DE19902924A1 - Use of organophosphorus compounds for the prophylactic and therapeutic treatment of infections - Google Patents
Use of organophosphorus compounds for the prophylactic and therapeutic treatment of infectionsInfo
- Publication number
- DE19902924A1 DE19902924A1 DE19902924A DE19902924A DE19902924A1 DE 19902924 A1 DE19902924 A1 DE 19902924A1 DE 19902924 A DE19902924 A DE 19902924A DE 19902924 A DE19902924 A DE 19902924A DE 19902924 A1 DE19902924 A1 DE 19902924A1
- Authority
- DE
- Germany
- Prior art keywords
- viruses
- substituted
- genus
- bacteria
- unsubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 208000015181 infectious disease Diseases 0.000 title claims abstract description 15
- 150000002903 organophosphorus compounds Chemical class 0.000 title claims description 15
- 238000011282 treatment Methods 0.000 title claims description 15
- 230000001225 therapeutic effect Effects 0.000 title abstract description 4
- 230000000069 prophylactic effect Effects 0.000 title 1
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- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 8
- 239000003899 bactericide agent Substances 0.000 claims abstract description 5
- 239000000417 fungicide Substances 0.000 claims abstract description 5
- 239000004009 herbicide Substances 0.000 claims abstract description 5
- -1 alkyl radicals Chemical class 0.000 claims description 108
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 22
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 12
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- 125000004434 sulfur atom Chemical group 0.000 claims description 5
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- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 claims description 4
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- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 4
- 208000000230 African Trypanosomiasis Diseases 0.000 claims description 4
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical group [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 claims description 4
- 229930186147 Cephalosporin Natural products 0.000 claims description 4
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 4
- 241000193403 Clostridium Species 0.000 claims description 4
- 241000711573 Coronaviridae Species 0.000 claims description 4
- 241000186216 Corynebacterium Species 0.000 claims description 4
- 241000709687 Coxsackievirus Species 0.000 claims description 4
- 241000709661 Enterovirus Species 0.000 claims description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 4
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- 208000007514 Herpes zoster Diseases 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
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- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 claims description 4
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 claims description 4
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- 229930101531 artemisinin Natural products 0.000 claims description 4
- JFIOVJDNOJYLKP-UHFFFAOYSA-N bithionol Chemical compound OC1=C(Cl)C=C(Cl)C=C1SC1=CC(Cl)=CC(Cl)=C1O JFIOVJDNOJYLKP-UHFFFAOYSA-N 0.000 claims description 4
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- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims description 4
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 claims description 4
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Landscapes
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Abstract
Description
Die Erfindung betrifft die Verwendung von phosphororganischen Verbindungen sowie ihren Salzen, Estern und Amiden zur thera peutischen und prophylaktischen Behandlung von Infektionen bei Mensch und Tier, die durch Viren, Bakterien, Pilze und Parasi ten hervorgerufen werden, und ihre Verwendung als Fungizid, Bakterizid und Herbizid bei Pflanzen. Erfindungsgemäß umfassen die phosphororganischen Verbindungen Phosphinoylderivate, Phosphinsäurederivate und Phosphonsäurederivate.The invention relates to the use of organophosphorus Compounds and their salts, esters and amides to thera therapeutic and prophylactic treatment of infections Humans and animals caused by viruses, bacteria, fungi and parasites and their use as a fungicide, Bactericide and herbicide in plants. According to the invention the organophosphorus compounds phosphinoyl derivatives, Phosphinic acid derivatives and phosphonic acid derivatives.
Es besteht ein starker Bedarf, für die Bereicherung der Be handlung von Mensch und Tier sowie den Schutz von Pflanzen Mittel bereitzustellen, die nicht nur eine starke Wirksamkeit besitzen, sondern auch im Gegensatz zu anderen Arzneimitteln bzw. Pflanzenschutzmitteln verringerte Nebenwirkungen zeigen und damit eine geringere Gesundheitsgefahr für den Menschen bedeuten.There is a strong need to enrich the Be action of humans and animals as well as the protection of plants Provide funds that are not just powerful own, but unlike other medicines or pesticides show reduced side effects and thus a lower risk to human health mean.
Aufgabe der vorliegenden Erfindung ist es daher, eine Substanz bereitzustellen, die bei Infektionen durch Viren, Bakterien, Pilze und Parasiten bei Menschen und Tieren und als Fungizid, Bakterizid und Herbizid bei Pflanzen einsetzbar ist und die oben angegebenen Bedingungen erfüllt.The object of the present invention is therefore a substance to provide, in the case of infections caused by viruses, bacteria, Fungi and parasites in humans and animals and as a fungicide, Bactericide and herbicide can be used in plants and the conditions specified above.
Diese Aufgabe wird in völlig überraschender Weise durch die Verwendung der in Anspruch 1 definierte Stoffgruppe gelöst. This task is done in a completely surprising way by Use of the group of substances defined in claim 1 solved.
Diese Stoffgruppe zeigt eine antiinfektiöse Wirkung gegen Vi ren, bestimmte Bakterien, Pilze, ein- und mehrzellige Parasi ten.This group of substances shows an anti-infectious effect against Vi certain bacteria, fungi, single and multicellular parasites ten.
Die erfindungsgemäß verwendeten phosphororganischen Verbindun
gen entsprechen der allgemeinen Formel (I):
The organophosphorus compounds used according to the invention correspond to the general formula (I):
in der X ein Phosphoratom oder ein Schwefelatom ist,
wobei A eine unverzweigte C2-9-Alkylenkette ist mit Substituen
ten, die gleich oder verschieden sind und aus der Gruppe aus
gewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, Amino-
und Oxogruppen, C1-26-Alkylresten, C1-26-Alkoxyresten, C1-26-
Alkoxy-C1-26-Alkylresten oder C3-8-Cycloalkyl-(C0-9)-alkylgruppen
besteht, wobei jeder C1-26-Alkylrest und jeder C1-26-Alkoxyrest
verzweigt oder unverzweigt und gesättigt oder mit ein oder
mehreren Doppelbindungen ungesättigt sein kann und mit Hy
droxy-, Amino-, Halogen- und Oxogruppen substituiert sein kann
und sowohl die C3-8-Cycloalkylgruppe als auch die C0-9-
Alkylgruppe der C3-8-Cycloalkyl-(C0-9)-alkylgruppe ein oder meh
rere Doppelbindungen aufweisen können und ein oder zwei Koh
lenstoffatome der Cycloalkylgruppe durch Stickstoff-, Sauer
stoff- oder Schwefelatome ersetzt sein können, und wobei so
wohl die Cycloalkylgruppe als auch die Alkylgruppe mit Hy
droxy-, Halogen-, Amino-, Oxogruppen mit verzweigten oder un
verzweigten C1-9-Alkylgruppen und C2-9-Alkenylgruppen substitu
iert sein können, wobei die C1-9-Alkylgruppen und C2-9-
Alkenylgruppen mit Wasserstoff-, Hydroxy-, Amino-, Halogen-
und Oxogruppen substituiert sein können
in der R1 und R2 gleich oder verschieden sind und aus der Grup-
pe ausgewählt sind, die aus Wasserstoff, substituiertem und
unsubstituiertem C1-9-Alkyl, substituiertem und unsubstituier
tem Hydroxy-C1-9-alkyl, substituiertem und unsubstituiertem
C1-9-Alkenyl, substituiertem und unsubstituiertem C1-9-Alkinyl,
substituiertem und unsubstituiertem Aryl, substituiertem und
unsubstituiertem Acyl, substituiertem und unsubstituiertem Cy
cloalkyl, substituiertem und unsubstituiertem Aralkyl, substi
tuiertem und unsubstituiertem heterocyclischen Rest, Halogen,
OX1 und OX2 besteht,
wobei X1 und X2 gleich oder verschieden sind und aus der Gruppe
ausgewählt ist, die aus Wasserstoff, substituiertem und unsub
stituiertem C1-9-Alkyl, substituiertem und unsubstituiertem Hy
droxy-C1-9-alkyl, substituiertem und unsubstituiertem C1-9-
Alkenyl, substituiertem und unsubstituiertem C1-9-Alkinyl, sub
stituiertem und unsubstituiertem Aryl, substituiertem und un
substituiertem Acyl, substituiertem und unsubstituiertem Cy
cloalkyl, substituiertem und unsubstituiertem Aralkyl, substi
tuiertem und unsubstituiertem heterocyclischen Rest besteht,
in der R3 und R4 gleich oder verschieden sind und aus der Grup
pe ausgewählt sind, die aus substituiertem und unsubstituier
tem C1-26-Alkyl, Hydroxy-C1-26-alkyl, substituiertem und unsub
stituiertem Aryl, substituiertem und unsubstituiertem Acyl,
substituiertem und unsubstituiertem Aralkyl, substituiertem
und unsubstituiertem C1-26-Alkenyl, substituiertem und unsubsti
tuiertem C1-26-Alkinyl, substituiertem und unsubstituiertem Cy
cloalkyl, substituiertem und unsubstituiertem heterocyclischem
Rest, Halogen, OX3 und OX4 besteht,
wobei X3 und X4 gleich oder verschieden sind und aus der Gruppe
ausgewählt sind, die aus Wasserstoff, substituiertem und un
substituiertem C1-26-Alkyl, substituiertem und unsubstituiertem
Hydroxy-C1-26-alkyl, substituiertem und unsubstituiertem Aryl,
substituiertem und unsubstituiertem Aralkyl, substituiertem
und unsubstituiertem C1-26-Alkenyl, substituiertem und unsubsti
tuiertem C1-26-Alkinyl, substituiertem und unsubstituiertem Cy
cloalkyl, substituiertem und unsubstituiertem heterocyclischem
Rest, einem Silyl, einem Kation einer organischen und anorga
nischen Base, insbesondere einem Metall der ersten, zweiten
oder dritten Hauptgruppe des Periodensystems, Ammonium, sub
stituiertem Ammonium und Ammoniumverbindungen, die sich von
Ethylendiamin oder Aminosäuren ableiten, besteht,
und deren pharmazeutisch akzeptablen Salze, Ester und Amide
und Salze der Ester.in which X is a phosphorus atom or a sulfur atom,
where A is an unbranched C 2-9 alkylene chain with substituents which are identical or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino and oxo groups, C 1-26 alkyl radicals, C 1-26 alkoxy, C 1-26 alkoxy-C 1-26 alkyl or C 3-8 cycloalkyl (C 0-9 ) alkyl groups, each C 1-26 alkyl and each C 1 -26 -Alkoxy radical is branched or unbranched and saturated or can be unsaturated with one or more double bonds and can be substituted with hydroxyl, amino, halogen and oxo groups and both the C 3-8 cycloalkyl group and the C 0-9 - Alkyl group of the C 3-8 cycloalkyl (C 0-9 ) alkyl group may have one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and so well the cycloalkyl group as well as the alkyl group with hy droxy, halogen, amino, oxo groups with branched or unbranched C 1-9 alkyl groups and C 2-9 alkenyl groups may be substituted, the C 1-9 alkyl groups and C 2-9 alkenyl groups having hydrogen, hydroxyl, amino, halogen and oxo groups can be substituted
in which R 1 and R 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1-9 alkyl, substituted and unsubstituted hydroxy-C 1-9 alkyl, substituted and unsubstituted C 1-9 alkenyl, substituted and unsubstituted C 1-9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OX 1 and OX 2 exists
wherein X 1 and X 2 are the same or different and is selected from the group consisting of hydrogen, substituted and unsubstituted C 1-9 alkyl, substituted and unsubstituted hydroxy C 1-9 alkyl, substituted and unsubstituted C 1 -9 - alkenyl, substituted and unsubstituted C 1-9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical,
in which R 3 and R 4 are the same or different and are selected from the group consisting of substituted and unsubstituted C 1-26 alkyl, hydroxyC 1-26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted Acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C 1-26 alkenyl, substituted and unsubstituted C 1-26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX 3 and OX 4 ,
wherein X 3 and X 4 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1-26 alkyl, substituted and unsubstituted hydroxyC 1-26 alkyl, substituted and unsubstituted aryl and unsubstituted aralkyl, substituted and unsubstituted C 1-26 alkenyl, substituted and unsubstituted C 1-26 alkynyl, 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 table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of the esters.
Bevorzugt sind X3 und X4 ein Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammonium, substitu iertes Ammonium, oder Ammoniumverbindungen, die sich von Ethy lendiamin oder Aminosäuren ableiten. D. h. es werden die Salz verbindungen der phosphororganischen Verbindungen mit organi schen oder anorganischen Basen (z. B. Natriumsalz, Kaliumsalz, Calciumsalz, Aluminiumsalz, Ammoniumsalz, Magnesiumsalz, Trie thylaminsalz, Ethanolaminsalz, Dicyclohexylaminsalz, Ethylen diaminsalz, N,N'-Dibenzylethylen-diaminsalz etc.) sowie Salze mit Aminosäuren (z. B. Argininsalz, Asparaginsäuresalz, Gluta minsäuresalz etc.) und dergleichen gebildet.X 3 and X 4 are preferably a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids. That is, there are the salt compounds of organophosphorus compounds with organic or inorganic bases (e.g. sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylene diamine salt, N, N'-dibenzylethylene diamine salt, etc .) and salts with amino acids (z. B. arginine salt, aspartic acid salt, glutamic acid salt, etc.) and the like.
Besonders bevorzugt sind X3 und X4 gleich oder verschieden und aus der Gruppe ausgewählt, die aus Wasserstoff, Natrium, Kali um, Methyl, Ethyl besteht.X 3 and X 4 are particularly preferably the same or different and selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl.
Bevorzugt ist A eine C3-5-Alkylkette.A is preferably a C 3-5 alkyl chain.
Besonders bevorzugt sind Verbindungen der Formel (II)
Compounds of the formula (II) are particularly preferred
wobei X, R1, R3, R4 wie oben definiert sind, wobei R1 bevorzugt
an dem dem Heteroatom benachbarten C-Atom mit einer Hydroxy
gruppe substituiert ist,
und Verbindungen der Formel (III)
where X, R 1 , R 3 , R 4 are as defined above, where R 1 is preferably substituted on the C atom adjacent to the hetero atom by a hydroxyl group,
and compounds of the formula (III)
wobei X, R1, R3, R4 wie oben definiert sind, wobei R1 bevorzugt eine Acylgruppe, besonders bevorzugt eine Formyl-, Acetyl-, Propionyl- oder Butyrylgruppe ist.wherein X, R 1 , R 3 , R 4 are as defined above, wherein R 1 is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group.
Ebenfalls sind Verbindungen mit den folgenden Strukturen be
vorzugt:
Connections with the following structures are also preferred:
Besonderheiten der obigen Definitionen und geeignete Beispiele
dafür werden nachfolgend angegeben:
"Acyl" ist ein Substituent, der von einer Säure stammt, wie
von einer organischen Carbonsäure, Kohlensäure, Carbaminsäure
oder der den einzelnen vorstehenden Säuren entsprechenden
Thiosäure oder Imidsäure, oder von einer organischen Sulfon
säure, wobei diese Säuren jeweils aliphatische, aromatische
und/oder heterocyclische Gruppen im Molekül umfassen sowie
Carbamoyl oder Carbamimidoyl.Special features of the above definitions and suitable examples are given below:
"Acyl" is a substituent derived from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual acids above, or from an organic sulfonic acid, these acids each being aliphatic, aromatic and / or include heterocyclic groups in the molecule as well as carbamoyl or carbamimidoyl.
Geeignete Beispiele für diese Acylgruppen werden nachfolgend angegeben.Suitable examples of these acyl groups are shown below specified.
Als aliphatische Acylgruppen werden von einer aliphatischen
Säure stammende Acylreste bezeichnet, zu denen die folgenden
gehören:
Alkanoyl (z. B. Formyl, Acetyl, Propionyl, Butyryl, Isobutyryl,
Valeryl, Isovaleryl, Pivaloyl etc.);
Alkenoyl (z. B. Acryloyl, Methacryloyl, Crotonoyl etc.);
Alkylthioalkanoyl (z. B. Methylthioacetyl, Ethylthioacetyl
etc.)
Alkansulfonyl (z. B. Mesyl, Ethansulfonyl, Propansulfonyl
etc.);
Alkoxycarbonyl (z. B. Methoxycarbonyl, Ethoxycarbonyl, Propoxy
carbonyl, Isopropoxycarbonyl, Butoxycarbonyl, Isobutoxycar
bonyl etc.);
Alkylcarbamoyl (z. B. Methylcarbamoyl etc.);
(N-Alkyl)-thiocarbamoyl (z. B. (N-Methyl)-thiocarbamoyl etc.);
Alkylcarbamimidöyl (z. B. Methylcarbamimidoyl etc.);
Oxalo;
Alkoxalyl (z. B. Methoxalyl, Ethoxalyl, Propoxalyl etc.).Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
Alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.);
Alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl etc.);
Alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl etc.)
Alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.);
Alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.);
Alkyl carbamoyl (e.g. methyl carbamoyl etc.);
(N-alkyl) thiocarbamoyl (e.g. (N-methyl) thiocarbamoyl etc.);
Alkyl carbamimidöyl (e.g. methyl carbamimidoyl etc.);
Oxalo;
Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
Bei den obigen Beispielen für aliphatische Acylgruppen kann der aliphatische Kohlenwasserstoffteil, insbesondere die Al kylgruppe bzw. der Alkanrest, ggf. einen oder mehrere geeigne te Substituenten aufweisen, wie Amino, Halogen (z. B. Fluor, Chlor, Brom etc.), Hydroxy, Hydroxyimino, Carboxy, Alkoxy (z. B. Methoxy, Ethoxy, Propoxy etc.), Alkoxycarbonyl, Acylami no (z. B. Benzyloxycarbonylamino etc.), Acyloxy (z. B. Acetoxy, Benzoyloxy etc.) und dergleichen; als bevorzugte aliphatische Acylreste mit solchen Substituenten sind z. B. mit Amino, Car boxy, Amino und Carboxy, Halogen, Acylamino oder dergleichen substituierte Alkanoyle zu nennen.In the above examples of aliphatic acyl groups the aliphatic hydrocarbon part, especially the Al kylgruppe or the alkane radical, optionally one or more suitable have substituents such as amino, halogen (e.g. fluorine, Chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylami no (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, Benzoyloxy etc.) and the like; as the preferred aliphatic Acyl radicals with such substituents are e.g. B. with amino, car boxy, amino and carboxy, halogen, acylamino or the like to name substituted alkanoyle.
Als aromatische Acylreste werden solche Acylreste bezeichnet,
die von einer Säure mit substituierter oder nicht substituier
ter Arylgruppe stammen, wobei die Arylgruppe Phenyl, Toluyl,
Xylyl, Naphthyl und dergleichen umfassen kann; geeignete Bei
spiele werden nachfolgend angegeben:
Aroyl (z. B. Benzoyl, Toluoyl, Xyloyl, Naphthoyl, Phthaloyl
etc.);
Aralkanoyl (z. B. Phenylacetyl etc.);
Aralkenoyl (z. B. Cinnamoyl etc.);
Aryloxyalkanoyl (z. B. Phenoxyacetyl etc.);
Arylthioalkanoyl (z. B. Phenylthioacetyl etc.);
Arylaminoalkanoyl (z. B. N-Phenylglycyl, etc.);
Arensulfonyl (z. B. Benzolsulfonyl, Tosyl bzw. Toluolsulfonyl,
Naphthalinsulfonyl etc.);
Aryloxycarbonyl (z. B. Phenoxycarbonyl, Naphthyl-oxycarbonyl
etc.);
Aralkoxycarbonyl (z. B. Benzyloxycarbonyl etc.);
Arylcarbamoyl (z. B. Phenylcarbamoyl, Naphthylcarbamoyl etc.);
Arylglyoxyloyl (z. B. Phenylglyoxyloyl etc.).Aromatic acyl radicals are those acyl radicals which derive from an acid having a substituted or unsubstituted aryl group, where the aryl group can include phenyl, toluyl, xylyl, naphthyl and the like; Suitable examples are given below:
Aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);
Aralkanoyl (e.g. phenylacetyl etc.);
Aralkenoyl (e.g. cinnamoyl etc.);
Aryloxyalkanoyl (e.g. phenoxyacetyl etc.);
Arylthioalkanoyl (e.g. phenylthioacetyl etc.);
Arylaminoalkanoyl (e.g. N-phenylglycyl, etc.);
Arenesulfonyl (e.g. benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl, etc.);
Aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.);
Aralkoxycarbonyl (e.g. benzyloxycarbonyl etc.);
Arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl etc.);
Arylglyoxyloyl (e.g. phenylglyoxyloyl etc.).
Bei den vorstehenden Beispielen für aromatische Acylreste kann
der aromatische Kohlenwasserstoffteil (insbesondere der Aryl
rest) und/oder der aliphatische Kohlenwasserstoffteil (insbe
sondere der Alkanrest) ggf. ein oder mehrere geeignete Substi
tuenten aufweisen, wie solche, die als geeignete Substituenten
für die Alkylgruppe bzw. den Alkanrest bereits angegeben wur
den. Insbesondere und als Beispiel für bevorzugte aromatische
Acylreste mit besonderen Substituenten werden mit Halogen und
Hydroxy oder mit Halogen und Acyloxy substituiertes Aroyl und
mit Hydroxy, Hydroxyimino, Dihalogenalkanoyloxyimino substitu
iertes Aralkanoyl angegeben sowie
Arylthiocarbamoyl (z. B. Phenylthiocarbamoyl etc.);
Arylcarbamimidoyl (z. B. Phenylcarbamimidoyl etc.).In the above 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 have one or more suitable substituents, such as those which are suitable substituents for the alkyl group or the alkane residue has already been given. In particular and as an example of preferred aromatic acyl radicals with special substituents, arylanoyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are also given
Arylthiocarbamoyl (e.g. phenylthiocarbamoyl etc.);
Arylcarbamimidoyl (e.g. phenylcarbamimidoyl etc.).
Als heterocyclischer Acylrest wird ein Acylrest verstanden,
der von einer Säure mit heterocyclischer Gruppe stammt; dazu
gehören:
Heterocyclisches Carbonyl, bei dem der heterocyclische Rest
ein aromatischer oder aliphatischer 5- bis 6-gliedriger He
terocyclus mit zumindest einem Heteroatom aus der Gruppe
Stickstoff, Sauerstoff und Schwefel ist (z. B. Thiophenyl, Fu
royl, Pyrrolcarbonyl, Nicotinoyl etc.);
Heterocyclus-Alkanoyl, bei dem der heterocyclische Rest 5- bis
6-gliedrig ist und zumindest ein Heteroatom aus der Gruppe
Stickstoff, Sauerstoff und Schwefel aufweist (z. B. Thiophen
yl-acetyl, Furylacetyl, Imidazolylpropionyl, Tetrazolylacetyl,
2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) und der
gleichen.A heterocyclic acyl radical is understood to mean an acyl radical which comes from an acid with a heterocyclic group; this includes:
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 consisting of nitrogen, oxygen and sulfur (e.g. thiophenyl, fuoyl, pyrrole carbonyl, nicotinoyl etc.);
Heterocycle alkanoyl, in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophene yl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2- Amino-4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
Bei den obigen Beispielen für heterocyclische Acylreste kann der Heterocyclus und/oder der aliphatische Kohlenwasserstoff teil ggf. einen oder mehrere geeignete Substituenten aufwei sen, wie die gleichen, die als geeignet für Alkyl- und Alkan gruppen angegeben wurden.In the above examples of heterocyclic acyl residues the heterocycle and / or the aliphatic hydrocarbon some may have one or more suitable substituents sen, like the same ones that are suitable for alkyl and alkane groups were specified.
"Alkyl" ist ein gerad- oder verzweigtkettiger Alkylrest mit bis zu 26 Kohlenstoffatomen, soweit er nicht anders definiert ist, wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Hexyl und dergleichen."Alkyl" is a straight or branched chain alkyl group with up to 26 carbon atoms, unless otherwise defined is like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
"Hydroxylalkyl" ist ein gerad- oder verzweigtkettiger Alkyl rest mit bis zu 26 Kohlenstoffatomen, soweit er nicht anders definiert ist, der mindestens eine Hydroxylgruppe aufweist, bevorzugt ein oder zwei Hydroxylgruppen."Hydroxylalkyl" is a straight or branched chain alkyl rest with up to 26 carbon atoms, unless otherwise is defined which has at least one hydroxyl group, preferably one or two hydroxyl groups.
Zu "Alkenyl" gehören gerad- oder verzweigtkettige Alkenylgrup pen mit bis zu 26 Kohlenstoffatomen, soweit er nicht anders definiert ist, wie z. B. Vinyl, Propenyl (z. B. 1-Propenyl, 2- Propenyl), 1-Methylpropenyl, 2-Methylpropenyl, Butenyl, 2- Ethylpropenyl, Pentenyl, Hexenyl."Alkenyl" includes straight or branched chain alkenyl groups pen with up to 26 carbon atoms, unless otherwise is defined as e.g. B. vinyl, propenyl (e.g. 1-propenyl, 2- Propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2- Ethyl propenyl, pentenyl, hexenyl.
Zu "Alkinyl" gehören gerad- oder verzweigtkettige Alkinylgrup pen mit bis zu 26 Kohlenstoffatomen, soweit er nicht anders definiert ist."Alkynyl" includes straight or branched chain alkynyl groups pen with up to 26 carbon atoms, unless otherwise is defined.
Cycloalkyl steht vorzugsweise für ein ggfs. substituiertes C3-8- Cycloalkyl; als mögliche Substituenten sind u. a. Alkyl, Alke nyl, Alkinyl, Alkoxy (z. B. Methoxy, Ethoxy etc.), Halogen (z. B. Fluor, Chlor, Brom etc.), Nitro und dergleichen geeig net.Cycloalkyl preferably represents an optionally substituted C 3-8 cycloalkyl; possible substituents include alkyl, alkylene, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like.
Aryl ist ein aromatischer Kohlenwasserstoffrest, wie Phenyl Naphthyl usw., der ggf. einen oder mehrere geeignete Substitu enten aufweisen kann, wie Alkyl, Alkenyl, Alkinyl, Alkoxy (z. B. Methoxy, Ethoxy etc.), Halogen (z. B. Fluor, Chlor, Brom etc.), Nitro unb dergleichen.Aryl is an aromatic hydrocarbon residue, such as phenyl Naphthyl, etc., which optionally one or more suitable substituents can have ducks, such as alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like.
Zu "Aralkyl" gehören Mono-, Di-, Triphenylalkyle wie Benzyl, Phenethyl, Benzhydryl, Trityl und dergleichen, wobei der aro matische Teil ggf. ein oder mehrere geeignete Substituenten aufweisen kann wie Alkoxy (z. B. Methoxy, Ethoxy etc.), Halogen (z. B. Fluor, Chlor, Brom etc.), Nitro und dergleichen."Aralkyl" includes mono-, di-, triphenylalkyls such as benzyl, Phenethyl, benzhydryl, trityl and the like, the aro Matic part optionally one or more suitable substituents may have such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine, etc.), nitro and the like.
Vorzugsweise können die Reste X3 und X4 so gewählt werden, daß
Ester an der Phosphinogruppe oder Phosphonogruppe gebildet
werden. Zu geeigneten Beispielen für solche Ester gemäß der
Formeln (I) bis (XI) zählen geeignete Mono- und Diester, und
zu bevorzugten Beispielen für solche Ester gehören Alkylester
(z. B. Hexadecanylester, Octadecanylester etc.);
Aralkylester (Benzylester, Phenethylester, Benzhydrylester,
Tritylester etc.).;
Arylester (z. B. Phenylester, Tolylester, Naphthylester etc.);
Aroylalkylester (z. B. Phenacylester etc.); und Silylester
(z. B. von Trialkylhalogensilyl, Dialkyldihalogensilyl, Alkyl
trihalogensilyl, Dialkylarylhalogensilyl, Trialkoxyhalogen
silyl, Dialkylaralkylhalogensilyl, Dialkoxydihalogensilyl,
Trialkoxyhalogensilyl etc.) und dergleichen.The radicals X 3 and X 4 can preferably be chosen such that esters are formed on the phosphino group or phosphono group. Suitable examples of such esters according to formulas (I) to (XI) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (e.g. hexadecanyl ester, octadecanyl ester, etc.);
Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, trityl esters etc.) .;
Aryl esters (e.g. phenyl esters, tolyl esters, naphthyl esters, etc.);
Aroyl alkyl esters (e.g. phenacyl esters etc.); and silyl esters (e.g., from trialkylhalosilyl, dialkyldihalosilyl, alkyl trihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.) and the like.
Beim obigen Ester kann der Alkan- und/oder Arenteil wahlweise zumindest einen geeigneten Substituenten aufweisen wie Halo gen, Alkoxy, Hydroxy, Nitro oder dergleichen.In the above ester, the alkane and / or arene part can be optional have at least one suitable substituent such as halo gene, alkoxy, hydroxy, nitro or the like.
Die erfindungsgemäß verwendeten Verbindungen gemäß der Formeln (I) bis (XI) können in ihrer protonierten Form als Ammonium salz organischer oder anorganischer Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Methansul fonsäure, p-Toluolsulfonsäure, Essigsäure, Milchsäure, Malein säure, Fumarsäure, Oxalsäure, Weinsäure, Benzoesäure, etc. vorliegen.The compounds used according to the invention according to the formulas (I) to (XI) can be in their protonated form as ammonium salt of organic or inorganic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesul fonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, malein acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc. available.
Die erfindungsgemäß verwendeten Verbindungen der Formeln (I) bis (XI) lassen beispielsweise für Doppelbindungen enthaltende oder chirale Gruppen R1, R2, R3, R4, X1, X2, X3, X4 oder A das Auftreten räumlicher Isomerer zu. Die erfindungsgemäße Verwen dung der Verbindungen umfaßt alle räumlichen Isomere sowohl als Reinstoffe als auch in Form ihrer Mischungen.The compounds of the formulas (I) to (XI) used according to the invention allow, for example for double-containing or chiral groups R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 or A, to occur spatial isomers to. The use of the compounds according to the invention comprises all spatial isomers both as pure substances and in the form of their mixtures.
Die phosphororganischen Verbindungen sind insbesondere für die therapeutische und prophylaktischen Behandlung von Infektionen bei Mensch und Tier geeignet, die durch Viren, Bakterien, ein- und mehrzellige Parasiten und Pilze hervorgerufen werden.The organophosphorus compounds are particularly suitable for therapeutic and prophylactic treatment of infections suitable for humans and animals that are infected by viruses, bacteria, and causing multicellular parasites and fungi.
Die Verbindungen sind gegen einzellige Parasiten (Protozoen) wirksam, insbesondere gegen Erreger der Malaria und der Schlafkrankheit sowie der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeglerose, der Kokzidio se, der Giardiose und der Lambliose.The compounds are against unicellular parasites (protozoa) effective, especially against malaria and Sleeping sickness as well as Chagas disease, toxoplasmosis, the amoebic dysentery, the leishmaniasis, the trichomoniasis, the Pneumocystosis, balantidiosis, cryptosporidiosis, Sarcocystosis, Acanthoma, Naeglerosis, Coccidio se, the Giardiosis and the Lambliosis.
Sie sind daher insbesondere als Malariaprophylaxe und als Pro phylaxe der Schlafkrankheit sowie der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomo niasis, der Pneumozystose, der Balantidiose, der Kryptospori diose, der Sarkozystose, der Akanthamöbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose geeignet.They are therefore especially as malaria prophylaxis and as a pro prevention of sleeping sickness and Chagas disease, the Toxoplasmosis, the amoebic dysentery, the leishmaniasis, the trichomo niasis, pneumocystosis, balantidiosis, cryptospori diose, sarcolocystosis, acanthoma, nail disease, coccidiosis, giardiosis and lambliosis.
Die erfindungsgemäßen Wirkstoffe sind insbesondere gegen die
folgenden Bakterien einsetzbar:
Bakterien der Familie Propionibacteriaceae, insbesondere der
Gattung Propionibacterium, insbesondere die Art Propionibacte
rium acnes,
Bakterien der Familie Actinomycetaceae, insbesondere der Gat
tung Actinomyces,
Bakterien der Gattung Corynebacterium, insbesondere die Arten
Corynebacterium diphteriae und Corynebacterium pseudotubercu
losis,
Bakterien der Familie Mycobacteriaceae, der Gattung Mycobacte
rium, insbesondere die Arten Mycobacterium leprae, Mycobacte
rium tuberculosis, Mycobacterium bovis und Mycobacterium avi
um,
Bakterien der Familie Chlamydiaceae, insbesondere die Spezies
Chlamydia trachomatis und Chlamydia psittaci,
Bakterien der Gattung Listeria, insbesondere die Art Listeria
monocytogenes,
Bakterien der Art Erysipelthrix rhusiopathiae,
Bakterien der Gattung Clostridium,
Bakterien der Gattung Yersinia, der Spezies Yersinia pestis,
Yersinia pseudotuberculosis, Yersinia enterocolitica und Yer
sinia ruckeri,
Bakterien der Familie Mycoplasmataceae, der Gattungen My
coplasma und Ureaplasma, insbesondere die Art Mycoplasma pneu
moniae,
Bakterien der Gattung Brucella,
Bakterien der Gattung Bordetella,
Bakterien der Familie Neisseriaceae, insbesondere der Gattun
gen Neisseria und Moraxella, insbesondere die Arten Neisseria
meningitides, Neisseria gonorrhoeae und Moraxella bovis,
Bakterien der Familie Vibrionaceae, insbesondere der Gattungen
Vibrio, Aeromonas, Plesiomonas und Photobacterium, insbesonde
re die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas
salmonicidas,
Bakterien der Gattung Campylobacter, insbesondere die Arten
Campylobacter jejuni, Campylobacter coli und Campylobacter fe
tus,
Bakterien der Gattung Helicobacter, insbesondere die Art Heli
cobacter pylori,
Bakterien der Familien Spirochaetaceae und der Leptospiraceae,
insbesondere der Gattungen Treponema, Borrelia und Leptospira,
insbesondere Borrelia burgdorferi,
Bakterien der Gattung Actinobacillus,
Bakterien der Familie Legionellaceae, der Gattung Legionella,
Bakterien der Familie Rickettsiaceae und Familie Bartonella
ceae,
Bakterien der Gattungen Nocardia und Rhodococcus,
Bakterien der Gattung Dermatophilus,
Bakterien der Familie Pseudomonadaceae, insbesondere der Gat
tungen Pseudomonas und Xanthomonas,
Bakterien der Familie Enterobacteriaceae, insbesondere der
Gattungen Escherichia, Klebstella, Proteus, Providencia, Sal
monella, Serratia und Shigella,
Bakterien der Familie Pasteurellaceae, insbesondere der Gat
tung Haemophilus,
Bakterien der Familie Micrococcaceae, insbesondere der Gattun
gen Micrococcus und Staphylococcus,
Bakterien der Familie Streptococcaceae, insbesondere der Gat
tungen Streptococcus und Enterococcus und
Bakterien der Familie Bacillaceae, insbesondere der Gattungen
Bacillus und Clostridium.The active compounds according to the invention can be used in particular against the following bacteria:
Bacteria of the Propionibacteriaceae family, in particular of the Propionibacterium genus, in particular the Propionibacte rium acnes species,
Bacteria of the Actinomycetaceae family, in particular the Actinomyces gate,
Bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotubercu losis,
Bacteria of the family Mycobacteriaceae, of the genus Mycobacte rium, in particular the species Mycobacterium leprae, Mycobacte rium tuberculosis, Mycobacterium bovis and Mycobacterium avi um,
Bacteria of the family Chlamydiaceae, in particular the species Chlamydia trachomatis and Chlamydia psittaci,
Bacteria of the genus Listeria, in particular the species Listeria monocytogenes,
Bacteria of the species Erysipelthrix rhusiopathiae,
Bacteria of the genus Clostridium,
Bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yer sinia ruckeri,
Bacteria of the family Mycoplasmataceae, the genera My coplasma and Ureaplasma, especially the species Mycoplasma pneu moniae,
Bacteria of the genus Brucella,
Bacteria of the genus Bordetella,
Bacteria of the Neisseriaceae family, in particular of the Neisseria and Moraxella genus, in particular the Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis species,
Bacteria of the Vibrionaceae family, in particular of the Vibrio, Aeromonas, Plesiomonas and Photobacterium genera, in particular the Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas species,
Bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fe tus,
Bacteria of the genus Helicobacter, in particular the species Heli cobacter pylori,
Bacteria of the Spirochaetaceae and Leptospiraceae families,
especially the genera Treponema, Borrelia and Leptospira,
especially Borrelia burgdorferi,
Bacteria of the genus Actinobacillus,
Bacteria of the Legionellaceae family, the genus Legionella,
Bacteria of the family Rickettsiaceae and family Bartonella ceae,
Bacteria of the genera Nocardia and Rhodococcus,
Bacteria of the genus Dermatophilus,
Bacteria of the Pseudomonadaceae family, in particular the Pseudomonas and Xanthomonas species,
Bacteria of the Enterobacteriaceae family, in particular of the genera Escherichia, Klebstella, Proteus, Providencia, Sal monella, Serratia and Shigella,
Bacteria of the Pasteurellaceae family, especially the Gat tung Haemophilus,
Bacteria of the Micrococcaceae family, in particular of the genera Micrococcus and Staphylococcus,
Bacteria of the Streptococcaceae family, especially the Streptococcus and Enterococcus and
Bacteria of the Bacillaceae family, especially the genera Bacillus and Clostridium.
Damit eignen sich phosphororganischen Verbindungen und ihre Derivate zur Behandlung der Diphterie, der Acne vulgaris, der Listeriosen, des Rotlaufs bei Tieren, der Gasbrand beim Mensch und beim Tier, Pararauschbrand bei Mensch und Tier, Tuberkulo se bei Mensch und Tier, Lepra, und weitere Mykobacteriosen bei Mensch und Tier, der Paratuberkulose der Tiere, Pest, mesente rialen Lymphadenitis und Pseudotuberkulose bei Mensch und Tier, Cholera, Legionärskrankheit, Borreliose bei Mensch und Tier, Leptospirosen bei Mensch und Tier, Syphilis, Campylobac ter-Enteritiden bei Mensch und Tier, Moraxella-Keratokonjunc tivitis und Serositis der Tiere, Brucellosen der Tiere und des Menschen, Milzbrand bei Mensch und Tier, Aktinomykose bei Mensch und Tier, Streptotrichosen, Psittakose/Ornithose bei Tieren, Q-Fieber, Ehrlichiose.Organophosphorus compounds and their are therefore suitable Derivatives for the treatment of the diphtheria, the acne vulgaris, the Listeriosis, the erysipelas in animals, the gas fire in humans and in animals, para-rage in humans and animals, tuberculosis se in humans and animals, leprosy, and other mycobacteriosis Man and animal, paratuberculosis of animals, plague, mesente rial lymphadenitis and pseudotuberculosis in humans and Animal, cholera, legionnaires' disease, Lyme disease in humans and Animal, leptospirosis in humans and animals, syphilis, campylobac enteritis in humans and animals, Moraxella keratoconjunc tivitis and serositis of animals, brucellosis of animals and Humans, anthrax in humans and animals, actinomycosis in Humans and animals, streptotrichoses, psittacosis / ornithosis Animals, Q fever, Ehrlichiosis.
Weiter ist der Einsatz nützlich bei der Helicobacter- Eradikationstherapie bei Ulcera des Magendarmtraktes.The use is also useful in the Helicobacter Eradication therapy for ulcers of the gastrointestinal tract.
Es können auch Kombinationen mit einem weiteren Antibiotikum zur Behandlung der obengenannten Erkrankungen eingesetzt wer den. Für Kombinationspräparate mit anderen Antiinfektiva eig nen sich insbesondere Isoniazid, Rifampicin, Ethambutol, Pyra zinamid, Streptomycin, Protionamid und Dapson zur Behandlung der Tuberkulose.Combinations with another antibiotic can also be used used to treat the above diseases the. For combination products with other anti-infectives especially isoniazid, rifampicin, ethambutol, pyra zinamid, streptomycin, protionamide and dapsone for treatment tuberculosis.
Die erfindungsgemäßen Wirkstoffe sind ferner insbesondere bei
Infektionen mit folgenden Viren einsetzbar:
Parvoviridae: Parvoviren, Dependoviren, Densoviren,
Adenoviridae: Adenoviren, Mastadenoviren, Aviadenoviren,
Papovaviridae: Papovaviren, insbesondere Papillomaviren (soge
nannte Warzenviren), Polyomaviren, insbesondere JC-Virus, BK-
Virus, und Miopapovaviren,
Herpesviridae: Alle Herpesviren, insbesondere Herpes-Simplex-
Viren, der Varizellen/Zoster-Viren, menschlicher Zytomegalie
virus, Epstein-Barr-Viren, alle humanen Herpesviren, humanes
Herpesvirus 6, Humanes Herpesvirus 7, humanes Herpesvirus 8,
Poxviridae: Pockenviren, Orthopox-, Parapox-, Molluscum-
Contagiosum-Virus, Aviviren, Capriviren, Leporipoxviren,
alle primär hepatotropen Viren, Hepatitisviren: Hepatitis-A-
Viren, Hepatitis-B-Viren, Hepatitis-C-Viren, Hepatitis-D-
Viren, Hepatitis-E-Viren, Hepatitis-F-Viren, Hepatits-G-Viren,
Hepadnaviren: sämtliche Hepatitisviren, Hepatitis-B-Virus, He
patitis-D-Viren,
Picornaviridae: Picornaviren, alle Enteroviren, alle Poliovi
ren, alle Coxsackieviren, alle Echoviren, alle Rhinoviren, Re
patitis-A-Virus, Aphthoviren,
Calciviridae: Hepatitis-E-Viren,
Reoviridae: Reoviren, Orbiviren, Rotaviren,
Togaviridae: Togaviren, Alphaviren, Rubiviren, Pestiviren, Ru
bellavirus,
Flaviviridae: Flaviviren, FSME-Virus, Hepatitis-C-Virus,
Orthomyxoviridae: Alle Influenzaviren,
Paramyxoviridae: Paramyxoviren, Morbillivirus, Pneumovirus,
Masernvirus, Mumpsvirus,
Rhabdoviridae: Rhabdoviren, Rabiesvirus, Lyssavirus, viskulä
res Stomatitisvirus,
Coronaviridae: Coronaviren,
Bunyaviridae: Bunyaviren, Nairovirus, Phlebovirus, Uukuvirus,
Hantavirus, Hantaanvirus,
Arenaviridae: Arenaviren, lymphozytäres Choriomeningitis-
Virus,
Retroviridae: Retroviren, alle HTL-Viren, humanes T-cell Leu
kämievirus, Oncornaviren, Spumaviren, Lentiviren, alle HI-
Viren,
Filoviridae: Marburg- und Ebolavirus,
Slow-virus-Infektionen, Prionen,
Onkoviren und Leukämieviren.The active compounds according to the invention can also be used in particular for infections with the following viruses:
Parvoviridae: Parvoviruses, Dependoviruses, Densoviruses,
Adenoviridae: adenoviruses, mastadenoviruses, aviadenoviruses,
Papovaviridae: papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC virus, BK virus, and miopapovaviruses,
Herpesviridae: all herpes viruses, in particular herpes simplex viruses, the varicella / zoster viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpes viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8,
Poxviridae: smallpox viruses, Orthopox, Parapox, Molluscum Contagiosum virus, Aviviruses, Capriviruses, Leporipoxviruses,
all primarily hepatotropic viruses, hepatitis viruses: hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatits G viruses,
Hepadnaviruses: all hepatitis viruses, hepatitis B virus, He patitis D viruses,
Picornaviridae: Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echoviruses, all rhinoviruses, Re patitis A virus, aphthoviruses,
Calciviridae: hepatitis E viruses,
Reoviridae: reoviruses, orbiviruses, rotaviruses,
Togaviridae: Togaviruses, Alphaviruses, Rubiviruses, Pestiviruses, Ru bellavirus,
Flaviviridae: flaviviruses, TBE virus, hepatitis C virus,
Orthomyxoviridae: all influenza viruses,
Paramyxoviridae: paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus,
Rhabdoviridae: rhabdoviruses, rabies virus, lyssavirus, viscous stomatitis virus,
Coronaviridae: Coronaviruses,
Bunyaviridae: Bunyaviren, Nairovirus, Phlebovirus, Uukuvirus, Hantavirus, Hantaanvirus,
Arenaviridae: arenaviruses, lymphocytic choriomeningitis virus,
Retroviridae: retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, all HI viruses,
Filoviridae: Marburg and Ebola viruses,
Slow virus infections, prions,
Oncoviruses and leukemia viruses.
Die erfindungsgemäßen phosphororganischen Verbindungen sind
somit zur Bekämpfung folgender viraler Infekte geeignet:
Eradikation von Papillomaviren zur Vorbeugung von Tumoren,
insbesondere von Tumoren der Geschlechtsorgane verursacht
durch Papillomaviren beim Menschen, Eradikation von JC-Viren
und BK-Viren, Eradikation von Herpesviren, Eradikation humaner
Herpesviren 8 zur Behandlung der Kaposi-Sarkoma, Eradikation
von Zytomegalie-Viren vor Transplantationen, Eradikation von
Eppstein-Barr-Viren vor Transplantation und zur Vorbeugung von
Eppstein-Barr-Viren-assozierten Tumoren, Eradikation von Hepa
titisviren zur Behandlung von chronischen Leber-Erkrankungen
und zur Vorbeugung von Lebertumoren und Leberzirrhosen, Eradi
kation von Coxsackieviren bei Kardiomyopathien, Eradikation
von Coxsackieviren bei Diabetes-mellitus-Patienten, Eradikati
on von Immunschwäche-Viren in Mensch und Tier, Behandlung von
Begleitinfektionen in AIDS-Patienten, Behandlung von Entzün
dungen viraler Genese des Respirationstraktes (Larynxpapillo
me, Hyperplasien, Rhinitis, Pharyngitis, Bronchitis, Pneumoni
en), der Sinnesorgane (Keratokonjunktivitis), des Nervensy
stems (Poliomyelitis, Meningoenzephalitis, Enzephalitis, suba
kute sklerosierende Panenzephalitis, SSPE, progressive multi
fokale Leukoenzephalopathie, Lymphozytäre Choriomeningitis),
des Magen-Darm-Traktes (Stomatitis, Gingivostomatitis, Ösopha
gitis, Gastritis, Gastroenteritis, Durchfallerkrankungen), der
Leber und des Gallensystems (Hepatitis, Cholangitis, hepato
zelluläres Karzinom), des lymphatischen Gewebes (Mononukleose,
Lymphadenitis), des hämatopoetischen Systems, der Geschlechts
organe (Mumpsorchitis), der Haut (Warzen, Dermatitis, Herpes
labialis, Fieberbläschen, Herpes Zoster, Gürtelrose), der
Schleimhäute (Papillome, Konjunktivapapillome, Hyperplasien,
Dysplasien), des Herz-Blutgefäß-Systems (Arteriitis, Myokardi
tis, Endokarditis, Perikarditis), des Nieren-Harnweg-Systems,
der Geschlechtsorgane (Anogenitale Läsionen, Warzen, Genital
warzen, spitzen Kondylome, Dysplasien, Papillome, Zervix
dysplasien, Condylomata acuminata, Epidermodysplasia verruci
formis), der Bewegungsorgane (Myositis, Myalgien), Behandlung
der Maul- und Klauenseuche der Paarhufer, des Colorado-
Zeckenfiebers, des Dengue-Syndroms, des hämorrhagisches Fie
bers, der Frühsommermeningoenzephalitis (FSME) und des Gelb
fiebers.The organophosphorus compounds according to the invention are therefore suitable for combating the following viral infections:
Eradication of papillomaviruses for the prevention of tumors, in particular tumors of the genital organs caused by papillomaviruses 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 cytomegaloviruses Transplants, eradication of Eppstein-Barr viruses before transplantation and for the prevention of Eppstein-Barr virus-associated tumors, eradication of Hepa titis viruses for the treatment of chronic liver diseases and for the prevention of liver tumors and cirrhosis, eradication of Coxsackieviruses in cardiomyopathies, Eradication of Coxsackieviruses in diabetes mellitus patients, eradication of immunodeficiency viruses in humans and animals, treatment of concomitant infections in AIDS patients, treatment of inflammation of the viral genesis of the respiratory tract (laryngeal papillo me, hyperplasia, rhinitis, pharyngitis, bronchitis, pneumoni en), the sense organ e (keratoconjunctivitis), of the Nervensy stems (poliomyelitis, meningoencephalitis, encephalitis, suba kute sclerosing panencephalitis, SSPE, progressive multi-focal leukoencephalopathy, lymphocytic choriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, Ösopha Gitis gastritis, gastroenteritis, diarrhea ), the liver and the biliary system (hepatitis, cholangitis, hepato cellular carcinoma), the lymphatic tissue (mononucleosis, lymphadenitis), the hematopoietic system, the genital organs (mumpsorchitis), the skin (warts, dermatitis, herpes labialis, cold sores, herpes Zoster, shingles), the mucous membranes (papillomas, conjunctival apillomas, hyperplasias, dysplasias), the cardiovascular system (arteritis, myocarditis, endocarditis, pericarditis), the kidney-urinary system, the genital organs (anogenital lesions, warts, genitalia warts, pointed condylomas, dysplasias, papillomas, cervical dysplasias, condylomata acuminata, Epidermodysplasia verruci formis), the locomotive organs (myositis, myalgia), treatment of foot and mouth disease of the cloven hoofed animals, Colorado tick fever, dengue syndrome, hemorrhagic fever, early summer meningoencephalitis (TBE) and yellow fever.
Die beschriebenen Verbindungen, d. h. die phosphororganische Verbindungen nach den Formeln (I) bis (XI) und Ester und Amide derselben an der Phosphinogruppe sowie Salze derselben zeigen eine starke zytotoxische Wirksamkeit gegenüber ein- und mehr zelligen Parasiten, insbesondere gegenüber den Erregern der Malaria und der Schlafkrankheit. Demgemäß sind die erfindungs gemäßen Verbindungen für die Behandlung von Infektionskrank heiten brauchbar, die durch Viren, Bakterien, Parasiten und Pilze bei Mensch und Tier verursacht werden. Die Verbindungen sind auch für den Einsatz zur Vorbeugung von Erkrankungen, die durch Viren, Bakterien, Parasiten und Pilze hervorgerufen wer den, insbesondere als Malariaprophylaxe und als Schlafkrank heitsprophylaxe geeignet.The compounds described, i. H. the organophosphorus Compounds according to formulas (I) to (XI) and esters and amides show the same on the phosphino group and salts thereof a strong cytotoxic activity against one and more cellular parasites, especially against the pathogens of the Malaria and sleeping sickness. Accordingly, the invention appropriate compounds for the treatment of infectious useful by viruses, bacteria, parasites and Fungi are caused in humans and animals. The connections are also for use to prevent diseases that caused by viruses, bacteria, parasites and fungi den, especially as malaria prophylaxis and as sleeping sick prophylaxis suitable.
Die erfindungsgemäßen phosphororganischen Verbindungen, hierzu gehören im allgemeinen pharmazeutisch verträgliche Salze, Ami de, Ester, ein Salz eines solchen Esters, oder aber Verbindun gen, die bei Applikation die erfindungsgemäß verwendeten Ver bindungen als Stoffwechselprodukte oder Abbauprodukte bereit stellen, auch "Prodrugs" genannt, können für die Verabreichung in irgendeiner geeigneten Weise analog zu bekannten antiinfek tiös wirkenden Mitteln (gemischt mit einem nicht toxischen pharmazeutisch akzeptablen Träger) zubereitet werden.The organophosphorus compounds according to the invention generally include pharmaceutically acceptable salts, ami de, ester, a salt of such an ester, or compound gene, the Ver used according to the invention when applied bonds as metabolic products or degradation products places, also called "prodrugs", can be used for administration in any suitable manner analogous to known antiinfec toxic agents (mixed with a non-toxic pharmaceutically acceptable carrier).
Zu pharmazeutisch akzeptablen Salzen der Verbindungen gehören Salze, die die erfindungsgemäß verwendeten Verbindungen der Formeln (I) bis (XI) in ihrer protonierten Form als Ammonium salz anorganischer oder organischer Säuren, wie Salzsäure, Schwefelsäure, Zitronensäure, Maleinsäure, Fumarsäure, Wein säure, p-Toluolsulfonsäure, bilden.Pharmaceutically acceptable salts of the compounds include Salts which the compounds of the invention used Formulas (I) to (XI) in their protonated form as ammonium salt of inorganic or organic acids, such as hydrochloric acid, Sulfuric acid, citric acid, maleic acid, fumaric acid, wine acid, p-toluenesulfonic acid.
Pharmazeutisch besonders geeignet sind auch die Salze, die durch geeignete Auswahl von X3 und X4 gebildet werden, wie Na triumsalz, Kaliumsalz, Calciumsalz, Ammoniumsalz, Ethanolamin salz, Triethylaminsalz, Dicyclohexylaminsalz und Salze einer Aminosäure wie Argininsalz, Asparaginsäuresalz, Glutaminsäu resalz.Also particularly pharmaceutically suitable are the salts which are formed by a suitable selection of X 3 and X 4 , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.
Die Aktivität der Substanzen wird in einem Versuchssystem be stimmt. Dieses System beruht auf die Messung der Inhibition des Wachstums von Bakterien, Parasiten, Viren, Pilze oder Pflanzen in vitro. Hierzu werden zum Teil Versuchsverfahren verwendet, die dem Fachmann bekannt sind.The activity of the substances is in a test system Right. This system is based on the measurement of inhibition the growth of bacteria, parasites, viruses, fungi or Plants in vitro. To this end, test procedures are used in part used, which are known to the expert.
Zum Beispiel wird zur Bestimmung der Antimalaria Aktivität die Inhibition des Wachstums von Malaria-Parasiten in Blutkulturen bestimmt.For example, to determine antimalaria activity Inhibition of malaria parasite growth in blood cultures certainly.
Die Bestimmung der antibakteriellen Aktivität beruht auf Mes sung der Hemmung von Bakterienwachstum auf Nährböden und in Flüssigkulturen.The determination of the antibacterial activity is based on Mes inhibition of bacterial growth on nutrient media and in Liquid cultures.
Die Bestimmung der antiviralen Aktivität beruht auf Inhibition der Bildung von viralen Elementen in Zellkulturen.The determination of the antiviral activity is based on inhibition the formation of viral elements in cell cultures.
Die Bestimmung der fungiziden Aktivität beruht auf Inhibition des Wachstums von Pilzen auf Nährböden und in Flüssigkulturen.The determination of the fungicidal activity is based on inhibition the growth of fungi on nutrient media and in liquid cultures.
Einige der Mikroorganismen, die untersucht werden sollen, kön nen nur in Tiermodellen untersucht werden. Hier werden die entsprechenden Modelle angewendet.Some of the microorganisms to be examined can can only be examined in animal models. Here are the corresponding models applied.
Substanzen, die eine Wirksamkeit in den in-vitro-Meßsystemen zeigen, werden in in-vivo-Modellen weiter untersucht. Die an tiparasitäre, antivirale, fungizide oder antibakterielle Akti vität wird in den entsprechenden Tiermodelle weiter evaluiert.Substances that have an effectiveness in in vitro measurement systems show are further investigated in in vivo models. The on tiparasitary, antiviral, fungicidal or antibacterial acti vity is further evaluated in the corresponding animal models.
Das Screening nach herbizider Aktivität wird mittels Algensy stemen und Messung der Isoprenemission von Pflanzen unter Standardbedingungen bestimmt.The screening for herbicidal activity is carried out using Algensy systems and measurement of isoprene emissions from plants under Standard conditions determined.
Die pharmazeutisch wirksamen Mittel können in Form von pharma zeutischen Zubereitungen in Dosierungseinheiten zubereitet werden. Dies bedeutet, daß die Zubereitung in Form einzelner Teile, z. B. Tabletten, Dragees, Kapseln, Pillen, Suppositori en und Ampullen vorliegen, deren Wirkstoffgehalt einem Bruch teil oder einem Vielfachen einer Einzeldosis entsprechen. Die Dosierungseinheiten können z. B. 1, 2, 3 oder 4 Einzeldosen oder 1/2, 1/3 oder 1/4 einer Einzeldosis enthalten. Eine Ein zeldosis enthält vorzugsweise die Menge Wirkstoff, die bei ei ner Applikation verabreicht wird und die gewöhnlich einer gan zen, einer halben oder einem Drittel oder einem Viertel einer Tagesdosis entspricht.The pharmaceutically active agents can be in the form of pharma zeutische preparations prepared in dosage units become. This means that the preparation in the form of individual Parts, e.g. B. tablets, dragees, capsules, pills, suppositories s and ampoules are present, the active ingredient content of a fraction part or a multiple of a single dose. The Dosage units can e.g. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. An on zeldose preferably contains the amount of active ingredient found in egg ner application is administered and usually a whole zen, a half or a third or a quarter of one Daily dose corresponds.
Unter nicht toxischen, inerten pharmazeutisch geeigneten Trä gerstoffen sind feste, halbfeste oder flüssige Verdünnungsmit tel, Füllstoffe und Formulierungshilfsmittel jeder Art zu ver stehen. Taking non-toxic, inert pharmaceutically acceptable drugs materials are solid, semi-solid or liquid diluents tel, fillers and formulation auxiliaries of all kinds stand.
Als bevorzugte pharmazeutische Zubereitungen seien Tabletten, Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lo tions, Puder und Sprays genannt. Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmit tel, z. B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsäure, (b) Bindemittel, z. B. Carboxymethylcellulo se, Alginate, Gelatine, Polyvinylpyrrolidon, (c) Feuchthal temittel, z. B. Glycerin, (d) Sprengmittel, z. B. Agar-Agar, Calciumcarbonat und Natriumcarbonat, (e) Lösungsverzögerer, z. B. Paraffin und (f) Resorptionsbeschleuniger, z. B. quarternä re Ammoniumverbindungen, (g) Netzmittel, z. B. Cetylalkohol, Glycerinmonostearat, (h) Adsorptionsmittel, z. B. Kaolin und Bentonit und (i) Gleitmittel, z. B. Talkum, Calcium- und Ma gnesiumstearat und feste Polyethylenglykole oder Gemische der unter (a) bis (i) aufgeführten Stoffe.The preferred pharmaceutical preparations are tablets, Coated tablets, capsules, pills, granules, suppositories, solutions, Suspensions and emulsions, pastes, ointments, gels, creams, lo tion, powder and sprays called. Tablets, coated tablets, capsules, Pills and granules can be the active ingredient or ingredients in addition to the contain conventional carriers, such as (a) filling and stretching tel, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. Carboxymethyl cellulo se, alginates, gelatin, polyvinylpyrrolidone, (c) damp means, e.g. B. glycerin, (d) disintegrant, e.g. B. agar, Calcium carbonate and sodium carbonate, (e) solution retarders, e.g. B. Paraffin and (f) absorption accelerators, e.g. B. quaternary re ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, Glycerol monostearate, (h) adsorbent, e.g. B. kaolin and Bentonite and (i) lubricants, e.g. B. talc, calcium and Ma magnesium stearate and solid polyethylene glycols or mixtures of substances listed under (a) to (i).
Die Tabletten, Dragees, Kapseln, Pillen und Granulate können mit den üblichen, gegebenenfalls Opakisierungsmittel enthal tenden Überzügen und Hüllen versehen sein und auch so zusam mengesetzt sein, daß sie den oder die Wirkstoffe nur oder be vorzugt in einem bestimmten Teil des Intestinaltraktes gegebe nenfalls verzögert abgeben, wobei als Einbettungsmassen z. B. Polymersubstanzen und Wachse verwendet werden können.The tablets, dragees, capsules, pills and granules can with the usual, optionally containing opacifiers tendency coatings and covers and so together be set that they only or be the active ingredients preferably in a certain part of the intestinal tract If necessary, deliver with a delay, with z. B. Polymer substances and waxes can be used.
Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebenen Trägerstoffe auch in mikrover kapselter Form vorliegen.The active ingredient (s) can optionally be combined with an or several of the above-mentioned carriers also in microver encapsulated form.
Suppositorien können neben dem oder den Wirkstoffen die übli chen wasserlöslichen oder wasserunlöslichen Trägerstoffe ent halten, z. B. Polyethylenglykole, Fette, z. B. Kakaofett und höhere Ester (z. B. C14-Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.Suppositories in addition to the active ingredient (s) can contain the usual water-soluble or water-insoluble carriers, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
Salben, Pasten, Cremes und Gele können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. tieri sche und pflanzliche Fette, Wachse, Paraffine, Stärke, Tra gant, Cellulosederivate, Polyethylenglykole, Silikone, Bento nite, Kieselsäure, Talkum und Zinkoxid oder Gemische dieser Stoffe.Ointments, pastes, creams and gels can next to the or Active substances contain the usual carriers, e.g. B. tieri vegetable and vegetable fats, waxes, paraffins, starch, tra gant, cellulose derivatives, polyethylene glycols, silicones, bento nite, silica, talc and zinc oxide or mixtures of these Fabrics.
Puder und Sprays können neben dem oder den Wirkstoffen die üb lichen Trägerstoffe enthalten, z. B. Milchzucker, Talkum, Kie selsäure, Aluminiumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe. Sprays können zusätzlich die üb lichen Treibmittel, z. B. Chlorfluorkohlenwasserstoffe, ent halten.Powders and sprays can in addition to the active ingredient (s) Lichen carriers included, for. B. milk sugar, talc, Kie silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used union blowing agents, e.g. B. chlorofluorocarbons, ent hold.
Lösungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z. B. Wasser, Ethylalkohol, Isopropylalkohol, Ethylcarbonat, Ethylacetat, Benzylalkohol, Benzylbenzoat, Pro pylenglykol, 1,3-Butylenglykol, Dimethylformamid, Öle, insbe sondere Baumwollsaatöl, Erdnußöl, Maiskeimöl, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydro furfurylalkohol, Polyethylenglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.Solutions and emulsions can be added to the active ingredient (s) the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, Ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Pro pylene glycol, 1,3-butylene glycol, dimethylformamide, oils, esp special cottonseed oil, peanut oil, corn oil, olive oil, Castor oil and sesame oil, glycerin, glycerin formal, tetrahydro furfuryl alcohol, polyethylene glycols and fatty acid esters of Contain sorbitans or mixtures of these substances.
Zur parenteralen Applikation können die Lösungen und Emulsio nen auch in steriler und blutisotonischer Form vorliegen.The solutions and emulsions can be used for parenteral administration are also available in sterile and blood isotonic form.
Suspensionen können neben dem oder den Wirkstoffen die übli chen Trägerstoffe wie flüssige Verdünnungsmittel, z. B. Was ser, Ethylalkohol, Propylenglykol, Suspendiermittel, z. B. ethoxylierte Isostearylalkohole, Polyoxyethylensorbit- und Sorbitan-Ester, mikrokristalline Cellulose, Aluminiummetahy droxid, Bentonit, Agar-Agar und Tragant oder Gemische dieser Stoffe enthalten.Suspensions can besides the active ingredient (s) the usual Chen carriers such as liquid diluents, e.g. B. What water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and Sorbitan esters, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar and tragacanth or mixtures of these Contain substances.
Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmacksverbessernde Zusätze, z. B. Pfefferminzöl und Eukalyptusöl und Süßmittel, z. B. Saccharin, enthalten.The formulation forms mentioned can also contain colorants, Preservatives as well as odor and taste improving Additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.
Die Wirkstoffe der Formeln (I) bis (XI) sollen in den oben aufgeführten pharmazeutischen Zubereitungen, vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5 Gew.-%, vorzugsweise von etwa 0,5 bis 95 Gew.-%, der Gesamtmischung vorhanden sein.The active ingredients of the formulas (I) to (XI) should be listed in the above listed pharmaceutical preparations, preferably in a concentration of about 0.1 to 99.5% by weight, preferably from about 0.5 to 95% by weight of the total mixture.
Die pharmazeutischen Zubereitungen können außer den Verbindun gen der Formeln (I) bis (XI) auch weitere pharmazeutische Wirkstoffe enthalten.In addition to the compounds, the pharmaceutical preparations can gene of formulas (I) to (XI) also other pharmaceutical Contain active ingredients.
Die Verbindungen können mit bisher beschriebenen Substanzen mit antibakterieller, antiviraler, antimyktoischer und antipa rasitärer Eigenschaften verwendet werden. Hierzu gehören ins besondere Verbindungen, die bereits in der Therapie Anwendung gefunden haben oder noch angewendet werden. Hierzu sind insbe sondere geeignet Stoffe, die in der in der Roten Liste oder in Simon/Stille, Antibiotika-Therapie in Klinik und Praxis, 9. Auflage 1998 Schattauer Verlag, oder unter http:/www.customs.treas.gov/imp exp/rulings/harmoniz/hrm129.html im Internet mitaufgeführt. Insbesondere können die Derivate mit Penicilline, Benzylpeni cillin (Penicillin G), Phenoxypenicilline, Isoxazolylpenicil line, Aminopenicilline, Ampicillin, Amoxixillin, Bacampicil lin, Carboxypenicillin, Ticarcillin, Temocillin, Acyalaminope nicilline, Azlocillin, Mezlocillin, Piperacillin, Apalcillin, Mecillinam, Cephalosporine, Cefazolin-Gruppe, Cefuroxim- Gruppe, Cefoxitin-Gruppe, Cefoxitin, Cefotetan, Cefmetazol, Latamoxef, Flomoxef, Cefotaxim-Guppe, Cefozidim, Ceftazidim- Gruppe, Ceftazidim, Cefpirom, Cefepim, übrige Cephalosporine, Cefsulodin, Cefoperazon, Oralcephalosporine der Cefalexin- Gruppe, Loracarbef, Cefprozil, neue Oralcephalosporine mit er weitertem Spektrum, Cefixim, Cefpodoxim-Proxetil, Cefuroxim- Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten, an dere β-Lactam-Antibiotika, Carbapenem, Imipenem /Cilastatin, Meropenem, Biapenem, Aztreonam, β-Lactamase-Hemmer, Clavulan säure/Amoxicillin, Clavulansäure/Ticarcillin, Sulbac tam/Ampicillin, Tazobactam/Piperacillin, Tetracycline, Oxyte tracyclin, Rolitetraxyxlin, Doxycyclin, Minocyclin, Chloram phenicol, Aminoglykoside, Gentamicin, Tobramycin, Netilmicin, Amikacin, Spectinomyxin, Makrolide, Erythromycin, Cla rithromycin, Roxithromycin, Azithromycin, Dirithromycin, Spi ramycin, Josamycin, Lincosamide, Clindamycin, Fusidinsäure, Glykopeptid-Antibiotika, Vancomycin, Tecoplanin, Pristi namycin-Derivate, Fosfomycin, Antimikrobielle Folsäureantago nisten, Sulfonamide, Co-Trimoxazol, Trimethoprim, andere Dia minopyrimidin-Sulfonamid-Kombinationen, Nitrofurane, Nitrofu rantoin, Nitrofurazon, Gyrase-Hemmer (Chinolone), Norfloxacin, Ciprofloxacin, Ofloxacin, Sparfloxacin, Enoxacin, Fleroxacin, Pefloxacin, Lomefloxacin, Bay Y3118, Nitroimidazole, antimyko bakterielle Mittel, Isoniazid, Rifampicin, Rifabutin, Ethambu tol, Pyrazinamid, Streptomycin, Capreomycin, Prothionamid, Te rizidon, Dapson, Clofazimin, Lokalantibiotika, Bacitracin, Ty rothricin, Polymyxine, Neomycin, Kanamycin, Paromomycin, Mupi rocin, antivirale Mittel, Acyclovir, Ganciclovir, Azidothymi din, Didanosin, Zalcitabin, Thiacytidin, Stavudin, Ribavirin, Idoxuridin, Trifluridin, Foscarnet, Amantadin, Interferone, Tibol-Derivate, Proteinase-Inhibitoren, Antimykotika, Polyene, Amphothericin B, Nystatin, Natamycin, Azole, Azole zur septi schen Therapie, Miconazol, Ketoconazol, Itraconazol, Flucona zol, UK-109.496, Azole für lokale Anwendung, Clotrimazol, Eco nazol, Isoconazol, Oxiconazol, Bifonazol, Flucytosin, Griseo fulvin, Ciclopiroxolamin, Tolnaftat, Naftifin, Terbinafin, Amorolfin, Antrachinone, Betulinic acid, Semianthrachinone, Xanthone, Naphtoquinone, Aryaminoalkohole, Chinin, Quinidine, Mefloquin, Halofantrin, Chloroquin, Amodiaquin, Acridin, Ben zonaphthyridin, Mepacrin, Pyronaridin, Dapson, Sulfonamide, Sulfadoxin, Sulfalene, Trimethoprim, Proguanil, Chlorprogua nil, Diaminopyrimidine, Pyrimethamin, Primaquin, Aminoquinoli ne, WR 238,605, Tetracyclin, Doxycyclin, Clindamycin, Norflox acin, Ciprofloxacin, Ofloxacin, Artemisinin, Dihydroartemisi nin, 10b artemether, Arteether, Atrtesunat, Atovaquon, Sura min. Melarsoprol, Nifurtmox, Stibogluconat-Natrium, Pentami din, Amphotericin B, Metronidazol, clioquinol, Mebendazol, Niclosamid, Praziquantel, Pyrantel, Tiabendazol, Diethylcarba mazin, Ivermectin, Bithionol, Oxamniquin, Metrifonat, Pipera zin, Embonat.The compounds can with substances described so far with antibacterial, antiviral, antimyctoic and antipa razor properties are used. This includes ins special compounds that are already used in therapy have found or are still being used. In particular, particularly suitable substances that are in the Red List or in Simon / Stille, antibiotic therapy in clinic and practice, 9th edition 1998 Schattauer Verlag, or at http: /www.customs.treas.gov/imp exp / rulings / harmoniz / hrm129.html listed on the Internet. In particular, the derivatives with penicillins, benzylpeni cillin (penicillin G), phenoxotypicillins, isoxazolylpenicil line, aminopenicillins, ampicillin, amoxixillin, bacampicil lin, carboxotypicillin, ticarcillin, temocillin, acyalaminope nicilline, azlocillin, mezlocillin, piperacillin, apalcillin, Mecillinam, cephalosporins, cefazolin group, cefuroxime Group, cefoxitin group, cefoxitin, cefotetan, cefmetazole, Latamoxef, Flomoxef, Cefotaxim-Guppe, Cefozidim, Ceftazidim- Group, ceftazidime, cefpirom, cefepim, other cephalosporins, Cefsulodin, cefoperazone, oral cephalosporins of cefalexin Group, Loracarbef, Cefprozil, new oral cephalosporins with he broad spectrum, cefixime, cefpodoxime proxetil, cefuroxime Axetil, Cefetamet, Cefotiam-Hexetil, Cefdinir, Ceftibuten other β-lactam antibiotics, carbapenem, imipenem / cilastatin, Meropenem, biapenem, aztreonam, β-lactamase inhibitor, clavulan acid / amoxicillin, clavulanic acid / ticarcillin, Sulbac tam / ampicillin, tazobactam / piperacillin, tetracycline, oxyte tracycline, rolitetraxyxlin, doxycycline, minocycline, chloram phenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, Amikacin, Spectinomyxin, Macrolides, Erythromycin, Cla rithromycin, roxithromycin, azithromycin, dirithromycin, Spi ramycin, josamycin, lincosamides, clindamycin, fusidic acid, Glycopeptide antibiotics, vancomycin, tecoplanin, Pristi namycin derivatives, fosfomycin, antimicrobial folic acid antago nest, sulfonamides, co-trimoxazole, trimethoprim, other dia minopyrimidine-sulfonamide combinations, nitrofurans, nitrofu rantoin, nitrofurazone, gyrase inhibitors (quinolones), norfloxacin, Ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, Pefloxacin, Lomefloxacin, Bay Y3118, Nitroimidazole, antimyko bacterial agents, isoniazid, rifampicin, rifabutin, ethambu tol, pyrazinamide, streptomycin, capreomycin, prothionamide, Te rizidon, dapsone, clofazimine, local antibiotics, bacitracin, ty rothricin, polymyxins, neomycin, kanamycin, paromomycin, mupi rocin, antivirals, acyclovir, ganciclovir, azidothymi din, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, Idoxuridine, trifluridine, foscarnet, amantadine, interferons, Tibol derivatives, proteinase inhibitors, antifungals, polyenes, Amphothericin B, nystatin, natamycin, azoles, azoles for septi therapy, miconazole, ketoconazole, itraconazole, flucona zol, UK-109.496, azoles for local use, clotrimazole, Eco nazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseo fulvin, ciclopiroxolamine, tolnaftat, naftifin, terbinafine, Amorolfin, Antrachinone, Betulinic acid, Semianthraquinones, Xanthones, naphtoquinones, aryamino alcohols, quinine, quinidines, Mefloquine, Halofantrine, Chloroquine, Amodiaquine, Acridine, Ben zonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, Sulfadoxin, Sulfalene, Trimethoprim, Proguanil, Chlorprogua nil, diaminopyrimidines, pyrimethamine, primaquin, aminoquinoli ne, WR 238,605, tetracycline, doxycycline, clindamycin, norflox acin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisi nin, 10b artemether, Arteether, Atrtesunat, Atovaquon, Sura min. Melarsoprol, Nifurtmox, Stibogluconate Sodium, Pentami din, amphotericin B, metronidazole, clioquinol, mebendazole, Niclosamide, praziquantel, pyrantel, tiabendazole, diethylcarba mazin, ivermectin, bithionol, oxamniquin, metrifonate, Pipera zin, embonate.
Ferner können die phosphororganischen Verbindungen in den pharmazeutischen Mitteln in Kombination mit Sulfonamid, Sulfa doxin, Artemisinin, Atovaquon, Chinin, Chloroquin, Hydroxy chloroquin, Mefloquin, Halofantrin, Pyrimethamin, Armesin, Te tracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tiabendazol, Diethylcarba zin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol oder Suramin oder mehreren dieser Substanzen vorliegen.Furthermore, the organophosphorus compounds in the pharmaceutical agents in combination with sulfonamide, sulfa doxin, artemisinin, atovaquone, quinine, chloroquine, hydroxy chloroquine, mefloquine, halofantrine, pyrimethamine, armesin, Te tracycline, doxycycline, proguanil, metronidazole, praziquantil, Niclosamide, mebendazole, pyrantel, tiabendazole, diethylcarba zin, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or more of these substances.
Die Herstellung der oben aufgeführten pharmazeutischen Zube reitungen erfolgt in üblicher Weise nach bekannten Methoden, z. B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.The manufacture of the pharmaceutical accessories listed above Horse riding is done in the usual way according to known methods, e.g. B. by mixing the active ingredient or ingredients with the or Carriers.
Die genannten Zubereitungen können bei Mensch und Tier entwe der oral, rektal, parenteral (intravenös, intramuskulär, sub kutan), intracisternal, intravaginal, intraperitoneal, lokal (Puder, Salbe, Tropfen) und zur Therapie von Infektionen in Hohlräumen, Körperhöhlen angewendet werden. Als geeignete Zu bereitungen kommen Injektionslösungen, Lösungen und Suspensio nen für die orale Therapie, Gele, Aufgußformulierungen, Emul sionen, Salben oder Tropfen in Frage. Zur lokalen Therapie können ophtalmologische und dermatologische Formulierungen, Silber- und andere Salze, Ohrentropfen, Augensalben, Puder oder Lösungen verwendet werden. Bei Tieren kann die Aufnahme auch über das Futter oder Trinkwasser in geeigneten Formulie rungen erfolgen. Ferner können Gele, Pulver, Puder, Tabletten, Retard-Tabletten, Premixe, Konzentrate, Granulate, Pellets, Tabletten, Boli, Kapseln, Aerosole, Sprays, Inhalate bei Mensch und Tier angewendet werden. Ferner können die erfin dungsgemäßen Verbindungen in andere Trägermaterialien wie zum Beispiel Kunststoffe, (Kunststoffketten zur lokalen Therapie), Kollagen oder Knochenzement eingearbeitet werden.The preparations mentioned can be used in humans and animals the oral, rectal, parenteral (intravenous, intramuscular, sub cutaneous), intracisternal, intravaginal, intraperitoneal, local (Powder, ointment, drops) and for the treatment of infections in Cavities, body cavities are applied. As a suitable addition Preparations come with injection solutions, solutions and suspensions NEN for oral therapy, gels, infusion formulations, emul ions, ointments or drops. For local therapy ophthalmic and dermatological formulations, Silver and other salts, ear drops, eye ointments, powder or solutions are used. In animals, the intake also in suitable form via the feed or drinking water take place. Gels, powders, powders, tablets, Prolonged-release tablets, premixes, concentrates, granules, pellets, Tablets, boluses, capsules, aerosols, sprays, inhalants Humans and animals can be used. Furthermore, the inventions compounds according to the invention in other carrier materials such as Example plastics, (plastic chains for local therapy), Collagen or bone cement can be incorporated.
Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinärmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe der Formel (I) bis (XI) in Gesamtmengen von etwa 0,05 bis etwa 600, vorzugsweise 0,5 bis 200 mg/kg Körperge wicht je 24 Stunden, gegebenenfalls in Form mehrerer Einzelga ben, zur Erzielung der gewünschten Ergebnisse zu verabreichen. Eine Einzelgabe enthält den oder die Wirkstoffe vorzugsweise in Mengen von etwa 1 bis etwa 200, insbesondere 1 bis 60 mg/kg Körpergewicht. Es kann jedoch erforderlich sein, von den ge nannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Körpergewicht des zu behandelnden Patienten, der Art und der Schwere der Erkrankung, der Art der Zuberei tung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt.In general, it has been in both human and of veterinary medicine has been shown to be advantageous Active ingredients of the formula (I) to (XI) in total amounts of about 0.05 to about 600, preferably 0.5 to 200 mg / kg body weight weight each 24 hours, possibly in the form of several individual ga ben to give the desired results. A single dose preferably contains the active ingredient (s) in amounts of about 1 to about 200, in particular 1 to 60 mg / kg Body weight. However, it may be necessary from the ge named doses vary, depending on the type and body weight of the patient to be treated, the type and severity of the disease, the type of preparation and the application of the drug and the period or interval within which the administration takes place.
So kann es in einigen Fällen ausreichend sein, mit weniger als der obengenannten Menge Wirkstoff auszukommen, während in an deren Fällen die oben angeführte Wirkstoffmenge überschritten werden muß. Die Festlegung der jeweils erforderlichen optima len Dosierung und Applikationsart der Wirkstoffe kann durch den Fachmann aufgrund seines Fachwissens erfolgen.So in some cases it may be sufficient with less than the above amount of active ingredient to get by while in at whose cases exceeded the amount of active ingredient mentioned above must become. The determination of the optima required in each case len dosage and type of application of the active ingredients can by the specialist on the basis of his specialist knowledge.
Die erfindungsgemäßen Verbindungen können in den üblichen Kon zentrationen und Zubereitungen bei Tieren zusammen mit dem Futter bzw. mit Futterzubereitungen oder mit dem Trinkwasser gegeben werden.The compounds of the invention can in the usual Kon concentrations and preparations in animals together with the Feed or with feed preparations or with drinking water are given.
Ferner können die erfindungsgemäßen Verbindungen hervorragend als Bakterizide, Fungizide und Herbizide bei Pflanzen einge setzt werden.Furthermore, the compounds according to the invention can be outstanding used as bactericides, fungicides and herbicides in plants be set.
Claims (13)
in der X ein Phosphoratom oder ein Schwefelatom ist,
wobei A eine C2-9-Alkylenkette ist mit Substituenten, die gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, Hydroxy-, Halogen-, Amino- und Oxogruppen, C1-26-Alkylresten, C1-26-Alkoxyresten, C1-26- Alkoxy-C1-25-Alkylresten oder C3-8-Cycloalkyl-(C0-9)- alkylgruppen besteht, wobei jeder C1-26-Alkylrest und jeder C1-26-Alkoxyrest verzweigt oder unverzweigt und gesättigt oder mit ein oder mehreren Doppelbindungen ungesättigt sein kann und mit Hydroxy-, Amino-, Halogen- und Oxogruppen sub stituiert sein kann und sowohl die C3-8-Cycloalkylgruppe als auch die C0-9-Alkylgruppe der C3-8-Cycloalkyl-(C0-9)-alkyl gruppe ein oder mehrere Doppelbindungen aufweisen können und ein oder zwei Kohlenstoffatome der Cycloalkylgruppe durch Stickstoff-, Sauerstoff- oder Schwefelatome ersetzt sein können, und wobei sowohl die Cycloalkylgruppe als auch die Alkylgruppe mit Hydroxy-, Halogen-, Amino-, Oxogruppen mit verzweigten oder unverzweigten C1-9-Alkylgruppen und C2-9- Alkenylgruppen substituiert sein können, wobei die C1-9- Alkylgruppen und C2-9-Alkenylgruppen mit Wasserstoff-, Hy droxy-, Amino-, Halogen- und Oxogruppen substituiert sein können,
in der R1 und R2 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem C1-9-Alkyl, substituiertem und unsub stituiertem Hydroxy-C1-9-alkyl, substituiertem und unsub stituiertem Hydroxyl, substituiertem und unsubstituiertem C1-9-Alkinyl, substituiertem und unsubstituiertem Aryl, sub stituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstitu iertem Aralkyl, substituiertem und unsubstituiertem he terocyclischen Rest, Halogen, OX1 und OX2 besteht,
wobei X1 und X2 gleich oder verschieden sind und aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsubstituiertem C1-9-Alkyl, substituiertem und unsub stituiertem Hydroxy-C1-9-alkyl, substituiertem und unsubsti tuiertem C1-9-Alkenyl, substituiertem und unsubstituiertem C1-9-Alkinyl, substituiertem und unsubstituiertem Aryl, sub stituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstitu iertem Aralkyl, substituiertem und unsubstituiertem he terocyclischen Rest besteht,
in der R3 und R4 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus substituiertem und unsub stituiertem C1-26-Alkyl, Hydroxy-C1-2-alkyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstitu iertem Acyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem C1-26-Alkenyl, substitu iertem und unsubstituiertem C1-26-Alkinyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsub stituiertem heterocyclischem Rest, Halogen, OX3 und OX4 be steht,
wobei X3 und X4 gleich oder verschieden sind und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem C1-26-Alkyl, substituiertem und unsub stituiertem Hydroxy-C1-26-alkyl, substituiertem und unsub stituiertem Aryl, substituiertem und unsubstituiertem Aral kyl, substituiertem und unsubstituiertem C1-26-Alkenyl, sub stituiertem und unsubstituiertem C1-26-Alkinyl, substituier tem und unsubstituiertem Cycloalkyl, substituiertem und un substituiertem heterocyclischem Rest, einem Silyl, einem Kation einer organischen und anorganischen Base, insbeson dere einem Metall der ersten, zweiten oder dritten Haupt gruppe des Periodensystems, Ammonium, substituiertem Ammo nium und Amfnoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht,
und deren pharmazeutisch akzeptablen Salze, Ester und Amide und Salze der Ester
zur Behandlung von infektiösen Prozessen bei Mensch und Tier, die durch Viren, Bakterien, Pilze oder Parasiten her vorgerufen werden und als Fungizid, Bakterizid oder Herbi zid bei Pflanzen.1. Use of organophosphorus compounds of the general formula (I)
in which X is a phosphorus atom or a sulfur atom,
wherein A is a C 2-9 alkylene chain with substituents which are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino and oxo groups, C 1-26 alkyl radicals, C 1- 26 -alkoxy radicals, C 1-26 -alkoxy-C 1-25 -alkyl radicals or C 3-8 -cycloalkyl- (C 0-9 ) - alkyl groups, where each C 1-26 -alkyl radical and each C 1-26 - Alkoxy radical may be branched or unbranched and saturated or unsaturated with one or more double bonds and may be substituted with hydroxyl, amino, halogen and oxo groups and both the C 3-8 cycloalkyl group and the C 0-9 alkyl group C 3-8 cycloalkyl (C 0-9 ) alkyl group may have one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and both the cycloalkyl group and the alkyl group with hydroxyl, halogen, amino, oxo groups with branched or unbranched C 1-9 alkyl groups and C 2-9 alkenyl groups can be substituted, it being possible for the C 1-9 alkyl groups and C 2-9 alkenyl groups to be substituted by hydrogen, hydroxy, amino, halogen and oxo groups ,
in which R 1 and R 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1-9 alkyl, substituted and unsubstituted hydroxyC 1-9 alkyl, substituted and unsubstituted hydroxyl , substituted and unsubstituted C 1-9 alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OX 1 and OX 2 ,
wherein X 1 and X 2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1-9 alkyl, substituted and unsubstituted hydroxyC 1-9 alkyl, substituted and unsubstituted C 1 -9 -alkenyl, substituted and unsubstituted C 1-9 -alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical,
in which R 3 and R 4 are the same or different and are selected from the group consisting of substituted and unsubstituted C 1-26 alkyl, hydroxyC 1-2 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl , substituted and unsubstituted aralkyl, substituted and unsubstituted C 1-26 alkenyl, substituted and unsubstituted C 1-26 alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OX 3 and OX 4 ,
where X 3 and X 4 are identical or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1-26 alkyl, substituted and unsubstituted hydroxyC 1-26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C 1-26 alkenyl, substituted and unsubstituted C 1-26 alkynyl, 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 table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids,
and their pharmaceutically acceptable salts, esters and amides and salts of the esters
for the treatment of infectious processes in humans and animals caused by viruses, bacteria, fungi or parasites and as a fungicide, bactericide or herbicide in plants.
entspricht, wobei X, R1, R3, R4 wie in Anspruch 1 definiert sind, wobei R1 bevorzugt an dem dem Heteroatom benachbarten C-Atom mit einer Hydroxygruppe substituiert ist.3. Use according to claim 1 or claim 2, characterized in that the organophosphorus compounds of For mel (II)
corresponds, where X, R 1 , R 3 , R 4 are as defined in claim 1, wherein R 1 is preferably substituted on the C atom adjacent to the hetero atom with a hydroxyl group.
entspricht, wobei X, R1, R3, R4 wie in Anspruch 1 definiert sind, wobei R1 bevorzugt eine Acylgruppe, besonders bevor zugt eine Formyl-, Acetyl-, Propionyl- oder Butyrylgruppe ist.4. Use according to claim 1 or claim 2, characterized in that the organophosphorus compounds of For mel (III)
corresponds, where X, R 1 , R 3 , R 4 are as defined in claim 1, wherein R 1 is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group.
besteht, wobei X, R1, R2, R3 und R4 die in Anspruch 1 defi nierte Bedeutung haben und die nicht definierten Valenzen der Kohlenstoffatome substituiert sein können, wie es in Anspruch 1 definiert ist. 5. Use according to claim 1 or claim 2, characterized in that the organophosphorus compounds are selected from the group consisting of
exists, wherein X, R 1 , R 2 , R 3 and R 4 have the meaning defined in claim 1 and the undefined valences of the carbon atoms can be substituted, as defined in claim 1.
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19902924A DE19902924A1 (en) | 1999-01-26 | 1999-01-26 | Use of organophosphorus compounds for the prophylactic and therapeutic treatment of infections |
CN00803129A CN1337881A (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
PL00349910A PL349910A1 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
TR2001/02151T TR200102151T2 (en) | 1999-01-26 | 2000-01-25 | The use of organophosphorus compositions in the prophylactic and therapeutic treatment of infections. |
HU0105310A HUP0105310A3 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
AU24399/00A AU2439900A (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
JP2000595662A JP2002535354A (en) | 1999-01-26 | 2000-01-25 | Use of organophosphorus compounds for prophylactic and therapeutic treatment of infectious diseases |
EP00902630A EP1146880A2 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
CA002360661A CA2360661A1 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
CZ20012584A CZ20012584A3 (en) | 1999-01-26 | 2000-01-25 | Use of phospohoroorganic compounds for prophylactic and therapeutic treatment of infections |
PCT/EP2000/000542 WO2000044358A2 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
SK1055-2001A SK10552001A3 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
IL14411500A IL144115A0 (en) | 1999-01-26 | 2000-01-25 | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
NO20013651A NO20013651L (en) | 1999-01-26 | 2001-07-25 | Use of phosphorus inorganic compounds for the prophylactic and therapeutic treatment of infections |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19902924A DE19902924A1 (en) | 1999-01-26 | 1999-01-26 | Use of organophosphorus compounds for the prophylactic and therapeutic treatment of infections |
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DE19902924A1 true DE19902924A1 (en) | 2000-08-03 |
Family
ID=7895365
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DE19902924A Ceased DE19902924A1 (en) | 1999-01-26 | 1999-01-26 | Use of organophosphorus compounds for the prophylactic and therapeutic treatment of infections |
Country Status (14)
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EP (1) | EP1146880A2 (en) |
JP (1) | JP2002535354A (en) |
CN (1) | CN1337881A (en) |
AU (1) | AU2439900A (en) |
CA (1) | CA2360661A1 (en) |
CZ (1) | CZ20012584A3 (en) |
DE (1) | DE19902924A1 (en) |
HU (1) | HUP0105310A3 (en) |
IL (1) | IL144115A0 (en) |
NO (1) | NO20013651L (en) |
PL (1) | PL349910A1 (en) |
SK (1) | SK10552001A3 (en) |
TR (1) | TR200102151T2 (en) |
WO (1) | WO2000044358A2 (en) |
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GB201509326D0 (en) | 2015-05-29 | 2015-07-15 | Antibio Tx Aps | Novel use |
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-
2000
- 2000-01-25 IL IL14411500A patent/IL144115A0/en unknown
- 2000-01-25 EP EP00902630A patent/EP1146880A2/en not_active Withdrawn
- 2000-01-25 WO PCT/EP2000/000542 patent/WO2000044358A2/en not_active Application Discontinuation
- 2000-01-25 CN CN00803129A patent/CN1337881A/en active Pending
- 2000-01-25 PL PL00349910A patent/PL349910A1/en not_active Application Discontinuation
- 2000-01-25 SK SK1055-2001A patent/SK10552001A3/en unknown
- 2000-01-25 TR TR2001/02151T patent/TR200102151T2/en unknown
- 2000-01-25 CZ CZ20012584A patent/CZ20012584A3/en unknown
- 2000-01-25 JP JP2000595662A patent/JP2002535354A/en active Pending
- 2000-01-25 AU AU24399/00A patent/AU2439900A/en not_active Abandoned
- 2000-01-25 HU HU0105310A patent/HUP0105310A3/en unknown
- 2000-01-25 CA CA002360661A patent/CA2360661A1/en not_active Abandoned
-
2001
- 2001-07-25 NO NO20013651A patent/NO20013651L/en not_active Application Discontinuation
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1585524A2 (en) * | 2002-10-31 | 2005-10-19 | Kemin Foods, L.C. | The use of endoperoxides for the treatment of infections caused by flaviviridae, including hepatitis c, bovine viral diarrhea and classical swine fever virus |
EP1585524A4 (en) * | 2002-10-31 | 2007-10-10 | Kemin Foods Lc | The use of endoperoxides for the treatment of infections caused by flaviviridae, including hepatitis c, bovine viral diarrhea and classical swine fever virus |
US7842719B2 (en) | 2002-10-31 | 2010-11-30 | Kemin Foods, L.C. | Use of endoperoxides for the treatment of infections caused by flaviviridae, including hepatitis C, bovine viral diarrhea and classical swine fever virus |
WO2004085448A2 (en) * | 2003-03-19 | 2004-10-07 | Genzyme Corporation | Unsaturated phosphinyl-phosphonate phosphate transport inhibitors |
WO2004085448A3 (en) * | 2003-03-19 | 2005-01-20 | Genzyme Corp | Unsaturated phosphinyl-phosphonate phosphate transport inhibitors |
WO2010108190A1 (en) * | 2009-03-20 | 2010-09-23 | University Of Iowa Research Foundation | Prenylated bisphosphonates as anti-tuberculosis agents |
Also Published As
Publication number | Publication date |
---|---|
TR200102151T2 (en) | 2002-05-21 |
JP2002535354A (en) | 2002-10-22 |
NO20013651L (en) | 2001-09-18 |
HUP0105310A2 (en) | 2002-06-29 |
WO2000044358A3 (en) | 2001-03-15 |
EP1146880A2 (en) | 2001-10-24 |
CN1337881A (en) | 2002-02-27 |
IL144115A0 (en) | 2002-05-23 |
CA2360661A1 (en) | 2000-08-03 |
WO2000044358A2 (en) | 2000-08-03 |
CZ20012584A3 (en) | 2002-01-16 |
PL349910A1 (en) | 2002-10-07 |
SK10552001A3 (en) | 2001-12-03 |
AU2439900A (en) | 2000-08-18 |
HUP0105310A3 (en) | 2002-08-28 |
NO20013651D0 (en) | 2001-07-25 |
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Legal Events
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OP8 | Request for examination as to paragraph 44 patent law | ||
8127 | New person/name/address of the applicant |
Owner name: JOMAA PHARMAKA GMBH, 35392 GIESSEN, DE |
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8181 | Inventor (new situation) |
Free format text: JOMAA, HASSAN, DR., 35398 GIESSEN, DE |
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8127 | New person/name/address of the applicant |
Owner name: BIOAGENCY AG, 22177 HAMBURG, DE |
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8131 | Rejection |