Method for preparing polyguanidines

Abstract

The invention relates to a method for preparing polycondensation products of guanidine, aminoguanidine or diaminoguanidine G with benzyl derivatives BA by solution polymerisation using NMP as a solvent according to the following reaction scheme (BA, G, (I), (II), (III)), where X is a leaving group, R1 is an aromatic ring system, Gua is a guanidine diyl, aminoguanidine diyl or diaminoguanidine diyl group, Y is H-Gua and Z is H or Y and Z together are a chemical bond in order to produce a cyclic structure, and n ≥ 2; wherein the benzyl derivatives BA are subjected to a polycondensation reaction with an excess of G, characterised in that the benzyl derivatives BA and the guanidine G are suspended in NMP and heated to a temperature of at least 150°C and thereby dissolved, after which the reaction mixture is cooled and the product is obtained a) by precipitation with a non-solvent, which can be mixed with NMP, for this in solid form or b) by extraction with a mixture of water and an apolar solvent, which cannot be mixed with water and NMP, as an aqueous solution.

Description

Process for the production of polyguanidines The present invention relates to a new process for the production of polyguanidines, polycondensation products produced in this way and their use as antimicrobial or anti-infective agents. STATE OF THE ART Polyguanidines of the general formula "PG" below, as well as various derivatives thereof, have been known for a long time. NH * - RN N - * HHH ]x " PG" Patent literature already described in 1943, specifically US patent 2,325,586, several manufacturing processes for various polyguanidines by polycondensation of i) guanidine or salts thereof, ii) cyanohalides, iii) dicyanamides or iv) isocyanide dihalides with diamines or v) two dicyandiamides together (resulting in cyano-substituted polyguanidines), as well as the use of the polyguanidines thus produced as dyeing aids: i) “ II R' R' • IR' II R' zHjN-C-NHj-|-a: HN-R-NH — — > 21NH3+L— R— N— C— N— Jx ü) R' R' HIM— R— NH-f-xCNX — N— C— N— R— R' R' - R' R' R' R' R' R' R' R' xNC— *■' -R— N— CN+xHN— R— NH — N— C— IST— R— AC- N— R— _ UH UH ■ NR”. HX' xR" NCXi+xHN— R-NH - ■> — RN— CN— Ä' R',V) HHR' R' NH NH - JNC—N— RN-CN+xNCN— R— N— CN -N— C>— N— R— N— C— N— R— The diamines in reactions i) to iv) already revealed both alkylene and phenylenediamines as well as oxyalkylene or polyether diamines, which would later become known as Jeffamine®. Decades later, such polyguanidines have also proven to be excellent biocides. For example, a group led by Oskar Schmidt disclosed in WO 99 / 54291 A1 the production of microbiocidal polyhexamethyleneguanidines, in WO 01 / 85676 A1 biocidal polyguanidines produced by condensation of guanidine with polyoxyalkylenes, and in WO 2006 / 047800 A1 polyguanidine derivatives acting as biocides, particularly fungicides, which are formed by polycondensation of guanidine with a mixture of alkylenediamine and oxalkylenediamine and are said to exhibit lower toxicity than polymers containing only one of the two types of the divalent residue Ri. In WO 02 / 30877 A1, similar polyguanidines are described as disinfectants, which additionally contain phenyl groups in the chains. A Russian research group (Tets, Tets and Krasnov) discloses in WO 2011 / 043690 A1, from which US 2011 / 0269936 A1 and EP 2520605 A1 were derived, biocidal polyguanidines of the following formula, which are prepared by polycondensation of guanidine and hexamethylenediamine in the presence of hydrazine hydrate: During polycondensation, the hydrazine thus replaces – at least formally – an amino group of either one or two guanidine groups, thereby yielding block copolymers in which poly(hexamethylene-guanidine) blocks alternate with poly(hexamethyleneaminoguanidine) blocks, and the two types of blocks are linked to each other via guanidine dimers, as shown below: These polymers and their acid addition salts are also intended to act as biocides against bacteria, viruses, and fungi. However, the examples in these applications, in which seven different polymers were produced, contain no physical data on the products obtained, apart from the statement that the one from Example 1 is a "solid, nearly colorless, transparent substance". Regarding the possible structures that can arise during the polycondensation of guanidines with diamines, several articles by a research group at the Graz University of Technology exist, e.g., Albert et al., Biomacromolecules 4(6), 1811-1817 (2003), and Feiertag et al., Macromol. Rap. Comm. 24(9), 567-570 (2003). In addition to the various possibilities of termination of the linear polymer chains with each of the starting monomers, cyclic molecules of the following general formula are also typically formed in a not insignificant proportion, which depends, among other things, on the chain length of the diamine: NH US patent 2005 / 225616 A1 also discloses the production of polyguanidine derivatives of the above general formula "PG", either by melt or solution polymerization in a strongly to moderately polar solvent with a log P of -1.5 to +1. In that paragraph

[0024] Twenty-four exemplary examples are listed, encompassing both aprotic and protic solvents. Five different solvents were used in the examples: the aprotic NMP, the two dialcohols propylene glycol (PG) and diethylene glycol (DEG), and the glycol monoethers DEGME and DPGME, in which the desired poly(hexamethyleneguanidine) acetate was obtained from guanidine acetate after heating to at least 160 °C for 10 to 20 hours. The main disadvantages of virtually all of the polyguanidine derivatives described above lie, firstly, in the not insignificant toxicity of these products and, in the case of the use of highly reactive components, in comparatively complex manufacturing processes, as well as in the use of components known to be problematic from a toxicological point of view, such as hydrazine, which is why the present inventors have begun to search for solutions. In the course of their research, the inventors discovered that polycondensation products of amino- and diaminoguanidine with amines surprisingly exhibit significantly lower toxicity than the structurally similar polycondensates with guanidine from the above-cited documents WO 2011 / 043690 A1, US 2011 / 0269936 A1 and EP 2.520.605 A1, but are also effective antimicrobial substances. These results are disclosed in Austrian patent AT 513,858 B1, in the PCT application WO 2014 / 113835 based thereon, and in the corresponding European patent EP 2,948,496 B1, in which polyguanidine derivatives of the following formula and salts thereof are claimed: wherein X is selected from — NH2, aminoguanidino and 1,3-diaminoguanidino; Y is selected from -H and -R1-NH2; or X and Y together represent a chemical bond to form a cyclic structure; Ri is selected from divalent organic residues with 2 to 20 carbon atoms, in which optionally one or more carbon atoms are replaced by O or N; a and b are each 0 or 1, where a+b ≠ 2 if no 1,3-diaminoguanidine units are present; R2 is selected from -H and -NH2 where R2 is -NH2 when a+b = 0, R2 –H or –NH2 is when a+b = 1 and R2 -H is the case when a+b = 2; and n > 2. As a method for producing these new poly(di)aminoguanidines, corresponding diamines were polycondensed with amino and / or diaminoguanidine by heating, analogous to the then-known state of the art. The inventors assumed that amino and diaminoguanidino groups (hereinafter collectively referred to as 'aminoguanidines' unless otherwise indicated in the context) are better tolerated by human eukaryotic cells than guanidino groups, and in particular than those polymers containing the hydrazo-bridged guanidine dimers described above. In fact, however, only preferred embodiments according to claim 3 therein were produced and investigated, in which the residue Ri is selected from alkylene residues in which at least one carbon atom is replaced by O or N to increase the hydrophilicity of the chains, more precisely from residues of the following formulas: - (CH2) C - 7 — (CH2)d - - (CH2) C - 7 — (CH2) d - Z2— (CH2) e - - (CH2) C - 7 — (CH2) d - Z,— (CH2) e - Z3- (CH2) f - - (CH2) C - 7 - (CH2) d - Z2- (CH2) e - Z3- (CH2) f - Z4- (CH2) g -where Zi to Z4 each independently represent a heteroatom selected from 0 and N and the indices c to g each independently represent such an integer in the range of 1 to 12 such that the total number of atoms of the residue Ri does not exceed 20. However, some of these new aminoguanidine compounds had not proven to be entirely satisfactory with regard to antimicrobial efficacy or toxicity, which is why the working group of inventors disclosed further poly(di)aminoguanidines produced for the first time, as well as a new process for their production, in AT 516.070 B1, WO 2016 / 015081 A1 and EP 3.174.848 B1, namely a process for the production of polycondensation products of guanidine, aminoguanidine or diaminoguanidine G with one or more benzyl or allyl derivatives BA according to the following reaction scheme: X-CH₂-R₁-CH₂-X + H-Gua-H CH₂-R₁-CH₂-Gua - HX BA G (I), (II), (Hl) wherein X each independently represents a departure group; Ri each independently stands either for an aromatic ring system with at least one aromatic ring, optionally containing one or more heteroatoms selected from O, N and S, and optionally substituted with one or two vinyl groups to which the group(s) -CH2-X is / are bonded, or for ethylene; Gua stands for a guanidindiyl, aminoguanidindiyl or diaminoguanidindiyl residue; Y stands for H-Gua and Z stands for H; or Y and Z together form a chemical bond to give a cyclic structure; wherein at least one benzyl or allyl derivative BA is subjected to a polycondensation reaction with an excess of guanidine, aminoguanidine or diaminoguanidine G with elimination of HX to give a polyguanidine of the following formula (I), (II) or (III): (I) (II) (III) or with a cyclic structure obtained by ring closure with elimination of a corresponding guanidine, or a salt of the respective polyguanidine. In contrast to the prior art, the polycondensation in this way did not proceed with the elimination of ammonia, but rather with the elimination of the leaving group X, preferably as a hydrogen halide, e.g., HCl or HBr, or as a sulfonic acid, e.g., CH3SO2OH (MsOH), which forms acid addition salts with the amino or imino groups present in the molecule, thus eliminating the need for an acid scavenger. And while the use of benzylic or allylic structures in the starting monomer BA did indeed result in mixtures of polycondensation products with different structures, as in the prior art, the main products contained not only singly substituted nitrogen atoms, as in the prior art at that time, but consistently doubly substituted nitrogen atoms.This means that the nitrogen atom that had already condensed with one molecule of BA apparently reacted preferentially a second time with another BA, so that only one N atom of the corresponding monomer G was incorporated into the main chain of the polymer, as shown in the formulas (I) to (III) above. In fact, some poly(di)aminoguanidines were produced and tested at that time, which were used as residue R 1 a divalent residue of benzene, pyridine, biphenyl, divinylbenzene or ethylene, which also proved to be more effective antibiotics than the previously produced polyguanidines with two guanidine nitrogen atoms in the main chain. However, this new polycondensation process, which proceeds with the elimination of the leaving group X as HX (instead of NH3), also took place via melt polymerization, whereby a not insignificant proportion of unreacted monomers BA and of by-products not corresponding to any of the above formulas (I) to (III) remained in the reaction products obtained as cooled melt. Against this background, the aim of the present invention was therefore to provide an improved manufacturing process for the above polyguanidine derivatives of formulas (I) to (III). REVELATION OF THE INVENTION The invention achieves this objective by providing a process for the production of polycondensation products of guanidine, aminoguanidine or diaminoguanidine G with at least one benzyl derivative BA according to the same reaction scheme as before: X-CH₂-R₁-CH₂-X + H-Gua-H CH₂-R₁-CH₂-Gua - HX BA G (I), (II), (III) wherein X independently represents a leaving group, R₁ independently represents an aromatic ring system with at least one aromatic ring optionally containing one or more heteroatoms selected from O, N and S and optionally substituted with one or two vinyl groups to which the group(s) -CH₂-X is / are bonded, Gua represents a guanidinediyl, aminoguanidinediyl or diaminoguanidinediyl residue, Y represents H-Gua and Z represents H or Y and Z together represent a chemical bond to give a cyclic structure, and n > 2; wherein at least one benzyl derivative BA is subjected to a polycondensation reaction with an excess of guanidine, aminoguanidine or diaminoguanidine G with elimination of HX to give a polyguanidine of the following formula (I), (II) or (Hl): (I) (H) (Hl) or with a cyclic structure obtained by ring closure with elimination of a corresponding guanidine, or to yield a salt of the polyguanidine; wherein the new process is now characterized in that the at least one benzyl derivative BA and the respective guanidine G are suspended in a polar aprotic solvent boiling above 150 °C at normal pressure and heated to a temperature of at least 150 °C and thereby dissolved, for which N-methylpyrrolidone (NMP) is used as the solvent, after which the reaction mixture was cooled and either a) is combined with a non-solvent for the polyguanidine of formula (I), (II) or (III) which is miscible with NMP to precipitate the product and obtain it in solid form, or b) is mixed with a mixture of water and a nonpolar solvent immiscible with water and NMP, which is a non-solvent for the product, and extracted to obtain an aqueous solution of the product. Thus, in the present application, the scope of protection is limited compared to the underlying priority application to the use of NMP as the solvent of choice, since the inventors have meanwhile discovered that all other "polar aprotic solvents boiling above 150 °C" that had been considered for solution polymerization are not equally suitable. In those cases where polymerization was carried out, at least initially, below 150 °C, either no conversion or a significantly lower yield (and the formation of by-products) was observed, while with reaction procedures analogous to the examples according to the invention, i.e., at temperatures of 160-180 °C, not the desired polyguanidine could be obtained, but only undefined products, as the subsequent comparative examples demonstrate.NMP, on the other hand, poses no problems, has a boiling point of 203 °C and therefore does not need to be refluxed, is chemically stable even at higher temperatures and is also miscible with water in unlimited quantities. In other words, the invention relates to the use of NMP as a solvent in a solution polymerization process for the production of polyguanidines of formula (I), (II) or (III) as defined above. The process of the present invention, using NMP as a solvent, thus represents an inventive choice compared to the prior art. While it involves the production of the same polyguanidines, the preparation of which by melt polymerization is disclosed by the inventors themselves, inter alia, in WO 2016 / 015081 A1, it now involves solution polymerization, specifically using a solvent as disclosed in US 2005 / 225616 A1 for the production of polyguanidines. However, the latter polymers, which correspond to the formula "PG" mentioned above, differ significantly not only formally from the polyguanidines of formula (I), (II), or (III), but also in that the mechanism of polycondensation is entirely different. This is probably also the reason why none of the alternative solvents to NMP, i.e., the other "polar aprotic solvents boiling above 150 °C," have proven to be even remotely as suitable.The alternatives last mentioned by the inventors themselves—dimethylformamide (DMF; boiling point: 153 °C), diethylene glycol dimethyl ether (Diglyme; boiling point: 160 °C), dimethylacetamide (DMA; boiling point: 165 °C), and dimethyl sulfoxide (DMSO; boiling point: 189 °C)—not only have mostly relatively low boiling points, which would necessitate pressurization at the preferred reaction temperatures of 160–180 °C, but also interfere with the polycondensation reactions in a similar way to propylene carbonate (PC) or triethylene glycol dimethyl ether (Triglyme) due to the presence of hydrolyzable or reactive groups. At these high reaction temperatures, during the multi-hour polycondensation reactions, which produce a hydrogen halide HX (preferably HCl, HBr) as a byproduct, i.e.,A strong acid is formed, apparently leading to at least partial cleavage of the ester, amide, and even ether bonds, and to reactions of the solvent molecules with the benzyl derivatives BA and / or the amino groups of guanidine G (the latter primarily with the sulfoxide DMSO), resulting in the formation of large quantities of undesired byproducts. Taken together, this was largely quite surprising to the average expert in the field. Furthermore, the other four solvents used in the examples of US 2005 / 225616 A1, namely 1,2-propanediol, diethylene glycol (DEG), diethylene glycol monomethyl ether (DEGME), and dipropylene glycol monomethyl ether (DPGME), each possess primary alcoholic OH groups and are therefore not "aprotic solvents." Rather, they are capable of reacting with the benzyl or allyl derivatives BA, also releasing HX, as demonstrated by the subsequent comparative examples. In contrast, these solvents do not interfere with the reactions in the synthesis of polyguanidines of formula "PG" by polycondensation of diamines with guanidine, releasing NH3, as disclosed in this document. Compared to the prior art cited at the beginning, the now restricted invention thus represents a double inventive selection. In contrast to the priority application, the choice of solvent in the main claim has been further specified in the two possible work-up steps a) and b) of the process according to the invention. In precipitation step a), a non-solvent miscible with NMP is used for the product, and in the alternative extraction step b), a non-polar solvent immiscible with water and NMP is used, which of course must also be a non-solvent for the product. Furthermore, the process according to the prior art published by the inventors would not necessarily have had to be carried out in the melt, as mentioned on page 7 of the previously cited WO 2016 / 015081 A1. However, it is also disclosed there that, for reasons of process economy, melt polymerization is the preferred reaction method, which is why the examples were carried out exclusively in this way. Surprisingly, however, the inventors have since discovered that melt polymerization is by no means preferable for reasons of process economy, and for several reasons: 1) Not particularly surprising to an average person skilled in the field of polymer chemistry, the conversions of the polycondensation (as well as the chain lengths of the polycondensates) in the presence of a solvent are generally higher for at least one of the reactants – and this is also the case here – which reduces the proportion of unreacted monomer BA. However, this proportion is surprisingly considerably lower in the polycondensates according to the invention than after the known melt polymerization process. More precisely, in AT 516.070 B1 and WO 2016 / 015081 A1, the result of the melt polymerization (after cooling the melt, adding water and thoroughly mixing) is characterized as follows: "a clear, slightly yellowish solution with traces of solid particles", the latter being unreacted BA, which had to be filtered off through a 0.2 pm PTFE membrane. As the inventors have now discovered, even in the case of melt polymerization of a stoichiometric 1:2 mixture of the two starting monomers, almost 20% of the monomer BA remains unreacted as a solid residue, and the latter was even used in a 2.5% excess according to the prior art (BA: G 1:1.95 equivalents). In contrast, according to the solution polymerization process of the invention, only 3-5% of unreacted BA remains, as the following examples and comparative examples demonstrate. 2) In the case of the novel solution polymerization according to the invention, sublimation of the monomer BA cannot occur, which in the past had further reduced sales, since a not insignificant proportion of the relatively volatile BA monomers sublimated from the melt. 3) During the work-up process, the unreacted BA monomers are practically completely removed from the polyguanidines obtained, both by precipitation from the reaction mixture according to feature a) and by extraction according to feature b), which significantly increases their purity, as can already be seen from the weaker color of the products produced according to the inventive process. 4) The polycondensation products of formulas (I) to (III), prepared in purer form according to the inventive process than previously, have since proven to be highly hygroscopic, so that prolonged contact with water vapor contained in the ambient air must be avoided if the respective product is to be obtained as a pure solid. According to feature a) of the present invention, in this case the product, which is obtained as a solution in the respective high-boiling, polar aprotic solvent, is precipitated by adding a non-solvent for the respective polyguanidine and can be stored immediately after separation from the solution under exclusion of air. 5) The inventors have since discovered that not only the pure solids of the polyguanidines of formulas (I) to (III), but also aqueous solutions thereof can be used as anti-infectives or biocides. Particularly in view of their strong hygroscopicity, this represents a particularly preferred use for these polymers. For this reason, according to alternative feature b) of the present invention, the solution of the desired product in the high-boiling, polar aprotic solvent is mixed with water, preferably an excess thereof, as well as with a water-immiscible nonpolar solvent, and then extracted.In this process, any unreacted residual monomer BA passes completely into the organic phase, and the desired polyguanidine of formula (I), (II) or (III) is obtained directly as an aqueous solution (which may also contain the high-boiling reaction solvent), which can be used directly, especially ex vivo, as an anti-infective or biocide in certain applications without further purification or work-up. 6) Finally, on the one hand, the solutions of the starting monomers are much easier to stir than the relatively highly viscous melts, and on the other hand, the polycondensation reaction is completed much faster, both of which significantly reduce the energy expenditure. All of this greatly increases the process economy in the production - especially in the case of obtaining the products as aqueous solutions, which is why feature b) is preferred in the process according to the invention, wherein a 20% or 10% aqueous solution of the desired polycondensate of formula (I), (II) or (III) is particularly preferably produced. Furthermore, the non-solvent miscible with NMP used for the polyguanidine in feature a) of the process according to the invention is not specifically restricted. However, in preferred embodiments of the invention, ethyl acetate (EE), dichloromethane (DCM), diethyl ether (Et₂O), or chloroform (CHCl₃) are used, which are miscible with NMP in a wide range and are also readily available at low cost. In particular, EE is used, which is preferable to the chlorinated agents, especially for environmental reasons. The selection of the nonpolar solvent, which is immiscible with water and NMP, in feature b) of the process according to the invention is also not specifically restricted, as long as it is a non-solvent for the product. In preferred embodiments of the invention, however, n-heptane is used, since, like its homologs pentane, hexane, and octane, or isomers or perfluorinated variants thereof, it is practically insoluble in water. Some of these, however, are even more volatile and flammable than heptane due to chain lengths and boiling points, and / or are harmful to health, and / or significantly more expensive. In further preferred embodiments of the invention, Ri is an optionally substituted phenylene residue, since the respective dichloro- or dibromoxylenes are readily available commercially, thus eliminating the need for a prior step to prepare the respective BA monomer.For the same reason, the leaving group is preferably chlorine or bromine, more preferably chlorine, since the brominated starting materials are usually somewhat more expensive and, moreover, the hydrobromide salts of the polycondensates have a somewhat stronger color than the corresponding hydrochlorides, which may be undesirable for subsequent applications. Furthermore, in preferred embodiments, the respective guanidine G selected as the starting monomer is also used as the hydrochloride, since these salts are also readily available commercially. In further preferred embodiments, the respective benzyl derivative BA and the respective guanidine G are used in a molar ratio of 1:2, or the respective guanidine G is used in a slight stoichiometric excess, e.g., in an excess of 0.5–1 mol%. This reduces the proportion of unreacted monomer BA, especially since in the earlier melt polymerization process the guanidine G had been used in a slight deficit (1.95 instead of 2 mol G per mol BA, i.e., a 2.5 mol% deficit), and increases the yield and purity of the products. In preferred embodiments, the polymerization reaction is carried out over a period of at least 2 hours, and more preferably at least 3 hours. In particular, the reaction—analogous to the inventors' earlier method—is carried out in two stages at different temperatures, a first, lower temperature and a second, higher temperature, to ensure the most complete conversion possible and thus greater chain lengths with a simultaneously reduced residual monomer content. Two hours at 160 °C followed by 1.5 hours at 180 °C have proven particularly effective, making the preferred reaction time of the present invention significantly shorter than that of the inventors' earlier method (3 hours at 160 °C, 2 hours at 180 °C) or the method disclosed in US 2005 / 225616 A1 (10–20 hours). In a second aspect, the present invention also relates to the polyguanidines of the above formulas (I), (II), and (III) produced according to the new method.with a cyclic structure obtained by ring closure with the elimination of a corresponding guanidine, as well as salts of these polyguanidines. Due to the significantly higher purity of the products resulting from the removal of unreacted BA monomers from the respective desired polyguanidine during work-up—both in the case of precipitation according to feature a) and extraction according to feature b)—these can be clearly distinguished, for example, by spectroscopy from those produced by melt polymerization according to the previous method. The polyguanidines according to the invention are, however, clearly distinguishable from the latter due to the unavoidable presence of traces of the solvent NMP, even in the purified and dried products, which can be detected by NMR or MALDI-TOF mass spectrometry. In a third aspect, the invention relates to these same polyguanidines for use as antibiotics, anti-infectives, or biocides, preferably for combating bacterial, viral, and fungal infections in human or animal patients, more preferably for topical or systemic administration, and particularly for administration in the form of a drug or pharmaceutical composition. Alternatively, the polyguanidines thus obtained can also be used as antimicrobial agents or biocides ex vivo, preferably as an active ingredient in antimicrobial paints, coatings, films, membranes, or the like. In a fourth aspect, the invention relates again to a medicament or pharmaceutical composition for combating bacterial, viral, and fungal infections in a human or animal patient, comprising at least one of the polyguanidines thus produced as an anti-infective and preferably further comprising at least one pharmaceutically acceptable carrier or excipient and optionally one or more adjuvants and / or one or more other active ingredients. More preferably, the medicament or pharmaceutical composition comprises at least one other active ingredient that also has antimicrobial activity in order to enhance the effect and utilize any synergistic effects. The at least one other active ingredient may also be effective against a condition other than a bacterial infection. Antidiarrheals and so-called stomach protectants are mentioned only as examples. The present invention is described in more detail below with reference to non-limiting examples. EXAMPLES The solvents and starting monomers used in the examples and comparative examples were all commercially available and used in standard purity. 1 H-NMR spectra were recorded on a Bruker Avance® AV400 spectrometer at 400 MHz. Monoisotopic MALDI-TOF mass spectrometry analyses were performed using a Bruker Auto-flex Speed ​​instrument equipped with a 1000 Hz Smartbeam. TMMS / MS was performed using a type II laser in positive ion and reflectron modes with 6-aza-2-thiothymine (ATT) as the matrix. MS / MS was performed by laser-induced dissociation, with the precursor ion selector generally set to ±0.6%. The detector voltage was generally set to 1.977 V for MS. Between 1,000 and 3,000 images were summed from various regions of the sample points. The spectra were processed using the manufacturer's software (Bruker Flexanalysis 3.4) with the SNAP algorithm and a signal-to-noise threshold of 6 for MS (unsmoothed). Example 1 from -Variant 1 according to characteristic NH H2N^NH α,α'-Dichloro-p-xylene (400 mg, 2.28 mmol) and 2 equivalents of aminoguanidine hydrochloride (505 mg, 4.56 mmol) were suspended in 2 mL of NMP in a reaction vessel equipped with a reflux condenser and drying tube, under magnetic stirring, and heated to form a clear, pale yellow, precipitate-free solution. The mixture was heated first to 160 °C for 2 h and then to 180 °C for 1.5 h. After cooling the reaction mixture, 6.1 mL of distilled water were added, and the mixture was treated with 50 mL of n-heptane (Hep) and extracted to remove unreacted dichloroxylene and to obtain an essentially pure 10% wt% solution of the hydrochloride of polyguanidine (1) in an approximately 3:1 mixture of water and NMP. Evaporation of the Hep solution and drying under vacuum yielded 13.2 mg (3.3% of the amount used) of solid dichloro-p-xylene as a yellowish residue. For analytical purposes, a portion of the water / NMP solution was treated with ethyl acetate (EE) to obtain the product as a slightly cream-colored, rubbery precipitate, which was washed with EE and Hep and dried under high vacuum, yielding a highly hygroscopic, slightly cream-colored foam which was then treated by 1 was characterized by H-NMR and MALDI-TOF-MS. 1 H-NMR (D2O; 4,4-dimethyl-4-silapentane-1-sulfonic acid, DSS, as internal standard) δ (ppm): 3.72-3.92 (ad, J=12.4 Hz), 3.93-4.08 (as), 4.11-4.23 (ad, J=12.4 Hz), 4.28-4.38 (m), 4.45-4.52 (m), 7.30-7.60 (m), 8.08 (as).MALDI-TOF (m / z): 425.4, 470.4, 529.4, 563.4, 601.4, 646.4, 705.5, 741.5, 777.5, 822.5, 858.6, 894.6, 953.7, 1034.7, 1093.7, 1129.8, 1210.8, 1305.9, 1386.9, 1482.0, 1563.1, 1658.1, 1834.2, 2010.2. The positions of the peaks in 1H-NMR spectra, which correspond quite closely to those of the product obtained by melt polymerization, confirm the preservation of polyguanidine (1). Example 2 Production of polyaminoguanidine (1) - Variant 2 according to feature a) The solution polymerization of the starting monomers was carried out analogously to Example 1. However, after cooling the reaction mixture, 30 ml of EE were added directly to the resulting clear, pale yellow solution to precipitate the product. The cream-colored, rubbery precipitate was washed with EE and Hep and dried under high vacuum, again yielding a hygroscopic, slightly cream-colored foam, the 1 H-NMR and MALDI-TOF spectra were consistent with those from Example 1. The EE / NMP solution was treated with 50 ml of Hep and extracted to separate unreacted dichloroxylene. Evaporation of the Hep solution and drying under vacuum yielded 16.4 mg (4.1% of the initial amount) of a yellowish residue of solid dichloro-p-xylene. Example 3 from - Variant 1 according to characteristic Example 3 was carried out analogously to Example 1, except that α,α'-dichloro-m-xylene (400 mg, 2.28 mmol) was used instead of α,α'-dichloro-p-xylene. After completion of the reaction following a total of 3.5 h of heating with stirring and cooling of the reaction mixture, water and hep were added, and the water / NMP phase was extracted with hep. Evaporation of the hep phase and drying under vacuum yielded 17.2 mg (4.3%) of solid dichloro-m-xylene as a yellowish residue. Again, a portion of the water / NMP solution was mixed with EE to obtain a slightly cream-colored, rubbery precipitate, which was washed with EE and Hep and dried under high vacuum to a highly hygroscopic, slightly cream-colored foam, which was then treated by means of 1 was characterized by H-NMR and MALDI-TOF-MS. 1 H-NMR (D2O; 4,4-dimethyl-4-silapentane-1-sulfonic acid, DSS, as internal standard) δ (ppm): 3.77-3.94 (ad, J=12.5 Hz), 3.97-4.09 (as), 4.14-4.25 (ad, J=12.5 Hz), 4.31-4.40 (m), 4.48-4.56 (m), 7.20-7.70 (m), 8.11 (as). MALDI-TOF (m / z): 425.4, 470.4, 529.4, 563.4, 601.4, 646.4, 705.5, 741.5, 777.5, 822.5, 858.6, 894.6, 953.7, 1034.7, 1093.7, 1129.8, 1210.8, 1305.9, 1386.9, 1482.0, 1563.1, 1658.1, 1834.2, 2010.2. Again, the positions of the peaks correspond to the 1The H-NMR spectrum closely matches the published spectrum for the product obtained by melt polymerization process and thus confirms the preservation of polyguanidine (2). Example 4 Production of polyaminoguanidine (2) - Variant 2 (according to feature a)) The solution polymerization of the monomers was carried out analogously to Example 3. However, after cooling the reaction mixture, EE was added to precipitate the product as a cream-colored, rubbery precipitate, which was washed with EE and Hep and dried under high vacuum, again yielding a hygroscopic, slightly cream-colored foam, the 1 H-NMR and MALDI-TOF spectra matched those from Example 3. The EE / NMP solution was treated with Hep and extracted to separate unreacted dichloroxylene. Evaporation of the Hep solution and drying under vacuum yielded 19.7 mg (4.9%) of a yellowish residue of solid dichloro-m-xylene. Comparison example 1 Production of polyaminoguanidine (1) - melt polymerization α,α'-Dichloro-p-xylene (25.00 g, 142.81 mmol) and 2 equivalents of aminoguanidine hydrochloride (31.57 g, 285.62 mmol) were heated in an open reaction vessel with stirring, first at 160 °C for 3 h, then at 180 °C for 2 h. After cooling the melt to below 60 °C, 500 mL of water were added, and after thorough mixing by stirring and ultrasonic treatment for 2 h, a yellowish precipitate and a clear, yellowish solution were obtained as a supernatant. To this, 400 mL of n-heptane (Hep) were added, thoroughly mixed, and extracted, after which the phases were separated. For analytical purposes, a portion of the aqueous solution was evaporated under high vacuum, yielding a highly hygroscopic, pale yellow amorphous residue, which was dissolved in D₂O and treated by 1 was characterized by H-NMR. 1H-NMR (D2O; 4, 4-dimethyl-4-silapentane-1 -sulfonic acid, DSS, as internal standard) δ (ppm): 3.73-3.93 (ad, J=12.3 Hz), 3.94-4.06 (as), 4.12-4.23 (ad, J=12.3 Hz), 4.27-4.38 (m), 4.47-4.52 (m), 7.30-7.72 (m), 8.09 (as). The chemical shifts of these peaks correspond quite closely to those published in the prior art as well as to those of the polyguanidines obtained in Examples 1 and 2 (1). By evaporating the hep phase obtained after extraction and drying the residue under vacuum, 4.83 g of solid dichloro-p-xylene were obtained as a yellowish residue, which corresponded to 19.3% of the amount used. Comparison example 2 Production of polyaminoguanidine (2) - melt polymerization In an analogous manner to Comparative Example 1, the hydrochloride of polyguanidine (2) was obtained from α,α'-dichloro-m-xylene and aminoguanidine hydrochloride as a clear, yellowish solution in water, and unreacted dichloro-m-xylene was obtained as a Hep solution. A portion of the aqueous solution was again evaporated under high vacuum, yielding a hygroscopic, yellowish amorphous residue, which was also dissolved in D₂O and treated by means of 1 was characterized by H-NMR. 1 H-NMR (D2O; 4,4-dimethyl-4-silapentane-1-sulfonic acid, DSS, as internal standard) δ (ppm): 3.70-3.96 (m), 3.93-4.05 (as), 4.09-4.22 (ad, J=12.6 Hz), 4.30-4.37 (m), 4.46-4.52 (m), 7.21-7.80 (m), 8.09 (as). The positions of these peaks correspond quite closely to those of the polyguanidines (2) obtained in Examples 3 and 4 and also to those published in the prior art. Evaporation of the obtained hep phase and drying of the residue under vacuum yielded 4.97 g (19.9% ​​of the amount used) of solid dichloro-p-xylene as a yellowish residue. Comparison examples 3 to 14 Preparation of polyaminoguanidine (1) - variation of the solvent The same setup as in Example 1, i.e., 400 mg (2.28 mmol) of α,α'-dichloro-p-xylene and 505 mg (5.20 mmol) of aminoguanidine hydrochloride, was placed as a reaction mixture in a reaction vessel equipped with a reflux condenser and drying tube, mixed with one of different solvents—protic and aprotic—and heated with magnetic stirring. Details and the results obtained are given below for each experiment. Comparative example 3 - Ethanol The above reaction mixture was treated with 15 ml of ethanol and refluxed for 5 h (EtOH; boiling point: 78 °C). A clear, colorless solution formed upon heating. After cooling, the solvent evaporated completely, leaving a solid precipitate. This was mixed with 50 ml of water and 50 ml of n-heptane and shaken off, after which the two phases were separated and each evaporated to dryness, leaving solid residues. A sample of each was dissolved in D₂O and CDCl₃, respectively, and treated by 1 H-NMR was investigated, which showed that no polycondensation reaction had taken place upon heating, as the characteristic signals of the polyguanidine (1) obtained in Examples 1 and 2 could not be detected. Comparison example 4 - Propanol The above reaction mixture was treated with 15 ml of 1-propanol and refluxed for 6 h (PrOH; boiling point: 97 °C). A clear, colorless solution formed upon heating. After cooling, the solvent evaporated completely, leaving a solid precipitate. This was then treated with 50 ml of water and 50 ml of n-heptane and shaken off, after which the two phases were separated and each evaporated to dryness, leaving solid residues. A sample of each was dissolved in D₂O and CDCl₃, respectively, and treated by 1 ¹H NMR was investigated, which again showed that no polycondensation reaction had taken place, as no signals characteristic of polyguanidine (1) were detected. Comparative example 5 - Propylene carbonate, Experiment A The above reaction mixture was treated with 8 ml of propylene carbonate (PC) and heated to 140 °C for 2 h (boiling point: 242 °C). A clear, cream-colored solution formed upon heating. After cooling, 50 ml of water and 50 ml of n-heptane were added, and the mixture was shaken off. The phases were then separated, and the organic phase was evaporated to dryness. The yellowish solid residue proved to be... 1 The ¹H NMR spectrum shows 342 mg of pure dichloroxylene, representing 85.5% of the starting monomer. Consequently, only 14.5% conversion occurred at 140 °C. Comparative example 6 - Propylene carbonate, experiment B The above reaction mixture was again treated with 8 ml of propylene carbonate and heated to 140 °C for 2 hours, again producing a clear, cream-colored solution, which was then heated to 160 °C. However, after only about 10 minutes at 160 °C, a dark-colored suspension rapidly formed. After switching off the stirrer, a dark brown precipitate settled at the bottom, which was insoluble in both water and propylene carbonate. Without committing to a specific theory, the inventors assume that a splitting of the solvent molecule occurred, along with side reactions with the dichloride and the guanidine that have not been investigated in detail. Comparative example 7 - Triethylene glycol dimethyl ether, experiment A The above reaction mixture was mixed with 6 ml of triethylene glycol dimethyl ether and heated to 140 °C for 2 h (Triglyme; boiling point: 216 °C), although a second, brown-colored, liquid phase formed shortly after reaching the desired temperature. After 2 hours and cooling of the mixture, 5 ml of water were added and thoroughly mixed. The resulting turbid solution was then filtered through Celite, leaving a brown filter cake which was washed with n-heptane. The two-phase filtrate was extracted by hand, after which the phases were separated and evaporated to dryness, leaving solid residues. These were then analyzed using 1 H-NMR or MALDI-TOF revealed approximately 40% unreacted dichloride in the Hep phase and approximately 50% of the desired polyguanidine (1) in the aqueous phase. Comparative example 8 - Triethylene glycol dimethyl ether, experiment B Experiment A was repeated, but this time the mixture was heated directly to 160 °C to investigate whether the higher temperature would increase the conversion to the desired polyguanidine (1). At this temperature, however, the mixture not only turned brown after a short time, but gradually black. After 2 hours at 160 °C, another 5 ml of water was added and thoroughly mixed, and the resulting cloudy solution was filtered through Celite, leaving a black filter cake – however, a significantly larger quantity than in experiment A, which made a more detailed investigation of this residue unnecessary. In this case as well, using Triglyme as a solvent, it can be assumed that the elevated temperatures led to the cleavage of the solvent molecules and (also not investigated in detail) side reactions with the dichloride and the guanidine. Whether Triglyme might be suitable as a solvent in the presence of the two starting monomers at a lower polymerization temperature, such as 120 °C, has not yet been investigated, but given the results above, this is unlikely and would also adversely extend the reaction time and thus reduce the economic viability of the process. The person skilled in the art may assume with near certainty that the homolog of this solvent, diethylene glycol dimethyl ether (diglyme), will yield similar results when the reaction is carried out in the same manner. Comparative Examples 9 to 14 - identical reaction procedure as in the examples. To investigate whether the solvents used in the priority application of the present application or in the examples of application US 2005 / 225616 A1 cited in the introduction, other than NMP, although all of them are protic solvents, would be suitable for the preparation of the polyguanidines according to the invention, the polymerization was carried out in the same manner as in Example 1. That is, α,α'-Dichloro-p-xylene (400 mg, 2.28 mmol) and 2 equivalents of aminoguanidine hydrochloride (505 mg, 4.56 mmol) were suspended in 2 mL of the respective solvent and heated with stirring. The reactions observed and the MALDI-TOF analyses are described below. Comparative example 9 - 1,2-propanediol After reaching 160 °C, the reaction mixture turned intensely yellow during a 2-hour holding time, and at 180 °C it turned dark yellow during a 1-hour holding time. After cooling, approximately 5 ml of water were added to obtain a 10% (wt%) polymer solution. This solution was washed with n-heptane to remove unreacted α,α'-dichloro-p-xylene (25 mg, approximately 6%). However, a subsequent analysis revealed the formation of a completely different product. MALDI-TOF (m / z): 783.50, 959.60. Comparative example 10 - Diethylene glycol (DEG) Similar to comparison example 9, the reaction mixture turned dark yellow during 2 h at 160 °C and 1 h at 180 °C. The 10% polymer solution obtained by adding water was again washed with n-heptane to remove unreacted α,α'-dichloro-p-xylene (30 mg, approximately 8%). Subsequent analysis again showed the formation of a completely different product. MALDI-TOF (m / z): 708.00, 843.46, 875.46, 907.46. Comparison example 11 - Diethylene glycol monomethyl ether (DEG ME) Similar to comparison examples 9 and 10, the reaction mixture changed color during the 2 h at 160 °C and 1 h at 180 °C, but in this case only to a pale yellow. 18 mg (approximately 4.5%) of unreacted α,α'-dichloro-p-xylene were detected. However, subsequent analysis revealed the formation of a completely different product. MALDI-TOF (m / z): 718.5, 779.5, 825.6, 857.6, 871.6, 1001.7. Comparative example 12- Dipropylene glycol monomethyl ether (DPGME) In this comparative example, the reaction mixture turned dark orange after reaching 140 °C, and subsequently a precipitate of an insoluble orange product formed, after which the reaction was stopped and further investigations were omitted. As mentioned previously, the presence of primary alcohols as solvents, i.e., protic solvents, thus obviously leads to the formation of large amounts of undesirable byproducts and hardly or not at all to the desired polyguanidines. Comparative example 13 - Dimethyl sulfoxide (DMSO) In this comparative example as well, the reaction mixture turned dark brown to black after reaching 140 °C, and subsequently formed an almost black, strongly unpleasant-smelling mixture, after which the reaction was again interrupted and further investigations were dispensed with. Comparative example 14- Dimethylformamide (DMF) In this comparative example, the reaction mixture turned dark red after reaching 150 °C, strong gas evolution occurred, and a precipitate of an insoluble dark red product formed, after which the reaction was stopped and further investigations were omitted. The average expert may assume with near certainty that, under the same reaction conditions, decomposition of the molecule will also occur with the homolog of this solvent, dimethylacetamide (DMA). In all the practical experiments, NMP has proven to be the only suitable solvent for use as a high-boiling, polar aprotic solvent in the solution polymerization process of the present invention – and it has even proven to be excellent. The person skilled in the art can therefore assume with near certainty that the other polyguanidines encompassed by the definition of formulas (I), (II) and (III) according to the present invention will also be producible in an analogous and thus advantageous manner according to the invention, especially since these were originally produced in a completely analogous manner using the melt polymerization process. In several initial activity tests, the polyguanidines produced using the new method proved to be more effective biocides than the polymers obtained using the old melt polymerization method. The inventors, without committing to this conclusion, attribute this to the higher purity. Conducting more reproducible and precise tests is currently the subject of the inventors' research. The solution polymerization process of the present invention using NMP as a solvent thus represents, as already mentioned, a double choice both compared to the inventors' own prior art, i.e., the melt polymerization process disclosed in AT 516.070 B1 and WO 2016 / 015081 A1, including the mention of alternative process options, and the solution polymerization process disclosed in US 2005 / 225616 A1 and the solvents mentioned therein. Furthermore, the opposite has been found to be true, contrary to the inventors' own disclosure that melt polymerization is preferable "for reasons of process economy," and this, as also already mentioned, is true for several reasons: i) the sales and purity of the products are significantly higher than according to the state of the art; ii) the products are obtained in a significantly shorter time, even if they are polycondensed at the same temperatures; iii) the reaction mixtures present as solutions are considerably easier to stir, which also reduces energy consumption; and iv) In preferred embodiments of the invention according to feature b), the products are obtained as aqueous solutions which can be directly applied to the intended use as an anti-infective or biocide. From the point of view of process economy, the present invention is therefore clearly superior to the previous method - and also provides the products in a higher purity. In addition, the solvents used can be easily separated and purified by distillation and then recycled in the process, which also speaks in favor of the process according to the invention from an environmental perspective.

Claims

1. PATENT CLAIM 1. Process for the preparation of polycondensation products of guanidine, aminoguanidine or diaminoguanidine G with at least one benzyl derivative BA according to the following reaction scheme: X-CH₂-R₁-CH₂-X + H-Gua-H CH₂-R₁-CH₂-Gua - HX BA G (I), (II), (III) wherein X independently represents a leaving group, R₁ independently represents an aromatic ring system with at least one aromatic ring, optionally containing one or more heteroatoms selected from O, N and S, and optionally substituted with one or two vinyl groups to which the group(s) -CH2-X is / are bonded, Gua represents a guanidindiyl, aminoguanidindiyl or diaminoguanidindiyl residue, Y represents H-Gua and Z represents H or Y and Z together represent a chemical bond to give a cyclic structure, and n > 2; wherein at least one benzyl derivative BA is subjected to a polycondensation reaction with an excess of guanidine, aminoguanidine or diaminoguanidine G with elimination of HX to give a polyguanidine of the following formula (I), (II) or (Hl): (I) (H) (Hl) or with a cyclic structure obtained by ring closure with elimination of a corresponding guanidine, or to yield a salt of the polyguanidine; characterized in that the at least one benzyl derivative BA and the respective guanidine G are suspended in a polar aprotic solvent boiling above 150 °C at normal pressure and heated to a temperature of at least 150 °C and thereby dissolved, for which N-methylpyrrolidone (NMP) is used as the solvent, after which the reaction mixture was cooled and either a) is combined with a non-solvent for the polyguanidine of formula (I), (II) or (III) which is miscible with NMP to precipitate the product and obtain it in solid form, or b) is mixed with a mixture of water and a nonpolar solvent immiscible with water and NMP, which is a non-solvent for the product, and extracted to obtain an aqueous solution of the product.

2. Use of N-methylpyrrolidone (NMP) as a solvent in a solution polymerization process for the preparation of polycondensation products of guanidine, aminoguanidine or diaminoguanidine G with at least one benzyl derivative BA according to the following reaction scheme: X-CH₂-R₁-CH₂-X + H-Gua-H CH₂-R₁-CH₂-Gua - HX BA G (I), (II), (III) wherein X independently represents a leaving group, R₁ independently represents an aromatic ring system with at least one aromatic ring, optionally containing one or more heteroatoms selected from O, N and S, and optionally substituted with one or two vinyl groups to which the group(s) -CH2-X is / are bonded, Gua represents a guanidindiyl, aminoguanidindiyl or diaminoguanidindiyl residue, Y represents H-Gua and Z represents H or Y and Z together represent a chemical bond to give a cyclic structure, and n > 2; wherein at least one benzyl derivative BA is subjected to a polycondensation reaction with an excess of guanidine, aminoguanidine or diaminoguanidine G with elimination of HX to give a polyguanidine of the following formula (I), (II) or (Hl): (I) (II) (III) or with a cyclic structure obtained by ring closure with elimination of a corresponding guanidine, or a salt of the polyguanidine; wherein the at least one benzyl derivative BA and the respective guanidine G are suspended in NMP and heated to a temperature of at least 150 °C and dissolved, after which the reaction mixture is cooled and either a) is combined with a non-solvent for the polyguanidine of formula (I), (II) or (III) which is miscible with NMP to precipitate the product and obtain it in solid form, or b) is mixed with a mixture of water and a nonpolar solvent immiscible with water and NMP, which is a non-solvent for the product, and extracted to obtain an aqueous solution of the product.

3. Method according to claim 1 or use according to claim 2, characterized in that: a) Ri is a possibly substituted phenylene residue; and / or b) the leaving group is chlorine; and / or c) the respective guanidine G is used as the hydrochloride; and / or d) the respective benzyl derivative BA and the respective guanidine G are used in a molar ratio of 1:2 or the respective guanidine G is used in a slight stoichiometric excess, e.g. in an excess of 0.5-1 mol%.

4. A method or use according to any one of claims 1 to 3, characterized in that in the above step a) the non-solvent miscible with NMP for the polyguanidine is ethyl acetate or dichloromethane; and / or In step b) above, the nonpolar solvent n-heptane, which is immiscible with water and NMP, is used.

5. Method or use according to any one of claims 1 to 4, characterized in that the polyguanidine of formula (I), (II) or (III) is obtained by extraction as an aqueous solution, optionally as a 10% aqueous solution.

6. Method or use according to any one of claims 1 to 5, characterized in that a) the reaction is carried out over a period of at least 2 h or at least 3 h; and / or b) the reaction mixture is first heated to a lower and then to a higher reaction temperature, optionally being heated first to 160 °C for 2 h and then to 180 °C for 1.5 h.

7. Polyguanidine of formula (I), (II) or (III) obtained by a process according to any one of claims 1 to 6.

8. Polyguanidine according to claim 7, obtained by a process according to claim 5 or 6 in the form of an aqueous solution.

9. Polyguanidine according to claim 7 or aqueous solution of the polyguanidine according to claim 8 for use as an anti-infective or biocide.

10. Polyguanidine for use according to claim 9, characterized in that the polyguanidine is used to combat bacterial, viral or fungal infections in a human or animal patient, wherein the polyguanidine is optionally available for topical or systemic administration, optionally for administration in the form of a medicament or a pharmaceutical composition.

11. Use of a polyguanidine according to claim 7 or an aqueous solution of the polyguanidine according to claim 8 as an antimicrobial agent or biocide ex vivo.

12. Use according to claim 11, characterized in that the polyguanidine serves as an active component of antimicrobial paints, coatings, films or membranes.

13. A pharmaceutical or medicinal product for combating bacterial infections in a human or animal patient, comprising a polyguanidine according to claim 7, optionally in the form of an aqueous solution according to claim 8, as an anti-infective.

14. Drug or pharmaceutical composition according to claim 13, characterized in that it / it further comprises at least one (further) pharmaceutically acceptable carrier or excipient and optionally one or more other active ingredients.

15. Drug or pharmaceutical composition according to claim 14, characterized in that it / it comprises at least one other active ingredient which also has an anti-infective effect and which may optionally be effective against a condition other than a bacterial infection.

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