DE102016204876A1 - Functionalized calixarenes - Google Patents

Abstract

The present invention relates to functionalized calixarenes of the formula (I) and their salts, pharmaceutical compositions containing at least one functionalized calixarene (I) or its salt, the use of such functionalized calixarenes for the treatment of poisoning with neurotoxic organic phosphorus compounds and the use of such functionalized calixarenes for the treatment of surfaces contaminated with neurotoxic organic phosphorus compounds. CAX (-R) n (I) In formula (I), the variables have the following meanings: CAX stands for a calixarene radical, n stands for 1, 2, 3, 4, 5 or 6, R stands for a radical of the formula XY (-Nu) m, where each R is attached to each cyclic repeat unit of the calixarene residue CAX, wherein X is a covalent bond, C1-C4 alkanediyl, O, OC (= O), C (= O) -O , NH, NH-C (= O), C (= O) -NH, NH-C (= O) -NH, NH-C (= S) -NH, NH-C (= NH), AO, AOC (= O), AC (= O) -O, A-NH, A-NH-C (= O) or AC (= O) -NH, wherein A in the 6 last-mentioned groups is C1-C4-alkanediyl ; Y is a covalent bond, C 1 -C 4 alkanediyl, C 2 -C 4 alkenediyl, a carbocyclic linker or a heterocyclic linker, m is 1 or 2, where m is 1 when Y is C 1 -C 4 alkanediyl or C 2 C4-alkenediyl, and Nu is a nucleophilic group selected from hydroxamic acid group, thiohydroxamic acid group, N-C1-C6 alkyl hydroxamic acid group, N-C6-C14 aryl hydroxamic acid group, N-C7-C15 aralkyl hydroxamic acid group, N-C1 -C7 acyl hydroxamic acid group, oxime group, guanidine group, N-hydroxycarbamide group, N-hydroxycarbamate group and a 1-hydroxybenzotriazole group.

Description

The present invention relates to functionalized calixarenes, pharmaceutical compositions comprising at least one functionalized calixarene, the use of functionalized calixarenes for the treatment of intoxications with neurotoxic organic phosphorus compounds and the use of functionalized calixarenes for the treatment of surfaces contaminated with neurotoxic organic phosphorus compounds.

BACKGROUND OF THE INVENTION

Even a few years after the entry into force of the Chemical Weapons Convention, chemical warfare agents still pose a threat that should not be underestimated. On the one hand, there are still large stocks of chemical warfare agents that have to be destroyed successively according to the Chemical Weapons Convention. The transport, handling and destruction of these substances generally entail the risk of unintentional release of such substances and thus also the risk of contamination of humans. On the other hand, it can not be ruled out that such substances are produced by terrorists and misused for attacks.

An important class of chemical warfare agents are the neurotoxic organic phosphorus compounds. Neurotoxic compounds are primarily damaging to nerve cells and nerve tissue and are therefore also called neurotoxins. Within the group of neurotoxic organic phosphorus compounds, a distinction is made between the classes of G substances and V substances. G-substances are, for example, sarin (GB), tabun (GA), soman (GD) and compounds derived therefrom such as cyclosarine (GF), gelan II (DFP) and 2-N, N-dimethylaminoethyl (dimethylamido) fluorophosphate (GV). V-substances are, for example, O, O-diethyl-S- [2-diethylaminoethyl] thiophosphate (VG), O-ethyl-S- [2-diisopropylaminoethyl] methylphosphonothiolate (VX), O-isobutyl-S-2- [diethylaminoethyl] methylphosphonothiolate (VR) and compounds derived therefrom such as O-ethyl-S- [2-diethylaminoethyl] methylphosphonothiolate (VM), O-ethyl-S- [2-diisopropylaminoethyl] ethylphosphonothiolate (VS), O-ethyl-S-2- [ diethylaminoethyl] ethylphosphonothiolate (VE), on-butyl S- [2-diethylaminoethyl] methylphosphonothiolate (CVX) and O-ethyl-S- [2-di-n-propylaminoethyl] methylphosphonothiolate (n-propyl-VX). The physiological mechanism of action of these neurotoxic organic phosphorus compounds is based primarily on the inhibition of acetylcholinesterase in the nervous system, so that it can lead to serious physical injury to death. Similar effects, although not so marked, include various pesticides structurally related to the above compounds, such as malathion, parathion and paraoxon.

Poisonings with neurotoxic organic phosphorus compounds are typically treated with drug combinations. To reactivate the inhibited acetylcholinesterase to administer nucleophilic substances, often oximes. In addition, an attempt is made to counteract the pathological changes in the area of the respiratory center, the smooth muscles and the exocrine glands by administering the muscarinic antagonist atropine (see RM Dawson, J. Appl. Toxicol. 1994, 14, 5, 317-331 ). However, it has been shown that this therapeutic concept only in the treatment of poisoning with neurotoxic organic phosphorus compounds which have a relatively low biological half-life, z. As sarin, or after exposure to relatively small amounts of poison is promising. The effectiveness of conventional antidote therapy is severely limited in the case of poisoning with persistent neurotoxic organic phosphorus compounds, for example VX, or contamination with large quantities of poison (see P. Eyer, Toxicol. Rev. 2003, 22, 3, 165-190 ). In such poisonings, the reactivated by oxime acetylcholinesterase is immediately inhibited again by free poison, and this process may last for days (see F. Worek et al., Toxicol. Appl. Pharmacol. 2005, 209, 3, 193-202 ).

An alternative or complementary therapy of poisoning with neurotoxic organic phosphorus compounds is the administration of scavenger compounds capable of binding and degrading the venom molecules.

DE Lenz et al., Toxicology 2007, 233, 31-39 , describe the administration of human butyrylcholinesterase as a bioscavenger to guinea pigs for the treatment of VX or soman poisoning.

K. Kim et al., Chem. Rev. 2011, 111, 5345-5403 , describe in a review article the degradation of sarin and soman by unfunctionalized and functionalized cyclodextrins.

D. Ajami et al., Org. Biomol. Chem. 2013, 11, 3936-3942 , sensors for chemical warfare agents and resorcinarenes derived cavitands for the complexation of various model compounds, such as cyclosarine. The information is partly purely theoretical. No scavenger compounds are described which are capable of effectively degrading neurotoxic organic phosphorus compounds, especially persistent neurotoxic organic phosphorus compounds such as VX or VX-derived compounds.

The scavenger compounds described in the prior art are associated with disadvantages. Genetically engineered, protein-based biocavelators are expensive and generally have inadequate physiological stability and tolerability. Cyclodextrin-based scavenger compounds have a comparably low rate of degradation for most neurotoxic organic phosphorus compounds. Particularly persistent neurotoxic organic phosphorus compounds such as VX and VX-derived compounds can not be degraded with cyclodextrins or only at very low rates.

SUMMARY OF THE INVENTION

An object of the invention is to provide compounds which reduce neurotoxic organic phosphorus compounds, in particular chemical warfare agents from the group of G-substances and V-substances and especially from the group of V-substances, with high efficiency. These compounds should be particularly effective under physiological conditions and be effective for the treatment of patients with poisoning with neurotoxic organic phosphorus compounds, especially G-substances and V-substances and especially V-substances. In addition, these compounds should be used prophylactically before poisoning symptoms occur. Therapeutic use, on the other hand, is of particular importance in the case of poisoning by V substances in which the symptoms of poisoning are generally delayed, so that even after exposure to these substances the harmful effects of administration of such a compound can be prevented or at least reduced , The preparation of the compounds should be relatively simple and inexpensive.

Surprisingly, it has been found that calixarenes, in particular calix [4] arenes, which carry a linker bound nucleophilic group Nu, as defined below, neurotoxic organic phosphorus compounds, especially chemical warfare agents from the group of G and V substances and specifically Degrease V substances such as VX and VX-derived compounds at high speed. These compounds are therefore suitable both for prophylactic use in individuals who are at risk of exposure to neurotoxic organic phosphorus compounds, in particular chemical warfare agents from the group of G-substances and V-substances, as well as for a therapeutic use in individuals, which were exposed to the action of neurotoxic organic phosphorus compounds, in particular chemical warfare agents from the group of G-substances and especially from the group of V-substances.

Accordingly, an object of the invention is achieved by the compounds of general formula (I) and their salts, CAX (-R) _n (I) wherein
CAX stands for a calixarene residue,
n is 1, 2, 3, 4, 5 or 6,
R is a radical of the formula -XY (-Nu) _m , where each R is bonded to one cyclic repeat unit of the calixarene radical CAX,
wherein
X is a covalent bond, C ₁ -C ₄ alkanediyl, O, OC (OO), C (OO) -O, NH, NH-C (OO), C (OO) -NH, NH- C (= O) -NH, NH-C (= S) -NH, NH-C (= NH), AO, AOC (= O), AC (= O) -O, A-NH, A-NH- C (= O) or AC (= O) -NH in which A in the 6 last-mentioned groups is C ₁ -C ₄ -alkanediyl,
Y is a covalent bond, C ₁ -C ₄ alkanediyl, C ₂ -C ₄ alkylenediyl, a carbocyclic linker or a heterocyclic linker,
m is 1 or 2, wherein m is 1 when Y is C ₁ -C ₄ alkanediyl or C ₂ -C ₄ alkylenediyl, and
Nu is a nucleophilic group selected from a hydroxamic acid group, thiohydroxamic acid group, NC ₁ -C ₆ -alkylhydroxamic acid group, NC ₆ -C ₁₄ -aryl hydroxamic acid group, NC ₇ -C ₁₅ -aralkylhydroxamic acid group, NC ₁ -C ₇ -acylhydroxamic acid group, oxime group, Guanidine group, N-hydroxycarbamide group, N-hydroxycarbamate group and a 1-hydroxybenzotriazole group.

The compounds of the formula (I) and their salts are suitable, optionally in combination with further measures, for the treatment of patients treated with neurotoxic organic phosphorus compounds, in particular chemical warfare agents from the group of G substances and V substances and especially from the group V substances such as VX or VX-derived compounds are poisoned. Accordingly, another object of the invention is the use of compounds of formula (I) or their pharmaceutically acceptable salts for the therapeutic or prophylactic treatment of conditions caused by poisoning with neurotoxic organic phosphorus compounds, in particular chemical warfare agents from the group of G substances and V Substances and specifically from the group of V-substances such as VX or VX-derived compounds, are caused. Another object of the invention are pharmaceutical compositions containing at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

The compounds of formula (I) and their salts are also suitable for the decontamination of surfaces containing neurotoxic organic phosphorus compounds, in particular chemical warfare agents from the group of G-substances and V-substances and especially from the group of V-substances such as VX or VX-derived compounds are contaminated. Accordingly, another object of the invention is the use of compounds of formula (I) or their salts for the treatment of surfaces containing neurotoxic organic phosphorus compounds, in particular chemical warfare agents from the group of G-substances and V-substances and especially from the group of V substances such as VX or VX-derived compounds are contaminated.

DETAILED DESCRIPTION OF THE INVENTION

The neurotoxic organic phosphorus compounds referred to herein are preferably organic compounds derived from phosphonic acid and phosphoric acid, especially their organic esters. Preferred classes of compounds are organic phosphonic acid esters, thiophosphonic acid esters, phosphoric acid esters and thiophosphoric acid esters. In the thiophosphonic acid esters, the oxygen atom bonded twice to the central phosphorus atom of the phosphonic acid ester is replaced by a sulfur atom; in the thiophosphoric acid esters, the oxygen atom bonded twice to the central phosphorus atom of the phosphoric acid ester is replaced by a sulfur atom.

Examples of neurotoxic organic phosphorus compounds are neurotoxic phosphorus-containing pesticides, in particular those from the group of phosphoric acid esters and thiophosphoric acid esters, especially malathion, parathion and paraoxon, and chemical warfare agents from the group of G substances and V substances, in particular from the group of V substances , Examples of representatives from the group of G-substances are sarin, analogs of sarin, in particular cyclosarin and O- (C ₁ -C ₆ -alkyl) analogs of sarin, tabun, tabun analogues such as N- (di-C ₂ - C ₆ alkyl) tabun, soman and compounds derived from these substances, such as DFP and GV. V-materials are, for example VG, VX, VR and derived O- _(C1-C4 alkyl) -2-di (C ₁ -C ₄ alkyl) aminoethyl-C ₁ -C ₂ -alkylphosphonothiolate as VM, VS , VE, CVX and O-ethyl-S- [2-di-n-propylaminoethyl] methylphosphonothiolate (n-propyl-VX). The compounds of the invention have particular advantages in the poorly metabolizable neurotoxic organic phosphorus compounds from the group of V-substances, in particular in compounds from the group of O- (C ₁ -C ₄ alkyl) -2-di (C ₁ -C ₄ -alkyl) aminoethyl-C ₁ -C ₂ -alkylphosphonothiolates, especially VX and VR and compounds derived therefrom such as VM, VS, VE, CVX and n-propyl-VX.

The terms halogen, alkyl, haloalkyl, hydroxyalkyl, aryl, aralkyl, alkanediyl, alkenediyl, alkoxy, acyl, carbocyclic linker, heterocyclic linker and the like used in connection with the description of the invention, in particular the calixarene compounds of the formula (I), are generic terms Here is the prefix C _x -C _y - for the possible number of carbon atoms, which may have such a radical, ie the respective radical has at least x and at most y carbon atoms.

Halogen is fluorine, chlorine, bromine or iodine.

C ₁ -C ₆ -alkyl is a saturated aliphatic hydrocarbon radical having 1 to 6 carbon atoms, in particular 1 to 4 C-atoms (C ₁ -C ₄ -alkyl). Examples of C ₁ -C ₆ -alkyl are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl , 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 1.1 Dimethylbutyl, 2,2-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

C ₁ -C ₄ -haloalkyl is C ₁ -C ₄ -alkyl, as defined above, in which at least one hydrogen atom is replaced by halogen, in particular by F or Cl. Examples of C ₁ -C ₄ -haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2, 2-tetrafluoroethyl and pentafluoroethyl.

C ₆ -C ₁₄ -aryl represents an aromatic hydrocarbon radical having 6 to 14 carbon atoms. Examples of C ₆ -C ₁₄ -aryl are phenyl, naphthyl, fluorenyl, phenanthrenyl and anthracenyl.

C ₇ -C ₁₅ -Aralkyl represents a hydrocarbon radical having a total of 7 to 15 carbon atoms, which consists of an alkyl radical in which a hydrogen atom is replaced by a C ₆ -C ₁₄ aryl radical. Examples of C ₇ -C ₁₅ aralkyl are benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-methyl-1-phenylethyl, 1-naphthylmethyl and 2-naphthylmethyl.

C ₁ -C ₄ alkanediyl represents a saturated aliphatic hydrocarbon radical having 1 to 4 carbon atoms, which is bonded to two further radicals. Examples of C ₁ -C ₄ -alkanediyl are methylene, ethane-1,2-diyl, propane-1,2-diyl, propane-1,3-diyl, butane-1,2-diyl, butane-1,3- diyl and butane-1,4-diyl.

C ₂ -C ₄ -alkenediyl represents an unsaturated aliphatic hydrocarbon radical having 2 to 4 carbon atoms, which is bonded to two further radicals. Examples of C ₂ -C ₄ alkylenedi are ethylene, prop-1-ene-1,2-diyl and prop-1-ene-1,3-diyl.

C ₁ -C ₄ alkoxy represents a saturated aliphatic hydrocarbon radical which is bonded to an oxygen atom and has 1 to 4 carbon atoms. Examples of C ₁ -C ₄ -alkoxy are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and tert-butoxy.

Hydroxy-C ₁ -C ₄ alkoxy represents alkoxy having 1 to 4 carbon atoms, which has 1 hydroxyl group as a substituent. Examples of hydroxy-C ₁ -C ₄ -alkoxy are hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-hydroxy-2-methylethoxy, 4-hydroxybutoxy and 2-hydroxybutoxy.

C ₁ -C ₇ -Acyl represents a radical of the formula R ^Ac -C (= O) -, in which R ^{Ac represents} hydrogen or an aliphatic or aromatic hydrocarbon radical having 1 to 6 carbon atoms, which is bonded via a carbonyl group. Examples of C ₁ -C ₇ acyl are formyl, acetyl, propionyl, butyryl and benzoyl.

The term "carbocyclic", in particular in connection with "carbocyclic linker" denotes cyclic radicals having as ring atoms exclusively carbon atoms. Carbocyclic radicals are generally 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic radicals or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic radicals. The carbocyclic radicals can be saturated, partially unsaturated or aromatic and can be unsubstituted or have as substituents one or two radicals R ^cyc which are halogen, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, = O and = S are selected, unless stated otherwise.

The term "heterocyclic", in particular in connection with "heterocyclic linker" denotes cyclic radicals which, as ring atoms, in addition to one or more carbon atoms, at least one heteroatom, for. B. 1, 2, 3 or 4 heteroatoms, which is preferably selected from O, S and N. Heterocyclic radicals are generally 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic radicals or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic radicals. The heterocyclic radicals may be saturated, partially unsaturated or aromatic and may be unsubstituted or have as substituents one or two radicals R ^cyc which are halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ -haloalkyl, = O and = S are selected, unless stated otherwise.

The compounds of the general formula (I) and their salts have at least one radical R, where each radical R is bonded to one cyclic repeat unit each of the calixarene radical CAX.

The calixarene CAX consists of cyclic repeat units, which together form the calixarene CAX. Each cyclic repeating unit typically has a benzene ring bearing a group Q. If a radical R is present in the respective cyclic repeat unit, this is preferably located on the benzene ring in the 4 position to the group Q. Each cyclic repeat unit has preferably on the benzene ring in the 2-position to the group Q a bridging group, eg. B. a group CR ^A R ^B , wherein R ^A and R ^{B are} independently H or C ₁ -C ₄ alkyl, in particular a methylene group (-CH ₂ -), via which the bond to an adjacent cyclic repeat unit , preferably at the 6-position to the group Q in the adjacent cyclic repeat unit. In the calixarene residue CAX the linkage of a cyclic repeat unit with the two adjacent cyclic repeat units therefore preferably via methylene groups in the 2- and 6-position to the group Q.

The group Q is preferably an OH group or a group obtainable by reaction with an OH group, in particular an ether group, or a hydrogen atom. Particularly preferably, the group Q is selected from C ₁ -C ₄ -alkoxy, hydroxy-C ₁ -C ₄ -acoxy, a radical of the formula [O-Alk] _q -OH, where Alk is C ₂ -C ₄ -alkoxy 1,2-diyl, especially 1,2-ethanediyl, and q is 2 to 50, especially 2 to 20, and a hydrogen atom.

worin
R für einen Rest der Formel -X-Y(-Nu)_m, sofern in der Wiederholungseinheit vorhanden, steht, und X, Y, Nu und m die für die Verbindungen der Formel (I) und deren Salze genannten Bedeutungen aufweisen,
Q für H, OH, C₁-C₄-Alkoxy, Hydroxy-C₁-C₄-alkoxy oder einen Rest der Formel [O-Alk]_q-OH steht, worin Alk für C₂-C₄-Alkan-1,2-diyl, insbesondere für 1,2-Ethandiyl, steht und q für 2 bis 50, insbesondere 2 bis 20, steht und
t für 4, 5, oder 6, insbesondere für 4, steht.Preferred cyclic repeat units of the calixarene residue CAX correspond to the formula (W)

wherein
R is a radical of the formula -XY (-Nu) _m , if present in the repeating unit, and X, Y, Nu and m have the meanings given for the compounds of the formula (I) and their salts,
Q is H, OH, C ₁ -C ₄ -alkoxy, hydroxy-C ₁ -C ₄ -alkoxy or a radical of the formula [O-Alk] _q -OH, where Alk is C ₂ -C ₄ -alkane-1 , 2-diyl, in particular 1,2-ethanediyl, and q is 2 to 50, in particular 2 to 20, and
t is 4, 5, or 6, especially 4.

The compounds of formula (I) and their salts are preferably calixarenes selected from calix [4] arenes, calix [5] arenes and calix [6] arenes. In particular, the compounds of formula (I) and their salts are calix [4] arenes. Accordingly, the calixarene radical CAX in the compounds of the formula (I) and salts thereof preferably has 4, 5 or 6 and in particular 4 cyclic repeat units.

In the compounds of the formula (I) and salts thereof, n is 1, 2, 3, 4, 5 or 6. Accordingly, the calixarene CAX in the compounds of the formula (I) and their salts 1, 2, 3, 4, 5 or 6 radicals R on. In the compounds of the formula (I) and their salts, n is preferably 1 or 2, in particular 1. Accordingly, the compounds of the formula (I) and salts thereof preferably contain 1 or 2 radicals R and in particular 1 radical R. The radical (s) R are preferably bonded to cyclic repeat units of the calixarene radical CAX. If the compounds of the formula (I) have more than one radical R, these are preferably each bonded to different cyclic repeat units of the calixarene radical CAX.

In the compounds of formula (I) and their salts R is a radical of the formula -XY (-Nu) _m . The rest of the formula -XY (-Nu) _m has at least one nucleophilic group Nu, which is linked via a linker -XY- to the calixarene CAX.

The radical -XY (-Nu) _m is bound in the compounds of the formula (I) and their salts via X to the calixarene CAX. In the radical of the formula -XY (-Nu) _m , X is a covalent bond, C ₁ -C ₄ alkanediyl, O, OC (OO), C (OO) -O, NH, NH-C (= O), C (= O) -NH, NH-C (= O) -NH, NH-C (= S) -NH, NH-C (= NH), AO, AOC (= O), AC (= O) -O, A-NH, A-NH-C (= O) or AC (= O) -NH, where A in the 6 last-mentioned groups is C ₁ -C ₄ -alkanediyl, in particular CH ₂ , CHCH ₃ or CH ₂ CH ₂ and especially CH ₂ or CH ₂ CH ₂ . X is preferably NH, NH-C (OO), A-NH or A-NH-C (OO), where A in the last two groups is C ₁ -C ₄ -alkanediyl, in particular CH ₂ , CHCH ₃ or CH ₂ CH ₂ and especially CH ₂ or CH ₂ CH ₂ , and in particular NH or NH-C (= O). Specifically, X is NH-C (= O).

The nucleophilic group Nu is linked to the linker -XY- in the radical of the formula -XY (-Nu) _m via Y. In the radical of the formula -XY (-Nu) _m , Y is a covalent bond, C ₁ -C ₄ -alkanediyl, C ₂ -C ₄ -alkendiyl, a carbocyclic linker or a heterocyclic linker. The carbocyclic linkers and the heterocyclic linkers preferably have 4, 5 or 6 ring atoms. They may be saturated and are preferably unsaturated or aromatic. Heterocyclic linkers have as ring atoms usually in addition to at least one carbon atoms at least 1 heteroatom from the group N, O and S, z. B. 1, 2 or 3 N atoms or 1 O atom and 0, 1 or 2 N atoms or 1 S atom and 0, 1 or 2 N atoms. The carbocyclic linker and the heterocyclic linker may be unsubstituted or have as substituents one or two radicals R ^cyc . Examples of carbocyclic linkers are 1,2-phenylene, 1,3-phenylene, 1,4-phenylene and cyclobut-3-ene-1,2-dione-3,4-diyl. Examples of heterocyclic linkers are, in particular, nitrogen-containing heterocyclic linkers, such as pyridine-2,4-diyl, pyridine-2,6-diyl, pyridine-2,5-diyl, pyridine-3,5-diyl, pyridinium-1,3-diyl, Pyridinium-1,2-diyl, pyridinium-1,4-diyl, pyrrole-2,5-diyl, 1,2,3-triazole-1,4-diyl, 1,2,3-triazole-1,5- diyl, 1,2,4-triazole-1,3-diyl, 1,2,3-triazole-1,4-diylmethyl, 1,2,3-triazole-1,5-diylmethyl, 1,2,4- Triazole-1,3-diylmethyl, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl, pyrimidine-4,6-diyl, s-triazine-2,4-diyl and s-triazine-2,4, 6-triyl.

In preferred groups of embodiments Y is ethene-1,2-diyl, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, pyridine-2,4-diyl, pyridine-2,6-diyl, Pyridine-2,5-diyl, pyridine-3,5-diyl, pyridinium-1,3-diyl, pyridinium-1,2-diyl, pyridinium-1,4-diyl, pyrrole-2,5-diyl, 1, 2,3-triazole-1,4-diyl, 1,2,3-triazole-1,5-diyl, 1,2,4-triazole-1,3-diyl, 1,2,3-triazole-1, 4-diylmethyl, 1,2,3-triazole-1,5-diylmethyl, 1,2,4-triazole-1,3-diylmethyl, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl, pyrimidine 4,6-diyl, s-triazine-2,4-diyl, s-triazine-2,4,6-triyl or cyclobut-3-ene-1,2-dione-3,4-diyl. Y is particularly preferably 1,3-phenylene, 1,4-phenylene or pyridine-2,6-diyl.

In the event that both X and Y in the same radical R are each a covalent bond, the nucleophilic group Nu is bound directly to the calixarene CAX without a linker.

Preferred linkers -XY- are those which result from combinations of the abovementioned meanings, in particular those mentioned as being preferred, of X and Y. Particularly preferred linkers -XY- are those of the following formulas (XY-1) to (XY-34):

Particularly preferably, the at least one nucleophilic group Nu in the radical of the formula -XY (-Nu) _{m is} attached to the calixarene radical CAX via a linker -XY- which is selected from the formulas (XY-1), (XY-6) , (XY-8), (XY-9), (XY-10), (XY-12), (XY-16), (XY-17), (XY-18), (XY-19), XY-21), (XY-27), (XY-28), (XY-29), (XY-30), (XY-32), (XY-33) and (XY-34). Very particularly preferred linkers -XY- are selected from the formulas (XY-10) and (XY-16).

According to the invention, the at least one nucleophilic group Nu in the radical of the formula -XY (-Nu) _{m is} selected from a hydroxamic acid group, thiohydroxamic acid group, NC ₁ -C ₆ -alkylhydroxamic acid group, NC ₆ -C ₁₄ -aryl hydroxamic acid group, NC ₇ -C ₁₅ -aralkylhydroxamic acid group , NC ₁ -C ₇ acyl hydroxamic acid group, oxime group, guanidine group, N-hydroxycarbamide group, N-hydroxycarbamate group and a 1-hydroxybenzotriazole group.

Accordingly, the at least one nucleophilic group Nu in the radical of the formula -XY (-Nu) _{m is} selected from nucleophilic groups which carry at least one hydroxyl group, in particular a nitrogen-bonded hydroxyl group, or an amino group.

In a preferred embodiment, the at least one nucleophilic group Nu in the radical of the formula -XY (-Nu) _{m is} selected from a hydroxamic acid group (C (= O) -NH-OH) and a thiohydroxamic acid group (C (= S) -NH- OH) which is bonded directly or via an oxygen atom (-O-), sulfur atom (-S-) or via an imino group (-NH-) to the linker -XY- and thus in the form of an N-hydroxycarbamide group (NH-C (= O) -NH-OH), N-hydroxythiocarbamide group (NH-C (= S) -NH-OH), N-hydroxycarbamate group (OC (= O) -NH-OH), N-hydroxythiocarbamate group (SC (= O ) -NH-OH), N-hydroxycarbamothioate group (OC (= S) -NH-OH) or N-hydroxydithiocarbamate group (SC (= S) -NH-OH).

In the hydroxamic acid group or thiohydroxamic acid group bonded directly or via O, S or NH to the -XY- linker, the nitrogen-bonded hydrogen atom may be replaced by a group which is especially selected from C ₁ -C ₆ -alkyl groups, especially methyl and ethyl, C ₆ -C ₁₄ aryl groups, especially phenyl and naphthyl, C ₇ -C ₁₅ aralkyl groups, especially benzyl, and C ₁ -C ₇ acyl groups, especially benzoyl.

The nucleophilic group Nu is furthermore preferably selected from an oxime group (CH = N-OH) and a 1-hydroxybenzotriazole group. Another preferred nucleophilic group Nu is the guanidine group (NH-C (= NH) -NH ₂ ).

More preferably, the at least one nucleophilic group Nu in the radical of the formula -XY (-Nu) _{m is} selected from a hydroxamic acid group, N-hydroxycarbamate group, N-hydroxycarbamide group, oxime group, guanidine group and a 1-hydroxybenzotriazole group.

Most preferably, the at least one nucleophilic group Nu in the radical of the formula -XY (-Nu) _{m is} selected from a hydroxamic acid group, N-hydroxycarbamate group, N-hydroxycarbamide group, oxime group and a guanidine group. Specifically, the at least one nucleophilic group Nu is a hydroxamic acid group.

In the radical R of the formula -XY (-Nu) _m , m is 1 or 2. Accordingly, each R has one or two nucleophilic groups Nu, where m is always 1, if Y is C ₁ -C ₄ -alkanediyl and C ₂ -C ₄ alkylenediyl. In a preferred embodiment, m is 1.

Preferred radicals R of the formula -XY (-Nu) _m are those in which the linker -XY- represents the groups of the formulas (XY-1), (XY-6), (XY-8), (XY-9) , (XY-10), (XY-12), (XY-16), (XY-17), (XY-18), (XY-19), (XY-21), (XY-27), XY-28), (XY-29), (XY-30), (XY-32), (XY-33) or (XY-34) and the at least one nucleophilic group Nu is selected from a hydroxamic acid group, thiohydroxamic acid group, NC ₁ -C ₆ alkyl hydroxamic acid group, NC ₆ -C ₁₄ aryl hydroxamic acid group, NC ₇ -C ₁₅ aralkyl hydroxamic acid group, NC ₁ -C ₇ acyl hydroxamic acid group, oxime group, guanidine group, N-hydroxycarbamide group, N-hydroxycarbamate group and a 1-hydroxybenzotriazole group, especially a hydroxamic acid group, N-hydroxycarbamate group, N-hydroxycarbamide group, oxime group and a guanidine group.

Particularly preferred radicals R of the formula -XY (-Nu) _m are selected from the radicals of the following formulas (R-1) to (R-44), where the radical R ^A in formula (R-44) is selected from C ₁ C ₆ alkyl, C ₆ -C ₁₄ aryl and C ₇ -C ₁₅ aralkyl, in particular C ₁ -C ₄ alkyl, phenyl and benzyl.

Particularly preferred radicals R of the formula -XY (-Nu) _m are selected from among the radicals of the formulas (R-1), (R-7), (R-14), (R-15), (R-16), (R-18), (R-22), (R-23), (R-24), (R-25), (R-27), (R-34), (R-39), (R -40), (R-41), (R-42) and (R-44) and especially among the radicals (R-16), (R-22), (R-23), (R-25), (R-34) and (R-40). More particularly, the radicals R are selected from the radicals of the formulas (R-16) and (R-22).

Preferred compounds of the formula (I) and salts thereof carry a sulfonic acid group (SO ₃ H) in at least one cyclic repeat unit in the calixarene radical CAX. In a special embodiment the calixarene radical CAX carries a sulfonic acid group in each cyclic repeat unit which carries no radical R. Preferably, the sulfonic acid group is in the cyclic repeating unit in the 4 position to the group Q on the benzene ring.

Very particularly preferred compounds of the formula (I) and salts thereof are those in which the calixarene radical CAX is built up from 4, 5 or 6, in particular 4, cyclic repeating units and in each case 1 or 2, in particular 1, cyclic repeating units , in particular one of the groups (R-1) to (R-44), and carry in each of the other cyclic repeat units which have no radical R, each having a sulfonic acid group. In a specific embodiment, the compounds of the formula (I) and their salts are selected from those which are composed of 4 cyclic repeat units and carry 1 group R and 3 sulfonic acid groups or carry 2 groups R and 2 sulfonic acid groups, which are composed of 5 cyclic repeat units and 1 group R and 4 carry sulfonic acid groups or carry 2 groups R and 3 sulfonic acid groups or which are composed of 6 cyclic repeating units and carry 1 group R and 5 sulfonic acid groups or carry 2 groups R and 4 sulfonic acid groups. In a very specific embodiment, the compounds of the formula (I) and their salts are selected from those which are composed of 4 cyclic repeat units and carry 1 group R and 3 sulfonic acid groups or carry 2 groups R and 2 sulfonic acid groups.

In a preferred group of embodiments of the compounds of the formula (I) according to the invention, at least one of the radicals R is arranged in one of those positions which form the further rim (upper rim) of the calixarene. Further groups may then be located in upper rim positions or in the lower rim of the calixarene. However, according to the invention are also those compounds of formula (I) which have exclusively R radicals which are arranged in positions of the Lower rim.

worin
R' gleich oder verschieden sind und für SO₃H oder einen Rest R stehen, mit der Maßgabe, dass wenigstens einer der Reste R' für einen Rest R, vorzugsweise für einen der als bevorzugt genannten Reste R, insbesondere für einen der hierin genannten Reste (R-1) bis (R-44), ganz besonders für (R-1), (R-7), (R-14), (R-15), (R-16), (R-18), (R-22), (R-23), (R-24), (R-25), (R-27), (R-34), (R-39), (R-40), (R-41), (R-42) oder (R-44), speziell für einen der Reste (R-16), (R-22), (R-23), (R-25), (R-34) oder (R-40) und ganz speziell für einen der Reste (R-16) oder (R-22) steht, und wenigstens einer der Reste R' für SO₃H steht;
k für 1, 2 oder 3, insbesondere für 1 oder 2 und speziell für 1, steht; und
Q für eine OH-Gruppe oder eine Gruppe, die durch Umsetzung mit einer OH-Gruppe erhältlich ist, insbesondere ein Etherrest, oder ein Wasserstoffatom und speziell für H, OH, C₁-C₄-Alkoxy, Hydroxy-C₁-C₄-alkoxy oder einen Rest der Formel [O-Alk]_q-OH steht, worin Alk für C₂-C₄-Alkan-1,2-diyl, insbesondere für 1,2-Ethandiyl, und q für 2 bis 50, insbesondere für 2 bis 20 steht, und wobei Q ganz speziell für OH steht.In a specific embodiment, the compounds of the formula (I) and salts thereof are selected from the compounds of the formula (Ia) and salts thereof

wherein
R 'are identical or different and are SO ₃ H or a radical R, with the proviso that at least one of the radicals R' is a radical R, preferably one of the radicals R mentioned as being preferred, in particular one of the radicals mentioned herein (R-1) to (R-44), especially for (R-1), (R-7), (R-14), (R-15), (R-16), (R-18) , (R-22), (R-23), (R-24), (R-25), (R-27), (R-34), (R-39), (R-40), ( R-41), (R-42) or (R-44), especially for one of the radicals (R-16), (R-22), (R-23), (R-25), (R-34 ) or (R-40) and especially for one of the radicals (R-16) or (R-22), and at least one of the radicals R 'is SO ₃ H;
k is 1, 2 or 3, in particular 1 or 2 and especially 1; and
Q is an OH group or a group obtainable by reaction with an OH group, in particular an ether radical, or a hydrogen atom and especially for H, OH, C ₁ -C ₄ -alkoxy, hydroxy-C ₁ -C ₄ alkoxy or a radical of the formula [O-Alk] _q -OH, where Alk is C ₂ -C ₄ -alkan-1,2-diyl, in particular 1,2-ethanediyl, and q is 2 to 50, in particular stands for 2 to 20, and where Q is especially OH.

One group of embodiments relates to compounds of formula (Ia) and their salts in which k is 2. These compounds preferably have 1 or 2 groups R, in particular 1 group R, and 3 or 4 sulfonic acid groups, especially 4 sulfonic acid groups, where the group (n) R is, in particular, among the groups mentioned as being preferred for the compounds of the formula (Ia) ( R-1) to (R-44) are selected.

A particularly preferred group of embodiments relates to compounds of the formula (Ia) and their salts in which k is 1. These compounds preferably have 1 or 2 groups R, in particular 1 group R, and 2 or 3 sulfonic acid groups, in particular 3 sulfonic acid groups, where the group (n) R is in particular among the groups mentioned as being preferred for the compounds of the formula (Ia) ( R-1) to (R-44) are selected.

worin
R'' für einen Rest R, insbesondere für einen der Reste (R-1) bis (R-44), ganz besonders für einen der Reste (R-1), (R-7), (R-14), (R-15), (R-16), (R-18), (R-22), (R-23), (R-24), (R-25), (R-27), (R-34), (R-39), (R-40), (R-41), (R-42) oder (R-44), speziell für einen der Reste (R-16), (R-22), (R-23), (R-25), (R-34) oder (R-40) und ganz speziell für einen der Reste (R-16) oder (R-22) steht.In a specific group of embodiments, the compounds of formula (I) and their salts are selected from the compounds of formula (Ia.1) and their salts

wherein
R '' is a radical R, in particular one of the radicals (R-1) to (R-44), very particularly one of the radicals (R-1), (R-7), (R-14), ( R-15), (R-16), (R-18), (R-22), (R-23), (R-24), (R-25), (R-27), (R- 34), (R-39), (R-40), (R-41), (R-42) or (R-44), especially for one of the radicals (R-16), (R-22), (R-23), (R-25), (R-34) or (R-40) and especially for one of the radicals (R-16) or (R-22).

The salts of the compounds of the formulas (I), (Ia) and (Ia.1) are obtainable in particular by reacting the compounds of the formulas (I), (Ia) and (Ia.1) with acids and bases. Preferred acids are organic and inorganic acids, in particular Brønsted acids, preferred bases are organic and inorganic bases, in particular Brønstedbasen.

In a preferred embodiment, the salts of the compounds of the formulas (I), (Ia) and (Ia.1) are pharmaceutically acceptable salts. Acids and bases which are suitable for the preparation of pharmaceutically acceptable salts are found, for example, in "Advances in Drug Research", 1966, Birkhäuser Verlag, vol. 10, pages 224-285 , Examples of preferred inorganic acids are hydrochloric, hydrobromic, phosphoric, nitric and sulfuric acids. Examples of preferred organic acids are methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, maleic, succinic, acetic, formic, fumaric, mandelic, lactic, tartaric and citric acids. Examples of preferred inorganic bases are alkali hydroxides and alkaline earth hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and magnesium hydroxide, zinc hydroxide, carbonates such as sodium carbonate and potassium carbonate and ammonia. Examples of preferred organic bases are organic amines such as diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine and dicyclohexylamine.

The preparation of the salts of the compounds of the formulas (I), (Ia) and (Ia.1) can be carried out by methods which are known in principle, for example by mixing a solution of the compound of the formula (I), (Ia) or (Ia. 1) with the appropriate acid or base. The preparation of the salts can also be carried out via ion exchangers.

The compounds of the formulas (I), (Ia) and (Ia.1) and salts thereof can also be present in the form of their tautomers. A tautomeric equilibrium may be present in particular in the radicals R of the compounds of the formulas (I), (Ia) and (Ia.1) and their salts, especially in all radicals R which have a hydroxamic acid group, thiohydroxamic acid group, oxime group or groups derived therefrom. For example, in the hydroxamic acid group (C (= O) -NH-OH) there is a tautomeric equilibrium with the hydroxyimine form (HO-C =N-OH). In the oxime group (CH = N-OH), especially under acidic conditions, there is a tautomeric equilibrium with the nitroso compound (CH ₂ -N = O).

The compounds of the formulas (I), (Ia) and (Ia.1) and salts thereof can be prepared starting from known calixarene compounds in principle by applying standard methods of organic synthesis, as described, for example, in MB Smith, March's Advanced Organic Chemistry, 7th Edition, Wiley 2013 ; J. Fuhrhop, G. Penzlin, Organic Synthesis, 2nd edition, VCH Verlagsgesellschaft 1994 ; C. Ferry, Reactions of Organic Synthesis, Georg Thieme Verlag, Stuttgart 1978 ; L. Kürti, B. Czako, Strategic Applications of Named Reactions in Organic Syntheses, Elsevier Academic Press 2005 , and in the primary literature quoted there. Suitable synthesis strategies are related to calixarenes CD Gutsche, Calixarenes Revisited, RSC 1998 and the primary literature cited therein.

In general, in a step a), a calixarene (II) will be provided which has one or more groups R ^R which have the desired reactivity or can be converted in situ into a reactive group. This calixarene is then reacted in step b) with a coupling partner (III) which carries the nucleophilic group Nu, optionally in protected form, and which in turn has a reactive group R ^RC which is complementary to the reactive group contained in the calixarene and reacting to form a covalent bond to obtain the object compound of the formula (I), (Ia) or (Ia.1) or a salt thereof. The process is illustrated in the following Scheme 1. Scheme 1:

Here, CAX, n, m, X, Y and Nu have the meanings given above. R ^R represents a reactive group or group from which a reactive group can be generated in-situ. R ^RC represents a reactive group which reacts with R ^R to form bonds and form the group X. Nu 'represents a nucleophilic radical Nu, as defined above, or a protected radical Nu, e.g. For a tetrahydropyran-2-yl (THP) protected hydroxamic acid residue C (= O) -NH-O-THP or THP-protected oxime residue C = NO-THP.

Examples of reactive groups R ^R are halogens, in particular Cl, Br, I, pseudohalogens, in particular the azide groups and the diazonium group, and also amino groups, in particular NH ₂ . Suitable reactive groups R ^R are also carboxylic acid groups and activated carboxylic acid groups, eg. B. Reactive ester, and isocyanate. Suitable reactive groups R ^R are also boronic acid groups of the formula -B (OR ^x ) ₂ , in which R ^{x is} H or C ₁ -C ₄ -alkyl or together are optionally alkyl-substituted ethane-1,2-diyl. Particularly preferably, the group R ^R is NH ₂ . If R ^{R is} halogen, z. As Cl, Br or I, this can in situ in a metal atom z. As Li or Mg can be converted.

The type of complementary reactive group R ^RC depends in a manner known per se on the nature of the reactive group R ^R. For example, when R ^{R is} NH ₂ , then R ^{RC is,} for example, a carboxylic acid group, an activated carboxylic acid group, e.g. B. Reactive ester (eg., A pentafluorophenoxyester or a 1-Oxybenzotriazolester), an imidzolid or a carbonyl chloride, isocyanate, an oxirane group or halogen or another, nucleophilically displaceable group, eg. As alkyl sulfonate or aryl sulfonate. If the group R ^R z. B. for halogen, R ^{RC is,} for example, a hydroxyl group, a boronic acid group -B (OR ^x ) ₂ , vinyl, ethynyl, NH ₂ or an organometallic radical. R ^{R is} , for example, a boronic acid group of the formula -B (OR ^x ) ₂ , For example, R ^RC is halogen. The required for the clutch Reaction conditions are well known to the skilled person, z. B. from the aforementioned literature on organic synthesis.

For example, to provide the calixarene in step a) one can start with a calixarene whose cyclic repeating units in the 1-positions forming the lower rim of calixaren carry OH groups and in the 4-positions which carry the calixarene form a further edge (upper rim) of the calixarene, carry alkyl groups, in particular tert-butyl groups. Preference is given to a 4-tert-Butylcalix [n] arene in which n is 4, 5 or 6, in particular of 4-tert-Butylcalix [4] arene, which is commercially available, from. Suitable starting calixarenes are also known from the literature, for. B. off CD Gutsche, Calixarenes Revisited, RSC (1989), The Royal Society of Chemistry, Cambridge , and the primary literature cited therein.

However, the calixarenes used as starting material can also be prepared by standard methods of calixarene synthesis, generally by acid- or base-catalyzed reaction of an optionally substituted phenol with formaldehyde. Thus, for example, 4-tert-butylcalix [4] arene can be prepared by acid-catalyzed condensation of 4-tert-butylphenol with formaldehyde (see CD Gutsche, Calixarenes Revisited, Ioc. Cit., And primary literature cited therein). In subsequent reaction steps, one or more reactive groups R ^{R are introduced} into the calixarene, optionally using a protecting group strategy for the OH groups of the calixarene. Via this one or more reactive groups, the linkage with the nucleophilic group Nu comprising coupling partners takes place in step b), wherein the nucleophilic group can be present in free form or in protected form.

The introduction of the reactive groups into the calixarene can be carried out in principle by standard methods of organic synthesis. Halogens can be introduced by aromatic halogenation reaction according to standard procedures. Amino groups may be obtained by aromatic nitration followed by reduction of the nitro group, e.g. B. with inorganic reducing agents such as tin (II) chloride, are introduced. Diazonium groups are obtainable by diazotization of the amino groups by standard methods. Azide groups can be introduced, for example, by halogen-azide exchange reaction with sodium azide, optionally with transition metal catalysis, by diazo-transfer reactions from amines, or by reaction of diazonium compounds with an azide compound such as sodium azide or trimethylsilyl azide. The introduction of isocyanate groups is possible, for example, starting from calixarenes which have a primary amino group. Methods for this are known to the expert z. B. off MB Smith, March's Advanced Organic Chemistry, 7th Edition, Wiley 2013 ; J. Fuhrhop, G. Penzlin, Organic Synthesis, 2nd edition, VCH Verlagsgesellschaft 1994 ; C. Ferry, Reactions of Organic Synthesis, Georg Thieme Verlag, Stuttgart 1978 ; L. Kürti, B. Czako, Strategic Applications of Named Reactions in Organic Syntheses, Elsevier Academic Press 2005 , and the primary literature quoted there.

In a special synthesis, the preparation of the calixarene coupling partner (II) is carried out in step a) starting from a 4-tert-butylcalix [n] arene in which n is 4, 5 or 6, in particular starting from the commercially available compound. tert-butylcalix [4] arene. First, the tert-butyl groups in 4-tert-butylcalix [n] arene, in particular in 4-tert-butylcalix [4] arene, cleaved, then partially protected the OH groups, then introduced a nitro group, then the OH Deprotected groups, then introduced sulfonic acid groups and finally reduced the nitro group to the amino group. Such a process is outlined in the following Scheme 2 using the example of a starting compound for the compound (Ia.1):

Here, initially 4-tert-butylcalix [4] arene (C-1), such as in B. Mokhtari, K. Pourabdollah, Bull. Korean Chem. Soc. 2011, 32, 3979-3990 described, reacted with phenol and aluminum chloride to calixarene (C-2). In the next step, the calixarene (C-2) is partially protected with benzoyl chloride to give the calixarene (C-3) (Bz is benzoyl). The implementation can, for example, according to the M.-D. Lee, K.-M. Yang, C.-Y. Tsoo, C.-M. Shu, L.-G. Lin, Tetrahedron 2001, 57, 8095-8099 described regulation. The calixarene (C-3) is nitrated in the subsequent step with nitric acid to introduce the nitro group in the 4-position to the free hydroxyl group to give the compound (C-4). The nitration can, for example, according to the rule of KC Nam, DS Kim, Bull. Korean Chem. Soc. 1994, 15, 284-286 be performed. Subsequently, the protected hydroxyl groups in (C-4) are deprotected by addition of sodium hydroxide to obtain the compound (C-5). The deprotection can be carried out, for example, according to the instructions of KC Nam, DS Kim, Bull. Korean Chem. Soc. 1994, 15, 284-286. Sulfonation of compound (C-5) with sulfuric acid leads to the trisulfonated calixarene (C-6). The sulfonation can be carried out according to the instructions of KD Daze, MCF Ma, F. Pineux, F. Hof, Org. Lett. 2012, 14, 1512-1515 be performed. The nitro group in (C-6) can then be reduced with tin (II) chloride to the desired calixarene coupling partner with amino group (C-7). The reduction can z. B. after the of Mokhtari, K. Pourabdollah, Bull. Korean Chem. Soc. 2011, 32, 3979-3990 described regulation.

The coupling partners used in step b), which comprise the optionally protected nucleophilic group Nu and the complementary reactive group R ^RC , are known or can be prepared by standard methods of organic synthesis, optionally with the use of a protective group strategy.

For hydroxamic acid-containing or thiohydroxamic acid-containing coupling partners, for example, one can assume a compound in which two masked carboxyl groups, eg. In the form of esters. In general, one will then release one of the two masked carboxyl groups, for. Example by saponification of one of the two ester functions, and the liberated carboxyl group with hydroxylamine, in which the hydroxyl group previously z. B. in the form of a Tetrahydropyranylethers was protected, couple to the amide. Subsequently, one can saponify the remaining ester function and reach via the released carboxyl group with coupling reagents, in particular those mentioned herein, known from peptide chemistry coupling reagents, the linkage with the amino-containing calixarene. By deprotection of the hydroxamic acid group function or thiohydroxamic acid group function in the end product, in particular the deprotection of the tetrahydropyranyl ether with trifluoroacetic acid, the desired nucleophilic hydroxamic acid group or thiohydroxamic acid group is then released.

For example, coupling partners having a carboxylic acid group can be prepared by the synthetic routes described in the following Schemes 3a to 3c. In Scheme 3a, R ^{L is} C ₁ -C ₄ alkyl and especially methyl or ethyl. Y has the meanings given above for formula (I) and is in particular a carbocyclic or heterocyclic linker, especially 1,3-phenylene, 1,4-phenylene or pyridine-2,6-diyl. Scheme 3a:

For example, coupling partners of formula (III) wherein R ^{RC is} a carboxyl group or an activated carboxyl group and Nu 'is a hydroxamic acid protected by a 2-tetrahydropyranyl group may be exemplified by reacting the dicarboxylic acid half ester (IV) with O-tetrahydropyran-2-ylhydroxylamine Use of a coupling agent, for example the commercially available coupling reagent O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) are produced. The half esters of the formula (IV) can be obtained by partial saponification of corresponding dicarboxylic acid esters with potassium hydroxide in analogy to the procedure of KG Hull, M. Visnick, W. Tautz, A. Sheffron, Tetrahedron 1997, 53, 12405-12414 getting produced. The subsequent saponification of the ester group C (OO) -OR ^L in the compound (V) provides the free carboxylic acid, which may optionally be converted into an activated carboxylic acid group before its reaction with the coupling partner (II). It will also be apparent to those skilled in the art that the ester group C (= O) -OR ^L in compound (V) can be converted to other reactive groups R ^RC by standard functional group conversion procedures.

For example, O-tetrahydropyran-2-ylhydroxylamine may be prepared from commercially available N-hydroxyphthalimide which is first reacted with dihydropyrane and p-toluenesulfonic acid to form the tetrahydropyranyl ether, e.g. B. after the in US 4,604,407 or after the of NI Martin, JJ Woodward, MA Marletta, Org. Lett. 2006, 8, 4035-4038 described regulation. The subsequent reaction of the tetrahydropyranyl ether with methylhydrazine gives O-tetrahydropyran-2-ylhydroxylamine.

The preparation of coupling partners (III) which have a heterocyclic pyridinium linker and a protected nucleophilic group Nu * and which carry as reactive group a carboxyl group bonded via a group A can be prepared by the method outlined in Scheme 3b. In Scheme 3b, R ^{L is} C ₁ -C ₄ alkyl and especially methyl or ethyl. A is C ₁ -C ₄ alkanediyl, in particular CH ₂ , CHCH ₃ or CH ₂ CH ₂ and especially CH ₂ or CH ₂ CH ₂ . Hal is Br or I. Scheme 3b:

Here, first, a pyridine compound (VI), the protected nucleophilic group Nu *, z. B. carries a THP-protected hydroxamic acid residue or a THP-protected oxime radical, reacted with a halocarboxylic acid ester of the formula (VII), to obtain the pyridinium compound (VIII). The saponification of the ester group C (= O) -OR ^{L is} then carried out to obtain the free carboxylic acid, which may optionally be converted into an activated carboxylic acid group before its reaction with the calixarene coupling partner (II). The deprotection of Nu * may be carried out before, during or after coupling with the calixarene derivative (II).

The preparation of coupling partners (III), which have a 1,2,3-triazole linker and a protected nucleophilic group Nu * and carry as a reactive group bound via a group A carboxyl group can be prepared by the method outlined in Scheme 3c become. In Scheme 3c, R ^{L is} C ₁ - C ₄ alkyl and in particular methyl or ethyl. A is C ₁ -C ₄ alkanediyl, in particular CH ₂ , CHCH ₃ or CH ₂ CH ₂ and especially CH ₂ or CH ₂ CH ₂ . Nu * is in particular C (= O) NH-O-THP. Scheme 3c:

In this case, first an acetylene compound, in particular a THP-protected N-hydroxypropiolamide (or a homologous hydroxamic acid derivative having terminal triple bond), with a ω-Azidocarbonsäureester of formula (X) to form the disubstituted 1,2,3-triazole compound (XI) implemented. The reaction can be carried out in the presence of copper (I) catalysts to give the 1,4-disubstituted triazole (XI). Reaction of (IX) with (X) in the presence of ruthenium (II) catalysts yields the 1,5-disubstituted triazole derivative (see L. Zhang, X. Chen, P. Xue, HHY Sun, ID Williams, KB Sharpless, VV Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127, 15998-15999 ). The saponification of the ester group C (= O) -OR ^{L is} then carried out to obtain the free carboxylic acid, which may optionally be converted into an activated carboxylic acid group before its reaction with the calixarene coupling partner (II). The deprotection of Nu * may be carried out before, during or after coupling with the calixarene derivative (II).

The reaction of both reactants (II) and (III) in step b) can be carried out by methods known in principle, as are known, for example, from peptide chemistry and transition metal-complex-catalyzed coupling reactions. Thus one can carry out the reaction of an amino-functionalized calixarene with a carboxy-functionalized coupling partner using customary coupling reagents known from peptide chemistry, for example with carbodiimides such as dicyclohexylcarbodiimide (DCC), N, N-diisopropylcarbodiimide (DIC), 3-ethyl-1- (N, N-dimethyl) aminopropylcarbodiimide (EDCI) and the like, uronium salts such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), O- (benzotriazol-1-yl) - N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), O- (6-chlorobenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HCTU) and the like, or halophosphonium salts such as chlorotripyrrolidine phosphonium hexafluorophosphate (PyCloP) , Bromotripyrrolidine phosphonium hexafluorophosphate (PyBroP) and the like, especially with chlorotripyrrolidine phosphonium hexafluorophosphate (PyCloP). The reaction of halogenated calixarenes with vinyl- or ethynyl-functionalized coupling partners or boronic acid coupling partners can be carried out, for example, under the conditions of a Heck reaction, Sonogashira coupling or Suzuki coupling. In a corresponding manner, the reaction of calixarenes having a boronic acid group with halogen-functionalized coupling partners succeeds.

For example, the calixarene (C-7) can be linked via the reactive amino group in step b) with the coupling partner having at least one nucleophilic group Nu, optionally in protected form, and a carboxyl group or an activated carboxyl group via an amide bond, for example Use of the coupling reagents known in peptide chemistry, such as DCC, DIC, EDCI, HATU, TBTU, HCTU, PyCloP or PyBroP.

The compounds of the formula (I) and their salts according to the invention are suitable for use as medicaments.

Another object of the invention therefore relates to pharmaceutical compositions containing at least one compound of formulas (I), (Ia) or (Ia.1) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. Preferred compounds of the formulas (I), (Ia) or (Ia.1) which are contained in the pharmaceutical composition are the abovementioned preferred compounds of the formulas (I), (Ia) and (Ia.1) which are those mentioned above as being preferred Have residues.

Preferred pharmaceutically acceptable salts for the pharmaceutical compositions are the pharmaceutically acceptable salts mentioned above for the compounds of the formulas (I), (Ia) and (Ia.1).

The pharmaceutical carriers contained in the pharmaceutical compositions are selected according to the pharmaceutical form of the composition and the desired mode of administration.

The pharmaceutical compositions of the present invention can be administered, for example, subcutaneously, intramuscularly, intravenously, orally, sublingually, topically, intratracheally, intranasally, rectally or transdermally. Thus, it is possible, the compounds of formulas (I), (Ia) or (Ia.1) or their pharmaceutically acceptable salts to humans or animals as such or in unit dosage forms, formulated with conventional pharmaceutical carriers, for the therapeutic or prophylactic treatment of conditions to be administered by poisoning with a neurotoxic organic phosphorus compound, in particular a chemical warfare agent from the group of G-substances and V-substances. In particular, the compounds according to the invention of the formulas (I), (Ia) or (Ia.1) or their pharmaceutically acceptable salts are suitable for the therapeutic or prophylactic treatment of conditions which are caused by poisoning with a neurotoxic organic phosphorus compound selected from among chemical warfare agents tabun, N- (di-C ₂ -C ₆ -alkyl) tabun, soman, sarin, O- (C ₁ -C ₆ -alkyl) analogs of sarin, cyclosarin and O- (C ₁ -C ₄ -) Alkyl) -2-di (C ₁ -C ₄ alkyl) aminoethyl C ₁ -C ₂ alkyl phosphonothiolates, and more particularly VX, VR and compounds derived therefrom such as VM, VS, VE, CVX and n propyl-VX.

Suitable administration forms of the pharmaceutical compositions of the invention include forms for oral administration such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms for rectal administration, forms for topical administration Administration such as creams, ointments or lotions and forms for subcutaneous, intramuscular or intravenous administration.

In order to achieve the desired prophylactic or therapeutic effect, the dose of the compounds of the formula (I), (Ia) or (Ia.1) may preferably be varied between 0.01 and 50 mg per kg of body weight and day.

When a solid pharmaceutical composition is prepared in the form of tablets, the compound of formula (I), (Ia) or (Ia.1) or its pharmaceutically acceptable salt is formulated with at least one solid pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate , Talc, silicic acid or the like. The tablets may be coated with sucrose, a cellulose derivative or other suitable substance, or otherwise treated to exhibit sustained or delayed activity and to continuously release a predetermined amount of the basic active ingredient. A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a filler and taking up the resulting mixture with soft or hard gelatin capsules.

For the preparation of preparations in the form of a syrup or elixir or for administration in the form of drops, the active ingredient may be formulated together with a sweetening agent, methylparaben or propylparaben as antiseptics, a flavoring agent and a suitable coloring matter.

Water-dispersible powders or granules will typically comprise the active ingredient and at least one dispersant or wetting or suspending agent such as polyvinylpyrrolidone and optionally sweetening or masking flavors.

Aqueous suspensions or solutions of the active ingredient in sterile and injectable isotonic saline solutions are particularly suitable for parenteral administration. These usually contain in addition to the active ingredient at least one pharmaceutically acceptable dispersant and / or wetting agent, for example polypropylene glycol or polyethylene glycol, and an aqueous, isotonic phase.

The compounds of the invention may also be formulated in the form of microcapsules or liposomes, optionally with one or more carriers or additives.

In addition to the compounds of formulas (I), (Ia) and (Ia.1) or their pharmaceutically acceptable salts, the pharmaceutical compositions according to the invention may comprise other active substances which are also advantageous for the treatment of poisoning with neurotoxic organic phosphorus compound, in particular chemical warfare agents from the Group of G-substances and V-substances, can be.

Another object of the invention is the use of compounds of formulas (I), (Ia) or (Ia.1) or their pharmaceutically acceptable salts for the therapeutic or prophylactic treatment of conditions caused by poisoning with a neurotoxic organic phosphorus compound, in particular a chemical Warfare agent from the group of G-substances and V-substances, which is selected from the warfare agents tabun, N- (di-C ₂ -C ₆ -alkyl) tabun, Soman, sarin, O- (C ₁ -C ₆ -alkyl ) Analogs of sarin, cyclosarin and O- (C ₁ -C ₄ alkyl) -2-di (C ₁ -C ₄ alkyl) aminoethyl C ₁ -C ₂ alkylphosphonothiolates, and especially VX or VR.

Another object of the invention is the use of compounds of formulas (I), (Ia) or (Ia.1) or salts thereof for the treatment of surfaces containing a neurotoxic organic phosphorus compound, in particular a chemical warfare agent from the group of G-substances and V-substances contaminated. Particularly preferred is the use of compounds of the formulas (I), (Ia) or (Ia.1) or salts thereof for the treatment of surfaces which are tabun with the warfare agents Tabun, N- (di-C ₂ -C ₆ alkyl) , Soman, sarin, O- (C ₁ -C ₆ alkyl) analogs of sarin, cyclosarin or O- (C ₁ -C ₄ alkyl) -2-di (C ₁ -C ₄ alkyl) aminoethyl-C ₁ -C ₂ -alkylphosphonothiolaten, in particular VX or VR, are contaminated.

In general, the compounds of the formulas (I), (Ia) or (Ia.1) or salts thereof are dissolved before the treatment of the contaminated surfaces in a solvent or solvent mixture, in particular in an aqueous solvent mixture and especially in water. Depending on the nature of the substrate, the treatment can be carried out in a manner known per se by spraying, brushing, dipping or impregnating the substrate with the solution, in particular an aqueous solution of the compounds of the formulas (I), (Ia) or (Ia.1) or their salts or by flooding the substrate in the solution of the compounds of formulas (I), (Ia) or (Ia.1) or salts thereof.

The use concentration of the compounds of the formulas (I), (Ia) or (Ia.1) or salts thereof depends on the degree of contamination of the substrate and on the particular treatment method and is usually in the range from 0.05 mg to 10 g of active ingredient per kg substrate.

The following examples serve to further illustrate the invention.

EXAMPLES

1. Abbreviations

• AChE:

  acetylcholinesterase

  Asch:

  acetylcholine

  DTNB:

  5,5'-dithiobis (2-nitrobenzoic acid)

  DIPEA:

  diisopropylethylamine

  DMF:

  N, N-dimethylformamide

  EtOH:

  ethanol

  GF:

  O Cyclohexylmethylphosphonofluoridat

  GA:

  N, N-Dimethylethylphosphoramidcyanidat

  GB:

  O Isopropylmethylphosphonofluoridat

  GD:

  3,3-dimethyl-2-butylmethylphosphonofluoridat

  n. B .:

  not determined

  PyCloP:

  Chlortripyrrolidinophosphoniumhexafluorophosphat

  TBTU:

  O- (benzotriazol-1-yl) -N, N, N, N-tetramethyluronium tetrafluoroborate

  TNB ^- :

  5-thio-2-nitrobenzoate

  Tris:

  Tris (hydroxymethyl) aminomethane

  VX:

  O-ethyl-S-2-diisopropylaminoethylmethylphosphonothiolat

  VR:

  O-isobutyl-S-2-diethylaminoethylmethylphosphonothiolat

  CVX:

  O-n-butyl-S-2-diethylaminoethylmethylphosphonothiolat

  VE:

  O-ethyl-S-2-diethylaminoethylethylphosphonothiolat

  VG:

  O, O-diethyl-S- (2-diethylaminoethyl) thiophosphate

  i-propyl-VE:

  O-ethyl-S-2-diisopropylaminoethylethylphosphonothiolat

  n-propyl-VX:

  O-ethyl-S-2-di-n-propylaminoethylmethylphosphonothiolat

  VM:

  O-ethyl-S-2-diethylaminoethylmethylphosphonothiolat

2. Analytics

Nuclear resonance spectra ( ¹ H-NMR and ¹³ C-NMR): All spectra were recorded at 20 ° C on the FT-NMR devices DRX 200 and DRX 400 from Bruker. The chemical shifts of the signals are given in units of the δ-scale (ppm). The respective multiplicities are indicated by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal. The signals of the solvents used were used as an internal standard in the interpretation of the spectra (CDCl ₃ = 7.26 ( ¹ H-NMR), 77.2 ( ¹³ C-NMR); DMSO-d ₆ = 2.50 ( ¹ H-NMR), 39.5 ( ¹³ C-NMR); D ₂ O = 4.79 ( ¹ H-NMR); CD ₃ OD = 49.0 ( ¹³ C-NMR)).
Column chromatography: silica gel, 0.063-0.200 mm, Sigma-Aldrich.
Thin Layer Chromatography: Silica gel aluminum foils 60 F254, Merck.
CHNS Elemental Analyzer: vario micro cube, Elementar Analysensysteme GmbH in Hanau.
HPLC method: UltiMate 3000, Dionex with a BetaBasic-18 column (250 x 21.2 mm, 5 μm particle size), Thermo-Scientific, Flow: 12 mL / min; Eluent 0.1% by volume of trifluoroacetic acid in water (aqueous portion), acetonitrile (organic portion). Gradient program: 0-5 minutes, 15% organic content; 5-38 minutes, linear increase to 36% organic content; 38-40 minutes, linear increase to 70% organic content; 40-43 minutes, 70% organic content, 43-44 minutes, linear decrease to 15% organic content; 44-46 minutes, 15% organic content.
Infrared spectroscopy: FT-ATR-IR spectrometer Spectrum 100, Perkin Elmer.
Melting point determination: SPM-X 300, Müller.

• – MALDI-Massenspektrometrie: MALDI-TOF-Gerät Daltonics Ultraflex, Bruker mit 2,5-Dihydroxybenzoesäure in Aceton als Matrix.
• – ESI-Massenspektrometrie: ESI-Gerät Esquire 3000, Fa. Bruker.

Mass spectrometry: The m / z values and the relative intensities (in parentheses) are given:

• - MALDI mass spectrometry: MALDI-TOF instrument Daltonics Ultraflex, Bruker with 2,5-dihydroxybenzoic acid in acetone as matrix.
• ESI mass spectrometry: ESI device Esquire 3000, Bruker.

3. Preparation of Sodium Salts of Sulfonatocalixarenes

The ion exchanger Dowex DR-2030 (H ⁺ form) was placed in a column, washed with water (200 mL), hydrochloric acid (1 M, 100 mL) and again with water (200 mL). Thereafter, the ion exchanger was converted into the Na ⁺ form by rinsing with sodium hydroxide solution (2 M, 100 mL). It was then washed with water (200 ml), methanol (200 ml) and water (100 ml). The product was dissolved in a little water (about 2 mL) and applied to the ion exchange column. It was then washed in small portions with water (200 mL in total). The solvent of the product-carrying fractions was removed by distillation to obtain the desired deprotonated product.

4. Production Examples

4.1 Preparation of intermediates

Reference Example 1: 6- (Methoxycarbonyl) -picolinic acid

To an ice-cooled solution of dimethyl pyridine-2,6-dicarboxylate (3.36 g, 17.2 mmol) in methanol (110 mL) was added slowly potassium hydroxide (1.35 g, 20.7 mmol). The ice bath was removed and the reaction mixture stirred for 16 h at 25 ° C. The solvent was removed by distillation and the residue was combined with ethyl acetate (50 ml). The insolubles were filtered off and taken up in water (40 mL). By adding 1 M hydrochloric acid, the pH of the solution was adjusted to pH 2, and the solution was then extracted with ethyl acetate (4 × 20 mL). The combined organic phases were dried over MgSO ₄ and the solvent was removed by distillation.
Yield: 2.29 g (12.6 mmol, 73%) of colorless solid; Melting point: 148 ° C;
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 4.03 (s, 3H), 8.13 (t, 1H, ³ J _HH = 7.8 Hz), 8.37 (dd, 1H, ³ J _HH = 7.8 Hz, ⁴ J _HH = 1.1 Hz), 8.42 (dd, 1H, ³ J _HH = 7.8 Hz, ⁴ J _HH = 1.1 Hz) ppm;
¹³ C-NMR (101 MHz, CDCl _3): δ = 53.3, 126.9, 129.0, 139.8, 146.5, 146.9, 163.5, 164.2 ppm.

Reference Example 2: 3- (Methoxycarbonyl) benzoic acid

To an ice-cooled solution of dimethyl isophthalate (10.0 g, 51.5 mmol) in methanol (310 mL) was added potassium hydroxide (4.03 g, 61.8 mmol) slowly. The ice bath was removed and the reaction mixture was stirred at 25 ° C for 3 d. The solvent was then removed by distillation and the residue was treated with water (80 ml). The insoluble constituents were filtered off and washed Filtrate with dichloromethane (3 x 60 mL) and adjusted the pH of the solution to pH 1 by addition of 1 M hydrochloric acid. The precipitated solid was filtered off and dried in vacuo.
Yield: 7.31 g (40.6 mmol, 79%) of a colorless solid; Melting point: 191 ° C;
¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ = 3.87 (s, 3H), 7.64 (t, 1H, ³ J _HH = 7.5 Hz), 8.14-8.18 (m, 2H), 8.46 (s , 1H), 13.33 (br, 1H) ppm;
¹³ C-NMR (101 MHz, DMSO-d ₆ ): δ = 52.5, 129.4, 129.8, 130.1, 131.4, 133.3, 133.8, 165.6, 166.5 ppm.

Reference Examples 3 to 5: General procedure for carrying out the coupling to the THP-protected hydroxamic acids

The respective carboxylic acid derivative (2.00 g, 11.0 mmol), commercial O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (1.29 g, 11.0 mmol) and TBTU (3.53 g, 11.0 mmol) are suspended in dichloromethane (40 mL) , The reaction mixture is treated dropwise with DIPEA (2.84 g, 22.0 mmol, 3.83 mL) and the resulting solution is stirred at 25 ° C for 20 h. The solvent is removed by distillation and the residue is purified by column chromatography.

Reference Example 3: 6 - ((((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) picolic acid methyl ester

The title compound was prepared starting from 6- (methoxycarbonyl) -picolinic acid according to the general procedure. The column chromatographic purification was carried out with ethyl acetate as the eluent.
Yield: 1.82 g (6.50 mmol, 59%) of colorless solid; Melting point: 94 ° C;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.55-1.73 (m, 6H), 3.49-3.55 (m, 1H), 4.13-4.19 (m, 1H), 5.19 (s, 1H), 8.16-8.23 (m, 3H), 11.75 (s, 1H) ppm;
¹³ C-NMR (101 MHz, DMSO-d ₆ ): δ = 18.1, 24.8, 27.8, 52.8, 61.2, 100.8, 125.7, 127.4, 139.4, 146.8, 150.2, 161.1, 164.8 ppm;
IR (ATR): υ~ = 3294 (w), 3078 (w), 2960 (m), 1725 (s), 1666 (s) cm ^-1 ;
MS (ESI / TOF): m / z (%) = 303.0 (42), 583.1 (100);
CHN calculated for C ₁₃ H ₁₆ N ₂ O ₅ (MW 280.11): C, 55.71; H, 5.75; N, 9.99; found C, 55.68; H, 5.73; N 10.03.

Reference Example 4: 3 - ((((tetrahydro-2H-pyran-2-yl) oxy) -carbamoyl) -benzoic acid methyl ester

The title compound was prepared starting from 3- (methoxycarbonyl) benzoic acid according to the general procedure. The column chromatographic purification was carried out with ethyl acetate / hexane = 1: 1 as the eluent.
Yield: 2.17 g (7.77 mmol, 70%) of colorless solid; Melting point: 115 ° C;
¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ = 1.55-1.73 (m, 6H), 3.52-3.55 (m, 1H), 3.89 (s, 3H), 4.03-4.09 (m, 1H) , 5.02 (s, 1H), 7.64 (t, 1H, ³ J _HH = 7.8 Hz), 8.04 (d, 1H, ³ J _HH = 7.9 Hz), 8.11 (d, 1H, ³ J _HH = 7.8 Hz), 8.36 (s, 1H), 11.89 (s, 1H) ppm;
¹³ C-NMR (101 MHz, DMSO-d ₆ ): δ = 18.3, 24.8, 27.9, 52.4, 61.4, 101.0, 127.9, 129.2, 129.9, 132.0, 132.1, 132.9, 163.3, 165.7 ppm;
IR (ATR): υ~ = 3181 (w), 2949 (m), 1725 (s), 1648 (s) cm ^-1 ;
MS (ESI / TOF): m / z (%) = 280 (2), 302 (4), 318 (10), 581 (100%), 597 (21);
CHN calculated for C ₁₄ H ₁₇ NO ₅ (MW 279.11): C, 60.21; H, 6.14; N, 5.02; found: C, 60.21; H, 6.14; N 5.02.

Reference Example 5: 4 - ((((tetrahydro-2H-pyran-2-yl) oxy) -carbamoyl) -benzoic acid methyl ester

The title compound was prepared starting from 4- (methoxycarbonyl) benzoic acid according to the general procedure. The column chromatographic purification was carried out with ethyl acetate / hexane = 1: 1 as the eluent.
Yield: 2.53 (9.06 mmol, 82%) of colorless solid; Melting point: 79 ° C;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.55-1.72 (m, 6H), 3.51-3.54 (m, 1H), 4.02-4.08 (m, 1H), 5.01 (s, 1H), 7.88 (d, 2H, ³ J _HH = 8.2 Hz), 8.04 (d, 2H, ³ J _HH = 8.3 Hz) ppm;
¹³ C-NMR (101 MHz, DMSO-d ₆ ): δ = 18.3, 24.7, 27.9, 52.5, 61.4, 101.0, 127.7, 129.3, 132.1, 136.5, 163.4, 165.7 ppm;
IR (ATR): υ~ = 3553 (m), 2944 (m), 1703 (s), 1655 (s) cm ^-1 ;
MS (ESI / TOF): m / z (%) = 280 (5), 302 (10), 318 (23), 581 (100), 597 (8);
CHN calculated for C ₁₃ H ₁₆ N ₂ O ₅ (MW 280.11): C, 60.21; H, 6.14; N, 4.93; found: C, 60.24; H, 6.15; N, 4.93.

Reference Example 6: Sodium 6 - (((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) pyridine-2-carboxylate

6 - ((((tetrahydro-2H-pyran-2-yl) oxy) -carbamoyl) -picolinic acid methyl ester (1.00 g, 3.57 mmol) was dissolved in a methanol / water mixture (40 mL, 3: 1 v / v) Sodium hydroxide (143mg, 3.57mmol) was added and the reaction mixture was stirred at reflux for 17 hours The solvent was removed by distillation and the residue was taken up in water (40 mL) The aqueous solution was washed with dichloromethane (4 × 25 mL) and ethyl acetate The solvent of the aqueous phase was removed by distillation and to the residue was added ethanol (25 mL), the insolubles were filtered off and the filtrate was concentrated to dryness.
Yield: 883 mg (3.07 mmol, 86%) of colorless solid; Melting point: decomposition above 185 ° C;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.53-1.75 (m, 6H), 4.09-4.15 (m, 1H), 5.10 (s, 1H), 7.89-7.95 (m, 2H) 8.06 (dd, 1H, ³ J _HH = 7.1 Hz, ⁴ J _HH = 1.8 Hz) ppm;
¹³ C-NMR (101 MHz, DMSO-d ₆ ): δ = 18.2, 24.8, 27.9, 61.1, 100.5, 121.9, 125.9, 137.6, 148.8, 156.1, 161.8, 167.5 ppm.

Reference Example 7: 3 - (((Tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) benzoic acid

To a solution of methyl 3 - (((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) benzoate (2.00 g, 7.16 mmol) in an ethanol / water mixture (40 mL, 3: 1 (v / v)). Potassium hydroxide (1.12 g, 17.2 mmol) was added and the reaction mixture was stirred at 25 ° C. for 16 h. The solvent was then removed by distillation. The residue was dissolved in water (30 mL), the insolubles were filtered off and the filtrate was washed with dichloromethane (3 × 20 mL) and ethyl acetate (1 × 25 mL). The pH of the aqueous solution was adjusted to pH 1 by addition of 1 M hydrochloric acid and the precipitated solid was filtered off.
Yield: 1.51 g (5.69 mmol, 79%) of a colorless solid; Melting point: decomposition from 182 ° C .;
¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ = 1.55-1.72 (m, 6H), 3.52-3.55 (m, 1H), 4.03-4.08 (m, 1H), 5.01 (s, 1H) , 7.61 (t, 1H, ³ J _HH = 7.7 Hz), 8.00 (d, 1H, ³ J _HH = 7.8 Hz), 8.10 (d, 1H, ³ J _HH = 7.7 Hz), 8.35 (s, 1H), 11.86 (s, 1H), 13.27 (br, 1H) ppm;
¹³ C-NMR (101 MHz, DMSO-d ₆ ): δ = 18.2, 24.8, 27.9, 61.3, 101.0, 128.1, 129.0, 131.0, 131.6, 132.3, 132.7, 163.5, 166.8 ppm.

Reference Example 8: 4 - (((Tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) benzoic acid

4 - ((((tetrahydro-2H-pyran-2-yl) oxy) -carbamoyl) -benzoic acid methyl ester (2.00 g, 7.16 mmol) was dissolved in a water / ethanol mixture (40 mL, 3: 1 (v / v)) and with potassium hydroxide (1.12 g, 17.2 mmol). The reaction mixture was stirred for 20 h at 25 ° C. The solvent was removed by distillation and the residue was added with water (30 mL). The insolubles were filtered off and the aqueous solution was washed with dichloromethane (3 x 20 mL) and ethyl acetate (1 x 25 mL). Thereafter, the aqueous solution was adjusted to pH 3 by addition of 1 M hydrochloric acid and the precipitated solid was filtered off.
Yield: 1.74 g (6.56 mmol, 92%) of colorless solid; Melting point: decomposition from 180 ° C .;
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.55-1.72 (m, 6H), 4.06 (br, 1H), 5.01 (s, 1H), 7.85 (d, 2H, ³ J _HH = 8.5 Hz), 8.01 (d, 2H, ³ J _HH = 8.5 Hz), 11.81 (s, 1H) ppm;
¹³ C-NMR (101 MHz, DMSO-d ₆ ): δ = 18.3, 24.8, 27.9, 61.4, 101.0, 127.5, 129.4, 134.0, 136.0, 163.5, 166.9 ppm.

Reference Example 9: 5-Amino-25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene

To a suspension of 5-nitro-25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene (4.00 g, 5.64 mmol - prepared according to the protocol of Mokhtari, K. Pourabdollah, Bull. Korean Chem. Soc. 2011, 32, 3979-3990 ) and stannous chloride dihydrate (6.36 g, 28.2 mmol) in EtOH (100 mL) were added 1 M hydrochloric acid until the solution was homogeneous. The reaction mixture was then stirred at reflux for 8 h. The precipitated solid was filtered off and the filter cake was washed with ethanol (3 x 25 mL) and diethyl ether (2 x 25 mL) and dried in vacuo. Yield: 3.01 g (4.43 mmol, 79%) of a gray-brown solid. ¹ H-NMR (400 MHz, D ₂ O): δ = 4.01 (br, 8H), 7.05 (s, 2H), 7.48 (s, 2H), 7.60 (s, 2H), 7.64 (s, 2H) ppm ;
MS (MALDI / TOF): m / z (%) 680 (40), 702 (100), 718 (21) 724 (81), 740 (38), 746 (20), 762 (17).

4.2 Preparation of calixarene compounds of the invention

General procedure for the preparation of calixarene compounds

The respective carboxylic acid or the corresponding sodium carboxylate (882 .mu.mol) and PyCloP (186 mg, 441 .mu.mol) are initially charged in DMF (5 mL) and treated dropwise with DIPEA (225 .mu.L, 1.32 mmol). The resulting solution is stirred for 3 h at 25 ° C and then to a suspension of 5-amino-25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene (300 mg, 441 .mu.mol) and Add DIPEA (299 μL, 1.76 mmol) in DMF (5 mL). The reaction mixture is stirred for 24 h at 25 ° C and then treated with trifluoroacetic acid (340 μL, 4.45 mmol). The resulting suspension is stirred for a further 24 h and then DIPEA (50 μL) is added. The reaction mixture is poured into diethyl ether (200 mL) and the precipitated solid is filtered off. The filter cake is washed with ethyl acetate (3 x 20 mL) and diethyl ether (2 x 20 mL) and then slurried in water (30 mL). By addition of 1 M sodium hydroxide solution, the pH is adjusted to pH 12. The solution thus obtained is washed with ethyl acetate (4 × 20 ml) and the solvent of the aqueous phase is removed by distillation. The residue is dissolved in a little water. The solution is adjusted to pH 5 with trifluoroacetic acid and the product is separated by HPLC. The sulfonic acid groups in the product thus obtained are converted with an ion exchanger into the corresponding sodium sulfonate groups. The deprotonated product is washed with ethanol (3 × 15 mL) and diethyl ether (3 × 15 mL) and dried in vacuo.

Example 1: 5- (6- (Hydroxycarbamoyl) -2-benzenecarboxamido) -25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene trisodium salt (trisodium salt of the compound of formula (Ia.1) with R '' = (R-16))

The preparation was carried out by reacting 5-amino-25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene with 3 - (((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl ) benzoic acid according to the general preparation instructions.
Yield: 64 mg (52 μmol, 12%) light brown solid;
¹ H-NMR (400 MHz, D ₂ O): δ = 3.96 (br, 8H), 7.15 (s, 2H), 7.48-7.51 (m, 3H), 7.55 (d, 2H, ⁴ J _HH = 2.1 Hz ), 7.57 (d, 2H, ⁴ J _HH = 2.1 Hz), 7.78 (d, 1H, ³ J _HH = 7.7 Hz), 7.87 (d, 1H, ³ J _HH = 7.8 Hz), 8.00 (s, 1H) ppm;
¹³ C-NMR (101 MHz, 101 MHz, D ₂ O / CD ₃ OD, 9: 1 (v / v)): δ = 32.1, 32.8, 124.4, 126.8, 126.9, 127.0, 127.0, 130.5, 130.7, 130.9 , 131.2, 131.3, 131.6, 131.8, 131.8, 132.8, 134.6, 135.3, 135.7, 148.9, 155.7, 156.9, 168.5, 169.2 ppm;
IR (ATR): υ~ = 3409 (m), 3267 (m), 2931 (w), 1646 (m), 1551 (m) cm ^-1 ;
MS (MALDI / TOF): m / z (%) = 827 (49), 843 (32), 849 (63), 865 (100), 871 (17), 881 (28), 887 (36), 903 (17), 909 (6);
CHN for C ₃₆ H ₂₇ N ₂ Na ₃ O ₁₆ S ₃ .CF ₃ CO ₂ Na. 10H ₂ O (MW 1224.93) Calcd: C, 37.26; H, 3.87; N, 2.29; S, 7.85; found: C, 37.08; H, 3.65; N, 2.23; S, 7.59.

Example 2: 5- (4- (Hydroxycarbamoyl) -2-benzenecarboxamido) -25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene trisodium salt (trisodium salt of the compound of formula (Ia.1) with R '' = (R-18))

The preparation was carried out by reacting 5-amino-25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene with 4 - (((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl ) benzoic acid according to the general preparation instructions.
Yield: 58 mg (52 μmol, 12%) light brown solid;
¹ H-NMR (400 MHz, D ₂ O): δ = 3.94 (br, 8H), 7.17 (s, 2H), 7.51 (s, 2H), 7.54 (d, 2H, ⁴ J _HH = 2.2 Hz), 7.56 (d, 2H, ⁴ J _HH = 2.2 Hz), 7.72 (d, 2H, ³ J _HH = 7.8 Hz), 7.81 (d, 2H, ³ J _HH = 7.4 Hz), 8.43 (br, 1H) ppm;
¹³ C-NMR (101 MHz, D ₂ O / CD ₃ OD, 9: 1 (v / v)): δ = 32.4, 33.4, 124.3, 126.7, 126.8, 127.9, 128.2, 128.6, 130.9, 131.2, 131.4, 132.0, 132.4, 133.6, 134.8, 137.4, 149.8, 156.8, 158.6, 169.5, 171.7 ppm;
IR (ATR): υ~ = 3418 (m), 2934 (w), 1605 (m) cm ^-1 ;
MS (MALDI / TOF): m / z (%) = 827 (5), 843 (8), 849 (43), 865 (74), 871 (51), 881 (11), 887 (100), 893 (16), 903 (38), 909 (38), 925 (18), 931 (9), 947 (7);
CHN for C ₃₆ H ₂₇ N ₂ Na ₃ O ₁₆ S ₃ · CF ₃ CO ₂ Na · 4.5H ₂ O (MW 1125.84): C, 40.54; H, 3.22; N, 2.49; S, 8.54; found C, 40.95; H, 3.65; N, 2.44; S, 8.40.

Example 3: 5- (6- (Hydroxycarbamoyl) -2-pyridinecarboxamido) -25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene trisodium salt (trisodium salt of the compound of formula (Ia.1) with R '' = (R-22))

The preparation was carried out by reacting 5-amino-25,26,27,28-tetrahydroxy-11,17,23-trisulfonatocalix [4] arene with sodium 6 - (((tetrahydro-2H-pyran-2-yl) oxy ) carbamoyl) pyridine-2-carboxylate according to the general preparation instructions.
Yield: 43 mg (39 μmol, 9%) yellowish solid;
¹ H-NMR (400 MHz, D ₂ O): δ = 3.94 (br, 8H), 7.25 (s, 2H), 7.47 (s, 2H), 7.53 (d, 2H, ⁴ J _HH = 2.2 Hz), 7.57 (d, 2H, ⁴ J _HH = 2.3 Hz), 7.98-8.15 (m, 3H) ppm;
¹³ C-NMR (101 MHz, D ₂ O / CD ₃ OD, 9: 1 (v / v)): δ = 32.3, 33.3, 125.9, 126.1, 126.7, 126.8, 127.8, 130.6, 131.2, 131.5, 132.2, 132.3, 133.2, 134.5, 140.2, 140.8, 148.1, 148.5, 149.3, 156.8, 158.9, 163.7 ppm;
IR (ATR): υ~ = 3420 (m), 3288 (m), 2942 (w), 1661 (m), 1542 (m) cm ^-1 ;
MS (MALDI / TOF): m / z (%) = 828 (51), 844 (51), 850 (78), 866 (100), 872 (37), 882 (23), 888 (63), 894 (4), 904 (27), 910 (10);
CHN for C ₃₅ H ₂₆ N ₃ Na ₃ O ₁₆ S ₃ .CF ₃ CO ₂ Na. 4H ₂ O (MW 1117.83) Calcd: C, 39.76; H, 3.07; N, 3.76; S, 8.61; found: C, 39.63; H, 3.25; N, 3.77; S, 8.62.

5. Investigation of the biological effect

5.1 materials

Acetylthiocholine iodide (ASCh), 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB, Ellman reagent) and tris (hydroxymethyl) aminomethane (Tris) were purchased from Sigma-Aldrich (Taufkirchen, Germany). Disodium hydrogen phosphate (Na ₂ HPO ₄ .2H ₂ O), potassium dihydrogen phosphate (KH ₂ PO ₄ .2H ₂ O), sodium hypochlorite and hydrochloric acid were obtained from Carl Roth (Karlsruhe, Germany). All other chemicals were purchased by Merck Eurolab GmbH (Darmstadt, Germany) with the highest possible purity.

The neurotoxic organic phosphorus compounds (GF, GA, GB, GD, VX, VR, CVX, VE, VG, i-propyl-VE, n-propyl-VX and VM) were provided by the Federal Ministry of Defense (Bonn, Germany) , They were> 90% pure ( ¹ H NMR and ³¹ P NMR).

Of the neurotoxic organic phosphorus compounds GF, GA, GB, GD, VX, CVX and VR, 0.1% v / v stock solutions were prepared in acetonitrile. Of the neurotoxic organophosphorus compounds VE, VG, i-propyl-VE, n-propyl-VX, VM, 1% v / v stock solutions were prepared. The stock solutions were stored at room temperature for a maximum of 3 months.

Immediately prior to the experiments, the respective stock solution was diluted to a suitable working concentration with Tris-HCl buffer (pH 7.4) and stored on ice. The respective concentrations are summarized in Table 1. Table 1: Concentrations of the stock solution, the working solutions after dilution with Tris-HCl buffer and in the assay. neurotoxic organic phosphorus compound stock solution Concentrations working solution assay GF 5.55 mM 20 μM 5 μM GA 6.17 mM 320 μM 80 μM GB 7.14 mM 120 μM 30 μM DG 5.49 mM 40 μM 10 μM VX 3.74 mM 40 μM 10 μM CVX 3.74 mM 40 μM 10 μM VR 3.74 mM 40 μM 10 μM i-propyl-VE 35.54 mM 80 μM 20 μM n-propyl-VX 37.40 mM 120 μM 30 μM VE 39.47 mM 120 μM 30 μM VG 37.13 mM 800 μM 200 μM VM 41.79 mM 60 μM 15 μM

Acetylcholinesterase (AChE) from hemoglobin-free erythrocyte membranes

The hemoglobin-free erythrocyte membranes were produced according to JT Dodge, C. Mitchell, DJ Hanahan, Arch. Biochem. Biophys. 1963, 100, 119-130 with modifications after F. Worek, G. Reiter, P. Eyer, L. Szinicz, Arch. Toxicol. 2002, 76, 523-529 and served as a source of acetylcholinesterase. Employee voluntarily donated heparin whole blood was centrifuged (3000 x g, 10 min) to remove the plasma supernatant. The erythrocytes were washed three times with two volumes of phosphate buffer (0.1 M, pH 7.4) and then diluted in 20 volumes of hypotonic phosphate buffer (6.7 mM, pH 7.4) and centrifuged at 50,000 x g (30 min, 4 ° C) to increase hemolysis favor. The supernatant was discarded and the pellet resuspended in hypotonic buffer. After two further washes, the erythrocytes were resuspended in phosphate buffer (0.1 M, pH 7.4), then concentrated by centrifugation at 100,000 x g (30 min, 4 ° C), and then the desired AchE activity was adjusted. The aliquots of the erythrocyte membranes were stored at -80 ° C. Prior to use, the thawed red cell membranes were homogenized on ice twice for 5 sec with a 20 sec interval between intervals (Sonoplus, HD 2070, Bandelin electronics, Berlin, Germany) to provide a homogeneous matrix for the kinetic measurements.

5.2 Methodology

Determination of acetylcholinesterase activity

The determination of acetylcholinesterase activity was carried out by a modified Ellman assay (see: GL Ellman, KD Courtney, V. Andres, RM Feather-Stone, Biochem. Pharmacol. 1961, 7, 88-95 ; P. Eyer, F. Worek, D. Kiderlen, G. Sinko, A. Stuglin, V. Simeon-Rudolf, E. Reiner, Anal. Biochem. 2003, 312, 224-227 ; F. Worek, U. Mast, D. Kiderlen, C. Diepold, P. Eyer, Clin. Chim. Acta 1999, 288, 73-90 ). ASCh is cleaved by the AChE into thiocholine and acetate. Thiocholine reacts with DTNB to release TNB ^- . The formation of TNB ^- is monitored photometrically and provides a measure of the activity of AChE.

Enzyme kinetic determination of the detoxification of neurotoxic organic phosphorus compounds by calixarenes

The ability of the synthesized calixarene derivatives to degrade neurotoxic organic phosphorus compounds was examined by means of an AChE inhibition assay. For this purpose, 150 .mu.l Calixaren (1 mM) in Tris-HCl (0.1 M, pH 7.4) with 75 .mu.l Tris-HCl (0.1 M, pH 7.4) and 75 .mu.L of a working solution of the respective neurotoxic organic phosphorus compound (see Table 1) in a Eppendorf reaction vessel and incubated at 37 ° C (t = 0 min). At certain time points (t = 0-60 min), 25 μL of this solution was placed in prewarmed (37 ° C) polystyrene disposable cuvettes containing 3 mL Tris-HCl (0.1 M, pH 7.4), 100 μL DTNB (0.3 mM fc) and 10 μL AChE contained, transferred. After addition of 50 μL ASCh (0.45 mM fc), the photometric recording (UV-VIS Spectrophotometer UV-2600, Shimadzu, Kyoto, Japan) for 5 min at 436 nm of the progressive TNB ^- formation. In each case 4 independent experiments were carried out. Analogous measurements without calixarene were performed to determine the spontaneous hydrolysis of neurotoxic organic phosphorus compounds (for the rate of spontaneous hydrolysis of VR and CVX, the rate constant determined for VX was assumed).

shows typical degradation kinetics exemplifying the reactions of Example 1 ((R-16), circles) and Example 3 ((R-22); squares) with VX.

The inhibition constant k _{obs was} determined by non-linear regression analysis (Prism 5.0, GraphPad Software, San Diego, USA) of the curves obtained for the relationship y = y _max (1-e ^(-kobsx) ). Subsequently, k _{obs was} plotted against the corresponding incubation time. By nonlinear fitting of the decay ^curves at y = m * e ^(-kx) (one-phase exponential decay), the first-order detoxification constants k _{1 were} determined. From k ₁ , the rate constant of spontaneous hydrolysis of the respective neurotoxic organic phosphorus compound was subtracted, and then the half-life was calculated according to t _1/2 = ln ₂ / k ₁ . The results are summarized in Table 2. Table 2: Half-life t _{1/2 of} the degradation of neurotoxic organic phosphorus compounds by calixarenes example Half-life t _{1/2 of} the detoxification of the respective neurotoxic organic phosphorus compound in min GF GA GB DG VX CVX VR 1 nb 45.9 24.9 49.6 9.8 25.0 28.6 3 nb nb nb 17.7 5.2 3.7 4.9 Continuation Table 2 example Half-life t _{1/2 of} the detoxification of the respective neurotoxic organic phosphorus compound in min n-propyl-VX VE VM i-propyl-VE 1 25.3 105.1 20.3 40.5 3 nb nb 6.4 nb

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

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Claims (17)

Compounds of the general formula (I) and their salts, CAX (-R) _n (I) wherein CAX is a calixarene radical, n is 1, 2, 3, 4, 5 or 6, R is a radical of the formula -XY (-Nu) _m , where each R is attached to each one cyclic repeat unit of the calixarene radical CAX where X is a covalent bond, C ₁ -C ₄ alkanediyl, O, OC (= O), C (= O) -O, NH, NH-C (= O), C (= O) -NH , NH-C (= O) -NH, NH-C (= S) -NH, NH-C (= NH), AO, AOC (= O), AC (= O) -O, A-NH, A -NH-C (= O) or AC (= O) -NH, wherein A in the 6 last-mentioned groups is C ₁ -C ₄ -alkanediyl; Y is a covalent bond, C ₁ -C ₄ alkanediyl, C ₂ -C ₄ alkylenediyl, a carbocyclic linker or a heterocyclic linker, m is 1 or 2, where m is 1, when Y is C ₁ - C ₄ alkanediyl or C ₂ -C ₄ alkylenedi, and Nu is a nucleophilic group selected from a hydroxamic acid group, thiohydroxamic acid group, NC ₁ -C ₆ alkyl hydroxamic acid group, NC ₆ -C ₁₄ aryl hydroxamic acid group, NC ₇ - C ₁₅ aralkyl hydroxamic acid group, NC ₁ -C ₇ acyl hydroxamic acid group, oxime group, guanidine group, N-hydroxycarbamide group, N-hydroxycarbamate group and a 1-hydroxybenzotriazole group. Compounds according to claim 1 and their salts, wherein n is 1. Compounds according to any one of the preceding claims and their salts, wherein X is NH or NH-C (= O). Compounds according to any one of the preceding claims and their salts, wherein Y is ethene-1,2-diyl, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, pyridine-2,4-diyl, pyridine-2 , 6-diyl, pyridine-2,5-diyl, pyridine-3,5-diyl, pyridinium-1,3-diyl, pyridinium-1,2-diyl, pyridinium-1,4-diyl, pyrrole-2,5 -diyl, 1,2,3-triazole-1,4-diyl, 1,2,3-triazole-1,5-diyl, 1,2,4-triazole-1,3-diyl, 1,2,3 Triazole-1,4-diylmethyl, 1,2,3-triazole-1,5-diylmethyl, 1,2,4-triazole-1,3-diylmethyl, pyrimidine-2,4-diyl, pyrimidine-2,5 -diyl, pyrimidine-4,6-diyl, s-triazine-2,4-diyl, s-triazine-2,4,6-triyl or cyclobut-3-ene-1,2-dione-3,4-diyl stands. Compounds according to any one of the preceding claims and their salts, wherein Nu is C (= O) -NH-OH, OC (= O) -NH-OH, NH-C (= O) -NH-OH, CH = N-OH or NH-C (= NH) -NH ₂ . Compounds according to any one of the preceding claims and their salts, wherein R is selected from the radicals of the following formulas (R-1) to (R-44)

wherein R ^A in formula (R-44) is selected from C ₁ -C ₆ alkyl, C ₆ -C ₁₄ aryl and C ₇ -C ₁₅ aralkyl. Compounds according to one of the preceding claims and their salts, in which the calixarene radical CAX has 4, 5 or 6 and in particular 4 cyclic repeating units. Compounds according to claim 7 and their salts, wherein at least one cyclic repeat unit in the calixarene radical CAX carries a sulfonic acid group. Compounds according to claim 8, which correspond to the formula (Ia) and their salts:

wherein R 'are the same or different and are SO ₃ H or a radical R, with the proviso that at least one of the radicals R' is a radical R and at least one of the radicals R 'is SO ₃ H; k is 1, 2 or 3; and Q is H, OH, C ₁ -C ₄ -alkoxy, hydroxy-C ₁ -C ₄ -alkoxy or a radical of the formula [O-Alk] _q -OH, where Alk is C ₂ -C ₄ -alkoxy 1,2-diyl and q is 2 to 50. Compounds according to claim 9 and their salts, wherein k is 1. Compounds according to claim 9 or 10 and their salts, in which Q is OH, one of the radicals R 'is a radical R and the remaining radicals R' are SO ₃ H. Compounds according to claim 11, which correspond to the formula (Ia.1), and their salts:

wherein R "is selected from the groups (R-1) to (R-44) given in claim 6. Compounds according to claim 12 and their salts, wherein R '' is selected from the groups indicated in claim 6 (R-1), (R-7), (R-14), (R-15), (R-16) , (R-18), (R-22), (R-23), (R-24), (R-25), (R-27), (R-34), (R-39), ( R-40), (R-41), (R-42) and (R-44). A pharmaceutical composition containing at least one compound of formulas (I), (Ia) or (Ia.1) according to any one of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. Use of compounds of the formulas (I), (Ia) or (Ia.1) according to one of the preceding claims or their pharmaceutically acceptable salts for the therapeutic or prophylactic treatment of conditions resulting from poisoning with a neurotoxic organic phosphorus compound, in particular a chemical warfare agent the group of G-substances and V-substances. Use of compounds of the formulas (I), (Ia) or (Ia.1) according to one of the preceding claims or their salts for the treatment of surfaces containing a neurotoxic organic phosphorus compound, in particular a chemical warfare agent from the group of G-substances and V substances are contaminated. Use according to claim 15 or 16, wherein the neurotoxic organic phosphorus compound is selected from the chemical warfare agents tabun, N- (di-C ₂ -C ₆ -alkyl) tabun, soman, sarin, O- (C ₁ -C ₆ -alkyl) Analogs of sarin, cyclosarin and O- (C ₁ -C ₄ alkyl) -2-di (C ₁ -C ₄ alkyl) aminoethyl C ₁ -C ₂ alkylphosphonothiolates.

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