DE10127922A1 - New organophosphorous-substituted hydroxamic acid compounds, useful as pre- or post-emergence selective herbicides in crops such as rice - Google Patents
New organophosphorous-substituted hydroxamic acid compounds, useful as pre- or post-emergence selective herbicides in crops such as riceInfo
- Publication number
- DE10127922A1 DE10127922A1 DE10127922A DE10127922A DE10127922A1 DE 10127922 A1 DE10127922 A1 DE 10127922A1 DE 10127922 A DE10127922 A DE 10127922A DE 10127922 A DE10127922 A DE 10127922A DE 10127922 A1 DE10127922 A1 DE 10127922A1
- Authority
- DE
- Germany
- Prior art keywords
- substituted
- viruses
- 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.)
- Withdrawn
Links
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- 239000002253 acid Substances 0.000 title abstract description 17
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- 239000004009 herbicide Substances 0.000 title description 2
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- 210000000653 nervous system Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000010466 nut oil Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000000901 ornithosis Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 229960000918 protionamide Drugs 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 208000012498 virus associated tumor Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5304—Acyclic saturated phosphine oxides or thioxides
-
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
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Abstract
Description
Die Erfindung betrifft die Verwendung von phosphororganischen Hydroxamsäurede rivaten und ihren Salzen, Estern und Amiden zur therapeutischen und prophylaktischen Be handlung von Infektionen.The invention relates to the use of organophosphorus hydroxamic acid derivatives and their salts, esters and amides for therapeutic and prophylactic use act of infections.
Es besteht ein starker Bedarf, für die Bereicherung der Behandlung von Mensch und Tier Mittel bereitzustellen, die nicht nur eine starke Wirksamkeit besitzen, sondern auch im Gegensatz zu anderen Arzneimitteln verringerte Nebenwirkungen zeigen und damit eine ge ringere Gesundheitsgefahr für den Menschen bedeuten.There is a strong need for enriching the treatment of people and To provide animal products that are not only highly effective, but also in In contrast to other medicinal products, they show reduced side effects and thus a certain side effect mean less danger to human health.
Aufgabe der vorliegenden Erfindung ist es daher, eine Substanz bereitzustellen, die universell bei Infektionen durch Viren, Bakterien, Pilze und Parasiten bei Menschen und Tie ren einsetzbar ist und die oben angegebenen Bedingungen erfüllt.The object of the present invention is therefore to provide a substance which universal for infections by viruses, bacteria, fungi and parasites in humans and tie ren can be used and meets the conditions specified above.
Phosphonomethylglycylhydroxamsäure und ihre Salze sind bereits in dem Europäi schen Patent mit der Veröffentlichungsnummer 0 039 310 als Herbizide beschrieben worden.Phosphonomethylglycylhydroxamic acid and its salts are already in the European Union patent with publication number 0 039 310 as herbicides.
Überraschend zeigt sich nun, daß Phosphonomethylglycylhydroxamsäure und ihre Derivate eine ausgezeichnete antiinfektiöse Wirkung gegen Viren, Bakterien, Pilze, ein- und mehrzellige Parasiten zeigt. Die Aufgabe wird somit durch in Anspruch 1 definierten Verbin dungen gelöst. Weiterbildungen der Erfindung sind durch die Unteransprüche gekennzeich net.Surprisingly, it now turns out that phosphonomethylglycylhydroxamic acid and its Derivatives have an excellent anti-infectious effect against viruses, bacteria, fungi, and shows multicellular parasites. The task is thus defined by the verb in claim 1 solutions solved. Developments of the invention are characterized by the subclaims net.
Die Verbindungen entsprechen der allgemeinen Formel (I):
The compounds correspond to the general formula (I):
in der A aus der Gruppe ausgewählt ist, die aus -CR5R6-, -CR5R6CH(OH)-,
-CR5R6CO- und -COCR5R6- besteht,
in der R1 aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und un
substituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsub
stituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstitu
iertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstitu
iertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und
unsubstituiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl-
heterocyclischem Rest, einem Metall der ersten, zweiten oder dritten Hauptgruppe des Peri
odensystems, Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich
von Ethylendiamin oder Aminosäuren ableiten, besteht,
in der R2, R3, R4, R5, R6 und R7 gleich oder verschieden sind und aus der Gruppe
ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituier
tem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituier
tem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und
unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substitu
iertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen
Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest und Benzolsulfonyl
besteht,
in der R8 und R9 gleich oder verschieden sind und aus der Gruppe ausgewählt sind,
die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubsti
tuiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubsti
tuiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem
Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsub
stituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem
und unsubstituiertem Alkyl-heterocyclischem Rest, OX3 oder OX4 besteht,
wobei X8 oder X9 gleich oder verschieden sein können und aus der Gruppe ausge
wählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und
unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und
unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsub
stituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem
und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest,
substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest, einem Metall der ersten,
zweiten oder dritten Hauptgruppe des Periodensystems, Ammonium, substituiertem Ammo
nium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten,
besteht,
wobei sämtliche Gruppen mit Phenylgruppen, Hydroxy-, Oxo-, Halogen-, CN-,
(C0-9)(C0-9)-Amino-, C1-9-Alkyl-, C1-9-Alkoxyguppen und die cyclischen Reste auch mit Nitro
gruppen und R2 auch mit einer Carboxygruppe substituiert sein können,
und deren Salze, Ester und Amide und Salze der Ester.in which A is selected from the group consisting of -CR 5 R 6 -, -CR 5 R 6 CH (OH) -, -CR 5 R 6 CO- and -COCR 5 R 6 -,
in which R 1 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted ized alkyl-cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl heterocyclic radical, a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds, which differ from ethylenediamine or amino acids deduce exists
in which R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are identical or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkylcycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, substituted and unsubstituted alkyl heterocyclic residue and benzenesulfonyl,
in which R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkyl-cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl-heterocyclic radical, OX 3 or OX 4 ,
wherein X 8 or X 9 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkylcycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl heterocyclic radical, a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds, which are derived from ethylenediamine or amino acids,
where all groups with phenyl groups, hydroxy, oxo, halogen, CN, (C 0-9 ) (C 0-9 ) amino, C 1-9 alkyl, C 1-9 alkoxy groups and the cyclic radicals can also be substituted with nitro groups and R 2 can also be substituted with a carboxy group,
and their salts, esters and amides and salts of the esters.
Bevorzugt ist R1 ein Wasserstoff ein Metall der ersten, zweiten oder dritten Haupt gruppe des Periodensystems, wie Na, K, Ca, Mg, Al, Cu sowie Ammonium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten.R 1 is preferably a hydrogen, a metal of the first, second or third main group of the periodic table, such as Na, K, Ca, Mg, Al, Cu and ammonium, substituted ammonium and ammonium compounds which are derived from ethylenediamine or amino acids.
Bevorzugt sind R8 und R9 unabhängig aus der Gruppe ausgewählt, die aus Wasser stoff, Methyl, Ethyl, OX8 und OX9 besteht, wobei OX8 und OX9 bevorzugt aus der Gruppe ausgewählt sind, die aus der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, wie Na, K, Ca, Mg, Al, Cu sowie Ammonium, substituiertem Ammonium und Ammonium verbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht. D. h. es wer den die Salzverbindungen der phosphororganischen Verbindungen mit organischen oder an organischen Basen (z. B. Natriumsalz, Kaliumsalz, Calciumsalz, Aluminiumsalz, Ammonium salz, Magnesiumsalz, Triethylaminsalz, Ethanolaminsalz, Dicyclohexylaminsalz, Ethylen diaminsalz, N,N'-Dibenzylethylendiaminsalz etc.) sowie Salze mit Aminosäuren (z. B. Argi ninsalz, Asparaginsäuresalz, Glutaminsäuresalz etc.) und dergleichen gebildet.R 8 and R 9 are preferably selected independently from the group consisting of hydrogen, methyl, ethyl, OX 8 and OX 9 , OX 8 and OX 9 preferably being selected from the group consisting of the first, second or third Main group of the periodic table, such as Na, K, Ca, Mg, Al, Cu as well as ammonium, substituted ammonium and ammonium compounds, which are derived from ethylenediamine or amino acids. That is, the salt compounds of the organophosphorus compounds with organic or organic bases (e.g. sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylene diamond salt, N, N'-dibenzylethylenediamine salt etc.) as well as salts with amino acids (e.g. argin salt, aspartic acid salt, glutamic acid salt etc.) and the like.
Besonderheiten der obigen Definitionen und geeignete Beispiele dafür werden nach
folgend angegeben:
"Acyl" ist ein Substituent, der von einer Säure stammt, wie von einer organischen
Carbonsäure, Kohlensäure, Carbaminsäure oder der den einzelnen vorstehenden Säuren ent
sprechenden Thiosäure oder Imidsäure, oder von einer organischen Sulfonsäure, wobei diese
Säuren jeweils aliphatische, aromatische und/oder heterocyclische Gruppen im Molekül um
fassen sowie Carbamoyl oder Carbamimidoyl.Peculiarities of the above definitions and suitable examples are given according to the following:
"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 and carbamoyl or carbamimidoyl.
Geeignete Beispiele für diese Acylgruppen werden nachfolgend angegeben.Suitable examples of these acyl groups are given below.
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, Propoxycarbonyl, Isopro
poxycarbonyl, Butoxycarbonyl, Isobutoxycarbonyl etc.);
Alkylcarbamoyl (z. B. Methylcarbamoyl etc.);
(N-Alkyl)-thiocarbamoyl (z. B. (N-Methyl)-thiocarbamoyl etc.);
Alkylcarbamimidoyl (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, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl etc.);
Alkyl carbamoyl (e.g. methyl carbamoyl etc.);
(N-alkyl) thiocarbamoyl (e.g. (N-methyl) thiocarbamoyl etc.);
Alkyl carbamimidoyl (e.g. methyl carbamimidoyl etc.);
Oxalo;
Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
Bei den obigen Beispielen für aliphatische Acylgruppen kann der aliphatische Koh lenwasserstoffteil, insbesondere die Alkylgruppe bzw. der Alkanrest, ggf. einen oder mehrere geeignete Substituenten aufweisen, wie Amino, Halogen (z. B. Fluor, Chlor, Brom etc.), Hy droxy, Hydroxyimino, Carboxy, Alkoxy (z. B. Methoxy, Ethoxy, Propoxy etc.), Alkoxycar bonyl, Acylamino (z. B. Benzyloxycarbonylamino etc.), Acyloxy (z. B. Acetoxy, Benzoyloxy etc.) und dergleichen; als bevorzugte aliphatische Acylreste mit solchen Substituenten sind z. B. mit Amino, Carboxy, Amino und Carboxy, Halogen, Acylamino oder dergleichen sub stituierte Alkanoyle zu nennen.In the above examples of aliphatic acyl groups, the aliphatic Koh hydrogen part, in particular the alkyl group or the alkane radical, optionally one or more have suitable substituents, such as amino, halogen (e.g. fluorine, chlorine, bromine, etc.), Hy droxy, hydroxyimino, carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycar bonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, benzoyloxy etc.) and the like; are preferred aliphatic acyl radicals with such substituents e.g. B. with amino, carboxy, amino and carboxy, halogen, acylamino or the like sub to call substituted alkanoyle.
Als aromatische Acylreste werden solche Acylreste bezeichnet, die von einer Säure
mit substituierter oder nicht substituierter Arylgruppe stammen, wobei die Arylgruppe Phe
nyl, Toluyl, Xylyl, Naphthyl und dergleichen umfassen kann; geeignete Beispiele 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 Arylrest) und/oder der aliphatische Kohlenwasser
stoffteil (insbesondere der Alkanrest) ggf. ein oder mehrere geeignete Substituenten aufwei
sen, wie solche, die als geeignete Substituenten für die Alkylgruppe bzw. den Alkanrest be
reits angegeben wurden. Insbesondere und als Beispiel für bevorzugte aromatische Acylreste
mit besonderen Substituenten werden mit Halogen und Hydroxy oder mit Halogen und Acy
loxy substituiertes Aroyl und mit Hydroxy, Hydroxyimino, Dihalogenalkanoyloxyimino sub
stituiertes 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 as substituents for the alkyl group or the alkane residue have already been specified. In particular and as an example of preferred aromatic acyl radicals with special substituents, aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are also indicated
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 Heterocyclus mit zumindest einem Heteroatom aus der Grup
pe Stickstoff, Sauerstoff und Schwefel ist (z. B. Thiophenyl, Furoyl, Pyrrolcarbonyl, Nicoti
noyl etc.);
Heterocyclus-Alkanoyl, bei dem der heterocyclische Rest 5- bis 6-gliedrig ist und
zumindest ein Heteroatom aus der Gruppe Stickstoff, Sauerstoffund Schwefel aufweist (z. B.
Thiophen-ylacetyl, Furylacetyl, Imidazolylpropionyl, Tetrazolylacetyl, 2-(2-Amino-4-
thiazolyl)-2-methoxyiminoacetyl etc.) und dergleichen.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, furoyl, 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-ylacetyl, 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 Kohlenwasserstoffteil ggf. einen oder mehrere geeignete Substitu enten aufweisen, wie die gleichen, die als geeignet für Alkyl- und Alkangruppen angegeben wurden.In the above examples of heterocyclic acyl radicals, the heterocycle and / or the aliphatic hydrocarbon part optionally one or more suitable substituents ducks, like the same ones, indicated as being suitable for alkyl and alkane groups were.
"Alkyl" ist ein gerad- oder verzweigtkettiger Alkylrest mit bis zu 18 Kohlenstoffa tomen, wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Hexyl und dergleichen."Alkyl" is a straight or branched chain alkyl radical with up to 18 carbon atoms toms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
Zu "Alkenyl" gehören gerad- oder verzweigtkettige Alkenylgruppen mit bis zu 18 Kohlenstoffatomen, 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 with up to 18 Carbon atoms such as B. vinyl, propenyl (e.g. 1-propenyl, 2-propenyl), 1- Methyl propenyl, 2-methyl propenyl, butenyl, 2-ethyl propenyl, pentenyl, hexenyl.
Zu "Alkinyl" gehören gerad- oder verzweigtkettige Alkinylgruppen mit bis zu 18 Kohlenstoffatomen."Alkynyl" includes straight or branched chain alkynyl groups with up to 18 Carbon atoms.
Cycloalkyl steht für ein ggfs. substituiertes C3-C7-Cycloalkyl oder einen Bi- oder Tricycloalkyl aus C3-C7-Ringen; als mögliche Substituenten sind u. a. Alkyl, Alkenyl, Alkinyl, Alkoxy (z. B. Methoxy, Ethoxy etc.), Halogen (z. B. Fluor, Chlor, Brom etc.), Nitro und der gleichen geeignet. Ein heterocyclischer Rest ist entsprechend ein wie oben definiertes Cy cloalkyl, bei dem ein, zwei oder mehrere Kohlenstoffatome im Ring unabhängig voneinander durch Sauerstoff-, Stickstoff oder Schwefelatome ersetzt sind.Cycloalkyl stands for an optionally substituted C 3 -C 7 cycloalkyl or a bi- or tricycloalkyl from C 3 -C 7 rings; Possible substituents include alkyl, alkenyl, alkynyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like. A heterocyclic radical is accordingly a cycloalkyl as defined above in which one, two or more carbon atoms in the ring are independently replaced by oxygen, nitrogen or sulfur atoms.
Aryl ist ein aromatischer Kohlenwasserstoffrest, wie Phenyl Naphthyl usw., der ggf einen oder mehrere geeignete Substituenten aufweisen kann, wie Alkyl, Alkenyl, Alkinyl, Alkoxy (z. B. Methoxy, Ethoxy etc.), Halogen (z. B. Fluor, Chlor, Brom etc.), Nitro und der gleichen.Aryl is an aromatic hydrocarbon radical, such as phenyl naphthyl etc., which may be used can have one or more suitable substituents, such as alkyl, alkenyl, alkynyl, Alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like same.
Zu "Aralkyl" gehören Mono-, Di-, Triphenylalkyle wie Benzyl, Phenethyl, Benzhy dryl, Trityl und dergleichen, wobei der aromatische Teil ggf. ein oder mehrere geeignete Sub stituenten 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, benzhy dryl, trityl and the like, the aromatic part optionally one or more suitable sub may have substituents such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, Chlorine, bromine, etc.), nitro and the like.
Beim obigen Ester kann der Alkan- und/oder Arenteil wahlweise zumindest einen geeigneten Substituenten aufweisen wie Halogen, Alkoxy, Hydroxy, Nitro oder dergleichen.In the above ester, the alkane and / or arene part can optionally have at least one have suitable substituents such as halogen, alkoxy, hydroxy, nitro or the like.
Die erfindungsgemäßen Verbindungen gemäß der Formel (I) können in ihrer proto nierten Form als Ammoniumsalz organischer oder anorganischer Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Methansulfonsäure, p- Toluolsulfonsäure, Essigsäure, Milchsäure, Maleinsäure, Fumarsäure, Oxalsäure, Weinsäure, Benzoesäure, etc. vorliegen.The compounds of the formula (I) according to the invention can in their proto form as the ammonium salt of organic or inorganic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p- Toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid, Benzoic acid, etc. are present.
Die erfindungsgemäß verwendeten Verbindungen der Formel (1) lassen beispielswei se für Doppelbindungen enthaltende oder chirale Gruppen R1 bis R9, X1, X8, X9 und A das Auftreten räumlicher Isomerer zu. Die erfindungsgemäße Verwendung der Verbindungen umfaßt alle räumlichen Isomere sowohl als Reinstoffe als auch in Form ihrer Mischungen.The compounds of the formula (1) used according to the invention allow, for example for double-containing or chiral groups R 1 to R 9 , X 1 , X 8 , X 9 and A, the occurrence of spatial isomers. The use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.
Besonders bevorzugt sind Einzelverbindungen, die den nachfolgenden Strukturfor
meln entsprechen:
Individual compounds which correspond to the following structural formulas are particularly preferred:
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 useful for therapeutic purposes and prophylactic treatment of human and animal infections caused by Viruses, bacteria, single and multicellular parasites and fungi are caused.
Die Verbindungen sind gegen einzellige Parasiten (Protozoen) wirksam, insbesonde re gegen Erreger der Malaria und der Schlafkrankheit sowie der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozysto se, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeg lerose, der Kokzidiose, der Giardiose und der Lambliose.The compounds are active against unicellular parasites (protozoa), in particular re against pathogens of malaria and sleeping sickness as well as Chagas disease, the Toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocysto se, balantidiosis, cryptosporidiosis, sarcocystosis, acanthamoebosis, naeg lerose, coccidiosis, giardiosis and lambliosis.
Sie sind daher insbesondere als Malariaprophylaxe und als Prophylaxe der Schlaf krankheit sowie der Chagas-Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmanio sen, der Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sar kozystose, der Akanthamöbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lam bliose geeignet.They are therefore particularly useful as malaria prophylaxis and as a prophylaxis of sleep disease as well as Chagas disease, toxoplasmosis, amoebic dysentery, Leishmanio sen, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, Sar cocystosis, acanthoma, nail disease, coccidiosis, giardiosis and lam suitable.
Die erfindungsgemäßen Wirkstoffe sind insbesondere gegen die folgenden Bakterien
einsetzbar:
Bakterien der Familie Propionibacteriaceae, insbesondere der Gattung Propionibacte
rium, insbesondere die Art Propionibacterium acnes, Bakterien der Familie Actinomyceta
ceae, insbesondere der Gattung Actinomyces, Bakterien der Gattung Corynebacterium, insbe
sondere die Arten Corynebacterium diphteriae und Corynebacterium pseudotuberculosis,
Bakterien der Familie Mycobacteriaceae, der Gattung Mycobacterium, insbesondere die Arten
Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis und Mycobacteri
um avium, Bakterien der Familie Chlamydiaceae, insbesondere die Spezies Chlamydia tra
chomatis und Chlamydia psittaci, Bakterien der Gattung Listeria, insbesondere die Art Liste
ria monocytogenes, Bakterien der Art Erysipelthrix rhusiopathiae, Bakterien der Gattung
Clostridium, Bakterien der Gattung Yersinia, der Spezies Yersinia pestis, Yersinia pseudotu
berculosis, Yersinia enterocolitica und Yersinia ruckeri, Bakterien der Familie Mycoplasma
taceae, der Gattungen Mycoplasma und Ureaplasma, insbesondere die Art Mycoplasma
pneumoniae, Bakterien der Gattung Brucella, Bakterien der Gattung Bordetella, Bakterien der
Familie Neiseriaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die
Arten Neisseria meningitides, Neisseria gonorrhoeae und Moraxella bovis, Bakterien der Fa
milie Vibrionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Pho
tobacterium, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas
salmonicidas, Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter
jejuni, Campylobacter coli und Campylobaeter fetus, Bakterien der Gattung Helicobacter,
insbesondere die Art Helicobacter pylori, Bakterien der Familien Spirochaetaceae und der
Leptospiraceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbeson
dere Borrelia burgdorferi, Bakterien der Gattung Actinobacillus, Bakterien der Familie Le
gionellaceae, der Gattung Legionella, Bakterien der Familie Rickettsiaceae und Familie Bar
tonellaceae, Bakterien der Gattungen Nocardia und Rhodococcus, Bakterien der Gattung
Dermatophilus, Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseu
domonas und Xanthomonas, Bakterien der Familie Enterobacteriaceae, insbesondere der
Gattungen Escherichia, Klebstella, Proteus, Providencia, Salmonella, Serratia und Shigella,
Bakterien der Familie Pasteurellaceae, insbesondere der Gattung Haemophilus, Bakterien der
Familie Micrococcaceae, insbesondere der Gattungen Mcrococcus und Staphylococcus,
Bakterien der Familie Streptococcaceae, insbesondere der Gattungen 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 Propionibacte rium genus, in particular the Propionibacterium acnes species, bacteria of the Actinomyceta ceae family, in particular of the Actinomyces genus, bacteria of the Corynebacterium genus, in particular the Corynebacterium diphteriae and Corynebculosis family, Bacterium family of bacteria, pseudotuberungung, bacterial pseudotuberungus, bacterial family pseudotuberung Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacteri um avium, bacteria of the Chlamydiaceae family, in particular the species Chlamydia tra chomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular the species List riahria monyt of the Art , Bacteria of the genus Clostridium, bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotu berculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the family Mycoplasma taceae, of the genera Mycoplasm a and ureaplasma, in particular the species Mycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella, bacteria of the family Neiseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the Vibrionaceae family, especially of the genera Vibrio, Aeromonas, Plesiomonas and Pho tobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas, bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobaeter fetus, bacteria of the genus Helicobacter, in particular the species Helicobacter pylori, bacteria of the Spirochaetaceae and Leptospiraceae families, especially the Treponema, Borrelia and Leptospira genera, in particular Borrelia burgdorferi, bacteria of the Actinobacillus genus, bacteria of the Le gionellaceae family, of the Legionella genus, bacteria of the Ri family ckettsiaceae and the Bar tonellaceae family, bacteria of the genera Nocardia and Rhodococcus, bacteria of the genus Dermatophilus, bacteria of the family Pseudomonadaceae, in particular of the genera Pseu domonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular of the genera Escherichia, Klebstella, Provella, Prote and Shigella, bacteria of the Pasteurellaceae family, in particular of the genus Haemophilus, bacteria of the family Micrococcaceae, in particular of the genera Mcrococcus and Staphylococcus, bacteria of the Streptococcaceae family, in particular of the genera Streptococcus and Enterococcus and bacteria of the family Bacillaceaus, in particular of the genus Bacillaceaium.
Damit eignen sich phosphororganischen Verbindungen und ihre Derivate zur Be handlung der Diphterie, der Acne vulgaris, der Listeriosen, des Rotlaufs bei Tieren, der Gas brand beim Mensch und beim Tier, Pararauschbrand bei Mensch und Tier, Tuberkulose bei Mensch und Tier, Lepra, und weitere Mykobacteriosen bei Mensch und Tier, der Paratuber kulose der Tiere, Pest, mesenterialen Lymphadenitis und Pseudotuberkulose bei Mensch und Tier, Cholera, Legionärskrankheit, Borreliose bei Mensch und Tier, Leptospirosen bei Mensch und Tier, Syphilis, Campylobacter-Enteritiden bei Mensch und Tier, Moraxella- Keratokonjunctivitis und Serositis der Tiere, Brucellosen der Tiere und des Menschen, Milz brand bei Mensch und Tier, Aktinomykose bei Mensch und Tier, Streptotrichosen, Psittako se/Ornithose bei Tieren, Q-Fieber, Ehrlichiose.Organophosphorus compounds and their derivatives are therefore suitable for loading act of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas burn in humans and animals, para-noise in humans and animals, tuberculosis Humans and animals, leprosy, and other mycobacteriosis in humans and animals, the Paratuber animal kulosis, plague, mesenteric lymphadenitis and pseudotuberculosis in humans and Animal, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in Humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella Keratoconjunctivitis and serositis of animals, brucellosis of animals and humans, spleen burn in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittaco se / ornithosis in animals, Q fever, Ehrlichiosis.
Weiter ist der Einsatz nützlich bei der Helicobacter-Eradikationstherapie bei Ulcera des Magendarmtraktes.The use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
Es können auch Kombination mit einem weiteren Antibiotikum zur Behandlung der obengenannten Erkrankungen eingesetzt werden. Für Kombinationspräparate mit anderen Antiinfektiva eignen sich insbesondere Isoniazid, Rifampicin, Ethambutol, Pyrazinamid, Streptomycin, Protionamid und Dapson zur Behandlung der Tuberkulose.It can also be combined with another antibiotic to treat the diseases mentioned above are used. For combination products with others Anti-infectives are particularly suitable for isoniazid, rifampicin, ethambutol, pyrazinamide, Streptomycin, protionamide and dapsone for the treatment of tuberculosis.
Die erfindungsgemäßen Wirkstoffe sind ferner insbesondere bei Infektionen mit fol
genden Viren einsetzbar:
Parvoviridae: Parvoviren, Dependoviren, Densoviren, Adenoviridae: Adenoviren,
Mastadenoviren, Aviadenoviren, Papovaviridae: Papovaviren, insbesondere Papillomaviren
(sogenannte Warzenviren), Polyomaviren, insbesondere JC-Virus, BK-Virus, und Miopapo
vaviren, Herpesviridae: Alle Herpesviren, insbesondere Herpes-Simplex-Viren, der Varizel
len/Zoster-Viren, menschlicher Zytomegalievirus, Epstein-Barr-Viren, alle humanen Herpes
viren, humanes Herpesvirus 6, Humanes Herpesvirus 7, humanes Herpesvirus 8, Poxviri
dae: Pockenviren, Orthopox-, Parapox-, Molluscum-Contagiosum-Virus, Aviviren, Caprivi
ren, Leporipoxviren, alle primär hepatotropen Viren, Hepatitisviren: Hepatitis-A-Viren, He
patitis-B-Viren, Hepatitis-C-Viren, Hepatitis-D-Viren, Hepatitis-E-Viren, Hepatitis-F-Viren,
Hepatits-G-Viren, Hepadnaviren: sämtliche Hepatitisviren, Hepatitis-B-Virus, Hepatitis-D-
Viren,
Picornaviridae: Picornaviren, alle Enteroviren, alle Polioviren, alle Coxsackieviren,
alle Echoviren, alle Rhinoviren, Hepatitis-A-Virus, Aphthoviren, Calciviridae: Hepatitis-E-
Viren, Reoviridae: Reoviren, Orbiviren, Rotaviren, Togaviridae: Togaviren, Alphaviren,
Rubiviren, Pestiviren, Rubellavirus, Flaviviridae: Flaviviren, FSME-Virus, Hepatitis-C-Virus,
Orthomyxoviridae: Alle Influenzaviren, Paramyxoviridae: Paramyxoviren, Morbillivirus,
Pneumovirus, Masernvirus, Mumpsvirus, Rhabdoviridae: Rhabdoviren, Rabiesvirus, Lyssavi
nis, viskuläres Stomatitisvirus, Coronaviridae: Coronaviren, Bunyaviridae: Bunyaviren, Nai
rovirus, Phlebovirus, Uukuvirus, Hantavirus, Arenaviridae: Arenaviren, lymphozytäres Cho
riomeningitis-Virus, Retroviridae: Retroviren, alle HTL-Viren, humanes T-cell leukämie-
Virus, Oncornaviren, Spumaviren, Lentiviren, Alle HI-Viren, Filoviridae: Marburg- und
Ebolavirus, Slow-virus-Infektionen, Prionen, Onkoviren, Leukämie-Viren.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, herpes virus, herpes virus, and herpes virus, herpes virus, and herpes virus 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, Poxviri dae: smallpox viruses, Orthopox, Parapox, Molluscum -Contagiosum virus, aviviruses, capriviruses, leporipox viruses, all primarily hepatotropic viruses, hepatitis viruses: hepatitis A viruses, He patitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, Hepatitis F viruses, Hepatits G viruses, hepadnaviruses: all hepatitis viruses, hepatitis B virus, hepatitis D viruses,
Picornaviridae: Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses, Calciviridae: hepatitis E viruses, Reoviridae: reoviruses, orbiviruses, rotaviruses, rotaviruses, Togaviruses, Togaviruses , Pestiviruses, rubella virus, flaviviridae: flaviviruses, TBE virus, hepatitis C virus, orthomyxoviridae: all influenza viruses, paramyxoviridae: paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus, rhabdovirovirida virus, rhabdovirovirida virus, rhabdovirovirida virus, rabhabvirovirus virus, rhabdovirovirida virus, rhabdovirovirida virus, rhabdovirovirida virus, ravdovirid virus virus Coronaviruses, Bunyaviridae: Bunyaviren, Nai rovirus, Phlebovirus, Uukuvirus, Hantavirus, Arenaviridae: Arenaviruses, Lymphocytic Cho riomeningitis Virus, Retroviridae: Retroviruses, all HTL Viruses, Human T-Cell Oncemia Viruses, Human T-cell leukemia virus -Viruses, Filoviridae: Marburg and Ebola viruses, slow virus infections, prions, onkoviruses, leukemia viruses.
Die erfindungsgemäßen phosphororganischen Verbindungen sind somit zur Bekämp
fung folgender viraler Infekte geeignet:
Eradikation von Papillomaviren zur Vorbeugung von Tumoren, insbesondere von
Tumoren der Geschlechtsorganen verursacht durch Papillomaviren beim Menschen, Eradika
tion von JC-Viren und BK-Viren, Eradikation von Herpesviren, Eradikation humaner Herpes
viren 8 zur Behandlung der Kaposi-Sarkoma, Eradikation von Zytomegalie-Viren vor Trans
plantationen, Eradikation von Eppstein-Barr-Viren vor Transplantation und zur Vorbeugung
von Eppstein-Barr-Viren-assozierten Tumoren, Eradikation von Hepatitisviren zur Behand
lung von chronischen Leber-Erkrankungen und zur Vorbeugung von Lebertumoren und Le
berzirrhosen, Eradikation von Coxsackieviren bei Kardiomyopathien, Eradikation von Cox
sackieviren bei Diabetes-mellitus-Patienten, Eradikation von Immunschwäche-Viren in
Mensch und Tier, Behandlung von Begleitinfektionen in AIDS-Patienten, Behandlung von
Entzündungen viraler Genese des Respirationstraktes (Larynxpapillome, Hyberplasien, Rhi
nitis, Pharyngitis, Bronchitis, Pneumonien), der Sinnesorgane (Keratokonjunktivitis), des
Nervensystems (Poliomyelitis, Meningoenzephalitis, Enzephalitis, subakute sklerosierende
Panenzephalitis, SSPE, progressive multifokale Leukoenzephalopathie, lymphozytäre Cho
riomeningitis), des Magen-Darm-Traktes (Stomatitis, Gingivostomatitis, Ösophagitis, Gastri
tis, Gastroenteritis, Durchfallerkrankungen), der Leber und des Gallensystems (Hepatitis,
Cholangitis, hepatozelluläres Karzinom), des lymphatischen Gewebes (Mononukleose, Lym
phadenitis), des hämatopoetischen Systems, der Geschlechtsorgane (Mumpsorchitis), der
Haut (Warzen, Dermatitis, Herpes labialis, Fieberbläschen, Herpes Zoster, Gürtelrose), der
Schleimhäute (Papillome, Konjunktivapapillome, Hyperplasien, Dysplasien), des Herz-
Blutgefäß-Systems (Arteriitis, Myokarditis, Endokarditis, Perikarditis), des Nieren-Harnweg-
Systems, der Geschlechtsorgane (Anogenitale Läsionen, Warzen, Genitalwarzen, spitzen
Kondylome, Dysplasien, Papillome, Zervixdysplasien, Condylomata acuminata, Epidermo
dysplasia verruciformis), der Bewegungsorgane (Myositis, Myalgien), Behandlung der Maul-
und Klauenseuche der Paarhufer, des Colorado-Zeckenfiebers, des Dengue-Syndroms, des
hämorrhagisches Fiebers, der Frühsommermeningoenzephalitis (FSME) und des Gelbfiebers.The organophosphorus compounds according to the invention are therefore suitable for combating the following viral infections:
Eradication of papillomaviruses for the prevention of tumors, especially 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 cytomegaly Viruses before transplantations, eradication of Eppstein-Barr viruses before transplantation and for the prevention of Eppstein-Barr virus-associated tumors, eradication of hepatitis viruses for the treatment of chronic liver diseases and for the prevention of liver tumors and liver cirrhosis, eradication of Coxsackieviruses in cardiomyopathies, eradication of Cox sackieviren 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 papillomas, hyberplasias, rhinitis, pharyngitis, bronchitis , Pneumonia), the sensory concern ane (keratoconjunctivitis), of the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocytic Cho riomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastri tis, gastroenteritis, diarrhea), the liver and the biliary system (hepatitis, cholangitis, hepatocellular carcinoma), the lymphatic tissue (mononucleosis, lymphadenitis), the hematopoietic system, the genital organs (mumps orchitis), the skin (warts, dermatitis, herpes labialis, cold sores, herpes sores, herpes ), 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, genital warts, acute condylomas) Dysplasia, papilloma, cervical dysplasia, condylomata acuminata, Ep idermo dysplasia verruciformis), the locomotive organs (myositis, myalgia), treatment of foot and mouth disease in 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 Formel (I) und Ester sowie Salze derselben zeigen eine starke zytotoxische Wirksamkeit ge genüber ein- und mehrzelligen Parasiten, insbesondere gegenüber den Erregern der Malaria und der Schlafkrankheit. Demgemäß sind die erfindungsgemäßen Verbindungen für die Be handlung von Infektionskrankheiten 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 hervorge rufen werden, insbesondere als Malariaprophylaxe und als Schlafkrankheitsprophylaxe geeig net. Unter einzelligen Parasiten sind erfindungsgemäß entsprechend der engeren Definition der Parasitologie Protozoen zu verstehen.The compounds described, i. H. the organophosphorus compounds after Formula (I) and esters and salts thereof show a strong cytotoxic activity against single and multicellular parasites, especially against the pathogens of malaria and sleeping sickness. Accordingly, the compounds of the invention for Be treatment of infectious diseases caused by viruses, bacteria, parasites and Fungi are caused in humans and animals. The connections are also for use to prevent diseases caused by viruses, bacteria, parasites and fungi are called, especially as malaria prophylaxis and sleep sickness prophylaxis net. According to the narrower definition, unicellular parasites are according to the invention to understand the parasitology of protozoa.
Die erfindungsgemäßen phosphororganischen Verbindungen, hierzu gehören im all gemeinen pharmazeutisch verträgliche Salze, Amide, Ester, ein Salz eines solchen Esters, oder aber Verbindungen, die bei Applikation die erfindungsgemäßen Verbindungen als Stoffwechselprodukte oder Abbauprodukte bereitstellen, auch "Prodrugs" genannt, können für die Verabreichung in irgendeiner geeigneten Weise analog zu bekannten antiinfektiös wir kenden Mitteln (gemischt mit einem nicht toxischen pharmazeutisch akzeptablen Träger) zu bereitet werden.The organophosphorus compounds according to the invention, these include in all common pharmaceutically acceptable salts, amides, esters, a salt of such an ester, or compounds which, when applied, the compounds of the invention as Providing metabolic products or breakdown products, also called "prodrugs", can be used for administration in any suitable manner analogous to known anti-infectious kenden agents (mixed with a non-toxic pharmaceutically acceptable carrier) be prepared.
Zu pharmazeutisch akzeptablen Salzen der Verbindungen gehören Salze, die die er findungsgemäßen Verbindungen der Formeln (I) in ihrer protonierten Form als Ammonium salz anorganischer oder organischer Säuren, wie Salzsäure, Schwefelsäure, Zitronensäure, Maleinsäure, Fumarsäure, Weinsäure, p-Toluolsulfonsäure, bilden.Pharmaceutically acceptable salts of the compounds include salts which he Compounds of the formulas (I) according to the invention in their protonated form as ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, Form maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
Pharmazeutisch besonders geeignet sind auch die Salze, die durch geeignete Aus wahl von X3 und X4 gebildet werden, wie Natriumsalz, Kaliumsalz, Calciumsalz, Ammoni umsalz, Ethanolaminsalz, Triethylaminsalz, Dicyclohexylaminsalz und Salze einer Ami nosäure wie Argininsalz, Asparaginsäuresalz, Glutaminsäuresalz.Also particularly pharmaceutically suitable are the salts formed by a suitable choice 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 pharmazeutisch wirksamen Mittel können in Form von pharmazeutische Zube reitungen in Dosierungseinheiten zubereitet werden. Dies bedeutet, daß die Zubereitung in Form einzelner Teile, z. B. Tabletten, Dragees, Kapseln, Pillen, Suppositorien und Ampullen vorliegen, deren Wirkstoffgehalt einem Bruchteil 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 Einzeldosis enthält vorzugsweise die Menge Wirk stoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer hal ben oder einem Drittel oder einem Viertel einer Tagesdosis entspricht.The pharmaceutically active agents can be in the form of pharmaceutical accessories preparations are prepared in dosage units. This means that the preparation in Shape of individual parts, e.g. B. tablets, dragees, capsules, pills, suppositories and ampoules are present, the active ingredient content of which is a fraction or a multiple of a single dose correspond. 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. A single dose preferably contains the amount of active ingredient substance that is administered in one application and that usually a whole, a hal ben or a third or a quarter of a daily dose.
Unter nicht toxischen, inerten pharmazeutisch geeigneten Trägerstoffen sind feste, halbfeste oder flüssige Verdünnungsmittel, Füllstoffe und Formulierungshilfsmittel jeder Art zu verstehen.Non-toxic, inert pharmaceutically suitable excipients include solid, Semi-solid or liquid diluents, fillers and formulation aids of all kinds to understand.
Als bevorzugte pharmazeutische Zubereitungen seien Tabletten, Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lotions, Puder und Sprays genannt. Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmittel, z. B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kie selsäure, (b) Bindemittel, z. B. Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrroli don, (c) Feuchthaltemittel, z. B. Glycerin, (d) Sprengmittel, z. B. Agar-Agar, Calciumcarbo nat und Natriumcarbonat, (e) Lösungsverzögerer, z. B. Paraffin und (f) Resorptionsbeschleu niger, z. B. quarternäre Ammoniumverbindungen, (g) Netzmittel, z. B. Cetylalkohol, Glyce rinmonostearat, (h) Adsorptionsmittel, z. B. Kaolin und Bentonit und (i) Gleitmittel, z. B. Talkum, Calcium- und Magnesiumstearat und feste Polyethylenglykole oder Gemische der unter (a) bis (i) aufgeführten Stoffe.The preferred pharmaceutical preparations are tablets, dragees, capsules, Pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, Called gels, creams, lotions, powders and sprays. Tablets, dragees, capsules, pills and Granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and Kie silica, (b) binder, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrroli don, (c) humectants, e.g. B. glycerin, (d) disintegrant, e.g. B. agar-agar, calcium carbo nate and sodium carbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption absorption niger, e.g. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. Cetyl alcohol, Glyce rinmonostearate, (h) adsorbent, e.g. B. kaolin and bentonite and (i) lubricants, e.g. B. Talc, calcium and 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, ge gebenenfalls Opakisierungsmittel enthaltenden Überzügen und Hüllen versehen sein und auch so zusammengesetzt sein, daß sie den oder die Wirkstoffe nur oder bevorzugt in einem be stimmten Teil des Intestinaltraktes gegebenenfalls verzögert abgeben, wobei als Einbettungs massen z. B. Polymersubstanzen und Wachse verwendet werden können.The tablets, dragees, capsules, pills and granules can with the usual, ge if necessary, coatings and casings containing opacifying agents are provided and also be composed such that they contain the active ingredient (s) only or preferably in one some parts of the intestinal tract may be delayed, whereby as embedding mass 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 mikroverkapselter Form vorliegen.The active ingredient (s) can optionally be combined with one or more of the above specified carrier substances are also present in microencapsulated form.
Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Trägerstoffe enthalten, z. B. Polyethylenglykole, Fette, z. B. Kakao fett und höhere Ester (z. B. C14-Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.Suppositories can be the usual water-soluble in addition to the active ingredient (s) or contain water-insoluble carriers, e.g. B. polyethylene glycols, fats, e.g. B. Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or mixtures of these substances.
Salben, Pasten, Cremes und Gele können neben dem oder den Wirkstoffen die übli chen Trägerstoffe enthalten, z. B. tierische und pflanzliche Fette, Wachse, Paraffine; Stärke, Tragant, Cellulosederivate, Polyethylenglykole, Silikone, Bentonite, Kieselsäure, Talkum und Zinkoxid oder Gemische dieser Stoffe.Ointments, pastes, creams and gels can besides the active ingredient (s) the usual Chen carriers, e.g. B. animal and vegetable fats, waxes, paraffins; Strength, Tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and Zinc oxide or mixtures of these substances.
Puder und Sprays können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z. B. Milchzucker, Talkum, Kieselsäure, Aluminiumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe. Sprays können zusätzlich die üblichen Treib mittel, z. B. Chlorfluorkohlenwasserstoffe, enthalten.In addition to the active ingredient (s), powders and sprays can contain the usual carriers included, e.g. As milk sugar, talc, silica, aluminum hydroxide, calcium silicate and Polyamide powder or mixtures of these substances. Sprays can also use the usual propellants medium, e.g. B. chlorofluorocarbons.
Lösungen und Emulsionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z. B. Wasser, Ethylal kohol, Isopropylalkohol, Ethylcarbonat, Ethylacetat, Benzylalkohol, Benzylbenzoat, Propy lenglykol, 1,3-Butylenglykol, Dimethylformamid, Öle, insbesondere Baumwollsaatöl, Erd nußöl, Maiskeimöl, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydro furfurylalkohol, Polyethylenglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), solutions and emulsions can be the usual ones Carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethylal alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propy lenglycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, earth nut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydro furfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures thereof Contain substances.
Zur parenteralen Applikation können die Lösungen und Emulsionen auch in steriler und blutisotonischer Form vorliegen.For parenteral administration, the solutions and emulsions can also be used in sterile and blood isotonic form.
Suspensionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie flüssige Verdünnungsmittel, z. B. Wasser, Ethylalkohol, Propylenglykol, Suspendiermittel, z. B. ethoxylierte Isostearylalkohole, Polyoxyethylensorbit- und Sorbitan-Ester, mikrokristalline Cellulose, Aluminiummetahydroxid, Bentonit, Agar-Agar und Tragant oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), suspensions can also contain the usual carriers such as liquid diluents, e.g. B. water, ethyl alcohol, propylene glycol, suspending agent, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these Contain substances.
Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmacksverbesserte 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-improved additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. saccharin.
Die Wirkstoffe der Formeln (I) sollen in den oben aufgeführten pharmazeutischen Zubereitungen, vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5 Gew.-%, vorzugs weise von etwa 0,5 bis 95 Gew.-%, der Gesamtmischung vorhanden sein.The active compounds of the formulas (I) are intended to be used in the pharmaceuticals listed above Preparations, preferably in a concentration of about 0.1 to 99.5% by weight, are preferred from about 0.5 to 95% by weight of the total mixture.
Die pharmazeutischen Zubereitungen können außer den Verbindungen der Formel (I) auch weitere pharmazeutische Wirkstoffe enthalten.In addition to the compounds of the formula (I), the pharmaceutical preparations can also contain other active pharmaceutical ingredients.
Ferner können die phosphororganischen Verbindungen in den pharmazeutischen Mitteln in Kombination mit Sulfonamid, Sulfadoxin, Artemisinin, Atovaquon, Chinin, Chlo roquin, Hydroxychloroquin, Mefloquin, Halofantrin, Pyrimethamin, Armesin, Tetracycline, Doxycyclin, Proguanil, Metronidazol, Praziquantil, Niclosamid, Mebendazol, Pyrantel, Tia bendazol, Diethylcarbazin, Piperazin, Pyrivinum, Metrifonat, Oxamniquin, Bithionol oder Suramin oder mehreren dieser Substanzen vorliegen.Furthermore, the organophosphorus compounds in the pharmaceutical Agents in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, Chlo roquin, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin, tetracycline, Doxycycline, proguanil, metronidazole, praziquantil, niclosamide, mebendazole, pyrantel, Tia bendazole, diethylcarbazine, piperazine, pyrivinum, metrifonate, oxamniquin, bithionol or Suramin or several of these substances are present.
Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z. B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.The pharmaceutical preparations listed above are produced in customarily by known methods, e.g. B. by mixing the active ingredient (s) with the carrier or carriers.
Die genannten Zubereitungen können bei Mensch und Tier entweder oral, rektal, pa renteral (intravenös, intramuskulär, subkutan), intracisternal, intravaginal, intraperitoneal, lokal (Puder, Salbe, Tropfen) und zur Therapie von Infektionen in Hohlräumen, Körperhöhlen angewendet werden. Als geeignete Zubereitungen kommen Injektionslösungen, Lösungen und Suspensionen für die orale Therapie, Gele, Aufgußformulierungen, Emulsionen, 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 Formulierungen 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 erfindungsge mäßen Verbindungen in andere Trägermaterialien wie zum Beispiel Kunststoffe, (Kunststoff ketten zur lokalen Therapie), Kollagen oder Knochenzement eingearbeitet werden.In humans and animals, the preparations mentioned can either be oral, rectal, pa renteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, locally (powder, ointment, drops) and for the treatment of infections in cavities, body cavities be applied. Injection solutions, solutions come as suitable preparations and suspensions for oral therapy, gels, infusion formulations, emulsions, ointments or drops in question. For local therapy, ophthalmic and dermatological Formulations, silver and other salts, ear drops, eye ointments, powder or solutions be used. In animals, the intake can also be in the feed or drinking water appropriate formulations. Furthermore, gels, powders, powders, tablets, slow-release Tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, Sprays, inhalants can be used in humans and animals. Furthermore, the fiction moderate connections in other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement.
Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinärmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe der Formel (I) in Gesamtmengen von etwa 0,05 bis etwa 600, vorzugsweise 0,5 bis 200 mg/kg Körpergewicht je 24 Stunden, gegebenen falls in Form mehrerer Einzelgaben, zur Erzielung der gewünschten Ergebnisse zu verabrei chen. 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 genannten 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 Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. In tervall, innerhalb welchem die Verabreichung erfolgt.In general, it has been found in both human and veterinary medicine proven advantageous, the active ingredient or formula (I) in total amounts of about 0.05 to about 600, preferably 0.5 to 200 mg / kg body weight per 24 hours given if in the form of multiple doses, to achieve the desired results chen. A single dose contains the active ingredient (s) preferably in amounts of about 1 up to about 200, in particular 1 to 60 mg / kg body weight. However, it may be necessary deviate from the doses mentioned, depending on the type and the body weight of the patient to be treated, the type and severity of the disease, the type of preparation and application of the medicinal product as well as the period or in 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 anderen Fällen die oben angeführte Wirkstoff menge überschritten werden muß. Die Festlegung der jeweils erforderlichen optimalen Dosie rung und Applikationsart der Wirkstoffe kann durch den Fachmann aufgrund seines Fachwis sens erfolgen.So in some cases it may be sufficient with less than the above Amount of active ingredient to get by while in other cases the active ingredient listed above quantity must be exceeded. The determination of the optimal dosage required in each case tion and type of application of the active ingredients can by the specialist based on his specialist knowledge sens done.
Die erfindungsgemäßen Verbindungen können in den üblichen Konzentrationen und Zubereitungen bei Tieren zusammen mit dem Futter bzw. mit Futterzubereitungen oder mit dem Trinkwasser gegeben werden.The compounds according to the invention can be used in the usual concentrations and Preparations in animals together with the feed or with feed preparations or with be given to the drinking water.
Grundsätzlich weiß der Fachmann, welchen Syntheseweg er zur Herstellung der er findungsgemäßen Substanzen zu wählen hat. Im folgenden werden beispielhaft einige Syn thesewege für Verbindungen der Erfindung angegeben.Basically, the expert knows which synthetic route he uses to produce the substances to choose according to the invention. In the following, some syn thesis routes for compounds of the invention are given.
Es werden Beispiele für die folgenden Substanzen angegeben:
Examples are given for the following substances:
HO-NR1-CO-CHR2-NR3-CHR4-P(=O)(OH)2
HO-NR 1 -CO-CHR 2 -NR 3 -CHR 4 -P (= O) (OH) 2
mit R1 = R2 = R3 = H
und R4 = n-Butyl: 1
mit R1 = R2 = H, R3 = Methyl und R4 = m-Pyridyl: 2
mit R1 = R2 = H, R3 = n-Butyl und R4 = Methyl: 3
mit R1 = R2 = R3 = H
und R4 = Methyl, Ethyl: 4
mit R1 = R4 = H, R2 = Methyl und R4 = Methyl: 5
mit R1 = H, R2 = R3 = R4 = Methyl: 6
mit R1 = Methyl, R2 = R3 = R4 = H: 7
mit R1 = Isopropyl, R2 = R3 = R4 = H: 8with R 1 = R 2 = R 3 = H
and R 4 = n-butyl: 1
with R 1 = R 2 = H, R 3 = methyl and R 4 = m-pyridyl: 2
with R 1 = R 2 = H, R 3 = n-butyl and R 4 = methyl: 3
with R 1 = R 2 = R 3 = H
and R 4 = methyl, ethyl: 4
with R 1 = R 4 = H, R 2 = methyl and R 4 = methyl: 5
with R 1 = H, R 2 = R 3 = R 4 = methyl: 6
with R 1 = methyl, R 2 = R 3 = R 4 = H: 7
with R 1 = isopropyl, R 2 = R 3 = R 4 = H: 8
2,51 g (20 mmol) Glycinmethylester-hydrochlorid werden mit 2,42 g (24 mmol) Triethylamin sowie 2,58 g (30 mmol) frisch destilliertem Pentanal - und zum Lösen mit dem minimalen Volumen Wasser - versetzt. Man läßt 3 d im Dunkeln bei RT rühren, extrahiert mit Ether, wäscht die vereinten Extrakte mit Wasser und engt unter reduziertem Druck ein. Man erhält Imin 1a als bräunliches Öl in zufriedenstellender Ausbeute, welches ohne zusätzliche Reinigung weiter umgesetzt wird.2.51 g (20 mmol) glycine methyl ester hydrochloride are mixed with 2.42 g (24 mmol) Triethylamine and 2.58 g (30 mmol) freshly distilled pentanal - and to dissolve with the minimal volume of water - added. The mixture is stirred for 3 d in the dark at RT and extracted with Ether, washes the combined extracts with water and concentrated under reduced pressure. Man receives Imin 1a as a brownish oil in a satisfactory yield, which without additional Cleaning is implemented further.
Eine Mischung aus 1,88 g (12 mmol) Imin 1a und 0,98 g (12 mmol) phosphoriger Säure werden auf 110°C erhitzt. Nach 10 min bei einer Reaktionstemperatur von 150°C kühlt man auf 90°C ab, gibt 10 ml 50%iges wäßriges Ethanol hinzu, wobei das Produkt 1b als weißer Feststoff in zufriedenstellender Ausbeute beim weiteren Abkühlen anfällt.A mixture of 1.88 g (12 mmol) imine 1a and 0.98 g (12 mmol) phosphorous Acid are heated to 110 ° C. After 10 min at a reaction temperature of 150 ° C is cooled to 90 ° C., 10 ml of 50% aqueous ethanol are added, the product 1b is obtained as a white solid in a satisfactory yield on further cooling.
Die Umsetzung von 1,19 g (5 mmol) Phosphonsäure 1b mit 30 mmol freiem Hy droxylamin in 50 ml wäßrigem Methanol unter Zusatz von 3,8 ml (15 mmol) 4-M-NaOH- Lsg. liefert nach Rühren über Nacht, einengen am Rotationsverdampfer und reinigen an einer Anionentauschersäule Hydroxamsäure 1 als farblosen Feststoff in mäßiger Ausbeute.The reaction of 1.19 g (5 mmol) of phosphonic acid 1b with 30 mmol of free Hy droxylamine in 50 ml aqueous methanol with the addition of 3.8 ml (15 mmol) 4-M-NaOH- Solute delivers overnight after stirring, concentrate on a rotary evaporator and clean on one Anion exchange column hydroxamic acid 1 as a colorless solid in moderate yield.
2,02 g (10 mmol) 1-(N-Methylamino)-1-(3-pyridyl)-methylphosphonsäure (nach B. Boduszek, J. S. Wieczorek, J. prakt. Chemie 328, 627 (1986)) werden mit 0,84 g (10 mmol) Natriumhydrogencarbonat in 30 ml Wasser gelöst. Nach Eintrag von 0,94 g (10 mmol) 2- Chloracetamid läßt man über Nacht rühren und erhitzt die Suspension anschließend 1 h unter Rückfluß. Die entstehende nahezu klare Lösung wird heiß filtriert. Das Filtrat wird unter re duziertem Druck eingeengt, der Rückstand in wenig Wasser aufgenommen und mit halbkonz. wäßriger HCl ein pH von 4-5 eingestellt. Das Säureamid 2a wird mit Aceton aus der Lösung heraus gefällt und ohne Reinigungsschritt weiter umgesetzt.2.02 g (10 mmol) 1- (N-methylamino) -1- (3-pyridyl) methylphosphonic acid (after B. Boduszek, J. S. Wieczorek, J. Prakt. Chemie 328, 627 (1986)) are mixed with 0.84 g (10 mmol) Sodium bicarbonate dissolved in 30 ml of water. After entry of 0.94 g (10 mmol) 2- Chloroacetamide is allowed to stir overnight and the suspension is then heated for 1 h Reflux. The resulting almost clear solution is filtered hot. The filtrate is under right reduced pressure, the residue taken up in a little water and with half-conc. aqueous HCl adjusted a pH of 4-5. The acid amide 2a is removed from the solution with acetone fallen out and implemented without cleaning step.
0,50 g des Rohproduktes 2a werden mit 0,15 g (2,2 mmol) Hydroxylaminhydrochlo rid in 5 ml Wasser gelöst. Nach 5 d bei RT wird mit Wasser verdünnt und das Produkt 2 in schlechter Ausbeute am Anionentauscher gereinigt. 0.50 g of the crude product 2a with 0.15 g (2.2 mmol) of hydroxylamine hydrochloride rid dissolved in 5 ml of water. After 5 d at RT, the mixture is diluted with water and the product is 2 in poor yield at the anion exchanger cleaned.
Umsetzung von 6,28 g (50 mmol) Glycinmethylester-hydrochlorid mit 3,30 g (75 mmol) Acetaldehyd analog zu Imin 1a liefert das Rohimin 3a in guter Ausbeute.Reaction of 6.28 g (50 mmol) of glycine methyl ester hydrochloride with 3.30 g (75 mmol) acetaldehyde analogous to imine 1a gives the crude imine 3a in good yield.
Umsetzung von 4,37 g (38 mmol) Rohimin 3a mit 3,12 g (38 mmol) phosphoriger Säure analog zu Verbindung 1b liefert die Aminomethanphosphonsäure 3b als fast farblosen Feststoff in mittlerer Ausbeute.Reaction of 4.37 g (38 mmol) of crude imine 3a with 3.12 g (38 mmol) of phosphorous Acid analogous to compound 1b provides aminomethanephosphonic acid 3b as almost colorless Solid in medium yield.
3,94 g (20 mmol) 3b werden analog zu Verbindung 6c mit 2,74 g (20 mmol) n- Butylbromid umgesetzt. Als Produkt fällt 3c als Gemisch des Methyl- und Butyl-esters in Form eines gelblichen Pulvers in geringer Ausbeute an.3.94 g (20 mmol) 3b are treated analogously to compound 6c with 2.74 g (20 mmol) n- Butyl bromide implemented. As a product, 3c is a mixture of the methyl and butyl esters Form of a yellowish powder in low yield.
Eine Suspension von 0,40 g (1,5 mmol) 3c in 15 ml absolutiertem Methanol wird mit 8,0 mmol freiem Hydroxylamin in Methanol und 0,10 g (4,5 mmol) Natrium in 20 ml abs. Methanol versetzt. Nach Rühren über Nacht bei RT engt man ein und wäscht den halbfesten Rückstand mehrmals mit Aceton. Nach Aufnehmen des jetzt festen Rückstands in 5 ml Was ser stellt man mit halbkonz. HCl einen pH-Wert von 5 bis 6 ein und fällt das Produkt durch Zugabe von Aceton. Hydroxamsäure 3 wird als farbloser Feststoff in mäßiger Ausbeute er halten.A suspension of 0.40 g (1.5 mmol) 3c in 15 ml of absolute methanol is added 8.0 mmol free hydroxylamine in methanol and 0.10 g (4.5 mmol) sodium in 20 ml abs. Methanol added. After stirring overnight at RT, the mixture is concentrated and the semi-solid is washed Residue several times with acetone. After taking up the now solid residue in 5 ml of what it is made with a half-conc. HCl a pH of 5 to 6 and the product falls through Add acetone. Hydroxamic acid 3 is a colorless solid in moderate yield hold.
Ann. Chem. 1990, 331) werden mit 0,98 g (10 mmol) Chloracetamid zu N-(1-Phosphono-1- methylpropyl)-alaninamid 4a umgesetzt. Nach Fällung aus Wasser/Aceton wird 4a durch Umkristallisieren aus Wasser/Aceton in guter Ausbeute rein erhalten.Ann. Chem. 1990, 331) with 0.98 g (10 mmol) chloroacetamide to N- (1-phosphono-1- methylpropyl) alaninamide 4a implemented. After precipitation from water / acetone, 4a Recrystallization from water / acetone obtained in good yield pure.
1,57 g (7,5 mmol) 4a werden mit 0,52 g (7,5 mmol) Hydroxylamin-hydrochlorid in wenig Wasser gelöst. Nach 7 d bei RT wird mit Wasser verdünnt und das Produkt 4 am Anio nenaustauscher gereinigt. Man erhält N-(1-Phosphono-1-methylpropyl)-L-alaninhydroxamat 4 in mäßiger Ausbeute als schwach-gelben Feststoff.1.57 g (7.5 mmol) of 4a are mixed with 0.52 g (7.5 mmol) of hydroxylamine hydrochloride little water dissolved. After 7 d at RT, the mixture is diluted with water and the product 4 on anio exchangers cleaned. N- (1-Phosphono-1-methylpropyl) -L-alanine hydroxamate is obtained 4 in moderate yield as a pale yellow solid.
1,03 g (10 mmol) N-Methyl-L-alanin werden in 10 ml Wasser mit 2,46 g (30 mmol) phosphoriger Säure und 10 ml konz. HCl zum Rückfluß erhitzt. Binnen 15 min werden 15 ml 37%ige Formalin-Lsg. zugetropft und eine weitere Stunde unter Rückfluß erhitzt. Nach dem Abkühlen fallen Kristalle aus, die filtriert und mit Isopropanol gewaschen werden. Umkri stallisieren aus Wasser/Isopropanol liefert farblose Kristalle von 5a in mittlerer Ausbeute.1.03 g (10 mmol) of N-methyl-L-alanine are mixed with 2.46 g (30 mmol) in 10 ml of water. phosphorous acid and 10 ml conc. HCl heated to reflux. 15 ml become within 15 min 37% formalin solution. added dropwise and heated under reflux for a further hour. After this When cooling, crystals precipitate, which are filtered and washed with isopropanol. Umkri stallize from water / isopropanol provides colorless crystals of 5a in medium yield.
1,18 g (6 mmol) 5a werden in 50 ml absolutiertem Ethanol mit einer Spatelspitze p- Toluolsulfonsäure suspendiert. Nach 5-stündigem Erhitzen unter Rückfluß wird die Lösung unter reduziertem Druck eingeengt, der ölige Rückstand in 25 ml absolutem Methanol gelöst und eine Lösung von 30 mmol Hydroxylamin in Methanol dazu getropft [aus 2,08 g (30 mmol) Hydroxylamin-hydrochlorid und Natriummethanolat in äquimolarer Menge]. Zu der resultierenden Suspension gibt man 0,41 g (18 mmol) Natrium in Methanol. Nach Rühren über Nacht zieht man das Lösungsmittel unter reduziertem Druck ab, nimmt in Wasser auf und trennt das Produkt 5 in mäßiger Ausbeute an einem Anionentauscher von anderen Salzen ab. 1.18 g (6 mmol) 5a are p- in 50 ml of absolute ethanol with a spatula tip Toluene sulfonic acid suspended. After refluxing for 5 hours, the solution concentrated under reduced pressure, the oily residue dissolved in 25 ml of absolute methanol and a solution of 30 mmol hydroxylamine in methanol added dropwise [from 2.08 g (30 mmol) Hydroxylamine hydrochloride and sodium methoxide in equimolar amounts]. To the resulting suspension is added 0.41 g (18 mmol) sodium in methanol. After stirring The solvent is removed overnight under reduced pressure and taken up in water and separates product 5 from other salts in moderate yield on an anion exchanger from.
Die Umsetzung von 6,98 g (50 mmol) L-Alaninmethylester mit 3,30 g (75 mmol) Acetaldehyd nach Vorschrift für Verbindung 1a liefert das Rohimin 6a in guter Ausbeute.The reaction of 6.98 g (50 mmol) of L-alanine methyl ester with 3.30 g (75 mmol) Acetaldehyde according to the instructions for compound 1a gives the crude imine 6a in good yield.
Die Umsetzung von 4,51 g (35 mmol) Rohimin 6a mit 2,87 g (35 mmol) phosphori ger Säure nach der Vorschrift für 1a liefert die Aminomethanphosphonsäure 1b als farblosen Feststoff in mittlerer Ausbeute.The reaction of 4.51 g (35 mmol) of crude imine 6a with 2.87 g (35 mmol) of phosphori ger acid according to the instructions for 1a provides the aminomethanephosphonic acid 1b as colorless Solid in medium yield.
3,17 g (15 mmol) 6b werden in 50 ml peroxidfreiem THF suspendiert. Diese Suspen sion wird nacheinander versetzt mit 5,0 g wasserfreiem K2CO3, 5 Tropfen 18-Krone-6, 0,5 g Bu4NI und 2,18 g (15 mmol) MeI. Nach Rühren über Nacht bei 30°C kühlt man auf 0°C ab und filtriert. Der Filterrückstand wird in Wasser aufgenommen. Auf Zusatz von Aceton fällt das Produkt aus. 6c wird als gelblicher Feststoff in mäßiger Ausbeute erhalten.3.17 g (15 mmol) 6b are suspended in 50 ml of peroxide-free THF. This suspension is successively mixed with 5.0 g of anhydrous K 2 CO 3 , 5 drops of 18-crown-6, 0.5 g of Bu 4 NI and 2.18 g (15 mmol) of MeI. After stirring overnight at 30 ° C., the mixture is cooled to 0 ° C. and filtered. The filter residue is taken up in water. The product precipitates when acetone is added. 6c is obtained as a yellowish solid in moderate yield.
Eine Lösung von 0,90 g (4 mmol) 6c in 15 ml Wasser wird mit einer methanolischen Lösung von 20 mmol freiem Hydroxylamin und mit 3,0 ml (12 mmol) 4-M-NaOH versetzt. Nach 1 h wird das Hydroxamat 6 als fast farbloser Feststoff in mittlerer Ausbeute durch Rei nigung am Anionenaustauscher isoliert.A solution of 0.90 g (4 mmol) 6c in 15 ml water is washed with a methanolic Solution of 20 mmol free hydroxylamine and mixed with 3.0 ml (12 mmol) 4-M-NaOH. After 1 h the hydroxamate 6 is an almost colorless solid in medium yield by Rei isolated on the anion exchanger.
1,50 g (8,8 mmol) N-Phosphonomethylglycin wird in 80 ml absolutem Ethanol unter Zusatz von 3 Tropfen konz. Schwefelsäure 3 h refluxiert. Nach dem Abkühlen setzt man 10 Äquivalente einer äquimolaren Mischung aus N-Methylhydroxylaminhydrochlorid und NaOH in Wasser zu, rührt 20 min und stellt den pH dann auf 13 ein. Der entstandene Nieder schlag wird gesammelt, in Wasser gelöst, mit HCl pH 8 eingestellt und über eine Anionentau schersäule gereinigt. Man erhält das gewünschte Hydroxamat 7 in mittlerer Ausbeute.1.50 g (8.8 mmol) of N-phosphonomethylglycine is placed in 80 ml of absolute ethanol Add 3 drops of conc. Sulfuric acid refluxed for 3 h. After cooling, set 10 Equivalents of an equimolar mixture of N-methylhydroxylamine hydrochloride and NaOH in water, stir for 20 min and then adjust the pH to 13. The resulting low Blow is collected, dissolved in water, adjusted to pH 8 with HCl and over an anion dew shear column cleaned. The desired hydroxamate 7 is obtained in medium yield.
Die Darstellung der Verbindung 8 erfolgt analog zu der Herstellung von Verbindung 7 durch Umsetzung von N-Phosphonomethylglycin mit N- Isopropylhydroxylaminhydrochlorid. Die Verbindung 8 wird in nur geringer Ausbeute erhal ten.The connection 8 is represented analogously to the production of the connection 7 by reacting N-phosphonomethylglycine with N- Isopropylhydroxylamine hydrochloride. Compound 8 is obtained in low yield ten.
Die Aktivität der Substanzen wird in einem Versuchssystem bestimmt. Dieses Sy stem beruht auf der Inhibition des Wachstums von Parasiten, Bakterien, Viren und Pilzen in vitro.The activity of the substances is determined in a test system. This sy stem is based on the inhibition of the growth of parasites, bacteria, viruses and fungi in vitro.
Zum Beispiel wird zur Bestimmung der Antimalaria-Aktivität die Inhibition des Wachstums von Malaria-Parasiten in Blutkulturen bestimmt.For example, to determine antimalarial activity, the inhibition of Growth of malaria parasites in blood cultures determined.
Einige der Mikroorganismen, die untersucht werden sollen, können nur in Tiermo dellen untersucht werden. Hier werden die entsprechenden Modelle angewendet.Some of the microorganisms to be examined can only be found in animal mo dents are examined. The corresponding models are used here.
Substanzen, die eine Wirksamkeit in den in vitro Meßsystemen zeigen, werden in in vivo Modellen weiter untersucht. Die antiparasitäre, antivirale, fungizide oder antibakterielle Aktivität wird in den entsprechenden Tiermodelle weiter evaluiert.Substances that show an effectiveness in the in vitro measuring systems are described in in vivo models further investigated. The antiparasitic, antiviral, fungicidal or antibacterial Activity is further evaluated in the corresponding animal models.
Experimente zeigen, daß die Wirkung vieler der hier beschriebenen Verbindungen auf einer Inhibition des 1-Desoxy-D-xylulose-5-phosphat-(DOXP)-Stoffwechselweges be ruht, der in Mikroorganismen, nicht jedoch für den Menschen nachgewiesen werden kann. Das folgende Beispiel zeigt demzufolge die Wirkung der erfindungsgemäßen Verbindungen auf die DOXP-Reductoisomerase.Experiments show that the effect of many of the compounds described here on an inhibition of the 1-deoxy-D-xylulose-5-phosphate (DOXP) pathway rests, which can be detected in microorganisms, but not for humans. The following example accordingly shows the effect of the compounds according to the invention to the DOXP reductoisomerase.
Die DOXP-Reductoisomerase von Escherichia coli wurde als rekombinantes Protein in E. coli exprimiert. Die Aktivität der DOXP-Reductoisomerase wurde in einem Ansatz, der 100 mM Tris-HCl (pH = 7,5), 1 mM MnCl2, 0,3 mM NADPH und 1 mM DOXP enthielt, be stimmt. Dabei wurde die Oxidation von NADPH in einem Spektrophotometer bei 365 nm gemessen. Zur Durchführung der Inhibitionsstudien wurde die Aktivität der DOXP- Reductoisomerase in Gegenwart der Verbindungen 1 bis 8 in verschiedenen Konzentrationen zwischen 0,1 und 100 µmol l-1 gemessen. Aus den Meßwerten wurde die Konzentration be stimmt, bei der das Enzym halbmaximal inhibiert wird (IC50). Die Ergebnisse, d. h. die IC50-Werte sind der Tabelle 1 aufgeführt.Escherichia coli DOXP reductoisomerase was expressed as a recombinant protein in E. coli. The activity of the DOXP reductoisomerase was determined in a mixture containing 100 mM Tris-HCl (pH = 7.5), 1 mM MnCl 2 , 0.3 mM NADPH and 1 mM DOXP. The oxidation of NADPH was measured in a spectrophotometer at 365 nm. To carry out the inhibition studies, the activity of the DOXP reductoisomerase was measured in the presence of the compounds 1 to 8 in various concentrations between 0.1 and 100 μmol l -1 . The concentration at which the enzyme is inhibited half-maximally (IC 50 ) was determined from the measured values. The results, ie the IC 50 values, are shown in Table 1.
Die Antimalaria-Wirksamkeit der Substanzen 1 bis 8 wurde an in-vitro-Kulturen des Malaria-Erregers Plasmodium falciparum bestimmt. Die Vertiefungen einer 96-well-Mikro titerplatte wurden mit je 200 µl einer asynchronen Plasmodium falciparum-Kultur bei 0,4% Parasitämie und 2% Hämatokrit beschickt. Dann wurde eine serielle Verdünnungsreihe der Verbindungen in Dreierschritten zwischen Konzentrationen von 100 bis 0,14 µmol l-1 herge stellt. Die Platten wurden bei 37°C, 3% CO2 und 5% O2 über einen Zeitraum von 48 Stunden inkubiert. Dann wurden zu jedem weil 30 µl Medium supplementiert mit 27 µCi ml-1 [3H]- Hypoxanthin zugefügt. Nach 24-stündiger Inkubation wurden die Parasiten durch Filtration auf Glasfaserfilter geerntet und die incorporierte Radioaktivität gemessen. Die Inhibition des Parasitenwachstums wurde als prozentuale Inhibition der Tritiumincorporation gemessen. Die Inhibition des Parasitenwachstums wurde als prozentuale Inbibition der Tritiumincorporation bezogen auf einen Vergleich ohne Substanz ausgedrückt. Durch Extrapolation der Werte wurde die halbmaximale inhibitorische Konzentration (IC50) der Substanz bestimmt.The antimalarial activity of substances 1 to 8 was determined on in vitro cultures of the malaria pathogen Plasmodium falciparum. The wells of a 96-well micro titer plate were each loaded with 200 ul of an asynchronous Plasmodium falciparum culture with 0.4% parasitemia and 2% hematocrit. Then a serial dilution series of the compounds in three steps between concentrations of 100 to 0.14 µmol l -1 was produced. The plates were incubated at 37 ° C, 3% CO 2 and 5% O 2 for 48 hours. Then 30 µl medium supplemented with 27 µCi ml -1 [ 3 H] - hypoxanthine was added to each. After 24 hours of incubation, the parasites were harvested by filtration on glass fiber filters and the incorporated radioactivity was measured. Inhibition of parasite growth was measured as a percentage inhibition of tritium incorporation. The inhibition of parasite growth was expressed as a percentage of tritium incorporation based on a comparison without substance. The half-maximum inhibitory concentration (IC 50 ) of the substance was determined by extrapolation of the values.
Die Ergebnisse, d. h. die IC50-Werte, sind in Tabelle 1 aufgeführt:The results, ie the IC 50 values, are shown in Table 1:
Claims (12)
in der A aus der Gruppe ausgewählt ist, die aus -CR5R6-, -CR5R6CH(OH)-, -CR5R6CO- und -COCR5R6- besteht,
in der R1 aus der Gruppe ausgewählt ist, die aus Wasserstoff, substituiertem und unsub stituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und un substituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocyclischen Rest, substituiertem und unsub stituiertem Alkyl-heterocyclischem Rest, einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Ammonium, substituiertem Ammonium und Am moniumverbindungen, die sich von Ethylendiamin oder Aminosäuren ableiten, besteht,
in der R2, R3, R4, R5, R6 und R7 gleich oder verschieden sind und aus der Gruppe aus gewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substitu iertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, sub stituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, sub stituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl- Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubsti tuiertem heterocyclischen Rest, substituiertem und unsubstituiertem Alkyl- heterocyclischem Rest und Benzolsulfonyl besteht,
in der R8 und R9 gleich oder verschieden sind und aus der Grippe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsub stituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und un substituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, sub stituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem heterocy clischen Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest, OX3 oder OX4 besteht,
wobei X8 oder X9 gleich oder verschieden sein können und aus der Gruppe ausgewählt sind, die aus Wasserstoff, substituiertem und unsubstituiertem Alkyl, substituiertem und unsubstituiertem Alkenyl, substituiertem und unsubstituiertem Alkinyl, substituiertem und unsubstituiertem Aryl, substituiertem und unsubstituiertem Acyl, substituiertem und unsubstituiertem Cycloalkyl, substituiertem und unsubstituiertem Alkyl-Cycloalkyl, substituiertem und unsubstituiertem Aralkyl, substituiertem und unsubstituiertem he terocyclischen Rest, substituiertem und unsubstituiertem Alkyl-heterocyclischem Rest, einem Metall der ersten, zweiten oder dritten Hauptgruppe des Periodensystems, Am monium, substituiertem Ammonium und Ammoniumverbindungen, die sich von Ethy lendiamin oder Aminosäuren ableiten, besteht,
wobei sämtliche Gruppen mit Phenylgruppen, Hydroxy-, Oxo-, Halogen-, CN-, (C0-9) (C0-9)-Amino-, C1-9-Alkyl-, C1-9-Alkoxyguppen und die cyclischen Reste auch mit Ni trogruppen R2 auch mit einer Carboxygruppe substituiert sein können substituiert sein können,
und deren Salze, Ester und Amide und Salze der Ester
zur Herstellung von Arzneimittel für die therapeutische und prophylaktische Behand lung von infektiösen Prozessen bei Mensch und Tier, die durch Viren, Bakterien, Pilze oder Parasiten hervorgerufen werden.1. Use of compounds of the general formula (I):
in which A is selected from the group consisting of -CR 5 R 6 -, -CR 5 R 6 CH (OH) -, -CR 5 R 6 CO- and -COCR 5 R 6 -,
wherein R 1 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkyl -Cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl heterocyclic radical, 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 , consists,
in which R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl , substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkylcycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl heterocyclonyl radical and benzene
in which R 8 and R 9 are the same or different and are selected from the flu consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and un substituted cycloalkyl, substituted and unsubstituted alkyl-cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl-heterocyclic radical, OX 3 or OX 4 ,
wherein X 8 or X 9 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted Cycloalkyl, substituted and unsubstituted alkyl-cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted alkyl-heterocyclic radical, 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,
where all groups with phenyl groups, hydroxy, oxo, halogen, CN, (C 0-9 ) (C 0-9 ) amino, C 1-9 alkyl, C 1-9 alkoxy groups and the cyclic radicals can also be substituted by nitro groups R 2 can also be substituted by a carboxy group,
and their salts, esters and amides and salts of the esters
for the manufacture of medicinal products for the therapeutic and prophylactic treatment of infectious processes in humans and animals which are caused by viruses, bacteria, fungi or parasites.
besteht. 5. Use according to claim 1, characterized in that the compounds are selected from the group consisting of
consists.
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WO2011071951A2 (en) * | 2009-12-07 | 2011-06-16 | Johns Hopkins University | N-acyloxysulfonamide and n-hydroxy-n-acylsulfonamide derivatives |
AU2015314287B2 (en) | 2014-09-12 | 2019-04-18 | UNION therapeutics A/S | Antibacterial use of halogenated salicylanilides |
GB201509326D0 (en) | 2015-05-29 | 2015-07-15 | Antibio Tx Aps | Novel use |
US11419834B2 (en) | 2019-02-25 | 2022-08-23 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide |
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TR200100068T2 (en) * | 1998-07-15 | 2001-06-21 | Jomaa,Hassan | Phosphorous organic compounds and their uses |
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2001
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