U.S. patent application number 13/159027 was filed with the patent office on 2011-12-15 for use of organophosphorus compounds for the therapeutic and prophylactic treatment of infections.
This patent application is currently assigned to BioAgency AG. Invention is credited to Hassan Jomaa.
Application Number | 20110306578 13/159027 |
Document ID | / |
Family ID | 27438787 |
Filed Date | 2011-12-15 |
United States Patent
Application |
20110306578 |
Kind Code |
A1 |
Jomaa; Hassan |
December 15, 2011 |
USE OF ORGANOPHOSPHORUS COMPOUNDS FOR THE THERAPEUTIC AND
PROPHYLACTIC TREATMENT OF INFECTIONS
Abstract
Use of organophosphorus compounds of general Formula (I)
##STR00001## for the therapeutic and prophylactic treatment of
infections in humans and animals caused by viruses, fungi and
parasites.
Inventors: |
Jomaa; Hassan; (Giessen,
DE) |
Assignee: |
BioAgency AG
|
Family ID: |
27438787 |
Appl. No.: |
13/159027 |
Filed: |
June 13, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10676131 |
Oct 2, 2003 |
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13159027 |
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09673561 |
Dec 8, 2000 |
6680308 |
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PCT/EP99/02462 |
Apr 13, 1999 |
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10676131 |
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Current U.S.
Class: |
514/119 |
Current CPC
Class: |
A61P 31/00 20180101;
Y02A 50/491 20180101; Y02A 50/409 20180101; Y02A 50/467 20180101;
Y02A 50/406 20180101; Y02A 50/397 20180101; A61K 31/662 20130101;
A61P 31/12 20180101; Y02A 50/30 20180101; A61P 33/06 20180101; A61P
33/02 20180101; Y02A 50/465 20180101; A61K 31/66 20130101; A61P
31/04 20180101; Y02A 50/414 20180101; Y02A 50/463 20180101; Y02A
50/415 20180101; Y02A 50/411 20180101 |
Class at
Publication: |
514/119 |
International
Class: |
A61K 31/662 20060101
A61K031/662; A61P 33/06 20060101 A61P033/06; A61K 31/683 20060101
A61K031/683 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 14, 1998 |
DE |
DE 19816196.4 |
Jun 9, 1998 |
DE |
DE 19825585.3 |
Sep 22, 1998 |
DE |
DE 19843222.4 |
Sep 22, 1998 |
DE |
DE 19843223.2 |
Claims
1-11. (canceled)
12. A method of treating malaria in an individual comprising:
administering to said individual a therapeutically effective amount
of a compound or a tautomer, ester or amide of the compound, or a
pharmaceutically acceptable salt of the compound, tautomer, ester
or aide, wherein the compound corresponds in structure to Formula
I: ##STR00005## wherein: R.sub.1 and R.sub.2 are independently
selected from the group consisting of hydrogen, substituted and
unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl,
substituted and unsubstituted alkenyl, substituted and
unsubstituted alkinyl, substituted and unsubstituted aryl,
substituted and unsubstituted acyl, substituted and unsubstituted
cycloalkyl, substituted and unsubstituted aralkyl, substituted and
unsubstituted heterocyclic radical, halogen, OX.sub.1 and OX.sub.2;
X.sub.1 and X.sub.2 being independently selected from the group
consisting of hydrogen, substituted and unsubstituted alkyl,
substituted and unsubstituted hydroxyalkyl, substituted and
unsubstituted alkenyl, substituted and unsubstituted alkinyl,
substituted and unsubstituted aryl, substituted and unsubstituted
acyl, substituted and unsubstituted cycloalkyl, substituted and
unsubstituted aralkyl, substituted and unsubstituted heterocyclic
radical; A is a 3-9 carbon moiety selected from the group
consisting of alkylene radical, alkenylene radical, and
hydroxyalkylene radical, wherein A includes a straight chain of at
least two carbon atoms between the nitrogen atom and the phosphorus
atom of general formula (I); and R.sub.3 and R.sub.4 are
independently selected from the group consisting of hydrogen,
substituted and unsubstituted C.sub.1-26-alkyl, substituted and
unsubstituted hydroxy-C.sub.1-26-alkyl, substituted and
unsubstituted aryl, substituted and unsubstituted acyl, substituted
and unsubstituted aralkyl, substituted and unsubstituted
C.sub.1-26-alkenyl, substituted and unsubstituted
C.sub.1-26-alkinyl, substituted and unsubstituted cycloalkyl,
substituted and unsubstituted heterocyclic radical, halogen,
OX.sub.3 and OX.sub.4; X.sub.3 and X.sub.4 being independently
selected from the group consisting of hydrogen, substituted and
unsubstituted C.sub.1-26-alkyl, substituted and unsubstituted
hydroxyl-C.sub.1-26-alkyl, substituted and unsubstituted aryl,
substituted and unsubstituted acyl, substituted and unsubstituted
aralkyl, substituted and unsubstituted C.sub.1-26-alkenyl,
substituted and unsubstituted C.sub.1-26-alkinyl, substituted and
unsubstituted cycloalkyl, substituted and unsubstituted
heterocyclic radical, silyl, a metal of the first, second or third
main group of the periodic table, ammonium, substituted ammonium,
ammonium salt of ethylene diamine and ammonium salt of an amino
acid.
13. A method of treating malaria according to claim 12, wherein:
the infectious agent has the potential to produce a malarial
infection in a human subject.
14. A method of treating malaria in an individual comprising:
administering to said individual a therapeutically effective amount
of a compound or a tautomer, ester or amide of the compound, or a
pharmaceutically acceptable salt of the compound, tautomer, ester
or aide, wherein the compound corresponds in structure to Formula
I: ##STR00006## wherein: R.sub.1 is OX.sub.1; R.sub.2 is
independently selected from the group consisting of hydrogen,
substituted and unsubstituted alkyl, substituted and unsubstituted
hydroxyalkyl, substituted and unsubstituted alkenyl, substituted
and unsubstituted alkinyl, substituted and unsubstituted aryl,
substituted and unsubstituted acyl, substituted and unsubstituted
cycloalkyl, substituted and unsubstituted aralkyl, substituted and
unsubstituted heterocyclic radical, halogen, and OX.sub.1 and
OX.sub.2; X.sub.1 and X.sub.2 being independently selected from the
group consisting of hydrogen, substituted and unsubstituted acyl,
substituted and unsubstituted alkyl, substituted and unsubstituted
aryl, substituted and unsubstituted aralkyl, substituted and
unsubstituted cycloalkyl, substituted and unsubstituted heterocylic
radical; A is a 2-9 carbon moiety selected from the group
consisting of alkylene radical, alkenylene radical, and
hydroxyalkylene radical, and includes a straight chain of at least
two carbon atoms between the nitrogen atom and the phosphorous atom
of Formula (I); R.sub.3 and R.sub.4 are independently selected from
the group consisting of hydrogen, substituted and unsubstituted
C.sub.1-26-alkyl, substituted and unsubstituted
hydroxy-C.sub.1-26-alkyl, substituted and unsubstituted aryl,
substituted and unsubstituted acyl, substituted and unsubstituted
aralkyl, substituted and unsubstituted C.sub.1-26-alkenyl,
substituted and unsubstituted C.sub.1-26-alkinyl, substituted and
unsubstituted cycloalkyl, substituted and unsubstituted
heterocyclic radical, halogen, OX.sub.3 and OX.sub.4; X.sub.3 and
X.sub.4 being independently selected from the group consisting of
hydrogen, substituted and unsubstituted C.sub.1-26-alkyl,
substituted and unsubstituted hydroxyl-C.sub.1-26-alkyl,
substituted and unsubstituted aryl, substituted and unsubstituted
acyl, substituted and unsubstituted aralkyl, substituted and
unsubstituted C.sub.1-26-alkenyl, substituted and unsubstituted
C.sub.1-26-alkinyl, substituted and unsubstituted cycloalkyl,
substituted and unsubstituted heterocyclic radical, silyl, a metal
of the first, second or third main group of the periodic table,
ammonium, substituted ammonium, ammonium salt of ethylene diamine
and ammonium salt of an amino acid.
15. The method of treating malaria according to claim 14, wherein:
R2 is a substituted or unsubstituted acyl; R3 is selected from a
group consisting of hydrogen, methyl and ethyl; R4 is selected from
a group consisting of hydrogen, methyl, ethyl and OX.sub.4; X.sub.4
being selected from hydrogen, sodium, potassium, methyl and ethyl;
and A is a 3 carbon moiety selected from the group consisting of
alkylene radical, alkenylene radical, and hydroxyalkylene
radical.
16. The method of treating malaria according to claim 15, wherein:
X.sub.1 is hydrogen; R.sub.2 is selected from formyl and acetyl;
and A is selected from propenylene and hydroxypropylene.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
10/676,131 filed Oct. 2, 2003, which is a divisional application of
application Ser. No. 09/673,561 filed Dec. 8, 2000, now U.S. Pat.
No. 6,680,308, which is a national stage application (under 35
U.S.C. .sctn.371) of PCT/EP99/02462, filed Apr. 13, 1999, which
claims benefit of German applications DE 19816196.4 filed on Apr.
14, 1998, DE 19825585.3 filed on Jun. 9, 1998, DE 19843222.4 filed
on Sep. 22, 1998, and DE 19843223.2 filed on Sep. 22, 1998, in
Germany. The entire contents of each of the aforementioned
applications are hereby incorporated by reference in their
entireties.
FIELD OF THE INVENTION
[0002] The invention relates to the use of organophosphorus
compounds and their salts, esters and amides for the therapeutic
and prophylactic treatment of infections which are caused by
viruses, fungi and parasites in humans and animals. According to
the invention the organophosphorus compounds comprise phosphonic
acid derivatives, phosphinoyl derivates and phosphinic acid
derivatives.
BACKGROUND OF THE INVENTION
[0003] The suitability of aminohydrocarbyl phosphonic acid
derivates and some of their esters and salts for use in
pharmaceutical compositions is already known. Up until now however
only their antimicrobial efficacy against bacteria in humans and
animals and against fungi in plants has been described (DE 27 33
658 A1, U.S. Pat. No. 4,143,135, U.S. Pat. No. 4,182,758 and U.S.
Pat. No. 4,206,156, U.S. Pat. No. 4,994,447, U.S. Pat. No.
4,888,330, U.S. Pat. No. 4,210,635, U.S. Pat. No. 3,955,958, U.S.
Pat. No. 4,196,193, U.S. Pat. No. 4,268,503, U.S. Pat. No.
4,330,529, U.S. Pat. No. 5,189,030, U.S. Pat. No. 3,764,677, U.S.
Pat. No. 3,764,676). Furthermore substances from this group have
been described as herbicides (U.S. Pat. No. 4,693,742, U.S. Pat.
No. 5,002,602, U.S. Pat. No. 4,131,448, U.S. Pat. No. 3,977,860,
U.S. Pat. No. 4,062,669), as algaecides (U.S. Pat. No. 3,887,353),
as means for regulating plant growth (U.S. Pat. No. 4,127,401, U.S.
Pat. No. 4,120,688, U.S. Pat. No. 3,961,934, U.S. Pat. No.
4,431,438, U.S. Pat. No. 3,853,530, U.S. Pat. No. 4,205,977, U.S.
Pat. No. 4,025,332, U.S. Pat. No. 3,894,861) and as reagents in dye
production (U.S. Pat. No. 4,051,175). In DE 27 33 658 A1 the use of
aminohydrocarbyl phosphonic acid derivatives for the treatment of
bacterial diseases has been described. Whilst the document speaks
of a microbial efficacy against pathogenic microorganisms in the
introduction to the description, from the overall context however
it is clear that the invention relates exclusively to bacteria.
Thus on page 16, second paragraph "antimicrobial efficacy" is
defined as "antibacterial efficacy".
[0004] 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 efficacy but
in contrast to other pharmaceutical compositions and plant
protective agents, contain reduced side effects and therefore
represent a lower risk to health for humans.
SUMMARY OF THE INVENTION
[0005] The object of the present invention is therefore to provide
a substance which fulfils the conditions given above in the case of
infections caused by viruses, fungi and parasites in humans and
animals.
[0006] 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,
fungi and unicellular and multicellular parasites. In the context
of this invention the strictly scientific definition of parasites
is to be used. This means that unicellular parasites are understood
to mean protozoa exclusively.
[0007] The organophosphorus compounds used according to the
invention correspond to the general Formula (I):
##STR00002##
in which R.sub.1 and R.sub.2 are the same or different and are
selected from the group which consists of hydrogen, substituted and
unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl,
substituted and unsubstituted alkenyl, substituted and
unsubstituted alkinyl, substituted and unsubstituted aryl,
substituted and unsubstituted acyl, substituted and unsubstituted
cycloalkyl, substituted and unsubstituted aralkyl, substituted and
unsubstituted heterocyclic radical, halogen, OX.sub.1 and OX.sub.2,
wherein X.sub.1 and X.sub.2 can be the same or different and are
selected from the group which consists of hydrogen, substituted and
unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl,
substituted and unsubstituted alkenyl, substituted and
unsubstituted alkinyl, substituted and unsubstituted aryl,
substituted and unsubstituted acyl, substituted and unsubstituted
cycloalkyl, substituted and unsubstituted aralkyl, substituted and
unsubstituted heterocyclic radicals, A is selected from the group
which consists of an alkylene radical, an alkenylene radical and a
hydroxyalkylene radical, R.sub.3 and R.sub.4 are selected
independently from the group which consists of hydrogen,
substituted and unsubstituted C.sub.1-26-alkyl, substituted and
unsubstituted hydroxy-C.sub.1-26-alkyl, substituted and
unsubstituted aryl, substituted and unsubstituted acyl, substituted
and unsubstituted aralkyl, substituted and unsubstituted
C.sub.1-26-alkenyl, substituted and unsubstituted
C.sub.1-26-alkinyl, substituted and unsubstituted cycloalkyl,
substituted and unsubstituted heterocyclic radical, halogen,
OX.sub.3 and OX.sub.4, wherein X.sub.3 and X.sub.4 are selected
independently from the group which consists of hydrogen,
substituted and unsubstituted substituted and unsubstituted
hydroxyl-C.sub.1-26-alkyl, substituted and unsubstituted aryl,
substituted and unsubstituted aralkyl, substituted and
unsubstituted C.sub.1-26-alkenyl, substituted and unsubstituted
C.sub.1-26-alkinyl, substituted and unsubstituted cycloalkyl,
substituted and unsubstituted heterocyclic radical, 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 system,
ammonium, substituted ammonium and ammonium compounds which derive
from ethylene diamine or amino acids, and their pharmaceutically
acceptable salts, esters and amides and salts of esters.
[0008] Phosphonic acid derivatives are particularly preferred.
BRIEF DESCRIPTION OF THE DRAWING
[0009] FIG. 1 shows a graph of the results of cytotoxicity tests
with the strains HB3 and Dd2 with known resistances against malaria
pharmaceutical compositions.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In particular compounds which contain the following Formula
(II) are suitable:
##STR00003##
wherein, X.sub.1 is selected from the group which consists of
hydrogen, substituted or unsubstituted acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted aryl, substituted
or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl,
substituted and unsubstituted heterocyclic radical; R.sub.2,
R.sub.3, R.sub.4 and A contain the same meaning as in Formula (I) A
is particularly preferably a chain of three carbon atoms which bind
the nitrogen atom to the phosphorus atom.
[0011] Compounds of Formula (II) are particularly preferred in
which R.sub.2=acyl, in particular an acetyl, R.sub.3=hydrogen,
methyl or ethyl, R.sub.4=hydrogen, methyl, ethyl or OX.sub.4 with
X.sub.4=hydrogen, sodium, potassium, methyl, ethyl, X.sub.1=H and
A=alkylene, alkenylene or hydroxyalkylene. Particularly good
results are achieved with R.sub.2=formyl or acetyl and A=propylene,
propenylene or hydroxypropylene.
[0012] Furthermore compounds are particularly preferred in which
R.sub.3 is an alkyl, hydroxyalkyl, alkinyl, or alkenyl group with
16 or 18 carbon atoms or OX.sub.3, wherein X.sub.3 is an alkyl,
alkinyl, hydroxyalkyl or alkenyl group with 16 or 18 carbon atoms,
R.sub.4 is an alkyl, alkinyl, hydroxyalkyl or alkenyl group with 16
or 18 carbon atoms or OX.sub.4, wherein X.sub.4 is an alkyl,
alkinyl, hydroxyalkyl or alkenyl group with 16 or 18 carbon
atoms.
[0013] Special features of the above definitions and suitable
examples thereof are given below:
[0014] "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 individually
present acids, or from an organic sulphonic acid, wherein these
acids comprise in each case aliphatic, aromatic and/or heterocyclic
groups in the molecule and carbamoyl or carbamimidoyl.
[0015] Suitable examples of these acyl groups will be given
below.
[0016] Acyl radicals originating from an aliphatic acid are
designated as aliphatic acyl groups and include:
Alkanoyl (for example formyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl etc.); Alkenoyl (for
example acryloyl, methacryloyl, crotonoyl etc.); Alkylthioalkanoyl
(for example methylthioacetyl, ethylthioacetyl etc.); Alkane
sulphfonyl (for example mesyl, ethane sulphonyl, propane sulphonyl
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;
[0017] Alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl
etc.).
[0018] In the above examples of aliphatic acyl groups the aliphatic
hydrocarbon part, in particular the alkyl group and the alkane
radical can optionally contain one or more suitable substituents
such as amino, halogen (for example fluorine, chlorine, bromine
etc.), hydroxy, hydroxyimino, carboxy, alkoxy (for example methoxy,
ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (for example
benzyloxycarbonylamino etc.), acyloxy (for example acetoxy,
benzoyloxy etc.) and the like. Preferred aliphatic acyl radicals
with such substitutes are for example alkanoyls substituted with
amino, carboxy, amino and carboxy, halogen, acylamino or the
like.
[0019] Acyl resides originate from an acid with substituted or
unsubstituted aryl groups, wherein the aryl group can comprise
phenyl, toluoyl, xylyl, naphthyl, and the like are designated as
aromatic acyl radicals. Suitable examples are given below:
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.); Arene
sulphonyl (for example benzene sulphonyl, tosyl toluene sulphonyl,
naphthalene sulphonyl etc.); Aryloxycarbonyl (for example
phenoxycarbonyl, naphthyl-oxycarbonyl etc.); Aralkoxycarbonyl (for
example benzyloxycarbonyl etc.); Arylcarbamoyl (for example
phenylcarbamoyl, naphthylcarbamoyl etc.); Arylglyoxyloyl (for
example phenylglyoxyloyl etc.).
[0020] In the above-mentioned examples of aromatic acyl radicals
the aromatic hydrocarbon part (in particular the aryl radical)
and/or the aliphatic hydrocarbon part (in particular the alkane
radical) can optionally contain one or more suitable substituents
such as those which were already mentioned as suitable substituents
for the alkyl group and the alkane radical. In particular and as an
example of preferred aromatic acyl radicals with particular
substituents, aroyl substituted by halogen and hydroxy or by
halogen and acyloxy and aralkanoyl substituted by hydroxy,
hydroxyimino, dihalogenalkanoyloxyimino are mentioned as well
as
Arylthiocarbamoyl (for example phenylthiocarbamoyl etc.);
Arylcarbamimidoyl (for example phenylcarbamimidoyl etc.). A
heterocyclic acyl radical is understood to be an acyl radical which
originates from an acid with hererocyclic 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 nitrogen, oxygen and sulphur (for example
thiophenyl, furoyl, pyrrolcarbonyl, nicotinoyl etc.); Heterocyclic
alkanoyl in which the heterocyclic radical is 5 to 6 membered and
has at least one heteroatom from the group nitrogen, oxygen and
sulphur (for example thiophenylacetyl, furylacetyl,
imidazolylpropionyl, tetrazolylacetyl,
2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the
like.
[0021] In the above examples of heterocyclic acyl radicals the
heterocycles and/or the aliphatic hydrocarbon part can optionally
contain one or more suitable substituents, such as the same as
those which were mentioned as suitable for alkyl and alkane
groups.
[0022] "Alkyl" is a straight- or branched-chain alkyl radical with
up to 9 carbon atoms, unless defined otherwise, such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl,
hexyl and the like.
[0023] "Hydroxylalkyl" is a straight- or branched-chain alkyl
radical with up to 9 carbon atoms, unless defined otherwise, which
contains at least one hydroxyl group, preferably one or two
hydroxyl groups.
[0024] "Alkenyl" includes straight- or branched-chain alkenyl
groups with up to 9 carbon atoms, unless defined otherwise, such
as, for example, vinyl, propenyl, (for example 1-propenyl,
2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl,
2-ethylpropenyl, pentenyl, hexenyl.
[0025] "Alkinyl" includes straight- or branched-chain alkinyl
groups with up to 9 carbon atoms, unless defined otherwise.
[0026] Cycloalkyl preferably represents an optionally substituted
C3 to C7 cycloalkyl. Alkyl, alkenyl, alkinyl, alkoxy (for example
methoxy, ethoxy etc.), halogen (for example fluorine, chlorine,
bromine etc.), nitro and the like are inter alia suitable as
possible substituents.
[0027] Aryl is an aromatic hydrocarbon radical such as phenyl
naphthyl etc., which can optionally contain one or more suitable
substituents such as alkyl, alkenyl, alkinyl, alkoxy (for example
methoxy, ethoxy etc.), halogen (for example fluorine, chlorine,
bromine etc.), nitro and the like.
[0028] "Aralkyl" includes mono-, di-, triphenylalkyls such as
benzyl, phenethyl, benzhydryl, trityl and the like, wherein the
aromatic part can optionally contain one or more suitable
substituents such as alkoxy (for example methoxy, ethoxy etc.),
halogen (for example fluorine, chlorine, bromine etc.), nitro and
the like.
[0029] "Alkylene" includes straight- or branched-chain alkylene
groups which contain up to 9 carbon atoms and can be reproduced by
the Formula
--(C.sub.nH.sub.2n)--
in which n is an integer from 1 to 9, such as methylene, ethylene,
trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene,
2-ethylethylene, pentamethylene, 2-methyltetramethylene,
isopropylethylene, hexamethylene, and the like. Preferred alkylene
radicals contain up to 4 carbon atoms and radicals with 3 carbon
atoms such as, for example, trimethylene are particularly
preferred. The hydrogen atoms can be replaced by other substituents
such as, for example, halogen radicals.
[0030] "Alkenylene" includes straight- or branched-chain alkenylene
groups with up to 9 carbon atoms which can be reproduced by the
Formula
--(C.sub.nH.sub.2n-2)--
in which n is an integer from 2 to 9, such as, for example,
vinylene, propenylene (for example 1-propenylene, 2-propenylene),
1-methylpropenylene, 2-methylpropenylene, butenylene,
2-ethylpropenylene, pentenylene, hexenylene and the like. The
alkenylene radical can particularly preferably contain up to 5
carbon atoms and in particular 3 carbon atoms such as, for example,
1-propenylene. The hydrogen atoms can be replaced by other
substituents such as, for example, halogen radicals.
[0031] "Hydroxyalkylene" can include straight- or branched-chain
alkylene radicals which contain up to 9 carbon atoms, wherein at
least one selected carbon atom is substituted by a hydroxy group.
These radicals can be reproduced by the Formula
--(C.sub.nH.sub.2n-z)(OH).sub.z--
in which n is an integer from 1 to 9 and z is an integer, to which
1.ltoreq.z.ltoreq.n applies. Suitable examples of such
hydroxyalkylene groups include hydroxymethylene, hydroxyethylene
(for example 1-hydroxyethylene and 2-hydroxyethylene),
hydroxytrimethylene (for example 1-hydroxytrimethylene,
2-hydroxytrimethylene and 3-hydroxytrimethylene),
hydroxytetramethylene (for example 2-hydroxytetramethylene),
2-hydroxy-2-methyltrimethylene, hydroxypentamethylene (for example
2-hydroxypentamethylene), hydroxyhexamethylene (for example
2-hydroxyhexamethylene) and the like. A lower hydroxyalkylene with
up to 4 carbon atoms is particularly preferred and in particular
one with 3 carbon atoms such as, for example,
2-hydroxytrimethylene. The hydrogen atoms can be replaced by other
substituents such as, for example, halogen radicals.
[0032] The radicals X.sub.3 and X.sub.4 can preferably be selected
such that esters form on the phosphinic group or phosphonic group.
Suitable examples of such esters in accordance with the Formulae
(I) and (II) include alkyl esters (for example methyl ester, ethyl
ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,
hexyl ester, hexadecanyl ester, octadecanyl ester etc.);
Aralkyl esters (benzyl ester, phenethyl ester, benzohydryl ester,
trityl ester etc.); Aryl esters (for example phenyl ester, tolyl
ester, naphthyl ester etc.); Aroylalkyl esters (for example
phenacyl ester etc.); and silyl esters (for example from
trialkylhalogensilyl, dialkyldihalogensilyl, alkyltrihalogensilyl,
dialkylarylhalogensilyl, trialkoxyhalogensilyl,
dialkylaralkylhalogensilyl, dialkoxydihalogensilyl,
trialkoxyhalogensilyl etc.) and the like.
[0033] With the above esters the alkane and/or arene part can
contain at least one suitable substituent as desired such as
halogen, alkoxy, hydroxy, nitro or the like.
[0034] X.sub.3 and X.sub.4 are preferably a metal from the first,
second or third main group of the periodic system, ammonium,
substituted ammonium or ammonium compounds which derive from
ethylenediamine or amino acids. In other words the salt compounds
of organophosphorus compounds are formed with organic or inorganic
bases (for example sodium salt, potassium salt, calcium salt,
aluminium salt, ammonium salt, magnesium salt, triethylamine salt,
ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt,
N,N'-dibenzylethylenediamine salt etc.) and salts with amino acids
(for example arginine salt, aspartic acid salt, glutamic acid salt
etc.) and the like.
[0035] The compounds used according to the invention in accordance
with the Formulae (I) or (II) can be present in their protonised
form as ammonium salt of organic or inorganic acids such as
hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid,
methane sulphonic acid, p-toluene sulphonic acid, acetic acid,
lactic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid,
benzoic acid etc.
[0036] The compounds used according to the invention of Formulas
(I) or (II) permit for example the emergence of spatial isomers for
groups containing double bonds or chiral groups R.sub.1, R.sub.2,
R.sub.3, R.sub.4, X.sub.1, X.sub.2, X.sub.3, X.sub.4 or A. The use
of compounds according to the invention consists of all spatial
isomers both as pure substances and in the form of their
mixtures.
[0037] The organophosphorus compounds are suitable in particular
for the therapeutic and prophylactic treatment of infections in
humans and animals which are caused by viruses, unicellular and
multicellular parasites and fungi.
[0038] The compounds are effective against unicellular parasites
(protozoa), in particular against pathogens of malaria and sleeping
sickness as well as Chagas' disease, toxoplasmosis, amoebic
dysentery, leishmaniasis, trichomoniasis, pneumocystosis,
balantidiasis, cryptosporidiasis, sarcocystosis, acanthamebiasis,
naegleriasis, coccidiosis, giardiasis and lambliosis.
[0039] They are therefore particularly suitable as malaria
prophylactics and as prophylactics for sleeping sickness as well as
Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniasis,
trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiasis,
sarcocystosis, acanthamebiasis, naegleriasis, coccidiosis,
giardiasis and lambliosis.
[0040] Combinations with an antibiotic can also be used to treat
the above-mentioned diseases. Isoniazid, rifampicin, ethambutol,
pyrazineamide, streptomycin, protionamide and dapsone are
particularly suitable for combination with other anti-infectives
for the treatment of tuberculosis.
[0041] The agents according to the invention can furthermore be
used in particular in infections with the 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 miopapova viruses, Herpesviridae: all herpes viruses, in
particular herpes simplex viruses, varicella-zoster viruses, human
cytomegalo virus, Epstein-Barr viruses, all human herpes viruses,
human herpes virus 6, human herpes virus 7, human herpes virus 8,
Poxyiridae: 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 viruses, hepatitis G
viruses, Hepadna viruses: all hepatitis viruses, hepatitis B virus,
hepatitis D viruses, Picornaviridae: picorna viruses, all entero
viruses, all polio viruses, all coxsackie viruses, all echo
viruses, all rhino viruses, hepatitis A virus, aphtho viruses,
Calciviridae: hepatitis E viruses, Reoviridae: reo viruses, orbi
viruses, rota viruses, Togaviridae: toga viruses, alpha viruses,
rubi viruses, pestiviruses, rubella virus, Flaviviridae: flavi
viruses, ESME virus, 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, Coronaviridae: corona viruses, Bunyaviridae: bunya viruses,
nairo virus, phlebo virus, uuku virus, hanta virus, hantaan virus,
Arenaviridae: arena viruses, lymphocytic choriomeningitis virus,
Retroviridae: retro viruses, all HTL viruses, human T-cell
leukaemia virus, oncorna viruses, spuma viruses, lenti viruses, all
HI viruses, Filoviridae: Marburg and Ebola virus, Slow virus
infections, prions, Oncoviruses and leukaemia viruses.
[0042] The organophosphorus compounds used according to the
invention are therefore suitable for fighting the following viral
infections:
Eradication of papilloma viruses to prevent tumours, in particular
tumours 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 sarcoma, eradication of cytomegalo viruses before
transplants, eradication of Epstein-Barr viruses before transplants
and to prevent tumours associated with Epstein-Barr viruses,
eradication of hepatitis viruses for the treatment of chronic liver
diseases and for the prevention of tumours of the liver and
cirrhosis of the liver, eradication of coxsackie viruses in
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, hyperplasias,
rhinitis, pharyngitis, bronchitis, pneumonias), of the sensory
organs (keratoconjunctivitis), of the nervous system
(poliomyelitis, meningoencephalitis, encephalitis, subacute
sclerosing panencephalitis SSPE, progessive multifocal
leukoencephalopathy, lymphocytic choriomeningitis), of the
gastro-intestinal tract (stomatitis, gingivostomatitis,
oesophagitis, gastritis, gastroenteritis, diarrhoea-causing
diseases), of the liver and gall bladder system (hepatitis,
cholangitis, hepatocellular carcinoma), of the lymphatic tissue
(mononucleosis, lymphadenitis), of the haematopoetic system, of the
sexual organs (mumpsorchitis), of the skin (warts, dermatitis,
herpes labialis, heat rash, herpes zoster, shingles), of the mucous
membranes (papillomas, conjunctiva papillomas, hyperplasias,
dysplasias), of the heart/blood vessel system (arteritis,
myocarditis, endocarditis, pericarditis), of the kidney/urinary
tract system, of the sexual organs (anogenital lesions, warts,
genital warts, acute condylomas, displasias, papillomas, cervix
dysplasias, condylomata acuminata, epidermodysplasia verruci
formis), of the organs of motion (myositis, myalgias), treatment of
foot and mouth diseases in cloven-hoofed animals, of Colorado tick
fever, of Dengue syndrome, of haemorrhagic fever, of early summer
meningoencephalitis (ESME) and of yellow fever.
[0043] The described compounds, i.e. the organophosphorus compounds
according to Formulae (I) and (II) and esters and amides thereof on
the phosphinic group or phosphonic group and salts thereof have a
strongly cytotoxic efficacy against unicellular and multicellular
parasites, in particular against pathogens of malaria and sleeping
sickness. Accordingly the compounds used according to the invention
can be used for the treatment of infectious diseases which are
caused by viruses, parasites and fungi in humans and animals. The
compounds are also suitable for use in the prevention of diseases
which are caused by viruses, parasites and fungi, in particular as
malaria prophylactics and as sleeping sickness prophylactics.
[0044] The organophosphorus compounds used according to the
invention, which generally include pharmaceutically acceptable
salts, amides, esters, a salt of such an ester or else compounds
which upon application provide the compounds used according to the
invention as metabolic products or decomposition products, also
called "prodrugs", can all prepared for administration like known
anti-infectious agents in any suitable manner (mixed with a
non-toxic pharmaceutically acceptable carrier). Pharmaceutically
acceptable salts of the compounds include salts which form the
compounds used according to the invention of Formulae (I) and (II)
in their protonised 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-toluene sulphonic
acid.
[0045] Salts which are formed by suitable selection of X.sub.3 and
X.sub.4 such as sodium salt, potassium salt, calcium salt, ammonium
salt, ethanolamine salt, triethylamine salt, dicylcohexylamine salt
and salts of an amino acid such as arginine salt, aspartic acid
salt, glutamine acid salt are particularly suitable
pharmaceutically.
[0046] The activity of substances is determined in a test system.
This system is based on the measuring of the inhibition of growth
of 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.
[0047] To determine the anti-malaria activity, for example, the
inhibition of the growth of malaria parasites in blood cultures is
determined.
[0048] The determining of antiviral activity is based on inhibition
of the formation of viral elements in cell cultures.
[0049] The determining of fungicidal activity is based on the
inhibition of the growth of fungi on culture media and in liquid
cultures.
[0050] Some of the microorganisms which should be investigated can
only be investigated in animal models. In this case we will use the
corresponding models.
[0051] Substances which demonstrate an efficacy in the in vitro
measuring systems will be further investigated in in vivo
models.
[0052] The anti-parasitic, antiviral or fungicide activity will be
further evaluated in the appropriate animal models.
[0053] The pharmaceutically effective preparations can be prepared
in the form of pharmaceutical preparations in dispensing units.
This means that the preparation 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, 3 or 4 single
doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably
contains the quantity of active ingredient which is administered
during one application and which usually corresponds to a whole, a
half or a third or a quarter of a daily dose.
[0054] Non-toxic, inert pharmaceutically suitable excipients are
understood to mean solid, semi-solid or liquid diluents, fillers
and formulation auxiliary agents of all kinds.
[0055] Tablets, dragees, capsules, pills, granules, suppositories,
solutions, suspensions and emulsions, pastes, ointments, gels,
creams, lotions, powders and sprays are mentioned as suitable
pharmaceutical preparations. Tablets, dragees, capsules, pills and
granules can contain in addition to the conventional excipients,
the active ingredient or active ingredients such as (a) fillers and
diluents, for example starches, lactose, cane sugar, glucose,
mannitol and silicic acid, (b) binders, for example
carboxymethylcellulose, alginates, gelatines, polyvinylpyrrolidone,
(c) moisture-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, for example kaolin and
betonite and (i) lubricants, for example talcum, calcium and
magnesium stearate and solid polyethylene glycols or mixtures of
the substances listed under (a) to (i).
[0056] The tablets, dragees, capsules, pills and granular materials
can be provided with the conventional coatings and casings
optionally containing opaquing agents and can also be put together
so that they release the active ingredient or active ingredients
only or preferably in a specific part of the intestinal tract
optionally with sustain release, wherein polymer substances and
waxes for example can be used as embedding compounds.
[0057] The active ingredient or active ingredients can optionally
also be present in microencapsulated form with one or more of the
above-mentioned excipients.
[0058] In addition to the active ingredient or active ingredients
suppositories can also contain the conventional water soluble or
water insoluble excipients, for example polyethylene glycols, fats,
for example cocoa fat and higher esters (for example C14-alcohol
with C16-fatty acid) or mixtures of these substances.
[0059] In addition to the active ingredient or active ingredients,
ointments, pastes, creams and gels can contain the conventional
excipients, for example animal and vegetable fats, waxes,
paraffins, starches, tragacanth, cellulose derivatives,
polyethylene glycols, silicones, bentonites, silicic acid, talc and
zinc oxide or mixtures of these substances.
[0060] In addition to the active ingredient or active ingredients,
powders and sprays can contain the conventional excipients, for
example lactose, talc, silicic acid, aluminium hydroxide, calcium
silicate, and polyamide powder or mixtures of these substances.
Sprays can additionally contain the conventional blowing agents,
for example chlorofluorohydrocarbons.
[0061] In addition to the active ingredient or active ingredients,
solutions and emulsions can contain the conventional excipients
such as solvents, solubilisers and emulsifiers, for example water,
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol, dimethyl formamide, oils, in particular cotton seed oil,
peanut oil, corn oil, olive oil, castor oil and sesame oil,
glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan or mixtures of these
substances.
[0062] The solutions and emulsions can also be present in sterile
and blood isotonic form for parenteral application.
[0063] In addition to the active ingredient or active ingredients,
suspensions can 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
tragacanth or mixtures of these substances.
[0064] 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
example saccharine.
[0065] The agents of Formulae (I) and (II) should be present in the
above-listed pharmaceutical preparations 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.
[0066] In addition to the compounds of Formulae (I) and (II) the
pharmaceutical preparations can also contain further pharmaceutical
agents.
[0067] The compounds can be used with hitherto described substances
with antibacterial, antiviral, antifungal and antiparasitic
properties. Compounds which have already found application in
treatment or are still being used belong to this group. Substances
which are listed in the Red List or in Simon/Stille,
Antibiotika-Therapie in Klinik and Praxis, 9th Edition 1998
Schattauer Verlag or under [0068]
http:/www.customs.treas.gv/imp-exp/rulings/harmoniz/hrm129.html on
the Internet are particularly suitable for this purpose. In
particular derivatives with penicillins, benzyl penicillin
(Penicillin G), phenoxy penicillins, isoxazolyl penicillins, amino
penicillins, ampicillin, amoxicillin, bacampicillin, carboxy
penicillin, ticarcillin, temocillin, acyalamino pencillins,
azlocillin, mezlocillin, piperacillin, apalcillin, mecillinam,
cephalosporins, cefazolin group, cefuroxime group, cefoxitin group,
cefoxitin, cefotetan, cefmetazole, latamoxef, flomoxef, cefotaxime
group, cefozidime, ceftazidime group, ceftazidime, cefpirom,
cefepim, other cephalosporins, cefsulodine, cefoperazone,
oralcephalosporins of the cefalexine group, loracarbef, cefprozil,
new oralcephalosporins with expanded spectrum, cefixime,
cefpodoxim-proxetil, cefuroxime-axetil, cefetamet, cefotiam
hexetil, cefdinir, ceftibutene, other .beta.-lactam antibiotics,
carbapenem, imipenem/cilastatin, meropenem, biapenem, aztreonam,
.beta.-lactamase inhibitors, calvulanic acid/amoxicillin,
clavulanic acid/ticarcillin, sulbactam/ampicillin,
tazobactam/piperacillin, tetracyclines, oxytetracycline,
rolitetracycline, doxycycline, minocycline, chloramphenicol,
aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin,
spectinomyxin, macrolides, erythromycin, clarithromycin,
roxithromycin, azithromycin, dirithromycin, spiramycin, josamycin,
lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics,
vancomycin, tecoplanin, pristinamycin derivates, fosfomycin,
antimicrobial folic acid antagonists, sulphonamides,
co-trimoxazole, trimethoprim, other diaminopyrimidine-sulphonamide
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, terizidon, dapsone, clofazimine,
topical antibiotics, bacitracin, tyrothricin, polymyxins, neomycin,
kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir,
ganciclovir, azidothymidine, didanosin, zalcitabin, thiacytidine,
stavudine, ribavirin, idoxuridine, trifluridine, foscarnet,
amantadine, interferons, tibol derivatives, proteinase inhibitors,
antitungal agents, polyenes, amphotericin B, nystatin, natamycin,
azoles, azoles for septic treatment, miconazole, ketoconazole,
itraconazole, fluconazole, UK-109.496, azoles for topical
application, clotrimazole, econazole, isoconazole, oxiconazole,
bifonazole, flucytosine, griseofulvin, ciclopiroxolamine,
tolnaftate, naftifine, terbinafine, amorolfine, anthraquinones,
betulinic acid, semianthraquinones, xanthones, napthtoquinones,
aryaminoalcohols, quinine, quinidines, mefloquine, halofantrine,
chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine,
pyronaridine, dapsone, sulphonamide, sulfadoxine, sulfalenes,
trimethoprim, proguanil, chlorproguanil, diaminopyrimidine,
pyrimethamine, primaquine, aminoquinolines, WR 238,605,
tetracycline, doxycyline, clindamycin, norfloxacin, ciprofloxacin,
ofloxacin, artemisinin, dihydroartemisinin, 10b arte mether, arte
ether, arte senate, atovaquon, suramin, melarsoprol, nifurtimnox,
stibogluconate-sodium, pentamidine, amphotericin B, metronidazole,
clioquinol, mebendazole, niclosamide, praziquantel, pyrantel,
tiabendazole, diethylcarbamazine, ivermectin, bithionol,
oxamniquine, metrifonate, piperazine, embonate can be [used].
[0069] The organophosphorus compounds can furthermore be present in
the pharmaceutical preparations in combination with sulphonamide,
sulfadoxin, artemisinine, atovaquon, quinine, chloroquine,
hydroxychloroquine, mefloquine, halofantrine, pyrimethamine,
armesin, tetracyclines, doxycycline, proguanil, metronidazole,
praziquantel, niclosamide, mebendazole, pyrantel, tiabendazole,
diethylecarbamazine, piperazine, pyrivinum, metrifonate,
oxamniquine, bithionol or suramin or several of these
substances.
[0070] The above-listed pharmaceutical preparations are produced in
the conventional manner by known methods, for example by mixing the
active ingredient or active ingredients with the excipient or
excipients.
[0071] The above-mentioned preparations can be used in humans and
animals either orally, rectally, parenterally, (intravenously,
intramuscularly, subcutaneously), intracisternally, intravaginally,
intraperitoneally, topically (powder, ointment, drops) and for the
treatment of infections in cavities, orifices. Suitable
preparations are injection solutions, solutions and suspensions for
oral treatment, gels, infusions, emulsions, ointments or drops.
Ophthalmological and dermatological 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 water in suitable formulations. Furthermore
gels, powders, tablets, sustain release tablets, premixes,
concentrates, granules, pellets, tablets, boli, capsules, aerosols,
sprays, inhalers can be used with humans and animals. The compounds
used according to the invention can furthermore be incorporated
into other carrier materials such as, for example, plastics
materials (plastics chains for topical treatment), collagen or bone
cement.
[0072] In general it has proved advantageous both in human and
veterinary medicine to administer the active ingredient or active
ingredients of Formulae (I) and (II) in total quantities of
approximately 0.05 to approximately 600, preferably 0.5 to 200
mg/kg body weight every 24 hours, optionally in the form of several
individual doses in order to achieve the desired results. An
individual dose contains the active ingredient or active
ingredients preferably in quantities from 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 of the preparation and the application of the
pharmaceutical composition as well as the time scale or interval
within which the administration takes place.
[0073] Thus in some cases it may be sufficient to get by with less
than the above-mentioned quantity of active ingredient whilst in
other cases the above-stated quantity of active ingredient must be
exceeded. The person skilled in the art can determine the optimum
dosage and method of application of the active ingredient required
in each case by virtue of their expert knowledge.
[0074] The compounds according to the invention can be given in the
conventional concentrations and preparations to animals together
with the feedstuff or the feedstuff preparations or with the
drinking water.
Example 1
Test of the Efficacy of Substances Against Malaria In Vivo
[0075] The various derivatives were tested by the modified Peters'
test. The substances were applied here in a quarter of the median
lethal dose (LD50). In the test batch ten mice were infected with
Plasmodium vinckeii, the pathogen of mouse malaria. After
confirmation of the infection by blood testing four mice were
treated. Six mice, which were not treated, served as a control
group. The treatment with 1,000 mg/kg/d,
3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodium salt
over 3 days led to a destruction of the parasites in the mice's
blood. After just one day the treated group was free of living
parasites. The control mice had to be killed on day 5 after
infection with parasitaemia of >80%. The treated mice were still
free from parasites 8 weeks after the treatment had stopped.
Further experiments showed an efficacy of 50 mg/kg/d
3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodium salt
in mice with a parasitaemia of 80%. These mice were also free of
living parasites after 1 day.
Example 2
[0076] Protection from Malaria in a Test with Infected Mice
[0077] The efficacy of compounds in vivo against malaria was tested
using male mice weighing 20 to 25 g (BALB/c-strain). Four mice were
treated intraperitoneally with 50 mg/kg
3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodium salt
one day before infection. The mice were then infected with
Plasmodium vinckeii. Mice which were not pretreated with the
substance served as a control group. No infection could be detected
in the treated mice, whilst the control mice were killed after 5
days with a parasitaemia of 80%. The treated mice were still free
of parasites 8 weeks after infection.
Example 3
In Vitro Cytotoxicity Against Malaria Parasites
[0078] On the Principle of IC50 Determination According to Vial et
al (the Concentration at which the Vitality of Parasites is Reduced
by a Half)
[0079] To determine the IC50 value according to Vial et al malaria
parasites are initially cultivated for a complete 48 hour cycle in
the presence of inhibitors, in the subsequent 24 hours the survival
rate is measured by [.sup.3H]-hypoxanthine insertion.
Carrying Out the Test
[0080] A dilution series of
3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodium salt
is placed in 20 .mu.l aliquots concentrated by 10 on a microtitre
plate. Then 180 .mu.l parasite suspension in culture medium is
added to each well. Asynchronous cultures with a parasitaemia of
approximately 0.4% and 2% haematocrite are used. The microtitre
plates are subsequently incubated for 48 hours. Then 30 .mu.l
[.sup.3H]-hypoxanthine are added to each well. After 24 hours of
incubation the cells were harvested and the incorporated
radioactivity was measured. In FIG. 1 the results with the strains
HB3 and Dd2 are shown with known resistances against other malaria
pharmaceutical compositions. In both strains there is a IC50 value
of approximately 100 .mu.g/l. The resistances of these strains
are:
Plasmodium falciparum HB3 (Honduras) is resistant to pyrimethamine.
Plasmodium falciparum Dd2 (Indo-China) is resistant to cloroquine,
quinine, pyrimethamine, cycloguanil and sulfadoxine.
[0081] No cross resistances with antimalarial agents were
found.
Example 4
Preparation of 3-bromopropylphosphonic acid diethylester
[0082] 471 g (238 ml, 2.33 mol) 1,3-dibromopropane and 77.6 g (81
ml, 0.467 mol) triethylphosphite were introduced into a 500 ml
flask and heated for 30 minutes to 155-160.degree. C. 20 ml ethyl
bromide (boiling point: 40.degree. C.) were distilled off under
normal pressure via a reflux condenser and a distilling apparatus.
Concentration of the solution under vacuum (8 torr (1.0710.sup.3
Pa)) resulted in 380 g (191 ml, 1.863 mol) 1.3 dibromopropane
(surplus educt). 88.1 g (0.34 mol) could be distilled as a
colourless liquid (boiling point: 96.degree. C., 0.1 torr (13.33
Pa)) from the remaining yellow oil. This corresponds to a yield of
73%. (Hewitt, Teese, Aust. J. Chem. 1984, 37, 205-10 U.S. Pat. No.
4,206,156).
[0083] .sup.1H-NMR (CDCl.sub.3) .delta.=4.08 (quintet, J=7 Hz, 4H),
1.33 (t, J=7 Hz, 6H)
[0084] .sup.13C-NMR (CDCl.sub.3) .delta.=61.2 (OCH.sub.2CH.sub.3),
33.10 (J=18, 3 Hz), 25.6 (J=4, 4 Hz), 24.14 (J=120, 6 Hz) 16.04
(OCH.sub.2CH.sub.3).
Example 5
Preparation of 3-(N-hydroxyamino)-propylphosphonic acid
diethylester
[0085] Firstly 32.0 g (0.8 mol) of sodium hydroxide dissolved in 75
ml water then 75 ml methanol, and finally 25.5 g (0.098 mol)
3-bromopropyl phosphonic acid diethylester were added drop by drop
to a solution of 55.6 g (0.8 mol) hydroxylamine hydrochloride in
100 ml water with cooling with ice. This led to a clouding of the
solution. After 3 hours stirring at a temperature of 40 to
45.degree. C. methanol was removed under reduced pressure, the
resulting aqueous solution was saturated with NaHCO.sub.3 (pH=8),
shaken out three times with 60 ml toluene in each case (the toluene
phase was discarded) and then shaken out with chloroform (1.times.
with 90 ml, 2.times. with 50 ml in each case). The slightly yellowy
chloroform phase was dried over MgSO.sub.4. After filtering of the
dehydrating agent the solution was concentrated under reduced
pressure. 15.43 g (0.0728 mol) 3-(N-hydroxyamino)-propylphosphonic
acid diethylester were obtained as an almost colourless oil. This
corresponds to a yield of 74.3% (DE-A-27 33 658).
[0086] .sup.1H-NMR (CDCl.sub.3) .delta.=5.94 (wide s, 2H), 4.13
(quintet, J=7 Hz, 4H) 2.90 (t, J=7 Hz, 2H) 1.5-2.2 (m, 4H), 1.33
(t, J=7 Hz, 6H);
[0087] .sup.13C-NMR (CDCl.sub.3) .delta.=61.23 (OCH.sub.2CH.sub.3),
53.34 (NCH.sub.2, J=15, 9 Hz), 22.75 (J=141, 9 Hz), 19.77 Hz, 16.08
(OCH.sub.2CH.sub.3).
Example 6
Preparation of 3-(N-hydroxyamino)-propylphosphonic acid
[0088] 12.9 g (0.0608 mol) 3-(N-hydroxylamino)-propylphosphonic
acid diethylester and 130 ml concentrated HCl were heated for 6
hours under reflux (oil bath temperature: 150.degree. C.). The
resulting yellow/orange solution is concentrated under-reduced
pressure. The remaining oil is taken up in 30 ml water, stirred
with 3 spoonfuls of activated carbon for 30 minutes, filtered out
from the activated carbon and the colourless solution is
concentrated in the entire diaphragm pump vacuum. After take-up in
30 ml water a pH of 4.0 to 4.5 is adjusted with approximately 4.7 g
(0.056 mol) NaHCO.sub.3 (from pH=1.5 the product precipitates).
Suction filtering of the white solid resulted in 5.83 g
3-(hydroxyamino)-propylphosphonic acid (melting point: 160.degree.
C., decomposition). This corresponds to a yield of 61.8%. (DE-A-27
33 658, Ohler Synthesis 1995, 539-543).
[0089] .sup.1H-NMR (CDCl.sub.3) .delta.=3.49 (t, J=7, 4 Hz, 2H),
2.1 (m, 2H), 1.82 (m, PCH.sub.2, 2H);
[0090] .sup.13C-NMR (CDCl.sub.3) .delta.=56.26 (NCH.sub.2, J=15
Hz), 29.61 (PC, J=134 Hz), 22.37 (C-2, J=3, 8 Hz).
Example 7
Preparation of 3-(N-formylhydroxyamino)-propylphosphonic acid
diethylester
[0091] 1.38 (0.030 mol) formic acid were added drop by drop at room
temperature to 2.04 g (0.020 mol) acetic anhydride and stirred at
the same temperature. This solution was added with cooling with ice
to 2.8 g (0.013 mol) 3-(N-hydroxyamino)-propylphosphonic acid
diethylester dissolved in chloroform. The reaction mixture is
stirred for 30 minutes at 0-5.degree. C. and for a further 1.5
hours at room temperature. After concentration under reduced
pressure until an oily residue is obtained, this oily residue is
taken up in 15 ml methanol and 5 ml water, adjusted to pH=8 with 2
n NaOH and stirred for a further 1.5 hours at room temperature.
Methanol is removed under reduced pressure and the resultant
aqueous solution is adjusted to pH=5 with concentrated HCl. The
yellow solution is extracted with chloroform (1.times.30 ml,
2.times.10 ml in each case) and the CHCl.sub.3 phases are dried
over MgSO.sub.4. After concentration of the solution in the entire
diaphragm pump vacuum 3 g of a yellow oil are obtained. After
removal of volatile constituents in the entire diaphragm pump
vacuum, chromatography on 60 g SiO.sub.2 with chloroform shows:
methanol in the ratio 25:1 2.65 g product as yellow oil (DE-A-27 33
658).
[0092] .sup.1H-NMR (CDCl.sub.3) .delta.=8.4 (CHO, 0.5H), 7.94 (CHO,
0.5H), 4.1 (quintet, 4H), 3.68 (t, 2H), 1.7-2.19 (m, 4H), 1.36 (t,
J=7 Hz, 6H);
[0093] .sup.13C-NMR (CDCl.sub.3) .delta.=162.65 (CHO), 156.96
(CHO), 61.72 (OCH.sub.2CH.sub.3), 46.31 (NCH.sub.2, J=15, 9 Hz),
22.15 (PC, J=142, 0 Hz), 19.13 (C-2), 16.08 (OCH.sub.2CH.sub.3)
Example 8
Preparation of 3-(N-acetylhydroxyamino)-propylphosphonic acid
diethylester
[0094] 2.8 g (0.013 mol) 3-(N-hydroxyamino)-propylphosphonic acid
diethylester are dissolved in 30 ml methylene chloride and added
drop by drop with cooling with ice to 2.65 g (0.026 mol) acetic
anhydride. The reaction mixture is stirred for 30 minutes at
0-5.degree. C. and for a further 1.5 hours at room temperature.
After concentration under reduced pressure until a yellow oily
radical is achieved, this oily residue is taken up in 15 ml
methanol and 5 ml water, adjusted to pH 8 with 2 n NaOH and stirred
for a further 1.5 hours at room temperature. Methanol is removed
under reduced pressure and the resultant solution is adjusted to
pH=5 with concentrated HCl. The yellow solution is extracted
repeatedly with methylene chloride (1.times.30 ml, 2.times.10 ml in
each case), the combined CH.sub.2Cl.sub.2 phases are dried over
MgSO.sub.4 and the solvent is removed at room temperature under
reduced pressure. 3.7 g of a yellow oil are obtained which are
freed from adhering volatile substances in the entire diaphragm
pump vacuum. 2.78 g yellow oil remain.
[0095] .sup.13C-NMR (CDCL.sub.3) .delta.=171.96 (C.dbd.O), 61.62
(OCH.sub.2CH.sub.3), 47.44 (J=15, 49 Hz), 22.13 (PC, J=141, 8 Hz),
19.3, 15.9 (OCH.sub.2CH.sub.3)
Example 9
Preparation of 3-(N-formylhydroxyamino)-propylphosphonic acid
monosodium salt
[0096] 2 ml formic acid are added drop by drop to 4 ml acetamide at
0-5.degree. C. The solution is stirred at this temperature for 10
minutes and for a further 15 minutes at room temperature,
subsequently cooled to 0.degree. C. again and 3.28 g (0.021 mol)
3-(N-hydroxyamino)-propylphosphonic acid dissolved in 6 ml formic
acid are added drop by drop at 0-5.degree. C. After 1 hour of
stirring at room temperature the solution is condensed in a rotary
evaporator under reduced pressure, the oil is dissolved in 50 ml
methanol, heated to 60.degree. C. and mixed with 10 ml ethanol. The
resulting oily separated material is separated without stirring by
decanting. To precipitate white crystals the methanolic solution is
mixed with a further 50 ml ethanol, boiled up and the white residue
filtered out. This residue is taken up in 80 ml methanol and 100 ml
ethanol are added with stirring. The mixture is stirred further
overnight at room temperature. A solid is obtained which is
filtered out. (DE-A-27 33 658)
Example 10
Preparation of 3-(N-acetylhydroxyamino)-propylphosphonic acid
monosodium salt
[0097] A suspension of 3.8 g (0.02 mol)
3-(N-hydroxyamino)-propylphosphonic acid is introduced into 20 ml
water and 4.51 g (0.044 mol) acetic anhydride are added drop by
drop at room temperature. After the solution has been stirred for
1.5 hours at room temperature a pH of 2.5 is adjusted with 0.2 n
NaOH, the solution is concentrated in the entire diaphragm pump
vacuum, taken up twice in 40 ml water in each case, which are again
removed by concentration and the oil is washed twice with 30 ml
ether in each case, taken up in 50 ml water and a pH of 6.5 is
adjusted with 1.6 g NaHCO.sub.3. After removal of volatile
constituents under vacuum, 20 ml n-butanol are added to remove the
residual water and are also removed under reduced pressure. The oil
is boiled up twice with isopropanol, the isopropanol phase is
discarded and the remaining glassy resin is pulverised with a
spatula to a yellow solid (5.65 g). In order to recrystallise it,
it is taken up in only a little methanol, filtered from the
undissolved component and acetone is added dropwise to the
filtrate. A first filtering results in 1 g product with a melting
point of 175.degree. C. Recrystallisation as described above is
carried out again for further purification. (DE-A-27 33 658)
Example 11
Preparation of Antiparasitically Effective Agents
Preparation for Injections:
[0098] (1) The required quantity of sterile antiparasitically
effective agent, 3-(N-formyl-N-hydroxylamino)-propylphosphonic acid
monosodium salt was divided into phials or ampoules which then
contained 500 mg active ingredient. The phials were hermetically
sealed to exclude bacteria. For injections 2 ml sterile water were
added to the phials in each case and the content was
administered.
[0099] In substantially the same manner as described under (1)
further injectable preparations of the antiparasitically effective
agent were prepared as described below:
(2) 250 mg 3-(N-formyl-N-hydroxylamino)-propylphosphonic acid
monosodium salt were used as active ingredient for the injections.
(3) 250 mg 3-(N-formyl-N-hydroxylamino)-trans-1-propenyl-phosphonic
acid monosodium salt were used as active ingredient for the
injections. (4) 500 mg
3-(N-acetyl-N-hydroxylamino)-2-hydroxypropyl-phosphonic acid
monosodium salt were used as active ingredient for the injections.
(5) 250 mg 3-(N-formyl-N-hydroxylamino)-2-hydroxypropyl-phosphonic
acid monopotassium salt were used as active ingredient for the
injections.
Preparation of Tablets:
[0100] A suitable tablet recipe is formed by the following
mixture:
TABLE-US-00001 3-(N-formyl-N-hydroxylamino)-propylphosphonic 200 mg
acid monosodium salt Mannitol 400 mg Starch 50 mg Magnesium
stearate 10 mg
Preparation of Capsules:
TABLE-US-00002 [0101] 3-(N-formyl-N-hydroxylamino)-propylphosphonic
300 mg acid monopotassium salt Magnesium stearate 15 mg
[0102] The present components were mixed and then introduced into a
hard gelatine capsule in the conventional manner.
Preparation of an Oily Suspension:
TABLE-US-00003 [0103] 3-(N-acetyl-N-hdroxylamino)-propylphosphonic
200 mg acid monosodium salt Lanette-Wax SX .RTM. 50 mg Soft
paraffin 100 mg Brilliant blue FCF 25 mg
[0104] The above components were mixed with liquid paraffin for a
total quantity of 3 g to achieve an infusion preparation.
Examples of Methods of Synthesis for Substances with the Following
Structure:
##STR00004##
Example 12
3-(N-formyl-N-hydroxylamino)-propylphosphonic acid
dioctadecyl-ester 12
[0105] 1 equivalent fosmidomycin (FR-31564) and 6 equivalents
tris(octadecyl)-orthoformic acid were heated under reduced pressure
and vigorous stirring for 2 hours under reflux. Then methanol and
formic acid octadecylester were distilled off--also under reduced
pressure--wherein the temperature must be kept below the
decomposition temperature of the product. Further volatile
secondary products are removed in the oil pump vacuum in order
finally to obtain 12 as a highly viscous oil. (On the carrying out
of the procedure cf.: D. A. Nicholson, A. Cilley, O. T. Quimby, J
Org. Chem. 1970, 35, 3149-50)
[0106] The monoesters can be provided starting from both
fosmidomycin and di-octadecylester 12.
Example 13
3-(N-formyl-N-hydroxylamino)-propylphosphonic acid
monooctadecyl-ester 13
First Proposal:
[0107] 0.21 mmol fosmidomycin (phosphonic acid) and 0.2 mmol
n-octadecanol are dissolved in 1-2 ml dry pyridine and 0.67 mmol
trichloracetonitrile is added dropwise thereto. The reaction
mixture is heated for 16 hours to 80.degree. C. and then condensed
under vacuum. After take up in water (for the diaphragm filtering
of undissolved components) the solution is condensed again under
reduced pressure and the product is chromatographed onto silica gel
with ethyl acetate, ethanol and water as eluent. The product 13 is
produced in this case as a viscous rubber-like to glass-like
compound.
[0108] (On the carrying out of the procedure cf.: G. B. Brookes, D.
Edwards, J. D. I. Hatto, T. C. Smale, R. Southgate, Tetrahedron
1995, 51, 7999-814)
Second Proposal:
[0109] 0.2 mmol of the diester
3-(N-formyl-N-hydroxylamino)-propylphosphonic acid dioctadecylester
13 dissolved in ethanol is added to 1 equivalent KOH (ethanolic
solution) and boiled for 10 hours under reflux. Owing to the
introduction of CO.sub.2, potassium salts can precipitate as
carbonates and can be removed by filtration. The filtrate is
condensed to dryness, the oil is dried over P.sub.2O.sub.5, washed
with petrol ether and the product can finally be recrystallised
from absolute ethanol by the addition of isopropanol.
[0110] (On the carrying out of the procedure cf.: V. Jagodic, Chem
Ber 1960, 93, 2308-13)
Example 14
3-(N-formyl-N-hydroxylamino)-propylphosphonic acid
monohexadecyl-ester 14
[0111] 14 can be synthesised in the same way as 13.
* * * * *
References