites,
fungi and plants is
based on an inhibition of the 1-deoxy-D-xylulose-5-phosphate-(DOXP)-metabolic
pathway
3o which is present in these organisms, however, which could not have been
proved for humans.
Thus, the following example shows the activity of the compounds according to
the invention
on DOXP-reductoisomerase.
Example 9
35 Inhibition of enzyme DOXP-reductoisomerase from Escherichia coli and
Helicobacter pylori
DOXP-reductoisomerase of Escherichia coli has been exprimed as recombinant
protein in
E.coli. The activity of DOXP-reductoisomerase was determined in a composition
containing
I 00 mM of Tris-HCl (pH=7.5), 1 mM of MnCl2, 0.3 mM of NADPH and 1 mM of DOXP.

CA 02399947 2002-08-12
-27-
The oxidation has been measured in a spectrophotometer at 365 nm. For
performing the
studies of inhibition the activity of DOXP-reductoisomerase in presence of the
compounds 1
and 2 was measured in different concentrations between 0.1 nmol 1-1 and 100
pmol hl. The
concentration was determined from the measured values, at which the enzyme was
half
maximally inhibited (ICso). In like manner the activity of DOXP
reductoisomerase of Helico-
bacter pylori has been determined. The results, i.e. IC50-values are listed in
table I.
l0 Table I
substance no. Escherichia coli Helicobacter pylori
IC50 (nM) ' IC50 nlV~
2 17 10
Ezample 10
Inhibition of growth of bacteria species Pseudomonas aeruginosa and
Escherichia coli
Antibacterial activity of the above stated compounds
A dilution series comprising the concentrations 32, 16, 8, 4, 2, 1 and 0 mg
1'1 of the individual
compounds 2 to 8 and 11 and 12 in LB-medium is introduced into culture
microtubes in a
volume of 0.5 ml. Each of the tubes was inoculated with 10 ~1 of an overnight
culture of E.
2o coli Kl2 and shaken overnight at 37°C. Bacterial growth was accessed
on the basis of turbid-
ity of the mediums. The results are listed in Table II.
Antibacterial activity with regard to P. aeruginosa was determined in the same
manner. The
results are also listed in Table II.

CA 02399947 2002-08-12
-28-
Table II
substance no. Escherichia coli Pseudomonas aeruginosa
MIC (mg/1) MIC (m )
2 4 4
3 1 1
4 8 1
2 16
6 16 8
7 1 4
g 1 1
11 2 1
12 16 4
Ezample 11
Inhibition of Plasmodium falciparum growth causative organism of malaria
tropica)
The antimalarial activity of substances 2 to 12 was determined using in vitro
cultures of the
causative organism of malaria Plasmodium falciparum. 200 ~.l of a asynchronous
Plasmodium
falciparum culture with a 0.4 % parasitemia and 2 % haematocrit were loaded
into each of the
wells of a 96 well microtitre plate. A serial dilution series of the compounds
was then pre-
pared in steps of three between concentrations of 100 ~.mol fI and 0.14 nmol
f1. The plates
are incubated at 3.7°C, 3 % COZ and 5 % 02 over a period of 48 hours.
30 ~,1 of medium sup-
plemented with 27 ~Ci m11 [3H]-hypoxanthine were then added to each well.
After 24 hours'
incubation, the parasites were harvested by filtration through glass fiber
filters and the incor-
porated radioactivity was measured. Inhibition of parasite growth was measured
as the per-
centage inhibition of tritium incorporation relative to a comparison without
substance. The
half maximum inhibition concentration (IC50) of the substance has been
determined by ex-
trapolation of the values. The results are listed in Table III.

CA 02399947 2002-08-12
-29-
able III
substance no. Plasmodium falcipaYUm
IC50 (nlV1)
2 114
3 405
4 175
340
6 587
7 600
8 570
9 100
400
11 154
12 480
The inhibition of growth of the different plants is stated in the following
tables as percentage.
The pictures of damages mean:
C: chlorosis - In dicot plants brightening of the subsequent leafs
(degradation of chlorophyll
10 = white coloring of the leafs, whereby the growth is totally inhibited).
In monocot plants the picture of damage is not quite as remarkable as in dicot
plants. The brightening is only present in the shoot tips.
I: general white coloring of leafs.

W 001/60$29 original PCT/EP0001313
- 30 -
Ezample 13
Herbicidal activity of monosodium salt of 4~hosphono-N-h~droxy-N-meth~but~ric
acid
amide
The herbicidal activity is tested as in example 12, however with N-4-phosphono-
N-hydroxy-
N-methylbutyric acid amide monosodium salt as the active ingredient. The
results are listed in
tables VII to IX.
Table VII
to
HYDRO ire-emergence
used amount of tested substance: 4000 g/ha
species of plant visual bonitur: damage/ picture of damage
inhibition of
the plants in comparison
to the non-
treated control
(%)
rice 20 I
Lepidium ~ 30 C
Eschinochios 0
Solanum 0
CA 02399947 2002-08-12

W001160$29 original PCT/EP0001313
- 31 -
Table VIII
EARTH_pre-emergence
nenr~ amnn7lt of tPCtPI~ substance: 2000 gJha
species of plant visual bonitos: damage/ picture of damage
inhibition of
plants on comparison to
the non treated
control
%)
maize (zea ma s) 0
sugar beet (beta vul 30
aris)
slender foxtail 0
(alopecurus m osuroides)
wild oats (avena atua) 0
yellow nutsedge #
(cy erus esculentus
green foxtail (setaYia 0
viridis)
velvet leaf (abutilon 0
then hrasti)
redroot amaranth (amaranthus0
retr-of lexus)
cleavers ( alium a Brine)
wild mustard (sina is 50
arvensis)
common cockleburs (xanthium0
strumarium)
CA 02399947 2002-08-12

WO01/60829 original PCT/EP0001313
- 32 -
Table IX
EARTH post-emergence
used amount of tested substance: 2000 ~/ha
visual bonitur: damage/ picture of
inhibition damage
of plants on comparison
to the non
treated control
(%)
maize (zea mays) 70 C
sugar beet (beta vulgaris)50
slender foxtail 70 C
(alo ecurus myosuroides)
wild oats avena atua) 70 C
yellow nutsedge #
(cy eras esculentus)
green foxtail (setaria 95 C
viridis)
velvet leaf (abutilon ~ 30 C
theo hrasti)
redroot amaranth (amaranthus0
ret
roflexus)
cleavers ( alium a Brine)70 C
wild mustard (sina is 90 C
arvensis)
common cockleburr (xanthium50 C
strumarium)
CA 02399947 2002-08-12

Dessin représentatif