OA11730A - Organo-phosphorus compounds and their utilization. - Google Patents
Organo-phosphorus compounds and their utilization. Download PDFInfo
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- OA11730A OA11730A OA00100153A OA00100153A OA11730A OA 11730 A OA11730 A OA 11730A OA 00100153 A OA00100153 A OA 00100153A OA 00100153 A OA00100153 A OA 00100153A OA 11730 A OA11730 A OA 11730A
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- 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
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
- A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
- A01N57/24—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing heterocyclic radicals
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- 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
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- C07—ORGANIC CHEMISTRY
- 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 System
- 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
- C07F9/5537—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom the heteroring containing the structure -C(=O)-N-C(=O)- (both carbon atoms belong to the heteroring)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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 System
- 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
- C07F9/572—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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 System
- 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
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention relates to organo-phosphorus compounds of formula (I), wherein A is selected from the group consisting of a (C1-9) alkylene radical, -C-O-C- and -C-N-C- or A corresponds to formula (II), wherein one or more carbon atoms selected from the group consisting of C3, C4, C5 and their substituents can also be absent and at least one of the substituents of B1 to B10 is a C3-8-cycloalkyl-(C0-9)-alkyl group in which R1 is selected from the group consisting of five and six membered heterocycles having at least one nitrogen atom in the ring or polycyclic carbon atoms containing one of said heterocycles, wherein at least one of said nitrogen atoms belongs to a hydroxamic acid group or a hydroxamic acid ester group. The invention also relates to the utilization of the above-mentioned compounds in the therapeutic and prophylactic treatment of infections in human beings and animals caused by virus, bacteria, fungi and parasites and as fungicides, bactericides and herbicides in plants.
Description
1
This invention relates to organophosphorus compounds, to the salts, esters and amides thereofand to the use thereof for the therapeutic and prophylactic treatment of infections in humansand animais which are caused by viruses, bacteria, fungi and parasites, to the use thereof as afungicide, bactéricide and herbicide in plants. According to the invention, the 5 organophosphorus compounds comprise phosphinoyl dérivatives, phosphinic acid dérivativesand phosphonic acid dérivatives. 3-Hydroxy-2-oxo-4-dimethylphosphono- and 3-hydroxy-2-oxo-4-diphenylphosphinyl-1,2-dihydroquinolines and the production thereof are described in Tetrahedron Letters, no. 38,1972, pages 3979-3982. N-Substituted alkylaminophosphates are described in Chemical Abstracts, vol. 093, no. 19, * 10th November 1989 and Curr. Chemother. Infect. Dis. Proc. Int. Congr. Chemother., 1 l‘h;1980; vol. 1; pages 355-8, in Chemical Abstracts, vol. 105, no. 19,10th November 1986 andJP 61 106504 A, in US-A-4206 156, in US-A-4 693 742 and in WO 99 525 15 A. Thesecompounds are described as suitable for the treatment of bacterial infections. WO 99 525 15 A fiirthermore describes the use thereof in viral, fungicidal and parasitic infections. 15
In order to widen the range of options for treating humans and animais, there is an urgentrequirement to provide agents which are not only highly active but, unlike otherpharmaceutical préparations, also exhibit reduced side-effects and thus constitute a reducedrisk to human health. 2q The object of the présent invention is accordingly to provide a substance which is universally usable in infections by viruses, bacteria, fungi and parasites in humans and animais and whichmeets the above-stated requirements.
This object is utterly surprisingly achieved by the group of substances defined in claim 1. Thisgroup of substances exhibits antiinfective action against viruses, bacteria, fungi and uni- and 2g multicellular parasites. Fungicidal, bactericidal and herbicidal action has also been observedin plants.
The organophosphorus compounds according to the invention are of the general formula (I):
-Ί- (I)
II
Rl_A_P-R3 wherein A is selected from the group which consiste of a (Ci.9) alkylene residue, which maycomprise one or more double bonds and may be substituted with hydroxy, halogen, amino,oxo groups with branched or unbranched C1.9 alkyl groups and C2-9 alkenyl groups, whereinthe Ci_9 alkyl groups and C2-9 alkenyl groups may be substituted with hydrogen, hydroxy,amino, halogen and oxo groups, -C-O-C- and -C-N-C-, wherein the carbon atoms of -C-O-C-and -C-N-C- may be substituted with an alkyl having up to 7 carbon atoms or hydroxygroups, or in which A is of the folio wing formula (II):
Bi B3 B5 B7 Bg
(II) B2 B4 Ββ Bg B10 wherein one or more of the carbon atoms selected from the group C3, C4, C5, together withtheir substituents, may also be absent, and at least one substituent présent in the range from Bito B10 is a C3-8-cycloalkyl-(Co-9)-alkyl group, wherein both the C3.8 cycloalkyl group and theC0-9 alkyl group may comprise one or more double bonds and one or two carbon atoms of thecycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein both thecycloalkyl group and the alkyl group may be substituted with hydroxy, halogen, amino, oxogroups with branched or unbranched C1.9 alkyl groups and C2.9 alkenyl groups, wherein theC1.9 alkyl groups and C2-9 alkenyl groups may be substituted with hydrogen, hydroxy, amino,halogen and oxo groups, and the remaining substituents Bi to B10 présent are selected from 20 the group which consists of hydrogen, hydroxy, halogen, amino groups, C1-26 alkyl residues,Ci.26 alkoxy residues, Ci-26-alkoxy-Ci.26-alkyl residues or both substituents of a C atomtogether form an oxo group, wherein each C1.26 alkyl residue and each Ci-26 alkoxy residuemay be branched or unbranched and be saturated or unsaturated with one or more doublebonds and may be substituted with hydroxy, amino, halogen and oxo groups, 25 in which Ri is selected from the group which consists of 5- and 6-membered heterocycleswith at least one ring nitrogen atom or a polycyclic carbon with at least one of theseheterocycles, wherein at least one of these nitrogen atoms belongs to a hydroxamic acid groupor a hydroxamic acid ester group, and may be saturated or unsaturated with one or moredouble or triple bonds and may thus also be aromatic and may be substituted with hydroxy, -3- halogen, amino, οχο groups and with branched or unbranched C1.9 alkyl groups and C2-9alkenyl groups, wherein the Ci.9 alkyl groups and C2-9 alkenyl groups may be saturated orunsaturated with one or more double or triple bonds and may be substituted with hydrogen,hydroxy, amino, halogen and oxo groups, wherein the nitrogen atom of the hydroxamic acidgroup or hydroxamic acid ester group is substituted with OR5 and R5 is selected from the group which consists of hydrogen, substituted and unsubstituted C1.9alkyl, substituted and unsubstituted hydroxy-Ci-9-alkyl, substituted and unsubstituted C1.9alkenyl, substituted and unsubstituted C1.9 alkynyl, substituted and unsubstituted aryl,substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted andunsubstituted aralkyl, substituted and unsubstituted heterocyclic residue, in which R3 and R4 are identical or different and are selected from the group which consists ofhydrogen, substituted and unsubstituted C1-26 alkyl, hydroxy-Ci-26-alkyl, substituted andunsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl,substituted and unsubstituted C1.26 alkenyl, substituted and unsubstituted Ci-26 alkynyl,substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue,halogen, OX3 and OX4, wherein X3 and X4 are identical or different and are selected from the group which consists ofhydrogen, substituted and unsubstituted C1.26 alkyl, substituted and unsubstituted hydroxy-Ci-26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl,substituted and unsubstituted Ci-26 alkenyl, substituted and unsubstituted Cj.26 alkynyl,substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, asilyl, a cation of an organic and inorganic base, in particular a métal of main groups I, II or IIIof the periodic System, ammonium, substituted ammonium and ammonium compoundsderived from ethylenediamine or amino acids, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters.
If two or more heteroatoms are présent in the heterocycle Rj, oxygen and sulfur atoms may beprésent.
The organophosphorus compounds are preferably of the formula (III)
O
II
Rl-A_p_R3
I 0X4 (III) wherein R3 is preferably hydrogen, methyl, ethyl, an amide residue or OX3 and X4 is selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl, wherein X3 is defined as above -4- and particularly preferably of the formula (IV)
O
II R1-A-P-OX3I 1 0X4 (IV) wherein X3 and X4 are identical or different and are selected from the group which consists ofhydrogen, a (Ci-3) alkyl, a métal of main groups I, II or III of the periodic System, ammonium,substituted ammonium, or ammonium compounds derived from ethylenediamine or aminoacids. X3 and X4 are preferably a métal of main groups I, II or III of the periodic System,ammonium, substituted ammonium or ammonium compounds derived from ethylenediamineor amino acids. In other words, the sait compounds of the organophosphorus compounds areformed with organic or inorganic bases (for example sodium sait, potassium sait, calcium sait,aluminium sait, ammonium sait, magnésium sait, triethylamine sait, ethanolamine sait,dicyclohexylamine sait, ethylenediamine sait, Ν,Ν'-dibenzylethylenediamine salts) as well assalts with amino acids (for example arginine sait, aspartic acid sait, glutamic acid sait etc.)and the like. X3 and X4 are particularly preferably identical or different and are selected from the groupwhich consists of hydrogen, sodium, potassium, methyl, ethyl. A is preferably selected such that a three-membered linking chain is formed between thephosphorus atom and the nitrogen atom of the heterocycle. A is for example advantageously amethylene, hydroxymethylene, ethylene, ethenylene, hydroxyethylene and may in particularalso be substituted with an oxo group.
The carbon chain of A with the formula (II) preferably also links, together with the atoms ofthe heterocycle, the nitrogen and phosphorus atom via three atoms. If the carbon atomarranged in a position relative to the nitrogen or phosphorus atom is substituted with an oxogroup in the linking chain, linking chains having four carbon atoms are also preferred. If bothan oxo group is in a position relative to the nitrogen atom and another oxo group is in aposition relative to the phosphorus atom in this linking chain, a linking chain with five carbon -5- atoms is also preferred. If the carbon atom arranged in a position relative to the phosphorusatom is substituted with a hydroxy group, linking chains having four carbon atoms arepreferred. In this case, methylene groups are also preferred for R3 and R4.
Very particularly preferred groups of compounds are listed below: -R. Ο Ο
IV α-ρο32- -6- /R5 Ν Α-ΡΟ32- Ο
VII
VIII
X
III
XI α-ρο32-
IX α-ρο32- -Ί- a-po32- O Ni
O
XII A-PO,2· R<
A-PO32- 0^ N1
O * A-PO,2· O^ N ' R5
A-POA
Rs
XVI
Rc R<
XIX
XVII
O^N
I
O a-po32- r5
XX xvin Α-ΡΟΛ A-PO32-
Rc
XXI
XXII
XXIII 4 ’ / Μ
I » / Μ U -8-
XXIV XXV
R<
XXVI α-ρο32-
*5
XXVII
XXIX Α-ΡΟ32 R<
XXXI
XXX -9-
-10- and the corresponding phosphinic acid and phosphinoyl dérivatives.
Spécial features of the above définitions and suitable examples thereof are given below: "Acyl" is a substituent which originates from an acid, such as from an organic carboxylicacid, carbonic acid, carbamic acid or the thio acid or imidic acid corresponding to the aboveindividual acids, or from an organic sulfonic acid, wherein these acids in each case comprisealiphatic, aromatic and/or heterocyclic groups in the molécule together with carbamoyl orcarbamimidoyl.
Suitable examples of these acyl groups are given below.
Aliphatic acyl groups are defined as acyl residues originating from an aliphatic acid andinclude the following: alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl etc.); alkenoyl (for example acryloyl, methacryloyl, crotonoyl etc.);alkylthioalkanoyl (for example methylthioacetyl, ethylthioacetyl etc.); alkanesulfonyl (forexample mesyl, ethanesulfonyl, propanesulfonyl etc.); alkoxycarbonyl (for examplemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl etc.); alkylcarbamoyl (for example methylcarbamoyl etc.); (N-alkyl)thiocarbamoyl (for example (N-methyl)thiocarbamoyl etc.); alkylcarbamimidoyl (forexample methylcarbamimidoyl etc.); oxalo; alkoxalyl (for example methoxalyl, ethoxalyl,propoxalyl etc.).
In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon moiety, in particularthe alkyl group or alkane residue, may optionally hâve one or more suitable substituents, suchas amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino,carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (forexample benzyloxycarbonylamino etc.), acyloxy (for example acetoxy, benzoyloxy etc.) andthe like; preferred aliphatic acyl residues with such substituents which may be mentioned are,for example, alkanoyls substituted with amino, carboxy, amino and carboxy, halogen,acylamino or the like.
Aromatic acyl residues are defined as those acyl residues which originate from an acid with asubstituted or unsubstituted aryl group, wherein the aryl group may comprise phenyl, toluyl,xylyl, naphthyl and the like; suitable examples are stated below: aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.); aralkanoyl (forexample phenylacetyl etc.); aralkenoyl (for example cinnamoyl etc.); aryloxyalkanoyl (forexample phenoxyacetyl etc.); arylthioalkanoyl (for example phenylthioacetyl etc.); - 11 - arylaminoalkanoyl (for example N-phenylglycyl, etc.); arenesulfonyl (for examplebenzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.); aryloxycarbonyl (forexample phenoxycarbonyl, naphthyloxycarbonyl etc.); aralkoxycarbonyl (for examplebenzyloxycarbonyl etc.); arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyletc.); arylglyoxyloyl (for example phenylglyoxyloyl etc.).
In the above-stated examples of aromatic acyl residues, the aromatic hydrocarbon moiety (inparticular the aryl residue) and/or the aliphatic hydrocarbon moiety (in particular the alkaneresidue) may optionally hâve one or more suitable substituents, such as those which hâvealready been stated as suitable substituents for the alkyl group or the alkane residue.Examples of preferred aromatic acyl residues with spécifie substituents which may inparticular be mentioned are aroyl substituted with halogen and hydroxy or with halogen andacyloxy, and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino,together with arylthiocarbamoyl (for example phenylthiocarbamoyl etc.); arylcarbamimidoyl(for example phenylcarbamimidoyl etc.). A heterocyclic acyl residue is taken to mean an acyl residue which originates from an acidwith a heterocyclic group; such residues include: heterocyclic carbonyl, in which the heterocyclic residue is an aromatic or aliphatic 5- to 6-membered heterocycle with at least one heteroatom from the group nitrogen, oxygen andsulfur (for example thiophenyl, furoyl, pyrrolecarbonyl, nicotinyl etc.); heterocycle-alkanoyl, in which the heterocyclic residue is 5- to 6-membered and comprises atleast one heteroatom from the group nitrogen, oxygen and sulfur (for examplethiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like.
In the above Examples of heterocyclic acyl residues, the heterocycle and/or the aliphatichydrocarbon moiety may optionally comprise one or more suitable substituents, such as thesame as were stated to be suitable for alkyl and alkane groups. "Alkyl" is a linear or branched alkyl residue, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert.-butyl, pentyl, hexyl and the like. "Hydroxyalkyl" is a linear or branched alkyl residue which comprises at least one hydroxylgroup, preferably one or two hydroxyl groups. « < ~ 7 ο -12- "Alkenyl" includes linear or branched alkenyl groups, such as for example vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2- ethylpropenyl, pentenyl, hexenyl. "Alkynyl" includes linear or branched alkynyl groups.
Cycloalkyl preferably dénotés an optionally substituted C3.8 cycloalkyl; possible substituentsare inter alia alkyl, alkenyl, alkynyl, alkoxy (for example methoxy, ethoxy etc.), halogen (forexample fluorine, chlorine, bromine etc.), nitro and the like.
Aryl is an aromatic hydrocarbon residue, such as phenyl, naphthyl etc., which may optionallycomprise one or more suitable substituents, such as alkyl, alkenyl, alkynyl, alkoxy (forexample methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitroand the like. "Aralkyl" includes mono-, di-, triphenylalkyls such as benzoyl, phenethyl, benzhydryl, trityland the like, wherein the aromatic moiety may optionally comprise one or more suitablesubstituents, such as alkoxy (for example methoxy, ethoxy etc.), halogen (for examplefluorine, chlorine, bromine etc.), nitro and the like.
The residues X3 and X4 may preferably be selected such that esters are formed on thephosphino group or phosphono group. Suitable examples of such esters according to theformulae (I), (III) and (IV) include suitable mono- and diesters, and preferred examples ofsuch esters include alkyl esters (for example hexadecanyl ester, octadecanyl ester etc.);aralkyl esters (benzyl ester, phenethyl ester, benzhydryl ester, trityl ester etc.); aryl esters (forexample phenyl ester, tolyl ester, naphthyl ester etc.); aroylalkyl esters (for example phenacylester etc.); and silyl esters (for example of trialkylhalosilyl, dialkyldihalosilyl,alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl,dialkoxydihalosilyl, trialkoxyhalosilyl etc.) and the like.
In the above esters, the alkane and/or arene moiety may optionally comprise at least onesuitable substituent, such as halogen, alkoxy, hydroxy, nitro or the like.
The compounds used according to the invention according to the formulae (I), (III) and (IV)may be présent in the protonated form thereof as an ammonium sait of organic or inorganicacids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonicacid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid,tartane acid, benzoic acid etc..
-13-
The compounds used according to the invention of the formulae (I), (III) and (IV) permit, forexample for groups Ri, R3, R4, X3, X4 or A which contain double bonds or are chiral, theoccurrence of steric isomers. The use according to the invention of the compounds includesail steric isomers, both as pure substances and in the form of mixtures.
The organophosphorus compounds are suitable for the therapeutic and prophylactic treatmentof infections in humans and animais caused by viruses, bacteria, uni- and multicellularparasites and fungi.
The compounds are active against unicellular parasites (protozoa), in particular against thecausative organisais of malaria and sleeping sickness and of Chagas' disease, toxoplasmosis,amoebic dysentery, leishmaniases, trichomoniasis, pneumocystosis, balantidiasis,cryptosporidiosis, sarcocytosis, acanthamoebosis, naeglerosis, coccidiosis, giardiasis andlambliasis.
They are accordingly in particular suitable for the prophylactic treatment of malaria and ofsleeping sickness and of Chagas' disease, of toxoplasmosis, amoebic dysentery,leishmaniases, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis,acanthamoebosis, naeglerosis, coccidiosis, giardiasis and lambliasis.
The active substances according to the invention may in particular be used against thefollowing bacteria: bacteria of the family Propionibacteriaceae, in particular of the genus Propionibacterium, inparticular the species Propionibacterium acnés, bacteria of the family Actinomycetaceae, inparticular of the genus Actinomyces, bacteria of the genus Comynebacterium, in particularthe species Corynebacterium diphtheriae and Corynebacterium pseudotuberculosis, bacteriaof the family Mycobacteriaceae, of the genus Mycobacterium, in particular the speciesMycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis andMycobacterium avium, bacteria of the family Chlamydiaceae, in particular the speciesChlamydia trachomatis and Chlamydia psittaci, bacteria of the genus Listeria, in particular thespecies Listeria monocytogenes, bacteria of the species Erysipelthrix rhusiopathiae, bacteriaof the genus Clostridium, bacteria of the genus Yersinia, the species Yersinia pestis, Yersiniapseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri, bacteria of the familyMycoplasmataceae, of the généra Mycoplasma and Ureaplasma, in particular the speciesMycoplasma pneumoniae, bacteria of the genus Brucella, bacteria of the genus Bordetella,bacteria of the family Neisseriaceae, in particular of the généra Neisseria and Moraxella, inparticular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, 117 3 0 -14- bacteria of the family Vibrionaceae, in particular of the généra Vibrio, Aeromonas,Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrioanguillarum and Aeromonas salmonicidas, bacteria of the genus Campylobacter, in particularthe species Campylobacter jejuni, Campylobacter coli and Campylobacter fétus, bacteria ofthe genus Hélicobacter, in particular the species Hélicobacter pylori, bacteria of the familiesSpirochaetaceae and Leptospiraceae, in particular of the généra Treponema, Borrelia andLeptospira, in particular Borrelia burgdorferi, bacteria of the genus Actinobacillus, bacteria ofthe family Legionellaceae, of the genus Légionella, bacteria of the family Rickettsiaceae andfamily Bartonellaceae, bacteria of the généra Nocardia and Rhodococcus, bacteria of thegenus Dermatophilus, bacteria of the family Pseudomonadaceae, in particular of the généraPseudomonas and Xanthomonas, bacteria of the family Enterobacteriaceae, in particular ofthe généra Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella,bacteria of the family Pasteurellaceae, in particular of the genus Haemophilus, bacteria of thefamily Micrococcaceae, in particular of the généra Micrococcus and Staphylococcus, bacteriaof the family Streptococcaceae, in particular of the généra Streptococcus and Enterococcusand bacteria of the family Bacillaceae, in particular of the généra Bacillus and Clostridium.
The organophosphorus compounds and the dérivatives thereof are consequently suitable fortreating diphtheria, acné vulgaris, listérioses, swine erysipelas in animais, gas gangrené inhumans and animais, malignant oedemain humans and animais, tuberculosis in humans andanimais, leprosy and further mycobacterioses in humans and animais, paratuberculosis inanimais, plague, mesenterial lymphadenitis and pseudotuberculosis in humans and animais,choiera, légionnaires' disease, borreliosis in humans and animais, leptospiroses in humans andanimais, syphilis, Campylobacter enteritis infections in humans and animais, Moraxellakeratoconjunctivitis and serositis in animais, brucellosis of animais and humans, anthrax inhumans and animais, actinomycosis in humans and animais, streptotrichoses,psittacosis/ortnithosis in animais, Q fever, ehrlichiosis.
Use is furthermore in particular preferred in thé éradication of Hélicobacter in ulcers of thegastrointestinal tract.
Combinations with another antibiotic may also be used to treat the above-stated diseases.Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone arein particular suitable for combination préparations with other antiinfective agents for thetreatment of tuberculosis.
The active substances according to the invention are furthermore in particular usable ininfections with the following viruses: -15-
Parvoviridae: parvoviruses, dependoviruses, densoviruses, Adenoviridae: adenoviruses,mastadenoviruses, aviadenoviruses, Papovaviridae: papovaviruses, in particularpapillomaviruses ("wart" viruses), polyomaviruses, in particular JC virus, BK virus andmiopapovaviruses,
Herpesviridae: ail herpesviruses, in particular herpes simplex viruses, varicella-zoster viruses,human cytomégalovirus, Epstein-Barr viruses, ail human herpesviruses, human herpesvirus 6,human herpesvirus 7, human herpesvirus 8, Poxiviridae: poxviruses, orthopoxviruses,parapoxviruses, molluscum contagiosum virus, aviviruses, capriviruses, leporipoxviruses, ailprimarily hepatotropic viruses, hepatitisviruses: hepatitis A viruses, hepatitis B viruses, 0 hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatitis Gviruses, hepadnaviruses: ail hepatitisviruses, hepatitis B virus, hepatitis D viruses,Picornaviridae: picomaviruses, ail enteroviruses, ail polioviruses, ail coxsackie-viruses, ailechoviruses, ail rhinoviruses, hepatitis A virus, aphthoviruses, Calciviridae: hepatitis Eviruses, Reoviridae: reoviruses, orbiviruses, rotaviruses, Togaviridae: togaviruses,alphaviruses, rubiviruses, pestiviruses, rubellavirus, Flaviviridae: flaviviruses, FSME virus,hepatitis C virus, Orthomyxoviridae: ail influenza viruses, Paramyxoviridae:paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus, Rhabdoviridae:rhabdoviruses, rabies virus, lyssavirus, vascular stomatitisvirus, Coronaviridae: coronaviruses,Bunyaviridae: bunyaviruses, nairovirus, phlebovirus, uukuvirus, hantavirus, hantaan virus, 20 Arenaviridae: arenaviruses, lymphocytic choriomeningitis virus, Retroviridae: retroviruses, ailHTL viruses, human T-cell leukaemia virus, oncomaviruses, spumaviruses, lentiviruses, ailHI viruses, Filoviridae: Marburg and Ebola virus, slow-virus infections, prions, oncovirusesand leukaemia viruses.
The organophosphorus compounds used according to the invention are consequently suitable 25 for combating the following viral infections: éradication of papillomaviruses to prevent tumours, in particular tumours of the reproductiveorgans caused by papillomaviruses in humans, éradication of JC viruses and BK viruses,éradication of herpesviruses, éradication of human herpesvirus 8 to treat Kaposi's sarcoma,éradication of cytomegaloviruses before transplantations, éradication of Epstein-Barr viruses 30 before transplantation and to prevent tumours associated with Epstein-Barr viruses, éradication of hepatitis viruses to treat chronic liver disease and to prevent liver tumours andcirrhosis of the liver, éradication of coxsackie-viruses in cardiomyopathy, éradication ofcoxsackie-viruses in diabètes mellitus patients, éradication of immunodefîciency viruses inhumans and animais, treatment of accompanying infections in AIDS patients, treatment of 35 respiratory tract inflammation of viral causation (laryngeal papilloma, hyperplasia, rhinitis,pharyngitis, bronchitis, pneumonia), of the sensory organs (keratoconjunctivitis), of thenervous System (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing
-16- panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocyticchoriomeningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis,gastritis, gastroenteritis, diarrhoea), of the liver and gall System (hepatitis, cholangitis,hepatocellular carcinoma), of the lymphatic tissue (mononucleosis, lymphadenitis), of thehaemopoietic system, of the reproductive organs (mumps orchitis), of the skin (warts,dermatitis, herpes labialis, herpes febrilis, herpes zoster, shingles), of the mucous membranes(papillomas, conjunctival papillomas, hyperplasia, dysplasia), of the cardiovascular system(arteriitis, myocarditis, endocarditis, pericarditis), of the kidney/urinary system, of thereproductive organs (anogenital lésions, warts, génital warts, sharp condylomas, dysplasia,papillomas, cervical dysplasia, condyloma acuminatum, epidermodysplasia verruciformis), ofthe locomotory organs (myositis, myalgia), treatment of foot-and-mouth disease in cloven-hoofed animais, of Colorado tick fever, Dengue syndrome, of haemorrhagic fever, of earlysummer meningoencephalitis (FSME) and of yellow fever.
The described compounds, i.e. the organophosphorus compounds of the formulae (I), (III) and (IV) and esters and amides thereof on the phosphino group and salts thereof exhibit strongcytotoxic activity against uni- and multicellular parasites, in particular against the causativeorganisms of malaria and sleeping sickness. The compounds according to the invention areaccordingly usable for the treatment of infective diseases which are caused in humans andanimais by viruses, bacteria, parasites and fungi. The compounds are also suitable for theprévention of diseases which are caused by viruses, bacteria, parasites and fungi, in particularfor the prophylactic treatment of malaria and of sleeping sickness.
The organophosphorus compounds used according to the invention, which generally includefor this purpose pharmaceutically acceptable salts, amides, esters, a sait of such an ester oralso compounds which, on administration, provide the compounds used according to theinvention as métabolites or breakdown products (also known as "prodrugs"), may beformulated for administration in any suitable manner analogous to known agents having anantiinfective action (mixed with a non-toxic, pharmaceutically acceptable excipient).
Pharmaceutically acceptable salts of the compounds include salts which the compounds of theformulae (I), (III) and (IV) according to the invention form in their protonated form as anammonium sait of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citricacid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
Particularly pharmaceutically suitable salts are also those formed by suitable sélection of X3and X4, such as sodium sait, potassium sait, calcium sait, ammonium sait, ethanolamine sait, -17- triethylamine sait, dicyclohexylamine sait and salts of an amino acid such as arginine sait,aspartic acid sait, glutamic acid sait.
The activity of the substances is determined using a test System. This System is based upon invitro measurement of the inhibition of growth of bacteria, parasites, viruses, fungi or plants. 5 Test methods known to the person skilled in the art are in part used for this purpose.
For example, antimalarial activity is determined by measuring the inhibition of the growth ofmalaria parasites in blood cultures.
Antibacterial activity is determined on the basis of measuring the inhibition of bacterialgrowth on nutrient media and in liquid cultures. 10 Anti viral activity is determined on the basis of the formation of viral éléments in cell cultures.
Fungicidal activity is determined on the basis of inhibition of fungal growth on nutrient mediaand in liquid cultures.
Some of the microorganisms which are to be investigated may only be investigated in animalmodels. In this case, the appropriate models will then be used. 15 Substances which exhibit activity in in vitro measurement Systems are then further investigated in in vivo models. Antiparasitic, antiviral, fungicidal or antibacterial activity isfurther evaluated in the appropriate animal models.
Screening for herbicidal activity is determined by means of algal Systems and measurement ofisoprene émissions from plants under standard conditions. 20 The pharmaceutically active agents may be prepared in dosage units in the form of pharmaceutical préparations. This means that the préparation is in the form of individualcomponents, for example tablets, coated tablets, capsules, pills, suppositories and ampoules,the active substance content of which corresponds to a fraction or multiple of an individualdose. The dosage units may contain, for example 1,2, 3 or 4 individual doses or 1/2, 1/3 or 25 1/4 of an individual dose. An individual dose preferably contains the quantity of active substance which is administered at one time and usually corresponds to a whole, half, third orquarter of a daily dose. 0 jt -18-
Non-toxic, inert, pharmaceutically suitable excipients should be taken to mean solid, semi-solid or liquid diluents, fîllers and formulation auxiliaries of ail kinds.
Preferred pharmaceutical préparations which may be mentioned are tablets, coated tablets,capsules, pills, granules, suppositories, solutions, suspensions and émulsions, pastes,ointments, gels, creams, lotions, powders and sprays. Tablets, coated tablets, capsules, pillsand granules may contain the active substances together with conventional excipients, such as(a) fîllers and extenders, for example starches, lactose, cane sugar, glucose, mannitol andsilica, (b) binders, for example carboxymethylcellulose, alginates, gélatine,polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) suspending agents, forexample agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retardants, forexample parafïin and (f) résorption accelerators, for example quatemary ammoniumcompounds, (g) wetting agents, for example cetyl alcohol, glycerol monostearate, (h)adsorbents, for example kaolin and bentonite and (i) lubricants, for example talcum, calciumand magnésium stéarate and solid polyethylene glycols or mixtures of the substances stated in(a) to (i).
The tablets, coated tablets, capsules, pills and granules may be provided with conventionalcoatings and shells optionally containing opacifying agents and may also be composed suchthat they release the active substances only with a delay or preferably in a particular part ofthe intestinal tract, wherein polymeric substances and waxes may, for example, be used as thematrices.
The active substance or substances, optionally together with one or more of the above-statedexcipients, may also be présent in microencapsulated form.
In addition to the active substance or substances, suppositories may contain conventionalwater-soluble or water-insoluble excipients, for example polyethylene glycols, fats, forexample cocoa butter and higher esters (for example C14 alcohol with Ci6 fatty acid) ormixtures of these substances.
In addition to the active substance or substances, ointments, pastes, creams and gels maycontain conventional excipients, for example animal and vegetable fats, waxes, paraffïns,starch, gum tragacanth, cellulose dérivatives, polyethylene glycols, silicones, bentonites,silica, talcum and zinc oxide or mixtures of these substances.
In addition to the active substance or substances, powders and sprays may containconventional excipients, for example lactose, talcum, silica, aluminium hydroxide, calcium - 19- silicate and polyamide powder or mixtures of these substances. Sprays may additionallycontain conventional propellants, for example chlorofluorocarbons.
In addition to the active substance or substances, solutions and émulsions may containconventional excipients, such as solvents, solubilising agents and emulsifiers, for examplewater, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylène glycol, dimethylformamide, oils, in particularcottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerolformai, tetrahydrofurforyl alcohol, polyethylene glycols and sorbitan fatty acid esters ormixtures of these substances.
For parentéral administration, the solutions and émulsions may also be présent in stérile,isotonie form.
In addition to the active substance or substances, suspensions may contain conventionalexcipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol,suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol andsorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agarand gum tragacanth or mixtures of these substances.
The stated formulations may also contain colorants, preservatives and odour- or flavour-enhancing additives, for example peppermint oil and eucalyptus oil, and sweeteners, forexample saccharin.
The active substances of the formulae (I), (III) and (IV) should preferably be présent in thepharmaceutical préparations listed above in a concentration of approx. 0.1 to 99.5 wt.%,preferably from approx. 0.5 to 95 wt.%, of the complété mixture.
Apart from the compounds of the formulae (I), (III) and (IV), the pharmaceutical préparationsmay also contain further pharmaceutical active substances.
The compounds may be used together with hitherto described substances having antibacterial,antiviral, antimycotic and antiparasitic properties.JSuch substances in particular includecompounds which hâve already been used in therapeutic applications or are still used.Substances which are suitable for this purpose are in particular those listed in the Red List orin Simon/Stille, Antibiokia-Therapie in Klinik und Praxis, 9th édition, 1998, SchatauerVerlag, or on the Internet at http ://www.customs .treas. gov/imp- exp/rulings/harmoniz/hrm 129.html. The dérivatives may in particular be présent with 117 3 0 -20- penicillins, benzylpenicillin (penicillin G), phenoxypenicillins, isoxazolylpenicillins,aminopenicillins, ampicillin, amoxicillin, bacampicillin, carboxypenicillin, ticarcillin,temocillin, acylaminopenicillins, azlocillin, mezlocillin, piperacillin, apalcillin, mecillinam,cephalosporins, cefazolin group, cefuroxime group, cefoxitin group, cefoxitin, cefotetan, 5 cefmetazole, latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group, ceftazidime, cefpirome, cefepime, conventional cephalosporins, cefsulodin, cefoperazone,oral cephalosporins of the cephalexin group, loracarbef, cefprozil, new broad-spectrum oralcephalosporins, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefotiam-hexetil, cefdinir, ceftibuten, other β-lactam antibiotics, carbapenem, imipenem/cilastatin, ^0 meropenem, biapenem, aztreonam, β-lactamase inhibitors, clavulanic acid/amoxicillin,clavulanic acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperacillin, tetracyclines,oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol,aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spectinomycin, macrolides,erythromycin, clarithromycin, roxithromycin, azithromycin, dirithromycin, spiramycin, U josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin,teicoplanin, pristinamycin dérivatives, fosfomycin, antimicrobial folie acid antagoniste,sulfonamides, co-trimoxazole, trimethoprim, other diaminopyrimidine-sulfonamidecombinations, nitrofurans, nitrofurantoin, nitrofurazone, gyrase inhibitors (quinolones),norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, 20 lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazid, rifampicin,rifabutin, ethambutol, pyrazinamide, streptomycin, capreomycin, prothionamide, terizidone,dapsone, clofazimine, topical antibiotics, bacitracin, tyrothricin, polymyxins, neomycin,kanamycin, paromomycin, mupirocin, antiviral agents, acyclovir, ganciclovir, azidothymidine, didanosine, zalcitabine, thiacytidine, stavudine, ribavirin, idoxuridine, 25 trifluridine, foscarnet, amantadine, interferons, tibol dérivatives, protéinase inhibitors, antimycotics, polyenes, amphotericin B, nystatin, natamycin, azoles, azoles for septic therapy,miconazole, kétoconazole, itraconazole, fluconazole, UK-109,496, azoles for topical use,clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, griseofulvin,ciclopirox olamine, tolnafnate, naftifîne, terbinafine, amorolfme, anthraquinones, betulinic 30 acid, semianthraquinones, xanthones, naphthoquinones, arylamino alcohols, quinine,quinidines, mefloquine, halofantrine, chloroquine, amodiaquine, acridine,benzonaphthyridine, mepacrine, pyronaridine, dapsone, sulfonamides, sulfadoxine, sulfalenes,trimethoprim, proguanil, chlorproguanil, diaminopyrimidines, pyrimethamine, primaquine,aminoquinolines, WR 238,605, tétracycline, doxycycline, clindamycin, norfloxacin, 35 ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin, 10b artemether, arteether, atresunate, atovaquone, suramin, melarsoprol, nifurtimox, stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide,
<1 4 -, 1 A ; (' ι -21 - praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin, bithionol, oxamniquine,metrifonate, piperazine, embonate.
The organophosphorus compounds may furthermore be présent in the pharmaceuticalpréparations in combination with sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine,chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin,tetracyclines, doxycycline, proguanil, metronidazole, praziquantel, niclosamide, mebendazole,pyrantel, tiabendazole, diethylcarbazine, piperazine, pyrivinium, metrifonate, oxamniquine,bithionol or suramin or two or more of these substances.
The above-stated pharmaceutical préparations are produced in the conventional manner usingknown methods, for example by mixing the active substance or substances with the excipientor excipients.
The stated préparations may be administered to humans and animais orally, rectally,parenterally (intravenously, intramuscularly, subcutaneously), intracistemally, intravaginally,intraperitoneally, topically (powders, ointments, drops) and for the treatment of infections incavities, body cavities. Suitable préparations which may be considered are solutions forinjections, solutions and suspensions for oral therapy, gels, infusion formulations, émulsions,ointments or drops. Topical treatment may be performed using ophthalmological anddermatological formulations, silver and other salts, ear drops, eye ointments, powders orsolutions. Administration to animais may also be achieved via the feed or drinking water insuitable formulations. Gels, pulvérulent formulations, powders, tablets, controlled-releasetablets, premixes, concentrâtes, granules, pellets, tablets, boli, capsules, aérosols, sprays,inhalation formulations may also be used in humans and animais. The compounds accordingto the invention may also be incorporated into other supports, such as for example plastics(plastic chains for topical treatment), collagen or bone cernent.
It has in general proved advantageous in both human and veterinary medicine to administerthe active substances of the formula (I), (III) and (IV) in total quantifies of approx. 0.05 toapprox. 600, preferably of 0.5 to 200 mg/kg body weight per 24 hours, optionally in the formof two or more individual doses in order to achieve the desired results. An individual dosepreferably contains the active substance or substances in quantities of approx. 1 to approx.200, in particular of 1 to 60 mg/kg body weight. It may, however, be necessary to deviatefrom the stated dosages, in particular as a fonction of the nature and body weight of thepatient to be treated, the nature and severity of the disease, the nature of the préparations andthe route of administration of the pharmaceutical préparation and the period of time overwhich administration is performed. -22-
In some cases, it may accordingly be sufficient to use less than the above-stated quantity ofactive substance, while in other cases more than the above-stated quantity of active substancemust be used. The person skilled in the art will use his/her skill to détermine the optimumdosage and route of administration required in each particular case.
The compounds according to the invention may be given to animais in conventionalconcentrations and préparations together with feed or feed préparations or with drinkingwater.
The compounds according to the invention are furthermore ideally usable as bactéricides,fungicides and herbicides in plants.
If the structure of the compound is known, it is generally possible for the person skilled in theart to develop a production process by analogy with known processes. The production ofsome compounds according to the invention is stated below by way of example:
Example 1: 5-f2-(Phosphono)ethyll-N-hvdroxvpvrrolidin-2-one il) N-Fluorenylmethoxycarbonyl-pyrrolidin-2-yl-methanol (la A solution of 476 g (1.85 mol) of chloroformic acid l-(9-fluorenylmethyl) ester (F-MOC) in 11 of dioxane is slowly added dropwise with ice cooling to a solution of 182 g (1.8 mol) ofpyrrolidin-2-yl-methanol in 1200 ml of dioxane and 1800 ml of a 10% sodium carbonatesolution. The mixture is stirred for 4 h at this température and for 8 h at room température,poured into 1.5 1 of ice water and extracted with diethyl ether. The ice-cooled aqueous phaseis weakly acidifïed with dilute HCl, left to stand ovemight at 0°C and the product la is thenfiltered with good purity and yield. Q-(MethanesulfonylmethyI)-N-fluorenylmethoxycarbonyl-pyrrolidine (lb) 470 g (1.4 mol) of la are redissolved in 300 ml of absolute pyridine and combined while coldwith 400 g (3.5 mol) of methanesulfonyl chloride. The mixture is stirred under argon initiallyfor 16 h at 0°C and then for a further 3 h at RT. Once the mixture has been poured onto ice,extraction is performed repeatedly with diethyl ether and the organic phase is washed insuccession with ice-cold dilute HCl, NaHCÛ3 and water. After drying over MgSÛ4 andévaporation, lb is obtained, which may be purifîed by recrystallisation from acetone/petroleum ether. » » / W t -23- 2-(Iodomethyl)-N-fluorenylmethoxycarbonyl-pyHolidine (le) 3 équivalents (359.7 g) of Nal in acetone are added to a solution of 331 g (0.8 mol) of lb inacetone. After 12 hours’ stirring at RT, the mixture is filtered, the filtrate added to 800 ml ofwater, which had been combined with sodium thiosulfate. After repeated extraction withdiethyl ether, the extracts were combined, washed with water, dried over MgSCU andevaporated under reduced pressure. Leaving the mixture to stand at low température initiallyyields an oil, which may be recrystallised from petroleum ether. 2- [2-(Dimethv lphosphono)ethvl] -pyrrolidine (1 d) 190 ml of a 1.6 M solution of n-butyllithium in hexane (corresponding to 0.30 mol) wereadded dropwise at -78°C under argon to 37.2 g (0.3 mol) of methanephosphonic aciddimethyl ester in 900 ml of dry THF. Stirring is continued for a further 15 minutes at thistempérature to permit complété formation of the carbanion. 133.9 g (0.3 mol) of le in 300 ml of dry THF were added dropwise to this solution at -78°Cwith stirring. Once the température has risen to room température, stirring is continued for afurther 4 h. 85.15 g (1 mol) of piperidine is then added and the mixture stirred ovemight. Themixture is filtered, the filtrate is poured into 21 of water, the organic phase separated and theaqueous phase extracted 4 times with 100 ml portions of dichloromethane. Once thecombined organic phases hâve been dried over MgSO<i, the solvent is removed and theresidue ffactionally distilled under a vacuum. 2-[2-(Dimethylphosphono)ethyî]-pyrrolidine(ld) is obtained as a colourless oil at yields of 30-40%. 5-[2-(Dimethylphosphono)ethyl3pyrrolidinone (le) A solution of 60 mmol of dimethyldioxirane in 120 ml of dry acetone is added dropwise to asolution, cooled to 0°C, of 3.32 g (15 mmol) of ld in 50 ml of dry acetone. The mixture isstirred for 30 min at 0°C and the solvent is then stripped out under a vacuum. The résultantcrude product is recrystallised from isopropanol. 5-[2- (Dimethylphosphono)ethyl]pyrrolidinone (le) is obtained in moderate yield as colourlesscrystals.
Dimethyldioxirane is produced in accordance with a method in Org. Synthèses IX, 288. 5-[2-(Phosphono)ethyl]-N-hydroxy-pynOlidin-2-one (lf) 3.06 g (20 mmol) of trimethylbromosilane are added dropwise to a solution, cooled to 0°C, of1.19 g (5 mmol) of le in 50 ml of dry acetonitrile. The mixture is stirred for 3 h at RT, thenthe solvent is stripped out under a vacuum, the residue is redissolved with 20 ml of ice water,the mixture is stirred for 1 h at room température, extracted twice with 20 ml portions ofether, a pH value of 4.5 is established with 2 M NaOH and the water is then stripped out in aRotavapor rotary evaporator at a maximum of 50°C. The solid residue is crystallised from -24- methanol/ethyl acetate. 5-[2-(Phosphono)ethyl]-N-hydroxy-pyrrolidin-2-one (lf) is obtainedin good yield in the form of yellowish microcrystals.
Example 2: 3-fPhosphonomethvll-N-hvdroxv-pyrrolidin-2-one (2) 3-Methyl-N-(2-trimethylsilylethoxy)-pyrrolidin-2-one (2a) A solution of 120 mmol of sodium ethanolate in 50 ml of absolute éthanol is added dropwiseat 0°C with exclusion of moisture to a solution of 20.37 g (120 mmol) of O-(2-trimethylsilyethyl)hydroxylamine hydrochloride in 100 ml of absolute éthanol. Anyprecipitated NaCl is filtered out with an argon sintered glass fîlter. The éthanol is removedffom the filtrate under reduced pressure and, once argon lias been passed through the residue,the latter is redissolved with absolute toluene. 1 mol% of RhCl3*3 H2O, 5 mol% of DMAPand, dropwise, 5.01 g (50 mmol) of 2-methylbutyrolactone are added thereto at 0°C. Themixture is allowed to thaw and is stirred ovemight while being refluxed on the waterseparator. After cooling, volatile constituents are stripped out under a vacuum at 50°C in aRotavapor rotary evaporator, a weakly yellow coloured oil being left behind. Redissolution in50 ml of ether, filtration through a short S1O2 column and stripping of the solvent gives rise to 3-methyl-N-(2-trimethylsilylethoxy)-pyrrolidin-2-one (2a) in moderate yield as a virtuallycolourless oil, which is obtained in good purity. 3-Bromomethyl-N-(2-trimethylsilylethoxy)-pyrrolidin-2-one (2b) 50 mmol of 2a, dissolved in 30 ml of absolute carbon tetrachloride, are combined with 1.2équivalents of N-bromosuccinimide and refluxed for 12 h. Small quantifies ofazobisisobutyronitrile (AIBN) are added at hourly intervals. After cooling, the product isfiltered ffom succinimide, the latter is washed with CCI4 and the combined CCI4 phases areevaporated under reduced pressure. The résultant oil may be chromatographed on S1O2, 2bbeing obtained in poor yield. 3-(Diethylphosphonomethyl)-N-(2-trimethylsilylethoxy)-pyrrolidin-2-one (2c) 100 mmol (17.3 ml) of triethyl phosphite are combined with 100 mmol of 2b and heated to150°C for 0.5 h without solvent. After cooling, the mixture is evaporated under reducedpressure and the yellowish brown oil is chromatographed on S1O2 with chloroform/methanolin a 25:1 ratio. Once volatile constituents hâve been stripped out, 2c is obtained in moderateyield as a yellow oil. 3-(Phosphonomethyl)-N-(2-trimethylsilylethoxy)-pyrrolidin-2-one (2d) 4 équivalents (120 mmol, 15.4 ml) of trimethylbromosilane are added dropwise with icecooling to 30 mmol of 2c in 50 ml of absoluted acetonitrile, the mixture is stirred for 15 min 11/ w w -25- at the same température, then for 2 h at RT, evaporated under reduced pressure until ayellowish oil is obtained, the product is redissolved in 100 ml of water and hydrolysed for 1 hat RT (pH less than 1). This solution is extracted twice with CHCI3, back-extracted once withwater and the combined aqueous phases are evaporated under reduced pressure at 45 °C. Therésultant yellow-brown oil is redissolved in water and a pH of 4.5 to 5.0 is established. Afterwashing with ice water, 2d is obtained as a virtually colourless sodium sait at a yield of 50%. 3 -(Phosphonomethyl)-N-hydroxy-pyrrolidin-2-one (2e) 5.3 mmol of BF3 etherate are added to a solution of 2.65 mmol of 2d in absoluted acetonitrileand stirred for 0.5 h at room température. Once the solution has been evaporated underreduced pressure, it is redissolved in 40 ml of ethyl acetate, washed with 3% common saitsolution, dried over MgSÜ4, filtered through a membrane filter and the solvent is stripped outunder reduced pressure. The crude product may be recrystallised from MeOH/EtOH, theproduct being obtained in pure form and good yield.
Example 3: 4-(Phosphonomethyl)-N-hydroxy-pvrroIidin-2-one (31 4-Methyl-2[5H]-furanone (3a) 10 g of 3-methylglutaric acid monoethyl ester and 31 g of lead tetraacetate dissolved in 400ml of absolute CCI4 are heated to boiling under argon. After 10 minutes' illumination bymeans of a tungsten daylight lamp, 23.1 g of iodine are added within 45 min whileillumination is continued. After cooling, the mixture is filtered, the filtrate washed withaqueous sodium thiosulfate solution, soda solution and water, dried over MgSÛ4 andevaporated under reduced pressure. The gamma-iodine ester 3a' is obtained as a oil whichmay be further reacted without further purification. 18.4 g of freshly precipitated silver acetateand 24 g of acetic anhydride are heated to 120°C in 82 ml of glacial acetic acid for 1 hour, 19.1 g of the gamma-iodine ester 3a' are added and the mixture refluxed for a further 2 hours.The mixture is then kept for 15 h at RT, combined with 300 ml of ether and filtered. Once thefiltrate has been washed with water and aqueous soda solution, the aqueous phase is extractedagain with ether, the combined organic extracts are dried over MgSÛ4 and evaporated underreduced pressure. Once this oil has been redissolved in 70 ml of 2 N NaOH, 10 ml of EtOHand 50 ml of water, the mixture is repeatedly extracted with ether, the ether phases beingquantitatively discarded. The aqueous phase, acidified with 150 ml of 6 N HCl, iscontinuously extracted with ether and, after drying over MgSÛ4 and évaporation underreduced pressure, is distilled (102-105°C at 34 Torr). 4.4 g of 4-methyl-2[5H]-furanone (3a)are obtained. -26-
The remaining steps for preparing 3 follow the synthesis sequence described in 2 by theintroduction of O-(2-trimethylsilylethyl)-hydroxylamine hydrochloride, NBS, triethylphosphite and the hydrolyses of phosphonic acid esters by trimethylbromosilane and thelibération of the cyclic hydroxamic acid by BF3 etherate. Référencé may also be made toT.Sakamoto, Y.Kikugawa J. Org. Chem. 1994,59, 929-931 with regard to the synthesissequence.
Example 4: N-Hvdroxy-3-amino-4-fphosphonomethyll-pyrrolidin-2-one (4) 2-Phenyl-4-(2-acetoxy-l-acetoxymethyl-ethylidene)-2-oxazolin-5-one (4a) 0.2 mol of hippuric acid, 0.6 mol of acetic anhydride, 0.24 mol of 1,3-diacetoxyacetone and0.1 mol of anhydrous lead(II) acetate are initially introduced into 500 ml of THF and refluxedfor 16 h under argon. After cooling to RT, inorganic salts are fïltered out, the mixture isevaporated under reduced pressure, redissolved in 500 mi of toluene, gaseous hydrogensulfide is introduced until PbS ceases to precipitate and, after filtration, the mixture isreevaporated. The product is chromatographed on S1O2 with hexane/chloroform as the solventmixture, 4b being obtained at a yield of 73%.
Diacetoxyacetone is synthesised in accordance with a method of A.O.L. Fischer, H.
Mildbrand Ber.Dt.chem.Ges. 57,707,1924. 2-Amino-3-methoxy-butyric acid (4b) A solution of 31.8 mol of 4a in 150 ml of dioxane is combined with 1 g of Pd/C andhydrogenated at standard pressure until 10 mol of hydrogen hâve been absorbed (4-6 h). Oncethe catalyst has been filtered out, the mixture is evaporated to dryness, redissolved in 40 ml ofwater and 60 ml of conc. HCl, refluxed for 4 h and kept ovemight in the refrigerator. Thefiltered solution is evaporated, redissolved in 50 ml of water and purified on Amberlite IR120, H+ ion exchanger by elution with 300 ml of aqueous ammonia solution. The mixture isboiled until no ammonia is any longer détectable, reevaporated under reduced pressure andrecrystallised.
Alpha-amino-beta-methoxy-gamma-butyrolactone (4c) 25 mmol of 4b are stirred for 15 min at RT with 20 ml of 2.5% HCl. The solution isevaporated to dryness and extracted overnight with chloroform in a Soxhlet apparatus. Oncethe solvent has been stripped out under reduced pressure, the lactone 4c is obtained invirtually quantitative yield. -27- N. N-Dibenzylamino-beta-methoxy-gamma-butvrolactone (4d) O. 2 mol of 4c, 72 g of K2CO3 and 300 mg of tetrabutylammonium iodide and 500 mg of 18-crown-6 are suspended in 100 ml of éthanol and heated to 40°C. 0.65 mol of benzyl bromideare added dropwise within 15 min, the mixture is stirred for 12 h at RT, the phases areseparated, the aqueous phase washed twice with 75 ml portions of ether, the organic phasesare combined, washed with saturated NaCl solution and dried over MgSC>4. After évaporationunder reduced pressure, the mixture is chromatographed on a short silica gel column. N.N-Dibenzylamino-beta-(bromomethyl)-butyrolactone (4e) 2.23 g (6.18 mmol) of CBr4 are added to a mixture of 4.12 mmol of 4d, 6.18 mmol of PPI13and 20 ml of absolute acetonitrile. The mixture is stirred for 20 h at RT, the solvent removedunder reduced pressure and chromatographed on silica gel with ethyl acetate/n-hexane assolvent. 4e is obtained in variable yield as a yellowish oil. N.N-Dibenzylamino-beta-(dimethylphosphonomethyl)-butyrolactone (4f) 40 mmol of 4e are refluxed for 0.5 to 1 h with 1 équivalent of trimethyl phosphite in toluene.After cooling, the mixture is evaporated under reduced pressure and the remaining oil ischromatographed on SiO2 with chloroform/methanol as the mobile solvent. Once volatileconstituents hâve been stripped out, 4f is obtained in moderate yield. N.N-Dibenzylamino-beta-(dimethylphosphonomethyl)-butyrolactam (4g) A solution of 100 ml of sodium ethanolate in 50 ml of absolute éthanol is added dropwise at0°C with exclusion of moisture to a solution of 120 mmol of O-benzylhydroxylaminehydrochloride in 100 ml of absolute éthanol. Any precipitated NaCl is filtered out with anargon sintered glass filter. The éthanol is removed from the filtrate under reduced pressureand, once argon has been passed through the residue, the latter is redissolved with absolutetoluene. 1 mol% of RI1CI3 3 H2O, 5 mol% DMAP and, dropwise, 50 mmol of 4f are addedthereto at 0°C. The mixture is allowed to thaw and is stirred ovemight while being refluxedon the water separator. After cooling, volatile constituents are stripped out under a vacuum at50°C in a Rotavapor rotary evaporator, an oil being left behind. Redissolution in 40 ml ofethyl acetate, filtration through a short S1O2 column and stripping of the solvent gives rise to(4g) in moderate yield as a yellow oil, which is obtained in good purity. N-Hydroxy-3-amino-4-(dimethylphosphonomethyl)-pyrrolidin-2-one (4h) 30 mmol of 4g in 60 ml of methanol and 10 ml of formic acid are hydrogenated with 5 mol%
Pd/C (10-20%) under standard pressure at RT for 13 h. Once the catalyst has been filtered out, the mixture is evaporated under reduced pressure and reacted without further purification.
-28- N-Hydroxy-3-amino-4-(Phosphonomethyl)-pyrrolidin-2-one (4i) 35 mmol of trimethylbromosilane are added dropwise with ice cooling to 10 mmol of 4h in 20ml of absoluted acetonitrile, the mixture is stirred for 15 min at the same température, then for2 h at RT, evaporated under reduced pressure until a yellowish oil is obtained, the product isredissolved in 100 ml of water and hydrolysed for 1 h at RT. This solution is extracted twicewith CHClj, back-extracted once with water and the combined aqueous phases are evaporatedunder reduced pressure at 45°C. The résultant dark oil is redissolved in water and a pH of 6.0is established. Precipitating 4i is filtered out and washed with ice water. 4i is obtained as thesodium sait in the form of beige crystals at a yield of 35-40%.
Example 5: N.2-Dihvdroxv-5-(2-phosDhonoethyB-pvrrole (51 N-Benzyloxy-5-[2-(dimethylphosphono)ethyl]pyrrolidin-2-one (5a) 20 mmol of 5-[2-(dimethylphosphono)ethyl]pyrrolidinone (le) are stirred ovemight at roomtempérature with 1.2 équivalents of benzyl bromide, 10 mg of tetrabutylammonium iodideand 1.3 équivalents of triethylamine in 30 ml of THF, are then poured into ice water,repeatedly extracted with small quantities of ether, the diethyl ether phase is washed with colddilute HCl and with saturated common sait solution, dried over MgSÛ4, evaporated and thecrude product chromatographed on silica gel with chloroform/methanol 25:1. 5a is obtainedin good yield. N-Benzyloxy-3-phenylseleno-5-[2-(dimethylphosphono)ethyl]pyrrolidin-2-one (5b) 2.0 mmol of 5a, which is dissolved in 1 ml of absolute THF and stirred for 20 min at -78°C,is added at the same température to 2.4 mmol of diisopropylamide in 3 ml of THF (LDA,produced ffom 0.35 ml of diisopropylamine and 1.6 ml of 1.65 M n-BuLi in hexane underargon at -78°C). 2.4 mmol of diphenyl diselenide, dissolved in 1 ml of THF and 1.2 mmol ofHMPT, are added at -78°C to the enolate of 5a. The reaction mixture is stirred for 40 min at -78°C and for 1.5 h at -40°C. Quenching with 0.1 N HCl and subséquent repeated extractionwith ether yields, after chromatography on silica gel, a yellowish oil 5b of a characteristicodour. N-Benzyloxy-2-hydroxy-4-[2-(dimethyIphosphono)ethyl]pyrrole (5c) 0.2 mmol of the phenylseleno compound 5b, dissolved in 1 ml of absolute THF, is combinedwith 30 μΐ of glacial acetic acid, 140 μΐ of Perhydrol (30% hydrogen peroxide solution) areadded dropwise with ice cooling and the mixture stirred for 30 min at the same température.The solution is poured into cold, saturated aqueous sodium hydrogen carbonate solution, themixture extracted with ether, dried over MgSÛ4, evaporated under reduced pressure and thecrude product chromatographed on silica gel. 5c is obtained in good yield as a yellowish oil. Λ ”**·
' « f Μ U -29- N. 2-Dihydroxy-4-[2-(dimethylphosphono)ethyl]pyrrole (5d) O. 15 mmol of 5c is placed in 50 ml of absolute EtOH, a spatula-tipfull of 10% Pd on activatedcarbon is added and the mixture hydrogenated for 1 h at RT in a standard pressurehydrogénation apparatus with vigorous stirring. Once the catalyst has been filtered out, themixture is evaporated and the crude product is reacted without further purification. N. 2-Dihydroxy-5-(2-phosphonoethyl)-pyrrole (5e) 4 équivalents (60 mmol, 8 ml) of trimethylbromosilane are added dropwise with ice coolingto 15 mmol of 5d in 50 ml of absoluted acetonitrile, the mixture is stirred for 15 min at thesame température, then for 2 h at RT, evaporated under reduced pressure until a yellowish oilis obtained, the product is redissolved in 80 ml of water and hydrolysed for 1 h at RT (pH < 1). This solution is extracted twice with CHCI3, back-extracted once with water and thecombined aqueous phases are evaporated under reduced pressure at a maximum of 45°C. Therésultant oil is redissolved in water and a pH of 4.5 to 5.0 is established with NaHCO3. 5e isremoved by suction filtration and, after washing with iced water, 5e is obtained as a virtuallycolourless sodium sait at a yield of 40%.
Example 6: N-Hvdroxv-3-f2-Îphosnhono)ethvll-lH-pyridone (61 2-Bromo-3 -(bromomethyl)pyridine (6a) 10 g (58.1 mmol) of 2-bromo-3-methylpyridine and 11.4 g (64 mmol) of [sic] are refluxed for24 h in 250 ml of CCI4. The succinimide is separated by filtration and the organic phase iswashed twice with water. After évaporation under reduced pressure, 6a is obtained as acolourless liquid by ffactional distillation (bp: 90°C, 1 Torr). 2-Bromo-3 -[2-(dimethylphosphono)ethyl]pyridine (6b) O. 21 mol of MeLi in ether is added dropwise to 100 ml of absolute THF, 0.1 mol of trimethylphosphite, dissolved in 50 ml of THF, is added dropwise within 15 min in such a manner thatthe internai température slowly reaches 0°C. 0.107 mol of 6a in 20 ml of THF is then addeddropwise at a température of-78°C, stirring is continued for a further 30 min at the sametempérature, the mixture is allowed to thaw and quenched at 0°C by dropwise addition of 80ml of 3 M HCl. The organic phase is separated, the aqueous phase extracted three times with40 ml portions of dichloromethane and, after drying over MgSCU, the combined organicphases are evaporated. The yellow crude product may be purified in a short column on S1O2. -30- 2-Bromo-3-[2-(dimethylphosphono)ethyl]pyridine N-oxide (6c) 100 mmol of 6b in 60 ml of glacial acetic acid are combined with 2 équivalents of a 40%peracetic acid solution, wherein the température should not exceed 50°C. After 5 hours'heating to 50°C and 12 hours' heating to 70°C, the solution is evaporated to half its volumeunder reduced pressure, poured onto ice and made highly alkaline with 40% aqueous KOH.Triple extraction with chloroform yields, after drying over K2CO3 and évaporation underreduced pressure, an N-oxide oil 6c, which was reacted without further purification. N -Hydroxv-3 -[2-(dimethvlphosphono)ethyl] -1 H-pvridone (6d) 6c is heated in a glass autoclave for 3 h to 120°C in absolute MeOH together with mortar-ground potassium hydroxide, potassium carbonate and tris(3,6-dioxaheptyl)amine. Aftercooling, the reaction mixture is poured into water, a pH value of 6 is established, the mixtureevaporated under a vacuum and, after addition of éthanol, a crude product is obtained whichmay be recrystallised in moderate yield from ethanol/toluene. N-Hydroxy-3-[2-(phosphono)ethyl]-l H-pvridone (6e) 40 mmol of trimethylbromosilane are added dropwise with ice cooling to 10 mmol of 6d in 30ml of absolute acetonitrile, the mixture is stirred for 15 min at the same température, then for2 h at RT, evaporated under reduced pressure until an oil is obtained, the product isredissolved in 20 ml of water and hydrolysed for 1 h at RT (acidic pH). This solution isextracted twice with CHCI3, back-extracted once with water and the combined aqueousphases are evaporated under reduced pressure at 45°C. The résultant brown oil is redissolvedin water, stirred twice with activated carbon, filtered therefrom and a pH of 5 is established.As a resuit, 6e précipitâtes out, is filtered, washed with ice water and may be recrystallisedfrom MeOH/EtOH.
Example 7: N-Hvdroxv-6-12-(nhosphonolethvll-lH-nvridone (71 2-Bromo-6-bromomethylpyridine (7a) 10.1 g (58.7 mmol) of 2-bromo-6-methylpyridine, 11.1g (62.4 mmol) ofN- bromosuccinimide (NBS) and 0.1 g (0.6 mmol) of AIBN are heated under argon for 6 h to110°C in 150 ml of toluene, the mixture simultaneously being illuminated with a tungstendaylight lamp (150 W, >320 nm). After cooling, succinimide is filtered out and the solutionevaporated under reduced pressure. Chromatography on silica gel (mobile solvent:hexane/dichloromethane) at first yields 2-bromo-6-dibromomethylpyridine, while 7a maysubsequently be eluted at a yield of up to 45% (mp: 138°C). -31 - 2-Bromo-6-[2-(dimethylphosphono)ethyljpyridine (7b) 0.21 mol of MeLi in ether is added dropwise to 100 ml of absolute THF, 0.1 mol of trimethylphosphite, dissolved in 50 ml of THF, is added dropwise within 15 min in such a manner thatthe internai température slowly reaches 0°C. 0.107 mol of 7a in 15 ml of THF is then added 5 dropwise at a température of -78°C, stirring is continued for a further 30 min at the same température, the mixture is allowed to thaw and quenched at 0°C by dropwise addition of 80ml of 3 M HCl. The organic phase is separated, the aqueous phase extracted repeatedly with40 ml portions of dichloromethane and, after drying over MgSÛ4, the combined organicphases are evaporated. The yellow crude product may be chromatographically purified onS1O2,7b being obtained at a yield of 47%. 2-Bromo-6-[2-(dimethylphosphono)ethyljpyridine N-oxide (7c) 50 mmol of 7b in 50 ml of glacial acetic acid are combined with 2 équivalents of a 40%peracetic acid solution, the température varying between 25 and 45°C. After 5 hours' heatingto 50°C and 12 hours’ heating to 70°C, the solution is poured onto ice and made highlyalkaline with 40% aqueous KOH. Triple extraction with chloroform yields, after drying overK2CO3 and évaporation under reduced pressure, an N-oxide oil 7c, which may berecrystallised from ether/ethanol. N-Hydroxy-6-[2-(dimethyîphosphono)ethyl]-1 H-pyridone (7d) 7c is heated in a glass autoclave for 2.5 h to 100°C in absolute MeOH together with mortar- 20 ground potassium hydroxide, potassium carbonate and tris(3,6-dioxaheptyl)amine. After cooling, the reaction mixture is poured into water, a pH value of 6 is established, the mixtureevaporated under a vacuum and, after addition of éthanol, a crude product is obtained which,similarly to 6d, may be recrystallised in moderate yield.
NrHydrQxyr6-{2-ljphQsph-QnQ)ethyl]-1 H-pyridone (7e) 25 40 mmol of trimethylbromosilane are added dropwise with ice cooling to 10 mmol of 7d in 25 ml of absolute acetonitrile, the mixture is stirred for 10 min at the same température, then for2 h at RT, evaporated under reduced pressure at 45°C until an oil is obtained, the product isredissolved in 20 ml of water and hydrolysed for 1 h at RT. This solution is extracted twicewith CHCI3, back-extracted once with water and the combined aqueous phases are evaporated 30 under reduced pressure at 45°C. The résultant dark-coloured oil is redissolved in water and apH of 4.8 is established. As a resuit, 7e précipitâtes out as the sodium sait. After filtration andwashing with ice water, 7e is obtained as a crude product, which may be recrystallised fromMeOH/toluene.
-32-
Example 8: N-Hvdroxv-5-f2-phosphono-2-hydroxy)ethyllpvrrolidin-2-one 181 N-Benzvl-2-(l .3-dithioylmethyll-pyrrolidine (8a) 100 mmol (12.0 g) of 1,3-dithiane are weighed out under protective gas, 250 ml of absoluteTHF are added thereto and a 5% excess of n-BuLi in hexane is added dropwise thereto within 5 3-5 min at -40°C. The mixture is stirred for 2 h at -25 to -15°C, the température is reduced to -60 to -78°C and 100 mmol of 2-iodomethyl-N-benzyloxy-pyrrolidine are slowly addedthereto under protective gas. After 5-6 hours' stirring at -20 to -10°C, the température isallowed to rise to 0°C and the reaction mixture is placed in the refrigerator for three days.After évaporation to approx. 20 ml, the mixture is poured into three times its volume of water, ^0 extraction performed three to five times with chloroform, the organic phases are combined,washed in succession with water, 6% KOH and again with water and the chloroform phase isdried over K2CO3. The residue obtained after évaporation under reduced pressure is reactedwithout further purification. N-Benzyl-2-(formylmethyl)-pyiTOlidine (8b) 1.1g of CaCCb and 2.5 ml of Hg(C104)2 of a 4 M aqueous solution are added to a solution of9 mmol of 8a in 30 ml of THF and 6 ml of water, stirring is continued for a further 5 to 10min, 150 ml of ether are added thereto and inorganic salts are filtered out. Once the solutionhas been evaporated under reduced pressure, a coloured crude product remains, which ispurified by flash chromatography. 20 N-Benzyl-2-[2-(diethylphosphono)-2-hydroxy]pyrrolidine (8c) 20 g (145 mmol) of diethyl phosphonate and 140 mmol of 8b are heated under argon to 80 to85°C for 8 h. After cooling, the mixture is evaporated under reduced pressure and the product8c is purified chromatographically on silica gel. N-Benzyl-2-[2-(diethylphosphono)-2-acetoxy]pyrrolidine (8d) 25 A mixture of 50 mmol of 1-hydroxyphosphonic acid ester 8c, 75 mmol of triethylamine, 75mmol of acetic anhydride and 4 mmol of dimethylaminopyridine (DMAP) is left to stand for14 h at RT and, after addition of 100 ml of ethér and 2 N HCl, the etheric phase is washedwith saturated aqueous NaHCCb solution, dried over MgSCU, evaporated and purified on ashort ALOX column. 30 2-[2-(N-Benzyl-2-[8-(diethylphosphono)-2-acetoxy]pyrrolidine (8e)
After addition of 400 mg of PtÛ2, a solution of 40 mmol of 8d in 30 ml of glacial acetic acidis hydrogenated at 70°C for 6 h at standard pressure. Once the catalyst has been filtered out,the mixture is repeatedly extracted with ether in a strongly alkaline medium, the combined -33- ether extracts are dried over MgSCU, evaporated and the product 8e, which is obtained ingood yield, is directly further reacted. N-Hydroxy-5-[2-phosphono-2-hydroxy)ethyl]pyrrolidin-2-one (8f) A solution of 70 mmol of dimethyldioxirane in 110 ml of dry acetone is added dropwise to asolution, cooled to 0°C, of 20 mmol of 8e in 50 ml of dry acetone. The mixture is stirred for30 min at 0°C and the solvent is then stripped out under a vacuum. A yellow oil is obtained,which may be purified on silica gel with a chloroform/methanol mobile solvent mixture. N-Hydroxy-5-[(2-diethyIphosphono-2-hydroxy)-ethyl]pyrrolidin-2-one (8g)
The yellow oil 8f is stirred ovemight with 5 M aqueous KOH in MeOH at RT, thenneutralised, MeOH is removed under reduced pressure and the mixture extracted with ether.The combined organic phases were dried over MgSÛ4 and evaporated to dryness. Therésultant 8g is used for the subséquent reactions without further purification. N-HvdrQxvr5-rf2-phosphono-2-hydroxy)-ethvllpvrrolidin-2-one(8h) 80 mmol of trimethylbromosilane are added dropwise to a solution, cooled to 0°C, of 20mmol of 8g in 50 ml of dry acetonitrile. The mixture is stirred for 3 h at RT, then the solventis stripped out under a vacuum, the residue is redissolved with 60 ml of iced water, themixture is stirred for 1 h at room température, extracted three times with 60 ml portions ofether, a pH value of 5.5 to 6.0 is established with 2 M NaOH and the water is then strippedout in a Rotavapor rotary evaporator at a maximum of 45°C. The solid residue is crystallisedfrom methanol/ethyl acetate. N-Hydroxy-5-[(2-phosphono-2-hydroxy)-ethyl]pyrrolidin-2-one(8h) is obtained in good yield in the form of yellowish-white microcrystals.
Example 9: 3-(MethvIphosphono)-N-hvdroxv-succinimide (9) 3-fBromomethyl-succinic anhydride (9a)
In a similar manner to the préparation of N-(2-trimethylsilylethoxy)-pyrrolidin-2-one (2b) 50 mmol of 2-methylsuccinic anhydride, dissolved in 30 ml of absoluted carbon tetrachloride,are reacted with 1.2 équivalents of N-bromosuccinimide by refluxing the mixture for 12 h.Small quantifies of azobisisobutyronitrile (AIBN) are added at hourly intervals. After cooling,the product is filtered from succinimide, the latter is washed with CCI4 and the combinedCCI4 phases are evaporated under reduced pressure. The résultant oil may be chromatographed on SiC>2,9a being obtained in low yield. -34- 3-[2-(Dimethylphosphono)ethyl]-succinic anhydride (9b) 40 mmol of 9a are refluxed for 0.5 to 1 h with 1 équivalent of trimethyl phosphite in toluene.After cooling, the mixture is evaporated under reduced pressure and the yellowish oil ischromatographed on S1O2. Once volatile constituents hâve been stripped out, 9b is obtained inlow yield. 3-[2-(Dimethylphosphono)methyl]-N-benzyloxy-succinimide (9c) 1.0 g of benzyloxyamine is heated in a glass autoclave with 1.0 équivalent of 9b to 180°C for30 min. After cooling, the oil is evaporated under reduced pressure, a poor crude productyield being observed, and 9c is further reacted without purification. 3 - [2-(Dimethv lphosphono)methy 1] -N-hydroxy-succinimide (9d) 9.28 mmol of the benzyloxy compound 9c dissolved in 60 ml of éthanol are combined with700 mg of Pd/C and hydrogenated at standard pressure for 4 h at RT. Once hydrogenabsorption has ceased, the catalyst is filtered out, the mixture evaporated under reducedpressure and recrystallised from ethyl acetate/hexane, 9d being obtained in good yield. 3-[2-Phosphonomethyl]-N-hydroxy-succinimide (9e) 110 mmol of trimethylbromosilane are added dropwise to a solution, cooled to 0°C, of 30mmol of 9g in 70 ml of dry acetonitrile. The mixture is stirred for 3 h at RT, then the solventis stripped out under a vacuum, the residue is redissolved with 80 ml of iced water, themixture is stirred for 1 h at room température, extracted three rimes with 50 ml portions ofether, a pH value of 5.5 to 6.0 is established with NaHCCh and the water is then stripped outin a Rotavapor rotary evaporator at a maximum of 45 °C. The solid residue is crystallised frommethanol/acetone. 9e is obtained in the form of beige crystals in good yield.
Example 10: l-N-(2-Phosphonoethyn-3-hvdroxy-7-methvl-xanthine (10) 1 -N-(2-Dimethylphosphono-ethyl)-7-methylxanthine (10a) 50 g of 7-methylxanthine (2,6-dihydroxy-7-methylpurine) are dissolved in 11 of boilingéthanol and 38 g of 50% potassium hydroxide solution are added thereto. Once the mixturehas cooled to 15 to 20°C, the potassium sait of 7-methylxanthine précipitâtes out, is filteredout and decocted with boiling acetone and boiling absolute éthanol. A solution of 20 mmol of 2-bromomethylphosphonic acid dimethyl ester and 2 mmol ofhexadecyltributyl-phosphonium bromide in 10 ml of toluene is combined with 25 mmol of thepotassium sait of 7-methylxanthine and the mixture heated to 100°C for 2 h. Once the reactionmixture has cooled, undissolved fractions are filtered out and the evaporated organic phase is
-35- chromatographed on silica gel with ether/chloroform as mobile solvent. In this manner, boththe desired l-N-(2-dimethylphosphono-ethyl)-7-methylxanthine (10a) and, at lower yield, 3-N-(2-dimethylphosphono-ethyl)-7-methylxanthine (10a’) are obtained. l-N-(2-Dimethylphosphono-ethyl)-3-hydroxy-7-methyl-xanthine (10b) A solution of 60 mmol of dimethyldioxirane in 120 ml of dry acetone is added dropwise to asolution, cooled to 0°C, of 25 mmol of 10a in 50 ml of dry acetone. The mixture is stirred for30 min at 0°C and the solvent is then stripped out under reduced pressure. The résultant crudeproduct is chromatographed on silica gel, l-N-(2-dimethylphosphono-ethyl)-3-hydroxy-7-methyl-xanthine (10b) being obtained in poor yield.
In a similar manner, 3-N-(2-dimethylphosphonoethyl)-7-methylxanthine (10a') may beconverted into 3-N-(2-dimethylphosphono-ethyl)-l-hydroxy-7-methylxanthine (10b'). 1 -N-(2-:PhQsphono-ethyl)-3-hydrQxy-7-methyl-xanthine (10c) 4 équivalents (100 mmol) of trimethylbromosilane are added dropwise with ice cooling to 25mmol of 10b in 50 ml of absoluted acetonitrile, the mixture is stirred for 15 min at the sametempérature, then for 2 h at RT, evaporated under reduced pressure until an oil is obtained, theproduct is redissolved in 100 ml of water and hydrolysed for 1 h at RT. In order to removehexamethyldisiloxane, this solution is extracted twice with CHCb, back-extracted once withwater and the combined aqueous phases are evaporated under reduced pressure at 45°C. Therésultant beige oil is redissolved in water and a pH of 6.5 to 7.0 is established. After washingwith iced water, 10c is obtained as a virtually colourless sodium sait at a yield of 55%.
In a similar manner, 3-N-(2-dimethylphosphono-ethyl)-l-hydroxy-7-methyl-xanthine (10b')is reacted with trimethylbromosilane to yield 3-N-(2-phosphono-ethyl)-l-hydroxy-7-methyl-xanthine (10c').
Example 11 : N-Hydroxy-1.2<3.4-tetrahvdro-l-oxo-3-i2-phosphonoethyl)l-isoauinoIine an 3-Phenyl-2-aminopropanol (lia) 3.0 mol of L1AIH4 are suspended in 900 ml of anhydrous tetrahydrofuran in a heat-treated andargon-flooded three-necked flask fitted with a KPG stirrer and 1.5 mol of phenylalanine areadded in portions with ice cooling. The mixture is then refïuxed for 6 h, allowed to cool andhydrolysed with crushed ice. The mixture is filtered and the solvent removed under a vacuum.The filtrate is redissolved with CH2CI2, washed with saturated NaCl solution and dried with -36- 9
Na2SO4. Vacuum distillation is then performed. 3-Phenyl-2-aminopropanol lia is obtained ata yield of 76%. 1 -Phenvl-3 -(tetrahydro-2-pyranyloxy)-2-aminopropane (11 b) 2.5 mol of dihydropyran and 5.3 g of p-toluenesulfonic acid are added to 1.4 mol of 3-phenyl- 2-aminopropanol 1 and the mixture then stirred for 20 h at RT. The excess dihydropyran is $ then removed under a vacuum, the residue redissolved with 700 ml of ethyl acetate and washed with 300 ml portions of saturated NaHCCh solution and saturated NaCl solution. Themixture is then dried with MgSCU, filtered and the solvent removed under a vacuum. 1-Phenyl-3-(tetrahydro-2-pyranyloxy)-2-aminopropane (11b) is obtained at a yield of 63%. 1 -Phenvl-3 -(tetrahydro-2-pyranyloxy)-2-isocyanopropane (1 le) ^0 0.88 mol of l-phenyl-3-(tetrahydro-2-pyranyloxy)-2-aminopropane 11b are added dropwise to a solution of 3.52 mol of phosgene in 1.5 1 of toluene and the mixture then boiled for 3 h at80°C. The solvent is then removed under a vacuum. The desired product l-phenyl-3-(tetrahydro-2-pyranyloxy)-2-isocyanopropane 11c is obtained at a yield of 83%. This is usedwithout further purification. ^5 1.2,3.4-Tetrahvdro-1 -oxo-3 -hydroxymethyl-isoquinoline (1 ld) A solution of 0.72 mol of l-phenyl-3-(tetrahydro-2-pyranyloxy)-2-isocyanopropane 11c in 80ml of anhydrous acetone is slowly added dropwise to 100 ml of ice-cooled phosphoric acidand stirred for 3 h at RT. Ice water is then added, the mixture stirred for 0.5 h and thenextracted with CH2CI2. The organic phase is washed with water, saturated Na2CO3 solution, 2Q again with water and with saturated NaCl solution and dried with MgSO4. After filtration andremoval of the solvent under a vacuum, the product is recrystallised from hexane/benzene,28% of l,2,3,4-tetrahydro-l-oxo-3-hydroxymethyl-isoquinoline (lld) being obtained. 1.2.3.4- Tetrahvdro-1 -oxo-3-bromomethyl-isoquinoline (lie) A solution of 180 mmol of PPI13 in 120 ml of CH2CI2 is added to a solution of 150 mmol of 1.2.3.4- tetrahydro-l-oxo-3-hydroxymethyl-isoquinoline 11c and 210 mmol of CBr4 in 150 ml 25 of CH2CI2 and stirred for 20 h at RT. The solvent is then removed under a vacuum and theresidue repeatedly recrystallised from benzene. The product l,2,3,4-tetrahydro-l-oxo-3-bromomethyl-isoquinoline lie is obtained at a yield of 31%. 1.2.3.4- Tetrahvdro-1 -oxo-3 -(2-diethylphosphonoethyl)-isoquinoline (1 lf) 30 66.2 mmol of solution of n-butyllithium (1.15 M) in hexane are added dropwise at -78°C to a solution of 75 mmol of dimethyl methylphosphonate in 120 ml of absolute THF under argonand the mixture stirred for 1.5 h at this température. 46.5 mmol of 1,2,3,4-tetrahydro-l-oxo-3- 4* * -37- bromomethyl-isoquinoline lie in 50 ml of absolute THF are added dropwise to this solutionat -78 °C, the mixture stirred for a further 1 h at -78°C and then allowed to rise to RTovernight. 100 ml of water are then added, the aqueous phase separated and extracted 3 timeswith 50 ml portions of ethyl acetate. The combined organic phases are dried with MgSO.4,filtered and the solvent removed under a vacuum. The residue is purified chromatographically(silica gel, hexane/ethyl acetate 5:1). 24% of the desired product 1,2,3,4-tetrahydro-1-oxo-3 -(2-diethyIphosphonoethyl)-isoquinoline llf are obtained. N-Hvdroxy-1,2.3.4-tetrahvdro-1 -oxo-3 -(2-diethylphosphonoethyl)-isoquinoline (11g) 5.36 mmol of l,2,3,4-tetrahydro-l-oxo-3-(2-diehtylphosphonoethyl)-isoquinoline 6 aredissolved in 30 ml of absolute acetone and cooled to 0°C. A solution of 17.15 mmol ofdimethyldioxirane is then added dropwise and the mixture stirred for 30 min at 0°C. Thesolvent is removed under a vacuum and the residue purified chromatographically (silica gel,hexane/ethyl acetate 4:1). 33% of the product N-hydroxy-1,2,3,4-tetrahydro-l-oxo-3-(2-diethylphosphonoethyl)-isoquinoline 11g are obtained. N-Hydroxy-1.2.3,4-tetrahvdro-1 -oxo-3-(2-phosphonoethyl)-isoquinoIine (llh) 1.77 mmol of N-hydroxy-1,2,3,4-tetrahydro-1 -oxo-3-(2-diethylphosphonoethyl)-isoquinoline11g are dissolved in 15 ml of absolute CH2CI2 under argon and cooled to 0°C. 10 mmol oftrimethylbromosilane are then added dropwise from a syringe, the mixture stirred for a further1 h at 0°C and then overnight at RT. The solvent is then removed under a vacuum, the residueredissolved in 20 ml of water and stirred for 1 h at RT. 15 ml of CHCI3 are then added and theorganic phase separated. The aqueous phase is extracted twice more with 10 ml portions ofCHCI3 and the mixture evaporated under a vacuum. The residue is purified chromatographically (silica gel, HaO/methanol 1:1). The desired product is obtained at a yieldof54%.
Example 12:
The antimalarial activity of the substances stated in Table I was determined using in vitrocultures of the causative organism of malaria, Plasmodium falciparum. The roman numeralsrefer to the particularly preferred compounds stated on pages [sic] to [sic]. 200 μΐ of anasynchronous Plasmodium falciparum culture with a 0.4% blood parasite content and ahaematocrit of 2% were loaded into each of the wells of a 96 well microtitre plate. A serialdilution sériés of the compounds was then prepared in steps of three between concentrationsof 100 and 1 pmol Γ1. The plates are incubated at 37°C, 3% CO2 and 5% O2 over a period of48 hours. 30 μΐ of medium supplemented with 27 pCi ml·1 of [3H]-hypoxanthine were thenadded to each well. After 24 hours' incubation, the parasites were harvested by filtration 1-1 -38- through glass fibre filters and the incorporated radioactivity was measured. Inhibition ofparasite growth was measured as the pércentage inhibition of tritium incorporation relative toa comparison without the substance. The results for the three different concentrations arestated in Table I.
Table I
Substance r5 A Form used 100 μΜ inhibition (%) 10 μΜ inhibition (%) 1 μΜ inhibition (%) I H C2H4 Na sait 98 98 98 III H ch2 Na sait 96 98 63 II H ch2 Na sait 98 87 59 I H ch2choh Na sait 98 97 78 X H ch2 Na sait 89 80 0 X H ch2 Na sait 98 97 98 III H ch2 Na saitpyrrole ring isNH2-substitutedin position 3 98 98 82 VII H c2h4 Na sait 98 98 98 XXXI H c2h4 Na sait 97 73 53 XXVIII H c2h4 Na sait 98 97 82 XXXVIII H c2h4 N-substituted in position 5 Na sait 92 78 30 XXXVI H c2h4 in position 3 Na sait 95 80 37
Example 13 20 The antibacterial action of the substances stated in Table II was determined. The romannumerals refer to the particularly preferred compounds stated on pages 5 to 8. A dilution sériés comprising the concentrations 500,100, 50 and 10 pmol Γ1 of the individualcompounds in LB medium is introduced into 5 culture microtubes in a volume of 0.5 ml. Eachof the microtubes was inoculated with 10 μΐ of an ovemight culture of E. coli Kl 2 and shaken 7 Λ -39- overnight at 37°C. Bacterial growth was assessed on the basis of the turbidity of the medium.The minimum concentration causing inhibition of bacterial growth was determined (minimuminhibition concentration, MIC).
Antibacterial activity with regard to P. aeruginosa was determined in the same manner. The5 results are shown in Table II.
Table II
Substance Rs A Form used E. coli MIC (mg/1) P. aeruginosa10 mg/1 I H c2h4 Na sait 2.5 5 III H ch2 Na saitpyrrole ring isNH2-substituted inposition 3 5 5 II H ch2 Na sait 10 5 I H ch2choh Na sait 2.5 1.25 X H ch2 Na sait 1.25 1.25 X H ch2 Na sait 10 20 III H ch2 Na sait 1.25 10 VII H c2h4 Na sait 10 40 XXXI H C2H4 Na sait 10 1.25 XXVIII H c2h4 Na sait 5 5 XXXVIII H C2H4 N-substituted inposition 5 Na sait 20 80 XXXVI H c2h4 in position 3 Na sait 40 20
Claims (11)
- τ η W \J -40- Patent Claims1. Organophosphorus compounds of the general formula (I) O 11 R1-A-P-R3 (I) I r4 wherein A is selected from the group which consists of a (C1.9) alkylene residue, whichmay comprise one or more double bonds and may be substituted with hydroxy, halogen, 5 amino, oxo groups with branched or unbranched Ci.9 alkyl groups and C2-9 alkenyl groups, wherein the C1.9 alkyl groups and C2-9 alkenyl groups may be substituted withhydrogen, hydroxy, amino, halogen and oxo groups, -C-O-C- and -C-N-C-, wherein thecarbon atoms of -C-O-C- and -C-N-C- may be substituted with an alkyl having up to 7carbon atoms or hydroxy groups, IQ or in which A is of the following formula (II): Bi B3 B5 B7 B9 -Ç1-Ç2-Ç3-Ç4-Ç5- (II) B2 B4 Ββ Ββ B10 wherein one or more of the carbon atoms selected from the group C3, C4, C5, together ^5 with their substituents, may also be absent, and at least one substituent présent in the range from Bi to B10 is a C3-8-cycloalkyl-(Co-9)-alkyl group, wherein both the C3.8cycloalkyl group and the C0-9 alkyl group may comprise one or more double bonds andone or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygenor sulfur atoms, and wherein both the cycloalkyl group and the alkyl group may be 20 substituted with hydroxy, halogen, amino, oxo groups with branched or unbranched C1.9alkyl groups and C2-9 alkenyl groups, wherein the Ci-9 alkyl groups and C2-9 alkenylgroups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, andthe remaining substituents Bi to B10 présent are selected from the group which consistsof hydrogen, hydroxy, halogen, amino groups, Ci.26 alkyl residues, C1-26 alkoxy 25 residues, Ci-26-alkoxy-Ci.26-alkyl residues or both substituents of a C atom together form an oxo group, wherein each Ci.26 alkyl residue and each Ci.26 alkoxy residue may be branched or unbranched and be saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups, -41 - in which Ri is selected from the group which consists of 5- and 6-memberedheterocycles wilh at least one ring nitrogen atom or a polycyclic carbon with at least oneof these heterocycles, wherein at least one of these nitrogen atoms belongs to ahydroxamic acid group or a hydroxamic acid ester group, and may be saturated or 5 unsaturated with one or more double or triple bonds and may thus also be aromatic and may be substituted with hydroxy, halogen, amino, oxo groups and with branched orunbranched Ci-9 alkyl groups and C2-9 alkenyl groups, wherein the Ci.9 alkyl groups andC2-9 alkenyl groups may be saturated or unsaturated with one or more double or triplebonds and may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups,wherein the nitrogen atom of the hydroxamic acid group or hydroxamic acid ester groupis substituted with OR5 and Rs is selected from the group which consists of hydrogen, substituted and unsubstitutedC1.9 alkyl, substituted and unsubstituted hydroxy-Ci.9-alkyl, substituted andunsubstituted C1.9 alkenyl, substituted and unsubstituted C1-9 alkynyl, substituted andunsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstitutedcycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstitutedheterocyclic residue, in which R3 and R4 are identical or different and are selected from the group whichconsists of hydrogen, substituted and unsubstituted C1.26 alkyl, hydroxy-Ci-26-alkyl, 20 substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1.26 alkenyl, substituted andunsubstituted Ci-26 alkynyl, substituted and unsubstituted cycloalkyl, substituted andunsubstituted heterocyclic residue, halogen, OX3 and OX4, wherein X3 and X4 are identical or different and are selected from the group which 2«j consists of hydrogen, substituted and unsubstituted Ci.26 alkyl, substituted and unsubstituted hydroxy-Ci-26-alkyl, substituted and unsubstituted aryl, substituted andunsubstituted aralkyl, substituted and unsubstituted C1.26 alkenyl, substituted andunsubstituted Ci-26 alkynyl, substituted and unsubstituted cycloalkyl, substituted andunsubstituted heterocyclic residue, a silyl, a cation of an organic and inorganic base, in 30 particular a métal of main groups I, II or III of the periodic System, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and the pharmaceutically acceptable salts, esters and amides thereof and salts of the esters. 7 5 0 -42
- 2. Compound according to claim 1, characterised in that the organophosphorus compoundsare of the formula (III) O II R1-A-P-R3 (III) I ox4 wherein R3 is preferably hydrogen, methyl, ethyl, an amide residue and X4 is selectedfrom the group which consists of hydrogen, sodium, potassium, methyl, ethyl.
- 3. Compound according to claim 1, characterised in that the organophosphorus compoundsare of the formula (IV) O II R1-A-P-OX3 I OX4 (IV) wherein X3 and X4 are identical or different and are selected from the group whichconsists of hydrogen, a (C1.3) alkyl, a métal of main groups I, II or III of the periodicsystem, ammonium, substituted ammonium, or ammonium compounds derived fromethylenediamine or amino acids.
- 4. Compound according to claim 3, characterised in that X3 and X4 are identical ordifferent and are selected from the group which consists of hydrogen, sodium,potassium, methyl, ethyl. Î5 5. Compound according to one of the preceding daims, characterised in that A is selectedfrom the group which consists of alkylene, alkenylene, hydroxyalkylene andoxoalkylene.
- 6. Compound according to claim 5, characterised in that A is selected such that threeatoms are présent between the nitrogen atom of the heterocyclic group and thephosphorus atom, wherein A is preferably a methylene, hydroxymethylene, ethylene,ethenylene or hydroxyethylene. 20 -43-
- 7. Compound according to one of daims 1 to 3, characterised in that the compound isselected from the group of compounds which consists ofA-POj2· vn VIIIXXI Ί 4 Ύ „ » Si ' ! Γ’ - έ w -44- *XVIXIXλ5 κ5 XXI χχπXXIII -45-XXVII XXVIIIXXIXXXXXXXI -46-ό 0 and the corresponding phosphinic acid and phosphinoyl dérivatives, wherein R5 is defined as in claim 1. -47 -
- 8. Use of a compound according to one of daims 1 to 7 as a fungicide, bactéricide orherbicide in plants.
- 9. Use according to one of daims 1 to 7 for the treatment of infections caused by bacteria,viruses, fungi or uni- or multicellular parasites.
- 10. Use according to claim 9 for the prévention and treatment of infections caused byunicellular parasites, namely the causative organisms of malaria, sleeping sickness,Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniases, trichomoniasis,pneumocystosis, balantidiasis, cryptosporidiosis, sarcocytosis, acanthamoebosis,naeglerosis, coccidiosis, giardiasis and lambliasis.
- 11. Pharmaceutical préparation for the therapeutic and prophylactic treatment of infectiousprocesses, characterised in that the préparation contains an active content of at least oneorganophosphorus compound according to one of daims 1 to 7 together with apharmaceutically acceptable excipient.
- 12. Pharmaceutical préparation according to claim 11, characterised in that the préparationcontains another pharmaceutical active substance. 47 Pages Jeaaa Pharoaka QahBpar procuration
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| ES2910024T3 (en) * | 2015-03-09 | 2022-05-11 | Univ Texas | Enolase inhibitors and methods of treatment with the same |
| 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 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4206156A (en) * | 1976-07-27 | 1980-06-03 | Fujisawa Pharmaceutical Company, Limited | Hydroxyaminohydrocarbonphosphonic acids |
| US4693742A (en) * | 1983-12-20 | 1987-09-15 | Rohm And Hass Company | Herbicidal hydroxyamino phosphonic acids and derivatives |
| JPS61106504A (en) * | 1984-10-30 | 1986-05-24 | Teijin Ltd | Herbicide |
| JP3657516B2 (en) * | 1998-04-14 | 2005-06-08 | ヨマー、ハッサン | Use of organophosphorus compounds for the treatment and prevention of infectious diseases |
-
1998
- 1998-12-22 DE DE19859426A patent/DE19859426A1/en not_active Withdrawn
-
1999
- 1999-12-22 PT PT99968365T patent/PT1140952E/en unknown
- 1999-12-22 DE DE59906907T patent/DE59906907D1/en not_active Expired - Fee Related
- 1999-12-22 AP APAP/P/2001/002168A patent/AP2001002168A0/en unknown
- 1999-12-22 OA OA00100153A patent/OA11730A/en unknown
- 1999-12-22 CN CN99814915A patent/CN1331695A/en active Pending
- 1999-12-22 ES ES99968365T patent/ES2204189T3/en not_active Expired - Lifetime
- 1999-12-22 DK DK99968365T patent/DK1140952T3/en active
- 1999-12-22 AU AU25385/00A patent/AU2538500A/en not_active Abandoned
- 1999-12-22 HU HU0104866A patent/HUP0104866A3/en unknown
- 1999-12-22 WO PCT/EP1999/010274 patent/WO2000037477A1/en not_active Application Discontinuation
- 1999-12-22 PL PL99349045A patent/PL349045A1/en not_active Application Discontinuation
- 1999-12-22 BR BR9916466-3A patent/BR9916466A/en not_active IP Right Cessation
- 1999-12-22 CA CA002356289A patent/CA2356289A1/en not_active Abandoned
- 1999-12-22 MX MXPA01006456A patent/MXPA01006456A/en unknown
- 1999-12-22 JP JP2000589547A patent/JP2002533350A/en active Pending
- 1999-12-22 CZ CZ20012284A patent/CZ20012284A3/en unknown
- 1999-12-22 EP EP99968365A patent/EP1140952B1/en not_active Expired - Lifetime
- 1999-12-22 TR TR2001/01832T patent/TR200101832T2/en unknown
- 1999-12-22 IL IL14347099A patent/IL143470A0/en unknown
- 1999-12-22 EA EA200100689A patent/EA200100689A1/en unknown
- 1999-12-22 SK SK889-2001A patent/SK8892001A3/en unknown
- 1999-12-22 KR KR1020017007908A patent/KR20010089670A/en not_active Application Discontinuation
- 1999-12-22 AT AT99968365T patent/ATE248846T1/en not_active IP Right Cessation
-
2001
- 2001-05-30 ZA ZA200104443A patent/ZA200104443B/en unknown
- 2001-06-21 NO NO20013085A patent/NO20013085L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CZ20012284A3 (en) | 2001-10-17 |
| DK1140952T3 (en) | 2004-01-12 |
| HUP0104866A3 (en) | 2002-08-28 |
| ATE248846T1 (en) | 2003-09-15 |
| HUP0104866A2 (en) | 2002-06-29 |
| NO20013085L (en) | 2001-08-22 |
| BR9916466A (en) | 2001-09-25 |
| WO2000037477A1 (en) | 2000-06-29 |
| NO20013085D0 (en) | 2001-06-21 |
| PL349045A1 (en) | 2002-07-01 |
| EA200100689A1 (en) | 2001-12-24 |
| AP2001002168A0 (en) | 2001-06-30 |
| IL143470A0 (en) | 2002-04-21 |
| TR200101832T2 (en) | 2001-12-21 |
| AU2538500A (en) | 2000-07-12 |
| ZA200104443B (en) | 2002-01-14 |
| KR20010089670A (en) | 2001-10-08 |
| CA2356289A1 (en) | 2000-06-29 |
| JP2002533350A (en) | 2002-10-08 |
| EP1140952B1 (en) | 2003-09-03 |
| DE59906907D1 (en) | 2003-10-09 |
| DE19859426A1 (en) | 2000-07-06 |
| EP1140952A1 (en) | 2001-10-10 |
| MXPA01006456A (en) | 2002-04-24 |
| CN1331695A (en) | 2002-01-16 |
| ES2204189T3 (en) | 2004-04-16 |
| SK8892001A3 (en) | 2001-12-03 |
| PT1140952E (en) | 2004-02-27 |
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